# Patent

## Title
Propane-1,3-dione derivative or salt thereof

## Abstract

It is intended to provide a compound useful as a GnRH receptor antagonist. The inventors further investigated propane-1,3-dione derivatives. As a result, they confirmed that a compound having a benzene ring or a thiophene ring substituted with a group represented by —SO2—R3 in a propane-1,3-dione derivative having 2-(1,3-dihydro-2H-benzimidazol-2-ylidene) has an excellent GnRH receptor antagonistic effect and accomplished the present invention. Because the compound of the present invention has a potent GnRH receptor antagonistic effect, it is useful for the treatment of sex hormone-dependent diseases, particularly GnRH-related diseases. Further, because the compound of the present invention has an excellent metabolic stability in human and few drug interactions, therefore it has preferable characteristics as a pharmaceutical used for the above-mentioned diseases.

## Background
TECHNICAL FIELD
The present invention relates to a novel propane-1,3-dione derivative useful as pharmaceuticals, especially as a therapeutical agent for sex hormone-dependent diseases.
BACKGROUND ART
It is known that hypothalamic hormone or pituitary hormone takes part in a control system of secretion of peripheral hormones. In general, secretion of anterior pituitary hormone is regulated by secretion stimulating hormones or secretion suppressing hormones secreted from its higher center, hypothalamus, or peripheral hormones secreted from the target organs of the respective hormones.
Gonadotropin releasing hormone (hereinafter, abbreviated as GnRH; also, GnRH is referred to as luteinizing hormone releasing hormone; LHRH) is known as a hormone which controls the secretion of sex hormones at the highest position, and regulates the secretion of luteinizing hormone (hereinafter, abbreviated as LH), follicle stimulating hormone (hereinafter, abbreviated as FSH), and sex hormones in the gonads through its specific receptor (hereinafter, abbreviated as GNRH receptor) which is present in anterior pituitary (Horumon to Rinsyo (Hormones and Clinical Medicine), spring extra number, 46, 46-57 (1998)). A specific and selective antagonist to the GnRH receptor is expected to be a drug for preventing and treating sex hormone-dependent diseases (e.g., prostate cancer, breast cancer, endometriosis, uterine fibroid, etc.), since it regulates the action of GnRH and controls the secretion of lower LH, FSH and sex hormones (Horumon to Rinsyo (Hormones and Clinical Medicine), spring extra number, (1998), ibid.; Cancer Res. 1, 293-297 (1941); Proc. Natl. Acad. Sci. USA 87, 7100-7104 (1990)).
At present, peptide compounds, cetrorelix (Proc. Natl. Acad. Sci. USA, 85, 1637-1641, 1988) and abarelix (J. Urol. 167, 1670-1674, 2002) are put on the market as GnRH receptor antagonists, and from these information, pharmaceuticals capable of controlling the secretion of sex hormones are also expected as therapeutical agents for benign prostatic hyperplasia (J. Clinical Endocrinology and Metabolism (1998) 83, 11, 3826-3831).
On the other hand, as non-peptidic compounds having a GNRH receptor antagonistic effect, for example, an uracil derivative, NBI-42902 (J. Med. Chem., 48, 1169-1178, 2005) was under clinical trials, but its development was stopped.
Patent Reference 1 discloses that a propane-1,3-dione derivative has a GnRH receptor antagonistic effect.




(In the formula, A and B are the same or different, each representing optionally substituted aryl or optionally substituted heterocyclic ring; for the details, referred to the above publication.)

However, there is no description of a substituted sulfonyl group (—SO2—R3) as the substituent on the ring A or the ring B or disclosure of specific compounds having such a group.
Further, Patent Reference 2 published after the priority date of the present application discloses that a propane-1,3-dione derivative has a GNRH receptor antagonistic effect.




(In the formula, the ring A represents optionally substituted benzene, optionally substituted pyridine, or thiophene ring, and the ring B represents benzene or thiophene ring; for the details, referred to the above publication.)

However, the structure differs from the compound of the present invention in that the former has a substituent derived from a 1-hydroxyalkyl group on the ring B.
Patent Reference 1: International publication No. 02/02533 pamphlet
Patent Reference 2: International publication No. 05/118556 pamphlet
DISCLOSURE OF THE INVENTION
Problems to be Solved by the Invention
An object of the present invention is to provide a novel compound useful as a pharmaceutical that exhibits an excellent in vivo GnRH receptor antagonistic effect, especially as a therapeutical agent for prostate cancer, benign prostatic hyperplasia, etc.
Means for Solving Problems
The present inventors have further studied propane-1,3-dione derivatives. As a result, they have confirmed that 2-(1,3-dihydro-2H-benzimidazol-2-ylidene)-having propane-1,3-dione derivatives having a benzene ring or a thiophene ring substituted with a group of —SO2—R3 have an excellent GnRH receptor antagonistic effect and an excellent activity through oral administration, and have accomplished the present invention.
Specifically, the present invention relates to the following:
[1] A propane-1,3-dione derivative represented by the general formula (I) or a pharmaceutically acceptable salt thereof:




(wherein the symbols in the formula have the following meanings:

A: optionally substituted aryl or optionally substituted heteroaryl,

ring B: benzene ring or thiophene ring,

ring C: benzene ring or 5- to 7-membered aliphatic hydrocarbon ring optionally having a double bond in the ring,

R1: the same or different, each representing halogen, optionally substituted hydrocarbon group,

—O-(optionally substituted hydrocarbon group), optionally substituted heterocyclic group,

—S-(optionally substituted hydrocarbon group), —CO-(optionally substituted hydrocarbon group), —CO2— (optionally substituted hydrocarbon group), —O—CO-(optionally substituted hydrocarbon group), —SO-(optionally substituted hydrocarbon group), —SO2— (optionally substituted hydrocarbon group), —NO2, —CN, —CO2H, optionally substituted carbamoyl, optionally substituted sulfamoyl, or optionally substituted amino group,

R2: the same or different, each representing halogen, R0, —O—R0 or halogeno lower alkyl,

m, n: the same or different, each indicating 0, 1 or 2,

R3: R0, —OH, —O-optionally substituted heteroaryl, —N(R51)(R52), —N(R73)-N(R74)(R75),





or, taken together with R2, —N═C(R45)—NH— or —NH—C(R45)═N—,

ring D: optionally substituted heterocyclic ring selected from the following group:





R0: the same or different, each representing lower alkyl,

R00: the same or different, each representing lower alkylene,

k: 1, 2, 3, or 4,

p: 0, 1 or 2,

R41, R42 and R43: the same or different, each representing H, optionally substituted lower alkyl,

—CHO, —CO-(optionally substituted lower alkyl), optionally substituted cycloalkyl, —CO2H, —CO2—R0, —CONH2, —CO—NH(R0), —CO—N(R0)2, —R00—CONH(R0), —R00—CON(R0)2, optionally substituted aryl, optionally substituted heterocyclic group, —R00—O-aryl, —R00—SO—R0, —R00—SO2—R0, —R00—N(OH)—R0 or —R00—N(O—R0)—R0,

R44 and R45: the same or different, each representing R0 or —R00-aryl,

R51 and R52: the same or different, each representing H, optionally substituted lower alkyl,

—R00-(optionally substituted cycloalkyl), —R00-(optionally substituted aryl), optionally substituted heteroaryl, —CO—R0, —CO2—R0, —OH, —O—R0, —O-benzyl, —R00—O—R00—OH or optionally substituted cycloalkyl,

R54, R55, R57, R58, R61, R64, R67, R68, R70, R72, R73 and R74: the same or different, each representing H or R0,

R56, R59, R66, R69 and R71: the same or different, each representing H, R0 or —CO—R0,

R60: H, R0, —R00—OH or —CO—R0,

R62: H, R0, —O—R0 or —O-benzyl,

R63: H, R0, —NH2 or —CO—R0,

R65: H, R0, —R00—OH, —CONH2 or —CO—R0,

R75: H, R0, —R00-aryl, aryl or heteroaryl, and

R54 and R41, R57 and R58, R61 and R42, R68 and R44, R62 and R63, R62 and R65, and R63 and R65, each taken together, may form lower aklene optionally substituted with oxo group; provided that, when A is phenyl substituted with —CH(OH)—CH2—OH, and when m and n are both 0, then R3 means a group except —N(CH3)2 the same shall be applied hereinafter);

[2] The compound of [1], wherein the ring C is benzene ring;
[3] The compound of [2], wherein the ring B is benzene ring;
[4] The compound of [3], wherein A is optionally substituted phenyl, optionally substituted naphthyl, optionally substituted thienyl, optionally substituted pyridyl, optionally substituted thiazolyl, benzofuranyl, or dihydrobenzofuranyl;
[5] The compound of [4], wherein R3 is —N(R51)(R52) or a group selected from the following:




[6] The compound of [5], wherein m is 0;
[7] A propane-1,3-dione derivative of the general formula (Ia) or a pharmaceutically acceptable salt thereof:




(wherein the symbols in the formula have the following meanings:

A1: phenyl or thienyl, each of which is optionally substituted with the same or different one to three substituents selected from the following group G:

Group G: halogen, lower alkyl or —O-lower alkyl,
R2a: halogen, lower alkyl or —O-lower alkyl,
R3a, R3b: the same or different, each representing H or lower alkyl,
R4: H, —C(═O)-lower alkyl or —C(═O)-heteroaryl,
n1: 0 or 1);
[8] The compound of [1] selected from the following group:

    
    
        (2R)-N-({3-[2-(1,3-dihydro-2H-benzimidazol-2-ylidene)-3-(3-fluorophenyl)-3-oxopropanoyl]phenyl}sulfonyl)-2-hydroxypropanimidamide,
        N-({3-[2-(1,3-dihydro-2H-benzimidazol-2-ylidene)-3-(3-fluorophenyl)-3-oxopropanoyl]phenyl}sulfonyl)-2-hydroxy-2-methylpropanimidamide,
        N-({5-[2-(1,3-dihydro-2H-benzimidazol-2-ylidene)-3-(3-fluorophenyl)-3-oxopropanoyl]-2-fluorophenyl}sulfonyl)-2-hydroxy-2-methylpropanimidamide,
        (2R)-N-({5-[2-(1,3-dihydro-2H-benzimidazol-2-ylidene)-3-(3-fluorophenyl)-3-oxopropanoyl]-2-fluorophenyl}sulfonyl)-2-hydroxypropanimidamide,
        (2R)-N-({5-[2-(1,3-dihydro-2H-benzimidazol-2-ylidene)-3-(3-methylphenyl)-3-oxopropanoyl]-2-fluorophenyl}sulfonyl)-2-hydroxypropanimidamide,
        N-({5-[3-(3,5-difluorophenyl)-2-(1,3-dihydro-2H-benzimidazol-2-ylidene)-3-oxopropanoyl]-2-fluorophenyl}sulfonyl)-2-hydroxy-2-methylpropanimidamide,
        (2R)-N-({5-[3-(3,5-difluorophenyl)-2-(1,3-dihydro-2H-benzimidazol-2-ylidene)-3-oxopropanoyl]-2-fluorophenyl}sulfonyl)-2-hydroxypropanimidamide,
        (2R)-N-({5-[3-(3-chlorophenyl)-2-(1,3-dihydro-2H-benzimidazol-2-ylidene)-3-oxopropanoyl]-2-fluorophenyl}sulfonyl)-2-hydroxypropanimidamide,
        N-({5-[2-(1,3-dihydro-2H-benzimidazol-2-ylidene)-3-oxo-3-(2,4,5-trifluorophenyl)propanoyl]-2-fluorophenyl}sulfonyl)-2-hydroxy-2-methylpropanimidamide,
        (2R)-N-({5-[2-(1,3-dihydro-2H-benzimidazol-2-ylidene)-3-oxo-3-(2,4,5-trifluorophenyl)propanoyl]-2-fluorophenyl}sulfonyl)-2-hydroxypropanimidamide,
        (2R)-N-({5-[2-(1,3-dihydro-2H-benzimidazol-2-ylidene)-3-(3-fluoro-4-methylphenyl)-3-oxopropanoyl]-2-fluorophenyl}sulfonyl)-2-hydroxypropanimidamide,
        (2R)-N-({5-[3-(2,5-difluorophenyl)-2-(1,3-dihydro-2H-benzimidazol-2-ylidene)-3-oxopropanoyl]-2-fluorophenyl}sulfonyl)-2-hydroxypropanimidamide,
        N-({5-[3-(2,5-difluorophenyl)-2-(1,3-dihydro-2H-benzimidazol-2-ylidene)-3-oxopropanoyl]-2-fluorophenyl}sulfonyl)-2-hydroxy-2-methylpropanimidamide,
        (2R)-N-({5-[3-(5-chloro-2-thienyl)-2-(1,3-dihydro-2H-benzimidazol-2-ylidene)-3-oxopropanoyl]-2-fluorophenyl}sulfonyl)-2-hydroxypropanimidamide,
        N-({5-[3-(5-chloro-2-thienyl)-2-(1,3-dihydro-2H-benzimidazol-2-ylidene)-3-oxopropanoyl]-2-fluorophenyl}sulfonyl)-2-hydroxy-2-methylpropanimidamide;
    
    


[9] A pharmaceutical composition comprising the compound of [1] as an active ingredient;
[10] The pharmaceutical composition of [9], which is a gonadotropin releasing hormone (GnRH) receptor antagonist;
[11] The pharmaceutical composition of [10], which is a therapeutical agent for prostate cancer, benign prostatic hyperplasia, breast cancer, endometriosis and/or uterine fibroid;
[12] Use of the compound of [1], for the manufacture of a gonadotropin releasing hormone (GNRH) receptor antagonist or a medicament for treating prostate cancer, benign prostatic hyperplasia, breast cancer, endometriosis and/or uterine fibroid;
[13] A method for treating prostate cancer, benign prostatic hyperplasia, breast cancer, endometriosis and/or uterine fibroid, comprising administering a therapeutically effective amount of the compound of [1] to a patient.
OUTCOMES OF THE INVENTION
The compounds of the present invention have a potent GnRH receptor antagonistic effect and additionally an excellent oral activity, and therefore are useful for treatment of sex hormone-dependent diseases, especially GnRH-related diseases, for example, prostate cancer, benign prostatic hyperplasia, breast cancer, endometriosis, uterine fibroid, etc. In addition, the compounds of the present invention have an excellent metabolic stability in human and few drug interactions, and therefore have preferable characteristics as pharmaceuticals for use for the above diseases.


BEST MODE FOR CARRYING OUT THE INVENTION
The present invention is described in detail hereinafter.
In this description, “alkyl” and “alkylene” mean linear or branched saturated hydrocarbon chains. “Lower alkyl” is an alkyl group having 1 to 6 carbon atoms, preferably methyl, ethyl, propyl, isopropyl, butyl, hexyl, etc. “Lower alkylene” means a divalent group derived from the above “lower alkyl” by removing any one hydrogen atom, preferably an alkylene having 1 to 4 carbon atoms, more preferably methylene, ethylene, methylmethylene, and propylene. “Lower alkenylene” is an alkenylene having 2 to 6 carbon atoms and having at least one double bond, concretely including vinylene, propenylene, 1-butenylene, 2-butenylene, etc. “Lower alkynylene” is an alkynylene having 2 to 6 carbon atoms and having at least one triple bond.
“Halogen” includes F, Cl, Br and I, preferably F, Cl. “Halogeno lower alkyl” means an alkyl having 1 to 6 carbon atoms and substituted with at least one halogen, preferably a C1-6 alkyl substituted with at least one F, more preferably fluoromethyl, difluoromethyl, trifluoromethyl, and trifluoroethyl.
“Cycloalkyl” is a cycloalkyl having 3 to 10 carbon atoms, which may be bridged. Preferably, it is a cycloalkyl having 3 to 7 carbon atoms, more preferably cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl. “Aryl” means a monocyclic, bicyclic or tricyclic aromatic hydrocarbon group having 6 to 14 carbon atoms, and includes a phenyl group fused with “cycloalkyl”, for example, indanyl, tetrahydronaphthyl, fluorenyl. Preferably, it is phenyl or naphthyl, more preferably phenyl.
“Hydrocarbon group” is a group having 1 to 15 carbon atoms with hydrogen atoms, and includes the above-mentioned alkyl, cycloalkyl and aryl, as well as aryl-lower alkylene-, aryl-lower alkenylene-, aryl-lower alkynylene-, cycloalkyl-lower alkylene-, cycloalkyl-lower alkenylene- and cycloalkyl-lower alkynylene-.
“5- to 7-membered aliphatic hydrocarbon ring” means a saturated hydrocarbon ring having 5 to 7 carbon atoms with hydrogen atoms, and concretely includes cyclopentane, cyclohexane, and cycloheptane.
“Heteroaryl” is a generic term for a 5- or 6-membered monocyclic aromatic group having 1 to 4 hetero atoms selected from O, S and N (monocyclic heteroaryl), and a bicyclic heteroaryl formed through condensation of monocyclic heteroaryls or benzene ring and monocyclic heteroaryl, in which the ring atom, S or N may be oxidized to form an oxide or dioxide. The monocyclic aryl concretely includes pyridyl, pyrrolyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, imidazolyl, triazolyl, tetrazolyl, thienyl, furyl, thiazolyl, pyrazolyl, isothiazolyl, oxazolyl, isoxazolyl, thiadiazolyl, oxadiazolyl. It further includes an tautomer of 2-hydroxypyridyl such as 2-oxo-1H-pyridyl. Preferred are thienyl, furyl, pyrrolyl, thiazolyl, pyridyl, pyrazinyl. The bicyclic heteroaryl concretely includes benzothienyl, benzofuryl, indazolyl, indolyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, quinazolyl, quinoxalinyl, quinolyl, isoquinolyl, phthalazinyl. Preferred are benzofuryl and benzothienyl.
“Heterocyclic group” is a 3- to 7-membered, monocyclic or bicyclic heterocyclic group having 1 to 4 hetero atoms selected from O, S and N; and it includes a saturated cyclic group, the above-mentioned heteroaryl and a partially-hydrogenated cyclic group thereof. For example, it includes pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, imidazolyl, benzimidazolyl, benzofuranyl, benzothienyl, benzothiadiazolyl, benzothiazolyl, benzisothiazolyl, benzoxazolyl, benzisoxazolyl, pyrrolyl, pyrrolidinyl, thienyl, furyl, dioxanyl, dioxolanyl, triazinyl, triazolyl, tetrazolyl, thiazolyl, thiadiazolyl, oxadiazolyl, pyrazolyl, pyrazolidinyl, isothiazolyl, oxazolyl, isoxazolyl, quinolyl, isoquinolyl, tetrahydroquinolyl, tetrahydroisoquinolyl, quinazolinyl, quinoxalinyl, phthalazinyl, piperidyl, piperazinyl, azepanyl, diazepanyl, tetrahydrofuranyl, morpholinyl, methylenedioxyphenyl, ethylenedioxyphenyl, trithianyl, indolyl, isoindolyl, indolinyl, indazolyl, tetrahydrobenzimidazolyl, chromanyl, chromonyl (4-oxo-4H-1-benzopyranyl), benzimidazolonyl (2,3-dihydro-2-oxobenzimidazolyl), 2-oxo-1H-pyridyl. Preferred is a 5- to 6-membered monocyclic heteroaryl; and more preferred are furyl, thienyl, imidazolyl, thiazolyl, or pyridyl.
“Acyl” includes HCO—, hydrocarbon group-CO—, heterocyclic group-CO—, heterocyclic group-alkylene-CO—, heterocyclic group-alkenylene-CO—, heterocyclic group-alkynylene-CO—, hydrocarbon group-CS—, heterocyclic group-CS—, heterocyclic group-alkylene-CS—, heterocyclic group-alkenylene-CS—, heterocyclic group-alkynylene-CS—. Preferred are HCO—, hydrocarbon group-CO— and heterocyclic group-CO—; and more preferred are HCO—, acetyl, propionyl, benzoyl, nicotinoyl, thenoyl, pyrrolidinylcarbonyl or piperidylcarbonyl.
“Optionally substituted” means “unsubstituted” or “having the same or different one to five substituents”. In case where the group has plural substituents, the substituents may be the same or different. Similarly, when m and/or n is 2, then two R1's and/or two R2's may be the same or different.
The substituent in “optionally substituted hydrocarbon group” is preferably —OH, —NO2, —CO2H, halogen, aryl, heterocyclic group, R1013SiO—, R101-T101-.
In this, R10l is (1) H, (2) C3-8 cycloalkyl, (3) heterocyclic group, (4) C1-10 alkyl optionally substituted with [C6-14 aryl optionally substituted with a group of R102, —OH, —NO2, —CO2H, halogen, heterocyclic group, —CO—C1-10 alkyl, —O—C1-10 alkyl or —CO—O—C1-10 alkyl], (5) C6-14 aryl optionally substituted with [—OH, —CN, —NO2, halogen or —NR103—CO—C1-10alkyl];
R102 is halogen, —NO2, —OH, —CO2H, —O—C1-10 alkyl or —CO—O—C1-10 alkyl;
R103 is (a) H, (b) C3-8 cycloalkyl, (c) heterocyclic group, (d) C1-10 alkyl optionally substituted with [C6-14 aryl optionally substituted with a group of R102, heterocyclic group optionally substituted with a group of R102, —OH, —NO2, —CO2H, halogen, heterocyclic group, —CO—C1-10 alkyl, —O—C1-10 alkyl or —CO—O—C1-10 alkyl], (e) C6-14 aryl optionally substituted with [—OH, —CN, —NO2, halogen or —NR104—CO—C1-10alkyl];
R104 is (a) H, (b) C3-8 cycloalkyl, (c) heterocyclic group, (d) C1-10 alkyl optionally substituted with [—CO2H, —CO—O—C1-10 alkyl, C6-14 aryl or heterocyclic group], (e) C6-14 aryl optionally substituted with [—OH, —CN, —NO2 or halogen];
T101 is —O—, —CO—, —CO—O—, —O—CO—, —CO—NR103—, —NR103—CO— or —NR103—. The same shall be applied hereinafter.
Of those, the substituent in “optionally substituted lower alkyl” is more preferably halogen, —OH, —O—R0, —O—CO—R0, —S—R0, —CO—R0, —O—CO-aryl, —O—SO2—R0, —O—SO2-aryl, —O—SO2-tolyl, —N3, —NH2, —NH(R0), —N(R0)2, —CN, —CO2H, —CO2—R0, —CONH2, cycloalkyl, aryl; even more preferably halogen, —OH, —O—R0, —S—R0, cycloalkyl, aryl. The substituent in “optionally substituted aryl” is more preferably halogen, R0, —OH, —O—R0, —S—R0, halogeno lower alkyl. The substituent in “optionally substituted cycloalkyl” is more preferably R0, —OH, —O—R0.
The substituent in “optionally substituted heterocyclic ring” is preferably (1) C3-8 cycloalkyl, (2) C6-14 aryl optionally substituted with C1-10 alkyl-O—, (3) heterocyclic group, (4) C1-10 alkyl optionally substituted with [C6-14 aryl optionally substituted with a group of R106, —OH, —NO2, halogen, heterocyclic group, —NR101R103, —O—C1-10 alkyl, —CO-hydrocarbon group or —CO-heterocyclic group]. More preferably, it is halogen, R0, —OH, —O—R0, —R00—OH, —CO—R0, —CO2—R0, halogeno lower alkyl, —O—R00-aryl, —CO2—R00-aryl, aryl, heteroaryl; even more preferably halogen, R0, —OH, —O—R0, R00—OH, halogeno lower alkyl, —O-benzyl, heteroaryl. The substituent in “optionally substituted heterocyclic ring” for the ring D is preferably —OH, R0, —NH2, —R00—OH, halogeno lower alkyl.
“Optionally substituted carbamoyl”, “optionally substituted sulfamoyl” or “optionally substituted amino group” means that one or two hydrogen atoms on the nitrogen atom therein may be substituted with any other group, in which the substituents may be the same or different. For the substituents, preferred are the group described for the substituents in “optionally substituted heterocyclic ring”.
The substituent in “optionally substituted aryl” and “optionally substituted heteroaryl” for the ring A is preferably (1) —CN, (2) —NO2, (3) halogen, (4) —OH, (5) —CO2H, (6)-T104-[C1-10 alkyl optionally substituted with (—OH, halogen, heterocyclic group, C6-14 aryl optionally substituted with halogen, —NR101R103, —CO—R101, —CO-T101-R101 or -T101-R10l)], (7) —CO-[hydrocarbon group optionally substituted with a group of R105], (8) —CO-[heterocyclic group optionally substituted with a group of R105], (9) —O-[acyl optionally substituted with a group of R105], (10) —NR106R107, or (11) —CO—NR106R107.
In this, T104 is a bond, —O—, —CO—O— or —O—CO—;
R105 is —OH, —CO2H, —CN, —NO2, halogen, heterocyclic group, —NR101R103, C1-10 alkyl optionally substituted with halogen, —O—C1-10 alkyl, —CO—O—C1-10 alkyl, C6-14 aryl optionally substituted with [C1-10 alkyl, —O—C1-10 alkyl or —NR10l acyl], acyl, —NR101-acyl, or —NR101—SO2—(C6-14 aryl optionally substituted with C1-10 alkyl);
R106 and R107 are the same or different, each representing H or a group of R105. The same shall be applied hereinafter.
In addition, preferred embodiments of the present invention are described below.
(1) The ring A is preferably, optionally substituted, phenyl, naphthyl, pyridyl, pyrazyl, thiazolyl, dihydrobenzofuranyl, benzofuranyl or thienyl; more preferably, optionally substituted, phenyl, naphthyl, pyridyl, thiazolyl, dihydrobenzofuranyl, benzofuranyl or thienyl; even more preferably, optionally substituted, phenyl, naphthyl, pyridyl or thienyl. The substituent on the ring A is preferably halogen, R0, —O—R0, —OH, —O-aryl, —S—R0, —SO2—R0, —CO—R0, aryl, heteroaryl, —CN, halogeno lower alkyl; more preferably halogen, R0, —O—R0, —OH, —S—R0, aryl, halogeno lower alkyl; even more preferably F, Cl, R0, —O—R0, halogeno lower alkyl.
(2) m is preferably 0 or 1, more preferably 0. R1 is preferably halogen, optionally substituted hydrocarbon group, —O-(optionally substituted hydrocarbon group), —S-(optionally substituted hydrocarbon group), —CO-(optionally substituted hydrocarbon group), —NO2, optionally substituted amino group; more preferably halogen, R0, —O—R0; even more preferably halogen.
(3) n is preferably 0 or 1. R2 is preferably halogen, R1, —O—R0; more preferably halogen, R0; even more preferably F. Regarding its position, the substituent R2 is preferably at the ortho- or para-position relative to the group —SO2—R3; more preferably at the ortho-position.
(4) —SO2—R3 preferably bonds to the meta-position relative to the propanoyl chain.
(5) R3 is preferably R0, —N(R1)(R2),




more preferably, R0, —N(R52)(R52), formula (i), formula (ii), formula (iii), formula (Iv); even more preferably formula (i), formula (iii).

Another preferred embodiment of R3 is the following heterocyclic ring, and the ring may be substituted with a group selected from —OH, R0, —NH2, —R00—OH, halogeno lower alkyl.




(6) R41 and R42 are preferably H, optionally substituted lower alkyl, —CO-(optionally substituted lower alkyl), optionally substituted cycloalkyl, —CONH2, optionally substituted heterocyclic ring, —R00—N(OH)—R0, —R00—N(O—R0)—R0; more preferably H, optionally substituted lower alkyl, —CO-(optionally substituted lower alkyl), optionally substituted cycloalkyl; even more preferably optionally substituted lower alkyl. The substituent in “optionally substituted lower alkyl” for R41 and R42 is preferably —NH2, —N(R0)2, —OH, —O—R0, —O—CO—R0, —O—CO-heteroaryl; more preferably —OH, —O—CO—R0 or —O—CO-heteroaryl; even more preferably —OH. The heterocyclic ring is preferably pyridyl, pyrimidyl, thienyl, furyl, pyrrolyl.
(7) R43 is preferably R0; more preferably methyl.
(8) R51 and R52 are preferably H, optionally substituted lower alkyl, optionally substituted heteroaryl, —O—R0; more preferably H, optionally substituted lower alkyl. In this, the substituent in the lower alkyl and heteroaryl is preferably —OH or —O—R0, more preferably —OH. The heteroaryl is preferably pyridyl or thiazolyl.
(9) R54, R55, R60 and R61 are preferably H, methyl; more preferably H.
(10) R56, R57, R58 and R59 are preferably H, methyl, —CO—R0; more preferably H or acetyl; even more preferably H.
(11) R62 is preferably H, —O—R0; more preferably H.
(12) R63 is preferably H, —NH2, —CO—R0; more preferably H.
(13) R64 and R65 are preferably H, methyl, —R00—OH, —CONH2, acetyl; more preferably H, methyl; even more preferably H.
(14) R66, R67, R68, R69, R70 and R72 are preferably H.
(15) R44 is preferably R0, more preferably methyl.
(16) R71 is preferably H, R0.
Especially preferred embodiments of the present invention are the compounds that comprise a combination of preferred groups of the above (1) to (16).
The compound (I) of the present invention includes geometric isomers via tautomers, and geometric isomers relative to the double bond at the 2-position of propane, as described below. Further, depending on the type of the substituent therein, the compound may include any other tautomers and geometric isomers. In this description, only one type of such isomers may be described, but the present invention encompasses these isomers, as well as isolated isomers or a mixtures thereof.








