U.S. patent application number 11/064319 was filed with the patent office on 2007-03-01 for tetracyclic fused heterocyclic compound and use thereof as hcv polymerase inhibitor.
This patent application is currently assigned to Japan Tobacco Inc.. Invention is credited to Izuru Ando, Shintaro Hirashima, Kazutaka Ikegashira, Yoko Matsumoto, Yasushi Niwa, Satoru Noji, Yukihiro Nomura, Takahiro Oka, Toshihiro Sato, Hiroshi Yamanaka.
Application Number | 20070049593 11/064319 |
Document ID | / |
Family ID | 37805154 |
Filed Date | 2007-03-01 |
United States Patent
Application |
20070049593 |
Kind Code |
A1 |
Oka; Takahiro ; et
al. |
March 1, 2007 |
Tetracyclic fused heterocyclic compound and use thereof as HCV
polymerase inhibitor
Abstract
The present invention relates to a tetracyclic fused
heterocyclic compound represented by the following formula [I]
##STR1## wherein each symbol is as defined in the specification, or
a pharmaceutically acceptable a salt thereof, and a hepatitis C
virus (HCV) polymerase inhibitor and a therapeutic agent for
hepatitis C containing this compound. The compound of the present
invention shows an anti-HCV activity based on the HCV polymerase
inhibitory activity, and useful as an agent for the prophylaxis or
treatment of hepatitis C.
Inventors: |
Oka; Takahiro; (Osaka,
JP) ; Ikegashira; Kazutaka; (Osaka, JP) ;
Hirashima; Shintaro; (Osaka, JP) ; Yamanaka;
Hiroshi; (Osaka, JP) ; Noji; Satoru; (Osaka,
JP) ; Niwa; Yasushi; (Osaka, JP) ; Matsumoto;
Yoko; (Osaka, JP) ; Sato; Toshihiro; (Osaka,
JP) ; Ando; Izuru; (Osaka, JP) ; Nomura;
Yukihiro; (Osaka, JP) |
Correspondence
Address: |
LEYDIG VOIT & MAYER, LTD
TWO PRUDENTIAL PLAZA, SUITE 4900
180 NORTH STETSON AVENUE
CHICAGO
IL
60601-6780
US
|
Assignee: |
Japan Tobacco Inc.
Tokyo
JP
|
Family ID: |
37805154 |
Appl. No.: |
11/064319 |
Filed: |
February 23, 2005 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
60623822 |
Oct 29, 2004 |
|
|
|
Current U.S.
Class: |
514/243 ;
514/248; 514/249; 514/265.1; 514/300; 514/406; 544/182; 544/236;
544/280; 544/330; 546/113; 548/495 |
Current CPC
Class: |
C07D 487/14 20130101;
C07D 513/04 20130101; C07D 487/04 20130101; C07D 498/04 20130101;
A61P 1/16 20180101; C07D 498/14 20130101; A61P 31/14 20180101 |
Class at
Publication: |
514/243 ;
514/249; 514/265.1; 514/300; 514/406; 514/248; 544/182; 544/236;
544/280; 544/330; 546/113; 548/495 |
International
Class: |
C07D 471/02 20060101
C07D471/02; A61K 31/53 20060101 A61K031/53; A61K 31/519 20060101
A61K031/519; A61K 31/498 20060101 A61K031/498; A61K 31/503 20060101
A61K031/503; A61K 31/4745 20060101 A61K031/4745 |
Foreign Application Data
Date |
Code |
Application Number |
Feb 24, 2004 |
JP |
2004-48815 |
Jun 7, 2004 |
JP |
2004-169190 |
Oct 8, 2004 |
JP |
2004-296390 |
Claims
1. A compound represented by the following formula [I] or a
pharmaceutically acceptable salt thereof: ##STR564## is C.dbd.C--N
or N--C.dbd.C, G.sup.3, G.sup.4 and G.sup.5 are each independently
a carbon atom or a nitrogen atom, when at least one of G.sup.3,
G.sup.4 and G.sup.5 is a carbon atom, said carbon atom is
optionally substituted by R.sup.3, Q is (1) --(CH.sub.2).sub.b-- or
(2) --(CH.sub.2).sub.c-Q.sup.1-(CH.sub.2).sub.d-- (wherein b is an
integer of 1 to 4, c and d are each independently 0 or an integer
of 1 to 4, Q.sup.1 is (1') --O--, (2') --NH--, (3') --S--, (4')
--OCO--, (5') --OCONH--, (6') --CO--, (7') --SO--, (8')
--SO.sub.2--, (9') --NHCO--, (10') --NHSO.sub.2--, (11') --NHCOO--,
(12') --COO--, (13') --CONH--, (14') --SO.sub.2NH--, (15')
--NHCONH--, (16') --NHSO.sub.2NH--, (17') --CH.dbd.CH--, (18')
--CH.dbd.N-- or (19') --N.dbd.CH--), ring A is (1) benzene, (2)
cyclopentane or cyclohexane, (3) cyclopentene or cyclohexene or (4)
a 5- or 6-membered heterocycle comprising 1 to 4 heteroatoms
selected from oxygen atom, nitrogen atom and sulfur atom, G.sup.6
is a carbon atom or a nitrogen atom, a broken line in ring A shows
a single bond or a double bond, R.sup.1 is (1) a carboxyl group,
(2) a carboxylic acid equivalent, (3) --CONR.sup.11R.sup.12
(wherein R.sup.11 and R.sup.12 are each independently (1') a
hydrogen atom, (2') a C.sub.1-6 alkyl group optionally substituted
by 1 to 3 substituents selected from the following group E, (3') a
C.sub.2-6 alkenyl group optionally substituted by 1 to 3
substituents selected from the following group E, (4') a C.sub.6-14
aryl group optionally substituted by 1 to 5 substituents selected
from the following group E, (5') a heterocyclic group optionally
substituted by 1 to 5 substituents selected from the following
group E (wherein said heterocyclic group comprises 1 to 4
heteroatoms selected from oxygen atom, nitrogen atom and sulfur
atom), (6') a C.sub.3-10 cycloalkyl group optionally substituted by
1 to 5 substituents selected from the following group E, (7')
--NR.sup.131R.sup.132 (8') --NHCOOR.sup.133, (9') --NHCOR.sup.134
(wherein R.sup.131, R.sup.132, R.sup.133 and R.sup.134 are each
independently a hydrogen atom or a group selected from the
following group F), (10')
--CR.sup.135R.sup.136-L.sup.100-R.sup.137, (11')
--CR.sup.135R.sup.136-L.sup.100-CONR.sup.140--R.sup.137, ##STR565##
(wherein R.sup.135, R.sup.136, R.sup.138 and R.sup.139 are each
independently (1'') a hydrogen atom or (2'') a group selected from
the following group G, group G: (1''') cyano group, (2''')
--COOR.sup.142 (wherein R.sup.142 is a hydrogen atom or a group
selected from the following group F) (3''') --CONR.sup.143R.sup.144
(wherein R.sup.143 and R.sup.144 are each independently a hydrogen
atom, a C.sub.1-6 alkoxy group or a group selected from the
following group F) (4''') a C.sub.1-6 alkyl group optionally
substituted by 1 to 3 substituents selected from the following
group A, (5''') a C.sub.2-6 alkenyl group optionally substituted by
1 to 3 substituents selected from the following group A, (6''') a
C.sub.6-14 aryl group optionally substituted by 1 to 5 substituents
selected from the following group B, (7''') a heterocyclic group
optionally substituted by 1 to 5 substituents selected from the
following group B (wherein said heterocyclic group comprises 1 to 4
heteroatoms selected from oxygen atom, nitrogen atom and sulfur
atom), (8''') a C.sub.3-10 cycloalkyl group optionally substituted
by 1 to 5 substituents selected from the following group B, (9''')
a C.sub.6-14 aryl C.sub.1-6 alkyl group optionally substituted by 1
to 5 substituents selected from the following group B, (10''') a
heterocycle C.sub.1-6 alkyl group optionally substituted by 1 to 5
substituents selected from the following group B and (11''') a
C.sub.3-10 cycloalkyl C.sub.1-6 alkyl group optionally substituted
by 1 to 5 substituents selected from the following group B; or
R.sup.135 and R.sup.136, or, R.sup.138 and R.sup.139 are bonded to
each other, and optionally form, together with the carbon atom
bonded thereto, (1'') a C.sub.3-10 cycloalkyl group optionally
substituted by 1 to 5 substituents selected from the following
group B or (2'') a heterocyclic group optionally substituted by 1
to 5 substituents selected from the following group B (wherein said
heterocyclic group comprises 1 to 4 heteroatoms selected from
oxygen atom, nitrogen atom and sulfur atom), R.sup.137 is (1'') a
hydrogen atom, (2'') a carboxyl group, (3'') a C.sub.1-6 alkyl
group optionally substituted by 1 to 3 substituents selected from
the following group E, (4'') a C.sub.2-6 alkenyl group optionally
substituted by 1 to 3 substituents selected from the following
group E, (5'') a C.sub.6-14 aryl group optionally substituted by 1
to 5 substituents selected from the following group E, (6'') a
heterocyclic group optionally substituted by 1 to 5 substituents
selected from the following group E (wherein said heterocyclic
group comprises 1 to 4 heteroatoms selected from oxygen atom,
nitrogen atom and sulfur atom) or (7'') a C.sub.3-10 cycloalkyl
group optionally substituted by 1 to 5 substituents selected from
the following group E, R.sup.140 and R.sup.141 are each
independently (1'') a hydrogen atom or (2'') a C.sub.1-6 alkyl
group, L.sup.100 is (1'') a bond, (2'') --CO--, (3'')
--CH.sub.2O--, (4'') --CH.sub.2NH--, (5'') --CH.sub.2NHCO--, (6'')
a C.sub.1-6 alkylene optionally substituted by hydroxyl group or
(7'') a C.sub.2-6 alkenylene, L.sup.101 and L.sup.102 are each
independently (1'') a bond, (2'') --CO--, (3'') a C.sub.1-6
alkylene optionally substituted by hydroxyl group or (4'') a
C.sub.2-6 alkenylene, L.sup.103 is (1'') a bond or (2'') a
C.sub.1-6 alkylene, L.sup.104 is a C.sub.1-6 alkylene, L.sup.105 is
(1'') a bond or (2'') a C.sub.1-6 alkylene, L.sup.106 is (1'') a
bond, (2'') a C.sub.1-6 alkylene, (3'') --NH--, (4'')
--NH--CH.sub.2-- or (5'') --CH.sub.2--CONH--, ring D.sup.3, ring
D.sup.4 and ring D.sup.5 are each independently (1'') a C.sub.6-14
aryl group optionally substituted by 1 to 5 substituents selected
from the following group E, (2'') a C.sub.3-10 cycloalkyl group
optionally substituted by 1 to 5 substituents selected from the
following group E or (3'') a heterocyclic group optionally
substituted by 1 to 5 substituents selected from the following
group E (wherein said heterocyclic group comprises 1 to 4
heteroatoms selected from oxygen atom, nitrogen atom and sulfur
atom))), (4) --COOR.sup.103 (wherein R.sup.103 is a group selected
from the following group C or a glucuronic acid residue),
##STR566## (wherein ring D.sup.6 is a heterocyclic group optionally
substituted by 1 to 5 substituents selected from the following
group E (wherein said heterocyclic group comprises 1 to 4
heteroatoms selected from oxygen atom, nitrogen atom and sulfur
atom), ring D.sup.7 is a C.sub.6-14 aryl group optionally
substituted by 1 to 5 substituents selected from the following
group E), R.sup.2 may substitute at a substitutable position on
carbon atom or nitrogen atom constituting Q and is (1) a hydrogen
atom, (2) a group selected from the following group E, (3) a
C.sub.1-6 alkyl group optionally substituted by 1 to 3 substituents
selected from the following group E, (4) a C.sub.2-6 alkenyl group
optionally substituted by 1 to 3 substituents selected from the
following group E, ##STR567## {wherein L.sup.1 and L.sup.2 are each
independently (1') a bond, (2') C.sub.1-6 alkylene, (3') C.sub.2-6
alkenylene, (4') --(CH.sub.2).sub.u1--O--(CH.sub.2).sub.v1--, (5')
--(CH.sub.2).sub.u1--S--(CH.sub.2).sub.v1--, (6')
--(CH.sub.2).sub.u1--NR.sup.L1--(CH.sub.2).sub.v1--, (7')
--(CH.sub.2).sub.u1--CO--(CH.sub.2).sub.v1--, (8')
--(CH.sub.2).sub.u1--CONR.sup.L2--(CH.sub.2).sub.v1--, (9')
--(CH.sub.2).sub.u1--NR.sup.L2CO.sub.2--(CH.sub.2).sub.v1--, (10')
--(CH.sub.2).sub.u1--NR.sup.L2CONR.sup.L3--(CH.sub.2).sub.v1--,
(11') --(CH.sub.2).sub.u1--NR.sup.L2CO--(CH.sub.2).sub.v1--, (12')
--(CH.sub.2).sub.u1--NR.sup.L2SO.sub.2--(CH.sub.2).sub.v1--, (13')
--(CH.sub.2).sub.u1--SO.sub.2--(CH.sub.2).sub.v1--, (14')
--(CH.sub.2).sub.u1--SO.sub.2NR.sup.L2--(CH.sub.2).sub.v1-- or
(15')
--(CH.sub.2).sub.u1--N.sup.+R.sup.L2R.sup.L2'--(CH.sub.2).sub.v1--,
(wherein u, v, u1 and v1 are each independently 0 or an integer of
1 to 6, R.sup.L1 is (1'') a hydrogen atom, (2'') a group selected
from the following group C, (3'') --COR.sup.L11, (4'')
--CONR.sup.L11R.sup.L12, (5'') --COOR.sup.L11 or (6'')
--SO.sub.2R.sup.L13 (wherein R.sup.L11 and R.sup.L12 are each
independently a hydrogen atom or a group selected from the
following group C, and R.sup.L13 is a group selected from the
following group C), R.sup.L2, R.sup.L2 and R.sup.L3 are each
independently (1'') a hydrogen atom, (2'') a group selected from
the following group C, (3'') --COR.sup.L11 or (4'')
--SO.sub.2R.sup.L13 (wherein R.sup.L11 and R.sup.L13 are as defined
above)), L.sup.3 is (1') --CHR.sup.L14-- or (2') --NR.sup.L14--
(wherein R.sup.L14 is a group selected from the following group F),
ring D.sup.1 and ring D.sup.2 are each independently (1') a
C.sub.6-14 aryl group optionally substituted by 1 to 5 substituents
selected from the following group E, (2') a C.sub.3-10 cycloalkyl
group optionally substituted by 1 to 5 substituents selected from
the following group E or (3') a heterocyclic group optionally
substituted by 1 to 5 substituents selected from the following
group E (wherein said heterocyclic group comprises 1 to 4
heteroatoms selected from oxygen atom, nitrogen atom and sulfur
atom)}, R.sup.3 is (1) a hydrogen atom, (2) a halogen atom, (3) a
C.sub.1-6 alkanoyl group, (4) a carboxyl group, (5) a cyano group,
(6) a nitro group, (7) a C.sub.1-6 alkyl group optionally
substituted by 1 to 3 substituents selected from the following
group A, (8) --OR.sup.101 (wherein R.sup.101 is a hydrogen atom or
a group selected from the following group C), (9)
--NR.sup.102R.sup.119 (wherein R.sup.102 and R.sup.119 are each
independently a hydrogen atom, a C.sub.1-6 alkanoyl group or a
C.sub.1-6 alkylsulfonyl group), (10) --COOR.sup.103 (wherein
R.sup.103 is a group selected from the following group C or a
glucuronic acid residue), (1) --CONR.sup.104R.sup.105 (wherein
R.sup.104 and R.sup.105 are each independently a hydrogen atom, a
hydroxyl group, a cyano group, a C.sub.1-6 alkoxy group or a
C.sub.1-6 alkyl group optionally substituted by 1 to 3 substituents
selected from the following group A), (12) --SO.sub.2R.sup.106
(wherein R.sup.106 is a hydroxyl group, an amino group, a C.sub.1-6
alkyl group or a C.sub.1-6 alkylamino group), (13) --NHCOR.sup.107
(wherein R.sup.107 is an amino group or a C.sub.1-6 alkylamino
group), (14) --C(.dbd.NR.sup.108)--NH.sub.2 (wherein R.sup.108 is a
hydrogen atom, a C.sub.1-6 alkyl group optionally substituted by 1
to 3 substituents selected from the following group A, a hydroxyl
group or a C.sub.1-6 alkoxy group), (15)
--P(.dbd.O)(OR.sup.109).sub.2 (wherein R.sup.109 are each
independently a hydrogen atom or a group selected from the
following group C), (16) --P(.dbd.O)(OR.sup.110)NR.sup.111R.sup.112
(wherein R.sup.110, R.sup.111 and R.sup.112 are each independently
a hydrogen atom or a group selected from the following group C),
(17) --CONHCO--R.sup.113 (wherein R.sup.113 is a group selected
from the following group C), (18) --CONHSO.sub.2--R.sup.114
(wherein R.sup.114 is a group selected from the following group C),
(19) --SO.sub.2NHCO--R.sup.115 (wherein R.sup.115 is a group
selected from the following group C) or (20) a heterocyclic group
optionally substituted by 1 to 5 substituents selected from the
following group B (wherein said heterocyclic group comprises 1 to 4
heteroatoms selected from oxygen atom, nitrogen atom and sulfur
atom), R.sup.4 may substitute at a substitutable position on carbon
atom or nitrogen atom constituting Q and each is independently (1)
a halogen atom, (2) a C.sub.1-6 alkyl group optionally substituted
by 1 to 3 substituents selected from the following group A, (3)
--OR.sup.116 (wherein R.sup.116 is a hydrogen atom or a group
selected from the following group C), (4) --NR.sup.117R.sup.118
(wherein R.sup.117 and R.sup.118 are each independently a hydrogen
atom, a C.sub.1-6 alkanoyl group or a group selected from the
following group C), (5) a C.sub.6-14 aryl group optionally
substituted by 1 to 5 substituents selected from the following
group B or (6) a heterocyclic group optionally substituted by 1 to
5 substituents selected from the following group B (wherein said
heterocyclic group comprises 1 to 4 heteroatoms selected from
oxygen atom, nitrogen atom and sulfur atom), a is 0, 1 or 2,
R.sup.5 and R.sup.6 are each independently (1) a hydrogen atom, (2)
a halogen atom, (3) a C.sub.1-6 alkyl group optionally substituted
by 1 to 3 substituents selected from the following group A, (4)
--OR.sup.120 (wherein R.sup.120 is a hydrogen atom or a group
selected from the following group C) or (5) --NR.sup.121R.sup.122
(wherein R.sup.121 and R.sup.122 are each independently a hydrogen
atom, a C.sub.1-6 alkanoyl group or a group selected from the
following group C), ring Cy is (1) a C.sub.3-10 cycloalkyl group
optionally substituted by 1 to 5 substituents selected from the
following group B, (2) a C.sub.3-10 cycloalkenyl group optionally
substituted by 1 to 5 substituents selected from the following
group B or (3) a heterocyclic group optionally substituted by 1 to
5 substituents selected from the following group B (wherein said
heterocyclic group comprises 1 to 4 heteroatoms selected from
oxygen atom, nitrogen atom and sulfur atom), X is (1) a group
selected from the following group D, (2) a C.sub.2-6 alkenyl group
optionally substituted by 1 to 3 substituents selected from the
following group A or ##STR568## wherein ring B is (1') a C.sub.6-14
aryl group, (2') a C.sub.3-10 cycloalkyl group or (3') a
heterocyclic group comprising 1 to 4 heteroatoms selected from
oxygen atom, nitrogen atom and sulfur atom, each Z is independently
(1') a group selected from the following group D, (2') a C.sub.6-14
aryl group optionally substituted by 1 to 5 substituents selected
from the following group D, (3') a C.sub.3-10 cycloalkyl group
optionally substituted by 1 to 5 substituents selected from the
following group D, (4') a C.sub.6-14 aryl C.sub.1-6 alkyl group
optionally substituted by 1 to 5 substituents selected from the
following group D, (5') a heterocyclic group optionally substituted
by 1 to 5 substituents selected from the following group D (wherein
said heterocyclic group comprises 1 to 4 heteroatoms selected from
oxygen atom, nitrogen atom and sulfur atom) or (6') a heterocycle
C.sub.1-6 alkyl group optionally substituted by 1 to 5 substituents
selected from the following group D
(wherein said heterocycle C.sub.1-6 alkyl group is a C.sub.1-6
alkyl group substituted by "a heterocyclic group optionally
substituted by 1 to 5 substituents selected from group D" as
defined above), w is an integer of 1 to 3, Y is (a) C.sub.1-6
alkylene, (b) C.sub.2-6 alkenylene or (c)
--Y.sup.1--(CH.sub.2).sub.m--Y.sup.2--(CH.sub.2).sub.n-- (wherein m
and n are each independently 0 or an integer of 1 to 6, Y.sup.1 and
Y.sup.2 are each independently (1') a bond, (2') --O--, (3')
--NR.sup.y1--, (4') --S--, (5') --CO--, (6') --SO--, (7')
--SO.sub.2--, (8') --CO.sub.2--, (9') --OCO--, (10')
--CONR.sup.y2--, (11') --NR.sup.y2CO--, (12')
--SO.sub.2NR.sup.y2--, (13') --NR.sup.y2SO.sub.2--, (14')
--NR.sup.2CO.sub.2--, (15') --OCONR.sup.y2--, (16')
--NR.sup.y2CONR.sup.y3--, (17') --CR.sup.y4R.sup.y5-- or (18')
--CH.dbd.CH-- (wherein R.sup.y1 is (1'') a hydrogen atom, (2'') a
group selected from the following group C, (3'')
--(CH.sub.2).sub.s--COOR.sup.y11, (4'')
--(CH.sub.2).sub.s--CONR.sup.y11R.sup.y12, (5'')
--(CH.sub.2).sub.s--COR.sup.y11 or (6'')
--(CH.sub.2).sub.s--SO.sub.2R.sup.y13 (wherein s is 0 or an integer
of 1 to 6, R.sup.y11 and R.sup.y12 are each independently a
hydrogen atom or a group selected from the following group C, and
R.sup.y13 is a group selected from the following group C), R.sup.y2
and R.sup.y3 are each independently (1'') a hydrogen atom, (2'') a
group selected from the following group C, (3'') --COR.sup.y11 or
(4'') --SO.sub.2R.sup.y13 (wherein R.sup.y11 and R.sup.y13 are as
defined above), R.sup.y4 and R.sup.y5 are each independently (1'')
a hydrogen atom, (2'') a carboxyl group, (3'') a group selected
from group F, (4'') --OR.sup.y14 or (5'') --NHR.sup.y15 (wherein
R.sup.y14 is a group selected from the following group C, R.sup.y15
is a hydrogen atom, a C.sub.1-6 alkyl group, a C.sub.1-6 alkanoyl
group, a C.sub.6-14 aryl C.sub.1-6 alkyloxycarbonyl group or a
C.sub.1-6 alkoxycarbonyl group))) group A: (1) a halogen atom, (2)
a C.sub.1-6 alkoxy C.sub.1-6 alkoxy group, (3) a cyano group, (4)
--OR.sup.a1, (5) --SR.sup.a1, (6) --NR.sup.a1R.sup.a2, (7)
--COOR.sup.a1, (8) --CONR.sup.a1R.sup.a2, (9) --SO.sub.3H, (10)
--SO.sub.2NR.sup.a1R.sup.a2, (11) --NHCOR.sup.a1, (12)
--NHSO.sub.2R.sup.a3, (13) --NHCO.sub.2R.sup.a4, (14) --COR.sup.a1
and (15) --N.sup.+R.sup.a1R.sup.a2R.sup.a3 (wherein R.sup.a1 and
R.sup.a2 are each a hydrogen atom, a C.sub.1-6 alkyl group or a
benzyl group, R.sup.a3 is a C.sub.1-6 alkyl group and R.sup.a4 is a
C.sub.1-6 alkyl group) group B: (1) a halogen atom, (2) a cyano
group, (3) a nitro group, (4) a C.sub.1-6 alkyl group, (5) a
C.sub.2-6 alkenyl group optionally substituted by carboxyl group,
(6) a halogenated C.sub.1-6 alkyl group, (7)
--(CH.sub.2).sub.r--OR.sup.b1, (8) --(CH.sub.2).sub.r--SR.sup.b1,
(9) --(CH.sub.2).sub.r--NR.sup.b1R.sup.b2, (10)
--(CH.sub.2).sub.r--COOR.sup.b1, (11)
--(CH.sub.2).sub.r--CONR.sup.b1R.sup.b2, (12)
--(CH.sub.2).sub.r--COR.sup.b1, (13)
--(CH.sub.2).sub.r--NR.sup.b1--COR.sup.b2, (14)
--(CH.sub.2).sub.r--NR.sup.b1--SO.sub.2R.sup.b3, (15)
--(CH.sub.2).sub.r--SO.sub.2R.sup.b3, (16)
--(CH.sub.2).sub.r--SO.sub.2NR.sup.b1R.sup.b2, (17)
--(CH.sub.2).sub.r--CONR.sup.b1--SO.sub.2R.sup.b3, (18)
--(CH.sub.2).sub.r--SO.sub.2NR.sup.b1--COR.sup.b2, (19)
--(CH.sub.2).sub.r--NR.sup.b1--COOR.sup.b3, (20)
--(CH.sub.2).sub.r--NR.sup.b1--CONR.sup.b2R.sup.b4, (21)
--O--(CH.sub.2).sub.r--COOR.sup.b1 and (22)
--CO--(CH.sub.2).sub.r--R.sup.b5 (wherein R.sup.b1, R.sup.b2 and
R.sup.b4 are each independently a hydrogen atom or a C.sub.1-6
alkyl group, R.sup.b3 is a C.sub.1-6 alkyl group, R.sup.b5 is a
heterocyclic group and r is 0 or an integer of 1 to 6) group C: (1)
a C.sub.1-6 alkyl group optionally substituted by 1 to 3
substituents selected from the aforementioned group A, (2) a
C.sub.6-14 aryl group optionally substituted by 1 to 5 substituents
selected from the aforementioned group B, (3) a C.sub.6-14 aryl
C.sub.1-6 alkyl group optionally substituted by 1 to 5 substituents
selected from the aforementioned group B, (4) a heterocyclic group
optionally substituted by 1 to 5 substituents selected from the
aforementioned group B and (5) a heterocycle C.sub.1-6 alkyl group
optionally substituted by 1 to 5 substituents selected from the
aforementioned group B group D: (a) a hydrogen atom, (b) a halogen
atom, (c) a cyano group, (d) a nitro group, (e) a C.sub.1-6 alkyl
group optionally substituted by 1 to 3 substituents selected from
the aforementioned group A, (f) --(CH.sub.2).sub.t--OR.sup.d1,
wherein R.sup.d1 is (1) a hydrogen atom, (2) a group selected from
the following group F, (3) a C.sub.2-6 alkenyl group optionally
substituted by 1 to 3 substituents selected from the aforementioned
group A or (4) a C.sub.2-6 alkynyl group optionally substituted by
1 to 3 substituents selected from the aforementioned group A,
hereinafter each t is independently 0 or an integer of 1 to 6, (g)
--(CH.sub.2).sub.t--S(O).sub.q--R.sup.d2, wherein R.sup.d2 is (1) a
hydrogen atom or (2) a group selected from the following group F, q
is 0, 1, 2 or 3, (h) --(CH.sub.2).sub.t--NR.sup.d3R.sup.d4, wherein
R.sup.d3 and R.sup.d4 are each independently (1) a hydrogen atom or
(2) a group selected from the following group F, (i)
--(CH.sub.2).sub.t--COOR.sup.d5, wherein R.sup.d5 is (1) a hydrogen
atom or (2) a group selected from the following group F, (j)
--(CH.sub.2).sub.t--CONR.sup.d6R.sup.d7, wherein R.sup.d6 and
R.sup.d7 are each independently (1) a hydrogen atom, (2) a hydroxyl
group, (3) a group selected from the following group F or (4) a
C.sub.1-6 alkoxy group, (k) --(CH.sub.2).sub.t--COR.sup.d8, wherein
R.sup.d8 is (1) a hydrogen atom or (2) a group selected from the
following group F, (1) --(CH.sub.2).sub.t--NR.sup.d9CO--R.sup.d10,
wherein R.sup.d9 is (1) a hydrogen atom, (2) a C.sub.1-6 alkyl
group optionally substituted by 1 to 3 substituents selected from
the aforementioned group A or (3) a C.sub.1-6 alkanoyl group,
R.sup.d10 is (1) an amino group, (2) a C.sub.1-6 alkylamino group
or (3) a group selected from the following group F, (m)
--(CH.sub.2).sub.t--NR.sup.d11SO.sub.2--R.sup.d12, wherein
R.sup.d11 is (1) a hydrogen atom, (2) a C.sub.1-6 alkyl group
optionally substituted by 1 to 3 substituents selected from the
aforementioned group A or (3) a C.sub.1-6 alkanoyl group, R.sup.d12
is (1) a hydrogen atom or (2) a group selected from the following
group F, (n) --(CH.sub.2).sub.t--SO.sub.2--NR.sup.d13R.sup.d14,
wherein R.sup.d13 and R.sup.d14 are each independently (1) a
hydrogen atom or (2) a group selected from the following group F,
(o) --(CH.sub.2).sub.t--CONR.sup.d15--SO.sub.2R.sup.d16, wherein
R.sup.d15 and R.sup.d16 are each independently (1) a hydrogen atom
or (2) a group selected from the following group F, (p)
--(CH.sub.2).sub.t--SO.sub.2NR.sup.d17--COR.sup.d18, wherein
R.sup.d17 is (1) a hydrogen atom or (2) a group selected from the
following group F, R.sup.d18 is a group selected from the following
group F, (q) --(CH.sub.2).sub.t--NR.sup.d19--COOR.sup.d20, wherein
R.sup.d19 and R.sup.d20 are each independently (1) a hydrogen atom
or (2) a group selected from the following group F, (r)
--(CH.sub.2).sub.t--NR.sup.d21--CONR.sup.d22R.sup.d23, wherein
R.sup.d21, R.sup.d22 and R.sup.d23 are each independently (1) a
hydrogen atom or (2) a group selected from the following group F,
(s) --(CH.sub.2).sub.t--C(.dbd.NR.sup.d24)NH.sub.2, wherein
R.sup.d24 is (1) a hydrogen atom, (2) a hydroxyl group, (3) a
C.sub.1-6 alkyl group optionally substituted by 1 to 3 substituents
selected from the aforementioned group A or (4) C.sub.1-6 alkoxy
group, (t) --(CH.sub.2).sub.t--O--(CH.sub.2).sub.p--COR.sup.d25,
wherein R.sup.d25 is (1) an amino group, (2) a C.sub.1-6 alkylamino
group or (3) a heterocyclic group optionally substituted by 1 to 5
substituents selected from the aforementioned group B, p is 0 or an
integer of 1 to 6, (u)
--(CH.sub.2).sub.t--O--(CH.sub.2).sub.p--NR.sup.d26R.sup.d27,
wherein R.sup.d26 and R.sup.d27 are each independently (1) a
hydrogen atom or (2) a C.sub.1-6 alkyl group optionally substituted
by 1 to 3 substituents selected from the aforementioned group A, p
is 0 or an integer of 1 to 6, (v)
--(CH.sub.2).sub.t--O--COOR.sup.d28, wherein R.sup.d28 is (1) a
hydrogen atom or (2) a group selected from the following group F,
and (w) a heterocyclic group optionally substituted by 1 to 5
substituents selected from the aforementioned group B (wherein said
heterocyclic group comprises 1 to 4 heteroatoms selected from
oxygen atom, nitrogen atom and sulfur atom) group E: (a) a halogen
atom, (b) a cyano group, (c) a nitro group, (d) an azido group, (e)
--OP(.dbd.O)(OH).sub.2, (f) --OR.sup.e1, wherein R.sup.e1 is (1) a
hydrogen atom, (2) a group selected from the following group F, (3)
a C.sub.2-6 alkenyl group optionally substituted by 1 to 3
substituents selected from the aforementioned group A or (4) a
C.sub.2-6 alkynyl group optionally substituted by 1 to 3
substituents selected from the aforementioned group A, (g)
--S(O).sub.q--R.sup.e2 wherein R.sup.e2 is (1) a hydrogen atom or
(2) a group selected from the following group F, q is 0, 1, 2 or 3,
(h) NR.sup.e3R.sup.e4, wherein R.sup.e3 and R.sup.e4 are each
independently (1) a hydrogen atom, (2) a cyano group or (3) a group
selected from the following group F, (i) --COOR.sup.e5, wherein
R.sup.e5 is (1) a hydrogen atom or (2) a group selected from the
following group F, (j) --CONR.sup.e6R.sup.e7, wherein R.sup.e6 and
R.sup.e7 are each independently (1) a hydrogen atom, (2) a hydroxyl
group, (3) a group selected from the following group F or (4) a
C.sub.1-6 alkoxy group, (k) --COR.sup.e8, wherein R.sup.e8 is a
group selected from the following group F, (1)
--NR.sup.e9CO--R.sup.e10, wherein R.sup.e9 is (1) a hydrogen atom,
(2) a C.sub.1-6 alkyl group or (3) a C.sub.1-6 alkanoyl group,
R.sup.e10 is (1) a hydrogen atom, (2) an amino group, (3) a
C.sub.1-6 alkylamino group, (4) a C.sub.2-6 alkenyl group
optionally substituted by 1 to 3 substituents selected from the
aforementioned group A or (5) a group selected from the following
group F, (m) --NR.sup.e11SO.sub.2--R.sup.e12, wherein R.sup.e11 is
(1) a hydrogen atom, (2) a C.sub.1-6 alkyl group or (3) a C.sub.1-6
alkanoyl group, R.sup.e12 is (1) a hydrogen atom or (2) a group
selected from the following group F, (n)
--SO.sub.2--NR.sup.e13R.sup.e14, wherein R.sup.e13 and R.sup.e14
are each independently (1) a hydrogen atom or (2) a group selected
from the following group F, (o) --CONR.sup.e15--SO.sub.2R.sup.16,
wherein R.sup.e15 and R.sup.e16 are each independently (1) a
hydrogen atom or (2) a group selected from the following group F,
(p) --SO.sub.2NR.sup.e17--COR.sup.e18, wherein R.sup.e17 is (1) a
hydrogen atom or (2) a group selected from the following group F,
R.sup.e18 is a group selected from the following group F, (q)
NR.sup.e19--COOR.sup.e20, wherein R.sup.e19 and R.sup.e20 are each
independently (1) a hydrogen atom or (2) a group selected from the
following group F, (r) --NR.sup.e21--CONR.sup.e22R.sup.e23 wherein
R.sup.e21, R.sup.e22 and R.sup.e23 are each independently (1) a
hydrogen atom or (2) a group selected from the following group F,
(s) --NHCO--COOR.sup.e24 wherein R.sup.e24 is (1) a hydrogen atom
or (2) a group selected from the following group F, (t)
--NHCO--CONR.sup.e25R.sup.e26 wherein R.sup.e25 and R.sup.e26 are
each independently (1) a hydrogen atom, (2) a hydroxyl group or (3)
a group selected from the following group F, (u) --CONH--COOH,
##STR569## (y) a C.sub.6-14 aryl group optionally substituted by 1
to 5 substituents selected from the aforementioned group B, (z) a
C.sub.3-10 cycloalkyl group optionally substituted by 1 to 5
substituents selected from the aforementioned group B, (aa) a
heterocyclic group optionally substituted by 1 to 5 substituents
selected from the aforementioned group B (wherein said heterocyclic
group comprises 1 to 4 heteroatoms selected from oxygen atom,
nitrogen atom and sulfur atom), (bb) a C.sub.3-10 cycloalkylidene
group optionally substituted by 1 to 5 substituents selected from
the aforementioned group B, and (cc) a heterocycle ylidene group
optionally substituted by 1 to 5 substituents selected from the
aforementioned group B (wherein said heterocycle ylidene group
comprises 1 to 4 heteroatoms selected from oxygen atom, nitrogen
atom and sulfur atom), when group E is a substituent on a
C.sub.6-14 aryl group, a C.sub.3-10 cycloalkyl group or a
heterocyclic group, it may be (dd) a C.sub.1-6 alkyl group
optionally substituted by 1 to 3 substituents selected from the
aforementioned group A, (ee) a C.sub.2-6 alkenyl group optionally
substituted by 1 to 3 substituents selected from the aforementioned
group A, (ff) a C.sub.2-6 alkynyl group optionally substituted by 1
to 3 substituents selected from the aforementioned group A, (gg)
C.sub.1-6 alkylidene group optionally substituted by 1 to 3
substituents selected from the aforementioned group A, (hh) a
C.sub.6-14 aryl C.sub.1-6 alkyl group optionally substituted by 1
to 5 substituents selected from the aforementioned group B, (ii) a
C.sub.3-10 cycloalkyl C.sub.1-6 alkyl group optionally substituted
by 1 to 5 substituents selected from the aforementioned group B, or
(jj) a heterocycle C.sub.1-6 alkyl group optionally substituted by
1 to 5 substituents selected from the aforementioned group B group
F: (1) a C.sub.1-6 alkyl group optionally substituted by 1 to 3
substituents selected from the aforementioned group A, (2) a
C.sub.6-14 aryl group optionally substituted by 1 to 5 substituents
selected from the aforementioned group B, (3) a heterocyclic group
optionally substituted by 1 to 5 substituents selected from the
aforementioned group B (wherein said heterocyclic group comprises 1
to 4 heteroatoms selected from oxygen atom, nitrogen atom and
sulfur atom), (4) a C.sub.3-10 cycloalkyl group optionally
substituted by 1 to 5 substituents selected from the aforementioned
group B, (5) a C.sub.6-14 aryl C.sub.1-6 alkyl group optionally
substituted by 1 to 5 substituents selected from the aforementioned
group B, (6) a heterocycle C.sub.1-6 alkyl group optionally
substituted by 1 to 5 substituents selected from the aforementioned
group B (wherein said heterocycle C.sub.1-6 alkyl group is a
C.sub.1-6 alkyl group substituted by "a heterocyclic group
optionally substituted by 1 to 5 substituents selected from group
B" as defined above) and (7) a C.sub.3-10 cycloalkyl C.sub.1-6
alkyl group optionally substituted by 1 to 5 substituents selected
from the aforementioned group B.
2. The compound of claim 1, wherein, in the formula [I], ##STR570##
G.sup.2G.sup.1 is N--C.dbd.C, or a pharmaceutically acceptable salt
thereof.
3. The compound of claim 1, wherein, in the formula [I], the moiety
##STR571## is a fused ring selected from the group consisting of
##STR572## ##STR573## ##STR574## or a pharmaceutically acceptable
salt thereof.
4.-6. (canceled)
7. The compound of claim 1, wherein G.sup.3, G.sup.4 and G.sup.5
are carbon atoms, or a pharmaceutically acceptable salt
thereof.
8. The compound of claim 1, wherein Q.sup.1 is --O--, --NH--, --S--
or --CONH--, or a pharmaceutically acceptable salt thereof.
9.-10. (canceled)
11. The compound of claim 1, wherein Q is --(CH.sub.2).sub.2--O--
or --(CH.sub.2).sub.2--NH--, or a pharmaceutically acceptable salt
thereof.
12. The compound of claim 1, wherein R.sup.1 is a carboxyl group or
--CONR.sup.11R.sup.12, or a pharmaceutically acceptable salt
thereof.
13.-29. (canceled)
30. The compound of claim 1, wherein R.sup.2 is a hydrogen atom, a
group selected from group E, a C.sub.1-6 alkyl group optionally
substituted by 1 to 3 substituents selected from group E,
##STR575## wherein each symbol is as defined in claim 1, or a
pharmaceutically acceptable salt thereof.
31.-36. (canceled)
37. The compound of claim 1, wherein R.sup.3 is a hydrogen atom, a
halogen atom, a C.sub.1-6 alkyl group optionally substituted by 1
to 3 substituents selected from group A or --OR.sup.101 (wherein
R.sup.101 is a hydrogen atom or a group selected from group C), or
a pharmaceutically acceptable salt thereof.
38. The compound of claim 1, wherein R.sup.5 and R.sup.6 are each
independently a hydrogen atom, a halogen atom, a C.sub.1-6 alkyl
group optionally substituted by 1 to 3 substituents selected from
group A or --OR.sup.120 (wherein R.sup.120 is a hydrogen atom or a
group selected from group C), or a pharmaceutically acceptable salt
thereof.
39. The compound of claim 1, wherein ring A is benzene or a 5- or
6-membered heterocycle comprising 1 to 4 heteroatoms selected from
oxygen atom, nitrogen atom and sulfur atom, or a pharmaceutically
acceptable salt thereof.
40. (canceled)
41. The compound of claim 1, wherein ring Cy is a C.sub.3-10
cycloalkyl group or a C.sub.3-10 cycloalkenyl group, or a
pharmaceutically acceptable salt thereof.
42. (canceled)
43. The compound of claim 1, wherein X is a hydrogen atom, a
halogen atom, a C.sub.1-6 alkyl group optionally substituted by 1
to 3 substituents selected from group A,
--(CH.sub.2).sub.t--OR.sup.d1,
--(CH.sub.2).sub.t--S(O).sub.q--R.sup.d2,
--(CH.sub.2).sub.t--NR.sup.d3R.sup.d4 or ##STR576## wherein each
symbol is as defined in claim 1, or a pharmaceutically acceptable
salt thereof.
44.-49. (canceled)
50. The compound of claim 1, which is represented by the following
formula [I-A], or a pharmaceutically acceptable salt thereof:
##STR577## wherein X' is a hydrogen atom, a halogen atom, a
C.sub.1-6 alkyl group optionally substituted by 1 to 3 substituents
selected from group A or --OR.sup.d1, and other symbols are as
defined in claim 1.
51. The compound of claim 1, which is represented by the following
formula [I-B], or a pharmaceutically acceptable salt thereof:
##STR578## wherein Q.sup.2 is --O-- or --NH--, and other symbols
are as defined in claim 1.
52. The compound of claim 1, which is represented by the following
formula [I-C], or a pharmaceutically acceptable salt thereof:
##STR579## wherein Q.sup.3 is --O-- or --NR.sup.2--, X' is a
hydrogen atom, a halogen atom, a C.sub.1-6 alkyl group optionally
substituted by 1 to 3 substituents selected from group A or
--OR.sup.d1, and other symbols are as defined in claim 1.
53. A composition comprising a compound of claim 1 and a
pharmaceutically acceptable carrier.
54.-64. (canceled)
65. A method for treating hepatitis C, which comprises
administering an effective amount of a compound of claim 1 to a
mammal.
66. The method of claim 65, further comprising administering an
effective amount of at least one pharmaceutical agent selected from
the group consisting of a different antiviral agent, an
antiinflammatory agent and an immunostimulant to the mammal.
67. The method of claim 65, further comprising administering an
effective amount of interferon to the mammal.
68. A method for inhibiting hepatitis C virus polymerase, which
comprises administering an effective amount of a compound of claim
1 to a mammal.
69. The method of claim 68, further comprising administering an
effective amount of at least one pharmaceutical agent selected from
the group consisting of a different antiviral agent, an
antiinflammatory agent and an immunostimulant to the mammal.
70. The method of claim 68, further comprising administering an
effective amount of interferon to the mammal.
Description
TECHNICAL FIELD
[0001] The present invention relates to a tetracyclic fused
heterocyclic compound or a pharmaceutically acceptable salt
thereof, which shows anti-hepatitis C virus (HCV) activity,
particularly anti-HCV activity based on an RNA-dependent RNA
polymerase inhibitory activity. In addition, the present invention
relates to a hepatitis C virus polymerase inhibitor, an
anti-hepatitis C virus agent and a therapeutic agent for hepatitis
C containing said tetracyclic fused heterocyclic compound or a
pharmaceutically acceptable salt thereof.
BACKGROUND ART
[0002] In 1989, a main causative virus of non-A non-B
posttransfusion hepatitis was found and named hepatitis C virus
(HCV). Since then, several types of hepatitis viruses have been
found besides type A, type B and type C, wherein hepatitis caused
by HCV is called hepatitis C.
[0003] The patients infected with HCV are considered to involve
several percent of the world population, and the infection with HCV
characteristically becomes chronic.
[0004] HCV is an envelope RNA virus, wherein the genome is a single
strand plus-strand RNA, and belongs to the genus Hepacivirus of
Flavivirus (from The International Committee on Taxonomy of
Viruses, International Union of Microbiological Societies). Of the
same hepatitis viruses, for example, hepatitis B virus (HBV), which
is a DNA virus, is eliminated by the immune system and the
infection with this virus ends in an acute infection except for
neonates and infants having yet immature immunological competence.
In contrast, HCV somehow avoids the immune system of the host due
to an unknown mechanism. Once infected with this virus, even an
adult having a mature immune system frequently develops persistent
infection. When chronic hepatitis is associated with the persistent
infection with HCV, it advances to cirrhosis or hepatic cancer in a
high rate. Enucleation of tumor by operation does not help much,
because the patient often develops recurrent hepatic cancer due to
the sequela inflammation in non-cancerous parts. In addition, there
is a report on the involvement of HCV infection in dermatosis such
as chronic urticaria, lichen planus, cryoglobulinemic purpura and
the like (The Japanese Journal of Dermatology, Vol. 111, No. 7,
pages 1075-1081, 2001).
[0005] Thus, an effective therapeutic method of hepatitis C is
desired. Apart from the symptomatic therapy to suppress
inflammation with an anti-inflammatory agent, the development of a
therapeutic agent that reduces HCV to a low level free from
inflammation and that eradicates HCV has been strongly
demanded.
[0006] At present, a treatment with interferon is the only
effective method known for the eradication of HCV. However,
interferon can eradicate the virus only in about one-third of the
patient population. For the rest of the patients, it has no effect
or provides only a temporary effect. In recent years, polyethylene
glycolated interferon has been put to practical use, and enhanced
effects and reduced side effects have been achieved. However,
complete response rate still remains at a low level, and therefore,
an anti-HCV drug to be used in the place of or concurrently with
interferon is awaited in great expectation.
[0007] In recent years, Ribavirin
(1-.beta.-D-ribofuranosyl-1H-1,2,4-triazole-3-carboxamide) has
become commercially available as a therapeutic agent for hepatitis
C, which is to be used concurrently with interferon. It enhances
the efficacy of interferon but only to a low efficacy rate, and a
different novel therapeutic agent for hepatitis C is desired.
[0008] Also, an attempt has been made to potentiate the
immunocompetence of the patient with an interferon agonist, an
interleukin-12 agonist and the like, thereby to eradicate the
virus, but an effective pharmaceutical agent has not been found
yet.
[0009] In addition, the inhibition of HCV growth, wherein
HCV-specific protein is targeted, has been drawing attention these
days.
[0010] The gene of HCV encodes a protein such as serine protease,
RNA helicase, RNA-dependent RNA polymerase and the like. These
proteins function as a specific protein essential for the growth of
HCV.
[0011] One of the specific proteins, RNA-dependent RNA polymerase
(hereinafter to be also briefly referred to as an HCV polymerase),
is an enzyme essential for the growth of the virus. The gene
replication of HCV having a plus-strand RNA gene is considered to
involve synthesis of a complementary minus-strand RNA by the use of
the plus-strand RNA as a template and using the obtained
minus-strand RNA as a template, amplifying the plus-strand RNA. The
portion called NS5B of a protein precursor, that HCV codes for, has
been found to show an RNA-dependent RNA polymerase activity (EMBO
J., Vol. 15, pages 12-22, 1996), and is considered to play a
central role in the HCV gene replication.
[0012] Therefore, an HCV polymerase inhibitor can be a target in
the development of an anti-HCV drug, and the development thereof is
eagerly awaited. However, an effective HCV polymerase inhibitor has
not been developed yet, like in other attempts to develop an
anti-HCV drug based on other action mechanisms. As the situation
stands, no pharmaceutical agent can treat hepatitis C
satisfactorily.
[0013] The following describes known compounds comparatively
similar to the present invention.
[0014] WO03/099824 discloses the following compound a etc. as
anti-HCV agents, and teaches that this compound shows an HCV
polymerase inhibitory action (WO03/099824, Example 4 (page 32, line
10-page 35), Table 1 (page 20)). ##STR2##
[0015] However, the compound of the present invention is not
disclosed therein and no description suggestive thereof is found in
the specification.
[0016] On the other hand, as known tetracyclic fused heterocyclic
compounds, whose pharmaceutical use is known, the following can be
mentioned.
[0017] EP226508 discloses that the following compound b etc. show
an anticancerous action (EP226508, Example 2 (page 4, last
line--page 6, line 2), formula VII of claim 5 (page 31)).
##STR3##
[0018] Other reference describes following compound c etc. and
synthetic methods of compounds usable as central nervous system
agents (Bollettino Chimico Farmaceutico, Vol. 120, No. 2, pages
102-107, 1981). ##STR4##
[0019] However, none of these references discloses the compound of
the present invention, not to mention disclosure of use of the
compounds of these references as antiviral agents or description
suggestive thereof.
[0020] As the compounds comparatively similar to the compound of
the present invention, relating to use other than a pharmaceutical
agent, the following can be mentioned.
[0021] JP-A-4-329547 discloses the following compound d known as an
electronic photographic-sensitized material (JP-A-4-329547, formula
52 (page 7, lower right column)). ##STR5##
[0022] A different reference discloses the following compound e
etc., wherein its synthetic method is described (J. Org. Chem.,
Vol. 66, No. 2, pages 412-420, 2001, Table 3 No. 19 (page 415)).
##STR6##
[0023] A yet different reference discloses the following compound f
etc., wherein its synthetic method is described (Organic Letters,
Vol. 4, No. 8, pages 1355-1358, 2002, Table 1 No. 17 (page 1357),
Scheme 4 (page 1356)). ##STR7##
[0024] Another different reference discloses the following compound
g etc., wherein its synthetic method is described (J. Org. Chem.,
Vol. 31, No. 6, pages 2009-2011, 1966, Scheme 1 (page 2010)).
##STR8##
[0025] However, none of these references discloses the compound of
the present invention, not to mention disclosure of use of the
compounds of these references as an antiviral agents or description
suggestive thereof.
[0026] As a therapeutic agent for hepatitis C having an indole
skeleton, WO03/010140 is known (WO03/010140, Example Nos. 1 (page
41), 10 (page 51), 14 (page 57), 18 (page 60), 20 (page 63), 22
(page 64), compound No. 149 (page 79)).
[0027] In this publication, as an anti-HCV agent having a
polymerase inhibitory activity, the following indole compounds A,
B, C, D etc. are described. ##STR9## wherein Ex. means Example No.
in the publication.
[0028] In this publication, as compounds having other skeleton, the
following compounds E, F, G etc. are described. ##STR10##
[0029] In WO03/010141, as a synthetic intermediate for an anti-HCV
agent having a polymerase inhibitory activity, the above-mentioned
compounds etc. are described (WO03/010141, page 92, page 101, page
108, page 112, page 115, page 116).
[0030] Furthermore, JP-A-2001-247550 (WO01/47883, EP1162196A1,
US2003/0050320) and WO03/000254 (US2003/0050320) describe, as an
anti-HCV agent having a polymerase inhibitory activity, the
following indole compound H etc., benzimidazole compound I etc.
(JP-A-2001-247550, Example compound Nos. 502 (page 206), 701 (page
417), 1198 (page 315); WO03/000254, Example compound Nos. 502 (page
206), 701 (page 417), 1198 (page 315), 371 (page 468), 405 (page
479), 407 (page 480), 423, 424 (page 485)). ##STR11##
[0031] This publication also describes the following compound J
etc. as compounds having other skeletons. ##STR12##
[0032] The above-mentioned WO03/000254 further describes the
following benzimidazole compounds K, L, M, N, O etc. ##STR13##
##STR14##
[0033] In addition, WO02/04425 describes the following
benzimidazole compound P etc. as anti-HCV agents having a
polymerase inhibitory activity (WO02/04425, entry No. 7005 (page
228), Example Nos. 28 (page 84), 148 (page 163)). ##STR15##
[0034] In this publication, the following compounds Q, R etc. are
described as compounds having other skeletons. ##STR16##
[0035] WO03/026587 also discloses the following compounds S, T etc.
as anti-HCV agents having a polymerase inhibitory activity
(WO03/026587, Example Nos. 12 (page 56), 65(page 65)).
##STR17##
[0036] As therapeutic agents for hepatitis C having a benzimidazole
skeleton, the compounds described in WO97/36866, JP-T-2000-511899
(EP906097) and WO99/51619 are also known.
[0037] WO03/007945 also describes benzimidazole compound etc. as
synthetic intermediates for anti-HCV agents having a polymerase
inhibitory activity.
[0038] Furthermore, WO99/09007 and U.S. Pat. No. 5,932,743 describe
the following indole compound U etc. as chemical library compounds
that can be used for screening of pharmaceutical products (see
WO99/09007, Example 12 (page 25); U.S. Pat. No. 5,932,743).
##STR18##
DISCLOSURE OF INVENTION
[0039] Based on the findings from the preceding studies, it has
been elucidated that a pharmaceutical agent having an anti-HCV
activity is effective for the prophylaxis and treatment of
hepatitis C, and particularly an anti-HCV agent having an
inhibitory activity on RNA-dependent RNA polymerase of HCV can be a
prophylactic and therapeutic agent effective against hepatitis C
and a prophylactic and therapeutic agent for the disease caused by
hepatitis C.
[0040] Accordingly, the present invention provides a compound
having an anti-HCV activity, particularly a compound having an
RNA-dependent RNA polymerase inhibitory activity.
[0041] The present inventors have made an in-depth study of
compounds having an anti-HCV activity, particularly RNA-dependent
RNA polymerase inhibitory activity, and completed the present
invention.
[0042] Thus, the present invention provides the following [1] to
[70]. [1] A compound represented by the following formula [I] or a
pharmaceutically acceptable salt thereof: ##STR19## is C.dbd.C--N
or N--C.dbd.C, G.sup.3, G.sup.4 and G.sup.5 are each independently
a carbon atom or a nitrogen atom, when at least one of G.sup.3,
G.sup.4 and G.sup.5 is a carbon atom, said carbon atom is
optionally substituted by R.sup.3, Q is (1) --(CH.sub.2).sub.b-- or
(2) --(CH.sub.2).sub.c-Q.sup.1-(CH.sub.2).sub.d-- (wherein b is an
integer of 1 to 4, c and d are each independently 0 or an integer
of 1 to 4, Q.sup.1 is
[0043] (1') --O--,
[0044] (2') --NH--,
[0045] (3') --S--,
[0046] (4') --OCO--,
[0047] (5') --OCONH--,
[0048] (6') --CO--,
[0049] (7') --SO--,
[0050] (8') --SO.sub.2--,
[0051] (9') --NHCO--,
[0052] (10') --NHSO.sub.2--,
[0053] (11') --NHCOO--,
[0054] (12') --COO--,
[0055] (13') --CONH--,
[0056] (14') --SO.sub.2NH--,
[0057] (15') --NHCONH--,
[0058] (16') --NHSO.sub.2NH--,
[0059] (17') --CH.dbd.CH--,
[0060] (18') --CH.dbd.N-- or
[0061] (19') --N.dbd.CH--),
ring A is
(1) benzene,
(2) cyclopentane or cyclohexane,
(3) cyclopentene or cyclohexene or
(4) a 5- or 6-membered heterocycle comprising 1 to 4 heteroatoms
selected from oxygen atom, nitrogen atom and sulfur atom,
G.sup.6 is a carbon atom or a nitrogen atom, a broken line in ring
A shows a single bond or a double bond,
R.sup.1 is
(1) a carboxyl group,
(2) a carboxylic acid equivalent,
(3) --CONR.sup.11R.sup.12
(wherein R.sup.11 and R.sup.12 are each independently
[0062] (1') a hydrogen atom,
[0063] (2') a C.sub.1-6 alkyl group optionally substituted by 1 to
3 substituents selected from the following group E,
[0064] (3') a C.sub.2-6 alkenyl group optionally substituted by 1
to 3 substituents selected from the following group E,
[0065] (4') a C.sub.6-14 aryl group optionally substituted by 1 to
5 substituents selected from the following group E,
[0066] (5') a heterocyclic group optionally substituted by 1 to 5
substituents selected from the following group E
(wherein said heterocyclic group comprises 1 to 4 heteroatoms
selected from oxygen atom, nitrogen atom and sulfur atom),
[0067] (6') a C.sub.3-10 cycloalkyl group optionally substituted by
1 to 5 substituents selected from the following group E,
[0068] (7') --NR.sup.131R.sup.132,
[0069] (8') --NHCOOR.sup.133,
[0070] (9') --NHCOR.sup.134,
(wherein R.sup.13, R.sup.132, R.sup.133 and R.sup.134 are each
independently a hydrogen atom or a group selected from the
following group F),
[0071] (10') --CR.sup.135R.sup.136-L.sup.100-R.sup.137,
[0072] (11')
--CR.sup.135R.sup.136-L.sup.101-CONR.sup.140--R.sup.137, ##STR20##
(wherein R.sup.135, R.sup.136, R.sup.138 and R.sup.139 are each
independently
[0073] (1'') a hydrogen atom or
[0074] (2'') a group selected from the following group G,
[0075] group G:
[0076] (1''') cyano group,
[0077] (2''') --COOR.sup.142
(wherein R.sup.142 is a hydrogen atom or a group selected from the
following group F)
[0078] (3''') --CONR.sup.143R.sup.144
(wherein R.sup.143 and R.sup.144 are each independently a hydrogen
atom, a C.sub.1-6 alkoxy group or a group selected from the
following group F)
[0079] (4''') a C.sub.1-6 alkyl group optionally substituted by 1
to 3 substituents selected from the following group A,
[0080] (5''') a C.sub.2-6 alkenyl group optionally substituted by 1
to 3 substituents selected from the following group A,
[0081] (6''') a C.sub.6-14 aryl group optionally substituted by 1
to 5 substituents selected from the following group B,
[0082] (7''') a heterocyclic group optionally substituted by 1 to 5
substituents selected from the following group B
(wherein said heterocyclic group comprises 1 to 4 heteroatoms
selected from oxygen atom, nitrogen atom and sulfur atom),
[0083] (8''') a C.sub.3-10 cycloalkyl group optionally substituted
by 1 to 5 substituents selected from the following group B,
[0084] (9''') a C.sub.6-14 aryl C.sub.1-6 alkyl group optionally
substituted by 1 to 5 substituents selected from the following
group B,
[0085] (10''') a heterocycle C.sub.1-6 alkyl group optionally
substituted by 1 to 5 substituents selected from the following
group B and
[0086] (11''') a C.sub.3-10 cycloalkyl C.sub.1-6 alkyl group
optionally substituted by 1 to 5 substituents selected from the
following group B; or
R.sup.135 and R.sup.136, or, R.sup.138 and R.sup.139 are bonded to
each other, and optionally form, together with the carbon atom
bonded thereto,
[0087] (1'') a C.sub.3-10 cycloalkyl group optionally substituted
by 1 to 5 substituents selected from the following group B or
[0088] (2'') a heterocyclic group optionally substituted by 1 to 5
substituents selected from the following group B
(wherein said heterocyclic group comprises 1 to 4 heteroatoms
selected from oxygen atom, nitrogen atom and sulfur atom),
R.sup.137 is
[0089] (1'') a hydrogen atom,
[0090] (2'') a carboxyl group,
[0091] (3'') a C.sub.1-6 alkyl group optionally substituted by 1 to
3 substituents selected from the following group E,
[0092] (4'') a C.sub.2-6 alkenyl group optionally substituted by 1
to 3 substituents selected from the following group E,
[0093] (5'') a C.sub.6-14 aryl group optionally substituted by 1 to
5 substituents selected from the following group E,
[0094] (6'') a heterocyclic group optionally substituted by 1 to 5
substituents selected from the following group E
(wherein said heterocyclic group comprises 1 to 4 heteroatoms
selected from oxygen atom, nitrogen atom and sulfur atom) or
[0095] (7'') a C.sub.3-10 cycloalkyl group optionally substituted
by 1 to 5 substituents selected from the following group E,
R.sup.140 and R.sup.141 are each independently
[0096] (1'') a hydrogen atom or
[0097] (2'') a C.sub.1-6 alkyl group,
L.sup.100 is
[0098] (1'') a bond,
[0099] (2'') --CO--,
[0100] (3'') --CH.sub.2O--,
[0101] (4'') --CH.sub.2NH--,
[0102] (5'') --CH.sub.2NHCO--,
[0103] (6'') a C.sub.1-6 alkylene optionally substituted by
hydroxyl group or
[0104] (7'') a C.sub.2-6 alkenylene,
L.sup.101 and L.sup.102 are each independently
[0105] (1'') a bond,
[0106] (2'') --CO--,
[0107] (3'') a C.sub.1-6 alkylene optionally substituted by
hydroxyl group or
[0108] (4'') a C.sub.2-6 alkenylene,
L.sup.103 is
[0109] (1'') a bond or
[0110] (2'') a C.sub.1-6 alkylene,
L.sup.104 is a C.sub.1-6 alkylene,
L.sup.105 is
[0111] (1'') a bond or
[0112] (2'') a C.sub.1-6 alkylene,
L.sup.106 is
[0113] (1'') a bond,
[0114] (2'') a C.sub.1-6 alkylene,
[0115] (3'') --NH--,
[0116] (4'') --NH--CH.sub.2-- or
[0117] (5'') --CH.sub.2--CONH--,
ring D.sup.3, ring D.sup.4 and ring D.sup.5 are each
independently
[0118] (1'') a C.sub.6-14 aryl group optionally substituted by 1 to
5 substituents selected from the following group E,
[0119] (2'') a C.sub.3-10 cycloalkyl group optionally substituted
by 1 to 5 substituents selected from the following group E or
[0120] (3'') a heterocyclic group optionally substituted by 1 to 5
substituents selected from the following group E
(wherein said heterocyclic group comprises 1 to 4 heteroatoms
selected from oxygen atom, nitrogen atom and sulfur atom))),
(4) --COOR.sup.103
[0121] (wherein R.sup.103 is a group selected from the following
group C or a glucuronic acid residue), ##STR21## (wherein ring
D.sup.6 is a heterocyclic group optionally substituted by 1 to 5
substituents selected from the following group E (wherein said
heterocyclic group comprises 1 to 4 heteroatoms selected from
oxygen atom, nitrogen atom and sulfur atom), ring D.sup.7 is a
C.sub.6-14 aryl group optionally substituted by 1 to 5 substituents
selected from the following group E), R.sup.2 may substitute at a
substitutable position on carbon atom or nitrogen atom constituting
Q and is (1) a hydrogen atom, (2) a group selected from the
following group E, (3) a C.sub.1-6 alkyl group optionally
substituted by 1 to 3 substituents selected from the following
group E, (4) a C.sub.2-6 alkenyl group optionally substituted by 1
to 3 substituents selected from the following group E, ##STR22##
(wherein L.sup.1 and L.sup.2 are each independently
[0122] (1') a bond,
[0123] (2') C.sub.3-6 alkylene,
[0124] (3') C.sub.2-6 alkenylene,
[0125] (4') --(CH.sub.2).sub.u1--O--(CH.sub.2).sub.v1--,
[0126] (5') --(CH.sub.2).sub.u1--S--(CH.sub.2).sub.v1--,
[0127] (6')
--(CH.sub.2).sub.u1--NR.sup.L1--(CH.sub.2).sub.v1--,
[0128] (7') --(CH.sub.2).sub.u1--CO--(CH.sub.2).sub.v1--,
[0129] (8')
--(CH.sub.2).sub.u1--CONR.sup.L2--(CH.sub.2).sub.v1--,
[0130] (9')
--(CH.sub.2).sub.u1--NR.sup.L2CO.sub.2--(CH.sub.2).sub.v1--,
[0131] (10')
--(CH.sub.2).sub.u1--NR.sup.L2CONR.sup.L3--(CH.sub.2).sub.v1--,
[0132] (11')
--(CH.sub.2).sub.u1--NR.sup.L2CO--(CH.sub.2).sub.v1--,
[0133] (12')
--(CH.sub.2).sub.u1--NR.sup.L2SO.sub.2--(CH.sub.2).sub.v1--,
[0134] (13')
--(CH.sub.2).sub.u1--SO.sub.2--(CH.sub.2).sub.v1--,
[0135] (14')
--(CH.sub.2).sub.u1--SO.sub.2NR.sup.L2--(CH.sub.2).sub.v1-- or
[0136] (15')
--(CH.sub.2).sub.u1--N.sup.+R.sup.L2R.sup.L2'--(CH.sub.2).sub.v1--,
(wherein u, v, u1 and v1 are each independently 0 or an integer of
1 to 6,
R.sup.L1 is
[0137] (1'') a hydrogen atom,
[0138] (2'') a group selected from the following group C,
[0139] (3'') --COR.sup.L11,
[0140] (4'') --CONR.sup.L11R.sup.L12,
[0141] (5'') --COOR.sup.L11 or
[0142] (6'') --SO.sub.2R.sup.L13
(wherein R.sup.L11 and R.sup.L12 are each independently a hydrogen
atom or a (group selected from the following group C, and R.sup.L13
is a group selected from the following group C),
R.sup.L2, R.sup.L2 and R.sup.L3 are each independently
[0143] (1'') a hydrogen atom,
[0144] (2'') a group selected from the following group C,
[0145] (3'') --COR.sup.L11 or
[0146] (4'') --SO.sub.2R.sup.L13
(wherein R.sup.L11 and R.sup.L13 are as defined above)),
L.sup.3 is
[0147] (1') --CHR.sup.L14-- or
[0148] (2') --NR.sup.L14--
(wherein R.sup.L14 is a group selected from the following group
F),
ring D.sup.1 and ring D.sup.2 are each independently
[0149] (1') a C.sub.6-14 aryl group optionally substituted by 1 to
5 substituents selected from the following group E,
[0150] (2') a C.sub.3-10 cycloalkyl group optionally substituted by
1 to 5 substituents selected from the following group E or
[0151] (3') a heterocyclic group optionally substituted by 1 to 5
substituents selected from the following group E
(wherein said heterocyclic group comprises 1 to 4 heteroatoms
selected from oxygen atom, nitrogen atom and sulfur atom)},
R.sup.3 is
(1) a hydrogen atom,
(2) a halogen atom,
(3) a C.sub.1-6 alkanoyl group,
(4) a carboxyl group,
(5) a cyano group,
(6) a nitro group,
(7) a C.sub.1-6 alkyl group optionally substituted by 1 to 3
substituents selected from the following group A,
(8) --OR.sup.101
(wherein R.sup.101 is a hydrogen atom or a group selected from the
following group C),
(9) --NR.sup.102R.sup.119
(wherein R.sup.102 and R.sup.119 are each independently a hydrogen
atom, a C.sub.1-6 alkanoyl group or a C.sub.1-6 alkylsulfonyl
group),
(10) --COOR.sup.103
(wherein R.sup.103 is a group selected from the following group C
or a glucuronic acid residue),
(11) --CONR.sup.104R.sup.105
(wherein R.sup.104 and R.sup.105 are each independently a hydrogen
atom, a hydroxyl group, a cyano group, a C.sub.1-6 alkoxy group or
a C.sub.1-6 alkyl group optionally substituted by 1 to 3
substituents selected from the following group A),
(12) --SO.sub.2R.sup.106
(wherein R.sup.106 is a hydroxyl group, an amino group, a C.sub.1-6
alkyl group or a C.sub.1-6 alkylamino group),
(13) --NHCOR.sup.107
(wherein R.sup.107 is an amino group or a C.sub.1-6 alkylamino
group),
(14) --C(.dbd.NR.sup.108)--NH.sub.2
(wherein R.sup.108 is a hydrogen atom, a C.sub.1-6 alkyl group
optionally substituted by 1 to 3 substituents selected from the
following group A, a hydroxyl group or a C.sub.1-6 alkoxy
group),
(15) --P(.dbd.O)(OR.sup.109).sub.2
(wherein R.sup.109 are each independently a hydrogen atom or a
group selected from the following group C),
(16) --P(.dbd.O)(OR.sup.110)NR.sup.111R.sup.112
(wherein R.sup.110, R.sup.111 and R.sup.112 are each independently
a hydrogen atom or a group selected from the following group
C),
(17) --CONHCO--R.sup.113
(wherein R.sup.113 is a group selected from the following group
C),
(18) --CONHSO.sub.2--R.sup.114
(wherein R.sup.114 is a group selected from the following group
C),
(19) --SO.sub.2NHCO--R.sup.115
(wherein R.sup.115 is a group selected from the following group C)
or
(20) a heterocyclic group optionally substituted by 1 to 5
substituents selected from the following group B
(wherein said heterocyclic group comprises 1 to 4 heteroatoms
selected from oxygen atom, nitrogen atom and sulfur atom),
R.sup.4 may substitute at a substitutable position on carbon atom
or nitrogen atom constituting Q and each is independently
(1) a halogen atom,
(2) a C.sub.1-6 alkyl group optionally substituted by 1 to 3
substituents selected from the following group A,
(3) --OR.sup.116
(wherein R.sup.116 is a hydrogen atom or a group selected from the
following group C),
(4) --NR.sup.117R.sup.118
(wherein R.sup.117 and R.sup.118 are each independently a hydrogen
atom, a C.sub.1-6 alkanoyl group or a group selected from the
following group C),
(5) a C.sub.6-14 aryl group optionally substituted by 1 to 5
substituents selected from the following group B or
(6) a heterocyclic group optionally substituted by 1 to 5
substituents selected from the following group B
(wherein said heterocyclic group comprises 1 to 4 heteroatoms
selected from oxygen atom, nitrogen atom and sulfur atom),
a is 0, 1 or 2,
R.sup.5 and R.sup.6 are each independently
(1) a hydrogen atom,
(2) a halogen atom,
(3) a C.sub.1-6 alkyl group optionally substituted by 1 to 3
substituents selected from the following group A,
(4) --OR.sup.120
(wherein R.sup.120 is a hydrogen atom or a group selected from the
following group C) or
(5) --NR.sup.121R.sup.122
(wherein R.sup.121 and R.sup.122 are each independently a hydrogen
atom, a C.sub.1-6 alkanoyl group or a group selected from the
following group C),
ring Cy is
(1) a C.sub.3-10 cycloalkyl group optionally substituted by 1 to 5
substituents selected from the following group B,
(2) a C.sub.3-10 cycloalkenyl group optionally substituted by 1 to
5 substituents selected from the following group B or
(3) a heterocyclic group optionally substituted by 1 to 5
substituents selected from the following group B
(wherein said heterocyclic group comprises 1 to 4 heteroatoms
selected from oxygen atom, nitrogen atom and sulfur atom),
X is
(1) a group selected from the following group D,
[0152] (2) a C.sub.2-6 alkenyl group optionally substituted by 1 to
3 substituents selected from the following group A or ##STR23##
wherein ring B is
[0153] (1') a C.sub.6-14 aryl group,
[0154] (2') a C.sub.3-10 cycloalkyl group or
[0155] (3') a heterocyclic group comprising 1 to 4 heteroatoms
selected from oxygen atom, nitrogen atom and sulfur atom,
each Z is independently
[0156] (1') a group selected from the following group D,
[0157] (2') a C.sub.6-14 aryl group optionally substituted by 1 to
5 substituents selected from the following group D,
[0158] (3') a C.sub.3-10 cycloalkyl group optionally substituted by
1 to 5 substituents selected from the following group D,
[0159] (4') a C.sub.6-14 aryl C.sub.1-6 alkyl group optionally
substituted by 1 to 5 substituents selected from the following
group D,
[0160] (5') a heterocyclic group optionally substituted by 1 to 5
substituents selected from the following group D
(wherein said heterocyclic group comprises 1 to 4 heteroatoms
selected from oxygen atom, nitrogen atom and sulfur atom) or
[0161] (6') a heterocycle C.sub.1-6 alkyl group optionally
substituted by 1 to 5 substituents selected from the following
group D
(wherein said heterocycle C.sub.1-6 alkyl group is a C.sub.1-6
alkyl group substituted by "a heterocyclic group optionally
substituted by 1 to 5 substituents selected from group D" as
defined above),
w is an integer of 1 to 3,
Y is
(a) C.sub.1-6 alkylene,
(b) C.sub.2-6 alkenylene or
(c) --Y.sup.1--(CH.sub.2).sub.m--Y.sup.2--(CH.sub.2).sub.n--
(wherein m and n are each independently 0 or an integer of 1 to
6,
Y.sup.1 and Y.sup.2 are each independently
[0162] (1') a bond,
[0163] (2') --O--,
[0164] (3') --NR.sup.y1--,
[0165] (4') --S--,
[0166] (5') --CO--,
[0167] (6') --SO--,
[0168] (7') --SO.sub.2--,
[0169] (8') --CO.sub.2--,
[0170] (9') --OCO--,
[0171] (10') --CONR.sup.y2--,
[0172] (11') --NR.sup.y2CO--,
[0173] (12') --SO.sub.2NR.sup.y2--,
[0174] (13') --NR.sup.y2SO.sub.2--,
[0175] (14') --NR.sup.y2CO.sub.2--,
[0176] (15') --OCONR.sup.y2--,
[0177] (16') --NR.sup.y2CONR.sup.y3--,
[0178] (17') --CR.sup.y4R.sup.y5-- or
[0179] (18') --CH.dbd.CH--
(wherein R.sup.y1 is
[0180] (1'') a hydrogen atom,
[0181] (2'') a group selected from the following group C,
[0182] (3'') --(CH.sub.2).sub.s--COOR.sup.y11,
[0183] (4'') --(CH.sub.2).sub.s--CONR.sup.y11R.sup.y12,
[0184] (5'') --(CH.sub.2).sub.s--COR.sup.y11 or
[0185] (6'') --(CH.sub.2).sub.s--SO.sub.2R.sup.y13
(wherein s is 0 or an integer of 1 to 6, R.sup.y11 and R.sup.y12
are each independently a hydrogen atom or a group selected from the
following group C, R.sup.y13 is a group selected from the following
group C),
R.sup.y2 and R.sup.y3 are each independently
[0186] (1'') a hydrogen atom,
[0187] (2'') a group selected from the following group C,
[0188] (3'') --COR.sup.y11 or
[0189] (4'') --SO.sub.2R.sup.y13 (wherein R.sup.y11 and R.sup.y13
are as defined above),
R.sup.y4 and R.sup.y5 are each independently
[0190] (1'') a hydrogen atom,
[0191] (2'') a carboxyl group,
[0192] (3'') a group selected from group F,
[0193] (4'') --OR.sup.y14 or
[0194] (5'') --NHR.sup.y15
(wherein R.sup.y14 is a group selected from the following group C,
R.sup.y15 is a hydrogen atom, a C.sub.1-6 alkyl group, a C.sub.1-6
alkanoyl group, a C.sub.6-14 aryl C.sub.1-6 alkyloxycarbonyl group
or a C.sub.1-6 alkoxycarbonyl group)))
[0195] group A:
(1) a halogen atom,
(2) a C.sub.1-6 alkoxy C.sub.1-6 alkoxy group,
(3) a cyano group,
(4) --OR.sup.a1,
(5) --SR.sup.a1,
(6) --NR.sup.a1R.sup.a2,
(7) --COOR.sup.a1,
(8) --CONR.sup.a1R.sup.a2,
(9) --SO.sub.3H,
(10) --SO.sub.2NR.sup.a1R.sup.a2,
(11) --NHCOR.sup.a1,
(12) --NHSO.sub.2R.sup.a3,
(13) --NHCO.sub.2R.sup.a4,
(14) --COR.sup.a1 and
(15) --N.sup.+R.sup.a1R.sup.a2R.sup.a3
(wherein R.sup.a1 and R.sup.a2 are each a hydrogen atom, a
C.sub.1-6 alkyl group or a benzyl group, R.sup.a3 is a C.sub.1-6
alkyl group and R.sup.a4 is a C.sub.1-6 alkyl group)
[0196] group B:
(1) a halogen atom,
(2) a cyano group,
(3) a nitro group,
(4) a C.sub.1-6 alkyl group,
(5) a C.sub.2-6 alkenyl group optionally substituted by carboxyl
group,
(6) a halogenated C.sub.1-6 alkyl group,
(7) --(CH.sub.2).sub.r--OR.sup.b1,
(8) --(CH.sub.2).sub.r--SR.sup.b1,
(9) --(CH.sub.2).sub.r--NR.sup.b1R.sup.b2,
(10) --(CH.sub.2).sub.r--COOR.sup.b1,
(11) --(CH.sub.2).sub.r--CONR.sup.b1R.sup.b2,
(12) --(CH.sub.2).sub.r--COR.sup.b1,
(13) --(CH.sub.2).sub.r--NR.sup.b1--COR.sup.b2,
(14) --(CH.sub.2).sub.r--NR.sup.b1--SO.sub.2R.sup.b3,
(15) --(CH.sub.2).sub.r--SO.sub.2R.sup.b3,
(16) --(CH.sub.2).sub.r--SO.sub.2NR.sup.b1R.sup.b2,
(17) --(CH.sub.2).sub.r--CONR.sup.b1--SO.sub.2R.sup.b3,
(18) --(CH.sub.2).sub.r--SO.sub.2NR.sup.b1--COR.sup.b2,
(19) --(CH.sub.2).sub.r--NR.sup.b1--COOR.sup.b3,
(20) --(CH.sub.2).sub.r--NR.sup.b1--CONR.sup.b2R.sup.b4,
(21) --O--(CH.sub.2).sub.r--COOR.sup.b1 and
(22) --CO--(CH.sub.2).sub.r--R.sup.b5
(wherein R.sup.b1, R.sup.b2 and R.sup.b4 are each independently a
hydrogen atom or a C.sub.1-6 alkyl group, R.sup.b3 is a C.sub.1-6
alkyl group, R.sup.b5 is a heterocyclic group and r is 0 or an
integer of 1 to 6)
[0197] group C:
(1) a C.sub.1-6 alkyl group optionally substituted by 1 to 3
substituents selected from the aforementioned group A,
(2) a C.sub.6-14 aryl group optionally substituted by 1 to 5
substituents selected from the aforementioned group B,
(3) a C.sub.6-14 aryl C.sub.1-6 alkyl group optionally substituted
by 1 to 5 substituents selected from the aforementioned group
B,
(4) a heterocyclic group optionally substituted by 1 to 5
substituents selected from the aforementioned group B and
(5) a heterocycle C.sub.1-6 alkyl group optionally substituted by 1
to 5 substituents selected from the aforementioned group B
[0198] group D:
(a) a hydrogen atom,
(b) a halogen atom,
(c) a cyano group,
(d) a nitro group,
(e) a C.sub.1-6 alkyl group optionally substituted by 1 to 3
substituents selected from the aforementioned group A,
(f) --(CH.sub.2).sub.t--OR.sup.d1,
wherein R.sup.d1 is
(1) a hydrogen atom,
(2) a group selected from the following group F,
(3) a C.sub.2-6 alkenyl group optionally substituted by 1 to 3
substituents selected from the aforementioned group A or
(4) a C.sub.2-6 alkynyl group optionally substituted by 1 to 3
substituents selected from the aforementioned group A,
hereinafter each t is independently 0 or an integer of 1 to 6,
(g) --(CH.sub.2).sub.t--S(O).sub.q--R.sup.d2,
wherein R.sup.d2 is
(1) a hydrogen atom or
(2) a group selected from the following group F,
q is 0, 1, 2 or 3,
(h) --(CH.sub.2).sub.t--NR.sup.d3R.sup.d4,
wherein R.sup.d3 and R.sup.d4 are each independently
(1) a hydrogen atom or
(2) a group selected from the following group F,
(i) --(CH.sub.2).sub.t--COOR.sup.d5,
wherein R.sup.d5 is
(1) a hydrogen atom or
(2) a group selected from the following group F,
(j) --(CH.sub.2).sub.t--CONR.sup.d6R.sup.d7,
wherein R.sup.d6 and R.sup.d7 are each independently
(1) a hydrogen atom,
(2) a hydroxyl group,
(3) a group selected from the following group F or
(4) a C.sub.1-6 alkoxy group,
(k) --(CH.sub.2).sub.t--COR.sup.d8,
wherein R.sup.d8 is
(1) a hydrogen atom or
(2) a group selected from the following group F,
(l) --(CH.sub.2).sub.t--NR.sup.d9CO--R.sup.d10,
wherein R.sup.d9 is
(1) a hydrogen atom,
(2) a C.sub.1-6 alkyl group optionally substituted by 1 to 3
substituents selected from the aforementioned group A or
(3) a C.sub.1-6 alkanoyl group,
R.sup.d10 is
(1) an amino group,
(2) a C.sub.1-6 alkylamino group or
(3) a group selected from the following group F,
(m) --(CH.sub.2).sub.t--NR.sup.d11SO.sub.2--R.sup.d12,
wherein R.sup.d11 is
(1) a hydrogen atom,
(2) a C.sub.1-6 alkyl group optionally substituted by 1 to 3
substituents selected from the aforementioned group A or
(3) a C.sub.1-6 alkanoyl group,
R.sup.d12 is
(1) a hydrogen atom or
(2) a group selected from the following group F,
(n) --(CH.sub.2).sub.t--SO.sub.2--NR.sup.d13R.sup.d14,
wherein R.sup.d13 and R.sup.d14 are each independently
(1) a hydrogen atom or
(2) a group selected from the following group F,
(o) --(CH.sub.2).sub.t--CONR.sup.d15--SO.sub.2R.sup.d16,
wherein R.sup.d15 and R.sup.d16 are each independently
(1) a hydrogen atom or
(2) a group selected from the following group F,
(p) --(CH.sub.2).sub.t--SO.sub.2NR.sup.d17--COR.sup.d18,
wherein R.sup.d17 is
(1) a hydrogen atom or
(2) a group selected from the following group F,
R.sup.d18 is a group selected from the following group F,
(q) --(CH.sub.2).sub.t--NR.sup.19--COOR.sup.d20,
wherein R.sup.d19 and R.sup.d20 are each independently
(1) a hydrogen atom or
(2) a group selected from the following group F,
(r) --(CH.sub.2).sub.t--NR.sup.d21--CONR.sup.d22R.sup.d23,
wherein R.sup.d21, R.sup.d22 and R.sup.d23 are each
independently
(1) a hydrogen atom or
(2) a group selected from the following group F,
(s) --(CH.sub.2).sub.t--C(.dbd.NR.sup.d24)NH.sub.2,
wherein R.sup.d24 is
(1) a hydrogen atom,
(2) a hydroxyl group,
(3) a C.sub.1-6 alkyl group optionally substituted by 1 to 3
substituents selected from the aforementioned group A or
(4) C.sub.1-6 alkoxy group,
(t) --(CH.sub.2).sub.t--O--(CH.sub.2).sub.p--COR.sup.d25,
wherein R.sup.d25 is
(1) an amino group,
(2) a C.sub.1-6 alkylamino group or
(3) a heterocyclic group optionally substituted by 1 to 5
substituents selected from the aforementioned group B,
p is 0 or an integer of 1 to 6,
(u) --(CH.sub.2).sub.t--O--(CH.sub.2).sub.p--NR.sup.26R.sup.27,
wherein R.sup.d26 and R.sup.d27 are each independently
(1) a hydrogen atom or
(2) a C.sub.1-6 alkyl group optionally substituted by 1 to 3
substituents selected from the aforementioned group A,
p is 0 or an integer of 1 to 6,
(v) --(CH.sub.2).sub.t--O--COOR.sup.d28,
wherein R.sup.d28 is
(1) a hydrogen atom or
(2) a group selected from the following group F, and
(w) a heterocyclic group optionally substituted by 1 to 5
substituents selected from the aforementioned group B
(wherein said heterocyclic group comprises 1 to 4 heteroatoms
selected from oxygen atom, nitrogen atom and sulfur atom)
[0199] group E:
(a) a halogen atom,
(b) a cyano group,
(c) a nitro group,
(d) an azido group,
(e) --OP(.dbd.O)(OH).sub.2,
(f) --OR.sup.e1,
wherein R.sup.e1 is
(1) a hydrogen atom,
(2) a group selected from the following group F,
(3) a C.sub.2-6 alkenyl group optionally substituted by 1 to 3
substituents selected from the aforementioned group A or
(4) a C.sub.2-6 alkynyl group optionally substituted by 1 to 3
substituents selected from the aforementioned group A,
(g) --S(O).sub.q--R.sup.e2
wherein R.sup.e2 is
(1) a hydrogen atom or
(2) a group selected from the following group F,
q is 0, 1, 2 or 3,
(h) --NR.sup.e3R.sup.e4,
wherein R.sup.e3 and R.sup.e4 are each independently
(1) a hydrogen atom,
(2) a cyano group or
(3) a group selected from the following group F,
(i) --COOR.sup.e5,
wherein R.sup.e5 is
(1) a hydrogen atom or
(2) a group selected from the following group F,
(j) --CONR.sup.e6R.sup.e7,
wherein R.sup.e6 and R.sup.e7 are each independently
(1) a hydrogen atom,
(2) a hydroxyl group,
(3) a group selected from the following group F or
(4) a C.sub.1-6 alkoxy group,
(k) --COR.sup.e8,
wherein R.sup.e8 is a group selected from the following group
F,
(l) --NR.sup.e9CO--R.sup.e10,
wherein R.sup.e9 is
(1) a hydrogen atom,
(2) a C.sub.1-6 alkyl group or
(3) a C.sub.1-6 alkanoyl group,
R.sup.e10 is
(1) a hydrogen atom,
(2) an amino group,
(3) a C.sub.1-6 alkylamino group,
(4) a C.sub.2-6 alkenyl group optionally substituted by 1 to 3
substituents selected from the aforementioned group A or
(5) a group selected from the following group F,
(m) --NR.sup.e11SO.sub.2--R.sup.e12,
wherein R.sup.e11 is
(1) a hydrogen atom,
(2) a C.sub.1-6 alkyl group or
(3) a C.sub.1-6 alkanoyl group,
R.sup.e12 is
(1) a hydrogen atom or
(2) a group selected from the following group F,
(n) --SO.sub.2--NR.sup.e13R.sup.e14,
wherein R.sup.e13 and R.sup.e14 are each independently
(1) a hydrogen atom or
(2) a group selected from the following group F,
(o) --CONR.sup.e15--SO.sub.2R.sup.e16,
wherein R.sup.e15 and R.sup.e16 are each independently
(1) a hydrogen atom or
(2) a group selected from the following group F,
(p) --SO.sub.2NR.sup.e17--COR.sup.e18,
wherein R.sup.e17 is
(1) a hydrogen atom or
(2) a group selected from the following group F,
R.sup.e18 is a group selected from the following group F,
(q) --NR.sup.e19--COOR.sup.e20,
wherein R.sup.e19 and R.sup.e20 are each independently
(1) a hydrogen atom or
(2) a group selected from the following group F,
(r) --NR.sup.e21--CONR.sup.e22R.sup.e23
wherein R.sup.e21, R.sup.e22 and R.sup.e23 are each
independently
(1) a hydrogen atom or
(2) a group selected from the following group F,
(s) --NHCO--COOR.sup.e24
wherein R.sup.e24 is
(1) a hydrogen atom or
(2) a group selected from the following group F,
(t) --NHCO--CONR.sup.e25R.sup.e26
wherein R.sup.e25 and R.sup.e26 are each independently
(1) a hydrogen atom,
(2) a hydroxyl group or
(3) a group selected from the following group F,
[0200] (u) --CONH--COOH, ##STR24## (y) a C.sub.6-14 aryl group
optionally substituted by 1 to 5 substituents selected from the
aforementioned group B, (z) a C.sub.3-10 cycloalkyl group
optionally substituted by 1 to 5 substituents selected from the
aforementioned group B, (aa) a heterocyclic group optionally
substituted by 1 to 5 substituents selected from the aforementioned
group B (wherein said heterocyclic group comprises 1 to 4
heteroatoms selected from oxygen atom, nitrogen atom and sulfur
atom), (bb) a C.sub.3-10 cycloalkylidene group optionally
substituted by 1 to 5 substituents selected from the aforementioned
group B, and (cc) a heterocycle ylidene group optionally
substituted by 1 to 5 substituents selected from the aforementioned
group B (wherein said heterocycle ylidene group comprises 1 to 4
heteroatoms selected from oxygen atom, nitrogen atom and sulfur
atom), when group E is a substituent on a C.sub.6-14 aryl group, a
C.sub.3-10 cycloalkyl group or a heterocyclic group, it may be (dd)
a C.sub.1-6 alkyl group optionally substituted by 1 to 3
substituents selected from the aforementioned group A, (ee) a
C.sub.2-6 alkenyl group optionally substituted by 1 to 3
substituents selected from the aforementioned group A, (ff) a
C.sub.2-6 alkynyl group optionally substituted by 1 to 3
substituents selected from the aforementioned group A, (gg)
C.sub.1-6 alkylidene group optionally substituted by 1 to 3
substituents selected from the aforementioned group A, (hh) a
C.sub.6-14 aryl C.sub.1-6 alkyl group optionally substituted by 1
to 5 substituents selected from the aforementioned group B, (ii) a
C.sub.3-10 cycloalkyl C.sub.1-6 alkyl group optionally substituted
by 1 to 5 substituents selected from the aforementioned group B, or
(jj) a heterocycle C.sub.1-6 alkyl group optionally substituted by
1 to 5 substituents selected from the aforementioned group B
[0201] group F:
(1) a C.sub.1-6 alkyl group optionally substituted by 1 to 3
substituents selected from the aforementioned group A,
(2) a C.sub.6-14 aryl group optionally substituted by 1 to 5
substituents selected from the aforementioned group B,
(3) a heterocyclic group optionally substituted by 1 to 5
substituents selected from the aforementioned group B
(wherein said heterocyclic group comprises 1 to 4 heteroatoms
selected from oxygen atom, nitrogen atom and sulfur atom),
(4) a C.sub.3-10 cycloalkyl group optionally substituted by 1 to 5
substituents selected from the aforementioned group B,
(5) a C.sub.6-14 aryl C.sub.1-6 alkyl group optionally substituted
by 1 to 5 substituents selected from the aforementioned group
B,
(6) a heterocycle C.sub.1-6 alkyl group optionally substituted by 1
to 5 substituents selected from the aforementioned group B
(wherein said heterocycle C.sub.1-6 alkyl group is a C.sub.1-6
alkyl group substituted by "a heterocyclic group optionally
substituted by 1 to 5 substituents selected from group B" as
defined above) and
(7) a C.sub.3-10 cycloalkyl C.sub.1-6 alkyl group optionally
substituted by 1 to 5 substituents selected from the aforementioned
group B.
[0202] [2] The compound of [1], wherein, in the formula [I],
##STR25## is N--C.dbd.C, or a pharmaceutically acceptable salt
thereof. [3] The compound of [1], wherein, in the formula [I], the
moiety ##STR26## is a fused ring selected from the group consisting
of ##STR27## ##STR28## ##STR29## or a pharmaceutically acceptable
salt thereof. [4] The compound of [3], wherein, in the formula [I],
the moiety ##STR30## is a fused ring selected from the group
consisting of ##STR31## or a pharmaceutically acceptable salt
thereof. [5] The compound of [4], wherein, in the formula [I], the
moiety ##STR32## or a pharmaceutically acceptable salt thereof. [6]
The compound of [5], wherein, in the formula [I], the moiety
##STR33## or a pharmaceutically acceptable salt thereof. [7] The
compound of [1], wherein G.sup.3, G.sup.4 and G.sup.5 are carbon
atoms, or a pharmaceutically acceptable salt thereof. [8] The
compound of [1], wherein Q.sup.1 is --O--, --NH--, --S-- or
--CONH--, or a pharmaceutically acceptable salt thereof. [9] The
compound of [8], wherein Q.sup.1 is --NH--, or a pharmaceutically
acceptable salt thereof. [10] The compound of [8], wherein b is an
integer of 1 to 3, c is an integer of 1 to 3 and d is 0, or a
pharmaceutically acceptable salt thereof. [11] The compound of [1],
wherein Q is --(CH.sub.2).sub.2--O-- or --(CH.sub.2).sub.2--NH--,
or a pharmaceutically acceptable salt thereof. [12] The compound of
[1], wherein R.sup.1 is a carboxyl group or --CONR.sup.11R.sup.12,
or a pharmaceutically acceptable salt thereof. [13] The compound of
[12], wherein R.sup.1 is a carboxyl group, or a pharmaceutically
acceptable salt thereof. [14] The compound of [12], wherein R.sup.1
is --CONR.sup.11R.sup.12, or a pharmaceutically acceptable salt
thereof. [15] The compound of [14], wherein R.sup.11 is a hydrogen
atom, and R.sup.2 is --CR.sup.135R.sup.136-L.sup.100-R.sup.137,
--CR.sup.135R.sup.136-L.sup.101-CONR.sup.140--R.sup.137, ##STR34##
or a pharmaceutically acceptable salt thereof. [16] The compound of
[15], wherein R.sup.12 is --CR.sup.135R.sup.136-L.sup.100-R.sup.37,
or a pharmaceutically acceptable salt thereof. [17] The compound of
[16], wherein L.sup.100 is a bond, and R.sup.137 is a C.sub.6-14
aryl group optionally substituted by 1 to 5 substituents selected
from group E or a heterocyclic group optionally substituted by 1 to
5 substituents selected from group E (wherein said heterocyclic
group comprises 1 to 4 heteroatoms selected from oxygen atom,
nitrogen atom and sulfur atom), or a pharmaceutically acceptable
salt thereof. [18] The compound of [17], wherein R.sup.135 and
R.sup.136 are each independently a group selected from group G, or,
R.sup.135 and R.sup.136 are bonded to each other, and form,
together with the carbon atom bonded thereto, a C.sub.3-10
cycloalkyl group optionally substituted by 1 to 5 substituents
selected from group B, or a heterocyclic group optionally
substituted by 1 to 5 substituents selected from group B, or a
pharmaceutically acceptable salt thereof. [19] The compound of
[16], wherein L.sup.100 is methylene, and R.sup.137 is a C.sub.6-14
aryl group optionally substituted by 1 to 5 substituents selected
from group E or a heterocyclic group optionally substituted by 1 to
5 substituents selected from group E (wherein said heterocyclic
group comprises 1 to 4 heteroatoms selected from oxygen atom,
nitrogen atom and sulfur atom), or a pharmaceutically acceptable
salt thereof. [20] The compound of [19], wherein R.sup.135 is a
group selected from group G, and R.sup.136 is a hydrogen atom, or a
pharmaceutically acceptable salt thereof. [21] The compound of
[15], wherein R.sup.12 is
--CR.sup.135R.sup.136-L.sup.101-CONR.sup.140--R.sup.137, or a
pharmaceutically acceptable salt thereof. [22] The compound of
[21], wherein L.sup.101 is a bond, or a pharmaceutically acceptable
salt thereof. [23] The compound of [22], wherein R.sup.135 and
R.sup.136 are each independently a group selected from group G, or,
R.sup.135 and R.sup.136 are bonded to each other, and form,
together with the carbon atom bonded thereto, a C.sub.3-10
cycloalkyl group optionally substituted by 1 to 5 substituents
selected from group B, or a heterocyclic group optionally
substituted by 1 to 5 substituents selected from group B, or a
pharmaceutically acceptable salt thereof. [24] The compound of
[23], wherein R.sup.140 is a hydrogen atom, and R.sup.137 is a
C.sub.6-14 aryl group optionally substituted by 1 to 5 substituents
selected from group E or a heterocyclic group optionally
substituted by 1 to 5 substituents selected from group E (wherein
said heterocyclic group comprises 1 to 4 heteroatoms selected from
oxygen atom, nitrogen atom and sulfur atom), or a pharmaceutically
acceptable salt thereof. [25] The compound of [15], wherein
R.sup.12 is ##STR35## or a pharmaceutically acceptable salt
thereof. [26] The compound of [15], wherein R.sup.12 is ##STR36##
or a pharmaceutically acceptable salt thereof. [27] The compound of
[25] or [26], wherien L.sup.102 is a bond, or a pharmaceutically
acceptable salt thereof. [28] The compound of [27], wherien
R.sup.138 and R.sup.139 are each independently a group selected
from group G, or, R.sup.138 and R.sup.139 are bonded to each other,
and form, together with the carbon atom bonded thereto, a
C.sub.3-10 cycloalkyl group optionally substituted by 1 to 5
substituents selected from group B, or a heterocyclic group
optionally substituted by 1 to 5 substituents selected from group
B, or a pharmaceutically acceptable salt thereof. [29] The compound
of [28], wherein L.sup.103 is a bond, ring D.sup.3 is a C.sub.6-14
aryl group optionally substituted by 1 to 5 substituents selected
from group E or a heterocyclic group optionally substituted by 1 to
5 substituents selected from group E (wherein said heterocyclic
group comprises 1 to 4 heteroatoms selected from oxygen atom,
nitrogen atom and sulfur atom), and R.sup.140 and R.sup.141 are
each independently a hydrogen atom, or a pharmaceutically
acceptable salt thereof. [30] The compound of [1], wherein R.sup.2
is a hydrogen atom, a group selected from group E, a C.sub.1-6
alkyl group optionally substituted by 1 to 3 substituents selected
from group E, ##STR37## wherein each symbol is as defined in [1],
or a pharmaceutically acceptable salt thereof. [31] The compound of
[30], wherein R.sup.2 is a C.sub.1-6 alkyl group optionally
substituted by 1 to 3 substituents selected from group E or
##STR38## wherein each symbol is as defined in [1], or a
pharmaceutically acceptable salt thereof. [32] The compound of
[31], wherein R.sup.2 is ##STR39## wherein each symbol is as
defined in [1], or a pharmaceutically acceptable salt thereof. [33]
The compound of [30], wherein L.sup.1 and L.sup.2 are each
independently a bond, C.sub.1-6 alkylene,
--(CH.sub.2).sub.u1--NR.sup.L1--(CH.sub.2).sub.v1--,
--(CH.sub.2).sub.u1--CO--(CH.sub.2).sub.v1-- or
--(CH.sub.2).sub.u1--CONR.sup.L2--(CH.sub.2).sub.v1--, or a
pharmaceutically acceptable salt thereof. [34] The compound of
[33], wherein L.sup.1 and L.sup.2 are each independently C.sub.1-6
alkylene, or a pharmaceutically acceptable salt thereof. [35] The
compound of [33], wherein u1 and v1 are each independently 0 or an
integer of 1 to 3, or a pharmaceutically acceptable salt thereof.
[36] The compound of [30], wherein ring D.sup.1 and ring D.sup.2
are each independently a C.sub.6-14 aryl group optionally
substituted by 1 to 5 substituents selected from group E or a
heterocyclic group optionally substituted by 1 to 5 substituents
selected from group E, or a pharmaceutically acceptable salt
thereof. [37] The compound of [1], wherein R.sup.3 is a hydrogen
atom, a halogen atom, a C.sub.1-6 alkyl group optionally
substituted by 1 to 3 substituents selected from group A or
--OR.sup.101 (wherein R.sup.101 is a hydrogen atom or a group
selected from group C), or a pharmaceutically acceptable salt
thereof. [38] The compound of [1], wherein R.sup.5 and R.sup.6 are
each independently a hydrogen atom, a halogen atom, a C.sub.1-6
alkyl group optionally substituted by 1 to 3 substituents selected
from group A or --OR.sup.120 (wherein R.sup.120 is a hydrogen atom
or a group selected from group C), or a pharmaceutically acceptable
salt thereof. [39] The compound of [1], wherein ring A is benzene
or a 5- or 6-membered heterocycle comprising 1 to 4 heteroatoms
selected from oxygen atom, nitrogen atom and sulfur atom, or a
pharmaceutically acceptable salt thereof. [40] The compound of
[39], wherein ring A is benzene, or a pharmaceutically acceptable
salt thereof. [41] The compound of [1], wherein ring Cy is a
C.sub.3-10 cycloalkyl group or a C.sub.3-10 cycloalkenyl group, or
a pharmaceutically acceptable salt thereof. [42] The compound of
[41], wherein ring Cy is a cyclohexyl group, or a pharmaceutically
acceptable salt thereof. [43] The compound of [1], wherein X is a
hydrogen atom, a halogen atom, a C.sub.1-6 alkyl group optionally
substituted by 1 to 3 substituents selected from group A,
--(CH.sub.2).sub.t--OR.sup.d1,
--(CH.sub.2).sub.t--S(O).sub.q--R.sup.d2,
--(CH.sub.2).sub.t--NR.sup.d3R.sup.d4 or ##STR40## wherein each
symbol is as defined in [1], or a pharmaceutically acceptable salt
thereof. [44] The compound of [43], wherein Y is
--(CH.sub.2).sub.m--O--(CH.sub.2).sub.n-- or
--NR.sup.y1--(CH.sub.2).sub.n--Y.sup.2-- wherein each symbol is as
defined in [1], or a pharmaceutically acceptable salt thereof. [45]
The compound of [43], wherein Y is --O--CH.sub.2-- or --O--, or a
pharmaceutically acceptable salt thereof. [46] The compound of
[43], wherein Y is --NR.sup.y1--CH.sub.2--CO-- or
--NR.sup.y1--(CH.sub.2).sub.2--, or a pharmaceutically acceptable
salt thereof. [47] The compound of [43], wherein ring B is a
C.sub.6-14 aryl group or a heterocyclic group comprising 1 to 4
heteroatoms selected from oxygen atom, nitrogen atom and sulfur
atom, or a pharmaceutically acceptable salt thereof. [48] The
compound of [47], wherein ring B is a phenyl group, a pyridyl
group, a piperidyl group, pyrrolidinyl group, piperazinyl group,
morpholinyl group, azepanyl group, 1,4-oxazepanyl group, isoxazolyl
group, thiazolyl group or 2-oxooxazolidinyl group, or a
pharmaceutically acceptable salt thereof. [49] The compound of
[43], wherein Z is 1 to 3 substituents selected from (1) a hydrogen
atom, (2) a halogen atom, (3) a nitro group, (4) a C.sub.6-14 aryl
group optionally substituted by 1 to 5 substituents selected from
group D, (5) a C.sub.3-10 cycloalkyl group optionally substituted
by 1 to 5 substituents selected from group D, (6) a heterocyclic
group optionally substituted by 1 to 5 substituents selected from
group D, (7) a C.sub.1-6 alkyl group optionally substituted by 1 to
3 substituents selected from the aforementioned group A, (8)
--(CH.sub.2).sub.t--OR.sup.d1, (9)
--(CH.sub.2).sub.t--S(O).sub.q--R.sup.d2, (10)
--(CH.sub.2).sub.t--NR.sup.d3R.sup.d4, (11)
--(CH.sub.2).sub.t--COOR.sup.d5, (12)
--(CH.sub.2).sub.t--CONR.sup.d6R.sup.d7, (13)
--(CH.sub.2).sub.t--COR.sup.d8, (14)
--(CH.sub.2).sub.t--NR.sup.d9CO--R.sup.d10, (15)
--(CH.sub.2).sub.t--NR.sup.d11SO.sub.2--R.sup.d12 and (16)
--(CH.sub.2).sub.t--NR.sup.d19--COOR.sup.d20 wherein each symbol is
as defined in [1], or a pharmaceutically acceptable salt thereof.
[50] The compound of [1], which is represented by the following
formula [I-A], or a pharmaceutically acceptable salt thereof:
##STR41## wherein X' is a hydrogen atom, a halogen atom, a
C.sub.1-6 alkyl group optionally substituted by 1 to 3 substituents
selected from group A or --OR.sup.d1, and other symbols are as
defined in [1]. [51] The compound of [1], which is represented by
the following formula [I-B], or a pharmaceutically acceptable salt
thereof: ##STR42## wherein Q.sup.2 is --O-- or --NH--, and other
symbols are as defined in [52] The compound of [1], which is
represented by the following formula [I-C], or a pharmaceutically
acceptable salt thereof: ##STR43## wherein Q.sup.3 is --O-- or
--NR.sup.2--, X' is a hydrogen atom, a halogen atom, a C.sub.1-6
alkyl group optionally substituted by 1 to 3 substituents selected
from group A or --OR.sup.d1, and other symbols are as defined in
[1]. [53] A pharmaceutical composition comprising a compound of any
of [1] to [52], or a pharmaceutically acceptable salt thereof, and
a pharmaceutically acceptable carrier. [54] A hepatitis C virus
polymerase inhibitor comprising a compound of any of [1] to [52] or
a pharmaceutically acceptable salt thereof as an active ingredient.
[55] An anti-hepatitis C virus agent comprising a compound of any
of [1] to [52] or a pharmaceutically acceptable salt thereof as an
active ingredient. [56] A therapeutic agent for hepatitis C, which
comprises a compound of any of [1] to [52] or a pharmaceutically
acceptable salt thereof as an active ingredient. [57] A therapeutic
agent for hepatitis C, which comprises (a) a hepatitis C virus
polymerase inhibitor of [54] and (b) at least one pharmaceutical
agent selected from the group consisting of a different antiviral
agent, an antiinflammatory agent and an immunostimulant. [58] A
therapeutic agent for hepatitis C, which comprises (a) a hepatitis
C virus polymerase inhibitor of [54] and (b) interferon. [59] An
anti-hepatitis C virus agent, which comprises (a) an anti-hepatitis
C virus agent of [55] and (b) at least one pharmaceutical agent
selected from the group consisting of a different antiviral agent,
an antiinflammatory agent and an immunostimulant. [60] An
anti-hepatitis C virus agent comprising (a) an anti-hepatitis C
virus agent of [55] and (b) interferon. [61] A pharmaceutical
composition comprising (a) a compound of any of [1] to [52] or a
pharmaceutically acceptable salt thereof, and (b) at least one
pharmaceutical agent selected from the group consisting of a
different antiviral agent, an antiinflammatory agent and an
immunostimulant. [62] A pharmaceutical composition comprising (a) a
compound of any of [1] to [52] or a pharmaceutically acceptable
salt thereof, and (b) interferon. [63] Use of a compound of any of
[1] to [52] or a pharmaceutically acceptable salt thereof for the
production of a pharmaceutical agent for treating hepatitis C. [64]
Use of a compound of any of [1] to [52] or a pharmaceutically
acceptable salt thereof for the production of a hepatitis C virus
polymerase inhibitor. [65] A method for treating hepatitis C, which
comprises administering an effective amount of a compound of any of
[1] to [52] or a pharmaceutically acceptable salt thereof to a
mammal. [66] The method of [65], further comprising administering
an effective amount of at least one pharmaceutical agent selected
from the group consisting of a different antiviral agent, an
antiinflammatory agent and an immunostimulant to the mammal. [67]
The method of [65], further comprising administering an effective
amount of interferon to the mammal. [68] A method for inhibiting
hepatitis C virus polymerase, which comprises administering an
effective amount of a compound of any of [1] to [52] or a
pharmaceutically acceptable salt thereof to a mammal. [69] The
method of [68], further comprising administering an effective
amount of at least one pharmaceutical agent selected from the group
consisting of a different antiviral agent, an antiinflammatory
agent and an immunostimulant to the mammal. [70] The method of
[681, further comprising administering an effective amount of
interferon to the mammal.
DETAILED DESCRIPTION OF THE INVENTION
[0203] The definitions of respective substituents and moieties used
in the present specification are as follows.
[0204] The "halogen atom" is a fluorine atom, chlorine atom,
bromine atom or iodine atom, preferably fluorine atom, chlorine
atom or bromine atom.
[0205] The "C.sub.1-6 alkyl group" is a linear or branched chain
alkyl group having 1 to 6 carbon atoms, 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.
[0206] The "C.sub.2-6 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, 1-butenyl
group, 2-butenyl group, 1,3-butadienyl group, 2-isopentenyl group,
3-isohexenyl group, 4-methyl-3-pentenyl group and the like can be
mentioned.
[0207] The "C.sub.2-6 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.
[0208] The "halogenated C.sub.1-6 alkyl group" is the above-defined
"C.sub.1-6 alkyl group" substituted by the above-defined "halogen
atom", which is preferably a halogenated alkyl group wherein the
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.
[0209] The "C.sub.1-6 alkylene" is a straight chain alkylene having
1 to 6 carbon atoms, and methylene, ethylene, trimethylene,
tetramethylene, pentamethylene, hexamethylene and the like can be
mentioned.
[0210] The "C.sub.2-6 alkenylene" is a straight chain alkenylene
having 2 to 6 carbon atoms, and vinylene, propenylene,
1-butenylene, 1,3-butadienylene and the like can be mentioned.
[0211] The "C.sub.1-6 alkoxy group" is an alkyl-oxy group wherein
the alkyl moiety is the above-defined "C.sub.1-6 alkyl group",
preferably an alkoxy group wherein the 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.
[0212] The "C.sub.1-6 alkoxy C.sub.1-6 alkoxy group" is an
alkyl-oxy-alkyl-oxy group wherein the above-defined "C.sub.1-6
alkoxy group" is substituted by the above-defined "C.sub.1-6 alkoxy
group", preferably that wherein the alkyl moiety is a linear or
branched chain alkyl group having 1 to 4 carbon atoms.
Specifically, methoxymethoxy group, ethoxymethoxy group,
1-(methoxy)ethoxy group, 2-(methoxy)ethoxy group, methoxypropoxy
group, isopropyloxyethoxy group and the like can be mentioned.
[0213] The "C.sub.1-6 alkanoyl group" is an alkyl-carbonyl group
wherein the alkyl moiety is the above-defined "C.sub.1-6 alkyl
group", preferably an alkyl-carbonyl group wherein the alkyl moiety
is a linear or branched chain alkyl group having 1 to 4 carbon
atoms. Specifically, acetyl group, propionyl group, butyryl group,
isobutyryl group, pivaloyl group and the like can be mentioned.
[0214] The "C.sub.1-6 alkoxycarbonyl group" is an
alkyl-oxy-carbonyl group wherein the alkoxy moiety is the
above-defined "C.sub.1-6 alkoxy group", preferably an
alkyl-oxy-carbonyl group wherein the alkyl moiety is a linear or
branched chain alkyl group having 1 to 4 carbon atoms.
Specifically, methoxycarbonyl group, ethoxycarbonyl group,
propoxycarbonyl group, isopropyloxycarbonyl group, butoxycarbonyl
group, isobutyloxycarbonyl group, tert-butyloxycarbonyl group,
pentyloxycarbonyl group, hexyloxycarbonyl group and the like can be
mentioned.
[0215] The "C.sub.1-6 alkylamino group" is an alkyl-amino group or
a dialkyl-amino group wherein the alkyl moiety is the above-defined
"C.sub.1-6 alkyl group", preferably an alkyl-amino group or a
dialkyl-amino group wherein the alkyl moiety is a linear or
branched chain alkyl group having 1 to 4 carbon atoms.
Specifically, methylamino group, ethylamino group, propylamino
group, isopropylamino group, butylamino group, isobutylamino group,
tert-butylamino group, pentylamino group, hexylamino group,
dimethylamino group, diethylamino group, N-ethyl-N-methylamino
group, N-isobutyl-N-isopropylamino group and the like can be
mentioned.
[0216] The "C.sub.1-6 alkanoylamino group" is an
alkyl-carbonyl-amino group wherein the alkanoyl moiety is the
above-defined "C.sub.1-6 alkanoyl group", preferably an
alkyl-carbonyl-amino group wherein the alkyl moiety is a linear or
branched chain alkyl group having 1 to 4 carbon atoms.
Specifically, acetylamino group, propionylamino group, butyrylamino
group, isobutyrylamino group, pivaloylamino group and the like can
be mentioned.
[0217] The "C.sub.1-6 alkylsulfonyl group" is an alkyl-sulfonyl
group wherein the alkyl moiety is the above-defined "C.sub.1-6
alkyl group", preferably an alkyl-sulfonyl group wherein the alkyl
moiety is a linear or branched chain alkyl group having 1 to 4
carbon atoms. Specifically, methanesulfonyl group, ethylsulfonyl
group, propylsulfonyl group, isopropylsulfonyl group, butylsulfonyl
group, isobutylsulfonyl group, tert-butylsulfonyl group,
pentylsulfonyl group, hexylsulfonyl group and the like can be
mentioned.
[0218] The "C.sub.6-14 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.
[0219] The "C.sub.3-10 cycloalkyl group" is a saturated cycloalkyl
group having 3 to 10, preferably 3 to 8, more preferably 5 to 7,
carbon atoms, and includes monocycle and fused ring. Specifically,
cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl
group, cycloheptyl group, cyclooctyl group, adamantyl group and the
like can be mentioned.
[0220] The "C.sub.3-10 cycloalkenyl group" is a cycloalkenyl group
having 3 to 10, preferably 3 to 8, more preferably 5 to 7, carbon
atoms, and includes 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,
cycloheptenyl group, cyclooctenyl group and the like can be
mentioned. It does not include aryl group such as phenyl group and
completely saturated cycloalkyl group.
[0221] The "C.sub.6-14 aryl C.sub.1-6 alkyloxycarbonyl group" is an
aryl-alkyl-oxy-carbonyl group wherein the alkyl moiety is the
above-defined "C.sub.1-6 alkyl group", and the aryl moiety is the
above-defined "C.sub.6-14 aryl group". Preferred is an
aryl-alkyl-oxy-carbonyl group wherein the alkyl moiety is a
straight or branched chain alkyl group having 1 to 4 carbon atoms
and the aryl moiety is a phenyl group. Specifically,
benzyloxycarbonyl group, phenethyloxycarbonyl group,
3-phenylpropyloxycarbonyl group, 2-phenylpropyloxycarbonyl group,
4-phenylbutyloxycarbonyl group and the like can be mentioned.
[0222] The "bond" means a direct connection. For example, when
L.sup.1 is a "bond" in --O-L.sup.1-Ph, it means --O-Ph.
[0223] The "glucuronic acid residue" is a group remaining after
removing any hydroxyl group from glucuronic acid, and preferably
substitutes at the 1-posotion of .beta.-D-glucuronic acid.
[0224] The "heterocyclic group" and "heterocyclic group comprising
1 to 4 heteroatoms selected from oxygen atom, nitrogen atom and
sulfur atom" has, as a ring-constituting atom, 1 to 4 heteroatoms
selected from oxygen atom, nitrogen atom and sulfur atom besides
carbon atom, wherein the number of atom constituting the ring is 3
to 14, includes saturated ring and unsaturated ring, monocycle and
fused ring, and may be a spiro ring.
[0225] As the monocyclic heterocyclic group, 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), pyrrolinyl group (1-pyrrolinyl group,
2-pyrrolinyl group, 3-pyrrolinyl group), pyrrolidinyl group,
4,5-dihydro-1H-imidazolyl group, 4,5-dihydro-1H-oxazolyl group,
4,5-dihydro-1H-thiazolyl group, imidazolidinyl group, azetidinyl
group, piperidyl group, piperazinyl group,
1,2,3,6-tetrahydropyridyl group, morpholinyl group, thiomorpholinyl
group, 3,6-dihydro-2H-pyranyl group, tetrahydropyranyl group,
tetrahydrofuranyl group, azepanyl group (e.g., azepan-1-yl group),
azocanyl group (e.g., azocan-1-yl group), azonanyl group (e.g.,
azonan-1-yl group), 1,4-diazepanyl group (e.g., 1,4-diazepan-1-yl
group), 1,4-oxazepanyl group (e.g., 1,4-oxazepan-4-yl group) and
the like can be mentioned.
[0226] This heterocyclic group includes the groups represented by
the following formulas. ##STR44## wherein E.sup.1 is an oxygen
atom, a sulfur atom or NH, E.sup.2 is an oxygen atom, CH.sub.2 or
NH, E.sup.3 is an oxygen atom or a sulfur atom, wherein f is an
integer of 1 to 3, h and h' are the same or different and each is
an integer of 1 to 3.
[0227] Specifically, ##STR45## ##STR46## and the like can be
mentioned.
[0228] As a fused heterocyclic group, specifically, quinolyl group,
isoquinolyl group, quinazolinyl group, quinoxalinyl group,
phthalazinyl group, cinnolinyl group, naphthyridinyl group,
1,2,3,4-tetrahydroquinolyl group, 5,6,7,8-tetrahydroquinolyl group,
1,2,3,4-tetrahydroisoquinolyl group, 5,6,7,8-tetrahydroisoquinolyl
group, indolyl group, benzimidazolyl group,
2,3-dihydrobenzimidazolyl group, 2,3-dihydro-2-oxobenzimidazolyl
group, indolinyl group, isoindolinyl group, octahydroindolyl group,
octahydroisoindolyl group, benzofuranyl group, benzothienyl group,
benzoxazolyl group, benzothiazolyl group,
3,4-dihydro-2H-benzo[1,4]oxazinyl group,
3-oxo-3,4-dihydro-2H-benzo[1,4]oxazinyl group,
octahydrocyclopenta[c]pyrrolyl group, 2-oxo-2H-chromenyl group,
benzo[1,3]dioxolanyl group, 4-oxo-1H-quinolinyl group,
2-oxohexahydrothieno[3,4-d]imidazolyl group,
7-azabicyclo[2.2.1]heptyl group, ##STR47## and the like can be
mentioned.
[0229] As a Spiro heterocyclic group, specifically, ##STR48##
wherein h'' is an integer of 1 to 6 and the like can be
mentioned.
[0230] The "5- or 6-membered heterocycle comprising 1 to 4
heteroatoms selected from oxygen atom, nitrogen atom and sulfur
atom" is a 5-membered or 6-membered saturated or unsaturated ring
containing G.sup.6, which contains, besides carbon atom, 1 to 4
heteroatoms selected from oxygen atom, nitrogen atom and sulfur
atom, wherein G.sup.6 is a nitrogen atom or a carbon atom, and a
broken line in ring A is a single bond or a double bond.
[0231] Preferably, it is a heterocycle containing 1 or 2, more
preferably 1, heteroatom selected from oxygen atom, nitrogen atom
and sulfur atom, besides carbon atom, wherein the heteroatom is
preferably a nitrogen atom.
[0232] As the ring A, specifically, benzene, cyclopentane,
cyclohexane, cyclopentene, cyclohexene, pyridine, pyrazine,
pyrimidine, pyridazine, 1,3,5-triazine, pyrrole, pyrazole,
imidazole, 1,2,3-triazole, 1,2,4-triazole, tetrazole, thiophene,
furan, oxazole, isoxazole, thiazole, isothiazole,
1,2,4-thiadiazole, 1,2,5-thiadiazole, 1,3,4-thiadiazole,
2,3-dihydro-1H-pyrrole, 2,5-dihydro-1H-pyrrole, pyrrolidine,
imidazolidine, piperidine, piperazine, morpholine, thiomorpholine,
tetrahydropyran, oxazolidine, 1,2,3,4-tetrahydropyridine,
1,2,3,6-tetrahydropyridine, ##STR49## and the like can be
mentioned.
[0233] As the mode of binding of the ##STR50## and the like can be
mentioned.
[0234] The "group A" means the substituent groups of the following
(1) to (15).
(R.sup.a1 and R.sup.a2 are each independently a hydrogen atom, the
above-defined "C.sub.1-6 alkyl group" or a benzyl group, R.sup.a3
is the above-defined "C.sub.1-6 alkyl group" and R.sup.a4 is the
above-defined "C.sub.1-6 alkyl group")
(1) the above-defined "halogen atom",
(2) the above-defined "C.sub.1-6 alkoxy C.sub.1-6 alkoxy
group",
(3) a cyano group,
(4) --OR.sup.a1 (e.g., hydroxyl group, methoxy group, ethoxy group,
isopropyloxy group, tert-butyloxy group, benzyloxy group etc.),
(5) --SR.sup.a1 (e.g., mercapto group, methylsulfanyl group
etc.),
(6) --NR.sup.a1R.sup.a2 (e.g., amino group, methylamino group,
ethylamino group, isopropylamino group, dimethylamino group,
diethylamino group, diisopropylamino group, di-tert-butylamino
group, N-ethyl-N-methylamino group etc.),
(7) --COOR.sup.a1 (e.g., carboxyl group, methoxycarbonyl group,
ethoxycarbonyl group, isopropyloxycarbonyl group,
tert-butoxycarbonyl group etc.),
[0235] (8) --CONR.sup.a1R.sup.a2 (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 etc.),
(9) --SO.sub.3H,
[0236] (10) --SO.sub.2NR.sup.a1R.sup.a2 (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 etc.),
(11) --NHCOR.sup.a1 (e.g., formylamino group, acetylamino group,
propionylamino group, isobutyrylamino group, pivaloylamino group
etc.),
(12) --NHSO.sub.2R.sup.a3 (e.g., methanesulfonylamino group,
ethylsulfonylamino group, isopropylsulfonylamino group,
tert-butylsulfonylamino group etc.),
(13) --NHCO.sub.2R.sup.a4 (e.g., tert-butoxycarbonylamino group
etc.),
(14) --COR.sup.a1 (e.g., formyl group, acetyl group, propionyl
group, isobutyryl group, pivaloyl group etc.) and
(15) --N.sup.+R.sup.a1R.sup.a2R.sup.a3 (e.g., trimethylammonio
group, triethylammonio group etc.).
[0237] The "group B" means the substituent groups of the following
(1) to (22).
[0238] (the following R.sup.b1, R.sup.b2 and R.sup.b4 are each
independently a hydrogen atom or the above-defined "C.sub.1-6 alkyl
group", R.sup.b3 is the above-defined "C.sub.1-6 alkyl group",
R.sup.b5 is the above-defined "heterocyclic group" and r is 0 or an
integer of 1 to 6)
(1) the above-defined "halogen atom",
(2) a cyano group,
(3) a nitro group,
(4) the above-defined "C.sub.1-6 alkyl group",
[0239] (5) the above-defined "C.sub.2-6 alkenyl group" optionally
substituted by carboxyl group (e.g., vinyl group, allyl group,
1-propenyl group, isopropenyl group, 1-butenyl group, 2-butenyl
group, 1,3-butadienyl group, 2-isopentenyl group, 3-isohexenyl
group, 4-methyl-3-pentenyl group, 2-carboxyethenyl group etc.),
(6) the above-defined "halogenated C.sub.1-6 alkyl group",
(7) --(CH.sub.2).sub.r--OR.sup.b1 (e.g., hydroxyl group, methoxy
group, ethoxy group, isopropyloxy group, tert-butyloxy group,
hydroxymethyl group, methoxymethyl group, 2-(methoxy)ethyl group
etc.),
(8) --(CH.sub.2).sub.r--SR.sup.b1 (e.g., mercapto group,
methylsulfanyl group, mercaptomethyl group, 2-(methylsulfanyl)ethyl
group etc.),
[0240] (9) --(CH.sub.2).sub.r--NR.sup.b1R.sup.b2 (e.g., amino
group, methylamino group, ethylamino group, isopropylamino group,
dimethylamino group, diethylamino group, diisopropylamino group,
di-tert-butylamino group, N-ethyl-N-methylamino group, aminomethyl
group, 2-(methylamino)ethyl group etc.),
(10) --(CH.sub.2).sub.r--COOR.sup.b1 (e.g., carboxyl group,
methoxycarbonyl group, ethoxycarbonyl group, isopropyloxycarbonyl
group, tert-butoxycarbonyl group, carboxymethyl group,
2-(carboxy)ethyl group etc.),
[0241] (11) --(CH.sub.2).sub.r--CONR.sup.b1R.sup.b2 (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, carbamoylmethyl group,
dimethylcarbamoylmethyl group, 2-(methylcarbamoyl)ethyl group
etc.),
(12) --(CH.sub.2).sub.r--COR.sup.b1 (e.g., formyl group, acetyl
group, propionyl group, isobutyryl group, pivaloyl group,
acetylmethyl group, 2-pivaloylethyl group etc.),
(13) --(CH.sub.2).sub.r--NR.sup.b1--COR.sup.b2 (e.g., formylamino
group, acetylamino group, propionylamino group, isobutyrylamino
group, pivaloylamino group, N-acetyl-N-methylamino group,
acetylaminomethyl group, 2-(isobutyrylamino)ethyl group etc.),
[0242] (14) --(CH.sub.2).sub.r--NR.sup.b1--SO.sub.2R.sup.b3 (e.g.,
methanesulfonylamino group, ethylsulfonylamino group,
isopropylsulfonylamino group, tert-butylsulfonylamino group,
N-methyl-N-(methanesulfonyl)amino group, methanesulfonylaminomethyl
group, 2-(tert-butylsulfonylamino)ethyl group etc.),
(15) --(CH.sub.2).sub.r--SO.sub.2R.sup.b3 (e.g., methanesulfonyl
group, ethylsulfonyl group, isopropylsulfonyl group,
tert-butylsulfonyl group, methanesulfonylmethyl group,
2-(ethylsulfonyl)ethyl group etc.),
[0243] (16) --(CH.sub.2).sub.r--SO.sub.2NR.sup.b1R.sup.b2 (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, sulfamoylmethyl group,
2-(methylsulfamoyl)ethyl group etc.),
[0244] (17) --(CH.sub.2).sub.r--CONR.sup.b1--SO.sub.2R.sup.b3
(e.g., methanesulfonylcarbamoyl group, ethylsulfonylcarbamoyl
group, isopropylsulfonylcarbamoyl group,
tert-butylsulfonylcarbamoyl group,
N-methyl-N-(methanesulfonyl)carbamoyl group,
methanesulfonylcarbamoylmethyl group,
2-(ethylsulfonylcarbamoyl)ethyl group etc.),
(18) --(CH.sub.2).sub.r--SO.sub.2NR.sup.b1--COR.sup.b2 (e.g.,
acetylsulfamoyl group, propionylsulfamoyl group,
isobutyrylsulfamoyl group, pivaloylsulfamoyl group,
N-acetyl-N-methylsulfamoyl group, acetylsulfamoylmethyl group,
2-(pivaloylsulfamoyl)ethyl group etc.),
(19) --(CH.sub.2).sub.r--NR.sup.b1--COOR.sup.b3 (e.g.,
methoxycarbonylamino group, ethoxycarbonylamino group,
isopropyloxycarbonylamino group, tert-butoxycarbonylamino group,
methoxycarbonylaminomethyl group, 2-(tert-butoxycarbonylamino)ethyl
group etc.),
[0245] (20) --(CH.sub.2).sub.r--NR.sup.b1--CONR.sup.b2R.sup.b4
(e.g., ureido group, 3-methylureido group, 3-ethylureido group,
3-isopropylureido group, 3,3-dimethylureido group,
3,3-diethylureido group, 3,3-diisopropylureido group,
3,3-di-tert-butylureido group, 3-ethyl-3-methylureido group,
1,3-dimethylureido group, trimethylureido group, ureidomethyl
group, 2-(3,3-dimethylureido)ethyl group),
(21) --O--(CH.sub.2).sub.r--COOR.sup.b1 (e.g., carboxymethoxy
group, 2-carboxyethoxy group, 3-carboxypropoxy group,
4-carboxybutoxy group, 5-carboxypentyloxy group,
methoxycarbonylmethoxy group, 2-ethoxycarbonylethoxy group etc.)
and
(22) --CO--(CH.sub.2).sub.r--R.sup.b5 (e.g.,
1-oxo-5-(2-oxohexahydrothieno[3,4-d]imidazol-6-yl)pentyl group
etc.).
[0246] The "C.sub.1-6 alkyl group optionally substituted by 1 to 3
substituents selected from group A" is a group wherein the
above-defined "C.sub.1-6 alkyl group" is optionally substituted by
1 to 3 substituents selected from the above-defined "group A",
which includes non-substituted alkyl group.
[0247] 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, hydroxymethyl group, 2-hydroxyethyl group, 3-hydroxypropyl
group, 4-hydroxybutyl group, 1-hydroxy-1-methylethyl group,
1-hydroxypropan-2-yl group, 1,3-dihydroxypropan-2-yl group,
1-hydroxy-2-methylpropan-2-yl group, carboxymethyl group,
ethoxycarbonylmethyl group, 2-carboxyethyl group, methoxymethyl
group, methoxyethyl group, ethoxyethoxyethyl group,
ethoxycarbonylmethyl group, 2-ethoxycarbonylethyl group,
2-dimethylaminoethyl group, carbamoylmethyl group,
methylcarbamoylmethyl group, sulfomethyl group, sulfamoylmethyl
group, 2-sulfamoylethyl group, methylsulfamoylmethyl group and the
like can be mentioned.
[0248] The "C.sub.2-6 alkenyl group optionally substituted by 1 to
3 substituents selected from group A" is the above-defined
"C.sub.2-6 alkenyl group" optionally substituted by 1 to 3
substituents selected from the above-defined "group A", which
includes non-substituted alkenyl group.
[0249] Specifically, vinyl group, allyl group, 1-propenyl group,
isopropenyl group, 1-butenyl group, 2-butenyl group, 1,3-butadienyl
group, 2-isopentenyl group, 3-isohexenyl group, 4-methyl-3-pentenyl
group, 2-carboxyethenyl group and the like can be mentioned.
[0250] The "C.sub.2-6 alkynyl group optionally substituted by 1 to
3 substituents selected from group A" is the above-defined
"C.sub.2-6 alkynyl group" optionally substituted by 1 to 3
substituents selected from the above-defined "group A", which
includes non-substituted alkynyl group.
[0251] Specifically, ethynyl group, 1-propynyl group, 2-propynyl
group, 3-butynyl group and the like can be mentioned.
[0252] The "C.sub.6-14 aryl group optionally substituted by 1 to 5
substituents selected from group B" is the above-defined
"C.sub.6-14 aryl group" optionally substituted by 1 to 5
substituents selected from the above-defined "group B", which
includes non-substituted aryl group.
[0253] Specifically, phenyl group, naphthyl group, anthryl group,
indenyl group, azulenyl group, fluorenyl group, phenanthryl group,
3-fluorophenyl group, 4-fluorophenyl group, 3-chlorophenyl group,
4-chlorophenyl group, 2,4-dichlorophenyl group, 3,5-dichlorophenyl
group, pentafluorophenyl group, 4-tolyl group, 4-tert-butylphenyl
group, 2-trifluoromethylphenyl group, 4-trifluoromethylphenyl
group, 4-nitrophenyl group, 4-cyanophenyl group, 4-acetylphenyl
group, 4-carboxyphenyl group, 4-carbamoylphenyl group,
4-aminophenyl group, 4-dimethylaminophenyl group,
4-acetylaminophenyl group, 4-(methylsulfonylamino)phenyl group,
4-methoxyphenyl group, 3,4,5-trimethoxyphenyl group,
4-methylthiophenyl group, 4-methylsulfonylphenyl group,
4-aminosulfonylphenyl group, 3-nitro-4-methoxyphenyl group and
4-nitro-3-methoxyphenyl group can be mentioned.
[0254] The "C.sub.3-10 cycloalkyl group optionally substituted by 1
to 5 substituents selected from group B" is the above-defined
"C.sub.3-10 cycloalkyl group" optionally substituted by 1 to 5
substituents selected from the above-defined "group B", which
includes non-substituted cycloalkyl group.
[0255] Specifically, cyclopropyl group, cyclobutyl group,
cyclopentyl group, cyclohexyl group, cycloheptyl group, 1-adamantyl
group, 4-fluorocyclohexyl group, 2-methylcyclopentyl group,
3-methylcyclohexyl group, 4-methylcyclohexyl group,
4,4-dimethylcyclohexyl group, 3,5-dimethylcyclohexyl group,
4-tert-butylcyclohexyl group, 4-hydroxycyclohexyl group,
4-methoxycyclohexyl group and 2,3,4,5,6-pentafluorocyclohexyl group
can be mentioned.
[0256] The "C.sub.3-10 cycloalkenyl group optionally substituted by
1 to 5 substituents selected from group B" is the above-defined
"C.sub.3-10 cycloalkenyl group" optionally substituted by 1 to 5
substituents selected from the above-defined "group B", which
includes non-substituted cycloalkenyl group.
[0257] Specifically, cyclopropenyl group, cyclobutenyl group,
cyclopentenyl group, cyclopentadienyl group, cyclohexenyl group
(cyclohex-1-enyl group, cyclohex-2-enyl group, cyclohex-3-enyl
group), 5-methylcyclohex-3-enyl group, 5-methoxycyclohex-3-enyl
group, 5-acetylcyclohex-3-enyl group, 2,4-cyclohexadien-1-yl group,
2,5-cyclohexadien-1-yl group, cycloheptenyl group and cyclooctenyl
group and the like can be mentioned.
[0258] The "heterocyclic group optionally substituted by 1 to 5
substituents selected from group B" is the above-defined
"heterocyclic group" optionally substituted by 1 to 5 substituents
selected from the above-defined "group B", which includes
non-substituted heterocyclic group.
