U.S. patent application number 14/679666 was filed with the patent office on 2015-07-30 for aminodihydrothiazine derivatives.
The applicant listed for this patent is Shionogi & Co., Ltd.. Invention is credited to Hidekazu HARAGUCHI, Akihiro HORI, Naohiro ITOH, Yasuhiko KANDA, Akira KATO, Naotake KOBAYASHI, Yuji KORIYAMA, Gaku SAKAGUCHI, Shinji SUZUKI, Kazuo UEDA, Ken YASUI, Akira YUKIMASA.
Application Number | 20150210680 14/679666 |
Document ID | / |
Family ID | 37967644 |
Filed Date | 2015-07-30 |
United States Patent
Application |
20150210680 |
Kind Code |
A1 |
KOBAYASHI; Naotake ; et
al. |
July 30, 2015 |
AMINODIHYDROTHIAZINE DERIVATIVES
Abstract
A composition having BACE 1 inhibitory activity containing a
compound represented by the general formula (I): ##STR00001##
wherein ring A is an optionally substituted carbocyclic group or an
optionally substituted heterocyclic group; E is lower alkylene; X
is S, O, or NR.sup.1; R.sup.1 is a hydrogen atom or lower alkyl;
R.sup.2a, R.sup.2b, R.sup.3a, R.sup.3b, R.sup.4a and R.sup.4b is
each independently a hydrogen atom, halogen, or hydroxy etc.; n and
m are each independently an integer of 0 to 3; n+m is an integer of
0 to 3; R.sup.5 is a hydrogen atom or substituted lower alkyl; its
pharmaceutically acceptable salt, or a solvate thereof.
Inventors: |
KOBAYASHI; Naotake;
(Osaka-shi, JP) ; UEDA; Kazuo; (Osaka-shi, JP)
; ITOH; Naohiro; (Koka-shi, JP) ; SUZUKI;
Shinji; (Osaka-shi, JP) ; SAKAGUCHI; Gaku;
(Koka-shi, JP) ; KATO; Akira; (Koka-shi, JP)
; YUKIMASA; Akira; (Osaka-shi, JP) ; HORI;
Akihiro; (Osaka-shi, JP) ; KORIYAMA; Yuji;
(Osaka-shi, JP) ; HARAGUCHI; Hidekazu; (Osaka-shi,
JP) ; YASUI; Ken; (Osaka-shi, JP) ; KANDA;
Yasuhiko; (Osaka-shi, JP) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Shionogi & Co., Ltd. |
Osaka |
|
JP |
|
|
Family ID: |
37967644 |
Appl. No.: |
14/679666 |
Filed: |
April 6, 2015 |
Related U.S. Patent Documents
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Application
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Filing Date |
Patent Number |
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13941082 |
Jul 12, 2013 |
9029358 |
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14679666 |
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13768557 |
Feb 15, 2013 |
8815851 |
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13941082 |
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13243971 |
Sep 23, 2011 |
8546380 |
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13768557 |
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12089409 |
Apr 18, 2008 |
8173642 |
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PCT/JP2006/321015 |
Oct 23, 2006 |
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13243971 |
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Current U.S.
Class: |
514/211.08 ;
514/211.01; 514/211.15; 514/227.2; 514/228.8; 514/275; 514/370;
540/544; 540/575; 540/598; 544/330; 544/331; 544/53; 544/54;
544/55; 544/88; 548/199 |
Current CPC
Class: |
C07D 417/12 20130101;
A61K 9/1623 20130101; A61P 27/02 20180101; C07D 417/10 20130101;
A61K 31/505 20130101; A61P 31/00 20180101; A61K 31/554 20130101;
C07D 279/06 20130101; C07D 405/10 20130101; C07D 417/04 20130101;
C07D 239/24 20130101; A61P 9/14 20180101; A61P 9/00 20180101; C07D
277/18 20130101; A61K 9/2018 20130101; A61K 31/541 20130101; C07D
239/14 20130101; C07D 405/04 20130101; A61K 31/55 20130101; C07D
279/08 20130101; A61K 31/506 20130101; C07D 281/02 20130101; C07D
417/14 20130101; C07D 279/12 20130101; A61P 25/16 20180101; A61K
31/551 20130101; A61K 31/5415 20130101; A61P 43/00 20180101; C07D
239/42 20130101; C07D 471/04 20130101; A61K 31/54 20130101; A61P
25/00 20180101; A61K 31/426 20130101; A61P 25/28 20180101; A61K
9/0019 20130101; A61K 31/535 20130101; C07D 265/08 20130101 |
International
Class: |
C07D 417/14 20060101
C07D417/14; C07D 281/02 20060101 C07D281/02; C07D 265/08 20060101
C07D265/08; C07D 239/14 20060101 C07D239/14; C07D 279/08 20060101
C07D279/08; C07D 417/12 20060101 C07D417/12; C07D 279/12 20060101
C07D279/12; C07D 417/04 20060101 C07D417/04; C07D 405/04 20060101
C07D405/04; C07D 279/06 20060101 C07D279/06; C07D 277/18 20060101
C07D277/18 |
Foreign Application Data
Date |
Code |
Application Number |
Oct 25, 2005 |
JP |
2005-309642 |
Mar 20, 2006 |
JP |
2006-076636 |
Claims
1. A compound represented by formula (I): ##STR01369## wherein ring
A is an optionally substituted carbocyclic group, the carbocyclic
group being substituted optionally with at least one selected from
the group consisting of (A) the substituent .alpha., the
substituent .alpha. being at least one selected from the group
consisting of halogen, hydroxy, lower alkoxy, hydroxy lower alkoxy,
lower alkoxy lower alkoxy, acyl, acyloxy, carboxy, lower
alkoxycarbonyl, amino, acylamino, lower alkylamino, lower
alkylthio, carbamoyl, lower alkylcarbamoyl, hydroxy lower
alkylcarbamoyl, sulfamoyl, lower alkylsulfamoyl, lower
alkylsulfinyl, cyano, nitro, aryl, and heterocyclic group; (B)
lower alkyl optionally substituted with one or more substituents
selected from the group of substituent .alpha.; (C) amino lower
alkyl substituted with one or more substituents selected from the
group of substituent .alpha.; (D) hydroxyimino lower alkyl; (E)
lower alkoxyimino lower alkyl; (F) lower alkenyl optionally
substituted with one or more substituents selected from the group
of substituent .alpha.; (G) lower alkynyl optionally substituted
with one or more substituents selected from the group of
substituent .alpha.; (H) lower alkoxy optionally substituted with
one or more substituents selected from the group of substituent
.alpha.; (I) lower alkylthio optionally substituted with one or
more substituents selected from the group of substituent .alpha.;
(J) lower alkylamino substituted with one or more substituents
selected from the group of substituent .alpha.; (K) lower
alkylsulfonyl optionally substituted with one or more substituents
selected from the group of substituent .alpha.; (L) aryl lower
alkoxycarbonyl optionally substituted with one or more substituents
selected from the group of substituent .alpha., azido, and lower
alkyl; (M) acyl substituted with one or more substituents selected
from the group of substituent .alpha.; and the ring part of the
carbocyclic carbonyl and the heterocyclic carbonyl is substituted
optionally with at least one selected from the group of lower
alkyl; the substituent group .alpha.; and lower alkyl substituted
with at least one selected from the group of the substituent
.alpha.; (N) cycloalkyl optionally substituted with one or more
substituents selected from the group of substituent .alpha., azido,
and lower alkyl; (O) lower alkylsulfinyl optionally substituted
with one or more substituents selected from the group of
substituent .alpha.; (P) sulfamoyl; (Q) aryl optionally substituted
with one or more substituents selected from the group of
substituent .alpha., azido, and lower alkyl; (R) heterocyclic group
optionally substituted with one or more substituents selected from
the group of substituent .alpha., azido, and lower alkyl; (S)
aryloxy optionally substituted with one or more substituents
selected from the group of substituent .alpha., azido, and lower
alkyl; (T) heterocyclicoxy optionally substituted with one or more
substituents selected from the group of substituent .alpha., azido,
and lower alkyl; (U) arylthio optionally substituted with one or
more substituents selected from the group of substituent .alpha.,
azido, and lower alkyl; (V) heterocyclicthio optionally substituted
with one or more substituents selected from the group of
substituent .alpha., azido, and lower alkyl; (W) arylamino
optionally substituted with one or more substituents selected from
the group of substituent .alpha., azido, and lower alkyl; (X)
heterocyclicamino optionally substituted with one or more
substituents selected from the group of substituent .alpha., azido,
and lower alkyl; (Y) aryl lower alkylamino optionally substituted
with one or more substituents selected from the group of
substituent .alpha., azido, and lower alkyl; (Z) heterocyclic lower
alkylamino optionally substituted with one or more substituents
selected from the group of substituent .alpha., azido, and lower
alkyl; (AA) lower alkyl sulfamoyl optionally substituted with one
or more substituents selected from the group of substituent
.alpha.; (AB) aryl sulfamoyl optionally substituted with one or
more substituents selected from the group of substituent .alpha.,
azido, and lower alkyl; (AC) heterocyclic sulfamoyl optionally
substituted with one or more substituents selected from the group
of substituent .alpha., azido, and lower alkyl; (AD) arylsulfonyl
substituted optionally with one or more substituents selected from
the group of substituent .alpha., azido, and lower alkyl; (AE)
heterocyclic sulfonyl optionally substituted with one or more
substituents selected from the group of substituent .alpha., azido,
and lower alkyl; (AF) aryl carbamoyl optionally substituted with
one or more substituents selected from the group of substituent
.alpha., azido, and lower alkyl; (AG) heterocyclic carbamoyl
optionally substituted with one or more substituents selected from
the group of substituent .alpha., azido, and lower alkyl; (AH) aryl
lower alkylcarbamoyl optionally substituted with one or more
substituents selected from the group of substituent .alpha., azido,
and lower alkyl; (AI) heterocyclic lower alkylcarbamoyl optionally
substituted with one or more substituents selected from the group
of substituent .alpha., azido, and lower alky; (AJ) aryloxycarbonyl
optionally substituted with one or more substituents selected from
the group of substituent .alpha., azido, and lower alkyl; (AK)
heterocyclicoxycarbonyl optionally substituted with one or more
substituents selected from the group of substituent .alpha., azido,
and lower alkyl; (AL) lower alkylenedioxy substituted optionally
with halogen; (AM) oxo; (AN) azido; and (AO) one of the following
formulae: ##STR01370## ##STR01371## wherein Q.sup.1, Q.sup.2 and
Q.sup.3 are each independently a bond, optionally substituted lower
alkylene or optionally substituted lower alkenylene, lower alkylene
and lower alkenylene being substituted optionally with the
substituent .alpha.; Q.sup.4 is optionally substituted lower
alkylene or optionally substituted lower alkenylene, lower alkylene
and lower alkenylene being substituted optionally with the
substituent .alpha.; W.sup.1 and W.sup.2 are each independently O
or S; W.sup.3 is O, S or NR.sup.12; R.sup.12 is a hydrogen atom,
lower alkyl, hydroxy lower alkyl, lower alkoxy lower alkyl, lower
alkoxycarbonyl lower alkyl, carbocyclic group lower alkyl or acyl;
R.sup.14 is a hydrogen atom or lower alkyl; ring B is an optionally
substituted carbocyclic group or an optionally substituted
heterocyclic group, the carbocyclic group and the heterocyclic
group being substituted optionally with at least one selected from
the group consisting of (a) the substituent .alpha.; (b) lower
alkyl optionally substituted with the substituent .alpha.; (c)
amino lower alky substituted with the substituent .alpha.; (d)
hydroxyimino lower alkyl; (e) lower alkoxyimino lower alkyl; (f)
lower alkenyl optionally substituted with the substituent .alpha.;
(g) lower alkynyl optionally substituted with the substituent
.alpha.; (h) lower alkoxy optionally substituted with the
substituent .alpha.; (i) lower alkylthio optionally substituted
with the substituent .alpha.; (i) lower alkylamino substituted with
the substituent .alpha.; (k) lower alkylsulfonyl optionally
substituted with the substituent .alpha.; (l) aryl lower
alkoxycarbonyl optionally substituted with one or more substituents
selected from the group of substituent .alpha. and lower alkyl; (m)
acyl substituted with the substituent .alpha.; and the ring part of
the carbocyclic carbonyl and the heterocyclic carbonyl is
substituted optionally with at least one selected from the group of
lower alkyl; the substituent group .alpha.; and lower alkyl
substituted with at least one selected from the group of the
substituent .alpha., (n) lower alkylsulfonyl optionally substituted
with the substituent .alpha.; (o) sulfamoyl; (p) lower alkyl
sulfamoyl optionally substituted with one or more substituents
selected from the group of substituent .alpha.; (q) cycloalkyl
optionally substituted with one or more substituents selected from
the group of substituent .alpha., azido and lower alkyl; (r) aryl
optionally substituted with one or more substituents selected from
the group of substituent .alpha., azido and lower alkyl; (s)
heterocyclic group optionally substituted with one or more
substituents selected from the group of substituent .alpha., azido
and lower alkyl; (t) aryloxy optionally substituted with one or
more substituents selected from the group of substituent .alpha.,
azido and lower alkyl; (u) heterocyclicoxy optionally substituted
with one or more substituents selected from the group of
substituent .alpha., azido and lower alkyl; (v) arylthio optionally
substituted with one or more substituents selected from the group
of substituent .alpha., azido and lower alkyl; (w) heterocyclic
thio optionally substituted with one or more substituents selected
from the group of substituent .alpha., azido and lower alkyl; (x)
arylamino optionally substituted with one or more substituents
selected from the group of substituent .alpha., azido and lower
alkyl; (y) heterocyclic amino optionally substituted with one or
more substituents selected from the group of substituent .alpha.,
azido and lower alkyl; (z) aryl lower alkylamino optionally
substituted with one or more substituents selected from the group
of substituent .alpha., azido and lower alkyl; (aa) heterocyclic
lower alkylamino optionally substituted with one or more
substituents selected from the group of substituent .alpha., azido
and lower alkyl; (ab) arylsulfamoyl optionally substituted with one
or more substituents selected from the group of substituent
.alpha., azido and lower alkyl; (ac) heterocyclic sulfamoyl
optionally substituted with one or more substituents selected from
the group of substituent .alpha., azido and lower alkyl; (ad)
arylsulfonyl optionally substituted with one or more substituents
selected from the group of substituent .alpha., azido and lower
alkyl; (ae) heterocyclic sulfonyl optionally substituted with one
or more substituents selected from the group of substituent
.alpha., azido and lower alkyl; (af) arylcarbamoyl optionally
substituted with one or more substituents selected from the group
of substituent .alpha., azido and lower alkyl; (ag) heterocyclic
carbamoyl optionally substituted with one or more substituents
selected from the group of substituent .alpha., azido and lower
alkyl; (ah) aryl lower alkylcarbamoyl optionally substituted with
one or more substituents selected from the group of substituent
.alpha., azido and lower alkyl; (ai) heterocyclic lower
alkylcarbamoyl optionally substituted with one or more substituents
selected from the group of substituent .alpha., azido and lower
alkyl; (aj) aryloxy carbonyl optionally substituted with one or
more substituents selected from the group of substituent .alpha.,
azido and lower alkyl; (ak) heterocyclicoxycarbonyl optionally
substituted with one or more substituents selected from the group
of substituent .alpha., azido and lower alkyl; (al) lower
alkylenedioxy substituted optionally with halogen; and (am) oxo;
Alk.sup.2 is optionally substituted lower alkyl, lower alkyl being
substituted optionally with at least one selected from the group
consisting of the substituent .alpha.; p is an integer of 1 or 2;
##STR01372## Alk.sup.1 is lower alkylene or lower alkenylene;
R.sup.0 is a hydrogen atom, lower alkyl, or acyl; X is O; R.sup.2a
and R.sup.2b are each independently a hydrogen atom, hydroxy,
optionally substituted lower alkyl, optionally substituted lower
alkenyl, optionally substituted amino, optionally substituted
amidino, optionally substituted acyl, optionally substituted
carbamoyl, optionally substituted carbamoylcarbonyl, optionally
substituted lower alkylsulfonyl, optionally substituted
arylsulfonyl, an optionally substituted carbocyclic group, or an
optionally substituted heterocyclic group; lower alkyl being
substituted optionally with at least one selected from the group
consisting of the substituent .alpha., lower alkenyl being
substituted optionally with the substituent .alpha., amino being
substituted optionally with at least one selected from the group
consisting of lower alkyl, acyl, hydroxy, lower alkoxy, lower
alkoxycarbonyl, a carbocyclic group and a heterocyclic group,
amidino being substituted optionally with at least one selected
from the group consisting of lower alkyl, acyl, hydroxy, lower
alkoxy, lower alkoxycarbonyl, a carbocyclic group and a
heterocyclic group, acyl includes aliphatic acyl of a carbon number
of 1 to 10, carbocyclic carbonyl and heterocyclic carbonyl; acyl
being substituted optionally with the substituent .alpha.; and the
ring part of the carbocyclic carbonyl and the heterocyclic carbonyl
is substituted optionally with at least one selected from the group
of lower alkyl; the substituent group .alpha.; and lower alkyl
substituted with at least one selected from the group of the
substituent .alpha., carbamoyl being substituted optionally with at
least one selected from the group consisting of lower alkyl, acyl,
hydroxy, lower alkoxy, lower alkoxycarbonyl, a carbocyclic group
and a heterocyclic group, carbamoylcarbonyl being substituted
optionally with at least one selected from the group consisting of
lower alkyl, acyl, hydroxy, lower alkoxy, lower alkoxycarbonyl, a
carbocyclic group and a heterocyclic group, lower alkylsulfonyl
being substituted optionally with the substituent .alpha.,
arylsulfonyl being substituted optionally with at least one
selected from the group consisting of the substituent .alpha. and a
lower alkyl, and the carbocyclic group and the heterocyclic group
being substituted optionally with at least one selected from the
group consisting of the substituent .alpha. and lower alkyl;
R.sup.3a, R.sup.3b, R.sup.4a, and R.sup.4b are each independently a
hydrogen atom, halogen, hydroxy, optionally substituted lower
alkyl, optionally substituted lower alkenyl, optionally substituted
acyl, carboxy, optionally substituted lower alkoxycarbonyl,
optionally substituted amino, optionally substituted carbamoyl, an
optionally substituted carbocyclic group, or an optionally
substituted heterocyclic group; lower alkyl being substituted
optionally with at least one selected from the group consisting of
the substituent .alpha., lower alkenyl being substituted optionally
with the substituent .alpha., acyl being substituted optionally
with the substituent .alpha.; and the ring part of the carbocyclic
carbonyl and the heterocyclic carbonyl is substituted optionally
with at least one selected from the group of lower alkyl; the
substituent group .alpha.; and lower alkyl substituted with at
least one selected from the group of the substituent .alpha., lower
alkoxycarbonyl being substituted optionally with the substituent
.alpha., amino being substituted optionally with at least one
selected from the group consisting of lower alkyl, acyl, hydroxy,
lower alkoxy, lower alkoxycarbonyl, a carbocyclic group and a
heterocyclic group,
carbamoyl being substituted optionally with at least one selected
from the group consisting of lower alkyl, acyl, hydroxy, lower
alkoxy, lower alkoxycarbonyl, a carbocyclic group and a
heterocyclic group, and the carbocyclic group and the heterocyclic
group being substituted optionally with at least one selected from
the group consisting of the substituent .alpha. and a lower alkyl;
n=0, 1, 2 or 3, m=0, 1, 2 or 3, with the proviso that n+m=3, each
R.sup.3a, each R.sup.3b, each R.sup.4a, and each R.sup.4b may be
independently different; R.sup.5 is a hydrogen atom, optionally
substituted lower alkyl, optionally substituted lower alkenyl,
optionally substituted lower alkynyl, an optionally substituted
carbocyclic group, an optionally substituted heterocyclic group;
lower alkyl being substituted optionally with at least one selected
from the group consisting of the substituent .alpha., lower alkenyl
being substituted optionally with the substituent .alpha., lower
alkynyl being substituted optionally with the substituent .alpha.,
and the carbocyclic group and the heterocyclic group being
substituted optionally with at least one selected from the group
consisting of the substituent .alpha. and a lower alkyl; wherein
acyl includes aliphatic acyl of a carbon number of 1 to 10,
carbocyclic carbonyl and heterocyclic carbonyl; when ##STR01373##
R.sup.5 and ring A can be taken together to form ##STR01374##
wherein R.sup.5a and R.sup.5b are each independently a hydrogen
atom or lower alkyl; s is an integer of 1 to 4; each R.sup.5a and
each R.sup.5b may be different; its pharmaceutically acceptable
salt, or a solvate thereof.
2. (canceled)
3. (canceled)
4. The compound according to claim 1, wherein E is a bond, its
pharmaceutically acceptable salt, or a solvate thereof.
5. (canceled)
6. (canceled)
7. (canceled)
8. The compound according to claim 1, wherein R.sup.5 is optionally
substituted lower alkyl, optionally substituted lower alkenyl,
optionally substituted lower alkynyl, an optionally substituted
carbocyclic group, or an optionally substituted heterocyclic group,
lower alkyl being substituted optionally with at least one selected
from the group consisting of the substituent .alpha., the
substituent .alpha. being at least one selected from the group
consisting of halogen, hydroxy, lower alkoxy, hydroxy lower alkoxy,
lower alkoxy lower alkoxy, acyl, acyloxy, carboxy, lower
alkoxycarbonyl, amino, acylamino, lower alkylamino, lower
alkylthio, carbamoyl, lower alkylcarbamoyl, hydroxy lower
alkylcarbamoyl, sulfamoyl, lower alkylsulfamoyl, lower
alkylsulfinyl, cyano, nitro, aryl, and heterocyclic group, lower
alkenyl being substituted optionally with the substituent .alpha.,
lower alkynyl being substituted optionally with the substituent
.alpha., and the carbocyclic group and the heterocyclic group being
substituted optionally with at least one selected from the group
consisting of the substituent .alpha. and lower alkyl, its
pharmaceutically acceptable salt, or a solvate thereof.
9. The compound according to claim 1, wherein R.sup.2a is a
hydrogen atom; R.sup.2b is a hydrogen atom, optionally substituted
lower alkyl, optionally substituted acyl, optionally substituted
lower alkylsulfonyl, or optionally substituted amidino, lower alkyl
being substituted optionally with at least one selected from the
group consisting of the substituent .alpha., the substituent
.alpha. being at least one selected from the group consisting of
halogen, hydroxy, lower alkoxy, hydroxy lower alkoxy, lower alkoxy
lower alkoxy, acyl, acyloxy, carboxy, lower alkoxycarbonyl, amino,
acylamino, lower alkylamino, lower alkylthio, carbamoyl, lower
alkylcarbamoyl, hydroxy lower alkylcarbamoyl, sulfamoyl, lower
alkylsulfamoyl, lower alkylsulfinyl, cyano, nitro, aryl, and
heterocyclic group, acyl being substituted optionally with the
substituent .alpha., and the ring part of the carbocyclic carbonyl
and the heterocyclic carbonyl is substituted optionally with at
least one selected from the group of lower alkyl; the substituent
group .alpha.; and lower alkyl substituted with at least one
selected from the group of the substituent .alpha., lower
alkylsulfonyl being substituted optionally with the substituent
.alpha., and amidino being substituted optionally with at least one
selected from the group consisting of lower alkyl, acyl, hydroxy,
lower alkoxy, lower alkoxycarbonyl, a carbocyclic group and a
heterocyclic group, its pharmaceutically acceptable salt, or a
solvate thereof.
10. The compound according to claim 1, wherein NR.sup.2aR.sup.2b is
represented by the formula: ##STR01375## R.sup.6, R.sup.7, and
R.sup.8 are each independently a hydrogen atom, lower alkyl, or
acyl; Y is optionally substituted lower alkylene, optionally
substituted lower alkenylene, or optionally substituted lower
alkynylene; lower alkylene being substituted optionally with the
substituent .alpha., the substituent .alpha. being at least one
selected from the group consisting of halogen, hydroxy, lower
alkoxy, hydroxy lower alkoxy, lower alkoxy lower alkoxy, acyl,
acyloxy, carboxy, lower alkoxycarbonyl, amino, acylamino, lower
alkylamino, lower alkylthio, carbamoyl, lower alkylcarbamoyl,
hydroxy lower alkylcarbamoyl, sulfamoyl, lower alkylsulfamoyl,
lower alkylsulfinyl, cyano, nitro, aryl, and heterocyclic group,
lower alkenylene being substituted optionally with the substituent
.alpha., and lower alkynylene being substituted optionally with the
substituent .alpha.; Z is O or S; its pharmaceutically acceptable
salt, or a solvate thereof.
11. The compound according to claim 1, wherein ring A is optionally
substituted phenyl, the phenyl being substituted optionally with at
least one selected from the group consisting of the above (A) to
(AO), its pharmaceutically acceptable salt, or a solvate
thereof.
12. The compound according to claim 1, wherein ring A is
represented by the formula: ##STR01376## wherein R.sup.9, R.sup.10,
and R.sup.11 are a hydrogen atom or G; G is <A>, <B>,
<C>, <D>, <E>, <F>, <G>, or
<H>, where <A>, <B>, <C>, <D>,
<E>, <F>, <G> and <H> are the following:
<A> halogen, hydroxy, cyano, nitro, mercapto, optionally
substituted lower alkyl, optionally substituted lower alkoxy,
optionally substituted lower alkenyl, optionally substituted lower
alkynyl, optionally substituted acyl, optionally substituted
acyloxy, carboxy, optionally substituted lower alkoxycarbonyl,
optionally substituted lower alkoxycarbonyloxy, optionally
substituted aryloxycarbonyloxy, optionally substituted amino,
optionally substituted carbamoyl, optionally substituted
carbamoyloxy, optionally substituted lower alkylthio, optionally
substituted arylthio, optionally substituted lower alkylsulfonyl,
optionally substituted arylsulfonyl, optionally substituted lower
alkylsulfinyl, optionally substituted arylsulfinyl, optionally
substituted lower alkylsulfonyloxy, optionally substituted
arylsulfonyloxy, optionally substituted sulfamoyl, an optionally
substituted carbocyclic group, optionally substituted
carbocyclicoxy, an optionally substituted heterocyclic group, or
optionally substituted heterocyclicoxy, lower alkyl being
substituted optionally with at least one selected from the group
consisting of the substituent .alpha., a hydroxyimino group, and a
lower alkoxyimino group, the substituent .alpha. being at least one
selected from the group consisting of halogen, hydroxy, lower
alkoxy, hydroxy lower alkoxy, lower alkoxy lower alkoxy, acyl,
acyloxy, carboxy, lower alkoxycarbonyl, amino, acylamino, lower
alkylamino, lower alkylthio, carbamoyl, lower alkylcarbamoyl,
hydroxy lower alkylcarbamoyl, sulfamoyl, lower alkylsulfamoyl,
lower alkylsulfinyl, cyano, nitro, aryl, and heterocyclic group,
lower alkoxy being substituted optionally with the substituent
.alpha., lower alkenyl being substituted optionally with the
substituent .alpha., lower alkynyl being substituted optionally
with the substituent .alpha., acyl includes aliphatic acyl of a
carbon number of 1 to 10, carbocyclic carbonyl and heterocyclic
carbonyl; and acyl being substituted optionally with the
substituent .alpha.; and the ring part of the "carbocyclic
carbonyl" and the "heterocyclic carbonyl" is substituted optionally
with at least one selected from the group of "lower alkyl"; the
"substituent group .alpha."; and "lower alkyl substituted with at
least one selected from the group of the substituent .alpha.",
acyloxy includes aliphatic acyloxy of a carbon number of 1 to 10,
carbocyclic carbonyloxy and heterocyclic carbonyloxy; and acyloxy
being substituted optionally with the substituent .alpha.; and the
ring part of the "carbocyclic carbonyloxy" and the "heterocyclic
carbonyloxy" is substituted optionally with at least one selected
from the group of "lower alkyl"; the "substituent group .alpha.";
and "lower alkyl substituted with at least one selected from the
group of the substituent .alpha.", lower alkoxycarbonyl being
substituted optionally with the substituent .alpha., lower
alkoxycarbonyloxy being substituted optionally with the substituent
.alpha., aryloxycarbonyloxy being substituted optionally with at
least one selected from the group consisting of lower alkyl and the
substituent .alpha., amino being substituted optionally with at
least one selected from the group consisting of lower alkyl, acyl,
hydroxy, lower alkoxy, lower alkoxycarbonyl, a carbocyclic group
and a heterocyclic group, carbamoyl being substituted optionally
with at least one selected from the group consisting of lower
alkyl, acyl, hydroxy, lower alkoxy, lower alkoxycarbonyl, a
carbocyclic group and a heterocyclic group, carbamoyloxy being
substituted optionally with at least one selected from the group
consisting of lower alkyl, acyl, hydroxy, lower alkoxy, lower
alkoxycarbonyl, a carbocyclic group and a heterocyclic group, lower
alkylthio being substituted optionally with the substituent
.alpha., arylthio being substituted optionally with at least one
selected from the group consisting of lower alkyl and the
substituent .alpha., lower alkylsulfonyl being substituted
optionally with the substituent .alpha., arylsulfonyl being
substituted optionally with at least one selected from the group
consisting of the substituent .alpha., azido, and lower alkyl,
lower alkylsulfinyl being substituted optionally with the
substituent .alpha., arylsulfinyl being substituted optionally with
at least one selected from the group consisting of lower alkyl and
the substituent .alpha., lower alkylsulfonyloxy being substituted
optionally with the substituent .alpha., arylsulfonyloxy being
substituted optionally with the substituent .alpha., sulfamoyl
being substituted optionally with the substituent .alpha., and the
carbocyclic group, carbocyclicoxy, the heterocyclic group, and
heterocyclicoxy being substituted optionally with at least one
selected from the group consisting of lower alkyl and the
substituent .alpha.; <B> one of the following (i), (ii),
(iv), (vi), (viii) and (x): ##STR01377## wherein each Q.sup.1 is
optionally substituted lower alkylene, lower alkylene being
substituted optionally with the substituent .alpha.; Q.sup.2 and
Q.sup.3 are each independently a bond, optionally substituted lower
alkylene or optionally substituted lower alkenylene, lower alkylene
and lower alkenylene being substituted optionally with the
substituent .alpha.; W.sup.1 and W.sup.2 are each independently O
or S; W.sup.3 is O, S, or NR.sup.12; R.sup.12 is a hydrogen atom,
lower alkyl, hydroxy lower alkyl, lower alkoxy lower alkyl, lower
alkoxycarbonyl lower alkyl, carbocyclic lower alkyl, or acyl; and
ring B is an optionally substituted carbocyclic group or an
optionally substituted heterocyclic group, the carbocyclic group
and the heterocyclic group being substituted optionally with at
least one selected from the group consisting of (a) the substituent
.alpha.; (b) lower alkyl optionally substituted with the
substituent .alpha.; (c) amino lower alky substituted with the
substituent .alpha.; (d) hydroxyimino lower alkyl; (e) lower
alkoxyimino lower alkyl; (f) lower alkenyl optionally substituted
with the substituent .alpha.; (g) lower alkynyl optionally
substituted with the substituent .alpha.; (h) lower alkoxy
optionally substituted with the substituent .alpha.; (i) lower
alkylthio optionally substituted with the substituent .alpha.; (j)
lower alkylamino substituted with the substituent .alpha.; (k)
lower alkylsulfonyl optionally substituted with the substituent
.alpha.; (l) aryl lower alkoxycarbonyl optionally substituted with
one or more substituents selected from the group of substituent
.alpha. and lower alkyl; (m) acyl substituted with the substituent
.alpha.; (n) lower alkylsulfonyl optionally substituted with the
substituent .alpha.; (o) sulfamoyl; (p) lower alkyl sulfamoyl
optionally substituted with one or more substituents selected from
the group of substituent .alpha.; (q) cycloalkyl optionally
substituted with one or more substituents selected from the group
of substituent .alpha., azido and lower alkyl; (r) aryl optionally
substituted with one or more substituents selected from the group
of substituent .alpha., azido and lower alkyl; (s) heterocyclic
group optionally substituted with one or more substituents selected
from the group of substituent .alpha., azido and lower alkyl; (t)
aryloxy optionally substituted with one or more substituents
selected from the group of substituent .alpha., azido and lower
alkyl; (u) heterocyclicoxy optionally substituted with one or more
substituents selected from the group of substituent .alpha., azido
and lower alkyl; (v) arylthio optionally substituted with one or
more substituents selected from the group of substituent .alpha.,
azido and lower alkyl; (w) heterocyclic thio optionally substituted
with one or more substituents selected from the group of
substituent .alpha., azido and lower alkyl; (x) arylamino
optionally substituted with one or more substituents selected from
the group of substituent .alpha., azido and lower alkyl; (y)
heterocyclic amino optionally substituted with one or more
substituents selected from the group of substituent .alpha., azido
and lower alkyl; (z) aryl lower alkylamino optionally substituted
with one or more substituents selected from the group of
substituent .alpha., azido and lower alkyl; (aa) heterocyclic lower
alkylamino optionally substituted with one or more substituents
selected from the group of substituent .alpha., azido and lower
alkyl; (ab) arylsulfamoyl optionally substituted with one or more
substituents selected from the group of substituent .alpha., azido
and lower alkyl; (ac) heterocyclic sulfamoyl optionally substituted
with one or more substituents selected from the group of
substituent .alpha., azido and lower alkyl; (ad) arylsulfonyl
optionally substituted with one or more substituents selected from
the group of substituent .alpha., azido and lower alkyl; (ae)
heterocyclic sulfonyl optionally substituted with one or more
substituents selected from the group of substituent .alpha., azido
and lower alkyl; (af) arylcarbamoyl optionally substituted with one
or more substituents selected from the group of substituent
.alpha., azido and lower alkyl; (ag) heterocyclic carbamoyl
optionally substituted with one or more substituents selected from
the group of substituent .alpha., azido and lower alkyl; (ah) aryl
lower alkylcarbamoyl optionally substituted with one or more
substituents selected from the group of substituent .alpha., azido
and lower alkyl; (ai) heterocyclic lower alkylcarbamoyl optionally
substituted with one or more substituents selected from the group
of substituent .alpha., azido and lower alkyl; (aj) aryloxy
carbonyl optionally substituted with one or more substituents
selected from the group of substituent .alpha., azido and lower
alkyl; (ak) heterocyclicoxycarbonyl optionally substituted with one
or more substituents selected from the group of substituent
.alpha., azido and lower alkyl; (al) lower alkylenedioxy
substituted optionally with halogen; and (am) oxo; <C> one of
the following (iii), (v), (vii), (ix) and (xii): ##STR01378##
wherein each Q.sup.2 is optionally substituted lower alkylene,
lower alkylene being substituted optionally with the substituent
.alpha.; Q.sup.1 and Q.sup.3 are each independently a bond,
optionally substituted lower alkylene or optionally substituted
lower alkenylene, lower alkylene and lower alkenylene being
substituted optionally with the substituent .alpha.; W.sup.1 and
W.sup.2 are each independently O or S; W.sup.3 is O, S, or
NR.sup.12; R.sup.12 is a hydrogen atom, lower alkyl, hydroxy lower
alkyl, lower alkoxy lower alkyl, lower alkoxycarbonyl lower alkyl,
carbocyclic lower alkyl, or acyl; p is an integer of 1 or 2; and
ring B is an optionally substituted carbocyclic group or an
optionally substituted heterocyclic group, the carbocyclic group
and the heterocyclic group being substituted optionally with at
least one selected from the group consisting of the above (a) to
(am); and R.sup.14 is a hydrogen atom or lower alkyl; <D> one
of the following (iii), (v), (vi) and (xi): ##STR01379## wherein
each Q.sup.1, Q.sup.2 and Q.sup.4 are each independently optionally
substituted lower alkylene, lower alkylene being substituted
optionally with the substituent .alpha.; Q.sup.3 are each
independently a bond, optionally substituted lower alkylene, or
optionally substituted lower alkenylene, lower alkylene and lower
alkenylene being substituted optionally with the substituent
.alpha.; W.sup.1 is O or S; W.sup.3 is O, S, or NR.sup.12; R.sup.12
is a hydrogen atom, lower alkyl, hydroxy lower alkyl, lower alkoxy
lower alkyl, lower alkoxycarbonyl lower alkyl, carbocyclic lower
alkyl, or acyl; and ring B is an optionally substituted carbocyclic
group or an optionally substituted heterocyclic group, the
carbocyclic group and the heterocyclic group being substituted
optionally with at least one selected from the group consisting of
the above (a) to (am); <E> one of the following (i), (ii),
(iv), (vi), (viii) and (x): ##STR01380## wherein each Q.sup.1 is
optionally substituted lower alkenylene, lower alkenylene being
substituted optionally with the substituent .alpha.; Q.sup.2 and
Q.sup.3 are each independently a bond, optionally substituted lower
alkylene or optionally substituted lower alkenylene, lower alkylene
and lower alkenylene being substituted optionally with the
substituent .alpha.; W.sup.1 and W.sup.2 are each independently O
or S; W.sup.3 is O, S, or NR.sup.12; R.sup.12 is a hydrogen atom,
lower alkyl, hydroxy lower alkyl, lower alkoxy lower alkyl, lower
alkoxycarbonyl lower alkyl, carbocyclic lower alkyl, or acyl; ring
B is an optionally substituted carbocyclic group or an optionally
substituted heterocyclic group, the carbocyclic group and the
heterocyclic group being substituted optionally with at least one
selected from the group consisting of the above (a) to (am);
<F> one of the following (iii), (v), (vii), and (ix):
##STR01381## wherein Q.sup.2 is optionally substituted lower
alkenylene, lower alkenylene being substituted optionally with the
substituent .alpha.; Q.sup.1 and Q.sup.3 are each independently a
bond, optionally substituted lower alkylene or optionally
substituted lower alkenylene, lower alkylene and lower alkenylene
being substituted optionally with the substituent .alpha.; W.sup.1
and W.sup.2 are each independently O or S; W.sup.3 is O, S, or
NR.sup.12; R.sup.12 is a hydrogen atom, lower alkyl, hydroxy lower
alkyl, lower alkoxy lower alkyl, lower alkoxycarbonyl lower alkyl,
carbocyclic lower alkyl, or acyl; p is an integer of 1 or 2; ring B
is an optionally substituted carbocyclic group or an optionally
substituted heterocyclic group, the carbocyclic group and the
heterocyclic group being substituted optionally with at least one
selected from the group consisting of the above (a) to (am); and
R.sup.14 is a hydrogen atom or lower alkyl; <G> one of the
following (ii), (iv),(v), (ix), (xiii) and (xiv): ##STR01382##
wherein each Q.sup.1, Q.sup.2 and Q.sup.3 are each independently a
bond, optionally substituted lower alkylene, or optionally
substituted lower alkenylene; lower alkylene and lower alkenylene
being substituted optionally with the substituent .alpha.; W.sup.1
is O or S; W.sup.3 is O, S, or NR.sup.12; R.sup.12 is a hydrogen
atom, lower alkyl, hydroxy lower alkyl, lower alkoxy lower alkyl,
lower alkoxycarbonyl lower alkyl, carbocyclic lower alkyl, or acyl;
Alk.sup.2 is optionally substituted lower alkyl, lower alkyl being
substituted optionally with at least one selected from the group
consisting of the substituent
.alpha.; p is an integer of 1 or 2; and ring B is an optionally
substituted carbocyclic group or an optionally substituted
heterocyclic group, the carbocyclic group and the heterocyclic
group being substituted optionally with at least one selected from
the group consisting of the above (a) to (am); <H> one of the
following (i), (viii) and (xv): ##STR01383## wherein Q.sup.2 is a
bond, optionally substituted lower alkylene, or optionally
substituted lower alkenylene, lower alkylene and lower alkenylene
being substituted optionally with the substituent .alpha.; W.sup.3
is O, S, or NR.sup.12, R.sup.12 is a hydrogen atom, lower alkyl,
hydroxy lower alkyl, lower alkoxy lower alkyl, lower alkoxycarbonyl
lower alkyl, carbocyclic lower alkyl, or acyl; Alk.sup.2 is
optionally substituted lower alkyl, lower alkyl being substituted
optionally with at least one selected from the group consisting of
the substituent .alpha.; ring B is an optionally substituted
carbocyclic group or an optionally substituted heterocyclic group,
the carbocyclic group and the heterocyclic group being substituted
optionally with at least one selected from the group consisting of
the above (a) to (am); each G may be independently different; its
pharmaceutically acceptable salt, or a solvate thereof.
13. The compound according to claim 12, wherein R.sup.9, R.sup.10,
and R.sup.11 are a hydrogen atom, halogen, hydroxy, cyano, nitro,
mercapto, optionally substituted lower alkyl, optionally
substituted lower alkoxy, optionally substituted lower alkenyl,
optionally substituted lower alkynyl, optionally substituted acyl,
optionally substituted acyloxy, carboxy, optionally substituted
lower alkoxycarbonyl, optionally substituted lower
alkoxycarbonyloxy, optionally substituted lower aryloxycarbonyloxy,
optionally substituted amino, optionally substituted carbamoyl,
optionally substituted carbamoyloxy, optionally substituted lower
alkylthio, optionally substituted lower arylthio, optionally
substituted lower alkylsulfonyl, optionally substituted
arylsulfonyl, optionally substituted lower alkylsulfinyl,
optionally substituted arylsulfinyl, optionally substituted lower
alkylsulfonyloxy, optionally substituted arylsulfonyloxy,
optionally substituted sulfamoyl, an optionally substituted
carbocyclic group, optionally substituted carbocyclicoxy, an
optionally substituted heterocyclic group, or optionally
substituted heterocyclicoxy; lower alkyl being substituted
optionally with at least one selected from the group consisting of
the substituent .alpha., a hydroxyimino group, and a lower
alkoxyimino group, the substituent .alpha. being at least one
selected from the group consisting of halogen, hydroxy, lower
alkoxy, hydroxy lower alkoxy, lower alkoxy lower alkoxy, acyl,
acyloxy, carboxy, lower alkoxycarbonyl, amino, acylamino, lower
alkylamino, lower alkylthio, carbamoyl, lower alkylcarbamoyl,
hydroxy lower alkylcarbamoyl, sulfamoyl, lower alkylsulfamoyl,
lower alkylsulfinyl, cyano, nitro, aryl, and heterocyclic group,
lower alkoxy being substituted optionally with the substituent
.alpha., lower alkenyl being substituted optionally with the
substituent .alpha., lower alkynyl being substituted optionally
with the substituent .alpha., acyl includes aliphatic acyl of a
carbon number of 1 to 10, carbocyclic carbonyl and heterocyclic
carbonyl; and acyl being substituted optionally with the
substituent .alpha.; and the ring part of the "carbocyclic
carbonyl" and the "heterocyclic carbonyl" is substituted optionally
with at least one selected from the group of "lower alkyl"; the
"substituent group .alpha."; and "lower alkyl substituted with at
least one selected from the group of the substituent .alpha.".
acyloxy includes aliphatic acyloxy of a carbon number of 1 to 10,
carbocyclic carbonyloxy and heterocyclic carbonyloxy; and acyloxy
being substituted optionally with the substituent .alpha.; and the
ring part of the "carbocyclic carbonyloxy" and the "heterocyclic
carbonyloxy" is substituted optionally with at least one selected
from the group of "lower alkyl"; the "substituent group .alpha.";
and "lower alkyl substituted with at least one selected from the
group of the substituent .alpha.", lower alkoxycarbonyl being
substituted optionally with the substituent .alpha., lower
alkoxycarbonyloxy being substituted optionally with the substituent
.alpha., aryloxycarbonyloxy being substituted optionally with at
least one selected from the group consisting of lower alkyl and the
substituent .alpha., amino being substituted optionally with at
least one selected from the group consisting of lower alkyl, acyl,
hydroxy, lower alkoxy, lower alkoxycarbonyl, a carbocyclic group
and a heterocyclic group, carbamoyl being substituted optionally
with at least one selected from the group consisting of lower
alkyl, acyl, hydroxy, lower alkoxy, lower alkoxycarbonyl, a
carbocyclic group and a heterocyclic group, carbamoyloxy being
substituted optionally with at least one selected from the group
consisting of lower alkyl, acyl, hydroxy, lower alkoxy, lower
alkoxycarbonyl, a carbocyclic group and a heterocyclic group, lower
alkylthio being substituted optionally with the substituent
.alpha., arylthio being substituted optionally with at least one
selected from the group consisting of lower alkyl and the
substituent .alpha., lower alkylsulfonyl being substituted
optionally with the substituent .alpha., arylsulfonyl being
substituted optionally with at least one selected from the group
consisting of the substituent .alpha. and lower alkyl, lower
alkylsulfinyl being substituted optionally with the substituent
.alpha., arylsulfinyl being substituted optionally with at least
one selected from the group consisting of lower alkylsulfonyloxy
being substituted optionally with the substituent .alpha.,
arylsulfonyloxy being substituted optionally with the substituent
.alpha., sulfamoyl being substituted optionally with the
substituent .alpha., and the carbocyclic group, carbocyclicoxy, the
heterocyclic group, and heterocyclicoxy being substituted
optionally with at least one selected from the group consisting of
lower alkyl and the substituent .alpha.; and G is represented by
the formula: ##STR01384## ##STR01385## Q.sup.1, Q.sup.2, and
Q.sup.3 are each independently a bond, optionally substituted lower
alkylene, or optionally substituted lower alkenylene; lower
alkylene and lower alkenylene being substituted optionally with the
substituent .alpha.; Q.sup.4 is optionally substituted lower
alkylene or optionally substituted lower alkenylene; lower alkylene
and lower alkenylene being substituted optionally with the
substituent .alpha.; W.sup.1 and W.sup.2 are each independently O
or S; W.sup.3 is O, S, or NR.sup.12; R.sup.12 is a hydrogen atom,
lower alkyl, hydroxy lower alkyl, lower alkoxy lower alkyl, lower
alkoxycarbonyl lower alkyl, carbocyclic lower alkyl, or acyl;
R.sup.14 is a hydrogen atom or lower alkyl; ring B is an optionally
substituted carbocyclic group or an optionally substituted
heterocyclic group; the carbocyclic group and the heterocyclic
group being substituted optionally with at least one selected from
the group consisting of the above (a) to (am); Alk.sup.2 is
optionally substituted lower alkyl; lower alkyl being substituted
optionally with at least one selected from the group consisting of
the substituent .alpha.; p is 1 or 2; if there are multiple
W.sup.1, multiple W.sup.3 and multiple R.sup.12, each are
independently different, its pharmaceutically acceptable salt, or a
solvate thereof.
14. The compound according to claim 13, wherein ring B is aryl
optionally substituted with one or more substituents selected from
the group consisting of halogen, hydroxy, optionally substituted
lower alkyl, optionally substituted lower alkoxy, optionally
substituted acyl, optionally substituted amino, cyano, optionally
substituted carbamoyl, an optionally substituted carbocyclic group,
optionally substituted carbocyclicoxy, and an optionally
substituted heterocyclic group or heteroaryl optionally substituted
with one or more substituents selected from the group consisting of
halogen, hydroxy, optionally substituted lower alkyl, optionally
substituted lower alkoxy, optionally substituted acyl, optionally
substituted amino, cyano, optionally substituted carbamoyl, an
optionally substituted carbocyclic group, optionally substituted
carbocyclicoxy, and an optionally substituted heterocyclic group,
lower alkyl being substituted optionally with the substituent
.alpha., the substituent .alpha. being at least one selected from
the group consisting of halogen, hydroxy, lower alkoxy, hydroxy
lower alkoxy, lower alkoxy lower alkoxy, acyl, acyloxy, carboxy,
lower alkoxycarbonyl, amino, acylamino, lower alkylamino, lower
alkylthio, carbamoyl, lower alkylcarbamoyl, hydroxy lower
alkylcarbamoyl, sulfamoyl, lower alkylsulfamoyl, lower
alkylsulfinyl, cyano, nitro, aryl, and heterocyclic group, lower
alkoxy being substituted optionally with the substituent .alpha.,
acyl includes aliphatic acyl of a carbon number of 1 to 10,
carbocyclic carbonyl and heterocyclic carbonyl; and acyl being
substituted optionally with the substituent .alpha.; and the ring
part of the "carbocyclic carbonyl" and the "heterocyclic carbonyl"
is substituted optionally with at least one selected from the group
of "lower alkyl"; the "substituent group .alpha."; and "lower alkyl
substituted with at least one selected from the group of the
substituent .alpha.", amino being substituted optionally with at
least one selected from the group consisting of lower alkyl, acyl,
hydroxy, lower alkoxy, lower alkoxycarbonyl, a carbocyclic group
and a heterocyclic group, carbamoyl being substituted optionally
with at least one selected from the group consisting of lower
alkyl, acyl, hydroxy, lower alkoxy, lower alkoxycarbonyl, a
carbocyclic group and a heterocyclic group, and the carbocyclic
group, carbocyclicoxy, and the heterocyclic group being substituted
optionally with at least one selected from the group consisting of
lower alkyl and the substituent .alpha., its pharmaceutically
acceptable salt, or a solvate thereof.
15. The compound according to claim 13, wherein G is represented by
the formula: ##STR01386## its pharmaceutically acceptable salt, or
a solvate thereof.
16. The compound according to claim 1, wherein R.sup.5 is C1 to C3
alkyl, its pharmaceutically acceptable salt, or a solvate
thereof.
17. The compound according to claim 1, wherein R.sup.5 is methyl,
its pharmaceutically acceptable salt, or a solvate thereof.
18. The compound according to claim 1, wherein R.sup.3a and
R.sup.3b are each independently a hydrogen atom, halogen, hydroxy,
optionally substituted lower alkyl, optionally substituted lower
alkoxy, or optionally substituted aryl, lower alkyl being
substituted optionally with at least one selected from the group
consisting of the substituent .alpha., the substituent .alpha.
being at least one selected from the group consisting of halogen,
hydroxy, lower alkoxy, hydroxy lower alkoxy, lower alkoxy lower
alkoxy, acyl, acyloxy, carboxy, lower alkoxycarbonyl, amino,
acylamino, lower alkylamino, lower alkylthio, carbamoyl, lower
alkylcarbamoyl, hydroxy lower alkylcarbamoyl, sulfamoyl, lower
alkylsulfamoyl, lower alkylsulfinyl, cyano, nitro, aryl, and
heterocyclic group, lower alkoxy being substituted optionally with
the substituent .alpha., and aryl being substituted optionally with
the substituent .alpha. or lower alkyl, its pharmaceutically
acceptable salt, or a solvate thereof.
19. The compound according to claim 1, wherein all of R.sup.3a and
all of R.sup.3b are hydrogen atoms, its pharmaceutically acceptable
salt, or a solvate thereof.
20. (canceled)
21. (canceled)
22. The compound according to claim 1, wherein n=3 and m=0, its
pharmaceutically acceptable salt, or a solvate thereof.
23. A pharmaceutical composition containing the compound as defined
in claim 1, its pharmaceutically acceptable salt, or a solvate
thereof as an active ingredient, and a pharmaceutically acceptable
carrier.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is a Division of application Ser. No.
13/941,082 filed Jul. 12, 2013, which is a Division of application
Ser. No. 13/768,557 filed Feb. 15, 2013, which is a Division of
application Ser. No. 13/243,971, filed Sep. 23, 2011, which is a
Division of application Ser. No. 12/089,409, filed Apr. 7, 2008,
which is a U.S. National Stage of PCT/JP2006/321015, filed Oct. 23,
2006, which applications are incorporated herein by reference.
TECHNICAL FIELD
[0002] The present invention relates to a compound which has
reducing effect to produce amyloid .beta. protein and is useful as
an agent for treating disease induced by production, secretion
and/or deposition of amyloid .beta. protein.
BACKGROUND ART
[0003] In the brain of Alzheimer's patient, the peptide composed of
about 40 amino acids residue as is called amyloid .beta. protein,
that accumulates to form insoluble specks (senile specks) outside
nerve cells is widely observed. It is concerned that this senile
specks kill nerve cells to cause Alzheimer's disease. The
therapeutic agents for Alzheimer's disease, such as decomposition
agents of amyloid .beta. protein and amyloid .beta. vaccine, are
under investigation.
[0004] Secretase is an enzyme which cleaves amyloid .beta.
precursor protein (APP) in cell and produce amyloid .beta. protein.
The enzyme which controls the production of N terminus of amyloid
.beta. protein is called as BACE 1 (beta-site APP-cleaving enzyme
1, .beta.-secretase). It is thought that inhibition of this enzyme
leads to reduction of producing amyloid .beta. protein and that the
therapeutic agent for Alzheimer's disease will be created by the
inhibition.
[0005] Patent Literature 1 describes the compounds which are
similar to those of the present invention, and the compounds have
NO synthase enzyme inhibitory activity and are useful for
dementia.
[0006] Patent Literatures 2 to 4 and Non-patent Literatures 1 and 2
describe the compounds which are similar to those of the present
invention, and are useful for hypertensive agent, analgesic like
morphine, or tranquilizers, intermediate for medicine, analgesic
respectively.
[0007] Patent Literature 5 to 13 are known as BACE 1 inhibitor,
however, all compounds in these literatures have different
structures from the present invention. [0008] [Patent Literature 1]
International Patent Application Publication WO96/014842 [0009]
[Patent Literature 2] U.S. Pat. No. 3,235,551 [0010] [Patent
Literature 3] U.S. Pat. No. 3,227,713 [0011] [Patent Literature 4]
JP Application Publication H09-067355 [0012] [Patent Literature 5]
International Patent Application Publication WO01/187293 [0013]
[Patent Literature 6] International Patent Application Publication
WO04/014843 [0014] [Patent Literature 7] JP Application Publication
2004-149429 [0015] [Patent Literature 8] International Patent
Application Publication WO02/96897 [0016] [Patent Literature 9]
International Patent Application Publication WO04/043916 [0017]
[Patent Literature 10] International Patent Application Publication
WO2005/058311 [0018] [Patent Literature 11] International Patent
Application Publication WO2005/097767 [0019] [Patent Literature 12]
International Patent Application Publication WO2006/041404 [0020]
[Patent Literature 13] International Patent Application Publication
WO2006/041405 [0021] [(Non-Patent Literature 1] Journal of
Heterocyclic Chemistry, 14, 717-723 (1977) [0022] [Non-Patent
Literature 2] Journal of Organic Chemistry, 33, 8, 3126-3132
(1968)
DISCLOSURE OF INVENTION
Problems to be Solved by the Invention
[0023] The present invention provides compounds which have reducing
effects to produce amyloid .beta. protein, especially BACE 1
inhibitory activity, and are useful as an agent for treating
disease induced by production, secretion and/or deposition of
amyloid .beta. protein.
Means to Solve the Problems
[0024] The present invention provides:
(a) a composition having BACE 1 inhibitory activity containing a
compound represented by the general formula (I):
##STR00002##
wherein ring A is an optionally substituted carbocyclic group or an
optionally substituted heterocyclic group;
##STR00003##
Alk.sup.1 is lower alkylene or lower alkenylene; R.sup.0 is a
hydrogen atom, lower alkyl or acyl;
X is S, O, or NR.sup.1;
[0025] R.sup.1 is a hydrogen atom or lower alkyl; R.sup.2a and
R.sup.2b are each independently a hydrogen atom, hydroxy,
optionally substituted lower alkyl, optionally substituted lower
alkenyl, optionally substituted amino, optionally substituted
amidino, optionally substituted acyl, optionally substituted
carbamoyl, optionally substituted carbamoylcarbonyl, optionally
substituted lower alkylsulfonyl, optionally substituted
arylsulfonyl, an optionally substituted carbocyclic group or an
optionally substituted heterocyclic group; R.sup.3a, R.sup.3b,
R.sup.4a and R.sup.4b are each independently a hydrogen atom,
halogen, hydroxy, optionally substituted lower alkyl, optionally
substituted lower alkenyl, optionally substituted acyl, carboxy,
optionally substituted lower alkoxycarbonyl, optionally substituted
amino, optionally substituted carbamoyl, an optionally substituted
carbocyclic group or an optionally substituted heterocyclic group;
n and m are each independently an integer of 0 to 3; n+m is an
integer of 1 to 3; each R.sup.3a, each R.sup.3b, each R.sup.4a, and
each R.sup.4b may be independently different; R.sup.5 is a hydrogen
atom, optionally substituted lower alkyl, optionally substituted
lower alkenyl, optionally substituted lower alkenyl, an optionally
substituted carbocyclic group or an optionally substituted
heterocyclic group;
##STR00004##
R.sup.5 and ring A can be taken together to form
##STR00005##
wherein R.sup.5a and R.sup.5b are each independently a hydrogen
atom or lower alkyl; s is an integer of 1 to 4; each R.sup.5a and
each R.sup.5b may be different; with the proviso that the compound
wherein n+m is 2; R.sup.5 is a hydrogen atom; and ring A is
non-substituted phenyl is excluded, its pharmaceutically acceptable
salt, or a solvate thereof, (a1) a composition having BACE 1
inhibitory activity containing a compound represented by the
general formula (I):
##STR00006##
wherein ring A is an optionally substituted carbocyclic group or an
optionally substituted heterocyclic group;
##STR00007##
Alk.sup.1 is lower alkylene; R.sup.0 is a hydrogen atom, lower
alkyl or acyl;
X is S, O, or NR.sup.1;
[0026] R.sup.1 is a hydrogen atom or lower alkyl; R.sup.2a and
R.sup.2b are each independently a hydrogen atom, hydroxy,
optionally substituted lower alkyl, optionally substituted lower
alkenyl, optionally substituted amino, optionally substituted
amidino, optionally substituted acyl, optionally substituted
carbamoyl, optionally substituted lower alkylsulfonyl, optionally
substituted arylsulfonyl, an optionally substituted carbocyclic
group or an optionally substituted heterocyclic group; R.sup.3a,
R.sup.3b, R.sup.4a, and R.sup.4b are each independently a hydrogen
atom, halogen, hydroxy, optionally substituted lower alkyl,
optionally substituted lower alkenyl, optionally substituted acyl,
carboxy, optionally substituted lower alkoxycarbonyl, optionally
substituted amino, optionally substituted carbamoyl, an optionally
substituted carbocyclic group or an optionally substituted
heterocyclic group; n and m are each independently an integer of 0
to 3; n+m is an integer of 1 to 3; each R.sup.3a, each R.sup.3b,
each R.sup.4a, and each R.sup.4b may be independently different;
R.sup.5 is a hydrogen atom, optionally substituted lower alkyl,
optionally substituted lower alkenyl, optionally substituted lower
alkynyl, an optionally substituted carbocyclic group or an
optionally substituted heterocyclic group;
##STR00008##
R.sup.5 and ring A can be taken together to form
##STR00009##
wherein R.sup.5a and R.sup.5b are each independently a hydrogen
atom or lower alkyl; s is an integer of 1 to 4; each R.sup.5a and
each R.sup.5b may be different; with the proviso that the compound
wherein n+m is 2; R.sup.5 is a hydrogen atom; and ring A is
non-substituted phenyl is excluded, its pharmaceutically acceptable
salt, or a solvate thereof, (b) a composition having BACE 1
inhibitory activity according to (a), wherein X is S, (c) a
composition having BACE 1 inhibitory activity according to (a),
wherein n is 2, and m is 0, (d) a composition having BACE 1
inhibitory activity according to (a), wherein E is a bond, (e) a
compound represented by the general formula (I):
##STR00010##
wherein each symbols are the same as described in (a), with the
proviso that the compounds as shown below; i) wherein n+m is 2,
R.sup.5 is a hydrogen atom, and ring A is non-substituted phenyl;
ii) wherein n is 2, m is 0, R.sup.2a is a hydrogen atom, R.sup.2b
is a hydrogen atom or acetyl, R.sup.5 is methyl, and ring A is
phenyl or 4-methoxyphenyl; iii) wherein n is 2, m is 0, R.sup.2a is
a hydrogen atom, R.sup.2b is a hydrogen atom or acetyl, R.sup.6 is
ethyl, and ring A is 3,4-dimethoxyphenyl; iv) wherein n is 2, m is
0, R.sup.2a is a hydrogen atom, R.sup.2b is a hydrogen atom or
acetyl, and R.sup.5 and ring A is phenyl; v) wherein n is 2, m is
0, R.sup.2a and R.sup.2b is a hydrogen atom, R.sup.5 and ring A are
taken together to form
##STR00011##
wherein Me is methyl, and each symbols are the same as described
above; and vi) wherein n+m is 2, R.sup.5 is a hydrogen atom, ring A
is phenyl substituted with one or two substituent(s) selected from
the group of hydroxy, halogen, lower alkyl, lower alkoxy, nitro,
amino, lower alkylcarbonylamino, mercapto, lower alkylthio, and
carbamoyl, non-substituted phenyl, or non-substituted naphthyl; are
excluded, its pharmaceutically acceptable salt, or a solvate
thereof, (f) the compound according to (e), wherein X is S, its
pharmaceutically acceptable salt, or a solvate thereof, (g) the
compound according to (e) or (i), wherein n is 2, and m is 0, its
pharmaceutically acceptable salt, or a solvate thereof, (h) the
compound according to any one of (e) to (g), wherein R.sup.5 is
optionally substituted lower alkyl, optionally substituted lower
alkenyl, optionally substituted lower alkynyl, an optionally
substituted carbocyclic group or an optionally substituted
heterocyclic group, its pharmaceutically acceptable salt, or a
solvate thereof, (i) the compound according to any one of (e) to
(h), wherein R.sup.2a is a hydrogen atom; R.sup.2b is a hydrogen
atom, optionally substituted lower alkyl, optionally substituted
acyl, optionally substituted lower alkylsulfonyl, or optionally
substituted amidino, its pharmaceutically acceptable salt, or a
solvate thereof, (j) the compound according to any one of (e) to
(h), wherein NR.sup.2aR.sup.2b is represented by the formula:
##STR00012##
R.sup.6, R.sup.7, and R.sup.8 are each independently a hydrogen
atom, lower alkyl or acyl, Y is optionally substituted lower
alkylene, optionally substituted lower alkenylene or optionally
substituted lower alkenylene;
Z is O or S;
[0027] its pharmaceutically acceptable salt, or a solvate thereof,
(k) the compound according to any one of (e) to (j), wherein ring A
is substituted phenyl, its pharmaceutically acceptable salt, or a
solvate thereof, (l) the compound according to any one of (e) to
(j), wherein ring A is represented by the formula:
##STR00013##
wherein R.sup.9, R.sup.10 and R.sup.11 are hydrogen atom or G; G is
halogen, hydroxy, cyano, nitro, mercapto, optionally substituted
lower alkyl, optionally substituted lower alkoxy, optionally
substituted lower alkenyl, optionally substituted lower alkynyl,
optionally substituted acyl, optionally substituted acyloxy,
carboxy, optionally substituted lower alkoxycarbonyl, optionally
substituted lower alkoxycarbonyloxy, optionally substituted
aryloxycarbonyloxy, optionally substituted amino, optionally
substituted carbamoyl, optionally substituted carbamoyloxy,
optionally substituted lower alkylthio, optionally substituted
arylthio, optionally substituted lower alkylsulfonyl, optionally
substituted arylsulfonyl, optionally substituted lower
alkylsulfinyl, optionally substituted arylsulfinyl, optionally
substituted lower alkylsulfonyloxy, optionally substituted
arylsulfonyloxy, an optionally substituted carbocyclic group,
optionally substituted carbocyclicoxy, an optionally substituted
heterocyclic group or optionally substituted heterocyclicoxy; each
G may be independently different; its pharmaceutically acceptable
salt, or a solvate thereof, (m) the compound according to (l),
wherein G is represented by the formula:
##STR00014## ##STR00015## ##STR00016##
Q.sup.1, Q.sup.2, w and Q.sup.3 are each independently a bond,
optionally substituted lower alkylene, or optionally substituted
lower alkenylene; Q.sup.4 is optionally substituted lower alkylene
or optionally substituted lower alkenylene; W.sup.1 and W.sup.2 are
each independently O or S;
W.sup.3 is O, S or NR.sup.12;
[0028] R.sup.12 is a hydrogen atom, lower alkyl, hydroxy lower
alkyl, lower alkoxy lower alkyl, lower alkoxycarbonyl lower alkyl,
carbocyclic lower alkyl or acyl; R.sup.14 is a hydrogen atom or
lower alkyl; ring B is an optionally substituted carbocyclic group
or an optionally substituted heterocyclic group; Alk.sup.2 is
optionally substituted lower alkyl; p is for 2; if there are
multiple W.sup.1, multiple W.sup.3, and multiple R.sup.12, each may
be independently different; in (xii), the position of an oxygen
atom may be cis or trans to a substituent R.sup.14, its
pharmaceutically acceptable salt, or a solvate thereof, (n) the
compound according to (m), wherein ring B is aryl optionally
substituted with one or more substituents selected from the group
of halogen, hydroxy, optionally substituted lower alkyl, optionally
substituted lower alkoxy, optionally substituted acyl, optionally
substituted amino, cyano, optionally substituted carbamoyl, an
optionally substituted carbocyclic group, optionally substituted
carbocyclicoxy or an optionally substituted heterocyclic group, or
heteroaryl optionally substituted with one or more substituents
selected from the group of halogen, hydroxy, optionally substituted
lower alkyl, optionally substituted lower alkoxy, optionally
substituted acyl, optionally substituted amino, cyano, optionally
substituted carbamoyl, an optionally substituted carbocyclic group,
optionally substituted carbocyclicoxy or an optionally substituted
heterocyclic group, its pharmaceutically acceptable salt, or a
solvate thereof, (o) the compound according to (m), wherein G is
represented by the formula:
##STR00017##
wherein, each symbols are the same as described above, its
pharmaceutically acceptable salt, or a solvate thereof, (p) the
compound according to any one of (e) to (o), wherein R.sup.5 is C1
to C3 alkyl, its pharmaceutically acceptable salt, or a solvate
thereof, (q) the compound according to any one of (e) to (o),
wherein R.sup.5 is methyl, its pharmaceutically acceptable salt, or
a solvate thereof, (r) the compound according to any one of (e) to
(q), wherein R.sup.3a and R.sup.3b are each independently a
hydrogen atom, halogen, hydroxy, optionally substituted lower
alkyl, optionally substituted lower alkoxy or optionally
substituted aryl, its pharmaceutically acceptable salt, or a
solvate thereof, (s) the compound according to any one of (e) to
(q), wherein R.sup.3a and R.sup.3b are both hydrogen atoms, its
pharmaceutically acceptable salt, or a solvate thereof, (t) a
pharmaceutical composition containing the compound according to any
one of (e) to (s), its pharmaceutically acceptable salt, or a
solvate thereof as an active ingredient, (u) a composition having
BACE 1 inhibitory activity containing the compound according to any
one of (e) to (s), its pharmaceutically acceptable salt, or a
solvate thereof, (v) a composition having BACE 1 inhibitory
activity containing the compound according to any one of (a) to (d)
or (u) as amyloid .beta. reducing agent, (w) a composition having
BACE 1 inhibitory activity according to any one of (a) to (d), (u)
or (v) as therapeutic agent for disease induced by production,
secretion and/or deposition of amyloid .beta. protein, (x) a
composition having BACE 1 inhibitory activity according to any one
of (a) to (d), (u) or (v) as therapeutic agent for Alzheimer's
disease. in addition, the present invention provides: (y) a method
for treating disease induced by production, secretion and/or
deposition of amyloid .beta. protein comprising administering the
compound as defined in any one of formula (I) in above (a), its
pharmaceutically acceptable salt, or a solvate thereof, (z) use of
compound as defined in any one of formula (I) in above (a), its
pharmaceutically acceptable salt, or a solvate thereof, in the
manufacture of a medicament for the treatment of disease induced by
production, secretion and/or deposition of amyloid .beta. protein,
(aa) a method for treating Alzheimer's disease characterizing in
administering the compound as defined in any one of formula (I) in
above (a), its pharmaceutically acceptable salt, or a solvate
thereof, (ab) use of compound as defined in any one of formula (I)
in above (a), its pharmaceutically acceptable salt, or a solvate
thereof, in the manufacture of a medicament for the treatment of
Alzheimer's disease.
Effect of the Invention
[0029] The compounds in this invention are useful as an agent for
treating disease such as Alzheimer's disease induced by production,
secretion and/or deposition of amyloid .beta. protein.
BEST MODE FOR CARRYING OUT THE INVENTION
[0030] As used herein, the "halogen" includes fluorine, chlorine,
bromine, and iodine. A halogen part of the "halogeno lower alkyl",
the "halogeno lower alkoxy", the "halogeno acyl", the "halogeno
lower alkylthio" and the "halogeno lower alkoxycarbonyl" is the
same.
[0031] The "lower alkyl" includes a straight or branched alkyl of a
carbon number of 1 to 15, preferably a carbon number of 1 to 10,
further preferably a carbon number of 1 to 6, and more further
preferably a carbon number of 1 to 3, and examples include methyl,
ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl,
tert-butyl, n-pentyl, isopentyl, neopentyl, hexyl, isohexyl,
n-heptyl, isoheptyl, n-octyl, isooctyl, n-nonyl, and n-decyl.
