U.S. patent application number 10/958225 was filed with the patent office on 2005-03-10 for nitrogen-containing fused ring compound and use thereof as hiv integrase inhibitor.
Invention is credited to Adachi, Kaoru, Isoshima, Hirotaka, Katoh, Susumu, Kiyonari, Shinichi, Kobayashi, Satoru, Matsuzaki, Yuji, Miyazaki, Susumu, Wamaki, Shuichi, Watanabe, Wataru, Yamataka, Kazunobu.
Application Number | 20050054645 10/958225 |
Document ID | / |
Family ID | 34197143 |
Filed Date | 2005-03-10 |
United States Patent
Application |
20050054645 |
Kind Code |
A1 |
Miyazaki, Susumu ; et
al. |
March 10, 2005 |
Nitrogen-containing fused ring compound and use thereof as HIV
integrase inhibitor
Abstract
The present invention relates to a nitrogen-containing fused
ring compound represented by the following formula [I] 1 wherein
each symbol is as defined in the specification, or a
pharmaceutically acceptable salt thereof, and an anti-HIV agent
containing such compound. The compound of the present invention has
an HIV integrase inhibitory activity, and is useful as an agent for
the prophylaxis or treatment of AIDS, or as an anti-HIV agent. In
addition, by the combined use with other anti-HIV agents such as a
protease inhibitor, a reverse transcriptase inhibitor and the like,
it can be a more effective anti-HIV agent. Becuae it shows
integrase-specific high inhibitory activity, the compound can be a
pharmaceutical agent safe on human body, which causes only a fewer
side effects.
Inventors: |
Miyazaki, Susumu; (Osaka,
JP) ; Katoh, Susumu; (Osaka, JP) ; Adachi,
Kaoru; (Osaka, JP) ; Isoshima, Hirotaka;
(Osaka, JP) ; Kobayashi, Satoru; (Osaka, JP)
; Matsuzaki, Yuji; (Osaka, JP) ; Watanabe,
Wataru; (Osaka, JP) ; Yamataka, Kazunobu;
(Osaka, JP) ; Kiyonari, Shinichi; (Osaka, JP)
; Wamaki, Shuichi; (Osaka, JP) |
Correspondence
Address: |
FINNEGAN, HENDERSON, FARABOW, GARRETT & DUNNER
LLP
1300 I STREET, NW
WASHINGTON
DC
20005
US
|
Family ID: |
34197143 |
Appl. No.: |
10/958225 |
Filed: |
October 5, 2004 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
10958225 |
Oct 5, 2004 |
|
|
|
PCT/JP04/11869 |
Aug 12, 2004 |
|
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|
Current U.S.
Class: |
514/243 ;
514/262.1; 514/265.1; 544/184; 544/281 |
Current CPC
Class: |
A61P 31/00 20180101;
A61P 43/00 20180101; C07D 471/04 20130101; A61P 31/12 20180101;
A61P 31/18 20180101; C07D 487/04 20130101 |
Class at
Publication: |
514/243 ;
514/262.1; 544/184; 544/281; 514/265.1 |
International
Class: |
A61K 031/53; A61K
031/519 |
Foreign Application Data
Date |
Code |
Application Number |
Aug 13, 2003 |
JP |
2003-293117 |
Apr 28, 2004 |
JP |
2004-134896 |
Claims
1. A nitrogen-containing fused ring compound represented by the
following formula [I] or a pharmaceutically acceptable salt
thereof: 536wherein R.sup.1 is (1) a C1-6 alkyl group optionally
substituted by 1 to 3 substituent(s) selected from the following
group A, (2) a C2-6 alkenyl group optionally substituted by 1 to 3
substituent(s) selected from the following group A or (3) a group
represented by the formula 537wherein Z is (1') a bond, (2') a C1-6
alkylene, (3') a C2-6 alkenylene or (4')
*-(CH.sub.2).sub.m--Q--(CH.sub.2).sub.n--wherein Q is (1") --O--,
(2") --NR.sup.5--wherein R.sup.5 is a hydrogen atom or a C1-6 alkyl
group, (3") --CO--, (4") --SO--, (5") --SO.sub.2.sup.- or (6")
**-CO--NR.sup.6--wherein R.sup.6 is a hydrogen atom or a C1-6 alkyl
group and ** shows the side to be bonded to (CH.sub.2).sub.m, m is
0 or an integer of 1 to 4, n is 0 or an integer of 1 to 4 and *
shows the side to be bonded to a nitrogen atom of ring A, and ring
D is (1') a C3-10 carbon ring group optionally substituted by 1 to
3 substituent(s) selected from the following group B or (2') a
heterocyclic group optionally substituted by 1 to 3 substituent(s)
selected from the following group B wherein the heterocyclic group
contains at least one hetero atom selected from nitrogen atom,
oxygen atom and sulfur atom; X is (1) C(R.sup.x1)(R.sup.x2)-#, (2)
--C(R.sup.x1)(R.sup.x2)--C(R.sup.x3)(R.sup.x- 4)-#, (3)
--C(R.sup.x1)(R.sup.x2)--C(R.sup.x3)(R.sup.x4)--C(R.sup.x5)(R.su-
p.x6)-#, (4) --C(R.sup.x7).dbd.C(R.sup.x8)-#, (5)
--C(R.sup.x1)(R.sup.x2)-- -C(R.sup.x7).dbd.C(R.sup.x8)-#, (6)
--C(R.sup.x7).dbd.C(R.sup.x8)--C(R.sup- .x1)(R.sup.x2)-#, (7)
--N.dbd.C(R.sup.x9)-# or (8) --C(R.sup.x10).dbd.N-#w- herein #
shows the side to be bonded to Y.sup.1 of ring B, R.sup.x1 to
R.sup.x10 are each independently selected from the following group
C, R.sup.x1 and R.sup.x2, R.sup.x3 and R.sup.x4, and R.sup.x5 and
R.sup.x6 each independently optionally form a C3-8 cycloalkyl
together with the adjacent carbon atom; 538of ring B is (1)
C.dbd.C(R.sup.y1)--N(R.sup.y2) (2) N--C(R.sup.y1).dbd.N, (3)
N--C(R.sup.y1).dbd.C(R.sup.y2) (4) C.dbd.N--N(R.sup.y2) or (5)
N--N.dbd.C(R.sup.y3) wherein R.sup.y1 to R.sup.y3 are each
independently selected from the following group C, when 539 s
N--C(R.sup.y1).dbd.C(R.sup.y2), ring B is optionally condensed with
a benzene ring to form a fused ring represented by 540wherein
R.sup.4 is selected from the following group C; and R.sup.2 is (1)
a hydrogen atom, (2) a C1-6 alkyl group, (3) a C6-14 aryl C1-6
alkyl group or (4) -SO.sub.2R.sup.d1 wherein R.sup.d1 is a hydrogen
atom, a C1-7 alkyl group optionally substituted by 1 to 3
substituent(s) selected from the following group A or a C6-14 aryl
group: group A: (1) a halogen atom, (2) a cyano group, (3)
--OR.sup.a1, (4) --SR.sup.a1, (5) --CO.sub.2R.sup.a1, (6)
--CONR.sup.a2R.sup.a3, (7) --COR.sup.a4, (8)
--SO.sub.2NR.sup.a2R.sup.a3, (9) --SO.sub.2R.sup.a4, (10) a C6-14
aryloxy group, (11) a C6-14 aryl C1-6 alkyloxycarbonyl group, (12)
a C1-6 alkylcarbonyloxy group optionally substituted by halogen
atom(s), (13) a C6-14 aryl group optionally substituted by 1 to 3
substituent(s) selected from the group consisting of a halogen
atom, a C1-6 alkyl group, a C1-6 alkylsulfonyl group, a di(C1-6
alkyl) amino group and a C1-6 alkylcarbonylamino group and (14) a
heterocyclic group optionally substituted by a C1-6 alkyloxy group,
wherein R.sup.a1, R.sup.a2, R.sup.a3 and R.sup.a4 are each
independently a hydrogen atom or a C1-6 alkyl group; group B: (1) a
halogen atom, (2) a cyano group, (3) a C1-6 alkyl group, (4) a halo
C1-6 alkyl group, (5) --OR.sup.b1, (6) --SR.sup.b1, (7)
--CO.sub.2R.sup.b1, (8) --CONR.sup.b2R.sup.b3, (9) --COR.sup.b4,
(10) --SO.sub.2NR.sup.b2R.sup.b3, (11) --SO.sub.2R.sup.b4, (12) a
C6-14 aryloxy group, (13) a C6-14 aryl C1-6 alkyloxycarbonyl group,
(14) a C6-14 aryl C1-6 alkyloxy group and (15)
--NR.sup.b5COR.sup.b6, wherein R.sup.b1, R.sub.b2, R.sub.b3,
R.sup.b4, R.sub.b5 and R.sub.b6 are each independently a hydrogen
atom or a C1-6 alkyl group; group C: (1) a hydrogen atom, (2) a
C3-8 cycloalkyl C1-6 alkyl group, (3) a cyano group, (4) a halogen
atom, (5) a C1-7 alkyl group, (6) a C2-6 alkenyl group, (7) a C2-6
alkynyl group, (8) a C6-14 aryl group, (9) a heterocyclic group
wherein said heterocyclic group is a saturated or unsaturated
5-membered or 6-membered heteromonocycle containing at least one
hetero atom selected from nitrogen atom, oxygen atom and sulfur
atom, or a fused ring of such heterocycles, or a fused ring of a
carbon ring selected from benzene, cyclopentane and cyclohexane and
the above-defined heterocycle, (10) a C1-6 alkyloxy group, (11) a
C6-14 aryl C1-6 alkyl group, (12) a C6-14 aryl C1-6 alkyloxy group,
(13) --CO.sub.2R.sup.c1, (14) --CONR.sup.c2R.sup.c3, (15)
--COR.sup.c4, (16) --SO.sub.2NR.sup.c2R.sup.c3, (17) a C6-14
arylcarbonyl group, (18) --NR.sup.c4R.sup.c5, (19)
--NR.sup.c6COR.sup.c7, (20) --NR.sup.c8SO.sub.2R.sup.c9, (21)
--SR.sup.c10, (22) --SOR.sup.c11 (23) --SO.sub.2R.sup.c12, (24)
--NR.sup.c13CONR.sup.c14R.sup.c15, (25)
--NR.sup.c16CO.sub.2R.sup.c17 and, (26) --NR.sup.c18COCOR.sup.c19,
wherein R.sup.c1, R.sup.c2, R.sup.c3, R.sup.c4, R.sup.c5, R.sup.c6,
R.sup.c7, R.sup.c8, R.sup.c9, R.sup.c10, R.sup.c11, R.sup.c12,
R.sup.c13, R.sup.c14, R.sup.c15, R.sup.c16, R.sup.c17, R.sup.c18
and R.sup.c19 are each independently (1') a hydrogen atom, (2') a
C1-7 alkyl group optionally substituted by 1 to 3 substituent(s)
selected from the above-mentioned group A, (3') a C6-14 aryl group
optionally substituted by 1 to 3 substituent(s) selected from the
above-mentioned group B, (4') a heterocyclic group optionally
substituted by 1 to 3 substituent(s) selected from the
above-mentioned group B or (5') a C3-8 cycloalkyl group, wherein
R.sup.c2 and R.sup.c3 optionally form, together with the adjacent
nitrogen atom, a nitrogen-containing heterocycle optionally
substituted by 1 to 3 substituent(s) selected from the
above-mentioned group B; the C1-7 alkyl group, C1-6 alkyl moiety,
C2-6 alkenyl group and C2-6 alkynyl group of the above-mentioned
group C are optionally substituted by 1 to 3 substituent(s)
selected from the above-mentioned group A, or a heterocyclic group;
and the C6-14 aryl group, C6-14 aryl moiety and heterocyclic group
of the above-mentioned group C are optionally substituted by 1 to 3
substituent(s) selected from the above-mentioned group B.
2. The nitrogen-containing fused ring compound of claim 1, wherein
541of ring B is C.dbd.C(R.sup.y1)--N(R.sup.y2),
N--C(R.sup.y1).dbd.N, N--C(R.sup.y1).dbd.C(R.sup.y2) or
C.dbd.N--N(R.sup.y2), wherein each symbol is as defined in claim 1,
or a pharmaceutically acceptable salt thereof.
3. The nitrogen-containing fused ring compound of claim 2, which is
represented by the following formula [I]-1, or a pharmaceutically
acceptable salt thereof: 542wherein each symbol is as defined in
claim 1.
4. The nitrogen-containing fused ring compound of claim 2, which is
represented by the following formula [I]-2, or a pharmaceutically
acceptable salt thereof: 543X-- wherein each symbol is as defined
in claim 1.
5. The nitrogen-containing fused ring compound of claim 2, which is
represented by the following formula [I]-3, or a pharmaceutically
acceptable salt thereof: 544wherein each symbol is as defined in
claim 1.
6. The nitrogen-containing fused ring compound of claim 2, which is
represented by the following formula [I]-4, or a pharmaceutically
acceptable salt thereof: 545wherein each symbol is as defined in
claim 1.
7. The nitrogen-containing fused ring compound of claim 1 wherein X
is --C(R.sup.x1)(R.sup.x2)--C(R.sup.x3)(R.sup.x4)-#,
--(R.sup.x1)(R.sup.x2)--
-C(R.sup.x3)(R.sup.x4)--C(R.sup.x5)(R.sup.x6)-#,
--C(R.sup.x7).dbd.C(R.sup- .x8)-#, --N.dbd.C(R.sup.x9)-# or
--C(R.sup.x10).dbd.N-# wherein each symbol is as defined in claim
1, or a pharmaceutically acceptable salt thereof.
8. The nitrogen-containing fused ring compound of claim 7, wherein
X is
--C(R.sup.x1)(R.sup.x2)--C(R.sup.x3)(R.sup.x4)--C(R.sup.x5)C(R.sup.x6)-#,
or --C(R.sup.x7).dbd.C(R X.sup.8)-# wherein each symbol is as
defined in claim 1, or a pharmaceutically acceptable salt
thereof.
9. The nitrogen-containing fused ring compound of claim 8, wherein
X is --C(R.sup.x1)(R.sup.x2)--C(R.sup.x3)(R.sup.x4)-# wherein each
symbol is as defined in claim 1, or a pharmaceutically acceptable
salt thereof.
10. The nitrogen-containing fused ring compound of claim 8, wherein
X is --C(R.sup.x7).dbd.C(R.sup.x8)-# wherein each symbol is as
defined in claim 1, or a pharmaceutically acceptable salt
thereof.
11. The nitrogen-containing fused ring compound of claim 1, wherein
R.sup.1 is a group represented by the formula 546wherein Z is C1-6
alkylene or *-(CH.sub.2).sub.m--Q--(CH.sub.2).sub.n--, and other
symbols are as defined in claim 1, or a pharmaceutically acceptable
salt thereof.
12. The nitrogen-containing fused ring compound of claim 11,
wherein Z is a C1-6 alkylene, or a pharmaceutically acceptable salt
thereof.
13. The nitrogen-containing fused ring compound of claim 11,
wherein ring D is a C3-10 carbon ring group optionally substituted
by 1 to 3 substituent(s) selected from group B, or a
pharmaceutically acceptable salt thereof.
14. The nitrogen-containing fused ring compound of claim 1, wherein
R.sup.x1 to R.sup.x10 are each independently selected from the
following groups and R.sup.x1 and R.sup.x2, R.sup.x3 and R.sup.x4,
and R.sup.x5 and R.sup.x6 each independently optionally form,
together with the adjacent carbon atom, a C3-8 cycloalkyl, or a
pharmaceutically acceptable salt thereof: a hydrogen atom, a C3-8
cycloalkyl C1-6 alkyl group, a cyano group, a C1-7 alkyl group, a
C6-14 aryl group, a C6-14 aryl C1-6 alkyl group,
--CO.sub.2R.sup.c1, --CONR.sup.c2R.sup.c3 and, --COR.sup.c4 wherein
the above-mentioned C1-7 alkyl group and C1-6 alkyl moiety are
optionally substituted by 1 to 3 substituent(s) selected from group
A or a heterocyclic group, and other symbols are as defined in
claim 1.
15. The nitrogen-containing fused ring compound of claim 14,
wherein R.sup.x1 to R.sup.x10 are each a hydrogen atom, or a
pharmaceutically acceptable salt thereof.
16. The nitrogen-containing fused ring compound of claim 1, wherein
R.sup.y1 is selected from the following groups, or a
pharmaceutically acceptable salt thereof: a hydrogen atom, a C1-7
alkyl group, a C6-14 aryl group, --CO.sub.2R.sup.c1,
--CONR.sup.c2R.sup.c3, --COR.sup.c4 and, a C6-14 arylcarbonyl group
wherein the above-mentioned C1-7 alkyl group is optionally
substituted by 1 to 3 substituent(s) selected from group A or a
heterocyclic group, the above-mentioned C6-14 aryl group is
optionally substituted by 1 to 3 substituent(s) selected from group
B, and other symbols are as defined in claim 1.
17. The nitrogen-containing fused ring compound of claim 16,
wherein R.sup.y1 is a hydrogen atom, or a pharmaceutically
acceptable salt thereof.
18. The nitrogen-containing fused ring compound of claim 1, wherein
R.sup.y2 is selected from the following groups, or a
pharmaceutically acceptable salt thereof: a hydrogen atom, a
halogen atom, a C1-7 alkyl group a C6-14 aryl group, a heterocyclic
group, --CO.sub.2R.sup.c1, --CONR.sup.c2R.sup.c3, --COR.sup.c4,
--NR.sup.c4R.sup.c5, --NR.sup.c6COR.sup.c7,
--NR.sup.c8SO.sub.2R.sup.c9, --SR.sup.c10, --SO.sub.2R.sup.c12
--NR.sup.c13CONR.sup.c14R.sup.c15, --NR.sup.c16CO.sub.2R.sup.c17
and, --NR.sup.c18COCOR.sup.c19 wherein the above-mentioned C1-7
alkyl group is optionally substituted by 1 to 3 substituent(s)
selected from group A or a heterocyclic group, the above-mentioned
C6-14 aryl group and heterocyclic group are optionally substituted
by 1 to 3 substituent(s) selected from group B, and other symbols
are as defined in claim 1.
19. The nitrogen-containing fused ring compound of claim 18,
wherein R.sup.y2 is a heterocyclic group optionally substituted by
1 to 3 substituent(s) selected from group B, or a pharmaceutically
acceptable salt thereof.
20. The nitrogen-containing fused ring compound of claim 19,
wherein R.sup.y2 is a heterocyclic group optionally substituted by
1 to 3 substituent(s) selected from group B, which is bonded to
Y.sup.3 via a carbon atom, wherein at least one .alpha.-position of
the carbon atom is a hetero atom selected from the group consisting
of nitrogen atom, oxygen atom and sulfur atom, or a
pharmaceutically acceptable salt thereof.
21. The nitrogen-containing fused ring compound of claim 18,
wherein R.sup.y2 is selected from --CO.sub.2R.sup.c1,
CONR.sup.c2R.sup.C3 and --COR.sup.c4 wherein each symbol is as
defined in claim 1, or a pharmaceutically acceptable salt
thereof.
22. The nitrogen-containing fused ring compound of claim 18,
wherein R.sup.y2 is selected from --NR.sup.c4R.sup.c5,
--NR.sup.c6COR.sup.c7, --NR.sup.c8SO.sub.2R.sup.c9,
--NR.sup.c13CONR.sup.c14R.sup.c15, --NR.sup.c16CO.sub.2R.sup.c17
and --NR.sup.c18COCOR.sup.c19 wherein each symbol is as defined in
claim 1, or a pharmaceutically acceptable salt thereof.
23. The nitrogen-containing fused ring compound of claim 22,
wherein R.sup.y2 is selected from --NR.sup.c6COR.sup.c7,
--NR.sup.c8SO.sub.2R.sup- .c9, --NR.sup.c13CONR.sup.c14R.sup.c15,
--NR.sup.c16CO.sub.2R.sup.c17 and --NR.sup.c18COCOR.sup.c19 wherein
each symbol is as defined in claim 1, or a pharmaceutically
acceptable salt thereof.
24. The nitrogen-containing fused ring compound of claim 1, wherein
R.sup.2 is a hydrogen atom, or a pharmaceutically acceptable salt
thereof.
25. The nitrogen-containing fused ring compound of claim 1, which
is selected from the group consisting of
2-(3,4-dichlorobenzyl)-9-hydroxy-3,-
4-dihydro-2H-pyrido[1,2-a]pyrazine-1,8-dione hydrochloride,
2-(3,4-dichlorobenzyl)-10-hydroxy-2,3,4,5-tetrahydropyrido[1,2-a][1,4]dia-
zepine-1,9-dione,
2-(3,4-dichlorobenzyl)-9-hydroxy-3-methyl-3,4-dihydro-2H-
-pyrido[1,2-a]pyrazine-1,8-dione,
2-(3,4-dichlorobenzyl)-9-hydroxy-4,4-dim-
ethyl-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,8-dione,
2-(3,4-dichlorobenzyl)-9-hydroxy-6-hydroxymethyl-3,4-dihydro-2H-pyrido[1,-
2-a]pyrazine-1,8-dione,
2-(3,4-dichlorobenzyl)-9-hydroxy-1,8-dioxo-1,3,4,8-
-tetrahydro-2H-pyrido[1,2-a]pyrazine-6-carboxylic acid,
2-(3,4-dichlorobenzyl)-6-(2,2-dimethylpropionyl)-9-hydroxy-3,4-dihydro-2H-
-pyrido[1,2-a]pyrazine-1,8-dione,
2-(3,4-dichlorobenzyl)-9-hydroxy-2H-pyri-
do[1,2-a]pyrazine-1,8-dione,
2-(3,4-dichlorobenzyl)-9-hydroxy-3-methyl-2H--
pyrido[1,2-a]pyrazine-1,8-dione,
2-(3-chlorobenzyl)-9-hydroxy-4-isopropyl--
2H-pyrido[1,2-a]pyrazine-1,8-dione hydrochloride,
2-[3-(2,6-dichlorophenyl- )
propyl]-9-hydroxy-2H-pyrido[1,2-a]pyrazine-1,8-dione,
2-(3,4-dichlorobenzyl)-9-hydroxy-2H-pyrazino[1,2-c]pyrimidine-1,8-dione
hydrochloride,
2-(3,4-dichlorobenzyl)-9-hydroxy-4-methyl-3,4-dihydro-2H-p-
yrido[1,2-a]pyrazine-1,8-dione,
4-benzyl-2-(3,4-dichlorobenzyl)-9-hydroxy--
3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,8-dione,
2-(3,4-dichlorobenzyl)-9-h-
ydroxy-4-phenyl-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,8-dione,
4-butyl-2-(3,4-dichlorobenzyl)-9-hydroxy-3,4-dihydro-2H-pyrido[1,2-a]pyra-
zine-1,8-dione,
2-(3,4-dichlorobenzyl)-9-hydroxy-4-isopropyl-3,4-dihydro-2-
H-pyrido[1,2-a]pyrazine-1,8-dione,
2-(3,4-dichlorobenzyl)-9-hydroxy-3,3-di-
methyl-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,8-dione,
2-(3,4-dichlorobenzyl)-9-hydroxy-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-4-s-
piro-1'-cyclopentane-1,8-dione,
2-(3,4-dichlorobenzyl)-9-hydroxy-3,4-dihyd-
ro-2H-pyrido[1,2-a]pyrazine-4-spiro-1'-cyclohexane-1,8-dione,
methyl
2-(3,4-dichlorobenzyl)-9-hydroxy-1,8-dioxo-1,3,4,8-tetrahydro-2H-pyrido[1-
,2-a]pyrazine-4-carboxylate,
2-(3,4-dichlorobenzyl)-9-hydroxy-1,8-dioxo-1,-
3,4,8-tetrahydro-2H-pyrido[1,2-a]pyrazine-4-carboxylic acid,
2-(3,4-dichlorobenzyl)-9-hydroxy-6-methoxymethyl-3,4-dihydro-2H-pyrido[1,-
2-a]pyrazine-1,8-dione,
N,N-dimethyl-2-(3,4-dichlorobenzyl)-9-hydroxy-1,8--
dioxo-1,3,4,8-tetrahydro-2H-pyrido[1,2-a]pyrazine-6-carboxamide,
3-benzyl-2-(3,4-dichlorobenzyl)-9-hydroxy-3,4-dihydro-2H-pyrido[1,2-a]pyr-
azine-1,8-dione,
3-butyl-2-(3,4-dichlorobenzyl)-9-hydroxy-3,4-dihydro-2H-p-
yrido[1,2-a]pyrazine-1,8-dione,
N,N-dimethyl-2-(3,4-dichlorobenzyl)-9-hydr-
oxy-1,8-dioxo-1,3,4,8-tetrahydro-2H-pyrido[1,2-a]pyrazine-4-carboxamide,
2-(3,4-dichlorobenzyl)-9-hydroxy-4-hydroxymethyl-3,4-dihydro-2H-pyrido[1,-
2-a]pyrazine-1,8-dione,
2-(3,4-dichlorobenzyl)-9-hydroxy-4-methoxymnethyl--
3,4-dihydro-2H-pyrido[1,2-a]pyrazine-], 8-dione,
2-(3,4-dichlorobenzyl)-9--
hydroxy-6-methylsulfanylmethyl-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,8-di-
one,
2-(3,4-dichlorobenzyl)-9-hydroxy-6-methanesulfonylmethyl-3,4-dihydro--
2H-pyrido[1,2-a]pyrazine-1,8-dione,
2-(3,4-dichlorobenzyl)-9-hydroxy-4-(2--
methanesulfonylethyl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,8-dione,
2-(3,4-dichlorobenzyl)-9-hydroxy-4-(2-methylsulfanylethyl)-3,4-dihydro-2H-
-pyrido[1,2-a]pyrazine-1,8-dione, methyl
2-(3,4-dichlorobenzyl)-9-hydroxy--
1,8-dioxo-1,3,4,8-tetrahydro-2H-pyrido[1,2-a]pyrazine-6-carboxylate,
6-acetyl-2-(3,4-dichlorobenzyl)-9-hydroxy-3,4-dihydro-2H-pyrido[1,2-a]pyr-
azine-1,8-dione,
2-(3,4-dichlorobenzyl)-9-hydroxy-6-isopropylsulfanylmethy-
l-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,8-dione,
2-(3,4-dichlorobenzyl)-9-
-hydroxy-6-isopropylsulfanylmethyl-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,-
8-dione,
2-(3,4-dichlorobenzyl)-9-hydroxy-6-isopropoxymethyl-3,4-dihydro-2-
H-pyrido[1,2-a]pyrazine-1,8-dione,
2-(3,4-dichlorobenzyl)-9-hydroxy-6-isob-
utoxymethyl-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,8-dione,
2-(3,4-dichlorobenzyl)-9-hydroxy-6-(1-hydroxyethyl)-3,4-dihydro-2H-pyrido-
[1,2-a]pyrazine-1,8-dione,
2-(3,4-dichlorobenzyl)-9-hydroxy-6-phenoxymethy-
l-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,8-dione,
2-(4-fluorobenzyl)-9-hyd-
roxy-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,8-dione,
2-(3-chlorobenzyl)-9-hydroxy-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,8-dio-
ne,
2-benzyl-9-hydroxy-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,8-dione,
2-(4-chlorobenzyl)-9-hydroxy-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,8-dio-
ne,
2-(3,4-dichlorobenzyl)-9-hydroxy-6-isopropyl-3,4-dihydro-2H-pyrido[1,2-
-a]pyrazine-1,8-dione,
2-(3,4-dichlorobenzyl)-9-hydroxy-6-isobutyryl-3,4-d-
ihydro-2H-pyrido[1,2-a]pyrazine-1,8-dione,
2-(3,4-dichlorobenzyl)-9-hydrox-
y-1,8-dioxo-1,3,4,8-tetrahydro-2H-pyrido[1,2-a]pyrazine-6-carbaldehyde,
2-(3,4-dichlorobenzyl)-9-hydroxy-6-phenyl-3,4-dihydro-2H-pyrido[1,2-a]pyr-
azine-1,8-dione,
9-hydroxy-2-(3-phenylpropyl)-3,4-dihydro-2H-pyrido[1,2-a]-
pyrazine-1,8-dione,
2-(3-chloro-2-fluorobenzyl)-9-hydroxy-3,4-dihydro-2H-p-
yrido[1,2-a]pyrazine-1,8-dione,
9-hydroxy-2-phenethyl-3,4-dihydro-2H-pyrid-
o[1,2-a]pyrazine-1,8-dione,
2-(3,4-dichlorobenzyl)-9-hydroxy-6-(1-hydroxy--
2-methylpropyl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,8-dione,
2-(3,4-dichlorobenzyl)-9-hydroxy-6-isobutyl-3,4-dihydro-2H-pyrido[1,2-a]p-
yrazine-1,8-dione,
2-(3,4-dichlorobenzyl)-9-hydroxy-1,8-dioxo-1,3,4,8-tetr-
ahydro-2H-pyrido[1,2-a]pyrazine-6-carboxamide,
N-methyl-2-(3,4-dichloroben-
zyl)-9-hydroxy-1,8-dioxo-1,3,4,8-tetrahydro-2H-pyrido[1,2-a]pyrazine-6-car-
boxamide,
2-(4-chloro-3-fluorobenzyl)-9-hydroxy-3,4-dihydro-2H-pyrido[1,2--
a]pyrazine-1,8-dione,
6-benzoyl-2-(3,4-dichlorobenzyl)-9-hydroxy-3,4-dihyd-
ro-2H-pyrido[1,2-a]pyrazine-1,8-dione,
2-(3,4-dichlorobenzyl)-9-hydroxy-6--
propionyl-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,8-dione,
2-(3,4-dichlorobenzyl)-9-hydroxy-6-methyl-3,4-dihydro-2H-pyrido[1,2-a]pyr-
azine-1,8-dione,
N,N-diethyl-2-(3,4-dichlorobenzyl)-9-hydroxy-1,8-dioxo-1,-
3,4,8-tetrahydro-2H-pyrido[1,2-a]pyrazine-6-carboxamide,
N-isopropyl-N-methyl-2-(3,4-dichlorobenzyl)-9-hydroxy-1,8-dioxo-1,3,4,8-t-
etrahydro-2H-pyrido[1,2-a]pyrazine-6-carboxamide,
N-ethyl-N-methyl-2-(3,4--
dichlorobenzyl)-9-hydroxy-1,8-dioxo-1,3,4,8-tetrahydro-2H-pyrido[1,2-a]pyr-
azine-6-carboxamide,
2-(3-chloro-4-fluorobenzyl)-9-hydroxy-3,4-dihydro-2H--
pyrido[1,2-a]pyrazine-1,8-dione,
2-(2-chlorobenzyl)-9-hydroxy-3,4-dihydro--
2H-pyrido[1,2-a]pyrazine-1,8-dione,
2-(3,5-dichlorobenzyl)-9-hydroxy-3,4-d-
ihydro-2H-pyrido[1,2-a]pyrazine-1,8-dione,
6-tert-butyl-2-(3,4-dichloroben-
zyl)-9-hydroxy-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,8-dione,
2-(3,4-dichlorobenzyl)-9-hydroxy-6-(1-hydroxy-2,2-dimethylpropyl)-3,4-dih-
ydro-2H-pyrido[1,2-a]pyrazine-1,8-dione,
3-benzyl-9-hydroxy-2-methyl-2H-py- rido[1,2-a]pyrazine-1,8-dione,
2-[3-(4-chlorophenyl)propyl]-9-hydroxy-2H-p-
yrido[1,2-a]pyrazine-1,8-dione,
2-[3-(2-chlorophenyl)propyl]-9-hydroxy-2H--
pyrido[1,2-a]pyrazine-1,8-dione,
2-(3,4-dichlorobenzyl)-9-hydroxy-4-methyl-
-2H-pyrido[1,2-a]pyrazine-1,8-dione hydrochloride,
2-(3-chloro-4-methoxybe-
nzyl)-9-hydroxy-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,8-dione,
9-hydroxy-2-methyl-3-phenethyl-2H-pyrido[1,2-a]pyrazine-1,8-dione,
[2-(3,4-dichlorobenzyl)-9-hydroxy-1,8-dioxo-1,3,4,8-tetrahydro-2H-pyrido[-
1,2-a]pyrazin-6-yl]acetonitrile,
2-[3-(3-chlorophenyl)propyl]-9-hydroxy-2H-
-pyrido[1,2-a]pyrazine-1,8-dione,
9-hydroxy-2-methyl-3-(3-phenyipropyl)-2H-
-pyrido[1,2-a]pyrazine-1,8-dione,
2-(3,4-dichlorobenzyl)-9-hydroxy-4-isopr-
opyl-2H-pyrido[1,2-a]pyrazine-1,8-dione,
2-[3-(3,4-dichlorophenyl)propyl]--
9-hydroxy-2H-pyrido[1,2-a]pyrazine-1,8-dione,
2-[3-(3,5-dichlorophenyl)pro-
pyl]-9-hydroxy-2H-pyrido[1,2-a]pyrazine-1,8-dione,
benzyl[2-(3,4-dichlorob-
enzyl)-9-hydroxy-1,8-dioxo-1,3,4,8-tetrahydro-2H-pyrido[1,2-a]pyrazin-6-yl-
]acetate, benzyl
2-[2-(3,4-dichlorobenzyl)-9-hydroxy-1,8-dioxo-1,3,4,8-tet-
rahydro-2H-pyrido[1,2-a]pyrazin-6-yl]-3-phenylpropionate,
2-(3,4-dichlorobenzyl)-9-hydroxy-6-(2-hydroxyethyl)-3,4-dihydro-2H-pyrido-
[1,2-a]pyrazine-1,8-dione,
2-(3,4-dichlorobenzyl)-9-hydroxy-4-propyl-2H-py-
rido[1,2-a]pyrazine-1,8-dione,
2-(3,4-dichlorobenzyl)-4-ethyl-9-hydroxy-2H-
-pyrido[1,2-a]pyrazine-1,8-dione,
2-(3,4-dichlorobenzyl)-9-hydroxy-4-hydro-
xymethyl-2H-pyrido[1,2-a]pyrazine-1,8-dione,
2-(3,4-dichlorobenzyl)-9-hydr-
oxy-4-isobutyl-2H-pyrido[1,2-a]pyrazine-1,8-dione,
2-(3-chlorobenzyl)-9-hy- droxy-2H-pyrido[1,2-a]pyrazine-1,8-dione
hydrochloride, methyl
2-(3,4-dichlorobenzyl)-9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido[1,2-a]py-
razine-4-carboxylate,
2-(3-chloro-4-fluorobenzyl)-9-hydroxy-2H-pyrido[1,2--
a]pyrazine-1,8-dione hydrochloride,
2-[3-(2,3-dichlorophenyl)propyl]-9-hyd-
roxy-2H-pyrido[1,2-a]pyrazine-1,8-dione hydrochloride,
2-(3-chloro-4-fluorobenzyl)-9-hydroxy-4-isopropyl-2H-pyrido[1,2-a]pyrazin-
e-1,8-dione hydrochloride, methyl
2-(3-chlorobenzyl)-9-hydroxy-1,8-dioxo-1-
,8-dihydro-2H-pyrido[1,2-a]pyrazine-4-carboxylate,
7-bromo-2-(3-chlorobenz-
yl)-9-hydroxy-2H-pyrido[1,2-a]pyrazine-1,8-dione hydrochloride,
2-[3-(2-chloro-6-fluorophenyl)propyl]-9-hydroxy-2H-pyrido[1,2-a]pyrazine--
1,8dione hydrochloride,
2-(3-chlorobenzyl)-9-hydroxy-7-phenyl-2H-pyrido[1,-
2-a]pyrazine-1,8-dione hydrochloride,
N,N-dimethyl-2-(3-chlorobenzyl)-9-hy-
droxy-1,8-dioxo-1,8-dihydro-2H-pyrido[1,2-a]pyrazine-4-carboxamide,
2-(3-chlorobenzyl)-9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido[1,2-a]pyrazi-
ne-4-carboxylic acid,
3-(3-chlorobenzyl)-5-hydroxy-3H-pyrazino[1,2-a]quino-
line-4,6-dione hydrochloride,
2-(3-chlorobenzyl)-9-hydroxy-2H-pyrazino[1,2-
-c]pyrimidine-1,8-dione hydrochloride,
2-(3-chlorobenzyl)-9-hydroxy-1,8-di-
oxo-1,8-dihydro-2H-pyrido[1,2-a]pyrazine-4-carbaldehyde,
2-(3-chlorobenzyl)-9-hydroxy-4-hydroxymethyl-2H-pyrido[1,2-a]pyrazine-1,8-
-dione,
2-(3-chlorobenzyl)-9-hydroxy-4-(1-hydroxyethyl)-2H-pyrido[1,2-a]py-
razine-1,8-dione,
2-(3-chlorobenzyl)-9-hydroxy-7-isopropyl-2H-pyrido[1,2-a-
]pyrazine-1,8-dione hydrochloride,
4-acetyl-2-(3-chlorobenzyl)-9-hydroxy-2-
H-pyrido[1,2-a]pyrazine-1,8-dione,
2-(3-chlorobenzyl)-8-hydroxy-6-methyl-2-
,3,4,6-tetrahydro-2,6-naphthyridine-1,7-dione,
2-(3-chlorobenzyl)-9-hydrox-
y-1,8-dioxo-1,8-dihydro-2H-pyrido[1,2-a]pyrazine-4-carbonitrile,
2-(3-chlorobenzyl)-9-hydroxy-3,4-dihydro-2H-pyrazino[1,2-c]pyrimnidine-1,-
8-dione,
7-bromo-2-(3-chlorobenzyl)-1,8-dioxo-1,8-dihydro-2H-pyrido[1,2-a]-
pyrazin-9-yl methanesulfonate,
7-bromo-2-(3-chlorobenzyl)-3,9-dihydroxy-3,-
4-dihydro-2H-pyrido[1,2-a]pyrazine-1,8-dione hydrochloride,
3-(3-chlorobenzyl)-5-hydroxy-2,3-dihydro-1H-pyrazino[1,2-a]quinoline-4,6--
dione,
2-(3-chlorobenzyl)-7-(3-chlorophenyl)-9-hydroxy-2H-pyrido[1,2-a]pyr-
azine-1,8-dione hydrochloride,
2-(3-chlorobenzyl)-7-(4-chlorophenyl)-9-hyd-
roxy-2H-pyrido[1,2-a]pyrazine-1,8-dione hydrochloride,
2-(3-chlorobenzyl)-7-(2-chlorophenyl)-9-hydroxy-2H-pyrido[1,2-a]pyrazine--
1,8-dione hydrochloride,
2-(3-chlorobenzyl)-9-hydroxy-7-(pyridin-3-yl)-2H--
pyrido[1,2-a]pyrazine-1,8-dione hydrochloride,
2-(3-chlorobenzyl)-9-hydrox-
y-7-(pyridin-4-yl)-2H-pyrido[1,2-a]pyrazine-1,8-dione
hydrochloride,
2-(3-chlorobenzyl)-9-hydroxy-7-(pyridin-2-yl)-2H-pyrido[1,2-a]pyrazine-1,-
8-dione hydrochloride,
2-(3-chlorobenzyl)-9-hydroxy-7-(1-hydroxy-2,2-dimet-
hylpropyl)-2H-pyrido[1,2-a]pyrazine-1,8-dione hydrochloride,
2-(3-chlorobenzyl)-4-cyclohexylmethyl-9-hydroxy-7-phenyl-2H-pyrido[1,2-a]-
pyrazine-1,8-dione hydrochloride,
2-(3-chlorobenzyl)-7-(furan-2-yl)-9-hydr-
oxy-2H-pyrido[1,2-a]pyrazine-1,8-dione hydrochloride,
2-(3,4-dichlorobenzyl)-8-hydroxy-6-methyl-2,3,4,6-tetrahydro-2,6-naphthyr-
idine-1,7-dione,
2-[3-(2-chloro-6-fluorophenyl)propyl]-8-hydroxy-6-methyl--
2,3,4,6-tetrahydro-2,6-naphthyridine-1,7-dione,
6-(3-chlorobenzyl)-4-hydro-
xy-2-methyl-2,6,7,8-tetrahydropyrido[4,3-c]pyridazine-3,5-dione,
7-(benzofuran-2-yl)-2-(3-chlorobenzyl)-9-hydroxy-2H-pyrido[1,2-a]pyrazine-
-1,8-dione hydrochloride,
2-(3-chlorobenzyl)-7-(2,2-dimethylpropionyl)-9-h-
ydroxy-2H-pyrido[1,2-a]pyrazine-]8-dione hydrochloride,
2-(3-chlorobenzyl)-7-(2,2-dimethylpropyl)-9-hydroxy-2H-pyrido[1,2-a]pyraz-
ine-1,8-dione hydrochloride,
2-(3-chlorobenzyl)-9-hydroxy-7-(2-trifluorome-
thylphenyl)-2H-pyrido[1,2-a]pyrazine-1,8-dione hydrochloride,
2-(3-chlorobenzyl)-9-hydroxy-7-(3-methoxyphenyl)-2H-pyrido[1,2-a]pyrazine-
-1,8-dione hydrochloride,
7-bromo-2-(3-chlorobenzyl)-9-hydroxy-4-isopropyl-
-2H-pyrido[1,2-a]pyrazine-1,8-dione hydrochloride,
2-(3-chlorobenzyl)-7-(2- -fluorophenyl)-9-hydroxy-2H
pyrido[1,2-a]pyrazine-1,8-dione hydrochloride,
2-(3-chlorobenzyl)-9-hydroxy-4-isopropyl-7-phenyl-2H-pyrido[1,2-a]pyrazin-
e-1,8-dione hydrochloride,
2-(3-chlorobenzyl)-9-hydroxy-7-(2-methoxyphenyl-
)-2H-pyrido[1,2-a]pyrazine-1,8-dione hydrochloride,
2-(3-chlorobenzyl)-9-hydroxy-7-(4-methoxyphenyl)-2H-pyrido[1,2-a]pyrazine-
-1,8-dione hydrochloride,
2-(3-chlorobenzyl)-7-ethyl-9-hydroxy-2H-pyrido[1-
,2-a]pyrazine-1,8-dione hydrochloride,
2-(3-chlorobenzyl)-7-(2,6-dimethylp-
henyl)-9-hydroxy-2H-pyrido[1,2-a]pyrazine-1,8-dione hydrochloride,
2-(3-chlorobenzyl)-9-hydroxy-7-(3-hydroxyphenyl)-2H-pyrido[1,2-a]pyrazine-
-1,8-dione,
7-benzoyl-2-(3-chlorobenzyl)-9-hydroxy-2H-pyrido[1,2-a]pyrazin-
e-1,8-dione hydrochloride,
2-(3-chlorobenzyl)-7-(2-ethylphenyl)-9-hydroxy--
2H-pyrido[1,2-a]pyrazine-1,8-dione hydrochloride,
2-(3-chlorobenzyl)-7-(3--
chlorophenyl)-9-hydroxy-4-isopropyl-2H-pyrido[1,2-a]pyrazine-1,8-dione,
7-benzyl-2-(3-chlorobenzyl)-9-hydroxy-2H-pyrido[1,2-a]pyrazine-1,8-dione
hydrochloride,
2-(3-chlorobenzyl)-9-hydroxy-7-(2-hydroxyphenyl)-2H-pyrido-
[1,2-a]pyrazine-1,8-dione,
2-(3-chlorobenzyl)-9-hydroxy-7-(4-hydroxyphenyl-
)-2H-pyrido[1,2-a]pyrazine-1,8-dione,
8-hydroxy-6-methyl-2-(3-trifluoromet-
hylbenzyl)-2,3,4,6-tetrahydro-2,6-naphthyridine-1,7-dione,
8-hydroxy-2-(3-methoxybenzyl)-6-methyl-2,3,4,6-tetrahydro-2,6-naphthyridi-
ne-1,7-dione,
6-(3-chlorobenzyl)-4-hydroxy-2-methyl-2,6-dihydropyrido[4,3--
c]pyridazine-3,5-dione,
3-(3-chlorobenzyl)-5-hydroxy-3H-pyrido[2,1-f][1,2,-
4]triazine-4,6-dione, methyl
2-(3-chlorobenzyl)-9-hydroxy-1,8-dioxo-1,8-di-
hydro-2H-pyrido[1,2-a]pyrazine-7-carboxylate hydrochloride,
2-(3-chlorobenzyl)-9-hydroxy-7-(1-methyl-1H-imidazol-2-yl)-2H-pyrido[1,2--
a]pyrazine-1,8-dione hydrochloride,
2-(3-chlorobenzyl)-9-hydroxy-7-isobuty-
ryl-2H-pyrido[1,2-a]pyrazine-1,8-dione hydrochloride, isopropyl
2-(3-chlorobenzyl)-9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido[1,2-a]pyrazi-
ne-7-carboxylate,
2-(4-chlorobenzyl)-9-hydroxy-2H-pyrido[1,2-a]pyrazine-1,- 8-dione
hydrochloride, 2-(3-chlorobenzyl)-9-hydroxy-1,8-dioxo-1,8-dihydro--
2H-pyrido[1,2-a]pyrazine-7-carboxylic acid hydrochloride,
N,N-dimethyl-2-(3-chlorobenzyl)-9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido-
[1,2-a]pyrazine-7-carboxamide,
2-(3-chlorobenzyl)-9-hydroxy-1,8-dioxo-1,8--
dihydro-2H-pyrido[1,2-a]pyrazine-7-carboxylic acid isopropylamide,
N-methyl-2-(3-chlorobenzyl)-9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido[1,2-
-a]pyrazine-7-carboxamide,
N,N-diethyl-2-(3-chlorobenzyl)-9-hydroxy-1,8-di-
oxo-1,8-dihydro-2H-pyrido[1,2-a]pyrazine-7-carboxamide,
2-(4-bromobenzyl)-9-hydroxy-2H-pyrido[1,2-a]pyrazine-1,8-dione
hydrochloride,
2-(3-bromobenzyl)-9-hydroxy-2H-pyrido[1,2-a]pyrazine-1,8-d- ione
hydrochloride, 2,2-dimethylpropyl
2-(3-chlorobenzyl)-9-hydroxy-1,8-di-
oxo-1,8-dihydro-2H-pyrido[1,2-a]pyrazine-7-carboxylate, cyclohexyl
2-(3-chlorobenzyl)-9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido[1,2-a]pyrazi-
ne-7-carboxylate,
7-amnino-2-(3-chlorobenzyl)-9-hydroxy-2H-pyrido[1,2-a]py-
razine-1,8-dione hydrochloride,
2-(3-chlorobenzyl)-9-hydroxy-4-methyl-2H-p-
yrido[1,2-d][1,2,4]triazine-1,8-dione hydrochloride,
2-(3-chlorobenzyl)-9-hydroxy-7-(thiazol-2-yl)-2H-pyrido[1,2-a]pyrazine-1,-
8-dione hydrochloride,
2-(3-chlorobenzyl)-9-hydroxy-7-(4H-1,2,4-triazol-3--
yl)-2H-pyrido[1,2-a]pyrazine-1,8-dione hydrochloride,
N-[2-(3-chlorobenzyl)-9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido[1,2-a]pyr-
azin-7-yl]acetamide,
2-(4-chloro-2-methoxybenzyl)-9-hydroxy-2H-pyrido[1,2--
a]pyrazine-1,8-dione hydrochloride,
2-(3-chlorobenzyl)-9-hydroxy-1,8-dioxo-
-1,8-dihydro-2H-pyrido[1,2-a]pyrazine-7-carboxamide,
2-(3-chloro-2-methoxybenzyl)-9-hydroxy-2H-pyrido[1,2-a]pyrazine-1,8-dione
hydrochloride,
2-[2-(2-chlorophenoxy)ethyl]-9-hydroxy-2H-pyrido[1,2-a]pyr-
azine-1,8-dione hydrochloride,
2-(3-chlorobenzyl)-9-hydroxy-7-(pyrimidin-2-
-yl)-2H-pyrido[1,2-a]pyrazine-1,8-dione hydrochloride,
N-propyl-2-(3-chlorobenzyl)-9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido[1,2-
-a]pyrazine-7-carboxamide,
N-butyl-2-(3-chlorobenzyl)-9-hydroxy-1,8-dioxo--
1,8-dihydro-2H-pyrido[1,2-a]pyrazine-7-carboxamide,
N-isobutyl-2-(3-chlorobenzyl)-9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido[1-
,2-a]pyrazine-7-carboxamide, methyl
{[2-(3-chlorobenzyl)-9-hydroxy-1,8-dio-
xo-1,8-dihydro-2H-pyrido[1,2-a]pyrazine-7-carbonyl]amino}acetate,
N-ethyl-2-(3-chlorobenzyl)-9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido[1,2--
a]pyrazine-7-carboxamide,
N-(2-methoxyethyl)-2-(3-chlorobenzyl)-9-hydroxy--
1,8-dioxo-1,8-dihydro-2H-pyrido[1,2-a]pyrazine-7-carboxamide,
2-{[2-(3-chlorobenzyl)-9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido[1,2-a]py-
razine-7-carbonyl]amino) ethyl trifluoroacetate,
N-(2-hydroxyethyl)-2-(3-c-
hlorobenzyl)-9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido[1,2-a]pyrazine-7-ca-
rboxamide,
2-(3-chloro-2-hydroxybenzyl)-9-hydroxy-2H-pyrido[1,2-a]pyrazine-
-1,8-dione hydrochloride,
N-benzyl-2-(3-chlorobenzyl)-9-hydroxy-1,8-dioxo--
1,8-dihydro-2H-pyrido[1,2-a]pyrazine-7-carboxamide,
N-(2,2,2-trifluoroethyl)-2-(3-chlorobenzyl)-9-hydraxy-1,8-dioxo-1,8-dihyd-
ro-2H-pyrido[1,2-a]pyrazine-7-carboxamide,
N-butyl-N-methyl-2-(3-chloroben-
zyl)-9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido[1,2-a]pyrazine-7-carboxamid-
e,
N-(2-methoxyethyl)-N-methyl-2-(3-chlorobenzyl)-9-hydroxy-1,8-dioxo-1,8--
dihydro-2H-pyrido[1,2-a]pyrazine-7-carboxamide,
2-(3-chlorobenzyl)-9-hydro-
xy-7-(pyrrolidine-1-carbonyl)-2H-pyrido[1,2-a]pyrazine-1,8-dione,
2-(3-chlorobenzyl)-9-hydroxy-7-(morpholine-4-carbonyl)-2H-pyrido[1,2-a]py-
razine-1,8-dione,
2-(4-chloro-3-methoxybenzyl)-9-hydroxy-2H-pyrido[1,2-a]p-
yrazine-1,8-dione hydrochloride, methyl
[2-(3-chlorobenzyl)-9-hydroxy-1,8--
dioxo-1,8-dihydro-2H-pyrido[1,2-a]pyrazin-7-yl]acetate,
2-(3-chlorobenzyl)-9-hydroxy-7-(1H-tetrazol-5-yl)-2H-pyrido[1,2-a]pyrazin-
e-1,8-dione hydrochloride,
2-[2-(3-chlorobenzyl)-9-hydroxy-1,8-dioxo-1,8-d-
ihydro-2H-pyrido[1,2-a]pyrazin-7-yl]-N-methylacetamide,2-[2-(3-chlorobenzy-
l)-9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido[1,2-a]pyrazin-7-yl]-N,N-dimet-
hylacetamide,
[2-(3-chlorobenzyl)-9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrid-
o[1,2-a]pyrazin-7-yl]acetic acid,
N-(2-hydroxypropyl)-2-(3-chlorobenzyl)-9-
-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido[1,2-a]pyrazine-7-carboxamide
hydrochloride,
{[2-(3-chlorobenzyl)-9-hydroxy-1,8-dioxo-1,8-dihydro-2H-py-
rido[1,2-a]pyrazine-7-carbonyl]amino}acetic acid,
N-dimethylcarbamoylmethy-
l-2-(3-chlorobenzyl)-9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido[1,2-a]pyraz-
ine-7-carboxamide,
N-methylcarbamoylmethyl-2-(3-chlorobenzyl)-9-hydroxy-1,-
8-dioxo-1,8-dihydro-2H-pyrido[1,2-a]pyrazine-7-carboxamide,
N-phenyl-2-(3-chlorobenzyl)-9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido[1,2-
-a]pyrazine-7-carboxamide hydrochloride,
2-(3-chlorobenzyl)-9-hydroxy-7-(o-
xazol-2-yl)-2H-pyrido[1,2-a]pyrazine-1,8-dione hydrochloride,
2-(3-chlorobenzyl)-9-hydroxy-7-(3-hydroxypyrrolidine-1-carbonyl)-2H-pyrid-
o[1,2-a]pyrazine-1,8-dione hydrochloride,
N-(2-oxopropyl)-2-(3-chlorobenzy-
l)-9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido[1,2-a]pyrazine-7-carboxamide,
2-(9-hydroxy-1,8-dioxo-1,8-dihydro-pyrido[1,2-a]pyrazin-2-yl)-N-phenylace-
tamide hydrochloride,
2-(3-chlorobenzyl)-9-hydroxy-7-(3-oxopyrrolidine-1-c-
arbonyl)-2H-pyrido[1,2-a]pyrazine-1,8-dione,
2-(5-chloro-2-methoxybenzyl)--
9-hydroxy-2H-pyrido[1,2-a]pyrazine-1,8-dione hydrochloride,
N-[2-(3-chlorobenzyl)-9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido[1,2-a]pyr-
azin-7-yl]methanesulfonamide,
7-acetyl-2-(3-chlorobenzyl)-9-hydroxy-2H-pyr-
ido[1,2-a]pyrazine-1,8-dione hydrochloride,
2-(3-chlorobenzyl)-9-hydroxy-7-
-propionyl-2H-pyrido[1,2-a]pyrazine-1,8-dione hydrochloride,
9-hydroxy-2-(3-phenylallyl)-2H-pyrido[1,2-a]pyrazine-1,8-dione,
N-methyl-2-(3-chloro-4-fluorobenzyl)-9-hydroxy-1,8-dioxo-1,8-dihydro-2H-p-
yrido[1,2-a]pyrazine-7-carboxamide,
N,N-dimethyl-2-(3-chloro-4-fluorobenzy-
l)-9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido[1,2-a]pyrazine-7-carboxamide,
N-(2-methanesulfonylethyl)-2-(3-chlorobenzyl)-9-hydroxy-1,8-dioxo-1,8-dih-
ydro-2H-pyrido[1,2-a]pyrazine-7-carboxamide,
N-[2-(2-oxopyrrolidin-1-yl)et-
hyl]-2-(3-chlorobenzyl)-9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido[1,2-a]py-
razine-7-carboxamide,
N-[2-(3-chlorobenzyl)-9-hydroxy-1,8-dioxo-1,8-dihydr-
o-2H-pyrido[1,2-a]pyrazin-7-yl]-N-methylmethanesulfonamide,
2-(3-chloro-5-methoxybenzyl)-9-hydroxy-2H-pyrido[1,2-a]pyrazine-1,8-dione
hydrochloride,
N-(pyridin-4-ylmethyl)-2-(3-chlorobenzyl)-9-hydroxy-1,8-di-
oxo-1,8-dihydro-2H-pyrido[1,2-a]pyrazine-7-carboxamide,
N-(4-fluorobenzyl)-2-(3-chlorobenzyl)-9-hydroxy-1,8-dioxo-1,8-dihydro-2H--
pyrido[1,2-a]pyrazine-7-carboxamide,
2-(3-chlorobenzyl)-9-hydroxy-7-(thiaz-
ol-2-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,8-dione,
2-(3-chlorobenzyl)-9-hydroxy-7-hydroxymethyl-2H-pyrido[1,2-a]pyrazine-1,8-
-dione hydrochloride,
2-(3-chloro-4-fluorobenzyl)-7-(2,2-dimethylpropionyl-
)-9-hydroxy-2H-pyrido[1,2-a]pyrazine-1,8-dione hydrochloride,
2-(3-chlorobenzyl)-9-hydroxy-7-(thiazol-5-yl)-2H-pyrido[1,2-a]pyrazine-1,-
8-dione hydrochloride,
2-(3-chlorobenzyl)-9-hydroxy-1,8-dioxo-1,3,4,8-tetr-
ahydro-2H-pyrido [1,2-a]pyrazine-7-carboxylic acid methylamide,
N,N-dimethyl-2-(3-chlorobenzyl)-9-hydroxy-1,8-dioxo-1,3,4,8-tetrahydro-2H-
-pyrido[1,2-a]pyrazine-7-carboxamide,
2-(3-chloro-4-fluorobenzyl)-7-(2,2-d-
imethylpropionyl)-9-hydroxy-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,8-dione
hydrochloride,
2-(3-chloro-4-fluorobenzyl)-9-hydroxy-4-hydroxymethyl-1,8--
dioxo-1,8-dihydro-2H-pyrido[1,2-a]pyrazine-7-carboxylic acid
methylamide hydrochloride,
2-(3-chlorobenzyl)-7-(2,2-dimethylpropionyl)-9-hydroxy-3,4-
-dihydro-2H-pyrido[1,2-a]pyrazine-1,8-dione hydrochloride,
2-(4-chloro-2-hydroxybenzyl)-9-hydroxy-2H-pyrido[1,2-a]pyrazine-1,8-dione
hydrochloride,
2-(3-chloro-4-fluorobenzyl)-9-hydroxy-7-(thiazol-2-yl)-3,4-
-dihydro-2H-pyrido[1,2-a]pyrazine-1,8-dione,
2-(9-hydroxy-1,8-dioxo-1,8-di-
hydro-pyrido[1,2-a]pyrazin-2-yl)-N-methyl-N-phenylacetamide
hydrochloride,
N-methyl-2-(3-chloro-4-fluorobenzyl)-9-hydroxy-1,8-dioxo-1,3,4,8-tetrahyd-
ro-2H-pyrido[1,2-a]pyrazine-7-carboxamide,
N,N-dimethyl-2-(3-chloro-4-fluo-
robenzyl)-9-hydroxy-1,8-dioxo-1,3,4,8-tetrahydro-2H-pyrido[1,2-a]pyrazine--
7-carboxamide,
3-[2-(3-chlorobenzyl)-9-hydroxy-1,8-dioxo-1,8-dihydro-2H-py-
rido[1,2-a]pyrazin-7-yl]-2,2-dimethyl-3-oxopropyl acetate
hydrochloride
2-(3-chlorobenzyl)-9-hydroxy-7-(3-hydroxy-2,2-dimethylpropionyl)-2H-pyrid-
o[1,2-a]pyrazine-1,8-dione hydrochloride,
2-(3-chlorobenzyl)-9-hydroxy-7-(-
pyrazin-2-yl)-2H-pyrido[1,2-a]pyrazine-1,8-dione hydrochloride,
2-(3-chlorobenzyl)-9-hydroxy-7-(2-methyl-2H-1,2,4-triazol-3-yl)-2H-pyrido-
[1,2-a]pyrazine-1,8-dione hydrochloride,
N-(2-fluoroethyl)-2-(3-chlorobenz-
yl)-9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido[1,2-a]pyrazine-7-carboxamide-
,
N-benzyl-N-methyl-2-(3-chlorobenzyl)-9-hydroxy-1,8-dioxo-1,8-dihydro-2H--
pyrido[1,2-a]pyrazine-7-carboxamide,
2-(3-chlorobenzyl)-9-hydroxy-7-phenyl-
sulfanyl-2H-pyrido[1,2-a]pyrazine-1,8-dione,
7-benzenesulfinyl-2-(3-chloro-
benzyl)-9-hydroxy-2H-pyrido[1,2-a]pyrazine-1,8-dione,
7-benzenesulfonyl-2-(3-chlorobenzyl)-9-hydroxy-2H-pyrido[1,2-a]pyrazine-1-
,8-dione,
2-(3,4-dichlorobenzyl)-7-(2,2-dimethylpropionyl)-9-hydroxy-3,4-d-
ihydro-2H-pyrido[1,2-a]pyrazine-1,8-dione,
N-[2-(3-chlorobenzyl)-9-hydroxy-
-1,8-dioxo-1,8-dihydro-2H-pyrido[1,2-a]pyrazin-7-yl]isobutyramide,
N-[2-(3-chloro-4-fluorobenzyl)-9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido[-
1,2-a]pyrazin-7-yl]acetamide,
2-(3-chloro-4-fluorobenzyl)-7-(2,2-dimethylp-
ropionyl)-9-hydroxy-4-hydroxymethyl-2H-pyrido[1,2-a]pyrazine-1,8-dione
hydrochloride,
N-[2-(3-chlorobenzyl)-9-hydroxy-1,8-dioxo-1,8-dihydro-2H-p-
yrido[1,2-a]pyrazin-7-yl]propionamide,
N-[2-(3-chlorobenzyl)-9-hydroxy-1,8-
-dioxo-1,8-dihydro-2H-pyrido[1,2-a]pyrazin-7-yl]-2-phenylacetamide,
7-acetyl-2-(3-chloro-4-fluorobenzyl)-9-hydroxy-2H-pyrido[1,2-a]pyrazine-1-
,8-dione hydrochloride,
2-(3-chlorobenzyl)-9-hydroxy-7-methylsulfanyl-2H-p-
yrido[1,2-a]pyrazine-1,8-dione,
2-(3-chlorobenzyl)-9-hydroxy-7-methanesulf-
onyl-2H-pyrido[1,2-a]pyrazine-1,8-dione,
2-(3-chlorobenzyl)-9-hydroxy-7-me-
thanesulfinyl-2H-pyrido[1,2-a]pyrazine-1,8-dione,
2-(3-chlorobenzyl)-9-hyd-
roxy-7-(5-methylthiazol-2-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,8-dio-
ne,
2-(3,4-dichlorobenzyl)-9-hydroxy-7-(thiazol-2-yl)-3,4-dihydro-2H-pyrid-
o[1,2-a]pyrazine-1,8-dione,
2-(4-fluorobenzyl)-9-hydroxy-2H-pyrido[1,2-a]p- yrazine-1,8-dione
hydrochloride, 7-(2,2-dimethylpropionyl)-2-(4-fluorobenz-
yl)-9-hydroxy-2H-pyrido[1,2-a]pyrazine-1,8-dione hydrochloride,
2-(4-fluorobenzyl)-9-hydroxy-7-(thiazol-2-yl)-2H-pyrido[1,2-a]pyrazine-1,-
8-dione hydrochloride,
N-methyl-2-(4-fluorobenzyl)-9-hydroxy-1,8-dioxo-1,8-
-dihydro-2H-pyrido[1,2-a]pyrazine-7-carboxamide,
2-[3-(2-chloro-6-fluaroph-
enyl)propyl]-7-(2,2-dimethylpropionyl)-9-hydroxy-2H-pyrido[1,2-a]pyrazine--
1,8-dione hydrochloride,
2-(3-chlorobenzyl)-9-hydroxy-7-(4-methylthiazol-2-
-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,8-dione,
N-[2-(3-chlorobenzyl)-9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido[1,2-a]pyr-
azin-7-yl]butyramide,
N-[2-(3-chlorobenzyl)-9-hydroxy-1,8-dioxo-1,8-dihydr-
o-2H-pyrido[1,2-a]pyrazin-7-yl]benzamide,
N-[2-(3-chlorobenzyl)-9-hydroxy--
1,8-dioxo-1,8-dihydro-2H-pyrido[1,2-a]pyrazin-7-yl]-3-phenylpropionamide,
N-[2-(3-chlorobenzyl)-9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido[1,2-a]pyr-
azin-7-yl]-N-methylacetamide,
N-[2-(3-chlorobenzyl)-9-hydroxy-1,8-dioxo-1,-
8-dihydro-2H-pyrido[1,2-a]pyrazin-7-yl]-2-methoxyacetamide, methyl
2-(3-chlorobenzyl)-9-hydroxy-1,8-dioxo-1,3,4,8-tetrahydro-2H-pyrido[1,2-a-
]pyrazine-7-carboxylate,
3-[2-(3-chlorobenzyl)-9-hydroxy-1,8-dioxo-1,8-dih-
ydro-2H-pyrido[1,2-a]pyrazin-7-yl]-1,1-dimethylurea,
methyl[2-(3-chlorobenzyl)-9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido[1,2-a-
]pyrazin-7-yl]carbamate,
2-[3-(2-chloro-6-fluorophenyl)propyl]-9-hydroxy-7-
-(thiazol-2-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,8-dione,
N-[2-(3-chlorobenzyl)-9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido[1,2-a]pyr-
azin-7-yl]-2-oxopropionamide,
N-benzyl-2-(3-chlorobenzyl)-9-hydroxy-1,8-di-
oxo-1,3,4,8-tetrahydro-2H-pyrido[1,2-a]pyrazine-7-carboxamide,
2-(3-chlorobenzyl)-9-hydroxy-7-(1H-pyrazol-3-yl)-3,4-dihydro-2H-pyrido[1,-
2-a]pyrazine-1,8-dione,
2-(3-chlorobenzyl)-9-hydroxy-7-(pyrimidin-4-yl)-3,-
4-dihydro-2H-pyrido[1,2-a]pyrazine-1,8-dione,
N-(naphthalen-1-ylmethyl)-2--
(3-chlorobenzyl)-9-hydroxy-1,8-dioxo-1,3,4,8-tetrahydro-2H-pyrido[1,2-a]py-
razine-7-carboxamide,
N-benzhydryl-2-(3-chlorobenzyl)-9-hydroxy-1,8-dioxo--
1,3,4,8-tetrahydro-2H-pyrido[1,2-a]pyrazine-7-carboxamide,
2-(3-chlorobenzyl)-9-hydroxy-7-(pyrimidin-2-yl)-3,4-dihydro-2H-pyrido[1,2-
-a]pyrazine-1,8-dione hydrochloride,
2-(3-chlorobenzyl)-9-hydroxy-7-(2-met-
hyl-2-phenylpropionyl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,8-dione,
N-(4-tert-butylbenzyl)-2-(3-chlorobenzyl)-9-hydroxy-1,8-dioxo-1,3,4,8-tet-
rahydro-2H-pyrido[1,2-a]pyrazine-7-carboxamide,
N-[2-(3-chlorobenzyl)-9-hy-
droxy-1,8-dioxo-1,8-dihydro-2H-pyrido[1,2-a]pyrazin-7-yl]cyclapentanecarbo-
xamide,
N-[2-(3-chlorobenzyl)-9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido[1,-
2-a]pyrazin-7-yl]-2-(4-fluorophenyl)acetamide,
N-[2-(3-chlorobenzyl)-9-hyd-
roxy-1,8-dioxo-1,8-dihydro-2H-pyrido[1,2-a]pyrazin-7-yl]-2,2-dimethylpropi-
onamide,
N-[2-(3-chlorobenzyl)-9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido[1-
,2-a]pyrazin-7-yl]-2-phenylisobutyramide,
N-[2-(3-chlorobenzyl)-9-hydroxy--
1,8-dioxo-1,8-dihydro-2H-pyrido[1,2-a]pyrazin-7-yl]-4-fluorobenzamide,
N-[2-(3-chlorobenzyl)-9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido[1,2-a]pyr-
azin-7-yl]pyridine-2-carboxamide trifluoroacetate,
2-(3-chlorobenzyl)-9-hy-
droxy-7-isopropylamino-2H-pyrido[1,2-a]pyrazine-1,8-dione
hydrochloride,
2-(3-chlorobenzyl)-7-diethylamino-9-hydroxy-2H-pyrido[1,2-a]pyrazine-1,8--
dione hydrochloride,
2-(3-chlorobenzyl)-9-hydroxy-7-(pyridin-2-yl)-3,4-dih-
ydro-2H-pyrido[1,2-a]pyrazine-1,8-dione hydrochloride,
2-(3-chlorobenzyl)-9-hydroxy-7-isobutylamino-2H-pyrido[1,2-a]pyrazine-1,8-
-dione hydrochloride,
N-[2-(3-chlorobenzyl)-9-hydroxy-1,8-dioxo-1,8-dihydr-
o-2H-pyrido[1,2-a]pyrazin-7-yl]-2-isopropyl-3-methylbutyramide,
2-(3-chlorobenzyl)-7-ethylamino-9-hydroxy-2H-pyrido[1,2-a]pyrazine-1,8-di-
one hydrochloride,
N-[2-(3-chlorobenzyl)-9-hydroxy-1,8-dioxo-1,8-dihydro-2-
H-pyrido[1,2-a]pyrazin-7-yl]nicotinamide trifluoroacetate,
N-[2-(3-chlorobenzyl)-9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido[1,2-a]pyr-
azin-7-yl]isonicotinamide trifluoroacetate,
N-[2-(3-chlorobenzyl)-9-hydrox-
y-1,8-dioxo-1,8-dihydro-2H-pyrido[1,2-a]pyrazin-7-yl]furan-2-carboxamide,
N-[2-(3-chlorobenzyl)-9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido[1,2-a]pyr-
azin-7-yl]thiophene-2-carboxamide,
2-(3-chlorobenzyl)-9-hydroxy-7-(pyridaz-
in-3-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,8-dione
hydrochloride,
2-(3,4-difluorobenzyl)-9-hydroxy-7-(thiazol-2-yl)-3,4-dihydro-2H-pyrido[1-
,2-a]pyrazine-1,8-dione,
2-(3-chloro-2-fluorobenzyl)-9-hydroxy-7-(thiazol--
2-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,8-dione,
2-(4-chlorobenzyl)-9-hydroxy-7-(thiazol-2-yl)-3,4-dihydro-2H-pyrido[1,2-a-
]pyrazine-1,8-dione,
2-(4-chloro-3-fluorobenzyl)-9-hydroxy-7-(thiazol-2-yl-
)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,8-dione,
2-(4-chloro-2-methoxyben-
zyl)-9-hydroxy-7-(thiazol-2-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,8-d-
ione,
N-[2-(3-chlorobenzyl)-9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido[1,2--
a]pyrazin-7-yl]-1-methyl-1H-pyrrole-2-carboxamide,
2-[3-(4-chlorophenyl)pr-
opyl]-9-hydroxy-7-(thiazol-2-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,8--
dione hydrochloride,
2-[3-(2-chlorophenyl)propyl]-9-hydroxy-7-(thiazol-2-y-
l)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,8-dione hydrochloride,
2-[3-(3-chlorophenyl)propyl]-9-hydroxy-7-(thiazol-2-yl)-3,4-dihydro-2H-py-
rido[1,2-a]pyrazine-1,8-dione hydrochloride,
2-(3-chlorobenzyl)-9-hydroxy--
7-(3-methyl-1,2,4-thiadiazol-5-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,-
8-dione hydrochloride,
5-fluoro-2-[9-hydroxy-1,8-dioxo-7-(thiazol-2-yl)-1,-
3,4,8-tetrahydro-pyrido[1,2-a]pyrazin-2-ylmethyl]-N-methylbenzamide,
N-[2-(3-chlorobenzyl)-9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido[1,2-a]pyr-
azin-7-yl]-N-isobutylacetamide,
N-[2-(4-fluorobenzyl)-9-hydroxy-1,8-dioxo--
1,8-dihydro-2H-pyrido[1,2-a]pyrazin-7-yl]acetamide,
N-[2-(4-fluorobenzyl)-9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido[1,2-a]pyr-
azin-7-yl]benzamide,
N-[2-(4-fluorobenzyl)-9-hydroxy-1,8-dioxo-1,8-dihydro-
-2H-pyrido[1,2-a]pyrazin-7-yl]methanesulfonamide,
2-(4-fluorobenzyl)-9-hyd-
roxy-7-(pyridin-2-yl)-2H-pyrido[1,2-a]pyrazine-1,8-dione
trifluoroacetate,
2-(2-fluorobenzyl)-9-hydroxy-7-(thiazol-2-yl)-3,4-dihydro-2H-pyrido[1,2-a-
]pyrazine-1,8-dione,
2-(3-fluorobenzyl)-9-hydroxy-7-(thiazol-2-yl)-3,4-dih-
ydro-2H-pyrido[1,2-a]pyrazine-1,8-dione,
2-(4-fluorobenzyl)-9-hydroxy-7-(t-
hiazol-2-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,8-dione,
2-(2-chlorobenzyl)-9-hydroxy-7-(thiazol-2-yl)-3,4-dihydro-2H-pyrido[1,2-a-
]pyrazine-1,8-dione,
9-hydroxy-2-(naphthalen-2-ylmethyl)-7-(thiazol-2-yl)--
3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,8-dione,
2-[3-(3-chloro-2-fluorophe-
nyl)propyl]-9-hydroxy-7-(thiazol-2-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazin-
e-1,8-dione,
2-[3-(4-chloro-3-fluorophenyl)propyl]-9-hydroxy-7-(thiazol-2--
yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,8-dione,
2-[3-(4-fluorophenyl)propyl]-9-hydroxy-7-(thiazol-2-yl)-3,4-dihydro-2H-py-
rido[1,2-a]pyrazine-1,8-dione,
2-[3-(3-fluorophenyl)propyl]-9-hydroxy-7-(t-
hiazol-2-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,8-dione,
9-hydroxy-2-(3-phenylpropyl)-7-(thiazol-2-yl)-3,4-dihydro-2H-pyrido[1,2-a-
]pyrazine-1,8-dione hydrochloride,
2-(3-chloro-2-fluorobenzyl)-9-hydroxy-7-
-(pyridin-2-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,8-dione
hydrochloride,
N-[2-(4-fluorobenzyl)-9-hydroxy-1,8-dioxo-1,8-dihydro-2H-p-
yrido[1,2-a]pyrazin-7-yl]-2-methoxyacetamide,
N-[2-(4-fluorobenzyl)-9-hydr- oxy-1,8-dioxo-1,8-dihydro-2H-pyrido[1
2-a]pyrazin-7-yl]-2-propanesulfonami- de,
N-[2-(4-fluorobenzyl)-9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido[1,2-a]-
pyrazin-7-yl]nicotinamide trifluoroacetate,
N-[2-(4-fluorobenzyl)-9-hydrox-
y-1,8-dioxo-1,8-dihydro-2H-pyrido[1,2-a]pyrazin-7-yl]isobutyramide,
N-(2-methoxyethyl)-2-(4-fluorobenzyl)-9-hydroxy-1,8-dioxo-1,8-dihydro-2H--
pyrido[1,2-a]pyrazine-7-carboxamide,
N-ethyl-2-(4-fluorobenzyl)-9-hydroxy--
1,8-dioxo-1,8-dihydro-2H-pyrido[1,2-a]pyrazine-7-carboxamide,
N-{2-[3-(2-chloro-6-fluorophenyl)propyl]-9-hydroxy-1,8-dioxo-1,8-dihydro--
2H-pyrido[1,2-a]pyrazin-7-yl}acetamide,
N-[2-(3-chloro-2-fluorobenzyl)-9-h-
ydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido[1,2-a]pyrazin-7-yl]acetamide
hydrochloride, methyl
5-fluoro-2-[9-hydroxy-1,8-dioxo-7-(thiazol-2-yl)-1,-
3,4,8-tetrahydro-pyrido[1,2-a]pyrazin-2-ylmethyl]benzoate,
2-(3-chloro-4-fluorobenzyl)-9-hydroxy-7-(pyridin-2-yl)-3,4-dihydro-2H-pyr-
ido[1,2-a]pyrazine-1,8-dione hydrochloride,
2-(3-chloro-2-fluorobenzyl)-9--
hydroxy-7-(pyridin-3-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,8-dione
hydrochloride,
2-[3-(2-chloro-6-fluorophenyl)propyl]-9-hydroxy-7-(pyridin-
-2-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,8-dione
hydrochloride,
2-(benzofuran-2-ylmethyl)-9-hydroxy-7-(thiazol-2-yl)-3,4-dihydro-2H-pyrid-
o[1,2-a]pyrazine-1,8-dione,
N-(1,2-diphenylethyl)-2-(3-chlorobenzyl)-9-hyd-
roxy-1,8-dioxo-1,3,4,8-tetrahydro-2H-pyrido[1,2-a]pyrazine-7-carboxamide,
N-[2-(3-chloro-2-fluorobenzyl)-9-hydroxy-1,8-dioxo-1,3,4,8-tetrahydro-2H--
pyrido[1,2-a]pyrazin-7-yl]acetamide,
2-[3-(2-fluorophenyl)propyl]-9-hydrox-
y-7-(thiazol-2-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,8-dione,
N-(1,3-diphenylpropyl)-2-(3-chlorobenzyl)-9-hydroxy-1,8-dioxo-1,3,4,8-tet-
rahydro-2H-pyrido[1,2-a]pyrazine-7-carboxamide,
5-fluoro-2-{3-[9-hydroxy-1-
,8-dioxo-7-(thiazol-2-yl)-1,3,4,8-tetrahydro-pyrido[1,2-a]pyrazin-2-yl]pro-
pyl}-N-methylbenzamide,
2-[3-(2-chloro-6-fluorophenyl)propyl]-7-(2,2-dimet-
hylpropionyl)-9-hydroxy-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,8-dione,
2-(3-chlorobenzyl)-9-hydroxy-7-isobutyryl-3,4-dihydro-2H-pyrido[1,2-a]pyr-
azine-1,8-dione,
9-hydroxy-2-(4-phenylbutyl)-7-(thiazol-2-yl)-3,4-dihydro--
2H-pyrido[1,2-a]pyrazine-1,8-dione hydrochloride,
9-hydroxy-2-pentyl-7-(th-
iazol-2-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,8-dione
hydrochloride,
2-(3-chloro-2-fluorobenzyl)-9-hydroxy-7-(pyridin-4-yl)-3,4-dihydro-2H-pyr-
ido[1,2-a]pyrazine-1,8-dione hydrochloride,
2-(4-fluorobenzyl)-9-hydroxy-7-
-(pyridin-4-yl)-2H-pyrido[1,2-a]pyrazine-1,8-dione hydrochloride,
2-(3-chloro-2-fluorobenzyl)-9-hydroxy-7-(pyrimidin-4-yl)-2H-pyrido[1,2-a]-
pyrazine-1,8-dione trifluoroacetate,
2-(3-chloro-4-fluorobenzyl)-9-hydroxy-
-7-(2-methyl-2H-1,2,4-triazol-3-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1-
,8-dione,
7-acetyl-2-(4-fluorobenzyl)-9-hydroxy-2H-pyrido[1,2-a]pyrazine-1-
,8-dione,
2-(4-fluorobenzyl)-9-hydroxy-7-isobutyryl-2H-pyrido[1,2-a]pyrazi-
ne-1,8-dione hydrochloride,
N-[2-(3-chlorobenzyl)-9-hydroxy-1,8-dioxo-1,3,-
4,8-tetrahydro-2H-pyrido[1,2-a]pyrazin-7-yl]isonicotinamide
hydrochloride,
2-(4-fluorobenzyl)-9-hydroxy-7-(pyrimidin-4-yl)-2H-pyrido[1,2-a]pyrazine--
1,8-dione,
2-(3-chloro-4-fluorobenzyl)-9-hydroxy-7-(pyrazin-2-yl)-3,4-dihy-
dro-2H-pyrido[1,2-a]pyrazine-1,8-dione,
N-[2-(3-chloro-4-fluorobenzyl)-9-h-
ydroxy-1,8-dioxo-1,3,4,8-tetrahydro-2H-pyrido[1,2-a]pyrazin-7-yl]isobutyra-
mide,
2-(4-chloro-2-hydroxybenzyl)-9-hydroxy-7-(thiazol-2-yl)-3,4-dihydro--
2H-pyrido[1,2-a]pyrazine-1,8-dione hydrochloride,
9-hydroxy-2-(3-phenylbut-
yl)-7-(thiazol-2-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,8-dione
hydrochloride,
N-[2-(3-chloro-2-fluorobenzyl)-9-hydroxy-1,8-dioxo-1,3,4,8-
-tetrahydro-2H-pyrido[1,2-a]pyrazin-7-yl]nicotinamide
hydrochloride,
N-[2-(3-chloro-4-fluorobenzyl)-9-hydroxy-1,8-dioxo-1,3,4,8-tetrahydro-2H--
pyrido[1,2-a]pyrazin-7-yl]methanesulfonamide,
2-(3-chloro-4-propoxybenzyl)-
-9-hydroxy-7-(thiazol-2-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,8-dione
hydrochloride,
2-(3-chloro-4-isopropoxybenzyl)-9-hydroxy-7-(thiazol-2-yl)-
-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,8-dione hydrochloride,
2-(4-benzyloxy-3-chlorobenzyl)-9-hydroxy-7-(thiazol-2-yl)-3,4-dihydro-2H--
pyrido[1,2-a]pyrazine-1,8-dione hydrochloride,
2-(4-chloro-2-propoxybenzyl-
)-9-hydroxy-7-(thiazol-2-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,8-dion-
e hydrochloride,
2-(4-chloro-2-isopropoxybenzyl)-9-hydroxy-7-(thiazol-2-yl-
)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,8-dione hydrochloride,
2-(2-benzyloxy-4-chlorobenzyl)-9-hydroxy-7-(thiazol-2-yl)-3,4-dihydro-2H--
pyrido[1,2-a]pyrazine-1,8-dione hydrochloride,
2-(4-fluorobenzyl)-9-hydrox-
y-7-(2-methyl-2H-1,2,4-triazol-3-yl)-2H-pyrido[1,2-a]-pyrazine-1,8-dione
hydrochloride,
N-methyl-2-(3-chloro-2-fluorobenzyl)-9-hydroxy-1,8-dioxo-1-
,3,4,8-tetrahydro-2H-pyrido[1,2-a]pyrazine-7-carboxamide,
2-(3-chlorobenzyl)-7-(2,2-dimethylbutyryl)-9-hydroxy-3,4-dihydro-2H-pyrid-
o[1,2-a]pyrazine-1,8-dione,
2-(4-fluorobenzyl)-9-hydroxy-7-(pyridin-2-yl)--
3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,8-dione hydrochloride,
2-(3-chloro-2-fluorobenzyl)-9-hydroxy-7-(pyridin-2-yl)-2H-pyrido[1,2-a]py-
razine-1,8-dione hydrochloride,
2-(3-fluorobenzyl)-9-hydroxy-7-(pyridin-2--
yl)-2H-pyrido[1,2-a]pyrazine-1,8-dione hydrochloride,
N-{5-fluoro-2-[9-hydroxy-1,8-dioxo-7-(thiazol-2-yl)-1,3,4,8-tetrahydro-py-
rido[1,2-a]pyrazin-2-ylmethyl]phenyl}acetamide hydrochloride,
2-(3-chloro-2-fluorobenzyl)-7-(2,2-dimethylpropionyl)-9-hydroxy-3,4-dihyd-
ro-2}1-pyrido[1,2-a]pyrazine-1,8-dione hydrochloride,
5-fluoro-2-[9-hydroxy-1,8-dioxo-7-(thiazol-2-yl)-1,3,4,8-tetrahydro-pyrid-
o[1,2-a]pyrazin-2-ylmethyl]benzoic acid hydrochloride,
2-(3,4-difluorobenzyl)-9-hydroxy-7-(pyridin-2-yl)-2H-pyrido[1,2-a]pyrazin-
e-1,8-dione hydrochloride,
N-benzyl-N-methyl-2-(3-chlorobenzyl)-9-hydroxy--
1,8-dioxo-1,3,4,8-tetrahydro-2H-pyrido[1,2-a]pyrazine-7-carboxamide
hydrochloride,
N-(pyridin-3-ylmethyl)-2-(3-chlorobenzyl)-9-hydroxy-1,8-di-
oxo-1,3,4,8-tetrahydro-2H-pyrido[1,2-a]pyrazine-7-carboxamide
hydrochloride,
N-(pyridin-2-ylmethyl)-2-(3-chlorobenzyl)-9-hydroxy-1,8-di-
oxo-1,3,4,8-tetrahydro-2H-pyrido[1,2-a]pyrazine-7-carboxamide
hydrochloride,
2-(3,4-dichlorobenzyl)-9-hydroxy-7-(pyridin-2-yl)-3,4-dihy-
dro-2H-pyrido[1,2-a]pyrazine-1,8-dione trifluoroacetate,
N-(2-oxopropyl)-2-(3-chlorobenzyl)-9-hydroxy-1,8-dioxo-1,3,4,8-tetrahydro-
-2H-pyrido[1,2-a]pyrazine-7-carboxamide hydrochloride,
2-(3-fluorobenzyl)-9-hydroxy-7-(pyridin-4-yl)-2H-pyrido[1,2-a]pyrazine-1,-
8-dione hydrochloride,
7-(2,2-dimethylpropionyl)-2-(3-fluorobenzyl)-9-hydr-
oxy-2H-pyrido[1,2-a]pyrazine-1,8-dione hydrochloride,
N-(2-fluorobenzyl)-2-(4-fluorobenzyl)-9-hydroxy-1,8-dioxo-1,3,4,8-tetrahy-
dro-2H-pyrido[1,2-a]pyrazine-7-carboxamide,
N-(4-fluorobenzyl)-2-(4-fluoro-
benzyl)-9-hydroxy-1,8-dioxo-1,3,4,8-tetrahydro-2H-pyrido[1,2-a]pyrazine-7--
carboxamide,
N-methyl-2-(4-fluorobenzyl)-9-hydroxy-1,8-dioxo-1,3,4,8-tetra-
hydro-2H-pyrido[1,2-a]pyrazine-7-carboxamide,
N-benzyl-2-(4-fluorobenzyl)--
9-hydroxy-1,8-dioxo-1,3,4,8-tetrahydro-2H-pyrido[1,2-a]pyrazine-7-carboxam-
ide,
N-methyl-2-(4-chlorobenzyl)-9-hydroxy-1,8-dioxo-1,3,4,8-tetrahydro-2H-
-pyrido[1,2-a]pyrazine-7-carboxamide,
7-(2,2-dimethylbutyryl)-2-(4-fluorob-
enzyl)-9-hydroxy-2H-pyrido[1,2-a]pyrazine-1,8-dione hydrochloride,
2-(3,4-dichlorobenzyl)-9-hydroxy-7-(pyrazin-2-yl)-3,4-dihydro-2H-pyrido[1-
,2-a]pyrazine-1,8-dione hydrochloride,
2-(3,4-dichlorobenzyl)-9-hydroxy-7--
isobutyryl-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,8-dione,
2-(4-fluorobenzyl)-9-hydroxy-7-isobutyryl-3,4-dihydro-2H-pyrido[1,2-a]pyr-
azine-1,8-dione,
7-(2,2-dimethylpropionyl)-2-(4-fluorobenzyl)-9-hydroxy-3,-
4-dihydro-2H-pyrido[1,2-a]pyrazme-1,8-dione,
2-(4-fluorobenzyl)-9-hydroxy--
7-(3-methylbutyryl)-2H-pyrido[1,2-a]pyrazine-1,8-dione
hydrochloride,
N-methyl-2-(3,4-difluorobenzyl)-9-hydroxy-1,8-dioxo-1,3,4,8-tetrahydro-2H-
-pyrido[1,2-a]pyrazine-7-carboxamide,
2-(4-fluorobenzyl)-9-hydroxy-7-(3-me-
thoxy-2,2-dimethylpropionyl)-3,4-dihydro-2H-pyrido
[1,2-a]pyrazine-1,8-dio- ne,
9-benzyloxy-7-bromo-2-(3-chlorobenzyl)-3,4-dihydro-2H-pyrido[1,2-a]pyr-
azine-1,8-dione,
2-(3-chlorobenzyl)-9-hydroxy-7-(pyrimidin-4-yl)-2H-pyrido-
[1,2-a]pyrazine-1,8-dione hydrochloride,
2-(4-fluorobenzyl)-9-hydroxy-7-(p-
yrimidin-4-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,8-dione
hydrochloride,
2-(4-chlorobenzyl)-9-hydroxy-7-(pyrimidin-4-yl)-3,4-dihydr-
o-2H-pyrido[1,2-a]pyrazine-1,8-dione hydrochloride,
2-(3-chloro-4-fluorobenzyl)-9-hydroxy-7-(pyrimidin-4-yl)-3,4-dihydro-2H-p-
yrido[1,2-a]pyrazine-1,8-dione hydrochloride,
2-(3-chloro-4-fluorobenzyl)--
9-hydroxy-7-(pyrimidin-4-yl)-2H-pyrido[1,2-a]pyrazine-1,8-dione
hydrochloride,
2-(3-chloro-5-propoxybenzyl)-9-hydroxy-7-(thiazol-2-yl)-3,-
4-dihydro-2H-pyrido[1,2-a]pyrazine-1,8-dione hydrochloride,
2-(3-chloro-5-isopropoxybenzyl)-9-hydroxy-7-(thiazol-2-yl)-3,4-dihydro-2H-
-pyrido[1,2-a]pyrazine-1,8-dione hydrochloride,
2-(3-benzyloxy-5-chloroben-
zyl)-9-hydroxy-7-(thiazol-2-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,8-d-
ione hydrochloride,
2-(4-chlorobenzyl)-9-hydroxy-7-(pyrimidin-4-yl)-2H-pyr-
ido[1,2-a]pyrazine-1,8-dione hydrochloride,
N-[2-(3-chlorobenzyl)-9-hydrox-
y-1,8-dioxo-1,8-dihydro-2H-pyrido[1,2-a]pyrazin-7-yl]-2-(pyridin-3-yl)
acetamide hydrochloride,
N-[2-(3-chlorobenzyl)-9-hydroxy-1,8-dioxo-1,8-di-
hydro-2H-pyrido[1,2-a]pyrazin-7-yl]-2-(pyridin-4-yl)acetamide
hydrochloride,
N-[2-(3-chlorobenzyl)-9-hydroxy-1,8-dioxo-1,8-dihydro-2H-p-
yrido[1,2-a]pyrazin-7-yl]-2-(pyridin-2-yl) acetamide hydrochloride,
2-(3-fluorobenzyl)-9-hydroxy-7-(pyrimidin-4-yl)-2H-pyrido[1,2-a]pyrazine--
1,8-dione hydrochloride,
2-(3-fluorobenzyl)-9-hydroxy-7-(pyrazin-2-yl)-2H--
pyrido[1,2-a]pyrazine-1,8-dione hydrochloride,
2-(3-chloro-4-fluorobenzyl)-
-9-hydroxy-7-(2-methyl-2H-1,2,4-triazol-3-yl)-2H-pyrido[1,2-a]pyrazine-1,8-
-dione hydrochloride,
N-[2-(3-chloro-4-fluorobenzyl)-9-hydroxy-1,8-dioxo-1-
,3,4,8-tetrahydro-2H-pyrido[1,2-a]pyrazin-7-yl]-3,3-dimethylbutyramide,2-(-
3-fluorobenzyl)-9-hydroxy-4-methyl-7-(pyridin-2-yl)-2H-pyrido[1,2-a]pyrazi-
ne-1,8-dione hydrochloride,
7-(2,2-dimethylpropionyl)-2-(4-fluorobenzyl)-9-
-hydroxy-4-methyl-2H-pyrido[1,2-a]pyrazine-1,8-dione hydrochloride,
7-(2,2-dimethylpropionyl)-2-(4-fluorobenzyl)-9-hydroxy-6-methoxymethyl-3,-
4-dihydro-2H-pyrido[1,2-a]pyrazine-1,8-dione hydrochloride,
N-(pyridin-2-ylmethyl)-2-(4-fluorobenzyl)-9-hydroxy-1,8-dioxo-1,3,4,8-tet-
rahydro-2H-pyrido[1,2-a]pyrazine-7-carboxamide hydrochloride,
N-(furan-2-ylmethyl)-2-(4-fluorobenzyl)-9-hydroxy-1,8-dioxo-1,3,4,8-tetra-
hydro-2H-pyrido[1,2-a]pyrazine-7-carboxamide hydrochloride,
7-(2,2-dimethylpropionyl)-2-(4-fluorobenzyl)-9-hydroxy-4,4-dimethyl-3,4-d-
ihydro-2H-pyrido[1,2-a]pyrazine-1,8-dione hydrochloride,
7-bromo-2-(4-fluorobenzyl)-9-hydroxy-4,4-dimethyl-3,4-dihydro-2H-pyrido[1-
,2-a]pyrazine-1,8-dione hydrochloride,
2-(4-fluorobenzyl)-9-hydroxy-4,4-di-
methyl-7-(pyridin-2-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,8-dione
hydrochloride,
N-(4-dimethylaminobenzyl)-2-(4-fluorobenzyl)-9-hydroxy-1,8-
-dioxo-1,3,4,8-tetrahydro-2H-pyrido[1,2-a]pyrazine-7-carboxamide
hydrochloride,
2-(3-chlorobenzyl)-9-hydroxy-7-(pyrazin-2-yl)-3,4-dihydro--
2H-pyrido[1,2-a]pyrazine-1,8-dione hydrochloride,
2-(4-fluorobenzyl)-9-hyd-
roxy-7-(pyrazin-2-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,8-dione
hydrochloride,
N-[2-(3-chloro-4-fluorobenzyl)-9-hydroxy-1,8-dioxo-1,3,4,8-
-tetrahydro-2H-pyrido[1,2-a]pyrazin-7-yl]benzenesulfonamide,
N-[2-(3-chloro-4-fluorobenzyl)-9-hydroxy-1,8-dioxo-1,3,4,8-tetrahydro-2H--
pyrido[1,2-a]pyrazin-7-yl]benzylsulfonamide,
N-[2-(3-chloro-4-fluorobenzyl-
)-9-hydroxy-1,8-dioxo-1,3,4,8-tetrahydro-2H-pyrido[1,2-a]pyrazin-7-yl]-2-t-
hiophenesulfonamide,
N-(4-methanesulfonylbenzyl)-2-(4-fluorobenzyl)-9-hydr-
oxy-1,8-dioxo-1,3,4,8-tetrahydro-2H-pyrido[1,2-a]pyrazine-7-carboxamide
hydrochloride,
2-(4-fluorobenzyl)-9-hydroxy-6-(2-hydroxy-3,3-dimethylbuty-
l)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,8-dione hydrochloride,
N-[2-(3-chlorobenzyl)-9-hydroxy-4-methyl-1,8-dioxo-1,8-dihydro-2H-pyrido[-
1,2-a]pyrazin-7-yl]acetamide,
2-(4-fluorobenzyl)-9-hydroxy-6-methoxymethyl-
-7-(pyridin-2-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,8-dione
hydrochloride,
2-(4-fluorobenzyl)-9-hydroxy-7-(3-methoxy-2,2-dimethylprop-
ionyl)-2H-pyrido[1,2-a]pyrazine-1,8-dione hydrochloride,
N-(4-methoxypyrimidin-2-ylmethyl)-2-(4-fluorobenzyl)-9-hydroxy-1,8-dioxo--
1,3,4,8-tetrahydro-2H-pyrido[1,2-a]pyrazine-7-carboxamide
hydrochloride,
6-(3,3-dimethyl-2-oxobutyl)-7-(2,2-dimethylpropionyl)-2-(4-fluorobenzyl)--
9-hydroxy-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,8-dione
hydrochloride,
N-(4-acetylaminobenzyl)-2-(4-fluorobenzyl)-9-hydroxy-1,8-dioxo-1,3,4,8-te-
trahydro-2H-pyrido[1,2-a]pyrazine-7-carboxamide,
2-(3,4-dichlorobenzyl)-9--
hydroxy-4-(2-hydroxyethyl)-2H-pyrido[1,2-a]pyrazine-1,8-dione
hydrochloride,
2-(3,4-dichlorobenzyl)-9-hydroxy-4-(1-hydroxypropyl)-2H-py-
rido[1,2-a]pyrazine-1,8-dione,
2-(3,4-dichlorobenzyl)-9-hydroxy-4-(3-hydro-
xypropyl)-2H-pyrido[1,2-a]pyrazine-1,8-dione,
2-(3,4-dichlorobenzyl)-9-hyd-
roxy-4-(1-hydroxy-2-methylpropyl)-2H-pyrido[1,2-a]pyrazine-1,8-dione,
2-(3,4-dichlorobenzyl)-9-hydroxy-4-phenethyl-2H-pyrido[1,2-a]pyrazine-1,8-
-dione,
2-(4-fluorobenzyl)-9-hydroxy-2H-pyrazino[1,2-c]pyrimidine-1,8-dion-
e hydrochloride,
2-(3,4-dichlorobenzyl)-9-hydroxy-4-isopropyl-2H-pyrido[1,-
2-a]pyrazine-1,8-dione hydrochloride,
2-(3-chlorobenzyl)-9-hydroxy-4-methy-
l-2H-pyrido[1,2-d][1,2,4]triazine-1,8-dione,
2-(3-chlorobenzyl)-7-(2,2-dim-
ethylpropionyl)-9-hydroxy-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,8-dione,
7-(2,2-dimethylpropionyl)-2-(4-fluorobenzyl)-9-hydroxy-2H-pyrido[1,2-a]py-
razine-1,8-dione,
7-(2,2-dimethylpropionyl)-2-(4-fluorobenzyl)-9-hydroxy-2-
H-pyrido[1,2-a]pyrazine-1,8-dione sodium salt,
N-[2-(3-chlorobenzyl)-9-hyd-
roxy-1,8-dioxo-1,8-dihydro-2H-pyrido[1,2-a]pyrazin-7-yl]acetamide
sodium salt, and
2-(3-chlorobenzyl)-7-(2,2-dimethylpropionyl)-9-hydroxy-3,4-dihy-
dro-2H-pyrido[1,2-a]pyrazine-1,8-dione sodium salt, or a
pharmaceutically acceptable salt thereof.
