U.S. patent application number 16/862125 was filed with the patent office on 2022-09-29 for tetracyclic compound.
This patent application is currently assigned to Chugai Seiyaku Kabushiki Kaisha. The applicant listed for this patent is Chugai Seiyaku Kabushiki Kaisha. Invention is credited to Kohsuke ASOH, Takashi EMURA, Noriyuki FURUICHI, WooSang HONG, Nobuya ISHII, Toshiya ITO, Yasuharu KATO, Hatsuo KAWADA, Kazutomo KINOSHITA, Kenji MORIKAMI, Nobuhiro OIKAWA, Yoshiyuki ONO, MinJeong PARK, Hiroshi SAKAMOTO.
Application Number | 20220306578 16/862125 |
Document ID | / |
Family ID | 1000005239926 |
Filed Date | 2022-09-29 |
United States Patent
Application |
20220306578 |
Kind Code |
A1 |
KINOSHITA; Kazutomo ; et
al. |
September 29, 2022 |
TETRACYCLIC COMPOUND
Abstract
A compound represented by the general Formula (I) below, or a
salt or solvate thereof, which is useful as an ALK inhibitor, and
is useful for prophylaxis or treatment of a disease accompanied by
abnormality in ALK, for example, cancer, cancer metastasis,
depression or cognitive function disorder: ##STR00001## (meanings
of the symbols that are included in the formula are as given in the
specification).
Inventors: |
KINOSHITA; Kazutomo;
(Kanagawa, JP) ; ASOH; Kohsuke; (Kanagawa, JP)
; FURUICHI; Noriyuki; (Kanagawa, JP) ; ITO;
Toshiya; (Kanagawa, JP) ; KAWADA; Hatsuo;
(Kanagawa, JP) ; ISHII; Nobuya; (Kanagawa, JP)
; SAKAMOTO; Hiroshi; (Kanagawa, JP) ; HONG;
WooSang; (Gyeonggi-do, KR) ; PARK; MinJeong;
(Gyeonggi-do, KR) ; ONO; Yoshiyuki; (Shizuoka,
JP) ; KATO; Yasuharu; (Shizuoka, JP) ;
MORIKAMI; Kenji; (Shizuoka, JP) ; EMURA; Takashi;
(Shizuoka, JP) ; OIKAWA; Nobuhiro; (Kanagawa,
JP) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Chugai Seiyaku Kabushiki Kaisha |
Tokyo |
|
JP |
|
|
Assignee: |
Chugai Seiyaku Kabushiki
Kaisha
Tokyo
JP
|
Family ID: |
1000005239926 |
Appl. No.: |
16/862125 |
Filed: |
April 29, 2020 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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16239839 |
Jan 4, 2019 |
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16862125 |
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15221926 |
Jul 28, 2016 |
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16239839 |
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14619242 |
Feb 11, 2015 |
9440922 |
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15221926 |
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13377300 |
Dec 9, 2011 |
9126931 |
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PCT/JP2010/059785 |
Jun 9, 2010 |
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14619242 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 31/496 20130101;
C07D 471/10 20130101; C07D 333/52 20130101; C07D 405/14 20130101;
C07D 491/107 20130101; C07H 15/26 20130101; C07D 401/14 20130101;
A61K 31/7056 20130101; C07D 403/04 20130101; C07F 7/0834 20130101;
A61K 31/4439 20130101; C07D 409/12 20130101; C07D 401/06 20130101;
A61K 31/404 20130101; C07D 403/12 20130101; C07D 307/92 20130101;
C07D 413/14 20130101; C07D 209/58 20130101; A61K 31/5377 20130101;
A61K 31/506 20130101; C07D 333/76 20130101; C07D 307/78 20130101;
A61K 31/454 20130101; C07D 401/04 20130101; C07D 209/88 20130101;
C07D 307/77 20130101; C07D 405/12 20130101; C07D 333/50 20130101;
C07D 209/56 20130101; C07D 471/04 20130101; C07D 401/12 20130101;
A61K 31/541 20130101; A61K 31/4178 20130101 |
International
Class: |
C07D 209/58 20060101
C07D209/58; C07D 209/88 20060101 C07D209/88; C07D 307/77 20060101
C07D307/77; C07D 307/92 20060101 C07D307/92; C07D 333/50 20060101
C07D333/50; C07D 333/76 20060101 C07D333/76; C07D 401/04 20060101
C07D401/04; C07D 401/06 20060101 C07D401/06; C07D 403/04 20060101
C07D403/04; C07D 405/12 20060101 C07D405/12; C07D 405/14 20060101
C07D405/14; C07D 471/04 20060101 C07D471/04; C07D 491/107 20060101
C07D491/107; C07D 209/56 20060101 C07D209/56; A61K 31/404 20060101
A61K031/404; A61K 31/4178 20060101 A61K031/4178; A61K 31/4439
20060101 A61K031/4439; A61K 31/454 20060101 A61K031/454; A61K
31/496 20060101 A61K031/496; A61K 31/506 20060101 A61K031/506; A61K
31/5377 20060101 A61K031/5377; A61K 31/541 20060101 A61K031/541;
A61K 31/7056 20060101 A61K031/7056; C07D 307/78 20060101
C07D307/78; C07D 333/52 20060101 C07D333/52; C07D 401/12 20060101
C07D401/12; C07D 401/14 20060101 C07D401/14; C07D 403/12 20060101
C07D403/12; C07D 409/12 20060101 C07D409/12; C07D 413/14 20060101
C07D413/14; C07D 471/10 20060101 C07D471/10; C07F 7/08 20060101
C07F007/08; C07H 15/26 20060101 C07H015/26 |
Foreign Application Data
Date |
Code |
Application Number |
Jun 10, 2009 |
JP |
2009-139691 |
Claims
1. A compound or salt or solvate thereof represented by Formula
(I): ##STR01235## wherein, A.sup.1, A.sup.2, A.sup.3, A.sup.4,
A.sup.7, A.sup.8, A.sup.9 and A.sup.10 all represent C, or any one
of A.sup.2, A.sup.3, A.sup.4, A.sup.7, A.sup.8 and A.sup.9
represents N (with the proviso that, when it represents N, no
substituent group exists therefor) and the remainings represent C;
A.sup.5 is selected from NR.sup.5, O and S; R.sup.1 and R.sup.10
each independently represent [1] a hydrogen atom, [2] a cyano
group, [3] a halogen atom or [4] a 4-to 10-membered
heterocycloalkyl group which may be substituted by 4- to
10-membered heterocycloalkyl group(s); R.sup.2 is selected from the
group consisting of: (1) a hydrogen atom, (2) a C.sub.1-8 alkyl
group, (3) a C.sub.2-8 alkenyl group, (4) a C.sub.2-8 alkynyl
group, (5) a cyano group, (6) a halogen atom, (7) a (C.sub.1-8
alkyl).sub.m2-amino group which may be substituted by C.sub.1-8
alkylsulfonyl group(s), m2: 0.about.2, and (8) a nitro group;
R.sup.3 is selected from the group consisting of: (1) a hydrogen
atom, (2) a C.sub.1-8 alkyl group which may be substituted by [1]
halogen atom(s), [2] hydroxy group(s) or [3] C.sub.1-8 alkoxy
group(s), (3) a C.sub.6-10 aryl group, (4) a cyano group, (5) a
C.sub.1-8 alkanoyl group which may be substituted by C.sub.6-10
aryl group(s), (6) a (C1-8 alkyl).sub.m3a-aminocarbonyl group which
may be substituted by one or more R.sup.3A, R.sup.3A: [1] a
C.sub.6-10 aryl group, [2] a C.sub.1-8 alkoxy group, [3] a 5- to
14-membered heteroaryl group, or [4] a C.sub.6-10 arylsulfonyl
group, m3a: 0.about.2, (7) a hydroxycarbonyl group, (8) a C.sub.1-8
alkoxycarbonyl group which may be substituted by [1] hydroxy
group(s) or [2] C.sub.1-8 alkoxy group(s), (9) a halogen atom, (10)
a (C.sub.1-8 alkyl).sub.m3b-amino group which may be substituted by
C.sub.6-10 aryl group(s), m3b: 0.about.2, (11) a C.sub.1-8
alkylcarbonyl (C.sub.0-8 alkyl) amino group which may be
substituted by [1] C.sub.6-10 aryl group(s) or [2] C.sub.6-10
aryloxy group(s), (12) a C.sub.6-10 arylcarbonyl (C.sub.0-8 alkyl)
amino group which may be substituted by C.sub.1-8 alkyl group(s)
which may be substituted by halogen atom(s), (13) a (C.sub.1-8
alkyl).sub.m3c-aminocarbonyl (C.sub.0-8 alkyl) amino group which
may be substituted by C.sub.6-10 aryl group(s), m3c: 0.about.2,
(14) a nitro group, (15) a hydroxy group, (16) a C.sub.1-8 alkoxy
group which may be substituted by one or more R.sup.3B, R.sup.3B:
[1] a hydroxy group, [2] a C.sub.1-8 alkoxy group, [3] a C.sub.6-10
aryl (C.sub.0-8 alkyl) aminocarbonyl group, [4] a (C.sub.1-8
alkyl).sub.m3d-amino group, or [5] a halogen atom, m3d: 0.about.2,
(17) a 4- to 10-membered heterocycloalkyloxy group, (18) a 5- to
14-membered heteroaryloxy group, (19) a (C.sub.1-8
alkyl).sub.m3e-aminocarbonyloxy group which may be substituted by
C.sub.6-10 aryl group(s) m3e: 0.about.2, (20) a 4- to 10-membered
nitrogen-containing heterocycloalkylcarbonyl group, (21) a
C.sub.1-8 alkylsulfonyloxy group which may be substituted by
halogen atom(s), (22) a C.sub.1-8 alkylthio group, (23) a C.sub.1-8
alkylsulfonyl group which may be substituted by C.sub.6-10 aryl
group(s), (24) a 5- to 14-membered heteroaryl group which may be
substituted by C.sub.1-8 alkyl group(s) which may be substituted by
C.sub.1-8 alkoxy group(s), (25) a C.sub.1-8 alkoxycarbonyl
(C.sub.0-8 alkyl) amino group which may be substituted by C.sub.1-8
alkoxy group(s), (26) a C.sub.6-10 aryloxycarbonyl (C.sub.0-8
alkyl) amino group which may be substituted by C.sub.1-8 alkyl
group(s) which may be substituted by halogen atom(s), (27) a
C.sub.6-10 aryl (C.sub.0-8 alkyl) aminocarbonyl (C.sub.0-8 alkyl)
amino group which may be substituted by one or more R.sup.3C,
R.sup.3C: [1] a C.sub.1-8 alkyl group which may be substituted by
halogen atom(s), or [2] a C.sub.1-8 alkoxy group, (28) a C.sub.3-8
cycloalkyl (C.sub.0-8 alkyl) aminocarbonyloxy group, and (29) a
C.sub.6-10 aryl (C.sub.0-8 alkyl) aminocarbonyloxy group which may
be substituted by substituent(s) selected from the group consisting
of [1] a C.sub.1-8 alkyl group and [2] a C.sub.1-8 alkoxy group;
R.sup.4 is selected from the group consisting of: (1) a hydrogen
atom, (2) a C.sub.1-8 alkyl group which may be substituted by
halogen atom(s), (3) a C.sub.2-8 alkenyl group, (4) a C.sub.2-8
alkynyl group, (5) a C.sub.3-8 cycloalkyl group, (6) a cyano group,
(7) an aminocarbonyl group, (8) a (C.sub.1-8
alkyl).sub.m4a-aminocarbonyl group, m4a: 1.about.2, (9) a
hydroxycarbonyl group, (10) a C.sub.1-8 alkoxycarbonyl group, (11)
a halogen atom, (12) a (C.sub.1-8 alkyl).sub.m4b-amino group, m4b:
0.about.2, (13) a hydroxy group, and (14) a C.sub.1-8 alkoxy group
which may be substituted by hydroxy group(s); R.sup.5 is selected
from the group consisting of: (1) a hydrogen atom, (2) a C.sub.1-8
alkyl group which may be substituted by one or more R.sup.5A,
R.sup.5A: [1] a hydroxycarbonyl group, [2] a C.sub.1-8
alkoxycarbonyl group, [3] a hydroxy group, [4] a C.sub.1-8 alkoxy
group, [5] a (C.sub.1-8 alkyl).sub.m5-amino group, [6] a C.sub.6-10
aryl group, or [7] a C.sub.1-8 alkylthio group, m5: 0.about.2, (3)
a C.sub.2-8 alkenyl group, (4) a C.sub.2-8 alkynyl group, (5) a
C.sub.3-8 cycloalkyl group, and (6) a C.sub.1-8 alkylsulfonyl
group; R.sup.6 and R.sup.6' are each independently selected from
the group consisting of: (1) a C.sub.1-8 alkyl group which may be
substituted by halogen atom(s), (2) a C.sub.2-8 alkenyl group, and
(3) a C.sub.2-8 alkynyl group; or R.sup.6 and R.sup.6' are taken
together with the carbon atoms to which they are bound to form: (4)
a C.sub.3-8 cycloalkyl group, or (5) a 4- to 10-membered
heterocycloalkyl group which may be substituted by C.sub.1-8 alkyl
C.sub.6-10 aryl sulfonyl group(s) which may be substituted by
C.sub.1-8 alkyl group(s); R.sup.7 is selected from the group
consisting of: (1) a hydrogen atom, (2) a halogen atom, (3) a
C.sub.1-8 alkoxy group which may be substituted by one or more
R.sup.7A, R.sup.7A: [1] a (C.sub.1-8 alkyl)m7a-amino group, [2] a
hydroxy, [3] a 4- to 10-membered heterocycloalkyl group which may
be substituted by C.sub.1-8 alkyl group(s), m7a: 0.about.2, (4) a
C.sub.1-8 alkylsulfonyl group, (5) a nitro group, and (6) a
hydroxyl group; R.sup.8 is selected from the group consisting of:
(1) a hydrogen atom, (2) a C.sub.1-8 alkyl group which may be
substituted by one or more R.sup.8A, R.sup.8A: [1] a 4- to
10-membered heterocycloalkyl group which may be substituted by one
or more R.sup.8A1, [2] a (C.sub.1-8 alkyl).sub.m8a-amino group
which may be substituted by a halogen atom, or [3] a hydroxy group,
m8a:0.about.2, R.sup.8A1: [1] a C.sub.1-8 alkyl group, [2] a
C.sub.1-8 alkylsulfonyl group, [3] a (C.sub.1-8
alkyl).sub.m8b-aminosulfonyl group, [4] an oxo group, [5] a
C.sub.1-8 alkoxycarbonyl, or [6] a C.sub.1-8 alkoxycarbonyl
(C.sub.0-8 alkyl) aminosulfonyl, m8b: 0.about.2, (3) a C.sub.2-8
alkenyl group, (4) a 4- to 10-membered heterocycloalkyl group which
may be substituted by one or more R.sup.8B, R.sup.8B: <1> a
C.sub.1-8 alkyl group which may be substituted by one or more
R.sup.8B1, <2> a C.sub.2-8 alkeynyl group, <3> a
C.sub.2-8 alkynyl group, <4> a C.sub.3-8 cycloalkyl group
which may be substituted by [1] cyano group(s) or [2] C.sub.1-8
alkyl group(s), <5> a 4- to 10-membered heterocycloalkyl
group which may be substituted by one or more R.sup.8B2, <6>
a C.sub.1-8 alkoxy group which may be substituted by substituent(s)
selected from the group consisting of [1] a C.sub.1-8 alkoxy group
and [2] a C.sub.3-8 cycloalkyl group, <7> a C.sub.1-8
alkoxycarbonyl group, <8> a C.sub.1-8 alkylsulfonyl group,
<9> a 5- to 14-membered heteroarylsulfonyl group, <10>
an oxo group, <11> a cyano group, <12> a C.sub.1-8
alkanoyl group which may be substituted by one or more R.sup.8B3,
<13> a C.sub.3-8 cycloalkylcarbonyl group, <14> a
(C.sub.1-8 alkyl).sub.m8c-aminosulfonyl group, <15> a
C.sub.1-8 alkylsulfonyl (C.sub.0-8 alkyl) amino group, <16> a
(C.sub.1-8 alkyl).sub.m8d-amino group which may be substituted by
one or more R.sup.8B4, <17> a hydroxy group, <18> a
(C.sub.1-8 alkyl).sub.m8e-aminocarbonyl group, or <19> a
C.sub.1-8 alkoxycarbonyl (C.sub.0-8 alkyl) amino group m8c:
0.about.2 m8d: 0.about.2 m8e: 0.about.2 R.sup.8B1: [1] a C.sub.3-8
cycloalkyl group, [2] a hydroxy group, or [3] a C.sub.1-8 alkoxy
group(s), R.sup.8B2: [1] a halogen atom, [2] a C.sub.1-8 alkyl
group, [3] an oxo group, [4] a hydroxy group, or [5] a deuterium
atom, R.sup.8B3: a (C.sub.1-8 alkyl).sub.m8f-amino group, m8f:
0.about.2, R.sup.8B4: [1] a C.sub.3-8 cycloalkyl group, or [2] a
hydroxy group, (5) a 5- to 14-membered heteroaryl group which may
be substituted by a C.sub.1-8 alkyl group, (6) a (C.sub.1-8
alkyl).sub.m8g-aminocarbonyl group which may be substituted by one
or more R.sup.8C, m8g: 0.about.2, R.sup.8C:[1] a hydroxy group, [2]
a (C.sub.1-8 alkyl).sub.m8h-amino group which may be substituted by
substituent(s) selected from the group consisting of <1> a
(C.sub.1-8 alkyl).sub.m8i-aminosulfonyl group, <2> a
C.sub.1-8 alkylsulfonyl group, <3> a C.sub.1-8 alkoxycarbonyl
group and 5<4> a C.sub.1-8 alkoxycarbonyl(C.sub.0-8 alkyl)
aminosulfonyl group, [3] a C.sub.1-8 alkylsulfonyl group, or [4] a
C.sub.1-8 alkoxy group which may be substituted by a hydroxy group,
m8h: 0.about.2, m8i: 0.about.2, (7) a 4- to 10-membered
heterocycloalkyl (C.sub.0-8 alkyl) aminocarbonyl group which may be
substituted by oxo group(s), (8) a 4- to 10-membered
nitrogen-containing heterocycloalkylcarbonyl group which may be
substituted by one or more R.sup.8D, R.sup.8D: [1] a C.sub.1-8
alkyl group which may be substituted by one or more R.sup.8D1, [2]
a hydroxy group, [3] a C.sub.1-8 alkylsulfonyl group, or [4] a
C.sub.1-8 alkoxycarbonyl group, R.sup.8D1: [1] a hydroxy group, or
[2] a C.sub.1-8 alkoxy group, (9) a hydroxycarbonyl group, (10) a
C.sub.0-8 alkoxy (C.sub.0-8 alkyl) aminocarbonyl group which may be
substituted by hydroxy group(s), (11) a halogen atom, (12) a
(C.sub.1-8 alkyl).sub.m8j-amino group which may be substituted by
one or more R.sup.8H, m8j: 0.about.2, R.sup.8H: [1] a hydroxy
group, or [2] a 4- to 10-membered heterocycloalkyl group, (13) a
hydroxyl group, (14) a C.sub.1-8 alkoxy group which may be
substituted by one or more R.sup.8E, R.sup.8E: <1> a hydroxy
group, <2> halogen atom, <3> a hydroxycarbonyl group,
<4> a C.sub.1-8 alkoxycarbonyl group, <5> a 4- to
10-membered nitrogen-containing heterocycloalkylcarbonyl group
which may be substituted by one or more R.sup.8E1, <6> a
(C.sub.1-8 alkyl).sub.m8k1-amino group which may be substituted by
one or more R.sup.8E2, m8k1: 0.about.2, <7> a 4- to
10-membered heterocycloalkyl group which may be substituted by one
or more R.sup.8E3, <8> a 5- to 14-membered heteroaryl group,
<9> a (C.sub.1-8 alkyl).sub.m8k2-aminocarbonyl group which
may be substituted by one or more R.sup.8E6, m8k2: 0.about.2,
<10> a C.sub.1-8 alkoxy group which may be substituted by one
or more R.sup.8E7, <11> a C.sub.1-8 alkylthio group,
<12> a C.sub.1-8 alkylsulfinyl group, <13> a C.sub.1-8
alkylsulfonyl group, R.sup.8E1: <1> a C.sub.1-8
alkoxycarbonyl group, <2> a C.sub.1-8 alkanoyl group,
<3> a C.sub.1-8 alkylsulfonyl group, <4> a (C.sub.1-8
alkyl).sub.m8k3-aminosulfonyl group, m8k3: 0.about.2, or <5>
a 4- to 10-membered heterocycloalkyl group, R.sup.8E2: <1> a
hydroxy group, <2> a C.sub.1-8 alkoxycarbonyl group which may
be substituted by halogen atom(s), <3> a C.sub.3-8 cycloalkyl
group which may be substituted by C.sub.1-8 alkyl group(s) which
may be substituted by hydroxy group(s), <4> a C.sub.1-8
alkanoyl group which may be substituted by substituent(s) selected
from the group consisting of [1] a (C.sub.1-8 alkyl).sub.m8k4-amino
group and [2] a halogen atom(s), m8k4: 0.about.2, <5> a
(C.sub.1-8 alkyl).sub.m8k5-aminocarbonyl group, m8k5: 0.about.2,
<6> a C.sub.1-8 alkylsulfonyl group, <7> a 4- to
10-membered nitrogen-containing heterocycloalkylsulfonyl group
which may be substituted by C.sub.1-8 alkyl group(s), <8> a
(C.sub.1-8 alkyl).sub.m8k6-aminosulfonyl group which may be
substituted by C.sub.1-8 alkoxycarbonyl group(s), m8k6: 0.about.2,
or R.sup.8E3: <1> a C.sub.1-8 alkyl group which may be
substituted by substituent(s) selected from the group consisting of
[1] a hydroxy group and [2] a C.sub.1-8 alkylcarbonyloxy group,
<2> a C.sub.1-8 alkylcarbonyloxy group, <3> a hydroxy
group, <4> a C.sub.3-8 cycloalkyl group, <5> a
C.sub.1-8 alkoxy group, <6> a C.sub.1-8 alkoxycarbonyl group,
<7> a C.sub.1-8 alkylsulfonyl group, <8> a (C.sub.1-8
alkyl).sub.m8k8-aminocarbonyl group m8k8: 0.about.2, <9> a
C.sub.1-8 alkanoyl group which may be substituted by hydroxy
group(s), <10> an oxo group, or <11> a 4- to
10-membered heterocycloalkyl group which may be substituted by
substituent(s) selected from the group consisting of [1] a
C.sub.1-8 alkanoyl group, [2] a C.sub.1-8 alkoxycarbonyl group and
[3] a C.sub.1-8 alkylsulfonyl group, R.sup.8E6: <1> a
C.sub.2-8 alkenylcarbonyloxy group, <2> a hydroxy group,
<3> a cyano group, <4> a (C.sub.1-8
alkyl).sub.m8k9-amino group which may be substituted by hydroxy
group(s) m8k9: 0.about.2, <5> a C.sub.1-8 alkoxy group which
may be substituted by hydroxy group(s), <6> a C.sub.1-8
alkylcarbonyloxy group, <7> a 4- to 10-membered
heterocycloalkyl group which may be substituted by C.sub.1-8 alkyl
group(s), or <8> a 5- to 14-membered heteroaryl group,
R.sup.8E7: <1> a hydroxy group, or <2> a C.sub.1-8
alkoxy group which may be substituted by hydroxy group(s), (15) a
4- to 10-membered heterocycloalkyloxy group which may be
substituted by one or more R.sup.8F, R.sup.8F: <1> a
C.sub.1-8 alkyl group which may be substituted by one or more
R.sup.8F1, <2> a C.sub.3-8 cycloalkyl group, <3> a
C.sub.1-8 alkanoyl group which may be substituted by halogen
atom(s), <4> a C.sub.1-8 alkylcarbonyloxy group, <5> a
C.sub.1-8 alkoxycarbonyl group, <6> a 4- to 10-membered
heterocycloalkyl group which may be substituted by one or more
R.sup.8F2, <7> a C.sub.1-8 alkyl sulfonyl group, <8> a
hydroxy group, or [9] a C.sub.6-10 aryl group, R.sup.8F1: [1] a
hydroxy group, [2] a C.sub.1-8 alkoxy group, or [3] a halogen atom,
R.sup.8F2: [1] a 4- to 10-membered heterocycloalkyl group, [2] a
C.sub.1-8 alkoxycarbonyl group, or [3] a C.sub.1-8 alkylsulfonyl
group, (16) a 5- to 14-membered heteroaryloxy group, (17) a 4- to
10-membered heterocycloalkylcarbonyloxy group, (18) a (C.sub.1-8
alkyl).sub.m8l1-aminosulfonyloxy group, m8l1: 0.about.2, (19) a
C.sub.1-8 alkyl thio group which may be substituted by [1] (C
.sub.1-8 alkyl).sub.m8l2-amino group(s), [2] hydroxy group(s) or
[3] hydroxycarbonyl group(s), m8l2: 0.about.2, (20) a C.sub.1-8
alkylsulfonyl group which may be substituted by one or more
R.sup.8G, R.sup.8G: [1] a hydroxycarbonyl group, [2] a hydroxy
group, or [3] a (C.sub.1-8 alkyl).sub.m8l3-amino group, m8l3:
0.about.2, (21) a 4- to 10-membered nitrogen-containing
heterocycloalkylsulfonyloxy group which may be substituted by
C.sub.1-8 alkyl group(s), (22) a C.sub.2-8 alkenyloxy group, and
(23) a C.sub.1-8 alkylsulfonyloxy group which may be substituted by
halogen atom(s); R.sup.9 is selected from the group consisting of:
(1) a hydrogen atom, (2) a C.sub.1-8 alkyl group which may be
substituted by one or more R.sup.9A, R.sup.9A: [1] a C.sub.3-8
cycloalkyl group, [2] a 4- to 10-membered heterocycloalkyl group
which may be substituted by one or more R.sup.9A1, [3] a hydroxy
group, [4] a C.sub.1-8 alkoxy group, or [5] a hydroxycarbonyl
group, R.sup.9A1: [1] a C.sub.1-8 alkyl group, [2] a C.sub.3-8
cycloalkyl group, or [3] a 4- to 10-membered heterocycloalkyl
group, (3) a C.sub.2-8 alkenyl group which may be substituted by
one or more R.sup.9B, R.sup.9B: [1] a (C.sub.1-8
alkyl).sub.m9a-amino group, [2] a 4- to 10-membered
heterocycloalkyl group which may be substituted by one or more
group R.sup.9B1, R.sup.9B1:[1] a C.sub.3-8 cycloalkyl group, or [2]
a 4- to 10-membered heterocycloalkyl group, m9a: 0.about.2, (4) a
C.sub.2-8 alkynyl group which may be substituted by one or more
R.sup.9C, R.sup.9C: [1] a C.sub.1-8 alkoxy group, [2] a (C.sub.1-8
alkyl).sub.m9b-amino group which may be substituted by C.sub.6-10
aryl group(s), [3] a 4- to 10-membered heterocycloalkyl group which
may be substituted by one or more R.sup.9C1, [4] a C.sub.3-8
cycloalkyl group, [5] a hydroxy group, [6] a hydroxycarbonyl group,
or [7] a C.sub.1-8 alkyloxycarbonyl group, m9b: 0.about.2,
R.sup.9C1: [1] a C.sub.3-8 cycloalkyl group, [2] a 4- to
10-membered heterocycloalkyl group, or [3] an oxo group, (5) a
C.sub.3-8 cycloalkyl group, (6) a 4- to 10-membered
heterocycloalkyl group which may be substituted by one or more
R.sup.9D, R.sup.9D: [1] a C.sub.1-8 alkyl group which may be
substituted by 4- to 10-membered heterocycloalkyl group(s), [2] a
C.sub.3-8 cycloalkyl group, [3] a 4- to 10-membered
heterocycloalkyl group, or [4] a C.sub.1-6 alkylsulfonyl group, or
[5] a C.sub.1-8 alkoxycarbonyl group, (7) a C.sub.6-10 aryl group
which may be substituted by one or more R.sup.9E, R.sup.9E: [1] a
halogen atom, [2] a hydroxy group, [3] a hydroxycarbonyl group, or
[4] a C.sub.1-8 alkyl group which may be substituted by hydroxy
group(s), or [5] a C.sub.1-8 alkoxy group, (8) a 5- to 14-membered
heteroaryl group which may be substituted by C.sub.1-8 alkyl
group(s), (9) a cyano group, (10) a C.sub.1-8 alkanoyl group, (11)
a 4- to 10-membered nitrogen-containing heterocycloalkylcarbonyl
group which may be substituted by C.sub.1-8 alkyl group(s), (12) a
halogen atom, (13) a (C.sub.1-8 alkyl).sub.m9c-amino group which
may be substituted by one or more R.sup.9F, m9c: 0.about.2, (14) a
C.sub.1-8 alkylcarbonyl(C.sub.0-8 alkyl)amino group which may be
substituted by (C.sub.1-8 alkyl).sub.m9d-amino group(s), m9d:
0.about.2, (15) a C.sub.1-8 alkylsulfonyl(C.sub.0-8 alkyl)amino
group, (16) a (C.sub.1-8 alkyl).sub.m9e-aminosulfonyl(C.sub.0-8
alkyl)amino group, m9e: 0.about.2, (17) a nitro group, (18) a
hydroxy group, (19) a C.sub.1-8 alkoxy group which may be
substituted by one or more R.sup.9G, R.sup.9G: [1] a hydroxy group,
[2] a hydroxycarbonyl group, [3] a C.sub.6-10 aryl group which may
be substituted by C.sub.1-8 alkoxy group(s), [4] a (C.sub.1-8
alkyl).sub.m9g1-amino group, [5] a C.sub.1-8 alkoxy group which may
be substituted by one or more R.sup.9G1, [6] a 5- to 14-membered
heteroaryl group, or [7] a 4- to 10-membered heterocycloalkyloxy
group which may be substituted by C.sub.1-8 alkyl group(s), m9g1:
0.about.2, R.sup.9G1: [1] a C.sub.1-8 alkoxy group, or [2] a
hydroxycarbonyl group, (20) a 4- to 10-membered heterocycloalkyloxy
group which may be substituted by [1] 4- to 10-membered
heterocycloalkyl group(s), or [2] C.sub.1-8 alkoxycarbonyl
group(s), (21) a C.sub.1-8 alkylsulfonyloxy group which may be
substituted by halogen atom(s), (22) a C.sub.1-8 alkylthio group
which may be substituted by (C.sub.1-8 alkyl).sub.m9f-amino
group(s), m9f: 0.about.2, (23) a C.sub.1-8 alkylsulfonyl group
which may be substituted by (C.sub.1-8 alkyl).sub.m9g-amino
group(s), m9g: 0.about.2, (24) a (C.sub.1-8
alkyl).sub.m9h-aminosulfonyl group, m9h: 0.about.2, (25) a 4- to
10-membered nitrogen-containing heterocycloalkylsulfonyl group
which may be substituted by C.sub.1-8 alkyl group(s), and (26) a
hydroxycarbonyl group.
2. The compound according to claim 1, or a salt or solvate thereof,
wherein R.sup.3 is a cyano group or a halogen atom.
3. The compound according to claim 1, or a salt or solvate thereof,
wherein A.sup.5 is NR.sup.5 and R.sup.5 is a hydrogen atom.
4. The compound according to claim 1, or a salt or solvate thereof,
wherein all of the A.sup.1, A.sup.2, A.sup.3, A.sup.4, A.sup.7,
A.sup.8, A.sup.9 and A.sup.10 are a carbon atom.