[0032] A lower alkyl part of the "carbocyclic lower alkyl", the
"lower alkoxy", the "halogeno lower alkyl", the "halogen lower
alkoxy", the "halogeno lower alkylthio", the "hydroxy lower alkyl",
the "lower alkoxycarbonyl", the "halogen lower alkoxycarbonyl", the
"lower alkoxycarbonyl lower alkyl", the "lower alkoxycarbonyloxy",
the "lower alkylamino", the "lower alkylcarbonylamino", the "lower
alkoxycarbonylamino", the "lower alkoxy lower alkyl", the "lower
alkylcarbamoyl", the "hydroxy lower alkylcarbamoyl", the "amino
lower alkyl", the "hydroxy imino lower alkyl", the "lower alkoxy
imino lower alkyl", the "lower alkylthio", the "lower
alkylsulfonyl", the "lower alkyl sulfamoyl", the "lower
alkylsulfinyl", the "lower alkylsulfonyloxy", the "lower
alkoxycarbonyl lower alkynyl", the "lower alkylthio lower alkyl",
the "aryl lower alkyl", the "aryl lower alkylamino", the "aryl
lower alkoxycarbonyl", the "aryl lower alkylcarbamoyl", the
"heterocyclic group lower alkylamino" and the "heterocyclic group
lower alkylcarbamoyl" is the same as that of the aforementioned
"lower alkyl".
[0033] The example of the "optionally substituted lower alkyl" as a
substituent of ring A is lower alkyl optionally substituted with
one or more substituents selected from the "substituent group
.alpha.", "hydroxyimino" and "lower alkoxyimino"; the group defined
as above (i), (ii), (iv), (vi), (viii), (x) (wherein each Q.sup.1
is optionally substituted lower alkylene); the group defined as
(v), (vii), (ix) (wherein Q.sup.2 is optionally substituted lower
alkylene); and the group (xii).
[0034] In other "optionally substituted lower alkyl" is optionally
substituted with one or more substituents selected from the
"substituent group .alpha.".
[0035] The "substituent group .alpha." is selected from the group
of halogen, hydroxy, lower alkoxy, hydroxy lower alkoxy, lower
alkoxy lower alkoxy, acyl, acyloxy, carboxy, lower alkoxycarbonyl,
amino, acylamino, lower alkylamino, lower alkylthio, carbamoyl,
lower alkylcarbamoyl, hydroxy lower alkylcarbamoyl, sulfamoyl,
lower alkylsulfamoyl, lower alkylsulfinyl, cyano, nitro, aryl, and
heterocyclic group.
[0036] Especially as a substituent of the "optionally substituted
lower alkyl" in Alk.sup.2, halogen, hydroxy, lower alkoxy, lower
alkoxy lower alkoxy, lower alkoxycarbonyl, amino, acylamino, lower
alkylamino and/or lower alkylthio are preferable.
[0037] The example of the "optionally substituted lower alkoxy" as
a substituent of ring A is lower alkoxy optionally substituted with
one or more substituents selected from the above "substituent group
.alpha."; above (iii) wherein Q.sup.1 is optionally substituted
lower alkylene, Q.sup.2 is a bond, W.sup.2 is O; above (v) wherein
Q.sup.1 is optionally substituted lower alkylene, Q.sup.2 is a
bond, W.sup.3 is O; above (vi) wherein Q.sup.1 is a bond, Q.sup.2
is optionally substituted lower alkylene, W.sup.2 is O; or above
(xi) wherein Q.sup.4 is optionally substituted lower alkylene,
W.sup.2 is O.
[0038] In other case, the substituents of the "optionally
substituted lower alkoxy", the "optionally substituted lower
alkoxycarbonyl", the "optionally substituted lower
alkoxycarbonyloxy", the "optionally substituted lower
alkylsulfonyl", the "optionally substituted lower alkylsulfinyl",
the "optionally substituted lower alkylsulfonyloxy" and the
"optionally substituted lower alkylthio" are one or more
substituents selected from the "substituent group .alpha.".
[0039] The "lower alkenyl" includes a straight or branched alkenyl
of a carbon number of 2 to 15, preferably a carbon number of 2 to
10, further preferably a carbon number of 2 to 6 and more further
preferably a carbon number of 2 to 4 having one or more double
bonds at an arbitrary position. Specifically examples include
vinyl, allyl, propenyl, isopropenyl, butenyl, isobutenyl, prenyl,
butadienyl, pentenyl, isopentenyl, hexenyl, isohexenyl, hexadienyl,
heptenyl, octenyl, nonenyl, decenyl, undecenyl, dodenyl,
tridecenyl, tetradecenyl, and pentadecenyl.
[0040] The "lower alkynyl" includes a straight or branched alkynyl
of a carbon number of 2 to 10, preferably a carbon number of 2 to
8, further preferably a carbon number of 3 to 6, having one or more
triple bonds at an arbitrary position. Specifically, examples
include ethynyl, propenyl, butynyl, pentynyl, hexynyl, heptynyl,
octynyl, nonynyl, and decynyl. These may further have a double bond
at an arbitrary position.
[0041] A lower alkynyl part of the "lower alkoxycarbonyl lower
alkynyl" is the same as that of above "lower alkynyl".
[0042] The example of the "optionally substituted lower alkenyl" as
a substituent of ring A is lower alkenyl optionally substituted
with one or more substituents selected from the above "substituent
group .alpha."; above (i), (ii), (iv), (vi), (viii) or (x), wherein
Q.sup.1 is optionally substituted lower alkenylene; (v), (vii) or
(ix), wherein Q.sup.2 is optionally substituted lower
alkenylene.
[0043] In other case, the substituents of the "optionally
substituted lower alkenyl" and the "optionally substituted lower
alkynyl" are one or more substituents selected from the
"substituent group .alpha.".
[0044] The example of the "optionally substituted lower amino" as a
substituent of ring A is amino optionally substituted with one or
more substituents selected from the group of lower alkyl, acyl,
hydroxy, lower alkoxy, lower alkoxycarbonyl, a carbocyclic group
and a heterocyclic group; (ii), wherein Q.sup.1 is a bond; (iv),
wherein Q.sup.1 is a bond; (v), wherein Q.sup.2 is a bond, W.sup.3
is NR.sup.12; (ix), wherein Q.sup.2 is a bond; (xiii); or
(xiv).
[0045] The example of the "optionally substituted carbamoyl" as a
substituent of ring A is carbamoyl optionally substituted with one
or more substituents selected from the group of lower alkyl, acyl,
hydroxy, lower alkoxy, lower alkoxycarbonyl, a carbocyclic group
and a heterocyclic group; (i), (viii), wherein each Q.sup.1 is
bond; or (xv).
[0046] In other case, the substituents of the "optionally
substituted amino", the "optionally substituted amidino", the
"optionally substituted carbamoyl", the "optionally substituted
carbamoylcarbonyl", and the "optionally substituted carbamoyloxy"
are one or two substituents selected from the group of lower alkyl,
acyl, hydroxy, lower alkoxy, lower alkoxycarbonyl, a carbocyclic
group and a heterocyclic group, and the like.
[0047] The "acyl" includes acyl of a carbon number of 1 to 10,
carbocyclic carbonyl and heterocyclic carbonyl. Specifically,
formyl, acetyl, propyonyl, butylyl, isobutylyl, valeryl, pivaloyl,
hexanoyl, acryloyl, propioloyl, methacryloyl, crotonoyl, benzoyl,
cyclohexanecarbonyl, pyridinecarbonyl, furancarbonyl,
thiophenecarbonyl, benzothiazolcarbonyl, pyradinecarbonyl,
piperidinecarbonyl, thiomorpholinocarbonyl, and the like.
[0048] The part of the acyl of the "halogenoacyl", the "acylamino"
and the "acyloxy" is the same as the aforementioned "acyl".
[0049] The substituent of the "optionally substituted acyl" and
"optionally substituted acyloxy" is one or more substituents
selected from the group of the "substituent group .alpha.". The
ring part of the "carbocyclic carbonyl" and the "heterocyclic
carbonyl" is optionally substituted with one or more substituents
selected from the group of "lower alkyl"; the "substituent group
.alpha."; and "lower alkyl substituted with one or more
substituents selected from the group of the substituent
.alpha.".
[0050] The "carbocyclic group" includes cycloalkyl, cycloalkenyl,
aryl and non-aromatic fused carbocyclic group.
[0051] The "cycloalkyl" includes a carbocyclic group of a carbon
number of 3 to 10, preferably a carbon number of 3 to 8, further
preferably a carbon number of 4 to 8, and examples include,
cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,
cyclooctyl, cyclononyl, and cyclodecyl, and the like.
[0052] The "cycloalkenyl" includes cycloalkenyl having one or more
double bonds at an arbitrary position in a ring of the
aforementioned cycloalkyl, and examples include cyclopropenyl,
cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptynyl,
cyclooctynyl, and cyclohexadienyl, and the like.
[0053] The "aryl" includes phenyl, naphthyl, anthryl, and
phenanthryl, and the like, and phenyl is particularly
preferable.
[0054] The "non-aromatic fused a carbocyclic group" includes group
fused with two or more ring groups selected from the group of the
above "cycloalkyl", the "cycloalkenyl" and the "aryl".
Specifically, examples include indanyl, indenyl,
tetrahydronaphthyl, and fluorenyl, and the like.
[0055] The carbocyclic part of the "carbocyclicoxy", and the
"carbocyclic lower alkyl" is the same as the aforementioned
"carbocyclic group".
[0056] The aryl part of the "aryl lower alkyl", the "aryloxy", the
"aryloxycarbonyl", the "aryloxycarbonyloxy", the "aryl lower
alkoxycarbonyl", the "arylthio", the "arylamino", the "aryl lower
alkylamino", the "arylsulfonyl", the "arylsulfonyloxy", the
"arylsulfinyl", the "arylsulfamoyl", the "arylcarbamoyl" and the
"aryl lower alkylcarbamoyl" is the same as the aforementioned
"aryl".
[0057] The "heterocyclic group" includes a heterocyclic group
having one or more heteroatoms arbitrary selected from O, S, and N
in a ring, specifically includes a 5- to 6-membered heteroaryl such
as pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyridazinyl,
pyrimidinyl, pyrazinyl, triazolyl, triazinyl, tetrazolyl,
isoxazolyl, oxazolyl, oxadiazolyl, isothiazolyl, thiazolyl,
thiadiazolyl, isothiazolyl, furyl and thienyl; a bicyclic fused
heterocyclic group such as indolyl, isoindolyl, indazolyl,
indolidinyl, indolinyl, isoindolinyl, quinolyl, isoquinolyl,
cinnolinyl, phthalazinyl, quinazolinyl, naphthridinyl,
quinoxalinyl, purinyl, pteridinyl, benzopyranyl, benzimidazolyl,
benzioxazolyl, benzoxazolyl, benzoxadiazolyl, benzoisothiazolyl,
benzothiazolyl, benzothiadiazolyl, benzofuryl, isobenzofuryl,
benzothienyl, benzotriazolyl, imidazopyridyl, pyrazolopyridyl,
triazolopyridyl, imidazothiazolyl, pyrazinopyridazinyl,
quinazolinyl, quinolyl, isoquinolyl, naphthyridinyl,
dihydrobenzofuryl, tetrahydroquinolyl, tetrahydroisoquinolyl,
dihydrobenzoxazine, tetrahydrobenzothienyl; a tricyclic fused
heterocyclic group such as carbazolyl, acridinyl, xanthenyl,
phenothiazinyl, phenoxathiinyl, phenoxazinyl, dibenzofuryl, and
imidazoquinolyl; a non-aromatic heterocyclic group such as
dioxanyl, thiiranyl, oxyranyl, oxathioranyl, azethidinyl, thianyl,
pyrrolidinyl, pyrrolinyl, imidazolidinyl, imidazolinyl,
pyrazolidinyl, pyrazolinyl, piperidyl, piperazinyl, morpholinyl,
morpholino, thiomorpholinyl, thiomorpholino, dihydropyridyl,
dihydrobenzoimidazolyl, tetrahydropyridyl, tetrahydrofuryl,
tetrahydropyranyl, tetrahydrothiazolyl, tetrahydroisothiazolyl,
dihydroxadinyl, hexahydroazepinyl, tetrahydroazepyinyl. Preferable
is a 5- to 6-membered heteroaryl, or a non-aromatic heterocyclic
group.
[0058] The heterocyclic part of the "heterocyclicoxy", the
"heterocyclic thio", the "heterocyclic carbonyl", the "heterocyclic
amino", the "heterocyclic carbonylamino", the "heterocyclic
sulfamoyl", the "heterocyclic sulfonyl", the "heterocyclic
carbamoyl", the "heterocyclicoxycarbonyl", the "heterocyclic lower
alkylamino" and the "heterocyclic lower alkyl carbamoyl" is the
same as the aforementioned "heterocyclic group".
[0059] The example of the substituent of the "optionally
substituted carbocyclic group" and the "optionally substituted
heterocyclic group" in ring A is;
the substituent .alpha., wherein preferable is for example,
halogen, hydroxy, acyl, acyloxy, carboxy, lower alkoxycarbonyl,
carbamoyl, amino, lower alkylamino, lower alkylthio; lower alkyl
substituted with one or more substituents selected from the group
of substituent .alpha., wherein preferable is halogen, hydroxy,
lower alkoxy, lower alkoxycarbonyl, and the like; amino lower alkyl
substituted with one or more substituents selected from the group
of substituent .alpha., wherein preferable is acyl, lower alkyl and
for lower alkoxy, and the like; hydroxyimino lower alkyl; lower
alkoxyimino lower alkyl; lower alkenyl substituted with one or more
substituents selected from the group of substituent .alpha.,
wherein preferable is lower alkoxycarbonyl, halogen and for
halogeno lower alkoxycarbonyl, and the like; lower alkynyl
substituted with one or more substituents selected from the group
of substituent .alpha., wherein preferable is for example, lower
alkoxycarbonyl, lower alkoxy substituted with one or more
substituents selected from the group of substituent .alpha.,
wherein preferable is for example, lower alkyl carbamoyl and for
hydroxy lower alkyl carbamoyl, lower alkylthio substituted with one
or more substituents selected from the group of substituent
.alpha., lower alkylamino substituted with one or more substituents
selected from the group of substituent .alpha., lower alkylsulfonyl
substituted with one or more substituents selected from the group
of substituent .alpha., aryl lower alkoxycarbonyl substituted with
one or more substituents selected from the group of substituent
.alpha., azido, and lower alkyl, acyl substituted with one or more
substituents selected from the group of substituent .alpha.,
cycloalkyl substituted with one or more substituents selected from
the group of substituent .alpha., azido, and lower alkyl, lower
alkylsulfinyl substituted with one or more substituents selected
from the group of substituent .alpha., sulfamoyl, aryl substituted
with one or more substituents selected from the group of
substituent .alpha., azido, and lower alkyl, heterocyclic group
substituted with one or more substituents selected from the group
of substituent .alpha., azido, and lower alkyl, aryloxy substituted
with one or more substituents selected from the group of
substituent .alpha., azido, and lower alkyl, heterocyclicoxy
substituted with one or more substituents selected from the group
of substituent .alpha., azido, and lower alkyl, arylthio
substituted with one or more substituents selected from the group
of substituent .alpha., azido, and lower alkyl, heteroarylthio
substituted with one or more substituents selected from the group
of substituent .alpha., azido, and lower alkyl, arylamino
substituted with one or more substituents selected from the group
of substituent .alpha., azido, and lower alkyl, heterocyclicamino
substituted with one or more substituents selected from the group
of substituent .alpha., azido, and lower alkyl, aryl lower
alkylamino substituted with one or more substituents selected from
the group of substituent .alpha., azido, and lower alkyl,
heterocyclic lower alkylamino substituted with one or more
substituents selected from the group of substituent .alpha., azido,
and lower alkyl, lower alkyl sulfamoyl substituted with one or more
substituents selected from the group of substituent .alpha., aryl
sulfamoyl substituted with one or more substituents selected from
the group of substituent .alpha., azido, and lower alkyl,
heterocyclic sulfamoyl substituted with one or more substituents
selected from the group of substituent .alpha., azido, and lower
alkyl, arylsulfonyl substituted with one or more substituents
selected from the group of substituent .alpha., azido, and lower
alkyl, heterocyclic sulfonyl substituted with one or more
substituents selected from the group of substituent .alpha., azido,
and lower alkyl, aryl carbamoyl substituted with one or more
substituents selected from the group of substituent .alpha., azido,
and lower alkyl, heterocyclic carbamoyl substituted with one or
more substituents selected from the group of substituent .alpha.,
azido, and lower alkyl, aryl lower alkylcarbamoyl substituted with
one or more substituents selected from the group of substituent
.alpha., azido, and lower alkyl, heterocyclic lower alkylcarbamoyl
substituted with one or more substituents selected from the group
of substituent .alpha., azido, and lower alkyl, aryloxycarbonyl
substituted with one or more substituents selected from the group
of substituent .alpha., azido, and lower alkyl,
heterocyclicoxycarbonyl substituted with one or more substituents
selected from the group of substituent .alpha., azido, and lower
alkyl, lower alkylenedioxy optionally substituted with halogen;
oxo; azido;
##STR00018## ##STR00019## ##STR00020##
wherein Q.sup.1, Q.sup.2 and Q.sup.3 are each independently a bond,
optionally substituted lower alkylene or optionally substituted
lower alkenylene; Q.sup.4 is optionally substituted lower alkylene
or optionally substituted lower alkenylene; W.sup.1 and W.sup.2 are
each independently O or S;
W.sup.3 is O, S or NR.sup.12;
[0060] R.sup.12 is a hydrogen atom, lower alkyl, hydroxy lower
alkyl, lower alkoxy lower alkyl, lower alkoxycarbonyl lower alkyl,
carbocyclic group lower alkyl or acyl; R.sup.14 is a hydrogen atom
or lower alkyl; ring B is an optionally substituted carbocyclic
group or an optionally substituted heterocyclic group; Alk.sup.2 is
optionally substituted lower alkyl; and the ring A is optionally
substituted with one or more substituents selected from these
groups.
[0061] If there are multiple W.sup.1, multiple W.sup.3, and
multiple R.sup.12, each may be independently different.
[0062] In addition, an oxygen atom in (xii) may be cis or trans
position to the substituent R.sup.14.
[0063] The substituent of the "substituted phenyl" is, in the same
way, phenyl substituted with one or two substituents selected
preferably from the group of the substituent .alpha. or (i) to
(xv).
[0064] The substituent of the "optionally substituted carbocyclic
group" or the "optionally substituted heterocyclic group" in ring B
is optionally substituted with one or more substituents selected
from the following group of, for example;
the substituent .alpha., wherein preferable is halogen, hydroxy,
lower alkoxy, carboxy, lower alkoxycarbonyl, acyl, amino, lower
alkylamino, acylamino, carbamoyl, lower alkylcarbamoyl, cyano, and
nitro, and the like; lower alkyl substituted with one or more
substituents selected from the group of the substituent .alpha.,
wherein preferable is halogen, hydroxy, and lower alkoxy, and the
like; amino lower alkyl, hydroxyimino lower alkyl, or lower
alkoxyimino lower alkyl, substituted with one or more substituents
selected from the group of substituent .alpha.; lower alkenyl
substituted with one or more substituents selected from the group
of substituent .alpha.; lower alkynyl substituted with one or more
substituents selected from the group of substituent .alpha.; lower
alkoxy substituted with one or more substituents selected from the
group of substituent .alpha., wherein preferable is halogen,
hydroxy, and the like; lower alkylthio substituted with one or more
substituents selected from the group of substituent .alpha.,
wherein preferable is halogen; lower alkylamino substituted with
one or more substituents selected from the group of substituent
.alpha., wherein preferable is amino; lower alkylsulfonyl
substituted with one or more substituents selected from the group
of substituent .alpha.; aryl lower alkoxycarbonyl substituted with
one or more substituents selected from the group of substituent
.alpha. and lower alkyl; acyl substituted with one or more
substituents selected from the group of substituent .alpha.,
wherein preferable is halogen; lower alkylsulfonyl substituted with
one or more substituents selected from the group of substituent
.alpha.; sulfamoyl; lower alkyl sulfamoyl substituted with one or
more substituents selected from the group of substituent .alpha.;
cycloalkyl substituted with one or more substituents selected from
the group of substituent .alpha., azido and lower alkyl; aryl
substituted with one or more substituents selected from the group
of substituent .alpha., azido and lower alkyl; heterocyclic group
substituted with one or more substituents selected from the group
of substituent .alpha., azido and lower alkyl, wherein preferable
is halogen, lower alkyl, and the like; aryloxy substituted with one
or more substituents selected from the group of substituent
.alpha., azido and lower alkyl; heterocyclicoxy substituted with
one or more substituents selected from the group of substituent
.alpha., azido and lower alkyl; arylthio substituted with one pr
more substituents selected from the group of substituent .alpha.,
azido and lower alkyl, wherein preferable is halogen, hydroxy,
lower alkoxy, acyl, and the like; heterocyclic thio substituted
with one or more substituents selected from the group of
substituent .alpha., azido and lower alkyl; arylamino substituted
with one or more substituents selected from the group of
substituent .alpha., azido and lower alkyl, wherein preferable is
halogen, hydroxy, lower alkoxy, acyl; heterocyclic amino
substituted with one or more substituents selected from the group
of substituent .alpha., azido and lower alkyl; aryl lower
alkylamino substituted with one or more substituents selected from
the group of substituent .alpha., azido and lower alkyl, wherein
preferable is halogen, hydroxy, lower alkoxy, acyl; heterocyclic
lower alkylamino substituted with one or more substituents selected
from the group of substituent .alpha., azido and lower alkyl;
arylsulfamoyl substituted with one or more substituents selected
from the group of substituent .alpha. azido and lower alkyl;
heterocyclic sulfamoyl substituted with one or more substituents
selected from the group of substituent .alpha., azido and lower
alkyl; arylsulfonyl substituted with one or more substituents
selected from the group of substituent .alpha., azido and lower
alkyl; heterocyclic sulfonyl substituted with one or more
substituents selected from the group of substituent .alpha., azido
and lower alkyl; arylcarbamoyl substituted with one or more
substituents selected from the group of substituent .alpha., ado
and lower alkyl; heterocyclic carbamoyl substituted with one or
more substituents selected from the group of substituent .alpha.,
azido and lower alkyl; aryl lower alkylcarbamoyl substituted with
one or more substituents selected from the group of substituent
.alpha., azido and lower alkyl; heterocyclic lower alkylcarbamoyl
substituted with one or more substituents selected from the group
of substituent .alpha., azido and lower alkyl; aryloxy carbonyl
substituted with one or more substituents selected from the group
of substituent .alpha., azido and lower alkyl;
heterocyclicoxycarbonyl substituted with one or more substituents
selected from the group of substituent .alpha., azido and lower
alkyl; lower alkylenedioxy optionally substituted with halogen;
oxo; and the like.
[0065] In other case, the substituent of the "optionally
substituted carbocyclic group", the "optionally substituted
heterocyclic group", the "optionally substituted carbocyclicoxy",
the "optionally substituted arylsulfonyl", the "optionally
substituted aryloxycarbonyloxy", the "optionally substituted
heterocyclicoxy", the "optionally substituted arylsulfinyl", the
"optionally substituted arylsulfonyloxy", the "optionally
substituted arylthio" is one or more substituents selected from the
group of "lower alkyl" and the "substituent .alpha.".
"heteroaryl" include aromatic ring group in the aforementioned
"heterocyclic group".
[0066] The substituent of the "optionally substituted 5- to
6-membered heteroaryl" is the same as the substituent of the
"optionally substituted heterocyclic group" in the aforementioned
"ring B". Preferable is one or more substituent selected from lower
alkyl and a substituent .alpha..
[0067] The "lower alkylene" includes a straight or branched
bivalent carbon chain of a carbon number of 1 to 10, preferably a
carbon number of 1 to 6, further preferably a carbon number of 1 to
3. Specifically, examples include methylene, dimethylene,
trimethylene, teteramethylene, and methyltrimethylene, and the
like.
[0068] The part of lower alkylene of the "lower alkylenedioxy" is
the same as the aforementioned "lower alkylene".
[0069] The "lower alkenylene" includes a straight or branched
bivalent carbon chain of a carbon number of 2 to 10, preferably a
carbon number of 2 to 6, further preferably a carbon number of 2 to
4 having double bond at an arbitrary position. Specifically,
examples include vinylene, propenylene, butenylene, butadienylene,
methylpropenylene, pentenylene, and hexenylene, and the like.
[0070] The "lower alkynylene" includes a straight or branched
bivalent carbon chain of a carbon number of 2 to 10, preferably a
carbon number of 2 to 6, further preferably a carbon number of 2 to
4 having triple bond at an arbitrary position. Specifically,
examples include ethynylene, propynylene, butynylene, pentynylene,
and hexynylene, and the like.
[0071] The substituent of the "optionally substituted lower
alkylene", the "optionally substituted lower alkenylene", the
"optionally substituted lower alkynylene" is the substituent
.alpha., preferable is halogen, hydroxy and the like.
[0072] The "each R.sup.3a, each R.sup.3b, each R.sup.4a, and each
R.sup.4b may be independently different" means when n is 2 or 3,
two or three R.sup.3b may be independently different, and two or
three R.sup.3b may be independently different. In the same way,
when m is 2 or 3, two or three R.sup.4a may be independently
different, and two or three R.sup.4b may be independently
different.
##STR00021##
R.sup.5 and ring A can be taken together to form
##STR00022##
means for example, include the following structures.
##STR00023##
wherein each symbols are the same as described above; preferably,
R.sup.5a and R.sup.5b are all hydrogen atoms.
[0073] In this description, "solvate" includes, for example, a
solvate with an organic solvent and a hydrate, and the like. When
hydrate is formed, arbitrary number of water molecules may be
coordinated.
[0074] The compound (I) includes a pharmaceutically acceptable
salt. Examples include salts with alkali metals (lithium, sodium or
potassium, and the like), alkaline earth metals (magnesium or
calcium, and the like), ammonium, organic bases or amino acids, and
salts with inorganic acids (hydrochloric acid, sulfuric acid,
nitric acid, hydrobromic acid, phosphoric acid or hydroiodic acid,
and the like), and organic acid (acetic acid, trifluoroacetic acid,
citric acid, lactic acid, tartaric acid, oxalic acid, maleic acid,
fumaric acid, manderic acid, glutaric acid, malic acid, benzoic
acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid,
methanesulfonic acid, or ethanesulfonic acid, and the like).
Particularly, hydrochloric acid, phosphoric acid, tartaric acid, or
methanesulfonic acid is preferable. These salts can be formed by a
conventional method.
[0075] In addition, the compound (I) is not limited to a specific
isomer, but includes all possible isomers (keto-enol isomer,
imine-enamine isomer, diastereo isomer, optical isomer, and
rotational isomer, and the like) and racemates. For example, the
compound (I), wherein R.sup.2a is a hydrogen atom, includes
following tautomer.
##STR00024##
[0076] The compound (I) in this invention can be prepared by the
process described in, for example Non-patent Document 1 or
following process.
[0077] The synthesis of aminodihydrothiazine ring; Method A
##STR00025##
[0078] In formula, at least either R.sup.2b or R.sup.2c is a
hydrogen atom, either R.sup.3c or R.sup.3d is each independently a
hydrogen atom, halogen, hydroxy, optionally substituted lower
alkyl, optionally substituted lower alkenyl, optionally substituted
acyl, carboxy, optionally substituted lower alkoxycarbonyl,
optionally substituted amino, optionally substituted carbamoyl, an
optionally substituted carbocyclic group or an optionally
substituted heterocyclic group. Other symbols are the same as
described above.
(Step 1)
[0079] To a solution of compound (a), which is commercially
available or prepared by known method, in appropriate solvent or
mixture of solvents, such as ether, tetrahydrofuran, and the like
is added the Grignard reagent having substituent corresponds to the
target compound; for example vinylmagnesium chloride,
vinylmagnesium bromide, or propenylmagnesium bromide, and the like;
at -100.degree. C. to 50.degree. C., preferably -80.degree. C. to
0.degree. C. The mixture is reacted for 0.2 to 24 hours, preferably
0.5 to 5 hours, to obtain compound (b).
(Step 2)
[0080] The compound (b) in solvent, such as toluene or absence of
solvent is treated with thiourea derivatives having substituent
corresponds to the target compound, such as thiourea,
N-methylthiourea, N,N'-dimethylthiourea, and the like in the
presence of an acid or mixture of acids, such as acetic acid,
trifluoroacetic acid, hydrochloric acid, or sulfuric acid, and the
like. The mixture is reacted at -20.degree. C. to 100.degree. C.,
preferably 0.degree. C. to 50.degree. C. for 0.5 to 120 hours,
preferably 1 to 72 hours, to obtain the compound (c).
(Step 3)
[0081] The compound (c) in solvent, such as toluene or absence of
solvent is treated with an acid or mixture of acids, such as
trifluoroacetic acid, methanesulfonic acid,
trifluoromethanesulfonic acid, and the like. The mixture is reacted
at -20.degree. C. to 100.degree. C., preferably 0.degree. C. to
60.degree. C. for 0.6 to 120 hours, preferably 1 to 72 hours, to
obtain the compound (I-2), wherein R.sup.2b is a hydrogen atom, or
the compound (I-1), wherein R.sup.2c is a hydrogen atom.
[0082] The synthesis of aminodihydrothiazine ring; Method B
##STR00026##
[0083] In formula, L is leaving group such as halogen or
sulfonyloxy, and the like. Other symbols are the same as described
above.
(Step 1)
[0084] The compound (d) which is commercially available or prepared
by known method is reacted with thiocyanic acid; for example,
sodium thiocyanic acid, ammonium thiocyanic acid, and the like; in
solvent; for example, toluene, chloroform, tetrahydrofuran, and the
like; in the presence of acid; for example, water, hydrochloric
acid, sulfuric acid, and the like; at 0.degree. C. to 150.degree.
C., preferably 20.degree. C. to 100.degree. C. for 0.5 to 24 hours,
preferably 1 to 12 hours, to obtain the compound (e).
(Step 2)
[0085] To the compound (e) in solvent or mixture of solvents; for
example, tetrahydrofuran, methanol, ethanol, water, and the like;
in the presence or the absence of buffer like sodium dihydorgen
phosphate, and the like; reducing agent; for example sodium
borohydride, and the like; is added and the mixture is reacted at
-80.degree. C. to 50.degree. C., preferably -20.degree. C. to
20.degree. C. for 0.1 to 24 hours, preferably 0.5 to 12 hours, to
obtain the compound (f).
(Step 3)
[0086] The compound (f) in the presence or the absence of solvent;
for example, toluene, dichloromethane, and the like; is reacted
with halogenating agent; for example thionyl chloride, phosphorus
oxychloride, carbon tetrabromide-triphenylphosphine, and the like;
at -80.degree. C. to 50.degree. C., preferably -20.degree. C. to
20.degree. C. for 0.1 to 24 hours, preferably 0.5 to 12 hours, to
obtain the compound (g). Alternatively, the compound (f) in the
presence or the absence of solvent; for example, toluene,
dichloromethane, and the like; under base; for example
triethylamine, and the like; is reacted with sulfonating agent; for
example, methanesulfonyl chloride, p-toluenesulfonylchloride, and
the like; at -80.degree. C. to 50.degree. C., preferably
-20.degree. C. to 20.degree. C. for 0.1 to 24 hours, preferably 0.5
to 12 hours, to obtain the compound (g).
(Step 4)
[0087] To the compound (g) in solvent or mixture of solvents, for
example methanol, ethanol, water, and the like; is reacted with
primary amine; for example, ammonia or methylamine, and the like;
at -20.degree. C. to 80.degree. C., preferably 0.degree. C. to
40.degree. C. for 0.5 to 48 hours, preferably 1 to 24 hours, to
obtain the compound (I-3).
[0088] The synthesis of aminodihydrothiazine ring; Method C
##STR00027##
[0089] In formula, R is a hydrogen atom or protective groups of
carboxyl group. Other symbols are the same as described above.
(Step 1)
[0090] The compound (h) which is commercially available or prepared
by known method is reacted with reducing agent; for example,
lithium aluminium hydride, diisobutyl aluminium hydride, and the
like; in solvent; for example tetrahydrofuran, ether, and the like;
at -80.degree. C. to 150.degree. C., preferably 25.degree. C. to
100.degree. C. for 0.1 to 24 hours, preferably 0.5 to 12 hours, to
obtain the compound (i).
(Step 2)
[0091] The compound (i) in solvent; for example, toluene,
chloroform, tetrahydrofuran, and the like; in the presence or the
absence of base; for example, diisopropylethylamine, triethylamine,
pyridine, sodium hydroxide, and the like; is reacted with
corresponding isothiocyanate; for example,
4-methoxybenzylisothiocyanate, t-butylisothiocyanate, and the like;
or corresponding thiocarbamoylhalide; for example,
N,N-dimethylthiocarbamoylchloride,
N,N-diethylthiocarbamoylchloride, and the like; at 0.degree. C. to
150.degree. C., preferably 20.degree. C. to 100.degree. C. for 0.5
to 120 hours, preferably 1 to 72 hours, to obtain the compound
(j).
(Step 3)
[0092] The compound (j) in solvent; for example, acetonitrile,
toluene, dichloromethane, and the like; is reacted with
halogenating agent; for example thionyl chloride, phosphorus
oxychloride, carbon tetrabromide-triphenylphosphine, and the like;
at -80.degree. C. to 50.degree. C., preferably -20.degree. C. to
20.degree. C. for 0.1 to 24 hours, preferably 0.5 to 12 hours, or
alternatively, the compound (j) in solvent; for example, toluene,
dichloromethane, and the like; in the presence of base; for example
triethylamine, and the like; is reacted with sulfonating agent; for
example, methanesulfonyl chloride, p-toluenesulfonylchloride, and
the like; at -80.degree. C. to 50.degree. C., preferably
-20.degree. C. to 20.degree. C. for 0.1 to 24 hours, preferably 0.5
to 12 hours. The obtained halogenated compound or sulfonylated
compound is reacted with base; for example, diisopropylamine,
potassium carbonate, sodium hydrogencarbonate, sodium hydride,
sodium hydroxide, and the like; at 0.degree. C. to 150.degree. C.,
preferably 20.degree. C. to 100.degree. C. for 0.5 to 120 hours,
preferably 1 to 72 hours, to obtain the compound (I-4).
[0093] The synthesis of aminodihydrothiazine ring; Method D
[0094] The synthesis of aminothiazoline ring; Method A
[0095] The synthesis of tetrahydrothiazepine ring; Method A
##STR00028##
[0096] In formula, L is leaving group such as halogen or
sulfonyloxy, and the like; m is an integer of 1 to 3; and the other
symbols are the same as described above.
(Step 1)
[0097] The compound (k) which is commercially available or prepared
by known method is reacted with azide reagent; for example, sodium
azide, and the like; in solvent; for example N,N-dimethylformamide,
tetrahydrofuran, and the like; at 0.degree. C. to 200.degree. C.,
preferably 40.degree. C. to 150.degree. C. for 0.5 to 24 hours,
preferably 1 to 12 hours, to obtain the compound (l).
(Step 2)
[0098] The compound (l) is reacted with reducing agent; for
example, lithium aluminium hydride, diisobutyl aluminium hydride,
and the like; in solvent; for example tetrahydrofuran, ether, and
the like; at -80.degree. C. to 150.degree. C., preferably
25.degree. C. to 100.degree. C. for 0.1 to 24 hours, preferably 0.5
to 12 hours, to obtain the compound (m).
(Step 3)
[0099] The compound (m) in solvent; for example, toluene,
chloroform, tetrahydrofuran, and the like; is reacted with
corresponding isothiocyanate; for example, methylisothiocyanate,
ethylisothiocyanate, and the like; or corresponding
thiocarbamoylhalide; for example,
N,N-dimethylthiocarbamoylchloride,
N,N-diethylthiocarbamoylchloride, and the like; at 0.degree. C. to
150.degree. C., preferably 20.degree. C. to 100.degree. C. for 0.5
to 120 hours, preferably 1 to 72 hours, to obtain the compound
(n).
(Step 4)
[0100] The compound (n) in solvent; for example, acetonitrile,
toluene, dichloromethane and the like; is reacted with halogenating
agent; for example thionyl chloride, phosphorus oxychloride, carbon
tetrabromide-triphenylphosphine, and the like; at -80.degree. C. to
50.degree. C., preferably -20.degree. C. to 20.degree. C. for 0.1
to 24 hours, preferably 0.5 to 12 hours, or alternatively, the
compound (n) in solvent; for example, toluene, dichloromethane, and
the like; in the presence of base; for example
diisopropylethylamine, triethylamine, and the like; is reacted with
sulfonating agent; for example, methanesulfonyl chloride,
p-toluenesulfonylchloride, and the like; at -80.degree. C. to
50.degree. C., preferably -20.degree. C. to 20.degree. C. for 0.1
to 24 hours, preferably 0.5 to 12 hours. The obtained halogenated
compound or sulfonylated compound is reacted with base; for
example, diisopropylamine, potassium carbonate, sodium
hydrogencarbonate, sodium hydride, sodium hydroxide, and the like;
at 0.degree. C. to 150.degree. C., preferably 20.degree. C. to
100.degree. C. for 0.5 to 120 hours, preferably 1 to 72 hours, to
obtain the compound (I-5).
[0101] The synthesis of aminodihydrothiazine ring; Method E
[0102] The synthesis of aminothiazoline ring; Method B
[0103] The synthesis of tetrahydrothiazepine ring; Method B
##STR00029##
[0104] In formula, at lease one of R.sup.2b and R.sup.2c is a
hydrogen atom, n is an integer of 1 to 3, and the other symbols are
the same as described above.
(Step 1)
[0105] The compound (o) which is commercially available or prepared
by known method is reacted with substituted thiourea; for example,
thiourea, N-methylthiourea, N,N,-dimethylthiourea,
N,N'-dimethylthiourea, and the like; in solvent; for example,
ethanol, methanol, tetrahydrofuran, toluene, and the like; at
-20.degree. C. to 200.degree. C., preferably 0.degree. C. to
150.degree. C. for 0.5 to 200 hours, preferably 1 to 120 hours, to
obtain the compound (p).
(Step 2)
[0106] To the compound (p) in solvent or mixture of solvents; for
example, ether, tetrahydrofuran, and the like; the Grignard reagent
having substituent corresponding to target compound; for example
methylmagnesium chloride, ethylmagnesium bromide, or
benzylmagnesium bromide, and the like; is added at -100.degree. C.
to 50.degree. C., preferably -80.degree. C. to 30.degree. C., and
the mixture is reacted for 0.2 to 24 hours, preferably 0.5 to 5
hours, to obtain the compound (q).
(Step 3)
[0107] To the compound (q) in the presence or the absence of
solvent; for example, toluene, and the like; acid or mixture of
acids, such as trifluoroacetic acid, methanesulfonic acid,
trifluoromethanesulfonic acid, and the like; is added and the
mixture is reacted at -20.degree. C. to 100.degree. C., preferably
0.degree. C. to 50.degree. C. for 0.5 to 200 hours, preferably 1 to
150 hours, to obtain the compound (I-6) (wherein R.sup.2c is H), or
the compound (I-7) (wherein R.sup.2b is H).
[0108] The synthesis of aminodihydrothiazine ring; Method F
##STR00030##
[0109] In formula, each symbols are the same as described
above.
(Step 1)
[0110] The compound (r) which is commercially available or prepared
by known method is reacted with ammonium chloride in solvent; for
example, acetic acid, and the like; at 0.degree. C. to 200.degree.
C., preferably 10.degree. C. to 100.degree. C. for 0.1 to 100
hours, preferably 0.5 to 24 hours, to obtain the compound (s).
(Step 2)
[0111] The compound (s) is reacted with reducing agent; for
example, lithium aluminium hydride, diisobutyl aluminium hydride,
and the like; in solvent; for example trahydrofuran, ether, and the
like; at -80.degree. C. to 150.degree. C., preferably 0.degree. C.
to 100.degree. C. for 0.1 to 24 hours, preferably 0.5 to 12 hours,
to obtain the compound (t).
(Step 3)
[0112] The compound (t) in solvent; for example, toluene,
chloroform, tetrahydrofuran, and the like; in the presence or the
absence of base; for example, diisopropylethylamine; triethylamine,
pyridine, sodium hydroxide, and the like; is reacted with
corresponding isothiocyanate; for example,
4-methoxybenzylisothiocyanate, t-butylisothiocyanate, and the like;
or corresponding carbamoylhalide; for example,
N,N-dimethylthiocarbamoylchloride,
N,N-diethylthiocarbamoylchloride, and the like; at 0.degree. C. to
150.degree. C., preferably 20.degree. C. to 100.degree. C. for 0.5
to 120 hours, preferably 1 to 72 hours, to obtain the compound
(u).
(Step 4)
[0113] The compound (u) in solvent; for example, acetonitrile,
toluene, dichloromethane, and the like; is reacted with
halogenating agent; for example thionyl chloride, phosphorus
oxychloride, carbon tetrabromide-triphenylphosphine, and the like;
at -80.degree. C. to 50.degree. C., preferably -20.degree. C. to
20.degree. C. for 0.1 to 24 hours, preferably 0.5 to 12 hours, or
alternatively, the compound (u) in solvent; for example, toluene,
dichloromethane, and the like; in the presence of base; for example
triethylamine, and the like; is reacted with sulfonating agent; for
example, methanesulfonyl chloride, p-toluenesulfonylchloride, and
the like; at -80.degree. C. to 50.degree. C., preferably
-20.degree. C. to 20.degree. C. for 0.1 to 24 hours, preferably 0.5
to 12 hours. The obtained halogenated compound or sulfonylated
compound is reacted with base; for example, diisopropylamine,
potassium carbonate, sodium hydrogencarbonate, sodium hydride,
sodium hydroxide, and the like; at 0.degree. C. to 150.degree. C.,
preferably 20.degree. C. to 100.degree. C. for 0.5 to 120 hours,
preferably 1 to 72 hours, to obtain the compound (I-8).
[0114] The synthesis of aminodihydrooxazine ring; Method A
[0115] The synthesis of aminotetrahydrooxazepine ring; Method A
##STR00031##
[0116] In formula, each symbols are the same as described
above.
(Step 1)
[0117] The compound (n) which is obtained by Step 3 (the compound
(m) to the compound (n)) of "The synthesis of aminodihydrothiazine
ring; Method D", in solvent; for example, methanol, ethanol,
N,N-dimethylformamide, tetrahydrofuran, and the like; in the
presence or the absence of base; for example,
diisopropylethylamine, triethylamine, pyridine, sodium hydroxide,
and the like; is reacted with alkylating agent; for example, methyl
iodide, dimethyl sulfate, benzyl bromide, and the like; at
0.degree. C. to 200.degree. C., preferably 40.degree. C. to
150.degree. C. for 0.1 to 48 hours, preferably 0.5 to 24 hours, to
obtain the compound (v).
(Step 2)
[0118] The compound (v) in solvent; for example, N,
N-dimethylformamide, tetrahydrofuran, dichloromethane, and the
like; in the presence or the absence of base; for example,
diisopropylethylamine, triethylamine, pyridine, sodium hydroxide,
and the like; is reacted with metallic oxide; for example, silver
oxide, mercury oxide, manganese dioxide, and the like; at 0.degree.
C. to 200.degree. C., preferably 10.degree. C. to 150.degree. C.
for 1 to 120 hours, preferably 0.5 to 100 hours, to obtain the
compound (I-9).
[0119] The synthesis of aminodihydrooxazine ring; Method B
[0120] The synthesis of aminoxazoline ring
[0121] The synthesis of aminotetrahydrooxazepine ring; Method B
##STR00032##
[0122] In formula, R.sup.15 is optionally substituted lower alkyl;
for example, t-butyl, benzyl, and the like; R.sup.16 is hydrogen
atom or lower alkyl; n is an integer of 1 to 3, and the other
symbols are the same as described above.
(Step 1)
[0123] The compound (w) which is commercially available or prepared
by known method in solvent; for example, toluene, t-butylalcohol,
tetrahydrofuran, and the like; in the presence of base; for
example, diisopropylethylamine, triethylamine, pyridine, and the
like; is reacted with azide reagent; for example, diphenyl
phosphoryl azide, and the like; at 0.degree. C. to 200.degree. C.,
preferably 40.degree. C. to 150.degree. C. for 1 to 48 hours,
preferably 0.5 to 24 hours, to obtain the compound (x).
(Step 2)
[0124] The compound (x) in solvent; for example, toluene, xylene,
N,N-dimethylformamide, tetrahydrofuran, and the like; is reacted
with alcohol; for example, t-butylalcohol,
3,4-dimethoxybenzylalcohol, 4-methoxybenzylalcohol, and the like;
at 0.degree. C. to 300.degree. C., preferably 50.degree. C. to
200.degree. C. for 1 to 800 hours, preferably 5 to 500 hours, to
obtain the compound (y).
(Step 3)
[0125] The compound (y) in the presence or the absence of solvent;
for example, water, toluene, dichloromethane, methanol,
1,4-dioxane, acetic acid, ethyl acetate, and the like; in the
presence of acid; for example, hydrochloric acid, sulfuric acid,
hydrobromic acid, trifluoroacetic acid, and the like; at 0.degree.
C. to 200.degree. C., preferably 25.degree. C. to 150.degree. C.
for 0.1 to 48 hours, preferably 0.5 to 24 hours, to obtain the
compound (z).
(Step 4)
[0126] The compound (z) in solvent; for example, toluene,
chloroform, tetrahydrofuran, and the like; in the presence of base;
for example, diisopropylethylamine, triethylamine, pyridine, and
the like; is reacted with corresponding isothiocyanate, or
thiocarbamoylhalide corresponding to target compound; for example,
N,N-dimethylthiocarbamoylchloride,
N,N-diethylthiocarbamoylchloride, and the like; at 0.degree. C. to
150.degree. C., preferably 20.degree. C. to 100.degree. C. for 0.5
to 120 hours, preferably 1 to 72 hours, to obtain the compound
(aa).
(Step 5)
[0127] The compound (aa) in solvent; for example, methanol,
ethanol, N,N-dimethylformamide, tetrahydrofuran, and the like; in
the presence or the absence of base; for example,
diisopropylethylamine, triethylamine, pyridine, sodium hydroxide,
and the like; is reacted with alkylating agent; for example, methyl
iodide, dimethyl sulfate, benzyl bromide, and the like; at
0.degree. C. to 200.degree. C., preferably 40.degree. C. to
150.degree. C. for 1 to 48 hours, preferably 0.5 to 24 hours, to
obtain the compound (ab).
(Step 6)
[0128] The compound (ab) in solvent; for example,
N,N-dimethylformamide, tetrahydrofuran, dichloromethane, and the
like; in the presence of base; for example, diisopropylethylamine,
triethylamine, pyridine, sodium hydroxide, and the like; is reacted
with metallic oxide; for example, silver oxide, mercury oxide,
manganese dioxide, and the like; at 0.degree. C. to 200.degree. C.,
preferably 10.degree. C. to 150.degree. C. for 1 to 120 hours,
preferably 0.5 to 100 hours, to obtain the compound (I-10).
[0129] The synthesis of aminotetrahydropyrimidine ring
##STR00033##
[0130] In formula, each symbols are the same as described
above.
(Step 1)
[0131] To the compound (ac) prepared by known method in solvent;
for example, N,N-dimethylformamide, methanol, and the like; is
reacted with azide reagent; for example, sodium azide, lithium
azide, and the like; at 20.degree. C. to 150.degree. C., preferably
50.degree. C. to 100.degree. C. for 0.5 to 120 hours, preferably 1
to 72 hours, to obtain the compound (ad).
(Step 2)
[0132] To the suspension of lithium aluminium hydride in solvent;
for example, tetrahydrofuran, or ether, and the like; the compound
(ad) dissolved in solvent; for example, tetrahydrofuran, or diethyl
ether, and the like; is added under nitrogen atmosphere, at
-80.degree. C. to 20.degree. C., preferably -30.degree. C. to
0.degree. C., and the mixture is reacted for 1 minute to 10 hours,
preferably 10 minutes to 1 hour, or alternatively to the compound
(ad) in solvent; for example, ethanol, isopropanol, or n-butanol,
and the like; Raney-Nickel is added at 10.degree. C. to 110.degree.
C., preferably 50.degree. C. to 80.degree. C., and reacted for 1
minute to 10 hours, preferably 10 minutes to 1 hour, to obtain the
compound (ae).
(Step 3)
[0133] The compound (ae) in solvent; for example, tetrahydrofuran,
dichloromethane, and the like; in the presence of acid; for
example, acetic acid, or propionic acid, and the like; is reacted
with reducing agent; for example, sodium cyanoborohydride, sodium
triacetoxyborohydride, and the like; at -50.degree. C. to
100.degree. C., preferably 0.degree. C. to 50.degree. C., for 0.1
to 48 hours, preferably 0.5 to 24 hours, or the compound (ae) in
solvent; for example, tetrahydrofuran, N,N-dimethylformamide, and
the like; in the presence of dehydrating agent; for example,
1-ehthyl-3-(3-dimethylaminopropyl)carbodiimide-N-hydroxybenzotriazole,
carbonyldiimidazole, and the like; or in the presence of base; for
example, triethylamine, potassium carbonate, and the like; is
reacted with carboxylic acid; for example, formic acid, acetic
acid, and the like; at -50.degree. C. to 100.degree. C., preferably
0.degree. C. to 50.degree. C. for 0.1 to 48 hours, preferably 0.5
to 16 hours, to obtain the compound (a0. And next, to the
suspension of lithium aluminium hydride in solvent; for example,
tetrahydrofuran, or diethyl ether, and the like; the aforementioned
amide compound dissolved in solvent; for example, tetrahydrofuran,
or ether, and the like; is added at -50.degree. C. to 60.degree.
C., preferably 0.degree. C. to 50.degree. C., and the mixture is
reacted for 1 minute to 48 hours, preferably 10 minutes to 10
hours, to obtain the compound (af).
(Step 4)
[0134] The compound (ae) or the compound (af) in solvent; for
example, acetonitrile, tetrahydrofuran, N,N-dimethylformamide, and
the like; is reacted with 3,5-dimethylpyrazole-1-carboxyamidine or
S-methylthiourea at 0.degree. C. to 150.degree. C., preferably
20.degree. C. to 100.degree. C., and the mixture is reacted for 0.5
to 120 hours, preferably 1 to 24 hours, to obtain the compound
(ag).
(Step 5)
[0135] To the compound (ag) (wherein at least either R.sup.2b or
R.sup.2c is a hydrogen atom) in the presence or the absence of
solvent; for example, toluene, and the like; acid; for example,
trifluoroacetic acid, methanesulfonic acid,
trifluoromethanesulfonic acid, and the like, or the mixture
thereof; is added and the mixture is reacted at -20.degree. C. to
100.degree. C., preferably 0.degree. C. to 50.degree. C., and the
mixture is reacted for 0.5 to 120 hours, preferably 1 to 72 hours,
to obtain the compound (I-2) (wherein R.sup.2b is a hydrogen atom)
or the compound (I-1) (wherein R.sup.2c is a hydrogen atom)
respectively. Proviso, if R.sup.2a, R.sup.2b, and R.sup.2c have
fragile structure under acidic condition; for example,
t-butyloxycarbonyl, and the like; R.sup.2a, R.sup.2b, and R.sup.2c
in the compound (I-1) or the compound (I-2) may be transformed into
a hydrogen atom.
[0136] The synthesis of aminothiazoline ring; Method C
##STR00034##
[0137] In formula, Hal is halogen, and other symbols are the same
as described above.
(Step 1)
[0138] The compound (ah) which is commercially available or
prepared by known method in solvent; for example, toluene,
chloroform, tetrahydrofuran, and the like; or in mixed-solvent; for
example, chloroform-water, and the like; is reacted with halogen;
for example, including iodine, bromine, chorine; phase transfer
catalyst; for example, sodium thiocyanic acid, ammonium thiocyanic
acid, and the like; at 0.degree. C. to 150.degree. C., preferably
20.degree. C. to 100.degree. C., for 0.5 to 48 hours, preferably 1
to 24 hours, to obtain the compound (ai).
(Step 2)
[0139] The compound (ai) in solvent; for example, toluene,
chloroform, tetrahydrofuran, and the like; is reacted with amine
having substituent corresponding to target compound; for example
ammonia, methylamine, diethylamine, and the like; at 0.degree. C.
to 150.degree. C., preferably 20.degree. C. to 100.degree. C., for
0.5 to 48 hours, preferably 1 to 24 hours, to obtain the compound
(I-11).
[0140] The aminoacyl derivative-1
##STR00035##
[0141] In formula, R.sup.17 is optionally substituted lower alkyl,
an optionally substituted carbocyclic group or an optionally
substituted heterocyclic group, and the other symbols are the same
as described above.
[0142] The compound (I-12) wherein R.sup.2b is a hydrogen atom in
the presence or the absence of solvent; for example,
tetrahydrofuran, dichloromethane, and the like; in the presence of
base; for example, pyridine, triethylamine, and the like; is
reacted with acylating agent having substituent corresponding to
target compound; for example, benzoyl chloride, 2-furoyl chloride,
acetic anhydride, and the like; at -80.degree. C. to 100.degree.
C., preferably -20.degree. C. to 40.degree. C., for 0.1 to 24
hours, preferably 1 to 12 hours, or alternatively, the compound
(I-12) in solvent; for example, N,N-dimethylformamide,
tetrahydrofuran, dichloromethane, and the like; in the presence of
dehydrating agent; for example, dicyclohexylcarbodiimide,
carbonyldiimidazole, and the like; is reacted with carboxylic acid
having substituent corresponding to target compound; for example,
amino acid, glycolic acid, and the like; at -80.degree. C. to
100.degree. C., preferably -20.degree. C. to 40.degree. C., for 0.1
to 24 hours, preferably 1 to 12 hours, to obtain the compound
(I-13) and/or the compound (I-14) (wherein R.sup.2a is a hydrogen
atom).
[0143] The guanidino derivative
##STR00036##
[0144] In formula, each symbols are the same as described
above.
[0145] The compound (I-12) wherein R.sup.2b is a hydrogen atom in
solvent; for example, acetonitrile, tetrahydrofuran,
N,N-dimethylformamide, and the like; in the presence or the absence
of base; for example, triethylamine, sodium hydrogencarbonate, and
the like; is reacted with 3,5-dimethylpyrazole-1-carboxyamidine, or
S-methylisothiourea etc. at 0.degree. C. to 150.degree. C.,
preferably 20.degree. C. to 100.degree. C., for 0.5 to 120 hours,
preferably 1 to 24 hours, to obtain the compound (I-15).
[0146] The carbamoyl derivatives
##STR00037##
[0147] In formula, CONR.sup.18R.sup.19 is optionally substituted
carbamoyl, and the other symbols axe the same as described
above.
[0148] The compound (I-16) having a carboxyl group as substituent
of ring A in solvent; for example, N,N-dimethylformamide,
tetrahydrofuran, dichloromethane, and the like; in the presence of
dehydrating agent; for example, dicyclohexylcarbodiimide,
carbonyldiimidazole,
dicyclohexylcarbodiimide-N-hydroxybenzotriazole, and the like; is
reacted with primary amine or secondary amine (aniline,
2-aminopyridine, dimethylamine etc.) at -80.degree. C. to
100.degree. C., preferably -20.degree. C. to 40.degree. C., for 0.1
to 24 hours, preferably 1 to 12 hours, to obtain the compound
(I-17).
[0149] The acylamino derivative-2
##STR00038##
[0150] In formula, NHR.sup.20 is optionally substituted amino;
NR.sup.20COR.sup.21 is optionally substituted acyl amino,
optionally substituted ureido, carboxy amino having substituent on
oxygen atom, and the other symbols are the same as described
above.
[0151] The compound (I-18) having an optionally substituted amino
group on ring A in the presence or the absence of solvent; for
example, tetrahydrofuran, dichloromethane, and the like; in the
presence or the absence of base; for example, pyridine,
triethylamine, and the like; is reacted with reagent including acid
chloride, acid anhydride, chloroformate ester derivatives,
isocyanate derivatives (benzoyl chloride, 2-furoyl chloride, acetic
anhydride, benzyl chloroformate, di-t-butyl dicarbonate, phenyl
isocyanate etc.), at -80.degree. C. to 100.degree. C., preferably
-20.degree. C. to 40.degree. C., for 0.1 to 24 hours, preferably 1
to 12 hours. Or alternatively, the compound (I-18) having an
optionally substituted amino group on ring A in solvent; for
example, N,N-dimethylformamide, tetrahydrofuran, dichloromethane,
and the like; in the presence of dehydrating agent; for example,
dicyclohexylcarbodiimide, carbonyldiimidazole,
dicyclohexylcarbodiimide-N-hydroxybenzotriazole, and the like; is
reacted with carboxylic acid having substituent corresponding to
target compound; for example, benzoic acid, 2-pyridinecarboxylic
acid, and the like; at -80.degree. C. to 100.degree. C., preferably
-20.degree. C. to 40.degree. C., for 0.1 to 24 hours, preferably 1
to 12 hours, to obtain the compound (I-19).
[0152] The alkylamino derivatives
##STR00039##
[0153] In formula, NHR.sup.22 is optionally substituted amino,
R.sup.22 is lower alkyl.
[0154] The compound (I-18) having an amino group on ring A in
solvent; for example, dichloromethane, tetrahydrofuran, and the
like; in the presence or the absence of acid; for example, acetic
acid, and the like; is reacted with aldehyde having substituent
corresponding to target compound; for example, benzaldehyde,
pyridine-2-carboaldehyde, and the like; and reducing agent; for
example, sodium borohydride, sodium triacetoxyborohydride, and the
like; at -80.degree. C. to 100.degree. C., preferably 0.degree. C.
to 40.degree. C., for 0.5 to 150 hours, preferably 1 to 24 hours,
to obtain the compound (I-20).
[0155] The substituted alkoxy derivatives
##STR00040##
[0156] In formula, R.sup.23 is optionally substituted lower alkyl,
an optionally substituted carbocyclic group or an optionally
substituted heterocyclic group, etc., and the other symbols are the
same as described above.
[0157] The compound (I-21) having a hydroxy group as substituent of
A ring in solvent; for example, N,N-dimethylformamide,
tetrahydrofuran, and the like; in the presence of base; for example
potassium carbonate, sodium hydroxide, sodium hydride, and the
like; is reacted with alkylating agent having substituent
corresponding to target compound; for example, benzylchloride,
methyl iodide, and the like; at -80.degree. C. to 100.degree. C.,
preferably 0.degree. C. to 40.degree. C., for 0.5 to 150 hours,
preferably 1 to 24 hours, or alternatively, the compound (I-18) in
solvent; for example, N,N-dimethylformamide, tetrahydrofuran, and
the like; under Mitsunobu reagent; for example
triphenylphosphine-azodicarboxylic acid ethyl ester, and the like;
is reacted with alcohol; for example, 2-aminoethanol, and the like;
at -80.degree. C. to 100.degree. C., preferably 0.degree. C. to
40.degree. C., for 0.5 to 72 hours, preferably 1 to 24 hours, to
obtain the compound (I-22).
[0158] The introduction of substituent with palladium coupling
reaction
##STR00041##
[0159] In formula, Hal is halogen, G is optionally substituted
lower alkenyl, optionally substituted lower alkynyl, optionally
substituted lower alkoxycarbonyl, an optionally substituted
carbocyclic group or an optionally substituted heterocyclic group
etc., and the other symbols are the same as described above.
[0160] The compound (I-23) having halogen as substituent of A ring
in solvent; for example, tetrahydrofuran, N,N-dimethylformamide,
1,2-dimethoxyethane, methanol, and the like; in the presence of
base; for example, triethylamine, sodium carbonate, and the like;
palladium catalyst; for example, palladium acetate, palladium
chloride, and the like; and ligand; for example triphenylphosphine,
and the like; is reacted with compound having substituent
corresponding to target compound (styrene, propargyl alcohol, aryl
boronic acid, carbon monoxide), with or without microwave
irradiation, at -80.degree. C. to 150.degree. C., preferably
0.degree. C. to 100.degree. C., for 0.5 to 72 hours, preferably 1
to 24 hours, to obtain the compound (I-24).
[0161] The oxime derivatives
##STR00042##
[0162] In formula, in R.sup.24 is a hydrogen atom or optionally
substituted lower alkyl etc., R.sup.25 is a hydrogen atom,
optionally substituted lower alkyl, optionally substituted lower
alkenyl or an optionally substituted carbocyclic group or an
optionally substituted heterocyclic group etc., and the other
symbols are the same as described above.
[0163] The compound (I-25) having an acyl group as substituent of A
ring in solvent; for example, methanol, ethanol, and the like; in
the presence or the absence of additives; for example, potassium
acetate, and the like; is reacted with hydroxylamine having
substituent corresponding to target compound (hydroxylamine,
methoxylamine, O-benzylhydroxylamine, etc.) or the salt thereof at
0.degree. C. to 100.degree. C., preferably 0.degree. C. to
40.degree. C., for 0.5 to 150 hours, preferably 1 to 72 hours, to
obtain the compound (I-26).
[0164] In all of above mentioned steps, if a compound having
substituent which interrupts the reaction; (for example, hydroxy,
mercapto, amino, formyl, carbonyl, carboxyl, etc.), the substituent
of the compound is protected by methods described in Protective
Groups in Organic Synthesis, Theodora W Green (John Wiley &
Sons) beforehand, and is deprotected at preferable step.
[0165] The compound (I) in this invention presented below; in
particular, X is S, and E is a bond or methylene; is
preferable.
1) A compound represented by the general formula (I'),
##STR00043##
in formula, t is 0 or 1, the other symbols are the same as above
(a), with the proviso that the compounds represented below; i)
wherein n+m is 2, R.sup.5 is a hydrogen atom, and ring A is
unsubstituted phenyl; ii) wherein n is 2, m is 0, R.sup.2a is a
hydrogen atom, R.sup.2b is a hydrogen atom or acetyl, R.sup.5 is
methyl, and ring A is phenyl or 4-methoxyphenyl; iii) Wherein n is
2, m is 0, R.sup.2a is a hydrogen atom, R.sup.2b is a hydrogen atom
or acetyl, R.sup.5 is ethyl, and ring A is 3,4-dimethoxyphenyl; iv)
wherein n is 2, m is 0, R.sup.2a is a hydrogen atom, R.sup.2b is a
hydrogen atom or acetyl, R.sup.5 and ring A are phenyl; v) wherein
n is 2, m is 0, R.sup.2a and R.sup.2b is a hydrogen atom, R.sup.5
and ring A are taken together to form
##STR00044##
and vi) the compound, wherein n+m is 1 or 2; R.sup.5 is a hydrogen
atom; ring A is phenyl substituted by one or two substituent
selected from hydroxy, halogen, lower alkyl, lower alkoxy, nitro,
amino, lower alkyl carbonylamino, mercapto, lower alkylthio,
carbamoyl, lower alkylamino, lower alkyl carbamoyl and lower
alkoxycarbonyl; non-substituted phenyl, or non-substituted
naphthyl; are excluded.
[0166] In addition, in formula (I'), preferable is the compound
represented below.