26. A pharmaceutical composition comprising a nitrogen-containing
fused ring compound of claim 1, or a pharmaceutically acceptable
salt thereof, and a pharmaceutically acceptable carrier.
27. An anti-HIV agent comprising a nitrogen-containing fused ring
compound of claim 1 or a pharmaceutically acceptable salt thereof
as an active ingredient.
28. An integrase inhibitor comprising a nitrogen-containing fused
ring compound of claim 1 or a pharmaceutically acceptable salt
thereof as an active ingredient.
29. An antivirus agent comprising a nitrogen-containing fused ring
compound of claim 1, or a pharmaceutically acceptable salt thereof
as an active ingredient.
30. An anti-HIV composition comprising a nitrogen-containing fused
ring compound of claim 1, or a pharmaceutically acceptable salt
thereof and one or more other kinds of anti-HIV active substances
as active ingredients.
31. An anti-HIV agent comprising a nitrogen-containing fused ring
compound of claim 1, or a pharmaceutically acceptable salt thereof
as an active ingredient, which is used for a multiple drug therapy
with other anti-HIV agents.
32. Use of a nitrogen-containing fused ring compound of claim 1, or
a pharmaceutically acceptable salt thereof for the production of an
anti-HIV agent.
33. Use of a nitrogen-containing fused ring compound of claim 1, or
a pharmaceutically acceptable salt thereof for the production of an
integrase inhibitor.
34. Use of a nitrogen-containing fused ring compound of claim 1, or
a pharmaceutically acceptable salt thereof for the production of an
antivirus agent.
35. A method for the prophylaxis or treatment of an HIV infectious
disease, which comprises administering an effective amount of a
nitrogen-containing fused ring compound of claim 1 or a
pharmaceutically acceptable salt thereof to a mammal.
36. The method of claim 35, further comprising administering an
effective amount of at least one kind of other anti-HIV active
substance to the mammal.
37. A method of inhibiting integrase, which comprises administering
an effective amount of a nitrogen-containing fused ring compound of
claim 1 or a pharmaceutically acceptable salt thereof to a
mammal.
38. A method for the prophylaxis or treatment of a viral infectious
disease, which comprises administering an effective amount of a
nitrogen-containing fused ring compound of claim 1 or a
pharmaceutically acceptable salt thereof to a mammal.
Description
TECHNICAL FIELD
[0001] The present invention relates to a novel nitrogen-containing
fused ring compound or a pharmaceutically acceptable salt thereof
useful as an anti-HIV agent. Moreover, the present invention
relates to novel use of a certain kind of nitrogen-containing fused
ring compound or a pharmaceutically acceptable salt thereof as an
anti-HIV agent. More specifically, the present invention relates to
an anti-HIV agent containing a nitrogen-containing fused ring
compound or a pharmaceutically acceptable salt thereof showing an
anti-HIV action particularly based on an integrase inhibitory
activity.
BACKGROUND ART
[0002] HIV (Human Immunodeficiency Virus (type 1)) belonging to
retrovirus is a causative virus of AIDS (Acquired Immunodeficiency
Syndrome).
[0003] HIV targets CD4 positive cell groups such as helper T cell,
macrophage and dendritic cell and destroys these immunocompetent
cells to cause immunodeficiency.
[0004] Accordingly, a pharmaceutical agent that eradicates HIV in a
living organism or suppresses its growth is effective for the
treatment or prophylaxis of AIDS.
[0005] HIV possesses a bimolecular RNA gene in a shell, and which
is covered with an envelope protein. The RNA codes for several
enzymes (protease, reverse transcriptase, integrase etc.)
characteristic of the virus and the like, and has translated
reverse transcriptase and integrase in the core, as well as
protease inside and outside the core.
[0006] HIV contacts and invades a host cell, causes uncoating, and
releases a complex of RNA and integrase, and the like into the
cytoplasm. From the RNA, DNA is transcribed by reverse
transcriptase, and a full length double stranded DNA is produced.
The DNA moves into the core of the host cell and is incorporated by
integrase into the DNA of the host cell. The incorporated DNA is
converted to an mRNA by polymerase of the host cell, from which
mRNA various proteins necessary for forming a virus are synthesized
by HIV protease and the like, and a virus particle is finally
formed, which then undergoes budding and its release.
[0007] These virus specific enzymes are considered to be essential
for the growth of HIV. These enzymes are drawing attention as the
target of the development of antiviral agents, and several anti-HIV
agents have been already developed.
[0008] For example, zidovudine, didanosine, lamivudine and the like
have been already on the market as reverse transcriptase
inhibitors, and indinavir, nelfinavir and the like as protease
inhibitors.
[0009] In addition, a multiple drug combination therapy
concurrently using these pharmaceutical agents has been employed.
For example, a combined use of two reverse transcriptase inhibitors
(zidovudine and didanosine), and a combined use of three agents of
reverse transcriptase inhibitors (zidovudine and lamivudine) and a
protease inhibitor (nelfinavir) have been clinically applied. Such
multiple drug combination therapy is becoming a mainstream of AIDS
therapy (Folia Pharmacologica Japonica, 118, 131-134, 2001).
[0010] However, some of these pharmaceutical agents are known to
HIV cause side effects such as liver function failure, central
nervous disorders (e.g., vertigo), and the like. In addition,
acquisition of resistance to a pharmaceutical agent causes a
problem. Even worse, emergence of an HIV that shows multiple drug
resistance in a multiple drug combination therapy has been
known.
[0011] Under the circumstances, a further development of a novel
pharmaceutical agent, particularly a development of an anti-HIV
agent based on a new mechanism, has been desired, wherein a
development of an anti-HIV agent having an integrase inhibitory
activity is expected, because an integrase characteristic of
retrovirus is an essential enzyme for the growth of HIV.
[0012] Nevertheless, an effective integrase inhibitor has not been
found as yet.
[0013] Known compounds comparatively similar to the anti-HIV agent
of the present invention are described in the following.
[0014] WO01/96283 describes, as an anti-HIV agent having an
integrase inhibitory activity, the following compound [A] (see
WO01/96283, p. 176, compound 70). 2
[0015] WO03/016266 describes the following compound [B] and the
like having an integrase inhibitory activity (see WO03/016266, p.
159, Example Nos. 3-17). 3
[0016] WO01/95905 describes the following compound [C] and the
like, as an anti-HIV agent having an integrase inhibitory activity
(see WO01/95905, p. 109, Example E-2). 4
[0017] In addition, WO03/047564 describes the following compound
[D] and the like, as an anti-HIV agent having an integrase
inhibitory activity (see WO03/047564, p. 73, Example 11). 5
[0018] Moreover, WO02/30930 and WO02/55079 describe, as an anti-HIV
agent having an integrase inhibitory activity, the following
compounds [E], [F] and the like, respectively (see WO02/30930, p.
171, Example 1; WO02/55079, p. 79, Example 1). WO02/30426,
WO02/30931 and WO02/36734 also disclose similar compounds. 6
[0019] In addition, WO03/031413 describes, as an anti-HIV agent
having an integrase inhibitory activity, the following compound [G]
and the like (see WO03/031413, p. 21, compound 8). 7
[0020] Moreover, WO03/035076 and WO03/035077 describe, as an
anti-HIV agent having an integrase inhibitory activity, the
following compounds [H], [i] and the like (WO03/035076, p. 188,
Example 1; WO03/035077, p. 146, Example 22). 8
[0021] However, these publications do not disclose
nitrogen-containing fused ring compound encompassed in the present
invention, or a description suggestive thereof.
[0022] Furthermore, WO2004/24078 describe, as an anti-HIV agent
having an integrase inhibitory activity, the following compound [J]
and the like. 9
[0023] This publication describes the following formula as the
formula (I) of claim 1 and a tautomer thereof. However, the
compound described in this publication is clearly different from
the compound of the present invention in that a hydroxyl group or a
carbonyl group is essential at a position corresponding to the
position of R.sup.y1 for Y.sup.2 in the formula [I] of the
nitrogen-containing fused ring compound of the present invention.
In addition, this publication does not suggest a compound free of a
hydroxyl group or a carbonyl group at said position. 10
[0024] A production method of the compound of the formula (I) is
disclosed in this publication from page 46 to page 113, but the
production method concretely disclosed here cannot produce a
nitrogen-containing fused ring compound encompassed in the present
invention, and a concrete production method of this compound is not
referred to at all.
DISCLOSURE OF THE INVENTION
[0025] From the findings based on the researches and clinical
results obtained so far, an anti-HIV agent is effective for the
prophylaxis of the onset of AIDS and the treatment thereof, and
particularly a compound having an integrase inhibitory action can
provide an effective anti-HIV agent.
[0026] It is therefore an object of the present invention to
provide a pharmaceutical agent having an anti-HIV action,
particularly a pharmaceutical agent having an integrase inhibitory
action.
[0027] The present inventors have conducted intensive studies in an
attempt to find a compound having an anti-HIV action, particularly
a compound having an integrase inhibitory action, and completed the
present invention.
[0028] More particularly, the present invention is as shown in the
following [1] to [38].
[0029] [1] A nitrogen-containing fused ring compound represented by
the following formula [I] or a pharmaceutically acceptable salt
thereof: 11
[0030] wherein
[0031] R.sup.1 is
[0032] (1) a C1-6 alkyl group optionally substituted by 1 to 3
substituent(s) selected from the following group A,
[0033] (2) a C2-6 alkenyl group optionally substituted by 1 to 3
substituent(s) selected from the following group A or
[0034] (3) a group represented by the formula 12
[0035] wherein Z is
[0036] (1') a bond,
[0037] (2') a C1-6 alkylene,
[0038] (3') a C2-6 alkenylene or
[0039] (4') *-(CH.sub.2).sub.m--Q--(CH.sub.2).sub.n--
[0040] wherein Q is
[0041] (1") --O--,
[0042] (2") --NR.sup.5--
[0043] wherein R.sup.5 is a hydrogen atom or a C1-6 alkyl
group,
[0044] (3") --CO--,
[0045] (4") --SO--,
[0046] (5") --SO.sub.2-- or
[0047] (6") **-CO--NR.sup.6--
[0048] wherein R.sup.6 is a hydrogen atom or a C1-6 alkyl group and
** shows the side to be bonded to (CH.sub.2).sub.m,
[0049] m is 0 or an integer of 1 to 4,
[0050] n is 0 or an integer of 1 to 4 and
[0051] * shows the side to be bonded to a nitrogen atom of ring A,
and
[0052] ring D is
[0053] (1') a C3-10 carbon ring group optionally substituted by 1
to 3 substituent(s) selected from the following group B or
[0054] (2') a heterocyclic group optionally substituted by 1 to 3
substituent(s) selected from the following group B
[0055] wherein the heterocyclic group contains at least one hetero
atom selected from nitrogen atom, oxygen atom and sulfur atom;
[0056] X is
[0057] (1) --C(R.sup.x1)(R.sup.x2)-#,
[0058] (2) --C(R.sup.x1)(R.sup.x2)--C(R.sup.x3)(R.sup.x4)-#,
[0059] (3)
--C(R.sup.x1)(R.sup.x2)--C(R.sup.x3)(R.sup.x4)--C(R.sup.x5)(R.s-
up.x6)-#,
[0060] (4) --C(R.sup.x7).dbd.C(R.sup.x8)-#,
[0061] (5)
--C(R.sup.x1)(R.sup.x2)--C(R.sup.x7).dbd.C(R.sup.x8)-#,
[0062] (6)
--C(R.sup.x7).dbd.C(R.sup.x8)--C(R.sup.x1)(R.sup.x2)-#,
[0063] (7) --N.dbd.C(R.sup.x9)-# or
[0064] (8) --C(R.sup.x10).dbd.N-#
[0065] wherein # shows the side to be bonded to Y.sup.1 of ring B,
R.sup.x1 to R.sup.x10 are each independently selected from the
following group C, R.sup.x1 and R.sup.x2, R.sup.x3 and R.sup.x4,
and R.sup.x5 and R.sup.x6 each independently optionally form a C3-8
cycloalkyl together with the adjacent carbon atom; 13
[0066] of ring B is
[0067] (1) C.dbd.C(R.sup.y1)--N(R.sup.y2),
[0068] (2) N--C(R.sup.y1).dbd.N,
[0069] (3) N--C(R.sup.y1).dbd.C(R.sup.y2),
[0070] (4) C.dbd.N--N(R.sup.y2) or
[0071] (5) N--N.dbd.C(R.sup.y3)
[0072] wherein R.sup.y1 to R.sup.y3 are each independently selected
from the following group C,
[0073] when 14
[0074] is N--C(R.sup.y1).dbd.C(R.sup.y2), ring B is optionally
condensed with a benzene ring to form a fused ring represented by
15
[0075] wherein R.sup.4 is selected from the following group C;
and
[0076] R.sup.2 is
[0077] (1) a hydrogen atom,
[0078] (2) a C1-6 alkyl group,
[0079] (3) a C6-14 aryl C1-6 alkyl group or
[0080] (4) --SO.sub.2R.sup.d1
[0081] wherein R.sup.d1 is a hydrogen atom, a C1-7 alkyl group
optionally substituted by 1 to 3 substituent(s) selected from the
following group A or a C6-14 aryl group:
[0082] group A:
[0083] (1) a halogen atom,
[0084] (2) a cyano group,
[0085] (3) --OR.sup.a1,
[0086] (4) --SR.sup.a1,
[0087] (5) --CO.sub.2R.sup.a1,
[0088] (6) --CONR.sup.a2R.sup.a3,
[0089] (7) --COR.sup.a4,
[0090] (8) --SO.sub.2NR.sup.a2R.sup.a3,
[0091] (9) --SO.sub.2R.sup.a4,
[0092] (10) a C6-14 aryloxy group,
[0093] (11) a C6-14 aryl C1-6 alkyloxycarbonyl group,
[0094] (12) a C1-6 alkylcarbonyloxy group optionally substituted by
halogen atom(s),
[0095] (13) a C6-14 aryl group optionally substituted by 1 to 3
substituent(s) selected from the group consisting of a halogen
atom, a C1-6 alkyl group, a C1-6 alkylsulfonyl group, a di(C1-6
alkyl)amino group and a C1-6 alkylcarbonylamino group and
[0096] (14) a heterocyclic group optionally substituted by a C1-6
alkyloxy group,
[0097] wherein R.sup.a1, R.sup.a2, R.sup.a3 and R.sup.a4 are each
independently a hydrogen atom or a C1-6 alkyl group;
[0098] group B:
[0099] (1) a halogen atom,
[0100] (2) a cyano group,
[0101] (3) a C1-6 alkyl group,
[0102] (4) a halo C1-6 alkyl group,
[0103] (5) --OR.sup.b1,
[0104] (6) --SR.sup.b1,
[0105] (7) --CO.sub.2R.sup.b1,
[0106] (8) --CONR.sup.b2R.sup.b3,
[0107] (9) --COR.sup.b4,
[0108] (10) --SO.sub.2NR.sup.b2R.sup.b3,
[0109] (11) --SO.sub.2R.sup.b4,
[0110] (12) a C6-14 aryloxy group,
[0111] (13) a C6-14 aryl C1-6 alkyloxycarbonyl group,
[0112] (14) a C6-14 aryl C1-6 alkyloxy group and
[0113] (15) --NR.sup.b5COR.sup.b6,
[0114] wherein R.sup.b1, R.sup.b2, R.sup.b3, R.sup.b4, R.sup.b5 and
R.sup.b6 are each independently a hydrogen atom or a C1-6 alkyl
group;
[0115] group C:
[0116] (1) a hydrogen atom,
[0117] (2) a C3-8 cycloalkyl C1-6 alkyl group,
[0118] (3) a cyano group,
[0119] (4) a halogen atom,
[0120] (5) a C1-7 alkyl group,
[0121] (6) a C2-6 alkenyl group,
[0122] (7) a C2-6 alkynyl group,
[0123] (8) a C6-14 aryl group,
[0124] (9) a heterocyclic group
[0125] wherein said heterocyclic group is a saturated or
unsaturated 5-membered or 6-membered heteromonocycle containing at
least one hetero atom selected from nitrogen atom, oxygen atom and
sulfur atom, or a fused ring of such heterocycles, or a fused ring
of a carbon ring selected from benzene, cyclopentane and
cyclohexane and the above-defined heterocycle,
[0126] (10) a C1-6 alkyloxy group,
[0127] (11) a C6-14 aryl C1-6 alkyl group,
[0128] (12) a C6-14 aryl C1-6 alkyloxy group,
[0129] (13) --CO.sub.2R.sup.c1,
[0130] (14) --CONR.sup.c2R.sup.c3,
[0131] (15) --COR.sup.c4,
[0132] (16) --SO.sub.2NR.sup.c2R.sup.c3,
[0133] (17) a C6-14 arylcarbonyl group,
[0134] (18) --NR.sup.c4R.sup.c5,
[0135] (19) --NR.sup.c6COR.sup.c7,
[0136] (20) --NR.sup.c8SO.sub.2R.sup.c9,
[0137] (21) --SR.sup.c10,
[0138] (22) --SOR.sup.c11,
[0139] (23) --SO.sub.2R.sup.c12,
[0140] (24) --NR.sup.c13CONR.sup.c14R.sup.c15,
[0141] (25) --NR.sup.c16CO.sub.2R.sup.c17, and,
[0142] (26) --NR.sup.c18COCOR.sup.c19,
[0143] wherein R.sup.c1, R.sup.c2, R.sup.c3, R.sup.c4, R.sup.c5,
R.sup.c6, R.sup.c7, R.sup.c8, R.sup.c9, R.sup.c10, R.sup.c11,
R.sup.c12, R.sup.c13, R.sup.c14, R.sup.c15, R.sup.c16, R.sup.c17,
R.sup.c18 and R.sup.c19 are each independently
[0144] (1') a hydrogen atom,
[0145] (2') a C1-7 alkyl group optionally substituted by 1 to 3
substituent(s) selected from the above-mentioned group A,
[0146] (3') a C6-14 aryl group optionally substituted by 1 to 3
substituent(s) selected from the above-mentioned group B,
[0147] (4') a heterocyclic group optionally substituted by 1 to 3
substituent(s) selected from the above-mentioned group B or
[0148] (5') a C3-8 cycloalkyl group,
[0149] wherein R.sup.c2 and R.sup.c3 optionally form, together with
the adjacent nitrogen atom, a nitrogen-containing heterocycle
optionally substituted by 1 to 3 substituent(s) selected from the
above-mentioned group B;
[0150] the C1-7 alkyl group, C1-6 alkyl moiety, C2-6 alkenyl group
and C2-6 alkynyl group of the above-mentioned group C are
optionally substituted by 1 to 3 substituent(s) selected from the
above-mentioned group A, or a heterocyclic group; and the C6-14
aryl group, C6-14 aryl moiety and heterocyclic group of the
above-mentioned group C are optionally substituted by 1 to 3
substituent(s) selected from the above-mentioned group B.
[0151] [2] The nitrogen-containing fused ring compound of [1],
wherein 16
[0152] of ring B is C.dbd.C(R.sup.y1)--N(R.sup.y2),
N--C(R.sup.y1).dbd.N, N--C(R.sup.y1).dbd.C(R.sup.y2) or
C.dbd.N--N(R.sup.y2), wherein each symbol is as defined in [1], or
a pharmaceutically acceptable salt thereof.
[0153] [3] The nitrogen-containing fused ring compound of [2]
represented by the following formula [I]-1, or a pharmaceutically
acceptable salt thereof: 17
[0154] wherein each symbol is as defined in [1].
[0155] [4] The nitrogen-containing fused ring compound of [2]
represented by the following formula [I]-2, or a pharmaceutically
acceptable salt thereof: 18
[0156] wherein each symbol is as defined in [1].
[0157] [5] The nitrogen-containing fused ring compound of [2]
represented by the following formula [I]-3, or a pharmaceutically
acceptable salt thereof: 19
[0158] wherein each symbol is as defined in [1].
[0159] [6] The nitrogen-containing fused ring compound of [2]
represented by the following formula [I]-4, or a pharmaceutically
acceptable salt thereof: 20
[0160] wherein each symbol is as defined in [1].
[0161] [7] The nitrogen-containing fused ring compound of any of
[1]-[6], wherein X is
--C(R.sup.x1)(R.sup.x2)--C(R.sup.x3)(R.sup.x4)-#,
--C(R.sup.x1)(R.sup.x2)--C(R.sup.x3)(R.sup.x4)--C(R.sup.x5)(R.sup.x6)-#,
--C(R.sup.x7).dbd.C(R.sup.x8)-#, --N.dbd.C(R.sup.x9)-# or
--C(R.sup.x10).dbd.N-# wherein each symbol is as defined in [1], or
a pharmaceutically acceptable salt thereof.
[0162] [8] The nitrogen-containing fused ring compound of [7],
wherein X is --C(R.sup.x1)(R.sup.x2)--C(R.sup.x3)(R.sup.x4)-# or
--C(R.sup.x7).dbd.C(R.sup.x8)-# wherein each symbol is as defined
in [1], or a pharmaceutically acceptable salt thereof.
[0163] [9] The nitrogen-containing fused ring compound of [8],
wherein X is --C(R.sup.x1)(R.sup.x2)--C(R.sup.x3)(R.sup.x4)-#
wherein each symbol is as defined in [1], or a pharmaceutically
acceptable salt thereof.
[0164] [10] The nitrogen-containing fused ring compound of [8],
wherein X is --C(R.sup.x7).dbd.C(R.sup.x8)-# wherein each symbol is
as defined in [1], or a pharmaceutically acceptable salt
thereof.
[0165] [11] The nitrogen-containing fused ring compound of any of
[1]-[6], wherein R.sup.1 is a group represented by the formula
21
[0166] wherein Z is C1-6 alkylene or
*-(CH.sub.2).sub.m--Q--(CH.sub.2).sub- .n--, and other symbols are
as defined in [1], or a pharmaceutically acceptable salt
thereof.
[0167] [12] The nitrogen-containing fused ring compound of [11],
wherein Z is a C1-6 alkylene, or a pharmaceutically acceptable salt
thereof.
[0168] [13] The nitrogen-containing fused ring compound of [11],
wherein ring D is a C3-10 carbon ring group optionally substituted
by 1 to 3 substituent(s) selected from group B, or a
pharmaceutically acceptable salt thereof.
[0169] [14] The nitrogen-containing fused ring compound of any of
[1]-[6], wherein R.sup.x1 to R.sup.x10 are each independently
selected from the following groups and R.sup.x1 and R.sup.x2,
R.sup.x3 and R.sup.x4, and R.sup.x5 and R.sup.x6 each independently
optionally form, together with the adjacent carbon atom, a C3-8
cycloalkyl, or a pharmaceutically acceptable salt thereof:
[0170] a hydrogen atom,
[0171] a C3-8 cycloalkyl C1-6 alkyl group,
[0172] a cyano group,
[0173] a C1-7 alkyl group,
[0174] a C6-14 aryl group,
[0175] a C6-14 aryl C1-6 alkyl group, --CO.sub.2R.sup.c1,
[0176] --CONR.sup.c2R.sup.c3 and,
[0177] --COR.sup.c4
[0178] wherein the above-mentioned C1-7 alkyl group and C1-6 alkyl
moiety are optionally substituted by 1 to 3 substituent(s) selected
from group A or a heterocyclic group, and other symbols are as
defined in [1].
[0179] [15] The nitrogen-containing fused ring compound of [14],
wherein R.sup.x1 to R.sup.x10 are each a hydrogen atom, or a
pharmaceutically acceptable salt thereof.
[0180] [16] The nitrogen-containing fused ring compound of any of
[1]-[6], wherein R.sup.y1 is selected from the following groups, or
a pharmaceutically acceptable salt thereof:
[0181] a hydrogen atom,
[0182] a C1-7 alkyl group,
[0183] a C6-14 aryl group,
[0184] --CO.sub.2R.sup.c1,
[0185] --CONR.sup.c2R.sup.c3,
[0186] --COR.sup.c4 and,
[0187] a C6-14 arylcarbonyl group
[0188] wherein the above-mentioned C1-7 alkyl group is optionally
substituted by 1 to 3 substituent(s) selected from group A or a
heterocyclic group, the above-mentioned C6-14 aryl group is
optionally substituted by 1 to 3 substituent(s) selected from group
B, and other symbols are as defined in [1].
[0189] [17] The nitrogen-containing fused ring compound of [16],
wherein R.sup.y1 is a hydrogen atom, or a pharmaceutically
acceptable salt thereof.
[0190] [18] The nitrogen-containing fused ring compound of any of
[1]-[6], wherein R.sup.y2 is selected from the following groups, or
a pharmaceutically acceptable salt thereof:
[0191] a hydrogen atom,
[0192] a halogen atom,
[0193] a C1-7 alkyl group
[0194] a C6-14 aryl group,
[0195] a heterocyclic group,
[0196] --CO.sub.2R.sup.c1,
[0197] --CONR.sup.c2R.sup.c3,
[0198] --COR.sup.c4,
[0199] --NR.sup.c4R.sup.c5,
[0200] --NR.sup.c6COR.sup.c7,
[0201] --NR.sup.c8SO.sub.2R.sup.c9,
[0202] --SR.sup.c10,
[0203] --SO.sub.2R.sup.c12,
[0204] --NR.sup.c13CONR.sup.c14R.sup.c15,
[0205] --NR.sup.c16CO.sub.2R.sup.c17, and,
[0206] --NR.sup.c18COCOR.sup.c19
[0207] wherein the above-mentioned C1-7 alkyl group is optionally
substituted by 1 to 3 substituent(s) selected from group A or a
heterocyclic group, the above-mentioned C6-14 aryl group and
heterocyclic group are optionally substituted by 1 to 3
substituent(s) selected from group B, and other symbols are as
defined in [1].
[0208] [19] The nitrogen-containing fused ring compound of [18],
wherein R.sup.y2 is a heterocyclic group optionally substituted by
1 to 3 substituent(s) selected from group B, or a pharmaceutically
acceptable salt thereof.
[0209] [20] The nitrogen-containing fused ring compound of [19],
wherein R.sup.y2 is a heterocyclic group optionally substituted by
1 to 3 substituent(s) selected from group B, which is bonded to
Y.sup.3 via a carbon atom, wherein at least one .alpha.-position of
the carbon atom is a hetero atom selected from the group consisting
of nitrogen atom, oxygen atom and sulfur atom, or a
pharmaceutically acceptable salt thereof.
[0210] [21] The nitrogen-containing fused ring compound of [18],
wherein R.sup.y2 is selected from --CO.sub.2R.sup.c1,
--CONR.sup.c2R.sup.c3 and --COR.sup.c4 wherein each symbol is as
defined in [1], or a pharmaceutically acceptable salt thereof.
[0211] [22] The nitrogen-containing fused ring compound of [18],
wherein R.sup.y2 is selected from --NR.sup.c4R.sup.c5,
--NR.sup.c6COR.sup.c7, --NR.sup.c8SO.sub.2R.sup.c9,
--NR.sup.c13CONR.sup.c14R.sup.c15, --NR.sup.c16CO.sub.2R.sup.c17
and --NR.sup.18COCOR.sup.c19 wherein each symbol is as defined in
[1], or a pharmaceutically acceptable salt thereof.
[0212] [23] The nitrogen-containing fused ring compound of [22],
wherein R.sup.y2 is selected from --NR.sup.c6COR.sup.c7,
--NR.sup.c8SO.sub.2R.sup- .c9, --NR.sup.c13CONR.sup.c14R.sup.c15,
--NR.sup.c16CO.sub.2R.sup.c17 and --NR.sup.c18COCOR.sup.c19 wherein
each symbol is as defined in [1], or a pharmaceutically acceptable
salt thereof.
[0213] [24] The nitrogen-containing fused ring compound of any of
[1]-[6], wherein R.sup.2 is a hydrogen atom, or a pharmaceutically
acceptable salt thereof.
[0214] [25] The nitrogen-containing fused ring compound of [1],
which is selected from the group consisting of
[0215]
2-(3,4-dichlorobenzyl)-9-hydroxy-3,4-dihydro-2H-pyrido[1,2-a]pyrazi-
ne-1,8-dione hydrochloride (Example 1),
[0216]
2-(3,4-dichlorobenzyl)-10-hydroxy-2,3,4,5-tetrahydropyrido[1,2-a][1-
,4]diazepine-1,9-dione (Example 2),
[0217]
2-(3,4-dichlorobenzyl)-9-hydroxy-3-methyl-3,4-dihydro-2H-pyrido[1,2-
-a]pyrazine-1,8-dione (Example 3),
[0218]
2-(3,4-dichlorobenzyl)-9-hydroxy-4,4-dimethyl-3,4-dihydro-2H-pyrido-
[1,2-a]pyrazine-1,8-dione (Example 4),
[0219]
2-(3,4-dichlorobenzyl)-9-hydroxy-6-hydroxymethyl-3,4-dihydro-2H-pyr-
ido[1,2-a]pyrazine-1,8-dione (Example 5),
[0220]
2-(3,4-dichlorobenzyl)-9-hydroxy-1,8-dioxo-1,3,4,8-tetrahydro-2H-py-
rido[1,2-a]pyrazine-6-carboxylic acid (Example 6),
[0221]
2-(3,4-dichlorobenzyl)-6-(2,2-dimethylpropionyl)-9-hydroxy-3,4-dihy-
dro-2H-pyrido[1,2-a]pyrazine-1,8-dione (Example 7),
[0222]
2-(3,4-dichlorobenzyl)-9-hydroxy-2H-pyrido[1,2-a]pyrazine-1,8-dione
(Example 8),
[0223]
2-(3,4-dichlorobenzyl)-9-hydroxy-3-methyl-2H-pyrido[1,2-a]pyrazine--
1,8-dione (Example 9),
[0224]
2-(3-chlorobenzyl)-9-hydroxy-4-isopropyl-2H-pyrido[1,2-a]pyrazine-1-
,8-dione hydrochloride (Example 10),
[0225]
2-[3-(2,6-dichlorophenyl)propyl]-9-hydroxy-2H-pyrido[1,2-a]pyrazine-
-1,8-dione (Example 11),
[0226]
2-(3,4-dichlorobenzyl)-9-hydroxy-2H-pyrazino[1,2-c]pyrimidine-1,8-d-
ione hydrochloride (Example 12),
[0227]
2-(3,4-dichlorobenzyl)-9-hydroxy-4-methyl-3,4-dihydro-2H-pyrido[1,2-
-a]pyrazine-1,8-dione (Example 13),
[0228]
4-benzyl-2-(3,4-dichlorobenzyl)-9-hydroxy-3,4-dihydro-2H-pyrido[1,2-
-a]pyrazine-1,8-dione (Example 14),
[0229]
2-(3,4-dichlorobenzyl)-9-hydroxy-4-phenyl-3,4-dihydro-2H-pyrido[1,2-
-a]pyrazine-1,8-dione (Example 15),
[0230]
4-butyl-2-(3,4-dichlorobenzyl)-9-hydroxy-3,4-dihydro-2H-pyrido[1,2--
a]pyrazine-1,8-dione (Example 16),
[0231]
2-(3,4-dichlorobenzyl)-9-hydroxy-4-isopropyl-3,4-dihydro-2H-pyrido[-
1,2-a]pyrazine-1,8-dione (Example 17),
[0232]
2-(3,4-dichlorobenzyl)-9-hydroxy-3,3-dimethyl-3,4-dihydro-2H-pyrido-
[1,2-a]pyrazine-1,8-dione (Example 18),
[0233]
2-(3,4-dichlorobenzyl)-9-hydroxy-3,4-dihydro-2H-pyrido[1,2-a]pyrazi-
ne-4-spiro-1'-cyclopentane-1,8-dione (Example 19),
[0234]
2-(3,4-dichlorobenzyl)-9-hydroxy-3,4-dihydro-2H-pyrido[1,2-a]pyrazi-
ne-4-spiro-1'-cyclohexane-1,8-dione (Example 20),
[0235] methyl
2-(3,4-dichlorobenzyl)-9-hydroxy-1,8-dioxo-1,3,4,8-tetrahydr-
o-2H-pyrido[1,2-a]pyrazine-4-carboxylate (Example 21),
[0236]
2-(3,4-dichlorobenzyl)-9-hydroxy-1,8-dioxo-1,3,4,8-tetrahydro-2H-py-
rido[1,2-a]pyrazine-4-carboxylic acid (Example 22),
[0237]
2-(3,4-dichlorobenzyl)-9-hydroxy-6-methoxymethyl-3,4-dihydro-2H-pyr-
ido[1,2-a]pyrazine-1,8-dione (Example 23),
[0238]
N,N-dimethyl-2-(3,4-dichlorobenzyl)-9-hydroxy-1,8-dioxo-1,3,4,8-tet-
rahydro-2H-pyrido[1,2-a]pyrazine-6-carboxamide (Example 24),
[0239]
3-benzyl-2-(3,4-dichlorobenzyl)-9-hydroxy-3,4-dihydro-2H-pyrido[1,2-
-a]pyrazine-1,8-dione (Example 25),
[0240]
3-butyl-2-(3,4-dichlorobenzyl)-9-hydroxy-3,4-dihydro-2H-pyrido[1,2--
a]pyrazine-1,8-dione (Example 26),
[0241]
N,N-dimethyl-2-(3,4-dichlorobenzyl)-9-hydroxy-1,8-dioxo-1,3,4,8-tet-
rahydro-2H-pyrido[1,2-a]pyrazine-4-carboxamide (Example 27),
[0242]
2-(3,4-dichlorobenzyl)-9-hydroxy-4-hydroxymethyl-3,4-dihydro-2H-pyr-
ido[1,2-a]pyrazine-1,8-dione (Example 28),
[0243]
2-(3,4-dichlorobenzyl)-9-hydroxy-4-methoxymethyl-3,4-dihydro-2H-pyr-
ido[1,2-a]pyrazine-1,8-dione (Example 29),
[0244]
2-(3,4-dichlorobenzyl)-9-hydroxy-6-methylsulfanylmethyl-3,4-dihydro-
-2H-pyrido[1,2-a]pyrazine-1,8-dione (Example 30),
[0245]
2-(3,4-dichlorobenzyl)-9-hydroxy-6-methanesulfonylmethyl-3,4-dihydr-
o-2H-pyrido[1,2-a]pyrazine-1,8-dione (Example 31),
[0246]
2-(3,4-dichlorobenzyl)-9-hydroxy-4-(2-methanesulfonylethyl)-3,4-dih-
ydro-2H-pyrido[1,2-a]pyrazine-1,8-dione (Example 32),
[0247]
2-(3,4-dichlorobenzyl)-9-hydroxy-4-(2-methylsulfanylethyl)-3,4-dihy-
dro-2H-pyrido[1,2-a]pyrazine-1,8-dione (Example 33),
[0248] methyl
2-(3,4-dichlorobenzyl)-9-hydroxy-1,8-dioxo-1,3,4,8-tetrahydr-
o-2H-pyrido[1,2-a]pyrazine-6-carboxylate (Example 34),
[0249]
6-acetyl-2-(3,4-dichlorobenzyl)-9-hydroxy-3,4-dihydro-2H-pyrido[1,2-
-a]pyrazine-1,8-dione (Example 35),
[0250]
2-(3,4-dichlorobenzyl)-9-hydroxy-6-isopropylsulfanylmethyl-3,4-dihy-
dro-2H-pyrido[1,2-a]pyrazine-1,8-dione (Example 36),
[0251]
2-(3,4-dichlorobenzyl)-9-hydroxy-6-isopropylsulfonylmethyl-3,4-dihy-
dro-2H-pyrido[1,2-a]pyrazine-1,8-dione (Example 37),
[0252]
2-(3,4-dichlorobenzyl)-9-hydroxy-6-isopropoxymethyl-3,4-dihydro-2H--
pyrido[1,2-a]pyrazine-1,8-dione (Example 38),
[0253]
2-(3,4-dichlorobenzyl)-9-hydroxy-6-isobutoxymethyl-3,4-dihydro-2H-p-
yrido[1,2-a]pyrazine-1,8-dione (Example 39),
[0254]
2-(3,4-dichlorobenzyl)-9-hydroxy-6-(1-hydroxyethyl)-3,4-dihydro-2H--
pyrido[1,2-a]pyrazine-1,8-dione (Example 40),
[0255]
2-(3,4-dichlorobenzyl)-9-hydroxy-6-phenoxymethyl-3,4-dihydro-2H-pyr-
ido[1,2-a]pyrazine-1,8-dione (Example 41),
[0256]
2-(4-fluorobenzyl)-9-hydroxy-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1-
,8-dione (Example 42),
[0257]
2-(3-chlorobenzyl)-9-hydroxy-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1-
,8-dione (Example 43),
[0258]
2-benzyl-9-hydroxy-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,8-dione
(Example 44),
[0259]
2-(4-chlorobenzyl)-9-hydroxy-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1-
,8-dione (Example 45),
[0260]
2-(3,4-dichlorobenzyl)-9-hydroxy-6-isopropyl-3,4-dihydro-2H-pyrido[-
1,2-a]pyrazine-1,8-dione (Example 46),
[0261]
2-(3,4-dichlorobenzyl)-9-hydroxy-6-isobutyryl-3,4-dihydro-2H-pyrido-
[1,2-a]pyrazine-1,8-dione (Example 47),
[0262]
2-(3,4-dichlorobenzyl)-9-hydroxy-1,8-dioxo-1,3,4,8-tetrahydro-2H-py-
rido[1,2-a]pyrazine-6-carbaldehyde (Example 48),
[0263]
2-(3,4-dichlorobenzyl)-9-hydroxy-6-phenyl-3,4-dihydro-2H-pyrido[1,2-
-a]pyrazine-1,8-dione (Example 49),
[0264]
9-hydroxy-2-(3-phenylpropyl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1-
,8-dione (Example 50),
[0265]
2-(3-chloro-2-fluorobenzyl)-9-hydroxy-3,4-dihydro-2H-pyrido[1,2-a]p-
yrazine-1,8-dione (Example 51),
[0266]
9-hydroxy-2-phenethyl-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,8-dion-
e (Example 52),
[0267]
2-(3,4-dichlorobenzyl)-9-hydroxy-6-(1-hydroxy-2-methylpropyl)-3,4-d-
ihydro-2H-pyrido[1,2-a]pyrazine-1,8-dione (Example 53),
[0268]
2-(3,4-dichlorobenzyl)-9-hydroxy-6-isobutyl-3,4-dihydro-2H-pyrido[1-
,2-a]pyrazine-1,8-dione (Example 54),
[0269]
2-(3,4-dichlorobenzyl)-9-hydroxy-1,8-dioxo-1,3,4,8-tetrahydro-2H-py-
rido[1,2-a]pyrazine-6-carboxamide (Example 55),
[0270]
N-methyl-2-(3,4-dichlorobenzyl)-9-hydroxy-1,8-dioxo-1,3,4,8-tetrahy-
dro-2H-pyrido[1,2-a]pyrazine-6-carboxamide (Example 56),
[0271]
2-(4-chloro-3-fluorobenzyl)-9-hydroxy-3,4-dihydro-2H-pyrido[1,2-a]p-
yrazine-1,8-dione (Example 57),
[0272]
6-benzoyl-2-(3,4-dichlorobenzyl)-9-hydroxy-3,4-dihydro-2H-pyrido[1,-
2-a]pyrazine-1,8-dione (Example 58),
[0273]
2-(3,4-dichlorobenzyl)-9-hydroxy-6-propionyl-3,4-dihydro-2H-pyrido[-
1,2-a]pyrazine-1,8-dione (Example 59),
[0274]
2-(3,4-dichlorobenzyl)-9-hydroxy-6-methyl-3,4-dihydro-2H-pyrido[1,2-
-a]pyrazine-1,8-dione (Example 60),
[0275]
N,N-diethyl-2-(3,4-dichlorobenzyl)-9-hydroxy-1,8-dioxo-1,3,4,8-tetr-
ahydro-2H-pyrido[1,2-a]pyrazine-6-carboxamide (Example 61),
[0276]
N-isopropyl-N-methyl-2-(3,4-dichlorobenzyl)-9-hydroxy-1,8-dioxo-1,3-
,4,8-tetrahydro-2H-pyrido[1,2-a]pyrazine-6-carboxamide (Example
62),
[0277]
N-ethyl-N-methyl-2-(3,4-dichlorobenzyl)-9-hydroxy-1,8-dioxo-1,3,4,8-
-tetrahydro-2H-pyrido[1,2-a]pyrazine-6-carboxamide (Example
63),
[0278]
2-(3-chloro-4-fluorobenzyl)-9-hydroxy-3,4-dihydro-2H-pyrido[1,2-a]p-
yrazine-1,8-dione (Example 64),
[0279]
2-(2-chlorobenzyl)-9-hydroxy-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1-
,8-dione (Example 65),
[0280]
2-(3,5-dichlorobenzyl)-9-hydroxy-3,4-dihydro-2H-pyrido[1,2-a]pyrazi-
ne-1,8-dione (Example 66),
[0281]
6-tert-butyl-2-(3,4-dichlorobenzyl)-9-hydroxy-3,4-dihydro-2H-pyrido-
[1,2-a]pyrazine-1,8-dione (Example 67),
[0282]
2-(3,4-dichlorobenzyl)-9-hydroxy-6-(1-hydroxy-2,2-dimethylpropyl)-3-
,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,8-dione (Example 68),
[0283]
3-benzyl-9-hydroxy-2-methyl-2H-pyrido[1,2-a]pyrazine-1,8-dione
(Example 69),
[0284]
2-[3-(4-chlorophenyl)propyl]-9-hydroxy-2H-pyrido[1,2-a]pyrazine-1,8-
-dione (Example 70),
[0285]
2-[3-(2-chlorophenyl)propyl]-9-hydroxy-2H-pyrido[1,2-a]pyrazine-1,8-
-dione (Example 71),
[0286]
2-(3,4-dichlorobenzyl)-9-hydroxy-4-methyl-2H-pyrido[1,2-a]pyrazine--
1,8-dione hydrochloride (Example 72),
[0287]
2-(3-chloro-4-methoxybenzyl)-9-hydroxy-3,4-dihydro-2H-pyrido[1,2-a]-
pyrazine-1,8-dione (Example 73),
[0288]
9-hydroxy-2-methyl-3-phenethyl-2H-pyrido[1,2-a]pyrazine-1,8-dione
(Example 74),
[0289]
[2-(3,4-dichlorobenzyl)-9-hydroxy-1,8-dioxo-1,3,4,8-tetrahydro-2H-p-
yrido[1,2-a]pyrazin-6-yl]acetonitrile (Example 75),
[0290]
2-[3-(3-chlorophenyl)propyl]-9-hydroxy-2H-pyrido[1,2-a]pyrazine-1,8-
-dione (Example 76),
[0291]
9-hydroxy-2-methyl-3-(3-phenylpropyl)-2H-pyrido[1,2-a]pyrazine-1,8--
dione (Example 77),
[0292]
2-(3,4-dichlorobenzyl)-9-hydroxy-4-isopropyl-2H-pyrido[1,2-a]pyrazi-
ne-1,8-dione (Example 78),
[0293]
2-[3-(3,4-dichlorophenyl)propyl]-9-hydroxy-2H-pyrido[1,2-a]pyrazine-
-1,8-dione (Example 79),
[0294]
2-[3-(3,5-dichlorophenyl)propyl]-9-hydroxy-2H-pyrido[1,2-a]pyrazine-
-1,8-dione (Example 80),
[0295] benzyl
[2-(3,4-dichlorobenzyl)-9-hydroxy-1,8-dioxo-1,3,4,8-tetrahyd-
ro-2H-pyrido[1,2-a]pyrazin-6-yl]acetate (Example 81),
[0296] benzyl
2-[2-(3,4-dichlorobenzyl)-9-hydroxy-1,8-dioxo-1,3,4,8-tetrah-
ydro-2H-pyrido[1,2-a]pyrazin-6-yl]-3-phenylpropionate (Example
82),
[0297]
2-(3,4-dichlorobenzyl)-9-hydroxy-6-(2-hydroxyethyl)-3,4-dihydro-2H--
pyrido[1,2-a]pyrazine-1,8-dione (Example 83),
[0298]
2-(3,4-dichlorobenzyl)-9-hydroxy-4-propyl-2H-pyrido[1,2-a]pyrazine--
1,8-dione (Example 84),
[0299]
2-(3,4-dichlorobenzyl)-4-ethyl-9-hydroxy-2H-pyrido[1,2-a]pyrazine-1-
,8-dione (Example 85),
[0300]
2-(3,4-dichlorobenzyl)-9-hydroxy-4-hydroxymethyl-2H-pyrido[1,2-a]py-
razine-1,8-dione (Example 86),
[0301]
2-(3,4-dichlorobenzyl)-9-hydroxy-4-isobutyl-2H-pyrido[1,2-a]pyrazin-
e-1,8-dione (Example 87),
[0302]
2-(3-chlorobenzyl)-9-hydroxy-2H-pyrido[1,2-a]pyrazine-1,8-dione
hydrochloride (Example 88),
[0303] methyl
2-(3,4-dichlorobenzyl)-9-hydroxy-1,8-dioxo-1,8-dihydro-2H-py-
rido[1,2-a]pyrazine-4-carboxylate (Example 89),
[0304]
2-(3-chloro-4-fluorobenzyl)-9-hydroxy-2H-pyrido[1,2-a]pyrazine-1,8--
dione hydrochloride (Example 90),
[0305]
2-[3-(2,3-dichlorophenyl)propyl]-9-hydroxy-2H-pyrido[1,2-a]pyrazine-
-1,8-dione hydrochloride (Example 91),
[0306]
2-(3-chloro-4-fluorobenzyl)-9-hydroxy-4-isopropyl-2H-pyrido[1,2-a]p-
yrazine-1,8-dione hydrochloride (Example 92),
[0307] methyl
2-(3-chlorobenzyl)-9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido-
[1,2-a]pyrazine-4-carboxylate (Example 93),
[0308]
7-bromo-2-(3-chlorobenzyl)-9-hydroxy-2H-pyrido[1,2-a]pyrazine-1,8-d-
ione hydrochloride (Example 94),
[0309]
2-[3-(2-chloro-6-fluorophenyl)propyl]-9-hydroxy-2H-pyrido[1,2-a]pyr-
azine-1,8-dione hydrochloride (Example 95),
[0310]
2-(3-chlorobenzyl)-9-hydroxy-7-phenyl-2H-pyrido[1,2-a]pyrazine-1,8--
dione hydrochloride (Example 96),
[0311]
N,N-dimethyl-2-(3-chlorobenzyl)-9-hydroxy-1,8-dioxo-1,8-dihydro-2H--
pyrido[1,2-a]pyrazine-4-carboxamide (Example 97),
[0312]
2-(3-chlorobenzyl)-9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido[1,2-a]-
pyrazine-4-carboxylic acid (Example 98),
[0313]
3-(3-chlorobenzyl)-5-hydroxy-3H-pyrazino[1,2-a]quinoline-4,6-dione
hydrochloride (Example 99),
[0314]
2-(3-chlorobenzyl)-9-hydroxy-2H-pyrazino[1,2-c]pyrimidine-1,8-dione
hydrochloride (Example 100),
[0315]
2-(3-chlorobenzyl)-9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido[1,2-a]-
pyrazine-4-carbaldehyde (Example 101),
[0316]
2-(3-chlorobenzyl)-9-hydroxy-4-hydroxymethyl-2H-pyrido[1,2-a]pyrazi-
ne-1,8-dione (Example 102),
[0317]
2-(3-chlorobenzyl)-9-hydroxy-4-(1-hydroxyethyl)-2H-pyrido[1,2-a]pyr-
azine-1,8-dione (Example 103),
[0318]
2-(3-chlorobenzyl)-9-hydroxy-7-isopropyl-2H-pyrido[1,2-a]pyrazine-1-
,8-dione hydrochloride (Example 104),
[0319]
4-acetyl-2-(3-chlorobenzyl)-9-hydroxy-2H-pyrido[1,2-a]pyrazine-1,8--
dione (Example 105),
[0320]
2-(3-chlorobenzyl)-8-hydroxy-6-methyl-2,3,4,6-tetrahydro-2,6-naphth-
yridine-1,7-dione (Example 106),
[0321]
2-(3-chlorobenzyl)-9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido[1,2-a]-
pyrazine-4-carbonitrile (Example 107),
[0322]
2-(3-chlorobenzyl)-9-hydroxy-3,4-dihydro-2H-pyrazino[1,2-c]pyrimidi-
ne-1,8-dione (Example 108),
[0323]
7-bromo-2-(3-chlorobenzyl)-1,8-dioxo-1,8-dihydro-2H-pyrido[1,2-a]py-
razin-9-yl methanesulfonate (Example 109),
[0324]
7-bromo-2-(3-chlorobenzyl)-3,9-dihydroxy-3,4-dihydro-2H-pyrido[1,2--
a]pyrazine-1,8-dione hydrochloride (Example 110),
[0325]
3-(3-chlorobenzyl)-5-hydroxy-2,3-dihydro-1H-pyrazino[1,2-a]quinolin-
e-4,6-dione (Example 111),
[0326]
2-(3-chlorobenzyl)-7-(3-chlorophenyl)-9-hydroxy-2H-pyrido[1,2-a]pyr-
azine-1,8-dione hydrochloride (Example 112),
[0327]
2-(3-chlorobenzyl)-7-(4-chlorophenyl)-9-hydroxy-2H-pyrido[1,2-a]pyr-
azine-1,8-dione hydrochloride (Example 113),
[0328]
2-(3-chlorobenzyl)-7-(2-chlorophenyl)-9-hydroxy-2H-pyrido[1,2-a]pyr-
azine-1,8-dione hydrochloride (Example 114),
[0329]
2-(3-chlorobenzyl)-9-hydroxy-7-(pyridin-3-yl)-2H-pyrido[1,2-a]pyraz-
ine-1,8-dione hydrochloride (Example 115),
[0330]
2-(3-chlorobenzyl)-9-hydroxy-7-(pyridin-4-yl)-2H-pyrido[1,2-a]pyraz-
ine-1,8-dione hydrochloride (Example 116),
[0331]
2-(3-chlorobenzyl)-9-hydroxy-7-(pyridin-2-yl)-2H-pyrido[1,2-a]pyraz-
ine-1,8-dione hydrochloride (Example 117),
[0332]
2-(3-chlorobenzyl)-9-hydroxy-7-(1-hydroxy-2,2-dimethylpropyl)-2H-py-
rido[1,2-a]pyrazine-1,8-dione hydrochloride (Example 118),
[0333]
2-(3-chlorobenzyl)-4-cyclohexylmethyl-9-hydroxy-7-phenyl-2H-pyrido[-
1,2-a]pyrazine-1,8-dione hydrochloride (Example 119),
[0334]
2-(3-chlorobenzyl)-7-(furan-2-yl)-9-hydroxy-2H-pyrido[1,2-a]pyrazin-
e-1,8-dione hydrochloride (Example 120),
[0335]
2-(3,4-dichlorobenzyl)-8-hydroxy-6-methyl-2,3,4,6-tetrahydro-2,6-na-
phthyridine-1,7-dione (Example 121),
[0336]
2-[3-(2-chloro-6-fluorophenyl)propyl]-8-hydroxy-6-methyl-2,3,4,6-te-
trahydro-2,6-naphthyridine-1,7-dione (Example 122),
[0337]
6-(3-chlorobenzyl)-4-hydroxy-2-methyl-2,6,7,8-tetrahydropyrido[4,3--
c]pyridazine-3,5-dione (Example 123),
[0338]
7-(benzofuran-2-yl)-2-(3-chlorobenzyl)-9-hydroxy-2H-pyrido[1,2-a]py-
razine-1,8-dione hydrochloride (Example 124),
[0339]
2-(3-chlorobenzyl)-7-(2,2-dimethylpropionyl)-9-hydroxy-2H-pyrido[1,-
2-a]pyrazine-1,8-dione hydrochloride (Example 125),
[0340]
2-(3-chlorobenzyl)-7-(2,2-dimethylpropyl)-9-hydroxy-2H-pyrido[1,2-a-
]pyrazine-1,8-dione hydrochloride (Example 126),
[0341]
2-(3-chlorobenzyl)-9-hydroxy-7-(2-trifluoromethylphenyl)-2H-pyrido[-
1,2-a]pyrazine-1,8-dione hydrochloride (Example 127),
[0342]
2-(3-chlorobenzyl)-9-hydroxy-7-(3-methoxyphenyl)-2H-pyrido[1,2-a]py-
razine-1,8-dione hydrochloride (Example 128),
[0343]
7-bromo-2-(3-chlorobenzyl)-9-hydroxy-4-isopropyl-2H-pyrido[1,2-a]py-
razine-1,8-dione hydrochloride (Example 129),
[0344]
2-(3-chlorobenzyl)-7-(2-fluorophenyl)-9-hydroxy-2H-pyrido[1,2-a]pyr-
azine-1,8-dione hydrochloride (Example 130),
[0345]
2-(3-chlorobenzyl)-9-hydroxy-4-isopropyl-7-phenyl-2H-pyrido[1,2-a]p-
yrazine-1,8-dione hydrochloride (Example 131),
[0346]
2-(3-chlorobenzyl)-9-hydroxy-7-(2-methoxyphenyl)-2H-pyrido[1,2-a]py-
razine-1,8-dione hydrochloride (Example 132),
[0347]
2-(3-chlorobenzyl)-9-hydroxy-7-(4-methoxyphenyl)-2H-pyrido[1,2-a]py-
razine-1,8-dione hydrochloride (Example 133),
[0348]
2-(3-chlorobenzyl)-7-ethyl-9-hydroxy-2H-pyrido[1,2-a]pyrazine-1,8-d-
ione hydrochloride (Example 134),
[0349]
2-(3-chlorobenzyl)-7-(2,6-dimethylphenyl)-9-hydroxy-2H-pyrido[1,2-a-
]pyrazine-1,8-dione hydrochloride (Example 135),
[0350]
2-(3-chlorobenzyl)-9-hydroxy-7-(3-hydroxyphenyl)-2H-pyrido[1,2-a]py-
razine-1,8-dione (Example 136),
[0351]
7-benzoyl-2-(3-chlorobenzyl)-9-hydroxy-2H-pyrido[1,2-a]pyrazine-1,8-
-dione hydrochloride (Example 137),
[0352]
2-(3-chlorobenzyl)-7-(2-ethylphenyl)-9-hydroxy-2H-pyrido[1,2-a]pyra-
zine-1,8-dione hydrochloride (Example 138),
[0353]
2-(3-chlorobenzyl)-7-(3-chlorophenyl)-9-hydroxy-4-isopropyl-2H-pyri-
do[1,2-a]pyrazine-1,8-dione (Example 139),
[0354]
7-benzyl-2-(3-chlorobenzyl)-9-hydroxy-2H-pyrido[1,2-a]pyrazine-1,8--
dione hydrochloride (Example 140),
[0355]
2-(3-chlorobenzyl)-9-hydroxy-7-(2-hydroxyphenyl)-2H-pyrido[1,2-a]py-
razine-1,8-dione (Example 141),
[0356]
2-(3-chlorobenzyl)-9-hydroxy-7-(4-hydroxyphenyl)-2H-pyrido[1,2-a]py-
razine-1,8-dione (Example 142),
[0357]
8-hydroxy-6-methyl-2-(3-trifluoromethylbenzyl)-2,3,4,6-tetrahydro-2-
,6-naphthyridine-1,7-dione (Example 143),
[0358]
8-hydroxy-2-(3-methoxybenzyl)-6-methyl-2,3,4,6-tetrahydro-2,6-napht-
hyridine-1,7-dione (Example 144),
[0359]
6-(3-chlorobenzyl)-4-hydroxy-2-methyl-2,6-dihydropyrido[4,3-c]pyrid-
azine-3,5-dione (Example 145),
[0360]
3-(3-chlorobenzyl)-5-hydroxy-3H-pyrido[2,1-f][1,2,4]triazine-4,6-di-
one (Example 146),
[0361] methyl
2-(3-chlorobenzyl)-9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido-
[1,2-a]pyrazine-7-carboxylate hydrochloride (Example 147),
[0362]
2-(3-chlorobenzyl)-9-hydroxy-7-(1-methyl-1H-imidazol-2-yl)-2H-pyrid-
o[1,2-a]pyrazine-1,8-dione hydrochloride (Example 148),
[0363]
2-(3-chlorobenzyl)-9-hydroxy-7-isobutyryl-2H-pyrido[1,2-a]pyrazine--
1,8-dione hydrochloride (Example 149),
[0364] isopropyl
2-(3-chlorobenzyl)-9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyr-
ido[1,2-a]pyrazine-7-carboxylate (Example 150),
[0365]
2-(4-chlorobenzyl)-9-hydroxy-2H-pyrido[1,2-a]pyrazine-1,8-dione
hydrochloride (Example 151),
[0366]
2-(3-chlorobenzyl)-9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido[1,2-a]-
pyrazine-7-carboxylic acid hydrochloride (Example 152),
[0367]
N,N-dimethyl-2-(3-chlorobenzyl)-9-hydroxy-1,8-dioxo-1,8-dihydro-2H--
pyrido[1,2-a]pyrazine-7-carboxamide (Example 153),
[0368]
2-(3-chlorobenzyl)-9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido[1,2-a]-
pyrazine-7-carboxylic acid isopropylamide (Example 154),
[0369]
N-methyl-2-(3-chlorobenzyl)-9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyri-
do[1,2-a]pyrazine-7-carboxamide (Example 155),
[0370]
N,N-diethyl-2-(3-chlorobenzyl)-9-hydroxy-1,8-dioxo-1,8-dihydro-2H-p-
yrido[1,2-a]pyrazine-7-carboxamide (Example 156),
[0371]
2-(4-bromobenzyl)-9-hydroxy-2H-pyrido[1,2-a]pyrazine-1,8-dione
hydrochloride (Example 157),
[0372]
2-(3-bromobenzyl)-9-hydroxy-2H-pyrido[1,2-a]pyrazine-1,8-dione
hydrochloride (Example 158),
[0373] 2,2-dimethylpropyl
2-(3-chlorobenzyl)-9-hydroxy-1,8-dioxo-1,8-dihyd-
ro-2H-pyrido[1,2-a]pyrazine-7-carboxylate (Example 159),
[0374] cyclohexyl
2-(3-chlorobenzyl)-9-hydroxy-1,8-dioxo-1,8-dihydro-2H-py-
rido[1,2-a]pyrazine-7-carboxylate (Example 160),
[0375]
7-amino-2-(3-chlorobenzyl)-9-hydroxy-2H-pyrido[1,2-a]pyrazine-1,8-d-
ione hydrochloride (Example 161),
[0376]
2-(3-chlorobenzyl)-9-hydroxy-4-methyl-2H-pyrido[1,2-d][1,2,4]triazi-
ne-1,8-dione hydrochloride (Example 162),
[0377]
2-(3-chlorobenzyl)-9-hydroxy-7-(thiazol-2-yl)-2H-pyrido[1,2-a]pyraz-
ine-1,8-dione hydrochloride (Example 163),
[0378]
2-(3-chlorobenzyl)-9-hydroxy-7-(4H-1,2,4-triazol-3-yl)-2H-pyrido[1,-
2-a]pyrazine-1,8-dione hydrochloride (Example 164),
[0379]
N-[2-(3-chlorobenzyl)-9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido[1,2-
-a]pyrazin-7-yl]acetamide (Example 165),
[0380]
2-(4-chloro-2-methoxybenzyl)-9-hydroxy-2H-pyrido[1,2-a]pyrazine-1,8-
-dione hydrochloride (Example 166),
[0381]
2-(3-chlorobenzyl)-9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido[1,2-a]-
pyrazine-7-carboxamide (Example 167),
[0382]
2-(3-chloro-2-methoxybenzyl)-9-hydroxy-2H-pyrido[1,2-a]pyrazine-1,8-
-dione hydrochloride (Example 168),
[0383]
2-[2-(2-chlorophenoxy)ethyl]-9-hydroxy-2H-pyrido[1,2-a]pyrazine-1,8-
-dione hydrochloride (Example 169),
[0384]
2-(3-chlorobenzyl)-9-hydroxy-7-(pyrimidin-2-yl)-2H-pyrido[1,2-a]pyr-
azine-1,8-dione hydrochloride (Example 170),
[0385]
N-propyl-2-(3-chlorobenzyl)-9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyri-
do[1,2-a]pyrazine-7-carboxamide (Example 171),
[0386]
N-butyl-2-(3-chlorobenzyl)-9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrid-
o[1,2-a]pyrazine-7-carboxamide (Example 172),
[0387]
N-isobutyl-2-(3-chlorobenzyl)-9-hydroxy-1,8-dioxo-1,8-dihydro-2H-py-
rido[1,2-a]pyrazine-7-carboxamide (Example 173),
[0388] methyl
{[2-(3-chlorobenzyl)-9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyri-
do[1,2-a]pyrazine-7-carbonyl]amino}acetate (Example 174),
[0389]
N-ethyl-2-(3-chlorobenzyl)-9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrid-
o[1,2-a]pyrazine-7-carboxamide (Example 175),
[0390]
N-(2-methoxyethyl)-2-(3-chlorobenzyl)-9-hydroxy-1,8-dioxo-1,8-dihyd-
ro-2H-pyrido[1,2-a]pyrazine-7-carboxamide (Example 176),
[0391]
2-{[2-(3-chlorobenzyl)-9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido[1,-
2-a]pyrazine-7-carbonyl]amino}ethyl trifluoroacetate (Example
177),
[0392]
N-(2-hydroxyethyl)-2-(3-chlorobenzyl)-9-hydroxy-1,8-dioxo-1,8-dihyd-
ro-2H-pyrido[1,2-a]pyrazine-7-carboxamide (Example 178),
[0393]
2-(3-chloro-2-hydroxybenzyl)-9-hydroxy-2H-pyrido[1,2-a]pyrazine-1,8-
-dione hydrochloride (Example 179),
[0394]
N-benzyl-2-(3-chlorobenzyl)-9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyri-
do[1,2-a]pyrazine-7-carboxamide (Example 180),
[0395]
N-(2,2,2-trifluoroethyl)-2-(3-chlorobenzyl)-9-hydroxy-1,8-dioxo-1,8-
-dihydro-2H-pyrido[1,2-a]pyrazine-7-carboxamide (Example 181),
[0396]
N-butyl-N-methyl-2-(3-chlorobenzyl)-9-hydroxy-1,8-dioxo-1,8-dihydro-
-2H-pyrido[1,2-a]pyrazine-7-carboxamide (Example 182),
[0397]
N-(2-methoxyethyl)-N-methyl-2-(3-chlorobenzyl)-9-hydroxy-1,8-dioxo--
1,8-dihydro-2H-pyrido[1,2-a]pyrazine-7-carboxamide (Example
183),
[0398]
2-(3-chlorobenzyl)-9-hydroxy-7-(pyrrolidine-1-carbonyl)-2H-pyrido[1-
,2-a]pyrazine-1,8-dione (Example 184),
[0399]
2-(3-chlorobenzyl)-9-hydroxy-7-(morpholine-4-carbonyl)-2H-pyrido[1,-
2-a]pyrazine-1,8-dione (Example 185),
[0400]
2-(4-chloro-3-methoxybenzyl)-9-hydroxy-2H-pyrido[1,2-a]pyrazine-1,8-
-dione hydrochloride (Example 186),
[0401] methyl
[2-(3-chlorobenzyl)-9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrid-
o[1,2-a]pyrazin-7-yl]acetate (Example 187),
[0402]
2-(3-chlorobenzyl)-9-hydroxy-7-(1H-tetrazol-5-yl)-2H-pyrido[1,2-a]p-
yrazine-1,8-dione hydrochloride (Example 188),
[0403]
2-[2-(3-chlorobenzyl)-9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido[1,2-
-a]pyrazin-7-yl]-N-methylacetamide (Example 189),
[0404]
2-[2-(3-chlorobenzyl)-9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido[1,2-
-a]pyrazin-7-yl]-N,N-dimethylacetamide (Example 190),
[0405]
[2-(3-chlorobenzyl)-9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido[1,2-a-
]pyrazin-7-yl]acetic acid (Example 191),
[0406]
N-(2-hydroxypropyl)-2-(3-chlorobenzyl)-9-hydroxy-1,8-dioxo-1,8-dihy-
dro-2H-pyrido[1,2-a]pyrazine-7-carboxamide hydrochloride (Example
192),
[0407]
{[2-(3-chlorobenzyl)-9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido[1,2--
a]pyrazine-7-carbonyl]amino}acetic acid (Example 193),
[0408]
N-dimethylcarbamoylmethyl-2-(3-chlorobenzyl)-9-hydroxy-1,8-dioxo-1,-
8-dihydro-2H-pyrido[1,2-a]pyrazine-7-carboxamide (Example 194),
[0409]
N-methylcarbamoylmethyl-2-(3-chlorobenzyl)-9-hydroxy-1,8-dioxo-1,8--
dihydro-2H-pyrido[1,2-a]pyrazine-7-carboxamide (Example 195),
[0410]
N-phenyl-2-(3-chlorobenzyl)-9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyri-
do[1,2-a]pyrazine-7-carboxamide hydrochloride (Example 196),
[0411]
2-(3-chlorobenzyl)-9-hydroxy-7-(oxazol-2-yl)-2H-pyrido[1,2-a]pyrazi-
ne-1,8-dione hydrochloride (Example 197),
[0412]
2-(3-chlorobenzyl)-9-hydroxy-7-(3-hydroxypyrrolidine-1-carbonyl)-2H-
-pyrido[1,2-a]pyrazine-1,8-dione hydrochloride (Example 198),
[0413]
N-(2-oxopropyl)-2-(3-chlorobenzyl)-9-hydroxy-1,8-dioxo-1,8-dihydro--
2H-pyrido[1,2-a]pyrazine-7-carboxamide (Example 199),
[0414]
2-(9-hydroxy-1,8-dioxo-1,8-dihydro-pyrido[1,2-a]pyrazin-2-yl)-N-phe-
nylacetamide hydrochloride (Example 200),
[0415]
2-(3-chlorobenzyl)-9-hydroxy-7-(3-oxopyrrolidine-1-carbonyl)-2H-pyr-
ido[1,2-a]pyrazine-1,8-dione (Example 201),
[0416]
2-(5-chloro-2-methoxybenzyl)-9-hydroxy-2H-pyrido[1,2-a]pyrazine-1,8-
-dione hydrochloride (Example 202),
[0417]
N-[2-(3-chlorobenzyl)-9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido[1,2-
-a]pyrazin-7-yl]methanesulfonamide (Example 203),
[0418]
7-acetyl-2-(3-chlorobenzyl)-9-hydroxy-2H-pyrido[1,2-a]pyrazine-1,8--
dione hydrochloride (Example 204),
[0419]
2-(3-chlorobenzyl)-9-hydroxy-7-propionyl-2H-pyrido[1,2-a]pyrazine-1-
,8-dione hydrochloride (Example 205),
[0420]
9-hydroxy-2-(3-phenylallyl)-2H-pyrido[1,2-a]pyrazine-1,8-dione
(Example 206),
[0421]
N-methyl-2-(3-chloro-4-fluorobenzyl)-9-hydroxy-1,8-dioxo-1,8-dihydr-
o-2H-pyrido[1,2-a]pyrazine-7-carboxamide (Example 207),
[0422]
N,N-dimethyl-2-(3-chloro-4-fluorobenzyl)-9-hydroxy-1,8-dioxo-1,8-di-
hydro-2H-pyrido[1,2-a]pyrazine-7-carboxamide (Example 208),
[0423]
N-(2-methanesulfonylethyl)-2-(3-chlorobenzyl)-9-hydroxy-1,8-dioxo-1-
,8-dihydro-2H-pyrido[1,2-a]pyrazine-7-carboxamide (Example
209),
[0424]
N-[2-(2-oxopyrrolidin-1-yl)ethyl]-2-(3-chlorobenzyl)-9-hydroxy-1,8--
dioxo-1,8-dihydro-2H-pyrido[1,2-a]pyrazine-7-carboxamide (Example
210),
[0425]
N-[2-(3-chlorobenzyl)-9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido[1,2-
-a]pyrazin-7-yl]-N-methylmethanesulfonamide (Example 211),
[0426]
2-(3-chloro-5-methoxybenzyl)-9-hydroxy-2H-pyrido[1,2-a]pyrazine-1,8-
-dione hydrochloride (Example 212),
[0427]
N-(pyridin-4-ylmethyl)-2-(3-chlorobenzyl)-9-hydroxy-1,8-dioxo-1,8-d-
ihydro-2H-pyrido[1,2-a]pyrazine-7-carboxamide (Example 213),
[0428]
N-(4-fluorobenzyl)-2-(3-chlorobenzyl)-9-hydroxy-1,8-dioxo-1,8-dihyd-
ro-2H-pyrido[1,2-a]pyrazine-7-carboxamide (Example 214),
[0429]
2-(3-chlorobenzyl)-9-hydroxy-7-(thiazol-2-yl)-3,4-dihydro-2H-pyrido-
[1,2-a]pyrazine-1,8-dione (Example 215),
[0430]
2-(3-chlorobenzyl)-9-hydroxy-7-hydroxymethyl-2H-pyrido[1,2-a]pyrazi-
ne-1,8-dione hydrochloride (Example 216),
[0431]
2-(3-chloro-4-fluorobenzyl)-7-(2,2-dimethylpropionyl)-9-hydroxy-2H--
pyrido[1,2-a]pyrazine-1,8-dione hydrochloride (Example 217),
[0432]
2-(3-chlorobenzyl)-9-hydroxy-7-(thiazol-5-yl)-2H-pyrido[1,2-a]pyraz-
ine-1,8-dione hydrochloride (Example 218),
[0433]
2-(3-chlorobenzyl)-9-hydroxy-1,8-dioxo-1,3,4,8-tetrahydro-2H-pyrido-
[1,2-a]pyrazine-7-carboxylic acid methylamide (Example 219),
[0434]
N,N-dimethyl-2-(3-chlorobenzyl)-9-hydroxy-1,8-dioxo-1,3,4,8-tetrahy-
dro-2H-pyrido[1,2-a]pyrazine-7-carboxamide (Example 220),
[0435]
2-(3-chloro-4-fluorobenzyl)-7-(2,2-dimethylpropionyl)-9-hydroxy-3,4-
-dihydro-2H-pyrido[1,2-a]pyrazine-1,8-dione hydrochloride (Example
221),
[0436]
2-(3-chloro-4-fluorobenzyl)-9-hydroxy-4-hydroxymethyl-1,8-dioxo-1,8-
-dihydro-2H-pyrido[1,2-a]pyrazine-7-carboxylic acid methylamide
hydrochloride (Example 222),
[0437]
2-(3-chlorobenzyl)-7-(2,2-dimethylpropionyl)-9-hydroxy-3,4-dihydro--
2H-pyrido[1,2-a]pyrazine-1,8-dione hydrochloride (Example 223),
[0438]
2-(4-chloro-2-hydroxybenzyl)-9-hydroxy-2H-pyrido[1,2-a]pyrazine-1,8-
-dione hydrochloride (Example 224),
[0439]
2-(3-chloro-4-fluorobenzyl)-9-hydroxy-7-(thiazol-2-yl)-3,4-dihydro--
2H-pyrido[1,2-a]pyrazine-1,8-dione (Example 225),
[0440]
2-(9-hydroxy-1,8-dioxo-1,8-dihydro-pyrido[1,2-a]pyrazin-2-yl)-N-met-
hyl-N-phenylacetamide hydrochloride (Example 226),
[0441]
N-methyl-2-(3-chloro-4-fluorobenzyl)-9-hydroxy-1,8-dioxo-1,3,4,8-te-
trahydro-2H-pyrido[1,2-a]pyrazine-7-carboxamide (Example 227),
[0442]
N,N-dimethyl-2-(3-chloro-4-fluorobenzyl)-9-hydroxy-1,8-dioxo-1,3,4,-
8-tetrahydro-2H-pyrido[1,2-a]pyrazine-7-carboxamide (Example
228),
[0443]
3-[2-(3-chlorobenzyl)-9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido[1,2-
-a]pyrazin-7-yl]-2,2-dimethyl-3-oxopropyl acetate hydrochloride
(Example 229),
[0444]
2-(3-chlorobenzyl)-9-hydroxy-7-(3-hydroxy-2,2-dimethylpropionyl)-2H-
-pyrido[1,2-a]pyrazine-1,8-dione hydrochloride (Example 230),
[0445]
2-(3-chlorobenzyl)-9-hydroxy-7-(pyrazin-2-yl)-2H-pyrido[1,2-a]pyraz-
ine-1,8-dione hydrochloride (Example 231),
[0446]
2-(3-chlorobenzyl)-9-hydroxy-7-(2-methyl-2H-1,2,4-triazol-3-yl)-2H--
pyrido[1,2-a]pyrazine-1,8-dione hydrochloride (Example 232),
[0447]
N-(2-fluoroethyl)-2-(3-chlorobenzyl)-9-hydroxy-1,8-dioxo-1,8-dihydr-
o-2H-pyrido[1,2-a]pyrazine-7-carboxamide (Example 233),
[0448]
N-benzyl-N-methyl-2-(3-chlorobenzyl)-9-hydroxy-1,8-dioxo-1,8-dihydr-
o-2H-pyrido[1,2-a]pyrazine-7-carboxamide (Example 234),
[0449]
2-(3-chlorobenzyl)-9-hydroxy-7-phenylsulfanyl-2H-pyrido[1,2-a]pyraz-
ine-1,8-dione (Example 235),
[0450]
7-benzenesulfinyl-2-(3-chlorobenzyl)-9-hydroxy-2H-pyrido[1,2-a]pyra-
zine-1,8-dione (Example 236),
[0451]
7-benzenesulfonyl-2-(3-chlorobenzyl)-9-hydroxy-2H-pyrido[1,2-a]pyra-
zine-1,8-dione (Example 237),
[0452]
2-(3,4-dichlorobenzyl)-7-(2,2-dimethylpropionyl)-9-hydroxy-3,4-dihy-
dro-2H-pyrido[1,2-a]pyrazine-1,8-dione (Example 238),
[0453]
N-[2-(3-chlorobenzyl)-9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido[1,2-
-a]pyrazin-7-yl]isobutyramide (Example 239),
[0454]
N-[2-(3-chloro-4-fluorobenzyl)-9-hydroxy-1,8-dioxo-1,8-dihydro-2H-p-
yrido[1,2-a]pyrazin-7-yl]acetamide (Example 240),
[0455]
2-(3-chloro-4-fluorobenzyl)-7-(2,2-dimethylpropionyl)-9-hydroxy-4-h-
ydroxymethyl-2H-pyrido[1,2-a]pyrazine-1,8-dione hydrochloride
(Example 241),
[0456]
N-[2-(3-chlorobenzyl)-9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido[1,2-
-a]pyrazin-7-yl]propionamide (Example 242),
[0457]
N-[2-(3-chlorobenzyl)-9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido[1,2-
-a]pyrazin-7-yl]-2-phenylacetamide (Example 243),
[0458]
7-acetyl-2-(3-chloro-4-fluorobenzyl)-9-hydroxy-2H-pyrido[1,2-a]pyra-
zine-1,8-dione hydrochloride (Example 244),
[0459]
2-(3-chlorobenzyl)-9-hydroxy-7-methylsulfanyl-2H-pyrido[1,2-a]pyraz-
ine-1,8-dione (Example 245),
[0460]
2-(3-chlorobenzyl)-9-hydroxy-7-methanesulfonyl-2H-pyrido[1,2-a]pyra-
zine-1,8-dione (Example 246),
[0461]
2-(3-chlorobenzyl)-9-hydroxy-7-methanesulfinyl-2H-pyrido[1,2-a]pyra-
zine-1,8-dione (Example 247),
[0462]
2-(3-chlorobenzyl)-9-hydroxy-7-(5-methylthiazol-2-yl)-3,4-dihydro-2-
H-pyrido[1,2-a]pyrazine-1,8-dione (Example 248),
[0463]
2-(3,4-dichlorobenzyl)-9-hydroxy-7-(thiazol-2-yl)-3,4-dihydro-2H-py-
rido[1,2-a]pyrazine-1,8-dione (Example 249),
[0464]
2-(4-fluorobenzyl)-9-hydroxy-2H-pyrido[1,2-a]pyrazine-1,8-dione
hydrochloride (Example 250),
[0465]
7-(2,2-dimethylpropionyl)-2-(4-fluorobenzyl)-9-hydroxy-2H-pyrido[1,-
2-a]pyrazine-1,8-dione hydrochloride (Example 251),
[0466]
2-(4-fluorobenzyl)-9-hydroxy-7-(thiazol-2-yl)-2H-pyrido[1,2-a]pyraz-
ine-1,8-dione hydrochloride (Example 252),
[0467]
N-methyl-2-(4-fluorobenzyl)-9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyri-
do[1,2-a]pyrazine-7-carboxamide (Example 253),
[0468]
2-[3-(2-chloro-6-fluorophenyl)propyl]-7-(2,2-dimethylpropionyl)-9-h-
ydroxy-2H-pyrido[1,2-a]pyrazine-1,8-dione hydrochloride (Example
254),
[0469]
2-(3-chlorobenzyl)-9-hydroxy-7-(4-methylthiazol-2-yl)-3,4-dihydro-2-
H-pyrido[1,2-a]pyrazine-1,8-dione (Example 255),
[0470]
N-[2-(3-chlorobenzyl)-9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido[1,2-
-a]pyrazin-7-yl]butyramide (Example 256),
[0471]
N-[2-(3-chlorobenzyl)-9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido[1,2-
-a]pyrazin-7-yl]benzamide (Example 257),
[0472]
N-[2-(3-chlorobenzyl)-9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido[1,2-
-a]pyrazin-7-yl]-3-phenylpropionamide (Example 258),
[0473]
N-[2-(3-chlorobenzyl)-9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido[1,2-
-a]pyrazin-7-yl]-N-methylacetamide (Example 259),
[0474]
N-[2-(3-chlorobenzyl)-9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido[1,2-
-a]pyrazin-7-yl]-2-methoxyacetamide (Example 260),
[0475] methyl
2-(3-chlorobenzyl)-9-hydroxy-1,8-dioxo-1,3,4,8-tetrahydro-2H-
-pyrido[1,2-a]pyrazine-7-carboxylate (Example 261),
[0476]
3-[2-(3-chlorobenzyl)-9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido[1,2-
-a]pyrazin-7-yl]-1,1-dimethylurea (Example 262),
[0477] methyl
[2-(3-chlorobenzyl)-9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrid-
o[1,2-a]pyrazin-7-yl]carbamate (Example 263),
[0478]
2-[3-(2-chloro-6-fluorophenyl)propyl]-9-hydroxy-7-(thiazol-2-yl)-3,-
4-dihydro-2H-pyrido[1,2-a]pyrazine-1,8-dione (Example 264),
[0479]
N-[2-(3-chlorobenzyl)-9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido[1,2-
-a]pyrazin-7-yl]-2-oxopropionamide (Example 265),
[0480]
N-benzyl-2-(3-chlorobenzyl)-9-hydroxy-1,8-dioxo-1,3,4,8-tetrahydro--
2H-pyrido[1,2-a]pyrazine-7-carboxamide (Example 266),
[0481]
2-(3-chlorobenzyl)-9-hydroxy-7-(1H-pyrazol-3-yl)-3,4-dihydro-2H-pyr-
ido[1,2-a]pyrazine-1,8-dione (Example 267),
[0482]
2-(3-chlorobenzyl)-9-hydroxy-7-(pyrimidin-4-yl)-3,4-dihydro-2H-pyri-
do[1,2-a]pyrazine-1,8-dione (Example 268),
[0483]
N-(naphthalen-1-ylmethyl)-2-(3-chlorobenzyl)-9-hydroxy-1,8-dioxo-1,-
3,4,8-tetrahydro-2H-pyrido[1,2-a]pyrazine-7-carboxamide (Example
269),
[0484]
N-benzhydryl-2-(3-chlorobenzyl)-9-hydroxy-1,8-dioxo-1,3,4,8-tetrahy-
dro-2H-pyrido[1,2-a]pyrazine-7-carboxamide (Example 270),
[0485]
2-(3-chlorobenzyl)-9-hydroxy-7-(pyrimidin-2-yl)-3,4-dihydro-2H-pyri-
do[1,2-a]pyrazine-1,8-dione hydrochloride (Example 271),
[0486]
2-(3-chlorobenzyl)-9-hydroxy-7-(2-methyl-2-phenylpropionyl)-3,4-dih-
ydro-2H-pyrido[1,2-a]pyrazine-1,8-dione (Example 272),
[0487]
N-(4-tert-butylbenzyl)-2-(3-chlorobenzyl)-9-hydroxy-1,8-dioxo-1,3,4-
,8-tetrahydro-2H-pyrido[1,2-a]pyrazine-7-carboxamide (Example
273),
[0488]
N-[2-(3-chlorobenzyl)-9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido[1,2-
-a]pyrazin-7-yl]cyclopentanecarboxamide (Example 274),
[0489]
N-[2-(3-chlorobenzyl)-9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido[1,2-
-a]pyrazin-7-yl]-2-(4-fluorophenyl)acetamide (Example 275),
[0490]
N-[2-(3-chlorobenzyl)-9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido[1,2-
-a]pyrazin-7-yl]-2,2-dimethylpropionamide (Example 276),
[0491]
N-[2-(3-chlorobenzyl)-9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido[1,2-
-a]pyrazin-7-yl]-2-phenylisobutyramide (Example 277),
[0492]
N-[2-(3-chlorobenzyl)-9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido[1,2-
-a]pyrazin-7-yl]-4-fluorobenzamide (Example 278),
[0493]
N-[2-(3-chlorobenzyl)-9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido[1,2-
-a]pyrazin-7-yl]pyridine-2-carboxamide trifluoroacetate (Example
279),
[0494]
2-(3-chlorobenzyl)-9-hydroxy-7-isopropylamino-2H-pyrido[1,2-a]pyraz-
ine-1,8-dione hydrochloride (Example 280),
[0495]
2-(3-chlorobenzyl)-7-diethylamino-9-hydroxy-2H-pyrido[1,2-a]pyrazin-
e-1,8-dione hydrochloride (Example 281),
[0496]
2-(3-chlorobenzyl)-9-hydroxy-7-(pyridin-2-yl)-3,4-dihydro-2H-pyrido-
[1,2-a]pyrazine-1,8-dione hydrochloride (Example 282),
[0497]
2-(3-chlorobenzyl)-9-hydroxy-7-isobutylamino-2H-pyrido[1,2-a]pyrazi-
ne-1,8-dione hydrochloride (Example 283),
[0498]
N-[2-(3-chlorobenzyl)-9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido[1,2-
-a]pyrazin-7-yl]-2-isopropyl-3-methylbutyramide (Example 284),
[0499]
2-(3-chlorobenzyl)-7-ethylamino-9-hydroxy-2H-pyrido[1,2-a]pyrazine--
1,8-dione hydrochloride (Example 285),
[0500]
N-[2-(3-chlorobenzyl)-9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido[1,2-
-a]pyrazin-7-yl]nicotinamide trifluoroacetate (Example 286),
[0501]
N-[2-(3-chlorobenzyl)-9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido[1,2-
-a]pyrazin-7-yl]isonicotinamide trifluoroacetate (Example 287),
[0502]
N-[2-(3-chlorobenzyl)-9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido[1,2-
-a]pyrazin-7-yl]furan-2-carboxamide (Example 288),
[0503]
N-[2-(3-chlorobenzyl)-9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido[1,2-
-a]pyrazin-7-yl]thiophene-2-carboxamide (Example 289),
[0504]
2-(3-chlorobenzyl)-9-hydroxy-7-(pyridazin-3-yl)-3,4-dihydro-2H-pyri-
do[1,2-a]pyrazine-1,8-dione hydrochloride (Example 290),
[0505]
2-(3,4-difluorobenzyl)-9-hydroxy-7-(thiazol-2-yl)-3,4-dihydro-2H-py-
rido[1,2-a]pyrazine-1,8-dione (Example 291),
[0506]
2-(3-chloro-2-fluorobenzyl)-9-hydroxy-7-(thiazol-2-yl)-3,4-dihydro--
2H-pyrido[1,2-a]pyrazine-1,8-dione (Example 292),
[0507]
2-(4-chlorobenzyl)-9-hydroxy-7-(thiazol-2-yl)-3,4-dihydro-2H-pyrido-
[1,2-a]pyrazine-1,8-dione (Example 293),
[0508]
2-(4-chloro-3-fluorobenzyl)-9-hydroxy-7-(thiazol-2-yl)-3,4-dihydro--
2H-pyrido[1,2-a]pyrazine-1,8-dione (Example 294),
[0509]
2-(4-chloro-2-methoxybenzyl)-9-hydroxy-7-(thiazol-2-yl)-3,4-dihydro-
-2H-pyrido[1,2-a]pyrazine-1,8-dione (Example 295),
[0510]
N-[2-(3-chlorobenzyl)-9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido[1,2-
-a]pyrazin-7-yl]-1-methyl-1H-pyrrole-2-carboxamide (Example
296),
[0511]
2-[3-(4-chlorophenyl)propyl]-9-hydroxy-7-(thiazol-2-yl)-3,4-dihydro-
-2H-pyrido[1,2-a]pyrazine-1,8-dione hydrochloride (Example
297),
[0512]
2-[3-(2-chlorophenyl)propyl]-9-hydroxy-7-(thiazol-2-yl)-3,4-dihydro-
-2H-pyrido[1,2-a]pyrazine-1,8-dione hydrochloride (Example
298),
[0513]
2-[3-(3-chlorophenyl)propyl]-9-hydroxy-7-(thiazol-2-yl)-3,4-dihydro-
-2H-pyrido[1,2-a]pyrazine-1,8-dione hydrochloride (Example
299),
[0514]
2-(3-chlorobenzyl)-9-hydroxy-7-(3-methyl-1,2,4-thiadiazol-5-yl)-3,4-
-dihydro-2H-pyrido[1,2-a]pyrazine-1,8-dione hydrochloride (Example
300),
[0515]
5-fluoro-2-[9-hydroxy-1,8-dioxo-7-(thiazol-2-yl)-1,3,4,8-tetrahydro-
-pyrido[1,2-a]pyrazin-2-ylmethyl]-N-methylbenzamide (Example
301),
[0516]
N-[2-(3-chlorobenzyl)-9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido[1,2-
-a]pyrazin-7-yl]-N-isobutylacetamide (Example 302),
[0517]
N-[2-(4-fluorobenzyl)-9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido[1,2-
-a]pyrazin-7-yl]acetamide (Example 303),
[0518]
N-[2-(4-fluorobenzyl)-9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido[1,2-
-a]pyrazin-7-yl]benzamide (Example 304),
[0519]
N-[2-(4-fluorobenzyl)-9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido[1,2-
-a]pyrazin-7-yl]methanesulfonamide (Example 305),
[0520]
2-(4-fluorobenzyl)-9-hydroxy-7-(pyridin-2-yl)-2H-pyrido[1,2-a]pyraz-
ine-1,8-dione trifluoroacetate (Example 306),
[0521]
2-(2-fluorobenzyl)-9-hydroxy-7-(thiazol-2-yl)-3,4-dihydro-2H-pyrido-
[1,2-a]pyrazine-1,8-dione (Example 307),
[0522]
2-(3-fluorobenzyl)-9-hydroxy-7-(thiazol-2-yl)-3,4-dihydro-2H-pyrido-
[1,2-a]pyrazine-1,8-dione (Example 308),
[0523]