[0259] Specifically, 2-pyridyl group, 3-pyridyl group, 4-pyridyl
group, 3-fluoropyridin-4-yl group, 3-chloropyridin-4-yl group,
4-chloropyridin-3-yl group, pyrazinyl group, pyrimidinyl group,
pyridazinyl group, 1,3,5-triazinyl group, pyrrolyl group, pyrazolyl
group, imidazolyl group, 1,2,4-triazolyl group, tetrazolyl group,
2-thienyl group, 3-thienyl group, furyl group, oxazolyl group,
2-methyloxazol-4-yl group, isoxazolyl group, thiazolyl group,
2-methylthiazol-4-yl group, 2,5-dimethylthiazol-4-yl group,
2,4-dimethylthiazol-5-yl group, isothiazolyl group, thiadiazolyl
group, pyrrolinyl group, pyrrolidinyl group, 3-hydroxypyrrolidinyl
group, imidazolidinyl group, azetidinyl group, piperidyl group,
3-hydroxypiperidino group, 4-hydroxypiperidino group,
3,4-dihydroxypiperidino group, 4-methoxypiperidino group,
4-carboxypiperidino group, 4-(hydroxymethyl)piperidino group,
2,2,6,6-tetramethylpiperidino group,
2,2,6,6-tetramethyl-4-hydroxypiperidino group,
N-methylpiperidin-4-yl group, N-(tert-butoxycarbonyl)piperidin-4-yl
group, N-acetylpiperidin-4-yl group, N-methylsulfonylpiperidin-4-yl
group, piperazinyl group, 4-methylpiperazinyl group,
4-methylsulfonylpiperazinyl group, morpholinyl group,
thiomorpholinyl group, 1-oxothiomorpholin-4-yl group,
1,1-dioxothiomorpholin-4-yl group, tetrahydropyranyl group,
tetrahydrofuranyl group, azepanyl group, azocanyl group, azonanyl
group, 1,4-diazepanyl group, 1,4-oxazepanyl group, quinolyl group,
isoquinolyl group, quinazolinyl group, quinoxalinyl group,
phthalazinyl group, cinnolinyl group, naphthyridinyl group,
1,2,3,4-tetrahydroquinolyl group, 5,6,7,8-tetrahydroquinolyl group,
1,2,3,4-tetrahydroisoquinolyl group, 5,6,7,8-tetrahydroisoquinolyl
group, indolyl group, benzimidazolyl group, indolinyl group,
isoindolinyl group, octahydroindolyl group, octahydroisoindolyl
group, benzofuranyl group, benzothienyl group, benzoxazolyl group,
benzothiazolyl group, octahydrocyclopenta[c]pyrrolyl group,
##STR51## ##STR52## and the like can be mentioned.
[0260] For ring Cy, preferable "heterocyclic group optionally
substituted by 1 to 5 substituents selected from group B" is
##STR53## wherein E.sup.4 is an oxygen atom, a sulfur atom,
CH.sub.2 or N(--R.sup.Cy1), wherein R.sup.Cy1 is a hydrogen atom or
a C.sub.1-6 alkyl group, and e and e' are each independently an
integer of 1 to 3.
[0261] Specifically, pyrrolidinyl group, imidazolidinyl group,
piperidyl group, piperazinyl group, morpholinyl group,
thiomorpholinyl group, tetrahydropyranyl group,
tetrahydrothiopyranyl group, 1-oxotetrahydrothiopyranyl group,
1,1-dioxotetrahydrothiopyranyl group and the like can be
mentioned.
[0262] The "C.sub.6-14 aryl C.sub.1-6 alkyl group optionally
substituted by 1 to 5 substituents selected from group B" is the
above-defined "C.sub.1-6 alkyl group" substituted by the
above-defined "C.sub.6-14 aryl group optionally substituted by 1 to
5 substituents selected from group B".
[0263] Specifically, benzyl group, 1-naphthylmethyl group,
2-naphthylmethyl group, phenethyl group, 3-phenylpropyl group,
2-phenylpropyl group, 3-fluorobenzyl group, 4-fluorobenzyl group,
3-chlorobenzyl group, 4-chlorobenzyl group, 2,4-dichlorobenzyl
group, 3,5-dichlorobenzyl group, pentafluorobenzyl group,
4-methylbenzyl group, 4-tert-butylbenzyl group,
2-trifluoromethylbenzyl group, 4-trifluoromethylbenzyl group,
4-nitrobenzyl group, 4-cyanobenzyl group, 4-acetylbenzyl group,
4-carboxybenzyl group, 4-carbamoylbenzyl group, 4-aminobenzyl
group, 4-dimethylaminobenzyl group, 4-acetylaminobenzyl group,
4-(methylsulfonylamino)benzyl group, 4-methoxybenzyl group,
3,4,5-trimethoxybenzyl group, 4-methylthiobenzyl group,
4-methylsulfonylbenzyl group, 4-aminosulfonylbenzyl group,
3-nitro-4-methoxybenzyl group, 4-nitro-3-methoxybenzyl group and
the like can be mentioned.
[0264] The "heterocycle C.sub.1-6 alkyl group optionally
substituted by 1 to 5 substituents selected from group B" is the
above-defined "C.sub.1-6 alkyl group" substituted by the
above-defined "heterocyclic group optionally substituted by 1 to 5
substituents selected from group B".
[0265] Specifically, 2-pyridylmethyl group, 3-pyridylmethyl group,
2-chloropyridin-4-ylmethyl group, 4-pyridylmethyl group,
pyrrolylmethyl group, imidazolylmethyl group, 2-thienylmethyl
group, 3-thienylmethyl group, 2-furylmethyl group, 2-oxazolylmethyl
group, 5-isothiazolylmethyl group, 2-methyloxazol-4-ylmethyl group,
2-thiazolylmethyl group, 4-thiazolylmethyl group, 5-thiazolylmethyl
group, 2-methylthiazol-4-ylmethyl group, 2-methylthiazol-5-ylmethyl
group, 2,5-dimethylthiazol-4-ylmethyl group,
4-methylthiazol-2-ylmethyl group, 2,4-dimethylthiazol-5-ylmethyl
group, 2-isothiazolylmethyl group, 2-pyrrolinylmethyl group,
pyrrolidinylmethyl group, piperidylmethyl group, 4-piperidylmethyl
group, 1-methylpiperidin-4-ylmethyl group,
4-hydroxypiperidinomethyl group, 3-hydroxypyrrolidinylmethyl group,
2-(4-hydroxypiperidino) ethyl group,
1-(tert-butoxycarbonyl)piperidin-4-ylmethyl group,
1-acetylpiperidin-4-ylmethyl group,
1-methylsulfonylpiperidin-4-ylmethyl group, piperazinylmethyl
group, morpholinomethyl group, thiomorpholinylmethyl group,
1-tetrahydropyranylmethyl group, 2-quinolylmethyl group,
1-isoquinolylmethyl group and the like can be mentioned.
[0266] The "C.sub.3-10 cycloalkyl C.sub.1-6 alkyl group optionally
substituted by 1 to 5 substituents selected from group B" is the
above-defined "C.sub.1-6 alkyl group" substituted by the
above-defined "C.sub.3-10 cycloalkyl group optionally substituted
by 1 to 5 substituents selected from group B".
[0267] Specifically, cyclopropylmethyl group, cyclobutylmethyl
group, cyclopentylmethyl group, cyclohexylmethyl group,
2-(cyclopentyl)ethyl group, 2-(cyclohexyl)ethyl group,
cycloheptylmethyl group, 4-fluorocyclohexylmethyl group,
2-methylcyclopentylmethyl group, 3-methylcyclohexylmethyl group,
4-methylcyclohexylmethyl group, 4,4-dimethylcyclohexylmethyl group,
3,5-dimethylcyclohexylmethyl group, 4-tert-butylcyclohexylmethyl
group, 4-hydroxycyclohexylmethyl group, 4-methoxycyclohexylmethyl
group, 2,3,4,5,6-pentafluorocyclohexylmethyl group,
1-adamantylmethyl group and the like can be mentioned.
[0268] The "C.sub.3-10 cycloalkylidene group optionally substituted
by 1 to 5 substituents selected from group B" is such group wherein
C.sub.3-10 cycloalkylidene group is optionally substituted by 1 to
5 substituents selected from the above-defined "group B", which
includes non-substituted cycloalkylidene group.
[0269] Specifically, cyclopropylidene group, cyclobutylidene group,
cyclopentylidene group, cyclohexylidene group, cycloheptylidene
group, 4-fluorocyclohexylidene group, 2-methylcyclopentylidene
group, 3-methylcyclohexylidene group, 4-methylcyclohexylidene
group, 4-ethylcyclohexylidene group, 4,4-dimethylcyclohexylidene
group, 3,5-dimethylcyclohexylidene group,
4-tert-butylcyclohexylidene group, 4-hydroxycyclohexylidene group,
4-methoxycyclohexylidene group, 4-methoxycarbonylcyclohexylidene
group, 2,3,4,5,6-pentafluorocyclohexylidene group and the like can
be mentioned.
[0270] In addition, a group wherein the cyclopentylidene group or
cyclohexylidene group is substituted by fluorine atom, chlorine
atom, bromine atom, nitro group, methyl group, ethyl group,
isopropyl group, tert-butyl group, carboxyl group, methoxycarbonyl
group, acetyl group, trifluoromethyl group, hydroxymethyl group,
methoxymethyl group, 2-carboxyethyl group, methoxy group, carbamoyl
group, methylthio group, dimethylaminocarbonyl group,
methylsulfonyl group or acetylamino group can be mentioned.
[0271] For group E for R.sup.2, it is preferably a cyclohexylidene
group.
[0272] The "heterocycle ylidene group optionally substituted by 1
to 5 substituents selected from group B" is such group wherein the
heterocycle ylidene group is optionally substituted by 1 to 5
substituents selected from the above-defined "group B", which
includes non-substituted heterocycle ylidene group.
[0273] The heterocycle ylidene group contains, as ring-constituting
atom, 1 to 4 heteroatoms selected from oxygen atom, nitrogen atom
and sulfur atom besides carbon atom, wherein the number of atom
constituting the ring is 3 to 14, which includes saturated ring and
unsaturated ring, monocycle and fused ring.
[0274] As the "heterocycle ylidene group optionally substituted by
1 to 5 substituents selected from group B", specifically,
dihydrofuran-3-ylidene group, pyrrolidin-3-ylidene group,
tetrahydropyran-4-ylidene group, piperidin-3-ylidene group,
piperidin-4-ylidene group, 1-methylpiperidin-4-ylidene group,
1-ethylpiperidin-4-ylidene group, 1-isopropylpiperidin-4-ylidene
group, 1-tert-butylpiperidin-4-ylidene group,
1-acetylpiperidin-4-ylidene group,
1-methanesulfonylpiperidin-4-ylidene group,
1-methoxycarbonylpiperidin-4-ylidene group,
tetrahydrothiopyran-4-ylidene group, pyran-4-ylidene group,
1H-pyridin-4-ylidene group, 2,3-dihydro-1H-quinolin-4-ylidene
group, 4-oxocyclohexylidene group and the like can be
mentioned.
[0275] For group E for R.sup.2, it is preferably
1-methylpiperidin-4-ylidene group, 1-ethylpiperidin-4-ylidene
group, 1-acetylpiperidin-4-ylidene group,
1-methanesulfonylpiperidin-4-ylidene group,
1-methoxypiperidin-4-ylidene group or
1-methoxycarbonylpiperidin-4-ylidene group.
[0276] The "C.sub.1-6 alkylidene group optionally substituted by 1
to 3 substituents selected from group A" is such group wherein a
linear or branched chain having 1 to 6 carbon atoms, preferably
having 1 to 4 carbon atoms, preferably a branched chain alkylidene
group, is optionally substituted by 1 to 3 substituents selected
from the above-defined "group A", which includes non-substituted
alkylidene group.
[0277] Specifically, methylidene group, ethylidene group,
propylidene group, isopropylidene group, butylidene group,
pentylidene group, dimethylaminomethylidene group,
methoxycarbonylmethylidene group, 2-methoxyethylidene group,
diaminomethylidene group and the like can be mentioned.
[0278] For group E for R.sup.2, it is preferably an isopropylidene
group.
[0279] The "group C" means the substituent groups of the following
(1) to (5).
(1) the above-defined "C.sub.1-6 alkyl group optionally substituted
by 1 to 3 substituents selected from group A",
(2) the above-defined "C.sub.6-14 aryl group optionally substituted
by 1 to 5 substituents selected from group B",
(3) the above-defined "C.sub.6-14 aryl C.sub.1-6 alkyl group
optionally substituted by 1 to 5 substituents selected from group
B",
(4) the above-defined "heterocyclic group optionally substituted by
1 to 5 substituents selected from group B" and
(5) the above-defined "heterocycle C.sub.1-6 alkyl group optionally
substituted by 1 to 5 substituents selected from group B".
[0280] The "group F" means the substituent groups of the following
(1) to (7).
(1) the above-defined "C.sub.1-6 alkyl group optionally substituted
by 1 to 3 substituents selected from group A",
(2) the above-defined "C.sub.6-14 aryl group optionally substituted
by 1 to 5 substituents selected from group B",
(3) the above-defined "heterocyclic group optionally substituted by
1 to 5 substituents selected from group B",
(4) the above-defined "C.sub.3-10 cycloalkyl group optionally
substituted by 1 to 5 substituents selected from group B",
(5) the above-defined "C.sub.6-14 aryl C.sub.1-6 alkyl group
optionally substituted by 1 to 5 substituents selected from group
B",
(6) the above-defined "heterocycle C.sub.1-6 alkyl group optionally
substituted by 1 to 5 substituents selected from group B" and
(7) the above-defined "C.sub.3-10 cycloalkyl C.sub.1-6 alkyl group
optionally substituted by 1 to 5 substituents selected from group
B".
[0281] The "group D" means the substituent groups of the following
(a) to (w).
(in the following, each t independently means 0 or an integer of 1
to 6)
(a) a hydrogen atom,
(b) the above-defined "halogen atom",
(c) a cyano group,
(d) a nitro group,
(e) the above-defined "C.sub.1-6 alkyl group optionally substituted
by 1 to 3 substituents selected from group A",
(f) --(CH.sub.2).sub.t--OR.sup.d1,
wherein R.sup.d1 is
(1) a hydrogen atom,
(2) the above-defined "group selected from group F",
(3) the above-defined "C.sub.2-6 alkenyl group optionally
substituted by 1 to 3 substituents selected from group A" or
[0282] (4) the above-defined "C.sub.2-6 alkynyl group optionally
substituted by 1 to 3 substituents selected from group A", (e.g.,
substituent exemplified for "--(CH.sub.2).sub.r--OR.sup.b1" in
group B, trifluoromethyloxy group, methoxymethoxy group, phenoxy
group, benzyloxy group, 4-pyridylmethoxy group, 4-carboxybenzyloxy
group, vinyloxy group, ethynyloxy group etc.)
(g) --(CH.sub.2).sub.t--S(O).sub.q--R.sup.d2,
wherein R.sup.d2 is
(1) a hydrogen atom or
(2) the above-defined "group selected from group F",
[0283] q is 0, 1, 2 or 3 (e.g., substituent exemplified for
"--(CH.sub.2).sub.r--SR.sup.b1" and
"--(CH.sub.2).sub.r--SO.sub.2R.sup.b3" in group B, methylsulfinyl
group, sulfo group, trifluoromethanesulfonyl group,
2-(methylamino)ethylsulfonyl group, 2-(dimethylamino)ethylsulfonyl
group, 3-(dimethylamino)propylsulfonyl group, phenylsulfonyl group,
4-tolylsulfonyl group, benzylsulfonyl group etc.)
(h) --(CH.sub.2).sub.t--NR.sup.d3R.sup.d4,
wherein R.sup.d3 and R.sup.d4 are each independently
(1) a hydrogen atom or
[0284] (2) the above-defined "group selected from group F", (e.g.,
substituent exemplified for "--(CH.sub.2).sub.r--NR.sup.b1R.sup.b2"
in group B, phenylamino group, benzyloxyamino group,
methoxymethylamino group, N-ethyl-N-(carbamoylmethyl)amino group,
N-ethyl-N-[2-(acetylamino)ethyl]amino group,
N-[2-amino-2-(dimethylcarbamoyl)ethyl]-N-ethylamino group,
N,N-bis(aminomethyl)amino group etc.)
(i) --(CH.sub.2).sub.t--COOR.sup.d5,
wherein R.sup.d5 is
(1) a hydrogen atom or
[0285] (2) the above-defined "group selected from group F", (e.g.,
substituent exemplified for "--(CH.sub.2).sub.r--COOR.sup.b1" in
group B, trifluoromethyloxycarbonyl group, phenoxycarbonyl group,
benzyloxycarbonyl group, 2-morpholinoethoxycarbonyl group,
2-(dimethylamino)ethoxycarbonyl group etc.)
(j) --(CH.sub.2).sub.t--CONR.sup.d6R.sup.d7,
wherein R.sup.d6 and R.sup.d7 are each independently
(1) a hydrogen atom,
(2) a hydroxyl group,
(3) the above-defined "group selected from group F" or
[0286] (4) the above-defined "C.sub.1-6 alkoxy group", (e.g.,
substituent exemplified for
"--(CH.sub.2).sub.r--CONR.sup.b1R.sup.b2" in group B,
hydroxycarbamoyl group, methoxycarbamoyl group, phenylcarbamoyl
group, benzylcarbamoyl group, 2-morpholinoethylcarbamoyl group,
2-(dimethylamino)ethylcarbamoyl group, methoxymethylcarbamoyl group
etc.)
(k) --(CH.sub.2).sub.t--COR.sup.d8
[0287] wherein R.sup.d8 is the above-defined "group selected from
group F", (e.g., substituent exemplified for
"--(CH.sub.2).sub.rCOR.sup.b1" in group B, trifluoroacetyl group,
methoxyacetyl group, carboxyacetyl group, benzoyl group,
phenylacetyl group, 3-(dimethylamino)propionyl group,
3-morpholinopropionyl group etc.)
(l) --(CH.sub.2).sub.t--NR.sup.d9CO--R.sup.d10,
wherein R.sup.d9 is
(1) a hydrogen atom,
(2) the above-defined "C.sub.1-6 alkyl group optionally substituted
by 1 to 3 substituents selected from group A" or
(3) the above-defined "C.sub.1-6 alkanoyl group",
(1) an amino group,
(2) the above-defined "C.sub.1-6 alkylamino group" or
[0288] (3) the above-defined "group selected from group F", (e.g.,
substituent exemplified for
"--(CH.sub.2).sub.r--NR.sup.b1--COR.sup.b2 in group B, ureido
group, 3-methylureido group, 3-ethylureido group, 3-isopropylureido
group, 3,3-dimethylureido group, 3,3-diethylureido group,
3,3-diisopropylureido group, 3,3-di-tert-butylureido group,
3-ethyl-3-methylureido group, 1,3-dimethylureido group,
trimethylureido group, ureidomethyl group,
2-(3,3-dimethylureido)ethyl group, benzoylamino group,
phenylacetylamino group, trifluoroacetylamino group,
methylaminoacetylamino group, N-acetyl-N-methylamino group,
N-isopropyl-N-pivaloylamino group, dimethylaminoacetylamino group,
N-(dimethylaminoacetyl)-N-methylamino group, morpholinoacetylamino
group, N-methyl-N-(morpholinoacetyl)amino group etc.)
(m) --(CH.sub.2).sub.t--NR.sup.d11SO.sub.2--R.sup.d12,
wherein R.sup.d11 is
(1) a hydrogen atom,
(2) the above-defined "C.sub.1-6 alkyl group optionally substituted
by 1 to 3 substituents selected from group A" or
(3) the above-defined "C.sub.1-6 alkanoyl group",
R.sup.d12 is
(1) a hydrogen atom or
[0289] (2) the above-defined "group selected from group F", (e.g.,
substituent exemplified for
"--(CH.sub.2).sub.r--NR.sup.b1--SO.sub.2R.sup.b3" in group B,
trifluoromethylsulfonylamino group, phenylsulfonylamino group,
benzylsulfonylamino group, 2-(dimethylamino)ethylsulfonylamino
group, 2-morpholinoethylsulfonylamino group,
N-acetyl-N-methanesulfonylamino group,
N-benzyl-N-methanesulfonylamino group etc.)
(n) --(CH.sub.2).sub.t--SO.sub.2--NR.sup.d13R.sup.d14,
wherein R.sup.d13 and R.sup.d14 are each independently
(1) a hydrogen atom or
[0290] (2) the above-defined "group selected from group F", (e.g.,
substituent exemplified for
"--(CH.sub.2).sub.r--SO.sub.2NR.sup.b1R.sup.b2" in group B,
trifluoromethylsulfamoyl group, 2-(dimethylamino)ethylsulfamoyl
group, phenylsulfamoyl group, benzylsulfamoyl group,
2-morpholinoethylsulfamoyl group etc.)
(o) --(CH.sub.2).sub.t--CONR.sup.d15--SO.sub.2R.sup.d16,
wherein R.sup.d15 and R.sup.d16 are each independently
(1) a hydrogen atom or
[0291] (2) the above-defined "group selected from group F", (e.g.,
substituent exemplified for
"--(CH.sub.2).sub.rCONR.sup.b1--SO.sub.2R.sup.b3" in group B,
trifluoromethylsulfonylcarbamoyl group,
2-(dimethylamino)ethylsulfonylcarbamoyl group,
phenylsulfonylcarbamoyl group, benzylsulfonylcarbamoyl group,
2-morpholinoethylsulfonylcarbamoyl group,
N-benzyl-N-(methanesulfonyl)carbamoyl group etc.)
(p) --(CH.sub.2).sub.t--SO.sub.2NR.sup.d17COR.sup.d18,
wherein R.sup.d17 is
(1) a hydrogen atom or
[0292] (2) the above-defined "group selected from group F",
R.sup.d18 is the above-defined "group selected from group F",
(e.g., substituent exemplified for
"--(CH.sub.2).sub.r--SO.sub.2NR.sup.b1 COR.sup.b2" in group B,
trifluoroacetylsulfamoyl group,
2-(dimethylamino)ethylcarbonylsulfamoyl group, benzoylsulfamoyl
group, phenylacetylsulfamoyl group, 3-morpholinopropionylsulfamoyl
group, N-acetyl-N-benzylsulfamoyl group etc.)
(q) --(CH.sub.2).sub.t--NR.sup.d19--COOR.sup.10,
wherein R.sup.d19 and R.sup.d20 are each independently
(1) a hydrogen atom or
[0293] (2) the above-defined "group selected from group F", (e.g.,
substituent exemplified for
"--(CH.sub.2).sub.r--NR.sup.b1--COOR.sup.b3" in group B,
trifluoromethyloxycarbonylamino group,
2-(dimethylamino)ethoxycarbonylamino group, phenoxycarbonylamino
group, benzyloxycarbonylamino group,
2-morpholinoethoxycarbonylamino group,
N-ethoxycarbonyl-N-benzylamino group etc.)
(r) --(CH.sub.2).sub.t--NR.sup.d21--CONR.sup.d22R.sup.d23,
wherein R.sup.d21, R.sup.d22 and R.sup.d23 are each
independently
(1) a hydrogen atom or
(2) the above-defined "group selected from group F", (e.g.,
substituent exemplified for
"--(CH.sub.2).sub.r--NR.sup.b1--CONR.sup.2R.sup.b4" in group B
etc.)
(s) --(CH.sub.2).sub.t--C(.dbd.NR.sup.d24) NH.sub.2,
wherein R.sup.d24 is
(1) a hydrogen atom,
(2) a hydroxyl group,
(3) the above-defined "C.sub.1-6 alkyl group optionally substituted
by 1 to 3 substituents selected from group A" or
(4) the above-defined "C.sub.1-6 alkoxy group", (e.g.,
carbamimidoyl group, N-hydroxycarbamimidoyl group,
N-methylcarbamimidoyl group, N-methoxycarbamimidoyl group,
N-(2-methoxyethyl)carbamimidoyl group etc.)
(t) --(CH.sub.2).sub.t--O--(CH.sub.2).sub.p--COR.sup.d25,
wherein R.sup.d25 is
(1) an amino group,
(2) the above-defined "C.sub.1-6 alkylamino group" or
(3) the above-defined "heterocyclic group optionally substituted by
1 to 5 substituents selected from group B",
[0294] p is 0 or an integer of 1 to 6 (e.g., carbamoylmethoxy
group, methylcarbamoylmethoxy group, 2-(dimethylcarbamoyl)ethoxy
group, 2-(pyridin-2-yl)-2-oxoethoxy group,
2-piperidin-1-yl-2-oxoethoxy group, 2-piperazin-1-yl-2-oxoethoxy
group, 2-pyrrolidin-1-yl-2-oxoethoxy group,
2-morpholin-4-yl-2-oxoethoxy group etc.)
(u)
--(CH.sub.2).sub.t--O--(CH.sub.2).sub.p--NR.sup.d26R.sup.d27,
wherein R.sup.d26 and R.sup.d27 are each independently
(1) a hydrogen atom or
(2) the above-defined "C.sub.1-6 alkyl group optionally substituted
by 1 to 3 substituents selected from the aforementioned group
A",
p is 0 or an integer of 1 to 6, (e.g.,
2-(2-hydroxyethylamino)ethoxy group, 2-(2-aminoethylamino)ethoxy
group etc.)
(v) --(CH.sub.2).sub.t--O--COOR.sup.d28,
wherein R.sup.d28 is
(1) a hydrogen atom or
(2) the above-defined "group selected from group F", (e.g.,
methoxycarbonyloxy group, ethoxycarbonyloxy group,
tert-butoxycarbonyloxy group, benzyloxycarbonyloxy group etc.)
and
(w) the above-defined "heterocyclic group optionally substituted by
1 to 5 substituents selected from group B".
[0295] The "group E" means the substituent groups of the following
(a) to (jj).
(a) the above-defined "halogen atom",
(b) a cyano group,
(c) a nitro group,
(d) an azido group,
(e) --OP(.dbd.O)(OH).sub.2,
(f) --OR.sup.e1,
wherein R.sup.e1 is
(1) a hydrogen atom,
(2) the above-defined "group selected from group F",
(3) the above-defined "C.sub.2-6 alkenyl group optionally
substituted by 1 to 3 substituents selected from group A" or
[0296] (4) the above-defined "C.sub.2-6 alkynyl group optionally
substituted by 1 to 3 substituents selected from group A", (e.g.,
hydroxyl group, methoxy group, ethoxy group, isopropyloxy group,
tert-butyloxy group, trifluoromethyloxy group, methoxymethoxy
group, phenoxy group, benzyloxy group, 4-pyridylmethoxy group,
4-carboxybenzyloxy group, vinyloxy group, ethynyloxy group
etc.)
(g) --S(O).sub.q--R.sup.e2,
wherein R.sup.e2 is
(1) a hydrogen atom or
(2) the above-defined "group selected from group F",
[0297] q is 0, 1, 2 or 3 (e.g., mercapto group, methylsulfanyl
group, methanesulfonyl group, ethylsulfonyl group,
isopropylsulfonyl group, tert-butylsulfonyl group, methylsulfinyl
group, sulfo group, trifluoromethanesulfonyl group,
2-(methylamino)ethylsulfonyl group, 2-(dimethylamino)ethylsulfonyl
group, 3-(dimethylamino)propylsulfonyl group, phenylsulfonyl group,
4-tolylsulfonyl group, benzylsulfonyl group etc.)
(h) --NR.sup.e3R.sup.e4,
wherein R.sup.13 and R.sup.e4 are each independently
(1) a hydrogen atom,
(2) a cyano group or
[0298] (3) the above-defined "group selected from group F", (e.g.,
amino group, methylamino group, ethylamino group, isopropylamino
group, dimethylamino group, diethylamino group, diisopropylamino
group, di-tert-butylamino group, N-ethyl-N-methylamino group,
phenylamino group, benzyloxyamino group, methoxymethylamino group,
N-ethyl-N-(carbamoylmethyl)amino group,
N-ethyl-N-[2-(acetylamino)ethyl]amino group,
N-[2-amino-2-(dimethylcarbamoyl)ethyl]-N-ethylamino group,
N,N-bis(aminomethyl)amino group etc.)
(i) --COOR.sup.e5,
wherein R.sup.e5 is
(1) a hydrogen atom or
[0299] (2) the above-defined "group selected from group F", (e.g.,
carboxyl group, methoxycarbonyl group, ethoxycarbonyl group,
isopropyloxycarbonyl group, tert-butoxycarbonyl group,
trifluoromethyloxycarbonyl group, phenoxycarbonyl group,
benzyloxycarbonyl group, 2-morpholinoethoxycarbonyl group,
2-(dimethylamino)ethoxycarbonyl group etc.)
(j) --CONR.sup.e6R.sup.e7,
wherein R.sup.e6 and R.sup.17 are each independently
(1) a hydrogen atom,
(2) a hydroxyl group,
(3) the above-defined "group selected from group F" or
[0300] (4) the above-defined "C.sub.1-6 alkoxy group", (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, hydroxycarbamoyl group,
methoxycarbamoyl group, phenylcarbamoyl group, benzylcarbamoyl
group, 2-morpholinoethylcarbamoyl group,
2-(dimethylamino)ethylcarbamoyl group, methoxymethylcarbamoyl group
etc.)
(k) --COR.sup.e8
[0301] wherein R.sup.e8 is the above-defined "group selected from
group F", (e.g., formyl group, acetyl group, propionyl group,
isobutyryl group, pivaloyl group, trifluoroacetyl group,
methoxyacetyl group, carboxyacetyl group, benzoyl group,
phenylacetyl group, 3-(dimethylamino)propionyl group,
3-morpholinopropionyl group etc.)
(l) --NR.sup.e9CO--R.sup.e10,
wherein R.sup.e9 is
(1) a hydrogen atom,
(2) the above-defined "C.sub.1-6 alkyl group" or
(3) the above-defined "C.sub.1-6 alkanoyl group",
R.sup.e10 is
(1) a hydrogen atom,
(2) an amino group,
(3) the above-defined "C.sub.1-6 alkylamino group",
(4) the above-defined "C.sub.2-6 alkenyl group optionally
substituted by 1 to 3 substituents selected from group A" or
[0302] (5) the above-defined "group selected from group F", (e.g.,
formylamino group, acetylamino group, propionylamino group,
isobutyrylamino group, pivaloylamino group, N-acetyl-N-methylamino
group, ureido group, 3-methylureido group, 3-ethylureido group,
3-isopropylureido group, 3,3-dimethylureido group,
3,3-diethylureido group, 3,3-diisopropylureido group,
3,3-di-tert-butylureido group, 3-ethyl-3-methylureido group,
1,3-dimethylureido group, trimethylureido group, benzoylamino
group, phenylacetylamino group, trifluoroacetylamino group,
methylaminoacetylamino group, N-acetyl-N-methylamino group,
N-isopropyl-N-pivaloylamino group, 3-carboxy-3-butenoylamino group
etc.)
(m) --NR.sup.e11SO.sub.2--R.sup.e12,
wherein R.sup.e11 is
(1) a hydrogen atom,
(2) the above-defined "C.sub.1-6 alkyl group" or
(3) the above-defined "C.sub.1-6 alkanoyl group", R.sup.e12 is
(1) a hydrogen atom or
[0303] (2) the above-defined "group selected from group F", (e.g.,
methanesulfonylamino group, ethylsulfonylamino group,
isopropylsulfonylamino group, tert-butylsulfonylamino group,
N-methyl-N-(methanesulfonyl)amino group,
trifluoromethylsulfonylamino group, phenylsulfonylamino group,
benzylsulfonylamino group, 2-(dimethylamino)ethylsulfonylamino
group, 2-morpholinoethylsulfonylamino group,
N-acetyl-N-methanesulfonylamino group,
N-benzyl-N-methanesulfonylamino group etc.)
(n) --SO.sub.2--NR.sup.e13R.sup.e14,
wherein R.sup.e13 and R.sup.e14 are each independently
(1) a hydrogen atom or
[0304] (2) the above-defined "group selected from group F", (e.g.,
sulfamoyl group, methylsulfamoyl group, ethylsulfamoyl group,
isopropylsulfamoyl group, dimethylsulfamoyl group, diethylsulfamoyl
group, diisopropylsulfamoyl group, di-tert-butylsulfamoyl group,
trifluoromethylsulfamoyl group, 2-(dimethylamino)ethylsulfamoyl
group, phenylsulfamoyl group, benzylsulfamoyl group,
2-morpholinoethylsulfamoyl group etc.)
(o) --CONR.sup.e15--SO.sub.2R.sup.e16,
wherein R.sup.e15 and R.sup.e16 are each independently
(1) a hydrogen atom or
[0305] (2) the above-defined "group selected from group F", (e.g.,
methanesulfonylcarbamoyl group, ethylsulfonylcarbamoyl group,
isopropylsulfonylcarbamoyl group, tert-butylsulfonylcarbamoyl
group, N-methyl-N-(methanesulfonyl)carbamoyl group,
trifluoromethylsulfonylcarbamoyl group,
2-(dimethylamino)ethylsulfonylcarbamoyl group,
phenylsulfonylcarbamoyl group, benzylsulfonylcarbamoyl group,
2-morpholinoethylsulfonylcarbamoyl group,
N-benzyl-N-(methanesulfonyl)carbamoyl group etc.)
(p) --SO.sub.2NR.sup.e17--COR.sup.e18,
wherein R.sup.e17 is
(1) a hydrogen atom or
[0306] (2) the above-defined "group selected from group F",
R.sup.e18 is the above-defined "group selected from group F",
(e.g., acetylsulfamoyl group, propionylsulfamoyl group,
isobutyrylsulfamoyl group, pivaloylsulfamoyl group,
N-acetyl-N-methylsulfamoyl group, trifluoroacetylsulfamoyl group,
2-(dimethylamino)ethylsulfamoyl group, benzoylsulfamoyl group,
phenylacetylsulfamoyl group, 3-morpholinopropionylsulfamoyl group,
N-acetyl-N-benzylsulfamoyl group etc.)
(q) --NR.sup.e9--COOR.sup.e20,
wherein R.sup.e19 and R.sup.e20 are each independently
(1) a hydrogen atom or
[0307] (2) the above-defined "group selected from group F", (e.g.,
methoxycarbonylamino group, ethoxycarbonylamino group,
isopropyloxycarbonylamino group, tert-butoxycarbonylamino group,
trifluoromethyloxycarbonylamino group,
2-(dimethylamino)ethyloxycarbonylamino group, phenoxycarbonylamino
group, benzyloxycarbonylamino group,
2-morpholinoethoxycarbonylamino group,
N-ethoxycarbonyl-N-benzylamino group etc.)
(r) --NR.sup.e21--CONR.sup.e22R.sup.e23
wherein R.sup.e21, R.sup.e22 and R.sup.e23 are each
independently
(1) a hydrogen atom or
[0308] (2) the above-defined "group selected from group F", (e.g.,
ureido group, 3-methylureido group, 3-ethylureido group,
3-isopropylureido group, 3,3-dimethylureido group,
3,3-diethylureido group, 3,3-diisopropylureido group,
3,3-di-tert-butylureido group, 3-ethyl-3-methylureido group,
1,3-dimethylureido group, trimethylureido group etc.)
(s) --NHCO--COOR.sup.e24
wherein R.sup.e24 is
(1) a hydrogen atom or
(2) the above-defined "group selected from group F",
(e.g., --NHCO--COOH etc.)
(t) --NHCO--CONR.sup.e25R.sup.e26
wherein R.sup.e25 and R.sup.e26 are each independently
(1) a hydrogen atom,
(2) a hydroxyl group or
(3) the above-defined "group selected from group F", (e.g.,
--NHCO--CONH.sub.2, --NHCO--CONHCH.sub.3, --NHCO--CONHOH etc.)
[0309] (u) --CONH--COOH, ##STR54## (y) the above-defined
"C.sub.6-14 aryl group optionally substituted by 1 to 5
substituents selected from group B", (z) the above-defined
"C.sub.3-10 cycloalkyl group optionally substituted by 1 to 5
substituents selected from group B", (aa) the above-defined
"heterocyclic group optionally substituted by 1 to 5 substituents
selected from group B", (bb) the above-defined "C.sub.3-10
cycloalkylidene group optionally substituted by 1 to 5 substituents
selected from group B", and (cc) the above-defined "heterocycle
ylidene group optionally substituted by 1 to 5 substituents
selected from group B", when group E is a substituent on a
C.sub.6-14 aryl group, a C.sub.3-10 cycloalkyl group or a
heterocyclic group, it may be (dd) the above-defined "C.sub.1-6
alkyl group optionally substituted by 1 to 3 substituents selected
from group A", (ee) the above-defined "C.sub.2-6 alkenyl group
optionally substituted by 1 to 3 substituents selected from group
A", (ff) the above-defined "C.sub.2-6 alkynyl group optionally
substituted by 1 to 3 substituents selected from group A", (gg) the
above-defined "C.sub.1-6 alkylidene group optionally substituted by
1 to 3 substituents selected from group A", (hh) the above-defined
"C.sub.6-14 aryl C.sub.1-6 alkyl group optionally substituted by 1
to 5 substituents selected from group B", (ii) the above-defined
"C.sub.3-10 cycloalkyl C.sub.1-6 alkyl group optionally substituted
by 1 to 5 substituents selected from group B", or (jj) the
above-defined "heterocycle C.sub.1-6 alkyl group optionally
substituted by 1 to 5 substituents selected from group B".
[0310] The "C.sub.6-14 aryl group optionally substituted by 1 to 5
substituents selected from group D" is the above-defined
"C.sub.6-14 aryl group" optionally substituted by 1 to 5
substituents selected from the above-defined "group D", which
includes non-substituted aryl group.
[0311] Specifically, phenyl group, naphthyl group, anthryl group,
indenyl group, azulenyl group, fluorenyl group, phenanthryl group,
3-fluorophenyl group, 4-fluorophenyl group, 3-chlorophenyl group,
4-chlorophenyl group, 2,4-dichlorophenyl group, 3,5-dichlorophenyl
group, 4-bromophenyl group, 4-nitrophenyl group, pentafluorophenyl
group, 4-methylphenyl group, 4-tert-butylphenyl group,
2-trifluoromethylphenyl group, 4-trifluoromethylphenyl group,
4-(hydroxymethyl)phenyl group, 4-(methoxymethyl)phenyl group,
4-(2-carboxyethyl)phenyl group, 3-carboxyphenyl group,
4-carboxyphenyl group, 4-methoxyphenyl group,
3,4,5-trimethoxyphenyl group, 4-carbamoylphenyl group,
4-methylthiophenyl group, 4-(dimethylaminocarbonyl)phenyl group,
4-methylsulfonylphenyl group, 4-acetylaminophenyl group,
4-cyanophenyl group, 4-acetylphenyl group, 4-aminophenyl group,
4-dimethylaminophenyl group, 4-(methylsulfonylamino)phenyl group,
4-methylsulfinylphenyl group, 4-aminosulfonylphenyl group,
3-nitro-4-methoxyphenyl group, 4-nitro-3-methoxyphenyl group,
4-(tetrazol-5-yl)phenyl group and the like can be mentioned.
[0312] The "C.sub.3-10 cycloalkyl group optionally substituted by 1
to 5 substituents selected from group D" is the above-defined
"C.sub.3-10 cycloalkyl group" optionally substituted by 1 to 5
substituents selected from the above-defined "group D", which
includes non-substituted cycloalkyl group.
[0313] Specifically, cyclopropyl group, cyclobutyl group,
cyclopentyl group, cyclohexyl group, cycloheptyl group,
4-fluorocyclohexyl group, 2-methylcyclopentyl group,
3-methylcyclohexyl group, 4-methylcyclohexyl group,
4,4-dimethylcyclohexyl group, 3,5-dimethylcyclohexyl group,
4-tert-butylcyclohexyl group, 4-hydroxycyclohexyl group,
4-methoxycyclohexyl group, 2,3,4,5,6-pentafluorocyclohexyl group,
1-adamantylmethyl group and the like can be mentioned.
[0314] In addition, such group wherein cyclopentyl group or
cyclohexyl group is substituted by fluorine atom, chlorine atom,
bromine atom, nitro group, methyl group, tert-butyl group, carboxyl
group, trifluoromethyl group, hydroxymethyl group, methoxymethyl
group, 2-carboxyethyl group, methoxy group, carbamoyl group,
methylthio group, dimethylaminocarbonyl group, methylsulfonyl group
or acetylamino group can be mentioned.
[0315] The "heterocyclic group optionally substituted by 1 to 5
substituents selected from group D" is the above-defined
"heterocyclic group" optionally substituted by 1 to 5 substituents
selected from the above-defined "group D", which includes
non-substituted heterocyclic group.
[0316] Specifically, 2-pyridyl group, 3-pyridyl group, 4-pyridyl
group, 3-fluoropyridin-4-yl group, 3-chloropyridin-4-yl group,
4-chloropyridin-3-yl group, pyrazinyl group, pyrimidinyl group,
pyridazinyl group, 1,3,5-triazinyl group, pyrrolyl group, pyrazolyl
group, imidazolyl group, 1,2,4-triazolyl group, tetrazolyl group,
2-thienyl group, 3-thienyl group, furyl group, oxazolyl group,
2-methyloxazol-4-yl group, isoxazolyl group, thiazolyl group,
2-methylthiazol-4-yl group, 2,5-dimethylthiazol-4-yl group,
2,4-dimethylthiazol-5-yl group, isothiazolyl group, thiadiazolyl
group, pyrrolinyl group, pyrrolidinyl group, imidazolidinyl group,
piperidyl group, N-methylpiperidin-4-yl group,
N-(tert-butoxycarbonyl)piperidin-4-yl group, N-acetylpiperidin-4-yl
group, N-methylsulfonylpiperidin-4-yl group, piperazinyl group,
4-ethylpiperazin-1-yl group, 4-methanesulfonylpiperazin-1-yl group,
4-dimethylcarbamoylmethylpiperazin-1-yl group, morpholinyl group,
thiomorpholinyl group, tetrahydropyranyl group, quinolyl group,
isoquinolyl group, quinazolinyl group, quinoxalinyl group,
phthalazinyl group, cinnolinyl group, naphthyridinyl group,
5,6,7,8-tetrahydroquinolyl group, indolyl group, benzimidazolyl
group, indolinyl group, benzofuranyl group, benzothienyl group,
benzoxazolyl group, benzothiazolyl group, ##STR55## and the like
can be mentioned.
[0317] In addition, such group wherein the 3, 4, 5 or 6-position of
2-pyridyl group, 2, 4, 5 or 6-position of 3-pyridyl group, 2, 3, 5
or 6-position of 4-pyridyl group, 3, 4 or 5-position of 2-thienyl
group, and 2, 4 or 5-position of 3-thienyl group are substituted by
fluorine atom, chlorine atom, bromine atom, nitro group, methyl
group, tert-butyl group, carboxyl group, trifluoromethyl group,
hydroxymethyl group, methoxymethyl group, 2-carboxyethyl group,
methoxy group, carbamoyl group, methylthio group,
dimethylaminocarbonyl group, methylsulfonyl group, amino group or
acetylamino group can be mentioned.
[0318] The "C.sub.6-14 aryl C.sub.1-6 alkyl group optionally
substituted by 1 to 5 substituents selected from group D" is the
above-defined "C.sub.1-6 alkyl group" substituted by the
above-defined "C.sub.6-14 aryl group optionally substituted by 1 to
5 substituents selected from group D".
[0319] Specifically, benzyl group, 1-naphthylmethyl group,
2-naphthylmethyl group, phenethyl group, 3-phenylpropyl group,
2-phenylpropyl group, 3-fluorobenzyl group, 4-fluorobenzyl group,
3-chlorobenzyl group, 4-chlorobenzyl group, 2,4-dichlorobenzyl
group, 3,5-dichlorobenzyl group, 4-bromobenzyl group, 4-nitrobenzyl
group, pentafluorobenzyl group, 4-methylbenzyl group,
4-tert-butylbenzyl group, 2-trifluoromethylbenzyl group,
4-trifluoromethylbenzyl group, 4-(hydroxymethyl)benzyl group,
4-(methoxymethyl)benzyl group, 4-(2-carboxyethyl)benzyl group,
3-carboxybenzyl group, 4-carboxybenzyl group, 4-methoxybenzyl
group, 3,4,5-trimethoxybenzyl group, 4-carbamoylbenzyl group,
4-methylthiobenzyl group, 4-(dimethylaminocarbonyl)benzyl group,
4-methylsulfonylbenzyl group, 4-(acetylamino)benzyl group,
4-cyanobenzyl group, 4-acetylbenzyl group, 4-aminobenzyl group,
4-dimethylaminobenzyl group, 4-(methylsulfonylamino)benzyl group,
4-methylsulfinylbenzyl group, 4-aminosulfonylbenzyl group,
(3-nitro-4-methoxyphenyl)methyl group,
(4-nitro-3-methoxyphenyl)methyl group and the like can be
mentioned.
[0320] The "heterocycle C.sub.1-6 alkyl group optionally
substituted by 1 to 5 substituents selected from group D" is the
above-defined "C.sub.1-6 alkyl group" substituted by the
above-defined "heterocyclic group optionally substituted by 1 to 5
substituents selected from group D".
[0321] Specifically, 2-pyridylmethyl group, 3-pyridylmethyl group,
2-chloropyridin-4-ylmethyl group, 4-pyridylmethyl group,
pyrrolylmethyl group, imidazolylmethyl group, 2-thienylmethyl
group, 3-thienylmethyl group, 2-furylmethyl group, 2-oxazolylmethyl
group, 5-isothiazolylmethyl group, 2-methyloxazol-4-ylmethyl group,
2-thiazolylmethyl group, 4-thiazolylmethyl group, 5-thiazolylmethyl
group, 2-methylthiazol-4-ylmethyl group, 2-methylthiazol-5-ylmethyl
group, 2,5-dimethylthiazol-4-ylmethyl group,
4-methylthiazol-2-ylmethyl group, 2,4-dimethylthiazol-5-ylmethyl
group, 2-isothiazolylmethyl group, 2-pyrrolinylmethyl group,
pyrrolidinylmethyl group, piperidylmethyl group, 4-piperidylmethyl
group, 1-methylpiperidin-4-ylmethyl group,
4-hydroxypiperidinomethyl group, 2-(4-hydroxypiperidino)ethyl
group, 1-(tert-butoxycarbonyl)piperidin-4-ylmethyl group,
1-acetylpiperidin-4-ylmethyl group,
1-methylsulfonylpiperidin-4-ylmethyl group, piperazinylmethyl
group, morpholinomethyl group, thiomorpholinylmethyl group,
1-tetrahydropyranylmethyl group, 2-quinolylmethyl group,
1-isoquinolylmethyl group and the like can be mentioned.
[0322] The "C.sub.1-6 alkyl group optionally substituted by 1 to 3
substituents selected from group E" is the above-defined "C.sub.1-6
alkyl group" optionally substituted by 1 to 3 substituents selected
from the above-defined "group E", which includes non-substituted
alkyl group.
[0323] 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, hydroxymethyl group, 2-hydroxyethyl group, 3-hydroxypropyl
group, 4-hydroxybutyl group, 1-hydroxy-1-methylethyl group,
1-hydroxypropan-2-yl group, 1,3-dihydroxypropan-2-yl group,
1-hydroxy-2-methylpropan-2-yl group, 1,1-dimethyl-2-hydroxyethyl
group, carboxymethyl group, ethoxycarbonylmethyl group,
2-carboxyethyl group, methoxymethyl group, methoxyethyl group,
methoxyethoxyethyl group, ethoxycarbonylmethyl group,
2-ethoxycarbonylethyl group, 2-dimethylaminoethyl group,
carbamoylmethyl group, methylcarbamoylmethyl group, sulfomethyl
group, sulfamoylmethyl group, 2-sulfamoylethyl group,
methylsulfamoylmethyl group and the like can be mentioned.
[0324] The "C.sub.2-6 alkenyl group optionally substituted by 1 to
3 substituents selected from group E" is the above-defined
"C.sub.2-6 alkenyl group" optionally substituted by 1 to 3
substituents selected from the above-defined "group E", which
includes non-substituted alkenyl group.
[0325] Specifically, vinyl group, allyl group, 1-propenyl group,
isopropenyl group, 1-butenyl group, 2-butenyl group, 1,3-butadienyl
group, 2-isopentenyl group, 3-isohexenyl group, 4-methyl-3-pentenyl
group and the like can be mentioned.
[0326] The "C.sub.6-14 aryl group optionally substituted by 1 to 5
substituents selected from group E" is the above-defined
"C.sub.6-14 aryl group" optionally substituted by 1 to 5
substituents selected from the above-defined "group E", which
includes non-substituted aryl group.
[0327] Specifically, phenyl group, naphthyl group, anthryl group,
indenyl group, azulenyl group, fluorenyl group, phenanthryl group,
3-fluorophenyl group, 4-fluorophenyl group, 3-chlorophenyl group,
4-chlorophenyl group, 2,4-dichlorophenyl group, 3,5-dichlorophenyl
group, 4-bromophenyl group, 4-nitrophenyl group, pentafluorophenyl
group, 4-methylphenyl group, 4-tert-butylphenyl group,
2-trifluoromethylphenyl group, 4-trifluoromethylphenyl group,
4-(hydroxymethyl)phenyl group, 4-(methoxymethyl)phenyl group,
4-(2-carboxyethyl)phenyl group, 3-carboxyphenyl group,
4-carboxyphenyl group, 4-methoxyphenyl group,
3,4,5-trimethoxyphenyl group, 4-carbamoylphenyl group,
4-methylthiophenyl group, 4-(dimethylaminocarbonyl)phenyl group,
4-methylsulfonylphenyl group, 4-acetylaminophenyl group,
4-cyanophenyl group, 4-acetylphenyl group, 4-aminophenyl group,
4-dimethylaminophenyl group, 4-(methylsulfonylamino)phenyl group,
4-methylsulfinylphenyl group, 4-aminosulfonylphenyl group,
3-nitro-4-methoxyphenyl group, 4-nitro-3-methoxyphenyl group,
4-(tetrazol-5-yl)phenyl group and the like can be mentioned.
[0328] The "C.sub.3-10 cycloalkyl group optionally substituted by 1
to 5 substituents selected from group E" is the above-defined
"C.sub.3-10 cycloalkyl group" optionally substituted by 1 to 5
substituents selected from the above-defined "group E", which
includes non-substituted cycloalkyl group.
[0329] Specifically, cyclopropyl group, cyclobutyl group,
cyclopentyl group, cyclohexyl group, cycloheptyl group, 1-adamantyl
group, 4-fluorocyclohexyl group, 2-methylcyclopentyl group,
3-methylcyclohexyl group, 4-methylcyclohexyl group,
4,4-dimethylcyclohexyl group, 3,5-dimethylcyclohexyl group,
4-tert-butylcyclohexyl group, 4-hydroxycyclohexyl group,
4-methoxycyclohexyl group, 2,3,4,5,6-pentafluorocyclohexyl group
and the like can be mentioned.
[0330] In addition, such group wherein the cyclopentyl group or
cyclohexyl group is substituted by fluorine atom, chlorine atom,
bromine atom, nitro group, methyl group, tert-butyl group, carboxyl
group, trifluoromethyl group, hydroxymethyl group, methoxymethyl
group, 2-carboxyethyl group, methoxy group, carbamoyl group,
methylthio group, dimethylaminocarbonyl group, methylsulfonyl group
or acetylamino group can be mentioned.
[0331] The "heterocyclic group optionally substituted by 1 to 5
substituents selected from group E" is the above-defined
"heterocyclic group" optionally substituted by 1 to 5 substituents
selected from the above-defined "group E", which includes
non-substituted heterocyclic group.
[0332] Specifically, 2-pyridyl group, 3-pyridyl group, 4-pyridyl
group, 3-fluoropyridin-4-yl group, 3-chloropyridin-4-yl group,
4-chloropyridin-3-yl group, pyrazinyl group, pyrimidinyl group,
pyridazinyl group, 1,3,5-triazinyl group, pyrrolyl group, pyrazolyl
group, imidazolyl group, 2-methylimidazol-1-yl group,
1,2,4-triazolyl group, tetrazolyl group, 2-thienyl group, 3-thienyl
group, furyl group, oxazolyl group, 2-methyloxazol-4-yl group,
isoxazolyl group, thiazolyl group, 2-methylthiazol-4-yl group,
2,5-dimethylthiazol-4-yl group, 2,4-dimethylthiazol-5-yl group,
2-(dimethylamino)thiazol-4-yl group, isothiazolyl group,
thiadiazolyl group, pyrrolinyl group, pyrrolidinyl group,
1-methylpyrrolidin-3-yl group, 1-acetylpyrrolidin-3-yl group,
1-methanesulfonylpyrrolidin-3-yl group,
1-methoxycarbonylpyrrolidin-3-yl group, imidazolidinyl group,
piperidyl group, 4-methylpiperidin-1-yl group,
2-methylpiperidin-1-yl group, 3-methylpiperidin-1-yl group,
4-ethylpiperidin-1-yl group, 4-propylpiperidin-1-yl group,
4-isopropylpiperidin-1-yl group, 4,4-dimethylpiperidin-1-yl group,
2,2,6,6-tetramethylpiperidin-1-yl group,
4-trifluoromethylpiperidin-1-yl group, 4-hydroxypiperidin-1-yl
group, 3-hydroxypiperidin-1-yl group, 4-methoxypiperidin-1-yl
group, 3-methoxypiperidin-1-yl group,
4-(dimethylamino)piperidin-1-yl group, 4-methylenepiperidin-1-yl
group, 4-ethylidenepiperidin-1-yl group,
4-isopropylidenepiperidin-1-yl group, 1-methylpiperidin-4-yl group,
1-ethylpiperidin-4-yl group, 1-methoxypiperidin-4-yl group,
1-methoxycarbonylpiperidin-4-yl group,
1-(tert-butoxycarbonyl)piperidin-4-yl group, 1-acetylpiperidin-4-yl
group, 1-methanesulfonylpiperidin-4-yl group,
1-methylpiperidin-3-yl group, 1-ethylpiperidin-3-yl group,
1-acetylpiperidin-3-yl group, 1-methanesulfonylpiperidin-3-yl
group, 1-methoxypiperidin-3-yl group,
1-methoxycarbonylpiperidin-3-yl group, 1-methylpiperidin-2-yl
group, 1-ethylpiperidin-2-yl group, 1-acetylpiperidin-2-yl group,
1-methanesulfonylpiperidin-2-yl group, 1-methoxypiperidin-2-yl
group, 1-methoxycarbonylpiperidin-2-yl group, piperazinyl group,
4-methylpiperazin-1-yl group, 4-ethylpiperazin-1-yl group,
4-isopropylpiperazin-1-yl group, 4-methoxypiperazin-1-yl group,
4-phenylpiperazin-1-yl group, 4-benzylpiperazin-1-yl group,
4-methoxycarbonylpiperazin-1-yl group,
4-ethoxycarbonylpiperazin-1-yl group,
4-(tert-butoxycarbonyl)piperazin-1-yl group,
4-cyclopentyloxycarbonylpiperazin-1-yl group,
4-acetylpiperazin-1-yl group, 4-isobutyrylpiperazin-1-yl group,
4-benzoylpiperazin-1-yl group, 4-(2-methoxyacetyl)piperazin-1-yl
group, 4-methylcarbamoylpiperazin-1-yl group,
4-dimethylcarbamoylpiperazin-1-yl group,
4-methanesulfonylpiperazin-1-yl group, 1,2,3,6-tetrahydropyridyl
group, morpholinyl group, thiomorpholinyl group, tetrahydropyranyl
group, tetrahydrofuranyl group, azepanyl group, azocanyl group,
azonanyl group, 1,4-diazepanyl group, 4-methyl-1,4-diazepan-4-yl
group, 4-ethyl-1,4-diazepan-4-yl group, 1,4-oxazepanyl group,
quinolyl group, isoquinolyl group, quinazolinyl group, quinoxalinyl
group, phthalazinyl group, cinnolinyl group, naphthyridinyl group,
1,2,3,4-tetrahydroquinolyl group, 5,6,7,8-tetrahydroquinolyl group,
1,2,3,4-tetrahydroisoquinolyl group, 5,6,7,8-tetrahydroisoquinolyl
group, indolyl group, benzimidazolyl group, indolinyl group,
isoindolinyl group, octahydroindolyl group, octahydroisoindolyl
group, benzofuranyl group, benzothienyl group, benzoxazolyl group,
benzothiazolyl group, octahydrocyclopenta[c]pyrrolyl group,
##STR56## and the like can be mentioned.
[0333] In addition, such group wherein the 3, 4, 5 or 6-position of
2-pyridyl group, 2, 4, 5 or 6-position of 3-pyridyl group, 2, 3, 5
or 6-position of 4-pyridyl group, 3, 4 or 5-position of 2-thienyl
group, and 2, 4 or 5-position of 3-thienyl group are substituted by
fluorine atom, chlorine atom, bromine atom, nitro group, methyl
group, tert-butyl group, carboxyl group, trifluoromethyl group,
hydroxymethyl group, methoxymethyl group, 2-carboxyethyl group,
methoxy group, carbamoyl group, methylthio group,
dimethylaminocarbonyl group, methylsulfonyl group, amino group or
acetylamino group can be mentioned.
[0334] The "carboxylic acid equivalent" means a bioisostere and may
only be a substituent having a similar polar effect as carboxylic
acid. Specifically, a chain substituent such as
--CONHR.sup.105'
(wherein R.sup.105' is a hydroxyl group, a cyano group, a C.sub.1-6
alkoxy group or a C.sub.6-14 aryloxy group),
--SO.sub.2R.sup.106'
(wherein R.sup.106' is a hydroxyl group, an amino group or a
C.sub.1-6 alkylamino group),
--NHCOR.sup.107'
(wherein R.sup.107' is an amino group or a C.sub.1-6 alkylamino
group),
--P(.dbd.O)(OH)(OR.sup.109)
(wherein R.sup.109 is a hydrogen atom or a substituent selected
from the above-mentioned group C),
--P(.dbd.O)(OH)NR.sup.111R.sup.112
(wherein R.sup.111 and R.sup.112 are each independently a hydrogen
atom or a substituent selected from the above-mentioned group
C),
--CONHCO--R.sup.113
(wherein R.sup.113 is a substituent selected from the
above-mentioned group C),
--CONHSO.sub.2--R.sup.114,
(wherein R.sup.114 is a substituent selected from the
above-mentioned group C),
--SO.sub.2NHCO--R.sup.115
[0335] (wherein R.sup.115 is a substituent selected from the
above-mentioned group C) and the like, or a cyclic substituent such
as a heterocyclic group having a hydrogen atom donor such as
##STR57## (wherein E.sup.h1 is an oxygen atom, a sulfur atom or
N(--R.sup.h1), R.sup.h1 is a hydrogen atom or a C.sub.1-6 alkyl
group, E.sup.h3 is an oxygen atom or a sulfur atom, R.sup.h2 is a
C.sub.1-6 alkyl group, R.sup.h3 is an electron-withdrawing group
such as a halogen atom, a cyano group, a C.sub.1-6 alkyl group, a
trifluoromethyl group, a formyl group, a chlorocarbonyl group, a
nitro group, an acetyl group, an ethoxycarbonyl group, a carbamoyl
group and the like) and the like, and said heterocyclic group
substituted by an electron-withdrawing group and the like can be
mentioned.
[0336] More specifically,
--CONHCN, --CONHOH, --CONHOMe,
--CONHOt-Bu, --CONHOBn,
--SO.sub.3H, --SO.sub.2NH.sub.2, --SO.sub.2NHMe,
--NHCONH.sub.2, --NHCON(Me).sub.2,
--P(.dbd.O)(OH).sub.2, --P(.dbd.O)(OH)(OEt),
--P(.dbd.O)(OH)NH.sub.2, --P(.dbd.O)(OH)NHMe,
--CONHCOMe, --CONHCOBn,
[0337] --CONHSO.sub.2Me, --CONHSO.sub.2Pr, --CONHSO.sub.2Ph,
##STR58## --SO.sub.2NHCOMe, --SO.sub.2NHCOPh wherein Me is a methyl
group, Et is an ethyl group, Pr is a propyl group, t-Bu is a
tert-butyl group, Ph is a phenyl group and Bn is a benzyl group,
and ##STR59## and the like can be mentioned.
[0338] As the carboxylic acid equivalent, preferred are
--CONHOt-Bu, --CONHOBn, --SO.sub.3H, --CONHSO.sub.2Me,
--CONHSO.sub.2Pr, --CONHSO.sub.2Ph, ##STR60## --SO.sub.2NHCOMe,
--SO.sub.2NHCOPh, ##STR61##
[0339] In the formula [I], as a ##STR62## moiety, N--C.dbd.C is
preferable, as a ##STR63## moiety, preferred is a fused ring
selected from the group consisting of ##STR64## ##STR65## ##STR66##
more preferably, a fused ring selected from the group consisting of
##STR67## still more preferably, ##STR68## particularly preferably,
##STR69##
[0340] For G.sup.3, G.sup.4 or G.sup.5, preferred is a carbon atom,
when pharmacological activity is not markedly degraded, it may be a
nitrogen atom, which may be substituted by R.sup.3.
Q is --(CH.sub.2).sub.b-- or
--(CH.sub.2).sub.c-Q.sup.1-(CH.sub.2).sub.d--, wherein the bond on
the left side is joined with G.sup.2, and the bond on the right
side is joined with G.sup.6.
[0341] Q.sup.1 is --O--, --NH--, --S--, --OCO--, --OCONH--, --CO--,
--SO--, --SO.sub.2--, --NHCO--, --NHSO.sub.2--, --NHCOO--, --COO--,
--CONH--, --SO.sub.2NH--, --NHCONH--, --NHSO.sub.2NH--,
--CH.dbd.CH-- or --CH.dbd.N--, wherein the bond on the left side is
joined with --(CH.sub.2).sub.c--, and the bond on the right side is
joined with --(CH.sub.2).sub.d--.
[0342] For Q.sup.1, preferred are --O--, --NH--, --S-- or --CONH--,
more preferred are --O--, --NH-- and --CONH--, particularly
preferred is --NH--.
[0343] For b, preferred is an integer of 1 to 3, particularly
preferably 1 or 3,
[0344] For c, preferred is an integer of 1 to 3, particularly
preferred is 2,
[0345] For d, preferred is 0,
[0346] For Q, preferred are --(CH.sub.2).sub.2--O-- and
--(CH.sub.2).sub.2--NH--.
[0347] For R.sup.1, preferred is a carboxyl group,
--CONR.sup.11R.sup.12, --COOR.sup.103, ##STR70## more preferably a
carboxyl group or --CONR.sup.11R.sup.12.
[0348] For R.sup.11, preferred is a hydrogen atom or a C.sub.1-6
alkyl group.
[0349] For R.sup.12, preferred is a hydrogen atom, "a C.sub.1-6
alkyl group optionally substituted by 1 to 3 substituents selected
from group E", "a C.sub.6-14 aryl group optionally substituted by 1
to 5 substituents selected from group E", "a heterocyclic group
optionally substituted by 1 to 5 substituents selected from group
E", "a C.sub.3-10 cycloalkyl group optionally substituted by 1 to 5
substituents selected from group E", --NR.sup.131R.sup.132,
--NHCOOR.sup.133, --NHCOR.sup.134,
--CR.sup.135R.sup.136-L.sup.100-R.sup.137, ##STR71##
[0350] For R.sup.103, preferred is "a C.sub.1-6 alkyl group
optionally substituted by 1 to 3 substituents selected from group
A", "a C.sub.6-14 aryl group optionally substituted by 1 to 5
substituents selected from group B" or "a C.sub.6-14 aryl C.sub.1-6
alkyl group optionally substituted by 1 to 5 substituents selected
from group B".
[0351] As the "heterocyclic group" of "a heterocyclic group
optionally substituted by 1 to 5 substituents selected from group
E" for ring D.sup.6, preferred is a pyrrolidinyl group, a piperidyl
group, a piperazinyl group, a 2,6-dioxopiperazinyl group or a
2,3,4,9-tetrahydro-1H-.beta.-carbolinyl group.
[0352] As the "C.sub.6-14 aryl group" of "a C.sub.6-14 aryl group
optionally substituted by 1 to 5 substituents selected from group
E" for ring D.sup.7, preferred is a phenyl group.
[0353] For group E in ring D.sup.6 and ring D.sup.7, preferred is a
hydroxyl group, a carboxyl group or a C.sub.2-6 alkenyl group
optionally substituted by carboxyl group.
[0354] For R.sup.131, R.sup.132, R.sup.133 and R.sup.134, preferred
for each independently is a hydrogen atom, "a C.sub.1-6 alkyl group
optionally substituted by 1 to 3 substituents selected from group
A", "a C.sub.6-14 aryl group optionally substituted by 1 to 5
substituents selected from group B" or "a C.sub.6-14 aryl C.sub.1-6
alkyl group optionally substituted by 1 to 5 substituents selected
from group B".
[0355] More preferably, R.sup.131 and R.sup.132 are each a
C.sub.1-6 alkyl group, R.sup.133 is a C.sub.6-14 aryl C.sub.1-6
alkyl group, R.sup.134 is a C.sub.6-14 aryl group optionally
substituted by carboxyl group.
[0356] For R.sup.135 and R.sup.136, preferred for each
independently is a hydrogen atom, --COOR.sup.142,
--CONR.sup.143R.sup.144, "a C.sub.1-6 alkyl group optionally
substituted by 1 to 3 substituents selected from group A" or "a
heterocyclic group optionally substituted by 1 to 5 substituents
selected from group B", or R.sup.135 and R.sup.136 are bonded to
each other, and form, together with the carbon atom bonded thereto,
"a C.sub.3-10 cycloalkyl group optionally substituted by 1 to 5
substituents selected from group B".
[0357] For R.sup.142, preferred is a hydrogen atom or "a C.sub.1-6
alkyl group optionally substituted by 1 to 3 substituents selected
from group A". More preferably, R.sup.142 is a hydrogen atom or a
C.sub.1-6 alkyl group.
[0358] For R.sup.143 and R.sup.144, preferred for each
independently is a hydrogen atom, a C.sub.1-6 alkoxy group, "a
C.sub.1-6 alkyl group optionally substituted by 1 to 3 substituents
selected from group A", "a heterocyclic group optionally
substituted by 1 to 5 substituents selected from group B" or "a
heterocycle C.sub.1-6 alkyl group optionally substituted by 1 to 5
substituents selected from group B". More preferably, R.sup.143 is
a hydrogen atom, R.sup.144 is a hydrogen atom, "a C.sub.1-6 alkyl
group optionally substituted by 1 to 3 substituents selected from
group A", "a heterocyclic group optionally substituted by 1 to 5
substituents selected from group B" or "a heterocycle C.sub.1-6
alkyl group optionally substituted by 1 to 5 substituents selected
from group B". For "a C.sub.1-6 alkyl group optionally substituted
by 1 to 3 substituents selected from group A" represented by
R.sup.144, preferred is a C.sub.1-6 alkyl group optionally
substituted by 1 to 3 substituents selected from a hydroxyl group
and --NR.sup.a1R.sup.a2 (wherein R.sup.a1 and R.sup.a2 are each
independently a hydrogen atom or a C.sub.1-6 alkyl group). For the
"heterocyclic group" of "a heterocyclic group optionally
substituted by 1 to 5 substituents selected from group B"
represented by R.sup.144, preferred is a pyridyl group. For the
"heterocycle" moiety of "a heterocycle C.sub.1-6 alkyl group
optionally substituted by 1 to 5 substituents selected from group
B" represented by R.sup.144, preferred is a morpholinyl group,
pyrrolidinyl group or a pyridyl group.
[0359] For the "heterocyclic group" of "a heterocyclic group
optionally substituted by 1 to 5 substituents selected from group
B" represented by R.sup.135 and R.sup.136, preferred is a thiazolyl
group or a pyridyl group.
[0360] For the "C.sub.3-10 cycloalkyl group" of "a C.sub.3-10
cycloalkyl group optionally substituted by 1 to 5 substituents
selected from group B" which is formed by R.sup.135 and R.sup.116
bonded to each other, together with the carbon atom bonded thereto,
preferred is "a C3-7 cycloalkyl group", more preferably a
cyclopropyl group, a cyclobutyl group, a cyclopentyl group or a
cyclohexyl group.
[0361] For L.sup.100, preferred is a bond, --CO--, --CH.sub.2O--,
--CH.sub.2NH--, --CH.sub.2NHCO-- or methylene, more preferably a
bond or methylene.
[0362] For L.sup.101, preferred is a bond or methylene.
[0363] For R.sup.137, preferred is "a C.sub.6-14 aryl group
optionally substituted by 1 to 5 substituents selected from group
E" or "a heterocyclic group optionally substituted by 1 to 5
substituents selected from group E".
[0364] For the "C.sub.6-14 aryl group" of "a C.sub.6-14 aryl group
optionally substituted by 1 to 5 substituents selected from group
E" represented by R.sup.137, preferred is a phenyl group.
[0365] For the "heterocyclic group" of "a heterocyclic group
optionally substituted by 1 to 5 substituents selected from group
E" represented by R.sup.137, preferred is an indolyl group, a
2-oxo-2H-chromenyl group, a benzo[1,3]dioxolanyl group, a
benzimidazolyl group, a benzofuranyl group, a benzothienyl group, a
benzothiazolyl group, a pyridyl group, a pyrimidinyl group, a
pyrazolyl group, a 4-oxo-1H-quinolinyl group, a furyl group, a
thienyl group, an oxazolyl group or a thiazolyl group, more
preferably, an indolyl group, a benzimidazolyl group, a
benzofuranyl group or a benzothienyl group, and particularly
preferably, an indolyl group.
[0366] For R.sup.138 and R.sup.139, preferred for each
independently is a hydrogen atom or "a C.sub.1-6 alkyl group
optionally substituted by 1 to 3 substituents selected from group
A", or R.sup.138 and R.sup.139 are bonded to each other, and form,
together with the carbon atom bonded thereto, "a C.sub.3-10
cycloalkyl group optionally substituted by 1 to 5 substituents
selected from group B" or "a heterocyclic group optionally
substituted by 1 to 5 substituents selected from group B".
[0367] For the "C.sub.3-10 cycloalkyl group" of "a C.sub.3-10
cycloalkyl group optionally substituted by 1 to 5 substituents
selected from group B", which is formed by R.sup.138 and R.sup.139
bonded to each other, together with the carbon atom bonded thereto,
preferred is "a C3-7 cycloalkyl group", more preferred is a
cyclopropyl group, a cyclobutyl group, a cyclopentyl group or a
cyclohexyl group.
[0368] For the "heterocyclic group" of "a heterocyclic group
optionally substituted by 1 to 5 substituents selected from group
B", which is formed by R.sup.138 and R.sup.139 bonded to each
other, together with the carbon atom bonded thereto, preferred is a
"4-, 5- or 6-membered heterocyclic group comprising 1 to 3
heteroatoms selected from oxygen atom, nitrogen atom and sulfur
atom", more preferably, a piperidyl group, a pyrrolidinyl group, a
tetrahydropyranyl group or a tetrahydrothiopyranyl group.
[0369] Particularly preferably, R.sup.138 and R.sup.139 are each
independently a hydrogen atom or a C.sub.1-6 alkyl group, or
R.sup.138 and R.sup.139 are bonded to each other, and form,
together with the carbon atom bonded thereto, a cyclobutyl group or
a cyclopentyl group.
[0370] For R.sup.140 and R.sup.141, preferred is a hydrogen
atom.
[0371] For L.sup.102, preferred is a bond or vinylene.
[0372] For L.sup.103, preferred is a bond.
[0373] For L.sup.104, preferred is propylene.
[0374] For ring D.sup.3, preferred is "a C.sub.6-14 aryl group
optionally substituted by 1 to 5 substituents selected from group
E" or "a heterocyclic group optionally substituted by 1 to 5
substituents selected from group E".
[0375] For the "C.sub.6-14 aryl group" of "a C.sub.6-14 aryl group
optionally substituted by 1 to 5 substituents selected from group
E" represented by ring D.sup.3, preferred is a phenyl group.
[0376] For the "heterocyclic group" of "a heterocyclic group
optionally substituted by 1 to 5 substituents selected from group
E" represented by ring D.sup.3, preferred is an indolyl group, a
2-oxo-2H-chromenyl group, a benzo[1,3]dioxolanyl group, a
benzimidazolyl group, a benzofuranyl group, a benzothienyl group, a
benzothiazolyl group, a pyridyl group, a pyrimidinyl group, a
pyrazolyl group, a 4-oxo-1H-quinolinyl group, a furyl group, a
thienyl group, an oxazolyl group or a thiazolyl group, more
preferably, an indolyl group, a benzimidazolyl group, a
benzofuranyl group or a benzothienyl group, particularly
preferably, an indolyl group.
[0377] For ring D.sup.4, preferred is "a C.sub.3-10 cycloalkyl
group optionally substituted by 1 to 5 substituents selected from
group E" or "a heterocyclic group optionally substituted by 1 to 5
substituents selected from group E".
[0378] For ring D.sup.5, preferred is "a C.sub.6-14 aryl group
optionally substituted by 1 to 5 substituents selected from group
E".
[0379] For the "C.sub.3-10 cycloalkyl group" of "a C.sub.3-10
cycloalkyl group optionally substituted by 1 to 5 substituents
selected from group E" represented by ring D.sup.4 and ring
D.sup.5, preferred is a cyclohexyl group.
[0380] For the "heterocyclic group" of "a heterocyclic group
optionally substituted by 1 to 5 substituents selected from group
E" represented by ring D.sup.4 and ring D.sup.5, preferred is a
piperidyl group or a pyrrolidinyl group.
[0381] For the "C.sub.6-14 aryl group" of "a C.sub.6-14 aryl group
optionally substituted by 1 to 5 substituents selected from group
E" represented by ring D.sup.4 and ring D.sup.5, preferred is a
phenyl group.
[0382] For the group E in R.sup.137, ring D.sup.3, ring D.sup.4 and
ring D.sup.5, preferred is a halogen atom, a cyano group, a nitro
group, an azido group, --OP(.dbd.O)(OH).sub.2, --OR.sup.e1,
--S(O).sub.q--R.sup.e2, --NR.sup.e3R.sup.e4, --COOR.sup.e5,
--CONR.sup.e6R.sup.e7, --COR.sup.e8, --NR.sup.e9CO--R.sup.e10,
--NR.sup.e11SO.sub.2--R.sup.e12,
--NR.sup.e21--CONR.sup.e22R.sup.e23, --NHCO--COOR.sup.e14,
--NHCO--CONR.sup.e25R.sup.e26, --CONH--COOH, ##STR72## "a
C.sub.6-14 aryl group optionally substituted by 1 to 5 substituents
selected from group B", "a C.sub.3-10 cycloalkyl group optionally
substituted by 1 to 5 substituents selected from group B", "a
heterocyclic group optionally substituted by 1 to 5 substituents
selected from group B", "a C.sub.1-6 alkyl group optionally
substituted by 1 to 3 substituents selected from group A", "a
C.sub.2-6 alkenyl group optionally substituted by 1 to 3
substituents selected from group A", "a C.sub.2-6 alkynyl group
optionally substituted by 1 to 3 substituents selected from group
A" or "a C.sub.6-14 aryl C.sub.1-6 alkyl group optionally
substituted by 1 to 5 substituents selected from group B", more
preferably, a carboxyl group, --OR.sup.e1 (wherein R.sup.e1 is a
hydrogen atom or a C.sub.1-6 alkyl group substituted by carboxyl
group), a C.sub.1-6 alkyl group substituted by carboxyl group or a
C.sub.2-6 alkenyl group substituted by carboxyl group, particularly
preferably, a carboxyl group, a hydroxyl group, --OCH.sub.2COOH,
--CH.dbd.CH--COOH or --CH.sub.2CH.sub.2COOH.
[0383] Preferably, R.sup.12 is ##STR73## wherein R.sup.12a is
preferably selected from a hydrogen atom, a 5- to 10-membered
heterocyclic group comprising 1 to 4 heteroatoms selected from
oxygen atom, nitrogen atom and sulfur atom (wherein the
heterocyclic group is optionally substituted by 1 to 4 substituents
selected from the group consisting of --CH.sub.3, --CF.sub.3, --OH,
--CH.sub.2COOH, --COOH, --NHCH(CH.sub.3).sub.2, --NHCOCH.sub.3,
--NH.sub.2, --NHCH.sub.3 and --N(CH.sub.3).sub.2), --COOH,
--COO(C.sub.1-6 alkyl), --CONH.sub.2, --COCH.sub.3,
--(CH.sub.2).sub.p1COOH (wherein p1 is an integer of 1 to 4),
benzyloxy, --CH.sub.2--(C.sub.6-14 aryl)-COOH, pyridylcarbamoyl,
pyridylmethylcarbamoyl and --CONH--(C.sub.2-4
alkyl)-N(CH.sub.3).sub.2.
[0384] More preferably, R.sup.12a is --COOR.sup.12g,
--CONHR.sup.12f or ##STR74## wherein, R.sup.12e is preferably a
hydrogen atom, a C.sub.1-6 alkyl group, an amino group,
--NH(C.sub.1-6 alkyl), --N(C.sub.1-6 alkyl).sub.2 or
--NHCO(C.sub.1-6 alkyl).
[0385] Preferably, R.sup.12f is a hydrogen atom, a heterocycle
C.sub.1-6 alkyl group (wherein the heterocycle is selected from
morpholinyl, pyrrolidinyl and N-methylpyrrolidinyl), --(C.sub.1-6
alkyl)-N(CH.sub.3).sub.2, --(C.sub.1-6 alkyl)-OH,
--CH(CH.sub.2OH).sub.2 or --CH.sub.2CH(OH)CH.sub.2OH. More
preferably, R.sup.12f is a hydrogen atom.
[0386] Preferably, R.sup.12g is a hydrogen atom or a C.sub.1-6
alkyl group. More preferably, R.sup.12g is a hydrogen atom or
--CH.sub.3.
[0387] Preferably, R.sup.12b is selected from a hydrogen atom, a
hydroxyl group, an amino group, a 5- to 10-membered heterocyclic
group comprising 1 to 4 heteroatoms selected from oxygen atom,
nitrogen atom, sulfur atom (wherein the heterocyclic group is
optionally substituted by hydroxyl group), --COOH, --CH.sub.3,
--CF.sub.3, --CH.sub.2COOH, --O(C.sub.1-6 alkyl)-COOH, --NHCOCOOH,
--NHSO.sub.2CH.sub.3, --NHSO.sub.2CF.sub.3, ##STR75## More
preferably, R.sup.12b is --OCH.sub.2COOH or a hydroxyl group.
[0388] Preferably, R.sup.12c is selected from a hydrogen atom, a
C.sub.1-6 alkyl group and --(CH.sub.2).sub.p1COOH (wherein p1 is an
integer of 1 to 4). More preferably, R.sup.12c is a hydrogen atom,
--CH.sub.3 or --CH.sub.2COOH.
[0389] Preferably, R.sup.12d is a hydrogen atom or a C.sub.1-6
alkyl group. More preferably, R.sup.12d is a hydrogen atom or
--CH.sub.3. Still more preferably, R.sup.12d is a hydrogen
atom.
[0390] Alternatively, R.sup.12 is preferably ##STR76## wherein
R.sup.12a is as defined above.
[0391] Preferably, R.sup.12j is a C.sub.1-6 alkoxy group, a
hydroxyl group, --O(C.sub.1-6 alkyl)-COOH, a C.sub.1-6 alkyl group,
a halogen atom, --(C.sub.2-6 alkenyl)-COOH, --(C.sub.1-6 alkyl)-OH,
--COOH or an azido group.
[0392] Preferably, R.sup.12k is a hydroxyl group,
--(CH.sub.2).sub.p1COOH (wherein p1 is an integer of 1 to 4), an
amino group, a C.sub.1-6 alkoxy group, --NHCOCOOH, --NH(C.sub.1-6
alkyl)-COOH, --O(C.sub.1-6 alkyl)-COOH, --COOH, a 5- or 6-membered
heterocyclic group comprising 1 to 4 heteroatoms selected from
oxygen atom, nitrogen atom and sulfur atom (wherein the 5- or
6-membered heterocyclic group is optionally substituted by 1 to 4
substituents selected from the group consisting of --CH.sub.3,
--CF.sub.3, --OH, --CH.sub.2COOH and --COOH), --O(C.sub.1-6
alkyl)-COOH, ##STR77## --NHCONH.sub.2, --NHCN, --NHCHO,
--NHSO.sub.2CF.sub.3, --NHCOCH.sub.3, --NHSO.sub.2CH.sub.3,
--CONH.sub.2, --(C.sub.3-10 cycloalkyl)-COOH, --(C.sub.2-6
alkenyl)-COOH or --NHCOCH.sub.2CH(OH)COOH.
[0393] Preferably, R.sup.12i is --O(C.sub.1-6 alkyl)-COOH, a
C.sub.1-6 alkyl group or a halogen atom.
[0394] Preferably, m1 is 0 or an integer of 1 to 4. More
preferably, m1 is 1.
[0395] Alternatively, R.sup.12 is preferably ##STR78## wherein
R.sup.12k is as defined above.
[0396] Preferably, R.sup.12m is a hydrogen atom or a hydroxyl
group.
[0397] Preferably, R.sup.12p is a hydrogen atom, a halogen atom or
a C.sub.1-6 alkyl group.
[0398] Preferably, R.sup.12r is a hydrogen atom, a halogen atom or
a C.sub.1-6 alkyl group.
[0399] Alternatively, R.sup.12 is preferably ##STR79## herein
R.sup.12o is preferably a hydroxyl group or --O(C.sub.1-6
alkyl)-COOH.
[0400] Alternatively, R.sup.12 is preferably ##STR80## wherein
R.sup.12a is as defined above.
[0401] Preferably, J is S or N(C.sub.1-6 alkyl). More preferably, J
is S or N(CH.sub.3).
[0402] Preferably, R.sup.12n is a hydrogen atom or an amino
group.
[0403] Alternatively, R.sup.12 is more preferably ##STR81## wherein
R.sup.12b is as defined above.
[0404] Alternatively, R.sup.12 is more preferably ##STR82## wherein
R.sup.12b and R.sup.12c are as defined above.
[0405] Alternatively, R.sup.12 is more preferably ##STR83## wherein
R.sup.12j and R.sup.12k are as defined above.
[0406] Alternatively, R.sup.12 is preferably ##STR84## wherein
R.sup.138 and R.sup.139 are each independently a hydrogen atom, "a
C.sub.1-6 alkyl group optionally substituted by 1 to 3 substituents
selected from group A", "a C.sub.3-10 cycloalkyl group optionally
substituted by 1 to 5 substituents selected from group B", "a
C.sub.6-14 aryl group optionally substituted by 1 to 5 substituents
selected from group B", "a heterocyclic group optionally
substituted by 1 to 5 substituents selected from group B", "a
C.sub.6-14 aryl C.sub.1-6 alkyl group optionally substituted by 1
to 5 substituents selected from group B", "a heterocycle C.sub.1-6
alkyl group optionally substituted by 1 to 5 substituents selected
from group B" or "a C.sub.3-10 cycloalkyl C.sub.1-6 alkyl group
optionally substituted by 1 to 5 substituents selected from group
B"; or R.sup.138 and R.sup.139 are bonded to each other and
optionally form, together with the carbon atom bonded thereto, "a
C.sub.3-10 cycloalkyl group optionally substituted by 1 to 5
substituents selected from group B" or "a heterocyclic group
optionally substituted by 1 to 5 substituents selected from group
B".
[0407] Here, as the substituent selected from group A, preferred
are 1 to 3 substituents selected from a halogen atom, --OR.sup.a1,
--NR.sup.a1R.sup.a2, --COOR.sup.a1, --CONR.sup.a1R.sup.a2 and
--COR.sup.a1 (wherein R.sup.a1 and R.sup.a2 are each independently
a hydrogen atom or a C.sub.1-6 alkyl group), and as the substituent
selected from group B, preferred are 1 to 5 substituents selected
from a halogen atom, a C.sub.1-6 alkyl group, a C.sub.2-6 alkenyl
group, --OR.sup.b1, --NR.sup.b1R.sup.b2, --COOR.sup.b1,
--CONR.sup.b1R.sup.b2, --COR.sup.b1 and --SO.sub.2R.sup.b3 (wherein
R.sup.b1 and R.sup.b2 are each independently a hydrogen atom or a
C.sub.1-6 alkyl group and R.sup.b3 is a C.sub.1-6 alkyl group).
[0408] Preferably, R.sup.140 is a hydrogen atom.
[0409] Preferably, ring D.sup.3 is "a C.sub.6-14 aryl group
optionally substituted by 1 to 5 substituents selected from group
E" or "a heterocyclic group optionally substituted by 1 to 5
substituents selected from group E".
[0410] Here, as the substituent selected from group E, preferred
are 1 to 5 substituent selected from
a halogen atom,
a cyano group,
a nitro group,
an azido group,
--OR.sup.e1
(wherein R.sup.e1 is a hydrogen atom or a C.sub.1-6 alkyl group
optionally substituted by carboxyl group),
--S(O).sub.q--R.sup.e2
(wherein R.sup.e2 is a hydrogen atom or a C.sub.1-6 alkyl group
optionally substituted by carboxyl group and q is 0, 1, 2 or
3),
--NR.sup.e3R.sup.e4
(wherein R.sup.e3 and R.sup.e4 is independently a hydrogen atom, a
C.sub.1-6 alkyl group or a heterocyclic group optionally
substituted by 1 to 5 substituents selected from group B),
--COOR.sup.e5
(wherein R.sup.5 is a hydrogen atom or a C.sub.1-6 alkyl
group),
--CONR.sup.e6R.sup.e7
(wherein R.sup.e6 and R.sup.e7 are each independently a hydrogen
atom or a C.sub.1-6 alkyl group optionally substituted by carboxyl
group),
--NR.sup.e9CO--R.sup.e10
(wherein R.sup.e9 is a hydrogen atom or a C.sub.1-6 alkyl group,
and R.sup.e10 is a hydrogen atom, an amino group, a C.sub.1-6
alkylamino group or a C.sub.1-6 alkyl group),
--SO.sub.2--NR.sup.e13R.sup.e14
(wherein R.sup.e13 and R.sup.e14 are each a hydrogen atom or a
C.sub.1-6 alkyl group),
--NR.sup.e21--CONR.sup.e22R.sup.e23
(wherein R.sup.e21, R.sup.e22 and R.sup.e23 are each independently
a hydrogen atom or a C.sub.1-6 alkyl group),
--NHCO--COOR.sup.e24
(wherein R.sup.e24 is a hydrogen atom or a C.sub.1-6 alkyl
group),
--NHCO--CONR.sup.e25R.sup.e26
(wherein R.sup.e25 and R.sup.e26 are each independently a hydrogen
atom, a hydroxyl group or a C.sub.1-6 alkyl group),
a C.sub.6-14 aryl group optionally substituted by 1 to 5
substituents selected from group B,
a C.sub.3-10 cycloalkyl group optionally substituted by 1 to 5
substituents selected from group B,
a heterocyclic group optionally substituted by 1 to 5 substituents
selected from group B,
a C.sub.1-6 alkyl group optionally substituted by 1 to 3
substituents selected from group A,
a C.sub.2-6 alkenyl group optionally substituted by 1 to 3
substituents selected from group A,
a C.sub.2-6 alkynyl group optionally substituted by 1 to 3
substituents selected from group A,
a C.sub.6-14 aryl C.sub.1-6 alkyl group optionally substituted by 1
to 5 substituents selected from group B,
a C.sub.3-10 cycloalkyl C.sub.1-6 alkyl group optionally
substituted by 1 to 5 substituents selected from group B, and
a heterocycle C.sub.1-6 alkyl group optionally substituted by 1 to
5 substituents selected from group B.
[0411] Here, as the substituent selected from group A, preferred
are 1 to 3 substituents selected from a halogen atom, a cyano
group, --OR.sup.a1, --NR.sup.a1R.sup.a2, --COOR.sup.a1,
--CONR.sup.a1R.sup.a2, --SO.sub.2NR.sup.a1R.sup.a2 and
--NHCOR.sup.a1
(wherein R.sup.a1 and R.sup.a2 are each independently a hydrogen
atom or a C.sub.1-6 alkyl group), and
[0412] as the substituent selected from group B, preferred are 1 to
5 substituent selected from a halogen atom, a C.sub.1-6 alkyl
group, a halogenated C.sub.1-6 alkyl group,
--(CH.sub.2).sub.r--OR.sup.b1,
--(CH.sub.2).sub.r--NR.sup.b1R.sup.b2,
--(CH.sub.2).sub.r--COOR.sup.b1,
--(CH.sub.2).sub.r--CONR.sup.b1R.sup.b2,
--(CH.sub.2).sub.r--SO.sub.2NR.sup.b1R.sup.b2 and
--(CH.sub.2).sub.r--NR.sup.b1--COR.sup.b2
(wherein R.sup.b1 and R.sup.b2 are each independently a hydrogen
atom or a C.sub.1-6 alkyl group, and r is 0 or an integer of 1 to
6).
[0413] For R.sup.1, preferred is --CONR.sup.11R.sup.12.
[0414] More preferably, R.sup.11 is a hydrogen atom, and
R.sup.12 is
--CR.sup.135R.sup.136-L.sup.100-R.sup.137,
[0415] --CR.sup.135R.sup.136-L.sup.101-CONR.sup.140-R.sup.137,
##STR85##
[0416] When R.sup.12 is --CR.sup.135R.sup.136-L.sup.100-R.sup.137,
preferably, L.sup.100 is a bond, and R.sup.137 is a C.sub.6-14 aryl
group optionally substituted by 1 to 5 substituents selected from
group E or a heterocyclic group optionally substituted by 1 to 5
substituents selected from group E (wherein said heterocyclic group
comprises 1 to 4 heteroatoms selected from oxygen atom, nitrogen
atom and sulfur atom).
[0417] More preferably, R.sup.135 and R.sup.136 are each
independently a group selected from group G, or R.sup.135 and
R.sup.136 are bonded to each other, and form, together with the
carbon atom bonded thereto, a C.sub.3-10 cycloalkyl group
optionally substituted by 1 to 5 substituents selected from group
B, or a heterocyclic group optionally substituted by 1 to 5
substituents selected from group B.
[0418] In a different preferable embodiment wherein R.sup.12 is
--CR.sup.135R.sup.136-L.sup.100-R.sup.137, L.sup.100 is methylene,
and R.sup.137 is a C.sub.6-14 aryl group optionally substituted by
1 to 5 substituents selected from group E or a heterocyclic group
optionally substituted by 1 to 5 substituents selected from group E
(wherein said heterocyclic group comprises 1 to 4 heteroatoms
selected from oxygen atom, nitrogen atom and sulfur atom).
[0419] More preferably, R.sup.135 is a group selected from group G
and R.sup.136 is a hydrogen atom.
[0420] When R.sup.12 is
--CR.sup.135R.sup.136-L.sup.101-CONR.sup.140--R.sup.137, L.sup.101
is preferably a bond.
[0421] More preferably, R.sup.135 and R.sup.136 are each
independently a group selected from group G, or R.sup.135 and
R.sup.136 are bonded to each other, and form, together with the
carbon atom bonded thereto, a C.sub.3-10 cycloalkyl group
optionally substituted by 1 to 5 substituents selected from group
B, or a heterocyclic group optionally substituted by 1 to 5
substituents selected from group B.
[0422] Still more preferably, R.sup.140 is a hydrogen atom and
R.sup.137 is a C.sub.6-14 aryl group optionally substituted by 1 to
5 substituents selected from group E or a heterocyclic group
optionally substituted by 1 to 5 substituents selected from group
E
(wherein said heterocyclic group comprises 1 to 4 heteroatoms
selected from oxygen atom, nitrogen atom and sulfur atom).
[0423] When R.sup.12 is ##STR86## L.sup.102 is preferably a
bond.
[0424] More preferably, R.sup.138 and R.sup.139 are each
independently a group selected from group G, or R.sup.138 and
R.sup.139 are bonded to each other, and form, together with the
carbon atom bonded thereto, a C.sub.3-10 cycloalkyl group
optionally substituted by 1 to 5 substituents selected from group
B, or a heterocyclic group optionally substituted by 1 to 5
substituents selected from group B.
[0425] Still more preferably, L.sup.103 is a bond, ring D.sup.3 is
a C.sub.6-14 aryl group optionally substituted by 1 to 5
substituents selected from group E or a heterocyclic group
optionally substituted by 1 to 5 substituents selected from group
E
(wherein said heterocyclic group comprises 1 to 4 heteroatoms
selected from oxygen atom, nitrogen atom and sulfur atom), and
R.sup.140 and R.sup.141 are each a hydrogen atom.
[0426] R.sup.1 is specifically a carboxyl group, a methoxycarbonyl
group, an ethoxycarbonyl group, a phenoxycarbonyl group, a
benzyloxycarbonyl group, a carbamoyl group, a methylcarbamoyl
group, a (2-hydroxyethyl)carbamoyl group, a
(1,1-dimethyl-2-hydroxyethyl)carbamoyl group, a
carboxymethylcarbamoyl group, an N-carboxymethyl-N-methylcarbamoyl
group, a (1-carboxy-3-methylbutyl)carbamoyl group, a
(1-carboxy-2-methoxyethyl)carbamoyl group, a
(1-carboxy-2-methylthioethyl)carbamoyl group, a (1-carboxy-2-o
dimethylaminoethyl)carbamoyl group, a 5-carboxypentylcarbamoyl
group, a (1-carboxy-1,3-dimethylbutyl)carbamoyl group, a
(1-carboxy-2-methyl-2-methylthiopropyl)carbamoyl group, a
(1-carboxy-2,2-dimethylpropyl)carbamoyl group, a
[2-(2-hydroxyethoxy)ethyl]carbamoyl group or a tert-butylcarbamoyl
group, particularly preferably a carboxyl group.
R.sup.1 may be a "carboxylic acid equivalent" which is a
substituent biologically equivalent to a carboxyl group, and as a
specific "carboxylic acid equivalent", the aforementioned
substituent and the like ca n be mentioned.
[0427] Moreover, an example of R.sup.1 is a group represented by
##STR87## wherein R.sup.12 is selected from the following formulas,
can be mentioned. ##STR88## ##STR89## ##STR90## ##STR91## ##STR92##
##STR93## ##STR94## ##STR95## ##STR96## ##STR97## ##STR98##
##STR99## ##STR100## ##STR101## ##STR102## ##STR103## ##STR104##
##STR105## ##STR106## ##STR107## ##STR108## ##STR109## ##STR110##
##STR111## ##STR112## ##STR113## ##STR114## ##STR115## ##STR116##
##STR117## ##STR118## ##STR119## ##STR120## ##STR121## ##STR122##
##STR123## ##STR124## ##STR125## ##STR126## ##STR127## ##STR128##
##STR129## ##STR130## ##STR131## ##STR132## ##STR133## ##STR134##
##STR135## ##STR136## ##STR137## ##STR138## ##STR139## ##STR140##
##STR141## ##STR142## ##STR143## ##STR144## ##STR145## ##STR146##
##STR147## ##STR148## ##STR149## ##STR150## ##STR151## ##STR152##
##STR153## ##STR154## ##STR155## ##STR156## ##STR157## ##STR158##
##STR159## ##STR160## ##STR161## ##STR162## ##STR163## ##STR164##
##STR165## ##STR166## ##STR167## ##STR168## ##STR169## ##STR170##
##STR171## ##STR172## ##STR173## ##STR174## ##STR175## ##STR176##
##STR177## ##STR178## ##STR179## ##STR180## ##STR181## ##STR182##
##STR183## ##STR184## ##STR185## ##STR186## ##STR187## ##STR188##
##STR189## ##STR190## ##STR191## ##STR192## ##STR193## ##STR194##
##STR195## ##STR196## ##STR197## ##STR198## ##STR199## ##STR200##
##STR201##
[0428] Furthermore, as other examples of R.sup.1, the groups
selected from the following formulae can be mentioned. ##STR202##
##STR203##
[0429] For R.sup.2, preferred are a hydrogen atom, "a group
selected from group E", "a C.sub.1-6 alkyl group optionally
substituted by 1 to 3 substituents selected from group E",
##STR204## more preferred are "a C.sub.1-6 alkyl group optionally
substituted by 1 to 3 substituents selected from group E" and
##STR205## particularly preferably, ##STR206##
[0430] Preferably, L.sup.1 and L.sup.2 are each independently a
bond, C.sub.1-6 alkylene,
--(CH.sub.2).sub.u1--NR.sup.L1--(CH.sub.2).sub.v1--,
--(CH.sub.2).sub.u1--CO--(CH.sub.2).sub.v1-- or
--(CH.sub.2).sub.u1--CONR.sup.L2--(CH.sub.2).sub.v1--, more
preferably C.sub.1-6 alkylene.
[0431] Preferably, u, v, u1 and v1 are each independently 0 or an
integer of 1 to 3, more preferably 0 or 1, particularly preferably
1.
[0432] For R.sup.L1, preferred is a hydrogen atom, preferably, ring
D.sup.1 and ring D.sup.2 are each independently "a C.sub.6-14 aryl
group optionally substituted by 1 to 5 substituents selected from
group E" or "a heterocyclic group optionally substituted by 1 to 5
substituents selected from group E".
[0433] As the "C.sub.6-14 aryl group" of "a C.sub.6-14 aryl group
optionally substituted by 1 to 5 substituents selected from group
E" for ring D.sup.1 and ring D.sup.2, preferred is a phenyl
group.
[0434] As the "heterocyclic group" of the "heterocyclic group
optionally substituted by 1 to 5 substituents selected from group
E" for ring D.sup.1 and ring D.sup.2, preferred is a 5- to
10-membered saturated or unsaturated monocyclic or fused
heterocyclic group having 1 or 2 nitrogen atoms and optionally
further having an oxygen atom or a sulfur atom, such as
pyrrolidinyl group, 2-oxopyrrolidinyl group, pyridyl group,
piperidyl group, piperazinyl group, morpholinyl group,
thiomorpholinyl group, 1,1-dioxomorpholinyl group, azepanyl group,
4-oxoazepanyl group" 1,4-diazepanyl group, 5-oxo-1,4-diazepanyl
group, 1,4-oxazepanyl group, azocanyl group, azonanyl group,
thiazolyl group, ##STR207## and the like. More preferred is a 5- to
7-membered saturated or unsaturated monocyclic heterocyclic group
having 1 or 2 nitrogen atoms and optionally further having an
oxygen atom or a sulfur atom, and particularly preferably,
pyrrolidinyl group, 2-oxopyrrolidinyl group, pyridyl group,
piperidyl group, piperazinyl group, morpholinyl group,
thiomorpholinyl group, 1,1-dioxomorpholinyl group, azepanyl group,
1,4-diazepanyl group and 1,4-oxazepanyl group can be mentioned.
[0435] As the group E in R.sup.2, preferred are "--OR.sup.e1",
"--S(O).sub.q--R.sup.e2", "--NR.sup.e3R.sup.e4", "--COOR.sup.e5",
"--CONR.sup.e6R.sup.e7", "--COR.sup.e8" and "a C.sub.6-14 aryl
group optionally substituted by 1 to 5 substituents selected from
group B", when group E is a substituent on ring D.sup.1 and ring
D.sup.2, it may be "a C.sub.1-6 alkyl group optionally substituted
by 1 to 3 substituents selected from group A".
[0436] As the "group selected from group E" represented by R.sup.2,
preferred are "--CONR.sup.e6R.sup.e7" and "--COR.sup.e8".
[0437] As the "C.sub.1-6 alkyl group optionally substituted by 1 to
3 substituents selected from group E" represented by R.sup.2,
preferred are a C.sub.1-6 alkyl group optionally substituted by 1
to 3 substituents selected from "--OR.sup.e1",
"--NR.sup.e3R.sup.e4", "--COOR.sup.e5", "--CONR.sup.e6R.sup.e7" and
"--COR.sup.e8".
[0438] With regard to group E in R.sup.2,
preferred for R.sup.e1 is a hydrogen atom or a C.sub.1-6 alkyl
group,
preferred for R.sup.e2 is a hydrogen atom or a C.sub.1-6 alkyl
group,
preferably, R.sup.e3 and R.sup.e4 are each independently a hydrogen
atom or a C.sub.1-6 alkyl group,
preferred for R.sup.e5 is a hydrogen atom or a C.sub.1-6 alkyl
group,
preferably, R.sup.e6 and R.sup.e7 are each independently a hydrogen
atom, a hydroxyl group, a C.sub.1-6 alkyl group optionally
substituted by C.sub.1-6 alkoxy group or C.sub.1-6 alkoxy
group,
preferred for R.sup.e8 is a C.sub.1-6 alkyl group or a C.sub.6-14
aryl group,
preferred for "C.sub.6-14 aryl group optionally substituted by 1 to
5 substituents selected from group B" is a C.sub.6-14 aryl
group,
when group E is a substituent on ring D.sup.1 or ring D.sup.2, "a
C.sub.1-6 alkyl group optionally substituted by 1 to 3 substituents
selected from group A" is preferably a C.sub.1-6 alkyl group.
[0439] For R.sup.2, hydrogen atom, phenylsulfonyl group,
benzyloxycarbonyl group, dimethylcarbamoyl group, acetyl group,
allyl group, methyl group, ethyl group, propyl group, isopropyl
group, butyl group, isobutyl group, sec-butyl group, tert-butyl
group, cyclohexyl group, 2,2,2-trifluoroethyl group, cyanomethyl
group, nitromethyl group, 2-(2-methoxyethoxy)ethyl group,
pivaloylmethyl group, ethoxycarbonylmethyl group,
3-(3-methylureido)propyl group, 2-(methylcarbamoyloxy)ethyl group,
2-(methylsulfanyl)ethyl group, 2-(methanesulfonyl)ethyl group,
2-(methylsulfamoyl)ethyl group, 2-hydroxy-2-methylpropyl group,
methanesulfonylcarbamoylmethyl group,
3-(dimethylamino)-2-hydroxypropyl group, carbamoylmethyl group,
methylcarbamoylmethyl group, isopropylcarbamoylmethyl group,
dimethylcarbamoylmethyl group, 2-(dimethylcarbamoyl)ethyl group,
3-(dimethylcarbamoyl)propyl group, isobutylcarbamoylmethyl group,
(1-ethylpropyl)carbamoylmethyl group, tert-butylcarbamoylmethyl
group, (2,2-dimethylpropyl)carbamoylmethyl group,
(3,3-dimethylbutyl)carbamoylmethyl group,
(2,2,2-trifluoroethyl)carbamoylmethyl group, methoxycarbamoylmethyl
group, 2-methoxyethylcarbamoylmethyl group,
3-methoxypropylcarbamoylmethyl group,
2-(methylsulfanyl)ethylcarbamoylmethyl group,
carboxymethylcarbamoylmethyl group, 2-carboxyethylcarbamoylmethyl
group, 3-carboxypropylcarbamoylmethyl group,
carbamoylmethylcarbamoylmethyl group,
2-(dimethylamino)ethylcarbamoylmethyl group,
N-[2-(dimethylamino)ethyl]-N-methylcarbamoylmethyl group,
N-(2-methoxyethyl)-N-methylcarbamoylmethyl group,
3-(dimethylamino)propylcarbamoylmethyl group,
2-(acetylamino)ethylcarbamoylmethyl group, 2-hydroxyethyl group,
3-hydroxypropyl group, 2-methoxyethyl group, 2-(dimethylamino)ethyl
group, carboxymethyl group, 2-(acetylamino)ethyl group,
3-(acetylamino)propyl group, 2-(methanesulfonylamino)ethyl group,
3-(methanesulfonylamino)propyl group,
2-[N-(methanesulfonyl)-N-methylamino]ethyl group,
3-(acetylsulfamoyl)propyl group, 2-(3-methyl-2-butenyloxy)ethyl
group, 2-(2-methoxyethoxy)ethylcarbamoylmethyl group,
2-(tetrahydropyran-2-yloxy)ethyl group, 2-(4-methylphenoxy)ethyl
group, 3-(4-chlorophenylamino)propyl group,
2-(4-methylthiazol-2-ylamino)ethyl group,
cyclopropylcarbamoylmethyl group, cyclobutylcarbamoylmethyl group,
cyclopentylcarbamoylmethyl group, cyclohexylcarbamoylmethyl group,
phenylcarbamoylmethyl group, benzylcarbamoylmethyl group,
phenethylcarbamoylmethyl group, N-benzyl-N-methylcarbamoylmethyl
group, 3-phenylpropylcarbamoylmethyl group,
4-phenylbutylcarbamoylmethyl group, 2-(3-chlorobenzyloxy)ethyl
group, 3-(4-methylbenzylsulfanyl)propyl group,
2-(phenylacetylamino)ethyl group, 2-pyridylmethylcarbamoylmethyl
group, 3-pyridylmethylcarbamoylmethyl group,
4-pyridylmethylcarbamoylmethyl group,
2-(pyridin-2-yl)ethylcarbamoylmethyl group,
2-(pyridin-3-yl)ethylcarbamoylmethyl group,
2-(pyridin-4-yl)ethylcarbamoylmethyl group,
N-methyl-N-(pyridin-2-ylmethyl)carbamoylmethyl group,
N-methyl-N-[2-(pyridin-2-yl)ethyl]carbamoylmethyl group,
3-(imidazol-1-yl)propylcarbamoylmethyl group, benzoylmethyl group,
2-(2,4-dimethylthiazol-5-yl)-2-oxoethyl group,
2-(3-methylisoxazol-4-yl)-2-oxoethyl group,
2-oxo-2-(pyrrolidin-1-yl)ethyl group,
2-(3-methoxypyrrolidin-1-yl)-2-oxoethyl group,
2-(2-carboxypyrrolidin-1-yl)-2-oxoethyl group,
2-(2-carbamoylpyrrolidin-1-yl)-2-oxoethyl group,
2-oxo-2-piperidinoethyl group, 2-morpholino-2-oxoethyl group,
2-(4-methylpiperidin-1-yl)-2-oxoethyl group,
2-(4-ethylpiperidin-1-yl)-2-oxoethyl group,
2-(3-methoxypiperidin-1-yl)-2-oxoethyl group,
2-(4-hydroxypiperidin-1-yl)-2-oxoethyl group,
2-(4-methoxypiperidin-1-yl)-2-oxoethyl group,
2-[4-(tert-butoxycarbonylamino)piperidin-1-yl]-2-oxoethyl group,
2-[4-(dimethylamino)piperidin-1-yl]-2-oxoethyl group,
2-oxo-2-(4-oxopiperidin-1-yl)ethyl group,
2-(4-methylpiperazin-1-yl)-2-oxoethyl group,
2-(4-ethylpiperazin-1-yl)-2-oxoethyl group,
2-(4-isopropylpiperazin-1-yl)-2-oxoethyl group,
2-(4-phenylpiperazin-1-yl)-2-oxoethyl group,
2-(4-acetylpiperazin-1-yl)-2-oxoethyl group,
2-(4-carboxypiperazin-1-yl)-2-oxoethyl group,
2-(4-ethoxycarbonylpiperazin-1-yl)-2-oxoethyl group,
2-(4-methanesulfonylpiperazin-1-yl)-2-oxoethyl group,
2-oxo-2-(thiomorpholin-4-yl)ethyl group,
2-oxo-2-(1-oxothiomorpholin-4-yl) ethyl group,
2-(1,1-dioxothiomorpholin-4-yl)-2-oxoethyl group,
2-(azepan-1-yl)-2-oxoethyl group, 2-(1,4-oxazepan-4-yl)-2-oxoethyl
group, 2-(4-methyl-1,4-diazepan-1-yl)-2-oxoethyl group,
4-morpholino-4-oxobutyl group, 4-(4-ethylpiperazin-1-yl)-4-oxobutyl
group, 2-(thiophen-2-ylcarbonylamino)ethyl group,
2-piperidinoethylcarbamoylmethyl group,
2-morpholinoethylcarbamoylmethyl group,
2-(1-methylpyrrolidin-2-yl)ethylcarbamoylmethyl group,
3-(2-oxopyrrolidin-1-yl)propylcarbamoylmethyl group and
2-(1-benzylpiperidin-4-yl)ethylcarbamoylmethyl group can be
specifically mentioned.
[0440] For R.sup.2, benzyl group, phenethyl group, 3-phenylpropyl
group, 2-methoxybenzyl group, 2-(dimethylamino)benzyl group,
3-methoxybenzyl group, 3-(dimethylamino)benzyl group,
3-phenoxybenzyl group, 4-fluorobenzyl group, 4-chlorobenzyl group,
4-methylbenzyl group, 4-hydroxybenzyl group, 4-methoxybenzyl group,
4-cyanobenzyl group, 4-(dimethylamino)benzyl group,
4-(methylcarbamoyl)benzyl group, 4-methanesulfonylbenzyl group,
2-pyridylmethyl group, 3-pyridylmethyl group, 4-pyridylmethyl
group, 6-aminopyridin-3-ylmethyl group,
6-acetylaminopyridin-3-ylmethyl group, 2-(pyrrolidin-1-yl)ethyl
group, 2-(2-oxopyrrolidin-1-yl)ethyl group, 2-piperidinoethyl
group, 2-(piperazin-1-yl)ethyl group,
2-(4-methylpiperidin-1-yl)ethyl group,
2-(4-ethylpiperidin-1-yl)ethyl group,
2-(1-ethylpiperidin-4-yl)ethyl group,
2-(4-hydroxypiperidin-1-yl)ethyl group,
2-(4-methoxypiperidin-1-yl)ethyl group,
2-(4-phenoxypiperidin-1-yl)ethyl group,
2-[4-(dimethylamino)piperidin-1-yl]ethyl group,
2-(1-acetylpiperidin-4-yl)ethyl group,
2-[1-(tert-butoxycarbonyl)piperidin-4-yl]ethyl group,
2-(1-methanesulfonylpiperidin-4-yl)ethyl group,
2-(4-methylpiperazin-1-yl)ethyl group,
2-(4-ethylpiperazin-1-yl)ethyl group,
2-(4-isopropylpiperazin-1-yl)ethyl group,
2-(4-phenylpiperazin-1-yl)ethyl group,
2-[4-(tert-butoxycarbonyl)piperazin-1-yl]ethyl group,
2-(4-benzoylpiperazin-1-yl)ethyl group,
2-(4-dimethylcarbamoylpiperazin-1-yl)ethyl group,
2-(4-methanesulfonylpiperazin-1-yl)ethyl group, 2-morpholinoethyl
group, 2-(thiomorpholin-4-yl)ethyl group, 2-(azepan-1-yl)ethyl
group, 2-(1,4-oxazepan-4-yl)ethyl group,
2-(4-methyl-1,4-diazepan-1-yl)ethyl group, 3-morpholinopropyl
group, 4-morpholinobutyl group, 1-methylimidazol-2-ylmethyl group,
4-tert-butylthiazol-2-ylmethyl group, 2-methylthiazol-4-ylmethyl
group, 3,5-dimethylisoxazol-4-ylmethyl group,
5-methylisoxazol-3-ylmethyl group, [1,2,4]oxadiazol-3-ylmethyl
group, 4,4-dimethyl-4,5-dihydrooxazol-2-ylmethyl group,
4-methyl-4H-[1,2,4]triazol-3-ylmethyl group,
1-methyl-1H-tetrazol-5-ylmethyl group, 2-methylpyrimidin-5-ylmethyl
group, 5-methylthiophen-2-ylmethyl group,
2,5-dimethyloxazol-4-ylmethyl group,
5-methyl-4-methylcarbamoyloxazol-2-ylmethyl group,
2-methoxymethyl-5-methyloxazol-4-ylmethyl group,
2-(2-dimethylaminothiazol-4-yl)ethyl group,
2-phenyl-4-methylthiazol-5-ylmethyl group,
5-(dimethylaminomethyl)-[1,2,4]oxadiazol-3-ylmethyl group,
5-(acetylaminomethyl)-[1,2,4]oxadiazol-3-ylmethyl group,
2-(dimethylcarbamoylmethyl)-2H-tetrazol-5-ylmethyl group,
1-methylindol-3-ylmethyl group, phenylpyridin-2-ylmethyl group,
benzhydrylcarbamoylmethyl group, 4-styrylbenzyl group,
2-(2-morpholino-2-oxoethoxy)ethyl group,
2-oxo-2-[4-(piperidinoacetyl)piperazino]ethyl group,
2-oxo-2-[4-(pyrrolidin-1-yl)piperidin-1-yl]ethyl group,
2-(2-phenoxyethylamino)ethyl group, 4-(morpholinocarbonyl)benzyl
group, 3-(3-morpholinophenyl)propyl group, 3-ethynyloxybenzyl
group,
2-{N-[3-(dimethylaminoacetylamino)benzyl]-N-methylamino}ethyl
group, 2-(dibenzylamino)ethylcarbamoylmethyl group,
4-(2-dibenzylaminomethyl)cyclohexylmethyl group,
2-(morpholinoacetylamino)ethoxycarbonylmethyl group,
3-{1-[2-(2-methoxyethoxy)phenylacetyl]piperidin-4-ylmethylcarbamoyl}benzy-
l group,
2-(2-morpholinoethoxy)-5-{N-methyl-N-[4-(4-nitrophenylsulfonyl)be-
nzoyl]amino}benzyl group, 2-[N-(2-pyridylmethyl)amino]ethyl group
and 2-[N-(2-methoxyethyl)-N-methylamino]ethyl group can be
specifically mentioned.
[0441] In addition, for R.sup.2, [0442] 3-oxo-3-piperidinopropyl
group, [0443] 3-morpholino-3-oxopropyl group, [0444]
3-(4-methylpiperazin-1-yl)-3-oxopropyl group, [0445]
3-(4-ethylpiperazin-1-yl)-3-oxopropyl group, [0446]
3-(4-acetylpiperazin-1-yl)-3-oxopropyl group, [0447]
3-(4-methanesulfonylpiperazin-1-yl)-3-oxopropyl group, [0448]
3-(4-methoxypiperazin-1-yl)-3-oxopropyl group, [0449]
3-(4-methoxycarbonylpiperazin-1-yl)-3-oxopropyl group, [0450]
3-piperidinopropyl group, [0451] 3-(4-methylpiperazin-1-yl)propyl
group, [0452] 3-(4-ethylpiperazin-1-yl)propyl group, [0453]
3-(4-acetylpiperazin-1-yl)propyl group, [0454]
3-(4-methanesulfonylpiperazin-1-yl)propyl group, [0455]
3-(4-methoxypiperazin-1-yl)propyl group, [0456]
3-(4-methoxycarbonylpiperazin-1-yl)propyl group, [0457]
(tetrahydropyran-4-yl)methyl group, [0458]
2-(tetrahydropyran-4-yl)ethyl group, [0459]
(1-methylpiperidin-4-yl)methyl group, [0460]
(1-ethylpiperidin-4-yl)methyl group, [0461]
(1-acetylpiperidin-4-yl)methyl group, [0462]
(1-methanesulfonylpiperidin-4-yl)methyl group, [0463]
(1-methoxypiperidin-4-yl)methyl group, [0464]
(1-methoxycarbonylpiperidin-4-yl)methyl group, [0465]
2-(tetrahydropyran-3-yl)ethyl group, [0466]
2-(1-methylpiperidin-3-yl)ethyl group, [0467]
2-(1-ethylpiperidin-3-yl)ethyl group, [0468]
2-(1-acetylpiperidin-3-yl)ethyl group, [0469]
2-(1-methanesulfonylpiperidin-3-yl)ethyl group, [0470]
2-(1-methoxypiperidin-3-yl)ethyl group, [0471]
2-(1-methoxycarbonylpiperidin-3-yl)ethyl group, [0472]
(tetrahydropyran-3-yl)methyl group, [0473]
(1-methylpiperidin-3-yl)methyl group, [0474]
(1-ethylpiperidin-3-yl)methyl group, [0475]
(1-acetylpiperidin-3-yl)methyl group, [0476]
(1-methanesulfonylpiperidin-3-yl)methyl group, [0477]
(1-methoxypiperidin-3-yl)methyl group, [0478]
(1-methoxycarbonylpiperidin-3-yl)methyl group, [0479]
2-(tetrahydropyran-2-yl)ethyl group, [0480]
2-(1-methylpiperidin-2-yl)ethyl group, [0481]
2-(1-ethylpiperidin-2-yl)ethyl group, [0482]
2-(1-acetylpiperidin-2-yl)ethyl group, [0483]
2-(1-methanesulfonylpiperidin-2-yl)ethyl group, [0484]
2-(1-methoxypiperidin-2-yl)ethyl group, [0485]
2-(1-methoxycarbonylpiperidin-2-yl)ethyl group, [0486]
(tetrahydropyran-2-yl)methyl group, [0487]
(1-methylpiperidin-2-yl)methyl group, [0488]
(1-ethylpiperidin-2-yl)methyl group, [0489]
(1-acetylpiperidin-2-yl)methyl group, [0490]
(1-methanesulfonylpiperidin-2-yl)methyl group, [0491]
(1-methoxypiperidin-2-yl)methyl group, [0492]
(1-methoxycarbonylpiperidin-2-yl)methyl group, [0493]
2-(2-oxopiperidin-1-yl)ethyl group, [0494]
2-(3-oxomorpholin-4-yl)ethyl group, [0495]
2-(4-methyl-2-oxopiperazin-1-yl)ethyl group, [0496]
2-(4-ethyl-2-oxopiperazin-1-yl)ethyl group, [0497]
2-(4-acetyl-2-oxopiperazin-1-yl)ethyl group, [0498]
2-(4-methanesulfonyl-2-oxopiperazin-1-yl)ethyl group, [0499]
2-(4-methoxy-2-oxopiperazin-1-yl)ethyl group, [0500]
3-(4-methoxycarbonyl-2-oxopiperazin-1-yl)ethyl group, [0501]
2-(4-ethylidenepiperidin-1-yl)ethyl group, [0502]
2-(4-methylenepiperidin-1-yl)ethyl group, [0503]
2-(4-isopropylidenepiperidin-1-yl)ethyl group, [0504]
2-(1-methylpiperidin-4-ylidene)ethyl group, [0505]
2-(1-ethylpiperidin-4-ylidene)ethyl group, [0506]
2-(1-acetylpiperidin-4-ylidene)ethyl group, [0507]
2-(1-methanesulfonylpiperidin-4-ylidene)ethyl group, [0508]
2-(1-methoxypiperidin-4-ylidene)ethyl group, [0509]
2-(1-methoxycarbonylpiperidin-4-ylidene)ethyl group, [0510]
2-cyclohexyloxyethyl group, [0511] 2-(tetrahydropyran-4-yloxy)ethyl
group, [0512] 2-(1-methylpiperidin-4-yloxy)ethyl group, [0513]
2-(1-ethylpiperidin-4-yloxy)ethyl group, [0514]
2-(1-acetylpiperidin-4-yloxy)ethyl group, [0515]
2-(1-methanesulfonylpiperidin-4-yloxy)ethyl group, [0516]
2-(1-methoxypiperidin-4-yloxy)ethyl group, [0517]
2-(1-methoxycarbonylpiperidin-4-yloxy)ethyl group, [0518]
2-isopropoxyethyl group, [0519] 2-(2-thiazolyl)ethyl group, [0520]
2-(2-methylimidazol-1-yl)ethyl group, [0521] 2-(2-pyridyl)ethyl
group, [0522] 2-(3-pyridyl)ethyl group, [0523] 2-(4-pyridyl)ethyl
group, [0524] 2-(2-dimethylaminothiazol-4-yl)ethyl group, [0525]
(2-thiazolyl)methyl group, [0526] (2-methylimidazol-1-yl)methyl
group, [0527] (2-pyridyl)methyl group, [0528] (3-pyridyl)methyl
group, [0529] (4-pyridyl)methyl group, [0530]
(2-dimethylaminothiazol-4-yl)methyl group, [0531]
2-(4-ethyl-1,4-diazepan-1-yl)-2-oxoethyl group, [0532]
2-(3-hydroxypiperidin-1-yl)-2-oxoethyl group, [0533]
2-(3-methoxypiperidin-1-yl)-2-oxoethyl group, [0534]
2-(3-methylpiperidin-1-yl)-2-oxoethyl group, [0535]
2-(azocan-1-yl)-2-oxoethyl group, [0536] 2-(azonan-1-yl)-2-oxoethyl
group, [0537] 2-oxo-2-(1,2,3,4-tetrahydroquinolin-1-yl)ethyl group,
[0538] 2-oxo-2-(1,2,3,4-tetrahydroisoquinolin-2-yl)ethyl group,
[0539] 2-(octahydrocyclopenta[c]pyrrol-2-yl)-2-oxoethyl group,
[0540] 2-oxo-2-(4-trifluoromethylpiperidin-1-yl)ethyl group, [0541]
2-oxo-2-(4-propylpiperidin-1-yl)ethyl group, [0542]
2-(4-isopropylpiperidin-1-yl)-2-oxoethyl group, [0543]
2-(4,4-dimethylpiperidin-1-yl)-2-oxoethyl group, [0544]
2-oxo-2-(2,2,6,6-tetramethylpiperidin-1-yl)ethyl group, [0545]
2-oxo-2-(1,2,3,6-tetrahydropyridin-1-yl)ethyl group, [0546]
2-(isoindolin-2-yl)-2-oxoethyl group, [0547]
2-(octahydroisoindol-2-yl)-2-oxoethyl group, [0548]
1-adamantylcarbamoylmethyl group, [0549]
2-(2-methylpiperidin-1-yl)-2-oxoethyl group, [0550]
diethylcarbamoylmethyl group, [0551] diisopropylcarbamoylmethyl
group, [0552] 2-(4-ethyl-1,4-diazepan-1-yl)ethyl group, [0553]
2-(3-hydroxypiperidin-1-yl)ethyl group, [0554]
2-(3-methoxypiperidin-1-yl)ethyl group, [0555]
2-(3-methylpiperidin-1-yl)ethyl group, [0556] 2-(azocan-1-yl)ethyl
group, [0557] 2-(azonan-1-yl)ethyl group, [0558]
2-(1,2,3,4-tetrahydroquinolin-1-yl)ethyl group, [0559]
2-(1,2,3,4-tetrahydroisoquinolin-2-yl)ethyl group, [0560]
2-(octahydrocyclopenta[c]pyrrol-2-yl)ethyl group, [0561]
2-(4-trifluoromethylpiperidin-1-yl)ethyl group, [0562]
2-(4-propylpiperidin-1-yl)ethyl group, [0563]
2-(4-isopropylpiperidin-1-yl)ethyl group, [0564]
2-(4,4-dimethylpiperidin-1-yl)ethyl group, [0565]
2-(2,2,6,6-tetramethylpiperidin-1-yl)ethyl group, [0566]
2-(1,2,3,6-tetrahydropyridin-1-yl)ethyl group, [0567]
2-(isoindolin-2-yl)ethyl group, [0568]
2-(octahydroisoindol-2-yl)ethyl group, [0569]
2-(1-adamantylamino)ethyl group, [0570]
2-(2-methylpiperidin-1-yl)ethyl group, [0571] 2-(diethylamino)ethyl
group, [0572] 2-(diisopropylamino)ethyl group, [0573]
2-(4-methoxycarbonylpiperazin-1-yl)-2-oxoethyl group, [0574]
2-(4-methylcarbamoylpiperazin-1-yl)-2-oxoethyl group, [0575]
2-[4-(2-methoxyacetyl)piperazin-1-yl]-2-oxoethyl group, [0576]
2-(4-cyclopentyloxycarbonylpiperazin-1-yl)-2-oxoethyl group, [0577]
2-(4-benzylpiperazin-1-yl)-2-oxoethyl group, [0578]
2-(4-isobutyrylpiperazin-1-yl)-2-oxoethyl group, [0579]
2-(4-methoxycarbonylpiperazin-1-yl)ethyl group, [0580]
2-(4-methylcarbamoylpiperazin-1-yl)ethyl group, [0581]
2-[4-(2-methoxyacetyl)piperazin-1-yl]ethyl group, [0582]
2-(4-cyclopentyloxycarbonylpiperazin-1-yl)ethyl group, [0583]
2-(4-benzylpiperazin-1-yl)ethyl group, [0584]
2-(4-isobutyrylpiperazin-1-yl)ethyl group, [0585] methylcarbamoyl
group, [0586] tert-butylcarbamoyl group, [0587]
N-tert-butyl-N-methylcarbamoyl group, [0588] cyclohexylcarbamoyl
group, [0589] (tetrahydropyran-4-yl)carbamoyl group, [0590]
(1-methylpiperidin-4-yl)carbamoyl group, [0591]
(1-acetylpiperidin-4-yl)carbamoyl group, [0592]
(1-methanesulfonylpiperidin-4-yl)carbamoyl group, [0593]
(1-methoxycarbonylpiperidin-4-yl)carbamoyl group, [0594]
cyclopentylcarbamoyl group, [0595] (tetrahydrofuran-3-yl)carbamoyl
group, [0596] (1-methylpyrrolidin-3-yl)carbamoyl group, [0597]
(1-acetylpyrrolidin-3-yl)carbamoyl group, [0598]
(1-methanesulfonylpyrrolidin-3-yl)carbamoyl group, [0599]
(1-methoxycarbonylpyrrolidin-3-yl)carbamoyl group, [0600]
N-cyclohexyl-N-methylcarbamoyl group, [0601]
N-methyl-N-(tetrahydropyran-4-yl)carbamoyl group, [0602]
N-methyl-N-(1-methylpiperidin-4-yl)carbamoyl group, [0603]
N-(1-acetylpiperidin-4-yl)-N-methylcarbamoyl group, [0604]
N-(1-methanesulfonylpiperidin-4-yl)-N-methylcarbamoyl group, [0605]
N-(1-methoxycarbonylpiperidin-4-yl)-N-methylcarbamoyl group, [0606]
N-cyclopentyl-N-methylcarbamoyl group, [0607]
N-methyl-N-(tetrahydrofuran-3-yl)carbamoyl group, [0608]
N-methyl-N-(1-methylpyrrolidin-3-yl)carbamoyl group, [0609]
N-(1-acetylpyrrolidin-3-yl)-N-methylcarbamoyl group, [0610]
N-(1-methanesulfonylpyrrolidin-3-yl)-N-methylcarbamoyl group,
[0611] N-(1-methoxycarbonylpyrrolidin-3-yl)-N-methylcarbamoyl
group, [0612] 2-(N-acetyl-N-methylamino)ethyl group, [0613]
2-(N-methyl-N-propionylamino)ethyl group, [0614]
2-(N-cyclohexanecarbonyl-N-methylamino)ethyl group, [0615]
2-[N-methyl-N-(tetrahydropyran-4-carbonyl)amino]ethyl group, [0616]
2-[N-methyl-N-(1-methylpiperidine-4-carbonyl)amino]ethyl group,
[0617] 2-[N-(1-acetylpiperidine-4-carbonyl)-N-methylamino]ethyl
group, [0618]
2-[N-(1-methanesulfonylpiperidine-4-carbonyl)-N-methylamino]ethyl
group, [0619]
2-[N-(1-methoxycarbonylpiperidine-4-carbonyl)-N-methylamino]ethyl
group, [0620] 2-(N-cyclopentanecarbonyl-N-methylamino)ethyl group,
[0621] 2-[N-methyl-N-(tetrahydrofuran-3-carbonyl)amino]ethyl group,
[0622] 2-[N-methyl-N-(1-methylpyrrolidine-3-carbonyl)amino]ethyl
group, [0623]
2-[N-(1-acetylpyrrolidine-3-carbonyl)-N-methylamino]ethyl group,
[0624]
2-[N-(1-methanesulfonylpyrrolidine-3-carbonyl)-N-methylamino]ethy-
l group, [0625]
2-[N-(1-methoxycarbonylpyrrolidine-3-carbonyl)-N-methylamino]ethyl
group, [0626] 2-(N-methanesulfonyl-N-methylamino)ethyl group,
[0627] 2-(N-methoxycarbonyl-N-methylamino)ethyl group, [0628]
2-(N-ethoxycarbonyl-N-methylamino)ethyl group, [0629]
2-(N-cyclohexyloxycarbonyl-N-methylamino)ethyl group, [0630]
2-[N-methyl-N-(tetrahydropyran-4-yloxycarbonyl)amino]ethyl group,
[0631] 2-[N-methyl-N-(1-methylpiperidin-4-yloxycarbonyl)amino]ethyl
group, [0632]
2-[N-(1-acetylpiperidin-4-yloxycarbonyl)-N-methylamino]ethyl group,
[0633]
2-[N-(1-methanesulfonylpiperidin-4-yloxycarbonyl)-N-methylamino]ethyl
group, [0634]
2-[N-(1-methoxycarbonylpiperidin-4-yloxycarbonyl)-N-methylamino]ethyl
group, [0635] 2-(N-cyclopentyloxycarbonyl-N-methylamino)ethyl
group, [0636]
2-[N-methyl-N-(tetrahydrofuran-3-yloxycarbonyl)amino]ethyl group,
[0637]
2-[N-methyl-N-(1-methylpyrrolidin-3-yloxycarbonyl)amino]ethyl
group, [0638]
2-[N-(1-acetylpyrrolidin-3-yloxycarbonyl)-N-methylamino]ethyl
group, [0639]
2-[N-(1-methanesulfonylpyrrolidin-3-yloxycarbonyl)-N-methylamino]-
ethyl group, and [0640]
2-[N-(1-methoxycarbonylpyrrolidin-3-yloxycarbonyl)-N-methylamino]ethyl
group can be mentioned. [0641] As specific examples of R.sup.2, the
following groups can be mentioned. [0642]
2-(4-acetylpiperazin-1-yl)ethyl group, [0643]
3-(tetrahydropyran-2-yloxy)propyl group, [0644]
2-(1-isopropylpiperidin-4-yl)ethyl group, [0645]
2-(3,6-dihydro-2H-pyridin-1-yl)-2-oxoethyl group, [0646]
2-(octahydroquinolin-1-yl)-2-oxoethyl group, [0647]
2-(1,3-dihydroisoindol-2-yl)-2-oxoethyl group, [0648]
2-(octahydroisoquinolin-2-yl)-2-oxoethyl group, [0649]
2-(octahydroquinolin-1-yl)ethyl group, [0650]
2-(1,3-dihydroisoindol-2-yl)ethyl group, [0651]
2-(octahydroisoquinolin-2-yl)ethyl group, [0652]
3-dimethylaminopropyl group, [0653]
1-tert-butoxycarbonylpiperidin-3-ylmethyl group [0654]
2-(1-cyclopentylpiperidin-4-yl)ethyl group, [0655]
2-(1-tert-butoxycarbonylpiperidin-2-yl)ethyl group, [0656]
2-(piperidin-3-yl)ethyl group, [0657]
2-(1-tert-butoxycarbonylpiperidin-3-yl)ethyl group, [0658]
2-(4,4-difluoropiperidin-1-yl)-2-oxoethyl group, [0659]
2-(1-propylpiperidin-4-yl)ethyl group, [0660]
2-(4,4-difluoropiperidin-1-yl)ethyl group, [0661]
2-(1-ethylpiperidin-4-ylidene)-2-fluoroethyl group, [0662]
cis-2-(octahydroisoindol-2-yl)ethyl group, [0663]
2-(8-azaspiro[4.5]decan-8-yl)ethyl], [0664]
2-(3,5-dimethylpiperidin-1-yl)-2-oxoethyl group, [0665]
2-(3-ethylpiperidin-1-yl)ethyl group, [0666]
2-(cis-2,6-dimethylpiperidin-1-yl)ethyl group, [0667]
3-(azepan-1-yl)propyl group, [0668]
2-(4-methoxymethylpiperidin-1-yl)ethyl group, [0669]
2-(N-methyl-N-propylamino)ethyl group, [0670]
2-(3-methoxymethylpiperidin-1-yl)ethyl group, [0671]
2-(1-isopropylpiperidin-3-yl)ethyl group, [0672]
2-(3,6-dihydro-2H-pyridin-1-yl)ethyl group, [0673]
2-((S)-2-methoxymethylpyrrolidin-1-yl)ethyl group, [0674]
2-(2-methylpyrrolidin-1-yl)ethyl group, [0675]
2-(N-isobutyl-N-methylamino)ethyl group, [0676]
2-(N-isopropyl-N-methylamino)ethyl group, [0677]
2-[N-(2-dimethylaminoethyl)-N-methylamino group, [0678]
2-(4-ethanesulfonylpiperazin-1-yl)ethyl group, [0679]
2-(4-propionylpiperazin-1-yl)ethyl group, [0680]
2-(4-isopropoxycarbonylpiperazin-1-yl)ethyl group, [0681]
2-(1-propylpiperidin-3-yl)ethyl group, [0682]
2-(N-cyclohexyl-N-methylamino)ethyl group, [0683]
2-(4-methanesulfonyl-1,4-diazepan-1-yl)ethyl group, [0684]
2-(4-methoxycarbonyl-1,4-diazepan-1-yl)ethyl group, [0685]
2-(3-methylpyrrolidin-1-yl)ethyl group, [0686]
2-(3-methoxypyrrolidin-1-yl)ethyl group, [0687]
2-(piperidin-4-yl)ethyl group, [0688]
2-(1-methylpiperidin-4-yl)ethyl group, [0689]
2-[N-(1-methoxycarbonylpyrrolidin-3-yl)-N-methylamino]ethyl group,
[0690] 2-[N-(1-acetylpyrrolidin-3-yl)-N-methylamino]ethyl group,
[0691] 2-[N-(1-methanesulfonylpyrrolidin-3-yl)-N-methylamino]ethyl
group, [0692] 2-(2-methylmorpholin-4-yl)ethyl group, [0693]
2-(2-ethylmorpholin-4-yl)ethyl group, [0694]
2-(3-ethylmorpholin-4-yl)ethyl group, [0695]
2-(1-isobutylpiperidin-3-yl)ethyl group, [0696]
2-(1-cyclopentylpiperidin-3-yl)ethyl group, [0697]
2-(3-propylpiperidin-1-yl)ethyl group, [0698]
3-(pyrrolidin-1-yl)propyl group, [0699] 3-(1,4-oxazepan-4-yl)propyl
group, [0700] 2-(2-methoxymethylpiperidin-1-yl)ethyl group, [0701]
2-[N-(1-acetylpiperidin-4-yl)-N-methylamino]ethyl group, [0702]
2-[N-(1-methanesulfonylpiperidin-4-yl)-N-methylamino]ethyl group,
[0703] 2-[N-(1-methoxycarbonylpiperidin-4-yl)-N-methylamino]ethyl
group, [0704] 2-[N-methyl-N-(1-methylpiperidin-4-yl)amino]ethyl
group, [0705] 2-[N-methyl-N-(tetrahydropyran-4-yl)amino]ethyl
group, [0706]
2-[N-methyl-N-(1-methylpyrrolidin-3-yl)amino]ethyl group, [0707]
2-[N-methyl-N-(pyrrolidin-3-yl)amino]ethyl group, [0708]
3-diethylaminopropyl group, [0709]
2-[3-(2-methoxyethyl)piperidin-1-yl]ethyl group, [0710]
2-((R)-2-methoxymethylpyrrolidin-1-yl)ethyl group, [0711]
2-(1-isopropylpiperidin-4-yloxy)ethyl group, [0712]
2-(N-cyclopentyl-N-methylamino)ethyl group, [0713]
3-(3-methylpiperidin-1-yl)propyl group, [0714]
2-[N-methyl-N-(tetrahydrofuran-3-yl)amino]ethyl group, [0715]
3-(2-methylpiperidin-1-yl)propyl group, [0716]
2-(3-ethoxypiperidin-1-yl)ethyl group,
[0717] 2-(2-ethylpiperidin-1-yl)ethyl group, [0718]
2-((S)-3-ethylpiperidin-1-yl)ethyl group, [0719]
2-((R)-3-ethylpiperidin-1-yl)ethyl group, [0720]
2-(1-cyclopropylpiperidin-3-yl)ethyl group, [0721]
2-[N,N-dimethyl-N-(5-methylisoxazol-3-ylmethyl)ammonio]ethyl group,
[0722] 3-(3-methoxymethylpiperidin-1-yl)propyl group, [0723]
3-(2-ethylpiperidin-1-yl)propyl group, [0724]
3-(2-methoxymethylpiperidin-1-yl)propyl group, [0725]
2-(3-isopropylpiperidin-1-yl)ethyl group, [0726]
3-(2-methylpyrrolidin-1-yl)propyl group, [0727]
2-(1-isopropylpiperidin-3-yloxy)ethyl group, [0728]
3-(3-ethylpiperidin-1-yl)propyl group, [0729]
2-(1-cyclohexylpiperidin-3-yl)ethyl group, [0730]
2-(3-ethylpyrrolidin-1-yl)ethyl group, [0731]
2-[1-(1-ethylpropyl)piperidin-3-yl]ethyl group, [0732]
2-(3-ethoxymethylpiperidin-1-yl)ethyl group, [0733]
2-(3-isopropoxypiperidin-1-yl)ethyl group, [0734]
2-[(S)-3-(2-methoxyethyl)piperidin-1-yl]ethyl group, [0735]
2-[(R)-3-(2-methoxyethyl)piperidin-1-yl]ethyl group, [0736]
2-(1-ethylpiperidin-3-yloxy)ethyl group, [0737]
3-(N-ethyl-N-isopropylamino)propyl group, [0738]
2-((S)-1-cyclopentylpiperidin-3-yl)ethyl group, [0739]
2-(3-isopropoxymethylpiperidin-1-yl)ethyl group, [0740]
2-((R)-1-cyclopentylpiperidin-3-yl)ethyl group, [0741]
3-(1-ethylpiperidin-3-yl)propyl group, [0742]
3-(1-cyclopentylpiperidin-3-yl)propyl group, [0743]
4-(piperidin-1-yl)butyl group, [0744]
2-((R)-3-methoxymethylpiperidin-1-yl)ethyl group, [0745]
2-((S)-3-methoxymethylpiperidin-1-yl)ethyl group, [0746]
4-diethylaminobutyl group, [0747] 2-(1-methylpyrrolidin-2-yl)ethyl
group, [0748] 3-(N-ethyl-N-propylamino)propyl group, [0749]
3-diisopropylaminopropyl group, [0750]
3-[N-ethyl-N-(2-methoxyethyl)amino]propyl group, [0751]
3-[N-ethyl-N-(3-methoxypropyl)amino]propyl group, [0752]
3-[N-(3-ethoxypropyl)-N-ethylamino]propyl group, [0753]
2-(3-hydroxymethylpiperidin-1-yl)ethyl group, [0754]
3-diethylamino-2,2-dimethylpropyl group, [0755]
2-(3,3-dimethylpiperidin-1-yl)ethyl group, [0756]
3-diethylamino-2-methoxypropyl group, [0757]
3-[N-ethyl-N-(2-hydroxyethyl)amino]propyl group, [0758]
2-(4-hydroxymethylpiperidin-1-yl)ethyl group, [0759]
2-[(S)-3-(2-phenoxyethyl)piperidin-1-yl]ethyl group, [0760]
2-((S)-3-phenoxymethylpiperidin-1-yl)ethyl group, [0761]
2-(7-benzyl-7-azabicyclo[2.2.1]hept-1-yl)ethyl group, [0762]
2-(7-azabicyclo[2.2.1]hept-1-yl)ethyl group, [0763]
2-(7-carboxymethyl-7-azabicyclo[2.2.1]hept-1-yl)ethyl group, [0764]
2-cyclohexylethyl group, [0765]
2-[(S)-3-(2-hydroxyethyl)piperidin-1-yl]ethyl group, [0766]
2-((R)-3-phenoxymethylpiperidin-1-yl)ethyl group, [0767]
2-[4-(2-methoxyethyl)piperidin-1-yl]ethyl group, [0768]
3-diethylamino-2-hydroxypropyl group, [0769]
2-(4-acetyl-1,4-diazepan-1-yl)ethyl group, [0770]
2-[(S)-3-(2-ethoxyethyl)piperidin-1-yl]ethyl group, [0771]
2-(5-oxo-1,4-diazepan-1-yl)ethyl group, [0772]
2-(4-methoxyazepan-1-yl)ethyl group, [0773]
2-(4-methyl-5-oxo-1,4-diazepan-1-yl)ethyl group, [0774]
2-[(S)-3-(dimethylcarbamoylmethyl)piperidin-1-yl]ethyl group,
[0775] 2-[(R)-3-(2-methoxyethoxymethyl)piperidin-1-yl]ethyl group,
[0776] 2-[(S)-3-(2-hydroxy-2-methylpropyl)piperidin-1-yl]ethyl
group, [0777] 2-[N-ethyl-N-(3-methoxypropyl)amino]ethyl group,
[0778] 2-(6-methyl-1,4-oxazepan-4-yl)ethyl group, [0779]
2-[(R)-3-(1-hydroxy-1-methylethyl)piperidin-1-yl]ethyl group,
[0780] 2-[1-(2-methoxyethyl)piperidin-3-yl]ethyl group, [0781]
2-(4-oxoazepan-1-yl)ethyl group, [0782]
2-[(S)-3-(2-dimethylcarbamoylethyl)piperidin-1-yl]ethyl group,
[0783] 2-(4-hydroxyazepan-1-yl)ethyl group, [0784]
2-[N-ethyl-N-(4-methoxybutyl)amino]ethyl group, [0785]
2-[(S)-3-(3-methoxypropyl)piperidin-1-yl]ethyl group, [0786]
2-[(R)-3-(1-methoxy-1-methylethyl)piperidin-1-yl]ethyl group,
[0787] 2-(3-dimethylcarbamoylpiperidin-1-yl)ethyl group, [0788]
2-[(R)-3-(2-methoxyethoxy)piperidin-1-yl]ethyl group, [0789]
2-(3-methoxymethylazepan-1-yl)ethyl group, [0790]
2-{(S)-3-[2-(N-acetyl-N-methylamino)ethyl]piperidin-1-yl]ethyl
group, [0791] 2-[(S)-3-(2-dimethylaminoethyl)piperidin-1-yl]ethyl
group, [0792] 2-((S)-3-carboxymethylpiperidin-1-yl)ethyl group,
[0793]
2-{(S)-3-[2-(N-tert-butoxycarbonyl-N-methylamino)ethyl]piperidin-1-yl}eth-
yl group, [0794] 1-benzyloxycarbonylpiperidin-4-yl group, [0795]
2-{(S)-3-[2-(trimethylureido)ethyl]piperidin-1-yl}ethyl group,
[0796] piperidin-4-yl group, [0797] 1-acetylpiperidin-4-yl group,
[0798] 1-methylpiperidin-4-yl group, [0799]
2-{(S)-3-[2-(2-oxopyrrolidin-1-yl)ethyl]piperidin-1-yl}ethyl group,
[0800] 2-[(S)-3-(2-methoxyethyl)piperidin-1-yl]-2-oxoethyl group,
[0801] 2-(1-methoxycarbonylpiperidin-4-yl)ethyl group, [0802]
2-(4-fluorophenyl)ethyl group, [0803] 2-(4-methylthiazol-2-yl)ethyl
group.