The compound (I) may have asymmetric carbon atoms or axial asymmetry, and based on it, the compound may includes optical isomers such as (R) form and (S) form, etc. The present invention includes all of mixtures of these isomers and isolated isomers.
Further, the present invention includes pharmaceutically acceptable prodrugs of compound (I). The pharmaceutically acceptable prodrugs are compounds having a group capable of being converted to amino group, OH, CO2H or the like of the present invention by solvolysis or under a physiological condition. Examples of a group to forms a prodrug are those described in Prog. Med., 5, 2157-2161 (1985), and those described in “PHARMACEUTICAL RESEARCH AND DEVELOPMENT” (Hirokawa Publishing, 1990), Vol. 7, Drug Design, pp. 163-198.
Further, the compound of the present invention may form acid-addition salts, or salts with bases depending on the type of the substituent therein. So far as the salts are pharmaceutically acceptable salts, they are within the scope of the present invention. Concretely, they includes acid-addition salts with an inorganic acid such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, etc.; or an organic acid 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, glutamic acid, etc.; as well as salts with an inorganic base such as sodium, potassium, magnesium, calcium, aluminium, etc.; or an organic base such as methylamine, ethylamine, ethanolamine, lysine, ornithine, etc.; and ammonium salts or the like.
The present invention encompasses various hydrates, solvates and crystalline polymorphs of a compound of the present invention, as well as pharmaceutically acceptable salts thereof.
(Production Methods)
Utilizing characteristics based on the basic skeleton thereof or on the type of the substituent therein, the compound of the present invention and the pharmaceutically acceptable salt thereof can be produced by applying various known synthetic methods. Depending on the type of functional group, the functional group in the starting compounds-to-intermediate stage may be substituted with a protected group (group that may be readily converted to said functional group), and this may be technically effective in producing the compounds. The functional group includes, for example, an amino group, a hydroxyl group and a carboxyl group. Their protective groups are described, for example, in “Protective Groups in Organic Synthesis, (3rd Ed., 1999)” by Greene & Wuts, which can be appropriately selected and used according to the reaction condition. In this method, the protective group is removed if necessary after it has been introduced and the reaction carried out, to obtain the desired compound.
Prodrugs of compound (I) can be produced by introducing a specific group into the starting compounds-to-intermediate stage, as with the above-mentioned protective group thereinto, or by further processing the obtained compound (I). The reaction may be attained by applying methods known to persons skilled in the art, such as common esterification, amidation, dehydration, etc.
Typical production methods for the compounds of the present invention are described below. However, the production methods of the present invention should not be limited to the examples shown below.
Production Method 1:




(In the Formula, L1 Represents a Leaving Group; and the Same Shall be Applied Hereinafter.)

This production method is a method for obtaining a compound of the general formula (Ib) of the present invention by reacting a 2-methylbenzimidazole compound (II) with a compound (III) and then with a phenylsulfonyl compound (VI). The leaving group for L1 includes an organic sulfonic acid group such as methanesulfonyloxy or p-toluenesulfonyloxy, a halogen, or the like. Various acid anhydrides may be used as (III).
The reaction may be attained in no solvent or in a solvent inert to the reaction, under cooling to reflux conditions. The reaction temperature can be suitably determined depending on the compounds. The solvent for use includes aromatic hydrocarbons such as benzene, toluene, xylene; ethers such as diethyl ether, tetrahydrofuran (THF), dioxane, diglyme, 1,2-dimethoxyethane, 2-methoxydiethyl ether; halogenohydrocarbons such as dichloromethane, 1,2-dichloroethane, chloroform; acetonitrile, ethyl acetate, or the like; and one or more of these may be used either singly or as combined. The compound (II), the compound (III) and the compound (VI) may be used each in an equimolar amount or an excess amount, depending on the reaction and the compounds. With some compounds, it may be often advantageous to carry out the reaction in the presence of an organic base (preferably diisopropylethylamine, N-methylmorpholine, 4-(N,N-dimethylamino)pyridine, triethylamine, pyridine, collidine, morpholine, 2,6-lutidine) or an inorganic base (preferably sodium hydride, potassium carbonate, sodium carbonate, sodium hydrogencarbonate, sodium hydroxide, potassium hydroxide). The basic solvent may serve also as a base.
After isolated or without isolation, the compound (IV) may be reacted in the next step.
In this description, for convenience' sake, the structure of compounds (IV), compound (V) and the compounds in Reference Example corresponding to them, are expressed as a single configuration with respect to the geometric isomerism thereof to be caused by the double bond existing in these compounds; but some compounds may have geometric isomers relative to the double bond therein, and therefore the present invention includes those geometric isomers and their mixtures.
Production Method 2:




This production method is for reaction of introducing a group corresponding to R3 into a starting compound (VII); and for the compound (VIII), usable are various basic nitrogen-having compounds and hydroxyl group-having compounds.
The reaction can be attained in no solvent or in a solvent inert to the reaction, under cooling to reflux conditions. The reaction temperature can be suitably determined depending on the compounds. The solvent for use includes aromatic hydrocarbons, ethers, halogenohydrocarbons, N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMA), N-methylpyrrolidone (NMP), ethyl acetate, acetonitrile, pyridine, or the like; and one or more of these may be used either singly or as combined. The compound (VIII) can be used in an equimolar amount or an excessive amount. Depending on the type of the compound, it may be often advantageous to carry out the reaction in the presence of an organic base or an inorganic base.
The starting compound (VII) can be produced according to the above-mentioned production method 1. It may also be produced by preparing a sulfonic acid compound (L1=OH) according to the production method 1, and processing it with a halogenating reagent such as thionyl chloride, oxalyl chloride, phosphorus oxychloride, or the like.
Production Method 3:
Compounds of general formula (I) having various substituent on the group R1, R2 or R3 or on the ring A can be readily produced through reaction obvious to persons skilled in the art or modified methods thereof, starting from the compounds (I) of the present invention. For example, the following reaction is applicable thereto.
(1) Amidation, Sulfonamidation and Esterification:
Starting from a compound of the present invention having a hydroxyl group or an amino group and using a carboxylic acid or sulfonic acid compound or its reactive derivative, various amide compounds or ester compounds can be produced. Alternatively, starting from a compound of the present invention having a carboxylic acid or a sulfonic acid, it may be reacted with a compound having a hydroxyl group or an amino group.
The reaction is as follows: Using a reactive derivative (e.g., acid halide, acid anhydride, active ester) of a carboxylic acid or sulfonic acid compound, the method described for the above-mentioned production method 1 and production method 2 can be applied thereto. The reaction can also be attained in the presence of a condensing agent (e.g., dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIPC), 3-ethyl-1-(3-dimethylaminopropyl)carbodiimide (WSC), 1,1′-carbonylbis-1H-imidazole (CDI), or as the case may be, further an additive (e.g., N-hydroxysuccinimide (HONSu), 1-hydroxybenzotriazole (HOBt), dimethylaminopyridine (DMAP)). The reaction can also be attained, for example, according to the method described in “Jikken Kagaku Koza (Courses in Experimental Chemistry, 4th Ed.)”, Vol. 22 (1992) (Maruzen) edited by the Chemical Society of Japan.
The acylation on the nitrogen atom of sulfonamide can also be attained in the same manner.
(2) Oxidation:
A compound having a primary or secondary hydroxyl group can be oxidized to obtain a compound of the present invention having the corresponding aldehyde or ketone.
The reaction may be effected in a well-known method (ADVANCED ORGANIC CHEMISTRY (John WILEY & SONS (1992) by J. March), in which, for example, usable is an oxidizing agent such as m-chloroperbenzoic acid, hydrogen peroxide, tetrapropylammonium perruthenate, Dess-Martin reagent, in an solvent inert to the reaction such as halogenohydrocarbons.
(3) Ureide Formation:
A compound of the present invention having an amino group or a sulfonamido group may be reacted with an isocyanate compound or potassium cyanate to give the corresponding urea derivative as a compound of the present invention.
The reaction can be attained in a solvent inert to the reaction such as aromatic hydrocarbons, halogenohydrocarbons, DMF, NMP, acetonitrile, from room temperature to refluxing temperature. Adding an organic base or an inorganic base, or an acid such as acetic acid may be advantageous for the reaction.
The isocyanate compound can be obtained from its starting material, that is, a carboxylic acid or its reactive derivative, through well-known rearrangement (e.g., ADVANCED ORGANIC CHEMISTRY (John WILEY & SONS (1992) by J. March).
(4) Hydrolysis:
Hydrolysis of a carboxylate ester may give a compound of the present invention having a carboxyl group. The hydrolysis can be attained in any ordinary manner, to which, for example, applicable is the method of carboxyl deprotection described in the above-mentioned “Protective Groups in Organic Synthesis (3rd Ed.)”.
(5) Reduction:
Well-known reduction reaction is applicable to reduction of nitro group to amino group, reduction of azido group to amino group and dehalogenation of halogen-substituted aromatic compounds (COMPREHENSIVE ORGANIC SYNTHESIS 8 REDUCTION (Pergamon Press (1991)).
For example, it includes (1) catalytic reduction to be attained under hydrogen atmosphere or in the presence of a hydrogen donor such as ammonium formate, using a catalyst such as palladium, platinum or nickel, in a solvent such as alcohols, e.g., methanol, ethanol, or chloroform, ethyl acetate or acetic acid, under cooling to heating conditions; (2) reaction using a metal such as iron or tin dichloride, in the presence of acetic acid or hydrochloric acid; or (3) reaction using a reducing agent such as sodium hydrosulfite, in a mixed solvent of water, alcohols, THF, under cooling to heating conditions.
(6) Amination or N-alkylation:
A compound having an alkyl halide or sulfonyloxy group may be reacted with various amines to give a compound of the present invention having an amino group. The amino group-having compound of the present invention may be reacted with any other alkylating agent whereby an alkyl group may be introduced thereinto. The alkylating agent is preferably alkyl halides, and organic sulfonates with alcohols.
The reaction may be attained in a solvent inert to the reaction such as aromatic hydrocarbons, halogenohydrocarbons, ethers, ketones (acetone, 2-butanone, etc.), acetonitrile, ethyl acetate, DMF, DMA or NMP, under cooling to heating conditions. The reaction in the presence of an organic base or an inorganic base may be advantageous to promote the reaction smoothly.
(7) Amidino Group and Guanidino Group:
A compound having an amidino group or a guanidino group can be obtained according to a well-known production method. For example, an amidino group-having compound can be produced according to the method described in “Jikken Kagaku Koza (Courses in Experimental Chemistry, 4th Ed.)”, Vol. 20 (1992) (Maruzen) edited by the Chemical Society of Japan; and a guanidino group-having compound can be produced according to the method described in “COMPREHENSIVE ORGANIC FUNCTIONAL GROUP TRANSFORMATIONS” (Pergamon Press (1995)) by A. R. Katritzky, et al.,
Production Method 4:




(In the Formula, L2 Represents —S-Lower Alkyl, and L3 Represents —S-Lower Alkyl or Imidazole.)

Step 1:

This step is to obtain a 1,3-diketone derivative (X) through reaction of a methyl ketone derivative (IX) and a compound (VI) in the presence of a base followed by processing it with various compounds (VIII) having a basic nitrogen. The reaction can be attained in the presence of a strong base such as lithium diisopropylamide (LDA) in a solvent inert to the reaction such as ethers, e.g., tetrahydrofuran (THF), under cooling to reflux conditions.
Step 2:
This step is to obtain a compound (XI) in which L2 and L3 are both —S-lower alkyl through reaction of the 1,3-diketone derivative (X) with carbon disulfide (CS2) in the presence of a base followed by processing it with a lower alkyl halide such as methyl iodide. The reaction can be attained in the presence of a base such as sodium hydride (NaH), in a solvent inert to the reaction, for example, an aprotic polar solvent such as N,N-dimethylformamide (DMF), under cooling to heating conditions. In this step, adding an additive such as potassium fluoride may be advantageous, as the case may be. In the series of reaction mentioned above, 1,1′-thiocarbonyldiimidazole may be used in place of carbon disulfide (CS2) to give a compound (XI) where L2 is —S-lower alkyl, and L3 is imidazole.
Step 3:
This step is to obtain the compound of general formula (I) through reaction of the compound (XI) having two leaving groups with a diamine compound (XII).
The reaction can be attained in a solvent inert to the reaction, for example, alcohols such as ethanol, or an aprotic polar solvent such as dimethylsulfoxide (DMSO), under cooling to reflux conditions.
Compounds of the present invention are isolated and purified as free compounds, pharmaceutically acceptable salts, hydrates, solvates or crystalline polymorphorous substances thereof. Pharmaceutically acceptable salts of the compounds (I) of the present invention can be produced through ordinary salt formation reaction.
Isolation and purification can be attained through ordinary chemical operations such as extraction, fractional crystallization, various fractional chromatography.
Various kind of isomers can be isolated by selecting suitable starting compounds, or by separating them based on the difference between the isomers in the physicochemical properties thereof. For example, an optical isomer can be led into stereochemically-pure isomer through ordinary racemic resolution (for example by fractional crystallization to convert the compound into a diastereomer salt with an optically active base or acid; or by chromatography using a chiral column, etc.). It can also be produced from a suitable, optically active starting compound.
The pharmacological activities of the compounds of the present invention were confirmed by the tests mentioned below.
Test Example 1
Test for GnRH Receptor Antagonistic Effect
The GnRH receptor antagonistic effects of the compounds of the present invention were evaluated by calculating their concentration that inhibit 50% of the binding of 125I-D-Trp6-LHRH to a human GnRH receptor (IC50), according to the description in Patent Reference 1, page 56 “1. Test for GNRH Receptor Antagonistic Effect”. The results are shown in Table 1.










TABLE 1







Compound
IC50 (nM)



















Example 211
0.094



Example 245
0.058



Example 302
0.092



Example 482
0.16



Example 662
0.24



Example 696
0.18










Patent Reference 1 mentioned above discloses a carbonyl group as the substituent on the phenyl group of propanoylphenyl, but does not disclose a sulfonyl group thereon. Accordingly, for confirming the usefulness of “group of —SO2—R3”, the activities of the compounds of the present invention was compared with those of the comparative compounds having —CO—R3 group. The results are shown in Table 2.







TABLE 2













 












Compound
X
R3
IC50 (nM)















Example 73
SO2
—NH—C(═NH)—Me
0.053



Comparative
CO

7.1



Example 1






Example 89
SO2
—N═C(NH2)2
0.022



Comparative
CO

5.0



Example 2





 



Example 74 Comparative Example 3
SO2 CO




0.56 16


 



Example 77
SO2
—NH(CH2)2OH
0.066



Comparative
CO

9.6



Example 4









As shown above, the compounds of the present invention having “group of —SO2—R3” exhibited an extremely more potent GNRH receptor antagonistic activities than the comparative compounds having —CO—R3 group.
Test Example 2
Test for Antagonistic Effect to GnRH-Induced Blood Testosterone Increase Reaction
The in vivo gonadotropin releasing hormone (GNRH) antagonistic effect of the compounds were evaluated by their inhibitory effects to blood testosterone increase reaction induced by GnRH administration in rats (Patent Reference 1, page 57). In the experiment, 9-week old Wistar male rats (Nippon SLC) were used. GNRH (Peptide Institute, LH-RH (human)) was administered intramuscularly in the hip of each rat (30 ng/rat). The test compounds were dissolved or suspended in an aqueous 0.5% methyl cellulose (MC) solution, and orally administered at a dose of 3 mg/kg, 2 or 6 hours prior to the GnRH administration. One hour after the GnRH administration, the blood was collected and the testosterone concentration in the serum was measured by specific radioimmunoassay (Iatron's RIA kit).
The inhibitory activity (%) (IA) of the test compounds were calculated according to a formula: IA=(Tc−Ts)/(Tc−Tn)×100 (when lowered to Tn, IA=100%). In this formula, Tn indicates the serum testosterone concentrations of the rats without GnRH administration; Tc indicates those with the solvent instead of the test compounds administration; Ts indicates those with the test compounds administration. As a result, for example, the inhibitory activities of the compounds of Examples 211, 302, 662 and 696 were at least 90% at a dose of 3 mg/kg.
From the test results above, it is obvious that the compounds of the present invention are useful as a preventive/therapeutical agents for various sex hormone-dependent diseases such as prostate cancer, breast cancer, endometriosis, uterine fibroid, benign prostatic hyperplasia, etc., as having a potent GnRH receptor antagonistic effect.
A composition containing, as an active ingredient thereof, one or more of the compounds (I) of the present invention or the salts thereof can be prepared according to a method generally used in the art, using pharmaceutical carriers and excipients generally used in the art.
Therapeutic administration can be accomplished either by oral administration via tablets, pills, capsules, granules, powders, liquids, etc., or parenteral administration via intraarticular, intravenous or intramuscular injections, suppositories, eye drops, eye ointments, transdermal liquids, ointments, transdermal plasters, transmucosal solutions, transmucosal plasters, inhalers, etc.
According to the present invention, solid compositions for oral administration include tablets, powders or granules, etc., in which one or more active ingredients are mixed with at least one inactive excipient, such as lactose, mannitol, glucose, hydroxypropyl cellulose, microcrystalline cellulose, starch, polyvinylpyrrolidone and/or magnesium aluminometasilicate. According to standard methods, the composition may contain inactive additives, such as lubricants (e.g., magnesium stearate), disintegrators (e.g., carboxymethyl starch sodium), stabilizers, solubilization assisting agents. The tablets or pills may be coated with sugar or a film of a gastric or enteric substance, if necessary.
Liquid compositions for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs, and contain a commonly used inert diluent such as purified water or ethanol. The liquid composition may contain, in addition to the inert diluent, auxiliary agents such as solubilization assisting agents, moistening agents, and suspending agents, as well as sweeteners, flavors, aromatics, and antiseptics.
Injections for parenteral administration include aseptic aqueous or non-aqueous solutions, suspensions or emulsions. Diluents for use in aqueous solutions include, for example, distilled water for injection use and physiological saline. Diluents for use in non-aqueous solutions include, for example, propylene glycol, polyethylene glycol, vegetable oil such as olive oil, alcohols such as ethanol, Polysorbate 80 (the name in the Japanese Pharmacopeia). Such compositions may further contain tonicity agents, antiseptics, moistening agents, emulsifiers, dispersants, stabilizers, or solubilization assisting agents. These compositions are sterilized by filtration through a bacteria-trapping filter, or by addition of germicide, or through irradiation. Furthermore, they may also be produced in the form of sterile solid compositions and dissolved or suspended in sterile solvent for injection prior to their use.
Transmucosal compositions, such as inhalers and transnasal agents, are used in solid, liquid or semi-solid, and can be produced according to conventional known methods. For example, known excipients and further pH adjusters, antiseptics, surfactants, lubricants, stabilizers and thickeners, etc. can be added if necessary. For administration, suitable devices for inhalation or insufflation can be used. For example, using known devices or sprayers such as a metered dose inhalers, the compound can be administered independently, or in the form of prescribed mixture powders. Furthermore, the compounds combined with pharmaceutically acceptable carriers can also be administered in the form of solutions or suspensions. Dry powder inhalers and the like may be devices for single or multiple administrations, Dry powders or capsules containing powders can also be used. Still further, the devices can be in the form of a pressure aerosol spray or the like using a suitable propellant, such as chlorofluoroalkane or hydrofluoroalkane, or a suitable gas such as carbon dioxide.
In the case of oral administration, a daily dose per body weight is usually about 0.001 to 100 mg/kg, preferably 0.1 to 30 mg/kg, more preferably 0.1 to 10 mg/kg. A dose can be administered once daily or by dividing it into from 2 to 4 doses. In the case of intravenous administration, the daily dose per body weight is appropriately about 0.0001 to 10 mg/kg and is administered once daily, or divided into multiple doses. In the case of transmucosal administration, the daily dose per body weight is appropriately about 0.001 to 100 mg/kg and is administered once daily, or it is divided into multiple doses. Doses are determined for each case according to symptom, age, sex, etc.
EXAMPLES
The production methods for the compounds (I) of the present invention are described in more detail with reference to the following Examples. The compounds of the present invention should not be limited to those described in the following Examples. The production methods for the starting compounds are shown in Reference Examples.
The abbreviations in Reference Examples, Examples and Tables mentioned below are as follows:

    
    
        Ex: Number of Example
        REx: Number of Reference Example
        No.: Number of Compound
        Dat: Physicochemical data (FA: FAB-MS (M+H)+, FN: FAB-MS (M−H)−, ES+: ESI-MS (M+H)+, ES−: ESI-MS (M−H)−, EI: EI-MS (M+), AP+: APCI-MS (M+H)+, AP−: APCI-MS(M−H)−, N1: δ (ppm) of characteristic peaks in 1H NMR in DMSO-d6, N2: δ (ppm) of characteristic peaks in 1H NMR in CDCl3)
        Sal: Salt (HCl: hydrochloride, no mark: free form)
        Str: Structural formula
        pos: Substituent position
        Syn: Production method (Numeral alone means the number of Example as referred to in producing the compound in the same manner; numeral with R means the number of Reference Example as referred to in producing the compound in the same manner. For example, R1 means that the compound is produced in the same manner as in Reference Example 1.)
        Not Isolated Not isolated
        Me: methyl
        Et: ethyl
        Pr: propyl
        iPr: 2-propyl
        cPr: cyclopropyl
        Bu: butyl
        tBu: tert-butyl
        Boc: tert-butoxycarbonyl
        cBu: cyclobutyl
        Ms: methanesulfonyl
        Ts: p-toluenesulfonyl
        Ph: phenyl
        2Py: 2-pyridyl
        3Py: 3-pyridyl
        4Py: 4-pyridyl
        1Naph: 1-naphthyl
        2Naph: 2-naphthyl
        Ac: acetyl
        Piv: pivaloyl
        Bn: benzyl
        2Fur: 2-furyl
        3Fur: 3-furyl
        4THP: tetrahydropyran-4-yl
        2THF: tetrahydrofuran-2-yl
        Pyra: pyrazin-2-yl
        2Thi: 2-thienyl
        3Thi: 3-thienyl
    
    