2) The compound, wherein n is 1 and m is 0 (this compound is
represented by nm-1), 3) the compound, wherein n is 2 and m is 0
(this compound is represented by nm-2), 4) the compound, wherein n
is 3 and m is 0 (this compound is represented by nm-3), 5) the
compound, wherein R.sup.2a is a hydrogen atom; R.sup.2b is a
hydrogen atom, optionally substituted lower alkyl, optionally
substituted acyl, optionally substituted lower alkylsulfonyl, or
optionally substituted amidino (this compound is represented by
R2-1), 6) the compound, wherein R.sup.2a is a hydrogen atom;
R.sup.2b is a hydrogen atom, optionally substituted lower alkyl or
optionally substituted acyl (this compound is represented by R2-2),
7) the compound, wherein NR.sup.2aR.sup.2b is represented by the
following formula:
##STR00045##
wherein each symbols are the same as described above. R.sup.6,
R.sup.7 and R.sup.8 are each independently a hydrogen atom, lower
alkyl or acyl, Y is optionally substituted lower alkylene,
optionally substituted lower alkenylene or optionally substituted
lower alkynylene, Z is O or S (this compound is represented by
R2-3), 8) the compound, wherein NR.sup.2aR.sup.2b is NH.sup.2 (this
compound is represented by R2-4), 9) the compound, wherein ring A
is substituted phenyl or substituted pyridyl (this compound is
represented by A-1), 10) the compound, wherein ring A is
represented by the following formula:
##STR00046##
wherein R.sup.9, R.sup.10 and R.sup.11 is a hydrogen atom or G, G
is halogen, hydroxy, cyano, nitro, mercapto, optionally substituted
lower alkyl, optionally substituted lower alkoxy, optionally
substituted lower alkenyl, optionally substituted lower alkynyl,
optionally substituted acyl, optionally substituted acyloxy,
carboxy, optionally substituted lower alkoxycarbonyl, optionally
substituted lower alkoxycarbonyloxy, optionally substituted
aryloxycarbonyloxy, optionally substituted amino, optionally
substituted carbamoyl, optionally substituted carbamoyloxy,
optionally substituted lower alkylthio, optionally substituted
arylthio, optionally substituted lower alkylsulfonyl, optionally
substituted arylsulfonyl, optionally substituted lower
alkylsulfinyl, optionally substituted arylsulfinyl, optionally
substituted lower alkylsulfonyloxy, optionally substituted
arylsulfonyloxy, optionally substituted sulfamoyl, an optionally
substituted carbocyclic group, optionally substituted
carbocyclicoxy, an optionally substituted heterocyclic group or
optionally substituted heterocyclicoxy, each G may be different
(this compound is represented by A-2), 11) the compound, wherein
ring A is represented by the following formula:
##STR00047##
wherein R.sup.9 and R.sup.10 are each independently a hydrogen
atom, halogen, hydroxy, optionally substituted lower alkyl, cyano,
nitro, optionally substituted lower alkoxy, optionally substituted
acyl, optionally substituted amino, optionally substituted
carbamoyl, optionally substituted carbamoyloxy, optionally
substituted lower alkylsulfonyl, optionally substituted
arylsulfonyl, optionally substituted lower alkylsulfonyloxy,
optionally substituted arylsulfonyloxy, an optionally substituted
carboncyclic group, optionally substituted carbocyclicoxy, an
optionally substituted heterocyclic group or optionally substituted
heterocyclicoxy, G is the same as described above 10) (this
compound is represented by A-3), 12) the compound, wherein ring A
is represented by the following formula:
##STR00048##
wherein R.sup.9 and R.sup.10 is the same as described in 11), G is
the same as described in 10) (this compound is represented by A-4),
13) the compound, wherein ring A, R.sup.9, and R.sup.10 are defined
in 11), G is optionally substituted amino (this compound is
represented by A-5), 14) the compound, wherein ring A, R.sup.9 and
R.sup.19 are defined in 11), G is optionally substituted
arylcarbonylamino or optionally substituted heterocyclic
carbonylamino, 15) the compound, wherein ring A, R.sup.9 and
R.sup.10 are defined in 11), G is optionally substituted
heterocyclic carbonylamino (this compound is represented by A-6),
16) the compound, wherein ring A is defined in 11), G is
represented by the following formula:
##STR00049## ##STR00050## ##STR00051##
wherein Q.sup.1, Q.sup.2 and Q.sup.3 are each independently a bond,
optionally substituted lower alkylene or optionally substituted
lower alkenylene; Q.sup.4 is optionally substituted lower alkylene
or optionally substituted lower alkenylene; W.sup.1 and W.sup.2 are
each independently O or S;
W.sup.3 is O, S or NR.sup.12;
[0167] R.sup.12 is a hydrogen atom, lower alkyl, hydroxy lower
alkyl, lower alkoxy lower alkyl, lower alkoxycarbonyl lower alkyl,
carbocyclic lower alkyl or acyl; R.sup.14 is hydrogen atom or lower
alkyl; ring B is an optionally substituted carbocyclic group or an
optionally substituted heterocyclic group; Alk.sup.2 is optionally
substituted lower alkyl; R.sup.9 and R.sup.19 are the same as
described in 11) (this compound is represented by A-7), 17) the
compound, wherein ring A, R.sup.9 and R.sup.10 are the group
defined in 11); G is the group defined in 16); ring B is aryl
optionally substituted with one or more substituents selected from
halogen, hydroxy, optionally substituted lower alkyl, optionally
substituted lower alkoxy, optionally substituted acyl, optionally
substituted amino, cyano, optionally substituted carbamoyl, an
optionally substituted carbocyclic group, optionally substituted
carbocyclicoxy or an optionally substituted heterocyclic group or
heteroaryl optionally substituted with one or more substituents
selected from halogen, hydroxy, optionally substituted lower alkyl,
optionally substituted lower alkoxy, optionally substituted acyl,
optionally substituted amino, cyano, optionally substituted
carbamoyl, an optionally substituted carbocyclic group, optionally
substituted carbocyclicoxy or an optionally substituted
heterocyclic group; and the other symbols are the same as described
in 16) (this compound is represented by A-8), 18) the compound,
wherein ring A, R.sup.9 and R.sup.10 are defined in 11), G is
represented by the following formula:
##STR00052##
in formula, wherein each symbols are the same as described in 16)
(this compound is represented by A-9), 19) the compound, wherein
ring A is represented by the following formula:
##STR00053##
G is defined in 16), ring B is optionally substituted aryl or
optionally substituted heteroaryl, either R.sup.9 or R.sup.10 is a
hydrogen atom; and the other is a hydrogen atom, halogen,
optionally substituted lower alkyl, cyano, nitro, optionally
substituted lower alkoxy, optionally substituted amino, optionally
substituted carbamoyl, optionally substituted lower alkylsulfonyl,
an optionally substituted carbocyclic group or an optionally
substituted heterocyclic group (this compound is represented by
A-10), 20) the compound, wherein ring A is represented by the
following formula:
##STR00054##
G is defined in 18), the other symbols are the same as described in
19) (this compound is represented by A-11), 21) the compound,
wherein ring A is represented by the following formula:
##STR00055##
G is defined in 16), ring B is optionally substituted phenyl, 6- to
6-membered heteroaryl, benzothiazolyl or benzothienyl, R.sup.9 and
R.sup.10 are the same as described in 19) (this compound is
represented by A-12), 22) the compound, wherein ring A is
represented by the following formula:
##STR00056##
G is defined in 18), ring B is defined in 21), R.sup.9 and R.sup.19
are the same as described in 19) (this compound is represented by
A-13), 23) the compound, wherein ring A is represented by the
following formula:
##STR00057##
wherein R.sup.9 is a hydrogen atom, halogen, optionally substituted
lower alkyl, cyano, nitro, optionally substituted lower alkoxy,
optionally substituted amino, optionally substituted carbamoyl,
optionally substituted lower alkylsulfonyl, an optionally
substituted carbocyclic group or an optionally substituted
heterocyclic group, ring B is the same as described in 21);
R.sup.12 is a hydrogen atom or lower alkyl (this compound is
represented by A-14), 24) the compound, wherein R.sup.6 is a
hydrogen atom or 01 to C3 alkyl (this compound is represented by
R5-1), 25) the compound, wherein R.sup.6 is C1 to C3 alkyl (this
compound is represented by R5-2), 26) the compound, wherein R.sup.6
is methyl (this compound is represented by R5-3), 27) the compound,
wherein R.sup.3a and R.sup.3b are each independently a hydrogen
atom, halogen, hydroxy, optionally substituted lower alkyl,
optionally substituted lower alkoxy or optionally substituted aryl
(this compound is represented by R3-1), 28) the compound wherein,
R.sup.3a is a hydrogen atom, halogen, hydroxy, optionally
substituted lower alkyl, optionally substituted lower alkoxy or
optionally substituted aryl, R.sup.3b is a hydrogen atom, one
R.sup.3 is a hydrogen atom when n is 2, one or two R.sup.2a is(are)
a hydrogen atom when n is 3 (this compound is represented by R3-2),
29) the compound, wherein R.sup.3a and R.sup.3b are all hydrogen
atoms (this compound is represented by R3-3), and in a compound
represented by the general formula (I'), a compound, wherein the
combination of n, m, R.sup.2a, R.sup.2b, ring A, R.sup.5, R.sup.3a,
and R.sup.3b, (nm, R.sup.2, A, R.sup.5, R.sup.3) is the following
compound. (nm, R.sup.2, A, R.sup.5,
R.sup.3)=(nm-1,R2-1,A-1,R5-1,R3-1),(nm-1,R2-1,A-1,R5-1,R3-2),(nm-
-1,R2-1,A-1,R5-2,R3-1),(nm-1,R2-1,A-1,R5-2,R3-2),(nm-1,R2-1,A-1,R5-3,R3-1)-
,(nm-1,R2-1,A-1,R5-3,R3-2),(nm-1,R2-1,A-2,R5-1,R3-1),(nm-1,R2-1,A-2,R5-1,R-
3-2),(nm-1,R2-1,A-2,R5-2,R3-1),(nm-1,R2-1,A-2,R5-2,R3-2),(nm-1,R2-1,A-2,R5-
-3,R3-1),(nm-1,R2-1,A-2,R5-3,R3-2),(nm-1,
R2-1,A-3,R5-1,R3-1),(nm-1,R2-1,A-3,R5-1,R3-2),(nm-1,R2-1,A-3,R5-2,R3-1),(-
nm-1,R2-1,A-3,R5-2,R3-2),(nm-1,R2-1,A-3,R5-3,R3-1),(nm-1,R2-1,A-3,R5-3,R3--
2),(nm-1,R2-1,A-4,R5-1,R3-1),(nm-1,R2-1,A-4,R5-1,R3-2),(nm-1,R2-1,A-4,R5-2-
,R3-1),(nm-1,R2-1,
A-4,R5-2,R3-2),(nm-1,R2-1,A-4,R5-3,R3-1),(nm-1,R2-1,A-4,R5-3,R3-2),(nm-1,-
R2-1,A-5,R5-1,R3-1),(nm-1,R2-1,A-5,R5-1,R3-2),(nm-1,R2-1,A-5,R5-2,R3-1),(n-
m-1,R2-1,A-5,R5-2,R3-2),(nm-1,R2-1,A-5,R5-3,R3-1),(nm-1,R2-1,A-5,R5-3,R3-2-
),(nm-1,R2-1,A-6,
R5-1,R3-1),(nm-1,R2-1,A-6,R5-1,R3-2),(nm-1,R2-1,A-6,R5-2,R3-1),(nm-1,R2-1-
,A-6,R5-2,R3-2),(nm-1,R2-1,A-6,R5-3,R3-1),(nm-1,R2-1,A-6,R5-3,R3-2),(nm-1,-
R2-1,A-7,R5-1,R3-1),(nm-1,R2-1,A-7,R5-1,R3-2),(nm-1,R2-1,A-7,R5-2,R3-1),(n-
m-1,R2-1,A-7,R5-2,
R3-2),(nm-1,R2-1,A-7,R5-3,R3-1),(nm-1,R2-1,A-7,R5-3,R3-2),(nm-1,R2-1,A-8,-
R5-1,R3-1),(nm-1,R2-1,A-8,R5-1,R3-2),(nm-1,R2-1,A-8,R5-2,R3-1),(nm-1,R2-1,-
A-8,R5-2,R3-2),(nm-1,R2-1,A-8,R5-3,R3-1),(nm-1,R2-1,A-8,R5-3,R3-2),(nm-1,R-
2-1,A-9,R5-1,R3-1),(nm-1,R2-1,A-9,R5-1,R3-2),(nm-1,R2-1,A-9,R5-2,R3-1),(nm-
-1,R2-1,A-9,R5-2,R3-2),(nm-1,R2-1,A-9,R5-3,R3-1),(nm-1,R2-1,A-9,R5-3,R3-2)-
,(nm-1,R2-1,A-10,R5-1,R3-1),(nm-1,R2-1,A-10,R5-1,R3-2),(nm-1,R2-1,A-10,R5--
2,R3-1),(nm-1,R2-1,A-10,R5-2,R3-2),(nm-1,R2-1,A-10,R5-3,R3-1),(nm-1,R2-1,A-
-10,R5-3,R3-2),(nm-1,R2-1,A-11,R5-1,R3-1),(nm-1,R2-1,A-11,R5-1,R3-2),(nm-1-
,R2-1,A-11,R5-2,R3-1),(nm-1,R2-1,A-11,R5-2,
R3-2),(nm-1,R2-1,A-11,R5-3,R3-1),(nm-1,R2-1,A-11,R5-3,R3-2),(nm-1,R2-1,A--
12,R5-1,R3-1),(nm-1,R2-1,A-12,R5-1,R3-2),(nm-1,R2-1,A-12,R5-2,R3-1),(nm-1,-
R2-1,A-12,R5-2,R3-2),(nm-1,R2-1,A-12,R5-3,R3-1),(nm-1,R2-1,A-12,R5-3,R3-2)-
,(nm-1,R2-1,A-13,
R5-1,R3-1),(nm-1,R2-1,A-13,R5-1,R3-2),(nm-1,R2-1,A-13,R5-2,R3-1),(nm-1,R2-
-1,A-13,R5-2,R3-2),(nm-1,R2-1,A-13,R5-3,R3-1),(nm-1,R2-1,A-13,R5-3,R3-2),(-
nm-1,R2-1,A-14,R5-1,R3-1),(nm-1,R2-1,A-14,R5-1,R3-2),(nm-1,R2-1,A-14,R5-2,-
R3-1),(nm-1,R2-1,
A-14,R5-2,R3-2),(nm-1,R2-1,A-14,R5-3,R3-1),(nm-1,R2-1,A-14,R5-3,R3-2),(nm-
-1,R2-2,A-1,R5-1,R3-1),(nm-1,R2-2,A-1,R5-1,R3-2),(nm-1,R2-2,
A-1,R5-2,R3-2),(nm-1,R2-2,A-1,R5-3,R3-1),(nm-1,R2-2,A-1,R5-3,R3-2),(nm-1,-
R2-2,A-2,R5-1,R3-1),(nm-1,R2-2,A-2,R5-1,R3-2),(nm-1,R2-2,A-2,R5-2,R3-1),(n-
m-1,R2-2,A-2,R5-2,R3-2),(nm-1,R2-2,A-2,R5-3,R3-1),(nm-1,R2-2,A-2,R5-3,R3-2-
),(nm-1,R2-2,A-3,
R5-1,R3-1),(nm-1,R2-2,A-3,R5-1,R3-2),(nm-1,R2-2,A-3,R5-2,R3-1),(nm-1,R2-2-
,A-3,R5-2,R3-2),(nm-1,R2-2,A-3,R5-3,R3-1),(nm-1,R2-2,A-3,R5-3,R3-2),(nm-1,-
R2-2,A-4,R5-1,R3-1),(nm-1,R2-2,A-4,R5-1,R3-2),(nm-1,R2-2,A-4,R5-2,R3-1),(n-
m-1,R2-2,A-4,R5-2,
R3-2),(nm-1,R2-2,A-4,R5-3,R3-1),(nm-1,R2-2,A-5,R5-1,R3-1),(nm-1,R2-2,A-5,-
R5-1,R3-2),(nm-1,R2-2,A-5,R5-2,R3-1),(nm-1,R2-2,A-5,R5-2,R3-2),(nm-1,R2-2,-
A-5,R5-3,R3-1),(nm-1,R2-2,A-5,R5-3,R3-2),(nm-1,R2-2,A-6,R5-1,R3-1),(nm-1,R-
2-2,A-6,R5-1,R3-2),(nm-1,R2-2,A-6,R5-2,R3-1),(nm-1,R2-2,A-6,R5-2,R3-2),(nm-
-1,R2-2,A-6,R5-3,R3-1),(nm-1,R2-2,A-6,R5-3,R3-2),(nm-1,R2-2,A-7,R5-1,R3-1)-
,(nm-1,R2-2,A-7,R5-1,R3-2),(nm-1,R2-2,A-7,R5-2,R3-1),(nm-1,R2-2,A-7,R5-2,R-
3-2),(nm-1,R2-2,A-7,R5-3,R3-1),(nm-1,R2-2,A-7,R5-3,R3-2),(nm-1,R2-2,A-8,R5-
-1,R3-1),(nm-1,R2-2,A-8,R5-1,R3-2),(nm-1,R2-2,A-8,R5-2,R3-1),(nm-1,R2-2,A--
8,R5-2,R3-2),(nm-1,
R2-2,A-8,R5-3,R3-1),(nm-1,R2-2,A-8,R5-3,R3-2),(nm-1,R2-2,A-9,R5-1,R3-1),(-
nm-1,R2-2,A-9,R5-1,R3-2),(nm-1,R2-2,A-9,R5-2,R3-1),(nm-1,R2-2,A-9,R5-2,R3--
2),(nm-1,R2-2,A-9,R5-3,R3-1),(nm-1,R2-2,A-10,R5-1,R3-1),(nm-1,R2-2,A-10,R5-
-1,R3-2),(nm-1,R2-2,A-10,R5-2,R3-1),(nm-1,R2-2,A-10,R5-2,R3-2),(nm-1,R2-2,-
A-10,R5-3,R3-1),(nm-1,R2-2,A-10,R5-3,R3-2),(nm-1,R2-2,A-11,R5-1,R3-1),(nm--
1,
R2-2,A-11,R5-1,R3-2),(nm-1,R2-2,A-11,R5-2,R3-1),(nm-1,R2-2,A-11,R5-2,R3-
-2),(nm-1,R2-2,A-11,R5-3,R3-1),(nm-1,R2-2,A-11,R5-3,R3-2),(nm-1,R2-2,A-12,-
R5-1,R3-1),(nm-1,R2-2,A-12,R5-1,R3-2),(nm-1,R2-2,A-12,R5-2,R3-1),(nm-1,R2--
2,A-12,R5-2,R3-2),
(nm-1,R2-2,A-12,R5-3,R3-1),(nm-1,R2-2,A-12,R5-3,R3-2),(nm-1,R2-2,A-13,R5--
1,R3-1),(nm-1,R2-2,A-13,R5-1,R3-2),(nm-1,R2-2,A-13,R5-2,R3-1),(nm-1,R2-2,A-
-13,R5-2,R3-2),(nm-1,R2-2,A-13,R5-3,R3-1),(nm-1,R2-2,A-13,R5-3,R3-2),(nm-1-
,R2-2,A-14,R5-1,
R3-1),(nm-1,R2-2,A-14,R5-1,R3-2),(nm-1,R2-2,A-14,R5-2,R3-1),(nm-1,R2-2,A--
14,R5-2,R3-2),(nm-1,R2-2,A-14,R5-3,R3-1),(nm-1,R2-2,A-14,R5-3,R3-2),(nm-1,-
R2-3,A-1,R5-1,R3-1),(nm-1,R2-3,A-1,R5-1,R3-2),(nm-1,R2-3,A-1,R5-2,R3-1),(n-
m-1,R2-3,A-1,R5-2,R3-2),(nm-1,R2-3,A-1,R5-3,R3-1),(nm-1,R2-3,A-1,R5-3,R3-2-
),(nm-1,R2-3,A-2,R5-1,
R3-1),(nm-1,R2-3,A-2,R5-1,R3-2),(nm-1,R2-3,A-2,R5-2,R3-1),(nm-1,R2-3,A-2,-
R5-2,R3-2),(nm-1,R2-3,A-2,R5-3,R3-1),(nm-1,R2-3,A-3,R5-1,R3-1),(nm-1,R2-3,-
A-3,R5-1,R3-2),(nm-1,R2-3,A-3,R5-2,R3-1),(nm-1,R2-3,A-3,R5-2,R3-2),(nm-1,R-
2-3,A-3,R5-3,R3-1),(nm-1,R2-3,A-3,R5-3,R3-2),(nm-1,R2-3,A-4,R5-1,R3-1),(nm-
-1,R2-3,A-4,R5-1,R3-2),(nm-1,R2-3,A-4,R5-2,R3-1),(nm-1,R2-3,A-4,R5-2,R3-2)-
,(nm-1,R2-3,A-4,R5-3,R3-1),(nm-1,R2-3,A-4,R5-3,R3-2),(nm-1,R2-3,A-5,R5-1,R-
3-1),(nm-1,R2-3,A-5,R5-1,R3-2),(nm-1,R2-3,A-5,R5-2,R3-1),(nm-1,R2-3,A-5,R5-
-2,R3-2),(nm-1,R2-3,A-6,R5-1,R3-1),(nm-1,
R2-3,A-6,R5-1,R3-2),(nm-1,R2-3,A-6,R5-2,R3-1),(nm-1,R2-3,A-6,R5-2,R3-2),(-
nm-1,R2-3,A-6,R5-3,R3-1),(nm-1,R2-3,A-6,R5-3,R3-2),(nm-1,R2-3,A-7,R5-1,R3--
1),(nm-1,R2-3,A-7,R5-1,R3-2),(nm-1,R2-3,A-7,R5-2,R3-1),(nm-1,R2-3,A-7,R5-2-
,R3-2),(nm-1,R2-3,
A-7,R5-3,R3-1),(nm-1,R2-3,A-7,R5-3,R3-2),(nm-1,R2-3,A-8,R5-1,R3-1),(nm-1,-
R2-3,A-8,R5-1,R3-2),(nm-1,R2-3,A-8,R5-2,R3-1),(nm-1,R2-3,A-8,R5-2,R3-2),(n-
m-1,R2-3,A-8,R5-3,R3-1),(nm-1,R2-3,A-8,R5-3,R3-2),(nm-1,R2-3,A-9,R5-1,R3-1-
),(nm-1,R2-3,A-9,
R5-1,R3-2),(nm-1,R2-3,A-9,R5-2,R3-1),(nm-1,R2-3,A-9,R5-2,R3-2),(nm-1,R2-3-
,A-9,R5-3,R3-1),(nm-1,R2-3,A-10,R5-1,R3-1),(nm-1,R2-3,A-10,
R5-1,R3-2),(mar
1,R2-3,A-10,R5-2,R3-1),(nm-1,R2-3,A-10,R5-2,R3-2),(nm-1,R2-3,A-10,R5-3,R3-
-1),(nm-1,R2-3,A-10,R5-3,R3-2),(nm-1,R2-3,A-11,R5-1,R3-1),(nm-1,R2-3,A-11,-
R5-1,R3-2),(nm-1,R2-3,A-11,R5-2,R3-1),(nm-1,R2-3,A-11,R5-2,R3-2),(nm-1,R2--
3,
A-11,R5-3,R3-1),(nm-1,R2-3,A-11,R5-3,R3-2),(nm-1,R2-3,A-12,R5-1,R3-1),(-
nm-1,R2-3,A-12,R5-1,R3-2),(nm-1,R2-3,A-12,R5-2,R3-1),(nm-1,R2-3,A-12,R5-2,-
R3-2),(nm-1,R2-3,A-12,R5-3,R3-1),(nm-1,R2-3,A-12,R5-3,R3-2),(nm-1,R2-3,A-1-
3,R5-1,R3-1),(nm-1,
R2-3,A-13,R5-1,R3-2),(nm-1,R2-3,A-13,R5-2,R3-1),(nm-1,R2-3,A-13,R5-2,R3-2-
),(nm-1,R2-3,A-13,R5-3,R3-1),(nm-1,R2-3,A-13,R5-3,R3-2),(nm-1,R2-3,A-14,R5-
-1,R3-1),(nm-1,R2-3,A-14,R5-1,R3-2),(nm-1,R2-3,A-14,R5-2,R3-1),(nm-1,R2-3,-
A-14,R5-2,R3-2),
(nm-1,R2-3,A-14,R5-3,R3-1),(nm-1,R2-3,A-14,R5-3,R3-2),(nm-1,R2-4,A-1,R5-1-
,R3-1),(nm-1,R2-4,A-1,R5-1,R3-2),(nm-1,R2-4,A-1,R5-2,R3-1),(nm-1,R2-4,A-1,-
R5-2,R3-2),(nm-1,R2-4,A-1,R5-3,R3-1),(nm-1,R2-4,A-1,R5-3,R3-2),(nm-1,R2-4,-
A-2,R5-1,R3-1),(nm-1,R2-4,A-2,R5-1,R3-2),(nm-1,R2-4,A-2,R5-2,R3-1),(nm-1,R-
2-4,A-2,R5-2,R3-2),(nm-1,R2-4,A-2,R5-3,R3-1),(nm-1,R2-4,A-2,R5-3,R3-2),1,R-
3-1),(nm-1,R2-4,A-3,R5-1,R3-2),(nm-1,R2-4,A-3,R5-2,R3-1),(nm-1,R2-4,A-3,R5-
-2,R3-2),(nm-1,
R2-4,A-3,R5-3,R3-1),(nm-1,R2-4,A-3,R5-3,R3-2),(nm-1,R2-4,A-4,R5-1,R3-1),(-
nm-1,R2-4,A-4,R5-1,R3-2),(nm-1,R2-4,A-4,R5-2,R3-1),(nm-1,R2-4,A-4,R5-2,R3--
2),(nm-1,R2-4,A-4,R5-3,R3-1),(nm-1,R2-4,A-5,R5-1,R3-1),(nm-1,R2-4,
A-5,R5-1,R3-2),(nm-1,R2-4,A-5,R5-2,R3-1),(nm-1,R2-4,A-5,R5-2,R3-2),(nm-1,-
R2-4,A-5,R5-3,R3-1),(nm-1,R2-4,A-5,R5-3,R3-2),(nm-1,R2-4,A-6,R5-1,R3-1),(n-
m-1,R2-4,A-6,R5-1,R3-2),(nm-1,R2-4,A-6,R5-2,R3-1),(nm-1,R2-4,A-6,R5-2,R3-2-
),(nm-1,R2-4,A-6,
R5-3,R3-1),(nm-1,R2-4,A-6,R5-3,R3-2),(nm-1,R2-4,A-7,R5-1,R3-1),(nm-1,R2-4-
,A-7,R5-1,R3-2),(nm-1,R2-4,A-7,R5-2,R3-1),(nm-1,R2-4,A-7,R5-2,R3-2),(nm-1,-
R2-4,A-7,R5-3,R3-1),(nm-1,R2-4,A-8,R5-1,R3-1),(nm-1,R2-4,A-8,R5-1,
R3-2),(nm-1,R2-4,A-8,R5-2,R3-1),(nm-1,R2-4,A-8,R5-2,R3-2),(nm-1,R2-4,A-8,-
R5-3,R3-1),(nm-1,R2-4,A-8,R5-3,R3-2),(nm-1,R2-4,A-9,R5-1,R3-1),(nm-1,R2-4,-
A-9,R5-1,R3-2),(nm-1,R2-4,A-9,R5-2,R3-1),(nm-1,R2-4,A-9,R5-2,R3-2),(nm-1,R-
2-4,A-9,R5-3,R3-1),(nm-1,R2-4,A-9,R5-3,R3-2),(nm-1,R2-4,A-10,R5-1,R3-1),(n-
m-1,R2-4,A-10,R5-1,R3-2),(nm-1,R2-4,A-10,R5-2,R3-1),(nm-1,R2-4,A-10,R5-2,R-
3-2),(nm-1,R2-4,A-10,R5-3,R3-1),(nm-1,R2-4,A-10,R5-3,R3-2),(nm-1,R2-4,A-11-
,R5-1,R3-1),(nm-1,R2-4,A-11,R5-1,
R3-2),(nm-1,R2-4,A-11,R5-2,R3-1),(nm-1,R2-4,A-11,R5-2,R3-2),(nm-1,R2-4,A--
11,R5-3,R3-1),(nm-1,R2-4,A-11,R5-3,R3-2),(nm-1,R2-4,A-12,R5-1,R3-1),(nm-1,-
R2-4,A-12,R5-1,R3-2),(nm-1,R2-4,A-12,R5-2,R3-1),(nm-1,R2-4,A-12,R5-2,R3-2)-
,(nm-1,R2-4,A-12,
R5-3,R3-1),(nm-1,R2-4,A-12,R5-3,R3-2),(nm-1,R2-4,A-13,R5-1,R3-1),(nm-1,R2-
-4,A-13,
R5-1,R3-2),(nm-1,R2-4,A-13,R5-2,R3-1),(nm-1,R2-4,A-13,R5-2,R3-2),-
(nm-1,R2-4,A-13,R5-3,R3-1),(nm-1,R2-4,A-13,R5-3,R3-2),(nm-1,R2-4,A-14,R5-1-
,R3-1),(nm-1,R2-4,
A-14,R5-1,R3-2),(nm-1,R2-4,A-14,R5-2,R3-1),(nm-1,R2-4,A-14,R5-2,R3-2),(nm-
-1,R2-4,A-14,R5-3,R3-1),(nm-1,R2-4,A-14,R5-3,R3-2),
(nm-2,R2-1,A-1,R5-1,R3-1),(nm-2,R2-1,A-1,R5-1,R3-2),(nm-2,R2-1,A-1,R5-2,R-
3-1),(nm-2,R2-1,A-1,R5-2,R3-2),(nm-2,R2-1,A-1,R5-3,R3-1),(nm-2,R2-1,A-1,R5-
-3,R3-2),(nm-2,R2-1,A-2,R5-1,R3-1),(nm-2,R2-1,A-2,R5-1,R3-2),(nm-2,R2-1,A--
2,R5-2,R3-1),(nm-2,R2-1,A-2,R5-2,R3-2),(nm-2,R2-1,A-2,R5-3,R3-1),(nm-2,R2--
1,A-2,R5-3,R3-2),(nm-2,
R2-1,A-3,R5-1,R3-1),(nm-2,R2-1,A-3,R5-1,R3-2),(nm-2,R2-1,A-3,R5-2,R3-1),(-
nm-2,R2-1,A-3,R5-2,R3-2),(nm-2,R2-1,A-3,R5-3,R3-1),(nm-2,R2-1,A-3,R5-3,R3--
2),(nm-2,R2-1,A-4,R5-1,R3-1),(nm-2,R2-1,A-4,R5-1,R3-2),(nm-2,R2-1,A-4,R5-2-
,R3-1),(nm-2,R2-1,
A-4,R5-2,R3-2),(nm-2,R2-1,A-4,R5-3,R3-1),(nm-2,R2-1,A-4,R5-3,R3-2),(nm-2,-
R2-1,A-5,R5-1,R3-1),(nm-2,R2-1,A-5,R5-1,R3-2),(nm-2,R2-1,A-5,R5-2,R3-1),(n-
m-2,R2-1,A-5,R5-2,R3-2),(nm-2,R2-1,A-5,R5-3,R3-1),(nm-2,R2-1,A-6,
R5-1,R3-1),(nm-2,R2-1,A-6,R5-1,R3-2),(nm-2,R2-1,A-6,R5-2,R3-1),(nm-2,R2-1-
,A-6,R5-2,R3-2),(nm-2,R2-1,A-6,R5-3,R3-1),(nm-2,R2-1,A-6,R5-3,R3-2),(nm-2,-
R2-1,A-7,R5-1,R3-1),(nm-2,R2-1,A-7,R5-1,R3-2),(nm-2,R2-1,A-7,R5-2,R3-1),(n-
m-2,R2-1,A-7,R5-2,
R3-2),(nm-2,R2-1,A-7,R5-3,R3-1),(nm-2,R2-1,A-7,R5-3,R3-2),(nm-2,R2-1,A-8,-
R5-1,R3-1),(nm-2,R2-1,A-8,R5-1,R3-2),(nm-2,R2-1,A-8,R5-2,R3-1),(nm-2,R2-1,-
A-8,R5-2,R3-2),(nm-2,R2-1,A-8,R5-3,R3-1),(nm-2,R2-1,A-9,R5-1,R3-1),(nm-2,R-
2-1,A-9,R5-1,R3-2),(nm-2,R2-1,A-9,R5-2,R3-1),(nm-2,R2-1,A-9,R5-2,R3-2),(nm-
-2,R2-1,A-9,R5-3,R3-1),(nm-2,R2-1,A-9,R5-3,R3-2),(nm-2,R2-1,A-10,R5-1,R3-1-
),(nm-2,R2-1,A-10,R5-1,R3-2),(nm-2,R2-1,A-10,R5-2,R3-1),(nm-2,R2-1,A-10,R5-
-2,R3-2),(nm-2,R2-1,A-10,R5-3,R3-1),(nm-2,R2-1,A-10,R5-3,R3-2),(nm-2,R2-1,-
A-11,R5-1,R3-1),(nm-2,R2-1,A-11,R5-1,R3-2),(nm-2,R2-1,A-11,R5-2,R3-1),(nm--
2,R2-1,A-11,R5-2,
R3-2),(nm-2,R2-1,A-11,R5-3,R3-1),(nm-2,R2-1,A-11,R5-3,R3-2),(nm-2,R2-1,A--
12,R5-1,R3-1),(nm-2,R2-1,A-12,R5-1,R3-2),(nm-2,R2-1,A-12,R5-2,R3-1),(nm-2,-
R2-1,A-12,R5-2,R3-2),(nm-2,R2-1,A-12,R5-3,R3-1),(nm-2,R2-1,A-12,R5-3,R3-2)-
,(nm-2,R2-1,A-13,
R5-1,R3-1),(nm-2,R2-1,A-13,R5-1,R3-2),(nm-2,R2-1,A-13,R5-2,R3-1),(nm-2,R2-
-1,A-13,
R5-2,R3-2),(nm-2,R2-1,A-13,R5-3,R3-1),(nm-2,R2-1,A-13,R5-3,R3-2),-
(nm-2,R2-1,A-14,R5-1,R3-1),(nm-2,R2-1,A-14,R5-1,R3-2),(nm-2,R2-1,A-14,R5-2-
,R3-1),(nm-2,R2-1,
A-14,R5-2,R3-2),(nm-2,R2-1,A-14,R5-3,R3-1),(nm-2,R2-1,A-14,R5-3,R3-2),(nm-
-2,R2-2,A-1,R5-1,R3-1),(nm-2,R2-2,A-1,R5-1,R3-2),(nm-2,R2-2,A-1,R5-2,R3-1)-
,(nm-2,R2-2,
A-1,R5-2,R3-2),(nm-2,R2-2,A-1,R5-3,R3-1),(nm-2,R2-2,A-1,R5-3,R3-2),(nm-2,-
R2-2,A-2,R5-1,R3-1),(nm-2,R2-2,A-2,R5-1,R3-2),(nm-2,R2-2,A-2,R5-2,R3-1),(n-
m-2,R2-2,A-2,R5-2,R3-2),(nm-2,R2-2,A-2,R5-3,R3-1),(nm-2,R2-2,A-2,R5-3,R3-2-
),(nm-2,R2-2,A-3,
R5-1,R3-1),(nm-2,R2-2,A-3,R5-1,R3-2),(nm-2,R2-2,A-3,R5-2,R3-1),(nm-2,R2-2-
,A-3,R5-2,R3-2),(nm-2,R2-2,A-3,R5-3,R3-1),(nm-2,R2-2,A-3,R5-3,R3-2),(nm-2,-
R2-2,A-4,R5-1,R3-1),(nm-2,R2-2,A-4,R5-1,R3-2),(nm-2,R2-2,A-4,R5-2,R3-1),(n-
m-2,R2-2,A-4,R5-2,
R3-2),(nm-2,R2-2,A-4,R5-3,R3-1),(nm-2,R2-2,A-4,R5-3,R3-2),(nm-2,R2-2,A-5,-
R5-1,R3-1),(nm-2,R2-2,A-5,R5-1,R3-2),(nm-2,R2-2,A-5,R5-2,R3-1),(nm-2,R2-2,-
A-5,R5-2,R3-2),(nm-2,R2-2,A-5,R5-3,R3-1),(nm-2,R2-2,A-5,R5-3,R3-2),(nm-2,R-
2-2,A-6,R5-1,R3-1),(nm-2,R2-2,A-6,R5-1,R3-2),(nm-2,R2-2,A-6,R5-2,R3-1),(nm-
-2,R2-2,A-6,R5-2,R3-2),(nm-2,R2-2,A-6,R5-3,R3-1),(nm-2,R2-2,A-6,R5-3,R3-2)-
,(nm-2,R2-2,A-7,R5-1,R3-1),(nm-2,R2-2,A-7,R5-2,R3-1),(nm-2,R2-2,A-7,R5-2,R-
3-2),(nm-2,R2-2,A-7,R5-3,R3-1),(nm-2,R2-2,A-7,R5-3,R3-2),(nm-2,R2-2,A-8,R5-
-1,R3-1),(nm-2,R2-2,A-8,R5-2,R3-1),(nm-2,R2-2,A-8,R5-2,R3-2),(nm-2,
R2-2,A-8,R5-3,R3-1),(nm-2,R2-2,A-8,R5-3,R3-2),(nm-2,R2-2,A-9,R5-1,R3-1),(-
nm-2,R2-2,A-9,R5-1,R3-2),(nm-2,R2-2,A-9,R5-2,R3-1),(nm-2,R2-2,A-9,R5-2,R3--
2),(nm-2,R2-2,A-9,R5-3,R3-1),(nm-2,R2-2,A-9,R5-3,R3-2),(nm-2,R2-2,A-10,R5--
1,R3-1),(nm-2,R2-2,A-10,R5-1,R3-2),(nm-2,R2-2,A-10,R5-2,R3-1),(nm-2,R2-2,A-
-10,R5-2,R3-2),(nm-2,R2-2,A-10,R5-3,R3-1),(nm-2,R2-2,A-10,R5-3,R3-2),(nm-2-
,R2-2,A-11,R5-1,R3-1),(nm-2,
R2-2,A-11,R5-1,R3-2),(nm-2,R2-2,A-11,R5-2,R3-1),(nm-2,R2-2,A-11,R5-2,R3-2-
),(nm-2,R2-2,A-11,R5-3,R3-1),(nm-2,R2-2,A-11,R5-3,R3-2),(nm-2,R2-2,A-12,R5-
-1,R3-1),(nm-2,R2-2,A-12,R5-1,R3-2),(nm-2,R2-2,A-12,R5-2,R3-1),(nm-2,R2-2,-
A-12,R5-2,R3-2),
(nm-2,R2-2,A-12,R5-3,R3-1),(nm-2,R2-2,A-12,R5-3,R3-2),(nm-2,R2-2,A-13,R5--
1,R3-1),(nm-2,R2-2,A-13,R5-1,R3-2),(nm-2,R2-2,A-13,R5-2,R3-1),(nm-2,R2-2,A-
-13,R5-2,R3-2),(nm-2,R2-2,A-13,R5-3,R3-1),(nm-2,R2-2,A-13,R5-3,R3-2),(nm-2-
,R2-2,A-14,R5-1,
R3-1),(nm-2,R2-2,A-14,R5-1,R3-2),(nm-2,R2-2,A-14,R5-2,R3-1),(nm-2,R2-2,A--
14,R5-2,R3-2),(nm-2,R2-2,A-14,R5-3,R3-1),(nm-2,R2-2,A-14,R5-3,R3-2),(nm-2,-
R2-3,A-1,R5-1,R3-1),(nm-2,R2-3,A-1,R5-1,R3-2),(nm-2,R2-3,A-1,R5-2,R3-1),(n-
m-2,R2-3,A-1,R5-2,R3-2),(nm-2,R2-3,A-1,R5-3,R3-1),(nm-2,R2-3,A-1,R5-3,R3-2-
),(nm-2,R2-3,A-2,R5-1,
R3-1),(nm-2,R2-3,A-2,R5-1,R3-2),(nm-2,R2-3,A-2,R5-2,R3-1),(nm-2,R2-3,A-2,-
R5-2,R3-2),(nm-2,R2-3,A-2,R5-3,R3-1),(nm-2,R2-3,A-2,R5-3,R3-2),(nm-2,R2-3,-
A-3,R5-1,R3-1),(nm-2,R2-3,A-3,R5-1,R3-2),(nm-2,R2-3,A-3,R5-2,R3-1),(nm-2,R-
2-3,A-3,R5-2,R3-2),(nm-2,R2-3,A-3,R5-3,R3-1),(nm-2,R2-3,A-3,R5-3,R3-2),(nm-
-2,R2-3,A-4,R5-1,R3-1),(nm-2,R2-3,A-4,R5-1,R3-2),(nm-2,R2-3,A-4,R5-2,R3-1)-
,(nm-2,R2-3,A-4,R5-2,R3-2),(nm-2,R2-3,A-4,R5-3,R3-1),(nm-2,R2-3,A-4,R5-3,R-
3-2),(nm-2,R2-3,A-5,R5-1,R3-1),(nm-2,R2-3,A-5,R5-1,R3-2),(nm-2,R2-3,A-5,R5-
-2,R3-1),(nm-2,R2-3,A-5,R5-2,R3-2),(nm-2,R2-3,A-5,R5-3,R3-1),(nm-2,R2-3,A--
5,R5-3,R3-2),(nm-2,R2-3,A-6,R5-1,R3-1),(nm-2,
R2-3,A-6,R5-1,R3-2),(nm-2,R2-3,A-6,R5-2,R3-1),(nm-2,R2-3,A-6,R5-2,R3-2),(-
nm-2,R2-3,A-6,R5-3,R3-1),(nm-2,R2-3,A-6,R5-3,R3-2),(nm-2,R2-3,A-7,R5-1,R3--
1),(nm-2,R2-3,A-7,R5-1,R3-2),(nm-2,R2-3,A-7,R5-2,R3-1),(nm-2,R2-3,A-7,R5-2-
,R3-2),(nm-2,R2-3,
A-7,R5-3,R3-1),(nm-2,R2-3,A-7,R5-3,R3-2),(nm-2,R2-3,A-8,R5-1,R3-1),(nm-2,-
R2-3,A-8,R5-1,R3-2),(nm-2,R2-3,A-8,R5-2,R3-1),(nm-2,R2-3,A-8,R5-2,R3-2),(n-
m-2,R2-3,A-8,R5-3,R3-1),(nm-2,R2-3,A-8,R5-3,R3-2),(nm-2,R2-3,A-9,R5-1,R3-1-
),(nm-2,R2-3,A-9,
R5-1,R3-2),(nm-2,R2-3,A-9,R5-2,R3-1),(nm-2,R2-3,A-9,R5-2,R3-2),(nm-2,R2-3-
,A-9,R5-3,R3-1),(nm-2,R2-3,A-9,R5-3,R3-2),(nm-2,R2-3,A-10,R5-1,R3-1),(nm-2-
,R2-3,A-10,
R5-1,R3-2),(nm-2,R2-3,A-10,R5-2,R3-1),(nm-2,R2-3,A-10,R5-2,R3-2),(nm-2,R2-
-3,A-10,R5-3,R3-1),(nm-2,R2-3,A-10,R5-3,R3-2),(nm-2,R2-3,A-11,R5-1,R3-1),(-
nm-2,R2-3,A-11,R5-1,R3-2),(nm-2,R2-3,A-11,R5-2,R3-1),(nm-2,R2-3,A-11,R5-2,-
R3-2),(nm-2,R2-3,
A-11,R5-3,R3-1),(nm-2,R2-3,A-11,R5-3,R3-2),(nm-2,R2-3,A-12,R5-1,R3-1),(nm-
-2,R2-3,A-12,R5-1,R3-2),(nm-2,R2-3,A-12,R5-2,R3-1),(nm-2,R2-3,A-12,R5-2,R3-
-2),(nm-2,R2-3,A-12,R5-3,R3-1),(nm-2,R2-3,A-12,R5-3,R3-2),(nm-2,R2-3,A-13,-
R5-1,R3-1),(nm-2,
R2-3,A-13,R5-1,R3-2),(nm-2,R2-3,A-13,R5-2,R3-1),(nm-2,R2-3,A-13,R5-2,R3-2-
),(nm-2,R2-3,A-13,R5-3,R3-1),(nm-2,R2-3,A-13,R5-3,R3-2),(nm-2,R2-3,A-14,R5-
-1,R3-1),(nm-2,R2-3,A-14,R5-1,R3-2),(nm-2,R2-3,A-14,R5-2,R3-1),(nm-2,R2-3,-
A-14,R5-2,R3-2),
(nm-2,R2-3,A-14,R5-3,R3-1),(nm-2,R2-3,A-14,R5-3,R3-2),(nm-2,R2-4,A-1,R5-1-
,R3-1),(nm-2,R2-4,A-1,R5-1,R3-2),(nm-2,R2-4,A-1,R5-2,R3-1),(nm-2,R2-4,A-1,-
R5-2,R3-2),(nm-2,R2-4,A-1,R5-3,R3-1),(nm-2,R2-4,A-1,R5-3,R3-2),(nm-2,R2-4,-
A-2,R5-1,R3-1),(nm-2,R2-4,A-2,R5-1,R3-2),(nm-2,R2-4,A-2,R5-2,R3-1),(nm-2,R-
2-4,A-2,R5-2,R3-2),(nm-2,R2-4,A-2,R5-3,R3-1),(nm-2,R2-4,A-2,R5-3,R3-2),(nm-
-2,R2-4,A-3,R5-1,R3-1),(nm-2,R2-4,A-3,R5-1,R3-2),(nm-2,R2-4,A-3,R5-2,R3-1)-
,(nm-2,R2-4,A-3,R5-2,R3-2),(nm-2,
R2-4,A-3,R5-3,R3-1),(nm-2,R2-4,A-3,R5-3,R3-2),(nm-2,R2-4,A-4,R5-1,R3-1),(-
nm-2,R2-4,A-4,R5-2,R3-1),(nm-2,R2-4,A-4,R5-2,R3-2),(nm-2,R2-4,A-4,R5-3,R3--
1),(nm-2,R2-4,A-4,R5-3,R3-2),(nm-2,R2-4,A-5,R5-1,R3-1),(nm-2,R2-4,
A-5,R5-1,R3-2),(nm-2,R2-4,A-5,R5-2,R3-1),(nm-2,R2-4,A-5,R5-2,R3-2),(nm-2,-
R2-4,A-5,R5-3,R3-1),(nm-2,R2-4,A-5,R5-3,R3-2),(nm-2,R2-4,A-6,R5-1,R3-1),(n-
m-2,R2-4,A-6,R5-1,R3-2),(nm-2,R2-4,A-6,R5-2,R3-1),(nm-2,R2-4,A-6,R5-2,R3-2-
),(nm-2,R2-4,A-6,
R5-3,R3-1),(nm-2,R2-4,A-6,R5-3,R3-2),(nm-2,R2-4,A-7,R5-1,R3-1),(nm-2,R2-4-
,A-7,R5-1,R3-2),(nm-2,R2-4,A-7,R5-2,R3-1),(nm-2,R2-4,A-7,R5-2,R3-2),(nm-2,-
R2-4,A-7,R5-3,R3-1),(nm-2,R2-4,A-7,R5-3,R3-2),(nm-2,R2-4,A-8,R5-1,R3-1),(n-
m-2,R2-4,A-8,R5-1,
R3-2),(nm-2,R2-4,A-8,R5-2,R3-1),(nm-2,R2-4,A-8,R5-2,R3-2),(nm-2,R2-4,A-8,-
R5-3,R3-1),(nm-2,R2-4,A-8,R5-3,R3-2),(nm-2,R2-4,A-9,R5-1,R3-1),(nm-2,R2-4,-
A-9,R5-1,R3-2),(nm-2,R2-4,A-9,R5-2,R3-1),(nm-2,R2-4,A-9,R5-2,R3-2),(nm-2,R-
2-4,A-9,R5-3,R3-1),(nm-2,R2-4,A-9,R5-3,R3-2),(nm-2,R2-4,A-10,R5-1,R3-1),(n-
m-2,R2-4,A-10,R5-1,R3-2),(nm-2,R2-4,A-10,R5-2,R3-1),(nm-2,R2-4,A-10,R5-2,R-
3-2),(nm-2,R2-4,A-10,R5-3,R3-1),(nm-2,R2-4,A-10,R5-3,R3-2),(nm-2,R2-4,A-11-
,R5-1,R3-1),(nm-2,R2-4,A-11,R5-1,
R3-2),(nm-2,R2-4,A-11,R5-2,R3-1),(nm-2,R2-4,A-11,R5-2,R3-2),(nm-2,R2-4,A--
11,R5-3,R3-1),(nm-2,R2-4,A-11,R5-3,R3-2),(nm-2,R2-4,A-12,R5-1,R3-1),(nm-2,-
R2-4,A-12,R5-1,R3-2),(nm-2,R2-4,A-12,R5-2,R3-1),(nm-2,R2-4,A-12,R5-2,R3-2)-
,(nm-2,R2-4,A-12,
R5-3,R3-1),(nm-2,R2-4,A-12,R5-3,R3-2),(nm-2,R2-4,A-13,R5-1,R3-1),(nm-2,R2-
-4,A-13,
R5-1,R3-2),(nm-2,R2-4,A-13,R5-2,R3-1),(nm-2,R2-4,A-13,R5-2,R3-2),-
(nm-2,R2-4,A-13,R5-3,R3-1),(nm-2,R2-4,A-13,R5-3,R3-2),(nm-2,R2-4,A-14,R5-1-
,R3-1),(nm-2,R2-4,
A-14,R5-1,R3-2),(nm-2,R2-4,A-14,R5-2,R3-1),(nm-2,R2-4,A-14,R5-2,R3-2),(nm-
-2,R2-4,A-14,R5-3,R3-1),(nm-2,R2-4,A-14,R5-3,R3-2),
(nm-3,R2-1,A-1,R5-1,R3-1),(nm-3,R2-1,A-1,R5-1,R3-2),(nm-3,R2-1,A-1,R5-2,R-
3-1),(nm-3,R2-1,A-1,R5-2,R3-2),(nm-3,R2-1,A-1,R5-3,R3-1),(nm-3,R2-1,A-1,R5-
-3,R3-2),(nm-3,R2-1,A-2,R5-1,R3-1),(nm-3,R2-1,A-2,R5-1,R3-2),(nm-3,R2-1,A--
2,R5-2,R3-1),(nm-3,R2-1,A-2,R5-3,R3-1),(nm-3,R2-1,A-2,R5-3,R3-2),(nm-3,
R2-1,A-3,R5-1,R3-1),(nm-3,R2-1,A-3,R5-1,R3-2),(nm-3,R2-1,A-3,R5-2,R3-1),(-
nm-3,R2-1,A-3,R5-2,R3-2),(nm-3,R2-1,A-3,R5-3,R3-1),(nm-3,R2-1,A-4,R5-1,R3--
1),(nm-3,R2-1,A-4,R5-2,R3-1),(nm-3,R2-1,
A-4,R5-2,R3-2),(nm-3,R2-1,A-4,R5-3,R3-1),(nm-3,R2-1,A-4,R5-3,R3-2),(nm-3,-
R2-1,A-5,R5-1,R3-1),(nm-3,R2-1,A-5,R5-1,R3-2),(nm-3,R2-1,A-5,R5-2,R3-1),(n-
m-3,R2-1,A-5,R5-2,R3-2),(nm-3,R2-1,A-5,R5-3,R3-1),(nm-3,R2-1,A-5,R5-3,R3-2-
),(nm-3,R2-1,A-6,
R5-1,R3-1),(nm-3,R2-1,A-6,R5-1,R3-2),(nm-3,R2-1,A-6,R5-2,R3-1),(nm-3,R2-1-
,A-6,R5-2,R3-2),(nm-3,R2-1,A-6,R5-3,R3-1),(nm-3,R2-1,A-6,R5-3,R3-2),(nm-3,-
R2-1,A-7,R5-1,R3-1),(nm-3,R2-1,A-7,R5-1,R3-2),(nm-3,R2-1,A-7,R5-2,R3-1),(n-
m-3,R2-1,A-7,R5-2,
R3-2),(nm-3,R2-1,A-7,R5-3,R3-1),(nm-3,R2-1,A-8,R5-1,R3-1),(nm-3,R2-1,A-8,-
R5-1,R3-2),(nm-3,R2-1,A-8,R5-2,R3-1),(nm-3,R2-1,A-8,R5-2,R3-2),(nm-3,R2-1,-
A-8,R5-3,R3-1),(nm-3,R2-1,A-8,R5-3,R3-2),(nm-3,R2-1,A-9,R5-1,R3-1),(nm-3,R-
2-1,A-9,R5-1,R3-2),(nm-3,R2-1,A-9,R5-2,R3-1),(nm-3,R2-1,A-9,R5-2,R3-2),(nm-
-3,R2-1,A-9,R5-3,R3-1),(nm-3,R2-1,A-9,R5-3,R3-2),(nm-3,R2-1,A-10,R5-1,R3-1-
),(nm-3,R2-1,A-10,R5-1,R3-2),(nm-3,R2-1,A-10,R5-2,R3-1),(nm-3,R2-1,A-10,R5-
-2,R3-2),(nm-3,R2-1,A-10,R5-3,R3-1),(nm-3,R2-1,A-10,R5-3,R3-2),(nm-3,R2-1,-
A-11,R5-1,R3-1),(nm-3,R2-1,A-11,R5-1,R3-2),(nm-3,R2-1,A-11,R5-2,R3-1),(nm--
3,R2-1,A-11,R5-2,
R3-2),(nm-3,R2-1,A-11,R5-3,R3-1),(nm-3,R2-1,A-11,R5-3,R3-2),(nm-3,R2-1,A--
12,R5-1,R3-1),(nm-3,R2-1,A-12,R5-1,R3-2),(nm-3,R2-1,A-12,R5-2,R3-1),(nm-3,-
R2-1,A-12,R5-2,R3-2),(nm-3,R2-1,A-12,R5-3,R3-1),(nm-3,R2-1,A-12,R5-3,R3-2)-
,(nm-3,R2-1,A-13,
R5-1,R3-1),(nm-3,R2-1,A-13,R5-1,R3-2),(nm-3,R2-1,A-13,R5-2,R3-1),(nm-3,R2-
-1,A-13,
R5-2,R3-2),(nm-3,R2-1,A-13,R5-3,R3-1),(nm-3,R2-1,A-13,R5-3,R3-2),-
(nm-3,R2-1,A-14,R5-1,R3-1),(nm-3,R2-1,A-14,R5-1,R3-2),(nm-3,R2-1,A-14,R5-2-
,R3-1),(nm-3,R2-1,
A-14,R5-2,R3-2),(nm-3,R2-1,A-14,R5-3,R3-1),(nm-3,R2-1,A-14,R5-3,R3-2),(nm-
-3,R2-2,A-1,R5-1,R3-1),(nm-3,R2-2,A-1,R5-1,R3-2),(nm-3,R2-2,A-1,R5-2,R3-1)-
,(nm-3,R2-2,
A-1,R5-2,R3-2),(nm-3,R2-2,A-1,R5-3,R3-1),(nm-3,R2-2,A-1,R5-3,R3-2),(nm-3,-
R2-2,A-2,R5-1,R3-1),(nm-3,R2-2,A-2,R5-1,R3-2),(nm-3,R2-2,A-2,R5-2,R3-1),(n-
m-3,R2-2,A-2,R5-2,R3-2),(nm-3,R2-2,A-2,R5-3,R3-1),(nm-3,R2-2,A-2,R5-3,R3-2-
),(nm-3,R2-2,A-3,
R5-1,R3-1),(nm-3,R2-2,A-3,R5-1,R3-2),(nm-3,R2-2,A-3,R5-2,R3-1),(nm-3,R2-2-
,A-3,R5-2,R3-2),(nm-3,R2-2,A-3,R5-3,R3-1),(nm-3,R2-2,A-3,R5-3,R3-2),(nm-3,-
R2-2,A-4,R5-1,R3-1),(nm-3,R2-2,A-4,R5-1,R3-2),(nm-3,R2-2,A-4,R5-2,R3-1),(n-
m-3,R2-2,A-4,R5-2,
R3-2),(nm-3,R2-2,A-4,R5-3,R3-1),(nm-3,R2-2,A-4,R5-3,R3-2),(nm-3,R2-2,A-5,-
R5-1,R3-1),(nm-3,R2-2,A-5,R5-1,R3-2),(nm-3,R2-2,A-5,R5-2,R3-1),(nm-3,R2-2,-
A-5,R5-2,R3-2),(nm-3,R2-2,A-5,R5-3,R3-1),(nm-3,R2-2,A-5,R5-3,R3-2),(nm-3,R-
2-2,A-6,R5-1,R3-1),(nm-3,R2-2,A-6,R5-1,R3-2),(nm-3,R2-2,A-6,R5-2,R3-1),(nm-
-3,R2-2,A-6,R5-2,R3-2),(nm-3,R2-2,A-6,R5-3,R3-1),(nm-3,R2-2,A-6,R5-3,R3-2)-
,(nm-3,R2-2,A-7,R5-1,R3-1),(nm-3,R2-2,A-7,R5-1,R3-2),(nm-3,R2-2,A-7,R5-2,R-
3-1),(nm-3,R2-2,A-7,R5-2,R3-2),(nm-3,R2-2,A-7,R5-3,R3-1),(nm-3,R2-2,A-7,R5-
-3,R3-2),(nm-3,R2-2,A-8,R5-1,R3-1),(nm-3,R2-2,A-8,R5-1,R3-2),(nm-3,R2-2,A--
8,R5-2,R3-1),(nm-3,R2-2,A-8,R5-2,R3-2),(nm-3,
R2-2,A-8,R5-3,R3-1),(nm-3,R2-2,A-8,R5-3,R3-2),(nm-3,R2-2,A-9,R5-1,R3-1),(-
nm-3,R2-2,A-9,R5-1,R3-2),(nm-3,R2-2,A-9,R5-2,R3-1),(nm-3,R2-2,A-9,R5-2;R3--
2),(nm-3,R2-2,A-9,R5-3,R3-1),(nm-3,R2-2,A-9,R5-3,R3-2),(nm-3,R2-2,A-10,R5--
1,R3-1),(nm-3,R2-2,A-10,R5-1,R3-2),(nm-3,R2-2,A-10,R5-2,R3-1),(nm-3,R2-2,A-
-10,R5-2,R3-2),(nm-3,R2-2,A-10,R5-3,R3-1),(nm-3,R2-2,A-10,R5-3,R3-2),(nm-3-
,R2-2,A-11,R5-1,R3-1),(nm-3,
R2-2,A-11,R5-1,R3-2),(nm-3,R2-2,A-11,R5-2,R3-1),(nm-3,R2-2,A-11,R5-2,R3-2-
),(nm-3,R2-2,A-11,R5-3,R3-1),(nm-3,R2-2,A-11,R5-3,R3-2),(nm-3,R2-2,A-12,R5-
-1,R3-1),(nm-3,R2-2,A-12,R5-1,R3-2),(nm-3,R2-2,A-12,R5-2,R3-1),(nm-3,R2-2,-
A-12,R5-2,R3-2),
(nm-3,R2-2,A-12,R5-3,R3-1),(nm-3,R2-2,A-12,R5-3,R3-2),(nm-3,R2-2,A-13,R5--
1,R3-1),(nm-3,R2-2,A-13,R5-1,R3-2),(nm-3,R2-2,A-13,R5-2,R3-1),(nm-3,R2-2,A-
-13,R5-2,R3-2),(nm-3,R2-2,A-13,R5-3,R3-1),(nm-3,R2-2,A-13,R5-3,R3-2),(nm-3-
,R2-2,A-14,R5-1,
R3-1),(nm-3,R2-2,A-14,R5-1,R3-2),(nm-3,R2-2,A-14,R5-2,R3-1),(nm-3,R2-2,A--
14,R5-2,R3-2),(nm-3,R2-2,A-14,R5-3,R3-1),(nm-3,R2-2,A-14,R5-3,R3-2),(nm-3,-
R2-3,A-1,R5-1,R3-1),(nm-3,R2-3,A-1,R5-1,R3-2),(nm-3,R2-3,A-1,R5-2,R3-1),(n-
m-3,R2-3,A-1,R5-2,R3-2),(nm-3,R2-3,A-1,R5-3,R3-1),(nm-3,R2-3,A-1,R5-3,R3-2-
),(nm-3,R2-3,A-2,R5-1,
R3-1),(nm-3,R2-3,A-2,R5-1,R3-2),(nm-3,R2-3,A-2,R5-2,R3-1),(nm-3,R2-3,A-2,-
R5-2,R3-2),(nm-3,R2-3,A-2,R5-3,R3-1),(nm-3,R2-3,A-2,R5-3,R3-2),(nm-3,R2-3,-
A-3,R5-1,R3-1),(nm-3,R2-3,A-3,R5-1,R3-2),(nm-3,R2-3,A-3,R5-2,R3-1),(nm-3,R-
2-3,A-3,R5-2,R3-2),(nm-3,R2-3,A-3,R5-3,R3-1),(nm-3,R2-3,A-3,R5-3,R3-2),(nm-
-3,R2-3,A-4,R5-1,R3-1),(nm-3,R2-3,A-4,R5-1,R3-2),(nm-3,R2-3,A-4,R5-2,R3-1)-
,(nm-3,R2-3,A-4,R5-2,R3-2),(nm-3,R2-3,A-4,R5-3,R3-1),(nm-3,R2-3,A-4,R5-3,R-
3-2),(nm-3,R2-3,A-5,R5-1,R3-1),(nm-3,R2-3,A-5,R5-1,R3-2),(nm-3,R2-3,A-5,R5-
-2,R3-1),(nm-3,R2-3,A-5,R5-2,R3-2),(nm-3,R2-3,A-5,R5-3,R3-1),(nm-3,R2-3,A--
5,R5-3,R3-2),(nm-3,R2-3,A-6,R5-1,R3-1),(nm-3,
R2-3,A-6,R5-1,R3-2),(nm-3,R2-3,A-6,R5-2,R3-1),(nm-3,R2-3,A-6,R5-2,R3-2),(-
nm-3,R2-3,A-6,R5-3,R3-1),(nm-3,R2-3,A-6,R5-3,R3-2),(nm-3,R2-3,A-7,R5-1,R3--
1),(nm-3,R2-3,A-7,R5-1,R3-2),(nm-3,R2-3,A-7,R5-2,R3-1),(nm-3,R2-3,A-7,R5-2-
,R3-2),(nm-3,R2-3,
A-7,R5-3,R3-1),(nm-3,R2-3,A-7,R5-3,R3-2),(nm-3,R2-3,A-8,R5-1,R3-1),(nm-3,-
R2-3,A-8,R5-1,R3-2),(nm-3,R2-3,A-8,R5-2,R3-1),(nm-3,R2-3,A-8,R5-2,R3-2),(n-
m-3,R2-3,A-8,R5-3,R3-1),(nm-3,R2-3,A-9,R5-1,R3-1),(nm-3,R2-3,A-9,
R5-1,R3-2),(nm-3,R2-3,A-9,R5-2,R3-1),(nm-3,R2-3,A-9,R5-2,R3-2),(nm-3,R2-3-
,A-9,R5-3,R3-1),(nm-3,R2-3,A-9,R5-3,R3-2),(nm-3,R2-3,A-10,R5-1,R3-1),(nm-3-
,R2-3,A-10,
R5-1,R3-2),(nm-3,R2-3,A-10,R5-2,R3-1),(nm-3,R2-3,A-10,R5-2,R3-2),(nm-3,R2-
-3,A-10,R5-3,R3-1),(nm-3,R2-3,A-10,R5-3,R3-2),(nm-3,R2-3,A-11,R5-1,R3-1),(-
nm-3,R2-3,A-11,R5-1,R3-2),(nm-3,R2-3,A-11,R5-2,R3-1),(nm-3,R2-3,A-11,R5-2,-
R3-2),(nm-3,R2-3,
A-11,R5-3,R3-1),(nm-3,R2-3,A-11,R5-3,R3-2),(nm-3,R2-3,A-12,R5-1,R3-1),(nm-
-3,R2-3,A-12,R5-1,R3-2),(nm-3,R2-3,A-12,R5-2,R3-1),(nm-3,R2-3,A-12,R5-2,R3-
-2),(nm-3,R2-3,A-12,R5-3,R3-1),(nm-3,R2-3,A-12,R5-3,R3-2),(nm-3,R2-3,A-13,-
R5-1,R3-1),(nm-3,
R2-3,A-13,R5-1,R3-2),(nm-3,R2-3,A-13,R5-2,R3-1),(nm-3,R2-3,A-13,R5-2,R3-2-
),(nm-3,R2-3,A-13,R5-3,R3-1),(nm-3,R2-3,A-13,R5-3,R3-2),(nm-3,R2-3,A-14,R5-
-1,R3-1),(nm-3,R2-3,A-14,R5-1,R3-2),(nm-3,R2-3,A-14,R5-2,R3-1),(nm-3,R2-3,-
A-14,R5-2,R3-2),
(nm-3,R2-3,A-14,R5-3,R3-1),(nm-3,R2-3,A-14,R5-3,R3-2),(nm-3,R2-4,A-1,R5-1-
,R3-1),(nm-3,R2-4,A-1,R5-1,R3-2),(nm-3,R2-4,A-1,R5-2,R3-1),(nm-3,R2-4,A-1,-
R5-2,R3-2),(nm-3,R2-4,A-1,R5-3,R3-1),(nm-3,R2-4,A-1,R5-3,R3-2),(nm-3,R2-4,-
A-2,R5-1,R3-1),(nm-3,R2-4,A-2,R5-1,R3-2),(nm-3,R2-4,A-2,R5-2,R3-1),(nm-3,R-
2-4,A-2,R5-2,R3-2),(nm-3,R2-4,A-2,R5-3,R3-1),(nm-3,R2-4,A-2,R5-3,R3-2),(nm-
-3,R2-4,A-3,R5-1,R3-1),(nm-3,R2-4,A-3,R5-1,R3-2),(nm-3,R2-4,A-3,R5-2,R3-1)-
,(nm-3,R2-4,A-3,R5-2,R3-2),(nm-3,
R2-4,A-3,R5-3,R3-1),(nm-3,R2-4,A-3,R5-3,R3-2),(nm-3,R2-4,A-4,R5-1,R3-1),(-
nm-3,R2-4,A-4,R5-1,R3-2),(nm-3,R2-4,A-4,R5-2,R3-1),(nm-3,R2-4,A-4,R5-2,R3--
2),(nm-3,R2-4,A-4,R5-3,R3-1),(nm-3,R2-4,A-4,R5-3,R3-2),(nm-3,R2-4,A-5,R5-1-
,R3-1),(nm-3,R2-4,
A-5,R5-1,R3-2),(nm-3,R2-4,A-5,R5-2,R3-1),(nm-3,R2-4,A-5,R5-2,R3-2),(nm-3,-
R2-4,A-5,R5-3,R3-1),(nm-3,R2-4,A-5,R5-3,R3-2),(nm-3,R2-4,A-6,R5-1,R3-1),(n-
m-3,R2-4,A-6,R5-1,R3-2),(nm-3,R2-4,A-6,R5-2,R3-1),(nm-3,R2-4,A-6,R5-2,R3-2-
),(nm-3,R2-4,A-6,
R5-3,R3-1),(nm-3,R2-4,A-6,R5-3,R3-2),(nm-3,R2-4,A-7,R5-1,R3-1),(nm-3,R2-4-
,A-7,R5-1,R3-2),(nm-3,R2-4,A-7,R5-2,R3-1),(nm-3,R2-4,A-7,R5-2,R3-2),(nm-3,-
R2-4,A-7,R5-3,R3-1),(nm-3,R2-4,A-7,R5-3,R3-2),(nm-3,R2-4,A-8,R5-1,R3-1),(n-
m-3,R2-4,A-8,R5-1,
R3-2),(nm-3,R2-4,A-8,R5-2,R3-1),(nm-3,R2-4,A-8,R5-2,R3-2),(nm-3,R2-4,A-8,-
R5-3,R3-1),(nm-3,R2-4,A-8,R5-3,R3-2),(nm-3,R2-4,A-9,R5-1,R3-1),(nm-3,R2-4,-
A-9,R5-1,R3-2),(nm-3,R2-4,A-9,R5-2,R3-1),(nm-3,R2-4,A-9,R5-2,R3-2),(nm-3,R-
2-4,A-9,R5-3,R3-1),(nm-3,R2-4,A-9,R5-3,R3-2),(nm-3,R2-4,A-10,R5-1,R3-1),(n-
m-3,R2-4,A-10,R5-1,R3-2),(nm-3,R2-4,A-10,R5-2,R3-1),(nm-3,R2-4,A-10,R5-2,R-
3-2),(nm-3,R2-4,A-10,R5-3,R3-1),(nm-3,R2-4,A-10,R5-3,R3-2),(nm-3,R2-4,A-11-
,R5-1,R3-1),(nm-3,R2-4,A-11,R5-1,
R3-2),(nm-3,R2-4,A-11,R5-2,R3-1),(nm-3,R2-4,A-11,R5-2,R3-2),(nm-3,R2-4,A--
11,R5-3,R3-1),(nm-3,R2-4,A-11,R5-3,R3-2),(nm-3,R2-4,A-12,R5-1,R3-1),(nm-3,-
R2-4,A-12,R5-1,R3-2),(nm-3,R2-4,A-12,R5-2,R3-1),(nm-3,R2-4,A-12,R5-2,R3-2)-
,(nm-3,R2-4,A-12,
R5-3,R3-1),(nm-3,R2-4,A-12,R5-3,R3-2),(nm-3,R2-4,A-13,R5-1,R3-1),(nm-3,R2-
-4,A-13,
R5-1,R3-2),(nm-3,R2-4,A-13,R5-2,R3-1),(nm-3,R2-4,A-13,R5-2,R3-2),-
(nm-3,R2-4,A-13,R5-3,R3-1),(nm-3,R2-4,A-13,R5-3,R3-2),(nm-3,R2-4,A-14,R5-1-
,R3-1),(nm-3,R2-4,
A-14,R5-1,R3-2),(nm-3,R2-4,A-14,R5-2,R3-1),(nm-3,R2-4,A-14,R5-2,R3-2),(nm-
-3,R2-4,A-14,R5-3,R3-1),(nm-3,R2-4,A-14,R5-3,R3-2),(nm-3,R2-4,A-14,R5-3,R3-
-3).
[0168] In a compound represented by the general formula (I'), a
compound, wherein the combination of n, m, R.sup.2a, R.sup.2b, ring
A, R.sup.5, R.sup.3a, and R.sup.3b (nm, R.sup.2, A, R.sup.5,
R.sup.3) is one of the above compound, and E is a bond.
[0169] The compounds of the invention can be employed in the
treatment and/or prevention of disease associated with the
generation, secretion or deposition of .beta.-amyloid protein, such
as dementia of the Alzheimer's type (Alzheimer's disease, senile
dementia of Alzheimer type), Down's syndrome, memory impairment,
prion disease (Creutzfeldt-Jakob disease), mild cognitive
impairment (MCI), Dutch type of hereditary cerebral hemorrhage with
amyloidosis, cerebral amyloid angiopathy, other type of
degenerative dementia, mixed dementia with Alzheimer's and vascular
type, dementia with Parkinson's Disease, dementia with progressive
supranuclear palsy, dementia with Cortico-basal degeneration,
Alzheimer's disease with diffuse Lewy body disease, age-related
macular degeneration, Parkinson's Disease, amyloid angiopathy and
so on.
[0170] The compounds of the invention can be administrated in
combination with other pharmaceutical agents such as other
therapeutic drugs for Alzheimer's disease, acetylcholinesterase
inhibitors and so on. The compounds of the invention can be treated
with concomitantly with the anti-dementia agents such as Donepezil
Hydrochloride, Tacrine, Galantamine, Rivastigmine, Zanapezil,
Memantine, Vinpocetine.
[0171] When the present compound is administered to a human, it can
be administered orally as powders, granules, tablets, capsules,
pills, solutions, or the like, or parenterally as injectables,
suppositories, transdermal absorbable agents, absorbable agents, or
the like. In addition, the present compound can be formulated into
pharmaceutical preparations by adding pharmaceutical additives such
as excipients, binders, wetting agents, disintegrating agents,
lubricants and the like, which are suitable for formulations and an
effective amount of the present compound.
[0172] A dose is different depending on state of disease, an
administration route, and an age and a weight of a patient, and is
usually 0.1 .mu.g to 1 g/day, preferably 0.01 to 200 mg/day when
orally administered to an adult, and is usually 0.1 .mu.g to 10
g/day, preferably 0.1 to 2 g/day when parenterally
administered.
[0173] Following examples and test examples illustrate the present
invention in more detail, but the present invention is not limited
by these examples.
[0174] In example, the meaning of each abbreviation is
following.
Me methyl Et ethyl iPr or Pr.sup.i isopropyl Ph phenyl Bn benzyl
Boc t-butoxycarbonyl TBDPS t-butyldiphenylsilyl
Example 1
The Synthesis of Compound 588
##STR00058## ##STR00059##
[0175] Step 1
[0176] Under nitrogen atmosphere, the compound (1-1) (7.98 g) was
dissolved into diethyl ether (330 ml)-tetrahydrofuran (36 ml),
vinylmagnesium chloride in tetrahydrofuran solution (1.32 mol/L,
44.8 ml) was added under cooling with dryice-acetone bath, and
stirred for 20 min. Then, the reaction solution was stirred for 30
min under cooling with ice-water bath and stirred for 36 min at
room temperature. And then, saturated ammonium chloride solution
was added to the mixture, the mixture was extracted with ethyl
acetate, and organic layer was washed with saturated ammonium
chloride solution, saturated sodium hydrogencarbonate solution, and
brine, and dried over anhydrous magnesium sulfate, and the solvent
was evaporated. Then, the residue was purified by silica gel column
chromatography to afford the compound (1-2) (6.00 g).
[0177] .sup.1H-NMR (CDCl.sub.3): 1.63 (3H, s), 2.08 (1H, br), 5.20
(1H, dd, J=10.6, 1.6 Hz), 6.31 (1H, dd, J=17.1, 1.6 Hz), 6.09 (1H,
m), 7.46 (1H, m), 7.52 (1H, dd, J=3.4, 2.6 Hz), 7.80 (1H, dd,
J=3.9, 2.6 Hz), 8.06 (1H, br)
Step 2
[0178] The compound (1-2) (6.36 g) was dissolved into acetic acid
(30 ml), and added thiourea (1.50 g), 1 mol/L hydrochloride-acetic
acid solution (20.7 ml). The reaction mixture was stirred at room
temperature for 3 hours, then stirred at 40.degree. C. for 3 hours,
then stirred at room temperature for 66 hours, and at 40.degree. C.
for 19 hours. Thiourea (0.450 g), and 1 mol/L hydrochloric
acid-acetic acid solution (7.53 ml) was added, and stirred at
40.degree. C. for 23 hours. After the consumption of the compound
(1-2), the solvent was evaporated under reduced pressure, then the
obtained residue was crystallized from methanol-diethyl ether to
afford the compound (1-3) (5.23 g) as crystal. On the other hand,
mother liquid was evaporated under reduced pressure, and the
compound (1-3) (3.00 g) was obtained as crude solid product.
[0179] .sup.1H-NMR (DMSO-d.sub.6): 2.09 (3H, 5), 4.10 (2H, d, J=7.3
Hz), 5.94 (1H, t, J=7.7 Hz), 7.50 (1H, s), 7.75 (1H, s), 7.87 (1H,
s), 9.17 (3H, br), 11.46 (1H, s)
Step 3
[0180] The compound (1-3) (5.23 g) dissolved in trifluoroacetic
acid (25 ml) was added methanesulfonic acid (2.14 ml) dropwise
under cooling with ice-water bath. After addition, the reaction
mixture was stirred at room temperature for 3.5 hours. After the
consumption of the compound (1-3), the solvent was evaporated under
reduced pressure. To the residue obtained was added water and
sodium carbonate, and then extracted with ethyl acetate. The
organic layer was washed with saturated sodium hydrogencarbonate
solution, and was dried over anhydrous magnesium sulfate, and the
solvent was evaporated under reduced pressure to afford the
compound (1-4) (4.90 g) as crude product.