2-(4-fluorobenzyl)-9-hydroxy-7-(thiazol-2-yl)-3,4-dihydro-2H-pyrido-
[1,2-a]pyrazine-1,8-dione (Example 309),
[0524]
2-(2-chlorobenzyl)-9-hydroxy-7-(thiazol-2-yl)-3,4-dihydro-2H-pyrido-
[1,2-a]pyrazine-1,8-dione (Example 310),
[0525]
9-hydroxy-2-(naphthalen-2-ylmethyl)-7-(thiazol-2-yl)-3,4-dihydro-2H-
-pyrido[1,2-a]pyrazine-1,8-dione (Example 311),
[0526]
2-[3-(3-chloro-2-fluorophenyl)propyl]-9-hydroxy-7-(thiazol-2-yl)-3,-
4-dihydro-2H-pyrido[1,2-a]pyrazine-1,8-dione (Example 312),
[0527]
2-[3-(4-chloro-3-fluorophenyl)propyl]-9-hydroxy-7-(thiazol-2-yl)-3,-
4-dihydro-2H-pyrido[1,2-a]pyrazine-1,8-dione (Example 313),
[0528]
2-[3-(4-fluorophenyl)propyl]-9-hydroxy-7-(thiazol-2-yl)-3,4-dihydro-
-2H-pyrido[1,2-a]pyrazine-1,8-dione (Example 314),
[0529]
2-[3-(3-fluorophenyl)propyl]-9-hydroxy-7-(thiazol-2-yl)-3,4-dihydro-
-2H-pyrido[1,2-a]pyrazine-1,8-dione (Example 315),
[0530]
9-hydroxy-2-(3-phenylpropyl)-7-(thiazol-2-yl)-3,4-dihydro-2H-pyrido-
[1,2-a]pyrazine-1,8-dione hydrochloride (Example 316),
[0531]
2-(3-chloro-2-fluorobenzyl)-9-hydroxy-7-(pyridin-2-yl)-3,4-dihydro--
2H-pyrido[1,2-a]pyrazine-1,8-dione hydrochloride (Example 317),
[0532]
N-[2-(4-fluorobenzyl)-9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido[1,2-
-a]pyrazin-7-yl]-2-methoxyacetamide (Example 318),
[0533]
N-[2-(4-fluorobenzyl)-9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido[1,2-
-a]pyrazin-7-yl]-2-propanesulfonamide (Example 319),
[0534]
N-[2-(4-fluorobenzyl)-9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido[1,2-
-a]pyrazin-7-yl]nicotinamide trifluoroacetate (Example 320),
[0535]
N-[2-(4-fluorobenzyl)-9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido[1,2-
-a]pyrazin-7-yl]isobutyramide (Example 321),
[0536]
N-(2-methoxyethyl)-2-(4-fluorobenzyl)-9-hydroxy-1,8-dioxo-1,8-dihyd-
ro-2H-pyrido[1,2-a]pyrazine-7-carboxamide (Example 322),
[0537]
N-ethyl-2-(4-fluorobenzyl)-9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrid-
o[1,2-a]pyrazine-7-carboxamide (Example 323),
[0538]
N-{2-[3-(2-chloro-6-fluorophenyl)propyl]-9-hydroxy-1,8-dioxo-1,8-di-
hydro-2H-pyrido[1,2-a]pyrazin-7-yl}acetamide (Example 324),
[0539]
N-[2-(3-chloro-2-fluorobenzyl)-9-hydroxy-1,8-dioxo-1,8-dihydro-2H-p-
yrido[1,2-a]pyrazin-7-yl]acetamide hydrochloride (Example 325),
[0540] methyl
5-fluoro-2-[9-hydroxy-1,8-dioxo-7-(thiazol-2-yl)-1,3,4,8-tet-
rahydro-pyrido[1,2-a]pyrazin-2-ylmethyl]benzoate (Example 326),
[0541]
2-(3-chloro-4-fluorobenzyl)-9-hydroxy-7-(pyridin-2-yl)-3,4-dihydro--
2H-pyrido[1,2-a]pyrazine-1,8-dione hydrochloride (Example 327),
[0542]
2-(3-chloro-2-fluorobenzyl)-9-hydroxy-7-(pyridin-3-yl)-3,4-dihydro--
2H-pyrido[1,2-a]pyrazine-1,8-dione hydrochloride (Example 328),
[0543]
2-[3-(2-chloro-6-fluorophenyl)propyl]-9-hydroxy-7-(pyridin-2-yl)-3,-
4-dihydro-2H-pyrido[1,2-a]pyrazine-1,8-dione hydrochloride (Example
329),
[0544]
2-(benzofuran-2-ylmethyl)-9-hydroxy-7-(thiazol-2-yl)-3,4-dihydro-2H-
-pyrido[1,2-a]pyrazine-1,8-dione (Example 330),
[0545]
N-(1,2-diphenylethyl)-2-(3-chlorobenzyl)-9-hydroxy-1,8-dioxo-1,3,4,-
8-tetrahydro-2H-pyrido[1,2-a]pyrazine-7-carboxamide (Example
331),
[0546]
N-[2-(3-chloro-2-fluorobenzyl)-9-hydroxy-1,8-dioxo-1,3,4,8-tetrahyd-
ro-2H-pyrido[1,2-a]pyrazin-7-yl]acetamide (Example 332),
[0547]
2-[3-(2-fluorophenyl)propyl]-9-hydroxy-7-(thiazol-2-yl)-3,4-dihydro-
-2H-pyrido[1,2-a]pyrazine-1,8-dione (Example 333),
[0548]
N-(1,3-diphenylpropyl)-2-(3-chlorobenzyl)-9-hydroxy-1,8-dioxo-1,3,4-
,8-tetrahydro-2H-pyrido[1,2-a]pyrazine-7-carboxamide (Example
334),
[0549]
5-fluoro-2-{3-[9-hydroxy-1,8-dioxo-7-(thiazol-2-yl)-1,3,4,8-tetrahy-
dro-pyrido[1,2-a]pyrazin-2-yl]propyl}-N-methylbenzamide (Example
335),
[0550]
2-[3-(2-chloro-6-fluorophenyl)propyl]-7-(2,2-dimethylpropionyl)-9-h-
ydroxy-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,8-dione (Example
336),
[0551]
2-(3-chlorobenzyl)-9-hydroxy-7-isobutyryl-3,4-dihydro-2H-pyrido[1,2-
-a]pyrazine-1,8-dione (Example 337),
[0552]
9-hydroxy-2-(4-phenylbutyl)-7-(thiazol-2-yl)-3,4-dihydro-2H-pyrido[-
1,2-a]pyrazine-1,8-dione hydrochloride (Example 338),
[0553]
9-hydroxy-2-pentyl-7-(thiazol-2-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyr-
azine-1,8-dione hydrochloride (Example 339),
[0554]
2-(3-chloro-2-fluorobenzyl)-9-hydroxy-7-(pyridin-4-yl)-3,4-dihydro--
2H-pyrido[1,2-a]pyrazine-1,8-dione hydrochloride (Example 340),
[0555]
2-(4-fluorobenzyl)-9-hydroxy-7-(pyridin-4-yl)-2H-pyrido[1,2-a]pyraz-
ine-1,8-dione hydrochloride (Example 341),
[0556]
2-(3-chloro-2-fluorobenzyl)-9-hydroxy-7-(pyrimidin-4-yl)-2H-pyrido[-
1,2-a]pyrazine-1,8-dione trifluoroacetate (Example 342),
[0557]
2-(3-chloro-4-fluorobenzyl)-9-hydroxy-7-(2-methyl-2H-1,2,4-triazol--
3-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,8-dione (Example
343),
[0558]
7-acetyl-2-(4-fluorobenzyl)-9-hydroxy-2H-pyrido[1,2-a]pyrazine-1,8--
dione (Example 344),
[0559]
2-(4-fluorobenzyl)-9-hydroxy-7-isobutyryl-2H-pyrido[1,2-a]pyrazine--
1,8-dione hydrochloride (Example 345),
[0560]
N-[2-(3-chlorobenzyl)-9-hydroxy-1,8-dioxo-1,3,4,8-tetrahydro-2H-pyr-
ido[1,2-a]pyrazin-7-yl]isonicotinamide hydrochloride (Example
346),
[0561]
2-(4-fluorobenzyl)-9-hydroxy-7-(pyrimidin-4-yl)-2H-pyrido[1,2-a]pyr-
azine-1,8-dione (Example 347),
[0562]
2-(3-chloro-4-fluorobenzyl)-9-hydroxy-7-(pyrazin-2-yl)-3,4-dihydro--
2H-pyrido[1,2-a]pyrazine-1,8-dione (Example 348),
[0563]
N-[2-(3-chloro-4-fluorobenzyl)-9-hydroxy-1,8-dioxo-1,3,4,8-tetrahyd-
ro-2H-pyrido[1,2-a]pyrazin-7-yl]isobutyramide (Example 349),
[0564]
2-(4-chloro-2-hydroxybenzyl)-9-hydroxy-7-(thiazol-2-yl)-3,4-dihydro-
-2H-pyrido[1,2-a]pyrazine-1,8-dione hydrochloride (Example
350),
[0565]
9-hydroxy-2-(3-phenylbutyl)-7-(thiazol-2-yl)-3,4-dihydro-2H-pyrido[-
1,2-a]pyrazine-1,8-dione hydrochloride (Example 351),
[0566]
N-[2-(3-chloro-2-fluorobenzyl)-9-hydroxy-1,8-dioxo-1,3,4,8-tetrahyd-
ro-2H-pyrido[1,2-a]pyrazin-7-yl]nicotinamide hydrochloride (Example
352),
[0567]
N-[2-(3-chloro-4-fluorobenzyl)-9-hydroxy-1,8-dioxo-1,3,4,8-tetrahyd-
ro-2H-pyrido[1,2-a]pyrazin-7-yl]methanesulfonamide (Example
353),
[0568]
2-(3-chloro-4-propoxybenzyl)-9-hydroxy-7-(thiazol-2-yl)-3,4-dihydro-
-2H-pyrido[1,2-a]pyrazine-1,8-dione hydrochloride (Example
354),
[0569]
2-(3-chloro-4-isopropoxybenzyl)-9-hydroxy-7-(thiazol-2-yl)-3,4-dihy-
dro-2H-pyrido[1,2-a]pyrazine-1,8-dione hydrochloride (Example
355),
[0570]
2-(4-benzyloxy-3-chlorobenzyl)-9-hydroxy-7-(thiazol-2-yl)-3,4-dihyd-
ro-2H-pyrido[1,2-a]pyrazine-1,8-dione hydrochloride (Example
356),
[0571]
2-(4-chloro-2-propoxybenzyl)-9-hydroxy-7-(thiazol-2-yl)-3,4-dihydro-
-2H-pyrido[1,2-a]pyrazine-1,8-dione hydrochloride (Example
357),
[0572]
2-(4-chloro-2-isopropoxybenzyl)-9-hydroxy-7-(thiazol-2-yl)-3,4-dihy-
dro-2H-pyrido[1,2-a]pyrazine-1,8-dione hydrochloride (Example
358),
[0573]
2-(2-benzyloxy-4-chlorobenzyl)-9-hydroxy-7-(thiazol-2-yl)-3,4-dihyd-
ro-2H-pyrido[1,2-a]pyrazine-1,8-dione hydrochloride (Example
359),
[0574]
2-(4-fluorobenzyl)-9-hydroxy-7-(2-methyl-2H-1,2,4-triazol-3-yl)-2H--
pyrido[1,2-a]pyrazine-1,8-dione hydrochloride (Example 360),
[0575]
N-methyl-2-(3-chloro-2-fluorobenzyl)-9-hydroxy-1,8-dioxo-1,3,4,8-te-
trahydro-2H-pyrido[1,2-a]pyrazine-7-carboxamide (Example 361),
[0576]
2-(3-chlorobenzyl)-7-(2,2-dimethylbutyryl)-9-hydroxy-3,4-dihydro-2H-
-pyrido[1,2-a]pyrazine-1,8-dione (Example 362),
[0577]
2-(4-fluorobenzyl)-9-hydroxy-7-(pyridin-2-yl)-3,4-dihydro-2H-pyrido-
[1,2-a]pyrazine-1,8-dione hydrochloride (Example 363),
[0578]
2-(3-chloro-2-fluorobenzyl)-9-hydroxy-7-(pyridin-2-yl)-2H-pyrido[1,-
2-a]pyrazine-1,8-dione hydrochloride (Example 364),
[0579]
2-(3-fluorobenzyl)-9-hydroxy-7-(pyridin-2-yl)-2H-pyrido[1,2-a]pyraz-
ine-1,8-dione hydrochloride (Example 365),
[0580]
N-{5-fluoro-2-[9-hydroxy-1,8-dioxo-7-(thiazol-2-yl)-1,3,4,8-tetrahy-
dro-pyrido[1,2-a]pyrazin-2-ylmethyl]phenyl}acetamide hydrochloride
(Example 366),
[0581]
2-(3-chloro-2-fluorobenzyl)-7-(2,2-dimethylpropionyl)-9-hydroxy-3,4-
-dihydro-2H-pyrido[1,2-a]pyrazine-1,8-dione hydrochloride (Example
367),
[0582]
5-fluoro-2-[9-hydroxy-1,8-dioxo-7-(thiazol-2-yl)-1,3,4,8-tetrahydro-
-pyrido[1,2-a]pyrazin-2-ylmethyl]benzoic acid hydrochloride
(Example 368),
[0583]
2-(3,4-difluorobenzyl)-9-hydroxy-7-(pyridin-2-yl)-2H-pyrido[1,2-a]p-
yrazine-1,8-dione hydrochloride (Example 369),
[0584]
N-benzyl-N-methyl-2-(3-chlorobenzyl)-9-hydroxy-1,8-dioxo-1,3,4,8-te-
trahydro-2H-pyrido[1,2-a]pyrazine-7-carboxamide hydrochloride
(Example 370),
[0585]
N-(pyridin-3-ylmethyl)-2-(3-chlorobenzyl)-9-hydroxy-1,8-dioxo-1,3,4-
,8-tetrahydro-2H-pyrido[1,2-a]pyrazine-7-carboxamide hydrochloride
(Example 371),
[0586]
N-(pyridin-2-ylmethyl)-2-(3-chlorobenzyl)-9-hydroxy-1,8-dioxo-1,3,4-
,8-tetrahydro-2H-pyrido[1,2-a]pyrazine-7-carboxamide hydrochloride
(Example 372),
[0587]
2-(3,4-dichlorobenzyl)-9-hydroxy-7-(pyridin-2-yl)-3,4-dihydro-2H-py-
rido[1,2-a]pyrazine-1,8-dione trifluoroacetate (Example 373),
[0588]
N-(2-oxopropyl)-2-(3-chlorobenzyl)-9-hydroxy-1,8-dioxo-1,3,4,8-tetr-
ahydro-2H-pyrido[1,2-a]pyrazine-7-carboxamide hydrochloride
(Example 374),
[0589]
2-(3-fluorobenzyl)-9-hydroxy-7-(pyridin-4-yl)-2H-pyrido[1,2-a]pyraz-
ine-1,8-dione hydrochloride (Example 375),
[0590]
7-(2,2-dimethylpropionyl)-2-(3-fluorobenzyl)-9-hydroxy-2H-pyrido[1,-
2-a]pyrazine-1,8-dione hydrochloride (Example 376),
[0591]
N-(2-fluorobenzyl)-2-(4-fluorobenzyl)-9-hydroxy-1,8-dioxo-1,3,4,8-t-
etrahydro-2H-pyrido[1,2-a]pyrazine-7-carboxamide (Example 377),
[0592]
N-(4-fluorobenzyl)-2-(4-fluorobenzyl)-9-hydroxy-1,8-dioxo-1,3,4,8-t-
etrahydro-2H-pyrido[1,2-a]pyrazine-7-carboxamide (Example 378),
[0593]
N-methyl-2-(4-fluorobenzyl)-9-hydroxy-1,8-dioxo-1,3,4,8-tetrahydro--
2H-pyrido[1,2-a]pyrazine-7-carboxamide (Example 379),
[0594]
N-benzyl-2-(4-fluorobenzyl)-9-hydroxy-1,8-dioxo-1,3,4,8-tetrahydro--
2H-pyrido[1,2-a]pyrazine-7-carboxamide (Example 380),
[0595]
N-methyl-2-(4-chlorobenzyl)-9-hydroxy-1,8-dioxo-1,3,4,8-tetrahydro--
2H-pyrido[1,2-a]pyrazine-7-carboxamide (Example 381),
[0596]
7-(2,2-dimethylbutyryl)-2-(4-fluorobenzyl)-9-hydroxy-2H-pyrido[1,2--
a]pyrazine-1,8-dione hydrochloride (Example 382),
[0597]
2-(3,4-dichlorobenzyl)-9-hydroxy-7-(pyrazin-2-yl)-3,4-dihydro-2H-py-
rido[1,2-a]pyrazine-1,8-dione hydrochloride (Example 383),
[0598]
2-(3,4-dichlorobenzyl)-9-hydroxy-7-isobutyryl-3,4-dihydro-2H-pyrido-
[1,2-a]pyrazine-1,8-dione (Example 384),
[0599]
2-(4-fluorobenzyl)-9-hydroxy-7-isobutyryl-3,4-dihydro-2H-pyrido[1,2-
-a]pyrazine-1,8-dione (Example 385),
[0600]
7-(2,2-dimethylpropionyl)-2-(4-fluorobenzyl)-9-hydroxy-3,4-dihydro--
2H-pyrido[1,2-a]pyrazine-1,8-dione (Example 386),
[0601]
2-(4-fluorobenzyl)-9-hydroxy-7-(3-methylbutyryl)-2H-pyrido[1,2-a]py-
razine-1,8-dione hydrochloride (Example 387),
[0602]
N-methyl-2-(3,4-difluorobenzyl)-9-hydroxy-1,8-dioxo-1,3,4,8-tetrahy-
dro-2H-pyrido[1,2-a]pyrazine-7-carboxamide (Example 388),
[0603]
2-(4-fluorobenzyl)-9-hydroxy-7-(3-methoxy-2,2-dimethylpropionyl)-3,-
4-dihydro-2H-pyrido[1,2-a]pyrazine-1,8-dione (Example 389),
[0604]
9-benzyloxy-7-bromo-2-(3-chlorobenzyl)-3,4-dihydro-2H-pyrido[1,2-a]-
pyrazine-1,8-dione (Example 390),
[0605]
2-(3-chlorobenzyl)-9-hydroxy-7-(pyrimidin-4-yl)-2H-pyrido[1,2-a]pyr-
azine-1,8-dione hydrochloride (Example 391),
[0606]
2-(4-fluorobenzyl)-9-hydroxy-7-(pyrimidin-4-yl)-3,4-dihydro-2H-pyri-
do[1,2-a]pyrazine-1,8-dione hydrochloride (Example 392),
[0607]
2-(4-chlorobenzyl)-9-hydroxy-7-(pyrimidin-4-yl)-3,4-dihydro-2H-pyri-
do[1,2-a]pyrazine-1,8-dione hydrochloride (Example 393),
[0608]
2-(3-chloro-4-fluorobenzyl)-9-hydroxy-7-(pyrimidin-4-yl)-3,4-dihydr-
o-2H-pyrido[1,2-a]pyrazine-1,8-dione hydrochloride (Example
394),
[0609]
2-(3-chloro-4-fluorobenzyl)-9-hydroxy-7-(pyrimidin-4-yl)-2H-pyrido[-
1,2-a]pyrazine-1,8-dione hydrochloride (Example 395),
[0610]
2-(3-chloro-5-propoxybenzyl)-9-hydroxy-7-(thiazol-2-yl)-3,4-dihydro-
-2H-pyrido[1,2-a]pyrazine-1,8-dione hydrochloride (Example
396),
[0611]
2-(3-chloro-5-isopropoxybenzyl)-9-hydroxy-7-(thiazol-2-yl)-3,4-dihy-
dro-2H-pyrido[1,2-a]pyrazine-1,8-dione hydrochloride (Example
397),
[0612]
2-(3-benzyloxy-5-chlorobenzyl)-9-hydroxy-7-(thiazol-2-yl)-3,4-dihyd-
ro-2H-pyrido[1,2-a]pyrazine-1,8-dione hydrochloride (Example
398),
[0613]
2-(4-chlorobenzyl)-9-hydroxy-7-(pyrimidin-4-yl)-2H-pyrido[1,2-a]pyr-
azine-1,8-dione hydrochloride (Example 399),
[0614]
N-[2-(3-chlorobenzyl)-9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido[1,2-
-a]pyrazin-7-yl]-2-(pyridin-3-yl)acetamide hydrochloride (Example
400),
[0615]
N-[2-(3-chlorobenzyl)-9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido[1,2-
-a]pyrazin-7-yl]-2-(pyridin-4-yl)acetamide hydrochloride (Example
401),
[0616]
N-[2-(3-chlorobenzyl)-9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido[1,2-
-a]pyrazin-7-yl]-2-(pyridin-2-yl)acetamide hydrochloride (Example
402),
[0617]
2-(3-fluorobenzyl)-9-hydroxy-7-(pyrimidin-4-yl)-2H-pyrido[1,2-a]pyr-
azine-1,8-dione hydrochloride (Example 403),
[0618]
2-(3-fluorobenzyl)-9-hydroxy-7-(pyrazin-2-yl)-2H-pyrido[1,2-a]pyraz-
ine-1,8-dione hydrochloride (Example 404),
[0619]
2-(3-chloro-4-fluorobenzyl)-9-hydroxy-7-(2-methyl-2H-1,2,4-triazol--
3-yl)-2H-pyrido[1,2-a]pyrazine-1,8-dione hydrochloride (Example
405),
[0620]
N-[2-(3-chloro-4-fluorobenzyl)-9-hydroxy-1,8-dioxo-1,3,4,8-tetrahyd-
ro-2H-pyrido[1,2-a]pyrazin-7-yl]-3,3-dimethylbutyramide (Example
406),
[0621]
2-(3-fluorobenzyl)-9-hydroxy-4-methyl-7-(pyridin-2-yl)-2H-pyrido[1,-
2-a]pyrazine-1,8-dione hydrochloride (Example 407),
[0622]
7-(2,2-dimethylpropionyl)-2-(4-fluorobenzyl)-9-hydroxy-4-methyl-2H--
pyrido[1,2-a]pyrazine-1,8-dione hydrochloride (Example 408),
[0623]
7-(2,2-dimethylpropionyl)-2-(4-fluorobenzyl)-9-hydroxy-6-methoxymet-
hyl-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,8-dione hydrochloride
(Example 409),
[0624]
N-(pyridin-2-ylmethyl)-2-(4-fluorobenzyl)-9-hydroxy-1,8-dioxo-1,3,4-
,8-tetrahydro-2H-pyrido[1,2-a]pyrazine-7-carboxamide hydrochloride
(Example 410),
[0625]
N-(furan-2-ylmethyl)-2-(4-fluorobenzyl)-9-hydroxy-1,8-dioxo-1,3,4,8-
-tetrahydro-2H-pyrido[1,2-a]pyrazine-7-carboxamide hydrochloride
(Example 411),
[0626]
7-(2,2-dimethylpropionyl)-2-(4-fluorobenzyl)-9-hydroxy-4,4-dimethyl-
-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,8-dione hydrochloride
(Example 412),
[0627]
7-bromo-2-(4-fluorobenzyl)-9-hydroxy-4,4-dimethyl-3,4-dihydro-2H-py-
rido[1,2-a]pyrazine-1,8-dione hydrochloride (Example 413),
[0628]
2-(4-fluorobenzyl)-9-hydroxy-4,4-dimethyl-7-(pyridin-2-yl)-3,4-dihy-
dro-2H-pyrido[1,2-a]pyrazine-1,8-dione hydrochloride (Example
414),
[0629]
N-(4-dimethylaminobenzyl)-2-(4-fluorobenzyl)-9-hydroxy-1,8-dioxo-1,-
3,4,8-tetrahydro-2H-pyrido[1,2-a]pyrazine-7-carboxamide
hydrochloride (Example 415),
[0630]
2-(3-chlorobenzyl)-9-hydroxy-7-(pyrazin-2-yl)-3,4-dihydro-2H-pyrido-
[1,2-a]pyrazine-1,8-dione hydrochloride (Example 416),
[0631]
2-(4-fluorobenzyl)-9-hydroxy-7-(pyrazin-2-yl)-3,4-dihydro-2H-pyrido-
[1,2-a]pyrazine-1,8-dione hydrochloride (Example 417),
[0632]
N-[2-(3-chloro-4-fluorobenzyl)-9-hydroxy-1,8-dioxo-1,3,4,8-tetrahyd-
ro-2H-pyrido[1,2-a]pyrazin-7-yl]benzenesulfonamide (Example
418),
[0633]
N-[2-(3-chloro-4-fluorobenzyl)-9-hydroxy-1,8-dioxo-1,3,4,8-tetrahyd-
ro-2H-pyrido[1,2-a]pyrazin-7-yl]benzylsulfonamide (Example
419),
[0634]
N-[2-(3-chloro-4-fluorobenzyl)-9-hydroxy-1,8-dioxo-1,3,4,8-tetrahyd-
ro-2H-pyrido[1,2-a]pyrazin-7-yl]-2-thiophenesulfonamide (Example
420),
[0635]
N-(4-methanesulfonylbenzyl)-2-(4-fluorobenzyl)-9-hydroxy-1,8-dioxo--
1,3,4,8-tetrahydro-2H-pyrido[1,2-a]pyrazine-7-carboxamide
hydrochloride (Example 421),
[0636]
2-(4-fluorobenzyl)-9-hydroxy-6-(2-hydroxy-3,3-dimethylbutyl)-3,4-di-
hydro-2H-pyrido[1,2-a]pyrazine-1,8-dione hydrochloride (Example
422),
[0637]
N-[2-(3-chlorobenzyl)-9-hydroxy-4-methyl-1,8-dioxo-1,8-dihydro-2H-p-
yrido[1,2-a]pyrazin-7-yl]acetamide (Example 423),
[0638]
2-(4-fluorobenzyl)-9-hydroxy-6-methoxymethyl-7-(pyridin-2-yl)-3,4-d-
ihydro-2H-pyrido[1,2-a]pyrazine-1,8-dione hydrochloride (Example
424),
[0639]
2-(4-fluorobenzyl)-9-hydroxy-7-(3-methoxy-2,2-dimethylpropionyl)-2H-
-pyrido[1,2-a]pyrazine-1,8-dione hydrochloride (Example 425),
[0640]
N-(4-methoxypyrimidin-2-ylmethyl)-2-(4-fluorobenzyl)-9-hydroxy-1,8--
dioxo-1,3,4,8-tetrahydro-2H-pyrido[1,2-a]pyrazine-7-carboxamide
hydrochloride (Example 426),
[0641]
6-(3,3-dimethyl-2-oxobutyl)-7-(2,2-dimethylpropionyl)-2-(4-fluorobe-
nzyl)-9-hydroxy-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,8-dione
hydrochloride (Example 427),
[0642]
N-(4-acetylaminobenzyl)-2-(4-fluorobenzyl)-9-hydroxy-1,8-dioxo-1,3,-
4,8-tetrahydro-2H-pyrido[1,2-a]pyrazine-7-carboxamide (Example
428),
[0643]
2-(3,4-dichlorobenzyl)-9-hydroxy-4-(2-hydroxyethyl)-2H-pyrido[1,2-a-
]pyrazine-1,8-dione hydrochloride (Example 429),
[0644]
2-(3,4-dichlorobenzyl)-9-hydroxy-4-(1-hydroxypropyl)-2H-pyrido[1,2--
a]pyrazine-1,8-dione (Example 430),
[0645]
2-(3,4-dichlorobenzyl)-9-hydroxy-4-(3-hydroxypropyl)-2H-pyrido[1,2--
a]pyrazine-1,8-dione (Example 431),
[0646]
2-(3,4-dichlorobenzyl)-9-hydroxy-4-(1-hydroxy-2-methylpropyl)-2H-py-
rido[1,2-a]pyrazine-1,8-dione (Example 432),
[0647]
2-(3,4-dichlorobenzyl)-9-hydroxy-4-phenethyl-2H-pyrido[1,2-a]pyrazi-
ne-1,8-dione (Example 433),
[0648]
2-(4-fluorobenzyl)-9-hydroxy-2H-pyrazino[1,2-c]pyrimidine-1,8-dione
hydrochloride (Example 434),
[0649]
2-(3,4-dichlorobenzyl)-9-hydroxy-4-isopropyl-2H-pyrido[1,2-a]pyrazi-
ne-1,8-dione hydrochloride (Example 435),
[0650]
2-(3-chlorobenzyl)-9-hydroxy-4-methyl-2H-pyrido[1,2-d][1,2,4]triazi-
ne-1,8-dione (Example 436),
[0651]
2-(3-chlorobenzyl)-7-(2,2-dimethylpropionyl)-9-hydroxy-3,4-dihydro--
2H-pyrido[1,2-a]pyrazine-1,8-dione (Example 437),
[0652]
7-(2,2-dimethylpropionyl)-2-(4-fluorobenzyl)-9-hydroxy-2H-pyrido[1,-
2-a]pyrazine-1,8-dione (Example 438),
[0653]
7-(2,2-dimethylpropionyl)-2-(4-fluorobenzyl)-9-hydroxy-2H-pyrido[1,-
2-a]pyrazine-1,8-dione sodium salt (Example 439),
[0654]
N-[2-(3-chlorobenzyl)-9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido[1,2-
-a]pyrazin-7-yl]acetamide sodium salt (Example 440), and
[0655]
2-(3-chlorobenzyl)-7-(2,2-dimethylpropionyl)-9-hydroxy-3,4-dihydro--
2H-pyrido[1,2-a]pyrazine-1,8-dione sodium salt (Example 441),
[0656] or a pharmaceutically acceptable salt thereof.
[0657] [26] A pharmaceutical composition comprising a
nitrogen-containing fused ring compound of any of [1] to [25], or a
pharmaceutically acceptable salt thereof, and a pharmaceutically
acceptable carrier.
[0658] [27] An anti-HIV agent comprising a nitrogen-containing
fused ring compound of any of [1] to [25] or a pharmaceutically
acceptable salt thereof as an active ingredient.
[0659] [28] An integrase inhibitor comprising a nitrogen-containing
fused ring compound of any of [1] to [25] or a pharmaceutically
acceptable salt thereof as an active ingredient.
[0660] [29] An antivirus agent comprising a nitrogen-containing
fused ring compound of any of [1] to [25] or a pharmaceutically
acceptable salt thereof as an active ingredient.
[0661] [30] An anti-HIV composition comprising a
nitrogen-containing fused ring compound of any of [1] to [25] or a
pharmaceutically acceptable salt thereof and one or more other
kinds of anti-HIV active substances as active ingredients.
[0662] [31] An anti-HIV agent comprising a nitrogen-containing
fused ring compound of any of [1] to [25] or a pharmaceutically
acceptable salt thereof as an active ingredient, which is used for
a multiple drug therapy with other anti-HIV agents.
[0663] [32] Use of a nitrogen-containing fused ring compound of any
of [1] to [25] or a pharmaceutically acceptable salt thereof for
the production of an anti-HIV agent.
[0664] [33] Use of a nitrogen-containing fused ring compound of any
of [1] to [25] or a pharmaceutically acceptable salt thereof for
the production of an integrase inhibitor.
[0665] [34] Use of a nitrogen-containing fused ring compound of any
of [1] to [25] or a pharmaceutically acceptable salt thereof for
the production of an antivirus agent.
[0666] [35] A method for the prophylaxis or treatment of an HIV
infectious disease, which comprises administering an effective
amount of a nitrogen-containing fused ring compound of any of [1]
to [25] or a pharmaceutically acceptable salt thereof to a
mammal.
[0667] [36] The method of [35], further comprising administering an
effective amount of at least one kind of other anti-HIV active
substance to the mammal.
[0668] [37] A method of inhibiting integrase, which comprises
administering an effective amount of a nitrogen-containing fused
ring compound of any of [1] to [25] or a pharmaceutically
acceptable salt thereof to a mammal.
[0669] [38] A method for the prophylaxis or treatment of a viral
infectious disease, which comprises administering an effective
amount of a nitrogen-containing fused ring compound of any of [1]
to [25] or a pharmaceutically acceptable salt thereof to a
mammal.
[0670] The compound of the present invention can be a
pharmaceutical agent effective for the prophylaxis or treatment of
AIDS, as an anti-HIV agent having an HIV integrase inhibitory
activity. In addition, by a combined use with other anti-HIV agents
such as protease inhibitors, reverse transcriptase inhibitors and
the like, the compound can be a more effective anti-HIV agent.
Moreover, since the compound has an integrase-specific high
inhibitory activity, it can be a pharmaceutical agent safe on the
human body, which is associated with a fewer side effects.
BEST MODE FOR EMBODYING THE INVENTION
[0671] The "bond" means a direct connection and in the case of
N--Z--Ph, for example, when Z is a "bond", it means N--Ph.
[0672] The "halogen atom" is a fluorine atom, a chlorine atom, a
bromine atom or an iodine atom, and is preferably a fluorine atom,
a chlorine atom or a bromine atom.
[0673] For group A, it is more preferably a fluorine atom, for
group B, it is more preferably a fluorine atom or a chlorine atom,
and for group C, it is more preferably a bromine atom.
[0674] The "C1-6 alkyl group" is a linear or branched chain alkyl
group having 1 to 6 carbon atoms, and preferably a linear or
branched chain alkyl group having 1 to 4 carbon atoms.
Specifically, methyl group, ethyl group, propyl group, isopropyl
group, butyl group, isobutyl group, sec-butyl group, tert-butyl
group, pentyl group, isopentyl group, tert-pentyl group, hexyl
group and the like can be mentioned.
[0675] It is preferably a methyl group for R.sup.6, R.sup.b2,
R.sup.b3, R.sup.b4, R.sup.b5 or R.sup.b6, preferably a methyl
group, a propyl group or an isopropyl group for R.sup.b1, and
preferably a methyl group, an ethyl group or a tert-butyl group for
group B.
[0676] The "C1-7 alkyl group" is a linear or branched chain alkyl
group having 1 to 7 carbon atoms, and is preferably a linear or
branched chain alkyl group having 1 to 4 carbon atoms.
Specifically, methyl group, ethyl group, propyl group, isopropyl
group, butyl group, isobutyl group, sec-butyl group, tert-butyl
group, pentyl group, isopentyl group, tert-pentyl group, hexyl
group, 1-isopropyl-2-methylpropyl group and the like can be
mentioned.
[0677] The "C2-6 alkenyl group" is a linear or branched chain
alkenyl group having 2 to 6 carbon atoms. Specifically, vinyl
group, allyl group, 1-propenyl group, isopropenyl group,
2-methyl-1-propenyl group, 1-butenyl group, 2-butenyl group,
1,3-butadienyl group, 3-methyl-2-butenyl group, 4-methyl-2-pentenyl
group, 4-methyl-3-pentenyl group, 1-methyl-2-butenyl group and the
like can be mentioned.
[0678] The "C2-6 alkynyl group" is a linear or branched chain
alkynyl group having 2 to 6 carbon atoms. Specifically, ethynyl
group, 1-propynyl group, 2-propynyl group, 3-butynyl group and the
like can be mentioned.
[0679] The "C1-6 alkylene" is a linear or branched chain alkylene
having 1 to 6 carbon atoms and methylene, ethylene, trimethylene,
tetramethylene, pentamethylene, hexamethylene, propylene,
--CH(CH.sub.3)--, C(CH.sub.3).sub.2--,
--CH(CH.sub.3)--(CH.sub.2).sub.2-- and the like can be
mentioned.
[0680] Preferably, it is methylene, ethylene, trimethylene or
tetramethylene, and more preferably methylene.
[0681] The "C2-6 alkenylene" is a linear or branched chain
alkenylene having 2 to 6 carbon atoms and vinylene, propenylene,
1-butenylene, 1,3-butadienylene, --CH(CH.sub.3)--CH.dbd.CH-- and
the like can be mentioned. Preferably, it is propenylene.
[0682] The "haloC1-6 alkyl group" is the above-defined "C1-6 alkyl
group" substituted by the above-defined "halogen atom", and
preferably it is a haloalkyl group wherein its alkyl moiety is a
linear or branched chain alkyl group having 1 to 4 carbon atoms.
Specifically, fluoromethyl group, difluoromethyl group,
trifluoromethyl group, bromomethyl group, chloromethyl group,
1,2-dichloroethyl group, 2,2-dichloroethyl group,
2,2,2-trifluoroethyl group and the like can be mentioned.
Preferably, it is trifluoromethyl group.
[0683] The "C1-6 alkyloxy group" is an alkyl-oxy group wherein its
alkyl moiety is the above-defined "C1-6 alkyl group", and
preferably an alkyl-oxy group wherein its alkyl moiety is a linear
or branched chain alkyl group having 1 to 4 carbon atoms.
Specifically, methoxy group, ethoxy group, propoxy group,
isopropyloxy group, butoxy group, isobutyloxy group, tert-butyloxy
group, pentyloxy group, hexyloxy group and the like can be
mentioned.
[0684] The "C6-14 aryl group" is an aromatic hydrocarbon group
having 6 to 14 carbon atoms. Specifically, phenyl group, naphthyl
group, anthryl group, indenyl group, azulenyl group, fluorenyl
group, phenanthryl group and the like can be mentioned, with
preference given to phenyl group.
[0685] The "C6-14 aryloxy group" is an aryl-oxy group wherein its
aryl moiety is the above-defined "C6-14 aryl group". Specifically,
phenoxy group, naphthyloxy group, anthryloxy group, indenyloxy
group, azulenyloxy group, fluorenyloxy group, phenanthryloxy group
and the like can be mentioned, with preference given to phenoxy
group.
[0686] The "C6-14 aryl C1-6 alkyl group" is an aryl-alkyl group
wherein its alkyl moiety is the above-defined "C1-6 alkyl group"
and its aryl moiety is the above-defined "C6-14 aryl group".
Preferably, it is an aryl-alkyl group wherein its alkyl moiety is a
linear or branched chain alkyl group having 1 to 4 carbon atoms and
its aryl moiety is phenyl group. Specifically, benzyl group,
phenethyl group, 3-phenylpropyl group, 2-phenylpropyl group,
4-phenylbutyl group and the like can be mentioned.
[0687] It is particularly preferably benzyl group for R.sup.2.
[0688] The "C6-14 aryl C1-6 alkyloxy group" is an aryl-alkyl-oxy
group wherein its C6-14 aryl C1-6 alkyl moiety is the above-defined
"C6-14 aryl C1-6 alkyl group". Preferably, it is an aryl-alkyl-oxy
group wherein its alkyl moiety is a linear or branched chain alkyl
group having 1 to 4 carbon atoms and its aryl moiety is phenyl
group. Specifically, benzyloxy group, phenethyloxy group,
3-phenylpropyloxy group, 2-phenylpropyloxy group, 4-phenylbutyloxy
group and the like can be mentioned.
[0689] The "C6-14 aryl C1-6 alkyloxycarbonyl group" is an
aryl-alkyl-oxy-carbonyl group wherein its C6-14 aryl C1-6 alkyl
moiety is the above-defined "C6-14 aryl C1-6 alkyl group".
Preferably, it is an aryl-alkyl-oxy-carbonyl group wherein its
alkyl moiety is a linear or branched chain alkyl group having 1 to
4 carbon atoms and its aryl moiety is phenyl group. Specifically,
benzyloxycarbonyl group, phenethyloxycarbonyl group,
3-phenylpropyloxycarbonyl group, 2-phenylpropyloxycarbonyl group,
4-phenylbutyloxycarbonyl group and the like can be mentioned.
[0690] It is preferably benzyloxycarbonyl group.
[0691] The "C6-14 arylcarbonyl group" is an aryl-carbonyl group
wherein its aryl moiety is the above-defined "C6-14 aryl group".
Specifically, benzoyl group, 1-naphthoyl group, 2-naphthoyl group,
anthrylcarbonyl group, indenylcarbonyl group, azulenylcarbonyl
group, fluorenylcarbonyl group, phenanthrylcarbonyl group and the
like can be mentioned, with preference given to benzoyl group.
[0692] The "C3-10 carbon ring group" is a saturated or unsaturated
cyclic hydrocarbon group having 3 to 10 carbon atoms and means aryl
group, cycloalkyl group, cycloalkenyl group, or a fused ring
thereof.
[0693] As the "aryl group", phenyl group, naphthyl group,
pentalenyl group, azulenyl group and the like can be specifically
mentioned. It is preferably phenyl group or naphthyl group, and
more preferably phenyl group.
[0694] As the "cycloalkyl group", cyclopropyl group, cyclobutyl
group, cyclopentyl group, cyclohexyl group, cycloheptyl group,
cyclooctyl group, adamantyl group, norbornanyl group and the like
can be specifically mentioned. It preferably includes cyclopentyl
group, cyclohexyl group and cycloheptyl group, and particularly
preferably includes cyclopentyl group and cyclohexyl group.
[0695] The "cycloalkenyl group" contains at least one, preferably 1
or 2, double bonds. Specifically, cyclopropenyl group, cyclobutenyl
group, cyclopentenyl group, cyclopentadienyl group, cyclohexenyl
group (2,4-cyclohexadien-1-yl group, 2,5-cyclohexadien-1-yl group
etc.), cycloheptenyl group and cyclooctenyl group and the like can
be mentioned.
[0696] As a fused ring of these "aryl group", "cycloalkyl group"
and "cycloalkenyl group", indenyl group, indanyl group,
1,4-dihydronaphthyl group, 1,2,3,4-tetrahydronaphthyl group
(1,2,3,4-tetrahydro-2-naphthyl group, 5,6,7,8-tetrahydro-2-naphthyl
group etc.), perhydronaphthyl group and the like can be
specifically mentioned. Preferably, it is a fused ring of phenyl
group and other ring, such as indenyl group, indanyl group,
1,4-dihydronaphthyl group, 1,2,3,4-tetrahydronaphthyl group and the
like.
[0697] The "heteroaryl group" is a 5 or 6-membered heteroaryl group
containing, as a ring-constituting atom, besides the carbon atom,
at least one hetero atom selected from nitrogen atom, oxygen atom
and sulfur atom.
[0698] Specifically, pyridyl group, pyrazinyl group, pyrimidinyl
group, pyridazinyl group, 1,3,5-triazinyl group, pyrrolyl group,
pyrazolyl group, imidazolyl group, triazolyl group (1,2,3-triazolyl
group, 1,2,4-triazolyl group), tetrazolyl group, thienyl group,
furyl group, oxazolyl group, isoxazolyl group, thiazolyl group,
isothiazolyl group, oxadiazolyl group (1,2,4-oxadiazolyl group,
1,3,4-oxadiazolyl group, 1,2,5-oxadiazolyl group), thiadiazolyl
group (1,2,4-thiadiazolyl group, 1,3,4-thiadiazolyl group,
1,2,5-thiadiazolyl group) and the like can be mentioned.
[0699] The "heterocyclic group" is a saturated or unsaturated
(including partially unsaturated and completely unsaturated)
monocyclic 5-membered or 6-membered heterocycle containing, besides
carbon atom, at least 1, preferably 1 to 4, hetero atoms selected
from nitrogen atom, oxygen atom and sulfur atom, or a fused ring of
such heterocycles, or a fused ring of a carbon ring selected from
benzene, cyclopentane and cyclohexane and the above-defined
heterocycle.
[0700] As the "saturated monocyclic heterocyclic group",
pyrrolidinyl group, tetrahydrofuryl group, tetrahydrothienyl group,
imidazolidinyl group, pyrazolidinyl group, 1,3-dioxolanyl group,
1,3-oxathiolanyl group, oxazolidinyl group, thiazolidinyl group,
piperidinyl group, piperazinyl group, tetrahydropyranyl group,
tetrahydrothiopyranyl group, dioxanyl group, morpholinyl group,
thiomorpholinyl group, 3-hydroxypyrrolidinyl group,
2-oxopyrrolidinyl group, 3-oxopyrrolidinyl group, 2-oxopiperidinyl
group, 4-oxopiperidinyl group, 2,6-dioxopiperidinyl group and the
like can be mentioned. Preferably, it is pyrrolidinyl group,
piperidinyl group or morpholinyl group.
[0701] As the "unsaturated monocyclic heterocyclic group", pyrrolyl
group, furyl group, thienyl group, imidazolyl group,
1,2-dihydro-2-oxoimidazolyl group, pyrazolyl group, oxazolyl group,
isoxazolyl group, thiazolyl group, isothiazolyl group,
1,2,4-triazolyl group, 1,2,3-triazolyl group, tetrazolyl group,
1,3,4-oxadiazolyl group, 1,2,4-oxadiazolyl group,
1,3,4-thiadiazolyl group, 1,2,4-thiadiazolyl group, furazanyl
group, pyridyl group, pyrimidinyl group,
3,4-dihydro-4-oxopyrimidinyl group, pyridazinyl group, pyrazinyl
group, 1,3,5-triazinyl group, imidazolinyl group, pyrazolinyl
group, oxazolinyl group (2-oxazolinyl group, 3-oxazolinyl group,
4-oxazolinyl group), isoxazolinyl group, thiazolinyl group,
isothiazolinyl group, pyranyl group, 2-oxopyranyl group and the
like can be mentioned. It is preferably imidazolyl group, pyrazolyl
group, isoxazolyl group, thiazolyl group, 1,2,4-triazolyl group,
tetrazolyl group, 1,3,4-oxadiazolyl group, pyridyl group,
pyrimidinyl group, pyridazinyl group, pyrazinyl group or oxazolinyl
group.
[0702] As the "fused heterocyclic group", indolyl group, isoindolyl
group, 1,3-dihydro-1,3-dioxoisoindolyl group, benzimidazolyl group,
indazolyl group, benzothiazolyl group, benzofuranyl group,
isobenzofuranyl group, indolizinyl group, quinolyl group,
isoquinolyl group, 1,2-dihydro-2-oxoquinolyl group, quinazolinyl
group, quinoxalinyl group, cinnolinyl group, phthalazinyl group,
quinolizinyl group, pyrinyl group, pteridinyl group, indolinyl
group, isoindolinyl group, 5,6,7,8-tetrahydroquinolyl group,
1,2,3,4-tetrahydroquinolyl group, 2-oxo-1,2,3,4-tetrahydroquinolyl
group, 1,3-benzodioxolyl group, 3,4-methylenedioxypyridyl group,
4,5-ethylenedioxypyrimidinyl group, chromenyl group, chromanyl
group, isochromanyl group, 1,2,4-benzotriazinyl group and the like
can be mentioned. Preferably, it is indolyl group, benzofuranyl
group, quinolyl group, benzothiazolyl group,
1,2,3,4-tetrahydroquinolyl group, 1,3-benzodidxolyl group or
1,2,4-benzotriazinyl group.
[0703] The "heterocyclic group" that substitutes C1-7 alkyl group,
C1-6 alkyl moiety, C2-6 alkenyl group and C2-6 alkynyl group of
group C is preferably a 2-oxopyrrolidin-1-yl group.
[0704] The "C3-8 cycloalkyl group" is a cycloalkyl group having 3
to 8 carbon atoms, and is specifically cyclopropyl group,
cyclobutyl group, cyclopentyl group, cyclohexyl group, cycloheptyl
group or cyclooctyl group.
[0705] As R.sup.c7 in group C, preferred is a cyclopentyl
group.
[0706] The "C3-8 cycloalkyl C1-6 alkyl group" is a cycloalkyl-alkyl
group wherein the above-defined "C1-6 alkyl group" is substituted
by the above-defined "C3-8 cycloalkyl group". The C1-6 alkyl moiety
is preferably a linear alkyl group having 1 to 4 carbon atoms, and
as C3-8 cycloalkyl, preferred are cyclopropyl group, cyclobutyl
group, cyclopentyl group and cyclohexyl group.
[0707] As the "C3-8 cycloalkyl C1-6 alkyl group", cyclopropylmethyl
group, cyclobutylmethyl group, cyclopentylmethyl group,
cyclohexylmethyl group, 2-cyclohexylethyl group, 3-cyclohexylpropyl
group and the like can be specifically mentioned.
[0708] It is preferably a cyclohexylmethyl group for group C.
[0709] The "C1-6 alkylsulfonyl group" is an alkyl-sulfonyl group
wherein its C1-6 alkyl moiety is the above-defined "C1-6 alkyl
group", preferably a linear or branched chain alkyl group having 1
to 4 carbon atoms.
[0710] Specifically, methylsulfonyl group, ethylsulfonyl group,
propylsulfonyl group, isopropylsulfonyl group, butylsulfonyl group,
isobutylsulfonyl group, sec-butylsulfonyl group, tert-butylsulfonyl
group, pentylsulfonyl group, isopentylsulfonyl group,
tert-pentylsulfonyl group, hexylsulfonyl group and the like can be
mentioned.
[0711] It is preferably a methylsulfonyl group for group A.
[0712] The "di(C1-6 alkyl)amino group" is a di(alkyl)-amino group
wherein its C1-6 alkyl moiety is the above-defined "C1-6 alkyl
group", preferably a linear or branched chain alkyl group having 1
to 4 carbon atoms.
[0713] Specifically, dimethylamino group, diethylamino group,
dipropylamino group, diisopropylamino group, N-ethyl-N-methylamino
group, N-isopropyl-N-methylamino group and the like can be
mentioned.
[0714] It is preferably a dimethylamino group for group A.
[0715] The "C1-6 alkylcarbonylamino group" is an
alkyl-carbonyl-amino group wherein its C1-6 alkyl moiety is the
above-defined "C1-6 alkyl group", and preferably a linear or
branched chain alkyl group having 1 to 4 carbon atoms.
[0716] Specifically, acetylamino group, propionylamino group,
butyrylamino group, isobutyrylamino group, pivaloylamino group and
the like can be mentioned.
[0717] It is preferably an acetylamino group for group A.
[0718] The "C1-6 alkylcarbonyloxy group optionally substituted by
halogen atom(s)" is an alkyl-carbonyl-oxy group wherein its C1-6
alkyl moiety is the above-defined "C1-6 alkyl group", which is
optionally substituted by the above-defined "halogen atom". It
includes unsubstituted C1-6 alkylcarbonyloxy group, and is
preferably one wherein its alkyl moiety is a linear or branched
chain alkyl group having 1 to 4 carbon atoms. Here, the halogen
atom is preferably a fluorine atom.
[0719] Specifically, acetyloxy group, propionyloxy group,
butyryloxy group, isobutyryloxy group, pivaloyloxy group,
fluoromethylcarbonyloxy group, trifluoromethylcarbonyloxy group,
2,2,2-trifluoroethylcarbonyloxy group can be mentioned.
[0720] It is preferably an acetyloxy group or a
trifluoromethylcarbonyloxy group for group A.
[0721] The "C6-14 aryl group optionally substituted by 1 to 3
substituent(s) selected from the group consisting of halogen atom,
C1-6 alkyl group, C1-6 alkylsulfonyl group, di(C1-6 alkyl)amino
group and C1-6 alkylcarbonylamino group" is the above-defined
"C6-14 aryl group", preferably a phenyl group, which is optionally
substituted by 1 to 3 substituent(s) selected from the group
consisting of the above-defined "halogen atom", the above-defined
"C1-6 alkyl group", the above-defined "C1-6 alkylsulfonyl group",
the above-defined "di(C1-6 alkyl)amino group" and the above-defined
"C1-6 alkylcarbonylamino group", and includes unsubstituted aryl
group.
[0722] As the "C6-14 aryl group optionally substituted by 1 to 3
substituent(s) selected from the group consisting of halogen atom,
C1-6 alkyl group, C1-6 alkylsulfonyl group, di(C1-6 alkyl)amino
group and C1-6 alkylcarbonylamino group", phenyl group,
2-fluorophenyl group, 3-fluorophenyl group, 4-fluorophenyl group,
4-chlorophenyl group, 4-bromophenyl group, 2,4-difluorophenyl
group, 3,5-dichlorophenyl group, 4-methylphenyl group,
4-isopropylphenyl group, 4-tert-butylphenyl group,
4-dimethylaminophenyl group, 4-methylsulfonylphenyl group,
4-acetylaminophenyl group and the like can be specifically
mentioned.
[0723] It is preferably phenyl group, 2-fluorophenyl group,
4-fluorophenyl group, 4-tert-butylphenyl group,
4-dimethylaminophenyl group, 4-methylsulfonylphenyl group or
4-acetylaminophenyl group for group A.
[0724] The "heterocyclic group optionally substituted by C1-6
alkyloxy group" is the above-defined "heterocyclic group", which is
optionally substituted by the above-defined "C1-6 alkyloxy group",
and includes unsubstituted heterocyclic group.
[0725] It is preferably a 5-membered or 6-membered monocyclic
heterocyclic group.
[0726] As the "heterocyclic group optionally substituted by C1-6
alkyloxy group", pyrrolidinyl group, piperidinyl group, piperazinyl
group, morpholinyl group, pyrrolyl group, furyl group, imidazolyl
group, pyrazolyl group, 1,2,4-triazolyl group, tetrazolyl group,
pyridyl group, pyrimidinyl group, pyrazinyl group, pyridazinyl
group, 3-methoxypyridin-2-yl group, 6-methoxypyridin-2-yl group,
5-isopropyloxypyridin-3-yl group and 4-methoxypyrimidin-2-yl group
and the like can be specifically mentioned.
[0727] It is-preferably 2-pyridyl group, 3-pyridyl group, 2-furyl
group, 6-methoxypyridin-2-yl group or 4-methoxypyrimidin-2-yl group
for group A.
[0728] The "group A" is the following substituent group, in which
R.sup.a1, R.sup.a2, R.sup.a3 and R.sup.a4 are each independently a
hydrogen atom or the above-defined "C1-6 alkyl group": the
above-defined "halogen atom", cyano group,
[0729] --OR.sup.a1 (e.g., hydroxyl group, methoxy group, ethoxy
group, propoxy group, isopropyloxy group, butoxy group, isobutyloxy
group, tert-butyloxy group etc.),
[0730] --SR.sup.a1 (e.g., mercapto group, methylsulfanyl group,
ethylsulfanyl group, isopropylsulfanyl group etc.),
[0731] --CO.sub.2R.sup.a1 (e.g., carboxyl group, methoxycarbonyl
group, ethoxycarbonyl group, isopropyloxycarbonyl group,
tert-butoxycarbonyl group etc.),
[0732] --CONR.sup.a2R.sup.a3 (e.g., carbamoyl group,
methylcarbamoyl group, ethylcarbamoyl group, isopropylcarbamoyl
group, dimethylcarbamoyl group, diethylcarbamoyl group,
diisopropylcarbamoyl group, di-tert-butylcarbamoyl group,
N-ethyl-N-methylcarbamoyl group, N-isopropyl-N-methylcarbamoyl
group etc.),
[0733] --COR.sup.a4 (e.g., formyl group, acetyl group, propionyl
group, butyryl group, isobutyryl group, pivaloyl group etc.),
[0734] --SO.sub.2NR.sup.a2R.sup.a3 (e.g., sulfamoyl group,
methylsulfamoyl group, ethylsulfamoyl group, isopropylsulfamoyl
group, dimethylsulfamoyl group, diethylsulfamoyl group,
diisopropylsulfamoyl group, di-tert-butylsulfamoyl group,
N-ethyl-N-methylsulfamoyl group, N-isopropyl-N-methylsulfamoyl
group etc.),
[0735] --SO.sub.2R.sup.a4 (e.g., methylsulfonyl group,
ethylsulfonyl group, isopropylsulfonyl group, tert-butylsulfonyl
group etc.), the above-defined "C6-14 aryloxy group", the
above-defined "C6-14 aryl C1-6 alkyloxycarbonyl group", the
above-defined "C1-6 alkylcarbonyloxy group optionally substituted
by halogen atom", the above-defined "C6-14 aryl group optionally
substituted by 1 to 3 substituent(s) selected from the group
consisting of halogen atom, C1-6 alkyl group, C1-6 alkylsulfonyl
group, di(C1-6 alkyl)amino group and C1-6 alkylcarbonylamino group"
and the above-defined "heterocyclic group optionally substituted by
C1-6 alkyloxy group".
[0736] The "C1-6 alkyl group optionally substituted by 1 to 3
substituent(s) selected from group A" is the above-defined "C1-6
alkyl group", which is optionally substituted by 1 to 3
substituent(s) selected from the above-defined "group A", and
includes unsubstituted alkyl group.
[0737] Specifically, methyl group, ethyl group, propyl group,
isopropyl group, butyl group, isobutyl group, sec-butyl group,
tert-butyl group, pentyl group, isopentyl group, tert-pentyl group,
neopentyl group, 1-ethylpropyl group, hexyl group, trifluoromethyl
group, cyanomethyl group, 2-cyanoethyl group, hydroxymethyl group,
1-hydroxyethyl group, 2-hydroxyethyl group, 3-hydroxypropyl group,
4-hydroxybutyl group, 1-hydroxy-1-methylethyl group,
1-hydroxypropane-2-yl group, 1,3-dihydroxypropane-2-yl group,
1-hydroxy-2-methylpropane-2-yl group, 1-hydroxy-2-methylpropyl
group, 1-hydroxy-2,2-dimethylpropyl group, methoxymethyl group,
2-methoxyethyl group, isopropyloxymethyl group, isobutyloxymethyl
group, mercaptomethyl group, methylsulfanylmethyl group,
isopropylsulfanylmethyl group, 2-methylsulfanylethyl group,
carboxymethyl group, ethoxycarbonylmethyl group, 2-carboxyethyl
group, 2-ethoxycarbonylethyl group, carbamoylmethyl group,
methylcarbamoylmethyl group, formylmethyl group, acetylmethyl
group, isobutyrylmethyl group, pivaloylmethyl group,
sulfamoylmethyl group, 2-sulfamoylethyl group,
methylsulfamoylmethyl group, methylsulfonylmethyl group,
isopropylsulfonylmethyl group, 2-methylsulfonylethyl group,
phenoxymethyl group, benzyloxycarbonylmethyl group and the like can
be mentioned.
[0738] It is preferably methyl group, ethyl group, propyl group or
pentyl group, particularly preferably methyl group or pentyl group,
for R.sup.1.
[0739] The "C1-7 alkyl group optionally substituted by 1 to 3
substituent(s) selected from group A" is the above-defined "C1-7
alkyl group", which is optionally substituted by 1 to 3
substituent(s) selected from "group A", and includes unsubstituted
alkyl group.
[0740] Specifically, the substituents for the "C1-6 alkyl group
optionally substituted by 1 to 3 substituent(s) selected from group
A" can be mentioned.
[0741] It is preferably a methyl group for R.sup.2. As group C,
preferred are methyl group, ethyl group, propyl group, isobutyl
group, isopropyl group, butyl group, isobutyl group, tert-butyl
group, cyanomethyl group, hydroxymethyl group, 2-hydroxyethyl
group, 1-hydroxyethyl group, 3-hydroxypropyl group, 1-hydroxypropyl
group, 1-hydroxy-2-methylpropyl group, methoxymethyl group,
isopropyloxymethyl group, isobutyloxymethyl group,
2,2-dimethylpropyl group, 2,2-dimethyl-1-hydroxypropyl group,
3,3-dimethyl-2-hydroxybutyl group, carboxymethyl group,
methoxycarbonylmethyl group, methylcarbamoylmethyl group,
dimethylcarbamoylmethyl group, methylsulfanylmethyl group,
2-(methylsulfanyl)ethyl group, methylsulfonylmethyl group,
isopropylsulfonylmethyl group, 2-(methylsulfonyl)ethyl group,
isopropylsulfanylmethyl group, pivaloylmethyl group, benzyl group,
phenethyl group, 3-phenylpropyl group, phenoxymethyl group and
benzyloxycarbonylmethyl group.
[0742] The "C2-6 alkenyl group optionally substituted by 1 to 3
substituent(s) selected from-group A" is the above-defined "C2-6
alkenyl group", which is optionally substituted by 1 to 3
substituent(s) selected from "group A", and includes unsubstituted
alkenyl group.
[0743] Specifically, vinyl group, allyl group, 1-propenyl group,
isopropenyl group, 2-methyl-1-propenyl group, 1-butenyl group,
2-butenyl group, 1,3-butadienyl group, 3-methyl-2-butenyl group,
4-methyl-2-pentenyl group, 4-methyl-3-pentenyl group,
1-methyl-2-butenyl group, carboxyvinyl group, carbamoylvinyl group
and the like can be mentioned.
[0744] The "C2-6 alkynyl group optionally substituted by 1 to 3
substituent(s) selected from group A" is the above-defined "C2-6
alkynyl group", which is optionally substituted by 1 to 3
substituent(s) selected from "group A", and includes unsubstituted
alkynyl group.
[0745] Specifically, ethynyl group, 1-propynyl group, 2-propynyl
group, 3-butynyl group, carboxyethynyl group, carbamoylethynyl
group and the like can be mentioned.
[0746] The "group B" is a group selected from the following
substituent group, in which R.sup.b1, R.sup.b2, R.sup.b3, R.sup.b4,
R.sup.b5 and R.sup.b6 are each independently a hydrogen atom or the
above-defined "C1-6 alkyl group": the above-defined "halogen atom",
cyano group, the above-defined "C1-6 alkyl group", the
above-defined "haloC1-6 alkyl group",
[0747] --OR.sup.b1 (e.g., hydroxyl group, methoxy group, ethoxy
group, propoxy group, isopropyloxy group, butoxy group, isobutyloxy
group, tert-butyloxy group etc.),
[0748] --SR.sup.b1 (e.g., mercapto group, methylsulfanyl group,
ethylsulfanyl group, isopropylsulfanyl group etc.),
[0749] --CO.sub.2R.sup.b1 (e.g., carboxyl group, methoxycarbonyl
group, ethoxycarbonyl group, isopropyloxycarbonyl group,
tert-butoxycarbonyl group etc.),
[0750] --CONR.sup.b2R.sup.b3 (e.g., carbamoyl group,
methylcarbamoyl group, ethylcarbamoyl group, isopropylcarbamoyl
group, dimethylcarbamoyl group, diethylcarbamoyl group,
diisopropylcarbamoyl group, di-tert-butylcarbamoyl group,
N-ethyl-N-methylcarbamoyl group, N-isopropyl-N-methylcarbamoyl
group etc.),
[0751] --COR.sup.b4 (e.g., formyl group, acetyl group, propionyl
group, butyryl group, isobutyryl group, pivaloyl group etc.),
[0752] --SO.sub.2NR.sup.b2R.sup.b3 (e.g., sulfamoyl group,
methylsulfamoyl group, ethylsulfamoyl group, isopropylsulfamoyl
group, dimethylsulfamoyl group, diethylsulfamoyl group,
diisopropylsulfamoyl group, di-tert-butylsulfamoyl group,
N-ethyl-N-methylsulfamoyl group, N-isopropyl-N-methylsulfamoyl
group etc.),
[0753] --SO.sub.2R.sup.b4 (e.g., methylsulfonyl group,
ethylsulfonyl group, isopropylsulfonyl group, tert-butylsulfonyl
group etc.), the above-defined "C6-14 aryloxy group" and the
above-defined "C6-14 aryl C1-6 alkyloxycarbonyl group"
[0754] --NR.sup.b5CORb.sup.6 (e.g., acetylamino group,
propionylamino group, butyrylamino group, isobutyrylamino group,
pivaloylamino group and the like.
[0755] The "C3-10 carbon ring group optionally substituted by 1 to
3 substituent(s) selected from group B" is the above-defined "C3-10
carbon ring group", preferably a phenyl group, which is optionally
substituted by 1 to 3 substituent(s) selected from the
above-defined "group C", and includes unsubstituted C3-10 carbon
ring group.
[0756] Specifically, phenyl group, 2-fluorophenyl group,
3-fluorophenyl group, 4-fluorophenyl group, 2,4-difluorophenyl
group, 3,4-difluorophenyl group, 2-chlorophenyl group,
3-chlorophenyl group, 4-chlorophenyl group, 2-bromophenyl group,
3-bromophenyl group, 4-bromophenyl group, 2,3-dichlorophenyl group,
2,4-dichlorophenyl group, 2,6-dichlorophenyl group,
3,4-dichlorophenyl group, 3,5-dichlorophenyl group,
3,4-dibromophenyl group, 3-chloro-2-fluorophenyl group,
2-chloro-3-fluorophenyl group, 4-chloro-3-fluorophenyl group,
3-chloro-4-fluorophenyl group, 2-chloro-6-fluorophenyl group,
2-methylphenyl group, 3-methylphenyl group, 4-methylphenyl group,
4-ethylphenyl group, 4-propylphenyl group, 3-isopropylphenyl group,
4-isopropylphenyl group, 3-butylphenyl group, 3-isobutylphenyl
group, 4-isobutylphenyl group, 3-(2-methyl-1-propenyl)phenyl group,
2-trifluoromethylphenyl group, 3-trifluoromethylphenyl group,
4-trifluoromethylphenyl group, 3,5-bistrifluoromethylphenyl group,
2-methoxyphenyl group, 3-methoxyphenyl group, 4-methoxyphenyl
group, 2-ethoxyphenyl group, 3-ethoxyphenyl group, 4-ethoxyphenyl
group, 2-isopropyloxyphenyl group, 3-isopropyloxyphenyl group,
4-isopropyloxyphenyl group, 3-phenoxyphenyl group, 4-phenoxyphenyl
group, 3-methylthiophenyl group, 4-methylthiophenyl group,
3-carboxyphenyl group, 4-carboxyphenyl group, 3-cyanophenyl group,
4-cyanophenyl group, 3-acetylphenyl group, 4-acetylphenyl group,
3-isobutyrylphenyl group, 4-isobutyrylphenyl group,
3-carbamoylphenyl group, 4-carbamoylphenyl group,
3-(methylcarbamoyl)phenyl group, 4-(methylcarbamoyl)phenyl group,
3-(isopropylcarbamoyl)phenyl group, 4-(isopropylcarbamoyl)phenyl
group, 3-(butylcarbamoyl)phenyl group,
3-(N-ethyl-N-methylcarbamoyl)phenyl group,
3-(dimethylcarbamoyl)phenyl group, 4-(dimethylcarbamoyl)phenyl
group, 3-(diethylcarbamoyl)phenyl group, 4-(diethylcarbamoyl)phenyl
group, 3-(N-methyl-N-(3-methylbutyl)carbamoyl)phenyl group,
4-{N-methyl-N-(3-methylbutyl)carbamoyl}phenyl group,
3-sulfamoylphenyl group, 4-sulfamoylphenyl group,
3-(methylsulfamoyl)phenyl group, 4-(methylsulfamoyl)phenyl group,
3-(ethylsulfamoyl)phenyl group, 4-(ethylsulfamoyl)phenyl group,
3-(isopropylsulfamoyl)phenyl group, 3-(butylsulfamoyl)phenyl group,
3-(dimethylsulfamoyl)phenyl group, 4-(dimethylsulfamoyl)phenyl
group, 3-(diethylsulfamoyl)phenyl group, 4-(diethylsulfamoyl)phenyl
group, 3-(N-ethyl-N-methylsulfamoyl)phenyl group,
3-(methylsulfonyl)phenyl group, 4-(methylsulfonyl)phenyl group,
3-(ethylsulfonyl)phenyl group, 4-(ethylsulfonyl)phenyl group,
3-(isopropylsulfonyl)phenyl group, 4-(isopropylsulfonyl)phenyl
group, 4-chloro-3-carboxyphenyl group,
4-chloro-3-dimethylcarbamoylphenyl group, 3-chloro-4-methylphenyl
group, 3-chloro-2-hydroxyphenyl group, 3-chloro-4-hydroxyphenyl
group, 3-chloro-2-methoxyphenyl group, 3-chloro-4-methoxyphenyl
group, 3-chloro-4-propyloxyphenyl group,
3-chloro-4-isopropyloxyphenyl group, 3-chloro-4-benzyloxyphenyl
group, 3-chloro-5-methoxyphenyl group, 3-chloro-6-methoxyphenyl
group, 3-chloro-4-ethbxyphenyl group, 3-chloro-4-isopropyloxyphenyl
group, 4-chloro-2-methoxyphenyl group, 4-chloro-3-methoxyphenyl
group, 4-chloro-2-hydroxyphenyl group,
4-chloro-2-isopropyloxyphenyl group, 4-chloro-2-propyloxyphenyl
group, 4-chloro-2-benzyloxyphenyl group,
3-carboxy-5-trifluoromethylphenyl group,
3-dimethylcarbamoyl-5-trifluorom- ethylphenyl group,
4-dimethylcarbamoyl-2-fluorophenyl group, 4-carboxy-3-chlorophenyl
group, 3-chloro-4-methylcarbamoylphenyl group,
3-chloro-4-dimethylcarbamoylphenyl group,
3-chloro-4-diethylcarbamoylphen- yl group,
4-carbamoyl-3-chlorophenyl group, 3-chloro-4-acetylphenyl group,
3-chloro-4-pivaloylphenyl group, 3-chloro-5-dimethylcarbamoylphenyl
group, 3-hydroxy-4-dimethylcarbamoylphenyl group,
3-hydroxy-5-dimethylcar- bamoylphenyl group,
3-cyano-5-dimethylcarbamoylphenyl group, 3-carboxy-5-methoxyphenyl
group, 3-carboxy-5-ethoxyphenyl group,
3-carboxy-5-isopropyloxyphenyl group, 3-carboxy-5-cyanophenyl
group, 3,5-dicarboxyphenyl group, 3,4-dicarboxyphenyl group,
3-carboxy-5-dimethylcarbamoylphenyl group,
3-carboxy-4-methoxyphenyl group, 3-carboxy-4-ethoxyphenyl group,
3-carboxy-4-isopropyloxyphenyl group, 3-carboxy-4-cyanophenyl
group, 3-carbamoyl-5-dimethylcarbamoylphen- yl group,
3-dimethylcarbamoyl-5-methylcarbamoylphenyl group,
4-carboxy-3-methoxyphenyl group, 4-carboxy-2-methoxyphenyl group,
4-carboxy-3-ethoxyphenyl group, 4-carboxy-3-isopropyloxyphenyl
group, 4-carboxy-3-cyanophenyl group, 4-carbamoyl-2-methoxyphenyl
group, 4-methylcarbamoyl-3-methoxyphenyl group,
4-dimethylcarbamoyl-3-methoxyphe- nyl group,
3,5-bis(dimethylcarbamoyl)phenyl group, 3-carbamoyl-5-cyanophen- yl
group, 3-carboxy-4-methylphenyl group,
3-dimethylcarbamoyl-4-methylphen- yl group,
4-methyl-3-methylcarbamoylphenyl group, 3-dimethylsulfamoyl-4-me-
thylphenyl group, 4-fluoro-3-chlorophenyl group,
4-fluoro-2-carboxyphenyl group, 4-fluoro-2-methoxycarbonylphenyl
group, 4-fluoro-2-methylcarbamoyl- phenyl group,
4-fluoro-2-acetylaminophenyl group, 3,5-dichloro-4-hydroxyph- enyl
group, 3,5-dichloro-4-methoxyphenyl group, 1-naphthyl group,
2-naphthyl group, 1-bromonaphthalen-2-yl group,
6-bromonaphthalen-2-yl group, 7-cyanonaphthalen-2-yl group,
7-methoxynaphthalen-2-yl group, 5-bromo-6-methoxynaphthalen-2-yl
group, cyclopentyl group, 1-methylcyclopentyl group,
1-ethylcyclopentyl group, 1-isopropylcyclopentyl group,
2,5-dimethylcyclopentyl group, 2,2-dimethylcyclopentyl group,
cyclohexyl group, 1-methylcyclohexyl group, 1-ethylcyclohexyl
group, 1-isopropylcyclohexyl group, 2,6-dimethylcyclohexyl group,
cycloheptyl group, 1-methylcycloheptyl group, 1-ethylcycloheptyl
group, 1-isopropylcycloheptyl group and the like can be
mentioned.
[0757] The ring D for R.sup.1 is preferably phenyl group,
2-fluorophenyl group, 3-fluorophenyl group, 4-fluorophenyl group,
3,4-difluorophenyl group, 2-chlorophenyl group, 3-chlorophenyl
group, 4-chlorophenyl group, 3-bromophenyl group, 4-bromophenyl
group, 2,3-dichlorophenyl group, 2,6-dichlorophenyl group,
3,4-dichlorophenyl group, 3,5-dichlorophenyl group,
3-chloro-2-fluorophenyl group, 4-chloro-3-fluorophenyl group,
2-chloro-6-fluorophenyl group, 3-trifluoromethylphenyl group,
3-methoxyphenyl group, 3-chloro-2-hydroxyphenyl group,
3-chloro-2-methoxyphenyl group, 3-chloro-4-methoxyphenyl group,
3-chloro-4-propyloxyphenyl group, 3-chloro-4-isopropyloxyphenyl
group, 3-chloro-4-benzyloxyphenyl group, 3-chloro-5-methoxyphenyl
group, 3-chloro-6-methoxyphenyl group, 4-chloro-2-methoxyphenyl
group, 4-chloro-3-methoxyphenyl group, 4-chloro-2-hydroxyphenyl
group, 4-chloro-2-isopropyloxyphenyl group,
4-chloro-2-propyloxyphenyl group, 4-chloro-2-benzyloxyphenyl group,
4-fluoro-3-chlorophenyl group, 4-fluoro-2-carboxyphenyl group,
4-fluoro-2-methoxycarbonylphenyl group,
4-fluoro-2-methylcarbamoylphenyl group,
4-fluoro-2-acetylaminophenyl group or 2-naphthyl group.
[0758] The "heterocyclic group optionally substituted by 1 to 3
substituent(s) selected from group B" is the above-defined
"heterocyclic group", which is optionally substituted by 1 to 3
substituent(s) selected from the above-defined "group C", and
includes unsubstituted heterocyclic group.
[0759] Specifically, 2-imidazolyl group, 5-methylpyrazol-3-yl
group, 5-methylisoxazol-3-yl group, 2-furyl group, 2-thiazolyl
group, 4-methylthiazol-2-yl group, 5-methylthiazol-2-yl group,
5-thiazolyl group, 2-oxazolyl group, 1-methylimidazol-2-yl group,
3-pyrazolyl group, 1,2,4-triazol-3-yl group,
2-methyl-1,2,4-triazol-3-yl group, 5-methyl-1,2,4-triazol-3-yl
group, 5-ethyl-1,2,4-triazol-3-yl group, 1-ethyl-1,2,4-triazol-3-yl
group, 1,5-dimethyl-1,2,4-triazol-3-yl group,
4-methyl-1,2,4-triazol-3-yl group, 4-ethyl-1,2,4-triazol-3-yl
group, 5-tetrazolyl group, 5-ethyl-1,2,4-oxadiazol-3-yl group,
5-ethyl-1,3,4-oxadiazol-2-yl group, 3-methyl-1,2,4-thiadiazol-5-yl
group, 2-pyridyl group, 3-pyridyl group, 4-pyridyl group,
4-methoxypyridin-2-yl group, 6-methylpyridin-2-yl group,
2-pyrimidinyl group, 4-pyrimidinyl group, 4-methylpyrimidin-2-yl
group, 4-ethylpyrimidin-2-yl group, 4-isopropylpyrimidin-2-yl
group, 4-butylpyrimidin-2-yl group, 4-sec-butylpyrimidin-2-yl
group, 4-carboxypyrimidin-2-yl group, 4-methoxypyrimidin-2-yl
group, 4-ethoxypyrimidin-2-yl group, 4-isopropyloxypyrimidin-2-yl
group, 4-tert-butyloxypyrimidin-2-yl group, 5-methylpyrimidin-2-yl
group, 5-ethylpyrimidin-2-yl group, 5-isopropylpyrimidin-2-yl
group, 5-butylpyrimidin-2-yl group, 5-sec-butylpyrimidin-2-yl
group, 5-carboxypyrimidin-2-yl group, 5-methoxypyrimidin-2-yl
group, 5-ethoxypyrimidin-2-yl group, 5-isopropyloxypyrimidin-2-yl
group, 5-tert-butyloxypyrimidin-2-yl group, 3-pyridazinyl group,
2-pyrazinyl group, 2-quinazolinyl group, 2-oxazolin-2-yl group,
5-ethyl-2-oxazolin-2-yl group, 4,4-dimethyloxazolin-2-yl group,
2-quinolyl group, 6-quinolyl group, 2-benzothiazolyl group,
1,2,4-triazin-3-yl group, 1,3,5-triazin-2-yl group,
1,2,3,4-tetrahydroquinolin-1-yl group, 5-indolyl group,
1-methylindol-2-yl group, 2-benzimidazolyl group, 2-benzofuranyl
group, 1,3-benzodioxol-5-yl group, 1,2,4-benzotriazin-3-yl group,
4-piperidyl group, 4-methylpiperidin-4-yl group,
4-ethylpiperidin-4-yl group, 4-isopropylpiperidin-4-yl group,
4-tetrahydropyranyl group, 4-methyltetrahydropyran-4-yl group,
4-ethyltetrahydropyran-4-yl group, 4-isopropyltetrahydropyran-4-yl
group, 3,5-dimethyltetrahydropyran-4-yl group,
4-tetrahydrothiopyranyl group, 4-methyltetrahydrothiopyran-4-yl
group, 4-ethyltetrahydrothiopyran-4-yl group,
4-isopropyltetrahydrothiopy- ran-4-yl group and the like can be
mentioned.
[0760] It is preferably 2-benzofuranyl group as ring D for
R.sup.1.
[0761] It is preferably 2-furyl group, 2-thiazolyl group,
4-methylthiazol-2-yl group, 5-methylthiazol-2-yl group, 5-thiazolyl
group, 2-oxazolyl group, 1-methylimidazol-2-yl group, 3-pyrazolyl
group, 1,2,4-triazol-3-yl group, 2-methyl-1,2,4-triazol-3-yl group,
5-tetrazolyl group, 3-methyl-1,2,4-thiadiazol-5-yl group, 2-pyridyl
group, 3-pyridyl group, 4-pyridyl group, 2-pyrimidinyl group,
4-pyrimidinyl group, 2-pyrazinyl group, 3-pyridazinyl group or
2-benzofuranyl group for group C.
[0762] The "C6-14 aryl group optionally substituted by 1 to 3
substituent(s) selected from group B" is the above-defined "C6-14
aryl group", which is optionally substituted by 1 to 3
substituent(s) selected from the above-defined "group B", and
includes unsubstituted C6-14 aryl group.
[0763] Specifically, phenyl group, 2-fluorophenyl group,
3-fluorophenyl group, 4-fluorophenyl group, 2,4-difluorophenyl
group, 3,4-difluorophenyl group, 2-chlorophenyl group,
3-chlorophenyl group, 4-chlorophenyl group, 2,4-dichlorophenyl
group, 3,4-dichlorophenyl group, 3,5-dichlorophenyl group,
3,4-dibromophenyl group, 3-chloro-2-fluorophenyl group,
2-chloro-3-fluorophenyl group, 4-chloro-3-fluorophenyl group,
3-chloro-4-fluorophenyl group, 2-methylphenyl group, 3-methylphenyl
group, 4-methylphenyl group, 2,6-dimethylphenyl group,
2-ethylphenyl group, 3-ethylphenyl group, 4-ethylphenyl group,
4-propylphenyl group, 3-isopropylphenyl group, 4-isopropylphenyl
group, 3-butylphenyl group, 3-isobutylphenyl group,
4-isobutylphenyl group, 3-(2-methyl-1-propenyl)ph- enyl group,
2-trifluoromethylphenyl group, 3-trifluoromethylphenyl group,
4-trifluoromethylphenyl group, 3,5-bistrifluoromethylphenyl group,
2-hydroxyphenyl group, 3-hydroxyphenyl group, 4-hydroxyphenyl
group, 2-methoxyphenyl group, 3-methoxyphenyl group,
4-methoxyphenyl group, 2-ethoxyphenyl group, 3-ethoxyphenyl group,
4-ethoxyphenyl group, 2-isopropyloxyphenyl group,
3-isopropyloxyphenyl group, 4-isopropyloxyphenyl group,
3-phenoxyphenyl group, 4-phenoxyphenyl group, 3-methylthiophenyl
group, 4-methylthiophenyl group, 3-carboxyphenyl group,
4-carboxyphenyl group, 3-cyanophenyl group, 4-cyanophenyl group,
3-acetylphenyl group, 4-acetylphenyl group, 3-isobutyrylphenyl
group, 4-isobutyrylphenyl group, 3-carbamoylphenyl group,
4-carbamoylphenyl group, 3-(methylcarbamoyl)phenyl group,
4-(methylcarbamoyl)phenyl group, 3-(isopropylcarbamoyl)phenyl
group, 4-(isopropylcarbamoyl)phenyl group, 3-(butylcarbamoyl)phenyl
group, 3-(N-ethyl-N-methylcarbamoyl)phenyl group,
3-(dimethylcarbamoyl)phenyl group, 4-(dimethylcarbamoyl)phenyl
group, 3-(diethylcarbamoyl)phenyl group, 4-(diethylcarbamoyl)phenyl
group, 3-{N-methyl-N-(3-methylbutyl)carbamoyl}phenyl group,
4-{N-methyl-N-(3-methylbutyl)carbamoyl}phenyl group,
3-sulfamoylphenyl group, 4-sulfamoylphenyl group,
3-(methylsulfamoyl)phenyl group, 4-(methylsulfamoyl)phenyl group,
3-(ethylsulfamoyl)phenyl group, 4-(ethylsulfamoyl)phenyl group,
3-(isopropylsulfamoyl)phenyl group, 3-(butylsulfamoyl)phenyl group,
3-(dimethylsulfamoyl)phenyl group, 4-(dimethylsulfamoyl)phenyl
group, 3-(diethylsulfamoyl)phenyl group, 4-(diethylsulfamoyl)phenyl
group, 3-(N-ethyl-N-methylsulfamoyl)phenyl group,
3-(methylsulfonyl)phenyl group, 4-(methylsulfonyl)phenyl group,
3-(ethylsulfonyl)phenyl group, 4-(ethylsulfonyl)phenyl group,
3-(isopropylsulfonyl)phenyl group, 4-(isopropylsulfonyl)phenyl
group, 4-chloro-3-carboxyphenyl group,
4-chloro-3-dimethylcarbamoylphenyl group, 3-chloro-4-methylphenyl
group, 3-chloro-4-hydroxyphenyl group, 3-chloro-4-methoxyphenyl
group, 3-chloro-4-ethoxyphenyl group, 3-chloro-4-isopropyloxyphenyl
group, 3-carboxy-5-trifluoromethylphenyl group,
3-dimethylcarbamoyl-5-trifluoromethylphenyl group,
4-dimethylcarbamoyl-2-fluorophenyl group, 4-carboxy-3-chlorophenyl
group, 3-chloro-4-methylcarbamoylphenyl group,
3-chloro-4-dimethylcarbamoylpheny- l group,
3-chloro-4-diethylcarbamoylphenyl group, 4-carbamoyl-3-chlorophen-
yl group, 3-chloro-4-acetylphenyl group, 3-chloro-4-pivaloylphenyl
group, 3-chloro-5-dimethylcarbamoylphenyl group,
3-hydroxy-4-dimethylcarbamoylph- enyl group,
3-hydroxy-5-dimethylcarbamoylphenyl group,
3-cyano-5-dimethylcarbamoylphenyl group, 3-carboxy-5-methoxyphenyl
group, 3-carboxy-5-ethoxyphenyl group,
3-carboxy-5-isopropyloxyphenyl group, 3-carboxy-5-cyanophenyl
group, 3,5-dicarboxyphenyl group, 3,4-dicarboxyphenyl group,
3-carboxy-5-dimethylcarbamoylphenyl group,
3-carboxy-4-methoxyphenyl group, 3-carboxy-4-ethoxyphenyl group,
3-carboxy-4-isopropyloxyphenyl group, 3-carboxy-4-cyanophenyl
group, 3-carbamoyl-5-dimethylcarbamoylphenyl group,
3-dimethylcarbamoyl-5-methyl- carbamoylphenyl group,
4-carboxy-3-methoxyphenyl group, 4-carboxy-2-methoxyphenyl group,
4-carboxy-3-ethoxyphenyl group, 4-carboxy-3-isopropyloxyphenyl
group, 4-carboxy-3-cyanophenyl group, 4-carbamoyl-2-methoxyphenyl
group, 4-methylcarbamoyl-3-methoxyphenyl group,
4-dimethylcarbamoyl-3-methoxyphenyl group, 3,5-bis(dimethylcarbamo-
yl)phenyl group, 3-carbamoyl-5-cyanophenyl group,
3-carboxy-4-methylphenyl group, 3-dimethylcarbamoyl-4-methylphenyl
group, 4-methyl-3-methylcarbamo- ylphenyl group,
3-dimethylsulfamoyl-4-methylphenyl group,
3,5-dichloro-4-hydroxyphenyl group, 3,5-dichloro-4-methoxyphenyl
group, 1-naphthyl group, 2-naphthyl group, 1-bromonaphthalen-2-yl
group, 6-bromonaphthalen-2-yl group, 7-cyanonaphthalen-2-yl group,
7-methoxynaphthalen-2-yl group, 5-bromo-6-methoxynaphthalen-2-yl
group and the like can be mentioned.