5. The compound according to claim 1, or a salt or solvate thereof,
wherein: A.sup.1, A.sup.2, A.sup.3, A.sup.4, A.sup.7, A.sup.8,
A.sup.9 and A.sup.10 all represent C, or any one of A.sup.2,
A.sup.3, A.sup.4, A.sup.7, A.sup.8 and A.sup.9 represents N (with
the proviso that, when it represents N, no substituent group exists
therefor) and the remainings represent C; A.sup.5 is selected from
NR.sup.5, O and S; R.sup.1 represents [1] a hydrogen atom, [2] a
cyano group, or [3] a halogen atom; R.sup.2 is selected from the
group consisting of: (1) a hydrogen atom, (2) a C.sub.1-8 alkyl
group, (3) a cyano group, (4) a halogen atom, and (5) a (C.sub.1-8
alkyl).sub.m2-amino group which may be substituted by C.sub.1-8
alkylsulfonyl group(s), m2: 0.about.2; R.sup.3 is selected from the
group consisting of: (1) a hydrogen atom, (2) a C.sub.1-8 alkyl
group which may be substituted by halogen atom(s), (3) a cyano
group, (4) a (C.sub.1-8 alkyl).sub.m3a-aminocarbonyl group which
may be substituted by one or more R.sup.3A, R.sup.3A: [1] a
C.sub.6-10 aryl group, [2] a C.sub.1-8 alkoxy group, [3] a 5- to
14-membered heteroaryl group, or [4] a C.sub.6-10 aryl sulfonyl
group, m3a: 0.about.2, (5) a hydroxycarbonyl group, (6) a C.sub.1-8
alkoxycarbonyl group which may be substituted by hydroxy group(s),
(7) a halogen atom, (8) a (C.sub.1-8 alkyl).sub.m3b-amino group
which may be substituted by C.sub.6-10 aryl group(s), m3b:
0.about.2, (9) a C.sub.1-8 alkylcarbonyl (C.sub.0-8 alkyl) amino
group which may be substituted by [1] C.sub.6-10 aryl group(s) or
[2] C.sub.6-10 aryloxy group(s), (10) a C.sub.6-10 arylcarbonyl
(C.sub.0-8 alkyl) amino group which may be substituted by C.sub.1-8
alkyl group(s) which may be substituted by halogen atom(s), (11) a
nitro group, (12) a hydroxy group, (13) a C.sub.1-8 alkoxy group
which may be substituted by one or more R.sup.3B, R.sup.3B: [1] a
hydroxy group, [2] a C.sub.1-8 alkoxy group, [3] a C.sub.6-10 aryl
(C.sub.0-8 alkyl) aminocarbonyl group, [4] a (C.sub.1-8
alkyl).sub.m3d-amino group, or [5] a halogen atom, m3d: 0.about.2,
(14) a 4- to 10-membered heterocycloalkyloxy group, (15) a 5- to
14-membered heteroaryloxy group, (16) a (C.sub.1-8
alkyl).sub.m3e-aminocarbonyloxy group which may be substituted by
C.sub.6-10 aryl group(s), m3e: 0.about.2, (17) a 4- to 10-membered
nitrogen-containing heterocycloalkylcarbonyl group, (18) a
C.sub.1-8 alkylthio group, (19) a 5- to 14-membered heteroaryl
group which may be substituted by C.sub.1-8 alkyl group(s) which
may be substituted by C.sub.1-8 alkoxy group(s), (20) a C.sub.1-8
alkoxycarbonyl (C.sub.0-8 alkyl) amino group which may be
substituted by C.sub.1-8 alkoxy group(s), (21) a C.sub.6-10
aryloxycarbonyl (C.sub.0-8 alkyl) amino group which may be
substituted by C.sub.1-8 alkyl group(s) which may be substituted by
halogen atom(s), (22) a C.sub.6-10 aryl (C.sub.0-8 alkyl)
aminocarbonyl (C.sub.0-8 alkyl) amino group which may be
substituted by C.sub.1-8 alkoxy group(s), (23) a C.sub.3-8
cycloalkyl (C.sub.0-8 alkyl) aminocarbonyloxy group, and (24) a
C.sub.6-10 aryl (C.sub.0-8 alkyl) aminocarbonyloxy group which may
be substituted by substituent(s) selected from the group consisting
of [1] a C.sub.1-8 alkyl group and [2] a C.sub.1-8 alkoxy group;
R.sup.4 is selected from the group consisting of: (1) a hydrogen
atom, (2) a C.sub.1-8 alkyl group which may be substituted by
halogen atom(s), (3) a C.sub.3-8 cycloalkyl group, (4) a cyano
group, (5) an aminocarbonyl group, (6) a hydroxycarbonyl group, (7)
a halogen atom, (8) a (C.sub.1-8 alkyl).sub.m4b-amino group, m4b:
0.about.2, (9) a hydroxy group, and (10) a C.sub.1-8 alkoxy group
which may be substituted by hydroxy group(s); R.sup.5 is selected
from the group consisting of: (1) a hydrogen atom, (2) a C.sub.1-8
alkyl group which may be substituted by one or more R.sup.5A,
R.sup.5A: [1] a hydroxycarbonyl group, [2] a C.sub.1-8
alkoxycarbonyl group, [3] a hydroxy group, [4] a C.sub.1-8 alkoxy
group, [5] a (C.sub.1-8 alkyl).sub.m5-amino group, or [6] a
C.sub.1-8 alkylthio group, m5: 0.about.2, and (3) a C.sub.1-8
alkylsulfonyl group; R.sup.6 and R.sup.6' are each independently:
(1) a C.sub.1-8 alkyl group, or R.sup.6 and R.sup.6' are taken
together with the carbon atoms to which they are bound to form, (2)
a C.sub.3-8 cycloalkyl group, or (3) a 4- to 10-membered
heterocycloalkyl group; R.sup.7 is selected from the group
consisting of: (1) a hydrogen atom, (2) a halogen atom, and (3) a
C.sub.1-8 alkoxy group which may be substituted by one or more
R.sup.7A, R.sup.7A: [1] a (C.sub.1-8 alkyl).sub.m7a-amino group, or
[2] a hydroxy group, m7a:0-2; R.sup.8 is selected from the group
consisting of: (1) a hydrogen atom, (2) a C.sub.1-8 alkyl group
which may be substituted by one or more R.sup.8A, R.sup.8A: [1] a
4- to 10-membered heterocycloalkyl group which may be substituted
by one or more R.sup.8A1, [2] a (C.sub.1-8 alkyl).sub.m8a-amino
group which may be substituted by a halogen atom, or [3] a hydroxy
group, m8a:0.about.2, R.sup.8A1: [1] a C.sub.1-8 alkyl group, [2] a
C.sub.1-8 alkylsulfonyl group, [3] a (C.sub.1-8
alkyl).sub.m8b-aminosulfonyl group, or [4] an oxo group, m8b:
0.about.2, (3) a C.sub.2-8 alkenyl group, (4) a 4- to 10-membered
heterocycloalkyl group which may be substituted by one or more
R.sup.8B, R.sup.8B: <1> a C.sub.1-8 alkyl group which may be
substituted by one or more R.sup.8B1, <2> a C.sub.2-8 alkynyl
group, <3> a C.sub.3-8 cycloalkyl group which may be
substituted by [1] cyano group(s) or [2] C.sub.1-8 alkyl group(s),
<4> a 4- to 10-membered heterocycloalkyl group which may be
substituted by one or more R.sup.8B2, <5> a C.sub.1-8 alkoxy
group which may be substituted by substituent(s) selected from the
group consisting of [1] a C.sub.1-8 alkoxy group and [2] a
C.sub.3-8 cycloalkyl group, <6> a C.sub.1-8 alkylsulfonyl
group, <7> an oxo group, <8> a cyano group, <9> a
C.sub.1-8 alkanoyl group which may be substituted by one or more
R.sup.8B3, <10> a C.sub.3-8 cycloalkylcarbonyl group,
<11> a (C.sub.1-8 alkyl).sub.m8c-aminosulfonyl group,
<12> a C.sub.1-8 alkylsulfonyl (C.sub.0-8 alkyl) amino group,
<13> a (C.sub.1-8 alkyl).sub.m8d-amino group which may be
substituted by one or more R.sup.8B4, <14> a hydroxy group,
or <15> a (C.sub.1-8 alkyl).sub.m8e-aminocarbonyl group, m8c:
0.about.2, m8d: 0.about.2, m8e: 0.about.2, R.sup.8B1: [1] a
C.sub.3-8 cycloalkyl group, [2] a hydroxy group, or [3] C.sub.1-8
alkoxy group which may be substituted by C.sub.1-8 alkoxy group(s),
R.sup.8B2: [1] a halogen atom, [2] a C.sub.1-8 alkyl group, [3] an
oxo group, or [4] a hydroxy group, R.sup.8B3: a (C.sub.1-8
alkyl).sub.m8f-amino group, m8f: 0.about.2, R.sup.8B4: [1] a
C.sub.3-8 cycloalkyl group, or [2] a hydroxy group, (5) a 5- to
14-membered heteroaryl group which may be substituted by a
C.sub.1-8 alkyl group, (6) a (C.sub.1-8
alkyl).sub.m8g-aminocarbonyl group which may be substituted by one
or more R.sup.8C, m8g: 0.about.2, R.sup.8C:[1] a hydroxy group, [2]
a (C.sub.1-8 alkyl).sub.m8h-amino group which may be substituted by
substituent(s) selected from the group consisting of <1> a
(C.sub.1-8 alkyl).sub.m8i-aminosulfonyl group and <2> a
C.sub.1-8 alkylsulfonyl group, or [3] a C.sub.1-8 alkylsulfonyl
group, m8h: 0.about.2, m8i: 0.about.2, (7) a 4- to 10-membered
heterocycloalkyl (C.sub.0-8 alkyl) aminocarbonyl group which may be
substituted by oxo group(s), (8) a 4- to 10-membered
nitrogen-containing heterocycloalkylcarbonyl group which may be
substituted by one or more R.sup.8D, R.sup.8D: [1] a C.sub.1-8
alkyl group which may be substituted by one or more R.sup.8D1, [2]
a hydroxy group, or [3] a C.sub.1-8 alkylsulfonyl group, R.sup.8D1:
[1] a hydroxy group, or [2] a C.sub.1-8 alkoxy group, (9) a
hydroxycarbonyl group, (10) a C.sub.0-8 alkoxy (C.sub.0-8 alkyl)
aminocarbonyl group which may be substituted by hydroxy group(s),
(11) a halogen atom, (12) a (C.sub.1-8 alkyl).sub.m8j-amino group
which may be substituted by 4- to 10-membered heterocycloalkyl
group(s), m8j: 0.about.2, (13) a hydroxyl group, (14) a C.sub.1-8
alkoxy group which may be substituted by one or more R.sup.8E,
R.sup.8E: <1> a hydroxy group, <2> a C.sub.1-8
alkoxycarbonyl group, <3> a 4- to 10-membered
nitrogen-containing heterocycloalkylcarbonyl group which may be
substituted by one or more R.sup.8E1, <4> a (C.sub.1-8
alkyl).sub.m8k1-amino group which may be substituted by one or more
R.sup.8E2, m8k1: 0.about.2, <5> a 4- to 10-membered
heterocycloalkyl group which may be substituted by one or more
R.sup.8E3, <6> a 5- to 14-membered heteroaryl group,
<7> a (C.sub.1-8 alkyl).sub.m8k2-aminocarbonyl group which
may be substituted by one or more R.sup.8E6 m8k2: 0.about.2,
<8> a C.sub.1-8 alkoxy group which may be substituted by one
or more R.sup.8E7, <9> a C.sub.1-8 alkylthio group,
<10> a C.sub.1-8 alkylsulfinyl group, or <11> a
C.sub.1-8 alkylsulfonyl group, R.sup.8E1: <1> a C.sub.1-8
alkoxycarbonyl group, <2> a C.sub.1-8 alkanoyl group,
<3> a C.sub.1-8 alkylsulfonyl group, <4> a (C.sub.1-8
alkyl).sub.m8k3-aminosulfonyl group m8k3: 0.about.2, or <5> a
4- to 10-membered heterocycloalkyl group, R.sup.8E2: <1> a
hydroxy group, <2> a C.sub.1-8 alkoxycarbonyl group,
<3> a C.sub.3-8 cycloalkyl group which may be substituted by
C.sub.1-8 alkyl group(s) which may be substituted by hydroxy
group(s), <4> a C.sub.1-8 alkanoyl group which may be
substituted by substituent(s) selected from the group consisting of
[1] a (C.sub.1-8 alkyl).sub.m8k4-amino group and [2] a halogen
atom, m8k4: 0.about.2, <5> a (C.sub.1-8
alkyl).sub.m8k5-aminocarbonyl group, m8k5: 0.about.2, <6> a
C.sub.1-8 alkylsulfonyl group, <7> a 4- to 10-membered
nitrogen-containing heterocycloalkylsulfonyl group which may be
substituted by C.sub.1-8 alkyl group(s), <8> a (C.sub.1-8
alkyl).sub.m8k6-aminosulfonyl group, m8k6: 0.about.2, or R.sup.8E3:
<1> a C.sub.1-8 alkyl group which may be substituted by
substituent(s) selected from the group consisting of [1] a hydroxy
group and [2] a C.sub.1-8 alkylcarbonyloxy group, <2> a
hydroxy group, <3> a C.sub.3-8 cycloalkyl group, <4> a
C.sub.1-8 alkylsulfonyl group, <5> a (C.sub.1-8
alkyl).sub.m8k8-aminocarbonyl group, m8k8: 0.about.2, <6> a
C.sub.1-8 alkanoyl group which may be substituted by hydroxy
group(s), <7> an oxo group, or <8> a 4- to 10-membered
heterocycloalkyl group which may be substituted by substituent(s)
selected from the group consisting of [1] a C.sub.1-8 alkanoyl
group, and [2] a C.sub.1-8 alkylsulfonyl group, R.sup.8E6:
<1> a C.sub.2-8 alkenylcarbonyloxy group, <2> a hydroxy
group, <3> a cyano group, <4> a (C.sub.1-8
alkyl).sub.m8k9-amino group which may be substituted by hydroxy
group(s), m8k9: 0.about.2, <5> a C.sub.1-8 alkoxy group which
may be substituted by hydroxy group(s), <6> a 4- to
10-membered heterocycloalkyl group which may be substituted by
C.sub.1-8 alkyl group(s), or <7> a 5- to 14-membered
heteroaryl group, R.sup.8E7: <1> a hydroxy group, or
<2> a C.sub.1-8 alkoxy group which may be substituted by
hydroxy group(s), (15) a 4- to 10-membered heterocycloalkyloxy
group which may be substituted by one or more R.sup.8F: R.sup.8F:
<1> a C.sub.1-8 alkyl group which may be substituted by one
or more R.sup.8F1, <2> a C.sub.3-8 cycloalkyl group,
<3> a C.sub.1-8 alkanoyl group which may be substituted by
halogen atom(s), <4> a C.sub.1-8 alkoxycarbonyl group,
<5> a 4- to 10-membered heterocycloalkyl group which may be
substituted by one or more R.sup.8F2, <6> a C.sub.1-8 alkyl
sulfonyl group, or <7> a hydroxy group, R.sup.8F1: [1] a
hydroxy group, [2] a C.sub.1-8 alkoxy group, or [3] a halogen atom,
R.sup.8F2: [1] a 4- to 10-membered heterocycloalkyl group, [2] a
C.sub.1-8 alkoxycarbonyl group, or [3] a C.sub.1-8 alkylsulfonyl
group, (16) a 5- to 14-membered heteroaryloxy group, (17) a
(C.sub.1-8 alkyl).sub.m8l1-aminosulfonyloxy group, m8l1: 0.about.2,
(18) a C.sub.1-8 alkylthio group which may be substituted by
(C.sub.1-8 alkyl).sub.m8l2-amino group(s), m8l2: 0.about.2, (19) a
C.sub.1-8 alkylsulfonyl group which may be substituted by one or
more R.sup.8G, R.sup.8G: [1] a hydroxycarbonyl group, [2] a hydroxy
group, or [3] a (C.sub.1-8 alkyl).sub.m813-amino group, m8l3:
0.about.2, (20) a C.sub.2-8 alkenyloxy group, and (21) a C.sub.1-8
alkylsulfonyloxy group which may be substituted by halogen atom(s);
R.sup.9 is selected from the group consisting of: (1) a hydrogen
atom, (2) a C.sub.1-8 alkyl group which may be substituted by one
or more R.sup.9A, R.sup.9A: [1] a C.sub.3-8 cycloalkyl group, [2] a
4- to 10-membered heterocycloalkyl group which may be substituted
by one or more R.sup.9A1, [3] a hydroxy group, or [4] a C.sub.1-8
alkoxy group, R.sup.9A1: [1] a C.sub.1-8 alkyl group, [2] a
C.sub.3-8 cycloalkyl group, or [3] a 4- to 10-membered
heterocycloalkyl group, (3) a C.sub.2-8 alkenyl group, (4) a
C.sub.2-8 alkynyl group which may be substituted by one or more
R.sup.9C, R.sup.9C: [1] a C.sub.1-8 alkoxy group, [2] a (C.sub.1-8
alkyl).sub.m9b-amino group which may be substituted by C.sub.6-10
aryl group(s), [3] a 4- to 10-membered heterocycloalkyl group which
may be substituted by one or more R.sup.9C1, [4] a C.sub.3-8
cycloalkyl group, [5] a hydroxy group, or [6] a hydroxycarbonyl
group, m9b: 0.about.2, R.sup.9C1: [1] a C.sub.3-8 cycloalkyl group,
[2] a 4- to 10-membered heterocycloalkyl group, or [3] an oxo
group, (5) a C.sub.3-8 cycloalkyl group, (6) a 4- to 10-membered
heterocycloalkyl group which may be substituted by one or more
R.sup.9D, R.sup.9D: [1] a C.sub.1-8 alkyl group which may be
substituted by 4- to 10-membered heterocycloalkyl group(s), [2] a
C.sub.3-8 cycloalkyl group, [3] a 4- to 10-membered
heterocycloalkyl group, or [4] a C.sub.1-6 alkylsulfonyl group, (7)
a C.sub.6-10 aryl group which may be substituted by one or more
R.sup.9E, R.sup.9E: [1] a halogen atom, [2] a hydroxy group, [3] a
hydroxycarbonyl group, or [4] a C.sub.1-8 alkyl group which may be
substituted by hydroxy group(s), (8) a 5- to 14-membered heteroaryl
group which may be substituted by C.sub.1-8 alkyl group(s), (9) a
cyano group, (10) a C.sub.1-8 alkanoyl group, (11) a 4- to
10-membered nitrogen-containing heterocycloalkylcarbonyl group
which may be substituted by C.sub.1-8 alkyl group(s), (12) a
halogen atom, (13) a (C.sub.1-8 alkyl).sub.m9c-amino group, m9c:
0.about.2, (14) a C.sub.1-8 alkylcarbonyl(C.sub.0-8 alkyl)amino
group which may be substituted by (C.sub.1-8 alkyl).sub.m9d-amino
group(s), m9d: 0.about.2, (15) a C.sub.1-8 alkylsulfonyl(C.sub.0-8
alkyl)amino group, (16) a (C.sub.1-8
alkyl).sub.m9e-aminosulfonyl(C.sub.0-8 alkyl)amino group, m9e:
0.about.2,
(17) a nitro group, (18) a hydroxy group, (19) a C.sub.1-8 alkoxy
group which may be substituted by one or more R.sup.9G, R.sup.9G:
[1] a hydroxy group, [2] a hydroxycarbonyl group, [3] a C.sub.6-10
aryl group which may be substituted by C.sub.1-8 alkoxy group(s),
[4] a (C.sub.1-8 alkyl).sub.m9g1-amino group, [5] a C.sub.1-8
alkoxy group which may be substituted by one or more R.sup.9G1, or
[6] a 5- to 14-membered heteroaryl group, m9g1: 0.about.2,
R.sup.9G1: [1] a C.sub.1-8 alkoxy group, or [2] a hydroxycarbonyl
group, (20) a 4- to 10-membered heterocycloalkyloxy group which may
be substituted by 4- to 10-membered heterocycloalkyl group(s), (21)
a C.sub.1-8 alkylthio group which may be substituted by (C.sub.1-8
alkyl).sub.m9f-amino group(s), m9f: 0.about.2, (22) a C.sub.1-8
alkylsulfonyl group which may be substituted by (C.sub.1-8
alkyl).sub.m9g-amino group(s), m9g: 0.about.2, (23) a (C.sub.1-8
alkyl).sub.m9h-aminosulfonyl group, m9h: 0.about.2, and (24) a 4-
to 10-membered nitrogen-containing heterocycloalkylsulfonyl group
which may be substituted by C.sub.1-8 alkyl group(s); R.sup.10
represents [1] a hydrogen atom, or [2] a 4- to 10-membered
heterocycloalkyl group which may be substituted by 4- to
10-membered heterocycloalkyl group(s)].
6. A compound or salt or solvate thereof, which said compound is
selected from the group consisting of:
9-(4-isopropyl-piperazin-1-yl)-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[-
b]carbazole-3-carbonitrile;
6,6-dimethyl-8-(4-oxetan-3-yl-piperazin-1-yl)-11-oxo-9-prop-1-ynyl-6,11-d-
ihydro-5H-benzo[b]carbazole-3-carbonitrile;
9-cyclopropylethynyl-6,6-dimethyl-8-(4-oxetan-3-yl-piperazin-1-yl)-11-oxo-
-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile;
6,6-dimethyl-8-(1-oxetan-3-yl-piperidin-4-yl)-11-oxo-6,11-dihydro-5H-benz-
o[b]carbazole-3-carbonitrile;
9-bromo-6,6-dimethyl-8-(4-oxetan-3-yl-piperazin-1-yl)-11-oxo-6,11-dihydro-
-5H-benzo[b]carbazole-3-carbonitrile;
9-bromo-8-(4-cyclopropyl-piperazin-1-yl)-6,6-dimethyl-11-oxo-6,11-dihydro-
-5H-benzo[b]carbazole-3-carbonitrile;
9-chloro-6,6-dimethyl-8-(4-morpholin-4-yl-piperidin-1-yl)-11-oxo-6,11-dih-
ydro-5H-benzo[b]carbazole-3-carbonitrile;
8-(4-cyclobutyl-piperazin-1-yl)-6,6-dimethyl-11-oxo-9-prop-1-ynyl-6,11-di-
hydro-5H-benzo[b]carbazole-3-carbonitrile;
6,6,9-trimethyl-8-(4-morpholin-4-yl-piperidin-1-yl)-11-oxo-6,11-dihydro-5-
H-benzo[b]carbazole-3-carbonitrile;
9-ethyl-6,6-dimethyl-8-(4-oxetan-3-yl-piperazin-1-yl)-11-oxo-6,11-dihydro-
-5H-benzo[b]carbazole-3-carbonitrile;
9-ethyl-6,6-dimethyl-8-(4-morpholin-4-yl-piperidin-1-yl)-11-oxo-6,11-dihy-
dro-5H-benzo[b]carbazole-3-carbonitrile;
9-ethynyl-6,6-dimethyl-8-(4-oxetan-3-yl-piperazin-1-yl)-11-oxo-6,11-dihyd-
ro-5H-benzo[b]carbazole-3-carbonitrile;
8-(4-cyclobutyl-piperazin-1-yl)-9-ethyl-6,6-dimethyl-11-oxo-6,11-dihydro--
5H-benzo[b]carbazole-3-carbonitrile;
9-ethynyl-6,6-dimethyl-11-oxo-8-(4-pyrrolidin-1-yl-piperidin-1-yl)-6,11-d-
ihydro-5H-benzo[b]carbazole-3-carbonitrile;
6,6-dimethyl-11-oxo-8-(4-pyrrolidin-1-yl-piperidin-1-yl)-6,11-dihydro-5H--
benzo[b]carbazole-3-carbonitrile;
8-(4-cyclobutyl-piperazin-1-yl)-9-ethynyl-6,6-dimethyl-11-oxo-6,11-dihydr-
o-5H-benzo[b]carbazole-3-carbonitrile;
8-(4-cyclobutyl-piperazin-1-yl)-6,6-dimethyl-11-oxo-9-propyl-6,11-dihydro-
-5H-benzo[b]carbazole-3-carbonitrile;
8-(1-isopropyl-piperidin-4-yl)-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[-
b]carbazole-3-carbonitrile;
8-(4-isopropyl-piperazin-1-yl)-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[-
b]carbazole-3-carbonitrile;
8-(4-cyclobutyl-piperazin-1-yl)-9-cyclopropyl-6,6-dimethyl-11-oxo-6,11-di-
hydro-5H-benzo[b]carbazole-3-carbonitrile;
8-(2-tert-butylamino-ethoxy)-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]-
carbazole-3-carbonitrile;
9-ethynyl-8-(4-methanesulfonyl-piperazin-1-yl)-6,6-dimethyl-11-oxo-6,11-d-
ihydro-5H-benzo[b]carbazole-3-carbonitrile;
9-bromo-8-(4-cyclobutyl-piperazin-1-yl)-6,6-dimethyl-11-oxo-6,11-dihydro--
5H-benzo[b]carbazole-3-carbonitrile;
6,6-dimethyl-8-(4-oxetan-3-yl-piperazin-1-yl)-11-oxo-9-propyl-6,11-dihydr-
o-5H-benzo[b]carbazole-3-carbonitrile; and
9-ethynyl-6,6-dimethyl-8-morpholin-4-yl-11-oxo-6,11-dihydro-5H-benzo[b]ca-
rbazole-3-carbonitrile.
7. A medicament comprising as an active ingredient the compound
according to claim 1, or a salt or solvate thereof.
8. An ALK inhibitor comprising as an active ingredient the compound
according to claim 1, or a salt or solvate thereof.
9. A pharmaceutical for the prophylaxis or treatment of cancer,
cancer metastasis, depression or cognitive function disorder,
comprising as an active ingredient the compound according to claim
1, or a salt or solvate thereof.
10. A pharmaceutical composition comprising the compound according
to claim 1, or a salt or solvate thereof and a pharmaceutically
acceptable carrier(s).
11. A method of treating or preventing cancer, cancer metastasis,
depression or cognitive function disorder in a subject in need
thereof comprising administering an effective amount of a
pharmaceutical for the treatment of cancer, cancer metastasis,
depression or cognitive function disorder, comprising as an active
ingredient a compound represented by Formula (I): ##STR01236##
wherein, A.sup.5 is selected from NR.sup.5, O and S; A.sup.4,
A.sup.7, and A.sup.9 represent CR.sup.4, CR.sup.7, and CR.sup.9
respectively, or wherein A.sup.4 is N and A.sup.7 and A.sup.9
represent CR.sup.7 and CR.sup.9 respectively; R.sup.1 and R.sup.10
each independently represent [1] a hydrogen atom, [2] a cyano
group, [3] a halogen atom or [4] a 4- to 10-membered
heterocycloalkyl group which may be substituted by 4- to
10-membered heterocycloalkyl group(s); R.sup.2 is selected from the
group consisting of: (1) a hydrogen atom, (2) a C.sub.1-8 alkyl
group, (3) a C.sub.2-8 alkenyl group, (4) a C.sub.2-8 alkynyl
group, (5) a cyano group, (6) a halogen atom, (7) a (C.sub.1-8
alkyl).sub.m2-amino group which may be substituted by C.sub.1-8
alkylsulfonyl group(s), m2: 0.about.2, and (8) a nitro group;
R.sup.3 is selected from the group consisting of: (1) a hydrogen
atom, (2) a C.sub.1-8 alkyl group which may be substituted by [1]
halogen atom(s), [2] hydroxy group(s) or [3] C.sub.1-8 alkoxy
group(s), (3) a C.sub.6-10 aryl group, (4) a cyano group, (5) a
C.sub.1-8 alkanoyl group which may be substituted by C.sub.6-10
aryl group(s), (6) a (C.sub.1-8 alkyl).sub.m3a-aminocarbonyl group
which may be substituted by one or more R.sup.3A, R.sup.3A: [1] a
C.sub.6-10 aryl group, [2] a C.sub.1-8 alkoxy group, [3] a 5- to
14-membered heteroaryl group, or [4] a C.sub.6-10 arylsulfonyl
group, m3a: 0.about.2, (7) a hydroxycarbonyl group, (8) a C.sub.1-8
alkoxycarbonyl group which may be substituted by [1] hydroxy
group(s) or [2] C.sub.1-8 alkoxy group(s), (9) a halogen atom, (10)
a (C.sub.1-8 alkyl).sub.m3b-amino group which may be substituted by
C.sub.6-10 aryl group(s), m3b: 0.about.2, (11) a C.sub.1-8
alkylcarbonyl (C.sub.0-8 alkyl) amino group which may be
substituted by [1] C.sub.6-10 aryl group(s) or [2] C.sub.6-10
aryloxy group(s), (12) a C.sub.6-10 arylcarbonyl (C.sub.0-8 alkyl)
amino group which may be substituted by C.sub.1-8 alkyl group(s)
which may be substituted by halogen atom(s), (13) a (C.sub.1-8
alkyl).sub.m3c-aminocarbonyl (C.sub.0-8 alkyl) amino group which
may be substituted by C.sub.6-10 aryl group(s), m3c: 0.about.2,
(14) a nitro group, (15) a hydroxy group, (16) a C.sub.1-8 alkoxy
group which may be substituted by one or more R.sup.3B, R.sup.3B:
[1] a hydroxy group, [2] a C.sub.1-8 alkoxy group, [3] a C.sub.6-10
aryl (C.sub.0-8 alkyl) aminocarbonyl group, [4] a (C.sub.1-8
alkyl).sub.m3a-amino group, or [5] a halogen atom, m3d: 0.about.2,
(17) a 4- to 10-membered heterocycloalkyloxy group, (18) a 5- to
14-membered heteroaryloxy group, (19) a (C.sub.1-8
alkyl).sub.m3e-aminocarbonyloxy group which may be substituted by
C.sub.6-10 aryl group(s) m3e: 0.about.2, (20) a 4- to 10-membered
nitrogen-containing heterocycloalkylcarbonyl group, (21) a
C.sub.1-8 alkylsulfonyloxy group which may be substituted by
halogen atom(s), (22) a C.sub.1-8 alkylthio group, (23) a C.sub.1-8
alkylsulfonyl group which may be substituted by C.sub.6-10 aryl
group(s), (24) a 5- to 14-membered heteroaryl group which may be
substituted by C.sub.1-8 alkyl group(s) which may be substituted by
C.sub.1-8 alkoxy group(s), (25) a C.sub.1-8 alkoxycarbonyl
(C.sub.0-8 alkyl) amino group which may be substituted by C.sub.1-8
alkoxy group(s), (26) a C.sub.6-10 aryloxycarbonyl (C.sub.0-8
alkyl) amino group which may be substituted by C.sub.1-8 alkyl
group(s) which may be substituted by halogen atom(s), (27) a
C.sub.6-10 aryl (C.sub.0-8 alkyl) aminocarbonyl (C.sub.0-8 alkyl)
amino group which may be substituted by one or more R.sup.3C,
R.sup.3C: [1] a C.sub.1-8 alkyl group which may be substituted by
halogen atom(s), or [2] a C.sub.1-8 alkoxy group, (28) a C.sub.3-8
cycloalkyl (C.sub.0-8 alkyl) aminocarbonyloxy group, and (29) a
C.sub.6-10 aryl (C.sub.0-8 alkyl) aminocarbonyloxy group which may
be substituted by substituent(s) selected from the group consisting
of [1] a C.sub.1-8 alkyl group and [2] a C.sub.1-8 alkoxy group;
R.sup.4 is selected from the group consisting of: (1) a hydrogen
atom, (2) a C.sub.1-8 alkyl group which may be substituted by
halogen atom(s), (3) a C.sub.2-8 alkenyl group, (4) a C.sub.2-8
alkynyl group, (5) a C.sub.3-8 cycloalkyl group, (6) a cyano group,
(7) an aminocarbonyl group, (8) a (C.sub.1-8
alkyl).sub.m4a-aminocarbonyl group, m4a: 1.about.2, (9) a
hydroxycarbonyl group, (10) a C.sub.1-8 alkoxycarbonyl group, (11)
a halogen atom, (12) a (C.sub.1-8 alkyl).sub.m4b-amino group, m4b:
0.about.2, (13) a hydroxy group, and (14) a C.sub.1-8 alkoxy group
which may be substituted by hydroxy group(s); R.sup.5 is selected
from the group consisting of: (1) a hydrogen atom, (2) a C.sub.1-8
alkyl group which may be substituted by one or more R.sup.5A,
R.sup.5A: [1] a hydroxycarbonyl group, [2] a C.sub.1-8
alkoxycarbonyl group, [3] a hydroxy group, [4] a C.sub.1-8 alkoxy
group, [5] a (C.sub.1-8 alkyl).sub.m5-amino group, [6] a C.sub.6-10
aryl group, or [7] a C.sub.1-8 alkylthio group, m5: 0.about.2, (3)
a C.sub.2-8 alkenyl group, (4) a C.sub.2-8 alkynyl group, (5) a
C.sub.3-8 cycloalkyl group, and (6) a C.sub.1-8 alkylsulfonyl
group; R.sup.6 and R.sup.6' are each independently selected from
the group consisting of: (1) a C.sub.1-8 alkyl group which may be
substituted by halogen atom(s), (2) a C.sub.2-8 alkenyl group, and
(3) a C.sub.2-8 alkynyl group; or R.sup.6 and R.sup.6' are taken
together with the carbon atoms to which they are bound to form: (4)
a C.sub.3-8 cycloalkyl group, or (5) a 4- to 10-membered
heterocycloalkyl group which may be substituted by C.sub.1-8 alkyl
C.sub.6-10 aryl sulfonyl group(s) which may be substituted by
C.sub.1-8 alkyl group(s); R.sup.7 is selected from the group
consisting of: (1) a hydrogen atom, (2) a halogen atom, (3) a
C.sub.1-8 alkoxy group which may be substituted by one or more
R.sup.7A, R.sup.7A: [1] a (C.sub.1-8 alkyl).sub.m7a-amino group,
[2] a hydroxy, [3] a 4- to 10-membered heterocycloalkyl group which
may be substituted by C.sub.1-8 alkyl group(s), m7a: 0.about.2, (4)
a C.sub.1-8 alkylsulfonyl group, (5) a nitro group, and (6) a
hydroxyl group; R.sup.8 is selected from the group consisting of:
(1) a hydrogen atom, (2) a C.sub.1-8 alkyl group which may be
substituted by one or more R.sup.7A, R.sup.8A: [1] a 4- to
10-membered heterocycloalkyl group which may be substituted by one
or more R.sup.8A1, [2] a (C.sub.1-8 alkyl).sub.m8a-amino group
which may be substituted by a halogen atom, or [3] a hydroxy group,
m8a:0.about.2, R.sup.8A1: [1] a C.sub.1-8 alkyl group, [2] a
C.sub.1-8 alkylsulfonyl group, [3] a (C.sub.1-8
alkyl).sub.m8b-aminosulfonyl group, [4] an oxo group, [5] a
C.sub.1-8 alkoxycarbonyl, or [6] a C.sub.1-8 alkoxycarbonyl
(C.sub.0-8 alkyl) aminosulfonyl, m8b: 0.about.2, (3) a C.sub.2-8
alkenyl group, (4) a 4- to 10-membered heterocycloalkyl group which
may be substituted by one or more R.sup.8B, R.sup.8B: <1> a
C.sub.1-8 alkyl group which may be substituted by one or more
R.sup.8B1, <2> a C.sub.2-8 alkeynyl group, <3> a
C.sub.2-8 alkynyl group, <4> a C.sub.3-8 cycloalkyl group
which may be substituted by [1] cyano group(s) or [2] C.sub.1-8
alkyl group(s), <5> a 4- to 10-membered heterocycloalkyl
group which may be substituted by one or more R.sup.8B2, <6>
a C.sub.1-8 alkoxy group which may be substituted by substituent(s)
selected from the group consisting of [1] a C.sub.1-8 alkoxy group
and [2] a C.sub.3-8 cycloalkyl group, <7> a C.sub.1-8
alkoxycarbonyl group, <8> a C.sub.1-8 alkylsulfonyl group,
<9> a 5- to 14-membered heteroarylsulfonyl group, <10>
an oxo group, <11> a cyano group, <12> a C.sub.1-8
alkanoyl group which may be substituted by one or more R.sup.8B3,
<13> a C.sub.3-8 cycloalkylcarbonyl group, <14> a
(C.sub.1-8 alkyl).sub.m8c-aminosulfonyl group, <15> a
C.sub.1-8 alkylsulfonyl (C.sub.0-8 alkyl) amino group, <16> a
(C.sub.1-8 alkyl).sub.m8d-amino group which may be substituted by
one or more R.sup.8B4, <17> a hydroxy group, <18> a
(C.sub.1-8 alkyl).sub.m8e-aminocarbonyl group, or <19> a
C.sub.1-8 alkoxycarbonyl (C.sub.0-8 alkyl) amino group m8c:
0.about.2 m8d: 0.about.2 m8e: 0.about.2 R.sup.8B1: [1] a C.sub.3-8
cycloalkyl group, [2] a hydroxy group, or [3] a C.sub.1-8 alkoxy
group(s), R.sup.8B2: [1] a halogen atom, [2] a C.sub.1-8 alkyl
group, [3] an oxo group, [4] a hydroxy group, or [5] a deuterium
atom, R.sup.8B3: a (C.sub.1-8 alkyl).sub.m8f-amino group, m8f:
0.about.2, R.sup.8B4: [1] a C.sub.3-8 cycloalkyl group, or [2] a
hydroxy group, (5) a 5- to 14-membered heteroaryl group which may
be substituted by a C.sub.1-8 alkyl group, (6) a (C.sub.1-8
alkyl).sub.m8g-aminocarbonyl group which may be substituted by one
or more R.sup.8C, m8g:0-2, R.sup.8C:[1] a hydroxy group, [2] a
(C.sub.1-8 alkyl).sub.m8h-amino group which may be substituted by
substituent(s) selected from the group consisting of <1> a
(C.sub.1-8 alkyl).sub.m8i-aminosulfonyl group, <2> a
C.sub.1-8 alkylsulfonyl group, <3> a C.sub.1-8 alkoxycarbonyl
group and <4> a C.sub.1-8 alkoxycarbonyl(C.sub.0-8 alkyl)
aminosulfonyl group, [3] a C.sub.1-8 alkylsulfonyl group, or [4] a
C.sub.1-8 alkoxy group which may be substituted by a hydroxy group,
m8h: 0.about.2, m8i: 0.about.2, (7) a 4- to 10-membered
heterocycloalkyl (C.sub.0-8 alkyl) aminocarbonyl group which may be
substituted by oxo group(s), (8) a 4- to 10-membered
nitrogen-containing heterocycloalkylcarbonyl group which may be
substituted by one or more R.sup.8D, R.sup.8D: [1] a C.sub.1-8
alkyl group which may be substituted by one or more R.sup.8D1, [2]
a hydroxy group, [3] a C.sub.1-8 alkylsulfonyl group, or [4] a
C.sub.1-8 alkoxycarbonyl group, R.sup.8D1: [1] a hydroxy group, or