[0804] For R.sup.3, preferred are hydrogen atom, halogen atom, "a
C.sub.1-6 alkyl group optionally substituted by 1 to 3 substituents
selected from group A" or --OR.sup.101 (wherein R.sup.101 is a
hydrogen atom or a group selected from group C), and specifically,
a hydrogen atom, fluorine atom, chlorine atom, methyl group,
methoxy group and the like can be specifically mentioned,
particularly preferably hydrogen atom.
[0805] For R.sup.4, preferred are a group that does not markedly
degrade pharmacological activity, such as fluorine atom, chlorine
atom, methyl group, methoxy group and the like can be
mentioned.
[0806] For a, preferred is 0.
[0807] Preferably, R.sup.5 and R.sup.6 are each independently a
hydrogen atom, "a halogen atom", "a C.sub.1-6 alkyl group
optionally substituted by 1 to 3 substituents selected from group
A" or "--OR.sup.120", which is specifically hydrogen atom, fluorine
atom, methyl group, ethyl group or trifluoromethyl group, more
preferably hydrogen atom.
[0808] For ring A, preferred are benzene or "a 5- or 6-membered
heterocycle comprising 1 to 4 heteroatoms selected from oxygen
atom, nitrogen atom and sulfur atom", more preprred are benzene and
pyrrole, particularly preferred is benzene.
[0809] For ring Cy, preferred are a C.sub.3-10 cycloalkyl group and
a C.sub.3-10 cycloalkenyl group, more preferred are cyclohexyl
group and cyclohexenyl group, particularly preferred is cyclohexyl
group.
[0810] For X, preferred are a hydrogen atom, a halogen atom, "a
C.sub.1-6 alkyl group optionally substituted by 1 to 3 substituents
selected from group A", "--(CH.sub.2).sub.t--OR.sup.d1",
"(CH.sub.2).sub.t--S(O).sub.q--R.sup.d2"
"--(CH.sub.2).sub.t--NR.sup.d3R.sup.d4" and ##STR208## wherein each
symbol is as defined above, more preferred are a hydrogen atom, a
halogen atom, "a C.sub.1-6 alkyl group optionally substituted by 1
to 3 substituents selected from group A",
"--(CH.sub.2).sub.t--OR.sup.d1",
"--(CH.sub.2).sub.t--S(O).sub.q--R.sup.d2" and ##STR209## wherein
each symbol is as defined above.
[0811] For Y, preferred is
--(CH.sub.2).sub.m--O--(CH.sub.2).sub.n-- (wherein each symbol is
as defined above), more preferred are --O--CH.sub.2-- and --O--,
still more preferred is --O--CH.sub.2--.
[0812] Other preferable embodiment of Y is
--NR.sup.y1--(CH.sub.2).sub.m--Y.sup.2--, more preferably,
--NR.sup.y1--CH.sub.2--CO-- or --NR.sup.y1--(CH.sub.2).sub.2--.
[0813] For R.sup.y1, preferred is "a heterocycle C.sub.1-6 alkyl
group optionally substituted by 1 to 5 substituents selected from
group B" or --(CH.sub.2).sub.s--COR.sup.y11. For R.sup.y11,
preferred is "a heterocyclic group optionally substituted by 1 to 5
substituents selected from group B".
[0814] For ring B, preferred are a C.sub.6-14 aryl group and "a
heterocyclic group comprising 1 to 4 heteroatoms selected from
oxygen atom, nitrogen atom and sulfur atom", more preferred are
phenyl group, pyridyl group, piperidyl group, pyrrolidinyl group,
piperazinyl group, morpholinyl group, azepanyl group,
1,4-oxazepanyl group, isoxazolyl group, thiazolyl group and
2-oxooxazolidinyl group, more preferred are phenyl group, pyridyl
group and piperidyl group, and still more preferred is phenyl
group.
[0815] For Z, preferred are 1 to 3 substituents selected from
(1) a hydrogen atom,
(2) a halogen atom,
(3) a nitro group,
(4) a C.sub.6-14 aryl group optionally substituted by 1 to 5
substituents selected from group D,
(5) a C.sub.3-10 cycloalkyl group optionally substituted by 1 to 5
substituents selected from group D,
(6) a heterocyclic group optionally substituted by 1 to 5
substituents selected from group D,
(7) a C.sub.1-6 alkyl group optionally substituted by 1 to 3
substituents selected from the aforementioned group A,
(8) --(CH.sub.2).sub.t--OR.sup.d1,
(9) --(CH.sub.2).sub.t--S(O).sub.q--R.sup.d2,
(10) --(CH.sub.2).sub.t--NR.sup.d3R.sup.d4,
(11) --(CH.sub.2).sub.t--COOR.sup.d5,
(12) --(CH.sub.2).sub.t--CONR.sup.d6R.sup.d7,
(13) --(CH.sub.2).sub.t--COR.sup.d8,
(14) --(CH.sub.2).sub.t--NR.sup.9CO--R.sup.d10,
(15) --(CH.sub.2).sub.t--NR.sup.d11SO.sub.2--R.sup.d12 and
(16) --(CH.sub.2).sub.t--NR.sup.d19--COOR.sup.d20
(wherein each symbol is as defined above), more preferably, 1 to 3
substituents selected from
(1) a hydrogen atom,
(2) a halogen atom,
(3) a C.sub.6-14 aryl group optionally substituted by 1 to 5
substituents selected from group D,
(4) a heterocyclic group optionally substituted by 1 to 5
substituents selected from group D,
(5) --(CH.sub.2).sub.t--OR.sup.d1,
(6) --(CH.sub.2).sub.t--S(O).sub.q--R.sup.d2,
(7) --(CH.sub.2).sub.t--NR.sup.d3R.sup.d4,
(8) --(CH.sub.2).sub.t--COOR.sup.d5,
(9) --(CH.sub.2).sub.t--NR.sup.d9CO--R.sup.d10, and
(10) --(CH.sub.2).sub.t--NR.sup.d11SO.sub.2--R.sup.d12
(wherein each symbol is as defined above).
[0816] The "C.sub.6-14 aryl group" of the "C.sub.6-14 aryl group
optionally substituted by 1 to 5 substituents selected from group
D" for Z is preferably a phenyl group.
[0817] The "heterocyclic group" of the "heterocyclic group
optionally substituted by 1 to 5 substituents selected from group
D" for Z is preferably a pyrrolidinyl group, a 2-oxopyrrolidinyl
group, a piperidinyl group, a piperazinyl group or a morpholinyl
group.
[0818] When Z is "a C.sub.6-14 aryl group optionally substituted by
1 to 5 substituents selected from group D" or "a heterocyclic group
optionally substituted by 1 to 5 substituents selected from group
D", the group D is preferably a hydrogen atom, "C.sub.1-6 alkyl
group optionally substituted by 1 to 3 substituents selected from
A", "--(CH.sub.2).sub.t--S(O).sub.q--R.sup.d2" or
"--(CH.sub.2).sub.t--CONR.sup.d6R.sup.d7".
[0819] With regard to group D in Z,
for R.sup.d1, preferred are a hydrogen atom and a C.sub.1-6 alkyl
group,
for R.sup.d2, preferred are a hydrogen atom and a C.sub.1-6 alkyl
group,
preferably, R.sup.d3 and R.sup.d4 are each independently a hydrogen
atom or a C.sub.1-6 alkyl group,
for R.sup.d5, preferred are a hydrogen atom and a C.sub.1-6 alkyl
group,
for R.sup.d9, preferred are a hydrogen atom, a C.sub.1-6 alkyl
group and a C.sub.1-6 alkanoyl group,
for R.sup.10, preferred are a C.sub.1-6 alkyl group optionally
substituted by --NR.sup.a1R.sup.a2 and a heterocycle C.sub.1-6
alkyl group (wherein the heterocycle C.sub.1-6 alkyl group is
preferably a morpholinomethyl group),
for R.sup.d12, preferred are a hydrogen atom, a C.sub.1-6 alkyl
group and a C.sub.1-6 alkanoyl group,
for R.sup.d12, preferred are a hydrogen atom and a C.sub.1-6 alkyl
group,
for the "C.sub.1-6 alkyl group optionally substituted by 1 to 3
substituents selected from A", preferred is a C.sub.1-6 alkyl
group.
[0820] X is specifically hydrogen atom, methyl group, ethyl group,
propyl group, isopropyl group, tert-butyl group, fluorineatom,
chlorine atom, bromine atom, trifluoromethyl group, hydroxyl group,
methoxy group, ethoxy group, isopropoxy group, methylsulfanyl
group, trifluoromethoxy group, cyano group, nitro group, amino
group, dimethylamino group, phenyl group, pyridyl group (2-pyridyl
group, 3-pyridyl group, 4-pyridyl group), carbamoyl group, carboxyl
group, 2-methoxyethoxy group, 2-(2-hydroxyethylamino)ethoxy group,
2-dimethylaminoethoxy group, carboxymethoxy group,
methoxycarbonyloxy group and the like can be mentioned. X is more
specifically ##STR210## ##STR211## ##STR212## ##STR213## ##STR214##
##STR215## ##STR216## ##STR217## ##STR218## ##STR219## ##STR220##
##STR221## ##STR222## ##STR223## ##STR224## ##STR225## ##STR226##
##STR227## ##STR228## ##STR229## ##STR230## ##STR231## ##STR232##
##STR233## ##STR234## ##STR235## ##STR236## ##STR237## ##STR238##
##STR239## ##STR240## ##STR241## ##STR242## ##STR243## ##STR244##
##STR245## ##STR246## ##STR247## ##STR248## ##STR249## ##STR250##
##STR251## ##STR252## ##STR253## ##STR254## ##STR255## ##STR256##
##STR257## ##STR258## ##STR259## ##STR260## ##STR261## ##STR262##
##STR263## ##STR264## ##STR265## ##STR266## ##STR267## and the like
can be mentioned.
[0821] In the formula [I], moreover, a compound represented by the
following formula [I-A], [I-B] or [I-C] is particularly preferable.
##STR268## wherein X' is a hydrogen atom, a halogen atom, "a
C.sub.1-6 alkyl group optionally substituted by 1 to 3 substituents
selected from group A" or "--OR.sup.d1", and other symbols are as
defined above. ##STR269## wherein Q.sup.2 is --O-- or --NH--, and
other symbols are as defined above. ##STR270## wherein Q.sup.3 is
--O-- or --NR.sup.2--, X' is a hydrogen atom, a halogen atom, a
C.sub.1-6 alkyl group optionally substituted by 1 to 3 substituents
selected from group A or --OR.sup.d1, and other symbols are as
defined above.
[0822] The "carboxyl-protecting group" only needs to be suitable
for reaction conditions, and is capable of protecting and
deprotecting and may be, for example, methyl; substituted methyl
group such as methoxymethyl, methylthiomethyl, 2-tetrahydropyranyl,
methoxyethoxymethyl, benzyloxymethyl, phenacyl, diacylmethyl,
phthalimidomethyl etc.; ethyl; substituted ethyl group such as
2,2,2-trichloroethyl, 2-chloroethyl, 2-(trimethylsilyl)ethyl,
2-methylthioethyl, 2-(p-toluenesulfonyl)ethyl, t-butyl etc.;
benzyl; substituted benzyl group such as diphenylmethyl,
triphenylmethyl, p-nitrobenzyl, 4-picolyl, p-methoxybenzyl,
2-(9,10-dioxo)anthrylmethyl etc.; silyl group such as
trimethylsilyl, t-butyldimethylsilyl, phenyldimethylsilyl etc.; and
the like.
[0823] The "pharmaceutically acceptable salt" may be any as long as
it forms a non-toxic salt with a compound of the above-mentioned
formula [I]. Such salt can be obtained by reacting the compound
with an inorganic acid, such as hydrochloric acid, sulfuric acid,
phosphoric acid, hydrobromic acid and the like; or 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, meglumine acid and the like; or an
inorganic base, such as sodium hydroxide, potassium hydroxide,
calcium hydroxide, magnesium hydroxide, ammonium hydroxide and the
like; or an organic base, such as methylamine, diethylamine,
triethylamine, triethanolamine, ethylenediamine,
tris(hydroxymethyl)methylamine, guanidine, choline, cinchonine and
the like; with an amino acid, such as lysine, arginine, alanine and
the like. The present invention encompasses water-retaining
product, hydrate and solvate of each compound.
[0824] The compounds of the above-mentioned formula [I] have
various isomers. For example, E compound and Z compound are present
as geometric isomers, and when the compound has asymmetric
carbon(s), an enantiomer and a diastereomer are present as a
stereoisomer due to the asymmetric carbon(s). When an axial
chirality exists, a stereoisomer based thereon exists. A tautomer
may be also present. The present invention encompasses all of these
isomers and mixtures thereof.
[0825] The present invention also encompasses a prodrug and a
metabolite of each compound.
[0826] A "prodrug" means a derivative of the compound of the
present invention, which is capable of chemical or metabolic
decomposition, which shows inherent efficacy by reverting to the
original compound after administration to a body, and which
includes salts and complexes without a covalent bond.
[0827] A prodrug is utilized for, for example, improving absorption
by oral administration, or targeting of a target site.
[0828] As the modification moiety, a functional group having high
reactivity in the compound of the present invention can be
mentioned such as hydroxyl group, carboxyl group, amino group,
thiol group and the like.
[0829] As preferable embodiments of the compound of the present
invention, a compound having fine pharmacological activity (e.g., a
compound having strong polymerase inhibitory activity, a compound
having strong inhibitory activity on enzyme complex comprising
polymerase, a compound having strong HCV replicon-inhibitory
activity, a compound having high anti-HCV activity in HCV infected
cells and the like), a compound having fine bioavailability (e.g.,
a compound showing high oral absorbability, a compound having high
cell-permeability, a compound stable to metabolic enzyme, a
compound with low binding ability to protein and the like), a
highly safe compound (e.g., a compound free of immunogenicity or
showing low allergic response, a compound free of or low in
increase in bilirubin value, a compound showing low P450
(CYP)-inhibitory activity and the like) and the like can be
mentioned.
[0830] When the inventive compound is used as a pharmaceutical
preparation, the inventive compound is generally admixed with
pharmaceutically acceptable carriers, excipients, diluents,
binders, disintegrators, stabilizers, preservatives, buffers,
emulsifiers, aromatics, coloring agents, sweeteners, thickeners,
correctives, solubilizers known per se, and other additives such as
water, vegetable oil, alcohol such as ethanol, benzyl alcohol and
the like, polyethylene glycol, glycerol triacetate, gelatin,
lactose, carbohydrate such as starch and the like, magnesium
stearate, talc, lanolin, petrolatum and the like, and prepared into
a dosage form of tablets, pills, powders, granules, suppositories,
injections, eye drops, liquids, capsules, troches, aerosols,
elixirs, suspensions, emulsions, syrups and the like, which can be
administered systemically or topically and orally or
parenterally.
[0831] While the dose varies depending on the age, body weight,
general condition, treatment effect, administration route and the
like, it is from 0.01 mg to 3 g for an adult per dose, which is
given one to several times a day.
[0832] The "prophylaxis of hepatitis C" means, for example,
administration of a pharmaceutical agent to an individual found to
carry an HCV by a test and the like but without a symptom of
hepatitis C, or to an individual who shows an improved disease
state of hepatitis after a treatment of hepatitis C, but who still
carries an HCV and is associated with a risk of recurrence of
hepatitis.
[0833] The therapeutic agent for hepatitis C of the present
invention is expected to provide a synergistic effect when
concurrently used with other antiviral agents, antiinflammatory
agents or immunostimulants.
[0834] The medicaments with the prospect of synergistic effect
include, for example, interferon-.alpha., interferon-.beta.,
interferon-.gamma., interleukin-2, interleukin-8, interleukin-10,
interleukin-12, TNF.alpha., recombinant or modified products
thereof, agonists, antibodies, vaccines, ribozymes, antisense
nucleotides and the like.
[0835] As evidenced in the combination therapy of anti-HIV agents,
which is also called a cocktail therapy, the combined use of
various anti-virus agents againt viruses showing frequent genetic
mutations is expected to show effect for suppressing emergence and
increase of drug tolerant viruses. For example, 2 or 3 agents from
HCV-IRES inhibitors, HCV-NS3 protease inhibitors, HCV-NS2NS3
protease inhibitors, HCV-NS5A inhibitors and HCV polymerase
inhibitor may be used in combination. Specifically, the combined
use with Ribavirin(R), interferon-.alpha. (IFN-.alpha., Roferon(R),
Intron A(R), Sumiferon(R), MultiFeron(R), Infergen(R),
Orniferon(R), Pegasys(R), PEG-Intron A(R)), interferon-.beta.
(Frone(R), Rebif(R), AvoneX(R), IFN.beta.MOCHIDA(R)),
interferon-.omega.,
1-.beta.-L-ribofuranosyl-1H-1,2,4-triazole-3-carboxamide,
16.alpha.-bromo-3.beta.-hydroxy-5.alpha.-androstan-17-one,
1H-imidazole-4-ethanamide dihydrochloride, HCV ribozyme
Heptazyme(R), polyclonal antibody Civacir(R), lactoferrin GPX-400,
(1S,2R,8R,8aR)-1,2,8-trihydroxyoctahydroindolizidinium chloride,
HCV vaccine (MTH-68/B, Innivax C(R), Engerix B(R)), antisense
oligonucleotide ISIS-14803, HCV-RNA transcriptase inhibitor
VP-50406, tetrachlorodecaoxide (high concentration Oxoferin(R)),
tetrahydrofuran-3-yl
(S)--N-3-[3-(3-methoxy-4-oxazol-5-ylphenyl)ureido]benzylcarbamate,
4-amino-2-ethoxymethyl-.alpha.,.alpha.-dimethyl-1H-imidazo[4,5-c]quinolin-
e-1-ethanol, interleukin-2 (Proleukin(R)), thymosin al and the like
is exemplified, wherein (R) shows product names.
[0836] Furthermore, the combined use with the compounds disclosed
in JP-A-08-268890, JP-A-10-101591, JP-A-07-069899, WO99/61613 and
the like as HCV-IRES inhibitors; the compounds disclosed in
WO98/22496, WO99/07733, WO99/07734, WO00/09543, WO00/09558,
WO01/59929, WO98/17679, EP932617, WO99/50230, WO0/74768,
WO97/43310, U.S. Pat. No. 5,990,276, WO01/58929, WO01/77113,
WO02/8198, WO02/8187, WO02/8244, WO02/8256, WO01/07407, WO01/40262,
WO01/64678, WO98/46630, JP-A-11-292840, JP-A-10-298151,
JP-A-11-127861, JP-A-2001-103993, WO98/46597, WO99/64442,
WO0/31129, WO01/32961, WO93/15730, U.S. Pat. No. 7,832,236,
WO00/200400, WO02/8251, WO01/16379, WO02/7761 and the like as HCV
protease inhibitors; the compounds disclosed in WO97/36554, U.S.
Pat. No. 5,830,905, WO97/36866, U.S. Pat. No. 5,633,388,
WO01/07027, WO0/24725 and the like as HCV helicase inhibitors; the
compounds disclosed in WO00/10573, WO00/13708, WO00/18231,
WO00/06529, WO02/06246, WO01/32153, WO01/60315, WO01/77091,
WO02/04425, WO02/20497, WO00/04141 and the like as HCV polymerase
inhibitors; the compounds disclosed in WO01/58877, JP-A-11-180981,
WO01/12214 and the like as interferon agonists or enhancers; and
the like is also exemplified.
[0837] In the case of combined administration, the compound of the
present invention can be administered simultaneously with a
pharmaceutical agent to be used in combination (hereinafter
combination drug) or administered at certain time intervals. In the
case of combined administration, a pharmaceutical composition
containing the compound of the present invention and a combination
drug can be administered. Alternatively, a pharmaceutical
composition containing the compound of the present invention and a
pharmaceutical composition containing a combination drug may be
administered separately. The administration route of the compound
of the present invention and that of the combination drug may be
the same or different.
[0838] In the case of a combined administration, the compound of
the present invention can be administered once a day or several
times a day in a single dose of 0.1 mg to 1 g, or may be
administered at a smaller dose. The combination drug can be
administered at a dose generally used for the prevention or
treatment of hepatitis C, for example, at a single dose of 0.2 mg
to 0.8 mg. Alternatively, it may be administered at a smaller
dose.
[0839] Inasmuch as HCV is known to be a virus associated with many
genetic mutations, a compound effective for many genotypes is one
of the preferable modes. If a compound ensures high blood
concentration and sustention thereof when administered as a
pharmaceutical agent to an animal infected with HCV, it is also one
of the preferable modes. From these aspects, a compound having high
inhibitory activity on both HCV type 1a and type 1b and high blood
concentration is particularly preferable.
[0840] Examples of the Production Method of the compound to be used
for the practice of the present invention are given in the
following. However, the Production Method of the compound of the
present invention is not limited to these examples.
[0841] Even if no directly corresponding disclosure is found in the
following Production Methods, the steps may be modified for
efficient production of the compound, such as introduction of a
protecting group into a functional group with deprotection in a
subsequent step, and changing the order of Production Methods and
steps.
[0842] The treatment after reaction in each step may be
conventional ones, for which typical methods, such as isolation and
purification, crystallization, recrystallization, silica gel
chromatography, preparative HPLC and the like, can be appropriately
selected and combined.
REFERENCE EXAMPLE 1
[0843] ##STR271## wherein Q.sup.10 is, for example, O or NH,
R.sup.c1 is a leaving group such as bromine atom, iodine atom,
--OTf (trifluoromethylsulfonyloxy group) and the like,
--B(OR.sup.c2)(OR.sup.c3) is --B(OH).sub.2,
4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl group, ring A' is ring
A wherein G.sup.6 is carbon atom, and other symbols are as defined
above.
[0844] Compound [2] can be obtained from commercially available
compound [1] or compound [1] obtained by a conventional method and
a boric acid ester.
[0845] As the boric acid ester, pinacolborane,
bis(pinacolato)diboron and the like can be mentioned.
[0846] As a catalyst, palladium catalysts such as
Pd(PPh.sub.3).sub.4, Pd(dppb)Cl.sub.2,
PdCl.sub.2(dppf)CH.sub.2Cl.sub.2, PdCl.sub.2(PPh.sub.3).sub.2,
Pd(OAc).sub.2, PdCl.sub.2, palladium black, palladium carbon and
the like can be mentioned.
[0847] As a base, strong bases such as ethylenediamine, sodium
carbonate, barium hydroxide, potassium phosphate, cesium carbonate,
sodium hydrogen carbonate, sodium tert-butoxide, potassium
tert-butoxide, triethylamine, potassium acetate and the like are
generally preferable. As the ligand, triphenylphosphine,
tri(2-tolyl)phosphine, (2-biphenyl)dicyclohexylphosphine and the
like may be added.
[0848] In addition, compound [1] may be reacted with a boric acid
ester such as triisopropyl borate, trimethyl borate and the like in
the presence of n-butyllithium. Where necessary, a protecting group
may be introduced into -Q.sup.10H and the protected compound may be
subjected to the reaction.
[0849] As a solvent, 1,4-dioxane, THF (tetrahydrofuran), toluene,
dimethoxyethane, water and the like can be mentioned.
REFERENCE EXAMPLE 2
[0850] ##STR272## wherein compound [4] is, for example, a compound
wherein cycloalkyl group having 3 to 10 carbon atoms is substituted
by oxo group, such as cyclopentanone, cyclohexanone and the like.
Step 1
[0851] Compound [5] can be obtained by reacting commercially
available compound [3] or compound [3] obtained by a conventional
method with compound [4] in the presence of a base, or under aldol
reaction conditions.
[0852] As a base, preferably, sodium methoxide, sodium ethoxide,
lithium diisopropylamide, sodium hydroxide, potassium hydroxide,
sodium hydride and the like can be mentioned.
[0853] As a solvent, alcohol solvent such as methanol, ethanol and
the like, THF, 1,4-dioxane, DMF (dimethylformamide), DMSO (dimethyl
sulfoxide), DMA (dimethylacetamide), water and a mixed solvent
thereof and the like can be mentioned.
[0854] As the reaction temperature, -20.degree. C. to 120.degree.
C. is preferable.
[0855] In addition, for a reaction under acidic conditions, in a
mixed solvent of acetic acid and phosphoric acid, they may be
treated at a reaction temperature of from 15.degree. C. to
120.degree. C.
Step 2
[0856] Compound [6] can be obtained by hydrogenation of compound
[5] in a solvent such as methanol, ethanol, THF, ethyl acetate,
acetic acid, formic acid, water and the like, in the presence of a
catalyst such as palladium carbon, palladium hydroxide, palladium
hydroxide on carbon, platinum oxide, Raney-nickel and the like, at
room temperature or under heating.
REFERENCE EXAMPLE 3
[0857] ##STR273## wherein R.sup.c4 is carboxyl-protecting group
such as methyl group, ethyl group, tert-butyl group, benzyl group
and the like, Hal.sup.1 is halogen atom such as bromine atom,
iodine atom and the like, and other symbols are as defined above.
Step 1
[0858] Compound [8] can be obtained by introducing a protecting
group into a carboxyl group of compound [7] obtained by a
conventional method or in the same manner as in Reference Example
2.
[0859] Where necessary, a protecting group may be introduced into a
nitrogen atom of indole.
Step 2
[0860] Compound [9] can be obtained by halogenating compound [8]
with a halogenating agent.
[0861] As the halogenating agent, bromine, N-bromosuccinimide,
pyridine tribromide, dibromohydantoin, pyridinium hydrobromide
perbromide, an iodide thereof and the like can be mentioned.
[0862] As a solvent, halogen solvents (dichloromethane, chloroform,
carbon tetrachloride etc.), hydrocarbon solvents (toluene etc.),
ether solvents (1,4-dioxane, DME (1,2-dimethoxyethane), THF etc.),
acetic acid, ethyl acetate, isopropyl alcohol or a mixed solvent
thereof and the like can be mentioned.
[0863] As the reaction temperature, from -40.degree. C. to
100.degree. C. is preferable. Production Method 1 ##STR274##
##STR275## wherein c' is an integer of 1 to 4, Q.sup.11 is --O--,
--S--, --OCO--, --OCONH--, --NHCO--, --NHSO.sub.2--, --NHCOO--,
--COO--, --CONH--, --SO.sub.2NH--, --NHCONH--, --NHSO.sub.2NH--,
--CH.dbd.CH--, --CH.dbd.N-- or --N.dbd.CH--, R.sup.c5 is --OH,
--SH, --NH.sub.2, --COOH, --SO.sub.2NH.sub.2, a protected group
thereof or --CHO, R.sup.c6 is --OH, --SH, --NH.sub.2, --COOH,
--SO.sub.2NH.sub.2 or --CHO, R.sup.c7 is a leaving group such as
Hal.sup.2 (wherein Hal.sup.2 is halogen atom such as chlorine atom,
bromine atom, iodine atom and the like), --OMs (mesyloxy group),
--OTs (tosyloxy group), --OTf and the like or a protected OH group,
R.sup.c8 is --OH, --NH.sub.2, --COOH, --CHO, --COHal.sup.2,
--OCOHal.sup.2, --SO.sub.2Hal.sup.2, --NHSO.sub.2Hal.sup.2,
--OC(.dbd.NH)C(Hal).sub.3 (wherein Hal is halogen atom such as
fluorine atom, chlorine atom and the like), --NCO, Hal.sup.2 or
--P.sup.+(Ph).sub.3, R.sup.9 is a leaving group such as Hal.sup.2,
--OMs or --OTs and the like, compound [11] is a metal compound,
wherein the metal moiety M includes boron, zinc, tin, magnesium,
lithium and the like, for example, phenylboronic acid derivative,
and other symbols are as defined above. Step 1
[0864] Compound [12] can be obtained by reacting compound [10]
obtained by a conventional method or in the same manner as in
Reference Example 3 with compound [11] obtained by a conventional
method or in the same manner as in Reference Example 1.
Step 2
[0865] When R.sup.c5 is a protected group, deprotection is
conducted by a conventional method to give compound [13] from
compound [12].
Step 3
[0866] Compound [15] can be obtained by reacting compound [13] with
compound [14].
[0867] For example, when a desired Q.sup.11 is --OCO--, Compound
[15] can be obtained by esterification of compound [14] wherein
R.sup.c8 is --OH and compound [13] wherein R.sup.c6 is HOOC-- by a
conventional method.
[0868] In the following, examples of reaction for each desired
Q.sup.11 are shown in the form of a Table. TABLE-US-00001 TABLE 1-1
Desired Q.sup.11 --R.sup.c8 R.sup.c6-- Reaction --OCO-- --OH HOOC--
esterification or --COO-- --COOH HO-- amidation by --CONH--
--COHal.sup.2 H.sub.2N-- reaction in the --NHCO-- --NH.sub.2 HOOC--
presence of --OCONH-- --OCOHal.sup.2 H.sub.2N-- condensing
--SO.sub.2NH-- --SO.sub.2Hal.sup.2 H.sub.2N-- agent, reaction
--NHSO.sub.2NH-- --NHSO.sub.2Hal.sup.2 as acid halide, Mitsunobu
reaction and the like. --NHCONH-- --NCO H.sub.2N-- urea formation
--NHCOO-- HO-- or carbamation with isocyanate. --NHSO.sub.2--
--OC(.dbd.NH)C(Hal).sub.3 H.sub.2NO.sub.2S-- reaction with --O--
HO-- imidoyloxy --S-- HS-- group in the presence of acid.
--CH.dbd.CH-- --P.sup.+(Ph).sub.3 HOC-- using Wittig reaction.
--CH.dbd.N-- --CHO H.sub.2N-- imine --N.dbd.CH-- --NH.sub.2 HOC--
formation with amine and aldehyde.
Step 4
[0869] When R.sup.c7 is a protected OH group, deprotection is
conducted by a conventional method, after which halogenation,
mesylation or tosylation is conducted to give compound [16] from
compound [15].
Step 5
[0870] Compound [I-1] can be obtained by condensation cyclization
of compound [16] by a conventional method.
Step 6
[0871] When Q.sup.11 is --CONH-- or --NHCO--, compounds [I-2] and
[I-3] can be respectively obtained by reduction of compound [I-1]
by a conventional method.
Step 7
[0872] When Q.sup.11 is --S--, compounds [I-4] and [I-5] can be
obtained by oxidation of compound [I-1] by a conventional method.
Production Method 1-1 ##STR276## wherein each symbol is as defined
above.
[0873] Compound [19] can be obtained by reacting compound [17]
obtained by a conventional method or in the same manner as in
Reference Example 3 with compound [18] obtained by a conventional
method or in the same manner as in Reference Example 1 using a
Suzuki reaction.
[0874] For example, Compound [19] can be obtained by a reaction in
a solvent such as DMF, acetonitrile, alcohol solvents (methanol,
ethanol etc.), DME, THF, toluene, water, or a mixed solvent thereof
and the like in the presence of a palladium catalyst such as
tetrakis(triphenylphosphine)palladium,
bis(triphenylphosphine)palladium(II) dichloride, palladium
acetate--triphenylphosphine and the like, a nickel catalyst such as
nickel chloride, 1,3-bis(diphenylphosphino)propane nickel(II)
chloride and the like and a base such as sodium carbonate,
potassium carbonate, potassium hydrogen carbonate, sodium hydrogen
carbonate, potassium phosphate, triethylamine, potassium fluoride,
cesium fluoride, sodium hydrogenphosphate, cesium carbonate and the
like, at room temperature or under heating.
[0875] The reactivity may be increased by adding lithium chloride
and the like.
[0876] In addition, the following compounds may be used instead of
the above-mentioned compounds [17] and [18]. ##STR277## Production
Method 1-2 ##STR278## wherein R.sup.c10 is halogen atom such as
chlorine atom, bromine atom and the like or hydroxyl group, and
other symbols are as defined above. Step 1
[0877] Compound [22] can be obtained by reacting compound [20] with
compound [21].
[0878] When R.sup.c10 is a hydroxyl group, compound [20] is
condensed with carboxylic acid compound [21] in a solvent such as
DMF, acetonitrile, THF, chloroform, ethyl acetate, methylene
chloride, toluene and the like by adding a condensing agent such as
dicyclohexylcarbodiimide,
1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride,
diphenylphosphoryl azide and the like and, where necessary,
N-hydroxysuccinimide, 1-hydroxybenzotriazole and the like to give
amide compound [22]. Alternatively, amide Compound [22] can be
obtained from compound [21] as follows. The carboxylic acid
compound [21] is converted to an acid halide with thionyl chloride,
oxalyl chloride and the like (a catalyst amount of DMF may be
added), or to an active ester of carboxylic acid compound [21]
(e.g., converting to a mixed acid anhydride with ethyl
chlorocarbonate and the like), which is then reacted with compound
[20] in the presence of a base, such as triethylamine, potassium
carbonate, pyridine and the like, or in an amine solvent such as
pyridine and the like, to give amide compound [22]. For the
reaction of active ester with compound [20], dimethylaminopyridine
may be adddd.
[0879] When R.sup.c10 is halogen atom such as chlorine atom,
bromine atom and the like, compound [21] is reacted with compound
[20] in the presence of a base such as triethylamine, potassium
carbonate, pyridine and the like, or in an amine solvent such as
pyridine and the like to give amide compound [22].
[0880] To increase selectivity of reaction with amino group, acetic
acid and sodium acetate may be added at an equivalent ratio.
Step 2
[0881] Compound [I-6] can be obtained by condensation cyclization
of compound [22] in a solvent such as ethanol, DMF, DMA, DMSO,
acetone, acetonitrile, 1,4-dioxane, THF, toluene, water and the
like, in the presence or absence of a base such as potassium
hydroxide, sodium hydride, potassium carbonate, triethylamine,
sodium ethoxide, potassium tert-butoxide and the like, under
cooling to under heating.
Step 3
[0882] Compound [I-7] can be obtained by reducing compound [I-6] by
a conventional method.
[0883] For example, reduction is carried out using a borohydride
(e.g., sodium borohydride, sodium triacetoxyborohydride and the
like), borane-THF complex and the like as a reducing agent. In this
case, an acid such as acetic acid, hydrochloric acid and the like
may be added.
[0884] As a preferable solvent, ether solvents (1,4-dioxane, THF
etc.), alcohol solvents (methanol, ethanol etc.), polar solvents
(DMF, DMSO, acetonitrile etc.), halogen solvents (dichloromethane,
chloroform etc.), hydrocarbon solvents (benzene, toluene etc.),
ester solvents (ethyl acetate, butyl acetate etc.), water, or a
mixed solvent thereof and the like can be mentioned. Production
Method 2 ##STR279## wherein Q.sup.12 is --O--, --S--, --OCO--,
--OCONH--, --NHCO--, --NHSO.sub.2--, --NHCOO--, --COO--, --CONH--,
--NHCONH--, --NHSO.sub.2NH--, --CH.dbd.N-- or --N.dbd.CH--,
R.sup.c11 is --OH, --NH.sub.2, --COOH, a protected group thereof,
--CHO, -Hal.sup.2, --OMs or --OTs, R.sup.c12 is --OH, --NH.sub.2,
--COOH, --CHO, -Hal.sup.2, --OMs or --OTs, and other symbols are as
defined above. Step 1
[0885] Compound [24] can be obtained by reacting compound [12] with
commercially available compound [23] or compound [23] obtained by a
conventional method.
Step 2
[0886] When R.sup.c5 and/or R.sup.c11 is a protected group,
deprotection is conducted by a conventional method to give compound
[25] from compound [24].
Step 3
[0887] Compound [I-8] can be obtained by intramolecular cyclization
of compound [25].
[0888] For example, when desired Q.sup.12 is --O--, Compound [I-8]
can be obtained by etherification of compound [25] wherein
R.sup.c12 is --OH and R.sup.c6 is HO-- using Mitsunobu
reaction.
[0889] In the following, examples of reaction for each desired
Q.sup.12 are shown in the form of a Table. TABLE-US-00002 TABLE 1-2
Desired Q.sup.12 --R.sup.c12 R.sup.c6-- Reaction --OCO-- --OH
HOOC-- esterification or --COO-- --COOH HO-- amidation by --CONH--
--COOH H.sub.2N-- reaction in the --NHCO-- --NH.sub.2 HOOC--
presence of condensing agent, reaction as acid halide, Mitsunobu
reaction and the like. --NHCOO-- --NH.sub.2 HO-- amidation with
--OCONH-- --OH H.sub.2N-- carbodiimidazole, --NHCONH-- --NH.sub.2
H.sub.2N-- COCl.sub.2. --NHSO.sub.2NH-- --NH.sub.2 H.sub.2N--
reaction with SO.sub.2Cl.sub.2. --NHSO.sub.2-- --OH
H.sub.2NO.sub.2S-- reaction in the --O-- --OH HO-- presence of
--S-- --OH HS-- condensing agent or by Mitsunobu reaction. --O--
--Hal.sup.2, HO-- alkylation in the --S-- --OMs, --OTs HS--
presence of a base. --CH.dbd.N-- --CHO H.sub.2N-- imine formation
--N.dbd.CH-- --NH.sub.2 HOC-- with amine and aldehyde.
[0890] Compounds [I-2], [I-3], [I-4] and [I-5] can be obtained from
compound [I-8] in the same manner as in Production Method 1, Step 6
or Step 7. Production Method 2-1 ##STR280## wherein R.sup.c13 and
R.sup.c14 are the same or different and each is hydroxyl-protecting
group, and other symbols are as defined above. Step 1
[0891] Compound [27] can be obtained by reacting compound [10] with
commercially available compound [26] or compound [26] obtained by a
conventional method, in the same manner as in Production Method
1-2, Step 2.
Step 2
[0892] Compound [29] can be obtained by reacting compound [27] with
compound [28] obtained by a conventional method or in the same
manner as in Reference Example 1, in the same manner as in
Production Method 1-1.
Step 3
[0893] Compound [30] can be obtained by reacting compound [10] with
compound [28], in the same manner as in Production Method 1-1.
Step 4
[0894] Compound [29] can be obtained by reacting compound [30] with
compound [26], in the same manner as in Production Method 1-2, Step
2.
Step 5
[0895] Compound [31] can be obtained by removing
hydroxyl-protecting group of compound [29] by a conventional
method.
[0896] As the hydroxyl-protecting group, tert-butyldimethylsilyl
group, acetyl group, benzyl group, methoxymethyl group,
methoxyethoxymethyl group, 2-tetrahydropyranyl group and the like
can be mentioned.
[0897] For example, when R.sup.c13 and R.sup.c14 are
methoxyethoxymethyl group or 2-tetrahydropyranyl group,
deprotection is conducted by a method such as treatment with
hydrochloric acid at room temperature in a mixed solvent of
tetrahydrofuran and methanol and the like.
[0898] In addition, when R.sup.c13 and R.sup.c14 are benzyl groups,
deprotection is conducted by a method such as treatment with a
palladium catalyst at room temperature in a mixed solvent of
tetrahydrofuran and methanol under a hydrogen atmosphere, treatment
under acidic conditions of hydrobromide/acetic acid and the like,
or reaction with an acid such as hydrochloric acid, sulfuric acid,
hydrobromic acid and the like in an acetic acid solvent, and the
like.
Step 6
[0899] Compound [I-9] can be obtained by Mitsunobu reaction using
compound [31] in a solvent such as DMF, acetonitrile, THF and the
like, using triphenylphosphine-diethyl azodicarboxylate,
triphenylphosphine-diisopropyl azodicarboxylate and the like.
[0900] In addition, compound [I-9] can be also obtained by
mesylation, tosylation, trifluoromethylsulfonylation of hydroxyl
group of compound [31], followed by reaction in the presence of a
strong base such as sodium hydride, potassium hydride and the like.
Production Method 3 ##STR281## wherein Q.sup.13 is --OCO--,
--OCONH--, --NHCO--, --NHCOO--, --NHCONH-- or --NHSO.sub.2NH--,
R.sup.c15 is --NH.sub.2 or --OH, R.sup.c16 is --OH, --NH.sub.2,
--COOH or a protected group thereof, R.sup.c17 is --OH, --NH.sub.2
or --COOH, d' is an integer of 1 to 4, and other symbols are as
defined above. Step 1
[0901] When R.sup.c15 is --NH.sub.2, Compound [32] can be obtained
from compound [10] by a method described in Synlett, (2), 222-225,
2001.
[0902] When R.sup.c15 is --OH, Compound [32] can be obtained from
compound [10] by a method described in Heterocycles, 46, 91-94,
1997.
Step 2
[0903] Compound [34] can be obtained by reacting compound [32] with
compound [33] in the same manner as in Production Method 1-1.
Step 3
[0904] When R.sup.c16 is a protected group, Compound [35] can be
obtained from compound [34] by deprotection by a conventional
method.
Step 4
[0905] When R.sup.c17 is --OH, Compound [36] can be obtained by
halogenation by a conventional method.
Step 5
[0906] Compound [I-10] can be obtained by intramolecular
cyclization of compound [36] in the same manner as in Production
Method 1-2, Step 2.
Step 6
[0907] Compound [I-11] can be obtained by intramolecular
cyclization of compound [35].
[0908] For example, when desired Q.sup.13 is --OCO--, Compound
[I-11] can be obtained from compound [35], wherein R.sup.c15 is
--OH and R.sup.c17 is HOOC--, by esterification by a conventional
method.
[0909] In the following, examples of reaction for each desired
Q.sup.13 are shown in the form of a Table. TABLE-US-00003 TABLE 1-3
Desired Q.sup.13 --R.sup.c15 R.sup.c17-- Reaction --OCO-- --OH
HOOC-- esterification or --NHCO-- --NH.sub.2 HOOC-- amidation by
reaction in the presence of condensing agent, reaction an acid
halide, Mitsunobu reaction and the like. --NHCOO-- --NH.sub.2 HO--
carbamoylation --OCONH-- --OH H.sub.2N-- with --NHCONH-- --NH.sub.2
H.sub.2N-- carbodiimidazole, COCl.sub.2. --NHSO.sub.2NH--
--NH.sub.2 H.sub.2N-- reaction with SO.sub.2Cl.sub.2.
Step 7
[0910] When Q.sup.13 is --NHCO--, Compound [I-12] can be obtained
by reducing compound [I-11] by a conventional method. Production
Method 4 ##STR282## wherein R.sup.c18 is --OH, --NH.sub.2 or --SH,
Q.sup.14 is --O--, --NH-- or --S--, and other symbols are as
defined above. Step 1
[0911] Compound [I-14] can be obtained by reacting compound [37]
obtained in the same manner as in Production Method 1-1 with
compound [38] in a solvent such as ethanol, DMF, DMA, acetone,
acetonitrile, THF, toluene, water and the like, in the presence of
a base.
[0912] Here, Hal.sup.2 is preferably bromine atom.
[0913] As a base, a weak base such as sodium carbonate, potassium
carbonate and the like is preferable.
Step 2
[0914] Compound [40] can be obtained by reacting compound [37] with
compound [39] in a solvent such as ethanol, DMF, DMA, acetone,
acetonitrile, THF, toluene, water and the like, in the presence of
a base.
[0915] Here, Hal.sup.1 and Hal.sup.2 are each preferably bromine
atom and chlorine atom.
[0916] As a base, a weak base such as sodium carbonate, potassium
carbonate and the like is preferable.
Step 3
[0917] Compound [I-14] can be obtained by cyclization of compound
[40] in the same manner as in Production Method 1-2, Step 2.
[0918] As a base, a strong base such as sodium hydride, potassium
hydroxide, potassium tert-butoxide and the like is preferable.
Step 4
[0919] When Q.sup.14 is --S--, compounds [I-15] and [I-16] can be
obtained by oxidation of compound [I-14] by a conventional method.
Production Method 5 ##STR283## wherein each symbol is as defined
above. Step 1
[0920] Compound [42] can be obtained by reacting compound [41]
obtained by a conventional method or in the same manner as in
Reference Example 2 with compound [23] obtained by a conventional
method.
Step 2
[0921] Compound [43] can be obtained by halogenation of compound
[42] by a conventional method.
Step 3
[0922] Compound [24] can be obtained by reacting compound [43] with
compound [11].
Step 4-Step 7
[0923] Compounds [I-8], [I-2], [I-3], [I-4] and [I-5] can be
obtained from compound [24] in the same manner as in Production
Method 2. Production Method 5-1 ##STR284## wherein each symbol is
as defined above. Step 1
[0924] Compound [44] can be obtained by reacting compound [41] and
compound [21] in the same manner as in Production Method 1-2, Step
2.
Step 2
[0925] Compound [45] can be obtained by halogenation of compound
[44] in the same manner as in Reference Example 3, Step 2.
Step 3
[0926] Compound [I-17] can be obtained by reacting compound [45]
with compound [46] in the same manner as in Production Method
1-1.
Step 4
[0927] Compound [I-18] can be obtained by reducing compound [I-17]
in the same manner as in Production Method 1-2, Step 3. Production
Method 5-2 ##STR285## wherein each symbol is as defined above. Step
1
[0928] Compound [45] can be obtained by reacting compound [10] with
compound [21] in the same manner as in Production Method 1-2, Step
2.
Step 2
[0929] Compound [I-17] can be obtained by reacting compound [45]
with compound [46] in the same manner as in Production Method
1-1.
Step 3
[0930] Compound [I-18] can be obtained by reducing compound [I-17]
in the same manner as in Production Method 1-2, Step 3. Production
Method 6 ##STR286## wherein, when d is 0, Q.sup.15 is --S--,
--SO--, --OCO--, --OCONH--, --NHCO--, --NHSO.sub.2--, --NHCOO--,
--COO--, --CONH--, --SO.sub.2NH--, --NHCONH--, --NHSO.sub.2NH--,
--CH.dbd.CH-- or --CO--, when d is an integer of 1 to 4, Q.sup.15
is, in addition to the above-mentioned, --O-- or --NH--, Q.sup.16
is --CO--, --SO.sub.2--, --COO--, --CONH-- or --SO.sub.2NH--, b' is
an integer of 1 to 4, and other symbols are as defined above. Step
1
[0931] Compounds [50], [51] and [52] can be obtained by reacting
compound [41] with compounds [47], [48] and [49] obtained by a
conventional method, respectively, in the same manner as in
Production Method 1-2, Step 2.
Step 2
[0932] Compounds [I-19], [I-20] and [I-21] can be obtained by
reacting compounds [50], [51] and [52], respectively, in a solvent
such as DME, DMF, DMA, 1,4-dioxane and the like, in the presence of
a base such as sodium carbonate, potassium acetate, sodium acetate
and the like and a palladium catalyst such as
tetrakis(triphenylphosphine)palladium,
bis(triphenylphosphine)palladium(II) dichloride, palladium
acetate-triphenylphosphine and the like, at room temperature or
under heating. Production Method 7 ##STR287## ##STR288## wherein
R.sup.e2' is a group selected from group F, and other symbols are
as defined above. Step 1
[0933] Compounds [53] and [54] can be obtained by treating
compounds [I-22] and [I-23] obtained by the above-mentioned
Production Method, respectively, with P.sub.2S.sub.5 or a Lawesson
reagent.
Step 2
[0934] Compounds [I-24] and [I-25] can be obtained by reacting
compounds [55] with compounds [53] and [54], respectively.
Step 3
[0935] Compounds [I-26] and [I-27] can be obtained by reacting
compound [56] with compounds [I-24] and [I-25], respectively.
Production Method 8 ##STR289## wherein R.sup.c19 is
amino-protecting group, ring A'' is ring A wherein G.sup.6 is
nitrogen atom, and other symbols are as defined above. Step 1
[0936] The Compound [58] can be obtained by reacting compound [10]
with compound [57] obtained by a conventional method or in the same
manner as in Reference Example 1 in the same manner as in
Production Method 1-1.
Step 2
[0937] Compound [60] can be obtained by reacting compound [58] with
compound [59] obtained by a conventional method in the same manner
as in Production Method 4, Step 3.
[0938] Here, Hal.sup.1 and Hal.sup.2 are each preferably bromine
atom or chlorine atom.
Step 3
[0939] Compound [61] can be obtained by removing amino-protecting
group of compound [60] by a conventional method.
[0940] As the amino-protecting group, benzoyl group, tert-butyl
group, tert-butylcarbonyl group, tert-butoxycarbonyl group and the
like can be mentioned.
[0941] For example, when R.sup.c19 is tert-butoxycarbonyl group,
deprotection is conducted by a method such as treatment with a
solution of hydrochloric acid in ethyl acetate at room temperature
in ethyl acetate or methanol solution; treatment with hydrochloric
acid at room temperature in tetrahydrofuran; treatment with
hydrochloric acid-1,4-dioxane at room temperature in methanol;
treatment with trifluoroacetic acid in chloroform solution and the
like.
Step 4
[0942] Compound [I-28] can be obtained by cyclization of compound
[61] in the same manner as in Production Method 4, Step 3.
REFERENCE EXAMPLE 4
[0943] ##STR290## ##STR291## wherein each symbol is as defined
above. Step 1
[0944] Compound [63] can be obtained by introducing cyano group
into compound [62] obtained by a conventional method or the method
described in WO03/010140, by a conventional method.
[0945] For example, Compound [63] can be obtained by reacting
compound [62] with trimethylsilyl cyanide under heating in a
solvent such as acetonitrile, in the presence of a base such as
triethylamine and the like.
Step 2
[0946] Compound [64] can be obtained by reacting compound [63] with
compound [26] in the same manner as in Production Method 1-2, Step
2.
Step 3
[0947] Compound [65] can be obtained by reacting cyano group of
compound [64] using acid chloride such as acetyl chloride and the
like in an alcohol solvent (R.sup.c4--OH) that becomes a source of
R.sup.c4, such as ethanol and the like under reflux.
Step 4
[0948] Compound [66] can be obtained by halogenation of compound
[65] in the same manner as in Reference Example 3, Step 2.
Step 5
[0949] Compound [67] can be obtained by reacting compound [63] with
compound [21] in the same manner as in Production Method 1-2, Step
2.
Step 6
[0950] Compound [68] can be obtained from compound [67] in the same
manner as in the above-mentioned Step 3.
Step 7
[0951] Compound [69] can be obtained by halogenation of compound
[68] in the same manner as in Reference Example 3, Step 2.
[0952] Compounds [66] and [69] obtained in this Production Method
can be used in the above-mentioned Production Methods to give the
final compound. Production Method 9 ##STR292## wherein each symbol
is as defined above. Step 1
[0953] Compound [71] can be obtained by reacting commercially
available compound [70] or compound [70] obtained by a conventional
method with compound [4] in a mixed solvent of THF-acetic acid, in
the presence of a reducing agent such as a borohydride (e.g.,
sodium borohydride, sodium cyanoborohydride, sodium
triacetoxyborohydride and the like) and the like.
Step 2
[0954] Compound [73] can be obtained by treating compound [72]
obtained in the same manner as in Step 1, with sodium nitrite in a
mixed solvent of acetic acid-water.
Step 3
[0955] Compound [74] can be obtained by reducing compound [73] by a
conventional method.
Step 4
[0956] Compound [I-291 can be obtained by reacting compound [74]
with compound [75] obtained by a conventional method, in the same
manner as in J. Med. Chem., 42 (15), 2902-2919, 1999. Production
Method 10 ##STR293## wherein R.sup.2' is C.sub.1-6 alkyl group
optionally substituted by 1 to 3 substituents selected from group E
and the like, R.sup.c20 is carboxyl-protecting group, ring D.sup.1'
is that containing NH as a component constituting a ring such as
piperidine, piperazine, pyrrolidine, morpholine, thiomorpholine,
azepane and the like, u1' is an integer of 1 to 6, and other
symbols are as defined above. Step 1
[0957] Compound [I-30] can be obtained by reacting compound [76]
obtained by the above-mentioned Production Method with compound
[77] in a solvent such as DMF, DMSO, acetonitrile, ethanol, THF and
the like or a mixed solvent thereof, in the presence of a base such
as sodium hydride, sodium hydroxide, potassium hydroxide, potassium
carbonate, sodium ethoxide, potassium tert-butoxide and the like,
under ice-cooling to under heating. In addition, potassium iodide
or tetrabutylammonium iodide may be used to increase
reactivity.
[0958] In this Production Method, R.sup.2' may be any group as long
as it is bonded to nitrogen atom of fused ring via carbon atom,
wherein C.sub.1-6 alkyl group optionally substituted by 1 to 3
substituents selected from group E, as well as, for example,
L.sup.2 of -L.sup.2-ring D.sup.2-L.sup.1-ring D.sup.1 and
-L.sup.2-CH.sub.2-L.sup.1-ring D.sup.1, and L.sup.1 of
-L.sup.1-(CH.sub.2).sub.u-L.sup.3-(CH.sub.2).sub.v-ring D.sup.1 and
-L.sup.1-ring D.sup.1 may be C.sub.1-6 alkylene, C.sub.2-6
alkenylene, --(CH.sub.2).sub.u1'--O--(CH.sub.2).sub.v1--,
--(CH.sub.2).sub.u1'--S--(CH.sub.2).sub.v1--,
--(CH.sub.2).sub.u1'--NR.sup.L1--(CH.sub.2).sub.v1--,
--(CH.sub.2).sub.u1'--CO--(CH.sub.2).sub.v1--,
--(CH.sub.2).sub.u1'--CONR.sup.L2--(CH.sub.2).sub.v1--,
--(CH.sub.2).sub.u1'--NR.sup.L2CO.sub.2--(CH.sub.2).sub.v1--,
--(CH.sub.2).sub.u1'--NR.sup.2CONR.sup.L3--(CH.sub.2).sub.v1--,
--(CH.sub.2).sub.u1'--NR.sup.L2CO(CH.sub.2).sub.v1--,
--(CH.sub.2).sub.u1'--NR.sup.2SO.sub.2--(CH.sub.2).sub.v1--,
--(CH.sub.2).sub.u1'--SO.sub.2--(CH.sub.2).sub.v1--,
--(CH.sub.2).sub.u1'--SO.sub.2NR.sup.L2 (CH.sub.2).sub.v1-- or
--(CH.sub.2).sub.u1--N.sup.+R.sup.L2R.sup.L2'--(CH.sub.2).sub.v1--
wherein each symbol is as defined above.
[0959] In addition, Hal.sup.2-R.sup.2' may be Hal-ring D.sup.1 or
Hal-ring D.sup.2-L.sup.1-ring D.sup.1.
Step 2
[0960] Compound [79] can be obtained by reacting compound [76] with
compound [78] in the same manner as in Step 1 above.
Step 3
[0961] Compound [I-31] can be obtained by reacting compound [79]
with compound [80] in the same manner as in Production Method 1-2,
Step 1.
[0962] Here, R.sup.c20, which is a carboxyl-protecting group of
compound [79], may be deprotected by a conventional method and then
reacted with compound [80].
[0963] For example, when R.sup.c20 is tert-butyl group,
deprotection can be conducted by treatment with trifluoroacetic
acid in a solvent such as methylene chloride, chloroform and the
like.
Step 4
[0964] Compound [I-32] can be obtained by reducing compound [I-31]
in the same manner as in Production Method 1-2, Step 3. Production
Method 11 ##STR294## wherein each symbol is as defined above. Step
1
[0965] Compound [I-35] can be obtained by deprotection of
carboxyl-protecting group R.sup.c20 of compound [I-34] obtained by
the above-mentioned Production Method, by a conventional
method.
[0966] Here, a reaction under conditions free from deprotection of
R.sup.c4 is preferable. For example, when R.sup.c4 is methyl group
or ethyl group and R.sup.c20 is tert-butyl group, deprotection can
be conducted by treatment with trifluoroacetic acid in a solvent
such as methylene chloride, chloroform and the like.
Step 2
[0967] Compounds [I-36] and [I-37] can be obtained by reacting
compound [I-35] with compounds [81] and [80], respectively, in the
same manner as in Production Method 1-2, Step 1. Production Method
12 ##STR295## wherein ring D.sup.6' is that containing NH as a
component constituting a ring such as piperidine, piperazine,
pyrrolidine and the like, and each symbol is as defined above. Step
1
[0968] Compound [I-39] can be obtained by hydrolysis of compound
[I-38] obtained in the same manner as in the above-mentioned
Production Methods, in a solvent such as methanol, ethanol, THF,
dioxane, water and the like, or a mixed solvent thereof under basic
conditions of sodium hydroxide, potassium hydroxide, potassium
carbonate, lithium hydroxide and the like or acidic conditions of
hydrochloric acid, sulfuric acid and the like.
Step 2
[0969] Compounds [I-40], [I-78] and [I-79] can be obtained by
reacting compound [I-39] with compounds [82], [124] and [125],
respectively, in the same manner as in Production Method 1-2, Step
1.
[0970] For compounds [82], [124] and [125], commercially available
products or compounds obtained by conventional methods or compounds
obtained by the methods described in WO02/04425, WO03/007945 and
WO03/010141 can be used.
Production Method 13
[0971] In this Production Method, conversion of the substituents
R.sup.1 and R.sup.3 on the fused ring is shown. This Production
Method is applicable irrespective of the position of
substitution.
Production Method 13-1
[0972] Conversion of cyano group to substituted amidino group
##STR296## wherein each symbol is as defined above.
[0973] The compound [I-41] obtained in the same manner as in the
above-mentioned Production Method is reacted with hydroxylamine in
a solvent such as water, methanol, ethanol, THF, DMF and the like
to give compound [I-42]. When a salt of hydroxylamine such as
hydrochloride and the like is used, the reaction is carried out in
the presence of a base such as sodium hydrogen carbonate, sodium
hydroxide, triethylamine and the like.
Production Method 13-2
[0974] Conversion of sulfonic acid ester moiety to sulfonic acid
##STR297## wherein R.sup.1 is C.sub.1-6 alkyl, and other symbols
are as defined above.
[0975] The compound [I-43] obtained in the same manner as in the
above-mentioned Production Method is reacted with iodide salt such
as sodium iodide, lithium iodide and the like, bromide salt such as
sodium bromide, tetrabutylammonium bromide and the like, amine such
as pyridine, trimethylamine, triazole and the like, phosphine such
as triphenylphosphine and the like in a solvent such as DMF, DMSO,
acetonitrile, methanol, ethanol, water and the like with heating to
give compound [I-44].
Production Method 14
[0976] This Production Method relates to conversion of the
substituent X on the ring A.
Production Method 14-1
[0977] Conversion of hydroxyl group to ether ##STR298## wherein
R.sup.c22 is hydroxyl-protecting group such as acetyl, benzyl and
the like, R.sup.c23 is halogen atom such as chlorine atom, bromine
atom and the like, hydroxyl or leaving group such as sulfonate
(e.g., mesyloxy, tosyloxy and the like), --B(OR.sup.c2)(OR.sup.c3)
and the like, R.sup.c24 is alkyl optionally substituted by 1 to 3
substituents selected from group A corresponding to R.sup.a11,
J.sup.1 is a bond, C.sub.1-6 alkylene, C.sub.2-6 alkenylene or
*--(CH.sub.2).sub.m--Y.sup.2--(CH.sub.2).sub.n--, wherein * shows
the side to be bonded to R.sup.c23, m is an integer of 1 to 6, and
other symbols are as defined above. Step 1
[0978] Compound [I-46] can be obtained by deprotection of compound
[I-45] obtained in the same manner as in the above-mentioned
Production Method, by a conventional method.
[0979] For example, when R.sup.c22 is acetyl group, compound [I-45]
is hydrolyzed, in a solvent such as methanol, ethanol, THF,
1,4-dioxane and the like, or a mixed solvent thereof, or a mixed
solvent of such solvent and water, under basic conditions of sodium
hydroxide, potassium hydroxide, potassium carbonate, lithium
hydroxide, sodium methoxide, sodium ethoxide and the like or acidic
conditions of hydrochloric acid, sulfuric acid and the like to give
compound [I-46].
[0980] When R.sup.c22 is benzyl group, compound [I-45] is subjected
to catalytic reduction in a solvent such as methanol, ethanol, THF,
ethyl acetate, acetic acid, water and the like in the presence of
palladium carbon, or by reacting with an acid such as hydrobromic
acid and the like in a solvent such as acetic acid to give compound
[I-46].
Step 2
[0981] When R.sup.c23 of compound [83] is halogen atom, --OMs or
--OTs, compound [I-46] is reacted with compound [83] in a solvent
such as DMF, DMSO, acetonitrile, ethanol, THF and the like in the
presence of a base such as sodium hydride, sodium hydroxide,
potassium hydroxide, potassium carbonate, sodium ethoxide,
potassium t-butoxide and the like at room temperature or with
heating to give compound [I-47]. The reaction may be accelerated by
adding sodium iodide or potassium iodide.
[0982] When R.sup.c23 of compound [83] is hydroxyl group, the
hydroxyl group of compound [83] is converted to halogen atom with
thionyl chloride, phosphorus trichloride, phosphorus tribromide,
carbon tetrabromide-triphenylphosphine, N-bromosuccinimide and the
like and reacted with compound [I-46] by the aforementioned method
to give compound [I-47]. In this case, compound [I-46] may be
subjected to Mitsunobu reaction with compound [83] in a solvent
such as DMF, acetonitrile, THF and the like using
triphenylphosphine-diethyl azodicarboxylate and the like to give
compound [I-47].
[0983] For example, when J.sup.1 is a bond and R.sup.c23 is
--B(OR.sup.c2)(OR.sup.c3), compound [I-46] is reacted with compound
[83] in a solvent such as chloroform, methylene chloride, THF,
toluene, 1,4-dioxane and the like in the presence of a base such as
copper acetate, pyridine, triethylamine and the like to give
compound [I-47].
[0984] The Compound [I-48] can be obtained in the same manner as
above from compound [I-46] and compound [84].
Production Method 14-2
[0985] Conversion of nitro to substituted amino group ##STR299##
wherein R.sup.c25 is C.sub.1-6 alkyl, J.sup.2 is
--(CH.sub.2).sub.n-- or
*--(CH.sub.2).sub.m--Y.sup.2--(CH.sub.2).sub.n-- and m is an
integer of 1 to 6, wherein * shows the side to be bonded to
R.sup.c23, J.sup.3 is
*--CO--(CH.sub.2).sub.m--Y.sup.2--(CH.sub.2).sub.n--,
*--CO.sub.2--(CH.sub.2).sub.m--Y.sup.2--(CH.sub.2).sub.n--,
*--CONR.sup.y3--(CH.sub.2).sub.m--Y.sup.2--(CH.sub.2).sub.n--,
*--SO.sub.2--(CH.sub.2).sub.m--Y.sup.2--(CH.sub.2).sub.n--,
*CO--(CH.sub.2).sub.n--, *--CO.sub.2--(CH.sub.2).sub.n--,
*--CONR.sup.y3--(CH.sub.2).sub.n-- or
*--SO.sub.2--(CH.sub.2).sub.n--, wherein * shows the side to be
bonded to Hal, and other symbols are as defined above. Step 1
[0986] The compound [I-49] obtained in the same manner as in the
above-mentioned Production Method, is hydrogenated in a solvent
such as methanol, ethanol, THF, ethyl acetate, acetic acid, water
and the like in the presence of a catalyst such as palladium
carbon, palladium hydroxide, platinum oxide, Raney nickel and the
like at room temperature or with heating to give compound [I-50].
In addition, compound [I-49] is reduced with a reducing agent such
as zinc, iron, tin(II) chloride, sodium sulfite and the like, or
reacted with hydrazine in the presence of iron(III) chloride to
give compound [I-50]. The compound [I-50] can be also obtained by
reacting compound [I-49] with sodium hydrosulfite under alkaline
conditions.
Step 2
[0987] The compound [I-50] is alkylated with compound [85] in the
same manner as in Step 2 of Production Method 14-1 to give compound
[I-51].
Step 3
[0988] When J.sup.3 of compound [86] is
*--CO--(CH.sub.2).sub.m--Y.sup.2--(CH.sub.2).sub.n--,
*--CO.sub.2--(CH.sub.2).sub.m--Y.sup.2--(CH.sub.2).sub.n--,
*--CONR.sup.y3--(CH.sub.2).sub.m--Y.sup.2--(CH.sub.2).sub.n--,
*--CO--(CH.sub.2).sub.n--, *--CO.sub.2--(CH.sub.2).sub.n-- or
*--CONR.sup.y3--(CH.sub.2).sub.n--, compound [I-50] is reacted with
compound [86] in a solvent such as DMF, acetonitrile, THF,
chloroform, ethyl acetate, methylene chloride, toluene and the like
in the presence of a base such as triethylamine, potassium
carbonate, pyridine and the like, or in an amine solvent such as
pyridine in the presence of acetic acid and sodium acetate in an
equivalent ratio to give compound [I-52].
[0989] When J.sup.3 of compound [86] is
*--SO.sub.2--(CH.sub.2).sub.m--Y.sup.2--(CH.sub.2).sub.n-- or
*--SO.sub.2--(CH.sub.2).sub.n--, compound [I-50] is sulfonylated
with compound [86] in the same manner as above to give compound
[I-52].
[0990] The compound [I-50] is acylated with compound [87] in the
same manner as above to give compound [I-53].
[0991] This Production Method is applied in the same manner as
above to give disubstituted compounds (tertiary amine) of compound
[I-51], compound [I-52] and compound [I-53].
Production Method 14-3
[0992] Conversion of carboxylic acid ester moiety to amide
##STR300## wherein J.sup.4 is --(CH.sub.2).sub.n-- or
#--(CH.sub.2).sub.m--Y.sup.2--(CH.sub.2).sub.n-- wherein # shows
the side to be bonded to amine, and other symbols are as defined
above.
[0993] The carboxylic acid compound [I-54] obtained in the same
manner as in the above-mentioned Production Method is condensed
with amine compound [88] in a solvent such as DMF, acetonitrile,
THF, chloroform, ethyl acetate, methylene chloride, toluene and the
like using a condensing agent such as dicyclohexylcarbodiimide,
1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride,
diphenylphosphoryl azide and the like and, where necessary, adding
N-hydroxysuccinimide, 1-hydroxybenzotriazole and the like to give
amide compound [I-55]. Alternatively, amide compound [I-55] can be
obtained from compound [I-54] as follows. The carboxylic acid
compound [I-54] is converted to an acid halide with thionyl
chloride, oxalyl chloride and the like, or to an active ester of
carboxylic acid compound [I-54] (e.g., converting to a mixed acid
anhydride with ethyl chlorocarbonate and the like), which is then
reacted with amine compound [88] in the presence of a base such as
triethylamine, potassium carbonate, pyridine,
4-(dimethylamino)pyridine and the like, to give amide compound
[I-55].
[0994] Compound [I-56] can be obtained by reacting carboxylic acid
compound [I-54] with amine compound [89] in the same manner as
above.
Production Method 15
[0995] In this Production Method, additional substituent(s) is(are)
introduced into ring B.
Production Method 15-1
[0996] Direct bonding of ring Z'' to ring B ##STR301## wherein ring
Z''-M is aryl metal compound, ring Z'' moiety is optionally
substituted C.sub.6-14 aryl or optionally substituted heterocyclic
group corresponding to substituent Z, and the metal moiety contains
boron, zinc, tin, magnesium and the like, such as phenylboronic
acid and 4-chlorophenylboronic acid, w'' is 0, 1 or 2, and other
symbols are as defined above.
[0997] The compound [I-57] obtained in the same manner as in the
above-mentioned Production Method is reacted with aryl metal
compound [90] in a solvent such as DMF, acetonitrile,
1,2-dimethoxyethane, THF, toluene, water and the like in the
presence of a palladium catalyst such as
tetrakis(triphenylphosphine)-palladium,
bis(triphenylphosphine)palladium(II) dichloride, palladium
acetate-triphenylphosphine and the like, a nickel catalyst such as
nickel chloride, 1,3-bis(diphenylphosphino)-propane nickel(II)
chloride and the like, and a base such as potassium carbonate,
potassium hydrogen carbonate, sodium hydrogen carbonate, potassium
phosphate, triethylamine, potassium fluoride, sodium hydrogen
phosphate, cesium carbonate and the like at room temperature or
with heating, to give compound [I-58].
Production Method 15-2
[0998] Conversion of hydroxyl group to ether ##STR302## wherein
R.sup.c26 is --R.sup.d1 or --(CH.sub.2).sub.p--COR.sup.d25
corresponding to substituent Z, and other symbols are as defined
above.
[0999] The compound [I-59] obtained in the same manner as in the
above-mentioned Production Method is reacted with compound [91] in
the same manner as in Step 2 of Production Method 14-1 to give
compound [I-60].
Production Method 15-3
[1000] Synthesis in advance of ring B part such as compound [83] in
Production Method 14-1 ##STR303## wherein R.sup.c27 leaving group
such as chlorine atom, bromine atom, iodine atom,
trifluoromethanesulfonyloxy, p-toluenesulfonyloxy,
methanesulfonyloxy and the like, R.sup.c28 is formyl, carboxyl or
carboxylic acid ester such as methoxycarbonyl, ethoxycarbonyl,
tert-butoxycarbonyl and the like, and other symbols are as defined
above. Step 1
[1001] Commercially available compound [92] or compound [92]
obtained by a conventional method is reacted with aryl metal
compound [90] in the same manner as in Production Method 15-1 to
give compound [93].
Step 2
[1002] The compound [93] obtained in the same manner as in the
above-mentioned Production Method is reduced according to a
conventional method to give compound [94].
[1003] For example, compound [93] is reacted in a solvent such as
methanol, ethanol, THF and the like in the presence of a reducing
agent such as lithium aluminum hydride, sodium borohydride and the
like under cooling to heating to give compound [94].
Step 3
[1004] The compound [94] obtained in the same manner as in the
above-mentioned Production Method is reacted in a solvent such as
1,4-dioxane, diethyl ether, THF, methylene chloride, chloroform,
toluene and the like with a halogenating agent, such as phosphorus
halides (e.g., phosphorus pentachloride, phosphorus tribromide and
the like), thionyl chloride and the like, to give compound [95].
For an accerelated reaction, the reaction may be carried out in the
presence of a tertiary amine such as triethylamine, DMF, pyridine
and the like, or under heating.
Step 4
[1005] The compound [94] or [95] obtained in the same manner as in
the above-mentioned Production Method is reacted with compound
[I-46] in the same manner as in Step 2 of Production Method 14-1 to
give compound [I-61]. Production Method 15-4 ##STR304## wherein M'
is a metal such as magnesium, lithium, zinc and the like, and other
symbols are as defined above. Step 1
[1006] Commercially available compound [96] or compound [96]
obtained by a conventional method is converted to aryl metal
reagent by a conventional method to give compound [97].
[1007] For example, when M' is magnesium, magnesium is reacted with
compound [96] in a solvent such as THF, diethyl ether, benzene,
toluene and the like, preferably THF, from cooling to heating,
preferably at -100.degree. C. to 100.degree. C. to give compound
[97].
Step 2
[1008] The compound [97] obtained in the same manner as in the
above-mentioned Production Method is reacted with compound [98] to
give compound [99].
[1009] The compound [97] is reacted with compound [98] in a solvent
such as diethyl ether, benzene, toluene, THF and the like,
preferably THF, from cooling to room temperature, preferably at
-100.degree. C. to 30.degree. C. to give compound [99].
Step 3
[1010] The compound [99] obtained in the same manner as in the
above-mentioned Production Method is halogenated in the same manner
as in Step 3 of Production Method 15-3 to give compound [100].
[1011] The compound [99] is reacted with thionyl chloride and
pyridine preferably in toluene solvent to give compound [100].
[1012] When compound [100] is symmetric, namely, when the ring
B-(Z)w moiety and the ring B'-(Z')w' moiety are the same, compound
[97] is reacted with formate such as methyl formate, ethyl formate
and the like, preferably ethyl formate, in a solvent such as
diethyl ether, benzene, toluene, THF and the like, preferably THF,
from cooling to room temperature, preferably at -100.degree. C. to
30.degree. C., to give compound [100].
Production Method 15-5
[1013] Method including steps to introduce a protecting group into
a functional group ##STR305## ##STR306## wherein R.sup.c29 is
carboxyl-protecting group such as tert-butyl and the like, and
other symbols are as defined above. Step 1
[1014] Commercially available compound [101] or compound [101]
obtained by a known method is protected by a conventional method to
give compound [102].
[1015] For example, when R.sup.c29 is tert-butyl, compound [101] is
converted to acid halide with thionyl chloride, oxalyl chloride and
the like in a solvent such as THF, chloroform, methylene chloride,
toluene and the like, and reacted with potassium tert-butoxide or
di-tert-butyl dicarbonate to give compound [102].
Step 2
[1016] The methyl group of compound [102] obtained in the same
manner as in the above-mentioned Production Method is converted to
bromomethyl with N-bromosuccinimide and N,N'-azobisisobutyronitrile
and reacted with compound [I-62] in the same manner as in Step 2 of
Production Method 14-1 to give compound [I-63].
Step 3
[1017] The compound [I-63] obtained in the same manner as in the
above-mentioned Production Method is reacted with aryl metal
compound [90] in the same manner as in Production Method 15-1 to
give compound [I-64].
Step 4
[1018] The R.sup.c29 of the compound [I-64] obtained in the same
manner as in the above-mentioned Production Method is removed by a
conventional method to give compound [I-65].
[1019] The carboxyl-protecting group can be removed by a
conventional deprotection method according to the protecting group.
In this Step, the conditions free from reaction of R.sup.c4 are
preferable. For example, when R.sup.c29 is tert-butyl, compound
[I-64] is treated with trifluoroacetic acid in a solvent such as
methylene chloride, chloroform and the like to give compound
[I-65]. In addition, compound [I-64] may be treated with hydrogen
chloride or hydrochloric acid in a solvent such as ethyl acetate,
dioxane, alcohol and the like to give compound [I-65].
Step 5
[1020] The compound [I-65] obtained in the same manner as in the
above-mentioned Production Method is subjected to amide
condensation with compound [103] in the same manner as in
Production Method 14-3 to give compound [I-66].
Step 6
[1021] The compound [I-66] obtained in the same manner as in the
above-mentioned Production Method is deprotected in the same manner
as in Step 1 of Production Method 12 to give compound [I-67].
[1022] As used herein, R.sup.c4 is preferably a protecting group
that does not react during the Step 1 through Step 5 but removed in
this Step.
[1023] For example, when R.sup.c4 is methyl, compound [I-66] is
reacted in an alcohol solvent such as methanol, ethanol,
n-propanol, isopropanol and the like or a mixed solvent of alcohol
solvent and water in the presence of a base such as potassium
carbonate, sodium carbonate, lithium hydroxide, sodium hydroxide,
potassium hydroxide and the like from cooling to heating for
deprotection, followed by acidifying the reaction solution to give
compound [I-67]. Production Method 15-6 ##STR307## wherein g is an
integer of 1 to 5, and other sumbols are as defined above. Step
1
[1024] The compound [I-62] obtained by the above-mentioned
Production Method is reacted with toluene derivative [104] in the
same manner as in Step 2 of Production Method 15-5 to give compound
[I-68].
Step 2
[1025] The compound [I-68] obtained by the above-mentioned
Production Method is reacted with aryl metal compound [90] in the
same manner as in Production Method 15-1 to give compound
[I-69].
Step 3
[1026] The compound [I-69] obtained by the above-mentioned
Production Method is reduced in the same manner as in Step 1 of
Production Method 14-2 to give compound [I-70].
Step 4
[1027] The compound [I-70] obtained by the above-mentioned
Production Method is amide condensed with compound [105] in the
same manner as in Production Method 14-3, which is then subjected
to cyclization in a solvent such as DMF, acetonitrile, THF, toluene
and the like in the presence or absence of a base such as potassium
carbonate, triethylamine, potassium tert-butoxide and the like at
room temperature or with heating, to give compound [I-71].
Step 5
[1028] The compound [I-71] obtained by the above-mentioned
Production Method is deprotected in the same manner as in Step 1 of
Production Method 12 to give compound [I-72]. Production Method
15-7 ##STR308## ##STR309## wherein each symbol is as defined above.
Step 1
[1029] Commercially available compound [106] or compound [106]
obtained by a conventional method is reacted with compound [90] in
the same manner as in Production Method 15-1 to give compound
[107].
Step 2
[1030] The compound [107] obtained in the same manner as in the
above-mentioned Production Method is reduced in the same manner as
in Step 1 of Production Method 14-2 to give compound [108].
Step 3
[1031] The compound [108] obtained in the same manner as in the
above-mentioned Production Method is reduced in the same manner as
in Step 2 of Production Method 15-3 to give compound [109].
Step 4
[1032] The compound [109] obtained in the same manner as in the
above-mentioned Production Method is reacted with compound [105] in
a solvent such as DMF, acetonitrile, THF, chloroform, ethyl
acetate, methylene chloride, toluene and the like to give compound
[110]. To enhance the reaction selectivity for amino group, acetic
acid and sodium acetate may be added in an equivalent ratio.
Step 5
[1033] The compound [110] obtained in the same manner as in the
above-mentioned Production Method is subjected to cyclization in a
solvent such as ethanol, DMF, acetonitrile, THF, toluene, water and
the like in the presence or absence of a base such as potassium
hydroxide, potassium carbonate, triethylamine, potassium
tert-butoxide and the like at room temperature or with heating, to
give compound [111].
Step 6
[1034] The compound [111] obtained in the same manner as in the
above-mentioned Production Method is halogenated in the same manner
as in Step 3 of Production Method 15-3 to give compound [112].
Step 7
[1035] The compound [112] obtained in the same manner as in the
above-mentioned Production Method is reacted in the same manner as
in Step 2 of Production Method 14-1 with compound [I-62] obtained
in the same manner as in the above-mentioned Production Method to
give compound [I-71].
Step 8
[1036] The compound [I-71] obtained in the same manner as in the
above-mentioned Production Method is deprotected in the same manner
as in Step 1 of Production Method 12 to give compound [I-72].
Production Method 15-8 ##STR310## wherein R.sup.N1 and R.sup.N2 are
the same or different and each is hydrogen atom or a group selected
from group F, or R.sup.N1 and R.sup.N2 are linked to form a
heterocycle containing NH such as piperidino group, 1-piperazinyl
group, morpholino group and the like, R.sup.d10, is a group
selected from group F, R.sup.d9' is a C.sub.1-6 alkyl group
optionally substituted by 1 to 3 substituents selected from group
A, and other symbols are as defined above. Step 1
[1037] The compound [I-68] obtained in the same manner as in the
above-mentioned Production Method is reacted with amine compound
[113] in a solvent such as DMSO, DMF, acetonitrile, THF, toluene
and the like in the presence or absence of a base such as potassium
carbonate, triethylamine, potassium tert-butoxide and the like at
room temperature or with heating, to give compound [I-73].
Step 2
[1038] The compound [I-73] is reduced in the same manner as in Step
1 of Production Method 14-2 to give compound [I-74].
Step 3
[1039] The compound [I-74] is reacted with carboxylic acid compound
[114] in the same manner as in Production Method 14-3 to give
compound [I-75].
Step 4
[1040] The compound [I-75] is alkylated with compound [115] in the
same manner as in Step 2 of Production Method 14-1 to give compound
[I-76].
Step 5
[1041] The compound [I-76] is deprotected in the same manner as in
Step 1 of Production Method 12 to give compound [I-77]. Production
Method 15-9 ##STR311## ##STR312## wherein each symbol is as defined
above. Step 1
[1042] Commercially available compound [106] or compound [106]
obtained by a conventional method is reacted with amine compound
[113] in the same manner as in Step 1 of Production Method 15-8 to
give compound [116].
Step 2
[1043] The compound [116] is reduced in the same manner as in Step
1 of Production Method 14-2 to give compound [117].
Step 3
[1044] The compound [117] is reduced in the same manner as in Step
2 of Production Method 15-3 to give compound [118].
Step 4
[1045] The hydroxyl group of the compound [118] is protected by a
conventional method to give compound [119].
[1046] For protection, for example, when R.sup.c22 is acetyl group,
the compound [118] is reacted with acetic anhydride in the presence
of pyridine or tertiary amine at room temperature to heating, when
R.sup.c22 is benzyl group, the compound [118] is heated under
reflux with benzyl chloride or benzyl bromide in benzene, toluene,
acetone, THF, chloroform and the like in the presence of a base
such as potassium hydroxide, potassium carbonate and the like, when
R.sup.c22 is tert-butyldiphenylsilyl group, the compound [118] is
treated with tert-butyldiphenylsilyl chloride and imidazole at room
temperature in DMF, and the like.
[1047] In addition, desired R.sup.d10'--CO group may be introduced
as a hydroxyl-protecting group in the next Step 5 without going
through this step.
Step 5
[1048] The compound [119] is reacted with carboxylic acid compound
[114] in the same manner as in Production Method 14-3 to give
compound [120].
Step 6
[1049] The compound [120] is alkylated with compound [115] in the
same manner as in Step 2 of Production Method 14-1 to give compound
[121].
Step 7
[1050] The compound [121] is deprotected in the same manner as in
Step 1 of Production Method 14-1 to give compound [122].
Step 8
[1051] The compound [122] is halogenated in the same manner as in
Step 3 of Production Method 15-3 to give compound [123].
Step 9
[1052] The compound [123] is reacted in the same manner as in Step
2 of Production Method 14-1 with compound [I-62] obtained in the
same manner as in the above-mentioned Production Method to give
compound [I-76].
Step 10
[1053] The compound [I-76] is deprotected in the same manner as in
Step 1 of Production Method 12 to give compound [I-77].
Production Method 16
[1054] A compound wherein Q is
--(CH.sub.2).sub.c-Q.sup.1-(CH.sub.2).sub.d--, Q.sup.1 is --CO--,
and c=d=0 can be obtained by a method similar to the method
described in Tetrahedron Lett., 32, 3317-3320, 1991.
[1055] A compound wherein Q is
--(CH.sub.2).sub.c-Q.sup.1-(CH.sub.2).sub.d--, Q.sup.1 is --CONH--,
c=d=0, and ##STR313## is C.dbd.C--N can be obtained by a method
similar to the method described in EP226508.
[1056] A compound wherein Q is
--(CH.sub.2).sub.c-Q.sup.1-(CH.sub.2).sub.d--, Q.sup.1 is
--CH.dbd.CH--, c=d=0, and ##STR314## is C.dbd.C--N can be obtained
by a method similar to the method described in Tetrahedron Lett.,
39, 8725-8728, 1998.
[1057] A compound wherein Q is
--(CH.sub.2).sub.c-Q.sup.1-(CH.sub.2).sub.d--, Q.sup.1 is
--CH.dbd.N--, c=d=0, and ##STR315## is C.dbd.C--N can be obtained
by a method similar to the method described in EP226508 and Organic
Lett., 4, 1355-1358, 2002.
[1058] A compound wherein Q is
--(CH.sub.2).sub.c-Q.sup.1-(CH.sub.2).sub.d--, Q.sup.1 is
--N.dbd.CH--, c=d=0, and ##STR316## is C.dbd.C--N can be obtained
by a method similar to the method described in J. Heterocycl.
Chem., 30(3), 603-609, 1993.
REFERENCE EXAMPLE 5
[1059] ##STR317## wherein each symbol is as defined above. Step
1
[1060] Compound [202] can be obtained by introducing a nitro group
into compound [201] by a conventional method.
Step 2
[1061] Compound [203] can be obtained by reacting compound [202]
with compound [82] in a solvent.
[1062] For example, compound [82] is added to a solvent such as
acetonitrile, THF, chloroform, ethyl acetate, methylene chloride,
toluene, pyridine, triethylamine and the like, under cooling and
allowed to react at room temperature to under heating.
Step 3
[1063] Compound [204] can be obtained by reacting compound [203]
with N,N-dimethylformamide dimethyl acetal under heating.
Step 4
[1064] Compound [205] can be obtained by reducing and cyclizing
compound [204] by a conventional method.
Step 5
[1065] Compound [206] can be obtained by reacting compound [205]
with compound [4] in the same manner as in Reference Example 2,
Step 1.
Step 6
[1066] Compound [207] can be obtained by hydrogenating compound
[206] in the same manner as in Reference Example 2, Step 2.
Step 7
[1067] Compound [208] can be obtained by halogenating compound
[207] in the same manner as in Reference Example 3, Step 2.
Production Method 17 ##STR318## wherein each symbol is as defined
above. Step 1
[1068] Compound [210] can be obtained by introducing a protecting
group into a hydroxyl group of compound [209] by a conventional
method.
[1069] For example, when R.sup.c13 is a tetrahydropyran-2-yl group,
3,4-dihydro-2H-pyran is reacted with compound [209] in a
non-alcoholic solvent such as chloroform, dichloromethane, diethyl
ether and the like, in the presence of an acid such as
p-toluenesulfonic acid, hydrochloric acid, phosphorus oxychloride
and the like.
Step 2
[1070] Compound [211] can be obtained by reacting compound [210]
with boric acid ester in the same manner as in Reference Example
1.
Step 3
[1071] Compound [212] can be obtained by reacting compound [211]
with compound [9] in the same manner as in Production Method
1-1.
Step 4
[1072] Compound [213] can be obtained by eliminating a
hydroxyl-protecting group of compound [212] by a conventional
method.
Step 5
[1073] Compound [214] can be obtained by converting a hydroxyl
groupa of compound [213] to a leaving group by halogen
substitution, mesylation or tosylation by a conventional
method.
Step 6
[1074] Compound [I-101] can be obtained by subjecting compound
[214] to condensation cyclization in the same manner as in
Production Method 1-2, Step 2.
Step 7
[1075] Compound [I-102] can be obtained by hydrolysis of compound
[I-101] in the same manner as in Production Method 12, Step 1.
Production Method 18 ##STR319## wherein Q.sup.17 is --O-- or --S--,
and other symbols are as defined above. Step 1
[1076] Compound [216] can be obtained by reacting compound [215]
with compound [26] in the same manner as in Production Method 14-1,
Step 2.
Step 2
[1077] Compound [217] can be obtained by reacting compound [216]
with compound [9'] in the same manner as in Production Method
1-1.
Step 3
[1078] Compound [218] can be obtained by eliminating a
hydroxyl-protecting group of compound [217] by a conventional
method.
Step 4
[1079] Compound [I-103] can be obtained converting a hydroxyl group
of compound [218] to a leaving group by halogen substitution,
mesylation or tosylation by a conventional method, and subjecting
the compound to condensation cyclization in the same manner as in
Production Method 1-2, Step 2.
[1080] Furthermore, a carboxylic acid form can be also obtained by
eliminating a carboxyl-protecting group of compound [I-103] by a
conventional method. Production Method 18-1 ##STR320## wherein
R.sup.y1' is a group selected from group C, m' is 0 or an integer
of 1 to 5, and other symbols are as defined above. Step 1
[1081] Compound [220] can be obtained by reacting compound [219]
with compound [9'] in the same manner as in Production Method
1-1.
Step 2
[1082] Compound [I-135] can be obtained by eliminating the
hydroxyl-protecting group of compound [220], then converting the
hydroxyl group to a leaving group by halogen substitution,
mesylation or tosylation by a conventional method, and then
subjecting the compound to condensation cyclization in the same
manner as in Production Method 1-2, Step 2.
Step 3
[1083] Compound [I-136] can be obtained by reducing the nitro group
of compound [I-135] by a conventional method.
Step 4
[1084] Compound [I-104] can be obtained by reacting compound
[I-103] with compound [223] in the same manner as in Production
Method 14-1, Step 2.
[1085] In this case, a compound wherein amino group is
disubstituted by compound [223] may be also obtained. In this
event, compound [I-104] isolated then can be used in the next
step.
Step 5
[1086] Compound [I-105] can be obtained by reacting compound
[I-104] with compound [224] in the same manner as in Production
Method 14-1, Step 2.
[1087] Here, the corresponding substituent can be also introduced
by reacting compound [I-104] with an aldehyde compound or a ketone
compound instead of compound [224] in the presence of a reducing
agent.
[1088] As the reducing agent, borohydrides such as sodium
borohydride, sodium cyanoborohydride, sodium triacetoxyborohydride
and the like can be mentioned.
[1089] As a solvent, THF, 1,4-dioxane, dichloromethane, chloroform,
methanol, ethanol, toluene, acetic acid and the like can be
mentioned. Acetic acid may be added.
Step 6
[1090] Compound [I-106] can be obtained by reducing carbonyl of
compound [I-105] by a conventional method.
Step 7
[1091] Compound [I-107] can be obtained by hydrolyzing compound
[I-106] in the same manner as in Production Method 12, Step 1.
Production Method 19 ##STR321## wherein each symbol is as defined
above. Step 1
[1092] Compound [226] can be obtained by reacting compound [9] with
compound [225] in the same manner as in Production Method 14-1,
Step 2.
Step 2
[1093] Compound [I-108] can be obtained by cyclizing compound [226]
in the same manner as in Production Method 6, Step 2. Production
Method 19-1 ##STR322## ##STR323## wherein each symbol is as defined
above. Step 1
[1094] Compound [227] can be obtained by reacting compound [221]
with compound [26] in the same manner as in Production Method 14-1,
Step 2.
Step 2
[1095] Compound [228] can be obtained by deprotecting the hydroxyl
group of compound [227] by a conventional method. Here, conditions
for deprotecting R.sup.c13 without affecting R.sup.c14 are
preferable, as R.sup.c13, preferred are tetrahydropyran-2-yl group,
tert-butyl group, acetyl group and the like, and as R.sup.c14,
preferred are benzyl group, methyl group and the like.
Step 3
[1096] Compound [229] can be obtained by converting the hydroxyl
group of compound [228] to a leaving group by halogen substitution,
mesylation or tosylation by a conventional method.
Step 4
[1097] Compound [230] can be obtained by reacting compound [229]
with compound [9] in the same manner as in Production Method 14-1,
Step 2.
Step 5
[1098] Compound [I-109] can be obtained cyclizing compound [230] in
the same manner as in Production Method 6, Step 2.
Step 6
[1099] Compound [I-110] can be obtained by eliminating the
hydroxyl-protecting group of compound [I-109] by a conventional
method.
Step 7
[1100] Compound [I-112] can be obtained by reacting compound
[I-110] with compound [223] in the same manner as in Production
Method 14-1, Step 2.
Step 8
[1101] Compound [I-113] can be obtained by reducing carbonyl of
compound [I-112] by a conventional method.
Step 9
[1102] Compound [I-114] can be obtained by hydrolyzing compound
[I-113] in the same manner as in Production Method 12, Step 1.
Production Method 20 ##STR324## ##STR325## wherein each symbol is
as defined above. Step 1
[1103] Compound [231] can be obtained by reacting compound [9] with
compound [26] in the same manner as in Production Method 14-1, Step
2.
Step 2
[1104] Compound [232] can be obtained by eliminating the
hydroxyl-protecting group of compound [2311 and then converting the
hydroxyl group to a leaving group by halogen substitution,
mesylation or tosylation by a conventional method.
Step 3
[1105] Compound [233] can be obtained by reacting compound [232]
with potassium phthalimide in DMF solvent in the presence of a base
such as potassium carbonate and the like at room temperature or
under heating.
Step 4
[1106] Compound [234] can be obtained by reacting compound [233] in
the presence of hydrazine in a solvent such as methanol, ethanol,
THF and the like at room temperature or under heating.
Step 5
[1107] Compound [235] can be obtained by introducing a protecting
group into the amino group of compound [234] by a conventional
method.
Step 6
[1108] Compound [237] can be obtained by reacting compound [235]
with compound [236] in the same manner as in Production Method
1-1.
Step 7
[1109] Compound [238] can be obtained by hydrogenating the formyl
group of compound [237] to give hydroxymethyl group by a
conventional method.
Step 8
[1110] Compound [239] can be obtained by converting the hydroxyl
group of compound [238] to a leaving group by halogen substitution,
mesylation or tosylation by a conventional method.
Step 9
[1111] Compound [I-115] can be obtained by subjecting compound
[239] to condensation cyclization in the same manner as in
Production Method 1-2, Step 2. Production Method 20-1 ##STR326##
##STR327## wherein each symbol is as defined above. Step 1
[1112] Compound [242] can be obtained by amide condensation of
compound [240] with compound [241] in the same manner as in
Production Method 1-2, Step 1.
Step 2
[1113] Compound [243] can be obtained by reacting compound [242]
with compound [9'] in the same manner as in Production Method 1
Step 3
[1114] Compound [244] can be obtained by reducing the carbonyl of
compound [243] and then introducing a protecting group into the
nitrogen atom of reduced compound [243] by a conventional
method.
Step 4
[1115] Compound [245] can be obtained by converting the hydroxyl
group of compound [244] to a leaving group by halogen substitution,
mesylation or tosylation by a conventional method.
Step 5
[1116] Compound [I-115] can be obtained by subjecting compound
[245] to condensation cyclization in the same manner as in
Production Method 1-2, Step 2.
Step 6
[1117] Compound [I-116] can be obtained by eliminating, by a
conventional method, the amino-protecting group of compound [I-115]
obtained in the previous step or in the same manner as in
Production Method 20.
Step 7
[1118] Compound [I-117] can be obtained by reacting compound
[I-116] with compound [77] in the same manner as in Production
Method 10, Step 1.
[1119] The substituent can be introduced into the nitrogen atom in
the same manner using compound [78] described in Production Method
10, compound [246] described in Production Method 21 and the like
instead of compound [77].
[1120] The substituent may be also introduced in the same manner as
in Production Method 18-1, Step 5, using an aldehyde compound or a
ketone compound.
Step 8
[1121] Compound [I-118] can be obtained by hydrolyzing compound
[I-117] in the same manner as in Production Method 12, Step 1.
Production Method 21 ##STR328## ##STR329## wherein each symbol is
as defined above. Step 1
[1122] Compound [248] can be obtained by introducing a
hydroxyl-protecting group into compound [247] by a conventional
method.
Step 2
[1123] Compound [249] can be obtained by reducing the nitro group
of compound [248] by a conventional method.
Step 3
[1124] Compound [250] can be obtained by reacting compound [249]
with boric acid ester in the same manner as in Reference Example
1.
Step 4
[1125] Compound [251] can be obtained by reacting compound [250]
with compound [9] in the same manner as in Production Method
1-1.
Step 5
[1126] Compound [252] can be obtained by reacting compound [251]
with compound [21] in the same manner as in Production Method 1-2,
Step 1.
Step 6
[1127] Compound [I-119] can be obtained by subjecting compound
[252] to condensation cyclization in the same manner as in
Production Method 1-2, Step 2.
Step 7
[1128] Compound [I-120] can be obtained by reacting compound
[I-119] with compound [246] in the same manner as in Production
Method 10, Step 1.
Step 8
[1129] Compound [I-121] can be obtained by eliminating the
hydroxyl-protecting group of compound [I-120] by a conventional
method.
Step 9
[1130] Compound [I-122] can be obtained by reacting compound
[I-121] with compound [83] in the same manner as in Production
Method 14-1, Step 2.
Step 10
[1131] Compound [I-123] can be obtained by reducing carbonyl of
compound [I-122] by a conventional method.
Step 11
[1132] Compound [I-124] can be obtained by hydrolyzing compound
[I-123] in the same manner as in Production Method 12, Step 1.
Production Method 22-1 ##STR330## wherein each symbol is as defined
above. Step 1
[1133] Compound [255] can be obtained by reacting compound [253]
with compound [254] in the same manner as in Production Method 1-2,
Step 1.
[1134] In general, compound [254], wherein a protecting group has
been introduced into an amino group, is used, and after reaction of
Step 1, compound [255] obtained by eliminating the amino-protecting
group can be used in the next step.
Step 2
[1135] Compound [I-126] can be obtained by reacting compound [I-38]
with compound [255] in the same manner as in Production Method 1-2,
Step 1.
[1136] Compound [I-38] can be used for this Step after hydrolyzing
the carboxyl-protecting group in the same manner as in Production
Method 12, Step 1.
Step 3
[1137] Compound [I-125] can be obtained by reacting compound [I-38]
with compound [254] in the same manner as in Production Method 1-2,
Step 1.
[1138] Compound [I-38] can be used for this Step after hydrolyzing
the carboxyl-protecting group in the same manner as in Production
Method 12, Step 1.
[1139] In general, compound [254], wherein a protecting group has
been introduced into carboxylic acid, is used, and after reaction
of Step 3, compound [I-125] obtained by eliminating the
carboxyl-protecting group can be used in the next step.
Step 4
[1140] Compound [I-126] can be obtained by reacting compound
[I-125] with compound [253] in the same manner as in Production
Method 1-2, Step 1. Production Method 22-2 ##STR331## wherein each
symbol is as defined above.
[1141] Compounds [257] and [I-127] can be obtained in the same
manner as in Production Method 22-1, using compound [256] instead
of compound [253]. Production Method 22-3 ##STR332## wherein each
symbol is as defined above. Step 1
[1142] Compound [I-129] can be obtained by subjecting compound
[I-128], obtained in the same manner as in Production Method 22-1
or Production Method 22-2, to condensation cyclization the in a
solvent such as an alcohol solvent, acetic acid and the like at
room temperature or under heating.
Step 2
[1143] Compound [I-130] can be obtained by hydrolyzing compound
[I-129] in the same manner as in Production Method 12, Step 1.
Step 3
[1144] Compound [I-131] can be obtained by reacting compound
[I-130] with compound [258] in the same manner as in Production
Method 1-2, Step 1. Production Method 23 ##STR333## wherein
R.sup.4' is a C.sub.1-6 alkyl group optionally substituted by 1 to
3 substituents selected from group A, a C.sub.6-14 aryl group
optionally substituted by 1 to 5 substituents selected from group B
or a heterocyclic group optionally substituted by 1 to 5
substituents selected from group B, and each symbol is as defined
above. Step 1
[1145] Compound [222] can be obtained by reacting compound [9] with
compound [259] in the same manner as in Production Method 14-1,
Step 2.
Step 2
[1146] Compound [261] can be obtained by reacting compound [222]
with compound [46] in the same manner as in Production Method
1-1.
Step 3
[1147] Compound [I-1321 can be obtained by subjecting compound
[261] to condensation cyclization in a solvent in the presence of a
reducing agent.
[1148] As the reducing agent, borohydrides such as sodium
borohydride, sodium cyanoborohydride, sodium triacetoxyborohydride
and the like can be mentioned.
[1149] As the solvent, THF, 1,4-dioxane, dichloromethane,
chloroform, methanol, ethanol, toluene, acetic acid and the like
can be mentioned. Acetic acid may be added.
Step 4
[1150] Compound [I-133] can be obtained by reacting compound
[I-132] with compound [77] in the same manner as in Production
Method 20-1, Step 7.
Step 5
[1151] Compound [I-134] can be obtained by hydrolyzing compound
[I-133] in the same manner as in Production Method 12, Step 1.
[1152] In the above-mentioned Production Method, substituents
R.sup.4 and/or R.sup.2 may be present on -Q-, as long as the
reaction is not adversely affected.
[1153] In the compounds of the formula [I], a desired heterocyclic
group (including carboxylic acid equivalent) can be formed
according to a method similar to the methods disclosed in known
publications. Examples of such heterocyclic group and reference
publications are recited in the following. [1154]
5-oxo-.DELTA..sup.2-1,2,4-oxadiazolin-3-yl (or
2,5-dihydro-5-oxo-4H-1,2,4-oxadiazol-3-yl),
5-oxo-.DELTA..sup.2-1,2,4-thiadiazolin-3-yl (or
2,5-dihydro-5-oxo-4H-1,2,4-thiadiazol-3-yl),
2-oxo-.DELTA..sup.3-1,2,3,5-oxathiadiazolin-4-yl (or
2-oxo-.DELTA..sup.3-1,2,3,5-oxathiadiazol-4-yl): Journal of
Medicinal Chemistry, 39(26), 5228-35, 1996, based on compound
[I-42], for example, 5-oxo-.DELTA..sup.2-1,2,4-oxadiazolin-3-yl,
5-thioxo-.DELTA..sup.2-1,2,4-oxadiazolin-3-yl can be formed. [1155]
5-oxo-.DELTA..sup.2-1,2,4-triazolin-3-yl: J Org Chem, 61(24),
8397-8401, 1996, [1156]
1-oxo-.DELTA..sup.3-1,2,3,5-thiatriazolin-4-yl: Liebigs Ann Chem,
1376, 1980, [1157] 3-oxo-.DELTA..sup.4-1,2,4-oxadiazolin-5-yl:
EP145095, [1158] 5-oxo-.DELTA..sup.2-1,3,4-oxadiazolin-2-yl: J Org
Chem, 20, 412, 1955, [1159]
5-oxo-.DELTA..sup.3-1,2,4-dioxazolin-3-yl: J Prakt Chem, 314, 145,
1972, [1160] 3-oxo-.DELTA..sup.4-1,2,4-thiadiazolin-5-yl:
JP-A-61-275271, [1161] 5-oxo-.DELTA..sup.3-1,2,4-dithiazolin-3-yl:
J Org Chem, 61(19), 6639-6645, 1996, [1162]
2-oxo-.DELTA..sup.4-1,3,4-dioxazolin-5-yl: J Org Chem, 39, 2472,
1974, [1163] 2-oxo-.DELTA..sup.4-1,3,4-oxathiazolin-5-yl: J Med
Chem, 35(20), 3691-98, 1992, [1164]
5-oxo-.DELTA..sup.2-1,3,4-thiadiazolin-2-yl: J Prakt Chem, 332(1),
55, 1990, [1165] 5-oxo-.DELTA..sup.2-1,4,2-oxathiazolin-3-yl: J Org
Chem, 31, 2417, 1966, [1166]
2-oxo-.DELTA..sup.4-1,3,4-dithiazolin-5-yl: Tetrahedron Lett, 23,
5453, 1982, [1167] 2-oxo-.DELTA..sup.4-1,3,2,4-dioxathiazolin-5-yl:
Tetrahedron Lett, 319, 1968, [1168] 3,5-dioxoisoxazolidin-4-yl:
Helv Chim Acta, 1973, 48, 1965, [1169] 2,5-dioxoimidazolidin-4-yl:
Heterocycles, 43(1), 49-52, 1996, [1170]
5-oxo-2-thioxoimidazolidin-4-yl: Heterocycles, 5, 391, 1983, [1171]
2,4-dioxooxazolidin-5-yl: J Am Chem Soc, 73, 4752, 1951, [1172]
4-oxo-2-thioxooxazolidin-5-yl: Chem Ber, 91, 300, 1958, [1173]
2,4-dioxothiazolidin-5-yl: JP-A-57-123175, [1174]
4-oxo-2-thioxothiazolidin-5-yl: Chem Pharm Bull, 30, 3563,
1982.
EXAMPLES
[1175] The tetracyclic fused heterocyclic compounds of the formula
[I] and production methods thereof of the present invention are
explained in detail in the following by way of Examples. It is
needless to say that the present invention is not limited by these
Examples. In the Examples, Me means methyl group, Et means ethyl
group, tBu means tert-butyl group, Ac means acetyl group, Bn means
benzyl group, Boc means tert-butoxycarbonyl group, THP means
2-tetrahydropyranyl group, and Tf means trifluoromethanesulfonyl
group.
Example 1-1
Production of methyl
.beta.-cyclohexyl-6-oxo-6,7-dihydro-5H-benzo[5,6][1,4]diazepino[7,1-a]ind-
ole-10-carboxylate
Step 1: Production of
2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenylamine
[1176] ##STR334##
[1177] To a solution of 2-bromoaniline (1.0 g, 5.81 mmol) in
1,4-dioxane (15 ml) were added triethylamine (3.24 ml, 23.2 mmol)
and [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium(II)
dichloromethane complex (PdCl.sub.2(dppf)CH.sub.2Cl.sub.2) (243 mg,
0.30 mmol) at room temperature. To the reaction mixture was added
dropwise pinacolborane (2.53 ml, 17.4 mmol), and the reaction
mixture was heated to 100.degree. C. and stirred for 3 hr. The
reaction mixture was cooled to room temperature and saturated
aqueous ammonium chloride solution was added. The mixture was
extracted with diethyl ether. The organic layer was washed with
saturated brine and dried over anhydrous sodium sulfate. After
filtration, the solvent was evaporated under reduced pressure, and
the residue was purified by silica gel column chromatography
(hexane:ethyl acetate=5:1) to give
2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenylamine (810 mg,
yield 63.6%).
[1178] .sup.1H-NMR(400 MHz, CDCl.sub.3): (ppm) 7.59(1H, dd, J=7.2,
1.6 Hz), 7.20(1H, ddd, J=15.2, 7.2, 2.0 Hz), 6.66(1H, t, J=7.4 Hz),
6.58(1H, d, J=8.0 Hz), 4.72(2H, brs), 1.33(12H, s).
Step 2: Production of methyl
2-(2-aminophenyl)-3-cyclohexyl-1H-indole-6-carboxylate
[1179] ##STR335##
[1180] To a suspension of methyl
2-bromo-3-cyclohexyl-1H-indole-6-carboxylate (6.50 g, 19.3 mmol)
obtained in the same manner as in the method described in
WO03/010140 and
2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenylamine (5.08 g,
23.2 mmol) in 1,2-dimethoxyethane (90 ml) and water (45 ml) were
added sodium hydrogen carbonate (4.81 g, 57.9 mmol) and
tetrakis(triphenylphosphine)palladium (1.12 mg, 0.965 mmol), and
the mixture was heated under reflux for 9 hr. The mixture was
allowed to cool to room temperature, and water was added to the
reaction mixture. The mixture was extracted with ethyl acetate and
the organic layer was washed successively with saturated aqueous
sodium hydrogen carbonate solution and saturated brine and dried
over anhydrous magnesium sulfate. After filtration, the solvent was
evaporated under reduced pressure. The residue was purified by
silica gel chromatography (hexane:ethyl acetate=4:1-3:1) to give
methyl 2-(2-aminophenyl)-3-cyclohexyl-1H-indole-6-carboxylate (6.48
g, yield 96%).
[1181] .sup.1H-NMR(400 MHz, DMSO-d.sub.6): .delta.(ppm) 11.30(1H,
s), 7.95(1H, d, J=1.2 Hz), 7.78(1H, d, J=8.4 Hz), 7.58(1H, dd,
J=8.4, 1.2 Hz), 7.14 (1H, td, J=8.0, 0.8 Hz), 7.04(1H, dd, J=7.6,
1.6 Hz), 6.79(1H, dd, J=8.0, 0.8 Hz), 6.65(1H, td, J=7.2, 0.4 Hz),
4.81(2H, brs), 3.84(3H, s), 2.53-2.63(1H, m), 1.63-1.94(7H, m),
1.16-1.37(3H, m).
Step 3: Production of methyl
2-[2-(2-chloroacetylamino)phenyl]-3-cyclohexyl-1H-indole-6-carboxylate
[1182] ##STR336##
[1183] To a suspension of methyl
2-(2-aminophenyl)-3-cyclohexyl-1H-indole-6-carboxylate (6.48 g,
18.6 mmol), sodium acetate (1.68 g, 20.5 mmol) and acetic acid
(1.17 ml, 20.5 mmol) in tetrahydrofuran (60 ml) was added dropwise
chloroacetyl chloride (1.63 ml, 20.5 mmol), and the mixture was
stirred at room temperature for 2 hr. Saturated aqueous sodium
hydrogen carbonate solution was added to the reaction mixture and
the mixture was extracted with ethyl acetate. The organic layer was
washed successively with saturated aqueous sodium hydrogen
carbonate solution and saturated brine and dried over anhydrous
magnesium sulfate. After filtration, the solvent was evaporated
under reduced pressure to give methyl
2-[2-(2-chloroacetylamino)phenyl]-3-cyclohexyl-1H-indole-6-carboxylate
(7.90 g, yield 100%).
[1184] .sup.1H-NMR(400 MHz, DMSO-d.sub.6): .delta.(ppm) 11.44(1H,
s), 9.38(1H, s), 7.98(1H, d, J=1.2 Hz), 7.90(1H, d, J=8.0 Hz),
7.82(1H, d, J=8.4 Hz), 7.60(1H, dd, J=8.0, 1.2 Hz), 7.47(1H, td,
J=8.4, 0.8 Hz), 7.36(1H, dd, J=7.6, 1.6 Hz), 7.30(1H, td, J=7.6,
0.6 Hz), 4.19(2H, s), 3.85(3H, s), 2.42-2.50(1H, m), 1.61-1.91(7H,
m), 1.11-1.34(3H, m).
Step 4: Production of methyl
13-cyclohexyl-6-oxo-6,7-dihydro-5H-benzo[5,6][1,4]diazepino[7,1-a]indole--
10-carboxylate
[1185] ##STR337##
[1186] To a solution of methyl
2-[2-(2-chloroacetylamino)phenyl]-3-cyclohexyl-1H-indole-6-carboxylate
(7.90 g, 18.6 mmol) in N,N-dimethylformamide (170 ml) was added
sodium hydride (1.64 g, 40.9 mmol) under ice-cooling and the
mixture was stirred for 2 hr. 1N Hydrochloric acid (45 ml) and
water (200 ml) were added to the reaction mixture and the
precipitated solid was collected by filtration. After washing
successively with water and hexane, the solid was dried in vacuo to
give methyl
13-cyclohexyl-6-oxo-6,7-dihydro-5H-benzo[5,6][1,4]diazepino[7,1-a]indole--
10-carboxylate (6.72 g, yield 93%).
[1187] .sup.1H-NMR(400 MHz, DMSO-d.sub.6): .delta.(ppm) 10.34(1H,
s), 8.27(1H, d, J=1.2 Hz), 7.96(1H, d, J=8.4 Hz), 7.68(1H, dd,
J=8.4, 1.6 Hz), 7.49-7.53(2H, m), 7.38(1H, t, J=7.6 Hz), 7.28(1H,
d, J=8.0 Hz), 5.07(1H, d, J=15.6 Hz), 4.52(1H, d, J=14.8 Hz),
3.89(3H, s), 2.81-2.91(1H, m), 1.98-2.11(3H, m), 1.84-1.94(1H, m),
1.66-1.78(2H, m), 1.34-1.56(3H, m), 1.10-1.27(1H, m).
Example 1-2
Production of methyl
13-cyclohexyl-6,7-dihydro-5H-benzo[5,6][1,4]diazepino[7,1-a]indole-10-car-
boxylate
[1188] ##STR338##
[1189] To a suspension of methyl
13-cyclohexyl-6-oxo-6,7-dihydro-5H-benzo[5,6][1,4]diazepino[7,1-a]indole--
10-carboxylate (6.72 g, 17.3 mmol) in tetrahydrofuran (13 ml) was
added 1M BH.sub.3 THF complex tetrahydrofuran solution (67 ml)
under ice-cooling, and the mixture was stirred at room temperature
for 4 hr. 2N Hydrochloric acid (40 ml) was added to the reaction
mixture at room temperature and the mixture was stirred at
70.degree. C. for 1 hr. The mixture was allowed to cool to room
temperature and 2N aqueous sodium hydroxide solution (40 ml) was
added to the reaction mixture. The mixture was extracted with ethyl
acetate. The organic layer was washed successively with saturated
aqueous sodium hydrogen carbonate solution and saturated brine and
dried over anhydrous magnesium sulfate. After filtration, the
solvent was evaporated under reduced pressure to give methyl
13-cyclohexyl-6,7-dihydro-5H-benzo[5,6][1,4]diazepino[7,1-a]indole-10-car-
boxylate (6.08 g, yield 94%).
[1190] .sup.1H-NMR(400 MHz, DMSO-d.sub.6): .delta.(ppm) 8.13(1H, d,
J=1.6 Hz), 7.86(1H, d, J=8.8 Hz), 7.61(1H, dd, J=8.8, 1.6 Hz),
7.17-7.21(2H, m), 6.91(1H, dd, J=8.4, 1.2 Hz), 6.83(1H, t, J=7.4
Hz), 5.80(1H, t, J=4.0 Hz), 4.41(2H, brs), 3.86(3H, s),
3.45-3.52(2H, m), 2.80-2.89(1H, m), 1.97-2.10(2H, m), 1.68-1.85(5H,
m), 1.21-1.46(3H, m).
Example 1-3
Production of
13-cyclohexyl-6,7-dihydro-5H-benzo[5,6][1,4]diazepino[7,1-a]indole-10-car-
boxylic acid monohydrochloride
[1191] ##STR339##
[1192] To a solution of methyl
13-cyclohexyl-6,7-dihydro-5H-benzo[5,6][1,4]diazepino[7,1-a]indole-10-car-
boxylate (60 mg, 0.16 mmol) in tetrahydrofuran (2 ml) and methanol
(1 ml) was added 4N aqueous sodium hydroxide solution (1 ml), and
the mixture was stirred for 36 hr. 1N Hydrochloric acid (4 ml) was
added to adjust to pH 7, and the mixture was extracted with ethyl
acetate. The organic layer was washed with saturated brine and
dried over anhydrous sodium sulfate. After filtration, the solvent
was evaporated under reduced pressure. To a solution of the residue
in tetrahydrofuran (2 ml) was added 4N HCl-ethyl acetate solution
(1 ml), and the solvent was evaporated under reduced pressure.
Diethyl ether was added to the residue and the precipitated solid
was collected by filtration, washed with diethyl ether and dried in
vacuo to give
13-cyclohexyl-6,7-dihydro-5H-benzo[5,6][1,4]diazepino[7,1-a]indole-10-car-
boxylic acid monohydrochloride (48 mg, yield 76.4%).
[1193] .sup.1H-NMR(300 MHz, DMSO-d.sub.6): (ppm) 8.18(1H, s),
7.89(1H, d, J=8.4 Hz), 7.65(1H, d, J=9.9 Hz), 7.18-7.44(4H, brm),
3.46-4.47(4H,brm), 2.81-2.91(1H, m), 1.96-2.11(2H, m),
1.68-1.86(5H, m), 1.22-1.45(3H, m).
[1194] MS 361(M+1).
Example 1-4
Production of methyl
5-tert-butoxycarbonylmethyl-13-cyclohexyl-6,7-dihydro-5H-benzo[5,6][1,4]d-
iazepino[7,1-a]indole-10-carboxylate
[1195] ##STR340##
[1196] To a solution of methyl
13-cyclohexyl-6,7-dihydro-5H-benzo[5,6][1,4]diazepino[7,1-a]indole-10-car-
boxylate (2.00 g, 5.34 mmol) obtained in Example 1-2 in
N,N-dimethylformamide (16 ml) were added potassium carbonate (1.85
g, 13.4 mmol), sodium iodide (800 mg, 5.34 mmol) and tert-butyl
bromoacetate (1.18 ml, 8.01 mmol), and the mixture was stirred at
90.degree. C. for 12 hr. The mixture was allowed to cool to room
temperature, and water (40 ml) was added. The precipitated solid
was collected by filtration, washed successively with water and
hexane and dried in vacuo to give methyl
5-tert-butoxycarbonylmethyl-13-cyclohexyl-6,7-dihydro-5H-benzo[5,6][1,4]d-
iazepino[7,1-a]indole-10-carboxylate (2.47 g, yield 95%).
[1197] .sup.1H-NMR(400 MHz, DMSO-d.sub.6): .delta.(ppm) 8.18(1H, d,
J=1.2 Hz), 7.88(1H, d, J=8.8 Hz), 7.62(1H, dd, J=8.0, 1.2 Hz),
7.38(1H, t, J=7.8 Hz), 7.28(1H, d, J=7.6 Hz), 7.14(1H, t, J=7.4
Hz), 7.02(1H, d, J=8.0 Hz), 3.87(5H, s), 3.51(2H, brs),
2.75-2.85(1H, m), 1.95-2.09(2H, m), 1.66-1.86(5H, m), 1.17-1.45(3H,
m), 1.29(9H, s).
[1198] MS 489(M+1).
Example 1-5
Production of
(13-cyclohexyl-10-methoxycarbonyl-6,7-dihydro-5H-benzo[5,6][1,4]diazepino-
[7,1-a]indol-5-yl)acetic acid
[1199] ##STR341##
[1200] To a solution of methyl
5-tert-butoxycarbonylmethyl-13-cyclohexyl-6,7-dihydro-5H-benzo[5,6][1,4]d-
iazepino[7,1-a]indole-10-carboxylate (2.47 g, 5.05 mmol) in
chloroform (17 ml) was added trifluoroacetic acid (17 ml) and the
mixture was stirred at room temperature for 5 hr. The reaction
mixture was evaporated under reduced pressure and the residue was
purified by silica gel chromatography
(chloroform:methanol=30:1-15:1) to give
(13-cyclohexyl-10-methoxycarbonyl-6,7-dihydro-5H-benzo[5,6][1,4]diazepino-
[7,1-a]indol-5-yl)acetic acid (1.34 g, yield 61%).
[1201] .sup.1H-NMR(400 MHz, DMSO-d.sub.6): .delta.(ppm) 12.60(1H,
brs), 8.18(1H, d, J=1.2 Hz), 7.87(1H, d, J=8.4 Hz), 7.62(1H, dd,
J=8.8, 1.6 Hz), 7.37(1H, td, J=8.0, 0.8 Hz), 7.27(1H, dd, J=7.6,
1.6 Hz), 7.11(1H, t, J=7.4 Hz), 7.05(1H, d, J=8.0 Hz), 4.40(2H,
brs), 3.88(2H, brs), 3.87(3H, s), 3.58(2H, t, J=5.4 Hz),
2.76-2.86(1H, m), 1.94-2.07(2H, m), 1.66-1.86(5H, m), 1.20-1.45(3H,
m)
[1202] MS 433(M+1).
Example 1-6
Production of methyl
13-cyclohexyl-5-[2-oxo-2-(thiomorpholin-4-yl)ethyl]-6,7-dihydro-5H-benzo[-
5,6][1,4]diazepino[7,1-a]indole-10-carboxylate
[1203] ##STR342##
[1204] To a solution of
(13-cyclohexyl-10-methoxycarbonyl-6,7-dihydro-5H-benzo[5,6][1,4]diazepino-
[7,1-a]indol-5-yl)acetic acid (400 mg, 0.46 mmol) in
N,N-dimethylformamide (2 ml) were added
1-ethyl-3-(3'-dimethylaminopropyl)carbodiimide monohydrochloride
(105 mg, 0.54 mmol), 1-hydroxybenzotriazole monohydrate (75 mg,
0.55 mmol) and thiomorpholine (0.05 ml, 0.49 mmol) and the mixture
was stirred overnight at room temperature. Water was added to the
reaction mixture and the mixture was extracted with ethyl acetate.
The organic layer was washed successively with water, saturated
aqueous sodium hydrogen carbonate solution and saturated brine and
dried over anhydrous sodium sulfate. After filtration, the solvent
was evaporated under reduced pressure and the residue was purified
by silica gel column chromatography (hexane:ethyl acetate=1:1-2:3)
to give methyl
13-cyclohexyl-5-[2-oxo-2-(thiomorpholin-4-yl)ethyl]-6,7-dihydro-5H-benzo[-
5,6][1,4]diazepino[7,1-a]indole-10-carboxylate (149 mg, yield
62.6%).
[1205] MS 518(M+1).
Example 1-7
Production of
13-cyclohexyl-5-[2-oxo-2-(thiomorpholin-4-yl)ethyl]-6,7-dihydro-5H-benzo[-
5,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid
monohydrochloride
[1206] ##STR343##
[1207] To a solution of methyl
13-cyclohexyl-5-[2-oxo-2-(thiomorpholin-4-yl)ethyl]-6,7-dihydro-5H-benzo[-
5,6][1,4]diazepino[7,1-a]indole-10-carboxylate (114 mg, 0.22 mmol)
in tetrahydrofuran (1 ml) and methanol (1 ml) was added 4N aqueous
sodium hydroxide solution (1 ml) and the mixture was stired at
70.degree. C. for 2 hr. The mixture was allowed to cool to room
temperature and 1N hydrochloric acid (4 ml) was added to adjust to
pH 7. The mixture was extracted with ethyl acetate. The organic
layer was washed with saturated brine and dried over anhydrous
sodium sulfate. After filtration, the solvent was evaporated under
reduced pressure. To a solution of the residue in ethyl acetate (1
ml) was added 4N HCl-ethyl acetate solution (1 ml) and the solvent
was evaporated under reduced pressure. Hexane was added to the
residue and the precipitated solid was collected by filtration,
washed with hexane, and dried in vacuo to give
13-cyclohexyl-5-[2-oxo-2-(thiomorpholin-4-yl)ethyl]-6,7-dihydro-5H-benzo[-
5,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid
monohydrochloride (68 mg, yield 57.6%).
[1208] MS 504(M+1).
Example 1-8
Production of methyl
13-cyclohexyl-5-[2-(thiomorpholin-4-yl)ethyl]-6,7-dihydro-5H-benzo[5,6][1-
,4]diazepino[7,1-a]indole-10-carboxylate
[1209] ##STR344##
[1210] To a solution of methyl
13-cyclohexyl-5-[2-oxo-2-(thiomorpholin-4-yl)ethyl]-6,7-dihydro-5H-benzo[-
5,6][1,4]diazepino[7,1-a]indole-10-carboxylate (149 mg, 0.28 mmol)
obtained in Example 1-6 in tetrahydrofuran (1 ml) was added 1M
BH.sub.3 THF complex tetrahydrofuran solution (2 ml) with stirring
under ice-cooling, and the mixture was stirred at room temperature
for 4 hr. 2N Hydrochloric acid was added to the reaction mixture at
room temperature and the mixture was stirred at 70.degree. C. for 2
hr. To the reaction mixture was added 4N aqueous sodium hydroxide
solution to adjust to pH 8 and the mixture was extracted with ethyl
acetate. The organic layer was washed with saturated brine and
dried over anhydrous sodium sulfate. After filtration, the solvent
was evaporated under reduced pressure and the residue was purified
by silica gel column chromatography (chloroform:methanol=30:1-20:1)
to give methyl
13-cyclohexyl-5-[2-(thiomorpholin-4-yl)ethyl]-6,7-dihydro-5H-benzo[5,6][1-
,4]diazepino[7,1-a]indole-10-carboxylate (88 mg, yield 61.1%).
[1211] MS 504(M+1).
Example 1-9
Production of
13-cyclohexyl-5-[2-(thiomorpholin-4-yl)ethyl]-6,7-dihydro-5H-benzo[5,6][1-
,4]diazepino[7,1-a]indole-10-carboxylic acid dihydrochloride
[1212] ##STR345##
[1213] To a solution of methyl
13-cyclohexyl-5-[2-(thiomorpholin-4-yl)ethyl]-6,7-dihydro-5H-benzo[5,6][1-
,4]diazepino[7,1-a]indole-10-carboxylate (88 mg, 0.17 mmol) in
tetrahydrofuran (1 ml) and methanol (1 ml) was added 4N aqueous
sodium hydroxide solution (1 ml) and the mixture was stirred at
room temperature for 20 hr. To the reaction mixture was added 1N
hydrochloric acid to adjust to pH 7. The mixture was extracted with
ethyl acetate and the organic layer was washed with saturated brine
and dried over anhydrous sodium sulfate. After filtration, the
solvent was evaporated under reduced pressure. To a solution of the
residue in ethyl acetate (1 ml) was added 4N HCl-ethyl acetate
solution (1 ml) and the solvent was evaporated under reduced
pressure. Ethyl acetate was added to the residue and the
precipitated solid was collected by filtration, washed with hexane
and dried in vacuo to give
13-cyclohexyl-5-[2-(thiomorpholin-4-yl)ethyl]-6,7-dihydro-5H-benzo[5,6][1-
,4]diazepino[7,1-a]indole-10-carboxylic acid dihydrochloride (44
mg, yield 44.9%).