The numeral before the substituent indicates the substituent position; and plural numerals indicate substitution with plural substituents. For example, 3,5-diMe-Ph means 3,5-dimethylphenyl.
Reference Example 1
3-Fluorobenzoyl chloride was added to a mixture of 2-methylbenzimidazole, triethylamine and dioxane, followed by heating under reflux for 3 hours and cooling to room temperature. Morpholine was added, followed by stirring under heat at 70° C. for 1 hour and work-up to obtain 1-(3-fluorophenyl)-2-(1,3-dihydro-2H-benzimidazol-2-ylidene)ethanone.
Reference Example 2
1-(3,5-Difluorophenyl)-2-(1,3-dihydro-2H-benzimidazol-2-ylidene)ethanone and 3-(chlorosulfonyl)benzoyl chloride were heated under reflux in dioxane for 1 hour, followed by cooling. After dilution with ethyl acetate, the insoluble matter was separated by filtration. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography. This was further diluted with ethyl acetate, washed with an aqueous saturated sodium hydrogencarbonate solution and water successively, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to obtain 3-[3-(3,5-difluorophenyl)-2-(1,3-dihydro-2H-benzimidazol-2-ylidene)-3-oxopropanoyl]benzenesulfonyl chloride.
Reference Example 3
A chloroform solution of tetrahydro-2H-thiopyran-4-carbonitrile was dropwise added to a chloroform solution of 77% m-chloroperbenzoic acid at 0° C., followed by stirring at room temperature for 3 hours. An excess amount of an aqueous saturated sodium sulfite solution was added, followed by work-up to obtain tetrahydro-2H-thiopyran-4-carbonitrile 1,1-dioxide.
Reference Example 4
The compound obtained in Reference Example 3 was suspended in ethanol and diethyl ether, and hydrogen chloride was bubbled thereto at 0° C. for 30 minutes. After further stirring at 0° C. for 15 hours, the insoluble matter was separated by filtration, and the filtrate was concentrated under reduced pressure to obtain ethyl tetrahydro-2H-thiopyran-4-*carboximidate 1,1-dioxide hydrochloride.
Reference Example 5
An ethanol suspension of the compound obtained in Reference Example 4 was added to a saturated ammonia/ethanol solution at 0° C., followed by stirring at room temperature for 13 hours. The insoluble matter was separated by filtration, and the filtrate was concentrated under reduced pressure to obtain tetrahydro-2H-thiopyran-4-carboximidamide 1,1-dioxide hydrochloride.
Reference Example 6
3,3,3-Trifluoropropanal was added to a mixture of sodium hydrogensulfate and water, with vigorously stirring at 0° C., followed by further stirring for 10 minutes. An aqueous solution of potassium cyanide was dropwise added, followed by reaction with stirring at 0° C. for 1 hour and then work-up and purification to obtain 4,4,4-trifluoro-2-hydroxybutanenitrile.
Reference Example 7
Iron powder was added to an acetic acid solution of benzyl 2-methyl-3-nitrobenzoate, followed by stirring at room temperature for 1.5 hours. The insoluble matter was separated by filtration, and the filtrate was concentrated under reduced pressure. This was diluted with ethyl acetate, neutralized with an aqueous saturated sodium hydrogencarbonate solution, and the insoluble matter was separated by filtration. The filtrate was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. Ethyl acetate was added and a solution of 4 M hydrogen chloride/ethyl acetate was dropwise added thereto at 0° C. The precipitate was collected by filtration to obtain benzyl 3-amino-2-methylbenzoate.
Reference Example 8
An aqueous solution (15 mL) of sodium nitrite (2.19 g) was dropwise added to an acetic acid (40 mL)/concentrated hydrochloric acid (12.5 mL) suspension of the compound obtained in Reference Example 7 at 0° C., followed by stirring for 30 minutes. To an acetic acid suspension of copper(II) chloride dihydrate, into which sulfur dioxide had been bubbled for 10 minutes, dropwise added was the reaction mixture previously prepared, at 0° C., followed by stirring at room temperature for 19 hours. The reaction mixture was poured into water with ice, followed by work-up and purification to obtain benzyl 3-(chlorosulfonyl)-2-methylbenzoate.
Reference Example 9
A trifluoroacetic acid solution of the compound obtained in Reference Example 8 was reacted with stirring under heat at 60° C. for 17 hour to obtain 3-(chlorosulfonyl)-2-methylbenzoic acid.
Reference Example 10
An aqueous 50% hydroxylamine solution was added to a methanol solution of 3-cyanobenzoic acid, followed by heating under reflux for 11 hours. The reaction liquid was concentrated, diluted with water, adjusted with 1 M hydrochloric acid to have a pH of from 2 to 3, and the precipitate was collected by filtration to obtain 3-[(hydroxyamino)(imino)methyl]benzoic acid. ES+: 181.
Reference Example 11
A mixture of the compound obtained in Reference Example 10, p-toluenesulfonic acid and triethoxymethane was heated under reflux for 30 minutes. After cooling, this was diluted with acetonitrile, and the insoluble matter was collected by filtration to obtain 3-(1,2,4-oxadiazol-3-yl)benzoic acid. FA: 191.
Reference Example 71
At room temperature, 3-(chlorosulfonyl)-4-fluorobenzoyl chloride (3.19 g) was added to a dioxane (75 mL) suspension of 2-(1,3-dihydro-2H-benzimidazol-2-ylidene)-1-(3-fluorophenyl)ethanone (1.50 g), followed by heating up to 110° C. and stirring for 1 hour. The reaction mixture was cooled to room temperature, the insoluble matter was separated by filtration, and then this was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=3/1) to obtain 5-[2-(1,3-dihydro-2H-benzimidazol-2-ylidene)-3-(3-fluorophenyl)-3-oxopropanoyl]-2-fluorobenzenesulfonyl chloride (2.10 g).
Reference Example 207
1.58 M n-butyllithium/hexane solution (13.8 mL) was dropwise added to an anhydrous THF (30 mL) solution of diisopropylamine (3.08 mL) cooled to −78° C. under Ar gas atmosphere, thereby preparing a LDA solution. This solution was warmed up to −20° C., and then again cooled to −78° C., and thereafter 3-fluoroacetophenone (2.07 g) was dropwise added thereto, followed by stirring at −78° C. for 30 minutes. Then, 3-(chlorosulfonyl)benzoyl chloride (2.44 g) was dropwise added, followed by stirring for 15 minutes. Separately, 2-hydroxy-2-methylpropanimidamide hydrochloride (3.05 g) was added to a THF (40 mL) solution of sodium hydride (60% purity, 0.88 g) at room temperature, followed by stirring for 30 minutes and cooling to 0° C. Then, the previous solution was added thereto all at once, followed by stirring at room temperature for 1 hour. An aqueous saturated ammonium chloride solution was added, followed by extraction with ethyl acetate. The organic layer was washed with water, dried, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform/methanol=50/1) to obtain N-({3-[3-(3-fluorophenyl)-3-oxopropanoyl]phenyl}sulfonyl)-2-hydroxy-2-methylpropanimidamide (2.17 g).
Reference Example 208
Potassium fluoride (3.30 g) was added to a DMF (20 mL) solution of N-({3-[3-(3-fluorophenyl)-3-oxopropanoyl]phenyl}sulfonyl)-2-hydroxy-2-methylpropanimidamide (1.13 g), followed by cooling to 0° C. Then, carbon disulfide (1.06 g) was dropwise added thereto. Then, a DMF (4 mL) solution containing methyl iodide (0.95 g) was dropwise added, warmed up to room temperature, followed by stirring for 15 minutes. Water was added, followed by extraction with ethyl acetate. The organic layer was washed with water, dried, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=1/2) to obtain N-({3-[2-(3-fluorobenzoyl)-3,3-bis(methylthio)acryloyl]phenyl}sulfonyl)-2-hydroxy-2-methylpropanimidamide (1.32 g).
Reference Example 209
At room temperature, benzyl bromide (8.85 mL) and potassium carbonate (10.3 g) were added to a DMF (150 mL) solution of 2-methoxy-3-nitrobenzoic acid (9.80 g), followed by stirring for 70 minutes. The insoluble matter was separated by filtration, followed by evaporation under reduced pressure. This was subjected to liquid-liquid separation with ethyl acetate, aqueous sodium hydrogencarbonate solution, and hexane added thereto. The organic layer was washed with water and saturated brine in that order, dried, and then evaporated under reduced pressure to obtain benzyl 2-methoxy-3-nitrobenzoate (14.3 g).
N2: 3.92 (3H, s), 5.39 (2H, s), 7.23-7.47 (6H, m), 7.90 (1H, dd, J=8 Hz, 2 Hz), 8.05 (1H, dd, J=8 Hz, 2 Hz).
Iron (13.9 g) was added to an acetic acid (150 mL) solution of benzyl 2-methoxy-3-nitrobenzoate (14.3 g), followed by stirring at room temperature for 17.5 hours. The insoluble matter was separated by filtration, followed by evaporation under reduced pressure. An aqueous sodium hydrogencarbonate solution, ethyl acetate and Celite were added, the insoluble matter was separated by filtration, and then this was subjected to liquid-liquid separation to collect the organic layer. At room temperature, 4 N hydrogen chloride/ethyl acetate solution (12.5 mL) was added, followed by stirring for 30 minutes and then evaporation under reduced pressure. This was azeotroped with toluene to obtain benzyl 3-amino-2-methoxybenzoate hydrochloride (14.4 g). FA: 258.
An aqueous solution (20 mL) of sodium nitrite (3.55 g) was dropwise added to an acetic acid (110 mL)/hydrochloric acid (35 mL) suspension of benzyl 3-amino-2-methoxybenzoate hydrochloride (14.4 g), with its inner temperature kept at 0° C., followed by stirring for 30 minutes. Separately, sulfur dioxide gas was bubbled into acetic acid (125 mL) at 0° C., and then copper(II) chloride dihydrate (2.09 g) was added to prepare a solution. The above diazonium salt suspension was added to this solution, followed by stirring at 0° C. for 35 minutes and at room temperature for 17 hours. This was poured into water with ice, then subjected to liquid-liquid separation with ethyl acetate/hexane (1/1) added thereto. The organic layer was washed with water and saturated brine, and then evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=4/1) to obtain benzyl 3-(chlorosulfonyl)-2-methoxybenzoate (12.9 g).
N1: 3.77 (3H, s), 5.34 (2H, s), 7.15 (1H, t, J=8 Hz), 7.35-7.50 (5H, m), 7.68 (1H, dd, J=8 Hz, 2 Hz), 7.93 (1H, dd, J=8 Hz, 2 Hz).
A trifluoroacetic acid (95 mL) solution of benzyl 3-(chlorosulfonyl)-2-methoxybenzoate (12.9 g) was stirred at 70° C. for 5 hours. The solution part was decanted and evaporated under reduced pressure. Toluene was added to the residue, and this was again evaporated. The resulting solid was collected by filtration, washed with toluene and dried to obtain 3-(chlorosulfonyl)-2-methoxybenzoic acid (6.52 g).
N1: 3.84 (3H, s), 7.13 (1H, t, J=8 Hz), 7.67 (1H, dd, J=8 Hz, 2 Hz), 7.91 (1H, dd, J=8 Hz, 2 Hz), 13.86 (1H, brs).
Three drops of N,N-dimethylformamide were added to a thionyl chloride (4.37 mL) suspension of 3-(chlorosulfonyl)-2-methoxybenzoic acid (3.00 g), followed by stirring at 60° C. for 2 hours. The solvent was evaporated, and this was azeotroped with toluene to obtain 3-(chlorosulfonyl)-2-methoxybenzoyl chloride (3.22 g).
Reference Example 210
At 10° C., cesium carbonate (5.81 g) was added to a DMF (30 mL) solution of 3-fluoro-5-nitrobenzoic acid (2.20 g), followed by stirring for 30 minutes. Then, benzyl bromide (2.07 g) was dropwise added with taking 30 minutes, and then followed by further stirring for 10 minutes. The insoluble matter was separated by filtration, followed by evaporation under reduced pressure. This was subjected to liquid-liquid separation with ether and water added thereto, and the organic layer was dried and then evaporated to obtain benzyl 3-fluoro-5-nitrobenzoate (3.11 g). EI: 275.
Iron (3.16 g) was added to an acetic acid (31 mL) solution of benzyl 3-fluoro-5-nitrobenzoate (3.11 g), followed by stirring at room temperature for 1 hour. (This reaction was exothermic and its temperature reached 40° C.) The insoluble matter was separated by filtration, followed by evaporation under reduced pressure. An aqueous sodium hydrogencarbonate solution, ethyl acetate and Celite were added, and the insoluble matter was separated by filtration. Then this was subjected to liquid-liquid-separation, and the organic layer was collected. At room temperature, a 4 N hydrogen choloride/ethyl acetate solution (4 mL) was added, followed by stirring for 30 minutes. Then, the resulting solid was collected by filtration to obtain benzyl 3-amino-5-fluorobenzoate hydrochloride (2.18 g). FA: 246.
An aqueous sodium nitrite (561 mg) solution was dropwise added to an acetic acid (17 mL)/concentrated hydrochloric acid (0.65 mL) suspension of benzyl 3-amino-5-fluorobenzoate hydrochloride (2.18 g), with its inner temperature being kept at 5 to 110° C., followed by stirring for 1 hour. Separately, sulfur dioxide gas was bubbled into acetic acid (100 mL) at 0° C., and then copper (II) chloride dihydrate (330 mg) was added to prepare a solution. The above diazonium salt suspension was added to this solution all at once, followed by stirring at 0° C. for 1 hour and at room temperature for 14 hours. This was poured into water with ice, then subjected to liquid-liquid separation with ethyl acetate added thereto. The organic layer was washed with water and saturated brine, and then evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=6/1) to obtain benzyl 3-(chlorosulfonyl)-5-fluorobenzoate (2.30 g).
N1: 5.37 (2H, s), 7.36-7.50 (5H, m), 7.58 (1H, m), 7.68 (1H, m), 8.03 (1H, m).
A trifluoroacetic acid (18 mL) solution of benzyl 3-(chlorosulfonyl)-5-fluorobenzoate (2.30 g) was stirred at 60° C. for 18 hours. The oily substance floating on the liquid surface was removed, and the solution part was decanted and evaporated under reduced pressure. Hexane was added to the residue, then this was sonicated for 10 minutes. The resulting solid was collected by filtration to obtain 3-(chlorosulfonyl)-5-fluorobenzoic acid (1.37 g). EI: 238
One drop of N,N-dimethylformamide was added to a thionyl chloride (2.03 g) suspension of 3-(chlorosulfonyl)-5-fluorobenzoic acid (1.36 g), followed by stirring at 75° C. for 1 hour. The solvent was evaporated, and this was azeotroped with toluene to obtain 3-(chlorosulfonyl)-5-fluorobenzoyl chloride (1.47 g).
Reference Example 211
Benzyl N,N′-dicyclohexylimidocarbamate (0.82 g) was added to a DMF (3 mL) solution of 2-amino-3-nitrobenzoic acid (0.36 g), followed by heating up to 70° C. and stirring for 2 hours. The reaction mixture was cooled to room temperature, then an ethyl acetate/ether (1/1) solution was poured into it, and the insoluble matter was separated by filtration. The filtrate was washed with aqueous sodium hydrogencarbonate solution and water in that order, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=3/1) to obtain benzyl 2-amino-3-nitrobenzoate (0.42 g). FA: 273.
Iron powder (0.78 g) and ammonium chloride (0.15 g) were added in that order to an ethanol/water (4/1) solution (40 mL) of benzyl 2-amino-3-nitrobenzoate (0.38 g), and this was heated under reflux for 20 minutes with vigorous stirring. The insoluble matter was separated by filtration while hot, and the filtrate was evaporated under reduced pressure to about 1⁄5, and then aqueous sodium hydrogencarbonate solution was added, followed by extraction with ethyl acetate. The organic layer was washed with water, dried, and evaporated under reduced pressure to obtain benzyl 2,3-diaminobenzoate (0.33 g).
In the same manner as in Reference Examples 1 to 11, 71 and 207 to 211, compounds of other Reference Examples shown in Tables 3 to 18 below were produced, using the corresponding starting materials. The structure, the production method and the physicochemical data of the compounds of Reference Examples are shown in the Tables.
Example 1
60% Sodium hydride (809 mg) was added to a DMF (30 mL) solution of formamidine hydrochloride (1.92 g), followed by stirring at room temperature for 15 minutes. A DMF (10 mL) solution of 3-[3-(3,5-difluorophenyl)-2-(1,3-dihydro-2H-benzimidazol-2-ylidene)-3-oxopropanoyl]benzenesulfonyl chloride (hereinafter referred to as starting compound A, 1.13 g) was added, followed by stirring at room temperature for 1.5 hours. The reaction mixture was poured into an excess amount of aqueous ammonium chloride solution, followed by extraction with ethyl acetate. The organic layer was washed with water, concentrated under reduced pressure, purified by silica gel column chromatography (chloroform/methanol=10/1), and crystallized from diethyl ether/n-hexane to obtain 3-[3-(3,5-difluorophenyl)-2-(1,3-dihydro-2H-benzimidazol-2-ylidene)-3-oxopropanoyl]-N-(iminomethyl)benzenesulfonamide (81 mg).
Example 2
A DMF (3 mL) solution of the starting compound A (300 mg) was added to a DMF (10 mL) solution of glycine ethyl ester hydrochloride (733 mg) and triethylamine (0.73 mL), followed by stirring at room temperature for 30 minutes. This was diluted with water, the precipitate was collected by filtration, and dried under reduced pressure to obtain ethyl [({3-[3-(3,5-difluorophenyl)-2-(1,3-dihydro-2H-benzimidazol-2-ylidene)-3-oxopropanoyl]phenyl}sulfonyl)amino]acetate (505 mg).
Example 3
Aminoacetonitrile (177 mg) was added to a DMF (10 mL) solution of the starting compound A (300 mg) at 0° C., followed by stirring at room temperature for 1.5 hours. An excess amount of an aqueous saturated ammonium chloride solution was added, and the precipitate was collected by filtration, and dried under reduced pressure to obtain N-(cyanomethyl)-3-[3-(3,5-difluorophenyl)-2-(1,3-dihydro-2H-benzimidazol-2-ylidene)-3-oxopropanoyl]benzenesulfonamide (242 mg).
Example 4
2-Aminopyridine (248 mg) was added to a pyridine (10 mL) solution of the starting compound A (250 mg), followed by stirring at room temperature for 1 hour, and then the reaction mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (n-hexane/ethyl acetate=1/2), and then recrystallized from ethyl acetate/n-hexane to obtain 3-[3-(3,5-difluorophenyl)-2-(1,3-dihydro-2H-benzimidazol-2-ylidene)-3-oxopropanoyl]-N-pyridin-2-ylbenzenesulfonamide (36 mg).
Example 5
A mixture of 3-[3-(3,5-difluorophenyl)-2-(1,3-dihydro-2H-benzimidazol-2-ylidene)-3-oxopropanoyl]benzenesulfonamide (hereinafter referred to as starting compound B, 500 mg), acetic anhydride (5 mL), pyridine (10 mL) and DMF (20 mL) was heated with stirring at 55° C. for 2 hours. The reaction mixture was concentrated under reduced pressure, diluted with ethyl acetate and washed with aqueous saturated sodium hydrogencarbonate solution and water successively. The solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (chloroform/methanol=10/1), and recrystallized from ethyl acetate/n-hexane to obtain N-({3-[3-(3,5-difluorophenyl)-2-(1,3-dihydro-2H-benzimidazol-2-ylidene)-3-oxopropanoyl]phenyl}sulfonyl)acetamide (58 mg).
Example 6
60% Sodium hydride (21 mg) was added to a 1-methyl-2-pyrrolidone (6 mL) solution of the starting compound B (240 mg) and isopropyl isocyanate (0.4 mL), followed by stirring at room temperature for 1.5 hours. This was diluted with 1 M hydrochloric acid, followed by extraction with ethyl acetate. The organic layer was washed with water, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane/ethyl acetate=1/1), and recrystallized from ethyl acetate/n-hexane to obtain 3-[3-(3,5-difluorophenyl)-2-(1,3-dihydro-2H-benzimidazol-2-ylidene)-3-oxopropanoyl]-N-[(isopropylamino)carbonyl]benzenesulfonamide (14 mg).
Example 7
A mixture of the starting compound B (797 mg), potassium cyanate (994 mg), acetic acid (10 mL), water (25 mL) and N-methylpyrrolidinone (30 mL) was heated with stirring at 100° C. for 31 hours. After cooling to room temperature, water was added. The insoluble matter was collected by filtration, purified by silica gel column chromatography (chloroform/methanol=10/1), and further washed with diethyl ether to obtain N-(aminocarbonyl)-3-[3-(3,5-difluorophenyl)-2-(1,3-dihydro-2H-benzimidazol-2-ylidene)-3-oxopropanoyl]benzenesulfonamide (15 mg).
Example 8
An aqueous 1 M sodium hydroxide solution (3.1 mL) was added to a THF (10 mL) solution of the compound (300 mg) obtained in Example 2, followed by stirring at room temperature for 3.5 hours. THF was evaporated under reduced pressure, and 1 M hydrochloric acid was excessively added. The precipitate was collected by filtration and dried under reduced pressure to obtain [({3-[3-(3,5-difluorophenyl)-2-(1,3-dihydro-2H-benzimidazol-2-ylidene)-3-oxopropanoyl]phenyl}sulfonyl)amino]acetic acid (250 mg).
Example 9
Dimethylamine hydrochloride (31 mg), triethylamine (0.05 mL), HOBt (51 mg) and WSC.HCl (73 mg) were added to a DMF (5 mL) solution of [({3-[3-(3,5-difluorophenyl)-2-(1,3-dihydro-2H-benzimidazol-2-ylidene)-3-oxopropanoyl]phenyl}sulfonyl)amino](imino)acetic acid (40 mg), followed by stirring at room temperature for 1.5 hours. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate/n-hexane to obtain 2-[({3-[3-(3,5-difluorophenyl)-2-(1,3-dihydro-2H-benzimidazol-2-ylidene)-3-oxopropanoyl]phenyl}sulfonyl)amino]-2-imino-N,N-dimethylacetamide (28 mg).
Example 10
At 0° C., benzyl piperazine-1-carboxylate (1.37 g) was added to an acetonitrile (5 mL) solution of N-({3-[3-(3,5-difluorophenyl)-2-(1,3-dihydro-2H-benzimidazol-2-ylidene)-3-oxopropanoyl]phenyl}sulfonyl)-3,5-dimethyl-1H-pyrazole-1-carboximidamide (205 mg), and heated under reflux for 3 days. After cooling, ethyl acetate was added, then washed with aqueous saturated ammonium chloride solution, water and saturated brine in that order, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (n-hexane/ethyl acetate=1/4) to obtain benzyl 4-[[({3-[3-(3,5-difluorophenyl)-2-(1,3-dihydro-2H-benzimidazol-2-ylidene)-3-oxopropanoyl]phenyl}sulfonyl)amino](imino)methyl]piperazine-1-carboxylate (76 mg).
Example 11
10% Pd—C (210 mg) was added to an ethanol (20 mL) solution of the compound (205 mg) obtained in Example 10, followed by stirring at room temperature for 19 hours under hydrogen atmosphere (1 atom). The insoluble matter was separated by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform/methanol=50/1), and recrystallized from ethyl acetate/n-hexane to obtain N-({3-[3-(3,5-difluorophenyl)-2-(1,3-dihydro-2H-benzimidazol-2-ylidene)-3-oxopropanoyl]phenyl}sulfonyl)piperazine-1-carboximidamide (46 mg).
Example 12
Dess-Martin reagent (15 wt. % dichloromethane solution, 0.73 mL) was added to a dichloromethane (2 mL) solution of N-({3-[3-(3,5-difluorophenyl)-2-(1,3-dihydro-2H-benzimidazol-2-ylidene)-3-oxopropanoyl]phenyl}sulfonyl)-2-hydroxypropanimidamide (90 mg), followed by stirring at room temperature for 4 hours. Ethyl acetate was added to the reaction mixture, washed with water, dried over anhydrous magnesium sulfate, and the organic layer was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (n-hexane/ethyl acetate=2/1), and recrystallized from ethyl acetate/n-hexane to obtain N-({3-[3-(3,5-difluorophenyl)-2-(1,3-dihydro-2H-benzimidazol-2-ylidene)-3-oxopropanoyl]phenyl}sulfonyl)-2-oxopropanimidamide (57 mg).
Example 13
2 M dimethylamine/THF solution (0.85 mL) was added to a DMF (5 mL) solution of 2-chloro-N-({3-[3-(3,5-difluorophenyl)-2-(1,3-dihydro-2H-benzimidazol-2-ylidene)-3-oxopropanoyl]phenyl}sulfonyl)ethanimidamide (181 mg), followed by stirring at room temperature for 1 hour. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform/methanol=50/1), and recrystallized from ethyl acetate/n-hexane to obtain N-({3-[3-(3,5-difluorophenyl)-2-(1,3-dihydro-2H-benzimidazol-2-ylidene)-3-oxopropanoyl]phenyl}sulfonyl)-2-(dimethylamino)ethanimidamide (76 mg).
Example 14
3-[(dimethylamino)sulfonyl]benzoyl chloride (1.97 g) was added to a mixture of 1-(3,5-difluorophenyl)-2-(1,3-dihydro-2H-benzimidazol-2-ylidene)ethanone (865 mg), triethylamine (1.6 mL) and 2-methoxyethyl ether (10 mL), followed by heating with stirring at 110° C. for 30 minutes. Water (0.06 mL) was added, followed by further heating under reflux for 30 minutes. After cooling, water was added, followed by extraction with ethyl acetate. The organic layer was washed with water, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane/ethyl acetate=1/1), and recrystallized from ethyl acetate/n-hexane to obtain 3-[3-(3,5-difluorophenyl)-2-(1,3-dihydro-2H-benzimidazol-2-ylidene)-3-oxopropanoyl]-N,N-dimethylbenzenesulfonamide (391 mg).
Example 15
The starting compound B (500 mg) was added to a DMF (20 mL) suspension of 60% sodium hydride, followed by stirring at room temperature. N,N-dimethylacetamide dimethyl acetal (0.48 mL) was added, followed by further stirring at room temperature for 15 hours. An aqueous saturated ammonium chloride solution was added to the reaction mixture, and the resulting precipitate was collected by filtration to obtain (1E)-N′-({3-[3-(3,5-difluorophenyl)-2-(1,3-dihydro-2H-benzimidazol-2-ylidene)-3-oxopropanoyl]phenyl}sulfonyl)-N,N-dimethylethanimidamide (267 mg).
Example 16
Acetic anhydride (90 mg) was added to a pyridine (5 mL) solution of N-({3-[3-(3,5-difluorophenyl)-2-(1,3-dihydro-2H-benzimidazol-2-ylidene)-3-oxopropanoyl]phenyl}sulfonyl)-2-hydroxyethanimidamide (225 mg), followed by stirring at room temperature for 2 hours. An excess amount of an aqueous saturated ammonium chloride solution was added, followed by extraction with ethyl acetate. The organic layer was washed with water, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform/methanol=80/1) and crystallized from ethyl acetate/n-hexane to obtain 2-[({3-[3-(3,5-difluorophenyl)-2-(1,3-dihydro-2H-benzimidazol-2-ylidene)-3-oxopropanoyl]phenyl}sulfonyl)amino]-2-iminoethylacetic acid (150 mg).
Example 17
10% Pd—C (85 mg) was added to an ethyl acetate (150 mL) suspension of N-({3-[3-(3,5-difluorophenyl)-2-(5-nitro-1,3-dihydro-2H-benzimidazol-2-ylidene)-3-oxopropanoyl]phenyl}sulfonyl)ethanimidamide (845 mg), followed by stirring at room temperature for 22 hours under hydrogen atmosphere (1 atm). The insoluble matter was separated by filtration, washed with ethanol, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform/methanol=30/1), and recrystallized from ethyl acetate/n-hexane to obtain N-({3-[2-(5-amino-1,3-dihydro-2H-benzimidazol-2-ylidene)-3-(3,5-difluorophenyl)-3-oxopropanoyl]phenyl}sulfonyl)ethanimidamide (667 mg).
Example 18
At −20° C., 77% m-chloroperbenzoic acid (132 mg) was added to a dichloromethane (10 mL) suspension of N-[(3-{2-(1,3-dihydro-2H-benzimidazol-2-ylidene)-3-[3-(methylsulfanyl)phenyl]-3-oxopropanoyl}phenyl)sulfonyl]ethanimidamide (100 mg), followed by stirring for 3 hours. An excess amount of an aqueous saturated ammonium chloride solution was added, followed by extraction with ethyl acetate. The organic layer was washed with water, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform/methanol=60/1) and crystallized from ethyl acetate/n-hexane to obtain N-[(3-{2-(1,3-dihydro-2H-benzimidazol-2-ylidene)-3-[3-(methanesulfonyl)phenyl]-3-oxopropanoyl}phenyl)sulfonyl]ethanimidamide (64 mg).
Example 19
Ammonium formate (260 mg) and 10% Pd—C (250 mg) were added to a DMF (25 mL) solution of N-({3-[3-(2-chloropyridin-4-yl)-2-(1,3-dihydro-2H-benzimidazol-2-ylidene)-3-oxopropanoyl]phenyl})ethanimidamide (500 mg), followed by stirring at room temperature for 3 hours. The insoluble matter was separated by filtration, the filtrate was concentrated under reduced pressure, and the residue was washed with ethyl acetate to obtain N-({3-[2-(1,3-dihydro-2H-benzimidazol-2-ylidene)-3-oxo-3-pyridin-4-ylpropanoyl]phenyl}sulfonyl)ethanimidamide (372 mg).
Example 532
1,2-Phenylenediamine (81 mg) was added to an EtOH (20 mL) solution of N-[(3-{2-[(2,4-dimethyl-1,3-thiazol-5-yl)carbonyl]-3,3-bis(methylthio)acryloyl}phenyl)sulfonyl]-2-hydroxy-2-methylpropanimidamide (370 mg), followed by heating under reflux for 13 hours. After cooling, the reaction mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (chloroform/methanol=50/1), and recrystallized from ethyl acetate/n-hexane to obtain N-({3-[2-(1,3-dihydro-2H-benzimidazol-2-ylidene)-3-(2,4-dimethyl-1,3-thiazol-5-yl)-3-oxopropanoyl]phenyl}sulfonyl)-2-hydroxy-2-methylpropanimidamide (310 mg).
Example 533
Under ice cooling, 4 N—HCl/ethyl acetate (0.09 mL) was added to an EtOH/dioxane (2/1) mixed solution (4 mL) of N-({3-[2-(1,3-dihydro-2H-benzimidazol-2-ylidene)-3-(2-methoxypyridin-4-yl)-3-oxopropanoyl]phenyl}sulfonyl)-2-hydroxy-2-methylpropanimidamide (127 mg), followed by stirring for 1 hour. The reaction mixture was concentrated under reduced pressure. An aqueous sodium hydrogencarbonate solution was added to the resulting residue, followed by extraction with ethyl acetate and concentration under reduced pressure. The resulting residue was purified by silica gel column chromatography (chloroform/methanol=10/1) to obtain N-({3-[2-(1,3-dihydro-2H-benzimidazol-2-ylidene)-3-oxo-3-(2-oxo-1,2-dihydropyridin-4-yl)propanoyl]phenyl}sulfonyl)-2-hydroxy-2-methylpropanimidamide (18 mg).
Example 696
At room temperature, sodium hydride (579 mg) was added to a THF (70 mL) suspension of (2R)-2-hydroxypropanimidamide hydrochloride (1.65 g), followed by heating up to 60° C. and stirring for 30 minutes. The reaction mixture was cooled to room temperature, and a THF (35 mL) solution of 5-[2-(1,3-dihydro-2H-benzimidazol-2-ylidene)-3-(3-fluorophenyl)-3-oxopropanoyl]-2-fluorobenzenesulfonyl chloride (2.10 g) was added, followed by stirring for 20 minutes. Then, this was subjected to liquid-liquid separation with water and ethyl acetate added thereto, the organic layer was washed with saturated brine, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform/methanol=50/1) to obtain (2R)-N-({5-[2-(1,3-dihydro-2H-benzimidazol-2-ylidene)-3-(3-fluorophenyl)-3-oxopropanoyl]-2-fluorophenyl}sulfonyl)-2-hydroxypropanimidamide (1.95 g).
In the same manner as in Examples 1 to 19, 532, 533 and 696, compounds of other Examples shown in Tables 19 to 57 below were synthesized, using the corresponding starting materials. The structure, the production method and the physicochemical data of the compounds of those Examples are shown in the Tables.
Tables 58 to 70 show the structures of other compounds of the present invention. These can be readily synthesized according to the above-mentioned production methods, the methods described in Examples and methods obvious to persons skilled in the art, or modified methods thereof. In Tables 58 to 70, the following abbreviations are used for the group R3:
C2: —NH(CH2)2OH, C3:—NH(CH2)3OH, GN: —N═C(NH2)2,











TABLE 3













 












REx
Syn
A
Dat















1
R1
3-F-Ph
FA: 255



12
R1
2-F-Ph
FA: 255



13
R1
4-F-Ph
ES+: 255



14
R1
2-Cl-Ph
ES+: 271



15
R1
3-Cl-Ph
ES+: 271



16
R1
2-OMe-Ph
ES+: 267



17
R1
3-OMe-Ph
ES−: 265



18
R1
3-OH-Ph
ES+: 253



19
R1
3-OEt-Ph
ES+: 281



20
R1
3-OiPr-Ph
ES+: 295



21
R1
3-OPr-Ph
ES+: 295



22
R1
3-OPh-Ph
ES+: 329



23
R1
2-Me-Ph
ES+: 251



24
R1
3-Me-Ph
ES+: 251



25
R1
4-Me-Ph
ES+: 251



26
R1
3-CN-Ph
ES+: 262



27
R1
2-CF3-Ph
FA: 305



28
R1
3-CF3-Ph
ES+: 305



29
R1
4-CF3-Ph
FA: 305



30
R1
2,3-diF-Ph
FA: 273



31
R1
3,4-diF-Ph
FA: 273



32
R1
2,5-diF-Ph
ES+: 273



33
R1
3-Cl-4-F-Ph
ES+: 289


 



34
R1




ES+: 305


 



35
R1




ES+: 279


 



36
R1
3,4-diCl-Ph
ES−: 303



37
R1
3,5-diCl-Ph
FA: 305



38
R1
2,3-diCl-Ph
ES−: 303



39
R1
2,5-diCl-Ph
ES−: 303



40
R1
3,5-diMe-Ph
ES+: 265



41
R1
2,3-diMe-Ph
ES+: 265



42
R1
3,4-diMe-Ph
FA: 265



43
R1
2-Me-3-F-Ph
ES+: 269



44
R1
2-Me-5-F-Ph
ES+: 269



45
R1
3-F-4-OMe-Ph
FA: 285



46
R1
2-OMe-5-Cl-Ph
FA: 301



47
R1
3-Cl-4-OMe-Ph
FA: 301



48
R1
3,4,5-triF-Ph
FA: 291



49
R1
2-Cl-4,5-diF-Ph
FA: 307



50
R1
2-Ph-Ph
ES+: 313



51
R1
3-Ph-Ph
AP+: 313



52
R1
2Naph
ES+: 287



53
R1
1Naph
ES+: 287



54
R1
4-F-1Naph
AP+: 305



55
R1
6-Cl-3Py
ES+: 272



56
R1
2-Cl-4Py
ES+: 272



57
R1
Pyra
ES+: 239



58
R1
2Thi
ES+: 243



59
R1
3Thi
ES+: 243


 



60
R1




ES+: 305


 



61
R1




ES+: 277
















TABLE 4













 