[0764] It is preferably phenyl group, 2-fluorophenyl group,
2-ethylphenyl group, 2,6-dimethylphenyl group, 2-chlorophenyl
group, 3-chlorophenyl group, 4-chlorophenyl group, 2-methoxyphenyl
group, 3-methoxyphenyl group, 4-methoxyphenyl group,
2-hydroxyphenyl group, 3-hydroxyphenyl group, 4-hydroxyphenyl group
or 2-trifluoromethylphenyl group for group C.
[0765] The "heteroaryl group optionally substituted by 1 to 3
substituent(s) selected from group B" is the above-defined
"heteroaryl group", which is optionally substituted by 1 to 3
substituent(s) selected from the above-defined "group B", and
includes unsubstituted heteroaryl group.
[0766] Specifically, 2-imidazolyl group, 5-methylpyrazol-3-yl
group, 5-methylisoxazol-3-yl group, 2-thiazolyl group,
1,2,4-triazol-3-yl group, 5-methyl-1,2,4-triazol-3-yl group,
5-ethyl-1,2,4-triazol-3-yl group, 1-ethyl-1,2,4-triazol-3-yl group,
1,5-dimethyl-1,2,4-triazol-3-yl group, 4-methyl-1,2,4-triazol-3-yl
group, 4-ethyl-1,2,4-triazol-3-yl group, 5-tetrazolyl group,
5-ethyl-1,2,4-oxadiazol-3-yl group, 5-ethyl-1,3,4-oxadiazol-2-yl
group, 2-pyridyl group, 4-methoxypyridin-2-yl group,
6-methylpyridin-2-yl group, 2-pyrimidinyl group, 4-pyrimidinyl
group, 4-methylpyrimidin-2-yl group, 4-ethylpyrimidin-2-yl group,
4-isopropylpyrimidin-2-yl group, 4-butylpyrimidin-2-yl group,
4-sec-butylpyrimidin-2-yl group, 4-carboxypyrimidin-2-yl group,
4-methoxypyrimidin-2-yl group, 4-ethoxypyrimidin-2-yl group,
4-isopropyloxypyrimidin-2-yl group, 4-tert-butyloxypyrimidin-2-yl
group, 5-methylpyrimidin-2-yl group, 5-ethylpyrimidin-2-yl group,
5-isopropylpyrimidin-2-yl group, 5-butylpyrimidin-2-yl group,
5-sec-butylpyrimidin-2-yl group, 5-carboxypyrimidin-2-yl group,
5-methoxypyrimidin-2-yl group, 5-ethoxypyrimidin-2-yl group,
5-isopropyloxypyrimidin-2-yl group, 5-tert-butyloxypyrimidin-2-yl
group, 3-pyridazinyl group, 2-pyrazinyl group and the like can be
mentioned.
[0767] The "group C" is a group selected from the following
substituent group:
[0768] (1) a hydrogen atom,
[0769] (2) the above-defined "C3-8 cycloalkyl C1-6 alkyl
group",
[0770] (3) a cyano group,
[0771] (4) the above-defined "halogen atom",
[0772] (5) the above-defined "C1-6 alkyl group",
[0773] (6) the above-defined "C2-6 alkenyl group",
[0774] (7) the above-defined "C2-6 alkynyl group",
[0775] (8) the above-defined "C6-14 aryl group",
[0776] (9) a heterocyclic group which is a saturated or unsaturated
5-membered or 6-membered heteromonocycle containing at least one
hetero atom selected from nitrogen atom, oxygen atom and sulfur
atom, or a fused ring of such heterocycles, or a fused ring of a
carbon ring selected from benzene, cyclopentane and cyclohexane and
the above-defined heterocycle,
[0777] (10) the above-defined "C1-6 alkyloxy group",
[0778] (11) the above-defined "C6-14 aryl C1-6 alkyl group",
[0779] (12) the above-defined "C6-14 aryl C1-6 alkyloxy group",
[0780] (13) --CO.sub.2R.sup.c1 (e.g., carboxyl group,
methoxycarbonyl group, ethoxycarbonyl group, isopropyloxycarbonyl
group, tert-butoxycarbonyl group, 2,2-dimethylpropyloxycarbonyl
group, cyclohexyloxycarbonyl etc.),
[0781] (14) --CONR.sup.c2R.sup.c3 (e.g., carbamoyl group,
methylcarbamoyl group, ethylcarbamoyl group, propylcarbamoyl group,
isopropylcarbamoyl group, butylcarbamoyl group, isobutylcarbamoyl
group, dimethylcarbamoyl group, diethylcarbamoyl group,
diisopropylcarbamoyl group, di-tert-butylcarbamoyl group,
N-ethyl-N-methylcarbamoyl group, N-isopropyl-N-methylcarbamoyl
group, N-butyl-N-methylcarbamoyl group, 2-fluoroethylcarbamoyl
group, 2-hydroxyethylcarbamoyl group, 2-methoxyethylcarbamoyl
group, N-methyl-N-(2-methoxyethyl)carbamoyl group,
2-oxopropylcarbamoyl group, 2-hydroxypropylcarbamoyl group,
carboxymethylcarbamoyl group, methoxycarbonylmethylcarbamoyl group,
2,2,2-trifluoroethylcarbamoyl group,
2-(trifluoroacetyloxy)ethylcarbamoyl group,
methylcarbamoylmethylcarbamoyl group, dimethylcarbamoylmethylcarba-
moyl group, 2-(methylsulfonyl)ethylcarbamoyl group, phenylcarbamoyl
group, benzylcarbamoyl group, N-benzyl-N-methylcarbamoyl group,
2-fluorobenzylcarbamoyl group, 4-fluorobenzylcarbamoyl group,
4-tert-butylbenzylcarbamoyl group, 4-(dimethylamino)benzylcarbamoyl
group, 4-(methylsulfonyl)benzylcarbamoyl group,
4-(acetylamino)benzylcarb- amoyl group, 1-naphthylmethylcarbamoyl
group, diphenylmethylcarbamoyl group, 1,2-diphenylethylcarbamoyl
group, 1,3-diphenylpropylcarbamoyl group, 2-pyridylmethylcarbamoyl
group, 3-pyridylmethylcarbamoyl group, 4-pyridylmethylcarbamoyl
group, 2-furylmethylcarbamoyl group,
4-methoxypyrimidin-2-ylmethylcarbamoyl group,
2-(2-oxopyrrolidin-1-yl)eth- ylcarbamoyl group,
1-pyrrolidinylcarbonyl group, 3-hydroxypyrrolidin-1-ylc- arbonyl
group, 3-oxopyrrolidin-1-ylcarbonyl group, morpholinocarbonyl group
etc.),
[0782] (15) --COR.sup.c4 (e.g., formyl group, acetyl group,
propionyl group, butyryl group, isobutyryl group, pivaloyl group,
benzoyl group, 3-methylbutyryl group, 2,2-dimethylbutyryl group,
2,2-dimethyl-1-hydroxyp- ropionyl group,
2,2-dimethyl-1-methoxypropionyl group,
1-acetyloxy-2,2-dimethylpropionyl group, 2-methyl-2-phenylpropionyl
group etc.),
[0783] (16) --SO.sub.2NR.sup.c2R.sup.c3 (e.g., sulfamoyl group,
methylsulfamoyl group, ethylsulfamoyl group, isopropylsulfamoyl
group, dimethylsulfamoyl group, diethylsulfamoyl group,
diisopropylsulfamoyl group, di-tert-butylsulfamoyl group,
N-ethyl-N-methylsulfamoyl group, N-isopropyl-N-methylsulfamoyl
group etc.),
[0784] (17) the above-defined "C6-14 arylcarbonyl group",
[0785] (18) --NR.sup.c4R.sup.c5 (e.g., amino group, methylamino
group, ethylamino group, propylamino group, isopropylamino group,
butylamino group, isobutylamino group, dimethylamino group,
diethylamino group, diisopropylamino group, di-tert-butylamino
group, N-ethyl-N-methylamino group, N-isopropyl-N-methylamino group
etc.),
[0786] (19) --NR.sup.c6COR.sup.c7 (e.g., acetylamino group,
propionylamino group, butyrylamino group, isobutyrylamino group,
pivaloylamino group, benzoylamino group, 4-fluorobenzoylamino
group, 3-methylbutyrylamino group, 3,3-dimethylbutyrylamino group,
(methoxyacetyl)amino group, 2-isopropyl-3-methylbutyrylamino group,
2,2-dimethyl-1-hydroxypropionylam- ino group,
2,2-dimethyl-1-methoxypropionylamino group,
1-acetyloxy-2,2-dimethylpropionylamino group,
2-methyl-2-phenylpropionyla- mino group, N-acetyl-N-methylamino
group, N-acetyl-N-isobutylamino group, benzylcarbonylamino group,
4-fluorobenzylcarbonylamino group, 3-phenylpropionylamino group,
cyclopentylcarbonylamino group, 2-pyridylcarbonylamino group,
3-pyridylcarbonylamino group, 4-pyridylcarbonylamino group,
2-furylcarbonylamino group, 2-thienylcarbonylamino group,
1-methylpyrrol-2-ylcarbonylamino group etc.)
[0787] (20) --NR.sup.c8SO.sub.2R.sup.c9 (e.g., methylsulfonylamino
group, ethylsulfonylamino group, isopropylsulfonylamino group,
phenylsulfonylamino group, benzylsulfonylamino group,
N-methyl-N-(methylsulfonyl)amino group,
N-methyl-N-(ethylsulfonyl)amino group,
N-methyl-N-(isopropylsulfonyl)amino group, 4-pyridylsulfonylamino
group, 2-furylsulfonylamino group, 2-thienylsulfonylamino group,
1-methylpyrrol-2-ylsulfonylamino group etc.),
[0788] (21) --SR.sup.c10 (e.g., methylsulfanyl group, ethylsulfanyl
group, isopropylsulfanyl group, phenylsulfanyl group etc.),
[0789] (22) --SOR.sup.c11 (e.g., methylsulfinyl group,
ethylsulfinyl group, isopropylsulfinyl group, phenylsulfinyl group
etc.),
[0790] (23) --SO.sub.2R.sup.c12 (e.g., methylsulfonyl group,
ethylsulfonyl group, isopropylsulfonyl group, phenylsulfonyl group
etc.),
[0791] (24) --NR.sup.c13CONR.sup.c14R.sup.c15 (e.g.,
methylcarbamoylamino group, dimethylcarbamoylamino group,
diethylcarbamoylamino group, diisopropylcarbamoylamino group,
N-ethyl-N-methylcarbamoylamino group etc.),
[0792] (25) --NR.sup.c16CO.sub.2R.sup.c17 (e.g.,
methoxycarbonylamino group, ethoxycarbonylamino group,
isopropyloxycarbonylamino group, phenoxycarbonylamino group etc.)
and
[0793] (26) --NR.sup.c18COCOR.sup.c19 (e.g., 2-oxopropionylamino
group, 2-oxobutyrylamino group, 3-methyl-2-oxobutyrylamino group,
2-oxo-2-(pyridin-2-yl)acetylamino group etc.).
[0794] Here, R.sup.c1, R.sup.c2, R.sup.c3, R.sup.c4, R.sup.c5,
R.sup.c6, R.sup.c7, R.sup.c8, R.sup.c9, R.sup.c10, R.sup.c11,
R.sup.c12, R.sup.c13, R.sup.c14, R.sup.c15, R.sup.c16, R.sup.c17,
R.sup.c18 and R.sup.c19 are each independently
[0795] (1') a hydrogen atom,
[0796] (2') a C1-7 alkyl group optionally substituted by 1 to 3
substituent(s) selected from the above-mentioned group A,
[0797] (3') a C6-14 aryl group optionally substituted by 1 to 3
substituent(s) selected from the above-mentioned group B,
[0798] (4') a heterocyclic group optionally substituted by 1 to 3
substituent(s) selected from the above-mentioned group B, or
[0799] (5') a C3-8 cycloalkyl group,
[0800] wherein R.sup.c2 and R.sup.c3 may form, together with the
adjacent nitrogen atom, a nitrogen-containing heterocycle, and the
nitrogen-containing heterocycle may contain an ether moiety or a
carbonyl moiety, and are optionally substituted by 1 to 3
substituent(s) selected from the above-mentioned group B.
[0801] The C1-7 alkyl group, C1-6 alkyl moiety, C2-6 alkenyl group
and C2-6 alkynyl group of the above-mentioned group C are
optionally substituted by 1 to 3 substituent(s) selected from the
above-mentioned group A, or a nitrogen-containing heterocyclic
group optionally containing a carbonyl moiety, and specifically
includes the above-defined "C1-7 alkyl group optionally substituted
by 1 to 3 substituent(s) selected from group A", the above-defined
"C2-6 alkenyl group optionally substituted by 1 to 3 substituent(s)
selected from group A", the above-defined "C2-6 alkynyl group
optionally substituted by 1 to 3 substituent(s) selected from group
A" and an oxy group substituted by the above-defined "C1-6 alkyl
group optionally substituted by 1 to 3 substituent(s) selected from
group A".
[0802] The C6-14 aryl group, C6-14 aryl moiety and heterocyclic
group of the above-mentioned group C are optionally substituted by
1 to 3 substituent(s) selected from the above-mentioned group B and
specifically include the above-defined "C6-14 aryl group optionally
substituted by 1 to 3 substituent(s) selected from group B", the
above-defined "heterocyclic group optionally substituted by 1 to 3
substituent(s) selected from group B", the above-defined "C1-6
alkyl group" substituted by the above-defined "C6-14 aryl group
optionally substituted by 1 to 3 substituent(s) selected from group
B", the above-defined "C1-6 alkyloxy group" substituted by the
above-defined "C6-14 aryl group optionally substituted by 1 to 3
substituent(s) selected from group B", and a carbonyl group
substituted by the "C6-14 aryl group optionally substituted by 1 to
3 substituent(s) selected from group B".
[0803] In addition, the "C6-14 aryl C1-6 alkyl group" of the
above-mentioned group C includes a "C1-6 alkyl group" substituted
by the above-defined "C6-14 aryl group optionally substituted by 1
to 3 substituent(s) selected from group B", wherein the alkyl group
moiety is substituted by 1 to 3 substituent(s) selected from the
above-defined "group A", and specifically, carbamoylphenylmethyl
group, 1-carboxy-2-phenylethyl group, 1-hydroxymethyl-2-phenylethyl
group, 1-carboxymethyl-2-phenylethyl group,
1-benzyloxycarbonyl-2-phenylethyl group and the like can be
mentioned.
[0804] In addition, the "C6-14 aryl C1-6 alkyloxy group" of the
above-mentioned group C includes a "C1-6 alkyloxy group"
substituted by the above-defined "C6-14 aryl group optionally
substituted by 1 to 3 substituent(s) selected from group B",
wherein the alkyl group moiety is substituted by 1 to 3
substituent(s) selected from the above-defined "group A", and
specifically, carbamoylphenylmethyloxy group,
1-carboxy-2-phenylethyloxy group, 1-hydroxymethyl-2-phenylethyloxy
group, 1-carboxymethyl-2-phenylethyloxy group,
1-benzyloxycarbonyl-2-phenylethyl- oxy group and the like can be
mentioned.
[0805] R.sup.c2 and R.sup.c3 may form, "together with the adjacent
nitrogen atom, a nitrogen-containing heterocycle", and the
"nitrogen-containing heterocycle" contains at least one nitrogen
atom among the above-mentioned "heterocyclic groups", and a bond
extends from the nitrogen atom. The "nitrogen-containing
heterocycle" may further contain, besides nitrogen atom, a hetero
atom selected from oxygen atom and sulfur atom.
[0806] Preferably, 1-pyrrolidinyl group, 3-hydroxypyrrolidin-1-yl
group, 3-oxopyrrolidin-1-yl group and morpholino group can be
mentioned.
[0807] When X is --C(R.sup.x1)(R.sup.x2)-#,
--C(R.sup.x1)(R.sup.x2)--C(R.s- up.x3)(R.sup.x4)-#,
--C(R.sup.x1)(R.sup.x2)--C(R.sup.x3)(R.sup.x4)--C(R.su-
p.x5)(R.sup.x6)-#,
--C(R.sup.x1)(R.sup.x2)--C(R.sup.x7).dbd.C(R.sup.x8)-#, or
--C(R.sup.x7).dbd.C(R.sup.x8)--C(R.sup.x1)(R.sup.x2)-#, and when
R.sup.x1 and R.sup.x2, R.sup.x3 and R.sup.x4, or R.sup.x5 and
R.sup.x6 form a C3-8 cycloalkyl together with the adjacent carbon
atom, X is, for example, 22
[0808] and as a cycloalkyl moiety, cyclopropyl group, cyclobutyl
group, cyclopentyl group, cyclohexyl group, cycloheptyl group and
cyclooctyl group can be mentioned.
[0809] The cycloalkyl moiety is preferably a cyclopentyl group or a
cyclohexyl group.
[0810] R.sup.1 is preferably 23
[0811] and Z is preferably the above-defined "C1-6 alkylene" or
*-(CH.sub.2).sub.m--Q--(CH.sub.2).sub.n--, more preferably, the
above-defined "C1-6 alkylene".
[0812] Ring D is preferably the above-defined "C3-10 carbon ring
group optionally substituted by 1 to 3 substituent(s) selected from
group B", more preferably, a phenyl group optionally substituted by
1 to 3 substituent(s) selected from the above-defined "group B",
and more preferably, a phenyl group optionally substituted by 1 to
3 substituent(s) selected from a halogen atom and --OR.sup.b1
wherein R.sup.b1 is a hydrogen atom or a C1-6 alkyl group.
[0813] R.sup.1 is preferably the above-defined "C1-6 alkyl group
optionally substituted by 1 to 3 substituent(s) selected from group
A", more preferably the above-defined "C1-6 alkyl group".
[0814] R.sup.2 is preferably a hydrogen atom, a C6-14 aryl C1-6
alkyl group or --SO.sub.2R.sup.d1, more preferably a hydrogen
atom.
[0815] X is preferably
--C(R.sup.x1)(R.sup.x2)--C(R.sup.x3)(R.sup.x4)-#,
--C(R.sup.x1)(R.sup.x2)--C(R.sup.x3)(R.sup.x4)--C(R.sup.x5)(R.sup.x6)-#,
--C(R.sup.x7).dbd.C(R.sup.x8)-#, --N.dbd.C(R.sup.x9)-#, or
--C(R.sup.x10).dbd.N-#, more preferably
--C(R.sup.x1)(R.sup.x2)--C(R.sup.- x3)(R.sup.x4)-#, or
--C(R.sup.x7).dbd.C(R.sup.x8)-#.
[0816] One of the more preferable embodiments is
--C(R.sup.x1)(R.sup.x2)--- C(R.sup.x3)(R.sup.x4)-#, and the other
is --C(R.sup.x7).dbd.C(R.sup.x8)-#. 24
[0817] of ring B is preferably C.dbd.C(R.sup.y1)--N(R.sup.y2),
N--C(R.sup.y1).dbd.N, N--C(R.sup.y1).dbd.C(R.sup.y2), or
C.dbd.N--N(R.sup.y2), more preferably N--C(R.sup.y1).dbd.C
(R.sup.y2).
[0818] Preferable embodiments of the formula [I] include the
following formulas [I]-1, [I]-2, [I]-3 and [I]-4: 25
[0819] wherein each symbol is as defined above.
[0820] R.sup.x1 to R.sup.x10 are preferably selected from
[0821] a hydrogen atom,
[0822] a C3-8 cycloalkyl C1-6 alkyl group,
[0823] a cyano group,
[0824] a C1-7 alkyl group,
[0825] a C6-14 aryl group,
[0826] a C6-14 aryl C1-6 alkyl group,
[0827] --CO.sub.2R.sup.c1,
[0828] --CONR.sup.c2R.sup.c3 or
[0829] --COR.sup.c4
[0830] wherein each symbol and substituent is as defined above.
[0831] It is also preferable that R.sup.x3 and R.sup.x4 form a C3-8
cycloalkyl together with the adjacent carbon atom.
[0832] As R.sup.x1 to R.sup.x10, hydrogen atom, cyano group, methyl
group, ethyl group, propyl group, isopropyl group, butyl group,
isobutyl group, hydroxymethyl group, 1-hydroxyethyl group,
2-hydroxyethyl group, 1-hydroxypropyl group, 3-hydroxypropyl group,
1-hydroxy-2-methylpropyl group, methoxymethyl group,
2-methylsulfanylethyl group, 2-methylsulfonylethyl group, phenyl
group, benzyl group, phenethyl group, 3-phenylpropyl group,
carboxyl group, methoxycarbonyl group, formyl group, acetyl group,
dimethylcarbamoyl group and the like can be mentioned, or R.sup.x3
and R.sup.x4 may form a cyclopentyl group or a cyclohexyl group,
together with the adjacent carbon atom.
[0833] R.sup.x1 to R.sup.x10 are more preferably hydrogen
atoms.
[0834] R.sup.y1 is preferably selected from
[0835] a hydrogen atom,
[0836] a C1-7 alkyl group,
[0837] a C6-14 aryl group,
[0838] --CO.sub.2R.sup.c1,
[0839] --CONR.sup.c2R.sup.c3,
[0840] --COR.sup.c4and
[0841] a C6-14 arylcarbonyl group
[0842] wherein each symbol and substituent is as defined above.
[0843] R.sup.y1 is specifically hydrogen atom, methyl group,
isopropyl group, isobutyl group, tert-butyl group, cyanomethyl
group, hydroxymethyl group, 1-hydroxyethyl group, 2-hydroxyethyl
group, 1-hydroxy-2-methylpropyl group, 1-hydroxy-2,2-dimethylpropyl
group, methoxymethyl group, isopropyloxymethyl group,
isobutyloxymethyl group, 2-hydroxy-3,3-dimethylbutyl group,
methylsulfanylmethyl group, isopropylsulfanylmethyl group,
methylsulfonylmethyl group, isopropylsulfonylmethyl group,
pivaloylmethyl group, phenoxymethyl group, benzyloxycarbonylmethyl
group, phenyl group, carboxyl group, methoxycarbonyl group,
carbamoyl group, methylcarbamoyl group, dimethylcarbamoyl group,
diethylcarbamoyl group, N-ethyl-N-methylcarbamoy- l group,
N-isopropyl-N-methylcarbamoyl group, formyl group, acetyl group,
propionyl group, isobutyryl group, pivaloyl group, benzoyl group,
1-(benzyloxycarbonyl)-2-phenylethyl group and the like.
[0844] These substituents are particularly preferable when X is
--C(R.sup.x1)(R.sup.x2)--C(R.sup.x3)(R.sup.x4)-#.
[0845] R.sup.y1 is particularly preferably a hydrogen atom.
[0846] R.sup.y2 is preferably selected from
[0847] a hydrogen atom,
[0848] a halogen atom,
[0849] a C1-7 alkyl group,
[0850] a C6-14 aryl group,
[0851] a heterocyclic group,
[0852] --CO.sub.2R.sup.c1,
[0853] --CONR.sup.c2R.sup.c3,
[0854] --COR.sup.c4,
[0855] --NR.sup.c4 R.sup.c5,
[0856] --NR.sup.c6COR.sup.c7,
[0857] --NR.sup.c8SO.sub.2R.sup.c9,
[0858] SR.sup.c10,
[0859] --SO.sub.2R.sup.c12,
[0860] --NR.sup.c13CONR.sup.c14R.sup.c15,
[0861] --NR.sup.c16CO.sub.2R.sup.c17, and
[0862] --NR.sup.c18COCOR.sup.c19
[0863] wherein each symbol and substituent is as defined above.
[0864] One of the preferable embodiments of R.sup.y2 is
heterocyclic group.
[0865] More preferably, R.sup.y2 is a heterocyclic group bonded to
Y.sup.3 via a carbon atom, wherein at least one of the
.alpha.-position of the carbon atom is a hetero atom selected from
the group consisting of nitrogen atom, oxygen atom and sulfur atom.
The heterocyclic group is optionally substituted by 1 to 3
substituent(s) selected from group B, and specifically, 2-thiazolyl
group, 4-methyl-thiazol-2-yl group, 5-methyl-thiazol-2-yl group,
5-thiazolyl group, 2-oxazolyl group, 1-methyl-imidazol-2-yl group,
3-pyrazolyl group, 1,2,4-triazol-3-yl group,
2-methyl-1,2,4-triazol-3-yl group, 5-tetrazolyl group,
3-methyl-1,2,4-thiadiazol-5-yl group, 2-pyridyl-group,
2-pyrimidinyl group, 4-pyrimidinyl group, 2-pyrazinyl group,
3-pyridazinyl group, 2-benzofuranyl group and the like can be
mentioned.
[0866] Other preferable embodiments of R.sup.y2 include
--CO.sub.2R.sup.c1 (carboxyl group, methoxycarbonyl group,
isopropyloxycarbonyl group, 2,2-dimethylpropyloxycarbonyl group and
cyclohexyloxycarbonyl group can be specifically mentioned),
--CONR.sup.c2R.sup.c3 (carbamoyl group, methylcarbamoyl group,
ethylcarbamoyl group, propylcarbamoyl group, isopropylcarbamoyl
group, butylcarbamoyl group, isobutylcarbamoyl group,
dimethylcarbamoyl group, diethylcarbamoyl group,
N-butyl-N-methylcarbamoy- l group, 2-fluoroethylcarbamoyl group,
2-hydroxyethylcarbamoyl group, 2-methoxyethylcarbamoyl group,
N-methyl-N-(2-methoxyethyl)carbamoyl group, 2-oxopropylcarbamoyl
group, 2-hydroxypropylcarbamoyl group, carboxymethylcarbamoyl
group, methoxycarbonylmethylcarbamoyl group,
2,2,2-trifluoroethylcarbamoyl group,
2-(trifluoroacetyloxy)ethylcarbamoyl group,
methylcarbamoylmethylcarbamoyl group, dimethylcarbamoylmethylcarba-
moyl group, 2-(methylsulfonyl)ethylcarbamoyl group, phenylcarbamoyl
group, benzylcarbamoyl group, N-benzyl-N-methylcarbamoyl group,
2-fluorobenzylcarbamoyl group, 4-fluorobenzylcarbamoyl group,
4-tert-butylbenzylcarbamoyl group, 4-(dimethylamino)benzylcarbamoyl
group, 4-(methylsulfonyl)benzylcarbamoyl group,
4-(acetylamino)benzylcarb- amoyl group, 1-naphthylmethylcarbamoyl
group, diphenylmethylcarbamoyl group, 1,2-diphenylethylcarbamoyl
group, 1,3-diphenylpropylcarbamoyl group, 2-pyridylmethylcarbamoyl
group, 3-pyridylmethylcarbamoyl group, 4-pyridylmethylcarbamoyl
group, 2-furylmethylcarbamoyl group,
4-methoxypyrimidin-2-ylmethylcarbamoyl group,
2-(2-oxopyrrolidin-1-yl)eth- ylcarbamoyl group,
1-pyrrolidinylcarbonyl group, 3-hydroxypyrrolidin-1-ylc- arbonyl
group, 3-oxopyrrolidin-1-ylcarbonyl group and morpholinocarbonyl
group can be specifically mentioned) and
[0867] --COR.sup.c4 (acetyl group, propionyl group,
2,2-dimethyl-3-hydroxypropionyl group, 2-methyl-2-phenylpropionyl
group, 2,2-dimethyl-3-methoxypropionyl group,
3-acetyloxy-2,2-dimethylpropionyl group, isobutyryl group,
2,2-dimethylbutyryl group, pivaloyl group, 3-methylbutyryl group,
2,2-dimethylbutyryl group and benzoyl group can be specifically
mentioned).
[0868] More preferred is --COR.sup.c4 wherein R.sup.c4 is more
preferably an unsubstituted C1-6 alkyl group.
[0869] Still more preferable embodiment of R.sup.y2 include
[0870] --NR.sup.c4R.sup.c5 (e.g., amino group, ethylamino group,
isopropylamino group, isobutylamino group and diethylamino
group),
[0871] --NR.sup.c6COR.sup.c7 (e.g., acetylamino group,
propionylamino group, butyrylamino group, isobutyrylamino group,
pivaloylamino group, benzoylamino group, 4-fluorobenzoylamino
group, 3,3-dimethylbutyrylamino group, (methoxyacetyl)amino group,
2-isopropyl-3-methylbutyrylamino group,
2-methyl-2-phenylpropionylamino group, N-acetyl-N-methylamino
group, N-acetyl-N-isobutylamino group, benzylcarbonylamino group,
4-fluorobenzylcarbonylamino group, 3-phenylpropionylamino group,
cyclopentylcarbonylamino group, 2-pyridylcarbonylamino group,
3-pyridylcarbonylamino group, 4-pyridylcarbonylamino group can be
mentioned.),
[0872] --NR.sup.c8SO.sub.2R.sup.c9 (e.g., methylsulfonylamino
group, phenylsulfonylamino group, benzylsulfonylamino group,
2-thienylsulfonylamino group and N-methyl-N-(methylsulfonyl)amino
group),
[0873] --NR.sup.c13CONR.sup.c14R.sup.c15 (e.g.,
dimethylcarbamoylamino group),
[0874] --NR.sup.c16CO.sub.2R.sup.c17 (e.g., methoxycarbonylamino
group) and
[0875] --NR.sup.c18COCOR.sup.c19 (e.g., 2-oxopropionylamino
group).
[0876] R.sup.y2 is still more preferably --NR.sup.c6COR.sup.c7,
--NR.sup.c8SO.sub.2R.sup.c9, --NR.sup.c13CONR.sup.c14R.sup.c15,
--NR.sup.c16CO.sub.2R.sup.c17 or --NR.sup.c18COCOR.sup.c19,
particularly preferably --NR.sup.c6COR.sup.c7 (R.sup.c6 is more
preferably a hydrogen atom and R.sup.c7 is more preferably an
unsubstituted C1-6 alkyl group).
[0877] The "pharmaceutically acceptable salt thereof" may be any
salt as long as it forms a non-toxic salt with the compounds of the
above-mentioned formulas [I], [I]-1, [I]-2, [I]-3 and [I]-4, and
can be obtained by a reaction with an inorganic acid such as
hydrochloric acid, sulfuric acid, phosphoric acid, hydrobromic acid
and the like; an organic acid such as oxalic acid, malonic acid,
citric acid, fumaric acid, lactic acid, malic acid, succinic acid,
tartaric acid, acetic acid, trifluoroacetic acid, gluconic acid,
ascorbic acid, methylsulfonic acid, benzylsulfonic acid and the
like; an inorganic base such as sodium hydroxide, potassium
hydroxide, calcium hydroxide, magnesium hydroxide, ammonium
hydroxide and the like; an organic base such as methylamine,
diethylamine, triethylamine, triethanolamine, ethylenediamine,
tris(hydroxymethyl)methylamine, guanidine, choline, cinchonine and
the like; or an amino acid such as lysin, arginine, alanine and the
like. The present invention also encompasses hydrate and solvate of
each compound.
[0878] The present invention also encompasses prodrugs and
metabolites of each compound.
[0879] By the "prodrug" is meant a derivative of the compound of
the present invention, which has a chemically or metabolically
decomposable group and which, after administration to a body,
restores to the original compound to show its inherent efficacy,
including a complex and a salt free of covalent bond.
[0880] The prodrug is utilized for, for example, improving
absorption by oral administration or targeting of a target
site.
[0881] As the site to be modified, highly reactive functional
groups in the compound of the present invention, such as hydroxyl
group, carboxyl group, amino group, thiol group and the like, are
mentioned.
[0882] Examples of the hydroxyl-modifying group include methyl
group, benzyl group, trimethylsilyloxymethyl group, acetyl group,
propionyl group, isobutyryl group, pivaloyl group, benzoyl group,
4-methylbenzoyl group, dimethylcarbamoyl group, sulfo group and the
like. Examples of the carboxyl-modifying group include ethyl group,
pivaloyloxymethyl group, 1-(acetyloxy)ethyl group,
1-(ethoxycarbonyloxy)ethyl group, 1-(cyclohexyloxycarbonyloxy)ethyl
group, carboxylmethyl group, (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl
group, phenyl group, o-tolyl group and the like. Examples of the
amino-modifying group include hexylcarbamoyl group,
3-methylthio-1-(acetylamino)propylcarbonyl group,
1-sulfo-1-(3-ethoxy-4-hydroxyphenyl)methyl group,
(5-methyl-2-oxo-1,3-dio- xol-4-yl)methyl group and the like.
[0883] Preferably, prodrugs of the compounds of the formulas [I],
[I]-1, [I]-2, [I]-3 and [I]-4, wherein the hydroxyl group on ring B
is modified by methyl group, benzyl group or
trimethylsilyloxymethyl group, can be mentioned.
[0884] The compound of the present invention can be administered to
a mammal (human, mouse, rat, hamster, rabbit, cat, dog, bovine,
sheep, monkey and the like) as an anti-HIV agent, an integrase
inhibitor, an antiviral agent and the like.
[0885] When the compound of the present invention is used as a
pharmaceutical preparation, it is admixed with pharmaceutically
acceptable carriers, excipients, diluents, extending agents,
disintegrants, stabilizers, preservatives, buffers, emulsifiers,
flavoring agents, coloring agents, sweetening agents, thickeners,
correctives, dissolution aids, and other additives, that are
generally known per se, such as water, vegetable oil, alcohol
(e.g., ethanol or benzyl alcohol etc.), polyethylene glycol,
glycerol triacetate, gelatin, carbohydrate (e.g., lactose, starch
etc.), magnesium stearate, talc, lanolin, petrolatum and the like,
formed into tablet, pill, powder, granule, suppository, injection,
eye drop, liquid, capsule, troche, aerosol, elixir, suspension,
emulsion, syrup and the like by a conventional method, and
administered systemically or topically, and orally or
parenterally.
[0886] While the dose varies depending on age, body weight,
symptom, treatment effect, administration method and the like, it
is generally 0.01 mg to 1 g per administration for an adult, which
is given once to several times a day orally or in a dosage form of
an injection such as intravenous injection and the like.
[0887] As a preferable embodiment of the compound of the present
invention, a compound having high pharmacological activity (e.g., a
compound having a strong HIV integrase-inhibitory activity, a
compound having a strong anti-HIV (e.g., HIV-1 IIIB strain)
activity, a compound that resists easy occurrence of drug resistant
viruses, a compound effective against multiple drug resistant
viruses), a compound having fine bioavailability (e.g., a compound
showing high oral absorbability, a compound showing high cell
membrane (e.g., Caco2) permeability, a compound stable to metabolic
enzyme (e.g., S9), a compound maintained at high blood
concentration for a long time (e.g., high blood concentration after
8 hours from administration), a compound showing low binding rate
to a protein (e.g., human plasma protein, human serum albumin,
.alpha.1-acidic glycoprotein), a highly safe compound (e.g., a
compound showing low inhibitory activity against P450(CYP)) and the
like can be mentioned.
[0888] An anti-HIV agent is generally required to sustain its
effect for a long time, so that can be effective not only for
temporal suppression of viral growth but also prohibition of viral
re-growth. This means that a prolonged administration is necessary
and that a high single dose may be frequently inevitable to sustain
effect for a longer period through the night. Such prolonged and
high dose administration increases the risk of causing side
effects.
[0889] In view of this, one of the preferable modes of the
nitrogen-containing fused ring compound of the present invention is
such compound permitting high absorption by oral administration,
and such compound capable of maintaining blood concentration of the
administered compound for an extended period of time.
[0890] Furthermore, a compound that exhibits a strong anti-HIV
activity, high absorbability by oral administration, and long-term
sustention of blood concentration is desirable.
[0891] A compound showing less effect of addition of serum (e.g.,
human serum, fetal bovine serum, equine serum) in in vitro tests
and capable of maintaining strong integrase inhibitory activity and
strong anti-HIV activity is also one of the preferable
embodiments.
[0892] By the "prophylaxis of AIDS" is meant, for example,
administration of a pharmaceutical agent to an individual who
tested HIV positive but has not yet developed the disease state of
AIDS, administration of a pharmaceutical agent to an individual who
shows an improved disease state of AIDS after treatment but who
carries HIV still to be eradicated and whose relapse of AIDS is
worried, and administration of a pharmaceutical agent out of a fear
of possible infection.
[0893] Examples of the "other anti-HIV agents" to be used for a
multiple drug combination therapy include an anti-HIV antibody, an
HIV vaccine, immunostimulants such as interferon and the like, an
HIV ribozyme, an HIV antisense drug, a reverse transcriptase
inhibitor, a protease inhibitor, an inhibitor of bond between a
bond receptor (CD4, CXCR4, CCR5 and the like) of a host cell
recognized by virus and the virus, and the like.
[0894] Specific examples of the HIV reverse transcriptase inhibitor
include Retrovir(R) (zidovudine), Epivir(R) (lamivudine), Zerit(R)
(sanilvudine), Videx(R) (didanosine), Hivid(R) (zalcitabine),
Ziagen(R) (abacavir sulfate) Viramune(R) (nevirapine), Stocrin(R)
(efavirenz), Rescriptor(R) (delavirdine mesylate), Combivir(R)
(zidovudine+lamivudine)- , Trizivir(R) (abacavir
sulfate+lamivudine+zidovudine), Coactinon(R) (emivirine),
Phosphonovir(R), Coviracil(R), alovudine
(3'-fluoro-3'-deoxythymidine), Thiovir (thiophosphonoformic acid),
Capravirin
(5-[(3,5-dichlorophenyl)thio]-4-isopropyl-1-(4-pyridylmethyl)i-
midazole-2-methanol carbamic acid), Tenofovir disoproxil fumarate
((R)-[[2-(6-amino-9H-purin-9-yl)-1-methylethoxy]methyl]phosphonic
acid bis(isopropoxycarbonyloxymethyl)ester fumarate), DPC-083
((4S)-6-chloro-4-[(1E)-cyclopropylethenyl]-3,4-dihydro-4-trifluoromethyl--
2 (1H)-quinazolinone), DPC-961
((4S)-6-chloro-4-(cyclopropylethynyl)-3,4-d-
ihydro-4-(trifluoromethyl)-2(1H)-quinazolinone), DAPD
((-)-.beta.-D-2,6-diaminopurine dioxolane), Immunocal, MSK-055,
MSA-254, MSH-143, NV-01, TMC-120, DPC-817 and the like, wherein (R)
means a registered trademark (hereinafter the same) and the names
of other pharmaceutical agents are general names.
[0895] Specific examples of the HIV protease inhibitor include
Crixivan(R) (indinavir sulfate ethanolate), saquinavir, Invirase(R)
(saquinavir mesylate), Norvir(R) (ritonavir), Viracept(R)
(nelfinavir mesylate), lopinavir, Prozei(R) (amprenavir),
Kaletra(R) (ritonavir+lopinavir), mozenavir dimesylate
([4R-(4.alpha.,5.alpha.,6.beta.)]-1,3-bis[(3-aminoph-
enyl)methyl]-hexahydro-5,6-dihydroxy-4,7-bis(phenylmethyl)
-2H-1,3-diazepin-2-one dimethanesulfonate), tipranavir
(3'-[(1R)-1-[(6R)-5,6-dihydro-4-hydroxy-2-oxo-6-phenylethyl-6-propyl-2H-p-
yran-3-yl]propyl]-5-(trifluoromethyl)-2-pyridinesulfonamide),
lasinavir (N-[5(S)-(tert-butoxycarbonylamino)-4
(S)-hydroxy-6-phenyl-2(R)-(2,3,4-tr-
imethoxybenzyl)hexanoyl]-L-valine 2-methoxyethylenamide), KNI-272
((R)-N-tert-butyl-3-[(2S,3S)-2-hydroxy-3-N-[(R)-2-N-(isoquinolin-5-yloxya-
cetyl)
amino-3-methylthiopropanoyl]amino-4-phenylbutanoyl]-5,5-dimethyl-1,-
3-thiazolidine-4-carboxamide), GW-433908, TMC-126, DPC-681,
buckminsterfullerene, MK-944A (MK944
(N-(2(R)-hydroxy-1(S)-indanyl)-2(R)--
phenylmethyl-4(S)-hydroxy-5-[4-(2-benzo[b]furanylmethyl)-2(S)-(tert-butylc-
arbamoyl)piperazin-1-yl]pentanamide)+indinavir sulfate), JE-2147
([2(S)-oxo-4-phenylmethyl-3(S)-[(2-methyl-3-oxy)phenylcarbonylamino]-1-ox-
abutyl]-4-[(2-methylphenyl)methylamino]carbonyl-4(R)-5,5-dimethyl-1,3-thia-
zole), BMS-232632
((3S,8S,9S,12S)-3,12-bis(1,1-dimethylethyl)-8-hydroxy-4,-
11-dioxo-9-(phenylmethyl)-6-[[4-(2-pyridinyl)phenyl]methyl]-2,5,6,10,13-pe-
ntaazatetradecanedicarboxylic acid dimethyl ester), DMP-850
((4R,5S,6S,7R)-1-(3-amino-1H-indazol-5-ylmethyl)-4,7-dibenzyl-3-butyl-5,6-
-dihydroxyperhydro-1,3-diazepin-2-one), DMP-851 and the like.
[0896] The HIV integrase inhibitor is exemplified by S-1360 and the
like, the DNA polymerase inhibitor or DNA synthesis inhibitor is
exemplified by Foscavir(R), ACH-126443
(L-2',3'-didehydro-dideoxy-5-fluorocytidine), entecavir
((1S,3S,4S)-9-[4-hydroxy-3-(hydroxymethyl)-2-methylenecyclopent-
yl]guanine), calanolide A
([10R-(10.alpha.,11.beta.,12.alpha.)]-11,12-dihy-
dro-12-hydroxy-6,6,10,11-tetramethyl-4-propyl-2H,6H,10H-benzo[1,2-b:3,4-b'-
:5,6-b"]tripyran-2-one), calanolide B, NSC-674447
(1,1'-azobisformamide), Iscador (viscum album extract) and the
like, the HIV antisense drug is exemplified by HGTV-43, GEM-92 and
the like, the anti-HIV antibody or other antibody is exemplified by
NM-01, PRO-367, KD-247, Cytolin(R), TNX-355 (CD4 antibody), AGT-1,
PRO-140 (CCR5 antibody) and the like, the HIV vaccine or other
vaccine is exemplified by ALVAC(R), AIDSVAX(R), Remune(R), HIV gp41
vaccine, HIV gp120 vaccine, HIV gp140 vaccine, HIV gp160 vaccine,
HIV p17 vaccine, HIV p24 vaccine, HIV p55 vaccine, AlphaVax Vector
System, canarypox gp160 vaccine, AntiTat, MVA-F6 Nef vaccine, HIV
rev vaccine, C4-V3 peptide, p2249f, VIR-201, HGP-30W, TBC-3B,
PARTICLE-3B and the like, Antiferon (interferon-.alpha. vaccine)
and the like, the interferon or interferon agonist is exemplified
by Sumiferon(R), MultiFeron(R), interferon-.tau., Reticulose and
the like, the CCR5 antagonist is exemplified by SCH-351125 and the
like, the pharmaceutical agent acting on HIV p24 is exemplified by
GPG-NH2 (glycyl-prolyl-glycinamide) and the like, the HIV fusion
inhibitor is exemplified by FP-21399
(1,4-bis[3-[(2,4-dichlorophenyl)carbonylamino]-2-- oxo-5,8-disodium
sulfonyl]naphthyl-2,5-dimethoxyphenyl-1,4-dihydrazone), T-1249,
Synthetic Polymeric Construction No3, pentafuside and the like, the
IL-2 agonist or antagonist is exemplified by interleukin-2,
Imunace(R), Proleukin(R), Multikine(R), Ontak(R) and the like, the
TNF-.alpha. antagonist is exemplified by Thalomid(R) (thalidomide),
Remicade(R) (infliximab), curdlan sulfate, the .alpha.-glucosidase
inhibitor is exemplified by Bucast(R) and the like, the purine
nucleoside phosphorylase inhibitor is exemplified by peldesine
(2-amino-4-oxo-3H,5H-7-[(3-pyridyl)methyl]pyrrolo[3,2-d]pyrimidine)
and the like, the apoptosis agonist or inhibitor is exemplified by
Arkin Z(R), Panavir(R), Coenzyme Q10
(2-deca(3-methyl-2-butenylene)-5,6-dimetho-
xy-3-methyl-p-benzoquinone) and the like, the cholinesterase
inhibitor is exemplified by Cognex(R) and the like, and the
immunomodulator is exemplified by Imunox(R), Prokine(R),
Met-enkephalin
(6-de-L-arginine-7-de-L-arginine-8-de-L-valinamide-adrenorphin),
WF-10 (10-fold dilute tetrachlorodecaoxide solution), Perthon,
PRO-542 and the like.
[0897] In addition, Neurotropin(R), Lidakol(R), Ancer 20(R),
Ampligen(R), Anticort(R), Inactivin(R) and the like, PRO-2000, Rev
M10 gene, HIV specific cytotoxic T cell (CTL immunotherapy, ACTG
protocol 080 therapy, CD4-.zeta. gene therapy), SCA binding
protein, RBC-CD4 complex and the like are exemplified.
[0898] As the "other anti-HIV agents" to be used for a multiple
drug combination therapy with the compound of the present
invention, preferred are a reverse transcriptase inhibitor and a
protease inhibitor. Two or three, or even a greater number of
pharmaceutical agents can be used in combination, wherein a
combination of pharmaceutical agents having different action
mechanisms is one of the preferable embodiments. In addition,
selection of pharmaceutical agents free of side effect duplication
is preferable. Specific examples of the combination of
pharmaceutical agents include a combination of a group consisting
of efavirenz, indinavir, nelfinavir, ritonavir+indinavir,
ritonavir+lopinavir and ritonavir+saquinavir, and a group
consisting of didanosine+lamivudine, zidovudine+didanosine,
stavudine+didanosine, zidovudine+lamivudine and
stavudine+lamivudine (Guidelines for the Use of Antiretroviral
Agents in HIV-Infected Adults and Adolescents. Aug. 13, 2001).
Particularly preferred is Invirase(R) (saquinavir mesylate).
[0899] Some examples of the production method of the compound used
for embodiment of the present invention are shown in the following.
However, the production method of the compound of the present
invention is not limited to these examples.
[0900] Even in the absence of description in the production method,
efficient production can be afforded by introducing, where
necessary, a protecting group into a functional group followed by
deprotection in a subsequent step, subjecting a functional group to
each step as a precursor and converting the group to a desired
functional group in a suitable step, exchanging the order of
respective production methods and steps, and the like.
[0901] The work-up treatment in each step can be applied by a
typical method, wherein isolation and purification is performed by
selecting or combining conventional methods as necessary, such as
crystallization, recrystallization, distillation, partitioning,
column chromatography, thin layer chromatography, preparative HPLC
and the like.
[0902] The abbreviations used in the present specification are as
follows. Me means methyl group, Et means ethyl group; Bn means
benzyl group, n-Bu (or Bu) means butyl group, t-Bu means tert-butyl
group, Ac means acetyl group, Boc means tert-butoxycarbonyl group,
MOM means methoxymethyl group and Ms means methanesulfonyl
group.
[0903] Production Method 1
[0904] Production Method 1-1 26
[0905] wherein L.sup.1 is a leaving group such as a chlorine atom,
a bromine atom, a methanesulfonyloxy group, a
trifluoromethanesulfonyloxy group, a toluenesulfonyloxy group and
the like, W.sup.1 is a protecting group such as an acetyl group, a
benzoyl group, a benzyl group, a methoxyethoxymethyl group, a
tert-butyldimethylsilyl group and the like, or a hydrogen atom, and
other symbols are as defined above.
[0906] Compound [I] can be synthesized by reacting compound [1] in
an organic solvent such as tetrahydrofuran, dioxane,
dimethylformamide, dimethylacetamide, N-methylpyrrolidone,
1,3-dimethyl-2-imidazolidinone, tert-butanol, isopropanol and the
like, in the presence of a base such as sodium hydride, lithium
diisopropylamide, lithium bis(trimethylsilyl)amid- e, potassium
tert-butoxide, triethylamine, diisopropylethylamine and the like at
room temperature to cooling to give Compound [I].
[0907] When a compound wherein R.sup.2 is a hydrogen atom is
desired, the reaction only needs to be conducted by a conventional
method under the conditions to make W.sup.1 leave. When a compound
wherein R.sup.2 is a C1-6 alkyl group, a C6-14 aryl C1-6 alkyl
group or --SO.sub.2R.sup.d1 is desired, the reaction only needs to
be conducted under mild conditions under which these substituents
do not leave (the same applied to the following production
methods).
[0908] Production Method 1-2 27
[0909] wherein L.sup.2--X.sup.1-- is
C(R.sup.x7)(OMe).sub.2--CH(R.sup.x8)-- - or
C(R.sup.x7)(OMe).sub.2--CH(R.sup.x8)--C(R.sup.x1)(R.sup.x2)--
wherein each symbol is as defined above, when L.sup.2--X.sup.1-- is
C(R.sup.x7)(OMe).sub.2--C(R.sup.x8)--, --X.sup.2-- is
--C(R.sup.x7).dbd.C(R.sup.x8)-#, when L.sup.2--X.sup.1-- is
C(R.sup.x7)(OMe).sub.2--CH(R.sup.x8)--C(R.sup.x1)(R.sup.x2)--,
--X.sup.2-- is
--C(R.sup.x7).dbd.C(R.sup.x8)--C(R.sup.x1)(R.sup.x2)-#, and other
symbols are as defined above.
[0910] A compound represented by the formula [I-1] can be
synthesized by subjecting compound [2] to a ring closure reaction
under acidic conditions in a solvent or without solvent at room
temperature to under heating.
[0911] As the acid to be used, inorganic acids such as hydrochloric
acid, sulfuric acid, phosphoric acid, polyphosphoric acid and the
like, organic acids such as acetic acid, trifluoroacetic acid,
camphorsulfonic acid, p-toluenesulfonic acid, methanesulfonic acid,
trifluoromethanesulfonic acid and the like, acidic salts such as
pyridinium p-toluenesulfonate and the like, and the like can be
mentioned, and as the solvent, ether solvents such as
tetrahydrofuran, dioxane, diethyl ether and the like, benzene
solvents such as benzene, toluene, chlorobenzene, dichlorobenzene
and the like, alcohol solvents such as ethanol, isopropanol,
tert-butanol and the like, and halogenated hydrocarbon solvents
such as methylene chloride, chloroform, dichloroethane and the like
can be mentioned. A combination of an organic acid and a benzene
solvent often produce good results. In addition, preferable options
include, for example, a reaction under the conditions of using an
acid such as phosphoric acid, polyphosphoric acid, sulfuric acid
and the like without using a solvent, and the conditions of using
acetic acid or trifluoroacetic acid as a solvent and adding aqueous
hydrochloric acid thereto.
[0912] Production Method 2 28
[0913] wherein W.sup.2 is an alkyl group such as methyl group,
ethyl group and the like, or a hydrogen atom, and other symbols are
as defined above.
[0914] Compound [I] can be synthesized by subjecting compound [3]
to ring closure reaction under acidic or basic conditions at room
temperature to under heating.
[0915] When W.sup.2 is a hydrogen atom, for example, a ring closure
reaction can be achieved using a condensation agent such as
dicyclohexylcarbodiimide,
1-ethyl-3-(3-dimethylaminopropyl)carbodiimide, carbonyldiimidazole
and the like and conducting a reaction in the presence or absence
of a condensation additive such as 1-hydroxybenzotriazole,
N-hydroxysuccinimide and the like in an ether solvent such as
tetrahydrofuran, dioxane, diethyl ether and the like, a benzene
solvent such as benzene, toluene and the like, a hydrocarbon
solvent such as cyclohexane and the like, an amide solvent such as
dimethylformamide, dimethylacetamide, 1,3-dimethylimidazolidinone
and the like, a ketone solvent such as acetone, 2-butanone and the
like or a halogenated hydrocarbon solvent such as methylene
chloride, chloroform and the like.
[0916] When W.sup.2 is an alkyl group, a ring closure reaction can
be achieved by conducting a reaction in the presence of an acid
catalyst such as camphorsulfonic acid, p-toluenesulfonic acid and
the like or a base catalyst such as dimethylaminopyridine and the
like in a solvent such as benzene, toluene and the like at room
temperature to under heating, particularly preferably under
heating.
[0917] Production Method 3
[0918] Production Method 3-1 29
[0919] wherein each symbol is as defined above.
[0920] Compound [I-2] can be synthesized by reacting compound [4]
in an organic solvent such as tetrahydrofuran, dioxane,
dimethylformamide, dimethylacetamide, N-methylpyrrolidone,
1,3-dimethyl-2-imidazolidinone, tert-butanol, isopropanol, ethanol
and the like, or a mixed solvent of these with water, in the
presence or absence of an organic base such as triethylamine,
diisopropylethylamine and the like or a carbonate base such as
sodium carbonate, potassium carbonate, sodium hydrogen carbonate
and the like at room temperature to under heating.
[0921] Production Method 3-2 30
[0922] wherein each symbol is as defined above.
[0923] Compound [I-2] can be synthesized by subjecting compound [5]
to the same reaction operation as in Production method 1-1.
[0924] Production Method 3-3 31
[0925] wherein --X.sup.3--L.sup.3 is
--CH(R.sup.x7)--C(R.sup.x8)(OMe).sub.- 2 or
--C(R.sup.x1)(R.sup.x2)--CH(R.sup.x7)--C(R.sup.x8)(OMe).sub.2
wherein each symbol is as defined above, when --X.sup.3--L.sup.3 is
--CH(R.sup.x7)--C(R.sup.x8)(OMe) .sub.2, --X.sup.2-- is
--C(R.sup.x7).dbd.C(R.sup.x8)-#, when --X.sup.3--L.sup.3 is
--C(R.sup.x1)(R.sup.x2)--CH(R.sup.x7)--C(R.sup.x8)(OMe).sub.2,
--X.sup.2-- is
--C(R.sup.x1)(R.sup.x2)--C(R.sup.x7).dbd.C(R.sup.x8)-#, and other
symbols are as defined above.
[0926] Compound [I-2] can be synthesized by subjecting compound [6]
to the same reaction operation as in production method 1-2.
[0927] Production Method 3-4 32
[0928] wherein --X.sup.4--L.sup.4 is
--CH(R.sup.x7)--C(.dbd.O)(R.sup.x8) or
--C(R.sup.x1)(R.sup.x2)--CH(R.sup.x7)--C(.dbd.O)(R.sup.x8) wherein
each symbol is as defined above, when --X.sup.4--L.sup.4 is
--CH(R.sup.x7)--C(.dbd.O)(R.sup.x8), --X.sup.2-- is
--C(R.sup.x7).dbd.C(R.sup.x8)-#, when --X.sup.4--L.sup.4 is
--C(R.sup.x1)(R.sup.x2)--CH(R.sup.x7)--C(.dbd.O)(R.sup.x8),
--X.sup.2-- is
--C(R.sup.x1)(R.sup.x2)--C(R.sup.7).dbd.C(R.sup.x8)-#, and other
symbols are as defined above.
[0929] Compound [I-3] can be obtained by subjecting compound [7] to
a ring closure reaction in the same manner as in Production method
3-3. 33
[0930] wherein each symbol is as defined above.
[0931] Compound [4], compound [5], compound [6] and compound [7]
can be obtained by performing a condensation amidation reaction as
illustrated above in the same manner as in Production method 2.
[0932] In addition, a method comprising converting a carboxyl group
to an acid halide, followed by condensation, is highly versatile,
and often leads to good results. Specifically, a starting compound
is reacted with thionyl chloride, oxalyl chloride and the like in a
halogenated hydrocarbon solvent such as methylene chloride,
chloroform and the like or a benzene solvent such as benzene,
toluene and the like in the presence or absence of a catalytic
amount of dimethylformamide, thereafter reacted in the presence of
a base to complete the condensation reaction. Examples of the base
to be used include potassium carbonate, sodium carbonate, sodium
hydrogen carbonate, triethylamine, pyridine and the like, and good
results are often obtained when an organic base such as
triethylamine, pyridine and the like is used.
[0933] When these reactions are conducted and when other reactive
moieties are present, the methods usually employed for general
organic reactions often produce good results, wherein they may be
protected beforehand and deprotected after the reaction, or
condensation reaction is conducted in the form of a stable
precursor and thereafter converted to a desired form and the like.
Specifically, when two nitrogen atoms are present, a method
comprising protecting the one desired to be free from reaction, a
method comprising carrying out a condensation reaction using a
compound wherein a leaving group moiety is a hydroxyl group,
thereby avoiding a reaction between leaving groups L.sup.1 to
L.sup.3 with a nitrogen atom, after which the hydroxyl group is
converted to a leaving group and the like can be mentioned.
[0934] Compound [8], compound [10] and compound [13] can be
prepared by a method described in JP-A-2-502281 (WO88/06588),
WO03/016275, J. Med. Chem., 42, 4814-4823, 1999 and the like, or a
method analogous thereto.
[0935] Compound [9], compound [11], compound [12] and compound [14]
can be prepared as a secondary amine by a conventional method.
34
[0936] wherein L.sup.5 is a leaving group such as chlorine atom,
bromine atom, methanesulfonyloxy group, trifluoromethanesulfonyloxy
group, toluenesulfonyloxy group and the like, and other symbols are
as defined above.
[0937] Compound [17] can be obtained by reacting compound [15] or
compound [18] as illustrated above in the same manner as in
Production method 3. When these reactions are conducted and when
other reactive moieties are present, as described in Production
method 4, the methods usually employed for general organic
reactions often produce good results, wherein they may be protected
beforehand and deprotected after the reaction, or condensation
reaction is conducted in the form of a stable precursor and
thereafter converted to a desired form and the like.
[0938] When the amide moiety (R.sup.1--HNCO--) of compound [15] and
compound [18] is carboxylic acid or carboxylic acid ester
(W.sup.2--OCO--), L.sup.5 may be R.sup.1--NH--.
[0939] Moreover, L.sup.5--X-- may be
C(R.sup.x7)(OMe).sub.2--CH(R.sup.x8)-- - or
C(R.sup.x7)(OMe).sub.2--CH(R.sup.x8)--C(R.sup.x1)(R.sup.x2)--
wherein each symbol is as defined above. 35
[0940] wherein each symbol is as defined above.
[0941] Compound [15] and compound [18] can be obtained by
performing a condensation amidation reaction as illustrated above
in the same manner as in Production method 2.
[0942] Production Method 7
[0943] Compound [I]-1 wherein, in the formula [I], 36
[0944] is N--C(R.sup.y1).dbd.C(R.sup.y2), can be synthesized by the
aforementioned production methods (except Production method 3-4).
37
[0945] wherein L.sup.6 is L.sup.1 or L.sup.2, L.sup.7 is L.sup.1 or
L.sup.3, and other symbols are as defined above. The production
method of each step may be as described for each Production method
No. indicated in the scheme.
[0946] Compound [10'] can be obtained by reacting compound [8']
with NH.sub.3.
[0947] When producing compound [I]-1, fine results may be achieved
by using a compound wherein R.sup.y2 is a hydrogen atom and
introducing R.sup.y2 or a precursor thereof in any of the
above-mentioned steps.
[0948] Specific examples are given in the following. 38
[0949] wherein each symbol is as defined above.
[0950] Production of compound wherein R.sup.y2 is a bromine
atom.
[0951] Compound [8'-2] can be obtained by reacting compound [8'-1]
with a brominating reagent such as bromine, phenyltrimethylammonium
tribromide and the like.
[0952] As the solvent, chloroform has high versatility, but acetic
acid, toluene, chlorobenzene and the like may be also used. In
addition, an alcohol solvent such as methanol, ethanol and the like
may be used in combination with these solvents.
[0953] Production of compound [8'-3] wherein R.sup.y2is C1-7 alkyl
group, C3-8 cycloalkyl C1-6 alkyl group, C6-14 aryl C1-6 alkyl
group, C1-6 alkyloxy group, C6-14 aryl C1-6 alkyloxy group, C6-14
aryl group, heterocyclic group, cyano group, --CO.sub.2R.sup.c1,
--CONR.sup.c2R.sup.c3, --SO.sub.2NR.sup.c2R.sup.c3, C6-14
arylcarbonyl group, --NR.sup.c4R.sup.c5, --NR.sup.c6COR.sup.c7,
--NR.sup.c8SO.sub.2R.sup.c9, --NR.sup.c13CONR.sup.c14R.sup.c15,
--NR.sup.c16CO.sub.2R.sup.c17 or --NR.sup.c18COCOR.sup.c19, wherein
each symbol is as defined above.
[0954] Synthesis is performed according to a method described
in
[0955] a) Handbook of Palladium-Catalysed Organic Reactions:
Synthetic Aspects and Catalytic Cycles. Jean-Luc Malleron et al.
(1997) Academic Pr.
[0956] b) Palladium in Heterocyclic Chemistry: A Guide for the
Synthetic Chemist (Tetrahedron Organic Chemistry Series, V. 20).
Jie Jack Li et al. (2000) Elsevier Science Ltd.
[0957] c) Handbook of Organopalladium Chemistry for Organic
Synthesis. Ei-Ichi Negishi et al. (2002) John Wiley & Sons Inc.
and the like, by subjecting compound [8'-2] to a coupling reaction
using palladium as a catalyst.
[0958] More specifically, the following methods can be
mentioned.
[0959] Production of compound wherein R.sup.y2 is C6-14 aryl group
or heterocyclic group.
[0960] For example, the corresponding compound [8'-3] can be
obtained by heating compound [8'-2] and R.sup.y2--SnBu.sub.3 in
dioxane in the presence of a catalytic amount of
tetrakis(triphenylphosphine)palladium(0- ).
[0961] When carrying out this reaction, fine results are often
obtained using R.sup.y2--B(OH).sub.2 instead of
R.sup.y2--SnBu.sub.3. While many useful options of palladium
catalyst are described in the above-mentioned reference
literatures, one of the options is a combined use of palladium(II)
acetate and 1,3-bis(diphenylphosphino)propane. The usable solvent
is not limited to those mentioned above, and unless the reaction is
particularly inhibited, a comparatively wide variety of solvents
such as tetrahydrofuran, toluene and the like can be used. When
carrying out this reaction, fine results are often obtained by
carrying out the reaction in an inert gas to avoid interference by
oxygen and water.
[0962] Production of compound wherein R.sup.y2 is C1-7 alkyl group,
C3-8 cycloalkyl C1-6 alkyl group or C6-14 aryl C1-6 alkyl
group.
[0963] A desired compound [8'-3] can be obtained by, for example,
reacting compound [8'-2] with R.sup.y2--SnBu.sub.3 in the same
manner as above.
[0964] Here, in the case of a compound wherein R.sup.y2 is
R.sup.y2'--CX.sup.5H--CY.sup.5H-- (wherein X.sup.5 and Y.sup.5 are
each a lower alkyl group such as methyl group, ethyl group and the
like and R.sup.y2' is a group such as a C1-7 alkyl group, a C3-8
cycloalkyl C1-6 alkyl group and a C6-14 aryl C1-6 alkyl group,
wherein the alkyl moiety is free of CX.sup.5H--CY.sup.5H moiety),
fine results are often obtained by using
R.sup.y2'--CX.sup.5.dbd.CY.sup.5--SnBu.sub.3 to give compound
[8'-3] wherein R.sup.y2 is R.sup.y2'--CX.sup.5.dbd.CY.sup.5--, and
subjecting this compound to a catalytic reduction to give compound
[8'-3] wherein R.sup.y2 is R.sup.y2'--CX.sup.5H--CY.sup.5H--.
[0965] Production of compound wherein R.sup.y2 is C1-6 alkyloxy
group or C6-14 aryl C1-6 alkyloxy group.
[0966] A desired compound [8'-3] can be obtained by, for example,
reacting compound [8'-2] with R.sup.y2'ONa (wherein R.sup.y2' is a
C1-6 alkyl group or C6-14 aryl C1-6 alkyl group) in toluene in the
presence of bis(dibenzylideneacetone)palladium(0) or
1,1'-bis(diphenylphosphino)ferro- cene.
[0967] Production of compound wherein R.sup.y2 is cyano group.
[0968] The corresponding compound [8'-3] can be obtained by, for
example, heating compound [8'-2] and zinc cyanide in the presence
of a catalytic amount of tetrakis(triphenylphosphine)palladium(0)
in dimethylformamide.
[0969] Production of compound wherein R.sup.y2 is
--CO.sub.2R.sup.c1 or --CONR.sup.c2R.sup.c3.
[0970] A compound [8'-3] wherein R.sup.y2 is --CO.sub.2R.sup.c1 can
be obtained by, for example, heating compound [8'-2] under a carbon
monoxide atmosphere in dimethyl sulfoxide in the presence of
R.sup.c1OH, triethylamine, palladium(II) acetate and
1,3-bis(diphenylphosphino)propan- e.
[0971] A compound [8'-3] wherein R.sup.y2 is --CO.sub.2H can be
obtained by using methanol for R.sup.c1OH to give compound [8'-3],
wherein R.sup.y2 is --CO.sub.2CH.sub.3, and subjecting this
compound to hydrolysis by a conventional method using aqueous
sodium hydroxide solution/tetrahydrofuran and the like.
[0972] Compound [8'-3] wherein R.sup.y2 is --CONR.sup.c2R.sup.c3
can be obtained by condensation of this compound with
NHR.sup.c2R.sup.c3. As used herein, the condensation reaction can
be carried out according to the aforementioned production method 2
and production method 4.
[0973] Production of compound wherein R.sup.y2 is
--NR.sup.c4R.sup.c5.
[0974] A desired compound [8'-3] can be obtained by, for example,
heating compound [8'-2] and HNR.sup.c4R.sup.c5 in the presence of
cesium carbonate and a catalytic amount of palladium(II) acetate
and 2,2'-bis(di-tert-butylphosphino)-1,1'-binaphthyl in
benzene.
[0975] Production of compound wherein R.sup.y2 is
--NRC.sup.c6COR.sup.c7, --NR.sup.c8SO.sub.2R.sup.c9,
--NR.sup.c13CONR.sup.c14R.sup.c15, --NR.sup.c16CO.sub.2R.sup.c17 or
--NR.sup.c18COCOR.sup.c19.
[0976] Compound [8'-3] wherein R.sup.y2 is --NR.sup.c6COR.sup.c7
can be obtained by, for example, heating compound [8'-2] and
HNR.sup.c6COR.sup.c7 in toluene in the presence of sodium
tert-butoxide and a catalytic amount of palladium(II) acetate or
1,1'-bis(diphenylphosphino)ferrocene.
[0977] While compound [8'-3] wherein R.sup.y2 is
--NR.sup.c8SO.sub.2R.sup.- c9, --NR.sup.c13CONR.sup.c14R.sup.c15,
--NR.sup.c16CO.sub.2R.sup.c7 and --NR.sup.c18COCOR.sup.c19 can be
also synthesized in the same manner, finer results are sometimes
obtained when the reaction is carried out step by step. That is,
NH.sub.2CO.sub.2t-Bu and compound [8'-2] are subjected to a
reaction similar to the one mentioned above, whereby compound
[8'-3] wherein R.sup.y2 is --NHCO.sub.2t-Bu can be obtained. This
is treated with trifluoroacetic acid, hydrochloric acid-dioxane and
the like according to a conventional method to give compound [8'-5]
wherein R.sup.y2 is --NH.sub.2 can be obtained.
[0978] The corresponding compound [8'-3] can be synthesized by
reacting the obtained compound [8'-5] with the corresponding
carboxylic acid (e.g., R.sup.c7CO.sub.2H), carboxylic acid
anhydride (e.g., R.sup.c7CO.sub.2COR.sup.c7) or acid chloride
(e.g., R.sup.c7COCl), chlorocarbonic acid ester (R.sup.c17OCOCl),
isocyanate (R.sup.c14--NCO), chlorocarbonic acid amide
(R.sup.c14R.sup.c15NCOCl), sulfonyl chloride (R.sup.c9SO.sub.2Cl)
and the like, as described in the above-mentioned Production method
2 and Production method 4.
[0979] R.sup.c6, R.sup.c8, R.sup.c13, R.sup.c16, or R.sup.c18 may
be introduced into --NH.sub.2 prior to the above-mentioned
reactions or after the reactions by a conventional method.
[0980] Production of compound wherein R.sup.y2 is amino group.
[0981] Compound [8'-4] can be obtained by reacting compound [8'-1]
with nitric acid, fuming nitric acid, nitronium tetrafluoroborate
and the like.
[0982] As the solvent, acetic acid, chloroform and the like are
generally used and various conditions known as nitration conditions
of aromatic ring may be used.
[0983] Compound [8'-5] can be obtained by subjecting [8'-4] to
catalytic reduction, reduction with a metal powder such as iron,
zinc and the like, or reduction with a metal ion such as tin
chloride and the like.
[0984] As a solvent for reduction with a metal powder, acetic acid,
hydrochloric acid-alcohol, hydrochloric acid-tetrahydrofuran and
the like are generally used and for reduction using tin chloride,
methanol or ethanol is generally used.
[0985] The above-mentioned introduction of Br and conversion to
R.sup.y2 are not limited by compound [8] and can be performed at a
desired or suitable timing in the whole steps in the already
described Production methods, wherein introduction of Br and
conversion to R.sup.y2 may be conducted in different steps.
Particularly, introduction of Br sometimes provide fine results
when done in compound [5], [6], [10], [17], [18], [10] or [I-1].
39
[0986] wherein E is a functional group derived from an electrophile
corresponding to R.sup.y2 such as --COR.sup.c4, --COOH,
--SR.sup.c10 and the like, and each symbol is as defined above.
[0987] As a different method of introducing a functional group, a
method comprising reacting compound [15'-1] with a base and then
reacting with an electrophile can be mentioned.
[0988] Specific examples of electrophile include esters, aldehydes,
ketones, disulfides, carbon dioxide and the like.
[0989] As the base to be used, lithium diisopropylamide, potassium
hexamethyldisilamide, n-butyllithium and the like can be mentioned,
and as a solvent, tetrahydrofuran, diethyl ether, dimethoxyethane
and the like can be mentioned. When lithium diisopropylamide is
used in tetrahydrofuran, fine results are often obtained. As the
reaction temperature, when a reaction is carried out at room
temperature to under cooling, fine results are often obtained. In
this way, the introduced functional group can be also converted to
a desired and suitable R.sup.y2 by various known reactions.
[0990] As concrete examples, the following production methods can
be mentioned.
[0991] Production of compound wherein R.sup.y2 is --COR.sup.c4.
[0992] Compound [15'-2] wherein R.sup.y2 is --CH(OH)R.sup.c4 can be
obtained by adding R.sup.c4--CHO as an electrophile to compound
[15'-1] treated with lithium diisopropylamide at -78.degree. C. in
tetrahydrofuran.
[0993] The obtained compound [15'-2] wherein R.sup.y2 is
--CH(OH)R.sup.c4 can be converted to compound [15'-2] wherein
R.sup.y2 is --COR.sup.c4 by a treatment with a sulfur trioxide
pyridine complex in the presence of triethylamine and dimethyl
sulfoxide in a solvent that does not itself inhibit the reaction
such as chloroform. This oxidation reaction is not limited to the
above-mentioned conditions, and the conditions comprising using
1,1,1-tris(acetoxy)-1,1-dihydro-1,2-benziodoxol-3-(1H)-one
(Dess-Martin reagent) as an oxidant in chloroform also affords fine
results. While the reaction is carried out at room temperature to
under cooling under any conditions, the range of from 0.degree. C.
to room temperature is more preferable.
[0994] Production of compound wherein R.sup.y2 is --COOH,
--SR.sup.c10, --SOR.sup.c11 or --SO.sub.2R.sup.c12.
[0995] Using carbon dioxide or disulfide (R.sup.c10SSR.sup.c10
etc.) as an electrophile, compound [15'-2] wherein R.sup.y2 is
--COOH or --SR.sup.c10 can be obtained. Compound [15'-2] wherein
R.sup.y2 is --SR.sup.c10 is treated with a peracid such as
m-chloroperbenzoic acid and the like in chloroform, whereby
compound [15'-2] wherein R.sup.y2 is --SOR.sup.c11 or
--SO.sub.2R.sup.c12 can be obtained.
[0996] The introduction of E by electrophile and conversion to
R.sup.y2 are not limited by compound [15] and can be performed at a
desired or suitable timing in the whole steps in the already
described Production methods, wherein introduction of E and
conversion to R.sup.y2 may be conducted in different steps.
[0997] However, in order to control side reaction, it is often
better to not introduce E by electrophile in the presence of a base
in compounds [3], [8] and [10].
[0998] Production Method 8 40
[0999] wherein each symbol is as defined above.
[1000] Compound [I-5] can be obtained by converting compound [10']
to compound [19] and sequentially condensing the compound with a
compound represented by R.sup.x9--CH(OMe).sub.2.
[1001] For conversion of compound [10'] to compound [19] here,
R.sup.1--NHNH--W (W is amino-protecting group) is used instead of
R.sup.1--NH.sub.2, and a method according to the method described
in Production method 6 is performed.
[1002] A condensation reaction of compound [19] to compound [I-5]
is carried out in the presence of an acid catalyst such as
hydrochloric acid, p-toluenesulfonic acid, pyridinium
p-toluenesulfonate and the like in a benzene solvent such as
benzene, toluene, chlorobenzene and the like or an alcohol solvent
such as methanol, ethanol and the like at room temperature to under
heating. 41
[1003] wherein each symbol is as defined above.
[1004] Compound [I-6] can be obtained by converting compound [8']
to compound [20] and sequentially condensing with a compound
represented by R.sup.x10--CH(OMe).sub.2.
[1005] For conversion of compound [8'] to compound [20] here,
W--NH--NH.sub.2 (W is amino-protecting group) is used instead of
L.sup.5--X--NH.sub.2, and a method according to the method
described in Production method 5 is performed. A condensation
reaction of compound [20] to compound [I-6] is carried out under
acidic conditions in the same manner as in Production method 8-1.
42
[1006] wherein each symbol is as defined above.
[1007] Compound [I]-2 is a part of the compound represented by the
formula [I] and produced according to the aforementioned method,
wherein preferable results are often obtained when the production
follows this production method.
[1008] That is, compound [22] is synthesized by reacting compound
[21] prepared according to the a method described in a reference
(Breslow, D. S. et al., J. Am. Chem. Soc., 1946, 68, 1232) or a
method analogous thereto with R.sup.y1--C(NH.sub.2).dbd.NH under
acidic conditions or basic conditions. As the acid to be used,
hydrochloric acid, p-toluenesulfonic acid and the like can be
mentioned, and the acid is generally applied to the reaction in the
form of an amidine salt. Where necessary, the acid may be further
added. As the base, sodium methoxide, potassium carbonate and the
like can be mentioned, and as the solvent, methanol, ethanol,
dioxane, tetrahydrofuran and the like can be mentioned. This
reaction can be carried out in such a solvent that does not
particularly inhibit the reaction under comparatively wide pH
conditions. As a preferable method, for example, conditions under
which the reaction is carried out in methanol using sodium
methoxide as a base under heating can be mentioned.
[1009] The subsequent production step to produce compound [I]-2
from compound [22] via compound [23] is performed according to the
aforementioned Production method 4 and Production method 3. Prior
to this conversion, it is necessary to hydrolyze compound [22] into
carboxylic acid in a solvent such as alcohol, tetrahydrofuran and
the like using sodium hydroxide and the like. 43
[1010] wherein each symbol is as defined above.
[1011] Preferable results are often obtained when the production of
compound [I]-3 follows this production method.
[1012] That is, compound [24] derived from amino acid is reacted
with methyl orthoformate in methanol or without solvent in the
presence of an acid catalyst such as hydrochloric acid,
p-toluenesulfonic acid, pyridinium p-toluenesulfonate and the like,
and thereafter deprotected, whereby compound [25] can be
obtained.
[1013] Compound [26] can be obtained by reacting compound [25] with
methyl chloroglyoxylate in the presence of a base such as pyridine,
triethylamine and the like in a solvent such as chloroform,
toluene, tetrahydrofuran and the like or without solvent. Fine
results are often obtained when this reaction is carried out under
cooling.
[1014] Compound [27] can be obtained by reacting compound [26] with
W.sup.2--OAc. When performing this reaction, fine results are often
obtained when W.sup.2--OAc is treated with a base such as lithium
diisopropylamide, lithium hexamethyldisilamide and the like in a
solvent such as tetrahydrofuran and the like to give an enolate,
which is then reacted with compound [26]. While the reaction is
carried out at room temperature to under cooling, preferable
results are often obtained when the reaction is particularly
carried out at a temperature not more than 0.degree. C.
[1015] Compound [28] can be obtained by hydrolyzing compound [27]
under acidic conditions. As the acid to be used, 4N (or below)
hydrochloric acid is preferable, and the reaction is carried out in
tetrahydrofuran or dioxane.
[1016] Compound [29] can be obtained by treating compound [28] with
a base. As the base to be used, a metal salt such as potassium
carbonate, sodium carbonate and the like, a metal amide such as
lithium diisopropylamide, potassium hexamethyldisilamide and the
like, and an organic base such as triethylamine,
ethyldiisopropylamine, pyridine and the like can be mentioned, and
preferable results are often obtained when triethylamine,
ethyldiisopropylamine and the like are used. There are many options
of solvent, and, for example, chloroform, tetrahydrofuran, dioxane,
methanol, ethanol, toluene and the like can be mentioned, which are
obviously subject to limitation depending on the kind of a base to
be used.
[1017] A step to produce compound [I]-3 from compound [29] via
compound [30] can be performed according to the aforementioned
Production method 5 and Production method 1-1 or 1-2. 44
[1018] wherein each symbol is as defined above.
[1019] Compound [32] can be synthesized by reacting compound [31]
prepared by the method described in a reference (Micovic, I.V. et
al., J. Chem. Soc., Perkin Trans. 1(1996) 16, 2041) or a method
analogous thereto with a compound H.sub.2N--NH--R.sup.y2 in a
solvent such as methanol, ethanol, tetrahydrofuran, dioxane,
toluene and the like at room temperature to under heating.
[1020] Compound [I]-4 can be obtained by reacting compound [32]
with oxalyl chloride in the presence of an organic base such as
triethylamine, ethyldiisopropylamine, pyridine and the like in a
solvent such as chloroform, tetrahydrofuran, dioxane, toluene and
the like. While the reaction temperature is subject to no
limitation, preferable results are often obtained when the reaction
is carried out under cooling to room temperature.
EXAMPLES
[1021] The nitrogen-containing fused ring compound represented by
the formula [I] and a pharmaceutically acceptable salt thereof of
the present invention and production methods thereof are now
specifically explained by way of Examples. However, the present
invention is not limited by these Examples.
Example 1
Synthesis of
2-(3,4-dichlorobenzyl)-9-hydroxy-3,4-dihydro-2H-pyrido[1,2-a]-
pyrazine-1,8-dione hydrochloride
[1022] 45
[1023] Step 1
[1024] To a solution of 3-benzyloxy-4-oxo-4H-pyran-2-carboxylic
acid (0.4 g) prepared according to the method described in
references (JP-A-2-502281 (WO88/06588), J. Med. Chem., 1999, 42,
4814-4823) in chloroform (30 ml) were added oxalyl chloride (0.21
ml) and dimethylformamide (0.01 ml), and the mixture was stirred at
room temperature for 30 min. The reaction solvent was evaporated
under reduced pressure, toluene was added, the mixture was
concentrated and dissolved in chloroform (5 ml).
3,4-Dichlorobenzylamine (0.23 ml) and triethylamine (0.34 ml) were
added successively under ice-cooling, and the mixture was stirred
under ice-cooling for 20 min. 5% Aqueous potassium hydrogen sulfate
solution was added to the obtained reaction mixture and the mixture
was extracted with chloroform. The organic layer was washed with
saturated brine and dried over sodium sulfate. The solvent was
evaporated and the residue was purified by silica gel column
chromatography (hexane:ethyl acetate=1:1-1:8) to give
N-(3,4-dichlorobenzyl)-3-benzyloxy- -4-oxo-4H-pyran-2-carboxamide
(0.43 g).
[1025] .sup.1H-NMR(CDCl.sub.3).delta. 9.15(t,1H,J=6.0 Hz),
8.19(d,1H,J=5.8 Hz), 7.54(s,1H), 7.53(d,1H,J=8.4 Hz),
7.31-7.20(m,5H), 6.51 (d,1H,J=5.8 Hz), 5.17(s,2H), 4.46(d,1H,J=6.0
Hz).
[1026] Step 2
[1027] To a solution of
N-(3,4-dichlorobenzyl)-3-benzyloxy-4-oxo-4H-pyran-- 2-carboxamide
obtained in the previous step in tetrahydrofuran (1 ml), ethanol (1
ml) and water (0.2 ml) were added successively ethanolamine (0.05
ml) and 2N aqueous sodium carbonate solution (0.06 ml), and the
mixture was stirred at room temperature for 1 hr and at 35.degree.
C. for 4 hrs. The solvent was evaporated, and the obtained crystals
were washed successively with ethyl acetate and water and dried to
give
N-(3,4-dichlorobenzyl)-3-benzyloxy-1-(2-hydroxyethyl)-4-oxo-1,4-dihydropy-
ridine-2-carboxamide (0.142 g).
[1028] .sup.1H-NMR(DMSO-d.sub.6).delta. 9.46(t,1H,J=5.8 Hz),
7.60(d,1H,J=7.7 Hz), 7.56(d,1H,J=2.1 Hz), 7.32(d,1H,J=8.3 Hz),
7.30-7.27(m,5H), 7.25(dd,1H,J=2.1,8.3 Hz), 6.24(d,1H,J=7.7 Hz),
5.05(s,2H), 5.06-5.01(m,1H), 4.41(d,1H,J=5.8 Hz), 3.88-3.81(m,2H),
3.65-3.57(m,2H).
[1029] Step 3
[1030] To
N-(3,4-dichlorobenzyl)-3-benzyloxy-1-(2-hydroxyethyl)-4-oxo-1,4--
dihydropyridine-2-carboxamide (0.142 g) obtained in the previous
step was added dry tetrahydrofuran (2 ml), and the mixture was
cooled under an argon atmosphere at 0.degree. C.
Diisopropylethylamine (0.026 ml) and methanesulfonyl chloride
(0.009 ml) were successively added dropwise at the same
temperature, and the mixture was stirred at room temperature for 1
hr. Diisopropylethylamine (0.053 ml) and methanesulfonyl chloride
(0.019 ml) were successively added dropwise again at 0.degree. C.,
and the mixture was stirred at room temperature for 1 hr. 1N
Aqueous hydrochloric acid was added to the obtained reaction
mixture under ice-cooling, and the mixture was extracted three
times with ethyl acetate. The organic layer was washed with
saturated brine and dried over sodium sulfate. The solvent was
evaporated and the obtained crude product was dissolved in dry
tetrahydrofuran (4 ml). Sodium hydride (60%) (8 mg) was added, and
the mixture was heated at 80.degree. C. Sodium hydride (60%) (8 mg)
was added every 30 minutes, and after adding 5 times in total, 1N
aqueous hydrochloric acid was added under ice-cooling, and the
mixture was extracted three times with ethyl acetate. The organic
layer was washed with saturated brine and dried over sodium
sulfate. The solvent was evaporated and the residue was purified by
thin layer chromatography (ethyl acetate:methanol=5:2) to give
9-benzyloxy-2-(3,4-dichlorobenzyl)-3,4-dihydro-2H-pyrido[1,2-a)pyrazine-1-
,8-dione (22 mg).
[1031] .sup.1H-NMR(DMSO-d.sub.6).delta. 7.64(d,1H,J=7.4 Hz),
7.62-7.56(m,2H), 7.51-7.46(m,2H), 7.34-7.22(m,4H), 6.26(d,1H,J=7.4
Hz), 5.08(s,2H), 4.67(s,2H), 4.17-4.08(m,2H), 3.63-3.55(m,2H).
[1032] Step 4
[1033] To
9-benzyloxy-2-(3,4-dichlorobenzyl)-3,4-dihydro-2H-pyrido[1,2-a]p-
yrazine-1,8-dione (12 mg) obtained in the previous step were added
acetic acid (0.75 ml) and conc. hydrochloric acid (0.15 ml) and the
mixture was stirred at 90.degree. C. for 20 min. The solvent was
evaporated, and the obtained residue was crystallized from
hexane:ethyl acetate=1:2 to give
2-(3,4-dichlorobenzyl)-9-hydroxy-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,8-
-dione hydrochloride (8 mg).
[1034] .sup.1H-NMR(DMSO-d.sub.6).delta. 7.96(d,1H,J=7.2 Hz),
7.67(d,1H,J=1.9 Hz), 7.62(d,1H,J=8.4 Hz), 7.36(dd,1H,J=1.9,8.4 Hz),
6.73(d,1H,J=7.2 Hz), 4.74(s,2H), 4.42-4.36(m,2H),
3.79-3.74(m,2H).
Example 2
Synthesis of
2-(3,4-dichlorobenzyl)-10-hydroxy-2,3,4,5-tetrahydropyrido[1,-
2-a][1,4]diazepine-1,9-dione
[1035] 46
[1036] Step 1
[1037]
N-(3,4-Dichlorobenzyl)-3-benzyloxy-4-oxo-4H-pyran-2-carboxamide (60
mg) obtained in the same manner as in Example 1, step 1 was
dissolved in tetrahydrofuran (0.5 ml), ethanol (0.5 ml) and water
(0.1 ml), and 3-amino-1-propanol (0.0226 ml) and sodium carbonate
(8 mg) were successively added. The mixture was stirred at room
temperature for 7 hr. The solvent was evaporated, and the obtained
residue was purified by silica gel column chromatography (ethyl
acetate:methanol=100:0-4:1) to give
N-(3,4-dichlorobenzyl)-3-benzyloxy-1-(3-hydroxypropyl)-4-oxo-1,4-dih-
ydropyridine-2-carboxamide (43 mg).
[1038] .sup.1H-NMR(DMSO-d.sub.6).delta. 9.47(t,1H,J=6.0 Hz),
7.65(d,1H,J=7.4 Hz), 7.57(d,1H,J=1.9 Hz), 7.34-7.25(m,7H),
6.26(d,1H,J=7.4 Hz), 5.05(s,2H), 4.65(t,1H,J=4.9 Hz),
4.42(d,2H,J=6.0 Hz), 3.86(dd,2H,J=7.2,7.2 Hz),
3.35(dd,2H,J=6.3,10.9 Hz), 1.84-1.77(m,2H).
[1039] Step 2
[1040]
N-(3,4-Dichlorobenzyl)-3-benzyloxy-1-(3-hydroxypropyl)-4-oxo-1,4-di-
hydropyridine-2-carboxamide (30 mg) obtained in the previous step
was dissolved in tetrahydrofuran (1.5 ml) and the mixture was
cooled to 0.degree. C. under an argon atmosphere.
Diisopropylethylamine (0.034 ml) and methanesulfonyl chloride
(0.0065 ml) were successively added dropwise at the same
temperature and the mixture was stirred at room temperature for 2
hr. Diisopropylethylamine (0.017 ml) and methanesulfonyl chloride
(0.005 ml) were successively added dropwise again at 0.degree. C.,
and the mixture was stirred at room temperature for 1.5 hr. To the
obtained reaction mixture was added 1N aqueous hydrochloric acid
under ice-cooling, and the mixture was extracted twice with ethyl
acetate. The combined organic layer was washed successively with
saturated aqueous sodium hydrogen carbonate solution and saturated
brine and dried over sodium sulfate. The solvent was evaporated and
the obtained crude product was dissolved in tetrahydrofuran (1.5
ml). Sodium hydride (60%) (5 mg) was added at room temperature, and
sodium hydride (60%) (8 mg) was added every 30 minutes. After
adding 3 times in total, 1N aqueous hydrochloric acid was added
under ice-cooling, and the mixture was extracted twice with ethyl
acetate. The combined organic layer was washed successively with
saturated aqueous sodium hydrogen carbonate solution and saturated
brine and dried over sodium sulfate. The solvent was evaporated,
and the obtained residue was purified by thin layer chromatography
(ethyl acetate:methanol=2:1) to give
10-benzyloxy-2-(3,4-dichlorobenzyl)-2,3,4,5-
-tetrahydropyrido[1,2-a][1,4]diazepine-1,9-dione (23 mg).
[1041] .sup.1H-NMR(CDCl.sub.3).delta. 7.49-7.46(m,3H),
7.39(d,1H,J=8.3 Hz), 7.30-7.26(m,3H), 7.22(dd,1H,J=2.3,8.3 Hz),
7.09(d,1H,J=7.5 Hz), 6.46(d,1H,J=7.5 Hz), 5.69(d,1H,J=10.9 Hz),
5.06(d,1H,J=10.9 Hz), 4.71(d,1H,J=14.7 Hz), 4.48(d,1H,J=14.7 Hz),
3.82-3.77(m,2H), 3.07(dd,1H,J=6.8,15.5 Hz), 2.96-2.85(m,1H),
1.92-1.79(m,1H), 1.74-1.61(m,1H).
[1042] Step 3
[1043]
10-Benzyloxy-2-(3,4-dichlorobenzyl)-2,3,4,5-tetrahydropyrido[1,2-a]-
[1,4]diazepine-1,9-dione (15 mg) obtained in the previous step was
dissolved in trifluoroacetic acid (1.0 ml), and the mixture was
stirred at room temperature for 30 min and then at 60.degree. C.
for 1.5 hr. The solvent was evaporated, toluene was added, and the
mixture was concentrated, which operations were performed 3 times.