[0181] .sup.1H-NMR (CDCl.sub.3): 1.53 (3H, s), 1.90 (1H, m), 2.09
(1H, m), 2.74 (1H, m), 2.97 (1H, m), 4.32 (2H, br), 7.34 (1H, t,
J=1.6 Hz), 7.37 (1H, t, J=1.8 Hz), 7.86 (1H, t, J=1.8 Hz)
Step 4
[0182] Under nitrogen atmosphere, the compound (1-4) (4.90 g)
dissolved in tetrahydrofuran was added di-t-butyl-dicarbonate (2.97
g) and triethylamine (1.89 ml) under cooling with ice-water bath
and then stirred for 2 hours. The reaction mixture was stirred at
room temperature for 3 hours. The reaction mixture was added water,
and then extracted with ethyl acetate. The organic layer was washed
with water, and dried over anhydrous magnesium sulfate, then the
solvent was evaporated under reduced pressure. Then the obtained
residue was crystallized from ethyl acetate-diethyl ether to afford
the compound (1-5) (4.62 g) as crystal.
[0183] .sup.1H-NMR (CDCl.sub.3): 1.36 (9H, s), 1.72 (3H, s), 2.10
(1H, m), 2.41 (1H, m), 2.62 (1H, m), 2.75 (1H, m), 7.22 (1H, s),
7.48 (1H, s), 8.29 (1H, s)
Step 5
[0184] The compound (1-5) (1.00 g) was dissolved into
tetrahydrofuran (8.7 ml), and 1 mol/L lithium hydroxide (4.43 ml)
was added and stirred at 50.degree. C. for 4 hours. Water was added
to the reaction mixture, and the mixture was extracted with ethyl
acetate, and the organic layer was washed with water, brine
successively, and dried over anhydrous magnesium sulfate, and the
solution was evaporated under reduced pressure. The obtained
residue was purified by medium-pressured silica gel column
chromatography to afford the compound (1-6) (0.668 g).
[0185] .sup.1H-NMR (CDCl.sub.3): 1.51 (9H, 5), 1.63 (3H, 5), 2.06
(1H, m), 2.40 (1H, m), 2.68-2.74 (2H, m), 3.83 (2H, br), 6.51 (1H,
t, J=1.8 Hz), 6.72-6.74 (2H, m)
Step 6
[0186] The compound (1-6) (20.0 mg) was dissolved into 4 mol/L
hydrochloric acid in 1,4-dioxane, and the mixture was stirred for
16 hours. The reaction solvent was evaporated under reduced
pressure and the obtained residue was crystallized from
methanol-diethyl ether to afford the compound (588) (14.7 mg).
[0187] .sup.1H-NMR (DMSO-d.sub.6): 1.59 (3H, s), 2.09-2.76 (4H, m),
6.44 (1H, t, J=1.6 Hz), 6.60 (1H, t J=1.9 Hz), 6.71 (1H, t, J=2.0
Hz), 10.4 (111, s)
Example 2
The Synthesis of Compound 835
##STR00060##
[0188] Step 1
[0189] The compound (2-1) (2020 mg) was dissolved into chloroform
(20 ml), then water (4 ml) and sodium thiocyanic acid (1470 mg)
were added at room temperature with stirring, and then sulfuric
acid (1.94 ml) was added dropwise under cooling with ice-water
bath. After an addition was complete, the reaction mixture was
warmed to room temperature and then stirred for 345 minutes, then
stirred at 60.degree. C. overnight. Because the compound (2-1) was
remained (checked by TLC), the reaction mixture was cooled to room
temperature, then sodium thiocyanic acid (1470 mg), water (5 ml)
and sulfuric acid (1.94 ml) were added successively. After the
reaction mixture was warmed to 60.degree. C., the mixture was
stirred for 1 day. Saturated sodium carbohydrate solution was added
to the reaction mixture to be basic condition under cooling with
ice-water bath, and then the reaction mixture was extracted with
ethyl acetate. The organic layer was washed with brine, then dried
over anhydrous magnesium sulfate. The solvent was evaporated and
the obtained residue was purified by silica gel column
chromatography to afford the compound (2-2) (968 mg).
[0190] .sup.1H-NMR (CDCl.sub.3, 270 MHz): 1.99 (3H, s), 3.55 (1H,
d, J=16.1 Hz), 3.69 (1H, d, J=16.1 Hz), 7.12-7.64 (8H, m),
7.82-7.96 (2H, m)
Step 2
[0191] The compound (2-2) (842 mg) was dissolved into ethanol (8.4
ml), sodium dihydorgen phosphate, sodium borohydride (113.2 mg),
and water (2.8 ml), were added successively under cooling with
ice-water bath with stirring, and the mixture was stirred for 30
minutes. After the consumption of the compound (2-2) (checked by
TLC), ethyl acetate and water were added to the reaction mixture
under cooling with ice-water bath, and then stirred for a few
minutes. The reaction mixture was extracted with ethyl acetate. The
organic layer was washed with water, brine successively, and dried
over anhydrous magnesium sulfate. The solvent was evaporated to
afford the compound (2-3) (904.8 mg) as crude product.
Step 3
[0192] To a solution of compound (2-3) (900 mg) in toluene (10 ml)
was added a solution of thionyl chloride (0.7 ml) in toluene (5 ml)
under cooling with ice-water bath, and then stirred for 1 hour.
After the consumption of the compound (2-3) (checked by TLC), the
reaction solvent was evaporated under reduced pressure to afford
the compound (2-4) (1076.8 mg) as crude product.
Step 4
[0193] The compound (2-4) (1070 mg) was dissolved into about 7
mol/L ammonia in methanol (20 ml) at room temperature, then the
mixture was stirred for 1 day. After the consumption of the
compound (2-4) (checked by TLC), the reaction solvent was
evaporated under reduced pressure to afford the compound (835)
(2633 mg) as crude product.
Example 3
The Synthesis of Compound 561
##STR00061##
[0194] Step 1
[0195] To tetrahydrofuran (30 ml) under cooling with ice-water bath
with stirring, lithium aluminium hydride (0.63 g) was added
portionwise, then a solution of compound (3-1) (1.94 g) in
tetrahydrofuran (40 ml) was added dropwise. The reaction mixture
was reacted for 20 minutes at room temperature, then reacted for 3
hours under reflux. Then ice was added in small portions under
cooling, and then stirred for 1 day at room temperature. The
reaction mixture was filtered and the filtrate was evaporated under
reduced pressure, and the residue was purified by silica gel column
chromatography to afford the compound (3-2) (0.90 g).
[0196] .sup.1H-NMR (CDCl.sub.3): 1.22 (3H, s), 3.08 (1H, d, J=12.5
Hz), 3.34 (1H, d, J=12.5 Hz), 3.85 (1H, d, J=11.0 Hz), 4.11 (1H, d,
J=11.0 Hz), 7.21-7.25 (1H, m), 7.34-7.40 (2H, m), 7.46-7.50 (2H,
m).
Step 2
[0197] The compound (3-2) (0.90 g) was dissolved into
tetrahydrofuran (15 ml), t-butylisothiocyanate (0.69 g) in
tetrahydrofuran (5 ml) was added under cooling with ice-water bath
with stirring. The reaction mixture was stirred for 3 days at room
temperature, water was added and extracted with dichloromethane.
The organic layer was dried over anhydrous magnesium sulfate, then
the solvent was evaporated under reduced pressure. The residue was
purified by silica gel column chromatography to afford the compound
(3-3) (1.33 g).
[0198] .sup.1H-NMR (CDCl.sub.3): 1.12 (9H, s), 1.34 (3H, s), 3.15
(1H, br), 3.76 (1H, d, J=11.2 Hz), 3.87 (1H, dd, J=14.2, 4.6 Hz),
4.13 (1H, d, J=11.2 Hz), 4.23 (1H, dd, J=14.2, 6.6 Hz), 5.18 (1H,
br), 6.01 (1H, br), 7.23-7.28 (1H, m), 7.34-7.41 (4H, m).
Step 3
[0199] The compound (3-3) (315 mg) was dissolved into acetonitrile
(3 ml), triphenylphosphine (440 mg), and carbon tetrachloride (520
mg) in acetonitrile (3 ml) were added under cooling with ice-water
bath with stirring. The reaction mixture was stirred for 1 hour at
room temperature, and then potassium carbonate (460 mg) was added
and stirred for 2 days at room temperature. Then water was added to
the reaction mixture and the mixture was extracted with
dichloromethane. The organic layer was dried over anhydrous
magnesium sulfate, and then the solvent was evaporated under
reduced pressure. The residue was purified by silica gel column
chromatography to afford the compound (3-4) (0.23 g).
[0200] .sup.1H-NMR (CDCl.sub.3): 1.30 (9H, s), 1.36 (3H, s), 3.13
(1H, d, J=12.2 Hz), 3.24 (1H, dd, J=12.2, 2.3 Hz), 3.51 (1H, br),
3.53 (1H, d, J=15.2 Hz), 3.99 (1H, dd, J=15.2, 2.3 Hz), 7.20-7.25
(1H, m), 7.30-7.36 (2H, m), 7.39-7.43 (2H, m).
Step 4
[0201] To the compound (3-4) (0.22 g), conc. hydrochloric acid (4.5
ml) was added, then stirred for 2 hours under reflux, and then the
reaction solvent was evaporated under reduced pressure. The
obtained residue was crystallized from methanol-diethyl ether to
afford the compound (561) (0.16 g).
[0202] .sup.1H-NMR (DMSO-d.sub.6): 1.33 (3H, s), 3.33-3.49 (2H, m),
3.65-3.96 (2H, m), 7.29 (1H, t. J=7.6 Hz), 7.40 (2H, t. J=7.6 Hz),
7.48 (2H, t. J=7.6 Hz).
Example 4
The Synthesis of Compound 534
##STR00062##
[0203] Step 1
[0204] The compound (4-1) (0.72 g) was dissolved into
N,N-dimethylformamide (15 ml), then sodium azide (0.31 g) was
added. The reaction mixture was stirred at 100.degree. C. for 13
hours, then water was added and the mixture was extracted with
diethyl ether, the organic layer was dried over anhydrous magnesium
sulfate to afford the compound (4-2) (0.71 g) as crude product.
Step 2
[0205] To a solution of the compound (4-2) (0.71 g) in
tetrahydrofuran (10 ml), lithium aluminium hydride (0.14 g) was
added portionwise under cooling with ice-water bath with stirring,
then stirred for 2 hours at room temperature. After the consumption
of the starting material, ice was added in small portions, then
stirred for 18 hours at room temperature. The reaction mixture was
filtered then filtrate was evaporated under reduced pressure to
afford the compound (4-3) (0.89 g) as crude product.
Step 3
[0206] The compound (4-3) (0.89 g) was dissolved into
tetrahydrofuran (10 ml), then t-butylisothiocyanate (0.56 g) in
tetrahydrofuran (5 ml) was added under cooling with ice-water bath
with stirring. The reaction mixture was stirred for 4 hours at room
temperature, and water was added, and then extracted with
dichloromethane, and the organic layer was dried over anhydrous
magnesium sulfate. Then the residue was purified by silica gel
column chromatography to afford the compound (4-4) (0.72 g).
[0207] .sup.1H-NMR (CDCl.sub.3): 1.39 (9H, s), 2.08 (3H, s),
2.09-2.15 (2H, m), 3.37-3.44 (1H, m), 3.80-3.87 (1H, m), 5.97 (1H,
br.), 6.86 (1H, br.), 7.28-7.43 (5H, m).
Step 4
[0208] The compound (4-4) (120 mg) was dissolved into acetonitrile
(2 ml), triphenylphosphine (170 mg), and carbon tetrachloride (200
mg) in acetonitrile (1 ml) were added under cooling with ice-water
bath with stirring. The reaction mixture was stirred for 5 hours at
room temperature, and then potassium carbonate (177 mg) was added
and stirred for 6 days at room temperature. Then water was added to
the reaction mixture and the mixture was extracted with
dichloromethane, the organic layer was dried over anhydrous
magnesium sulfate, then the solvent was evaporated under reduced
pressure. The residue was purified by silica gel column
chromatography to afford the compound (4-6) (0.06 g).
[0209] .sup.1H-NMR (CDCl.sub.3): 1.35 (9H, s), 1.59 (3H, s), 1.91
(1H, ddd, J=13.5, 8.8, 6.0 Hz), 2.06 (1H, dt, J=13.6, 6.0 Hz), 3.00
(1H, ddd, J=16.1, 8.8, 6.0 Hz), 3.30 (1H, dt, J=16.1, 6.0 Hz),
7.24-7.38 (6H, m).
Step 6
[0210] To the compound (4-5) (0.06 g), conc. hydrochloric acid (3
ml) was added, then the mixture was stirred for 1 hour under
reflux, and the solvent was evaporated under reduced pressure. The
obtained residue was crystallized from methanol-water to afford the
compound (634) (0.02 g).
[0211] .sup.1H-NMR (DMSO-d.sub.6): 1.43 (3H, s), 1.77 (1H, dt.
J=8.4, 3.4 Hz), 2.11 (1H, d. J=9.2 Hz), 2.48-2.50 (1H, m),
2.83-2.99 (1H, m), 6.12 (1H, br), 6.65 (1H, br), 7.21-7.24 (1H, m),
7.31-7.37 (4H, m).
Example 5
The Synthesis of Compound 1008
##STR00063##
[0212] Step 1
[0213] The compound (5-1) (3.00 g) was dissolved into ethanol (30
ml), and thiourea (1.13 g) was added, and then the mixture was
refluxed for 26 hours, and the solvent was evaporated under reduced
pressure. The obtained residue was crystallized from ethyl
acetate/hexane to afford the compound (5-2) (4.03 g).
[0214] .sup.1H-NMR (DMSO-d6): 1.95 (2H, quint, J=6.8 Hz), 3.13 (2H,
t, J=6.8 Hz), 3.21 (2H, t, J=6.8 Hz), 3.85 (3H, s), 7.06 (2H, d,
J=8.8 Hz), 7.95 (2H, d, J=8.8 Hz), 9.18 (4H, br).
Step 2
[0215] The compound (5-2) (1.00 g) was dissolved into
tetrahydrofuran (25 ml), then di-t-butyl-dicarbonate (1.74 g), and
triethylamine (0.88 g) were added, and then the mixture was stirred
for 3 hours at room temperature. Water was added to the reaction
mixture, and the mixture was extracted with dichloromethane. The
organic layer was dried over anhydrous magnesium sulfate, and then
the solvent was evaporated under reduced pressure. The residue was
purified by silica gel column chromatography to afford the compound
(5-3) (1.24 g).
[0216] .sup.1H-NMR (CDCl.sub.3): 1.50 (9H, 5), 2.07-2.17 (2H, m),
2.98 (2H, t, J=7.8 Hz), 3.09 (2H, t, J=6.3 Hz), 6.95 (2H, d, J=8.9
Hz), 7.95 (2H, d, J=8.9 Hz).
Step 3
[0217] The compound (5-3) (1.18 g) was dissolved into
tetrahydrofuran (12 ml), then 0.9 mol/L methylmagnesium bromide in
tetrahydrofuran solution (10.1 ml) was added under cooling with
acetonitrile-dryice bath with stirring, and then reaction mixture
was stirred for 1 hour, then stirred for 30 minutes at room
temperature. After the reaction, saturated ammonium chloride
solution was added under cooling with ice-water bath with stirring,
then the mixture was extracted with diethyl ether, and the organic
layer was dried over anhydrous magnesium sulfate, and then the
solvent was evaporated under reduced pressure. The obtained residue
was purified by silica gel column chromatography to afford the
compound (5-4) (0.39 g).
[0218] .sup.1H-NMR(CDCl.sub.3): 1.51 (9H, s), 1.63 (3H, s),
1.55-1.65 (2H, m), 1.87-1.91 (2H, m), 2.96-3.1.2 (2H, m), 6.86 (2H,
d, J=8.9 Hz), 7.36 (2H, d, J=8.9 Hz).
Step 4
[0219] The compound (5-4) (0.24 g) was dissolved into
trifluoroacetic acid (6 ml), and stirred for 20 hours at room
temperature, then the reaction solvent was evaporated under reduced
pressure. To the residue, water and saturated sodium
hydrogencarbonate was added, and then extracted with
dichloromethane. The organic layer was dried over anhydrous sodium
sulfate, and then the solvent was evaporated under reduced
pressure. The residue was purified by silica gel column
chromatography to afford the compound (1008) (0.06 g).
[0220] .sup.1H-NMR (CDCl.sub.3): 1.54 (3H, s), 1.77-1.87 (1H, m),
1.90-1.97 (1H, m), 2.20-2.36 (2H, m), 2.67-2.79 (2H, m), 3.81 (3H,
s), 5.30 (2H, br), 6.87 (2H, d, J=9.0 Hz), 7.33 (2H, d, J=9.0
Hz).
Example 6
The Synthesis of Compound 783
##STR00064##
[0221] Step 1
[0222] The compound (6-1) (0.55 g) was dissolved into methanol (7
ml), and methyl iodide (0.36 g) was added at room temperature with
stirring. The mixture was stirred at room temperature for 18 hours,
then the reaction solvent was evaporated under reduced pressure to
afford the compound (6-2) (0.92 g) as crude product.
Step 2
[0223] The compound (6-2) (0.92 g) was dissolved into
tetrahydrofuran (7 ml), then triethylamine (0.24 g) and silver
oxide (1.1 g) was added. The mixture was stirred at room
temperature for 3 days, then the insolubles was removed by
filtration, then the filtrate was evaporated under reduced
pressure, and then the obtained residue was purified by silica gel
column chromatography to afford the compound (6-3) (0.31 g).
[0224] .sup.1H-NMR (CDCl.sub.3): 1.35 (9H, s), 1.60 (3H, s), 1.92
(1H, ddd, J=9.2, 5.8, 3.4 Hz), 2.07 (1H, dt, J=9.2, 3.4 Hz), 3.00
(1H, ddd, J=9.2, 5.8, 3.4 Hz), 3.30 (1H, dt, J=9.2, 3.4 Hz),
7.24-7.38 (5H, m).
Step 3
[0225] To the compound (6-3) (0.22 g), conc. hydrochloric acid (3
ml) was added, then the mixture was stirred for 1 hour under
reflux, and then the reaction solvent was evaporated under reduced
pressure. The obtained residue was crystallized from water to
afford the compound (783) (0.13 g).
[0226] .sup.1H-NMR (DMSO-d.sub.6): 1.44 (3H, s), 1.78 (1H, dt.
J=12.4, 4.2 Hz), 2.12 (1H, d. J=8.9 Hz), 2.51-2.52 (1H, m), 2.96
(1H, d. J=4.2 Hz), 6.12 (1H, br), 6.66 (1H, br), 7.21-7.24 (1H, m),
7.32-7.37 (4H, m).
Example 7
The Synthesis of Compound 69
##STR00065##
[0227] Step 1
[0228] A solution of the compound (7-1) (1.93 g),
diphenylphosphoryl azide (1.60 g), and triethylamine (0.59 g) in
toluene (20 ml) was stirred at 80.degree. C. for 3 hours, and water
was added, and then the mixture was extracted with diethyl ether.
The organic layer was dried over anhydrous sodium sulfate, and then
the solvent was evaporated under reduced pressure. The obtained
residue was purified by silica gel column chromatography to afford
the compound (7-2) (1.69 g).
[0229] .sup.1H-NMR (CDCl.sub.3): 1.00 (9H, s), 1.72 (3H, 5),
2.17-2.22 (2H, m), 3.49-3.58 (1H, m), 3.70-3.80 (1H, m), 7.20-7.42
(10H, m), 7.58-7.63 (5H, m).
Step 2
[0230] The compound (7-2) (1.68 g) was dissolved into toluene (9
ml), and 3,4-dimethoxybenzylalcohol (0.79 g) was added, the mixture
was refluxed for 8 hours. To the reaction mixture, water was added,
then the mixture was extracted with dichloromethane, and the
organic layer was dried over anhydrous sodium sulfate, and the
solvent was evaporated under reduced pressure. The obtained residue
was purified by silica gel column chromatography to afford the
compound (7-3) (2.09 g).
[0231] .sup.1H-NMR (CDCl.sub.3): 1.03 (9H, s), 1.87 (3H, s), 2.04
(2H, m), 3.48 (1H, m), 3.51 (1H, m), 3.62 (3H, s), 3.65 (3H, s),
4.95 (1H, d, J=12.2 Hz), 5.03 (1H, d, J=12.2 Hz), 6.80-7.09 (3H,
m), 7.22-7.42 (10H, m), 7.56-7.64 (5H, m).
Step 3
[0232] The compound (7-3) (2.09 g) was dissolved into 1,4-dioxane
(15 ml), and 4 mol/L hydrochloric acid-1,4-dioxane (15 ml) solution
was added, then stirred at room temperature for 24 hours. To the
reaction mixture, water and 1 mol/L--sodium hydroxide solution were
added and extracted with dichloromethane, then the organic layer
was dried over anhydrous sodium sulfate, and then the solvent was
evaporated under reduced pressure. The obtained residue was
purified by silica gel column chromatography to afford the compound
(7-4) (0.45 g).
[0233] .sup.1H-NMR (CDCl.sub.3): 1.57 (3H, s), 1.07-1.98 (2H, m),
3.48-3.56 (1H, m), 3.72-3.86 (1H, m), 7.23-7.45 (15H, m).
Step 4
[0234] The compound (7-4) (0.44 g) was dissolved into
tetrahydrofuran (15 ml), t-butylisothiocyanate (0.41 g) and
diisopropylethylamine (0.46 g) were added. After the mixture was
stirred at room temperature for 3 days, water was added, and
extracted with dichloromethane, then the organic layer was dried
over anhydrous sodium sulfate, and then the solvent was evaporated
under reduced pressure. The obtained residue was purified by silica
gel column chromatography to afford the compound (7-5) (0.17
g).
[0235] .sup.1H-NMR (CDCl.sub.3): 1.79 (3H, s), 1.82-2.20 (2H, m),
3.71-3.81 (2H, m), 5.09 (1H, br), 7.30-7.52 (5H, m).
Step 5
[0236] The compound (7-5) (0.17 g) was dissolved into
tetrahydrofuran (3.4 ml), then methyl iodide (0.11 g) was added at
room temperature with stirring. The mixture was stirred for 23
hours, the reaction solvent was evaporated under reduced pressure
to afford the compound (7-6) (0.28 g) as crude product.
Step 6
[0237] The compound (7-6) (0.28 g) was dissolved into
tetrahydrofuran (5 ml), then triethylamine (74 mg) and silver oxide
(0.34 g) were added. The mixture was stirred at room temperature
for 20 hours, then insolubles were removed by filtration, and then
the filtrate was evaporated under reduced pressure. The obtained
residue was purified by silica gel column chromatography to afford
the compound (7-7) (0.14 g).
[0238] .sup.1H-NMR (CDCl.sub.3): 1.36 (9H, s), 1.49 (3H, s),
1.96-2.09 (2H, m), 2.77-3.83 (1H, m), 4.05-4.10 (1H, m), 7.19 (1H,
t, J=7.3 Hz), 7.31 (2H, t, J=7.3 Hz), 7.44 (2H, d, J=7.3 Hz).
Step 7
[0239] To the compound (7-7) (0.12 g) conc. hydrochloric acid (9
ml) was added, then stirred for 1 hour under reflux, and then the
reaction solvent was evaporated under reduced pressure. The
obtained residue was crystallized from methanol-water to afford the
compound (69) (0.10 g).
[0240] .sup.1H-NMR (DMSO-d.sub.6): 1.65 (3H, s), 2.28-2.35 (1H, m),
2.39-2.44 (1H, m), 3.97 (1H, dt, J=7.8, 3.0 Hz), 4.53 (1H, dt,
J=7.8, 3.0 Hz), 7.32-7.44 (5H, m), 8.44 (2H, br), 10.33 (1H,
s).
Example 8
The Synthesis of Compound 256
##STR00066## ##STR00067##
[0241] Step 1
[0242] The compound (8-1) (4890 mg) was dissolved into
N,N-dimethylformamide (100 ml), then sodium azide (5720 mg) was
added at room temperature with stirring, and the solution was
warmed to 80.degree. C., and stirred for 12 hours. After the
consumption of the compound (8-1) (checked by TLC), the reaction
mixture was cooled to room temperature, then diethyl ether and
water were added, and then the mixture was extracted with diethyl
ether. The organic layer was washed with brine, and dried over
magnesium sulfate. The solvent was evaporated under reduced
pressure to afford the compound (8-2) (4940 mg) as crude
product.
Step 2
[0243] To the suspension of lithium aluminium hydride (1080 mg) in
tetrahydrofuran (90 ml) under nitrogen atmosphere under cooling
with ice-water bath, the compound (8-2) (4940 mg) in
tetrahydrofuran (15 ml) solution was added, the reaction mixture
was stirred for 30 minutes. After the consumption of the compound
(8-2) (checked by TLC), 1 mol/L sodium hydroxide solution was added
under cooling with ice-water bath, then stirred for a while. The
generated gel was removed with filtration, and the mother liquid
was extracted with diethyl ether. The organic layer was washed with
brine, and dried over magnesium sulfate. The solvent was evaporated
under reduced pressure to afford the compound (8-3) (4219.1 mg) as
crude product.
Step 3
[0244] The compound (8-3) (800 mg) was dissolved into acetonitrile
(16 ml), the compound (8-4) (1840 mg) was added with stirring at
room temperature, and stirred for 13 hours. After the consumption
of the compound (8-3) (checked by no, the reaction solvent was
evaporated under reduced pressure, the obtained residue was
purified by silica gel column chromatography to afford the compound
(8-5) (1550.7 mg).
[0245] 8-5-(Z): .sup.1H-NMR (CDCl.sub.3, 270 MHz): 1.49 (18H, s),
2.06 (3H, d, J=1.4 Hz), 3.91-4.00 (2H, m), 5.54 (1H, td, J=7.1, 1.4
Hz), 7.12-7.41 (5H, m), 8.17-8.25 (1H, m), 11.47 (1H, s)
[0246] 8-5-(E): .sup.1H-NMR (CDCl.sub.3, 270 MHz): 1.49 (9H, s),
1.52 (9H, s), 2.09 (3H, d, J=1.5 Hz), 4.24 (2H, dd, J=6.6, 5.3 Hz),
5.80 (1H, td, J=6.6, 1.5 Hz), 7.21-7.48 (5H, m), 8.28-8.38 (1H, m),
11.51 (1H, s)
Step 4
[0247] The compound (8-5) (474.1 mg) was dissolved into
trifluoroacetic acid (4.5 ml) under cooling with ice-water bath,
then warmed to room temperature, and stirred for 4 hours. After the
consumption of the compound (8-5) (checked by NMR), the reaction
mixture was poured into floating ice--1 mol/L sodium hydroxide
solution to be neutralized, then the mixture was extracted with
ethyl acetate. The organic layer was washed with brine, and dried
over magnesium sulfate. The solvent was evaporated under reduced
pressure to afford the compound (8-6) (326.4 mg) as crude
product.
Step 5
[0248] The compound (8-6) (326.4 mg) was dissolved into 1,4-dioxane
(2.4 ml), sodium hydroxide (195 mg) and water (1.2 ml) were added
successively, then di-t-butyl dicarbonate (0.84 ml) was added under
cooling with ice-water bath. The reaction mixture was warmed to
room temperature, and stirred for 15 hours, then the consumption of
the compound (8-6) was checked by LC-MS. After added water to the
reaction mixture, the mixture was extracted with ethyl acetate. The
organic layer was washed with brine, and dried over magnesium
sulfate. The solvent was evaporated under reduced pressure, and the
obtained residue was purified by silica gel column chromatography
to afford the compound (8-7) (113.6 mg).
[0249] .sup.1H-NMR (CDCl.sub.3, 400 MHz): 1.46 (9H, s), 1.51 (9H,
s), 1.64 (3H, s), 2.06 (1H, ddd, J=13.4, 11.4, 5.0 Hz), 2.27 (1H,
dt, J=13.4, 4.6 Hz), 3.15 (1H, ddd, J=12.9, 11.3, 4.6 Hz), 3.70
(1H, dt, J=12.9, 4.7 Hz), 7.23-7.29 (1H, m), 7.33-7.38 (4H, m)
Step 6
[0250] The compound (8-7) (110 mg) was dissolved into 4 mol/L
hydrochloric acid-1,4-dioxane solution (1 ml) under cooling
ice-water bath, the mixture was warmed to room temperature, and
stirred for 2 days, then the consumption of the compound (8-7) was
checked by LC-MS, and diethyl ether and water were added at room
temperature. After separation of diethyl ether layer, water layer
was evaporated under reduced pressure. To the obtained residue,
methanol was added, then the generated crystal was filtered. The
methanol in mother liquid was evaporated under reduced pressure to
afford the compound (256) (69 mg).
[0251] .sup.1H-NMR (DMSO-d.sub.6, 400 MHz): 1.57 (3H, s), 1.87-1.96
(1H, m), 2.30 (1H, dt, J=13.6, 3.8 Hz), 2.60 (1H, td, J=12.0, 3.7
Hz), 3.25 (1H, ddd, J=12.8, 8.2, 4.4 Hz), 6.93 (2H, s), 7.27-7.44
(5H, m), 7.94 (1H, s), 8.63 (1H, s)
Example 9
The Synthesis of Compound 24
##STR00068##
[0252] Step 1
[0253] The compound (9-1) (0.39 g) was dissolved into chloroform
(20 ml), iodine (1.53 g), potassium thiocyanate (1.25 g), catalytic
amount of tetrabutylammonium chloride, and water (1 ml) were added
at room temperature, then stirred for 15 hours. To the reaction
mixture, 10% thiosodium sulfate solution and water were added, and
the mixture was extracted with dichloromethane. The organic layer
was dried over anhydrous sodium sulfate, the solvent was evaporated
under reduced pressure. The obtained residue was purified by silica
gel column chromatography to afford the compound (9-2) (0.56
g).
[0254] .sup.1H-NMR (CDCl.sub.3): 1.95 (3H, s), 3.62 (2H, s),
7.30-7.40 (4H, m).
Step 2
[0255] To a solution of the compound (9-2) (0.56 g) in
tetrahydrofuran (10 ml), t-butylamine (0.24 g) was added and
stirred at room temperature for 18 hours. The reaction solvent was
evaporated under reduced pressure, then the obtained residue was
purified by silica gel column chromatography to afford the compound
(9-3) (190 mg).
[0256] .sup.1H-NMR (CDCl.sub.3): 1.43 (9H, s), 1.56 (3H, s), 3.27
(1H, d, J=10.6 Hz), 3.36 (1H, d, J=10.6 Hz), 7.28 (2H, d, J=8.2
Hz), 7.43 (2H, d, J=8.2 Hz).
Step 3
[0257] To the compound (9-3) (190 mg), conc. hydrochloric acid (3
ml) was added, then stirred at 100.degree. C. for 3 hours. To the
reaction mixture, 6 mol/L sodium hydroxide was added to neutralize,
the mixture was extracted with dichloromethane. The organic layer
was dried with anhydrous sodium sulfate, and the solvent was
evaporated under reduced pressure. The obtained residue was
purified by silica gel column chromatography, then crystallized
from dichloromethane/n-hexane to afford the compound (24) (110
mg).
[0258] .sup.1H-NMR (CDCl.sub.3): 1.62 (3H, s), 3.47 (1H, d, J=10.6
Hz), 3.52 (1H, d, J=10.6 Hz), 4.59 (2H, br), 7.29 (2H, d, J=8.6
Hz), 7.39 (2H, d, J=8.6 Hz).
Example 10
The Synthesis of Compound 48
##STR00069##
[0259] Step 1
[0260] The compound (10-1) (79.6 mg) and (10-2) (120 mg) were
dissolved into N,N-dimethylformamide (3 ml), then
1-hydroxybenzotriazole (54.6 mg) and N,N'-diisopropylcarbodiimide
(0.063 ml) were added, then the reaction mixture was stirred
overnight at room temperature. Then after the consumption of the
compound (10-1), water was added, and the mixture was extracted
with ethyl acetate. The organic layer was washed with brine, and
dried over magnesium sulfate, and the solvent was evaporated under
reduced pressure. The obtained residue was purified by silica gel
column chromatography to afford the compound (10-3) (110.2 mg) as
crude product of diastereomer.
[0261] .sup.1H-NMR (CDCl.sub.3): 0.78-1.00 (6H, m), 1.14 (9/2H, e),
1.16 (9/2H, s) 1.52 (3/2H, s), 1.54 (3/2H, s) 1.86-2.28 (3H, m),
2.56-2.89 (2H, m), 3.80 (3/2H, s), 3.81 (3/2H, s) 4.04-4.14 (1H,
m), 6.80-6.91 (2H, m), 7.08-7.22 (2H, m), 7.30-7.51 (6H, m),
7.61-7.76 (4H, m)
Step 2
[0262] The compound (10-3) (100 mg) was dissolved into
tetrahydrofuran (3 ml) under nitrogen atmosphere, then 1 mol/L
tetrabutylammonium fluoride in tetrahydrofuran (0.18 ml) was added
at 0.degree. C. with stirring, then the reaction mixture was
stirred at 0.degree. C. for 5 minutes. After the consumption of the
compound (10-3), water was added, and the mixture was extracted
with ethyl acetate. The organic layer was washed with brine, and
dried over magnesium sulfate, then the solvent was evaporated under
reduced pressure. The obtained residue was purified by silica gel
column chromatography to afford the compound (48) (40.7 mg) as a
mixture of diastereomers.
[0263] .sup.1H-NMR (CDCl.sub.3): 0.80-0.90 (3H, m) 1.01-1.12 (3H,
m) 1.70 (3H, m), 2.02-2.31 (2H, m) 2.39-2.55 (1H, m), 2.61-2.90
(2H, m) 3.53-3.70 (1H, m) 3.81 (3H, m), 3.96-4.08 (1H, m) 6.87-6.96
(2H, m), 7.13-7.22 (2H, m)
Example 11
The Synthesis of Compound 707
##STR00070##
[0264] Step 1
[0265] The compound (11-1) (150 mg) was dissolved into acetonitrile
(5 ml), then the compound (11-2) (219.6 mg) was added at room
temperature with stirring, and then the reaction mixture was warmed
to 60.degree. C., and stirred for 25 hours. The compound (11-1) was
remained (checked by TLC). The reaction solvent was evaporated
under reduced pressure, then the obtained residue was purified by
silica gel column chromatography to afford the compound (11-1)
(211.4 mg).
[0266] .sup.1H-NMR (CDCl.sub.3, 400 MHz): 1.46 (9H, s), 1.50 (9H,
s), 1.57 (3H, s), 1.90 (1H, ddd, J=13.7, 10.0, 3.8 Hz) 2.11 (1H,
ddd, J=13.7, 6.5, 3.7 Hz) 2.68-2.76 (1H, m), 2.86-2.93 (1H, m),
3.88 (3H, s), 6.91 (1H, t, J=8.6 Hz) 6.99-7.03 (1H, m), 7.06 (1H,
dd, J=13.0, 2.2 Hz), 10.14 (1H, s), 13.93 (1H, s)
Step 2
[0267] The compound (11-3) (210 mg) was dissolved into 4 mol/L
hydrochloric acid in 1,4-dioxane (4 ml) under cooling with
ice-water bath, then the mixture was warmed to room temperature and
stirred for 67 hours. After the consumption of the compound (11-3)
(checked by LC/MS), the reaction solvent was evaporated under
reduced pressure. The obtained residue was crystallized from
methanol-diethyl ether, and crystal was collected by filtration and
washed with diethyl ether to afford compound (707) (140.2 mg).
[0268] .sup.1H-NMR (DMSO-d.sub.6, 400 MHz): 1.56 (3H, s), 1.90-2.01
(1H, m), 2.43-2.62 (2H, m), 2.95-3.03 (1H, m), 3.84 (3H, s),
7.10-7.27 (3H, m), 7.76 (3H, br s), 8.26 (1H, br s), 9.42 (1H,
s)
Example 12
The Synthesis of Compound 845
##STR00071##
[0269] Step 1
[0270] The compound (12-1) (50 mg) and piperidine (17.9 mg) were
dissolved into N,N-dimethylformamide (2 ml), then
O-(7-azabenzotriazo-1-yl)-1,1,3,3-tetramethyluroniumhexafluorophosphate
(79.8 mg) was added, and then the mixture was stirred at room
temperature for 40 hours. After the consumption of the compound
(12-1), the solvent was evaporated under reduced pressure with
heating. To the obtained residue, saturated sodium
hydrogencarbonate solution was added, and extracted with ethyl
acetate. The organic layer was washed with brine, and dried over
magnesium sulfate, then the solvent was evaporated under reduced
pressure. The obtained residue was purified by silica gel column
chromatography to afford the compound (845) (30.7 mg).
[0271] .sup.1H-NMR (CDCl.sub.3): 1.60 (3H, s), 1.51-1.82 (6H, m),
1.87-1.98 (1H, m), 2.09-2.19 (1H, m), 2.91-2.97 (2H, m), 3.64-3.68
(4H, m), 6.73 (1H, d, J=4.05 Hz), 7.14 (1H, d, J=4.05 Hz)
Example 13
The Synthesis of Compound 1262
##STR00072##
[0272] Step 1
[0273] The compound (13-1) (50.0 mg) was dissolved into
tetrahydrofuran (1 ml) under nitrogen atmosphere, then
triethylamine (19 .mu.l), and 4-bromobenzoyl chloride (30.1 mg)
were added under cooling with ice-water bath, and stirred for 40
minutes. The reaction solvent was evaporated under reduced
pressure, and then the obtained residue was dissolved into ethyl
acetate. The solution was washed with saturated sodium
hydrogencarbonate solution, and dried over magnesium sulfate, and
then the solvent was evaporated under reduced pressure. The
generated crystal was collected by filtration to afford the
compound (13-2) (57.2 mg).
[0274] .sup.1H-NMR (CDCl.sub.3): 1.48 (9H, s), 1.68 (3H, s), 2.08
(1H, m), 2.44 (1H, m), 2.65 (1H, m), 2.78 (1H, m), 7.18 (1H, s),
7.32 (1H, s), 7.64 (2H, d, J=8.2 Hz), 7.78 (2H, d, J=8.2 Hz), 8.15
(1H, s), 8.25 (1H, br)
Step 2
[0275] The compound (13-2) (62.3 mg) was dissolved into 4 mol/L
hydrochloric acid-1,4-dioxane and stirred for 24 hours. The
reaction solvent was evaporated under reduced pressure. The
obtained residue was crystallized from methanol/diethyl ether to
afford the compound (1262) (44.7 mg).
[0276] .sup.1H-NMR (DMSO-d.sub.6): 1.67 (3H, s), 2.10 (1H, m),
2.50-2.61 (3H, m), 7.33 (1H, s), 7.74 (1H, s), 7.77 (2H, d, J=8.6
Hz), 7.91 (2H, d, J=8.6 Hz), 8.08 (1H, s), 10.6 (1H, s)
Example 14
The Synthesis of Compound 753
##STR00073##
[0277] Step 1
[0278] The compound (14-1) (46 mg) was dissolved into
dichloromethane (2 ml), then 4-chlorobenzaldehyde (20 mg) and
acetic acid (17 mg) was added at room temperature, and then stirred
for 20 minutes, and then sodium triacetoxyborohydride (45 mg) was
added under cooling with ice-water bath. The mixture was stirred at
room temperature for 14 hours, and then water was added and
extracted with dichloromethane. The organic layer was dried over
sodium sulfate, and then the solvent was evaporated under reduced
pressure. The obtained residue was purified by silica gel column
chromatography to afford the compound (14-2) (52 mg).
[0279] .sup.1H-NMR(CDCl.sub.3): 1.50 (9H, s), 1.64 (3H, s),
2.02-2.10 (1H, m), 2.40 (1H, dt, J=14.0, 4.1 Hz), 2.62-2.74 (2H,
m), 4.30 (2H, s), 6.49 (1H, ddd, J=, 7.8, 2.0, 0.8 Hz), 6.52 (1H,
t, J=2.0 Hz), 6.60 (1H, ddd, J=, 7.8, 2.0, 0.8 Hz), 7.16 (1H, t,
J=7.8 Hz), 7.18-7.33 (4H, m).
Step 2
[0280] To the compound (14-2) (52 mg), 4 mol/L hydrochloric acid in
1,4-dioxane solution (4 ml) was added, then the mixture was stirred
at room temperature for 4 days, and then the reaction solvent was
evaporated under reduced pressure. The obtained residue was
crystallized from methanol/diethyl ether to afford the compound
(753) (42 mg).
[0281] .sup.1H-NMR (DMSO-d.sub.6): 1.58 (3H, s), 2.00 (1H, ddd, J=,
14.3, 11.3, 3.3 Hz),2.49-2.57 (2H, m), 3.07 (1H, dt, J=12.7, 3.3
Hz), 4.27 (2H, s), 6.47 (1H, d, J=8.2 Hz), 6.51-6.53 (2H, m), 7.08
(1H, t, J=8.2 Hz), 7.37 (4H, s), 8.80 (2.H, br).
Example 15
The Synthesis of Compound 1135
##STR00074##
[0282] Step 1
[0283] To a solution of the compound (15-1) (101 mg), 2-propanol
(56 .mu.l), and triphenylphosphine (189 mg) in tetrahydrofuran (2
ml), diethyl azodicarboxylate (2.2 mol/L) in toluene (328 .mu.l)
was added dropwise, then stirred for 1 hour at room temperature.
After the consumption of the compound (15-1), the solvent was
evaporated under reduced pressure. The obtained residue was
purified by silica gel column chromatography to afford the compound
(15-2) (280 mg) as a mixture of triphenylphosphine oxide and
diethyl hydrazodicarboxylate.
Step 2
[0284] To the suspension of 5-chloropyridine-2-carboxylic acid (47
mg) in toluene (1 ml), N,N-dimethylformamide (1 drop) and
tlaionylchloride (91 .mu.l) were added and stirred at 100.degree.
C. for 1 hour. The solvent was evaporated under reduced pressure,
then the obtained residue was dissolved into tetrahydrofuran (1
ml), and then the mixture of the compound (15-2) (280 mg), and
pyridine (194 .mu.l) in tetrahydrofuran (0.5 ml) were added
dropwise at 0.degree. C. and stirred for 10 minutes. After the
consumption of the compound (15-2), water was added and the mixture
was extracted with ethyl acetate. The organic layer was washed with
water, and then the solvent was evaporated under reduced pressure.
The obtained residue was purified by silica gel column
chromatography to afford the compound (15-3) (68 mg) as a mixture
of diethyl hydrazodicarboxylate.
Step 3
[0285] To the compound (15-3) (68 mg) as a mixture of diethyl
hydrazodicarboxylate, 4 mol/L in hydrochloric acid in 1,4-dioxane
solution (1 ml) was added, then the mixture was stirred at room
temperature for 16 hours. After the consumption of the compound
(44), the reaction solvent was evaporated under reduced pressure.
The obtained residue was crystallized from 2-propanol/diethyl ether
to afford the compound (1135) (36 mg).
[0286] .sup.1H-NMR (DMSO-.sub.6): 1.30 (3H, d, J=6.4 Hz), 1.31 (3H,
d, J=6.4 Hz), 1.65 (3H, s), 2.04-2.11 (1H, m), 2.50-2.64 (2H, m),
3.12-3.16 (1H, m), 4.61 (1H, sep, J=6.4 Hz), 6.66 (1H, t, J=2.0
Hz), 7.48 (1H, t, J=2.0 Hz), 7.60 (1H, t, J=2.0 Hz), 8.16 (1H, dd,
J=8.4, 0.8 Hz), 8.22 (1H, dd, J=8.4, 2.4 Hz), 8.79 (1H, dd, J=2.4,
0.8 Hz), 10.33 (1H, a), 10.72 (1H, s).
Example 16
The Synthesis of Compound 161
##STR00075##
[0287] Step 1
[0288] The compound (16-1) (200 mg), palladium acetate (4.7 mg),
and tri-(o-tolyl)phosphine (12.5 mg), were dissolved into
N,N-dimethylformamide (2 ml) under nitrogen atmosphere, then
n-butylamine (0.196 ml), and p-chlorostyrene (0.074 ml) were added
at room temperature with stirring, then the solution was warmed to
80.degree. C., and stirred for 3 hours. After the consumption of
the compound (16-1) (checked by TLC), the reaction mixture was
cooled to room temperature, and saturated ammonium chloride
solution was added to the mixture. The mixture was extracted with
ethyl acetate, the organic layer was washed with water and brine,
and dried over magnesium sulfate, and then the solvent was
evaporated under reduced pressure. The obtained residue was
purified by silica gel column chromatography to afford the compound
(16-2) (213.1 mg).
[0289] .sup.1H-NMR (CDCl.sub.3, 400 MHz): 1.54 (18H, s), 1.64 (3H,
s), 1.96 (1H, ddd, J=13.7, 9.1, 4.0 Hz) 2.10 (1H, ddd, J=13.7, 8.1,
3.4 Hz) 2.86 (1H, ddd, J=12.3, 9.1, 3.4 Hz), 3.03 (1H, ddd, J=12.3,
8.1, 4.0 Hz), 7.08 (1H, d, J=16.4 Hz) 7.15 (1H, d, J=16.4 Hz),
7.27-7.40 (5H, m) 7.44 (2H, d, J=8.8 Hz), 7.58 (1H, 5)
Step 2
[0290] The compound (16-2) (213 mg) was dissolved into 4 mol/L
hydrochloric acid in 1,4-dioxane (5 ml) under cooling with
ice-water bath, then the mixture was warmed to room temperature and
stirred for 63 hours. After the consumption of the compound (16-2)
(checked by LC/MS), the reaction mixture was diluted with diethyl
ether. The generated crystal was collected by filtration, and
washed with diethyl ether to afford the compound (161) (108.6
mg).
[0291] .sup.1H-NMR (DMSO-d.sub.6, 400 MHz): 1.69 (3H, s), 2.08-2.18
(1H, m), 2.56-2.70 (2H, m), 3.13-3.20 (1H, m), 7.23 (1H, d, J=8.0
Hz), 7.31 (1H, d, J=17.0 Hz), 7.35 (1H, d, J=17.0 Hz), 7.45 (2H, d,
J=8.6 Hz), 7.46 (1H, t, 7.6 Hz), 7.59 (1H, d, J=2.0 Hz), 7.61-7.64
(1H, m), 7.64 (2H, d, J=8.6 Hz), 8.53-9.50 (2H, br), 10.67 (1H,
br
Example 17
The Synthesis of Compound 597
##STR00076##
[0292] Step 1
[0293] The solution of compound (17-1) (135 mg),
O-methxylhydroxylamine hydrochloride (39 mg), and potassium acetate
(27 mg) in methanol (3 ml) was stirred at room temperature for 16
hours, then water was added. The mixture was extracted with
dichloromethane, the organic layer was dried over anhydrous sodium
sulfate, then the solvent was evaporated under reduced pressure.
The obtained residue was purified by silica gel column
chromatography to afford the compound (17-2) (110 mg).
[0294] .sup.1H-NMR (CDCl.sub.3): 1.51 (9H, s), 1.70 (3H, s), 2.14
(1H, ddd, J=14.4, 11.4, 3.4 Hz), 2.22 (3H, s), 2.48 (1H, m), 2.65
(1H, dt, J=12.6, 11.4 Hz), 2.78 (1H, ddd, J=12.6, 5.6, 3.4 Hz),
4.00 (3H, 5), 7.30 (1H, d, J=7.8 Hz), 7.38 (1H, d, J=7.8 Hz),
7.54-7.57 (2H, m).
Step 2
[0295] To the compound (17-2) (110 mg), 4 mol/L hydrochloric acid
in 1,4-dioxane (4.5 ml) solution was added and stirred for 4 days
at room temperature, then the reaction solvent was evaporated under
reduced pressure. The obtained residue was crystallized from
methanol/diethyl ether to afford compound (597) (65 mg).
[0296] .sup.1H-NMR (DMSO-d.sub.6): 1.67 (3H, s), 2.08-2.15 (1H, m),
2.20 (3H, s), 2.56-2.64 (2H, m), 3.14-3.17 (1H, m), 3.92 (3H, s),
7.37 (1H, d, J=8.0 Hz), 7.48 (1H, d, J=8.0 Hz), 7.56 (1H, s), 7.62
(1H, d, J=8.0 Hz).
[0297] The other compounds were synthesized in the same way. The
structural formulas and physical constants are shown below.
TABLE-US-00001 TABLE 1 Compound No. Chemical structure 1
##STR00077## 2 ##STR00078## 3 ##STR00079## 4 ##STR00080## 5
##STR00081## 6 ##STR00082## 7 ##STR00083## 8 ##STR00084## 9
##STR00085##
TABLE-US-00002 TABLE 2 10 ##STR00086## 11 ##STR00087## 12
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1042 ##STR01116## 1043 ##STR01117## 1044 ##STR01118##
TABLE-US-00111 TABLE 111 1045 ##STR01119## 1046 ##STR01120## 1047
##STR01121## 1048 ##STR01122## 1049 ##STR01123## 1050 ##STR01124##
1051 ##STR01125## 1052 ##STR01126##
TABLE-US-00112 TABLE 112 1053 ##STR01127## 1054 ##STR01128## 1055
##STR01129## 1056 ##STR01130## 1057 ##STR01131## 1058 ##STR01132##
1059 ##STR01133## 1060 ##STR01134## 1061 ##STR01135## 1062
##STR01136##
TABLE-US-00113 TABLE 113 1063 ##STR01137## 1064 ##STR01138## 1065
##STR01139## 1066 ##STR01140## 1067 ##STR01141## 1068 ##STR01142##
1069 ##STR01143## 1070 ##STR01144## 1071 ##STR01145##
TABLE-US-00114 TABLE 114 1072 ##STR01146## 1073 ##STR01147## 1074
##STR01148## 1075 ##STR01149## 1076 ##STR01150## 1077 ##STR01151##
1078 ##STR01152## 1079 ##STR01153## 1080 ##STR01154##
TABLE-US-00115 TABLE 115 1081 ##STR01155## 1082 ##STR01156## 1083
##STR01157## 1084 ##STR01158## 1085 ##STR01159## 1086 ##STR01160##
1087 ##STR01161## 1088 ##STR01162## 1089 ##STR01163## 1090
##STR01164##
TABLE-US-00116 TABLE 116 1091 ##STR01165## 1092 ##STR01166## 1093
##STR01167## 1094 ##STR01168## 1095 ##STR01169## 1096 ##STR01170##
1097 ##STR01171## 1098 ##STR01172##
TABLE-US-00117 TABLE 117 1099 ##STR01173## 1100 ##STR01174## 1101
##STR01175## 1102 ##STR01176## 1103 ##STR01177## 1105 ##STR01178##
1106 ##STR01179## 1107 ##STR01180##
TABLE-US-00118 TABLE 118 1108 ##STR01181## 1109 ##STR01182## 1110
##STR01183## 1111 ##STR01184## 1112 ##STR01185## 1113 ##STR01186##
1114 ##STR01187## 1115 ##STR01188##
TABLE-US-00119 TABLE 119 1116 ##STR01189## 1117 ##STR01190## 1118
##STR01191## 1119 ##STR01192## 1120 ##STR01193## 1121 ##STR01194##
1122 ##STR01195## 1123 ##STR01196## 1124 ##STR01197##
TABLE-US-00120 TABLE 120 1125 ##STR01198## 1126 ##STR01199## 1127
##STR01200## 1128 ##STR01201## 1129 ##STR01202## 1130 ##STR01203##
1131 ##STR01204## 1132 ##STR01205##
TABLE-US-00121 TABLE 121 ##STR01206## 1133 ##STR01207## 1134
##STR01208## 1135 ##STR01209## 1136 ##STR01210## 1137 ##STR01211##
1138 ##STR01212## 1139 ##STR01213## 1140
TABLE-US-00122 TABLE 122 ##STR01214## 1141 ##STR01215## 1142
##STR01216## 1143 ##STR01217## 1144 ##STR01218## 1145 ##STR01219##
1146 ##STR01220## 1147 ##STR01221## 1148 ##STR01222## 1149
##STR01223## 1150 ##STR01224## 1151 ##STR01225## 1152
TABLE-US-00123 TABLE 123 ##STR01226## 1153 ##STR01227## 1154
##STR01228## 1155 ##STR01229## 1156 ##STR01230## 1157 ##STR01231##
1158 ##STR01232## 1159 ##STR01233## 1160
TABLE-US-00124 TABLE 124 ##STR01234## 1161 ##STR01235## 1162
##STR01236## 1163 ##STR01237## 1164 ##STR01238## 1165 ##STR01239##
1166 ##STR01240## 1167 ##STR01241## 1168
TABLE-US-00125 TABLE 125 ##STR01242## 1169 ##STR01243## 1170
##STR01244## 1171 ##STR01245## 1172 ##STR01246## 1173 ##STR01247##
1174 ##STR01248## 1175 ##STR01249## 1176 ##STR01250## 1177
TABLE-US-00126 TABLE 126 ##STR01251## 1178 ##STR01252## 1179
##STR01253## 1180 ##STR01254## 1181 ##STR01255## 1182 ##STR01256##
1183 ##STR01257## 1184 ##STR01258## 1185 ##STR01259## 1186
##STR01260## 1187 ##STR01261## 1188
TABLE-US-00127 TABLE 127 ##STR01262## 1189 ##STR01263## 1190
##STR01264## 1191 ##STR01265## 1192 ##STR01266## 1193 ##STR01267##
1194 ##STR01268## 1195 ##STR01269## 1196 ##STR01270## 1197
##STR01271## 1198
TABLE-US-00128 TABLE 128 ##STR01272## 1199 ##STR01273## 1200
##STR01274## 1201 ##STR01275## 1202 ##STR01276## 1203 ##STR01277##
1204 ##STR01278## 1205 ##STR01279## 1206 ##STR01280## 1207
TABLE-US-00129 TABLE 129 ##STR01281## 1208 ##STR01282## 1209
##STR01283## 1210 ##STR01284## 1211 ##STR01285## 1212 ##STR01286##
1213 ##STR01287## 1214 ##STR01288## 1215 ##STR01289## 1216
##STR01290## 1217
TABLE-US-00130 TABLE 130 ##STR01291## 1218 ##STR01292## 1219
##STR01293## 1220 ##STR01294## 1221 ##STR01295## 1222 ##STR01296##
1223 ##STR01297## 1224 ##STR01298## 1225 ##STR01299## 1226
TABLE-US-00131 TABLE 131 ##STR01300## 1227 ##STR01301## 1228
##STR01302## 1229 ##STR01303## 1230 ##STR01304## 1231 ##STR01305##
1232 ##STR01306## 1233 ##STR01307## 1234 ##STR01308## 1235
##STR01309## 1236
TABLE-US-00132 TABLE 132 ##STR01310## 1237 ##STR01311## 1238
##STR01312## 1239 ##STR01313## 1240 ##STR01314## 1241 ##STR01315##
1242 ##STR01316## 1243 ##STR01317## 1244 ##STR01318## 1245
##STR01319## 1246
TABLE-US-00133 TABLE 133 ##STR01320## 1247 ##STR01321## 1248
##STR01322## 1249 ##STR01323## 1250 ##STR01324## 1251 ##STR01325##
1252 ##STR01326## 1253 ##STR01327## 1254 ##STR01328## 1255
##STR01329## 1256 ##STR01330## 1257
TABLE-US-00134 TABLE 134 ##STR01331## 1258 ##STR01332## 1259
##STR01333## 1260 ##STR01334## 1261 ##STR01335## 1262 ##STR01336##
1263 ##STR01337## 1264 ##STR01338## 1265 ##STR01339## 1266
##STR01340## 1267 ##STR01341## 1268 ##STR01342## 1269
TABLE-US-00135 TABLE 135 ##STR01343## 1270 ##STR01344## 1271
##STR01345## 1272 ##STR01346## 1273 ##STR01347## 1274 ##STR01348##
1275 ##STR01349## 1276 ##STR01350## 1277 ##STR01351## 1279
##STR01352## 1280 ##STR01353## 1281 ##STR01354## 1282
##STR01355##
TABLE-US-00136 TABLE 136 Com- Melting UV pound Point MS
(.lamda.max: No. (.degree. C.) 1H-NMR (d) (m/z) nm) 1 213.4 305.3 3
285 (dec.) 4 amorphous 219 5 215, 262 6 147-148 8 214-217 9 oil 220
18 181-183 23 213.4 272.2 305.3 24 116-117 26 182-184 30 267.4 33
253.3 305.3 37 amorphous 219, 275 38 240-244 (dec.) 39 285.2 42
187-188 43 218.1 275.7 48 230 275 57 197-198 58 234-240 62 198-201
69 194-195 71 216.9 268.6 73 266-269 77 d in d20-DMSO:1.67(3H, s),
422.543 2.13-2.06(1H, m), 2.63- 2.55(2H, m), 3.16-3.13 (4H, m),
3.65-3.63(2H, m), 4.76-4.73 (2H, m), 7.15-7.08 (2H, m), 7.30(1H, t,
J = 8.0 Hz), 7.35(1H, s), 7.42(1H, t, J = 8.0Hz), 7.60(1H, d, J =
8.0 Hz), 7.69(1H, d, J = 8.0 Hz), 7.73(1H, brs), 7.86(1H, d, J =
8.0 Hz), 10.52(1H, s) 78 .sup.1H-NMR (CDCl.sub.3) 365 d: 1.76 (3H,
s), [M + 1] 2.02 (1H, s), 2.58 (1H, d, J = 14.1 Hz), 2.78 (2H, d, J
= 6.9 Hz), 3.80 (3H, d, J = 13.1 Hz), 4.54 (2H, s), 6.45 (1H, s),
6.55- 6.57 (2H, m), 6.66 (1H, d, J =8.7 Hz), 7:10 (1H, t, J = 7.0
Hz), 7.22 (2H, td, J = 71, 1.4 Hz), 7.34 (1H, d, J= 9.1 Hz), 7.56
(1H, d, J =7.7 Hz). 80 220.4 280.4
TABLE-US-00137 TABLE 137 Com- Melting UV pound Point MS
(.lamda.max: No. (.degree. C.) 1H-NMR (d) (m/z) nm) 85 147-148
1.54(3H, s), 1.75-1.86(1H, m), 2.08-2.18(1H, m), 2.33(3H, s),
2.63-2.74(1H, m), 2.81-2.90(1H, m), 4.36(2H, br), 7.13(2H, d, J =
8.6 Hz), 7.20(2H, d, J = 8.6 Hz) (solvent: CDCl3) 86 141-142 91 372
201 [M + 1] 206 296 216 96 309 97 d in d13-DMS0:1.64(3H, s),
2.03-1.97(1H, m), 2.63 2.57(2H, m), 3.28-3.25(1H, m), 7.22(1H, q, J
= 12.4, 9.0 Hz), 7.82-7.77(2H, m), 8.60(1H, s), 8.79(1H, s),
10.37(1H, s) 99 221-224 101 264-265 104 amorphous 229, 280 113 1.58
(s, 3H), 1.88 (ddd, J = 14.1, 10.9, 3.7 Hz, 1H), 2.24 (ddd, J =
14.1, 5.9, 3.5 Hz, 1H), 2.73 (ddd, J = 12.3,10.9, 3.5 Hz, 1H), 2.88
(ddd, J = 12.3, 5.9, 3.7 Hz, 1H), 3.83 (d, J = 15.4 Hz, 1H), 3.87
(d, J = 15.4 Hz, 1H), 7.02-7.04 (m,1H), 7.25-7.31 (m, 2H), 7.36 (d,
J = 2.0 Hz, 1H), 7.45-7.50 (m, 2H), 8.52 (d, J = 5.2Hz, 1H), 9.43
(s, 1H) (solvent: CDCl3) 114 214.5 306.5 115 d in d6-DMSO:1.47(3H,
s), 1.80-1.74(1H, m, 2.22- 2.18(1H, m), 2.60-2.55(1H, m),
2.96-2.93(1H, m), 6.14(1H, s), 6.93(1H, s), 7.09-7.04(2H, m),
7.63-7.61(1H, m), 7.68-7.66(1H, m), 9.85(1H, s), 11.63(1H, brs) 120
amorphous 213 121 166-167 125 >300 126 amorphous 229, 271 127
280-285 128 159-163 129 219-222 130 128-131 1.56 (3H, s), 1.83-1.93
(1H, m), 344 2.16 (1H, dq, J = [M + 1] 13.85, 3.41 Hz), 2.29 (3H,
s), 2.72-2.77 (1H, m), 2.90-2.94 (1H, m), 4.13 (3H, s), 6.42 (1H,
s), 7.10- 7.14 (1H, m), 7.32 (1H, d, J = 7.91 Hz), 7.37-7.38 (1H,
m), 7.60-7.63 (1H, m). (solvent: CDCl3) 132 147-150 134 228.5
TABLE-US-00138 TABLE 138 Com- Melting UV pound Point MS
(.lamda.max: No. (.degree. C.) 1H-NMR (d) (m/z) nm) 139 287-290
1.77 (s, 3H), g.10 (ddd, J = 14.0, 10.8, 3.6 Hz, 1H), 2.64-2.70
(411, m), 2.76 (td, J = 12.8, 3.6 Hz, 1H), 2.90 (dt, J = 12.8, 3.6
Hz, 1H), 7.05 (ddd, J = 8.0, 2.0, 0.8 Hz, 1H), 7.41 (t, J = 8.0 Hz,
1H), 7.69-7.72 (m, 2H), 8.32 (dd, J = 8.0, 0.8 Hz, 1H), 8.40 (dd, J
= 8.0, 2.0 Hz, 1H), 9.14 (dd, J = 2.0, 0.8 Hz, 1H) (solvent: CDCl3
+ CD3OD) 141 d in d17-DMSO:1.41(3H, s), 1.75-1.70(1H, m), 2.03-
1.99(1H, m), 2.62-2.56(1H, m), 2.94-2.89(1H, m), 3.89(3H, s),
6.88(1H, d, J = 8.8Hz), 7.05(1H, d, J = 7.6 Hz), 7.24(1H, t, J =
8.0 Hz), 7.66-7.63(3H, m), 8.45-8.44(1H, m), 9.90(1H, s) 148
362[M+1] 200 286 208 212 218 262 149 143-145 157 d in d6-DMSO:
1.20(6H, d, J = 6.6 Hz), 1.41(3H, s), 1.65-1.77(1H, m), 1.96-2.07
(1H, m), 2.55-2.63(1H, m), 2.85-2.95(1H, m), 4.04-4.16 (1H, m),
5.79(2H, bs), 7.07(1H, d, J = 8.1 Hz), 7.25(1H, t, J = 8.1 Hz),
7.72- 7.78(3H, m), 7.93(1H, s), 8.64 (1H, s), 9.96(1H, s). 159
amorphous 285 161 247-251 163 amorphous 164 91-96 1.68(s, 3H),
2.07-2.15(m, 1H), 3.13-3.20(m; 1H), 7.12(d, J = 7.6 Hz, 1H), 7.46
(t, J = 7.6 Hz, 1H), 7.90- 7.94(m, 2H), 8.83(br s, 1H), 8.96(br s,
1H), 9.31(br s, 1H), 10.36(s, 1H), 10.86(s, 1H) 165 246-248 166
amorphous 220, 275 176 amorphous 217, 278 178 224-225 181 261.5 189
259 193 266-268 196 212 202 117-118 0.85(3H, t, J = 7.3 Hz),
1.02-1.19(1H, m), 1.34- 1.54(1H, m), 1.72-1.89 (3H, m),
2.04-2.15(1H, m), 2.61-2.82(2H, m), 3.80(3H, s), 4.32(2H, br),
6.85(2H, d, J = 8.9 Hz), 7.18 (2H, d, J = 3.9Hk) (solvent:
CDCl3)
TABLE-US-00139 TABLE 139 Com- Melting UV pound Point MS
(.lamda.max: No. (.degree. C.) 1H-NMR (d) (m/z) nm) 204 205-208
1.64 (d, J = 1.2 Hz, 3H), 1.95 (ddd, J = 14.0, 10.8, 3.6 Hz, 1H),
2.45 (ddd, J = 14.0, 6.4, 3.6 Hz, 1H), 2.75 (ddd, J = 12.4, 10.8,
3.6 Hz, 1H), 2.99 (ddd, J = 12.4, 6.4, 3.6 Hz, 1H), 7.09 (dd, J =
11.6, 8.8 Hz, 1H), 7.47 (dd, J = 7.2, 2.8 Hz, 1H), 8.03 (ddd, J =
8.8, 4.4, 2.8 Hz, 1H), 8.89 (s, 2 H), 9.75 (s, 1H) (solvent: CDCl3)
213 oil 216, 272 214 212.2 292.3 356.5 216 242.7 220 191-193 363 [M
+ 3] 361 [M + 1] 287 285 224 oil 1.58(3H, s), 1.87(1H, ddd, 222 J =
13.9, 10.5, 3.7), 2.13(1H, ddd, J = 13.9, 6.3, 3.7), 2.25(3H, s),
2.68(1H, ddd, J = 12.1, 10.5, 6.2), 2.89(1H, ddd, J = 12.1, 6.3,
3.7), 5.23(2H, s), 7.28-7.48(4H, m), 7.60(1 H, s), 7.75(1H, d, J =
8.0), 8.56(1H, dd, J = 5.0, 1.4),.8.70(1H, d, J = 1.4) (solvent:
CDCl3) 227 213 232 1 H-NMR (CDCl3) d: 1.59 378 (3H, s), 1.83-1.90
(1H, m), [M + 1] 2.35-2.47 (4 H, m), 2.60-2.67 (1H, m), 2.87-2.92
(1H, m), 4.70 (2H, br s), 6.87-6.98 (2H, m), 7.16 (1H, d, J = 6.6
Hz), 7.27 (2H, d, J = 7.8 Hz), 7.61 (2H, d, J = 8.1 Hz). 233 oil
224, 272 235 196-200 238 .sup.1H-NMR (CDCl.sub.3) d: 1.68 (3H, s),
362 1.97-2.00 (1H, m), [M + 1] 2.53 (1H, dt, J = 14.4, 3.7 Hz),
2.63-2.79 (2H, m), 4.52 (2H, s), 6.56-6.66 (3H, m), 7.17 (1H, t, J
= 8.0 Hz), 7.43-7.52 (3H, m), 7.81 (4H, dd, J = 11.6, 5.7 Hz). 241
187-190 1H-NMR (DMSO-d6) d: 1.49 (3H, s), 1.78-1.86 (1H, m),
2.13-2.21 (1H, m), 2.59- 2.67 (1H, m), 2.96-3.02 (1H, m), 7.11 (1H,
t, J = 10.7 Hz), 7.29 (1H, t, J = 7.8 Hz), 7.45 (1H, t, J =7.5 Hz),
7.66 (1H, d, J = 8.8 Hz), 7.74-7.78 (1H, m), 7.80-7.83 (1H, m),
8.21 (1H, d, J = 8.6 Hz), 10.25 (1H, s). 243 182-184 1.46(s, 3H),
1.75-1.83 (m, 1H), 2.08-2.16(m, 1H), 2.55-2.63(m, 1H), 2.92-2.98
(m, 1H), 4.02(s, 3H), 7.11(d, J = 8.0 Hz, 1H), 7.31(t, J = 8.0 Hz,
1H), 7.77(d, J = 8.0 Hz, 1H), 7.82(br s, 1H), 8.41(d, J = 1.2 Hz,
1H), 8.90(d, J = 1.2 Hz, 1H), 10.38(s, 1H) (solvent: CDCl3)
TABLE-US-00140 TABLE 140 Com- Melting UV pound Point MS
(.lamda.max: No. (.degree. C.) 1H-NMR (d) (m/z) nm) 244 222-224 251
351 200 [M + 1] 311 204 275 215 285 255 238-239 256 oil 215, 257
259 amorphous 1.58(3H, s), 2.01(1H, ddd, 229 J = 15.2, 12.2, 3.4),
2.46- 298 2.56(2H, m), 3.07(1H, ddd, J = 13.3, 5.7, 3.5), 4.24(2H,
s), 6.53(1H, d, J = 7.6), 6.59-6.61(2H, m), 7.09-7.12(1H, m),
7.11(2H, d, J = 7.6), 7.24(2H, d, J = 7.6), 8.82(2H, br) (solvent:
DMSO-d6) 263 363 200 [M + 1] 287 284 267 114-115 268 214.5 298.2
271 oil 229, 276 275 (CDCl3) 1.66(3H, d, J = 1.2 Hz), 1.98(1H, ddd,
J = 14.0, 10.4, 3.7 Hz), 2.47(1H, ddd, J = 14.0, 6.7, 3.5 Hz),
2.79(1H, ddd, J = 12.0, 10.4, 3.5 Hz), 3.02(1H, ddd, J = 12,0, 6.7,
3.7 Hz), 4.45 (2H, br), 6.16(2H, br), 7.04 7.11(2H, m), 7.38(1H,
dd, J = 7.2, 2.9 Hz), 7.88(1H, d, J = 2.0 Hz), 7.96(1H, ddd, J =
8.9, 4.2, 2.9 Hz), 9.88(1H, s) 277 216 228 281 279 214.5 292.3 281
amorphous 1.55(3H, s), 233 1.83(1H, ddd, J = 13.9, 301 10.6, 3.9),
2.10(1H, ddd, J = 13.9, 6.5, 3.6), 2.67 (1H, ddd, J = 12.2, 10.6,
3.6), 2.87(1H, ddd, J = 12.2, 6.5, 3.9), 4.49(2H, d, J = 5.6),
4.85(1H, br), 6.38(1H, dt, J = 8.5, 0.9), 6.59(1H, ddd, J = 7.2,
5.2, 0.9), 7.21- 7.24(2H, m), 7.28-7.32 (2H, m), 7.40(1H, ddd, J =
8.5, 7.2, 1.8), 8.11(1H, ddd, J =5.2, 1.8, 0.8) (solvent: CDCl3)
282 146-147 284 181.5 293 1.57 (s, 3H), 1.78-1.89 (m, 1H),
2.10-2.19 (m, 1H), . 2.69 (ddd, J = 11.9, 10.8, 3.5 Hz, 1H),
2.83-2.91 (m, 1H), 7.15-7.35 (m, 5H) (solvent: CDCl3) 299 293.5
TABLE-US-00141 TABLE 141 Com- Melting UV pound Point MS
(.lamda.max: No. (.degree. C.) 1H-NMR (d) (m/z) nm) 301 (CDCl3)
1.53(3H, s), 1.80(1H, ddd, J = 14.0, 10.4, 3.6 Hz), 2.12(1H, ddd, J
= 14.0, 6.0, 3.6 Hz), 2.75(1H, ddd, J = 12.0, 10.4, 3.6 Hz),
2.85(1H, ddd, J = 12,0, 6.0, 3.6 Hz), 3.64(2H, s), 4.32(2H, br),
6.55(1H, ddd, J = 8.0, 2.0, 0.8 Hz), 6.66 (1H, t, J = 2.0 Hz),
6.70(1H, ddd, J = 8.0, 2.0, 0.8 Hz), 7.11 (1H, t, J = 8.0 Hz) 302
122-126 1.41(s, 3H), 1.67-1.76 (m, 1H), 1.98-2.06(m, 1H),
2.55-2.63(m, 1H), 2.86-2.94 (m, 1H), 3.19(s, 6H), 5.75(s, 2H),
7.08(d, J = 8.0 Hz, 1H), 7.26(t, J = 8.0 Hz, 1H), 7.73(d, J = 8:0
Hz, 1H), 7.76(br s, 1H), 8.16(s, 1H), 8.73(s, 1H), 10.00 (s,
1H)(solvent: CDCl3) 306 231, 258, 289 307 1.83 (ddd, J = 13.9,
10.3, 3.6 Hz, 1H), 2.13 (ddd, J = 13.6, 6.2, 3.5 Hz, 1H), 2.53 (s,
3H), 2.66-2.75 (m, 1H), 2.90 (ddd, J = 12.2, 6.3, 3.8 Hz, 1H), 7.09
(d, J = 7.8 Hz, 1H), 7.32 (t, J = 8.0 Hz, 1H), 7.37 (s, 1H), 7.63
(d, J = 7.8 Hz, 1H), 8.79 (s, 1H) (solvent: CDCl3) 308 167-168 309
241-244 319 308.9 329 238-239 330 213.4 263.9 332 212.2 333 154-158
339 217-218 341 amorphous 216 249 342 184-187 344 (DMSO) 1.49(3H,
s), 1.73-1.85 (1H, m), 2.15- 2.28(1H, m), 2.54-2.66(1H, m),
2.92-3.04(1H, m), 5.86(2H, s), 7.03-7.25 (3H, m), 7.40-7.48(2H, m),
7.64-7.78(3H, m), 10.31 (1H, s), 11.74(1H, s) . 353 279.3 364.5 354
102-103 356 amorphous 1.73 (s, 3H), 2.09-2.17 267 (m, 1H), 2.40(s,
3H), 2.65- 2.73 (m, 2H), 3.15-3.23 (m, 1H), 3.81(s, 3H), 7.07 (d, J
= 7.2 Hz, 2H), 7.29 (br s, 1H), 7.36 (d, J = 8.0 Hz, 2H), 7.61 (d,
J = 8.0 Hz, 2H), 7.78 (br s, 1H), 7.90 (d, J = 7.2 Hz, 2H), 8.00
(br s, 1H), 10.32 (s, 11-1)(solvent: DMSO-d6) 357 amorphous 224,
298
TABLE-US-00142 TABLE 142 Com- Melting UV pound Point MS
(.lamda.max: No. (.degree. C.) 1H-NMR (d) (m/z) nm) 358 1.57 (3 H,
s), 1.80-1.91 360 (1H, m), 2.15-2.18 (1H, m) [M + 1] 2.70-2.94 (2H,
m), 3.94 (3H, s), 4.67 (2H, s), 6.75 (1H, s), 7.05-7.08 (1H, m),
7.31 (1H, t, J = 7.91 Hz), 7.53 (1H, t, J = 1.98 Hz), 7.64-7.67
(1H, m), 8.64 (1H, s).(solvent: CDCl3) 359 212-214 1.46(s, 3H),
1.73-1.83(m, 1H), 2.13-2.20(m, 1H), 2.54-2.61(m, 1H), 2.62(s, 3H),
2.93-3.00(m, 1H), 5.84(br s, 2H), 7.12(dd, J = 12.0, 8.8 Hz, 1H),
7.73- 7.78(m, 1H), 7.81(dd, J = 72, 2.4 Hz, 1H), 8.68(s 1H),
9.13(s, 1H), 10.59 (s, 1H)(solvent: CDCl3) 360 amorphous 222 361
280.4 364 oil 344 227, 271 [M + 1] 367 (CDCl3) 1.78(3H, s), 2.07(1
H, ddd, J = 14.0, 12,4, 3.6 Hz), 2.61(1 H, br d, J = 14.0 Hz),
2.84(1 H, td, J = 12.4, 3.2 Hz), 2.94(1H, td, J = 12.4, 3.6 Hz),
4.08(3H, s), 7.07(1H, ddd, J = 8.0, 2.0, 0.8 Hz), 7.40(1 H, t, J =
8.0 Hz), 7.63(1H, ddd, J = 8.0, 2.0, 0.8 Hz), 7.74(1H, t, J = 2.0
Hz), 8.18(1H, d, J = 1.2 Hz), 9.02(1H, d, J = 1.2 Hz), 9.56(1H, s)
375 217 380 181-182 0.86 (t, J = 7.2 Hz, 3H), 1.82-1.98 (m, 3H),
2.24 (br, 1H), 2.74 (td, J = 12.0, 3.6 Hz, 1H), 2.84 (dt, J =12.0,
4.0 Hz, 1H), 7.08 (ddd, J = 8.0, 2.0, 0.8 Hz, 1H), 7.37 (t, J = 8.0
Hz, 1H), 7.58 (t, J = 2.0 Hz, 2H), 7.76 (ddd, J = 8.0, 2.0, 0.8 Hz,
1H), 7.88 (dd, J = 8.4, 2.4 Hz, 1H), 8.25 (dd, J = 8.4, 0.8 Hz,
1H), 8.57 (dd, J = 2.4,0.8 Hz, 1H), 9.84 (s, 1H) (solvent: CDCl3)
383 oil 225, 269, 288 389 amorphous 292 393 213.4 316.0 395
amorphous 217, 269 396 211-213 1.64 (s, 3H), 1.96 (ddd, J = 14.0,
10.4, 4.0 Hz, 1H), 2.44 (ddd, J = 14.0, 6.8, 3.6 Hz, 1H), 2.75
(ddd, J = 12.4, 10.4, 3.6 Hz, 1H), , 2.99 (ddd, J = 12.4, 6.8, 4.0
Hz, 1H), 4.50 (2H, br), 7.08 (dd, J = 11.6, 8.8 Hz, 1H), 7.45 (dd,
J = 6.8, 2.8 Hz, 1H), 8.01 (ddd, J = 8.8, 4.4, 2.8 Hz, 1H), 8.16
(ddd, J = 8.0, 2.0, 0.8 Hz, 1H), 8.43 (d, J = 8.0 Hz, 1H), 8.89
(dd, J = 2.0.0.8 Hz, 1H), 9.91 (s, 1H) (solvent: CDCl3) 401
106-107
TABLE-US-00143 TABLE 143 Com- Melting UV pound Point MS
(.lamda.max: No. (.degree. C.) 1H-NMR (d) (m/z) nm) 405 192-194
1.41(s, 3H), 1.68-1.77(m, 1H), 1.96-2.05(m, 1H), 2.55-2.63(m, 1H),
2.88-2.95 (m, 1H), 4.15(s, 3H), 5.74(s, 2H), 7.13(d, J = 8.0 Hz,
1H), 7.29(t, J = 8.0 Hz, 1H), 7.44(d, J = 8.8 Hz, 1H), 7.75(d, J =
8.0 Hz, 1H), 7.86(br s, 1H), 8.20(d, J = 8.8 Hz, 1H), 10.73(s, 1H)
(solvent: CDCl3) 406 276.9 408 221-224 1.74 (3H, s) 2.28 (2H, m)
2.67 (2H, m) 2.91 (3H, s) 3.82 (3H, s), 6.90 (2H, d, J = 9.0), 7.19
(2H, d, J = 9.0) (solvent: CDCl3) 409 oil 215 410 178-182 1.37(d, J
= 6.0 Hz, 6H), 1.42 (5, 3H), 1.70-1.78(m, 1H), 2.00-2.08(m, 1H),
2.53-2.61(m, 1H), 2.88- 2.95(m, 1H), 5.36(quintet, J = 6.0 Hz, 1H),
7.11(d, J = 8.0 Hz 1H), 7.29(t, J = 8.0 Hz, 1H), 7.75(d, J = 8.0
Hz, 1H), 7.80(br s, 1H), 8.32 (d, J = 1.2 Hz, 1H), 8.87(d, J = 1.2
Hz, 1H), 10.32(s, 1H) (solvent: CDCl3) 411 218, 264 413 251-254 415
amorphous 226, 290 417 137-139 422 (CDCl3) 1.45(3H, s),
1.70-1.84(1H, m), 1.96- 2.04(1H, m), 2.88-2.96 (1H, m),
3.04-3.14(1H, m), 6.86(1H, d, J = 15.9Hz), 6.42(1H, d, J = 15.9Hz),
7.22- 7.41(5H, m) 426 211.0 312.4 427 216 429 oil 211 259 430
(DMSO) 1.07(3H, s), 1.53-1.66(4H, m), 2.50- 2.70(2H, m),
2.92-3.10(2H, m), 5.48(1H, s), 7.11- 7.21(3H, m), 7.23-7.29(2H, m)
432 oil 216, 272 436 254-256 441 161-165 443 .sup.1H-NMR
(CDCl.sub.3) d: 1.55 (4H, s), 362 1.74-1.80 (1H, m), [M + 1]
2.13-2.17 (1H, m), 2.68-2.73 (2H, m), 4.33 (1H, br s), 4.48 (2H, d,
J = 4.0 Hz), 4.76 (2H, t, J = 20.1 Hz), 6.52 (1H, dd, J = 7.9, 1.8
Hz), 6.63-6.65 (2H, m), 7.13 (1H, t, J = 1.8 Hz), 7.45-7.51 (2H,
m), 7.79-7.82 (4H, m).