REx
Syn
A
R1a
R1b
R2
Dat
















2
R2
3,5-diF-Ph
H
H
H
ES+: 475


62
R2
Ph
H
H
H
ES+: 439


63
R2
Ph
H
H
2-Me
Not Isolated


64
R2
Ph
BnS
H
H
ES+: 561


65
R2
2-F-Ph
H
H
H
ES+: 457


66
R2
3-F-Ph
H
H
H
ES+: 457


67
R2
3-F-Ph
H
H
2-Me
FA: 471


68
R2
3-F-Ph
H
H
6-Me
FA: 471


69
R2
3-F-Ph
H
H
4-Me
FA: 471


70
R2
3-F-Ph
H
H
2-Cl
FA: 491


71
R2
3-F-Ph
H
H
4-F
FA: 475


72
R2
3-F-Ph
H
H
4-Cl
FA: 491


73
R2
3-F-Ph
PhCO
H
H
ES+: 561


74
R2
3-F-Ph
MeO
MeO
H
ES+: 517


75
R2
4-F-Ph
H
H
H
Not Isolated


76
R2
2-Cl-Ph
H
H
H
ES+: 473


77
R2
2-Cl-Ph
H
H
2-Me
Not Isolated


78
R2
3-Cl-Ph
H
H
H
ES+: 473


79
R2
3-Cl-Ph
H
H
2-Me
Not Isolated


80
R2
3-Cl-Ph
H
H
4-Me
Not Isolated


81
R2
4-Cl-Ph
H
H
H
ES+: 473


82
R2
4-Cl-Ph
H
H
2-Me
Not Isolated


83
R2
3-Br-Ph
H
H
H
ES+: 519


84
R2
2-OMe-Ph
H
H
H
ES+: 469


85
R2
3-OMe-Ph
H
H
H
Not Isolated


86
R2
4-OMe-Ph
H
H
H
ES+: 469


87
R2
3-SMe-Ph
H
H
H
ES+: 485


88
R2
3-Ac-Ph
H
H
H
ES+: 481






















TABLE 5







89
R2
2-Me-Ph
H
H
H
Not Isolated


90
R2
3-Me-Ph
H
H
H
ES+: 453


91
R2
3-Me-Ph
H
H
2-Me
Not Isolated


92
R2
3-Me-Ph
H
H
6-Me
ES+: 467


93
R2
3-Me-Ph
H
H
4-Me
ES+: 467


94
R2
3-Me-Ph
H
H
2-Cl
FA: 487


95
R2
4-Me-Ph
H
H
H
FA: 453


96
R2
3-OH-Ph
H
H
H
ES+: 455


97
R2
3-OEt-Ph
H
H
H
Not Isolated


98
R2
3-OPr-Ph
H
H
H
Not Isolated


99
R2
3-OiPr-Ph
H
H
H
Not Isolated


100
R2
3-OPh-Ph
H
H
H
ES+: 531


101
R2
2-CF3-Ph
H
H
H
Not Isolated


102
R2
3-CF3-Ph
H
H
H
Not Isolated


103
R2
4-CF3-Ph
H
H
H
Not Isolated


104
R2
3-CN-Ph
H
H
H
Not Isolated


105
R2
3,5-diF-Ph
H
H
2-Me
FA: 489


106
R2
3,5-diF-Ph
H
H
4-Me
FN: 487


107
R2
3,5-diF-Ph
H
H
6-Me
ES+: 489


108
R2
3,5-diF-Ph
H
H
4-Me
ES+: 489


109
R2
3,5-diF-Ph
H
H
2-Cl
FA: 509


110
R2
3,5-diF-Ph
H
H
6-OMe
Not Isolated


111
R2
2,3-diF-Ph
H
H
H
Not Isolated


112
R2
2,3-diF-Ph
H
H
2-Me
ES+: 489


113
R2
3,4-diF-Ph
H
H
H
Not Isolated


114
R2
2,5-diF-Ph
H
H
H
FA: 475


115
R2
2,5-diF-Ph
H
H
2-Me
ES+: 489


116
R2
2-Cl-3-F-Ph
H
H
H
FN: 489


117
R2
3-Cl-4-F-Ph
H
H
H
ES+: 491


118
R2
2-Cl-5-F-Ph
H
H
H
ES+: 491


119
R2
3-Cl-5-F-Ph
H
H
H
ES+: 491


120
R2
2-Cl-4,5-diF-Ph
H
H
H
FA: 509


121
R2
3,4-diCl-Ph
H
H
H
Not Isolated


122
R2
3,5-diCl-Ph
H
H
H
Not Isolated


123
R2
2,3-diCl-Ph
H
H
H
Not Isolated


124
R2
2,5-diCl-Ph
H
H
H
Not Isolated






















TABLE 6







125
R2
2-Me-3-F-Ph
H
H
H
ES+: 471


126
R2
2-Me-5-F-Ph
H
H
H
Not Isolated


127
R2
2-Me-5-F-Ph
H
H
2-Me
N1: 2.10 (3H, s), 2.42 (3H, s),








6.62-6.86 (4H, m), 6.89-6.98 (1H,








m), 7.26-7.38 (2H, m), 7.47 (1H,








dd, J = 7.7 Hz, 1.5 Hz), 7.73-7.82








(2H, m), 13.32 (2H, s)


128
R2
3-F-4-Me-Ph
H
H
H
FN: 469


129
R2
3,5-diMe-Ph
H
H
H
Not Isolated


130
R2
3,4-diMe-Ph
H
H
H
FA: 467


131
R2
3,4-diMe-Ph
H
H
2-Me
FA: 481


132
R2
2,3-diMe-Ph
H
H
H
Not Isolated


133
R2
3-F-4-OMe-Ph
H
H
H
FA: 487


134
R2
2-OMe-5-F-Ph
H
H
H
ES+: 487


135
R2
2-OMe-5-Cl-Ph
H
H
H
FA: 503


136
R2
3-Cl-4-OMe-Ph
H
H
H
FA: 503


137
R2
2-Me-3-Cl-Ph
H
H
H
FA: 487


138
R2
3,4,5-triF-Ph
H
H
H
FA: 491


139
R2
3,4,5-triF-Ph
H
H
2-Me
Not Isolated


140
R2
3,4,5-triF-Ph
H
H
4-Me
Not Isolated


141
R2
2-Ph-Ph
H
H
H
Not Isolated


142
R2
3-Ph-Ph
H
H
H
ES+: 515


 


143
R2




H
H
H
Not Isolated


 


144
R2




H
H
H
ES+: 507


 


145
R2
2Naph
H
H
H
Not Isolated


146
R2
2Naph
H
H
2-Me
FA: 503


147
R2
1Naph
H
H
H
Not Isolated


148
R2
1Naph
H
H
2-Me
FA: 503


149
R2
1Naph
H
H
4-Me
Not Isolated


150
R2
4-F-1Naph
H
H
H
ES+: 507






















TABLE 7







151
R2




H
H
H
ES+: 481


 


152
R2




H
H
H
Not Isolated


 


153
R2
6-Cl-3Py
H
H
H
Not Isolated


154
R2
6-Cl-3Py
H
H
2-Me
Not Isolated


155
R2
6-Cl-3Py
H
H
4-Me
Not Isolated


156
R2
5,6-diCl-3Py
H
H
H
Not Isolated


157
R2
2-Cl-4Py
H
H
H
ES+: 474


158
R2
Pyra
H
H
H
Not Isolated


159
R2
2Thi
H
H
H
ES+: 445


160
R2
3Thi
H
H
H
Not Isolated


161
R2
3,5-diF-Ph
Me
Me
H
Not Isolated


162
R2
3,5-diF-Ph
F
F
H
Not Isolated


163
R2
3,5-diF-Ph
F
H
H
FA: 493


164
R2
3,5-diF-Ph
Cl
H
H
Not Isolated


165
R2
3,5-diF-Ph
Me
H
H
Not Isolated


166
R2
3,5-diF-Ph
O2N
H
H
ES+: 520


167
R2
3,5-diOMe-Ph
H
H
H
FA: 499



















TABLE 8





REx
Syn
Str
Dat


















3
R3




ES+: 160


 


4
R4




Not Isolated Sal: HCl


 


5
R5




ES+: 177 Sal: HCl


 


6
R6




ES+: 140


 


7
R7




FA: 242 Sal: HCl


 


8
R8




EI: 324


 


9
R9




FN: 233


 


168
R9




FN: 253


 


169
R7




FA: 261 Sal: HCl


 


170
9




Not Isolated


 


171
R5




FA: 115 Sal: HCl


 


172
R5




FA: 101 Sal: HCl


 


181
R5




FA: 103 Sal: HCl


 


182
R4




FA: 132 Sal: HCl


 


183
R5




FA: 119 Sal: HCl


 


184
R4




FA: 148 Sal: HCl


 


185
R5




FA: 117 Sal: HCl


 


186
R4




FA: 146 Sal: HCl


 


187
R5




FA: 117 Sal: HCl


 


188
R4




FA: 146 Sal: HCl


 


189
R5




FA: 115 Sal: HCl


 


190
R4




FA: 144 Sal: HCl


 


191
R5




FA: 103 Sal: HCl


 


192
R4




FA: 132 Sal: HCl























TABLE 9







173
R4




FA: 130 Sal: HCl
193
R5




FA: 157 Sal: HCl


 


174
R5




FA: 115 Sal: HCl
194
R4




FA: 186 Sal: HCl


 


175
R4




FA: 144 Sal: HCl
195
R5




FA: 139 Sal: HCl


 


176
R5




FA: 129 Sal: HCl
196
R4




FA: 168 Sal: HCl


 


177
R4




FA: 158 Sal: HCl
197
R5




FA: 143 Sal: HCl


 


178
R5




FA: 143 Sal: HCl
198
R4




ES−: 171 Sal: HCl


 










179
R4




N1: 1.35 (3H, t, J = 7.0 Hz), 1.76-2.39 (4H, m), 3.75-4.07 (2H, m), 4.42-4.60 (2H, m), 4.75 (1H, dd, J =8.8 Hz, 5.0 Hz), 11.42 (1H, br) Sal: HCl


 


180
R8




N1: 5.35 (2H, s), 7.32-7.68 (7H, m), 7.99-8.10 (1H, m)



















TABLE 10





REx
Syn
Str
Dat







199
R1




ES+: 301


 


200
R1




ES+: 291


 


201
R1




FA: 291


 


202
R1




ES+: 307


 


203
R1




ES+: 287


 


204
R1




FA: 359


 


205
R1




ES+: 359


 


206
R2




ES+: 475
















TABLE 11













 










REx
Syn
A
Dat













212
R1
3-Cl-4,5-diF-Ph
ES+: 307


213
R1
3-F-5-Me-Ph
ES+: 269


214
R1
6-Cl-3Py
ES+: 272


215
R1
2,4,5-triF-Ph
FA: 291


216
R1
2,3,4-triF-Ph
ES+: 291


217
R1
5,6-diCl-3Py
ES+: 306


218
R1
2-Cl-6-Me-4Py
FA: 286


219
R1
2,5-diF-4-Cl-Ph
ES+: 307


220
R1
2,4-diCl-5-F-Ph
ES+: 323


221
R1
2-Cl-6-OMe-4Py
FA: 302


222
R1
2,5-diCl-4Py
FA: 306


223
R1
2,4-diF-3-Cl-Ph
ES+: 307


224
R1
6-Cl-2Py
FA: 272


225
R1
3-Cl-4-Me-Ph
ES−: 283


226
R1
6-CN-3Py
N1: 6.07 (1H, s), 7.20 (2H, m), 7.48





(2H, m), 8.10 (1H, d, J = 8 Hz), 8.40





(1H, d, J = 8, 2 Hz), 9.17 (1H, s)


227
R1
3-F-4-Me-Ph
ES+: 269


228
R1
2,6-diCl-5-F-3Py
ES+: 324


229
R1
2-F-5-Cl-Ph
ES+: 289


230
R1
2-Me-3-Cl-Ph
ES+: 285


231
R1
2-Cl-3-F-4Py
FA: 290


232
R1
2-Cl-3-Me-4Py
FA: 286


233
R1
2,5-diF-Ph
FA: 273


234
R1
2-Cl-4,5-diF-Ph
FA: 307


235
R1
5-Cl-2Thi
ES+: 277


236
R1
2-F-3-Cl-Ph
ES+: 289
















TABLE 12













 













REx
Syn
A
R1a
R1b
R2
Dat
















237
R2
2-F-5-Cl-Ph
H
H
H
ES+: 493


238
R2
3-Cl-4,5-diF-Ph
H
H
H
ES+: 509


239
R2
3-Cl-4-Me-Ph
H
H
H
Not Isolated


240
R2
3-F-5-Me-Ph
H
H
H
ES+: 471


241
R2
5,6-diCl-3Py
H
H
H
Not Isolated


242
R2
3-F-Ph
H
H
4-iPr
Not Isolated


243
R2
2-Me-5-Cl-Ph
H
H
H
ES+: 487


244
R2
3-F-Ph
H
H
H
ES+: 457


245
R2
6-Cl-3Py
H
H
H
ES+: 474


246
R2
6-Cl-3Py
H
H
4-F
ES+: 492


247
R2
2,4,5-triF-Ph
H
H
H
FA: 493


248
R2
2,3,4-triF-Ph
H
H
H
ES+: 493


249
R2
2-Cl-6-Me-4Py
H
H
H
ES+: 488


250
R2
3-F-Ph
H
H
4-F
ES+: 475


251
R2
2,5-diF-4-Cl-Ph
H
H
H
ES+: 509


252
R2
2,4-diCl-5-F-Ph
H
H
H
ES−: 525


253
R2
Ph
H
H
4-F
ES+: 457


254
R2
3-Me-Ph
H
H
4-F
ES+: 471


255
R2
2-Cl-6-OMe-4Py
H
H
H
ES+: 504


256
R2
3,5-diF-Ph
H
H
4-F
ES+: 493


257
R2
2,5-diCl-4Py
H
H
4-F
FA: 528


258
R2
2,4-diF-3-Cl-Ph
H
H
H
ES+: 509


259
R2
2,5-diCl-4Py
H
H
H
FA: 507


260
R2
6-Cl-2Py
H
H
4-F
FA: 492


261
R2
2,4-diCl-5-F-Ph
H
H
4-F
FN: 541


262
R2
3-Cl-4-Me-Ph
H
H
4-F
ES+: 505


263
R2
4-Cl-Ph
H
H
4-F
FA: 491






















TABLE 13







264
R2
6-CN-3Py
H
H
H
ES−: 463


265
R2
3,4-diMe-Ph
H
H
4-F
FA: 485


266
R2
2,4,5-triF-Ph
H
H
4-F
ES+: 511


267
R2
2,4-diCl-5-F-3Py
H
H
H
ES+: 528


268
R2
3-F-4-Me-Ph
H
H
4-F
ES+: 489


269
R2
3,4,5-triF-Ph
H
H
4-F
ES+: 511


270
R2
2-F-5-Cl-Ph
H
H
4-F
ES+: 509


271
R2
2-Me-5-F-Ph
H
H
4-F
ES+: 489


272
R2
2-Me-3-F-Ph
H
H
4-F
ES+: 489


273
R2
2-Me-3-Cl-Ph
H
H
4-F
ES+: 505


274
R2
2-Cl-5-F-Ph
H
H
4-F
FN: 507


275
R2
3-F-5-Me-Ph
H
H
4-F
FA: 489


276
R2
2-Cl-6-OMe-4Py
H
H
4-F
ES+: 522


277
R2
2-Cl-4,5-diF-Ph
H
H
4-F
Not Isolated


278
R2
3-Cl-Ph
H
H
4-F
FA: 491


279
R2
2-Cl-3-F-4Py
H
H
H
Not Isolated


280
R2
2-Cl-3-Me-4Py
H
H
4-F
FA: 506


281
R2
2,5-diF-4-Cl-Ph
H
H
4-F
ES+: 527


282
R2
2,5-diF-Ph
H
H
4-F
ES+: 493


283
R2
3-F-4-Me-Ph
H
H
H
ES+: 471


284
R2
2,5-diF-Ph
H
H
H
ES+: 475


285
R2
3-F-Ph
H
H
6-F
Not Isolated


286
R2
3-F-Ph
H
H
5-F
ES+: 475


287
R2
3-Cl-4,5-diF-Ph
H
H
4-F
ES+: 527


288
R2
3,4,5-triF-Ph
H
H
H
ES+: 493


289
R2
5-Cl-2Thi
H
H
H
ES+: 481


290
R2
5-Cl-2Thi
H
H
4-F
FA: 497


291
R2
2,6-diCl-4Py
H
H
H
Not Isolated


292
R2
3-F-Ph
CO2Bn
H
H
FA: 591


293
R2
3-CO2Me-Ph
H
H
H
ES+: 497


294
R2
3-F-4-Me-Ph
H
H
2-Me
ES+: 485


295
R2
3-F-Ph
H
H
4-OMe
FA: 487


296
R2
3-F-Ph
H
H
2-OMe
FA: 487


297
R2
2-F-3-Cl-Ph
H
H
H
Not Isolated
















TABLE 14













 












REx
Syn
A
R2
R3
Dat















207
R207
3-F-Ph
H




FA: 407


 


298
R207
2Py
H




FA: 390


 


299
R207




H




FA: 424


 


300
R207




H




FA: 392


 


301
R207




H




FA: 392


 


302
R207
3-Thi
H




FA: 395


 


303
R207
2-Thi
H




FA: 395


 


304
R207
5-Me-2Thi
H




FA: 409


 


305
R207
5-Me-2Fur
H




FA: 393





















TABLE 15







306
R207




H




ES+: 447


 


307
R207
4-Me-2Thi
H




FA: 409


 


308
R207




H




ES+: 432


 


309
R207




F




ES+: 465


 


310
R207




F




ES+: 451


 


311
R207
3-Me-2Thi
H




FA: 409


 


312
R207




H




FA: 518


 


313
R207
2,6-diF-3-Me-Ph
H




ES+: 439
















TABLE 16













 












REx
Syn
A
R2
R3
Dat















314
R208
2Py
H




FA: 494


 


315
R208




H




FA: 528


 


316
R208




H




FA: 496


 


317
R208




H




FA: 496


 


208
R208
3-F-Ph
H




FA: 511


 


318
R208
3-Thi
H




FA: 499


 


319
R208
2-Thi
H




FA: 499


 


320
R208
5-Me-2Thi
H




FA: 513


 


321
R208
5-Me-2Fur
H




FA: 497


 


322
R208




H




ES+: 551





















TABLE 17







323
R208
4-Me-2Thi
H




FA: 513


 


324
R208




H




ES+: 537


 


325
R208




F




ES+: 569


 


326
R208




F




ES+: 555


 


327
R208
3-Me-2Thi
H




FA: 513


 


328
R208




H




FA: 622


 


329
R208
2,6-diF-3-Me-Ph
H




ES+: 543
















TABLE 18







(1)












REx
Syn
Str
Dat







330





Not Isolated



 



331





Not Isolated



 



210
R210




Not Isolated



 



332





Not Isolated



 



333





Not Isolated



 



209
R209




Not Isolated



 



211
R211




EI: 242











(2)










REx
Syn
Str
Dat





334
R1 




FA: 389


 


335
R2 




ES+: 463


 


336
R2 




ES+: 487


 


337
R208




FA: 531
















TABLE 19













 


(1)










Ex
Syn
R3
Dat





20
3
—NH(CH2)3OH
FA: 496; N1: 1.47-1.59 (2H, m), 2.58-2.68 (2H, m), 3.34-





3.42 (2H, m), 4.44 (1H, t, J = 5.2 Hz), 6.88-6.98 (1H, m),





7.02-7.15 (3H, m), 7.24-7.36 (3H, m), 7.49-7.57 (3H, m),





7.66-7.79 (3H, m), 13.13 (2H, s)


21
3
(R)-NHCH2CH(Me)OH
FA: 496: n1: 1.02 (3H, d, J = 6.4 Hz), 2.41-2.59 (2H, m),





3.53-3.67 (1H, m), 4.70 (1H, br), 6.87-7.82 (13H, m),





13.13 (2H, s)


22
2
—NHCH2C(Me)2OH
FA: 510; N1: 1.06 (6H, s), 2.43-2.55 (2H, m), 4.41 (1H,





s), 6.87-7.17 (4H, m), 7.22-7.38 (3H, m), 7.44-7.60 (3H,





m), 7.67-7.81 (3H, m), 13.13 (2H, s)










(2)












Ex
Syn
R3
Dat







23
3
(S)-NHCH2CH(Me)OH
FA: 496



24
3
(R)-NHCH2CH(OH)CH2OH
FA: 512



25
3
(S)-NHCH2CH(OH)CH2OH
FA: 512



26
3
—NHCH(Me)CH2OH
FA: 496



27
1
—NH—C(═NH)—CH(OH)-Et
FA: 523



28
1
—NH—C(═NH)-Pyra
FA: 543



29
12
—NH—C(═NH)-Ac
FA: 507



30
2
—N(OMe)—C(═NH)—NH2
FA: 510



31
1
—NH—C(═NH)—CH(OH)-Me
FA: 509



32
3
—NHCH2C(Me)2CH2OH
FA: 524



 



33
4




FA: 600



 



34
4




FA: 5335



 



35
4




FA: 503



 



48
3
—NH2
FA: 438



49
5
—NHAc
FA: 480



50
5
—NHCOiPr
FA: 508



51
4
—NH-(5-Cl-2Py)
ES+: 549



52
4
—NH-(5-Me-2Py)
FA: 529



53
4
—NH-(4-Me-2Py)
FA: 529



54
4
—NHNH-(2-Py)
FA: 530



55
4
—NH-(6-Cl-2Py)
FA: 549



56
4
—NH-(4-Et-2Py)
FA: 543



57
3
—NH(CH2)2OH
FA: 482



58
4
—NH-(2Py)
ES+: 515



 



59
1




FA: 509



 



60
4




FA: 489






















TABLE 20









36
4




FA: 490



 



37
4
—NH-(5-CF3-2Py)
FA: 583



38
4
—NH-(4,6-diMe-2Py)
FA: 543



39
4
—H-(3-CH2OH-2Py)
ES+: 545



40
2
—N(OBn)—C(═NH)—NH2
FA: 586



 



41
4




FA: 565



 



42
4




FA: 535



 



43
4




FA: 516



 



44
4




FA: 550



 



45
4




FA: 603



 



46
4




FA: 503



 



47
4




FA: 490



 



61
4




FA: 517



 



62
4
—NMe-(2-Py)
FA: 529



63
4
—O-(2-NH2-3Py)
FA: 531



64
4
—NH-Pyra
FA: 516



65
4
—N(Me)-NH2
FA: 467



 



66
4




FA: 550



 



67
1




ES+: 543



 



68
4




ES+: 523



 



69
4




FA: 537



 



70
4




FA: 522



 



71
4




FA: 557

















TABLE 21













 


(1)










Ex
Syn
R3
Dat













4
4
—NH-(2Py)
FA: 533; N1: 6.74-6.95 (4H, m), 7.00-7.20 (1H, m),





7.25-7.37 (3H, m), 7.45-7.57 (1H, m), 7.62-8.07 (6H,





m), 13.12 (2H, s)


5
5
—NHAc
FA: 498; N1: 1.92 (3H, s), 6.85-7.04 (3H, m), 7.28-





7.47 (3H, m), 7.62-7.82 (5H, m), 12.06 (1H, br),





13.16 (2H, s)


12
12
—H—C(═NH)-Ac
FA: 525; N1: 2.35 (3H, s), 6.82-6.94 (3H, m), 7.26-





7.40 (3H, m), 7.52-7.62 (1H, m), 7.70-7.81 (4H, m),





8.30 (1H, br), 8.77 (1H, br), 13.16 (2H, s)


15
15




FA: 525; N1: 2.32 (3H, s), 3.00 (3H, s), 3.11 (3H, s), 6.86-7.02 (3H, m), 7.25-7.36 (3H, m), 7.46-7.52 (1H, m), 7.56-7.62 (1H, m), 7.66-7.80 (3H, m), 13.12 (2H, br)


 


72
3




FA: 526; N1: 2.77 (4H, t, J = 4.4 Hz), 3.62 (4H, t, J = 4.4 Hz), 6.92-7.02 (3H, m), 7.30-7.38 (2H, m), 7.40- 7.48 (1H, m), 7.53-7.82 (5H, m), 13.17 (2H, s)


 


73
1
—NH—C(═NH)-Me
FA: 497; N1: 2.02 (3H, s), 6.84-7.00 (3H, m), 7.25-





7.37 (3H, m), 7.49-7.80 (5H, m), 8.07 (1H, br), 8.50





(1H, br), 13.13 (2H, s)


 


74
2




FA: 540; N1: 2.05 (3H, s), 6.84-6.97 (3H, m), 7.26- 7.40 (3H, m), 7.53-7.80 (5H, m), 7.98 (1H, s), 8.97 (1H, s), 11.07 (1H, s), 13.13 (2H, s)


 


75
1
—NH—C(═NH)-2Py
FA: 560; N1: 6.73-6.90 (3H, m), 7.25-7.40 (3H, m),





7.52-7.60 (1H, m), 7.64-7.85 (5H, m), 7.95-8.05 (1H,





m), 8.07-8.15 (1H, m), 8.34 (1H, br), 8.72 (1H, d,





J = 3.7 Hz), 9.03 (1H, br), 13.14 (2H, s)


76
1
—NH—C(═NH)-OMe
FA: 513; N1: 3.66 (3H, s), 6.79-7.00 (3H, m), 7.21-





7.40 (4H, m), 7.47-7.58 (1H, m), 7.62-7.82 (4H, m),





8.28 (1H, br), 13.15 (2H, s)


77
3
—NH(CH2)2OH
FA: 500; N1: 2.65 (2H, d, J = 12.2 Hz, 5.9 Hz), 3.28-





3.42 (2H, m), 4.69 (1H, br), 6.90-7.00 (3H, m), 7.28-





7.36 (2H, m), 7.38 (1H, t, J = 7.8 Hz), 7.54-7.80





(6H, m), 13.15 (2H, s)


 


78
3




FA: 530; N1: 2.65-2.83 (1H, m), 3.18-3.58 (4H, m), 4.67 (2H, br), 6.82-7.02 (3H, m), 7.21-7.43 (3H, m), 7.45-7.83 (6H, m), 13.15 (2H, s)



















TABLE 22







79
1
—N═C(NH2)—NH-Me
FA: 512, N1: 2.64 (3H, d, J = 4.4 Hz), 6.63 (2H, br),





6.82-6.96 (3H, m), 7.02 (1H, br), 7.22-7.37 (3H, m),





7.42-7.50 (1H, m), 7.52-7.60 (1H, m), 7.64 (1H, br),





7.71-7.79 (2H, m), 13.11 (2H, s)


80
1
—NH—C(═NH)-cBu
FA: 537; N1: 1.64-1.77 (1H, m), 1.78-1.92 (1H, m),





1.98-2.18 (4H, m), 3.10-3.20 (1H, m), 6.84-6.96 (3H,





m), 7.26-7.36 (3H, m), 7.49-7.56 (1H, m), 7.62-7.80





(4H, m), 7.83 (1H, br), 8.45 (1H, br), 13.13 (2H, s)


81
1
—H—C(═NH)—CH2SMe
FA: 543; N1: 2.04 (3H, s), 3.18 (2H, s), 6.82-7.02





(3H, m), 7.25-7.42 (3H, m), 7.48-7.84 (5H, m), 8.03





(1H, br), 8.64 (1H, br), 13.14 (2H, s)


82
1
—NH—C(═NH)—C(Me)2OH
FA: 541; N1: 1.25 (6H, s), 5.77 (1H, s), 6.84-6.98





(3H, m), 7.24-7.38 (3H, m), 7.47-7.64 (2H, m), 7.67-





7.82 (3H, m), 8.02 (1H, br), 8.10 (1H, br), 13.14





(2H, s)


83
1
—NH—C(═NH)—CH(cPr)OH
FA: 553; N1: 0.21-0.41 (4H, m), 0.95-1.09 (1H,





m), 3.69 (1H, t, J = 5.4 Hz), 5.79 (1H, d, J = 5.4 Hz),





6.84-6.98 (3H, m), 7.26-7.38 (3H, m), 7.50-7.58 (1H,





m), 7.60-7.67 (1H, m), 7.69-7.80 (3H, m), 8.01 (1H,





br), 8.17 (1H, br), 13.14 (2H, s)


 


84
1




FA: 553; N1: 1.64-1.85 (2H, m), 1.98-2.12 (2H, m), 2.25-2.38 (2H, m), 6.32 (1H, s), 6.85-6.96 (3H, m), 7.27-7.38 (3H, m), 7.50-7.57 (1H, m), 7.62-7.68 (1H, m), 7.70-7.80 (3H, m), 7.94 (1H, br), 8.01 (1H, br), 13.13 (2H, s)


 


85
1
—NH—C(═NH)—CH2OH
FA: 513; N1: 4.06 (2H, d, J = 5.9 Hz), 5.86 (1H, t,





J = 5.9 Hz), 6.86-6.99 (3H, m), 7.28-7.38 (3H, m),





7.50- 7.80 (5H, m), 8.18 (1H, br), 8.33 (1H, br),





13.14 (2H, s)


86
1
—NH—C(═NH)—CH(Me)OH
FA: 527; N1: 1.21 (3H, d, J = 6.6 Hz), 4.07-4.17 (1H,





m), 5.85 (1H, d, J = 4.9 Hz), 6.83-6.98 (3H, m),





7.26-7.38 (3H, m), 7.48-7.82 (5H, m), 8.06 (1H, br),





8.16 (1H, br), 13.14 (2H, s)