[2] a C.sub.1-8 alkoxy group, (9) a hydroxycarbonyl group, (10) a
C.sub.0-8 alkoxy (C.sub.0-8 alkyl) aminocarbonyl group which may be
substituted by hydroxy group(s), (11) a halogen atom, (12) a
(C.sub.1-8 alkyl).sub.m8j-amino group which may be substituted by
one or more R.sup.8H, m8j: 0.about.2, R.sup.8H: [1] a hydroxy
group, or [2] a 4- to 10-membered heterocycloalkyl group, (13) a
hydroxyl group, (14) a C.sub.1-8 alkoxy group which may be
substituted by one or more R.sup.8E, R.sup.8E: <1> a hydroxy
group, <2> halogen atom, <3> a hydroxycarbonyl group,
<4> a C.sub.1-8 alkoxycarbonyl group, <5> a 4- to
10-membered nitrogen-containing heterocycloalkylcarbonyl group
which may be substituted by one or more R.sup.8E1, <6> a
(C.sub.1-8 alkyl).sub.m8k1-amino group which may be substituted by
one or more R.sup.8E2, m8k1: 0.about.2, <7> a 4- to
10-membered heterocycloalkyl group which may be substituted by one
or more R.sup.8E3, <8> a 5- to 14-membered heteroaryl group,
<9> a (C.sub.1-8 alkyl).sub.m8k2-aminocarbonyl group which
may be substituted by one or more R.sup.8E6, m8k2: 0.about.2,
<10> a C.sub.1-8 alkoxy group which may be substituted by one
or more R.sup.8E7, <11> a C.sub.1-8 alkylthio group,
<12> a C.sub.1-8 alkylsulfinyl group, <13> a C.sub.1-8
alkylsulfonyl group, R.sup.8E1: <1> a C.sub.1-8
alkoxycarbonyl group, <2> a C.sub.1-8 alkanoyl group,
<3> a C.sub.1-8 alkylsulfonyl group, 25<4> a (C.sub.1-8
alkyl).sub.m8k3-aminosulfonyl group, m8k3: 0.about.2, or <5>
a 4- to 10-membered heterocycloalkyl group, R.sup.8E2: <1> a
hydroxy group, <2> a C.sub.1-8 alkoxycarbonyl group which may
be substituted by halogen atom(s), <3> a C.sub.3-8 cycloalkyl
group which may be substituted by C.sub.1-8 alkyl group(s) which
may be substituted by hydroxy group(s), <4> a C.sub.1-8
alkanoyl group which may be substituted by substituent(s) selected
from the group consisting of [1] a (C.sub.1-8 alkyl).sub.mk4-amino
group and [2] a halogen atom(s), m8k4: 0.about.2, <5> a
(C.sub.1-8 alkyl).sub.m8k5-aminocarbonyl group, m8k5: 0.about.2,
<6> a C.sub.1-8 alkylsulfonyl group, <7> a 4- to
10-membered nitrogen-containing heterocycloalkylsulfonyl group
which may be substituted by C.sub.1-8 alkyl group(s), <8> a
(C.sub.1-8 alkyl).sub.m8k6-aminosulfonyl group which may be
substituted by C.sub.1-8 alkoxycarbonyl group(s), m8k6: 0.about.2,
or R.sup.8E3: <1> a C.sub.1-8 alkyl group which may be
substituted by substituent(s) selected from the group consisting of
[1] a hydroxy group and [2] a C.sub.1-8 alkylcarbonyloxy group,
<2> a C.sub.1-8 alkylcarbonyloxy group, <3> a hydroxy
group, <4> a C.sub.3-8 cycloalkyl group, <5> a
C.sub.1-8 alkoxy group, <6> a C.sub.1-8 alkoxycarbonyl group,
<7> a C.sub.1-8 alkylsulfonyl group, <8> a (C.sub.1-8
alkyl).sub.m8k8-aminocarbonyl group, m8k8: 0.about.2, <9> a
C.sub.1-8 alkanoyl group which may be substituted by hydroxy
group(s), <10> an oxo group, or <11> a 4- to
10-membered heterocycloalkyl group which may be substituted by
substituent(s) selected from the group consisting of [1] a
C.sub.1-8 alkanoyl group, [2] a C.sub.1-8 alkoxycarbonyl group and
[3] a C.sub.1-8 alkylsulfonyl group, R.sup.8E6: <1> a
C.sub.2-8 alkenylcarbonyloxy group, <2> a hydroxy group,
<3> a cyano group, <4> a (C.sub.1-8
alkyl).sub.m8k9-amino group which may be substituted by hydroxy
group(s) m8k9: 0.about.2, <5> a C.sub.1-8 alkoxy group which
may be substituted by hydroxy group(s), <6> a C.sub.1-8
alkylcarbonyloxy group, <7> a 4- to 10-membered
heterocycloalkyl group which may be substituted by C.sub.1-8 alkyl
group(s), or <8> a 5- to 14-membered heteroaryl group,
R.sup.8E7: <1> a hydroxy group, or <2> a C.sub.1-8
alkoxy group which may be substituted by hydroxy group(s), (15) a
4- to 10-membered heterocycloalkyloxy group which may be
substituted by one or more R.sup.8F, R.sup.8F: <1> a
C.sub.1-8 alkyl group which may be substituted by one or more
R.sup.8F1, <2> a C.sub.3-8 cycloalkyl group, <3> a
C.sub.1-8 alkanoyl group which may be substituted by halogen
atom(s), <4> a C.sub.1-8 alkylcarbonyloxy group, <5> a
C.sub.1-8 alkoxycarbonyl group, <6> a 4- to 10-membered
heterocycloalkyl group which may be substituted by one or more
R.sup.8F2, <7> a C.sub.1-8 alkyl sulfonyl group, <8> a
hydroxy group, or [9] a C.sub.6-10 aryl group, R.sup.8F1: [1] a
hydroxy group, [2] a C.sub.1-8 alkoxy group, or [3] a halogen atom,
R.sup.8F2: [1] a 4- to 10-membered heterocycloalkyl group, [2] a
C.sub.1-8 alkoxycarbonyl group, or [3] a C.sub.1-8 alkylsulfonyl
group, (16) a 5- to 14-membered heteroaryloxy group,
(17) a 4- to 10-membered heterocycloalkylcarbonyloxy group, (18) a
(C.sub.1-8 alkyl).sub.m8l1-aminosulfonyloxy group, m8l1: 0.about.2,
(19) a C.sub.1-8 alkyl thio group which may be substituted by [1]
(C.sub.1-8 alkyl) m8l2-amino group(s), [2] hydroxy group(s) or [3]
hydroxycarbonyl group(s), m8l2: 0.about.2, (20) a C.sub.1-8
alkylsulfonyl group which may be substituted by one or more
R.sup.8G, R.sup.8G: [1] a hydroxycarbonyl group, [2] a hydroxy
group, or [3] a (C.sub.1-8 alkyl).sub.m13-amino group, m8l3:
0.about.2, (21) a 4- to 10-membered nitrogen-containing
heterocycloalkylsulfonyloxy group which may be substituted by
C.sub.1-8 alkyl group(s), (22) a C.sub.2-8 alkenyloxy group, and
(23) a C.sub.1-8 alkylsulfonyloxy group which may be substituted by
halogen atom(s); R.sup.9 is selected from the group consisting of:
(1) a hydrogen atom, (2) a C.sub.1-8 alkyl group which may be
substituted by one or more R.sup.9A, R.sup.9A: [1] a C.sub.3-8
cycloalkyl group, [2] a 4- to 10-membered heterocycloalkyl group
which may be substituted by one or more R.sup.9A, [3] a hydroxy
group, [4] a C.sub.1-8 alkoxy group, or [5] a hydroxycarbonyl
group, R.sup.9A1: [1] a C.sub.1-8 alkyl group, [2] a C.sub.3-8
cycloalkyl group, or [3] a 4- to 10-membered heterocycloalkyl
group, (3) a C.sub.2-8 alkenyl group which may be substituted by
one or more R.sup.9B, R.sup.9B: [1] a (C.sub.1-8
alkyl).sub.m9a-amino group, [2] a 4- to 10-membered
heterocycloalkyl group which may be substituted by one or more
group R.sup.9B1, R.sup.9B1:[1] a C.sub.3-8 cycloalkyl group, or [2]
a 4- to 10-membered heterocycloalkyl group, m9a: 0.about.2, (4) a
C.sub.2-8 alkynyl group which may be substituted by one or more
R.sup.9C, R.sup.9C: [1] a C.sub.1-8 alkoxy group, [2] a (C.sub.1-8
alkyl).sub.m9b-amino group which may be substituted by C.sub.6-10
aryl group(s), [3] a 4- to 10-membered heterocycloalkyl group which
may be substituted by one or more R.sup.9C1, [4] a C.sub.3-8
cycloalkyl group, [5] a hydroxy group, [6] a hydroxycarbonyl group,
or [7] a C.sub.1-8 alkyloxycarbonyl group, m9b: 0.about.2,
R.sup.9C1: [1] a C.sub.3-8 cycloalkyl group, [2] a 4- to
10-membered heterocycloalkyl group, or [3] an oxo group, (5) a
C.sub.3-8 cycloalkyl group, (6) a 4- to 10-membered
heterocycloalkyl group which may be substituted by one or more
R.sup.9D, R.sup.9D: [1] a C.sub.1-8 alkyl group which may be
substituted by 4- to 10-membered heterocycloalkyl group(s), [2] a
C.sub.3-8 cycloalkyl group, [3] a 4- to 10-membered
heterocycloalkyl group, or [4] a C.sub.1-6 alkylsulfonyl group, or
[5] a C.sub.1-8 alkoxycarbonyl group, (7) a C.sub.6-10 aryl group
which may be substituted by one or more R.sup.9E, R.sup.9E: [1] a
halogen atom, [2] a hydroxy group, [3] a hydroxycarbonyl group, or
[4] a C.sub.1-8 alkyl group which may be substituted by hydroxy
group(s), or [5] a C.sub.1-8 alkoxy group, (8) a 5- to 14-membered
heteroaryl group which may be substituted by C.sub.1-8 alkyl
group(s), (9) a cyano group, (10) a C.sub.1-8 alkanoyl group, (11)
a 4- to 10-membered nitrogen-containing heterocycloalkylcarbonyl
group which may be substituted by C.sub.1-8 alkyl group(s), (12) a
halogen atom, (13) a (C.sub.1-8 alkyl).sub.m9c-amino group which
may be substituted by one or more R.sup.9F, m9c: 0.about.2,
R.sup.9F: [9F-1] a C.sub.1-3 alkylsulfonyl group, [9F-2] a
(C.sub.1-3 alkyl).sub.m9f1-aminosulfonyl group (m9f1: 0.about.2),
or [9F-3] a C.sub.1-3 alkanoyl group which may be substituted by
(C.sub.1-3 alkyl).sub.m9f2-amino group(s) (m9f2: 0.about.2), (14) a
C.sub.1-8 alkylcarbonyl(C.sub.0-8 alkyl)amino group which may be
substituted by (C.sub.1-8 alkyl).sub.m9d-amino group(s), m9d:
0.about.2, (15) a C.sub.1-8 alkylsulfonyl(C.sub.0-8 alkyl)amino
group, (16) a (C.sub.1-8 alkyl).sub.m9e-aminosulfonyl(C.sub.0-8
alkyl)amino group, m9e: 0.about.2, (17) a nitro group, (18) a
hydroxy group, (19) a C.sub.1-8 alkoxy group which may be
substituted by one or more R.sup.9G, R.sup.9G: [1] a hydroxy group,
[2] a hydroxycarbonyl group, [3] a C.sub.6-10 aryl group which may
be substituted by C.sub.1-8 alkoxy group(s), [4] a (C.sub.1-8
alkyl).sub.m9g1-amino group, [5] a C.sub.1-8 alkoxy group which may
be substituted by one or more R.sup.9G1, [6] a 5- to 14-membered
heteroaryl group, or [7] a 4- to 10-membered heterocycloalkyloxy
group which may be substituted by C.sub.1-8 alkyl group(s), m9g1:
0.about.2, R.sup.9G1: [1] a C.sub.1-8 alkoxy group, or [2] a
hydroxycarbonyl group, (20) a 4- to 10-membered heterocycloalkyloxy
group which may be substituted by [1] 4- to 10-membered
heterocycloalkyl group(s), or [2] C.sub.1-8 alkoxycarbonyl
group(s), (21) a C.sub.1-8 alkylsulfonyloxy group which may be
substituted by halogen atom(s), (22) a C.sub.1-8 alkylthio group
which may be substituted by (C.sub.1-8 alkyl).sub.m9f-amino
group(s), m9f: 0.about.2, (23) a C.sub.1-8 alkylsulfonyl group
which may be substituted by (C.sub.1-8 alkyl).sub.m9g-amino
group(s), m9g: 0.about.2, (24) a (C.sub.1-8
alkyl).sub.m9h-aminosulfonyl group, m9h: 0.about.2, (25) a 4- to
10-membered nitrogen-containing heterocycloalkylsulfonyl group
which may be substituted by C.sub.1-8 alkyl group(s), and (26) a
hydroxycarbonyl group, or a salt or solvate thereof.
12. The method of claim 11, wherein the method comprises treating
cancer or cancer metastasis in the subject in need thereof.
13. The method of claim 12, wherein the cancer is selected from the
group consisting of lung cancer, anaplastic large cell lymphoma,
inflammatory myofibroblastic tumor, esophageal cancer, and
neuroblastoma.
14. The method of claim 11, wherein the method comprises treating
depression or cognitive function disorder in the subject in need
thereof.
15. The method of claim 11, wherein the pharmaceutical comprises as
an active ingredient a compound selected from the group consisting
of
9-(4-isopropyl-piperazin-1-yl)-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[-
b]carbazole-3-carbonitrile;
6,6-dimethyl-8-(4-oxetan-3-yl-piperazin-1-yl)-11-oxo-9-prop-1-ynyl-6,11-d-
ihydro-5H-benzo[b]carbazole-3-carbonitrile;
9-cyclopropylethynyl-6,6-dimethyl-8-(4-oxetan-3-yl-piperazin-1-yl)-11-oxo-
-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile;
6,6-dimethyl-8-(1-oxetan-3-yl-piperidin-4-yl)-11-oxo-6,11-dihydro-5H-benz-
o[b]carbazole-3-carbonitrile;
9-bromo-6,6-dimethyl-8-(4-oxetan-3-yl-piperazin-1-yl)-11-oxo-6,11-dihydro-
-5H-benzo[b]carbazole-3-carbonitrile;
9-bromo-8-(4-cyclopropyl-piperazin-1-yl)-6,6-dimethyl-11-oxo-6,11-dihydro-
-5H-benzo[b]carbazole-3-carbonitrile;
9-chloro-6,6-dimethyl-8-(4-morpholin-4-yl-piperidin-1-yl)-11-oxo-6,11-dih-
ydro-5H-benzo[b]carbazole-3-carbonitrile;
8-(4-cyclobutyl-piperazin-1-yl)-6,6-dimethyl-11-oxo-9-prop-1-ynyl-6,11-di-
hydro-5H-benzo[b]carbazole-3-carbonitrile;
6,6,9-trimethyl-8-(4-morpholin-4-yl-piperidin-1-yl)-11-oxo-6,11-dihydro-5-
H-benzo[b]carbazole-3-carbonitrile;
9-ethyl-6,6-dimethyl-8-(4-oxetan-3-yl-piperazin-1-yl)-11-oxo-6,11-dihydro-
-5H-benzo[b]carbazole-3-carbonitrile;
9-ethyl-6,6-dimethyl-8-(4-morpholin-4-yl-piperidin-1-yl)-11-oxo-6,11-dihy-
dro-5H-benzo[b]carbazole-3-carbonitrile;
9-ethynyl-6,6-dimethyl-8-(4-oxetan-3-yl-piperazin-1-yl)-11-oxo-6,11-dihyd-
ro-5H-benzo[b]carbazole-3-carbonitrile;
8-(4-cyclobutyl-piperazin-1-yl)-9-ethyl-6,6-dimethyl-11-oxo-6,11-dihydro--
5H-benzo[b]carbazole-3-carbonitrile;
9-ethynyl-6,6-dimethyl-11-oxo-8-(4-pyrrolidin-1-yl-piperidin-1-yl)-6,11-d-
ihydro-5H-benzo[b]carbazole-3-carbonitrile;
6,6-dimethyl-11-oxo-8-(4-pyrrolidin-1-yl-piperidin-1-yl)-6,11-dihydro-5H--
benzo[b]carbazole-3-carbonitrile;
8-(4-cyclobutyl-piperazin-1-yl)-9-ethynyl-6,6-dimethyl-11-oxo-6,11-dihydr-
o-5H-benzo[b]carbazole-3-carbonitrile;
8-(4-cyclobutyl-piperazin-1-yl)-6,6-dimethyl-11-oxo-9-propyl-6,11-dihydro-
-5H-benzo[b]carbazole-3-carbonitrile;
8-(1-isopropyl-piperidin-4-yl)-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[-
b]carbazole-3-carbonitrile;
8-(4-isopropyl-piperazin-1-yl)-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[-
b]carbazole-3-carbonitrile;
8-(4-cyclobutyl-piperazin-1-yl)-9-cyclopropyl-6,6-dimethyl-11-oxo-6,11-di-
hydro-5H-benzo[b]carbazole-3-carbonitrile;
8-(2-tert-butylamino-ethoxy)-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]-
carbazole-3-carbonitrile;
9-ethynyl-8-(4-methanesulfonyl-piperazin-1-yl)-6,6-dimethyl-11-oxo-6,11-d-
ihydro-5H-benzo[b]carbazole-3-carbonitrile;
9-bromo-8-(4-cyclobutyl-piperazin-1-yl)-6,6-dimethyl-11-oxo-6,11-dihydro--
5H-benzo[b]carbazole-3-carbonitrile;
6,6-dimethyl-8-(4-oxetan-3-yl-piperazin-1-yl)-11-oxo-9-propyl-6,11-dihydr-
o-5H-benzo[b]carbazole-3-carbonitrile; and
9-ethynyl-6,6-dimethyl-8-morpholin-4-yl-11-oxo-6,11-dihydro-5H-benzo[b]ca-
rbazole-3-carbonitrile, or a salt or solvate thereof.
16. The method of claim 11, wherein the pharmaceutical comprises as
an active ingredient
9-ethynyl-6,6-dimethyl-8-morpholin-4-yl-11-oxo-6,11-dihydro-5H-benzo[b]ca-
rbazole-3-carbonitrile, or a salt or solvate thereof.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is a Continuation of U.S. application Ser.
No. 15/221,926, filed Jul. 28, 2016, which is a Continuation of
U.S. application Ser. No. 14/619,242, filed Feb. 11, 2015, which is
a Divisional of U.S. application Ser. No. 13/377,300, which is the
U.S. National Stage application of PCT/JP2010/059785, filed Jun. 9,
2010, which claims priority from Japanese application JP
2009-139691, filed Jun. 10, 2009.
TECHNICAL FIELD
[0002] The present invention relates to tetracyclic compounds,
salts or solvates thereof. More specifically, the present invention
relates to the tetracyclic compounds and provides a medicament,
pharmaceutical compositions comprising the compounds, ALK
inhibitors, and pharmaceuticals for the prophylaxis or treatment of
the diseases including cancer, cancer metastasis, depression or
cognitive function disorder comprising the compounds. Furthermore,
the present invention relates to a method for the treatment of the
diseases comprising administering to the patient who is in need of
the treatment of the disease the compounds described herein, salts
or solvates thereof in an effective amount for the treatment of the
diseases, and use of the tetracyclic compounds for the preparation
of the pharmaceutical composition.
BACKGROUND ART
[0003] Anaplastic Lymphoma Kinase (ALK) is one of the receptor
tyrosine kinases belonging to insulin receptor family (Non-Patent
Document Nos. 1 and 2).
[0004] It was reported that, due to gene alteration of ALK
(translocation, point mutation and gene amplification), an abnormal
activation of ALK is eventually involved in oncogenesis.
[0005] For example, in lung cancer, ALK forms EML4-ALK due to
chromosomal translocation, leading to constitutive activation of
tyrosine kinase, and it acquires a tumorigenic activity (Non-Patent
Document 1). In addition, the ALK translocation were reported in
systemic anaplastic large cell lymphoma (ALCL) and inflammatory
myofibroblastic tumors (IMTs) (Non-Patent Document Nos. 3 and 4),
and esophageal cancer (Non-Patent Document 5). It was also found
that active point mutation (approximately 10%) or gene
amplification of ALK is involved in oncogenesis of neuroblastoma
(Non-Patent Document Nos. 6 and 7).
[0006] On the other hand, it was also reported in tumors activated
by pleiotrophin (PTN) or midkine (MK) (Non-Patent Document Nos. 8
and 9), both a ligand for ALK.
[0007] Further, from the study using ALK knock-out mouse, it was
suggested that an inhibitor for ALK is useful as an anti-depression
agent or as a preventive or therapeutic agent for cognitive
function disorders (Non-Patent Document 10 and Patent Document
1).
[0008] Therefore, a compound having an inhibitory activity on ALK
will be very useful for the prevention and treatment of cancer,
depression and cognitive function disorders, etc.
[0009] Meanwhile, as an ALK inhibiting material, there are some
compounds among multi-kinase inhibitors which have an inhibitory
activity on ALK as one of their activities. For example, as an
inhibitor for c-MET (mesenchymal-epithelial transition factor) and
ALK, PF02341066 having a 2-aminopyridine structure was reported
(Patent Document 2, Non-Patent Document Nos. 11 and 12). As an
inhibitor for FAK, ZAP70, IGF-1R and ALK, etc., NVP-TAE684 having a
2,4-diaminopyrimidine structure was reported (Patent Document 3 and
Non-Patent Document 13). In addition, 2,4-diaminopyrimidines and
2,4-diaminoquinazolines (Patent Document 4), pyridopyrazines
(Patent Document 5), pyrazolo [3,4-C] isoquinolines (Patent
Document 6), thiazoles (Patent Document 7), tricyclic compounds
(Patent Document 8), and indazoles (Patent Document 9) and the like
have been reported.
[0010] However, the tetracyclic compounds of the present invention
are not disclosed in any of the documents described above.
[0011] As a tetracyclic compound exhibiting an anti-tumor activity,
tetracyclic compounds comprising carbazole structure like
ellipticine are known.
[0012] However, their action mechanism is based on interaction with
DNA to exhibit cell toxicity (Non-Patent Document 15), and there is
no description at all regarding the activity of inhibiting ALK by
the tetracyclic compounds.
DOCUMENT LIST
[0013] [Patent Document 1] WO 2007/023310 A2 [0014] [Patent
Document 2] WO 2006/021884 A2 [0015] [Patent Document 3] WO
2004/080980 A1 [0016] [Patent Document 4] WO 2009/008371 A1 [0017]
[Patent Document 5] WO 2007/130468 A2 [0018] [Patent Document 6] WO
2005/009389 A2 [0019] [Patent Document 7] WO 2005/097765 A1 [0020]
[Patent Document 8] WO 2008/021369 A2 [0021] [Patent Document 9] WO
2009/013126 A1 [0022] [Non-Patent Document 1] Proc Natl Acad Sci
USA, Vol. 101, pages 13306-13311, 2004 [0023] [Non-Patent Document
2] Nature, Vol. 448, pages 561-566, 2007 [0024] [Non-Patent
Document 3] Blood, Vol. 72, pages 234-240, 1988 [0025] [Non-Patent
Document 4] Cancer Res, Vol. 59, pages 2776-2780, 1999 [0026]
[Non-Patent Document 5] World J Gastroenterol, Vol. 12, pages
7104-7112, 2006 [0027] [Non-Patent Document 6] Nature, Vol. 455,
pages 930-935, 2008 [0028] [Non-Patent Document 7] Nature, Vol.
455, pages 971-974, 2008 [0029] [Non-Patent Document 8] J Biol
Chem, Vol. 276, pages 16772-16779, 2001 [0030] [Non-Patent Document
9] J Biol Chem, Vol. 277, pages 35990-35999, 2002 [0031]
[Non-Patent Document 10] Neuropsychopharmacology, Vol. 33, pages
685-700, 2008 [0032] [Non-Patent Document 11] Proc Am Assoc Cancer
Res (AACR) 2006, 47: Abst LB-271 [0033] [Non-Patent Document 12]
Proc Am Assoc Cancer Res (AACR) 2006, 47: Abst LB-273 [0034]
[Non-Patent Document 13] Proc Natl Acad Sci USA Vol. 104, pages
270-275, 2007 [0035] [Non-Patent Document 14] Current Organic
Chemistry, Vol. 5, Issue No. 5, pages 507-518, 2001 [0036]
[Non-Patent Document 15] Current Medicinal Chemistry: Anti-Cancer
Agents, Vol. 4, Issue No. 2, pages 149-172, 2004
SUMMARY OF THE INVENTION
Problems to be Solved by the Invention
[0037] The present invention is to provide ALK-inhibiting compounds
having a novel structure. In addition, object of the present
invention is to provide a pharmaceuticals for the prophylaxis or
treatment comprising the ALK-inhibiting compounds that is effective
for prophylaxising or treating a disease accompanied by abnormality
in ALK, for example, cancer, cancer metastasis, depression and
cognitive function disorder.
Means for Solving the Problems
[0038] As a result of extensive studies by the inventors of the
present invention, it was found that the tetracyclic compounds that
are represented by the following Formula (1) with a structure
clearly different from any other existing pharmaceutical compounds
have an excellent ALK-inhibiting activity, are useful for the
treatment and prophylaxis of the diseases including cancer, cancer
metastasis, depression and cognitive function disorder, and have a
remarkable efficacy against said diseases. Accordingly, the present
invention was completed.
[0039] Thus, according to one aspect of the present invention, the
tetracyclic compounds, a medicament and a pharmaceutical
composition comprising the compounds, etc. shown below are
provided.
[1] A compound or salt or solvate thereof represented by Formula
(I):
##STR00002##
[wherein,
[0040] A.sup.1, A.sup.2, A.sup.3, A.sup.4, A.sup.7, A.sup.8,
A.sup.9 and A.sup.10 all represent C, or any one of A.sup.2,
A.sup.3, A.sup.4, A.sup.7, A.sup.8 and A.sup.9 represents N (with
the proviso that, when it represents N, no substituent group exists
therefor) and the remainings represent C;
[0041] A.sup.5 is selected from NR.sup.5, O and S;
[0042] R.sup.1 and R.sup.10 each independently represent [1] a
hydrogen atom, [2] a cyano group,
[3] a halogen atom or [4] a 4- to 10-membered heterocycloalkyl
group which may be substituted by 4- to 10-membered
heterocycloalkyl group(s);
[0043] R.sup.2 is selected from the group consisting of:
[0044] (1) a hydrogen atom,
[0045] (2) a C.sub.1-8 alkyl group,
[0046] (3) a C.sub.2-8 alkenyl group,
[0047] (4) a C.sub.2-8 alkynyl group,
[0048] (5) a cyano group,
[0049] (6) a halogen atom,
[0050] (7) a (C.sub.1-8 alkyl).sub.m2-amino group which may be
substituted by C.sub.1-8 alkylsulfonyl group(s), [0051] m2:
0.about.2, and
[0052] (8) a nitro group; [0053] R.sup.3 is selected from the group
consisting of:
[0054] (1) a hydrogen atom,
[0055] (2) a C.sub.1-8 alkyl group which may be substituted by [1]
halogen atom(s), [2]hydroxy group(s) or [3] C.sub.1-8 alkoxy
group(s),
[0056] (3) a C.sub.6-10 aryl group,
[0057] (4) a cyano group,
[0058] (5) a C.sub.1-8 alkanoyl group which may be substituted by
C.sub.6-10 aryl group(s),
[0059] (6) a (C1-8 alkyl).sub.m3a-aminocarbonyl group which may be
substituted by one or more R.sup.3A,
[0060] R.sup.3A: [1] a C.sub.6-10 aryl group, [2] a C.sub.1-8
alkoxy group, [3] a 5- to 14-membered heteroaryl group, or [4] a
C.sub.6-10 aryl sulfonyl group,
[0061] m3a: 0.about.2,
[0062] (7) a hydroxycarbonyl group,
[0063] (8) a C.sub.1-8 alkoxycarbonyl group which may be
substituted by [1] hydroxy group(s) or [2] C.sub.1-8 alkoxy
group(s),
[0064] (9) a halogen atom,
[0065] (10) a (C.sub.1-8 alkyl).sub.m3b-amino group which may be
substituted by C.sub.6-10 aryl group(s), [0066] m3b: 0.about.2,
[0067] (11) a C.sub.1-8 alkylcarbonyl (C.sub.0-8 alkyl) amino group
which may be substituted by [1]C.sub.6-10 aryl group(s) or [2]
C.sub.6-10 aryloxy group(s),
[0068] (12) a C.sub.6-10 arylcarbonyl (C.sub.0-8 alkyl) amino group
which may be substituted by C.sub.1-8 alkyl group(s) which may be
substituted by halogen atom(s),
[0069] (13) a (C.sub.1-8 alkyl).sub.m3c-aminocarbonyl (C.sub.0-8
alkyl) amino group which may be substituted by C.sub.6-10 aryl
group(s), [0070] m3c: 0.about.2,
[0071] (14) a nitro group,
[0072] (15) a hydroxy group,
[0073] (16) a C.sub.1-8 alkoxy group which may be substituted by
one or more R.sup.3B
[0074] R.sup.3B: [1] a hydroxy group, [2] a C.sub.1-8 alkoxy group,
[3] a C.sub.6-10 aryl (C.sub.0-8 alkyl) aminocarbonyl group, [4] a
(C.sub.1-8 alkyl).sub.m3d-amino group, or [5] a halogen atom,
[0075] m3d: 0.about.2,
[0076] (17) a 4- to 10-membered heterocycloalkyloxy group,
[0077] (18) a 5- to 14-membered heteroaryloxy group,
[0078] (19) a (C.sub.1-8 alkyl).sub.m3e-aminocarbonyloxy group
which may be substituted by C.sub.6-10 aryl group(s) [0079] m3e:
0.about.2,
[0080] (20) a 4- to 10-membered nitrogen-containing
heterocycloalkylcarbonyl group,
[0081] (21) a C.sub.1-8 alkylsulfonyloxy group which may be
substituted by halogen atom(s),
[0082] (22) a C.sub.1-8 alkylthio group,
[0083] (23) a C.sub.1-8 alkylsulfonyl group which may be
substituted by C.sub.6-10 aryl group(s),
[0084] (24) a 5- to 14-membered heteroaryl group which may be
substituted by C.sub.1-8 alkyl group(s) which may be substituted by
C.sub.1-8 alkoxy group(s),
[0085] (25) a C.sub.1-8 alkoxycarbonyl (C.sub.0-8 alkyl) amino
group which may be substituted by C.sub.1-8 alkoxy group(s),
[0086] (26) a C.sub.6-10 aryloxycarbonyl (C.sub.0-8 alkyl) amino
group which may be substituted by C.sub.1-8 alkyl group(s) which
may be substituted by halogen atom(s),
[0087] (27) a C.sub.6-10 aryl (C.sub.0-8 alkyl) aminocarbonyl
(C.sub.0-8 alkyl) amino group which may be substituted by one or
more R.sup.3C,
[0088] R.sup.3C: [1] a C.sub.1-8 alkyl group which may be
substituted by halogen atom(s), or [2] a C.sub.1-8 alkoxy
group,
[0089] (28) a C.sub.3-8 cycloalkyl (C.sub.0-8 alkyl)
aminocarbonyloxy group, and
[0090] (29) a C.sub.6-10 aryl (C.sub.0-8 alkyl) aminocarbonyloxy
group which may be substituted by substituent(s) selected from the
group consisting of [1] a C.sub.1-8 alkyl group and [2] a C.sub.1-8
alkoxy group;
[0091] R.sup.4 is selected from the group consisting of:
[0092] (1) a hydrogen atom,
[0093] (2) a C.sub.1-8 alkyl group which may be substituted by
halogen atom(s),
[0094] (3) a C.sub.2-8 alkenyl group,
[0095] (4) a C.sub.2-8 alkynyl group,
[0096] (5) a C.sub.3-8 cycloalkyl group,
[0097] (6) a cyano group,
[0098] (7) an aminocarbonyl group,
[0099] (8) a (C.sub.1-8 alkyl).sub.m4a-aminocarbonyl group, [0100]
m4a: 1.about.2,
[0101] (9) a hydroxycarbonyl group,
[0102] (10) a C.sub.1-8 alkoxycarbonyl group,
[0103] (11) a halogen atom,
[0104] (12) a (C.sub.1-8 alkyl).sub.m4b-amino group, [0105] m4b:
0.about.2,
[0106] (13) a hydroxy group, and
[0107] (14) a C.sub.1-8 alkoxy group which may be substituted by
hydroxy group(s);
[0108] R.sup.5 is selected from the group consisting of:
[0109] (1) a hydrogen atom,
[0110] (2) a C.sub.1-8 alkyl group which may be substituted by one
or more RA,
[0111] R.sup.5A: [1] a hydroxycarbonyl group, [2] a C.sub.1-8
alkoxycarbonyl group, [3] a hydroxy group, [4] a C.sub.1-8 alkoxy
group, [5] a (C.sub.1-8 alkyl).sub.m5-amino group, [6] a C.sub.6-10
aryl group, or [7] a C.sub.1-8 alkylthio group, [0112] m5:
0.about.2,
[0113] (3) a C.sub.2-8 alkenyl group,
[0114] (4) a C.sub.2-8 alkynyl group,
[0115] (5) a C.sub.3-8 cycloalkyl group, and
[0116] (6) a C.sub.1-8 alkylsulfonyl group;
[0117] R.sup.6 and R.sup.6' are each independently selected from
the group consisting of:
[0118] (1) a C.sub.1-8 alkyl group which may be substituted by
halogen atom(s),
[0119] (2) a C.sub.2-8 alkenyl group, and
[0120] (3) a C.sub.2-8 alkynyl group; or
[0121] R.sup.6 and R.sup.6' are taken together with the carbon
atoms to which they are bound to form:
[0122] (4) a C.sub.3-8 cycloalkyl group, or
[0123] (5) a 4- to 10-membered heterocycloalkyl group which may be
substituted by C.sub.1-8 alkyl C.sub.6-10 aryl sulfonyl group(s)
which may be substituted by C.sub.1-8 alkyl group(s);
[0124] R.sup.7 is selected from the group consisting of:
[0125] (1) a hydrogen atom,
[0126] (2) a halogen atom,
[0127] (3) a C.sub.1-8 alkoxy group which may be substituted by one
or more R.sup.7A,
[0128] R.sup.7A: [1] a (C.sub.1-8 alkyl).sub.m7a-amino group, [2] a
hydroxy, [3] a 4- to 10-membered heterocycloalkyl group which may
be substituted by C.sub.1-8 alkyl group(s),
[0129] m7a: 0.about.2,
[0130] (4) a C.sub.1-8 alkylsulfonyl group,
[0131] (5) a nitro group, and
[0132] (6) a hydroxyl group;
[0133] R.sup.8 is selected from the group consisting of:
[0134] (1) a hydrogen atom,
[0135] (2) a C.sub.1-8 alkyl group which may be substituted by one
or more R.sup.8A,
[0136] R.sup.8A: [1] a 4- to 10-membered heterocycloalkyl group
which may be substituted by one or more R.sup.8A1, [2] a (C.sub.1-8
alkyl).sub.m8a-amino group which may be substituted by a halogen
atom, and [3] a hydroxy group, [0137] m8a:0.about.2,
[0138] R.sup.8A1: [1] a C.sub.1-8 alkyl group, [2] a C.sub.1-8
alkylsulfonyl group, [3] a (C.sub.1-8 alkyl).sub.m8b-aminosulfonyl
group, [4] an oxo group, [5] a C.sub.1-8 alkoxycarbonyl, or [6] a
C.sub.1-8 alkoxycarbonyl (C.sub.0-8 alkyl) aminosulfonyl,
[0139] m8b: 0.about.2,
[0140] (3) a C.sub.2-8 alkenyl group,
[0141] (4) a 4- to 10-membered heterocycloalkyl group which may be
substituted by one or more R.sup.8B
[0142] R.sup.8B:
<1> a C.sub.1-8 alkyl group which may be substituted by one
or more R.sup.8B1, <2> a C.sub.2-8 alkenyl group, <3> a
C.sub.2-8 alkynyl group, <4> a C.sub.3-8 cycloalkyl group
which may be substituted by [1] cyano group(s) or [2] C.sub.1-8
alkyl group(s), <5> a 4- to 10-membered heterocycloalkyl
group which may be substituted by one or more R.sup.8B2 <6> a
C.sub.1-8 alkoxy group which may be substituted by substituent(s)
selected from the group consisting of [1] a C.sub.1-8 alkoxy group
and [2] a C.sub.3-8 cycloalkyl group, <7> a C.sub.1-8
alkoxycarbonyl group, <8> a C.sub.1-8 alkylsulfonyl group,
<9> a 5- to 14-membered heteroarylsulfonyl group, <10>
an oxo group, <11> a cyano group, <12> a C.sub.1-8
alkanoyl group which may be substituted by one or more R.sup.8B3
<13> a C.sub.3-8 cycloalkylcarbonyl group, <14> a
(C.sub.1-8 alkyl).sub.m8c-aminosulfonyl group, <15> a
C.sub.1-8 alkylsulfonyl (C.sub.0-8 alkyl) amino group, <16> a
(C.sub.1-8 alkyl).sub.m8a-amino group which may be substituted by