[1214] MS 490(M+1).
Example 1-10
Production of methyl
3-chloro-13-cyclohexyl-6-oxo-6,7-dihydro-5H-benzo[5,6][1,4]diazepino[7,1--
a]indole-10-carboxylate
Step 1: Production of
5-chloro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenylamine
[1215] ##STR346##
[1216] To a solution of 2-bromo-5-chloroaniline (20.0 g, 96.9 mmol)
in 1,4-dioxane (200 ml) were added triethylamine (54.0 ml, 487
mmol) and
[1,1-bis(diphenylphosphino)ferrocene]dichloropalladium(II)
dichloromethane complex (3.96 g, 4.84 mmol), and under a nitrogen
stream, 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (42.3 ml, 290 mmol)
was added dropwise. The mixture was stirred at 100.degree. C. for
10.5 hr. The mixture was allowed to cool to room temperature and
filtered through celite. To the filtrate was added dropwise
methanol (25 ml) at 0.degree. C. The solvent was evaporated under
reduced pressure, and the obtained residue was purified by silica
gel chromatography (hexane:ethyl acetate=20:1) to give
5-chloro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenylamine
(16.5 g, yield 65%).
[1217] .sup.1H-NMR(400 MHz, DMSO-d.sub.6): (ppm) 7.28(1H, d, J=6.0
Hz), 6.59(1H, d, J=1.2 Hz), 6.43(1H, dd, J=6.3, 1.5 Hz), 5.70(2H,
s), 1.24(12H, s).
Step 2: Production of methyl
2-(2-amino-4-chlorophenyl)-3-cyclohexyl-1H-indole-6-carboxylate
[1218] ##STR347##
[1219] To a suspension of methyl
2-bromo-3-cyclohexyl-1H-indole-6-carboxylate (5.20 g, 15.4 mmol)
obtained in the same manner as in the method described in
WO03/010140 and
5-chloro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenylamine
(4.11 g, 16.2 mmol) in 1,2-dimethoxyethane (20 ml) and water (10
ml) were added sodium hydrogen carbonate (4.10 g, 48.6 mmol) and
tetrakis(triphenylphosphine)palladium (1.87 g, 1.62 mmol) and the
mixture was heated under reflux for 12 hr. The mixture was allowed
to cool to room temperature, and water was added to the reaction
mixture. The mixture was extracted with ethyl acetate and the
organic layer was washed successively with saturated aqueous sodium
hydrogen carbonate solution and saturated brine and dried over
anhydrous magnesium sulfate. After filtration, the solvent was
evaporated under reduced pressure and the residue was purified by
silica gel chromatography (hexane:ethyl acetate=5:1) to give methyl
2-(2-amino-4-chlorophenyl)-3-cyclohexyl-1H-indole-6-carboxylate
(6.17 g, yield 100%).
[1220] .sup.1H-NMR(400 MHz, DMSO-d.sub.6): (ppm) 11.33(1H, br),
7.95(1H, d, J=1.2 Hz), 7.79(1H, d, J=8.4 Hz), 7.58(1H, dd, J=8.0,
1.6 Hz), 7.02(1H, d, J=8.0 Hz), 6.83(1H, d, J=2.0 Hz), 6.65(1H, dd,
J=8.0, 2.4 Hz), 5.17(2H, br), 3.84(3H, s), 2.55-2.55(1H, m),
1.64-1.91(6H, m), 1.20-1.37(4H, m).
Step 3: Production of methyl
2-[4-chloro-2-(2-chloroacetylamino)phenyl]-3-cyclohexyl-1H-indole-6-carbo-
xylate
[1221] ##STR348##
[1222] To a suspension of methyl
2-(2-amino-4-chlorophenyl)-3-cyclohexyl-1H-indole-6-carboxylate
(6.17 g, 16.1 mmol), sodium acetate (1.39 g, 17.0 mmol) and acetic
acid (0.98 ml, 17.0 mmol) in tetrahydrofuran (50 ml) was added
dropwise chloroacetyl chloride (1.35 ml, 17.0 mmol), and the
mixture was stirred at room temperature for 2 hr. The reaction
mixture was concentrated under reduced pressure, and water was
added. The precipitate was collected by filtration, washed with
water and dried in vacuo to give methyl
2-[4-chloro-2-(2-chloroacetylamino)phenyl]-3-cyclohexyl-1H-indole-6-carbo-
xylate (6.71 g, yield 95%).
Step 4: Production of methyl
3-chloro-13-cyclohexyl-6-oxo-6,7-dihydro-5H-benzo[5,6][1,4]diazepino[7,1--
a]indole-10-carboxylate
[1223] ##STR349##
[1224] To a solution of methyl
2-[4-chloro-2-(2-chloroacetylamino)phenyl]-3-cyclohexyl-1H-indole-6-carbo-
xylate (6.71 g, 14.6 mmol) in N,N-dimethylformamide (40 ml) and
tetrahydrofuran (10 ml) was added sodium hydride (1.29 g, 3.21
mmol) under ice-cooling, and the mixture was stirred for 2 hr. The
reaction mixture was concentrated under reduced pressure and water
was added. The precipitate was collected by filtration, washed
successively with water and hexane and dried in vacuo to give
methyl
3-chloro-13-cyclohexyl-6-oxo-6,7-dihydro-5H-benzo[5,6][1,4]diazepino[7,1--
a]indole-10-carboxylate (6.97 g, yield 100%).
[1225] .sup.1H-NMR(400 MHz, DMSO-d.sub.6): (ppm) 8.28(1H, d, J=1.2
Hz), 7.96(1H, d, J=8.4 Hz), 7.68(1H, dd, J=8.4, 1.6 Hz), 7.52(1H,
d, J=8.4 Hz), 7.44(1H, dd, J=8.4, 2.0 Hz), 7.31(1H, d, J=2.0 Hz),
5.10(1H, d, J=14.4 Hz), 4.58(1H, d, J=14.8 Hz), 3.89(3H, s),
2.81-2.81(1H, m), 1.67-2.10(5H, m), 1.37-1.56(2H, m), 1.13-1.29(3H,
m).
Example 1-11
Production of methyl
3-chloro-13-cyclohexyl-6-oxo-5-[2-oxo-2-(piperidin-1-yl)ethyl]-6,7-dihydr-
o-5H-benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylate
[1226] ##STR350##
[1227] A suspension of methyl
3-chloro-13-cyclohexyl-6-oxo-6,7-dihydro-5H-benzo[5,6][1,4]diazepino[7,1--
a]indole-10-carboxylate (2.00 g, 4.73 mmol),
1-(2-chloroacetyl)piperidine (1.15 g, 7.09 mmol) and potassium
carbonate (1.31 g, 9.46 mmol) in N,N-dimethylformamide (20 ml) was
stirred at 90.degree. C. for 24 hr. The reaction mixture was
concentrated under reduced pressure and water was added. The
precipitate was collected by filtration, washed with water and
dried in vacuo. A crude product was washed with a mixed solvent of
hexane (45 ml) and diethyl ether (15 ml) and dried in vacuo to give
methyl
3-chloro-13-cyclohexyl-6-oxo-5-[2-oxo-2-(piperidin-1-yl)ethyl]-6,7-dihydr-
o-5H-benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylate (2.16 g,
yield 83%).
[1228] .sup.1H-NMR(400 MHz, DMSO-d.sub.6): .delta.(ppm) 8.29(1H, d,
J=1.6 Hz), 7.95(1H, d, J=8.8 Hz), 7.68(1H, dd, J=8.8; 1.6 Hz),
7.51-7.57(3H, m), 5.22(1H, d, J=14.8 Hz), 4.71(1H, d, J=16.8 Hz),
4.56(1H, d, J=14.8 Hz), 4.50(1H, d, J=16.8 Hz), 3.89(3H, s),
3.29-3.43(4H,m), 2.83-2.83(1H, m), 1.33-2.08(16H, m).
Example 1-12
Production of methyl
3-chloro-13-cyclohexyl-5-[2-(piperidin-1-yl)ethyl]-6,7-dihydro-5H-benzo[5-
,6][1,4]diazepino[7,1-a]indole-10-carboxylate
[1229] ##STR351##
[1230] To a solution of methyl
3-chloro-13-cyclohexyl-6-oxo-5-[2-oxo-2-(piperidin-1-yl)ethyl]-6,7-dihydr-
o-5H-benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylate (3.80 g,
6.94 mmol) in tetrahydrofuran (10 ml) was added 1M BH.sub.3 THF
complex tetrahydrofuran solution (50 ml) under ice-cooling, and the
mixture was stirred at room temperature for 4 hr. 2N Hydrochloric
acid (40 ml) was added to the reaction mixture under ice-cooling,
and the mixture was stirred at 70.degree. C. for 12 hr. The
reaction mixture was allowed to cool to room temperature,
neutralized with saturated aqueous sodium hydrogen carbonate
solution and extracted with ethyl acetate. The organic layer was
washed with saturated brine and dried over anhydrous magnesium
sulfate. After filtration, the solvent was evaporated under reduced
pressure, and the residue was purified by silica gel chromatography
(ethyl acetate:methanol=50:1) to give methyl
3-chloro-13-cyclohexyl-5-[2-(piperidin-1-yl)ethyl]-6,7-dihydro-5H-benzo[5-
,6][1,4]diazepino[7,1-a]indole-10-carboxylate (2.30 g, yield
64%).
[1231] .sup.1H-NMR(400 MHz, DMSO-d.sub.6): .delta.(ppm) 8.15(1H, d,
J=1.6 Hz), 7.84(1H, d, J=8.8 Hz), 7.59(1H, dd, J=8.4, 1.2 Hz),
7.30(1H, d, J=2.0 Hz), 7.24(1H, d, J=8.0 Hz), 7.15(1H, dd,J=8.4,
2.4 Hz), 3.86-4.75(4H, m), 3.84(3H, s), 3.12-3.51(4H, m),
2.74-2.74(1H, m), 1.60-2.33(12H, m), 1.09-1.40(8H, m).
Example 1-13
Production of
3-chloro-13-cyclohexyl-5-[2-(piperidin-1-yl)ethyl]-6,7-dihydro-5H-benzo[5-
,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid
[1232] ##STR352##
[1233] To a suspension of methyl
3-chloro-13-cyclohexyl-5-[2-(piperidin-1-yl)ethyl]-6,7-dihydro-5H-benzo[5-
,6][1,4]diazepino[7,1-a]indole-10-carboxylate (1.21 g, 2.32 mmol)
in tetrahydrofuran (10 ml) and methanol (10 ml) was added 4N
aqueous sodium hydroxide solution (3 ml), and the mixture was
stirred at 90.degree. C. for 8 hr. 1N Hydrochloric acid (12 ml) was
added to adjust to pH 7, and the mixture was extracted with a mixed
solvent of ethyl acetate and tetrahydrofuran. The organic layer was
washed with saturated brine and dried over anhydrous sodium
sulfate. After filtration, the solvent was evaporated under reduced
pressure and crude crystals were washed with methanol, collected by
filtration and dried in vacuo to give
3-chloro-13-cyclohexyl-5-[2-(piperidin-1-yl)ethyl]-6,7-dihydro-5H-benzo[5-
,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid (884 mg, yield
72%).
[1234] .sup.1H-NMR(400 MHz, DMSO-d.sub.6): (ppm) 11.64(1H, br),
8.14(1H, d, J=1.2 Hz), 7.83(1H, d, J=8.4 Hz), 7.60(1H, dd, J=8.4,
1.2 Hz), 7.32(1H, d, J=2.0 Hz), 7.26(1H, d, J=8.0 Hz), 7.17(1H, dd,
J=8.4, 2.0 Hz), 3.03-4.93(8H, m), 2.76-2.76(1H, m), 1.59-2.34(12H,
m), 1.19-1.47(8H, m).
[1235] MS 506(M+1:Cl.sup.35), 508(M+1:Cl.sup.37).
Example 1-14
Production of
3-chloro-13-cyclohexyl-5-[2-(piperidin-1-yl)ethyl]-6,7-dihydro-5H-benzo[5-
,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid
dihydrochloride
[1236] ##STR353##
[1237] To a solution of
3-chloro-13-cyclohexyl-5-[2-(piperidin-1-yl)ethyl]-6,7-dihydro-5H-benzo[5-
,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid (1.86 g, 3.67
mmol) in ethyl acetate (20 ml) was added 4N HCl-ethyl acetate
solution (7 ml) at room temperature, and the mixture was stirred
for 30 min. The reaction mixture was concentrated under reduced
pressure. Diethyl ether was added to the crude crystals and the
crystals were collected by filtration and washed with diethyl
ether. The crystals were dried in vacuo to give
3-chloro-13-cyclohexyl-5-[2-(piperidin-1-yl)ethyl]-6,7-dihydro-5H-benzo[5-
,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid dihydrochloride
(2.13 g, yield 92%).
[1238] .sup.1H-NMR(400 MHz, DMSO-d.sub.6): (ppm) 10.23(1H, br),
8.18(1H, d, J=1.2 Hz), 7.85(1H, d, J=8.4 Hz), 7.60(1H, dd, J=8.4,
1.2 Hz), 7.35-7.38(2H, m), 7.32(1H, dd, J=8.0, 1.6 Hz),
2.88-4.98(6H, m), 2.79-2.79(1H, m), 2.52-2.61(2H, m),
0.98-2.07(20H, m).
[1239] MS 506(M+1).
Example 1-15
Production of methyl
13-cyclohexyl-2-fluoro-6-oxo-6,7-dihydro-5H-benzo[5,6][1,4]diazepino[7,1--
a]indole-10-carboxylate
Step 1: Production of
4-fluoro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenylamine
[1240] ##STR354##
[1241] To a solution of 2-bromo-4-fluoroaniline (5.0 g, 26.3 mmol)
in 1,4-dioxane (50 ml) were added triethylamine (18.5 ml, 132.7
mmol) and
[1,1-bis(diphenylphosphino)ferrocene]dichloropalladium(II)
dichloromethane complex (PdCl.sub.2(dppf)CH.sub.2Cl.sub.2) (1.07 g,
1.3 mmol) at room temperature. To the mixture was added dropwise
pinacolborane (11.5 ml, 79.2 mmol) at room temperature and the
mixture was stirred at 100.degree. C. for 27 hr. Saturated aqueous
ammonium chloride solution was added to the reaction mixture and
the mixture was extracted with ethyl acetate. The organic layer was
washed with saturated brine and dried over anhydrous sodium
sulfate. After filtration, the solvent was evaporated under reduced
pressure and the residue was purified by silica gel chromatography
(toluene) to give
4-fluoro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl
amine (2.0 g, yield 32.0%).
[1242] .sup.1H-NMR(400 MHz, CDCl.sub.3): .delta.(ppm) 7.28(1H, d,
J=3.2 Hz), 6.91(1H, ddd, J=8.8, 8.8, 3.2 Hz), 6.53(1H, dd, J=8.8,
3.6 Hz), 4.45(2H, brs), 1.34(12H, s).
[1243] MS 238(M+1).
Step 2: Production of methyl
2-(2-amino-5-fluorophenyl)-3-cyclohexyl-1H-indole-6-carboxylate
[1244] ##STR355##
[1245] To a suspension of methyl
2-bromo-3-cyclohexyl-1H-indole-6-carboxylate (2.35 g, 6.98 mmol)
obtained in the same manner as in the method described in
WO03/010140 and
4-fluoro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenylamine
(1.99 g, 8.38 mmol) in 1,2-dimethoxyethane (24 ml) and water (12
ml) were added sodium hydrogen carbonate (2.00 g, 24.0 mmol) and
tetrakis(triphenylphosphine)palladium (400 mg, 0.34 mmol), and the
mixture was heated under reflux for 14 hr. The mixture was allowed
to cool to room temperature, and water was added to the reaction
mixture. The mixture was extracted with ethyl acetate and the
organic layer was washed with saturated brine and dried over
anhydrous sodium sulfate. After filtration, the solvent was
evaporated under reduced pressure and the residue was purified by
silica gel chromatography (hexane:ethyl acetate=4:1-3:1) to give
methyl
2-(2-amino-5-fluorophenyl)-3-cyclohexyl-1H-indole-6-carboxylate
(2.44 g, yield 95.7%).
[1246] .sup.1H-NMR(300 MHz, CDCl.sub.3): .delta.(ppm) 8.22(1H,
brs), 8.09(1H, brs), 7.82(1H, d, J=6.0 Hz), 7.37-7.49(1H, m),
7.17(1H, brd, J=6.6 Hz), 6.89-7.03(1H, m), 6.74(1H, dd, J=8.1, 4.8
Hz), 3.94(3H, s), 3.66(2H, brs), 2.63-2.78(1H, m), 1.70-2.01(7H,
m), 1.23-1.50(3H, m).
Step 3: Production of methyl
2-[2-(2-chloroacetylamino)-5-fluorophenyl]-3-cyclohexyl-1H-indole-6-carbo-
xylate
[1247] ##STR356##
[1248] To a suspension of methyl
2-(2-amino-5-fluorophenyl)-3-cyclohexyl-1H-indole-6-carboxylate
(2.44 g, 6.68 mmol), sodium acetate (602 mg, 7.3 mmol) and acetic
acid (0.45 ml, 7.86 mmol) in tetrahydrofuran (20 ml) was added
dropwise chloroacetyl chloride (0.60 ml, 7.53 mmol), and the
mixture was stirred at room temperature for 2 hr. Saturated aqueous
sodium hydrogen carbonate solution was added to the reaction
mixture and the mixture was extracted with ethyl acetate. The
organic layer was washed successively with saturated aqueous sodium
carbonate solution and saturated brine and dried over anhydrous
sodium sulfate. After filtration, the solvent was evaporated under
reduced pressure and a mixed solvent of hexane:ethyl acetate (4:1)
was added to the residue. The precipitated solid was collected by
filtration to give methyl
2-[2-(2-chloroacetylamino)-5-fluorophenyl]-3-cyclohexyl-1H-indole-6-carbo-
xylate (2.5 g, yield 84.7%).
[1249] .sup.1H-NMR(400 MHz, DMSO-d.sub.6): .delta.(ppm) 11.50(1H,
s), 9.49(1H, s), 7.99(1H, d, J=1.6 Hz), 7.85(1H, dd, J=4.8, 4.8
Hz), 7.83(1H, d, J=8.8 Hz), 7.60(1H, dd, J=8.8, 1.6 Hz), 7.34(1H,
ddd, J=8.4, 8.4, 2.8 Hz), 7.21(1H, dd, J=9.2, 3.2 Hz), 4.18(2H, s),
3.85(3H, s), 2.41-2.48(1H, m), 1.78-1.92(2H, m), 1.61-1.77(5H, m),
1.21-1.34(3H, m).
Step 4: Production of methyl
13-cyclohexyl-2-fluoro-6-oxo-6,7-dihydro-5H-benzo[5,6][1,4]diazepino[7,1--
a]indole-10-carboxylate
[1250] ##STR357##
[1251] To a solution of methyl
2-[2-(2-chloroacetylamino)-5-fluorophenyl]-3-cyclohexyl-1H-indole-6-carbo-
xylate (2.5 g, 5.6 mmol) in N,N-dimethylformamide was added sodium
hydride (250 mg, 6.25 mmol) under ice-cooling, and the mixture was
stirred for 2 hr. To the reaction mixture was added 1N hydrochloric
acid and the mixture was extracted with ethyl acetate. The organic
layer was washed with saturated brine and dried over anhydrous
sodium sulfate. After filtration, the solvent was evaporated under
reduced pressure and the residue was purified by silica gel
chromatography (hexane:ethyl acetate=3:2-2:3) to give methyl
13-cyclohexyl-2-fluoro-6-oxo-6,7-dihydro-5H-benzo[5,6][1,4]diazepino[7,1--
a]indole-10-carboxylate (1.81 g, yield 79.7%).
[1252] .sup.1H-NMR(400 MHz, DMSO-d.sub.6): .delta.(ppm) 10.33(1H,
s), 8.29(1H, d, J=1.2 Hz), 7.98(1H, d, J=8.4 Hz), 7.68(1H, dd,
J=8.4, 1.6 Hz), 7.41(1H, ddd, J=8.4, 8.4, 2.8 Hz), 7.30(1H,dd,
J=8.8, 5.6 Hz), 7.26(1H, dd, J=9.2, 3.2 Hz), 5.10(1H, d, J=14.8
Hz), 4.57(1H, d, J=14.8 Hz), 3.89(3H, s), 2.79-2.90(1H, m),
1.98-2.12(3H, m), 1.86-1.94(1H, m), 1.67-1.78(2H, m), 1.48-1.57(1H,
m), 1.34-1.45(2H, m), 1.16-1.28(1H, m).
Example 1-16
Production of methyl
13-cyclohexyl-2-fluoro-6-oxo-5-[2-oxo-2-(piperidin-1-yl)ethyl]-6,7-dihydr-
o-5H-benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylate
[1253] ##STR358##
[1254] To a solution of methyl
13-cyclohexyl-2-fluoro-6-oxo-6,7-dihydro-5H-benzo[5,6][1,4]diazepino[7,1--
a]indole-10-carboxylate (150 mg, 0.37 mmol) and
1-(2-chloroacetyl)piperidine (90 mg, 0.55 mmol) in
N,N-dimethylformamide (2 ml) were added potassium carbonate (102
mg, 0.73 mmol) and potassium iodide (5 mg, 0.03 mmol) and the
mixture was stirred at 90.degree. C. for 3 hr. Water was added to
the reaction mixture and the mixture was extracted with ethyl
acetate. The organic layer was washed with saturated brine and
dried over anhydrous sodium sulfate. After filtration, the solvent
was evaporated under reduced pressure and the residue was purified
by silica gel chromatography (hexane:ethyl acetate=1:1-1:2) to give
methyl
13-cyclohexyl-2-fluoro-6-oxo-5-[2-oxo-2-(piperidin-1-yl)ethyl]-6,7-dihydr-
o-5H-benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylate (137 mg,
yield 69.9%).
[1255] .sup.1H-NMR(400 MHz, CDCl.sub.3): .delta.(ppm) 8.22(1H,
brs), 7.89(1H, d, J=8.4 Hz), 7.79(1H, dd, J=8.4, 1.2 Hz), 7.61(1H,
dd, J=9.6, 5.2 Hz), 7.13-7.20(2H, m), 5.00(1H, d, J=14.4 Hz),
4.80(1H, d, J=16.4 Hz), 4.55(1H, d, J=14.4 Hz), 3.95(1H, d, J=16.0
Hz), 3.95(3H, s), 3.66-3.74(1H, m), 3.49-3.58(1H, m), 3.33-3.42(1H,
m), 3.22-3.31(1H, m), 2.88-2.99(1H, m), 1.92-2.17(4H, m),
1.76-1.87(2H, m), 1.23-1.72(10H, m).
Example 1-17
Production of methyl
13-cyclohexyl-2-fluoro-5-[2-(piperidin-1-yl)ethyl]-6,7-dihydro-5H-benzo[5-
,6][1,4]diazepino[7,1-a]indole-10-carboxylate
[1256] ##STR359##
[1257] To a solution of methyl
13-cyclohexyl-2-fluoro-6-oxo-5-[2-oxo-2-(piperidin-1-yl)ethyl]-6,7-aihydr-
o-5H-benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylate (137 mg,
0.25 mmol) in tetrahydrofuran (1.0 ml) was added 1M BH.sub.3 THF
complex tetrahydrofuran solution (2.0 ml) under ice-cooling
stirred, and the mixture was stirred at room temperature for 3 hr.
2N Hydrochloric acid was added to the reaction mixture, and the
mixture was stirred at 70.degree. C. for 3 hr. 4N Aqueous sodium
hydroxide solution was added to adjust to pH 8 and the mixture was
extracted with ethyl acetate. The organic layer was washed with
saturated brine and dried over anhydrous sodium sulfate. After
filtration, the solvent was evaporated under reduced pressure and
the residue was purified by silica gel chromatography
(chloroform:methanol=30:1-10:1) to give methyl
13-cyclohexyl-2-fluoro-5-[2-(piperidin-1-yl)ethyl]-6,7-dihydro-5H-benzo[5-
,6][1,4]diazepino[7,1-a]indole-10-carboxylate (91 mg, yield
70.5%).
[1258] MS 504(M+1).
Example 1-18
Production of
13-cyclohexyl-2-fluoro-5-[2-(piperidin-1-yl)ethyl]-6,7-dihydro-5H-benzo[5-
,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid
dihydrochloride
[1259] ##STR360##
[1260] To a solution of methyl
13-cyclohexyl-2-fluoro-5-[2-(piperidin-1-yl)ethyl]-6,7-dihydro-5H-benzo[5-
,6][1,4]diazepino[7,1-a]indole-10-carboxylate (91 mg, 0.18 mmol) in
tetrahydrofuran (1.0 ml) and methanol (1.0 ml) was added 4N aqueous
sodium hydroxide solution (1.0 ml), and the mixture was stirred at
60.degree. C. for 3 hr. 1N Hydrochloric acid was added to the
reaction mixture to adjust to pH 7 and the mixture was extracted
with ethyl acetate. The organic layer was washed with saturated
brine and dried over anhydrous sodium sulfate. After filtration,
the solvent was evaporated under reduced pressure. To a solution of
the residue in tetrahydrofuran (1.0 ml) was added 4N HCl-ethyl
acetate solution (1 ml) and the solvent was evaporated under
reduced pressure. Hexane was added and the precipitated solid was
collected by filtration. The solid was washed with hexane and dried
in vacuo to give
13-cyclohexyl-2-fluoro-5-[2-(piperidin-1-yl)ethyl]-6,7-dihydro-5H-benzo[5-
,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid dihydrochloride
(64 mg, yield 63.4%).
[1261] MS 490.2(M+1).
[1262] The compounds of Examples 1-19 to 1-95 were produced by the
same method as in Examples 1-1 to 1-18 or a method similar thereto,
and where necessary, employing other conventional methods. Chemical
structural formulas are shown in Tables 2-20. [1263]
5-acetyl-13-cyclohexyl-6,7-dihydro-5H-benzo[5,6][1,4]diazepino[7,1-a]indo-
le-10-carboxylic acid (Example 1-19), [1264]
13-cyclohexyl-5-methyl-6,7-dihydro-5H-benzo[5,6][1,4]diazepino[7,1-a]indo-
le-10-carboxylic acid (Example 1-20), [1265]
13-cyclohexyl-5-dimethylcarbamoylmethyl-6,7-dihydro-5H-benzo[5,6][1,4]dia-
zepino[7,1-a]indole-10-carboxylic acid (Example 1-21), [1266]
5-benzyl-13-cyclohexyl-6,7-dihydro-5H-benzo[5,6][1,4]diazepino[7,1-a]indo-
le-10-carboxylic acid (Example 1-22), [1267]
13-cyclohexyl-5-isopropyl-6,7-dihydro-5H-benzo[5,6][1,4]diazepino[7,1-a]i-
ndole-10-carboxylic acid monohydrochloride (Example 1-23), [1268]
13-cyclohexyl-6-oxo-6,7-dihydro-5H-benzo[5,6][1,4]diazepino[7,1-a]indole--
10-carboxylic acid (Example 1-24), [1269]
5-(benzylcarbamoylmethyl)-13-cyclohexyl-6,7-dihydro-5H-benzo[5,6][1,4]dia-
zepino[7,1-a]indole-10-carboxylic acid (Example 1-25), [1270]
13-cyclohexyl-5-[2-(morpholin-4-yl)-2-oxoethyl]-6,7-dihydro-5H-benzo[5,6]-
[1,4]diazepino[7,1-a]indole-10-carboxylic acid (Example 1-26),
[1271]
13-cyclohexyl-5-[2-(morpholin-4-yl)ethyl]-6,7-dihydro-5H-benzo[5,6][1,4]d-
iazepino[7,1-a]indole-10-carboxylic acid dihydrochloride (Example
1-27), [1272]
13-cyclohexyl-5-dimethylcarbamoylmethyl-3-methoxy-6,7-dihydro-5H--
benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid (Example
1-28), [1273]
13-cyclohexyl-5-[2-oxo-2-(piperidin-1-yl)ethyl]-6,7-dihydro-5H-be-
nzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid (Example
1-29), [1274]
13-cyclohexyl-5-[2-(4-ethylpiperazin-1-yl)-2-oxoethyl]-6,7-dihydr-
o-5H-benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid
dihydrochloride (Example 1-30), [1275]
13-cyclohexyl-5-dimethylcarbamoyl-6,7-dihydro-5H-benzo[5,6][1,4]diazepino-
[7,1-a]indole-10-carboxylic acid (Example 1-31), [1276]
13-cyclohexyl-5-[2-(piperidin-1-yl)ethyl]-6,7-dihydro-5H-benzo[5,6][1,4]d-
iazepino[7,1-a]indole-10-carboxylic acid dihydrochloride (Example
1-32), [1277]
13-cyclohexyl-5-{[(pyridin-2-ylmethyl)carbamoyl]methyl}-6,7-dihyd-
ro-5H-benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid
dihydrochloride (Example 1-33), [1278]
13-cyclohexyl-5-{2-[(pyridin-2-ylmethyl)amino]ethyl}-6,7-dihydro-5H-benzo-
[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid
trihydrochloride (Example 1-34), [1279]
13-cyclohexyl-5-[2-(4-hydroxypiperidin-1-yl)-2-oxoethyl]-6,7-dihydro-5H-b-
enzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid
monohydrochloride (Example 1-35), [1280]
13-cyclohexyl-5-[2-(4-methoxypiperidin-1-yl)-2-oxoethyl]-6,7-dihydro-5H-b-
enzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid
monohydrochloride (Example 1-36), [1281]
13-cyclohexyl-5-{[N-(2-methoxyethyl)-N-methylcarbamoyl]methyl}-6,7-dihydr-
o-5H-benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid
monohydrochloride (Example 1-37), [1282]
13-cyclohexyl-5-[2-(4-ethylpiperazin-1-yl)ethyl]-6,7-dihydro-5H-benzo[5,6-
][1,4]diazepino[7,1-a]indole-10-carboxylic acid dihydrochloride
(Example 1-38), [1283]
13-cyclohexyl-5-[2-(4-methoxypiperidin-1-yl)ethyl]-6,7-dihydro-5H-benzo[5-
,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid dihydrochloride
(Example 1-39), [1284]
13-cyclohexyl-5-{2-[N-(2-methoxyethyl)-N-methylamino]ethyl}-6,7-dihydro-5-
H-benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid
dihydrochloride (Example 1-40), [1285]
13-cyclohexyl-5-phenethyl-6,7-dihydro-5H-benzo[5,6][1,4]diazepino[7,1-a]i-
ndole-10-carboxylic acid monohydrochloride (Example 1-41), [1286]
13-cyclohexyl-5-[2-(4-hydroxypiperidin-1-yl)ethyl]-6,7-dihydro-5H-benzo[5-
,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid dihydrochloride
(Example 1-42), [1287]
13-cyclohexyl-5-[2-(4-dimethylaminopiperidin-1-yl)-2-oxoethyl]-6,7-dihydr-
o-5H-benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid
dihydrochloride (Example 1-43), [1288]
13-cyclohexyl-5-[2-(4-dimethylaminopiperidin-1-yl)ethyl]-6,7-dihydro-5H-b-
enzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid
trihydrochloride (Example 1-44), [1289]
13-cyclohexyl-5-[2-(1,1-dioxothiomorpholin-4-yl)-2-oxoethyl]-6,7-dihydro--
5H-benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid
monohydrochloride (Example 1-45), [1290]
13-cyclohexyl-5-[2-(4-ethoxycarbonylpiperazin-1-yl)-2-oxoethyl]-6,7-dihyd-
ro-5H-benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid
monohydrochloride (Example 1-46), [1291]
13-cyclohexyl-5-[2-(4-isopropylpiperazin-1-yl)-2-oxoethyl]-6,7-dihydro-5H-
-benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid
dihydrochloride (Example 1-47), [1292]
13-cyclohexyl-5-[2-(4-isopropylpiperazin-1-yl)ethyl]-6,7-dihydro-5H-benzo-
[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid
trihydrochloride (Example 1-48), [1293]
13-cyclohexyl-5-[2-(1,4-oxazepan-4-yl)-2-oxoethyl]-6,7-dihydro-5H-benzo[5-
,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid monohydrochloride
(Example 1-49), [1294]
13-cyclohexyl-5-[2-(4-methylpiperazin-1-yl)-2-oxoethyl]-6,7-dihydro-5H-be-
nzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid
dihydrochloride (Example 1-50), [1295]
5-[2-(4-acetylpiperazin-1-yl)-2-oxoethyl]-13-cyclohexyl-6,7-dihydro-5H-be-
nzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid
monohydrochloride (Example 1-51), [1296]
13-cyclohexyl-5-[2-(4-methylpiperazin-1-yl)ethyl]-6,7-dihydro-5H-benzo[5,-
6][1,4]diazepino[7,1-a]indole-10-carboxylic acid trihydrochloride
(Example 1-52), [1297]
13-cyclohexyl-5-[2-(4-methyl-1,4-diazepan-1-yl)ethyl]-6,7-dihydro-5H-benz-
o[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid
trihydrochloride (Example 1-53), [1298]
13-cyclohexyl-5-[2-(4-methyl-1,4-diazepan-1-yl)-2-oxoethyl]-6,7-dihydro-5-
H-benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid
dihydrochloride (Example 1-54), [1299]
13-cyclohexyl-5-[2-(4-ethylpiperazin-1-yl)-2-oxoethyl]-6,7-dihydro-5H-ben-
zo[5,6][1,4]diazepino[7,1-a]indole-10-carboxamide (Example 1-55),
[1300]
13-cyclohexyl-5-[2-oxo-2-(pyrrolidin-1-yl)ethyl]-6,7-dihydro-5H-benzo[5,6-
][1,4]diazepino[7,1-a]indole-10-carboxylic acid monohydrochloride
(Example 1-56), [1301]
13-cyclohexyl-5-[2-(pyrrolidin-1-yl)ethyl]-6,7-dihydro-5H-benzo[5,6][1,4]-
diazepino[7,1-a]indole-10-carboxylic acid dihydrochloride (Example
1-57), [1302]
13-cyclohexyl-5-[2-(morpholin-4-yl)-2-oxoethyl]-7-phenyl-6,7-dihy-
dro-5H-benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid
monohydrochloride (Example 1-58), [1303]
13-cyclohexyl-7-phenyl-6,7-dihydro-5H-benzo[5,6][1,4]diazepino[7,1-a]indo-
le-10-carboxylic acid monohydrochloride (Example 1-59), [1304]
3-chloro-13-cyclohexyl-5-[2-(morpholin-4-yl)-2-oxoethyl]-6,7-dihydro-5H-b-
enzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid
monohydrochloride (Example 1-60), [1305]
13-cyclohexyl-5-[4-(morpholin-4-yl)-4-oxobutyl]-6,7-dihydro-5H-benzo[5,6]-
[1,4]diazepino[7,1-a]indole-10-carboxylic acid monohydrochloride
(Example 1-61), [1306]
13-cyclohexyl-5-[4-(4-ethylpiperazin-1-yl)-4-oxobutyl]-6,7-dihydro-5H-ben-
zo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid
dihydrochloride (Example 1-62), [1307]
13-cyclohexyl-3-methyl-5-[2-(morpholin-4-yl)-2-oxoethyl]-6,7-dihydro-5H-b-
enzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid
monohydrochloride (Example 1-63), [1308]
13-cyclohexyl-3-methoxy-5-[2-(morpholin-4-yl)-2-oxoethyl]-6,7-dihydro-5H--
benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid
monohydrochloride (Example 1-64), [1309]
13-cyclohexyl-3-methoxy-5-[2-oxo-2-(piperidin-1-yl)ethyl]-6,7-dihydro-5H--
benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid
monohydrochloride (Example 1-65), [1310]
13-cyclohexyl-5-[2-(4-ethylpiperazin-1-yl)-2-oxoethyl]-3-methoxy-6,7-dihy-
dro-5H-benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid
dihydrochloride (Example 1-66), [1311]
13-cyclohexyl-3-methoxy-5-[2-(morpholin-4-yl)ethyl]-6,7-dihydro-5H-benzo[-
5,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid dihydrochloride
(Example 1-67), [1312]
13-cyclohexyl-3-methyl-5-[2-(morpholin-4-yl)ethyl]-6,7-dihydro-5H-benzo[5-
,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid dihydrochloride
(Example 1-68), [1313]
13-cyclohexyl-5-[2-(1,4-oxazepan-4-yl)ethyl]-6,7-dihydro-5H-benzo[5,6][1,-
4]diazepino[7,1-a]indole-10-carboxylic acid dihydrochloride
(Example 1-69), [1314]
13-cyclohexyl-5-[2-(4-methanesulfonylpiperazin-1-yl)-2-oxoethyl]-6,7-dihy-
dro-5H-benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid
monohydrochloride (Example 1-70), [1315]
13-cyclohexyl-5-[2-(4-ethylpiperidin-1-yl)-2-oxoethyl]-6,7-dihydro-5H-ben-
zo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid
monohydrochloride (Example 1-71), [1316]
13-cyclohexyl-5-[2-(4-methylpiperidin-1-yl)-2-oxoethyl]-6,7-dihydro-5H-be-
nzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid
monohydrochloride (Example 1-72), [1317]
13-cyclohexyl-5-[2-(4-ethylpiperidin-1-yl)ethyl]-6,7-dihydro-5H-benzo[5,6-
][1,4]diazepino[7,1-a]indole-10-carboxylic acid dihydrochloride
(Example 1-73), [1318]
13-cyclohexyl-3-methoxy-5-[2-(piperidin-1-yl)ethyl]-6,7-dihydro-5H-benzo[-
5,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid dihydrochloride
(Example 1-74), [1319]
13-cyclohexyl-5-[2-(4-methylpiperidin-1-yl)ethyl]-6,7-dihydro-5H-benzo[5,-
6][1,4]diazepino[7,1-a]indole-10-carboxylic acid dihydrochloride
(Example 1-75), [1320]
3-chloro-13-cyclohexyl-5-[2-(4-ethylpiperazin-1-yl)-2-oxoethyl]-6,7-dihyd-
ro-5H-benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid
dihydrochloride (Example 1-76), [1321]
3-chloro-13-cyclohexyl-5-[2-oxo-2-(piperidin-1-yl)ethyl]-6,7-dihydro-5H-b-
enzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid
monohydrochloride (Example 1-77), [1322]
5-[2-(azepan-1-yl)-2-oxoethyl]-13-cyclohexyl-6,7-dihydro-5H-benzo[5,6][1,-
4]diazepino[7,1-a]indole-10-carboxylic acid monohydrochloride
(Example 1-78), [1323]
3-chloro-13-cyclohexyl-5-[2-(morpholin-4-yl)ethyl]-6,7-dihydro-5H-benzo[5-
,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid dihydrochloride
(Example 1-79), [1324]
13-cyclohexyl-5-[4-(morpholin-4-yl)butyl]-6,7-dihydro-5H-benzo[5,6][1,4]d-
iazepino[7,1-a]indole-10-carboxylic acid dihydrochloride (Example
1-80), [1325]
13-cyclohexyl-5-[2-oxo-2-(4-phenylpiperazin-1-yl)ethyl]-6,7-dihyd-
ro-5H-benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid
dihydrochloride (Example 1-81), [1326]
13-cyclohexyl-5-[2-(4-phenylpiperazin-1-yl)ethyl]-6,7-dihydro-5H-benzo[5,-
6][1,4]diazepino[7,1-a]indole-10-carboxylic acid trihydrochloride
(Example 1-82), [1327]
5-[2-(azepan-1-yl)ethyl]-13-cyclohexyl-6,7-dihydro-5H-benzo[5,6][1,4]diaz-
epino[7,1-a]indole-10-carboxylic acid dihydrochloride (Example
1-83), [1328]
13-cyclohexyl-5-[2-(4-ethylpiperazin-1-yl)-2-oxoethyl]-N-methyl-6-
,7-dihydro-5H-benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxamide
(Example 1-84), [1329]
13-cyclohexyl-5-[2-(4-ethylpiperazin-1-yl)-2-oxoethyl]-N-(2-hydroxyethyl)-
-6,7-dihydro-5H-benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxamide
(Example 1-85), [1330]
13-cyclohexyl-5-[2-(4-ethylpiperazin-1-yl)-2-oxoethyl]-N-(2-hydroxy-1,1-d-
imethylethyl)-6,7-dihydro-5H-benzo[5,6][1,4]diazepino[7,1-a]indole-10-carb-
oxamide (Example 1-86), [1331]
13-cyclohexyl-5-[2-(4-dimethylcarbamoylpiperazin-1-yl)ethyl]-6,7-dihydro--
5H-benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid
dihydrochloride (Example 1-87), [1332]
5-[2-(4-benzoylpiperazin-1-yl)ethyl]-13-cyclohexyl-6,7-dihydro-5H-benzo[5-
,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid dihydrochloride
(Example 1-88), [1333]
5-[2-(1-tert-butoxycarbonylpiperidin-4-yl)ethyl]-13-cyclohexyl-6,7-dihydr-
o-5H-benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid
(Example 1-89), [1334]
13-cyclohexyl-5-[2-(2-oxopyrrolidin-1-yl)ethyl]-6,7-dihydro-5H-benzo[5,6]-
[1,4]diazepino[7,1-a]indole-10-carboxylic acid monohydrochloride
(Example 1-90), [1335]
13-cyclohexyl-5-[2-(4-methanesulfonylpiperazin-1-yl)ethyl]-6,7-dihydro-5H-
-benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid
dihydrochloride (Example 1-91), [1336]
5-[2-(1-acetylpiperidin-4-yl)ethyl]-13-cyclohexyl-6,7-dihydro-5H-benzo[5,-
6][1,4]diazepino[7,1-a]indole-10-carboxylic acid monohydrochloride
(Example 1-92), [1337]
13-cyclohexyl-5-[2-(1-ethylpiperidin-4-yl)ethyl]-6,7-dihydro-5H-benzo[5,6-
][1,4]diazepino[7,1-a]indole-10-carboxylic acid dihydrochloride
(Example 1-93), [1338]
13-cyclohexyl-5-[2-(1-methanesulfonylpiperidin-4-yl)ethyl]-6,7-dihydro-5H-
-benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid
monohydrochloride (Example 1-94), [1339]
5-[2-(4-tert-butoxycarbonylpiperazin-1-yl)ethyl]-13-cyclohexyl-6,7-dihydr-
o-5H-benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid
dihydrochloride (Example 1-95).
Example 1-168
Production of
13-cyclohexyl-3-methyl-5-[2-(1,4-oxazepan-4-yl)ethyl]-6,7-dihydro-5H-benz-
o[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid
Step 1: Production of N-chloroacetyl-1,4-oxazepane
[1340] ##STR361##
[1341] A suspension of 1,4-oxazepane hydrochloride (24.80 g, 180
mmol), sodium acetate (29.60 g, 360 mmol) and acetic acid (20.6 ml,
360 mmol) in tetrahydrofuran (400 ml) was stirred for 1 hr, a
solution of chloroacetyl chloride (14.3 ml, 180 mmol) in
tetrahydrofuran (100 ml) was added dropwise under ice-cooling, and
the mixture was stirred overnight at room temperature. To the
reaction mixture was added sodium hydrogen carbonate (65.7 g, 792
mmol), and the mixture was stirred for 1 hr. The insoluble material
was filtered, and the filtrate was concentrated. The obtained
residue was purified by silica gel column chromatography
(hexane:ethyl acetate=2:1-1:2) to give N-chloroacetyl-1,4-oxazepane
(29.8 g, yield 93%).
[1342] .sup.1H-NMR(400 MHz, DMSO-d.sub.6): .delta.(ppm) 4.42(1H,
s), 4.39(1H, s), 3.70-3.72(1H, m), 3.54-3.65(7H, m), 1.82-1.88(1H,
m), 1.72-1.78(1H, m).
Step 2: Production of methyl
13-cyclohexyl-3-methyl-5-[2-(1,4-oxazepan-4-yl)-2-oxoethyl]-6-oxo-6,7-dih-
ydro-5H-benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylate
[1343] ##STR362##
[1344] A suspension of methyl
13-cyclohexyl-3-methyl-6-oxo-6,7-dihydro-5H-benzo[5,6][1,4]diazepino[7,1--
a]indole-10-carboxylate (2.53 g, 6.30 mmol),
N-chloroacetyl-1,4-oxazepane (1.23 g, 6.92 mmol) and potassium
carbonate (1.73 g, 12.6 mmol) in N,N-dimethylformamide (13 ml) was
stirred at 90.degree. C. for 3 hr. To the reaction mixture was
added 2N hydrochloric acid (13 ml), and the precipitated solid was
collected by filtration. After washing with water, the solid was
dried in vacuo and suspended in methanol. The suspension was
stirred for 1 hr, and the obtained crystals were collected by
filtration. The crystals were washed with methanol and dried in
vacuo to give methyl
13-cyclohexyl-3-methyl-5-[2-(1,4-oxazepan-4-yl)-2-oxoethyl]-6-oxo-6,7-dih-
ydro-5H-benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylate (2.85
g, yield 83%).
[1345] .sup.1H-NMR(400 MHz, DMSO-d.sub.6): .delta.(ppm) 8.28(1H,
s), 7.95(1H, d, J=8.8 Hz), 7.68(1H, dd, J=8.0, 1.2 Hz), 7.42(1H, d,
J=7.6 Hz), 7.29-7.33(2H, m), 5.20(1H, d, J=14.4 Hz), 4.68(1H, dd,
J=16.8, 9.6 Hz), 4.48(1H, d, J=14.4 Hz), 4.40(1H, d, J=18.0 Hz),
3.89(3H, s), 3.38-3.71(8H, m), 2.82-2.93(1H, m), 2.41(3H, s),
1.67-2.09(8H, m), 1.53-1.61(1H, m), 1.34-1.48(2H, m), 1.12-1.26(1H,
m).
Step 3: Production of methyl
13-cyclohexyl-3-methyl-5-[2-(1,4-oxazepan-4-yl)ethyl]-6,7-dihydro-5H-benz-
o[5,6][1,4]diazepino[7,1-a]indole-10-carboxylate
[1346] ##STR363##
[1347] To a solution of methyl
13-cyclohexyl-3-methyl-5-[2-(1,4-oxazepan-4-yl)-2-oxoethyl]-6-oxo-6,7-dih-
ydro-5H-benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylate (2.70
g, 4.97 mmol) in tetrahydrofuran (8 ml) was added a solution (20
ml) of 1M BH.sub.3 THF complex in tetrahydrofuran, and the mixture
was stirred at room temperature for 3 hr. To the reaction mixture
was added 4N hydrochloric acid (14 ml), and the mixture was stirred
at 70.degree. C. for 4 hr. The reaction mixture was allowed to cool
to room temperature, neutralized with 4N aqueous sodium hydroxide
solution and saturated aqueous sodium hydrogen carbonate solution,
and extracted with ethyl acetate. The organic layer was washed with
saturated brine and dried over anhydrous sodium sulfate. After
filtration, the solvent was evaporated under reduced pressure. The
residue was crystallized from methanol (10 ml) and collected by
filtration. After washing with methanol, the crystals were dried in
vacuo to give methyl
13-cyclohexyl-3-methyl-5-[2-(1,4-oxazepan-4-yl)ethyl]-6,7-dihydro-5H-benz-
o[5,6][1,4]diazepino[7,1-a]indole-10-carboxylate (2.27 g, yield
89%).
[1348] .sup.1H-NMR(400 MHz, DMSO-d.sub.6): .delta.(ppm) 8.17(1H, d,
J=1.2 Hz), 7.85(1H, d, J=8.8 Hz), 7.61(1H, dd, J=8.4, 1.2 Hz),
7.19(1H, d, J=7.6 Hz), 7.07(1H, s), 6.98(1H, d, J=7.6 Hz), 3.87(3H,
s), 3.42(2H, t, J=6.0 Hz), 3.26-3.29(2H, m), 2.76-2.85(1H, m),
2.42-2.48(4H, m), 2.38(3H, s), 1.91-2.06(2H, m), 1.63-1.86(5H, m),
1.49-1.54(2H, m), 1.19-1.44(3H, m).
Step 4: Production of
13-cyclohexyl-3-methyl-5-[2-(1,4-oxazepan-4-yl)ethyl]-6,7-dihydro-5H-benz-
o[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid
[1349] ##STR364##
[1350] To a solution of methyl
13-cyclohexyl-3-methyl-5-[2-(1,4-oxazepan-4-yl)ethyl]-6,7-dihydro-5H-benz-
o[5,6][1,4]diazepino[7,1-a]indole-10-carboxylate (2.00 g, 3.88
mmol) in tetrahydrofuran (12 ml) and methanol (12 ml) was added 4N
aqueous sodium hydroxide solution (3 ml), and the mixture was
stirred at 80.degree. C. for 3 hr. The reaction mixture was
adjusted to pH 6.5 with 2N hydrochloric acid, and extracted with
chloroform. The organic layer was washed with saturated brine and
dried over anhydrous sodium sulfate. After filtration, the solvent
was evaporated under reduced pressure. The residue was crystallized
from methanol (10 ml) and collected by filtration. After washing
with methanol, the crystals were dried in vacuo to give
13-cyclohexyl-3-methyl-5-[2-(1,4-oxazepan-4-yl)ethyl]-6,7-dihydro-
-5H-benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid (1.48
g, yield 76%).
[1351] .sup.1H-NMR(400 MHz, DMSO-d.sub.6): .delta.(ppm) 12.53(1H,
brs), 8.13(1H, d, J=1.2 Hz), 7.82(1H, d, J=8.4 Hz), 7.59(1H, dd,
J=8.4, 1.2 Hz), 7.18(1H, d, J=7.6 Hz), 7.07(1H, s), 6.98(1H, d,
J=7.6 Hz), 3.43(2H, t, J=5.8 Hz), 3.27-3.29(2H, m), 2.76-2.85(1H,
m), 2.43-2.47(4H, m), 2.38(3H, s), 1.92-2.07(2H, m), 1.59-1.88(5H,
m), 1.49-1.55(2H, m), 1.19-1.44(3H, m).
[1352] MS 502.3(M+1).
Example 1-413
Production of
13-cyclohexyl-5-{2-[(S)-3-(2-methoxyethyl)piperidin-1-yl]ethyl}-3-methyl--
6,7-dihydro-5H-benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic
acid dihydrochloride
Step 1: Production of
(3'S)-2-[1-(tert-butoxycarbonyl)piperidin-3-yl]ethanol
[1353] ##STR365##
[1354] To a suspension of lithium aluminum hydride (11.90 g, 313
mmol) in tetrahydrofuran (250 ml) was added a solution of
(3'S)-ethyl-2-[1-(tert-butoxycarbonyl)piperidin-3-yl]acetate (85.0
g, 313 mmol), obtained in the same manner as in the method
described in WO97/25041, in tetrahydrofuran (600 ml) over 2 hr
under ice-cooling, and the mixture was further stirred for 3 hr. To
the reaction mixture were successively added water (12 ml), 4N
aqueous sodium hydroxide solution (36 ml), water (12 ml) and
anhydrous magnesium sulfate, and the mixture was stirred at room
temperature for 1 hr. Insoluble material was filtered off, and the
solvent was evaporated under reduced pressure to give
(3'S)-2-[1-(tert-butoxycarbonyl)piperidin-3-yl]ethanol (58.10 g,
yield 97.6%).
[1355] .sup.1H-NMR(400 MHz, CDCl.sub.3): .delta.(ppm) 3.84(1H, m),
3.71(3H, m), 2.80(1H, m), 2.53(1H, br), 1.82(2H, m), 1.60(2H, m),
1.46(3H, m), 1.43(9H, s), 1.12(1H, m).
Step 2: Production of tert-butyl
(S)-3-(2-methoxyethyl)piperidine-1-carboxylate
[1356] ##STR366##
[1357] To a suspension of sodium hydride (13.00 g, 325 mmol) in
tetrahydrofuran (60 ml) and N,N-dimethylformamide (350 ml) was
added a solution of
(3'S)-2-[1-(tert-butoxycarbonyl)piperidin-3-yl]ethanol (62.00 g,
270 mmol) in N,N-dimethylformamide (200 ml) at room temperature,
and the mixture was stirred for 15 min. To the reaction mixture was
added methyl iodide (18.5 ml, 297 mmol) at room temperature, and
the mixture was stirred at room temperature for 3 hr. To the
reaction mixture was added water, and the mixture was extracted
with ethyl acetate. The organic layer was washed with saturated
brine and dried over anhydrous magnesium sulfate. After filtration,
the solvent was evaporated under reduced pressure to give
tert-butyl (S)-3-(2-methoxyethyl)piperidine-1-carboxylate (65.0 g,
yield 98%).
[1358] .sup.1H-NMR(300 MHz, CDCl.sub.3): .delta.(ppm) 3.85-3.88(1H,
m), 3.40(2H, t, J=6.6 Hz), 3.31(3H, s), 2.77-2.77(1H, m),
1.80-1.80(2H, m), 1.48-1.63(4H, m), 1.43(9H, s), 1.10-1.10(1H, m),
0.84-0.84(1H, m).
Step 3: Production of (S)-3-(2-methoxyethyl)piperidine
hydrochloride
[1359] ##STR367##
[1360] To a solution of tert-butyl
(S)-3-(2-methoxyethyl)piperidine-1-carboxylate (64 g, 263 mmol) in
ethyl acetate (100 ml) was added 4N HCl-ethyl acetate solution (320
ml), and the mixture was stirred at room temperature for 2 hr. The
solvent was evaporated under reduced pressure to give
(S)-3-(2-methoxyethyl)piperidine hydrochloride as a crude product
(46.7 g, yield 98%). The obtained crude product was used for Step 4
without further purification.
[1361] .sup.1H-NMR(400 MHz, CDCl.sub.3): .delta.(ppm) 9.59(1H, br),
9.26(1H, br), 3.35-3.45(4H, m), 3.28(3H, s), 2.67-2.80(1H, m),
2.48-2.60(1H, m), 2.03-2.14(1H, m), 1.80-1.99(3H, m), 1.45-1.59(2H,
m), 1.09-1.21(1H, m).
Step 4: Production of
(S)-3-(2-methoxyethyl)-N-(chloroacetyl)piperidine
[1362] ##STR368##
[1363] To a suspension of (S)-3-(2-methoxyethyl)piperidine
hydrochloride (46.70 g, 260 mmol), sodium acetate (46.90 g, 572
mmol) and acetic acid (33.1 ml, 572 mmol) in tetrahydrofuran (470
ml) was added dropwise chloroacetyl chloride (28.3 ml, 7.53 mmol)
under ice-cooling, and the mixture was stirred overnight at
temperature. To the 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 and saturated
brine and dried over anhydrous magnesium sulfate. After filtration,
the solvent was evaporated under reduced pressure, and the obtained
residue was purified by silica gel column chromatography
(hexane:ethyl acetate=1:1) to give
(S)-3-(2-methoxyethyl)-N-(chloroacetyl)piperidine (45.0 g, yield
78.8%).
[1364] .sup.1H-NMR(400 MHz, CDCl.sub.3): .delta.(ppm) 4.28-4.37(1H,
m), 3.69-3.81(1H, m), 3.37-3.46(2H, m), 3.32(1.5H, s), 3.30(1.5H,
s), 3.05-3.12(0.5H, m), 2.75-2.81(0.5H, m), 2.63-2.70(0.5H, m),
2.45-2.51(0.5H, m), 1.83-1.91(1H, m), 1.40-1.77(5H, m),
1.14-1.23(1H, m).
Step 5: Production of 2-iodo-5-methylphenylamine hydrochloride
[1365] ##STR369##
[1366] To a solution of 1-iodo-4-methyl-2-nitrobenzene (5.00 g, 19
mmol) in tetrahydrofuran (12.5 ml), methanol (25 ml) and water (6.3
ml) were added reduced iron (5.30 g, 95 mmol) and ammonium chloride
(6.10 g, 114 mmol), and the mixture was stirred overnight at
70.degree. C. The reaction mixture was allowed to cool to room
temperature, tetrahydrofuran (50 ml) was added to the reaction
mixture. After filtration through celite, the filtrate was
concentrated under reduced pressure. Water was added to the
residue, and the mixture was extracted with ethyl acetate. The
organic layer was washed with saturated brine and dried over
anhydrous sodium sulfate. After filtration, the solvent was
evaporated under reduced pressure. To a solution of the residue in
ethyl acetate (20 ml) was added 4N HCl-ethyl acetate solution (10
ml). The precipitated solid was collected by filtration, washed
with ethyl acetate, and dried in vacuo to give
2-iodo-5-methylphenylamine hydrochloride (2.56 g, yield 50%).
[1367] .sup.1H-NMR(300 MHz, DMSO-d.sub.6): .delta.(ppm) 8.34(2H,
brs), 7.56(1H, d, J=8.1 Hz), 6.93(1H, s), 6.51(1H, d, J=7.8 Hz),
2.20(3H, s).
Step 6: Production of
5-methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenylamine
[1368] ##STR370##
[1369] To a solution of 2-iodo-5-methylphenylamine hydrochloride
(1.00 g, 3.7 mmol) in 1,4-dioxane (15 ml) were added triethylamine
(2.6 ml, 18.6 mmol) and PdCl.sub.2(dppf) CH.sub.2Cl.sub.2 (151 mg,
0.19 mmol) at room temperature. To the mixture was added dropwise
pinacolborane (1.62 ml, 11.1 mmol) at room temperature, and the
mixture was stirred at 100.degree. C. for 4 hr. To the reaction
mixture was added saturated aqueous ammonium chloride solution, and
the mixture was extracted with diethyl ether. The organic layer was
washed with saturated brine and dried over anhydrous sodium
sulfate. After filtration, the solvent was evaporated under reduced
pressure, and the obtained residue was purified by silica gel
chromatography (hexane:ethyl acetate=5:1) to give
5-methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenylamine
(570 mg, yield 66%).
[1370] .sup.1H-NMR(400 MHz, CDCl.sub.3): .delta.(ppm) 7.48(1H, d,
J=6.0 Hz), 6.49(1H, d, J=6.0 Hz), 6.41(1H, s), 4.66(2H, brs),
2.24(3H, s), 1.32(12H, s).
Step 7: Production of methyl
2-(2-amino-4-methylphenyl)-3-cyclohexyl-1H-indole-6-carboxylate
hydrochloride
[1371] ##STR371##
[1372] To a suspension of methyl
2-bromo-3-cyclohexyl-1H-indole-6-carboxylate (656 mg, 2.0 mmol),
obtained in the same manner as in the method described in
WO03/010140, and
5-methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenylamine
(570 mg, 2.4 mmol) in 1,2-dimethoxyethane (13 ml) and water (6.5
ml) were added sodium hydrogen carbonate (508 mg, 7.1 mmol) and
tetrakis(triphenylphosphine)palladium (118 mg, 0.10 mmol), and the
mixture was stirred at 80.degree. C. for 3 hr. The reaction mixture
was allowed to cool to room temperature. Water was added to the
reaction mixture, and the mixture was extracted with ethyl acetate.
The organic layer was washed with saturated brine and dried over
anhydrous sodium sulfate. After filtration, the solvent was
evaporated under reduced pressure. To a solution of the residue in
ethyl acetate (2 ml) was added 4N HCl-ethyl acetate solution (2
ml). The precipitated solid was collected by filtration, washed
with diethyl ether, and dried in vacuo. The obtained crude product
(638 mg) was used for Step 8 without further purification.
Step 8: Production of methyl
2-[2-(2-chloroacetylamino)-4-methylphenyl]-3-cyclohexyl-1H-indole-6-carbo-
xylate
[1373] ##STR372##
[1374] To a suspension of methyl
2-(2-amino-4-methylphenyl)-3-cyclohexyl-1H-indole-6-carboxylate
(638 mg, 1.6 mmol), sodium acetate (289 mg, 3.5 mmol) and acetic
acid (0.10 ml, 1.8 mmol) in tetrahydrofuran (7 ml) was added
dropwise chloroacetyl chloride (0.14 ml, 1.8 mmol), and the mixture
was stirred at room temperature for 12 hr. Water was added to the
reaction mixture, and the mixture was extracted with ethyl acetate.
The organic layer was washed with saturated brine and dried over
anhydrous sodium sulfate. After filtration, the solvent was
evaporated under reduced pressure. The obtained crude product (640
mg) was used for Step 9 without further purification.
Step 9: Production of methyl
13-cyclohexyl-3-methyl-6-oxo-6,7-dihydro-5H-benzo[5,6][1,4]diazepino[7,1--
a]indole-10-carboxylate
[1375] ##STR373##
[1376] To a solution of methyl
2-[2-(2-chloroacetylamino)-4-methylphenyl]-3-cyclohexyl-1H-indole-6-carbo-
xylate (640 mg, 1.5 mmol) in N,N-dimethylformamide (10 ml) was
added sodium hydride (141 mg, 3.5 mmol) under ice-cooling, and the
mixture was stirred for 5 hr. 1N Hydrochloric acid (5 ml) was added
to the reaction mixture, and the mixture was diluted with water.
The precipitated solid was collected by filtration, washed with
water and hexane, and dried in vacuo to give methyl
13-cyclohexyl-3-methyl-6-oxo-6,7-dihydro-5H-benzo[5,6][1,4]diazepino[7,1--
a]indole-10-carboxylate (614 mg, yield 95%).
[1377] .sup.1H-NMR(300 MHz, DMSO-d.sub.6): .delta.(ppm) 10.28(1H,
s), 8.26(1H, s), 7.95(1H, d, J=8.4 Hz), 7.68(1H, dd, J=9.0, 1.5
Hz), 7.43(1H, d, J=8.1 Hz), 7.22(1H, d, J=7.8 Hz), 7.09(1H, s),
5.06(1H, d, J=15.0 Hz), 4.50(1H, d, J=14.4 Hz), 3.89(3H, s),
2.80-2.89(1H, m), 2.40(3H, s), 1.98-2.08(3H, m), 1.86-1.93(1H, m),
1.68-1.79(2H, m), 1.36-1.55(3H, m), 1.13-1.25(1H, m).
Step 10: Production of methyl
13-cyclohexyl-5-{2-[(S)-3-(2-methoxyethyl)piperidin-1-yl]-2-oxoethyl}-3-m-
ethyl-6-oxo-6,7-dihydro-5H-benzo[5,6][1,4]diazepino[7,1-a]indole-10-carbox-
ylate
[1378] ##STR374##
[1379] A suspension of methyl
13-cyclohexyl-3-methyl-6-oxo-6,7-dihydro-5H-benzo[5,6][1,4]diazepino[7,1--
a]indole-10-carboxylate (1.00 g, 2.48 mmol),
(S)-3-(2-methoxyethyl)-N-(chloroacetyl)piperidine (819 mg, 3.72
mmol) and potassium carbonate (696 mg, 4.96 mmol) in
N,N-dimethylformamide (20 ml) was stirred at 80.degree. C. for 3
hr. The reaction mixture was allowed to cool to room temperature.
Water was added and the mixture was extracted with ethyl acetate.
The organic layer was washed successively with saturated aqueous
sodium hydrogen carbonate solution and saturated brine, and dried
over anhydrous magnesium sulfate. After filtration, the solvent was
evaporated under reduced pressure, and the obtained residue was
purified by silica gel chromatography (hexane:ethyl acetate=1:1) to
give methyl
13-cyclohexyl-5-{2-[(S)-3-(2-methoxyethyl)piperidin-1-yl]-2-oxoethyl}-3-m-
ethyl-6-oxo-6,7-dihydro-5H-benzo[5,6][1,4]diazepino[7,1-a]indole-10-carbox-
ylate (967 mg, yield 67%).
[1380] .sup.1H-NMR(400 MHz, DMSO-d.sub.6): .delta.(ppm) 8.24(1H,
s), 7.91(1H, d, J=6.0 Hz), 7.65(1H, dd, J=6.3, 1.2 Hz), 7.38(1H, d,
J=6.0 Hz), 7.24-7.28(2H, m), 5.15(1H, d, J=10.8 Hz), 4.56-4.66(1H,
m), 4.34-4.47(2H, m), 3.93-4.06(1H, m), 3.86(3H, s), 3.51-3.67(1H,
m), 3.21-3.31(1H, m), 3.09-3.18(3H, m), 2.80-3.02(2H, m),
2.55-2.68(1H,m), 2.38(3H, s), 1.93-2.03(3H, m), 1.84-1.88(1H, m),
1.66-1.75(3H, m), 1.52-1.59(2H, m), 1.05-1.45(9H, m).
Step 11: Production of methyl
13-cyclohexyl-5-{2-[(S)-3-(2-methoxyethyl)piperidin-1-yl]ethyl}-3-methyl--
6,7-dihydro-5H-benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylate
[1381] ##STR375##
[1382] To a solution of methyl
13-cyclohexyl-5-{2-[(S)-3-(2-methoxyethyl)piperidin-1-yl]-2-oxoethyl}-3-m-
ethyl-6-oxo-6,7-dihydro-5H-benzo[5,6][1,4]diazepino[7,1-a]indole-10-carbox-
ylate (967 mg, 1.6 mmol) in tetrahydrofuran (3 ml) was added a
solution (15 ml) of 1.0M BH.sub.3 THF complex in tetrahydrofuran,
and the mixture was stirred at room temperature for 1 hr. 5N
Hydrochloric acid (18 ml) was added to the reaction mixture, and
the mixture was stirred at 60.degree. C. for 5 hr. The reaction
mixture was allowed to cool to room temperature, and the reaction
mixture was neutralized with 1N aqueous sodium hydroxide solution
and saturated aqueous sodium hydrogen carbonate solution, and
extracted with ethyl acetate. The organic layer was washed with
saturated brine and dried over anhydrous magnesium sulfate. After
filtration, the solvent was evaporated under reduced pressure, and
the obtained residue was purified by silica gel chromatography
(ethyl acetate:methanol=10:1) to give methyl
13-cyclohexyl-5-{2-[(S)-3-(2-methoxyethyl)piperidin-1-yl]ethyl}-3-methyl--
6,7-dihydro-5H-benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylate
(820 mg, yield 89%).
[1383] .sup.1H-NMR(400 MHz, DMSO-d.sub.6): .delta.(ppm) 8.13(1H, d,
J=0.9 Hz), 7.81(1H, d, J=6.3 Hz), 7.57(1H, dd, J=6.6, 1.5 Hz),
7.15(1H, d, J=5.7 Hz), 7.04(1H, s), 6.94(1H, d, J=6.0 Hz), 3.83(3H,
s), 3.05-3.40(8H, m), 2.75-2.82(1H, m), 2.48-2.62(5H, m),
2.22-2.39(5H, m), 1.88-2.01(3H, m), 1.62-1.81(5H, m), 1.41-1.54(2H,
m), 1.06-1.38(8H, m), 0.60-0.71(1H, m).
Step 12: Production of
13-cyclohexyl-5-{2-[(S)-3-(2-methoxyethyl)piperidin-1-yl]ethyl}-3-methyl--
6,7-dihydro-5H-benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic
acid dihydrochloride
[1384] ##STR376##
[1385] To a solution of methyl
13-cyclohexyl-5-{2-[(S)-3-(2-methoxyethyl)piperidin-1-yl]ethyl}-3-methyl--
6,7-dihydro-5H-benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylate
(820 mg, 1.47 mmol) in tetrahydrofuran (16 ml) and methanol (8 ml)
was added 4N aqueous sodium hydroxide solution (8 ml), and the
mixture was stirred at 60.degree. C. for 5 hr. The reaction mixture
was adjusted to pH 7 with 1N hydrochloric acid, and extracted with
ethyl acetate. The organic layer was washed with saturated brine
and dried over anhydrous sodium sulfate. After filtration, the
solvent was evaporated under reduced pressure. To a solution of the
residue in ethyl acetate (10 ml) was added 4N HCl-ethyl acetate
solution (5 ml). The solvent was evaporated under reduced pressure
and diethyl ether was added. The precipitated solid was collected
by filtration, washed with diethyl ether, and dried in vacuo to
give
13-cyclohexyl-5-{2-[(S)-3-(2-methoxyethyl)piperidin-1-yl]ethyl}-3-me-
thyl-6,7-dihydro-5H-benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic
acid dihydrochloride (535 mg, yield 59%).
[1386] .sup.1H-NMR(400 MHz, DMSO-d.sub.6): .delta.(ppm) 10.26(1H,
brs), 8.12(1H, s), 7.78(1H, d, J=6.3 Hz), 7.56(1H, dd, J=6.3, 0.9
Hz), 7.21(1H, d, J=5.7 Hz), 7.13(1H, s), 7.04(1H, d, J=5.4 Hz),
2.76-2.84(1H, m), 2.37(3H, s), 1.89-2.00(2H, m), 1.64-1.84(3H, m),
1.42-1.57(1H, m), 1.18-1.37(2H, m), 0.86-0.95(1H, m).
[1387] MS 544.3(M+1).
Example 1-416
Production of
13-cyclohexyl-5-[2-((R)-3-methoxymethylpiperidin-1-yl)ethyl]-3-methyl-6,7-
-dihydro-5H-benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic
acid dihydrochloride
Step 1: Production of 1-tert-butyl 3-ethyl
(R)-piperidine-1,3-dicarboxylate
[1388] ##STR377##
[1389] To a solution of ethyl (R)-piperidine-3-carboxylate (10.00
g, 63.6 mmol) in diethyl ether (100 ml) was added dropwise
di-tert-butyl dicarbonate (16.00 g, 73.2 mmol) under ice-cooling,
and the mixture was stirred for 40 min. The solvent was evaporated
under reduced pressure to give 1-tert-butyl 3-ethyl
(R)-piperidine-1,3-dicarboxylate (16.80 g). The obtained compound
was used for Step 2 without purification.
[1390] .sup.1H-NMR(300 MHz, CDCl.sub.3): .delta.(ppm) 4.00-4.30(1H,
m), 4.14(2H, q, J=7.2 Hz), 3.84-3.98(1H, m), 2.88-3.17(1H, m),
2.75-2.87(1H, m), 2.35-2.51(1H, m), 1.98-2.10(1H, m), 1.57-1.78(2H,
m), 1.37-1.51(1H, m), 1.46(9H, s), 1.27(3H, t, J=7.2 Hz).
Step 2: Production of tert-butyl
(R)-3-hydroxymethylpiperidine-1-carboxylate
[1391] ##STR378##
[1392] To a suspension of lithium aluminum hydride (2.90 g, 76.3
mmol) in tetrahydrofuran (100 ml) was added a solution of
1-tert-butyl 3-ethyl (R)-piperidine-1,3-dicarboxylate (16.30 g,
63.6 mmol) in tetrahydrofuran (60 ml) over 20 min under
ice-cooling, and the mixture was further stirred for 20 min. To the
reaction mixture were successively added water (2.9 ml), 4N aqueous
sodium hydroxide solution (2.9 ml), water (8.7 ml) and anhydrous
sodium sulfate, and the mixture was stirred at room temperature for
1 hr. The reaction mixture was filtered, and the solvent was
evaporated under reduced pressure to give tert-butyl
(R)-3-hydroxymethylpiperidine-1-carboxylate (13.00 g, yield
95.0%).
[1393] .sup.1H-NMR(300 MHz, CDCl.sub.3): .delta.(ppm) 3.39-3.95(2H,
m), 3.51(2H, d, J=6.8 Hz), 2.72-3.30(2H, m), 1.52-1.94(4H, m),
1.35-1.50(1H, m), 1.46(9H, s), 1.15-1.34(1H, m).
Step 3: Production of tert-butyl
(R)-3-methoxymethylpiperidine-1-carboxylate
[1394] ##STR379##
[1395] To a solution of tert-butyl
(R)-3-hydroxymethylpiperidine-1-carboxylate (11.50 g, 53.7 mmol) in
N,N-dimethylformamide (110 ml) was added sodium hydride (3.22 g,
80.6 mmol) under ice-cooling, and the mixture was stirred at room
temperature for 20 min. To the reaction mixture was added methyl
iodide (4.35 ml, 69.9 mmol) under ice-cooling, and the mixture was
stirred at room temperature 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 and dried over
anhydrous sodium sulfate. After filtration, the solvent was
evaporated under reduced pressure, and the obtained residue was
purified by silica gel column chromatography (hexane:ethyl
acetate=1:1) to give tert-butyl
(R)-3-methoxymethylpiperidine-1-carboxylate (13.00 g, yield
100%).
[1396] .sup.1H-NMR(300 MHz, CDCl.sub.3): .delta.(ppm) 3.84-4.05(2H,
m), 3.32(3H, s), 3.24(2H, d, J=6.0 Hz), 2.75-2.89(1H, m),
2.52-2.71(1H, m), 1.70-1.86(2H, m), 1.57-1.69(1H, m), 1.36-1.52(1H,
m), 1.46(9H, s), 1.15-1.28(1H, m).
Step 4: Production of (R)-3-methoxymethylpiperidine
hydrochloride
[1397] ##STR380##
[1398] To a solution of tert-butyl
(R)-3-methoxymethylpiperidine-1-carboxylate (13.00 g, 56.6 mmol) in
ethyl acetate (26 ml) was added 4N HCl-ethyl acetate solution (26
ml), and the mixture was stirred at room temperature for 3 hr. The
solvent was evaporated under reduced pressure to give
(R)-3-methoxymethylpiperidine hydrochloride as a crude product. A
mixed solvent (100 ml) of hexane:ethyl acetate=1:4 was added to the
obtained solid, and the mixture was stirred. The solid was
collected by filtration to give (R)-3-methoxymethylpiperidine
hydrochloride (7.82 g, yield 84%).
[1399] .sup.1H-NMR(300 MHz, CDCl.sub.3): .delta.(ppm) 9.11(2H, br),
3.37-3.53(2H, m), 3.22-3.37(2H, m), 3.31(3H, s), 2.62-2.88(2H, m),
2.19-2.38(1H, m), 1.72-2.11(3H, m), 1.21-1.44(1H, m).
Step 5: Production of
(R)-3-methoxymethyl-N-(chloroacetyl)piperidine
[1400] ##STR381##
[1401] To a suspension of (R)-3-methoxymethylpiperidine
hydrochloride (6.00 g, 36.3 mmol), sodium acetate (6.55 g, 79.9
mmol) and acetic acid (4.57 ml, 79.9 mmol) in tetrahydrofuran (120
ml) was added dropwise chloroacetyl chloride (3.18 ml, 39.9 mmol)
under ice-cooling, and the mixture was stirred overnight at room
temperature. To the reaction mixture was added saturated aqueous
sodium hydrogen carbonate solution, and the mixture was extracted
with ethyl acetate. The organic layer was washed with saturated
brine and dried over anhydrous sodium sulfate. After filtration,
the solvent was evaporated under reduced pressure, and the obtained
residue was purified by silica gel column chromatography
(hexane:ethyl acetate=1:4) to give
(R)-3-methoxymethyl-N-(chloroacetyl)piperidine (6.00 g, yield
80.0%).
[1402] .sup.1H-NMR(400 MHz, CDCl.sub.3): .delta.(ppm)
4.32-4.43(0.4H, m), 4.02-4.23(2.6H, m), 3.67-3.85(1H, m),
3.20-3.39(5H, m), 3.07-3.18(0.4H, m), 3.03(0.6H, dd, J=7.0, 10.1
Hz), 2.87-2.99(0.6H, m), 2.62(0.4H, dd, J=7.7, 9.7 Hz),
1.20-2.02(5H, m).
Step 6: Production of methyl
13-cyclohexyl-5-[2-((R)-3-methoxymethylpiperidin-1-yl)-2-oxoethyl]-3-meth-
yl-6-oxo-6,7-dihydro-5H-benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxyla-
te
[1403] ##STR382##
[1404] A suspension of methyl
13-cyclohexyl-3-methyl-6-oxo-6,7-dihydro-5H-benzo[5,6][1,4]diazepino[7,1--
a]indole-10-carboxylate (1.00 g, 2.48 mmol),
(R)-3-methoxymethyl-N-(chloroacetyl)piperidine (613 mg, 2.98 mmol)
and potassium carbonate (687 mg, 4.97 mmol) in
N,N-dimethylformamide (15 ml) was stirred at 80.degree. C. for 2
hr. The reaction mixture was allowed to cool to room temperature
and water was added to the reaction mixture. The precipitate was
collected by filtration, washed with water, and dried in vacuo to
give methyl
13-cyclohexyl-5-[2-((R)-3-methoxymethylpiperidin-1-yl)-2-oxoethyl]-3-meth-
yl-6-oxo-6,7-dihydro-5H-benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxyla-
te (1.45 g) as a crude product. The obtained crude product was used
for Step 7 without further purification.
[1405] .sup.1H-NMR(300 MHz, DMSO-d.sub.6): .delta.(ppm) 8.27(1H,
s), 7.94(1H, d, J=8.3 Hz), 7.68(1H, d, J=8.7 Hz), 7.42(1H, d, J=7.9
Hz), 7.25-7.36(2H, m), 5.18(1H, d, J=14.3 Hz), 4.58-4.73(1H, m),
4.33-4.55(2H, m), 4.05-4.19(0.5H, m), 3.78-3.94(0.5H, m), 3.89(3H,
s), 3.49-3.69(1H, m), 3.20(3H, s), 3.17(2H, d, J=10.2 Hz),
2.79-3.01(2H, m), 2.41(3H, s), 1.06-2.15(16H, m).
Step 7: Production of methyl
13-cyclohexyl-5-[2-((R)-3-methoxymethylpiperidin-1-yl)ethyl]-3-methyl-6,7-
-dihydro-5H-benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylate
[1406] ##STR383##
[1407] To a solution of methyl
13-cyclohexyl-5-[2-((R)-3-methoxymethylpiperidin-1-yl)-2-oxoethyl]-3-meth-
yl-6-oxo-6,7-dihydro-5H-benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxyla-
te (1.40 g, 2.45 mmol) in tetrahydrofuran (5.6 ml) was added a
solution (14 ml) of 1.07M BH.sub.3 THF complex in tetrahydrofuran
under ice-cooling, and the mixture was stirred at room temperature
for 16 hr. 5N Hydrochloric acid (5 ml) was added to the reaction
mixture under ice-cooling, and the mixture was stirred at
70.degree. C. for 4 hr. The reaction mixture was allowed to cool to
room temperature, and the reaction mixture was neutralized with
saturated aqueous sodium hydrogen carbonate solution and extracted
with ethyl acetate. The organic layer was washed with saturated
brine and dried over anhydrous sodium sulfate. After filtration,
the solvent was evaporated under reduced pressure, and the obtained
residue was purified by silica gel chromatography
(chloroform:methanol=9:1) to give methyl
13-cyclohexyl-5-[2-((R)-3-methoxymethylpiperidin-1-yl)ethyl]-3-methyl-6,7-
-dihydro-5H-benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylate
(1.19 g, yield 83%).
[1408] .sup.1H-NMR(300 MHz, DMSO-d.sub.6): .delta.(ppm) 8.15(1H, d,
J=1.6 Hz), 7.84(1H, d, J=8.8 Hz), 7.59(1H, dd, J=8.4, 1.2 Hz),
7.30(1H, d, J=2.0 Hz), 7.24(1H, d, J=8.0 Hz), 7.15(1H, dd, J=8.4,
2.4 Hz), 3.86-4.75(4H, m), 3.84(3H, s), 3.12-3.51(4H, m),
2.74-2.74(1H, m), 1.60-2.33(12H, m), 1.09-1.40(8H, m).
Step 8: Production of
13-cyclohexyl-5-[2-((R)-3-methoxymethylpiperidin-1-yl)ethyl]-3-methyl-6,7-
-dihydro-5H-benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic
acid dihydrochloride
[1409] ##STR384##
[1410] To a solution of methyl
13-cyclohexyl-5-[2-((R)-3-methoxymethylpiperidin-1-yl)ethyl]-3-methyl-6,7-
-dihydro-5H-benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylate
(1.19 g, 2.18 mmol) in tetrahydrofuran (20 ml) and methanol (15 ml)
was added 4N aqueous sodium hydroxide solution (10 ml), and the
mixture was stirred at 55.degree. C. for 3 hr. The reaction mixture
was adjusted to pH 6.5 with 2N hydrochloric acid (20 ml), and
extracted with a mixed solvent of ethyl acetate and
tetrahydrofuran. The organic layer was washed with saturated brine
and dried over anhydrous sodium sulfate. After filtration, the
solvent was evaporated under reduced pressure to give
13-cyclohexyl-5-[2-((R)-3-methoxymethylpiperidin-1-yl)ethyl]-3-methyl-6,7-
-dihydro-5H-benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic
acid as a crude product. To a solution of the obtained crude
product in ethyl acetate (5 ml) wad added 4N HCl-ethyl acetate
solution (10 ml) at room temperature, and the mixture was stirred
for 30 min. The reaction mixture was concentrated under reduced
pressure, diethyl ether was added to the obtained solid, and the
solid was collected by filtration and dried in vacuo to give
13-cyclohexyl-5-[2-((R)-3-methoxymethylpiperidin-1-yl)ethyl]-3-methyl-6,7-
-dihydro-5H-benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic
acid dihydrochloride (705 mg, yield 61.3%).
[1411] .sup.1H-NMR(300 MHz, DMSO-d.sub.6): .delta.(ppm)
10.64-11.09(1H, m), 8.16(1H, s), 7.84(1H, d, J=8.7 Hz), 7.61(1H, d,
J=7.9 Hz), 7.25(1H, d, J=7.9 Hz), 7.19(1H, s), 7.08(1H, d, J=7.5
Hz), 4.08-5.02(2H, m), 3.30-3.96(2H, m), 3.10-3.25(2H, m),
2.93-3.09(2H, m), 3.04(3H, s), 2.57-2.92(4H, m), 2.22-2.48(2H, m),
2.41(3H, s), 1.90-2.12(4H, m), 1.45-1.89(7H, m), 1.21-1.43(5H,
m).
[1412] MS 530.3(M+1)
[1413] The compounds of Examples 1-96 to 1-445 were produced by the
same methods as in Examples 1-1 to 1-18, 1-168, 1-413 and 1-416 or
methods similar thereto, and where necessary, employing other
conventional methods. The chemical structural formulas are shown in
Tables 20-100.
Example 2-1
Production of methyl
12-cyclohexyl-3-hydroxy-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-car-
boxylate
Step 1: Production of 1-bromo-2,4-bismethoxymethoxybenzene
[1414] ##STR385##
[1415] To a solution of 4-bromoresorcinol (30 g, 159 mmol) in
acetone (300 ml) were added potassium carbonate (66 g, 471 mmol)
and chloromethyl methyl ether (30 ml, 397 mmol) under ice-cooling
and the mixture was stirred at room temperature for 22 hr. The
reaction mixture was concentrated and water was added. The mixture
was extracted with ethyl acetate and the organic layer was washed
with saturated brine and dried over anhydrous magnesium sulfate.
After filtration, the solvent was evaporated under reduced pressure
to give 1-bromo-2,4-bismethoxymethoxybenzene as a crude product.
The obtained compound was used in Step 2 without further
purification.
[1416] .sup.1H-NMR(400 MHz, CDCl.sub.3): .delta.(ppm) 7.39(1H, d,
J=8.4 Hz), 6.85(1H, d, J=2.8 Hz), 6.61(1H, dd, J=8.8, 2.8 Hz),
5.22(2H, s), 5.13(2H, s), 3.51(3H, s), 3.46(3H, s).
Step 2: Production of 2,4-bismethoxymethoxyphenylboronic acid
[1417] ##STR386##
[1418] To a solution of 1-bromo-2,4-bismethoxymethoxybenzene in
hexane (250 ml) and tetrahydrofuran (110 ml) was added triisopropyl
borate (45 g, 238 mmol), and the mixture was cooled to -78.degree.
C. A solution (151 ml, 238 mmol) of 1.58M n-butyllithium in hexane
was added dropwise and the mixture was stirred for 5 hr. 1N
Hydrochloric acid (240 ml) was added under ice-cooling, and the
mixture was stirred for 15 min. The reaction mixture was extracted
with ethyl acetate, and the organic layer was washed with saturated
brine and dried over anhydrous magnesium sulfate. After filtration,
the solvent was evaporated under reduced pressure, and the obtained
residue was purified by silica gel column chromatography
(hexane:ethyl acetate=4:1) to give
2,4-bismethoxymethoxyphenylboronic acid (13.6 g, yield 35%).
[1419] .sup.1H-NMR(400 MHz, CDCl.sub.3): .delta.(ppm) 7.75(1H, d,
J=8.4 Hz), 6.79(1H, d, J=2.4 Hz), 6.75(1H, dd, J=8.0, 2.0 Hz),
5.58(2H, s), 5.27(2H, s), 5.19(2H, s), 3.50(3H, s), 3.48(3H,
s).
Step 3: Production of methyl
2-(2,4-bismethoxymethoxyphenyl)-3-cyclohexyl-1H-indole-6-carboxylate
[1420] ##STR387##
[1421] To a suspension of methyl
2-bromo-3-cyclohexyl-1H-indole-6-carboxylate (14.5 g, 43.2 mmol),
obtained in the same manner as in the method described in
WO03/010140, and 2,4-bismethoxymethoxyphenylboronic acid (13.6 g,
56.2 mmol) in 1,2-dimethoxyethane (140 ml) and water (70 ml) were
added lithium chloride (5.5 g, 129 mmol), sodium carbonate (13.7 g,
129 mmol) and tetrakis(triphenylphosphine)palladium (5.0 g, 4.3
mmol), and the mixture was stirred at 90.degree. C. for 22 hr. The
mixture was allowed to cool to room temperature, and filtered
through celite. The filtrate was extracted with ethyl acetate and
the organic layer was washed successively with saturated aqueous
ammonium chloride solution and saturated brine, and dried over
anhydrous magnesium sulfate. After filtration, the solvent was
evaporated under reduced pressure, and the obtained residue was
purified by silica gel chromatography (hexane:ethyl acetate=3:1) to
give methyl
2-(2,4-bismethoxymethoxyphenyl)-3-cyclohexyl-1H-indole-6-carboxylate
(16.9 g, yield 86%).
[1422] .sup.1H-NMR(400 MHz, CDCl.sub.3): .delta.(ppm) 8.38(1H, s),
7.82(1H, d, J=8.4 Hz), 7.74(1H, dd, J=8.4, 1.2 Hz), 6.96(1H, d,
J=2.4 Hz), 6.83(1H, dd, J=8.4, 8.4 Hz), 5.22(2H, s), 5.12(2H, s),
3.92(3H, s), 3.53(3H, s), 3.35(3H, s), 2.73-2.86(1H, m),
1.92-2.07(2H, m), 1.71-1.88(5H, m), 1.26-1.41(3H, m).
[1423] MS 454(M+1).
Step 4: Production of methyl
2-(2,4-bismethoxymethoxyphenyl)-3-cyclohexyl-1-[2-(tetrahydropyran-2-ylox-
y)ethyl]-1H-indole-6-carboxylate
[1424] ##STR388##
[1425] To a solution of methyl
2-(2,4-bismethoxymethoxyphenyl)-3-cyclohexyl-1H-indole-6-carboxylate
(16.9 g, 37.3 mmol) in N,N-dimethylformamide (120 ml) was added
sodium hydride (2.1 g, 52.2 mmol) under ice-cooling, and the
mixture was stirred for 20 min. To the reaction mixture was added
2-(2-bromoethoxy)tetrahydro-2H-pyran (8.5 ml, 55.9 mmol), and the
mixture was stirred at room temperature for 4 hr. To the reaction
mixture was added saturated aqueous sodium hydrogen carbonate
solution and the mixture was extracted with ethyl acetate. The
organic layer was washed with saturated brine, and dried over
anhydrous magnesium sulfate. After filtration, the solvent was
evaporated under reduced pressure to give methyl
2-(2,4-bismethoxymethoxyphenyl)-3-cyclohexyl-1-[2-(tetrahydropyran-
-2-yloxy)ethyl]-1H-indole-6-carboxylate as a crude product. The
obtained compound was used in Step 5 without further
purification.
[1426] .sup.1H-NMR(400 MHz, CDCl.sub.3): (ppm) 8.21(1H, d, J=5.2
Hz), 7.70-7.78(2H, m), 7.11(1H, dd, J=8.4, 1.6 Hz), 6.95(1H, t,
J=2.2 Hz), 6.78(1H, dd, J=8.4, 2.4 Hz), 5.23(2H, s), 5.03(2H, ddd,
J=15.6, 5.4, 1.5 Hz), 4.33-4.40(1H, m), 3.97-4.24(3H, m),
3.92(3H,s), 3.69-3.83(2H, m), 3.54(3H, s), 3.42-3.53(2H, m),
2.44-2.54(1H, m), 1.22-1.90(16H, m).
[1427] MS 582(M+1).
Step 5: Production of methyl
3-cyclohexyl-2-(2,4-dihydroxyphenyl)-1-(2-hydroxyethyl)-1H-indole-6-carbo-
xylate
[1428] ##STR389##
[1429] To a solution of methyl
2-(2,4-bismethoxymethoxyphenyl)-3-cyclohexyl-1-[2-(tetrahydropyran-2-ylox-
y)ethyl]-1H-indole-6-carboxylate in methanol (525 ml) and
tetrahydrofuran (30 ml) was added 6N hydrochloric acid (105 ml) and
the mixture was stirred for 10 hr. The reaction mixture was
concentrated and water was added. The mixture was extracted with
ethyl acetate. The organic layer was washed with saturated brine,
and dried over anhydrous magnesium sulfate. After filtration, the
solvent was evaporated under reduced pressure, and the obtained
residue was purified by silica gel chromatography (hexane:ethyl
acetate=1:1) to give methyl
3-cyclohexyl-2-(2,4-dihydroxyphenyl)-1-(2-hydroxyethyl)-1H-indole-6-carbo-
xylate (10.3 g, yield 68%).
[1430] .sup.1H-NMR(400 MHz, CDCl.sub.3): .delta.(ppm) 8.12(1H, s),
7.76-7.83(2H, m), 7.00(1H, d, J=8.0 Hz), 6.49-6.55(2H, m), 5.67(1H,
brs), 5.18(1H, s), 4.06-4.15(2H, m), 3.94(3H, s), 3.87-3.93(1H, m),
3.73-3.81(1H, m), 2.45-2.56(1H, m), 1.63-1.84(7H, m), 1.20-1.29(3H,
m).
[1431] MS 410(M+1).
Step 6: Production of methyl
12-cyclohexyl-3-hydroxy-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-car-
boxylate
[1432] ##STR390##
[1433] To a solution of methyl
3-cyclohexyl-2-(2,4-dihydroxyphenyl)-1-(2-hydroxyethyl)-1H-indole-6-carbo-
xylate (10.3 g, 28.2 mmol) in tetrahydrofuran (500 ml) were added
triphenylphosphine (7.3 g, 27.7 mmol) and diethyl azodicarboxylate
(4.4 ml, 27.7 mmol) under ice-cooling, and the mixture was stirred
for 4 hr. The reaction mixture was concentrated and the obtained
residue was purified by silica gel chromatography (hexane:ethyl
acetate=3:2) to give methyl
12-cyclohexyl-3-hydroxy-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulen-
e-9-carboxylate (6.5 g, yield 66%).
[1434] .sup.1H-NMR(400 MHz, CDCl.sub.3): .delta.(ppm) 8.04(1H, s),
7.85(1H, d, J=8.4 Hz), 7.74(1H, dd, J=8.4, 1.2 Hz), 7.27(1H, d,
J=8.4 Hz), 6.76(1H, dd, J=8.0, 2.4 Hz), 6.72(1H, d, J=2.4 Hz),
5.18(1H, s), 4.48(2H, t, J=5.6 Hz), 4.28(2H, t, J=5.6 Hz), 3.94(3H,
s), 2.87-2.97(1H, m), 1.98-2.12(2H, m), 1.74-1.90(5H, m),
1.29-1.43(3H, m).
[1435] MS 392(M+1).
Example 2-2
Production of methyl
3-benzyloxy-12-cyclohexyl-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-c-
arboxylate
[1436] ##STR391##
[1437] To a solution of methyl
12-cyclohexyl-3-hydroxy-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-car-
boxylate (150 mg, 0.38 mmol) in N,N-dimethylformamide (2.0 ml) were
added potassium carbonate (132 mg, 0.96 mmol) and benzyl bromide
(0.07 ml, 0.61 mmol) and the mixture was stirred at 60.degree. C.
for 3 hr. To the reaction mixture was added saturated aqueous
sodium hydrogen carbonate solution and the mixture was extracted
with ethyl acetate. The organic layer was washed with saturated
brine, and dried over anhydrous magnesium sulfate. After
filtration, the solvent was evaporated under reduced pressure, and
the obtained residue was purified by silica gel chromatography
(hexane:ethyl acetate=3:1) to give methyl
3-benzyloxy-12-cyclohexyl-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-c-
arboxylate (173 mg, yield 94%).
[1438] .sup.1H-NMR(400 MHz, CDCl.sub.3): .delta.(ppm) 8.03(1H, s),
7.85(1H, d, J=8.4 Hz), 7.73(1H, dd, J=8.4, 1.2 Hz), 7.25-7.48(6H,
m), 6.90(1H, dd, J=8.4, 2.8 Hz), 6.85(1H, d, J=2.4 Hz), 5.11(2H,
s), 4.49(2H, t, J=5.6 Hz), 4.29(2H, t, J=5.6 Hz), 3.93(3H, s),
2.88-2.98(1H, m), 1.99-2.12(2H, m), 1.75-1.90(5H, m), 1.30-1.43(3H,
m).
Example 2-3
Production of
3-benzyloxy-12-cyclohexyl-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-c-
arboxylic acid
[1439] ##STR392##
[1440] To a solution of methyl
3-benzyloxy-12-cyclohexyl-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-c-
arboxylate (173 mg, 0.36 mmol) in methanol (3.5 ml) and
tetrahydrofuran (3.5 ml) was added 4N aqueous sodium hydroxide
solution (1.7 ml), and the mixture was stirred for 13 hr. To the
reaction mixture were added 2N hydrochloric acid (3.7 ml) and
water, and the precipitated solid was collected by filtration and
dried in vacuo. The obtained solid was purified by silica gel
chromatography (hexane:ethyl acetate=1:1) to give
3-benzyloxy-12-cyclohexyl-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-c-
arboxylic acid (81 mg, yield 48%).
[1441] .sup.1H-NMR(300 MHz, DMSO-d.sub.6): (ppm) 12.54(1H, brs),
8.17(1H, d, J=1.2 Hz), 7.86(1H, d, J=8.4 Hz), 7.63(1H, dd, J=8.4,
1.2 Hz), 7.32-7.53(6H, m), 7.03(1H, dd, J=9.0, 2.7 Hz), 6.92(1H, d,
J=2.4 Hz), 5.18(2H, s), 4.41-4.49(2H, m), 4.33-4.40(2H, m),
2.79-2.93(1H, m), 1.93-2.12(2H, m), 1.68-1.87(5H, m), 1.24-1.45(3H,
m).
[1442] MS 468(M+1).
[1443] The compounds of Examples 2-4 to 2-53 were produced by the
same methods as in Examples 2-1 to 2-3 or methods similar thereto,
and where necessary, by employing other conventional methods. The
chemical structural formulas are shown in Tables 101-111. [1444]
12-cyclohexyl-3-methoxy-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-car-
boxylic acid (Example 2-4), [1445]
12-cyclohexyl-3-[2-(morpholin-4-yl)-5-(2-oxopyrrolidin-1-yl)benzyloxy]-6,-
7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carboxylic acid
monohydrochloride (Example 2-5), [1446]
12-cyclohexyl-2-methoxy-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-car-
boxylic acid (Example 2-6), [1447]
2-benzyloxy-12-cyclohexyl-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-c-
arboxylic acid (Example 2-7), [1448]
12-cyclohexyl-2-[2-(morpholin-4-yl)-5-(2-oxopyrrolidin-1-yl)benzyloxy]-6,-
7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carboxylic acid
monohydrochloride (Example 2-8), [1449]
12-cyclohexyl-3-[2-(morpholin-4-yl)-4-(2-oxopyrrolidin-1-yl)benzyloxy]-6,-
7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carboxylic acid
(Example 2-9), [1450]
3-(1-tert-butoxycarbonylpiperidin-4-yloxy)-12-cyclohexyl-6,7-dih-
ydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carboxylic acid (Example
2-10), [1451]
3-(1-tert-butoxycarbonylpiperidin-3-yloxy)-12-cyclohexyl-6,7-dihy-
dro-5-oxa-7a-azadibenzo[a,e]azulene-9-carboxylic acid (Example
2-11), [1452]
12-cyclohexyl-3-[5-methanesulfonyl-2-(morpholin-4-yl)benzyloxy]-6-
,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carboxylic acid
monohydrochloride (Example 2-12), [1453]
12-cyclohexyl-3-[2-(4-methanesulfonylpiperazin-1-yl)-5-(2-oxopyrrolidin-1-
-yl)benzyloxy]-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carboxylic
acid monohydrochloride (Example 2-13), [1454]
12-cyclohexyl-3-[2-(morpholin-4-yl)benzyloxy]-6,7-dihydro-5-oxa-7a-azadib-
enzo[a,e]azulene-9-carboxylic acid monohydrochloride (Example
2-14), [1455]
3-[5-acetylamino-2-(morpholin-4-yl)benzyloxy]-12-cyclohexyl-6,7-d-
ihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carboxylic acid
monohydrochloride (Example 2-15), [1456]
12-cyclohexyl-3-[5-(2-dimethylaminoacetylamino)-2-(morpholin-4-yl)benzylo-
xy]-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carboxylic acid
dihydrochloride (Example 2-16), [1457]
12-cyclohexyl-3-[5-methanesulfonylamino-2-(morpholin-4-yl)benzyloxy]-6,7--
dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carboxylic acid
monohydrochloride (Example 2-17), [1458]
3-[5-(N-acetyl-N-methylamino)-2-(morpholin-4-yl)benzyloxy]-12-cyclohexyl--
6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carboxylic acid
monohydrochloride (Example 2-18), [1459]
12-cyclohexyl-3-[5-(N-methanesulfonyl-N-methylamino)-2-(morpholin-4-yl)be-
nzyloxy]-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carboxylic
acid monohydrochloride (Example 2-19), [1460]
12-cyclohexyl-3-phenoxy-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-car-
boxylic acid (Example 2-20), [1461]
12-cyclohexyl-3-{2-(morpholin-4-yl)-5-[2-(morpholin-4-yl)acetylamino]benz-
yloxy}-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carboxylic
acid dihydrochloride (Example 2-21), [1462]
12-cyclohexyl-3-[5-{N-methyl-N-[2-(morpholin-4-yl)acetyl]amino}-2-(morpho-
lin-4-yl)benzyloxy]-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carboxyl-
ic acid dihydrochloride (Example 2-22), [1463]
12-cyclohexyl-3-(5-[N-(2-dimethylaminoacetyl)-N-methylamino]-2-(morpholin-
-4-yl)benzyloxy]-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carboxylic
acid dihydrochloride (Example 2-23), [1464]
12-cyclohexyl-3-(1-methoxycarbonylpiperidin-3-yloxy)-6,7-dihydro-5-oxa-7a-
-azadibenzo[a,e]azulene-9-carboxylic acid (Example 2-24), [1465]
12-cyclohexyl-3-(4-methoxyphenoxy)-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]az-
ulene-9-carboxylic acid (Example 2-25), [1466]
3-(3-chlorophenoxy)-12-cyclohexyl-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azu-
lene-9-carboxylic acid (Example 2-26), [1467]
12-cyclohexyl-3-[2-(4-dimethylcarbamoylmethylpiperazin-1-yl)-5-(2-oxopyrr-
olidin-1-yl)benzyloxy]-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carbo-
xylic acid dihydrochloride (Example 2-27), [1468]
12-cyclohexyl-3-[2-(4-ethylpiperazin-1-yl)-5-(2-oxopyrrolidin-1-yl)benzyl-
oxy]-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carboxylic acid
dihydrochloride (Example 2-28), [1469]
12-cyclohexyl-3-(pyridin-3-yloxy)-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azu-
lene-9-carboxylic acid monohydrochloride (Example 2-29), [1470]
3-(2-chlorophenoxy)-12-cyclohexyl-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azu-
lene-9-carboxylic acid (Example 2-30), [1471]
3-(4-chlorophenoxy)-12-cyclohexyl-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azu-
lene-9-carboxylic acid (Example 2-31).
Example 3-1
Production of 6-ethyl 9-methyl
12-cyclohexyl-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-6,9-dicarboxyla-
te
Step 1: Production of methyl
3-cyclohexyl-2-(2-hydroxyphenyl)-1H-indole-6-carboxylate
[1472] ##STR393##
[1473] To a suspension of methyl
2-bromo-3-cyclohexyl-1H-indole-6-carboxylate (2 g, 5.95 mmol)
obtained in the same manner as in the method described in
WO03/010140 and 2-hydroxyphenylboronic acid (1.23 g, 8.91 mmol) in
1,2-dimethoxyethane (20 ml) and water (10 ml) were added lithium
chloride (504 mg, 11.9 mmol), sodium carbonate (1.9 g, 17.9 mmol)
and tetrakis(triphenylphosphine)palladium (687 mg, 0.59 mmol), and
the mixture was heated under reflux for 10 hr. The mixture was
allowed to cool to room temperature, and extracted with ethyl
acetate. The organic layer was washed with saturated brine and
dried over anhydrous sodium sulfate. After filtration, the solvent
was evaporated under reduced pressure and the residue was purified
by silica gel chromatography (hexane:ethyl acetate=3:1-2:1) to give
methyl 3-cyclohexyl-2-(2-hydroxyphenyl)-1H-indole-6-carboxylate
(1.81 g, yield 87.7%).
[1474] .sup.1H-NMR(300 MHz, DMSO-d.sub.6): .delta.(ppm) 11.24(1H,
brs), 9.71(1H, brs), 7.98(1H, d, J=1.5 Hz), 7.78(1H, d, J=8.7 Hz),
7.58(1H, dd, J=1.5, 8.4 Hz), 7.20-7.31(2H, m), 7.00(1H, d, J=7.5
Hz), 6.92(1H, t, J=7.5 Hz), 3.85(3H, s), 2.60-2.75(1H, m),
1.62-1.98(7H, m), 1.14-1.41(3H, m).
Step 2: Production of 6-ethyl 9-methyl
12-cyclohexyl-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-6,9-dicarboxyla-
te
[1475] ##STR394##
[1476] To a solution of methyl
3-cyclohexyl-2-(2-hydroxyphenyl)-1H-indole-6-carboxylate (300 mg,
0.85 mmol) in N,N-dimethylacetamide (15 ml) were added ethyl
2,3-dibromopropionate (0.14 ml, 0.96 mmol) and potassium carbonate
(356 mg, 2.57 mmol), and the mixture was stirred at 80.degree. C.
for 9 hr. Water was added to the reaction mixture and the mixture
was extracted with ethyl acetate. The organic layer was washed
successively with water and saturated brine, and dried over
anhydrous sodium sulfate. After filtration, the solvent was
evaporated under reduced pressure and the residue was purified by
silica gel column chromatography (hexane:ethyl acetate=10:1-6:1) to
give 6-ethyl 9-methyl
12-cyclohexyl-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-6,9-dicarboxyla-
te (186 mg, yield 48.6%).
[1477] .sup.1H-NMR(400 MHz, DMSO-d.sub.6): .delta.(ppm) 8.18(1H,
brs), 7.92(1H, d, J=8.4 Hz), 7.65(1H, dd, J=8.8, 1.6 Hz),
7.42-7.52(2H, m), 7.39(1H, td, J=7.6, 0.8 Hz), 7.33(1H, dd, J=8.0,
1.2 Hz), 5.33(1H, dd, J=5.6, 5.2 Hz), 4.57-4.85(2H, m),
4.07-4.21(2H, m), 3.88(3H, s), 2.84-2.94(1H, m), 1.95-2.09(2H, m),
1.69-1.88(5H, m), 1.31-1.44(3H, m), 1.23(3H, t, J=7.4 Hz).
[1478] MS 448(M+1).
Example 3-2
Production of
12-cyclohexyl-9-methoxycarbonyl-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azule-
ne-6-carboxylic acid
[1479] ##STR395##
[1480] To a solution of 6-ethyl 9-methyl
12-cyclohexyl-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-6,9-dicarboxyla-
te (270 mg, 0.60 mmol) in tetrahydrofuran (1 ml), methanol (1 ml)
and water (1 ml) was added lithium hydroxide monohydrate (30 mg,
0.71 mmol) under ice-cooling, and the mixture was stirred at room
temperature for 20 hr. 1N Hydrochloric acid was added to the
reaction mixture and the mixture was extracted with ethyl acetate.
The organic layer was washed with saturated brine and dried over
anhydrous magnesium sulfate. After filtration, the solvent was
evaporated under reduced pressure to give
12-cyclohexyl-9-methoxycarbonyl-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azule-
ne-6-carboxylic acid as a crude product. The obtained crude product
was used in Example 3-3 without further purification.
Example 3-3
Production of methyl
12-cyclohexyl-6-dimethylcarbamoyl-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azu-
lene-9-carboxylate
[1481] ##STR396##
[1482] To a solution of
12-cyclohexyl-9-methoxycarbonyl-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azule-
ne-6-carboxylic acid obtained as a crude product in Example 3-2 in
N,N-dimethylformamide (5 ml) were added dimethylamine hydrochloride
(246 mg, 3.01 mmol), 1-ethyl-3-(3'-dimethylaminopropyl)carbodiimide
monohydrochloride (231 mg, 1.20 mol), 1-hydroxybenzotriazole
monohydrate (163 mg, 1.20 mmol) and triethylamine (0.42 ml, 3.01
mmol), and the mixture was stirred at room temperature for 16 hr.
1N Hydrochloric acid was added to the reaction mixture and the
mixture was extracted with ethyl acetate. The organic layer was
washed successively with water, saturated aqueous sodium hydrogen
carbonate solution and saturated brine, and dried over anhydrous
sodium sulfate. After filtration, the solvent was evaporated under
reduced pressure and the residue was purified by silica gel
chromatography (hexane:ethyl acetate=1:1) to give methyl
12-cyclohexyl-6-dimethylcarbamoyl-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azu-
lene-9-carboxylate (100 mg, yield 37.2%).
[1483] .sup.1H-NMR(300 MHz, CDCl.sub.3): .delta.(ppm) 8.11(1H, d,
J=1.2 Hz), 7.90(1H, d, J=9.0 Hz), 7.77(1H, dd, J=8.4, 1.5 Hz),
7.44(1H, td, J=6.6, 1.0 Hz), 7.38(1H, dd, J=7.5, 1.8 Hz), 7.31(1H,
td, J=7.2, 0.6 Hz), 7.09(1H, dd, J=7.8, 1.5 Hz), 5.27(1H, dd,
J=8.4, 6.0 Hz), 4.49-4.56(2H, m), 3.95(3H, s), 3.25(3H, s),
3.05(3H, s), 2.92-3.03(1H, m), 1.72-2.17(7H, m), 1.22-1.49(3H,
m).
Example 3-4
Production of
12-cyclohexyl-6-dimethylcarbamoyl-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azu-
lene-9-carboxylic acid
[1484] ##STR397##
[1485] To a solution of methyl
12-cyclohexyl-6-dimethylcarbamoyl-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azu-
lene-9-carboxylate (100 mg, 0.22 mmol) in tetrahydrofuran (1 ml)
and methanol (1 ml) was added 4N aqueous sodium hydroxide solution
(1 ml), and the mixture was stirred at room temperature for 18 hr.
1N Hydrochloric acid was added to the reaction mixture and the
mixture was extracted with ethyl acetate. The organic layer was
washed with saturated brine, and dried over anhydrous magnesium
sulfate. After filtration, the solvent was evaporated under reduced
pressure and the residue was purified by silica gel chromatography
(chloroform:methanol=30:1-20:1) to give
12-cyclohexyl-6-dimethylcarbamoyl-6,7-dihydro-5-oxa-7a-azadibenzo[a,-
e]azulene-9-carboxylic acid (9 mg, yield 9.4%).
[1486] .sup.1H-NMR(400 MHz, DMSO-d.sub.6): .delta.(ppm) 12.45(1H,
brs), 8.24(1H, d, J=1.2 Hz), 7.87(1H, d, J=8.8 Hz), 7.62(1H, dd,
J=8.4, 1.6 Hz), 7.34-7.48(3H, m), 7.12(1H, brd, J=8.0 Hz), 5.52(1H,
dd, J=8.8, 5.2 Hz), 4.52-4.65(1H, m), 4.23-4.37(1H, m), 3.21(3H,
s), 2.84-2.94(1H, m), 2.92(3H, s), 1.59-2.10(7H, m), 1.17-1.46(3H,
m).
[1487] MS 433(M+1).
Example 4-1
Production of methyl
11-cyclohexyl-5-oxa-6a-azabenzo[a]fluorene-8-carboxylate
[1488] ##STR398##
[1489] To a solution of methyl
3-cyclohexyl-2-(2-hydroxyphenyl)-1H-indole-6-carboxylate (150 mg,
0.42 mmol) obtained in the same manner as in the method described
in Example 3-1, Step 1 in N,N-dimethylformamide (7.5 ml) were added
dibromomethane (0.15 ml, 2.13 mmol) and potassium carbonate (1.0 g,
7.23 mmol), and the mixture was stirred at 70.degree. C. for 13 hr.
Water was added to the reaction mixture and the mixture was
extracted with ethyl acetate. The organic layer was washed
successively with water and saturated brine, and dried over
anhydrous sodium sulfate. After filtration, the solvent was
evaporated under reduced pressure. The residue was purified by
silica gel chromatography (hexane:ethyl acetate=10:1-5:1) to give
methyl 11-cyclohexyl-5-oxa-6a-azabenzo[a]fluorene-8-carboxylate (30
mg, yield 26.0%).
[1490] .sup.1H-NMR(400 MHz, CDCl.sub.3): .delta.(ppm) 8.00(1H, d,
J=11.6 Hz), 7.89(1H, d, J=8.4 Hz), 7.78(1H, dd, J=8.0, 1.6 Hz),
7.75(1H, dd, J=8.8, 1.6 Hz), 7.31(1H, td, J=7.6, 0.8 Hz), 7.19(1H,
td, J=7.6, 0.4 Hz), 7.15(1H, dd, J=8.0, 1.2 Hz), 5.86(2H, s),
3.95(3H, s), 3.24-3.34(1H, m), 2.02-2.15(2H, m), 1.81-1.98(5H, m),
1.36-1.55(3H, m).
[1491] MS 362(M+1).
Example 4-2
Production of
11-cyclohexyl-5-oxa-6a-azabenzo[a]fluorene-8-carboxylic acid
[1492] ##STR399##
[1493] To a solution of methyl
11-cyclohexyl-5-oxa-6a-azabenzo[a]fluorene-8-carboxylate (40 mg,
0.11 mmol) in tetrahydrofuran (1 ml) and methanol (1 ml) was added
4N aqueous sodium hydroxide solution (1 ml), and the mixture was
stirred at 60.degree. C. for 3 hr. 1N Hydrochloric acid was added
to the reaction mixture, and the precipitated solid was collected
by filtration, washed with hexane and dried in vacuo to give
11-cyclohexyl-5-oxa-6a-azabenzo[a]fluorene-8-carboxylic acid (26
mg, yield 68.4%).
[1494] .sup.1H-NMR(400 MHz, DMSO-d.sub.6): (ppm) 12.65(1H, brs),
8.19(1H, d, J=1.2 Hz), 7.91(1H, d, J=8.8 Hz), 7.82(1H, dd, J=8.0,
1.6 Hz), 7.63(1H, dd, J=8.8, 1.6 Hz), 7.37(1H, td, J=8.4, 1.0 Hz),
7.27(1H, td, J=7.6, 0.8 Hz), 7.21(1H, dd, J=8.0, 1.2 Hz),
6.07(2H,s), 3.21-3.35(1H, m), 1.99-2.13(2H, m), 1.72-1.91(5H, m),
1.37-1.55(3H, m).
[1495] MS 348(M+1).
Example 5-1
Production of methyl
13-cyclohexyl-6,7-dihydro-5H-benzo[3,4]azepino[1,2-a]indole-10-carboxylat-
e
Step 1: Production of methyl
1-[3-(2-bromophenyl)propyl]-3-cyclohexyl-1H-indole-6-carboxylate
[1496] ##STR400##
[1497] To a solution of methyl 3-cyclohexyl-1H-indole-6-carboxylate
(500 mg, 1.94 mmol) obtained in the same manner as in the method
described in WO03/010140 in N,N-dimethylformamide (2 ml) was added
sodium hydride (93 mg, 2.33 mmol) under ice-cooling, and the
mixture was stirred for 30 min. A solution of
1-bromo-2-(3-iodopropyl)benzene (695 mg, 2.14 mmol), obtained in
the same manner as in the method described Tetrahedron Letter, Vol.
32, No. 28, pp. 3317-3320, 1991, in N,N-dimethylformamide (1.5 ml)
was added and the mixture was stirred for 1 hr. Saturated aqueous
ammonium chloride solution was added to the reaction mixture and
the mixture was extracted with ethyl acetate. The organic layer was
washed successively with water and saturated brine, and dried over
anhydrous magnesium sulfate. After filtration, the solvent was
evaporated under reduced pressure and the residue was purified by
silica gel chromatography (hexane:ethyl acetate=6:1) to give methyl
1-[3-(2-bromophenyl)propyl]-3-cyclohexyl-1H-indole-6-carboxylate
(770 mg, yield 79%).
[1498] .sup.1H-NMR(400 MHz, DMSO-d.sub.6): (ppm) 8.03(1H, s),
7.65(1H, d, J=8.0 Hz), 7.60(1H, dd, J=8.0, 1.2 Hz), 7.54(1H, d,
J=7.6 Hz), 7.40(1H, s), 7.27-7.33(2H, m), 7.11-7.15(1H, m),
4.27(2H, t, J=7.0 Hz), 3.85(3H, s), 2.75-2.83(1H, m), 2.67(2H, dd,
J=8.4, 5.6 Hz), 1.92-2.10(4H, m), 1.69-1.84(3H, m), 1.37-1.50(4H,
m), 1.21-1.32(1H, m).
Step 2: Production of methyl
13-cyclohexyl-6,7-dihydro-5H-benzo[3,4]azepino[1,2-a]indole-10-carboxylat-
e
[1499] ##STR401##
[1500] To a solution of methyl
1-[3-(2-bromophenyl)propyl]-3-cyclohexyl-1H-indole-6-carboxylate
(250 mg, 0.550 mmol) in N,N-dimethylacetamide (7.5 ml) were added
potassium acetate (59 mg, 0.605 mmol) and
tetrakis(triphenylphosphine)palladium (32 mg, 0.0275 mmol), and the
mixture was stirred at 160.degree. C. for 5 hr. The reaction
mixture was allowed to cool to room temperature. Water was added to
the reaction mixture and the mixture was extracted with ethyl
acetate. The organic layer was washed successively with water and
saturated brine, and dried over anhydrous magnesium sulfate. After
filtration, the solvent was evaporated under reduced pressure and
the residue was purified by silica gel chromatography (hexane:ethyl
acetate=8:1-4:1) to give methyl
13-cyclohexyl-6,7-dihydro-5H-benzo[3,4]azepino[1,2-a]indole-10-carboxylat-
e (55 mg, yield 27%).
[1501] .sup.1H-NMR(400 MHz, DMSO-d.sub.6): .delta.(ppm) 8.14(1H, d,
J=1.2 Hz), 7.89(1H, d, J=8.0 Hz), 7.61(1H, dd, J=8.4, 1.6 Hz),
7.37-7.46(4H, m), 4.56-4.65(1H, m), 3.87(3H, s), 3.47-3.57(1H, m),
2.77-2.88(1H, m), 2.66-2.75(1H, m), 2.27-2.41(2H, m),
1.12-2.08(10H, m).
[1502] MS 374(M+1).
Example 5-2
Production of
13-cyclohexyl-6,7-dihydro-5H-benzo[3,4]azepino[1,2-a]indole-10-carboxylic
acid
[1503] ##STR402##
[1504] To a solution of methyl
13-cyclohexyl-6,7-dihydro-5H-benzo[3,4]azepino[1,2-a]indole-10-carboxylat-
e (55 mg, 0.147 mmol) in tetrahydrofuran (2 ml) and methanol (2 ml)
was added 4N aqueous sodium hydroxide solution (1 ml), and the
mixture was stirred at 50.degree. C. for 2 hr. The reaction mixture
was allowed to cool to room temperature, and 2N hydrochloric acid
(2.5 ml) and water were added to the reaction mixture. The
precipitated solid was collected by filtration, washed with water
and dried in vacuo to give
13-cyclohexyl-6,7-dihydro-5H-benzo[3,4]azepino[1,2-a]indole-10-carboxylic
acid (44 mg, yield 83%).
[1505] .sup.1H-NMR(400 MHz, DMSO-d.sub.6): .delta.(ppm) 12.54(1H,
brs), 8.10(1H, s), 7.85(1H, d, J=8.4 Hz), 7.60(1H, d, J=8.4 Hz),
7.36-7.45(4H, m), 4.53-4.62(1H, m), 3.45-3.58(1H, m), 2.77-2.88(1H,
m), 2.65-2.75(1H, m), 2.27-2.42(2H, m), 1.11-2.10(10H, m).
[1506] MS 360(M+1).
[1507] The compound of Example 5-3 was produced by the same method
as in Examples 5-1 to 5-2 or a method similar thereto, and where
necessary, by employing other conventional methods. The chemical
structural formulas are shown in Table 112. [1508]
11-cyclohexyl-6H-isoindolo[2,1-a]indole-3-carboxylic acid (Example
5-3).
Example 6-1
Production of methyl
13-cyclohexyl-6,7-dihydro-5H-pyrrolo[2',1':3,4][1,4]diazepino[1,2-a]indol-
e-10-carboxylate
Step 1: Production of methyl
2-(1-tert-butoxycarbonyl-1H-pyrrol-2-yl)-3-cyclohexyl-1H-indole-6-carboxy-
late
[1509] ##STR403##
[1510] To a suspension of methyl
2-bromo-3-cyclohexyl-1H-indole-6-carboxylate (800 mg, 2.38 mmol)
obtained in the same manner as in the method described in
WO03/010140 and N-tert-butoxycarbonylpyrrole-2-boronic acid (1.00
g, 4.76 mmol) in dimethoxyethane (10 ml) and water (5 ml) were
added sodium carbonate (757 mg, 7.14 mmol), lithium chloride (202
mg, 4.76 mmol) and tetrakis(triphenylphosphine)palladium (275 mg,
0.238 mmol), and the mixture was heated under reflux for 9 hr. The
reaction mixture was allowed to cool to room temperature. Water was
added to the reaction mixture and the mixture was extracted with
ethyl acetate. The organic layer was washed successively with
saturated aqueous sodium hydrogen carbonate solution and saturated
brine, and dried over anhydrous magnesium sulfate. After
filtration, the solvent was evaporated under reduced pressure and
the residue was purified by silica gel chromatography (hexane:ethyl
acetate=8:1-6:1) to give methyl
2-(1-tert-butoxycarbonyl-1H-pyrrol-2-yl)-3-cyclohexyl-1H-indole-6-carboxy-
late (642 mg, yield 64%).
[1511] .sup.1H-NMR(400 MHz, DMSO-d.sub.6): .delta.(ppm) 11.41(1H,
s), 7.90(1H, d, J=1.2 Hz), 7.75(1H, d, J=8.4 Hz), 7.56(1H, dd,
J=8.0, 1.2 Hz), 7.48(1H, t, J=2.6 Hz), 6.38(2H, d, J=2.8 Hz),
3.84(3H, s), 1.62-1.84(7H, m), 1.21-1.32(3H, m), 1.12(9H, s).
Step 2: Production of methyl
2-(1-tert-butoxycarbonyl-1H-pyrrol-2-yl)-1-(3-chloropropyl)-3-cyclohexyl--
1H-indole-6-carboxylate
[1512] ##STR404##
[1513] To a solution of methyl
2-(1-tert-butoxycarbonyl-1H-pyrrol-2-yl)-3-cyclohexyl-1H-indole-6-carboxy-
late (140 mg, 0.331 mmol) and 1-bromo-3-chloropropane (156 mg,
0.994 mmol) in N,N-dimethylformamide (4 ml) was added sodium
hydride (17 mg, 0.430 mmol) under ice-cooling, and the mixture was
stirred for 2 hr. Water was added to the reaction mixture and the
mixture was extracted with ethyl acetate. The organic layer was
washed successively with water and saturated brine, and dried over
anhydrous magnesium sulfate. After filtration, the solvent was
evaporated under reduced pressure and the residue was purified by
silica gel chromatography (hexane:ethyl acetate=5:1) to give methyl
2-(1-tert-butoxycarbonyl-1H-pyrrol-2-yl)-1-(3-chloropropyl)-3-cyclohexyl--
1H-indole-6-carboxylate (167 mg, yield 100%).
[1514] .sup.1H-NMR(400 MHz, DMSO-d.sub.6): (ppm) 11.39(1H, s),
7.88(1H, d, J=1.2 Hz), 7.73(1H, d, J=8.4 Hz), 7.54(1H, dd, J=8.4,
1.6 Hz), 7.46(1H, t, J=2.6 Hz), 6.36(2H, d, J=2.8 Hz), 3.82(3H, s),
2.62-2.72(1H, m), 1.60-1.82(7H, m), 1.19-1.30(3H, m), 1.10(9H,
s).
Step 3: Production of methyl
1-(3-chloropropyl)-3-cyclohexyl-2-(1H-pyrrol-2-yl)-1H-indole-6-carboxylat-
e
[1515] ##STR405##
[1516] To a solution of methyl
2-(1-tert-butoxycarbonyl-1H-pyrrol-2-yl)-1-(3-chloropropyl)-3-cyclohexyl--
1H-indole-6-carboxylate (167 mg, 0.344 mmol) in chloroform (1.5 ml)
was added trifluoroacetic acid (1 ml), and the mixture was stirred
at room temperature for 8 hr. The reaction mixture was evaporated
under reduced pressure. To the residue 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 and saturated
brine, and dried over anhydrous magnesium sulfate. After
filtration, the solvent was evaporated under reduced pressure to
give methyl
1-(3-chloropropyl)-3-cyclohexyl-2-(1H-pyrrol-2-yl)-1H-indole-6-carboxylat-
e (135 mg, yield 98%).
[1517] .sup.1H-NMR(400 MHz, DMSO-d.sub.6): .delta.(ppm) 11.13(1H,
brs), 8.13(1H, s), 7.82(1H, d, J=8.4 Hz), 7.64(1H, d, J=8.4 Hz),
6.97-7.02(1H, m), 6.20-6.26(2H, m), 4.21(2H, t, J=7.3 Hz), 3.87(3H,
s), 3.48(2H, t, J=6.3 Hz), 2.63-2.76(1H, m), 1.63-1.97(9H, m),
1.18-1.33(3H, m).
Step 4: Production of methyl
13-cyclohexyl-6,7-dihydro-5H-pyrrolo[2',1':3,4][1,4]diazepino[1,2-a]indol-
e-10-carboxylate
[1518] ##STR406##
[1519] To a solution of methyl
1-(3-chloropropyl)-3-cyclohexyl-2-(1H-pyrrol-2-yl)-1H-indole-6-carboxylat-
e (130 mg, 0.326 mmol) in N,N-dimethylformamide (4 ml) was added
sodium hydride (17 mg, 0.424 mmol) 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 successively with water and saturated
brine, and dried over anhydrous magnesium sulfate. After
filtration, the solvent was evaporated under reduced pressure and
the residue was purified by silica gel chromatography (hexane:ethyl
acetate=4:1) to give methyl
13-cyclohexyl-6,7-dihydro-5H-pyrrolo[2',1':3,4][1,4]diazepino[1,2-a]indol-
e-10-carboxylate (91 mg, yield 77%).
[1520] .sup.1H-NMR(400 MHz, DMSO-d.sub.6): .delta.(ppm) 8.13(1H, d,
J=1.2 Hz), 7.82(1H, d, J=8.8 Hz), 7.60(1H, dd, J=8.4, 1.6 Hz),
7.04(1H, dd, J=2.4, 1.6 Hz), 6.29(1H, dd, J=3.6, 1.6 Hz), 6.18(1H,
dd, J=4.0, 2.8 Hz), 4.11(2H, t, J=6.4 Hz), 3.98(2H, t, J=6.4 Hz),
3.86(3H,s), 2.91-3.01(1H, m), 2.25-2.33(2H, m), 1.91-2.03(2H, m),
1.69-1.85(5H, m), 1.26-1.43(3H, m).
[1521] MS 363(M+1).
Example 6-2
Production of
13-cyclohexyl-6,7-dihydro-5H-pyrrolo[2',1':3,4][1,4]diazepino[1,2-a]indol-
e-10-carboxylic acid
[1522] ##STR407##
[1523] To a solution of methyl
13-cyclohexyl-6,7-dihydro-5H-pyrrolo[2',1':3,4][1,4]diazepino[1,2-a]indol-
e-10-carboxylate (88 mg, 0.17 mmol) in tetrahydrofuran (2 ml) and
methanol (2 ml) was added 4N aqueous sodium hydroxide solution (1
ml) and the mixture was stirred at 50.degree. C. for 2 hr. The
reaction mixture was allowed to cool to room temperature, and 2N
hydrochloric acid (2.5 ml) and water were added to the reaction
mixture. The precipitated solid was collected by filtration, washed
with water and dried in vacuo to give
13-cyclohexyl-6,7-dihydro-5H-pyrrolo[2',1':3,4][1,4]diazepino[1,2-a]indol-
e-10-carboxylic acid (74 mg, yield 85%).
[1524] .sup.1H-NMR(400 MHz, DMSO-d.sub.6): .delta.(ppm) 12.54(1H,
brs), 8.09(1H, d, J=1.6 Hz), 7.78(1H, d, J=8.4 Hz), 7.58(1H, dd,
J=8.8, 1.6 Hz), 7.04(1H, dd, J=2.4, 1.6 Hz), 6.28(1H, dd, J=4.0,
1.6 Hz), 6.17(1H, dd, J=3.2, 2.4 Hz), 4.09(2H, t, J=6.0 Hz),
3.97(2H, t, J=6.4 Hz), 3.32(3H, s), 2.91-3.01(1H, m), 2.25-2.32(2H,
m), 1.90-2.04(2H, m), 1.69-1.85(5H, m), 1.27-1.42(3H, m).
[1525] MS 349(M+1).
Example 7-1
Production of ethyl
12-cyclohexyl-3-hydroxy-6,7-dihydro-5-oxo-7a,8-diazadibenzo[a,e]azulene-9-
-carboxylate
Step 1: Production of
3-cyclohexyl-1H-pyrrolo[2,3-b]pyridine-6-carbonitrile
[1526] ##STR408##
[1527] To a solution of
3-cyclohexyl-1H-pyrrolo[2,3-b]pyridine-N-oxide (3.0 g, 13.7 mmol)
obtained in the same manner as in the method described in
WO03/010140 in acetonitrile (30 ml) were added triethylamine (5.8
ml, 41.2 mmol) and trimethylsilyl cyanide (8.3 ml, 61.8 mmol), and
the mixture was heated under reflux at 110.degree. C. for 10 hr.
The mixture was allowed to cool to room temperature, and saturated
aqueous sodium hydrogen carbonate solution was added. The
precipitated solid was collected by filtration and the obtained
solid was purified by silica gel chromatography (hexane:ethyl
acetate=2:1) to give
3-cyclohexyl-1H-pyrrolo[2,3-b]pyridine-6-carbonitrile (1.60 g,
yield 52%).
[1528] .sup.1H-NMR(400 MHz, CDCl.sub.3): .delta.(ppm) 9.48(1H,
brs), 8.03(1H, d, J=8.0 Hz), 7.44(1H, d, J=8.0 Hz), 7.32(1H, d,
J=2.4 Hz), 2.74-2.88(1H, m), 2.00-2.11(2H, m), 1.74-1.92(3H, m),
1.39-1.53(4H, m), 1.24-1.36(1H, m).
[1529] MS 226(M+1).
Step 2: Production of
1-(2-benzyloxyethyl)-3-cyclohexyl-1H-pyrrolo[2,3-b]pyridine-6-carbonitril-
e
[1530] ##STR409##
[1531] To a solution of
3-cyclohexyl-1H-pyrrolo[2,3-b]pyridine-6-carbonitrile (1.0 g, 13.7
mmol) in N,N-dimethylformamide (10 ml) was added sodium hydride
(213 mg, 5.33 mmol) under ice-cooling, and the mixture was stirred
for 15 min. After stirring, benzyl 2-bromoethyl ether (0.77 ml,
4.88 mmol) was added and the mixture was stirred at 50.degree. C.
for 1 hr. The mixture was allowed to cool to room temperature and
water was added. The mixture was extracted with ethyl acetate. The
organic layer was washed successively with water and saturated
brine, and dried over anhydrous magnesium sulfate. After
filtration, the solvent was evaporated under reduced pressure and
the residue was purified by silica gel chromatography (hexane:ethyl
acetate=4:1) to give
1-(2-benzyloxyethyl)-3-cyclohexyl-1H-pyrrolo[2,3-b]pyridine-6-carbonitril-
e (1.44 g, yield 90%).
[1532] .sup.1H-NMR(400 MHz, CDCl.sub.3): .delta.(ppm) 7.95(1H, d,
J=8.0 Hz), 7.37(1H, d, J=8.0 Hz), 7.33(1H, s), 7.16-7.29(5H, m),
4.48(2H, s), 4.46(2H, t, J=5.2 Hz), 3.81(2H, t, J=5.0 Hz),
2.73-2.83(1H, m), 2.00-2.07(2H, m), 1.74-2.00(3H, m), 1.37-1.52(4H,
m), 1.26-1.35(1H, m).
MS 360(M+1).
Step 3: Production of ethyl
1-(2-benzyloxyethyl)-3-cyclohexyl-1H-pyrrolo[2,3-b]pyridine-6-carboxylate
[1533] ##STR410##
[1534] To a solution of
1-(2-benzyloxyethyl)-3-cyclohexyl-1H-pyrrolo[2,3-b]pyridine-6-carbonitril-
e (1.44 g, 4.00 mmol) in ethanol (30 ml) was added acetyl chloride
(8.5 ml, 120 mmol) under ice-cooling, and the mixture was heated
under reflux for 3 hr. The mixture was allowed to cool to room
temperature, and the solvent was evaporated under reduced pressure.
The residue was dissolved in ethyl acetate and water was added. The
mixture was extracted with ethyl acetate, and the organic layer was
washed successively with water and saturated brine, and dried over
anhydrous magnesium sulfate. After filtration, the solvent was
evaporated under reduced pressure and the residue was purified by
silica gel chromatography (hexane:ethyl acetate=4:1) to give ethyl
1-(2-benzyloxyethyl)-3-cyclohexyl-1H-pyrrolo[2,3-b]pyridine-6-carboxylate
(1.14 g, yield 70%).
[1535] .sup.1H-NMR(400 MHz, CDCl.sub.3): .delta.(ppm) 7.96(1H, d,
J=8.0 Hz), 7.86(1H, d, J=8.0 Hz), 7.32(1H, s), 7.19-7.30(5H, m),
4.55(2H, t, J=5.2 Hz), 4.49(2H, s), 4.44(2H, q, J=7.2 Hz), 3.84(2H,
t, J=5.0 Hz), 2.75-2.85(1H, m), 2.01-2.12(2H, m), 1.73-1.90(3H, m),
1.38-1.53(7H, m), 1.26-1.34(1H, m).
[1536] MS 407(M+1).
Step 4: Production of ethyl
1-(2-benzyloxyethyl)-2-bromo-3-cyclohexyl-1H-pyrrolo[2,3-b]pyridine-6-car-
boxylate
[1537] ##STR411##
[1538] To a solution of ethyl
1-(2-benzyloxyethyl)-3-cyclohexyl-1H-pyrrolo[2,3-b]pyridine-6-carboxylate
(888 mg, 2.18 mmol) in carbon tetrachloride (20 ml) was added
N-bromosuccinimide (505 mg, 2.84 mmol), and the mixture was heated
under reflux for 12 hr. The mixture was allowed to cool to room
temperature, and the solvent was evaporated under reduced pressure.