Ethyl acetate was added and the mixture was concentrated, which
operations were performed 2 times. The obtained residue was
crystallized from ethyl acetate/hexane to give
2-(3,4-dichlorobenzyl)-10-hydroxy-2,3,4,5-tetrahydropyrido[1,2-a][1,-
4]diazepine-1,9-dione (11 mg).
[1044] .sup.1H-NMR(DMSO-d.sub.6).delta. 7.79(brs,1H),
7.66(d,1H,J=8.3 Hz), 7.65(d,1H,J=2.3 Hz), 7.38(dd,1H,J=2.3,8.3 Hz),
6.50(brs,1H), 4.68(brs,2H), 4.10(brs,2H), 3.33(bt,2H,J=6.4 Hz),
1.94(bt,2H,J=6.4 Hz)
Example 3
Synthesis of
2-(3,4-dichlorobenzyl)-9-hydroxy-3-methyl-3,4-dihydro-2H-pyri-
do[1,2-a]pyrazine-1,8-dione
[1045] 47
[1046]
N-(3,4-Dichlorobenzyl)-3-benzyloxy-4-oxo-4H-pyran-2-carboxamide (50
mg) obtained in the same manner as in Example 1, Step 1 was
dissolved in tetrahydrofuran (0.5 ml), ethanol (0.5 ml) and water
(0.1 ml). DL-1-Amino-2-propanol (0.0191 ml) and sodium carbonate (7
mg) were successively added, and the mixture was stirred overnight
at room temperature. The solvent was evaporated, and the obtained
residue was purified by silica gel column chromatography (ethyl
acetate:methanol=100:0-4:1) to give
N-(3,4-dichlorobenzyl)-3-benzyloxy-1--
(2-hydroxypropyl)-4-oxo-1,4-dihydropyridine-2-carboxamide (34
mg).
[1047] .sup.1H-NMR(DMSO-d.sub.6).delta. 9.43(t,1H,J=6.3 Hz),
7.57(s,1H), 7.57(d,1H,J=7.4 Hz), 7.36(d,1H,J=8.1 Hz),
7.31-7.26(m,6H), 6.23(d,1H,J=7.4 Hz), 5.08(d,1H,J=10.9 Hz),
5.04(d,1H,J=10.9 Hz), 5.02(d,1H,J=6.3 Hz), 4.44(dd,1H,J=6.3,14.8
Hz), 4.37(dd,1H, J=6.3,14.8 Hz), 3.81(brs,1H),
3.69(dd,1H,J=3.7,14.4 Hz), 3.60(dd,1H,J=8.8,14.4 Hz),
0.94(d,3H,J=6.3 Hz).
[1048] Step 2
[1049]
N-(3,4-Dichlorobenzyl)-3-benzyloxy-1-(2-hydroxypropyl)-4-oxo-1,4-di-
hydropyridine-2-carboxamide (34 mg) obtained in the previous step
was dissolved in tetrahydrofuran (1.5 ml) and the mixture was
cooled to 0.degree. C. under an argon atmosphere.
Diisopropylethylamine (0.0385 ml) and methanesulfonyl chloride
(0.0074 ml) were successively added dropwise at the same
temperature, and the mixture was stirred at room temperature for 1
hr. Diisopropylethylamine (0.0385 ml) and methanesulfonyl chloride
(0.0074 ml) were successively added dropwise at 0.degree. C. and
the mixture was stirred at room temperature for 1.5 hr. To the
obtained reaction mixture was added 1N aqueous hydrochloric acid
under ice-cooling, and the mixture was extracted twice with ethyl
acetate. The combined organic layer was washed successively with
saturated aqueous sodium hydrogen carbonate solution and saturated
brine, and dried over sodium sulfate. The solvent was evaporated
and the obtained crude product was dissolved in tetrahydrofuran
(1.5 ml). Sodium hydride (60%)(5 mg) was added at room temperature,
and sodium hydride (60%)(8 mg) was added every 30 minutes. After
adding 3 times in total, 1N aqueous hydrochloric acid was added
under ice-cooling, and the mixture was extracted twice with ethyl
acetate. The combined organic layer was washed successively with
saturated aqueous sodium hydrogen carbonate solution and saturated
brine, and dried over sodium sulfate. The solvent was evaporated,
and the obtained residue was purified by thin layer chromatography
(ethyl acetate:methanol=2:1) to give
9-benzyloxy-2-(3,4-dichlorobenzyl)-3-methyl-
-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,8-dione (8 mg).
[1050] .sup.1H-NMR(CDCl.sub.3).delta. 7.62-7.59(m,2H),
7.45-7.42(m,2H), 7.35-7.27(m,3H), 7.20(dd,1H,J=2.3,8.3 Hz),
7.13(d,1H,J=7.5 Hz), 6.52(d,1H,J=7.5 Hz), 5.58(d,1H,J=10.2 Hz),
5.25(d,1H,J=14.7 Hz), 5.24(d,1H,J=10.2 Hz), 4.09(dd,1H,J=3.8,12.8
Hz), 3.97(d,1H,J=14.7 Hz), 3.62-3.58(m,2H), 1.04(d,3H,J=6.8
Hz).
[1051] Step 3
[1052]
9-Benzyloxy-2-(3,4-dichlorobenzyl)-3-methyl-3,4-dihydro-2H-pyrido[1-
,2a]pyrazine-1,8-dione (8 mg) obtained in the previous step was
dissolved in trifluoroacetic acid (1.0 ml) and the mixture was
stirred at 60.degree. C. for 1.5 hr. The solvent was evaporated,
toluene was added, and the mixture was concentrated, which
operations were performed 3 times. Ethyl acetate was added and the
mixture was concentrated, which operations were performed twice.
The obtained residue was crystallized from ethyl acetate/hexane to
give 2-(3,4-dichlorobenzyl)-9-hydroxy-3-meth-
yl-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,8-dione (6 mg).
[1053] .sup.1H-NMR(DMSO-d.sub.6).delta. 7.84(brs,1H),
7.70(d,1H,J=1.9 Hz), 7.63(d,1H,J=8.4 Hz), 7.40(dd,1H,J=1.9,8.4 Hz),
6.57(brs,1H), 5.03(d,1H,J=15.3 Hz), 4.45(d,1H,J=15.3 Hz),
4.42-4.39(m,1H), 4.22-4.19(m,1H), 4.00(m,1H), 1.18(d,3H,J=6.5
Hz).
Example 4
Synthesis of
2-(3,4-dichlorobenzyl)-9-hydroxy-4,4-dimethyl-3,4-dihydro-2H--
pyrido[1,2-a]pyrazine-1,8-dione
[1054] 48
[1055] Step 1
[1056] 2-tert-Butoxycarbonylamino-2-methylpropionic acid (2 g) was
dissolved in tetrahydrofuran (20 ml), and 3,4-dichlorobenzylamine
(1.2 ml), 1-hydroxybenzotriazole (1.81 g) and
1-ethyl-3-(3-dimethylaminopropyl- )carbodiimide (2.26 g) were
added. The mixture was stirred at room temperature for 1 hr. To the
obtained reaction mixture was added saturated aqueous sodium
hydrogen carbonate solution, and the mixture was extracted with
ethyl acetate. The organic layer was washed successively with
saturated aqueous sodium hydrogen carbonate solution, 5% aqueous
potassium hydrogen sulfate solution and saturated brine and dried
over sodium sulfate. The solvent was evaporated, and the obtained
solid was washed with ethyl acetate/hexane and collected by
filtration to give crude crystals (2.98 g) of tert-butyl
[1-(3,4-dichlorobenzylcarbamoyl)-1-- methylethyl]carbamate.
[1057] Step 2
[1058] The crude crystals (1.0 g) of tert-butyl
[1-(3,4-dichlorobenzylcarb- amoyl)-1-methylethyl]carbamate obtained
in the previous step was dissolved in tetrahydrofuran (5 ml) and
cooled to 0.degree. C. under an argon atmosphere. A
borane--tetrahydrofuran complex (1.0 M/tetrahydrofuran solution)(15
ml) was added dropwise at the same temperature, removed from an
ice-bath and stirred at room temperature for 2 hr. A
borane--tetrahydrofuran complex (1.0 M/tetrahydrofuran solution)(5
ml) was added every 30 minutes twice in total. To the obtained
reaction mixture was added methanol (10 ml) under ice-cooling, and
the solvent was evaporated. The obtained residue was dissolved in
tetrahydrofuran (10 ml) and 1N aqueous sodium hydroxide solution (4
ml) and the mixture was stirred at 90.degree. C. for 1 hr. The
obtained reaction mixture was extracted twice with toluene, and the
combined organic layer was washed with saturated brine and dried
over sodium sulfate. The solvent was evaporated and the obtained
residue was purified by silica gel column chromatography
(hexane:ethyl acetate=1:1) to give tert-butyl
[2-(3,4-dichlorobenzylamino)-1,1-dimethylethyl]carbamate (290
mg).
[1059] .sup.1H-NMR(DMSO-d.sub.6).delta. 7.59(d,1H,J=1.9 Hz),
7.56(d,1H,J=8.3 Hz), 7.31(dd,1H,J=1.9,8.3 Hz), 6.20(brs,1H),
3.69(brs,2H), 2.48(brs,2H), 2.17(brs,1H), 1.35(s,9H), 1.16(s,6H).
49
[1060] Step 3
[1061] To a solution of 3-benzyloxy-4-oxo-4H-pyran-2-carboxylic
acid (150 mg) obtained in the same manner as in Example 1, Step 1
in chloroform (3 ml) were added oxalyl chloride (0.069 ml) and
dimethylformamide (0.005 ml) and the mixture was stirred at room
temperature for 1 hr. The reaction solvent was evaporated under
reduced pressure. Toluene was added and the mixture was
concentrated, which operations were performed twice and the residue
was dissolved in chloroform (2 ml). This solution was added
dropwise under ice-cooling to a solution of tert-butyl
[2-(3,4-dichlorobenzylamino)-1,1-dimethylethyl]carbamate (192 mg)
obtained in Step 2 and triethylamine (0.11 ml) in chloroform (3
ml), and the mixture was stirred under ice-cooling for 1 hr. 5%
Aqueous potassium hydrogen sulfate solution was added to the
obtained reaction mixture and the mixture was extracted with
chloroform. The organic layer was washed successively with
saturated aqueous sodium hydrogen carbonate solution and saturated
brine and dried over sodium sulfate. The solvent was evaporated and
the residue was purified by silica gel column chromatography
(hexane:ethyl acetate=1:1) to give crude tert-butyl
{2-[N-(3-benzyloxy-4-oxo-4H-pyran-2-carbonyl)-N-(3,4-dichlorobenzyl)amino-
]-1,1-dimethylethyl}carbamate (270 mg).
[1062] Step 4
[1063] Crude tert-butyl
(2-[N-(3-benzyloxy-4-oxo-4H-pyran-2-carbonyl)-N-(3-
,4-dichlorobenzyl)amino]-1,1-dimethylethyl]carbamate (90 mg)
obtained in the previous step was dissolved in 4N hydrochloric
acid/dioxane solution (2 ml) and the mixture was stirred at room
temperature for 30 min. The solvent was evaporated and azeotropic
distillation with chloroform was performed 3 times. The obtained
residue was dissolved in ethanol (3 ml) and saturated aqueous
sodium carbonate solution (1.5 ml) and stirred at 50.degree. C. for
30 min. Water was added to the obtained reaction mixture and the
mixture was extracted twice with ethyl acetate. The combined
organic layer was washed with saturated brine and dried over sodium
sulfate. The solvent was evaporated and the obtained residue was
purified by thin layer chromatography (ethyl acetate:methanol=3:2)
to give
9-benzyloxy-2-(3,4-dichlorobenzyl)-4,4-dimethyl-3,4-dihydro-2H-pyrid-
o[1,2-a]pyrazine-1,8-dione (50 mg).
[1064] .sup.1H-NMR(CDCl.sub.3).delta. 7.65(dd,2H,J=1.5,7.9 Hz),
7.46(d,1H,J=1.9 Hz), 7.45(d,1H,J=8.3 Hz), 7.37-7.29(m,4H),
7.22(dd,1H,J=1.9,8.3 Hz), 6.50(d,1H,J=7.5 Hz), 5.37(s,2H),
4.65(s,2H), 3.26(s,2H), 1.39(s,6H).
[1065] Step 5
[1066]
9-Benzyloxy-2-(3,4-dichlorobenzyl)-4,4-dimethyl-3,4-dihydro-2H-pyri-
do[1,2-a]pyrazine-1,8-dione (30 mg) obtained in the previous step
was dissolved in trifluoroacetic acid (2.0 ml) and the mixture was
stirred at 65.degree. C. for 2 hr. The solvent was evaporated,
toluene was added and the mixture was concentrated, which
operations were performed 3 times. Ethyl acetate was added and the
mixture was concentrated, which operations were performed twice.
The obtained residue was crystallized from diisopropyl ether to
give 2-(3,4-dichlorobenzyl)-9-hydroxy-4,4-dimet-
hyl-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,8-dione (22 mg).
[1067] .sup.1H-NMR(DMSO-d.sub.6).delta. 7.96(bd,1H,J=7.9 Hz),
7.68(d,1H,J=1.9 Hz), 7.65(d,1H,J=8.1 Hz), 7.40(dd,1H,J=1.9,8.1 Hz),
6.49(brs,1H), 4.74(s,2H), 3.67(s,2H), 1.44(s,6H).
Example 5
Synthesis of
2-(3,4-dichlorobenzyl)-9-hydroxy-6-hydroxymethyl-3,4-dihydro--
2H-pyrido[1,2-a]pyrazine-1,8-dione
[1068] 50
[1069] Step 1
[1070] tert-Butyl N-(2-aminoethyl) carbamate (1.51 g) was dissolved
in chloroform (20 ml) and 3,4-dichlorobenzaldehyde (1.65 g), acetic
acid (0.54 ml) and sodium triacetoxyborohydride (2.6 g) were added
at room temperature. The mixture was stirred overnight. Saturated
aqueous sodium hydrogen carbonate solution was added to the
obtained reaction mixture and the mixture was stirred and extracted
three times with chloroform. The combined organic layer was washed
with saturated brine and dried over sodium sulfate. The solvent was
evaporated and the obtained residue was purified by silica gel
column chromatography (chloroform:methanol=9:1) to give tert-butyl
[2-(3,4-dichlorobenzylamino)ethyl]carbamate (2.1 g).
[1071] .sup.1H-NMR(DMSO-d.sub.6).delta. 7.59(d,1H,J=1.9 Hz),
7.56(d,1H,J=8.3 Hz), 7.31(dd,1H,J=1.9,8.3 Hz), 6.73(brs,1H),
3.67(brs,2H), 3.00(bdd,2H,J=6.0,12.4 Hz), 2.47(m,2H), 2.27(brs,1H),
1.37(s,9H). 51
[1072] Step 2
[1073] Kojic acid (5 g) was dissolved in chloroform (50 ml) and
triethylamine (7.4 ml) and dimethylaminopyridine (5 mg) were added.
Then tert-butyldimethylsilyl chloride (5.3 g) was added under
ice-cooling, and the mixture was stirred at the same temperature
for 1 hr. To the obtained reaction mixture was added 5% aqueous
potassium hydrogen sulfate solution, and the mixture was extracted
with chloroform. The organic layer was washed with saturated
aqueous sodium hydrogen carbonate solution and saturated brine, and
dried over sodium sulfate. The solvent was evaporated and the
obtained residue was dissolved in chloroform (50 ml).
Diisopropylethylamine (8.0 ml) was added and chloromethyl methyl
ether (3.2 ml) was added. The mixture was stirred under ice-cooling
for 30 min. The ice-bath was removed and the mixture was stirred
overnight at room temperature. 5% Aqueous potassium hydrogen
sulfate solution was added to the obtained reaction mixture and the
mixture was extracted with chloroform. The organic layer was washed
with saturated aqueous sodium hydrogen carbonate solution and
saturated brine, and dried over sodium sulfate. The solvent was
evaporated and the obtained residue was purified by silica gel
column chromatography (hexane:ethyl acetate=4:1-2:1) to give
5-(tert-butyldimethylsilyloxy)-2-methoxymethoxymethyl-4H-pyran-4-one
(5.5 g).
[1074] .sup.1H-NMR(DMSO-d.sub.6).delta. 8.19(s,1H), 6.41(s,1H),
4.66(s,2H), 4.39(s,2H), 3.28(s,3H), 0.92(s,9H), 0.16(s,6H).
[1075] Step 3
[1076]
5-(tert-Butyldimethylsilyloxy)-2-methoxymethoxymethyl-4H-pyran-4-on-
e (5.5 g) obtained in the previous step was dissolved in
tetrahydrofuran (30 ml), tetra(n-butyl)ammonium fluoride (1.0
M/tetrahydrofuran solution) (19.2 ml) was added under ice-cooling
and the mixture was stirred for 30 min. 5% Aqueous potassium
hydrogen sulfate solution was added to the obtained reaction
mixture to adjust to pH=3, and the mixture was extracted 4 times
with ethyl acetate. The combined organic layer was washed with
saturated brine and dried over sodium sulfate. The solvent was
evaporated and the obtained solid was washed with ethyl
acetate/hexane. The obtained solid (2.3 g) was dissolved in water
(20 ml) and IN aqueous sodium hydroxide solution (12.7 ml). 36%
Aqueous formaldehyde solution was added at room temperature and the
mixture was stirred for 6 hr. 5% Aqueous potassium hydrogen sulfate
solution was added to the obtained reaction mixture to adjust to
pH=3, and sodium chloride was added. The mixture was extracted 5
times with ethyl acetate, and the combined organic layer was washed
with saturated brine and dried over sodium sulfate. The solvent was
evaporated and the obtained residue was dissolved in
dimethylformamide (10 ml). Potassium carbonate (1.97 g) was added
and benzyl chloride (0.82 ml) was added at room temperature, and
the mixture was stirred overnight. 5% Aqueous potassium hydrogen
sulfate solution was added to the obtained reaction mixture to
adjust to pH=3, and the mixture was extracted three times with
ethyl acetate. The combined organic layer was washed with saturated
brine and dried over sodium sulfate. The solvent was evaporated and
the obtained residue was purified by silica gel column
chromatography (hexane:ethyl acetate=1:1-1:4) to give
3-benzyloxy-2-hydroxymethyl-6-methoxymethoxymeth- yl-4H-pyran-4-one
(783 mg)
[1077] .sup.1H-NMR(DMSO-d.sub.6).delta. 7.47-7.32(m,5H),
6.43(s,1H), 5.48(t,1H,J=6.0 Hz), 5.03(s,2H), 4.68(s,2H),
4.40(s,2H), 4.28(d,2H,J=6.0 Hz), 3.29(s,3H).
[1078] Step 4
[1079]
3-Benzyloxy-2-hydroxymethyl-6-methoxymethoxymethyl-4H-pyran-4-one
(783 mg) obtained in the previous step was dissolved in acetone
(8.0 ml) and saturated aqueous sodium hydrogen carbonate solution
(8.0 ml), and potassium bromide (30 mg),
2,2,6,6-tetramethylpiperidine 1-oxyl, free radical (39 mg) were
added, and 6% aqueous sodium hypochlorite solution (3.4 ml) was
added dropwise under ice-cooling. The mixture was stirred for 30
min and 6% aqueous sodium hypochlorite solution (3.3 ml) was
further added dropwise. The mixture was further stirred for 30 min.
Water was added to the obtained reaction mixture and washed twice
with ethyl acetate. 5% Aqueous potassium hydrogen sulfate solution
was added to the aqueous layer to adjust to pH=3, and the mixture
was extracted twice with ethyl acetate. The combined organic layer
was washed with saturated brine and dried over sodium sulfate. The
solvent was evaporated to give
3-benzyloxy-6-methoxymethoxymethyl-4-oxo-4H-pyran-2-carboxylic acid
(710 mg).
[1080] .sup.1H-NMR(DMSO-d.sub.6).delta. 7.44-7.30(m,5H),
6.54(s,1H), 5.11(s,2H), 4.65(s,2H), 4.43(s,2H), 3.27(s,3H).
5253
[1081] Step 5
[1082]
3-Benzyloxy-6-methoxymethoxymethyl-4-oxo-4H-pyran-2-carboxylic acid
(658 mg) obtained in Step 4 was dissolved in dimethylformamide (5
ml), and tert-butyl [2-(3,4-dichlorobenzylamino)ethyl]carbamate
(596 mg) obtained in Step 1,
1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (429 mg) and
1-hydroxybenzotriazole (343 mg) were added at room temperature, and
the mixture was stirred for 1 hr. Saturated aqueous sodium hydrogen
carbonate solution was added to the obtained reaction mixture and
the mixture was extracted twice with ethyl acetate. The combined
organic layer was washed with saturated brine and dried over sodium
sulfate. The solvent was evaporated and the obtained residue was
purified by silica gel column chromatography
(chloroform:methanol=15:1) to give crude tert-butyl
{2-[N-(3-benzyloxy-6-methoxymethoxymethyl-4-oxo-4H-pyran-2-car-
bonyl)-N-(3,4-dichlorobenzyl)amino]ethyl}carbamate (1.12 g).
[1083] Step 6
[1084] The crude tert-butyl
{2-[N-(3-benzyloxy-6-methoxymethoxymethyl-4-ox-
o-4H-pyran-2-carbonyl)-N-(3,4-dichlorobenzyl)amino]ethyl}carbamate
(1.12 g) obtained in the previous step was dissolved in 4N
hydrochloric acid/dioxane solution (10 ml) and the mixture was
stirred at room temperature for 30 min. The solvent was evaporated,
toluene was added, and the mixture was concentrated, which
operations were performed 3 times. The obtained residue was
dissolved in ethanol (40 ml) and saturated aqueous sodium carbonate
solution (10 ml), and the mixture was stirred at 50.degree. C. for
30 min. The solvent was evaporated, and the resulting crystals were
washed with 5% aqueous potassium hydrogen sulfate solution and a
small amount of ethyl acetate, and collected by filtration to give
9-benzyloxy-2-(3,4-dichlorobenzyl)-6-hydroxymethyl-3,4-dihydro-2H-
-pyrido[1,2-a]pyrazine-1,8-dione (433 mg).
[1085] .sup.1H-NMR(DMSO-d.sub.6).delta. 7.64(d,1H,J=1.5 Hz),
7.63(d,1H,J=8.3 Hz), 7.51(dd,2H,J=1.5,8.3 Hz), 7.37-7.29(m,4H),
6.40(s,1H), 5.67(t,1H,J=5.7 Hz), 5.08(s,2H), 4.68(s,2H),
4.43(d,2H,J=5.7 Hz), 4.10-4.04(m,2H), 3.63-3.57(m,2H).
[1086] Step 7
[1087]
9-Benzyloxy-2-(3,4-dichlorobenzyl)-6-hydroxymethyl-3,4-dihydro-2H-p-
yrido[1,2a-]pyrazine-1,8-dione (15 mg) obtained in the previous
step was dissolved in trifluoroacetic acid (1 ml) and the mixture
was stirred at room temperature for 1 hr. The solvent was
evaporated, toluene was added, and the mixture was concentrated,
which operations were performed 3 times. Ethyl acetate was added
and the mixture was concentrated, which operations were performed
twice. The obtained residue was crystallized from ethyl
acetate/diisopropyl ether to give 2-(3,4-dichlorobenzyl)-9-hyd-
roxy-6-hydroxymethyl-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,8-dione
(12 mg).
[1088] .sup.1H-NMR(DMSO-d.sub.6).delta. 12.20(brs,1H),
7.66(d,1H,J=1.9 Hz) 7.62(d,1H,J=8.1 Hz), 7.36(dd,2H,J=1.9,8.1 Hz),
6.25(s,1H), 5.65(t,1H,J=5.6 Hz), 4.71(s,2H), 4.41(d,2H,J=5.6 Hz),
4.15-4.13(m,2H), 3.68-3.65(m,2H).
Example 6
Synthesis of
2-(3,4-dichlorobenzyl)-9-hydroxy-1,8-dioxo-1,3,4,8-tetrahydro-
-2H-pyrido[1,2-a]pyrazine-6-carboxylic acid
[1089] 54
[1090] Step 1
[1091]
9-Benzyloxy-2-(3,4-dichlorobenzyl)-6-hydroxymethyl-3,4-dihydro-2H-p-
yrido[1,2-a]pyrazine-1,8-dione (100 mg) obtained in Example 5, Step
6 was dissolved in acetone (1.6 ml) and saturated aqueous sodium
hydrogen carbonate solution (1.0 ml) and potassium bromide (3 mg),
2,2,6,6-tetramethylpiperidine 1-oxyl and free radical (3 mg) were
added, and 6% aqueous sodium hypochlorite solution (3.4 ml) was
added dropwise under ice-cooling. After stirring for 15 min, the
ice bath was removed and the mixture was stirred at room
temperature for 4 hr. Furthermore, 6% aqueous sodium hypochlorite
solution (0.1 ml) was added dropwise and the mixture was stirred
for 1.5 hr. The obtained reaction mixture was poured into 5%
aqueous potassium hydrogen sulfate solution and stirred for 30 min.
The resulting crystals were collected by filtration to give
9-benzyloxy-2-(3,4-dichlorobenzyl)-1,8-dioxo-1,3,4,8-tetrahydro-2H-pyrido-
[1,2-a]pyrazine-6-carboxylic acid (94 mg).
[1092] .sup.1H-NMR(DMSO-d.sub.6).delta. 7.64(d,1H,J=1.9 Hz),
7.62(d,1H,J=8.4 Hz), 7.49(dd,2H,J=1.9,8.4 Hz), 7.36-7.29(m,4H),
6.70(s,1H), 5.11(s,2H), 4.67(s,2H), 4.26-4.24(m,2H),
3.59-3.56(m,2H).
[1093] Step 2
[1094]
9-Benzyloxy-2-(3,4-dichlorobenzyl)-1,8-dioxo-1,3,4,8-tetrahydro-2H--
pyrido[1,2-a]pyrazine-6-carboxylic acid (25 mg) obtained in the
previous step was dissolved in trifluoroacetic acid (2 ml) and the
mixture was stirred at room temperature for 1 hr. The solvent was
evaporated, toluene was added, and the mixture was concentrated,
which operations were performed 3 times. Methanol was added and the
mixture was concentrated. Ethyl acetate was added and the mixture
was concentrated. The obtained residue was crystallized from
methanol/ethyl acetate to give
2-(3,4-dichlorobenzyl)-9-hydroxy-1,8-dioxo-1,3,4,8-tetrahydro-2H-pyrido[1-
,2-a]pyrazine-6-carboxylic acid (20 mg).
[1095] .sup.1H-NMR(DMSO-d.sub.6).delta. 7.69(d,1H,J=2.2 Hz),
7.64(d,1H,J=8.4 Hz), 7.39(dd,2H,J=2.2,8.4 Hz), 6.58(s,1H),
4.73(s,2H), 4.44-4.41(m,2H), 3.71-3.68(m,2H).
Example 7
Synthesis of
2-(3,4-dichlorobenzyl)-6-(2,2-dimethylpropionyl)-9-hydroxy-3,-
4-dihydro-2H-pyrido[1,2-a]pyrazine-1,8-dione
[1096] 55
[1097] Step 1
[1098] To a solution of
9-benzyloxy-2-(3,4-dichlorobenzyl)-6-hydroxymethyl-
-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,8-dione (860 mg) obtained
in Example 5, Step 6 in chloroform (80 ml) was added Dess-Martin
reagent (843 mg). After stirring at room temperature for 1 hr, the
solvent was evaporated and chloroform (50 ml) was added to the
obtained residue and a solid product was filtered off. The filtrate
was concentrated and purified by silica gel column chromatography
(chloroform:acetone=1:2) to give
9-benzyloxy-2-(3,4-dichlorobenzyl)-1,8-dioxo-1,3,4,8-tetrahydro-2H-p-
yrido[1,2-a]pyrazine-6-carbaldehyde (621 mg).
[1099] .sup.1H-NMR(CDCl.sub.3).delta. 9.58(s,1H), 7.62-7.55(m,2H),
7.46-7.40(m,2H), 7.37-7.26(m,3H), 7.16(dd,1H,J=2.0,8.1 Hz),
6.97(s,1H), 5.39(s,2H), 4.65(s,2H), 4.43-4.37(m,2H),
3.43-3.36(m,2H).
[1100] Step 2
[1101] A solution of
9-benzyloxy-2-(3,4-dichlorobenzyl)-1,8-dioxo-1,3,4,8--
tetrahydro-2H-pyrido[1,2-a]pyrazine-6-carbaldehyde (205 mg)
obtained in the previous step in dry tetrahydrofuran (40 ml) was
cooled in a dry ice-acetone bath. tert-Butylmagnesium chloride (2.0
M/diethyl ether solution) (0.448 ml) was added dropwise at the same
temperature and the mixture was stirred for 30 min. Then 5% aqueous
potassium hydrogen sulfate solution was added to adjust to pH=2,
and the mixture was extracted with ethyl acetate. The organic layer
was washed with saturated brine and dried over sodium sulfate. The
solvent was evaporated and the residue was purified by silica gel
column chromatography (chloroform:methanol=12:1) to give crude
9-benzyloxy-2-(3,4-dichlorobenzy-
l)-6-(1-hydroxy-2,2-dimethylpropyl)-3,4-dihydro-2H-pyrido[1,2a-]pyrazine-1-
,8-dione (220 mg).
[1102] To a solution of the above-mentioned crude
9-benzyloxy-2-(3,4-dichl-
orobenzyl)-6-(1-hydroxy-2,2-dimethylpropyl)-3,4-dihydro-2H-pyrido[1,2-a]py-
razine-1,8-dione (132 mg) in chloroform-(4 ml) was added
Dess-Martin reagent (65 mg) and the mixture was stirred at room
temperature for 20 min. Saturated aqueous sodium hydrogen carbonate
solution and sodium sulfite were added to the reaction mixture, and
the mixture was extracted with ethyl acetate. The organic layer was
washed with saturated brine and dried over sodium sulfate. The
solvent was evaporated and the residue was purified by silica gel
column chromatography (ethyl acetate:chloroform=4:1) to give
9-benzyloxy-2-(3,4-dichlorobenzyl)-6-(2,2-
-dimethylpropionyl)-3,4-dihydro-2H-pyrido[1,2a]pyrazine-1,8-dione
(38 mg).
[1103] .sup.1H-NMR(CDCl.sub.3).delta. 7.63-7.57 (m,2H),
7.46-7.38(m,2H), 7.37-7.26(m,3H), 7.15(dd,1H,J=2.1,8.1 Hz),
6.42(s,1H), 5.38(s,2H), 4.63(s,2H), 3.69-3.61(m,2H),
3.43-3.36(m,2H), 1.27(s,9H).
[1104] Step 3
[1105] To
9-benzyloxy-2-(3,4-dichlorobenzyl)-6-(2,2-dimethylpropionyl)-3,4-
-dihydro-2H-pyrido[1,2-a]pyrazine-1,8-dione (36 mg) obtained in the
previous step was added trifluoroacetic acid (4 ml) and the mixture
was stirred at room temperature for 1 hr. The solvent was
evaporated, toluene was added, and the mixture was concentrated,
which operations were performed twice. The obtained residue was
crystallized from ethyl acetate:diisopropyl ether=1:4 to give
2-(3,4-dichlorobenzyl)-6-(2,2-dimet-
hylpropionyl)-9-hydroxy-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,8-dione
(26 mg).
[1106] .sup.1H-NMR(DMSO-d.sub.6).delta. 12.40(brs,1H),
7.68(d,1H,J=2.1 Hz), 7.62(d,1H,J=8.4 Hz), 7.38(dd,1H,J=2.1,8.4 Hz),
6.15(s,1H), 4.71(s,2H), 3.92-3.85(m,2H), 3.67-3.59(m,2H),
1.22(s,9H).
Example 8
Synthesis of
2-(3,4-dichlorobenzyl)-9-hydroxy-2H-pyrido[1,2-a]pyrazine-1,8-
-dione
[1107] 56
[1108] Step 1
[1109] To a solution of
N-(3,4-dichlorobenzyl)-3-benzyloxy-4-oxo-4H-pyran-- 2-carboxamide
(49 mg) obtained in the same manner as in Example 1, Step 1 in
tetrahydrofuran (0.5 ml), ethanol (0.5 ml) and water (0.1 ml) were
successively added aminoacetaldehyde dimethyl acetal (0.026 ml) and
sodium carbonate (6.4 mg), and the mixture was stirred at room
temperature for 1 hr and then at 45.degree. C. for 4 hr, and at
60.degree. C. for 20 hr. The solvent was evaporated and the residue
was purified by silica gel column chromatography (ethyl
acetate:methanol=100:0-5:1) to give
N-(3,4-dichlorobenzyl)-3-benzyloxy-1--
(2,2-dimethoxyethyl)-4-oxo-1,4-dihydropyridine-2-carboxamide (30
mg).
[1110] .sup.1H-NMR(CDCl.sub.3).delta. 7.35(d,1H,J=2.0 Hz),
7.30-7.20(m,7H), 7.09(t,1H,J=6.3 Hz), 7.05(dd,1H,J=2.0,8.0 Hz),
6.33(d,1H,J=7.4 Hz), 5.20(s,2H), 4.51(t,1H,J=5.1 Hz),
4.32(d,2H,J=6.3 Hz), 3.86(d,1H,J=5.1 Hz), 3.31(s,6H).
[1111] Step 2
[1112] To a solution of
N-(3,4-dichlorobenzyl)-3-benzyloxy-1-(2,2-dimethox-
yethyl)-4-oxo-1,4-dihydropyridine-2-carboxamide (30 mg) obtained in
the previous step in toluene (3 ml) was added camphorsulfonic acid
(15 mg) and the mixture was stirred at 110.degree. C. for 30 min. A
saturated aqueous sodium hydrogen carbonate solution was added to
the reaction mixture and the mixture was extracted twice with ethyl
acetate. The organic layers were combined, washed with saturated
brine, and dried over sodium sulfate. The solvent was evaporated
and the residue was purified by silica gel column chromatography
(ethyl acetate:methanol=5:1-4:1) to give
9-benzyloxy-2-(3,4-dichlorobenzyl)-2H-pyrido[1,2-a]pyrazine-1,8-dion-
e (17 mg).
[1113] .sup.1H-NMR(CDCl.sub.3).delta. 7.63(d,1H,J=7.4 Hz),
7.43(d,1H,J=8.4 Hz), 7.39(d,1H,J=2.0 Hz), 7.38-7.25(m,5H),
7.15(dd,1H,J=2.0,8.4 Hz), 6.70(d,1H,J=7.4 Hz), 6.41(d,1H,J=6.3 Hz),
6.20(d,1H,J=6.3 Hz), 5.39(s,2H), 4.89(s,2H).
[1114] Step 3
[1115] To
9-benzyloxy-2-(3,4-dichlorobenzyl)-2H-pyrido[1,2-a]pyrazine-1,8--
dione (16 mg) obtained in the previous step was added
trifluoroacetic acid (2 ml) and the mixture was stirred at room
temperature for 1 hr. The solvent was evaporated, toluene was
added, and the mixture was concentrated, which operations were
performed twice. The obtained residue was crystallized from
diisopropyl ether to give 2-(3,4-dichlorobenzyl)-9--
hydroxy-2H-pyrido[1,2-a]pyrazine-1,8-dione (9 mg).
[1116] .sup.1H-NMR(DMSO-d.sub.6).delta. 8.11(d,1H,J=7.3 Hz),
7.71(d,1H,J=1.8 Hz), 7.66(d,1H,J=8.4 Hz), 7.40(dd,1H,J=1.8,8.4 Hz),
7.35(d,1H,J=6.2 Hz), 7.03(d,1H,J=6.2 Hz), 6.76(d,1H,J=7.3 Hz),
4.99(s,2H).
Example 9
Synthesis of
2-(3,4-dichlorobenzyl)-9-hydroxy-3-methyl-2H-pyrido[1,2-a]pyr-
azine-1,8-dione
[1117] 57
[1118] Step 1
[1119] To a solution of
N-(3,4-dichlorobenzyl)-3-benzyloxy-4-oxo-4H-pyran-- 2-carboxamide
(0.04 g) obtained in the same manner as in Example 1, Step 1 in
tetrahydrofuran (3 ml) were added 1-amino-2-propanol (0.224 g) and
saturated aqueous sodium hydrogen carbonate solution (1 ml), and
the mixture was stirred at 60.degree. C. for 4 hr. The reaction
solvent was evaporated under reduced pressure, and ethyl acetate
was added to the residue. The mixture was washed successively with
1N aqueous hydrochloric acid solution and saturated brine. After
drying over magnesium sulfate, the solvent was evaporated and the
residue was purified by silica gel column chromatography
(chloroform:methanol=20:1) to give
N-(3,4-dichlorobenzyl)-3-benzyloxy-1-(2-hydroxypropyl)-4-oxo-1,4-dihydrop-
yridine-2-carboxamide (0.334 g).
[1120] .sup.1H-NMR(DMSO-d.sub.6).delta. 9.45(t,1H),
7.58-7.56(m,2H), 7.37-7.23(m,7H), 6.62(d,1H,J=5.7 Hz),
5.09-5.05(m,3H), 4.50-4.31(m,4H), 3.81-3.42(m,4H), 0.92(d,3H,J=5.7
Hz).
[1121] Step 2
[1122]
N-(3,4-Dichlorobenzyl)-3-benzyloxy-1-(2-hydroxypropyl)-4-oxo-1,4-di-
hydropyridine-2-carboxamide (0.250 g) obtained in the previous step
was dissolved in chloroform (10 ml), Dess-Martin reagent (0.5 g)
was added, and the mixture was stirred overnight at room
temperature. The obtained reaction mixture was washed with
saturated aqueous sodium hydrogen carbonate solution and dried over
magnesium sulfate. The solvent was evaporated and the residue was
purified by silica gel column chromatography
(chloroform:methanol=10:1) to give crude crystals (0.304 g) of
N-(3,4-dichlorobenzyl)-3-benzyloxy-4-oxo-1-(2-oxopropyl)-1,4-dihydr-
opyridine-2-carboxamide. The crude crystals were dissolved in
tetrahydrofuran-toluene (5:2, 7 ml), p-toluenesulfonic acid (0.03
g) was added, and the mixture was stirred at 80.degree. C. for 10
hr. The obtained reaction mixture was purified by silica gel column
chromatography (chloroform:methanol=10:1) to give
9-benzyloxy-2-(3,4-dich-
lorobenzyl)-3-methyl-2H-pyrido[1,2-a]pyrazine-1,8-dione (0.063
g).
[1123] .sup.1H-NMR(DMSO-d.sub.6).delta. 7.93(d,1H,J=5.7 Hz),
7.84-7.69(m,4H), 7.32-7.20(m,4H), 7.03(s,1H), 6.62(d,1H,J=5.7 Hz),
5.12(s,2H), 5.07(s,2H), 2.01(s,3H).
[1124] Step 3
[1125]
9-Benzyloxy-2-(3,4-dichlorobenzyl)-3-methyl-2H-pyrido[1,2-a]pyrazin-
e-1,8-dione (0.063 g) obtained in the previous step was dissolved
in trifluoroacetic acid (2 ml) and the mixture was stirred at room
temperature for 3 hr. Thereafter, the reaction mixture was
subjected to azeotropic distillation 3 times with toluene.
Crystallization from ethyl acetate--diisopropyl ether gave
2-(3,4-dichlorobenzyl)-9-hydroxy-3-methyl-
-2H-pyrido[1,2-a]pyrazine-1,8-dione (0.05 g).
[1126] .sup.1H-NMR(DMSO-d.sub.6).delta. 8.19(d,1H,J=10 Hz),
7.64-7.61(m,2H), 7.44(s,1H), 7.33(dd,1H,J=7.3,11.2 Hz),
7.05(d,1H,J=9.6 Hz), 5.21(s,2H), 2.12(s,3H).
Example 10
Synthesis of
2-(3-chlorobenzyl)-9-hydroxy-4-isopropyl-2H-pyrido[1,2-a]pyra-
zine-1,8-dione hydrochloride
[1127] 58
[1128] Step 1
[1129] To a solution of 3-benzyloxy-4-oxo-4H-pyran-2-carboxylic
acid (3.00 g) in chloroform (30 ml) were added oxalyl chloride
(2.00 g) and dimethylformamide (50 .mu.l) and the mixture was
stirred at room temperature for 30 min. The solvent was evaporated
from the reaction mixture, toluene was added and the mixture was
concentrated to give acid chloride. To a solution of
3-chlorobenzylamine (1.90 g) in chloroform (30 ml) was added
triethylamine (1.85 g) and a solution of the above-mentioned acid
chloride in chloroform (30 ml) was added dropwise with stirring the
mixture at 0.degree. C. After stirring at 0.degree. C. for 30 min,
saturated aqueous sodium hydrogen carbonate solution (40 ml) was
added to the reaction mixture, and the mixture was warmed to room
temperature and the organic layer was separated. The aqueous layer
was extracted with chloroform. The organic layers were combined,
washed with saturated brine, and dried over sodium sulfate. The
solvent was evaporated and the residue was purified by silica gel
column chromatography (hexane:ethyl acetate=1:1-1:2) to give
3-benzyloxy-4-oxo-4H-pyran-2-carboxylic acid 3-chlorobenzylamide
(3.90 g).
[1130] .sup.1H-NMR(CDCl.sub.3).delta. 8.08(brs,1H), 7.84(d,1H,J=5.5
Hz), 7.37-7.20(m,7H), 7.15(m,1H), 7.05(m,1H), 5.38(s,2H),
4.37(d,2H,J=5.8 Hz).
[1131] Step 2
[1132] To a solution of 3-benzyloxy-4-oxo-4H-pyran-2-carboxylic
acid 3-chlorobenzylamide (1.20 g) obtained in the previous step in
toluene (120 ml) were added pyridinium p-toluenesulfonate (815 mg)
and 2-amino-3-methylbutanol (702 mg)'and the mixture was stirred at
110.degree. C. for 15 hr. 2-Amino-3-methylbutanol (833 mg) was
added and the mixture was further stirred at 110.degree. C. for 30
hr. The solvent was evaporated from the reaction mixture, saturated
aqueous sodium carbonate solution (30 ml) was added and the mixture
was extracted twice with chloroform. The organic layer was washed
with saturated brine and dried over sodium sulfate. The solvent was
evaporated and the residue was purified by silica gel column
chromatography (ethyl acetate-chloroform:methanol=10:1) to give a
crude product containing
N-(3-chlorobenzyl)-3-benzyloxy-1-(1-hydroxymethyl-2-methylpropyl)-4-oxo-1-
,4-dihydropyridine-2-carboxamide as a main component. The total
amount of this crude product was used in the next step without
further purification.
[1133] Step 3
[1134] To a solution of crude product of
N-(3-chlorobenzyl)-3-benzyloxy-1--
(1-hydroxymethyl-2-methylpropyl)-4-oxo-1,4-dihydropyridine-2-carboxamide
obtained in the previous step in dimethyl sulfoxide (8.5 ml) were
successively added triethylamine (1.60 g) and sulfur trioxide
pyridine complex (900 mg) and the mixture was stirred at room
temperature for 20 min. 1M Hydrochloric acid (50 ml) was added to
the reaction mixture and the mixture was extracted twice with ethyl
acetate. The organic layer was washed successively with water and
saturated brine, and dried over sodium sulfate. The solvent was
evaporated and the residue was purified by silica gel column
chromatography (chloroform:methanol=100:1-20:1) to give
9-benzyloxy-2-(3-chlorobenzyl)-3-hydroxy-4-isopropyl-3,4-dihydro-2H-pyrid-
o[1,2a]pyrazine-1,8-dione (202 mg).
[1135] .sup.1H-NMR(DMSO-d.sub.6).delta. 7.70(d,1H,J=7.4 Hz),
7.53-7.46(m,3H), 7.40-7.27(m,5H), 6.83(d,1H,J=5.6 Hz),
29(d,1H,J=7.4 Hz), 5.12-5.02(m,4H), 4.31(d,1H,J=14.6 Hz),
3.83(dd,1H,J=10.0,1.5 Hz), 1.41(m,1H), 0.66(d,3H,J=6.7 Hz),
0.55(d,3H,J=6.5 Hz).
[1136] Step 4
[1137] To
9-benzyloxy-2-(3-chlorobenzyl)-3-hydroxy-4-isopropyl-3,4-dihydro-
-2H-pyrido[1,2a]pyrazine-1,8-dione (200 mg) obtained in the
previous step were successively added acetic acid (5 ml) and conc.
hydrochloric acid (5 ml) and the mixture was stirred at 90.degree.
C. for 15 hr. The solvent was evaporated from the reaction mixture,
toluene was added and the mixture was concentrated. Crystallization
from diisopropyl ether-ethyl acetate gave
2-(3-chlorobenzyl)-9-hydroxy-4-isopropyl-2H-pyrido[1,2-a]pyr-
azine-1,8-dione hydrochloride-(164 mg).
[1138] .sup.1H-NMR(DMSO-d.sub.6).delta. 13.0(brs,1H),
8.52(d,1H,J=7.4 Hz), 7.50(s,1H), 7.43-7.35(m,3H), 7.25(m,1H),
7.22(s,1H), 5.13(s,2H), 3.25(Hept,1H,J=6.7 Hz), 1.25(d,6H,J=6.7
Hz).
Example 11
Synthesis of
2-[3-(2,6-dichlorophenyl)propyl]-9-hydroxy-2H-pyrido[1,2-a]py-
razine-1,8-dione
[1139] 5960
[1140] Step 1
[1141] Lithium aluminum hydride (1.31 g) was suspended in
tetrahydrofuran (30 ml) and 3-(2,6-dichlorophenyl)acrylic acid
(4.62 g) was added dropwise under ice-cooling over about 20 min.
During the dropwise addition, tetrahydrofuran (20 ml) was added.
After stirring at 0.degree. C. for 3.5 hr, the mixture was stirred
at room temperature for 18 hr. 4N Aqueous potassium hydroxide
solution was added to the reaction mixture and a solid component
was filtered off. The filtrate was concentrated under reduced
pressure, and to the residue was added 1N aqueous hydrochloric acid
solution. The mixture was extracted twice with ethyl acetate, and
the organic layer was washed with saturated brine and dried over
sodium sulfate. The solvent was evaporated to give a crude product
(5.40 g) of 3-(2,6-dichlorophenyl)propan-1-ol.
[1142] Step 2
[1143] To a solution of triphenylphosphine (6.14 g), phthalimide
(3.44 g) and 3-(2,6-dichlorophenyl)propan-1-ol (crude product: 5.40
g) obtained in the previous step in tetrahydrofuran (90 ml) was
added dropwise diethyl azodicarboxylate (40% toluene
solution)(10.19 g) under ice-cooling. After stirring at room
temperature for 2 hr, the reaction mixture was concentrated under
reduced pressure. Diethyl ether was added to the residue and
precipitated solid component was filtered off. The filtrate was
concentrated. Diethyl ether was added again to the obtained residue
and the precipitated solid component was filtered off. The filtrate
was concentrated and purified by silica gel column chromatography
(chloroform-hexane:ethyl acetate=4:1) to give a crude product (4.28
g) of 2-[3-(2,6-dichlorophenyl)propyl]isoindole-1,3-dione.
[1144] Step 3
[1145] To a solution of
2-[3-(2,6-dichlorophenyl)propyl]isoindole-1,3-dion- e (crude
product: 4.28 g) obtained in the previous step in ethanol (50 ml)
was added hydrazine monohydrate (2.79 ml) and the mixture was
heated under reflux for 1 hr. The reaction mixture was cooled to
room temperature, and 10% aqueous sodium carbonate solution (90 ml)
was added. The mixture was extracted with chloroform (100
ml.times.2). The organic layer was washed with water and dried over
sodium sulfate. The solvent was evaporated to give a crude product
(3.20 g) of 3-(2,6-dichlorophenyl)propylamine.
[1146] Step 4
[1147] To a suspension of 3-benzyloxy-4-oxo-4H-pyran-2-carboxylic
acid (0.30 g) in chloroform (10 ml) were added oxalyl chloride
(0.13 ml) and dimethylformamide (0.01 ml), and the mixture was
stirred at room temperature for 30 min. The reaction solvent was
evaporated under reduced pressure and toluene was added. The
mixture was concentrated and chloroform (5 ml) was added. A
solution of 3-(2,6-dichlorophenyl)propylam- ine (0.31 g) obtained
in the previous step in chloroform (1 ml) and triethylamine (0.21
ml) were successively added under ice-cooling, and the mixture was
stirred under ice-cooling for 10 min. 1N Aqueous hydrochloric acid
solution was added to the obtained reaction mixture and the mixture
was extracted with chloroform. The organic layer was dried over
sodium sulfate. The solvent was evaporated and the residue was
purified by silica gel column chromatography (hexane:ethyl
acetate=1:1-1:2) to give
N-[3-(2,6-dichlorophenyl)propyl]-3-benzyloxy-4-o-
xo-4H-pyran-2-carboxamide (0.24 g).
[1148] .sup.1H-NMR(CDCl.sub.3).delta. 7.81(d,1H,J=5.6 Hz),
7.79(br,1H), 7.39-7.26(m,7H), 7.08(dd,1H,J=7.6,8.6 Hz),
6.49(d,1H,J=5.6 Hz), 5.40(s,2H), 3.31(dt,2H,J=5.2,7.2 Hz),
2.82(dd,2H,J=7.9,8.1 Hz), 1.62-1.57(m,2H).
[1149] Step 5
[1150] To
N-[3-(2,6-dichlorophenyl)propyl]-3-benzyloxy-4-oxo-4H-pyran-2-ca-
rboxamide (0.24 g) obtained in the previous step were added
tetrahydrofuran (1.8 ml), ethanol (1.8 ml) and aminoacetaldehyde
dimethyl acetal (0.012 ml), and the mixture was stirred at
60.degree. C. for 46 hr. The solvent was evaporated and the residue
was purified by silica gel column chromatography
(chloroform:methanol=100:0-10:1) to give
N-[3-(2,6-dichlorophenyl)propyl]-3-benzyloxy-1-(2,2-dimethoxyethyl)-4-oxo-
-1,4-dihydropyridine-2-carboxamide (0.24 g).
[1151] .sup.1H-NMR(CDCl.sub.3).delta. 7.35-7.24(m,8H),
7.07(dd,1H,J=7.6,8.1 Hz), 6.42(d,1H,J=7.5 Hz), 6.25(br,1H),
5.28(s,2H), 4.57(dd,1H,J=3.1,5.1 Hz), 3.89(d,2H,J=4.8 Hz),
3.41-3.36(m,6H), 3.29(m,2H), 2.85(dd,2H,J=7.2,8.6 Hz),
1.71-1.62(m,2H).
[1152] Step 6
[1153] To a solution of
N-[3-(2,6-dichlorophenyl)propyl]-3-benzyloxy-1-(2,-
2-dimethoxyethyl)-4-oxo-1,4-dihydropyridine-2-carboxamide (237 mg)
obtained in the previous step in toluene (20 ml) was added
camphorsulfonic acid (106 mg) and the mixture was stirred at
110.degree. C. for 5 hr. After stirring at room temperature for 15
hr, camphorsulfonic acid (21 mg) was added and the mixture was
stirred at 110.degree. C. for 3 hr. Triethylamine (1 ml) was added
to the reaction mixture at room temperature and the precipitated
solid was filtered off. The filtrate was concentrated and purified
by silica gel column chromatography (ethyl
acetate:methanol=10:1-5:1) and thin layer chromatography (ethyl
acetate:methanol=5:1) to give
9-benzyloxy-2-[3-(2,6-dichlorophenyl)propyl]-2H-pyrido[1,2-a]pyrazine-1,8-
-dione (120 mg).
[1154] .sup.1H-NMR(CDCl.sub.3).delta. 7.64(d,2H,J=7.9 Hz),
7.38(d,1H,J=7.4 Hz), 7.38-7.23(m,5H), 7.08(dd,1H,J=7.7,8.4 Hz),
6.71(d,1H,J=7.4 Hz), 6.43(d,1H,5.8 Hz), 6.28(d,1H,J=6.0 Hz),
5.35(s,2H), 3.89(t,2H,J=7.4 Hz), 2.98(dd,2H,J=7.2,8.4 Hz),
1.99(m,2H).
[1155] Step 7
[1156] Trifluoroacetic acid (1 ml) was added to
9-benzyloxy-2-[3-(2,6-dich-
lorophenyl)propyl]-2H-pyrido[1,2-a]pyrazine-1,8-dione (120 mg)
obtained in the previous step and the mixture was left standing at
room temperature for 1 hr. The solvent was evaporated, toluene was
added, and the mixture was concentrated, which operations were
performed twice. The obtained crystals were washed with diisopropyl
ether to give
2-[3-(2,6-dichlorophenyl)propyl]-9-hydroxy-2H-pyrido[1,2-a]pyrazine-1,8-d-
ione (92 mg).
[1157] hu 1H-NMR(DMSO-d.sub.6).delta. 8.16(d,1H,J=7.3 Hz),
7.46(d,2H,J=7.7 Hz), 7.41(d,1H,J=6.2 Hz), 7.28(m,1H),
7.11(d,1H,J=5.9 Hz), 6.85(d,1H,J=7.7 Hz), 4.43(br,1H),
3.92(t,2H,J=7.0 Hz), 2.93(dd,2H,J=7.7,8.4 Hz), 1.92(m,2H).
Example 12
Synthesis of
2-(3,4-dichlorobenzyl)-9-hydroxy-2H-pyrazino[1,2-c]pyrimidine-
-1,8-dione hydrochloride
[1158] 61
[1159] Step 1
[1160] To a solution of dimethyl
2-benzyloxy-3-hydroxy-2-butenedicarboxyla- te (3.0 g) in methanol
(60 ml) were added sodium methoxide (1.28 g) and formamidine
hydrochloride (953 mg) under ice-cooling, and the mixture was
stirred at 70.degree. C. for 1.5 hr. The reaction solvent was
evaporated under reduced pressure, and water was added to dissolve
the residue. 5% Aqueous potassium hydrogen sulfate solution was
added, and the precipitated solid was collected by filtration,
washed with water and dried to give methyl
5-benzyloxy-6-hydroxypyrimidine-4-carboxylate (1.1 g).
[1161] .sup.1H-NMR(DMSO-d.sub.6).delta. 13.1(brs,1H), 8.01(s,1H),
7.2-7.5(m,5H), 5.12(s,2H), 3.75(s,3H).
[1162] Step 2
[1163] Methanol (6 ml) and 1N aqueous sodium hydroxide solution
(2.5 ml) were added to methyl
5-benzyloxy-6-hydroxypyrimidine-4-carboxylate (530 mg) obtained in
the previous step, and the mixture was stirred at room temperature
for 1 hr. 2N Hydrochloric acid (2.5 ml) was added to the reaction
mixture, and methanol was evaporated under reduced pressure. The
precipitate was collected by filtration, washed with water and
dried to give 5-benzyloxy-6-hydroxypyrimidine-4-carboxylic acid
(253 mg).
[1164] .sup.1H-NMR(DMSO-d.sub.6).delta. 13.5(brs,1H), 13.0(brs,1H),
8.00(s,2H), 7.2-7.5(s,2H).
[1165] Step 3
[1166] 5-Benzyloxy-6-hydroxypyrimidine-4-carboxylic acid (103 mg)
obtained in the previous step was dissolved in
acetonitrile/tetrahydrofuran (2 ml), carbonyldiimidazole (88 mg)
was added, and the mixture was stirred at room temperature for 30
min. The mixture was added to a solution of
N-(3,4-dichlorobenzyl)-N-(2,2-dimethoxyethyl)amine obtained in the
same manner as in Example 5, Step 1 in acetonitrile (2 ml), and the
mixture was stirred overnight at room temperature. The reaction
mixture was evaporated under reduced pressure, and the residue was
dissolved in chloroform, washed with saturated brine and dried over
magnesium sulfate. The solvent was evaporated and the residue was
purified by silica gel column chromatography (hexane:ethyl
acetate=1:2-ethyl acetate) to give an oil (210 mg).
[1167] This oil was dissolved in dioxane (5 ml), pyridinium
p-toluenesulfonate (22 mg) was added, and the mixture was heated
under reflux overnight. The reaction solvent was evaporated under
reduced pressure, and the residue was dissolved in chloroform,
washed with saturated aqueous sodium hydrogen carbonate solution
and saturated brine and dried over magnesium sulfate. The solvent
was evaporated and the residue was purified by silica gel column
chromatography (ethyl acetate-ethyl acetate:methanol=9:1) to give
an oil (40 mg). This oil was dissolved in acetic acid (600 .mu.l)
and conc. hydrochloric acid (200 .mu.l) and the mixture was stirred
at 100.degree. C. for 1.5 days. The reaction solvent was evaporated
under reduced pressure. Toluene was added to the residue and the
mixture was concentrated, which operations were performed twice,
after which the residue was crystallized from methanol. The
crystals were collected by filtration and dried to give
2-(3,4-dichlorobenzyl)-9-hydroxy-2H-pyrazino[1,2-c]pyrimidine-1,8-dione
hydrochloride (12 mg).
[1168] .sup.1H-NMR(DMSO-d.sub.6).delta. 1.08(brs,1H), 8.48(s,1H),
7.68(d,1H,J=4 Hz), 7.63(d,1H, J=8 Hz), 7.3-7.4(m, 2H),
7.16(d,1H,J=8 Hz), 6.80(d,1H,J=8 Hz), 4.90(s,2H).
Examples 13-92
[1169] In the same manner as in Example 1-12 or by a similar method
or by a conventional method, the compounds of Example 13-92 to be
shown in the Tables below were obtained.
Example 118
Synthesis of
2-(3-chlorobenzyl)-9-hydroxy-7-(1-hydroxy-2,2-dimethylpropyl)-
-2H-pyrido[1,2-a]pyrazine-1,8-dione hydrochloride
[1170] 62
[1171] Step 1
[1172] To a solution of 3-benzyloxy-4-oxo-4H-pyran-2-carboxylic
acid 3-chlorobenzylamide (300 mg) obtained in Example 10, Step 1
and 2,2-dimethylpropionaldehyde (9 ml) in tetrahydrofuran (9 ml)
was added dropwise 1.5 M lithium
diisopropylamide--tetrahydrofuran/cyclohexane solution (4.5 ml)
under nitrogen at -78.degree. C. After stirring at the same
temperature for 2 hr, the cooling bath was removed and 1N aqueous
hydrochloric acid (15 ml) and ethyl acetate (25 ml) were added, and
the mixture was warmed to room temperature. The organic layer was
separated from the aqueous layer and extracted with ethyl acetate
(25 ml). The combined organic layer was dried, concentrated and
purified by silica gel column chromatography (ethyl
acetate:hexane=1:3) to give
3-benzyloxy-5-(1-hydroxy-2,2-dimethylpropyl)-4-oxo-4H-pyran-2-carboxylic
acid 3-chlorobenzylamide (0.22 g).
[1173] .sup.1H-NMR(CDCl.sub.3).delta. 8.07(brt,1H,J=5.8 Hz),
7.82(s,1H), 7.35-7.18(m,7H), 7.15(s,1H), 7.05(d,1H,J=7.0 Hz),
5.33(s,2H), 4.43(d,1H,J=7.2 Hz), 4.39(d,2H,J=5.8 Hz),
3.61(d,1H,J=7.2 Hz), 0.96(s,9H).
[1174] Step 2
[1175] To a solution of
3-benzyloxy-5-(1-hydroxy-2,2-dimethylpropyl)-4-oxo-
-4H-pyran-2-carboxylic acid 3-chlorobenzylamide (0.22 g) in
tetrahydrofuran (1.5 ml)-ethanol (1.5 ml) was added
aminoacetaldehyde dimethyl acetal (0.16 ml) and the mixture was
stirred at 60.degree. C. for 24 hr. The solvent was evaporated and
purified by silica gel column chromatography (ethyl
acetate:hexane=1:1-ethyl acetate) to give
3-benzyloxy-1-(2,2-dimethoxyethyl)-5-(1-hydroxy-2,2-dimethylpropyl)-4-oxo-
-1,4-dihydropyridine-2-carboxylic acid 3-chlorobenzylamide (198
mg).
[1176] .sup.1H-NMR(CDCl.sub.3).delta. 7.73(brdd,1H,J=6.2,5.8 Hz),
7.33-7.10(m,10H), 5.76(brd,1H,J=7.4 Hz), 5.17(d,1H,J=11.0 Hz),
5.01(d,1H,J=11.0 Hz), 4.50(t,1H,J=5.0 Hz), 4.39(dd,1H,J=6.2,15.1
Hz), 4.23(dd,1H,J=5.8,15.1 Hz), 4.14(d,1H,J=7.4 Hz), 3.29(s,3H),
3.27(s,3H), 0.89(s,9H).
[1177] Step 3
[1178] To a solution of
3-benzyloxy-1-(2,2-dimethoxyethyl)-5-(1-hydroxy-2,-
2-dimethylpropyl)-4-oxo-1,4-dihydropyridine-2-carboxylic acid
3-chlorobenzylamide (60 mg) in dioxane (0.55 ml) was added conc.
hydrochloric acid (0.55 ml) and the mixture was stirred at
90.degree. C. for 2 hr. The solvent was evaporated, toluene was
added, and the mixture was concentrated, which operations were
performed twice. Crystallization from ethyl acetate-diisopropyl
ether gave 2-(3-chlorobenzyl)-9-hydroxy-7--
(1-hydroxy-2,2-dimethylpropyl)-2H-pyrido[1,2-a]pyrazine-1,8-dione
hydrochloride (44 mg).
[1179] .sup.1H-NMR(DMSO-d.sub.6).delta. 8.30(s,1H), 7.70(d,1H,J=6.2
Hz), 7.50(s), 7.44-7.34(m,3H), 7.26(d,1H,J=6.2 Hz),
5.09(d,1H,J=14.9 Hz), 4.99(d,1H,J=14.9 Hz), 4.76(s,1H),
0.87(s,9H).
Example 125
Synthesis of
2-(3-chlorobenzyl)-7-(2,2-dimethylpropionyl)-9-hydroxy-2H-pyr-
ido[1,2-a]pyrazine-1,8-dione hydrochloride
[1180] 63
[1181] Step 1
[1182] To a solution of
3-benzyloxy-1-(2,2-dimethoxyethyl)-5-(1-hydroxy-2,-
2-dimethylpropyl)-4-oxo-1,4-dihydropyridine-2-carboxylic acid
3-chlorobenzylamide (120 mg) obtained in Example 118, Step 2 in
dimethyl sulfoxide (5 ml) were added triethylamine (1.1 ml) and
sulfur trioxide pyridine complex (450 mg) and the mixture was
stirred at room temperature for 1 hr. A saturated aqueous ammonium
chloride solution was added to the reaction mixture and the mixture
was extracted twice with ethyl acetate (30 ml). The combined ethyl
acetate layer washed with water, dried, concentrated and purified
by silica gel column chromatography (ethyl acetate:hexane=1:3) to
give 3-benzyloxy-1-(2,2-dimethoxyethyl)-5-(2,2-dim-
ethylpropionyl)-4-oxo-1,4-dihydropyridine-2-carboxylic acid
3-chlorobenzylamide (104 mg).
[1183] .sup.1H-NMR(CDCl.sub.3).delta. 8.27(brt,1H,J=6.0 Hz),
7.26-7.14(m,8H), 7.06(t,1H,J=7.7 Hz), 5.08(s,2H), 4.54(t,1H,J=5.1
Hz), 4.34(d,2H,J=6.0 Hz), 3.81(d,2H,J=5.1 Hz), 3.28(s,6H),
1.20(s,9H).
[1184] Step 2
[1185] To a solution of
3-benzyloxy-1-(2,2-dimethoxyethyl)-5-(2,2-dimethyl-
propionyl)-4-oxo-1,4-dihydropyridine-2-carboxylic acid
3-chlorobenzylamide (100 mg) in dioxane (1 ml) was added conc.
hydrochloric acid (1 ml) and the mixture was stirred at 90.degree.
C. for 2 hr. The solvent was evaporated, toluene was added, and the
mixture was concentrated, which operations were performed twice.
Crystallization from ethyl acetate-diisopropyl ether gave
2-(3-chlorobenzyl)-7-(2,2-dimethylpropiony-
l)-9-hydroxy-2H-pyrido[1,2-a]pyrazine-1,8-dione hydrochloride (71
mg).
[1186] .sup.1H-NMR(DMSO-d.sub.6).delta. 8.09(s,1H), 7.48(s,1H),
7.43-7.32(m,3H), 7.22(d,1H,J=6.2 Hz), 6.94(d,1H,J=6.2 Hz),
4.98(s,2H), 1.19(s,9H).
Example 161
Synthesis of
7-amino-2-(3-chlorobenzyl)-9-hydroxy-2H-pyrido[1,2-a]pyrazine-
-1,8-dione hydrochloride
[1187] 64
[1188] Step 1
[1189] To a solution of 3-benzyloxy-4-oxo-4H-pyran-2-carboxylic
acid 3-chlorobenzylamide (5.13 g) obtained in Example 10, Step 1 in
chloroform (100 ml) was added a solution of bromine (1.5 ml) in
chloroform (50 ml) and the mixture was stirred with heating under
reflux for 2 hr. A solution of bromine in chloroform (1.0 ml) was
added, and after stirring with heating for 16 hr, the solvent was
evaporated. Toluene was added to the residue and the mixture was
concentrated, which operations were performed twice to give a crude
product of 5-bromo-3-hydroxy-4-oxo-4H-pyr- an-2-carboxylic acid
3-chlorobenzylamide. The obtained crude product was dissolved in
dimethylformamide (50 ml), and potassium carbonate (3.87 g) and
benzyl bromide (2.75 ml) were added thereto. The reaction mixture
was stirred at room temperature for 1 hr. Water (100 ml) and 1N
aqueous hydrochloric acid (50 ml) were added to the reaction
mixture and the mixture was extracted twice with ethyl acetate (200
ml each). The ethyl acetate layer was washed, dried, concentrated
and purified by silica gel column chromatography (ethyl
acetate:hexane=1:3) to give
3-benzyloxy-5-bromo-4-oxo-4H-pyran-2-carboxylic acid
3-chlorobenzylamide (3.31 g).
[1190] .sup.1H-NMR(CDCl.sub.3).delta. 8.21(s,1H), 8.01(brt,1H,J=5.9
Hz), 7.41-7.20(m,7H), 7.15(s,1H), 7.05(d,1H,J=7.3 Hz), 5.38(s,2H),
4.39(d,2H,J=5.9 Hz).
[1191] Step 2
[1192] To a solution of
3-benzyloxy-5-bromo-4-oxo-4H-pyran-2-carboxylic acid
3-chlorobenzylamide (1.50 g) in tetrahydrofuran (10 ml)-ethanol (10
ml) was added aminoacetaldehyde dimethyl acetal (0.73 ml) and the
mixture was stirred at 60.degree. C. for 1 hr. The solvent was
evaporated and the residue was purified by silica gel column
chromatography (ethyl acetate:hexane=1:3-1:2) to give
3-benzyloxy-5-bromo-1-(2,2-dimethoxyethyl-
)-4-oxo-1,4-dihydropyridine-2-carboxylic acid 3-chlorobenzylamide
(1.35 g).
[1193] .sup.1H-NMR(CDCl.sub.3).delta. 8.03(brt,1H,J=6.2 Hz),
7.65(s,1H), 7.33-7.11(m,9H), 5.04(s,2H), 4.53(t,1H,J=5.1 Hz),
4.34(d,2H,J=6.2 Hz), 3.83(d,2H,J=5.1 Hz), 3.30(s,6H).
[1194] Step 3
[1195] To a solution of
3-benzyloxy-5-bromo-1-(2,2-dimethoxyethyl)-4-oxo-1-
,4-dihydropyridine-2-carboxylic acid 3-chlorobenzylamide (3.89 g)
in dimethyl sulfoxide (26 ml)-methanol (13 ml) were added
palladium(II) acetate (0.16 g), 1,3-bis(diphenylphosphino)propane
(0.3 g) and triethylamine (2 ml) and the mixture was stirred under
carbon monoxide at 70.degree. C. for 24 hr. The reaction mixture
was concentrated and water was added, and the mixture was extracted
twice with ethyl acetate (200 ml each). The ethyl acetate layer
was-washed with water, dried and concentrated to give a crude
product of methyl 5-benzyloxy-6-(3-chloroben-
zylcarbamoyl)-1-(2,2-dimethoxyethyl)-4-oxo-1,4-dihydropyridine-3-carboxyla-
te (4.12 g).
[1196] .sup.1H-NMR(CDCl.sub.3) 8.50(brs,1H), 7.95(s,1H),
7.29-7.12(m,9H), 4.97(s,2H), 4.56(t,1H,J=5.1 Hz), 4.46(d,2H,J=6.3
Hz), 3.83(d,2H,J=5.1 Hz), 3.73(s,3H), 3.27(s,6H).
[1197] Step 4
[1198] To a solution of methyl
5-benzyloxy-6-(3-chlorobenzylcarbamoyl)-1-(-
2,2-dimethoxyethyl)-4-oxo-1,4-dihydropyridine-3-carboxylate (2.0 g)
in tetrahydrofuran (20 ml)-methanol (10 ml) was added 4N aqueous
lithium hydroxide solution (1.5 ml) and the mixture was stirred at
70.degree. C. for 1 hr. The precipitated solid was removed by thin
layer of celite and washed with methanol. The solvent was
evaporated and 1N aqueous hydrochloric acid (6.5 ml) and water (50
ml) were added. The mixture was extracted twice with ethyl acetate
(75 ml each). The ethyl acetate layer was dried, concentrated and
crystallized from ethyl acetate-diisopropyl ether to give
5-benzyloxy-6-(3-chlorobenzylcarbamoyl)-1-(2,2-dimethoxyeth-
yl)-4-oxo-1,4-dihydropyridine-3-carboxylic acid (1.2 g).
[1199] .sup.1H-NMR(CDCl.sub.3).delta. 8.35(s,1H), 7.42-7.09(m,9H),
6.55(brs,1H), 5.34(s,2H), 4.50(t,1H,J=4.4 Hz), 4.40(d,2H,J=5.9 Hz),
4.10(d,2H,J=4.4 Hz), 3.31(s,6H).
[1200] Step 5
[1201] To a solution of
5-benzyloxy-6-(3-chlorobenzylcarbamoyl)-1-(2,2-dim-
ethoxyethyl)-4-oxo-1,4-dihydropyridine-3-carboxylic acid (50 mg) in
dimethylformamide (0.3 ml) were added triethylamine (0.07 ml) and
diphenylphosphoryl azide (0.054 ml). After stirring at room
temperature for 1 hr, tert-butanol (0.3 ml) was added, and the
mixture was heated to 100.degree. C. and stirred for 1 hr. After
cooling to room temperature, saturated aqueous ammonium chloride
solution (5 ml) and water (5 ml) were added, and the mixture was
extracted twice with ethyl acetate (15 ml each). The ethyl acetate
layer was washed with water, dried and concentrated. The obtained
residue was purified by silica gel column chromatography (ethyl
acetate:hexane=1:2) to give tert-butyl
[5-benzyloxy-6-(3-chlorobenzylcarbamoyl)-1-(2,2-dimethoxyethyl)-4-oxo-1,4-
-dihydropyridin-3-yl]carbamate (40 mg).
[1202] .sup.1H-NMR(CDCl.sub.3).delta. 8.39(s,1H), 7.70(s,1H),
7.36-7.08(m,9H), 6.43(brt,1H,J=6.2 Hz), 5.27(s,2H), 4.52(t,1H,J=5.1
Hz), 4.37(d,2H,J=6.2 Hz), 4.06(d,2H,J=5.1 Hz), 3.28(s,6H),
1.55(s,9H).
[1203] Step 6
[1204] tert-Butyl
[5-benzyloxy-6-(3-chlorobenzylcarbamoyl)-1-(2,2-dimethox-
yethyl)-4-oxo-1,4-dihydropyridin-3-yl]carbamate (40 mg) was
dissolved in acetic acid (0.4 ml) and conc. hydrochloric acid (0.4
ml) was added. The mixture was stirred at 90.degree. C. for 5 hr.
The reaction mixture was concentrated, toluene was added to the
residue and the mixture was concentrated, which operations were
performed twice. Methanol was further added, and the mixture was
concentrated, which operations were performed twice.
Crystallization from ethyl acetate-methanol-diisopropyl ether gave
7-amino-2-(3-chlorobenzyl)-9-hydroxy-2H-pyrido[1,2-a]pyrazine-1,8-dione
hydrochloride (23 mg).
[1205] .sup.1H-NMR(DMSO-d.sub.6).delta. 12.29(brs,1H), 7.99(s,1H),
7.78(d,1H,J=6.0 Hz), 7.58(d,1H,J=6.0 Hz), 7.49(s,1H),
7.43-7.33(m,3H), 5.10(s,2H).
Example 165
Synthesis of
N-[2-(3-chlorobenzyl)-9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyri-
do[1,2-a]pyrazin-7-yl]acetamide
[1206] 65
[1207]
7-Amino-2-(3-chlorobenzyl)-9-hydroxy-2H-pyrido[1,2-a]pyrazine-1,8-d-
ione hydrochloride (23 mg) obtained in Example 161 was dissolved in
pyridine (0.1 ml) and acetic anhydride (0.0123 ml) was added. After
stirring at room temperature for 1 hr, water (3 ml) was added to
the reaction mixture, and the mixture was extracted twice with
chloroform (6 ml each). The chloroform layer was dried,
concentrated and crystallized from chloroform-methanol-diisopropyl
ether to give 22 mg of a solid. This solid was suspended in
tetrahydrofuran (0.4 ml)-methanol (1 ml)-chloroform (1 ml) and 2N
aqueous sodium hydroxide solution (0.043 ml) was added. The mixture
was stirred at room temperature for 30 min. The reaction mixture
was concentrated, 1N aqueous hydrochloric acid (6 ml) was added,
and the mixture was extracted three times with chloroform (8 ml
each). The chloroform layer was dried, concentrated and
crystallized from chloroform-methanol-diisopropyl ether to give
N-[2-(3-chlorobenzyl)-9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido[1,2-a]pyr-
azin-7-yl]acetamide (18 mg).
[1208] .sup.1H-NMR(DMSO-d.sub.6).delta. 11.59(bs,1H), 9.44(s,1H),
9.08(s,1H), 7.49(s,1H), 7.47(d,1H,J=6.0 Hz), 7.42-7.32(m,3H),
6.95(d,1H,J=6.0 Hz), 4.97(s,2H), 2.17(s,3H).
Example 94
Synthesis of
7-bromo-2-(3-chlorobenzyl)-9-hydroxy-2H-pyrido[1,2-a]pyrazine-
-1,8-dione hydrochloride
[1209] 66
[1210] By subjecting
3-benzyloxy-5-bromo-1-(2,2-dimethoxyethyl)-4-oxo-1,4--
dihydropyridine-2-carboxylic acid 3-chlorobenzylamide (50 mg)
obtained in Example 161, Step 2 to a reaction operation similar to
that in Example 161, Step 6 and crystallization from ethyl
acetate-methanol-diisopropyl ether,
7-bromo-2-(3-chlorobenzyl)-9-hydroxy-2H-pyrido[1,2-a]pyrazine-1,8--
dione hydrochloride (30 mg) was obtained.
[1211] .sup.1H-NMR(DMSO-d.sub.6).delta. 8.63(s,1H), 7.48(s,1H),
7.44-7.33(m,3H), 7.21(d,1H,J=6.2 Hz), 6.95(d,1H,J=6.2 Hz),
4.98(s,2H).
Example 96
Synthesis of
2-(3-chlorobenzyl)-9-hydroxy-7-phenyl-2H-pyrido[1,2a]pyrazine-
-1,8-dione hydrochloride
[1212] 67
[1213] Step 1
[1214] To a solution of
3-benzyloxy-5-bromo-1-(2,2-dimethoxyethyl)-4-oxo-1-
,4-dihydropyridine-2-carboxylic acid 3-chlorobenzylamide (70 mg)
obtained in Example 161, Step 2 in dimethoxyethane (1.4 ml)-water
(0.7 ml) were successively added phenylboronic acid (32 mg),
tetrakis(triphenylphosphin- e)palladium(0) (31 mg) and sodium
carbonate (42 mg), and the mixture was stirred at 80.degree. C. for
2 hr. After cooling to room temperature, the mixture was purified
by silica gel column chromatography (ethyl acetate:hexane=1:3-1:1)
to give 3-benzyloxy-1-(2,2-dimethoxyethyl)-4-oxo--
5-phenyl-1,4-dihydropyridine-2-carboxylic acid 3-chlorobenzylamide
(56 mg).
[1215] .sup.1H-NMR(CDCl.sub.3).delta. 7.27(brs,1H), 7.50(s,1H),
7.40-7.09(m,14H), 5.15(s,2H), 4.55(t,1H,J=5.1 Hz), 4.16(d,2H,J=6.0
Hz), 3.85(d,2H,J=5.1 Hz), 3.28(s,6H).
[1216] Step 2
[1217]
3-Benzyloxy-1-(2,2-dimethoxyethyl)-4-oxo-5-phenyl-1,4-dihydropyridi-
ne-2-carboxylic acid 3-chlorobenzylamide (52 mg) was dissolved in
acetic acid (0.5 ml) and conc. hydrochloric acid (0.5 ml) was
added, and the mixture was stirred at 90.degree. C. for 2 hr. The
reaction mixture was concentrated, toluene was added to the residue
and the mixture was concentrated, which operations were performed
twice. Methanol was further added and the mixture was concentrated
and crystallized from ethyl acetate-diisopropyl ether to give
2-(3-chlorobenzyl)-9-hydroxy-7-phenyl-2-
H-pyrido[1,2-a]pyrazine-1,8-dione hydrochloride (39 mg).
[1218] .sup.1H-NMR(DMSO-d.sub.6).delta. 8.50(s,1H), 7.73(d,2H,J=7.0
Hz), 7.53-7.36(m,8H), 7.10(d,1H,J=6.2 Hz), 5.04(s,2H).
Example 104
Synthesis of
2-(3-chlorobenzyl)-9-hydroxy-7-isopropyl-2H-pyrido[1,2-a]pyra-
zine-1,8-dione hydrochloride
[1219] 68
[1220] Step 1
[1221] To a solution of
3-benzyloxy-5-bromo-1-(2,2-dimethoxyethyl)-4-oxo-1-
,4-dihydropyridine-2-carboxylic acid 3-chlorobenzylamide (138 mg)
obtained in Example 161, Step 2 in dioxane (2.5 ml) were added
tributyl-2-propenyltin (245 mg) and
tetrakis(triphenylphosphine)palladium- (0) (60 mg), and the mixture
was stirred at 100.degree. C. for 4 hr. The solvent was evaporated,
toluene was added, and the mixture was concentrated again. The
obtained residue was purified by silica gel column chromatography
(ethyl acetate:hexane=1:3) to give
3-benzyloxy-1-(2,2-dimethoxyethyl)-5-isopropenyl-4-oxo-1,4-dihydropyridin-
e-2-carboxylic acid 3-chlorobenzylamide (89 mg).
[1222] .sup.1H-NMR(CDCl.sub.3).delta. 7.75(brt,1H,J=6.0 Hz),
7.31-7.09(m,10H), 5.80(d,2H,J=2.3 Hz), 5.19(dq,1H,J=2.3,1.4 Hz),
5.09(s,2H), 4.52(t,1H,J=5.1 Hz), 4.31(d,2H,J=6.0 Hz),
3.82(d,2H,J=5.1 Hz), 3.29(s,6H), 2.05(brs,3H).
[1223] Step 2
[1224] To a solution of
3-benzyloxy-1-(2,2-dimethoxyethyl)-5-isopropenyl-4-
-oxo-1,4-dihydropyridine-2-carboxylic acid 3-chlorobenzylamide (60
mg) in methanol (1 ml) was added 5% palladium-carbon (20 mg) and
the mixture was stirred under an atmospheric pressure of hydrogen
for 16 hr. A solid was filtered off and the filtrate was
concentrated to give
1-(2,2-dimethoxyethyl)-3-hydroxy-5-isopropyl-4-oxo-1,4-dihydropyridine-2--
carboxylic acid 3-chlorobenzylamide (43 mg).
[1225] .sup.1H-NMR(CDCl.sub.3).delta. 8.89(brt,1H,J=5.8 Hz),
7.38-7.24(m,5H), 4.63(d,2H,J=5.8 Hz), 4.60(d,1H,J=4.9 Hz),
4.51(d,2H,J=4.9 Hz), 3.23(sep,1H,J=6.8 Hz), 1.23(d,6H,J=6.8
Hz).
[1226] Step 3
[1227] By subjecting
1-(2,2-dimethoxyethyl)-3-hydroxy-5-isopropyl-4-oxo-1,-
4-dihydropyridine-2-carboxylic acid 3-chlorobenzylamide (42 mg) to
a reaction operation similar to that in Example 161, Step 6 and
crystallization from ethyl acetate-methanol-diisopropyl ether, and
further crystallization from ethyl acetate-methanol,
2-(3-chlorobenzyl)-9-hydroxy-7-isopropyl-2H-pyrido[1,2-a]pyrazine-1,8-dio-
ne hydrochloride (18 mg) was obtained.
[1228] .sup.1H-NMR(DMSO-d.sub.6).delta. 8.27(s,1H),
7.51-7.45(m,2H), 7.42-7.31(m,3H), 7.17(brd,1H,J=6.2 Hz),
5.04(s,2H), 3.23(sep,1H,J=7.0 Hz), 1.19(d,6H,J=7.0 Hz).
Example 187
Synthesis of methyl
[2-(3-chlorobenzyl)-9-hydroxy-1,8-dioxo-1,8-dihydro-2H-
-pyrido[1,2-a]pyrazin-7-yl]acetate
[1229] 69
[1230] Step 1
[1231] To a solution of
3-benzyloxy-5-bromo-1-(2,2-dimethoxyethyl)-4-oxo-1-
,4-dihydropyridine-2-carboxylic acid 3-chlorobenzylamide (300 mg)
obtained in Example 161, Step 2 in toluene were added under an
argon stream tributyltin fluoride (518 mg),
tris(dibenzylideneacetone)dipalladium(0)-c- hloroform adduct (58
mg), 1,1'-bis(diphenylphosphino)ferrocene (64 mg) and
1-(tert-butyldimethylsilyloxy)-1-methoxyethane (525 mg), and the
mixture was stirred at 100.degree. C. for 15 hr. After cooling to
room temperature, aqueous sodium hydrogen carbonate was added to
the reaction mixture and the mixture was extracted three times with
ethyl acetate. The extract was dried, concentrated and purified by
silica gel column chromatography (ethyl acetate) to give methyl
[5-benzyloxy-6-(3-chloroben-
zylcarbamoyl)-1-(2,2-dimethoxyethyl)-4-oxo-1,4-dihydropyridin-3-yl]acetate
(184 mg).
[1232] .sup.1H-NMR(CDCl.sub.3).delta. 7.38(s,1H), 7.32-7.07(m,9H),
6.76(brt,1H, J=6.0 Hz), 5.24(s,2H), 4.52(t,1H,J=5.1 Hz),
4.37(d,2H,J=6.0 Hz), 3.90(d,2H,J=5.1 Hz), 3.72(s,3H), 3.48(s,2H),
3.31(s,6H).
[1233] Step 2
[1234] Methyl
[5-benzyloxy-6-(3-chlorobenzylcarbamoyl)-1-(2,2-dimethoxyeth-
yl)-4-oxo-1,4-dihydropyridin-3-yl]acetate (30 mg) was dissolved in
trifluoroacetic acid (1 ml) and the mixture was stirred at
70.degree. C. for 4 hr. The mixture was cooled and concentrated.
Toluene was added to the residue and the mixture was concentrated
again, which operations were performed twice. Crystallization from
ethyl acetate-diisopropyl ether gave methyl,
[2-(3-chlorobenzyl)-9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrid-
o[1,2-a]pyrazin-7-yl]acetate (17 mg).
[1235] .sup.1H-NMR(DMSO-d.sub.6).delta. 11.50(brs,1H), 8.05(s,1H),
7.48(s,1H), 7.42-7.31(m,3H), 7.18(d,1H,J=6.1 Hz), 6.86(d,1H,J=6.1
Hz), 4.96(s,2H), 3.59(s,3H), 3.47(s,2H).
Example 191
Synthesis of
[2-(3-chlorobenzyl)-9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido-
[1,2-a]pyrazin-7-yl]acetic acid
[1236] 70
[1237] Step 1
[1238] To a solution of methyl
[5-benzyloxy-6-(3-chlorobenzylcarbamoyl)-1--
(2,2-dimethoxyethyl)-4-oxo-1,4-dihydropyridin-3-yl]acetate (150 mg)
obtained in Example 187, Step 1 in tetrahydrofuran (1.5
ml)-methanol (1.5 ml) was added 4N aqueous sodium hydroxide
solution (0.11 ml), and the mixture was stirred at 70.degree. C.
for 30 min. The reaction mixture was warmed to room temperature, 1N
aqueous hydrochloric acid (0.5 ml) and water (15 ml) were added,
and the mixture was extracted twice with ethyl acetate (30 ml
each). The ethyl acetate layer was washed with water, dried,
concentrated, and crystallized from ethyl acetate-diisopropyl ether
to give
[5-benzyloxy-6-(3-chlorobenzylcarbamoyl)-1-(2,2-dimethoxyet-
hyl)-4-oxo-1,4-dihydropyridin-3-yl]acetic acid (116 mg).
[1239] .sup.1H-NMR(CDCl.sub.3).delta. 7.42(s,1H), 7.43-7.08(m,9H),
6.81(brt,1H,J=5.8 Hz), 5.27(s,2H), 4.51(t,1H,J=4.6 Hz),
4.39(d,2H,J=5.8 Hz), 4.01(d,2H,J=4.6 Hz), 3.55(s,2H),
3.30(s,6H).
[1240] Step 2
[1241] By subjecting
[5-benzyloxy-6-(3-chlorobenzylcarbamoyl)-1-(2,2-dimet-
hoxyethyl)-4-oxo-1,4-dihydropyridin-3-yl]acetic acid (20 mg) to a
reaction operation similar to that in Example 187, Step 2, and
crystallization from ethyl acetate-diisopropyl ether,
[2-(3-chlorobenzyl)-9-hydroxy-1,8-d-
ioxo-1,8-dihydro-2H-pyrido[1,2-a]pyrazin-7-yl]acetic acid (13 mg)
was obtained.
[1242] .sup.1H-NMR(DMSO-d.sub.6).delta. 12.40(brs,1H),
11.52(brs,1H), 8.05(s,1H), 7.48(s,1H), 7.42-7.31(m,3H),
7.19(d,1H,J=6.3 Hz), 6.87(d,1H,J=6.3 Hz), 4.96(s,2H),
3.40(s,2H).
Exanple 189
Synthesis of
2-[2-(3-chlorobenzyl)-9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyri-
do[1,2-a]pyrazin-7-yl]-N-methylacetamide
[1243] 71
[1244] Step 1
[1245] To a solution of
[5-benzyloxy-6-(3-chlorobenzylcarbamoyl)-1-(2,2-di-
methoxyethyl)-4-oxo-1,4-dihydropyridin-3-yl]acetic acid (25 mg)
obtained in Example 191, Step 1 in dimethylformamide (0.2 ml), were
successively added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide
hydrochloride (19 mg), 1-hydroxybenzotriazole hydrate (15 mg) and
methylamine (2M tetrahydrofuran solution)(0.073 ml), and the
mixture was stirred at room temperature for 2 hr. The obtained
reaction mixture was applied as it was to silica gel thin layer
chromatography (chloroform:methanol=10:1) and crystallized from
ethyl acetate-diisopropyl ether to give
3-benzyloxy-1-(2,2-dimethoxyethyl)-5-methylcarbamoylmethyl-4-oxo-1,4-dihy-
dropyridine-2-carboxylic acid 3-chlorobenzylamide (22 mg).
[1246] .sup.1H-NMR(CDCl.sub.3).delta. 7.48(s,1H), 7.45(brd,1H,J=4.8
Hz), 7.34-7.05(m,9H), 6.38(brt,1H,J=6.0 Hz), 5.27(s,2H),
4.49(t,1H,J=4.8 Hz), 4.36(d,2H,J=6.0 Hz), 3.95(d,2H,J=4.8 Hz),
3.40(s,2H), 3.30(s,6H), 2.73(d,3H,J=4.8 Hz).
[1247] Step 2
[1248] By subjecting
3-benzyloxy-1-(2,2-dimethoxyethyl)-5-methylcarbamoylm-
ethyl-4-oxo-1,4-dihydropyridine-2-carboxylic acid
3-chlorobenzylamide (21 mg) to a reaction operation similar to that
in Example 187, Step 2, and crystallization from ethyl
acetate-diisopropyl ether,
2-[2-(3-chlorobenzyl)-9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido[1,2-a]pyr-
azin-7-yl]-N-methylacetamide (11 mg) was obtained.
[1249] .sup.1H-NMR(DMSO-d.sub.6).delta. 11.44(brs,1H), 8.01(s,1H),
7.77(s,1H), 7.47(s,1H), 7.43-7.31(m,3H), 7.23(d,1H,J=6.0 Hz),
6.87(d,1H,J=6.0 Hz), 4.96(s,2H), 3.27(s,2H), 2.55(d,3H,J=4.6
Hz).