one or more R.sup.8B4, <17> a hydroxy group, <18> a
(C.sub.1-8 alkyl).sub.m8e-aminocarbonyl group, or <19> a
C.sub.1-8 alkoxycarbonyl (C.sub.0-8 alkyl) amino group [0143] m8c:
0.about.2 [0144] m8d: 0.about.2 [0145] m8e: 0.about.2
[0146] R.sup.8B1 [1] a C.sub.3-8 cycloalkyl group, [2] a hydroxy
group, or [3] a C.sub.1-8 alkoxy group(s),
[0147] R.sup.8B2: [1] a halogen atom, [2] a C.sub.1-8 alkyl group,
[3] an oxo group, [4] a hydroxy group, or [5] a deuterium atom,
[0148] R.sup.8B3: a (C.sub.1-8 alkyl).sub.m8f-amino group, [0149]
m8f: 0.about.2,
[0150] R.sup.8B4: [1] a C.sub.3-8 cycloalkyl group, or [2] a
hydroxy group,
[0151] (5) a 5- to 14-membered heteroaryl group which may be
substituted by a C.sub.1-8 alkyl group,
[0152] (6) a (C.sub.1-8 alkyl).sub.m8g-aminocarbonyl group which
may be substituted by one or more R.sup.8C, [0153] m8g:
0.about.2,
[0154] R.sup.8C:[1] a hydroxy group, [2] a (C.sub.1-8
alkyl).sub.m8h-amino group which may be substituted by
substituent(s) selected from the group consisting of <1> a
(C.sub.1-8 alkyl).sub.m8i-aminosulfonyl group, <2> a
C.sub.1-8 alkylsulfonyl group, <3> a C.sub.1-8 alkoxycarbonyl
group and
<4> a C.sub.1-8 alkoxycarbonyl(C.sub.0-8 alkyl) aminosulfonyl
group, [3] a C.sub.1-8 alkylsulfonyl group, or [4] a C.sub.1-8
alkoxy group which may be substituted by a hydroxy group, [0155]
m8h: 0.about.2, [0156] m8i: 0.about.2,
[0157] (7) a 4- to 10-membered heterocycloalkyl (C.sub.0-8 alkyl)
aminocarbonyl group which may be substituted by oxo group(s),
[0158] (8) a 4- to 10-membered nitrogen-containing
heterocycloalkylcarbonyl group which may be substituted by one or
more R.sup.8D
[0159] R.sup.8D: [1] a C.sub.1-8 alkyl group which may be
substituted by one or more R.sup.8D1, [2] a hydroxy group, [3] a
C.sub.1-8 alkylsulfonyl group, or [4] a C.sub.1-8 alkoxycarbonyl
group,
[0160] R.sup.8D1: [1] a hydroxy group, or [2] a C.sub.1-8 alkoxy
group,
[0161] (9) a hydroxycarbonyl group,
[0162] (10) a C.sub.0-8 alkoxy (C.sub.0-8 alkyl) aminocarbonyl
group which may be substituted by hydroxy group(s),
[0163] (11) a halogen atom,
[0164] (12) a (C.sub.1-8 alkyl).sub.m8j-amino group which may be
substituted by one or more R.sup.8H, [0165] m8j: 0.about.2,
[0166] R.sup.8H: [1] a hydroxy group, or [2] a 4- to 10-membered
heterocycloalkyl group,
[0167] (13) a hydroxyl group,
[0168] (14) a C.sub.1-8 alkoxy group which may be substituted by
one or more R.sup.8E,
[0169] R.sup.8E:
<1> a hydroxy group, <2> halogen atom, <3> a
hydroxycarbonyl group, <4> a C.sub.1-8 alkoxycarbonyl group,
<5> a 4- to 10-membered nitrogen-containing
heterocycloalkylcarbonyl group which may be substituted by one or
more R.sup.8E1 <6> a (C.sub.1-8 alkyl).sub.m8k1-amino group
which may be substituted by one or more R.sup.8E2 [0170] m8k1:
0.about.2, <7> a 4- to 10-membered heterocycloalkyl group
which may be substituted by one or more R.sup.8E3 <8> a 5- to
14-membered heteroaryl group, <9> a (C.sub.1-8
alkyl).sub.m8k2-aminocarbonyl group which may be substituted by one
or more R.sup.8E6 [0171] m8k2: 0.about.2, <10> a C.sub.1-8
alkoxy group which may be substituted by one or more R.sup.8E7,
<11> a C.sub.1-8 alkylthio group, <12> a C.sub.1-8
alkylsulfinyl group, <13> a C.sub.1-8 alkylsulfonyl
group,
[0172] R.sup.8E1:
<1> a C.sub.1-8 alkoxycarbonyl group, <2> a C.sub.1-8
alkanoyl group, <3> a C.sub.1-8 alkylsulfonyl group,
5<4> a (C.sub.1-8 alkyl).sub.m8k3-aminosulfonyl group, [0173]
m8k3: 0.about.2, or <5> a 4- to 10-membered heterocycloalkyl
group,
[0174] R.sup.8E2:
<1> a hydroxy group, <2> a C.sub.1-8 alkoxycarbonyl
group which may be substituted by halogen atom(s), <3> a
C.sub.3-8 cycloalkyl group which may be substituted by C.sub.1-8
alkyl group(s) which may be substituted by hydroxy group(s),
<4> a C.sub.1-8 alkanoyl group which may be substituted by
substituent(s) selected from the group consisting of [1] a
(C.sub.1-8 alkyl).sub.m8k4-amino group and [2] a halogen atom(s),
[0175] m8k4: 0.about.2, <5> a (C.sub.1-8
alkyl).sub.m8k5-aminocarbonyl group, [0176] m8k5: 0.about.2,
<6> a C.sub.1-8 alkylsulfonyl group, <7> a 4- to
10-membered nitrogen-containing heterocycloalkylsulfonyl group
which may be substituted by C.sub.1-8 alkyl group(s), <8> a
(C.sub.1-8 alkyl).sub.m8k6-aminosulfonyl group which may be
substituted by C.sub.1-8 alkoxycarbonyl group(s), [0177] m8k6:
0.about.2, or
[0178] R.sup.8E3:
<1> a C.sub.1-8 alkyl group which may be substituted by
substituent(s) selected from the group consisting of [1] a hydroxy
group and [2] a C.sub.1-8 alkylcarbonyloxy group, <2> a
C.sub.1-8 alkylcarbonyloxy group, <3> a hydroxy group,
<4> a C.sub.3-8 cycloalkyl group, <5> a C.sub.1-8
alkoxy group, <6> a C.sub.1-8 alkoxycarbonyl group, <7>
a C.sub.1-8 alkylsulfonyl group, <8> a (C.sub.1-8
alkyl).sub.m8k8-aminocarbonyl group [0179] m8k8: 0.about.2,
<9> a C.sub.1-8 alkanoyl group which may be substituted by
hydroxy group(s), <10> an oxo group, or <11> a 4- to
10-membered heterocycloalkyl group which may be substituted by
substituent(s) selected from the group consisting of [1] a
C.sub.1-8 alkanoyl group, [2] a C.sub.1-8 alkoxycarbonyl group and
[3] a C.sub.1-8 alkylsulfonyl group,
[0180] R.sup.8E6:
<1> a C.sub.2-8 alkenylcarbonyloxy group, <2> a hydroxy
group, <3> a cyano group, <4> a (C.sub.1-8
alkyl).sub.m8k9-amino group which may be substituted by hydroxy
group(s) [0181] m8k9: 0.about.2, <5> a C.sub.1-8 alkoxy group
which may be substituted by hydroxy group(s), <6> a C.sub.1-8
alkylcarbonyloxy group, <7> a 4- to 10-membered
heterocycloalkyl group which may be substituted by C.sub.1-8 alkyl
group(s), or <8> a 5- to 14-membered heteroaryl group,
[0182] R.sup.8E7:
<1> a hydroxy group, or <2> a C.sub.1-8 alkoxy group
which may be substituted by hydroxy group(s),
[0183] (15) a 4- to 10-membered heterocycloalkyloxy group which may
be substituted by one or more R.sup.8F
[0184] R.sup.8F:
<1> a C.sub.1-8 alkyl group which may be substituted by one
or more R.sup.8F1 <2> a C.sub.3-8 cycloalkyl group, <3>
a C.sub.1-8 alkanoyl group which may be substituted by halogen
atom(s), <4> a C.sub.1-8 alkylcarbonyloxy group, <5> a
C.sub.1-8 alkoxycarbonyl group, <6> a 4- to 10-membered
heterocycloalkyl group which may be substituted by one or more
R.sup.8F2 <7> a C.sub.1-8 alkyl sulfonyl group, <8> a
hydroxy group, or [9] a C.sub.6-10 aryl group,
[0185] R.sup.8F1: [1] a hydroxy group, [2] a C.sub.1-8 alkoxy
group, or [3] a halogen atom,
[0186] R.sup.8F2: [1] a 4- to 10-membered heterocycloalkyl group,
[2] a C.sub.1-8 alkoxycarbonyl group, or [3] a C.sub.1-8
alkylsulfonyl group,
[0187] (16) a 5- to 14-membered heteroaryloxy group,
[0188] (17) a 4- to 10-membered heterocycloalkylcarbonyloxy
group,
[0189] (18) a (C.sub.1-8 alkyl).sub.m8l1-aminosulfonyloxy group,
[0190] m8l1: 0.about.2,
[0191] (19) a C.sub.1-8 alkyl thio group which may be substituted
by [1] (C.sub.1-8 alkyl).sub.m8l2-amino group(s), [2] hydroxy
group(s) or [3] hydroxycarbonyl group(s), [0192] m8l2:
0.about.2,
[0193] (20) a C.sub.1-8 alkylsulfonyl group which may be
substituted by one or more R.sup.8G,
[0194] R.sup.8G: [1] a hydroxycarbonyl group, [2] a hydroxy group,
or [3] a (C.sub.1-8 alkyl).sub.m8l3-amino group, [0195] m8l3:
0.about.2,
[0196] (21) a 4- to 10-membered nitrogen-containing
heterocycloalkylsulfonyloxy group which may be substituted by
C.sub.1-8 alkyl group(s),
[0197] (22) a C.sub.2-8 alkenyloxy group, and
[0198] (23) a C.sub.1-8 alkylsulfonyloxy group which may be
substituted by halogen atom(s);
[0199] R.sup.9 is selected from the group consisting of:
[0200] (1) a hydrogen atom,
[0201] (2) a C.sub.1-8 alkyl group which may be substituted by one
or more R.sup.9A,
[0202] R.sup.9A: [1] a C.sub.3-8 cycloalkyl group, [2] a 4- to
10-membered heterocycloalkyl group which may be substituted by one
or more R.sup.9A, [3] a hydroxy group, [4] a C.sub.1-8 alkoxy
group, or [5] a hydroxycarbonyl group,
[0203] R.sup.9A1: [1] a C.sub.1-8 alkyl group, [2] a C.sub.3-8
cycloalkyl group, or [3] a 4- to 10-membered heterocycloalkyl
group,
[0204] (3) a C.sub.2-8 alkenyl group which may be substituted by
one or more R.sup.9B,
[0205] R.sup.9B: [1] a (C.sub.1-8 alkyl).sub.m9a-amino group, [2] a
4- to 10-membered heterocycloalkyl group which may be substituted
by one or more group R.sup.9B1
[0206] R.sup.9B1:[1] a C.sub.3-8 cycloalkyl group, or [2] a 4- to
10-membered heterocycloalkyl group, [0207] m9a: 0.about.2,
[0208] (4) a C.sub.2-8 alkynyl group which may be substituted by
one or more R.sup.9C,
[0209] R.sup.9C: [1] a C.sub.1-8 alkoxy group, [2] a (C.sub.1-8
alkyl).sub.m9b-amino group which may be substituted by C.sub.6-10
aryl group(s), [3] a 4- to 10-membered heterocycloalkyl group which
may be substituted by one or more R.sup.9C1, [4] a C.sub.3-8
cycloalkyl group, [5] a hydroxy group,
[6] a hydroxycarbonyl group, or [7] a C.sub.1-8 alkyloxycarbonyl
group, [0210] m9b: 0.about.2,
[0211] R.sup.9C1: [1] a C.sub.3-8 cycloalkyl group, [2] a 4- to
10-membered heterocycloalkyl group, or [3] an oxo group,
[0212] (5) a C.sub.3-8 cycloalkyl group,
[0213] (6) a 4- to 10-membered heterocycloalkyl group which may be
substituted by one or more R.sup.9D
[0214] R.sup.9D: [1] a C.sub.1-8 alkyl group which may be
substituted by 4- to 10-membered heterocycloalkyl group(s), [2] a
C.sub.3-8 cycloalkyl group, [3] a 4- to 10-membered
heterocycloalkyl group, or [4] a C.sub.1-6 alkylsulfonyl group, or
[5] a C.sub.1-8 alkoxycarbonyl group,
[0215] (7) a C.sub.6-10 aryl group which may be substituted by one
or more R.sup.9E
[0216] R.sup.9E: [1] a halogen atom, [2] a hydroxy group, [3] a
hydroxycarbonyl group, or [4] a C.sub.1-8 alkyl group which may be
substituted by hydroxy group(s), or [5] a C.sub.1-8 alkoxy
group,
[0217] (8) a 5- to 14-membered heteroaryl group which may be
substituted by C.sub.1-8 alkyl group(s),
[0218] (9) a cyano group,
[0219] (10) a C.sub.1-8 alkanoyl group,
[0220] (11) a 4- to 10-membered nitrogen-containing
heterocycloalkylcarbonyl group which may be substituted by
C.sub.1-8 alkyl group(s),
[0221] (12) a halogen atom,
[0222] (13) a (C.sub.1-8 alkyl).sub.m9c-amino group which may be
substituted by one or more R.sup.9F [0223] m9c: 0.about.2,
[0224] (14) a C.sub.1-8 alkylcarbonyl(C.sub.0-8 alkyl)amino group
which may be substituted by (C.sub.1-s alkyl).sub.m9a-amino
group(s), [0225] m9d: 0.about.2,
[0226] (15) a C.sub.1-8 alkylsulfonyl(C.sub.0-8 alkyl)amino
group,
[0227] (16) a (C.sub.1-8 alkyl).sub.m9e-aminosulfonyl(C.sub.0-8
alkyl)amino group, [0228] m9e: 0.about.2,
[0229] (17) a nitro group,
[0230] (18) a hydroxy group,
[0231] (19) a C.sub.1-8 alkoxy group which may be substituted by
one or more R.sup.9G
[0232] R.sup.9G: [1] a hydroxy group, [2] a hydroxycarbonyl group,
[3] a C.sub.6-10 aryl group which may be substituted by C.sub.1-8
alkoxy group(s), [4] a (C.sub.1-8 alkyl).sub.m9g1-amino group, [5]
a C.sub.1-8 alkoxy group which may be substituted by one or more
R.sup.9G1, [6] a 5- to 14-membered heteroaryl group, or [7] a 4- to
10-membered heterocycloalkyloxy group which may be substituted by
C.sub.1-8 alkyl group(s),
[0233] m9g1: 0.about.2,
[0234] R.sup.9G1: [1] a C.sub.1-8 alkoxy group, or [2] a
hydroxycarbonyl group,
[0235] (20) a 4- to 10-membered heterocycloalkyloxy group which may
be substituted by
[1] 4- to 10-membered heterocycloalkyl group(s), or [2] C.sub.1-8
alkoxycarbonyl group(s),
[0236] (21) a C.sub.1-8 alkylsulfonyloxy group which may be
substituted by halogen atom(s),
[0237] (22) a C.sub.1-8 alkylthio group which may be substituted by
(C.sub.1-8 alkyl).sub.m9f-amino group(s), [0238] m9f:
0.about.2,
[0239] (23) a C.sub.1-8 alkylsulfonyl group which may be
substituted by (C.sub.1-8 alkyl).sub.m9g-amino group(s), [0240]
m9g: 0.about.2,
[0241] (24) a (C.sub.1-8 alkyl).sub.m9h-aminosulfonyl group, [0242]
m9h: 0.about.2,
[0243] (25) a 4- to 10-membered nitrogen-containing
heterocycloalkylsulfonyl group which may be substituted by
C.sub.1-8 alkyl group(s), and (26) a hydroxycarbonyl group].
[2] The compound according to the above [1], or a salt or solvate
thereof, wherein R.sup.3 is a cyano group or a halogen atom. [3]
The compound according to the above [1], or a salt or solvate
thereof, wherein A.sup.5 is NR.sup.5 and R.sup.5 is a hydrogen
atom. [4] The compound according to the above [1], or a salt or
solvate thereof, wherein all of the A.sup.1, A.sup.2, A.sup.3,
A.sup.4, A.sup.7, A.sup.8, A.sup.9 and A.sup.10 are a carbon atom.
[5] The compound according to claim 1, or a salt or solvate
thereof, wherein: A.sup.1, A.sup.2, A.sup.3, A.sup.4, A.sup.7,
A.sup.8, A.sup.9 and A.sup.10 all represent C, or any one of
A.sup.2, A.sup.3, A.sup.4, A.sup.7, A.sup.8 and A.sup.9 represents
N (with the proviso that, when it represents N, no substituent
group exists therefor) and the remainings represent C;
[0244] A.sup.5 is selected from NR.sup.5, O and S;
[0245] R.sup.1 represents [1] a hydrogen atom, [2] a cyano group,
or [3] a halogen atom;
[0246] R.sup.2 is selected from the group consisting of:
[0247] (1) a hydrogen atom,
[0248] (2) a C.sub.1-8 alkyl group,
[0249] (3) a cyano group,
[0250] (4) a halogen atom, and
[0251] (5) a (C.sub.1-8 alkyl).sub.m2-amino group which may be
substituted by C.sub.1-8 alkylsulfonyl group(s), [0252] m2:
0.about.2; [0253] R.sup.3 is selected from the group consisting
of:
[0254] (1) a hydrogen atom,
[0255] (2) a C.sub.1-8 alkyl group which may be substituted by
halogen atom(s),
[0256] (3) a cyano group,
[0257] (4) a (C.sub.1-8 alkyl).sub.m3a-aminocarbonyl group which
may be substituted by one or more R.sup.3A,
[0258] R.sup.3A: [1] a C.sub.6-10 aryl group, [2] a C.sub.1-8
alkoxy group, [3] a 5- to 14-membered heteroaryl group, or [4] a
C.sub.6-10 aryl sulfonyl group, [0259] m3a: 0.about.2,
[0260] (5) a hydroxycarbonyl group,
[0261] (6) a C.sub.1-8 alkoxycarbonyl group which may be
substituted by hydroxy group(s),
[0262] (7) a halogen atom,
[0263] (8) a (C.sub.1-8 alkyl).sub.m3b-amino group which may be
substituted by C.sub.6-10 aryl group(s), [0264] m3b: 0.about.2,
[0265] (9) a C.sub.1-8 alkylcarbonyl (C.sub.0-8 alkyl) amino group
which may be substituted by [1]C.sub.6-10 aryl group(s) or [2]
C.sub.6-10 aryloxy group(s),
[0266] (10) a C.sub.6-10 arylcarbonyl (C.sub.0-8 alkyl) amino group
which may be substituted by C.sub.1-8 alkyl group(s) which may be
substituted by halogen atom(s),
[0267] (11) a nitro group,
[0268] (12) a hydroxy group,
[0269] (13) a C.sub.1-8 alkoxy group which may be substituted by
one or more R.sup.3B
[0270] R.sup.3B: [1] a hydroxy group, [2] a C.sub.1-8 alkoxy group,
[3] a C.sub.6-10 aryl (C.sub.0-8 alkyl) aminocarbonyl group, [4] a
(C.sub.1-8 alkyl).sub.m3a-amino group, or [5] a halogen atom,
[0271] m3d: 0.about.2,
[0272] (14) a 4- to 10-membered heterocycloalkyloxy group,
[0273] (15) a 5- to 14-membered heteroaryloxy group,
[0274] (16) a (C.sub.1-8 alkyl).sub.m3e-aminocarbonyloxy group
which may be substituted by C.sub.6-10 aryl group(s), [0275] m3e:
0.about.2,
[0276] (17) a 4- to 10-membered nitrogen-containing
heterocycloalkylcarbonyl group,
[0277] (18) a C.sub.1-8 alkylthio group,
[0278] (19) a 5- to 14-membered heteroaryl group which may be
substituted by C.sub.1-8 alkyl group(s) which may be substituted by
C.sub.1-8 alkoxy group(s),
[0279] (20) a C.sub.1-8 alkoxycarbonyl (C.sub.0-8 alkyl) amino
group which may be substituted by C.sub.1-8 alkoxy group(s),
[0280] (21) a C.sub.6-10 aryloxycarbonyl (C.sub.0-8 alkyl) amino
group which may be substituted by C.sub.1-8 alkyl group(s) which
may be substituted by halogen atom(s),
[0281] (22) a C.sub.6-10 aryl (C.sub.0-8 alkyl) aminocarbonyl
(C.sub.0-8 alkyl) amino group which may be substituted by C.sub.1-8
alkoxy group(s),
[0282] (23) a C.sub.3-8 cycloalkyl (C.sub.0-8 alkyl)
aminocarbonyloxy group, and
[0283] (24) a C.sub.6-10 aryl (C.sub.0-8 alkyl) aminocarbonyloxy
group which may be substituted by substituent(s) selected from the
group consisting of [1] a C.sub.1-8 alkyl group and [2] a C.sub.1-8
alkoxy group;
[0284] R.sup.4 is selected from the group consisting of:
[0285] (1) a hydrogen atom,
[0286] (2) a C.sub.1-8 alkyl group which may be substituted by
halogen atom(s),
[0287] (3) a C.sub.3-8 cycloalkyl group,
[0288] (4) a cyano group,
[0289] (5) an aminocarbonyl group,
[0290] (6) a hydroxycarbonyl group,
[0291] (7) a halogen atom,
[0292] (8) a (C.sub.1-8 alkyl).sub.m4b-amino group, [0293] m4b:
0.about.2,
[0294] (9) a hydroxy group, and
[0295] (10) a C.sub.1-8 alkoxy group which may be substituted by
hydroxy group(s);
[0296] R.sup.5 is selected from the group consisting of:
[0297] (1) a hydrogen atom,
[0298] (2) a C.sub.1-8 alkyl group which may be substituted by one
or more R.sup.5A,
[0299] R.sup.5A: [1] a hydroxycarbonyl group, [2] a C.sub.1-8
alkoxycarbonyl group, [3] a hydroxy group, [4] a C.sub.1-8 alkoxy
group, [5] a (C.sub.1-8 alkyl).sub.m5-amino group, or [6], a
C.sub.1-8 alkylthio group, [0300] m5: 0.about.2, and
[0301] (3) a C.sub.1-8 alkylsulfonyl group;
[0302] R.sup.6 and R.sup.6' are each independently:
[0303] (1) a C.sub.1-8 alkyl group, or
[0304] R.sup.6 and R.sup.6' are taken together with the carbon
atoms to which they are bound to form,
[0305] (2) a C.sub.3-8 cycloalkyl group, or
[0306] (3) a 4- to 10-membered heterocycloalkyl group;
[0307] R.sup.7 is selected from the group consisting of:
[0308] (1) a hydrogen atom,
[0309] (2) a halogen atom, and
[0310] (3) a C.sub.1-8 alkoxy group which may be substituted by one
or more R.sup.7A,
[0311] R.sup.7A: [1] a (C.sub.1-8 alkyl).sub.m7a-amino group, or
[2] a hydroxy group, [0312] m7a:0-2;
[0313] R.sup.8 is selected from the group consisting of:
[0314] (1) a hydrogen atom,
[0315] (2) a C.sub.1-8 alkyl group which may be substituted by one
or more R.sup.8A, R.sup.5A: [1] a 4- to 10-membered
heterocycloalkyl group which may be substituted by one or more
R.sup.8A1, [2] a (C.sub.1-8 alkyl).sub.m8a-amino group which may be
substituted by a halogen atom, and [3] a hydroxy group, [0316]
m8a:0.about.2,
[0317] R.sup.8A1: [1] a C.sub.1-8 alkyl group, [2] a C.sub.1-8
alkylsulfonyl group, [3] a (C.sub.1-8 alkyl).sub.m8b-aminosulfonyl
group, or [4] an oxo group, [0318] m8b: 0.about.2,
[0319] (3) a C.sub.2-8 alkenyl group,
[0320] (4) a 4- to 10-membered heterocycloalkyl group which may be
substituted by one or more R.sup.8B,
[0321] R.sup.8B:
<1> a C.sub.1-8 alkyl group which may be substituted by one
or more R.sup.8B1 <2> a C.sub.2-8 alkynyl group, <3> a
C.sub.3-8 cycloalkyl group which may be substituted by [1] cyano
group(s) or [2] C.sub.1-8 alkyl group(s), <4> a 4- to
10-membered heterocycloalkyl group which may be substituted by one
or more R.sup.8B2 <5> a C.sub.1-8 alkoxy group which may be
substituted by substituent(s) selected from the group consisting of
[1] a C.sub.1-8 alkoxy group and [2] a C.sub.3-8 cycloalkyl group,
<6> a C.sub.1-8 alkylsulfonyl group, <7> an oxo group,
<8> a cyano group, <9> a C.sub.1-8 alkanoyl group which
may be substituted by one or more R.sup.8B3 <10> a C.sub.3-8
cycloalkylcarbonyl group, <11> a (C.sub.1-8
alkyl).sub.m8c-aminosulfonyl group, <12> a C.sub.1-8
alkylsulfonyl (C.sub.0-8 alkyl) amino group, <13> a
(C.sub.1-8 alkyl).sub.m8d-amino group which may be substituted by
one or more R.sup.8B4, <14> a hydroxy group, or <15> a
(C.sub.1-8 alkyl).sub.m8e-aminocarbonyl group, [0322] m8c:
0.about.2, [0323] m8d: 0.about.2, [0324] m8e: 0.about.2,
[0325] R.sup.8B1: [1] a C.sub.3-8 cycloalkyl group, [2] a hydroxy
group, or [3] C.sub.1-8 alkoxy group which may be substituted by
C.sub.1-8 alkoxy group(s),
[0326] R.sup.8B2: [1] a halogen atom, [2] a C.sub.1-8 alkyl group,
[3] an oxo group, or [4] a hydroxy group,
[0327] R.sup.8B3: a (C.sub.1-8 alkyl).sub.m8f-amino group, [0328]
m8f: 0.about.2,
[0329] R.sup.8B4: [1] a C.sub.3-8 cycloalkyl group, or [2] a
hydroxy group,
[0330] (5) a 5- to 14-membered heteroaryl group which may be
substituted by a C.sub.1-8 alkyl group,
[0331] (6) a (C.sub.1-8 alkyl).sub.m8g-aminocarbonyl group which
may be substituted by one or more R.sup.8C, [0332] m8g:
0.about.2,
[0333] R.sup.8C:[1] a hydroxy group, [2] a (C.sub.1-8
alkyl).sub.m8h-amino group which may be substituted by
substituent(s) selected from the group consisting of <1> a
(C.sub.1-8 alkyl).sub.m8i-aminosulfonyl group and <2> a
C.sub.1-8 alkylsulfonyl group, or [3] a C.sub.1-8 alkylsulfonyl
group, [0334] m8h: 0.about.2, [0335] m8i: 0.about.2,
[0336] (7) a 4- to 10-membered heterocycloalkyl (C.sub.0-8 alkyl)
aminocarbonyl group which may be substituted by oxo group(s),
[0337] (8) a 4- to 10-membered nitrogen-containing
heterocycloalkylcarbonyl group which may be substituted by one or
more R.sup.8D,
[0338] R.sup.8D: [1] a C.sub.1-8 alkyl group which may be
substituted by one or more R.sup.8D1, [2] a hydroxy group, or [3] a
C.sub.1-8 alkylsulfonyl group,
[0339] R.sup.8D1: [1] a hydroxy group, or [2] a C.sub.1-8 alkoxy
group,
[0340] (9) a hydroxycarbonyl group,
[0341] (10) a C.sub.0-8 alkoxy (C.sub.0-8 alkyl) aminocarbonyl
group which may be substituted by hydroxy group(s),
[0342] (11) a halogen atom,
[0343] (12) a (C.sub.1-8 alkyl).sub.m8j-amino group which may be
substituted by 4- to 10-membered heterocycloalkyl group(s), [0344]
m8j: 0.about.2,
[0345] (13) a hydroxyl group,
[0346] (14) a C.sub.1-8 alkoxy group which may be substituted by
one or more R.sup.8E, R.sup.8E:
<1> a hydroxy group, <2> a C.sub.1-8 alkoxycarbonyl
group, <3> a 4- to 10-membered nitrogen-containing
heterocycloalkylcarbonyl group which may be substituted by one or
more R.sup.8E1 <4> a (C.sub.1-8 alkyl).sub.m8k1-amino group
which may be substituted by one or more R.sup.8E2 [0347] m8k1:
0.about.2, <5> a 4- to 10-membered heterocycloalkyl group
which may be substituted by one or more R.sup.8E3 <6> a 5- to
14-membered heteroaryl group, <7> a (C.sub.1-8
alkyl).sub.m8k2-aminocarbonyl group which may be substituted by one
or more R.sup.8E6 [0348] m8k2: 0.about.2, <8> a C.sub.1-8
alkoxy group which may be substituted by one or more R.sup.8E7,
<9> a C.sub.1-8 alkylthio group, <10> a C.sub.1-8
alkylsulfinyl group, or <11> a C.sub.1-8 alkylsulfonyl
group,
[0349] R.sup.8E1:
<1> a C.sub.1-8 alkoxycarbonyl group, <2> a C.sub.1-8
alkanoyl group, <3> a C.sub.1-8 alkylsulfonyl group,
<4> a (C.sub.1-8 alkyl).sub.mk3-aminosulfonyl group [0350]
m8k3: 0.about.2, or <5> a 4- to 10-membered heterocycloalkyl
group,
[0351] R.sup.8E2:
<1> a hydroxy group, <2> a C.sub.1-8 alkoxycarbonyl
group, <3> a C.sub.3-8 cycloalkyl group which may be
substituted by C.sub.1-8 alkyl group(s) which may be substituted by
hydroxy group(s), <4> a C.sub.1-8 alkanoyl group which may be
substituted by substituent(s) selected from the group consisting of
[1] a (C.sub.1-8 alkyl).sub.mk4-amino group and [2] a halogen atom,
[0352] m8k4: 0.about.2, <5> a (C.sub.1-8
alkyl).sub.m8k5-aminocarbonyl group, [0353] m8k5: 0.about.2,
<6> a C.sub.1-8 alkylsulfonyl group, <7> a 4- to
10-membered nitrogen-containing heterocycloalkylsulfonyl group
which may be substituted by C.sub.1-8 alkyl group(s), <8> a
(C.sub.1-8 alkyl).sub.m8k6-aminosulfonyl group, [0354] m8k6:
0.about.2, or
[0355] R.sup.8E3:
<1> a C.sub.1-8 alkyl group which may be substituted by
substituent(s) selected from the group consisting of [1] a hydroxy
group and [2] a C.sub.1-8 alkylcarbonyloxy group, <2> a
hydroxy group, <3> a C.sub.3-8 cycloalkyl group, <4> a
C.sub.1-8 alkylsulfonyl group, <5> a (C.sub.1-8
alkyl).sub.m8k8-aminocarbonyl group, [0356] m8k8: 0.about.2,
<6> a C.sub.1-8 alkanoyl group which may be substituted by
hydroxy group(s), <7> an oxo group, or <8> a 4- to
10-membered heterocycloalkyl group which may be substituted by
substituent(s) selected from the group consisting of [1] a
C.sub.1-8 alkanoyl group, and [2] a C.sub.1-8 alkylsulfonyl
group,
[0357] R.sup.8E6:
<1> a C.sub.2-8 alkenylcarbonyloxy group, <2> a hydroxy
group, <3> a cyano group, <4> a (C.sub.1-8
alkyl).sub.m8k9-amino group which may be substituted by hydroxy
group(s), [0358] m8k9: 0.about.2, <5> a C.sub.1-8 alkoxy
group which may be substituted by hydroxy group(s), <6> a 4-
to 10-membered heterocycloalkyl group which may be substituted by
C.sub.1-8 alkyl group(s), or <7> a 5- to 14-membered
heteroaryl group,
[0359] R.sup.8E7:
<1> a hydroxy group, or <2> a C.sub.1-8 alkoxy group
which may be substituted by hydroxy group(s),
[0360] (15) a 4- to 10-membered heterocycloalkyloxy group which may
be substituted by one or more R.sup.8F:
[0361] R.sup.8F:
<1> a C.sub.1-8 alkyl group which may be substituted by one
or more R.sup.8F1 <2> a C.sub.3-8 cycloalkyl group, <3>
a C.sub.1-8 alkanoyl group which may be substituted by halogen
atom(s), <4> a C.sub.1-8 alkoxycarbonyl group, <5> a 4-
to 10-membered heterocycloalkyl group which may be substituted by
one or more R.sup.8F2 <6> a C.sub.1-8 alkyl sulfonyl group,
or <7> a hydroxy group,
[0362] R.sup.8F1: [1] a hydroxy group, [2] a C.sub.1-8 alkoxy
group, or [3] a halogen atom,
[0363] R.sup.8F2: [1] a 4- to 10-membered heterocycloalkyl group,
[2] a C.sub.1-8 alkoxycarbonyl group, or [3] a C.sub.1-8
alkylsulfonyl group,
[0364] (16) a 5- to 14-membered heteroaryloxy group,
[0365] (17) a (C.sub.1-8 alkyl).sub.m8l1-aminosulfonyloxy group,
[0366] m8l1: 0.about.2,
[0367] (18) a C.sub.1-8 alkylthio group which may be substituted by
(C.sub.1-8 alkyl).sub.m8l2-amino group(s), [0368] m8l2:
0.about.2,
[0369] (19) a C.sub.1-8 alkylsulfonyl group which may be
substituted by one or more R.sup.8G,
[0370] R.sup.8G: [1] a hydroxycarbonyl group, [2] a hydroxy group,
or [3] a (C.sub.1-8 alkyl).sub.m8l3-amino group, [0371] m8l3:
0.about.2,
[0372] (20) a C.sub.2-8 alkenyloxy group, and
[0373] (21) a C.sub.1-8 alkylsulfonyloxy group which may be
substituted by halogen atom(s);
[0374] R.sup.9 is selected from the group consisting of:
[0375] (1) a hydrogen atom,
[0376] (2) a C.sub.1-8 alkyl group which may be substituted by one
or more R.sup.9A,
[0377] R.sup.9A: [1] a C.sub.3-8 cycloalkyl group, [2] a 4- to
10-membered heterocycloalkyl group which may be substituted by one
or more R.sup.9A, [3] a hydroxy group, or [4] a C.sub.1-8 alkoxy
group,
[0378] R.sup.9A1: [1] a C.sub.1-8 alkyl group, [2] a C.sub.3-8
cycloalkyl group, or [3] a 4- to 10-membered heterocycloalkyl
group,
[0379] (3) a C.sub.2-8 alkenyl group,
[0380] (4) a C.sub.2-8 alkynyl group which may be substituted by
one or more R.sup.9C,
[0381] R.sup.9C: [1] a C.sub.1-8 alkoxy group, [2] a (C.sub.1-8
alkyl).sub.m9b-amino group which may be substituted by C.sub.6-10
aryl group(s), [3] a 4- to 10-membered heterocycloalkyl group which
may be substituted by one or more R.sup.9C1, [4] a C.sub.3-8
cycloalkyl group, [5] a hydroxy group, or [6] a hydroxycarbonyl
group, [0382] m9b: 0.about.2,
[0383] R.sup.9C1: [1] a C.sub.3-8 cycloalkyl group, [2] a 4- to
10-membered heterocycloalkyl group, or [3] an oxo group,
[0384] (5) a C.sub.3-8 cycloalkyl group,
[0385] (6) a 4- to 10-membered heterocycloalkyl group which may be
substituted by one or more R.sup.9D
[0386] R.sup.9D: [1] a C.sub.1-8 alkyl group which may be
substituted by 4- to 10-membered heterocycloalkyl group(s), [2] a
C.sub.3-8 cycloalkyl group, [3] a 4- to 10-membered
heterocycloalkyl group, or [4] a C.sub.1-6 alkylsulfonyl group,
[0387] (7) a C.sub.6-10 aryl group which may be substituted by one
or more R.sup.9E
[0388] R.sup.9E: [1] a halogen atom, [2] a hydroxy group, [3] a
hydroxycarbonyl group, or [4] a C.sub.1-8 alkyl group which may be
substituted by hydroxy group(s),
[0389] (8) a 5- to 14-membered heteroaryl group which may be
substituted by C.sub.1-8 alkyl group(s),
[0390] (9) a cyano group,
[0391] (10) a C.sub.1-8 alkanoyl group,
[0392] (11) a 4- to 10-membered nitrogen-containing
heterocycloalkylcarbonyl group which may be substituted by
C.sub.1-8 alkyl group(s),
[0393] (12) a halogen atom,
[0394] (13) a (C.sub.1-8 alkyl).sub.m9c-amino group, [0395] m9c:
0.about.2,
[0396] (14) a C.sub.1-8 alkylcarbonyl(C.sub.0-8 alkyl)amino group
which may be substituted by (C.sub.1-8 alkyl).sub.m9d-amino
group(s), [0397] m9d: 0.about.2,
[0398] (15) a C.sub.1-8 alkylsulfonyl(C.sub.0-8 alkyl)amino
group,
[0399] (16) a (C.sub.1-8 alkyl).sub.m9e-aminosulfonyl(C.sub.0-8
alkyl)amino group, [0400] m9e: 0.about.2,
[0401] (17) a nitro group,
[0402] (18) a hydroxy group,
[0403] (19) a C.sub.1-8 alkoxy group which may be substituted by
one or more R.sup.9G
[0404] R.sup.9G: [1] a hydroxy group, [2] a hydroxycarbonyl group,
[3] a C.sub.6-10 aryl group which may be substituted by C.sub.1-8
alkoxy group(s), [4] a (C.sub.1-8 alkyl).sub.m9g1-amino group, [5]
a C.sub.1-8 alkoxy group which may be substituted by one or more
R.sup.9G1, or [6] a 5- to 14-membered heteroaryl group, [0405]
m9g1: 0.about.2,
[0406] R.sup.9G1: [1] a C.sub.1-8 alkoxy group, or [2] a
hydroxycarbonyl group,
[0407] (20) a 4- to 10-membered heterocycloalkyloxy group which may
be substituted by 4- to 10-membered heterocycloalkyl group(s),
[0408] (21) a C.sub.1-8 alkylthio group which may be substituted by
(C.sub.1-8 alkyl).sub.m9f-amino group(s), [0409] m9f:
0.about.2,
[0410] (22) a C.sub.1-8 alkylsulfonyl group which may be
substituted by (C.sub.1-8 alkyl).sub.m9g-amino group(s), [0411]
m9g: 0.about.2,
[0412] (23) a (C.sub.1-8 alkyl).sub.m9h-aminosulfonyl group, [0413]
m9h: 0.about.2, and
[0414] (24) a 4- to 10-membered nitrogen-containing
heterocycloalkylsulfonyl group which may be substituted by
C.sub.1-8 alkyl group(s);
[0415] R.sup.10 represents [1] a hydrogen atom, or [2] a 4- to
10-membered heterocycloalkyl group which may be substituted by 4-
to 10-membered heterocycloalkyl group(s)].