The residue was purified by silica gel chromatography (hexane:ethyl
acetate=6:1) to give ethyl
1-(2-benzyloxyethyl)-2-bromo-3-cyclohexyl-1H-pyrrolo[2,3-b]pyridine-
-6-carboxylate (592 mg, yield 56%).
[1539] .sup.1H-NMR(400 MHz, CDCl.sub.3): (ppm) 8.03(1H, d, J=8.0
Hz), 7.84(1H, d, J=8.0 Hz), 7.15-7.25(5H, m), 4.66(2H, t, J=6.2
Hz), 4.55(2H, s), 4.43(2H, q, J=7.1 Hz), 3.88(2H, t, J=6.0 Hz),
2.80-2.93(1H, m), 1.76-1.92(6H, m), 1.23-1.49(7H, m).
[1540] MS 485(M+1).
Step 5: Production of ethyl
1-(2-benzyloxyethyl)-2-(2,4-bismethoxymethoxyphenyl)-3-cyclohexyl-1H-pyrr-
olo[2,3-b]pyridine-6-carboxylate
[1541] ##STR412##
[1542] To a suspension of ethyl
1-(2-benzyloxyethyl)-2-bromo-3-cyclohexyl-1H-pyrrolo[2,3-b]pyridine-6-car-
boxylate (592 mg, 1.22 mmol) and 2,4-bismethoxymethoxyphenylboronic
acid (384 mg, 1.59 mmol) obtained in the same manner as in Example
2-1, Step 2 in 1,2-dimethoxyethane (12 ml) and water (6 ml) were
added lithium chloride (155 mg, 3.66 mmol), sodium carbonate (388
mg, 3.66 mmol) and tetrakis(triphenylphosphine)palladium (141 mg,
0.12 mmol), and the mixture was stirred with heating at 110.degree.
C. for 2.5 hr. The reaction mixture was allowed to cool to room
temperature. Water was added to the reaction mixture and the
mixture was extracted with ethyl acetate. The organic layer was
washed with saturated brine and dried over anhydrous magnesium
sulfate. After filtration, the solvent was evaporated under reduced
pressure and the obtained residue was purified by silica gel
chromatography (hexane:ethyl acetate=3:1) to give ethyl
1-(2-benzyloxyethyl)-2-(2,4-bismethoxymethoxyphenyl)-3-cyclohexyl-1H-pyrr-
olo[2,3-b]pyridine-6-carboxylate (727 mg, yield 99%).
[1543] .sup.1H-NMR(400 MHz, CDCl.sub.3): .delta.(ppm) 8.07(1H, d,
J=8.0 Hz), 7.87(1H, d, J=8.0 Hz), 7.18-7.21(3H, m), 7.06-7.09(3H,
m), 6.92(1H, d, J=2.4 Hz), 6.74(1H, dd, J=8.4, 2.4 Hz), 5.23(2H,
s), 4.97(2H, dd, J=21.6, 6.8 Hz), 4.55-4.64(1H, m), 4.33-4.49(4H,
m), 4.07-4.18(1H, m), 3.66-3.75(1H, m), 3.56-3.64(1H, m), 3.54(3H,
s), 3.27(3H, s), 2.43-2.54(1H, m), 1.65-1.84(7H, m), 1.43(3H, t,
J=7.0 Hz), 1.17-1.31(3H, m).
[1544] MS 603(M+1).
Step 6: Production of ethyl
2-(2,4-bismethoxymethoxyphenyl)-3-cyclohexyl-1-(2-hydroxyethyl)-1H-pyrrol-
o[2,3-b]pyridine-6-carboxylate
[1545] ##STR413##
[1546] To a solution of ethyl
1-(2-benzyloxyethyl)-2-(2,4-bismethoxymethoxyphenyl)-3-cyclohexyl-1H-pyrr-
olo[2,3-b]pyridine-6-carboxylate (727 mg, 1.20 mmol) in
tetrahydrofuran (10 ml) and methanol (10 ml) was added 7.5%
palladium carbon (225 mg), and the mixture was stirred at
atmospheric pressure and in a hydrogen atmosphere at room
temperature for 12 hr. The reaction mixture was filtered and the
filtrate was concentrated under reduced pressure to give ethyl
2-(2,4-bismethoxymethoxyphenyl)-3-cyclohexyl-1-(2-hydroxyethyl)-1H--
pyrrolo[2,3-b]pyridine-6-carboxylate as a crude product. The
obtained compound was used in Step 7 without further
purification.
[1547] .sup.1H-NMR(400 MHz, CDCl.sub.3): .delta.(ppm) 8.15(1H, d,
J=8.4 Hz), 7.91(1H, d, J=8.4 Hz), 7.10(1H, d, J=8.4 Hz), 6.97(1H,
d, J=2.0 Hz), 6.82(1H, dd, J=8.4, 2.4 Hz), 5.24(2H, s), 5.05(2H,
dd, J=22.0, 7.2 Hz), 4.45(2H, q, J=7.2 Hz), 3.87-4.15(4H, m),
3.55(3H, s), 3.30(3H, s), 2.44-2.56(1H, m), 1.66-1.84(7H, m),
1.45(3H, t, J=7.0 Hz), 1.19-1.34(3H, m).
[1548] MS 513(M+1).
Step 7: Production of ethyl
3-cyclohexyl-2-(2,4-dihydroxyphenyl)-1-(2-hydroxyethyl)-1H-pyrrolo[2,3-b]-
pyridine-6-carboxylate
[1549] ##STR414##
[1550] To a solution of ethyl
2-(2,4-bismethoxymethoxyphenyl)-3-cyclohexyl-1-(2-hydroxyethyl)-1H-pyrrol-
o[2,3-b]pyridine-6-carboxylate obtained as a crude product in the
previous step in tetrahydrofuran (10 ml) and methanol (10 ml) was
added 6N hydrochloric acid (10 ml), and the mixture was stirred at
room temperature for 1 hr. The reaction mixture was ice-cooled. 4N
Aqueous sodium hydroxide solution (15 ml) was added and the mixture
was extracted with ethyl acetate. The organic layer was washed with
saturated brine and dried over anhydrous magnesium sulfate. After
filtration, the solvent was evaporated under reduced pressure to
give ethyl
3-cyclohexyl-2-(2,4-dihydroxyphenyl)-1-(2-hydroxyethyl)-1H-pyrrolo[2,3-b]-
pyridine-6-carboxylate as a crude product. The obtained compound
was used in Step 8 without further purification.
[1551] .sup.1H-NMR(400 MHz, CDCl.sub.3): .delta.(ppm) 8.15(1H, d,
J=8.4 Hz), 7.89(1H, d, J=8.0 Hz), 6.98(1H, d, J=8.4 Hz), 6.89(1H,
d, J=2.4 Hz), 6.52(1H, dd, J=8.0, 2.0 Hz), 4.40-4.48(2H, m),
4.08-4.15(2H, m), 4.00-4.08(1H, m), 3.92-3.99(1H, m), 2.53-2.66(1H,
m), 1.64-1.89(7H, m), 1.43(3H, t, J=7.0 Hz), 1.33-1.33(3H, m).
[1552] MS 425(M+1).
Step 8: Production of ethyl
12-cyclohexyl-3-hydroxy-6,7-dihydro-5-oxo-7a,8-diazadibenzo[a,e]azulene-9-
-carboxylate
[1553] ##STR415##
[1554] To a solution of ethyl
3-cyclohexyl-2-(2,4-dihydroxyphenyl)-1-(2-hydroxyethyl)-1H-pyrrolo[2,3-b]-
pyridine-6-carboxylate in tetrahydrofuran (25 ml) obtained as a
crude product in the previous step were added triphenylphosphine
(463 mg, 1.77 mmol) and diisopropyl azodicarboxylate (0.35 ml, 1.77
mmol) under ice-cooling, and the mixture was stirred at room
temperature for 2 hr. The reaction mixture was concentrated and the
obtained residue was purified by silica gel chromatography
(hexane:ethyl acetate=3:2) to give ethyl
12-cyclohexyl-3-hydroxy-6,7-dihydro-5-oxo-7a,8-diazadibenzo[a,e]azu-
lene-9-carboxylate (344 mg, yield 72%).
[1555] .sup.1H-NMR(400 MHz, CDCl.sub.3): (ppm) 8.15(1H, d, J=8.0
Hz), 7.88(1H, d, =8.4 Hz), 7.27(1H, d, J=8.0 Hz), 6.77(1H, dd,
J=8.4, 2.8 Hz), 6.72(1H, d, J=2.8 Hz), 5.85(1H, brs), 4.52-4.58(2H,
m), 4.43-4.51(4H, m), 2.88-2.98(1H, m), 1.74-2.01(7H, m), 1.45(3H,
t, J=7.2 Hz), 1.32-1.40(3H, m).
[1556] MS 407(M+1).
Example 7-2
Production of ethyl
3-benzyloxy-12-cyclohexyl-6,7-dihydro-5-oxo-7a,8-diazadibenzo[a,e]azulene-
-9-carboxylate
[1557] ##STR416##
[1558] To a solution of ethyl
12-cyclohexyl-3-hydroxy-6,7-dihydro-5-oxo-7a,8-diazadibenzo[a,e]azulene-9-
-carboxylate (50 mg, 0.12 mmol) in N,N-dimethylformamide (1 ml)
were added potassium carbonate (20 mg, 0.15 mmol) and benzyl
bromide (0.02 ml, 0.14 mmol), and the mixture was stirred at
80.degree. C. for 3 hr. The reaction mixture was allowed to cool to
room temperature. To the reaction mixture was added saturated
aqueous sodium hydrogen carbonate solution and the mixture was
extracted with ethyl acetate. The organic layer was washed with
saturated brine and dried over anhydrous magnesium sulfate. After
filtration, the solvent was evaporated under reduced pressure and
the obtained residue was purified by silica gel chromatography
(hexane:ethyl acetate=3:1) to give ethyl
3-benzyloxy-12-cyclohexyl-6,7-dihydro-5-oxo-7a,8-diazadibenzo[a,e]azulene-
-9-carboxylate (50 mg, yield 82%).
[1559] .sup.1H-NMR(400 MHz, CDCl.sub.3): .delta.(ppm) 8.15(1H, d,
J=8.4 Hz), 7.88(1H, d, J=8.4 Hz), 7.31-7.48(6H, m), 6.90(1H, dd,
J=8.4, 2.4 Hz), 6.86(1H, d, J=2.8 Hz), 5.11(2H, s), 4.51-4.61(4H,
m), 4.47(2H, q, J=7.1 Hz), 2.90-3.00(1H, m), 1.72-2.00(7H, m),
1.45(3H, t, J=7.0 Hz), 1.32-1.41(3H, m).
[1560] MS 497(M+1).
Example 7-3
Production of
3-benzyloxy-12-cyclohexyl-6,7-dihydro-5-oxo-7a,8-diazadibenzo[a,e]azulene-
-9-carboxylic acid
[1561] ##STR417##
[1562] To a solution of ethyl
3-benzyloxy-12-cyclohexyl-6,7-dihydro-5-oxo-7a,8-diazadibenzo[a,e]azulene-
-9-carboxylate (50 mg, 0.10 mmol) in tetrahydrofuran (2 ml) and
methanol (2 ml) was added 4N aqueous sodium hydroxide solution (1
ml), and the mixture was stirred with heating at 60.degree. C. for
1 hr. The reaction mixture was allowed to cool to room temperature.
2N Hydrochloric acid (2 ml) was added to the reaction mixture and
the mixture was extracted with ethyl acetate. The organic layer was
washed with saturated brine and dried over anhydrous magnesium
sulfate. After filtration, the solvent was evaporated under reduced
pressure. Hexane was added to the residue, and the precipitated
solid was collected by filtration and dried in vacuo to give
3-benzyloxy-12-cyclohexyl-6,7-dihydro-5-oxo-7a,8-diazadibenzo[a,e]az-
ulene-9-carboxylic acid (21 mg, yield 41%).
[1563] .sup.1H-NMR(400 MHz, DMSO-d.sub.6): .delta.(ppm) 12.75(1H,
brs), 8.30(1H, d, J=8.4 Hz), 7.78(1H, d, J=8.0 Hz), 7.45-7.49(2H,
m), 7.31-7.44(4H, m), 7.02(1H, dd, J=8.8, 2.8 Hz), 6.93(1H, d,
J=2.8 Hz), 5.17(2H, s), 4.45(4H, brs), 2.82-2.92(1H, m),
1.88-2.01(2H, m), 1.65-1.85(4H, m), 1.19-1.46(3H, m).
[1564] MS 469(M+1).
[1565] The compounds of Examples 7-4 to 7-8 were produced by the
same methods as in Examples 7-1 to 7-3 or methods similar thereto,
and where necessary, by employing other conventional methods. The
chemical structural formulas are shown in Tables 113 and 114.
[1566]
12-cyclohexyl-3-[2-(morpholin-4-yl)-5-(2-oxopyrrolidin-1-yl)benzyloxy]-6,-
7-dihydro-5-oxa-7a,8-diazadibenzo[a,e]azulene-9-carboxylic acid
dihydrochloride (Example 7-4), [1567]
12-cyclohexyl-3-[5-methanesulfonyl-2-(morpholin-4-yl)benzyloxy]-6,7-dihyd-
ro-5-oxa-7a,8-diazadibenzo[a,e]azulene-9-carboxylic acid
monohydrochloride (Example 7-5), [1568]
3-[5-(N-acetyl-N-methylamino)-2-(morpholin-4-yl)benzyloxy]-12-cyclohexyl--
6,7-dihydro-5-oxa-7a,8-diazadibenzo[a,e]azulene-9-carboxylic acid
dihydrochloride (Example 7-6), [1569]
12-cyclohexyl-3-[2-(4-methanesulfonylpiperazin-1-yl)-5-(2-oxopyrrolidin-1-
-yl)benzyloxy]-6,7-dihydro-5-oxa-7a,8-diazadibenzo[a,e]azulene-9-carboxyli-
c acid dihydrochloride (Example 7-7). [1570]
3-benzyloxy-12-cyclohexyl-6,7-dihydro-5-oxa-7a,8-diazadibenzo[a,e]azulene-
-9-carboxylic acid (Example 7-8)
Example 8-1
Production of ethyl
12-cyclohexyl-6-oxo-6,7-dihydro-5H-5,7a,8-triazadibenzo[a,e]azulene-9-car-
boxylate
Step 1: Production of methyl
(6-cyano-3-cyclohexylpyrrolo[2,3-b]pyridin-1-yl)acetate
[1571] ##STR418##
[1572] To a solution of
3-cyclohexyl-1H-pyrrolo[2,3-b]pyridine-6-carbonitrile (541 mg, 2.40
mmol) obtained in the same manner as in the method described in
Example 7-1, Step 1 in N,N-dimethylformamide (5 ml) was added
sodium hydride (115 mg, 2.88 mmol) under ice-cooling, and the
mixture was stirred for 20 min. Methyl bromoacetate (0.27 ml, 2.88
mmol) was added and the mixture was stirred at room temperature for
1.5 hr. Water was added to the reaction mixture, and the
precipitated solid was collected by filtration, washed with water
and dried in vacuo to give methyl
(6-cyano-3-cyclohexylpyrrolo[2,3-b]pyridin-1-yl)acetate (647 mg,
yield 91%).
[1573] .sup.1H-NMR(400 MHz, CDCl.sub.3): (ppm) 7.98(1H, d, J=8.0
Hz), 7.41(1H, d, J=8.0 Hz), 7.17(1H, s), 5.03(2H, s), 3.78(3H, s),
2.72-2.85(1H, m), 1.99-2.11(2H, m), 1.73-1.92(3H, m), 1.37-1.51(4H,
m), 1.20-1.34(1H, m).
[1574] MS 297(M+1).
Step 2: Production of ethyl
3-cyclohexyl-1-ethoxycarbonylmethyl-1H-pyrrolo[2,3-b]pyridine-6-carboxyla-
te
[1575] ##STR419##
[1576] To a solution of methyl
(6-cyano-3-cyclohexylpyrrolo[2,3-b]pyridin-1-yl)acetate (647 mg,
2.18 mmol) in ethanol (13 ml) was added acetyl chloride (4.7 ml,
65.4 mmol) under ice-cooling, and the mixture was heated under
reflux for 3 hr. The mixture was allowed to cool to room
temperature and the solvent was evaporated under reduced pressure.
Water was added to the residue and the mixture was extracted with
ethyl acetate. The organic layer was washed successively with water
and saturated brine, and dried over anhydrous magnesium sulfate.
After filtration, the solvent was evaporated under reduced pressure
and the residue was purified by silica gel chromatography
(hexane:ethyl acetate=4:1) to give ethyl
3-cyclohexyl-1-ethoxycarbonylmethyl-1H-pyrrolo[2,3-b]pyridine-6-carboxyla-
te (563 mg, yield 75%).
[1577] .sup.1H-NMR(400 MHz, CDCl.sub.3): .delta.(ppm) 7.98(1H, d,
J=8.0 Hz), 7.89(1H, d, J=8.4 Hz), 7.15(1H, s), 5.11(2H, s),
4.45(2H, q, J=7.1 Hz), 4.22(2H, q, J=7.1 Hz), 2.75-2.85(1H, m),
2.02-2.14(2H, m), 1.71-1.91(3H, m), 1.37-1.53(7H, m), 1.23-1.33(4H,
m).
[1578] MS 359(M+1).
Step 3: Production of ethyl
2-bromo-3-cyclohexyl-1-ethoxycarbonylmethyl-1H-pyrrolo[2,3-b]pyridine-6-c-
arboxylate
[1579] ##STR420##
[1580] To a solution of ethyl
3-cyclohexyl-1-ethoxycarbonylmethyl-1H-pyrrolo[2,3-b]pyridine-6-carboxyla-
te (463 mg, 1.34 mmol) in carbon tetrachloride (10 ml) was added
N-bromosuccinimide (287 mg, 1.61 mmol), and the mixture was heated
under reflux for 4 hr. The mixture was allowed to cool to room
temperature and the solvent was evaporated under reduced pressure.
The residue was purified by silica gel chromatography (hexane:ethyl
acetate=5:1) to give ethyl
2-bromo-3-cyclohexyl-1-ethoxycarbonylmethyl-1H-pyrrolo[2,3-b]pyridi-
ne-6-carboxylate (457 mg, yield 64%).
[1581] .sup.1H-NMR(400 MHz, CDCl.sub.3): .delta.(ppm) 8.06(1H, d,
J=8.0 Hz), 7.88(1H, d, J=8.4 Hz), 5.18(2H, s), 4.44(2H, q, J=7.1
Hz), 4.21(2H, q, J=7.1 Hz), 2.82-2.93(1H, m), 1.76-1.93(7H, m),
1.36-1.48(6H, m), 1.27(3H, t, J=7.2 Hz).
[1582] MS 438(M+1).
Step 4: Production of ethyl
12-cyclohexyl-6-oxo-6,7-dihydro-5H-5,7a,8-triazadibenzo[a,e]azulene-9-car-
boxylate
[1583] ##STR421##
[1584] To a suspension of ethyl
2-bromo-3-cyclohexyl-1-ethoxycarbonylmethyl-1H-pyrrolo[2,3-b]pyridine-6-c-
arboxylate (457 mg, 1.05 mmol) and
2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenylamine (275 mg,
1.25 mmol) obtained in the same manner as in the method described
in Example 1-1, Step 1 in 1,2-dimethoxyethane (7.5 ml) and water
(3.5 ml) were added sodium hydrogen carbonate (260 mg, 3.14 mmol)
and tetrakis(triphenylphosphine)palladium (60 mg, 0.05 mmol) and
the mixture was stirred with heating at 110.degree. C. for 3.5 hr.
The mixture was allowed to cool to room temperature and the
reaction mixture was extracted with ethyl acetate. The organic
layer was washed with saturated brine and dried over anhydrous
magnesium sulfate. After filtration, the solvent was evaporated
under reduced pressure and the obtained residue was purified by
silica gel chromatography (hexane:ethyl acetate=1:1) to give ethyl
12-cyclohexyl-6-oxo-6,7-dihydro-5H-5,7a,8-triazadibenzo[a,e]azulene-9-car-
boxylate (111 mg, yield 26%).
[1585] MS 404(M+1).
Example 8-2
Production of ethyl
12-cyclohexyl-6,7-dihydro-5H-5,7a,8-triazadibenzo[a,e]azulene-9-carboxyla-
te
[1586] ##STR422##
[1587] To a solution of ethyl
12-cyclohexyl-6-oxo-6,7-dihydro-5H-5,7a,8-triazadibenzo[a,e]azulene-9-car-
boxylate (111 mg, 0.28 mmol) in tetrahydrofuran (1 ml) was added 1M
BH.sub.3 THF complex tetrahydrofuran solution (1.6 ml) with
stirring under ice-cooling, and the mixture was stirred at room
temperature for 5 hr. To the reaction mixture was added saturated
aqueous sodium hydrogen carbonate solution, and the mixture was
extracted with ethyl acetate. The organic layer was washed with
saturated brine and dried over anhydrous magnesium sulfate. After
filtration, the solvent was evaporated under reduced pressure and
the obtained residue was purified by silica gel chromatography
(hexane:ethyl acetate=3:2) to give ethyl
12-cyclohexyl-6,7-dihydro-5H-5,7a,8-triazadibenzo[a,e]azulene-9-carboxyla-
te (74 mg, yield 69%).
[1588] .sup.1H-NMR(400 MHz, CDCl.sub.3): .delta.(ppm) 8.15(1H, d,
J=8.4 Hz), 7.87(1H, d, J=8.0 Hz), 7.34(1H, d, J=8.0 Hz),
7.24-7.29(1H, m), 6.99(1H, t, J=7.8 Hz), 6.85(1H, d, J=8.0 Hz),
4.67(2H, brs), 4.47(2H, q, J=7.2 Hz), 3.69(2H, t, J=5.2 Hz),
2.90-3.02(1H, m), 1.71-2.03(7H, m), 1.45(3H, t, J=7.0 Hz),
1.30-1.41(3H, m).
[1589] MS 404(M+1).
Example 8-3
Production of ethyl
12-cyclohexyl-5-[2-oxo-2-(morpholin-4-yl)ethyl]-6,7-dihydro-5H-5,7a,8-tri-
azadibenzo[a,e]azulene-9-carboxylate
[1590] ##STR423##
[1591] To a solution of ethyl
12-cyclohexyl-6,7-dihydro-5H-5,7a,8-triazadibenzo[a,e]azulene-9-carboxyla-
te (74 mg, 0.19 mmol) in N,N-dimethylformamide (2 ml) and
acetonitrile (2 ml) were added 4-(2-chloroacetyl)morpholine (94 mg,
0.57 mmol), potassium iodide (64 mg, 0.38 mmol) and potassium
carbonate (66 mg, 0.48 mmol), and the mixture was stirred with
heating at 90.degree. C. for 12 hr. The reaction mixture was
allowed to cool to room temperature, and water was added to the
reaction mixture. The mixture was extracted with ethyl acetate, and
the organic layer was washed with saturated brine and dried over
anhydrous magnesium sulfate. After filtration, the solvent was
evaporated under reduced pressure and the obtained residue was
purified by silica gel chromatography (ethyl acetate) to give ethyl
12-cyclohexyl-5-[2-oxo-2-(morpholin-4-yl)ethyl]-6,7-dihydro-5H-5,7a,8-tri-
azadibenzo[a,e]azulene-9-carboxylate (62 mg, yield 63%).
[1592] MS 517(M+1).
Example 8-4
Production of
12-cyclohexyl-5-[2-oxo-2-(morpholin-4-yl)ethyl]-6,7-dihydro-5H-5,7a,8-tri-
azadibenzo[a,e]azulene-9-carboxylic acid dihydrochloride
[1593] ##STR424##
[1594] To a solution of ethyl
12-cyclohexyl-5-[2-oxo-2-(morpholin-4-yl)ethyl]-6,7-dihydro-5H-5,7a,8-tri-
azadibenzo[a,e]azulene-9-carboxylate (62 mg, 0.12 mmol) in
tetrahydrofuran (3 ml) and methanol (3 ml) was added 4N aqueous
sodium hydroxide solution (1.5 ml) under ice-cooling, and the
mixture was stirred at room temperature for 2 hr. 2N Hydrochloric
acid (3 ml) was added to the reaction mixture to adjust to pH 7,
and the mixture was extracted with ethyl acetate. The organic layer
was washed with saturated brine and dried over anhydrous sodium
sulfate. After filtration, the solvent was evaporated under reduced
pressure and the obtained residue was purified by silica gel
chromatography (chloroform:methanol=8:1) and the solvent was
evaporated under reduced pressure. To a solution of the residue in
ethyl acetate (1 ml) was added 4N HCl-ethyl acetate solution (1 ml)
and the solvent was evaporated under reduced pressure. Hexane was
added to the residue, and the precipitated solid was collected by
filtration, washed with hexane and dried in vacuo to give
12-cyclohexyl-5-[2-oxo-2-(morpholin-4-yl)ethyl]-6,7-dihydro-5H-5,7a,8-tri-
azadibenzo[a,e]azulene-9-carboxylic acid dihydrochloride (20 mg,
yield 30%).
[1595] MS 562(M+1).
Example 8-7
Production of
3-chloro-14-cyclohexyl-5-[2-(piperidin-1-yl)ethyl]-5,6,7,8-tetrahydrobenz-
o[6,7][1,5]diazocino[8,1-a]indole-11-carboxylic acid
dihydrochloride
Step 1: Production of methyl
2-bromo-3-cyclohexyl-1-(2-ethoxycarbonylethyl)-1H-indole-6-carboxylate
[1596] ##STR425##
[1597] To a solution of methyl
2-bromo-3-cyclohexyl-1H-indole-6-carboxylate (5.00 g, 14.9 mmol)
obtained in the same manner as in the method described in
WO03/010140 in N,N-dimethylformamide (30 ml) were added ethyl
3-bromopropionate (3.84 ml, 30.1 mmol) and potassium carbonate
(6.20 g, 44.6 mmol), and the mixture was stirred at 90.degree. C.
for 3.5 hr. The reaction mixture was allowed to cool to room
temperature, water was added to the reaction mixture and the
mixture was extracted with ethyl acetate. The organic layer was
successively washed with water and saturated brine and dried over
anhydrous magnesium sulfate. After filtration, the solvent was
evaporated under reduced pressure. The residue was purified by
silica gel chromatography (hexane:ethyl acetate=4:1) to give methyl
2-bromo-3-cyclohexyl-1-(2-ethoxycarbonylethyl)-1H-indole-6-carboxylate
(6.40 g, yield 98%).
[1598] .sup.1H-NMR(400 MHz, CDCl.sub.3): .delta.(ppm) 8.04(1H, s),
7.70-7.76(2H, m), 4.53(2H, t, J=5.8 Hz), 4.13(2H, q, J=5.4 Hz),
3.93(3H, s), 2.81-2.90(1H, m), 2.75(2H, t, J=5.7 Hz), 1.73-1.95(7H,
m), 1.29-1.48(3H, m), 1.22(3H, t, J=5.4 Hz).
Step 2: Production of methyl
2-(2-amino-4-chlorophenyl)-3-cyclohexyl-1-(2-ethoxycarbonylethyl)-1H-indo-
le-6-carboxylate
[1599] ##STR426##
[1600] To a suspension of methyl
2-bromo-3-cyclohexyl-1-(2-ethoxycarbonylethyl)-1H-indole-6-carboxylate
(1.00 g, 2.29 mmol) and
5-chloro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenylamine
(697 mg, 2.75 mmol) in 1,2-dimethoxyethane (12 ml) and water (6 ml)
were added lithium chloride (291 mg, 6.87 mmol), sodium carbonate
(729 mg, 6.87 mmol) and tetrakis(triphenylphosphine)palladium (265
mg, 0.229 mmol), and the mixture was stirred at 90.degree. C. for
3.5 hr. The mixture was allowed to cool to room temperature and
saturated aqueous ammonium chloride solution and ethyl acetate were
added. The mixture was filtered through celite, and the filtrate
was washed with saturated brine and dried over anhydrous sodium
sulfate. After filtration, the solvent was evaporated under reduced
pressure and the residue was purified by silica gel chromatography
(hexane:acetone=3:1) to give methyl
2-(2-amino-4-chlorophenyl)-3-cyclohexyl-1-(2-ethoxycarbonylethyl)-1H-indo-
le-6-carboxylate (1.10 g, yield 100%).
[1601] .sup.1H-NMR(400 MHz, CDCl.sub.3): .delta.(ppm) 8.10(1H, s),
7.78(2H, s), 6.99(1H, dd, J=6.0, 0.6 Hz), 6.79-6.83(2H, m),
4.12-4.31(2H, m), 4.01(2H, q, J=5.4 Hz), 3.94(3H, s), 3.76(2H,
brs), 2.45-2.64(3H, m), 1.66-1.85(7H, m), 1.21-1.31(3H, m),
1.15(3H, t, J=5.4 Hz).
Step 3: Production of methyl
2-(2-amino-4-chlorophenyl)-1-(2-carboxyethyl)-3-cyclohexyl-1H-indole-6-ca-
rboxylate
[1602] ##STR427##
[1603] To a suspension of methyl
2-(2-amino-4-chlorophenyl)-3-cyclohexyl-1-(2-ethoxycarbonylethyl)-1H-indo-
le-6-carboxylate (1.05 g, 2.17 mmol) in tetrahydrofuran (11 ml) and
methanol (11 ml) was added 4N aqueous sodium hydroxide solution
(1.08 ml, 4.34 mmol), and the mixture was stirred for 2 hr. 2N
Hydrochloric acid (2.2 ml) and water 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
anhydrous magnesium sulfate. After filtration, the solvent was
evaporated under reduced pressure to give methyl
2-(2-amino-4-chlorophenyl)-1-(2-carboxyethyl)-3-cyclohexyl-1H-indole-6-ca-
rboxylate (949 mg) as a crude product. The obtained crude product
was used for Step 4 without further purification.
[1604] .sup.1H-NMR(400 MHz, CDCl.sub.3): .delta.(ppm) 8.12(1H, s),
7.78(2H, s), 6.98(1H, d, J=5.7 Hz), 6.77-6.83(2H, m), 4.14-4.31(2H,
m), 3.94(3H, s), 2.45-2.73(3H, m), 1.66-1.85(7H, m), 1.20-1.30(3H,
m).
Step 4: Production of methyl
3-chloro-14-cyclohexyl-6-oxo-5,6,7,8-tetrahydrobenzo[6,7][1,5]diazocino[8-
,1-a]indole-11-carboxylate
[1605] ##STR428##
[1606] To a solution of methyl
2-(2-amino-4-chlorophenyl)-1-(2-carboxyethyl)-3-cyclohexyl-1H-indole-6-ca-
rboxylate (949 mg) in N,N-dimethylformamide (33 ml) were added
triethylamine (0.61 ml, 4.35 mmol) and
benzotriazol-1-yloxytris(pyrrolidino)phosphonium
hexafluorophosphate (1.36 g, 2.61 mmol) under ice-cooling, and the
mixture was stirred for 22.5 hr. Water was added to the reaction
mixture and the mixture was extracted with ethyl acetate. The
organic layer was successively washed with water and saturated
brine and dried over anhydrous magnesium sulfate. After filtration,
the solvent was evaporated under reduced pressure. The residue was
purified by silica gel chromatography (hexane:ethyl acetate=2:3),
and hexane: diisopropy ether (3:2) mixture was added to the
obtained residue. The precipitated solid was collected by
filtration and washed with hexane: diisopropy ether (3:2) mixture.
The obtained solid was dried in vacuo to give methyl
3-chloro-14-cyclohexyl-6-oxo-5,6,7,8-tetrahydrobenzo[6,7][1,5]diazocino[8-
,1-a]indole-11-carboxylate (657 mg, yield 72%).
[1607] .sup.1H-NMR(400 MHz, CDCl.sub.3): .delta.(ppm) 8.08(1H, s),
7.80(1H, d, J=6.3 Hz), 7.77(1H, dd, J=6.3, 0.6 Hz), 7.41-7.45(2H,
m), 7.36(1H, d, J=6.0 Hz), 7.29(1H, d, J=1.5 Hz), 4.59-4.66(1H, m),
3.93(3H, s), 3.87-3.92(1H, m), 2.83-2.99(2H, m), 2.40-2.49(1H, m),
1.51-1.94(7H, m), 1.13-1.32(3H, m).
Step 5: Production of methyl
3-chloro-14-cyclohexyl-6-oxo-5-[2-oxo-2-(piperidin-1-yl)ethyl]-5,6,7,8-te-
trahydrobenzo[6,7][1,5]diazocino[8,1-a]indole-11-carboxylate
[1608] ##STR429##
[1609] A suspension of methyl
3-chloro-14-cyclohexyl-6-oxo-5,6,7,8-tetrahydrobenzo[6,7][1,5]diazocino[8-
,1-a]indole-11-carboxylate (200 mg, 0.457 mmol),
1-(chloroacetyl)piperidine (85 mg, 0.526 mmol) and potassium
carbonate (126 mg, 0.914 mmol) in N,N-dimethylformamide (4 ml) was
stirred at 80.degree. C. for 4.5 hr. The mixture was allowed to
cool to room temperature and water was added. The precipitate was
collected by filtration, washed with water, and dried in vacuo to
give methyl
3-chloro-14-cyclohexyl-6-oxo-5-[2-oxo-2-(piperidin-1-yl)ethyl]-5,6,7,8-te-
trahydrobenzo[6,7][1,5]diazocino[8,1-a]indole-11-carboxylate (245
mg, yield 95%) as a crude product. The obtained crude product was
used for Step 6 without further purification.
[1610] .sup.1H-NMR(400 MHz, CDCl.sub.3): .delta.(ppm) 8.09(1H, s),
7.96(1H, d, J=1.8 Hz), 7.77(2H, s), 7.44(1H, dd, J=6.3, 1.5 Hz),
7.36(1H, d, J=6.0 Hz), 4.69-4.79(2H, m), 3.92(3H, s), 3.81-3.89(1H,
m), 3.62-3.69(1H, m), 3.41-3.48(1H, m), 3.36(1H, d, J=12.0 Hz),
3.23-3.30(1H, m), 3.12-3.20(1H, m), 2.99-3.08(1H, m), 2.77-2.85(1H,
m), 2.38-2.48(1H, m), 1.68-1.92(7H, m), 1.41-1.64(6H, m),
1.15-1.32(3H, m).
Step 6: Production of methyl
3-chloro-14-cyclohexyl-5-[2-(piperidin-1-yl)ethyl]-5,6,7,8-tetrahydrobenz-
o[6,7][1,5]diazocino[8,1-a]indole-11-carboxylate
[1611] ##STR430##
[1612] To a solution of methyl
3-chloro-14-cyclohexyl-6-oxo-5-[2-oxo-2-(piperidin-1-yl)ethyl]-5,6,7,8-te-
trahydrobenzo[6,7][1,5]diazocino[8,1-a]indole-11-carboxylate (245
mg, 0.436 mmol) in tetrahydrofuran (2 ml) was added a solution (3
ml) of 1.0M BH.sub.3 THF complex in tetrahydrofuran, and the
mixture was stirred at room temperature for 17.5 hr. 4N
Hydrochloric acid (3 ml) was added to the reaction mixture, and the
mixture was stirred at 70.degree. C. for 7.5 hr. The reaction
mixture was allowed to cool to room temperature, neutralized with
2N aqueous sodium hydroxide solution and saturated aqueous sodium
hydrogen carbonate solution, and extracted with ethyl acetate. The
organic layer was washed with saturated brine and dried over
anhydrous magnesium sulfate. After filtration, the solvent was
evaporated under reduced pressure, and the residue was purified by
silica gel chromatography (chloroform:methanol=50:1-20:1) to give
methyl
3-chloro-14-cyclohexyl-5-[2-(piperidin-1-yl)ethyl]-5,6,7,8-tetrahydrobenz-
o[6,7][1,5]diazocino[8,1-a]indole-11-carboxylate (50 mg, yield
21%).
[1613] .sup.1H-NMR(400 MHz, CDCl.sub.3): .delta.(ppm) 8.05(1H, s),
7.81(1H, d, J=6.3 Hz), 7.75(1H, dd, J=6.6, 1.2 Hz), 6.99(1H, d,
J=6.3 Hz), 6.84(1H, s), 6.66-6.71(1H, m), 4.39-4.47(1H, m),
3.93(3H, s), 3.76-3.86(1H, m), 3.28-3.72(6H, m), 2.82-2.90(2H, m),
2.64-2.75(1H, m), 2.40-2.64(4H, m), 1.20-2.09(16H, m).
Step 7: Production of
3-chloro-14-cyclohexyl-5-[2-(piperidin-1-yl)ethyl]-5,6,7,8-tetrahydrobenz-
o[6,7][1,5]diazocino[8,1-a]indole-11-carboxylic acid
dihydrochloride
[1614] ##STR431##
[1615] To a solution of methyl
3-chloro-14-cyclohexyl-5-[2-(piperidin-1-yl)ethyl]-5,6,7,8-tetrahydrobenz-
o[6,7][1,5]diazocino[8,1-a]indole-11-carboxylate (50 mg, 0.094
mmol) in tetrahydrofuran (1 ml) and methanol (1 ml) wad added 4N
aqueous sodium hydroxide solution (0.5 ml), and the mixture was
stirred at 60.degree. C. for 2 hr. 2N Hydrochloric acid (1.1 ml)
was added to the reaction mixture, and the mixture was extracted
with ethyl acetate:tetrahydrofuran (2:1). The organic layer was
washed saturated brine and dried over anhydrous magnesium sulfate.
After filtration, the solvent was evaporated under reduced
pressure. To a solution of the obtained residue in tetrahydrofuran
(1 ml) was added 4N HCl-ethyl acetate solution (1 ml), and the
solvent was evaporated under reduced pressure. Hexane:ethyl acetate
(4:1) was added and the precipitated solid was collected by
filtration, washed with hexane:ethyl acetate (4:1) and dried in
vacuo to give
3-chloro-14-cyclohexyl-5-[2-(piperidin-1-yl)ethyl]-5,6,7,8-tetrahydr-
obenzo[6,7][1,5]diazocino[8,1-a]indole-11-carboxylic acid
dihydrochloride (26 mg, yield 47%).
[1616] .sup.1H-NMR(300 MHz, DMSO-d.sub.6): .delta.(ppm) 12.57(1H,
s), 9.96(1H, s), 8.12(1H, s), 7.84(1H, d, J=8.4 Hz), 7.65(1H, d,
J=8.4 Hz), 7.05-7.10(2H, m), 6.88(1H, d, J=8.1 Hz), 4.58-4.68(1H,
m), 3.56-3.78(4H, m), 3.41-3.50(2H, m), 3.11-3.29(1H, m),
2.54-3.04(7H, m), 1.21-2.04 (16H, m).
[1617] MS 520.2(M+1).
[1618] The compounds of Examples 8-5 and 8-6 were produced by the
same methods as in Examples 8-1 to 8-4 and 8-7 or methods similar
thereto, and where necessary, by employing other conventional
methods. The chemical structural formulas are shown in Table 115.
[1619]
3-chloro-12-cyclohexyl-5-(2-piperidin-1-ylethyl)-6,7-dihydro-5H-5,7a,8-tr-
iazadibenzo[a,e]azulene-9-carboxylic acid trihydrochloride (Example
8-5) [1620]
3-chloro-12-cyclohexyl-5-[2-(4-ethylpiperazin-1-yl)ethyl]-6,7-dih-
ydro-5H-5,7a,8-triazadibenzo[a,e]azulene-9-carboxylic acid
trihydrochloride (Example 8-6)
Example 9-1
Production of methyl
12-cyclohexyl-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carboxylate
Step 1: Production of methyl
2-[2-(2-chloroethoxy)phenyl]-3-cyclohexyl-1H-indole-6-carboxylate
[1621] ##STR432##
[1622] To a solution of methyl
3-cyclohexyl-2-(2-hydroxyphenyl)-1H-indole-6-carboxylate (500 mg,
1.43 mmol), obtained in the same manner as in the method described
in Example 3-1, Step 1, in acetone (20 ml) were added
1-bromo-2-chloroethane (0.14 ml, 1.72 mmol) and potassium carbonate
(237 mg, 1.72 mmol), and the mixture was stirred at 50.degree. C.
for 2 hr. 1-Bromo-2-chloroethane (0.28 ml, 3.44 mmol) and potassium
carbonate (474 mg, 3.44 mmol) were further added and the mixture
was stirred at 50.degree. C. for 24 hr. The reaction mixture was
allowed to cool to room temperature. Water was added to the
reaction mixture and the mixture was extracted with ethyl acetate.
The organic layer was washed with saturated brine and dried over
anhydrous sodium sulfate. After filtration, the solvent was
evaporated under reduced pressure and the residue was purified by
silica gel column chromatography (hexane:ethyl acetate=3:1) to give
methyl
2-[2-(2-chloroethoxy)phenyl]-3-cyclohexyl-1H-indole-6-carboxylate
(370 mg, yield 62.8%).
[1623] .sup.1H-NMR(400 MHz, CDCl.sub.3): .delta.(ppm) 9.00(1H, s),
8.06-8.07(1H, m), 7.85(1H, d, J=8.4 Hz), 7.74(1H, ddd, J=10.0, 8.0,
1.2 Hz), 7.41(1H, dd, J=7.6, 1.6 Hz), 7.37(1H, td, J=7.8, 1.8 Hz),
7.12(1H, t, J=7.6 Hz), 6.99(1H, d, J=8.0 Hz), 4.28(2H, t, J=5.2
Hz), 3.93(3H, s), 3.81(2H, t, J=5.2 Hz), 2.88-2.95(1H, m),
1.99-2.10(2H, m), 1.76-1.87(5H, m), 1.32-1.41(3H, m).
Step 2: Production of methyl
12-cyclohexyl-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carboxylate
[1624] ##STR433##
[1625] To a solution of methyl
2-[2-(2-chloroethoxy)phenyl]-3-cyclohexyl-1H-indole-6-carboxylate
(180 mg, 0.44 mmol) in N,N-dimethylformamide (6 ml) was added
sodium hydride (20 mg, 0.49 mmol) under ice-cooling, and the
mixture was stirred at room temperature for 24 hr. Water was added
to the reaction mixture and the mixture was extracted with ethyl
acetate. The organic layer was washed with saturated brine and
dried over anhydrous sodium sulfate. After filtration, the solvent
was evaporated under reduced pressure, and diisopropyl ether was
added to the residue. The precipitated solid was collected by
filtration, washed with diisopropyl ether and dried in vacuo to
give methyl
12-cyclohexyl-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carboxylate
(70 mg, yield 42.3%).
[1626] .sup.1H-NMR(400 MHz, DMSO-d.sub.6): .delta.(ppm) 8.20(1H, d,
J=1.6 Hz), 7.89(1H, d, J=8.4 Hz), 7.62(1H, dd, J=8.4, 1.2 Hz),
7.40-7.47(2H, m), 7.33(1H, td, J=7.4, 1.2 Hz), 7.23(1H, dd, J=8.0,
1.2 Hz), 4.33-4.45(4H, m), 3.85(3H, s), 2.83-2.90(1H, m),
1.95-2.06(2H,m), 1.67-1.83(5H, m), 1.24-1.44(3H, m).
[1627] MS 376(M+1).
Example 9-2
Production of
12-cyclohexyl-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carboxylic
acid
[1628] ##STR434##
[1629] To a solution of methyl
12-cyclohexyl-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carboxylate
(70 mg, 0.19 mmol) in tetrahydrofuran (2 ml) and methanol (1 ml)
was added 4N aqueous sodium hydroxide solution (1 ml) and the
mixture was stirred at room temperature for 24 hr. 1N Hydrochloric
acid was added to the reaction mixture, and the precipitated solid
was collected by filtration, washed with water and dried in vacuo
to give
12-cyclohexyl-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carboxylic
acid (59 mg, yield 85.2%).
[1630] .sup.1H-NMR(400 MHz, DMSO-d.sub.6): .delta.(ppm) 12.54(1H,
brs), 8.17(1H, s), 7.86(1H, d, J=8.4 Hz), 7.60(1H, dd, J=8.8, 1.6
Hz), 7.40-7.47(2H, m), 7.33(1H, td, J=7.4, 0.8 Hz), 7.22(1H, d,
J=8.0 Hz), 4.33-4.44(4H, m), 2.83-2.91(1H, m), 1.95-2.05(2H, m),
1.68-1.81(5H, m), 1.25-1.37(3H, m).
[1631] MS 362(M+1).
[1632] The compounds of Examples 9-3 and 9-4 were produced by the
same methods as in Examples 9-1 and 9-2 or methods similar thereto,
and where necessary, by employing other conventional methods. The
chemical structural formulas are shown in Tables 116. [1633]
13-cyclohexyl-7,8-dihydro-6H-indolo[2,1-d]-benzo[b][1,5]oxazocine-10-carb-
oxylic acid (Example 9-3),
3-chloro-12-cyclohexyl-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carb-
oxylic acid (Example 9-4).
Example 10-2
Production of ethyl
3-chloro-12-cyclohexyl-5-[2-(piperidin-1-yl)ethyl]-5,6,7,12-tetrahydroben-
zo[2,3]azepino[4,5-b]indole-9-carboxylate
Step 1: Production of methyl
4-chloro-2-(3-ethoxycarbonylpropionylamino)benzoate
[1634] ##STR435##
[1635] To a solution of methyl 2-amino-4-chlorobenzoate (18.60 g,
100 mmol) and pyridine (11.5 ml, 142 mmol) in toluene (138 ml), was
added dropwise a solution of ethyl succinyl chloride (18.9 ml, 133
mmol) in toluene (19 ml) at a temperature between 0.degree. C. and
10.degree. C. The mixture was stirred at 10.degree. C. f or 1 hr,
water was added and the mixture was extracted with ethyl acetate.
The organic layer was successively washed with 0.1N hydrochloric
acid and 10% aqueous sodium hydrogen carbonate solution and dried
over anhydrous magnesium sulfate. After filtration, the solvent was
evaporated under reduced pressure to give methyl
4-chloro-2-(3-ethoxycarbonylpropionylamino)benzoate (27.90 g, yield
89%).
[1636] .sup.1H-NMR(300 MHz, DMSO-d.sub.6): .delta.(ppm) 10.73 (1H,
s), 8.40 (1H, d, J=2.3 Hz), 7.93 (1H, d, J=8.3 Hz), 7.26 (1H, d,
J=12.8 Hz), 4.06 (2H, q, J=7.0 Hz), 3.87 (3H, s), 2.70-2.68 (2H,
m), 2.63-2.61 (2H, m), 1.18 (3H, t, J=7.2 Hz).
Step 2: Production of a mixture of ethyl
8-chloro-5-hydroxy-2-oxo-2,3-dihydro-1H-benzo[b]azepine-4-carboxylate
and methyl
8-chloro-5-hydroxy-2-oxo-2,3-dihydro-1H-benzo[b]azepine-4-carboxyl-
ate
[1637] ##STR436##
[1638] To a suspension of sodium hydride (60% in oil) (25.90 g, 648
mmol) in N,N-dimethylformamide (250 ml) was added dropwise a
solution of methyl
4-chloro-2-(3-ethoxycarbonylpropionylamino)benzoate (27.90 g, 88.9
mmol) in N,N-dimethylformamide (300 ml). The reaction mixture was
stirred at room temperature for 1 hr, and poured into diluted
hydrochloric acid under ice-cooling. The mixture was stirred under
ice-cooling for 1 hr, and the precipitated solid was collected by
filtration to give a crude product of a mixture of ethyl
8-chloro-5-hydroxy-2-oxo-2,3-dihydro-1H-benzo[b]azepine-4-carboxylate
and methyl
8-chloro-5-hydroxy-2-oxo-2,3-dihydro-1H-benzo[b]azepine-4-carboxyl-
ate (wet weight 21.30 g). The obtained crude product was used for
Step 3 without purification. ethyl
8-chloro-5-hydroxy-2-oxo-2,3-dihydro-1H-benzo[b]azepine-4-carboxylate
[1639] .sup.1H-NMR(300 MHz, DMSO-d.sub.6): .delta.(ppm) 12.51 (1H,
brs), 10.48 (1H, s), 7.81 (1H, d, J=8.7 Hz), 7.33 (1H, dd, J=8.7,
2.3 Hz), 7.26 (1H, d, J=1.9 Hz), 4.30 (2H, q, J=7.2 Hz), 2.97 (2H,
s), 1.30 (3H, t, J=7.0 Hz).
methyl
8-chloro-5-hydroxy-2-oxo-2,3-dihydro-1H-benzo[b]azepine-4-carboxyla-
te
[1640] .sup.1H-NMR(300 MHz, DMSO-d.sub.6): .delta.(ppm) 12.44 (1H,
brs), 10.48 (1H, s), 7.81 (1H, d, J=8.7 Hz), 7.33 (1H, dd, J=8.7,
2.3 Hz), 7.26 (1H, d, J=1.9 Hz), 3.84 (3H, s), 2.97 (2H, s).
Step 3: Production of
8-chloro-3,4-dihydro-1H-benzo[b]azepine-2,5-dione
[1641] ##STR437##
[1642] A solution of ethyl
8-chloro-5-hydroxy-2-oxo-2,3-dihydro-1H-benzo[b]azepine-4-carboxylate
(wet weight 21.3 g) obtained as a crude product in Step 2 in
dimethyl sulfoxide (200 ml) and water (10 ml) was heated at
150.degree. C. Under stirring, water was added 3 times in total by
10 ml every one hour. The mixture was allowed to cool to room
temperature, water (400 ml) was added, and the precipitated solid
was collected by filtration. The crude product was washed with
water and dried in vacuo. A mixed solvent (200 ml) of hexane:ethyl
acetate (10:1) was added to the obtained crude product to give a
suspension. After filtration, the obtained solid was washed with a
mixed solvent (50 ml) of hexane:ethyl acetate (10:1) and dried in
vacuo to give 8-chloro-3,4-dihydro-1H-benzo[b]azepine-2,5-dione
(12.60 g, yield 80%).
[1643] .sup.1H-NMR(300 MHz, DMSO-d.sub.6): .delta.(ppm) 10.18 (1H,
s), 7.86-7.80 (1H, m), 7.25-7.18 (2H, m), 2.93-2.87 (2H, m),
2.71-2.64(2H, m).
Step 4: Production of ethyl 4-cyclohexylaminobenzoate
[1644] ##STR438##
[1645] To a solution of ethyl 4-aminobenzoate (20.00 g, 0.120 vol)
and cyclohexanone (17.80 g, 0.180 mol) in tetrahydrofuran (100 ml)
and acetic acid (10 ml) was added sodium triacetoxyborohydride
(38.50 g, 0.180 mol) at room temperature, and the mixture was
stirred for 2 hr. Water was added to the reaction mixture and the
mixture was extracted with toluene. The organic layer was
successively washed with water, saturated aqueous sodium hydrogen
carbonate and saturated brine and dried over anhydrous magnesium
sulfate. After filtration, the solvent was evaporated under reduced
pressure, and hexane was added to the obtained residue. The
precipitated solid was collected by filtration and washed with
hexane. The obtained solid was dried in vacuo to give ethyl
4-cyclohexylaminobenzoate (25.20 g, yield 84%).
[1646] .sup.1H-NMR(400 MHz, CDCl.sub.3): .delta.(ppm) 7.85 (2H, d,
J=8.8 Hz), 6.53 (2H, d, J=8.8 Hz), 4.32 (2H, q, J=7.1 Hz), 4.03
(1H, brs), 3.34 (1H, brs), 2.08-2.05 (2H, m), 1.80-1.78 (2H, m),
1.68-1.65 (2H, m), 1.44-1.43 (2H, m), 1.37 (3H, t, J=7.2 Hz),
1.26-1.19 (2H, m).
Step 5: Production of ethyl 4-(N-cyclohexylnitroso)benzoate
[1647] ##STR439##
[1648] To a solution of ethyl 4-cyclohexylaminobenzoate (24.00 g,
97.0 mmol) in acetic acid (120 ml) was added dropwise an aqueous
solution (120 ml) of sodium nitrite (13.40 g, 194 mmol) over 15 min
at room temperature, and the mixture was further stirred for 2 hr.
Water was added to the reaction mixture and the mixture was
extracted with ethyl acetate. The organic layer was successively
washed with water and saturated brine and dried over anhydrous
magnesium sulfate. After filtration, the solvent was evaporated
under reduced pressure to give ethyl
4-(N-cyclohexylnitroso)benzoate (26.90 g). The obtained compound
was used for Step 6 without purification.
[1649] .sup.1H-NMR(400 MHz, CDCl.sub.3): .delta.(ppm) 8.17 (2H, d,
J=8.8 Hz), 8.13 (2H, d, J=8.8 Hz), 4.92-4.88 (1H, m), 4.43 (2H, q,
J=7.1 Hz), 2.21-2.18 (1H, m), 1.94-1.58 (6H, m), 1.51-1.49 (2H, m),
1.44 (3H, t, J=7.0 Hz), 1.17-1.13 (1H, m).
Step 6: Production of ethyl 4-(N-cyclohexylhydrazino)benzoate
[1650] ##STR440##
[1651] To a suspension of zinc powder (18.50 g, 282 mmol) in water
(130 ml) was added dropwise a solution of ethyl
4-(N-cyclohexylnitroso)benzoate (26.00 g, 94.1 mmol) in acetic acid
(250 ml) over 15 min under ice-cooling, and the mixture was stirred
at room temperature for 2 hr. The reaction mixture was filtered
through celite, and the filtrate was extracted with ethyl acetate.
The organic layer was successively washed with water and saturated
brine and dried over anhydrous magnesium sulfate. After filtration,
the solvent was evaporated under reduced pressure. The obtained
residue was purified by silica gel chromatography (hexane:ethyl
acetate=10:1) to give ethyl 4-(N-cyclohexylhydrazino)benzoate (7.60
g, yield 31%).
[1652] .sup.1H-NMR(400 MHz, CDCl.sub.3): .delta.(ppm) 7.91 (2H, d,
J=8.3 Hz), 6.97 (2H, d, J=8.3 Hz), 4.34 (2H, q, J=7.1 Hz), 3.71
(1H, tt, J=11.4, 3.6 Hz), 1.92-1.88 (2H, m), 1.77-1.73 (3H, m),
1.64-1.58 (2H, m), 1.47-1.42 (2H, m), 1.38 (3H, t, J=7.2 Hz), 1.20
(1H, tt, J=13.0, 3.7 Hz).
Step 7: Production of ethyl
3-chloro-12-cyclohexyl-6-oxo-5,6,7,12-tetrahydrobenzo[2,3]azepino[4,5-b]i-
ndole-9-carboxylate (Example 10-5)
[1653] ##STR441##
[1654] A mixture of
8-chloro-3,4-dihydro-1H-benzo[b]azepine-2,5-dione (1.18 g, 5.65
mmol) and ethyl 4-(N-cyclohexylhydrazino)benzoate (1.14 g, 4.35
mmol) in acetic acid (11 ml) was stirred at 85.degree. C. for for 1
hr. The reaction mixture was allowed to cool to room temperature,
and conc. sulfuric acid (0.55 ml) was added to the reaction
mixture. The mixture was stirred at 85.degree. C. for 3 hr. The
mixture was allowed to cool, and the reaction mixture was poured
into water (230 ml) and extracted with a mixed solvent of ethyl
acetate (200 ml) and ethanol (30 ml). The organic layer was washed
twice with saturated brine and dried over anhydrous magnesium
sulfate. After filtration, the solvent was evaporated under reduced
pressure. Water (10 ml) and ethanol (10 ml) were added to the
obtained crude product and the precipitated solid was collected by
filtration. The obtained solid was washed with a mixed solvent (10
ml) of water:ethanol (1:1) and dried in vacuo to give ethyl
3-chloro-12-cyclohexyl-6-oxo-5,6,7,12-tetrahydrobenzo[2,3]azepino[4,5-b]i-
ndole-9-carboxylate (0.97 g, yield 39%).
[1655] .sup.1H-NMR(300 MHz, DMSO-d.sub.6): .delta.(ppm) 10.18 (1H,
s), 8.37 (1H, s), 7.93 (1H, d, J=9.0 Hz), 7.82 (1H, dd, J=9.0, 1.5
Hz), 7.51 (1H, d, J=8.3 Hz), 7.45-7.39 (2H, m), 4.40-4.23 (1H, m),
4.35 (2H, q, J=7.0 Hz), 3.84 (1H, d, J=14.3 Hz), 3.09 (1H, d,
J=14.3 Hz), 2.48-2.17 (3H, m), 2.05-1.93 (1H, m), 1.79-1.60 (2H,
m), 1.54-1.11 (4H, m), 1.37 (3H, t, J=7.0 Hz).
Step 8: Production of ethyl
3-chloro-12-cyclohexyl-6-oxo-5-[2-oxo-2-(piperidin-1-yl)ethyl]-5,6,7,12-t-
etrahydrobenzo[2,3]azepino[4,5-b]indole-9-carboxylate (Example
10-6)
[1656] ##STR442##
[1657] To a suspension of ethyl
3-chloro-12-cyclohexyl-6-oxo-5,6,7,12-tetrahydrobenzo[2,3]azepino[4,5-b]i-
ndole-9-carboxylate (772 mg, 1.77 mmol) in N,N-dimethylformamide
(7.7 ml) were added a solution of 1-(2-chloroacetyl)piperidine (343
mg, 2.12 mmol) in N,N-dimethylformamide (2 ml) and potassium
carbonate (488 mg, 3.53 mmol), and the mixture was stirred at
90.degree. C. for 1 hr. Furthermore, a solution of
1-(2-chloroacetyl)piperidine (171 mg, 1.06 mmol) in
N,N-dimethylformamide (1 ml) and potassium carbonate (244 mg, 1.77
mmol) were added, and the mixture was stirred at 90.degree. C. for
1.5 hr. The mixture was allowed to cool to room temperature, water
(10 ml) was added, and the precipitated solid was collected by
filtration. The obtained solid was washed with water (10 ml) and
dried in vacuo to give ethyl
3-chloro-12-cyclohexyl-6-oxo-5-[2-oxo-2-(piperidin-1-yl)ethyl]-5,6,7,12-t-
etrahydrobenzo[2,3]azepino[4,5-b]indole-9-carboxylate (911 mg,
yield 92%).
[1658] .sup.1H-NMR(300 MHz, DMSO-d.sub.6): .delta.(ppm) 8.37 (1H,
s), 7.97-7.87 (1H, m), 7.82 (1H, d, J=8.7 Hz), 7.71 (1H, s), 7.52
(1H, d, J=8.3 Hz), 7.51 (1H, s), 4.74-4.55 (2H, m), 4.40-4.26 (1H,
m), 4.35 (2H, q, J=7.0 Hz), 3.94 (1H, d, J=13.9 Hz), 3.44-3.18 (4H,
m), 3.02 (1H, d, J=13.6 Hz), 2.47-2.12 (3H, m), 2.05-1.94 (1H, m),
1.83-1.10 (12H, m), 1.37 (3H, t, J=7.2 Hz).
Step 9: Production of ethyl
3-chloro-12-cyclohexyl-5-[2-(piperidin-1-yl)ethyl]-5,6,7,12-tetrahydroben-
zo[2,3]azepino[4,5-b]indole-9-carboxylate (Example 10-2)
[1659] ##STR443##
[1660] To a solution of ethyl
3-chloro-12-cyclohexyl-6-oxo-5-[2-oxo-2-(piperidin-1-yl)ethyl]-5,6,7,12-t-
etrahydrobenzo[2,3]azepino[4,5-b]indole-9-carboxylate (886 mg, 1.57
mmol) in tetrahydrofuran (15 ml) was added dropwise a solution (8.2
ml) of 1M BH.sub.3 THF complex in tetrahydrofuran under
ice-cooling, and the mixture was stirred under ice-cooling for 30
min., at room temperature for 3 hr, at 30.degree. C. for 2 hr, and
further at 60-70.degree. C. for 1 hr. The reaction mixture was
allowed to cool, a solution (4.1 ml) of 1M BH.sub.3 THF complex in
tetrahydrofuran was added, and the mixture was allowed to stand
overnight at room temperature. The reaction mixture was stirred at
70.degree. C. for 2 hr, 5M hydrochloric acid (8 ml) was added under
ice-cooling, and the mixture was stirred at 70.degree. C. for 2 hr.
The reaction mixture was neutralized with 1N aqueous sodium
hydroxide solution under ice-cooling, saturated sodium hydrogen
carbonate solution was added and the mixture was extracted with
ethyl acetate. The organic layer was successively washed with water
and saturated brine and dried over anhydrous magnesium sulfate.
After filtration, the solvent was evaporated under reduced pressure
and the residue was purified by silica gel column chromatography
(ethyl acetate) to give ethyl
3-chloro-12-cyclohexyl-5-[2-(piperidin-1-yl)ethyl]-5,6,7,12-tetrahydroben-
zo[2,3]azepino[4,5-b]indole-9-carboxylate (512 mg, yield 61%).
[1661] .sup.1H-NMR(300 MHz, DMSO-d.sub.6): .delta.(ppm) 8.22 (1H,
s), 7.82 (1H, d, J=8.7 Hz), 7.73 (1H, dd, J=9.0, 1.9 Hz), 7.36 (1H,
s), 7.23-7.16 (2H, m), 4.32 (2H, q, J=7.2 Hz), 4.27-4.14 (1H, m),
3.53-3.42 (2H, m), 3.29-3.20 (2H, m), 2.89-2.71 (2H, m), 2.40-2.15
(9H, m), 1.90-1.59 (5H, m), 1.40-1.19 (8H, m), 1.34 (3H, t, J=7.5
Hz).
Example 10-1
Production of
3-chloro-12-cyclohexyl-5-[2-(piperidin-1-yl)ethyl]-5,6,7,12-tetrahydroben-
zo[2,3]azepino[4,5-b]indole-9-carboxylic acid
[1662] ##STR444##
[1663] To a solution of ethyl
3-chloro-12-cyclohexyl-5-[2-(piperidin-1-yl)ethyl]-5,6,7,12-tetrahydroben-
zo[2,3]azepino[4,5-b]indole-9-carboxylate (309 mg, 0.579 mmol) in
tetrahydrofuran (4 ml) and methanol (4 ml) was added 1N aqueous
sodium hydroxide solution (2 ml), and the mixture was stirred at
70.degree. C. for 2 hr. The mixture was allowed to cool to room
temperature, 4N aqueous lithium hydroxide solution (2 ml) was
added, and the mixture was stirred at 70.degree. C. for 2 hr. The
mixture was allowed to cool to room temperature, water (100 ml) was
added, and the mixture was extracted with ethyl acetate (20 ml) and
ether (10 ml). The aqueous layer was adjusted to pH 7 with 1N
hydrochloric acid, and the precipitated solid was collected by
filtration. The obtained solid was washed with water and dried in
vacuo to give
3-chloro-12-cyclohexyl-5-[2-(piperidin-1-yl)ethyl]-5,6,7,12-tetrahydro-be-
nzo[2,3]azepino[4,5-b]indole-9-carboxylic acid (212 mg, yield
72%).
[1664] .sup.1H-NMR(300 MHz, DMSO-d.sub.6): .delta.(ppm) 8.22 (1H,
s), 7.80 (1H, d, J=8.7 Hz), 7.74 (1H, d, J=8.7 Hz), 7.37 (1H, s),
7.21 (2H, brs), 4.26-4.15 (1H, m), 3.55-3.45 (2H, m), 3.32-3.20
(2H, m), 2.89-2.75 (2H, m), 2.45-2.20 (8H, m), 1.90-1.60 (5H, m),
1.49-1.20 (9H, m).
Example 10-3
Production of
3-chloro-12-cyclohexyl-5-[2-(piperidin-1-yl)ethyl]-5,6,7,12-tetrahydroben-
zo[2,3]azepino[4,5-b]indole-9-carboxamide
[1665] ##STR445##
[1666] To a solution of
3-chloro-12-cyclohexyl-5-[2-(piperidin-1-yl)ethyl]-5,6,7,12-tetrahydroben-
zo[2,3]azepino[4,5-b]indole-9-carboxylic acid (100 mg, 0.198 mmol)
in N,N-dimethylformamide (3 ml) were added triethylamine (0.041 ml,
0.297 mmol), (benzotriazol-1-yloxy)tripyrrolidinophosphonium
hexafluorophosphate (155 mg, 0.297 mmol) and 28% aqueous ammonia
(0.1 ml), and the mixture was stirred overnight at room
temperature. Water (15 ml) was added to the reaction mixture, and
the mixture was extracted with ethyl acetate (20 ml). The organic
layer was washed with saturated brine (15 ml) and dried over
anhydrous magnesium sulfate. After filtration, the solvent was
evaporated under reduced pressure. The residue was purified by
silica gel column chromatography to give an oil (36 mg).
Tetrahydrofuran (2 ml), methanol (2 ml) and water (2 ml) were added
to the oil, and the precipitated solid was collected by filtration.
The obtained solid was dried in vacuo to give
3-chloro-12-cyclohexyl-5-[2-(piperidin-1-yl)ethyl]-5,6,7,12-tetrahydroben-
zo[2,3]azepino[4,5-b]indole-9-carboxamide (32 mg, yield 32%).
[1667] .sup.1H-NMR(300 MHz, DMSO-d.sub.6): .delta.(ppm) 8.18 (1H,
s), 7.84 (1H, brs), 7.74 (1H, d, J=8.7 Hz), 7.69 (1H, dd, J=8.7,
1.9 Hz), 7.36 (1H, d, J=1.9 Hz), 7.25-7.15 (2H, m), 7.10 (1H, brs),
4.26-4.10 (1H, m), 3.51-3.47 (2H, m), 3.40-3.29 (2H, m), 2.81 (2H,
brs), 2.40-2.20 (8H, m), 1.90-1.55 (5H, m), 1.40-1.15 (9H, m).
[1668] The compound of Example 10-4 was produced by the same method
as in Examples 10-1 and 10-2 or methods similar thereto, and where
necessary, by employing other conventional methods. The chemical
structural formula is shown in Table 118. [1669]
12-cyclohexyl-5-[2-(piperidin-1-yl)ethyl]-5,6,7,12-tetrahydrobenzo[2,3]az-
epino[4,5-b]indole-9-carboxylic acid (Example 10-4)
Example 1-157
Production of
13-cyclohexyl-5-[2-(1-cyclopentylpiperidin-4-yl)ethyl]-6,7-dihydro-5H-ben-
zo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid
dihydrochloride
Step 1: Production of methyl
5-[2-(1-tert-butoxycarbonylpiperidin-4-yl)ethyl]-13-cyclohexyl-6,7-dihydr-
o-5H-benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylate (Example
1-601)
[1670] ##STR446##
[1671] To a solution of methyl
13-cyclohexyl-6,7-dihydro-5H-benzo[5,6][1,4]diazepino[7,1-a]indole-10-car-
boxylate (1.00 g, 2.67 mmol) obtained in Example 1-2 and
1-(tert-butoxycarbonyl)-4-(2-methanesulfonyloxyethyl)piperidine
(2.46 g, 8.02 mmol) in N,N-dimethylformamide (10 ml) were added
potassium carbonate (1.85 g, 13.4 mmol) and potassium iodide (2.00
g, 8.02 mmol), and the mixture was stirred at 90.degree. C. for 36
hr. The reaction mixture was cooled to room temperature, water was
added, and the mixture was extracted with ethyl acetate. The
organic layer was washed successively with water and saturated
brine and dried over anhydrous magnesium sulfate. After filtration,
the solvent was evaporated under reduced pressure. The residue was
purified by silica gel column chromatography (hexane:ethyl
acetate=4:1-2:1) to give methyl
5-[2-(1-tert-butoxycarbonylpiperidin-4-yl)ethyl]-13-cyclohexyl-6,7-dihydr-
o-5H-benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylate (1.16 g,
yield 74%).
[1672] .sup.1H-NMR(400 MHz, DMSO-d.sub.6): .delta.(ppm) 8.18 (1H,
d, J=1.4 Hz), 7.87 (1H, d, J=8.3 Hz), 7.61 (1H, dd, J=8.3, 1.4 Hz),
7.44 (1H, td, J=7.6, 1.4 Hz), 7.31 (1H, dd, J=7.6, 1.4 Hz), 7.22
(1H, d, J=7.6 Hz), 7.18 (1H, t, J=7.6 Hz), 3.87 (3H, s), 3.65 (2H,
brs), 3.10 (2H, brs), 2.83 (1H, brt, J=12.8 Hz), 2.33 (2H, brs),
2.07-1.92 (2H, m), 1.87-1.49 (4H, m), 1.41-1.10 (11H, m), 1.33 (9H,
s), 0.85-0.67 (2H, m).
[1673] MS 586.2(M+1).
Step 2: Production of methyl
13-cyclohexyl-5-[2-(piperidin-4-yl)ethyl]-6,7-dihydro-5H-benzo[5,6][1,4]d-
iazepino[7,1-a]indole-10-carboxylate (Example 1-602)
[1674] ##STR447##
[1675] To a solution of methyl
5-[2-(1-tert-butoxycarbonylpiperidin-4-yl)ethyl]-13-cyclohexyl-6,7-dihydr-
o-5H-benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylate (1.06 g,
1.81 mmol) in chloroform (10 ml) was added trifluoroacetic acid (2
ml), and the mixture was stirred at room temperature for 2 hr.
Saturated aqueous sodium hydrogen carbonate solution was added to
the reaction mixture and the mixture was extracted with ethyl
acetate. The organic layer was successively washed with saturated
aqueous sodium hydrogen carbonate solution and saturated brine and
dried over anhydrous sodium sulfate. After filtration, the solvent
was evaporated under reduced pressure to give methyl
13-cyclohexyl-5-[2-(piperidin-4-yl)ethyl]-6,7-dihydro-5H-benzo[5,6][1,4]d-
iazepino[7,1-a]indole-10-carboxylate (859 mg, yield 98%).
[1676] .sup.1H-NMR(400 MHz, DMSO-d.sub.6): .delta.(ppm) 8.17 (1H,
d, J=1.4 Hz), 7.87 (1H, d, J=8.5 Hz), 7.61 (1H, dd, J=8.5, 1.4 Hz),
7.43 (1H, td, J=7.7, 1.4 Hz), 7.30 (1H, dd, J=7.7, 1.6 Hz),
7.26-7.11 (3H, m), 6.16 (1H, brs), 4.68 (1H, brs), 3.87 (3H, s),
3.71-2.92 (4H, m), 2.88-2.72 (3H, m), 2.37-2.21 (2H, m), 2.09-1.53
(6H, m), 1.48-1.09 (8H, m), 1.03-0.86 (2H, m).
[1677] MS 468.3(M+1)
Step 3: Production of methyl
13-cyclohexyl-5-[2-(1-cyclopentylpiperidin-4-yl)ethyl]-6,7-dihydro-5H-ben-
zo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylate (Example
1-603)
[1678] ##STR448##
[1679] To a solution of methyl
13-cyclohexyl-5-[2-(piperidin-4-yl)ethyl]-6,7-dihydro-5H-benzo[5,6][1,4]d-
iazepino[7,1-a]indole-10-carboxylate (140 mg, 0.288 mmol) and
cyclopentanone (127 .mu.l, 1.44 mmol) in tetrahydrofuran (60 ml)
and acetic acid (0.3 ml), was added sodium triacetoxyborohydride
(183 mg, 0.865 mmol) under ice-cooling, and the mixture was stirred
for 2 days. Saturated aqueous sodium hydrogen carbonate solution
was added to the reaction mixture and the mixture was extracted
with ethyl acetate. The organic layer was successively washed with
saturated aqueous sodium hydrogen carbonate solution and saturated
brine and dried over anhydrous magnesium sulfate. After filtration,
the solvent was evaporated under reduced pressure. The residue was
purified by silica gel column chromatography
(chloroform:methanol=30:1-15:1) to give methyl
13-cyclohexyl-5-[2-(1-cyclopentylpiperidin-4-yl)ethyl]-6,7-dihydro-5H-ben-
zo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylate (124 mg, yield
78%).
[1680] .sup.1H-NMR(400 MHz, DMSO-d.sub.6): .delta.(ppm) 8.17 (1H,
s), 7.86 (1H, d, J=8.3 Hz), 7.60 (1H, d, J=8.3 Hz), 7.43 (1H, t,
J=7.4 Hz), 7.30 (1H, d, J=7.4 Hz), 7.21 (1H, d, J=7.4 Hz), 7.16
(1H, t, J=7.4 Hz), 4.69 (2H, brs), 3.86 (3H, s), 3.11 (4H, brs),
2.87-2.75 (1H, m), 2.69-2.54 (1H, m), 2.31-2.13 (1H, m), 2.07-0.78
(28H, m).
Step 4: Production of
13-cyclohexyl-5-[2-(1-cyclopentylpiperidin-4-yl)ethyl]-6,7-dihydro-5H-ben-
zo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid
dihydrochloride (Example 1-157)
[1681] ##STR449##
[1682] To a solution of methyl
13-cyclohexyl-5-[2-(1-cyclopentylpiperidin-4-yl)ethyl]-6,7-dihydro-5H-ben-
zo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylate (124 mg, 0.224
mmol) in tetrahydrofuran (2 ml) and methanol (2 ml) was added 4N
aqueous sodium hydroxide solution (1 ml), and the mixture was
stirred at 70.degree. C. for 2 hr. The reaction mixture was
adjusted to pH 6.5 by adding 2N hydrochloric acid, and the mixture
was extracted with chloroform. The organic layer was washed with
saturated brine and dried over anhydrous sodium sulfate. After
filtration, the solvent was evaporated under reduced pressure. To a
solution of the obtained residue in chloroform was added 4N
HCl-ethyl acetate solution (10 ml), and the solvent was evaporated
under reduced pressure. A mixed solvent (hexane:ethyl acetate=4:1)
was added to the residue. The precipitated solid was collected by
filtration to give
13-cyclohexyl-5-[2-(1-cyclopentylpiperidin-4-yl)ethyl]-6,7-dihydro-5H-ben-
zo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid
dihydrochloride (125 mg, yield 91%).
[1683] .sup.1H-NMR(400 MHz, DMSO-d.sub.6): .delta.(ppm) 9.55-9.35
(1H, m), 8.15 (1H, d, J=1.2 Hz), 7.85 (1H, d, J=8.4 Hz), 7.60 (1H,
dd, J=8.4, 1.2 Hz), 7.44 (1H, t, J=7.4 Hz), 7.32 (1H, d, J=7.4 Hz),
7.26-7.15 (2H, m), 4.53 (3H, brs), 3.17 (4H, brs), 2.88-2.76 (1H,
m), 2.10-1.11 (29H, m).
[1684] MS 540.4(M+1).
Example 2-44
Production of
12-cyclohexyl-3-(1-methanesulfonylpiperidin-3-yloxy)-6,7-dihydro-5-oxa-7a-
-azadibenzo[a,e]azulene-9-carboxylic acid
Step 1: Production of tert-butyl
3-(toluene-4-sulfonyloxy)piperidine-1-carboxylate
[1685] ##STR450##
[1686] To a solution of tert-butyl
3-hydroxypiperidine-1-carboxylate (2.00 g, 9.94 mmol) in chloroform
(20 ml) were successively added p-toluenesulfonyl chloride (2.27 g,
11.9 mmol) and triethylamine (1.66 ml, 11.9 mmol) at 0.degree. C.,
and the mixture was stirred at 70.degree. C. for 9 hr. The reaction
mixture was allowed to cool to room temperature, water was added to
the reaction mixture and the mixture was extracted with chloroform.
The organic layer was successively washed with water and saturated
brine and dried over anhydrous magnesium sulfate. After filtration,
the solvent was concentrated under reduced pressure, and the
residue was purified by silica gel chromatography (ethyl
acetate:hexane=1:1) to give tert-butyl
3-(toluene-4-sulfonyloxy)piperidine-1-carboxylate (1.00 g, yield
28%).
[1687] .sup.1H-NMR(300 MHz, DMSO-d.sub.6): .delta.(ppm) 7.81(2H, d,
J=9.0 Hz), 7.49(2H, d, J=9.0 Hz), 4.54-4.36 (1H, m), 3.67-2.89 (4H,
m), 2.42(3H, s), 1.81-1.52 (3H, m), 1.47-1.21 (1H, m), 1.35(9H,
s).
Step 2: Production of methyl
3-(1-tert-butoxycarbonylpiperidin-3-yloxy)-12-cyclohexyl-6,7-dihydro-5-ox-
a-7a-azadibenzo[a,e]azulene-9-carboxylate (Example 2-501)
[1688] ##STR451##
[1689] To a solution of methyl
12-cyclohexyl-3-hydroxy-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-car-
boxylate (0.80 g, 2.04 mmol) in N,N-dimethylformamide (8 ml) were
successively added tert-butyl
3-(toluene-4-sulfonyloxy)piperidine-1-carboxylate (1.09 g, 3.07
mmol) and potassium carbonate (0.57 g, 4.08 mmol) at room
temperature, and the mixture was stirred overnight at 60.degree. C.
The reaction mixture was allowed to cool to room temperature, water
was added to the reaction mixture and the mixture was extracted
with ethyl acetate. The organic layer was successively washed with
water and saturated brine and dried over anhydrous magnesium
sulfate. After filtration, the solvent was concentrated under
reduced pressure to give methyl
3-(1-tert-butoxycarbonylpiperidin-3-yloxy)-12-cyclohexyl-6,7-dihydro-5-ox-
a-7a-azadibenzo[a,e]azulene-9-carboxylate (0.68 g). The obtained
compound was used for Step 3 without purification.
Step 3: Production of methyl
12-cyclohexyl-3-(piperidin-3-yloxy)-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]a-
zulene-9-carboxylate (Example 2-502)
[1690] ##STR452##
[1691] Methyl
3-(1-tert-butoxycarbonylpiperidin-3-yloxy)-12-cyclohexyl-6,7-dihydro-5-ox-
a-7a-azadibenzo[a,e]azulene-9-carboxylate (0.68 g) was dissolved in
trifluoroacetic acid (20 ml), and the mixture was stirred at room
temperature for 3 hr. Toluene was added to the reaction mixture and
the solvent was evaporated under reduced pressure. 4N HCl-ethyl
acetate solution (2.0 ml) was added to the obtained residue and the
mixture was stirred, and the solvent was evaporated under reduced
pressure. The residue was neutralized with saturated aqueous sodium
hydrogen carbonate solution and extracted with ethyl acetate. The
organic layer was successively washed with water and saturated
brine and dried over anhydrous magnesium sulfate. After filtration,
the solvent was concentrated under reduced pressure, and the
residue was purified by silica gel chromatography
(chloroform:methanol=9:1) to give methyl
12-cyclohexyl-3-(piperidin-3-yloxy)-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]a-
zulene-9-carboxylate (0.16 g, yield 17%).
[1692] .sup.1H-NMR(300 MHz, CDCl.sub.3): .delta.(ppm) 8.05(1H, s),
7.87(1H, d, J=8.3 Hz), 7.75(1H, d, J=8.7 Hz), 7.31(1H, d, J=8.3
Hz), 6.85(1H, dd, J=2.3, 8.3 Hz), 6.79(1H, d, J=2.3 Hz), 4.50(1H,
t, J=5.5 Hz), 4.39-4.24 (3H, m), 3.94(3H, s), 3.28-3.17 (1H, m),
3.02-2.73 (4H, m), 2.17-1.96 (4H, m), 1.95-1.74 (7H, m), 1.64-1.48
(1H, m), 1.47-1.30 (3H, m).
Step 4: Production of methyl
12-cyclohexyl-3-(1-methanesulfonylpiperidin-3-yloxy)-6,7-dihydro-5-oxa-7a-
-azadibenzo[a,e]azulene-9-carboxylate (Example 2-503)
[1693] ##STR453##
[1694] To a solution of methyl
12-cyclohexyl-3-(piperidin-3-yloxy)-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]a-
zulene-9-carboxylate (43 mg, 0.091 mmol) in pyridine (0.5 ml) was
added dropwise methanesulfonyl chloride (8.5 .mu.l, 0.11 mmol), and
the mixture was stirred at 0.degree. C. for 2 hr. Toluene was added
to the reaction mixture and the solvent was evaporated under
reduced pressure. Hexane and ethyl acetate were added to the
obtained residue, and the precipitate was collected by filtration,
washed with hexane, and dried in vacuo to give methyl
12-cyclohexyl-3-(1-methanesulfonylpiperidin-3-yloxy)-6,7-dihydro-5-
-oxa-7a-azadibenzo[a,e]azulene-9-carboxylate (47 mg, yield
94%).
[1695] .sup.1H-NMR(300 MHz, DMSO-d.sub.6): .delta.(ppm) 8.20(1H,
s), 7.89(1H, d, J=8.6 Hz), 7.63(1H, dd, J=1.1, 8.3 Hz), 7.35(1H, d,
J=8.3 Hz), 6.99(1H, dd, J=2.3, 8.3 Hz), 6.89(1H, d, J=2.6 Hz),
4.67-4.56 (1H, m), 4.51-4.31 (4H, m), 3.87(3H, s), 3.59-3.51 (1H,
m), 3.32-3.05 (3H, m), 2.94(3H, s), 2.92-2.79 (1H, m), 2.11-1.92
(4H, m), 1.92-1.59 (7H, m), 1.46-1.22 (3H, m).
Step 5: Production of
12-cyclohexyl-3-(1-methanesulfonylpiperidin-3-yloxy)-6,7-dihydro-5-oxa-7a-
-azadibenzo[a,e]azulene-9-carboxylic acid (Example 2-44)
[1696] ##STR454##
[1697] To a solution of methyl
12-cyclohexyl-3-(1-methanesulfonylpiperidin-3-yloxy)-6,7-dihydro-5-oxa-7a-
-azadibenzo[a,e]azulene-9-carboxylate (47 mg, 0.085 mmol) in
tetrahydrofuran (1 ml) and methanol (1 ml) was added 4N aqueous
sodium hydroxide solution (0.5 ml), and the mixture was stirred at
55.degree. C. for 2 hr. The mixture was adjusted to pH 6.5 by
adding 1N hydrochloric acid (2 ml), and extracted with a mixed
solvent of ethyl acetate and tetrahydrofuran. The organic layer was
washed with saturated brine and dried over anhydrous sodium
sulfate. After filtration, the solvent was concentrated under
reduced pressure. Hexane and ethyl acetate were added to the
obtained residue, and the precipitate was collected by filtration,
washed with hexane and dried in vacuo to give
12-cyclohexyl-3-(1-methanesulfonylpiperidin-3-yloxy)-6,7-dihydro-5-oxa-7a-
-azadibenzo[a,e]azulene-9-carboxylic acid (25 mg, yield 56%).
[1698] .sup.1H-NMR(300 MHz, DMSO-d.sub.6): .delta.(ppm) 12.55(1H,
brs), 8.17(1H, s), 7.86(1H, d, J=8.7 Hz), 7.62(1H, d, J=7.9 Hz),
7.34(1H, d, J=7.9 Hz), 6.98(1H, d, J=7.9 Hz), 6.88(1H, s),
4.71-4.55 (1H, m), 4.53-4.25 (4H, m), 3.67-3.49 (2H, m), 3.29-3.02
(3H, m), 3.00-2.78 (1H, m), 2.94(3H, s), 2.14-1.53 (11H, m),
1.47-1.29 (2H, m).
[1699] MS 539.2(M+1).
Example 2-53
Production of
12-cyclohexyl-4-[2-(piperidin-1-yl)ethoxy]-6,7-dihydro-5-oxa-7a-azadibenz-
o[a,e]azulene-9-carboxylic acid hydrochloride
Step 1: Production of
2-[2-(2-benzyloxyphenoxy)ethoxy]tetrahydropyran
[1700] ##STR455##
[1701] To a solution of 2-benzyloxyphenol (3.00 g, 15.0 mmol) in
N,N-dimethylformamide (15 ml) was added sodium hydride (60% in oil)
(719 mg, 18.0 mmol) under ice-cooling, and the mixture was stirred
at 30 min. 2-(2-Bromoethoxy)tetrahydropyran (2.72 ml, 18.0 mmol)
was added to the reaction mixture and the mixture was stirred at 18
hr. Water was added to the reaction mixture and the mixture was
extracted with ethyl acetate. The organic layer was washed with
saturated brine and dried over anhydrous magnesium sulfate. After
filtration, the solvent was evaporated under reduced pressure to
give 2-[2-(2-benzyloxyphenoxy)ethoxy]tetrahydropyran (4.90 g). The
obtained compound was used for Step 2 without purification.
[1702] .sup.1H-NMR(400 MHz, CDCl.sub.3): .delta.(ppm) 7.47-7.28
(5H, m), 6.99-6.85 (4H, m), 5.13 (2H, s), 4.73 (1H, t, J=3.5 Hz),
4.23 (2H, t, J=5.1 Hz), 3.92-3.83 (2H, m), 3.55-3.45 (2H, m),
1.87-1.77 (1H, m), 1.74-1.67 (1H, m), 1.64-1.46 (4H, m).
Step 2: Production of 2-(2-benzyloxyphenoxy)ethanol
[1703] ##STR456##
[1704] To a solution of
2-[2-(2-benzyloxyphenoxy)ethoxy]tetrahydropyran (4.90 g) in
tetrahydrofuran (25 ml) and methanol (25 ml) was added 6N
hydrochloric acid (15 ml), and the mixture was stirred at room
temperature for 1 hr. Water was added to the reaction mixture and
the mixture was extracted with ethyl acetate. The organic layer was
washed successively with saturated aqueous sodium hydrogen
carbonate solution and saturated brine and dried over anhydrous
magnesium sulfate. After filtration, the solvent was evaporated
under reduced pressure. The obtained residue was purified by silica
gel chromatography (hexane:ethyl acetate=1:1) to give
2-(2-benzyloxyphenoxy)ethanol (3.07 g, yield 84%).
[1705] .sup.1H-NMR(400 MHz, CDCl.sub.3): .delta.(ppm) 7.47-7.31
(5H, m), 7.01-6.93 (4H, m), 5.13 (2H, s), 4.15 (2H, t, J=4.4 Hz),
3.89 (2H, t, J=4.4 Hz), 2.48 (1H, brs).
Step 3: Production of 2-(2-benzyloxyphenoxy)ethyl
methanesulfonate
[1706] ##STR457##
[1707] To a solution of 2-(2-benzyloxyphenoxy)ethanol (3.07 g, 12.6
mmol) and triethylamine (2.63 ml, 18.8 mmol) in chloroform (30 ml)
was added methanesulfonyl chloride (1.12 ml, 14.4 mmol) under
ice-cooling, and the mixture was stirred for 2 hr. Saturated
aqueous ammonium chloride solution was added to the reaction
mixture, and the mixture was extracted with ethyl acetate. The
organic layer was washed with saturated brine and dried over
anhydrous magnesium sulfate. After filtration, the solvent was
evaporated under reduced pressure. Hexane was added to the obtained
residue and the precipitated solid was collected by filtration and
washed with hexane. The obtained solid was dried in vacuo to give
2-(2-benzyloxyphenoxy)ethyl methanesulfonate (3.77 g, yield
93%).
[1708] .sup.1H-NMR(400 MHz, CDCl.sub.3): .delta.(ppm) 7.46-7.35
(5H, m), 7.00-6.91 (4H, m), 5.06 (2H, s), 4.59 (2H, t, J=4.4 Hz),
4.26 (2H, t, J=4.4 Hz), 2.88 (3H, s).
Step 4: Production of methyl
1-[2-(2-benzyloxyphenoxy)ethyl]-2-bromo-3-cyclohexyl-1H-indole-6-carboxyl-
ate
[1709] ##STR458##
[1710] To a solution of methyl
2-bromo-3-cyclohexyl-1H-indole-6-carboxylate (1.50 g, 4.46 mmol)
obtained in the same manner as in the method described in
WO03/010140 and 2-(2-benzyloxyphenoxy)ethyl methanesulfonate (1.73
g, 5.35 mmol) in N,N-dimethylformamide (15 ml) were added potassium
iodide (740 mg, 4.46 mmol) and potassium carbonate (1.85 g, 13.4
mmol), and the mixture was stirred at 90.degree. C. for 7 hr. The
reaction mixture was allowed to cool to room temperature, water was
added to the reaction mixture and the mixture was extracted with
ethyl acetate. The organic layer was washed with saturated brine
and dried over anhydrous magnesium sulfate. After filtration, the
solvent was evaporated under reduced pressure and the obtained
residue was purified by silica gel chromatography (hexane:ethyl
acetate=6:1) to give methyl
1-[2-(2-benzyloxyphenoxy)ethyl]-2-bromo-3-cyclohexyl-1H-indole-6-carboxyl-
ate (2.61 g). The obtained compound was used as it was for Step
5.
[1711] .sup.1H-NMR(400 MHz, CDCl.sub.3): .delta.(ppm) 8.15 (1H, s),
7.76-7.75 (2H, m), 7.35-7.29 (5H, m), 6.89-6.81 (4H, m), 5.06 (2H,
s), 4.68 (2H, t, J=6.3 Hz), 4.34 (2H, t, J=6.3 Hz), 3.88 (3H, s),
2.93-2.85 (1H, m), 1.98-1.78 (7H, m), 1.49-1.35 (3H, m).
Step 5: Production of methyl
4-benzyloxy-12-cyclohexyl-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-c-
arboxylate (Example 2-504)
[1712] ##STR459##
[1713] To a solution of methyl
1-[2-(2-benzyloxyphenoxy)ethyl]-2-bromo-3-cyclohexyl-1H-indole-6-carboxyl-
ate (2.61 g) in N,N-dimethylacetamide (100 ml) were added potassium
acetate (905 mg, 9.22 mmol) and
tetrakis(triphenylphosphine)palladium (800 mg, 0.69 mmol), and the
mixture was stirred at 130.degree. C. for 41 hr. The mixture was
allowed to cool to room temperature, and filtered through celite.
Saturated aqueous ammonium chloride solution was added to the
filtrate, and the mixture was extracted with ethyl acetate. The
organic layer was washed successively with saturated aqueous
ammonium chloride solution and saturated brine and dried over
anhydrous magnesium sulfate. After filtration, the solvent was
evaporated under reduced pressure and the obtained residue was
purified by silica gel chromatography (hexane:ethyl acetate=6:1) to
give methyl
4-benzyloxy-12-cyclohexyl-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-c-
arboxylate (745 mg, yield 34%).
[1714] .sup.1H-NMR(400 MHz, CDCl.sub.3): .delta.(ppm) 8.09 (1H, s),
7.90 (1H, d, J=8.8 Hz), 7.77 (1H, dd, J=8.3, 1.4 Hz), 7.48 (2H, d,
J=7.0 Hz), 7.43-7.39 (2H, m), 7.36-7.33 (1H, m), 7.18 (1H, t, J=7.9
Hz), 7.08-7.03 (2H, m), 5.22 (2H, s), 4.53 (2H, t, J=5.8 Hz),
4.32-4.26 (2H, m), 3.96 (3H, s), 3.04-2.96 (1H, m), 2.12-2.02 (2H,
m), 1.92-1.77 (5H, m), 1.43-1.34 (3H, m).
Step 6: Production of methyl
12-cyclohexyl-4-hydroxy-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-car-
boxylate (Example 2-505)
[1715] ##STR460##
[1716] To methyl
4-benzyloxy-12-cyclohexyl-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-c-
arboxylate (745 mg, 1.55 mmol) was added 25% hydrogen
bromide-acetic acid solution (5 ml), and the mixture was stirred at
room temperature for 30 min. Water was added to the reaction
mixture and the mixture was extracted with ethyl acetate. The
organic layer was washed successively with saturated aqueous sodium
hydrogen carbonate solution and saturated brine and dried over
anhydrous magnesium sulfate. After filtration, the solvent was
evaporated under reduced pressure. Hexane: diisopropy ether (3:1)
solution was added to the obtained residue and the precipitated
solid was collected by filtration. The solid was washed with
hexane: diisopropy ether (3:1) solution. The obtained solid was
dried in vacuo to give methyl
12-cyclohexyl-4-hydroxy-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-car-
boxylate (470 mg, yield 78%).
[1717] .sup.1H-NMR(400 MHz, CDCl.sub.3): .delta.(ppm) 8.09 (1H, s),
7.91 (1H, d, J=8.3 Hz), 7.78 (1H, dd, J=8.3, 1.4 Hz), 7.17 (1H, t,
J=7.9 Hz), 7.08 (1H, dd, J=8.1, 1.6 Hz), 6.97 (1H, dd, J=7.7, 1.6
Hz), 5.88 (1H, s), 4.60 (2H, t, J=5.6 Hz), 4.37 (2H, t, J=5.6 Hz),
3.96 (3H, s), 3.04-2.96 (1H, m), 2.12-2.02 (2H, m), 1.91-1.78 (5H,
m), 1.43-1.34 (3H, m).
Step 7: Production of methyl
12-cyclohexyl-4-[2-oxo-2-(piperidin-1-yl)ethoxy]-6,7-dihydro-5-oxa-7a-aza-
dibenzo[a,e]azulene-9-carboxylate (Example 2-506)
[1718] ##STR461##
[1719] To a solution of methyl
12-cyclohexyl-4-hydroxy-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-car-
boxylate (200 mg, 0.51 mmol) and 1-chloroacetylpiperidine (99 mg,
0.61 mmol) in N,N-dimethylformamide (4 ml) was added potassium
carbonate (106 mg, 0.77 mmol), and the mixture was stirred at room
temperature for 13 hr. The mixture was heated to 80.degree. C., and
the mixture was stirred for 3 hr. The mixture was allowed to cool
to room temperature and water was added. The precipitated solid was
collected by filtration and washed with water, and the obtained
solid was dried in vacuo to give methyl
12-cyclohexyl-4-[2-oxo-2-(piperidin-1-yl)ethoxy]-6,7-dihydro-5-oxa-7a-aza-
dibenzo[a,e]azulene-9-carboxylate (254 mg, yield 96%).
[1720] .sup.1H-NMR(400 MHz, CDCl.sub.3): .delta.(ppm) 8.08 (1H, s),
7.90 (1H, d, J=8.3 Hz), 7.77 (1H, dd, J=8.3, 1.4 Hz), 7.21 (1H, t,
J=7.9 Hz), 7.11-7.06 (2H, m), 4.82 (2H, s), 4.55 (2H, t, J=5.8 Hz),
4.33-4.27 (2H, m), 3.96 (3H, s), 3.60 (2H, t, J=5.3 Hz), 3.53 (2H,
t, J=5.1 Hz), 3.03-2.95 (1H, m), 2.12-2.01 (2H, m), 1.91-1.77 (5H,
m), 1.69-1.53 (6H, m), 1.43-1.34 (3H, m).
Step 8: Production of methyl
12-cyclohexyl-4-[2-(piperidin-1-yl)ethoxy]-6,7-dihydro-5-oxa-7a-azadibenz-
o[a,e]azulene-9-carboxylate (Example 2-507)
[1721] ##STR462##
[1722] To a solution of methyl
12-cyclohexyl-4-[2-oxo-2-(piperidin-1-yl)ethoxy]-6,7-dihydro-5-oxa-7a-aza-
dibenzo[a,e]azulene-9-carboxylate (254 mg, 0.49 mmol) in
tetrahydrofuran (1 ml) was added a solution (1 ml) of 1M BH.sub.3
THF complex in tetrahydrofuran, and the mixture was stirred at room
temperature for 3 hr. 2N Hydrochloric acid (2 ml) was added to the
reaction mixture, and the mixture was stirred at 70.degree. C. for
4 hr. The reaction mixture was allowed to cool to room temperature,
and the reaction mixture was neutralized by adding 2N aqueous
sodium hydroxide solution and saturated aqueous sodium hydrogen
carbonate solution. Water was added, and the precipitated solid was
collected by filtration and washed with water. The obtained solid
was dried in vacuo to give methyl
12-cyclohexyl-4-[2-(piperidin-1-yl)ethoxy]-6,7-dihydro-5-oxa-7a-azadibenz-
o[a,e]azulene-9-carboxylate (240 mg, yield 97%).
[1723] .sup.1H-NMR(400 MHz, CDCl.sub.3): .delta.(ppm) 8.09 (1H, s),
7.91 (1H, d, J=8.3 Hz), 7.77 (1H, d, J=8.8 Hz), 7.26-7.22 (1H, m),
7.09 (2H, t, J=7.4 Hz), 4.68 (2H, t, J=4.4 Hz), 4.52 (2H, t, J=5.6
Hz), 4.34-4.29 (2H, m), 3.96 (3H, s), 3.79-3.69 (2H, m), 3.44 (2H,
t, J=4.2 Hz), 3.02-2.84 (3H, m), 2.38-2.23 (2H, m), 2.12-2.00 (2H,
m), 1.95-1.77 (5H, m), 1.69-1.33 (7H, m).
Step 9: Production of
12-cyclohexyl-4-[2-(piperidin-1-yl)ethoxy]-6,7-dihydro-5-oxa-7a-azadibenz-
o[a,e]azulene-9-carboxylic acid hydrochloride (Example 2-53)
[1724] ##STR463##
[1725] To a solution of methyl
12-cyclohexyl-4-[2-(piperidin-1-yl)ethoxy]-6,7-dihydro-5-oxa-7a-azadibenz-
o[a,e]azulene-9-carboxylate (240 mg, 0.48 mmol) in tetrahydrofuran
(4 ml) and methanol (4 ml) was added 4N aqueous sodium hydroxide
(2.5 ml), and the mixture was stirred at 60.degree. C. for 2 hr. 2N
Hydrochloric acid (5.1 ml) was added to the reaction mixture, and
the mixture was extracted with ethyl acetate:tetrahydrofuran (2:1).
The organic layer was washed with saturated brine and dried over
anhydrous magnesium sulfate. After filtration, the solvent was
evaporated under reduced pressure. To a solution of the obtained
residue in tetrahydrofuran (1 ml) was added 4N HCl-ethyl acetate
solution (2 ml). The solvent was evaporated under reduced pressure,
and hexane:ethyl acetate (4:1) solution was added to the obtained
residue. The precipitated solid was collected by filtration and
washed with hexane:ethyl acetate (4:1) solution. The obtained solid
was dried in vacuo to give
12-cyclohexyl-4-[2-(piperidin-1-yl)ethoxy]-6,7-dihydro-5-oxa-7a-azadibenz-
o[a,e]azulene-9-carboxylic acid hydrochloride (160 mg, yield
64%).
[1726] .sup.1H-NMR(400 MHz, DMSO-d.sub.6): .delta.(ppm) 12.59 (1H,
brs), 10.26 (1H, brs), 8.20 (1H, s), 7.88 (1H, d, J=8.3 Hz), 7.63
(1H, dd, J=8.3, 1.4 Hz), 7.32 (1H, t, J=7.9 Hz), 7.25 (1H, d, J=8.3
Hz), 7.07 (1H, dd, J=7.4, 1.4 Hz), 4.54-4.25 (6H, m), 3.63-3.46
(4H, m), 3.13-2.99 (2H, m), 2.93-2.85 (1H, m), 2.07-1.96 (2H, m),
1.86-1.65 (9H, m), 1.46-1.21 (5H, m).
[1727] MS 489.2 (M+1).
Example 2-57
Production of
(E)-3-[4-({1-[(12-cyclohexyl-3-methoxy-6,7-dihydro-5-oxa-7a-azadibenzo[a,-
e]azulene-9-carbonyl)amino]cyclobutanecarbonyl}amino)phenyl]acrylic
acid
Step 1: Production of ethyl
(E)-3-{4-[(1-tert-butoxycarbonylaminocyclobutanecarbonyl)amino]phenyl}acr-
ylate
[1728] ##STR464##
[1729] To a solution of ethyl 4-aminocinnamate (1.00 g, 5.23 mmol)
and 1-tert-butoxycarbonylaminocyclobutanecarboxylic acid (1.24 g,
5.75 mmol) in N,N-dimethylformamide (10 ml) were added
1-hydroxybenzotriazole monohydrate (1.44 g, 9.41 mmol) and
1-ethyl-3-(3'-dimethylaminopropyl)carbodiimide hydrochloride (1.80
g, 9.41 mmol) under ice-cooling, and the mixture was stirred at
room temperature for 21 hr. Water was added to the reaction mixture
and the mixture was extracted with ethyl acetate. The organic layer
was successively washed with saturated aqueous sodium hydrogen
carbonate solution and saturated brine and dried over anhydrous
magnesium sulfate. After filtration, the solvent was evaporated
under reduced pressure and hexane: diethyl ether (2:3) solution was
added to the obtained residue. The precipitated solid was collected
by filtration and washed with hexane: diethyl ether (2:3) solution.
The obtained solid was dried in vacuo to give ethyl
(E)-3-{4-[(1-tert-butoxycarbonylaminocyclobutanecarbonyl)amino]phenyl}acr-
ylate (943 mg, yield 46%).
[1730] .sup.1H-NMR(400 MHz, CDCl.sub.3): .delta.(ppm) 9.43 (1H, s),
7.64 (1H, d, J=16.2 Hz), 7.58 (2H, d, J=8.8 Hz), 7.49 (2H, d, J=8.3
Hz), 6.36 (1H, d, J=15.8 Hz), 5.08 (1H, s), 4.26 (2H, q, J=7.3 Hz),
2.83-2.77 (2H, m), 2.21-1.93 (4H, m), 1.46 (9H, s), 1.33 (3H, t,
J=7.7 Hz).
Step 2: Production of ethyl
(E)-3-{4-[(1-aminocyclobutanecarbonyl)amino]phenyl}acrylate
hydrochloride
[1731] ##STR465##
[1732] To a solution of ethyl
(E)-3-{4-[(1-tert-butoxycarbonylaminocyclobutanecarbonyl)amino]phenyl}acr-
ylate (943 mg, 2.43 mmol) in chloroform (10 ml) was added 4N
HCl-ethyl acetate solution (10 ml) under ice-cooling, and the
mixture was stirred for 4 hr. The solvent was evaporated under
reduced pressure and hexane: diethyl ether (1:1) solution was added
to the obtained residue. The precipitated solid was collected by
filtration and washed with hexane: diethyl ether (1:1) solution.
The obtained solid was dried in vacuo to give ethyl
(E)-3-{4-[(1-aminocyclobutanecarbonyl)amino]phenyl}acrylate
hydrochloride (720 mg, yield 91%).
[1733] .sup.1H-NMR(400 MHz, DMSO-d.sub.6): .delta.(ppm) 10.73 (1H,
s), 8.94 (3H, s), 7.80 (2H, d, J=8.3 Hz), 7.72 (2H, d, J=8.8 Hz),
7.59 (1H, d, J=15.8 Hz), 6.55 (1H, d, J=15.8 Hz), 4.17 (2H, q,
J=7.1 Hz), 2.80-2.73 (2H, m), 2.35-2.20 (3H, m), 2.01-1.91 (1H, m),
1.24 (3H, t, J=7.2 Hz).
Step 3: Production of ethyl
(E)-3-[4-({1-[(12-cyclohexyl-3-methoxy-6,7-dihydro-5-oxa-7a-azadibenzo[a,-
e]azulene-9-carbonyl)amino]cyclobutanecarbonyl}amino)phenyl]acrylate
(Example 2-508)
[1734] ##STR466##
[1735] To a solution of
12-cyclohexyl-3-methoxy-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-car-
boxylic acid (100 mg, 0.26 mmol) and ethyl
(E)-3-{4-[(1-aminocyclobutanecarbonyl)amino]phenyl}acrylate
hydrochloride (74 mg, 0.26 mmol) in N,N-dimethylformamide (2 ml)
were added 1-hydroxybenzotriazole monohydrate (59 mg, 0.38 mmol),
1-ethyl-3-(3'-dimethylaminopropyl)carbodiimide hydrochloride (73
mg, 0.38 mmol) and triethylamine (78 .mu.l, 0.56 mmol) under
ice-cooling, and the mixture was stirred at room temperature for 18
hr. Water was added to the reaction mixture and the mixture was
extracted with ethyl acetate. The organic layer was successively
washed with saturated aqueous sodium hydrogen carbonate solution
and saturated brine and dried over anhydrous magnesium sulfate.
After filtration, the solvent was evaporated under reduced
pressure, and the obtained residue was purified by silica gel
chromatography (hexane:ethyl acetate=2:1-1:2). Hexane: diethyl
ether (1:1) solution was added to the obtained residue, and the
precipitated solid was collected by filtration, and washed with
hexane: diethyl ether (1:1) solution. The obtained solid was dried
in vacuo to give ethyl
(E)-3-[4-({1-[(12-cyclohexyl-3-methoxy-6,7-dihydro-5-oxa-7a-azadibenzo[a,-
e]azulene-9-carbonyl)amino]cyclobutanecarbonyl}amino)phenyl]acrylate
(102 mg, yield 60%).
[1736] .sup.1H-NMR(400 MHz, CDCl.sub.3): .delta.(ppm) 10.20 (1H,
s), 7.94 (1H, s), 7.89 (1H, d, J=8.3 Hz), 7.65-7.61 (3H, m), 7.48
(2H, d, J=8.3 Hz), 7.35 (2H, t, J=9.0 Hz), 6.86 (1H, d, J=8.3 Hz),
6.80 (1H, s), 6.73 (1H, s), 6.35 (1H, d, J=15.8 Hz), 4.51 (2H, t,
J=5.3 Hz), 4.34-4.28 (2H, m), 4.25 (2H, q, J=7.1 Hz), 3.88 (3H, s),
3.03-2.90 (3H, m), 2.45-2.36 (2H, m), 2.12-1.98 (4H,m), 1.91-1.76
(5H,m), 1.43-1.28 (6H, m).
Step 4: Production of
(E)-3-[4-({1-[(12-cyclohexyl-3-methoxy-6,7-dihydro-5-oxa-7a-azadibenzo[a,-
e]azulene-9-carbonyl)amino]cyclobutanecarbonyl}amino)phenyl]acrylic
acid (Example 2-57)
[1737] ##STR467##
[1738] To a solution of ethyl
(E)-3-[4-({1-[(12-cyclohexyl-3-methoxy-6,7-dihydro-5-oxa-7a-azadibenzo[a,-
e]azulene-9-carbonyl)amino]cyclobutanecarbonyl}amino)phenyl]acrylate
(102 mg, 0.154 mmol) in tetrahydrofuran (3 ml) and methanol (2 ml),
was added 2N aqueous sodium hydroxide solution (1.2 ml), and the
mixture was stirred at room temperature for 17 hr. 2N Hydrochloric
acid (1.3 ml) was added and the mixture was extracted with ethyl
acetat. The organic layer was washed with saturated brine and dried
over anhydrous magnesium sulfate. After filtration, the solvent was
evaporated under reduced pressure. Hexane: diethyl ether (1:1)
solution was added to the obtained residue, and the precipitated
solid was collected by filtration and washed with hexane: diethyl
ether (1:1) solution. The obtained solid was dried in vacuo to give
(E)-3-[4-({1-[(12-cyclohexyl-3-methoxy-6,7-dihydro-5-oxa-7a-azadibenzo[a,-
e]azulene-9-carbonyl)amino]cyclobutanecarbonyl}amino)phenyl]acrylic
acid (84 mg, yield 86%).
[1739] .sup.1H-NMR(300 MHz, DMSO-d.sub.6): .delta.(ppm) 12.22 (1H,
s), 9.67 (1H, s), 8.74 (1H, s), 8.21 (1H, s), 7.83 (1H, d, J=8.4
Hz), 7.68-7.58 (5H, m), 7.50 (1H, d, J=16.1 Hz), 7.35 (1H, d, J=8.4
Hz), 6.95 (1H, dd, J=8.6, 2.8 Hz), 6.83 (1H, d, J=2.6 Hz), 6.39
(1H, d, J=16.1 Hz), 4.50-4.43 (2H, m), 4.40-4.32 (2H, m), 3.83 (3H,
s), 2.91-2.81 (1H, m), 2.80-2.69 (2H, m), 2.41-2.30 (2H, m),
2.08-1.69 (9H, m), 1.44-1.23 (3H, m).
[1740] MS 634.3(M+1).
Example 1-520
Production of
N-acetyl-13-cyclohexyl-3-methyl-5-[2-(piperidin-1-yl)ethyl]-6,7-dihydro-5-
H-benzo[5,6][1,4]diazepino[7,1-a]indole-10-sulfonamide
dihydrochloride
Step 1: Production of 4-methyl-3-nitrobenzenesulfonyl chloride
[1741] ##STR468##
[1742] To a mixed solution of fuming nitric acid (3.5 ml) and conc.
sulfuric acid (5.4 ml) was added p-toluenesulfonyl chloride (5.00
g, 26.2 mmol) in several portions under ice-cooling, and the
mixture was stirred under ice-cooling for 2 hr. To the reaction
mixture was added ice, and the mixture was extracted with diethyl
ether. The organic layer was successively washed with water,
saturated aqueous sodium hydrogen carbonate solution and saturated
brine and dried over anhydrous sodium sulfate. After filtration,
the solvent was evaporated under reduced pressure to give
4-methyl-3-nitrobenzenesulfonyl chloride (5.43 g, yield 88.0%).
[1743] .sup.1H-NMR(400 MHz, CDCl.sub.3): .delta.(ppm) 8.64 (1H, d,
J=1.9 Hz), 8.16 (1H, dd, J=8.2, 2.1 Hz), 7.67 (1H, d, J=8.3 Hz),
2.77 (3H, s).
Step 2: Production of
N-tert-butyl-4-methyl-3-nitrobenzenesulfonamide
[1744] ##STR469##
[1745] To a solution of 4-methyl-3-nitrobenzenesulfonyl chloride
(5.40 g, 22.9 mmol) in chloroform (50 ml) was added tert-butylamine
(6.00 ml, 57.1 mmol) under ice-cooling, and the mixture was stirred
at room temperature for 2.5 hr. To the reaction mixture was added
1N hydrochloric acid, and the mixture was extracted with
chloroform. The organic layer was successively washed with water,
saturated aqueous sodium hydrogen carbonate solution and saturated
brine, and dried over anhydrous sodium sulfate. After filtration,
the solvent was evaporated under reduced pressure, and hexane was
added to the residue. The precipitated solid was collected by
filtration and dried in vacuo to give
N-tert-butyl-4-methyl-3-nitrobenzenesulfonamide (5.89 g, yield
94.6%).
[1746] .sup.1H-NMR(400 MHz, CDCl.sub.3): .delta.(ppm) (1H, d, J=2.3
Hz), 8.01 (1H, dd, J=8.1, 2.1 Hz), 7.50 (1H, d, J=7.9 Hz), 4.64
(1H, s), 2.69 (3H, s), 1.28 (9H, s).
Step 3: Production of
N-tert-butyl-4-((E)-2-dimethylaminovinyl)-3-nitrobenzenesulfonamide
[1747] ##STR470##
[1748] A solution of
N-tert-butyl-4-methyl-3-nitrobenzenesulfonamide (5.89 g, 21.6 mmol)
in N,N-dimethylformamide dimethyl acetal (10 ml) was stirred with
heating at 110.degree. C. for 10 hr. The reaction solvent was
evaporated under reduced pressure and diethyl ether was added. The
precipitated solid was collected by filtration, washed with diethyl
ether and dried in vacuo to give
N-tert-butyl-4-((E)-2-dimethylaminovinyl)-3-nitrobenzenesulfonamide
(5.41 g, yield 76.6%).
[1749] .sup.1H-NMR(400 MHz, CDCl.sub.3): .delta.(ppm) (1H, d, J=1.9
Hz), 7.74-7.71 (1H, m), 7.51 (1H, d, J=8.1 Hz), 7.16 (1H, d, J=10.7
Hz), 5.95 (1H, d, J=6.7 Hz), 4.56 (1H, s), 3.00 (6H, s), 1.26 (9H,
s).
Step 4: Production of N-tert-butyl-1H-indole-6-sulfonamide
[1750] ##STR471##
[1751] A suspension of
N-tert-butyl-4-((E)-2-dimethylaminovinyl)-3-nitrobenzenesulfonamide
(5.41 g, 16.5 mmol) and 7.5% palladium/carbon (500 mg) in
tetrahydrofuran (50 ml) and ethanol (50 ml) was stirred at room
temperature for 3.5 hr under a hydrogen atmosphere of 3.5 atm. The
reaction mixture was filtered through celite and the filtrate was
concentrated under reduced pressure. Ethyl acetate was added to the
residue, and the mixture was successively washed with 1N
hydrochloric acid and saturated brine and dried over anhydrous
sodium sulfate. After filtration, the solvent was evaporated under
reduced pressure to give N-tert-butyl-1H-indole-6-sulfonamide (3.62
g, yield 87.1%).
[1752] MS 253.1(M+1).
Step 5: Production of
N-tert-butyl-3-(cyclohex-1-enyl)-1H-indole-6-sulfonamide
[1753] ##STR472##
[1754] To a solution of N-tert-butyl-1H-indole-6-sulfonamide (3.60
g, 14.2 mmol) and cyclohexanone (4.50 ml, 43.4 mmol) in methanol
(72 ml) was added 28% sodium methoxide in methanol solution (17
ml), and the mixture was stirred for 12 hr with heating under
reflux. The reaction mixture was cooled to room temperature and
concentrated under reduced pressure. 2N Hydrochloric acid was added
to the residue, and the mixture was extracted with ethyl acetate.
The organic layer was washed with saturated brine and dried over
anhydrous sodium sulfate. After filtration, the solvent was
evaporated under reduced pressure. The residue was purified by
silica gel chromatography (hexane:ethyl acetate=3:1-2:1) to give
N-tert-butyl-3-(cyclohex-1-enyl)-1H-indole-6-sulfonamide (2.82 g,
yield 59.7%).
[1755] .sup.1H-NMR(300 MHz, CDCl.sub.3): .delta.(ppm) 8.62 (1H,
brs), 7.98 (1H, d, J=1.1 Hz), 7.95 (1H, d, J=8.4 Hz), 7.59 (1H, dd,
J=8.4, 1.8 Hz), 7.32 (1H, d, J=2.6 Hz), 6.28-6.23 (1H, m), 4.56
(1H, s), 2.50-2.40 (2H, m), 2.31-2.22 (2H, m), 1.86-1.78 (2H, m),
1.73-1.69 (2H, m), 1.20 (9H, s).
Step 6: Production of
N-tert-butyl-3-cyclohexyl-1H-indole-6-sulfonamide
[1756] ##STR473##
[1757] A suspension of
N-tert-butyl-3-(2-cyclohexen-1-yl)-1H-indole-6-sulfonamide (2.82 g,
8.48 mmol) and 20% palladium hydroxide/carbon (300 mg) in methanol
(30 ml) was stirred at room temperature for 4 hr under a hydrogen
atmosphere of 1 atm. The reaction mixture was filtered through
celite and the filtrate was concentrated under reduced pressure.
Hexane was added to the residue. The precipitated solid was
collected by filtration and dried in vacuo to give
N-tert-butyl-3-cyclohexyl-1H-indole-6-sulfonamide (2.29 g, yield
82.0%).
[1758] .sup.1H-NMR(300 MHz, CDCl.sub.3): .delta.(ppm) 8.41 (1H,
brs), 7.98 (1H, d, J=1.5 Hz), 7.71 (1H, d, J=8.4 Hz), 7.56 (1H, dd,
J=8.4, 1.5 Hz), 7.13 (1H, d, J=2.6 Hz), 4.55 (1H, brs), 2.90-2.75
(1H, m), 2.15-2.04 (2H, m), 1.92-1.72 (3H, m), 1.52-1.40 (3H, m),
1.35-1.20 (2H, m), 1.20 (9H, s).
Step 7: Production of
N-tert-butyl-2-bromo-3-cyclohexyl-1H-indole-6-sulfonamide
[1759] ##STR474##
[1760] To a solution of
N-tert-butyl-3-cyclohexyl-1H-indole-6-sulfonamide (2.29 g, 6.86
mmol) in chloroform (30 ml) was added pyridinium hydrobromide
perbromide (2.40 g, 7.50 mmol) under ice-cooling, and the mixture
was stirred under ice-cooling for 30 min. 1M aqueous sodium
hydrogen sulfite solution was added to the reaction mixture and the
mixture was extracted with chloroform. The organic layer was washed
with saturated brine and dried over anhydrous sodium sulfate. After
filtration, the solvent was evaporated under reduced pressure. A
mixed solvent of hexane:ethyl acetate (5:1) was added to the
residue. The precipitated solid was collected by filtration and
dried in vacuo to give
N-tert-butyl-2-bromo-3-cyclohexyl-1H-indole-6-sulfonamide (2.19 g,
yield 78.3%).
[1761] .sup.1H-NMR(300 MHz, CDCl.sub.3): .delta.(ppm) 8.48 (1H,
brs), 7.90 (1H, d, J=1.1 Hz), 7.76 (1H, d, J=8.4 Hz), 7.55 (1H, dd,
J=8.6, 1.7 Hz), 4.58 (1H, brs), 2.90-2.77 (1H, m), 1.95-1.79 (7H,
m), 1.45-1.26 (3H, m), 1.23 (9H, s).
Step 8: Production of
N-tert-butyl-2-(2-amino-4-methylphenyl)-3-cyclohexyl-1H-indole-6-sulfonam-
ide
[1762] ##STR475##
[1763] To a suspension of
N-tert-butyl-2-bromo-3-cyclohexyl-1H-indole-6-sulfonamide (2.10 g,
5.08 mmol) and
2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-methylphenyla-
mine (1.86 g, 8.00 mmol) in 1,2-dimethoxyethane (20 ml) and water
(10 ml) were added sodium hydrogen carbonate (1.60 g, 19.2 mmol)
and tetrakis(triphenylphosphine)palladium (176 mg, 0.15 mmol), and
the mixture was heated under reflux for 14 hr. The reaction mixture
was allowed to cool to room temperature, water was added to the
reaction mixture and the mixture was extracted with toluene. The
organic layer was successively washed with water and saturated
brine and dried over anhydrous sodium sulfate. After filtration,
the solvent was evaporated under reduced pressure and diisopropy
ether was added to the residue. The precipitated solid was
collected by filtration and dried in vacuo to give
N-tert-butyl-2-(2-amino-4-methylphenyl)-3-cyclohexyl-1H-indole-6-sulfonam-
ide (2.14 g, yield 96.3%).
[1764] .sup.1H-NMR(300 MHz, CDCl.sub.3): .delta.(ppm) 8.23 (1H, s),
7.90 (1H, d, J=1.8 Hz), 7.86 (1H, d, J=8.4 Hz), 7.55 (1H, dd,
J=8.4, 1.8 Hz), 7.07 (1H, d, J=7.7 Hz), 6.67 (1H, d, J=8.1 Hz),
6.64 (1H, s), 4.43 (1H, s), 3.72 (2H, s), 2.76-2.68 (1H, m), 2.34
(3H, s), 1.89-1.84 (7H, m), 1.30-1.23 (3H, m), 1.25 (9H, s).
Step 9: Production of
N-tert-butyl-2-[2-(chloroacetylamino)-4-methylphenyl]-3-cyclohexyl-1H-ind-
ole-6-sulfonamide
[1765] ##STR476##
[1766] To a suspension of
N-tert-butyl-2-(2-amino-4-methylphenyl)-3-cyclohexyl-1H-indole-6-sulfonam-
ide (2.14 g, 4.86 mmol), sodium acetate (472 mg, 5.75 mmol) and
acetic acid (0.33 ml, 5.76 mmol) in tetrahydrofuran (20 ml) was
added dropwise chloroacetyl chloride (0.45 ml, 5.64 mmol) under
ice-cooling, and the mixture was stirred at room temperature for 2
hr. the reaction mixture was concentrated under reduced pressure,
and water was added to the residue. The precipitated solid was
collected by filtration and dried in vacuo. A suspension of the
obtained solid in diethyl ether was stirred at room temperature for
1 hr. The solid was collected by filtration and dried in vacuo to
give
N-tert-butyl-2-[2-(chloroacetylamino)-4-methylphenyl]-3-cyclohexyl-1H-ind-
ole-6-sulfonamide (2.22 g, yield 89.9%). The obtained crude product
was used for Step 10 without further purification.
Step 10: Production of
N-tert-butyl-13-cyclohexyl-3-methyl-6-oxo-6,7-dihydro-5H-benzo[5,6][1,4]d-
iazepino[7,1-a]indole-10-sulfonamide (Example 1-604)
[1767] ##STR477##
[1768] A suspension of
N-tert-butyl-2-[2-(chloroacetylamino)-4-methylphenyl]-3-cyclohexyl-1H-ind-
ole-6-sulfonamide (2.22 g, 4.30 mmol) and potassium carbonate (714
mg, 5.16 mmol) in N,N-dimethylformamide (22 ml) was stirred at
80.degree. C. for 1 hr. The reaction mixture was allowed to cool to
room temperature, and 1N hydrochloric acid and water were added to
the reaction mixture. The precipitated solid was collected by
filtration and dried in vacuo. A mixed solvent of hexane:ethyl
acetate (1:1) was added to the obtained solid, and the mixture was
stirred at room temperature for 1 hr. The solid was collected by
filtration and dried in vacuo to give
N-tert-butyl-13-cyclohexyl-3-methyl-6-oxo-6,7-dihydro-5H-benzo[5,6][1,4]d-
iazepino[7,1-a]indole-10-sulfonamide (1.77 g, yield 86.2%).
[1769] .sup.1H-NMR(300 MHz, CDCl.sub.3): .delta.(ppm) 10.29 (1H,
s), 8.10 (1H, d, J=1.5 Hz), 8.01 (1H, d, J=8.8 Hz), 7.52 (1H, dd,
J=8.4, 1.5 Hz), 7.42 (1H, d, J=7.7 Hz), 7.40 (1H, s), 7.21 (1H, d,
J=8.1 Hz), 7.09 (1H, s), 4.96 (1H, d, J=15.0 Hz), 4.54 (1H, d,
J=15.4 Hz), 2.89-2.84 (1H, m), 2.39 (3H, s), 2.10-2.02 (3H, m),
1.89-1.73 (4H, m), 1.52-1.41 (3H, m), 1.08 (9H, s).
Step 11: Production of
N-tert-butyl-13-cyclohexyl-3-methyl-6-oxo-5-[2-oxo-2-(piperidin-1-yl)ethy-
l]-6,7-dihydro-5H-benzo[5,6][1,4]diazepino[7,1-a]indole-10-sulfonamide
(Example 1-605)
[1770] ##STR478##
[1771] A suspension of
N-tert-butyl-13-cyclohexyl-3-methyl-6-oxo-6,7-dihydro-5H-benzo[5,6][1,4]d-
iazepino[7,1-a]indole-10-sulfonamide (150 mg, 0.31 mmol),
1-(2-chloroacetyl)piperidine (55 mg, 0.34 mmol) and potassium
carbonate (107 mg, 0.77 mmol) in N,N-dimethylformamide (2 ml) was
stirred at 80.degree. C. for 2 hr. The reaction mixture was allowed
to cool to room temperature, and 2N hydrochloric acid and water
were added to the reaction mixture. The precipitated solid was
collected by filtration and dried in vacuo to give
N-tert-butyl-13-cyclohexyl-3-methyl-6-oxo-5-[2-oxo-2-(piperidin-1-yl)ethy-
l]-6,7-dihydro-5H-benzo[5,6][1,4]diazepino[7,1-a]indole-10-sulfonamide
(202 mg, yield 100%). The obtained crude product was used for Step
12 without further purification.
Step 12: Production of
N-tert-butyl-13-cyclohexyl-3-methyl-5-[2-(piperidin-1-yl)ethyl]-6,7-dihyd-
ro-5H-benzo[5,6][1,4]diazepino[7,1-a]indole-10-sulfonamide (Example
1-606)
[1772] ##STR479##
[1773] To a suspension of
N-tert-butyl-13-cyclohexyl-3-methyl-6-oxo-5-[2-oxo-2-(piperidin-1-yl)ethy-
l]-6,7-dihydro-5H-benzo[5,6][1,4]diazepino[7,1-a]indole-10-sulfonamide
(184 mg, 0.30 mmol) in tetrahydrofuran (1 ml) was added 1M BH.sub.3
THF complex tetrahydrofuran solution (2.0 ml) under ice-cooling,
and the mixture was stirred at room temperature for 12 hr. 2N
Hydrochloric acid (3 ml) was added to the reaction mixture, and the
mixture was stirred at 70.degree. C. for 4 hr. The reaction mixture
was allowed to cool to room temperature, neutralized with 4N
aqueous sodium hydroxide solution and saturated aqueous sodium
hydrogen carbonate solution, and extracted with ethyl acetate. The
organic layer was washed with saturated brine and dried over
anhydrous sodium sulfate. After filtration, the solvent was
evaporated under reduced pressure. The residue was purified by
silica gel chromatography (chloroform:methanol=20:1-10:1) to give
N-tert-butyl-13-cyclohexyl-3-methyl-5-[2-(piperidin-1-yl)ethyl]-6,7-dihyd-
ro-5H-benzo[5,6][1,4]diazepino[7,1-a]indole-10-sulfonamide (169 mg,
yield 94.9%).
[1774] MS 577.1(M+1).
Step 13: Production of
13-cyclohexyl-3-methyl-5-[2-(piperidin-1-yl)ethyl]-6,7-dihydro-5H-benzo[5-
,6][1,4]diazepino[7,1-a]indole-10-sulfonamide (Example 1-607)
[1775] ##STR480##
[1776] A solution of
N-tert-butyl-13-cyclohexyl-3-methyl-5-[2-(piperidin-1-yl)ethyl]-6,7-dihyd-
ro-5H-benzo[5,6][1,4]diazepino[7,1-a]indole-10-sulfonamide (169 mg,
0.29 mmol) in trifluoroacetic acid (2 ml) was stirred at 60.degree.
C. for 1 hr. The mixture was allowed to cool to room temperature
and concentrated under reduced pressure. Saturated aqueous sodium
carbonate solution was added to the residue, and the mixture was
extracted with ethyl acetate. The organic layer was washed with
saturated brine and dried over anhydrous sodium sulfate. After
filtration, the solvent was evaporated under reduced pressure to
give
13-cyclohexyl-3-methyl-5-[2-(piperidin-1-yl)ethyl]-6,7-dihydro-5H-benzo[5-
,6][1,4]diazepino[7,1-a]indole-10-sulfonamide (152 mg, yield
100%).
[1777] MS 521.2(M+1).
Step 14: Production of
N-acetyl-13-cyclohexyl-3-methyl-5-[2-(piperidin-1-yl)ethyl]-6,7-dihydro-5-
H-benzo[5,6][1,4]diazepino[7,1-a]indole-10-sulfonamide
dihydrochloride (Example 1-520)
[1778] ##STR481##
[1779] To a suspension of
13-cyclohexyl-3-methyl-5-[2-(piperidin-1-yl)ethyl]-6,7-dihydro-5H-benzo[5-
,6][1,4]diazepino[7,1-a]indole-10-sulfonamide (152 mg, 0.29 mmol)
and potassium carbonate (88 mg, 0.63 mmol) in acetone (2 ml) was
added acetyl chloride (0.02 ml, 0.30 mmol), and the mixture was
stirred at room temperature for 12 hr. 2N Hydrochloric acid was
added to the reaction mixture, and the mixture was extracted with
ethyl acetate. The organic layer was washed with saturated brine
and dried over anhydrous sodium sulfate. After filtration, the
solvent was evaporated under reduced pressure. The residue was
purified by silica gel chromatography
(chloroform:methanol=20:1-10:1) to give
N-acetyl-13-cyclohexyl-3-methyl-5-[2-(piperidin-1-yl)ethyl]-6,7-dihydro-5-
H-benzo[5,6][1,4]diazepino[7,1-a]indole-10-sulfonamide. To a
solution of the obtained
N-acetyl-13-cyclohexyl-3-methyl-5-[2-(piperidin-1-yl)ethyl]-6,7-dihydro-5-
H-benzo[5,6][1,4]diazepino[7,1-a]indole-10-sulfonamide in ethyl
acetate was added 4N HCl-ethyl acetate solution (2 ml), and the
mixture was concentrated under reduced pressure. Hexane was added
to the residue. The precipitated solid was collected by filtration
and dried in vacuo to give
N-acetyl-13-cyclohexyl-3-methyl-5-[2-(piperidin-1-yl)ethyl]-6,7-dihydro-5-
H-benzo[5,6][1,4]diazepino[7,1-a]indole-10-sulfonamide
dihydrochloride (74 mg, yield 40%).
[1780] .sup.1H-NMR(300 MHz, DMSO-d.sub.6): .delta.(ppm) 11.91 (1H,
s), 9.96 (1H, s), 8.12 (1H, d, J=2.4 Hz), 7.98 (1H, d, J=8.4 Hz),
7.48 (1H, dd, J=8.6, 1.7 Hz), 7.26 (1H, d, J=7.3 Hz), 7.19 (1H, s),
7.10 (1H, d, J=7.7 Hz), 3.62-3.58 (4H, m), 3.10-3.07 (4H, m),
2.85-2.82 (1H, m), 2.62-2.57 (2H, m), 2.42 (3H, s), 1.99-1.95 (2H,
m), 1.91 (3H, s), 1.88-1.75 (4H, m), 1.79-1.70 (2H, m), 1.34-1.12
(6H, m).
[1781] MS 563.3(M+1).
Example 1-567
Production of
13-cyclohexyl-3,5,6-trimethyl-6,7-dihydro-5H-benzo[5,6][1,4]diazepino[7,1-
-a]indole-10-carboxylic acid
Step 1: Production of methyl
2-bromo-3-cyclohexyl-1-(2-oxopropyl)-1H-indole-6-carboxylate
[1782] ##STR482##
[1783] To a solution of methyl
2-bromo-3-cyclohexyl-1H-indole-6-carboxylate (2.00 g, 5.95 mmol)
obtained in the same manner as in the method described in
WO03/010140 and bromoacetone (0.55 ml, 6.55 mmol) in
N,N-dimethylformamide (10 ml) was added sodium hydride (60% in oil)
(262 mg, 6.55 mmol) under ice-cooling, and the mixture was stirred
for 2 hr. Water was added to the reaction mixture and the mixture
was extracted with ethyl acetate. The organic layer was
successively washed with water and saturated brine and dried over
anhydrous magnesium sulfate. After filtration, the solvent was
evaporated under reduced pressure. The residue was purified by
silica gel chromatography (hexane:ethyl acetate=4:1) to give methyl
2-bromo-3-cyclohexyl-1-(2-oxopropyl)-1H-indole-6-carboxylate (1.72
g, yield 74%).
[1784] .sup.1H-NMR(400 MHz, CDCl.sub.3): .delta.(ppm) 7.83(1H, s),
7.79-7.71(2H, m), 4.92(2H, s), 3.91(3H, s), 2.93-2.83(1H, m),
2.08(3H, s), 1.98-1.74(7H, m), 1.49-1.31(3H, m).
Step 2: Production of methyl
2-(2-amino-4-methylphenyl)-3-cyclohexyl-1-(2-oxopropyl)-1H-indole-6-carbo-
xylate
[1785] ##STR483##
[1786] To a suspension of methyl
2-bromo-3-cyclohexyl-1-(2-oxopropyl)-1H-indole-6-carboxylate (700
mg, 1.78 mmol) and
5-methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenylamine
(456 mg, 1.96 mmol) in 1,2-dimethoxyethane (6 ml) and water (2 ml)
were added sodium hydrogen carbonate (177 mg, 2.14 mmol) and
tetrakis(triphenylphosphine)palladium (103 mg, 0.09 mmol), and the
mixture was heated under reflux for 4 hr. The reaction mixture was
allowed to cool to room temperature, water was added to the
reaction mixture and the mixture was extracted with ethyl acetate.
The organic layer was successively washed with saturated aqueous
sodium hydrogen carbonate solution and saturated brine and dried
over anhydrous magnesium sulfate. After filtration, the solvent was
evaporated under reduced pressure, and the residue was purified by
silica gel chromatography (hexane:ethyl acetate=3:1) to give methyl
2-(2-amino-4-methylphenyl)-3-cyclohexyl-1-(2-oxopropyl)-1H-indole-6-carbo-
xylate (727 mg, yield 97%).
[1787] .sup.1H-NMR(400 MHz, CDCl.sub.3): .delta.(ppm) 8.14(1H, s),
7.88(1H, d, J=8.8 Hz), 7.76(1H, d, J=8.8 Hz), 7.40(1H, d, J=8.0
Hz), 7.17(1H, s), 7.12(1H, d, J=8.0 Hz), 4.88(1H, d, J=13.6 Hz),
4.15(1H, d, J=13.6 Hz), 3.95(3H, s), 3.00-2.91(1H, m), 2.44(3H, s),
2.32(3H, s), 2.10-1.98(3H, m), 1.81-1.72(2H, m), 1.68-1.59(1H, m),
1.50-1.29(4H, m).