87
3
—NH(CH2)3OH
FA: 514; N1: 1.46-1.58 (2H, m), 2.58-2.70 (2H, m),





3.26-3.46 (2H, m), 4.43 (1H, br), 6.89-7.02 (3H, m),





7.27-7.42 (3H, m), 7.53-7.82 (6H, m), 13.15 (2H, s)


88
3
—NHCH2CH(Me)OH
FA: 5114; N1: 1.00 (3H, d, J = 6.4 Hz), 2.40-2.61





(2H, m), 3.50-3.68 (1H, m), 4.67 (1H, br), 6.85-





7.02 (3H, m), 7.25-7.43 (3H, m), 7.47-7.83 (6H, m),





13.15 (2H, s)


89
1
—N═C(NH2)2
FA: 498; N1: 6.70 (4H, br), 6.82-6.98 (3H, m), 7.23-





7.38 (3H, m), 7.43-7.88 (5H, m), 13.11 (2H, s)


90
1
—H—C(═NH)—CH2OMe
ES+: 527; N1: 3.32 (3H, s), 4.06 (2H, s), 6.85-6.99





(3H, m), 7.26-7.39 (3H, m), 7.49-7.82 (5H, m), 8.31





(1H, br), 8.35 (1H, br), 13.14 (2H, s)


91
1
—NH—C(═NH)-(2THF)
FA: 553; N1: 1.68-1.88 (3H, m), 2.12-2.28 (1H, m),





3.70-3.82 (1H, m), 3.86-3.97 (1H, m), 4.31-4.42 (1H,





m), 6.83-6.98 (3H, m), 7.26-7.37 (3H, m), 7.48-7.80





(5H, m), 8.12 (1H, br), 8.28 (1H, br), 13.14 (2H, s)



















TABLE 23







92
4




FA: 539; N1: 6.77-6.93 (4H, m), 7.22-7.38 (4H, m), 7.45-7.85 (5H, m), 12.78 (1H, br), 13.11 (2H, s)


 


93
3
—NHMe
FA: 470; N1: 2.31 (3H, d, J = 4.4 Hz), 6.91-7.03 (3H, m),





7.27-7.45 (3H, m), 7.46-7.82 (6H, m), 13.15 (2H, s)


94
1
—NH—C(═NH)—CH2CONH2
FA: 540; N1: 3.15 (2H, s), 6.82-6.97 (3H, m), 7.10 (1H,





br), 7.26-7.37 (3H, m), 7.41-7.82 (6H, m), 8.10 (1H,





br), 8.66 (1H, br), 13.14 (2H, s)


 


95
1




FA: 527; N1: N1: 1.20 (3H, d, J = 6.9 Hz), 4.06-4.17 (1H, m), 5.85 (1H, d, J = 4.9 Hz), 6.86-6.98 (3H, m), 7.27-7.37 (3H, m), 7.50-7.57 (1H, m), 7.59-7.65 (1H, m), 7.67-7.80 (3H, m)(, 8.06 (1H, br), 8.16 (1H, br), 13.14 (2H, s)


 


96
16




FA: 569; N1: 1.31 (3H, d, J = 7.2 Hz), 2.00 (3H, s), 4.94- 5.05 (1H, m), 6.83-6.97 (3H, m), 7.26-7.38 (3H, m), 7.50-7.64 (2H, m), 7.65-7.81 (3H, m), 8.09 (1H, br), 8.68 (1H, br), 13.14 (2H, s)


 


97
10
—NH—C(═NNH2)—H2
FA: 513; N1: 4.46 (2H, br), 6.81-7.05 (5H, m), 7.22-





7.37 (3H, m), 7.41-7.58 (2H, m), 7.60-7.67 (1H, m),





7.69-7.81 (2H, m), 8.43 (1H, br), 13.11 (2H, s)










(2)












Ex
Syn
R3
Dat







98
3




FA: 539 Sal: HCl



 



99
3




FA: 525



 



100
2




FA: 513



 



101
4




FA: 523



 



102
4




FA: 538



 



120
1




FA: 539



 



121
1




FA: 567



 



122
1




FA: 581



 



123
1




FA: 557



 



124
1




FA: 555






















TABLE 24









103
4




FA: 524



 



104
4




FA: 522



 



105
4




ES+: 525



 



106
4




FA: 552



 



107
3




FA: 568



 



108
3




FA: 554



 



109
3




FA: 507



 



110
3




FA: 521



 



111
3




FA: 523



 



112
4




FA: 523



 



113
3




FA: 557



 



125
1




FA: 541



 



126
1




FA: 595



 



127
12




FN: 591



 



128
1




FA: 577



 



129
1




FA: 527



 



130
13




FA: 554



 



131
17




FA: 526



 



132
2




FA: 581



 



133
13




FA: 542



 



134
13




FA: 556



 



135
1




FA: 615




















TABLE 25







114
3




FA: 567


 


115
1




FA: 537


 


116
1




FA: 537


 


117
1




FA: 524


 


118
1




FN: 536


 


119
2




ES+: 577


 


140
1




FA: 572


 


136
1




FA: 568


 


137
2




FA: 548


 


11
11




FA: 567


 


138
2




FA: 526


 


139
1




FA: 538


 


10
10




ES+: 701










(3)












Ex
Syn
R3
Dat







141
1
—NH—C(═NH)-(3Fur)
FA: 549



142
1
—NH—C(═NH)—CH(iPr)OH
FA: 555



143
1
—NH—C(═NH)—CONH2
FA: 526



144
3
—NH—C(═NH)-(2Fur)
FA: 549



145
1
—NH—C(═NH)—CH(Pr)OH
FA: 555



146
3
(S)-NHCH2CH(Me)OH
FA: 514



147
3
(R)-NHCH2CH(OH)CH2OH
FA: 530



148
3
(R)-NHCH2CH(Me)OH
FA: 514



149
3
(S)-NHCH2CH(OH)CH2OH
FA: 530



150
1
—NH—C(═NH)—CH(Ph)OH
FA: 589



1
1
—NH—CH═NH
FA: 483



2
2
—NHCH2CO2Et
FA: 542



3
3
—NHCH2CN
FA: 495



6
6
—NHCONH-iPr
FA: 541



7
7
—NHCONH2
ES+: 499



8
8
—NHCH2CO2H
FA: 514



178
14
Me
FA: 455



179
1
—NH—C(═NH)-Ph
FA: 559



180
1
—NH—C(═NH)-iPr
FA: 525



181
1
—NH—C(═NH)-cPr
FA: 523
























TABLE 26







151
1
—NH—C(═NH)—CH2CO2Et
FA: 569
182
1
—NH—C(═NH)-tBu
FA: 539


152
1
—NH—C(═NH)—CH2NH2
FA: 512
183
1
—NH—C(═NH)-Et
FA: 511


153
3
—NH(CH2)2O(CH2)2OH
FA: 544
184
3
—NH2
FA: 456


154
2
—NHCH(CO2Me)CH2OH
FA: 558
185
1
—NH—C(═NH)—Pr
FA: 525


155
6
—NHCH(CO2H)CH2OH
FA: 544
186
4
—NH-(4Py)
FA: 533


156
1
—NH—C(═NH)—CH2CH2OMe
FA: 541
187
4
—NH-(3-Me-2Py)
FA: 547


157
1
—NH—C(═NH)—CH2SO2Me
FA: 575
188
11
—NH-(3-OH-2Py)
FA: 549


158
3
—NHCH2C(Me)2CH2OH
FA: 542
189
4
—NH-(6-Me-2Py)
FA: 547


159
3
—NHCH(Me)CH2OH
FA: 514
190
3
—OH
FA: 457


160
1
—NH—C(═NH)—CH2CH2OH
FA: 527
191
5
—NH—COiPr
FA: 526


161
1
—NH—C(═NH)-(4THP)
FA: 567
192
4
—NH-(3Py)
FA: 533


162
1
—NH—C(═NH)—NH(CH2)2OH
FA: 542
193
4
—NH-(3-OBn-2Py)
FA: 639


163
3
—NH—C(═NH)—CH2OPh
FA: 589
194
5
—NHCO2Et
FA: 528


164
1
—NH—C(═NH)—CH(Et)OH
FA: 541
195
3
—NH(CH2)2NH2
FA: 499


165
12
—NH—C(═NH)—CO-Et
FA: 539
196
3
—NH(CH2)4OH
FA: 528


166
12
—NH—C(═NH)—CO—Pr
FA: 553
197
3
—NH(CH2)2OMe
FA: 514


167
1
—N═C(NH2)—N(Me)2
FA: 526
198
3
—N[(CH2)2OH]2
FA: 544


168
1
—NH—C(═NH)—CO2Et
FA: 555
199
3
—NHCH(CH2OH)2
FA: 530


169
8
—NH—C(═NH)—CO2H
FN: 525
200
2
—NHCH2C(Me)2OH
FA: 528


9
9
—NH—C(═NH)—CON(Me)2
FA: 554
201
12
—NHC(═NH)—CHO
FN: 509


13
13
—NH—C(═NH)—CH2N(Me)2
FA: 540
202
3
—NHC(Me)2CH2OH
FA: 528


16
16
—NH—C(═NH)—CH2OAc
FA: 555
203
3
—NH—C(═NH)—CF3
ES+: 551


170
1
—NH—C(═NH)—CH2Cl
FA: 531
14
14
—N(Me)2
FA: 484


171
1
—NH—C(═NH)—NHCONH2
FA: 541
204
4
—NH(CH2)2OAc
FN: 540


172
1
—NH—C(═NH)-2Thi
FA: 565
205
1
—NH—C(═NH)-3Py
ES+: 560


173
3
—N(Me)-(CH2)2OH
FA: 514
206
15
—N═CH—N(Me)2
FA: 511


174
2
—NH—CH2-(3-OH-Ph)
FA: 562
207
2
—NHOMe
FA: 486


175
3
(S)—NH(CH2)2CH(CO2Me)OH
FA: 572
208
2
—NHOH
FA: 472


176
13
—NH—C(═NH)—CH(Me)-N3
FA: 552
209
1
—NH—C(═NH)-4Py
FA: 560


177
16
—NH—C(═NH)—CH(Me)-OTs
FA: 681
210
1
—NH—C(═NH)-Pyra
FA: 561
















TABLE 27













 


(1)










Ex
Syn
A
Dat





211
1
3-F-Ph
N1: 1.25 (6H, s), 5.78 (1H, s), 6.85-6.94





(1H, m), 6.99-7.12 (3H, m), 7.24 (1H, t,





J = 7.5 Hz), 7.27-7.35 (2H, m), 7.44-7.58





(2H, m), 7.68-7.78 (3H, m), 7.98 (1H, br), 8.13





(1H, br), 13.12 (2H, s)


212
1
3-Me-Ph
FA: 519; N1: 1.25 (6H, s), 2.12 (3H, s), 5.77





(1H, s), 6.82- 6.97 (2H, m), 7.00-7.23 (3H, m),





7.25-7.55 (4H, m), 7.66- 7.79 (3H, m), 7.97





(1H, br), 8.11 (1H, br), 13.12 (2H, s)


213
1
3-Cl-Ph
FA: 539; N1: 1.26 (6H, s), 5.77 (1H, s),





7.00-7.35 (7H, m), 7.43-7.60 (2H, m), 7.67-





7.79 (3H, m), 7.98 (1H, br), 8.14 (1H, br),





13.12 (2H, s)










(2)












Ex
Syn
A
Dat







214
1
2-Me-3-F-Ph
FA: 537



215
1
Ph
FA: 505



216
1
1Naph
ES+: 555



217
1
2-Cl-Ph
ES+: 539



218
1
3-F-4-Ome-Ph
FA: 553



 



219
1




FA: 573



 



220
1
4-F-1Naph
FA: 573



221
1
2-Cl-5-F-Ph
FA: 557



 



222
1




FA: 573



 



223
1
3,5-diOMe-Ph
FA: 565



224
1
4-F-Ph
FA: 523



225
1
5,6-diCl-3Py
FA: 574



226
1
3-Cl-2-Me-Ph
FA: 553



227
1
5-Cl-2-OMe-Ph
FA: 569



228
1
4-Cl-Ph
FA: 539



229
1
4-Me-Ph
FA: 519



230
1
3,4,5-triF-Ph
FA: 559



231
1
2,5-diF-Ph
FA: 541



232
1
2-Cl-4,5-diF-Ph
FA: 575



233
1
6-Cl-3Py
FA: 540



234
1
2-F-Ph
FA: 523



235
1
2-Me-Ph
FA: 519



 



236
2




FA: 545



 



237
1
3-Cl-4Py
FA: 540



238
1
3-F-4-me-Ph
FA: 537



239
1
5-F-2-OMe-Ph
FN: 551



240
1
3-Cl-4-OMe-Ph
FA: 569


















TABLE 28








(1)








 










Ex
Syn
A
Dat





241
1
3,4-diMe-Ph
FA: 489; N1: 1.99 (3H, s), 2.01 (3H, s), 2.02 (3H, s), 6.76-





6.83 (1H, m), 6.99-7.06 (2H, m), 7.18





(1H, t, J = 7.8 Hz), 7.26-7.33





(2H, m), 7.37-7.43 (1H, m),





7.46-7.52 (1H, m),





7.62-7.67 (1H, m), 7.69-7.76 (2H, m), 8.09 (1H, br), 8.47





(1H, br), 13.08 (2H, s)


242
1
6-Cl-3Py
ES+: 496; N1: 2.04 (3H, s), 7.13 (1H, d, J = 8.3 Hz), 7.25-7.38





(3H, m), 7.49-7.81 (6H, m), 8.15 (1H, br), 8.22 (1H, d,





J = 2.2 Hz), 8.56 (1H, br), 13.20 (2H, s)


243
1
3-Br-Ph
FA: 541; N1: 2.02 (3H, s), 6.99 (1H, t, J = 7.8 Hz), 7.22-7.43





(6H, m), 7.45-7.51 (1H, m), 7.53-7.60 (1H, m), 7.63-7.68





(1H, m), 7.72-7.79 (2H, m), 8.09 (1H, br), 8.49 (1H, br),





13.11 (2H, s)


244
1
3-CF3-Ph
FA: 529; N1: 2.01 (3H, s), 7.16-7.36 (4H, m), 7.38-7.60 (5H,





m), 7.62-7.66 (1H, m), 7.70-7.80 (2H, m), 8.08 (1H, br),





8.49 (1H, br), 13.15 (2H, s)


245
1
3-F-Ph
FA: 479; N1: 2.01 (3H, s), 6.87-6.98 (1H, m), 6.99-7.15 (3H,





m), 7.21-7.34 (3H, m), 7.45-7.58 (2H, m), 7.64-7.81 (3H,





m), 8.09 (1H, br), 8.50 (1H, br), 13.11 (2H, s)


246
1
3,4,5-triF-Ph
FA: 515; N1: 2.02 (3H, s), 7.06-7.20 (2H, m), 7.27-7.38 (3H,





m), 7.48-7.67 (3H, m), 7.72-7.81 (2H, m), 8.08 (1H, br),





8.52 (1H, br), 13.16 (2H, s)










(2)












Ex
Syn
A
Dat







19
19
4Py
ES+: 462



247
1
4-F-1-Naph
FA: 529



248
1
2,3-diMe-Ph
FA: 489



249
1
2-CF3-Ph
FA: 529



250
1
4-CF3-Ph
FA: 529



251
1
3,4-diCl-Ph
ES+: 529



252
1
3,5-diCl-Ph
FA: 529



253
1
3,4-diF-Ph
FA: 497



254
1
2,3-diF-Ph
FA: 497



255
1
2,5-diF-Ph
FA: 497



273
1
2Thi
FA: 467



274
1
3Thi
FA: 467



275
1
Ph
FA: 461



276
1
3-OMe-Ph
FA: 491



277
1
4-F-Ph
FA: 479



278
1
3-OH-Ph
FA: 477



279
1
3-SO2NHCMeNH-Ph
FA: 581



280
1
3-CN-Ph
FA: 486



281
1
2-OPh-Ph
FA: 553



282
1
3-OiPr-Ph
FA: 519






















TABLE 29









256
1
2,3-diCl-Ph
FA: 529



257
1
2,5-diCl-Ph
FA: 529



258
1
2-Cl-Ph
ES+: 495



259
1
3-Cl-Ph
FA: 495



260
1
2-F-Ph
ES+: 479



261
1
3-Me-Ph
ES+: 475



262
1
2-OMe-Ph
ES+: 491



263
1
2-Cl-4Py
ES+: 496



264
11
3Py
ES+: 462



 



265
1




FA: 529



 



266
1




FA: 503



 



267
1
2-Cl-4,5-diF-Ph
FA: 531



268
1
3-F-4-Me-Ph
FA: 493



269
1
5-Cl-2-OMe-Ph
FA: 525



270
1
3-Cl-5-F-Ph
FA: 513



271
1
5-Cl-2-Me-Ph
FA: 509



272
1
3-SMe-Ph
FA: 507



531
1
2-Me-Ph
FA: 475



283
1
3-OPr-Ph
FA: 519



284
1
3-OEt-Ph
FA: 505



285
1
2-Me-5-F-Ph
FA: 493



286
1
2Naph
FA: 511



287
1
2-Me-3-F-Ph
FA: 493



288
1
3,5-diMe-Ph
FA: 489



289
1
2-Ph-Ph
FA: 537



290
1
3-Ph-Ph
FA: 537



291
1
Pyra
FN: 461



 



292
1




FA: 529



 



293
2




FA: 501



 



294
1
3-F-4-OMe-Ph
FA: 509



295
1
2-Cl-3-F-Ph
FA: 513



296
1
3-Cl-4-OMe-Ph
FA: 525



297
1
5-F-2-OMe-Ph
FA: 509



298
1
3,5-diOMe-Ph
FA: 521



299
1
3-Ac-Ph
FA: 503



322
1
5,6-diCl-3Py
FA: 530


















TABLE 30








(1)








 










Ex
Syn
A
Dat





300
1
1Naph
FA: 541; N1: 1.20 (3H, d, J = 6.4 Hz), 4.04-





4.16 (1H, m), 5.87





(1H, d, J = 5.2 Hz), 6.53-6.65(1H, m), 7.05-





7.60 (10H, m),





7.64-7.71 (1H, m), 7.73-7.83 (2H, m), 7.94 (1H, br), 8.10-





8.22 (2H, m), 13.26 (2H, s)


301
1
3-Me-Ph
ES+: 505; N1: 1.21 (3H, d, J = 6.8 Hz), 2.11 (3H, s), 4.05-4.18





(1H, m), 5.85 (1H, d, J = 4.8 Hz), 6.81-6.97 (2H, m), 7.00-7.56





(7H, m), 7.66-7.79 (3H, m), 8.02 (1H, br), 8.17





(1H, br), 13.12 (2H, s)


302
1
3-F-Ph
ES+: 509; N1: 1.21 (3H, d, J = 6.6 Hz), 4.06-





4.17 (1H, m),





5.86 (1H, d, J = 5.3 Hz), 6.84-6.96 (1H, m), 6.99-7.12 (3H, m),





7.20-7.37 (3H, m), 7.45-7.61 (2H, m), 7.68-





7.80 (3H, m),





8.03 (1H, br), 8.18 (1H, br), 13.12 (2H, s)


303
1
3-Cl-Ph
FA: 525; N1: 1.21 (3H, d, J = 6.0 Hz), 4.07-





4.18 (1H, m), 5.86





(1H, d, J = 4.8 Hz), 7.00-7.36 (7H, m), 7.42-





7.62 (2H, m),





7.67-7.80 (3H, m), 8.03 (1H, br), 8.19 (1H, br), 13.12 (2H, s)


304
1
3,4,5-triF-Ph
FA: 545; N1: 1.20 (3H, d, J = 6.4 Hz), 4.05-





4.17 (1H, m), 5.85





(1H, d, J = 4.4 Hz), 7.08-7.20 (2H, m), 7.28-





7.40 (3H, m),





7.51-7.59 (1H, m), 7.62-7.70 (2H, m), 7.72-





7.82 (2H, m),





8.09 (1H, br), 8.16 (1H, br), 13.17 (2H, s)


305
1
2,5-diF-Ph
FA: 527; N1: 1.23 (3H, d, J = 6.8 Hz), 4.07-





4.20 (1H, m), 5.87





(1H, d, J = 4.8 Hz), 6.67-6.79 (1H, m), 6.84-





7.08 (2H, m),





7.22-7.40 (3H, m), 7.46-7.66 (2H, m), 7.68-





7.72 (3H, m),





8.04 (1H, br), 8.20 (1H, br), 13.22 (2H, s)










(2)












Ex
Syn
A
Dat







306
1
Ph
FA: 491



307
1
2-Me-5-F-Ph
FA: 523



308
1
3,4-diMe-Ph
FA: 519



309
1
2Naph
ES+: 541



310
1
2-Cl-Ph
FA: 525



311
1
2,3-diF-Ph
FA: 527



312
1
4-F-Ph
FA: 509



313
1
3-Cl-4-OMe-Ph
FA: 555



314
1
5,6-diCl-3Py
FA: 560



317
1
3,5-diOMe-Ph
FA: 551



318
1
2-F-Ph
FA: 509



319
1
4-Me-Ph
FA: 505



320
1
4-Cl-Ph
ES+: 525



321
1
6-Cl-3Py
FA: 526



323
1
2-Me-Ph
FA: 505



324
1
3-Cl-4Py
FA: 526



325
1
2-Cl-4,5-diF-Ph
FA: 561



326
1
2-Cl-5-F-Ph
FA: 543






















TABLE 31









315
1
3-F-4-Me-Ph
FA: 523



316
1
5-F-2-OMe-Ph
FA: 539



327
1
5-Cl-2-OMe-Ph
FA: 555



328
1
3-Cl-2-Me-Ph
FA: 539


















TABLE 32








(1)








 











Ex
Syn
A
R3
Dat














329
1
3-F-Ph
—NH—C(═NH)-iPr
FA: 507; N1: 1.01






(6H, d, J =






7.3 Hz), 2.45-2.55






(1H, m), 6.85-6.95






(1H, m), 6.99-7.13






(3H, m), 7.20-7.33






(3H, m), 7.42-7.60






(2H, m), 7.70-7.80






(3H, m), 7.85 (1H,






br), 8.57 (1H, br),






13.12 (2H, s)


330
1
4-OMe-Ph
—NH—C(═NH)-Me
FA: 491; N1: 1.99






(3H, s), 3.63 (3H,






s), 6.52- 6.65






(2H, m), 7.18-7.37






(3H, m), 7.43-7.56






(2H, m), 7.64-7.77






(3H, m), 8.14 (1H,






br), 8.50 (1H, br),






13.06 (2H, s)


331
1
4-Cl-Ph
—NH—C—(═NH)-Me
FA: 495; N1: 2.01






(3H, s), 7.05-7.11






(2H, m), 7.20-7.35






(5H, m), 7.44-7.50






(1H, m), 7.53-7.59






(1H, m), 7.65-7.79






(3H, m), 8.15 (1H,






br), 8.54 (1H, br),






13.12 (2H, s)


332
1
3-Cl-4-F-Ph
—NH—C(═NH)-Me
FA: 513; N1: 2.02






(3H, s), 6.97-7.10






(1H, m), 7.20-7.43






(5H, m), 7.45-7.81






(5H, m), 8.10 (1H,






br), 8.51 (1H, br),






13.14 (2H, s)


333
1
4-Me-Ph
—NH—C(═NH)-Me
FA: 475; N1: 1.99






(3H, s), 2.12 (3H,






s), 6.85 (2H, d,






J = 8.3 Hz),






7.15-7.35 (5H, m),






7.43-7.55 (2H, m),






7.67-7.77 (3H, m),






8.15 (1H, br), 8.52






(1H, br), 13.09 (2H,






s)


334
3
2,5-diF-Ph
—NH(CH2)2OH
FA: 500; N1: 2.61-






2.74 (2H, m),






3.34-3.44 (2H,






m), 4.71 (1H, t,






J = 5.6 Hz),






6.72-6.84 (1H, m),






6.85-6.99 (1H, m),






7.00-7.14 (1H, m),






7.25-7.40 (3H, m),






7.46-7.66 (3H, m),






7.68-7.82 (3H, m),






13.22 (2H, s)


335
3
3,4,5-triF-Ph
—NH(CH2)2OH
FA: 518; N1: 2.60-






2.72 (2H, m),






3.16-3.48 (2H,






m), 4.71 (1H, br),






7.14-7.46 (5H, m),






7.53-7.82 (6H, m),






13.17 (2H, s)




















TABLE 33







336
1
1Naph
—NH—C(═NH)-Me
FA: 511; N1: 1.97 (3H, s), 6.60 (1H, t,






J = 7.8 Hz), 7.07-7.20 (3H, m), 7.25-7.38 (3H, m),






7.40-7.57 (4H, m), 7.65-7.71 (1H, m), 7.75-7.82






(2H, m), 8.04 (1H, br), 8.18 (1H, d, J = 8.3 Hz),






8.47 (1H, br), 13.26 (2H, s)


337
1
3-F-Ph
—N═C(NH2)2
ES+: 480; N1: 6.72 (4H, br), 6.85-6.94 (1H, m),






6.99-7.12 (3H, m), 7.17-7.24 (1H, m), 7.27-7.35






(2H, m), 7.39-7.44 (1H, m), 7.47-7.53 (1H, m),






7.63-7.67 (1H, m), 7.72-7.79 (2H, m), 13.11






(2H, s)


 


338
16
3,5-diF-Ph




ES+: 569; N1: 1.32 (3H, d, J = 6.8 Hz), 2.02 (3H, s), 4.96-5.08 (1H, m), 6.67-6.81 (1H, m), 6.86- 7.09 (2H, m), 7.22-7.42 (3H, m), 7.48-7.64 (2H, m), 7.70-7.84 (3H, m), 8.09 (1H, br), 8.70 (1H, br), 13.22 (2H, s)


 


339
1
1Naph
—N═C(NH2)2
FA: 512; N1: 6.45-6.56 (1H, m), 6.69 (4H, br),






6.96 (1H, d, J = 7.8 Hz), 7.06-7.18 (2H, m), 7.20-






7.60 (7H, m), 7.64-7.83 (3H, m), 8.16 (1H, d,






J = 8.8 Hz), 13.26 (2H, s)


340
16
3-Cl-Ph
—NH(CH2)2OH
FA: 567: N1: 1.31 (3H, d, J = 6.8 Hz), 2.01 (3H,






s), 4.95-5.07 (1H, m), 7.00-7.38 (7H, m), 7.45-






7.60 (2H, m), 7.65-7.80 (3H, m), 8.07 (1H, br),






8.69 (1H, br), 13.13 (2H, s)










(2)













Ex
Syn
A
R3
Dat







18
18
3-SO2Me-Ph
—NH—C(═NH)-Me
ES+: 539



341
3
Ph
—NH2
FA: 420



342
3
3-Cl-Ph
—NH2
FA: 454



343
1
Ph
—N═C(NH2)2
FA: 462



344
1
Ph
—NH—C(═NH)-iPr
FA: 489



345
3
Ph
—NH(CH2)2OH
FA: 464



346
1
3-CF3-Ph
—N═C(NH2)2
FA: 530



347
1
3-Br-Ph
—N═C(NH2)2
ES+: 540



348
3
3,5-diF-Ph
—NHOBn
FA: 562



 



349 350
1 3




—NH—C(═NH)-iPr —NH2
FA: 557 ES+: 488



 



351
3




—NH(CH2)2OH
FA: 532



 



352
3
2-Cl-Ph
—NH(CH2)2OH
FA: 498





















TABLE 34







353
 3
2-F-Ph
—NH(CH2)2OH
FA: 482


354
 3
3-Cl-Ph
—NH(CH2)2OH
FA: 498


355
 3
3-Me-Ph
—NH(CH2)2OH
ES+:






478


356
 3
2-Me-3-F-Ph
—NH(CH2)2OH
FA: 496


 


357
 3




—NH(CH2)2OH
FA: 504


 


358
 3
4-F-1Naph
—NH(CH2)2OH
FA: 532


359
 1
3-Cl-Ph
—NH—C(═NH)—CH(OH)-Et
FA: 539


360
 1
2,3-diMe-Ph
—N═C(NH2)2
FA: 490


361
 1
3,4-diMe-Ph
—N═C(NH2)2
FA: 490


362
 1
2-CF3-Ph
—N═C(NH2)2
FA: 530


363
 1
4-CF3-Ph
—N═C(NH2)2
FA: 530


 


364
 1
Ph




FA: 491


 


365 366
 1  1
3-Me-Ph Ph




FA: 505 FA: 491


 


367
 4
Ph
—NH-(2-Py)
FA: 497


368
 4
2-Cl-Ph
—NH-(2-Py)
FA: 531


369
 4
2-F-Ph
—NH-(2-Py)
FA: 515


370
 1
3,4-diCl-Ph
—N═C(NH2)2
FA: 530


371
 1
3,5-diCl-Ph
—N═C(NH2)2
FA: 530


372
 1
3,4-diF-Ph
—N═C(NH2)2
FA: 498


373
 1
2,3-diF-Ph
—N═C(NH2)2
FA: 498


374
 1
2,3-diCl-Ph
—N═C(NH2)2
FA: 530


375
 1
2,5-diCl-Ph
—N═C(NH2)2
FN: 528


376
 1
2Naph
—N═C(NH2)2
FA: 512


377
 1
3-Me-Ph
—NH—C(═NH)—CH(OH)-Me
FA: 505


378
12
3-Me-Ph
—NH—C(═NH)-Ac
FA: 503


379
 4
3-Cl-Ph
—NH-(2Py)
ES+:






531


380
 1
2-Cl-Ph
—NH—C(═NH)-iPr
FA: 523


381
 1
2-Cl-Ph
—NH—C(═NH)-cPr
FA: 521


382
 1
2-F-Ph
—NH—C(═NH)-iPr
ES+:






507


383
 1
2-OMe-Ph
—NH—C(═NH)-iPr
ES+:






519




















TABLE 35







384
3
2-Cl-4,5-
—NH(CH2)2OH
FA: 534




diF-Ph


385
3
2-Cl-4,5-
—NH(CH2)3OH
FA: 548




diF-Ph


386
3
3-F-4-OMe-Ph
—NH(CH2)2OH
ES+: 512


387
3
3-F-4-OMe-Ph
—NH(CH2)3OH
FA: 526


388
1
3-F-4-Me-Ph
—NH(CH2)2OH
FA: 496


389
3
3-F-4-Me-Ph
—NH(CH2)3OH
FA: 510


390
3
2-Cl-3-F-Ph
—NH(CH2)2OH
FA: 516


391
3
3-Cl-5-F-Ph
—NH(CH2)2OH
FA: 516


392
3
2-Cl-5-F-Ph
—NH(CH2)2OH
FA: 516


393
3
2-Cl-5-F-Ph
—NH(CH2)3OH
FA: 530


394
3
5-F-2-OMe-Ph
—NH(CH2)2OH
FA: 512


395
3
5-F-2-OMe-Ph
—NH(CH2)3OH
FA: 526


396
3
5-Cl-2-OMe-Ph
—NH(CH2)2OH
FA: 528


397
3
5-Cl-2-OMe-Ph
—NH(CH2)3OH
FA: 542


398
3
3-Cl-4-OMe-Ph
—NH(CH2)2OH
FN: 526


399
3
3-Cl-4-OMe-Ph
—NH(CH2)3OH
FA: 540


400
3
3-Cl-2-Me-Ph
—NH(CH2)2OH
FA: 512


401
3
3-Cl-2-Me-Ph
—NH(CH2)3OH
FA: 526


402
1
3-Cl-Ph
—NH—C(═NH)—(CH2)2OH
FA: 525


403
3
3,5-diOMe-Ph
—NH(CH2)2OH
FA: 524


404
3
3,5-diOMe-Ph
—NH(CH2)3OH
FN: 536


405
3
3-SMe-Ph
—NH(CH2)2OH
FA: 510


406
3
3-Ac-Ph
—NH(CH2)2OH
FA: 506


407
3
3-Cl-Ph
—NH(CH2)3OH
FA: 512


408
3
2-F-Ph
—NH(CH2)3OH
ES+: 496
















TABLE 36
























Ex
Syn
A
R2
Dat

















409
1
3-F-Ph
2-Me
FA: 537



410
1
3-F-Ph
4-Me
ES+: 537



411
1
3-F-Ph
6-Me
FA: 537



412
1
3,4,5-triF-Ph
2-Me
FA: 573



413
1
3-Cl-Ph
2-Me
FA: 553



414
1
3,5-diF-Ph
2-Me
FA: 555



415
1
3,4,5-triF-Ph
4-Me
FA: 573



416
1
1Naph
4-Me
FA: 569



417
1
3-Me-Ph
4-Me
ES+: 533



418
1
3-Me-Ph
6-Me
FA: 533



419
1
3-Me-Ph
2-Me
FA: 533



420
1
3,5-diF-Ph
4-Me
ES+: 555



421
1
3,5-diF-Ph
6-Me
FA: 555



422
1
6-Cl-3-Py
2-Me
FA: 554



423
1
3-Cl-Ph
4-Me
FA: 553



424
1
3-F-Ph
4-Cl
FA: 557

















TABLE 37













 













Ex
Syn
A
R2
Dat

















425
1
Ph
2-Me
FA: 505



426
1
3,4,5-triF-Ph
2-Me
FA: 559



427
1
3-Cl-Ph
2-Me
FA: 539



428
1
3-F-Ph
4-Me
FA: 523



429
1
3-F-Ph
6-Me
FA: 523



430
1
3,5-diF-Ph
2-Me
FA: 541



431
1
3-F-Ph
2-Me
FA: 523



432
1
3-F-Ph
2-Cl
FA: 543



433
1
3,5-diF-Ph
2-Cl
FA: 561



434
1
3-Me-Ph
2-Cl
ES+: 539



435
1
2,5-diF-Ph
2-Me
ES+: 541



440
1
2,3-diF-Ph
2-Me
FA: 541



441
1
3,4-diMe-Ph
2-Me
ES+: 533



442
1
2-Me-5-F-Ph
2-Me
ES+: 537



443
1
3-Me-Ph
2-Me
ES+: 519



444
1
3-Me-Ph
4-Me
ES+: 519



445
1
3,5-diF-Ph
4-Me
ES+: 541



446
1
3,5-diF-Ph
6-Me
FA: 541



447
1
3-Me-Ph
6-Me
FA: 519



448
1
6-Cl-3-Py
2-Me
FA: 540



449
1
2-Cl-Ph
2-Me
FA: 539



450
1
4-Cl-Ph
2-Me
FA: 539























TABLE 38









436
1
1Naph
2-Me
FA: 555



437
1
2Naph
2-Me
FA: 555



438
1
1Naph
4-Me
FA: 555



439
1
3-F-Ph
4-Cl
FA: 543



451
1
3,4,5-triF-Ph
4-Me
FA: 559



452
1
6-Cl-3-Py
4-Me
FA: 540



453
1
3-Cl-Ph
4-Me
FA: 539

















TABLE 39













 












Ex
Syn
A
R2
R3
Dat















454
3
3-F-Ph
2-Me
—NH(CH2)2OH
ES+: 496; N1:







2.51 (3H, s),







2.63-2.76







(2H, m),







3.38-3.46







(2H, m),







4.72 (1H, t,







J = 5.6 Hz),







6.83-7.12







(5H, m),







7.20-7.37







(3H, m),







7.47-7.63







(2H, m),







7.71-7.81







(2H, m),







13.23 (2H, s)


455
3
3-Me-Ph
2-Me
—NH(CH2)2OH
ES+: 492


456
3
3-F-Ph
2-Me
—NH(CH2)3OH
FA: 510;







N1: 1.52-







1.64 (2H,







m), 2.51







(3H, s),







2.64-2.75







(2H, m),







3.38-3.48







(2H, m),







4.46 (1H,







t, J = 4.8







Hz), 6.84-







7.13 (5H,







m), 7.20-







7.37 (3H,







m), 7.45-







7.57 (2H,







m), 7.71-







7.82 (2H,







m), 13.23







(2H, s)


457
3
3,5-diF-Ph
2-Me
—NH(CH2)3OH
FA: 528;







N1: 1.50-







1.66 (2H,







m), 2.50







(3H, s),







2.64-2.84







(2H, m),







3.36-3.46







(2H, m),







4.46 (1H,







t, J = 5.0







Hz), 6.79-







6.94 (3H,







m), 7.13







(1H, t, J =







7.6 Hz),







7.25-7.38







(3H, m),







7.50-7.64







(2H, m),







7.73-7.82







(2H, m),







13.25 (2H, s)


458
3
3-Cl-Ph
2-Me
—NH(CH2)2OH
FA: 512;







N1: 2.62-







2.82 (2H,







m), 3.42







(2H, t, J =







6.4 Hz),







4.71 (1H,







br), 6.99-







7.41 (8H,







m), 7.46-







7.65 (2H,







m), 7.70-







7.85 (2H,







m), 13.23







(2H, s)


459
1
Ph
2-Me
—NH—C(═NH)-Me
FA: 475


460
1
3-Cl-Ph
2-Me
—NH—C(═NH)-Me
FA: 509;







N1: 1.97







(3H, s),







2.52 (3H,







s), 6.96-







7.25 (6H,







m), 7.28-







7.37 (2H,







m), 7.56-







7.64 (1H,







m), 7.72-







7.81 (2H,







m), 8.04







(1H, br),







8.44 (1H,







br), 13.19







(2H, s)


461
1
3-Me-Ph
2-Me
—NH—C(═NH)-Me
ES+: 489


462
1
3,4,5-triF-Ph
2-Me
—NH—C(═NH)-Me
FA: 529





















TABLE 40







463
3
3,4,5-triF-Ph
2-Me
—NH(CH2)2OH
FA: 532


464
3
3-F-Ph
6-Me
—NH(CH2)2OH
FA: 496


465
3
3-F-Ph
6-Me
—NH(CH2)3OH
FA: 510


466
3
3,5-diF-Ph
6-Me
—NH(CH2)2OH
FA: 514


467
14
3,5-diF-Ph
4-Cl
—N(Me)2
FA: 518; N1: 2.76 (6H, s),







6.94-7.12 (3H, m), 7.28-7.39 (2H, m), 7.47 (1H, d,







J = 8.3 Hz), 7.54-7.62 (1H, m),







7.71-7.82 (2H, m), 7.85 (1H, d, J = 1.5 Hz),







13.19 (2H, s)


468
14
3,5-diF-Ph
6-OMe
—N(Me)2
FA: 514


469
1
3,5-diF-Ph
6-OMe
—NH—C(═NH)-Me
FA: 527; N1: 2.01 (3H, s), 3.73 (3H, s),







6.72-6.83 (3H, m), 6.90-7.00 (1H, m),







7.27-7.36 (2H, m), 7.41 (1H, d,







J = 2.5 Hz), 7.52 (1H, dd, J = 8.8 Hz,







2.4 Hz), 7.72-7.80 (2H, m), 7.99 (1H,







br), 8.44 (1H, br), 13.17 (2H, s)


470
3
3,5-diF-Ph
2-Me
—NH(CH2)2OH
ES+: 514; N1: 2.49 (3H, s),







2.68-2.84 (2H, m), 3.37-3.45 (2H, m), 4.72 (1H, t,







J = 5.6 Hz), 6.78-6.92 (3H, m),







7.08-7.16 (1H, m), 7.25-7.38 (3H, m),







7.52-7.60 (1H, m), 7.62-7.68 (1H, m),







7.73-7.82 (2H, m), 13.24 (2H, s)


471
3
3,5-diF-Ph
6-Me
—NH(CH2)3OH
FA: 528


472
1
3,5-diF-Ph
2-Me
—NH—C(═NH)-Me
FA: 511; N1: 2.00 (3H, s), 2.51 (3H, s),







6.77-6.92 (3H, s), 7.05-7.14 (1H, m),







7.20-7.38 (3H, m), 7.62-7.69 (1H, m),







7.72-7.82 (2H, m), 8.00 (1H, br),







8.45 (1H, br), 13.21 (2H, s)


473
1
3-F-Ph
2-Cl
—NH—C(═NH)-Me
FA: 531


474
1
3-Me-Ph
2-Cl
—NH—C(═NH)-Me
ES+: 509


475
1
1Naph
2-Me
—NH—C(═NH)-Me
FA: 525; N1: 1.90 (3H, s), 2.45 (3H,







br), 6.28 (1H, br), 6.94-7.19 (3H, m),







7.23-7.72 (7H, m), 7.75-7.85 (2H, m),







8.01 (2H, br), 8.44 (1H, br), 13.40 (2H, s)


476
1
2Naph
2-Me
—NH—C(═NH)-Me
FA: 525


477
1
2,5-diF-Ph
2-Me
—NH—C(═NH)-Me
ES+: 511


478
1
2,3-diF-Ph
2-Me
—NH—C(═NH)-Me
ES+: 511


479
1
2-Me-5-F-Ph
2-Me
—NH—C(═NH)-Me
FA: 507


480
1
3,4-diMe-Ph
2-Me
—NH—C(═NH)-Me
ES+: 503


481
1
3-F-Ph
4-Cl
—NH—C(═NH)-Me
FA: 513


482
1
3-F-Ph
4-F
—NH—C(═NH)-Me
FA: 497


483
2
3-F-Ph
2-Me
—NH—C(═NH)-Me
FA: 493


484
2
3-F-Ph
4-Me
—NH—C(═NH)-Me
FA: 493





















TABLE 41







485
 2
3-F-Ph
6-Me
—NH—C(═NH)-Me
FA: 493


486
 2
3-F-Ph
2-Cl
—NH—C(═NH)-Me
ES+: 513


487
 1
3,5-diF-Ph
4-Me
—NH—C(═NH)-Me
ES+: 511


488
 1
3-Me-Ph
4-Me
—H—(═NH)-Me
ES+: 489


489
 1
3,5-diF-Ph
6-Me
—NH—C(═NH)-Me
FA: 511


490
 1
3-Me-Ph
6-Me
—NH—C(═NH)-Me
FA: 489


491
 1
4-Cl-Ph
2-Me
—NH—C(═NH)-Me
FA: 509


492
 1
2-Cl-Ph
2-Me
—NH—C(═NH)-Me
FA: 509


493
 1
6-Cl-3-Py
2-Me
—NH—C(═NH)-Me
FA: 510


494
 1
3,4,5-triF-Ph
4-Me
—NH—C(═NH)-Me
FA: 529


495
 1
3-Cl-Ph
4-Me
—NH—C(═NH)-Me
FA: 509


496
 3
3,5-diF-Ph
4-Me
—NH—(CH2)2OH
FA: 514


497
 3
3,5-diF-Ph
4-Me
—NH—(CH2)3OH
FA: 528


498
 3
3-F-Ph
4-Me
—NH(CH2)2OH
FA: 496


499
 3
3-F-Ph
4-Me
—NH(CH2)3OH
FA: 510


500
 3
3-F-Ph
4-Cl
—NH—(CH2)2OH
FA: 516


501
 3
3-F-Ph
4-Cl
—NH—(CH2)3OH
FA: 530


 


502 503
 3  3
3,5-diF-Ph 3-F-Ph
2-Me 2-Me




FA: 528 FA: 510; N1: 1.04 (3H, d, J = 6.4 Hz), 2.46-2.66 (2H, m), 3.54-3.71 (1H, m), 4.70 (1H, br), 6.82-7.12 (5H, m), 7.19- 7.37 (3H, m), 7.44-7.62 (2H, m), 7.72- 7.80 (2H, m), 13.23 (2H, s)


 


504 505
 3  3
3,5-diF-Ph 3-F-Ph
2-Me 2-Me




FA: 528 FA: 510


 


506
 3
3-Me-Ph
2-Me
—NH—(CH2)3OH
FA: 506


 











507
14
3,5-diF-Ph




FN: 493
















TABLE 42













 

















 














Ex
Syn
A
R1a
R1b
pos
R3
Dat

















17
17
3,5-diF-Ph
H2N
H
3
—NH—C(═NH)-Me
FA: 512


508
 3
3,5-diF-Ph
H
H
4
—NH2
FA: 456


509
 1
3,5-diF-Ph
Me
Me
3
—N═C(NH2)2
FA: 526; N1: 2.33 (6H,









s), 6.69 (4H, br), 6.84-









6.96 (3H, m), 7.27 (1H,









t, J = 7.8 Hz), 7.44-7.57









(4H, m), 7.61-7.65 (1H,









m), 12.97 (2H, s)


510
 1
3-F-Ph
F
F
3
—N═C(NH2)2
FA: 516; N1: 6.70 (4H,









br), 6.84-6.94 (1H, m),









6.96-7.12 (3H, m),









7.14-7.24 (1H, m),









7.36-7.53 (2H, m),









7.60-7.78 (3H, m),









13.20 (2H, s)


511
 1
3,5-diF-Ph
F
H
3
—N═C(NH2)2
FA: 516


512
 1
3,5-diF-Ph
Cl
H
3
—N═C(NH2)2
FA: 532


513
 1
3,5-diF-Ph
Me
H
3
—N═C(NH2)2
FA: 512


514 515
 1  1
3-F-Ph 3,5-diF-Ph
F F
H H
3 3




FA: 527 ES+: 545


 


516 517
 1  1
3,5-diF-Ph 3-F-Ph
F F
H H
3 3




FA: 559 FA: 541


 


518
 1
3,5-diF-Ph
F
H
3
—NH—C(═NH)-Me
FA: 515


519
 1
3-F-Ph
F
H
3
—NH—C(═NH)-Me
FA: 497


520
 1
Ph
Bn-S
H
3
—NH—C(═NH)-Me
FA: 583


521
 1
3-F-Ph
PhCO
H
3
—NH—C(═NH)-Me
FA: 583


522
 1
3-F-Ph
MeO
MeO
3
—NH—C(═NH)-Me
FA: 539























TABLE 43







523
1
3,5-diF-Ph
O2N
H
3
—NH—C(═NH)-Me
FN: 540


524
3
3-F-Ph
MeO
MeO
3
—NH—(CH2)2OH
FA: 542


525
3
3,5-diF-Ph
O2N
H
3
—NH—(CH2)2OH
FA: 545


526
9
3,5-diF-Ph
(4-(AcNH)-Ph)-
H
3
—NH—C(═NH)-Me
FA: 673





CONH—


527
17
3,5-diF-Ph
H2N
H
3
—NH—(CH2)2OH
FA: 515


528
1
3,5-diF-Ph
H
H
4
—NH—C(═NH)-Me
ES+: 497


529
3
3,5-diF-Ph
H
H
4
—NH—(CH2)2OH
FA: 500


530
3
3,5-diF-Ph
H
H
4
—NH—(CH2)3OH
FA: 514
















TABLE 44













 












Ex
Syn
A
R1a
R3
Dat















534
16
3-F-Ph
H




565: FA


 


535
1






495: FA


 


536
16






551: FA


 


537
2


—NH(CH2)4OH
510: ES+


 


538
2
3,5-diF-Ph
H




526: ES+


 


539
1
3-F-Ph
CO2Bn




613: FA


 


540
11

CO2H




521: FN
















TABLE 45













 










Ex
Syn
R1c
Dat













541
532
Me
537: FA


542
532
Cl
557: FA


 


543
532




621: FA


 


544
532
—CH2OH
553: FA


545
532
—CO2Bn
657: FA


546
11
—CO2H
567: ES+


547
9
—CONH2
566: FA


 


548
9




693: FA
















TABLE 46













 












Ex
Syn
A
Dat














549
1
2-Cl-6-OMe-4Py
570: FA


550
1
2,4-diCl-5-F-Ph
591: FA


551
1
3-Cl-4,5-diF-Ph
575: FA


552
1
2-F-3-Cl-Ph
557: FA


553
1
3-F-5-Me-Ph
537: FA


554
1
2-F-5-Cl-Ph
557: FA


555
1
3-Cl-4-Me-Ph
553: FA


556
1
2-Me-5-Cl-Ph
553: FA


557
19
5-Cl-3-Py
540: FA


558
19
3Py
506: FA


559
1
2,4,5-triF-Ph
559: FA


560
1
2-Cl-6-Me-4Py
554: FA


561
19
2-Me-4Py
520: FA


562
1
2,5-diF-4-Cl-Ph
575: FA


563
1
2,5-diCl-4Py
574: FA


564
19
2-OMe-4Py
536: FA


 


533
533




522: FA


 


532
532




540: FA


 


565
532




508: FA


 


566
532




508: ES+


 


567
19
3-Cl-4Py
540: FA


568
19
4Py
506: FA


569
1
2,6-diCl-5-F-3Py
592: FA


570
1
2,4-diF-3-Cl-Ph
575: FA


571
1
2-Cl-3-F-4Py
558: FA


572
19
3-F-4Py
524: FA


573
532
2Py
506: FA


574
532
3THi
511: FA


575
532
2Thi
511: FA


576
532
5-Me-2Thi
525: FA


577
532
5-Me-2Fur
509: FA


578
532
4-Me-2Thi
525: FA


579
532
3-Me-2Thi
525: FA


580
1
5-Cl-2Thi
545: FA


581
1
2,3,4-triF-Ph
559: FA


582
532
2,6-diF-3-Me-Ph
555: FA


 


583
532




563: FA


 


584
532




634: ES+


 


585
532




494: ES+
















TABLE 47













 












Ex
Syn
A
Dat
















586
1
3-CO2Me-Ph
519: FA



587
1
3-Cl-4,5-diF-Ph
531: FA



588
1
2,4-diCl-5-F-Ph
547: FA



589
1
2-F-3-Cl-Ph
513: FA



590
1
3-F-5-Me-Ph
493: FA



591
1
2-F-5-Cl-Ph
513: FA



592
1
3-Cl-4-Me-Ph
509: FA



593
19
5-Cl-3Py
496: FA



594
1
2-Me-5-Cl-Ph
509: FA



595
1
2,4,5-triF-Ph
515: FA



596
1
2-Cl-6-Me-4Py
510: FA



597
19
2-Me-4Py
476: FA



598
1
2-Cl-6-OMe-4Py
526: FA



599
19
2-OMe-4Py
492: FA



600
1
2,5-diCl-4Py
530: FA



601
1
2,5-diF-4-Cl-Ph
531: FA

















TABLE 48













 












Ex.
Syn
A
Dat
















602
1
2-Cl-6-OMe-4Py
556: FA



603
1
2,6-diCl-4Py
560: FA



604
1
2,4-diCl-5-F-Ph
577: FA



605
1
3-Cl-4,5-diF-Ph
561: FA



606
1
2-F-3-Cl-Ph
543: FA



607
1
2-F-5-Cl-Ph
543: FA



608
1
3-Cl-4-Me-Ph
539: FA



609
1
3-F-5-Me-Ph
523: FA



610
1
2,4,5-triF-Ph
545: FA



611
1
2-Me-5-Cl-Ph
539: FA



612
19
5-Cl-3-Py
526: FA



613
19
3Py
492: FA



614
1
2-Cl-6-Me-4Py
540: FA



615
19
2-Me-4Py
506: FA



616
1
2,5-diF-4-Cl-Ph
561: FA



617
19
2-OMe-4Py
522: FA



 



618
533




508: FA



 



619
1
2,5-diCl-4Py
560: FA



620
19
3-Cl-4Py
526: FA



621
1
2,3,4-triF-Ph
545: FA



622
1
6-CN-3Py
517: FA



623
1
2,4-diF-3-Cl-Ph
561: FA



624
1
2-Cl-3-F-4Py
544: FA



625
19
3-F-4Py
510: FA



 



626
532




549: ES+



 



627
1
5-Cl-2Thi
533: ES+

















TABLE 49













 











Ex
Syn
A
R3
Dat














628
2
2,5-diF-Ph
—NH(CH2)2OH
500: FA


629
2
2,4-diCl-5-F-Ph
—NH(CH2)2OH
550: FA


630
2

—NH(CH2)3OH
564: FA


631
2
3-Cl-4,5-diF-Ph
—NH(CH2)2OH
534: FA


632
2

—NH(CH2)3OH
548: FA


633
2
2-F-3-Cl-Ph
—NH(CH2)2OH
516: FA


634
2

—NH(CH2)3OH
530: FA


635
2
3-F-5-Me-Ph
—NH(CH2)3OH
510: FA


636
2
2-F-5-Cl-Ph
—NH(CH2)2OH
516: FA


637
2

—NH(CH2)3OH
530: FA


638
2
3-Cl-4-Me-Ph
—NH(CH2)2OH
512: FA


639
2

—NH(CH2)3OH
526: FA


 


640
16
Ph




547: FA


 


641
16
6-Cl-3Py




566: FN


 


642
2





513: ES+


 


643
2
2-Me-5-Cl-Ph
—NH(CH2)2OH
512: FA


644
2
5,6-diCl-3Py
—NH(CH2)2OH
533: ES+


645
19
5-Cl-3Py
—NH(CH2)2OH
499: FA


646
19
3Py
—NH(CH2)2OH
465: FA


647
2
2,3,4-triF-Ph
—NH(CH2)2OH
518: FA


648
2
2,4,5-triF-Ph
—NH(CH2)2OH
518: ES+


649
2
3,4,5-triF-Ph
—NH(CH2)3OH
532: ES+




















TABLE 50







650
2
2,5-diF-4-Cl-Ph
—NH(CH2)2OH
534: FA


651
19
2-Me-4Py
—NH(CH2)2OH
479: FA


652
2
2-Cl-6-Me-4Py
—NH(CH2)2OH
511: ES−


653
2
2-Cl-6-OMe-4Py
—NH(CH2)2OH
529: FA


654
19
2-OMe-4Py
—NH(CH2)2OH
495: FA


 


655
2
3-F-4-Me-Ph




510: ES+


 


656
2





526: ES+


 


657
2
2,5-diF-Ph
—NMe(CH2)2OH
514: ES+


 


658
2





514: ES+


 


659
2





514: ES+


 


660
2





514: ES+


 


661
2

—NH(CH2)3OH
514: ES+

















TABLE 51








(1)








 











Ex
Syn
A
R2
Dat














662
696
3-F-Ph
4-F
541: FA; N1: 1.25 (6H, s), 5.83 (1H,






m), 6.94 (1H, m), 7.04 (1H, m),






7.10 (3H, m), 7.32 (2H, m), 7.56






(1H, m), 7.76 (3H, m), 8.12 (1H,






m), 8.22 (1H, m), 13.14 (2H, m)


672
696
3,5-diF-Ph
4-F
559: FA; N1: 1.25 (6H, s), 5.82 (1H,






s), 6.90-6.99 (3H, m), 7.15-






7.20 (1H, m), 7.31-7.35 (2H, m),






7.60-7.64 (1H, m), 7.74-7.77 (3H,






m), 8.15-8.17 (2H, m), 13.15 (2H, m)


677
696
2,4,5-triF-Ph
4-F
577: FA; N1: 1.27 (6H, s), 5.84 (1H,






s), 7.05 (1H, m), 7.19 (1H, m),






7.31-7.39 (3H, m), 7.63 (1H, m),






7.78 (3H, 1), 8.16 (1H, m), 8.25






(1H, m), 13.23 (2H, m)


691
696
2,5-diF-Ph
4-F
559: FA; N1: 1.27 (6H, s), 5.83 (1H,






m), 6.79 (1H, m), 6.95 (1H, m),






7.05 (1H, m), 7.13 (1H, m), 7.33






(2H, m), 7.60 (1H, m), 7.77 (3H,






m), 8.13 (1H, m), 8.24 (1H, m),






13.21 (2H, m)


695
696
5-Cl-2Thi
4-F
563: FA; N1: 1.27 (6H, s), 3.40-3.48






(1H, m), 5.85 (1H, s), 6.71






(1H, d, J = 4.0 Hz), 6.84






(1H, d, J = 4.0 Hz), 7.19-






7.34 (3H, m), 7.61-7.75 (3H, m),






7.99-8.04 (1H, m), 8.13 (1H, br),






8.28 (1H, br), 13.01 (2H, s)
















TABLE 52







(2)













Ex
Syn
A
R2
Dat

















663
1
3-F-Ph
6-F
541: FA



664
1

5-F
541: FA



665
1

4-iPr
565: FA



666
1
6-Cl-3Py
4-F
558: FA



667
1
2,5-diCl-4Py
4-F
592: FA



668
19
3-Cl-4Py
4-F
558: FA



669
19
4Py
4-F
524: FA



670
1
Ph
4-F
523: FA



671
1
3-Me-Ph
4-F
537: FA



673
1
2,4-diCl-5-F-Ph
4-F
609: FA



674
1
2-Cl-6-OMe-4Py
4-F
588: FA



675
19
2-OMe-4Py
4-F
554: ES+



676
1
3-Cl-Ph
4-F
557: ES+



678
1
4-Cl-Ph
4-F
557: FA



679
1
3,4-diMe-Ph
4-F
551: FA



680
1
3-Cl-4-Me-Ph
4-F
571: FA



681
1
2-Me-3-F-Ph
4-F
555: FA



682
1
2-Me-3-Cl-Ph
4-F
571: FA



683
1
3-F-4-Me-Ph
4-F
555: FA



684
1
3,4,5-triF-Ph
4-F
577: FA



685
1
2-F-5-Cl-Ph
4-F
575: FA



686
1
2-Me-5-F-Ph
4-F
555: FA



687
1
2-Cl-5-F-Ph
4-F
575: FA



688
1
3-F-5-Me-Ph
4-F
555: FA



 



689
532




4-F
581: ES+



 



690
1
2-Cl-3-Me-4Py
4-F
572: FA



692
1
2-Cl-4,5-diF-Ph
4-F
593: FA



693
1
2,5-diF-4-Cl-Ph
4-F
593: FA



694
1
3-Cl-4,5-diF-Ph
4-F
593: FA


















TABLE 53








(1)








 











Ex
Syn
A
R2
Dat














696
696
3-F-Ph
4-F
527: FA; N1: 1.20 (3H, m), 4.13 (1H,






m), 5.92 (1H, m), 6.94-7.12 (5H,






m), 7.32 (2H, m), 7.56 (1H, m),






7.73-7.78 (3H, m), 8.16 (1H, m),






8.29 (1H, m), 13.13 (2H, m)


704
696
3-Me-Ph
4-F
523: FA; N1: 1.20 (3H, m), 2.14 (3H,






s), 4.12 (1H, m), 5.91 (1H, m),






6.90-7.08 (5H, m), 7.30 (2H, m),






7.48 (1H, m), 7.71-7.75 (3H, m),






8.14 (1H, m), 8.26 (1H, m), 13.13






(2H, m)