[6] A compound according to claim 1, or salt or solvate thereof,
which said compound is selected from the group consisting of:
[0416]
9-(4-isopropyl-piperazin-1-yl)-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[-
b]carbazole-3-carbonitrile; [0417]
6,6-dimethyl-8-(4-oxetan-3-yl-piperazin-1-yl)-11-oxo-9-prop-1-ynyl-6,11-d-
ihydro-5H-benzo[b]carbazole-3-carbonitrile; [0418]
9-cyclopropylethynyl-6,6-dimethyl-8-(4-oxetan-3-yl-piperazin-1-yl)-11-oxo-
-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile; [0419]
6,6-dimethyl-8-(1-oxetan-3-yl-piperidin-4-yl)-11-oxo-6,11-dihydro-5H-benz-
o[b]carbazole-3-carbonitrile; [0420]
9-bromo-6,6-dimethyl-8-(4-oxetan-3-yl-piperazin-1-yl)-11-oxo-6,11-dihydro-
-5H-benzo[b]carbazole-3-carbonitrile; [0421]
9-bromo-8-(4-cyclopropyl-piperazin-1-yl)-6,6-dimethyl-11-oxo-6,11-dihydro-
-5H-benzo[b]carbazole-3-carbonitrile; [0422]
9-chloro-6,6-dimethyl-8-(4-morpholin-4-yl-piperidin-1-yl)-11-oxo-6,11-dih-
ydro-5H-benzo[b]carbazole-3-carbonitrile; [0423]
8-(4-cyclobutyl-piperazin-1-yl)-6,6-dimethyl-11-oxo-9-prop-1-ynyl-6,11-di-
hydro-5H-benzo[b]carbazole-3-carbonitrile; [0424]
6,6,9-trimethyl-8-(4-morpholin-4-yl-piperidin-1-yl)-11-oxo-6,11-dihydro-5-
H-benzo[b]carbazole-3-carbonitrile; [0425]
9-ethyl-6,6-dimethyl-8-(4-oxetan-3-yl-piperazin-1-yl)-11-oxo-6,11-dihydro-
-5H-benzo[b]carbazole-3-carbonitrile; [0426]
9-ethyl-6,6-dimethyl-8-(4-morpholin-4-yl-piperidin-1-yl)-11-oxo-6,11-dihy-
dro-5H-benzo[b]carbazole-3-carbonitrile; [0427]
9-ethynyl-6,6-dimethyl-8-(4-oxetan-3-yl-piperazin-1-yl)-11-oxo-6,11-dihyd-
ro-5H-benzo[b]carbazole-3-carbonitrile; [0428]
8-(4-cyclobutyl-piperazin-1-yl)-9-ethyl-6,6-dimethyl-11-oxo-6,11-dihydro--
5H-benzo[b]carbazole-3-carbonitrile; [0429]
9-ethynyl-6,6-dimethyl-11-oxo-8-(4-pyrrolidin-1-yl-piperidin-1-yl)-6,11-d-
ihydro-5H-benzo[b]carbazole-3-carbonitrile; [0430]
6,6-dimethyl-11-oxo-8-(4-pyrrolidin-1-yl-piperidin-1-yl)-6,11-dihydro-5H--
benzo[b]carbazole-3-carbonitrile; [0431]
8-(4-cyclobutyl-piperazin-1-yl)-9-ethynyl-6,6-dimethyl-11-oxo-6,11-dihydr-
o-5H-benzo[b]carbazole-3-carbonitrile; [0432]
8-(4-cyclobutyl-piperazin-1-yl)-6,6-dimethyl-11-oxo-9-propyl-6,11-dihydro-
-5H-benzo[b]carbazole-3-carbonitrile; [0433]
8-(1-isopropyl-piperidin-4-yl)-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[-
b]carbazole-3-carbonitrile; [0434]
8-(4-isopropyl-piperazin-1-yl)-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[-
b]carbazole-3-carbonitrile; [0435]
8-(4-cyclobutyl-piperazin-1-yl)-9-cyclopropyl-6,6-dimethyl-11-oxo-6,11-di-
hydro-5H-benzo[b]carbazole-3-carbonitrile; [0436]
8-(2-tert-butylamino-ethoxy)-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]-
carbazole-3-carbonitrile; [0437]
9-ethynyl-8-(4-methanesulfonyl-piperazin-1-yl)-6,6-dimethyl-11-oxo-6,11-d-
ihydro-5H-benzo[b]carbazole-3-carbonitrile; [0438]
9-bromo-8-(4-cyclobutyl-piperazin-1-yl)-6,6-dimethyl-11-oxo-6,11-dihydro--
5H-benzo[b]carbazole-3-carbonitrile; [0439]
6,6-dimethyl-8-(4-oxetan-3-yl-piperazin-1-yl)-11-oxo-9-propyl-6,11-dihydr-
o-5H-benzo[b]carbazole-3-carbonitrile; and [0440]
9-ethynyl-6,6-dimethyl-8-morpholin-4-yl-11-oxo-6,11-dihydro-5H-benzo[b]ca-
rbazole-3-carbonitrile. [7] A medicament comprising as an active
ingredient the compound according to any one of the above [1] to
[5], or a salt or solvate thereof. [8] An ALK inhibitor comprising
as an active ingredient the compound according to any one of the
above [1] to [5], or a salt or solvate thereof. [9] A
pharmaceutical for the prophylaxis or treatment of cancer, cancer
metastasis, depression or cognitive function disorder, comprising
as an active ingredient the compound according to any one of the
above [1] to [5], or a salt or solvate thereof. [10] A
pharmaceutical composition comprising the compound according to any
one of the above [1] to [5], or a salt or solvate thereof and a
pharmaceutically acceptable carrier(s). [11] A method of treating a
patient suffering from the disease including cancer, cancer
metastasis, depression or cognitive function disorder, comprising
administering to the patient who is in need of the treatment of the
disease the compound described in any one of the above [1] to [5],
salt or solvate thereof in an effective amount for the treatment of
the disease. [12] Use of the compound described in any one of the
above [1] to [5], salt or solvate thereof in the manufacture of a
pharmaceutical. [13] The use according to above [11] in the
manufacture of a pharmaceutical composition for the treatment or
prophylaxis of the disease of mammals including human, wherein the
disease is related with ALK activity.
Effect of the Invention
[0441] The compounds of the present invention or salts or salvates
thereof have an excellent activity of inhibiting ALK, excellent
stability in organisms, and excellent solubility in water, and
therefore are useful as a prophylactic or therapeutic agent for
proliferative disorders (in particular, therapeutic agent).
Further, the compounds of the present invention or salts salts or
solvates thereof are useful as a prophylactic or therapeutic agent
(in particular, therapeutic agent) for various diseases such as
cancers including leukemia (acute myelogenous leukemia, chronic
myelogenous leukemia, acute lymphatic leukemia, chronic lymphatic
leukemia and the like), malignant lymphoma (Hodgkin lymphoma,
non-Hodgkin lymphoma and the like), brain tumor, neuroblastoma,
gliomatosis, thyroid cancer, myelodysplastic syndrome, head and
neck cancer, esophageal cancer, stomach cancer, colon cancer,
colorectal cancer, breast cancer, ovarian cancer, lung cancer,
pancreatic cancer, liver cancer, gall bladder cancer, skin cancer,
malignant melanoma, kidney cancer, renal pelvis-ureter cancer,
bladder cancer, uterine cancer, testicle cancer, prostate cancer,
and the like. Further, the compounds of the present invention are
useful as a prophylactic or therapeutic agent (in particular,
therapeutic agent) for infiltration/metastasis of solid tumors.
Still further, the compounds of the present invention are useful as
a prophylactic or therapeutic agent for other diseases that are
related with ALK, for example, depression or a cognitive function
disorder.
[0442] The method of the present invention comprises a step of
administering a pharmaceutically effective amount of the
pharmaceutical composition comprising the compounds of the present
invention or salts or solvates thereof to a patient who is in need
of such treatment or suffers from such diseases or conditions.
MODE FOR CARRYING OUT THE INVENTION
[0443] Hereinbelow, the compounds of the present invention, the
method of preparing the same, and the pharmaceutical agent
comprising the same will be explained.
Definition
[0444] According to the present invention, the "halogen atom" means
a fluorine atom, a chlorine atom, a bromine atom, an iodine atom
and the like. According to the present invention, when the halogen
atom is a substituent group for an aromatic carbon ring, an
aromatic heterocycle and the like, the preferred halogen atom
includes a fluorine atom, a chlorine atom and a bromine atom.
According to the present invention, when the halogen atom is a
substituent group for an alkyl group or a group which comprises the
alkyl as at least a part of the group (e.g., alkoxy, alkenyl,
unsaturated carbocycle, unsaturated heterocycle and the like), the
preferred halogen atom includes a fluorine atom. Specifically,
examples thereof include a trifluoromethyl group, a
pentafluoroethyl group, a heptafluoropropyl group, a
nonafluorobutyl group, a trifluoromethoxy group, a
pentafluoroethoxy group, a heptafluoropropoxy group, a
nonafluorobutoxy group, a trifluoroacetyl group, a
pentafluoropropionyl group, a heptafluorobutyryl group and a
nonafluoropentanoyl group.
[0445] The "C.sub.1-8 alkyl group" means a monovalent group which
is derived by removing any one of hydrogen atoms from a linear or
branched aliphatic hydrocarbon having 1 to 8 carbon atoms.
Specifically, examples thereof include a methyl group, an ethyl
group, an isopropyl group, a butyl group, a n-butyl group, an
isobutyl group, a sec-butyl group, a t-butyl group, a pentyl group,
an isopentyl group, a 2,3-dimethyl propyl group, a hexyl group, a
2,3-dimethyl hexyl group, a 1,1-dimethyl pentyl group, a heptyl
group and an octyl group. Preferably, it is a C.sub.1-6 alkyl
group, more preferably a C.sub.1-5 alkyl group, still more
preferably a C.sub.1-4 alkyl group, and still even more preferably
a C.sub.1-3 alkyl group.
[0446] The "C.sub.1-8 alkyl group which may be substituted" means
an unsubstituted C.sub.1-8 alkyl group or a C.sub.1-8 alkyl group
of which at least one hydrogen atom on the alkyl group is
substituted by a defined substituent(s). When two or more
substituent groups are present, each substituent group can be the
same or different from each other. In addition, the alkyl group may
be substituted by a cyclic substituent group through a spiro bond.
Preferably, it is a C.sub.1-8 alkyl group which may be substituted
by 1 to 3 substituent(s). More preferably, it is 1 to 3
substituent(s) for C.sub.1-6 alkyl group and a C.sub.1-4 alkyl
group, and 1 to 2 substituent(s) for a C.sub.1-3 alkyl group.
[0447] The "C.sub.2-8 alkenyl group" means a monovalent group
wherein at least one double bond (two adjacent SP2 carbon atoms) is
comprised in a linear or branched aliphatic hydrocarbon group
having 1 to 8 carbon atoms. Specific examples of the C.sub.2-8
alkenyl group include a vinyl group, an allyl group, a 1-propenyl
group, a 2-propenyl group, a 1-butenyl group, a 2-butenyl group
(including both cis and trans), a 3-butenyl group, a pentenyl group
and a hexenyl group. Preferably, it is a C.sub.2-6 alkenyl group,
more preferably a C.sub.2-5 alkenyl group, still more preferably a
C.sub.2-4 alkenyl group, and still even more preferably a C.sub.2-3
alkenyl group.
[0448] The "C.sub.2-8 alkenyl group which may be substituted" means
the unsubstituted C.sub.2-8 alkenyl group described above or a
C.sub.2-8 alkenyl group of which at least one hydrogen atom on the
alkenyl group is substituted by a defined substituent(s). When two
or more substituent groups are present, each substituent group can
be the same or different from each other. In addition, the
single-bonded carbon atom may be substituted by a cyclic
substituent group through a spiro bond. Preferably, it is a
C.sub.2-8 alkenyl group which may be substituted by 1 to 3
substituent(s). More preferably, it is 1 to 3 substituent(s) for a
C.sub.2-6 alkenyl group and a C.sub.2-4 alkenyl group, 1 to 2
substituent(s) for a C.sub.2-3 alkenyl group.
[0449] The "C.sub.2-8 alkynyl group" means a monovalent group
wherein at least one triple bond (two adjacent SP carbon atoms) is
comprised in a linear or branched aliphatic hydrocarbon group
having 1 to 8 carbon atoms. Specific examples of the C.sub.2-8
alkynyl group include an ethynyl group, a 1-propynyl group, a
propargyl group and a 3-butynyl group. Preferably, it is a
C.sub.2-6 alkynyl group, more preferably a C.sub.2-5 alkynyl group,
still more preferably a C.sub.2-4 alkynyl group, and still even
more preferably a C.sub.2-3 alkynyl group.
[0450] The "C.sub.2-8 alkynyl group which may be substituted" means
the unsubstituted C.sub.2-8 alkynyl group described above or a
C.sub.2-8 alkynyl group of which at least one hydrogen atom on the
alkynyl group is substituted by a defined substituent(s). When two
or more substituent groups are present, each substituent group can
be the same or different from each other. In addition, the
single-bonded carbon atom may be substituted by a cyclic
substituent group through a spiro bond. Preferably, it is a
C.sub.2-8 alkynyl group which may be substituted by 1 to 3
substituent(s). More preferably, it is 1 to 3 substituent(s) for a
C.sub.2-6 alkynyl group and a C.sub.2-4 alkynyl group, and 1 to 2
substituent(s) for C.sub.2-3 alkynyl group.
[0451] The "C.sub.3-8 cycloalkyl group" means an aliphatic
hydrocarbon group in cyclic form. Preferably, it includes a
C.sub.3-6 cycloalkyl group. Specifically, examples thereof include
a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a
cyclohexyl group, a cycloheptyl group and a cyclooctyl group.
Preferably, it is a C.sub.3-6 cycloalkyl group.
[0452] The "C.sub.3-8 cycloalkyl group which may be substituted"
means the unsubstituted C.sub.3-8 cycloalkyl group described above
or a C.sub.3-8 cycloalkyl group of which at least one hydrogen atom
is substituted by a defined substituent group(s). When two or more
substituent groups are present, each substituent group can be the
same or different from each other. In addition, the single-bonded
carbon atom may be substituted by a cyclic substituent group
through a spiro bond. Preferably, it is a C.sub.3-8 cycloalkyl
group which may be substituted by 1 to 3 substituent(s).
[0453] The "4- to 10-membered heterocycloalkyl group" means a
saturated or partially unsaturated heterocyclic group which
consists of 4 to 10 ring-constituting atoms and comprises 1 to 3
hetero atoms that are selected from O, S and N. The
heterocycloalkyl group can be a monocyclic, a bicyclic or a
spirocyclic type heterocycloalkyl group. Specifically, examples
thereof include an oxetanyl group, a tetrahydrofuryl group, a
tetrahydrothienyl group, a tetrahydropyranyl group, a pyrrolidino
group, a pyrrolidinyl group, a piperidino group, a piperidinyl
group, a piperazino group, a piperazinyl group, a morpholino group,
a morpholinyl group, a tetrahydrothiopyranyl group, a
thiomorpholino group, an imidazolidinyl group, a 1,3-dioxolanyl
group, a tetrahydropyranyl group, a 1,3-dioxanyl group, a
1,2,3,6-tetrahydropyridinyl group, a
1,4-Dioxa-8-aza-spiro[4.5]decanyl group, and a
1-oxa-8-aza-spiro[4.5]decanyl group. Preferably, it is a 4- to
8-membered heterocycloalkyl group, more preferably, 4- to
6-membered heterocycloalkyl group.
[0454] The "4- to 10-membered heterocycloalkyl group which may be
substituted" means the unsubstituted 4- to 10-membered
heterocycloalkyl group described above or a 4- to 10-membered
heterocycloalkyl group of which at least one hydrogen atom on the
heterocycloalkyl group is substituted by a defined substituent(s).
When two or more substituent groups are present, each substituent
group can be the same or different from each other. In addition,
the alkyl group may be substituted by a cyclic substituent group
through a spiro bond. Preferably, it is a 4-to 10-membered
heterocycloalkyl group which may be substituted by 1 to 4
substituent(s). More preferably, it is 1 to 4 substituent(s) for a
4- to 8-membered heterocycloalkyl group, and 1 to 3 substituent(s)
for a 4- to 6-membered heterocycloalkyl group. When the substituent
is an oxo group, 2 oxo group can combine with the same sulfur atom.
When the salt is formed, 2 alkyl group can combine with the same
nitrogen atom.
[0455] The "C.sub.6-10 aryl group" means a monovalent aromatic
hydrocarbon ring. Specific examples of the C.sub.6-10 aryl group
include a phenyl group, a 1-naphthyl group and a 2-naphthyl group.
Preferably, it is a C.sub.6 aryl group or a C.sub.10 aryl
group.
[0456] The "C.sub.6-10 aryl group which may be substituted" means
the unsubstituted C.sub.6-10 aryl group described above or a
C.sub.6-10 aryl group of which at least one hydrogen atom is
substituted by a defined substituent group(s). When two or more
substituent groups are present, each substituent group can be the
same or different from each other. Preferably, it is a C.sub.6-10
aryl group which may be substituted by 1 to 3 substituent(s).
[0457] The "5- to 14-membered heteroaryl group" means an aromatic
cyclic group comprising one or more hetero atoms among 5 to 14
ring-constituting atoms. The cycle can be a monocyclic or bicyclic
heteroaryl group fused to a benzene ring or a monocyclic heteroaryl
ring. Specific examples thereof include a furyl group, a thienyl
group, a pyrrolyl group, an imidazolyl group, a pyrazolyl group, a
thiazolyl group, an isothiazolyl group, an oxazolyl group, an
isooxazolyl group, an oxadiazolyl group, a thiadiazolyl group, a
triazolyl group, a tetrazolyl group, a pyridyl group, a pyrimidyl
group, a pyridazinyl group, a pyrazinyl group, a triazinyl group, a
benzofuranyl group, a benzothienyl group, a benzothiadiazolyl
group, a benzothiazolyl group, a benzoxazolyl group, a
benzoxadiazolyl group, a benzoimidazolyl group, an indolyl group,
an isoindolyl group, an indazolyl group, a quinolyl group, an
isoquinolyl group, a cinnolinyl group, a quinazolinyl group, a
quinoxalinyl group, a benzodioxolyl group, an indolizinyl group, an
imidazopyridyl group and the like. Preferably, it is a 5- to
6-membered heteroaryl group.
[0458] The "5- to 14-membered heteroaryl group which may be
substituted" means the unsubstituted 5- to 14-membered ring
heteroaryl group described above or a 5- to 14-membered ring
heteroaryl group of which at least one hydrogen atom on the
heteroaryl group is substituted by a defined substituent(s). When
two or more substituent groups are present, each substituent group
can be the same or different from each other. Preferably, it is a
5- to 14-membered heteroaryl group which may be substituted by 1 to
3 substituent(s). More preferably, it is 1 to 3 substituent(s) or 1
to 2 substituent(s) for a 5- to 6-membered heteroaryl group.
[0459] The "C.sub.1-8 alkanoyl group" means a C.sub.1-8
alkyl-C(O)-- group, and the C.sub.1-8 alkyl group is described
above. Specifically, examples thereof include acetyl, propionyl,
butyryl, isobutyryl, pentanoyl, tert-butylcarbonyl and a hexanoyl
group. Preferably, it is a C.sub.1-6 alkanoyl group, and more
preferably a C.sub.1-3 alkanoyl group.
[0460] The "C.sub.1-8 alkanoyl group which may be substituted"
means the unsubstituted C.sub.1-8 alkanoyl group described above or
a C.sub.1-8 alkanoyl group of which at least one hydrogen atom on
the alkanoyl group is substituted by a defined substituent(s). When
two or more substituent groups are present, each substituent group
can be the same or different from each other. Preferably, it is a
C.sub.1-8 alkanoyl group which may be substituted by 1 to 3
substituent(s). More preferably, it is 1 to 2 substituent(s) for a
C.sub.1-6 alkanoyl group and a C.sub.1-3 alkanoyl group.
[0461] The "C.sub.3-8 cycloalkylcarbonyl group" means a C.sub.3-8
cycloalkyl-C(O)-- group, and the C.sub.3-8 cycloalkyl group is
described above. Specifically, examples thereof include a
cyclopropylcarbonyl group, a cyclobutylcarbonyl group, a
cyclopentylcarbonyl group, a cyclohexylcarbonyl group, a
cycloheptylcarbonyl group and a cyclooctylcarbonyl group.
[0462] The "4- to 10-membered heterocycloalkylcarbonyl group" means
a 4- to 10-membered heterocycloalkyl-CO-- group, and the 4- to
10-membered heterocycloalkyl is described above.
[0463] The "4- to 10-membered heterocycloalkylcarbonyl group which
may be substituted" means the unsubstituted 4- to 10-membered
heterocycloalkylcarbonyl group described above or a 4- to
10-membered heterocycloalkylcarbonyl group in which at least one
hydrogen atom of the heterocycloalkyl moiety is substituted by a
defined substituent(s). When two or more substituent groups are
present, each substituent group can be the same or different from
each other. In addition, the heterocycloalkyl moiety may be
substituted by a cyclic substituent group through a spiro bond.
Preferably, it is a 4-to 10-membered heterocycloalkylcarbonyl group
which may be substituted by 1 to 3 substituent(s).
[0464] The "aminocarbonyl group which may be substituted" means an
unsubstituted aminocarbonyl group or an aminocarbonyl group in
which one or two hydrogen atoms on the nitrogen atom are
substituted by a defined substituent(s). When two substituent
groups are present, each substituent group can be the same or
different from each other.
[0465] The "C.sub.3-8 cycloalkyl (C.sub.0-8 alkyl) aminocarbonyloxy
group" means a C.sub.3-8 cycloalkyl-NHC(O)O-- group or a C.sub.3-8
cycloalkyl-N(C.sub.1-8 alkyl) C(O)O-- group, and the C.sub.3-8
cycloalkyl group is described above. Specifically, examples thereof
include a cyclopropylaminocarbonyloxy group, a
cyclobutylaminocarbonyloxy group, a cyclopentylaminocarbonyloxy
group, a cyclohexylaminocarbonyloxy group, a
cyclopropyl(N-methyl)aminocarbonyloxy group, and a
cyclobutyl(N-methyl)aminocarbonyloxy group.
[0466] The "(C.sub.1-8 alkyl).sub.x-aminocarbonyl group", wherein x
is a symbol defined in claims, means a NH.sub.2C(O)-- group, a
(C.sub.1-8 alkyl)NH--C(O)-- group, or a (C.sub.1-8
alkyl).sub.2N--C(O)-- group. Specifically, examples thereof include
a N-methyl-aminocarbonyl group, N-ethyl-aminocarbonyl group,
N-n-buthyl-aminocarbonyl group, a N,N-dimethyl-aminocarbonyl
group.
[0467] The "(C.sub.1-8 alkyl).sub.x-aminocarbonyl group which may
be substituted" means an unsubstituted (C.sub.1-8
alkyl).sub.x-aminocarbonyl group described above or an (C.sub.1-8
alkyl).sub.x-aminocarbonyl group in which at least one hydrogen
atom on the nitrogen atom or the alkyl moiety are substituted by a
defined substituent(s). When plural substituent groups are present,
each substituent group can be the same or different from each
other.
[0468] The "C.sub.6-10 aryl(C.sub.0-8 alkyl)aminocarbonyl group"
means a C.sub.6-10 aryl-NHC(O)-- group, or a C.sub.6-10
aryl-N(C.sub.1-8 alkyl)-C(O)-- group. Specifically, examples
thereof include a phenyl-NHC(O)-- group, or a
phenyl-(N-methyl)-aminocarbonyl group, wherein the C.sub.6-10 aryl
group and C.sub.1-8 alkyl are described above. Specifically,
examples thereof include a phenylaminocarbonylamino group and a
phenylaminocarbonyl(N-methyl)amino group.
[0469] The "4- to 10-membered nitrogen-containing
heterocycloalkylcarbonyl group" means a carbonyl group to which a
4- to 10-membered nitrogen-containing heterocycloalkyl group is
bonded. Herein, the 4- to 10-membered nitrogen-containing
heterocycloalkyl group (i.e., 4- to 10-membered heterocycloalkyl
group comprising a nitrogen atom(s)) means a heterocycloalkyl group
which consists of 4 to 10 ring-constituting atoms and comprises at
least one nitrogen atom as a hetero atom. Preferably, it is bonded
to the carbonyl group via a nitrogen atom that is comprised in the
heterocycloalkyl ring. Specific examples of the 4- to 10-membered
nitrogen-containing heterocycloalkyl group include a pyrrolidinyl
group, an imidazolidinnyl group, a morpholino group, a
thiomorphorino group, a piperazino group and a piperidino group. As
for the 4- to 10-membered nitrogen-containing
heterocycloalkylcarbonyl group, examples thereof include a
pyrrolidinocarbonyl group, a piperidinocarbonyl group, a
piperazinocarbonyl group and a morpholinocarbonyl group.
[0470] The "4- to 10-membered nitrogen-containing
heterocycloalkylcarbonyl group, which may be substituted" means the
unsubstituted 4- to 10-membered nitrogen-containing
heterocycloalkylcarbonyl group as described above or a 4- to
10-membered heterocycloalkylcarbonyl group in which at least one
hydrogen atom of the heterocycloalkyl moiety is substituted by a
defined substituent(s). When two or more substituent groups are
present, each substituent group can be the same or different from
each other. In addition, the heterocycloalkyl moiety may be
substituted by a cyclic substituent group through a spiro bond.
Preferably, it is a 4- to 10-membered nitrogen-containing
heterocycloalkylcarbonyl group which may be substituted by 1 to 3
substituent(s).
[0471] The "4- to 10-membered heterocycloalkyl (C.sub.0-8 alkyl)
aminocarbonyl group" means 4- to 10-membered heterocycloalkyl
NHC(O)-- group, or a 4- to 10-membered heterocycloalkyl N(C.sub.1-8
alkyl)-C(O)-- group. Specifically, examples thereof include a
oxetan-3-yl amide group, and a
(1,1-dioxo-tetrahydro-thiophen-3-yl)-amide group.
[0472] The "4- to 10-membered heterocycloalkyl (C.sub.0-8 alkyl)
aminocarbonyl group which may be substituted by one or more oxo
groups" means the unsubstituted 4- to 10-membered
heterocycloalkylaminocarbonyl group described above or the 4- to
10-membered heterocycloalkylaminocarbonyl group in which the
heterocycloalkyl moiety is substituted by at least one oxo
group.
[0473] The "C.sub.6-10 arylsulfonyl group" means a C.sub.6-10
aryl-S(O).sub.2-- group and the C.sub.6-10 aryl group is described
above. Specifically, examples thereof include a phenylsulfonyl
group.
[0474] The "5- to 14-membered heteroarylsulfonyl group" means a 5-
to 14-membered heteroaryl-S(O).sub.2-- group, and the 5- to
14-membered heteroaryl is described above. Specifically, examples
thereof include a imidazol-sulfonyl group.
[0475] The "(C.sub.1-8 alkyl).sub.x-amino group", wherein x is a
symbol defined in claims, means an amino group, a NH(C.sub.1-8
alkyl) group, or a N(C.sub.1-8 alkyl).sub.2- group. Specifically,
examples thereof include amino, methylamino, ethylamino,
butylamino, isopropylamino, dimethylamino and diethylamino.
Preferably, it is a C.sub.1-3 alkylamino group.
[0476] The "(C.sub.1-8 alkyl).sub.x-amino group which may be
substituted" means an unsubstituted (C.sub.1-8 alkyl).sub.x-amino
group or an amino group in which one or two hydrogen atoms on the
nitrogen atom or the alkyl moiety are substituted by a defined
substituent(s). When two substituent groups are present, each
substituent group can be the same or different from each other.
[0477] The "C.sub.1-8 alkylcarbonyl (C.sub.0-8 alkyl) amino group"
means a C.sub.1-8 alkyl-C(O)--NH-- group or a C.sub.1-8
alkyl-C(O)--N(C.sub.1-8 alkyl)- group, and the C.sub.1-8 alkyl is
described above. Specifically, examples thereof include a
methylcarbonylamino group, an ethylcarbonylamino group, a
propylcarbonylamino group and a butylcarbonylamino group.
[0478] The "C.sub.1-8 alkylcarbonyl (C.sub.0-8 alkyl) amino group
which may be substituted" means the unsubstituted C.sub.1-8
alkylcarbonyl (C.sub.0-8 alkyl) amino group described above or the
C.sub.1-8 alkylcarbonyl (C.sub.0-8 alkyl) amino group in which at
least one hydrogen atoms of the terminal alkyl moiety is
substituted by a defined substituent(s). When two or more
substituent groups are present, each substituent group can be the
same or different from each other. In addition, the alkyl moiety
may be substituted by a cyclic substituent group through a spiro
bond. Preferably, it is a C.sub.1-8 alkylcarbonyl (C.sub.0-8 alkyl)
amino group which may be substituted by 1 to 3 substituent(s).
[0479] The "C.sub.6-10 arylcarbonyl (C.sub.0-8 alkyl) amino group"
means a C.sub.6-10 aryl-C(O)--NH-- group or a C.sub.6-10
aryl-C(O)--N(C.sub.1-8 alkyl)- group and the C.sub.6-10 aryl group
and the C.sub.1-8 alkyl group are described above. Specifically,
examples thereof include a phenylcarbonylamino group.
[0480] The "C.sub.6-10 arylcarbonyl (C.sub.0-8 alkyl) amino group
which may be substituted" means the unsubstituted C.sub.6-10
arylcarbonyl (C.sub.0-8 alkyl) amino group described above or the
C.sub.6-10 arylcarbonyl (C.sub.0-8 alkyl) amino group in which at
least one hydrogen atoms of the aryl moiety is substituted by a
defined substituent(s). When two or more substituent groups are
present, each substituent group can be the same or different from
each other. Preferably, it is a C.sub.6-10 arylcarbonyl (C.sub.0-8
alkyl) amino group which may be substituted by 1 to 3
substituent(s).
[0481] The "(C.sub.1-8 alkyl).sub.x-aminocarbonyl (C.sub.0-8 alkyl)
amino group", wherein x is a symbol defined in claims, means a
NH.sub.2C(O)NH-- group, a (C.sub.1-8 alkyl)NHC(O)NH-- group, a
NH.sub.2C(O)N(C.sub.1-8 alkyl)- group, or a (C.sub.1-8
alkyl)NHC(O)N(C.sub.1-8 alkyl)- group, and the C.sub.1-8 alkyl is
described above. Specifically, examples thereof include
aminocarbonyl-(N-methyl)amino, and
(N-methyl)aminocarbonyl-(N'-methyl)amino.
[0482] The "(C.sub.1-8 alkyl).sub.x-aminocarbonyl (C.sub.0-8 alkyl)
amino group which may be substituted" means an unsubstituted
(C.sub.1-8 alkyl).sub.x-aminocarbonyl (C.sub.0-8 alkyl) amino
group, or a (C.sub.1-8 alkyl).sub.x-aminocarbonyl (C.sub.0-8 alkyl)
amino group in which at least one hydrogen atom on the nitrogen
atom or the alkyl moiety is substituted by a defined substituent.
Preferably, it is a (C.sub.1-8 alkyl).sub.x-aminocarbonyl
(C.sub.0-8 alkyl) amino group which may be substituted by a phenyl
group.
[0483] The "C.sub.1-8 alkylsulfonylamino group" means a C.sub.1-8
alkyl-S(O).sub.2--NH-- group and the C.sub.1-6 alkyl group is
described above. Specifically, examples thereof include a
methylsulfonylamino group and an ethylsulfonylamino group.
[0484] The "(C.sub.1-8 alkyl).sub.x-aminosulfonyl(C.sub.0-8
alkyl)amino group", wherein x is a symbol defined in claims, means
a NH.sub.2S(O).sub.2NH-- group, a NH(C.sub.1-8
alkyl)-S(O).sub.2NH-- group, or a N(C.sub.1-8
alkyl).sub.2-S(O).sub.2NH-- group, a NH.sub.2S(O).sub.2N (C.sub.1-8
alkyl).sub.x- group, a NH(C.sub.1-8 alkyl)-S(O).sub.2 (C.sub.1-8
alkyl)N-- group, or a N(C.sub.1-8 alkyl).sub.2-S(O).sub.2
(C.sub.1-8 alkyl)N-- group, and the C.sub.1-8 alkyl group is
described above. Specifically, examples thereof include a
methylamino-sulfonylamino group and a dimethylamino-sulfonylamino
group.
[0485] The "C.sub.1-8 alkoxy group" means a C.sub.1-8 alkyl-O--
group. Specifically, examples thereof include a methoxy group, an
ethoxy group, a 1-propoxy group, a 2-propoxy group, a n-butoxy
group, an i-butoxy group, a sec-butoxy group, a t-butoxy group, a
1-pentyloxy group, a 2-pentyloxy group, a 3-pentyloxy group, a
2-methyl-1-butyloxy group, a 3-methyl-1-butyloxy group, a
2-methyl-2-butyloxy group, a 3-methyl-2-butyloxy group, a
2,2-dimethyl-1-propyloxy group, a 1-hexyloxy group, a 2-hexyloxy
group, a 3-hexyloxy group, a 2-methyl-1-pentyloxy group, a
3-methyl-1-pentyloxy group, a 4-methyl-1-pentyloxy group, a
2-methyl-2-pentyloxy group, a 3-methyl-2-pentyloxy group, a
4-methyl-2-pentyloxy group, a 2-methyl-3-pentyloxy group, a
3-methyl-3-pentyloxy group, a 2,3-dimethyl-1-butyloxy group, a
3,3-dimethyl-1-butyloxy group, a 2,2-dimethyl-1-butyloxy group, a
2-ethyl-1-butyloxy group, a 3,3-dimethyl-2-butyloxy group, a
2,3-dimethyl-2-butyloxy group and a 1-methyl-cyclopropylmethoxy
group. Preferably, it is a C.sub.1-6 alkoxy group, more preferably
a C.sub.1-5 alkoxy group, still more preferably a C.sub.1-4 alkoxy
group, and still even more preferably a C.sub.1-3 alkoxy group.