TABLE-US-00144 TABLE 144 Compound Melting Point MS UV No. (.degree.
C.) 1H-NMR (d) (m/z) (.lamda.max: nm) 444 214-215 1.41(s, 3H),
1.66-1.76(m, 1H), 1.97-2.05(m, 1H), 2.53-2.62(m, 1H), 2.62(s, 3H),
2.86-2.93(m, 1H), 5.79(br s, 2H), 7.12(d, J = 8.0 Hz, 1H), 7.28(t,
J = 8.0 Hz, 1H), 7.74(d, J = 8.0 Hz, 1H), 7.81(br s, 1H), 8.68(s,
1H), 9.14(s, 1H), 10.52(s, 1H) (solvent: CDCl3) 445 92-93 446 oil
1.57(3H, s), 1.86(1H, ddd, J = 13.9, 10.4, 3.7), 219 2.13(1H, ddd,
J = 13.9, 6.5, 3.6), 2.25(3H, s), 252 2.35(3H, s), 2.70(1H, ddd, J
= 12.2, 10.4, 3.6), 2.89(1H, ddd, J = 12.2, 6.5, 3.7), 4.35(2H,
br), 5.19(2H, s), 7.17(2H, d, J = 8.0), 7.31-7.34(4H, m), 7.50(1H,
ddd, J = 5.8, 3.0, 1.8), 7.55-7.60(1H, m) (solvent: CDCl3) 448 d in
d6-DMSO: 1.41(3H, s), 1.67-1.75(1H, m), 1.98- 2.05(1H, m),
2.52-2.61(1H, m), 2.86-2.94(1H, m), 5.79(2H, bs), 7.14(1H, d, J =
7.8 Hz), 7.30(1H, t, J = 7.8 Hz), 7.73(1H, bd, J = 7.8 Hz),
7.81(1H, t, J = 1.8 Hz), 8.94(1H, m), 9.11(1H, m), 10.63(1H, bs).
452 132-134 456 147-149 457 153-155 465 194.6 466 211 470 281
(dec.) 482 1.60 (s, 3H), 1.91 (ddd, J = 14.0, 10.8, 4.0 Hz, 1H),
2.23 (ddd, J = 14.0, 6.4, 3.6 Hz, 1H), 2.77 (ddd, J = 12.0, 10.8,
3.6 Hz, 1H), 2.93 (ddd, J = 12.0, 6.4, 4.0 Hz, 1H), 7.16 (ddd, J =
8.0, 2.0, 0.8 Hz, 1H), 7.37 (t, J = 8.0 Hz, 1H), 7.61 (t, J = 2.0
Hz, 1H), 7.75 (ddd, J = 8.0, 2.0, 0.8 Hz, 1H), 8.14 (d, J = 1.6 Hz,
1H), 8.80(d, J = 1.6 Hz, 1H), 9.79 (s, 1H) (solvent: CDCl3) 483
224-227 211, 289 490 1.64 (3H, s) 2.03-2.12 (1H, m) 2.49-2.62 (m)
3.12- 3.16 (1H m) 7.22 (1H, dd, J = 4.2 Hz) 7.27 (1H, bs) 7.75 (1H
bs) 7.87 (1H, dd, J = 4.2 Hz) 8.04 (1H, s) 8.12 (1H, dd, J = 4.2
Hz) 10.64 (1H, s) 10.72 (1H, s) (solvent: DMSO-d6) 1.58 (s, 3H),
1.85-1.96 (m, 1H), 2.15-2.24 (m, 1H), 2.50 (s, 3H), 2.67 (s, 3H),
2.71-2.81 (m, 1H), 2.90- 491 2.98 (m, 1H), 7.13 (d, J = 6.2 Hz,
1H), 7.35 (t, J = 8.0 Hz, 1H), 7.40 (s, 1H), 7.55 (d, J = 7.6 Hz,
1H) (solvent: CDCl3) 493 216
TABLE-US-00145 TABLE 145 Compound Melting Point MS UV No. (.degree.
C.) 1H-NMR (d) (m/z) (.lamda.max: nm) 494 d in d6-DMSO: 1.37(3H,
s), 1.62-1.70(1H, m), 2.0- 366[M + 1] 2.12(1H, m), 2.40-2.50(1H,
m), 2.79-2.83(1H, m), 3.82(3H, s), 4.52(2H, d, J = 5.4 Hz),
6.19(1H, m), 6.54(1H, d, J = 7.8 Hz), 6.62(1H, d, J = 8.1 Hz), 6.75
(1H, s), 7.01(1H, t, J = 8.1 Hz), 7.14-7.25(2H, m), 7.51(1H, d, J =
8.1 Hz), 7.60(1H, d, J = 7.5 Hz). 496 152-154 497 d in
d6-DMSO:1.48(3H, s), 1.83-1.77(1H, m), 2.61- 2.56(1H, m),
2.99-2.95(1H, m), 3.86(3H, s), 6.07(1H, s), 6.95(1H, s),
7.03-7.02(1H, m), 7.09-7.06(1H, m), 7.58-7.57(1H, m), 7.64-7.62(1H,
m), 9.83(1H, s) 498 122-125 500 181-184 501 155-156 502 137-138 504
209-219 511 211-214 1.58 (s, 3H), 1.90 (ddd, J = 14.0, 10.0, 3.6
Hz, 1H), 2.15 (ddd, J = 14.0, 6.8, 3.6 Hz, 1H), 2.77 (ddd, J =
12.4, 10.0, 3.6 Hz, 1H), 2.94 (ddd, J = 12.4, 6.8; 3.6 Hz, 1H),
4.34 (2H, br), 7.17 (ddd, J = 8.0, 2.0, 0.8 Hz, 1H), 7.38 (t, J =
8.0 Hz, 1H), 7.50 (d, J = 2.0 Hz, 1H), 7.56 (td, J = 2.0 Hz, 1H),
7.70 (ddd, J = 8.0, 2.0, 0.8 Hz, 1H), 8.08 (d, J = 1.6 Hz), 9.70
(s, 1H) (solvent: CDCl3) 515 204-206 1.61 (s, 3H), 1.90 (ddd, J =
14.0, 10.8, 3.6 Hz, 1H), 2.22 (ddd, J = 14.0, 6.0, 3.6 Hz, 1H),
2.77 (ddd, J = 12.4, 10.8, 3.6 Hz, 1H), 2.93 (ddd, J = 12.4, 6.0,
3.6 Hz, 1H), 7.15 (ddd, J = 8.0, 2.0, 0.8 Hz, 1H), 7.39 (t, J = 8.0
Hz, 1H), 7.65 (t, J = 2.0 Hz, 1H), 7.80 (ddd, J = 8.0, 2.0, 0.8 Hz,
1H), 8.89 (s, 2H), 9.77 (s, 1H) (solvent: CDCl3) 516 292.3 525
105-106 528 173-174 1.60 (s, 3H), 1.89 (ddd, J = 14.0, 10.8, 3.6
Hz, 1H), 2.22 (ddd, J = 14.0, 6.4, 3.2 Hz, 1H), 2.44 (s, 3H), 2.77
(ddd, J = 12.4, 10.8, 3.2 Hz, 1H), 2.91 (ddd, J = 12.4, 6.4, 3.6
Hz, 1H), 4.50 (br, 2H), 7.11 (ddd, J = 8.0, 2.0, 0.8 Hz, 1H), 7.35
(t, J = 8.0 Hz, 1H), 7.67- 7.71 (m, 2H), 7.74 (ddd, J = 8.0, 2.0,
0.8 Hz, 1H), 8.18 (d, J = 8.4 Hz, 1H), 8.44(d, J = 1.6 Hz, 1H),
9.98 (s, 1H) (solvent: CDCl3) 532 305.3 533 180-181 534 201-204 549
100-101 551 139-141 554 216
TABLE-US-00146 TABLE 146 Compound Melting Point MS UV No. (.degree.
C.) 1H-NMR (d) (m/z) (.lamda.max: nm) 556 (CDCl3) 1.67(3H, d, J =
1.2 Hz), 1.98(1H, ddd, J = 14.0, 10.4, 3.7 Hz), 2.47(1H, ddd, J =
14.0, 6.7, 3.5 Hz), 2.79(1H, ddd, J = 12.0, 10.4, 3.5 Hz), 3.02(1H,
ddd, J = 12,0, 6.7, 3.7 Hz), 4.11(3H, s), 4.45(2H, br), 7.10(1H,
dd, J = 11.7, 8.8 Hz), 7.41(1H, dd, J = 6.9, 2.8 Hz), 8.04(1H, ddd,
J = 8.8, 4.0, 2.8 Hz), 8.20(1H, d, J = 1.4 Hz); 9.06(1H, d, J = 1.4
Hz), 9.51(1H, s) 558 358[M + 1] 200 282 559 224 560 d in
d10-DMSO:1.72(3H, s), 2.12-2.05(1H, m), 2.71- 2.61(2H, m),
3.22-3.19(1H, m), 6.52(1H, s), 7.26(1H, q, J = 11.6, 9.2 Hz),
7.55(1H, s), 7.66-7.62(2H, m), 7.79-7.77(1H, m), 7.90-7.88(1H, m),
8.07(1H, s), 10.42(1H, s), 11.55(1H, s) 561 235-240 567 oil 212 570
186-187 573 112-114 577 d in d19-DMSO:2.14-2.07(1H, m),
2.88-2.70(3H, m), 3.07, 3.26(2H, abq, J = 12.0 Hz), 3.73(3H, s),
5.40(2H, s), 6.51(1H, s), 6.85(1H, d, J = 12.0 Hz), 7.34(1H, d, J =
8.0 Hz) 584 152-153 586 d in d7-DMSO:1.71(3H, s), 2.10-2.04(1H, m),
2.69- 2.59(2H, m), 3.20-3.17(1H, m), 4.00(3H, s), 7.13(1H, d, J =
7.4 Hz), 7.33-7.23(3H, m), 7.55(1H, d, J = 8.4 Hz), 7.72-7.68(1H,
m), 7.92-7.90(1H, m), 10.60(1H, s) 588 155-156 593 oil 226 595 oil
1.56(3H, s), 1.86(1H, ddd, J = 13.9, 10.1, 3.7), 220 2.11(1H, ddd,
J = 13.9, 6.6, 3.6), 2.32(3H, s), 2.70(1H, ddd, J = 12.3, 10.1,
3.6), 2.90(1H, ddd, J = 12.3, 6.6, 3.7), 5.25(2H, s), 7.29-7.35(4H,
m), 7.47(1H, dt, J = 6.8, 2.0), 7.56-7.58(1H, m), 8.59(2H, d, J =
6.0) (solvent: CDCl3) 596 215 597 192-194 600 178-180 601 181-192
1.59 (3H, s), 1.85-1.95 (1H, m), 2.15-2.22 (1H, m), 375[M + 1]
2.72-2.78 (1H, m), 2.88-2.96 (1H, m), 4.31 (3H, s), 7.13 (1H, d, J
= 7.25 Hz), 7.33 (1H, t, J = 7.91 Hz), 7.59 (1H, s), 7.68 (1H, d, J
= 7.91 Hz), 7.75 (1H, s). (solvent: CDCl3) 602 272-285 (dec.)
TABLE-US-00147 TABLE 147 Compound Melting Point MS UV No. (.degree.
C.) 1H-NMR (d) (m/z) (.lamda.max: nm) 605 230-233 1.63 (s, 3H),
1.94 (ddd, J = 14.0, 10.4, 3.6 Hz, 1H), 2.44 (ddd, J = 14.0, 6.4,
3.6 Hz, 1H), 2.75 (ddd, J = 12.4, 10.4,3.6 Hz, 1H),, 2.98 (ddd, J =
12.4, 6.4, 3.6 Hz, 1H), 4.50 (2H, br), 7.06 (dd, J = 11.6, 8.8 Hz,
1H), 7.40 (dd, J = 7.2, 2.8 Hz, 1H), 7.59 (ddd, J = 8.8, 8.0, 2.8
Hz, 1H), 7.99 (ddd, J = 8.8, 4.4, 2.8 Hz, 1H), 8.33 (dd, J = 8.8,
4.4 Hz, 1H), 8.45 (d, J = 2.8 Hz, 1H), 9.78 (s, 1H) (solvent:
CDCl3) 608 213.4 304.1 611 200-202 613 238 618 1.74(s, 3H),
1.97-2.07(m, 1H), 2.45-2.55(m, 1H), 2.77-2.85(m, 1H), 2.84(s, 3H),
2.90-2.96(m, 1H), 7.11(d, J = 8.0 Hz, 1H), 7.42(t, J = 8.0 Hz, 1H),
7.57(d, J = 8.8 Hz, 1H), 7.70(d, J = 8.0 Hz, 1H), 7.74(br s, 1H),
8.29(d, J = 8.8 Hz, 1H), 10.12(s, 1H) (solvent: CDCl3) 620 212, 253
625 107-109 629 d in d14-DMSO:1.66(3H, s), 2.11-2.05(1H, m),
2.37(3H, s), 2.63-2.53(2H, m), 3.14-3.11(1H, m), 7.08-7.04(2H, t, J
= 7.0 Hz), 7.43-7.35(4H, m), 7.83- 7.80(2H, m), 10.39(1H, s),
11.69(1H, s) 630 1.28 (3H, t, J = 7.7 Hz), 1.96 (1H, ddd, J = 3.8,
9.9, 301[M + 1] 13.7 Hz), 2.19 (1H, ddd, J = 3.5, 7.0, 13.7 Hz),
2.74 (1H, ddd, J = 3.6, 9.9, 12.2 Hz), 2.93 (1H, ddd, J = 3.8, 7.0,
12.1 Hz), 4.05-4.49 (4H, m), 7.40-7.50 (3H, m), 7.77-7.86 (1H, m)
(solvent: CDCl3) 634 (CDCl3) 1.67(3H, d, J = 1.2 Hz), 1.98(1H, ddd,
J = 14.0, 10.4, 3.7 Hz), 2.47(1H, ddd, J = 14.0, 6.7, 3.5 Hz),
2.79(1H, ddd, J = 12.0, 10.4, 3.5 Hz), 3.02(1H, ddd, J = 12,0, 6.7,
3.7 Hz), 4.11(3H, s), 4.45(2H, br), 7.10(1H, dd, J = 11.7, 8.8 Hz),
7.41(1H, dd, J = 6.9, 2.8 Hz), 8.04(1H, ddd, J = 8.8, 4.0, 2.8 Hz),
8.20(1H, d, J = 1.4 Hz), 9.06(1H, d, J = 1.4 Hz), 9.51(1H, s) 636
118-119 637 229, 275 643 155-157 1.60 (s, 3H), 1.90 (ddd, J = 14.0,
10.4, 3.6 Hz, 1H), 2.20 (ddd, J = 14.0, 6.8, 3.6 Hz; 1H), 2.77
(ddd, J = 12.0, 10.4, 3.6 Hz, 1H),, 2.93 (ddd, J = 12.0, 6.8, 3.6
Hz, 1H), 4.59 (brs, 1H), 7.16 (ddd, J = 8.0, 2.0, 0.8 Hz, 1H), 7.37
(t, J = 8.0 Hz, 1H), 7.67 (t, J = 2.0 Hz, 1H), 7.71 (ddd, J = 8.0,
2.0, 0.8 Hz, 1H), 7.87 (dd, J = 10.0, 1.2 Hz, 1H), 8.73 (d, J = 1.2
Hz, 1H), 9.74 (s, 1H) (solvent: CDCl3) 644 201-203
TABLE-US-00148 TABLE 148 Compound Melting Point MS UV No. (.degree.
C.) 1 H-NMR (d) (m/z) (.lamda.max: nm) 645 oil 1.58(3H, s),
1.87(1H, ddd, J = 14.0, 10.4, 3.6), 222 2.16(1H, ddd, J = 14.0,
6.3, 3.5), 2.34(3H, s), 2.70(1H, ddd, J = 12.3, 10.4, 3.5),
2.90(1H, ddd, J = 12.3, 6.3, 3.6), 5.38(2H, s), 7.18-7.33(3H, m),
7.42(1H, d, J = 8.0), 7.49-7.60(2H, m), 7.69(1H, dt, J = 7.7, 1.9),
8.59(1H, ddd, J = 4.9, 1.9, 1.1) (solvent: CDCl3) 649 161-162 651
193-196 1.59 (s, 3H), 1.90 (ddd, J = 14.0, 10.4, 3.6 Hz, 1H), 2.18
(ddd, J = 14.0, 6.4, 3.6 Hz, 1H), 2.76 (ddd, J = 12.4, 10.4, 3.6
Hz, 1H),, 2.93 (ddd, J = 12.4, 6..4, 3.6 Hz, 1H), 4.42 (br, 2 H),
7.17 (ddd, J = 8.0, 2.0, 0.8 Hz, 1H), 7.38.(t, J = 8.0 Hz, 1H),
7.64 (t, J = 2.0 Hz, 1H), 7.77 (ddd, J = 8.0, 2.0, 0.8 Hz, 1H),
8.20 (dd, J = 8.0, 2.0 Hz, 1H), 8.44 (dd, J = 8.0, 0.8 Hz, 1H),
8.91 (dd, J = 2.0, 0.8 Hz, 1H), 9.87 (s, 1H) (solvent: CDCl3) 652 d
in d21-DMSO:1.67(3H, s), 2.14-2.07(1H, m), 2.62- 2.57(2H, m),
3.17-3.14(1H, m), 5.74(1H, s), 7.14(1H, d, J = 8.0 Hz), 7.44(1H, t,
J = 8.0 Hz), 7.85- 7.81(2H, m), 8.01(1H, d, J = 12.0 Hz), 8.16(1H,
d, J = 8.0 Hz), 8.77(1H, s), 10.95(1H, s) 653 193-194 654 oil 257
657 199-203 660 amorphous 223, 266 661 d in d9-DMSO:1.30(3H, t, J =
7.0 Hz), 1.69(3H, s), 2.10-2.04(1H, m), 2.20(3H, s), 2.67-2.62(2H,
m), 3.20-3.17(1H, m), 4.40(2H, q, J = 14.0, 7.0 Hz), 6.83(1H, s),
7.25(1H, q, J = 12.0, 9.0 Hz), 7.62- 7.61(1H, m), 7.85-7.83(1H, m),
10.42(1H, s) 664 amorphous 225, 267 667 amorphous 226 673 oil 224
677 amorphous 216 680 159-160 1.63(3H, 5), 1.65-1.80(1H, m),
2.53-2.64(1H, m), 2.75-2.88(2H, m), 3.83(3H, s), 4.32(2H, br),
6.87- 6.96(2H, m), 7.19-7.33(2H, m) (solvent : CDCl3) 681 d in
d6-DMSO: 1.43(3H, s), 1.66-1.74(1H, m), 2.02- 338[M + 1] 2.07(1H,
m), 2.56-2.63(1H, m), 2.85-2.90(1H, m), 5.80(2H, bs), 6.91(1H, d, J
= 7.8 Hz), 6.96-6.98(2H, m), 7.25(1H, t, J = 7.8 Hz), 7.2-7.36(2H,
m), 7.40(1H, m), 7.89-7.92(1H, m), 9.42(1H, bs), 10.78(1H, bs). 683
166-168
TABLE-US-00149 TABLE 149 Compound Melting Point MS UV No. (.degree.
C.) 1H-NMR (d) (m/z) (.lamda.max: nm) 687 164-167 1.60 (3H, s),
1.84-1.95 (1H, m), 2.21-2.26 (1H, m), 388[M + 1] 2.73-2.94 (2H, m),
3.92 (3H, s), 4.25 (3H, s), 7.10 (1H, d, J = 7.58 Hz), 7.34 (1H, t,
J = 7.91 Hz), 7.40 (1H, s), 7.57 (1H, br s), 7.66 (1H, d, J = 7.91
Hz), 8.67 (1H, s). (solvent: CDCl3) 692 (CDCl3) 1.50(3H, s),
1.75-1.88(1H, m), 2.00- 2.10(1H, m), 2.91-2.99(1H, m),
3.08-3.18(1H, m), 6.21(1H, d, J = 15.9 Hz), 6.59(1H, d, J = 15.9
Hz), 7.42- 7.47(3H, m), 7.59(1H, dd, J = 8.6, 2,0 Hz), 7.74-
7.83(4H, m) 698 269 700 177-178 701 1.61(s, 3H), 1.90(m, 1H),
2.25(m, 1H), 2.81(m, 1H), 2.92(m, 1H), 3.86(s, 3H), 6.71(t-like, J
= 1.8 Hz, 1H), 7.12(t-like, J = 1.8 Hz, 1H), 7.53(t-like, J = 1.8
Hz, 1H), 7.89(dd, J = 8.3 Hz, 2.4 Hz, 1H), 8.24(d, J = 8.3 Hz, 1H),
8.58(d, J = 2.4 Hz, 1H), 9.85(br, 1H) (solvent: CDCl3) 702 1H-NMR
(CDCl3) d: 1.65 (3H, s), 1.91-1.98 (1H, m), 2.57-2.62 (1H, m),
2.68-2.75 (1H, m), 2.92-2.97 (1H, m), 4.18 (3H, s), 6.82 (1H, br
s), 7.02-7.08 (1H, m), 7.28-7.32 (1H, m), 7.44 (1H, s), 7.92-7.96
(1H, m). 707 167-174 709 99-100 0.82(3H, t, J = 7.3 Hz),
1.72-1.90(3H, m), 2.06- 2.15(1H, m), 2.61-2.82(2H, m), 3.80(3H, s),
4.36(2H, br), 6.86(2H, d, J = 8.9 Hz), 7.17(2H, d, J = 8.9 Hz)
(solvent: CDCl3) 717 157-162 1.58 (s, 3H), 1.90 (ddd, J = 14.0,
10.4, 3.6 Hz, 1H), 2.15 (ddd, J = 14.0, 6.8, 3.6 Hz, 1H), 2.76
(ddd, J = 12.4, 10.4, 3.6 Hz, 1H), 2.94 (ddd, J = 12.4, 6.8, 3.6
Hz, 1H), 3.49 (1H, S), 3.76 (2H, br), 7.17 (ddd, J = 8.0, 2.0, 0.8
Hz, 1H), 7.36 (t, J = 8.0 Hz, 1H), 7.38 (d, J = 1.6 Hz, 1H), 7.50
(t, J = 2.0 Hz, 1H), 7.73 (ddd, J = 8.0, 2.0, 0.8 Hz, 1H), 8.22 (d,
J = 2.4 Hz), 9.26 (d, J = 2.4 Hz, 1H), 10.12 (s, 1H) (solvent:
CDCl3) 719 oil 226 254 720 133-138 725 amorphous 1.62 (s, 3H),
1.96-2.03(m, 1H), 2.38-2.49 (m, 1H), 265 2.63-2.71 (m, 1H),
3.05-3.12 (m, 1H), 6.73 (dd, J = 3.2, 1.6 Hz, 2H), 7.35(d, J = 3.2
Hz, 1H), 7.37 (br s, 1H), 7.57 (d, J = 3.4 Hz, 2H), 7.67 (d, J =
8.4 Hz, 2H), 7.77 (br s, 1H), 7.96(br s, 1H), 8.01(br s, 1H), 10.35
(s, 1H) (solvent: DMSO-d6) 728 179-182 729 167-169
TABLE-US-00150 TABLE 150 Compound Melting Point MS UV No. (.degree.
C.) 1H-NMR (d) (m/z) (.lamda.max: nm) 730 211.0 289.9 731 91-94 732
amorphous 211 735 166-168 737 1H-NMR (CDCl3) d: 1.59 (3H, s),
1.87-1.94 (1H, m), 2.47-2.53 (1H, m), 2.67-2.73 (1H, m), 2.93-2.99
(1H, m), 4.10 (3H, s), 6.62 (1H, s), 7.04 (1H; t, J = 10.2 Hz),
7.33 (1H, d, J = 4.3 Hz), 7.85 (1H, br s). 738 181-183 739 285 740
250 (dec.) 743 148-150 1.60 (s, 3H), 179-2.93 (m, 4H), 4.48 (2H,
br); 7.09 (d, J = 2.0 Hz, 1H), 7.12 (ddd, J = 7.6, 2.0, 0.8 Hz,
1H), 7.18 (t, J = 2.0 Hz, 1H), 7.36 (d, J = 7.6, 2.0, 0.8 Hz, 1H),
7.43 (t, J = 7.6 Hz, 1H), 8.21(d, J = 2.0 Hz) (solvent: CDCl3) 744
d in d8-DMSO:1.47(3H, s), 1.82-1.78(1H, m), 2.22- 2.18(1H, m),
2.62-2.56(1H, m), 3.00-2.96(1H, m), 6.79(1H, s), 6.63(1H, s),
7.08-7.03(1H, m), 7.51(1H, s), 7.64-7.57(2H, m), 9.57(1H, s),
11.25(1H, s) 753 amorphous 225, 299 756 110-111 1.55(3H, s),
1.76-1.87(1H, m), 2.08-2.17(1H, m), 2.35(3H, s), 2.65-2.76(1H, m),
2.82-2.92(1H, m), 4.35(2H, br), 7.01-7.25(4H, m) (solvent: CDCl3)
758 156-157 766 336[M + 1] 203 260 212 767 98-100 768 1.60 (3H, d,
J = 1.3 Hz), 1.89-1.99 (1H, m), 2.29 362[M + 1] 213 (3H, s),
2.37-2.42 (1H, m), 2.70-2.75 (1H, m), 2.96- 263 3.00(1H, m), 4.12
(3H, s), 6.39 (1H, s), 7.04 (1H, dd, J = 11.5, 8.9 Hz), 7.18 (1H,
dd, J = 6.9, 2.6 Hz), 7.60(1H, s), 7.82-7.86 (1H, m). (solvent:
CDCl3) 771 417[M + 1] 201 341 774 .sup.1H-NMR (CDCl3) d: 1.77 (3H,
s), 2.11-2.21 (1H, m), 400[M + 1] 2.71-2.80 (1H, m), 2.87-2.99 (2H,
m), 6.91 (1H, d, J = 6.9 Hz), 7.28 (2H, s), 7.47 (1H, t, J = 8.1
Hz), 7.75 (1H, t, J = 8.6 Hz), 8.04 (1H, dd, J = 8.6, 2.3 Hz), 8.29
(1H, d, J = 8.2 Hz), 8.46 (1H, d, J = 2.2 Hz).
TABLE-US-00151 TABLE 151 Compound Melting Point MS UV No. (.degree.
C.) 1H-NMR (d) (m/z) (.lamda.max: nm) 781 1.63 (s, 3H), 1.92 (ddd,
J = 14.0, 10.8, 4.0 Hz, 1H), 2.29 (m, 1H), 2.78 (ddd, J = 12.4,
10.8, 3.6 Hz, 1H),, 2.91 (ddd, J = 12.4, 6.4, 4.0 Hz, 1H), 3.94
(3H, s), 7.09 (ddd, J = 8.0, 2.0, 0.8 Hz, 1H), 7.34 (dd, J = 8.8,
2.8 Hz, 1H), 7.35 (t, J = 8.0 Hz, 1H), 7.68 (t, J = 2.0 Hz, 1H),
7.71 (ddd, J = 8.0, 2.0, 0.8 Hz, 1H), 8.24 (d, J = 8.8 Hz, 1H),
8.28 (d, J = 2.8 Hz, 1H), 9.86 (s, 1H) (solvent: CDCl3) 783 205-206
786 1.66(3H, s), 2.10(1H, m), 2.57-2.64(2H, m), 3.16(1H, m),
6.74(1H, s), 7.30(1H, s), 7.36(1H, s), 7.74(1H, s), 7.98(1H, s),
8.06(1H, s), 10.33(1H, s), 10.47(1H, s) (solvent: DMSO-d6) 790
amorphous 223, 290 791 d in d18-DMSO:1.41(3H, s), 1.76-1.69(1H, m),
2.02- 1.98(1H, m), 2.62-2.55(1H, m), 2.92-2.89(1H, m), 7.13(1H, d,
J = 7.6 Hz), 7.29(1H, t, J = 7.6 Hz), 7.62- 7.59(2H, m), 8.71(1H,
s), 9.28(1H, s), 10.46(1H, brs) 792 299.4 793 269 (dec.) 797 213.4
312.4 799 215, 240 800 225, 275 802 1.63 (s, 3H), 1.92 (ddd, J =
14.0, 11.2, 3.6 Hz, 1H), 2.28 (br, 1H), 2.78 (ddd, J = 12.4, 11.2,
3.6 Hz, 1H), 2.81 (s, 3H), 2.92 (ddd, J = 12.4, 6.4, 4.0 Hz, 1H),
7.10 (ddd, J = 8.0, 2.0, 0.8 Hz, 1H), 7.35 (t, J = 8.0 Hz, 1H),
7.56 (t, J = 2.0 Hz, 1H), 7.65 (d, J = 2.4 Hz, 1H), 7.74 (ddd, J =
8.0, 2.0, 0.8 Hz, 1H), 8:41 (d, J = 2.4 Hz, 1H), 10.03 (s, 1H)
(solvent: CDCl3) 803 271 804 135-136 810 47-48 811 138-139 813
204-205 182 (s, 3H), 1.89-1.94 (m, 1H), 2.78 (ddd, J = 12.4,
6.4,3.6 Hz, 1H), 4.50 (2H, br), 7.06 (dd, J = 11.6, 8.8 Hz, 1H),
7.40 (dd, J = 7.2, 2.8 Hz, 1H), 7.59 (ddd, J = 8.8, 8.0, 2.8 Hz,
1H), 7.99 (ddd, J = 8.8, 4.4, 2.8 Hz, 1H), 8.33 (dd, J = 8.8, 4.4
Hz, 1H), 8.45 (d, J = 2.8 Hz, 1H), 9.78 (s, 1H)(solvent: CDCl3) 814
oil 218, 272 816 214.5
TABLE-US-00152 TABLE 152 Compound Melting Point MS UV No. (.degree.
C.) 1H-NMR (d) (m/z) (.lamda.max: nm) 820 (CDCl3) 1.66(3H, d, J =
1.2 Hz), 1.98(1H, ddd, J = 14.0, 10.4, 3.7 Hz), 2.47(1H, ddd, J =
14.0, 6.7, 3.5 Hz), 2.79(1H, ddd, J = 12.0, 10.4, 3.5 Hz), 3.02(1H,
ddd, J = 12,0, 6.7, 3.7 Hz), 4.45(2H, br), 6.16(2H, br), 7.04-
7.11(2H, m), 7.38(1H, dd, J = 7.2, 2.9 Hz), 7.88(1H, d, J = 2.0
Hz), 7:96(1 H, ddd, J = 8,9, 4.2, 2.9 Hz), 9.88(1H, s) 822 279 827
134-137 214.5 284.0 832 212, 299 833 oil 212, 273 834 217, 267 835
139-140 836 221.6 279.3 840 223-225 848 oil 223, 254 849 143-145
850 d in d16-DMSO:1.41(3H, s), 1.75-1.70(1H, m), 2.02- 1.99(1H, m),
2.61-2.56(1H, m), 2.93-2.88(1H, m), 7.13(1H, d, J = 8.0), 7.29(1H,
t, J = 7.8 Hz), 7.35(1H, q, J = 8.4, 2.4 Hz), 7.66-7.63(2H, m),
8.52;8.47(1H, m), 8.81(1H, s), 10.44(1H, s) 851 82-83 1.55(3H, s),
1.76-1.88(1H, m), 2.10-2.18(1H, m), 2.66-2.77(1H, m), 2.82-2.91(1H,
m), 3.81(3H, s), 6.73-6.78(1H, m), 6.88-6.92(2H, m), 7.21-7.29(1H,
m) (solvent: CDCl3) 855 oil 219 859 350[M + 1] 200 274 208 254 863
192-194 1.39(t, J = 7.2 Hz, 3H), 1.42(s, 3H), 1.71-1.79(m, 1H),
2.02-2.10(m, 1H), 2.55-2.62(m, 1H), 2.88- 2.96(m, 1H), 4.47(q, J =
7.2 Hz, 2H), 5.70-6.20(br s, 2H), 7.11(d, J = 8.0 Hz, 1H), 7.29(t,
J = 8.0 Hz, 1H), 7.75(d, J = 8.0 Hz, H), 7.80(br s, 1H), 8.38(d, J
= 1.2 Hz, 1H), 8.87(d, J = 1.2 Hz, 1H), 10.34(s, 1H) (solvent:
CDCl3) 866 293.5 869 1.65 (s, 3H), 1.90-2.01 (m, 3H), 2.32 (br,
1H), 2.80 (td, J = 12.0, 3.6 Hz, 1H), 2.85 (t, J = 8.0 Hz, 2H),
2.92 (ddd, J = 12.0, 5.6, 3.6, 1H), 3.75 (t, J = 8.0 Hz, 2H), 7.11
(ddd, J = 8.0, 2.0, 0.8 Hz, 1H), 7.37 (t, J = 8.0 Hz, 1H), 7.70 (t,
J = 2.0 Hz, 1H), 7.73-7.76 (m, 2H), 8.22 (d, J = 7.6 Hz, 1H), 8.48
(d, J = 2.0 Hz, 1H), 10.00 (s, 1H) (solvent: CDCl3) 871 212-213
TABLE-US-00153 TABLE 153 Compound Melting Point MS UV No. (.degree.
C.) 1H-NMR (d) (m/z) (.lamda.max: nm) 875 oil 222, 271 876 oil 222
878 oil 211 881 141-144 887 262.7 892 251 (dec.) 893 d in
d12-DMSO:1.70(3H, s), 2.10-2.04(1H, m), 2.69- 2.59(2H, m),
3.20-3.17(1H, m), 6.80(1H, brs), 7.26- 7.20(1H, m), 7.88-7.81(3H,
m), 10.35(1H, s) 13.53(1H, brs) 895 378[M + 1] 202 302 208 216 221
265 896 amorphous 219, 264 897 212-214 900 205-207 1.61 (s, 3H),
1.91 (ddd, J = 14.0, 10.8, 4.0 Hz, 1H), 2.23 (ddd, J = 14.0, 6.4,
3.6 Hz, 1H), 2.77 (ddd, J = 12.4, 10.8, 3.6 Hz, 1H), 2.92 (ddd, J =
12.4, 6.4, 4.0 Hz, 1H), 7.15 (ddd, J = 8.0, 2.0, 0.8 Hz, 1H), 7.38
(t, J = 8.0 Hz, 1H), 7.65 (t, J = 2.0 Hz, 1H), 7.79 (ddd, J = 8.0,
2.0, 0.8 Hz, 1H), 8.99 (s, 2H), 9.78 (s, 1H) (solvent: CDCl3) 906
212.2 273.4 350.5 908 d in d15-DMSO:1.66(3H, s), 2.11-2.05(1H, m),
2.37(3H, s), 2.63-2.54(2H, m), 3.16-3.11(1H, m), 3.16(3H, s),
7.08-6.96(3H, m), 7.49-7.41(3H, m), 7.85-7.81(2H, m), 10.52(1H,
s)11.69(1H, s) 910 oil 211, 276 916 131-132 926 1.89(3H, s),
2.15(1H, m), 2.71-2.82(2H, m), 2.96(1H, m), 3.04(3H, d, J = 4.9),
7.35(1H, dd, J = 8.7, 1.8), 7.50-7.55(2H, m), 7.74(1H, s),
7.82-7.90(3H, s), 10.40(1H, br), 11.36(1H, Br) (solvent:
CDCl.sub.3) 928 1.20(t, J = 7.6 Hz, 3H), 1.53(br s, 3H),
1.82-1.97(m, 1H), 2.39(s, 3H), 2.61(q, J = 7.6 Hz, 2H), 2.99-
3.07(m, 1H), 6.93(br s, 1H), 7.33(d, J = 8.4 Hz, 2H), 7.54-7.58(m,
2H), 7.87(d, J = 8.4 Hz, 2H), 10.13(s, 1H) (solvent: CDCl3) 930
132.1-134.4 328[M + 1] 931 299 933 amorphous 212, 259
TABLE-US-00154 TABLE 154 Compound Melting Point MS UV No. (.degree.
C.) 1H-NMR (d) (m/z) (.lamda.max: nm) 935 161-165 1.62 (s, 3H),
1.91 (ddd, J = 14.0, 10.4, 4.0 Hz, 1H), 2.24 (ddd, J = 14.0, 6.4,
3.6 Hz, 1H), 2.80 (ddd, J = 12.0, 10.4, 3.6 Hz, 1H), 2.93 (ddd, J =
12.0, 6.4, 4.0 Hz, 1H), 7.15 (ddd, J = 8.0, 2.0, 1.2 Hz, 1H), 7.39
(t, J = 8.0 Hz, 1H), 7.66 (ddd, J = 8.4, 7.2, 1.2 Hz, 1H), 7.75 (t,
J = 2.0 Hz, 1H), 7.80-7.84 (m, 2H), 7.93 (ddd, J = 8.0, 2.0, 1.2
Hz), 8.21 (d, J = 8.4 Hz, 1H), 8.38 (d, J = 8.0 Hz, 1H), 8.41 (d, J
= 8.0 Hz, 1H), 10.25 (s, 1H) (solvent: CDCl3) 936 169-170 939 d in
d6-DMSO:1.72(3H, s), 2.11-2.05(1H, m), 2.70- 2.60(2H, m),
3.21-3.18(1H, m), 7.20(1H, d, J = 9.2 Hz), 7.28(1H, q, J = 11.6,
9.2 Hz), 8.56-7.54(2H, m), 7.69(1H, s), 7.90-7.85(2H, m), 10.69(1H,
s), 12.17(1H, brs) 941 220 944 amorphous 219, 256 946 1.61 (s, 3H),
1.91 (ddd, J = 14.0, 10.8, 3.6 Hz, 1H), 2.26 (ddd, J = 14.0, 6.4,
3.6 Hz, 1H), 2.77 (ddd, J = 12.4, 10.8, 3.6 Hz, 1H),, 2.92 (ddd, J
= 12.4, 6.4, 3.6 Hz, 1H), 7.13 (ddd, J = 8.0, 2.0, 1.2 Hz, 1H),
7.36 (t, J = 8.0 Hz, 1H), 7.61 (t, J = 2.0 Hz, 1H), 7.72 (ddd, J =
8.0, 2.0, 1.2 Hz, 1H), 7.91 (d, J = 2.4 Hz, 1H), 8.49 (d, J = 2.4
Hz, 1H), 9.75 (s, 1H)(solvent: CDCl3) 947 215.7 276.9 960 261.5 964
185-187 966 oil 216 968 107-109 970 1.57 (s, 3H), 1.78-1.89 (m,
1H), 2.10-2.19 (m, 1H), 2.69 (ddd, J = 11.9, 10.8, 3.5 Hz, 1H),
2.83-2.91 (m, 1H), 7.15-7.35 (m, 5H) (solvent: CDCl3) 971 (DMSO)
1.49(3H, s), 1.73-1.86(1H, m), 2.16- 2.30(1H, m), 2.54-2.65(1H, m),
2.92-3.03(1H, m), 5.86(2H, s), 7.04-7.18(2H, m), 7.38-7.50(3H, m),
7.66-7.78(2H, m), 10.35(1H, s), 11.84(1H, s) 972 1.51 (3H, s)
1.91-1.95 (1H, m) 2.37 (3H,s) 3.00-3.05 (1H, m) 7.24 (1H s) 7.33
(2H, d J = 9.0 Hz) 7.66 (1H,s) 7.85 (2H, d J = 9.0 Hz) 8.03 (1H, s)
10.37 (1H, s) (solvent: DMSO-d6) 974 amorphous 219 978 oil 222 984
255.7 318.4 990 126-129 994 130-131
TABLE-US-00155 TABLE 155 Compound Melting Point MS UV No. (.degree.
C.) 1H-NMR (d) (m/z) (.lamda.max: nm) 998 amorphous 229, 290 1005
191-193 1006 88-90 2.42-2.47(2H, m), 2.80-2.86(2H, m), 7.78(6H, s),
6.83(4H, d, J = 8.9 Hz), 7.22(4H, d, J = 8.9 Hz) (solvent: CDCl3)
1008 125-126 1010 90-91 1014 206-210 1020 216.9 245.1 1028 105-106
1034 212.2 286.4 1035 247-251 (dec.) 1037 amorphous 224, 272 1039
amorphous 217 249 1043 277-281 1044 (DMSO) 1.12(3H, s), 1.60(2H, d,
J = 6.2 Hz), 1.73(2H, d, J = 8.6 Hz), 2.65-2.90(2H, m),
2.93-3.13(2H, m), 5.55(1H, s), 7.34-7.52(3H, m), 7.68(1H, s), 7.79-
7.90(3H, m) 1052 1.75(s, 3H), 2.12-2.21(m, 1H), 2.40(s, 3H), 2.65-
2.73(m, 2H), 3.17-3.23(m, 1H), 7.37(d, J = 8.4 Hz, 2H),
7.40-7.44(m, 1H), 7.77(br s, 1H), 7.92-7.99(m, 5H), 8.47(br s, 1H),
8.70(d, J = 4.8 Hz, 1H), 10.37(s, 1H), 10.41(s, 1H) (solvent:
CDCl3) 1055 169-170 1.56(3H, s), 1.78-1.89(1H; m), 2.04-2.15(1H,
m), 2.68-2.79(1H, m), 2.86-2.95(1H, m), 4.32(2H, br), 6.94-7.02(4H,
m), 7.05-7.12(1H, m), 7.25-7.37(4H, m) (solvent: CDCl3) 1056 219
1059 262-267 1061 216 1062 136-137 1.53(3H, s), 1.76-1.88(1H, m),
2.03-2.13(1H, m), 2.63-2.73(1H, m), 2.85-2.94(1H, m), 4.35(2H, br),
7.23-7.32(4H, m) (solvent: CDCl3) 1064 84-85 1.52(3H, s),
1.73-1.89(1H, m), 1.97-2.07(1H, m), 2.64-2.81(1H, m), 2.82-2.91(1H,
m),2.87(3H, s), 3.77(3H, s), 4.10(1H, brs), 6.84(2H, d, J = 8.9
Hz), 7.28(2H, d, J = 8.6 Hz) (solvent: CDCl3) 1067 162-165 1068
132-134 230 1069 194-196 1074 324[M + 1] 200 248 207 1076 amorphous
217
TABLE-US-00156 TABLE 156 Compound Melting Point MS UV No. (.degree.
C.) 1H-NMR (d) (m/z) (.lamda.max: nm) 1084 146-149 1087 311.2 1088
amorphous 1.55(3H, s), 1.83(1H, ddd, J = 13.9, 10.5, 3.7), 229
2.09(1H, ddd, J = 13.9, 6,6, 3.6), 2.67(1H, ddd, J = 318 12.3,
10.5, 3.6), 2.88(1H, ddd, J = 12.3, 6.6, 3.7), 4.48(2H, d, J =
6.0), 4.91(1H, br), 6.33(1H, dd, J = 8..8, 0.8), 7.19(1H, d, J =
7.3, 7.23-7.30(2H, m), 7.35(1H, dd, J = 8.8, 2.8), 8.05(1H, dd, J =
2.8, 0.8) (solvent: CDCl3) 1094 216, 322 1100 278 (dec.) 1107 oil
1.58(3H, s), 1.90(1H, ddd, J = 13.9, 10.1, 3.7), 226 2.14(1H, ddd,
J = 13.9, 6.8, 3.6), 2.69(1H, ddd, J = 284 12.2, 10.1, 3.6),
2.94(1H, ddd, J = 12.2, 6.8, 3.7), 3.81(3H, s), 4.62(2H, s),
6.90(2H, d, J = 8.8), 7.30(2H, d, J = 8.8), 7.43(1H, t, J = 7.4),
7.57(1H, ddd, J = 7.4, 1.6, 1.2), 7.81(1H, ddd, J = 7.6, 1.6, 1.2),
7.95(1H, t, J = 1.6) (solvent: CDCl3) 1109 134-140 1110 109-110
1111 118-119 1114 121-124 1115 167-170 1.63 (s, 3H), 1.93 (ddd, J =
14.0, 10.4, 4.0 Hz, 1H), 2.24 (ddd, J = 14.0, 6.4, 3.6 Hz, 1H),
2.81 (ddd, J = 12.4, 10.4, 3.6 Hz, 1H), 2.96 (ddd, J = 12.4, 6.4,
4.0 Hz, 1H), 4.49 (br, 2 H), 7.19 (ddd, J = 8.0, 2.0, 0.8 Hz, 1H),
7.42 (t, J = 8.0 Hz, 1H), 7.74 (t, J = 2.0 Hz, 1H), 7.84 (ddd, J =
8.0, 2.0, 0.8 Hz, 1H), 7.88-7.95 (m, 2H), 8.22-8.26 (m, 2H), 9.80
(s, 1H), 9.89 (s, 1H) (solvent: CDCl3) 1116 oil 220, 255, 307 1119
153-157 1120 213-214 1124 169-172 225 1125 195-198 222 256 289 1131
189-191 1132 175-180 (dec) 1133 amorphous 219, 292 1135 255-260
(dec.) 1139 140-141 1140 oil 218 1142 182-186 (dec.)
TABLE-US-00157 TABLE 157 Compound Melting Point MS UV No. (.degree.
C.) 1H-NMR (d) (m/z) (.lamda.max: nm) 1147 214.5 275.7 1150 221.6
279.3 1153 156-159 1160 1.64 (3H, s) 2.02-2.12 (1H, m) 2.54-2.63
(1H, m) 3.11-3.16 (1H, m) 7.28 (1H, s) 7.70 (1H, dd J = 8.1 Hz)
7.85 (1H,s) 8.04-8.17 (2H, m) 8.28 (1H s) 8.74 (1H d J = 5.1 Hz)
10.81 (1H, s) 10.96 (1H, s) (solvent: DMSO-d6) 1161 192-193 1166
290-295 444[M + 3] 442[M + 1] 368 366 1172 1.55 (3H, s) 1.94-2.03
(1H,m) 2.18-2.27 (1H, m) 2.32 (3H, s) 3.03-3.07 (1H, m) 7.05 (1H.
s) 7.09 (1H, s) 7.14 (1H, s) 7.37 (2H, d J = 9.0 Hz) 7.66 (2H, d J
= 9.0 Hz) 10.65 (1H, s) 10.70 (1H,s) (solvent: DMSO-d6) 1181
194-195 1.60(3H, s), 1.81-1.93(1H, m), 2.13-2.22(1H, m),
2.70-2.81(1H, m), 2.86-2.96(1H, m), 4.36(2H, br), 7.29-7.46(5H, m),
7.53-7.61(4H, m) (solvent: CDCl3) 1184 149-150 1185 225.1 280.4
1193 182-183 1194 344[M + 1] 209 268 214 261 1197 250-255 (dec.)
1199 274-283 1205 oil E 213, 273 Z 219, 275 1207 106-108 1211 1.77
(s, 3H), 1.98- 2.54 (m, 2H), 2.81 (s, 3H), 2.81- 2.94 (m, 2H), 3.93
(s, 3H), 7.03 (ddd, J = 8.0, 2.0, 0.8 Hz, 1H), 7.08 (d, J = 2.4 Hz,
1H), 7.36 (t, J = 8.0 Hz, 1H), 7.63 (t, J = 2.0 Hz, 1H), 7.69 (ddd,
J = 8.0, 2.0, 0.8 Hz, 1H), 8.14 (d, J = 2.4 Hz, 1H), 10.13 (s, 1H)
(solvent: CDCl3) 1213 406[M + 1] 20 330 209 213
TABLE-US-00158 TABLE 158 Compound Melting Point MS UV No. (.degree.
C.) 1H-NMR (d) (m/z) (.lamda.max: nm) 1215 amorphous 1.64 (s, 3H),
2.07 (ddd, J = 14.1, 11.5, 3.8 Hz, 1H), 2.17 (s, 3H), 2.39 (ddd, J
= 14.1, 5.3, 3.5 Hz, 1H), 2.72 (ddd, J = 12.6, 11.5, 3.5 Hz, 1H),
2.80 (ddd, J = 12.6, 5.3, 3.8 Hz, 1H), 3.21 (t, J = 8.9 Hz, 2H),
4.58 (t, J = 8.9 Hz, 2H), 6.76 (d, J = 8.4 Hz, 1H), 6.97-7.02 (m,
1H), 7.08-7.11 (m, 1H) (solvent: CDCl3) 1216 305.3 1217 263-266
1221 amorphous 220, 253 1223 226.3 280.4 1224 d in
d11-DMSO:1.46(3H, s), 1.83-1.77(1H, m), 2.18- 2.15(1H, m),
2.61-2.56(1H, m), 2.99-2.95(1H, m), 7.08(1H, q, J = 12.0, 8.4 Hz),
7.72-7.66(2H, m), 7.79(2H, d, J = 9.2)9.67(1H, s) 1228 oil 224 1230
232-234 1240 216.9 285.2 1241 194-195 1242 d in d21-DMSO:1.41(3H,
m), 1.75-1.68(1H, m), 2.04- 1.99(1H, m), 2.61-2.56(1H, m), 2.89(4H,
s), 5.75(2H, brs), 7.07(1H, d, J = 4.0 Hz), 7.25(1H, t, J = 8.0
Hz), 7.72(1H, d, J = 8.0 Hz), 7.75(1H, 5), 7.83(1H, brs), 7.96(1H,
s), 8.67(1H, s), 9.96(1H, s) 1243 amorphous 1.58(3H, s), 2.00(1H,
ddd, J = 14.3, 11.5; 3.1), 223 2.53(1H, m), 2.56(1H, m), 3.07(1H,
dt, J = 12.5, 299 3.1), 4.26(2H, s), 6.47-6.56(3H, m),
7.07-7.15(1H, m), 7.12(2H, t, J = 8.8), 7.39(2H, dd, J = 8.8, 5.6),
8.76(2H, br) (solvent: DMSO-d6) 1244 268-288 1.68 (s, 3H), 2.11
(ddd, J = 15.2,12.0, 4.0 Hz, 1H), 219 2.57-2.64 (m, 2H), 3.16 (dt,
J = 12.0, 4.0 Hz, 1H), 288 7.13 (ddd, J = 8.0, 2.0, 0.8 Hz, 1H),
7.46 (t, J = 8.0 Hz, 1H), 7.89 (t, J = 2.0 Hz, 1H), 7.97 (ddd, J =
8.0, 2.0, 0.8 Hz, 1H), 8.35 (d, J = 8.0 Hz, 1H), 8.52 (dd, J = 8.0,
2.4 Hz, 1H), 9.12 (d, J = 2.4 Hz, 1H), 10.68 (s, 1H), 10.92 (s, 1H)
(solvent: DMSO-d6) 1245 oil 286 1247 211 1255 242.7 1257 amorphous
211 1258 352[M + 1] 228 276 301 1261 179-180 1262 278-281
TABLE-US-00159 TABLE 159 Compound Melting Point MS UV No. (.degree.
C.) 1H-NMR (d) (m/z) (.lamda.max: nm) 1263 1H-NMR(d in d6-DMSO):
1.41(3H, s), 1.65-1.77 387[M + 1] (1H, m), 1.95-2.07(1H, m),
2.54-2.63(1H, m), 2.84- 2.94(1 H, m), 3.39-3.46(2H, m),
3.53-3.61(2H, m), 4.83(1H, t, J = 5:4 Hz), 5.79(2H, bs), 7.07(1H,
d, J = 7.5 Hz), 7.25(1H, t, J = 7.8 Hz), 7.73(1H, d, J = 7.8 Hz),
7.76(1H, m), 7.87-7.93(1H, m), 8.62(1H, d, J = 1.2 Hz), 8.63(1H, d,
J = 1.2 Hz), 9.97(1H, s). 1264 1H-NMR(d in d6-DMSO): 1.41(3H, s),
1.65-1.77 413[M + 1] (1H, m), 1.95-2.07(1H, m), 2.53-2.63(1H, m),
2.84- 2.95(1H, m), 3.73(8H, s), 5.79(2H, bs), 7.09(1H, d, J = 7.8
Hz), 7.26(1H, t, J = 7.8 Hz), 7.72(1H, d, J = 7.8 Hz),
7.75-7.78(1H, m), 8.34(1H, d, J = 1.2 Hz), 8.76(1H, d, J = 1.2 Hz),
10.08(1H, bs). 1265 1H-NMR (DMSO-d6) d: 1.42 (3H, s), 1.70-1.76
(1H, m), 2.02-2.05 (1H, m), 2.56-2.59 (1H, m), 2.87-2.93 (2H, m),
7.07 (1H, d, J = 7.6 Hz), 7.23-7.26 (3H, m), 7.72-7.74 (2H, m),
7.93 (1H, s), 8.60 (1H, s), 9.99 (1H, s). 1266 1H-NMR(d in
d6-DMSO): 1.43(3H, s), 1.70-1.81 369[M + 1] (1H, m), 1.97-2.10(1H,
m), 2.55-2.64(1H, m), 2.89- 2.95(1H, m), 5.84(2H, bs), 7.17(1H, d,
J = 7.8 Hz), 7.33(1H, t, J = 7.8 Hz), 9.98(1H, d, J = 1.2 Hz),
10.01(1H, d, J = 1.2 Hz), 10.74(1H, bs). 1267 1H-NMR (CDCl3) d:
1.82-1.91 (1H, m), 2.04 (3H, s), 338[M + 1] 2.22 (1H, ddd, J =
13.8, 52, 3.6 Hz), 2.67 (1H, dt, J = 16.7, 5.8 Hz), 2.80 (1H, dt, J
= 12.4, 4.7 Hz), 6.95 (2H, d, J = 8.1 Hz), 7.06 (2H, td, J = 7.8,
1.2 Hz), 7.18 (1H, td, J = 7.6, 1.1 Hz), 7.27 (1H, d, J = 1.7 Hz),
7.32 (1H, d, J = 7.9 Hz), 7.42-7.44 (2H, m), 7.80 (1H, dd, J = 8.0,
1.9 Hz). 1268 1H-NMR (CDCl3) d: 1.62 (3H, s), 1.89 (1H, t, J =
327[M + 1] 12.3 Hz), 2.27-2.30 (1H, m), 2.69-2.76 (1H, m), 2.85-
2.88 (1H, m), 7.11 (1H, dd, J = 11.4, 7.7 Hz), 7.30- 7.53 (2H, m),
7.63 (1H, s), 7.71 (1H, d, J = 6.9 Hz). 1269 1H-NMR (DMSO-d6) d:
1.40 (3H, s), 1.70-1.73 (1H, m), 1.99-2.02 (1H, m), 2.57-2.60 (1H,
m), 2.88-2.90 (1H, m), 3.29 (3H, s), 3.52 (4H, s), 5.75 (2H, br s),
7.07 (1H, d, J = 7.6 Hz), 7.25 (1H, t, J = 7.7 Hz), 7.72 (1H, d, J
= 8.3 Hz), 7.75 (1H, s), 7.92 (1H, br s), 8.03 (1H, s), 8.64 (1H,
s), 9.96 (1H, s). 1271 1H-NMR(d in d6-DMSO): 1.41(3H, s), 1.65-1.75
397[M + 1] (1H, m), 1.99-2.06(5H, m), 2.52-2.61(1H, m), 2.85-
2.93(1H, m), 3.55(4H, t, J = 6.6 Hz), 5.79(2H, bs), 7.05(1H, d, J =
7.8 Hz), 7.25(1H, t, J = 7.8 Hz), 7.70- 7.75(1H, m), 7.73-7.77(1H,
m), 7.97(1H, d, J = 1.2 Hz), 8.72(1H, d, J = 1.2 Hz), 10.00(1H,
s).
TABLE-US-00160 TABLE 160 Compound Melting Point MS UV No. (.degree.