Step 3: Production of methyl
13-cyclohexyl-3,6-dimethyl-6,7-dihydro-5H-benzo[5,6][1,4]diazepino[7,1-a]-
indole-10-carboxylate (Example 1-608)
[1788] ##STR484##
[1789] To a solution of methyl
2-(2-amino-4-methylphenyl)-3-cyclohexyl-1-(2-oxopropyl)-1H-indole-6-carbo-
xylate (727 mg, 1.74 mmol) in tetrahydrofuran (10 ml) and acetic
acid (3 ml) was added sodium triacetoxyborohydride (736 mg, 3.47
mmol) at room temperature, 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 successively
washed with saturated aqueous sodium hydrogen carbonate and
saturated brine and dried over anhydrous magnesium sulfate. After
filtration, the solvent was evaporated under reduced pressure, and
the residue was purified by silica gel chromatography (hexane:ethyl
acetate=2:1) to give methyl
13-cyclohexyl-3,6-dimethyl-6,7-dihydro-5H-benzo[5,6][1,4]diazepino[7,1-a]-
indole-10-carboxylate (578 mg, yield 83%).
[1790] .sup.1H-NMR(400 MHz, CDCl.sub.3): .delta.(ppm) 8.04(1H, s),
7.85(1H, d, J=8.4 Hz), 7.72(1H, dd, J=8.4, 1.6 Hz), 7.24(1H, d,
J=7.6 Hz), 6.88(1H, d, J=7.6 Hz), 6.71(1H, s), 4.29-4.26(1H, m),
3.93(3H, s), 3.97-3.88(2H, m), 2.97-2.88(1H, m), 2.35(3H, s),
2.12-1.99(2H, m), 1.92-1.72(5H, m), 1.66-1.53(1H, m), 1.41-1.30(3H,
m), 1.21(3H, d, J=6.4 Hz),
Step 4: Production of methyl
13-cyclohexyl-3,5,6-trimethyl-6,7-dihydro-5H-benzo[5,6][1,4]diazepino[7,1-
-a]indole-10-carboxylate (Example 1-609)
[1791] ##STR485##
[1792] To a solution of methyl
13-cyclohexyl-3,6-dimethyl-6,7-dihydro-5H-benzo[5,6][1,4]diazepino[7,1-a]-
indole-10-carboxylate (150 mg, 0.373 mmol) in 37% aqueous formalin
solution (1.5 ml), chloroform (3 mL) and acetic acid (0.3 ml) was
added sodium triacetoxyborohydride (395 mg, 1.86 mmol) at room
temperature, and the mixture was stirred overnight. Water was added
to the reaction mixture and the mixture was extracted with ethyl
acetate. The organic layer was successively washed with saturated
aqueous sodium hydrogen carbonate and saturated brine and dried
over anhydrous magnesium sulfate. After filtration, the solvent was
evaporated under reduced pressure to give methyl
13-cyclohexyl-3,5,6-trimethyl-6,7-dihydro-5H-benzo[5,6][1,4]diazepino[7,1-
-a]indole-10-carboxylate (155 mg, yield 98%).
[1793] .sup.1H-NMR(400 MHz, CDCl.sub.3): .delta.(ppm) 8.05(1H, s),
7.84(1H, d, J=8.4 Hz), 7.71(1H, dd, J=8.4, 1.2 Hz), 7.23-7.19(1H,
m), 6.98-6.90(2H, m), 4.41-4.30(1H, m), 3.93(3H, s), 3.87-3.78(1H,
m), 3.56-3.44(1H, m), 2.95-2.85(1H, m), 2.76(3H, s), 2.41(3H, s),
2.12-1.64(7H, m), 1.45-1.30(3H, m), 1.09(3H, d, J=6.0 Hz).
Step 5: Production of
13-cyclohexyl-3,5,6-trimethyl-6,7-dihydro-5H-benzo[5,6][1,4]diazepino[7,1-
-a]indole-10-carboxylic acid (Example 1-567)
[1794] ##STR486##
[1795] To a solution of methyl
13-cyclohexyl-3,5,6-trimethyl-6,7-dihydro-5H-benzo[5,6][1,4]diazepino[7,1-
-a]indole-10-carboxylate (155 mg, 0.373 mmol) in tetrahydrofuran (3
ml) and methanol (1 ml) was added 4N aqueous sodium hydroxide
solution (2 ml), and the mixture was stirred at 60.degree. C. for 1
hr. The mixture was adjusted to pH 7 by adding 2N hydrochloric acid
(4 ml), and extracted with chloroform. The organic layer was washed
with saturated brine and dried over anhydrous sodium sulfate. After
filtration, the solvent was evaporated under reduced pressure, and
the residue was purified by silica gel chromatography
(chloroform:methanol=15:1) to give
13-cyclohexyl-3,5,6-trimethyl-6,7-dihydro-5H-benzo[5,6][1,4]diazepino[7,1-
-a]indole-10-carboxylic acid (100 mg, yield 67%).
[1796] .sup.1H-NMR(400 MHz, DMSO-d.sub.6): .delta.(ppm) 12.46(1H,
brs), 8.15(1H, s) 7.79(1H, d, J=8.4 Hz), 7.56(1H, dd, J=8.4, 1.2
Hz), 7.21-7.09(1H, m), 7.01-7.6.90(2H, m), 4.69(1H, brm), 3.75(1H,
brm), 2.82-2.72(1H, m), 2.67(3H, s), 2.34(3H, s), 2.04-1.60(7H, m),
1.52-1.28(3H, m), 0.98(1H, d, J=5.6 Hz).
[1797] MS 403.2(M+1).
Example 1-595
Production of
13-cyclohexyl-5-[2-(piperidin-1-yl)ethyl]-3-(pyridin-2-ylmethoxy)-6,7-dih-
ydro-5H-benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid
trihydrochloride
Step 1: Production of 4-benzyloxy-1-iodo-2-nitrobenzene
[1798] ##STR487##
[1799] To a solution of 4-iodo-3-nitrophenol (5.00 g, 18.9 mmol) in
acetone (50 ml) were added potassium carbonate (3.39 g, 24.6 mmol)
and benzyl bromide (2.92 ml, 24.6 mmol), and the mixture was
stirred at 50.degree. C. for 6 hr. Water was added to the reaction
mixture and the mixture was extracted with ethyl acetate. The
organic layer was washed with saturated brine and dried over
anhydrous sodium sulfate. After filtration, the solvent was
evaporated under reduced pressure to give
4-benzyloxy-1-iodo-2-nitrobenzene. The obtained crude product (6.20
g) was used for Step 2 without further purification.
Step 2: Production of 5-benzyloxy-2-iodophenylamine
hydrochloride
[1800] ##STR488##
[1801] To a solution of 4-benzyloxy-1-iodo-2-nitrobenzene (6.20 g,
17.5 mmol) in methanol (31 ml) were added iron trichloride
hexahydrate (142 mg, 0.53 mmol) and activated carbon (1.24 g), and
the mixture was stirred at 60.degree. C. for 5 min. The mixture was
heated to 70.degree. C., a solution of hydrazine monohydrate (2.55
ml) in methanol (4.3 ml) was added dropwise, and the mixture was
stirred for 3 hr. After filtration through celite, the filtrate was
concentrated under reduced pressure. Water was added to the residue
and the mixture was extracted with ethyl acetate. The organic layer
was washed with saturated brine and dried over anhydrous sodium
sulfate. After filtration, the solvent was evaporated under reduced
pressure. To a solution of the residue in ethyl acetate (30 ml) was
added 4N HCl-ethyl acetate solution (20 ml). The precipitated solid
was collected by filtration, washed with ethyl acetate and dried in
vacuo to give 5-benzyloxy-2-iodophenylamine hydrochloride. The
obtained crude product (5.70 g) was used for Step 3 without further
purification.
Step 3: Production of
5-benzyloxy-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenylamine
[1802] ##STR489##
[1803] To a solution of 5-benzyloxy-2-iodophenylamine hydrochloride
(5.70 g, 15.8 mmol) in 1,4-dioxane (86 ml) were added triethylamine
(11.0 ml, 79.0 mmol) and PdCl.sub.2(dppf) CH.sub.2Cl.sub.2 (645 mg,
0.79 mmol) at room temperature. To the mixture was added dropwise
pinacolborane (6.86 ml, 47.4 mmol) at room temperature, and the
mixture was stirred at 100.degree. C. for 12 hr. A saturated
aqueous ammonium chloride solution was added to the reaction
mixture, and the mixture was extracted with diethyl ether. The
organic layer was washed with saturated brine and dried over
anhydrous sodium sulfate. After filtration, the solvent was
evaporated under reduced pressure, and the residue was purified by
silica gel chromatography (hexane:ethyl acetate=5:1) to give
5-benzyloxy-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenylamine
(3.93 g, yield 76%).
[1804] .sup.1H-NMR(400 MHz, DMSO-d.sub.6): .delta.(ppm) 7.42-7.25
(6H, m), 6.20-6.15 (2H, m), 5.50 (2H, s), 5.02 (2H, s), 1.26 (12H,
s).
Step 4: Production of methyl
2-(2-amino-4-benzyloxyphenyl)-3-cyclohexyl-1H-indole-6-carboxylate
[1805] ##STR490##
[1806] To a suspension of methyl
2-bromo-3-cyclohexyl-1H-indole-6-carboxylate (3.38 g, 10.0 mmol)
obtained in the same manner as in the method described in
WO03/010140 and
5-benzyloxy-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenylamine
(3.93 g, 12.1 mmol) in 1,2-dimethoxyethane (70 ml) and water (35
ml) were added sodium hydrogen carbonate (2.49 g, 30.0 mmol) and
tetrakis(triphenylphosphine)palladium (582 mg, 0.50 mmol), and the
mixture was stirred at 90.degree. C. for 3 hr. The reaction mixture
was allowed to cool to room temperature, saturated aqueous ammonium
chloride solution was added to the reaction mixture, and the
mixture was extracted with diethyl ether. The organic layer was
washed with saturated brine and dried over anhydrous sodium
sulfate. The obtained crude product (6.20 g) was used for Step 5
without further purification.
Step 5: Production of methyl
2-[4-benzyloxy-2-(2-chloroacetylamino)phenyl]-3-cyclohexyl-1H-indole-6-ca-
rboxylate
[1807] ##STR491##
[1808] To a suspension of methyl
2-(2-amino-4-benzyloxyphenyl)-3-cyclohexyl-1H-indole-6-carboxylate
(6.17 g, 13.5 mmol), sodium acetate (1.22 g, 14.9 mmol) and acetic
acid (0.86 ml, 14.9 mmol) in tetrahydrofuran (62 ml) was added
dropwise chloroacetyl chloride (1.19 ml, 14.9 mmol), and the
mixture was stirred at room temperature for 2 hr. Water was added
to the reaction mixture and the mixture was extracted with ethyl
acetate. The organic layer was washed with saturated brine and
dried over anhydrous sodium sulfate. After filtration, the solvent
was evaporated under reduced pressure and methanol was added. The
precipitated solid was collected by filtration, washed with
methanol and dried in vacuo to give methyl
2-[4-benzyloxy-2-(2-chloroacetylamino)phenyl]-3-cyclohexyl-1H-indole-6-ca-
rboxylate (3.90 g, yield 54%).
[1809] .sup.1H-NMR(400 MHz, DMSO-d.sub.6): .delta.(ppm) 11.38 (1H,
s), 9.32 (1H, s), 7.96 (1H, d, J=0.9 Hz), 7.80 (1H, d, J=8.8 Hz),
7.66 (1H, d, J=2.3 Hz), 7.59 (1H, dd, J=8.3, 1.4 Hz), 7.50 (2H, d,
J=7.9 Hz), 7.45-7.40 (2H, m), 7.35 (1H, t, J=8.6 Hz), 7.27 (1H, d,
J=8.8 Hz), 6.97 (1H, dd, J=8.6, 2.6 Hz), 5.17 (2H, s), 4.20 (2H,
s), 3.84 (3H, s), 2.50-2.43 (1H, m), 1.85-1.71 (7H, m), 1.34-1.13
(3H, m).
Step 6: Production of methyl
3-benzyloxy-13-cyclohexyl-6-oxo-6,7-dihydro-5H-benzo[5,6][1,4]diazepino[7-
,1-a]indole-10-carboxylate (Example 1-610)
[1810] ##STR492##
[1811] To a solution of methyl
2-[4-benzyloxy-2-(2-chloroacetylamino)phenyl]-3-cyclohexyl-1H-indole-6-ca-
rboxylate (3.90 g, 7.34 mmol) in N,N-dimethylformamide (98 ml) was
added 60% sodium hydride (1.08 g, 16.1 mmol) under ice-cooling, and
the mixture was stirred for 5 hr. Water was added to the reaction
mixture, and the precipitated solid was collected by filtration and
washed with water and hexane. The obtained solid was dried in vacuo
to give methyl
3-benzyloxy-13-cyclohexyl-6-oxo-6,7-dihydro-5H-benzo[5,6][1,4]diazepino[7-
,1-a]indole-10-carboxylate (3.60 g, yield 99%).
[1812] .sup.1H-NMR(400 MHz, DMSO-d.sub.6): .delta.(ppm) 10.31 (1H,
s), 8.25 (1H, s), 7.93 (1H, d, J=8.8 Hz), 7.67 (1H, dd, J=8.4, 1.1
Hz), 7.52-7.37 (6H, m), 7.10 (1H, dd, J=8.4, 2.6 Hz), 6.91 (1H, d,
J=2.6 Hz), 5.18 (2H, d, J=8.1 Hz), 5.06 (1H, d, J=15.4 Hz), 4.52
(1H, d, J=14.7 Hz), 3.89 (3H, s), 2.75-2.71 (1H, m), 2.04-2.00 (3H,
m), 1.92-1.89 (1H, m), 1.73-1.70 (2H, m), 1.43-1.40 (3H, m),
1.25-1.22 (1H, m).
Step 7: Production of methyl
3-benzyloxy-13-cyclohexyl-6-oxo-5-[2-oxo-2-(piperidin-1-yl)ethyl]-6,7-dih-
ydro-5H-benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylate
(Example 1-611)
[1813] ##STR493##
[1814] A suspension of methyl
3-benzyloxy-13-cyclohexyl-6-oxo-6,7-dihydro-5H-benzo[5,6][1,4]diazepino[7-
,1-a]indole-10-carboxylate (1.00 g, 2.02 mmol),
1-chloroacetylpiperidine (425 mg, 2.63 mmol) and potassium
carbonate (558 mg, 4.02 mmol) in N,N-dimethylformamide (20 ml) was
stirred at 90.degree. C. for 4 hr. The reaction mixture was allowed
to cool to room temperature, water was added to the reaction
mixture and the mixture was extracted with ethyl acetate. The
organic layer was washed with saturated brine and dried over
anhydrous sodium sulfate. After filtration, the solvent was
evaporated under reduced pressure. The obtained crude product was
suspended in a mixed solvent (hexane:ethyl acetate=5:1) and
filtered. The solid was collected by filtration and dried in vacuo
to give methyl
3-benzyloxy-13-cyclohexyl-6-oxo-5-[2-oxo-2-(piperidin-1-yl)ethyl]-6,7-dih-
ydro-5H-benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylate (800
mg, yield 64%).
[1815] .sup.1H-NMR(400 MHz, DMSO-d.sub.6): .delta.(ppm) 8.26 (1H,
d, J=1.4 Hz), 7.93 (1H, d, J=8.8 Hz), 7.67 (1H, dd, J=8.3, 1.4 Hz),
7.52-7.35 (6H, m), 7.18 (1H, dd, J=8.8, 2.3 Hz), 7.12 (1H, d, J=2.3
Hz), 5.19 (2H, s), 5.17 (1H, d, J=14.8 Hz), 4.68 (1H, d, J=16.2
Hz), 4.49 (1H, d, J=14.8 Hz), 4.40 (1H, d, J=16.2 Hz), 3.89 (3H,
s), 3.44-3.26 (4H, m), 2.91-2.81 (1H, m), 2.10-1.83 (4H, m),
1.79-1.66 (2H, m), 1.63-1.32 (9H, m), 1.27-1.12 (1H, m).
Step 8: Production of methyl
3-cyclohexyl-3-hydroxy-6-oxo-5-[2-oxo-2-(piperidin-1-yl)ethyl]-6,7-dihydr-
o-5H-benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylate (Example
1-612)
[1816] ##STR494##
[1817] To a solution of methyl
3-benzyloxy-13-cyclohexyl-6-oxo-5-[2-oxo-2-(piperidin-1-yl)ethyl]-6,7-dih-
ydro-5H-benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylate (7.40
g, 11.9 mmol) in acetic acid (15 ml) was added 25% hydrogen
bromide-acetic acid solution (15 ml), and the mixture was stirred
at room temperature for 2 hr. The reaction mixture was concentrated
under reduced pressure. Toluene was added to the residue and the
mixture was concentrated to dryness under reduced pressure. The
obtained crystals were suspended in a mixed solvent (hexane:ethyl
acetate=3:1) and filtered. The solid was collected by filtration
and dried in vacuo to give methyl
13-cyclohexyl-3-hydroxy-6-oxo-5-[2-oxo-2-(piperidin-1-yl)ethyl]-6,7-dihyd-
ro-5H-benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylate (6.30 g,
yield 100%).
[1818] .sup.1H-NMR(400 MHz, DMSO-d.sub.6): .delta.(ppm) 8.24 (1H,
d, J=0.9 Hz), 7.91 (1H, d, J=8.8 Hz), 7.66 (1H, dd, J=8.3, 1.4 Hz),
7.33 (1H, d, J=7.9 Hz), 6.90-6.85 (2H, m), 5.15 (1H, d, J=14.4 Hz),
4.64 (1H, d, J=16.7 Hz), 4.47 (1H, d, J=14.4 Hz), 4.31 (1H, d,
J=16.7 Hz), 3.88(3H, s), 3.51-3.26 (5H, m), 2.91-2.79 (1H, m),
2.10-1.81 (4H, m), 1.80-1.66 (2H, m), 1.64-1.33 (9H, m), 1.29-1.12
(1H, m).
Step 9: Production of methyl
13-cyclohexyl-6-oxo-5-[2-oxo-2-(piperidin-1-yl)ethyl]-3-(pyridin-2-ylmeth-
oxy)-6,7-dihydro-5H-benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylate
(Example 1-613)
[1819] ##STR495##
[1820] A suspension of methyl
13-cyclohexyl-3-hydroxy-6-oxo-5-[2-oxo-2-(piperidin-1-yl)ethyl]-6,7-dihyd-
ro-5H-benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylate (400 mg,
0.76 mmol), 2-chloromethylpyridine hydrochloride (186 mg, 1.14
mmol), potassium carbonate (315 mg, 2.28 mmol) and potassium iodide
(63.0 mg, 0.38 mmol) in N,N-dimethylformamide (8 ml) was stirred at
80.degree. C. for 3 hr. The reaction mixture was allowed to cool to
room temperature and 1N aqueous hydrochloric acid solution was
added to the reaction mixture. The precipitated solid was collected
by filtration, washed with water and dried in vacuo. The obtained
crude product (393 mg) was used for Step without further
purification.
Step 10: Production of methyl
13-cyclohexyl-5-[2-(piperidin-1-yl)ethyl]-3-(piperidin-2-ylmethoxy)-6,7-d-
ihydro-5H-benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylate
(Example 1-614)
[1821] ##STR496##
[1822] To a solution of methyl
13-cyclohexyl-6-oxo-5-[2-oxo-2-(piperidin-1-yl)ethyl]-3-(pyridin-2-ylmeth-
oxy)-6,7-dihydro-5H-benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylate
(393 mg, 0.63 mmol) in tetrahydrofuran (1.2 ml) was added a
solution (3.2 ml) of 1M BH.sub.3 THF complex in tetrahydrofuran
under ice-cooling, and the mixture was stirred at room temperature
for 3 hr. 4N Aqueous hydrochloric acid solution (4.4 ml) was added
to the reaction mixture, and the mixture was stirred at 60.degree.
C. for 12 hr. The reaction mixture was allowed to cool to room
temperature. The reaction mixture was adjusted to pH 7 with 1N
aqueous sodium hydroxide solution, and extracted with ethyl
acetate. The organic layer was washed with saturated brine and
dried over anhydrous sodium sulfate. After filtration, the solvent
was evaporated under reduced pressure. The obtained crude product
(298 mg) was used for Step 11 without further purification.
Step 11: Production of
13-cyclohexyl-5-[2-(piperidin-1-yl)ethyl]-3-(pyridin-2-ylmethoxy)-6,7-dih-
ydro-5H-benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid
trihydrochloride (Example 1-595)
[1823] ##STR497##
[1824] To a solution of methyl
13-cyclohexyl-5-[2-(piperidin-1-yl)ethyl]-3-(piperidin-2-ylmethoxy)-6,7-d-
ihydro-5H-benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylate (298
mg, 0.50 mmol) in tetrahydrofuran (6 ml) and methanol (3 ml) was
added 4N aqueous sodium hydroxide solution (3 ml), and the mixture
was stirred at room temperature for 24 hr. The reaction solution
was adjusted to pH 7 with 1N aqueous hydrochloric acid solution,
and extracted with ethyl acetate. The organic layer was washed with
saturated brine and dried over anhydrous sodium sulfate. After
filtration, the solvent was concentrated under reduced pressure.
Ethyl acetate (6 ml) and 4N HCl-ethyl acetate solution (3 ml) were
added to the crude product at room temperature, and the mixture was
concentrated under reduced pressure. The obtained solid was
suspended in diethyl ether, collected by filtration and washed with
diethyl ether. The solid was dried in vacuo to give
13-cyclohexyl-5-(2-piperidin-1-ylethyl)-3-(pyridin-2-ylmethoxy)-6,7-dihyd-
ro-5H-benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid
trihydrochloride (242 mg, yield 70%).
[1825] .sup.1H-NMR(400 MHz, DMSO-d.sub.6): .delta.(ppm) 10.08 (1H,
br s), 8.71 (1H, d, J=4.6 Hz), 8.15 (1H, d, J=1.4 Hz), 8.09 (1H, t,
J=7.2 Hz), 7.82 (1H, d, J=8.8 Hz), 7.78 (1H, d, J=7.4 Hz), 7.59
(1H, dd, J=8.6, 1.2 Hz), 7.56 (1H, d, J=5.6 Hz), 7.30 (1H, d, J=8.3
Hz), 7.01 (1H, d, J=2.3 Hz), 6.97 (1H, dd, J=8.3, 2.3 Hz), 5.38
(2H, s), 4.98-4.42 (1H, m), 3.94-3.36 (2H, m), 3.20-3.01 (4H, m),
2.81 (1H, t, J=12.1 Hz), 2.59-2.50 (2H, m), 2.05-1.96 (3H, m),
1.89-1.73 (6H, m), 1.48-1.28 (9H, m), 1.10-1.00 (1H, m).
[1826] MS 579.3(M+1).
Example 2-175
Production of methyl
(S)-2-[(12-cyclohexyl-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carbo-
nyl)amino]-3-(4-hydroxyphenyl)propionate
Step 1: Production of
12-cyclohexyl-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carbonyl
chloride
[1827] ##STR498##
[1828] To a solution of
12-cyclohexyl-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carboxylic
acid (500 mg, 1.38 mmol) in chloroform (10 ml) were added oxalyl
chloride (0.15 ml, 1.66 mmol) and several drops of
N,N-dimethylformamide. The mixture was stirred at room temperature
for 2 hr and concentrated. Hexane was added to the obtained
residue, and the precipitated solid was collected by filtration.
The solid was washed with hexane to give
12-cyclohexyl-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carbonyl
chloride (476 mg, yield 91%).
[1829] .sup.1H-NMR(400 MHz, CDCl.sub.3): .delta.(ppm) 8.16 (1H, d,
J=1.4 Hz), 7.94 (1H, d, J=8.3 Hz), 7.83 (1H, dd, J=8.6, 1.6 Hz),
7.49-7.42 (2H, m), 7.33 (1H, td, J=7.5, 1.4 Hz), 7.30-7.25 (1H, m),
4.57-4.52 (2H, m), 4.33 (2H, t, J=5.8 Hz), 3.01-2.97 (1H, m),
2.14-2.06 (2H, m), 1.75-1.95 (5H, m), 1.40-1.35 (3H, m).
Step 2: Production of methyl
(S)-2-[(12-cyclohexyl-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carbo-
nyl)amino]-3-(4-hydroxyphenyl)propionate (Example 2-175)
[1830] ##STR499##
[1831] To a solution of
12-cyclohexyl-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carbonyl
chloride (100 mg, 0.26 mmol) in chloroform (2 ml) was added methyl
(S)-2-amino-3-(4-hydroxyphenyl)propionate (154 mg, 0.78 mmol). The
mixture was stirred at room temperature for 12 hr, 1N hydrochloric
acid was added to the reaction solution, and the mixture was
extracted with ethyl acetate. The organic layer was successively
washed with water and saturated brine and dried over anhydrous
sodium sulfate. After filtration and concentration, diethyl ether
was added to the obtained residue, and the precipitated solid was
collected by filtration. The solid was washed with diethyl ether to
give methyl
(S)-2-[(12-cyclohexyl-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carbo-
nyl)amino]-3-(4-hydroxyphenyl)propionate (102 mg, yield 82%).
[1832] .sup.1H-NMR(400 MHz, DMSO-d.sub.6): .delta.(ppm) 9.18 (1H,
s), 8.58 (1H, d, J=7.4 Hz), 8.08 (1H, d, J=0.9 Hz), 7.85 (1H, d,
J=8.3 Hz), 7.53-7.42 (3H, m), 7.35 (1H, td, J=7.4, 0.9 Hz), 7.25
(1H, dd, J=8.1, 1.2 Hz), 7.09 (2H, d, J=8.3 Hz), 6.65 (2H, d, J=5.8
Hz), 4.64-4.59 (1H, m), 4.46 (2H, t, J=5.6 Hz), 4.32 (2H, s), 3.64
(3H, s), 3.08-2.98 (2H, m), 2.88 (1H, t, J=12.3 Hz), 2.05-1.94 (1H,
m), 1.89-1.70 (6H, m), 1.43-1.23 (3H, m).
[1833] MS 539.3(M+1).
Example 2-180
Production of
(S)-2-[(12-cyclohexyl-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carbo-
nyl)amino]-3-(4-hydroxyphenyl)propionic acid
[1834] ##STR500##
[1835] To a solution of methyl
(S)-2-[(12-cyclohexyl-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carbo-
nyl)amino]-3-(4-hydroxyphenyl)propionate (87 mg, 0.16 mmol) in
tetrahydrofuran (2 ml) and methanol (1 ml) was added 4N aqueous
sodium hydroxide solution (1 ml), and the mixture was stirred at
room temperature for 12 hr. The mixture was adjusted to pH 6.5 with
1N hydrochloric acid (4 ml) and extracted with ethyl acetate. The
organic layer was washed with saturated brine and dried over
anhydrous sodium sulfate. After filtration and concentration,
diethyl ether was added to the obtained residue, and the
precipitated solid was collected by filtration. The solid was
washed with diethyl ether to give
(S)-2-[(12-cyclohexyl-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carbo-
nyl)amino]-3-(4-hydroxyphenyl)propionic acid (61 mg, yield
74%).
[1836] .sup.1H-NMR(400 MHz, DMSO-d.sub.6): .delta.(ppm) 8.15-8.03
(2H, m), 7.83 (1H, d, J=8.3 Hz), 7.43-7.36 (3H, m), 7.34 (1H, ddd,
J=15.3, 7.9, 6.5 Hz), 7.24 (1H, dd, J=7.9, 1.4 Hz), 7.02 (2H, d,
J=8.3 Hz), 6.58 (2H, d, J=8.8 Hz), 4.45 (2H, t, J=5.3 Hz),
4.25-4.40 (3H, m), 3.10 (1H, dd, J=4.6, 13.4 Hz), 2.97 (1H, dd,
J=7.9, 13.4 Hz), 2.88 (1H, dd, J=13.2, 10.9 Hz), 2.04-2.01 (2H, m),
1.82-1.76 (5H, m), 1.36-1.29 (3H, m).
[1837] MS 525.3(M+1).
Example 2-298
Production of
12-cyclohexyl-4-(pyridin-3-yl)-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulen-
e-9-carboxylic acid hydrochloride
Step 1: Production of methyl
12-cyclohexyl-4-trifluoromethanesulfonyloxy-6,7-dihydro-5-oxa-7a-azadiben-
zo[a,e]azulene-9-carboxylate (Example 2-509)
[1838] ##STR501##
[1839] To a solution of methyl
12-cyclohexyl-4-hydroxy-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-car-
boxylate (1.00 g, 2.55 mmol) obtained in the same manner as in Step
6 of Example 2-53 and triethylamine (427 .mu.l, 3.06 mmol) in
chloroform (10 ml) was added dropwise trifluoromethanesulfonic
anhydride (476 .mu.l, 2.81 mmol) under ice-cooling, and the mixture
was stirred for 3 hr. Saturated aqueous ammonium chloride solution
was added to the reaction mixture, and the mixture was extracted
with ethyl acetate. The organic layer was successively washed with
saturated aqueous ammonium chloride solution, saturated aqueous
sodium hydrogen carbonate solution and saturated brine, and dried
over anhydrous magnesium sulfate. After filtration, the solvent was
evaporated under reduced pressure to give methyl
12-cyclohexyl-4-trifluoromethanesulfonyloxy-6,7-dihydro-5-oxa-7a-a-
zadibenzo[a,e]azulene-9-carboxylate (1.30 g, yield 97%).
[1840] .sup.1H-NMR(400 MHz, CDCl.sub.3): .delta.(ppm) 8.27 (1H, d,
J=1.4 Hz), 7.97 (1H, d, J=8.4 Hz), 7.68 (1H, dd, J=8.4, 1.4 Hz),
7.63 (1H, dd, J=7.9, 1.9 Hz), 7.54 (1H, dd, J=7.9, 1.9 Hz), 7.49
(1H, t, J=7.9 Hz), 4.62 (2H, brt, J=5.1 Hz), 4.52 (1H, brs), 3.88
(3H, s), 2.87 (1H, brt, J=12.3 Hz), 2.10-1.96 (2H, m), 1.86-1.68
(5H, m), 1.48-1.26 (3H, m).
Step 2: Production of methyl
12-cyclohexyl-4-(pyridin-3-yl)-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulen-
e-9-carboxylate (Example 2-510)
[1841] ##STR502##
[1842] To a suspension of methyl
12-cyclohexyl-4-trifluoromethanesulfonyloxy-6,7-dihydro-5-oxa-7a-azadiben-
zo[a,e]azulene-9-carboxylate (130 mg, 0.248 mmol),
3-(1,3,2-dioxaborinan-2-yl)pyridine (53 mg, 0.323 mmol) and sodium
hydrogen carbonate (62 mg, 0.744 mmol) in 1,2-dimethoxyethane (2
ml) and water (0.75 ml) was added
tetrakis(triphenylphosphine)palladium (16 mg, 0.014 mmol), and the
mixture was heated at 90.degree. C. for 3 hr. The reaction mixture
was cooled to room temperature, saturated aqueous sodium hydrogen
carbonate solution was added, and the mixture was extracted with
ethyl acetate. The organic layer was successively washed with
saturated sodium hydrogen carbonate solution and saturated brine,
and dried over anhydrous magnesium sulfate. After filtration, the
solvent was evaporated under reduced pressure and the residue was
purified by silica gel column chromatography (hexane:ethyl
acetate=1:2) to give methyl
12-cyclohexyl-4-(pyridin-3-yl)-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulen-
e-9-carboxylate (92 mg, yield 82%).
[1843] .sup.1H-NMR(400 MHz, DMSO-d.sub.6): .delta.(ppm) 8.77 (1H,
d, J=2.2 Hz), 8.60 (1H, dd, J=6.3, 2.2 Hz), 8.25 (1H, d, J=1.5 Hz),
8.00 (1H, dt, J=8.0, 2.2 Hz), 7.94 (1H, d, J=8.5 Hz), 7.66 (1H, dd,
J=8.5, 1.5 Hz), 7.57 (1H, dd, J=6.3, 2.2 Hz), 7.53-7.44 (3H, m),
4.46 (2H, brs), 4.34 (2H, brs), 3.87 (3H, s), 2.92 (1H, brt, J=11.6
Hz), 2.12-1.97 (2H, m), 1.89-1.70 (5H, m), 1.48-1.27 (3H, m).
Step 3: Production of
12-cyclohexyl-4-(pyridin-3-yl)-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulen-
e-9-carboxylic acid hydrochloride (Example 2-298)
[1844] ##STR503##
[1845] To a solution of methyl
12-cyclohexyl-4-(pyridin-3-yl)-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulen-
e-9-carboxylate (130 mg, 0.203 mmol) in tetrahydrofuran (2 ml) and
methanol (2 ml) was added 4N aqueous sodium hydroxide solution (1
ml), and the mixture was stirred at room temperature for 12 hr. The
reaction mixture was adjusted to pH 6.5 with 2N hydrochloric acid,
and extracted with chloroform. The organic layer was washed with
saturated brine and dried over anhydrous sodium sulfate. After
filtration, the solvent was evaporated under reduced pressure. To a
solution of the residue in chloroform was added 4N HCl-ethyl
acetate solution (0.5 ml), and the solvent was evaporated under
reduced pressure. A mixed solvent (hexane:ethyl acetate=4:1) was
added to the residue. The precipitated solid was collected by
filtration to give
12-cyclohexyl-4-(pyridin-3-yl)-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulen-
e-9-carboxylic acid hydrochloride (88 mg, yield 91%).
[1846] .sup.1H-NMR(400 MHz, DMSO-d.sub.6): .delta.(ppm) 9.01 (1H,
s), 8.82 (1H, d, J=5.1 Hz), 8.50 (1H, d, J=7.9 Hz), 8.23 (1H, d,
J=0.9 Hz), 7.92 (2H, d, J=8.3 Hz), 7.68-7.63 (2H, m), 7.58-7.50
(2H, m), 4.48 (2H, brs), 4.37 (2H, brs), 2.91 (1H, br t, J=11.8
Hz), 2.12-1.98 (2H, m), 1.90-1.69 (5H, m), 1.49-1.22 (3H, m).
[1847] MS 439.2(M+1).
Example 2-332
Production of
2-{1-[(12-cyclohexyl-3-methoxy-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulen-
e-9-carbonyl)amino]-1-methylethyl}-3H-benzimidazole-5-carboxylic
acid
Step 1: Production of methyl
2-[(12-cyclohexyl-3-methoxy-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-
-carbonyl)amino]-2-methylpropionate (Example 2-511)
[1848] ##STR504##
[1849] To a solution of
12-cyclohexyl-3-methoxy-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-car-
boxylic acid (2.40 g, 6.13 mmol) in N,N-dimethylformamide (20.0 mL)
were successively added methyl 2-amino-2-methylpropionate
hydrochloride (1.13 g, 7.36 mmol),
1-ethyl-3-(3'-dimethylaminopropyl)carbodiimide monohydrochloride
(1.41 g, 7.36 mmol), 1-hydroxybenzotriazole (0.99 g, 7.36 mmol) and
triethylamine (1.00 ml, 7.36 mmol) at room temperature, and the
mixture was stirred overnight. To the reaction mixture were adde
saturated aqueous sodium hydrogen carbonate solution, methanol and
water. The precipitate was collected by filtration, washed with
water, and dried in vacuo to give methyl
2-[(12-cyclohexyl-3-methoxy-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-
-carbonyl)amino]-2-methylpropionate (3.10 g). The obtained compound
was used for Step 2 without purification.
[1850] .sup.1H-NMR(300 MHz, DMSO-d.sub.6): .delta.(ppm) 8.40(1H,
s), 8.12(1H, s), 7.81(1H, d, J=8.7 Hz), 7.56(1H, d, J=8.3 Hz),
7.34(1H, d, J=8.3 Hz), 6.94(1H, dd, J=2.6, 8.7 Hz), 6.84(1H, d,
J=2.6 Hz), 4.51-4.28 (4H, m), 3.83(3H, s), 3.59(3H, s), 2.93-2.79
(1H, m), 2.12-1.91 (2H, m), 1.88-1.61 (5H, m), 1.50(6H, s),
1.45-1.22 (3H, m).
Step 2: Production of
2-[(12-cyclohexyl-3-methoxy-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-
-carbonyl)amino]-2-methylpropionic acid (Example 2-512)
[1851] ##STR505##
[1852] To a solution of methyl
2-[(12-cyclohexyl-3-methoxy-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-
-carbonyl)amino]-2-methylpropionate (3.00 g, 6.11 mmol) in
tetrahydrofuran (20.0 ml) and methanol (20.0 ml) was added 2N
aqueous sodium hydroxide solution (10.00 ml, 20.00 mmol) at room
temperature, and the mixture was stirred overnight. To the reaction
mixture were successively added 2N hydrochloric acid (11.00 ml,
22.00 mmol), water and methanol, and the mixture was stirred at
room temperature for 30 min. The precipitate was collected by
filtration, washed with water, and dried in vacuo to give
2-[(12-cyclohexyl-3-methoxy-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-
-carbonyl)amino]-2-methylpropionic acid (2.60 g, yield 89%).
[1853] .sup.1H-NMR(300 MHz, DMSO-d.sub.6): .delta.(ppm) 8.27(1H,
s), 8.10(1H, s), 7.81(1H, d, J=8.3 Hz), 7.54(1H, d, J=9.0 Hz),
7.34(1H, d, J=8.3 Hz), 6.94(1H, d, J=8.7 Hz), 6.83(1H, d, J=2.3
Hz), 4.52-4.28 (4H, m), 3.83(3H, s), 2.93-2.78 (1H, m), 2.12-1.91
(2H, m), 1.88-1.64 (5H, m), 1.50(6H, s), 1.44-1.21 (3H, m).
Step 3: Production of methyl
4-amino-3-{2-[(12-cyclohexyl-3-methoxy-6,7-dihydro-5-oxa-7a-azadibenzo[a,-
e]azulene-9-carbonyl)amino]-2-methylpropionylamino}benzoate
(Example 2-513)
[1854] ##STR506##
[1855] To a solution of
2-[(12-cyclohexyl-3-methoxy-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-
-carbonyl)amino]-2-methylpropionic acid (0.60 g, 1.26 mmol) in
chloroform (18.0 ml) was added a catalytic amount of
N,N-dimethylformamide, and thionyl chloride (0.28 ml, 3.78 mmol)
was added dropwise under ice-cooling. The mixture was stirred for 2
hr. Then, the reaction mixture was evaporated under reduced
pressure to give a yellow solid. Further, the obtained solid was
dissolved in chloroform (2.5 ml) and added dropwise to a solution
of methyl 3,4-diaminobenzoate (0.29 g, 1.76 mmol) in pyridine (1.5
ml) under ice-cooling. After dropwise addition, the mixture was
warmed to room temperature, and the mixture was stirred at
overnight. To the reaction mixture were added saturated aqueous
sodium hydrogen carbonate solution, methanol and water. The
precipitate was collected by filtration, washed with water, and
dried in vacuo to give methyl
4-amino-3-{2-[(12-cyclohexyl-3-methoxy-6,7-dihydro-5-oxa-7a-azadib-
enzo[a,e]azulene-9-carbonyl)amino]-2-methylpropionylamino}benzoate
(0.73 g, yield 93%).
[1856] .sup.1H-NMR(400 MHz, DMSO-d.sub.6): (ppm) 9.14(1H, s),
8.45(1H, s), 8.17 (1H, s), 7.83(1H, d, J=6.3 Hz), 7.60(1H, d, J=6.4
Hz), 7.56(1H, dd, J=6.2, 1.2 Hz), 7.49(1H, d, J=1.1 Hz), 7.35(1H,
d, J=6.2 Hz), 6.94(1H, dd, J=1.6, 6.2 Hz), 6.84(1H, d, J=1.7 Hz),
6.67(1H, d, J=6.2 Hz), 5.87(2H, br), 4.51-4.30 (4H, m), 3.83(3H,
s), 3.74(3H, s), 2.91-2.79 (1H, m), 2.10-1.94 (2H, m), 1.86-1.66
(5H, m), 1.57(6H, s), 1.43-1.21 (3H, m).
Step 4: Production of methyl
2-{1-[(12-cyclohexyl-3-methoxy-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulen-
e-9-carbonyl)amino]-1-methylethyl}-3H-benzimidazole-5-carboxylate
(Example 2-514)
[1857] ##STR507##
[1858] Methyl
4-amino-3-{2-[(12-cyclohexyl-3-methoxy-6,7-dihydro-5-oxa-7a-azadibenzo[a,-
e]azulene-9-carbonyl)amino]-2-methylpropionylamino}benzoate (0.73
g, 1.16 mmol) was dissolved in acetic acid (14.0 ml), and the
mixture was stirred at 100.degree. C. for 2 hr. The mixture was
allowed to cool to room temperature, toluene was added, and the
solvent was evaporated under reduced pressure. To the obtained
residue were added methanol and water. The precipitate was
collected by filtration, washed with water, and dried in vacuo to
give methyl
2-{1-[(12-cyclohexyl-3-methoxy-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulen-
e-9-carbonyl)amino]-1-methylethyl}-3H-benzimidazole-5-carboxylate
(0.67 g, yield 95%).
[1859] .sup.1H-NMR(400 MHz, DMSO-d.sub.6): .delta.(ppm) 12.49-12.40
(1H, m), 8.49-8.43(1H, m), 8.18-8.14 (1.5H, m), 8.04-8.01 (0.5H,
m), 7.85-7.75 (2H, m), 7.65-7.60 (0.5H, m), 7.60-7.55 (1H, m),
7.50-7.47 (0.5H, m), 7.37-7.33 (1H, m), 7.27-7.22 (0.5H, m),
7.20-7.14 (0.5H, m), 6.97-6.92 (1H, m), 6.84(1H, d, J=1.7 Hz),
4.50-4.31 (4H, m), 3.86(3H, s), 2.91-2.80 (1H, m), 2.09-1.95 (2H,
m), 1.82(6H, s), 1.87-1.68 (5H, m), 1.43-1.25 (3H, m).
Step 5: Production of
2-{1-[(12-cyclohexyl-3-methoxy-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulen-
e-9-carbonyl)amino]-1-methylethyl}-3H-benzimidazole-5-carboxylic
acid (Example 2-332)
[1860] ##STR508##
[1861] To a mixed solution of methyl
2-{1-[(12-cyclohexyl-3-methoxy-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulen-
e-9-carbonyl)amino]-1-methylethyl}-3H-benzimidazole-5-carboxylate
(0.66 g, 1.09 mmol) in tetrahydrofuran (10.0 ml) and methanol (10.0
ml) was added 4N aqueous lithium hydroxide solution (5.00 ml, 20.00
mmol) at room temperature, and the mixture was stirred at
70.degree. C. for 7 hr. The mixture was allowed to cool to room
temperature, and 2N hydrochloric acid (11.00 ml, 22.00 mmol) and
water were successively added. The mixture was stirred at room
temperature for 30 min. Then, the precipitate was collected by
filtration, washed with water, and dried in vacuo to give
2-{1-[(12-cyclohexyl-3-methoxy-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulen-
e-9-carbonyl)amino]-1-methylethyl}-3H-benzimidazole-5-carboxylic
acid (0.65 g, yield 100%).
[1862] .sup.1H-NMR(300 MHz, DMSO-d.sub.6): .delta.(ppm) 12.49(1H,
brs), 9.00(1H, s), 8.26(1H, d, J=12.4 Hz), 8.03(1H, d, J=8.3 Hz),
7.88-7.74 (2H, m), 7.59(1H, d, J=8.7 Hz), 7.35(1H, d, J=8.3 Hz),
6.95(1H, dd, J=2.6, 8.7 Hz), 6.84(1H, d, J=2.6 Hz), 4.54-4.30 (4H,
m), 3.83(3H, s), 2.94-2.78 (1H, m), 2.12-1.95 (2H, m), 1.92(6H, s),
1.87-1.65 (5H, m), 1.45-1.20 (3H, m).
[1863] MS 593.3(M+1).
Example 2-346
Production of
N-[1-(6-dimethylcarbamoyl-1H-benzimidazol-2-yl)-1-methylethyl]-12-cyclohe-
xyl-3-methoxy-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carboxamide
[1864] ##STR509##
[1865] To a solution of
2-{1-[(12-cyclohexyl-3-methoxy-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulen-
e-9-carbonyl)amino]-1-methylethyl}-3H-benzimidazole-5-carboxylic
acid (0.07 g, 0.12 mmol) in N,N-dimethylformamide (1.0 ml) were
successively added 2M dimethylamine-tetrahydrofuran solution (0.30
ml, 0.59 mmol), N-ethyl-N'-3-dimethylaminopropylcarbodiimide
hydrochloride (0.03 g, 0.15 mmol) and 1-hydroxybenzotriazole
monohydrate (0.02 g, 0.15 mmol) at room temperature, and the
mixture was stirred overnight. Saturated aqueous sodium hydrogen
carbonate solution, methanol and water were added to the reaction
mixture. The precipitate was collected by filtration, washed with
water, and dried in vacuo to give
N-[1-(6-dimethylcarbamoyl-1H-benzimidazol-2-yl)-1-methylethyl]-12-cyclohe-
xyl-3-methoxy-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carboxamide
(0.05 g, yield 63%).
[1866] .sup.1H-NMR(300 MHz, DMSO-d.sub.6): .delta.(ppm) 12.67-11.54
(1H, m), 8.56(1H, brs), 8.15(1H, s), 7.83(1H, d, J=8.7 Hz),
7.56(1H, d, J=8.3 Hz), 7.49(1H, s), 7.46(1H, d, J=8.3 Hz), 7.35(1H,
d, J=8.6 Hz), 7.13(1H, d, J=9.4 Hz), 6.95(1H, dd, J=2.6, 8.7 Hz),
6.84(1H, d, J=2.6 Hz), 4.51-4.28 (4H, m), 3.83(3H, s), 2.98(6H, s),
2.93-2.79 (1H, m), 2.13-1.93 (2H, m), 1.82(6H, s), 1.89-1.66 (5H,
m), 1.45-1.21 (3H, m)
[1867] MS 620.3(M+1).
Example 2-349
Production of methyl
4-{2-[(12-cyclohexyl-3-methoxy-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulen-
e-9-carbonyl)amino]-2-methylpropionylamino}benzoate
[1868] ##STR510##
[1869] To a solution of
2-[(12-cyclohexyl-3-methoxy-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-
-carbonyl)amino]-2-methylpropionic acid (200 mg, 0.42 mmol) in
chloroform (4.0 ml) was added a catalytic amount of
N,N-dimethylformamide solution, thionyl chloride (0.07 ml, 1.26
mmol) was added dropwise under ice-cooling, and the mixture was
stirred at room temperature for 3 hr. Then, and the solvent was
evaporated under reduced pressure to give a yellow solid. The
obtained solid was dissolved in chloroform (1.5 ml), and added
dropwise to a solution of methyl 4-aminobenzoate (95.2 mg, 0.63
mmol) in a mixture of chloroform (1.0 ml) and pyridine (1.0 ml)
under ice-cooling. Then, methyl 4-aminobenzoate (32 mg, 0.21 mmol)
and pyridine (2.0 ml) were added, and the mixture was stirred at
room temperature for 24 hr. To the reaction mixture was added
aqueous sodium hydrogen carbonate solution and the mixture was
extracted with chloroform. The organic layer was washed with
saturated brine and dried over anhydrous sodium sulfate. After
filtration, the solvent was evaporated under reduced pressure.
Methanol and chloroform were added to the residue, and the mixture
was stirred. The precipitate was collected by filtration to give
methyl
4-{2-[(12-cyclohexyl-3-methoxy-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulen-
e-9-carbonyl)amino]-2-methylpropionylamino}benzoate (105 mg, yield
41%).
[1870] .sup.1H-NMR(300 MHz, CDCl.sub.3): .delta.(ppm) 9.75(1H, s),
8.21(2H, d, J=15.0 Hz), 7.89-7.75(5H, m), 7.61(1H, d, J=9.0 Hz),
7.34(1H, d, J=12.0 Hz), 6.96-6.91(1H, m), 6.84(1H, d, J=3.0 Hz),
4.49-4.43(2H, m), 4.39-4.33(2H, m), 3.83(3H, s), 3.81(3H, s),
2.91-2.80(1H, m), 2.10-1.95(2H, m), 1.87-1.69(5H, m), 1.58(6H, s),
1.44-1.25(3H, m). 610.3(M+1).
Example 2-350
Production of
4-{2-[(12-cyclohexyl-3-methoxy-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulen-
e-9-carbonyl)amino]-2-methylpropionylamino}benzoic acid
[1871] ##STR511##
[1872] To a solution of methyl
4-{2-[(12-cyclohexyl-3-methoxy-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulen-
e-9-carbonyl)amino]-2-methylpropionylamino}benzoate (81 mg, 0.13
mmol) in tetrahydrofuran (8.0 ml) and methanol (2.0 ml) was added
2N aqueous sodium hydroxide solution (1.0 ml, 2.0 mmol), and the
mixture was stirred at room temperature for 64 hr. The solvent was
evaporated under reduced pressure, 1N aqueous HCl solution (3.0 ml,
3.0 mmol) and methanol (1.0 ml) were added, and the mixture was
stirred. The precipitate was collected by filtration to give
4-{2-[(12-cyclohexyl-3-methoxy-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulen-
e-9-carbonyl)amino]-2-methylpropionylamino}benzoic acid (73 mg,
yield 92%).
[1873] .sup.1H-NMR(300 MHz, CDCl.sub.3): .delta.(ppm) 12.63(1H, s),
9.72(1H, s), 8.21(2H, d, J=12.0 Hz), 7.86-7.72(5H, m), 7.61(1H, d,
J=9.0 Hz), 7.35(1H, d, J=9.0 Hz), 6.96-6.93(1H, m), 6.84(1H, d,
J=3.0 Hz), 4.51-4.45(2H, m), 4.39-4.34(2H, m), 3.83(3H, s),
2.92-2.79(1H, m), 2.13-1.93(2H, m), 1.87-1.69(5H, m), 1.58(6H, s),
1.46-1.27(3H, m). 596.2(M+1).
Example 2-369
Production of
N--(S)-[2-(4-benzyloxyphenyl)-1-(thiazol-2-yl)ethyl]-12-cyclohexyl-3-meth-
oxy-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carboxamide
Step 1: Production of tert-butyl
(S)-[2-(4-benzyloxyphenyl)-1-carbamoylethyl]carbamate
[1874] ##STR512##
[1875] To a solution of
(S)-3-(4-benzyloxyphenyl)-2-tert-butoxycarbonylaminopropionic acid
(5.00 g, 13.5 mmol) and 1-hydroxybenzotriazole monohydrate (2.50 g,
16.1 mmol) in N,N-dimethylformamide (50 ml) were added
1-ethyl-3-(3'-dimethylaminopropyl)carbodiimide hydrochloride (3.10
g, 16.1 mmol) and 28% aqueous ammonia solution (5 ml) under
ice-cooling, and the mixture was stirred at room temperature for 24
hr. Water was added to the reaction mixture and the mixture was
extracted with ethyl acetate. The organic layer was successively
washed with saturated aqueous sodium hydrogen carbonate solution
and saturated brine and dried over anhydrous magnesium sulfate.
After filtration, the solvent was evaporated under reduced
pressure, and the residue was purified by silica gel chromatography
(chloroform:ethyl acetate=2:1-1:1) to give tert-butyl
(S)-[2-(4-benzyloxyphenyl)-1-carbamoylethyl]carbamate (1.53 g,
yield 31%).
[1876] .sup.1H-NMR(400 MHz, CDCl.sub.3): .delta.(ppm) 7.44-7.32
(5H, m), 7.15 (2H, d, J=8.8 Hz), 6.93 (2H, d, J=8.3 Hz), 5.79 (1H,
brs), 5.48 (1H, brs), 5.07-5.00 (3H, m), 4.37-4.26 (1H, m),
3.09-2.95 (2H, m), 1.42 (9H, s).
Step 2: Production of tert-butyl
(S)-[2-(4-benzyloxyphenyl)-1-thiocarbamoylethyl]carbamate
[1877] ##STR513##
[1878] To a solution of tert-butyl
(S)-[2-(4-benzyloxyphenyl)-1-carbamoylethyl]carbamate (1.53 g, 4.12
mmol) in tetrahydrofuran (15 ml) was added Lawesson reagent (1.70
g, 4.12 mmol), and the mixture was stirred at room temperature for
5 hr. Saturated aqueous sodium hydrogen carbonate solution was
added to the reaction mixture, and the mixture was extracted with
ethyl acetate. The organic layer was washed with saturated brine
and dried over anhydrous magnesium sulfate. After filtration, the
solvent was evaporated under reduced pressure, and the residue was
purified by silica gel chromatography (chloroform:ethyl
acetate=8:1-5:1). Diisopropy ether was added to the obtained
residue. The precipitated solid was collected by filtration and
washed with diisopropy ether. The obtained solid was dried in vacuo
to give tert-butyl
(S)-[2-(4-benzyloxyphenyl)-1-thiocarbamoylethyl]carbamate (540 mg,
yield 34%).
[1879] .sup.1H-NMR(400 MHz, CDCl.sub.3): .delta.(ppm) 7.44-7.31
(6H, m), 7.21 (1H, brs), 7.17 (2H, d, J=8.3 Hz), 6.92 (2H, d, J=8.8
Hz), 5.29 (1H, brs), 5.04 (2H, s), 4.56 (1H, dd, J=7.3, 3.6 Hz),
3.18-3.03 (2H, m), 1.42 (9H, s).
Step 3: Production of tert-butyl
(S)-[2-(4-benzyloxyphenyl)-1-(thiazol-2-yl)ethyl]carbamate
[1880] ##STR514##
[1881] To a solution of tert-butyl
(S)-[2-(4-benzyloxyphenyl)-1-thiocarbamoylethyl]carbamate (250 mg,
0.647 mmol) in acetone (5 ml) was added bromoacetaldehyde diethyl
acetal (149 .mu.l, 0.970 mmol), and the mixture was stirred at
65.degree. C. for 14 hr. The mixture was further heated to
75.degree. C. and stirred for 5 hr. The solvent was evaporated
under reduced pressure, and the obtained residue was purified by
silica gel chromatography (hexane:ethyl acetate=4:1) to give
tert-butyl
(S)-[2-(4-benzyloxyphenyl)-1-(thiazol-2-yl)ethyl]carbamate (112 mg,
yield 42%).
[1882] .sup.1H-NMR(400 MHz, CDCl.sub.3): .delta.(ppm) 7.76 (1H, d,
J=3.2 Hz), 7.44-7.30 (5H, m), 7.22 (1H, d, J=3.2 Hz), 6.99 (2H, d,
J=8.3 Hz), 6.87 (2H, d, J=8.3 Hz), 5.25 (2H, brs), 5.03 (2H, s),
3.27-3.19 (2H, m), 1.42 (9H, s).
Step 4: Production of
(S)-2-(4-benzyloxyphenyl)-1-(thiazol-2-yl)ethylamine
hydrochloride
[1883] ##STR515##
[1884] To a solution of tert-butyl
(S)-[2-(4-benzyloxyphenyl)-1-(thiazol-2-yl)ethyl]carbamate (112 mg,
0.273 mmol) in ethyl acetate (1 ml) was added 4N HCl-ethyl acetate
solution (1 ml), and the mixture was stirred at room temperature
for 30 min. The solvent was evaporated under reduced pressure, and
hexane: diethyl ether (3:1) solution was added to the obtained
residue. The precipitated solid was collected by filtration and
washed with hexane: diethyl ether (3:1) solution. The obtained
solid was dried in vacuo to give
(S)-2-(4-benzyloxyphenyl)-1-(thiazol-2-yl)ethylamine hydrochloride
(66 mg, yield 70%).
[1885] .sup.1H-NMR(400 MHz, DMSO-d.sub.6): .delta.(ppm) 8.81 (3H,
brs), 7.87 (1H, d, J=3.2 Hz), 7.74 (1H, d, J=3.2 Hz), 7.43-7.29
(5H, m), 7.05 (2H, d, J=8.8 Hz), 6.90 (2H, d, J=8.3 Hz), 5.04 (2H,
s), 5.03-4.94 (1H, m), 3.34 (1H, dd, J=13.7, 5.3 Hz), 3.10 (1H, dd,
J=13.4, 9.7 Hz).
Step 5: Production of
N--(S)-[2-(4-benzyloxyphenyl)-1-(thiazol-2-yl)ethyl]-12-cyclohexyl-3-meth-
oxy-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carboxamide
(Example 2-369)
[1886] ##STR516##
[1887] To a solution of
12-cyclohexyl-3-methoxy-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-car-
boxylic acid (50 mg, 0.13 mmol) and
(S)-2-(4-benzyloxyphenyl)-1-(thiazol-2-yl)ethylamine hydrochloride
(49 mg, 0.14 mmol) in N,N-dimethylformamide (1 ml) were added
1-hydroxybenzotriazole monohydrate (24 mg, 0.15 mmol),
1-ethyl-3-(3'-dimethylaminopropyl)carbodiimide hydrochloride (29
mg, 0.15 mmol) and triethylamine (43 .mu.l, 0.31 mmol) under
ice-cooling, and the mixture was stirred at room temperature for 18
hr. Water was added to the reaction mixture and the mixture was
extracted with ethyl acetate. The organic layer was successively
washed with saturated aqueous sodium hydrogen carbonate solution
and saturated brine and dried over anhydrous magnesium sulfate.
After filtration, the solvent was evaporated under reduced
pressure. Hexane: diethyl ether (2:1) solution was added to the
obtained residue. The precipitated solid was collected by
filtration and washed with hexane: diethyl ether (2:1) solution.
The obtained solid was dried in vacuo to give
N--(S)-[2-(4-benzyloxyphenyl)-1-(thiazol-2-yl)ethyl]-12-cyclohexyl-3-meth-
oxy-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carboxamide (68
mg, yield 77%).
[1888] .sup.1H-NMR(300 MHz, DMSO-d.sub.6): .delta.(ppm) 8.95 (1H,
d, J=8.8 Hz), 8.06 (1H, s), 7.82 (1H, d, J=8.8 Hz), 7.78 (1H, d,
J=3.3 Hz), 7.63 (1H, d, J=3.3 Hz), 7.54 (1H, d, J=8.8 Hz), 7.34
(8H, m), 6.94 (1H, dd, J=8.4, 2.6 Hz), 6.89 (2H, d, J=8.8 Hz), 6.83
(1H, d, J=2.6 Hz), 5.62-5.53 (1H, m), 5.01 (2H, s), 4.49-4.42 (2H,
m), 4.36-4.28 (2H, m), 3.83 (3H, s), 3.45 (1H, dd, J=13.9, 4.0 Hz),
3.27-3.20 (1H, m), 2.91-2.80 (1H, m), 2.08-1.94 (2H, m), 1.86-1.68
(5H, m), 1.41-1.25 (3H, m).
[1889] MS 684.2 (M+1).
Example 2-381
Production of
N--(S)-[2-(4-hydroxyphenyl)-1-(thiazol-2-yl)ethyl]-12-cyclohexyl-3-methox-
y-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carboxamide
[1890] ##STR517##
[1891] To
N--(S)-[2-(4-benzyloxyphenyl)-1-(thiazol-2-yl)ethyl]-12-cyclohe-
xyl-3-methoxy-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carboxamide
(58 mg, 0.10 mmol) was added 25% hydrogen bromide-acetic acid
solution (1 ml), and the mixture was stirred at room temperature
for 30 min. Saturated aqueous sodium hydrogen carbonate solution
was added to the reaction mixture, and the mixture was extracted
with ethyl acetate. The organic layer was washed with saturated
brine and dried over anhydrous magnesium sulfate. After filtration,
the solvent was evaporated under reduced pressure. To the obtained
residue was added hexane: diethyl ether (2:1) solution, and the
precipitated solid was collected by filtration and washed with
hexane: diethyl ether (2:1) solution. The obtained solid was dried
in vacuo to give
N--(S)-[2-(4-hydroxyphenyl)-1-(thiazol-2-yl)ethyl]-12-cyclohexyl-3-methox-
y-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carboxamide (50 mg,
yield 85%).
[1892] .sup.1H-NMR(300 MHz, DMSO-d.sub.6): .delta.(ppm) 9.12 (1H,
s), 8.91 (1H, d, J=8.8 Hz), 8.05 (1H, s), 7.82 (1H, d, J=8.4 Hz),
7.78 (1H, d, J=2.9 Hz), 7.62 (1H, d, J=3.3 Hz), 7.53 (1H, d, J=7.3
Hz), 7.33 (1H, d, J=8.4 Hz), 7.14 (2H, d, J=8.4 Hz), 6.94 (1H, dd,
J=8.4, 2.6 Hz), 6.83 (1H, d, J=2.6 Hz), 6.63 (2H, d, J=8.4 Hz),
5.57-5.49 (1H, m), 4.49-4.42 (2H, m), 4.36-4.28 (2H, m), 3.83 (3H,
s), 3.43-3.35 (1H, m), 3.22-3.14 (1H, m), 2.90-2.80 (1H, m),
2.08-1.94 (2H, m), 1.85-1.69 (5H, m), 1.41-1.23 (3H, m).
[1893] MS 594.2 (M+1).
Example 2-427
Production of
N--[(S)-2-(4-hydroxyphenyl)-1-(N-methoxy-N-methylcarbamoyl)ethyl]-12-cycl-
ohexyl-3-methoxy-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carboxamide
[1894] ##STR518##
[1895] To a solution of
(S)-2-[(12-cyclohexyl-3-methoxy-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azule-
ne-9-carbonyl)amino]-3-(4-hydroxyphenyl)propionic acid (50.0 mg,
0.090 mmol) synthesized in the same manner as in Examples 2-175 and
2-180, N,O-dimethylhydroxylamine hydrochloride (10.5 mg, 0.180
mmol), 1-hydroxybenzotriazole monohydrate (15.2 mg, 0.38 mmol) and
1-ethyl-3-(3'-dimethylaminopropyl)carbodiimide hydrochloride (20.7
mg, 0.108 mmol) in N,N-dimethylformamide (1 ml) was added
triethylamine (25.1 .mu.l, 0.180 mmol), and the mixture was stirred
overnight at room temperature. Saturated aqueous sodium hydrogen
carbonate solution was added to the reaction mixture. The
precipitated solid was collected by filtration, further washed with
water and dried in vacuo. The obtained residue was purified by
silica gel chromatography (hexane:ethyl acetate=1:4). To the
obtained residue was added a mixed solvent of hexane:ethyl acetate
(5:1), and the precipitated solid was collected by filtration and
washed with a mixed solvent of hexane:ethyl acetate (5:1). The
obtained solid was dried in vacuo to give
N--[(S)-2-(4-hydroxyphenyl)-1-(N-methoxy-N-methylcarbamoyl)ethyl]-12-cycl-
ohexyl-3-methoxy-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carboxamide
(30.0 mg, yield 54.1%).
[1896] .sup.1H-NMR(400 MHz, DMSO-d.sub.6): .delta.(ppm) 9.18 (1H,
s), 8.46 (1H, d, J=8.6 Hz), 8.12 (1H, brs), 7.81 (1H, d, J=8.6 Hz),
7.53 (1H, dd, J=8.6, 1.4 Hz), 7.34 (1H, d, J=8.6 Hz), 7.13 (2H, d,
J=8.6 Hz), 6.95 (1H, dd, J=8.6, 2.6 Hz), 6.84 (1H, d, J=2.6 Hz),
6.66 (2H, d, J=8.6 Hz), 5.18-5.04 (1H, m), 4.47 (2H, brt, J=5.6
Hz), 4.37-4.30 (2H, brm), 3.83 (1H, s), 3.80 (3H, brs), 3.14 (3H,
s), 2.95-2.79 (3H, m), 2.08-1.95 (2H, m), 1.85-1.67 (5H, m),
1.48-1.21 (3H, m).
[1897] MS 598.2(M+1).
Example 2-481
Production of
12-cyclohexyl-4-{N-[2-(piperidin-1-yl)ethyl]-N-propylamino}-6,7-dihydro-5-
-oxa-7a-azadibenzo[a,e]azulene-9-carboxylic acid
dihydrochloride
Step 1: Production of methyl
3-cyclohexyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole-6--
carboxylate
[1898] ##STR519##
[1899] To a solution of methyl
2-bromo-3-cyclohexyl-1H-indole-6-carboxylate (40.00 g, 119.0 mmol)
obtained in the same manner as in the method described in
WO03/010140 in 1,4-dioxane (400 ml) was added pinacolborane (51.8
ml, 357.0 mmol). Triethylamine (66.3 ml, 476.0 mmol) was added
dropwise at room temperature and the mixture was stirred for 3 hr.
(2-Biphenyl)dicyclohexylphosphine (5.01 g, 14.3 mmol) and
palladium(II) acetate (802 mg, 3.57 mmol) were added and the
reaction mixture was heated to 85.degree. C. and stirred for 1.5
hr. The reaction mixture was cooled to room temperature, saturated
aqueous ammonium chloride solution was added, and the mixture was
extracted with ethyl acetate. The organic layer was successively
washed with saturated aqueous ammonium chloride solution and
saturated brine and dried over anhydrous magnesium sulfate. After
filtration, the solvent was evaporated under reduced pressure. The
residue was subjected to azeotropic evaporation with toluene and
the precipitated solid was washed with a mixed solvent of
(hexane:ethyl acetate=20:1). The solid was collected by filtration
to give methyl
3-cyclohexyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole-6--
carboxylate (39.20 g, yield 86%).
[1900] .sup.1H-NMR(400 MHz, DMSO-d.sub.6): .delta.(ppm) 11.28 (1H,
s), 8.04 (1H, d, J=1.4 Hz), 7.82 (1H, d, J=8.6 Hz), 7.53 (1H, dd,
J=8.6, 1.4 Hz), 3.85 (3H, s), 2.53-2.48 (1H, m), 2.00-1.64 (7H, m),
1.45-1.27 (3H, m), 1.35 (12H, s).
Step 2: Production of methyl
3-cyclohexyl-2-{3-nitro-2-[2-(tetrahydropyran-2-yloxy)ethoxy]phenyl}-1H-i-
ndole-6-carboxylate
[1901] ##STR520##
[1902] To a solution of
2-[2-(2-bromo-6-nitrophenoxy)ethoxy]tetrahydropyran (12.30 g, 35.6
mmol) in 1,2-dimethoxyethane (150 ml) and water (75 ml) was added
sodium hydrogen carbonate (9.74 g, 117.0 mmol) and
tetrakis(triphenylphosphine)palladium (4.52 g, 3.91 mmol) and the
mixture was heated at 85.degree. C. for 15 min. Methyl
3-cyclohexyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole-6--
carboxylate (16.40 g, 35.6 mmol) was added in 6 divided portions to
the reaction mixture at 30 min intervals, and the mixture was
stirred at the same temperature for 1 hr. The reaction mixture was
allowed to cool to room temperature, water was added to the
reaction mixture and the mixture was extracted with ethyl acetate.
The organic layer was successively washed with saturated aqueous
sodium hydrogen carbonate solution and saturated brine and dried
over anhydrous magnesium sulfate. After filtration, the solvent was
evaporated under reduced pressure, and the residue was purified by
silica gel chromatography (hexane:ethyl acetate=3.5:1) to give
methyl
3-cyclohexyl-2-{3-nitro-2-[2-(tetrahydropyran-2-yloxy)ethoxy]phenyl}-1H-i-
ndole-6-carboxylate (14.40 g, yield 77%).
[1903] .sup.1H-NMR(400 MHz, DMSO-d.sub.6): .delta.(ppm) 11.65 (1H,
s), 8.02 (1H, d, J=1.4 Hz), 7.98 (1H, dd, J=8.8, 1.4 Hz), 7.87 (1H,
d, J=8.8 Hz), 7.66 (1H, dd, J=8.1, 1.6 Hz), 7.62 (1H, dd, J=8.1,
1.6 Hz), 7.45 (1H, t, J=8.1 Hz), 4.27-4.24 (1H, m), 3.86 (3H, s),
3.73-3.63 (2H, m), 3.53-3.13 (4H, m), 2.64 (1H, brt, J=12.3 Hz),
2.01-1.62 (7H, m), 1.55-1.15 (9H, m).
Step 3: Production of methyl
3-cyclohexyl-2-[2-(2-hydroxyethoxy)-3-nitrophenyl]-1H-indole-6-carboxylat-
e
[1904] ##STR521##
[1905] To a solution of methyl
3-cyclohexyl-2-{3-nitro-2-[2-(tetrahydropyran-2-yloxy)ethoxy]phenyl}-1H-i-
ndole-6-carboxylate (6.48 g, 18.6 mmol) in tetrahydrofuran (30 ml)
and methanol (90 ml) was added 6N hydrochloric acid (15 ml), and
the mixture was stirred at room temperature for 1 hr. The reaction
mixture was neutralized with 4N aqueous sodium hydroxide solution
(22.5 ml), saturated aqueous sodium hydrogen carbonate solution was
added, and the mixture was extracted with ethyl acetate. The
organic layer was washed with saturated brine and dried over
anhydrous magnesium sulfate. After filtration, the solvent was
evaporated under reduced pressure, and the residue was purified by
silica gel chromatography (hexane:ethyl acetate=3:1-2:1) to give
methyl
3-cyclohexyl-2-[2-(2-hydroxyethoxy)-3-nitrophenyl]-1H-indole-6-carboxylat-
e (11.00 g, yield 91%).
[1906] .sup.1H-NMR(400 MHz, DMSO-d.sub.6): .delta.(ppm) 11.63 (1H,
s), 8.02 (1H, d, J=1.6 Hz), 7.97 (1H, dd, J=8.1, 1.6 Hz), 7.88 (1H,
d, J=8.1 Hz), 7.65 (1H, dd, J=7.9, 1.4 Hz), 7.62 (1H, dd, J=7.9,
1.4 Hz), 7.44 (1H, t, J=7.9 Hz), 4.61 (1H, t, J=5.1 Hz), 3.87 (3H,
s), 3.56 (2H, t, J=5.6 Hz), 3.33 (2H, t, J=5.6 Hz), 2.64 (1H, brt,
J=12.1 Hz), 2.01-1.63 (7H, m), 1.43-1.17 (3H, m).
Step 4: Production of methyl
3-cyclohexyl-2-[2-(2-methanesulfonyloxyethoxy)-3-nitrophenyl]-1H-indole-6-
-carboxylate
[1907] ##STR522##
[1908] To a solution of methyl
3-cyclohexyl-2-[2-(2-hydroxyethoxy)-3-nitrophenyl]-1H-indole-6-carboxylat-
e (11.00 g, 25.1 mmol) and triethylamine (5.25 ml, 37.7 mmol) in
chloroform (77 ml) was added dropwise methanesulfonyl chloride
(2.33 ml, 30.1 mmol) under ice-cooling, and the mixture was stirred
for 30 min. Saturated aqueous sodium hydrogen carbonate solution
was added to the reaction mixture, and the mixture was extracted
with ethyl acetate. The organic layer was successively washed with
saturated aqueous ammonium chloride solution, saturated aqueous
sodium hydrogen carbonate solution and saturated brine and dried
over anhydrous magnesium sulfate. After filtration, the solvent was
evaporated under reduced pressure to give methyl
3-cyclohexyl-2-[2-(2-methanesulfonyloxyethoxy)-3-nitrophenyl]-1H-i-
ndole-6-carboxylate (12.60 g, yield 97%).
[1909] .sup.1H-NMR(400 MHz, DMSO-d.sub.6): .delta.(ppm) 11.66 (1H,
s), 8.02 (1H, d, J=1.4 Hz), 8.02 (1H, dd, J=8.3, 1.4 Hz), 7.88 (1H,
d, J=8.3 Hz), 7.68 (1H, dd, J=8.3, 1.4 Hz), 7.63 (1H, dd, J=8.3,
1.4 Hz), 7.49 (1H, t, J=8.3 Hz), 4.14-4.10 (2H, m), 3.86 (3H, s),
3.80-3.75 (2H, m), 2.94 (3H, s), 2.64 (1H, brt, J=12.1 Hz),
1.99-1.96 (7H, m), 1.42-1.40 (3H, m).
Step 5: Production of methyl
12-cyclohexyl-4-nitro-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carbo-
xylate (Example 2-515)
[1910] ##STR523##
[1911] To a solution of methyl
3-cyclohexyl-2-[2-(2-methanesulfonyloxyethoxy)-3-nitrophenyl]-1H-indole-6-
-carboxylate (12.60 g, 24.4 mmol) in N,N-dimethylformamide (190 ml)
was added potassium carbonate (5.06 g, 36.6 mmol), and the mixture
was stirred at 90.degree. C. for 1.5 hr. The reaction mixture was
allowed to cool to room temperature, water was added to the
reaction mixture, and the mixture was extracted with ethyl acetate.
The organic layer was successively washed with water and saturated
brine and dried over anhydrous magnesium sulfate. After filtration,
the solvent was concentrated under reduced pressure to give methyl
12-cyclohexyl-4-nitro-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carbo-
xylate (9.96 g, yield 97%).
[1912] .sup.1H-NMR(400 MHz, DMSO-d.sub.6): .delta.(ppm) 8.29 (1H,
d, J=1.4 Hz), 8.05 (1H, dd, J=8.5, 1.4 Hz), 7.97 (1H, d, J=8.5 Hz),
7.75 (1H, dd, J=8.0, 1.4 Hz), 7.67 (1H, dd, J=8.0, 1.4 Hz), 7.58
(1H, t, J=8.0 Hz), 4.68-4.61 (2H, m), 4.55 (2H, brs), 3.89 (3H, s),
2.84 (1H, brt, J=12.1 Hz), 2.10-1.95 (2H, m), 1.88-1.68 (5H, m),
1.48-1.26 (3H, m).
Step 6: Production of methyl
4-amino-12-cyclohexyl-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carbo-
xylate (Example 2-516)
[1913] ##STR524##
[1914] To a solution of methyl
12-cyclohexyl-4-nitro-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carbo-
xylate (9.94 g, 23.6 mmol) in tetrahydrofuran (85 ml), ethanol (170
ml) and water (42.5 ml) were added ammonium chloride (6.31 g, 118
mmol) and reduced iron (6.60 g, 118 mmol), and the mixture was
stirred at 100.degree. C. for 2 hr. After filtration of the
reaction solution, saturated aqueous sodium hydrogen carbonate
solution was added to the filtrate, and the mixture was extracted
with ethyl acetate. The organic layer was washed with saturated
brine and dried over anhydrous magnesium sulfate. After filtration,
the solvent was concentrated under reduced pressure to give a
solid. The obtained solid was washed with a mixed solvent
(hexane:ethyl acetate=20:1). The solid was collected by filtration
to give methyl
4-amino-12-cyclohexyl-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carbo-
xylate (8.62 g, yield 93%).
[1915] .sup.1H-NMR(300 MHz, DMSO-d.sub.6): .delta.(ppm) 8.20 (1H,
d, J=1.4 Hz), 7.88 (1H, d, J=8.3 Hz), 7.63 (1H, dd, J=8.3, 1.4 Hz),
7.01 (1H, t, J=7.9 Hz), 6.82 (1H, dd, J=7.9, 1.4 Hz), 6.58 (1H, dd,
J=7.9, 1.4 Hz), 5.15 (2H, s), 4.44-4.38 (2H, m), 4.33 (2H, brs),
2.95 (1H, brt, J=12.1 Hz), 2.07-1.93 (2H, m), 1.86-1.65 (5H, m),
1.46-1.21 (3H, m).
Step 7: Production of methyl
4-{bis[2-oxo-2-(piperidin-1-yl)ethyl]amino}-12-cyclohexyl-6,7-dihydro-5-o-
xa-7a-azadibenzo[a,e]azulene-9-carboxylate (Example 2-517) and
methyl
12-cyclohexyl-4-[2-oxo-2-(piperidin-1-yl)ethylamino]-6,7-dihydro-5-oxa-7a-
-azadibenzo[a,e]azulene-9-carboxylate (Example 2-518)
[1916] ##STR525##
[1917] To a solution of methyl
4-amino-12-cyclohexyl-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carbo-
xylate (3.50 g, 8.96 mmol) in N,N-dimethylformamide (35.0 ml) were
added potassium carbonate (6.20 g, 44.8 mmol), sodium iodide (1.48
g, 8.91 mmol) and 1-(2-bromoacetyl)piperidine (3.60 g, 17.4 mmol),
and the mixture was stirred at 90.degree. C. for 3 hr. The mixture
was allowed to cool to room temperature and water was added, and
the mixture was extracted with ethyl acetate. The organic layer was
successively washed with water and hexane and dried in vacuo. The
residue was purified by silica gel chromatography (hexane:ethyl
acetate=2:1-1:5) to give methyl
4-{bis[2-oxo-2-(piperidin-1-yl)ethyl]amino}-12-cyclohexyl-6,7-dihydro-5-o-
xa-7a-azadibenzo[a,e]azulene-9-carboxylate (3.31 g, yield 58%) and
methyl
12-cyclohexyl-4-[2-oxo-2-(piperidin-1-yl)ethylamino]-6,7-dihydro-5-oxa-7a-
-azadibenzo[a,e]azulene-9-carboxylate (2.15 g, yield 47%).
methyl
4-{bis[2-oxo-2-(piperidin-1-yl)ethyl]amino}-12-cyclohexyl-6,7-dihyd-
ro-5-oxa-7a-azadibenzo[a,e]azulene-9-carboxylate (Example
2-517)
[1918] .sup.1H-NMR(300 MHz, CDCl.sub.3): .delta.(ppm) 8.05 (1H, d,
J=1.5 Hz), 7.87 (1H, d, J=8.4 Hz), 7.74 (1H, dd, J=8.4, 1.5 Hz),
7.10 (1H, t, J=7.9 Hz), 6.87 (1H, dd, J=7.7, 1.5 Hz), 6.82 (1H, d,
J=8.1 Hz), 4.39 (2H, t, J=5.7 Hz), 4.30 (4H, brs), 4.25-4.12 (2H,
m), 3.94 (3H, s), 3.58 (4H, t, J=5.1 Hz), 3.37 (4H, t, J=5.1 Hz),
2.95 (1H, brt, J=10.5 Hz), 2.12-1.95 (3H, m), 1.91-1.74 (3H, m),
1.69-1.47 (14H, m), 1.42-1.30 (2H, m).
methyl
12-cyclohexyl-4-[2-oxo-2-(piperidin-1-yl)ethylamino]-6,7-dihydro-5--
oxa-7a-azadibenzo[a,e]azulene-9-carboxylate (Example 2-518)
[1919] .sup.1H-NMR(300 MHz, CDCl.sub.3): .delta.(ppm) 8.07 (1H, s),
7.88 (1H, d, J=8.4 Hz), 7.75 (1H, dd, J=8.4, 1.5 Hz), 7.13 (1H, t,
J=7.9 Hz), 6.76 (1H, dd, J=7.7, 1.5 Hz), 6.64 (1H, dd, J=7.7, 1.5
Hz), 5.62 (1H, brs), 4.57 (2H, t, J=5.7 Hz), 4.30 (2H, t, J=5.1
Hz), 3.96-3.92 (2H, m), 3.94 (3H, s), 3.65-3.61 (2H, m), 3.43-3.40
(2H, m), 3.02 (1H, t, J=11.9 Hz), 2.07-2.00 (2H, m), 1.90-1.50
(12H, m), 1.36 (2H, s).
Step 8: Production of methyl
4-{bis[2-(piperidin-1-yl)ethyl]amino}-12-cyclohexyl-6,7-dihydro-5-oxa-7a--
azadibenzo[a,e]azulene-9-carboxylate (Example 2-519)
[1920] ##STR526##
[1921] To a solution of methyl
4-{bis[2-oxo-2-(piperidin-1-yl)ethyl]amino}-12-cyclohexyl-6,7-dihydro-5-o-
xa-7a-azadibenzo[a,e]azulene-9-carboxylate (500 mg, 0.78 mmol) in
tetrahydrofuran (2.0 ml) was added a solution (5.0 ml) of 1M
BH.sub.3 THF complex in tetrahydrofuran, and the mixture was
stirred at room temperature for 14 hr. 2N Hydrochloric acid was
added to the reaction mixture, and the mixture was stirred at
70.degree. C. for 4 hr. The reaction mixture was allowed to cool to
room temperature, neutralized with 4N aqueous sodium hydroxide
solution and saturated aqueous sodium hydrogen carbonate solution,
and extracted with ethyl acetate. The organic layer was washed with
saturated brine and dried over anhydrous sodium sulfate. After
filtration, the solvent was evaporated under reduced pressure, and
the residue was purified by silica gel chromatography
(chloroform:methanol=10:1-5:1) to give methyl
4-{bis[2-(piperidin-1-yl)ethyl]amino}-12-cyclohexyl-6,7-dihydro-5-oxa-7a--
azadibenzo[a,e]azulene-9-carboxylate (401 mg, yield 84%).
[1922] .sup.1H-NMR(300 MHz, CDCl.sub.3): .delta.(ppm) 8.06 (1H, s),
7.88 (1H, d, J=8.4 Hz), 7.75 (1H, d, J=8.4 Hz), 7.20-7.05 (2H, m),
6.97 (1H, d, J=6.6 Hz), 4.46 (2H, t, J=5.7 Hz), 4.23 (2H, brs),
3.95 (3H, s), 3.50-3.33 (4H, m), 3.02-2.95 (1H, m), 2.60-2.47 (4H,
m), 2.46-2.36 (6H, m), 2.17-1.98 (2H, m), 1.95-1.75 (6H, m),
1.70-1.49 (9H, m), 1.47-1.33 (7H, m).
Step 9: Production of
4-{bis[2-(piperidin-1-yl)ethyl]amino}-12-cyclohexyl-6,7-dihydro-5-oxa-7a--
azadibenzo[a,e]azulene-9-carboxylic acid trihydrochloride (Example
2-52b)
[1923] ##STR527##
[1924] To a solution of methyl
4-{bis[2-(piperidin-1-yl)ethyl]amino}-12-cyclohexyl-6,7-dihydro-5-oxa-7a--
azadibenzo[a,e]azulene-9-carboxylate (401 mg, 0.65 mmol) in
tetrahydrofuran (4.0 ml) and methanol (4.0 ml) was added 4N aqueous
sodium hydroxide solution (4.0 ml), and the mixture was stirred at
room temperature for 12 hr. The reaction mixture was adjusted to pH
6 with 2N hydrochloric acid, and extracted with chloroform. The
organic layer was washed with saturated brine and dried over
anhydrous sodium sulfate. After filtration, the mixture was
concentrated under reduced pressure, and ethyl acetate was added to
the residue. The precipitated solid was collected by filtration to
give
4-{bis[2-(piperidin-1-yl)ethyl]amino}-12-cyclohexyl-6,7-dihydro-5-oxa-7a--
azadibenzo[a,e]azulene-9-carboxylic acid. To a solution of the
obtained
4-{bis[2-(piperidin-1-yl)ethyl]amino}-12-cyclohexyl-6,7-dihydro-5-oxa-7a--
azadibenzo[a,e]azulene-9-carboxylic acid in chloroform was added 4N
HCl-ethyl acetate solution (4.0 ml). The reaction mixture was
concentrated under reduced pressure and ethyl acetate was added.
The precipitated solid was collected by filtration and dried in
vacuo to give
4-{bis[2-(piperidin-1-yl)ethyl]amino}-12-cyclohexyl-6,7-dihydro-5-oxa-7a--
azadibenzo[a,e]azulene-9-carboxylic acid trihydrochloride (338 mg,
yield 73%).
[1925] .sup.1H-NMR(400 MHz, DMSO-d.sub.6): .delta.(ppm) 10.61 (2H,
brs), 8.22 (1H, d, J=0.9 Hz), 7.89 (1H, d, J=8.3 Hz), 7.63 (1H, dd,
J=8.3, 1.4 Hz), 7.41 (1H, t, J=4.6 Hz), 7.29 (1H, t, J=7.9 Hz),
7.09 (1H, dd, J=16.5, 7.2 Hz), 5.20 (1H, brs), 4.50 (2H, t, J=5.1
Hz), 4.45-4.21 (2H, m), 3.59 (4H, t, J=7.0 Hz), 3.45 (4H, d, J=11.6
Hz), 3.24 (4H, dd, J=11.6, 7.0 Hz), 2.97-2.77 (5H, m), 2.10-1.95
(2H, m), 1.90-1.67 (15H, m), 1.45-1.20 (5H, m).
[1926] MS 599.4(M+1).
Step 10: Production of methyl
12-cyclohexyl-4-{N-[2-oxo-2-(piperidin-1-yl)ethyl]-N-propylamino}-6,7-dih-
ydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carboxylate (Example
2-521)
[1927] ##STR528##
[1928] To a solution of methyl
12-cyclohexyl-4-[2-oxo-2-(piperidin-1-yl)ethylamino]-6,7-dihydro-5-oxa-7a-
-azadibenzo[a,e]azulene-9-carboxylate (3.40 g, 6.59 mmol) obtained
in Step 7 and propionaldehyde (4.76 ml, 65.9 mmol) in chloroform
(20 ml), water (20 ml) and acetic acid (1 ml) was added sodium
triacetoxyborohydride (6.98 g, 33.0 mmol) under ice-cooling, and
the mixture was stirred for 8 hr. Saturated aqueous sodium hydrogen
carbonate solution was added to the reaction mixture, and the
mixture was extracted with ethyl acetate. The organic layer was
successively washed with saturated aqueous sodium hydrogen
carbonate solution, water and saturated brine and dried over
anhydrous magnesium sulfate. After filtration, the solvent was
evaporated under reduced pressure, and the residue was purified by
silica gel column chromatography (hexane:ethyl acetate=2:1-1.5:1)
to give methyl
12-cyclohexyl-4-{N-[2-oxo-2-(piperidin-1-yl)ethyl]-N-propylamino}-6,7-dih-
ydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carboxylate (3.63 g, yield
99%).
[1929] .sup.1H-NMR(400 MHz, CDCl.sub.3): .delta.(ppm) 8.20 (1H, d,
J=1.4 Hz), 7.89 (1H, d, J=8.5 Hz), 7.63 (1H, dd, J=8.5, 1.4 Hz),
7.18 (1H, t, J=7.9 Hz), 7.07 (1H, dd, J=7.9, 1.4 Hz), 6.87 (1H, dd,
J=7.9, 1.4 Hz), 4.37 (2H, brs), 4.12 (2H, brs), 3.87 (3H, s), 3.37
(4H, brs), 3.21 (2H, brs), 2.88 (1H, brt, J=12.1 Hz), 2.08-1.93
(2H, m), 1.86-1.66 (5H, m), 1.60-1.47 (4H, m), 1.46-1.22 (7H, m),
0.86 (3H, t, J=7.2 Hz).
Step 11: Production of methyl
12-cyclohexyl-4-{N-[2-(piperidin-1-yl)ethyl]-N-propylamino}-6,7-dihydro-5-
-oxa-7a-azadibenzo[a,e]azulene-9-carboxylate (Example 2-522)
[1930] ##STR529##
[1931] To a solution of methyl
12-cyclohexyl-4-{N-[2-oxo-2-(piperidin-1-yl)ethyl]-N-propylamino}-6,7-dih-
ydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carboxylate (3.63 g, 6.51
mmol) in tetrahydrofuran (7 ml) was added a solution (50 ml) of 1M
BH.sub.3 THF complex in tetrahydrofuran under ice-cooling, and the
mixture was stirred at room temperature for 11 hr. 4N Hydrochloric
acid was added to the reaction mixture under ice-cooling, and the
mixture was stirred at 65.degree. C. for 3 hr. The reaction mixture
was adjusted to pH 8 with 4N aqueous sodium hydroxide solution, and
extracted with ethyl acetate. The organic layer was washed with
saturated brine and dried over anhydrous sodium sulfate. After
filtration, the solvent was evaporated under reduced pressure, and
the residue was purified by silica gel column chromatography
(chloroform:methanol=35:1-15:1) to give methyl
12-cyclohexyl-4-{N-[2-(piperidin-1-yl)ethyl]-N-propylamino}-6,7-dihydro-5-
-oxa-7a-azadibenzo[a,e]azulene-9-carboxylate (3.25 g, yield
92%).
[1932] .sup.1H-NMR(400 MHz, DMSO-d.sub.6): .delta.(ppm) 8.21 (1H,
d, J=1.4 Hz), 7.90 (1H, d, J=8.3 Hz), 7.64 (1H, dd, J=8.3, 1.4 Hz),
7.20 (1H, t, J=7.3 Hz), 7.12 (1H, d, J=7.3 Hz), 6.92 (1H, d, J=7.3
Hz), 4.40 (4H, brs), 3.87 (3H, s), 3.28 (2H, brs), 3.13 (2H, brs),
2.90 (1H, brt, J=12.1 Hz), 2.41 (2H, brs), 2.29 (2H, brs),
2.09-1.92 (2H, m), 1.87-1.65 (5H, m), 1.57-1.21 (14H, m), 0.86 (3H,
t, J=7.4 Hz).
Step 12: Production of
12-cyclohexyl-4-{N-[2-(piperidin-1-yl)ethyl]-N-propylamino}-6,7-dihydro-5-
-oxa-7a-azadibenzo[a,e]azulene-9-carboxylic acid dihydrochloride
(Example 2-481)
[1933] ##STR530##
[1934] To a solution of methyl
12-cyclohexyl-4-{N-[2-(piperidin-1-yl)ethyl]-N-propylamino}-6,7-dihydro-5-
-oxa-7a-azadibenzo[a,e]azulene-9-carboxylate (3.25 g, 5.98 mmol) in
tetrahydrofuran (16 ml) and methanol (8 ml) was added 4N aqueous
sodium hydroxide solution (4.5 ml), and the mixture was stirred at
65.degree. C. for 2 hr. The reaction mixture was adjusted to pH 6.5
with 2N hydrochloric acid and extracted with chloroform. The
organic layer was washed with saturated brine and dried over
anhydrous sodium sulfate. After filtration, the solvent was
evaporated under reduced pressure. 4N HCl-ethyl acetate solution
(10 ml) was added to a solution of the residue in chloroform, and
the solvent was evaporated under reduced pressure. A mixed solvent
(hexane:ethyl acetate=4:1) was added to the residue and the
precipitated solid was collected by filtration to give
12-cyclohexyl-4-{N-[2-(piperidin-1-yl)ethyl]-N-propylamino}-6,7-dihydro-5-
-oxa-7a-azadibenzo[a,e]azulene-9-carboxylic acid dihydrochloride
(3.41 g, yield 95%).
[1935] .sup.1H-NMR(400 MHz, DMSO-d.sub.6): .delta.(ppm) 10.53 (1H,
brs), 8.21 (1H, d, J=1.4 Hz), 7.89 (1H, d, J=8.6 Hz), 7.64 (1H, dd,
J=8.6, 1.4 Hz), 7.29 (2H, brs), 7.09 (1H, brs), 4.48 (4H, brs),
3.62 (2H, brs), 3.45 (2H, brs), 3.17 (4H, brs), 2.99-2.80 (2H, m),
2.11-1.95 (2H, m), 1.87-1.61 (10H, m), 1.57-1.22 (6H, m), 0.87 (3H,
t, J=7.2 Hz).
[1936] MS 530.3(M+1).
Example 5-4
Production of
12-cyclohexyl-5,6-dihydroindolo[2,1-a]isoquinoline-9-carboxylic
acid
Step 1: Production of
2-[2-(2-bromophenyl)ethoxy]tetrahydropyran
[1937] ##STR531##
[1938] A solution of 2-(2-bromophenyl)ethanol (3.10 g, 15.4 mmol),
3,4-dihydro-2H-pyran (1.70 ml, 18.6 mmol) and p-toluenesulfonic
acid monohydrate (10.0 mg, 5.35 mmol) in chloroform (30 ml) was
stirred at room temperature for 1 hr. Saturated aqueous sodium
hydrogen carbonate solution was added to the reaction mixture, and
the mixture was extracted with chloroform. The organic layer was
washed with saturated brine and dried over anhydrous sodium
carbonate. After filtration, the solvent was evaporated under
reduced pressure, and the residue was purified by silica gel
chromatography (hexane:ethyl acetate=30:1-10:1) to give
2-[2-(2-bromophenyl)ethoxy]tetrahydropyran (3.58 g, yield
81.7%).
[1939] .sup.1H-NMR(400 MHz, CDCl.sub.3): .delta.(ppm) 7.53 (1H, dd,
J=8.1, 1.2 Hz), 7.30 (1H, dd, J=7.4, 1.9 Hz), 7.23 (1H, td, J=7.4,
1.4 Hz), 7.07 (1H, td, J=7.7, 1.7 Hz), 4.61 (1H, t, J=3.7 Hz), 3.95
(1H, dt, J=12.8, 4.9 Hz), 3.79-3.73 (1H, m), 3.65 (1H, dt, J=12.8,
4.9 Hz), 3.47-3.45 (1H, m), 3.07 (2H, t, J=7.2 Hz), 1.82-1.80 (1H,
m), 1.72-1.67 (1H, m), 1.57-1.53 (4H, m).
Step 2: Production of
2-[2-(tetrahydropyran-2-yloxy)ethyl]phenylboronic acid
[1940] ##STR532##
[1941] To a solution of 2-[2-(2-bromophenyl)ethoxy]tetrahydropyran
(3.58 g, 12.5 mmol) and triisopropyl borate (3.70 ml, 16.1 mmol) in
tetrahydrofuran (10.0 ml) was added a solution (10.0 ml) of 1.6M
n-butyllithium in hexane at -78.degree. C., and the mixture was
stirred for 2 hr while gradually raising the temperature to
0.degree. C. 1N Hhydrochloric acid was added to the reaction
mixture, and the mixture was extracted with ethyl acetate. The
organic layer was washed with saturated brine and dried over
anhydrous sodium sulfate. After filtration, the solvent was
evaporated under reduced pressure, and the residue was purified by
silica gel chromatography (hexane:ethyl acetate=3:1-2:1) to give
2-[2-(tetrahydropyran-2-yloxy)ethyl]phenylboronic acid (1.77 g,
yield 56.6%).
[1942] .sup.1H-NMR(400 MHz, CDCl.sub.3): .delta.(ppm) 7.67 (1H, d,
J=7.4 Hz), 7.38 (1H, t, J=7.7 Hz), 7.24-7.23 (2H, m), 6.42 (2H,
brs), 4.60-4.58 (1H, m), 4.34-4.31 (1H, m), 3.71-3.66 (1H, m),
3.36-3.33 (2H, m), 3.05-3.01 (2H, m), 1.66-1.26 (4H, m), 0.95-0.90
(2H, m).
Step 3: Production of methyl
3-cyclohexyl-2-{2-[2-(tetrahydropyran-2-yloxy)ethyl]phenyl}-1H-indole-6-c-
arboxylate
[1943] ##STR533##
[1944] To a suspension of methyl
2-bromo-3-cyclohexyl-1H-indole-6-carboxylate (2.10 g, 6.24 mmol)
obtained in the same manner as in the method described in
WO03/010140 and 2-[2-(tetrahydropyran-2-yloxy)ethyl]phenylboronic
acid (1.77 g, 7.10 mmol) in 1,2-dimethoxyethane (20 ml) and water
(10 ml) were added sodium hydrogen carbonate (2.00 g, 24.0 mmol)
and tetrakis(triphenylphosphine)palladium (360 mg, 0.31 mmol), and
the mixture was heated under reflux for 7 hr. The reaction mixture
was allowed to cool to room temperature, water was added to the
reaction mixture and the mixture was extracted with ethyl acetate.
The organic layer was succesively washed with water and saturated
brine and dried over anhydrous sodium sulfate. After filtration,
the solvent was evaporated under reduced pressure, and the residue
was purified by silica gel chromatography (hexane:ethyl
acetate=6:1-5:1) to give methyl
3-cyclohexyl-2-{2-[2-(tetrahydropyran-2-yloxy)ethyl]phenyl}-1H-indole-6-c-
arboxylate (2.21 g, yield 77.2%).
[1945] MS 462.0(M+1).
Step 4: Production of methyl
3-cyclohexyl-2-[2-(2-hydroxyethyl)phenyl]-1H-indole-6-carboxylate
[1946] ##STR534##
[1947] A solution of methyl
3-cyclohexyl-2-{2-[2-(tetrahydropyran-2-yloxy)ethyl]phenyl}-1H-indole-6-c-
arboxylate (2.21 g, 4.80 mmol) in tetrahydrofuran (10 ml), methanol
(10 ml) and 6N hydrochloric acid (20 ml) was stirred at room
temperature for 2 hr. Water was added to the reaction mixture and
the mixture was extracted with ethyl acetate. The organic layer was
successively washed with water, saturated aqueous sodium hydrogen
carbonate solution and saturated brine and dried over anhydrous
sodium sulfate. After filtration, the solvent was evaporated under
reduced pressure, and the residue was purified by silica gel
chromatography (hexane:ethyl acetate=5:1-2:1) to give methyl
3-cyclohexyl-2-[2-(2-hydroxyethyl)phenyl]-1H-indole-6-carboxylate
(1.20 g, yield 66.7%).
[1948] .sup.1H-NMR(400 MHz, CDCl.sub.3): .delta.(ppm) 9.85 (1H, s),
8.10 (1H, s), 7.84 (1H, d, J=8.3 Hz), 7.76 (1H, dd, J=8.3, 1.4 Hz),
7.46-7.31 (4H, m), 4.01-3.97 (2H, m), 3.94 (3H, s), 2.72-2.69 (3H,
m), 1.98-1.80 (7H, m), 1.30-1.26 (3H, m).
Step 5: Production of methyl
2-[2-(2-bromomethyl)phenyl]-3-cyclohexyl-1H-indole-6-carboxylate
[1949] ##STR535##
[1950] To a solution of methyl
3-cyclohexyl-2-[2-(2-hydroxyethyl)phenyl]-1H-indole-6-carboxylate
(600 mg, 1.58 mmol) in chloroform (6 ml) were added carbon
tetrabromide (790 mg, 2.38 mmol) and triphenylphosphine (497 mg,
1.89 mmol), and the mixture was stirred at room temperature for 5
min. Saturated aqueous sodium hydrogen carbonate solution was added
to the reaction mixture, and the mixture was extracted with
chloroform. The organic layer was washed with saturated brine and
dried over anhydrous sodium sulfate. After filtration, the solvent
was evaporated under reduced pressure, and the residue was purified
by silica gel chromatography (hexane:ethyl acetate=7:1-6:1) to give
methyl
2-[2-(2-bromomethyl)phenyl]-3-cyclohexyl-1H-indole-6-carboxylate
(500 mg, yield 71.9%).
Step 6: Production of methyl
12-cyclohexyl-5,6-dihydroindolo[2,1-a]isoquinoline-9-carboxylate
(Example 5-5)
[1951] ##STR536##
[1952] To a solution of methyl
2-[2-(2-bromomethyl)phenyl]-3-cyclohexyl-1H-indole-6-carboxylate
(500 mg, 1.13 mmol) in N,N-dimethylformamide (10 ml) was added
sodium hydride (60% in oil, 48 mg, 1.20 mmol) under ice-cooling,
and the mixture was stirred for 30 min. 2N Hydrochloric acid was
added to the reaction mixture and the mixture was extracted with
ethyl acetate. The organic layer was successively washed with water
and saturated brine and dried over anhydrous sodium sulfate. After
filtration, the solvent was evaporated under reduced pressure, and
the residue was purified by silica gel chromatography (hexane:ethyl
acetate=10:1-8:1) to give methyl
12-cyclohexyl-5,6-dihydroindolo[2,1-a]isoquinoline-9-carboxylate
(337 mg, yield 83.0%).
[1953] .sup.1H-NMR(400 MHz, CDCl.sub.3): .delta.(ppm) 8.06 (1H, d,
J=1.4 Hz), 7.88 (1H, d, J=8.3 Hz), 7.71 (1H, d, J=8.3 Hz),
7.40-7.25 (4H, m), 4.24 (2H, t, J=6.3 Hz), 3.94 (3H, s), 3.34 (1H,
brt, J=12.3 Hz), 3.11 (2H, t, J=6.3 Hz), 2.14-2.11 (2H, m),
1.92-1.87 (5H, m), 1.50-1.45 (3H, m).
[1954] MS 360.1(M+1).
Step 7: Production of
12-cyclohexyl-5,6-dihydroindolo[2,1-a]isoquinoline-9-carboxylic
acid (Example 5-4)
[1955] ##STR537##
[1956] To a solution of methyl
12-cyclohexyl-5,6-dihydroindolo[2,1-a]isoquinoline-9-carboxylate
(337 mg, 0.93 mmol) in tetrahydrofuran (3 ml) and methanol (3 ml)
was added 4N aqueous sodium hydroxide solution (3.0 ml), and the
mixture was stirred at room temperature for 15 hr. The reaction
mixture was acidified with 2N hydrochloric acid. The precipitated
solid was collected by filtration and dried in vacuo to give
12-cyclohexyl-5,6-dihydroindolo[2,1-a]isoquinoline-9-carboxylic
acid (298 mg, yield 92.3%).
[1957] .sup.1H-NMR(300 MHz, DMSO-d.sub.6): .delta.(ppm) 12.5 (1H,
br s), 8.06 (1H, s), 7.88 (1H, d, J=8.4 Hz), 7.68 (1H, d, J=8.1
Hz), 7.59 (1H, d, J=8.4 Hz), 7.44-7.42 (1H, m), 7.33 (1H, t, J=7.5
Hz), 4.27 (2H, br s), 3.08 (2H, brs), 2.57-2.45 (1H, m), 2.08-2.04
(2H, m), 1.85-1.76 (5H, m), 1.46-1.42 (3H, m).
[1958] MS 346.2(M+1).
Example 11-1
Production of
14-cyclohexyl-6-methyl-5,6,7,8-tetrahydrobenzo[6,7][1,4]diazocino[8,1-a]i-
ndole-11-carboxylic acid monohydrochloride
Step 1: Production of N-(2-hydroxyethyl)-2-iodobenzamide
[1959] ##STR538##
[1960] To a solution of 2-iodobenzoic acid (5.00 g, 20.1 mmol) in
chloroform (50 ml) were added oxalyl chloride (1.9 ml, 21.7 mmol)
and N,N-dimethylformamide (5 drops with Pasteur pipette) under
ice-cooling, and the mixture was stirred at room temperature for 2
hr. The reaction mixture was concentrated under reduced pressure
and ethyl acetate (5 ml) was added to the residue to give a
solution of 2-iodobenzoyl chloride in ethyl acetate.
[1961] To a solution of sodium hydrogen carbonate (3.30 g, 39.7
mmol) and 2-aminoethanol (1.80 ml, 29.8 mmol) in ethyl acetate (25
ml) and water (15 ml) was added dropwise the solution of
2-iodobenzoyl chloride in ethyl acetate prepared above under
ice-cooling, and the mixture was stirred at room temperature for 12
hr. Water was added to the reaction mixture and the mixture was
extracted with ethyl acetate. The organic layer was washed with
saturated brine and dried over anhydrous sodium sulfate. After
filtration, the solvent was evaporated under reduced pressure to
give N-(2-hydroxyethyl)-2-iodobenzamide (5.12 g, yield 87.6%).
[1962] .sup.1H-NMR(400 MHz, CDCl.sub.3): .delta.(ppm) 7.86 (1H, d,
J=7.9 Hz), 7.40-7.38 (2H, m), 7.11 (1H, ddd, J=8.6, 6.3, 1.6 Hz),
6.29 (1H, brs), 3.86 (2H, dd, J=5.6, 4.6 Hz), 3.62 (2H, dt, J=5.3,
4.9 Hz), 2.22 (1H, brs).
Step 2: Production of methyl
3-cyclohexyl-2-[2-(2-hydroxyethylcarbamoyl)phenyl]-1H-indole-6-carboxylat-
e
[1963] ##STR539##
[1964] To a suspension of N-(2-hydroxyethyl)-2-iodobenzamide (5.12
g, 17.5 mmol), sodium hydrogen carbonate (5.80 g, 69.8 mmol) and
tetrakis(triphenylphosphine)palladium (2.00 g, 1.73 mmol) in
1,2-dimethoxyethane (70 ml) and water (35 ml) was added methyl
3-cyclohexyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole-6--
carboxylate (7.50 g, 19.5 mmol) in five divided portions at
90.degree. C., 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 successively washed with water
and saturated brine and dried over anhydrous sodium sulfate. After
filtration, the solvent was evaporated under reduced pressure, and
the residue was purified by silica gel column chromatography
(chloroform:methanol=30:1-20:1) to give methyl
3-cyclohexyl-2-[2-(2-hydroxyethylcarbamoyl)phenyl]-1H-indole-6-carboxylat-
e (7.40 g, yield 100%).
[1965] .sup.1H-NMR(400 MHz, CDCl.sub.3): .delta.(ppm) 9.94 (1H,
brs), 8.17 (1H, s), 7.85 (1H, d, J=8.3 Hz), 7.80 (1H, dd, J=8.3,
1.4 Hz), 7.73 (1H, dd, J=8.5, 1.4 Hz), 7.49 (1H, dd, J=7.2, 1.4
Hz), 7.42-7.38 (2H, m), 5.98 (1H, t, J=5.6 Hz), 3.94 (3H, s), 3.22
(2H, dt, J=5.6, 4.6 Hz), 3.15 (2H, t, J=4.6 Hz), 2.75 (1H,br t,
J=12.1 Hz), 1.96-1.77 (8H, m), 1.32-1.26 (3H, m).
Step 3: Production of methyl
2-(2-{[N-tert-butoxycarbonyl-N-(2-hydroxyethyl)amino]methyl}phenyl)-3-cyc-
lohexyl-1H-indole-6-carboxylate
[1966] ##STR540##
[1967] To a solution of methyl
3-cyclohexyl-2-[2-(2-hydroxyethylcarbamoyl)phenyl]-1H-indole-6-carboxylat-
e (2.00 g, 4.75 mmol) in tetrahydrofuran (5.0 ml) was added a
solution (20.0 ml, 20.0 mmol) of 1M BH.sub.3 THF complex in
tetrahydrofuran under ice-cooling, and the mixture was stirred at
room temperature for 17 hr. 2N Hydrochloric acid (20 ml) was added
to the reaction mixture, and the mixture was stirred at 70.degree.
C. for 1.5 hr. The reaction mixture was allowed to cool to room
temperature, the reaction mixture was neutralized with 4N aqueous
sodium hydroxide solution and aqueous sodium hydrogen carbonate
solution. To this mixture was added di-tert-butyl dicarbonate (1.60
g, 7.33 mmol), and the mixture was stirred at room temperature for
6 hr. The reaction mixture was extracted with ethyl acetate, and
the organic layer was washed with saturated brine and dried over
anhydrous sodium sulfate. After filtration, the solvent was
evaporated under reduced pressure, and the residue was purified by
silica gel chromatography (chloroform:methanol=30:1-10:1) to give
methyl
2-(2-{[N-tert-butoxycarbonyl-N-(2-hydroxyethyl)amino]methyl}phenyl)-3-cyc-
lohexyl-1H-indole-6-carboxylate (524 mg, yield 22.1%).
[1968] .sup.1H-NMR(400 MHz, CDCl.sub.3): .delta.(ppm) 8.08 (1H, s),
7.82 (1H, d, J=8.3 Hz), 7.78 (1H, dd, J=8.3, 1.4 Hz), 7.46-7.39
(3H, m), 7.32 (1H, d, J=7.0 Hz), 4.37-4.35 (2H, m), 3.94 (3H, s),
3.41-3.39 (4H, m), 2.55 (1H, brs), 1.96-1.71 (7H, m), 1.40-1.09
(3H, m), 1.25 (9H, s).
[1969] MS 407.0(M+1).
Step 4: Production of methyl
2-(2-{[N-tert-butoxycarbonyl-N-(2-methanesulfonyloxyethyl)amino]methyl}ph-
enyl)-3-cyclohexyl-1H-indole-6-carboxylate
[1970] ##STR541##
[1971] To a solution of methyl
2-(2-{[N-tert-butoxycarbonyl-N-(2-hydroxyethyl)amino]methyl}phenyl)-3-cyc-
lohexyl-1H-indole-6-carboxylate (424 mg, 0.830 mmol) and
triethylamine (0.14 ml, 1.0 mmol) in chloroform (5.0 ml) was added
dropwise methanesulfonyl chloride (0.07 ml, 0.90 mmol) under
ice-cooling, and the mixture was stirred at room temperature for 1
hr. 1N Hydrochloric acid was added to the reaction mixture, and the
mixture was extracted with chloroform. The organic layer was washed
with saturated brine and dried over anhydrous sodium sulfate. After
filtration, the solvent was evaporated under reduced pressure to
give methyl
2-(2-{[N-tert-butoxycarbonyl-N-(2-methanesulfonyloxyethyl)amino]methyl}ph-
enyl)-3-cyclohexyl-1H-indole-6-carboxylate as a crude product. The
obtained crude product was used for Step 5 without
purification.
Step 5: Production of methyl
6-tert-butoxycarbonyl-14-cyclohexyl-5,6,7,8-tetrahydrobenzo[6,7][1,4]diaz-
ocino[8,1-a]indole-11-carboxylate (Example 11-2)
[1972] ##STR542##
[1973] To a solution of methyl
2-(2-{[N-tert-butoxycarbonyl-N-(2-methanesulfonyloxyethyl)amino]methyl}ph-
enyl)-3-cyclohexyl-1H-indole-6-carboxylate (crude product obtained
in Step 4) in N,N-dimethylformamide (10 ml) was added sodium
hydride (60% in oil, 36 mg, 0.90 mmol) under ice-cooling, and the
mixture was stirred at room temperature for 4 hr. Water was added
to the reaction mixture and the mixture was extracted with ethyl
acetate. The organic layer was successively washed with water and
saturated brine and dried over anhydrous sodium sulfate. After
filtration, the solvent was evaporated under reduced pressure, and
the residue was purified by silica gel chromatography (hexane:ethyl
acetate=2:1-3:2) to give methyl
6-tert-butoxycarbonyl-14-cyclohexyl-5,6,7,8-tetrahydrobenzo[6,7][1,4]diaz-
ocino[8,1-a]indole-11-carboxylate (89 mg, yield 21.9%).
[1974] .sup.1H-NMR(400 MHz, CDCl.sub.3): d(ppm) 8.08 (0.5H, s),
8.07 (0.5H, s), 7.90-7.78 (3.0H, m), 7.53-7.34 (3.0H, m), 4.98
(0.5H, d, J=14.8 Hz), 4.90 (0.5H, d, J=14.4 Hz), 4.66 (0.5H, dd,
J=14.6, 4.9 Hz), 4.50 (1.0H, dd, J=19.5, 8.3 Hz), 4.31 (0.5H, d,
J=14.4 Hz), 3.97 (3.0H, s), 3.75-3.67 (1.0H, m), 3.43 (0.5H, d,
J=14.8 Hz), 3.29 (0.5H, d, J=14.8 Hz), 3.26 (0.5H, d, J=9.3 Hz),
3.03-2.97 (0.5H, m), 2.75-2.57 (1.0H, m), 2.03-1.72 (4.0H, m),
1.77-1.74 (2.0H, m), 1.60 (4.5H, s), 1.41 (4.5H, s), 1.35-1.18
(4.0H, m).
Step 6: Production of methyl
14-cyclohexyl-6-methyl-5,6,7,8-tetrahydrobenzo[6,7][1,4]diazocino[8,1-a]i-
ndole-11-carboxylate (Example 11-3)
[1975] ##STR543##
[1976] A solution of methyl
6-tert-butoxycarbonyl-14-cyclohexyl-5,6,7,8-tetrahydrobenzo[6,7][1,4]diaz-
ocino[8,1-a]indole-11-carboxylate (89 mg, 0.18 mmol) in 4N
HCl-ethyl acetate was stirred at room temperature for 3 hr. The
reaction mixture was concentrated under reduced pressure and
chloroform (2.0 ml) was added to the residue. To this solution were
successively added sodium acetate (30 mg, 0.36 mmol), acetic acid
(0.01 ml, 0.20 mmol), 37% aqueous formaldehyde solution (2.0 ml)
and sodium triacetoxyborohydride (46 mg, 0.21 mmol), and the
mixture was stirred for 13 hr. Saturated aqueous sodium hydrogen
carbonate solution was added to the reaction mixture, and the
mixture was extracted with chloroform. The organic layer was washed
with saturated brine and dried over anhydrous sodium sulfate. After
filtration, the solvent was evaporated under reduced pressure, and
the residue was purified by silica gel chromatography
(chloroform:methanol=50:1-40:1) to give methyl
14-cyclohexyl-6-methyl-5,6,7,8-tetrahydrobenzo[6,7][1,4]diazocino[8,1-a]i-
ndole-11-carboxylate (73 mg, yield 100%).
[1977] .sup.1H-NMR(300 MHz, CDCl.sub.3): .delta.(ppm) 8.06 (1H, s),
7.88 (1H, d, J=8.4 Hz), 7.81 (1H, t, J=4.2 Hz), 7.52-7.30 (4H, m),
4.31 (1H, dd, J=15.4, 5.5 Hz), 4.03-3.92 (1H, m), 3.95 (3H, s),
3.72 (1H, dd, J=15.6, 10.1 Hz), 3.61 (1H, d, J=13.2 Hz), 3.22 (1H,
dd, J=13.2, 5.9 Hz), 3.04 (1H, d, J=13.6 Hz), 2.72-2.62 (1H, m),
2.51 (3H, s), 2.10-1.81 (3H, m), 1.80-1.55 (5H, m), 1.40-1.10 (2H,
m).
Step 7: Production of
14-cyclohexyl-6-methyl-5,6,7,8-tetrahydrobenzo[6,7][1,4]diazocino[8,1-a]i-
ndole-11-carboxylic acid monohydrochloride (Example 11-1)
[1978] ##STR544##
[1979] To a solution of methyl
14-cyclohexyl-6-methyl-5,6,7,8-tetrahydrobenzo[6,7][1,4]diazocino[8,1-a]i-
ndole-11-carboxylate (73 mg, 0.18 mmol) in tetrahydrofuran (1 ml)
and methanol (1 ml) solution was added 4N aqueous sodium hydroxide
solution (1 ml), and the mixture was stirred at room temperature
for 3 hr. 2N Hydrochloric acid was added to the reaction mixture,
and the mixture was extracted with ethyl acetate and dried over
anhydrous sodium carbonate. After filtration, the solvent was
evaporated under reduced pressure, and the residue was purified by
silica gel chromatography (chloroform:methanol=30:1-10:1) to give
14-cyclohexyl-6-methyl-5,6,7,8-tetrahydrobenzo[6,7][1,4]diazocino[8,1-a]i-
ndole-11-carboxylic acid. To a solution of the obtained
14-cyclohexyl-6-methyl-5,6,7,8-tetrahydrobenzo[6,7][1,4]diazocino[8,1-a]i-
ndole-11-carboxylic acid in ethyl acetate was added 4N HCl-ethyl
acetate solution (2 ml), and the mixture was concentrated under
reduced pressure. A mixed solvent of ethyl acetate:hexane (1:1) was
added to the residue. The precipitated solid was collected by
filtration and dried in vacuo to give
14-cyclohexyl-6-methyl-5,6,7,8-tetrahydrobenzo[6,7][1,4]diazocino[8,-
1-a]indole-11-carboxylic acid hydrochloride (25 mg, yield
32.9%).
[1980] .sup.1H-NMR(400 MHz, DMSO-d.sub.6): .delta.(ppm) 12.69 (1H,
brs), 10.68 (1H, brs), 8.21 (1H, s), 7.96-7.90 (2H, m), 7.93 (2H,
d, J=8.8 Hz), 7.73 (1H, dd, J=8.6, 1.2 Hz), 7.67-7.60 (2H, m),
7.49-7.42 (1H, m), 4.79 (1H, d, J=13.0 Hz), 4.40 (1H, d, J=13.0
Hz), 3.73-3.62 (3H, m), 3.47-3.30 (1H, m), 2.98 (3H, s), 2.68-2.55
(1H, m), 2.01-1.75 (4H, m), 1.72-1.52 (3H, m), 1.40-1.05 (3H,
m).
[1981] MS 389.2(M+1).
Example 12-1
Production of
12-cyclohexyl-6,7-dihydro-5-thia-7a-azadibenzo[a,e]azulene-9-carboxylic
acid
Step 1: Production of
2-[2-(2-bromophenylsulfanyl)ethoxy]tetrahydropyran
[1982] ##STR545##
[1983] To a solution of 2-bromobenzenethiol (3.0 ml, 24.9 mmol) in
N,N-dimethylformamide (50 ml) was added sodium hydride (60% in oil,
1.10 g, 27.5 mmol) under ice-cooling, and the mixture was stirred
for 1 hr. To this reaction mixture was added
2-(2-bromoethoxy)tetrahydropyran (4.5 ml, 29.7 mmol) under
ice-cooling, and the mixture was stirred at room temperature for 3
hr. Aqueous sodium carbonate solution was added to the reaction
mixture and the mixture was extracted with ethyl acetate. The
organic layer was successively washed with water and saturated
brine and dried over anhydrous sodium sulfate. After filtration,
the solvent was evaporated under reduced pressure, and the residue
was purified by silica gel chromatography (hexane:ethyl
acetate=10:1) to give
2-[2-(2-bromophenylsulfanyl)ethoxy]tetrahydropyran (7.91 g, yield
100%).
[1984] .sup.1H-NMR(400 MHz, CDCl.sub.3): .delta.(ppm) 7.55 (1H, dd,
J=8.1, 1.2 Hz), 7.36 (1H, dd, J=8.1, 1.6 Hz), 7.29-7.25 (1H, m),
7.03 (1H, dt, J=1.4, 7.7 Hz), 4.65 (1H, t, J=3.5 Hz), 4.00-3.94
(1H, m), 3.91-3.85 (1H, m), 3.70 (1H, dt, J=12.8, 5.3 Hz),
3.54-3.49 (1H, m), 3.20 (2H, dt, J=2.0, 6.8 Hz), 1.83-1.69 (2H, m),
1.63-1.50 (4H, m).
Step 2: Production of methyl
3-cyclohexyl-2-{2-[2-(tetrahydropyran-2-yloxy)ethylsulfanyl]phenyl}-1H-in-
dole-6-carboxylate
[1985] ##STR546##
[1986] To a suspension of
2-[2-(2-bromophenylsulfanyl)ethoxy]tetrahydropyran (1.00 g, 3.2
mmol), sodium hydrogen carbonate (1.10 g, 13.2 mmol) and
tetrakis(triphenylphosphine)palladium (363 mg, 0.310 mmol) in
1,2-dimethoxyethane (10 ml) and water (5 ml) was added methyl
3-cyclohexyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole-6--
carboxylate (1.45 g, 3.78 mmol) with heating under reflux and the
mixture was heated under reflux for 2.5 hr. The reaction mixture
was allowed to cool to room temperature, water was added to the
reaction mixture and the mixture was extracted with ethyl acetate.
The organic layer was successively washed with water and saturated
brine and dried over anhydrous sodium sulfate. After filtration,
the solvent was evaporated under reduced pressure, and the residue
was purified by silica gel chromatography (hexane:ethyl
acetate=5:1-3:1) to give methyl
3-cyclohexyl-2-{2-[2-(tetrahydropyran-2-yloxy)ethylsulfanyl]phenyl}-1H-in-
dole-6-carboxylate (1.38 g, yield 74.5%).
[1987] .sup.1H-NMR(300 MHz, CDCl.sub.3): .delta.(ppm) 8.86 (1H, s),
8.11 (1H, d, J=0.7 Hz), 7.82 (1H, d, J=8.4 Hz), 7.76 (1H, dd,
J=8.4, 0.7 Hz), 7.54 (1H, d, J=7.7 Hz), 7.41-7.25 (3H, m), 4.50
(1H, t, J=3.9 Hz), 4.12 (1H, q, J=7.1 Hz), 3.93 (3H, s), 3.84 (1H,
tt, J=11.6, 4.7 Hz), 3.61 (1H, dt, J=11.6, 5.3 Hz), 3.44 (1H, q,
J=5.5 Hz), 3.05 (1H, dt, J=5.9, 5.8 Hz), 2.96 (1H, dt, J=6.1, 6.2
Hz), 2.69-2.59 (1H, m), 1.98-1.69 (7H, m), 1.68-1.40 (7H, m),
1.38-1.22 (2H, m).
Step 3: Production of methyl
3-cyclohexyl-2-[2-(2-hydroxyethylsulfanyl)phenyl]-1H-indole-6-carboxylate
[1988] ##STR547##
[1989] To a solution of methyl
3-cyclohexyl-2-{2-[2-(tetrahydropyran-2-yloxy)ethylsulfanyl]phenyl}-1H-in-
dole-6-carboxylate (1.38 g, 2.81 mmol) in tetrahydrofuran (4 ml)
and methanol (4 ml) was added 6N hydrochloric acid (4 ml), and the
mixture was stirred at room temperature for 30 min. Water was added
to the reaction mixture and the mixture was extracted with ethyl
acetate. The organic layer was successively washed with water,
saturated aqueous sodium hydrogen carbonate solution and saturated
brine and dried over anhydrous sodium sulfate. After filtration,
the solvent was evaporated under reduced pressure, and the residue
was purified by silica gel chromatography (hexane:ethyl
acetate=2:1-1:1) to give methyl
3-cyclohexyl-2-[2-(2-hydroxyethylsulfanyl)phenyl]-1H-indole-6-carboxylate
(1.00 g, yield 87.5%).
Step 4: Production of methyl
3-cyclohexyl-2-[2-(2-methanesulfonyloxyethylsulfanyl)phenyl]-1H-indole-6--
carboxylate
[1990] ##STR548##
[1991] To a solution of methyl
3-cyclohexyl-2-[2-(2-hydroxyethylsulfanyl)phenyl]-1H-indole-6-carboxylate
(500 mg, 1.22 mmol) and triethylamine (0.19 ml, 1.4 mmol) in
chloroform (5 ml) was added dropwise methanesulfonyl chloride (0.10
ml, 1.3 mmol) under ice-cooling, and the mixture was stirred for 30
min. Water was added to the reaction mixture and the mixture was
extracted with chloroform. The organic layer was successively
washed with water and saturated brine and dried over anhydrous
sodium sulfate. After filtration, the solvent was evaporated under
reduced pressure to give methyl
3-cyclohexyl-2-[2-(2-methanesulfonyloxyethylsulfanyl)phenyl]-1H-in-
dole-6-carboxylate as a crude product. The obtained crude product
was used for Step 5 without purification.
Step 5: Production of methyl
12-cyclohexyl-6,7-dihydro-5-thia-7a-azadibenzo[a,e]azulene-9-carboxylate
(Example 12-3)
[1992] ##STR549##
[1993] To a solution of methyl
3-cyclohexyl-2-[2-(2-methanesulfonyloxyethylsulfanyl)phenyl]-1H-indole-6--
carboxylate obtained as a crude product in Step 4 in
N,N-dimethylformamide (10 ml) was added sodium hydride (60% in oil,
53 mg, 1.3 mmol) under ice-cooling, and the mixture was stirred for
30 min. 2N Hydrochloric acid was added to the reaction mixture, and
the mixture was extracted with ethyl acetate. The organic layer was
successively washed with water and saturated brine and dried over
anhydrous sodium sulfate. After filtration, the solvent was
evaporated under reduced pressure, and the residue was purified by
silica gel chromatography (hexane:ethyl acetate=30:1-10:1) to give
methyl
12-cyclohexyl-6,7-dihydro-5-thia-7a-azadibenzo[a,e]azulene-9-carboxylate
(186 mg, yield 39.0%).
[1994] .sup.1H-NMR(300 MHz, CDCl.sub.3): .delta.(ppm) 8.08 (1H, d,
J=1.1 Hz), 7.90 (1H, d, J=8.4 Hz), 7.77 (1H, dd, J=8.4, 1.5 Hz),
7.72 (1H, dd, J=7.3, 1.1 Hz), 7.52-7.37 (3H, m), 4.70 (1H, dd,
J=15.0, 4.8 Hz), 3.95 (3H, s), 3.92-3.88 (1H, m), 3.47 (1H, dd,
J=11.7, 3.3 Hz), 3.28 (1H, dt, J=5.5, 12.5 Hz), 2.89-2.80 (1H, m),
2.06-1.95 (4H, m), 1.75-1.71 (3H, m), 1.35-1.28 (3H, m).
[1995] MS 392.1(M+1).
Step 6: Production of
12-cyclohexyl-6,7-dihydro-5-thia-7a-azadibenzo[a,e]azulene-9-carboxylate
(Example 12-1)
[1996] ##STR550##
[1997] To a solution of methyl
12-cyclohexyl-6,7-dihydro-5-thia-7a-azadibenzo[a,e]azulene-9-carboxylate
(186 mg, 0.470 mmol) in tetrahydrofuran (2 ml) and methanol (2 ml)
was added 4N aqueous sodium hydroxide solution (2 ml), and the
mixture was stirred at room temperature for 13 hr. 2N hydrochloric
acid and water were added to the reaction mixture. The precipitated
solid was collected by filtration and dried in vacuo to give
12-cyclohexyl-6,7-dihydro-5-thia-7a-azadibenzo[a,e]azulene-9-carboxylic
acid (157 mg, yield 87.7%).
[1998] .sup.1H-NMR(300 MHz, DMSO-d.sub.6): .delta.(ppm) 12.57 (1H,
brs), 8.18 (1H, d, J=1.1 Hz), 7.89 (1H, d, J=8.4 Hz), 7.73-7.70
(1H, m), 7.65 (1H, dd, J=8.4, 1.5 Hz), 7.59 (1H, d, J=4.4 Hz),
7.49-7.47 (2H, m), 4.93 (1H, dd, J=15.0, 4.8 Hz), 3.80-3.70 (1H,
m), 3.44 (1H, dd, J=12.1, 3.7 Hz), 3.36-3.28 (1H, m), 2.76-2.73
(1H, m), 1.99-1.89 (4H, m), 1.78-1.71 (2H, m), 1.49-1.24 (4H,
m).
[1999] MS 378.1(M+1).
Example 12-2
Production of
11-cyclohexyl-5-thia-6a-azabenzo[a]fluorene-8-carboxylic acid
Step 1: Production of methyl
2-bromo-3-cyclohexyl-1-phenylsulfanylmethyl-1H-indole-6-carboxylate
[2000] ##STR551##
[2001] To a solution of methyl
2-bromo-3-cyclohexyl-1H-indole-6-carboxylate (1.00 g, 2.97 mmol) in
N,N-dimethylformamide (10 ml) was added sodium hydride (60% in oil,
139 mg, 3.47 mmol) under ice-cooling, and the mixture was stirred
for 1 hr. To this reaction mixture was added
chloromethylsulfanylbenzene (0.38 ml, 2.94 mmol) under ice-cooling,
and the mixture was stirred at room temperature for 1.5 hr. Water
was added to the reaction mixture and the mixture was extracted
with ethyl acetate. The organic layer was washed with saturated
brine and dried over anhydrous sodium sulfate. After filtration,
the solvent was evaporated under reduced pressure, and the residue
was purified by silica gel chromatography (hexane:ethyl
acetate=20:1-7:1) to give methyl
2-bromo-3-cyclohexyl-1-phenylsulfanylmethyl-1H-indole-6-carboxylate
(1.10 g, yield 84.0%).
[2002] .sup.1H-NMR(300 MHz, CDCl.sub.3): .delta.(ppm) 7.79(1H,
brs), 7.74(1H, dd, J=8.4, 1.6 Hz), 7.69(1H, brd, J=8.4 Hz),
7.23-7.29(1H, m), 7.21(2H, brd, J=6.8 Hz), 7.16(2H, dd, J=8.4, 7.6
Hz), 5.52(2H, s), 3.92(3H, s), 2.75-2.85(1H, m), 1.95-1.83 (4H, m),
1.82-1.71 (3H, m), 1.48-1.30 (3H, m).
Step 2: Production of methyl
11-cyclohexyl-5-thia-6a-azabenzo[a]fluorene-8-carboxylate (Example
12-4)
[2003] ##STR552##
[2004] A suspension of methyl
2-bromo-3-cyclohexyl-1-phenylsulfanylmethyl-1H-indole-6-carboxylate
(1.10 g, 2.41 mmol), potassium acetate (260 mg, 2.64 mmol) and
tetrakis(triphenylphosphine)palladium (279 mg, 0.24 mmol) in
N,N-dimethylacetamide (30 ml) was stirred at 100.degree. C. for 3
hr. The reaction mixture was allowed to cool to room temperature,
2N hydrochloric acid was added to the reaction mixture, and the
mixture was extracted with ethyl acetate. The organic layer was
successively washed with water and saturated brine and dried over
anhydrous sodium sulfate. After filtration, the solvent was
evaporated under reduced pressure, and the residue was purified by
silica gel chromatography (hexane:ethyl acetate=20:1-7:1) to give
methyl 11-cyclohexyl-5-thia-6a-azabenzo[a]fluorene-8-carboxylate
(100 mg, yield 11.0%).
[2005] .sup.1H-NMR(300 MHz, CDCl.sub.3): .delta.(ppm) 8.08 (1H, d,
J=0.7 Hz), 7.91 (1H, d, J=8.4 Hz), 7.75 (1H, dd, J=8.8, 1.5 Hz),
7.65 (1H, dd, J=7.7, 1.5 Hz), 7.52 (1H, dd, J=7.5, 1.3 Hz), 7.37
(1H, dt, J=1.6, 7.6 Hz), 7.29 (1H, dt, J=1.6, 7.5 Hz), 5.22 (2H,
s), 3.95 (3H, s), 3.19 (1H, t, J=12.3 Hz), 2.12-2.05 (2H, m),
1.90-1.85 (5H, m), 1.44-1.41 (3H, m).
Step 3: Production of
11-cyclohexyl-5-thia-6a-azabenzo[a]fluorene-8-carboxylic acid
(Example 12-2)
[2006] ##STR553##
[2007] To a solution of methyl
11-cyclohexyl-5-thia-6a-azabenzo[a]fluorene-8-carboxylate (100 mg,
0.26 mmol) in tetrahydrofuran (2 ml) and methanol (2 ml) was added
4N aqueous sodium hydroxide solution (2 ml), and the mixture was
stirred at room temperature for 15 hr. 2N Hydrochloric acid was
added to the reaction mixture, and the mixture was extracted with
ethyl acetate. The organic layer was successively washed with water
and saturated brine and dried over anhydrous sodium sulfate. After
filtration, the solvent was evaporated under reduced pressure, and
the residue was purified by silica gel chromatography (hexane:ethyl
acetate=2:1-1:1) to give
11-cyclohexyl-5-thia-6a-azabenzo[a]fluorene-8-carboxylic acid (32
mg, yield 33.3%).
[2008] .sup.1H-NMR(300 MHz, DMSO-d.sub.6): .delta.(ppm) 12.62 (1H,
brs), 8.23 (1H, d, J=1.1 Hz), 7.94 (1H, d, J=8.4 Hz), 7.64-7.61
(3H, m), 7.47 (1H, td, J=7.6, 1.2 Hz), 7.40-7.35 (1H, m), 5.53 (2H,
s), 3.13 (1H, t, J=11.7 Hz), 2.12-2.08 (2H, m), 1.82-1.76 (5H, m),
1.42-1.38 (3H, m).
[2009] MS 364.0(M+1).
Example 11-2 (2)
Production of methyl
6-tert-butoxycarbonyl-14-cyclohexyl-5,6,7,8-tetrahydrobenzo[6,7][1,4]diaz-
ocino[8,1-a]indole-11-carboxylate
Step 1: Production of methyl
2-bromo-3-cyclohexyl-1-[2-(tetrahydropyran-2-yloxy)ethyl]-1H-indole-6-car-
boxylate
[2010] ##STR554##
[2011] To a solution of methyl
2-bromo-3-cyclohexyl-1H-indole-6-carboxylate (5.00 g, 14.8 mmol) in
N,N-dimethylformamide (50 ml) was added sodium hydride (60% in oil,
713 mg, 17.8 mmol) under ice-cooling, and the mixture was stirred
under ice-cooling for 1 hr. 2-(2-Bromoethoxy)tetrahydropyran (2.90
ml, 19.2 mmol) was added to the reaction mixture under ice-cooling,
and the mixture was stirred at room temperature for 4 hr. Water was
added to the reaction mixture and the mixture was extracted with
ethyl acetate. The organic layer was successively washed with water
and saturated brine and dried over anhydrous sodium sulfate. After
filtration, the solvent was evaporated under reduced pressure to
give methyl
2-bromo-3-cyclohexyl-1-[2-(tetrahydropyran-2-yloxy)ethyl]-1H-indole-6-car-
boxylate as a crude product. The obtained crude product was used
for Step 2 without purification.