[0486] The "C.sub.1-8 alkoxy group which may be substituted" means
an unsubstituted C.sub.1-8 alkoxy group or a C.sub.1-8 alkoxy group
in which at least one hydrogen atom of the alkyl moiety is
substituted by a defined substituent(s). When two or more
substituent groups are present, each substituent group can be the
same or different from each other. In addition, the alkyl moiety
may be substituted by a cyclic substituent group through a spiro
bond. Preferably, it is a C.sub.1-8 alkoxy group which may be
substituted by 1 to 3 substituent(s). More preferably, it is 1 to 3
substituent(s) for C.sub.1-6 alkoxy group and a C.sub.1-4 alkoxy
group, and 1 to 2 substituent(s) for a C.sub.1-3 alkoxy group.
[0487] The "C.sub.1-8 alkoxycarbonyl group" means a C.sub.1-8
alkyl-O--C(O)-- group and the C.sub.1-8 alkyl group is described
above. Specifically, examples thereof include a methoxycarbonyl
group, an ethoxycarbonyl group, a n-propoxycarbonyl group and an
i-propoxycarbonyl group. Preferably, it is a C.sub.1-6
alkoxycarbonyl group, and more preferably a C.sub.1-3
alkoxycarbonyl group.
[0488] The "C.sub.1-8 alkoxycarbonyl group which may be
substituted" means the unsubstituted C.sub.1-8 alkoxycarbonyl group
described above or a C.sub.1-8 alkoxycarbonyl group of which at
least one hydrogen atom is substituted by a defined substituent(s).
When two or more substituent groups are present, each substituent
group can be the same or different from each other. In addition,
the alkyl moiety of the alkoxycarbonyl group may be substituted by
a cyclic substituent group through a spiro bond. Preferably, it is
a C.sub.1-8 alkoxycarbonyl group which may be substituted by 1 to 3
substituent(s).
[0489] The "C.sub.0-8 alkoxy (C.sub.0-8 alkyl) aminocarbonyl group"
means a HO--NH--C(O)-- group, a C.sub.1-8 alkyl-NH--C(O)-- group, a
HO--N(C.sub.1-8 alkyl)-C(O)-- group, or a C.sub.1-8
alkyl-N(C.sub.1-8 alkyl)-C(O)-- group, and has a C.sub.1-8 alkoxy
group or a C.sub.1-8 alkyl group as described above. Specifically,
examples thereof include a methoxyaminocarbonyl group, an
ethoxyaminocarbonyl group, a n-propoxyaminocarbonyl group and an
i-propoxyaminocarbonyl group. Preferably, it is a C.sub.1-6
alkoxyaminocarbonyl group, and more preferably a C.sub.1-3
alkoxyaminocarbonyl group.
[0490] The "C.sub.0-8 alkoxy (C.sub.0-8 alkyl) aminocarbonyl group
which may be substituted" means the unsubstituted
hydroxyaminocarbonyl group described above, or a C.sub.1-8
alkoxyaminocarbonyl group, a hydroxy (C.sub.1-8 alkyl)
aminocarbonyl group or a C.sub.1-8 alkoxy (C.sub.1-8 alkyl)
aminocarbonyl group, wherein at least one hydrogen atom of the
alkyl moiety is substituted by a defined substituent(s). When two
or more substituent groups are present, each substituent group can
be the same or different from each other. In addition, the alkyl
moiety may be substituted by a cyclic substituent group through a
spiro bond. Preferably, it is a C.sub.1-8 alkoxy aminocarbonyl
group which may be substituted by 1 to 3 substituent(s).
[0491] The "4- to 10-membered heterocycloalkyloxy group" means a 4-
to 10-membered heterocycloalkyl-O-- group, and the 4- to
10-membered heterocycloalkyl is described above.
[0492] The "4- to 10-membered heterocycloalkyloxy group which may
be substituted" means the unsubstituted 4- to 10-membered
heterocycloalkyloxy group described above or a 4- to 10-membered
heterocycloalkyloxy group in which at least one hydrogen atom of
the heterocycloalkyl moiety is substituted by a defined
substituent(s). When two or more substituent groups are present,
each substituent group can be the same or different from each
other. In addition, the heterocycloalkyl moiety may be substituted
by a cyclic substituent group through a spiro bond. Preferably, it
is a 4-to 10-membered heterocycloalkyloxy group which may be
substituted by 1 to 3 substituent(s).
[0493] The "C.sub.6-10 aryloxy group" means a C.sub.6-10 aryl-O--
group, and the C.sub.6-10 aryl group is described above.
[0494] The "5- to 14-membered heteroaryloxy group" means a 5- to
14-membered heteroaryl-O-- group, and the 5- to 14-membered
heteroaryl is described above. Specifically, examples thereof
include a pyrimidinyloxy group.
[0495] The "C.sub.1-8 alkylcarbonyloxy group" means a C.sub.1-8
alkyl-C(O)--O-- group, and the C.sub.1-8 alkyl is described above.
Specifically, examples thereof include a methylcarbonyloxy group,
an ethylcarbonyloxy group and a propylcarbonyloxy group.
[0496] The "C.sub.2-8 alkenylcarbonyloxy group" means a C.sub.2-8
alkenyl-C(O)--O-- group, and the C.sub.2-8 alkenyl is described
above. Specifically, examples thereof include a
2-methyl-2-butenoyloxy group.
[0497] The "4- to 10-membered heterocycloalkylcarbonyloxy group"
means a 4- to 10-membered heterocycloalkyl-C(O)--O-- group, and the
4- to 10-membered heterocycloalkyl is described above.
[0498] The "(C.sub.1-8 alkyl).sub.x-aminocarbonyloxy group",
wherein x is a symbol defined in claims, means a NH.sub.2C(O)--O--
group, a NH(C.sub.1-8 alkyl)-C(O)--O-- group, or a N(C.sub.1-8
alkyl).sub.2-C(O)--O-- group. Specifically, examples thereof
include a methylamino-carbonyloxy group, an ethylamino-carbonyloxy
group and a propylamino-carbonyloxy group.
[0499] The "(C.sub.1-8 alkyl).sub.x-aminocarbonyloxy group which
may be substituted" means an unsubstituted (C.sub.1-8
alkyl).sub.x-aminocarbonyloxy group or a (C.sub.1-8
alkyl).sub.x-aminocarbonyloxy group group in which one or two
hydrogen atoms on the nitrogen atom or the alkyl moiety are
substituted by a defined substituent(s). When two substituent
groups are present, each substituent group can be the same or
different from each other.
[0500] The "4- to 10-membered nitrogen-containing
heterocycloalkylsulfonyl group" means the 4- to 10-membered
nitrogen-containing heterocycloalkyl-S(O).sub.2-- group described
above. Specifically, examples thereof include a morphorino-sulfonyl
group.
[0501] The "4- to 10-membered nitrogen-containing
heterocycloalkylsulfonyl group which may be substituted" means the
unsubstituted 4- to 10-membered nitrogen-containing
heterocycloalkylsulfonyl group described above or the 4- to
10-membered nitrogen-containing heterocycloalkylsulfonyloxy group
in which at least one hydrogen atom of the 4- to 10-membered
nitrogen-containing heterocycloalkyl moiety is substituted by a
defined substituent(s). When two or more substituent groups are
present, each substituent group can be the same or different from
each other. Preferably, it is a 4-to 10-membered
nitrogen-containing heterocycloalkylsulfonyl which may be
substituted by 1 to 3 substituent(s).
[0502] The "4- to 10-membered nitrogen-containing
heterocycloalkylsulfonyloxy group" means the 4- to 10-membered
nitrogen-containing heterocycloalkyl-S(O).sub.2--O-- group
described above. Specifically, examples thereof include a
morphorino-sulfonyloxy group and a piperadino-sulfonyloxy
group.
[0503] The "4- to 10-membered nitrogen-containing
heterocycloalkylsulfonyloxy group which may be substituted" means
the unsubstituted 4- to 10-membered nitrogen-containing
heterocycloalkylsulfonyloxy group described above or the 4- to
10-membered nitrogen-containing heterocycloalkylsulfonyloxy group
in which at least one hydrogen atom of the 4- to 10-membered
nitrogen-containing heterocycloalkyl moiety is substituted by a
defined substituent(s). When two or more substituent groups are
present, each substituent group can be the same or different from
each other. Preferably, it is a 4-to 10-membered
nitrogen-containing heterocycloalkylsulfonyloxy which may be
substituted by 1 to 3 substituent(s).
[0504] The "C.sub.1-8 alkylsulfonyloxy group" means a C.sub.1-8
alkyl-S(O).sub.2--O-- group, and the C.sub.1-8 alkyl is described
above.
[0505] The "C.sub.1-8 alkylsulfonyloxy group which may be
substituted" means the unsubstituted C.sub.1-8 alkylsulfonyloxy
group described above or a C.sub.1-8 alkylsulfonyloxy group in
which at least one hydrogen atom of the alkyl moiety is substituted
by a defined substituent(s). When two or more substituent groups
are present, each substituent group can be the same or different
from each other. In addition, the alkyl moiety may be substituted
by a cyclic substituent group through a spiro bond. Preferably, it
is a C.sub.1-8 alkylsulfonyloxy group which may be substituted by 1
to 3 substituent(s). Specifically, examples thereof include a
trifluoromethylsulfonyloxy group.
[0506] The "(C.sub.1-8 alkyl).sub.x-aminosulfonyloxy group" wherein
x is a symbol defined in claims, means a NH.sub.2S(O).sub.2--
group, a N(C.sub.1-8 alkyl)S(O).sub.2-- group, or a N(C.sub.1-8
alkyl).sub.2S(O).sub.2-- group. Specifically, examples thereof
include a N-methylaminosulfonyloxy group.
[0507] The "C.sub.1-8 alkylthio group" means a C.sub.1-8 alkyl-S--
group, and the C.sub.1-8 alkyl group is described above. Examples
thereof include methylthio, ethylthio, n-propylthio, i-propylthio,
n-butylthio, s-butylthio, i-butylthio, t-butylthio, n-pentylthio,
3-methylbutylthio, 2-methylbutylthio, 1-methylbutylthio,
1-ethylpropylthio, n-hexylthio, 4-methylpentylthio,
3-methylpentylthio, 2-methylpentylthio, 1-methylpentylthio,
3-ethylbutylthio, and 2-ethylbutylthio and the like. Preferably, it
is a C.sub.1-6 alkylthio group, and more preferably a C.sub.1-3
alkylthio group.
[0508] The "C.sub.1-8 alkylthio group which may be substituted"
means an unsubstituted C.sub.1-8 alkylthio group or a C.sub.1-8
alkylthio group in which at least one hydrogen atom of the alkyl
moiety is substituted by a defined substituent(s). When two or more
substituent groups are present, each substituent group can be the
same or different from each other. In addition, the alkyl moiety
may be substituted by a cyclic substituent group through a spiro
bond. Preferably, it is a C.sub.1-8 alkylthio group which may be
substituted by 1 to 3 substituent(s).
[0509] The "C.sub.1-8 alkylsulfonyl group" means a C.sub.1-8
alkyl-S(O).sub.2-- group, and the C.sub.1-8 alkyl group is
described above. Specifically, examples thereof include a
methylsulfonyl group, an ethylsulfonyl group and a n-propylsulfonyl
group. Preferably, it is a C.sub.1-6 alkylsulfonyl group, and more
preferably a C.sub.1-3 alkylsulfonyl group.
[0510] The "C.sub.1-8 alkylsulfinyl group" means a C.sub.1-8
alkyl-S(O)-- group, and the C.sub.1-8 alkyl group is described
above. Specifically, examples thereof include a methylsulfinyl
group, an ethylsulfinyl group and a n-propylsulfinyl group.
Preferably, it is a C.sub.1-6 alkylsulfinyl group, and more
preferably a C.sub.1-3 alkylsulfinyl group.
[0511] The "C.sub.1-8 alkylsulfonyl group which may be substituted"
means the unsubstituted C.sub.1-8 alkylsulfonyl group described
above or a C.sub.1-8 alkylsulfonyl group in which at least one
hydrogen atom of the alkyl moiety is substituted by a defined
substituent(s). When two or more substituent groups are present,
each substituent group can be the same or different from each
other. Preferably, it is a C.sub.1-8 alkylsulfonyl group which may
be substituted by 1 to 3 substituent(s).
[0512] The "C.sub.1-8 alkylsulfinyl group which may be substituted"
means the unsubstituted C.sub.1-8 alkylsulfinyl group described
above or a C.sub.1-8 alkylsulfinyl group in which at least one
hydrogen atom of the alkyl moiety is substituted by a defined
substituent(s). When two or more substituent groups are present,
each substituent group can be the same or different from each
other. Preferably, it is a C.sub.1-8 alkylsulfinyl group which may
be substituted by 1 to 3 substituent(s).
[0513] The "4- to 10-membered heterocycloalkylsulfonyl group" means
a 4- to 10-membered heterocycloalkyl-S(O).sub.2-- group, and the 4-
to 10-membered heterocycloalkyl is described above.
[0514] The "4- to 10-membered heterocycloalkylsulfonyl group which
may be substituted" means the unsubstituted 4- to 10-membered
heterocycloalkylsulfonyl group described above or a 4- to
10-membered heterocycloalkylsulfonyl group in which at least one
hydrogen atom of the heterocycloalkyl moiety is substituted by a
defined substituent(s). When two or more substituent groups are
present, each substituent group can be the same or different from
each other. In addition, the heterocycloalkyl moiety may be
substituted by a cyclic substituent group through a spiro bond.
Preferably, it is a 4-to 10-membered heterocycloalkylsulfonyl group
which may be substituted by 1 to 3 substituent(s).
[0515] The "(C.sub.1-8 alkyl).sub.x-aminosulfonyl group", wherein x
is a symbol defined in claims, means a NH.sub.2--S(O).sub.2--
group, a C.sub.1-8 alkylamino-S(O).sub.2-- group, or a (C.sub.1-8
alkyl).sub.2amino-S (O).sub.2-- group and the C.sub.1-8 alkyl is
described above. Specifically, examples thereof include an
aminosulfonyl group, a methylaminosulfonyl group and a
dimethylaminosulfonyl group.
[0516] The "(C.sub.1-8 alkyl).sub.x-aminosulfonyl group which may
be substituted" means an unsubstituted aminosulfonyl group or a
(C.sub.1-8 alkyl).sub.x-aminosulfonyl group in which one or two
hydrogen atoms on the nitrogen atom or the alkyl moiety are
substituted by a defined substituent(s). When two substituent
groups are present, each substituent group can be the same or
different from each other.
[0517] The "C.sub.1-8 alkoxycarbonyl (C.sub.0-8 alkyl) amino group"
means a C.sub.1-8 alkoxy-C(O)--NH-- group or a C.sub.1-8
alkoxy-C(O)--N(C.sub.1-8 alkyl)- group, wherein the C.sub.1-8
alkoxy group and C.sub.1-8 alkyl) are described above.
Specifically, examples thereof include a methoxycarbmamoyl group
and an N-ethylcarbonyl-N-methyl-amino group.
[0518] The "C.sub.1-8 alkoxycarbony(C.sub.0-8 alkyl) amino group
which may be substituted" means the unsubstituted C.sub.1-8
alkoxycarbony(C.sub.0-8 alkyl) amino group described above, or a
C.sub.1-8 alkoxycarbony(C.sub.0-8 alkyl) amino group, wherein at
least one hydrogen atom of the alkyl moiety is substituted by a
defined substituent(s). When two or more substituent groups are
present, each substituent group can be the same or different from
each other. Preferably, it is a C.sub.1-8 alkoxycarbony(C.sub.0-8
alkyl) amino group which may be substituted by 1 to 3
substituent(s).
[0519] The "C.sub.1-8 alkoxycarbonyl (C.sub.0-8 alkyl)
aminosulfonyl group" means a C.sub.1-8 alkoxy-C(O)--NHS(O).sub.2--
group or a C.sub.1-8 alkoxy-C(O)--N(C.sub.1-8 alkyl)S(O).sub.2--
group, wherein the C.sub.1-8 alkoxy group and C.sub.1-8 alkyl group
are described above. Specifically, examples thereof include a
methoxy carbonyl aminosulfonyl group and an
ethoxycarbonyl-N-methyl-aminosulfonyl group.
[0520] The "C.sub.6-10 aryloxycarbonyl (C.sub.0-8 alkyl) amino
group" means a C.sub.6-10 aryl-O--C(O)--NH-- group or a C.sub.6-10
aryl-O--C(O)--N(C.sub.1-8 alkyl)- group, wherein the C.sub.6-10
aryl group and C.sub.1-8 alkyl are described above. Specifically,
examples thereof include a phenyloxycarbonylamino group and a
N-methyl-N-phenyloxycarbonyl-amino group.
[0521] The "C.sub.6-10 aryloxycarbonyl (C.sub.0-8 alkyl) amino
group which may be substituted" means the unsubstituted C.sub.6-10
aryloxycarbonyl (C.sub.0-8 alkyl) amino group described above or
the C.sub.6-10 aryloxycarbonyl (C.sub.0-8 alkyl) amino group in
which at least one hydrogen atoms of the aryl moiety is substituted
by a defined substituent(s). When two or more substituent groups
are present, each substituent group can be the same or different
from each other. Preferably, it is a C.sub.6-10 aryloxycarbonyl
(C.sub.0-8 alkyl) amino group which may be substituted by 1 to 3
substituent(s).
[0522] The "C.sub.6-10 aryl (C.sub.0-8 alkyl) aminocarbonyl
(C.sub.0-8 alkyl) amino group" means a C.sub.6-10 aryl NHC(O)NH--
group, a C.sub.6-10 aryl-N(C.sub.1-8 alkyl)-C(O)NH-- group, a
C.sub.6-10 aryl-N(C.sub.1-8 alkyl)-C(O)N(C.sub.1-8 alkyl)- group,
or a C.sub.6-10 aryl-NH--C(O)N(C.sub.1-8 alkyl)- group, wherein the
C.sub.6-10 aryl group and C.sub.1-8 alkyl are described above.
Specifically, examples thereof include a phenylaminocarbonylamino
group and a phenylaminocarbonyl(N-methyl)amino group.
[0523] The "C.sub.6-10 aryl (C.sub.0-8 alkyl) aminocarbonyl
(C.sub.0-8 alkyl) amino group which may be substituted" means the
unsubstituted C.sub.6-10 aryl (C.sub.0-8 alkyl) aminocarbonyl
(C.sub.0-8 alkyl) amino group described above or the C.sub.6-10
aryl (C.sub.0-8 alkyl) aminocarbonyl (C.sub.0-8 alkyl) amino group
in which at least one hydrogen atoms of the aryl moiety is
substituted by a defined substituent(s). When two or more
substituent groups are present, each substituent group can be the
same or different from each other. Preferably, it is a C.sub.6-10
aryl (C.sub.0-8 alkyl) aminocarbonyl (C.sub.0-8 alkyl) amino group
which may be substituted by 1 to 3 substituent(s).
[0524] The "C.sub.6-10 aryl (C.sub.0-8 alkyl) aminocarbonyloxy
group" means a C.sub.6-10 aryl-NHC(O)--O--, or a C.sub.6-10
aryl-N(C.sub.1-8 alkyl)-C(O)--O-- group, wherein the C.sub.6-10
aryl group and C.sub.1-8 alkyl are described above. Specifically,
examples thereof include a phenylaminocarbonyloxy group and a
phenylaminocarbonyl(N-methyl)amino carbonyloxy group.
[0525] The "C.sub.6-10 aryl (C.sub.0-8 alkyl) aminocarbonyloxy
group which may be substituted" means the unsubstituted C.sub.6-10
aryl (C.sub.0-8 alkyl) aminocarbonyloxy group described above or
the C.sub.6-10 aryl (C.sub.0-8 alkyl) aminocarbonyloxy group in
which at least one hydrogen atoms of the aryl moiety is substituted
by a defined substituent(s). When two or more substituent groups
are present, each substituent group can be the same or different
from each other. Preferably, it is a C.sub.6-10 aryl (C.sub.0-8
alkyl) aminocarbonyloxy group which may be substituted by 1 to 3
substituent(s).
[0526] The "C.sub.1-8 alkylsulfonyl (C.sub.0-8 alkyl) amino group"
means a C.sub.1-8 alkyl-S(O).sub.2--NH-- group, or a C.sub.1-8
alkyl-S(O).sub.2--N(C.sub.1-8 alkyl)- group. Specifically, examples
thereof include a methylsulphonylamino group and a
methylsulphonyl-(N-methyl)amino group.
[0527] The "C.sub.2-8 alkenyloxy group" means a C.sub.2-8
alkenyl-O-- group, wherein the C.sub.2-8 alkenyl group is described
above. Specific examples of the C.sub.2-8 alkenyloxy group include
a vinyloxy group and a allyloxy group.
[0528] Preferably, all of A.sup.1, A.sup.2, A.sup.3, A.sup.4,
A.sup.7, A.sup.8, A.sup.9 and A.sup.10 are C, or any one of
A.sup.2, A.sup.4, A.sup.7 and A.sup.9 is N and the remainings are C
(with the proviso that, when A.sup.2, A.sup.4, A.sup.7 or A.sup.9
is N, they do not have a substituent group R.sup.2, R.sup.4,
R.sup.7 or R.sup.9). More preferably, all of them are C, or A.sup.4
is N while the remainings are C, even more preferably, all of them
are C, or A.sup.4, A.sup.7, and A.sup.9 is N and the remainings are
C (with the proviso that, when A.sup.4, A.sup.7, or A.sup.9 is N,
they do not have a substituent group R.sup.4, R.sup.7,
R.sup.9).
[0529] A.sup.5 is preferably NR.sup.5 or O, more preferably
NR.sup.5, even more preferably NH.
[0530] R.sup.1 is preferably
[1] a hydrogen atom, [2] a halogen atom, and more preferably [1] a
hydrogen atom, [2] a fluorine atom, [3] a chlorine atom.
[0531] R.sup.10 is preferably a hydrogen atom.
[0532] R.sup.2 is preferably
[1] a hydrogen atom, [2] a C.sub.1-5 alkyl group, [3] a cyano, [4]
a halogen atom, and more preferably [1] a hydrogen atom, [2] a
C.sub.1-3 alkyl group, [3] a fluorine atom, [4] a chlorine atom,
[5] a bromine atom. And even more preferably [1] a hydrogen atom,
[2] a halogen atom, Still more preferably [1] a hydrogen atom,
[0533] R.sup.4 is preferably
[1] a hydrogen atom, [2] a C.sub.1-5 alkyl group which may be
substituted by 1-11 halogen atom(s), [3] a C.sub.3-6 cycloalkyl
group, [4] a cyano, [5] a halogen atom, [6] a (C.sub.1-3
alkyl).sub.m4b-amino group (m4b: 0.about.2), [7] a hydroxy, [8] a
C.sub.1-5 alkoxy group which may be substituted by 1-4 hydroxy(s),
and more preferably [1] a hydrogen atom, [2] a C.sub.1-3 alkyl
group which may be substituted by 1-7 halogen atom(s), [3] a
C.sub.3-5 cycloalkyl group, [4] a cyano, [5] a florine atom, [6] a
bromine atom, [7] an amino (C.sub.1-3 alkyl).sub.m4b-amino group,
[8] a hydroxy, [9] a C.sub.1-3 alkoxy group which may be
substituted by 1-2 hydroxy(s). Even more preferably [1] a hydrogen
atom, [2] a C.sub.1-8 alkyl group which may be substituted by at
least one halogen atom, [3] a C.sub.3-8 cycloalkyl group, [4] a
cyano, [5] a halogen atom, [6] a hydroxy, [7] a C.sub.1-8 alkoxy
group which may be substituted by a hydroxy, Still more preferably
[1] a hydrogen atom, [2] a halogen atom,
[0534] R.sup.5 is preferably
[1] a hydrogen atom, [2] a C.sub.1-5 alkyl group which may be
substituted by 1-5 R.sup.5A substituent(s), [3] a C.sub.1-5
alkylsulfonyl group, and more preferably [1] a hydrogen atom, [2] a
C.sub.1-3 alkyl group which may be substituted by 1-3 R.sup.5A
substituent(s), [3] a C.sub.1-3 alkylsulfonyl group. Even more
preferably [1] a hydrogen atom, [2] a C.sub.1-8 alkyl group, Still
more preferably [1] a hydrogen atom.
[0535] R.sup.5A is preferably
[1] a C.sub.1-5 alkoxycarbonyl group, [2] a hydroxy, [3] a
C.sub.1-5 alkoxy group, [4] a (C.sub.1-5 alkyl).sub.m5-amino group
(m5: 0.about.2), [5] a C.sub.6 aryl, [6] a C.sub.1-8 alkylthio
group, and more preferably [1] a C.sub.1-3 alkoxycarbonyl group,
[2] a hydroxy, [3] a C.sub.1-3 alkoxy group, [4] a (C.sub.1-3
alkyl).sub.m5-amino group (m5: 0.about.2), [5] a C.sub.1-3
alkylthio group, even more preferably [1] a hydroxy, [2] a
C.sub.1-5 alkoxy group, [3] a (C.sub.1-5 alkyl).sub.m5-amino group
(m5: 0.about.2), [4] a C.sub.1-5 alkylthio group.
[0536] R.sup.6 and R.sup.6' are preferably
[1] a C.sub.1-8 alkyl group, taken together with carbon atoms to
which they are bound to form [2] a C.sub.3-8 cycloalkyl group, [3]
a 4- to 10-membered heterocycloalkyl group, more preferably [1] a
C.sub.1-3 alkyl group, taken together with carbon atoms to which
they are bound to form [2] a C.sub.3-6 cycloalkyl group, [3] a 4-
to 6-membered heterocycloalkyl group, even more preferably [1] a
methyl, taken together with carbon atoms to which they are bound to
form [2] a cyclopentane, [3] a tetrahydropyran, [4] or a
piperidine.
[0537] R.sup.7 is preferably
[1] a hydrogen atom, [2] a fluorine atom, [3] a bromine atom, [4] a
chlorine atom, [5] a C.sub.1-5 alkoxy group which may be
substituted by 1-4 R.sup.7A substituent(s), and more preferably [1]
a hydrogen atom, [2] a halogen atom, and even more preferably [1] a
hydrogen atom, [2] a fluorine atom, [3] a bromine atom, [4] a
chlorine atom, and still more preferably [1] a hydrogen atom.
[0538] R.sup.7A is preferably
[1] a (C.sub.1-5 alkyl).sub.m7-amino group (m7: 0.about.2), [2] a
hydroxy, [3] a 4- to 6-membered heterocycloalkyl group which may be
substituted by C.sub.1-5 alkyl group(s), and more preferably [1] a
(C.sub.1-3 alkyl).sub.m7-amino group (m7: 2), [2] a hydroxy, [3] a
4- to 6-membered heterocycloalkyl group which may be substituted by
C.sub.1-3 alkyl group(s).
[0539] R.sup.3 is preferably
[1] a hydrogen atom, [2] a C.sub.1-5 alkyl group which may be
substituted by 1-11 halogen atom(s), [3] a cyano, [4] a (C.sub.1-5
alkyl).sub.m3a-aminocarbonyl group (m3a: 0.about.2) which may be
substituted by 1-5 R.sup.3A substituents, [5] a hydroxycarbonyl,
[6] a C.sub.1-5 alkylcarbonyl group which may be substituted by 1-4
hydroxy(s), [7] a halogen atom, [8] a (C.sub.1-3
alkyl).sub.m3b-amino group (m3b: 0.about.2) which may be
substituted by 1-2 C.sub.6 aryl(s), [9] a C.sub.1-5 alkyl carbonyl
(C.sub.0-3 alkyl) amino group which may be substituted by 1-2
C.sub.6 aryl(s) or 1-2 C.sub.6 aryloxy(s), [10] a C.sub.6
arylcarbonyl (C.sub.0-3 alkyl) amino group which may be substituted
by 1-5 C.sub.1-3 alkyl group(s) which may be substituted by 1-7
halogen atom(s), [11] a (C.sub.1-3 alkyl).sub.m3c-aminocarbonyl(C-3
alkyl) amino group (m3c: 0.about.1) which may be substituted by a
C.sub.6 aryl, [12] a nitro, [13] a hydroxy, [14] a C.sub.1-5 alkoxy
group which may be substituted by 1-4 R.sup.3B(s), [15] a 4- to
6-membered heterocycloalkyloxy group, [16] a 6-membered
heteroaryloxy, [17] a (C.sub.1-5 alkyl).sub.m3e-aminocarbonyloxy
group (m3e: 0.about.2) which may be substituted by 1-3 C.sub.6
aryl(s), [18] a 4- to 6-membered nitrogen-containing
heterocycloalkylaminocarbonyl group, [19] a C.sub.1-5 alkylthio
group, [20] a 5- to 6-membered heteroaryl group which may be
substituted by 1-4 C.sub.1-5 alkyl group(s) which may be
substituted by 1-3 C.sub.1-5 alkoxy group(s), [21] a C.sub.1-3
alkoxycarbonyl (C.sub.0-3 alkyl) amino group which may be
substituted by a C.sub.1-3 alkoxy group, [22] a C.sub.6
aryloxycarbonyl (C.sub.0-3 alkyl) amino group which may be
substituted by 1-3 C.sub.1-3 alkyl group(s) which may be
substituted by 1-9 halogen atom(s), [23] a C.sub.6 aryloxycarbonyl
(C.sub.0-3 alkyl) aminocarbonyl (C.sub.0-3 alkyl)amino group which
may be substituted by 1-3 R.sup.3C, [24] a C.sub.3-6 cycloalkyl
(C.sub.0-3 alkyl) aminocarbonyloxy group, and [25] a C.sub.6 aryl
(C.sub.0-3 alkyl) aminocarbonyloxy group which may be substituted
by 1-3 substituent(s) selected from the group consisting of a
C.sub.1-5 alkyl group and a C.sub.1-5 alkoxy group(s).
[0540] R.sup.3 is more preferably
[1] a hydrogen atom, [2] a C.sub.1-3 alkyl group which may be
substituted by 1-7 halogen atom(s), [3] a cyano, [4] a (C.sub.1-4
alkyl).sub.m3a-aminocarbonyl group (m3a: 0.about.1) which may be
substituted by 1-4 R.sup.3A substituents, [5] a hydroxycarbonyl,
[6] a halogen atom, [7] a C.sub.1-4 alkyl carbonyl (C.sub.1-3
alkyl) amino group which may be substituted by 1-2 C.sub.6 aryl(s)
or 1-2 C.sub.6 aryloxy(s), [8] a C.sub.6 arylcarbonyl (C.sub.0-3
alkyl) amino group which may be substituted by a C.sub.1-3 alkyl
group which may be substituted by 1-7 halogen atom(s), [9] a nitro,
[10] a hydroxy, [11] a C.sub.1-4 alkoxy group which may be
substituted by 1-3 R.sup.3B substituent(s), [12] a 4-membered
heterocycloalkyloxy group, [13] a (C.sub.1-3
alkyl).sub.m3e-aminocarbonyloxy group (m3e:1) which may be
substituted by a C.sub.6 aryl(s), [14] a 6-membered
nitrogen-containing heterocycloalkylaminocarbonyl group, [15] a
C.sub.1-3 alkylthio group, [16] a 5-membered heteroaryl group which
may be substituted by a C.sub.1-5 alkyl group which may be
substituted by a C.sub.1-3 alkoxy group, [17] a C.sub.6
aryloxycarbonyl (C.sub.0-3 alkyl) aminocarbonyl (C.sub.0-3
alkyl)amino group which may be substituted by a R.sup.3C
substituent, [18] a C.sub.6 cycloalkyl (C0-2 alkyl)
aminocarbonyloxy group, and [19] a C.sub.6 aryl (C.sub.0-3 alkyl)
aminocarbonyloxy group which may be substituted by 1-2
substituent(s) selected from the group consisting of a C.sub.1-4
alkyl group and a C.sub.1-3 alkoxy group.
[0541] R.sup.3 is still more preferably
[1] a hydrogen atom, [2] a cyano, [3] a halogen atom,
[0542] R.sup.3 is still even more preferably
[1] a cyano, [2] a halogen atom.
[0543] R.sup.3A is preferably
[1] a C.sub.6 aryl, [2] a C.sub.1-5 alkoxy group, [3] a 5- or
6-membered heteroaryl group, [4] a C.sub.6 arylsulfonyl.
[0544] R.sup.3B is preferably
[1] a hydroxy, [2] a C.sub.1-5 alkoxy group, [3] a C.sub.6 aryl
(C.sub.0-3 alkyl) aminocarbonyl group, [4] a (C.sub.1-3
alkyl).sub.m3d-amino group (m3d: 0.about.2), [5] a halogen atom,
more preferably [1] a hydroxy, [2] a C.sub.1-5 alkoxy group.
[0545] R.sup.3C is preferably
[1] a C.sub.1-5 alkyl group which may be substituted by 1-11
halogen atom(s), [2] a C.sub.1-5 alkoxy group, more preferably [1]
a C.sub.1-4 alkyl group which may be substituted by 1-9 halogen
atom(s), [2] a C.sub.1-3 alkoxy group.