Example 390
Synthesis of
9-benzyloxy-7-bromo-2-(3-chlorobenzyl)-3,4-dihydro-2H-pyrido[-
1,2-a]pyrazine-1,8-dione
[1250] 72
[1251] Step 1
[1252] To a solution of
3-benzyloxy-5-bromo-4-oxo-4H-pyran-2-carboxylic acid
3-chlorobenzylamide (2.0 g) obtained in Example 161, Step 1 in
tetrahydrofuran (10 ml)-ethanol (10 ml) was added 2-aminoethanol
(0.33 ml) and the mixture was stirred at room temperature and at
50.degree. C. respectively for 30 min. The solvent was evaporated
and the residue was crystallized from ethyl acetate-diisopropyl
ether to give
3-benzyloxy-5-bromo-1-(2-hydroxyethyl)-4-oxo-1,4-dihydropyridine-2-carbox-
ylic acid 3-chlorobenzylamide (1.95 g).
[1253] .sup.1H-NMR(DMSO-d.sub.6).delta. 9.44(brt,1H,J=5.8 Hz),
8.19(s,1H), 7.39-7.16(m,9H), 5.08(t,1H,J=5.1 Hz), 5.05(s,2H),
4.43(d,2H,J=5.8 Hz), 3.92(t,2H,J=5.1 Hz), 3.62(q,2H,J=5.1 Hz).
[1254] Step 2
[1255]
3-Benzyloxy-5-bromo-1-(2-hydroxyethyl)-4-oxo-1,4-dihydropyridine-2--
carboxylic acid 3-chlorobenzylamide (1.75 g) was suspended in
tetrahydrofuran (50 ml), and N,N-diisopropylethylamine (3.72 ml)
and methanesulfonyl chloride (1.38 ml) were added. After stirring
at room temperature for 1 hr, 0.5N aqueous hydrochloric acid (40
ml) was added, and the mixture was extracted twice with ethyl
acetate (100 ml each). The ethyl acetate layer was washed with
aqueous sodium hydrogen carbonate, dried and concentrated. The
obtained residue was dissolved in dimethylformamide (50 ml) and 60%
sodium hydride was added by small portions with stirring at room
temperature. After confirming the completion of the reaction by
thin layer chromatography (TLC), the reaction mixture was
ice-cooled, 0.33N aqueous hydrochloric acid (300 ml) was added, and
the mixture was extracted twice with ethyl acetate (250 ml each).
The ethyl acetate layer was washed with water, dried, concentrated,
and crystallized from ethyl acetate-hexane to give
9-benzyloxy-7-bromo-2-(3-chlorobenzyl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazi-
ne-1,8-dione (1.58 g).
[1256] .sup.1H-NMR(CDCl.sub.3).delta. 7.66(d,2H,J=6.7 Hz),
7.56(s,1H), 7.37-7.25(m,6H), 7.16(m,1H), 5.32(s,2H), 4.62(s,2H),
3.94-3.88(m,2H), 3.52-3.45(m,2H).
Example 244
Synthesis of
7-acetyl-2-(3-chloro-4-fluorobenzyl)-9-hydroxy-2H-pyrido[1,2--
a]pyrazine-1,8-dione hydrochloride
[1257] 73
[1258] Step 1
[1259] To a solution of
3-benzyloxy-5-bromo-1-(2,2-dimethoxyethyl)-4-oxo-1-
,4-dihydropyridine-2-carboxylic acid 3-chloro-4-fluorobenzylamide
(150 mg) produced in the same manner as for the compound described
in Example 161, Step 2 in toluene (2 ml) were added
tris(dibenzylideneacetone)dipalladium- (0)-chloroform adduct (14
mg), 1,1'-bis(diphenylphosphino)ferrocene (15 mg) and
tributyl(1-ethoxyvinyl)tin (189 mg) under an argon stream and the
mixture was stirred at 90.degree. C. for 4 hr. After cooling to
room temperature, the reaction mixture was concentrated and
purified by subjecting to silica gel thin layer chromatography
(ethyl acetate:hexane=2:1)(toluene:acetone=3:1) twice to give
5-acetyl-3-benzyloxy-1-(2,2-dimethoxyethyl)-4-oxo-1,4-dihydropyridine-2-c-
arboxylic acid 3-chloro-4-fluorobenzylamide (60 mg).
[1260] .sup.1H-NMR(CDCl.sub.3).delta. 8.07(s,1H), 7.34-7.25(m,6H),
7.09-6.96(m,2H), 6.67(brt,1H,J=6.0 Hz), 5.25(s,2H), 4.48(t,1H,J=4.7
Hz), 4.31(d,2H,J=6.0 Hz), 4.03(d,2H,J=4.7 Hz), 3.31(s,6H),
2.73(s,3H).
[1261] Step 2
[1262] By subjecting
5-acetyl-3-benzyloxy-1-(2,2-dimethoxyethyl)-4-oxo-1,4-
-dihydropyridine-2-carboxylic acid 3-chloro-4-fluorobenzylamide (59
mg) to a reaction operation similar to that in Example 96, Step 2,
and crystallization from ethyl acetate-diisopropyl ether,
7-acetyl-2-(3-chloro-4-fluorobenzyl)-9-hydroxy-2H-pyrido[1,2-a]pyrazine-1-
,8-dione hydrochloride (35 mg) was obtained.
[1263] .sup.1H-NMR(DMSO-d.sub.6).delta. 8.48(s,1H), 7.65(m,1H),
7.43-7.40(m,2H), 7.38(d,1H,J=6.3 Hz), 6.93(d,1H,J=6.3 Hz),
4.92(s,2H), 2.61(s,3H).
Example 251
Synthesis of
7-(2,2-dimethylpropionyl)-2-(4-fluorobenzyl)-9-hydroxy-2H-pyr-
ido[1,2a-]pyrazine-1,8-dione hydrochloride
[1264] 74
[1265] Step 1
[1266] To a solution of 3-benzyloxy-4-oxo-4H-pyran-2-carboxylic
acid 4-fluorobenzylamide (0.6 g) produced in the same manner as for
the compound described in Example 10, Step 1 and
2,2-dimethylpropionaldehyde (1.88 ml) in tetrahydrofuran (6 ml) was
added dropwise 1.5 M lithium
diisopropylamide-tetrahydrofuran/cyclohexane solution (14.9 ml)
under nitrogen at -78.degree. C. After stirring at the same
temperature for 2 hr, the cooling-bath was removed and 2N aqueous
hydrochloric acid (15 ml) and ethyl acetate were immediately added,
and the mixture was heated to room temperature. The organic layer
was separated and the aqueous layer was extracted with ethyl
acetate. The combined organic layer was dried, concentrated, and
purified by silica gel column chromatography (ethyl
acetate:hexane=1:2-ethyl acetate) to give
3-benzyloxy-5-(1-hydroxy-2,2-di-
methylpropyl)-4-oxo-4H-pyran-2-carboxylic acid 4-fluorobenzylamide
(0.27 g). The total amount thereof was dissolved in chloroform (3
ml) and 1,1,1-tris(acetoxy)-1,1-dihydro-1,2-benziodoxol-3-(1H)-one
(Dess-Martin reagent)(291 mg) was added at room temperature, and
the mixture was stirred for 2.5 hr. 2-Propanol was added and the
mixture was stirred for 30 min, after which aqueous sodium hydrogen
carbonate solution and aqueous sodium sulfite solution were added.
The mixture was extracted with ethyl acetate. The ethyl acetate
layer was washed with saturated brine, dried and concentrated. The
obtained residue was purified by silica gel thin layer
chromatography (ethyl acetate:hexane=1:1) to give
3-benzyloxy-5-(2,2-dimethylpropionyl)-4-oxo-4H-pyran-2-carboxylic
acid 4-fluorobenzylamide (0.13 g).
[1267] .sup.1H-NMR(CDCl.sub.3).delta. 8.00(m,1H), 7.80(s,1H),
7.40-6.93(m,9H), 5.34(s,2H), 4.39(d,2H,J=5.76 Hz), 1.24(s,9H).
[1268] Step 2
[1269] To a solution of
3-benzyloxy-5-(2,2-dimethylpropionyl)-4-oxo-4H-pyr- an-2-carboxylic
acid 4-fluorobenzylamide (0.13 g) in tetrahydrofuran (0.5
ml)-ethanol (0.5 ml) was added aminoacetaldehyde dimethyl acetal
(0.033 ml) and the mixture was stirred at 70.degree. C. for 3 days.
After cooling to room temperature, the solvent was evaporated to
give
3-benzyloxy-1-(2,2-dimethoxyethyl)-5-(2,2-dimethylpropionyl)-4-oxo-1,4-di-
hydropyridine-2-carboxylic acid 4-fluorobenzylamide (157 mg).
[1270] .sup.1H-NMR(CDCl.sub.3).delta. 8.08(m,1H), 7.31-7.15(m,8H),
6.84-6.78(m,2H), 5.06(s,2H), 4.55(t,1H,J=5.1 Hz), 4.35(d,2H,J=6.0
Hz), 3.82(d,2H,J=5.1 Hz), 3.30(s,6H), 1.21(s,9H).
[1271] Step 3
[1272]
3-Benzyloxy-1-(2,2-dimethoxyethyl)-5-(2,2-dimethylpropionyl)-4-oxo--
1,4-dihydropyridine-2-carboxylic acid 4-fluorobenzylamide (157 mg)
was dissolved in acetic acid (1.5 ml) and conc. hydrochloric acid
(0.5 ml) was added. The mixture was stirred at 90.degree. C. for 3
hr. The reaction mixture was concentrated and crystallized from
ethyl acetate to give
7-(2,2-dimethylpropionyl)-2-(4-fluorobenzyl)-9-hydroxy-2H-pyrido[1,2-
-a]pyrazine-1,8-dione hydrochloride (92 mg).
[1273] .sup.1H-NMR(DMSO-d.sub.6).delta. 8.07(s,1H),
7.46-7.41(m,2H), 7.22-7.16(m,3H), 6.91(d,1H,J=6.0 Hz), 4.93(s,2H),
1.18(s,9H).
Example 223
Synthesis of
2-(3-chlorobenzyl)-7-(2,2-dimethylpropionyl)-9-hydroxy-3,4-di-
hydro-2H-pyrido[1,2-a]pyrazine-1,8-dione hydrochloride
[1274] 75
[1275] Step 1
[1276] To a solution of
3-benzyloxy-5-(1-hydroxy-2,2-dimethylpropyl)-4-oxo-
-4H-pyran-2-carboxylic acid 3-chlorobenzylamide (0.22 g) obtained
in the same manner as in Example 118, Step 1 in chloroform (2 ml)
was added
1,1,1-tris(acetoxy)-1,1-dihydro-1,2-benziodoxol-3-(1H)-one (0.23
g). The mixture was stirred at room temperature for 30 min, aqueous
sodium hydrogen carbonate solution and aqueous sodium sulfite
solution were added and the reaction mixture was extracted with
ethyl acetate. The organic layer was washed with saturated brine,
dried and concentrated to give
3-benzyloxy-5-(2,2-dimethylpropionyl)-4-oxo-4H-pyran-2-carboxylic
acid 3-chlorobenzylamide (225 mg).
[1277] .sup.1H-NMR(CDCl.sub.3) 8.02(1H,t,J=6.0 Hz), 7.81(1H,s),
7.36-7.16(7H,m), 7.14(1H,s), 7.04(1H,d,J=7.0 Hz), 5.36(2H,s),
4.39(2H,d,J=6.0 Hz), 1.26(9H,s).
[1278] Step 2
[1279] To a solution of
3-benzyloxy-5-(2,2-dimethylpropionyl)-4-oxo-4H-pyr- an-2-carboxylic
acid 3-chlorobenzylamide (113 mg) in tetrahydrofuran (0.7
ml)-ethanol (0.7 ml) was added 2-aminoethanol (0.015 ml) and the
mixture was stirred at 60.degree. C. for 11 hr. The solvent was
evaporated and the obtained residue was purified by silica gel
column chromatography (ethyl acetate:hexane=3:1) to give
3-benzyloxy-5-(2,2-dimethylpropionyl)--
1-(2-hydroxyethyl)-4-oxo-1,4-dihydropyridine-2-carboxylic acid
3-chlorobenzylamide (91 mg).
[1280] .sup.1H-NMR(CDCl.sub.3).delta. 8.37(1H,t,J=6.0 Hz),
7.36(1H,s), 7.30(1H,s), 7.28-7.07(8H,m), 4.94(2H,s), 4.76(1H,br s),
4.28(2H,d,J=6.0 Hz), 4.03-3.95(2H,m), 3.84-3.76(2H,m),
1.15(9H,s).
[1281] Step 3
[1282] To a solution of
3-benzyloxy-5-(2,2-dimethylpropionyl)-1-(2-hydroxy-
ethyl)-4-oxo-1,4-dihydropyridine-2-carboxylic acid
3-chlorobenzylamide (91 mg) in tetrahydrofuran (3 ml) was added
N,N-diisopropylethylamine (0.187 ml) and the mixture was
ice-cooled. Methanesulfonyl chloride (0.07 ml) was added at the
same temperature over 30 min with stirring. After confirmation of
the completion of the reaction by thin layer chromatography, 5%
aqueous potassium hydrogen sulfate solution was added to the
reaction mixture and the mixture was extracted with ethyl acetate.
The ethyl acetate layer was washed successively with brine, aqueous
sodium hydrogen carbonate solution and brine, dried and
concentrated. The obtained residue was dissolved in
dimethylformamide (2 ml) and 60% sodium hydride (50 mg) was added
by small portions with stirring at room temperature. After stirring
for 30 min, the reaction mixture was ice-cooled and 5% aqueous
potassium hydrogen sulfate solution was added, and the mixture was
extracted with ethyl acetate. The ethyl acetate layer was washed
with brine, dried and concentrated. The obtained residue was
purified by silica gel thin layer chromatography (ethyl acetate) to
give
9-benzyloxy-2-(3-chlorobenzyl)-7-(2,2-dimethylpropionyl)-3,4-dihydro-2H-p-
yrido[1,2-a]pyrazine-1,8-dione (44 mg).
[1283] .sup.1H-NMR(CDCl.sub.3).delta. 7.61-7.59(2H,m),
7.29-7.22(8H,m), 5.39(2H,s), 4.68(2H,s), 3.96-3.92(2H,m),
3.52-3.46(2H,m), 1.32(9H,s).
[1284] Step 4
[1285]
9-Benzyloxy-2-(3-chlorobenzyl)-7-(2,2-dimethylpropionyl)-3,4-dihydr-
o-2H-pyrido[1,2-a]pyrazine-1,8-dione (43 mg) was dissolved in
trifluoroacetic acid (2 ml) and the mixture was stirred at room
temperature for 1 hr. The solvent was evaporated and toluene was
added, and the mixture was concentrated again. Subsequently, a
suitable amount of hydrochloric acid/ethyl acetate solution was
added, and the mixture was concentrated again. Ethyl acetate (0.6
ml)-diisopropyl ether (1 ml) was added to the obtained residue and
the obtained solid was collected by filtration to give
2-(3-chlorobenzyl)-7-(2,2-dimethylpropionyl)-9-hydroxy-
-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,8-dione hydrochloride (25.6
mg).
[1286] .sup.1H-NMR(DMSO-d.sub.6).delta. 7.73(1H,s),
7.45-7.30(4H,m), 4.71(2H,s), 4.25(2H,t,J=5.6 Hz), 3.72(2H,t,J=5.6
Hz), 1.20(9H,s).
Example 154
Synthesis of
2-(3-chlorobenzyl)-9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido[-
1,2-a]pyrazine-7-carboxylic acid isopropylamide
[1287] 76
[1288] To a solution of
5-benzyloxy-6-(3-chlorobenzylcarbamoyl)-1-(2,2-dim-
ethoxyethyl)-4-oxo-1,4-dihydropyridine-3-carboxylic acid (25.4 mg)
obtained in Example 161, Step 4 in tetrahydrofuran (0.3 ml) were
successively added triethylamine (0.021 ml) and thionyl chloride
(0.0056 ml) at 0.degree. C. with stirring. After stirring at room
temperature for 10 min, the mixture was ice-cooled again and
isopropylamine (0.0086 ml) was added. After stirring at room
temperature for 30 min, 5% aqueous potassium hydrogen sulfite
solution was added, and the mixture was extracted with ethyl
acetate. The ethyl acetate layer was washed with brine, dried and
concentrated. Trifluoroacetic acid was added to the obtained
residue and the mixture was stirred at 70.degree. C. for 5.5 hr.
Trifluoroacetic acid was evaporated, toluene was added and the
mixture was concentrated, which operations were performed twice.
Crystallization from ethyl acetate (2 ml) gave
2-(3-chlorobenzyl)-9-hydroxy-1,8-dioxo-1,8-
-dihydro-2H-pyrido[1,2-a]pyrazine-7-carboxylic acid isopropylamide
(13.6 mg).
[1289] .sup.1H-NMR(DMSO-d.sub.6).delta. 11.79(1H,s), 10.10(1H,d,
J=7.9 Hz), 8.74(1H,s), 7.51-7.49(2H,m), 7.40-7.34(3H,m),
7.01(1H,d,J=6.5 Hz), 4.96(2H,s), 4.05(1H,sept,J=6.5 Hz),
1.18(6H,d,J=6.5 Hz).
Example 249
Synthesis of
2-(3,4-dichlorobenzyl)-9-hydroxy-7-(thiazol-2-yl)-3,4-dihydro-
-2H-pyrido[1,2-a]pyrazine-1,8-dione
[1290] 77
[1291] Step 1
[1292] To a solution of
9-benzyloxy-2-(3,4-dichlorobenzyl)-3,4-dihydro-2H--
pyrido[1,2-a]pyrazine-1,8-dione (3.8 g) obtained in Example 1, Step
3 in chloroform (90 ml)-methanol (60 ml) was added
phenyltrimethylammonium tribromide (5.0 g) and the mixture was
stirred at room temperature for 13 hr. An aqueous sodium sulfite
solution was added to the reaction mixture and the mixture was
extracted twice with chloroform. The combined extract was washed
with brine and purified as it was by silica gel column
chromatography (chloroform-methanol=19:1-10:1) to give
9-benzyloxy-7-bromo-2-(3,4-dichlorobenzyl)-3,4-dihydro-2H-pyrido[1,2a]pyr-
azine-1,8-dione (2.44 g).
[1293] .sup.1H-NMR(DMSO-d.sub.6).delta. 8.36(s,1H), 7.6-7.7(m,2H),
7.5-7.6(m,2H), 7.2-7.4(m,4H), 5.08(s,2H), 4.68(s,2H),
4.1-4.3(m,2H), 3.6-3.8(m,2H).
[1294] Step 2
[1295] To a solution of
9-benzyloxy-7-bromo-2-(3,4-dichlorobenzyl)-3,4-dih-
ydro-2H-pyrido[1,2-a]pyrazine-1,8-dione (150 mg) in dioxane (5 ml)
were added tris(dibenzylideneacetone)dipalladium(0)-chloroform
adduct (63 mg), tri-2-furylphosphine (57 mg) and
(2-thiazolyl)tributyltin (0.285 ml) under an argon stream and a
microwave at 80 W was irradiated under sealing for 1 hr. The
obtained reaction mixture was concentrated, and then purified by
silica gel column chromatography (chloroform:methanol=40- :1) to
give
9-benzyloxy-2-(3,4-dichlorobenzyl)-7-(thiazol-2-yl)-3,4-dihydr-
o-2H-pyrido[1,2-a]pyrazine-1,8-dione (95 mg).
[1296] .sup.1H-NMR(CDCl.sub.3).delta. 8.49(s,1H), 7.85(d,1H,J=3.3
Hz), 7.6-7.8(m,2H), 7.1-7.5(m,7H), 5.47(s,2H), 4.64(s,2H),
4.11(t,2H,J=5.4 Hz), 3.56(t,2H,J=5.4 Hz).
[1297] Step 3
[1298]
9-Benzyloxy-2-(3,4-dichlorobenzyl)-7-(thiazol-2-yl)-3,4-dihydro-2H--
pyrido[1,2a]pyrazine-1,8-dione (93 mg) was dissolved in
trifluoroacetic acid (2 ml). After leaving at room temperature for
1.5 hr, the mixture was concentrated. Toluene was added to the
residue and the mixture was concentrated again, which operations
were performed twice. Ethyl acetate was added and the solid was
collected by filtration to give
2-(3,4-dichlorobenzyl)-9-hydroxy-7-(thiazol-2-yl)-3,4-dihydro-2H-pyrido[1-
,2-a]pyrazine-1,8-dione (53 mg).
[1299] .sup.1H-NMR(DMSO-d.sub.6).delta. 12.25(brs,1H), 8.71(s,1H),
7.89(d,1H,J=3.2 Hz), 7.69(d,1H,J=2 Hz), 7.6-7.65(m,2H),
7.39(dd,1H,J=8.4 Hz,2 Hz), 4.74(s,2H), 4.4-4.5(m,2H),
3.75-3.85(m,2H).
Example 219
Synthesis of
2-(3-chlorobenzyl)-9-hydroxy-1,8-dioxo-1,3,4,8-tetrahydro-2H--
pyrido[1,2-a]pyrazine-7-carboxylic acid methylamide
[1300] 78
[1301] Step 1
[1302] By subjecting
9-benzyloxy-7-bromo-2-(3-chlorobenzyl)-3,4-dihydro-2H-
-pyrido[1,2-a]pyrazine-1,8-dione (600 mg) produced by the same
method as in Example 249, Step 1 to a reaction operation similar to
that in Example 161, Step 3, a mixture of methyl
9-benzyloxy-2-(3-chlorobenzyl)-1,8-dioxo-
-1,3,4,8-tetrahydro-2H-pyrido[1,2-a]pyrazine-7-carboxylate and
methyl
2-(3-chlorobenzyl)-1,8-dioxo-9-hydroxy-1,3,4,8-tetrahydro-2H-pyrido[1,2-a-
]pyrazine-7-carboxylate was obtained (13 mg). This mixture was
dissolved in dimethylformamide (17 ml) and treated with benzyl
bromide (1.36 g) and potassium carbonate (1.75 g) and purified by
silica gel column chromatography (ethyl
acetate-chloroform:methanol=10:1) to give methyl
9-benzyloxy-2-(3-chlorobenzyl)-1,8-dioxo-1,3,4,8-tetrahydro-2H-pyrido[1,2-
-a]pyrazine-7-carboxylate (480 mg).
[1303] .sup.1H-NMR(CDCl.sub.3).delta. 8.02(s,1H), 7.66(d,2H,J=6
Hz), 7.2-7.4(m,6H), 7.1-7.2(m,1H), 5.33(s,2H), 4.62(s,2H),
3.94(t,2H,J=5.3 Hz), 3.91(s,3H), 3.50(t,2H,J=5.3 Hz).
[1304] Step 2
[1305] Methyl
9-benzyloxy-2-(3-chlorobenzyl)-1,8-dioxo-1,3,4,8-tetrahydro--
2H-pyrido[1,2-a]pyrazine-7-carboxylate (420 mg) was dissolved in
tetrahydrofuran (8 ml)-water (2 ml), and 4N aqueous lithium
hydroxide solution (0.58 ml) was added with stirring. After
stirring at 70.degree. C. for 1 hr, the mixture was concentrated.
Water (5 ml) and then 5% aqueous potassium hydrogen sulfate
solution (15 ml) were added with stirring. The precipitated
crystals were collected by filtration to give
9-benzyloxy-2-(3-chlorobenzyl)-1,8-dioxo-1,3,4,8-tetrahydro-2H-pyrido[1,2-
-a]pyrazine-7-carboxylic acid (352 mg).
[1306] .sup.1H-NMR(DMSO-d.sub.6).delta. 8.70(brs,1H),
7.2-7.6(m,9H), 5.16(s,2H), 4.72(s,2H), 4.3-4.6(m,2H),
3.6-3.8(m,2H).
[1307] Step 3
[1308] By subjecting
9-benzyloxy-2-(3-chlorobenzyl)-1,8-dioxo-1,3,4,8-tetr-
ahydro-2H-pyrido[1,2-a]pyrazine-7-carboxylic acid (350 mg) to a
reaction operation similar to that in Example 154,
2-(3-chlorobenzyl)-9-hydroxy-1,-
8-dioxo-1,3,4,8-tetrahydro-2H-pyrido[1,2-a]pyrazine-7-carboxylic
acid methylamide (182 mg) was obtained.
[1309] .sup.1H-NMR(DMSO-d.sub.6).delta. 12.28(s,1H),
9.8-10.0(m,1H), 8.38(s,1H), 7.46(s,1H), 7.25-7.4(m,3H), 4.72(s,2H),
4.40(t,2H,J=5.5 Hz), 3.75(t,2H,J=5.5 Hz), 2.83(d,3H,J=4.9 Hz).
Example 362
Synthesis of
2-(3-chlorobenzyl)-7-(2,2-dimethylbutyryl)-9-hydroxy-3,4-dihy-
dro-2H-pyrido[1,2-a]pyrazine-1,8-dione
[1310] 79
[1311] Step 1
[1312]
9-Benzyloxy-2-(3-chlorobenzyl)-1,8-dioxo-1,3,4,8-tetrahydro-2H-pyri-
do[1,2-a]pyrazine-7-carboxylic acid (200 mg) obtained in Example
219, Step 2 was suspended in tetrahydrofuran (6 ml), and
triethylamine (0.07 ml) and thionyl chloride (0.037 ml) were added
at room temperature with stirring. After stirring at room
temperature for 10 min, the mixture was cooled to -78.degree. C.
and 1.0 M 1,1-dimethylpropylmagnesium chloride/ether solution was
added dropwise. After further stirring at the same temperature for
20 min, 5% aqueous potassium hydrogen sulfate solution (5 ml) and
ethyl acetate (6 ml) were added, and water (5 ml) was further
added. The mixture was extracted twice with ethyl
acetate-tetrahydrofuran (1:1, 30 ml each). The organic layer was
dried and concentrated, and ethyl acetate was added to the residue.
The obtained solid was collected by filtration to give
9-benzyloxy-2-(3-chlorobenzyl)-7-(2,2-dimethylbutyryl)-3,4-dihydro-2H-pyr-
ido[1,2a]pyrazine-1,8-dione (59 mg).
[1313] .sup.1H-NMR(CDCl.sub.3).delta. 7.63-7.59(m,2H), 7.36-7.17
(m,8H), 5.89(s,2H), 4.68(s,2H), 3.97-3.91(m,2H), 3.51-3.46(m,2H),
1.78(q,2H,J=7.6 Hz), 1.28(s,6H), 0.83(t,3H,J=7.6 Hz).
[1314] Step 2
[1315]
9-Benzyloxy-2-(3-chlorobenzyl)-7-(2,2-dimethylbutyryl)-3,4-dihydro--
2H-pyrido[1,2a]pyrazine-1,8-dione (55 mg) was dissolved in
trifluoroacetic acid (0.5 ml) and the mixture was stirred at room
temperature for 30 min. The solvent was evaporated and toluene was
added, and the mixture was concentrated, which operations were
performed twice. Crystallization from chloroform-diisopropyl ether
gave 2-(3-chlorobenzyl)-7-(2,2-dimethylbutyr-
yl)-9-hydroxy-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,8-dione (32
mg).
[1316] .sup.1H-NMR(DMSO-d.sub.6).delta. 12.08(bs,1H) 7.70(s,1H),
7.46(s,1H), 7.44-7.32(m,3H), 4.72(s,2H), 4.30-4.22(m,2H),
3.76-3.69(m,2H), 1.65(q,2H,J=7.4 Hz), 1.16(s,6H), 0.77(t,3H,J=7.4
Hz).
Example 205
Synthesis of
2-(3-chlorobenzyl)-9-hydroxy-7-propionyl-2H-pyrido[1,2-a]pyra-
zine-1,8-dione hydrochloride
[1317] 80
[1318] Step 1
[1319]
5-Benzyloxy-6-(3-chlorobenzylcarbamoyl)-1-(2,2-dimethoxyethyl)-4-ox-
o-1,4-dihydropyridine-3-carboxylic acid (517 mg) obtained in
Example 161, Step 4 and triethylamine (0.43 ml) were added to
tetrahydrofuran (7 ml), and thionyl chloride (0.098 ml) was
subsequently added at 0.degree. C. The mixture was stirred at room
temperature for 3 min and the reaction mixture was cooled to
-78.degree. C. 1M Lithium aluminum hydride/tetrahydrofuran solution
(1.55 ml) was added dropwise. After stirring at the same
temperature for 3 min, 5% aqueous potassium hydrogen sulfate
solution was added, and the mixture was extracted with ethyl
acetate. The ethyl acetate layer was dried, concentrated and
purified by silica gel column chromatography (ethyl acetate-ethyl
acetate:methanol=20:1) to give
3-benzyloxy-1-(2,2-dimethoxyethyl)-5-hydro-
xymethyl-4-oxo-1,4-dihydropyridine-2-carboxylic acid
3-chlorobenzylamide (240 mg).
[1320] .sup.1H-NMR(CDCl.sub.3) 7.33-7.15(8H,m), 7.11(1H,d,J=7.4
Hz), 6.88(1H,t,J=6.0 Hz), 5.23(2H,s), 4.54-4.35(3H,m),
4.34(2H,d,J=6.0 Hz), 3.93(2H,d,J=5.1 Hz), 3.32(6H,s).
[1321] Step 2
[1322] By subjecting
3-benzyloxy-1-(2,2-dimethoxyethyl)-5-hydroxymethyl-4--
oxo-1,4-dihydropyridine-2-carboxylic acid 3-chlorobenzylamide (235
mg) to a reaction operation similar to that in Example 223, Step 1,
3-benzyloxy-1-(2,2-dimethoxyethyl)-5-formyl-4-oxo-1,4-dihydropyridine-2-c-
arboxylic acid 3-chlorobenzylamide (197 mg) was obtained.
[1323] .sup.1H-NMR(CDCl.sub.3).delta. 10.28(1H,s), 7.89(1H,s),
7.31-7.19(8H,m), 7.11(1H,d,J=7.9 Hz), 6.72(1H,t,J=6.0 Hz),
5.29(2H,s), 4.49(1H,t,J=4.9 Hz), 4.37(2H,d,J=6.0 Hz),
3.99(2H,d,J=4.9 Hz), 3.30(6H,s).
[1324] Step 3
[1325] To a solution of
3-benzyloxy-1-(2,2-dimethoxyethyl)-5-formyl-4-oxo--
1,4-dihydropyridine-2-carboxylic acid 3-chlorobenzylamide (168 mg)
in tetrahydrofuran (6 ml) was added dropwise 0.89 M ethylmagnesium
bromide (1.09 ml) with stirring at -78.degree. C. After stirring at
the same temperature for 10 min, 5% aqueous potassium hydrogen
sulfate solution was added, and the mixture was extracted with
ethyl acetate. The ethyl acetate layer was washed with saturated
brine, dried and concentrated. The obtained residue was purified by
silica gel column chromatography (ethyl acetate:hexane=2:1-4:1) to
give 3-benzyloxy-1-(2,2-dimethoxyethyl)-
-5-(1-hydroxypropyl)-4-oxo-1,4-dihydropyridine-2-carboxylic acid
3-chlorobenzylamide (137 mg).
[1326] .sup.1H-NMR(CDCl.sub.3).delta. 7.30-7.16(8H,m),
7.10(1H,d,J=7.4 Hz), 6.78(1H,t,J=5.1 Hz), 5.23(2H,s),
4.56(1H,d,J=7.4 Hz), 4.49(1H,t,J=4.9 Hz), 4.46(1H,dd,J=7.4,10.2
Hz), 4.35(2H,d,J=5.1 Hz), 3.92(2H,d,J=4.9 Hz), 3.30(3H,s),
3.29(3H,s), 1.83(2H,dq,J=7.2,10.2 Hz), 0.94(3H,t,J=7.2 Hz).
[1327] Step 4
[1328] By subjecting
3-benzyloxy-1-(2,2-dimethoxyethyl)-5-(1-hydroxypropyl-
)-4-oxo-1,4-dihydropyridine-2-carboxylic acid 3-chlorobenzylamide
(102 mg) to a reaction operation similar to that in Example 223,
Step 1,
3-benzyloxy-1-(2,2-dimethoxyethyl)-4-oxo-5-propionyl-1,4-dihydropyridine--
2-carboxylic acid 3-chlorobenzylamide (92 mg) was obtained.
[1329] .sup.1H-NMR(CDCl.sub.3).delta. 8.09(1H,s), 7.28-7.21(8H,m),
7.08(1H,d,J=7.4 Hz), 6.54(1H,d,J=6.0 Hz), 5.27(2H,s),
4.47(1H,t,J=5.1 Hz), 4.34(2H,d,J=6.0 Hz), 4.04(2H,d,J=5.1 Hz),
3.29(6H,s), 3.21(2H,q,J=7.1 Hz), 1.16(3H,t,J=7.1 Hz).
[1330] Step 5
[1331] By subjecting
3-benzyloxy-1-(2,2-dimethoxyethyl)-4-oxo-5-propionyl--
1,4-dihydropyridine-2-carboxylic acid 3-chlorobenzylamide (89 mg)
to a reaction operation similar to that in Example 96, Step 2,
2-(3-chlorobenzyl)-9-hydroxy-7-propionyl-2H-pyrido[1,2-a]pyrazine-1,8-dio-
ne hydrochloride (56 mg) was obtained.
[1332] .sup.1H-NMR(DMSO-d.sub.6).delta. 8.48(1H,s), 7.47(1H,s),
7.44-7.29(4H,m), 6.93(1H,d,J=6.0 Hz), 4.94(2H,s), 3.10(3H,q,J=7.2
Hz), 1.03(3H,t,J=7.2 Hz).
Example 242
Synthesis of
N-[2-(3-chlorobenzyl)-9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyri-
do[1,2-a]pyrazin-7-yl]propionamide
[1333] 81
[1334] Step 1
[1335] To a solution of
5-benzyloxy-6-(3-chlorobenzylcarbamnoyl)-1-(2,2-di-
methoxyethyl)-4-oxo-1,4-dihydropyridine-3-carboxylic acid (1 g)
obtained in Example 161, Step 4 in tetrahydrofuran (15 ml)-toluene
(15 ml) were added triethylamine (0.61 ml) and diphenylphosphoryl
azide (0.47 ml) and the mixture was stirred at room temperature for
30 min. The solvent was evaporated, and the residue was dissolved
in tetrahydrofuran (8 ml). Triethylamine (0.61 ml) and
diphenylphosphoryl azide (0.47 ml) were added again and 2 hr later,
and 3 hr later, triethylamine (1.22 ml, 0.61 ml) and
diphenylphosphoryl azide (0.94 ml, 0.47 ml) were respectively
added, and stirring was continued. After confirmation of
disappearance of the starting material, 9-fluorenylmethanol (7.7 g)
and toluene (10 ml) were added, and the mixture was stirred under
reflux with heating. After 20 min, triethylamine (2.5 ml) was
added, and stirring was continued with heating for 1.5 hr. The
mixture was concentrated, water was added to the residue and the
mixture was extracted twice with ethyl acetate. The combined ethyl
acetate layer was washed with brine, dried and concentrated. The
residue was subjected to silica gel column chromatography (ethyl
acetate:hexane=1:1-chloroform:methanol=15:1) to give
5-amino-3-benzyloxy-1-(2,2-dimethoxyethyl)-4-oxo-1,4-dihydropyridine-
-2-carboxylic acid 3-2.5 chlorobenzylamide (886 mg).
[1336] .sup.1H-NMR (CDCl.sub.3).delta. 7.41-7.18(m,8H),
7.15-7.12(m,2H), 6.96(s,1H), 5.15(s,2H), 4.53(t,1H,J=5.0 Hz),
4.32(d,2H,J=5.8 Hz), 3.93(brs,2H), 3.86(d,2H,J=5.0 Hz),
3.29(s,6H).
[1337] Step 2
[1338] To a solution of
5-amino-3-benzyloxy-1-(2,2-dimethoxyethyl)-4-oxo-1-
,4-dihydropyridine-2-carboxylic acid 3-chlorobenzylamide (55 mg) in
chloroform (1 ml) were added, triethylamine (0.033 ml) and
propanoyl chloride (0.012 ml) at 0.degree. C. After stirring at the
same temperature for 20 min, aqueous sodium hydrogen carbonate
solution was added and the reaction mixture was extracted with
ethyl acetate. The ethyl acetate layer was dried, concentrated and
purified by silica gel thin layer chromatography
(chloroform:methanol=10:1) to give
N-[5-benzyloxy-6-(3-chlorobenzylcarbamoyl)-1-(2,2-dimethoxyethyl)-4-oxo-1-
,4-dihydropyridin-3-yl]propionamide (55 mg). By subjecting 51 mg of
the obtained compound to a reaction operation similar to that in
Example 187, Step 2,
N-[2-(3-chlorobenzyl)-9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido[1-
,2-a]pyrazin-7-yl]propionamide (27 mg) was obtained.
[1339] .sup.1H-NMR(DMSO-d.sub.6).delta. 11.59(s,1H), 9.34(s,1H),
9.12(s,1H), 7.50-7.45(m,2H), 7.41-7.33(m,3H), 6.96(d,1H,J=6.0 Hz),
4.98(s,1H), 2.50(q,2H,J=7.5 Hz), 1.06(t,3H,J=7.5 Hz).
Example 382
Synthesis of
7-(2,2-dimethylbutyryl)-2-(4-fluorobenzyl)-9-hydroxy-2H-pyrid-
o[1,2-a]pyrazine-1,8-dione hydrochloride
[1340] 82
[1341] Step 1
[1342] By subjecting
5-benzyloxy-6-(4-fluorobenzylcarbamoyl)-1-(2,2-dimeth-
oxyethyl)-4-oxo-1,4-dihydropyridine-3-carboxylic acid (100 mg)
obtained by the same production method as in Example 161, Step 4 to
a reaction operation similar to that in Example 362, Step 1, and
purification by silica gel thin layer chromatography
(chloroform:acetone=3:1),
3-benzyloxy-1-(2,2-dimethoxyethyl)-5-(2,2-dimethylbutyryl)-4-oxo-1,4-dihy-
dropyridine-2-carboxylic acid 4-fluorobenzylamide (40 mg) was
obtained.
[1343] .sup.1H-NMR(CDCl.sub.3).delta. 7.86(br,1H), 7.29-7.18(m,8H),
6.84(dd,2H,J=8.7 Hz,8.7 Hz), 5.10(s,2H), 4.54(t,1H,J=5.0 Hz),
4.35(d,2H,J=5.8 Hz), 3.83(d,2H,J=5.0 Hz), 3.30(s,6H),
1.65(q,2H,J=7.5 Hz), 1.19(s,6H), 0.83(t,3H,J=7.5 Hz).
[1344] Step 2
[1345] By subjecting
3-benzyloxy-1-(2,2-dimethoxyethyl)-5-(2,2-dimethylbut-
yryl)-4-oxo-1,4-dihydropyridine-2-carboxylic acid
4-fluorobenzylamide (40 mg) to a reaction operation similar to that
in Example 161, Step 6,
7-(2,2-dimethylbutyryl)-2-(4-fluorobenzyl)-9-hydroxy-2H-pyrido[1,2-a]pyra-
zine-1,8-dione hydrochloride (25 mg) was obtained.
[1346] .sup.1H-NMR(DMSO-d.sub.6).delta. 8.01(s,1H), 7.43(dd,2H,
J=9.0 Hz,5.5 Hz), 7.22(d,1H,J=6.3 Hz), 7.19(dd,2H,J=9.0 Hz,9.0 Hz),
6.90(d,1H,J=6.3 Hz), 1.60(q,2H,J=7.5 Hz), 1.13(s,6H),
0.77(t,3H,J=7.5 Hz).
Example 283
Synthesis of
2-(3-chlorobenzyl)-9-hydroxy-7-isobutylamino-2H-pyrido[1,2a-]-
pyrazine-1,8-dione hydrochloride
[1347] 83
[1348] Step 1
[1349] To a solution of
5-amino-3-benzyloxy-1-(2,2-dimethoxyethyl)-4-oxo-1-
,4-dihydropyridine-2-carboxylic acid 3-chlorobenzylamide (65 mg)
obtained in Example 242, Step 1 in chloroform (1 ml) were
successively added isobutylaldehyde (0.025 ml), acetic acid (0.016
ml), sodium triacetoxyborohydride and the mixture was stirred at
room temperature for 1 hr. Saturated brine (10 ml) was added to the
reaction mixture and the mixture was extracted twice with
chloroform (10 ml each). The organic layer was dried, concentrated
and purified by silica gel thin layer chromatography
(chloroform:methanol=10:1) to give 3-benzyloxy-1-(2,2-dime-
thoxyethyl)-5-isobutylamino-4-oxo-1,4-dihydropyridine-2-carboxylic
acid 3-chlorobenzylamide (68 mg).
[1350] .sup.1H-NMR(CDCl.sub.3).delta. 7.26-7.20(8H,m),
7.10(1H,d,J=7.4 Hz), 6.80(1H,t,J=6.0 Hz), 6.63(1H,s), 5.22(2H,s),
4.55(1H,t,J=5.1 Hz), 4.34(2H,d,J=6.0 Hz), 3.99(2H,d,J=5.1 Hz),
3.31(6H,s), 2.82(2H,d,J=7.0 Hz), 1.93(1H,dt,J=6.5,7.0 Hz),
1.01(6H,d,J=6.5 Hz).
[1351] Step 2
[1352] By subjecting
3-benzyloxy-1-(2,2-dimethoxyethyl)-5-isobutylamino-4--
oxo-1,4-dihydropyridine-2-carboxylic acid 3-chlorobenzylamide (66
mg) to a reaction operation similar to that in Example 161, Step 6,
2-(3-chlorobenzyl)-9-hydroxy-7-isobutylamino-2H-pyrido[1,2-a]pyrazine-1,8-
-dione hydrochloride (43.5 mg) was obtained.
[1353] .sup.1H-NMR(DMSO-d.sub.6).delta. 8.07(1H,s), 7.64(1H,d,J=6.0
Hz), 7.50-7.30(5H,m), 5.09(2H,s), 2.99(2H,d,J=7.0 Hz),
1.95(1H,dt,J=6.0,7.0 Hz), 0.91(6H,d,J=7.0 Hz).
Example 302
Synthesis of
N-[2-(3-chlorobenzyl)-9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyri-
do[1,2-a]pyrazin-7-yl]-N-isobutylacetamide
[1354] 84
[1355]
2-(3-Chlorobenzyl)-9-hydroxy-7-isobutylamino-2H-pyrido[1,2-a]pyrazi-
ne-1,8-dione hydrochloride (23 mg) was added to chloroform (2 ml),
and pyridine (0.062 ml) and acetyl chloride (0.024 ml) were
successively added at 0.degree. C. The mixture was stirred at room
temperature for 2 hr. 5% Aqueous potassium hydrogen sulfate
solution was added to the obtained reaction mixture, and the
mixture was extracted with ethyl acetate. The solvent was
evaporated and the obtained residue was dissolved in
tetrahydrofuran (0.5 ml)-methanol (0.1 ml), and 1N aqueous sodium
hydroxide solution (0.084 ml) was added. The mixture was stirred at
room temperature for 30 min. 2N Aqueous hydrochloric acid (0.056
ml) was added to the reaction mixture and the mixture was extracted
with ethyl acetate. The ethyl acetate layer was washed with
saturated brine, dried and concentrated. Crystallization from ethyl
acetate-diisopropyl ether gave
N-[2-(3-chlorobenzyl)-9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrid-
o[1,2-a]pyrazin-7-yl]-N-isobutylacetamide (18.2 mg).
[1356] .sup.1H-NMR(DMSO-d.sub.6).delta. 8.27(1H,s), 7.49(1H,s),
7.39-7.32(3H,m), 7.18(1H,d,J=6.0 Hz), 6.92(1H,d,J=6.0 Hz),
4.97(2H,s), 3.53(1H,dd,J=13.7,8.6 Hz), 3.12(1H,dd,J=13.7,7.2 Hz),
1.76(3H,s), 1.62(1H,ddt,J=7.2,8.6,6.5 Hz), 0.82(6H,d,J=6.5 Hz).
Example 349
Synthesis of
N-[2-(3-chloro-4-fluorobenzyl)-9-hydroxy-1,8-dioxo-1,3,4,8-te-
trahydro-2H-pyrido[1,2-a]pyrazin-7-yl]isobutyramide
[1357] 85
[1358] Step 1
[1359] To a solution of
9-benzyloxy-7-bromo-2-(3-chloro-4-fluorobenzyl)-3,-
4-dihydro-2H-pyrido[1,2-a]pyrazine-1,8-dione (170 mg) produced by
the same method as in Example 249, Step 1 in dioxane (1.7 ml) were
added tert-butyl carbamate (49 mg),
tris(dibenzylideneacetone)dipalladium(0)-ch- loroform adduct (1.8
mg), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (3 mg) and
cesium carbonate (158 mg) under an argon stream and the mixture was
stirred at 100.degree. C. After 10 hr, tert-butyl carbamate (49
mg), tris(dibenzylideneacetone)dipalladium(0)-chloroform adduct (18
mg) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (30 mg)
were added, and the mixture was continuously stirred for 18 hr with
heating. After cooling to room temperature, insoluble materials
were filtered off through celite. The solvent was evaporated and
the residue was purified by silica gel column chromatography
(chloroform:acetone=2:1) to give tert-butyl
[9-benzyloxy-2-(3-chloro-4-fluorobenzyl)-1,8-dioxo-1,3,4,8-tet-
rahydro-2H-pyrido[1,2-a]pyrazin-7-yl]carbamate (156 mg).
[1360] .sup.1H-NMR(CDCl.sub.3).delta. 8.31(s,1H), 7.80(s,1H),
7.62(m,2H), 7.38-7.10(m,5H), 7.12(dd,1H,J=8.3,8.3 Hz), 5.33(s,2H),
4.65(s,2H), 4.38(br,1H), 4.02-3.98(m,2H), 3.50-3.47(m,2H),
1.50(s,9H).
[1361] Step 2
[1362] To a solution of tert-butyl
[9-benzyloxy-2-(3-chloro-4-fluorobenzyl-
)-1,8-dioxo-1,3,4,8-tetrahydro-2H-pyrido[1,2-a]pyrazin-7-yl]carbamate
(179 mg) in dioxane (2 ml) was added 4N hydrochloric acid/dioxane
solution (2 ml) and the mixture was stirred at room temperature for
3.5 hr. The solvent was evaporated and aqueous sodium hydrogen
carbonate solution was added to the obtained residue. The mixture
was extracted with chloroform. The chloroform layer was dried,
concentrated and purified by silica gel column chromatography
(ethyl acetate:methanol=5:1) to give
7-amino-9-benzyloxy-2-(3-chloro-4-fluorobenzyl)-3,4-dihydro-2H-pyrido[1,2-
a]pyrazine-1,8-dione (88 mg).
[1363] .sup.1H-NMR(CDCl.sub.3).delta. 7.66-7.64(m,2H),
7.35-7.24(m,4H), 7.19-7.15(ddd,1H,J=1.9,4.4,8.6 Hz),
7.10(dd,1H,J=8.3,8.6 Hz), 6.96(s,1H), 5.27(s,2H), 4.59(s,2H),
3.91-3.88(m,2H), 3.45-3.42(m,2H), 2.42(br,2H).
[1364] Step 3
[1365] To a solution of
7-amino-9-benzyloxy-2-(3-chloro-4-fluorobenzyl)-3,-
4-dihydro-2H-pyrido[1,2-a]pyrazine-1,8-dione (29 mg) in chloroform
(0.6 ml) were added pyridine (0.0082 ml) and isobutyryl chloride
(0.01 ml) at 0.degree. C., and the mixture was stirred at room
temperature for 1.5 hr. 5% Aqueous potassium hydrogen sulfate
solution was added and the mixture was extracted with ethyl
acetate. The obtained ethyl acetate layer was dried, concentrated
and purified by silica gel thin layer chromatography
(chloroform:methanol=10:1) to give
N-[9-benzyloxy-2-(3-chloro-4-fluoroben-
zyl)-1,8-dioxo-1,3,4,8-tetrahydro-2H-pyrido[1,2-a]pyrazin-7-yl]isobutyrami-
de (29 mg).
[1366] .sup.1H-NMR(CDCl.sub.3).delta. 8.80(s,1H), 8.62(s,1H),
7.66-7.64(m,2H), 7.39(dd,1H,J=2.3,6.7 Hz), 7.36-7.30(m,3H),
7.21(ddd,1H,J=2.3,4.6,8.4 Hz), 7.14(dd,1H,J=8.3,8.8 Hz),
5.35(s,2H), 4.66(s,2H), 4.03-4.00(m,2H), 3.52-3.50(m,2H),
2.63(sept,1H,J=7.0 Hz), 1.25(d,6H,J=7.0 Hz).
[1367] Step 4
[1368] By subjecting
N-[9-benzyloxy-2-(3-chloro-4-fluorobenzyl)-1,8-dioxo--
1,3,4,8-tetrahydro-2H-pyrido[1,2-a]pyrazin-7-yl]isobutyramide (27
mg) to a reaction operation similar to that in Example 223, Step 4,
N-[2-(3-chloro-4-fluorobenzyl)-9-hydroxy-1,8-dioxo-1,3,4,8-tetrahydro-2H--
pyrido[1,2-a]pyrazin-7-yl]isobutyramide (17 mg) was obtained.
[1369] .sup.1H-NMR(DMSO-d.sub.6).delta. 11.91(br,1H), 9.13(s,1H),
8.71(s,1H), 7.64(dd,1H,J=1.6,7.9 Hz), 7.43-7.39(m,2H), 4.70(s,2H),
4.30-4.26(m,2H), 3.74-3.71(m,2H), 2.88(sept,1H,J=6.7 Hz),
1.07(d,6H,J=6.7 Hz).
Example 353
Synthesis of
N-[2-(3-chloro-4-fluorobenzyl)-9-hydroxy-1,8-dioxo-1,3,4,8-te-
trahydro-2H-pyrido[1,2-a]pyrazin-7-yl]methanesulfonamide
[1370] 86
[1371] By subjecting
7-amino-9-benzyloxy-2-(3-chloro-4-fluorobenzyl)-3,4-d-
ihydro-2H-pyrido[1,2-a]pyrazine-1,8-dione (29 mg) obtained in
Example 349, Step 2 to a reaction operation similar to that in
Example 349, Steps 3 and 4 except that methanesulfonyl chloride was
used instead of isobutyryl chloride,
N-[2-(3-chloro-4-fluorobenzyl)-9-hydroxy-1,8-dioxo-1,3,4,8-tetr-
ahydro-2H-pyrido[1,2-a]pyrazin-7-yl]methanesulfonamide (4.7 mg)
was-obtained.
[1372] .sup.1H-NMR(DMSO-d.sub.6).delta. 12.08(br,1H), 8.83(br,1H),
7.78(s,1H), 7.63(dd,1H,J=1.7,7.7 Hz), 7.42-7.40(m,2H), 4.71(s,2H),
4.30-4.27(m,2H), 3.74-3.72(m,2H), 2.97(s,3H).
Example 222
Synthesis of
2-(3-chloro-4-fluorobenzyl)-9-hydroxy-4-hydroxymethyl-1,8-dio-
xo-1,8-dihydro-2H-pyrido[1,2-a]pyrazine-7-carboxylic acid
methylamide hydrochloride
[1373] 87
[1374] Step 1
[1375] 3-Benzyloxy-5-bromo-4-oxo-4H-pyran-2-carboxylic acid
3-chloro-4-fluorobenzylamide (380 mg) obtained by the same method
as in Example 161, Step 1 and 2-amino-3-methoxymethoxy-1-propanol
(275 mg) were dissolved in tetrahydrofuran (2 ml)-ethanol (2 ml)
and the mixture was stirred at 60.degree. C. for 1 hr. The reaction
mixture was concentrated and purified by silica gel column
chromatography (chloroform:methanol=10:- 1) to give
3-benzyloxy-5-bromo-1-(1-hydroxy-3-methoxymethoxy-2-propyl)-4-o-
xo-1,4-dihydropyridine-2-carboxylic acid
3-chloro-4-fluorobenzylamide (410 mg).
[1376] Step 2
[1377] To a solution of oxalyl chloride (0.245 ml) in methylene
chloride (1 ml) was added dropwise a solution of dimethyl sulfoxide
(0.269 ml) in methylene chloride (1 ml) under a nitrogen stream at
-78.degree. C. and the mixture was stirred for 10 min. A solution
of 3-benzyloxy-5-bromo-1-(-
1-hydroxy-3-methoxymethoxy-2-propyl)-4-oxo-1,4-dihydropyridine-2-carboxyli-
c acid 3-chloro-4-fluorobenzylamide (410 mg) in methylene chloride
(16 ml) was added at the same temperature over 5 min. After
stirring for further 10 min after the completion of the dropwise
addition, triethylamine (1.37 ml) was added and the mixture was
heated to room temperature. The mixture was stirred at room
temperature for 1 hr and concentrated. Water was added and the
mixture was extracted twice with ethyl acetate. The combined ethyl
acetate layer was washed with saturated brine, dried and
concentrated. The obtained crude product was dissolved in
chloroform (8 ml), and N,N-diisopropylethylamine (0.734 ml) and
methanesulfonyl chloride (0.101 ml) were successively added under
ice-cooling. After stirring at room temperature for 2 hr,
methanesulfonyl chloride (0.05 ml) was added and the mixture was
further stirred for 1 hr. The reaction mixture was concentrated,
and aqueous sodium hydrogen carbonate solution was added to the
residue. The mixture was extracted twice with ethyl acetate. The
combined ethyl acetate layer was washed with saturated brine,
dried, concentrated and purified by silica gel column
chromatography (ethyl acetate:hexane=1:2-ethyl acetate) to give
9-benzyloxy-7-bromo-2-(3-chloro-4-fluorobenzyl)-4-(methoxymethoxy)methyl--
2H-pyrido[1,2-a]pyrazine-1,8-dione (163 mg).
[1378] .sup.1H-NMR(CDCl.sub.3).delta. 8.35(s,1H), 7.69-7.65(m,2H),
7.37-7.16(m,5H), 7.13(dd,1H,J=8.7 Hz,8.7 Hz), 6.32(s,1H),
5.37(s,2H), 4.88(s,2H), 4.68(s,2H), 4.46(s,2H), 3.42(s,3H).
[1379] Step 3
[1380] By subjecting
9-benzyloxy-7-bromo-2-(3-chloro-4-fluorobenzyl)-4-(me-
thoxymethoxy)methyl-2H-pyrido[1,2a-]pyrazine-1,8-dione (125 mg) to
a reaction operation similar to that in Example 161, Step 3, methyl
9-benzyloxy-2-(3-chloro-4-fluorobenzyl)-4-(methoxymethoxy)methyl-1,8-diox-
o-1,8-dihydro-2H-pyrido[1,2-a]pyrazine-7-carboxylate (28 mg) was
obtained.
[1381] .sup.1H-NMR(CDCl.sub.3).delta. 8.68(s,1H), 7.69-7.65(m,2H),
7.38-7.18(m,5H), 7.13(dd,1H,J=8.5 Hz,8.5 Hz), 6.32(s,1H),
5.39(s,2H), 4.87(s,2H), 4.69(s,2H), 4.46(s,2H), 3.96(s,3H),
3.41(s,3H).
[1382] Step 4
[1383] By hydrolyzing methyl
9-benzyloxy-2-(3-chloro-4-fluorobenzyl)-4-(me-
thoxymethoxy)methyl-1,8-dioxo-1,8-dihydro-2H-pyrido[1,2-a]pyrazine-7-carbo-
xylate (27 mg) by the same method as in Example 161, Step 4, and
subsequently subjecting to a method analogous to Example 154,
2-(3-chloro-4-fluorobenzyl)-9-hydroxy-4-hydroxymethyl-1,8-dioxo-1,8-dihyd-
ro-2H-pyrido[1,2-a]pyrazine-7-carboxylic acid methylamide
hydrochloride (2.2 mg) was obtained.
[1384] .sup.1H-NMR(DMSO-d.sub.6).delta. 12.22(s,1H), 9.97(s,1H),
8.83(s,1H), 7.69-7.66(m,1H), 7.44-7.41(m,2H), 7.16(s,1H),
5.68(t,1H,J=5.3 Hz), 4.96(s,2H), 4.50(d,2H,J=5.3 Hz),
2.85(d,3H,J=4.6 Hz).
Example 316
Synthesis of
9-hydroxy-2-(3-phenylpropyl)-7-(thiazol-2-yl)-3,4-dihydro-2H--
pyrido[1,2-a]pyrazine-1,8-dione hydrochloride
[1385] 88
[1386] Step 1
[1387] 3-Benzyloxy-4-oxo-4H-pyran-2-carboxylic acid (6.82 g) was
suspended in methanol (20 ml)-tetrahydrofuran (50 ml) and 2M
(trimethylsilyl)diazomethane/hexane solution (25.8 ml) was added
dropwise under ice-cooling, and the mixture was stirred at room
temperature for 1.5 hr. The solvent was evaporated under reduced
pressure and the obtained residue was dissolved in chloroform (50
ml). Thereto was added bromine (14.2 ml) and the mixture was
stirred at 75.degree. C. for 2 days. After allowing the mixture to
return to room temperature, the mixture was concentrated under
reduced pressure, and hexane was added to the residue. The
precipitated solid was collected by filtration. The obtained solid
was dissolved in dimethylformamide (40 ml) and potassium carbonate
(4.59 g) and benzyl bromide (3.62 ml) were added. The mixture was
stirred at 80.degree. C. for 40 min. The solvent was evaporated and
1N aqueous hydrochloric acid was added to the obtained residue. The
mixture was extracted twice with ethyl acetate. The combined ethyl
acetate layer was washed with saturated brine, dried, concentrated
and purified by silica gel column chromatography (ethyl
acetate:hexane=1:4-1:1). The eluate was concentrated and the
precipitated crystals were collected by filtration to give methyl
3-benzyloxy-5-bromo-4-oxo-4H-pyran-2-carboxylate (4.69 g).
[1388] .sup.1H-NMR(CDCl.sub.3).delta. 8.10(s,1H), 7.47-7.44(m,2H),
7.38-7.32(m,3H), 5.32(s,2H), 3.88(s,3H).
[1389] Step 2
[1390] To a solution of methyl
3-benzyloxy-5-bromo-4-oxo-4H-pyran-2-carbox- ylate (2.3 g) in
dioxane (25 ml) were added tetrakis(triphenylphosphine)pa-
lladium(0) (1.57 g) and (2-thiazolyl)tributyltin (5.08 g) under an
argon stream, and the mixture was stirred at 100.degree. C. for 1.5
hr. The obtained reaction mixture was concentrated, and
subsequently purified by silica gel column chromatography (ethyl
acetate:hexane=1:4-1:2) to give methyl
3-benzyloxy-4-oxo-5-(thiazol-2-yl)-4H-pyran-2-carboxylate (1.47
g).
[1391] .sup.1H-NMR(CDCl.sub.3).delta. 8.98(s,1H), 7.92(d,1H,J=3.2
Hz), 7.53-7.48(m,3H), 7.48-7.25(m,3H), 5.41(s,2H), 3.91(s,3H).
[1392] Step 3
[1393] Methyl
3-benzyloxy-4-oxo-5-(thiazol-2-yl)-4H-pyran-2-carboxylate (1.47 g)
was suspended in ethanol (15 ml)-dioxane (15 ml), and tert-butyl
(2-aminoethyl)carbamate (0.816 ml) was added. After stirring at
70.degree. C. for 1.5 hr, the solvent was evaporated and 4N
hydrochloric acid/dioxane solution (70 ml) and chloroform (10 ml)
were added to the residue. After stirring at room temperature for 2
hr, the reaction mixture was concentration under reduced pressure.
Saturated aqueous sodium hydrogen carbonate solution (20 ml) and
methanol (50 ml) were added to the residue and the mixture was
stirred for 2 hr. The solvent was evaporated and the obtained solid
was collected by filtration and washed thoroughly with water to
give 9-benzyloxy-7-(thiazol-2-yl)-3,4-dih-
ydro-2H-pyrido[1,2-a]pyrazine-1,8-dione (1.07 g).
[1394] .sup.1H-NMR(DMSO-d.sub.6).delta. 8.84(s,1H),
8.66(brt,1H,J=3.7 Hz), 7.93(d,1H,J=3.2 Hz), 7.68(d,1H,J=3.2 Hz),
7.59(d,2H,J=6.8 Hz), 7.40-7.30(m,3H), 5.17(s,2H), 4.41-4.36(m,2H),
3.54-3.48(m,2H).
[1395] Step 4
[1396]
9-Benzyloxy-7-(thiazol-2-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1-
,8-dione (30 mg) and 3-phenylpropyl bromide (0.02 ml) were added to
dimethyl sulfoxide (1 ml), and sodium hydride (7 mg) was added with
stirring. After stirring for 20 min, 5% aqueous potassium hydrogen
sulfate solution was added and the mixture was extracted twice with
ethyl acetate. The ethyl acetate layer was washed with brine,
dried, concentrated, and subsequently purified by silica gel thin
layer chromatography (chloroform-methanol=15:1) to give
9-benzyloxy-2-(3-phenyl-
propyl)-7-(thiazol-2-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,8-dione
(27 mg).
[1397] .sup.1H-NMR(CDCl.sub.3).delta. 8.50(s,1H), 7.86(d,1H,J=3.2
Hz), 7.69-7.65(m,2H), 7.42(d,1H,J=3.2 Hz), 7.36-7.16(m,8H),
5.45(s,2H), 4.11-4.07(m,2H), 3.62-3.53(m,4H), 2.70(t,2H,J=7.5 Hz),
1.96(tt,2H,J=7.5 Hz,7.5 Hz).
[1398] Step 5
[1399] To a solution of
9-benzyloxy-2-(3-phenylpropyl)-7-(thiazol-2-yl)-3,-
4-dihydro-2H-pyrido[1,2-a]pyrazine-1,8-dione (27 mg) in acetic acid
(1 ml) was added conc. aqueous hydrochloric acid (0.5 ml) and the
mixture was stirred at 90.degree. C. for 2 hr. The solvent was
evaporated and ethyl acetate was added to the residue. The obtained
solid was collected by filtration to give
9-hydroxy-2-(3-phenylpropyl)-7-(thiazol-2-yl)-3,4-dihy-
dro-2H-pyrido[1,2-a]pyrazine-1,8-dione hydrochloride (25 mg).
[1400] .sup.1H-NMR(DMSO-d.sub.6).delta. 8.72(s,1H), 7.89(d,1H,J=3.1
Hz), 7.63(d,1H,J=3.1 Hz), 7.30-7.14(m,5H), 4.45-4.40(m,2H),
3.82-3.77(m,2H), 3.55(t,2H,J=7.1 Hz), 2.64(t,2H,J=7.7 Hz),
1.91(tt,2H,J=7.1 Hz,7.7 Hz).
Example 291
Synthesis of
2-(3,4-difluorobenzyl)-9-hydroxy-7-(thiazol-2-yl)-3,4-dihydro-
-2H-pyrido[1,2-a]pyrazine-1,8-dione
[1401] 89
[1402] Step 1
[1403] According to a method analogous to the method described in
Example 316, Step 3,
9-benzyloxy-7-bromo-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,8-
-dione (1.05 g) was obtained from methyl
3-benzyloxy-5-bromo-4-oxo-4H-pyra- n-2-carboxylate (1.2 g) obtained
in Example 316, Step 1.
[1404] .sup.1H-NMR(DMSO-d.sub.6).delta. 8.61(brt,1H,J=4.0 Hz),
8.37(s,1H), 7.53(dd,2H,J=8.4 Hz,1.7 Hz), 7.37-7.26(m,3H),
5.05(s,2H), 4.20-4.15(m,2H), 3.46-3.41(m,2H).
[1405] Step 2
[1406] According to a method analogous to the method described in
Example 316, Step 4,
9-benzyloxy-7-bromo-2-(3,4-difluorobenzyl)-3,4-dihydro-2H-py-
rido[1,2a]pyrazine-1,8-dione (60 mg) was obtained from
9-benzyloxy-7-bromo-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,8-dione
(50 mg).
[1407] .sup.1H-NMR(CDCl.sub.3).delta. 7.67-7.64(m,2H), 7.57(s,1H),
7.37-7.29(m,3H), 7.18-7.10(m,2H), 7.04-6.99(m,1H), 5.33(s,2H),
4.61(s,2H), 3.96-3.92(m,2H), 3.53-3.48(m,2H).
[1408] Step 3
[1409] According to a method analogous to the method described in
Example 249, Step 2,
9-benzyloxy-2-(3,4-difluorobenzyl)-7-(thiazol-2-yl)-3,4-dihy-
dro-2H-pyrido[1,2-a]pyrazine-1,8-dione (35 mg) was obtained from
9-benzyloxy-7-bromo-2-(3,4-difluorobenzyl)-3,4-dihydro-2H-pyrido[1,2a-]py-
razine-1,8-dione (60 mg).
[1410] .sup.1H-NMR(CDCl.sub.3).delta. 8.50(s,1H), 7.85(d,1H,J=3.3
Hz), 7.69-7.65(m,2H), 7.42(d,1H,J=3.3 Hz), 7.38-7.30(m,3H),
7.20-7.12(m,2H), 7.07-7.02(m,1H), 5.47(s,2H), 4.66(s,2H),
4.14-4.09(m,2H), 3.59-3.54(m,2H).
[1411] Step 4
[1412]
9-Benzyloxy-2-(3,4-difluorobenzyl)-7-(thiazol-2-yl)-3,4-dihydro-2H--
pyrido[1,2-a]pyrazine-1,8-dione (35 mg) was dissolved in
trifluoroacetic acid (1 ml) and the mixture was stirred at room
temperature for 3 hr. Trifluoroacetic acid was evaporated under
reduced pressure, toluene was added to the obtained residue and the
mixture was concentrated, which operations were performed twice.
Ethyl acetate was further added and the obtained solid was
collected by filtration to give
2-(3,4-difluorobenzyl)-9-hydroxy-7-(thiazol-2-yl)-3,4-dihydro-2H-pyrido[1-
,2-a]pyrazine-1,8-dione (14 mg).
[1413] .sup.1H-NMR(DMSO-d.sub.6).delta. 12.30(s,1H), 8.71(s,1H),
7.89(d,1H,J=3.2 Hz), 7.63(d,1H,J=3.2 Hz), 7.52-7.40(m,2H),
7.28-7.22(m,1H), 4.72(s,2H), 4.49-4.43(m,2H), 3.81-3.76(m,2H).
Example 106
Synthesis of
2-(3-chlorobenzyl)-8-hydroxy-6-methyl-2,3,4,6-tetrahydro-2,6--
naphthyridine-1,7-dione
[1414] Step 1 90
[1415] To a solution of (N-benzyloxycarbonyl-N-methylamino)acetic
acid (15 g) in tetrahydrofuran (150 ml) was added
carbonyldiimidazole (16.3 g) under ice-cooling, and the mixture was
stirred at room temperature for 2 hr. A suspension of magnesium
chloride (6.21 g) and ethyl potassium malonate (17.2 g) in
tetrahydrofuran (250 ml) was separately stirred at 50.degree. C.
for 7 hr and ice-cooled. The above-mentioned solution was added
dropwise thereto over 30 min with stirring. The mixture was stirred
for 12 hr and the solvent was evaporated under reduced pressure.
Ethyl acetate and 5% aqueous potassium hydrogen sulfate solution
were added to the residue and the mixture was stirred. The organic
layer was washed with saturated aqueous sodium hydrogen carbonate
solution and saturated brine, dried over sodium sulfate and
concentrated under reduced pressure to give an oil (16.8 g). This
oil was dissolved in tetrahydrofuran (120 ml)/ethanol (180 ml) and
sodium borohydride (6.5 g) was added under ice-cooling. After 20
min, calcium chloride (9.54 g) was added, and the mixture was
stirred at room temperature for 1 hr. 1N Aqueous hydrochloric acid
and ethyl acetate were added to the reaction mixture. The separated
organic layer was washed with saturated brine, dried over sodium
sulfate, and concentrated under reduced pressure to give an oil
(12.48 g). This oil was dissolved in dimethylformamide (100 ml),
and tert-butyldiphenylchlorosilane (12.81 ml) and imidazole (6.71
g) were added under ice-cooling, and the mixture was stirred for 1
hr. Water was added to the reaction mixture and the mixture was
extracted with ethyl acetate. The organic layer was washed with
saturated brine, subsequently dried over sodium sulfate, and
concentrated under reduced pressure. The residue was purified by
silica gel column chromatography (ethyl acetate:hexane=1:3) to give
benzyl N-[4-(tert-butyldiphenylsilanyloxy)-2--
hydroxybutyl]-N-methylcarbamate (12.84 g).
[1416] .sup.1H-NMR(CDCl.sub.3).delta. 7.67(4H,d,J=7.0 Hz),
7.48-7.28(11H,m), 5.14(2H,s), 4.14(1H,br s), 3.89(2H,br s),
3.47-3.27(2H,m), 3.04(3H,s), 1.79-1.60(2H,m), 1.07(9H,s).
[1417] Step 2 91
[1418] To a solution of benzyl
N-[4-(tert-butyldiphenylsilanyloxy)-2-hydro-
xybutyl]-N-methylcarbamate (12.84 g) in chloroform (150 ml) was
added 1,1,1-tris(acetoxy)-1,1-dihydro-1,2-benziodoxol-3-(1H)-one
(Dess-Martin reagent) (15.50 g) under ice-cooling, and the mixture
was stirred for 1 hr. The reaction mixture was washed successively
with saturated aqueous sodium hydrogen carbonate solution,
saturated aqueous sodium sulfite solution and saturated brine and
dried over sodium sulfate. The solvent was evaporated under reduced
pressure and the obtained residue was purified by silica gel column
chromatography (ethyl acetate:hexane=1:4) to give benzyl
N-[4-(tert-butyldiphenylsilanyloxy)-2-oxobutyl]-N-methylca- rbamate
(10.92 g). To a solution of the obtained compound (7.95 g) in
methanol (70 ml) were added methyl orthoformate (70 ml) and
pyridinium p-toluenesulfonate (4.08 g) and the mixture was stirred
at 60.degree. C. for 18 hr. The reaction mixture was concentrated,
and ethyl acetate was added to the residue and the precipitated
solid was filtered off. The filtrate was concentrated under reduced
pressure and the residue was purified by silica gel column
chromatography (ethyl acetate:hexane=1:5) to give benzyl
N-[4-(tert-butyldiphenylsilanyloxy)-2,2-dimethoxybutyl]-N--
methylcarbamate (2.25 g).
[1419] .sup.1H-NMR(CDCl.sub.3).delta. 7.74-7.62(4H,m),
7.45-7.22(11H,m), 5.07(1H,br s), 4.96(1H,d,J=10.0 Hz), 3.79(2H,br
s), 3.41(2H,br s), 3.12(6H,br s), 2.95(3H,s), 1.99(2H,s),
1.06(9H,s).
[1420] Step 3 92
[1421] To a solution of benzyl
N-[4-(tert-butyldiphenylsilanyloxy)-2,2-dim-
ethoxybutyl]-N-methylcarbamate (3.22 g) in methanol (60 ml) was
added 10% palladium-carbon under a hydrogen atmosphere (3 atm), and
the mixture was stirred for 2.5 hr. Palladium-carbon was filtered
off and the filtrate was concentrated to give an oil (2.44 g). This
oil was dissolved in pyridine (30 ml), methyl chloroglyoxylate
(0.839 ml) was added under ice-cooling, and the mixture was stirred
at the same temperature for 30 min and at room temperature for 30
min. The solvent was evaporated and saturated aqueous sodium
hydrogen carbonate solution was added to the obtained residue. The
mixture was extracted with ethyl acetate and the organic layer was
washed with saturated brine and dried over sodium sulfate. The
solvent was evaporated under reduced pressure to give an oil (2.968
g). To a solution of lithium enolate prepared from lithium
bis(trimethylsilyl)amide (1M tetrahydrofuran solution, 12.14 ml)
and benzyl acetate (1.753 ml) at -78.degree. C. in tetrahydrofuran
(60 ml) was added the above-mentioned oil at -78.degree. C. and the
mixture was stirred at the same temperature for 20 min. Acetic acid
(1.04 ml), water and ethyl acetate were successively added to the
reaction mixture and the mixture was heated to room temperature and
partitioned. The aqueous layer was extracted with ethyl acetate,
and the combined organic layer was washed with saturated brine,
dried over sodium sulfate, and concentrated under reduced pressure.
Dioxane (50 ml) and 2N aqueous hydrochloric acid solution (5 ml)
were added to the residue and the mixture was stirred at room
temperature for 1 hr. The solvent was evaporated and subsequently,
toluene was added and concentrated again. The obtained residue was
dissolved in chloroform (40 ml) and triethylamine (20 ml) and the
mixture was stirred for 1 hr. The solvent was evaporated and the
residue was dissolved in pyridine (60 ml), and benzoyl chloride
(1.41 ml) was added under ice-cooling. After stirring for 1 hr, the
solvent was evaporated. Water was added to the residue and the
mixture was extracted twice with ethyl acetate. The organic layer
was washed with saturated brine, dried over sodium sulfate and
concentrated under reduced pressure. The residue was purified by
silica gel column chromatography (ethyl acetate:hexane=1:2) to give
benzyl 3-benzoyloxy-5-[2-(tert-butyldiphenyls-
ilanyloxy)ethyl]-1-methyl-2-oxo-1,2-dihydropyridine-4-carboxylate
(2.519 g). This compound was dissolved in methanol (75 ml) and 7.5%
palladium-carbon was added. The mixture was stirred under a
hydrogen atmosphere (1 atm) for 1 hr. Palladium-carbon was filtered
off and the filtrate was concentrated. Crystallization from ethyl
acetate/hexane gave
3-benzoyloxy-5-[2-(tert-butyldiphenylsilanyloxy)ethyl]-1-methyl-2-oxo-1,2-
-dihydropyridine-4-carboxylic acid (1.32 g).
[1422] .sup.1H-NMR(CDCl.sub.3).delta. 8.15(2H,d,J=8.3 Hz),
7.62-7.56(5H,m), 7.49-7.36(8H,m), 7.07(1H,s), 3.83(2H,t,J=6.0 Hz),
3.52(3H,s), 2.70(2H,t,J=6.0 Hz), 1.06(9H,s).
[1423] Step 4 93
[1424] To a solution of
3-benzoyloxy-5-[2-(tert-butyldiphenylsilanyloxy)et-
hyl]-1-methyl-2-oxo-1,2-dihydropyridine-4-carboxylic acid (0.956 g)
in dimethylformamide (10 ml) were added 1-hydroxybenzotriazole
hydrate (HOBT) (0.395 g),
1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (WSC)
(0.495 g) and 3-chlorobenzylamine (0.274 ml) and the mixture was
stirred at room temperature for 2 hr. Water was added and the
mixture was extracted twice with ethyl acetate. The organic layer
was washed with saturated brine, dried over sodium sulfate and
concentrated under reduced pressure. The residue was purified by
silica gel column chromatography (ethyl acetate:hexane=1:2) to give
5-[2-(tert-butyldipheny-
lsilanyloxy)ethyl]-4-(3-chlorobenzylcarbamoyl)-1-methyl-2-oxo-1,2-dihydrop-
yridin-3-yl benzoate (0.615 g). This compound was dissolved in
tetrahydrofuran (20 ml), and acetic acid (0.259 ml) and
tetrabutylammonium fluoride (0.474 g) were added, and the mixture
was stirred overnight at room temperature. The reaction mixture was
concentrated, and the residue was purified by silica gel thin layer
chromatography (chloroform:methanol=10:1) to give
4-(3-chlorobenzylcarbam-
oyl)-5-(2-hydroxyethyl)-1-methyl-2-oxo-1,2-dihydropyridin-3-yl
benzoate (0.213 g).
[1425] .sup.1H-NMR(CDCl.sub.3).delta. 8.04(2H,d,J=7.4 Hz),
7.64(1H,t,J=7.4 Hz), 7.46(2H,t,J=7.9 Hz), 7.22(1H,s), 7.15(1H,s),
6.99(2H,d,J=7.9 Hz), 6.86(1H,t,J=7.9 Hz), 6.67(1H,t,J=6.5 Hz),
4.43(2H,d,J=6.0 Hz), 3.86-3.78(2H,m), 2.69(2H,t,J=6.0 Hz),
2.67(1H,br s).
[1426] Step 5 94
[1427] To a solution of
4-(3-chlorobenzylcarbamoyl)-5-(2-hydroxyethyl)-1-m-
ethyl-2-oxo-1,2-dihydropyridin-3-yl benzoate (0.1 g) in
tetrahydrofuran (4 ml) were successively added
diisopropylethylamine (0.119 ml) and methanesulfonyl chloride
(0.035 ml) under ice-cooling. After 20 min, diisopropylethylamine
(0.119 ml) and methanesulfonyl chloride (0.035 ml) were further
added and the mixture was stirred under ice-cooling for 20 min.
Water was added and the mixture was extracted twice with ethyl
acetate. The organic layer was washed with saturated brine, dried
over sodium sulfate, and concentrated under reduced pressure. The
residue was crystallized from ethyl acetate/hexane and the crystals
were collected by filtration to give crystals (0.15 g). The
crystals were dissolved in dimethylformamide (3 ml) and sodium
hydride (0.09 g, 60%) was added under ice-cooling. The mixture was
stirred at room temperature for 30 min. Ethyl acetate and 2N
aqueous hydrochloric acid solution were added and the mixture was
extracted. The organic layer was washed with saturated brine, dried
over sodium sulfate, and concentrated under reduced pressure. The
residue was purified by silica gel thin layer chromatography (ethyl
acetate-chloroform:methanol=6:1) and crystallized from ethyl
acetate/hexane and the crystals were collected by filtration to
give
2-(3-chlorobenzyl)-8-hydroxy-6-methyl-2,3,4,6-tetrahydro-2,6-naph-
thyridine-1,7-dione (0.029 g).
[1428] .sup.1H-NMR(CDCl.sub.3).delta. 12.75(1H,s), 7.33-7.29(3H,m),
7.24-7.19(1H,m), 6.61(1H,s), 4.71(2H,s), 3.57(3H,s),
3.46(2H,t,J=6.4 Hz), 2.73(2H,t,J=6.4 Hz).
Example 123
Synthesis of
6-(3-chlorobenzyl)-4-hydroxy-2-methyl-2,6,7,8-tetrahydropyrid-
o[4,3-c]pyridazine-3,5-dione
[1429] Step 1 95
[1430] To a solution of 3-chlorobenzylamine (15 g) in ethanol (150
ml) was added dropwise a solution of ethyl acrylate (11.5 ml) in
ethanol at room temperature and the mixture was stirred overnight.
The reaction mixture was concentrated under reduced pressure and
chloroform (500 ml), pyridine (50 ml) and 4-dimethylaminopyridine
(3.9 g) were added to the residue. Ethyl malonyl chloride (13.6 ml)
was added dropwise to this mixture under ice-cooling, and the
mixture was stirred under ice-cooling for 1 hr, and further at room
temperature for 1 hr. The reaction mixture was washed with 2N
aqueous hydrochloric acid, saturated aqueous sodium hydrogen
carbonate solution and saturated brine, and dried over magnesium
sulfate. The mixture was concentrated under reduced pressure and
the obtained residue was purified by silica gel column
chromatography (n-hexane:ethyl acetate=2:1-3:2) to give an oil
(25.6 g). A solution of this oil (25.6 g) in toluene (50 ml) was
added dropwise to a suspension of potassium carbonate (50 g) and
18-crown-6 (1.9 g) in toluene (250 ml) with heating under reflux
and the mixture was stirred at the same temperature for 12 hr.
After cooling to room temperature, the reaction mixture was poured
into iced water, 6N aqueous hydrochloric acid was added to adjust
the pH of the reaction mixture to not more than 1 and the mixture
was extracted three times with chloroform. The chloroform layer was
dried, concentrated and 10% aqueous oxalic acid solution (200 ml)
was added to the obtained residue. The mixture was heated under
reflux for 3 hr. The reaction mixture was cooled, extracted three
times with chloroform, and dried over magnesium sulfate. The
solvent was evaporated under reduced pressure and the obtained
residue was purified by silica gel column chromatography
(n-hexane:ethyl acetate=2:3-1:2) to give
1-(3-chlorobenzyl)piperidine-2,4- -dione (6.2 g).
[1431] .sup.1H-NMR(CDCl.sub.3).delta. 7.1-7.4(4H,m), 4.67(2H,s),
3.51(2H,t,J=6.3 Hz), 3.44(2H,s), 2.58(2H,t,J=6.3 Hz). Step 2 96
[1432] 1-(3-Chlorobenzyl)piperidine-2,4-dione (1.2 g) was dissolved
in ethanol (25 ml), and methylhydrazine (0.5 ml) was added. The
mixture was heated under reflux for 1 hr. The reaction mixture was
concentrated under reduced pressure and the obtained residue was
purified by silica gel column chromatography
(chloroform:methanol=95:1) to give
1-(3-chlorobenzyl)-4-(methylhydrazono)piperidin-2-one (1.05 g).
[1433] .sup.1H-NMR(CDCl.sub.3).delta. 7.1-7.4(4H,m), 4.2-4.8(3H,m),
3.2-3.5(4H,m), 2.95(3H,s), 2.3-2.7(2H,m).
[1434] Step 3 97
[1435] 1-(3-Chlorobenzyl)-4-(methylhydrazono)piperidin-2-one (1.05
g) was dissolved in chloroform (20 ml) and triethylamine (1.2 ml)
and methyl oxalyl chloride (0.735 ml) were successively added under
ice-cooling. After stirring at room temperature for 2 hr, the
reaction mixture was washed with saturated aqueous sodium hydrogen
carbonate solution and saturated aqueous sodium chloride solution,
and dried over magnesium sulfate. The mixture was concentrated
under reduced pressure and the obtained residue was purified by
silica gel column chromatography (n-hexane:ethyl acetate=2:3-ethyl
acetate-chloroform:methanol=90:10) to give an oil (200 mg). This
oil was dissolved in tetrahydrofuran (4 ml), sodium hydride (27 mg)
was added under ice-cooling and the mixture was stirred at the same
temperature for 30 min. 5% Aqueous potassium hydrogen sulfate
solution was added to the reaction mixture and the mixture was
extracted three times with ethyl acetate. The ethyl acetate layer
was washed with saturated brine and dried over magnesium sulfate.
The solvent was evaporated under reduced pressure and the obtained
residue was purified by silica gel column chromatography
(chloroform:methanol=90:10) to give
6-(3-chlorobenzyl)-4-hydroxy-2-methyl-2,6,7,8-tetrahydropyrido[4,-
3-c]pyridazine-3,5-dione (92 mg).
[1436] .sup.1H-NMR(DMSO-d.sub.6).delta. 13.41(1H,s),
7.39-7.33(4H,m), 4.70(2H,s), 3.64-3.56(5H,m), 2.85(2H,t,J=6.5
Hz).
Example 438
[1437]
7-(2,2-Dimethylpropionyl)-2-(4-fluorobenzyl)-9-hydroxy-2H-pyrido[1,-
2a]pyrazine-1,8-dione hydrochloride (7.5 g) obtained in the same
manner as in Example 251 was suspended in ethyl acetate (1.5 L) and
saturated aqueous sodium hydrogen carbonate (500 ml) was added with
stirring. After the suspended substance was dissolved, the aqueous
layer was separated and extracted with a small amount of ethyl
acetate. The combined ethyl acetate layer was washed with saturated
brine, dried over sodium sulfate, and concentrated. Acetone-ethyl
acetate was added to the obtained residue and the obtained crystals
were collected by filtration to give
7-(2,2-dimethylpropionyl)-2-(4-fluorobenzyl)-9-hydroxy-2H-pyrido[1,2-a]py-
razine-1,8-dione (6.38 g).
[1438] .sup.1H-NMR(DMSO-d.sub.6).delta. 11.65(1H,br), 8.04(1H,s),
7.44(2H,dd,J=8.8,5.1 Hz), 7.19(2H,dd,J=8.8,8.8 Hz), 7.18(1H,d,J=6.0
Hz), 6.88(1H,d,J=6.0 Hz), 4.92(2H,s), 1.17(9H,s).
Example 439
[1439]
7-(2,2-Dimethylpropionyl)-2-(4-fluorobenzyl)-9-hydroxy-2H-pyrido[1,-
2-a]pyrazine-1,8-dione (100 mg) obtained in Example 438 was
suspended in tetrahydrofuran-methanol (3:1) (4 ml). 1M Aqueous
sodium hydroxide solution (270 .mu.l) was added and the mixture was
stirred for 24.5 hr. The precipitate was collected by filtration,
washed with tetrahydrofuran and dried in vacuo at 50.degree. C. to
give 7-(2,2-dimethylpropionyl)-2-(-
4-fluorobenzyl)-9-hydroxy-2H-pyrido[1,2-a]pyrazine-1,8-dione sodium
salt (94 mg).
[1440] .sup.1H-NMR(DMSO-d.sub.6).delta. 7.48(1H,s),
7.37(2H,dd,J=8.8,5.6 Hz), 7.12(2H,t,J=8.8 Hz), 6.86(1H,d,J=6.3 Hz),
6.57(1H,d,J=6.3 Hz), 4.78(2H,s), 1.21(9H,s).
[1441] Sodium salt, potassium salt, hydrochloride,
trifluoroacetate, methanesulfonate, benzenesulfonate and
toluenesulfonate were obtained from the compound of Example 165 by
conventional methods.
[1442]
N-[2-(3-chlorobenzyl)-9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido[1,2-
-a]pyrazin-7-yl]acetamide sodium salt (Example 440)
[1443] .sup.1H-NMR(DMSO-d.sub.6).delta. 8.92(1H,brs), 8.54(1H,s),
7.41-7.26(4H,m), 6.97(1H,brs), 6.60(1H,brs), 4.83(2H,s),
2.08(3H,s).
[1444] A free compound and a sodium salt were obtained from the
compound of Example 223 by conventional methods.
2-(3-chlorobenzyl)-7-(2,2-dimethy-
lpropionyl)-9-hydroxy-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,8-dione
sodium salt (Example 441)
[1445] .sup.1H-NMR(DMSO-d.sub.6).delta. 7.39-7.24(5H,m),
4.65(2H,s), 4.17-4.05(2H,m), 3.54-3.47(2H,m), 1.23(9H,s).
[1446] A free compound, a sodium salt, a potassium salt and a
benzenesulfonic acid salt were obtained from the compound of
Example 251 by conventional methods.
Examples 93-437
[1447] The compounds of Examples 93-437 other than the
above-mentioned compounds were obtained by methods similar or
analogous to those of Examples 1-12, 118, 125, 161, 165, 94, 96,
104, 187, 191, 189, 390, 244, 251, 223, 154, 249, 219, 362, 205,
242, 382, 283, 302, 349, 353, 222, 316, 291, 106, 123, 438 and 439
or conventional methods.
[1448] The chemical structural formulas and physicochemical data of
Example compounds are shown in Tables 1-37.