C.) 1H-NMR (d) (m/z) (.lamda.max: nm) 1272 (CDCl3) 1.61(3H, s),
1.85-1.96(1H, m), 2.17- 2.27(1H, m), 2.69-2.79(1H, m),
2.87-2.97(1H, m), 7.17 (1H, d, J = 8.1 Hz), 7.38 (1H, t, J = 8.1
Hz), 7.48- 7.74(5H, m), 8.40(2H, d, J = 7.5 Hz) 1273 1H-NMR (CDCl3)
d: 1.58 (3H, s), 1.89 (1H, t, J = 395[M + 1] 11.2 Hz), 2.27 (1H,
s), 2.75-2.82 (2H, m), 6.61 (1H, dd, J = 20.3, 8.4 Hz), 7.10 (1H,
d, J = 7.2 Hz), 7.37 (1H, dd, J = 15.0, 8.8 Hz), 7.90 (1H, d, J =
7.6 Hz), 8.10 (1H, d, J = 3.2 Hz), 9.37 (1H, d, J = 4.9 Hz), 9.69
(1H, s). 1274 1H-NMR (CDCl3) d: 1.61 (3H, s), 1.84-1.93 (1H, 327[M
+ 1] m), 2.30 (1H, t, J = 13.1 Hz), 2.77-2.86 (2H, m), 6.64 (1H,
dd, J = 20.6, 8.6 Hz), 7.13 (1H, d, J = 7.9 Hz), 7.38-7.43 (1H, m),
7.93 (1H, d, J = 8.1 Hz), 8.13 (1H, s), 9.40 (1H, d, J = 4.9 Hz),
9.72 (1H, s). 1275 1H-NMR (DMSO-d6) d: 1.40 (3H, s), 1.70-1.72 (1H,
m), 2.01-2.04 (1H, m), 2.18 (6H, s), 2.44 (2H, t, J = 6.3 Hz),
2.56-2.59 (1H, m), 2.86-2.92 (1H, m), 7.06 (1H, d, J = 7.6 Hz),
7.25 (1H, t, J = 7.7 Hz), 7.71-7.73 (3H, m), 8.0211H, s), 8.64 (1H,
s), 9.95 (1H, s). 1276 1H-NMR (DMSO-d6) d: 1.70-1.73 (1H, m), 1.99-
2.02 (1H, m), 2.57-2.60 (1H, m), 2.88-2.91 (1H, m), 3.04 (3H, s),
3.4.3 (3H, t, J = 6.3 Hz), 3.79-3.81 (2H, m), 5.75 (3H, br s), 7.08
(1H, d, J = 7.3 Hz), 7.26 (1H, t, J = 7.8 Hz), 7.72 (1H, d, J = 7.8
Hz), 7.76 (1H, s), 8.04 (1H, s), 8.09 (1H, br s), 8.70 (1H, s),
10.01 (1H, s). 1279 1H-NMR (CDCl3) d: 1.73 (3H, s), 2.04 (1H, dt, J
= 328[M + 1] 18.2, 6.5 Hz), 2.45 (1H, d, J = 13.6 Hz), 2.78 (2H, t,
J = 11.8 Hz), 2.89 (2H, t, J = 11.5 Hz), 6.60 (1H, s), 6.99 (1H, d,
J = 8.2 Hz), 7.34 (1H, t, J = 8.0 Hz), 7.48 (1H, s), 7.70 (1 H, d,
J = 8.2 Hz). 1280 1H-NMR(d in d6-DMSO): 1.42(3H, s), 1.68-1.82
426[M + 1] (1H, m), 2.02-2.09(1H, m), 2.23(3H, s), 2.43(4H, t, J =
5.1 Hz), 2.53-2.61(1H, m), 2.87-2.95(1H, m), 3.73(4H, t, J = 5.1
Hz), 6.01(2H, bs), 7.07(1H, d, J = 7.8 Hz), 7.26(1H, t, J = 7.8
Hz), 7.73(1H, d, J = 7.8 Hz), 7.73-7.78(1H, m), 8.33(1H, d, J = 1.2
Hz), 8.72(1H, d, J = 1.2 Hz), 10.06(1H, s). 1281 1H-NMR(d in
d6-DMSO): 1.40(3H, s), 1.30-1.50 427[M + 1] (2H, m), 1.69-1.76(1H,
m), 1.82-1.88(2H, m), 2.01- 2.07(1H, m), 2.52-2.61(1H, m),
2.86-2.94(1H, m), 3.76-3.83(1H, m), 4.10-4.18(2H, m), 4.82(1H, d, J
= 4.2 Hz), 5.91(2H, bs), 7.07(1H, d, J = 7.8 Hz), 7.26(1H, t, J =
7.8 Hz), 7.70-7.77(2H, m), 8.33(1H, d, J = 1.2 Hz), 8.70(1H, d, J =
1.2 Hz), 10.02(1H, s).
TABLE-US-00161 TABLE 161 compound No. MS(m/z) 2 336[M + 1] 76 363[M
+ 3] 7 394[M + 1] 361[M + 1] 10 431[M + 3] 79 310[M + 1] 429[M + 1]
81 386[M + 1] 11 356[M + 1] 82 308[M + 1] 12 354[M + 1] 83 336[M +
1] 13 363[M + 3] 84 380[M + 1] 361[M + 1] 87 415[M + 1] 14 394[M +
1] 88 426[M + 1] 15 409[M + 1] 89 370[M + 1] 16 425[M + 1] 90 354[M
+ 1] 17 374[M + 1] 92 417[M + 1] 19 362[M + 3] 93 407[M + 1] 360[M
+ 1] 94 350[M + 1] 20 438[M + 1] 95 406[M + 3] 21 380[M + 3] 404[M
+ 1] 378[M + 1] 98 398[M + 3] 22 380[M + 3] 396[M + 1] 378[M + 1]
100 332[M + 1] 25 354[M + 1] 102 424[M + 3] 27 338[M + 1] 422[M +
1] 28 356[M + 1] 103 444[M + 1] 29 372[M + 1] 105 424[M + 1] 31
378[M + 1] 348 32 417[M + 1] 106 490[M + 1] 34 358[M + 1] 414 35
398[M + 3] 107 414[M + 3] 396[M + 1] 412[M + 1] 36 370[M + 1] 108
332[M + 1] 40 416[M + 1] 109 412[M + 1] 340 110 404[M + 1] 41 414[M
+ 1] 111 469[M + 1] 44 362[M + 3] 393 360[M + 1] 112 377[M + 1] 45
365[M + 1] 116 408[M + 1] 46 362[M + 1] 117 413[M + 1] 47 416[M +
3] 118 372[M + 1] 414[M + 1] 119 424[M + 1] 49 394[M + 3] 122 338[M
+ 1] 392[M + 1] 124 471[M + 1] 50 292[M + 1] 131 412[M + 3] 51
388[M + 1] 410[M + 1] 52 360[M + 1] 133 404[M + 1] 284 135 416[M +
1] 53 380[M + 1] 136 380[M + 1] 54 332[M + 1] 137 327[M + 1] 55
412[M + 3] 138 394[M + 1] 410[M + 1] 140 456[M + 1] 56 397[M + 1]
142 446[M + 1] 395[M + 1] 143 399[M + 1] 59 412[M + 1] 144 432[M +
1] 60 422[M + 1] 145 394[M + 3] 420[M + 1] 392[M + 1] 61 394[M + 1]
146 433[M + 3] 63 366[M + 1] 431[M + 1] 64 441[M + 1] 147 324[M +
1] 385 150 410[M + 1] 65 384[M + 1] 151 458[M + 3] 66 398[M + 1]
456[M + 1] 67 386[M + 1] 152 371[M + 1] 310 153 398[M + 1] 68 376[M
+ 1] 154 401[M + 1] 70 372[M + 1] 155 322[M + 1] 72 330[M + 1] 156
332[M + 3] 74 322[M + 1] 330[M + 1] 75 412[M + 1] 158 394[M +
1]
TABLE-US-00162 TABLE 162 160 427[M + 1] 230 368[M + 1] 162 416[M +
3] 231 336[M + 1] 414[M + 1] 234 376[M + 1] 167 392[M + 3] 236
392[M + 1] 390[M + 1] 237 348[M + 1] 168 380[M + 3] 239 384[M + 1]
378[M + 1] 240 341[M + 1] 169 346[M + 1] 242 446[M + 1] 170 356[M +
1] 245 374[M + 1] 171 334[M + 1] 246 390[M + 1] 172 376[M + 3] 314
374[M + 1] 247 374[M + 1] 173 424[M + 3] 248 370[M + 1] 422[M + 3]
249 336[M + 1] 174 369[M + 1] 250 366[M + 1] 175 410[M + 1] 252
401[M + 1] 177 357[M + 1] 253 397[M + 1] 179 334[M + 1] 254 434[M +
1] 180 426[M + 1] 257 321[M + 1] 182 396[M + 3] 258 398[M + 1]
394[M + 1] 260 440[M + 1] 183 372[M + 1] 261 308[M + 1] 184 346[M +
1] 262 466[M + 3] 185 330[M + 1] 464[M + 1] 186 393[M + 3] 264
336[M + 1] 391[M + 1] 265 435[M + 1] 187 374[M + 1] 266 432[M + 3]
188 423[M + 1] 430[M + 1] 190 278[M + 1] 269 372[M + 1] 191 448[M +
1] 296 192 436[M + 3] 270 338[M + 1] 434[M + 1] 272 349[M + 1] 194
384[M + 1] 273 406[M + 3] 195 369[M + 1] 404[M + 1] 197 382[M + 1]
274 380[M + 1] 198 355[M + 1] 276 398[M + 3] 199 361[M + 1] 396[M +
1] 200 356[M + 1] 278 404[M + 1] 280 280 433[M + 3] 201 452[M + 1]
431[M + 1] 203 397[M + 1] 283 322[M + 1] 205 427[M + 1] 285 340[M +
1] 206 386[M + 3] 286 433[M + 1] 310 431[M + 1] 207 384[M + 1] 287
440[M + 1] 208 386[M + 3] 288 354[M + 1] 384[M + 1] 289 341[M + 1]
209 371[M + 1] 290 363[M + 3] 210 366 291 361[M + 1] 211 442[M + 1]
317[M + 1] 366 292 426[M + 1] 212 345[M + 1] 294 424[M + 3] 215
425[M + 3] 422[M + 1] 423[M + 1] 295 394[M + 3] 217 362[M + 1]
392[M + 1] 218 322 [M + 1] 296 389[M + 1] 219 347[M + 1] 297 448[M
+ 3] 221 444[M + 1] 446[M + 1] 222 329[M + 1] 299 363[M + 3] 223
413[M + 1] 361[M + 1] 225 402[M + 1] 300 356[M + 1] 226 390[M + 1]
303 366[M + 1] 228 383[M + 1] 304 402[M + 1] 229 366[M + 1] 305
407[M + 3] 405[M + 1] 310 411[M + 1]
TABLE-US-00163 TABLE 163 311 388[M + 1] 394 363[M + 3] 312 428[M +
1] 361[M + 1] 313 453[M + 1] 397 460[M + 3] 314 368[M + 1] 458[M +
1] 315 322[M + 1] 398 408[M + 1] 316 386[M + 1] 399 372[M + 1] 317
328[M + 1] 400 374[M + 1] 318 382[M + 1] 402 372[M + 1] 320 327[M +
1] 296 321 392[M + 1] 403 436[M + 1] 322 404[M + 1] 404 376[M + 3]
328 374[M + 1] 323 394[M + 1] 407 449[M + 3] 324 384[M + 1] 447[M +
1] 325 399[M + 1] 412 410[M + 1] 326 440[M + 1] 414 331[M + 1] 364
416 282[M + 1] 327 314[M + 1] 418 322[M + 1] 328 384[M + 1] 419
420[M + 3] 331 360[M + 1] 418[M + 1] 334 412[M + 1] 420 332[M + 1]
335 316[M + 1] 421 388[M + 3] 336 356[M + 1] 386[M + 1] 337 428[M +
1] 423 412[M + 3] 338 466[M + 3] 410[M + 1] 464[M + 1] 424 370[M +
1] 340 344[M + 1] 425 378[M + 1] 343 399[M + 1] 428 350[M + 1] 345
412[M + 1] 431 391[M + 1] 346 384[M + 1] 433 454[M + 3] 347 430[M +
1] 452[M + 1] 348 341[M + 1] 434 448[M + 3] 349 335[M + 1] 446[M +
1] 350 412[M + 1] 435 431[M + 3] 351 322[M + 1] 429[M + 1] 352
327[M + 1] 437 382[M + 1] 355 397[M + 1] 400[M + 1] 362 366[M + 1]
438 324 363 376[M + 3] 439 380[M + 1] 374[M + 1] 440 358[M + 1] 365
366[M + 1] 442 394[M + 1] 366 409[M + 1] 318 368 384[M + 1] 447
370[M + 1] 369 394[M + 3] 449 336[M + 1] 396[M + 1] 450 455[M + 1]
371 398[M + 3] 451 390[M + 3] 396[M + 1] 388[M + 1] 372 348[M + 1]
453 358[M + 1] 373 358[M + 1] 454 407[M + 1] 374 364[M + 1] 331 376
412[M + 1] 455 296[M + 1] 377 425[M + 1] 458 382[M + 1] 378 380[M +
3] 459 392[M + 1] 378[M + 1] 460 431[M + 1] 379 377[M + 1] 461
369[M + 1] 381 409[M + 1] 462 381[M + 3] 382 340[M + 1] 379[M + 1]
384 388[M + 1] 463 440[M + 3] 385 384[M + 1] 438[M + 1] 386 352[M +
1] 464 338[M + 1] 387 376[M + 1] 262 388 440[M + 1] 467 387[M + 1]
390 407[M + 1] 468 439[M + 1] 331 363 391 362[M + 1] 469 360[M + 1]
392 390[M + 1] 471 363[M + 3] 361[M + 1]
TABLE-US-00164 TABLE 164 472 378[M + 1] 555 383[M + 1] 473 414[M +
1] 557 304[M + 1] 474 334[M + 1] 562 374[M + 1] 475 317[M + 1] 563
366[M + 1] 476 324[M + 1] 564 395[M + 1] 477 437[M + 1] 565 336[M +
1] 478 379[M + 1] 566 427[M + 1] 479 394[M + 1] 351 480 370[M + 1]
568 362[M + 3] 481 431[M + 1] 360[M + 1] 484 314[M + 3] 569 356[M +
1] 312[M + 1] 571 356[M + 1] 485 448[M + 1] 572 473[M + 3] 486
350[M + 1] 471[M + 1] 487 338[M + 1] 574 381[M + 3] 488 306[M + 1]
379[M + 1] 489 335[M + 1] 575 360[M + 1] 492 380[M + 1] 576 384[M +
1] 495 334[M + 1] 578 344[M + 1] 499 370[M + 1] 579 370[M + 1] 503
412[M + 1] 580 347[M + 1] 505 363[M + 3] 581 409[M + 1] 361[M + 1]
582 334[M + 1] 506 386[M + 1] 583 392[M + 1] 507 400[M + 1] 585
358[M + 1] 508 372[M + 1] 587 348[M + 1] 509 414[M + 1] 589 407[M +
3] 338 405[M + 1] 510 374[M + 1] 590 410[M + 3] 512 320[M + 1]
408[M + 1] 513 420[M + 3] 591 460[M + 1] 418[M + 1] 384 514 372[M +
1] 592 380[M + 3] 517 369[M + 1] 378[M + 1] 518 376[M + 1] 594
390[M + 1] 519 411[M + 1] 598 394[M + 1] 520 395[M + 1] 599 377[M +
1] 521 372[M + 1] 603 398[M + 3] 522 390[M + 1] 396[M + 1] 523
414[M + 1] 604 395[M + 1] 524 341[M + 1] 606 358[M + 1] 526 426[M +
1] 607 362[M + 1] 527 381[M + 3] 609 413[M + 1] 379[M + 1] 610
409[M + 1] 529 320[M + 1] 612 385[M + 1] 530 390[M + 3] 614 322[M +
1] 388[M + 1] 615 441[M + 1] 531 410[M + 1] 616 346[M + 3] 535
356[M + 1] 344[M + 1] 536 372[M + 1] 270 537 377[M + 1] 268 538
406[M + 1] 617 406[M + 3] 539 411[M + 1] 404[M + 1] 540 354[M + 1]
619 404[M + 1] 541 342[M + 1] 621 366[M + 1] 542 361[M + 1] 623
422[M + 1] 543 344[M + 1] 346 544 412[M + 1] 624 370[M + 1] 545
366[M + 1] 626 402[M + 1] 546 383[M + 1] 627 398[M + 3] 547 430[M +
1] 396[M + 1] 428[M + 1] 628 413[M + 1] 548 427[M + 1] 631 370[M +
1] 550 340[M + 1] 632 414[M + 3] 552 400[M + 1] 412[M + 1] 553
304[M + 1]
TABLE-US-00165 TABLE 165 633 322[M + 1] 721 322[M + 1] 635 420[M +
1] 722 377[M + 1] 638 408[M + 1] 723 440[M + 1] 639 386[M + 1] 364
310 724 457[M + 3] 640 370[M + 1] 455[M + 1] 641 437[M + 1] 726
362[M + 1] 642 380[M + 1] 727 366[M + 1] 646 395[M + 1] 734 370[M +
1] 647 334[M + 1] 736 338[M + 1] 648 403[M + 1] 741 404[M + 1] 650
370[M + 1] 742 351[M + 1] 655 362[M + 1] 745 386[M + 1] 656 308[M +
1] 746 370[M + 1] 658 430[M + 1] 294 659 340[M + 3] 747 336[M + 1]
388[M + 1] 748 381[M + 3] 662 330[M + 1] 379[M + 1] 663 334[M + 1]
749 416[M + 1] 665 316[M + 1] 340 666 345[M + 1] 750 437[M + 1] 668
430[M + 1] 751 362[M + 1] 669 377[M + 1] 752 352[M + 3] 670 368[M +
3] 350[M + 1] 366[M + 1] 754 366[M + 1] 671 334[M + 1] 755 354[M +
1] 672 442[M + 1] 757 425[M + 1] 674 340[M + 1] 759 346[M + 1] 675
306[M + 1] 760 344[M + 1] 676 392[M + 1] 761 402[M + 1] 678 386[M +
1] 762 251[M + 1] 679 426[M + 1] 763 355[M + 1] 682 414[M + 3] 764
362[M + 3] 412[M + 1] 360[M + 1] 684 364[M + 1] 765 392[M + 3] 685
369[M + 1] 390[M + 1] 686 446[M + 1] 769 366[M + 1] 688 414[M + 1]
770 372[M + 1] 689 306[M + 1] 772 292[M + 1] 690 348[M + 1] 773
424[M + 1] 691 452[M + 1] 775 396[M + 3] 693 371[M + 1] 394[M + 1]
694 448[M + 1] 776 388[M + 1] 695 364[M + 1] 777 383[M + 1] 696
392[M + 3] 778 404[M + 1] 390[M + 1] 779 398[M + 1] 697 358[M + 1]
780 366[M + 1] 699 426[M + 1] 782 368[M + 1] 703 451[M + 3] 784
369[M + 1] 449[M + 1] 785 431[M + 3] 704 342[M + 1] 429[M + 1] 705
372[M + 1] 787 473[M + 1] 706 368[M + 1] 397 708 383[M + 1] 788
375[M + 1] 710 396[M + 3] 789 467[M + 1] 394[M + 1] 794 327[M + 1]
711 351[M + 1] 795 384[M + 1] 712 376[M + 1] 796 370[M + 1] 713
398[M + 3] 798 370[M + 1] 396[M + 1] 801 404[M + 3] 714 366[M + 1]
402[M + 1] 715 454[M + 1] 805 376[M + 1] 716 381[M + 3] 806 411[M +
1] 379[M + 1] 807 356[M + 1] 718 388[M + 1]
TABLE-US-00166 TABLE 166 808 354[M + 1] 889 451[M + 1] 809 400[M +
1] 449[M + 1] 324 890 400[M + 1] 812 425[M + 1] 881 292[M + 1] 815
386[M + 1] 894 347[M + 1] 817 377[M + 1] 412[M + 3] 818 398[M + 1]
898 410[M + 1] 819 352[M + 1] 898 397[M + 1] 821 336[M + 1] 901
411[M + 1] 823 362[M + 1] 902 377[M + 1] 824 363[M + 1] 903 370[M +
1] 287 904 422[M + 1] 825 420[M + 1] 905 392[M + 1] 826 430[M + 1]
907 308[M + 1] 828 377[M + 1] 909 393[M + 1] 829 437[M + 1] 911
415[M + 1] 830 370[M + 1] 912 383[M + 1] 831 327[M + 1] 913 413[M +
1] 837 324[M + 1] 914 400[M + 1] 248 915 389[M + 1] 838 377[M + 1]
313 839 376[M + 3] 917 358[M + 1] 374[M + 1] 918 433[M + 3] 841
363[M + 3] 431[M + 1] 361[M + 1] 919 354[M + 1] 842 386[M + 1] 920
381[M + 3] 843 466[M + 3] 379[M + 1] 464[M + 1] 921 389[M + 1] 844
381[M + 1] 922 413[M + 1] 845 324[M + 1] 337 248 923 437[M + 1] 846
358[M + 1] 924 376[M + 1] 847 373[M + 1] 925 390[M + 1] 852 489[M +
1] 927 355[M + 1] 853 376[M + 1] 929 370[M + 1] 854 448[M + 1] 932
380[M + 3] 856 420[M + 1] 378[M + 1] 344 934 507[M + 1] 857 341[M +
1] 937 388[M + 1] 858 383[M + 1] 938 366[M + 1] 860 370[M + 1] 940
388[M + 1] 861 334[M + 3] 942 378[M + 1] 332[M + 1] 943 413[M + 1]
862 358[M + 1] 945 372[M + 1] 864 392[M + 1] 948 462[M + 1] 865
398[M + 3] 949 363[M + 1] 396[M + 1] 950 368[M + 1] 867 399[M + 1]
951 412[M + 1] 868 430[M + 1] 952 378[M + 1] 870 362[M + 3] 953
318[M + 1] 360[M + 1] 954 363[M + 3] 872 428[M + 1] 361[M + 1] 873
351[M + 1] 955 406[M + 3] 874 341[M + 1] 404[M + 1] 877 399[M + 1]
956 292[M + 1] 323 957 398[M + 3] 879 332[M + 1] 396[M + 1] 880
363[M + 3] 958 310[M + 1] 361[M + 1] 959 406[M + 3] 882 426[M + 1]
404[M + 1] 883 360[M + 1] 961 382[M + 3] 884 320[M + 1] 360[M + 1]
885 361[M + 1] 962 327[M + 1] 886 380[M + 1] 963 392[M + 1] 888
292[M + 1]
TABLE-US-00167 TABLE 167 965 438[M + 3] 1036 350[M + 1] 436[M + 1]
1038 364[M + 1] 967 425[M + 3] 1040 317[M + 1] 423[M + 1] 1041
407[M + 1] 969 413[M + 1] 1042 382[M + 1] 973 386[M + 1] 1045 425[M
+ 3] 407[M + 3] 423[M + 1] 975 405[M + 1] 1046 366[M + 1] 976 358[M
+ 1] 1047 390[M + 1] 977 369[M + 1] 1048 440[M + 1] 979 395[M + 1]
1049 396[M + 1] 980 402[M + 1] 1050 400[M + 1] 981 392[M + 3] 1051
315[M + 1] 390[M + 1] 1053 363[M + 3] 982 366[M + 1] 381[M + 1] 983
379[M + 1] 1054 360[M + 1] 985 408[M + 1] 1057 427[M + 1] 986 440[M
+ 3] 1058 360[M + 1] 438[M + 1] 1060 381[M + 3] 987 356[M + 1]
379[M + 1] 988 294[M + 1] 1063 395[M + 1] 989 332[M + 1] 1065 451[M
+ 1] 991 358[M + 1] 449[M + 1] 992 477(M + 1] 1068 485[M + 1] 993
416[M + 3] 1070 380[M + 3] 414[M + 1] 378[M + 1] 995 425[M + 3]
1071 345[M + 1] 423[M + 1] 1072 381[M + 3] 996 416[M + 3] 379[M +
1] 414[M + 1] 1073 397[M + 1] 997 363[M + 3] 1075 342[M + 1] 361[M
+ 1] 1077 344[M + 1] 999 336[M + 1] 1078 370[M + 1] 1000 388[M + 1]
1079 387[M + 1] 312 1080 370[M + 1] 1001 374[M + 1] 294 1002 400[M
+ 1] 1081 355[M + 1] 1003 394[M + 1] 1082 398[M + 3] 1004 397[M +
1] 396[M + 1] 1007 448[M + 1] 1083 318[M + 1] 372 1085 439[M + 3]
1009 366[M + 1] 437[M + 1] 1011 419[M + 1] 1086 428[M + 1] 1012
316[M + 1] 1089 399[M + 1] 1013 431[M + 1] 1090 398[M + 1] 1015
372[M + 1] 1091 434[M + 3] 1016 470[M + 1] 432[M + 1] 1017 413[M +
1] 1092 398[M + 3] 1018 386[M + 1] 396[M + 1] 1019 433[M + 3] 1093
401[M + 1] 431[M + 1] 1095 400[M + 1] 1021 464[M + 1] 1096 409[M +
1] 1022 384[M + 1] 1097 384[M + 1] 1023 407[M + 3] 1098 395[M + 1]
405[M + 1] 1099 511[M + 4] 1024 346[M + 1] 510[M + 3] 1025 455[M +
3] 509[M + 2] 453[M + 1] 508[M + 1] 1026 425[M + 1] 1101 350[M + 1]
1027 444[M + 1] 1102 442[M + 1] 1029 410[M + 1] 1103 397[M + 1]
1030 413[M + 1] 1105 372[M + 1] 1031 404[M + 1] 1106 346[M + 1]
1032 472[M + 1] 1108 383[M + 1] 396 1112 445[M + 1] 1033 377[M +
1]
TABLE-US-00168 TABLE 168 1113 358[M + 1] 1187 427[M + 1] 1117 394[M
+ 1] 1188 350[M + 1] 1118 336[M + 1] 1189 408[M + 3] 260 406[M + 1]
1121 392[M + 3] 1190 386[M + 1] 390[M + 1] 1191 377[M + 1] 1122
322[M + 1] 1192 335[M + 1] 1123 316[M + 1] 412[M + 3] 1126 386[M +
1] 1195 410[M + 1] 1127 368[M + 1] 1196 380[M + 1] 1128 416[M + 3]
1198 398[M + 1] 414[M + 1] 322 1129 341[M + 1] 1200 352[M + 1] 1130
432[M + 1] 1201 424[M + 3] 1134 396[M + 1] 422[M + 1] 1136 396[M +
3] 1202 369[M + 1] 394[M + 1] 1203 420[M + 1] 1137 292[M + 1] 1204
398[M + 3] 1138 413[M + 1] 396[M + 1] 1141 344[M + 1] 1206 416[M +
1] 1143 384[M + 1] 1208 344[M + 1] 1144 446[M + 1] 1209 422[M + 1]
1145 390[M + 1] 1210 408[M + 1] 314 1212 391[M + 1] 1146 405[M + 1]
1214 360[M + 1] 1148 380[M + 1] 1218 372[M + 1] 304 1219 470[M + 1]
1149 364[M + 1] 1220 264[M + 1] 1151 442[M + 1] 1222 362[M + 3]
1152 365[M + 1] 360[M + 1] 1154 318[M + 1] 1225 413[M + 1] 1155
427[M + 1] 1226 374[M + 1] 1156 368[M + 1] 1227 425[M + 1] 1157
366[M + 1] 1229 455[M + 3] 1158 415[M + 3] 453[M + 1] 413[M + 1]
1231 413[M + 1] 1159 414[M + 3] 1232 340[M + 1] 412[M + 1] 1233
394[M + 1] 1162 370[M + 1] 1234 416[M + 3] 294 414[M + 1] 1163
416[M + 3] 1235 427[M + 1] 414[M + 1] 1236 348[M + 1] 1164 396[M +
1] 272 320 1237 353[M + 1] 1165 361[M + 1] 1238 419[M + 1] 1167
424[M + 1] 1239 416[M + 3] 348 414[M + 1] 1188 428[M + 1] 1246
474[M + 1] 1169 422[M + 1] 1248 414[M + 1] 1170 411[M + 1] 1249
338[M + 1] 1171 390[M + 3] 1250 352[M + 1] 388[M + 1] 1251 393[M +
1] 1173 361[M + 1] 1252 357[M + 1] 1174 342[M + 1] 1253 430[M + 1]
1175 431[M + 1] 1254 412[M + 1] 1176 345[M + 1] 1256 333[M + 1]
1177 376[M + 3] 1259 358[M + 1] 374[M + 1] 1280 348[M + 1] 1178
351[M + 1] 1270 374[M + 1] 1179 344[M + 1] 1282 362[M + 1] 1180
398[M + 3] 396[M + 1] 1182 426[M + 1] 376[M + 3] 1183 374[M + 1]
1186 374[M + 1] 298
##STR01356## ##STR01357##
[0298] In above structural formula (Ia) to (Ih), the combination of
NR.sup.2aR.sup.2b, R.sup.3c, R.sup.3d, R.sup.5 and G
(NR.sup.2aR.sup.2b, R.sup.3c, R.sup.3d, R.sup.5, G) are the
following compounds.
(NHMe,H,H,Me,CONHPh),(NHMe,H,H,Me,CONH-3-pyridyl),(NHMe,H,H,Me,NHCOPh),(N-
HMe,H,H,Me,NHCO-2-furyl),(NHMe,H,H,Me,NHCONHPh),(NHMe,H,H,
Me,NHCOCONHPh),(NHMe,H,H,Et,CONHPh),(NHMe,H,H,Et,CONH-3-pyridyl),(NHMe,H,-
H,Et,NHCOPh),(NHMe,H,H,Et,NHCO-2-furyl,(NHMe,H,H,Et,NHCONHPh),(NHMe,H,H,Et-
,NHCOCONHPh),(NHMe,H,H,CH2OH,CONHPh),(NHMe,H,H,CH2OH,CONH-3-pyridyl),(NHMe-
,H,H,CH2OH,NHCOPh),(NHMe,H,H,CH2OH,
NHCO-2-furyl),CH2OH,NHCONHPh),(NHMe,H,H,CH2OH,NHCOCONHPh),(NHMe,H,Me,Me,C-
ONHPh),(NHMe,H,Me,Me,CONH-3-pyridyl),(NHMe,H,
Me,Me,NHCOPh),(NHMe,H,Me,Me,NHCO-2-furyl),(NHMe,H,Me,Me,NHCONHPh),(NHMe,H-
,Me,Me,NHCOCONHPh),(NHMe,H,Me,Et,CONHPh),(NHMe,H,Me,Et,CONH-3-pyridyl),(NH-
Me,H,Me,Et,NHCOPh),(NHMe,H,Me,Et,NHCO-2-furyl),(NHMe,H,Me,Et,NHCONHPh),(NH-
Me,H,Me,Et,NHCOCONHPh),(NHMe,H,Me,CH2OH,
CONHPh),(NHMe,H,Me,CH2OH,CONH-3-pyridyl),(NHMe,H,Me,CH2OH,NHCOPh),(NHMe,H-
,Me,CH2OH,NHCO-2-furyl),(NHMe,H,Me,CH2OH,NHCONHPh),(NHMe,H,Me,CH2OH,NHCOCO-
NHPh),(NHMe,H,Ph,Me,CONHPh),(NHMe,H,Ph,Me,
CONH-3-pyridyl),(NHMe,H,Ph,Me,NHCOPh),(NHMe,H,Ph,Me,NHCO-2-furyl),(NHMe,H-
,Ph,Me,NHCONHPh),(NHMe,H,Ph,Me,NHCOCONHPh),(NEHMe,H,Ph,Et,CONHPh),(NHMe,H,-
Ph,Et,CONH-3-pyridyl),(NHMe,H,Ph,Et,NHCOPh),(NHMe,H,Ph,Et,NHCO-2-furyl),(N-
HMe,H,Ph,Et,NHCONHPh),(NHMe,H,Ph,Et,NHCOCONHPh),(NHMe,H,Ph,CH2OH,CONHPh),(-
NHMe,H,Ph,CH2OH,CONH-3-pyridyl),(NHMe,H,Ph,CH2OH,NHCOPh),(NHMe,H,Ph,CH2OH,-
NHCO-2-furyl),(NHMe,H,Ph,CH2OH,NHCONHPh),(NHMe,H,Ph,CH2OH,NHCOCONHPh),(NHM-
e,H,OH,Me,CONHPh),(NHMe,H,OH,Me,CONH-3-pyridyl),(NHMe,H,OH,Me,NHCOPh),(NHM-
e,H,
OH,Me,NHCO-2-furyl),(NHMe,H,OH,Me,NHCONHPh),(NHMe,H,OH,Me,NHCOCONHPh)-
,(NHMe,H,OH,Et,CONHPh),(NHMe,H,OH,Et,CONH-3-pyridyl),(NHMe,H,
OH,Et,NHCOPh),(NHMe,H,OH,Et,NHCO-2-furyl),(NHMe,H,OH,Et,NHCONHPh),
(NHMe,H,OH,Et,NHCOCONHPh),(NHMe,H,OH,CH2OH,CONHPh),(NHMe,H,OH,CH2OH,CONH--
3-pyridyl),(NHMe,H,OH,CH2OH,NHCOPh),(NHMe,H,OH,CH2OH,NHCO-2-furyl),(NHMe,H-
,OH,CH2OH,NHCONHPh),(NHMe,H,OH,CH2OH,NHCOCONHPh),(NHMe,Me,H,Me,CONHPh),(NH-
Me,Me,H,Me,CONH-3-pyridyl),(NHMe,Me,H,Me,NHCOPh),(NHMe,Me,H,Me,NHCO-2-fury-
l),(NHMe,Me,H,Me,NHCONHPh),(NHMe,Me,H,Me,NHCOCONHPh),(NHMe,Me,H,Et,CONPh),-
(NHMe,Me,H,Et,CONH-3-pyridyl),(NHMe,Me,H,Et,NHCOPh),(NHMe,Me,H,Et,NHCO-2-f-
uryl),(NHMe,Me,H,Et,NHCONHPh),(NHMe,Me,H,Et,NHCOCONHPh),(NHMe,Me,H,CH2OH,C-
ONHPh),(NHMe,Me,H,CH2OH,CONH-3-pyridyl),(NHMe,Me,H,CH2OH,NHCOPh),(NHMe,Me,-
H,CH2OH,NHCO-2-furyl),(NHMe,Me,H,CH2OH,NHCONHPh),(NHMe,Me,H,CH2OH,NHCOCONH-
Ph),(NHMe,Me,Me,Me,CONHPh),(NHMe,Me,Me,Me,CONH-3-pyridyl),(NHMe,Me,Me,Me,N-
HCOPh),(NHMe,Me,Me,Me,NHCO-2-furyl),(NHMe,Me,Me,Me,NHCONHPh),(NHMe,Me,Me,M-
e,NHCOCONHPh),(NHMe,Me,Me,Et,CONHPh),(NHMe,Me,Me,Et,CONH-3-pyridyl),(NHfMe-
,Me,Me,Et,NHCOPh),(NHMe,Me,Me,Et,NHCO-2-furyl),(NHMe,Me,Me,Et,NHCONHPh),(N-
HMe,
Me,Me,Et,NHCOCONHPh),(NHMe,Me,Me,CH2OH,CONHPh),(NHMe,Me;Me,CH2OH,CONH-
-3-pyridyl),(NHMe,Me,Me,CH2OH,NHCOPh),(NHMe,Me,Me,CH2OH,NHCO-2-furyl),(NHM-
e,Me,Me,CH2OH,NHCONHPh),(NHMe,Me,Me,CH2OH,NHCOCONHPh),(NHMe,Me,Ph,Me,CONHP-
h),(NHMe,Me,Ph,Me,CONH-3-pyridyl),(NHMe,Me,Ph,Me,NHCOPh),(NHMe,Me,Ph,Me,NH-
CO-2-furyl),(NHMe,Me,Ph,Me,NHCONHPh),(NHMe,Me,Ph,Me,NHCOCONHPh),(NHMe,Me,P-
h,Et,CONHPh),(NHMe,Me,Ph,Et,CONH-3-pyridyl),(NHMe,Me,Ph,Et,NHCOPh),(NHMe,M-
e,Ph,Et,NHCO-2-furyl),(NHMe,Me,Ph,Et,NHCONHPh),(NHMe,Me,Ph,Et,NHCOCONHPh),-
(NHMe,Me,Ph,CH2OH,CONHPh),(NHMe,Me,Ph,CH2OH,CONH-3-pyridyl),(NHMe,Me,Ph,CH-
2OH,NHCOPh),(NHMe,Me,Ph,CH2OH,NHCO-2-furyl),(NHMe,Me,Ph,CH2OH,NHCONHPh),(N-
HMe,Me,Ph,CH2OH,NHCOCONHPh),(NHMe,Me,OH,Me,CONHPh),(NHMe,Me,OH,Me,CONH-3-p-
yridyl),(NHMe,Me,OH,Me,NHCOPh),(NHMe,
Me,OH,Me,NHCO-2-furyl),(NHMe,Me,OH,Me,NHCONHPh),(NHMe,Me,OH,Me,NHCOCONHPh-
),(NHMe,Me,OH,Et,CONHPh),(NHMe,Me,OH,Et,CONH-3-pyridyl),(NHMe,Me,OH,Et,NHC-
OPh),(NHMe,Me,OH,Et,NHCO-2-furyl),(NHMe,Me,OH,Et,
NHCONHPh),(NHMe,Me,OH,Et,NHCOCONHPh),(NHMe,Me,OH,CH2OH,CONHPh),(NHMe,Me,O-
H,CH2OH,CONH-3-pyridyl),(NHMe,Me,OH,CH2OH,NHCOPh),(NHMe,Me,OH,CH2OH,NHCO-2-
-furyl),(NHMe,Me,OH,CH2OH,NHCONHPh),(NHMe,Me,OH,CH2OH,NHCOCONHPh),(NHMe,Ph-
,H,Me,CONHPh),(NHMe,Ph,H,Me,CONH-3-pyridyl),(NHMe,Ph,H,Me,NHCOPh),(NHMe,Ph-
,H,Me,NHCO-2-furyl,(NHMe,Ph,H,Me,NHCONHPh),(NHMe,Ph,H,Me,NHCOCONHPh),(NHMe-
,Ph,H,Et,CONHPh),(NHMe,Ph,H,Et,CONH-3-pyridyl),(NHMe,Ph,H,Et,NHCOPh),(NHMe-
,Ph,H,Et,NHCO-2-furyl),(NHMe,Ph,H,Et,NHCONHPh),(NHMe,Ph,H,Et,NHCOCONHPh),(-
NHMe,Ph,H,CH2OH,CONHPh),(NHMe,Ph,H,CH2OH,CONH-3-pyridyl),(NHMe,Ph,H,CH2OH,-
NHCOPh),(NHMe,Ph,H,CH2OH,NHCO-2-furyl),(NHMe,Ph,H,CH2OH,NHCONHPh),(NHMe,Ph-
,H,CH2OH,NHCOCONHPh),(NHRMe,Ph,Me,Me,CONHPh),(NHMe,Ph,Me,Me,CONH-3-pyridyl-
),(NHMe,Ph,Me,Me,NHCOPh),(NHMe,Ph,Me,Me,NHCO-2-furyl),(NHMe,Ph,Me,Me,NHCON-
HPh),(NHMe,Ph,Me,Me,NHCOCONHPh),(NHMe,Ph,Me,Et,CONHPh),(NHMe,Ph,Me,Et,CONH-
-3-pyridyl),(NHMe,Ph,Me,Et,NHCOPh),(NHMe,Ph,Me,Et,NHCO-2-furyl),(NHMe,Ph,M-
e,Et,NHCONHPh),(NHMe,Ph,Me,Et,NHCOCONHPh),(NHMe,Ph,Me,CH2OH,CONHPh),(NHMe,-
Ph,Me,CH2OH,CONH-3-pyridyl),(NHMe,Ph,Me,CH2OH,NHCOPh),(NHMe,Ph,Me,CH2OH,NH-
CO-2-furyl),(NHMe,Ph,Me,CH2OH,NHCONHPh),(NHMe,Ph,Me,CH2OH,NHCOCONHPh),(NHM-
e,Ph,Ph,Me,CONHPh),(NHMe,Ph,Ph,Me,CONH-3-pyridyl),(NHMe,Ph,Ph,Me,NHCOPh),(-
NHMe,Ph,Ph,Me,NHCO2-furyl),(NHMe,Ph,Ph,Me,NHCONHPh),(NHMe,Ph,Ph,Me,NHCOCON-
HPh),(NHMe,Ph,Ph,Et,CONHPh),(NHMe,Ph,Ph,Et,CONH-3-pyridyl),(NHMe,Ph,Ph,Et,-
NHCOPh),(NHMe,Ph,Ph,Et,
NHCO-2-furyl),(NHMe,Ph,Ph,Et,NHCONHPh),(NHMe,Ph,Ph,Et,NHCOCONHPh),
(NHMe,Ph,Ph,CH2OH,CONHPh),(NHMe,Ph,Ph,CH2OH,CONH-3-pyridyl),(NH Me,
Ph,Ph,CH2OH,NHCOPh),(NHMe,Ph,Ph,CH2OH,NHCO-2-furyl),(NHMe,Ph,Ph,CH2H,NHCO-
NHPh),(NHMe,Ph,Ph,CH2OH,NHCOCONHPh),(NHMe,Ph,OH,Me,CONHPh),(NHMe,Ph,OH,Me,-
CONH-3-pyridyl),(NHMe,Ph,OH,Me,NHCOPh),(NHMe,
Ph,OH,Me,NHCO-2-furyl),(NHMe,Ph,OH,Me,NHCONHPh),(NHMe,Ph,OH,Me,NHCOCONHPh-
),(NHMe,Ph,OH,Et,CONHPh),(NHMe,Ph,OH,Et,CONH-3-pyridyl),(NHMe,Ph,OH,Et,NHC-
OPh),(NHMe,Ph,OH,Et,NHCO-2-furyl),(NHMe,Ph,OH,Et,NHCONHPh),(NHMe,Ph,OH,Et,-
NHCOCONHPh),(NHMe,Ph,OH,CH2OH,CONHPh),(NHMe,Ph,OH,CH2OH,CONH-3-pyridyl),(N-
HMe,Ph,OH,CH2OH,NHCOPh),(NHMe,Ph,OH,CH2OH,NHCO-2-furyl),(NHMe,Ph,OH,CH2OH,-
NHCONHPh),(NHMe,Ph,OH,CH2OH,NHCOCONHPh),
(NHCH2CH2OH,H,H,Me,CONHPh),(NHCH2CH2OH,H,H,Me,CONH-3-pyridyl),(NHCH2CH2OH-
,H,H,Me,NHCOPh),(NHCH2CH2OH,H,H,Me,NHCO-2-furyl),(NHCH2CH2OH,H,H,Me,NHCONP-
h),(NHCH2CH2OH,H,H,Me,NHCOCONHPh),(NHCH2CH2OH,H,H,Et,CONHPh),(NHCH2CH2OH,H-
,H,Et,CONH-3-pyridyl),(NHCH2CH2OH,H,H,Et,NHCOPh),(NHCH2CH2OH,H,H,Et,NHCO-2-
-furyl),(NHCH2CH2OH,H,H,Et,NHCONHPh),(NHCH2CH2OH,H,H,Et,NHCOCONHPh),(NHCH2-
CH2OH,H,H,CH2OH,CONHPh),(NHCH2CH2OH,H,H,CH2OH,CONH-3-pyridyl),(NHCH2CH2OH,-
H,H,CH2OH,NHCOPh),(NHCH2CH2OH,H,H,CH2OH,NHCO-2-furyl),(NHCH2CH2OH,H,H,CH2O-
H,NHCONPh),(NHCH2CH2OH,H,H,CH2OH,NCOCONHPh),(NHCH2CH2OH,H,Me,Me,CONHPh),(N-
HCH2CH2OH,H,Me,Me,CONH-3-pyridyl),(NHCH2CH2OH,H,Me,Me,NHCOPh),(NHCH2CH2OH,-
H,Me,Me,NHCO-2-furyl),(NHCH2CH2OH,H,Me,Me,NHCONHPh),(NHCH2CH2OH,H,Me,Me,NH-
COCONHPh),(NHCH2CH2OH,H,Me,Et,CONHPh),(NHCH2CH2OH,H,Me,Et,CONH-3-pyridyl),-
(NHCH2CH2OH,H,Me,Et,NHCOPh),(NHCH2CH2OH,H,Me,Et,NHCO-2-furyl),(NHCH2CH2OH,-
H,Me,Et,NHCONHPh),(NHCH2CH2OH,H,Me,Et,NHCOCONHPh),(NHCH2CH2OH,H,Me,CH2OH,C-
ONHPh),(NHCH2CH2OH,H,Me,CH2OH,CONH-3-pyridyl),(NHCH2CH2OH,H,Me,CH2OH,NHCOP-
h),(NHCH2CH2OH,
H,Me,CH2OH,NHCO-2-furyl),(NHCH2CH2OH,H,Me,CH2OH,NHCONPh),(NHCH2CH2OH,H,Me-
,CH2OH,NHCOCONHPh),(NHCH2CH2OH,H,Ph,Me,CONHPh),(NHCH2CH2OH,H,Ph,Me,CONH-3--
pyridyl),(NHCH2CH2OH,H,Ph,Me,NHCOPh),(NHCH2CH2OH,H,Ph,Me,NHCO-2-furyl),(NH-
CH2CH2OH,H,Ph,Me,NHCONHPh),
(NHCH2CH2OH,H,Ph,Me,NHCOCONHPh),(NHCH2CH2OH,H,Ph,Et,CONHPh),(NHCH2CH2OH,H-
,Ph,Et,CONH-3-pyridyl),(NHCH2CH2OH,H,Ph,Et,NHCOPh),(NHCH2CH2OH,H,Ph,Et,NHC-
O-2-furyl),(NHCH2CH2OH,H,Ph,Et,NHCONHPh),(NHCH2CH2OH,H,Ph,Et,NHCOCONHPh),(-
NHCH2CH2OH,H,Ph,CH2OH,CONHPh),(NHCH2CH2OH,H,Ph,CH2OH,CONH-3-pyridyl),(NHCH-
2CH2OH,H,Ph,CH2OH,
NHCOPh),(NHCH2CH2OH,H,Ph,CH2OH,NHCO-2-furyl),(NHCH2CH2OH,H,Ph,CH2OH,NHCON-
HPh),(NHCH2CH2OH,H,Ph,CH2OH,NHCOCONHPh),(NHCH2CH2OH,H,OH,Me,CONHPh),(NHCH2-
CH2OH,H,OH,Me,CONH-3-pyridyl),(NHCH2CH2OH,H,OH,Me,NHCOPh),(NHCH2CH2OH,H,OH-
,Me,NHCO-2-furyl),(NHCH2CH2OH,H,OH,Me,NHCONHPh),(NHCH2CH2OH,H,OH,Me,NHCOCO-
NHPh),(NHCH2CH2OH,H,OH,Et,CONHPh),(NHCH2CH2OH,H,OH,Et,CONH-3-pyridyl),(NHC-
H2CH2OH,H,OH,Et,NHCOPh),(NHCH2CH2OH,H,OH,Et,NHCO-2-furyl),(NHCH2CH2OH,H,OH-
,Et,NHCONHPh),(NHCH2CH2OH,H,OH,Et,NHCOCONHPh),(NHCH2CH2OH,H,OH,CH2OH,CONHP-
h),(NHCH2CH2OH,H,OH,CH2OH,CONH-3-pyridyl),(NHCH2CH2OH,H,OH,CH2OH,NHCOPh),(-
NHCH2CH2OH,H,OH,CH2OH,NHCO-2-fu
yl),(NHCH2CH2OH,H,OH,CH2OH,NHCONHPh),(NHCH2CH2OH,H,OH,CH2OH,NHCOCONHPh),(-
NHCH2CH2OH,Me,H,Me,CONHPh),(NHCH2CH2OH,Me,H,Me,CONH-3-pyridyl),(NHCH2CH2OH-
,Me,H,Me,NHCOPh),(NHCH2CH2OH,Me,H,Me,NHCO-2-furyl),(NHCH2CH2OH,Me,H,Me,NHC-
ONHPh),(NHCH2CH2OH,Me,H,Me,NHCOCONHPh),(NHCH2CH2OH,Me,H,Et,CONHPh),(NHCH2C-
H2OH,Me,H,Et,CONH-3-pyridyl),(NHCH2CH2OH,Me,H,Et,NHCOPh),(NHCH2CH2OH,Me,H,-
Et,NHCO-2-furyl),(NHCH2CH2OH,Me,H,Et,NHCONHPh),(NHCH2CH2OH,Me,H,Et,NHCOCON-
HPh),(NHCH2CH2OH,Me,H,CH2OH,CONHPh),(NHCH2CH2OH,Me,H,CH2OH,CONH-3-pyridyl)-
,(NHCH2CH2OH,Me,H,CH2OH,NHCOPh),(NHCH2CH2OH,Me,H,CH2OH,NHCO-2-furyl),(NHCH-
2CH2OH,Me,H,CH2OH,NHCONHPh),(NHCH2CH2OH,Me,H,CH2OH,NHCOCONHPh),(NHCH2CH2OH-
,Me,Me,Me,CONHPh),(NHCH2CH2OH,Me,Me,Me,CONH-3-pyridyl),(NHCH2CH2OH,
Me,Me,Me,NHCOPh),(NHCH2CH2OH,Me,Me,Me,NHCO-2-furyl),(NHCH2CH2OH,Me,Me,Me,-
NHCONHPh),(NHCH2CH2OH,Me,Me,Me,NHCOCONHPh),(NHCH2CH2OH,Me,Me,Et,CONHPh),(N-
HCH2CH2OH,Me,Me,Et,CONH3-pyridyl),(NHCH2CH2OH,Me,Me,Et,NHCOPh),(NHCH2CH2OH-
,Me,Me,Et,NHCO-2-furyl),(NHCH2CH2OH,Me,Me,Et,NHCONHPh),(NHCH2CH2OH,Me,Me,E-
t,NHCOCONHPh),(NHCH2CH2OH,Me,Me,CH2OH,CONHPh),(NHCH2CH2OH,Me,Me,CH2OH,CONH-
-3-pyridyl),(NHCH2CH2OH,Me,Me,CH2OH,NHCOPh),(NHCH2CH2OH,Me,Me,CH2OH,NHCO-2-
-furyl),(NHCH2CH2OH,Me,Me,CH2OH,NHCONHPh),(NHCH2CH2OH,Me,Me,CH2OH,NHCOCONH-
Ph),(NHCH2CH2OH,Me,Ph,Me,CONHPh),(NHCH2CH2OH,Me,Ph,Me,CONH-3-pyridyl),(NHC-
H2CH2OH,Me,Ph,Me,NHCOPh),(NHCH2CH2OH,Me,Ph,Me,NHCO-2-furyl),(NHCH2CH2OH,Me-
,Ph,Me,NHCONHPh),(NHCH2CH2OH,Me,Ph,Me,NHCOCONHPh),(NHCH2CH2OH,Me,Ph,Et,CON-
HPh),(NHCH2CH2OH,Me,Ph,Et,CONH-3-pyridyl),(NHCH2CH2OH,Me,Ph,Et,NHCOPh),(NH-
CH2CH2OH,Me,Ph,Et,NHCO-2-furyl),(NHCH2CH2OH,Me,Ph,Et,NHCONHPh),(NHCH2CH2OH-
,Me,Ph,Et,NHCOCONHPh),(NHCH2CH2OH,Me,Ph,CH2OH,CONHPh),(NHCH2CH2OH,Me,Ph,CH-
2OH,CONH-3-pyridyl,(NHCH2CH2OH,Me,
Ph,CH2OH,NHCOPh),(NHCH2CH2OH,Me,Ph,CH2OH,NHCO-2-furyl),(NHCH2CH2OH,Me,Ph,-
CH2OH,NHCONHPh),(NHCH2CH2OH,Me,Ph,CH2OH,NHCOCONHPh),(NHCH2CH2OH,Me,OH,Me,C-
ONHPh),(NHCH2CH2OH,Me,OH,Me,CONH-3-pyridyl),(NHCH2CH2OH,Me,OH,Me,NHCOPh),(-
NHCH2CH2OH,Me,OH,Me,NHCO-2-furyl,(NHCH2CH2OH,Me,OH,Me,NHCONHPh),(NHCH2CH2O-
H,Me,OH,Me,
NHCOCONHPh),(NHCH2CH2OH,Me,OH,Et,CONHPh),(NHCH2CH2OH,Me,OH,
Et,CONH-3-pyridyl),(NHCH2CH2OH,Me,OH,Et,NHCOPh),(NHCH2CH2OH,Me,OH,Et,NHCO-
-2-furyl),(NHCH2CH2OH,Me,OH,Et,NHCONHPh),(NHCH2CH2OH,Me,OH,Et,NHCOCONHPh),-
(NHCH2CH2OH,Me,OH,CH2OH,CONHPh),(NHCH2CH2OH,Me,OH,CH2OH,CONH-3-pyridyl),(N-
HCH2CH2OH,Me,OH,CH2OH,NHCOPh),(NHCH2CH2OH,Me,OH,CH2OH,NHCO-2-furyl,(NHCH2C-
H2OH,Me,OH,CH2OH,NHCONHPh),(NHCH2CH2OH,Me,OH,CH2OH,NHCOCONHPh),(NHCH2CH2OH-
,Ph,H,Me,CONHPh),(NHCH2CH2OH,Ph,H,Me,CONH-3-pyridyl,(NHCH2CH2OH,Ph,H,Me,NH-
COPh),(NHCH2CH2OH,Ph,H,Me,NHCO-2-furyl),(NHCH2CH2OH,Ph,H,Me,NHCONHPh),(NHC-
H2CH2OH,Ph,H,Me,NHCOCONHPh),(NHCH2CH2OH,Ph,H,Et,CONHPh),(NHCH2CH2OH,Ph,H,E-
t,CONH-3-pyridyl,(NHCH2CH2OH,Ph,H,Et,NHCOPh),(NHCH2CH2OH,Ph,H,Et,NHCO-2-fu-
ryl,(NHCH2CH2OH,
Ph,H,Et,NHCONHPh),(NHCH2CH2OH,Ph,H,Et,NHCOCONHPh),(NHCH2CH2OH,Ph,H,CH2OH,-
CONHPh),(NHCH2CH2OH,Ph,H,CH2OH,CONH-3-pyridyl),(NHCH2CH2OH,Ph,H,CH2OH,NHCO-
Ph),(NHCH2CH2OH,Ph,H,CH2OH,NHCO-2-furyl),(NH
CH2CH2OH,Ph,H,CH2OH,NHCONHPh),(NHCH2CH2OH,Ph,H,CH2OH,NHCOCONHPh),(NHCH2CH-
2OH,Ph,Me,Me,CONHPh),(NHCH2CH2OH,Ph,Me,Me,CONH-3-pyridyl),(NHCH2CH2OH,Ph,M-
e,Me,NHCOPh),(NHCH2CH2OH,Ph,Me,Me,NHCO-2-furyl),(NHCH2CH2OH,Ph,Me,Me,NHCON-
HPh),(NHCH2CH2OH,Ph,Me,
Me,NHCOCONHPh),(NHCH2CH2OH,Ph,Me,Et,CONHPh),(NHCH2CH2OH,Ph,Me,Et,CONH-3-p-
yridyl),(NHCH2CH2OH,Ph,Me,Et,NHCOPh),(NHCH2CH2OH,Ph,
Me,Et,NHCO-2-furyl),(NHCH2CH2OH,Ph,Me,Et,NHCONHPh),(NHCH2CH2OH,Ph,Me,Et,N-
HCOCONHPh),(NHCH2CH2OH,Ph,Me,CH2OH,CONHPh),(NHCH2CH2OH,Ph,Me,CH2OH,CONH-3--
pyridyl,(NHCH2CH2OH,Ph,Me,CH2OH,NHCOPh),
(NHCH2CH2OH,Ph,Me,CH2OH,NHCO-2-furyl),(NHCH2CH2OH,Ph,Me,CH2OH,
NHCONHPh),(NHCH2CH2OH,Ph,Me,CH2OH,NHCOCONHPh),(NHCH2CH2OH,
Ph,Ph,Me,CONHPh),(NHCH2CH2OH,Ph,Ph,Me,CONH-3-pyridyl),(NHCH2CH2OH,Ph,Ph,M-
e,NHCOPh),(NHCH2CH2OH,Ph,Ph,Me,NHCO-2-furyl,(NHCH2CH2OH,Ph,Ph,Me,NHCONHPh)-
,(NHCH2CH2OH,Ph,Ph,Me,NHCOCONHPh),(NHCH2CH2OH,Ph,Ph,Et,CONHPh),(NHCH2CH2OH-
,Ph,Ph,Et,CONH-3-pyridyl),(NHCH2CH2OH,Ph,Ph,Et,NHCOPh),(NHCH2CH2OH,Ph,Ph,E-
t,NHCO-2-furyl),(NHCH2CH2OH,Ph,Ph,Et,NHCONHPh),(NHCH2CH2OH,Ph,Ph,EtNHCOCON-
HPh),(NHCH2CH2OH,Ph,Ph,CH2OH,CONHPh),(NHCH2CH2OH,Ph,Ph,CH2OH,CONH-3-pyridy-
l),(NHCH2CH2OH,Ph,Ph,CH2OH,NHCOPh),(NHCH2CH2OH,Ph,Ph,CH2OH,NHCO-2-furyl),(-
NHCH2CH2OH,Ph,Ph,CH2OH,NHCONHPh),(NHCH2CH2OH,Ph,Ph,CH2OH,NHCOCONHPh),(NHCH-
2CH2OH,Ph,OH,Me,CONHPh),(NHCH2CH2OH,Ph,OH,Me,CONH-3-pyridyl),(NHOH2CH2OH,P-
h,OH,Me,NHCOPh),(NHCH2CH2OH,Ph,OH,Me,NHCO-2-furyl),(NHCH2CH2OH,Ph,OH,Me,NH-
CONHPh),(NHCH2CH2OH,Ph,OH,Me,NHCOCONHPh),(NHCH2CH2OH,Ph,OH,Et,CONHPh),(NHC-
H2CH2OH,Ph,OH,Et,CONH-3-pyridyl),(NHCH2CH2OH,Ph,OH,Et,NHCOPh),(NHCH2CH2OH,-
Ph,OH,Et,NHCO-2-furyl),(NHCH2CH2OH,Ph,OH,Et,NHCONHPh),(NHCH2CH2OH,Ph,OH,Et-
,NHCOCONHPh),(NHCH2CH2OH,Ph,OH,CH2OH,CONHPh),(NHCH2CH2OH,Ph,OH,CH2OH,CONH--
3-pyridyl),(NHCH2CH2OH,Ph,OH,
CH2OH,NHCOPh),(NHCH2CH2OH,Ph,OH,CH2OH,NHCO-2-furyl),(NHCH2CH2OH,Ph,OH,CH2-
OH,NHCONHPh),(NHCH2CH2OH,Ph,OH,CH2OH,NHCOCONHPh),
(NHCH2CONH2,H,H,Me,CONHPh),(NHCH2CONH2,H,H,Me,CONH-3-pyridyl),(NHCH2CONH2-
,H,H,Me,NHCOPh),(NHCH2CONH2,H,H,Me,NHCO-2-furyl),(NHCH2CONH2,H,H,Me,NHCONH-
Ph),(NHCH2CONH2,H,H,Me,NHCOCONHPh),(NHCH2CONH2,H,H,Et,CONHPh),(NHCH2CONH2,-
H,H,Et,CONH-3-pyridyl),(NHCH2CONH2,H,H,Et,NCOPh),(NHCH2CONH2,H,H,Et,NHCO-2-
-furyl),(NHCH2CONH2,H,H,Et,NHCONHPh),(NHCH2CONH2,H,H,Et,NHCOCONHPh),(NHCH2-
CONH2,H,H,CH2OH,CONHPh),(NHCH2CONH2,H,H,CH2OH,CONH-3-pyridyl),(NHCH2CONH2,-
H,H,CH2OH,NHCOPh),(NHCH2CONH2,H,H,CH2OH,NHCO-2-furyl),(NHCH2CONH2,H,H,CH2O-
H,NHCONHPh),(NHCH2CONH2,H,H,CH2OH,NHCOCONHPh),(NHCH2CONH2,H,Me,Me,CONHPh),-
(NHCH2CONH2,H,Me,Me,CONH-3-pyridyl),(NHCH2CONH2,H,Me,Me,NHCOPh),(NHCH2CONH-
2,H,Me,Me,NHCO-2-furyl),(NHCH2CONH2,H,Me,Me,NHCONHPh),(NHCH2CONH2,H,Me,Me,-
NHCOCONHPh),(NHCH2CONH2,H,Me,Et,CONHPh),(NHCH2CONH2,H,Me,Et,CONH-3-pyridyl-
),(NHCH2CONH2,H,Me,Et,NHCOPh),(NHCH2CONH2,H,Me,Et,NHCO-2-furyl),(NHCH2CONH-
2,H,Me,Et,NHCONHPh),(NHCH2CONH2,H,Me,Et,NHCOCONHPh),(NHCH2CONH2,H,Me,CH2OH-
,CONHPh),(NHCH2CONH2,H,Me,CH2OH,CONH-3-pyridyl),(NHCH2CONH2,H,Me,CH2OH,NHC-
OPh),(NHCH2CONH2,
H,Me,CH2OH,NHCO-2-furyl),(NHCH2CONH2,H,Me,CH2OH,NHCONHPh),(NHCH2CONH2,H,M-
e,CH2OH,NHCOCONHPh),(NHCH2CONH2,H,Ph,Me,CONHPh),(NHCH2CONH2,H,Ph,Me,CONH-3-
-pyridyl),(NHCH2CONH2,H,Ph,Me,NHCOPh),(NHCH2CONH2,H,Ph,Me,NHCO-2-furyl),(N-
HCH2CONH2,H,Ph,Me,NHCONHPh),
(NHCH2CONH2,H,Ph,Me,NHCOCONHPh),(NHCH2CONH2,H,Ph,Et,CONHPh),(NHCH2CONH2,H-
,Ph,Et,CONH-3-pyridyl),(NHCH2CONH2,H,Ph,Et,NHCOPh),(NHCH2CONH2,H,Ph,Et,NHC-
O-2-furyl),(NHCH2
CONH2,H,Ph,Et,NCONHPh),(NHCH2CONH2,H,Ph,Et,NHCOCONPh),(NHCH2CONH2,H,Ph,CH-
2OH,CONHPh),(NHCH2CONH2,H,Ph,CH2OH,CONH-3-pyridyl),(NHCH2CONH2,H,Ph,CH2OH,
NHCOPh),(NHCH2CONH2,H,Ph,CH2OH,NHCO-2-furyl),(NHCH2CONH2,H,Ph,CH2OH,NHCON-
HPh),(NHCH2CONH2,H,Ph,CH2OH,NHCOCONHPh),(NHCH2CONH2,H,OH,Me,CONHPh),(NHCH2-
CONH2,H,OH,Me,CONH-3-pyridyl),(NHCH2CONH2,H,OH,Me,NHCOPh),(NHCH2CONH2,H,OH-
,Me,NHCO-2-furyl),(NHCH2CONH2,H,OH,Me,NHCONHPh),(NHCH2CONH2,H,OH,Me,NHCOCO-
NHPh),(NHCH2CONH2,H,OH,Et,CONHPh),(NHCH2CONH2,H,OH,Et,CONH-3-pyridyl),(NHC-
H2CONH2,H,OH,Et,NHCOPh),(NHCH2CONH2,H,OH,Et,NHCO-2-furyl),(NHCH2CONH2,H,OH-
,Et,NHCONHPh),(NHCH2CONH2,H,OH,Et,NHCOCONHPh),(NHCH2CONH2,H,OH,CH2OH,CONHP-
h),(NHCH2CONH2,H,OH,CH2OH,CONH-3-pyridyl),(NHCH2CONH2,H,OH,CH2OH,NHCOPh),(-
NHCH2CONH2,H,OH,CH2OH,NHCO-2-furyl),(NHCH2CONH2,H,OH,CH2OH,NHCONHPh),(NHCH-
2CONH2,H,OH, CH2OH,NHCO CONHPh),(NHCH2CONH2,Me,H,Me,CONHPh),(NHCH2
CONH2,
Me,H,Me,CONH-3-pyridyl),(NHCH2CONH2,Me,H,Me,NHCOPh),(NHCH2CONH2,
Me,H,Me,NHCO-2-furyl),(NHCH2CONH2,Me,H,Me,NHCONHPh),(NHCH2CONH2,Me,H,Me,N-
HCOCONHPh),(NHCH2CONH2,Me,H,Et,CONHPh),(NHCH2CONH2,Me,H,Et,CONH-3-pyridyl)-
,(NHCH2CONH2,Me,H,Et,NHCOPh),(NHCH2CONH2,Me,H,Et,NHCO-2-furyl),(NHCH2CONH2-
,Me,H,Et,NHCONHPh),(NHCH2CONH2,Me,H,Et,NHCOCONHPh),(NHCH2CONH2,Me,H,CH2OH,-
CONHPh),(NHCH2CONH2,Me,H,CH2OH,CONH-3-pyridyl),(NHCH2CONH2,Me,H,CH2OH,NHCO-
Ph),(NHCH2CONH2,Me,H,CH2OH,NHCO-2-furyl),(NHCH2CONH2,Me,H,CH2OH,NHCONHPh),-
(NHCH2CONH2,Me,H,CH2OH,NHCOCONHPh),(NHCH2CONH2,Me,
Me,Me,CONHPh),(NHCH2CONH2,Me,Me,Me,CONH-3-pyridyl),(NHCH2CONH2,
Me,Me,Me,NHCOPh),(NHCH2CONH2,Me,Me,Me,NHCO-2-furyl),(NHCH2CONH2,Me,Me,Me,-
NHCONHPh),(NHCH2CONH2,Me,Me,Me,NHCOCONHPh),(NHCH2CONH2,Me,Me,Et,CONHPh),(N-
HCH2CONH2,Me,Me,Et,CONH-3-pyridyl),(NHCH2CONH2,Me,Me,Et,NHCOPh),(NHCH2CONH-