[0546] R.sup.8 is preferably
[1] a hydrogen atom, [2] a C.sub.1-5 alkyl group which may be
substituted by 1-5 R.sup.5A substituent(s), [3] a C.sub.2-8 alkenyl
group, [4] a 4- to 6-membered heterocycloalkyl group which may be
substituted by 1-4 R.sup.8B substituent(s), [5] a 5- to 6-membered
heteroaryl group which may be substituted by 1-4 C.sub.1-8 alkyl
group(s), [6] a (C.sub.1-5 alkyl).sub.m8g-aminocarbonyl group (m8g:
0.about.2) which may be substituted by 1-3 R.sup.8C substituent(s),
[7] a 4- to 6-membered heterocycloalkyl (C.sub.0-3 alkyl)
aminocarbonyl group which may be substituted by 1-2 oxo group(s),
[8] a 4- to 6-membered nitrogen-containing heterocycloalkylcarbonyl
group which may be substituted by 1-4 R.sup.8D substituent(s), [9]
a hydroxycarbonyl, [10] a C.sub.1-5 alkoxy (C.sub.0-3 alkyl)
aminocarbonyl group which may be substituted by 1-3 hydroxy
group(s), [11] a halogen atom, [12] a (C.sub.1-5
alkyl).sub.m8j-amino group (m8j:0-2) which may be substituted by
1-2 R.sup.8H substituent(s), [13] a hydroxyl, [14] a C.sub.1-5
alkoxy group which may be substituted by 1-4 R.sup.8E
substituent(s), [15] a 4- to 6-membered heterocycloalkyloxy group
which may be substituted by 1-5 R.sup.8F substituent(s), [16] a
6-membered heteroaryloxy group, [17] a (C.sub.1-5
alkyl).sub.m8l1-aminosulfonyloxy group (m8l1:0-2), [18] a C.sub.1-5
alkyl thio group which may be substituted by 1-4 R.sup.8I
substituent(s), [19] a C.sub.1-5 alkylsulfonyl group which may be
substituted by 1-4 R.sup.8G substituent(s), [20] a 6-membered
heterocycloalkylsulfonyl group which may be substituted by a
C.sub.1-3 alkyl group, [21] a C.sub.2-8 alkenyloxy group, and [22]
a C.sub.1-3 alkylsulfonyloxy group which may be substituted by 1-7
halogen atom(s). And more preferably [1] a hydrogen atom, [2] a
C.sub.1-3 alkyl group which may be substituted by 1-3 R.sup.5A
substituent(s), [3] a C.sub.2-4 alkenyl group, [4] a 6-membered
heterocycloalkyl group which may be substituted by 1-3 R.sup.8B
substituent(s), [5] a 5- to 6-membered heteroaryl group which may
be substituted by 1-2 C.sub.1-3 alkyl group(s), [6] a (C.sub.1-3
alkyl).sub.m8g-aminocarbonyl group (m8g: 0.about.2) which may be
substituted by 1-2 R.sup.C substituent(s), [7] a 4- to 6-membered
heterocycloalkyl (C.sub.0-1 alkyl) aminocarbonyl group which may be
substituted by 1-2 oxo group(s), [8] a 6-membered
nitrogen-containing heterocycloalkylcarbonyl group which may be
substituted by 1-2 R.sup.8D substituent(s), [9] a hydroxycarbonyl,
[10] a C.sub.1-3 alkoxy (C.sub.0-3 alkyl) aminocarbonyl group which
may be substituted by 1-2 hydroxy group(s), [11] a bromine atom,
[12] a (C.sub.1-3 alkyl).sub.m8j-amino group (m8j:0-2) which may be
substituted by 1-2 R.sup.8H substituent(s), [13] a hydroxyl, [14] a
C.sub.1-5 alkoxy group which may be substituted by 1-3 R.sup.8E
substituent(s), [15] a 4- to 6-membered heterocycloalkyloxy group
which may be substituted by 1-3 R.sup.8F substituent(s), [16] a
6-membered heteroaryloxy group, [17] a (C.sub.1-3
alkyl).sub.m8l1-aminosulfonyloxy group (m8l1:0-2), [18] a C.sub.1-3
alkyl thio group which may be substituted by 1-2 R.sup.8I
substituent(s), [19] a C.sub.1-3 alkylsulfonyl group which may be
substituted by 1-2 R.sup.8G substituent(s), [20] a 6-membered
heterocycloalkylsulfonyl group which may be substituted by a
C.sub.1-3 alkyl group, [21] a C.sub.2-3 alkenyloxy group, and [22]
a trifluoromethylsulfonyloxy group, Even more preferably [1] a
hydrogen atom, [2] a C.sub.1-3 alkyl group which may be substituted
by 1-3 R.sup.5A substituent(s), [3] a 6-membered heterocycloalkyl
group which may be substituted by 1-3 R.sup.8B substituent(s), [4]
a 5- to 6-membered heteroaryl group which may be substituted by 1-2
C.sub.1-3 alkyl group(s), [5] a 4- to 6-membered heterocycloalkyl
(C0-1 alkyl) aminocarbonyl group which may be substituted by 1-2
oxo group(s), [6] a 6-membered nitrogen-containing
heterocycloalkylcarbonyl group which may be substituted by 1-2
R.sup.8D substituent(s), [7] a (C.sub.1-3 alkyl).sub.m8j-amino
group (m8j:0-2) which may be substituted by 1-2 R.sup.8H
substituent(s), [8] a hydroxyl, [9] a C.sub.1-5 alkoxy group which
may be substituted by 1-3 R.sup.8E substituent(s), [10] a 4- to
6-membered heterocycloalkyloxy group which may be substituted by
1-3 R.sup.8F substituent(s), [11] a 6-membered heteroaryloxy group,
[12] a C.sub.1-3 alkyl thio group which may be substituted by 1-2
R.sup.8I substituent(s), [13] a C.sub.1-3 alkylsulfonyl group which
may be substituted by 1-2 R.sup.8G substituent(s), and [14] a
C.sub.2-3 alkenyloxy group, further preferably [1] a hydrogen atom,
[2] a C.sub.1-3 alkyl group which may be substituted by 1-3
R.sup.5A substituent(s), [3] a 6-membered heterocycloalkyl group
which may be substituted by 1-3 R.sup.8B substituent(s), [4] a
(C.sub.1-3 alkyl).sub.m8j-amino group (m8j:0-2) which may be
substituted by 1-2 R.sup.8H substituent(s), [5] a C.sub.1-5 alkoxy
group which may be substituted by 1-3 R.sup.8E substituent(s), and
[6] a 4- to 6-membered heterocycloalkyloxy group which may be
substituted by 1-3 R.sup.8F substituent(s), Still more preferably
[1] a 4- to 10-membered heterocycloalkyl group which may be
substituted by one or more R.sup.8B described below, Still even
more preferably [1] a 4- to 10-membered heterocycloalkyl group
which may be substituted by at least one halogen atom, C.sub.1-8
alkyl group, or an oxo.
[0547] R.sup.5A is preferably
[8A-1] a 4- to 6-membered heterocycloalkyl group which may be
substituted by 1-4 R.sup.8A1 substituent(s), [8A-2] a (C.sub.1-5
alkyl).sub.m8a-amino group (m8a:0.about.2) which may be substituted
by 1-11 halogen atom(s), and [8A-3] a hydroxy; [0548] R.sup.8A is
more preferably [8A-1] a 6-membered heterocycloalkyl group which
may be substituted by 1-2 R.sup.8A1 substituent(s), [8A-2] a
(C.sub.1-3 alkyl).sub.m8a-amino group (m8a:0.about.2) which may be
substituted by 1-11 halogen atom(s), and [8A-3] a hydroxy;
R.sup.8A1 is preferably [8A1-1] a C.sub.1-5 alkyl group, [8A1-2] a
C.sub.1-5 alkylsulfonyl group, [8A1-3] a (C.sub.1-5
alkyl).sub.m8b-aminosulfonyl group (m8b: 0.about.2), or [8A1-4] an
oxo group, more preferably [8A1-1] a C.sub.1-3 alkyl group, [8A1-2]
a C.sub.1-3 alkylsulfonyl group, or [8A1-3] a (C.sub.1-3
alkyl).sub.m8b-aminosulfonyl group (m8b: 0),
[0549] R.sup.8B1 is preferably
[8B-1] a C.sub.1-6 alkyl group which may be substituted by 1-13
R.sup.8B1 substituent(s), [8B-2] a C.sub.2-6 alkynyl group, [8B-3]
a C.sub.3-6 cycloalkyl group which may be substituted by [1]
cyano(s) or [2] C.sub.1-6 alkyl group(s), [8B-4] a 4- to 6-membered
heterocycloalkyl group which may be substituted by 1-10 R.sup.8B2
substituent(s), [8B-5] a C.sub.1-6 alkoxy group which may be
substituted by 1-5 substituent(s) selected from the group
consisting of [1] a C.sub.1-5 alkoxy group and [2] a C.sub.3-6
cycloalkyl group, [8B-6] a C.sub.1-5 alkoxycarbonyl group, [8B-7] a
C.sub.1-5 alkylsulfonyl group, [8B-8] a 5- to 6-membered
heteroarylsulfonyl group, [8B-9] a cyano, [8B-10] a C.sub.1-6
alkanoyl group which may be substituted by 1-2 R.sup.8B3
substituent(s), [8B-11] a C.sub.3-8 cycloalkylcarbonyl group,
[8B-12] a (C.sub.1-5 alkyl).sub.m8c-aminosulfonyl group (m8c:0-2),
[8B-13] a C.sub.1-6 alkylsulfonyl (C.sub.0-6 alkyl) amino group,
[8B-14] a (C.sub.1-5 alkyl).sub.m8a-amino group (m8d:0-2) which may
be substituted by 1-3 R.sup.8B4 substituent(s), [8B-15] a hydroxy,
[8B-16] a (C.sub.1-6 alkyl).sub.m8e-aminocarbonyl group (m8e:0-2),
or [8B-17] a C.sub.1-4 alkoxycarbonylamino group more preferably
[8B-1] a C.sub.1-5 alkyl group which may be substituted by 1-3
R.sup.8B1, [8B-2] a C.sub.2-5 alkynyl group, [8B-3] a C.sub.3-5
cycloalkyl group which may be substituted by [1] a cyano or [2] a
C.sub.1-6 alkyl group, [8B-4] a 4- to 6-membered heterocycloalkyl
group which may be substituted by 1-8 R.sup.8B2 substituent(s),
[8B-5] a C.sub.1-5 alkoxy group which may be substituted by 1-2
substituent(s) selected from the group consisting of [1] a
C.sub.1-3 alkoxy group and [2] a C.sub.3-6 cycloalkyl group, [8B-6]
a C.sub.1-3 alkylsulfonyl group, [8B-7] a cyano, [8B-8] a C.sub.1-6
alkanoyl group which may be substituted by a R.sup.8B3 substituent,
[8B-9] a C.sub.3-5 cycloalkylcarbonyl group, [8B-10] a (C.sub.1-3
alkyl).sub.m8c-aminosulfonyl group (m8c:1-2), [8B-11] a C.sub.1-3
alkylsulfonyl (C.sub.0-3 alkyl) amino group, [8B-12] a (C.sub.1-5
alkyl).sub.m8a-amino group (m8d:0-1) which may be substituted by
1-2 R.sup.8B4 substituent(s), [8B-13] a hydroxy, or [8B-14] a
(C.sub.1-3 alkyl).sub.m8e-aminocarbonyl group (m8e:0-1).
[0550] R.sup.8B1 is preferably
[8B1-1] a C.sub.3-6 cycloalkyl group, [8B1-2] a hydroxy, [8B1-3] a
C.sub.1-8 alkoxy group which may be substituted by 1-2 C.sub.1-5
alkoxy group(s), or [8B1-4] a cyano, More preferably [8B1-1] a
C.sub.3-5 cycloalkyl group, [8B1-2] a hydroxy, [8B1-3] a C.sub.1-8
alkoxy group which may be substituted by 1 C.sub.1-3 alkoxy group,
or [8B1-4] a cyano,
[0551] R.sup.8B2 is preferably
[8B2-1] a halogen atom, [8B2-2] a C.sub.1-6 alkyl group, [8B2-3] an
oxo, [8B2-4] a hydroxy, or [8B2-5] a deuterium atom, more
preferably [8B2-1] a fluorine atom, [8B2-2] a C.sub.1-3 alkyl
group, [8B2-3] an oxo, or [8B2-4] a hydroxyl.
[0552] R.sup.8B3 is preferably
[8B3-1] a (C.sub.1-6 alkyl).sub.m8f-amino group (m8f:0-2), more
preferably [8B3-1] a (C.sub.1-3 alkyl).sub.m8f-amino group (m8f:
2).
[0553] R.sup.8B4 is preferably
[8B4-1] a C.sub.3-6 cycloalkyl group, or [8B4-2] a hydroxy;
[0554] R.sup.8C is preferably
[8C-1] a hydroxyl, [8C-2] a (C.sub.1-3 alkyl).sub.m8h-amino group
(m8h:0-1) which may be substituted by a (C.sub.1-3
alkyl).sub.m8i-aminosulfonyl group (m8i:0-2), [8C-3] a C.sub.1-3
alkylsulfonyl group,
[0555] R.sup.8D1 is preferably
[8D-1] a C.sub.1-6 alkyl group which may be substituted by a
R.sup.8D1 substituent, [8D-2] a hydroxy group, [8D-3] a C.sub.1-3
alkylsulfonyl group, or [8D-4] a C.sub.1-4 alkoxycarbonyl
group;
[0556] R.sup.8D1 is preferably
[8D1-1] a hydroxy group, or [8D1-2] a C.sub.1-3 alkoxy group;
[0557] R.sup.8H is preferably
[8H-1] a 4- to 6-membered heterocycloalkyl group,
[0558] R.sup.8E is preferably
[8E-1] a hydroxy group, [8E-2] a C.sub.1-8 alkoxy group which may
be substituted by 1-2 R.sup.8E7 substituent(s), [8E-3] a C.sub.1-3
alkylsulfonyl group, [8E-4] a C.sub.1-4 alkoxycarbonyl group,
[8E-5] a 4- to 6-membered nitrogen-containing
heterocycloalkylcarbonyl group which may be substituted by 1-2
R.sup.8E1 substituent(s), [8E-6] a (C.sub.1-5 alkyl).sub.m8k1-amino
group (m8k1: 0.about.2) which may be substituted by a R.sup.8E2
substituent, [8E-7] a 4- to 6-membered heterocycloalkyl group which
may be substituted by 1-4 R.sup.8E3 substituent(s), [8E-8] a 5- to
6-membered heteroaryl group, [8E-9] a (C.sub.1-6
alkyl).sub.m8k2-aminocarbonyl group (m8k2: 0.about.2) which may be
substituted by 1-2 R.sup.8E6 substituent(s), [8E-10] a C.sub.1-5
alkoxy group which may be substituted by a R.sup.8E7 substituent,
[8E-11] a C.sub.1-3 alkylthio group, [8E-12] a C.sub.1-3
alkylsulfinyl group, [8E-13] a C.sub.1-5 alkylsulfonyl group,
[8E-14] a C.sub.1-3 alkylsulfonyl (C.sub.0-8 alkyl) amino group,
[8E-15] a 4- to 6-membered heterocycloalkylsulfonyl (C.sub.0-3
alkyl) amino group which may be substituted by 1-3 C.sub.1-5 alkyl
group(s); [0559] more preferably [8E-1] a (C.sub.1-3
alkyl).sub.m8k1-amino group (m8k1: 2) which may be substituted by
one or more R.sup.8E2 [8E-2] a C.sub.1-8 alkoxy group which may be
substituted by one or more R.sup.8E7 [8E-3] a C.sub.1-3
alkylsulfonyl group, [8E-4] a (C.sub.1-5 alkyl).sub.m8k1-amino
group (m8k1: 0.about.2) which may be substituted by a R.sup.8E2
substituent, [8E-5] a 4- to 6-membered heterocycloalkyl group which
may be substituted by 1-4 R.sup.8E3 substituent(s), [8E-6] a 4- to
6-membered heterocycloalkylsulfonylamino group which may be
substituted by 1-2 C.sub.1-3 alkyl group(s);
[0560] R.sup.8E1 is preferably
[8E1-1] a C.sub.1-4 alkoxycarbonyl group, [8E1-2] a C.sub.1-3
alkanoyl group, 2 0 [8E1-3] a C.sub.1-5 alkylsulfonyl group,
[8E1-4] a (C.sub.1-3 alkyl).sub.m8k3-aminosulfonyl group (m8k3:
0.about.2), [8E1-5] a 4- to 6-membered heterocycloalkyl group;
[0561] R.sup.8E2 is preferably
[8E2-1] a hydroxy group, [8E2-2] a C.sub.1-6 alkoxycarbonyl group,
[8E2-3] a C.sub.3-6 cycloalkyl group which may be substituted by a
C.sub.1-8 alkyl group which may be substituted by a hydroxy,
[8E1-4] a C.sub.1-5 alkanoyl group which may be substituted by 1-3
substituent(s) selected from the group consisting of [1] a
(C.sub.1-3 alkyl).sub.m8k4-amino group (m8k4: 0.about.2) and [2] a
halogen atom, [8E2-5] a (C.sub.1-3 alkyl).sub.m8k5-aminocarbonyl
group (m8k5: 0.about.2), [8E2-6] a C.sub.1-3 alkylsulfonyl group,
[8E2-7] a (C.sub.1-3 alkyl).sub.m8k6-aminosulfonyl group (m8k6:
0.about.1) which may be substituted by a C.sub.1-4 alkoxycarbonyl
group. more preferably [8E2-1] a hydroxy group.
[0562] R.sup.8E3 is preferably
[8E3-1] a C.sub.1-6 alkyl group which may be substituted by 1-3
substituent(s) selected from the group consisting of [1] a hydroxy
group or [2] a C.sub.1-3 alkylcarbonyloxy group, [8E3-2] a
C.sub.1-4 alkylcarbonyloxy group, [8E3-3] a hydroxy group, [8E3-4]
a C.sub.3-5 cycloalkyl group, [8E3-5] a C.sub.1-4 alkoxycarbonyl
group, [8E3-6] a C.sub.1-5 alkylsulfonyl group, [8E3-7] a
(C.sub.1-3 alkyl).sub.m8k8-aminocarbonyl group (m8k8: 0.about.2),
[8E3-8] a C.sub.1-3 alkanoyl group which may be substituted by a
hydroxy, [8E3-9] an oxo group, or [8E3-10] a 4- to 6-membered
heterocycloalkyl group which may be substituted by 1-3
substituent(s) selected from the group consisting of [1] a
C.sub.1-3 alkanoyl group, [2] a C.sub.1-4 alkoxycarbonyl group, or
[3] a C.sub.1-3 alkylsulfonyl group; [0563] more preferably [8E3-1]
a (C.sub.1-3 alkyl).sub.m8k8-aminocarbonyl group (m8k8: 0.about.2),
or [8E3-2] an oxo group;
[0564] R.sup.8E4 is preferably
[8E4-1] a 4- to 6-membered heterocycloalkyl group, [8E4-2] a
C.sub.1-3 alkanoyl group, [8E4-3] a C.sub.1-3 alkoxycarbonyl group,
[8E4-4] a C.sub.1-3 alkylsulfonyl group, [8E4-5] a C.sub.1-3
alkylaminosulfonyl group;
[0565] R.sup.8E6 is preferably
[8E6-1] a C.sub.2-3 alkenylcarbonyloxy group, [8E6-2] a hydroxy
group, [8E6-3] a cyano, [8E6-4] a (C.sub.1-3 alkyl).sub.m89-amino
group (m8k9: 0.about.2) which may be substituted by 1-2 hydroxy
group(s), [8E6-5] a C.sub.1-3 alkoxy group which may be substituted
by a hydroxy, [8E6-6] a C.sub.1-4 alkylcarbonyloxy group, [8E6-7] a
4- to 6-membered heterocycloalkyl group which may be substituted by
1-3 C.sub.1-8 alkyl group(s), [8E6-8] a 5- to 6-membered heteroaryl
group;
[0566] R.sup.8E7 is preferably
[8E7-1] a hydroxy group, [8E7-2] a C.sub.1-3 alkoxy group which may
be substituted by a hydroxy;
[0567] R.sup.8F is preferably
[8F-1] a C.sub.1-5 alkyl group which may be substituted by 1-3
R.sup.8F1 substituent(s), [8F-2] a C.sub.3-6 cycloalkyl group,
[8F-3] a C.sub.1-3 alkanoyl group which may be substituted by 1-7
halogen atom(s), [8F-4] a C.sub.1-5 alkylcarbonyloxy group, [8F-5]
a C.sub.1-5 alkoxycarbonyl group, [8F-6] a 4- to 6-membered
heterocycloalkyl group which may be substituted by 1-3 R.sup.8F2
substituent(s), [8F-7] a C.sub.1-5 alkylsulfonyl group, or [8F-8] a
hydroxy group; More preferably [8F-1] a C.sub.1-3 alkyl group which
may be substituted by a R.sup.8F substituent,] [8F-2] a C.sub.3-5
cycloalkyl group, [8F-3] a 4- to 6-membered heterocycloalkyl group
which may be substituted by a R.sup.8F2 substituent, [8F-4] a
C.sub.1-3 alkylsulfonyl group,
[0568] R.sup.8F1 is preferably
[8F1-1] a hydroxy group, [8F1-2] a C.sub.1-8 alkoxy group, or
[8F1-3] a halogen atom;
[0569] R.sup.8F2 is preferably
[8F2-1] a 4- to 6-membered heterocycloalkyl group, [8F2-2] a
C.sub.1-5 alkoxycarbonyl group, or [8F2-3] a C.sub.1-3
alkylsulfonyl group,
[0570] R.sup.8G is preferably
[8G-1] a hydroxycarbonyl group, [8G-2] a hydroxy group, or [8G-3] a
(C.sub.1-5 alkyl).sub.m8l3-amino group (m8l3: 0.about.2),
[0571] R.sup.9 is preferably
[1] a hydrogen atom, [2] a C.sub.1-8 alkyl group which may be
substituted by 1-8 R.sup.9A substituent(s), [3] a C.sub.2-6 alkenyl
group, [4] a C.sub.2-8 alkynyl group which may be substituted by
1-6 R.sup.9C substituent(s), [5] a C.sub.3-6 cycloalkyl group, [6]
a 4- to 6-membered heterocycloalkyl group which may be substituted
by 1-5 R.sup.9D substituent(s), [7] a C.sub.6 aryl group which may
be substituted by 1-2 R.sup.9E substituent(s), [8] a 5- to
6-membered heteroaryl group which may be substituted by 1-3
C.sub.1-5 alkyl group(s), [9] a cyano, [10] a C.sub.1-6 alkanoyl
group, [11] a 4- to 6-membered nitrogen-containing
heterocycloalkylcarbonyl group which may be substituted by a
C.sub.1-5 alkyl group, [12] a halogen atom, [13] a (C.sub.1-4
alkyl).sub.m9c-amino group (m9c: 0.about.2) which may be
substituted by a R.sup.9F substituent, [14] a hydroxy, [15] a
C.sub.1-6 alkoxy group which may be substituted by 1-5 R.sup.9G
substituent(s), [16] a 4- to 6-membered heterocycloalkyloxy group
which may be substituted by one or two 4- to 6-membered
heterocycloalkyl group(s), [17] a C.sub.1-5 alkylthio group which
may be substituted by (C.sub.1-3 alkyl).sub.m9f-amino group(s)
(m9f: 0.about.2), [18] a C.sub.1-5 alkylsulfonyl group which may be
substituted by (C-3 alkyl).sub.m9g-amino group(s) (m9g: 0.about.2),
[19] a (C.sub.1-3 alkyl).sub.m9h-aminosulfonyl group (m9h:
0.about.2), [20] a 4- to 6-membered nitrogen-containing
heterocycloalkylsulfonyl group which may be substituted by a
C.sub.1-3 alkyl group; More preferably [1] a hydrogen atom, [2] a
C.sub.1-6 alkyl group which may be substituted by a R.sup.9A
substituent, [3] a C.sub.2-5 alkenyl group, [4] a C.sub.2-8 alkynyl
group which may be substituted by a R.sup.9C substituent, [5] a
C.sub.3-6 cycloalkyl group, [6] a 4- to 6-membered heterocycloalkyl
group which may be substituted by a R.sup.9D substituent, [7] a 5-
to 6-membered heteroaryl group which may be substituted by a
C.sub.1-5 alkyl group, [8] a cyano, [9] a C.sub.1-3 alkanoyl group,
[10] a halogen atom, [11] a (C.sub.1-4 alkyl).sub.m9b-n amino group
(m9b: 0), [12] a hydroxy, [13] a C.sub.1-6 alkoxy group which may
be substituted by 1-3 R.sup.9G substituent(s), [14] a 4- to
6-membered heterocycloalkyloxy group which may be substituted by a
4- to 6-membered heterocycloalkyl group, Even more preferably [1] a
hydrogen atom, [2] a C.sub.1-8 alkyl group which may be substituted
by one or more R.sup.9A substituent(s), [3] a C.sub.2-8 alkenyl
group which may be substituted by one or more R.sup.9B
substituent(s), [4] a C.sub.2-8 alkynyl group which may be
substituted by one or more R.sup.9C substituent(s), [5] a C.sub.3-8
cycloalkyl group, [6] a halogen atom, Still more preferably [1] a
hydrogen atom, [2] a C.sub.1-8 alkyl group which may be substituted
by one or more R.sup.9A substituent(s), [3] a C.sub.2-8 alkynyl
group which may be substituted by one or more R.sup.9C
substituent(s). R.sup.9A is preferably [9A-1] a C.sub.3-6
cycloalkyl group, [9A-2] a 4- to 6-membered heterocycloalkyl group
which may be substituted by 1-3 R.sup.9A1 substituent(s), [9A-3] a
hydroxy group, or [9A-4] a C.sub.1-6 alkoxy group, More preferably
[9A-1] a 4- to 6-membered heterocycloalkyl group which may be
substituted by a R.sup.9A1 substituent, [9A-2] a hydroxy group, or
[9A-3] a C.sub.1-3 alkoxy group,
[0572] R.sup.9A1 is preferably
[9A1-1] a C.sub.1-5 alkyl group, [9A1-2] a C.sub.3-5 cycloalkyl
group, or [9A1-3] a 4- to 6-membered heterocycloalkyl group, More
preferably [9A1-1] a C.sub.1-3 alkyl group, [9A1-2] a C.sub.3
cycloalkyl group, or [9A.sup.1-3] a 4-membered heterocycloalkyl
group,
[0573] R.sup.9C is preferably
[9C-1] a C.sub.1-8 alkoxy group, [9C-2] a (C.sub.1-5
alkyl).sub.m9b-amino group (m9b: 0.about.2) which may be
substituted by 1-2 C.sub.6 aryl group(s), [9C-3] a 4- to 6-membered
heterocycloalkyl group which may be substituted by 1-3 R.sup.9C1
substituent(s), [9C-4] a C.sub.3-6 cycloalkyl group, [9C-5] a
hydroxy group, or [9C-6] a hydroxycarbonyl group; More preferably
[9C-1] a C.sub.1-5 alkoxy group, [9C-2] a (C.sub.1-3
alkyl).sub.m9b-amino group (m9b: 2) which may be substituted by 1-2
C.sub.6 aryl group(s), [9C-3] a 4- to 6-membered heterocycloalkyl
group which may be substituted by 1-2 R.sup.91 substituent(s),
[9C-4] a C.sub.3-5 cycloalkyl group, [9C-5] a hydroxy group.
[0574] R.sup.9C1 is preferably
[9C1-1] a C.sub.3-5 cycloalkyl group, [9C1-2] a 4- to 6-membered
heterocycloalkyl group, or [9C1-3] an oxo group, More preferably
[9C1-1] a C.sub.3 cycloalkyl group, [9C1-2] a 4- to 6-membered
heterocycloalkyl group, or [9C1-3] an oxo group,
[0575] R.sup.9D is preferably
[9D-1] a C.sub.1-5 alkyl group which may be substituted by one or
two 4- to 6-membered heterocycloalkyl group(s), [9D-2] a C.sub.3-5
cycloalkyl group, [9D-3] a 4- to 6-membered heterocycloalkyl group,
or [9D-4] a C.sub.1-3 alkylsulfonyl group; More preferably [9D-1] a
C.sub.1-5 alkyl group which may be substituted by a 4- to
6-membered heterocycloalkyl group, [9D-2] a 4- to 6-membered
heterocycloalkyl group, or [9D-3] a methylsulfonyl group;
[0576] R.sup.9E is preferably
[9E-1] a halogen atom, [9E-2] a hydroxy group, [9E-3] a
hydroxycarbonyl group, or [9E-4] a C.sub.1-3 alkyl group which may
be substituted by a hydroxy;
[0577] R.sup.9F is preferably
[9F-1] a C.sub.1-3 alkylsulfonyl group, [9F-2] a (C.sub.1-3
alkyl).sub.m9f1-aminosulfonyl group (m9f1: 0.about.2), or [9F-3] a
C.sub.1-3 alkanoyl group which may be substituted by (C.sub.1-3
alkyl).sub.m9f2-amino group(s) (m9f2: 0.about.2),
[0578] R.sup.9G is preferably
[9G-1] a hydroxy group, [9G-2] a hydroxycarbonyl group, [9G-3] a
C.sub.6 aryl group which may be substituted by C.sub.1-3 alkoxy
group(s), [9G-4] a (C.sub.1-3 alkyl).sub.m9gl-amino group (m9g1:
0.about.2), [9G-5] a C.sub.1-5 alkoxy group which may be
substituted by 1-3 R.sup.9G1 substituent(s), or [9G-6] a 5- to
6-membered heteroaryl group; More preferably [9G-1] a hydroxy
group, [9G-2] a (C.sub.1-3 alkyl).sub.m9g1-amino group (m9g1:
0.about.2), [9G-3] a C.sub.1-3 alkoxy group which may be
substituted by a R.sup.9G substituent, or [9G-4] a 5- to 6-membered
heteroaryl group;
[0579] R.sup.9G1 is preferably
[9G1-1] a C.sub.1-3 alkoxy group, or [9G1-2] a hydroxycarbonyl
group.
[0580] Preferably, A.sup.5 is NH, while the remaining are C,
R.sup.3 is a cyano group, R.sup.6 and R.sup.6' are methyl, R.sup.8
is (1) a hydrogen atom, (2) a C.sub.1-8 alkyl group which may be
substituted by one or more R.sup.8A, (3) a C.sub.2-8 alkenyl group,
(4) a 4- to 10-membered heterocycloalkyl group which may be
substituted by one or more R.sup.8B, (5) a 5- to 14-membered
heteroaryl group which may be substituted by a C.sub.1-8 alkyl
group, (6) a (C.sub.1-8 alkyl).sub.m8g-aminocarbonyl group which
may be substituted by one or more R.sup.C, (7) a 4- to 10-membered
nitrogen-containing heterocycloalkylcarbonyl group which may be
substituted by one or more R.sup.8D, (8) a hydroxycarbonyl group,
(9) a C.sub.0-8 alkoxy (C.sub.0-8 alkyl) aminocarbonyl group which
may be substituted by one or more hydroxy group(s), (10) a halogen
atom, (11) a hydroxy group, (12) a C.sub.1-8 alkoxy group which may
be substituted by one or more R.sup.E, (13) a 4- to 10-membered
heterocycloalkyloxy group which may be substituted by one or more
R.sup.8F, (14) an aminosulfonyloxy group which may be substituted
by one or more C.sub.1-8 alkyl group(s), (15) a C.sub.1-8 alkyl
thio group which may be substituted by a (C.sub.1-8 alkyl)-amino
group, or (16) a C.sub.1-8 alkylsulfonyl group which may be
substituted by R.sup.8G, R.sup.9 is (1) a hydrogen atom, (2) a
C.sub.1-8 alkyl group which may be substituted by one or more
R.sup.9A, (3) a C.sub.2-8 alkenyl group which may be substituted by
one or more R.sup.9B, (4) a C.sub.2-8 alkynyl group which may be
substituted by one or more R.sup.9C, (5) a C.sub.3-8 cycloalkyl
group, (6) a 4- to 10-membered heterocycloalkyl group which may be
substituted by one or more R.sup.9D, (7) a C.sub.6-aryl group which
may be substituted by one or more R.sup.9E, (8) a 5- to 14-membered
heteroaryl group which may be substituted by a C.sub.1-8 alkyl
group, (9) a cyano group, (10) a C.sub.1-8 alkanoyl group, (11) a
4- to 10-membered nitrogen-containing heterocycloalkylcarbonyl
group which may be substituted by a C.sub.1-8 alkyl group, (12) a
halogen atom, (13) a (C.sub.1-8 alkyl).sub.m9e-amino group which
may be substituted by one or more R.sup.9F, (14) a C.sub.1-8
alkylsulfonylamino group, (15) a nitro group, (16) a hydroxy group,
(17) a C.sub.1-8 alkoxy group which may be substituted by one or
more R.sup.9G, (18) a C.sub.1-8 alkyl thio group which may be
substituted by a (C.sub.1-8 alkyl).sub.m9f-amino group, (19) a
C.sub.1-8 alkylsulfonyl group which may be substituted by a
(C.sub.1-8 alkyl).sub.m9g-amino group, (20) a (C.sub.1-8
alkyl).sub.m9h-aminosulfonyl group, or (21) a 4- to 10-membered
nitrogen-containing heterocycloalkylsulfonyl group which may be
substituted by a C.sub.1-8 alkyl group, and R.sup.1, R.sup.2,
R.sup.5, R.sup.7 and R.sup.10 are defined above.
[0581] More preferably, A.sup.5 is NH while the remaining are C,
R.sup.3 is a cyano group, R.sup.6 and R.sup.6' are methyl groups,
R.sup.8 is (1) a hydrogen atom, (2) a C.sub.1-8 alkyl group which
may be substituted by one or more R.sup.8A, (3) a 4- to 10-membered
heterocycloalkyl group which may be substituted by one or more
R.sup.8B, or (4) a C.sub.1-8 alkoxy group which may be substituted
by one or more R.sup.8E, R.sup.9 is (1) a hydrogen atom, (2) a
C.sub.1-8 alkyl group which may be substituted by one or more
R.sup.9A, (3) a C.sub.2-8 alkynyl group which may be substituted by
one or more R.sup.9C, (4) a C.sub.3-8 cycloalkyl group, or (5) a
halogen atom, and R.sup.1, R.sup.2, R.sup.5, R.sup.7 and R.sup.10
are an hydrogen atom.
[0582] According to the present invention, examples of the salts of
the compounds that are represented by the Formula (I) include
hydrochloric acid salt, hydrobromic acid salt, hydriodic acid salt,
phosphoric acid salt, phosphonic acid salt, sulfuric acid salt,
sulfonic acid salt such as methanesulfonic acid salt, p-toluene
sulfonic acid salt and the like, carboxylic acid salt such as
acetic acid salt, citric acid salt, malic acid salt, tartaric acid
salt, succinic acid salt, salicylic acid salt and the like, or
alkali metal salt such as sodium salt, potassium salt and the like,
alkaline earth metal salt such as magnesium salt, calcium salt and
the like, ammonium salt such as ammonium salt, alkyl ammonium salt,
dialkyl ammonium salt and trialkyl ammonium salt tetraalkyl
ammonium salt. Preferably, the salts are pharmaceutically
acceptable salts. These salts are produced by brining the compounds
described above in contact with an acid or a base which can be used
for the production of a pharmaceutical product.
[0583] According to the present invention, the compounds that are
represented by the Formula (I) or salts thereof can be an anhydride
or a solvate such as a hydrate and the like. Herein, the term
"solvate (d)" indicates a phenomenon by which solute molecules or
ions contained in a solution strongly attract neighboring solvent
molecules to form a huge group of molecules. When the solvent is
water, it is called "hydrate (d)." The solvate can be any one of a
hydrate and a non-hydrate. Preferably, the solvates are
pharmaceutically acceptable solvates. For the non-hydrate, alcohol
(for example, methanol, ethanol, n-propanol), dimethylformamide and
the like can be used.
[0584] The compounds of the present invention and salts thereof may
be present in several tautomer forms, for example, enol and imine
form, keto and enamine form, and a mixture thereof. In a solution,
a tautomer is present as a mixture of tautomeric set. In case of
solid form, one type of tautomer is generally present in dominant
ratio. In this regard, even if only one type of tautomer is
described, the present invention includes all types of tautomer of
the compounds of the present invention.
[0585] The present invention includes all types of stereoisomer of
the compounds of the present invention that are represented by the
Formula (I) (for example, enantiomer, diastereomer (including cis
and trans geometric isomer)), racemate of the isomer and a mixture
thereof. For example, the compounds having the Formula (I) of the
present invention may have one or more asymmetric center, and the
present invention includes a racemic mixture, a diastereomer
mixture and enantiomer of such compound.
[0586] When the compounds of the present invention are obtained in
free form, they can be converted into a salt, a hydrate or solvate
thereof which can be formed from the compounds according to a
method generally known in the art.
[0587] Further, when the compounds of the present invention are
obtained in the form of a salt, hydrate or solvate of the
compounds, they can be converted to free form according to a method
generally known in the art.
[0588] The present invention include all isotopes of compounds that
are represented by the Formula (I). The isotopes of the compounds
of the present invention indicate the compounds of the present
invention in which at least one atom is substituted by an atom with
the same atomic number (i.e., number of protons) but with different
mass number (sum of the number of protons and the number of
neutrons). Example of the isotopes that are included in the
compounds of the present invention includes a hydrogen atom, a
carbon atom, a nitrogen atom, an oxygen atom, a phosphorus atom, a
sulfur atom, a fluorine atom, a chlorine atom and the like, and
.sup.2H, .sup.3H, .sup.13C, .sup.14C, .sup.15N, .sup.17O, .sup.18O,
.sup.31P, .sup.32P, .sup.35S, .sup.18F, .sup.36Cl and the like are
included. In particular, a radioisotope which decays by emitting
radiation, for example .sup.3H and .sup.14C, are useful for
determining the distribution of a pharmaceutical agent or a
compound in a living tissue, etc. On the other hand, a stable
isotope does not degrade and remains in almost the same amount
without exhibiting radioactivity, and therefore can be safely used.
Isotopes of the compounds of the present invention can be converted
by replacing a chemical reagent used for synthesis with a chemical
reagent comprising a corresponding radioisotope according to a
method generally known in the art.
[0589] Further, the compounds (I) of the present invention can be
administered in the form of prodrug. Herein, the term "prodrug"
indicates the derivatives of the compounds having the Formula (I)
that can be converted to the compounds having the Formula (I) or
salts or solvates thereof after administration by enzymatic or
non-enzymatic degradation under a physiological condition. The
prodrug can be in inactive form when it is administered to a
patient. However, in organisms, it converts to the compounds having
the Formula (I) and present therein in the active form.