Step 2: Production of methyl
2-bromo-3-cyclohexyl-1-(2-hydroxyethyl)-1H-indole-6-carboxylate
[2012] ##STR555##
[2013] To a solution of methyl
2-bromo-3-cyclohexyl-1-[2-(tetrahydropyran-2-yloxy)ethyl]-1H-indole-6-car-
boxylate obtained as a crude product in Step 1 in tetrahydropyran
(30 ml) and methanol (30 ml) was added 6N hydrochloric acid (30
ml), and the mixture was stirred at room temperature for 3 hr.
Water was added to the reaction mixture and the mixture was
extracted with ethyl acetate. The organic layer was washed with
saturated brine and dried over anhydrous sodium sulfate. After
filtration, the solvent was evaporated under reduced pressure, and
the residue was purified by silica gel chromatography (hexane:ethyl
acetate=4:1-1:1) to give methyl
2-bromo-3-cyclohexyl-1-(2-hydroxyethyl)-1H-indole-6-carboxylate
(3.43 g, yield 61%).
[2014] .sup.1H-NMR(400 MHz, CDCl.sub.3): .delta.(ppm) 8.12 (1H, s),
7.79-7.71 (2H, m), 4.43 (2H, t, J=5.8 Hz), 3.99 (2H, t, J=5.6 Hz),
3.94 (3H, s), 2.95-2.84 (1H, m), 1.99-1.76 (7H, m), 1.51-1.33 (3H,
m).
Step 3: Production of methyl
2-bromo-3-cyclohexyl-1-(2-methanesulfonyloxyethyl)-1H-indole-6-carboxylat-
e
[2015] ##STR556##
[2016] To a solution of methyl
2-bromo-3-cyclohexyl-1-(2-hydroxyethyl)-1H-indole-6-carboxylate
(3.43 g, 9.01 mmol) in chloroform (30 ml) were added triethylamine
(1.40 ml, 10.0 mmol) and methanesulfonyl chloride (0.77 ml, 9.90
mmol) under ice-cooling, and the mixture was stirred under
ice-cooling for 30 min. Water was added to the reaction mixture and
the mixture was extracted with chloroform. The organic layer was
successively washed with 1N hydrochloric acid, saturated aqueous
sodium hydrogen carbonate solution and saturated brine and dried
over anhydrous sodium sulfate. After filtration, the solvent was
evaporated under reduced pressure to give methyl
2-bromo-3-cyclohexyl-1-(2-methanesulfonyloxyethyl)-1H-indole-6-car-
boxylate as a crude product. The obtained crude product was used
for Step 4 without purification.
Step 4: Production of methyl
2-bromo-3-cyclohexyl-1-[2-(1,3-dioxo-1,3-dihydroisoindol-2-yl)ethyl]-1H-i-
ndole-6-carboxylate
[2017] ##STR557##
[2018] To a solution of methyl
2-bromo-3-cyclohexyl-1-(2-methanesulfonyloxyethyl)-1H-indole-6-carboxylat-
e obtained as a crude product in Step 3 in N,N-dimethylformamide
(40 ml) were added potassium phthalimide (2.50 g, 13.4 mmol) and
potassium carbonate (2.50 g, 18.0 mmol), and the mixture was
stirred at 80.degree. C. for 7 hr. Water was added to the reaction
mixture, and the mixture was stirred at room temperature for 1 hr.
The precipitated solid was collected by filtration and dried in
vacuo to give methyl
2-bromo-3-cyclohexyl-1-[2-(1,3-dioxo-1,3-dihydroisoindol-2-yl)ethyl]-1H-i-
ndole-6-carboxylate (3.96 g, yield 86%).
[2019] .sup.1H-NMR(400 MHz, CDCl.sub.3): .delta.(ppm) 8.02 (1H, s),
7.75 (1H, d, J=2.8 Hz), 7.74 (1H, d, J=2.8 Hz), 7.68-7.65 (4H, m),
4.54 (2H, t, J=6.0 Hz), 4.04 (2H, t, J=6.0 Hz), 3.91 (3H, s), 2.82
(1H, brt, J=12.1 Hz), 1.95-1.72 (7H, m), 1.46-1.30 (3H, m).
Step 5: Production of methyl
1-(2-aminoethyl)-2-bromo-3-cyclohexyl-1H-indole-6-carboxylate
[2020] ##STR558##
[2021] To a suspension of methyl
2-bromo-3-cyclohexyl-1-[2-(1,3-dioxo-1,3-dihydroisoindol-2-yl)ethyl]-1H-i-
ndole-6-carboxylate (3.96 g, 7.78 mmol) in methanol (50 ml) and
tetrahydrofuran (30 ml) was added hydrazine monohydrate (1.88 ml,
38.7 mmol), and the mixture was stirred at room temperature for 14
hr. The reaction mixture was filtered with celite and washed with
ethyl acetate. The solvent was evaporated under reduced pressure,
and the residue was purified by silica gel column chromatography
(chloroform:methanol=30:1-15:1) to give methyl
1-(2-aminoethyl)-2-bromo-3-cyclohexyl-1H-indole-6-carboxylate (2.95
g, yield 100%).
[2022] .sup.1H-NMR(400 MHz, CDCl.sub.3): .delta.(ppm) 8.07 (1H,
brs), 7.77-7.73 (2H, m), 4.30 (2H, t, J=6.5 Hz), 3.94 (3H, s), 3.10
(2H, t, J=6.7 Hz), 2.89 (1H, brt, J=12.3 Hz), 2.00-1.75 (7H, m),
1.50-1.30 (4H, m).
Step 6: Production of methyl
2-bromo-1-(2-tert-butoxycarbonylaminoethyl)-3-cyclohexyl-1H-indole-6-carb-
oxylate
[2023] ##STR559##
[2024] To a solution of methyl
1-(2-aminoethyl)-2-bromo-3-cyclohexyl-1H-indole-6-carboxylate (2.95
g, 7.78 mmol) in ethyl acetate (30 ml) and saturated aqueous sodium
hydrogen carbonate solution (10 ml) was added di-tert-butyl
dicarbonate (2.10 g, 9.62 mmol), and the mixture was stirred at
room temperature for 3 hr. Water was added to the reaction mixture
and the mixture was extracted with ethyl acetate. The organic layer
was washed with saturated brine and dried over anhydrous sodium
sulfate. After filtration, the solvent was evaporated under reduced
pressure, and the residue was purified by silica gel column
chromatography (hexane:ethyl acetate=8:1-3:1) to give methyl
2-bromo-1-(2-tert-butoxycarbonylaminoethyl)-3-cyclohexyl-1H-indole-6-carb-
oxylate (2.78 g, yield 74%).
[2025] .sup.1H-NMR(400 MHz, CDCl.sub.3): .delta.(ppm) 8.04 (1H, s),
7.76 (2H, brs), 4.58 (1H, brs), 4.39 (2H, t, J=6.0 Hz), 3.93 (3H,
s), 3.51 (2H, q, J=6.0 Hz), 2.92-2.86 (1H, m), 2.00-1.76 (7H, m),
1.50-1.32 (3H, m), 1.42 (9H, s).
Step 7: Production of methyl
1-(2-tert-butoxycarbonylaminoethyl)-3-cyclohexyl-2-(2-formylphenyl)-1H-in-
dole-6-carboxylate
[2026] ##STR560##
[2027] To a suspension of methyl
2-bromo-1-(2-tert-butoxycarbonylaminoethyl)-3-cyclohexyl-1H-indole-6-carb-
oxylate (500 mg, 1.04 mmol), 2-formylphenylbononic acid (187 mg,
1.24 mmol) and sodium hydrogen carbonate (345 mg, 4.15 mmol) in
1,2-dimethoxyethane (5 ml) and water (2.5 ml) was added
tetrakis(triphenylphosphine)palladium (60.0 mg, 0.05 mmol), and the
mixture was stirred at 90.degree. C. for 2 hr. Water was added to
the reaction mixture and the mixture was extracted with ethyl
acetate. The organic layer was successively washed with water and
saturated brine and dried over anhydrous sodium sulfate. After
filtration, the solvent was evaporated under reduced pressure, and
the residue was purified by silica gel chromatography (hexane:ethyl
acetate=5:1-3:1) to give methyl
1-(2-tert-butoxycarbonylaminoethyl)-3-cyclohexyl-2-(2-formylphenyl)-1H-in-
dole-6-carboxylate (450 mg, yield 85%).
[2028] .sup.1H-NMR(400 MHz, CDCl.sub.3): .delta.(ppm) 9.79 (1H,
brs), 8.15 (1H, brs), 8.11 (1H, dd, J=7.7, 1.2 Hz), 7.84 (2H, brs),
7.75 (1H, t, J=7.2 Hz), 7.67 (1H, t, J=7.4 Hz), 7.46 (1H, d, J=7.4
Hz), 4.38 (1H, brs), 4.16-4.10 (2H, m), 3.96 (3H, s), 3.27 (2H, t,
J=5.8 Hz), 2.49-2.36 (1H, m), 1.85-1.60 (7H, m), 1.31 (9H, s),
1.26-1.10 (3H, m).
Step 8: Production of methyl
1-(2-tert-butoxycarbonylaminoethyl)-3-cyclohexyl-2-(2-hydroxymethylphenyl-
)-1H-indole-6-carboxylate
[2029] ##STR561##
[2030] To a solution of methyl
1-(2-tert-butoxycarbonylaminoethyl)-3-cyclohexyl-2-(2-formylphenyl)-1H-in-
dole-6-carboxylate (450 mg, 0.89 mmol) in methanol (4 ml) was added
borosodium hydride (50.0 mg, 1.32 mmol) under ice-cooling, and the
mixture was stirred under ice-cooling for 1 hr. 1N Hydrochloric
acid was added to the reaction mixture, and the mixture was
extracted with ethyl acetate. The organic layer was washed with
saturated brine and dried over anhydrous sodium sulfate. After
filtration, the solvent was evaporated under reduced pressure to
give methyl
1-(2-tert-butoxycarbonylaminoethyl)-3-cyclohexyl-2-(2-hydroxymethylphenyl-
)-1H-indole-6-carboxylate (440 mg, yield 97%).
[2031] .sup.1H-NMR(400 MHz, CDCl.sub.3): .delta.(ppm) 8.11 (1H,
brs), 7.81 (2H, brs), 7.72 (1H, d, J=7.9 Hz), 7.53 (1H, t, J=7.7
Hz), 7.40 (1H, t, J=7.7 Hz), 7.23 (1H, d, J=7.9 Hz), 4.63 (1H,
brs), 4.53 (2H, s), 4.03 (2H, t, J=6.0 Hz), 3.96 (3H, s), 3.30 (1H,
q, J=6.0 Hz), 2.41-2.30 (1H, m), 1.88-1.55 (7H, m), 1.29-1.10 (3H,
m), 1.29 (9H, s).
Step 9: Production of methyl
1-(2-tert-butoxycarbonylaminoethyl)-3-cyclohexyl-2-(2-methanesulfonyloxym-
ethylphenyl)-1H-indole-6-carboxylate
[2032] ##STR562##
[2033] To a solution of methyl
1-(2-tert-butoxycarbonylaminoethyl)-3-cyclohexyl-2-(2-hydroxymethylphenyl-
)-1H-indole-6-carboxylate (100 mg, 0.19 mmol) in chloroform (2 ml)
was added triethylamine (0.04 ml, 0.28 mmol) and methanesulfonyl
chloride (0.02 ml, 0.25 mmol) under ice-cooling, and the mixture
was stirred under ice-cooling for 10 min. Water was added to the
reaction mixture and the mixture was extracted with chloroform. The
organic layer was successively washed with 1N hydrochloric acid,
saturated aqueous sodium hydrogen carbonate solution and saturated
brine and dried over anhydrous sodium sulfate. After filtration,
the solvent was evaporated under reduced pressure to give methyl
1-(2-tert-butoxycarbonylaminoethyl)-3-cyclohexyl-2-(2-methanesulfonyloxym-
ethylphenyl)-1H-indole-6-carboxylate as a crude product. The
obtained crude product was used for Step 10 without
purification.
Step 10: Production of methyl
6-tert-butoxycarbonyl-14-cyclohexyl-5,6,7,8-tetrahydrobenzo[6,7][1,4]diaz-
ocino[8,1-a]indole-11-carboxylate (Example 11-2)
[2034] ##STR563##
[2035] To a solution of methyl
1-(2-tert-butoxycarbonylaminoethyl)-3-cyclohexyl-2-(2-methanesulfonyloxym-
ethylphenyl)-1H-indole-6-carboxylate obtained as a crude product in
Step 9 in N,N-dimethylformamide (5 ml) was added sodium hydride
(60% in oil, 12 mg, 0.30 mmol) under ice-cooling, and the mixture
was stirred at room temperature for 1.5 hr. 1N Hydrochloric acid
was added to the reaction mixture, and the mixture was stirred at
room temperature for 1 hr. The precipitated solid was collected by
filtration and dried in vacuo to give methyl
6-tert-butoxycarbonyl-14-cyclohexyl-5,6,7,8-tetrahydrobenzo[6,7][1-
,4]diazocino[8,1-a]indole-11-carboxylate (92 mg, yield 100%).
[2036] .sup.1H-NMR(400 MHz, CDCl.sub.3): .delta.(ppm) 8.08 (0.5H,
s), 8.07 (0.5H, s), 7.90-7.78 (3H, m), 7.53-7.34 (3H, m), 4.98
(0.5H, d, J=14.8 Hz), 4.90 (0.5H, d, J=14.4 Hz), 4.66 (0.5H, dd,
J=14.6, 4.9 Hz), 4.50 (1H, dd, J=19.5, 8.3 Hz), 4.31 (0.5H, d,
J=14.4 Hz), 3.97 (3H, s), 3.75-3.67 (1H, m), 3.43 (0.5H, d, J=14.8
Hz), 3.29 (0.5H, d, J=14.8 Hz), 3.26 (0.5H, d, J=9.3 Hz), 3.03-2.97
(0.5H, m), 2.75-2.57 (1H, m), 2.03-1.72 (4H, m), 1.77-1.74 (2H, m),
1.60 (4.5H, s), 1.41 (4.5H, s), 1.35-1.18 (4H, m).
[2037] MS 489.0(M+1).
[2038] The compounds of Examples 1-446 to 1-472 and Examples 2-54
to 2-150 were produced by the same methods as in the
above-mentioned Examples, particularly, Examples 2-57, 2-175,
2-180, 2-332, 2-346, 2-349, 2-350, 2-369 and 2-381 or methods
similar thereto, and where necessary, by employing other
conventional methods. The chemical structural formulas are shown in
Tables 119-144.
[2039] The compounds of Examples 1-473 to 1-623, Examples 2-151 to
2-556, Examples 5-6 and 5-7, Examples 7-9 and 7-10, Examples 8-8
and 8-9 and Examples 11-4 to 11-8 were produced by the same methods
as in the above-mentioned Examples or methods similar thereto, and
where necessary, by employing other conventional methods. The
chemical structural formulas are shown in Tables 145-268. [2040]
2-[13-cyclohexyl-10-(2H-tetrazol-5-yl)-6,7-dihydrobenzo[5,6][1,4]diazepin-
o[7,1-a]indol-5-yl]-1-(4-ethylpiperazin-1-yl)ethanone (Example
1-96) [2041]
13-cyclohexyl-5-[2-(4-ethoxycarbonylpiperazin-1-yl)ethyl]-6,7-dih-
ydro-5H-benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid
dihydrochloride (Example 1-97) [2042]
5-[2-(4-acetylpiperazin-1-yl)ethyl]-13-cyclohexyl-6,7-dihydro-5H-benzo[5,-
6][1,4]diazepino[7,1-a]indole-10-carboxylic acid dihydrochloride
(Example 1-98) [2043]
13-cyclohexyl-5-(2-dimethylaminoethyl)-6,7-dihydro-5H-benzo[5,6][1,4]diaz-
epino[7,1-a]indole-10-carboxylic acid dihydrochloride (Example
1-99) [2044]
13-cyclohexyl-3-[2-(morpholin-4-yl)-5-(2-oxopyrrolidin-1-yl)benzy-
loxy]-6,7-dihydro-5H-benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic
acid dihydrochloride (Example 1-100) [2045]
13-cyclohexyl-3-[5-methanesulfonyl-2-(morpholin-4-yl)benzyloxy]-6,7-dihyd-
ro-5H-benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid
dihydrochloride (Example 1-101) [2046]
N-acetyl-13-cyclohexyl-5-[2-(4-ethylpiperazin-1-yl)-2-oxoethyl]-6,7-dihyd-
ro-5H-benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxamide (Example
1-102) [2047]
13-cyclohexyl-3-[5-methanesulfonyl-2-(morpholin-4-yl)benzyloxy]--
5-methyl-6,7-dihydro-5H-benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxyli-
c acid dihydrochloride (Example 1-103) [2048]
13-cyclohexyl-5-[2-(4-methoxycarbonylpiperazin-1-yl)ethyl]-6,7-dihydro-5H-
-benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid
dihydrochloride (Example 1-104) [2049]
13-cyclohexyl-5-[3-(tetrahydropyran-2-yloxy)propyl]-6,7-dihydro-5H-benzo[-
5,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid (Example 1-105)
[2050]
13-cyclohexyl-5-[2-(3-hydroxypiperidin-1-yl)-2-oxoethyl]-6,7-dihydro-5H--
benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid
monohydrochloride (Example 1-106) [2051]
13-cyclohexyl-3-fluoro-5-[2-(morpholin-4-yl)ethyl]-6,7-dihydro-5H-benzo[5-
,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid dihydrochloride
(Example 1-107) [2052]
13-cyclohexyl-3-methyl-5-[2-(piperidin-1-yl)ethyl]-6,7-dihydro-5H-benzo[5-
,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid dihydrochloride
(Example 1-108) [2053]
13-cyclohexyl-3-fluoro-5-[2-(morpholin-4-yl)-2-oxoethyl]-6,7-dihydro-5H-b-
enzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid
monohydrochloride (Example 1-109) [2054]
13-cyclohexyl-5-[2-(4-ethylpiperazin-1-yl)ethyl]-3-methyl-6,7-dihydro-5H--
benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid
trihydrochloride (Example 1-110) [2055]
13-cyclohexyl-5-[3-(piperidin-1-yl)propyl]-6,7-dihydro-5H-benzo[5,6][1,4]-
diazepino[7,1-a]indole-10-carboxylic acid dihydrochloride (Example
1-111) [2056]
13-cyclohexyl-5-(3-hydroxypropyl)-6,7-dihydro-5H-benzo[5,6][1,4]d-
iazepino[7,1-a]indole-10-carboxylic acid monohydrochloride (Example
1-112) [2057]
13-cyclohexyl-5-[2-(3-hydroxypiperidin-1-yl)ethyl]-6,7-dihydro-5-
H-benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid
dihydrochloride (Example 1-113) [2058]
13-cyclohexyl-3-fluoro-5-[2-oxo-2-(piperidin-1-yl)ethyl]-6,7-dihydro-5H-b-
enzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid
monohydrochloride (Example 1-114) [2059]
13-cyclohexyl-3-methyl-5-[2-oxo-2-(piperidin-1-yl)ethyl]-6,7-dihydro-5H-b-
enzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid
monohydrochloride (Example 1-115) [2060]
13-cyclohexyl-3-fluoro-5-[2-(piperidin-1-yl)ethyl]-6,7-dihydro-5H-benzo[5-
,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid dihydrochloride
(Example 1-116) [2061]
13-cyclohexyl-5-[2-(4-ethylpiperazin-1-yl)-2-oxoethyl]-3-methyl-6,7-dihyd-
ro-5H-benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid
dihydrochloride (Example 1-117) [2062]
5-(1-acetylpiperidin-4-ylmethyl)-13-cyclohexyl-6,7-dihydro-5H-benzo[5,6][-
1,4]diazepino[7,1-a]indole-10-carboxylic acid monohydrochloride
(Example 1-118) [2063]
13-cyclohexyl-5-[2-(1-isopropylpiperidin-4-yl)ethyl]-6,7-dihydro-5H-benzo-
[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid dihydrochloride
(Example 1-119) [2064]
13-cyclohexyl-5-(tetrahydropyran-4-ylmethyl)-6,7-dihydro-5H-benzo[5,6][1,-
4]diazepino[7,1-a]indole-10-carboxylic acid monohydrochloride
(Example 1-120) [2065]
13-cyclohexyl-2-fluoro-5-[2-(piperidin-1-yl)ethyl]-6,7-dihydro-5H-benzo[5-
,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid dihydrochloride
(Example 1-121) [2066]
13-cyclohexyl-5-[2-(3-methylpiperidin-1-yl)-2-oxoethyl]-6,7-dihydro-5H-be-
nzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid
monohydrochloride (Example 1-122) [2067]
13-cyclohexyl-5-[2-(1-ethylpiperidin-4-ylidene)ethyl]-6,7-dihydro-5H-benz-
o[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid
dihydrochloride (Example 1-123) [2068]
13-cyclohexyl-5-[2-(4-isopropylpiperidin-1-yl)-2-oxoethyl]-6,7-dihydro-5H-
-benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid
monohydrochloride (Example 1-124) [2069]
13-cyclohexyl-5-[2-(3-methoxypiperidin-1-yl)-2-oxoethyl]-6,7-dihydro-5H-b-
enzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid
monohydrochloride (Example 1-125) [2070]
13-cyclohexyl-5-(pyridin-2-ylmethyl)-6,7-dihydro-5H-benzo[5,6][1,4]diazep-
ino[7,1-a]indole-10-carboxylic acid dihydrochloride (Example 1-126)
[2071]
3-chloro-13-cyclohexyl-5-[2-(piperidin-1-yl)ethyl]-6,7-dihydro-5H-
-benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid (Example
1-127) [2072] methyl
3-chloro-13-cyclohexyl-5-[2-(piperidin-1-yl)ethyl]-6,7-dihydro-5H-benzo[5-
,6][1,4]diazepino[7,1-a]indole-10-carboxylate (Example 1-128)
[2073]
N-{13-cyclohexyl-5-[2-(4-ethylpiperazin-1-yl)-2-oxoethyl]-6,7-dihydro-5H--
benzo[5,6][1,4]diazepino[7,1-a]indole-10-carbonyl}propane-1-sulfonamide
dihydrochloride (Example 1-129) [2074]
13-cyclohexyl-5-(1-ethylpiperidin-4-ylmethyl)-6,7-dihydro-5H-benzo[5,6][1-
,4]diazepino[7,1-a]indole-10-carboxylic acid (Example 1-130) [2075]
5-[2-(azocan-1-yl)-2-oxoethyl]-13-cyclohexyl-6,7-dihydro-5H-benzo[5,6][1,-
4]diazepino[7,1-a]indole-10-carboxylic acid (Example 1-131) [2076]
5-[2-(azonan-1-yl)-2-oxoethyl]-13-cyclohexyl-6,7-dihydro-5H-benzo[5,6][1,-
4]diazepino[7,1-a]indole-10-carboxylic acid (Example 1-132) [2077]
13-cyclohexyl-5-(1-ethylpiperidin-4-ylmethyl)-6,7-dihydro-5H-benzo[5,6][1-
,4]diazepino[7,1-a]indole-10-carboxylic acid dihydrochloride
(Example 1-133) [2078]
13-cyclohexyl-5-(pyridin-4-ylmethyl)-6,7-dihydro-5H-benzo[5,6][1,4]diazep-
ino[7,1-a]indole-10-carboxylic acid dihydrochloride (Example 1-134)
[2079]
13-cyclohexyl-5-(pyridin-3-ylmethyl)-6,7-dihydro-5H-benzo[5,6][1,-
4]diazepino[7,1-a]indole-10-carboxylic acid dihydrochloride
(Example 1-135) [2080]
13-cyclohexyl-5-[2-(3,6-dihydro-2H-pyridin-1-yl)-2-oxoethyl]-6,7-dihydro--
5H-benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid
(Example 1-136) [2081]
13-cyclohexyl-5-[2-(2-methylpiperidin-1-yl)-2-oxoethyl]-6,7-dihydro-5H-be-
nzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid (Example
1-137) [2082]
13-cyclohexyl-5-[2-(3,4-dihydro-1H-isoquinolin-2-yl)-2-oxoethyl]--
6,7-dihydro-5H-benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic
acid monohydrochloride (Example 1-138) [2083]
13-cyclohexyl-5-[2-(octahydroquinolin-1-yl)-2-oxoethyl]-6,7-dihydro-5H-be-
nzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid
monohydrochloride (Example 1-139) [2084]
13-cyclohexyl-5-[2-(1,3-dihydroisoindol-2-yl)-2-oxoethyl]-6,7-dihydro-5H--
benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid
monohydrochloride (Example 1-140) [2085]
13-cyclohexyl-5-[2-(octahydroisoquinolin-2-yl)-2-oxoethyl]-6,7-dihydro-5H-
-benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid
monohydrochloride (Example 1-141) [2086]
13-cyclohexyl-5-[2-(3,4-dihydro-1H-isoquinolin-2-yl)ethyl]-6,7-dihydro-5H-
-benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid
dihydrochloride (Example 1-142) [2087]
13-cyclohexyl-5-[2-(3-methylpiperidin-1-yl)ethyl]-6,7-dihydro-5H-benzo[5,-
6][1,4]diazepino[7,1-a]indole-10-carboxylic acid dihydrochloride
(Example 1-143) [2088]
13-cyclohexyl-5-[2-(octahydroquinolin-1-yl)ethyl]-6,7-dihydro-5H-benzo[5,-
6][1,4]diazepino[7,1-a]indole-10-carboxylic acid dihydrochloride
(Example 1-144) [2089]
13-cyclohexyl-5-[2-(1,3-dihydroisoindol-2-yl)ethyl]-6,7-dihydro-5H-benzo[-
5,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid dihydrochloride
(Example 1-145) [2090]
13-cyclohexyl-5-[2-(octahydroisoquinolin-2-yl)ethyl]-6,7-dihydro-5H-benzo-
[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid dihydrochloride
(Example 1-146) [2091]
3-chloro-13-cyclohexyl-5-[2-(piperidin-1-yl)ethyl]-6,7-dihydro-5H-benzo[5-
,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid monohydrochloride
(Example 1-147) [2092]
13-cyclohexyl-5-(3-dimethylaminopropyl)-6,7-dihydro-5H-benzo[5,6][1,4]dia-
zepino[7,1-a]indole-10-carboxylic acid dihydrochloride (Example
1-148) [2093]
13-cyclohexyl-4-fluoro-5-[2-(piperidin-1-yl)ethyl]-6,7-dihydro-5H-
-benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid
dihydrochloride (Example 1-149) [2094]
13-cyclohexyl-5-[2-(4-isopropylpiperidin-1-yl)ethyl]-6,7-dihydro-5H-benzo-
[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid dihydrochloride
(Example 1-150) [2095]
13-cyclohexyl-5-[2-(3-methoxypiperidin-1-yl)ethyl]-6,7-dihydro-5H-benzo[5-
,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid dihydrochloride
(Example 1-151) [2096]
5-(1-tert-butoxycarbonylpiperidin-3-ylmethyl)-13-cyclohexyl-6,7-dihydro-5-
H-benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid (Example
1-152) [2097]
13-cyclohexyl-5-(1-ethylpiperidin-3-ylmethyl)-6,7-dihydro-5H-ben-
zo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid
dihydrochloride (Example 1-153) [2098]
5-[2-(azocan-1-yl)ethyl]-13-cyclohexyl-6,7-dihydro-5H-benzo[5,6][1,4]diaz-
epino[7,1-a]indole-10-carboxylic acid (Example 1-154) [2099]
5-[2-(azonan-1-yl)ethyl]-13-cyclohexyl-6,7-dihydro-5H-benzo[5,6][1,4]diaz-
epino[7,1-a]indole-10-carboxylic acid (Example 1-155) [2100]
13-cyclohexyl-5-[2-(2-methylpiperidin-1-yl)ethyl]-6,7-dihydro-5H-benzo[5,-
6][1,4]diazepino[7,1-a]indole-10-carboxylic acid (Example 1-156)
[2101]
13-cyclohexyl-5-[2-(1-cyclopentylpiperidin-4-yl)ethyl]-6,7-dihydro-5H-ben-
zo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid
dihydrochloride (Example 1-157) [2102]
13-cyclohexyl-5-[2-oxo-2-(4-trifluoromethylpiperidin-1-yl)ethyl]-6,7-dihy-
dro-5H-benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid
monohydrochloride (Example 1-158) [2103]
13-cyclohexyl-5-[2-(piperidin-1-yl)ethyl]-3-trifluoromethyl-6,7-dihydro-5-
H-benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid
dihydrochloride (Example 1-159) [2104]
13-cyclohexyl-5-[2-(4-ethylpiperazin-1-yl)ethyl]-3-fluoro-6,7-dihydro-5H--
benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid
trihydrochloride (Example 1-160) [2105]
5-[2-(1-tert-butoxycarbonylpiperidin-2-yl)ethyl]-13-cyclohexyl-6,7-dihydr-
o-5H-benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid
monohydrochloride (Example 1-161) [2106]
13-cyclohexyl-5-[2-(4-ethylpiperazin-1-yl)-2-oxoethyl]-3-fluoro-6,7-dihyd-
ro-5H-benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid
dihydrochloride (Example 1-162) [2107]
13-cyclohexyl-5-[2-(pyridin-2-yl)ethyl]-6,7-dihydro-5H-benzo[5,6][1,4]dia-
zepino[7,1-a]indole-10-carboxylic acid dihydrochloride (Example
1-163) [2108]
13-cyclohexyl-5-(2-methoxyethyl)-6,7-dihydro-5H-benzo[5,6][1,4]di-
azepino[7,1-a]indole-10-carboxylic acid monohydrochloride (Example
1-164) [2109]
13-cyclohexyl-5-[2-(piperidin-3-yl)ethyl]-6,7-dihydro-5H-benzo[5,-
6][1,4]diazepino[7,1-a]indole-10-carboxylic acid dihydrochloride
(Example 1-165) [2110]
13-cyclohexyl-5-[2-(1-ethylpiperidin-3-yl)ethyl]-6,7-dihydro-5H-benzo[5,6-
][1,4]diazepino[7,1-a]indole-10-carboxylic acid dihydrochloride
(Example 1-166) [2111]
5-[2-(1-tert-butoxycarbonylpiperidin-3-yl)ethyl]-13-cyclohexyl-6,7-dihydr-
o-5H-benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid
(Example 1-167) [2112]
13-cyclohexyl-3-methyl-5-[2-(1,4-oxazepan-4-yl)ethyl]-6,7-dihydro-5H-benz-
o[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid
dihydrochloride (Example 1-168) [2113]
3-chloro-13-cyclohexyl-5-[2-(1,4-oxazepan-4-yl)ethyl]-6,7-dihydro-5H-benz-
o[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid
monohydrochloride (Example 1-169) [2114]
13-cyclohexyl-3-fluoro-5-[2-(1,4-oxazepan-4-yl)ethyl]-6,7-dihydro-5H-benz-
o[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid
dihydrochloride (Example 1-170) [2115]
13-cyclohexyl-5-[2-(4,4-difluoropiperidin-1-yl)-2-oxoethyl]-6,7-dihydro-5-
H-benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid
monohydrochloride (Example 1-171) [2116]
13-cyclohexyl-5-[2-(4-trifluoromethylpiperidin-1-yl)ethyl]-6,7-dihydro-5H-
-benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid
dihydrochloride (Example 1-172) [2117]
13-cyclohexyl-5-[2-(1-propylpiperidin-4-yl)ethyl]-6,7-dihydro-5H-benzo[5,-
6][1,4]diazepino[7,1-a]indole-10-carboxylic acid dihydrochloride
(Example 1-173) [2118]
13-cyclohexyl-5-[2-(4,4-difluoropiperidin-1-yl)ethyl]-6,7-dihydro-5H-benz-
o[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid
dihydrochloride (Example 1-174) [2119]
13-cyclohexyl-5-[2-(1-ethylpiperidin-4-ylidene)-2-fluoroethyl]-6,7-dihydr-
o-5H-benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid
dihydrochloride (Example 1-175) [2120]
2-chloro-13-cyclohexyl-5-[2-(piperidin-1-yl)ethyl]-6,7-dihydro-5H-benzo[5-
,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid dihydrochloride
(Example 1-176) [2121]
13-cyclohexyl-5-[2-(piperidin-2-yl)ethyl]-6,7-dihydro-5H-benzo[5,6][1,4]d-
iazepino[7,1-a]indole-10-carboxylic acid dihydrochloride (Example
1-177) [2122]
13-cyclohexyl-5-[2-(1-ethylpiperidin-2-yl)ethyl]-6,7-dihydro-5H-b-
enzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid
dihydrochloride (Example 1-178) [2123]
13-cyclohexyl-3-methylsulfanyl-5-[2-(piperidin-1-yl)ethyl]-6,7-dihydro-5H-
-benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid
dihydrochloride (Example 1-179) [2124]
3-chloro-13-cyclohexyl-5-[2-(piperidin-1-yl)ethyl]-6,7-dihydro-5H-benzo[5-
,6][1,4]diazepino[7,1-a]indole-10-carboxamide dihydrochloride
(Example 1-180) [2125]
13-cyclohexyl-5-[2-(pyridin-3-yl)ethyl]-6,7-dihydro-5H-benzo[5,6][1,4]dia-
zepino[7,1-a]indole-10-carboxylic acid dihydrochloride (Example
1-181) [2126]
13-cyclohexyl-5-[2-(pyridin-4-yl)ethyl]-6,7-dihydro-5H-benzo[5,6]-
[1,4]diazepino[7,1-a]indole-10-carboxylic acid dihydrochloride
(Example 1-182) [2127]
13-cyclohexyl-5-[(3aS,7aR)-2-(octahydroisoindol-2-yl)ethyl]-6,7-dihydro-5-
H-benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid
dihydrochloride (Example 1-183) [2128]
5-[2-(8-azaspiro[4.5]decan-8-yl)ethyl]-13-cyclohexyl-6,7-dihydro-5H-benzo-
[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid dihydrochloride
(Example 1-184) [2129]
13-cyclohexyl-5-(2-diethylaminoethyl)-6,7-dihydro-5H-benzo[5,6][1,4]diaze-
pino[7,1-a]indole-10-carboxylic acid dihydrochloride (Example
1-185)
[2130]
13-cyclohexyl-5-(2-diisopropylaminoethyl)-6,7-dihydro-5H-benzo[5,-
6][1,4]diazepino[7,1-a]indole-10-carboxylic acid dihydrochloride
(Example 1-186) [2131]
13-cyclohexyl-5-[2-(3,5-dimethylpiperidin-1-yl)-2-oxoethyl]-6,7-dihydro-5-
H-benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid
monohydrochloride (Example 1-187) [2132]
13-cyclohexyl-5-[2-(3-ethylpiperidin-1-yl)-2-oxoethyl]-6,7-dihydro-5H-ben-
zo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid
monohydrochloride (Example 1-188) [2133]
13-cyclohexyl-5-[2-(3,5-dimethylpiperidin-1-yl)ethyl]-6,7-dihydro-5H-benz-
o[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid
dihydrochloride (Example 1-189) [2134]
13-cyclohexyl-5-[2-(3-ethylpiperidin-1-yl)ethyl]-6,7-dihydro-5H-benzo[5,6-
][1,4]diazepino[7,1-a]indole-10-carboxylic acid dihydrochloride
(Example 1-190) [2135]
13-cyclohexyl-2-methyl-5-[2-(piperidin-1-yl)ethyl]-6,7-dihydro-5H-benzo[5-
,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid dihydrochloride
(Example 1-191) [2136]
13-cyclohexyl-5-[2-(4-propylpiperidin-1-yl)ethyl]-6,7-dihydro-5H-benzo[5,-
6][1,4]diazepino[7,1-a]indole-10-carboxylic acid dihydrochloride
(Example 1-192) [2137]
13-cyclohexyl-5-[2-((2S,6R)-2,6-dimethylpiperidin-1-yl)ethyl]-6,7-dihydro-
-5H-benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid
dihydrochloride (Example 1-193) [2138]
5-[3-(azepan-1-yl)propyl]-13-cyclohexyl-6,7-dihydro-5H-benzo[5,6][1,4]dia-
zepino[7,1-a]indole-10-carboxylic acid dihydrochloride (Example
1-194) [2139]
5-(adamantan-1-ylcarbamoylmethyl)-13-cyclohexyl-6,7-dihydro-5H-be-
nzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid
monohydrochloride (Example 1-195) [2140]
5-[2-(adamantan-1-ylamino)ethyl]-13-cyclohexyl-6,7-dihydro-5H-benzo[5,6][-
1,4]diazepino[7,1-a]indole-10-carboxylic acid dihydrochloride
(Example 1-196) [2141]
13-cyclohexyl-5-[2-(4-methoxymethylpiperidin-1-yl)ethyl]-6,7-dihydro-5H-b-
enzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid
dihydrochloride (Example 1-197) [2142]
13-cyclohexyl-5-[2-(N-methyl-N-propylamino)ethyl]-6,7-dihydro-5H-benzo[5,-
6][1,4]diazepino[7,1-a]indole-10-carboxylic acid dihydrochloride
(Example 1-198) [2143]
13-cyclohexyl-5-[2-(4,4-dimethylpiperidin-1-yl)ethyl]-6,7-dihydro-5H-benz-
o[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid
dihydrochloride (Example 1-199) [2144]
13-cyclohexyl-5-[2-(3-methoxymethylpiperidin-1-yl)ethyl]-6,7-dihydro-5H-b-
enzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid
dihydrochloride (Example 1-200) [2145]
13-cyclohexyl-5-[2-(1-methylpiperidin-3-yl)ethyl]-6,7-dihydro-5H-benzo[5,-
6][1,4]diazepino[7,1-a]indole-10-carboxylic acid dihydrochloride
(Example 1-201) [2146]
13-cyclohexyl-5-[2-(1-isopropylpiperidin-3-yl)ethyl]-6,7-dihydro-5H-benzo-
[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid dihydrochloride
(Example 1-202) [2147]
13-cyclohexyl-6-oxo-5-[2-oxo-2-(piperidin-1-yl)ethyl]-6,7-dihydro-5H-benz-
o[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid (Example
1-203) [2148]
13-cyclohexyl-5-[2-(4-ethylpiperazin-1-yl)-2-oxoethyl]-6-oxo-6,7--
dihydro-5H-benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid
monohydrochloride (Example 1-204) [2149]
13-cyclohexyl-5-[2-(3,6-dihydro-2H-pyridin-1-yl)ethyl]-6,7-dihydro-5H-ben-
zo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid (Example
1-205) [2150]
13-cyclohexyl-4-methyl-5-[2-(piperidin-1-yl)ethyl]-6,7-dihydro-5H-
-benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid
dihydrochloride (Example 1-206) [2151]
13-cyclohexyl-5-[2-((S)-2-methoxymethylpyrrolidin-1-yl)ethyl]-6,7-dihydro-
-5H-benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid
dihydrochloride (Example 1-207) [2152]
13-cyclohexyl-5-[2-(2-methylpyrrolidin-1-yl)ethyl]-6,7-dihydro-5H-benzo[5-
,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid dihydrochloride
(Example 1-208) [2153]
13-cyclohexyl-5-[2-(N-isobutyl-N-methylamino)ethyl]-6,7-dihydro-5H-benzo[-
5,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid dihydrochloride
(Example 1-209) [2154]
13-cyclohexyl-5-[2-(morpholin-4-yl)-2-oxoethyl]-6-oxo-6,7-dihydro-5H-benz-
o[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid (Example
1-210) [2155]
3-benzyloxy-13-cyclohexyl-5-[2-(piperidin-1-yl)ethyl]-6,7-dihydro-
-5H-benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid
dihydrochloride (Example 1-211) [2156]
13-cyclohexyl-5-[2-(N-isopropyl-N-methylamino)ethyl]-6,7-dihydro-5H-benzo-
[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid dihydrochloride
(Example 1-212) [2157]
3-chloro-13-cyclohexyl-5-[2-(2-methylpiperidin-1-yl)ethyl]-6,7-dihydro-5H-
-benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid
dihydrochloride (Example 1-213) [2158]
3-chloro-13-cyclohexyl-5-[2-(3-methylpiperidin-1-yl)ethyl]-6,7-dihydro-5H-
-benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid
dihydrochloride (Example 1-214) [2159]
3-chloro-13-cyclohexyl-5-[2-(4-methylpiperidin-1-yl)ethyl]-6,7-dihydro-5H-
-benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid
dihydrochloride (Example 1-215) [2160]
3-chloro-13-cyclohexyl-5-[2-(pyrrolidin-1-yl)ethyl]-6,7-dihydro-5H-benzo[-
5,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid dihydrochloride
(Example 1-216) [2161]
5-[2-(azepan-1-yl)ethyl]-3-chloro-13-cyclohexyl-6,7-dihydro-5H-benzo[5,6]-
[1,4]diazepino[7,1-a]indole-10-carboxylic acid dihydrochloride
(Example 1-217) [2162]
5-[2-(azepan-1-yl)ethyl]-13-cyclohexyl-3-methyl-6,7-dihydro-5H-benzo[5,6]-
[1,4]diazepino[7,1-a]indole-10-carboxylic acid dihydrochloride
(Example 1-218) [2163]
3-chloro-13-cyclohexyl-5-[2-(piperidin-3-yl)ethyl]-6,7-dihydro-5H-benzo[5-
,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid dihydrochloride
(Example 1-219) [2164]
13-cyclohexyl-5-[2-(3-methylmorpholin-4-yl)ethyl]-6,7-dihydro-5H-benzo[5,-
6][1,4]diazepino[7,1-a]indole-10-carboxylic acid dihydrochloride
(Example 1-220) [2165]
3-chloro-13-cyclohexyl-5-[2-(1-methylpiperidin-3-yl)ethyl]-6,7-dihydro-5H-
-benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid
dihydrochloride (Example 1-221) [2166]
13-cyclohexyl-5-{[N-(2-dimethylaminoethyl)-N-methylcarbamoyl]methyl}-6,7--
dihydro-5H-benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid
dihydrochloride (Example 1-222) [2167]
13-cyclohexyl-5-{2-[N-(2-dimethylaminoethyl)-N-methylamino]ethyl}-6,7-dih-
ydro-5H-benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid
trihydrochloride (Example 1-223) [2168]
13-cyclohexyl-5-[2-(4-ethanesulfonylpiperazin-1-yl)ethyl]-6,7-dihydro-5H--
benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid
dihydrochloride (Example 1-224) [2169]
13-cyclohexyl-5-[2-(4-propionylpiperazin-1-yl)ethyl]-6,7-dihydro-5H-benzo-
[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid dihydrochloride
(Example 1-225) [2170]
13-cyclohexyl-5-[2-(4-isopropoxycarbonylpiperazin-1-yl)ethyl]-6,7-dihydro-
-5H-benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid
dihydrochloride (Example 1-226) [2171]
13-cyclohexyl-3-isopropoxy-5-[2-(piperidin-1-yl)ethyl]-6,7-dihydro-5H-ben-
zo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid
dihydrochloride (Example 1-227) [2172]
3-benzyloxy-13-cyclohexyl-5-(2-dimethylaminoethyl)-6,7-dihydro-5H-benzo[5-
,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid dihydrochloride
(Example 1-228) [2173]
3-chloro-13-cyclohexyl-5-[2-(1-isopropylpiperidin-3-yl)ethyl]-6,7-dihydro-
-5H-benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid
dihydrochloride (Example 1-229) [2174]
3-chloro-13-cyclohexyl-5-[2-(1-propylpiperidin-3-yl)ethyl]-6,7-dihydro-5H-
-benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid
dihydrochloride (Example 1-230) [2175]
13-cyclohexyl-5-[2-(N-cyclohexyl-N-methylamino)ethyl]-6,7-dihydro-5H-benz-
o[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid (Example
1-231) [2176]
13-cyclohexyl-5-[2-(4-methanesulfonyl-1,4-diazepan-1-yl)ethyl]-6,-
7-dihydro-5H-benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic
acid dihydrochloride (Example 1-232) [2177]
13-cyclohexyl-5-[2-(4-methoxycarbonyl-1,4-diazepan-1-yl)ethyl]-6,7-dihydr-
o-5H-benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid
dihydrochloride (Example 1-233) [2178]
5-[2-(azepan-1-yl)ethyl]-13-cyclohexyl-3-fluoro-6,7-dihydro-5H-benzo[5,6]-
[1,4]diazepino[7,1-a]indole-10-carboxylic acid dihydrochloride
(Example 1-234) [2179]
13-cyclohexyl-6-oxo-5-[2-(piperidin-1-yl)ethyl]-6,7-dihydro-5H-benzo[5,6]-
[1,4]diazepino[7,1-a]indole-10-carboxylic acid monohydrochloride
(Example 1-235) [2180]
13-cyclohexyl-5-(2-{N-[2-(N-methoxycarbonyl-N-methylamino)ethyl]-N-methyl-
amino}ethyl)-6,7-dihydro-5H-benzo[5,6][1,4]diazepino[7,1-a]indole-10-carbo-
xylic acid dihydrochloride (Example 1-236) [2181]
13-cyclohexyl-5-[2-(3-methylpyrrolidin-1-yl)ethyl]-6,7-dihydro-5H-benzo[5-
,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid dihydrochloride
(Example 1-237) [2182]
13-cyclohexyl-5-[2-(3-methoxypyrrolidin-1-yl)ethyl]-6,7-dihydro-5H-benzo[-
5,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid dihydrochloride
(Example 1-238) [2183]
13-cyclohexyl-5-[2-(4-ethyl-1,4-diazepan-1-yl)-2-oxoethyl]-6,7-dihydro-5H-
-benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid
dihydrochloride (Example 1-239) [2184]
3-chloro-13-cyclohexyl-5-[2-(1-isopropylpiperidin-4-yl)ethyl]-6,7-dihydro-
-5H-benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid
dihydrochloride (Example 1-240) [2185]
13-cyclohexyl-1-methyl-5-[2-(piperidin-1-yl)ethyl]-6,7-dihydro-5H-benzo[5-
,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid dihydrochloride
(Example 1-241) [2186]
3-chloro-13-cyclohexyl-5-[3-(piperidin-1-yl)propyl]-6,7-dihydro-5H-benzo[-
5,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid dihydrochloride
(Example 1-242) [2187]
3-chloro-13-cyclohexyl-5-[2-(1-ethylpiperidin-4-yl)ethyl]-6,7-dihydro-5H--
benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid
dihydrochloride (Example 1-243) [2188]
3-chloro-13-cyclohexyl-5-[2-(piperidin-4-yl)ethyl]-6,7-dihydro-5H-benzo[5-
,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid dihydrochloride
(Example 1-244) [2189]
5-[3-(azepan-1-yl)propyl]-3-chloro-13-cyclohexyl-6,7-dihydro-5H-benzo[5,6-
][1,4]diazepino[7,1-a]indole-10-carboxylic acid dihydrochloride
(Example 1-245) [2190]
3-chloro-13-cyclohexyl-5-[2-(1-methylpiperidin-4-yl)ethyl]-6,7-dihydro-5H-
-benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid
dihydrochloride (Example 1-246) [2191]
3-chloro-13-cyclohexyl-5-(3-dimethylaminopropyl)-6,7-dihydro-5H-benzo[5,6-
][1,4]diazepino[7,1-a]indole-10-carboxylic acid dihydrochloride
(Example 1-247) [2192]
13-cyclohexyl-2,3-difluoro-5-[2-(piperidin-1-yl)ethyl]-6,7-dihydro-5H-ben-
zo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid
dihydrochloride (Example 1-248) [2193]
3-chloro-13-cyclohexyl-5-[2-(3-ethylpiperidin-1-yl)ethyl]-6,7-dihydro-5H--
benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid
dihydrochloride (Example 1-249) [2194]
13-cyclohexyl-5-{2-[N-(1-methoxycarbonylpyrrolidin-3-yl)-N-methylamino]et-
hyl}-6,7-dihydro-5H-benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic
acid monohydrochloride (Example 1-250) [2195]
5-{2-[N-(1-acetylpyrrolidin-3-yl)-N-methylamino]ethyl}-13-cyclohexyl-6,7--
dihydro-5H-benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid
monohydrochloride (Example 1-251) [2196]
13-cyclohexyl-5-{2-[N-(1-methanesulfonylpyrrolidin-3-yl)-N-methylamino]et-
hyl}-6,7-dihydro-5H-benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic-ac-
id (Example 1-252) [2197]
13-cyclohexyl-3-methyl-5-[2-(3-methylpiperidin-1-yl)ethyl]-6,7-dihydro-5H-
-benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid
dihydrochloride (Example 1-253) [2198]
13-cyclohexyl-3-fluoro-5-[2-(3-methylpiperidin-1-yl)ethyl]-6,7-dihydro-5H-
-benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid
dihydrochloride (Example 1-254) [2199]
13-cyclohexyl-5-[2-(2-methylmorpholin-4-yl)ethyl]-6,7-dihydro-5H-benzo[5,-
6][1,4]diazepino[7,1-a]indole-10-carboxylic acid dihydrochloride
(Example 1-255) [2200]
13-cyclohexyl-5-[2-(2-ethylmorpholin-4-yl)ethyl]-6,7-dihydro-5H-benzo[5,6-
][1,4]diazepino[7,1-a]indole-10-carboxylic acid dihydrochloride
(Example 1-256) [2201]
13-cyclohexyl-5-[2-(3-ethylmorpholin-4-yl)ethyl]-6,7-dihydro-5H-benzo[5,6-
][1,4]diazepino[7,1-a]indole-10-carboxylic acid dihydrochloride
(Example 1-257) [2202]
13-cyclohexyl-3-methyl-5-[2-(2-methylpiperidin-1-yl)ethyl]-6,7-dihydro-5H-
-benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid
dihydrochloride (Example 1-258) [2203]
13-cyclohexyl-3-methyl-5-[2-(4-methylpiperidin-1-yl)ethyl]-6,7-dihydro-5H-
-benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid
dihydrochloride (Example 1-259) [2204]
13-cyclohexyl-3-methyl-5-[2-(pyrrolidin-1-yl)ethyl]-6,7-dihydro-5H-benzo[-
5,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid dihydrochloride
(Example 1-260) [2205]
3-chloro-13-cyclohexyl-5-[2-(1-ethylpiperidin-3-yl)ethyl]-6,7-dihydro-5H--
benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid
dihydrochloride (Example 1-261) [2206]
3-chloro-13-cyclohexyl-5-[2-(1-methylpiperidin-4-yloxy)ethyl]-6,7-dihydro-
-5H-benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid
dihydrochloride (Example 1-262) [2207]
3-chloro-13-cyclohexyl-5-[2-(1-isobutylpiperidin-3-yl)ethyl]-6,7-dihydro--
5H-benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid
dihydrochloride (Example 1-263) [2208]
3-chloro-13-cyclohexyl-5-[2-(1-cyclopentylpiperidin-3-yl)ethyl]-6,7-dihyd-
ro-5H-benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid
dihydrochloride (Example 1-264) [2209]
3-chloro-13-cyclohexyl-5-[2-(3-methoxypiperidin-1-yl)ethyl]-6,7-dihydro-5-
H-benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid
dihydrochloride (Example 1-265) [2210]
13-cyclohexyl-5-[2-(3-methoxypiperidin-1-yl)ethyl]-3-methyl-6,7-dihydro-5-
H-benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid
dihydrochloride (Example 1-266) [2211]
3-chloro-13-cyclohexyl-5-[2-(3-propylpiperidin-1-yl)ethyl]-6,7-dihydro-5H-
-benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid
dihydrochloride (Example 1-267) [2212]
13-cyclohexyl-3-methyl-5-[2-(3-propylpiperidin-1-yl)ethyl]-6,7-dihydro-5H-
-benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid
dihydrochloride (Example 1-268) [2213]
3-chloro-13-cyclohexyl-5-[3-(pyrrolidin-1-yl)propyl]-6,7-dihydro-5H-benzo-
[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid dihydrochloride
(Example 1-269) [2214]
3-chloro-13-cyclohexyl-5-[3-(1,4-oxazepan-4-yl)propyl]-6,7-dihydro-5H-ben-
zo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid
dihydrochloride (Example 1-270) [2215]
13-cyclohexyl-5-[2-(2-methoxymethylpiperidin-1-yl)ethyl]-6,7-dihydro-5H-b-
enzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid
dihydrochloride (Example 1-271) [2216]
13-cyclohexyl-5-[2-(3-ethylpiperidin-1-yl)ethyl]-3-methyl-6,7-dihydro-5H--
benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid
dihydrochloride (Example 1-272) [2217]
13-cyclohexyl-5-[2-(1-ethylpiperidin-3-yl)ethyl]-3-methyl-6,7-dihydro-5H--
benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid
dihydrochloride (Example 1-273) [2218]
13-cyclohexyl-3-methyl-5-[2-(1-methylpiperidin-3-yl)ethyl]-6,7-dihydro-5H-
-benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid
dihydrochloride (Example 1-274) [2219]
13-cyclohexyl-5-[2-(1-isopropylpiperidin-3-yl)ethyl]-3-methyl-6,7-dihydro-
-5H-benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid
dihydrochloride (Example 1-275)
[2220]
13-cyclohexyl-3-ethoxy-5-[2-(piperidin-1-yl)ethyl]-6,7-dihydro-5H-
-benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid
dihydrochloride (Example 1-276) [2221]
5-[2-(azocan-1-yl)ethyl]-3-chloro-13-cyclohexyl-6,7-dihydro-5H-benzo[5,6]-
[1,4]diazepino[7,1-a]indole-10-carboxylic acid dihydrochloride
(Example 1-277) [2222]
5-[2-(azocan-1-yl)ethyl]-13-cyclohexyl-3-methyl-6,7-dihydro-5H-benzo[5,6]-
[1,4]diazepino[7,1-a]indole-10-carboxylic acid dihydrochloride
(Example 1-278) [2223]
5-{2-[N-(1-acetylpiperidin-4-yl)-N-methylamino]ethyl}-13-cyclohexyl-6,7-d-
ihydro-5H-benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid
monohydrochloride (Example 1-279) [2224]
13-cyclohexyl-5-{2-[N-(1-methanesulfonylpiperidin-4-yl)-N-methylamino]eth-
yl}-6,7-dihydro-5H-benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic
acid (Example 1-280) [2225]
13-cyclohexyl-5-{2-[N-(1-methoxycarbonylpiperidin-4-yl)-N-methylamino]eth-
yl}-6,7-dihydro-5H-benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic
acid monohydrochloride (Example 1-281) [2226]
13-cyclohexyl-5-{2-[N-methyl-N-(1-methylpiperidin-4-yl)amino]ethyl}-6,7-d-
ihydro-5H-benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid
dihydrochloride (Example 1-282) [2227]
13-cyclohexyl-5-{2-[N-methyl-N-(tetrahydropyran-4-yl)amino]ethyl}-6,7-dih-
ydro-5H-benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid
(Example 1-283) [2228]
13-cyclohexyl-5-{2-[N-methyl-N-(1-methylpyrrolidin-3-yl)amino]ethyl}-6,7--
dihydro-5H-benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid
dihydrochloride (Example 1-284) [2229]
13-cyclohexyl-5-{2-[N-methyl-N-(pyrrolidin-3-yl)amino]ethyl}-6,7-dihydro--
5H-benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid
dihydrochloride (Example 1-285) [2230]
13-cyclohexyl-5-[2-(4-ethyl-1,4-diazepan-1-yl)ethyl]-6,7-dihydro-5H-benzo-
[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid
trihydrochloride (Example 1-286) [2231]
13-cyclohexyl-3-methyl-5-[2-(1-methylpiperidin-2-yl)ethyl]-6,7-dihydro-5H-
-benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid
dihydrochloride (Example 1-287) [2232]
13-cyclohexyl-5-[2-(1-ethylpiperidin-2-yl)ethyl]-3-methyl-6,7-dihydro-5H--
benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid
dihydrochloride (Example 1-288) [2233]
5-[2-(azepan-1-yl)ethyl]-13-cyclohexyl-3-methylsulfanyl-6,7-dihydro-5H-be-
nzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid
dihydrochloride (Example 1-289) [2234]
3-chloro-13-cyclohexyl-5-[2-(2-ethylmorpholin-4-yl)ethyl]-6,7-dihydro-5H--
benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid
dihydrochloride (Example 1-290) [2235]
13-cyclohexyl-5-[2-(2-ethylmorpholin-4-yl)ethyl]-3-methyl-6,7-dihydro-5H--
benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid
dihydrochloride (Example 1-291) [2236]
13-cyclohexyl-5-[2-(3-ethylmorpholin-4-yl)ethyl]-3-methyl-6,7-dihydro-5H--
benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid
dihydrochloride (Example 1-292) [2237]
3-chloro-13-cyclohexyl-5-[2-(3-methoxymethylpiperidin-1-yl)ethyl]-6,7-dih-
ydro-5H-benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid
dihydrochloride (Example 1-293) [2238]
13-cyclohexyl-5-[2-(3-methoxymethylpiperidin-1-yl)ethyl]-3-methyl-6,7-dih-
ydro-5H-benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid
dihydrochloride (Example 1-294) [2239]
13-cyclohexyl-3-ethyl-5-[2-(piperidin-1-yl)ethyl]-6,7-dihydro-5H-benzo[5,-
6][1,4]diazepino[7,1-a]indole-10-carboxylic acid dihydrochloride
(Example 1-295) [2240]
13-cyclohexyl-3-isopropyl-5-[2-(piperidin-1-yl)ethyl]-6,7-dihydro-5H-benz-
o[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid
dihydrochloride (Example 1-296) [2241]
13-cyclohexyl-3-methylsulfanyl-5-[3-(piperidin-1-yl)propyl]-6,7-dihydro-5-
H-benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid
dihydrochloride (Example 1-297) [2242]
13-cyclohexyl-3-methyl-5-[3-(piperidin-1-yl)propyl]-6,7-dihydro-5H-benzo[-
5,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid dihydrochloride
(Example 1-298) [2243]
13-cyclohexyl-3-methyl-5-[3-(pyrrolidin-1-yl)propyl]-6,7-dihydro-5H-benzo-
[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid dihydrochloride
(Example 1-299) [2244]
5-[3-(azepan-1-yl)propyl]-13-cyclohexyl-3-methyl-6,7-dihydro-5H-benzo[5,6-
][1,4]diazepino[7,1-a]indole-10-carboxylic acid dihydrochloride
(Example 1-300) [2245]
13-cyclohexyl-5-(3-dimethylaminopropyl)-3-methyl-6,7-dihydro-5H-benzo[5,6-
][1,4]diazepino[7,1-a]indole-10-carboxylic acid dihydrochloride
(Example 1-301) [2246]
3-chloro-13-cyclohexyl-5-(3-diethylaminopropyl)-6,7-dihydro-5H-benzo[5,6]-
[1,4]diazepino[7,1-a]indole-10-carboxylic acid dihydrochloride
(Example 1-302) [2247]
13-cyclohexyl-3-methylsulfanyl-5-[2-(pyrrolidin-1-yl)ethyl]-6,7-dihydro-5-
H-benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid
dihydrochloride (Example 1-303) [2248]
3-chloro-13-cyclohexyl-5-[2-(2-methoxymethylpiperidin-1-yl)ethyl]-6,7-dih-
ydro-5H-benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid
dihydrochloride (Example 1-304) [2249]
13-cyclohexyl-5-[2-(2-methoxymethylpiperidin-1-yl)ethyl]-3-methyl-6,7-dih-
ydro-5H-benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid
dihydrochloride (Example 1-305) [2250]
13-cyclohexyl-5-{2-[3-(2-methoxyethyl)piperidin-1-yl]ethyl}-6,7-dihydro-5-
H-benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid
dihydrochloride (Example 1-306) [2251]
3-chloro-13-cyclohexyl-5-{2-[3-(2-methoxyethyl)piperidin-1-yl]ethyl}-6,7--
dihydro-5H-benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid
dihydrochloride (Example 1-307) [2252]
13-cyclohexyl-5-{2-[3-(2-methoxyethyl)piperidin-1-yl]ethyl}-3-methyl-6,7--
dihydro-5H-benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid
dihydrochloride (Example 1-308) [2253]
13-cyclohexyl-5-(2-dimethylaminoethyl)-3-[5-methanesulfonyl-2-(morpholin--
4-yl)benzyloxy]-6,7-dihydro-5H-benzo[5,6][1,4]diazepino[7,1-a]indole-10-ca-
rboxylic acid trihydrochloride (Example 1-309) [2254]
13-cyclohexyl-5-(2-dimethylaminoethyl)-3-methoxycarbonyloxy-6,7-dihydro-5-
H-benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid
dihydrochloride (Example 1-310) [2255]
13-cyclohexyl-5-(2-dimethylaminoethyl)-3-phenoxy-6,7-dihydro-5H-benzo[5,6-
][1,4]diazepino[7,1-a]indole-10-carboxylic acid dihydrochloride
(Example 1-311) [2256]
3-chloro-13-cyclohexyl-5-[2-(1-methylpiperidin-2-yl)ethyl]-6,7-dihydro-5H-
-benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid
dihydrochloride (Example 1-312) [2257]
3-chloro-13-cyclohexyl-5-[2-(piperidin-1-yl)ethyl]-6,7-dihydro-5H-benzo[5-
,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid dihydrochloride
(Example 1-313) [2258]
3-chloro-13-cyclohexyl-5-[2-(4-methoxymethylpiperidin-1-yl)ethyl]-6,7-dih-
ydro-5H-benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid
dihydrochloride (Example 1-314) [2259]
13-cyclohexyl-5-[2-(4-methoxymethylpiperidin-1-yl)ethyl]-3-methyl-6,7-dih-
ydro-5H-benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid
dihydrochloride (Example 1-315) [2260]
13-cyclohexyl-5-[2-((R)-2-methoxymethylpyrrolidin-1-yl)ethyl]-6,7-dihydro-
-5H-benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid
dihydrochloride (Example 1-316) [2261]
3-chloro-13-cyclohexyl-5-[2-(1-ethylpiperidin-4-yloxy)ethyl]-6,7-dihydro--
5H-benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid
dihydrochloride (Example 1-317) [2262]
3-chloro-13-cyclohexyl-5-[2-(1-isopropylpiperidin-4-yloxy)ethyl]-6,7-dihy-
dro-5H-benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid
dihydrochloride (Example 1-318) [2263]
13-cyclohexyl-5-[2-(N-cyclopentyl-N-methylamino)ethyl]-6,7-dihydro-5H-ben-
zo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid (Example
1-319) [2264]
3-chloro-13-cyclohexyl-5-[3-(3-methylpiperidin-1-yl)propyl]-6,7-d-
ihydro-5H-benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid
(Example 1-320) [2265]
13-cyclohexyl-5-{2-[N-methyl-N-(tetrahydrofuran-3-yl)amino]ethyl}-6,7-dih-
ydro-5H-benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid
(Example 1-321) [2266]
3-chloro-13-cyclohexyl-5-[3-(2-methylpiperidin-1-yl)propyl]-6,7-dihydro-5-
H-benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid (Example
1-322) [2267]
3-chloro-13-cyclohexyl-5-[2-(1-ethylpiperidin-2-yl)ethyl]-6,7-di-
hydro-5H-benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid
dihydrochloride (Example 1-323) [2268]
13-cyclohexyl-5-[2-(3-ethoxypiperidin-1-yl)ethyl]-6,7-dihydro-5H-benzo[5,-
6][1,4]diazepino[7,1-a]indole-10-carboxylic acid monohydrochloride
(Example 1-324) [2269]
13-cyclohexyl-5-[2-(3-ethoxypiperidin-1-yl)ethyl]-3-methyl-6,7-dihydro-5H-
-benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid
monohydrochloride (Example 1-325) [2270]
3-chloro-13-cyclohexyl-5-[2-(3-ethoxypiperidin-1-yl)ethyl]-6,7-dihydro-5H-
-benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid
monohydrochloride (Example 1-326) [2271]
3-chloro-13-cyclohexyl-5-[2-(3-ethylmorpholin-4-yl)ethyl]-6,7-dihydro-5H--
benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid
dihydrochloride (Example 1-327) [2272]
3-chloro-13-cyclohexyl-5-[2-(2-methylmorpholin-4-yl)ethyl]-6,7-dihydro-5H-
-benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid
dihydrochloride (Example 1-328) [2273]
13-cyclohexyl-3-methyl-5-[2-(2-methylmorpholin-4-yl)ethyl]-6,7-dihydro-5H-
-benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid
dihydrochloride (Example 1-329) [2274]
13-cyclohexyl-5-[2-(4-methylcarbamoylpiperazin-1-yl)ethyl]-6,7-dihydro-5H-
-benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid
dihydrochloride (Example 1-330) [2275]
13-cyclohexyl-5-[2-(3-propylpiperidin-1-yl)ethyl]-6,7-dihydro-5H-benzo[5,-
6][1,4]diazepino[7,1-a]indole-10-carboxylic acid dihydrochloride
(Example 1-331) [2276]
13-cyclohexyl-5-[2-(2-ethylpiperidin-1-yl)ethyl]-6,7-dihydro-5H-benzo[5,6-
][1,4]diazepino[7,1-a]indole-10-carboxylic acid dihydrochloride
(Example 1-332) [2277]
13-cyclohexyl-5-[2-(2-ethylpiperidin-1-yl)ethyl]-3-methyl-6,7-dihydro-5H--
benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid
dihydrochloride (Example 1-333) [2278]
3-chloro-13-cyclohexyl-5-[2-(2-ethylpiperidin-1-yl)ethyl]-6,7-dihydro-5H--
benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid
dihydrochloride (Example 1-334) [2279]
3-chloro-13-cyclohexyl-5-[2-((S)-3-ethylpiperidin-1-yl)ethyl]-6,7-dihydro-
-5H-benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid
dihydrochloride (Example 1-335) [2280]
3-chloro-13-cyclohexyl-5-[2-((R)-3-ethylpiperidin-1-yl)ethyl]-6,7-dihydro-
-5H-benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid
dihydrochloride (Example 1-336) [2281]
5-[2-(azepan-1-yl)ethyl]-13-cyclohexyl-3-isopropyl-6,7-dihydro-5H-benzo[5-
,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid dihydrochloride
(Example 1-337) [2282]
5-[2-(azepan-1-yl)ethyl]-13-cyclohexyl-3-ethyl-6,7-dihydro-5H-benzo[5,6][-
1,4]diazepino[7,1-a]indole-10-carboxylic acid dihydrochloride
(Example 1-338) [2283]
13-cyclohexyl-3-ethyl-5-[2-(3-methylpiperidin-1-yl)ethyl]-6,7-dihydro-5H--
benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid
dihydrochloride (Example 1-339) [2284]
13-cyclohexyl-3-isopropyl-5-[2-(3-methylpiperidin-1-yl)ethyl]-6,7-dihydro-
-5H-benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid
dihydrochloride (Example 1-340) [2285]
13-cyclohexyl-5-[2-(3-ethylpiperidin-1-yl)ethyl]-3-isopropyl-6,7-dihydro--
5H-benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid
dihydrochloride (Example 1-341) [2286]
3-chloro-13-cyclohexyl-5-[2-(1-cyclopropylpiperidin-3-yl)ethyl]-6,7-dihyd-
ro-5H-benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid
dihydrochloride (Example 1-342) [2287]
13-cyclohexyl-5-[2-(piperidin-1-yl)ethyl]-3-propyl-6,7-dihydro-5H-benzo[5-
,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid dihydrochloride
(Example 1-343) [2288]
N-{2-[10-carboxy-13-cyclohexyl-3-(5-methylisoxazol-3-ylmethoxy)-6,7-dihyd-
ro-benzo[5,6][1,4]diazepino[7,1-a]indol-5-yl]ethyl}-N,N-dimethyl-N-(5-meth-
ylisoxazol-3-ylmethyl)ammonium chloride monohydrochloride (Example
1-344) [2289]
13-cyclohexyl-3-ethoxy-5-[2-(3-methylpiperidin-1-yl)ethyl]-6,7-di-
hydro-5H-benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid
dihydrochloride (Example 1-345) [2290]
13-cyclohexyl-5-[2-(3-methoxymethylpiperidin-1-yl)ethyl]-3-propyl-6,7-dih-
ydro-5H-benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid
dihydrochloride (Example 1-346) [2291]
13-cyclohexyl-3-ethoxy-5-[2-(3-ethylpiperidin-1-yl)ethyl]-6,7-dihydro-5H--
benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid
dihydrochloride (Example 1-347) [2292]
3-benzyloxy-13-cyclohexyl-5-[2-(3-ethylpiperidin-1-yl)ethyl]-6,7-dihydro--
5H-benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid
dihydrochloride (Example 1-348) [2293]
13-cyclohexyl-3-ethoxy-5-[2-(1-isopropylpiperidin-3-yl)ethyl]-6,7-dihydro-
-5H-benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid
dihydrochloride (Example 1-349) [2294]
13-cyclohexyl-3-ethyl-5-[2-(3-ethylpiperidin-1-yl)ethyl]-6,7-dihydro-5H-b-
enzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid
dihydrochloride (Example 1-350) [2295]
3-chloro-13-cyclohexyl-5-[2-(3-isopropylpiperidin-1-yl)ethyl]-6,7-dihydro-
-5H-benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid
dihydrochloride (Example 1-351) [2296]
3-chloro-13-cyclohexyl-5-[3-(3-methoxymethylpiperidin-1-yl)propyl]-6,7-di-
hydro-5H-benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid
monohydrochloride (Example 1-352) [2297]
3-chloro-13-cyclohexyl-5-[3-(2-ethylpiperidin-1-yl)propyl]-6,7-dihydro-5H-
-benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid
dihydrochloride (Example 1-353) [2298]
13-cyclohexyl-5-[2-(1-isopropylpiperidin-3-yl)ethyl]-3-propyl-6,7-dihydro-
-5H-benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid
dihydrochloride (Example 1-354) [2299]
3-chloro-13-cyclohexyl-5-[3-(2-methoxymethylpiperidin-1-yl)propyl]-6,7-di-
hydro-5H-benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid
dihydrochloride (Example 1-355) [2300]
13-cyclohexyl-5-[2-(3-methylpiperidin-1-yl)ethyl]-3-propyl-6,7-dihydro-5H-
-benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid
dihydrochloride (Example 1-356) [2301]
13-cyclohexyl-5-[2-(3-ethylpiperidin-1-yl)ethyl]-3-propyl-6,7-dihydro-5H--
benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid
dihydrochloride (Example 1-357) [2302]
3-benzyloxy-13-cyclohexyl-5-[2-(3-methoxymethylpiperidin-1-yl)ethyl]-6,7--
dihydro-5H-benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid
dihydrochloride (Example 1-358) [2303]
13-cyclohexyl-3-isopropyl-5-[2-(pyrrolidin-1-yl)ethyl]-6,7-dihydro-5H-ben-
zo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid
monohydrochloride (Example 1-359) [2304]
13-cyclohexyl-3-ethyl-5-[2-(pyrrolidin-1-yl)ethyl]-6,7-dihydro-5H-benzo[5-
,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid monohydrochloride
(Example 1-360) [2305]
3-benzyloxy-13-cyclohexyl-5-[2-(3-methylpiperidin-1-yl)ethyl]-6,7-dihydro-
-5H-benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid
dihydrochloride (Example 1-361) [2306]
3-benzyloxy-13-cyclohexyl-5-[2-(1-isopropylpiperidin-3-yl)ethyl]-6,7-dihy-
dro-5H-benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid
dihydrochloride (Example 1-362)
[2307]
13-cyclohexyl-3-(5-methylisoxazol-3-ylmethoxy)-5-[2-(piperidin-1--
yl)ethyl]-6,7-dihydro-5H-benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxyl-
ic acid dihydrochloride (Example 1-363) [2308]
13-cyclohexyl-5-[2-(3-isopropylpiperidin-1-yl)ethyl]-6,7-dihydro-5H-benzo-
[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid dihydrochloride
(Example 1-364) [2309]
13-cyclohexyl-5-[2-(3-isopropylpiperidin-1-yl)ethyl]-3-methyl-6,7-dihydro-
-5H-benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid
dihydrochloride (Example 1-365) [2310]
13-cyclohexyl-3-ethyl-5-[2-(3-methoxymethylpiperidin-1-yl)ethyl]-6,7-dihy-
dro-5H-benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid
dihydrochloride (Example 1-366) [2311]
13-cyclohexyl-3-isopropyl-5-[2-(3-methoxymethylpiperidin-1-yl)ethyl]-6,7--
dihydro-5H-benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid
dihydrochloride (Example 1-367) [2312]
3-chloro-13-cyclohexyl-5-[3-(2-methylpyrrolidin-1-yl)propyl]-6,7-dihydro--
5H-benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid
(Example 1-368) [2313]
13-cyclohexyl-3-ethyl-5-[2-(1-isopropylpiperidin-3-yl)ethyl]-6,7-dihydro--
5H-benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid
(Example 1-369) [2314]
13-cyclohexyl-3-ethoxy-5-[2-(3-methoxymethylpiperidin-1-yl)ethyl]-6,7-dih-
ydro-5H-benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid
(Example 1-370) [2315]
3-chloro-13-cyclohexyl-5-[2-(1-isopropylpiperidin-3-yloxy)ethyl]-6,7-dihy-
dro-5H-benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid
(Example 1-371) [2316]
3-chloro-13-cyclohexyl-5-[3-(3-ethylpiperidin-1-yl)propyl]-6,7-dihydro-5H-
-benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid
dihydrochloride (Example 1-372) [2317]
13-cyclohexyl-3-isobutoxy-5-[2-(piperidin-1-yl)ethyl]-6,7-dihydro-5H-benz-
o[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid
dihydrochloride (Example 1-373) [2318]
13-cyclohexyl-5-(2-dimethylaminoethyl)-3-(5-methylisoxazol-3-ylmethoxy)-6-
,7-dihydro-5H-benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic
acid dihydrochloride (Example 1-374) [2319]
13-cyclohexyl-3-isobutoxy-5-[2-(3-methylpiperidin-1-yl)ethyl]-6,7-dihydro-
-5H-benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid
dihydrochloride (Example 1-375) [2320]
13-cyclohexyl-5-[2-(3-ethylpiperidin-1-yl)ethyl]-3-isobutoxy-6,7-dihydro--
5H-benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid
dihydrochloride (Example 1-376) [2321]
13-cyclohexyl-3-isobutoxy-5-[2-(3-methoxymethylpiperidin-1-yl)ethyl]-6,7--
dihydro-5H-benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid
dihydrochloride (Example 1-377) [2322]
13-cyclohexyl-5-(3-diethylaminopropyl)-3-methyl-6,7-dihydro-5H-benzo[5,6]-
[1,4]diazepino[7,1-a]indole-10-carboxylic acid dihydrochloride
(Example 1-378) [2323]
3-chloro-13-cyclohexyl-5-[2-(1-cyclohexylpiperidin-3-yl)ethyl]-6,7-dihydr-
o-5H-benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid
dihydrochloride (Example 1-379) [2324]
13-cyclohexyl-5-[2-(1-cyclopentylpiperidin-3-yl)ethyl]-3-methyl-6,7-dihyd-
ro-5H-benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid
dihydrochloride (Example 1-380) [2325]
13-cyclohexyl-3-isopropyl-5-[2-(1-isopropylpiperidin-3-yl)ethyl]-6,7-dihy-
dro-5H-benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid
dihydrochloride (Example 1-381) [2326]
13-cyclohexyl-5-[2-(3-ethylpyrrolidin-1-yl)ethyl]-6,7-dihydro-5H-benzo[5,-
6][1,4]diazepino[7,1-a]indole-10-carboxylic acid dihydrochloride
(Example 1-382) [2327]
3-chloro-13-cyclohexyl-5-[2-(3-ethylpyrrolidin-1-yl)ethyl]-6,7-dihydro-5H-
-benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid
dihydrochloride (Example 1-383) [2328]
13-cyclohexyl-5-[2-(3-ethylpyrrolidin-1-yl)ethyl]-3-methyl-6,7-dihydro-5H-
-benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid
dihydrochloride (Example 1-384) [2329]
13-cyclohexyl-3-isobutoxy-5-[2-(1-isopropylpiperidin-3-yl)ethyl]-6,7-dihy-
dro-5H-benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid
dihydrochloride (Example 1-385) [2330]
3-chloro-13-cyclohexyl-5-{2-[1-(1-ethylpropyl)piperidin-3-yl]ethyl}-6,7-d-
ihydro-5H-benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid
dihydrochloride (Example 1-386) [2331]
13-cyclohexyl-5-[2-(3-ethoxymethylpiperidin-1-yl)ethyl]-6,7-dihydro-5H-be-
nzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid
dihydrochloride (Example 1-387) [2332]
3-chloro-13-cyclohexyl-5-[2-(piperidin-1-yl)ethyl]-6,7-dihydro-5H-benzo[5-
,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid (Example 1-388)
[2333]
3-chloro-13-cyclopentyl-5-[2-(3-ethylpiperidin-1-yl)ethyl]-6,7-dihydro-5H-
-benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid (Example
1-389) [2334]
3-chloro-13-cyclopentyl-5-[2-(3-methoxymethylpiperidin-1-yl)ethyl-
]-6,7-dihydro-5H-benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic
acid (Example 1-390) [2335]
3-chloro-13-cyclohexyl-5-[2-(3-ethoxymethylpiperidin-1-yl)ethyl]-6,7-dihy-
dro-5H-benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid
dihydrochloride (Example 1-391) [2336]
13-cyclohexyl-5-[2-(3-ethoxymethylpiperidin-1-yl)ethyl]-3-methyl-6,7-dihy-
dro-5H-benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid
dihydrochloride (Example 1-392) [2337]
3-chloro-13-cyclohexyl-5-[2-(3-isopropoxypiperidin-1-yl)ethyl]-6,7-dihydr-
o-5H-benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid
monohydrochloride (Example 1-393) [2338]
13-cyclohexyl-5-[2-(3-isopropoxypiperidin-1-yl)ethyl]-3-methyl-6,7-dihydr-
o-5H-benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid
monohydrochloride (Example 1-394) [2339]
13-cyclohexyl-5-[2-(3-isopropoxypiperidin-1-yl)ethyl]-6,7-dihydro-5H-benz-
o[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid
monohydrochloride (Example 1-395) [2340]
3-chloro-13-cyclohexyl-5-[3-(1-isopropylpiperidin-3-yl)propyl]-6,7-dihydr-
o-5H-benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid
dihydrochloride (Example 1-396) [2341]
3-chloro-13-cyclohexyl-5-{2-[(S)-3-(2-methoxyethyl)piperidin-1-yl]ethyl}--
6,7-dihydro-5H-benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic
acid dihydrochloride (Example 1-397) [2342]
3-chloro-13-cyclohexyl-5-{2-[(R)-3-(2-methoxyethyl)piperidin-1-yl]ethyl}--
6,7-dihydro-5H-benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic
acid dihydrochloride (Example 1-398) [2343]
13-cyclopentyl-5-[2-(piperidin-1-yl)ethyl]-6,7-dihydro-5H-benzo[5,6][1,4]-
diazepino[7,1-a]indole-10-carboxylic acid monohydrochloride
(Example 1-399) [2344]
3-chloro-13-cyclohexyl-5-[2-(1-ethylpiperidin-3-yloxy)ethyl]-6,7-dihydro--
5H-benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid
dihydrochloride (Example 1-400) [2345]
13-cyclohexyl-3-(2-methylthiazol-4-ylmethoxy)-5-[2-(piperidin-1-yl)ethyl]-
-6,7-dihydro-5H-benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic
acid dihydrochloride (Example 1-401) [2346]
13-cyclohexyl-3-(2,4-dimethylthiazol-5-ylmethoxy)-5-[2-(piperidin-1-yl)et-
hyl]-6,7-dihydro-5H-benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic
acid dihydrochloride (Example 1-402) [2347]
3-chloro-13-cyclohexyl-5-[3-(N-ethyl-N-isopropylamino)propyl]-6,7-dihydro-
-5H-benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid
dihydrochloride (Example 1-403) [2348]
3-chloro-13-cyclohexyl-5-[2-((S)-1-cyclopentylpiperidin-3-yl)ethyl]-6,7-d-
ihydro-5H-benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid
dihydrochloride (Example 1-404) [2349]
13-cyclohexyl-5-[2-(3-isopropoxymethylpiperidin-1-yl)ethyl]-6,7-dihydro-5-
H-benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid
dihydrochloride (Example 1-405) [2350]
3-chloro-13-cyclohexyl-5-[2-(3-isopropoxymethylpiperidin-1-yl)ethyl]-6,7--
dihydro-5H-benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid
dihydrochloride (Example 1-406) [2351]
13-cyclohexyl-5-[2-(3-isopropoxymethylpiperidin-1-yl)ethyl]-3-methyl-6,7--
dihydro-5H-benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid
dihydrochloride (Example 1-407) [2352]
3-chloro-13-cyclohexyl-5-[2-((R)-1-cyclopentylpiperidin-3-yl)ethyl]-6,7-d-
ihydro-5H-benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid
dihydrochloride (Example 1-408) [2353]
13-cyclohexyl-5-{2-[(R)-3-(2-methoxyethyl)piperidin-1-yl]ethyl}-3-methyl--
6,7-dihydro-5H-benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic
acid dihydrochloride (Example 1-409) [2354]
13-cyclohexyl-3-methyl-5-[2-(1-propylpiperidin-3-yl)ethyl]-6,7-dihydro-5H-
-benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid
dihydrochloride (Example 1-410) [2355]
3-chloro-13-cyclohexyl-5-[3-(1-ethylpiperidin-3-yl)propyl]-6,7-dihydro-5H-
-benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid
dihydrochloride (Example 1-411) [2356]
3-chloro-13-cyclohexyl-5-[3-(1-cyclopentylpiperidin-3-yl)propyl]-6,7-dihy-
dro-5H-benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid
dihydrochloride (Example 1-412) [2357]
13-cyclohexyl-5-{2-[(S)-3-(2-methoxyethyl)piperidin-1-yl]ethyl}-3-methyl--
6,7-dihydro-5H-benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic
acid dihydrochloride (Example 1-413) [2358]
3-chloro-13-cyclopentyl-5-[2-(1-isopropylpiperidin-3-yl)ethyl]-6,7-dihydr-
o-5H-benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid
monohydrochloride (Example 1-414) [2359]
3-chloro-13-cyclohexyl-5-[4-(piperidin-1-yl)butyl]-6,7-dihydro-5H-benzo[5-
,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid (Example 1-415)
[2360]
13-cyclohexyl-5-[2-((R)-3-methoxymethylpiperidin-1-yl)ethyl]-3-methyl-6,7-
-dihydro-5H-benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic
acid dihydrochloride (Example 1-416) [2361]
13-cyclohexyl-5-[2-((S)-3-methoxymethylpiperidin-1-yl)ethyl]-3-methyl-6,7-
-dihydro-5H-benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic
acid dihydrochloride (Example 1-417) [2362]
13-cyclohexyl-3-(3-methanesulfonylbenzyloxy)-5-[2-(piperidin-1-yl)ethyl]--
6,7-dihydro-5H-benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic
acid dihydrochloride (Example 1-418) [2363]
3-chloro-13-cyclohexyl-5-[2-((R)-3-ethylpiperidin-1-yl)ethyl]-6,7-dihydro-
-5H-benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid
(Example 1-419) [2364]
13-cyclohexyl-5-[2-((R)-3-ethylpiperidin-1-yl)ethyl]-3-methyl-6,7-dihydro-
-5H-benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid
dihydrochloride (Example 1-420) [2365]
3-chloro-13-cyclohexyl-5-[2-((S)-3-ethylpiperidin-1-yl)ethyl]-6,7-dihydro-
-5H-benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid
(Example 1-421) [2366]
13-cyclohexyl-5-[2-((S)-3-ethylpiperidin-1-yl)ethyl]-3-methyl-6,7-dihydro-
-5H-benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid
dihydrochloride (Example 1-422) [2367]
5-[2-(azocan-1-yl)ethyl]-13-cyclohexyl-6,7-dihydro-5H-benzo[5,6][1,4]diaz-
epino[7,1-a]indole-10-carboxylic acid dihydrochloride (Example
1-423) [2368]
3-chloro-13-cyclohexyl-5-(4-diethylaminobutyl)-6,7-dihydro-5H-ben-
zo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid (Example
1-424) [2369]
13-cyclohexyl-3-methyl-5-[4-(piperidin-1-yl)butyl]-6,7-dihydro-5H-
-benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid
dihydrochloride (Example 1-425) [2370]
3-chloro-13-cyclohexyl-5-[2-(1-methylpyrrolidin-2-yl)ethyl]-6,7-dihydro-5-
H-benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid
dihydrochloride (Example 1-426) [2371]
13-cyclohexyl-3-ethoxy-5-{2-[(S)-3-(2-methoxyethyl)piperidin-1-yl]ethyl}--
6,7-dihydro-5H-benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic
acid dihydrochloride (Example 1-427) [2372]
3-chloro-13-cyclohexyl-5-[3-(N-ethyl-N-propylamino)propyl]-6,7-dihydro-5H-
-benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid
dihydrochloride (Example 1-428) [2373]
3-chloro-13-cyclohexyl-5-(3-diisopropylaminopropyl)-6,7-dihydro-5H-benzo[-
5,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid dihydrochloride
(Example 1-429) [2374]
13-cyclohexyl-3-ethyl-5-{2-[(S)-3-(2-methoxyethyl)piperidin-1-yl]ethyl}-6-
,7-dihydro-5H-benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic
acid dihydrochloride (Example 1-430) [2375]
3-chloro-13-cyclohexyl-5-{3-[N-ethyl-N-(2-methoxyethyl)amino]propyl}-6,7--
dihydro-5H-benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid
dihydrochloride (Example 1-431) [2376]
3-chloro-13-cyclohexyl-5-{3-[N-ethyl-N-(3-methoxypropyl)amino]propyl}-6,7-
-dihydro-5H-benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic
acid dihydrochloride (Example 1-432) [2377]
3-chloro-13-cyclohexyl-5-{3-[N-(3-ethoxypropyl)-N-ethylamino]propyl}-6,7--
dihydro-5H-benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid
dihydrochloride (Example 1-433) [2378]
13-cyclohexyl-3-fluoro-5-{2-[(S)-3-(2-methoxyethyl)piperidin-1-yl]ethyl}--
6,7-dihydro-5H-benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic
acid dihydrochloride (Example 1-434) [2379]
13-cyclohexyl-5-[2-(3-hydroxymethylpiperidin-1-yl)ethyl]-3-methyl-6,7-dih-
ydro-5H-benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid
dihydrochloride (Example 1-435) [2380]
3-chloro-13-cyclohexyl-5-(3-diethylamino-2,2-dimethylpropyl)-6,7-dihydro--
5H-benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid
dihydrochloride (Example 1-436) [2381]
13-cyclohexyl-5-methyl-3-[2-(piperidin-1-yl)ethoxy]-6,7-dihydro-5H-benzo[-
5,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid dihydrochloride
(Example 1-437) [2382]
13-cyclohexyl-5-methyl-3-[2-(piperidin-4-yl)ethoxy]-6,7-dihydro-5H-benzo[-
5,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid dihydrochloride
(Example 1-438) [2383]
13-cyclohexyl-5-methyl-3-[2-(1-methylpiperidin-4-yl)ethoxy]-6,7-dihydro-5-
H-benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid
dihydrochloride (Example 1-439) [2384]
13-cyclohexyl-5-[2-(3,3-dimethylpiperidin-1-yl)ethyl]-3-methyl-6,7-dihydr-
o-5H-benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid
dihydrochloride (Example 1-440) [2385]
3-chloro-13-cyclohexyl-5-(3-diethylamino-2-methoxypropyl)-6,7-dihydro-5H--
benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid
dihydrochloride (Example 1-441) [2386]
3-chloro-13-cyclohexyl-5-{3-[N-ethyl-N-(2-hydroxyethyl)amino]propyl}-6,7--
dihydro-5H-benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid
dihydrochloride (Example 1-442) [2387]
13-cyclohexyl-5-[2-(4-hydroxymethylpiperidin-1-yl)ethyl]-3-methyl-6,7-dih-
ydro-5H-benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid
dihydrochloride (Example 1-443) [2388]
13-cyclohexyl-5-{2-[(S)-3-(2-phenoxyethyl)piperidin-1-yl]ethyl}-6,7-dihyd-
ro-5H-benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid
dihydrochloride (Example 1-444) [2389]
13-cyclohexyl-3-methoxy-5-{2-[(S)-3-(2-methoxyethyl)piperidin-1-yl]ethyl}-
-6,7-dihydro-5H-benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic
acid dihydrochloride (Example 1-445) [2390]
12-cyclohexyl-3-(5-methylisoxazol-3-ylmethoxy)-6,7-dihydro-5-oxa-7a-azadi-
benzo[a,e]azulene-9-carboxylic acid (Example 2-32) [2391]
3-[2-(tert-butoxycarbonylamino)ethoxy]-12-cyclohexyl-6,7-dihydro-5-oxa-7a-
-azadibenzo[a,e]azulene-9-carboxylic acid (Example 2-33) [2392]
12-cyclohexyl-3-(2-methylthiazol-4-ylmethoxy)-6,7-dihydro-5-oxa-7a-azadib-
enzo[a,e]azulene-9-carboxylic acid (Example 2-34) [2393]
3-[(S)-1-(tert-butoxycarbonyl)pyrrolidin-2-ylmethoxy]-12-cyclohexyl-6,7-d-
ihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carboxylic acid (Example
2-35) [2394]
12-cyclohexyl-3-[2-(methoxycarbonylamino)ethoxy]-6,7-dihydro-5-ox-
a-7a-azadibenzo[a,e]azulene-9-carboxylic acid (Example 2-36)
[2395]
12-cyclohexyl-3-((S)-1-methoxycarbonylpyrrolidin-2-ylmethoxy)-6,7-
-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carboxylic acid (Example
2-37) [2396]
12-cyclohexyl-3-[2-(2-oxooxazolidin-3-yl)ethoxy]-6,7-dihydro-5-ox-
a-7a-azadibenzo[a,e]azulene-9-carboxylic acid (Example 2-38) [2397]
4-benzyloxy-12-cyclohexyl-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-c-
arboxylic acid (Example 2-39) [2398]
3-[(S)-1-(tert-butoxycarbonyl)pyrrolidin-3-yloxy]-12-cyclohexyl-6,7-dihyd-
ro-5-oxa-7a-azadibenzo[a,e]azulene-9-carboxylic acid (Example 2-40)
[2399]
3-((S)-2-tert-butoxycarbonylamino-3-phenylpropoxy)-12-cyclohexyl--
6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carboxylic acid
(Example 2-41) [2400]
12-cyclohexyl-3-((S)-pyrrolidin-3-yloxy)-6,7-dihydro-5-oxa-7a-azadibenzo[-
a,e]azulene-9-carboxylic acid monohydrochloride (Example 2-42)
[2401]
3-((S)-2-tert-butoxycarbonylamino-3-methylbutoxy)-12-cyclohexyl-6,7-dihyd-
ro-5-oxa-7a-azadibenzo[a,e]azulene-9-carboxylic acid (Example 2-43)
[2402]
12-cyclohexyl-3-(1-methanesulfonylpiperidin-3-yloxy)-6,7-dihydro--
5-oxa-7a-azadibenzo[a,e]azulene-9-carboxylic acid (Example 2-44)
[2403]
12-cyclohexyl-3-(1-methylpiperidin-2-ylmethoxy)-6,7-dihydro-5-oxa-7a-azad-
ibenzo[a,e]azulene-9-carboxylic acid (Example 2-45) [2404]
12-cyclohexyl-3-(piperidin-3-yloxy)-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]a-
zulene-9-carboxylic acid monohydrochloride (Example 2-46) [2405]
12-cyclohexyl-3-[2-(morpholin-4-yl)-5-(2-oxopyrrolidin-1-yl)benzyloxy]-6,-
7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carboxamide
monohydrochloride (Example 2-47) [2406]
12-cyclohexyl-3-[5-methanesulfonyl-2-(morpholin-4-yl)benzyloxy]-6,7-dihyd-
ro-5-oxa-7a-azadibenzo[a,e]azulene-9-carboxamide monohydrochloride
(Example 2-48) [2407]
12-cyclohexyl-3-((S)-2-methoxycarbonylamino-3-phenylpropoxy)-6,7-dihydro--
5-oxa-7a-azadibenzo[a,e]azulene-9-carboxylic acid (Example 2-49)
[2408]
12-cyclohexyl-3-((S)-1-methoxycarbonylpyrrolidin-3-yloxy)-6,7-dihydro-5-o-
xa-7a-azadibenzo[a,e]azulene-9-carboxylic acid (Example 2-50)
[2409]
12-cyclohexyl-3-((S)-2-methanesulfonylamino-3-methylbutoxy)-6,7-dihydro-5-
-oxa-7a-azadibenzo[a,e]azulene-9-carboxylic acid (Example 2-51)
[2410]
12-cyclohexyl-3-[2-(methoxycarbonylamino)phenoxy]-6,7-dihydro-5-oxa-7a-az-
adibenzo[a,e]azulene-9-carboxylic acid (Example 2-52) [2411]
12-cyclohexyl-4-[2-(piperidin-1-yl)ethoxy]-6,7-dihydro-5-oxa-7a-azadibenz-
o[a,e]azulene-9-carboxylic acid monohydrochloride (Example 2-53)
[2412]
3-benzyloxy-12-cyclohexyl-6,7-dihydro-5-oxa-7a,8-diazadibenzo[a,e]azulene-
-9-carboxylic acid (Example 7-8) [2413]
3-chloro-12-cyclohexyl-5-[2-(piperidin-1-yl)ethyl]-6,7-dihydro-5H-5,7a,8--
triazadibenzo[a,e]azulene-9-carboxylic acid trihydrochloride
(Example 8-5) [2414]
3-chloro-12-cyclohexyl-5-[2-(4-ethylpiperazin-1-yl)ethyl]-6,7-di-
hydro-5H-5,7a,8-triazadibenzo[a,e]azulene-9-carboxylic acid
trihydrochloride (Example 8-6) [2415]
3-chloro-12-cyclohexyl-5-[2-(piperidin-1-yl)ethyl]-5,6,7,12-tetrahydroben-
zo[2,3]azepino[4,5-b]indole-9-carboxylic acid (Example 10-1) [2416]
ethyl
3-chloro-12-cyclohexyl-5-[2-(piperidin-1-yl)ethyl]-5,6,7,12-tetrahy-
drobenzo[2,3]azepino[4,5-b]indole-9-carboxylate (Example 10-2)
[2417]
3-chloro-12-cyclohexyl-5-[2-(piperidin-1-yl)ethyl]-5,6,7,12-tetrahydroben-
zo[2,3]azepino[4,5-b]indole-9-carboxamide (Example 10-3) [2418]
12-cyclohexyl-5-[2-(piperidin-1-yl)ethyl]-5,6,7,12-tetrahydrobenzo[2,3]az-
epino[4,5-b]indole-9-carboxylic acid (Example 10-4) [2419]
13-cyclohexyl-5-[2-(4-ethylpiperazin-1-yl)-2-oxoethyl]-6,7-dihydro-5H-ben-
zo[5,6][1,4]diazepino[7,1-a]indole-10-carboxamide (Example 1-446)
[2420]
N-methyl-13-cyclohexyl-5-[2-(4-ethylpiperazin-1-yl)-2-oxoethyl]-6,7-dihyd-
ro-5H-benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxamide (Example
1-447) [2421]
N-(2-hydroxyethyl)-13-cyclohexyl-5-[2-(4-ethylpiperazin-1-yl)-2--
oxoethyl]-6,7-dihydro-5H-benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxam-
ide (Example 1-448) [2422]
N-(2-hydroxy-1,1-dimethylethyl)-13-cyclohexyl-5-[2-(4-ethylpiperazin-1-yl-
)-2-oxoethyl]-6,7-dihydro-5H-benzo[5,6][1,4]diazepino[7,1-a]indole-10-carb-
oxamide (Example 1-449) [2423]
(E)-3-[4-({1-[(13-cyclohexyl-5-methyl-3-methylsulfanyl-6,7-dihydro-5H-ben-
zo[5,6][1,4]diazepino[7,1-a]indole-10-carbonyl)amino]cyclobutanecarbonyl}a-
mino)phenyl]acrylic acid (Example 1-450) [2424]
9-chloro-13-cyclohexyl-3-methyl-5-[2-(piperidin-1-yl)ethyl]-6,7-dihydro-5-
H-benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid
dihydrochloride (Example 1-451) [2425]
9-chloro-13-cyclohexyl-3,5-dimethyl-6,7-dihydro-5H-benzo[5,6][1,4]diazepi-
no[7,1-a]indole-10-carboxylic acid (Example 1-452) [2426]
(S)-6-amino-2-({13-cyclohexyl-3-methyl-5-[2-(piperidin-1-yl)ethyl]-6,7-di-
hydro-5H-benzo[5,6][1,4]diazepino[7,1-a]indole-carbonyl}amino)hexanoic
acid dihydrochloride (Example 1-453) [2427] benzyl
4-(13-cyclohexyl-3-methyl-10-methylcarbamoyl-6,7-dihydrobenzo[5,6][1,4]di-
azepino[7,1-a]indol-5-yl)piperidine-1-carboxylate (Example 1-454)
[2428]
(E)-3-[4-({1-[(13-cyclohexyl-3,5-dimethyl-6,7-dihydro-5H-benzo[5,6][1,4]d-
iazepino[7,1-a]indole-10-carbonyl)amino]cyclobutanecarbonyl}amino)phenyl]a-
crylic acid (Example 1-455) [2429]
N-methyl-5-(1-acetylpiperidin-4-yl)-13-cyclohexyl-3-methyl-6,7-dihydro-5H-
-benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxamide (Example
1-456) [2430]
N-methyl-13-cyclohexyl-5-{2-[(S)-3-(2-methoxyethyl)piperidin-1-yl-
]-2-oxoethyl}-3-methyl-6,7-dihydro-5H-benzo[5,6][1,4]diazepino[7,1-a]indol-
e-10-carboxamide (Example 1-457) [2431]
N-methyl-13-cyclohexyl-5-[2-(4-methoxypiperidin-1-yl)-2-oxoethyl]-3-methy-
l-6,7-dihydro-5H-benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxamide
(Example 1-458) [2432]
[(13-cyclohexyl-3,5-dimethyl-6,7-dihydro-5H-benzo[5,6][1,4]diazepino[7,1--
a]indole-10-carbonyl)amino]acetic acid (Example 1-459) [2433]
methyl
4-[2-(3-chloro-13-cyclohexyl-10-methylcarbamoyl-6,7-dihydrobenzo[5,6][1,4-
]diazepino[7,1-a]indol-5-yl)ethyl]piperidine-1-carboxylate (Example
1-460) [2434]
N-methyl-13-cyclohexyl-5-[2-(4-fluorophenyl)ethyl]-3-methyl-6,7--
dihydro-5H-benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxamide
(Example 1-461) [2435]
(E)-3-[4-({1-[(13-cyclohexyl-3-isopropoxy-5-methyl-6,7-dihydro-5H-benzo[5-
,6][1,4]diazepino[7,1-a]indole-10-carbonyl)amino]cyclobutanecarbonyl}amino-
)phenyl]acrylic acid (Example 1-462) [2436]
(E)-3-[4-({1-[(13-cyclohexyl-3-fluoro-5-methyl-6,7-dihydro-5H-benzo[5,6][-
1,4]diazepino[7,1-a]indole-10-carbonyl)amino]cyclobutanecarbonyl}amino)phe-
nyl]acrylic acid (Example 1-463) [2437]
(E)-3-[4-({1-[(13-cyclohexyl-3-methoxy-5-methyl-6,7-dihydro-5H-benzo[5,6]-
[1,4]diazepino[7,1-a]indole-10-carbonyl)amino]cyclobutanecarbonyl}amino)ph-
enyl]acrylic acid (Example 1-464) [2438]
(E)-3-[4-({1-[(3-chloro-13-cyclohexyl-5-methyl-6,7-dihydro-5H-benzo[5,6][-
1,4]diazepino[7,1-a]indole-10-carbonyl)amino]cyclobutanecarbonyl}amino)phe-
nyl]acrylic acid (Example 1-465) [2439]
(E)-3-[4-({1-[(13-cyclohexyl-2,3-difluoro-5-methyl-6,7-dihydro-5H-benzo[5-
,6][1,4]diazepino[7,1-a]indole-10-carbonyl)amino]cyclobutanecarbonyl}amino-
)phenyl]acrylic acid (Example 1-466) [2440]
(E)-3-(4-{[1-({13-cyclohexyl-3-methyl-5-[2-(1,4-oxazepan-4-yl)ethyl]-6,7--
dihydro-5H-benzo[5,6][1,4]diazepino[7,1-a]indole-10-carbonyl}amino)cyclobu-
tanecarbonyl]amino}phenyl)acrylic acid (Example 1-467) [2441]
(E)-3-[4-({1-[(3-benzyloxy-13-cyclohexyl-5-methyl-6,7-dihydro-5H-benzo[5,-
6][1,4]diazepino[7,1-a]indole-10-carbonyl)amino]cyclobutanecarbonyl}amino)-
phenyl)acrylic acid (Example 1-468) [2442]
(E)-3-[4-({1-[(13-cyclohexyl-3-ethoxy-5-methyl-6,7-dihydro-5H-benzo[5,6][-
1,4]diazepino[7,1-a]indole-10-carbonyl)amino]cyclobutanecarbonyl}amino)phe-
nyl]acrylic acid (Example 1-469) [2443]
(E)-3-[4-({1-[(13-cyclohexyl-4-fluoro-5-methyl-6,7-dihydro-5H-benzo[5,6][-
1,4]diazepino[7,1-a]indole-10-carbonyl)amino]cyclobutanecarbonyl}amino)phe-
nyl]acrylic acid (Example 1-470) [2444]
(E)-3-[4-({1-[(13-cyclohexyl-3-ethyl-5-methyl-6,7-dihydro-5H-benzo[5,6][1-
,4]diazepino[7,1-a]indole-10-carbonyl)amino]cyclobutanecarbonyl}amino)phen-
yl]acrylic acid (Example 1-471) [2445]
(E)-3-[4-({1-[(5-acetyl-13-cyclohexyl-3-methyl-6,7-dihydro-5H-benzo[5,6][-
1,4]diazepino[7,1-a]indole-10-carbonyl)amino]cyclobutanecarbonyl}amino)phe-
nyl]acrylic acid (Example 1-472) [2446]
6-({1-[(12-cyclohexyl-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carbo-
nyl)amino]cyclobutanecarbonyl}amino)nicotinic acid (Example 2-54)
[2447]
({1-[(12-cyclohexyl-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carbony-
l)amino]cyclobutanecarbonyl}amino)acetic acid (Example 2-55) [2448]
N-methyl-12-cyclohexyl-4-[2-(piperidin-1-yl)ethoxy]-6,7-dihydro-5-oxa-7a--
azadibenzo[a,e]azulene-9-carboxamide monohydrochloride (Example
2-56) [2449]
(E)-3-[4-({1-[(12-cyclohexyl-3-methoxy-6,7-dihydro-5-oxa-7a-azadi-
benzo[a,e]azulene-9-carbonyl)amino]cyclobutanecarbonyl}amino)phenyl]acryli-
c acid (Example 2-57) [2450]
1-[2-(12-cyclohexyl-9-methylcarbamoyl-6,7-dihydro-5-oxa-7a-azadibenzo[a,e-
]azulen-4-yloxy)ethyl]piperidine-4-carboxylic acid
monohydrochloride (Example 2-58) [2451]
N-benzyloxy-12-cyclohexyl-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-c-
arboxamide (Example 2-59) [2452] ethyl
4-[(12-cyclohexyl-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carbonyl)-
amino]piperidine-1-carboxylate (Example 2-60) [2453]
(12-cyclohexyl-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulen-9-yl)-(4-hydrox-
ypiperidin-1-yl)-methanone (Example 2-61) [2454]
4-(12-cyclohexyl-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carbonyl)p-
iperazine-2,6-dione (Example 2-62) [2455]
1-(12-cyclohexyl-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carbonyl)p-
iperidine-4-carboxylic acid (Example 2-63) [2456]
(12-cyclohexyl-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulen-9-yl)-(piperazi-
n-1-yl)-methanone monohydrochloride (Example 2-64) [2457]
[(12-cyclohexyl-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carbonyl)am-
ino]acetic acid (Example 2-65) [2458]
[N-(12-cyclohexyl-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carbonyl)-
-N-methylamino]acetic acid (Example 2-66) [2459]
2-[(12-cyclohexyl-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carbonyl)-
amino]-4-methylpentanoic acid (Example 2-67) [2460]
2-[(12-cyclohexyl-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carbonyl)-
amino]-3-methoxypropionic acid (Example 2-68) [2461]
2-[(12-cyclohexyl-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carbonyl)-
amino]-3-methylsulfanylpropionic acid (Example 2-69) [2462]
2-[(12-cyclohexyl-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carbonyl)-
amino]-3-dimethylaminopropionic acid (Example 2-70) [2463]
(E)-3-(4-{2-[(12-cyclohexyl-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-
-carbonyl)amino]acetylamino}phenyl)acrylic acid (Example 2-71)
[2464]
1-[(12-cyclohexyl-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carbonyl)-
amino]cyclopentanecarboxylic acid (Example 2-72) [2465]
2-[(12-cyclohexyl-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carbonyl)-
amino]-2-methylpropionic acid (Example 2-73) [2466]
2-[(12-cyclohexyl-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carbonyl)-
amino]-2-phenylacetic acid (Example 2-74) [2467]
2-[(12-cyclohexyl-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carbonyl)-
amino]-3-phenylpropionic acid (Example 2-75) [2468]
2-{[(12-cyclohexyl-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carbonyl-
)amino]methyl}benzoic acid (Example 2-76) [2469]
4-{[(12-cyclohexyl-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carbonyl-
)amino]methyl}benzoic acid (Example 2-77) [2470] ethyl
(E)-3-[4-({1-[(12-cyclohexyl-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene--
9-carbonyl)amino]cyclobutanecarbonyl}amino)phenyl]acrylate (Example
2-78) [2471]
(E)-3-[4-({1-[(12-cyclohexyl-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]-
azulene-9-carbonyl)amino]cyclobutanecarbonyl}amino)phenyl]acrylic
acid (Example 2-79) [2472]
[4-(12-cyclohexyl-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carbonyl)-
piperazin-1-yl]acetic acid (Example 2-80) [2473]
3-[4-({1-[(12-cyclohexyl-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-ca-
rbonyl)amino]cyclobutanecarbonyl}amino)phenyl]propionic acid
(Example 2-81) [2474]
cis-4-[(12-cyclohexyl-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carbo-
nyl)amino]cyclohexanecarboxylic acid (Example 2-82) [2475]
6-[(12-cyclohexyl-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carbonyl)-
amino]hexanoic acid (Example 2-83) [2476]
1-{6-[(12-cyclohexyl-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carbon-
yl)amino]hexanoyl}piperidine-4-carboxylic acid (Example 2-84)
[2477]
trans-4-[(12-cyclohexyl-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-car-
bonyl)amino]cyclohexanecarboxylic acid (Example 2-85) [2478]
N-tert-butoxy-12-cyclohexyl-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-
-carboxamide (Example 2-86) [2479]
(4-{6-[(12-cyclohexyl-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carbo-
nyl)amino]hexanoylamino}phenyl)acetic acid (Example 2-87) [2480]
(4-[(12-cyclohexyl-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carbonyl-
)amino]phenyl}acetic acid (Example 2-88) [2481]
(E)-3-(4-{2-[(12-cyclohexyl-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-
-carbonyl)amino]-2-methylpropionylamino}phenyl)acrylic acid
(Example 2-89) [2482]
(E)-3-{4-[(2-[(12-cyclohexyl-6,7-dihydro-5-oxa-7a-azadibenzo[a,e-
]azulene-9-carbonyl)amino]-3-phenylpropionylamino}phenyl)acrylic
acid (Example 2-90) [2483]
4-{2-[(12-cyclohexyl-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carbon-
yl)amino]-2-methylpropionylamino}benzoic acid (Example 2-91) [2484]
3-{[(12-cyclohexyl-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carbonyl-
)amino]methyl}benzoic acid (Example 2-92) [2485]
1-(2-{4-[(12-cyclohexyl-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-car-
bonyl)amino]phenyl}acetylamino)cyclopentanecarboxylic acid (Example
2-93) [2486]
(E)-3-[4-({1-[(12-cyclohexyl-3-fluoro-6,7-dihydro-5-oxa-7a-azadib-
enzo[a,e]azulene-9-carbonyl)amino]cyclobutanecarbonyl}amino)phenyl]acrylic
acid (Example 2-94) [2487]
(E)-3-[4-({1-[(12-cyclohexyl-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene--
9-carbonyl)amino]cyclopentanecarbonyl}amino)phenyl]acrylic acid
(Example 2-95) [2488]
1-[(12-cyclohexyl-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carbonyl)-
amino]cyclopropanecarboxylic acid (Example 2-96) [2489]
1-[(12-cyclohexyl-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carbonyl)-
amino]cyclohexanecarboxylic acid (Example 2-97) [2490]
1-[(12-cyclohexyl-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carbonyl)-
amino]-4,4-dimethylcyclohexanecarboxylic acid (Example 2-98) [2491]
2-[(12-cyclohexyl-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carbonyl)-
amino]-2-ethylbutyric acid (Example 2-99) [2492]
4-({1-[(12-cyclohexyl-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carbo-
nyl)amino]cyclobutanecarbonyl}amino)benzoic acid (Example 2-100)
[2493]
(E)-3-[4-({1-[N-(12-cyclohexyl-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulen-
e-9-carbonyl)-N-methylamino]cyclobutanecarbonyl}amino)phenyl]acrylic
acid (Example 2-101) [2494]
[4-({1-[(12-cyclohexyl-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carb-
onyl)amino]cyclobutanecarbonyl}amino)phenyl]acetic acid (Example
2-102) [2495]
N-(1-phenylcarbamoylcyclobutyl)-12-cyclohexyl-6,7-dihydro-5-oxa-7-
a-azadibenzo[a,e]azulene-9-carboxamide (Example 2-103)
[2496]
4-[({1-[(12-cyclohexyl-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulen-
e-9-carbonyl)amino]cyclobutanecarbonyl}amino)methyl]benzoic acid
(Example 2-104) [2497]
(E)-3-[4-({cis-4-[(12-cyclohexyl-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azul-
ene-9-carbonyl)amino]cyclohexanecarbonyl}amino)phenyl]acrylic acid
(Example 2-105) [2498]
6-({1-[(12-cyclohexyl-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carbo-
nyl)amino]cyclobutanecarbonyl}amino)hexanoic acid (Example 2-106)
[2499]
4-[(12-cyclohexyl-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carbonyl)-
amino]benzoic acid (Example 2-107) [2500]
(N-(12-cyclohexyl-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carbonyl)-
-N-(2-methoxyethyl)amino]acetic acid (Example 2-108) [2501]
(E)-3-(4-{2-[N-(12-cyclohexyl-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-
-9-carbonyl)-N-(2-methoxyethyl)amino]acetylamino)phenyl)acrylic
acid (Example 2-109) [2502]
3-[(12-cyclohexyl-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carbonyl)-
amino]-3-methylbutyric acid (Example 2-110) [2503]
(E)-3-(4-{2-[(12-cyclohexyl-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-
-carbonyl)amino]-4-methylpentanoylamino}phenyl)acrylic acid
(Example 2-111) [2504]
1-[(12-cyclohexyl-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carbonyl)-
amino]cyclobutanecarboxylic acid (Example 2-112) [2505]
1-[N-(12-cyclohexyl-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carbony-
l)-N-methylamino]cyclobutanecarboxylic acid (Example 2-113) [2506]
4-([1-[(12-cyclohexyl-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carbo-
nyl)amino]cyclobutanecarbonyl}amino)cyclohexanecarboxylic acid
(Example 2-114) [2507]
1-{1-[(12-cyclohexyl-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carbon-
yl)amino]cyclobutanecarbonyl)piperidine-4-carboxylic acid (Example
2-115) [2508]
(E)-3-[4-({1-[(12-cyclohexyl-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]-
azulene-9-carbonyl)amino]cyclopropanecarbonyl}amino)phenyl]acrylic
acid (Example 2-116) [2509]
(E)-3-[4-({1-[(12-cyclohexyl-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene--
9-carbonyl)amino]-4,4-dimethylcyclohexanecarbonyl}amino)phenyl]acrylic
acid (Example 2-117) [2510]
(E)-3-[4-({1-[(12-cyclohexyl-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene--
9-carbonyl)amino]cyclohexanecarbonyl}amino)phenyl]acrylic acid
(Example 2-118) [2511]
(E)-3-[4-({4-[(12-cyclohexyl-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene--
9-carbonyl)amino]piperidine-1-carbonyl}amino)phenyl]acrylic acid
(Example 2-119) [2512]
N-{1-[4-(3-hydroxypropyl)phenylcarbamoyl]cyclobutyl}-12-cyclohexyl-6,7-di-
hydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carboxamide (Example 2-120)
[2513]
[4-({1-[(12-cyclohexyl-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulen-
e-9-carbonyl)amino]cyclobutanecarbonyl}amino)phenoxy]acetic acid
(Example 2-121) [2514]
(E)-3-[4-({1-[(12-cyclohexyl-4-methoxy-6,7-dihydro-5-oxa-7a-azadibenzo[a,-
e]azulene-9-carbonyl)amino]cyclobutanecarbonyl}amino)phenyl]acrylic
acid (Example 2-122) [2515]
(E)-3-(4-{2-[(12-cyclohexyl-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-
-carbonyl)amino]-2-ethylbutyrylamino}phenyl)acrylic acid (Example
2-123) [2516]
(E)-3-[4-({1-[(12-cyclohexyl-3-methyl-6,7-dihydro-5-oxa-7a-azadib-
enzo[a,e]azulene-9-carbonyl)amino]cyclobutanecarbonyl}amino)phenyl]acrylic
acid (Example 2-124) [2517]
3-{4-[(12-cyclohexyl-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carbon-
yl)sulfamoyl]phenyl}propionic acid (Example 2-125) [2518]
(E)-3-(4-{3-[(12-cyclohexyl-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-
-carbonyl)amino]-3-methylbutyrylamino}phenyl)acrylic acid (Example
2-126) [2519]
N-[1-(4-acetylphenylcarbamoyl)cyclobutyl]-12-cyclohexyl-6,7-dihyd-
ro-5-oxa-7a-azadibenzo[a,e]azulene-9-carboxamide (Example 2-127)
[2520]
2-([1-[(12-cyclohexyl-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carbo-
nyl)amino]cyclobutanecarbonyl}amino)benzoic acid (Example 2-128)
[2521]
4-(N-{1-[(12-cyclohexyl-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-car-
bonyl)amino]cyclobutanecarbonyl}-N-methylamino)benzoic acid
(Example 2-129) [2522]
3-({1-[(12-cyclohexyl-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carbo-
nyl)amino]cyclobutanecarbonyl}amino)benzoic acid (Example 2-130)
[2523]
2-[(12-cyclohexyl-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carbonyl)-
amino]-2,4-dimethylpentanoicacid (Example 2-131) [2524]
(E)-3-[4-({1-[(3-chloro-12-cyclohexyl-6,7-dihydro-5-oxa-7a-azadibenzo[a,e-
]azulene-9-carbonyl)amino]cyclobutanecarbonyl}amino)phenyl]acrylic
acid (Example 2-132) [2525]
4-{1-[(12-cyclohexyl-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carbon-
yl)amino]-1-methylethyl}benzoic acid (Example 2-133) [2526]
(E)-3-[4-({1-[(12-cyclohexyl-4-dimethylamino-6,7-dihydro-5-oxa-7a-azadibe-
nzo[a,e]azulene-9-carbonyl)amino]cyclobutanecarbonyl}amino)phenyl]acrylic
acid (Example 2-134) [2527]
(E)-3-(4-{2-[(12-cyclohexyl-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-
-carbonyl)amino]-2,4-dimethylpentanoylamino}phenyl)acrylic acid
(Example 2-135) [2528]
3-[(12-cyclohexyl-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carbonyl)-
amino]cyclohexanecarboxylic acid (Example 2-136) [2529]
(E)-3-[4-({1-[(12-cyclohexyl-1-fluoro-6,7-dihydro-5-oxa-7a-azadibenzo[a,e-
]azulene-9-carbonyl)amino]cyclobutanecarbonyl}amino)phenyl]acrylic
acid (Example 2-137) [2530]
(1R,2R)-2-[(12-cyclohexyl-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-c-
arbonyl)amino]cyclohexanecarboxylic acid (Example 2-138) [2531]
(E)-3-[4-({3-[(12-cyclohexyl-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene--
9-carbonyl)amino]cyclohexanecarbonyl}amino)phenyl]acrylic acid
(Example 2-139) [2532]
2-[(12-cyclohexyl-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carbonyl)-
amino]-3-methyl-3-methylsulfanylbutyric acid (Example 2-140) [2533]
(E)-3-[4-({1-[(12-cyclohexyl-2,3-difluoro-6,7-dihydro-5-oxa-7a-azadibenzo-
[a,e]azulene-9-carbonyl)amino]cyclobutanecarbonyl}amino)phenyl]acrylic
acid (Example 2-141) [2534]
(E)-3-[4-({(1R,2R)-2-[(12-cyclohexyl-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]-
azulene-9-carbonyl)amino]cyclohexanecarbonyl}amino)phenyl]acrylic
acid (Example 2-142) [2535]
2-[(12-cyclohexyl-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carbonyl)-
amino]-3,3-dimethylbutyric acid (Example 2-143) [2536]
(E)-3-(4-{2-[(12-cyclohexyl-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-
-carbonyl)amino]-3,3-dimethylbutyrylamino}phenyl)acrylic acid
(Example 2-144) [2537]
4-[1-({1-[(12-cyclohexyl-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-ca-
rbonyl)amino]cyclobutanecarbonyl}amino)-1-methylethyl]benzoic acid
(Example 2-145) [2538]
N-[1-(2-hydroxyethylcarbamoyl)cyclobutyl]-12-cyclohexyl-6,7-dihydro-5-oxa-
-7a-azadibenzo[a,e]azulene-9-carboxamide (Example 2-146) [2539]
N-[1-(2-methoxyethylcarbamoyl)cyclobutyl]-12-cyclohexyl-6,7-dihydro-5-oxa-
-7a-azadibenzo[a,e]azulene-9-carboxamide (Example 2-147) [2540]
12-cyclohexyl-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carboxamide
(Example 2-148) [2541]
N-[(1R,2R)-2-(4-cyanophenylamino)cyclohexyl]-12-cyclohexyl-6,7-dihydro-5--
oxa-7a-azadibenzo[a,e]azulene-9-carboxamide (Example 2-149). [2542]
(E)-3-[3-({1-[(12-cyclohexyl-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene--
9-carbonyl)amino]cyclobutanecarbonyl}amino)phenyl]acrylic acid
(Example 2-150) [2543] methyl
(S)-2-[(13-cyclohexyl-3,5-dimethyl-6,7-dihydro-5H-benzo[5,6][1,4]diazepin-
o[7,1-a]indole-10-carbonyl)amino]-3-(4-hydroxyphenyl)propionate
(Example 1-473) [2544]
13-cyclohexyl-5-ethyl-3-methoxy-6,7-dihydro-5H-benzo[5,6][1,4]diazepino[7-
,1-a]indole-10-carboxylic acid (Example 1-474) [2545]
13-cyclohexyl-5-isopropyl-3-methoxy-6,7-dihydro-5H-benzo[5,6][1,4]diazepi-
no[7,1-a]indole-10-carboxylic acid monohydrochloride (Example
1-475) [2546] sodium salt of
13-cyclohexyl-3-methyl-5-[2-(1,4-oxazepan-4-yl)-2-oxoethyl]-6,7-dihydro-5-
H-benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid (Example
1-476) [2547]
(E)-3-[4-({1-[(13-cyclohexyl-5-ethyl-3-methoxy-6,7-dihydro-5H-be-
nzo[5,6][1,4]diazepino[7,1-a]indole-10-carbonyl)amino]cyclobutanecarbonyl}-
amino)phenyl]acrylic acid (Example 1-477) [2548]
(E)-3-[4-({1-[(13-cyclohexyl-5-isopropyl-3-methoxy-6,7-dihydro-5H-benzo[5-
,6][1,4]diazepino[7,1-a]indole-10-carbonyl)amino]cyclobutanecarbonyl}amino-
)phenyl]acrylic acid (Example 1-478) [2549]
13-cyclohexyl-3-methoxy-5-(2-methoxyethyl)-6,7-dihydro-5H-benzo[5,6][1,4]-
diazepino[7,1-a]indole-10-carboxylic acid (Example 1-479) [2550]
13-cyclohexyl-5-(2-isopropoxyethyl)-3-methoxy-6,7-dihydro-5H-benzo[5,6][1-
,4]diazepino[7,1-a]indole-10-carboxylic acid (Example 1-480) [2551]
(E)-3-{4-[(1-{[13-cyclohexyl-3-methoxy-5-(2-methoxyethyl)-6,7-dihydro-5H--
benzo[5,6][1,4]diazepino[7,1-a]indole-10-carbonyl]amino}cyclobutanecarbony-
l)amino]phenyl}acrylic acid (Example 1-481) [2552]
(E)-3-{4-[(1-{[13-cyclohexyl-5-(2-isopropoxyethyl)-3-methoxy-6,7-dihydro--
5H-benzo[5,6][1,4]diazepino[7,1-a]indole-10-carbonyl]amino}cyclobutanecarb-
onyl)amino]phenyl}acrylic acid (Example 1-482) [2553]
13-cyclohexyl-5-isobutyl-3-methoxy-6,7-dihydro-5H-benzo[5,6][1,4]diazepin-
o[7,1-a]indole-10-carboxylic acid (Example 1-483) [2554]
(E)-3-[4-({1-[(13-cyclohexyl-5-isobutyl-3-methoxy-6,7-dihydro-5H-benzo[5,-
6][1,4]diazepino[7,1-a]indole-10-carbonyl)amino]cyclobutanecarbonyl}amino)-
phenyl]acrylic acid (Example 1-484) [2555]
1-({1-[(12-cyclohexyl-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carbo-
nyl)amino]cyclobutanecarbonyl}amino)cyclobutanecarboxylic acid
(Example 2-151) [2556] methyl
2-{1-[(12-cyclohexyl-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carbon-
yl)amino]cyclobutyl}-3H-benzimidazole-5-carboxylate (Example 2-152)
[2557]
4-{(1R,2R)-2-[(12-cyclohexyl-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]-
azulene-9-carbonyl)amino]cyclohexylamino}benzoic acid (Example
2-153) [2558]
2-[(12-cyclohexyl-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-c-
arbonyl)amino]-3-methoxy-2-methylpropionic acid (Example 2-154)
[2559] tert-butyl
4-[4-((E)-2-carboxyvinyl)phenylcarbamoyl]-4-[(12-cyclohexyl-6,7-dihydro-5-
-oxa-7a-azadibenzo[a,e]azulene-9-carbonyl)amino]piperidine-1-carboxylate
(Example 2-155) [2560]
4-{2-[(12-cyclohexyl-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carbon-
yl)amino]-2-methylpropoxy}benzoic acid (Example 2-156) [2561]
N-[2-(4-cyanophenoxy)-1,1-dimethylethyl]-12-cyclohexyl-6,7-dihydro-5-oxa--
7a-azadibenzo[a,e]azulene-9-carboxamide (Example 2-157) [2562]
N-[2-(4-cyanophenylamino)-1,1-dimethylethyl]-12-cyclohexyl-6,7-dihydro-5--
oxa-7a-azadibenzo[a,e]azulene-9-carboxamide (Example 2-158) [2563]
N-(2-hydroxy-1,1-dimethylethyl)-12-cyclohexyl-6,1-dihydro-5-oxa-7a-azadib-
enzo[a,e]azulene-9-carboxamide (Example 2-159) [2564]
2-{1-[(12-cyclohexyl-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carbon-
yl)amino]cyclobutyl}-3H-benzimidazole-5-carboxylic acid (Example
2-160) [2565]
12-cyclohexyl-4-{N-isopropyl-N-[2-(piperidin-1-yl)ethyl]amino}-6,-
7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carboxylic acid
dihydrochloride (Example 2-161) [2566]
12-cyclohexyl-4-[N-(2-dimethylaminoethyl)-N-methylamino]-6,7-dihydro-5-ox-
a-7a-azadibenzo[a,e]azulene-9-carboxylic acid dihydrochloride
(Example 2-162) [2567]
(E)-3-(4-{2-[(12-cyclohexyl-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-
-carbonyl)amino]-3-methoxy-2-methylpropionylamino}phenyl)acrylic
acid (Example 2-163) [2568]
N-[2-(2-hydroxyethoxy)ethyl]-12-cyclohexyl-6,7-dihydro-5-oxa-7a-azadibenz-
o[a,e]azulene-9-carboxamide (Example 2-164) [2569]
N-tert-butyl-12-cyclohexyl-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9--
carboxamide (Example 2-165) [2570]
N-(trans-4-hydroxycyclohexyl)-12-cyclohexyl-6,7-dihydro-5-oxa-7a-azadiben-
zo[a,e]azulene-9-carboxamide (Example 2-166) [2571]
2-{1-[(12-cyclohexyl-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carbon-
yl)amino]-1-methylethyl}thiazole-4-carboxylic acid (Example 2-167)
[2572]
12-cyclohexyl-4-{N-ethyl-N-[2-(1,4-oxazepan-4-yl)ethyl]amino}-6,7-dihydr-
o-5-oxa-7a-azadibenzo[a,e]azulene-9-carboxylic acid dihydrochloride
(Example 2-168) [2573]
12-cyclohexyl-4-{N-ethyl-N-[3-(piperidin-1-yl)propyl]amino}-6,7-dihydro-5-
-oxa-7a-azadibenzo[a,e]azulene-9-carboxylic acid dihydrochloride
(Example 2-169) [2574]
12-cyclohexyl-4-{N-ethyl-N-[2-(morpholin-4-yl)ethyl]amino}-6,7-dihydro-5--
oxa-7a-azadibenzo[a,e]azulene-9-carboxylic acid dihydrochloride
(Example 2-170) [2575]
N-[1-(4-hydroxymethylphenyl)-1-methylethyl]-12-cyclohexyl-6,7-dihydro-5-o-
xa-7a-azadibenzo[a,e]azulene-9-carboxamide (Example 2-171) [2576]
ethyl
2-{1-[(12-cyclohexyl-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carbon-
yl)amino]-1-methylethyl}thiazole-4-carboxylate (Example 2-172)
[2577]
N-methyl-12-cyclohexyl-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carb-
oxamide (Example 2-173) [2578]
(E)-3-[4-({4-[(12-cyclohexyl-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene--
9-carbonyl)amino]piperidine-4-carbonyl}amino)phenyl]acrylic acid
(Example 2-174) [2579] methyl
(S)-2-[(12-cyclohexyl-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carbo-
nyl)amino]-3-(4-hydroxyphenyl)propionate (Example 2-175) [2580]
12-cyclohexyl-4-(dimethylcarbamoylmethylamino)-6,7-dihydro-5-oxa-7a-azadi-
benzo[a,e]azulene-9-carboxylic acid (Example 2-176) [2581]
N-[1-(trans-4-hydroxycyclohexylcarbamoyl)-1-methylethyl]-12-cyclohexyl-6,-
7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carboxamide (Example
2-177) [2582]
12-cyclohexyl-4-{N-ethyl-N-[2-(piperidin-1-yl)acetyl]amino}-6,7-d-
ihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carboxylic acid
monohydrochloride (Example 2-178) [2583]
N-(4-benzyloxyphenyl)-12-cyclohexyl-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]a-
zulene-9-carboxamide (Example 2-179) [2584]
(S)-2-[(12-cyclohexyl-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carbo-
nyl)amino]-3-(4-hydroxyphenyl)propionic acid (Example 2-180) [2585]
1-acetyl-4-[(12-cyclohexyl-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9--
carbonyl)amino]piperidine-4-carboxylic acid (Example 2-181) [2586]
4-[(12-cyclohexyl-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carbonyl)-
amino]-1-methylpiperidine-4-carboxylic acid (Example 2-182) [2587]
4-{2-[(12-cyclohexyl-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carbon-
yl)amino]-2-methylpropylamino}benzoic acid (Example 2-183) [2588]
N-[2-(4-carbamoylphenylamino)-1,1-dimethylethyl]-12-cyclohexyl-6,7-dihydr-
o-5-oxa-7a-azadibenzo[a,e]azulene-9-carboxamide (Example 2-184)
[2589] tert-butyl
{2-[(12-cyclohexyl-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carbonyl-
)amino]-2-methylpropyl}carbamate (Example 2-185) [2590]
N-(2-amino-1,1-dimethylethyl)-12-cyclohexyl-6,7-dihydro-5-oxa-7a-azadiben-
zo[a,e]azulene-9-carboxamide monohydrochloride (Example 2-186)
[2591]
(2-[(12-cyclohexyl-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carbonyl-
)amino]-2-methylpropylamino)acetic acid (Example 2-187) [2592]
N-[1,1-dimethyl-2-(4-nitrophenoxy)ethyl]-12-cyclohexyl-6,7-dihydro-5-oxa--
7a-azadibenzo[a,e]azulene-9-carboxamide (Example 2-188) [2593]
2-[(12-cyclohexyl-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carbonyl)-
amino]-3-dimethylamino-2-methylpropionic acid (Example 2-189)
[2594]
N-[2-(4-hydroxypiperidin-1-yl)-1,1-dimethyl-2-oxoethyl]-12-cyclohexyl-6,7-
-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carboxamide (Example