1TABLE 1 Example No. Structural formula 1 98 2 99 3 100 4 101 5 102
6 103 7 104 8 105 9 106 10 107 11 108 12 109
[1449]
2TABLE 2 Example No. Structural formula 13 110 14 111 15 112 16 113
17 114 18 115 19 116 20 117 21 118 22 119
[1450]
3TABLE 3 Example No. Structural formula 23 120 24 121 25 122 26 123
27 124 28 125 29 126 30 127 31 128 32 129
[1451]
4TABLE 4 Example No. Structural formula 33 130 34 131 35 132 36 133
37 134 38 135 39 136 40 137
[1452]
5TABLE 5 Example No. Structural formula 41 138 42 139 43 140 44 141
45 142 46 143 47 144 48 145 49 146 50 147
[1453]
6TABLE 6 Example No. Structural formula 51 148 52 149 53 150 54 151
55 152 56 153 57 154 58 155 59 156 60 157
[1454]
7TABLE 7 Example No. Structural formula 61 158 62 159 63 160 64 161
65 162 66 163 67 164 68 165 69 166 70 167
[1455]
8TABLE 8 Example No. Structural formula 71 168 72 169 73 170 74 171
75 172 76 173 77 174 78 175 79 176 80 177
[1456]
9TABLE 9 Ex- ample No. Structural formula 81 178 82 179 83 180 84
181 85 182 86 183 87 184 88 185 89 186 90 187
[1457]
10TABLE 10 Example No. Structural formula 91 188 92 189 93 190 94
191 95 192 96 193 97 194 98 195 99 196 100 197 101 198 102 199
[1458]
11TABLE 11 Ex- am- ple No. Structural formula 103 200 104 201 105
202 106 203 107 204 108 205 109 206 110 207 111 208 112 209
[1459]
12TABLE 12 Example No. Structural formula 113 210 114 211 115 212
116 213 117 214 118 215 119 216 120 217 121 218 122 219 123 220 124
221
[1460]
13TABLE 13 Example No. Structural formula 125 222 126 223 127 224
128 225 129 226 130 227 131 228 132 229 133 230 134 231 135 232 136
233
[1461]
14TABLE 14 Ex- am- ple No. Structural formula 137 234 138 235 139
236 140 237 141 238 142 239 143 240 144 241 145 242 146 243 147 244
148 245
[1462]
15TABLE 15 Example No. Structural formula 149 246 150 247 151 248
152 249 153 250 154 251 155 252 156 253 157 254 158 255 159 256 160
257
[1463]
16TABLE 16 Example No. Structural formula 161 258 162 259 163 260
164 261 165 262 166 263 167 264 168 265 169 266 170 267 171 268 172
269
[1464]
17TABLE 17 Example No. Structural formula 173 270 174 271 175 272
176 273 177 274 178 275 179 276 180 277 181 278 182 279 183 280 184
281
[1465]
18TABLE 18 Example No. Structural formula 185 282 186 283 187 284
188 285 189 286 190 287 191 288 192 289 193 290 194 291 195 292 196
293 197 294 198 295
[1466]
19TABLE 19 Example No. Structural formula 199 296 200 297 201 298
202 299 203 300 204 301 205 302 206 303 207 304 208 305 209 306 210
307 211 308 212 309
[1467]
20TABLE 20 Example No. Structural formula 213 310 214 311 215 312
216 313 217 314 218 315 219 316 220 317 221 318 222 319 224 320 223
321 225 322 226 323
[1468]
21TABLE 21 Exam- ple No. Structural formula 227 324 228 325 229 326
230 327 231 328 232 329 233 330 234 331 235 332 236 333 237 334 238
335 239 336 240 337
[1469]
22TABLE 22 Exam- ple No. Structural formula 241 338 242 339 243 340
244 341 245 342 246 343 247 344 248 345 249 346 250 347 251 348 252
349 253 350 254 351 255 352 256 353
[1470]
23TABLE 23 Exam- ple No. Structural formula 257 354 258 355 259 356
260 357 261 358 262 359 263 360 264 361 265 362 266 363 267 364 268
365 269 366 270 367
[1471]
24TABLE 24 Ex- am- ple No. Structural formula 271 368 272 369 273
370 274 371 275 372 276 373 277 374 278 375 279 376 280 377 281 378
282 379 282 380 284 381
[1472]
25TABLE 25 Exam- ple No. Structural formula 285 382 286 383 287 384
288 385 289 386 290 387 291 388 292 389 293 390 294 391 295 392 296
393 297 394 298 395
[1473]
26TABLE 26 Exam- ple No. Structural formula 299 396 300 397 301 398
302 399 303 400 304 401 305 402 306 403 307 404 308 405 309 406 310
407
[1474]
27TABLE 27 Exam- ple No. Structural formula 311 408 312 409 313 410
314 411 315 412 316 413 317 414 318 415 319 416 320 417 321 418 322
419 323 420 324 421
[1475]
28TABLE 28 Exam- ple No. Structural formula 325 422 326 423 327 424
328 425 329 426 330 427 331 428 332 429 333 430 334 431 335 432 336
433 337 434 338 435
[1476]
29TABLE 29 Exam- ple No. Structural formula 339 436 340 437 341 438
342 439 343 440 344 441 345 442 346 443 347 444 348 445 349 446 350
447 351 448 352 449
[1477]
30TABLE 30 Ex- am- ple No. Stuctural formula 353 450 354 451 355
452 356 453 357 454 358 455 359 456 360 457 361 458 362 459 363 460
364 461
[1478]
31TABLE 31 Example No. Structural formula 365 462 366 463 367 464
368 465 369 466 370 467 371 468 372 469 373 470 374 471 375 472 376
473 377 474 378 475
[1479]
32TABLE 32 Example No. Structural formula 379 476 380 477 381 478
382 479 383 480 384 481 385 482 386 483 387 484 388 485 389 486 390
487
[1480]
33TABLE 33 Example No. Structural formula 391 488 392 489 393 490
394 491 395 492 396 493 397 494 398 495 399 496 400 497 401 498 402
499
[1481]
34TABLE 34 Example No. Structural formula 403 500 404 501 405 502
406 503 407 504 408 505 409 506 410 507 411 508 412 509 413 510 414
511
[1482]
35TABLE 35 Example No. Structural formula 415 512 416 513 417 514
418 515 419 516 420 517 421 518 422 519 423 520 424 521 425 522 426
523
[1483]
36TABLE 36 Example No. Structural formula 427 524 428 525 429 526
430 527 431 528 432 529 433 530 434 531 435 532 436 533 437 534 438
535
[1484]
37TABLE 37 Example .sup.1H-NMR 13 .sup.1H-NMR(DMSO-d.sub.6)
.delta.: 7.92(1H, d, J=7.0Hz), 7.69(2H, d, J=1.9Hz), 7.65(2H, d,
J=8.3Hz), 7.39(1H, dd, J=8.3, 2.3Hz), 6.57(1H, d, J=7.4Hz),
4.81(1H, d, J=14.8Hz), 4.67(1H, d, J=14.8Hz), 3.98(1H, dd, J=13.4,
3.7Hz), 3.53(1H, dd, J=13.4, 2.8Hz), 1.29(3H, d, J=6.5Hz). 14
.sup.1H-NMR(DMSO-d.sub.6) .delta.: 7.69(1H, s), 7.66(1H, d,
J=8.3Hz), 7.42(1H, dd, J=1.9, 8.3Hz), 7.27(1H, d, J=7.4Hz),
7.24-7.14(3H, m), 6.94-6.84(2H, m), 6.02(1H, d, J=7.4Hz), 4.87(1H,
d, J=14.8Hz), 4.64-4.56(1H, m), 4.52(1H, d, J=14.8Hz), 3.97(1H, dd,
J=13.4, 4.2Hz), 3.36(1H, d, J=13.4Hz), 2.90-2.80(2H, m).10958225.16
15 .sup.1H-NMR(DMSO-d.sub.- 6) .delta.: 7.65(1H, d, J=7.4Hz),
7.35(1H, d, J=8.3Hz), 7.31-7.22 (3H, m), 7.15(1H, d, J=2.3Hz),
6.92(1H, dd, J=8.3, 2.3Hz), 6.89-6.82(2H, m), 6.24(1H, d, J=7.4Hz),
5.68(1H, br s), 4.81(1H, d, J=15.3Hz), 4.35-4.22(2H, m), 3.91(1H,
dd, J=13.7, 2.6Hz). 16 .sup.1H-NMR(DMSO-d.sub.6) .delta.: 7.90(1H,
d, J=7.4Hz), 7.70(1H, d, J=1.9Hz), 7.66(1H, d, J=8.3Hz), 7.41(1H,
dd, J=8.3, 2.3Hz), 6.57(1H, d, J=7.4Hz), 4.98(1H, d, J=14.8Hz),
4.51-4.40(1H, m), 4.45(1H, d, J=14.8Hz), 4.07-3.97(1H, m), 3.54
(1H, d, J=13.9Hz), 1.55-1.42(2H, m), 1.19-0.86(4H, m), 0.74(3H, t,
J=7.2Hz). 17 .sup.1H-NMR(DMSO-d.sub.6) .delta.: 7.72(1H, d,
J=1.9Hz), 7.64(2H, dd, J=7.7, 3.9Hz), 7.41 (1H, dd, J=8.3, 1.9Hz),
6.16(1H, d, J=7.5Hz), 4.82(1H, d, J=14.7Hz), 4.59 (1H, d,
J=14.7Hz), 3.96(2H, d, J=10.9Hz), 3.66(1H, d, J=12.4Hz), 1.82-1.79
(1H, m), 0.71(3H, d, J=6.4Hz), 0.65(3H, d, J=6.8Hz). 18
.sup.1H-NMR(DMSO-d.sub.6) .delta.: 7.72(1H, d, J=7.1Hz), 7.66(1H,
d, J=2.0Hz), 7.60(1H, d, J=8.2Hz), 7.37(1H, dd, J=8.2, 2.0Hz),
6.44(1H, d, J=7.1Hz), 4.80(2H, s), 4.24(2H, s), 1.25(6H, s). 19
.sup.1H-NMR(DMSO-d.sub.6) .delta.: 7.67(1H, d, J=2.2Hz),
7.66-7.63(1H, m), 7.64(1H, d, J= 8.4Hz), 7.38(1H, dd, J=8.4,
2.2Hz), 6.18(1H, d, J=7.7Hz), 4.72(2H, s), 3.67 (2H, s),
2.03-1.58(8H,m). 20 .sup.1H-NMR(DMSO-d.sub.6- ) .delta.: 12.44(1H,
s), 7.87(1H, d, J=7.7Hz), 7.72(1H, d, J=1.5 Hz), 7.64(1H, d,
J=8.3Hz), 7.42(1H, dd, J=8.3, 1.7Hz), 6.15(1H, d, J=7.7Hz),
4.73(2H, s), 3.80(2H, s), 1.92-1.69(4H, m), 1.64-1.44(3H, m),
1.41-1.08(3H, m). 21 .sup.1H-NMR(CDCl.sub.3) .delta.: 11.70(1H, s),
7.66(1H, d, J=8.3Hz), 7.58(1H, d, J=7.4Hz), 7.55(1H, d, J=1.9Hz),
7.27(1H, dd, J=8.3, 1.9Hz), 6.20(1H, d, J=7.4Hz), 5.43-5.37(1H, m),
4.93(1H, d, J=14.8Hz), 4.34(1H, d, J=14.8Hz), 4.19(1H, dd, J=13.4,
4.2Hz), 3.87(1H, dd, J=13.4, 1.4Hz), 3.49(3H, s). 22
.sup.1H-NMR(DMSO-d.sub.6) .delta.: 13.85(1H, br s), 11.75(1H, br
s), 7.63-7.57(3H, m), 7.29 (1H, dd, J=8.3, 1.9Hz), 6.18(1H, d,
J=7.4Hz), 5.24(1H, br s), 4.79(1H, d, J= 14.8Hz), 4.51(1H, d,
J=14.8Hz), 4.14(1H, dd, J=13.2, 4.4Hz), 3.93(1H, dd, J= 12.5,
1.9Hz). 23 .sup.1H-NMR(DMSO-d.sub.6) .delta.: 7.68(1H, d, J=2.2Hz),
7.63(1H, d, J=8.4Hz), 7.38(1H, dd, J=8.3, 2.0Hz), 6.58(1H, s),
4.73(2H, s), 4.47(2H, s), 4.25-4.23(2H, m), 3.73-3.70(2H, m),
3.31(3H, s). 24 .sup.1H-NMR(DMSO-d.sub.6) .delta.: 7.69(1H, d,
J=1.9Hz), 7.63(1H, d, J=8.3Hz), 7.39(1H, dd, J=8.3, 1.9Hz),
6.12(1H, s), 4.83(1H, d, J=15.1Hz), 4.62(1H, d, J=16.2 Hz),
4.03-3.98(2H, m), 3.68(2H, t, J=5.7Hz), 2.97(3H, s), 2.90(3H, s).
25 .sup.1H-NMR(DMSO-d.sub.6) .delta.: 7.73(1H, d, J=7.1Hz),
7.70(1H, d, J=1.8Hz), 7.64(1H, d, J=8.1Hz), 7.41(1H, dd, J=8.1,
1.8Hz), 7.29-7.10(6H, m), 6.45(1H, d, J=7.1 Hz), 5.14(1H, d,
J=15.4Hz), 4.39-4.30(2H, m), 4.19-4.10(2H, m), 3.00(1H, dd, J=13.7,
4.4Hz), 2.87(1H, dd, J=13.7, 8.1Hz). 26 .sup.1H-NMR(DMSO-d.sub.6)
.delta.: 7.88(1H, d, J=7.1Hz), 7.71(1H, d, J=2.1Hz), 7.63(1H, d,
J=8.2Hz), 7.41(1H, dd, J=8.2, 2.1Hz), 6.52(1H, d, J=7.1Hz),
5.07(1H, d, J=15.2Hz), 4.42(1H, d, J=15.2Hz), 4.34(2H, s),
3.88-3.77(1H, m), 1.70-1.12(6H, m), 0.82(3H, t, J=6.7Hz). 27
.sup.1H-NMR(DMSO-d.sub.6) .delta.: 11.70(1H, br s), 7.64(1H, d,
J=8.3Hz), 7.57-7.49(2H, m), 7.24(1H, d, J=6.5Hz), 6.15(1H, d,
J=7.4Hz), 5.60(1H, s), 5.00(1H, d, J=15.3Hz), 4.22-4.13(1H, m),
4.22(1H, d, J=15.3Hz), 3.68(1H, d, J=13.9Hz), 2.91 (3H, s),
2.61(3H, s). 28 .sup.1H-NMR(DMSO-d.sub.6) .delta.: 7.66(1H, d,
J=1.9Hz), 7.63(1H, d, J=8.3Hz), 7.54(1H, d, J=7.4Hz), 7.36(1H, dd,
J=8.3, 1.9Hz), 6.14(1H, d, J=7.4Hz), 5.22(1H, s), 4.71(1H, d,
J=14.8Hz), 4.64(1H, d, J=14.8Hz), 4.32-4.22(1H, m), 3.96(1H, dd,
J=13.2, 4.4Hz), 3.60(1H, dd, J=13.2, 1.4Hz), 3.53-3.42(2H, m). 29
.sup.1H-NMR(DMSO-d.sub.6) .delta.: 12.02(1H, br s), 7.67(1H, d,
J=1.9Hz), 7.62(1H, d, J= 8.3Hz), 7.62(1H, d, J=7.4Hz), 7.37(1H, dd,
J=8.3, 1.9Hz), 6.15(1H, d, J=7.4 Hz), 4.85(1H, d, J=15.3Hz),
4.55-4.46(1H, m), 4.50(1H, d, J=15.3Hz), 3.98 (1H, dd, J=13.4,
4.6Hz), 3.57(1H, dd, J=13.4, 1.4Hz), 3.47-3.36(2H, m), 3.12 (3H,
s). 30 .sup.1H-NMR(DMSO-d.sub.6) .delta.: 7.69(1H, d, J=1.9Hz),
7.63(1H, d, J=8.7Hz), 7.38(1H, dd, J=8.3, 1.9Hz), 6.23(1H, s),
4.72(2H, s), 4.21-4.19(2H, m), 3.76(2H, s), 3.68-3.66(2H, m),
2.02(3H, s). 31 .sup.1H-NMR(DMSO-d.sub.6) .delta.: 7.67(1H, d,
J=1.8Hz), 7.62(1H, d, J=8.4Hz), 7.36(1H, dd, J=8.3, 2.0Hz),
6.32(1H, s), 4.78(2H, s), 4.71(2H, s), 4.27-4.25(2H, m),
3.68-3.66(2H, m), 3.08(3H, s). 32 .sup.1H-NMR(DMSO-d.sub.6)
.delta.: 7.72(1H, d, J=7.2Hz), 7.68(1H, d, J=1.9Hz), 7.63(1H, d,
J=8.3Hz), 7.38(1H, dd, J=8.3, 1.9Hz), 6.33(1H, d, J=7.2Hz),
4.80(1H, d, J=14.8Hz), 4.68(1H, d, J=14.8Hz), 4.55-4.47(1H, m),
4.00(1H, dd, J=13.9, 4.2 Hz), 3.68-3.55(1H, m), 3.20-3.10(1H, m),
3.00-2.91(1H, m), 2.93(3H, s), 2.10-1.99(2H, m). 33
.sup.1H-NMR(DMSO-d.sub.6) .delta.: 7.80(1H, d, J=7.1Hz), 7.70(1H,
d, J=1.8Hz), 7.66(1H, d, J=8.4Hz), 7.41(1H, dd, J=8.4, 1.8Hz),
6.46(1H, d, J=7.1Hz), 4.84(1H, d, J=14.7Hz), 4.62(1H, d, J=14.7Hz),
4.57-4.47(1H, m), 4.02(1H, dd, J=13.8, 3.5 Hz), 3.65-3.55(1H, m),
2.29-2.21(2H, m), 1.96(3H, s), 1.88-1.76(2H, m). 34
.sup.1H-NMR(DMSO-d.sub.6) .delta.: 7.69(1H, d, J=2.0Hz), 7.63(1H,
d, J=8.2Hz), 7.39(1H, dd, J=8.2, 2.0Hz), 6.56(1H, s), 4.72(2H, s),
4.39-4.31(2H, m), 3.87(3H, s), 3.73-3.65(2H, m). 35
.sup.1H-NMR(DMSO-d.sub.6) .delta.: 7.68(1H, d, J=1.9Hz), 7.63(1H,
d, J=8.4Hz), 7.38(1H, dd, J=8.4, 1.9Hz), 6.70(1H, s), 4.72(2H, s),
4.21-4.13(2H, m), 3.69-3.61(2H, m), 2.57(3H, s). 36
.sup.1H-NMR(CDCl.sub.3) .delta.: 7.46(1H, d, J=8.0Hz), 7.43(1H, d,
J=2.0Hz), 7.20(1H, dd, J=8.0, 2.0Hz), 6.25(1H, s), 4.71(2H, s),
4.24-4.14(2H, m), 3.67-3.59(2H, m), 3.56 (2H, s), 2.88(1H, sept,
J=6.5Hz), 1.25(6H, d, J=6.5Hz). 37 .sup.1H-NMR(DMSO-d.sub.6)
.delta.: 12.48(1H, br s), 7.69(1H, d, J=2.2Hz), 7.63(1H, d, J=
8.2Hz), 7.38(1H, dd, J=8.2, 2.2Hz), 6.28(1H, s), 4.76(2H, s),
4.71(2H, s), 4.30-4.18(2H, m), 3.73-3.63(2H, m), 3.43(1H, sept,
J=7.0Hz), 1.31(6H, d, J= 7.0Hz). 38 .sup.1H-NMR(DMSO-d.sub.6)
.delta.: 7.68(1H, d, J=1.8Hz), 7.63(1H, d, J=8.4Hz), 7.38(1H, dd,
J=8.4, 2.0Hz), 6.69(1H, s), 4.73(2H, s), 4.52(2H, s), 4.32-4.22(2H,
m), 3.79-3.58(3H, m), 1.14(7H, d, J=6.2Hz). 39
.sup.1H-NMR(DMSO-d.sub.6) .delta.: 7.69(1H, s), 7.66(1H, d,
J=8.8Hz), 7.40(1H, d, J=8.8 Hz), 6.66(1H, s), 4.75(2H, s), 4.54(2H,
s), 4.28(2H, s), 3.75(2H, s), 3.24(2H, d, J= 6.2Hz), 1.93-1.75(1H,
m), 0.87(6H, d, J=7.3Hz). 40 .sup.1H-NMR(DMSO-d.sub.6) .delta.:
7.67(1H, d, J=1.5Hz), 7.63(1H, d, J=8.2Hz), 7.38(1H, dd, J=8.2,
1.5Hz), 6.35(1H, s), 5.71-5.62(1H, m), 4.85-4.76(1H, m), 4.76(1H,
d, J=15.5Hz), 4.69(1H, d, J=15.5Hz), 4.31-4.23(2H, m),
3.71-3.63(2H, m), 1.34 (3H, d, J=6.2Hz). 41 .sup.1H-NMR(CDCl.sub.3)
.delta.: 8.25(1H, t, J=5.6Hz), 7.51-7.45(1H, m), 7.42-7.27(3H, m),
7.27-7.21(2H, m), 7.16-7.10(1H, m), 6.98(1H, dd, J=8.1, 2.1Hz),
5.47(2H, s), 5.03(2H, s), 4.37-4.30(2H, m), 3.73-3.63(2H, m). 42
.sup.1H-NMR(DMSO-d.sub.6) .delta.: 7.86(1H, d, J=7.2Hz), 7.44(2H,
dd, J=8.8, 5.6Hz), 7.21 (2H, t, J=8.8Hz), 6.60(1H, d, J=7.2Hz),
4.73(2H, s), 4.35(2H, t, J=5.8Hz), 3.75(2H, t, J=5.8Hz). 43
.sup.1H-NMR(DMSO-d.sub.6) .delta.: 7.86(1H, d, J=6.8Hz), 7.48(1H,
s), 7.41-7.37(3H, m), 6.58(1H, d, J=6.8Hz), 4.75(2H, s), 4.36(2H,
t, J=5.6Hz), 3.77(2H, t, J=5.6 Hz). 44 .sup.1H-NMR(DMSO-d.sub.6)
.delta.: 7.91(1H, d, J=7.0Hz), 7.42-7.30(5H, m), 6.67(1H, d, J=
7.0Hz), 4.75(2H, s), 4.38(2H, t, J=5.6Hz), 3.76(2H, t, J=5.8Hz). 45
.sup.1H-NMR(DMSO-d.sub.6) .delta.: 7.89(1H, d, J=7.0Hz),
7.44-7.42(4H, m), 6.64(1H, d, J= 7.0Hz), 4.74(2H, s), 4.37(2H, t,
J=5.6Hz), 3.76(2H, t, J=5.8Hz). 46 .sup.1H-NMR(DMSO-d.sub.6)
.delta.: 7.67(1H, d, J=1.9Hz), 7.63(1H, d, J=8.3Hz), 7.37(1H, dd,
J=8.3, 1.9Hz), 6.24(1H, s), 4.73(2H, s), 4.30-4.23(2H, m),
3.72-3.66(2H, m), 3.13(1H, sept, J=6.5Hz), 1.17(7H, d, J=6.5Hz). 47
.sup.1H-NMR(DMSO-d.sub.6) .delta.: 12.42(1H, br s), 7.68(1H, d,
J=2.1Hz), 7.63(1H, d, J= 8.3Hz), 7.38(1H, dd, J=8.3, 2.1Hz),
6.57(1H, s), 4.73(2H, s), 4.08-3.98(2H, m), 3.71-3.61(2H, m),
3.38-3.28(1H, m), 1.10(6H, d, J=7.0Hz). 48
.sup.1H-NMR(DMSO-d.sub.6) .delta.: 9.77(1H, s), 7.69(1H, d,
J=2.1Hz), 7.64(1H, d, J=8.1 Hz), 7.39(1H, dd, J=8.1, 2.1Hz),
6.84(1H, s), 4.75(2H, s), 4.66-4.58(2H, m), 3.77-3.68(2H, m). 49
.sup.1H-NMR(DMSO-d.sub.6) .delta.: 7.67-7.64(2H, m), 7.59-7.44(5H,
m), 7.37(1H, dd, J=7.9, 1.4Hz), 6.54(1H, s), 4.75(2H, s),
4.16-4.14(2H, m), 3.72-3.63(2H, m). 50 .sup.1H-NMR(DMSO-d.sub.6)
.delta.: 7.87(1H, d, J=7.0Hz), 7.29-7.08(5H, m), 6.62(1H, d, J=
7.0Hz), 4.34(2H, t, J=5.8Hz), 3.78(2H, t, J=5.8Hz), 3.53(2H, t,
J=7.2Hz), 2.62(2H, t, J=7.9Hz), 1.93-1.82(2H, m). 51
.sup.1H-NMR(DMSO-d.sub.6) .delta.: 7.86(1H, d, J=7.0Hz),
7.58-7.52(1H, m), 7.44(1H, t, J= 7.2Hz), 7.23(1H, t, J=7.9Hz),
6.58(1H, d, J=7.0Hz), 4.80(2H, s), 4.36(2H, t, J=5.6Hz), 3.80(2H,
t, J=5.6Hz). 52 .sup.1H-NMR(DMSO-d.sub.6) .delta.: 7.79(1H, d,
J=7.0Hz), 7.32-7.16(5H, m), 6.52(1H, d, J= 7.0Hz), 4.25(2H, t,
J=5.8Hz), 3.75-3.67(4H, m), 2.90(2H, t, J=7.4Hz). 53
.sup.1H-NMR(DMSO-d.sub.6) .delta.: 12.37(1H, br s), 7.68(1H, d,
J=2.1Hz), 7.63(1H, d, J= 8.3Hz), 7.38(1H, dd, J=8.3, 2.1Hz),
6.27(1H, s), 5.75(1H, d, J=4.6Hz), 4.72 (2H, s), 4.41-4.30(2H, m),
4.29-4.17(1H, m), 3.65(2H, t, J=5.3Hz), 1.95-1.83 (1H, m), 0.87(6H,
dd, J=10.0, 6.7Hz). 54 .sup.1H-NMR(DMSO-d.sub.6) .delta.: 7.68(1H,
d, J=1.9Hz), 7.64(1H, d, J=8.1Hz), 7.39(1H, dd, J=8.1, 1.9Hz),
6.56(1H, s), 4.75(2H, s), 4.38-4.31(2H, m), 3.76-3.69(2H, m),
2.64(2H, d, J=7.0Hz), 1.93-1.80(1H, m), 0.91(9H, d, J=6.5Hz). 55
.sup.1H-NMR(DMSO-d.sub.6) .delta.: 12.35(0H, s), 8.31(1H, s),
8.05(1H, s), 7.67(1H, d, J=2.0 Hz), 7.62(1H, d, J=8.3Hz), 7.37(1H,
dd, J=8.3, 2.0Hz), 6.25(1H, s), 4.72(2H, s), 4.25-4.17(2H, m),
3.71-3.64(2H, m). 56 .sup.1H-NMR(DMSO-d.sub.6) .delta.: 12.34(1H,
br s), 8.86-8.77(1H, m), 7.67(1H, d, J=2.3Hz), 7.62(1H, d,
J=8.3Hz), 7.36(1H, dd, J=8.3, 2.3Hz), 6.22(1H, s), 4.72(2H, s),
4.20-4.12(2H, m), 3.70-3.62(2H, m), 2.74(3H, d, J=4.6Hz). 57
.sup.1H-NMR(DMSO-d.sub.6) .delta.: 7.93(1H, d, J=7.0Hz), 7.60(1H,
t, J=7.9Hz), 7.48(1H, dd, J=10.2, 1.9Hz), 7.27(1H, d, J=8.3Hz),
6.68(1H, d, J=7.0Hz), 4.76(2H, s), 4.41(2H, t, J=5.6Hz), 3.79(2H,
t, J=5.6Hz). 58 .sup.1H-NMR(DMSO-d.sub.6) .delta.: 12.44(1H, br s),
7.93(2H, d, J=7.4Hz), 7.79(1H, t, J=7.4 Hz), 7.71-7.58(4H, m),
7.38(1H, dd, J=8.3, 1.9Hz), 6.22(1H, s), 4.73(2H, s), 4.07-3.97(2H,
m), 3.68-3.60(2H, m). 59 .sup.1H-NMR(DMSO-d.sub.6) .delta.:
12.39(1H, s), 7.68(1H, d, J=1.9Hz), 7.63(1H, d, J=8.3 Hz), 7.38(1H,
dd, J=8.3, 1.9Hz), 6.63(1H, s), 4.73(2H, s), 4.15-4.06(2H, m),
3.70-3.61(2H, m), 2.98(2H, q, J=7.1Hz), 1.05(3H, t, J=7.1Hz). 60
.sup.1H-NMR(DMSO-d.sub.6) .delta.: 12.19(1H, s), 7.65(1H, d,
J=2.1Hz), 7.62(1H, d, J=8.3 Hz), 7.36(1H, dd, J=8.3, 2.1Hz),
6.10(1H, s), 4.71(2H, s), 4.14-4.07(2H, m), 3.70-3.63(2H, m),
2.26(3H, s). 61 .sup.1H-NMR(DMSO-d.sub.6) .delta.: 12.32(1H, br s),
7.68(1H, d, J=1.9Hz), 7.62(1H, d, J= 8.1Hz), 7.38(1H, dd, J=8.1,
1.9Hz), 6.11(1H, s), 4.83(1H, d, J=15.3Hz), 4.60 (1H, d, J=15.3Hz),
4.08-3.98(1H, m), 3.95-3.85(1H, m), 3.72-3.64(2H, m), 3.58-3.47(1H,
m), 3.36-3.18(3H, m), 1.55-0.72(1H, m), 1.13(3H, t, J=7.0Hz),
1.06(3H, t, J=7.0Hz). 62 .sup.1H-NMR(DMSO-d.sub.- 6) .delta.:
7.68(1H, s), 7.62(1H, d, J=8.3Hz), 7.38(1H, d, J=8.3 Hz),
6.25-6.19(1H, m), 4.90-4.54(2H, m), 4.14-3.89(2H, m), 3.87-3.62(3H,
m), 2.86-2.71(2H, m), 1.18-1.08(7H, m). 63
.sup.1H-NMR(DMSO-d.sub.6) .delta.: 12.31(1H, br s), 7.68(1H, s),
7.62(1H, d, J=8.1Hz), 7.38 (1H, d, J=8.1Hz), 6.12-6.08(1H, m),
4.89-4.54(2H, m), 4.09-3.87(2H, m), 3.73-3.62(2H, m), 3.52-3.15(2H,
m), 2.96-2.85(3H, m), 1.16-1.02(3H, m). 64
.sup.1H-NMR(DMSO-d.sub.6) .delta.: 11.94(1H, s), 7.62(1H, dd,
J=7.9, 1.9Hz), 7.56(1H, d, J= 7.4Hz), 7.42-7.40(2H, m), 6.13(1H, d,
J=7.4Hz), 4.69(2H, s), 4.20-4.15(2H, m), 3.72-3.67(2H, m). 65
.sup.1H-NMR(DMSO-d.sub.6) .delta.: 7.91(1H, d, J=7.2Hz),
7.48-7.35(4H, m), 6.65(1H, d, J= 7.2Hz), 4.82(2H, s), 4.42(2H, t,
J=5.8Hz), 3.80(2H, t, J=5.8Hz). 66 .sup.1H-NMR(DMSO-d.sub.6)
.delta.: 7.89(1H, d, J=7.0Hz), 7.56(1H, t, J=1.9Hz), 7.48(2H, d,
J=1.9Hz), 6.64(1H, d, J=7.0Hz), 4.74(2H, s), 4.39(2H, t, J=5.6Hz),
3.79(2H, t, J=5.6Hz). 67 .sup.1H-NMR(DMSO-d.sub.6) .delta.:
7.68(1H, d, J=2.0Hz), 7.64(1H, d, J=8.2Hz), 7.38(1H, dd, J=8.2,
2.0Hz), 6.69(1H, s), 4.76(2H, s), 4.58-4.51(2H, m), 3.75-3.67(2H,
m), 1.41(9H, s). 68 .sup.1H-NMR(DMSO-d.sub.6) .delta.: 7.70(1H, d,
J=1.9Hz), 7.64(1H, d, J=8.3Hz), 7.40(1H, dd, J=8.3, 1.9Hz),
6.74(1H, s), 4.83-4.64(3H, m), 4.61-4.45(2H, m), 3.73-3.63 (2H, m),
0.91(9H, s). 69 .sup.1H-NMR(DMSO-d.sub.6) .delta.: 8.07(1H, d,
J=7.2Hz), 7.41-7.24(6H, m), 6.77(1H, d, J= 7.2Hz), 3.97(2H, s),
3.19(3H, s). 70 .sup.1H-NMR(DMSO-d.sub.6) .delta.: 8.14(1H, d,
J=7.2Hz), 7.38(1H, d, J=6Hz), 7.32(2H, d, J=8.4Hz), 7.25(2H, d,
J=8.4Hz), 7.02(1H, d, J=6Hz), 6.84(1H, d, J=7.2Hz), 3.82(2H, t,
J=7Hz), 2.65(2H, t, J=7.8Hz), 1.9-2.1(2H, m). 71
.sup.1H-NMR(DMSO-d.sub.6) .delta.: 8.08(1H, d, J=7.2Hz),
7.2-7.5(5H, m), 6.98(1H, d, J= 6.3Hz), 6.73(1H, d, J=7.2Hz),
3.85(2H, t, J=7Hz), 2.76(2H, t, J=7.8Hz), 1.9-2.1(2H, m). 72
1H-NMR(DMSO-d.sub.6) .delta.: 12.14(1H, br s), 7.90(1H, d,
J=7.4Hz), 7.69(1H, d, J= 1.9Hz), 7.64(1H, d, J=8.3Hz), 7.38(1H, dd,
J=8.3, 1.9Hz), 6.78(1H, s), 6.49 (1H, d, J=7.4Hz), 4.94(2H, s),
2.20(3H, s). 73 1H-NMR(DMSO-d.sub.6) .delta.: 7.92(1H, d, J=7.0Hz),
7.47(1H, d, J=2.3Hz), 7.33(1H, dd, J=8.6, 2.3Hz), 7.14(1H, d,
J=8.6Hz), 6.69(1H, d, J=7.0Hz), 4.67(2H, s), 4.37(2H, t, J=5.8Hz),
3.85(3H, s), 3.74(2H, t, J=5.8Hz). 74 .sup.1H-NMR(DMSO-d.sub.6)
.delta.: 8.04(1H, d, J=7.0Hz), 7.41-7.21(6H, m), 6.76(1H, d, J=
7.0Hz), 3.41(3H, s), 2.92-2.79(4H, m). 75 .sup.1H-NMR(DMSO-d.sub.6)
.delta.: 7.68(1H, d, J=2.0Hz), 7.63(1H, d, J=8.0Hz), 7.38(1H, dd,
J=8.0, 2.0Hz), 6.29(1H, s), 4.72(2H, s), 4.26(2H, s), 4.14(2H, t,
J=5.4Hz), 3.71(2H, t, J=5.4Hz). 76 .sup.1H-NMR(DMSO-d.sub.6)
.delta.: 8.13(1H, d, J=7.4Hz), 7.37(1H, d, J=6.3Hz), 7.32-7.25 (2H,
m), 7.23-7.16(2H, m), 7.01(1H, d, J=6.3Hz), 6.83(1H, d, J=7.4Hz),
3.82 (2H, t, J=7.0Hz), 2.66(2H, t, J=7.9Hz), 1.98(2H, tt, J=7.9,
7.0Hz). 77 .sup.1H-NMR(DMSO-d.sub.6) .delta.: 8.18(1H, d, J=7.0Hz),
7.36(1H, s), 7.32-7.10(5H, m), 6.99(1H, d, J=7.0Hz), 3.37(3H, s),
2.71(2H, t, J=7.7Hz), 2.62(2H, t, J=7.4 Hz), 1.87(2H, tt, J=7.7,
7.4Hz). 78 .sup.1H-NMR(DMSO-d.sub.6) .delta.: 12.26(1H, s),
8.08(1H, d, J=7.9Hz), 7.69(1H, d, J=1.9 Hz), 7.62(1H, d, J=8.3Hz),
7.37(1H, dd, J=8.3, 1.9Hz), 6.70(1H, s), 6.49(1H, d, J=7.9Hz),
4.99(2H, s), 3.13(1H, sept, J=6.5Hz), 1.19(6H, d, J=6.5Hz). 79
.sup.1H-NMR(DMSO-d.sub.6) .delta.: 7.90(1H, d, J=7.4Hz), 7.51(1H,
d, J=2.3Hz), 7.49(1H, d, J=7.9Hz), 7.23(1H, dd, J=8.3, 1.9Hz),
7.15(1H, d, J=6.0Hz), 6.74(1H, d, J=6.5Hz), 6.46(1H, d, J=7.4Hz),
3.76(2H, t, J=6.7Hz), 2.65(2H, t, J=7.4Hz), 2.00-1.93(2H, m). 80
.sup.1H-NMR(DMSO-d.sub.6) .delta.: 7.90(1H, d, J=7.4Hz),
7.32-7.34(1H, m), 7.31(2H, d, J= 1.9Hz), 7.15(1H, d, J=6.0Hz),
6.74(1H, d, J=6.5Hz), 6.49(1H, d, J=7.4Hz), 3.76(2H, t, J=6.7Hz),
2.66(2H, t, J=7.7Hz), 2.01-1.93(2H, m). 81 .sup.1H-NMR(DMSO-d.sub.-
6) .delta.: 7.66(1H, d, J=2.3Hz), 7.63(1H, d, J=8.3Hz), 7.36-7.29
(6H, m), 6.22(1H, s), 5.14(2H, s), 4.70(2H, s), 4.05-3.97(4H, m),
3.59-3.55(2H, m). 82 .sup.1H-NMR(DMSO-d.sub.6) .delta.: 12.44(1H,
s), 7.66-7.61(2H, m), 7.34-7.13(11H, m), 6.22 (1H, s), 5.11(2H, dd,
J=18.1, 12.5Hz), 4.66(2H, dd, J=18.1, 14.8Hz), 4.50(1H, t,
J=7.7Hz), 4.20-4.10(1H, m), 4.09-3.97(1H, m), 3.54-3.26(3H, m),
3.09(1H, dd, J=13.4, 7.4Hz). 83 .sup.1H-NMR(DMSO-d.sub.6) .delta.:
7.66(1H, d, J=2.1Hz), 7.63(1H, d, J=8.3Hz), 7.36(1H, dd, J=8.3,
2.1Hz), 6.13(1H, s), 4.85(1H, s), 4.72(2H, s), 4.20(2H, t,
J=5.3Hz), 3.66-3.64(4H, m), 2.76(2H, t, J=6.5Hz). 84
.sup.1H-NMR(DMSO-d.sub.6) .delta.: 7.98(1H, d, J=7.9Hz),
7.71-7.68(1H, m), 7.63(1H, d, J= 8.3Hz), 7.40-7.35(1H, m), 6.73(1H,
s), 6.47(1H, d, J=7.9Hz), 4.95(2H, s), 2.57-2.52(2H, m),
1.61-1.48(2H, m), 0.94(3H, t, J=7.2Hz). 85 .sup.1H-NMR(DMSO-d.sub.-
6) .delta.: 8.00(1H, d, J=7.9Hz), 7.69(1H, d, J=1.9Hz), 7.63(1H, d,
J=8.3Hz), 7.38(1H, dd, J=8.3, 1.9Hz), 6.75(1H, s), 6.55-6.49(1H,
m), 4.97 (2H, s), 2.62(3H, q, J=7.2Hz), 1.16(3H, t, J=7.2Hz). 86
.sup.1H-NMR(DMSO-d.sub.6) .delta.: 7.99(1H, d, J=7.7Hz), 7.70(1H,
d, J=2.2Hz), 7.64(1H, d, J=8.3Hz), 7.38(1H, dd, J=8.3, 2.2Hz),
6.94(1H, s), 6.51(1H, d, J=7.7Hz), 5.54(1H, br s), 4.95(2H, s),
4.43(2H, d, J=4.0Hz). 87 .sup.1H-NMR(DMSO-d.sub.6) .delta.:
7.96(1H, d, J=7.9Hz), 7.69(1H, d, J=1.9Hz), 7.63(1H, d, J=8.3Hz),
7.37(1H, dd, J=8.3, 1.9Hz), 6.74(1H, s), 6.49(1H, d, J=7.9Hz),
4.95(2H, s), 2.46(2H, d, J=7.0Hz), 1.91-1.77(1H, m), 0.91(6H, d,
J=6.5Hz). 88 .sup.1H-NMR(CDCl.sub.3) .delta.: 8.42(1H, d, J=7.0Hz),
7.65(1H, d, J=6.5Hz), 7.50(1H, s), 7.45-7.43(4H, m), 7.31(1H, d,
J=7.4Hz), 5.08(2H, s). 89 1H-NMR(DMSO-d.sub.6) .delta.: 8.76(1H, d,
J=8.1Hz), 7.92(1H, brs), 7.73(1H s), 7.63 (1H, d, J=8.4Hz),
7.3-7.5(1H, m), 6.5(1H, d, J=8.1Hz), 5.05(2H, s), 3.84(3H, s). 90
.sup.1H-NMR(DMSO-d.sub.6) .delta.: 8.42(1H, d, J=7.2Hz),
7.72-7.61(2H, m), 7.49-7.42(2H, m), 7.37(1H, d, J=6.4Hz), 7.30(1H,
d, J=7.2Hz), 5.06(2H, s). 91 .sup.1H-NMR(DMSO-d.sub.6) .delta.:
8.48(1H, d, J=6.5Hz), 7.70(1H, d, J=6.5Hz), 7.49(1H, dd, J=7.4,
1.4Hz), 7.43(1H, d, J=7.4Hz), 7.41(1H, d, J=6.5Hz), 7.36(1H, dd,
J=7.4, 1.4Hz), 7.30(1H, dd, J=7.9, 7.9Hz), 3.95(2H, t, J=7.2Hz),
2.84(2H, dd, J=9.3, 7.9Hz), 2.05-1.98(2H, m). 92
.sup.1H-NMR(DMSO-d.sub.6) .delta.: 8.58(1H, d, J=7.4Hz), 7.68(1H,
dd, J=7.0, 1.9Hz), 7.49-7.37(3H, m), 7.29(1H, s), 5.13(2H, s),
3.27(1H, d, J=6.5Hz), 1.26(6H, d, J=6.5Hz). 93
.sup.1H-NMR(DMSO-d.sub.6) .delta.: 8.76(1H, d, J=7.9Hz), 7.91(1H,
s), 7.51(1H, s), 7.43-7.34 (3H, m), 6.51(1H, d, J=7.9Hz), 5.07(2H,
s), 3.84(3H, s). 95 .sup.1H-NMR(DMSO-d.sub.6) .delta.: 8.50(1H, d,
J=7.0Hz), 7.72(1H, d, J=6.0Hz), 7.46(1H, d, J=7.0Hz), 7.45(1H, d,
J=6.0Hz), 7.33-7.28(2H, m), 7.25-7.19(1H, m), 3.95 (2H, t,
J=7.4Hz), 2.82(2H, td, J=7.4, 1.9Hz), 2.00-1.91(2H, m). 97
.sup.1H-NMR(DMSO-d.sub.6) .delta.: 7.76(1H, d, J=7.9Hz), 7.53(1H,
s), 7.43-7.34(3H, m), 7.24(1H, s), 6.61(1H, d, J=7.9Hz), 4.98(2H,
s), 3.06(3H, s), 3.01(3H, s). 98 .sup.1H-NMR(DMSO-d.sub.6) .delta.:
9.04(1H, d, J=8.1Hz), 7.94(1H, s), 7.51(1H, s), 7.43-7.33 (3H, m),
6.60(1H, d, J=8.1Hz), 5.08(2H, s). 99 .sup.1H-NMR(DMSO-d.sub.6- )
.delta.: 11.93(1H, s), 8.31(1H, dd, J=7.9, 1.9Hz), 8.23(1H, d, J=
8.8Hz), 7.95(1H, d, J=6.5Hz), 7.81(1H, ddd, J=8.8, 7.0, 1.9Hz),
7.53(1H, s), 7.48(1H, dd, J=7.9, 7.0Hz), 7.42-7.37(3H, m), 6.93(1H,
d, J=6.5Hz), 5.03(2H, s). 100 .sup.1H-NMR(DMSO-d.sub.6) .delta.:
8.52(1H, s), 7.47-7.18(5H, m), 6.83(1H, d, J=6.0Hz), 4.92(2H, s).
101 .sup.1H-NMR(DMSO-d.sub.6) .delta.: 9.28(1H, d, J=7.9Hz),
9.25(1H, s), 8.07(1H, s), 7.55(1H, s), 7.45-7.36(3H, m), 6.54(1H,
d, J=7.9Hz), 5.08(2H, s). 102 .sup.1H-NMR(DMSO-d.sub.6) .delta.:
8.00(1H, d, J=7.9Hz), 7.49(1H, s), 7.44-7.32(3H, m), 6.96(1H, s),
6.52(1H, d, J=7.9Hz), 5.61-5.50(1H, m), 4.96(2H, s), 4.45(2H, d,
J=4.2Hz). 103 .sup.1H-NMR(DMSO-d.sub.6) .delta.: 8.23(1H, d,
J=7.9Hz), 7.49(1H, s), 7.41-7.34(3H, m), 6.94(1H, s), 6.56(1H, d,
J=7.9Hz), 5.68(1H, s), 5.01(2H, s), 4.83(1H, d, J=6.5 Hz), 1.44(3H,
d, J=6.5Hz). 105 .sup.1H-NMR(DMSO-d.sub.6) .delta.: 8.78(1H, d,
J=8.3Hz), 8.16(1H, s), 7.54(1H, s), 7.48-7.32 (3H, m), 6.47(1H, d,
J=7.9Hz), 5.07(2H, s), 2.50(3H, s). 107 .sup.1H-NMR(DMSO-d.sub.6)
.delta.: 8.13(1H, s), 7.95(1H, d, J=7.4Hz), 7.52(1H, s), 7.45-7.30
(3H, m), 6.54(1H, d, J=7.4Hz), 4.95(2H, s). 108
.sup.1H-NMR(DMSO-d.sub.6) .delta.: 11.62(1H, s), 8.09(1H, s),
7.47-7.28(4H, m), 4.70(2H, s), 4.22-4.13(2H, m), 3.76-3.67(2H, m).
109 .sup.1H-NMR(DMSO-d.sub.6) .delta.: 8.85(1H, s), 7.45-7.28(4H,
m), 7.21(1H, d, J=6.5 Hz), 7.12(1H, d, J=6.0Hz), 4.99(2H, s),
3.50(3H, s). 110 .sup.1H-NMR(DMSO-d.sub.6) .delta.: 11.92(1H, s),
8.33(1H, s), 7.46(1H, s), 7.43-7.31(4H, m), 5.28-5.22(1H, m),
5.02(1H, d, J=15.3Hz), 4.54(1H, d, J=15.3Hz), 4.38-4.20(2H, m). 111
.sup.1H-NMR(DMSO-d.sub.6) .delta.: 12.22(1H, s), 8.21(1H, dd,
J=8.3, 1.4Hz), 7.78(1H, d, J= 8.8Hz), 7.71(1H, ddd, J=8.3, 7.4,
1.9Hz), 7.50(1H, s), 7.45-7.35(3H, m), 7.30 (1H, t, J=7.4Hz),
4.80(2H, s), 4.50-4.42(2H, m), 3.86-3.77(2H, m). 112
.sup.1H-NMR(DMSO-d.sub.6) .delta.: 8.48(1H, s), 7.87(1H, t,
J=1.6Hz), 7.72(1H, dt, J=7.4, 1.6Hz), 7.52-7.24(7H, m), 7.00(1H, d,
J=6.0Hz), 5.00(2H, s). 113 1H-NMR(DMSO-d.sub.6) .delta.: 8.47(1H,
s), 7.80(2H, d, J=8.4Hz), 7.3-7.6(7H, m), 7.02 (1H, d, J=6Hz),
5.01(2H, s). 114 H-NMR(DMSO-d.sub.6) .delta.: 8.23(1H, s),
7.3-7.6(8H, m), 7.26(1H, d, J=6Hz), 6.98 (1H, d, J=6Hz), 5.00(s,
2H). 115 .sup.1H-NMR(DMSO-d.sub.6) .delta.: 9.28(1H, s), 8.77(1H,
d, J=5.5Hz), 8.73-8.63(2H, m), 7.93(1H, dd, J=8.1, 5.5Hz), 7.50(1H,
s), 7.44-7.34(3H, m), 7.24(1H, dd, J=6.6, 1.7Hz), 6.98(1H, dd,
J=6.2, 1.7Hz), 5.01(2H, s). 116 .sup.1H-NMR(DMSO-d.sub.6) .delta.:
8.87(2H, d, J=6.8Hz), 8.83(1H, s), 8.47(2H, d, J=6.8 Hz), 7.50(1H,
s), 7.45-7.34(3H, m), 7.26(1H, d, J=6.4Hz), 6.99(1H, d, J=6.4 Hz),
5.00(2H, s). 117 .sup.1H-NMR(DMSO-d.sub.6) .delta.: 9.27(1H, s),
8.82(1H, d, J=5.1Hz), 8.65(1H, d, J=7.9Hz), 8.33(1H, t, J=7.9 Hz),
7.72(1H, t, J=5.9Hz), 7.52(1H, s), 7.47(1H, d, J= 6.2Hz),
7.44-7.35(3H, m), 7.11(1H, d, J=6.2Hz), 5.03(2H, s). 119
.sup.1H-NMR(CDCl.sub.3) .delta.: 7.69(1H, s), 7.67(2H, d, J=7.2Hz),
7.48-7.30(7H, m), 7.26-7.21(1H, m), 5.99(1H, br s), 4.94(2H, s),
2.42(2H, d, J=6.8Hz), 1.81-1.63 (5H, m), 1.35-0.89(6H, m). 120
.sup.1H-NMR(CDCl.sub.3) .delta.: 8.60(1H, s), 7.77(1H, s),
7.50-7.49(1H, m), 7.48(1H, d, J=6.0 Hz), 7.43-7.35(4H, m), 7.01(1H,
d, J=6.0Hz), 6.62(1H, dd, J=1.9, 3.2Hz), 4.98(2H, s). 121
.sup.1H-NMR(CDCl.sub.3) .delta.: 12.68(1H, s), 7.44(1H, d,
J=8.3Hz), 7.41(1H, d, J=1.9Hz), 7.18(1H, dd, J=8.3, 1.9Hz),
6.62(1H, s), 4.68(2H, s), 3.56(3H, s), 3.46(2H, t, J= 6.5Hz),
2.73(2H, t, J=6.5Hz). 122 .sup.1H-NMR(CDCl.sub.3) .delta.:
12.86(1H, s), 7.19-7.08(2H, m), 7.00-6.92(1H, m), 6.60(1H, s),
3.62(2H, t, J=7.2Hz), 3.54(3H, s), 3.52(2H, t, J=6.2Hz), 2.84(2H,
td, J=7.9, 2.1Hz), 2.77-2.71(2H, m), 1.97-1.85(2H, m). 124
.sup.1H-NMR(DMSO-d.sub.6) .delta.: 8.77(1H, s), 7.92(1H, s),
7.71(1H, d, J=7.2Hz), 7.57(1H, d, J=8.3Hz), 7.53(1H, d, J=6.4Hz),
7.52(1H, s), 7.43-7.24(5H, m), 7.00(1H, d, J=6.4Hz), 4.99(2H, s).
126 .sup.1H-NMR(DMSO-d.sub.6) .delta.: 8.23(1H, s), 7.52-7.47(2H,
m), 7.44-7.34(3H, m), 7.20(1H, d, J=6.0Hz), 5.04(2H, s), 0.90(9H,
s). 127 .sup.1H-NMR(DMSO-d.sub.6) .delta.: 8.20(1H, s), 7.83(1H, d,
J=7.4Hz), 7.74(1H, t, J=7.4 Hz), 7.64(1H, t, J=7.7Hz), 7.52(1H, s),
7.44-7.36(4H, m), 7.28(1H, d, J=6.5 Hz), 7.02(1H, d, J=6.5Hz),
5.01(2H, s). 128 .sup.1H-NMR(DMSO-d.sub.6) .delta.: 8.49(1H, s),
7.50(1H, s), 7.44-7.34(4H, m), 7.41(1H, d, J= 7.9Hz), 7.36(1H, d,
J=7.9Hz), 7.30(1H, d, J=7.4Hz), 7.08(1H, d, J=6.0Hz), 6.97(1H, dd,
J=7.9, 2.3Hz), 5.03(2H, s), 4.48(1H, br s), 3.80(3H, s). 129
.sup.1H-NMR(DMSO-d.sub.6) .delta.: 12.40(1H, br s), 8.43(1H, s),
7.48(1H, s), 7.43-7.30(3H, m), 6.79(1H, s), 5.03(2H, s), 3.31(1H,
sept, J=5.6Hz), 1.19(6H, d, J=5.6Hz). 130 .sup.1H-NMR(DMSO-d.sub.6)
.delta.: 7.68(1H, s), 7.62(1H, d, J=8.3Hz), 7.38(1H, d, J=8.3 Hz),
6.25-6.19(1H, m), 4.90-4.54(2H, m), 4.14-3.89(2H, m), 3.87-3.62(3H,
m), 2.86-2.71(2H, m), 1.18-1.08(7H, m). 131 .sup.1H-NMR(CDCl.sub.3)
.delta.: 7.94(1H, br s), 7.71-7.63(2H, m), 7.49-7.26(7H, m),
6.36(1H, br s), 5.05(2H, br s), 3.14(1H, br s), 1.36(6H, br s). 132
.sup.1H-NMR(DMSO-d.sub.- 6) .delta.: 8.43(1H, s), 7.51(1H, s),
7.48(1H, d, J=6.0Hz), 7.45-7.37(4H, m), 7.29(1H, dd, J=7.4, 1.4Hz),
7.23(1H, d, J=6.0Hz), 7.14(1H, d, J=7.9Hz), 7.05(1H, t, J=7.4Hz),
5.08(2H, s), 4.19(1H, br s), 3.74(3H, s). 133
.sup.1H-NMR(DMSO-d.sub.6) .delta.: 8.48(1H, s), 7.71(2H, d,
J=8.3Hz), 7.49(1H, s), 7.44-7.36 (4H, m), 7.10(1H, d, J=6.5Hz),
7.03(2H, d, J=8.8Hz), 5.04(2H, s), 4.02(1H, br s), 3.81(3H, s). 134
.sup.1H-NMR(DMSO-d.sub.6) .delta.: 8.38(1H, br s), 7.55-7.47(2H,
m), 7.44-7.33(3H, m), 7.33-7.24(1H, m), 5.07(2H, s), 2.61(2H, q,
J=7.5Hz), 1.17(3H, t, J=7.5Hz). 135 .sup.1H-NMR(DMSO-d.sub.6)
.delta.: 8.37(1H, s), 7.54(1H, s), 7.49-7.29(5H, m), 7.23(1H, t, J=
7.7Hz), 7.14(2H, d, J=7.4Hz), 5.09(2H, s), 2.03(6H, s). 136
.sup.1H-NMR(DMSO-d.sub.6) .delta.: 9.41(1H, br s), 8.27(1H, s),
7.49(1H, s), 7.43-7.35(3H, m), 7.26(1H, d, J=6.0Hz), 7.24(1H, dd,
J=2.8, 4.2Hz), 7.20(1H, d, J=7.9Hz), 7.09 (1H, d, J=7.9Hz),
6.89(1H, d, J=6.0Hz), 6.74(1H, dd, J=8.1, 2.6Hz), 4.98(2H, s). 137
.sup.1H-NMR(DMSO-d.sub.6) .delta.: 8.32(1H, s), 7.76(2H, dd, J=8.3,
1.6Hz), 7.62(1H, tt, J= 7.4, 1.6Hz), 7.52-7.34(6H, m), 7.27(1H, d,
J=6.5Hz), 6.93(1H, d, J=6.0Hz), 4.98(2H, s). 138
.sup.1H-NMR(DMSO-d.sub.6) .delta.: 8.39(1H, s), 7.13(1H, d,
J=7.3Hz), 6.84-6.84(9H, m), 5.07(2H, s), 2.44(1H, q, J=7.4Hz),
1.04(3H, t, J=7.4Hz). 139 .sup.1H-NMR(DMSO-d.sub.6) .delta.:
12.35(1H, s), 8.10(1H, s), 7.83(1H, t, J=1.9Hz), 7.64(1H, dt,
J=7.5, 1.4Hz), 7.50-7.34(6H, m), 6.78(1H, s), 5.04(2H, s),
3.47-3.35(1H, m), 1.22(6H, d, J=7.0Hz). 140
.sup.1H-NMR(DMSO-d.sub.6) .delta.: 8.18(1H, br s), 7.47(1H, br s),
7.42-7.30(4H, m), 7.29-7.22 (4H, m), 7.21-7.14(1H, m), 7.05(1H, br
s), 5.00(2H, s), 3.86(2H, s). 141 .sup.1H-NMR(DMSO-d.sub.6)
.delta.: 10.55(1H, s), 8.46(1H, br s), 7.50(1H, s), 7.44-7.33(5H,
m), 7.28(1H, t, J=7.2Hz), 7.08(1H, br s), 6.95-6.85(2H, m),
5.03(2H, s). 142 .sup.1H-NMR(DMSO-d.sub.6) .delta.: 8.57(1H, s),
7.63-7.57(2H, m), 7.51(1H, d, J=6.0Hz), 7.50(1H, s), 7.44-7.36(3H,
m), 7.25(1H, d, J=6.0Hz), 6.87(2H, d, J=8.8Hz), 5.07(2H, s). 143
.sup.1H-NMR(CDCl.sub.3) .delta.: 12.72(1H, s), 7.63-7.48(4H, m),
6.62(1H, s), 4.80(2H, s), 3.57 (3H, s), 3.47(2H, t, J=6.4Hz),
2.73(2H, t, J=6.4Hz). 144 .sup.1H-NMR(CDCl.sub.3) .delta.:
12.86(1H, s), 7.31-7.25(1H, m), 6.90-6.85(3H, m), 6.60(1H, t,
J=1.2Hz), 4.71(2H, s), 3.82(3H, s), 3.56(3H, s), 3.45(2H, t,
J=6.5Hz), 2.70 (2H, td, J=6.5, 0.9Hz). 145 1H-NMR(DMSO-d.sub.6)
.delta.: 7.2-7.5(5H, m), 6.39(1H, d, J=8.1Hz), 5.05(2H, s), 3.74
(3H, s). 146 .sup.1H-NMR(DMSO-d.sub.6) .delta.: 8.17(1H, s),
8.07(1H, d, J=7.4Hz), 7.53(1H, s), 7.42-7.35 (3H, m), 6.45(1H, d,
J=7.4Hz), 4.96(2H, s). 147 .sup.1H-NMR(DMSO-d.sub.6) .delta.:
11.64(1H, br s), 8.59(1H, s), 7.48(1H, br s), 7.43-7.33(3H, m),
7.31(1H, d, J=6.0Hz), 6.90(1H, d, J=6.5Hz), 4.93(2H, s), 3.77(3H,
s). 148 .sup.1H-NMR(DMSO-d.sub.6) .delta.: 12.00(1H, s), 8.61(1H,
s), 7.85(1H, d, J=1.9Hz), 7.81 (1H, d, J=1.9Hz), 7.51(1H, s),
7.45-7.33(4H, m), 7.05(1H, d, J=6.5Hz), 5.02 (2H, s), 3.79(3H, s).
149 .sup.1H-NMR(DMSO-d.sub.6) .delta.: 8.45(1H, s), 7.48(1H, br s),
7.44-7.31(4H, m), 6.93(1H, d, J=6.2Hz), 4.95(2H, s), 3.95(1H, sept,
J=6.8Hz), 1.05(6H, d, J=6.8Hz). 150 .sup.1H-NMR(DMSO-d.sub.6- )
.delta.: 8.50(1H, s), 7.47(1H, br s), 7.42-7.32(3H, m), 7.31(3H, d,
J=6.0Hz), 6.89(1H, d, J=6.0Hz), 5.06(1H, t, J=6.5Hz), 4.93(2H, s),
1.28(6H, d, J=6.5Hz). 151 .sup.1H-NMR(DMSO-d.sub.6) .delta.:
8.48(1H, d, J=7.4Hz), 7.70(1H, d, J=6.0Hz), 7.45(4H, s), 7.43(1H,
d, J=6.5Hz), 7.41(1H, d, J=7.0Hz), 5.08(2H, s). 152
.sup.1H-NMR(DMSO-d.sub.6) .delta.: 15.97(1H, s), 12.21(1H, s),
8.92(1H, s), 7.58(1H, d, J=6.5 Hz), 7.50(1H, s), 7.45-7.32(3H, m),
7.20(1H, d, J=6.5Hz), 5.02(2H, s). 153 .sup.1H-NMR(DMSO-d.sub.6)
.delta.: 8.14(1H, s), 7.48(1H, s), 7.44-7.30(3H, m), 7.20(1H, d, J=
6.0Hz), 6.91(1H, d, J=6.5Hz), 4.96(2H, s), 2.95(3H, s), 2.85(3H,
s). 155 .sup.1H-NMR(DMSO-d.sub.6) .delta.: 11.83(1H, s), 10.00(1H,
d, J=5.1Hz), 8.77(1H, s), 7.56-7.46(2H, m), 7.45-7.32(3H, m),
7.01(1H, d, J=6.0Hz), 4.97(2H, s), 2.86 (3H, d, J=5.1Hz). 156
.sup.1H-NMR(DMSO-d.sub.6) .delta.: 8.13(1H, s), 7.49(1H, s),
7.44-7.30(3H, m), 7.18(1H, d, J= 6.0Hz), 6.89(1H, d, J=6.5Hz),
4.96(2H, s), 3.40(2H, q, J=7.1Hz), 3.16(2H, q, J=7.3Hz), 1.12(3H,
t, J=7.0Hz), 1.03(3H, t, J=7.2Hz). 157 .sup.1H-NMR(DMSO-d.sub.6)
.delta.: 8.40(1H, d, J=7.2Hz), 7.63(1H, d, J=6.3Hz), 7.58(2H, d,
J=8.6Hz), 7.38(2H, d, J=8.6Hz), 7.34(1H, d, J=6.3Hz), 7.27(1H, d,
J=7.2 Hz), 5.05(2H, s). 158 .sup.1H-NMR(DMSO-d.sub.6) .delta.:
8.42(1H, d, J=7.0Hz), 7.66-7.63(2H, m), 7.54(1H, d, J= 7.9Hz),
7.42(1H, d, J=7.9Hz), 7.37(1H, t, J=3.0Hz), 7.34(1H, d, J=7.9Hz),
7.29(1H, d, J=7.0Hz), 5.08(2H, s). 159 .sup.1H-NMR(DMSO-d.sub.6)
.delta.: 11.59(1H, br s), 8.53(1H, s), 7.48(1H, s), 7.43-7.32(4H,
m), 6.91(1H, d, J=6.5Hz), 4.94(2H, s), 3.91(2H, s), 0.99(9H, s).
160 .sup.1H-NMR(DMSO-d.sub.6) .delta.: 11.58(1H, s), 8.51(1H, s),
7.48(1H, s), 7.43-7.30(4H, m), 6.91(1H, br s), 4.94(2H, s),
4.91-4.84(1H, m), 1.88-1.69(4H, m), 1.57-1.25(6H, m). 162
.sup.1H-NMR(acetone-d.sub.6) .delta.: 8.06(1H, d, J=7.9Hz),
7.50(1H, s), 7.46-7.32(3H, m), 6.67(1H, s), 6.49(1H, d, J=7.9Hz),
5.11(2H, s), 2.57(3H, s). 163 .sup.1H-NMR(DMSO-d.sub.6) .delta.:
9.10(1H, s), 7.97(1H, d, J=3.2Hz), 7.74(1H, d, J=3.2 Hz), 7.58(1H,
d, J=6.0Hz), 7.51(1H, s), 7.44-7.35(3H, m), 7.05(1H, d, J=6.0 Hz),
5.00(2H, s). 164 .sup.1H-NMR(DMSO-d.sub.6) .delta.: 8.94(1H, s),
8.23(1H, s), 7.53(1H, d, J=6.5Hz), 7.51(1H, s), 7.44-7.35(3H, m),
7.04(1H, d, J=6.5Hz), 5.00(2H, s). 166 .sup.1H-NMR(DMSO-d.sub.6)
.delta.: 8.49(1H, d, J=7.4Hz), 7.71-7.62(1H, m), 7.42-7.28(3H, m),
7.21(1H, d, J=1.9Hz), 7.06(1H, dd, J=8.3, 1.9Hz), 5.02(2H, s),
3.92(3H, s). 167 .sup.1H-NMR(DMSO-d.sub.6) .delta.: 11.80(1H, br
s), 9.43(1H, d, J=4.2Hz), 8.76(1H, s), 7.68 (1H, d, J=3.7Hz),
7.48(2H, d, J=6.0Hz), 7.44-7.31(3H, m), 7.00(1H, d, J=6.0 Hz),
4.97(2H, s). 168 .sup.1H-NMR(DMSO-d.sub.6) .delta.: 8.35(1H, d,
J=7.0Hz), 7.57(1H, d, J=6.5Hz), 7.47(1H, dd, J=7.9, 1.4Hz),
7.29(1H, d, J=6.5Hz), 7.20(1H, d, J=6.0Hz), 7.18-7.13(2H, m),
5.10(2H, s), 3.87(3H, s). 169 .sup.1H-NMR(DMSO-d.sub.6) .delta.:
8.39(1H, d, J=7.0Hz), 7.63(1H, d, J=6.5Hz), 7.40(1H, dd, J=8.0,
1.3Hz), 7.32-7.24(3H, m), 7.16(1H, dd, J=8.0, 1.3Hz), 6.96(1H, td,
J=7.7, 1.4Hz), 4.38-4.30(4H, m). 170 .sup.1H-NMR(DMSO-d.sub.6)
.delta.: 8.93-8.92(2H, m), 8.66(1H, s), 7.52-7.47(2H, m), 7.44-7.35
(4H, m), 6.97(1H, d, J=6.0Hz), 4.98(2H, s). 171
1H-NMR(DMSO-d.sub.6) .delta.: 11.81(1H, s), 10.18(1H, t, J=5.8Hz),
8.75(1H, s), 7.53-7.33(5H, m), 7.01(1H, d, J=6.0Hz), 4.97(2H, s),
3.34-3.28(2H, m), 1.59-1.46(2H, m), 0.91(3H, t, J=7.4Hz). 172
1H-NMR(DMSO-d.sub.6) .delta.: 11.80(1H, s), 10.16(1H, t, J=5.6Hz),
8.75(1H, s), 7.53-7.33(5H, m), 7.01(1H, d, J=6.0Hz), 4.97(2H, s),
3.35-3.29(2H, m), 1.55-1.28(4H, m), 0.91(3H, t, J=7.4Hz). 173
.sup.1H-NMR(DMSO-d.sub.6) .delta.: 11.81(1H, s), 10.26(1H, t,
J=5.6Hz), 8.76(1H, s), 7.54-7.47(2H, m), 7.43-7.33(3H, m), 7.01(1H,
d, J=6.0Hz), 4.97(2H, s), 3.18 (2H, t, J=6.3Hz), 1.86-1.74(1H, m),
0.92(6H, d, J=7.0Hz). 174 .sup.1H-NMR(DMSO-d.sub.6) .delta.:
11.87(1H, brs), 10.44(1H, t, J=5.5Hz), 8.76(1H, s), 7.2-7.7(5H, m),
7.01(1H, d, J=6.3Hz), 5.00(2H, s), 4.17(2H, d, J=5.4Hz), 3.66(s,
3H). 175 .sup.1H-NMR(DMSO-d.sub.6) .delta.: 11.82(1H, s), 10.12(1H,
t, J=5.7Hz), 8.76(1H, s), 7.3-7.7 (5H, m), 7.01(1H, d, J=6Hz),
4.97(2H, s), 3.3-3.5(2H, m), 1.14(3H, t, J=7Hz). 176
.sup.1H-NMR(DMSO-d.sub.6) .delta.: 11.78(1H, s), 10.25(1H, d,
J=5.6Hz), 8.75(1H, s), 7.56-7.44(2H, m), 7.43-7.29(3H, m), 7.01(1H,
d, J=6.0Hz), 4.96(2H, s), 3.50-3.46(4H, m), 3.29(3H, s). 177
.sup.1H-NMR(DMSO-d.sub.6) .delta.: 10.35(1H, br s), 8.76(1H, s),
7.57-7.45(2H, m), 7.43-7.29 (3H, m), 7.01(1H, d, J=6.5Hz), 4.97(2H,
s), 4.52(2H, t, J=5.3Hz), 3.73(2H, q, J=5.6Hz). 178
.sup.1H-NMR(DMSO-d.sub.6) .delta.: 11.80(1H, s), 10.24(1H, t,
J=5.6Hz), 8.75(1H, s), 7.56-7.46(2H, m), 7.45-7.30(3H, m), 7.01(1H,
d, J=6.0Hz), 4.97(2H, s), 4.81 (1H, t, J=5.6Hz), 3.51(2H, q,
J=5.6Hz), 3.39(2H, q, J=5.6Hz). 179 .sup.1H-NMR(DMSO-d.sub.6)
.delta.: 8.27(1H, d,
J=7.4Hz), 7.49(1H, d, J=6.0Hz), 7.34(1H, dd, J=8.0, 1.6Hz),
7.17(1H, d, J=7.0Hz), 7.07(1H, d, J=6.0Hz), 7.01(1H, d, J=7.4Hz),
6.86(1H, t, J=7.7Hz), 5.01(2H, s). 180 .sup.1H-NMR(DMSO-d.sub.6)
.delta.: 11.84(1H, br s), 10.56(1H, t, J=6.0Hz), 8.80(1H, s),
7.54-7.03(11H, m), 4.98(2H, s), 4.57(2H, d, J=6.0Hz). 181
.sup.1H-NMR(DMSO-d.sub.6) .delta.: 11.92(1H, s), 10.66(1H, t,
J=6.5Hz), 8.82(1H, s), 7.53 (1H, d, J=6.0Hz), 7.49(1H, s),
7.43-7.35(3H, m), 7.05(1H, d, J=6.0Hz), 4.98 (2H,s), 4.34-4.14(2H,
m). 182 .sup.1H-NMR(DMSO-d.sub.6)(mixture of two isomers) .delta.:
8.14(1H, s), 7.48(1H, s), 7.45-7.30 (3H, m), 7.21(1H, s),
6.98-6.84(1H, m), 4.96(2H, s), 3.57-3.04 (2H, m), 2.92(1.2H, s),
2.82(1.8H, s), 1.56-1.09(4H, m), 0.92(1.8H, t, J=7.2 Hz),
0.77(1.2H, t, J=7.4Hz). 183 .sup.1H-NMR(DMSO-d.sub.6)(mixture of
two isomers) .delta.: 8.16(0.5H, s), 8.12 (0.5H, s), 7.49(1H, s),
7.44-7.29(3H, m), 7.22(1H, d, J=6.5Hz), 6.91(1H, d, J= 6.0Hz),
4.96(2H, s), 3.67-3.33(4H, m), 3.29(1.5H, s), 3.17(1.5H, s),
2.96(1.5H, s), 2.89(1.5H, s). 184 .sup.1H-NMR(DMSO-d.sub.6)
.delta.: 8.18(1H, s), 7.48(1H, s), 7.43-7.30(3H, m), 7.21(1H, d, J=
6.0Hz), 6.91(1H, d, J=6.0Hz), 4.96(2H, s), 3.43-3.29(4H, m),
1.87-1.78(4H, m). 185 .sup.1H-NMR(DMSO-d.sub.6) .delta.: 8.18(1H,
s), 7.47(1H, s), 7.44-7.29(3H, m), 7.20(1H, d, J= 6.0Hz), 6.91(1H,
d, J=6.5Hz), 4.96(2H, s), 3.65-3.50(6H, m), 3.26-3.17(2H, m). 186
.sup.1H-NMR(DMSO-d.sub.6) .delta.: 8.46-8.45(1H, m), 7.67-7.66(1H,
m), 7.42(1H, d, J=8.3 Hz), 7.39-7.36(2H, m), 7.23(1H, d, J=1.9Hz),
6.98(1H, dd, J=7.9, 1.9Hz), 5.06 (2H, s), 3.86(3H, s). 188
.sup.1H-NMR(DMSO-d.sub.6) .delta.: 16.33(1H, br s), 12.00(1H, br
s), 9.05(1H, s), 7.54-7.50 (2H, m), 7.44-7.35(3H, m), 7.03(1H, d,
J=6.5Hz), 5.00(2H, s). 190 .sup.1H-NMR(DMSO-d.sub.6) .delta.:
7.94(1H, s), 7.47(1H, br s), 7.42-7.31(3H, m), 7.25(1H, d,
J=6.0Hz), 6.86(1H, d, J=6.5Hz), 4.96(2H, s), 3.49(2H, s), 3.06(3H,
s), 2.82(3H, s). 192 .sup.1H-NMR(DMSO-d.sub.6) .delta.: 11.80(1H,
br s), 10.26(1H, t, J=5.6Hz), 8.76(1H, s), 7.55-7.29(5H, m),
7.01(1H, d, J=6.5Hz), 4.97(2H, s), 4.83(1H, d, J=4.2Hz),
3.82-3.69(1H, m), 3.46-3.14(2H, m), 1.08(3H, d, J=6.0Hz). 193
1H-NMR(DMSO-d.sub.6) .delta.: 11.85(1H, brs), 10.3-10.5(1H, m),
8.76(1H, s), 7.3-7.7(5H, m), 7.01(1H, d, J=6.6Hz), 4.98(2H, s),
4.06(2H, d, J=5.1Hz). 194 1H-NMR(DMSO-d.sub.6) .delta.: 11.8(1H,
brs), 10.4-10.6(1H, m), 8.75(1H, s), 7.3-7.6(5H, m), 6.9-7.1(1H,
m), 4.96(2H, s), 4.21(2H, d, J=4Hz), 2.98(3H, s), 2.87(3H, s). 195
1H-NMR(DMSO-d.sub.6) .delta.: 11.8(1H, brs), 10.3-10.5(1H, m),
8.76(1H, s), 7.8-8.0(1H, m), 7.3-7.6(5H, m), 6.9-7.1(1H, m),
4.97(2H, s), 3.96(2H, d, J=5.4Hz), 2.61(3H, d, J=5Hz). 196
1H-NMR(DMSO-d.sub.6) .delta.: 12.64(1H, s), 11.9(1H, brs), 8.90(1H,
s), 7.70(2H, d, J= 7.8Hz), 7.3-7.65(7H, m), 7.0-7.2(2H, m), 5.0(2H,
s). 197 .sup.1H-NMR(DMSO-d.sub.6) .delta.: 8.73(1H, s), 8.24(1H,
s), 7.49(1H, s), 7.44-7.34(5H, m), 6.97(1H, d, J=6.5Hz), 4.97(2H,
s). 198 .sup.1H-NMR(DMSO-d.sub.6)(mixture of two isomers) .delta.:
8.21(0.5H, s), 8.18(0.5H, s), 7.48 (1H, s), 7.43-7.30(3H, m),
7.28-7.20(1H, m), 6.93(1H, d, J=6.0Hz), 4.96(2H, s), 4.31(0.5H, br
s), 4.23(0.5H, br s), 3.55-3.01(2H, m), 2.02-1.71(2H, m). 199
.sup.1H-NMR(CF.sub.3COOD) .delta.: 9.44(1H, s), 7.72(1H, d,
J=6.0Hz), 7.57-7.33(5H, m), 5.31(2H, s), 4.80(2H, s), 2.59(3H, s).
200 .sup.1H-NMR(DMSO-d.sub.6) .delta.: 10.52(1H, s), 8.44(1H, d,
J=7.4Hz), 7.63(1H, d, J=6.0 Hz), 7.58(2H, d, J=7.4Hz),
7.38-7.23(4H, m), 7.08(1H, t, J=7.4Hz), 4.78(2H, s). 201
.sup.1H-NMR(DMSO-d.sub.6) .delta.: 8.25-8.18(1H, m), 7.47(1H, s),
7.45-7.31(3H, m), 7.30-7.21 (1H, m), 6.98-6.89(1H, m), 4.96(2H, s),
3.95-3.68(4H, m), 2.70-2.50(2H, m). 202 .sup.1H-NMR(DMSO-d.sub.6)
.delta.: 8.45(1H, d, J=7.2Hz), 7.63(1H, d, J=6.4Hz), 7.37-7.30 (4H,
m), 7.09(1H, d, J=9.0Hz), 4.98(2H, s), 3.84(3H, s). 203
.sup.1H-NMR(DMSO-d.sub.6) .delta.: 11.65(1H, br s), 8.94(1H, br s),
8.18(1H, s), 7.48(1H, br s), 7.43-7.32(4H, m), 6.96(1H, d,
J=6.5Hz), 4.98(2H, s), 3.02(3H, s). 204 .sup.1H-NMR(DMSO-d.sub.6)
.delta.: 11.69(1H, br s), 8.48(1H, s), 7.47(1H, br s),
7.40-7.33(4H, m), 6.93(1H, d, J=6.0Hz), 4.94(2H, s), 2.61(3H, s).
206 .sup.1H-NMR(DMSO-d.sub.6) .delta.: 7.94(1H, d, J=7.4Hz),
7.45(2H, d, J=7.1Hz), 7.33(2H, t, J=7.4Hz), 7.26(1H, t, J=7.2Hz),
7.20(1H, d, J=6.5Hz), 6.76(1H, d, J=6.0 Hz), 6.67(1H, d, J=16.2Hz),
6.48(1H, d, J=7.4Hz), 6.36(1H, dt, J=16.2, 6.0 Hz), 4.53(2H, dd,
J=6.0, 0.9Hz). 207 .sup.1H-NMR(DMSO-d.sub.6) .delta.: 11.82(1H, s),
10.00(1H, d, J=4.6Hz), 8.76(1H, s), 7.66 (1H, d, J=7.4Hz), 7.52(1H,
d, J=6.5Hz), 7.42(2H, dd, J=6.5, 1.4Hz), 7.01(1H, d, J=6.0Hz),
4.95(2H, s), 2.86(3H, d, J=4.6Hz). 208 .sup.1H-NMR(DMSO-d.sub.6)
.delta.: 8.14(1H, s), 7.65(1H, d, J=7.4Hz), 7.42(2H, dd, J=6.7,
1.6Hz), 7.19(1H, d, J=6.5Hz), 6.90(1H, d, J=6.5Hz), 4.94(2H, s),
2.95(3H, s), 2.85(3H, s). 209 1H-NMR(DMSO-d.sub.6) .delta.:
11.8(1H, brs), 10.3-10.5(1H, m), 8.77(1H, s), 7.3-7.6(5H, m),
7.01(1H, d, J=6.3Hz), 4.97(2H, s), 3.75-3.9(2H, m), 3.2-3.5(2H, m),
3.02(3H, s). 210 .sup.1H-NMR(DMSO-d.sub.6) .delta.: 11.84(1H, s),
10.18(1H, t, J=6.0Hz), 8.75(1H, s), 7.54-7.46(2H, m), 7.43-7.32(3H,
m), 7.01(1H, d, J=6.0Hz), 4.97(2H, s), 3.52-3.32(6H, m), 2.18(2H,
t, J=8.1Hz), 1.97-1.84(2H, m). 211 .sup.1H-NMR(DMSO-d.sub.6)
.delta.: 11.68(1H, br s), 8.29(1H, s), 7.47(1H, br s),
7.42-7.30(3H, m), 7.26(1H, d, J=6.5Hz), 6.93(1H, d, J=6.0Hz),
4.97(2H, s), 3.18(3H, s), 3.07(3H, s). 212
.sup.1H-NMR(DMSO-d.sub.6) .delta.: 8.45(1H, d, J=7.4Hz), 7.67(1H,
d, J=6.0Hz), 7.37(2H, t, J=7.0Hz), 7.06(1H, d, J=1.4Hz),
7.01-6.97(2H, m), 5.04(2H, s), 3.78(3H, s). 213
.sup.1H-NMR(DMSO-d.sub.6) .delta.: 11.90(1H, br s), 10.70(1H, t,
J=6.0Hz), 8.78(1H, s), 8.67 (2H, d, J=6.0Hz), 7.61(2H, d, J=5.6Hz),
7.52(1H, d, J=6.5Hz), 7.49(1H, br s), 7.44-7.33(3H, m), 7.04(1H, d,
J=6.5Hz), 4.98(2H, s), 4.73(2H, d, J=6.0Hz). 214
.sup.1H-NMR(DMSO-d.sub.6) .delta.: 11.83(1H, br s), 10.55(1H, t,
J=5.9Hz), 8.79(1H, br s), 7.49(1H, br s), 7.43-7.31(6H, m),
7.15(3H, t, J=9.0Hz), 4.97(2H, s), 4.54(3H, d, J=5.9Hz). 215
.sup.1H-NMR(DMSO-d.sub.6) .delta.: 12.32(1H, br s), 8.71(1H, s),
7.90(1H, d, J=3.2Hz), 7.64 (1H, d, J=3.2Hz), 7.48(1H, s),
7.45-7.33(3H, m), 4.76(2H, s), 4.47(2H, t, J=5.6 Hz), 3.80(2H, t,
J=5.6Hz). 216 .sup.1H-NMR(DMSO-d.sub.6) .delta.: 7.97(1H, s),
7.49(1H, s), 7.45-7.24(4H, m), 6.87(1H, d, J=6.0 Hz), 5.23(1H, t,
J=3.7Hz), 4.96(2H, s), 4.42(2H, d, J=3.7Hz). 217
.sup.1H-NMR(DMSO-d.sub.6) .delta.: 8.09(1H, s), 7.67(1H, d,
J=7.5Hz), 7.45-7.40(2H, m), 7.23(1H, d, 6.3Hz), 6.94(1H, d,
J=6.2Hz), 4.95(2H, s), 1.19(9H, s). 218 .sup.1H-NMR(DMSO-d.sub.6)
.delta.: 9.09(1H, s), 8.98(1H, s), 8.51(1H, s), 7.50(1H, s),
7.44-7.34(3H, m), 7.25(1H, d, J=6.5Hz), 7.01(1H, d, J=6.5Hz),
5.00(2H, s). 220 .sup.1H-NMR(DMSO-d.sub.6) .delta.: 7.81(1H, s),
7.45(1H, br s), 7.43-7.30(3H, m), 4.72(2H, s), 4.29-4.20(2H, m),
3.77-3.69(2H, m), 2.93(3H, s), 2.85(3H, s). 221
.sup.1H-NMR(DMSO-d.sub.6) .delta.: 7.74(1H, s), 7.62(1H, dd, J=7.4,
1.4Hz), 7.43-7.38(2H, m), 4.69(2H, s), 4.25(2H, t, J=5.6Hz),
3.73(2H, t, J=5.6Hz), 1.20(9H, s). 224 .sup.1H-NMR(DMSO-d.sub.6)
.delta.: 10.48(1H, br s), 8.43(1H, d, J=7.0Hz), 7.62(1H, d, J=
6.0Hz), 7.30-7.19(3H, m), 6.90(1H, d, J=2.3Hz), 6.85(1H, dd, J=8.1,
2.3Hz), 4.95(2H, s). 225 .sup.1H-NMR(DMSO-d.sub.6) .delta.:
12.29(1H, br s), 8.70(1H, s), 7.89(1H, d, J=3.2Hz), 7.65 (1H, s),
7.63(2H, d, J=3.2Hz), 7.41(2H, d, J=8.8Hz), 4.73(2H, s), 4.46(2H,
t, J=5.6Hz), 3.79(2H, t, J=5.6Hz). 226 .sup.1H-NMR(DMSO-d.sub.6)
.delta.: 8.25(1H, d, J=7.0Hz), 7.63-7.37(6H, m), 7.05-6.96(2H, m),
4.38(2H, s), 3.22(3H, s). 227 .sup.1H-NMR(DMSO-d.sub.6) .delta.:
12.25(1H, s), 9.86(1H, q, J=4.6Hz), 8.37(1H, s), 7.63 (1H, d,
J=7.4Hz), 7.44-7.37(2H, m), 4.70(2H, s), 4.42-4.36(2H, m),
3.79-3.71 (2H, m), 2.82(3H, d, J=4.6Hz). 228
.sup.1H-NMR(DMSO-d.sub.6) .delta.: 7.81(1H, s), 7.62(1H, dd, J=6.0,
3.0Hz), 7.42-7.40(2H, m), 4.70(2H, s), 4.23(2H, t, J=6.0Hz),
3.73(2H, t, J=5.7Hz), 2.93(6H, s), 2.86 (6H, s). 229
.sup.1H-NMR(DMSO-d.sub.6) .delta.: 8.05(1H, s), 7.50-7.46(1H, m),
7.43-7.31(3H, m), 7.26(1H, d, J=6.0Hz), 6.91(1H, d, J=6.0Hz),
4.95(2H, s), 4.16(2H, s), 1.97(3H, s), 1.25(6H, s). 230
.sup.1H-NMR(DMSO-d.sub.6) .delta.: 11.64(1H,br s), 7.95(1H, s),
7.50-7.46(1H, m), 7.43-7.32 (3H, m), 7.24(1H, d, J=6.0Hz), 6.91(1H,
d, J=6.0Hz), 4.98-4.90(3H, m), 3.49 (2H, d, J=4.6Hz), 1.13(6H, s).
231 .sup.1H-NMR(DMSO-d.sub.6) .delta.: 11.65(1H, br s), 9.89(1H, d,
J=1.9Hz), 8.89(1H, s), 8.72-8.67(1H, m), 8.59(1H, d, J=2.3Hz),
7.50(2H, s), 7.44-7.33(3H, m), 6.96 (1H, d, J=6.0Hz), 4.97(2H, s).
232 1H-NMR(DMSO-d.sub.6) .delta.: 8.39(1H, s), 8.00(1H, s),
7.50(1H, s), 7.2-7.5(4H, m), 6.95 (1H, d, J=6.3Hz), 4.99(2H, s),
3.76(3H, s). 233 .sup.1H-NMR(DMSO-d.sub.- 6) .delta.: 10.37(1H, t,
J=6.0Hz), 8.77(1H, s), 7.52(1H, d, J=6.5 Hz), 7.49(1H, s),
7.42-7.33(3H, m), 7.02(1H, d, J=6.0Hz), 4.97(2H, s), 4.60(1H, t,
J=5.1Hz), 4.48(1H, t, J=5.1Hz), 3.69(1H, q, J=5.1Hz), 3.62(1H, q,
J=5.1Hz). 234 .sup.1H-NMR(DMSO-d.sub.6) .delta. (mixture of two
isomers): 8.27(0.3H, s), 8.25(0.7H, s), 7.51-7.14(10H, m),
6.92(0.7H, d, J=5.6Hz), 6.89(0.3H, d, J=6.5Hz), 4.97(1.4H, s),
4.95(0.6H, s), 4.68(1.4H, s), 4.39(0.6H, s), 2.82(2.1H, s),
2.80(0.9H, s). 235 .sup.1H-NMR(DMSO-d.sub.6) .delta.: 11.66(1H, br
s), 8.20(1H, s), 7.48(1H, br s), 7.44-7.16(9H, m), 6.89(1H, d,
J=6.0Hz), 4.96(2H, s). 236 .sup.1H-NMR(DMSO-d.sub.6) .delta.:
11.88(1H, br s), 8.41(1H, s), 7.83-7.76(2H, m), 7.57-7.48 (4H, m),
7.46(1H, br s), 7.41-7.30(3H, m), 6.96(1H, d, J=6.0Hz), 5.00(1H, d,
J=15.3Hz), 4.90(1H, d, J=15.3Hz). 237 .sup.1H-NMR(DMSO-d.sub.6)
.delta.: 11.90(1H, br s), 8.85(1H, s), 7.99(2H, d, J=7.4Hz), 7.68
(1H, t, J=7.4Hz), 7.59(2H, t, J=7.7Hz), 7.46(1H, d, J=6.5Hz),
7.45(1H, br s), 7.42-7.29(3H, m), 6.97(1H, d, J=6.5Hz), 4.94(2H,
s). 238 1H-NMR(DMSO-d.sub.6) .delta.: 12.1(1H, brs), 7.73(1H, s),
7.6-7.7(2H, m), 7.3-7.5(1H, m), 4.71(2H, s), 4.2-4.3(2H, m),
3.7-3.8(2H, m), 1.20(9H, s). 239 .sup.1H-NMR(DMSO-d.sub.6) .delta.:
11.59(1H, br s), 9.31(1H, s), 9.13(1H, s), 7.49(1H, s), 7.45 (1H,
d, J=6.0Hz), 7.42-7.31(3H, m), 6.98(1H, d, J=6.0Hz), 4.98(2H, s),
3.33 (4H, s), 2.94(1H, sept, J=7.0Hz), 1.09(6H, d, J=7.0Hz). 240
.sup.1H-NMR(DMSO-d.sub.6) .delta.: 11.58(1H, br s), 9.45(1H, s),
9.08(1H, s), 7.67(1H, d, J=6.0 Hz), 7.47(1H, d, J=6.5Hz),
7.45-7.40(2H, m), 6.96(1H, d, J=6.0Hz), 4.96 (2H, s), 2.17(3H, s).
241 .sup.1H-NMR(DMSO-d.sub.6) .delta.: 7.95(1H, s), 7.67(1H, d,
J=7.9Hz), 7.43(2H, dd, J=7.9, 0.9Hz), 7.05(1H, s), 4.96(2H, s),
4.46(2H, s), 1.20(9H, s). 243 .sup.1H-NMR(DMSO-d.sub.6) .delta.:
11.60(1H, s), 9.60(1H, s), 9.09(1H, s), 7.49-7.22(10H, m), 6.96(1H,
d, J=6.5Hz), 4.97(2H, s), 3.86(2H, s). 245
.sup.1H-NMR(DMSO-d.sub.6) .delta.: 7.91(1H, s), 7.48(1H, br s),
7.43-7.28(4H, m), 6.92(1H, d, J=5.9Hz), 4.98(2H, s), 2.35(3H, s).
246 .sup.1H-NMR(DMSO-d.sub.6- ) .delta.: 12.01(1H, br s), 8.65(1H,
s), 7.50-7.44(2H, m), 7.44-7.31 (3H, m), 6.99(1H, d, J=6.5Hz),
4.96(2H, s), 3.27(3H, s). 247 .sup.1H-NMR(DMSO-d.sub.6) .delta.:
11.91(1H, br s), 8.21(1H, s), 7.55(1H, d, J=6.0Hz), 7.48 (1H, br
s), 7.44-7.32(3H, m), 6.98(1H, d, J=6.0Hz), 5.00(1H, d, J=15.3Hz),
4.95(1H, d, J=15.3Hz), 2.82(3H, s). 248 .sup.1H-NMR(DMSO-d.sub.6)
.delta.: 12.29(1H, s), 8.63(1H, s), 7.56(1H, s), 7.48(1H, s),
7.45-7.33(3H, m), 4.75(2H, s), 4.44(2H, t, J=5.6Hz), 3.79(2H, t,
J=5.6Hz), 2.47(3H, s). 250 .sup.1H-NMR(DMSO-d.sub.6) .delta.:
8.46(1H, d, J=7.4Hz), 7.69(1H, d, J=6.5Hz), 7.50-7.45 (2H, m),
7.42-7.38(2H, m), 7.23-7.21(2H, m), 5.07(2H, s). 252
.sup.1H-NMR(CDCl.sub.3) .delta.: 9.11(1H, s), 7.97(1H, d, J=3.4Hz),
7.74(1H, d, J=3.4Hz), 7.58(1H, d, J=6.4Hz), 7.49(2H, dd, J=8.7,
5.7Hz), 7.22(2H, t, J=8.9Hz), 7.05 (1H, d, J=6.4Hz), 4.98(2H, s).