2,Me,Me,Et,NHCO-2-furyl),(NHCH2CONH2,Me,Me,Et,NHCONHPh),(NHCH2CONH2,Me,Me,-
Et,NHCOCONHPh),(NHCH2CONH2,Me,Me,CH2OH,CONHPh),(NHCH2
CONH2,Me,Me,CH2OH,CONH-3-pyridyl),(NHCH2CONH2,Me,Me,CH2OH,NHCOPh),(NHCH2C-
ONH2,Me,Me,CH2OH,NHCO-2-furyl),(NHCH2CONH2,Me,Me,CH2OH,NHCONHPh),(NHCH2CON-
H2,Me,Me,CH2OH,NHCOCONHPh),(NHCH2CONH2,Me,Ph,Me,CONHPh),(NHCH2CONH2,Me,Ph,-
Me,CONH-3-pyridyl),(NHCH2CONH2,Me,Ph,Me,NHCOPh),(NHCH2CONH2,Me,Ph,Me,NHCO--
2-furyl),(NHCH2CONH2,Me,Ph,Me,NHCONHPh),(NHCH2CONH2,Me,Ph,Me,NHCOCONHPh),(-
NHCH2CONH2,Me,Ph,Et,CONHPh),(NHCH2CONH2,Me,Ph,Et,CONH-3-pyridyl),(NHCH2CON-
H2,Me,Ph,Et,NRCOPh),
(NHCH2CONH2,Me,Ph,Et,NHCO-2-furyl),(NHCH2CONH2,Me,Ph,Et,NHCONHPh),(NHCH2C-
ONH2,Me,Ph,Et,NHCOCONHPh),(NHCH2CONH2,Me,Ph,CH2OH,CONHPh),(NHCH2CONH2,Me,P-
h,CH2OH,CONH-3-pyridyl),(NHCH2CONH2,Me,Ph,CH2OH,NHCOPh),(NHCH2CONH2,Me,Ph,-
CH2OH,NHCO-2-furyl),(NHCH2CONH2,Me,Ph,CH2OH,NHCONHPh),(NHCH2CONH2,Me,Ph,CH-
2OH,NHCOCONHPh),(NHCH2CONH2,Me,OH,Me,CONHPh),(NHCH2CONH2,Me,OH,Me,CONH-3-p-
yridyl),(NHCH2CONH2,Me,OH,Me,NHCOPh),(NHCH2CONH2,Me,OH,Me,NHCO-2-furyl),(N-
HCH2CONH2,Me,OH,Me,NHCONHPh),(NHCH2CONH2,Me,OH,Me, NHCO
CONHPh),(NHCH2CONH2,Me,OH,Et,CONHPh),(NHCH2CONH2,Me,OH,
Et,CONH-3-pyridyl),(NHCH2CONH2,Me,OH,Et,NCOPh),(NHCH2CONH2,Me,OH,Et,NHCO--
2-furyl),(NHCH2CONH2,Me,OH,Et,NHCONPh),(NHCH2CONH2,Me,OH,Et,NHCOCONHPh),(N-
HCH2
CONH2,Me,OH,CH2OH,CONHPh),(NHCH2CONH2,Me,OH,CH2OH,CONH-3-pyridyl),(NH-
CH2CONH2,Me,OH,CH2OH,NHCOPh),(NHCH2
CONH2,Me,OH,CH2OH,NHCO-2-furyl),(NHCH2CONH2,Me,OH,CH2OH,NHCONHPh),(NHCH2C-
ONH2,Me,OH,CH2OH,NHCO CONHPh),(NHCH2
CONH2,Ph,H,Me,CONHPh),(NHCH2CONH2,Ph,H,Me,CONH-3-pyridyl),(NHCH2CONH2,Ph,-
H,Me,NHCOPh),(NHCH2CONH2,Ph,H,Me,NHCO-2-furyl),(NHCH2CONH2,Ph,H,Me,NHCONHP-
h),(NHCH2CONH2,Ph,H,Me,NHCOCONHPh),(NHCH2CONH2,Ph,H,Et,CONHPh),(NHCH2CONH2-
,Ph,H,Et,CONH-3-pyridyl),(NHCH2CONH2,Ph,H,Et,NHCOPh),(NHCH2CONH2,Ph,H,Et,N-
HCO-2-furyl),(NHCH2CONH2,Ph,H,Et,NHCONHPh),(NHCH2CONH2,Ph,H,Et,NHCOCONHPh)-
,(NHCH2CONH2,Ph,H,CH2OH,CONHPh),(NHCH2OCONH2,Ph,H,CH2OH,CONH-3-pyridyl),(N-
HCH2CONH2,Ph,H,CH2OH,NHCOPh),(NHCH2CONH2,Ph,H,CH2OH,NHCO-2-furyl),(NHCH2CO-
NH2,Ph,H,CH2OH,NHCONHPh),(NHCH2CONH2,Ph,H,CH2OH,NHCOCONHPh),(NHCH2CONH2,Ph-
,Me,Me,CONHPh),(NHCH2CONH2,Ph,Me,Me,CONH-3-pyridyl),(NHCH2CONH2,Ph,Me,Me,N-
HCOPh),(NHCH2CONH2,Ph,Me,Me,
NHCO-2-furyl),(NHCH2CONH2,Ph,Me,Me,NHCONHPh),(NHCH2CONH2,Ph,Me,
Me,NHCOCONHPh),(NHCH2CONH2,Ph,Me,Et,CONHPh),(NHCH2CONH2,Ph,Me,Et,CONH-3-p-
yridyl),(NHCH2CONH2,Ph,Me,Et,NHCOPh),(NHCH2CONH2,Ph,
Me,Et,NHCO-2-fu
yl),(NHCH2CONH2,Ph,Me,Et,NHCONHPh),(NHCH2CONH2,Ph,Me,Et,NHCOCONHPh),(NHCH-
2 CONH2,Ph,Me,CH2OH,CONHPh),(NHCH2
CONH2,Ph,Me,CH2OH,CONH-3-pyridyl),(NHCH2OCONH2,Ph,Me,CH2OH,NHCOPh),
(NHCH2CONH2,Ph,Me,CH2OH,NHCO-2-furyl),(NHCH2CONH2,Ph,Me,CH2OH,
NHCONHPh),(NHCH2CONH2,Ph,Me,CH2OH,NHCOCONHPh),(NHCH2CONH2,
Ph,Ph,Me,CONHPh),(NHCH2CONH2,Ph,Ph,Me,CONH-3-pyridyl),(NHCH2CONH
2,Ph,Ph,Me,NHCOPh),(NHCH2CONH2,Ph,Ph,Me,NHCO-2-furyl),(NHCH2CONH2,Ph,Ph,M-
e,NHCONHPh),(NHCH2CONH2,Ph,Ph,Me,NHCOCONHPh),(NHCH2CONH2,Ph,Ph,Et,CONHPh),-
(NHCH2CONH2,Ph,Ph,Et,CONH-3-pyridyl,(NHCH2CONH2,Ph,Ph,Et,NHCOPh),(NHCH2CON-
H2,Ph,Ph,Et,NHCO-2-furyl),(NHCH2CONH2,Ph,Ph,Et,NHCONHPh),(NHCH2CONH2,Ph,Ph-
,Et,NHCOCONHPh),(NHCH2CONH2,Ph,Ph,CH2OH,CONHPh),(NHCH2CONH2,Ph,Ph,CH2OH,CO-
NH-3-pyridyl)(NHCH2CONH2,Ph,Ph,CH2OH,NHCOPh),(NHCH2CONH2,Ph,Ph,CH2OH,NHCO--
2-furyl),(NH
CH2CONH2,Ph,Ph,CH2OH,NHCONHPh),(NHCH2OCONH2,Ph,Ph,CH2OH,NHCOCONHPh),(NHCH-
2CONH2,Ph,OH,Me,CONHPh),(NHCH2CONH2,Ph,OH,Me,CONH3-pyridyl),(NHCH2
CONH2,Ph,OH,Me,NHCOPh),(NHCH2CONH2,Ph,OH,Me,NHCO2-furyl),(NHCH2CONH2,Ph,O-
H,Me,NHCONHPh),(NHCH2CONH2,Ph,OH,Me,NHCOCONHPh),(NHCH2CONH2,Ph,OH,Et,CONHP-
h),(NHCH2CONH2,Ph,OH,Et,CONH-3-pyridyl),(NHCH2CONH2,Ph,OH,Et,NHCOPh),(NHCH-
2CONH2,Ph,OH,Et,HCO-2-furyl),(NHCH2CONH2,Ph,OH,Et,NHCONHPh),(NHCH2CONH2,Ph-
,OH,Et,NHCOCONHPh),(NHCH2CONH2,Ph,OH,CH2OH,CONHPh),(NHCH2CONH2,Ph,OH,CH2OH-
,CONH-3-pyridyl),(NHCH2CONH2,Ph,OH,CH2OH,NHCOPh),(NHCH2CONH2,Ph,OH,CH2OH,N-
HCO-2-furyl),(NHCH2CONH2,Ph,OH,CH2OH,NHCONHPh),(NHCH2
CONH2,Ph,OH,CH2OH,NHCO CONHPh),
(NHCH(Bn)CONH2,H,H,Me,CONHPh),(NHCH(Bn)CONH2,H,H,Me,CONH-3-pyridyl),(NHCH-
(Bn)CONH2,H,H,Me,NBCOPh),(NHCH(Bn)CONH2,H,H,Me,NHCO-2-furyl),(NHCH(Bn)CONH-
2,H,H,Me,NHCONHPh),(NHCH(Bn)CONH2,H,H,Me,NHCOCONHPh),(NHCH(Bn)CONH2,H,H,Et-
,CONHPh),(NHCH(Bn)CONH2,H,H,Et,CONH-3-pyridyl),(NHCH(Bn)CONH2,H,H,Et,NHCOP-
h),(NHCH(Bn)CONH2,H,H,Et,NHCO-2-furyl),(NHCH(Bn)CONH2,H,H,Et,NHCONHPh),(NH-
CH(Bn)CONH2,H,
H,Et,NHCOCONHPh),(NHCH(Bn)CONH2,H,H,CH2OH,CONHPh),(NHCH(Bn)CONH2,H,H,CH2O-
H,CONH-3-pyridyl),(NHCH(Bn)CONH2,H,H,CH2OH,NHCOPh),(NHCH(Bn)CONH2,H,H,CH2O-
H,NHCO-2-furyl),(NHCH(Bn)CONH2,H,H,CH2OH,
NHCONHPh),(NHCH(Bn)CONH2,H,H,CH2OH,NHCOCONHPh),(NHCH(Bn)CONH2,H,Me,Me,CON-
HPh),(NHCH(Bn)CONH2,H,Me,Me,CONH-3-pyridyl),(NHCH(Bn)CONH2,H,Me,Me,NHCOPh)-
,(NHCH(Bn)CONH2,H,Me,Me,NHCO-2-furyl),(NHCH(Bn)CONH2,H,Me,Me,NHCONHPh),(NH-
CH(Bn)CONH2,H,Me,Me,NHCOCONHPh),(NHCH(Bn)CONH2,H,Me,Et,CONHPh),(NHCH(Bn)CO-
NH2,H,Me,Et,CONH-3-pyridyl),(NHCH(Bn)CONH2,H,Me,Et,NHCOPh),(NHCH(Bn)CONH2,-
H,Me,Et,NHCO-2-furyl),(NHCH(Bn)CONH2,H,Me,Et,NHCONHPh),(NHCH(Bn)CONH2,H,Me-
,
Et,NHCOCONHPh),(NHCH(Bn)CONH2,H,Me,CH2OH,CONHPh),(NHCH(Bn)CONH2,H,Me,CH2-
OH,CONH-3-pyridyl),(NHCH(Bn)CONH2,H,Me,CH2OH,NHCOPh),(NHCH(Bn)CONH2,H,Me,C-
H2OH,NHCO-2-furyl),(NHCH(Bn)CONH2,H,Me,CH2OH,NHCONHPh),(NHCH(Bn)CONH2,H,Me-
,CH2OH,NHCOCONHPh),(NHCH(Bn)CONH2,H,Ph,Me,CONHPh),(NHCH(Bn)CONH2,H,Ph,Me,C-
ONH-3-pyridyl),(NHCH(Bn)CONH2,H,Ph,Me,NHCOPh),(NHCH(Bn)CONH2,H,Ph,Me,NHCO--
2-furyl),(NHCH(Bn)CONH2,H,Ph,Me,NHCONHPh),(NHCH(Bn)CONH2,H,Ph,Me,NHCONHPh)-
,(NHCH(Bn)CONH2,H,Ph,Et,CONHPh),(NHCH(Bn)CONH2,H,Ph,Et,CONH-3-pyridyl),(NC-
H(Bn)CONH2,H,Ph,Et,NBCOPh),(NHCH(Bn)CONH2,H,Ph,Et,
NHCO-2-furyl),(NHCH(Bn)CONH2,H,Ph,Et,NBCONHPh),(NHCH(Bn)CONH2,H,
Ph,Et,NBCOCONHPh),(NHCH(Bn)CONH2,H,Ph,CH2OH,CONHPh),(NHCH(Bn)CONH2,H,Ph,C-
H120,CONH-3-pyridyl),(NHCH(Bn)CONH2,H,Ph,CH2OH,NHCONHPh),(NHCH(Bn)CONH2,H,-
Ph,CH2OH,NHCO-2-furyl),(NHCH(Bn)CONH2,H,Ph,CH2OH,NBCONHPh),(NHCH(Bn)CONH2,-
H,Ph,CH2OH,NHCOCONHPh),(NHCH(Bn)CONH2,H,OH,Me,CONHPh),(NHCH(Bn)CONH2,H,OH,-
Me,CONH-3-pyridyl),(NHCH(Bn)CONH2,H,OH,Me,NHCOPh),(NHCH(Bn)CONH2,H,OH,Me,N-
HCO2-furyl),(NHCH(Bn)CONH2,H,OH,Me,NHCONHPh),(NHCH(Bn)CONH2,H,OH,Me,NHCOCO-
NHPh),(NHCH(Bn)CONH2,H,OH,Et,CONHPh),(NHCH(Bn)CONH2,H,OH,
Et,CONH-3-pyridyl),(NHCH(Bn)CONH2,H,OH,Et,NHCOPh),(NHCH(Bn)CONH2,
H,OH,Et,NHCO-2-furyl),(NHCH(Bn)CONH2,H,OH,Et,NHCONHPh),(NHCH(Bn)CONH2,H,O-
H,Et,NHCOCONHPh),(NHCH(Bn)CONH2,H,OH,CH2OH,CONHPh),(NHCH(Bn)CONH2,H,OH,CH2-
OH,CONH-3-pyridyl),(NHCH(Bn)CONH2,H,OH,CH2OH,NHCOPh),(NHCH(Bn)CONH2,H,OH,C-
H2OH,NHCO-2-furyl),(NHCH(Bn)CONH2,H,OH,CH2OH,NHCONHPh),(NHCH(Bn)CONH2,H,OH-
,CH2OH,NHCOCONHPh),(NHCH(Bn)CONH2,Me,H,Me,CONHPh),(NHCH(Bn)CONH2,Me,H,Me,C-
ONH-3-pyridyl),(NHCH(Bn)CONH2,Me,H,Me,NHCOPh),(NHCH(Bn)CONH2,Me,H,Me,
NHCO-2-furyl),(NHCH(Bn)CONH2,Me,H,Me,NHCONHPb),(NHCH(Bn)CONH2,Me,H,Me,NHC-
OCONHPh),(NHCH(Bn)CONH2,Me,H,Et,CONHPh),(NHCH(Bn)CONH2,Me,H,Et,CONH-3-pyri-
dyl),(NHCH(Bn)CONH2,Me,H,Et,NHCOPh),(NHCH(Bn)CONH2,Me,H,Et,NHCO-2-furyl),(-
NHCH(Bn)CONH2,Me,H,Et,NHCONHPh),(NHCH(Bn)CONH2,Me,H,Et,NHCOCONHPh),(NHCH(B-
n)CONH2,Me,H,CH2OH,CONHPh),(NHCH(Bn)CONH2,Me,H,CH2OH,CONH-3-pyridyl),(NHCH-
(Bn)CONH2,Me,
H,CH2OH,NHCOPh),(NHCH(Bn)CONH2,Me,H,CH2OH,NHCO-2-furyl),(NHCH(Bn)CONH2,Me-
,H,CH2OH,NHCONHPh),(NHCH(Bn)CONH2,Me,H,CH2OH,NHCO
CONHPh),(NHCH(Bn)CONH2,Me,Me,Me,CONHPh),(NHCH(Bn)CONH2,Me,Me,
Me,CONH-3-pyridyl),(NHCH(Bn)CONH2,Me,Me,Me,NHCOPh),(NHCH(Bn)CONH2,Me,Me,M-
e,NHCO-2-furyl),(NHCH(Bn)CONH2,Me,Me,Me,NHCONHPh),(NHCH(Bn)CONH2,Me,Me,Me,-
NHCO CONHPh),(NHCH(Bn)CONH2,Me,Me,Et,CONHPh),
(NHCH(Bn)CONH2,Me,Me,Et,CONH-3-pyridyl),(NHCH(Bn)CONH2,Me,Me,Et,NHCOPh),(-
NHCH(Bn)CONH2,Me,Me,Et,NHCO-2-furyl),(NHCH(Bn)CONH2,Me,Me,Et,NHCONHPh),(NH-
CH(Bn)CONH2,Me,Me,Et,NHCOCONHPh),(NHCH(Bn)CONH2,Me,Me,CH2OH,CONHPh),(NHCH(-
Bn)CONH2,Me,Me,CH2OH,CONH-3-pyridyl),
(NHCH(Bn)CONH2,Me,Me,CH2OH,NHCOPh),(NHCH(Bn)CONH2,Me,Me,CH2OH,NHCO-2-fury-
l),(NHCH(Bn)CONH2,Me,Me,CH2OH,NHCONHPh),(NHCH(Bn)CONH2,Me,Me,CH2OH,NHCOCON-
HPh),(NHCH(Bn)CONH2,Me,Ph,Me,CONHPh),
(NHCH(Bn)CONH2,Me,Ph,Me,CONH-3-pyridyl),(NHCH(Bn)CONH2,Me,Ph,Me,NHCOPh),(-
NHCH(Bn)CONH2,Me,Ph,Me,NHCO2-furyl),(NHCH(Bn)CONH2,Me,Ph,Me,NHCONHPh),(NHC-
H(Bn)CONH2,Me,Ph,Me,NHCOCONHPh),(NHCH(Bn)CONH12,Me,Ph,Et,CONHPh),(NHCH(Bn)-
CONH2,Me,Ph,Et,CONH-3-pyridyl),(NHCH(Bn)CONH2,Me,Ph,Et,NHCOPh),(NHCH(Bn)CO-
NH2,Me,Ph,Et,NHCO-2-furyl),(NHCH(Bn)CONH2,Me,Ph,Et,NHCONHPh),(NHCH(Bn)CONH-
2,Me,Ph,Et,NHCOCONHPh),(NHCH(Bn)CONH2,Me,Ph,CH2OH,CONHPh),(NHCH(Bn)CONH2,M-
e,Ph,
CH2OH,CONH-3-pyridyl),(NHCH(Bn)CONH2,Me,Ph,CH2OH,NHCOPh),(NHCH(Bn)CO-
NH2,Me,Ph,CH2OH,NHCO-furyl),(NHCH(Bn)CONH2,Me,Ph,CH2OH,NHCONHPh),(NHCH(Bn)-
CONH2,Me,Ph,CH2OH,NHCOCONHPh),(NHCH(Bn)CONH2,Me,OH,Me,CONHPh),(NHCH(Bn)CON-
H2,Me,OH,Me,CONH-3-pyridyl),(NHCH(Bn)CONH2,Me,OH,Me,NHCOPh),(NHCH(Bn)CONH2-
,Me,OH,Me,NHCO2-furyl),(NHCH(Bn)CONH2,Me,OH,Me,NHCONHPh),(NHCH(Bn)CONH2,Me-
,OH,Me,NHCOCONHPh),(NHCH(Bn)CONH2,Me,OH,Et,CONHPh),(NHCH(Bn)CONH2,Me,OH,Et-
,CONH-3-pyridyl),(NHCH(Bn)CONH2,Me,OH,Et,NHCOPh),(NHCH(Bn)CONH2,Me,OH,Et,N-
HCO-2-furyl),(NHCH(Bn)CONH2,Me,OH,Et,NHCONHPh),(NHCH(Bn)CONH2,Me,OH,Et,NHC-
OCONHPh),(NHCH(Bn)CONH2,Me,OH,CH2OH,CONHPh),(NHCH(Bn)CONH2,Me,OH,CH2OH,CON-
H-3-pyridyl),(NHCH(Bn)CONH2,Me,OH,CH2OH,NHCOPh),(NHCH(Bn)CONH2,Me,OH,CH2OH-
,NHCO-2-furyl),(NHCH(Bn)CONH2,Me,OH,CH2OH,NHCONHPh),(NHCH(Bn)CONH2,Me,OH,C-
H2OH,NHCO
CONHPh),(NHCH(Bn)CONH2,Ph,H,Me,CONHPh),(NHCH(Bn)CONH2,Ph,H,Me,CO-
NH-3-pyridyl),(NHCH(Bn)CONH2,Ph,H,Me,NHCOPh),(NHCH(Bn)CONH2,Ph,H,Me,NHCO-2-
-furyl),(NHCH(Bn)CONH2,Ph,H,Me,NHCONHPh),(NHCH(Bn)CONH2,Ph,H,Me,NHCOCONHPh-
),(NHCH(Bn)CONH2,Ph,H,Et,CONHPh),(NHCH(Bn)CONH2,Ph,H,Et,CONH-3-pyridyl),(N-
HCH(Bn)CONH2,Ph,H,Et,NHCOPh),(NHCH(Bn)CONH2,Ph,H,Et,NHCO-2-furyl),(NHCH(Bn-
)CONH2,Ph,H,Et,NHCONHPh),(NHCH(Bn)CONH2,Ph,H,Et,NHCOCONHPh),(NHCH(Bn)CONH2-
,Ph,H,
CH2OH,CONHPh),(NHCH(Bn)CONH2,Ph,H,CH2OH,CONH-3-pyridyl),(NHCH(Bn)CO-
NH2,Ph,H,CH2OH,NHCOPh),(NHCH(Bn)CONH2,Ph,H,CH2OH,NHCO-2-furyl),(NHCH(Bn)CO-
NH2,Ph,H,CH2OH,NHCONHPh),(NHCH(Bn)CONH2,Ph,H,CH2OH,NHCOCONHPh),(NHCH(Bn)CO-
NH2,Ph,Me,Me,CONHPh),(NHCH(Bn)CONH2,Ph,Me,Me,CONH-3-pyridyl),(NHCH(Bn)CONH-
2,Ph,Me,Me,NHCOPh),(NHCH(Bn)CONH2,Ph,Me,Me,NHCO-2-furyl),(NHCH(Bn)CONH2,Ph-
,Me,Me,NHCONHPh),
(NHCH(Bn)CONH2,Ph,Me,Me,NHCOCONHPh),(NHCH(Bn)CONH2,Ph,Me,Et,CONHPh),(NHCH-
(Bn)CONH2,Ph,Me,Et,CONH-3-pyridyl),(NHCH(Bn)CONH2,Ph,Me,Et,NHCOPh),(NHCH(B-
n)CONH2,Ph,Me,Et,NHCO-2-furyl)(NHCH(Bn)CONH2,Ph,Me,Et,NHCONHPh),(NHCH(Bn)C-
ONH2,Ph,Me,Et,NHCO
CONHPh),(NHCH(Bn)CONH2,Ph,Me,CH2OH,CONHPh),(NHCH(Bn)CONH2,Ph,Me,CH2OH,CON-
H-3-pyridyl),(NHCH(Bn)CONH2,Ph,Me,CH2OH,NHCOPh),(NHCH(Bn)CONH2,Ph,Me,CH2OH-
,NHCO-2-furyl),(NHCH(Bn)CONH2,Ph,Me,CH2OH,NHCONHPh),(NHCH(Bn)CONH2,Ph,Me,C-
H2OH,NHCOCONHPh),(NHCH(Bn)CONH2,Ph,Ph,Me,CONHPh),(NHCH(Bn)CONH2,Ph,Ph,Me,C-
ONH-3-pyridyl),(NHCH(Bn)CONH2,Ph,Ph,Me,
NHCOPh),(NHCH(Bn)CONH2,Ph,Ph,Me,NHCO-2-furyl),(NHCH(Bn)CONH2,Ph,Ph,Me,NHC-
ONHPh),(NHCH(Bn)CONH2,Ph,Ph,Me,NHCOCONHPh),(NHCH(Bn)CONH2,Ph,Ph,Et,CONHPh)-
,(NHCH(Bn)CONH2,Ph,Ph,Et,CONH-3-pyridyl),(NHCH(Bn)CONH2,Ph,Ph,Et,NHCOPh),(-
NHCH(Bn)CONH2,Ph,Ph,Et,NHCO-2-furyl),(NHCH(Bn)CONH2,Ph,Ph,Et,NHCONHPh),(NH-
CH(Bn)CONH2,Ph,Ph,Et,NHCOCONHPh),(NHCH(Bn)CONH2,Ph,Ph,CH2OH,CONHPh),(NHCH(-
Bn)CONH2,Ph,Ph,CH2OH,CONH-3-pyridyl),(NHCH(Bn)CONH2,Ph,Ph,CH2OH,NHCOPh),(N-
HCH(Bn)CONH2,Ph,Ph,CH2OH,NHCO-2-furyl),(NHCH(Bn)CONH2,Ph,Ph,CH2OH,NHCONHPh-
),(NHCH(Bn)CONH2,Ph,Ph,CH2OH,NHCOCONHPh),(NHCH(Bn)CONH2,Ph,OH,Me,CONHPh),(-
NHCH(Bn)CONH2,Ph,OH,Me,CONH-3-pyridyl),(NHCH(Bn)CONH2,Ph,OH,Me,NHCOPh),(NH-
CH(Bn)CONH2,Ph,OH,Me,NHCO-2-furyl),(NHCH(Bn)CONH2,Ph,OH,Me,NHCONHPh),(NHCH-
(Bn)CONH2,Ph,OH,Me,NHCOCONHPh),(NHCH(Bn)CONH2,Ph,OH,Et,CONHPh),(NHCH(Bn)CO-
NH2,Ph,OH,Et,
CONH-3-pyridyl),(NHCH(Bn)CONH2,Ph,OH,Et,NHCOPh),(NHCH(Bn)CONH2,Ph,OH,Et,N-
HCO-2-furyl),(NHCH(Bn)CONH2,Ph,OH,Et,NHCONHPh),(NHCH(Bn)CONH2,Ph,OH,Et,NHC-
OCONHPh),(NHCH(Bn)CONH2,Ph,OH,CH2OH,CONHPh),(NHCH(Bn)CONH2,Ph,OH,CH2OH,CON-
H-3-pyridyl),(NHCH(Bn)CONH2,Ph,OH,CH2OH,NHCOPh),(NHCH(Bn)CONH2,Ph,OH,CH2OH-
,NHCO-2-furyl),(NHCH(Bn)CONH2,Ph,OH,CH2OH,NHCONHPh),(NHCH(Bn)CONH2,Ph,OH,C-
H2OH,NHCOCONHPh),
(NHCH(Me)CH2OH,H,H,Me,CONHPh),(NHCH(Me)CH2OH,H,H,Me,CONH-3-pyridyl),(NHCH-
(Me)CH2OH,H,H,Me,NHCOPh),(NHCH(Me)CH2OH,H,H,Me,NHCO-2-furyl),(NHCH(Me)CH2O-
H,H,H,Me,NHCONHPh),(NHCH(Me)CH2OH,H,H,Me,NHCOCONHPh),(NHCH(Me)CH2OH,H,H,Et-
,CONHPh),(NHCH(Me)CH2OH,H,H,Et,
CONH-3-pyridyl),(NHCH(Me)CH2OH,H,H,Et,NHCOPh),(NHCH(Me)CH2OH,H,H,
Et,NHCO-2-furyl),(NHCH(Me)CH2OH,H,H,Et,NHCONHPh),(NHCH(Me)CH2OH,
H,H,Et,NHCOCONHPh),(NHCH(Me)CH2OH,H,H,CH2OH,CONHPh),(NHCH(Me)CH2OH,H,H,CH-
2OH,CONH-3-pyridyl),(NHCH(Me)CH2OH,H,H,CH2OH,NHCOPh),(NHCH(Me)CH2OH,H,H,CH-
2OH,NHCO-2-furyl),(NHCH(Me)CH2OH,H,H,CH2OH,NHCONHPh),(NHCH(Me)CH2OH,H,H,CH-
2OH,NHCOCONHPh),(NHCH(Me)CH2OH,H,Me,Me,CONHPh),(NHCH(Me)CH2OH,H,Me,Me,CONH-
-3-pyridyl),(NHCH(Me)CH2OH,H,Me,Me,NHCOPh),(NHCH(Me)CH2OH,H,Me,Me,NHCO-2-f-
uryl),(NHCH(Me)CH2OH,H,Me,Me,NHCONHPh),(NHCH(Me)CH2OH,H,Me,Me,NHCOCONHPh),-
(NHCH(Me)CH2OH,H,Me,Et,CONHPh),(NHCH(Me)CH2OH,H,Me,Et,CONH-3-pyridyl),(NHC-
H(Me)CH2OH,H,Me,Et,NHCOPh),(NHCH(Me)CH2OH,H,Me,Et,NHCO-2-furyl),(NHCH(Me)C-
H2OH,H,Me,Et,NHCONHPh),(NHCH(Me)CH2OH,H,Me,Et,NHCOCONHPh),(NHCH(Me)CH2OH,H-
,Me,CH2OH,CONHPh),(NHCH(Me)CH2OH,H,Me,CH2OH,CONH-3-pyridyl),(NHCH(Me)CH2OH-
,H,Me,CH2OH,NHCOPh),(NHCH(Me)CH2OH,H,Me,CH2OH,NHCO-2-furyl),(NHCH(Me)CH2OH-
,H,Me,CH2OH,NHCONHPh),(NHCH(Me)CH2OH,H,Me,CH2OH,NHCOCONHPh),(NHCH(Me)CH2OH-
,H,Ph,Me,CONHPh),(NHCH(Me)CH2OH,H,Ph,Me,CONH-3-pyridyl),(NHCH(Me)CH2OH,H,P-
h,Me,NHCOPh),(NHCH(Me)CH2OH,H,Ph,Me,NHCO-2-furyl),(NHCH(Me)CH2OH,H,Ph,Me,N-
HCONHPh),(NHCH(Me)CH2OH,H,Ph,Me,
NHCOCONHPh),(NHCH(Me)CH2OH,H,Ph,Et,CONHPh),(NHCH(Me)CH2OH,H,Ph,Et,CONH-3--
pyridyl),(NHCH(Me)CH2OH,H,Ph,Et,NHCOPh),(NHCH(Me)CH2OH,H,Ph,Et,NHCO-2-fury-
l),(NHCH(Me)CH2OH,H,Ph,Et,NHCONHPh),(NHCH(Me)CH2OH,H,Ph,Et,NHCOCONHPh),(NH-
CH(Me)CH2OH,H,Ph,CH2OH,CONHPh),(NHCH(Me)CH2OH,H,Ph,CH2OH,CONH-3-pyridyl),(-
NHCH(Me)CH2OH,H,Ph,CH2OH,NHCOPh),(NHCH(Me)CH2OH,H,Ph,CH2OH,NHCO-2-furyl),(-
NHCH(Me)CH2OH,H,Ph,CH2OH,NHCONHPh),(NHCH(Me)CH2OH,H,Ph,CH2OH,NHCOCONHPh),(-
NHCH(Me)CH2OH,H,OH,Me,CONHPh),(NHCH(Me)CH2OH,H,OH,Me,CONH-3-pyridyl),(NHCH-
(Me)CH2OH,H,OH,Me,NHCOPh),(NHCH(Me)CH2OH,H,OH,
Me,NHCO-2-furyl),(NHCH(Me)CH2OH,H,OH,Me,NHCONHPh),(NHCH(Me)CH2OH,H,OH,Me,-
NHCOCONHPh),(NHCH(Me)CH2OH,H,OH,Et,CONHPh),(NHCH(Me)CH2OH,H,OH,Et,CONH-3-p-
yridyl),(NHCH(Me)CH2OH,H,OH,Et,NHCOPh),(NHCH(Me)CH2OH,H,OH,Et,NHCO-2-furyl-
),(NHCH(Me)CH2OH,H,OH,Et,NHCONHPh),(NHCH(Me)CH2OH,H,OH,Et,NHCOCONHPh),(NHC-
H(Me)CH2OH,H,OH,CH2OH,CONHPh),(NHCH(Me)CH2OH,H,OH,CH.sub.2OH,CONH-3-pyridy-
l),(NHCH(Me)CH2OH,H,OH,CH2OH,NHCOPh),(NHCH(Me)CH2OH,H,OH,CH2OH,NHCO-2-fury-
l),(NHCH(Me)CH2OH,H,OH,CH2OH,NHCONHPh),(NHCH(Me)CH2OH,H,OH,CH2OH,NHCOCONHP-
h),(NHCH(Me)CH2OH,Me,H,Me,CONHPh),(NHCH(Me)CH2OH,Me,H,Me,CONH-3-pyridyl),(-
NHCH(Me)CH2OH,Me,H,Me,NHCOPh),(NHCH(Me)CH2OH,Me,H,Me,NHCO-2-furyl),(NHCH(M-
e)CH2OH,Me,H,Me,NHCONHPh),
(NHCH(Me)CH2OH,Me,H,Me,NHCOCONHPh),(NHCH(Me)CH2OH,Me,H,Et,CONHPh),(NHCH(M-
e)CH2OH,Me,H,Et,CONH-3-pyridyl),(NHCH(Me)CH2OH,Me,H,Et,NHCOPh),(NHCH(Me)CH-
2OH,Me,H,Et,NHCO-2-furyl),(NHCH(Me)CH2OH,Me,H,Et,NHCONHPh),(NHCH(Me)CH2OH,-
Me,H,Et,NHCOCONHPh),(NHCH(Me)CH2OH,Me,H,CH2OH,CONHPh),(NHCH(Me)CH2OH,Me,H,-
CH2OH,CONH-3-pyridyl),
(NHCH(Me)CH2OH,Me,H,CH2OH,NHCOPh),(NHCH(Me)CH2OH,Me,H,CH2OH,
NHCO-2-furyl),(NHCH(Me)CH2OH,Me,H,CH2OH,NHCONHPh),(NHCH(Me)CH2OH,Me,H,CH2-
OH,NHCO
CONHPh),(NHCH(Me)CH2OH,Me,Me,Me,CONHPh),(NHCH(Me)CH2OH,Me,Me,Me,CO-
NH-3-pyridyl),(NHCH(Me)CH2OH,Me,Me,Me,NHCOPh),(NHCH(Me)CH2OH,Me,Me,Me,NHCO-
-2-furyl),(NHCH(Me)CH2OH,Me,Me,
Me,NHCONHPh),(NHCH(Me)CH2OH,Me,Me,Me,NHCOCONHPh),(NHCH(Me)CH2OH,Me,Me,Et,-
CONHPh),(NHCH(Me)CH2OH,Me,Me,Et,CONH-3-pyridyl),(NHCH(Me)CH2OH,Me,Me,Et,NH-
COPh),(NHCH(Me)CH2OH,Me,Me,Et,NHCO-2-furyl),(NHCH(Me)CH2OH,Me,Me,Et,NHCONH-
Ph),(NHCH(Me)CH2OH,Me,Me,Et,NHCOCONHPh),(NHCH(Me)CH2OH,Me,Me,CH2OH,CONHPh)-
,(NHCH(Me)CH2OH,Me,
Me,CH2OH,CONH-3-pyridyl),(NHCH(Me)CH2OH,Me,Me,CH2OH,NHCOPh),(NHCH(Me)CH2O-
H,Me,Me,CH2OH,NHCO-2-furyl),(NHCH(Me)CH2OH,Me,Me,CH2OH,NHCONHPh),(NHCH(Me)-
CH2OH,Me,Me,CH2OH,NHCO
CONHPh),(NHCH(Me)CH2OH,Me,Ph,Me,CONHPh),(NHCH(Me)CH2OH,Me,Ph,Me,CONH-3-py-
ridyl),(NHCH(Me)CH2OH,Me,Ph,Me,NHCOPh),(NHCH(Me)CH2OH,Me,Ph,Me,NHCO-2-fury-
l),(NHCH(Me)CH2OH,Me,Ph,Me,NHCONHPh),(NHCH(Me)CH2OH,Me,Ph,Me,
NHCOCONHPh),(NHCH(Me)CH2OH,Me,Ph,Et,CONHPh),(NHCH(Me)CH2OH,Me,Ph,Et,CONH--
3-pyridyl),(NHCH(Me)CH2OH,Me,Ph,Et,NHCOPh),(NHCH(Me)CH2OH,Me,Ph,Et,NHCO-2--
furyl),(NHCH(Me)CH2OH,Me,Ph,Et,NHCONPh),(NHCH(Me)CH2OH,Me,Ph,Et,NHCOCONHPh-
),(NHCH(Me)CH2OH,Me,Ph,CH2OH,CONHPh),(NHCH(Me)CH2OH,Me,Ph,CH2OH,CONH-3-pyr-
idyl),(NHCH(Me)CH2OH,Me,Ph,CH2OH,NHCOPh),(NHCH(Me)CH2OH,Me,Ph,CH2OH,NHCO-2-
-furyl),(NHCH(Me)CH2OH,Me,Ph,CH2OH,NHCONHPh),(NHCH(Me)CH2OH,Me,Ph,CH2OH,NH-
COCONHPh),(NHCH(Me)CH2OH,Me,OH,Me,CONHPh),(NHCH(Me)CH2OH,Me,OH,Me,CONH-3-p-
yridyl),(NHCH(Me)CH2OH,Me,OH,Me,NHCOPh),(NHCH(Me)CH2OH,Me,OH,Me,NHCO-2-fur-
yl),(NHCH(Me)CH2OH,Me,OH,Me,NHCONHPh),(NHCH(Me)CH2OH,Me,OH,Me,NHCOCONHPh),-
(NHCH(Me)CH2OH,Me,OH,Et,CONHPh),(NHCH(Me)CH2OH,Me,OH,Et,CONH-3-pyridyl),(N-
HCH(Me)CH2OH,Me,OH,Et,NHCOPh),(NHCH(Me)CH2OH,Me,OH,Et,NHCO-2-furyl),(NHCH(-
Me)CH2OH,Me,OH,Et,NHCONHPh),(NHCH(Me)CH2OH,Me,OH,Et,NHCO
CONHPh),(NHCH(Me)CH2OH,Me,OH,CH2OH,CONHPh),(NHCH(Me)CH2OH,Me,OH,CH2OH,CON-
H-3-pyridyl),(NHCH(Me)CH2OH,Me,OH,CH2OH,NHCOPh),(NHCH(Me)CH2OH,Me,OH,CH2OH-
,NHCO-2-furyl),(NHCH(Me)CH2OH,Me,OH,CH2OH,NHCONHPh),(NHCH(Me)CH2OH,Me,OH,C-
H2OH,NHCOCONHPh),(NHCH(Me)CH2OH,Ph,H,
Me,CONHPh),(NHCH(Me)CH2OH,Ph,H,Me,CONH-3-pyridyl),(NHCH(Me)CH2OH,Ph,H,Me,-
NHCOPh),(NHCH(Me)CH2OH,Ph,H,Me,NHCO-2-furyl),(NHCH(Me)CH2OH,Ph,H,Me,NHCONH-
Ph),(NHCH(Me)CH2OH,Ph,H,Me,NHCOCONHPh),(NHCH(Me)CH2OH,Ph,H,Et,CONHPh),(NHC-
H(Me)CH2OH,Ph,H,Et,CONH-3-pyridyl),(NHCH(Me)CH2OH,Ph,H,Et,NHCOPh),(NHCH(Me-
)CH2OH,Ph,H,Et,NHCO-2-furyl),(NHCH(Me)CH2OH,Ph,H,Et,NHCONHPh),(NHCH(Me)CH2-
OH,Ph,H,Et,NHCOCONHPh),(NHCH(Me)CH2OH,Ph,H,CH2OH,CONHPh),(NHCH(Me)CH2OH,Ph-
,H,CH2OH,CONH-3-pyridyl),(NHCH(Me)CH2OH,Ph,H,CH2OH,NHCOPh),(NHCH(Me)CH2OH,-
Ph,H,CH2OH,NHCO-2-furyl),(NHCH(Me)CH2OH,Ph,H,CH2OH,NHCONHPh),(NHCH(Me)CH2O-
H,Ph,H,CH2OH,NHCOCONHPh),(NHCH(Me)CH2OH,
Ph,Me,Me,CONHPh),(NHCH(Me)CH2OH,Ph,Me,Me,CONH-3-pyridyl),(NHCH(Me)CH2OH,P-
h,Me,Me,NHCOPh),(NHCH(Me)CH2OH,Ph,Me,Me,NHCO-2-furyl),(NHCH(Me)CH2OH,Ph,Me-
,Me,NHCONHPh),(NHCH(Me)CH2OH,Ph,Me,Me,NHCOCONHPh),(NHCH(Me)CH2OH,Ph,Me,Et,-
CONHPh),(NHCH(Me)CH2OH,Ph,Me,Et,CONH-3-pyridyl),(NHCH(Me)CH2OH,Ph,Me,Et,NH-
COPh),(NHCH(Me)CH2OH,Ph,
Me,Et,NHCO-2-furyl),(NHCH(Me)CH2OH,Ph,Me,Et,NHCONHPh),(NHCH(Me)CH2OH,Ph,M-
e,Et,NHCOCONHPh),(NHCH(Me)CH2OH,Ph,Me,CH2OH,CONHPh),(NHCH(Me)CH2OH,Ph,Me,C-
H2OH,CONH-3-pyridyl),(NHCH(Me)CH2OH,Ph,Me,CH2OH,NHCOPh),(NHCH(Me)CH2OH,Ph,-
Me,CH2OH,NHCO-2-furyl),(NHCH(Me)CH2OH,Ph,Me,CH2OH,NHCONHPh),(NHCH(Me)CH2OH-
,Ph,Me,CH2OH,NHCOCONHPh),(NHCH(Me)CH2OH,Ph,Ph,Me,CONHPh),(NHCH(Me)CH2OH,Ph-
,Ph,Me,
CONH-3-pyridyl),(NHCH(Me)CH2OH,Ph,Ph,Me,NHCOPh),(NHCH(Me)CH2OH,Ph,-
Ph,Me,NHCO-2-furyl),(NHCH(Me)CH2OH,Ph,Ph,Me,NHCONHPh),(NHCH(Me)CH2OH,Ph,Ph-
,Me,NHCOCONHPh),(NHCH(Me)CH2OH,Ph,Ph,Et,CONHPh),(NHCH(Me)CH2OH,Ph,Ph,Et,CO-
NH-3-pyridyl),(NHCH(Me)CH2OH,Ph,Ph,Et,NHCOPh),(NHCH(Me)CH2OH,Ph,Ph,Et,NHCO-
-2-furyl),(NHCH(Me)CH2OH,Ph,Ph,Et,NCONHPh),(NHCH(Me)CH2OH,Ph,Ph,Et,NHCOCON-
HPh),(NHCH(Me)CH2OH,Ph,
Ph,CH2OH,CONHPh),(NHCH(Me)CH2OH,Ph,Ph,CH2OH,CONH-3-pyridyl),(NHCH(Me)CH2O-
H,Ph,Ph,CH2OH,NHCOPh),(NHCH(Me)CH2OH,Ph,Ph,CH2OH,NHCO-2-furyl),(NHCH(Me)CH-
2OH,Ph,Ph,CH2OH,NHCONHPh),(NHCH(Me)CH2OH,Ph,Ph,CH2OH,NHCOCONHPh),(NHCH(Me)-
CH2OH,Ph,OH,Me,CONHPh),(NHCH(Me)CH2OH,Ph,OH,Me,CONH-3-pyridyl),(NHCH(Me)CH-
2OH,Ph,OH,Me,NHCOPh),(NHCH(Me)CH2OH,Ph,OH,Me,NHCO-2-furyl),(NHCH(Me)CH2OH,-
Ph,OH,Me,NHCONHPh),(NHCH(Me)CH2OH,Ph,OH,Me,NHCOCONHPh),(NHCH(Me)CH2OH,
Ph,OH,Et,CONHPh),(NHCH(Me)CH2OH,Ph,OH,Et,CONH-3-pyridyl),(NHCH(Me)CH2OH,P-
h,OH,Et,NHCOPh),(NHCH(Me)CH2OH,Ph,OH,Et,NHCO-2-furyl),(NHCH(Me)CH2OH,Ph,OH-
,Et,NHCONHPh),(NHCH(Me)CH2OH,Ph,OH,Et,NHCOCONHPh),(NHCH(Me)CH2OH,Ph,OH,CH2-
OH,CONHPh),(NHCH(Me)CH2OH,Ph,OH,
CH2OH,CONH-3-pyridyl),(NHCH(Me)CH2OH,Ph,OH,CH2OH,NHCOPh),(NHCH(Me)CH2OH,P-
h,OH,CH2OH,NHCO-2-furyl),(NHCH(Me)CH2OH,Ph,OH,CH2OH,NHCONHPh),(NHCH(Me)CH2-
OH,Ph,OH,CH2OH,NHCOOONHPh),
(NHCH(Me)CONHMe,H,H,Me,CONHPh),(NHCH(Me)CONHMe,H,H,Me,CONH-3-pyridyl),(NH-
CH(Me)CONHMe,H,H,Me,NHCOPh),(NHCH(Me)CONHMe,H,H,Me,NHCO-2-furyl),(NHCH(Me)-
CONHMe,H,H,Me,NHCONHPh),(NHCH(Me)CONHMe,H,H,Me,NHCOCONHPh),(NHCH(Me)CONHMe-
,H,H,Et,CONHPh),(NHCH(Me)CONHMe,H,H,Et,CONH-3-pyridyl),(NHCH(Me)CONHMe,H,H-
,Et,NHCOPh),(NHCH(Me)CONHMe,H,H,Et,NHCO-2-furyl),(NHCH(Me)CONHMe,H,H,Et,NH-
CONHPh),(NHCH(Me)CONHMe,H,H,Et,NHCOCONHPh),(NHCH(Me)CONHMe,H,H,CH2OH,CONHP-
h),(NHCH(Me)CONHMe,H,H,CH2OH,CONH-3-pyridyl),(NHCH(Me)CONHMe,H,H,CH2OH,NHC-
OPh),(NHCH(Me)CONHMe,H,H,CH2OH,NHCO-2-furyl),(NHCH(Me)CONHMe,H,H,CH2OH,NHC-
ONHPh),(NHCH(Me)CONHMe,H,H,CH2OH,NHCOCONHPh),(NHCH(Me)CONHMe,H,Me,Me,CONHP-
h),(NHCH(Me)CONHMe,H,Me,Me,CONH-3-pyridyl),(NHCH(Me)CONHMe,H,Me,Me,NHCOPh)-
,(NHCH(Me)CONHMe,H,Me,Me,NHCO-2-furyl),(NHCH(Me)CONHMe,H,Me,Me,NHCONHPh),(-
NHCH(Me)CONHMe,H,Me,Me,NHCOCONHPh),(NHCH(Me)CONHMe,H,
Me,Et,CONHPh),(NHCH(Me)CONMe,H,Me,Et,CONH-3-pyridyl),(NHCH(Me)CONHMe,H,Me-
,Et,NHCOPh),(NHCH(Me)CONHMe,H,Me,Et,NHCO-2-furyl),(NHCH(Me)CONHMe,H,Me,Et,-
NHCONHPh),(NHCH(Me)CONHMe,H,Me,Et,NHCOCONHPh),(NHCH(Me)CONHMe,H,Me,CH2OH,C-
ONHPh),(NHCH(Me)CONHMe,H,Me,CH2OH,CONH-3-pyridyl),(NHCH(Me)CONHMe,H,Me,CH2-
OH,NHCOPh),(NHCH(Me)CONHMe,H,Me,CH2OH,NHCO-2-furyl),(NHCH(Me)CONHMe,H,Me,C-
H2OH,
NHCONHPh),(NHCH(Me)CONHMe,H,Me,CH2OH,NHCOCONHPh),(NHCH(Me)CONHMe,H,P-
h,Me,CONHPh),(NHCH(Me)CONHMe,H,Ph,Me,CONH-3-pyridyl),(NHCH(Me)CONHMe,H,Ph,-
Me,NHCOPh),(NHCH(Me)CONHMe,H,Ph,Me,NHCO-2-furyl),(NHCH(Me)CONHMe,H,Ph,Me,N-
HCONHPh),(NHCH(Me)CONHMe,H,Ph,Me,NHCOCONHPh),(NHCH(Me)CONHMe,H,Ph,Et,CONHP-
h),(NHCH(Me)CONHMe,H,Ph,Et,CONH-3-pyridyl),(NHCH(Me)CONHMe,H,Ph,Et,NHCOPh)-
,(NHCH(Me)CONHMe,H,Ph,Et,NHCO-2-furyl),(NHCH(Me)CONHMe,H,Ph,Et,NHCONHPh),(-
NHCH(Me)CONHMe,H,Ph,Et,NHCOCONHPh),(NHCH(Me)CONHMe,H,Ph,CH2OH,CONHPh),(NHC-
H(Me)CONHMe,H,Ph,CH2OH,CONH-3-pyridyl),(NHCH(Me)CONHMe,H,Ph,CH2OH,NHCOPh),-
(NHCH(Me)CONHMe,H,Ph,CH2OH,NHCO-2-furyl),(NHCH(Me)CONHMe,H,Ph,CH2OH,NHCONH-
Ph),(NHCH(Me)CONHMe,H,Ph,
CH2OH,NHCOCONHPh),(NHCH(Me)CONHMe,H,OH,Me,CONHPh),(NHCH(Me)CONHMe,H,OH,Me-
,CONH-3-pyridyl),(NCH(Me)CONHMe,H,OH,Me,NHCOPh),(NHCH(Me)CONHMe,H,OH,Me,NH-
CO-2-furyl),(NHCH(Me)CONHMe,H,OH,Me,NHCONHPh),(NHCH(Me)CONHMe,H,OH,Me,NHCO-
CONHPh),(NHCH(Me)CONHMe,H,OH,Et,CONHPh),(NHCH(Me)CONHMe,H,OH,Et,CONH-3-pyr-
idyl),(NHCH(Me)CONHMe,H,OH,Et,NHCOPh),(NHCH(Me)CONHMe,H,OH,Et,NHCO-2-furyl-
),(NHCH(Me)CONHMe,H,OH,Et,NHCONHPh),(NHCH(Me)CONHMe,H,OH,Et,NHCOCONHPh),(N-
HCH(Me)CONHMe,H,OH,CH2OH,CONHPh),(NHCH(Me)CONHMe,H,OH,CH2OH,CONH-3-pyridyl-
),(NHCH(Me)CONHMe,H,OH,CH2OH,NHCOPh),(NHCH(Me)CONHMe,H,OH,CH2OH,NHCO-2-fur-
yl),(NHCH(Me)CONH2Me,H,OH,CH2OH,NHCONHPh),(NHCH(Me)CONHMe,H,OH,CH2OH,NHCOC-
ONHPh),(NHCH(Me)CONHMe,Me,H,Me,CONHPh),(NHCH(Me)CONHMe,Me,H,Me,CONH-3-pyri-
dyl),(NHCH(Me)CONHMe,Me,H,Me,NHCOPh),(NHCH(Me)CONHMe,Me,H,Me,NHCO-2-furyl)-
,(NHCH(Me)CONHMe,Me,H,Me,NHCONHPh),(NHCH(Me)CONHMe,Me,H,Me,NHCOCONHPh),(NH-
CH(Me)CONHMe,Me,H,Et,CONHPh),(NHCH(Me)CONHMe,Me,H,Et,CONH-3-pyridyl),(NHCH-
(Me)CONHMe,Me,H,Et,NHCOPh),(NHCH(Me)CONHMe,Me,H,Et,NHCO-2-furyl),(NHCH(Me)-
CONHMe,Me,H,Et,NHCONHPh),(NHCH(Me)CONHMe,Me,H,Et,NHCOCONHPh),(NHCH(Me)CONH-
Me,Me,H,CH2OH,CONHPh),(NHCH(Me)CONHMe,Me,H,CH2OH,CONH-3-pyridyl),(NHCH(Me)-
CONHMe,Me,H,CH2OH,NHCOPh),(NHCH(Me)CONHMe,Me,H,CH2OH,
NHCO-2-furyl),(NHCH(Me)CONHMe,Me,H,CH2OH,NHCONHPh),(NHCH(Me)CONHMe,Me,H,C-
H2OH,NHCOCONHPh),(NHCH(Me)CONHMe,Me,Me,Me,CONHPh),(NHCH(Me)CONHMe,Me,Me,Me-
,CONH-3-pyridyl),(NHCH(Me)CONHMe,Me,Me,
Me,NHCOPh),(NHCH(Me)CONHMe,Me,Me,Me,NHCO-2-furyl),(NHCH(Me)CONHMe,Me,Me,M-
e,NHCONHPh),(NHCH(Me)CONHMe,Me,Me,Me,NHCOCONHPh),(NHCH(Me)CONHMe,Me,Me,Et,-
CONHPh),(NHCH(Me)CONHMe,Me,Me,Et,CONH-3-pyridyl),(NHCH(Me)CONHMe,Me,Me,Et,-
NHCOPh),(NHCH(Me)CONHMe,Me,Me,
Et,NHCO-2-furyl),(NHCH(Me)CONHMe,Me,Me,Et,NHCONHPh),(NHCH(Me)CONHMe,Me,Me-
,Et,NHCOCONHPh),(NHCH(Me)CONHMe,Me,Me,CH2OH,CONHPh),
(NHCH(Me)CONHMe,Me,Me,CH2OH,CONH-3-pyridyl),(NHCH(Me)CONHMe,Me,
Me,CH2OH,NHCOPh),(NHCH(Me)CONHMe,Me,Me,CH2OH,NHCO-2-furyl),(NHCH(Me)CONHM-
e,Me,Me,CH2OH,NHCONHPh),(NHCH(Me)CONHMe,Me,Me,CH2OH,NHCOCONHPh),(NHCH(Me)C-
ONHMe,Me,Ph,Me,CONHPh),(NHCH(Me)CONHMe,Me,Ph,Me,CONH-3-pyridyl),(NHCH(Me)C-
ONHMe,Me,Ph,Me,NHCOPh),(NHCH(Me)CONHMe,Me,Ph,Me,NHCO-2-furyl),(NHCH(Me)CON-
HMe,Me,Ph,Me,NHCONHPh),(NHCH(Me)CONHMe,Me,Ph,Me,NHCOCONHPh),(NHCH(Me)CONHM-
e,Me,Ph,Et,CONHPh),(NHCH(Me)CONHMe,Me,Ph,Et,CONH-3-pyridyl),(NHCH(Me)CONHM-
e,Me,Ph,Et,NHCOPh),(NHCH(Me)CONHMe,Me,Ph,Et,NHCO-2-furyl),(NHCH(Me)CONHMe,-
Me,Ph,Et,NHCONHPh),(NHCH(Me)CONHMe,Me,Ph,Et,NHCOCONHPh),(NHCH(Me)CONHMe,Me-
,Ph,CH2OH,CONHPh),(NHCH(Me)CONHMe,Me,Ph,CH2OH,CONH-3-pyridyl),(NHCH(Me)CON-
HMe,Me,Ph,CH2OH,NHCOPh),(NHCH(Me)CONHMe,Me,Ph,CH2OH,NHCO-2-furyl),(NHCH(Me-
)CONHMe,Me,Ph,CH2OH,NHCONHPh),(NHCH(Me)CONHMe,Me,Ph,CH2OH,NHCOCONHPh),(NHC-
H(Me)CONHMe,Me,OH,Me,CONHPh),(NHCH(Me)CONHMe,Me,OH,Me,CONH-3-pyridyl),(NHC-
H(Me)CONHMe,Me,OH,Me,NHCOPh),(NHCH(Me)CONHMe,
Me,OH,Me,NHCO2-furyl),(NHCH(Me)CONHMe,Me,OH,Me,NHCONHPh),(NHCH(Me)CONHMe,-
Me,OH,Me,NHCOCONHPh),(NHCH(Me)CONHMe,Me,OH,Et,CONHPh),(NHCH(Me)CONHMe,Me,O-
H,Et,CONH-3-pyridyl),(NHCH(Me)CONHMe,Me,OH,Et,NHCOPh),(NHCH(Me)CONHMe,Me,O-
H,Et,NHRCO-2-furyl),(NCH(Me)CONHMe,Me,OH,Et,NHCONHPh),(NHCH(Me)CONHMe,Me,O-
H,Et,NHCOCONHPh)(NHCH(Me)CONHMe,Me,OH,CH2OH,CONHPh),(NHCH(Me)CONHMe,Me,OH,-
CH2OH,CONH-3-pyridyl),(NHCH(Me)CONHMe,Me,OH,CH2OH,NHCOPh),(NHCH(Me)CONHMe,-
Me,OH,CH2OH,NHCO-2-furyl),(NHCH(Me)CONHMe,Me,OH,CH2OH,NHCONHPh),(NHCH(Me)C-
ONHMe,Me,OH,CH2OH,NHCOCONHPh),(NHCH(Me)CONHMe,Ph,H,Me,CONHPh),(NHCH(Me)CON-
HMe,Ph,H,Me,CONH-3-pyridyl),(NHCH(Me)CONHMe,Ph,H,Me,NHCOPh),(NHCH(Me)CONHM-
e,Ph,H,Me,NHCO-2-furyl),(NHCH(Me)CONHMe,Ph,H,Me,NHCONHPh),(NHCH(Me)CONHMe,-
Ph,H,Me,NHCOCONHPh),(NHCH(Me)CONHMe,Ph,H,Et,CONHPh),(NHCH(Me)CONHMe,Ph,H,E-
t,CONH-3-pyridyl),(NHCH(Me)CONHMe,Ph,H,Et,NHCOPh),(NHCH(Me)CONHMe,Ph,H,Et,-
NHCO-2-furyl),(NHCH(Me)CONHMe,Ph,H,Et,NHCONHPh),(NHCH(Me)CONHMe,Ph,H,Et,NH-
COCONHPh),(NHCH(Me)CONHMe,Ph,H,CH2OH,CONHPh),(NHCH(Me)CONHMe,Ph,H,CH2OH,CO-
NH-3-pyridyl),(NHCH(Me)CONHMe,Ph,H,CH2OH,NHCOPh),(NHCH(Me)CONHMe,Ph,H,CH2O-
H,NHCO-2-furyl),(NHCH(Me)CONHMe,Ph,H,CH2OH,NHCONHPh),(NHCH(Me)CONHMe,Ph,
H,CH2OH,NHCOCONHPh),(NHCH(Me)CONHMe,Ph,Me,Me,CONHPh),(NHCH(Me)CONHMe,Ph,M-
e,Me,CONH-3-pyridyl),(NHCH(Me)CONHMe,Ph,Me,Me,NHCOPh),(NHCH(Me)CONHMe,Ph,M-
e,Me,NHCO-2-furyl),(NHCH(Me)CONHMe,Ph,Me,
Me,NHCONHPh),(NHCH(Me)CONHMe,Ph,Me,Me,NHCONHPh),(NHCH(Me)CONHMe,Ph,Me,Et,-
CONHPh),(NHCH(Me)CONHMe,Ph,Me,Et,CONH-3-pyridyl),(NHCH(Me)CONHMe,Ph,Me,Et,-
NHCOPh),(NHCH(Me)CONHMe,Ph,Me,Et,NHCO-2-furyl),(NHCH(Me)CONHMe,Ph,Me,Et,NH-
CONHPh),(NHCH(Me)CONHMe,Ph,Me, Et,NHCO
CONHPh),(NHCH(Me)CONHMe,Ph,Me,CH2OH,CONHPh),(NHCH(Me)CONHMe,Ph,Me,CH2OH,C-
ONH-3-pyridyl),(NHCH(Me)CONHMe,Ph,Me,CH2OH,
NHCOPh),(NHCH(Me)CONHMe,Ph,Me,CH2OH,NHCO-2-furyl),(NHCH(Me)CONHMe,Ph,Me,C-
H2OH,NHCONHPh),(NHCH(Me)CONHMe,Ph,Me,CH2OH,NHCOCONHPh),(NHCH(Me)CONHMe,Ph,-
Ph,Me,CONHPh),(NHCH(Me)CONHMe,Ph,Ph,Me,CONH-3-pyridyl),(NHCH(Me)CONHMe,Ph,-
Ph,Me,NHCOPh),(NHCH(Me)CONHMe,Ph,Ph,Me,NHCO-2-furyl),(NHCH(Me)CONHMe,Ph,Ph-
,Me,NHECONHPh),(NHCH(Me)CONHMe,Ph,Ph,Me,NHCOCONHPh),(NHCH(Me)CONHMe,Ph,Ph,-
Et,CONHPh),(NHCH(Me)CONHMe,Ph,Ph,Et,CONH-3-pyridyl),(NHCH(Me)CONHMe,Ph,Ph,-
Et,NHCOPh),(NHCH(Me)CONHMe,Ph,Ph,Et,NHCO-2-furyl),(NHCH(Me)CONHMe,Ph,Ph,Et-
,NHCONHPh),(NHCH(Me)CONHMe,Ph,Ph,Et,NHCOCONHPh),(NHCH(Me)CONHMe,Ph,Ph,CH2O-
H,CONHPh),(NHCH(Me)CONHMe,Ph,Ph,CH2OH,CONH-3-pyridy),(NHCH(Me)CONHMe,Ph,Ph-
,CH2OH,NHCOPh),(NHCH(Me)CONHMe,Ph,Ph,CH2OH,NHCO-2-furyl),(NHCH(Me)CONHMe,P-
h,Ph,CH2OH,NHCONHPh),(NHCH(Me)CONHMe,Ph,Ph,CH2OH,NHCOCONHPh),(NHCH(Me)CONH-
Me,Ph,OH,Me,CONHPh),(NHCH(Me)CONHMe,Ph,OH,Me,CONH3-pyridy),(NHCH(Me)CONHMe-
,Ph,OH,Me,NHCOPh),(NHCH(Me)CONHMe,Ph,OH,Me,NHCO-2-furyl),(NHCH(Me)CONHMe,P-
h,OH,Me,NHCONHPh),(NHCH(Me)CONHMe,Ph,
OH,Me,NHCOCONHTPh),(NHCH(Me)CONHMe,Ph,OH,Et,CONHPh),(NHCH(Me)CONHMe,Ph,OH-
,Et,CONH-3-pyridyl),(NHCH(Me)CONHMe,Ph,OH,Et,NHCOPh),(NHCH(Me)CONHMe,Ph,OH-
,Et,NHCO-2-furyl),(NHCH(Me)CONHMe,Ph,OH,Et,NHCONHPh),(NHCH(Me)CONHMe,Ph,OH-
,Et,NHCO
CONHPh),(NHCH(Me)CONHMe,Ph,OH,CH2OH,CONHPh),(NHCH(Me)CONHMe,Ph,OH-
,CH2OH,CONH-3-pyridyl),(NHCH(Me)CONHMe,Ph,OH,CH2OH,NHCOPh),(NHCH(Me)CONHMe-
,Ph,OH,CH2OH,NHCO-2-furyl),(NHCH(Me)CONBMe,Ph,OH,CH2OH,NHCONHPh),(NHCH(Me)-
CONHMe,Ph,OH,CH2OH,NHCOCONHPh),
(NHCOCH(iPr)OH,H,H,Me,CONHPh),(NHCOCH(iPr)OH,H,H,Me,CONH-3-pyridyl),(NHCO-
CH(iPr)OH,H,H,Me,NHCOPh),(NHCOCH(iPr)OH,H,H,Me,NHCO-2-furyl)
(NHCOCH(iPr)OH,H,H,Me,NHCONHPh),(NHCOCH(iPr)OH,H,H,Me,NHCOCONHPh),(NHCOCH-
(iPr)
OH,H,H,Et,CONHPh),(NHCOCH(iPr)OH,H,H,Et,CONH-3-pyridyl),(NHCOCH(iPr)-
OH,H,H,Et,NHCOPh),(NHCOCH(iPr)OH,H,H,Et,NHCO-2-furyl),(NHCOCH(iPr)
OH,H,H,Et,NHCONHPh),(NHCOCH(iPr)OH,H,H,Et,NHCONHPh),(NHCOCH(iPr)
OH,H,H,CH2OH,CONHPh),(NHCOCH(iPr)
OH,H,H,CH2OH,CONH3-pyridyl),(NHCOCH(iPr)OH,H,H,CH2OH,NHCOPh),(NHCOCH(iPr)-
OH,H,H,CH2OH,NHCO-2-furyl),(NHCOCH(iPr)
OH,H,H,CH2OH,NHCONHPh),(NHCOCH(iPr)OH,H,H,CH2OH,NHCOCONHPh),(NHCOCH(iPr)O-
H,H,Me,Me,CONHPh),(NHCOCH(iPr)OH,H,Me,Me,CONH-3-pyridyl),(NHCOCH(iPr)OH,H,-
Me,Me,NHCOPh),(NHCOCH(iPr)OH,H,Me,Me,NHCO2-furyl),(NHCOCH(iPr)OH,H,Me,Me,N-
HCONHPh),(NHCOCH(iPr)OH,H,Me,Me,NHCOCONHPh),(NHCOCH(iPr)OH,H,Me,Et,CONHPh)-
,(NHCOCH(iPr)OH,H,Me,Et,CONH-3-pyridyl),(NHCOCH(iPr)OH,H,Me,Et,NHCOPh),(NH-
COCH(iPr)OH,H,Me,Et,NHCO-2-furyl),(NHCOCH(iPr)OH,H,Me,Et,NHCONHPh),(NHCOCH-
(iPr)OH,H,Me,Et,NHCOCONHPh),(NHCOCH(iPr)
OH,H,Me,CH2OH,CONHPh),(NHCOCH(iPr)
OH,H,Me,CH2OH,CONH-3-pyridyl),(NHCOCH(iPr)OH,H,Me,CH2OH,NHCOPh),(NHCOCH(i-
Pr) OH,H,Me,CH2OH,
NHCO-2-furyl),(NHCOCH(iPr)OH,H,Me,CH2OH,NHCONHPh),(NHCOCH(iPr)OH,H,Me,CH2-
OH,NHCOCONHPh),(NHCOCH(iPr)OH,H,Ph,Me,CONHPh),(NHCOCH(iPr)OH,H,Ph,Me,CONH--
3-pyridyl),(NHCOCH(iPr)OH,H,Ph,Me,NHCOPh),(NHCOCH(iPr)OH,H,Ph,Me,NHCO-2-fu-
ryl),(NHCOCH(iPr)OH,H,Ph,Me,NHCONHPh),(NHCOCH(iPr)OH,H,Ph,Me,NHCOCONHPh),(-
NHCOCH(iPr)OH,H,Ph,Et,CONHPh),(NHCOCH(iPr)OH,H,Ph,Et,CONH-3-pyridyl),(NHCO-
CH(iPr)OH,H,Ph,Et,NHCOPh),(NHCOCH(iPr)OH,H,Ph,Et,NHCO-2-fu
yl),(NHCOCH(iPr)OH,H,Ph,Et,NHCONHPh),(NHCOCH(iPr)OH,H,Ph,Et,NHCOCONHPh),(-
NHCOCH(iPr)OH,H,Ph,CH2OH,CONHPh),(NHCOCH(iPr)OH,H,Ph,CH2OH,CONH-3-pyridyl)-
,(NHCOCH(iPr)OH,H,Ph,CH2OH,NHCOPh),(NHCOCH(iPr)OH,H,Ph,CH2OH,NHCO-2-furyl)-
,(NHCOCH(iPr)
OH,H,Ph,CH2OH,NHCONHPh),(NHCOCH(iPr)OH,H,Ph,CH2OH,NHCOCONHPh),(NHCOCH(iPr-
)OH,H,OH,Me,CONHPh),(NHCOCH(iPr)OH,H,OH,Me,CONH-3-pyridyl),(NHCOCH(iPr)OH,-
H,OH,Me,NHCOPh),(NHCOCH(iPr)OH,H,
OH,Me,NHCO-2-furyl),(NHCOCH(iPr)OH,H,OH,Me,NHCONHPh),(NHCOCH(iPr)OH,H,OH,-
Me,NHCOCONHPh),(NHCOCH(iPr)OH,H,OH,Et,CONHPh),(NHCOCH(iPr)
OH,H,OH,Et,CONH-3-pyridyl),(NHCOCH(iPr)OH,H,OH,Et,NHCOPh),(NHCOCH(iPr)
OH,H,OH,Et,NHCO-2-furyl),(NHCOCH(iPr)OH,H,OH,Et,NHCONHPh),(NHCOCH(iPr)OH,-
H,OH,Et,NHCOCONHPh),(NHCOCH(iPr)OH,H,OH,CH2OH,CONHPh),(NHCOCH(iPr)OH,H,OH,-
CH2OH,CONH-3-pyridyl),(NHCOCH(iPr)OH,H,
OH,CH2OH,NHCOPh),(NHCOCH(iPr)
OH,H,OH,CH2OH,NHCO-2-furyl),(NHCOCH(iPr)OH,H,OH,CH2OH,NHCONHPh),(NHCOCH(i-
Pr)OH,H,OH,CH2OH,NHCOCONHPh),(NHCOCH(iPr)OH,Me,H,Me,CONHPh),(NHCOCH(iPr)OH-
,Me,H,Me,CONH-3-pyridyl),(NHCOCH(iPr)OH,Me,H,Me,NHCOPh),(NHCOCH(iPr)OH,Me,-
H,Me,NHCO2-furyl),(NHCOCH(iPr)OH,Me,H,Me,NHCONHPh),(NHCOCH(iPr)OH,Me,H,Me,-
NHCOCONHPh),(NHCOCH(iPr)OH,Me,H,Et,CONHPh),(NHCOCH(iPr)OH,Me,H,Et,CONH-3-p-
yridyl),(NHCOCH(iPr)OH,Me,H,Et,NHCOPh),(NHCOCH(iPr)OH,Me,H,Et,NHCO-2-furyl-
),(NHCOCH(iPr)OH,Me,H,Et,NHCONHPh),(NHCOCH(iPr)OH,Me,H,Et,NHCOCONHPh),(NHC-
OCH(iPr)OH,Me,H,CH2OH,CONHPh),(NHCOCH(iPr)OH,Me,H,CH2OH,CONH-3-pyridyl),(N-
HCOCH(iPr)OH,Me,H,CH2OH,NHCOPh),(NHCOCH(iPr)OH,Me,H,CH2OH,NHCO-2-furyl),(N-
HCOCH(iPr)OH,
Me,H,CH2OH,NHCONHPh),(NHCOCH(iPr)OH,Me,H,CH2OH,NHCOCONHPh),(NHCOCH(iPr)OH-
,Me,Me,Me,CONHPh),(NHCOCH(iPr)OH,Me,Me,Me,CONH-3-pyridyl),(NHCOCH(iPr)OH,M-
e,Me,Me,NHCOPh),(NHCOCH(iPr)OH,Me,Me,Me,NHCO-2-furyl),(NHCOCH(iPr)OH,Me,Me-
,Me,NHCONHPh),(NHCOCH(iPr)OH,Me,Me,
Me,NHCOCONHPh),(NHCOCH(iPr)OH,Me,Me,Et,CONHPh),(NHCOCH(iPr)OH,
Me,Me,Et,CONH-3-pyridyl),(NHCOCH(iPr)OH,Me,Me,Et,NHCOPh),(NHCOCH(iPr)OH,M-
e,Me,Et,NHCO-2-furyl),(NHCOCH(iPr)OH,Me,Me,Et,NHCONHPh),(NHCOCH(iPr)OH,Me,-
Me,Et,NHCOCONHPh),(NHCOCH(iPr)OH,Me,Me,CH2OH,CONH7Ph),(NHCOCH(iPr)OH,Me,Me-
,CH2OH,CONH-3-pyridyl),(NHCOCH(iPr)OH,Me,
Me,CH2OH,NHCOPh),(NHCOCH(iPr)OH,Me,Me,CH2OH,NHCO-2-furyl),(NHCOCH(iPr)OH,-
Me,Me,CH2OH,NHCONHPh),(NHCOCH(iPr)OH,Me,Me,CH2OH,NHCOCONHPh),(NHCOCH(iPr)
OH,Me,Ph,Me,CONHPh),(NHCOCH(iPr)OH,Me,Ph,Me,CONH-3-pyridyl),(NHCOCH(iPr)O-
H,Me,Ph,Me,NHCOPh),(NHCOCH(iPr)OH,Me,
Ph,Me,NHCO-2-furyl),(NHCOCH(iPr)OH,Me,Ph,Me,NHCONHPh),(NHCOCH(iPr)OH,Me,P-
h,Me,NHCOCONHPh),(NHCOCH(iPr)OH,Me,Ph,Et,CONHPh),(NHCOCH(iPr)OH,Me,Ph,Et,C-
ONH-3-pyridyl),(NHCOCH(iPr)OH,Me,Ph,Et,NHCOPh),(NHCOCH(iPr)OH,Me,Ph,Et,NHC-
O-2-furyl),(NCOCH(iPr)OH,Me,Ph,Et,NCONHPh),(NHCOCH(iPr)OH,Me,Ph,Et,NHCOCON-
HPh),(NHCOCH(iPr)OH,Me,Ph,CH2OH,CONHPh),(NH C OCH(iPr) OH,Me,Ph,CH2
OH,CONH-3-pyridyl,(NHCOCH(iPr)
OH,Me,Ph,CH2OH,NHCOPh),(NHCOCH(iPr)OH,Me,Ph,CH2OH,NHCO-2-furyl),(NHCOCH(i-
Pr)OH,Me,Ph,CH2OH,NHCONHPh),(NHCOCH(iPr)OH,Me,Ph,CH2OH,
NHCOCONHPh),(NHCOCH(iPr)OH,Me,OH,Me,CONHPh),(NHCOCH(iPr)OH,Me,
OH,Me,CONH-3-pyridyl),(NHCOCH(iPr)OH,Me,OH,Me,NHCOPh),(NHCOCH(iPr)OH,Me,O-
H,Me,NHCO-2-furyl),(NHCOCH(iPr)OH,Me,OH,Me,NHCONHPh),(NHCOCH(iPr)OH,Me,OH,-
Me,NHCOCONHPh),(NHCOCH(iPr)OH,Me,OH,Et,CONHPh),(NHCOCH(iPr)
OH,Me,OH,Et,CONH-3-pyridyl),(NHCOCH(iPr)
OH,Me,OH,Et,NHCOPh),(NHCOCH(iPr)OH,Me,OH,Et,NHCO-2-furyl),(NHCOCH(iPr)OH,-
Me,OH,Et,
NHCONHPh),(NHCOCH(iPr)OH,Me,OH,Et,NHCOCONHPh),(NHCOCH(iPr)OH,
Me,OH,CH2OH,CONHPh),(NHCOCH(iPr)OH,Me,OH,CH2OH,CONH-3-pyridy),(NHCOCH(iPr-
)OH,Me,OH,CH2OH,NHCOPh),(NHCOCH(iPr)OH,Me,OH,CH2OH,
NHCO-2-furyl),(NHCOCH(iPr) OH,Me,OH,CH2OH,NHCONHPh),(NHCOCH(iPr)
OH,Me,OH,CH2OH,NHCOCONHPh),(NHCOCH(iPr)OH,Ph,H,Me,CONHPh),(NHCOCH(iPr)OH,-
Ph,H,Me,CONH-3-pyridyl),(NHCOCH(iPr)OH,Ph,H,Me,NHCOPh),(NHCOCH(iPr)
OH,Ph,H,Me,NHCO-2-furyl),(NHCOCH(iPr)OH,Ph,H,Me,NHCONPh),(NHCOCH(iPr)OH,P-
h,H,Me,NHCOCONHPh),(NHCOCH(iPr)OH,Ph,H,Et,CONHPh),(NHCOCH(iPr)OH,Ph,H,Et,C-
ONH-3-pyridyl),(NHCOCH(iPr)OH,Ph,H,Et,NHCOPh),(NHCOCH(iPr)
OH,Ph,H,Et,NHCO-2-furyl),(NHCOCH(iPr)OH,Ph,H,Et,NHCONHPh),(NHCOCH(iPr)OH,-
Ph,H,Et,NHCOCONHPh),(NHCOCH(iPr)OH,Ph,H,CH2OH,CONHPh),(NHCOCH(iPr)OH,Ph,H,-
CH2OH,CONH-3-pyridyl),(NHCOCH(iPr)OH,Ph,H,CH2OH,NHCOPh),(NHCOCH(iPr)OH,Ph,-
H,CH2OH,NHCO-2-furyl)(NHCOCH(iPr)OH,Ph,H,CH2OH,NHCONHPh),(NHCOCH(iPr)OH,Ph-