706
696
3,5-diF-Ph
4-F
545: FA: N1: 1.20 (3H, d, J = 4.0






Hz), 4.11-4.13 (1H, m), 5.91 (1H, d,






J = 4.0 Hz), 6.89-6.91 (2H, m),






6.97-7.02 (1H, m), 7.15-7.20 (1H,






m), 7.31-7.34 (2H, m), 7.61-7.65






(1H, m), 7.73-7.77 (3H, m), 8.18






(1H, m), 8.24 (1H, m), 13.15 (2H, s)


711
696
3-Cl-Ph
4-F
543: FA; N1: 1.20 (3H, m), 4.13 (1H,






m), 5.91 (1H, m), 7.07-7.24 (5H, m),






7.31 (2H, m), 7.55 (1H, m), 7.75






(3H, m), 8.15 (1H, m), 8.29 (1H,






m), 13.13 (2H, m)


712
696
2,4,5-triF-Ph
4-F
563: FA; N1: 1.21 (3H, m), 4.13 (1H,






m), 5.93 (1H, m), 7.05 (1H, m),






7.19 (1H, m), 7.28-7.37 (3H, m),






7.63 (1H, m), 7.75-7.78 (3H, m),






8.19 (1H, m), 8.31 (1H, m), 13.23






(2H, m)


717
696
3-F-4-Me-Ph
4-F
541: FA; N1: 1.19 (3H, m), 2.07 (3H,






s), 4.12 (1H, m), 5.93 (1H, m),






6.93-7.01 (3H, m), 7.10 (1H, m),






7.31 (2H, m), 7.55 (1H, m), 7.72-






7.78 (3H, m), 8.16 (1H, m), 8.29






(1H, m), 13.11 (2H, m)


726
696
2,5-diF-Ph
4-F
545: FA; N1: 1.22 (3H, m), 4.14 (1H,






m), 5.93 (1H, m), 6.78 (1H, m),






6.97-7.13 (3H, m), 7.33 (2H, m),






7.59 (1H, m), 7.77 (3H, m), 8.16






(1H, m), 8.30 (1H, m), 13.21 (2H,






m)


730
696
5-Cl-2Thi
4-F
549: FA; N1: 1.20 (3H, d, J = 6.8






Hz), 4.10-4.18 (1H, m), 5.93 (1H, d,






J = 5.2 Hz), 6.72 (1H, d,






J = 4.0 Hz), 6.84 (1H, d,






J = 4.0 Hz), 7.19-7.33 (3H,






m), 7.62-7.75 (3H, m), 8.00-8.04






(1H, m), 8.16 (1H, brs), 8.37 (1H,






brs), 13.00 (2H, s)
















TABLE 54







(2)













Ex
Syn
A
R2
Dat

















697
1
3-F-Ph
6-F
527: FA



698
1

5-F
527: FA



699
1

4-iPr
551: FA



700
1
6-Cl-3Py
4-F
544: ES+



701
19
3Py
4-F
510: ES+



702
1
2,5-diCl-4Py
4-F
578: FA



703
1
Ph
4-F
509: FA



705
19
3-Cl-4Py
4-F
544: FA



707
1
2,4-diCl-5-F-Ph
4-F
595: FA



708
1
6-Cl-2Py
4-F
544: FA



709
1
2-Cl-6-OMe-4Py
4-F
574: FA



710
19
2-OMe-4Py
4-F
540: ES+



713
1
4-Cl-Ph
4-F
543: FA



714
1
3,4-diMe-Ph
4-F
537: FA



715
1
3-Cl-4-Me-Ph
4-F
557: FA



716
1
2-Me-3-F-Ph
4-F
541: FA



718
1
3,4,5-triF-Ph
4-F
563: FA



719
1
2-F-5-Cl-Ph
4-F
561: FA



720
1
2-Me-3-Cl-Ph
4-F
557: FA



721
1
2-Me-5-F-Ph
4-F
541: FA



722
1
2-Cl-5-F-Ph
4-F
559: FA



723
1
3-F-5-Me-Ph
4-F
541: FA



 



724
532




4-F
567: ES+



 



725
1
2-Cl-3-Me-4Py
4-F
558: FA



727
1
2-Cl-4,5-diF-Ph
4-F
579: FA



728
1
2,5-diF-4-Cl-Ph
4-F
579: ES+



729
1
3-Cl-4,5-diF-Ph
4-F
579: FA

















TABLE 55













 












Ex
Syn
A
R2
R3
Dat















731
2
3-F-Ph
4-F
—NH(CH2)2OH
500: FA


732
2


—NH(CH2)3OH
514: FA


 


733
16






569: FA


 


734
16






611: FA


 


735
16






632: FA


 


736
16






583: FA


 


737
16






646: FA


 


738
1






527: FA


 


739
2

4-iPr
—NH(CH2)2OH
524: FA


740
1


—NH—C(═NH)-Me
521: FA


741
1

4-OMe
—NH—C(═NH)-Me
509: FA


742
1

2-OMe
—NH—C(═NH)-Me
509: FA


743
1


—NH(CH2)2OH
512: FA


744
2
3-F-4-Me-Ph
2-Me
—NH(CH2)2OH
510: FA


745
2


—NH(CH2)3OH
524: ES+


746
1
6-Cl-3Py
4-F
—NH—C(═NH)-Me
514: ES+


747
1
6-Cl-2Py

—NH—C(═NH)-Me
514: FA





















TABLE 56





Ex
Syn
A
R2
R3
Dat




















748
2
3,5-diF-Ph
4-F
—NH(CH2)2OH
518: FA


749
1


—NH—C(═NH)-Me
515: FA


 


750
1






545: ES+


 


751
1
2,4-diCl-5-F-Ph

—NH—C(═NH)-Me
565: FA


752
2


—NH(CH2)2OH
568: FA


 


753
16
3-Me-Ph
4-F




565: FA


 


754
16






607: FA


 


755
16






628: FA


 


756
1






523: FA


 


757
1
2,4,5-triF-Ph
4-F




563: FA


 


758
1
2,5-diF-Ph
4-F




545: FA



















TABLE 57





Ex
Syn
Str
Dat


















759
532




529: FA


 


760
1




515: FA


 


761
1




535: FN


 


762
1




529: FA


 


763
1




488: ES+


 


764
1




515: ES+


 


765
1




535: ES−
















TABLE 58













 










No
A
R2
R3













1
3-F-Ph
H
SM


2
3-F-Ph
2-Me
SM


3
3-F-Ph
2-Me
GN


4
3-F-Ph
4-Me
SM


5
3-F-Ph
4-Me
GN


6
3-F-Ph
6-Me
SM


7
3-F-Ph
6-Me
GN


8
3-F-Ph
4-F
GN


9
3-F-Ph
2-Cl
SM


10
3-F-Ph
2-Cl
DM


11
3-F-Ph
2-Cl
C2


12
3-F-Ph
2-Cl
C3


13
3-F-Ph
2-Cl
GN


14
3-F-Ph
4-Cl
SM


15
3-F-Ph
4-Cl
GN


16
3-Cl-Ph
H
SM


17
3-Cl-Ph
H
GN


18
3-Cl-Ph
2-Me
SM


19
3-Cl-Ph
2-Me
C3


20
3-Cl-Ph
2-Me
GN


21
3-Cl-Ph
4-Me
SM


22
3-Cl-Ph
4-Me
C2


23
3-Cl-Ph
4-Me
C3


24
3-Cl-Ph
4-Me
GN


25
3-Cl-Ph
6-Me
RM


26
3-Cl-Ph
6-Me
SM


27
3-Cl-Ph
6-Me
DM


28
3-Cl-Ph
6-Me
C2


29
3-Cl-Ph
6-Me
C3


30
3-Cl-Ph
6-Me
GN


31
3-Cl-Ph
4-F
SM


32
3-Cl-Ph
4-F
C2


33
3-Cl-Ph
4-F
C3


34
3-Cl-Ph
4-F
GN


35
3-Cl-Ph
2-Cl
RM


36
3-Cl-Ph
2-Cl
SM


37
3-Cl-Ph
2-Cl
DM


38
3-Cl-Ph
2-Cl
C2


39
3-Cl-Ph
2-Cl
C3


40
3-Cl-Ph
2-Cl
GN


41
3-Cl-Ph
4-Cl
RM


42
3-Cl-Ph
4-Cl
SM


43
3-Cl-Ph
4-Cl
DM


44
3-Cl-Ph
4-Cl
C2


45
3-Cl-Ph
4-Cl
C3


46
3-Cl-Ph
4-Cl
GN


47
3-Me-Ph
H
C3


48
3-Me-Ph
H
GN


49
3-Me-Ph
2-Me
SM


50
3-Me-Ph
2-Me
GN


51
3-Me-Ph
4-Me
SM


52
3-Me-Ph
4-Me
C2


53
3-Me-Ph
4-Me
C3


54
3-Me-Ph
4-Me
GN


55
3-Me-Ph
6-Me
SM


56
3-Me-Ph
6-Me
C2


57
3-Me-Ph
6-Me
C3


58
3-Me-Ph
6-Me
GN


59
3-Me-Ph
4-F
C2


60
3-Me-Ph
4-F
C3


61
3-Me-Ph
4-F
GN


62
3-Me-Ph
2-Cl
SM


63
3-Me-Ph
2-Cl
DM


64
3-Me-Ph
2-Cl
C2


65
3-Me-Ph
2-Cl
C3


66
3-Me-Ph
2-Cl
GN


67
3-Me-Ph
4-Cl
RM


68
3-Me-Ph
4-Cl
SM


69
3-Me-Ph
4-Cl
DM


70
3-Me-Ph
4-Cl
C2


71
3-Me-Ph
4-Cl
C3


72
3-Me-Ph
4-Cl
GN


73
3-F-4-Me-Ph
H
SM


74
3-F-4-Me-Ph
H
GN


75
3-F-4-Me-Ph
2-Me
RM


76
3-F-4-Me-Ph
2-Me
SM


77
3-F-4-Me-Ph
2-Me
DM


78
3-F-4-Me-Ph
2-Me
GN


79
3-F-4-Me-Ph
4-Me
RM


80
3-F-4-Me-Ph
4-Me
SM


81
3-F-4-Me-Ph
4-Me
DM


82
3-F-4-Me-Ph
4-Me
C2


83
3-F-4-Me-Ph
4-Me
C3


84
3-F-4-Me-Ph
4-Me
GN


85
3-F-4-Me-Ph
6-Me
RM


86
3-F-4-Me-Ph
6-Me
SM


87
3-F-4-Me-Ph
6-Me
DM



















TABLE 59





No
A
R2
R3


















88
3-F-4-Me-Ph
6-Me
C2


89
3-F-4-Me-Ph
6-Me
C3


90
3-F-4-Me-Ph
6-Me
GN


91
3-F-4-Me-Ph
4-F
SM


92
3-F-4-Me-Ph
4-F
C2


93
3-F-4-Me-Ph
4-F
C3


94
3-F-4-Me-Ph
4-F
GN


95
3-F-4-Me-Ph
2-Cl
RM


96
3-F-4-Me-Ph
2-Cl
SM


97
3-F-4-Me-Ph
2-Cl
DM


98
3-F-4-Me-Ph
2-Cl
C2


99
3-F-4-Me-Ph
2-Cl
C3


100
3-F-4-Me-Ph
2-Cl
GN


101
3-F-4-Me-Ph
4-Cl
RM


102
3-F-4-Me-Ph
4-Cl
SM


103
3-F-4-Me-Ph
4-Cl
DM


104
3-F-4-Me-Ph
4-Cl
C2


105
3-F-4-Me-Ph
4-Cl
C3


106
3-F-4-Me-Ph
4-Cl
GN


107
2,5-diF-Ph
H
SM


108
2,5-diF-Ph
H
GN


109
2,5-diF-Ph
2-Me
SM


110
2,5-diF-Ph
2-Me
DM


111
2,5-diF-Ph
2-Me
C2


112
2,5-diF-Ph
2-Me
C3


113
2,5-diF-Ph
2-Me
GN


114
2,5-diF-Ph
4-Me
RM


115
2,5-diF-Ph
4-Me
SM


116
2,5-diF-Ph
4-Me
DM


117
2,5-diF-Ph
4-Me
C2


118
2,5-diF-Ph
4-Me
C3


119
2,5-diF-Ph
4-Me
GN


120
2,5-diF-Ph
6-Me
RM


121
2,5-diF-Ph
6-Me
SM


122
2,5-diF-Ph
6-Me
DM


123
2,5-diF-Ph
6-Me
C2


124
2,5-diF-Ph
6-Me
C3


125
2,5-diF-Ph
6-Me
GN


126
2,5-diF-Ph
4-F
C2


127
2,5-diF-Ph
4-F
C3


128
2,5-diF-Ph
4-F
GN


129
2,5-diF-Ph
2-Cl
RM


130
2,5-diF-Ph
2-Cl
SM


131
2,5-diF-Ph
2-Cl
DM


132
2,5-diF-Ph
2-Cl
C2


133
2,5-diF-Ph
2-Cl
C3


134
2,5-diF-Ph
2-Cl
GN


135
2,5-diF-Ph
4-Cl
RM


136
2,5-diF-Ph
4-Cl
SM


137
2,5-diF-Ph
4-Cl
DM


138
2,5-diF-Ph
4-Cl
C2


139
2,5-diF-Ph
4-Cl
C3


140
2,5-diF-Ph
4-Cl
GN


141
3,5-diF-Ph
2-Me
SM


142
3,5-diF-Ph
2-Me
GN


143
3,5-diF-Ph
4-Me
SM


144
3,5-diF-Ph
4-Me
GN


145
3,5-diF-Ph
6-Me
SM


146
3,5-diF-Ph
6-Me
GN


147
3,5-diF-Ph
4-F
C3


148
3,5-diF-Ph
4-F
GN


149
3,5-diF-Ph
2-Cl
SM


150
3,5-diF-Ph
2-Cl
DM


151
3,5-diF-Ph
2-Cl
C2


152
3,5-diF-Ph
2-Cl
C3


153
3,5-diF-Ph
2-Cl
GN


154
3,5-diF-Ph
4-Cl
RM


155
3,5-diF-Ph
4-Cl
SM


156
3,5-diF-Ph
4-Cl
DM


157
3,5-diF-Ph
4-Cl
C2


158
3,5-diF-Ph
4-Cl
C3


159
3,5-diF-Ph
4-Cl
GN


160
2,4,5-triF-Ph
H
SM


161
2,4,5-triF-Ph
H
C3


162
2,4,5-triF-Ph
H
GN


163
2,4,5-triF-Ph
2-Me
RM


164
2,4,5-triF-Ph
2-Me
SM


165
2,4,5-triF-Ph
2-Me
DM


166
2,4,5-triF-Ph
2-Me
C2


167
2,4,5-triF-Ph
2-Me
C3


168
2,4,5-triF-Ph
2-Me
GN


169
2,4,5-triF-Ph
4-Me
RM


170
2,4,5-triF-Ph
4-Me
SM


171
2,4,5-triF-Ph
4-Me
DM


172
2,4,5-triF-Ph
4-Me
C2


173
2,4,5-triF-Ph
4-Me
C3


174
2,4,5-triF-Ph
4-Me
GN


175
2,4,5-triF-Ph
6-Me
RM


176
2,4,5-triF-Ph
6-Me
SM


177
2,4,5-triF-Ph
6-Me
DM


178
2,4,5-triF-Ph
6-Me
C2


179
2,4,5-triF-Ph
6-Me
C3


180
2,4,5-triF-Ph
6-Me
GN


181
2,4,5-triF-Ph
4-F
C2


182
2,4,5-triF-Ph
4-F
C3


183
2,4,5-triF-Ph
4-F
GN


184
2,4,5-triF-Ph
2-Cl
RM


185
2,4,5-triF-Ph
2-Cl
SM


186
2,4,5-triF-Ph
2-Cl
DM


187
2,4,5-triF-Ph
2-Cl
C2


188
2,4,5-triF-Ph
2-Cl
C3


189
2,4,5-triF-Ph
2-Cl
GN


190
2,4,5-triF-Ph
4-Cl
RM


191
2,4,5-triF-Ph
4-Cl
SM


192
2,4,5-triF-Ph
4-Cl
DM


193
2,4,5-triF-Ph
4-Cl
C2


194
2,4,5-triF-Ph
4-Cl
C3


195
2,4,5-triF-Ph
4-Cl
GN



















TABLE 60





No
A
R2
R3


















196
4-F-2Thi
H
RM


197
4-F-2Thi
H
SM


198
4-F-2Thi
H
DM


199
4-F-2Thi
H
C2


200
4-F-2Thi
H
C3


201
4-F-2Thi
H
GN


202
4-F-2Thi
2-Me
RM


203
4-F-2Thi
2-Me
SM


204
4-F-2Thi
2-Me
DM


205
4-F-2Thi
2-Me
C2


206
4-F-2Thi
2-Me
C3


207
4-F-2Thi
2-Me
GN


208
4-F-2Thi
4-Me
RM


209
4-F-2Thi
4-Me
SM


210
4-F-2Thi
4-Me
DM


211
4-F-2Thi
4-Me
C2


212
4-F-2Thi
4-Me
C3


213
4-F-2Thi
4-Me
GN


214
4-F-2Thi
6-Me
RM


215
4-F-2Thi
6-Me
SM


216
4-F-2Thi
6-Me
DM


217
4-F-2Thi
6-Me
C2


218
4-F-2Thi
6-Me
C3


219
4-F-2Thi
6-Me
GN


220
4-F-2Thi
4-F
RM


221
4-F-2Thi
4-F
SM


222
4-F-2Thi
4-F
DM


223
4-F-2Thi
4-F
C2


224
4-F-2Thi
4-F
C3


225
4-F-2Thi
4-F
GN


226
4-F-2Thi
2-Cl
RM


227
4-F-2Thi
2-Cl
SM


228
4-F-2Thi
2-Cl
DM


229
4-F-2Thi
2-Cl
C2


230
4-F-2Thi
2-Cl
C3


231
4-F-2Thi
2-Cl
GN


232
4-F-2Thi
4-Cl
RM


233
4-F-2Thi
4-Cl
SM


234
4-F-2Thi
4-Cl
DM


235
4-F-2Thi
4-Cl
C2


236
4-F-2Thi
4-Cl
C3


237
4-F-2Thi
4-Cl
GN


238
5-F-2Thi
H
RM


239
5-F-2Thi
H
SM


240
5-F-2Thi
H
DM


241
5-F-2Thi
H
C2


242
5-F-2Thi
H
C3


243
5-F-2Thi
H
GN


244
5-F-2Thi
2-Me
RM


245
5-F-2Thi
2-Me
SM


246
5-F-2Thi
2-Me
DM


247
5-F-2Thi
2-Me
C2


248
5-F-2Thi
2-Me
C3


249
5-F-2Thi
2-Me
GN


250
5-F-2Thi
4-Me
RM


251
5-F-2Thi
4-Me
SM


252
5-F-2Thi
4-Me
DM


253
5-F-2Thi
4-Me
C2


254
5-F-2Thi
4-Me
C3


255
5-F-2Thi
4-Me
GN


256
5-F-2Thi
6-Me
RM


257
5-F-2Thi
6-Me
SM


258
5-F-2Thi
6-Me
DM


259
5-F-2Thi
6-Me
C2


260
5-F-2Thi
6-Me
C3


261
5-F-2Thi
6-Me
GN


262
5-F-2Thi
4-F
RM


263
5-F-2Thi
4-F
SM


264
5-F-2Thi
4-F
DM


265
5-F-2Thi
4-F
C2


266
5-F-2Thi
4-F
C3


267
5-F-2Thi
4-F
GN


268
5-F-2Thi
2-Cl
RM


269
5-F-2Thi
2-Cl
SM


270
5-F-2Thi
2-Cl
DM


271
5-F-2Thi
2-Cl
C2


272
5-F-2Thi
2-Cl
C3


273
5-F-2Thi
2-Cl
GN


274
5-F-2Thi
4-Cl
RM


275
5-F-2Thi
4-Cl
SM


276
5-F-2Thi
4-Cl
DM


277
5-F-2Thi
4-Cl
C2


278
5-F-2Thi
4-Cl
C3


279
5-F-2Thi
4-Cl
GN


280
5-Cl-2Thi
H
SM


281
5-Cl-2Thi
H
C2


282
5-Cl-2Thi
H
C3


283
5-Cl-2Thi
H
GN


284
5-Cl-2Thi
2-Me
RM


285
5-Cl-2Thi
2-Me
SM


286
5-Cl-2Thi
2-Me
DM


287
5-Cl-2Thi
2-Me
C2


288
5-Cl-2Thi
2-Me
C3


289
5-Cl-2Thi
2-Me
GN


290
5-Cl-2Thi
4-Me
RM


291
5-Cl-2Thi
4-Me
SM


292
5-Cl-2Thi
4-Me
DM


293
5-Cl-2Thi
4-Me
C2


294
5-Cl-2Thi
4-Me
C3


295
5-Cl-2Thi
4-Me
GN


296
5-Cl-2Thi
6-Me
RM


297
5-Cl-2Thi
6-Me
SM


298
5-Cl-2Thi
6-Me
DM


299
5-Cl-2Thi
6-Me
C2


300
5-Cl-2Thi
6-Me
C3


301
5-Cl-2Thi
6-Me
GN


302
5-Cl-2Thi
4-F
SM


303
5-Cl-2Thi
4-F
C2



















TABLE 61





No
A
R2
R3







304
5-Cl-2Thi
4-F
C3


305
5-Cl-2Thi
4-F
GN


306
5-Cl-2Thi
2-Cl
RM


307
5-Cl-2Thi
2-Cl
SM


308
5-Cl-2Thi
2-Cl
DM


309
5-Cl-2Thi
2-Cl
C2


310
5-Cl-2Thi
2-Cl
C3


311
5-Cl-2Thi
2-Cl
GN


312
5-Cl-2Thi
4-Cl
RM


313
5-Cl-2Thi
4-Cl
SM


314
5-Cl-2Thi
4-Cl
DM


315
5-Cl-2Thi
4-Cl
C2


316
5-Cl-2Thi
4-Cl
C3


317
5-Cl-2Thi
4-Cl
GN
















TABLE 62













 










No.
A
R2
R3













318
3-F-Ph
H
C3


319
3-F-Ph
H
GN


320
3-F-Ph
Me
RM


321
3-F-Ph
Me
SM


322
3-F-Ph
Me
DM


323
3-F-Ph
Me
C2


324
3-F-Ph
Me
C3


325
3-F-Ph
Me
GN


326
3-Cl-Ph
H
RM


327
3-Cl-Ph
H
SM


328
3-Cl-Ph
H
DM


329
3-Cl-Ph
H
C2


330
3-Cl-Ph
H
C3


331
3-Cl-Ph
H
GN


332
3-Cl-Ph
Me
RM


333
3-Cl-Ph
Me
SM


334
3-Cl-Ph
Me
DM


335
3-Cl-Ph
Me
C2


336
3-Cl-Ph
Me
C3


337
3-Cl-Ph
Me
GN


338
3-Me-Ph
H
RM


339
3-Me-Ph
H
SM


340
3-Me-Ph
H
DM


341
3-Me-Ph
H
C2


342
3-Me-Ph
H
C3


343
3-Me-Ph
H
GN


344
3-Me-Ph
Me
RM


345
3-Me-Ph
Me
SM


346
3-Me-Ph
Me
DM


347
3-Me-Ph
Me
C2


348
3-Me-Ph
Me
C3


349
3-Me-Ph
Me
GN


350
3-F-4-Me-Ph
H
RM


351
3-F-4-Me-Ph
H
SM


352
3-F-4-Me-Ph
H
DM


353
3-F-4-Me-Ph
H
C2


354
3-F-4-Me-Ph
H
C3


355
3-F-4-Me-Ph
H
GN


356
3-F-4-Me-Ph
Me
RM


357
3-F-4-Me-Ph
Me
SM


358
3-F-4-Me-Ph
Me
DM


359
3-F-4-Me-Ph
Me
C2


360
3-F-4-Me-Ph
Me
C3


361
3-F-4-Me-Ph
Me
GN


362
2,5-diF-Ph
H
RM


363
2,5-diF-Ph
H
SM


364
2,5-diF-Ph
H
DM


365
2,5-diF-Ph
H
C2


366
2,5-diF-Ph
H
C3


367
2,5-diF-Ph
H
GN


368
2,5-diF-Ph
Me
RM


369
2,5-diF-Ph
Me
SM


370
2,5-diF-Ph
Me
DM


371
2,5-diF-Ph
Me
C2


372
2,5-diF-Ph
Me
C3


373
2,5-diF-Ph
Me
GN


374
3,5-diF-Ph
H
RM


375
3,5-diF-Ph
H
SM


376
3,5-diF-Ph
H
DM


377
3,5-diF-Ph
H
C2


378
3,5-diF-Ph
H
C3


379
3,5-diF-Ph
H
GN


380
3,5-diF-Ph
Me
RM


381
3,5-diF-Ph
Me
SM


382
3,5-diF-Ph
Me
DM


383
3,5-diF-Ph
Me
C2



















TABLE 63





No
A
R2
R3







384
3,5-diF-Ph
Me
C3


385
3,5-diF-Ph
Me
GN


386
2,4,5-triF-Ph
H
RM


387
2,4,5-triF-Ph
H
SM


388
2,4,5-triF-Ph
H
DM


389
2,4,5-triF-Ph
H
C2


390
2,4,5-triF-Ph
H
C3


391
2,4,5-triF-Ph
H
GN


392
2,4,5-triF-Ph
Me
RM


393
2,4,5-triF-Ph
Me
SM


394
2,4,5-triF-Ph
Me
DM


395
2,4,5-triF-Ph
Me
C2


396
2,4,5-triF-Ph
Me
C3


397
2,4,5-triF-Ph
Me
GN


398
4-F-2Thi
H
RM


399
4-F-2Thi
H
SM


400
4-F-2Thi
H
DM


401
4-F-2Thi
H
C2


402
4-F-2Thi
H
C3


403
4-F-2Thi
H
GN


404
4-F-2Thi
Me
RM


405
4-F-2Thi
Me
SM


406
4-F-2Thi
Me
DM


407
4-F-2Thi
Me
C2


408
4-F-2Thi
Me
C3


409
4-F-2Thi
Me
GN


410
5-F-2Thi
H
RM


411
5-F-2Thi
H
SM


412
5-F-2Thi
H
DM


413
5-F-2Thi
H
C2


414
5-F-2Thi
H
C3


415
5-F-2Thi
H
GN


416
5-F-2Thi
Me
RM


417
5-F-2Thi
Me
SM


418
5-F-2Thi
Me
DM


419
5-F-2Thi
Me
C2


420
5-F-2Thi
Me
C3


421
5-F-2Thi
Me
GN


422
5-Cl-2Thi
H
DM


423
5-Cl-2Thi
H
C2


424
5-Cl-2Thi
H
C3


425
5-Cl-2Thi
H
GN


426
5-Cl-2Thi
Me
RM


427
5-Cl-2Thi
Me
SM


428
5-Cl-2Thi
Me
DM


429
5-Cl-2Thi
Me
C2


430
5-Cl-2Thi
Me
C3


431
5-Cl-2Thi
Me
GN
















TABLE 64













 