253 .sup.1H-NMR(DMSO-d.sub.6) .delta.: 11.91(1H, s), 10.01(1H, d,
J=4.5Hz), 8.77(1H, s), 7.53 (1H, d, J=6.4Hz), 7.47(2H, dd, J=8.3,
5.7Hz), 7.21(2H, t, J=8.9Hz), 7.02(1H, d, J=6.0Hz), 4.95(2H, s),
2.86(3H, d, J=4.9Hz). 254 .sup.1H-NMR(DMSO-d.sub.6) .delta.:
8.08(1H, s), 7.35-7.25(2H, m), 7.24-7.13(2H, m), 6.94(1H, d,
J=6.5Hz), 3.83(2H, t, J=7.4Hz), 2.79(2H, t, J=7.7Hz), 1.99-1.83(2H,
m), 1.20(9H, s). 255 .sup.1H-NMR(DMSO-d.sub.6) .delta.: 12.30(1H,
s), 8.64(1H, s), 7.48(1H, s), 7.44-7.34(3H, m), 7.18(1H, d,
J=0.9Hz), 4.75(2H, s), 4.47(2H, t, J=5.6Hz), 3.79(2H, t, J=5.6 Hz),
2.42(3H, s). 256 .sup.1H-NMR(DMSO-d.sub.6) .delta.: 11.60(1H, s),
9.34(1H, s), 9.13(1H, s), 7.51-7.45(2H, m), 7.43-7.34(3H, m),
6.97(1H, d, J=6.5Hz), 4.98(2H, s), 2.48(2H, q, J=10.0Hz), 1.60(2H,
q, J=7.3Hz), 0.91(3H, t, J=7.4Hz). 257 .sup.1H-NMR(DMSO-d.sub.6)
.delta.: 11.73(1H, s), 9.52(1H, s), 9.21(1H, s), 7.96(2H, d, J=6.8
Hz), 7.67-7.56(4H, m), 7.51(1H, s), 7.44-7.36(3H, m), 7.04(1H, d,
J=6.5Hz), 5.01(2H, s). 258 .sup.1H-NMR(DMSO-d.sub.6) .delta.:
11.59(1H, s), 9.47(1H, s), 9.13(1H, s), 7.50-7.46(2H, m),
7.43-7.34(3H, m), 7.29-7.24(4H, m), 7.19-7.14(1H, m), 6.97(1H, d,
J=6.0Hz), 4.98(2H, s), 2.92-2.81(4H, m). 259
.sup.1H-NMR(DMSO-d.sub.6) .delta.: 11.67(1H, br s), 8.33(1H, s),
7.49(1H, s), 7.44-7.33(3H, m), 7.13(1H, d, J=6.0Hz), 6.94(1H, d,
J=6.0Hz), 5.02-4.95(2H, m), 3.00(3H, br s), 1.78(3H, br s). 260
.sup.1H-NMR(DMSO-d.sub.6) .delta.: 11.70(1H, s), 9.36(1H, s),
9.11(1H, s), 7.55(1H, d, J=6.0 Hz), 7.50(1H, s), 7.44-7.34(3H, m),
7.00(1H, d, J=6.0Hz), 4.99(2H, s), 4.09(2H, s), 3.43(3H, s). 261
.sup.1H-NMR(DMSO-d.sub.6) .delta.: 12.19(1H, br s), 8.26(1H, s),
7.45(1H, br s), 7.43-7.30(3H, m), 4.71(2H, s), 4.34-4.26(2H, m),
3.76-3.68(2H, m), 3.52(3H, s). 262 .sup.1H-NMR(DMSO-d.sub.6)
.delta.: 11.58(1H, br s), 8.92(1H, s), 7.97(1H, s), 7.51-7.47(2H,
m), 7.43-7.32(3H, m), 6.99(1H, d, J=6.0Hz), 4.98(2H, s), 2.97(6H,
s). 263 .sup.1H-NMR(DMSO-d.sub.6) .delta.: 11.59(1H, br s),
8.70(1H, s), 8.44(1H, s), 7.51-7.46(2H, m), 7.43-7.31(3H, m),
6.98(1H, d, J=6.5Hz), 4.98(2H, s), 3.70(3H, s). 264
.sup.1H-NMR(DMSO-d.sub.6) .delta.: 12.45(1H, s), 8.71(1H, s),
7.89(1H, d, J=3.2Hz), 7.63 (1H, d, J=3.2Hz), 7.37-7.13(3H, m),
4.45(2H, t, J=5.6Hz), 3.94(2H, t, J=5.6 Hz), 3.60(2H, t, J=7.4Hz),
2.79(2H, t, J=7.4Hz), 1.94-1.78(2H, m). 265
.sup.1H-NMR(DMSO-d.sub.6) .delta.: 11.77(1H, br s), 9.68(1H, s),
9.12(1H, s), 7.58(1H, d, J=6.0 Hz), 7.50(1H, s), 7.43-7.32(3H, m),
7.03(1H, d, J=6.0Hz), 4.99(2H, s), 2.44(3H, s). 266
.sup.1H-NMR(DMSO-d.sub.6) .delta.: 10.45(1H, br s), 8.41(1H, s),
7.46-7.25(9H, m), 4.73(2H, s), 4.54(2H, d, J=6.0Hz), 4.46-4.35(2H,
m), 3.81-3.70(2H, m). 267 1H-NMR(DMSO-d.sub.6) .delta.: 8.36(1H,
s), 7.64(1H, d, J=2.1Hz), 7.3-7.5(4H, m), 6.85-7.0(1H, m), 4.75(2H,
s), 4.25-4.45(2H, m), 3.7-3.9(2H, m). 268 1H-NMR(DMSO-d.sub.6)
.delta.: 12.22(1H, brs), 9.14(1H, s), 8.7-9.0(3H, m), 7.3-7.6(4H,
m), 4.75(2H, s), 4.4-4.6(2H, m), 3.7-3.9(2H, m). 269
.sup.1H-NMR(DMSO-d.sub.6) .delta.: 12.25(1H, s), 10.49(1H, t,
J=5.8Hz), 8.47(1H, s), 8.13-8.12(1H, m), 7.97-7.96(1H, m),
7.88-7.86(1H, m), 7.57-7.55(1H, m), 7.51-7.47(3H, m), 7.43-7.33(3H,
m), 7.29-7.22(1H, m), 5.01(2H, d, J=5.6Hz), 4.73(2H, s),
4.45-4.42(2H, m), 3.77-3.76(2H, m). 270 .sup.1H-NMR(DMSO-d.sub.6)
.delta.: 12.30(1H, s), 11.18(1H, d, J=7.9Hz), 8.39(1H, s), 7.46
(1H, s), 7.38-7.34(10H, m), 7.28-7.23(2H, m), 6.28(1H, d, J=7.9Hz),
4.74(2H, s), 4.41(2H, t, J=5.6Hz), 3.76(2H, t, J=5.6Hz). 271
.sup.1H-NMR(DMSO-d.sub.6) .delta.: 9.20(2H, d, J=5.1Hz), 9.10(1H,
s), 7.86(1H, t, J=5.3 Hz), 7.51(1H, s), 7.46-7.34(3H, m), 4.79(2H,
s), 4.66(2H, t, J=5.6Hz), 3.87(2H, t, J=5.6Hz). 272
.sup.1H-NMR(DMSO-d.sub.6) .delta.: 11.95(1H, s), 7.60(1H, s),
7.45-7.22(8H, m), 7.21-7.11(1H, m), 4.69(2H, s), 4.22-4.12(2H, m),
3.73-3.62(2H, m), 1.54(6H, s). 273 .sup.1H-NMR(DMSO-d.sub.6)
.delta.: 12.19(1H, br s), 10.39(1H, t, J=5.6Hz), 8.41(1H, s), 7.46
(1H, s), 7.43-7.30(5H, m), 7.26-7.18(2H, m), 4.73(2H, s), 4.49(2H,
d, J=6.0Hz), 4.41(2H, t, J=5.6Hz), 3.76(2H, t, J=5.6Hz), 1.27(9H,
s). 274 .sup.1H-NMR(DMSO-d.sub.6) .delta.: 9.28(1H, s), 9.13(1H,
s), 7.49(1H, s), 7.47-7.33(4H, m), 6.97(1H, d, J=6.0Hz), 4.98(2H,
s),
3.19-3.06(1H, m), 1.96-1.43(8H, m). 275 .sup.1H-NMR(DMSO-d.sub.6)
.delta.: 11.60(1H, br s), 9.63(1H, s), 9.08(1H, s), 7.48(1H, s),
7.43 (1H, d, J=6.5Hz), 7.41-7.31(5H, m), 7.20-7.07(2H, m), 6.95(1H,
d, J=6.0Hz), 4.97(2H, s), 3.85(2H, s). 276
.sup.1H-NMR(DMSO-d.sub.6) .delta.: 11.67(1H, br s), 9.11(1H, s),
8.85(1H, s), 7.52-7.46(2H, m), 7.43-7.33(3H, m), 7.01(1H, d,
J=6.0Hz), 4.99(2H, s), 1.26(9H, s). 277 .sup.1H-NMR(DMSO-d.sub.6)
.delta.: 11.59(1H, br s), 9.11(1H, s), 8.41(1H, s), 7.50-7.29(10H,
m), 7.00(1H, d, J=6.5Hz), 4.97(2H, s), 1.61(6H, s). 278
.sup.1H-NMR(CDCl.sub.3) .delta.: 11.72(1H, br s), 9.39(1H, s),
9.21(1H, s), 7.99(2H, dd, J=8.6, 5.3Hz), 7.41-7.32(3H, m),
7.29-7.15(3H, m), 6.73(1H, d, J=6.0Hz), 6.35(1H, d, J=6.0Hz),
4.98(2H, s). 279 .sup.1H-NMR(DMSO-d.sub.6) .delta.: 11.76(1H, br
s), 10.85(1H, s), 9.32(1H, s), 8.79(1H, d, J= 4.6Hz), 8.19(1H, d,
J=7.9Hz), 8.11(1H, td, J=7.5, 1.5Hz), 7.74-7.70(1H, m), 7.59(1H, d,
J=6.0Hz), 7.51(1H, s), 7.44-7.35(3H, m), 7.04(1H, d, J=6.5Hz),
5.01(2H, s). 280 .sup.1H-NMR(DMSO-d.sub.6) .delta.: 12.01(1H, br
s), 8.19(1H, br s), 7.65(1H, br s), 7.54-7.32 (6H, m), 5.10(2H, s),
3.67(1H, br s), 1.22(6H, d, J=6.0Hz). 281 .sup.1H-NMR(DMSO-d.sub.6)
.delta.: 8.12(1H, br s), 7.47(1H, br s), 7.44-7.31(5H, m), 7.10(1H,
br s), 5.01(2H, s), 3.38(4H, q, J=7.0Hz), 1.02(6H, t, J=7.0Hz). 282
.sup.1H-NMR(DMSO-d.sub.6) .delta.: 9.05(1H, s), 8.82(1H, d,
J=5.6Hz), 8.58(1H, d, J=8.3 Hz), 8.44(1H, t, J=7.7Hz), 7.79(1H, t,
J=6.5Hz), 7.50(1H, s), 7.46-7.33(3H, m), 4.78(2H, s), 4.49(2H, t,
J=5.6Hz), 3.83(2H, t, J=5.6Hz). 284 .sup.1H-NMR(DMSO-d.sub.6)
.delta.: 11.60(1H, br s), 9.18(1H, s), 9.13(1H, s), 7.52-7.44(2H,
m), 7.42-7.29(3H, m), 6.96(1H, d, J=6.0Hz), 4.98(2H, s), 2.41(1H,
t, J=7.0Hz), 2.03-1.87(2H, m), 0.97-0.81(12H, m). 285
.sup.1H-NMR(DMSO-d.sub.6) .delta.: 8.18(1H, s), 7.69(1H, d,
J=6.0Hz), 7.54(1H, d, J=6.0 Hz), 7.49(1H, s), 7.45-7.33(3H, m),
5.11(2H, s), 3.23(2H, q, J=7.2Hz), 1.19(3H, t, J=7.2Hz). 286
.sup.1H-NMR(DMSO-d.sub.6) .delta.: 11.72(1H, br s), 9.82(1H, s),
9.16(1H, s), 9.11(1H, d, J= 2.3Hz), 8.80(1H, dd, J=4.6, 1.4Hz),
8.35(1H, td, J=1.9, 7.9Hz), 7.61(1H, dd, J= 7.9, 3.2Hz), 7.55(1H,
d, J=6.0Hz), 7.52(1H, s), 7.42-7.37(3H, m), 7.03(1H, d, J=5.6Hz),
5.01(2H, s). 287 .sup.1H-NMR(DMSO-d.sub.6) .delta.: 11.74(1H, br
s), 9.86(1H, s), 9.15(1H, s), 8.83(2H, dd, J= 4.6, 1.4Hz), 7.92(2H,
q, J=2.2Hz), 7.55(1H, d, J=6.0Hz), 7.52(1H, s), 7.44-7.36(3H, m),
7.04(1H, d, J=6.0Hz), 5.01(2H, s). 288 .sup.1H-NMR(DMSO-d.sub.6)
.delta.: 11.75(1H, br s), 9.38(1H, s), 9.14(1H, s), 8.02(1H, s),
7.57 (1H, d, J=6.0Hz), 7.51(1H, s), 7.44-7.34(4H, m), 7.04(1H, d,
J=6.0Hz), 6.75 (1H, dd, J=3.2, 2.3Hz), 5.01(2H, s). 289
.sup.1H-NMR(DMSO-d.sub.6) .delta.: 11.70(1H, br s), 9.48(1H, s),
9.04(1H, s), 7.99(1H, dd, J= 3.7, 0.9Hz), 7.90(1H, dd, J=5.1,
0.9Hz), 7.51-7.49(2H, m), 7.43-7.34(3H, m), 7.23(1H, dd, J=4.6,
3.7Hz), 7.01(1H, d, J=6.0Hz), 4.99(2H, s). 290
.sup.1H-NMR(DMSO-d.sub.6) .delta.: 9.14(1H, dd, J=4.9, 1.6Hz),
8.78(1H, dd, J=8.8, 1.9Hz), 8.73(1H, s), 7.76(1H, q, J=4.5Hz),
7.48(1H, s), 7.44-7.31(3H, m), 4.75(2H, s), 4.44(2H, t, J=5.6Hz),
3.79(1H, t, J=5.6Hz). 292 .sup.1H-NMR(DMSO-d.sub.6) .delta.:
12.22(1H, s), 8.71(1H, s), 7.89(1H, d, J=3.2Hz), 7.63 (1H, d,
J=3.2Hz), 7.55(1H, td, J=7.9, 1.4Hz), 7.45(1H, td, J=7.9, 1.4Hz),
7.23 (1H, td, J=7.9, 0.9Hz), 4.81(2H, s), 4.47(2H, t, J=5.6Hz),
3.83(2H, t, J=5.6Hz). 293 .sup.1H-NMR(DMSO-d.sub.6) .delta.:
12.34(1H, s), 8.70(1H, s), 7.89(1H, d, J=3.2Hz), 7.63 (1H, d,
J=3.2Hz), 7.44-7.40(4H, m), 4.73(2H, s), 4.45-4.44(2H, m),
3.77-3.76(2H, m). 294 .sup.1H-NMR(DMSO-d.sub.6) .delta.: 12.27(1H,
s), 8.71(1H, s), 7.89-7.25(1H, m), 7.63(1H, d, J=3.2Hz), 7.58(1H,
t, J=7.9Hz), 7.47(1H, dd, J=10.2, 1.9Hz), 7.26(1H, dd, J=4.9,
2.4Hz), 4.74(2H, s), 4.47-4.46(2H, m), 3.80-3.78(2H, m). 295
.sup.1H-NMR(DMSO-d.sub.6) .delta.: 12.36(1H, s), 8.71(1H, s),
7.89(1H, d, J=3.2Hz), 7.63 (1H, d, J=3.2Hz), 7.31(1H, d, J=7.9Hz),
7.12(1H, d, J=2.6Hz), 6.99(1H, dd, J=8.1, 2.1Hz), 4.64(2H, s),
4.45(2H, t, J=5.6Hz), 3.85(3H, s), 3.77(2H, t, J=5.6Hz). 296
.sup.1H-NMR(DMSO-d.sub.6) .delta.: 11.68(1H, br s), 9.13(1H, s),
9.03(1H, s), 7.56(1H, d, J= 6.0Hz), 7.50(1H, s), 7.43-7.34(3H, m),
7.09(1H, t, J=2.1Hz), 7.02(1H, d, J=6.0 Hz), 6.90(1H, dd, J=1.9,
4.2Hz), 6.14(1H, dd, J=1.4, 4.2Hz), 5.00(2H, s), 3.91(3H, s). 297
.sup.1H-NMR(DMSO-d.sub.6) .delta.: 8.73(1H, s), 7.90(1H, d,
J=3.4Hz), 7.64(1H, d, J=3.4 Hz), 7.33-7.30(4H, m), 4.45-4.43(2H,
m), 3.84-3.81(2H, m), 2.65-2.62(2H, m), 1.89-1.87(2H, m). 298
.sup.1H-NMR(DMSO-d.sub.6) .delta.: 8.73(1H, s), 7.90(1H, d,
J=3.2Hz), 7.64(1H, d, J=3.2 Hz), 7.42-7.41(2H, m), 7.30-7.22(2H,
m), 4.46(2H, t, J=5.6Hz), 3.83(2H, t, J= 5.6Hz), 3.60(2H, t,
J=7.2Hz), 2.75(2H, t, J=7.9Hz), 1.94-1.89(2H, m). 299
.sup.1H-NMR(DMSO-d.sub.6) .delta.: 8.73(1H, s), 7.90(1H, d,
J=3.2Hz), 7.64(1H, d, J=3.2 Hz), 7.34-7.31(2H, m), 7.24-7.23(2H,
m), 4.45(2H, t, J=5.6Hz), 3.81(2H, t, J= 5.6Hz), 3.56(2H, t,
J=7.0Hz), 2.65(2H, t, J=7.9Hz), 1.95-1.87(2H, m). 300
.sup.1H-NMR(DMSO-d.sub.6) .delta.: 8.80(1H, s), 7.49(1H, s),
7.43-7.35(3H, m), 4.76(2H, s), 4.52(2H, t, J=5.6Hz), 3.82(2H, t,
J=5.6Hz), 2.60(3H, s). 301 .sup.1H-NMR(DMSO-d.sub.6) .delta.:
12.35(1H, s), 8.71(1H, s), 8.49(1H, q, J=4.6Hz), 7.90 (1H, d,
J=3.2Hz), 7.64(1H, d, J=3.2Hz), 7.49(1H, dd, J=9.7, 5.6Hz),
7.32-7.26 (2H, m), 4.84(2H, s), 4.45(2H, t, J=5.6Hz), 3.72(2H, t,
J=5.6Hz), 2.75(3H, d, J=4.6Hz). 303 .sup.1H-NMR(DMSO-d.sub.6)
.delta.: 11.62(1H, br s), 9.45(1H, s), 9.08(1H, s), 7.51-7.41(3H,
m), 7.26-7.14(2H, m), 6.96(1H, d, J=6.0Hz), 4.96(2H, s), 2.17(3H,
s). 304 .sup.1H-NMR(DMSO-d.sub.6) .delta.: 11.78(1H, br s),
9.51(1H, s), 9.20(1H, s), 7.99-7.92(2H, m), 7.69-7.41(6H, m),
7.26-7.15(2H, m), 7.03(1H, d, J=6.0Hz), 4.98(2H, s). 305
.sup.1H-NMR(DMSO-d.sub.- 6) .delta.: 8.18(1H, s), 7.49-7.41(2H, m),
7.39(1H, d, J=6.5Hz), 7.24-7.14(2H, m), 6.96(1H, d, J=6.5Hz),
4.96(2H, s), 3.01(3H, s). 306 .sup.1H-NMR(DMSO-d.sub.6) .delta.:
9.06(1H, s), 8.73(1H, d, J=4.6Hz), 8.64(1H, d, J=8.3 Hz), 8.14(1H,
t, J=7.9Hz), 7.57(1H, t, J=6.0Hz), 7.48-7.42(3H, m), 7.23-7.18 (2H,
m), 7.02(1H, d, J=6.0Hz), 4.97(2H, s). 307
.sup.1H-NMR(DMSO-d.sub.6) .delta.: 12.29(1H, s), 8.70(1H, s),
7.88(1H, d, J=3.2Hz), 7.62 (1H, d, J=3.2Hz), 7.46(1H, td, J=7.7,
1.7Hz), 7.40-7.35(1H, m), 7.23-7.21(2H, m), 4.78(2H, s),
4.47-4.45(2H, m), 3.81-3.79(2H, m). 308 .sup.1H-NMR(DMSO-d.sub.6)
.delta.: 12.31(1H, s), 8.70(1H, s), 7.88(1H, d, J=3.2Hz), 7.62 (1H,
d, J=3.2Hz), 7.42-7.40(1H, m), 7.24-7.21(2H, m), 7.13(1H, td,
J=8.7, 2.5 Hz), 4.75(2H, s), 4.46(2H, t, J=5.6Hz), 3.78(2H, t,
J=5.8Hz). 309 .sup.1H-NMR(DMSO-d.sub.6) .delta.: 12.37(1H, s),
8.69(1H, s), 7.88(1H, d, J=3.2Hz), 7.62 (1H, d, J=3.2Hz),
7.44-7.42(2H, m), 7.21-7.18(2H, m), 4.72(2H, s), 4.43(2H, t, J=
5.6Hz), 3.75(2H, t, J=5.6Hz). 310 .sup.1H-NMR(DMSO-d.sub.6)
.delta.: 12.24(1H, s), 8.72(1H, s), 7.89(1H, d, J=3.2Hz), 7.63 (1H,
d, J=3.2Hz), 7.52-7.44(2H, m), 7.36-7.34(2H, m), 4.81(2H, s),
4.50(2H, t, J= 5.6Hz), 3.81(2H, t, J=5.6Hz). 311
.sup.1H-NMR(DMSO-d.sub.6) .delta.: 12.45(1H, s), 8.73(1H, s),
7.95-7.90(5H, m), 7.64(1H, d, J= 3.0Hz), 7.53-7.52(3H, m), 4.93(2H,
s), 4.49-4.47(2H, m), 3.83-3.81(2H, m). 312 .sup.1H-NMR(CDCl.sub.3)
.delta.: 12.24(1H, br s), 8.50(1H, s), 7.83(1H, d, J=3.2Hz),
7.40(1H, d, J=3.2Hz), 7.30-7.24(1H, m), 7.14(1H, t, J=7.2Hz),
7.02(1H, t, J=7.9Hz), 4.26(2H, t, J=5.6Hz), 3.79(2H, t, J=5.6Hz),
3.66(2H, t, J=7.4Hz), 2.77(2H, t, J=7.7Hz), 2.06-1.98(2H, m). 313
.sup.1H-NMR(CDCl.sub.3) .delta.: 12.21(1H, br s), 8.41(1H, s),
7.79(1H, d, J=3.2Hz), 7.38(1H, d, J=3.2Hz), 7.32(1H, t, J=7.9Hz),
7.02(1H, dd, J=9.7, 1.9Hz), 6.95(1H, d, J= 8.3Hz), 4.26(2H, t,
J=5.6Hz), 3.80(2H, t, J=5.6Hz), 3.62(2H, t, J=7.4Hz), 2.71(2H, t,
J=7.7Hz), 2.04-1.97(2H, m). 314 .sup.1H-NMR(CDCl.sub.3) .delta.:
12.29(1H, br s), 8.43(1H, s), 7.80(1H, d, J=3.2Hz), 7.38(1H, d,
J=3.2Hz), 7.17(2H, dd, J=8.6, 5.3Hz), 7.02-6.96(2H, m), 4.22(2H, t,
J=5.6 Hz), 3.79-3.74(2H, m), 3.62(2H, t, J=7.4Hz), 2.71(2H, t,
J=7.4Hz), 2.04-1.97(2H, m). 315 .sup.1H-NMR(CDCl.sub.3) .delta.:
8.52(1H, s), 7.81(1H, d, J=3.3Hz), 7.39(1H, d, J=3.3Hz),
7.30-7.18(1H, m), 7.00-6.88(3H, m), 4.22(2H, t, J=5.7Hz), 3.75(2H,
t, J=5.5 Hz), 3.62(2H, t, J=7.3Hz), 2.73(2H, t, J=7.5Hz),
2.07-1.97(2H, m). 317 .sup.1H-NMR(DMSO-d.sub.6) .delta.: 9.01(1H,
s), 8.85-8.80(1H, m), 8.57(1H, d, J=8.3Hz), 8.43(1H, t, J=7.5Hz),
7.79(1H, t, J=7.5Hz), 7.58(1H, t, J=7.5Hz), 7.49(1H, t, J=7.2Hz),
7.26(1H, t, J=7.2Hz), 4.85(2H, s), 4.53-4.46(2H, m), 3.91-3.83(2H,
m). 318 .sup.1H-NMR(DMSO-d.sub.6) .delta.: 11.74(1H, br s),
9.09(1H, s), 7.52(1H, d, J=6.0Hz), 7.48 (1H, s), 7.46-7.43(2H, m),
7.23-7.14(2H, m), 6.98(1H, d, J=6.5Hz), 4.95(2H, s), 4.07(2H, s),
3.41(3H, s). 319 .sup.1H-NMR(DMSO-d.sub.6) .delta.: 8.17(1H, s),
7.48-7.33(3H, m), 7.24-7.12(2H, m), 6.94(1H, d, J=6.0Hz), 4.94(2H,
s), 2.59-2.51(1H, m), 1.24(6H, d, J=7.0Hz). 320
.sup.1H-NMR(DMSO-d.sub.6) .delta.: 9.78(1H, s), 9.14(1H, s),
9.08(1H, d, J=2.3Hz), 8.77(1H, dd, J=4.9, 1.6Hz), 8.31(1H, dt,
J=7.9, 2.3Hz), 7.61-7.55(1H, m), 7.52(1H, d, J=6.0Hz),
7.49-7.42(2H, m), 7.24-7.15(2H, m), 7.01(1H, d, J=6.5Hz), 4.97(2H,
s). 321 .sup.1H-NMR(DMSO-d.sub.6) .delta.: 11.64(1H, br s),
9.29(1H, s), 9.11(1H, s), 7.48-7.37(3H, m), 7.24-7.13(2H, m),
6.95(1H, d, J=6.0Hz), 4.95(2H, s), 2.92(1H, sept, J=6.5 Hz),
1.07(6H, d, J=6.5Hz). 322 1H-NMR(DMSO-d.sub.6) .delta.: 11.86(1H,
brs), 10.2-10.4(1H, m), 8.76(1H, s), 7.4-7.6(3H, m), 7.21(2H, t,
J=8.9Hz), 7.01(1H, d, J=6.3Hz), 4.95(2H, s), 3.4-3.65(4H, m),
3.28(3H, s). 323 .sup.1H-NMR(DMSO-d.sub.6) .delta.: 11.90(1H, s),
10.17-10.07(1H, m), 8.76(1H, s), 7.56-7.41 (3H, m), 7.27-7.15(2H,
m), 7.02(1H, d, J=6.4Hz), 4.95(2H, s), 3.40-3.29(2H, m), 1.13(3H,
t, J=7.2Hz). 324 .sup.1H-NMR(DMSO-d.sub.6) .delta.: 9.43(1H, s),
9.07(1H, s), 7.45(1H, d, J=6.0Hz), 7.34-7.25 (2H, m), 7.24-7.14(1H,
m), 6.94(1H, d, J=6.0Hz), 3.84(2H, t, J=7.2Hz), 2.78 (2H, t,
J=7.2Hz), 2.16(3H, s), 1.98-1.82(2H, m). 325
.sup.1H-NMR(DMSO-d.sub.6) .delta.: 9.45(1H, s), 9.09(1H, s),
7.60-7.44(1H, m), 7.41-7.34(1H, m), 7.25-7.18(1H, m), 6.91(1H, d,
J=6.5Hz), 5.06(2H, s), 2.17(3H, s), 0.00(6H, t, J=3.5Hz). 326
.sup.1H-NMR(DMSO-d.sub.6) .delta.: 8.73(1H, s), 7.89(1H, d,
J=3.2Hz), 7.68(1H, dd, J=9.3, 2.8Hz), 7.63(1H, d, J=3.2Hz),
7.55(1H, dd, J=8.3, 5.6Hz), 7.45(1H, td, J=8.3, 2.8Hz), 5.02(2H,
s), 4.52-4.47(2H, m), 3.87(3H, s), 3.81-3.76(2H, m). 327
.sup.1H-NMR(DMSO-d.sub.6) .delta.: 8.99-8.94(1H, m), 8.81-8.76(1H,
m), 8.57(1H, d, J=8.3 Hz), 8.42-8.32(1H, m), 7.76-7.69(1H, m),
7.66(1H, d, J=7.4Hz), 7.43(2H, dd, J= 6.5, 1.4Hz), 4.75(2H, s),
4.47(2H, t, J=5.3Hz), 3.82(2H, t, J=5.3Hz). 328
.sup.1H-NMR(DMSO-d.sub.6) .delta.: 9.45(1H, s), 8.90(1H, d,
J=8.3Hz), 8.81(1H, d, J=5.6 Hz), 8.46(1H, s), 8.08(1H, dd, J=7.9,
5.6Hz), 7.57(1H, t, J=7.4Hz), 7.46(1H, t, J=7.4Hz), 7.25(1H, t,
J=7.9Hz), 4.83(2H, s), 4.36(2H, t, J=5.3Hz), 3.83(2H, t, J=5.6Hz).
329 .sup.1H-NMR(DMSO-d.sub.6) .delta.: 8.98(1H, s), 8.80(1H, d,
J=4.6Hz), 8.54(1H, d, J=8.8 Hz), 8.41(1H, t, J=7.7Hz), 7.76(1H, t,
J=6.7Hz), 7.35-7.27(2H, m), 7.26-7.19 (1H, m), 4.47(2H, t,
J=5.6Hz), 3.87(2H, t, J=5.6Hz), 3.61(2H, t, J=7.4Hz), 2.80(2H, td,
J=7.9, 1.9Hz), 1.88(2H, t, J=7.4Hz). 330 .sup.1H-NMR(CDCl.sub.3)
.delta.: 12.26(1H, s), 8.72(1H, s), 7.90(1H, d, J=3.0Hz), 7.62-7.58
(3H, m), 7.33-7.22(2H, m), 7.01(1H, s), 4.94(2H, s), 4.48(2H, t,
J=5.7Hz), 3.89 (2H, t, J=5.7Hz). 331 .sup.1H-NMR(DMSO-d.sub.6)
.delta.: 12.25(1H, s), 10.69(1H, d, J=8.3Hz), 8.26(1H, s),
7.39-7.34(8H, m), 7.22-7.15(6H, m), 5.28(1H, dd, J=13.9, 8.3Hz),
4.70(2H, s), 4.34(2H, t, J=5.6Hz), 3.11-3.03(2H, m). 332
.sup.1H-NMR(DMSO-d.sub.6) .delta.: 11.82(1H, s), 9.26(1H, s),
8.65(1H, s), 7.54(1H, td, J=7.0, 1.9Hz), 7.42(1H, td, J=7.0,
1.9Hz), 7.22(1H, t, J=7.9Hz), 4.79(2H, s), 4.29 (2H, t, J=5.6Hz),
3.76(2H, t, J=5.6Hz), 2.12(3H, s). 333 .sup.1H-NMR(CDCl.sub.3)
.delta.: 12.26(1H, br s), 8.44(1H, s), 7.82(1H, d, J=3.2Hz),
7.39(1H, d, J=3.2Hz), 7.25-7.15(2H, m), 7.09-7.00(2H, m), 4.22(2H,
t, J=5.6Hz), 3.76 (2H, t, J=5.6Hz), 3.66(2H, t, J=7.2Hz), 2.76(2H,
t, J=7.7Hz), 2.06-1.99(2H, m). 334 .sup.1H-NMR(CDCl.sub.3) .delta.:
12.21(1H, br s), 10.69(1H, d, J =8.1Hz), 8.28(1H, s),
7.37-7.15(14H, m), 5.21-5.06(1H, m), 4.73(2H, s), 4.13(2H, t,
J=5.7Hz), 3.61 (2H, t, J=5.3Hz), 2.79-2.58(2H, m), 2.31-2.08(2H,
m). 335 .sup.1H-NMR(CDCl.sub.3) .delta.: 9.03(1H, s), 7.93(1H, d,
J=3.7Hz), 7.47(1H, d, J=3.7Hz), 7.27-7.20(1H, m), 7.09-7.04(2H, m),
5.89(1H, br s), 4.47(2H, t, J=5.7Hz), 3.85 (2H, t, J=5.7Hz),
3.70-3.65(2H, m), 2.92(3H, d, J=5.1Hz), 2.81-2.72(2H, m). 336
.sup.1H-NMR(DMSO-d.sub.6) .delta.: 12.24(1H, br s), 7.71(1H, s),
7.35-7.15(3H, m), 4.23(2H, t, J=5.1Hz), 3.76(2H, t, J=5.1Hz),
3.55(2H, t, J=7.4Hz), 2.76(2H, t, J=7.4 Hz), 1.89-1.74(2H, m),
1.19(9H, s). 337 .sup.1H-NMR(DMSO-d.sub.6) .delta.: 12.22(1H, s),
8.14(1H, s), 7.48-7.28(4H, m), 4.71(2H, s), 4.32(2H, t, J=5.6Hz),
3.93(1H, sept, J=5.3Hz), 3.72(2H, t, J=5.6 Hz), 1.02(6H, t,
J=5.3Hz). 338 .sup.1H-NMR(DMSO-d.sub.6) .delta.: 8.73(1H, s),
7.91-7.91(1H, m), 7.65-7.64(1H, m), 7.30-7.14 (5H, m),
4.45-4.43(2H, m), 3.80-3.78(2H, m), 3.56-3.53(2H, m), 2.64-2.61(2H,
m), 1.63-1.62(4H, m). 339 .sup.1H-NMR(DMSO-d.sub.6) .delta.:
8.75-8.74(1H, m), 7.91-7.91(1H, m), 7.65-7.65(1H, m), 4.45-4.44(2H,
m), 3.81-3.80(2H, m), 3.51(2H, t, J=7.3Hz), 1.61-1.59(2H, m),
1.34-1.29(4H, m), 0.89(3H, t, J=7.0Hz). 340
.sup.1H-NMR(DMSO-d.sub.6) .delta.: 8.83(2H, d, J=6.5Hz), 8.59(1H,
s), 8.55(2H, d, J=6.5 Hz), 7.57(1H, t, J=7.9Hz), 7.46(1H, t,
J=7.4Hz), 7.25(1H, t, J=7.9Hz), 4.82 (2H, s), 4.38(2H, t, J=5.1Hz),
3.82(2H, t, J=5.1Hz). 341 .sup.1H-NMR(DMSO-d.sub.6) .delta.:
8.88(2H, d, J=6.5Hz), 8.84(1H, s), 8.49(2H, d, J=6.5 Hz),
7.49-7.43(2H, m), 7.27-7.18(3H, m), 6.99(1H, d, J=6.5Hz), 4.97(2H,
s). 342 .sup.1H-NMR(DMSO-d.sub.6) .delta.: 11.61(1H, s),
9.23-9.19(1H, m), 9.10(1H, s), 8.89-8.82(2H, m), 7.61-7.52(2H, m),
7.45-7.38(1H, m), 7.27-7.20(1H, m), 6.95(1H, d, J=6.0 Hz), 5.06(2H,
s). 343 .sup.1H-NMR(DMSO-d.sub.6) .delta.: 12.27(1H, br s),
8.05(1H, s), 7.97(1H, s), 7.67-7.62(1H, m), 7.46-7.39(2H, m),
4.73(2H, s), 4.36-4.29(2H, m), 3.80-3.72(5H, m). 344
.sup.1H-NMR(DMSO-d.sub.6) .delta.: 8.49(1H, s), 7.49-7.41(2H, m),
7.37(1H, d, J=6.5Hz), 7.25-7.17(2H, m), 6.94(1H, d, J=6.5Hz),
4.92(2H, s), 2.63-2.60(3H, m). 345 .sup.1H-NMR(DMSO-d.sub.6)
.delta.: 8.43(1H, s), 7.48-7.39(2H, m), 7.35(1H, d, J=6.0Hz),
7.24-7.15(2H, m), 6.92(1H, d, J=6.5Hz), 4.91(2H, s), 3.93(1H, sept,
J=6.5Hz), 1.03(6H, d, J=6.5Hz). 346 .sup.1H-NMR(DMSO-d.sub.6)
.delta.: 9.84(1H, s), 8.85(2H, t, J=3.2Hz), 8.67(1H, s), 7.96(2H,
d, J=6.0Hz), 7.48(1H, s), 7.41-7.35(3H, m), 4.74(2H, s), 4.37(2H,
t, J=5.8Hz), 3.77(2H, t, J=5.6Hz). 347 .sup.1H-NMR(DMSO-d.sub.6)
.delta.: 11.78(1H, br s), 9.21(1H, d, J=0.9Hz), 9.08(1H, s),
8.91-8.81(2H, m), 7.54(1H, d, J=6.5Hz), 7.48(2H, dd, J=8.8, 5.6Hz),
7.26-7.13 (2H, m), 6.98(1H, d, J=6.0Hz), 4.95(2H, s). 348
.sup.1H-NMR(DMSO-d.sub.6) .delta.: 12.15(1H, br s), 9.87(1H, d,
J=1.5Hz), 8.69-8.61(1H, m), 8.58-8.49(2H, m), 7.65(1H, d, J=7.2Hz),
7.47-7.36(2H, m), 4.73(2H, s), 4.41 (2H, t, J=5.3Hz), 3.77(2H, t,
J=5.3Hz). 350 .sup.1H-NMR(DMSO-d.sub.6) .delta.: 10.34(1H, s),
8.70(1H, s), 7.89(1H, d, J=3.2Hz), 7.64 (1H, d, J=3.2Hz), 7.24(1H,
d, J=8.3Hz), 6.89(1H, d, J=2.3Hz), 6.84(1H, dd, J= 8.1, 2.1Hz),
4.62(2H, s), 4.44-4.43(2H, m), 3.77-3.76(2H, m). 351
.sup.1H-NMR(DMSO-d.sub.6) .delta.: 8.69(1H, s), 7.89(1H, d,
J=3.2Hz), 7.63(1H, d, J=3.2 Hz), 7.32-7.25(4H, m), 7.20-7.14(1H,
m), 4.39-4.34(2H, m), 3.75-3.69(2H, m), 3.46-3.37(2H, m), 2.76(1H,
q, J=7.0Hz), 1.95-1.82(2H, m), 1.24(3H, d, J=7.0Hz). 352
.sup.1H-NMR(DMSO-d.sub.6) .delta.: 9.97(1H, s), 9.18(1H, d,
J=1.9Hz), 8.87(1H, dd, J=5.1, 1.9Hz), 8.71(1H, s), 8.52(1H, dt,
J=7.9, 1.9Hz), 7.77(1H, dd, J=7.9, 5.1Hz), 7.56(1H, td, J=7.8,
1.4Hz), 7.46(1H, td, J=7.0, 1.4Hz), 7.24(1H, t, J=7.9Hz), 4.82(2H,
s), 4.41(2H, t, J=5.6Hz), 3.82(2H, t, J=5.6Hz).
354 .sup.1H-NMR(DMSO-d.sub.6) .delta.: 8.71(1H, s), 7.90(1H, d,
J=3.2Hz), 7.64(1H, d, J=3.2 Hz), 7.47(1H, d, J=2.3Hz), 7.31(1H, dd,
J=8.6, 2.1Hz), 7.13(1H, d, J=8.3Hz), 4.66(2H, s), 4.42(2H, t,
J=5.6Hz), 4.00(2H, t, J=6.3Hz), 3.75(2H, t, J=5.6 Hz),
1.79-1.69(2H, m), 0.98(3H, t, J=7.4Hz). 355
.sup.1H-NMR(DMSO-d.sub.6) .delta.: 8.71(1H, s), 7.90(1H, d,
J=3.2Hz), 7.64(1H, d, J=3.2 Hz), 7.46(1H, d, J=2.3Hz), 7.30(1H, dd,
J=8.6, 2.3Hz), 7.15(1H, d, J=8.6Hz), 4.68-4.62(3H, m), 4.43(2H, t,
J=5.3Hz), 3.76(2H, t, J=5.6Hz), 1.28(6H, d, J=6.0Hz). 356
.sup.1H-NMR(DMSO-d.sub.6) .delta.: 8.71(1H, s), 7.90(1H, d,
J=3.2Hz), 7.64(1H, d, J=3.2 Hz), 7.50(1H, d, J=2.3Hz), 7.46(2H, d,
J=7.0Hz), 7.40(2H, t, J=7.2Hz), 7.35-7.30(2H, m), 7.22(1H, d,
J=8.8Hz), 5.21(2H, s), 4.66(2H, s), 4.43(2H, t, J= 5.6Hz), 3.75(2H,
t, J=5.8Hz). 357 .sup.1H-NMR(DMSO-d.sub.6) .delta.: 8.71(1H, s),
7.90(1H, d, J=3.2Hz), 7.64(1H, d, J=3.2 Hz), 7.33(1H, d, J=8.3Hz),
7.09(1H, d, J=1.9Hz), 6.99(1H, dd, J=8.1, 2.1Hz), 4.67(2H, s),
4.45-4.43(2H, m), 3.99(2H, t, J=6.5Hz), 3.73-3.72(2H, m), 1.71(2H,
td, J=13.9, 7.0Hz), 0.97(3H, t, J=4.9Hz). 358
.sup.1H-NMR(DMSO-d.sub.6) .delta.: 8.70(1H, s), 7.90(1H, d,
J=3.2Hz), 7.64(1H, d, J=3.2 Hz), 7.34(1H, d, J=7.9Hz), 7.13(1H, d,
J=1.9Hz), 6.97(1H, dd, J=7.9, 1.9Hz), 4.72(1H, sept, J=6.0Hz),
4.64(2H, s), 4.43-4.42(2H, m), 3.70-3.68(2H, m), 1.24 (6H, d,
J=6.0Hz). 359 .sup.1H-NMR(DMSO-d.sub.6) .delta.: 8.70(1H, s),
7.90-7.90(1H, m), 7.64(1H, dd, J=1.5, 0.8 Hz), 7.47-7.46(2H, m),
7.39-7.30(4H, m), 7.25(1H, d, J=1.9Hz), 7.02(1H, dd, J=7.9, 1.9Hz),
5.19(2H, s), 4.69(2H, s), 4.39-4.38(2H, m), 3.71-3.69(2H, m). 360
.sup.1H-NMR(DMSO-d.sub.6) .delta.: 8.41(1H, s), 8.00(1H, s),
7.50-7.43(2H, m), 7.32(1H, d, J= 6.0Hz), 7.25-7.18(2H, m), 6.97(1H,
d, J=6.0Hz), 4.97(2H, s), 3.75(3H, s). 361
.sup.1H-NMR(DMSO-d.sub.6) .delta.: 12.20(1H, s), 9.91-9.83(1H, m),
8.40(1H, s), 7.59-7.52(1H, m), 7.44(1H, t, J=6.7Hz), 7.24(1H, t,
J=7.9Hz), 4.80(2H, s), 4.42(2H, t, J=5.6Hz), 3.80(2H, t, J=5.6Hz),
2.83(3H, d, J=4.6Hz). 363 1H-NMR(DMSO-d.sub.6) .delta.: 12.5(1H,
brs), 9.00(1H, s), 8.7-8.9(1H, m), 8.58(1H, d, J= 6.9Hz),
8.3-8.5(1H, m), 7.7-7.8(1H, m), 7.4-7.5(2H, m), 7.2-7.3(2H, m),
4.76(2H, s), 4.4-4.6(2H, m), 3.6-3.9(2H, m). 364
1H-NMR(DMSO-d.sub.6) .delta.: 9.27(1H, s), 8.82(1H, d, J=5.4Hz),
8.65(1H, d, J=8Hz), 8.2-8.4(1H, m), 7.73(1H, t, J=6Hz), 7.59(1H, t,
J=7.5Hz), 7.3-7.5(2H, m), 7.25 (1H, t, J=8Hz), 7.07(1H, d, J=6Hz),
5.11(2H, s). 365 .sup.1H-NMR(DMSO-d.sub.6) .delta.: 9.21(1H, s),
8.80(1H, d, J=4.2Hz), 8.64(1H, d, J=8.3 Hz), 8.28(1H, t, J=7.2Hz),
7.68(1H, t, J=6.5Hz), 7.43(1H, d, J=6.5Hz), 7.43 (1H, dd, J=7.9,
6.5Hz), 7.26(2H, td, J=8.3, 1.4Hz), 7.16(1H, td, J=8.7, 2.3Hz),
7.07(1H, d, J=6.5Hz), 5.03(2H, s). 366 .sup.1H-NMR(DMSO-d.sub.6)
.delta.: 9.64(1H, s), 8.71(1H, s), 7.90(1H, d, J=3.2Hz), 7.64(1H,
d, J=3.2Hz), 7.47-7.41(2H, m), 7.03(1H, td, J=8.3, 2.8Hz), 4.72(2H,
s), 4.46-4.40(2H, m), 3.69-3.64(2H, m), 2.07(3H, s). 367
.sup.1H-NMR(DMSO-d.sub.6) .delta.: 7.75(1H, s), 7.57-7.53(1H, m),
7.43(1H, t, J=6.5Hz), 7.23 (1H, t, J=7.9Hz), 4.78(2H, s), 4.27(2H,
t, J=5.6Hz), 3.77(2H, t, J=5.6Hz), 1.19(9H, s). 368
.sup.1H-NMR(DMSO-d.sub.6) .delta.: 8.75(1H, s), 7.91(1H, d,
J=3.2Hz), 7.68(1H, dd, J=9.7, 2.8Hz), 7.65(1H, d, J=3.2Hz),
7.52(1H, dd, J=8.8, 5.6Hz), 7.42(1H, td, J=8.8, 2.8Hz), 5.06(2H,
s), 4.54-4.48(2H, m), 3.84-3.78(2H, m). 369
.sup.1H-NMR(DMSO-d.sub.6) .delta.: 9.15(1H, s), 8.80-8.75(1H, m),
8.66(1H, d, J=8.3Hz), 8.26-8.17(1H, m), 7.60-7.44(4H, m),
7.33-7.26(1H, m), 7.04(1H, d, J=6.0Hz), 5.00(2H, s). 370
.sup.1H-NMR(DMSO-d.sub.6) .delta.: 12.15(1H, br s), 7.93(0.3H, s),
7.91(0.7H, s), 7.46-7.22 (9H, m), 4.72(1.4H, s), 4.71(0.6H, s),
4.65(1.4H, s), 4.39(0.6H, s), 4.31-4.21(2H, m), 3.77-3.69(2H, m),
2.81(2.1H, s), 2.77(0.9H, s). 371 .sup.1H-NMR(DMSO-d.sub.6)
.delta.: 12.34(1H, br s), 10.57(1H, t, J=6.0Hz), 8.77(1H, s), 8.73
(1H, d, J=5.6Hz), 8.39(1H, s), 8.31(1H, d, J=7.4Hz), 7.87(1H, t,
J=6.3Hz), 7.46(1H, s), 7.43-7.32(3H, m), 4.73(2H, s), 4.68(2H, d,
J=6.0Hz), 4.39(2H, t, J=5.8Hz), 3.75(2H, t, J=5.6Hz). 372
.sup.1H-NMR(DMSO-d.sub.6) .delta.: 12.34(1H, br s), 10.66(1H, t,
J=5.6Hz), 8.70(1H, d, J= 4.6Hz), 8.39(1H, s), 8.20(1H, t, J=7.7Hz),
7.66(2H, d, J=7.9Hz), 7.46(1H, s), 7.43-7.33(3H, m), 4.78(2H, d,
J=6.0Hz), 4.73(2H, s), 4.40(2H, t, J=5.6Hz), 3.75(2H, t, J=5.8Hz).
373 .sup.1H-NMR(DMSO-d.sub.6) .delta.: 8.93(1H, s), 8.80(1H, d,
J=4.6Hz), 8.56(1H, d, J=8.3 Hz), 8.38(1H, t, J=7.4Hz),
7.80-7.69(2H, m), 7.66(1H, d, J=8.3Hz), 7.42(1H, dd, J=8.3, 1.9Hz),
4.77(2H, s), 4.47(2H, t, J=5.6Hz), 3.83(2H, t, J=5.6Hz). 374
.sup.1H-NMR(DMSO-d.sub.6) .delta.: 12.30(1H, br s), 10.30(1H, t,
J=5.3Hz), 8.37(1H, s), 7.46 (1H, s), 7.42-7.32(3H, m), 4.73(2H, s),
4.39(2H, t, J=5.6Hz), 4.23(2H, d, J=5.1 Hz), 3.75(2H, t, J=5.6Hz),
2.11(3H, s). 375 .sup.1H-NMR(DMSO-d.sub.6) .delta.: 8.92-8.86(3H,
m), 8.53(2H, d, J=6.5Hz), 7.46-7.40(1H, m), 7.29-7.22(3H, m),
7.16(1H, td, J=8.6, 1.7Hz), 6.99(1H, d, J=6.0Hz), 5.01(2H, s). 376
.sup.1H-NMR(DMSO-d.sub.6) .delta.: 8.09(1H, s), 7.41(1H, td, J=7.9,
6.0Hz), 7.27-7.19(3H, m), 7.15(1H, td, J=8.7, 2.0Hz), 6.92(1H, d,
J=6.5Hz), 4.98(2H, s), 1.19(9H, d, J=4.6Hz). 377
.sup.1H-NMR(DMSO-d.sub.6) .delta.: 12.37(1H, s), 10.44(1H, t,
J=6.0Hz), 8.40(1H, s), 7.46-7.39(2H, m), 7.38-7.29(2H, m),
7.25-7.14(4H, m), 4.71(2H, s), 4.58(2H, d, J= 5.6Hz), 4.42-4.35(2H,
m), 3.76-3.68(2H, m). 378 .sup.1H-NMR(DMSO-d.sub.6) .delta.:
12.35(1H, br s), 10.44(1H, t, J=6.0Hz), 8.41(1H, s), 7.46-7.39(2H,
m), 7.38-7.32(2H, m), 7.25-7.12(4H, m), 4.71(2H, s), 4.52(2H, d,
J=6.0Hz), 4.42-4.35(2H, m), 3.76-3.69(2H, m). 379
.sup.1H-NMR(DMSO-d.sub.6) .delta.: 12.35(1H, s), 9.8-10.0(1H, m),
8.38(1H, s), 7.4-7.5(2H, m), 7.20(2H, t, J=8.7Hz), 4.71(2H, s),
4.3-4.5(2H, m), 3.6-3.8(2H, m), 2.83(3H, d, J=4.8Hz). 380
1H-NMR(DMSO-d.sub.6) .delta.: 12.3(1H, brs), 10.3-10.5(1H, m),
8.41(1H, s), 7.1-7.5(9H, m), 4.71(2H, s), 4.54(2H, d, J=6Hz),
4.3-4.5(2H, m), 3.6-3.8(2H, m). 381 .sup.1H-NMR(DMSO-d.sub.6)
.delta.: 12.31(1H, s), 9.87(1H, d, J=5.1Hz), 8.38(1H, s),
7.43-7.40(4H, m), 4.71(2H, s), 4.39-4.37(2H, m), 3.73-3.72(2H, m),
2.82(3H, d, J=4.6Hz). 383 .sup.1H-NMR(DMSO-d.sub.6) .delta.:
9.87(1H, d, J=1.4Hz), 8.68-8.63(1H, m), 8.57-8.51(2H, m), 7.69(1H,
d, J=2.3Hz), 7.64(1H, d, J=8.3Hz), 7.40(1H, dd, J=8.3, 2.3Hz),
4.74(2H, s), 4.42(2H, t, J=5.6Hz, 3.78(2H, t, J=5.6Hz). 384
.sup.1H-NMR(DMSO-d.sub.6) .delta.: 12.18(1H, br s), 8.15(1H, s),
7.67(1H, d, J=1.9Hz), 7.63 (1H, d, J=8.3Hz), 7.37(1H, dd, J=8.3,
1.9Hz), 4.71(2H, s), 4.33(2H, t, J=5.3 Hz), 3.94(1H, sept,
J=7.0Hz), 3.74(2H, t, J=5.3Hz), 1.03(6H, d, J=7.0Hz). 385
.sup.1H-NMR(DMSO-d.sub.6) .delta.: 12.28(1H, br s), 8.13(1H, s),
7.46-7.36(2H, m), 7.25-7.14 (2H, m), 4.69(2H, s), 4.30(2H, t,
J=5.6Hz), 3.92(1H, t, J=7.0Hz), 3.69(2H, sept, J=5.8Hz), 1.01(6H,
d, J=7.0Hz). 386 .sup.1H-NMR(DMSO-d.sub.6) .delta.: 12.14(1H, br
s), 7.72(1H, s), 7.47-7.35(2H, m), 7.26-7.13 (2H, m), 4.69(2H, s),
4.22(2H, t, J=5.6Hz), 3.69(2H, t, J=5.6Hz), 1.19(9H, s). 387
.sup.1H-NMR(DMSO-d.sub.6) .delta.: 8.47(1H, s), 7.44(2H, td, J=5.9,
2.5Hz), 7.35(1H, d, J= 6.5Hz), 7.20(2H, tt, J=8.8, 2.6Hz), 6.93(1H,
d, J=6.5Hz), 4.92(2H, s), 2.97 (2H, d, J=6.5Hz), 2.08(1H, dsept,
J=6.7, 6.7Hz), 0.89(6H, d, J=7.0Hz). 388 .sup.1H-NMR(DMSO-d.sub.6)
.delta.: 12.27(1H, br s), 9.93-9.82(1H, m), 8.38(1H, s), 7.52-7.37
(2H, m), 7.30-7.18(1H, m), 4.70(2H, s), 4.40(2H, t, J=5.6Hz),
3.74(2H, t, J=5.6 Hz), 2.82(3H, d, J=5.1Hz). 389
.sup.1H-NMR(DMSO-d.sub.6) .delta.: 7.61(1H, s), 7.43-7.41(2H, m),
7.20-7.18(2H, m), 4.69(2H, s), 4.26-4.25(2H, m), 3.70-3.68(2H, m),
3.45(2H, s), 3.17(3H, s), 1.18(6H, s). 391
.sup.1H-NMR(DMSO-d.sub.6) .delta.: 9.23(1H, s), 9.10(1H, s),
8.93-8.80(2H, m), 7.59-7.33(5H, m), 6.99(1H, d, J=6.4Hz), 4.98(2H,
s). 392 .sup.1H-NMR(DMSO-d.sub.6) .delta.: 9.20(1H, d, J=1.4Hz),
8.90(1H, dd, J=5.6, 1.4Hz), 8.83 (1H, d, J=5.6Hz), 8.78(1H, s),
7.44(2H, dd, J=8.7, 5.3Hz), 7.21(2H, t, J=8.7 Hz), 4.73(2H, s),
4.47-4.40(2H, m), 3.79-3.72(2H, m). 393 .sup.1H-NMR(DMSO-d.sub.6)
.delta.: 9.22(1H, d, J=1.4Hz), 8.92(1H, dd, J=5.6, 1.4Hz), 8.84
(1H, d, J=5.6Hz), 8.80(1H, s), 7.50-7.38(4H, m), 4.80-4.69(2H, m),
4.48-4.41 (2H, m), 3.81-3.71(2H, m). 394 .sup.1H-NMR(DMSO-d.sub.6)
.delta.: 9.19(1H, br s), 8.92-8.87(1H, m), 8.82(1H, dd, J=5.6, 1.9
Hz), 8.79(1H, d, J=1.9Hz), 7.65(1H, d, J=7.4Hz), 7.43(2H, d,
J=7.4Hz), 4.73 (2H, s), 4.48-4.42(2H, m), 3.82-3.74(2H, m). 395
.sup.1H-NMR(DMSO-d.sub.6) .delta.: 9.21(1H, d, J=1.4Hz), 9.09(1H,
s), 8.88(1H, dd, J=5.6, 1.4Hz), 8.85(1H, d, J=5.6Hz), 7.69-7.66(1H,
m), 7.54(1H, d, J=6.5Hz), 7.46-7.42(2H, m), 6.98(1H, d, J=6.5Hz),
4.95(2H, s). 396 .sup.1H-NMR(DMSO-d.sub.- 6) .delta.: 8.71(1H, s),
7.90(1H, d, J=3.2Hz), 7.64(1H, d, J=3.2 Hz), 7.03-7.01(1H, m),
6.96-6.95(1H, m), 6.92-6.90(1H, m), 4.69(2H, s), 4.46-4.44 (2H, m),
3.94(2H, t, J=6.5Hz), 3.78-3.77(2H, m), 1.73-1.66(2H, m), 0.95(3H,
t, J=7.4Hz). 397 .sup.1H-NMR(DMSO-d.sub.6) .delta.: 8.72(1H, s),
7.90(1H, d, J=3.2Hz), 7.64(1H, d, J=3.2 Hz), 7.01-6.98(1H, m),
6.94-6.93(1H, m), 6.88-6.88(1H, m), 4.69-4.64(3H, m), 4.46-4.44(2H,
m), 3.79-3.77(2H, m), 1.24(6H, d, J=6.0Hz). 398
.sup.1H-NMR(DMSO-d.sub.6) .delta.: 8.71(1H, s), 7.90(1H, d,
J=3.2Hz), 7.64(1H, d, J=3.2 Hz), 7.43-7.42(2H, m), 7.35-7.31(3H,
m), 7.06-7.06(2H, m), 6.99-6.96(1H, m), 5.13(2H, s), 4.69(2H, s),
4.43-4.42(2H, m), 3.75-3.74(2H, m). 399 .sup.1H-NMR(DMSO-d.sub.6)
.delta.: 9.22(1H, d, J=1.4Hz), 9.09(1H, s), 8.92-8.80(2H, m),
7.54(1H, d, J=6.5Hz), 7.49-7.37(4H, m), 6.98(1H, d, J=6.0Hz),
4.96(2H, s). 400 .sup.1H-NMR(DMSO-d.sub.6) .delta.: 9.96(1H, s),
9.07(1H, s), 8.79(1H, s), 8.73(1H, d, J=5.6 Hz), 8.31(1H, d,
J=7.9Hz), 7.85(1H, dd, J=7.9, 5.6Hz), 7.48(1H, s), 7.42(1H, d,
J=6.0Hz), 7.40-7.33(3H, m), 6.97(1H, d, J=6.0Hz), 4.97(2H, s),
4.11(2H, s). 401 .sup.1H-NMR(DMSO-d.sub.6) .delta.: 10.02(1H, s),
9.07(1H, s), 8.80(2H, dd, J=5.1, 1.0Hz), 7.89(2H, d, J=6.5Hz),
7.49(1H, s), 7.43(1H, d, J=6.5Hz), 7.41-7.33(3H, m), 6.98(1H, d,
J=6.5Hz), 4.97(2H, s), 4.22(2H, s). 402 .sup.1H-NMR(DMSO-d.sub.6 )
.delta.: 10.14(1H, s), 9.07(1H, s), 8.79(1H, d, J=6.0Hz), 8.30 (1H,
t, J=7.9Hz), 7.83(1H, d, J=7.9Hz), 7.75(1H, t, J=6.5Hz), 7.49(1H,
s), 7.44(1H, d, J=6.5Hz), 7.41-7.34(3H, m), 6.99(1H, d, J=6.5Hz),
4.98(2H, s), 4.32(2H, d, J=8.8Hz). 403 .sup.1H-NMR(DMSO-d.sub.6)
.delta.: 9.21(1H, d, J=0.9Hz), 9.09(1H, s), 8.88(1H, dd, J=5.6,
1.4Hz), 8.84(1H, d, J=5.6Hz), 7.54(1H, d, J=6.5Hz), 7.45-7.39(1H,
m), 7.29-7.21(2H, m), 7.18-7.11(1H, m), 6.97(1H, d, J=6.5Hz),
4.98(2H, s). 404 .sup.1H-NMR(DMSO-d.sub.6) .delta.: 9.89(1H, d,
J=1.4Hz), 8.90(1H, s), 8.71(1H, dd, J=2.3, 1.4Hz), 8.59(1H, d,
J=2.3Hz), 7.51(1H, d, J=6.0Hz), 7.42(1H, td, J=7.9, 6.5 Hz),
7.29-7.22(2H, m), 7.15(1H, td, J=8.5, 2.8Hz), 6.96(1H, d, J=6.0Hz),
4.99 (2H, s). 405 .sup.1H-NMR(DMSO-d.sub.6) .delta.: 8.41(1H, s),
8.01(1H, s), 7.67(1H, d, J=7.4Hz), 7.44-7.41 (2H, m), 7.32(1H, d,
J=6.5Hz), 6.96(1H, d, J=6.5Hz), 4.96(2H, s), 3.75(3H, s). 406
.sup.1H-NMR(DMSO-d.sub.6) .delta.: 9.03(1H, s), 8.71(1H, s),
7.63(1H, d, J=7.4Hz), 7.44-7.38 (2H, m), 4.70(2H, s), 4.28(2H, t,
J=5.6Hz), 3.72(2H, t, J=5.8Hz), 2.34(2H, s), 0.98(9H, s). 407
.sup.1H-NMR(DMSO-d.sub.6) .delta.: 8.81-8.76(2H, m), 8.72(1H, s),
8.23(1H, t, J=7.9Hz), 7.65 (1H, t, J=6.5Hz), 7.46-7.41(1H, m),
7.30-7.24(2H, m), 7.20-7.14(1H, m), 7.02 (1H, s), 5.02(2H, s),
2.38(3H, s). 408 .sup.1H-NMR(DMSO-d.sub.6) .delta.: 7.74(1H, s),
7.49-7.37(2H, m), 7.27-7.12(2H, m), 6.86(1H, s), 4.92(2H, s),
2.20(3H, s), 1.18(9H, s). 409 .sup.1H-NMR(DMSO-d.sub.6) .delta.:
12.48(1H, dd, J=11.4, 4.9Hz), 7.46-7.36(2H, m), 7.24-7.11(2H, m),
4.70(2H, s), 4.17(2H, t, J=5.6Hz), 4.12(2H, s), 3.64(2H, t, J=
5.6Hz), 3.24(3H, s), 1.12(9H, s). 410 H-NMR(DMSO-d.sub.6) .delta.:
10.5-10.7(1H, m), 8.6-8.7(1H, m), 8.39(1H, s), 7.9-8.1 (1H, m),
7.4-7.6(4H, m), 7.20(2H, t, J=8.7Hz), 4.7-4.8(4H, m), 4.4-4.5(2H,
m), 3.6-3.8(2H, m). 411 .sup.1H-NMR(DMSO-d.sub.6) .delta.:
12.36(1H, br s), 10.39-10.32(1H, m), 8.41(1H, s), 7.61-7.58(1H, m),
7.46-7.39(2H, m), 7.24-7.17(2H, m), 6.42-6.39(1H, m), 6.29 (1H, d,
J=3.2Hz), 4.71(2H, s), 4.53(2H, d, J=5.6Hz), 4.43-4.35(2H, m),
3.76-3.69(2H, m). 412 .sup.1H-NMR(DMSO-d.sub.6) .delta.: 12.68(1H,
s), 7.70(1H, s), 7.47-7.41(2H, m), 7.24-7.17(2H, m), 4.70(2H, s),
3.60(2H, s), 1.40(6H, s), 1.18(9H, s). 413
.sup.1H-NMR(DMSO-d.sub.6) .delta.: 12.75(1H, s), 8.15(1H, s),
7.44(2H, dd, J=8.8, 5.6Hz), 7.20(2H, t, J=8.8Hz), 4.70(2H, s),
3.59(2H, s), 1.41(6H, s). 414 .sup.1H-NMR(DMSO-d.sub.6) .delta.:
8.81(1H, d, J=4.6Hz), 8.70(1H, d, J=8.3Hz), 8.66(1H, s), 8.40(1H,
t, J=7.9Hz), 7.78(1H, t, J=6.7Hz), 7.48(2H, dd, J=8.3, 5.6Hz),
7.23(2H, t, J=1.4Hz), 4.75(2H, s), 3.70(2H, s), 1.55(6H, s). 415
.sup.1H-NMR(DMSO-d.sub.6) .delta.: 12.36(1H, br s), 10.39(1H, br
s), 8.41(1H, s), 7.52-7.14 (8H, m), 4.71(2H, s), 4.50(2H, d,
J=5.6Hz), 4.42-4.35(2H, m), 3.77-3.68(2H, m), 3.02(6H, s). 416
.sup.1H-NMR(DMSO-d.sub.6) .delta.: 9.86(1H, d, J=1.4Hz),
8.67-8.62(1H, m), 8.56-8.49 (2H, m), 7.49-7.30(4H, m), 4.74(2H, s),
4.42(2H, t, J=5.6Hz), 3.77(2H, t, J=5.6Hz). 417
.sup.1H-NMR(DMSO-d.sub.6) .delta.: 9.85(1H, d, J=1.4Hz), 8.64(1H,
t, J=2.1Hz), 8.55-8.51 (2H, m), 7.47-7.39(2H, m), 7.25-7.16(2H, m),
4.72(2H, s), 4.40(2H, t, J=5.6Hz), 3.74(2H, t, J=5.6Hz). 418
.sup.1H-NMR(DMSO-d.sub.6) .delta.: 7.86-7.79(3H, m), 7.65-7.56(2H,
m), 7.53-7.47(2H, m), 7.43-7.36(2H, m), 4.67(2H, s), 4.32-4.25(2H,
m), 3.74-3.67(2H, m). 419 .sup.1H-NMR(DMSO-d.sub.6) .delta.:
7.67-7.61(2H, m), 7.46-7.38(4H, m), 7.37-7.31(3H, m), 4.71(2H, s),
4.50(2H, s), 4.26-4.20(2H, m), 3.75-3.69(2H, m). 420
.sup.1H-NMR(DMSO-d.sub.6) .delta.: 7.90-7.86(1H, m), 7.84(1H, s),
7.65-7.58(2H, m), 7.44-7.38 (2H, m), 7.12-7.08(1H, m), 4.68(2H, s),
4.33-4.26(2H, m), 3.76-3.68(2H, m). 421 .sup.1H-NMR(DMSO-d.sub.6)
.delta.: 12.39(1H, s), 10.55(1H, t, J=6.3Hz), 8.41(1H, s), 7.89
(2H, d, J=8.3Hz), 7.55(2H, d, J=8.3Hz), 7.43(2H, dd, J=8.8, 5.6Hz),
7.21(2H, t, J=8.8Hz), 4.72(2H, s), 4.65(2H, d, J=6.3Hz),
4.42-4.36(2H, m), 3.77-3.69 (2H, m), 3.19(3H, s). 422
.sup.1H-NMR(DMSO-d.sub.6) .delta.: 7.49-7.42(2H, m), 7.27-7.19(2H,
m), 7.01(1H, br s), 4.79 (1H, d, J=14.8Hz), 4.74(1H, d, J=14.8Hz),
4.63-4.52(1H, m), 4.47-4.34(1H, m), 3.80-3.68(2H, m), 3.41-3.32(1H,
m), 3.06-2.96(1H, m), 2.87-2.74(1H, m), 0.91 (9H, s). 423
.sup.1H-NMR(DMSO-d.sub.6) .delta.: 9.55(1H, s), 9.18(1H, s),
7.49(1H, s), 7.44-7.30(4H, m), 6.97(1H, s), 4.98(2H, s), 2.22(3H,
s), 2.17(3H, s). 424 .sup.1H-NMR(DMSO-d.sub.6) .delta.: 8.79(1H, d,
J=4.6Hz), 8.31-8.12(1H, m), 7.68(1H, t, J= 6.3Hz), 7.59(1H, d,
J=7.9Hz), 7.51-7.38(2H, m), 7.28-7.13(2H, m), 4.74(2H, d, J=7.0Hz),
4.30(2H, t, J=5.6Hz), 4.26(2H, s), 3.70(2H, t, J=5.3Hz), 3.12(3H,
s). 425 .sup.1H-NMR(DMSO-d.sub.6) .delta.: 7.91(1H, s),
7.49-7.42(2H, m), 7.32-7.16(3H, m), 6.92(1H, d, J=6.0Hz), 4.94(2H,
s), 3.42(2H, s), 3.17(3H, s), 1.16(6H, s). 426
.sup.1H-NMR(DMSO-d.sub.6) .delta.: 10.81-10.75(1H, m), 8.51(1H, d,
J=6.0Hz), 8.40(1H, s), 7.47-7.40(2H, m), 7.24-7.16(2H, m), 6.87(1H,
d, J=6.0Hz), 4.72(2H, s), 4.66 (2H, d, J=5.1Hz), 4.43-4.36(2H, m),
3.98(3H, s), 3.76-3.71(2H, m). 427 .sup.1H-NMR(DMSO-d.sub.6)
.delta.: 7.43(2H, dd, J=8.8, 5.6Hz), 7.20(2H, t, J=8.8Hz), 4.71
(2H, s), 3.96(1H, br s), 3.84(2H, br s), 3.63-3.54(2H, m), 1.13(9H,
s), 1.11(9H, s). 428 .sup.1H-NMR(DMSO-d.sub.6) .delta.: 12.36(1H,
br s), 10.38(1H, t, J=5.8Hz), 9.92(1H, s), 8.41 (1H, s),
7.55-7.50(2H, m), 7.46-7.39(2H, m), 7.25-7.17(4H, m), 4.71(2H, s),
4.47-4.38(4H, m), 3.76-3.70(2H, m), 2.02(3H, s). 429
.sup.1H-NMR(DMSO-d.sub.6) .delta.: 8.52-8.44(1H, m), 7.72(1H, d,
J=2.1Hz), 7.66(1H, d, J= 8.3Hz), 7.43(1H, dd, J=8.3, 2.1Hz),
7.29-7.14(2H, m), 5.08(2H, s), 3.67(2H, t, J= 5.9Hz), 2.90(2H, t,
J=5.9Hz). 430 .sup.1H-NMR(DMSO-d.sub.6) .delta.: 8.51(1H, br s),
7.72(1H, br s), 7.66(1H, dd, J=8.3, 3.7 Hz), 7.41(1H, d, J=8.3Hz),
7.22(1H, br s), 6.98(1H, br s), 5.07(2H, s), 4.65-4.54 (1H, m),
1.89-1.69(2H,
m), 0.98-0.89(3H, m). 431 .sup.1H-NMR(DMSO-d.sub.6) .delta.:
7.76-7.68(2H, m), 7.65(1H, d, J=8.8Hz), 7.56-7.37(2H, m),
7.12-7.02(1H, m), 6.93(1H, br s), 5.03(2H, s), 3.49(2H, t,
J=6.0Hz), 2.71 (2H, t, J=7.4Hz), 1.75-1.64(2H, m). 432
.sup.1H-NMR(DMSO-d.sub.6) .delta.: 8.34(1H, d, J=7.6Hz), 7.70(1H,
d, J=1.9Hz), 7.65(1H, d, J=8.3Hz), 7.39(1H, dd, J=8.3, 1.9Hz),
6.94(1H, s), 6.60(1H, d, J=7.6Hz), 5.94(1H, br s), 5.03(1H, d,
J=14.8Hz), 4.96(1H, d, J=14.8Hz), 4.21(1H, d, J=7.9Hz),
2.13-1.99(1H, m), 0.97(3H, d, J=6.5Hz), 0.81(3H, d, J=6.5Hz). 433
.sup.1H-NMR(DMSO-d.sub.6) .delta.: 8.23(1H, d, J=7.6Hz),
7.69-7.58(2H, m), 7.32-7.13 (6H, m), 6.79(1H, s), 6.72(1H, d,
J=7.6Hz), 4.94(2H, s), 3.01-2.82(4H, m). 434
.sup.1H-NMR(DMSO-d.sub.6) .delta.: 8.47(1H, s), 7.44(2H, dd, J=8.6,
5.7Hz), 7.26-7.13 (3H, m), 6.80(1H, d, J=6.2Hz), 4.89(2H, s). 435
.sup.1H-NMR(DMSO-d.sub.- 6) .delta.: 8.48(1H, d, J=7.4Hz), 7.71(1H,
d, J=1.9Hz), 7.64(1H, d, J=8.3Hz), 7.41(1H, dd, J=8.3, 1.9Hz),
7.17(1H, s), 5.11(2H, s), 3.24(1H, sept, J=6.5Hz), 1.24(6H, d,
J=6.5Hz). 436 .sup.1H-NMR(DMSO-d.sub.6) .delta.: 11.40(1H, br s),
8.08(1H, d, J=7.9Hz), 7.46(1H, br s), 7.43-7.32(3H, m), 6.53(1H, d,
J=7.9Hz), 5.04(2H, s), 2.43(3H, s). 437 .sup.1H-NMR(DMSO-d.sub.6)
.delta.: 12.07(1H, br s), 7.72(1H, s), 7.45(1H, br s), 7.43-7.30
(3H, m), 4.71(2H, s), 4.29-4.21(2H, m), 3.76-3.69(2H, m), 1.20(9H,
s).
Experimental Example 1
[1485] The following explains evaluation methods of the HIV
integrase inhibitory activity of the compound of the present
invention.
[1486] (i) Construction of Recombinant Integrase Gene Expression
System
[1487] The 185th phenylalanine of HIV integrase full length gene
(J. Virol., 67, 425-437 (1993)) was substituted by histidine and
inserted into the restriction enzyme NdeI and XhoI sites of plasmid
pET21a(+) (Novagen), whereby an integrase expression vector
pET21a-INH was constructed.
[1488] (ii) Production and Purification of Integrase Protein
[1489] Escherichia coli recombinant BL21(DE3) transformed with
plasmid pET21a-INH obtained in (i) was shake cultured at 37.degree.
C. in a liquid medium containing ampicillin. When the culture
reached the logarithmic growth phase,
isopropyl-.beta.-D-thiogalactopyranoside was added to promote
expression of integrase gene. The culture was continued for 3 hr to
promote accumulation of the integrase protein. The recombinant E.
coli was collected in pellets by centrifugal separation and
preserved at -80.degree. C.
[1490] The E. coli was suspended in Lysis buffer (20 mM HEPES (pH
7.5), 5 mM DTT, 10 mM CHAPS, 10% glycerol) containing 1M sodium
chloride and subjected to repeat pressurization and
depressurization for rupture, and centrifugal separation at
4.degree. C., 40,000.times.g, 60 min to recover a water-soluble
fraction (supernatant). This was diluted 10-fold with Lysis buffer
free of sodium chloride, mixed with SP-Sepharose (Pharmacia
Corporation) and stirred at 4.degree. C. for 30 min to allow
adsorption of integrase protein to the resin. The resin was washed
with Lysis buffer containing 100 mM sodium chloride and the
integrase protein was eluted with Lysis buffer containing 1M sodium
chloride.
[1491] The eluted integrase protein solution was applied to a
Superdex 75 (Pharmacia Corporation) column for gel filtration. The
protein was eluted with Lysis buffer containing 1M sodium
chloride.
[1492] The obtained fractions of the integrase protein were
collected and preserved at -80.degree. C.
[1493] (iii) Preparation of DNA Solution
[1494] The following DNA synthesized by Greiner was dissolved in TE
buffer (10 mM Tris-hydrochloric acid (pH 8.0), 1 mM EDTA) and mixed
with donor DNA, target DNA, and each complementary strand (+ and -
strands) to 1 .mu.M. The mixture was heated at 95.degree. C. for 5
min, 80.degree. C. for 10 min, 70.degree. C. for 10 min, 60.degree.
C. for 10 min, 50.degree. C. for 10 min and 40.degree. C. for 10
min and preserved at 25.degree. C. to give a double stranded DNA,
which was used for the test.
[1495] Donor DNA (- strand having biotin attached to the 5'
terminal)
[1496] Donor+ strand: 5'-Biotin-ACC CTT TTA GTC AGT GTG GAA AAT CTC
TAG CA-3' (SEQ ID NO:1)
[1497] Donor- strand: 5'-ACT GCT AGA GAT TTT CCA CAC TGA CTA AAA
G-3' (SEQ ID NO:2)
[1498] Target DNA (+, - strands both having digoxigenin added at 3'
terminal)
38 Target + strand: 5'-TGA CCA AGG GCT AAT TCA CT-Dig-3' (SEQ ID
NO: 3) Target - strand: 5'-AGT GAA TTA GCC CTT GGT CA-Dig-3' (SEQ
ID NO: 4)
[1499] (iv) Determination of Enzyme (HIV Integrase) Inhibitory
Activity
[1500] The donor DNA was diluted with TE buffer to 10 nM, of which
50 .mu.l was added to each well of streptavidin-coated microtiter
plate (Roche) and allowed to adsorb at 37.degree. C. for 60 min.
The DNA was washed with phosphate buffer (Dulbecco PBS, Sanko
Junyaku Co., Ltd.) containing 0.1% Tween 20 and phosphate buffer.
Then, a reaction mixture (70 .mu.l) having the following
composition, a test substance (10 .mu.l) diluted with the reaction
mixture and 100 .mu.g/ml integrase protein (10 .mu.l) were added to
each well and reacted at 37.degree. C. for 60 min.
[1501] Composition of the reaction mixture: 30 mM MOPS
(3-morpholinopropanesulfonic acid), 5 mM magnesium chloride, 3 mM
DTT (dithiothreitol), 0.1 mg/ml BSA (bovine serum albumin), 5%
glycerol, 10% DMSO (dimethyl sulfoxide), 0.01% Tween 20.
[1502] Then, 50 nM target DNA (10 .mu.l) was added, reacted at
37.degree. C. for 10 min and washed with phosphate buffer
containing 0.1% Tween 20 to stop the reaction.
[1503] Then, 100 mU/ml peroxidase labeled anti-digoxigenin antibody
solution (Roche, 100 .mu.l) was added, and the mixture was reacted
at 37.degree. C. for 60 min, followed by washing with phosphate
buffer containing 0.1% Tween 20.
[1504] A peroxidase color solution (Bio Rad, 100 .mu.l) was added
and allowed to react at room temperature for 4 min. The color
reaction was stopped by adding 1N sulfuric acid (100 .mu.l). The
absorbance at 450 nm was measured.
[1505] The HIV integrase inhibitory activity (IC.sub.50) of the
compound of the present invention was calculated from the
inhibition rate according to the following formula.
inhibition rate(%)=[1-(Object-Blank)/(Control-Blank)].times.100
[1506] Object; absorbance of well in the presence of test
compound
[1507] Control; absorbance of well in the absence of test
compound
[1508] Blank; absorbance of well in the absence of test compound,
in the absence of integrase protein
[1509] The results are shown in Tables 38-46. IC.sub.50 shows the
following ranges.
[1510] +: not less than 1 .mu.M and less than 10 .mu.M
[1511] ++: not less than 0.1 .mu.M and less than 1 .mu.M
[1512] +++: not less than 0.01 .mu.M and less than 0.1 .mu.M
[1513] ++++: less than 0.01 .mu.M
Experimental Example 2
Evaluation of Antivirus Activity
[1514] The effect of combined use of the compound of the present
invention and existent anti-HIV agents can be determined in the
following manner.
[1515] For example, the effect of combined use of two agents from
existent nucleoside reverse transcriptase inhibitors (zidovudine,
lamivudine, tenofovir), non-nucleoside reverse transcriptase
inhibitors (efavirenz) or protease inhibitors (indinavir,
nelfinavir) and test substance A and the like are evaluated using
CEM-SS cells infected with HIV-1 IIIB by XTT method.
[1516] In addition, the effect of combined use of three agents of
test substance A, zidovudine and lamivudine, or test substance A,
tenofovir and lamivudine, and the like is evaluated.
[1517] Prior to the combined use test, IC.sub.50 and CC.sub.50 of
each pharmaceutical agent alone are measured. 5 concentrations of
pharmaceutical agent A and 9 concentrations of pharmaceutical agent
B, determined based on these results, are combined to evaluate the
effect of combined use of two agents. For combined use of three
agents, a high concentration pharmaceutical agent B and a
pharmaceutical agent C are mixed and pharmaceutical agent A and the
concentration are combined for evaluation.
[1518] The test results of the test substance and combination drug
alone or in combination thereof are analyzed based on the programs
of Prichard and Shipman MacSynergy II version 2.01 and Deltagraph
version 1.5 d. A three-dimensional plot is drawn from % inhibition
at the concentrations of each combined pharmaceutical agent,
obtained from 3 times of tests, with 95% (or 68%, 99%) confidence
limits, and the effect of the combined use is evaluated based on
the numerical values of .mu.M.sup.2% calculated therefrom. The
criteria of evaluation are shown in the following.
[1519] Definition of interaction .mu.M.sup.2%
[1520] Strong synergistic action >100
[1521] Slight synergistic action +51-+100
[1522] Additive action +50--50
[1523] Slight antagonistic action -51--100
[1524] Strong antagonistic action <-100
39 TABLE 38 Example No. IC.sub.50 Example No. IC.sub.50 1 ++++ 3
+++ 4 +++ 5 +++ 6 +++ 7 ++++ 8 ++++ 9 +++ 10 +++ 11 ++++ 12 +++ 13
+++ 14 +++ 15 +++ 16 +++ 17 +++ 18 +++ 19 +++ 20 +++ 21 +++ 22 +++
23 +++ 24 +++ 25 +++ 26 +++ 27 ++ 28 +++ 29 +++ 30 +++ 31 +++ 32
+++ 33 +++ 34 +++ 35 +++ 36 +++ 37 +++ 38 +++ 39 +++ 40 +++ 41 +++
42 +++ 43 +++ 44 ++ 45 +++ 46 +++ 47 ++++ 48 +++ 49 +++
[1525]
40 TABLE 39 Example No. IC.sub.50 Example No. IC.sub.50 50 +++ 51
+++ 53 +++ 54 +++ 55 +++ 56 +++ 57 +++ 58 ++++ 59 ++++ 60 +++ 61
+++ 62 +++ 63 ++++ 64 +++ 65 ++ 66 +++ 67 +++ 68 +++ 70 +++ 71 +++
72 ++++ 73 +++ 75 +++ 76 +++ 78 ++++ 79 +++ 80 +++ 81 ++++ 82 +++
83 +++ 84 ++++ 85 +++ 86 ++++ 87 ++++ 88 +++ 89 +++ 90 ++++ 91 +++
92 ++++ 93 +++ 94 +++ 95 +++ 96 ++++ 97 +++ 98 +++ 99 +++ 100 +++
101 +++
[1526]
41 TABLE 40 Example No. IC.sub.50 Example No. IC.sub.50 102 +++ 103
+++ 104 +++ 105 +++ 106 +++ 107 +++ 108 +++ 109 ++ 110 ++ 111 +++
112 +++ 113 +++ 114 ++++ 115 ++++ 116 ++++ 117 ++++ 118 +++ 119 ++
120 ++++ 121 ++++ 122 ++++ 123 ++ 124 +++ 125 ++++ 126 +++ 127 ++++
128 +++ 129 +++ 130 ++++ 131 +++ 132 +++ 133 ++++ 134 +++ 135 +++
136 ++++ 137 +++ 138 +++ 139 +++ 140 +++ 141 ++++ 142 +++ 143 ++
144 +++ 145 ++ 146 ++ 147 +++ 148 +++ 149 ++++
[1527]
42 TABLE 41 Example No. IC.sub.50 Example No. IC.sub.50 150 +++ 151
+++ 152 ++ 153 +++ 154 +++ 155 ++++ 156 +++ 157 +++ 158 +++ 159 +++
160 +++ 161 +++ 162 +++ 163 ++++ 164 +++ 165 +++ 166 +++ 167 +++
168 +++ 169 ++ 170 +++ 171 ++++ 172 ++++ 173 +++ 174 +++ 175 ++++
176 +++ 177 +++ 178 +++ 179 +++ 180 ++++ 181 +++ 182 +++ 183 +++
184 +++ 185 +++ 186 +++ 187 +++ 188 +++ 189 +++ 190 +++ 191 +++ 192
+++ 193 +++ 194 +++ 195 +++ 196 +++ 197 +++
[1528]
43 TABLE 42 Example No. IC.sub.50 Example No. IC.sub.50 198 +++ 199
+++ 200 ++ 201 +++ 202 +++ 203 ++++ 204 ++++ 205 ++++ 206 +++ 207
++++ 208 ++++ 209 +++ 210 +++ 211 ++++ 212 +++ 213 +++ 214 ++++ 215
++++ 216 +++ 217 ++++ 218 ++++ 219 +++ 220 +++ 221 ++++ 222 ++++
223 +++ 224 +++ 225 ++++ 226 ++ 227 +++ 228 +++ 229 ++++ 230 ++++
231 ++++ 232 ++++ 233 ++++ 234 ++++ 235 +++ 236 +++ 237 +++ 238
++++ 239 ++++ 240 ++++ 241 ++++ 242 ++++ 243 ++++ 244 ++++ 245
+++
[1529]
44 TABLE 43 Example No. IC.sub.50 Example No. IC.sub.50 246 +++ 247
+++ 248 ++++ 249 ++++ 250 +++ 251 ++++ 252 ++++ 253 ++++ 254 ++++
255 ++++ 256 ++++ 257 ++++ 258 ++++ 259 ++++ 260 ++++ 261 +++ 262
++++ 263 ++++ 264 ++++ 265 ++++ 266 ++++ 267 +++ 268 ++++ 269 ++++
270 +++ 271 +++ 272 +++ 273 +++ 274 +++ 275 ++++ 276 ++++ 277 ++++
278 ++++ 279 ++++ 280 +++ 281 +++ 282 ++++ 283 +++ 284 +++ 285 +++
286 ++++ 287 ++++ 288 ++++ 289 ++++ 290 +++ 291 +++ 292 ++++ 293
+++
[1530]
45 TABLE 44 Example No. IC.sub.50 Example No. IC.sub.50 294 ++++
295 +++ 296 ++++ 297 +++ 298 ++++ 299 +++ 300 +++ 301 ++ 302 +++
303 +++ 304 ++++ 305 ++++ 306 +++ 307 ++ 308 +++ 309 +++ 310 ++ 311
++++ 312 +++ 313 +++ 314 +++ 315 +++ 316 +++ 317 +++ 318 +++ 319
+++ 320 ++++ 321 +++ 322 +++ 323 +++ 324 +++ 325 +++ 326 ++ 327
++++ 328 +++ 329 +++ 330 ++++ 331 +++ 332 +++ 333 +++ 334 +++ 335
+++ 336 ++++ 337 ++++ 338 +++ 339 ++ 340 ++++ 341 ++++
[1531]
46 TABLE 45 Example No. IC.sub.50 Example No. IC.sub.50 342 ++++
343 ++++ 344 ++++ 345 ++++ 346 +++ 347 ++++ 348 +++ 349 +++ 350
++++ 351 +++ 352 +++ 353 ++++ 354 +++ 355 +++ 356 +++ 357 +++ 358
+++ 359 +++ 360 ++++ 361 +++ 362 +++ 363 +++ 364 ++++ 365 +++ 366
++ 367 +++ 368 +++ 369 ++++ 370 ++++ 371 +++ 372 +++ 373 ++++ 374
+++ 375 +++ 376 +++ 377 ++++ 378 ++++ 379 ++ 380 +++ 381 +++ 382
+++ 383 +++ 384 ++++ 385 +++ 386 +++ 387 +++ 388 ++ 389 +++
[1532]
47 TABLE 46 Example No. IC.sub.50 Example No. IC.sub.50 391 +++ 392
+++ 393 +++ 394 +++ 395 ++++ 396 +++ 397 +++ 398 +++ 399 ++++ 400
++++ 401 +++ 402 +++ 403 +++ 404 +++ 405 ++++ 406 +++ 407 +++ 408
+++ 409 +++ 410 +++ 411 +++ 412 +++ 413 ++ 414 ++ 415 +++ 416 +++
417 +++ 418 +++ 419 ++++ 420 +++ 421 +++ 422 +++ 423 +++ 424 +++
425 ++++ 426 +++ 427 +++ 428 +++ 429 +++ 430 +++ 431 +++ 432
++++
[1533] As is clear from the above-mentioned results, the compound
of the invention shows high inhibitory activity against HIV
integrase.
[1534] Therefore, these compounds can be a pharmaceutical agent
effective prophylaxis or treatment of AIDS, as an anti-HIV agent
having an HIV integrase inhibitory activity. In addition, by the
combined use with other anti-HIV agents such as a protease
inhibitor, a reverse transcriptase inhibitor and the like, it can
be a more effective anti-HIV agent. Because it shows
integrase-specific high inhibitory activity, the compound can be a
pharmaceutical agent safe on human body, which causes only a fewer
side effects.
[1535] While a Formulation Example is given in the following, the
present invention is not limited to this example.
Formulation Example
[1536]
48 (a) Compound of Example 1 10 g (b) Lactose 50 g (c) Cornstarch
15 g (d) Carboxymethylcellulose sodium 44 g (e) Magnesium stearate
1 g
[1537] The total amount of (a), (b) and (c) and 30 g of (d) are
kneaded with water, and, after vacuum drying, granulated. The
granules are mixed with 14 g of (d) and 1 g of (e) and applied to a
tableting machine to give 1000 tablets, each containing 10 mg of
(a).
Industrial Applicability
[1538] The present invention relates to a novel nitrogen-containing
fused ring compound and a pharmaceutically acceptable salt thereof,
which are useful as anti-HIV agents, and novel use of a certain
kind of nitrogen-containing fused ring compound and a
pharmaceutically acceptable salt thereof as anti-HIV agents. More
specifically, the present invention relates to an anti-HIV agent
containing a nitrogen-containing fused ring compound or a
pharmaceutically acceptable salt thereof showing an anti-HIV
activity particularly based on an integrase inhibitory activity.
They are effective for the prophylaxis or treatment of the onset of
AIDS. Particularly, since they have an integrase inhibitory
activity, they can be effective anti-HIV agents and the present
invention can provide pharmaceutical agents having an anti-HIV
activity, particularly pharmaceutical agents having an integrase
inhibitory activity.
Sequence Listing Free Text
[1539] SEQ ID NO:1: Donor+ strand for activity determination of HIV
integrase
[1540] SEQ ID NO:2: Donor- strand for activity determination of HIV
integrase
[1541] SEQ ID NO:3: Target+ strand for activity determination of
HIV integrase
[1542] SEQ ID NO:4: Target- strand for activity determination of
HIV integrase
[1543] This application is based on patent application Nos.
2003-293117 and 2004-134896 filed in Japan, the contents of which
are hereby incorporated by reference.
* * * * *