,H,CH2OH,NHCOCONHPh),(NHCOCH(iPr)OH,Ph,Me,Me,CONHPh),(NHCOCH(iPr)OH,Ph,Me,-
Me,CONH-3-pyridyl),(NHCOCH(iPr)OH,Ph,Me,Me,NHCOPh),(NHCOCH(iPr)OH,
Ph,Me,Me,NHCO-2-furyl),(NHCOCH(iPr)OH,Ph,Me,Me,NHCONHPh),(NHCOCH(iPr)OH,P-
h,Me,Me,NHCOCONHPh),(NHCOCH(iPr)OH,Ph,Me,Et,CONHPh),(NHCOCH(iPr)OH,Ph,Me,E-
t,CONH-3-pyridyl),(NHCOCH(iPr)OH,Ph,Me,Et,NHCOPh),(NHCOCH(iPr)OH,Ph,Me,Et,-
NHCO-2-furyl),(NHCOCH(iPr)OH,Ph,Me,Et,NHCONHPh),(NHCOCH(iPr)OH,Ph,Me,Et,NH-
COCONHPh),(NHCOCH(iPr)OH,Ph,Me,CH2OH,CONHPh),(NHCOCH(iPr)
OH,Ph,Me,CH2OH,CONH3-pyridyl),(NHCOCH(iPr)
OH,Ph,Me,CH2OH,NHCOPh),(NHCOCH(iPr) OH,Ph,Me,CH2OH,NHCO-2-furyl),
(NHCOCH(iPr)OH,Ph,Me,CH2OH,NHCONHPh),(NHCOCH(iPr)OH,Ph,Me,CH2OH,NHCOCONHP-
h),(NHCOCH(iPr)OH,Ph,Ph,Me,CONHPh),(NHCOCH(iPr)OH,Ph,Ph,Me,CONH-3-pyridyl)-
,(NHCOCH(iPr)OH,Ph,Ph,Me,NHCOPh),(NHCOCH(iPr)OH,Ph,Ph,Me,NHCO-2-furyl),(NH-
COCH(iPr)OH,Ph,Ph,Me,NHCONHPh),(NHCOCH(iPr)OH,Ph,Ph,Me,NHCOCONHPh),(NHCOCH-
(iPr)OH,Ph,Ph,Et,CONHPh),(NHCOCH(iPr)OH,Ph,Ph,Et,CONH-3-pyridyl),(NHCOCH(i-
Pr)OH,Ph,Ph,Et,NHCOPh),
(NHCOCH(iPr)OH,Ph,Ph,Et,NHCO-2-furyl),(NHCOCH(iPr)OH,Ph,Ph,Et,NHCONHPh),(-
NCOCH(iPr)OH,Ph,Ph,Et,NHCOCONHPh),(NHCOCH
(iPr)OH,Ph,Ph,CH2OH,CONHPh),(NHCOCH(iPr)OH,Ph,Ph,CH2OH,CONH-3-pyridyl),(N-
HCOCH(iPr)OH,Ph,Ph,CH2OH,NHCOPh),(NHCOCH(iPr)
OH,Ph,Ph,CH2OH,NHCO-2-furyl),(NHCOCH(iPr)OH,Ph,Ph,CH2OH,NHCONHPh),(NHCOCH-
(iPr) OH,Ph,Ph,CH2OH,
NHCOCONHPh),(NHCOCH(iPr)OH,Ph,OH,Me,CONHPh),(NHCOCH(iPr)OH,Ph,
OH,Me,CONH-3-pyridy),(NHCOCH(iPr)OH,Ph,OH,Me,NHCOPh),(NHCOCH(iPr)OH,Ph,OH-
,Me,NHCO-2-furyl),(NHCOCH(iPr)OH,Ph,OH,Me,NHCONHPh),(NHCOCH(iPr)OH,Ph,OH,M-
e,NHCOCONHPh),(NHCOCH(iPr)OH,Ph,OH,Et,CONHPh),(NH C OCH (iPr)
OH,Ph,OH,Et,CONH-3-pyridyl),(NHCOCH(iPr)OH,Ph,OH,Et,NHCOPh),(NHCOCH(iPr)O-
H,Ph,OH,Et,NHCO-2-furyl),(NHCOCH(iPr)OH,Ph,OH,Et,NHCONHPh),(NHCOCH(iPr)OH,-
Ph,OH,Et,NHCOCONHPh),(NHCOCH(iPr)OH,Ph,OH,CH2OH,CONHPh),(NHCOCH(iPr)OH,Ph,-
OH,CH2OH,CONH-3-pyridyl),(NHCOCH(iPr)OH,Ph,OH,CH2OH,NHCOPh),(NHCOCH(iPr)
OH,Ph,OH,CH2OH,NHCO-2-furyl),(NHCOCH(iPr)OH,Ph,OH,CH2OH,NHCONHPh),(NHCOCH-
(iPr)OH,Ph,OH,CH2OH,NHCOCONHPh),
(NHSO2Me,H,H,Me,CONHPh),(NHSO2Me,H,H,Me,CONH-3-pyridyl),(NHSO2Me,
H,H,Me,NHCOPh),(NHSO2Me,H,H,Me,NHCO-2-furyl),(NHSO2Me,H,H,Me,NHCONHPh),(N-
HSO2Me,H,H,Me,NHCOCONHPh),(NHSO2Me,H,H,Et,CONHPh),(NHSO2Me,H,H,Et,CONH-3-p-
yridyl),(NHSO2Me,H,H,Et,NHCOPh),(NHSO2Me,H,H,Et,
NHCO-2-furyl),(NHSO2Me,H,H,Et,NHCONHPh),(NHSO2Me,H,H,Et,NHCOCONHPh),(NHSO-
2Me,H,H,CH2OH,CONHPh),(NHSO2Me,H,H,CH2OH,CONH-3-pyridyl),(NHSO2Me,H,H,CH2O-
H,NHCOPh),(NHSO2Me,H,H,CH2OH,NHCO-2-furyl),(NHSO2Me,H,H,CH2OH,NHCONHPh),(N-
HSO2Me,H,H,CH2OH,NHCOCONHPh),(NHSO2Me,H,Me,Me,CONHPh),(NHSO2Me,H,Me,Me,CON-
H-3-pyridyl),(NHSO2Me,
H,Me,Me,NHCOPh),(NHSO2Me,H,Me,Me,NHCO-2-furyl),(NHSO2Me,H,Me,Me,NHCONHPh)-
,(NHSO2Me,H,Me,Me,NHCOCONHPh),(NHSO2Me,H,Me,Et,CONHPh),(NHSO2Me,H,Me,Et,CO-
NH-3-pyridyl),(NHSO2Me,H,Me,Et,NHCOPh),(NHSO2Me,H,Me,Et,NHCO-2-furyl),(NHS-
O2Me,H,Me,Et,NHCONHPh),(NHSO2Me,H,Me,Et,NHCOCONHPh),(NHSO2Me,H,Me,CH2OH,CO-
NHPh),(NHSO2Me,H,Me,CH2OH,
CONH-3-pyridyl),(NHSO2Me,H,Me,CH2OH,NHCOPh),(NHSO2Me,H,Me,CH2OH,
NHCO-2-furyl),(NHSO2Me,H,Me,CH2OH,NHCONHPh),(NHSO2Me,H,Me,CH2OH,NHCOCONHP-
h),(NHSO2Me,H,Ph,Me,CONHPh),(NHSO2Me,H,Ph,Me,CONH-3-pyridyl),(NHSO2Me,H,Ph-
,Me,NHCOPh),(NHSO2Me,H,Ph,Me,NHCO-2-furyl),(NHSO2Me,H,Ph,Me,NHCONHPh),(NHS-
O2Me,H,Ph,Me,NHCOCONHPh),(NHSO2Me,
H,Ph,Et,CONHPh),(NHSO2Me,H,Ph,Et,CONH-3-pyridyl),(NHSO2Me,H,Ph,Et,NHCOPh)-
,(NHSO2Me,H,Ph,Et,NHCO-2-furyl),(NHSO2Me,H,Ph,Et,NHCONHPh),(NHSO2Me,H,Ph,E-
t,NHCOCONHPh),(NHSO2Me,H,Ph,CH2OH,CONHPh),(NHSO2Me,H,Ph,CH2OH,CONH-3-pyrid-
yl),(NHSO2Me,H,Ph,CH2OH,NHCOPh),(NHSO2Me,H,Ph,CH2OH,NHCO-2-furyl),(NHSO2Me-
,H,Ph,CH2OH,NHCONHPh),(NHSO2Me,H,Ph,CH2OH,NHCOCONHPh),(NHSO2Me,H,OH,Me,CON-
HPh),(NHSO2Me,H,OH,Me,CONH-3-pyridyl),(NHSO2Me,H,OH,Me,NHCOPh),(NHSO2Me,H,-
OH,Me,
NHCO-2-furyl),(NHSO2Me,H,OH,Me,NHCONHPh),(NHSO2Me,H,OH,Me,NHCOCONHP-
h),(NHSO2Me,H,OH,Et,CONHPh),(NHSO2Me,H,OH,Et,CONH-3-pyridyl),(NHSO2Me,H,OH-
,Et,NHCOPh),(NHSO2Me,H,OH,Et,NHCO-2-furyl),(NHSO2Me,H,OH,Et,NHCONHPh),(NHS-
O2Me,H,OH,Et,NHCOCONHPh),(NHSO2Me,H,OH,CH2OH,CONHPh),(NHSO2Me,H,OH,CH2OH,C-
ONH-3-pyridyl),(NHSO2Me,H,OH,CH2OH,NHCOPh),(NHSO2Me,H,OH,CH2OH,NHCO-2-fury-
l),(NHSO2Me,H,OH,CH2OH,NHCONHPh),(NHSO2Me,H,OH,CH2OH,NHCOCONHPh),(NHSO2Me,-
Me,H,
Me,CONHPh),(NHSO2Me,Me,H,Me,CONH-3-pyridyl),(NHSO2Me,Me,H,Me,NHCOPh)-
,(NHSO2Me,Me,H,Me,NHCO-2-furyl),(NHSO2Me,Me,H,Me,NHCONHPh),(NHSO2Me,Me,H,M-
e,NHCOCONHPh),(NHSO2Me,Me,H,Et,CONHPh),(NHSO2Me,Me,H,Et,CONH-3-pyridyl),(N-
HSO2Me,Me,H,Et,NHCOPh),(NHSO2Me,Me,H,Et,NHCO-2-furyl),(NHSO2Me,Me,H,Et,NHC-
ONHPh),(NHSO2Me,Me,H,Et,NHCOCONHPh),(NHSO2Me,Me,H,CH2OH,CONHPh),(NHSO2Me,M-
e,H,CH2OH,CONH-3-pyridyl),(NHSO2Me,Me,H,CH2OH,NHCOPh),(NHSO2Me,Me,H,CH2OH,-
NHCO-2-furyl),(NHSO2Me,Me,H,CH2OH,NHCONHPh),(NHSO2Me,Me,H,CH2OH,NHCOCONHPh-
),(NHSO2Me,Me,Me,Me,CONHPh),(NHSO2Me,Me,Me,Me,CONH-3-pyridyl),(NHSO2Me,Me,-
Me,Me,NHCOPh),(NHSO2Me,Me,Me,Me,NHCO-2-furyl),(NHSO2Me,Me,Me,Me,NHCONHPh),-
(NHSO2Me,Me,Me,Me,NHCOCONHPh),(NHSO2Me,Me,Me,Et,CONHPh),(NHSO2Me,Me,Me,Et,-
CONH-3-pyridyl),(NHSO2Me,Me,Me,Et,NHCOPh),(NHSO2Me,Me,Me,Et,NHCO-2-furyl),-
(NHSO2Me,Me,Me,Et,NHCONHPh),(NHSO2Me,Me,Me,Et,NHCOCONHPh),(NHSO2Me,Me,Me,C-
H2OH,CONHPh),(NHSO2Me,Me,Me,CH2OH,CONH-3-pyridyl),(NHSO2Me,Me,Me,CH2OH,NHC-
OPh),(NHSO2Me,Me,Me,CH2OH,NHCO-2-furyl),(NHSO2Me,Me,Me,CH2OH,NHCONHPh),(NH-
SO2Me,Me,Me,CH2OH,NHCOCONHPh),(NHSO2Me,Me,Ph,Me,CONHPh),(NHSO2Me,Me,Ph,Me,-
CONH-3-pyridyl),(NHSO2Me,Me,Ph,Me,NHCOPh),(NHSO2Me,Me,Ph,Me,NHCO-2-furyl),-
(NHSO2Me,Me,Ph,Me,NHCONHPh),(NHSO2Me,Me,Ph,Me,NHCOCONHPh),(NHSO2Me,Me,Ph,E-
t,CONHPh),(NHSO2Me,Me,Ph,Et,CONH-3-pyridyl),(NHSO2Me,Me,Ph,Et,NHCOPh),(NHS-
O2Me,Me,Ph,Et,NHCO-2-furyl),(NHSO2Me,Me,Ph,Et,NHCONHPh),(NHSO2Me,Me,Ph,Et,-
NHCOCONHPh),(NHSO2Me,Me,Ph,CH2OH,CONHPh),(NHSO2Me,Me,Ph,CH2OH,CONH-3-pyrid-
yl),(NHSO2Me,Me,Ph,CH2OH,NHCOPh),(NHSO2Me,Me,Ph,CH2OH,NHCO-2-furyl),(NHSO2-
Me,Me,Ph,CH2OH,NHCONHPh),(NHSO2Me,Me,Ph,CH2OH,NHCOCONHPh),(NHSO2Me,Me,OH,M-
e,CONHPh),(NHSO2Me,Me,OH,Me,CONH-3-pyridyl),(NHSO2Me,Me,OH,Me,NHCOPh),(NHS-
O2Me,Me,OH,Me,NHCO-2-furyl),(NHSO2Me,Me,OH,Me,NHCONHPh),(NHSO2Me,Me,OH,Me,-
NHCOCONHPh),(NHSO2Me,Me,OH,Et,CONHPh),(NHSO2Me,Me,OH,Et,CONH-3-pyridyl),(N-
HSO2Me,Me,OH,Et,
NHCOPh),(NHSO2Me,Me,OH,Et,NHCO-2-furyl),(NHSO2Me,Me,OH,Et,NHCONHPh),(NHSO-
2Me,Me,OH,Et,NHCOCONHPh),(NHSO2Me,Me,OH,CH2OH,CONHPh),(NHSO2Me,Me,OH,CH2OH-
,CONH-3-pyridyl),(NHSO2Me,Me,OH,CH2OH,NHCO
Ph),(NHSO2Me,Me,OH,CH2OH,NHCO-2-furyl),(NHSO2Me,Me,OH,CH2OH,NHCONHPh),(NH-
SO2Me,Me,OH,CH2OH,NHCOCONHPh),(NHSO2Me,Ph,H,Me,CONHPh),(NHSO2Me,Ph,H,Me,CO-
NH-3-pyridyl),(NHSO2Me,Ph,H,Me,NHCOPh),(NHSO2Me,Ph,H,Me,NHCO-2-furyl),(NHS-
O2Me,Ph,H,Me,NHCONHPh),(NHSO2Me,Ph,H,Me,NHCOCONHPh),(NHSO2Me,Ph,H,Et,CONHP-
h),(NHSO2Me,Ph,H,Et,CONH-3-pyridyl),(NHSO2Me,Ph,H,Et,NHCOPh),(NHSO2Me,Ph,H-
,Et,NHCO2-furyl),
(NHSO2Me,Ph,H,Et,NHCONHPh),(NHSO2Me,Ph,H,Et,NHCOCONHPh),(NHSO2Me,Ph,H,CH2-
OH,CONHPh),(NHSO2Me,Ph,H,CH2OH,CONH-3-pyridyl),(NHSO2Me,Ph,H,CH2OH,NHCOPh)-
,(NHSO2Me,Ph,H,CH2OH,NHCO-2-furyl),(NHSO2Me,
Ph,H,CH2OH,NHCONHPh),(NHSO2Me,Ph,H,CH2OH,NHCO
CONHPh),(NHSO2Me,Ph,Me,Me,CONHPh),(NHSO2Me,Ph,Me,Me,CONH-3-pyridyl),(NHSO-
2Me,Ph,
Me,Me,NHCOPh),(NHSO2Me,Ph,Me,Me,NHCO-2-furyl),(NHSO2Me,Ph,Me,Me,NH-
CONPh),(NHSO2Me,Ph,Me,Me,NHCOCONHPh),(NHSO2Me,Ph,Me,Et,CONHPh),(NHSO2Me,Ph-
,Me,Et,CONH-3-pyridyl),(NHSO2Me,Ph,Me,Et,NHCOPh),(NHSO2Me,Ph,Me,Et,NHCO2-f-
uryl),(NHSO2Me,Ph,Me,Et,NHCONHPh),(NHSO2Me,Ph,Me,Et,NHCOCONHPh),(NHSO2Me,P-
h,Me,CH2OH,CONHPh),(NHSO2Me,Ph,Me,CH2OH,CONH-3-pyridyl),(NHSO2Me,Ph,Me,CH2-
OH,NHCOPh),(NHSO2Me,Ph,Me,CH2OH,NHCO-2-furyl),(NHSO2Me,Ph,Me,CH2OH,NHCONHP-
h),(NHSO2Me,
Ph,Me,CH2OH,NHCOCONHPh),(NHSO2Me,Ph,Ph,Me,CONHPh),(NHSO2Me,Ph,
Ph,Me,CONH-3-pyridyl),(NHSO2Me,Ph,Ph,Me,NHCOPh),(NHSO2Me,Ph,Ph,Me,NHCO-2--
furyl),(NHSO2Me,Ph,Ph,Me,NHCONHPh),(NHSO2Me,Ph,Ph,Me,NHCOCONHPh),(NHSO2Me,-
Ph,Ph,Et,CONHPh),(NHSO2Me,Ph,Ph,Et,CONH-3-pyridyl),(NHSO2Me,Ph,Ph,Et,NHCOP-
h),(NHSO2Me,Ph,Ph,Et,NHCO-2-furyl),(NHSO2Me,Ph,Ph,Et,NHCONHPh),(NHSO2Me,Ph-
,Ph,Et,NHCOCONHPh),(NHSO2Me,Ph,Ph,CH2OH,CONHPh),(NHSO2Me,Ph,Ph,CH2OH,CONH--
3-pyridyl),(NHSO2Me,Ph,Ph,
CH2OH,NHCOPh),(NHSO2Me,Ph,Ph,CH2OH,NHCO-2-furyl),(NHSO2Me,Ph,Ph,CH2OH,NHC-
ONHPh),(NHSO2Me,Ph,Ph,CH2OH,NHCOCONHPh),(NHSO2Me,Ph,
OH,Me,CONHPh),(NHSO2Me,Ph,OH,Me,CONH-3-pyridyl),(NHSO2Me,Ph,OH,Me,
NHCOPh),(NHSO2Me,Ph,OH,Me,NHCO-2-furyl),(NHSO2Me,Ph,OH,Me,NHCONHPh),(NHSO-
2Me,Ph,OH,Me,NHCOCONHPh),(NHSO2Me,Ph,OH,Et,CONHPh),(NHSO2Me,Ph,OH,Et,CONH--
3-pyridyl),(NHSO2Me,Ph,OH,Et,NHCOPh),(NHSO2Me,Ph,OH,Et,NHCO-2-furyl),(NHSO-
2Me,Ph,OH,Et,NHCONHPh),(NHSO2Me,Ph,OH,
Et,NHCOCONHPh),(NHSO2Me,Ph,OH,CH2OH,CONHPh),(NHSO2Me,Ph,OH,CH2OH,CONH-3-p-
yridyl),(NHSO2Me,Ph,OH,CH2OH,NHCOPh),(NHSO2Me,Ph,OH,
CH2OH,NHCO-2-furyl),(NHSO2Me,Ph,OH,CH2OH,NHCONHPh),(NHSO2Me,Ph,
OH,CH2OH,NHCO CONHPh),
(NH2,H,H,Me,CONHPh),(NH2,H,H,Me,CONH-3-pyridyl),(NH2,H,H,Me,NHCOPh),
(NH2,H,H,Me,NHCO-2-furyl),(NH2,H,H,Me,NHCONHPh),(NH2,H,H,Me,NHCOCONPh),(N-
H2,H,H,Et,CONHPh),(NH2,H,H,Et,CONH-3-pyridyl),(NH12,H,H,Et,NHCOPh),(NH2,H,-
H,Et,NHCO-2-furyl),(NH12,H,H,Et,NHCONHPh),(NH2,H,H,Et,NHCOCONHPh),(NH2,H,H-
,CH2OH,CONHPh),(NH2,H,H,CH2OH,CONH-3-pyridyl),(NH2,H,H,CH2OH,NHCONHPh),(NH-
2,H,H,CH2OH,NHCOCONHPh),(NH2,H,Me,
Me,CONHPh),(NH2,H,Me,Me,CONH-3-pyridyl),(NH2,H,Me,Me,NHCONHPh),(NH2,H,Me,-
Me,NHCOCONHPh),(NH2,H,Me,Et,CONHPh),(NH2,H,Me,Et,CONH-3-pyridyl),(NH2,H,Me-
,Et,NHCOPh),(NH2,H,Me,Et,NHCO-2-fury),(NH2,H,Me,Et,NHCONHPh),(NH2,H,Me,Et,-
NHCOCONHPh),(NH2,H,Me,CH2OH,CONHPh),(NH12,H,
Me,CH2OH,CONH-3-pyridyl),(NH2,H,Me,CH2OH,NHCONHPh),(NH2,H,Me,CH2OH,NHCO
CONHPh),(NH2,H,Ph,Me,CONHPh),(NH2,H,Ph,Me,CONH-3-pyridyl),(NH2,H,Ph,Me,NH-
CONHPh),(NH2,H,Ph,Me,NHCOCONHPh),(NH2,H,Ph,Et,CONHPh),(NH2,H,Ph,Et,CONH-3--
pyridyl),(NH2,H,Ph,Et,NHCOPh),(NH2,H,Ph,Et,NHCO-2-furyl,(NH2,H,Ph,Et,NHCON-
HPh),(NH2,H,Ph,Et,NHCOCONHPh),(NH2,H,
Ph,CH2OH,CONHPh),(NH2,H,Ph,CH2OH,CONH-3-pyridyl),(NH2,H,Ph,CH2OH,NHCONHPh-
),(NH2,H,Ph,CH2OH,NHCOCONHPh),(NH2,H,OH,Me,CONHPh),(NH2,H,OH,Me,CONH-3-pyr-
idyl),(NH2,H,OH,Me,NHCONHPh),(NIH2,H,OH,Me,NHCOCONHPh),(NH2,H,OH,Et,CONHPh-
),(NH2,H,OH,Et,CONH-3-pyridyl),(NH2,H,OH,
Et,NHCOPh),(NH2,H,OH,Et,NHCO-2-furyl),(NH2,H,OH,Et,NHCONHPh),(NH2,H,OH,Et-
,NHCOCONHPh),(NH2,H,OH,CH2OH,CONHPh),(NH2,H,OH,CH2OH,CONH-3-pyridyl),(NH2,-
H,OH,CH2OH,NHCONHPh),(NH2,H,OH,CH2OH,NHCOCONHPh),(NH2,Me,H,Me,CONHPh),(NH1-
2,Me,H,Me,CONH-3-pyridyl),(NH2,Me,H,Me,
NHCONHPh),(NH12,Me,H,Me,NHCOCONHPh),(NH2,Me,H,Et,CONHPh),(NH2,Me,H,Et,CON-
H-3-pyridyl),(NH12,Me,H,Et,NHCOPh),(NH2,Me,H,Et,NHCO-2-fury),(NH2,Me,H,Et,-
NHCONHPh),(NH2,Me,H,Et,NHCOCONHPh),(NH2,Me,H,CH2OH,CONHPh),(NH2,Me,H,CH2OH-
,CONH-3-pyridy),(NH12,Me,H,CH2OH,NHCONHPh),
(NH2,Me,H,CH2OH,NHCOCONHPh),(NH2,Me,Me,Me,CONHPh),(NH2,Me,Me,Me,CONH-3-py-
ridyl),(NH2,Me,Me,Me,NHCONHPh),(NH2,Me,Me,Me,NHCOCONHPh),(NH2,Me,Me,Et,CON-
HPh),(NH2,Me,Me,Et,CONH-3-pyridyl),(NH2,Me,Me,Et,NHCOPh),(NH2,Me,Me,Et,NHC-
O-2-furyl),(NH2,Me,Me,Et,NHCONHPh),(NH2,Me,
Me,Et,NHCOCONHPh),(NH2,Me,Me,CH2OH,CONHPh),(NH2,Me,Me,CH2OH,CONH-3-pyridy-
l),(NH2,Me,Me,CH2OH,NHCONHPh),(NH2,Me,Me,CH2OH,NHCOCONHPh),(NH2,Me,Ph,Me,C-
ONHPh),(NH2,Me,Ph,Me,CONH-3-pyridyl),(NH2,Me,Ph,
Me,NHCOPh),(NH2,Me,Ph,Me,NHCO-2-furyl),(NH2,Me,Ph,Me,NHCONHPh),(NH2,Me,Ph-
,Me,NHCOCONHPh),(NH2,Me,Ph,Et,CONHPh),(NH2,Me,Ph,Et,CONH-3-pyridyl),(NH2,M-
e,Ph,Et,NHCOPh),(NH2,Me,Ph,Et,NHCO-2-furyl),(NH2,Me,Ph,Et,
NHCONHPh),(NH2,Me,Ph,Et,NHCOCONHPh),(NH2,Me,Ph,CH2OH,CONHPh),(NH2,Me,Ph,C-
H2OH,CONH-3-pyridyl),(NH2,Me,Ph,CH2OH,NHCONHPh),(NH2,Me,
Ph,CH2OH,NHCOCONHPh),(NH2,Me,OH,Me,CONHPh),(NH2,Me,OH,Me,CONH-3-pyridyl),-
(NH2,Me,OH,Me,NHCONHPh),(NH2,Me,OH,Me,NHCOCONHPh),(NH2,Me,OH,Et,CONHPh),(N-
H2,Me,OH,Et,CONH-3-pyridyl),(NH2,Me,OH,Et,NHCOPh),(NH2,Me,OH,Et,NHCO-2-fur-
yl),(NH2,Me,OH,Et,NHCONHPh),(NH2,Me,OH,Et,
NHCOCONHPh),(NH2,Me,OH,CH2OH,CONHPh),(NH2,Me,OH,CH2OH,CONH-3-pyridyl),(NH-
2,Me,OH,CH2OH,NHCONHPh),(NH2,Me,OH,CH2OH,NHCOCONHPh),(NH2,Ph,H,Me,CONHPh),-
(NH12,Ph,H,Me,CONH-3-pyridyl),(NH2,Ph,H,Me,NHCONHPh),(NH2,Ph,H,Me,NHCOCONH-
Ph),(NH2,Ph,H,Et,CONHPh),(NH2,Ph,H,Et,CONH-3-pyridyl),(NH2,Ph,H,Et,NHCOPh)-
,(NH12,Ph,H,Et,NHCO-2-fury),(NH2,Ph,H,Et,NHCONHPh),(NH2,Ph,H,Et,NHCOCONHPh-
),(NH2,Ph,H,CH2OH,CONHPh),(NH2,Ph,H,CH2OH,CONH-3-pyridyl),(NH2,Ph,H,CH2OH,-
NHCONHPh),(NH2,Ph,H,CH2OH,NHCOCONHPh),(NH2,Ph,Me,Me,CONHPh),(NH2,Ph,Me,Me,-
CONH-3-pyridyl),(NH2,Ph,Me,Me,NHCONHPh),(NH2,Ph,Me,Me,NHCOCONHPh),(NH2,
Ph,Me,Et,CONHPh),(NH2,Ph,Me,Et,CONH-3-pyridyl),(NH2,Ph,Me,Et,NHCOPh),(NH2-
,Ph,Me,Et,NHCO-2-furyl),(NH2,Ph,Me,Et,NHCONHPh),(NH2,Ph,Me,Et,NHCOCONHPh),-
(NH12,Ph,Me,CH2OH,CONHPh),(NH2,Ph,Me,CH2OH,CONH-3-pyridyl),(NH2,Ph,Me,CH2O-
H,NHCONHPh),(NH2,Ph,Me,CH2OH,NHCOCONHPh),(NH2,Ph,Ph,Me,CONHPh),(NH2,Ph,Ph,-
Me,CONH-3-pyridyl),(NH2,Ph,Ph,Me,NHCOPh),(NH2,Ph,Ph,Me,NHCO-2-furyl),(NH2,-
Ph,Ph,Me,NHCONHPh),(NH2,Ph,Ph,Me,NHCOCONHPh),(NH2,Ph,Ph,Et,CONHPh),(NIH2,P-
h,Ph,Et,CONH-3-pyridy),(NH2,
Ph,Ph,Et,NHCOPh),(NH2,Ph,Ph,Et,NHCO-2-furyl),(NH2,Ph,Ph,Et,NHCONHPh),(NH2-
,Ph,Ph,Et,NHCOCONHPh),(NH2,Ph,Ph,CH2OH,CONHPh),(NH2,Ph,Ph,CH2OH,CONH-3-pyr-
idyl),(NH2,Ph,Ph,CH2OH,NHCOPh),(NH2,Ph,Ph,CH2OH,NHCO-2-furyl),(NH2,Ph,Ph,C-
H2OH,NHCONHPh),(NH2,Ph,Ph,CH2OH,NHCOCONPh),
(NIH2,Ph,OH,Me,CONHPh),(NH2,Ph,OH,Me,CONH-3-pyridyl),(NH2,Ph,OH,Me,NHCONH-
Ph),(NH2,Ph,OH,Me,NHCOCONHPh),(NH2,Ph,OH,Et,CONHPh),(NH2,Ph,OH,Et,CONH-3-p-
yridyl),(NH2,Ph,OH,Et,NHCOPh),(NH2,Ph,OH,Et,NHCO-2-furyl),(NH2,Ph,OH,Et,NH-
CONPh),(NH2,Ph,OH,Et,NHOCONHPh),(NH2,Ph,OH,CH2OH,CONHPh),(NH2,Ph,OH,CH2OH,-
CONH-3-pyridyl),(NH2,Ph,OH,CH2OH,NHCOPh),(NH2,Ph,OH,CH2OH,NHCO-2-furyl),(N-
H2,Ph,OH,CH2OH,NCONHPh), (NH2,Ph,OH,CH2OH,NHCOCONHPh),
(NHCH2CH(OH)CH2OH,H,H,Me,CONHPh),(NHCH2CH(OH)CH2OH,H,H,Me,CONH-3-pyridyl)-
,(NHCH2CH(OH)CH2OH,H,H,Me,NHCOPh),(NHCH2CH(OH)CH2OH,H,H,Me,NHCO-2-furyl),(-
NHCH2CH(OH)CH2OH,H,H,Me,NHCONHPh),(NHCH2CH(OH)CH2OH,H,H,Me,NHCOCONHPh),(NH-
CH2CH(OH)CH2OMe,H,H,Me,CONHPh),(NHCH2CH(OH)CH2OMe,H,H,Me,CONH-3-pyridy),(N-
HCH2CH(OH)CH2OMe,H,H,Me,NHCOPh),(NHCH2CH(OH)CH2OMe,H,H,Me,NHCO-2-furyl),(N-
HCH2CH(OH)CH2OMe,H,H,Me,NHCONHPh),(NHCH2CH(OH)CH2OMe,H,H,Me,NHCOCONHPh),(N-
HCH2CH(OH)CH2NH2,H,H,Me,CONHPh),(NHCH2CH(OH)CH2NH2,H,H,Me,CONH-3-pyridyl),-
(NHCH2CH(OH)CH2NH2,H,H,Me,NHCOPh),(NHCH2CH(OH)CH2NH2,H,H,Me,NHCO-2-furyl),-
(NHCH2CH(OH)CH2NH2,H,H,Me,
NHCONHPh),(NHCH2CH(OH)CH2NH2,H,H,Me,NHCOCONHPh),(NHCH2CH(OH)CH2NHMe,H,H,M-
e,CONHPh),(NHCH2CH(OH)CH2NHMe,H,H,Me,CONH-3-pyridyl),(NHCH2CH(OH)CH2NHMe,H-
,H,Me,NHCOPh),(NHCH2CH(OH)CH2NHMe,
H,H,Me,NHCO-2-furyl),(NHCH2CH(OH)CH2NHMe,H,H,Me,NHCONHPh),(NHCH2CH(OH)CH2-
NHMe,H,H,Me,NHCOCONHPh),(NHCH2CH(OH)CH2NHCOMe,H,H,Me,CONHPh),(NHCH2CH(OH)C-
H2NHCOMe,H,H,Me,CONH-3-pyridyl),(NHCH2CH(OH)CH2NHCOMe,H,H,Me,NHCOPh),(NHCH-
2CH(OH)CH2NHCOMe,H,H,
Me,NHCO-2-furyl),(NHCH2CH(OH)CH2NHCOMe,H,H,Me,NHCONHPh),(NHCH2CH(OH)CH2NH-
COMe,H,H,Me,NHCOCONHPh),(NHCH2CH(OH)CH2N(Me)Me,H,H,Me,CONHPh),(NHCH2CH(OH)-
CH2N(Me)Me,H,H,Me,CONH-3-pyridyl),(NHCH2CH(OH)OCH2N(Me)Me,H,H,Me,NHCOPh),(-
NHCH2CH(OH)CH2N(Me)Me,H,H,Me,NHCO-2-furyl),(NHCH2CH(OH)CH2N(Me)Me,H,H,Me,N-
HCONHPh),(NHCH2CH(OH)CH2N(Me)Me,H,H,Me,NHCOCONHPh),(NHC(O)C(O)NH2,H,H,Me,C-
ONHPh),(NHC(O)C(O)NH2,H,H,Me,CONH-3-pyridy),(NHC(O)
C(O)NH2,H,H,Me,NHCOPh),(NHC(O)C(O)NH2,H,H,Me,NHCO-2-furyl),(NHC(O)C(O)NH2-
,H,H,Me,NHCONHPh),(NHC(O)C(O)NH2,H,H,Me,NHCOCONHPh),(NC(O)C(O)NHMe,H,H,Me,-
CONHPh),(NHC(O)C(O)NHMe,H,H,Me,CONH-3-pyridyl),(NHC(O)C(O)NHMe,H,H,
Me,NHCOPh),(NHC(O)C(O)NHMe,H,H,Me,NHCO-2-furyl),(NHC(O)C(O)NHMe,H,
H,Me,NHCONHPh),(NHC(O)
C(O)NHMe,H,H,Me,NHCOCONHPh),(NHC(O)C(O)N(Me)Me,H,H,Me,CONHPh),(NHC(O)C(O)-
N(Me)Me,H,H,Me,CONH-3-pyridyl),(NHC(O)
C(O)N(Me)Me,H,H,Me,NHCOPh),(NHC(O)C(O)N(Me)Me,H,H,Me,NHCO-2-furyl),(NHC(O-
)C(O)N(Me)Me,H,H,Me,NHCONHP),(NHC(O)C(O)N(Me)Me,H,H,Me,NHCOCONHPh).
##STR01358##
[0299] In above structural formula (Ii) or (Ij), the combination of
B, Linker, A, R.sup.5 (B, Linker, A, R.sup.5) are the following
compounds.
TABLE-US-00169 TABLE 169 B B1 Ph-- B2 2-piridyl- B3 4-Me--Ph-- B4
cHex-- B5 cHex--CH2-- Linker L1 ##STR01359## L2 ##STR01360## L3
##STR01361## L4 ##STR01362## L5 ##STR01363## A A1 ##STR01364## A2
##STR01365## A3 ##STR01366## A4 ##STR01367## A5 ##STR01368## R5 R51
--CN R52 --C.ident.CH R53 --C.ident.CMe R54 --CF3 R55 --CH2Cl R56
CHCl2
(B, Linker, A,
R.sup.5)=(B1,L1,A1,R51),(B1,L1,A1,R52),(B1,L1,A1,R53),(B1,L1,A1,R54),(B1,-
L1,A1,R55),(B1,L1,A1,R56),(B1,L1,A2,R51),(B1,L1,A2,R52),(B1,L1,A2,R53),(B1-
,L1,A2,R54),(B1,L1,A2,R55),(B1,L1,A2,R56),(B1,L1,A3,R51),(B1,L1,A3,R52),(B-
1,L1,A3,R53),(B1,L1,A3,R54),(B1,L1,A3,R55),(B1,L1,A3,R56),(B1,L1,A4,R51),(-
B1,L1,A4,R52),(B1,L1,A4,R53),(B1,L1,A4,R54),(B1,L1,A4,R55),(B1,L1,A4,R56),-
(B1,L1,A5,R51),(B1,L1,A5,R52),(B1,L1,A5,R53),(B1,L1,A5,R54),(B1,L1,A5,R55)-
,(B1,L1,A5,R56),(B1,L2,A1,R51),(B1,
L2,A1,R52),(B1,L2,A1,R53),(B1,L2,A1,R54),(B1,L2,A1,R55),(B1,L2,A1,R56),(B-
1,L2,
A2,R51),(B1,L2,A2,R52),(B1,L2,A2,R53),(B1,L2,A2,R54),(B1,L2,A2,R55),-
(B1,L2,A2,
R56),(B1,L2,A3,R51),(B1,L2,A3,R52),(B1,L2,A3,R53),(B1,L2,A3,R54-
),(B1,L2,A3,R55),(B1,L2,A3,R56),(B1,L2,A4,R51),(B1,L2,A4,R52),(B1,L2,A4,R5-
3),(B1,L2,A4,R54),(B1,L2,A4,R55),(B1,L2,A4,R56),(B1,L2,A5,R51),(B1,L2,A5,R-
52),(B1,L2,A5,R53),(B1,
L2,A5,R54),(B1,L2,A5,R55),(B1,L2,A5,R56),(B1,L3,A1,R51),(B1,L3,A1,R52),(B-
1,L3,
A1,R53),(B1,L3,A1,R54),(B1,L3,A1,R55),(B1,L3,A1,R56),(B1,L3,A2,R51),-
(B1,L3,A2,
R52),(B1,L3,A2,R53),(B1,L3,A2,R54),(B1,L3,A2,R55),(B1,L3,A2,R56-
),(B1,L3,A3,R51),(B1,L3,A3,R52,(B1,L3,A3,R53),(B1,L3,A3,R54),(B1,L3,A3,R55-
),(B1,L3,A3,R56),(B1,L3,A4,R51),(B1,L3,A4,R52),(B1,L3,A4,R53),(B1,L3,A4,R5-
4),(B1,L3,A4,R55),(B1,
L3,A4,R56),(B1,L3,A5,R51),(B1,L3,A5,R52),(B1,L3,A5,R53),(B1,L3,A5,R54),(B-
1,L3,
A5,R55),(B1,L3,A5,R56),(B1,L4,A1,R51),(B1,L4,A1,R52),(B1,L4,A1,R53),-
(B1,L4,A1,
R54),(B1,L4,A1,R55),(B1,L4,A1,R56),(B1,L4,A2,R51),(B1,L4,A2,R52-
),(B1,L4,A2,R53),(B1,L4,A2,R54),(B1,L4,A2,R55),(B1,L4,A2,R56),(B1,L4,A3,R5-
1),(B1,L4,A3,R52),(B1,L4,A3,R53),(B1,L4,A3,R54),(B1,L4,A3,R55),(B1,L4,A3,R-
56),(B1,L4,A4,R51),(B1,
L4,A4,R52),(B1,L4,A4,R53),(B1,L4,A4,R54),(B1,L4,A4,R55),(B1,L4,A4,R56),(B-
1,L4,
A5,R51),(B1,L4,A5,R52),(B1,L4,A5,R53),(B1,L4,A5,R54),(B1,L4,A5,R55),-
(B1,L4,A5,
R56),(B1,L5,A1,R51),(B1,L5,A1,R52),(B1,L5,A1,R53),(B1,L5,A1,R54-
),(B1,L5,A1,R55),(B1,L5,A1,R56),(B1,L5,A2,R51),(B1,L5,A2,R52),(B1,L5,A2,R5-
3),(B1,L5,A2,R54),(B1,L5,A2,R55),(B1,L5,A2,R56),(B1,L5,A3,R51),(B1,L5,A3,R-
52),(B1,L5,A3,R53),(B1,
L5,A3,R54),(B1,L5,A3,R55),(B1,L5,A3,R56),(B1,L5,A4,R51),(B1,L5,A4,R52),(B-
1,L5,
A4,R53),(B1,L5,A4,R54),(B1,L5,A4,R55),(B1,L5,A4,R56),(B1,L5,A5,R51),-
(B1,L5,A5,
R52),(B1,L5,A5,R53),(B1,L5,A5,R54),(B1,L5,A5,R55),(B1,L5,A5,R56-
),(B2,L1,A1,R51),(B2,L1,A1,R52),(B2,L1,A1,R53),(B2,L1,A1,R54),(B2,L1,A1,R5-
5),(B2,L1,A1,R56),(B2,L1,A2,R51),(B2,L1,A2,R52),(B2,L1,A2,R53),(B2,L1,A2,R-
54),(B2,L1,A2,R55),(B2,
L1,A2,R56),(B2,L1,A3,R51),(B2,L1,A3,R52),(B2,L1,A3,R53),(B2,L1,A3,R54),(B-
2,L1,
A3,R55),(B2,L1,A3,R56),(B2,L1,A4,R51),(B2,L1,A4,R52),(B2,L1,A4,R53),-
(B2,L1,A4,
R54),(B2,L1,A4,R55),(B2,L1,A4,R56),(B2,L1,A5,R51),(B2,L1,A5,R52-
),(B2,L1,A5,R53),(B2,L1,A5,R54),(B2,L1,A5,R55),(B2,L1,A5,R56),(B2,L2,A1,R5-
1),(B2,L2,A1,R52),(B2,L2,A1,R53),(B2,L2,A1,R54),(B2,L2,A1,R55),(B2,L2,A1,R-
56),(B2,L2,A2,R51),(B2,
L2,A2,R52),(B2,L2,A2,R53),(B2,L2,A2,R54),(B2,L2,A2,R55),(B2,L2,A2,R56),(B-
2,L2,
A3,R51),(B2,L2,A3,R52),(B2,L2,A3,R3),(B2,L2,A3,R54),(B2,L2,A3,R55),(-
B2,L2,A3,
R56),(B2,L2,A4,R51),(B2,L2,A4,R52),(B2,L2,A4,R53),(B2,L2,A4,R54)-
,(B2,L2,A4,R55),(B2,L2,A4,R56),(B2,L2,A5,R51),(B2,L2,A5,R52),(B2,L2,A5,R53-
),(B2,L2,A5,R54),(B2,L2,A5,R55),(B2,L2,A5,R56),(B2,L3,A1,R51),(B2,L3,A1,R5-
2),(B2,L3,A1,R53),(B2,
L3,A1,R54),(B2,L3,A1,R55),(B2,L3,A1,R56),(B2,L3,A2,R51),(B2,L3,A2,R52),(B-
2,L3,
A2,R53),(B2,L3,A2,R54),(B2,L3,A2,R55),(B2,L3,A2,R56),(B2,L3,A3,R51),-
(B2,L3,A3,
R52),(B2,L3,A3,R53),(B2,L3,A3,R54),(B2,L3,A3,R55),(B2,L3,A3,R56-
),(B2,L3,A4,R51),(B2,L3,A4,R52),(B2,L3,A4,R53),(B2,L3,A4,R54),(B2,L3,A4,R5-
5),(B2,L3,A4,R56),(B2,L3,A5,R51),(B2,L3,A5,R52),(B2,L3,A5,R53),(B2,L3,A5,R-
54),(B2,L3,A5,R55),(B2,
L3,A5,R56),(B2,L4,A1,R51),(B2,L4,A1,R52),(B2,L4,A1,R53),(B2,L4,A1,R54),(B-
2,L4,
A1,R55),(B2,L4,A1,R56),(B2,L4,A2,R51),(B2,L4,A2,R52),(B2,L4,A2,R53),-
(B2,L4,A2,
R54),(B2,L4,A2,R55),(B2,L4,A2,R56),(B2,L4,A3,R51),(B2,L4,A3,R52-
),(B2,L4,A3,R53),(B2,L4,A3,R54),(B2,L4,A3,R55),(B2,L4,A3,R56),(B2,L4,A4,R5-
1),(B2,L4,A4,R52),(B2,L4,A4,R53),(B2,L4,A4,R54),(B2,L4,A4,R55),(B2,L4,A4,R-
56),(B2,L4,A5,R51),(B2,
L4,A5,R52),(B2,L4,A5,R53),(B2,L4,A5,R54),(B2,L4,A5,R55),(B2,L4,A5,R56),(B-
2,L5,
A1,R51),(B2,L5,A1,R52),(B2,L5,A1,R53),(B2,L5,A1,R54),(B2,L5,A1,R55),-
(B2,L5,A1,
R56),(B2,L5,A2,R51),(B2,L5,A2,R52),(B2,L5,A2,R53),(B2,L5,A2,R54-
),(B2,L5,A2,R55),(B2,L5,A2,R56),(B2,L5,A3,R51),(B2,L5,A3,R52),(B2,L5,A3,R5-
3),(B2,L5,A3,R54),(B2,L5,A3,R55),(B2,L5,A3,R56),(B2,L5,A4,R51),(B2,L5,A4,R-
52),(B2,L5,A4,R53),(B2,
L5,A4,R54),(B2,L5,A4,R55),(B2,L5,A4,R56),(B2,L5,A5,R51),(B2,L5,A5,R52),(B-
2,L5,
A5,R53),(B2,L5,A5,R54),(B2,L5,A5,R55),(B2,L5,A5,R56),(B3,L1,A1,R51),-
(B3,L1,A1,
R52),(B3,L1,A1,R53),(B3,L1,A1,R54),(B3,L1,A1,R55),(B3,L1,A1,R56-
),(B3,L1,A2,R51),(B3,L1,A2,R52),(B3,L1,A2,R53),(B3,L1,A2,R54),(B3,L1,A2,R5-
5),(B3,L1,A2,R56),(B3,L1,A3,R51),(B3,L1,A3,R52),(B3,L1,A3,R53),(B3,L1,A3,R-
54),(B3,L1,A3,R55),(B3,
L1,A3,R56),(B3,L1,A4,R51),(B3,L1,A4,R52),(B3,L1,A4,R53),(B3,L1,A4,R54),(B-
3,L1,
A4,R55),(B3,L1,A4,R56),(B3,L1,A5,R51),(B3,L1,A5,R52),(B3,L1,A5,R53),-
(B3,L1,A5,
R54),(B3,L1,A5,R55),(B3,L1,A5,R56),(B3,L2,A1,R51),(B3,L2,A1,R52-
),(B3,L2,A1,R53),(B3,L2,A1,R54),(B3,L2,A1,R55),(B3,L2,A1,R56),(B3,L2,A2,R5-
1),(B3,L2,A2,R52),(B3,L2,A2,R53),(B3,L2,A2,R54),(B3,L2,A2,R55),(B3,L2,A2,R-
56),(B3,L2,A3,R51),(B3,
L2,A3,R52),(B3,L2,A3,R53),(B3,L2,A3,R54),(B3,L2,A3,R55),(B3,L2,A3,R56),(B-
3,L2,
A4,R51),(B3,L2,A4,R52),(B3,L2,A4,R53),(B3,L2,A4,R54),(B3,L2,A4,R55),-
(B3,L2,A4,
R56),(B3,L2,A5,R51),(B3,L2,A5,R52),(B3,L2,A5,R53),(B3,L2,A5,R54-
),(B3,L2,A5,R55),(B3,L2,A5,R56),(B3,L3,A1,R51),(B3,L3,A1,R52),(B3,L3,A1,R5-
3),(B3,L3,A1,R54),(B3,L3,A1,R55),(B3,L3,A1,R56),(B3,L3,A2,R51),(B3,L3,A2,R-
52),(B3,L3,A2,R53),(B3,
L3,A2,R54),(B3,L3,A2,R55),(B3,L3,A2,R56),(B3,L3,A3,R51),(B3,L3,A3,R52),(B-
3,L3,
A3,R53),(B3,L3,A3,R54),(B3,L3,A3,R55),(B3,L3,A3,R56),(B3,L3,A4,R51),-
(B3,L3,A4,
R52),(B3,L3,A4,R53),(B3,L3,A4,R54),(B3,L3,A4,R55),(B3,L3,A4,R56-
),(B3,L3,A5,R51),(B3,L3,A5,R52),(B3,L3,A5,R53),(B3,L3,A5,R54),(B3,L3,A5,R5-
5),(B3,L3,A5,R56),(B3,L4,A1,R51),(B3,L4,A1,R52),(B3,L4,A1,R53),(B3,L4,A1,R-
54),(B3,L4,A1,R55),(B3,
L4,A1,R56),(B3,L4,A2,R51),(B3,L4,A2,R52),(B3,L4,A2,R53),(B3,L4,A2,R54),(B-
3,L4,
A2,R55),(B3,L4,A2,R56),(B3,L4,A3,R51),(B3,L4,A3,R52),(B3,L4,A3,R53),-
(B3,L4,A3,
R54),(B3,L4,A3,R55),(B3,L4,A3,R56),(B3,L4,A4,R51),(B3,L4,A4,R52-
),(B3,L4,A4,R53),(B3,L4,A4,R54),(B3,L4,A4,R55),(B3,L4,A4,R56),(B3,L4,A5,R5-
1),(B3,L4,A5,R52),(B3,L4,A5,R53),(B3,L4,A5,R54),(B3,L4,A5,R55),(B3,L4,A5,R-
56),(B3,L5,A1,R51),(B3,
L5,A1,R52),(B3,L5,A1,R53),(B3,L5,A1,R54),(B3,L5,A1,R55),(B3,L5,A1,R56),(B-
3,L5,
A2,R51),(B3,L5,A2,R52),(B3,L5,A2,R53),(B3,L5,A2,R54),(B3,L5,A2,R55),-
(B3,L5,A2,
R56),(B3,L5,A3,R51),(B3,L5,A3,R52),(B3,L5,A3,R53),(B3,L5,A3,R54-
),(B3,L5,A3,R55),(B3,L5,A3,R56),(B3,L5,A4,R51),(B3,L5,A4,R52),(B3,L5,A4,R5-
3),(B3,L5,A4,R54),(B3,L5,A4,R55),(B3,L5,A4,R56),(B3,L5,A5,R51),(B3,L5,A5,R-
52),(B3,L5,A5,R53),(B3,
L5,A5,R54),(B3,L5,A5,R55),(B3,L5,A5,R56),(B4,L1,A1,R51),(B4,L1,A1,R52),(B-
4,L1,
A1,R53),(B4,L1,A1,R54),(B4,L1,A1,R55),(B4,L1,A1,R56),(B4,L1,A2,R51),-
(B4,L1,A2,
R52),(B4,L1,A2,R53),(B4,L1,A2,R54),(B4,L1,A2,R55),(B4,L1,A2,R56-
),(B4,L1,A3,R51),(B4,L1,A3,R52),(B4,L1,A3,R53),(B4,L1,A3,R54),(B4,L1,A3,R5-
5),(B4,L1,A3,R56),(B4,L1,A4,R51),(B4,L1,A4,R52),(B4,L1,A4,R53),(B4,L1,A4,R-
54),(B4,L1,A4,R55),(B4,
L1,A4,R56),(B4,L1,A5,R51),(B4,L1,A5,R52),(B4,L1,A5,R53),(B4,L1,A5,R54),(B-
4,L1,
A5,R55),(B4,L1,A5,R56),(B4,L2,A1,R51),(B4,L2,A1,R52),(B4,L2,A1,R53),-
(B4,L2,A1,
R54),(B4,L2,A1,R55),(B4,L2,A1,R56),(B4,L2,A2,R51),(B4,L2,A2,R52-
),(B4,L2,A2,R53),(B4,L2,A2,R54),(B4,L2,A2,R55),(B4,L2,A2,R56),(B4,L2,A3,R5-
1),(B4,L2,A3,R52),(B4,L2,A3,R53),(B4,L2,A3,R54),(B4,L2,A3,R55),(B4,L2,A3,R-
56),(B4,L2,A4,R51),(B4,
L2,A4,R52),(B4,L2,A4,R53),(B4,L2,A4,R54),(B4,L2,A4,R55),(B4,L2,A4,R56),(B-
4,L2,
A5,R51),(B4,L2,A5,R52),(B4,L2,A5,R53),(B4,L2,A5,R54),(B4,L2,A5,R55),-
(B4,L2,A5,
R56),(B4,L3,A1,R51),(B4,L3,A1,R52),(B4,L3,A1,R53),(B4,L8,A1,R54-
),(B4,L3,A1,R55),(B4,L3,A1,R56),(B4,L3,A2,R51),(B4,L3,A2,R52),(B4,L3,A2,R5-
3),(B4,L3,A2,R54),(B4,L3,A2,R55),(B4,L3,A2,R56),(B4,L3,A3,R51),(B4,L3,A3,R-
52),(B4,L3,A3,R53),(B4,
L3,A3,R54),(B4,L3,A3,R55),(B4,L3,A3,R56),(B4,L3,A4,R51),(B4,L3,A4,R52),(B-
4,L3,
A4,R53),(B4,L3,A4,R54),(B4,L3,A4,R55),(B4,L3,A4,R56),(B4,L3,A5,R51),-
(B4,L3,A5,
R52),(B4,L3,A5,R53),(B4,L3,A5,R54),(B4,L3,A5,R55),(B4,L3,A5,R56-
),(B4,L4,A1,R51),(B4,L4,A1,R52),(B4,L4,A1,R53),(B4,L4,A1,R54),(B4,L4,A1,R5-
5),(B4,L4,A1,R56),(B4,L4,A2,R51),(B4,L4,A2,R52),(B4,L4,A2,R53),(B4,L4,A2,R-
54),(B4,L4,A2,R55),(B4,
L4,A2,R56),(B4,L4,A3,R51),(B4,L4,A3,R52),(B4,L4,A3,R53),(B4,L4,A3,R54),(B-
4,L4,
A3,R55),(B4,L4,A3,R56),(B4,L4,A4,R51),(B4,L4,A4,R52),(B4,L4,A4,R53),-
(B4,L4,A4,
R54),(B4,L4,A4,R55),(B4,L4,A4,R56),(B4,L4,A5,R51),(B4,L4,A5,R52-
),(B4,L4,A5,R53),(B4,L4,A5,R54),(B4,L4,A5,R55),(B4,L4,A5,R56),(B4,L5,A1,R5-
1),(B4,L5,A1,R52),(B4,L5,A1,R53),(B4,L5,A1,R54),(B4,L5,A1,R55),(B4,L5,A1,R-
56),(B4,L5,A2,R51),(B4,
L5,A2,R52),(B4,L5,A2,R53),(B4,L5,A2,R54),(B4,L5,A2,R55),(B4,L5,A2,R56),(B-
4,L5,
A3,R51),(B4,L5,A3,R52),(B4,L5,A3,R53),(B4,L5,A3,R54),(B4,L5,A3,R55),-
(B4,L5,A3,
R56),(B4,L5,A4,R51),(B4,L5,A4,R52),(B4,L5,A4,R53),(B4,L5,A4,R54-
),(B4,L5,A4,R55),(B4,L5,A4,R56),(B4,L5,A5,R51),(B4,L5,A5,R52),(B4,L5,A5,R5-
3),(B4,L5,A5,R54),(B4,L5,A5,R55),(B4,L5,A5,R56),(B5,L1,A1,R51),(B5,L1,A1,R-
52),(B5,L1,A1,R53),(B5,
L1,A1,R54),(B5,L1,A1,R55),(B5,L1,A1,R56),(B5,L1,A2,R51),(B5,L1,A2,R52),(B-
5,L1,
A2,R53),(B5,L1,A2,R54),(B5,L1,A2,R55),(B5,L1,A2,R56),(B5,L1,A3,R51),-
(B5,L1,A3,
R52),(B5,L1,A3,R53),(B5,L1,A3,R54),(B5,L1,A3,R55),(B5,L1,A3,R56-
),(B5,L1,A4,R51),(B5,L1,A4,R52),(B5,L1,A4,R53),(B5,L1,A4,R54),(B5,L1,A4,R5-
5),(B5,L1,A4,R56),(B5,L1,A5,R51),(B5,L1,A5,R52),(B5,L1,A5,R53),(B5,L1,A5,R-
54),(B5,L1,A5,R55),(B5,
L1,A5,R56),(B5,L2,A1,R51),(B5,L2,A1,R52),(B5,L2,A1,R53),(B5,L2,A1,R54),(B-
5,L2,
A1,R55),(B5,L2,A1,R56),(B5,L2,A2,R51),(B5,L2,A2,R52),(B5,L2,A2,R53),-
(B5,L2,A2,
R54),(B5,L2,A2,R55),(B5,L2,A2,R56),(B5,L2,A3,R51),(B5,L2,A3,R52-
),(B5,L2,A3,R53),(B5,L2,A3,R54),(B5,L2,A3,R55),(B5,L2,A3,R56),(B5,L2,A4,R5-
1),(B5,L2,A4,R52),(B5,L2,A4,R53),(B5,L2,A4,R54),(B5,L2,A4,R55),(B5,L2,A4,R-
56),(B5,L2,A5,R51),(B5,
L2,A5,R52),(B5,L2,A5,R53),(B5,L2,A5,R54),(B5,L2,A5,R55),(B5,L2,A5,R56),(B-
5,L3,
A1,R51),(B5,L3,A1,R52),(B5,L3,A1,R53),(B5,L3,A1,R54),(B5,L3,A1,R55),-
(B5,L3,A1,
R56),(B5,L3,A2,R51),(B5,L3,A2,R52),(B5,L3,A2,R53),(B5,L3,A2,R54-
),(B5,L3,A2,R55),(B5,L3,A2,R56),(B5,L3,A3,R51),(B5,L3,A3,R52),(B5,L3,A3,R5-
3),(B5,L3,A3,R54),(B5,L3,A3,R55),(B5,L3,A3,R56),(B5,L3,A4,R51),(B5,L3,A4,R-
52),(B5,L3,A4,R53),(B5,
L3,A4,R54),(B5,L3,A4,R55),(B5,L3,A4,R56),(B5,L3,A5,R51),(B5,L3,A5,R52),(B-
5,L3,
A5,R53),(B5,L3,A5,R54),(B5,L3,A5,R55),(B5,L3,A5,R56),(B5,L4,A1,R51),-
(B5,L4,A1,
R52),(B5,L4,A1,R53),(B5,L4,A1,R54),(B5,L4,A1,R55),(B5,L4,A1,R56-
),(B5,L4,A2,R51),(B5,L4,A2,R52),(B5,L4,A2,R53),(B5,L4,A2,R54),(B5,L4,A2,R5-
5),(B5,L4,A2,R56),(B5,L4,A3,R51),(B5,L4,A3,R52),(B5,L4,A3,R53),(B5,L4,A3,R-
54),(B5,L4,A3,R55),(B5,
L4,A3,R56),(B5,L4,A4,R51),(B5,L4,A4,R52),(B5,L4,A4,R53),(B5,L4,A4,R54),(B-
5,L4,
A4,R55),(B5,L4,A4,R56),(B5,L4,A5,R51),(B5,L4,A5,R52),(B5,L4,A5,R53),-
(B5,L4,A5,
R54),(B5,L4,A5,R55),(B5,L4,A5,R56),(B5,L5,A1,R51),(B5,L5,A1,R52-
),(B5,L5,A1,R53),(B5,L5,A1,R54),(B5,L5,A1,R55),(B5,L5,A1,R56),(B5,L5,A2,R5-
1),(B5,L5,A2,R52),(B5,L5,A2,R53),(B5,L5,A2,R54),(B5,L5,A2,R55),(B5,L5,A2,R-
56),(B5,L5,A3,R51),(B5,
L5,A3,R52),(B5,L5,A3,R53),(B5,L5,A3,R54),(B5,L5,A3,R55),(B5,L5,A3,R56),(B-
5,L5,
A4,R51),(B5,L5,A4,R52),(B5,L5,A4,R53),(B5,L5,A4,R54),(B5,L5,A4,R55),-
(B5,L5,A4,
R56),(B5,L5,A5,R51),(B5,L5,A5,R52),(B5,L5,A5,R53),(B5,L5,A5,R54-
),(B5,L5,A5,R55),(B5,L5,A5,R56).
Test: Measurement of Inhibition of .beta.-Secretase Activity
[0300] Zero point five .mu.L of the test compounds (dissolved in
N,N'-dimethylsulfoxide) were incubated with 48.5 .mu.L of the
fluorescence-quenched peptide substrate solution
(Biotin-XSEVNLDAEFRHDSGC-Eu:X=.epsilon.-amino-n-capronic acid,
Eu=Europium cryptate) and 1 .mu.L of recombinant human BACE-1
protein (R&D systems) for 3 h at 30.degree. C. in the 96 well
half-area plate (black color plate, Costar). The substrate peptide
was synthesized by reacting with Biotin-XSEVNLDAEFRHDSGC (Peptide
Institute) and Cryptate TBPCOOH mono SMP (CIS bio international).
The final-concentration of the substrate peptide and recombinant
human BACE-1 protein were 18 nM and 7.4 nM, respectively. The
enzymatic reaction was performed in sodium acetate buffer (50 mM
sodium acetate (pH5.0), 0.008% Triton X-100). After the reaction, a
50 .mu.L of 8.0 g/mL Streptavidin-XL665 (CIS bio international)
dissolved in phosphate buffer (150 mM
K.sub.2HPO.sub.4--KH.sub.2PO.sub.4 (pH 7.0), 0.008% Triton X-100,
0.8 M KF) was add to each well and incubated for 1 h at 30.degree.
C. Then, the fluorescence intensity (excitation wavelength 320 nm,
emission wavelength 620 nM and 665 nM) in each well was measured
using Wallac 1420 multilabel counter (Perkin Elmer life sciences).
The enzymatic activity was calculated by the each fluorescence
intensity ratio ([ratio of fluorescence at 665 nm to that at 620
nm].times.10,000). IC.sub.50 values of test compounds were
indicated in table 170.
TABLE-US-00170 TABLE 170 Compound IC.sub.50 value No. (.mu.M) 1186
5.7 639 7.9 1000 8.0 246 2.9 269 7.0 1010 2.8 417 5.0 161 7.7 220
1.5 1207 4.0 998 4.5 1205 8.1 616 5.9 504 2.5 799 6.7 490 5.1 972
0.45 1160 0.72 753 5.6 786 0.156 165 0.0394 1132 2.563 570 0.149
1014 0.165 731 0.278 1262 0.140 964 0.264 793 0.061 625 1.288 498
0.930 26 1.977 465 3.239 1197 0.912 395 1.500 896 8.497 660 4.586
664 3.642 176 1.479 284 0.229 912 0.175 212 0.220 163 2.278 1244
0.130 52 10.0 698 0.165 96 0.163 822 0.243 739 0.049 832 0.222 897
0.816 1100 0.037 740 0.505 436 0.160 1043 0.027 1199 0.032 73 0.435
127 0.054 309 0.833 1135 2.296 1035 0.174
[0301] The IC.sub.50 value of the following compounds were less
than 100 .mu.M by the same test.
[0302] 3, 4, 6, 8, 12, 17, 18, 30, 31, 35, 36, 38, 39, 42, 43, 57,
61, 67, 67, 71, 77, 78, 80, 85, 97, 99, 105, 106, 113, 114, 115,
117, 120, 121, 125, 128, 129, 130, 134, 139, 144, 154, 157, 159,
164, 172, 175, 178, 181, 182, 186, 189, 200, 200, 201, 204, 207,
209, 211, 214, 215, 216, 228, 232, 240, 241, 243, 243, 243, 251,
255, 259, 267, 273, 275, 278, 279, 281, 282, 293, 298, 299, 300,
302, 303, 307, 314, 319, 321, 322, 326, 328, 330, 333, 335, 339,
341, 344, 345, 346, 348, 352, 353, 357, 358, 359, 359, 359, 360,
361, 363, 369, 370, 373, 378, 380, 383, 389, 390, 393, 396, 397,
402, 405, 406, 409, 410, 413, 415, 426, 442, 443, 444, 451, 452,
454, 456, 463, 467, 469, 472, 472, 479, 480, 482, 482, 483, 491,
493, 497, 500, 501, 502, 509, 511, 515, 516, 517, 527, 528, 532,
542, 544, 549, 550, 551, 558, 560, 568, 569, 575, 578, 584, 586,
588, 591, 600, 607, 608, 611, 613, 618, 620, 629, 634, 634, 637,
643, 646, 652, 657, 661, 671, 677, 681, 687, 691, 708, 711, 719,
720, 723, 725, 728, 729, 730, 732, 735, 743, 746, 756, 758, 761,
770, 775, 781, 787, 788, 790, 791, 792, 796, 797, 802, 803, 804,
808, 809, 813, 816, 819, 820, 824, 833, 835, 836, 847, 850, 861,
865, 866, 871, 876, 887, 893, 894, 900, 905, 906, 908, 910, 919,
922, 928, 932, 933, 935, 936, 939, 941, 943, 944, 946, 947, 949,
959, 966, 971, 984, 986, 988, 990, 1004, 1005, 1007, 1009, 1013,
1020, 1028, 1034, 1039, 1046, 1055, 1062, 1063, 1069, 1074, 1077,
1084, 1089, 1096, 1099, 1108, 1109, 1114, 1124, 1125, 1131, 1140,
1142, 1145, 1147, 1148, 1150, 1164, 1165, 1172, 1174, 1184, 1185,
1193, 1211, 1217, 1221, 1237, 1241, 1243, 1255, 1256, 1257, 1258,
1261, 1263, 1264, 1265, 1266, 1268, 1269, 1270, 1271, 1272, 1274,
and so on.
Formulation Example 1
[0303] A granule containing the following ingredients is
prepared.
TABLE-US-00171 Ingredient Compound represented by formula (I) 10 mg
Lactose 700 mg Corn starch 274 mg HPC-L 16 mg 1000 mg
[0304] The compound represented by the formula (I) and lactose are
passed through a 60 mesh sieve. Corn starch is passed through a 120
mesh sieve. These are mixed with a V-type mixer. To a mixed powder
is added a HPC-L (lower viscosity hydroxypropylcellulose) aqueous
solution, the materials are kneaded, granulated (extrusion
granulation, pore diameter 0.5 to 1 mm), and dried. The resulting
dry granule is passed through a sieve using a vibration sieve
(12/60 mesh) to obtain a granule.
Formulation Example 2
[0305] A granule for filling into a capsule containing the
following ingredients is prepared.
TABLE-US-00172 Ingredient Compound represented by formula (I) 15 mg
Lactose 90 mg Corn starch 42 mg HPC-L 3 mg 150 mg
[0306] The compound represented by the formula (I) and lactose are
passed through a 60 mesh sieve. Corn starch is passed through a 120
mesh sieve. These are mixed, to a mixed powder is added a HPC-L
solution, the materials are kneaded, granulated, and dried. The
resulting dry granule is size-adjusted, 150 mg of which is filled
into a No. 4 hard gelatin capsule.
Formulation Example 3
[0307] A tablet containing the following ingredients is
prepared.
TABLE-US-00173 Ingredient Compound represented by the formula (I)
10 mg Lactose 90 mg Microcrystalline cellulose 30 mg CMC-Na 15 mg
Magnesium stearate 5 mg 150 mg
[0308] The compound represented by the formula (I), lactose,
microcrystalline cellulose, CMC-Na (carboxymethylcellulose sodium
salt) are passed through a 60 mesh sieve, and mixed. Into a mixed
powder is mixed magnesium stearate to obtain a mixed powder for
tabletting. The present mixed powder is compressed to obtain 150 mg
of a tablet.
Formulation Example 4
[0309] The following ingredients are warmed, mixed, and sterilized
to obtain an injectable.
TABLE-US-00174 Ingredient Compound represented by the formula (I) 3
mg Nonionic surfactant 15 mg Purified water for injection 1 ml
INDUSTRIAL APPLICABILITY
[0310] The present invention is useful as an agent for treating
disease induced by production, secretion and/or deposition of
amyloid .beta..
* * * * *