2-190) [2595]
4-{N-benzyl-N-[2-(piperidin-1-yl)ethyl]amino}-12-cyclohexyl-6,7-d-
ihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carboxylic acid
dihydrochloride (Example 2-191)
[2596]
N-(4-hydroxyphenyl)-12-cyclohexyl-6,7-dihydro-5-oxa-7a-azadibenzo-
[a,e]azulene-9-carboxamide (Example 2-192) [2597]
N-[1-(4-carbamoylphenylcarbamoyl)-1-methylethyl]-12-cyclohexyl-6,7-dihydr-
o-5-oxa-7a-azadibenzo[a,e]azulene-9-carboxamide (Example 2-193)
[2598]
N-[1-(4-dimethylcarbamoylphenylcarbamoyl)-1-methylethyl]-12-cyclohexyl-6,-
7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carboxamide (Example
2-194) [2599]
N-[1-(4-hydroxymethylphenylcarbamoyl)-1-methylethyl]-12-cyclohexy-
l-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carboxamide
(Example 2-195) [2600] methyl
2-{1-[(12-cyclohexyl-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carbon-
yl)amino]-1-methylethyl}-3H-benzimidazole-5-carboxylate (Example
2-196) [2601]
2-{[(12-cyclohexyl-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9--
carbonyl)amino]methyl}-3H-benzimidazole-5-carboxylic acid (Example
2-197) [2602]
N-[1-(1H-benzimidazol-2-yl)-1-methylethyl]-12-cyclohexyl-6,7-dihy-
dro-5-oxa-7a-azadibenzo[a,e]azulene-9-carboxamide (Example 2-198)
[2603]
N-[1-(5-chloro-1H-benzimidazol-2-yl)-1-methylethyl]-12-cyclohexyl-6,7-dih-
ydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carboxamide (Example 2-199)
[2604]
5-{2-[(12-cyclohexyl-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carbo-
nyl)amino]-2-methylpropionylamino}-2-methylbenzoic acid (Example
2-200) [2605]
3-{2-[(12-cyclohexyl-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene--
9-carbonyl)amino]-2-methylpropionylamino}benzoic acid (Example
2-201) [2606]
N-[1-(4-hydroxyphenylcarbamoyl)-1-methylethyl]-12-cyclohexyl-6,7--
dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carboxamide (Example
2-202) [2607]
N-{1-[2-(4-hydroxyphenyl)ethylcarbamoyl]-1-methylethyl}-12-cycloh-
exyl-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carboxamide
(Example 2-203) [2608]
N-[1-(4-fluorophenylcarbamoyl)-1-methylethyl]-12-cyclohexyl-6,7-dihydro-5-
-oxa-7a-azadibenzo[a,e]azulene-9-carboxamide (Example 2-204) [2609]
N-[2-(4-hydroxyphenyl)ethyl]-12-cyclohexyl-6,7-dihydro-5-oxa-7a-azadibenz-
o[a,e]azulene-9-carboxamide (Example 2-205) [2610]
N-(1-hydroxycyclohexylmethyl)-12-cyclohexyl-6,7-dihydro-5-oxa-7a-azadiben-
zo[a,e]azulene-9-carboxamide (Example 2-206) [2611]
N--[(S)-1-carbamoyl-2-(4-hydroxyphenyl)ethyl]-12-cyclohexyl-6,7-dihydro-5-
-oxa-7a-azadibenzo[a,e]azulene-9-carboxamide (Example 2-207) [2612]
4-{1-[(12-cyclohexyl-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carbon-
yl)amino]-1-methylethyl}cyclohexanecarboxylic acid (Example 2-208)
[2613] methyl
2-{1-[(12-cyclohexyl-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene--
9-carbonyl)amino]-1-methylethyl]-5-methyl-3H-imidazole-4-carboxylate
(Example 2-209) [2614] methyl
2-[(12-cyclohexyl-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carbonyl)-
amino]-3-(5-hydroxy-1H-indol-2-yl)propionate (Example 2-210) [2615]
N-{2-[(12-cyclohexyl-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carbon-
yl)amino]-2-methylpropyl}terephthalamic acid (Example 2-211) [2616]
methyl
N-{2-[(12-cyclohexyl-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-
-carbonyl)amino]-2-methylpropyl}-terephthalamate (Example 2-212)
[2617]
N-[1-(4-dimethylaminomethylphenylcarbamoyl)-1-methylethyl]-12-cyclohexyl--
6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carboxamide (Example
2-213) [2618]
2-{1-[(12-cyclohexyl-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene--
9-carbonyl)amino]-1-methylethyl}-1H-benzimidazole-5-carboxylic acid
(Example 2-214) [2619] methyl
4-{2-[(12-cyclohexyl-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carbon-
yl)amino]-2-methylpropyl}benzoate (Example 2-215) [2620]
4-{2-[(12-cyclohexyl-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carbon-
yl)amino]-2-methylpropyl}benzoic acid (Example 2-216) [2621]
N--[(S)-1-hydroxymethyl-2-(4-hydroxyphenyl)ethyl]-12-cyclohexyl-6,7-dihyd-
ro-5-oxa-7a-azadibenzo[a,e]azulene-9-carboxamide (Example 2-217)
[2622] methyl
(S)-2-[(12-cyclohexyl-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene--
9-carbonyl)amino]-3-(4-methoxyphenyl)propionate (Example 2-218)
[2623]
N-[2-(4-methoxyphenyl)-1,1-dimethylethyl]-12-cyclohexyl-6,7-dihydro-5-oxa-
-7a-azadibenzo[a,e]azulene-9-carboxamide (Example 2-219) [2624]
N-[2-(4-hydroxyphenyl)-1,1-dimethylethyl]-12-cyclohexyl-6,7-dihydro-5-oxa-
-7a-azadibenzo[a,e]azulene-9-carboxamide (Example 2-220) [2625]
12-cyclohexyl-4-{N-phenethyl-N-[2-(piperidin-1-yl)ethyl]amino}-6,7-dihydr-
o-5-oxa-7a-azadibenzo[a,e]azulene-9-carboxylic acid (Example 2-221)
[2626]
(E)-3-[4-({1-acetyl-4-[(12-cyclohexyl-6,7-dihydro-5-oxa-7a-azadib-
enzo[a,e]azulene-9-carbonyl)amino]piperidine-4-carbonyl}amino)phenyl]acryl-
ic acid (Example 2-222) [2627]
(E)-3-[4-({4-[(12-cyclohexyl-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene--
9-carbonyl)amino]-1-methylpiperidine-4-carbonyl]amino)phenyl]acrylic
acid (Example 2-223) [2628]
N-[2-(4-aminophenoxy)-1,1-dimethylethyl]-12-cyclohexyl-6,7-dihydro-5-oxa--
7a-azadibenzo[a,e]azulene-9-carboxamide (Example 2-224) [2629]
N-[1-(6-carbamoyl-1H-benzimidazol-2-yl)-1-methylethyl]-12-cyclohexyl-6,7--
dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carboxamide (Example
2-225) [2630]
N-{1,1-dimethyl-2-[4-(2-oxopyrrolidin-1-yl)phenoxy]ethyl}-12-cycl-
ohexyl-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carboxamide
(Example 2-226) [2631]
2-{1-[(12-cyclohexyl-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carbon-
yl)amino]-1-methylethyl}-5-methyl-3H-imidazole-4-carboxylic acid
(Example 2-227) [2632]
N-[1-(4-benzyloxyphenyl)-1-methylethyl]-12-cyclohexyl-6,7-dihydro-5-oxa-7-
a-azadibenzo[a,e]azulene-9-carboxamide (Example 2-228) [2633]
1-carboxymethyl-4-[(12-cyclohexyl-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azu-
lene-9-carbonyl)amino]piperidine-4-carboxylic acid
monohydrochloride (Example 2-229) [2634]
N-[1-(4-hydroxyphenyl)-1-methylethyl]-12-cyclohexyl-6,7-dihydro-5-oxa-7a--
azadibenzo[a,e]azulene-9-carboxamide (Example 2-230) [2635]
4-{N-[2-(azepan-1-yl)ethyl]-N-ethylamino}-12-cyclohexyl-6,7-dihydro-5-oxa-
-7a-azadibenzo[a,e]azulene-9-carboxylic acid dihydrochloride
(Example 2-231) [2636]
4-{N-[2-(1-acetylpiperidin-4-yl)ethyl]-N-ethylamino)-12-cyclohexyl-6,7-di-
hydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carboxylic acid (Example
2-232) [2637]
4-(N-acetyl-N-[2-(1-acetylpiperidin-4-yl)ethyl]amino}-12-cyclohex-
yl-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carboxylic acid
(Example 2-233) [2638]
N-[2-(4-hydroxypiperidin-1-yl)-1,1-dimethylethyl]-12-cyclohexyl-6,7-dihyd-
ro-5-oxa-7a-azadibenzo[a,e]azulene-9-carboxamide (Example 2-234)
[2639] methyl
2-{1-[(12-cyclohexyl-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-
-carbonyl)amino]-1-methylethyl}-5-methyloxazole-4-carboxylate
(Example 2-235) [2640]
2-{1-[(12-cyclohexyl-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carbon-
yl)amino]-1-methylethyl}-5-methyloxazole-4-carboxylic acid (Example
2-236) [2641]
(S)-2-[(12-cyclohexyl-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulen-
e-9-carbonyl)amino]-3-(4-methoxyphenyl)propionic acid (Example
2-237) [2642] methyl
(R)-2-[(12-cyclohexyl-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carbo-
nyl)amino]-3-(4-hydroxyphenyl)propionate (Example 2-238) [2643]
N-[2-(trans-4-hydroxycyclohexylamino)-1,1-dimethylethyl]-12-cyclohexyl-6,-
7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carboxamide (Example
2-239) [2644]
N-[2-(3-hydroxypiperidin-1-yl)-1,1-dimethyl-2-oxoethyl]-12-cycloh-
exyl-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carboxamide
(Example 2-240) [2645]
(4-{1-[(12-cyclohexyl-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carbo-
nyl)amino]-1-methylethyl}phenoxy)acetic acid (Example 2-241) [2646]
N-[2-(4-hydroxymethylpiperidin-1-yl)-1,1-dimethyl-2-oxoethyl]-12-cyclohex-
yl-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carboxamide
(Example 2-242) [2647]
12-cyclohexyl-4-{N-ethyl-N-[2-(1-ethylpiperidin-4-yl)ethyl]amino}-6,7-dih-
ydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carboxylic acid
dihydrochloride (Example 2-243) [2648]
N-{2-[4-(2-hydroxyethyl)piperazin-1-yl]-1,1-dimethylethyl}-12-cyclohexyl--
6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carboxamide (Example
2-244) [2649]
[(S)-2-(4-hydroxyphenyl)-1-(methylcarbamoyl)ethyl]-12-cyclohexyl--
6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carboxamide (Example
2-245) [2650]
(R)-2-[(12-cyclohexyl-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-
-9-carbonyl)amino]-3-(4-hydroxyphenyl)propionic acid (Example
2-246) [2651]
{4-(1H-benzimidazol-2-yl)-4-[(12-cyclohexyl-6,7-dihydro-5-oxa-7a--
azadibenzo[a,e]azulene-9-carbonyl)amino]piperidin-1-yl}acetic acid
(Example 2-247) [2652] methyl
(4-(1H-benzimidazol-2-yl)-4-[(12-cyclohexyl-6,7-dihydro-5-oxa-7a-azadiben-
zo[a,e]azulene-9-carbonyl)amino]piperidin-1-yl]acetate
monohydrochloride (Example 2-248) [2653]
N-(1-methyl-1H-benzimidazol-2-ylmethyl)-12-cyclohexyl-6,7-dihydro-5-oxa-7-
a-azadibenzo[a,e]azulene-9-carboxamide (Example 2-249) [2654]
(2-{[(12-cyclohexyl-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carbony-
l)amino]methyl}benzimidazol-1-yl)acetic acid (Example 2-250) [2655]
methyl
(2-{[(12-cyclohexyl-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9--
carbonyl)amino]methyl}benzimidazol-1-yl)acetate (Example 2-251)
[2656]
N-(1H-benzimidazol-2-ylmethyl)-12-cyclohexyl-6,7-dihydro-5-oxa-7a-azadibe-
nzo[a,e]azulene-9-carboxamide (Example 2-252) [2657]
2-[(12-cyclohexyl-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carbonyl)-
amino]-3-(5-hydroxy-1H-indol-2-yl)propionic acid (Example 2-253)
[2658]
(E)-3-{2-[(12-cyclohexyl-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-ca-
rbonyl)amino]-2-methylpropylamino}acrylic acid (Example 2-254)
[2659]
6-{2-[(12-cyclohexyl-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carbon-
yl)amino]-2-methylpropylamino}nicotinic acid (Example 2-255) [2660]
4-{N-(2-benzyloxyethyl)-N-[2-(piperidin-1-yl)ethyl]amino}-12-cyclohexyl-6-
,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carboxylic acid
dihydrochloride (Example 2-256) [2661]
12-cyclohexyl-4-(N-(2-isopropoxyethyl)-N-[2-(piperidin-1-yl)ethyl]amino}--
6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carboxylic acid
dihydrochloride (Example 2-257) [2662]
N-[1-(4,5-dimethyl-1H-imidazol-2-yl)-1-methylethyl]-12-cyclohexyl-6,7-dih-
ydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carboxamide (Example 2-258)
[2663]
N-[1-methyl-1-(1,4,5-trimethyl-1H-imidazol-2-yl)ethyl]-12-cyclohexyl-6,7-
-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carboxamide (Example
2-259) [2664]
N-[1-(3-hydroxyphenylcarbamoyl)-1-methylethyl]-12-cyclohexyl-6,7--
dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carboxamide (Example
2-260) [2665]
12-cyclohexyl-4-{N-(2-hydroxyethyl)-N-[2-(piperidin-1-yl)ethyl]am-
ino}-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carboxylic acid
dihydrochloride (Example 2-261) [2666]
N--[(S)-1-dimethylcarbamoyl-2-(4-hydroxyphenyl)ethyl]-12-cyclohexyl-3-met-
hoxy-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carboxamide
(Example 2-262) [2667]
N--[(S)-2-(4-hydroxyphenyl)-1-(methylcarbamoyl)ethyl]-12-cyclohexyl-3-met-
hoxy-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carboxamide
(Example 2-263) [2668] methyl
(2-{1-[(12-cyclohexyl-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carbo-
nyl)amino]-1-methylethyl}-4,5-dimethylimidazol-1-yl)acetate
(Example 2-264) [2669]
(2-{1-[(12-cyclohexyl-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carbo-
nyl)amino]-1-methylethyl}-4,5-dimethylimidazol-1-yl)acetic acid
(Example 2-265) [2670] methyl
2-[(12-cyclohexyl-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carbonyl)-
amino]-3H-benzimidazole-5-carboxylate (Example 2-266) [2671]
N-(1H-benzimidazol-2-yl)-12-cyclohexyl-6,7-dihydro-5-oxa-7a-azadibenzo[a,-
e]azulene-9-carboxamide (Example 2-267) [2672]
2-[(12-cyclohexyl-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carbonyl)-
amino]-3H-benzimidazole-5-carboxylic acid (Example 2-268) [2673]
N-[1-(6-cyano-1H-benzimidazol-2-yl)-1-methylethyl]-12-cyclohexyl-6,7-dihy-
dro-5-oxa-7a-azadibenzo[a,e]azulene-9-carboxamide (Example 2-269)
[2674] methyl
(S)-2-[(12-cyclohexyl-3-methoxy-6,7-dihydro-5-oxa-7a-azadibenzo[a,-
e]azulene-9-carbonyl)amino]-2-(4-hydroxyphenyl)acetate (Example
2-270) [2675] methyl
(R)-2-[(12-cyclohexyl-3-methoxy-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azule-
ne-9-carbonyl)amino]-2-(4-hydroxyphenyl)acetate (Example 2-271)
[2676]
12-cyclohexyl-4-{N-ethyl-N-[2-(4-methoxypiperidin-1-yl)ethyl]amino}-6,7-d-
ihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carboxylic acid
dihydrochloride (Example 2-272) [2677]
12-cyclohexyl-4-phenyl-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carb-
oxylic acid (Example 2-273) [2678]
12-cyclohexyl-4-{N-ethyl-N-[2-(3-methoxymethylpiperidin-1-yl)ethyl]amino}-
-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carboxylic acid
dihydrochloride (Example 2-274) [2679]
12-cyclohexyl-4-{N-ethyl-N-[2-(4-methoxymethylpiperidin-1-yl)ethyl]amino}-
-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carboxylic acid
dihydrochloride (Example 2-275) [2680]
2-[(12-cyclohexyl-4-{N-[2-(piperidin-1-yl)ethyl]-N-propylamino}-6,7-dihyd-
ro-5-oxa-7a-azadibenzo[a,e]azulene-9-carbonyl)amino]-2-methylpropionic
acid (Example 2-276) [2681]
4-{bis[2-oxo-2-(piperidin-1-yl)ethyl]amino}-12-cyclohexyl-6,7-dihydro-5-o-
xa-7a-azadibenzo[a,e]azulene-9-carboxylic acid (Example 2-277)
[2682]
4-{bis[2-(piperidin-1-yl)ethyl]amino}-12-cyclohexyl-6,7-dihydro-5-oxa-7a--
azadibenzo[a,e]azulene-9-carboxylic acid dihydrochloride (Example
2-278) [2683] methyl
(S)-2-[(12-cyclohexyl-3-methoxy-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azule-
ne-9-carbonyl)amino]-3-(4-fluorophenyl)propionate (Example 2-279)
[2684] methyl
(S)-2-[(12-cyclohexyl-3-methoxy-6,7-dihydro-5-oxa-7a-azadibenzo[a,-
e]azulene-9-carbonyl)amino]-3-(1H-imidazol-4-yl)propionate (Example
2-280) [2685] methyl
(S)-2-(12-cyclohexyl-3-methoxy-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulen-
e-9-carbonyl)-7-hydroxy-1,2,3,4-tetrahydroisoquinoline-3-carboxylate
(Example 2-281) [2686] methyl
2-{1-[(12-cyclohexyl-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carbon-
yl)amino]-1-methylethyl}-6-methyl-3H-benzimidazole-5-carboxylate
(Example 2-282) [2687]
2-[(1-[(12-cyclohexyl-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carbo-
nyl)amino]-1-methylethyl}-6-methyl-3H-benzimidazole-5-carboxylic
acid (Example 2-283) [2688] methyl
(2-{1-[(12-cyclohexyl-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carbo-
nyl)amino]-1-methylethyl}benzimidazol-1-yl)acetate (Example 2-284)
[2689]
N-[1-methyl-1-(1-methyl-1H-benzimidazol-2-yl)ethyl]-12-cyclohexyl-6,7-di-
hydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carboxamide (Example 2-285)
[2690]
N-(1-methyl-1H-benzimidazol-2-yl)-12-cyclohexyl-6,7-dihydro-5-oxa-
-7a-azadibenzo[a,e]azulene-9-carboxamide (Example 2-286) [2691]
{4-[(12-cyclohexyl-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carbonyl-
)amino]-4-hydroxymethylpiperidin-1-yl}acetic acid monohydrochloride
(Example 2-287) [2692]
N-[1-(2-hydroxyethyl)-1H-benzimidazol-2-ylmethyl]-12-cyclohexyl-6,7-dihyd-
ro-5-oxa-7a-azadibenzo[a,e]azulene-9-carboxamide (Example 2-288)
[2693]
N-[1,1-dimethyl-2-(morpholin-4-yl)-2-oxoethyl]-12-cyclohexyl-6,7-dihydro--
5-oxa-7a-azadibenzo[a,e]azulene-9-carboxamide (Example 2-289)
[2694]
N-[1,1-dimethyl-2-(4-methylpiperazin-1-yl)-2-oxoethyl]-12-cyclohexyl-6,7--
dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carboxamide (Example
2-290) [2695]
N-[1,1-dimethyl-2-oxo-2-(4-phenylpiperazin-1-yl)ethyl]-12-cyclohe-
xyl-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carboxamide
(Example 2-291)
[2696]
N-{1-[1-(2-hydroxyethyl)-4,5-dimethyl-1H-imidazol-2-yl]-1-methyle-
thyl}-12-cyclohexyl-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carboxam-
ide (Example 2-292) [2697]
N-[1-(1-dimethylcarbamoylmethyl-4,5-dimethyl-1H-imidazol-2-yl)-1-methylet-
hyl]-12-cyclohexyl-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carboxami-
de (Example 2-293) [2698]
N-[2-(4-methoxypiperidin-1-yl)-1,1-dimethyl-2-oxoethyl]-12-cyclohexyl-6,7-
-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carboxamide (Example
2-294) [2699]
N-{(S)-2-(4-hydroxyphenyl)-1-[N-(2-methoxyethyl)-N-methylcarbamoy-
l]ethyl}-12-cyclohexyl-3-methoxy-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azule-
ne-9-carboxamide (Example 2-295) [2700]
N--[(S)-2-(4-hydroxyphenyl)-1-(2-methoxyethylcarbamoyl)ethyl]-12-cyclohex-
yl-3-methoxy-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carboxamide
(Example 2-296) [2701]
N--[(S)-1-(4-hydroxybenzyl)-2-(4-methoxypiperidin-1-yl)-2-oxoethyl]-12-cy-
clohexyl-3-methoxy-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carboxami-
de (Example 2-297) [2702]
12-cyclohexyl-4-(pyridin-3-yl)-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulen-
e-9-carboxylic acid monohydrochloride (Example 2-298) [2703]
12-cyclohexyl-4-(pyridin-4-yl)-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulen-
e-9-carboxylic acid monohydrochloride (Example 2-299) [2704]
12-cyclohexyl-4-{N-[2-(piperidin-1-yl)ethyl]-N-propylamino}-6,7-dihydro-5-
-oxa-7a-azadibenzo[a,e]azulene-9-carboxamide (Example 2-300) [2705]
12-cyclohexyl-4-{N-ethyl-N-[2-(4-ethylpiperazin-1-yl)-2-oxoethyl]amino}-6-
,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carboxylic acid
dihydrochloride (Example 2-301) [2706]
12-cyclohexyl-4-(3-hydroxymethylphenyl)-6,7-dihydro-5-oxa-7a-azadibenzo[a-
,e]azulene-9-carboxylic acid (Example 2-302) [2707]
N-[2-(4-acetylpiperazin-1-yl)-1,1-dimethyl-2-oxoethyl]-12-cyclohexyl-6,7--
dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carboxamide (Example
2-303) [2708]
N-{2-[4-(2-hydroxyethyl)piperazin-1-yl]-1,1-dimethyl-2-oxoethyl}--
12-cyclohexyl-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carboxamide
(Example 2-304) [2709]
N-{2-[4-(2-methoxyethyl)piperazin-1-yl]-1,1-dimethyl-2-oxoethyl}-12-cyclo-
hexyl-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carboxamide
(Example 2-305) [2710]
4-{2-[(12-cyclohexyl-4-methoxy-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulen-
e-9-carbonyl)amino]-2-methylpropionylamino}benzoic acid (Example
2-306) [2711]
N-{1-[5-(4-methoxyphenyl)-1H-imidazol-2-yl]-1-methylethyl}-12-cyc-
lohexyl-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carboxamide
(Example 2-307) [2712]
N--[(S)-2-dimethylamino-1-(4-hydroxybenzyl)ethyl]-12-cyclohexyl-3-methoxy-
-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carboxamide (Example
2-308) [2713] methyl
(S)-6-tert-butoxycarbonylamino-2-[(12-cyclohexyl-3-methoxy-6,7-dihydro-5--
oxa-7a-azadibenzo[a,e]azulene-9-carbonyl)amino]hexanoate (Example
2-309) [2714]
(S)-2-[(12-cyclohexyl-3-methoxy-6,7-dihydro-5-oxa-7a-azadibenzo[a-
,e]azulene-9-carbonyl)amino]-3-(1H-imidazol-4-yl)propionic acid
(Example 2-310) [2715]
N-{1-methyl-1-[5-(1H-tetrazol-5-yl)-1H-benzimidazol-2-yl]ethyl}-12-cycloh-
exyl-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carboxamide
(Example 2-311) [2716]
(2-{1-[(12-cyclohexyl-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carbo-
nyl)amino]-1-methylethyl}benzimidazol-1-yl)acetic acid (Example
2-312) [2717] methyl
2-{4-[(12-cyclohexyl-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carbon-
yl)amino]-1-methylpiperidin-4-yl]-3H-benzimidazole-5-carboxylate
(Example 2-313) [2718]
N--[(S)-1-(4-hydroxybenzyl)-2-methoxyethyl]-12-cyclohexyl-3-methoxy-6,7-d-
ihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carboxamide (Example
2-314) [2719] methyl
2-[(12-cyclohexyl-3-methoxy-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-
-carbonyl)amino]-3-(3-fluoro-4-hydroxyphenyl)propionate (Example
2-315) [2720] methyl
(S)-2-[(12-cyclohexyl-3-methoxy-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azule-
ne-9-carbonyl)amino]-3-(5-hydroxy-1H-indol-3-yl)propionate (Example
2-316) [2721] methyl
(S)-3-(4-benzyloxycarbonylaminophenyl)-2-[(12-cyclohexyl-3-methoxy-6,7-di-
hydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carbonyl)amino]propionate
(Example 2-317) [2722]
(S)-3-(4-benzyloxycarbonylaminophenyl)-2-[(12-cyclohexyl-3-methoxy-6,7-di-
hydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carbonyl)amino]propionic
acid (Example 2-318) [2723] methyl
(S)-3-(4-aminophenyl)-2-[(12-cyclohexyl-3-methoxy-6,7-dihydro-5-oxa-7a-az-
adibenzo[a,e]azulene-9-carbonyl)amino]propionate (Example 2-319)
[2724]
(S)-3-(4-aminophenyl)-2-[(12-cyclohexyl-3-methoxy-6,7-dihydro-5-oxa-7a-az-
adibenzo[a,e]azulene-9-carbonyl)amino]propionic acid (Example
2-320) [2725] tert-butyl
(1-{2-[(12-cyclohexyl-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carbo-
nyl)amino]-2-methylpropionyl)piperidin-4-yl)carbamate (Example
2-321) [2726]
N-[2-(3-hydroxypyrrolidin-1-yl)-1,1-dimethyl-2-oxoethyl]-12-cyclo-
hexyl-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carboxamide
(Example 2-322) [2727]
12-cyclohexyl-4-(3-methoxymethylphenyl)-6,7-dihydro-5-oxa-7a-azadibenzo[a-
,e]azulene-9-carboxylic acid (Example 2-323) [2728]
12-cyclohexyl-4-phenylamino-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-
-carboxylic acid (Example 2-324) [2729]
12-cyclohexyl-4-(2-hydroxymethylphenyl)-6,7-dihydro-5-oxa-7a-azadibenzo[a-
,e]azulene-9-carboxylic acid (Example 2-325) [2730]
N-[2-cyclohexyl-9-(1H-tetrazol-5-yl)-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]-
azulen-4-yl]-N-[2-(piperidin-1-yl)ethyl]propylamine (Example 2-326)
[2731]
12-cyclohexyl-4-(2-methoxymethylphenyl)-6,7-dihydro-5-oxa-7a-azad-
ibenzo[a,e]azulene-9-carboxylic acid (Example 2-327) [2732]
12-cyclohexyl-4-(3-dimethylaminomethylphenyl)-6,7-dihydro-5-oxa-7a-azadib-
enzo[a,e]azulene-9-carboxylic acid monohydrochloride (Example
2-328) [2733] ethyl
2-{1-[(12-cyclohexyl-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carbon-
yl)amino]-1-methylethyl}-1-methyl-1H-benzimidazole-5-carboxylate
(Example 2-329) [2734]
2-{1-[(12-cyclohexyl-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carbon-
yl)amino]-1-methylethyl}-1-methyl-1H-benzimidazole-5-carboxylic
acid (Example 2-330) [2735] methyl
2-{1-[(12-cyclohexyl-3-methoxy-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulen-
e-9-carbonyl)amino]-1-methylethyl}-6-methoxy-1H-benzimidazole-5-carboxylat-
e (Example 2-331) [2736]
2-{1-[(12-cyclohexyl-3-methoxy-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulen-
e-9-carbonyl)amino]-1-methylethyl}-1H-benzimidazole-5-carboxylic
acid (Example 2-332) [2737]
N-{1-[N-ethyl-N-(4-methoxybutyl)carbamoyl]-1-methylethyl}-12-cyclohexyl-6-
,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carboxamide (Example
2-333) [2738]
N-[2-(4-acetylaminopiperidin-1-yl)-1,1-dimethyl-2-oxoethyl]-12-cy-
clohexyl-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carboxamide
(Example 2-334) [2739]
N-[2-(4-methanesulfonylaminopiperidin-1-yl)-1,1-dimethyl-2-oxoethyl]-12-c-
yclohexyl-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carboxamide
(Example 2-335) [2740] methyl
2-{1-[(12-cyclohexyl-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carbon-
yl)amino]-1-methylethyl}-3-methyl-3H-benzimidazole-5-carboxylate
(Example 2-336) [2741]
2-{1-[(12-cyclohexyl-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carbon-
yl)amino]-1-methylethyl}-3-methyl-3H-benzimidazole-5-carboxylic
acid (Example 2-337) [2742] methyl
(S)-3-(4-acetylaminophenyl)-2-[(12-cyclohexyl-3-methoxy-6,7-dihydro-5-oxa-
-7a-azadibenzo[a,e]azulene-9-carbonyl)amino]propionate (Example
2-338) [2743] methyl
(S)-2-[(12-cyclohexyl-3-methoxy-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azule-
ne-9-carbonyl)amino]-3-(4-methanesulfonylaminophenyl)propionate
(Example 2-339) [2744]
(S)-3-(4-acetylaminophenyl)-2-[(12-cyclohexyl-3-methoxy-6,7-dihydro-5-oxa-
-7a-azadibenzo[a,e]azulene-9-carbonyl)amino]propionic acid (Example
2-340) [2745]
(S)-2-[(12-cyclohexyl-3-methoxy-6,7-dihydro-5-oxa-7a-azadibenzo[-
a,e]azulene-9-carbonyl)amino]-3-(4-methanesulfonylaminophenyl)propionic
acid (Example 2-341) [2746]
12-cyclohexyl-4-[(N-(3-methoxypropyl)-N-[2-(piperidin-1-yl)ethyl]amino}-6-
,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carboxylic acid
(Example 2-342) [2747]
12-cyclohexyl-4-(2-dimethylaminomethylphenyl)-6,7-dihydro-5-oxa-7a-azadib-
enzo[a,e]azulene-9-carboxylic acid (Example 2-343) [2748]
12-cyclohexyl-4-(2-oxopiperidin-1-yl)-6,7-dihydro-5-oxa-7a-azadibenzo[a,e-
]azulene-9-carboxylic acid (Example 2-344) [2749]
12-cyclohexyl-4-(piperidin-1-yl)-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azul-
ene-9-carboxylic acid (Example 2-345) [2750]
N-[1-(5-dimethylcarbamoyl-1H-benzimidazol-2-yl)-1-methylethyl]-12-cyclohe-
xyl-3-methoxy-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carboxamide
(Example 2-346) [2751]
2-{1-[(12-cyclohexyl-3-methoxy-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulen-
e-9-carbonyl)amino]-1-methylethyl}-6-methoxy-1H-benzimidazole-5-carboxylic
acid (Example 2-347) [2752]
N-[1-(benzoxazol-2-yl)-1-methylethyl]-12-cyclohexyl-3-methoxy-6,7-dihydro-
-5-oxa-7a-azadibenzo[a,e]azulene-9-carboxamide (Example 2-348)
[2753] methyl
4-{2-[(12-cyclohexyl-3-methoxy-6,7-dihydro-5-oxa-7a-azadibenzo[a,e-
]azulene-9-carbonyl)amino]-2-methylpropionylamino}benzoate (Example
2-349) [2754]
4-{2-[(12-cyclohexyl-3-methoxy-6,7-dihydro-5-oxa-7a-azadibenzo[a-
,e]azulene-9-carbonyl)amino]-2-methylpropionylamino}benzoic acid
(Example 2-350) [2755]
N-{1-[1-(2-hydroxyethyl)-1H-benzimidazol-2-yl]-1-methylethyl}-12-cyclohex-
yl-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carboxamide
(Example 2-351) [2756] methyl
(S)-2-[(12-cyclohexyl-3-methoxy-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azule-
ne-9-carbonyl)amino]-3-(3-trifluoromethylphenyl)propionate (Example
2-352) [2757] methyl
2-[(12-cyclohexyl-3-methoxy-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-
-carbonyl)amino]-3-(3-hydroxyphenyl)propionate (Example 2-353)
[2758]
(S)-2-[(12-cyclohexyl-3-methoxy-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azule-
ne-9-carbonyl)amino]-3-(3-trifluoromethylphenyl)propionic acid
(Example 2-354) [2759]
2-[(12-cyclohexyl-3-methoxy-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-
-carbonyl)amino]-3-(3-hydroxyphenyl)propionic acid (Example 2-355)
[2760] methyl
(S)-2-[(12-cyclohexyl-3-methoxy-6,7-dihydro-5-oxa-7a-azadibenzo[a-
,e]azulene-9-carbonyl)amino]-3-(pyridin-4-yl)propionate (Example
2-356) [2761]
4-{bis[2-(1,4-oxazepan-4-yl)-2-oxoethyl]amino}-12-cyclohexyl-6,7--
dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carboxylic acid (Example
2-357) [2762]
N-{2-[4-(4-fluorophenyl)-4-hydroxypiperidin-1-yl]-1,1-dimethyl-2--
oxoethyl]-12-cyclohexyl-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carb-
oxamide (Example 2-358) [2763]
4-{bis[2-(morpholin-4-yl)-2-oxoethyl]amino}-12-cyclohexyl-6,7-dihydro-5-o-
xa-7a-azadibenzo[a,e]azulene-9-carboxylic acid (Example 2-359)
[2764]
4-{bis[2-(1,4-oxazepan-4-yl)ethyl]amino}-12-cyclohexyl-6,7-dihydro-5-oxa--
7a-azadibenzo[a,e]azulene-9-carboxylic acid trihydrochloride
(Example 2-360) [2765]
4-{bis[2-(morpholin-4-yl)ethyl]amino}-12-cyclohexyl-6,7-dihydro-5-oxa-7a--
azadibenzo[a,e]azulene-9-carboxylic acid trihydrochloride (Example
2-361) [2766] methyl
(S)-2-[(12-cyclohexyl-3-methoxy-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azule-
ne-9-carbonyl)amino]-3-(4-methoxycarbonylaminophenyl)propionate
(Example 2-362) [2767] methyl
(S)-3-(3-chloro-4-hydroxyphenyl)-2-[(12-cyclohexyl-3-methoxy-6,7-dihydro--
5-oxa-7a-azadibenzo[a,e]azulene-9-carbonyl)amino]propionate
(Example 2-363) [2768]
(S)-2-[(12-cyclohexyl-3-methoxy-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azule-
ne-9-carbonyl)amino]-3-(4-methoxycarbonylaminophenyl)propionic acid
(Example 2-364) [2769]
(S)-3-(3-chloro-4-hydroxyphenyl)-2-[(12-cyclohexyl-3-methoxy-6,7-dihydro--
5-oxa-7a-azadibenzo[a,e]azulene-9-carbonyl)amino]propionic acid
(Example 2-365) [2770] methyl
(S)-2-[(12-cyclohexyl-3-methoxy-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azule-
ne-9-carbonyl)amino]-4-(4-hydroxyphenyl)butyrate (Example 2-366)
[2771]
N-[1-(5-dimethylamino-1H-benzimidazol-2-yl)-1-methylethyl]-12-cyclohexyl--
3-methoxy-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carboxamide
(Example 2-367) [2772]
N-[2-(4-hydroxypiperidin-1-yl)-1-methoxymethyl-2-oxoethyl]-12-cyclohexyl--
3-methoxy-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carboxamide
(Example 2-368) [2773]
N--[(S)-2-(4-benzyloxyphenyl)-1-(thiazol-2-yl)ethyl]-12-cyclohexyl-3-meth-
oxy-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carboxamide
(Example 2-369) [2774]
N-(1-methyl-1-[5-(3-methyl-1,2,4-oxadiazol-5-yl)-1H-benzimidazol-2-yl]eth-
yl}-12-cyclohexyl-3-methoxy-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9--
carboxamide (Example 2-370) [2775] tert-butyl
(S)-4-carbamoyl-2-[(12-cyclohexyl-3-methoxy-6,7-dihydro-5-oxa-7a-azadiben-
zo[a,e]azulene-9-carbonyl)amino]butyrate (Example 2-371) [2776]
(S)-4-carbamoyl-2-[(12-cyclohexyl-3-methoxy-6,7-dihydro-5-oxa-7a-azadiben-
zo[a,e]azulene-9-carbonyl)amino]butyric acid (Example 2-372) [2777]
methyl
(S)-2-[(12-cyclohexyl-3-methoxy-6,7-dihydro-5-oxa-7a-azadibenzo[a,-
e]azulene-9-carbonyl)amino]-3-(4-hydroxyphenyl)propionate (Example
2-373) [2778] methyl
2-[(12-cyclohexyl-3-methoxy-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-
-carbonyl)amino]-3-(4-trifluoromethylphenyl)propionate (Example
2-374) [2779]
(S)-2-[(12-cyclohexyl-3-methoxy-6,7-dihydro-5-oxa-7a-azadibenzo[a-
,e]azulene-9-carbonyl)amino]-3-(4-hydroxyphenyl)propionic acid
(Example 2-375) [2780]
(S)-2-[(12-cyclohexyl-3-methoxy-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azule-
ne-9-carbonyl)amino]-4-(4-hydroxyphenyl)butyric acid (Example
2-376) [2781] methyl
(S)-3-(4-tert-butoxycarbonylmethoxyphenyl)-2-[(12-cyclohexyl-3-methoxy-6,-
7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carbonyl)amino]propionate
(Example 2-377) [2782] methyl
(S)-3-(4-carboxymethoxyphenyl)-2-[(12-cyclohexyl-3-methoxy-6,7-dihydro-5--
oxa-7a-azadibenzo[a,e]azulene-9-carbonyl)amino]propionate (Example
2-378) [2783] methyl
2-[(12-cyclohexyl-3-methoxy-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-
-carbonyl)amino]-3-(4-hydroxypiperidin-1-yl)propionate
monohydrochloride (Example 2-379) [2784]
N-[1-(5-fluoro-1H-benzimidazol-2-yl)-1-methylethyl]-12-cyclohexyl-3-metho-
xy-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carboxamide
(Example 2-380) [2785]
N--[(S)-2-(4-hydroxyphenyl)-1-(thiazol-2-yl)ethyl]-12-cyclohexyl-3-methox-
y-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carboxamide
(Example 2-381) [2786] methyl
(S)-2-[(12-cyclohexyl-3-methoxy-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azule-
ne-9-carbonyl)amino]-3-[4-(methylcarbamoylmethoxy)phenyl]propionate
(Example 2-382) [2787] methyl
(S)-2-[(12-cyclohexyl-3-methoxy-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azule-
ne-9-carbonyl)amino]-3-[4-(dimethylcarbamoylmethoxy)phenyl]propionate
(Example 2-383) [2788] methyl
(4-{(S)-2-[(12-cyclohexyl-3-methoxy-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]a-
zulene-9-carbonyl)amino]-2-(methylcarbamoyl)ethyl}phenyl)carbamate
(Example 2-384)
[(S)-2-(5-hydroxy-1H-indol-3-yl)-1-(2-methylthiazol-4-yl)ethyl]-12-cycloh-
exyl-3-methoxy-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carboxamide
(Example 2-385) [2789]
N-{1-[5-(4-hydroxypiperidine-1-carbonyl)-1H-benzimidazol-2-yl]-1-methylet-
hyl}-12-cyclohexyl-3-methoxy-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-
-carboxamide (Example 2-386)
[2790]
N--[(S)-1-(2-hydroxyethylcarbamoyl)-2-(4-hydroxyphenyl)ethyl]-12--
cyclohexyl-3-methoxy-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carboxa-
mide (Example 2-387) [2791]
N--[(S)-2-(4-hydroxyphenyl)-1-(3-methyl-1,2,4-oxadiazol-5-yl)ethyl]-12-cy-
clohexyl-3-methoxy-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carboxami-
de (Example 2-388) [2792]
N--[(S)-1-(2-dimethylaminoethylcarbamoyl)-2-(4-hydroxyphenyl)ethyl]-12-cy-
clohexyl-3-methoxy-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carboxami-
de (Example 2-389) [2793]
N-{1-[5-(2-hydroxyethylcarbamoyl)-1H-benzimidazol-2-yl]-1-methylethyl}-12-
-cyclohexyl-3-methoxy-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carbox-
amide (Example 2-390) [2794] methyl
(S)-2-[(12-cyclohexyl-3-methoxy-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azule-
ne-9-carbonyl)amino]-3-[4-(3,3-dimethylureido)phenyl]propionate
(Example 2-391) [2795] methyl
(S)-2-[(12-cyclohexyl-3-methoxy-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azule-
ne-9-carbonyl)amino]-3-[4-(3-hydroxypropoxy)phenyl]propionate
(Example 2-392) [2796] methyl
2-[(12-cyclohexyl-3-methoxy-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-
-carbonyl)amino]-3-(4-hydroxymethylphenyl)propionate (Example
2-393) [2797]
N-[1-(3H-imidazo[4,5-b]pyridin-2-yl)-1-methylethyl]-12-cyclohexyl-
-3-methoxy-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carboxamide
(Example 2-394) [2798]
2-{1-[(12-cyclohexyl-3-methoxy-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulen-
e-9-carbonyl)amino]-1-methylethyl]-1-[2-(morpholin-4-yl)ethyl]-1H-benzimid-
azole-5-carboxylic acid (Example 2-395) [2799]
N-[1-methyl-1-(5-methylcarbamoyl-1H-benzimidazol-2-yl)ethyl]-12-cyclohexy-
l-3-methoxy-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carboxamide
(Example 2-396) [2800]
4-([4-[(12-cyclohexyl-3-methoxy-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azule-
ne-9-carbonyl)amino]-1-methylpiperidine-4-carbonyl)amino)benzoic
acid (Example 2-397) [2801] ethyl
4-(2-{1-[(12-cyclohexyl-3-methoxy-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azu-
lene-9-carbonyl)amino]-1-methylethyl}-3H-imidazol-4-yl)benzoate
(Example 2-398) [2802]
4-(2-{1-[(12-cyclohexyl-3-methoxy-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azu-
lene-9-carbonyl)amino]-1-methylethyl}-3H-imidazol-4-yl)benzoic acid
(Example 2-399) [2803]
4-[(12-cyclohexyl-3-methoxy-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-
-carbonyl)amino]tetrahydropyran-4-carboxylic acid (Example 2-400)
[2804]
(E)-3-[4-({4-[(12-cyclohexyl-3-methoxy-6,7-dihydro-5-oxa-7a-azadibenzo[a,-
e]azulene-9-carbonyl)amino]tetrahydropyran-4-carbonyl}amino)phenyl]acrylic
acid (Example 2-401) [2805]
4-({4-[(12-cyclohexyl-3-methoxy-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azule-
ne-9-carbonyl)amino]tetrahydropyran-4-carbonyl}amino)benzoic acid
(Example 2-402) [2806]
2-{1-[(12-cyclohexyl-3-methoxy-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulen-
e-9-carbonyl)amino]-1-methylethyl}-4-oxo-3,4-dihydroquinazoline-7-carboxyl-
ic acid (Example 2-403) [2807]
2-{1-[(12-cyclohexyl-3-methoxy-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulen-
e-9-carbonyl)amino]-1-methylethyl]-4-dimethylaminoquinazoline-7-carboxylic
acid (Example 2-404) [2808]
N-[1-(5-hydroxymethyl-1H-benzimidazol-2-yl)-1-methylethyl]-12-cyclohexyl--
3-methoxy-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carboxamide
(Example 2-405) [2809]
2-[4-({1-[(12-cyclohexyl-3-methoxy-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]az-
ulene-9-carbonyl)amino]cyclobutanecarbonyl}amino)phenyl]-2-methylpropionic
acid (Example 2-406) [2810] methyl
{4-[(S)-2-[(12-cyclohexyl-3-methoxy-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]a-
zulene-9-carbonyl)amino]-2-(3-methyl-1,2,4-oxadiazol-5-yl)ethyl]phenyl}car-
bamate (Example 2-407) [2811]
N-[1-(1H-benzimidazol-2-yl)-1-methylethyl]-12-cyclohexyl-3-methoxy-6,7-di-
hydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carboxamide (Example 2-408)
[2812]
2-{4-[(12-cyclohexyl-3-methoxy-6,7-dihydro-5-oxa-7a-azadibenzo[a,-
e]azulene-9-carbonyl)amino]tetrahydropyran-4-yl]-3H-benzimidazole-5-carbox-
ylic acid (Example 2-409) [2813] benzyl
(4-[(S)-2-[(12-cyclohexyl-3-methoxy-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]a-
zulene-9-carbonyl)amino]-2-(2-methylthiazol-4-yl)ethyl]phenyl}carbamate
(Example 2-410) [2814]
(E)-3-(2-{1-[(12-cyclohexyl-3-methoxy-6,7-dihydro-5-oxa-7a-azadibenzo[a,e-
]azulene-9-carbonyl)amino]-1-methylethyl}-1H-benzimidazol-5-yl)acrylic
acid (Example 2-411) [2815]
3-(2-{1-[(12-cyclohexyl-3-methoxy-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azu-
lene-9-carbonyl)amino]-1-methylethyl}-1H-benzimidazol-5-yl)propionic
acid (Example 2-412) [2816]
N-[1-(5-hydroxymethyl-6-methoxy-1H-benzimidazol-2-yl)cyclobutyl]-12-cyclo-
hexyl-3-methoxy-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carboxamide
(Example 2-413) [2817]
N--[(S)-2-(4-aminophenyl)-1-(2-methylthiazol-4-yl)ethyl]-12-cyclohexyl-3--
methoxy-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carboxamide
(Example 2-414) [2818] methyl
(4-[(S)-2-[(12-cyclohexyl-3-methoxy-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]a-
zulene-9-carbonyl)amino]-2-(2-methylthiazol-4-yl)ethyl]phenyl}carbamate
(Example 2-415) [2819]
2-[(S)-2-[(12-cyclohexyl-3-methoxy-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]az-
ulene-9-carbonyl)amino]-3-(4-hydroxyphenyl)propionylamino]-2-methylpropion-
ic acid (Example 2-416) [2820] methyl
{3-[(S)-2-[(12-cyclohexyl-3-methoxy-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]a-
zulene-9-carbonyl)amino]-2-(2-methylthiazol-4-yl)ethyl]-1H-indol-5-yloxy}a-
cetate (Example 2-417) [2821]
N-(1-methyl-1-[6-(4-methylpiperazine-1-carbonyl)-1H-benzimidazol-2-yl]eth-
yl}-12-cyclohexyl-3-methoxy-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9--
carboxamide (Example 2-418) [2822]
N-(1-methyl-1-[6-(morpholine-4-carbonyl)-1H-benzimidazol-2-yl]ethyl}-12-c-
yclohexyl-3-methoxy-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carboxam-
ide (Example 2-419) [2823]
N-[1-(6-benzyloxy-1H-benzimidazol-2-yl)cyclobutyl]-12-cyclohexyl-3-methox-
y-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carboxamide
(Example 2-420) [2824]
N--[(S)-2-[5-(2-hydroxyethoxy)-1H-indol-3-yl]-1-(2-methylthiazol-4-yl)eth-
yl]-12-cyclohexyl-3-methoxy-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9--
carboxamide (Example 2-421) [2825]
(E)-3-(4-{1-[(12-cyclohexyl-3-methoxy-6,7-dihydro-5-oxa-7a-azadibenzo[a,e-
]azulene-9-carbonyl)amino]-1-methylethyl}phenyl)acrylic acid
(Example 2-422) [2826]
3-(4-{1-[(12-cyclohexyl-3-methoxy-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azu-
lene-9-carbonyl)amino]-1-methylethyl}phenyl)propionic acid (Example
2-423) [2827] methyl
(S)-2-[(12-cyclohexyl-3-methoxy-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azule-
ne-9-carbonyl)amino]-3-[4-(3-methoxypropoxy)phenyl]propionate
(Example 2-424) [2828]
(S)-2-[(12-cyclohexyl-3-methoxy-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azule-
ne-9-carbonyl)amino]-3-[4-(3,3-dimethylureido)phenyl]propionic acid
(Example 2-425) [2829]
N--[(S)-2-(4-hydroxyphenyl)-1-(methoxycarbamoyl)ethyl]-12-cyclohexyl-3-me-
thoxy-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carboxamide
(Example 2-426) [2830]
N--[(S)-2-(4-hydroxyphenyl)-1-(N-methoxy-N-methylcarbamoyl)ethyl]-12-cycl-
ohexyl-3-methoxy-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carboxamide
(Example 2-427) [2831]
N--[(S)-2-(4-benzyloxyphenyl)-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)e-
thyl]-12-cyclohexyl-3-methoxy-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene--
9-carboxamide (Example 2-428) [2832]
N--[(S)-2-(4-hydroxyphenyl)-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)eth-
yl]-12-cyclohexyl-3-methoxy-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9--
carboxamide (Example 2-429) [2833]
4-[(S)-2-[(12-cyclohexyl-3-methoxy-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]az-
ulene-9-carbonyl)amino]-2-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)ethyl]ph-
enyl acetate (Example 2-430) [2834]
4-[(S)-2-[(12-cyclohexyl-3-methoxy-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]az-
ulene-9-carbonyl)amino]-2-(4,4-dimethyl-5-oxo-4,5-dihydrooxazol-2-yl)ethyl-
]phenyl acetate (Example 2-431) [2835]
N-(1-methyl-1-{1-[2-(morpholin-4-yl)ethyl]-1H-benzimidazol-2-yl}ethyl)-12-
-cyclohexyl-3-methoxy-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carbox-
amide (Example 2-432) [2836]
N-{1-[1-(2-hydroxyethyl)-1H-benzimidazol-2-yl]-1-methylethyl}-12-cyclohex-
yl-3-methoxy-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carboxamide
(Example 2-433) [2837]
N-{1-[1-(2-methoxyethyl)-1H-benzimidazol-2-yl]-1-methylethyl}-12-cyclohex-
yl-3-methoxy-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carboxamide
(Example 2-434) [2838] ethyl
(S)-2-[(12-cyclohexyl-3-methoxy-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azule-
ne-9-carbonyl)amino]-3-(4-hydroxyphenyl)propionate (Example 2-435)
[2839]
N-[1-(4-hydroxybenzyl)-2-methylpropyl]-12-cyclohexyl-3-methoxy-6,7-dihyd-
ro-5-oxa-7a-azadibenzo[a,e]azulene-9-carboxamide (Example 2-436)
[2840]
2-{1-[(12-cyclohexyl-3-methoxy-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulen-
e-9-carbonyl)amino]cyclobutyl}-6-(2-methoxyethoxy)-1H-benzimidazole-5-carb-
oxylic acid (Example 2-437) [2841]
N-{1-[5-hydroxymethyl-6-(2-methoxyethoxy)-1H-benzimidazol-2-yl]cyclobutyl-
}-12-cyclohexyl-3-methoxy-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-ca-
rboxamide (Example 2-438) [2842]
N-[1-(6-hydroxy-1H-benzimidazol-2-yl)cyclobutyl]-12-cyclohexyl-3-methoxy--
6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carboxamide (Example
2-439) [2843]
{3-[(S)-2-[(12-cyclohexyl-3-methoxy-6,7-dihydro-5-oxa-7a-azadiben-
zo[a,e]azulene-9-carbonyl)amino]-2-(2-methylthiazol-4-yl)ethyl]-1H-indol-5-
-yloxy}acetic acid (Example 2-440) [2844]
N--[(S)-cyano-(4-hydroxybenzyl)-methyl]-12-cyclohexyl-3-methoxy-6,7-dihyd-
ro-5-oxa-7a-azadibenzo[a,e]azulene-9-carboxamide (Example 2-441)
[2845] methyl
2-amino-3-(4-{1-[(12-cyclohexyl-3-methoxy-6,7-dihydro-5-oxa-7a-aza-
dibenzo[a,e]azulene-9-carbonyl)amino]-1-methylethyl}phenyl)propionate
monohydrochloride (Example 2-442) [2846]
2-acetylamino-3-(4-{1-[(12-cyclohexyl-3-methoxy-6,7-dihydro-5-oxa-7a-azad-
ibenzo[a,e]azulene-9-carbonyl)amino]-1-methylethyl}phenyl)propionic
acid (Example 2-443) [2847]
2-amino-3-(4-{1-[(12-cyclohexyl-3-methoxy-6,7-dihydro-5-oxa-7a-azadibenzo-
[a,e]azulene-9-carbonyl)amino]-1-methylethyl}phenyl)propionic acid
(Example 2-444) [2848]
2-(2-{1-[(12-cyclohexyl-3-methoxy-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azu-
lene-9-carbonyl)amino]cyclobutyl}-3H-benzimidazol-5-yl)-2-methylpropionic
acid (Example 2-445) [2849]
(E)-3-[4-({1-[(12-cyclohexyl-3-ethoxy-6,7-dihydro-5-oxa-7a-azadibenzo[a,e-
]azulene-9-carbonyl)amino]cyclobutanecarbonyl}amino)phenyl]acrylic
acid (Example 2-446) [2850]
N-{1-[5-(1-hydroxy-1-methylethyl)-6-methoxy-1H-benzimidazol-2-yl]cyclobut-
yl}-12-cyclohexyl-3-methoxy-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9--
carboxamide (Example 2-447) [2851]
N-[1-(3H-benzimidazol-5-ylcarbamoyl)cyclobutyl]-12-cyclohexyl-3-methoxy-6-
,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carboxamide (Example
2-448) [2852]
2-{4-[(12-cyclohexyl-3-methoxy-6,7-dihydro-5-oxa-7a-azadibenzo[a,-
e]azulene-9-carbonyl)amino]-1-methylpiperidin-4-yl}-3H-benzimidazole-5-car-
boxylic acid (Example 2-449) [2853]
N--[(S)-1-(4,5-dihydro-1H-imidazol-2-yl)-2-(4-hydroxyphenyl)ethyl]-12-cyc-
lohexyl-3-methoxy-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carboxamid-
e (Example 2-450) [2854]
(E)-3-[4-({1-[(12-cyclohexyl-3-methoxy-6,7-dihydro-5-oxa-7a-azadibenzo[a,-
e]azulene-9-carbonyl)amino]cyclobutanecarbonyl}amino)-3-methoxyphenyl]acry-
lic acid (Example 2-451) [2855] tert-butyl
(S)-2-[(12-cyclohexyl-3-methoxy-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azule-
ne-9-carbonyl)amino]-3-(4-hydroxyphenyl)propionate (Example 2-452)
[2856]
N--[(S)-2-(4-hydroxyphenyl)-1-(2-methyl-5-oxo-2,5-dihydro-1,2,4-oxadiazo-
l-3-yl)ethyl]-12-cyclohexyl-3-methoxy-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]-
azulene-9-carboxamide (Example 2-453) [2857]
N--[(S)-2-(4-hydroxyphenyl)-1-(1-methyl-1H-tetrazol-5-yl)ethyl]-12-cycloh-
exyl-3-methoxy-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carboxamide
(Example 2-454) [2858]
(2-{1-[(12-cyclohexyl-3-methoxy-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azule-
ne-9-carbonyl)amino]cyclobutyl}-1H-benzimidazol-5-yloxy)acetic acid
(Example 2-455) [2859]
13-cyclohexyl-5-[2-((S)-3-phenoxymethylpiperidin-1-yl)ethyl]-6,7-dihydro--
5H-benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid
dihydrochloride (Example 1-485) [2860]
3-chloro-13-cycloheptyl-5-[2-(piperidin-1-yl)ethyl]-6,7-dihydro-5H-benzo[-
5,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid (Example 1-486)
[2861]
5-[2-(7-benzyl-7-azabicyclo[2.2.1]hept-1-yl)ethyl]-13-cyclohexyl-3-methy-
l-6,7-dihydro-5H-benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic
acid (Example 1-487) [2862]
5-[2-(7-azabicyclo[2.2.1]hept-1-yl)ethyl]-13-cyclohexyl-3-methyl-6,7-dihy-
dro-5H-benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid
monohydrochloride (Example 1-488) [2863]
5-[2-(7-carboxymethyl-7-azabicyclo[2.2.1]hept-1-yl)ethyl]-13-cyclohexyl-3-
-methyl-6,7-dihydro-5H-benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic
acid (Example 1-489) [2864]
3-cyano-13-cyclohexyl-5-[2-(piperidin-1-yl)ethyl]-6,7-dihydro-5H-benzo[5,-
6][1,4]diazepino[7,1-a]indole-10-carboxylic acid monohydrochloride
(Example 1-490) [2865]
3-carbamoyl-13-cyclohexyl-5-[2-(piperidin-1-yl)ethyl]-6,7-dihydro-5H-benz-
o[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid
monohydrochloride (Example 1-491) [2866]
13-cyclohexyl-5-(2-cyclohexylethyl)-3-methyl-6,7-dihydro-5H-benzo[5,6][1,-
4]diazepino[7,1-a]indole-10-carboxylic acid (Example 1-492) [2867]
13-cyclohexyl-5-(4-diethylaminobutyl)-3-methyl-6,7-dihydro-5H-benzo[5,6][-
1,4]diazepino[7,1-a]indole-10-carboxylic-acid dihydrochloride
(Example 1-493) [2868]
13-cyclohexyl-5-{2-[(S)-3-(2-hydroxyethyl)piperidin-1-yl)ethyl}-3-methyl--
6,7-dihydro-5H-benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic
acid dihydrochloride (Example 1-494) [2869]
13-cyclohexyl-5-[2-(piperidin-1-yl)ethyl]-6,7-dihydro-5H-benzo[5,6][1,4]d-
iazepino[7,1-a]indole-3,10-dicarboxylic acid monohydrochloride
(Example 1-495) [2870]
13-cyclohexyl-5-methyl-3-[3-(piperidin-1-yl)propoxy]-6,7-dihydro-5H-benzo-
[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid dihydrochloride
(Example 1-496) [2871]
13-cyclohexyl-5-[2-((R)-3-phenoxymethylpiperidin-1-yl)ethyl]-6,7-dihydro--
5H-benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid
dihydrochloride (Example 1-497) [2872]
5-[2-(azocan-1-yl)ethyl]-13-cyclohexyl-3-ethoxy-6,7-dihydro-5H-benzo[5,6]-
[1,4]diazepino[7,1-a]indole-10-carboxylic acid monohydrochloride
[2873]
13-cyclohexyl-3-ethoxy-5-[2-((R)-3-methoxymethylpiperidin-1-yl)ethyl]-6,7-
-dihydro-5H-benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic
acid dihydrochloride (Example 1-499) [2874]
13-cyclohexyl-3-ethoxy-5-[2-(1,4-oxazepan-4-yl)ethyl]-6,7-dihydro-5H-benz-
o[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid
dihydrochloride (Example 1-500) [2875]
13-cyclohexyl-3-ethoxy-5-{2-[4-(2-methoxyethyl)piperidin-1-yl]ethyl}-6,7--
dihydro-5H-benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid
dihydrochloride (Example 1-501) [2876]
13-cyclohexyl-5-{2-[4-(2-methoxyethyl)piperidin-1-yl]ethyl}-3-methyl-6,7--
dihydro-5H-benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid
dihydrochloride (Example 1-502) [2877]
3-chloro-13-cyclohexyl-5-(3-diethylamino-2-hydroxypropyl)-6,7-dihydro-5H--
benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid
dihydrochloride
(Example 1-503)
[2878]
5-[2-(4-acetyl-1,4-diazepan-1-yl)ethyl]-13-cyclohexyl-3-methyl-6,-
7-dihydro-5H-benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic
acid dihydrochloride (Example 1-504) [2879]
N-tert-butyl-13-cyclohexyl-3-methyl-6,7-dihydro-5H-benzo[5,6][1,4]diazepi-
no[7,1-a]indole-10-sulfonamide (Example 1-505) [2880]
13-cyclohexyl-3-methyl-6,7-dihydro-5H-benzo[5,6][1,4]diazepino[7,1-a]indo-
le-10-sulfonamide (Example 1-506) [2881]
13-cyclohexyl-3-methyl-5-[2-(piperidin-1-yl)ethyl]-6,7-dihydro-5H-benzo[5-
,6][1,4]diazepino[7,1-a]indole-10-sulfonamide dihydrochloride
(Example 1-507) [2882]
13-cyclohexyl-3-methoxy-5-[2-((R)-3-methoxymethylpiperidin-1-yl)ethyl]-6,-
7-dihydro-5H-benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic
acid dihydrochloride (Example 1-508) [2883]
13-cyclohexyl-3-fluoro-5-[2-((R)-3-methoxymethylpiperidin-1-yl)ethyl]-6,7-
-dihydro-5H-benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic
acid dihydrochloride (Example 1-509) [2884]
13-cyclohexyl-3-methoxy-5-[2-(1,4-oxazepan-4-yl)ethyl]-6,7-dihydro-5H-ben-
zo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid
dihydrochloride (Example 1-510) [2885]
13-cyclohexyl-5-{3-[N-ethyl-N-(2-methoxyethyl)amino]propyl}-3-methyl-6,7--
dihydro-5H-benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid
dihydrochloride (Example 1-511) [2886]
13-cyclohexyl-5-{3-[N-ethyl-N-(2-hydroxyethyl)amino]propyl}-3-methyl-6,7--
dihydro-5H-benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid
dihydrochloride (Example 1-512) [2887]
13-cyclohexyl-5-{3-[N-ethyl-N-(3-methoxypropyl)amino]propyl}-3-ethyl-6,7--
dihydro-5H-benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid
dihydrochloride (Example 1-513) [2888]
13-cyclohexyl-5-{2-[(S)-3-(2-ethoxyethyl)piperidin-1-yl]ethyl}-3-methyl-6-
,7-dihydro-5H-benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic
acid dihydrochloride (Example 1-514). [2889]
13-cyclohexyl-3-ethoxy-5-{2-[(S)-3-(2-ethoxyethyl)piperidin-1-yl]ethyl}-6-
,7-dihydro-5H-benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic
acid dihydrochloride (Example 1-515) [2890]
N-tert-butyl-13-cyclohexyl-3,5-dimethyl-6,7-dihydro-5H-benzo[5,6][1,4]dia-
zepino[7,1-a]indole-10-sulfonamide (Example 1-516) [2891]
13-cyclohexyl-3,5-dimethyl-6,7-dihydro-5H-benzo[5,6][1,4]diazepino[7,1-a]-
indole-10-sulfonamide (Example 1-517) [2892]
13-cyclohexyl-5-[2-(4-methoxycarbonyl-1,4-diazepan-1-yl)ethyl]-3-methyl-6-
,7-dihydro-5H-benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic
acid dihydrochloride (Example 1-518) [2893]
13-cyclohexyl-5-[2-(5-oxo-1,4-diazepan-1-yl)ethyl]-6,7-dihydro-5H-benzo[5-
,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid dihydrochloride
(Example 1-519) [2894]
N-acetyl-13-cyclohexyl-3-methyl-5-[2-(piperidin-1-yl)ethyl]-6,7-dihydro-5-
H-benzo[5,6][1,4]diazepino[7,1-a]indole-10-sulfonamide
dihydrochloride (Example 1-520) [2895]
13-cyclohexyl-5-(3-diisopropylaminopropyl)-3-methyl-6,7-dihydro-5H-benzo[-
5,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid dihydrochloride
(Example 1-521) [2896]
13-cyclohexyl-5-[2-(piperidin-1-yl)ethyl]-3-trifluoromethoxy-6,7-dihydro--
5H-benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid
dihydrochloride (Example 1-522) [2897]
13-cyclohexyl-5-{2-[(S)-3-(2-methoxyethyl)piperidin-1-yl]ethyl}-3-trifluo-
romethoxy-6,7-dihydro-5H-benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxyl-
ic acid dihydrochloride (Example 1-523) [2898]
13-cyclohexyl-5-[3-(N-ethyl-N-isopropylamino)propyl]-3-methyl-6,7-dihydro-
-5H-benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid
dihydrochloride (Example 1-524) [2899]
13-cyclohexyl-5-[2-(4-methoxyazepan-1-yl)ethyl]-3-methyl-6,7-dihydro-5H-b-
enzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid
dihydrochloride (Example 1-525) [2900]
13-cyclohexyl-3-methyl-5-[2-(4-methyl-5-oxo-1,4-diazepan-1-yl)ethyl]-6,7--
dihydro-5H-benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid
dihydrochloride (Example 1-526) [2901]
13-cyclohexyl-5-{2-[(S)-3-(dimethylcarbamoylmethyl)piperidin-1-yl]ethyl}--
3-methyl-6,7-dihydro-5H-benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxyli-
c acid dihydrochloride (Example 1-527) [2902]
13-cyclohexyl-5-{2-[(R)-3-(2-methoxyethoxymethyl)piperidin-1-yl]ethyl}-3--
methyl-6,7-dihydro-5H-benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic
acid dihydrochloride (Example 1-528) [2903]
13-cyclohexyl-5-{2-[(S)-3-(2-hydroxy-2-methylpropyl)piperidin-1-yl]ethyl}-
-3-methyl-6,7-dihydro-5H-benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxyl-
ic acid dihydrochloride (Example 1-529) [2904]
13-cyclohexyl-2,3-difluoro-5-[2-7((R)-3-methoxymethylpiperidin-1-yl)ethyl-
]-6,7-dihydro-5H-benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic
acid dihydrochloride (Example 1-530) [2905]
13-cyclohexyl-5-{2-[N-ethyl-N-(3-methoxypropyl)amino]ethyl}-3-methyl-6,7--
dihydro-5H-benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid
dihydrochloride (Example 1-531) [2906]
13-cyclohexyl-3-methyl-5-[2-(6-methyl-1,4-oxazepan-4-yl)ethyl]-6,7-dihydr-
o-5H-benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid
dihydrochloride (Example 1-532) [2907]
13-cyclohexyl-5-{2-[(R)-3-(1-hydroxy-1-methylethyl)piperidin-1-yl]ethyl}--
3-methyl-6,7-dihydro-5H-benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxyli-
c acid dihydrochloride (Example 1-533) [2908]
3-chloro-13-cyclohexyl-5-{2-[1-(2-methoxyethyl)piperidin-3-yl]ethyl}-6,7--
dihydro-5H-benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid
dihydrochloride (Example 1-534) [2909]
13-cyclohexyl-5-(2-dimethylaminoethyl)-3-(3,5-dimethylisoxazol-4-ylmethox-
y)-6,7-dihydro-5H-benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic
acid dihydrochloride (Example 1-535) [2910]
13-cyclohexyl-3-methyl-5-[2-(4-oxoazepan-1-yl)ethyl]-6,7-dihydro-5H-benzo-
[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid dihydrochloride
(Example 1-536) [2911]
13-cyclohexyl-5-{2-[(S)-3-(2-dimethylcarbamoylethyl)piperidin-1-yl]ethyl}-
-3-methyl-6,7-dihydro-5H-benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxyl-
ic acid dihydrochloride (Example 1-537) [2912]
13-cyclohexyl-5-[2-(4-hydroxyazepan-1-yl)ethyl]-3-methyl-6,7-dihydro-5H-b-
enzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid
dihydrochloride (Example 1-538) [2913]
13-cyclohexyl-5-{2-[N-ethyl-N-(4-methoxybutyl)amino]ethyl}-3-methyl-6,7-d-
ihydro-5H-benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid
dihydrochloride (Example 1-539) [2914]
13-cyclohexyl-5-{2-[(S)-3-(3-methoxypropyl)piperidin-1-yl]ethyl}-3-methyl-
-6,7-dihydro-5H-benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic
acid dihydrochloride (Example 1-540) [2915]
13-cyclohexyl-5-{2-[(R)-3-(1-methoxy-1-methylethyl)piperidin-1-yl]ethyl}--
3-methyl-6,7-dihydro-5H-benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxyli-
c acid dihydrochloride (Example 1-541) [2916]
13-cyclohexyl-5-{2-[2-(2-methoxyethyl)piperidin-1-yl]ethyl}-3-methyl-6,7--
dihydro-5H-benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid
dihydrochloride (Example 1-542) [2917]
13-cyclohexyl-5-(2-dimethylaminoethyl)-3-(pyridin-2-ylmethoxy)-6,7-dihydr-
o-5H-benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid
trihydrochloride (Example 1-543) [2918]
13-cyclohexyl-2,3-difluoro-5-{2-[(S)-3-(2-methoxyethyl)piperidin-1-yl]eth-
yl}-6,7-dihydro-5H-benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic
acid dihydrochloride (Example 1-544) [2919]
13-cyclohexyl-5-[2-(3-dimethylcarbamoylpiperidin-1-yl)ethyl]-3-methyl-6,7-
-dihydro-5H-benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic
acid dihydrochloride (Example 1-545) [2920]
13-cyclohexyl-3-(2-methoxyethoxy)-5-[2-(piperidin-1-yl)ethyl]-6,7-dihydro-
-5H-benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid
dihydrochloride (Example 1-546) [2921]
13-cyclohexyl-5-{2-[(R)-3-(2-methoxyethoxy)piperidin-1-yl]ethyl}-3-methyl-
-6,7-dihydro-5H-benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic
acid dihydrochloride (Example 1-547) [2922]
13-cyclohexyl-5-(2-dimethylaminoethyl)-3-(2-phenoxyethoxy)-6,7-dihydro-5H-
-benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid
dihydrochloride (Example 1-548) [2923]
12-cyclohexyl-5-[2-(piperidin-1-yl)ethyl]-6,7-dihydro-5H-4,5,7a-triazadib-
enzo[a,e]azulene-9-carboxylic acid dihydrochloride (Example 1-549)
[2924]
13-cyclohexyl-2,3-difluoro-5-[2-(1,4-oxazepan-4-yl)ethyl]-6,7-dihydro-5H-
-benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid
dihydrochloride (Example 1-550) [2925]
13-cyclohexyl-5-[2-(3-methoxymethylazepan-1-yl)ethyl]-3-methyl-6,7-dihydr-
o-5H-benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid
dihydrochloride (Example 1-551) [2926]
13-cyclohexyl-5-methyl-4-[2-(piperidin-1-yl)ethoxy]-6,7-dihydro-5H-benzo[-
5,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid dihydrochloride
(Example 1-552) [2927]
5-(2-{(S)-3-[2-(N-acetyl-N-methylamino)ethyl]piperidin-1-yl}ethyl)-13-cyc-
lohexyl-3-methyl-6,7-dihydro-5H-benzo[5,6][1,4]diazepino[7,1-a]indole-10-c-
arboxylic acid dihydrochloride (Example 1-553) [2928]
13-cyclohexyl-3,9-dimethyl-5-[2-(piperidin-1-yl)ethyl]-6,7-dihydro-5H-ben-
zo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid
dihydrochloride (Example 1-554) [2929]
13-cyclohexyl-5-{2-[(S)-3-(2-dimethylaminoethyl)piperidin-1-yl]ethyl}-3-m-
ethyl-6,7-dihydro-5H-benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic
acid dihydrochloride (Example 1-555) [2930]
5-[2-((S)-3-carboxymethylpiperidin-1-yl)ethyl]-13-cyclohexyl-3-methyl-6,7-
-dihydro-5H-benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic
acid dihydrochloride (Example 1-556) [2931]
5-(2-{(S)-3-[2-(N-tert-butoxycarbonyl-N-methylamino)ethyl]piperidin-1-yl)-
ethyl)-13-cyclohexyl-3-methyl-6,7-dihydro-5H-benzo[5,6][1,4]diazepino[7,1--
a]indole-10-carboxylic acid monohydrochloride (Example 1-557)
[2932]
5-(1-benzyloxycarbonylpiperidin-4-yl)-13-cyclohexyl-3-methyl-6,7-dihydro--
5H-benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid
(Example 1-558) [2933]
13-cyclohexyl-3-methyl-5-(2-{(S)-3-[2-(trimethylureido)ethyl]piperidin-1--
yl}ethyl)-6,7-dihydro-5H-benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxyl-
ic acid dihydrochloride (Example 1-559) [2934]
3-(5-chlorothiophen-2-ylmethoxy)-13-cyclohexyl-5-(2-dimethylaminoethyl)-6-
,7-dihydro-5H-benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic
acid dihydrochloride (Example 1-560) [2935]
13-cyclohexyl-3-methyl-5-[2-(thiomorpholin-4-yl)ethyl]-6,7-dihydro-5H-ben-
zo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid
dihydrochloride (Example 1-561) [2936]
13-cyclohexyl-3-methyl-5-(piperidin-4-yl)-6,7-dihydro-5H-benzo[5,6][1,4]d-
iazepino[7,1-a]indole-10-carboxylic acid dihydrochloride (Example
1-562) [2937]
5-(1-acetylpiperidin-4-yl)-13-cyclohexyl-3-methyl-6,7-dihydro-5H--
benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid (Example
1-563) [2938]
13-cyclohexyl-3-methyl-5-(1-methylpiperidin-4-yl)-6,7-dihydro-5H--
benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid
dihydrochloride (Example 1-5.64) [2939]
13-cyclohexyl-5-(2-dimethylaminoethyl)-3-(pyridin-4-ylmethoxy)-6,7-dihydr-
o-5H-benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid
trihydrochloride (Example 1-565) [2940]
13-cyclohexyl-3-methyl-5-(2-{(S)-3-[2-(2-oxopyrrolidin-1-yl)ethyl]piperid-
in-1-yl]ethyl}-6,7-dihydro-5H-benzo[5,6][1,4]diazepino[7,1-a]indole-10-car-
boxylic acid dihydrochloride (Example 1-566) [2941]
13-cyclohexyl-3,5,6-trimethyl-6,7-dihydro-5H-benzo[5,6][1,4]diazepino[7,1-
-a]indole-10-carboxylic acid (Example 1-567) [2942]
13-cyclohexyl-3-methoxy-5-[2-(thiomorpholin-4-yl)ethyl]-6,7-dihydro-5H-be-
nzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid
dihydrochloride (Example 1-568) [2943]
13-cyclohexyl-3,5,9-trimethyl-6,7-dihydro-5H-benzo[5,6][1,4]diazepino[7,1-
-a]indole-10-carboxylic acid (Example 1-569) [2944]
13-cyclohexyl-5-{2-[(S)-3-(2-methoxyethyl)piperidin-1-yl]-2-oxoethyl}-3-m-
ethyl-6,7-dihydro-5H-benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic
acid (Example 1-570) [2945]
13-cyclohexyl-5-[2-(4-methanesulfonylpiperazin-1-yl)-2-oxoethyl]-3-methyl-
-6,7-dihydro-5H-benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic
acid (Example 1-571) [2946]
13-cyclohexyl-5-[2-(4-methoxypiperidin-1-yl)-2-oxoethyl]-3-methyl-6,7-dih-
ydro-5H-benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid
(Example 1-572) [2947]
N-methyl-13-cyclohexyl-5-[2-(4-methanesulfonylpiperazin-1-yl)-2-oxoethyl]-
-3-methyl-6,7-dihydro-5H-benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxam-
ide (Example 1-573) [2948]
13-cyclohexyl-3,5-dimethyl-6,7-dihydro-5H-benzo[5,6][1,4]diazepino[7,1-a]-
indole-10-carboxylic acid (Example 1-574) [2949]
13-cyclohexyl-5-(2-dimethylaminoethyl)-3-[2-(2-oxooxazolidin-3-yl)ethoxy]-
-6,7-dihydro-5H-benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic
acid dihydrochloride (Example 1-575) [2950]
13-cyclohexyl-5-(2-dimethylaminoethyl)-3-[2-(2-hydroxyethylamino)ethoxy]--
6,7-dihydro-5H-benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic
acid trihydrochloride (Example 1-576) [2951]
13-cyclohexyl-5-(2-dimethylaminoethyl)-3-(3-methoxybenzyloxy)-6,7-dihydro-
-5H-benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid
dihydrochloride (Example 1-577) [2952]
3-(3-aminobenzyloxy)-13-cyclohexyl-5-(2-dimethylaminoethyl)-6,7-dihydro-5-
H-benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid
trihydrochloride (Example 1-578) [2953]
13-cyclohexyl-5-(2-dimethylaminoethyl)-3-(3-nitrobenzyloxy)-6,7-dihydro-5-
H-benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid
dihydrochloride (Example 1-579) [2954]
3-chloro-13-cyclohexyl-5-[2-(1-methoxycarbonylpiperidin-4-yl)ethyl]-6,7-d-
ihydro-5H-benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid
(Example 1-580) [2955]
13-cyclohexyl-5-[2-(4-fluorophenyl)ethyl]-3-methyl-6,7-dihydro-5H-benzo[5-
,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid (Example 1-581)
[2956]
3-(3-acetylaminobenzyloxy)-13-cyclohexyl-5-(2-dimethylaminoethyl)-6,7-dih-
ydro-5H-benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid
dihydrochloride (Example 1-582) [2957] methyl
3-(3-carboxybenzyloxy)-13-cyclohexyl-5-(2-dimethylaminoethyl)-6,7-dihydro-
-5H-benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylate
dihydrochloride (Example 1-583), [2958]
13-cyclohexyl-5-(2-dimethylaminoethyl)-3-[3-(piperidin-1-yl)propoxy]-6,7--
dihydro-5H-benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid
trihydrochloride (Example 1-584) [2959]
13-cyclohexyl-5-(2-dimethylaminoethyl)-3-[3-(2-oxopyrrolidin-1-yl)benzylo-
xy]-6,7-dihydro-5H-benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic
acid trihydrochloride (Example 1-585) [2960]
3-(3-carboxybenzyloxy)-13-cyclohexyl-5-(2-dimethylaminoethyl)-6,7-dihydro-
-5H-benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid
dihydrochloride (Example 1-586) [2961]
13-cyclohexyl-5-(2-dimethylaminoethyl)-3-(3-dimethylcarbamoylbenzyloxy)-6-
,7-dihydro-5H-benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic
acid dihydrochloride (Example 1-587) [2962]
13-cyclohexyl-3-methyl-5-[2-(4-methylthiazol-2-yl)ethyl]-6,7-dihydro-5H-b-
enzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid (Example
1-588) [2963]
13-cyclohexyl-5-(2-dimethylaminoethyl)-3-(6-methylpyridin-2-ylmet-
hoxy)-6,7-dihydro-5H-benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic
acid trihydrochloride (Example 1-589) [2964]
13-cyclohexyl-5-(2-dimethylaminoethyl)-3-(3-methylcarbamoylbenzyloxy)-6,7-
-dihydro-5H-benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic
acid dihydrochloride (Example 1-590)
[2965]
13-cyclohexyl-3-(3-dimethylaminobenzyloxy)-5-(2-dimethylaminoethy-
l)-6,7-dihydro-5H-benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic
acid trihydrochloride (Example 1-591) [2966]
13-cyclohexyl-3-ethoxy-5-methyl-6,7-dihydro-5H-benzo[5,6][1,4]diazepino[7-
,1-a]indole-10-carboxylic acid (Example 1-592) [2967]
3-benzyloxy-13-cyclohexyl-5-methyl-6,7-dihydro-5H-benzo[5,6][1,4]diazepin-
o[7,1-a]indole-10-carboxylic acid (Example 1-593) [2968]
13-cyclohexyl-3-methoxy-5-methyl-6,7-dihydro-5H-benzo[5,6][1,4]diazepino[-
7,1-a]indole-10-carboxylic acid (Example 1-594) [2969]
13-cyclohexyl-5-[2-(piperidin-1-yl)ethyl]-3-(pyridin-2-ylmethoxy)-6,7-dih-
ydro-5H-benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylic acid
trihydrochloride (Example 1-595) [2970] methyl
5-[2-(1-tert-butoxycarbonylpiperidin-4-yl)ethyl]-13-cyclohexyl-6,7-dihydr-
o-5H-benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylate (Example
1-601) [2971] methyl
13-cyclohexyl-5-[2-(piperidin-4-yl)ethyl]-6,7-dihydro-5H-benzo[5,6][1,4]d-
iazepino[7,1-a]indole-10-carboxylate (Example 1-602) [2972] methyl
13-cyclohexyl-5-[2-(1-cyclopentylpiperidin-4-yl)ethyl]-6,7-dihydro-5H-ben-
zo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylate (Example 1-603)
[2973]
N-tert-butyl-13-cyclohexyl-3-methyl-6-oxo-6,7-dihydro-5H-benzo[5,6][1,4]d-
iazepino[7,1-a]indole-10-sulfonamide (Example 1-604) [2974]
N-tert-butyl-13-cyclohexyl-3-methyl-6-oxo-5-[2-oxo-2-(piperidin-1-yl)ethy-
l]-6,7-dihydro-5H-benzo[5,6][1,4]diazepino[7,1-a]indole-10-sulfonamide
(Example 1-605) [2975]
N-tert-butyl-13-cyclohexyl-3-methyl-5-[2-(piperidin-1-yl)ethyl]-6,7-dihyd-
ro-5H-benzo[5,6][1,4]diazepino[7,1-a]indole-10-sulfonamide (Example
1-606) [2976]
13-cyclohexyl-3-methyl-5-[2-(piperidin-1-yl)ethyl]-6,7-dihydro-5-
H-benzo[5,6][1,4]diazepino[7,1-a]indole-10-sulfonamide (Example
1-607) [2977] methyl
13-cyclohexyl-3,6-dimethyl-6,7-dihydro-5H-benzo[5,6][1,4]diazepino[7,1-a]-
indole-10-carboxylate (Example 1-608) [2978] methyl
13-cyclohexyl-3,5,6-trimethyl-6,7-dihydro-5H-benzo[5,6][1,4]diazepino[7,1-
-a]indole-10-carboxylate (Example 1-609) [2979] methyl
3-benzyloxy-13-cyclohexyl-6-oxo-6,7-dihydro-5H-benzo[5,6][1,4]diazepino[7-
,1-a]indole-10-carboxylate (Example 1-610) [2980] methyl
3-benzyloxy-13-cyclohexyl-6-oxo-5-[2-oxo-2-(piperidin-1-yl)ethyl]-6,7-dih-
ydro-5H-benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylate
(Example 1-611) [2981] methyl
13-cyclohexyl-3-hydroxy-6-oxo-5-[2-oxo-2-(piperidin-1-yl)ethyl]-6,7-dihyd-
ro-5H-benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylate (Example
1-612) [2982] methyl
13-cyclohexyl-6-oxo-5-[2-oxo-2-(piperidin-1-yl)ethyl]-3-(pyridin-2-ylmeth-
oxy)-6,7-dihydro-5H-benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylate
(Example 1-613) [2983] methyl
13-cyclohexyl-5-[2-(piperidin-1-yl)ethyl]-3-(pyridin-2-ylmethoxy)-6,7-dih-
ydro-5H-benzo[5,6][1,4]diazepino[7,1-a]indole-10-carboxylate
(Example 1-614) [2984]
12-cyclohexyl-4-[2-(4-ethylpiperazin-1-yl)ethoxy]-6,7-dihydro-5-oxa-7a-az-
adibenzo[a,e]azulene-9-carboxylic acid dihydrochloride (Example
2-456) [2985]
4-[2-(1-tert-butoxycarbonylpiperidin-4-yl)ethoxy]-12-cyclohexyl-6-
,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carboxylic acid
(Example 2-457) [2986]
12-cyclohexyl-4-[2-(piperidin-4-yl)ethoxy]-6,7-dihydro-5-oxa-7a-azadibenz-
o[a,e]azulene-9-carboxylic acid monohydrochloride (Example 2-458)
[2987]
12-cyclohexyl-4-[2-(1-methylpiperidin-4-yl)ethoxy]-6,7-dihydro-5-oxa-7a-a-
zadibenzo[a,e]azulene-9-carboxylic acid monohydrochloride (Example
2-459) [2988]
12-cyclohexyl-4-[3-(piperidin-1-yl)propoxy]-6,7-dihydro-5-oxa-7a--
azadibenzo[a,e]azulene-9-carboxylic acid monohydrochloride (Example
2-460) [2989]
12-cyclohexyl-4-[2-oxo-2-(piperidin-1-yl)ethyl]-6,7-dihydro-5-ox-
a-7a-azadibenzo[a,e]azulene-9-carboxylic acid (Example 2-461)
[2990]
12-cyclohexyl-4-[2-(morpholin-4-yl)ethoxy]-6,7-dihydro-5-oxa-7a-azadibenz-
o[a,e]azulene-9-carboxylic acid monohydrochloride (Example 2-462)
[2991]
12-cyclohexyl-4-(2-dimethylaminoethoxy)-6,7-dihydro-5-oxa-7a-azadibenzo[a-
,e]azulene-9-carboxylic acid monohydrochloride (Example 2-463)
[2992]
12-cyclohexyl-4-[2-(piperidin-1-yl)ethyl]-6,7-dihydro-5-oxa-7a-azadibenzo-
[a,e]azulene-9-carboxylic acid monohydrochloride (Example 2-464)
[2993]
4-[2-(1-tert-butoxycarbonylpiperidin-4-yloxy)ethoxy]-12-cyclohexyl-6,7-di-
hydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carboxylic acid (Example
2-465) [2994]
12-cyclohexyl-4-[2-(piperidin-4-yloxy)ethoxy]-6,7-dihydro-5-oxa-7-
a-azadibenzo[a,e]azulene-9-carboxylic acid monohydrochloride
(Example 2-466) [2995]
12-cyclohexyl-4-[2-(1-methylpiperidin-4-yloxy)ethoxy]-6,7-dihydro-5-oxa-7-
a-azadibenzo[a,e]azulene-9-carboxylic acid monohydrochloride
(Example 2-467) [2996]
12-cyclohexyl-4-[2-(1-cyclopentylpiperidin-4-yl)ethoxy]-6,7-dihydro-5-oxa-
-7a-azadibenzo[a,e]azulene-9-carboxylic acid monohydrochloride
(Example 2-468) [2997]
12-cyclohexyl-4-(1-methylpiperidin-3-yloxy)-6,7-dihydro-5-oxa-7a-azadiben-
zo[a,e]azulene-9-carboxylic acid monohydrochloride (Example 2-469)
[2998]
12-cyclohexyl-4-[1-(2-methoxyethyl)piperidin-3-yloxy]-6,7-dihydro-5-oxa--
7a-azadibenzo[a,e]azulene-9-carboxylic acid monohydrochloride
(Example 2-470) [2999]
12-cyclohexyl-4-[2-(morpholin-4-yl)-5-(2-oxopyrrolidin-1-yl)benzyloxy]-6,-
7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carboxylic acid
monohydrochloride (Example 2-471) [3000]
12-cyclohexyl-4-{2-[N-methyl-N-(1-methylpiperidin-4-yl)amino]ethoxy}-6,7--
dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carboxylic acid
trihydrochloride (Example 2-472) [3001] methyl
4-carboxymethoxy-12-cyclohexyl-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulen-
e-9-carboxylate (Example 2-473) [3002]
12-cyclohexyl-4-(N-methyl-N-[2-(piperidin-1-yl)ethyl]amino}-6,7-dihydro-5-
-oxa-7a-azadibenzo[a,e]azulene-9-carboxylic acid dihydrochloride
(Example 2-474) [3003]
12-cyclohexyl-4-methoxy-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-car-
boxylic acid (Example 2-475) [3004]
4-amino-12-cyclohexyl-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carbo-
xylic acid (Example 2-476) [3005]
12-cyclohexyl-4-nitro-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carbo-
xylic acid (Example 2-477) [3006]
12-cyclohexyl-4-[2-(piperidin-1-yl)ethylamino]-6,7-dihydro-5-oxa-7a-azadi-
benzo[a,e]azulene-9-carboxylic acid dihydrochloride (Example 2-478)
[3007]
12-cyclohexyl-3-methyl-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulen-
e-9-carboxylic acid (Example 2-479) [3008]
12-cyclohexyl-4-{N-ethyl-N-[2-(piperidin-1-yl)ethyl]amino}-6,7-dihydro-5--
oxa-7a-azadibenzo[a,e]azulene-9-carboxylic acid dihydrochloride
(Example 2-480) [3009]
12-cyclohexyl-4-{N-[2-(piperidin-1-yl)ethyl]-N-propylamino}-6,7-dihydro-5-
-oxa-7a-azadibenzo[a,e]azulene-9-carboxylic acid dihydrochloride
(Example 2-481) [3010]
12-cyclohexyl-4-{N-(2-methoxyethyl)-N-[2-(piperidin-1-yl)ethyl]amino}-6,7-
-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carboxylic acid
dihydrochloride (Example 2-482) [3011]
12-cyclohexyl-4-dimethylamino-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-
-9-carboxylic acid (Example 2-483) [3012]
12-cyclohexyl-1-fluoro-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carb-
oxylic acid (Example 2-484) [3013]
4-{N-acetyl-N-[2-(piperidin-1-yl)ethyl]amino}-12-cyclohexyl-6,7-dihydro-5-
-oxa-7a-azadibenzo[a,e]azulene-9-carboxylic acid (Example 2-485)
[3014]
12-cyclohexyl-4-{N-methyl-N-[2-oxo-2-(piperidin-1-yl)ethyl]amino}-6,7-dih-
ydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carboxylic acid (Example
2-486) [3015] methyl
3-(1-tert-butoxycarbonylpiperidin-3-yloxy)-12-cyclohexyl-6,7-dihydro-5-ox-
a-7a-azadibenzo[a,e]azulene-9-carboxylate (Example 2-501) [3016]
methyl
12-cyclohexyl-3-(piperidin-3-yloxy)-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]a-
zulene-9-carboxylate (Example 2-502) [3017] methyl
12-cyclohexyl-3-(1-methanesulfonylpiperidin-3-yloxy)-6,7-dihydro-5-oxa-7a-
-azadibenzo[a,e]azulene-9-carboxylate (Example 2-503) [3018] methyl
4-benzyloxy-12-cyclohexyl-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-c-
arboxylate (Example 2-504) [3019] methyl
12-cyclohexyl-4-hydroxy-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-car-
boxylate (Example 2-505) [3020] methyl
12-cyclohexyl-4-[2-oxo-2-(piperidin-1-yl)ethoxy]-6,7-dihydro-5-oxa-7a-aza-
dibenzo[a,e]azulene-9-carboxylate (Example 2-506) [3021] methyl
12-cyclohexyl-4-[2-(piperidin-1-yl)ethoxy]-6,7-dihydro-5-oxa-7a-azadibenz-
o[a,e]azulene-9-carboxylate (Example 2-507) [3022] ethyl
(E)-3-[4-({1-[(12-cyclohexyl-3-methoxy-6,7-dihydro-5-oxa-7a-azadibenzo[a,-
e]azulene-9-carbonyl)amino]cyclobutanecarbonyl}amino)phenyl]acrylate
(Example 2-508) [3023] methyl
12-cyclohexyl-4-trifluoromethanesulfonyloxy-6,7-dihydro-5-oxa-7a-azadiben-
zo[a,e]azulene-9-carboxylate (Example 2-509) [3024] methyl
12-cyclohexyl-4-(pyridin-3-yl)-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulen-
e-9-carboxylate (Example 2-510) [3025] methyl
2-[(12-cyclohexyl-3-methoxy-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-
-carbonyl)amino]-2-methylpropionate (Example 2-511) [3026]
2-[(12-cyclohexyl-3-methoxy-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-
-carbonyl)amino]-2-methylpropionic acid (Example 2-512) [3027]
methyl
4-amino-3-{2-[(12-cyclohexyl-3-methoxy-6,7-dihydro-5-oxa-7a-azadibenzo[a,-
e]azulene-9-carbonyl)amino]-2-methylpropionylamino}benzoate
(Example 2-513) [3028] methyl
2-{1-[(12-cyclohexyl-3-methoxy-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulen-
e-9-carbonyl)amino]-1-methylethyl}-3H-benzimidazole-5-carboxylate
(Example 2-514) [3029] methyl
12-cyclohexyl-4-nitro-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carbo-
xylate (Example 2-515) [3030] methyl
4-amino-12-cyclohexyl-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carbo-
xylate (Example 2-516) [3031] methyl
4-{bis[2-oxo-2-(piperidin-1-yl)ethyl]amino}-12-cyclohexyl-6,7-dihydro-5-o-
xa-7a-azadibenzo[a,e]azulene-9-carboxylate (Example 2-517) [3032]
methyl
12-cyclohexyl-4-[2-oxo-2-(piperidin-1-yl)ethylamino]-6,7-dihydro-5-oxa-7a-
-azadibenzo[a,e]azulene-9-carboxylate (Example 2-518) [3033] methyl
4-{bis[2-(piperidin-1-yl)ethyl]amino}-12-cyclohexyl-6,7-dihydro-5-oxa-7a--
azadibenzo[a,e]azulene-9-carboxylate (Example 2-519) [3034]
4-{bis[2-(piperidin-1-yl)ethyl]amino}-12-cyclohexyl-6,7-dihydro-5-oxa-7a--
azadibenzo[a,e]azulene-9-carboxylic acid trihydrochloride (Example
2-520) [3035] methyl
12-cyclohexyl-4-{N-[2-oxo-2-(piperidin-1-yl)ethyl]-N-propylamino}-6,7-dih-
ydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carboxylate (Example 2-521)
[3036] methyl
12-cyclohexyl-4-{N-[2-(piperidin-1-yl)ethyl]-N-propylamino}-6,7-d-
ihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carboxylate (Example
2-522) [3037]
12-cyclohexyl-5,6-dihydroindolo[2,1-a]isoquinoline-9-carboxylic
acid (Example 5-4) [3038] methyl
12-cyclohexyl-5,6-dihydroindolo[2,1-a]isoquinoline-9-carboxylate
(Example 5-5) [3039]
11-cyclohexyl-6-hydroxy-6H-isoindolo[2,1-a]indole-3-carboxylic acid
(Example 5-6) [3040]
11-cyclohexyl-6-methoxy-6H-isoindolo[2,1-a]indole-3-carboxylic acid
(Example 5-7) [3041]
12-cyclohexyl-3-methoxy-6,7-dihydro-5-oxa-7a,8-diazadibenzo[a,e]azulene-9-
-carboxylic acid (Example 7-9) [3042]
(E)-3-[4-({1-[(12-cyclohexyl-3-methoxy-6,7-dihydro-5-oxa-7a,8-diazadibenz-
o[a,e]azulene-9-carbonyl)amino]cyclobutanecarbonyl}amino)phenyl]acrylic
acid (Example 7-10) [3043]
12-cyclohexyl-3,5-dimethyl-6,7-dihydro-5H-5,7a,8-triazadibenzo[a,e]azulen-
e-9-carboxylic acid (Example 8-8) [3044]
(E)-3-[4-({1-[(12-cyclohexyl-3,5-dimethyl-6,7-dihydro-5H-5,7a,8-triazadib-
enzo[a,e]azulene-9-carbonyl)amino]cyclobutanecarbonyl}amino)phenyl]acrylic
acid (Example 8-9) [3045]
14-cyclohexyl-6-methyl-5,6,7,8-tetrahydrobenzo[6,7][1,4]diazocino[8,1-a]i-
ndole-11-carboxylic acid monohydrochloride (Example 11-1) [3046]
methyl
6-tert-butoxycarbonyl-14-cyclohexyl-5,6,7,8-tetrahydrobenzo[6,7][1,4]diaz-
ocino[8,1-a]indole-11-carboxylate (Example 11-2) [3047] methyl
14-cyclohexyl-6-methyl-5,6,7,8-tetrahydrobenzo[6,7][1,4]diazocino[8,1-a]i-
ndole-11-carboxylate (Example 11-3) [3048]
6-tert-butoxycarbonyl-14-cyclohexyl-3-methoxy-5,6,7,8-tetrahydrobenzo[6,7-
][1,4]diazocino[8,1-a]indole-11-carboxylic acid (Example 11-4)
[3049]
14-cyclohexyl-3-methoxy-5,6,7,8-tetrahydrobenzo[6,7][1,4]diazocino[8,1-a]-
indole-11-carboxylic acid monohydrochloride (Example 11-5) [3050]
14-cyclohexyl-3-methoxy-6-methyl-5,6,7,8-tetrahydrobenzo[6,7][1,4]diazoci-
no[8,1-a]indole-11-carboxylic acid monohydrochloride (Example 11-6)
[3051]
14-cyclohexyl-3-methoxy-6-(2-methoxyacetyl)-5,6,7,8-tetrahydroben-
zo[6,7][1,4]diazocino[8,1-a]indole-11-carboxylic acid (Example
11-7) [3052]
(E)-3-[4-({1-[(14-cyclohexyl-6-methyl-5,6,7,8-tetrahydrobenzo[6,7-
][1,4]diazocino[8,1-a]indole-11-carbonyl)amino]cyclobutanecarbonyl}amino)p-
henyl]acrylic acid monohydrochloride (Example 11-8) [3053]
12-cyclohexyl-6,7-dihydro-5-thia-7a-azadibenzo[a,e]azulene-9-carboxylic
acid (Example 12-1) [3054]
11-cyclohexyl-5-thia-6a-azabenzo[a]fluorene-8-carboxylic acid
(Example 12-2) [3055] methyl
12-cyclohexyl-6,7-dihydro-5-thia-7a-azadibenzo[a,e]azulene-9-carboxylate
(Example 12-3) [3056] methyl
11-cyclohexyl-5-thia-6a-azabenzo[a]fluorene-8-carboxylate (Example
12-4) [3057]
(E)-3-(4-{2-[(13-cyclohexyl-3-ethoxy-5-methyl-6,7-dihydro-5H-benz-
o[5,6][1,4]diazepino[7,1-a]indole-10-carbonyl)amino]-2-methylpropionylamin-
o}phenyl)acrylic acid (Example 1-615) [3058]
(E)-3-[3-({1-[(13-cyclohexyl-3-ethoxy-5-methyl-6,7-dihydro-5H-benzo[5,6][-
1,4]diazepino[7,1-a]indole-10-carbonyl)amino]cyclobutanecarbonyl}amino)phe-
nyl]acrylic acid (Example 1-616) [3059]
(E)-3-[4-({1-[(13-cyclohexyl-3-ethoxy-5-methyl-6,7-dihydro-5H-benzo[5,6][-
1,4]diazepino[7,1-a]indole-10-carbonyl)amino]cyclobutanecarbonyl}amino)-3--
methoxyphenyl]acrylic acid (Example 1-617) [3060]
(E)-3-[2-chloro-5-({1-[(13-cyclohexyl-3-ethoxy-5-methyl-6,7-dihydro-5H-be-
nzo[5,6][1,4]diazepino[7,1-a]indole-10-carbonyl)amino]cyclobutanecarbonyl}-
amino)phenyl]acrylic acid (Example 1-618) [3061]
(E)-3-[5-({1-[(13-cyclohexyl-3-ethoxy-5-methyl-6,7-dihydro-5H-benzo[5,6][-
1,4]diazepino[7,1-a]indole-10-carbonyl)amino]cyclobutanecarbonyl}amino)-2--
methoxyphenyl]acrylic acid (Example 1-619) [3062]
(E)-3-[5-({1-[(13-cyclohexyl-3-ethoxy-5-methyl-6,7-dihydro-5H-benzo[5,6][-
1,4]diazepino[7,1-a]indole-10-carbonyl)amino]cyclobutanecarbonyl}amino)-2--
methylphenyl]acrylic acid (Example 1-620) [3063]
(E)-3-[4-({1-[(13-cyclohexyl-3-ethoxy-5-methyl-6,7-dihydro-5H-benzo[5,6][-
1,4]diazepino[7,1-a]indole-10-carbonyl)amino]cyclobutanecarbonyl}amino)-2--
methylphenyl]acrylic acid (Example 1-621) [3064]
(E)-3-[4-({1-[(13-cyclohexyl-3-ethoxy-5-methyl-6,7-dihydro-5H-benzo[5,6][-
1,4]diazepino[7,1-a]indole-10-carbonyl)amino]cyclobutanecarbonyl}amino)-2--
methoxyphenyl]acrylic acid (Example 1-622) [3065]
(E)-3-[2-chloro-4-({1-[(13-cyclohexyl-3-ethoxy-5-methyl-6,7-dihydro-5H-be-
nzo[5,6][1,4]diazepino[7,1-a]indole-10-carbonyl)amino]cyclobutanecarbonyl}-
amino)phenyl]acrylic acid (Example 1-623) [3066]
4-({1-[(12-cyclohexyl-3-methoxy-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azule-
ne-9-carbonyl)amino]cyclobutanecarbonyl}amino)benzenesulfonic acid
(Example 2-523) [3067]
N--[(S)-1-(4,4-dimethyl-5-oxo-4,5-dihydrooxazol-2-yl)-2-(4-hydroxyphenyl)-
ethyl]-12-cyclohexyl-3-methoxy-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-
-9-carboxamide (Example 2-524)
[3068]
N--[(S)-2-(4-benzyloxyphenyl)-1-(5-methyl-1H-1,2,4-triazol-3-yl)e-
thyl]-12-cyclohexyl-3-methoxy-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene--
9-carboxamide (Example 2-525) [3069]
N--[(S)-2-(4-hydroxyphenyl)-1-(5-methyl-1H-1,2,4-triazol-3-yl)ethyl]-12-c-
yclohexyl-3-methoxy-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carboxam-
ide (Example 2-526) [3070]
N-[1-(5-methylcarbamoylmethoxy-1H-benzimidazol-2-yl)cyclobutyl]-12-cycloh-
exyl-3-methoxy-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carboxamide
(Example 2-527) [3071]
(E)-3-[4-({1-[(12-cyclohexyl-3-methoxy-6,7-dihydro-5-oxa-7a-azadibenzo[a,-
e]azulene-9-carbonyl)amino]cyclobutanecarbonyl}amino)phenyl]-2-methylacryl-
ic acid (Example 2-528) [3072]
(E)-3-[4-({1-[(12-cyclohexyl-3-methoxy-6,7-dihydro-5-oxa-7a-azadibenzo[a,-
e]azulene-9-carbonyl)amino]cyclobutanecarbonyl}amino)phenyl]but-2-enoic
acid (Example 2-529) [3073]
(E)-3-[3-(2-benzyloxyethoxy)-4-({1-[(12-cyclohexyl-3-methoxy-6,7-dihydro--
5-oxa-7a-azadibenzo[a,e]azulene-9-carbonyl)amino]cyclobutanecarbonyl}amino-
)phenyl]acrylic acid (Example 2-530) [3074]
(E)-3-[4-({1-[(12-cyclohexyl-3-methoxy-6,7-dihydro-5-oxa-7a-azadibenzo[a,-
e]azulene-9-carbonyl)amino]cyclobutanecarbonyl}amino)-2-methoxyphenyl]acry-
lic acid (Example 2-531) [3075]
(S)-2-[(12-cyclohexyl-3-methoxy-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azule-
ne-9-carbonyl)amino]-3-methoxy-2-methylpropionic acid (Example
2-532) [3076]
N--[(S)-1-(4-ethyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)-2-(4--
hydroxyphenyl)ethyl]-12-cyclohexyl-3-methoxy-6,7-dihydro-5-oxa-7a-azadiben-
zo[a,e]azulene-9-carboxamide (Example 2-533) [3077]
12-cyclohexyl-4-{2-[(E)-3-oxo-3-(piperidin-1-yl)propenyl]phenyl}-6,7-dihy-
dro-5-oxa-7a-azadibenzo[a,e]azulene-9-carboxylic acid (Example
2-534) [3078]
12-cyclohexyl-4-{2-[3-oxo-3-(piperidin-1-yl)propyl]phenyl}-6,7-di-
hydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carboxylic acid (Example
2-535) [3079]
12-cyclohexyl-4-{2-[3-(piperidin-1-yl)propyl]phenyl}-6,7-dihydro--
5-oxa-7a-azadibenzo[a,e]azulene-9-carboxylic acid monohydrochloride
(Example 2-536) [3080]
(E)-3-{4-((S)-2-[(12-cyclohexyl-3-methoxy-6,7-dihydro-5-oxa-7a-azadibenzo-
[a,e]azulene-9-carbonyl)amino]-3-methoxy-2-methylpropionylamino}phenyl)acr-
ylic acid (Example 2-537) [3081]
N--[(S)-2-(4-benzyloxyphenyl)-1-(1,3-dioxolan-2-yl)ethyl]-12-cyclohexyl-3-
-methoxy-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carboxamide
(Example 2-538) [3082]
N-(4-{2-[(12-cyclohexyl-3-methoxy-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azu-
lene-9-carbonyl)amino]-2-(methoxycarbonyl)ethyl}benzyl)-N,N,N-triethylammo-
nium chloride (Example 2-539) [3083]
4-(2-{1-[(12-cyclohexyl-3-methoxy-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azu-
lene-9-carbonyl)amino]-1-methylethyl}-3H-imidazol-4-yl)benzoic acid
monohydrochloride (Example 2-540) [3084]
N-[1-(2-oxo-2H-chromen-6-ylcarbamoyl)cyclobutyl]-12-cyclohexyl-3-methoxy--
6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carboxamide (Example
2-541) [3085]
N--[(S)-2-(4-benzyloxyphenyl)-1-(5-methyl-1,2,4-oxadiazol-3-yl)et-
hyl]-12-cyclohexyl-3-methoxy-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-
-carboxamide (Example 2-542) [3086]
N-{1-[4-((E)-2-carbamoylvinyl)phenylcarbamoyl]cyclobutyl}-12-cyclohexyl-3-
-methoxy-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carboxamide
(Example 2-543) [3087]
N-{1-[4-((E)-2-methylcarbamoylvinyl)phenylcarbamoyl]cyclobutyl}-12-cycloh-
exyl-3-methoxy-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carboxamide
(Example 2-544) [3088]
N-{1-[5-(4-hydroxymethylphenyl)-1H-imidazol-2-yl]-1-methylethyl}-12-cyclo-
hexyl-3-methoxy-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carboxamide
(Example 2-545) [3089]
N-{1-[5-(4-carbamoylphenyl)-1H-imidazol-2-yl]-1-methylethyl}-12-cyclohexy-
l-3-methoxy-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carboxamide
(Example 2-546) [3090]
N-{1-methyl-1-[5-(4-methylcarbamoylphenyl)-1H-imidazol-2-yl]ethyl}-12-cyc-
lohexyl-3-methoxy-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carboxamid-
e (Example 2-547) [3091]
(E)-3-[4-(2-{1-[(12-cyclohexyl-3-methoxy-6,7-dihydro-5-oxa-7a-azadibenzo[-
a,e]azulene-9-carbonyl)amino]-1-methylethyl}-3H-imidazol-4-yl)phenyl]acryl-
ic acid (Example 2-548) [3092]
12-cyclohexyl-4-{2-[2-(piperidin-1-yl)acetylamino]phenyl}-6,7-dihydro-5-o-
xa-7a-azadibenzo[a,e]azulene-9-carboxylic acid (Example 2-549)
[3093]
(E)-3-[3-({1-[(12-cyclohexyl-3-methoxy-6,7-dihydro-5-oxa-7a-azadibenzo[a,-
e]azulene-9-carbonyl)amino]cyclobutanecarbonyl}amino)phenyl]acrylic
acid (Example 2-550) [3094]
(E)-3-[3-({1-[(12-cyclohexyl-3-ethoxy-6,7-dihydro-5-oxa-7a-azadibenzo[a,e-
]azulene-9-carbonyl)amino]cyclobutanecarbonyl}amino)phenyl]acrylic
acid (Example 2-551) [3095]
(E)-3-[4-({1-[(12-cyclohexyl-3-ethoxy-6,7-dihydro-5-oxa-7a-azadibenzo[a,e-
]azulene-9-carbonyl)amino]cyclobutanecarbonyl}amino)-3-methoxyphenyl]acryl-
ic acid (Example 2-552) [3096]
12-cyclohexyl-4-{2-[2-(piperidin-1-yl)ethyl]phenyl}-6,7-dihydro-5-oxa-7a--
azadibenzo[a,e]azulene-9-carboxylic acid monohydrochloride (Example
2-553) [3097]
12-cyclohexyl-4-{2-[2-(piperidin-1-yl)ethylamino]phenyl}-6,7-dih-
ydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carboxylic acid
dihydrochloride (Example 2-554) [3098]
12-cyclohexyl-3-isopropoxy-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9--
carboxylic acid (Example 2-555)
[3099] 25
(E)-3-[4-({1-[(12-cyclohexyl-3-isopropoxy-6,7-dihydro-5-oxa-7a--
azadibenzo[a,e]azulene-9-carbonyl)amino]cyclobutanecarbonyl}amino)phenyl]a-
crylic acid (Example 2-556) TABLE-US-00004 LENGTHY TABLE REFERENCED
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[3100] The evaluation of the HCV polymerase inhibitory activity of
the compound of the present invention is explained in the
following. This polymerase is an enzyme coded for by the
non-structural protein region called NS5B on the genome RNA of HCV
(EMBO J., 15:12-22, 1996).
Experimental Example [I]
i) Preparation of Enzyme (HCV Polymerase)
[3101] Using, as a template, a cDNA clone corresponding to the full
length genome RNA of HCV BK strain obtained from the blood of a
patient with hepatitis C, a region encoding NS5B (J Virol 1991
March, 65(3), 1105-13, 544 amino acids after deletion of 47 amino
acids on the C-terminal) was amplified by PCR. The objective gene
was prepared by adding a 6 His tag {base pair encoding 6 continuous
histidine (His)}to the 3' end thereof and transformed to
Escherichia coli. The Escherichia coli capable of producing the
objective protein was cultured. The obtained cells were suspended
in a buffer solution and crushed in a microfluidizer. The
supernatant was obtained by centrifugation and applied to various
column chromatographys {mono-S, Sephacryl S-200 (Pharmacia)},
inclusive of metal chelate chromatography, to give a standard
enzyme product.
ii) Synthesis of Substrate RNA
[3102] Using a synthetic primer designed based on the sequence of
HCV genomic 3' untranslated region, a DNA fragment (148 bp)
containing polyU and 3'X sequence was entirely synthesized and
cloned into plasmid pBluescript SK II(+) (Stratagene). The cDNA
encoding full length NS5B, which was prepared in i) above, was
digested with restriction enzyme KpnI to give a cDNA fragment
containing the nucleotide sequence of from the restriction enzyme
cleavage site to the termination codon. This cDNA fragment was
inserted into the upstream of 3' untranslated region of the DNA in
pBluescript SK II(+) and ligated. The about 450 bp inserted DNA
sequence was used as a template in the preparation of substrate
RNA. This plasmid was cleaved immediately after the 3'X sequence,
linearized and purified by phenol-chloroform treatment and ethanol
precipitation to give DNA.
[3103] RNA was synthesized (37.degree. C., 3 hr) by run-off method
using this purified DNA as a template, a promoter of pBluescript SK
II(+), MEGAscript RNA synthesis kit (Ambion) and T7 RNA polymerase.
DNase I was added and the mixture was incubated for 1 hr. The
template DNA was removed by decomposition to give a crude RNA
product. This crude product was treated with phenol-chloroform and
purified by ethanol precipitation to give the objective substrate
RNA.
[3104] This RNA was applied to formaldehyde denaturation agarose
gel electrophoresis to confirm the quality thereof and preserved at
-80.degree. C.
iii) Assay of Enzyme (HCV Polymerase) Inhibitory Activity
[3105] A test substance (compound of the present invention) and a
reaction mixture (30 .mu.l) having the following composition were
reacted at 25.degree. C. for 90 min.
[3106] 10% Trichloroacetic acid at 4.degree. C. and 1% sodium
pyrophosphate solution (150 .mu.l) were added to this reaction
mixture to stop the reaction. The reaction mixture was left
standing in ice for 15 min to insolubilize RNA. This RNA was
trapped on a glass filter (Whatman GF/C and the like) upon
filtration by suction. This filter was washed with a solution
containing 1% trichloroacetic acid and 0.1% sodium pyrophosphate,
washed with 90% ethanol and dried. A liquid scintillation cocktail
(Packard) was added and the radioactivity of RNA synthesized by the
enzyme reaction was measured on a liquid scintillation counter.
[3107] The HCV polymerase inhibitory activity (IC.sub.50) of the
compound of the present invention was calculated from the values of
radioactivity of the enzyme reaction with and without the test
substance.
[3108] The results are shown in Tables 269-293.
[3109] As the compound of the present invention, preferred is a
compound showing less than 1 .mu.M of HCV polymerase inhibitory
activity (IC.sub.50), more preferred is a compound showing less
than 0.1 .mu.M of HCV polymerase inhibitory activity (IC.sub.50),
and still more preferred is a compound showing less than 0.01 .mu.M
of HCV polymerase inhibitory activity (IC.sub.50).
[3110] Reaction mixture: HCV polymerase (0.5 .mu.g/ml) obtained in
i), substrate RNA (5 .mu.g/ml) obtained in ii), ATP (50 .mu.M), GTP
(50 .mu.M), CTP (50 M), UTP (2 .mu.M), [5,6-.sup.3H]UTP (46 Ci/mmol
(Amersham), 1 .mu.Ci) 20 mM Tris-HCl (pH 7.5), EDTA (1 mM),
MgCl.sub.2 (5 mM), NaCl (50 mM), DTT (1 mM), BSA (0.01%)
TABLE-US-00271 TABLE 269 Ex- HCV polymerase Ex- HCV polymerase
ample inhibitory activity ample inhibitory activity No. IC.sub.50
No. IC.sub.50 1-3 B 1-7 B 1-9 B 1-14 B 1-18 B 1-19 A 1-20 B 1-21 B
1-22 B 1-23 B 1-24 B 1-25 B 1-26 B 1-27 B 1-28 B 1-29 B 1-30 B 1-31
A 1-32 B 1-33 B 1-34 B 1-35 B 1-36 B 1-37 B 1-38 B 1-39 B 1-40 B
1-41 B 1-42 B 1-43 B 1-44 B 1-45 B 1-46 B 1-47 B 1-48 B 1-49 B 1-50
B 1-51 B 1-52 B 1-53 B 1-54 B 1-55 B
[3111] TABLE-US-00272 TABLE 270 Ex- HCV polymerase Ex- HCV
polymerase ample inhibitory activity ample inhibitory activity No.
IC.sub.50 No. IC.sub.50 1-56 B 1-57 B 1-60 B 1-61 B 1-62 B 1-63 B
1-64 B 1-65 B 1-66 B 1-67 B 1-68 B 1-69 B 1-70 B 1-71 B 1-72 B 1-73
B 1-74 B 1-75 B 1-76 B 1-77 B 1-78 B 1-79 B 1-80 B 1-81 B 1-82 B
1-83 B 1-84 B 1-85 B 1-86 A 1-87 B 1-88 B 1-89 B 1-90 B 1-91 B 1-92
B 1-93 B 1-94 B 1-95 B 2-3 B 2-4 B 2-5 B 2-6 A
[3112] TABLE-US-00273 TABLE 271 Ex- HCV polymerase Ex- HCV
polymerase ample inhibitory activity ample inhibitory activity No.
IC.sub.50 No. IC.sub.50 2-9 B 2-10 B 2-11 B 2-12 B 2-13 B 2-14 B
2-15 B 2-16 B 2-17 B 2-18 B 2-19 B 2-20 B 2-21 B 2-22 B 2-23 B 2-24
B 2-25 B 2-26 B 2-27 B 2-28 B 2-29 B 2-30 B 2-31 B 3-4 B 4-2 A 5-2
B 5-3 A 6-2 A 7-4 B 7-5 B 7-6 B 7-7 B 8-4 B 9-2 B 9-3 B 9-4 B
[3113] TABLE-US-00274 TABLE 272 Ex- HCV polymerase Ex- HCV
polymerase ample inhibitory activity ample inhibitory activity No.
IC.sub.50 No. IC.sub.50 1-96 B 1-97 B 1-98 B 1-99 B 1-100 B 1-101 B
1-102 B 1-103 B 1-104 B 1-105 B 1-106 B 1-107 B 1-108 B 1-109 B
1-110 B 1-111 B 1-112 B 1-113 B 1-114 B 1-115 B 1-116 B 1-117 B
1-118 B 1-119 B 1-120 B 1-121 B 1-122 B 1-123 B 1-124 B 1-125 B
1-126 B 1-129 B 1-130 B 1-131 B 1-132 B 1-133 B 1-134 B 1-135 B
1-136 B 1-137 B 1-138 B 1-139 B
[3114] TABLE-US-00275 TABLE 273 Ex- HCV polymerase Ex- HCV
polymerase ample inhibitory activity ample inhibitory activity No.
IC.sub.50 No. IC.sub.50 1-140 B 1-141 B 1-142 B 1-143 B 1-144 B
1-145 B 1-146 B 1-147 B 1-148 B 1-149 B 1-150 B 1-151 B 1-152 B
1-153 B 1-154 B 1-155 B 1-156 B 1-157 B 1-158 B 1-159 B 1-160 B
1-161 B 1-162 B 1-163 B 1-164 B 1-165 B 1-166 B 1-167 A 1-168 B
1-169 B 1-170 B 1-171 B 1-172 B 1-173 B 1-174 B 1-175 B 1-176 B
1-177 B 1-178 B 1-179 B 1-180 B 1-181 B
[3115] TABLE-US-00276 TABLE 274 Ex- HCV polymerase Ex- HCV
polymerase ample inhibitory activity ample inhibitory activity No.
IC.sub.50 No. IC.sub.50 1-182 B 1-183 B 1-184 B 1-185 B 1-186 B
1-187 B 1-188 B 1-189 B 1-190 B 1-191 A 1-192 B 1-193 B 1-194 B
1-195 B 1-196 B 1-197 B 1-198 B 1-199 B 1-200 B 1-201 B 1-202 B
1-203 B 1-204 B 1-205 B 1-206 B 1-207 B 1-208 B 1-209 B 1-210 B
1-211 B 1-212 B 1-213 B 1-214 B 1-215 B 1-216 B 1-217 B 1-218 B
1-219 B 1-220 B 1-221 B 1-222 B 1-223 B
[3116] TABLE-US-00277 TABLE 275 Ex- HCV polymerase Ex- HCV
polymerase ample inhibitory activity ample inhibitory activity No.
IC.sub.50 No. IC.sub.50 1-224 B 1-225 B 1-226 B 1-227 B 1-228 B
1-229 B 1-230 B 1-231 B 1-232 B 1-233 B 1-234 B 1-235 B 1-236 B
1-237 B 1-238 B 1-239 B 1-240 B 1-241 B 1-242 B 1-243 B 1-244 B
1-245 B 1-246 B 1-247 B 1-248 B 1-249 B 1-250 B 1-251 B 1-252 B
1-253 B 1-254 B 1-255 B 1-256 B 1-257 B 1-258 B 1-259 B 1-260 B
1-261 B 1-262 B 1-263 B 1-264 B 1-265 B
[3117] TABLE-US-00278 TABLE 276 HCV HCV polymerase polymerase
Example inhibitory Example inhibitory No. activity IC.sub.50 No.
activity IC.sub.50 1-266 B 1-267 B 1-268 B 1-269 B 1-270 B 1-271 B
1-272 B 1-273 B 1-274 B 1-275 B 1-276 B 1-277 B 1-278 B 1-279 B
1-280 B 1-281 B 1-282 B 1-283 B 1-284 B 1-285 B 1-286 B 1-287 B
1-288 B 1-289 B 1-290 B 1-291 B 1-292 B 1-293 B 1-294 B 1-295 B
1-296 B 1-297 B 1-298 B 1-299 B 1-300 B 1-301 B 1-302 B 1-303 B
1-304 B 1-305 B 1-306 B 1-307 B
[3118] TABLE-US-00279 TABLE 277 HCV HCV polymerase polymerase
Example inhibitory Example inhibitory No. activity IC.sub.50 No.
activity IC.sub.50 1-308 B 1-309 B 1-310 B 1-311 B 1-312 B 1-314 B
1-315 B 1-316 B 1-317 B 1-318 B 1-319 B 1-320 B 1-321 B 1-322 B
1-323 B 1-324 B 1-325 B 1-326 B 1-327 B 1-328 B 1-329 B 1-330 B
1-331 B 1-332 B 1-333 B 1-334 B 1-335 B 1-336 B 1-337 B 1-338 B
1-339 B 1-340 B 1-341 B 1-342 B 1-343 B 1-344 B 1-345 B 1-346 B
1-347 B 1-348 B 1-349 B 1-350 B
[3119] TABLE-US-00280 TABLE 278 HCV HCV polymerase polymerase
Example inhibitory Example inhibitory No. activity IC.sub.50 No.
activity IC.sub.50 1-351 B 1-352 B 1-353 B 1-354 B 1-355 B 1-356 B
1-357 B 1-358 B 1-359 B 1-360 B 1-361 B 1-362 B 1-363 B 1-364 B
1-365 B 1-366 B 1-367 B 1-368 B 1-369 B 1-370 B 1-371 B 1-372 B
1-373 B 1-374 B 1-375 B 1-376 B 1-377 B 1-378 B 1-379 B 1-380 B
1-381 B 1-382 B 1-383 B 1-384 B 1-385 B 1-386 B 1-387 B 1-388 B
1-389 B 1-390 B 1-391 B 1-392 B
[3120] TABLE-US-00281 TABLE 279 HCV HCV polymerase polymerase
Example inhibitory Example inhibitory No. activity IC.sub.50 No.
activity IC.sub.50 1-393 B 1-394 B 1-395 B 1-396 B 1-397 B 1-398 B
1-399 B 1-400 B 1-401 B 1-402 B 1-403 B 1-404 B 1-405 B 1-406 B
1-407 B 1-408 B 1-409 B 1-410 B 1-411 B 1-412 B 1-413 B 1-414 B
1-415 B 1-416 B 1-417 B 1-418 B 1-419 B 1-420 B 1-421 B 1-422 B
1-423 B 1-424 B 1-425 B 1-426 B 1-427 B 1-428 B 1-429 B 1-430 B
1-431 B 1-432 B 1-433 B 1-434 B
[3121] TABLE-US-00282 TABLE 280 HCV HCV polymerase polymerase
Example inhibitory Example inhibitory No. activity IC.sub.50 No.
activity IC.sub.50 1-435 B 1-436 B 1-437 B 1-438 B 1-439 B 1-440 B
1-441 B 1-442 B 1-443 B 1-444 B 1-445 B 2-32 B 2-33 B 2-34 B 2-35 B
2-36 B 2-37 B 2-38 B 2-39 B 2-40 B 2-41 B 2-42 B 2-43 B 2-44 B 2-45
B 2-46 B 2-47 B 2-48 B 2-49 B 2-50 B 2-51 B 2-52 B 2-53 B 7-8 B 8-5
B 8-6 B 8-7 B 10-1 B 10-2 A 10-3 B 10-4 A
[3122] TABLE-US-00283 TABLE 281 HCV polymerase Example inhibitory
activity No. IC.sub.50 1-450 B 1-451 B 1-452 B 1-473 B 1-474 B
1-475 B 1-476 B 1-477 B 1-478 B 1-479 B 1-480 B 1-481 B 1-482 B
1-483 B 1-484 B 2-54 B 2-55 B 2-151 B 2-152 B 2-153 B 2-154 A 2-155
B 2-156 B 2-157 A 2-158 B 2-159 A 2-160 B 2-161 B 2-162 B 2-163 B
2-164 A 2-165 A 2-166 B 2-167 B 2-168 B 2-169 B 2-170 B 2-171 B
2-172 B 2-173 B 2-174 B 2-175 B
[3123] TABLE-US-00284 TABLE 282 HCV polymerase Example inhibitory
activity No. IC.sub.50 2-176 B 2-177 B 2-178 B 2-179 A 2-180 B
2-181 B 2-182 B 2-183 B 2-184 B 2-185 A 2-186 A 2-187 A 2-188 A
2-189 A 2-190 B 2-191 B 2-192 B 2-193 B 2-194 B 2-195 B 2-196 B
2-197 B 2-198 B 2-199 B 2-200 B 2-201 B 2-202 B 2-203 B 2-204 B
2-205 B 2-206 A 2-207 B 2-208 A 2-209 B 2-210 B 2-211 A 2-212 A
2-213 B 2-214 B 2-216 A 2-217 B 2-218 B
[3124] TABLE-US-00285 TABLE 283 HCV polymerase Example inhibitory
activity No. IC.sub.50 2-219 A 2-220 A 2-221 B 2-222 B 2-223 B
2-224 B 2-225 B 2-226 B 2-227 B 2-228 B 2-229 B 2-230 B 2-231 B
2-232 B 2-233 B 2-234 A 2-235 B 2-236 B 2-237 B 2-238 B 2-239 A
2-240 B 2-241 B 2-242 B 2-243 B 2-244 A 2-245 B 2-246 B 2-247 B
2-248 B 2-249 B 2-250 B 2-251 B 2-252 B 2-253 B 2-254 A 2-255 B
2-256 B 2-257 B 2-258 B 2-259 B 2-260 B
[3125] TABLE-US-00286 TABLE 284 HCV polymerase Example inhibitory
activity No. IC.sub.50 2-261 B 2-262 B 2-263 B 2-264 B 2-265 A
2-266 A 2-267 A 2-268 A 2-269 B 2-270 B 2-271 B 2-272 B 2-273 B
2-274 B 2-275 B 2-276 B 2-277 B 2-278 B 2-279 B 2-280 B 2-281 A
2-282 B 2-283 B 2-284 B 2-285 B 2-286 A 2-287 A 2-288 B 2-289 B
2-290 A 2-291 B 2-292 A 2-293 A 2-294 B 2-295 B 2-296 B 2-297 B
2-298 B 2-299 B 2-300 B 2-301 B 2-302 B
[3126] TABLE-US-00287 TABLE 285 HCV polymerase Example inhibitory
activity No. IC.sub.50 2-303 B 2-304 B 2-305 B 2-306 B 2-307 B
2-308 B 2-309 A 2-310 B 2-311 B 2-312 B 2-313 B 2-314 B 2-315 B
2-316 B 2-317 B 2-318 B 2-319 B 2-320 B 2-321 B 2-322 B 2-323 B
2-324 B 2-325 B 2-326 B 2-327 B 2-328 B 2-329 B 2-330 B 2-331 B
2-332 B 2-333 B 2-334 B 2-335 B 2-336 B 2-337 B 2-338 B 2-339 B
2-340 B 2-341 B 2-342 B 2-343 B 2-344 B
[3127] TABLE-US-00288 TABLE 286 HCV polymerase Example inhibitory
activity No. IC.sub.50 2-345 B 2-346 B 2-347 B 2-348 B 2-349 B
2-350 B 2-351 B 2-352 B 2-353 B 2-354 B 2-355 B 2-356 B 2-357 B
2-358 B 2-359 B 2-360 B 2-361 B 2-362 B 2-363 B 2-364 B 2-365 B
2-366 B 2-367 B 2-368 B 2-369 B 2-370 B 2-371 B 2-372 B 2-373 B
2-374 B 2-375 B 2-376 B 2-377 B 2-378 B 2-379 A 2-380 B 2-381 B
2-382 B 2-383 B 2-384 B 2-385 B 2-386 B
[3128] TABLE-US-00289 TABLE 287 HCV polymerase Example inhibitory
activity No. IC.sub.50 2-387 B 2-388 B 2-389 B 2-390 B 2-391 B
2-392 B 2-393 B 2-394 B 2-395 B 2-396 B 2-397 B 2-398 B 2-399 B
2-400 B 2-401 B 2-402 B 2-403 B 2-404 B 2-405 B 2-406 B 2-407 B
2-408 B 2-409 B 2-410 B 2-411 B 2-412 B 2-413 B 2-414 B 2-415 B
2-416 B 2-417 B 2-418 B 2-419 B 2-420 B 2-421 B 2-422 B 2-423 B
2-424 B 2-425 B 2-426 B 2-427 B 2-428 B
[3129] TABLE-US-00290 TABLE 288 HCV polymerase Example inhibitory
activity No. IC.sub.50 2-429 B 2-430 B 2-431 B 2-432 B 2-433 B
2-434 B 2-435 B 2-436 B 2-437 B 2-438 B 2-439 B 2-440 B 2-441 B
2-442 B 2-443 B 2-444 B 2-445 B 2-446 B 2-447 B 2-448 B 2-449 B
2-450 B 2-451 B 2-452 B 2-453 B 2-454 B 2-455 B
[3130] TABLE-US-00291 TABLE 289 HCV polymerase Example inhibitory
activity No. IC.sub.50 1-485 B 1-486 B 1-487 B 1-488 B 1-489 B
1-490 B 1-491 B 1-492 B 1-493 B 1-494 B 1-495 B 1-496 B 1-497 B
1-498 B 1-499 B 1-500 B 1-501 B 1-502 B 1-503 B 1-504 B 1-506 A
1-507 A 1-508 B 1-509 B 1-510 B 1-511 B 1-512 B 1-513 B 1-514 B
1-515 B 1-517 A 1-518 B 1-519 B 1-520 B 1-521 B 1-522 B 1-523 B
1-524 B 1-525 B 1-526 B 1-527 B 1-528 B
[3131] TABLE-US-00292 TABLE 290 HCV polymerase Example inhibitory
activity No. IC.sub.50 1-529 B 1-530 B 1-531 B 1-532 B 1-533 B
1-534 B 1-535 B 1-536 B 1-537 B 1-538 B 1-539 B 1-540 B 1-541 B
1-542 B 1-543 B 1-544 B 1-545 B 1-546 B 1-547 B 1-548 B 1-549 B
1-550 B 1-551 B 1-552 B 1-553 B 1-554 B 1-555 B 1-556 B 1-557 B
1-558 A 1-559 B 1-560 B 1-561 B 1-562 B 1-563 B 1-564 B 1-565 B
1-566 B 1-567 B 1-568 B 1-569 A 1-570 B
[3132] TABLE-US-00293 TABLE 291 HCV polymerase Example inhibitory
activity No. IC.sub.50 1-571 B 1-572 B 1-573 B 1-574 B 1-575 B
1-576 B 1-577 B 1-578 B 1-579 B 1-580 B 1-581 B 1-582 B 1-583 A
1-584 B 1-585 B 1-586 B 1-587 B 1-588 B 1-589 B 1-590 B 1-591 B
1-592 B 1-593 B 1-594 B 1-595 B 2-456 B 2-457 B 2-458 B 2-459 B
2-460 B 2-461 B 2-462 B 2-463 B 2-464 B 2-465 B 2-466 B 2-467 B
2-468 B 2-469 B 2-470 B 2-471 B 2-472 B
[3133] TABLE-US-00294 TABLE 292 HCV polymerase Example inhibitory
activity No. IC.sub.50 2-473 A 2-474 B 2-475 B 2-476 B 2-477 B
2-478 B 2-479 B 2-480 B 2-481 B 2-482 B 2-483 B 2-484 B 2-485 B
2-486 B 5-4 A 7-9 B 7-10 B 8-8 A 8-9 B 11-1 B 12-1 B 12-2 A 1-615 B
1-616 B 1-617 B 1-618 B 1-619 B 1-620 B 1-621 B 1-622 B 1-623 B
2-523 B 2-524 B 2-525 B 2-526 B 2-527 B 2-528 B 2-529 B 2-530 B
2-531 B 2-532 B 2-533 B
[3134] TABLE-US-00295 TABLE 293 HCV polymerase Example inhibitory
activity No. IC.sub.50 2-534 B 2-535 B 2-536 B 2-537 B 2-538 B
2-539 B 2-540 B 2-541 B 2-542 B 2-543 B 2-544 B 2-545 B 2-546 B
2-547 B 2-548 B 2-549 B 2-550 B 2-551 B 2-552 B 2-553 B 2-554 B
2-555 B 2-556 B 5-6 A 11-4 B 11-5 B 11-6 B 11-7 B 11-8 B IC.sub.50:
A not less than 0.1 .mu.M, less than 1 .mu.M B less than 0.1
.mu.M
Experimental Example [II]
[3135] The test compound was dissolved in DMSO (dimethyl sulfoxide;
final concentration 0.5%), and adjusted to a 10-fold concentration
of the final concentration with a medium.
[3136] Replicon cells (Huh-5-2: manufactured by ReBLikon GmbH) were
inoculated on a medium at 5.times.10.sup.3/90 .mu.l/well in a
96-well plate.
[3137] The medium was changed to a 4% HSA (human serum
albumin)-containing medium (90 .mu.l) the next day, and 10 .mu.l of
the above-mentioned adjusted product at each concentration was
added.
[3138] At 48 hr later, luciferase activity was measured with
Steady-Glo (manufactured by PROMEGA). The inhibitory rate relative
to the control group (0.5% DMSO addition group) was calculated and
EC.sub.50 value was determined by proportional calculation, based
on the data of two points across 50%, with the concentration of the
compound taken as logarithm. Composition of medium: Dulbecco's
modified Eagle's medium (DMEM), 10% fetal bovine serum (FBS), 2 mM
L-glutamine, 0.1 mM MEM non-essential amino acid, 100 U/ml
penicillin, 0.1 mg/ml streptomycin
[3139] As in the test, one showing high replication inhibitory, or
HCV polymerase inhibitory activity in the presence of a protein is
one of the preferable embodiments.
[3140] As is evident from the above-mentioned results, the compound
of the present invention shows a high inhibitory activity against
HCV polymerase.
[3141] Therefore, the compound of the present invention can provide
a pharmaceutical agent effective for the prophylaxis or treatment
of hepatitis C, based on the anti-HCV effect afforded by the HCV
polymerase inhibitory activity. When used concurrently with a
different anti-HCV agent, such as interferon, and/or an
anti-inflammatory agent and the like, it can provide a
pharmaceutical agent more effective for the prophylaxis or
treatment of hepatitis C. Its high inhibitory activity specific to
HCV polymerase suggests the possibility of the compound being a
pharmaceutical agent with slight side effects, which can be used
safely for humans.
[3142] Formulation Example is given in the following. This example
is merely for the purpose of exemplification and does not limit the
invention.
Formulation Example
[3143] TABLE-US-00296 (a) compound of Example 1-9 10 g (b) lactose
50 g (c) corn starch 15 g (d) sodium carboxymethylcellulose 44 g
(e) magnesium stearate 1 g
[3144] The entire amounts of (a), (b) and (c) and 30 g of (d) are
kneaded with water, dried in vacuo and granulated. The obtained
granules are mixed with 14 g of (d) and 1 g of (e) and processed
into tablets with a tableting machine to give 1000 tablets each
containing 10 mg of (a).
[3145] This application is based on a patent application Nos.
2004-48815, 2004-169190 and 2004-296390 filed in Japan, the
contents of which are hereby incorporated by reference.
TABLE-US-00297 LENGTHY TABLE The patent application contains a
lengthy table section. A copy of the table is available in
electronic form from the USPTO web site
(http://seqdata.uspto.gov/?pageRequest=docDetail&DocID=US20070049593A1).
An electronic copy of the table will also be available from the
USPTO upon request and payment of the fee set forth in 37 CFR
1.19(b)(3).
* * * * *
References