No
A
R2
R3













432
3-F-Ph
H
RM


433
3-F-Ph
H
SM


434
3-F-Ph
H
DM


435
3-F-Ph
H
C2


436
3-F-Ph
H
C3


437
3-F-Ph
H
GN


438
3-F-Ph
Me
RM


439
3-F-Ph
Me
SM


440
3-F-Ph
Me
DM


441
3-F-Ph
Me
C2


442
3-F-Ph
Me
C3


443
3-F-Ph
Me
GN


444
3-Cl-Ph
H
RM


445
3-Cl-Ph
H
SM


446
3-Cl-Ph
H
DM


447
3-Cl-Ph
H
C2


448
3-Cl-Ph
H
C3


449
3-Cl-Ph
H
GN


450
3-Cl-Ph
Me
RM


451
3-Cl-Ph
Me
SM


452
3-Cl-Ph
Me
DM


453
3-Cl-Ph
Me
C2


454
3-Cl-Ph
Me
C3


455
3-Cl-Ph
Me
GN


456
3-Me-Ph
H
RM


457
3-Me-Ph
H
SM


458
3-Me-Ph
H
DM


459
3-Me-Ph
H
C2


460
3-Me-Ph
H
C3


461
3-Me-Ph
H
GN


462
3-Me-Ph
Me
RM


463
3-Me-Ph
Me
SM


464
3-Me-Ph
Me
DM



















TABLE 65





No
A
R2
R3







465
3-Me-Ph
Me
C2


466
3-Me-Ph
Me
C3


467
3-Me-Ph
Me
GN


468
3-F-4-Me-Ph
H
RM


469
3-F-4-Me-Ph
H
SM


470
3-F-4-Me-Ph
H
DM


471
3-F-4-Me-Ph
H
C2


472
3-F-4-Me-Ph
H
C3


473
3-F-4-Me-Ph
H
GN


474
3-F-4-Me-Ph
Me
RM


475
3-F-4-Me-Ph
Me
SM


476
3-F-4-Me-Ph
Me
DM


477
3-F-4-Me-Ph
Me
C2


478
3-F-4-Me-Ph
Me
C3


479
3-F-4-Me-Ph
Me
GN


480
2,5-diF-Ph
H
RM


481
2,5-diF-Ph
H
SM


482
2,5-diF-Ph
H
DM


483
2,5-diF-Ph
H
C2


484
2,5-diF-Ph
H
C3


485
2,5-diF-Ph
H
GN


486
2,5-diF-Ph
Me
RM


487
2,5-diF-Ph
Me
SM


488
2,5-diF-Ph
Me
DM


489
2,5-diF-Ph
Me
C2


490
2,5-diF-Ph
Me
C3


491
2,5-diF-Ph
Me
GN


492
3,5-diF-Ph
H
RM


493
3,5-diF-Ph
H
SM


494
3,5-diF-Ph
H
DM


495
3,5-diF-Ph
H
C2


496
3,5-diF-Ph
H
C3


497
3,5-diF-Ph
H
GN


498
3,5-diF-Ph
Me
RM


499
3,5-diF-Ph
Me
SM


500
3,5-diF-Ph
Me
DM


501
3,5-diF-Ph
Me
C2


502
3,5-diF-Ph
Me
C3


503
3,5-diF-Ph
Me
GN


504
2,4,5-triF-Ph
H
RM


505
2,4,5-triF-Ph
H
SM


506
2,4,5-triF-Ph
H
DM


507
2,4,5-triF-Ph
H
C2


508
2,4,5-triF-Ph
H
C3


509
2,4,5-triF-Ph
H
GN


510
2,4,5-triF-Ph
Me
RM


511
2,4,5-triF-Ph
Me
SM


512
2,4,5-triF-Ph
Me
DM


513
2,4,5-triF-Ph
Me
C2


514
2,4,5-triF-Ph
Me
C3


515
2,4,5-triF-Ph
Me
GN


516
4-F-2Thi
H
RM


517
4-F-2Thi
H
SM


518
4-F-2Thi
H
DM


519
4-F-2Thi
H
C2


520
4-F-2Thi
H
C3


521
4-F-2Thi
H
GN


522
4-F-2Thi
Me
RM


523
4-F-2Thi
Me
SM


524
4-F-2Thi
Me
DM


525
4-F-2Thi
Me
C2


526
4-F-2Thi
Me
C3


527
4-F-2Thi
Me
GN


528
5-F-2Thi
H
RM


529
5-F-2Thi
H
SM


530
5-F-2Thi
H
DM


531
5-F-2Thi
H
C2


532
5-F-2Thi
H
C3


533
5-F-2Thi
H
GN


534
5-F-2Thi
Me
RM


535
5-F-2Thi
Me
SM


536
5-F-2Thi
Me
DM


537
5-F-2Thi
Me
C2


538
5-F-2Thi
Me
C3


539
5-F-2Thi
Me
GN


540
5-Cl-2Thi
H
RM


541
5-Cl-2Thi
H
SM


542
5-Cl-2Thi
H
DM


543
5-Cl-2Thi
H
C2


544
5-Cl-2Thi
H
C3


545
5-Cl-2Thi
H
GN


546
5-Cl-2Thi
Me
RM


547
5-Cl-2Thi
Me
SM


548
5-Cl-2Thi
Me
DM


549
5-Cl-2Thi
Me
C2


550
5-Cl-2Thi
Me
C3


551
5-Cl-2Thi
Me
GN
















TABLE 66













 










No
A
R2
R3













552
3-F-Ph
H
RM


553
3-F-Ph
H
SM


554
3-F-Ph
H
DM


555
3-F-Ph
H
C2


556
3-F-Ph
H
C3


557
3-F-Ph
H
GN


558
3-F-Ph
Cl
RM


559
3-F-Ph
Cl
SM


560
3-F-Ph
Cl
DM


561
3-F-Ph
Cl
C2


562
3-F-Ph
Cl
C3


563
3-F-Ph
Cl
GN


564
3-Cl-Ph
H
RM


565
3-Cl-Ph
H
SM


566
3-Cl-Ph
H
DM


567
3-Cl-Ph
H
C2


568
3-Cl-Ph
H
C3


569
3-Cl-Ph
H
GN


570
3-Cl-Ph
Cl
RM


571
3-Cl-Ph
Cl
SM


572
3-Cl-Ph
Cl
DM


573
3-Cl-Ph
Cl
C2


574
3-Cl-Ph
Cl
C3


575
3-Cl-Ph
Cl
GN


576
3-Me-Ph
H
RM


577
3-Me-Ph
H
SM


578
3-Me-Ph
H
DM


579
3-Me-Ph
H
C2


580
3-Me-Ph
H
C3


581
3-Me-Ph
H
GN


582
3-Me-Ph
Cl
RM


583
3-Me-Ph
Cl
SM


584
3-Me-Ph
Cl
DM


585
3-Me-Ph
Cl
C2


586
3-Me-Ph
Cl
C3


587
3-Me-Ph
Cl
GN


588
3-F-4-Me-Ph
H
RM


589
3-F-4-Me-Ph
H
SM


590
3-F-4-Me-Ph
H
DM


591
3-F-4-Me-Ph
H
C2


592
3-F-4-Me-Ph
H
C3


593
3-F-4-Me-Ph
H
GN


594
3-F-4-Me-Ph
Cl
RM


595
3-F-4-Me-Ph
Cl
SM


596
3-F-4-Me-Ph
Cl
DM


597
3-F-4-Me-Ph
Cl
C2


598
3-F-4-Me-Ph
Cl
C3


599
3-F-4-Me-Ph
Cl
GN


600
2,5-diF-Ph
H
RM


601
2,5-diF-Ph
H
SM


602
2,5-diF-Ph
H
DM


603
2,5-diF-Ph
H
C2


604
2,5-diF-Ph
H
C3


605
2,5-diF-Ph
H
GN


606
2,5-diF-Ph
Cl
RM


607
2,5-diF-Ph
Cl
SM


608
2,5-diF-Ph
Cl
DM


609
2,5-diF-Ph
Cl
C2


610
2,5-diF-Ph
Cl
C3


611
2,5-diF-Ph
Cl
GN


612
3,5-diF-Ph
H
RM


613
3,5-diF-Ph
H
SM


614
3,5-diF-Ph
H
DM


615
3,5-diF-Ph
H
C2


616
3,5-diF-Ph
H
C3


617
3,5-diF-Ph
H
GN


618
3,5-diF-Ph
Cl
RM


619
3,5-diF-Ph
Cl
SM


620
3,5-diF-Ph
Cl
DM


621
3,5-diF-Ph
Cl
C2


622
3,5-diF-Ph
Cl
C3


623
3,5-diF-Ph
Cl
GN


624
2,4,5-triF-Ph
H
RM


625
2,4,5-triF-Ph
H
SM


626
2,4,5-triF-Ph
H
DM


627
2,4,5-triF-Ph
H
C2


628
2,4,5-triF-Ph
H
C3


629
2,4,5-triF-Ph
H
GN


630
2,4,5-triF-Ph
Cl
RM


631
2,4,5-triF-Ph
Cl
SM


632
2,4,5-triF-Ph
Cl
DM


633
2,4,5-triF-Ph
Cl
C2


634
2,4,5-triF-Ph
Cl
C3


635
2,4,5-triF-Ph
Cl
GN


636
4-F-2Thi
H
RM


637
4-F-2Thi
H
SM


638
4-F-2Thi
H
DM


639
4-F-2Thi
H
C2


640
4-F-2Thi
H
C3


641
4-F-2Thi
H
GN



















TABLE 67





No
A
R2
R3







642
4-F-2Thi
Cl
RM


643
4-F-2Thi
Cl
SM


644
4-F-2Thi
Cl
DM


645
4-F-2Thi
Cl
C2


646
4-F-2Thi
Cl
C3


647
4-F-2Thi
Cl
GN


648
5-F-2Thi
H
RM


649
5-F-2Thi
H
SM


650
5-F-2Thi
H
DM


651
5-F-2Thi
H
C2


652
5-F-2Thi
H
C3


653
5-F-2Thi
H
GN


654
5-F-2Thi
Cl
RM


655
5-F-2Thi
Cl
SM


656
5-F-2Thi
Cl
DM


657
5-F-2Thi
Cl
C2


658
5-F-2Thi
Cl
C3


659
5-F-2Thi
Cl
GN


660
5-Cl-2Thi
H
RM


661
5-Cl-2Thi
H
SM


662
5-Cl-2Thi
H
DM


663
5-Cl-2Thi
H
C2


664
5-Cl-2Thi
H
C3


665
5-Cl-2Thi
H
GN


666
5-Cl-2Thi
Cl
RM


667
5-Cl-2Thi
Cl
SM


668
5-Cl-2Thi
Cl
DM


669
5-Cl-2Thi
Cl
C2


670
5-Cl-2Thi
Cl
C3


671
5-Cl-2Thi
Cl
GN
















TABLE 68













 










No
A
R2
R3













672
3-F-Ph
H
RM


673
3-F-Ph
H
SM


674
3-F-Ph
H
DM


675
3-F-Ph
H
C2


676
3-F-Ph
H
C3


677
3-F-Ph
H
GN


678
3-F-Ph
Cl
RM


679
3-F-Ph
Cl
SM


680
3-F-Ph
Cl
DM


681
3-F-Ph
Cl
C2


682
3-F-Ph
Cl
C3


683
3-F-Ph
Cl
GN


684
3-F-Ph
Me
RM


685
3-F-Ph
Me
SM


686
3-F-Ph
Me
DM


687
3-F-Ph
Me
C2


688
3-F-Ph
Me
C3


689
3-F-Ph
Me
GN


690
3-Cl-Ph
H
RM


691
3-Cl-Ph
H
SM


692
3-Cl-Ph
H
DM


693
3-Cl-Ph
H
C2


694
3-Cl-Ph
H
C3


695
3-Cl-Ph
H
GN


696
3-Cl-Ph
Cl
RM


697
3-Cl-Ph
Cl
SM


698
3-Cl-Ph
Cl
DM


699
3-Cl-Ph
Cl
C2


700
3-Cl-Ph
Cl
C3


701
3-Cl-Ph
Cl
GN


702
3-Cl-Ph
Me
RM


703
3-Cl-Ph
Me
SM


704
3-Cl-Ph
Me
DM


705
3-Cl-Ph
Me
C2


706
3-Cl-Ph
Me
C3


707
3-Cl-Ph
Me
GN


708
3-Me-Ph
H
RM


709
3-Me-Ph
H
SM


710
3-Me-Ph
H
DM


711
3-Me-Ph
H
C2


712
3-Me-Ph
H
C3


713
3-Me-Ph
H
GN


714
3-Me-Ph
Cl
RM


715
3-Me-Ph
Cl
SM


716
3-Me-Ph
Cl
DM


717
3-Me-Ph
Cl
C2


718
3-Me-Ph
Cl
C3


719
3-Me-Ph
Cl
GN


720
3-Me-Ph
Me
RM


721
3-Me-Ph
Me
SM


722
3-Me-Ph
Me
DM



















TABLE 69





No
A
R2
R3







723
3-Me-Ph
Me
C2


724
3-Me-Ph
Me
C3


725
3-Me-Ph
Me
GN


726
3-F-4-Me-Ph
H
RM


727
3-F-4-Me-Ph
H
SM


728
3-F-4-Me-Ph
H
DM


729
3-F-4-Me-Ph
H
C2


730
3-F-4-Me-Ph
H
C3


731
3-F-4-Me-Ph
H
GN


732
3-F-4-Me-Ph
Cl
RM


733
3-F-4-Me-Ph
Cl
SM


734
3-F-4-Me-Ph
Cl
DM


735
3-F-4-Me-Ph
Cl
C2


736
3-F-4-Me-Ph
Cl
C3


737
3-F-4-Me-Ph
Cl
GN


738
3-F-4-Me-Ph
Me
RM


739
3-F-4-Me-Ph
Me
SM


740
3-F-4-Me-Ph
Me
DM


741
3-F-4-Me-Ph
Me
C2


742
3-F-4-Me-Ph
Me
C3


743
3-F-4-Me-Ph
Me
GN


744
2,5-diF-Ph
H
RM


745
2,5-diF-Ph
H
SM


746
2,5-diF-Ph
H
DM


747
2,5-diF-Ph
H
C2


748
2,5-diF-Ph
H
C3


749
2,5-diF-Ph
H
GN


750
2,5-diF-Ph
Cl
RM


751
2,5-diF-Ph
Cl
SM


752
2,5-diF-Ph
Cl
DM


753
2,5-diF-Ph
Cl
C2


754
2,5-diF-Ph
Cl
C3


755
2,5-diF-Ph
Cl
GN


756
2,5-diF-Ph
Me
RM


757
2,5-diF-Ph
Me
SM


758
2,5-diF-Ph
Me
DM


759
2,5-diF-Ph
Me
C2


760
2,5-diF-Ph
Me
C3


761
2,5-diF-Ph
Me
GN


762
2,5-diF-Ph
H
RM


763
3,5-diF-Ph
H
SM


764
3,5-diF-Ph
H
DM


765
3,5-diF-Ph
H
C2


766
3,5-diF-Ph
H
C3


767
3,5-diF-Ph
H
GN


768
3,5-diF-Ph
Cl
RM


769
3,5-diF-Ph
Cl
SM


770
3,5-diF-Ph
Cl
DM


771
3,5-diF-Ph
Cl
C2


772
3,5-diF-Ph
Cl
C3


773
3,5-diF-Ph
Cl
GN


774
3,5-diF-Ph
Me
RM


775
3,5-diF-Ph
Me
SM


776
3,5-diF-Ph
Me
DM


777
3,5-diF-Ph
Me
C2


778
3,5-diF-Ph
Me
C3


779
3,5-diF-Ph
Me
GN


780
2,4,5-triF-Ph
H
RM


781
2,4,5-triF-Ph
H
SM


782
2,4,5-triF-Ph
H
DM


783
2,4,5-triF-Ph
H
C2


784
2,4,5-triF-Ph
H
C3


785
2,4,5-triF-Ph
H
GN


786
2,4,5-triF-Ph
Cl
RM


787
2,4,5-triF-Ph
Cl
SM


788
2,4,5-triF-Ph
Cl
DM


789
2,4,5-triF-Ph
Cl
C2


790
2,4,5-triF-Ph
Cl
C3


791
2,4,5-triF-Ph
Cl
GN


792
2,4,5-triF-Ph
Me
RM


793
2,4,5-triF-Ph
Me
SM


794
2,4,5-triF-Ph
Me
DM


795
2,4,5-triF-Ph
Me
C2


796
2,4,5-triF-Ph
Me
C3


797
2,4,5-triF-Ph
Me
GN


798
4-F-2Thi
H
RM


799
4-F-2Thi
H
SM


800
4-F-2Thi
H
DM


801
4-F-2Thi
H
C2


802
4-F-2Thi
H
C3


803
4-F-2Thi
H
GN


804
4-F-2Thi
Cl
RM


805
4-F-2Thi
Cl
SM


806
4-F-2Thi
Cl
DM


807
4-F-2Thi
Cl
C2


808
4-F-2Thi
Cl
C3


809
4-F-2Thi
Cl
GN


810
4-F-2Thi
Me
RM


811
4-F-2Thi
Me
SM


812
4-F-2Thi
Me
DM


813
4-F-2Thi
Me
C2


814
4-F-2Thi
Me
C3


815
4-F-2Thi
Me
GN


816
5-F-2Thi
H
RM


817
5-F-2Thi
H
SM


818
5-F-2Thi
H
DM


819
5-F-2Thi
H
C2


820
5-F-2Thi
H
C3


821
5-F-2Thi
H
GN


822
5-F-2Thi
Cl
RM


823
5-F-2Thi
Cl
SM


824
5-F-2Thi
Cl
DM


825
5-F-2Thi
Cl
C2


826
5-F-2Thi
Cl
C3


827
5-F-2Thi
Cl
GN


828
5-F-2Thi
Me
RM


829
5-F-2Thi
Me
SM


830
5-F-2Thi
Me
DM



















TABLE 70





No
A
R2
R3







831
5-F-2Thi
Me
C2


832
5-F-2Thi
Me
C3


833
5-F-2Thi
Me
GN


834
5-Cl-2Thi
H
RM


835
5-Cl-2Thi
H
SM


836
5-Cl-2Thi
H
DM


837
5-Cl-2Thi
H
C2


838
5-Cl-2Thi
H
C3


839
5-Cl-2Thi
H
GN


840
5-Cl-2Thi
Cl
RM


841
5-Cl-2Thi
Cl
SM


842
5-Cl-2Thi
Cl
DM


843
5-Cl-2Thi
Cl
C2


844
5-Cl-2Thi
Cl
C3


845
5-Cl-2Thi
Cl
GN


846
5-Cl-2Thi
Me
RM


847
5-Cl-2Thi
Me
SM


848
5-Cl-2Thi
Me
DM


849
5-Cl-2Thi
Me
C2


850
5-Cl-2Thi
Me
C3


851
5-Cl-2Thi
Me
GN









INDUSTRIAL APPLICABILITY
The compounds of the present invention have a potent GnRH receptor antagonistic effect and additionally an excellent oral activity, and therefore are useful as pharmaceuticals for sex hormone-dependent diseases, especially GnRH-related diseases, for example, prostate cancer, benign prostatic hyperplasia, breast cancer, endometriosis, uterine fibroid, etc.

## Claims

1. A propane-1,3-dione derivative represented by the general formula (I) or a pharmaceutically acceptable salt thereof:



wherein the symbols in the formula have the following meanings:
ring A: optionally substituted aryl or optionally substituted heteroaryl,
ring B: benzene ring or thiophene ring,
ring C: benzene ring or 5- to 7-membered aliphatic hydrocarbon ring optionally having a double bond in the ring,
R1: the same or different, each representing halogen, optionally substituted hydrocarbon group, —O-(optionally substituted hydrocarbon group), optionally substituted heterocyclic group, —S-(optionally substituted hydrocarbon group), —CO-(optionally substituted hydrocarbon group), —CO2-(optionally substituted hydrocarbon group), —O—CO-(optionally substituted hydrocarbon group), —SO-(optionally substituted hydrocarbon group), —SO2— (optionally substituted hydrocarbon group), —NO2, —CN, —CO2H, optionally substituted carbamoyl, optionally substituted sulfamoyl, or optionally substituted amino group,
R2: the same or different, each representing halogen, R0, —O—R0 or halogen lower alkyl,
m, n: the same or different, each indicating 0, 1 or 2,
R3: R0, —OH, —O-optionally substituted heteroaryl, —N(R51)(R52), —N(R73)-N(R74)(R75),





or, taken together with R2, —N═C(R45)—NH— or —NH—C(R45)═N—,
ring D: optionally substituted heterocyclic ring selected from the following group:




R0: the same or different, each representing lower alkyl,
R00: the same or different, each representing lower alkylene,
k: 1, 2, 3, or 4,
p: 0, 1 or 2,
R41, R42 and R43: the same or different, each representing H, optionally substituted lower alkyl, —CHO, —CO-(optionally substituted lower alkyl), optionally substituted cycloalkyl, —CO2H, —CO2—R0, —CONH2, —CO—NH(R0—CO—N(R0)2, —R00—CONH(R0), —R00—CON(R0)2, optionally substituted aryl, optionally substituted heterocyclic group, —R00—O-aryl, —R00—SO—R0—O—R00—SO2—R0, —R00—N(OH)—R0 or —R00—N(O—R0)—R0,
R44 and R45: the same or different, each representing R0 or —R00-aryl,
R51 and R52: the same or different, each representing H, optionally substituted lower alkyl, —R00-(optionally substituted cycloalkyl), —R00-(optionally substituted aryl), optionally substituted heteroaryl, —CO—R0, —CO2—R0, —OH, —O—R0, —O-benzyl, —R00—O—R00—OH or optionally substituted cycloalkyl,
R54, R55, R57, R58, R61, R64, R67, R68, R70, R72, R73 and R74: the same or different, each representing H or R0,
R56, R59, R66, R69, and R71: the same or different, each representing H, R0 or —CO—R0,
R60: H, R0, —R00—OH or —CO—R0,
R62: H, R0, —O—R0 or —O-benzyl,
R63: H, R0, —NH2 or —CO—R0,
R65: H, R0, —R00—OH—CONH2 or —CO—R0,
R75: H, R0, —R00-aryl, aryl or heteroaryl, or
R54 and R41, R57 and R58, R61 and R42, R68 and R44, R62 and R63, R62 and R65, and R63 and R65, each taken together, may form lower alkylene optionally substituted with oxo group;
provided that, when ring A is phenyl substituted with —CH(OH)—CH2—OH, and when m and n are both 0, then R3 means a group except —N(CH3)2).

2. The compound according to claim 1, wherein the ring C is benzene ring, or a pharmaceutically acceptable salt thereof.

3. The compound according to claim 2, wherein the ring B is benzene ring, or a pharmaceutically acceptable salt thereof.

4. The compound according to claim 3, wherein ring A is optionally substituted phenyl, optionally substituted naphthyl, optionally substituted thienyl, optionally substituted pyridyl, optionally substituted thiazolyl, or benzofuranyl, or a pharmaceutically acceptable salt thereof.

5. The compound according to claim 4, wherein R3 is —N(R51)(R52) or a group selected from the following group, or a pharmaceutically acceptable salt thereof:

6. The compound according to claim 5, wherein m is 0 or a pharmaceutically acceptable salt thereof.

7. A propane-1,3-dione derivative of the general formula (Ia) or a pharmaceutically acceptable salt thereof:



wherein the symbols in the formula have the following meanings:
ring A1: phenyl or thienyl, each of which is optionally substituted with the same or different one to three substituents selected from the following group G:
Group G: halogen, lower alkyl and —O-lower alkyl,
R2a: halogen, lower alkyl or —O-lower alkyl,
R3a, R3b: the same or different, each representing H or lower alkyl,
R4: H, —C(═O)-lower alkyl or —C(═O)-heteroaryl,
n1: 0 or 1.

8. The compound according to claim 1, selected from the following group, or a pharmaceutically acceptable salt thereof:
(2R)-N-({3-[2-(1,3-dihydro-2H-benzimidazol-2-ylidene)-3-(3-fluorophenyl)-3-oxopropanoyl]phenyl}sulfonyl)-2-hydroxypropanimidamide,
N-({3-[2-(1,3-dihydro-2H-benzimidazol-2-ylidene)-3-(3-fluorophenyl)-3-oxopropanoyl]phenyl}sulfonyl)-2-hydroxy-2-methylpropanimidamide,
N-({5-[2-(1,3-dihydro-2H-benzimidazol-2-ylidene)-3-(3-fluorophenyl)-3-oxopropanoyl]-2-fluorophenyl}sulfonyl)-2-hydroxy-2-methylpropanimidamide,
(2R)-N-({5-[2-(1,3-dihydro-2H-benzimidazol-2-ylidene)-3-(3-fluorophenyl)-3-oxopropanoyl]-2-fluorophenyl}sulfonyl)-2-hydroxypropanimidamide,
(2R)-N-({5-[2-(1,3-dihydro-2H-benzimidazol-2-ylidene)-3-(3-methylphenyl)-3-oxopropanoyl]-2-fluorophenyl}sulfonyl)-2-hydroxypropanimidamide,
N-({5-[3-(3,5-difluorophenyl)-2-(1,3-dihydro-2H-benzimidazol-2-ylidene)-3-oxopropanoyl]-2-fluorophenyl}sulfonyl)-2-hydroxy-2-methylpropanimidamide,
(2R)-N-({5-[3-(3,5-difluorophenyl)-2-(1,3-dihydro-2H-benzimidazol-2-ylidene)-3-oxopropanoyl]-2-fluorophenyl}sulfonyl)-2-hydroxypropanimidamide,
(2R)-N-({5-[3-(3-chlorophenyl)-2-(1,3-dihydro-2H-benzimidazol-2-ylidene)-3-oxopropanoyl]-2-fluorophenyl}sulfonyl)-2-hydroxypropanimidamide,
N-({5-[2-(1,3-dihydro-2H-benzimidazol-2-ylidene)-3-oxo-3-(2,4,5-trifluorophenyl)propanoyl]-2-fluorophenyl}sulfonyl)-2-hydroxy-2-methylpropanimidamide,
(2R)-N-({5-[1,3-dihydro-2H-benzimidazol-2-ylidene)-3-oxo-3-(2,4,5-trifluorophenyl)propanoyl]-2-fluorophenyl}sulfonyl)-2-hydroxypropanimidamide,
(2R)-N-({5-[2-(1,3-dihydro-2H-benzimidazol-2-ylidene)-3-(3-fluoro-4-methylphenyl)-3-oxopropanoyl]-2-fluorophenyl}sulfonyl)-2-hydroxypropanimidamide,
(2R)-N-({5-[3-(2,5-difluorophenyl)-2-(1,3-dihydro-2H-benzimidazol-2-ylidene)-3-oxopropanoyl]-2-fluorophenyl}sulfonyl)-2-hydroxypropanimidamide,
N-({5-[3-(2,5-difluorophenyl)-2-(1,3-dihydro-2H-benzimidazol-2-ylidene)-3-oxopropanoyl]-2-fluorophenyl}sulfonyl)-2-hydroxy-2-methylpropanimidamide,
(2R)-N-({5-[3-(5-chloro-2-thienyl)-2-(1,3-dihydro-2H-benzimidazol-2-ylidene)-3-oxopropanoyl]-2-fluorophenyl}sulfonyl)-2-hydroxypropanimidamide, and
N-({5-[3-(5-chloro-2-thienyl)-2-(1,3-dihydro-2H-benzimidazol-2-ylidene)-3-oxopropanoyl]-2-fluorophenyl}sulfonyl)-2-hydroxy-2-methylpropanimidamide.

9. A pharmaceutical composition comprising the compound of claim 1 or a pharmaceutically acceptable salt thereof as an active ingredient.

10. A method for treating prostate cancer, benign prostatic hyperplasia, breast cancer, endometriosis and/or uterine fibroid, comprising administering a therapeutically effective amount of the compound of claim 1 or a pharmaceutically acceptable salt thereof to a patient in need thereof.

11. The compound according to claim 1, which is the following compound, or a pharmaceutically acceptable salt thereof:
(2R)-N-({3-[2-(1,3-dihydro-2H-benzimidazol-2-ylidene)-3-(3-fluorophenyl)-3-oxopropanoyl]phenyl}sulfonyl)-2-hydroxypropanimidamide.

12. The compound according to claim 1, which is the following compound, or a pharmaceutically acceptable salt thereof:
N-({3-[2-(1,3-dihydro-2H-benzimidazol-2-ylidene)-3-(3-fluorophenyl)-3-oxopropanoyl]phenyl}sulfonyl)-2-hydroxy-2-methylpropanimidamide.

13. The compound according to claim 1, which is the following compound, or a pharmaceutically acceptable salt thereof:
N-({5-[2-(1,3-dihydro-2H-benzimidazol-2-ylidene)-3-(3-fluorophenyl)-3-oxopropanoyl]-2-fluorophenyl}sulfonyl)-2-hydroxy-2-methylpropanimidamide.

14. The compound according to claim 1, which is the following compound, or a pharmaceutically acceptable salt thereof:
(2R)-N-({5-[2-(1,3-dihydro-2H-benzimidazol-2-ylidene)-3-(3-fluorophenyl)-3-oxopropanoyl]-2-fluorophenyl}sulfonyl)-2-hydroxypropanimidamide.

15. The compound according to claim 1, which is the following compound, or a pharmaceutically acceptable salt thereof:
N-({5-[3-(3,5-difluorophenyl)-2-(1,3-dihydro-2H-benzimidazol-2-ylidene)-3-oxopropanoyl]-2-fluorophenyl}sulfonyl)-2-hydroxy-2-methylpropanimidamide.

16. The compound according to claim 1, which is the following compound, or a pharmaceutically acceptable salt thereof:
(2R)-N-({5-[3-(3,5-difluorophenyl)-2-(1,3-dihydro-2H-benzimidazol-2-ylidene)-3-oxopropanoyl]-2-fluorophenyl}sulfonyl)-2-hydroxypropanimidamide.

17. The compound according to claim 1, which is the following compound, or a pharmaceutically acceptable salt thereof:
(2R)-N-({5-[3-(3-chlorophenyl)-2-(1,3-dihydro-2H-benzimidazol-2-ylidene)-3-oxopropanoyl]-2-fluorophenyl}sulfonyl)-2-hydroxypropanimidamide.

18. The compound according to claim 1, which is the following compound, or a pharmaceutically acceptable salt thereof:
(2R)-N-({5-[3-(2,5-difluorophenyl)-2-(1,3-dihydro-2H-benzimidazol-2-ylidene)-3-oxopropanoyl]-2-fluorophenyl}sulfonyl)-2-hydroxypropanimidamide.

19. The compound according to claim 1, which is the following compound, or a pharmaceutically acceptable salt thereof:
N-({5-[3-(2,5-difluorophenyl)-2-(1,3-dihydro-2H-benzimidazol-2-ylidene)-3-oxopropanoyl]-2-fluorophenyl}sulfonyl)-2-hydroxy-2-methylpropanimidamide.