[0590] For example, the prodrug converts into desired drug form at
specific pH or by an enzymatic action. Conventional prodrug is a
compound having a hydrolyzable ester residue which produces a free
acid in organisms. Examples of such hydrolyzable ester residue
include a residue having a carboxyl moiety of which free hydrogen
(for example, a free hydrogen in a carboxyl group when Y in the
Formula (I) has a carboxyl group) is replaced by a C.sub.1-4 alkyl
group, a C.sub.2-7 alkanoyloxymethyl group, a 1-(alkanoyloxy)ethyl
group having 4 to 9 carbon atoms, a 1-methyl-1-(alkanoyloxy)-ethyl
group having 5 to 10 carbon atoms, an alkoxycarbonyloxymethyl group
having 3 to 5 carbon atoms, a 1-(alkoxycarbonyloxy)ethyl group
having 4 to 7 carbon atoms, a 1-methyl-1-(alkoxycarbonyloxy)ethyl
group having 5 to 8 carbon atoms, a N-(alkoxycarbonyl)aminomethyl
having 3 to 9 carbon atoms, a 1-(N-(alkoxycarbonyl)amino)ethyl
group having 4 to 10 carbon atoms, a 3-phthalidyl group, a
4-crotonolactonyl group, a y-butyrolacton-4-yl group, a
di-N,N--(C.sub.1-2)alkylamino(C.sub.2-3)alkyl group (for example,
N,N-dimethylaminoethyl group), a carbamoyl(C.sub.1-2)alkyl group, a
N,N-di(C.sub.1-2)alkylcarbamoyl-(C.sub.1-2)alkyl group, a
piperidino(C.sub.2-3)alkyl group, a pyrrolidino(C.sub.2-3)alkyl
group, or a morpholino(C.sub.2-3) alkyl group, but not limited
thereto.
Representative Preparation Method
[0591] The compounds having the Formula (I) of the present
invention can be produced by the method described below, for
example. However, method of preparing the compounds of the present
invention is not limited thereto. Further, depending on necessity,
order of the reaction step like introduction of a substituent
group, etc. can be changed. Although the compounds of the present
invention are novel compounds which have not been described in
literatures, they can be prepared according to a chemical method
that is generally known in the art. Still further, as for the
reacting compounds that are used for the preparation, commercially
available ones can be used or they can be produced according to a
method that is generally known in the art depending on
necessity.
[0592] In the following reaction schemes showing the reaction step,
A.sup.1 to A.sup.10 and R.sup.1 to R.sup.10 are as defined in the
Formula (I). PR.sup.1 to PR.sup.10 are the same as R.sup.1 to
R.sup.10 that are defined in the Formula (I) or represent a group
which can be converted to R.sup.1 to R.sup.1I according to
modification or deprotection of a functional group.
[0593] Other abbreviated symbols described in the following
reaction schemes have the general meanings that can be understood
by a skilled person in the art.
[0594] PG represents a protecting group (for example, methyl,
ethyl, t-butyl, benzyl, substituted benzyl, acetyl,
t-butoxycarbonyl, benzyloxycarbonyl, methanesulfonyl,
trifluoromethanesulfonyl, trimethylsilyl, triethylsilyl,
triisopropylsilyl, t-butyldimethylsilyl, tetrahydropyranyl and the
like). In the preparation method described below, when a defined
group is subjected to undesirable chemical modification under a
condition for implementing the method, the preparation can be
carried out by using means such as protection and deprotection of a
functional group, etc.
[0595] Herein, regarding selection, addition and removal of a
protecting group include the methods described in "Protective
Groups in Organic Synthesis" (Greene and Wuts, 4.sup.th edition,
John Wiley & Sons 2007), and they can be suitably employed
according to each reaction condition.
[0596] LG represents a leaving group such as fluorine, chlorine,
bromine, iodine, methanesulfonate, trifluoromethanesulfonate and
the like, which can be applied for the reaction described
above.
[0597] In addition, abbreviated symbols that are typically used to
describe the general synthetic method and examples below and names
of the chemical reagents and solvents corresponding to the chemical
formulae are listed in the following.
[0598] 9-BBN 9-borabicyclo[3.3.1]nonane
[0599] AcOH acetic acid
[0600] BINAP 2,2'-bis (diphenylphosphino)-1,1'-binaphthyl
[0601] BF.sub.3OEt.sub.2 trifluoroboron etherate
[0602] t-BuOK potassium t-butoxy
[0603] n-BuLi n-butyl lithium
[0604] t-BuONa sodium t-butoxy
[0605] CDI carbonyl diimidazole
[0606] CPME c-pentylmethyl ether
[0607] DBU 1,8-diazabicyclo[5.4.0]-7-undecene
[0608] DCM dichloromethane
[0609] DEAD diethyl azodicarboxylate
[0610] DDQ 2,3-dichloro-5,6-dicyano-p-benzoquinone
[0611] DIPEA N,N-diisopropylethylamine
[0612] DMA N,N-dimethylacetamide
[0613] DME dimethoxyethane
[0614] DMF N,N-dimethyl formamide
[0615] DMSO dimethyl sulfoxide
[0616] DPPF bis (diphenylphosphino)ferrocene
[0617] EDC 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide
hydrochloride
[0618] EtOAc ethyl acetate
[0619] HOBt 1-hydroxybenzotriazole
[0620] KHMDS potassium hexamethyldisilazide
[0621] LDA lithium diisopropylamide
[0622] LiHMDS lithium hexamethyldisilazide
[0623] MeCN acetonitrile
[0624] Mel methyl iodide
[0625] MeOH methanol
[0626] MTBE t-butylmethyl ether
[0627] NaHMDS sodium hexamethyldisilazide
[0628] NMP N-methylpyrrolidone
[0629] Pd.sub.2(dba).sub.3 tris (dibenzylideneacetone) dipalladium
(O)
[0630] Pd(OAc).sub.2 palladium acetate
[0631] PdCl.sub.2(CH.sub.3CN).sub.2 dichloro(bisacetonitrile)
palladium (II)
[0632] PdCl.sub.2(PPh.sub.3).sub.2 dichlorobis (triphenylphosphine)
palladium (II)
[0633] Pd(PPh.sub.3).sub.4 tetrakis (triphenylphosphine) palladium
(O)
[0634] P(t-Bu).sub.3 tri t-butylphosphine
[0635] PPh.sub.3 triphenylphosphine
[0636] P(o-tol).sub.3 tri o-tolylphosphine
[0637] TEA triethylamine
[0638] TEMPO 2,2,6,6-tetramethylpiperidin-1-oxyl
[0639] TFA trifluoroacetic acid
[0640] TFAA trifluoroacetic anhydride
[0641] TFE trifluoroethanol
[0642] THF tetrahydrofuran
[0643] TMAD 1,1'-azobis (N,N-dimethylformamide)
[0644] TMSC trimethylsilyl chloride
[0645] TMSI trimethylsilyl iodide
[0646] DavePhos
2-dicyclohexylphosphino-2'-(N,N-dimethylamino)biphenyl
[0647] JohnPhos 2-(di-t-butylphosphino)biphenyl
[0648] c-Hexyl JohnPhos 2-(dicyclohexylphosphino)biphenyl
[0649] S-Phos 2',6'-dimethoxy-2-(dicyclohexylphosphino)biphenyl
[0650] X-Phos
2',4',6'-triisopropyl-2-(dicyclohexylphosphino)biphenyl
[0651] t-ButylX-Phos
2',4',6'-triisopropyl-2-(di-t-butylphosphino)biphenyl
[0652] Xantphos 4,5'-bis
(diphenylphosphino)-9,9'-dimethylxanthene
Preparation Method I
[0653] This is one of the methods for producing the compounds of
the Formula (I) in which A.sup.5 is N and R.sup.5 is H.
##STR00003##
Step I-1
[0654] It is an alkylation step of a cyclic ketone derivative Ia.
The step can be carried out by reacting cyclic ketone derivative Ia
with an alkylating agent corresponding to R.sup.6 and R.sup.6' in
the presence of a base. For example, it can be carried out in view
of the method described in Journal of the American Chemical
Society, 115(23), 10628-36; 1993 and Organic Letters, 9(24),
5027-5029; 2007, etc. The reaction is carried out in a solvent
under the condition of a reaction temperature of -20.degree. C. to
boiling point of the solvent, in the presence or the absence of a
catalyst. When R.sup.6 and R.sup.6' are atomic groups other than a
hydrogen atom, the reaction order can be optionally selected, and
separation and purification can be carried out at each step or the
reaction can be carried out continuously.
[0655] As for the alkylating agent, examples thereof include an
alkyl halide such as Mel, ethyl iodide, 2-iodopropane,
1,4-dibromobutane, 1,1'-oxybis (2-bromoethane) and the like,
dimethyl sulfate, and sulfonic acid ester such as
methylmethanesulfonate, methyl tosylate and
methyltrifluoromethanesulfonate. Preferably, it is an alkyl halide
such as Mel and the like. As for the catalyst, examples thereof
include a phase transfer catalyst such as tetrabutylammonium
chloride and tetrabutylammonium hydrogen sulfate. Preferably, it is
tetrabutylammonium hydrogen sulfate. As for the base, examples
thereof include an inorganic base such as sodium hydroxide,
potassium hydroxide, sodium carbonate, potassium carbonate, cesium
carbonate, sodium hydride, potassium hydride, calcium hydride and
the like or an organic base such as t-BuOK, t-BuONa, pyridine, TEA,
DIPEA, LDA, LiHMDS and n-BuLi. Preferably, it is potassium
hydroxide, potassium t-butoxy, or sodium t-butoxy. As for the
solvent, examples thereof include toluene, xylene, n-hexane,
cyclohexane, DMF, DMA, EtOAc, DMSO, dichloromethane, carbon
tetrachloride, THF, dioxane, acetonitrile, water, methanol, ethanol
and a mixture thereof. Preferably, it is a mixture solvent of
water-THF or THF.
Step I-2
[0656] It is the synthesis of carbazole skeleton Id according to
Fischer method. This step is generally carried out by using cyclic
ketone Ib in the presence of hydrazine compound Ic and an acid in a
solvent or by using an acid as a solvent under the condition of a
reaction temperature of 0.degree. C. to boiling point of the
solvent, and also can be carried out in view of the method
described in Journal of Heterocyclic Chemistry, 28(2), 321-3; 1991
and Bioorganic & Medicinal Chemistry Letters (2008), 18(24),
6479-6481. Further, when the reaction proceeds slowly, a zinc
chloride catalyst and the like can be also used in view of the
reaction condition disclosed in Organic Letters (2006), 8(3),
367-370. The reaction consists of a step of producing phenyl
hydrazone and a step of sigmatropic rearrangement. Separation and
purification can be carried out at each step or the reaction can be
carried out continuously. Further, according to the structure of
aryl hydrazine, which is a reacting material of this reaction step,
mixture of a position isomer can be obtained as a reaction product.
Such position isomer can be separated from each other or used as a
mixture for the next reaction step.
[0657] As for the acid used for the reaction, examples thereof
include formic acid, acetic acid, methanesulfonic acid,
p-toluenesulfonic acid, benzenesulfonic acid, TFA, hydrochloric
acid, sulfuric acid and pyridinium p-toluenesulfonate. Preferably,
it is acetic acid, sulfuric acid, or TFA. As for the solvent,
examples thereof include toluene, xylene, NMP, DMF, DMA, DMSO,
sulfolane, dioxane, DME, TFE, diethylene glycol, triethylene glycol
and a mixture thereof.
Step I-3
[0658] It is a step of oxidation at benzyl at 11-position of
carbazole skeleton Id. This step is carried out by applying an
oxidizing agent to a substrate in a solvent in the presence or
absence of a catalyst under the condition of a reaction temperature
of -20.degree. C. to boiling point of the solvent. As for the
reaction condition, the method described in Journal of Medicinal
Chemistry, 51(13), 3814-3824; 2008, etc. can be considered.
[0659] As for the oxidizing agent and the catalyst used for the
reaction, DDQ, peracid such as, mCPBA and the like, cerium ammonium
nitrate (IV) (CAN), permanganate such as potassium permanganate,
barium permanganate and the like, sodium chlorite, hydrogen
peroxide, or N-hydroxyphthalimide and the like can be used alone or
in a combination thereof. Preferably, it is DDQ or
N-hydroxyphthalimide. As for the reaction solvent used for the
reaction, examples thereof include water, t-butanol, acetonitrile,
THF, dichloromethane, ethyl acetate and a mixture thereof.
Preferably, it is THF.
Preparation Method II
[0660] It is an exemplary method of producing 3-ketoester
intermediate IIg, which is used for constructing the skeleton of
the compounds that are represented by the Formula (I).
##STR00004##
Step II-1, Step II-2
[0661] It is an alkylation step at a position of carboxylic acid
ester IIc or nitrile IIa. The step can be carried out by reacting
with an alkylating agent corresponding to R.sup.6 and R.sup.6' in a
solvent under the condition of a reaction temperature of
-20.degree. C. to boiling point of the solvent, in the presence of
abase. For example, it can be carried out in view of the method
described in J. Org. Chem., 2007, 72 (25), 9541-9549 and European
Journal of Organic Chemistry (21), 3449-3462, etc. The reagents and
the condition for the reaction are the same as those described for
Step I-1.
Step II-3
[0662] It is an ester hydrolysis step of carboxylic acid ester IId.
This step can be carried out by hydrolysis in an aqueous solvent at
the reaction temperature of 0.degree. C. to boiling point of the
solvent in the presence of an inorganic base, for example in view
of the method described in Tetrahedron Lett. 3529, 1977.
Alternatively, it can be carried out according to a method in which
hydrolysis is carried out in the presence of an acid, in view of
the method described in J. Am. Chem. Soc, 1977, 99, 2353, for
example. As for the inorganic base, examples thereof include sodium
hydroxide, potassium hydroxide, sodium carbonate, potassium
carbonate and cesium carbonate. Preferably, it is sodium hydroxide
or potassium hydroxide. As for the solvent, water, methanol,
ethanol, tetrahydrofuran, dioxane, and the like can be used alone
or in a combination thereof. Preferably, it is methanol comprising
water or ethanol comprising water. As for the acid which can be
used for acid hydrolysis, hydrochloric acid, sulfuric acid,
trifluoroacetic acid and methanesulfonic acid can be used alone in
a combination thereof. Preferably, it is sulfuric acid.
Step II-4, Step II-5
[0663] It is a direct (hetero)arylation step at a position of
carboxylic acid ester or nitrile. This step can be carried out by
S.sub.NAr reaction in which carboxylic acid ester or nitrile is
reacted with aromatic compound IIf having a leaving group in the
presence of a base. It can be carried out in view of the method
described in J. Am. Chem. Soc. 2000, 122, 712-713. Alternatively,
it can be also carried out according to a method in which
carboxylic acid ester or nitrile is reacted with aromatic compound
IIf having a leaving group in the presence of a catalyst, a ligand
and abase. For example, it can be carried out in view of the method
described in Org. Lett, 2008, 10(8), 1545, J. Org. Chem. 2003, 68,
8003 and Angew. Chem. Int. Ed. 2003, 42, 5051, etc.
[0664] As for the base used for the reaction, sodium phosphate,
potassium phosphate, sodium carbonate, potassium carbonate, cesium
carbonate, sodium hydride, LiHMDS, NaHMDS, LDA, lithium
dicyclohexylamide, lithium 2,2,6,6-tetramethyl pyrrolidide, KHMDS,
t-BuONa, t-BuOK and the like can be used. Preferably, it is NaHMDS,
KHMDS, or t-BuONa. As for the catalyst, ligand, or catalyst-ligand
complex which are used for the reaction, palladium acetate,
Pd.sub.2(dba).sub.3, .pi.-allyl palladium chloride dimer,
PdCl.sub.2(CH.sub.3CN).sub.2, trialkylproazaphosphatrane,
{P(t-Bu).sub.3PdBr}.sub.2, PPh.sub.3, P(o-tol).sub.3, BINAP, DPPF,
P(t-Bu).sub.3, DavePhos, JohnPhos, c-Hexyl JohnPhos, S-Phos,
X-Phos, t-ButylX-Phos, Xantphos, 4,5-bis[bis
(3,5-bistrifluoromethylphenyl)phosphanyl]-9,9-dimethyl-9H-xanthene,
1,3-diallyldihydroimidazolium salt and the like can be used, for
example. Preferably, it is triisobutylproazaphosphatrane.
Step II-6
[0665] It is a step of hydrolyzing nitrile IIb to carboxylic acid.
This step can be carried out by hydrolysis in the presence of an
acid under the condition of a reaction temperature of 0.degree. C.
to boiling point of the solvent, and the reaction conditions
include that described in, for example, Tetrahedron, 64(36),
8464-8475; 2008, etc. For the reaction, the acid itself can be used
as a solvent or diluted with other solvent. Alternatively, it can
be carried out by hydrolysis in the presence of an inorganic base
under the condition of a reaction temperature of 0.degree. C. to
boiling point of the solvent, and the reaction condition described
in, for example, Bioorganic & Medicinal Chemistry Letters,
18(2), 749-754; 2008, etc. can be employed.
[0666] The reaction consists of the hydrolysis of nitrile IIb to
acid amide and further conversion into carboxylic acid. Separation
and purification can be carried out at each step or the reaction
can be carried out continuously.
[0667] As for the acid which is used for the reaction, examples
thereof include methanesulfonic acid, p-toluenesulfonic acid,
benzenesulfonic acid, trifluoroacetic acid, hydrochloric acid and
sulfuric acid. As for the solvent, examples thereof include
toluene, xylene, dioxane, dimethoxyethane, diethylene glycol,
triethylene glycol, TFE and the like and a mixture thereof. As for
the inorganic base, examples thereof include sodium hydroxide,
potassium hydroxide, sodium carbonate, potassium carbonate and
cesium carbonate.
Step II-7
[0668] It is a step of converting carboxylic acid IIe to
.beta.-ketoester. According to this step, the carboxylic acid as a
reacting material is converted into an acid chloride, active ester
and the like by an action of an activating agent in a solvent under
the condition of a reaction temperature of 0.degree. C. to boiling
point of the solvent. Thereafter, the acid chloride or active ester
is reacted with enolate of malonic acid monoester under the
condition of a reaction temperature of 0.degree. C. to boiling
point of the solvent to give a target compound through
decarboxylation. As for the reaction condition, a method described
in J. Chem. Soc. Perkin Trans. 1 1988, 2345-2352 and Synthesis
1993, 290-292 can be used, for example. As for the method of
activating carboxylic acid, examples thereof include a method of
converting into an acid chloride by using thionyl chloride, oxalyl
chloride, phosphorus oxychloride, etc. or a method of converting
into an active ester by using CDI. Preferably, thionyl chloride or
CDI is used. The activated carboxylic acid itself can be subjected
to separation and purification, or can be used continuously for the
next reaction. As for the method of producing an enolate of malonic
acid monoester, a combination of magnesium salt like magnesium
chloride, etc. and malonic acid monoester (and a salt thereof) or a
Grignard reagent like i-propyl magnesium chloride, etc. and malonic
acid monoester (and a salt thereof), etc. can be used. In order to
improve the reaction yield, an organic base such as TEA, DIPEA and
the like can be also added to the reaction system. As for the
solvent, examples thereof include toluene, xylene, MeCN, THF, CPME,
MTBE, NMP, DMF, DMA, DMSO, sulfolane, dioxane, DME, and the like
and a mixture thereof. Preferably, it is MeCN, THF or DME.
Step II-8
[0669] It is a step of converting nitrile IIb to .beta.-ketoester.
This step can be carried out by so-called Blaise reaction in which
2-halo carboxylic acid ester is reacted with nitrile in the
presence of activated zinc powder under the condition of a reaction
temperature of 0.degree. C. to boiling point of the solvent, and
the reaction method described in, for example, SYNTHESIS 2004, No.
16, pp 2629-2632x. can be used. As for the method of activating
zinc powder, a method in which acid washing and drying are carried
out in advance, or a method in which a catalytic amount of an acid
such as methanesulfonic acid, etc. is included in the reaction
system can be employed.
Preparation Method III
[0670] It is an exemplary method of preparing compound IIIh from
intermediate IIg that is obtained from Preparation method II.
##STR00005##
Step III-1
[0671] This step can be carried out by nucleophilic aromatic
substitution reaction in which an aromatic nitro compound having a
leaving group is reacted with .beta.-ketoester IIg in the presence
of a base under the condition of a reaction temperature of
0.degree. C. to boiling point of the solvent, and the reaction
method include that described in, for example, Synlett, (5),
883-885; 2004 and Tetrahedron, 38(23), 3479-83; 1982.
[0672] As for the base used for the reaction, sodium phosphate,
potassium phosphate, sodium carbonate, potassium carbonate, cesium
carbonate, sodium hydride, LiHMDS, NaHMDS, LDA, lithium
dicyclohexylamide, lithium 2,2,6,6-tetramethylpyrrolidide, KHMDS,
t-BuOK, t-BuONa and the like can be used. Preferably, it is
potassium carbonate, cesium carbonate, t-BuOK, or t-BuONa. As for
the solvent, examples thereof include toluene, xylene, MeCN, THF,
CPME, MTBE, NMP, DMF, DMA, DMSO, sulfolane, dioxane, DME, acetone,
methylethyl ketone, and a mixture thereof. Preferably, it is THF,
DMF, DMA, NMP or a mixture thereof.
[0673] Further, the present step can be also carried out in the
presence of a catalyst and a base, as described in Step III-5 or
Journal of Organic Chemistry, 72(14), 5337-5341; 2007.
Step III-2
[0674] It is a reductive cyclization step to form an indole ring
following the reduction of a nitro group. This reaction can be
carried out by reacting .beta.-ketoester IIIa with a reducing agent
under the condition of a reaction temperature of 0.degree. C. to
boiling point of the solvent to reduce the nitro group. As for the
reducing agent used for the reaction, the condition generally used
for reduction of a nitro group, for example, iron as exemplified in
Synthesis, (18), 2943-2952, 2008, zinc as exemplified in
Tetrahedron, 64(40), 9607-9618, 2008, titanium (III) chloride as
exemplified in Organic & Biomolecular Chemistry, 3(2), 213-215,
2005, tin (II) chloride as exemplified in Journal of Organic
Chemistry, 58(19), 5209-5220,1993, sodium hydrosulphite as
exemplified in Gazzetta Chimica Italiana, 121(11), 499-504, 1991,
and catalytic reduction condition as exemplified in Synlett, (17),
2689-2691, 2008, etc. can be employed. Preferably, the reducing
agent is iron or sodium hydrosulphite.
Step III-3
[0675] It is a step of deprotecting an ester protecting group of
indole-3-carboxylic acid ester IIb. As an example of an ester
protecting group, a methyl group, an ethyl group, a t-butyl group,
a benzyl group, a substituted benzyl group and the like can be
used. Preferably, it is a t-butyl. As for the deprotection,
examples thereof include a method described in "Protective Groups
in Organic Synthesis" (Greene and Wuts, 4.sup.th edition, John
Wiley & Sons 2007), and it can be appropriately used according
to each reaction condition. When the ester protecting group is a
t-butyl, as a deprotection condition, TMSI, TMSCl, and
BF.sub.3.OEt.sub.2 can be used. As for the solvent, examples
thereof include toluene, xylene, diethyl ether, THF, CPME, MTBE,
NMP, DMF, DMA, DMSO, sulfolane, dioxane, DME, TFE and the like and
a mixture thereof. Preferably, it is THF or TFE.
Step III-4
[0676] It is a step of cyclizing indole-3-carboxylic acid IIIc to
carbazole based on Friedel-Crafts reaction. According to the
reaction, a mixed acid anhydride is formed by using acetic
anhydride, trifluoroacetic anhydride and the like, or acid chloride
is formed by using thionyl chloride, oxalyl chloride, phosphorus
oxychloride and the like, which results in activiation of the
carboxylic acid. Preferably, acetic anhydride or trifluoroacetic
anhydride is used. The reaction is carried out in the absence or
presence of a solvent. As for the solvent, examples thereof include
toluene, xylene, diethyl ether, THF, CPME, MTBE, NMP, DMF, DMA,
DMSO, sulfolane, dioxane, DME and the like and a mixture thereof.
Preferably, it is THF, DMF, DMA or DME. Further, an organic base
such as TEA, DIPEA, pyridine and the like can be used.
[0677] Thereafter, under the condition of a reaction temperature of
0.degree. C. to boiling point of the solvent, the cyclization is
carried out without a catalyst or with Bronsted acid or Lewis acid
catalyst (Heterocycles 1999, 51, 2127). As for the Lewis acid
catalyst, examples thereof include aluminum chloride, aluminum
triflate, bismuth triflate, ytterbium triflate and
BF.sub.3.OEt.sub.2. Preferably, it is BF.sub.3.OEt.sub.2. Depending
on the type of a substituent group, it is also possible to carry
out the reaction by applying methanesulfonic acid-phosphorus
pentoxide (Eaton reagent), polyphosphoric acid and the like to
indole-3-carboxylic acid ester IIIb without undergoing Step
111-3.
Step III-5, III-6
[0678] The step can be carried out by reacting an aromatic
acylamide compound having a leaving group with .beta.-ketoester IIg
in the presence of a base, a catalyst, and a ligand under the
condition of a reaction temperature of 0.degree. C. to boiling
point of the solvent, followed by deprotection of an acyl
protecting group. Examples thereof include a method described in
Journal of Organic Chemistry 2007, 72, 9329-9334 and Organic
Letters 10(4), 625-628, 2008. As for the metal catalyst, copper (I)
iodide and palladium acetate can be used. As for the ligand,
(S)-proline, tri t-butylphosphine, bis (t-butyl)
(2'-methyl[1,1'-biphenyl]-2-yl)phosphine and the like can be used.
As for the base which is used for the reaction, sodium phosphate,
potassium phosphate, sodium carbonate, potassium carbonate, cesium
carbonate, sodium hydride, LiHMDS, NaHMDS, LDA, lithium
dicyclohexylamide, lithium 2,2,6,6-tetramethylpyrrolidide,
potassium hexamethyldisilazide, t-BuONa, t-BuOK and the like can be
used.
Step III-7, III-8
[0679] It is a step of reacting an aromatic amino compound with
.beta.-ketoester IIg to form an enamine intermediate followed by
catalytic cyclization. Examples thereof include a method described
in Journal of Organic Chemistry, 68(15), 6011-6019; 2003 and
European Journal of Organic Chemistry, (24), 3977-3980; 2007.
[0680] Alternatively, the cyclization can be carried out based on
an oxidative method. For example, a reaction condition described in
Angewandte Chemie, International Edition, 47(38), 7230-7233; 2008
can be also employed, for example.
Step III-9
[0681] It is a step of synthesizing 1,3-diketone based on
cyclization of .beta.-keto ester IIg. As for the condition and
reagents for the reaction, a method described in Bioorganic &
Medicinal Chemistry Letters, 18(2), 568-570; 2008 wherein
.beta.-keto ester IIg is reacted in an solvent in the presence of
Bronsted acid catalyst or Lewis acid catalyst, or a method of using
a condensing agent such as methanesulfonic acid-phosphorus
pentoxide (Eaton reagent), polyphosphoric acid and the like can be
employed.
Step III-10, III-11
[0682] This step can be carried out in the same manner as Step
III-1 and III-2 or Step III-5 and III-6.
Preparation Method IV
[0683] An exemplary method of producing compound IIIh wherein
formula Iva is employed as a starting material.
##STR00006##
Step IV-1, IV-3
[0684] It is a step of constructing di-substituted indole
derivatives based on Sonogashira reaction in which a terminal
alkyne is reacted with aromatic amine derivative IVa having a
leaving group at ortho position in the presence of a base and a
catalyst with or without a catalytic amount of a copper reagent.
Specifically, examples thereof include a method described in
Organic Letters, 11(1), 221-224; 2009. The reaction is carried out
in an appropriate solvent in the presence of a palladium catalyst
and a ligand (or a complex thereof) with or without a base and a
copper catalyst. Example of the copper catalyst used for the
reaction include copper iodide. As an example of the catalyst and
the ligand (or a complex thereof), palladium acetate,
Pd.sub.2(dba).sub.3, r-allyl palladium chloride dimer,
PdCl.sub.2(CH.sub.3CN).sub.2, PdCl.sub.2(PPh.sub.3).sub.2,
trialkylproazaphosphatrane, {P(t-Bu).sub.3PdBr}.sub.2, PPh.sub.3,
P(o-tol).sub.3, BINAP, DPPF, P(t-Bu).sub.3, DavePhos, JohnPhos,
c-Hexyl JohnPhos, S-Phos, X-Phos, t-ButylX-Phos, Xantphos,
4,5-bis[bis
(3,5-bistrifluoromethylphenyl)phosphanyl]-9,9-dimethyl-9H-xanthene,
1,3-diallyldihydroimidazolium salt and the like can be used. As for
the base used for the reaction, sodium phosphate, potassium
phosphate, sodium carbonate, potassium carbonate, cesium carbonate,
TEA, DIPEA and the like can be used. Preferably, it is cesium
carbonate, TEA or DIPEA.
Step IV-2
[0685] This step corresponds to a tandem Friedel-Crafts reaction in
which acylation at 3-position of di-substituted indole derivative
IVb is carried out in the presence of Lewis acid catalyst under the
condition of a reaction temperature of 0.degree. C. to boiling
point of the solvent, followed by intramolecular cyclization. As
for the catalyst used for the reaction, examples thereof include
aluminum chloride, aluminum triflate, bismuth triflate, ytterbium
triflate and BF.sub.3.OEt.sub.2. Preferably, it is aluminum
chloride.
Step IV-4
[0686] This step consists of deprotection of carboxylic acid ester
comprised in di-substituted indole derivative IVc and subsequent
intramolecular cyclization at 3-position of the indole either in
catalytic or non-catalytic manner. As for the deprotection,
examples thereof include a method described in "Protective Groups
in Organic Synthesis" (Greene and Wuts, 4.sup.th edition, John
Wiley & Sons 2007), and it can be appropriately used according
to the type of each protecting group. When an activated indole
derivative is used for the reaction, cyclization occurs more easily
so that the reaction can be carried out in a non-catalytic manner.
Further, the cylclization can be also carried out by using a
condensing agent such as polyphosphoric acid, methanesulfonic
acid-phosphorus pentoxide (Eaton reagent) and the like.
Alternatively, it is also possible that carboxylic acid is first
converted into carboxylic acid chloride, a mixed acid anhydride and
the like under the same condition as defined in Step III-4 and the
cyclization is carried out under Friedel-Crafts condition in the
presence of Lewis acid catalyst. As for the Lewis acid catalyst
used for the reaction, examples thereof include aluminum chloride,
aluminum triflate, bismuth triflate, ytterbium triflate and
BF.sub.3.OEt.sub.2.
Preparation Method V
[0687] It is one of the methods for constructing the skeleton of
the compounds having the Formula (I) in which A.sup.5 is O, S or
NH.
##STR00007##
Step V-1
[0688] It is a step of arylation of cyclic ketone derivative Ib
using aromatic compound Va having a leaving group. The reaction is
catalytically carried out in the presence of a base with
combination of a transition metal catalyst and a ligand, and the
condition described in J. Am. Chem. Soc. 2000, 122, 1360-1370 and
Journal of Organic Chemistry (2003), 68(25), 9865-9866 can be used,
for example. As for the base used for the reaction, examples
thereof include t-BuONa, t-BuOK, LiHMDS, NaHMDS, potassium
phosphate, sodium carbonate, potassium carbonate and cesium
carbonate. As for the catalyst and a ligand (or a catalyst-ligand
complex), palladium acetate, Pd.sub.2(dba).sub.3,
.pi.-allylpalladium chloride dimer, PdCl.sub.2(CH.sub.3CN).sub.2,
PdCl.sub.2(PPh.sub.3).sub.2, trialkylproazaphosphatrane,
{P(t-Bu).sub.3PdBr}.sub.2, PPh.sub.3, P(o-tol).sub.3, BINAP, DPPF,
P(t-Bu).sub.3, DavePhos, JohnPhos, c-Hexyl JohnPhos, S-Phos,
X-Phos, t-ButylX-Phos, Xantphos, 4,5-bis[bis
(3,5-bistrifluoromethylphenyl)phosphanyl]-9,9-dimethyl-9H-xanthene
1,3-diallyldihydroimidazolium salt and the like can be used.
Step V-2
[0689] It is a step of deprotecting a protecting group. When
A.sup.5 is O or S, a t-butyl group, a benzyl group and a
substituted benzyl group can be used as a protecting group. When
A.sup.5 is O, a t-butyldimethylsilyl group and a tetrahydropyranyl
group can be used. When it is NH, a t-butoxycarbonyl group, a
benzyloxycarbonyl group, a methanesulfonyl group, a trifluoroacetyl
group and the like can be used. As for the deprotection, examples
thereof include a method described in "Protective Groups in Organic
Synthesis" (Greene and Wuts, 4.sup.th edition, John Wiley &
Sons 2007), and it can be appropriately used according to the type
of each protecting group.
Step V-3
[0690] It is a cyclization step of cyclic .alpha.-aryl ketone
derivative Vc to a benzofuran derivative, benzothiophene or indole
Vd. The reaction can be carried out under condition of using an
acid catalyst or dehydrating condition. For example, the reaction
condition described in Acta Pharmaceutica Hungarica (2003), 73(3),
171-178 can be employed. In addition, depending on the type of a
protecting group for hydroxyl group, it can be carried out
simultaneously with the deprotection of Step V-2, as described in
Heterocycles, 26(7), 1863-71; 1987. With respect to the condition
for dehydration, a combination of an organic base and an acid
anhydride such as trifluoromethanesulfonic acid and the like can be
used.
Step V-4
[0691] It is a step of oxidation at benzyl at 11-position of
tetracyclic compound Vd. This step is carried out by applying an
oxidizing agent to a substrate in a solvent in the presence or
absence of a catalyst under the condition of a reaction temperature
of -20.degree. C. to boiling point of the solvent. As for the
reaction condition, the method described in Journal of Medicinal
Chemistry, 51(13), 3814-3824; 2008, etc. can be employed.
[0692] As for the oxidizing agent and the catalyst used for the
reaction, DDQ, peracid such as, mCPBA and the like, cerium ammonium
nitrate (IV) (CAN), permanganate such as potassium permanganate,
barium permanganate and the like, sodium chlorite, hydrogen
peroxide, N-hydroxyphthalimide and the like can be used alone or in
a combination thereof. As for the solvent used for the reaction,
examples thereof include water, t-butanol, acetonitrile,
tetrahydrofuran, dichloromethane, ethyl acetate and a mixture
thereof.
Preparation Method VI
[0693] It is an exemplary method of constructing the skeleton of
the compounds that are represented by the Formula (I) in which
A.sup.5 is S.
##STR00008##
Step VI-1
[0694] It is a reaction to construct a benzothiophene ring based on
the reaction between ylide VIa having a thiol at ortho position and
acyl chloride VIb. The reaction can be carried out in the presence
of a base, and the condition include that described in Synthesis,
(2), 155-7; 1988, for example. As for the base, examples thereof
include n-butyl lithium, sodium methylate and triethylamine.
Step VI-2
[0695] It is a reaction for the synthesis of an aromatic carboxylic
acid. The reaction can be carried out by metallization like
addition of lithium or magnesium based on exchange between halogen
and metal in the presence of a base, followed by carboxylation
using carbonate gas, dry ice, etc. The reaction condition as
described in Journal of Organic Chemistry (2008), 73(19), 7785-7788
can be employed. As for the base, n-butyl lithium, s-butyl lithium,
t-butyl lithium, a Grignard reagent, and various ate complexes can
be used. Alternatively, as described in e-EROS Encyclopedia of
Reagents for Organic Synthesis 2001 (electronic edition;
http://www3.interscience.wiley.com/cgi-bin/mrwhome/104554785/HOME),
carboxylation condition using a transition metal catalyst can be
also employed.
Step VI-3
[0696] This step corresponds to intramolecular cyclization at
3-position of di-substituted benzothiophene derivative VId either
in catalytic or non-catalytic manner. For example, the reaction
condition as described in Journal of the American Chemical Society,
130(23), 7286-7299; 2008 can be employed. The reaction can be
carried out by using a condensing agent such as polyphosphoric
acid, methanesulfonic acid-phosphorus pentoxide (Eaton reagent) and
the like. Alternatively, it is also possible that carboxylic acid
is first converted into carboxylic acid chloride, a mixed acid
anhydride and the like and the cyclization is carried out under
Friedel-Crafts condition in the presence of Lewis acid catalyst. As
for the Lewis acid catalyst used for the reaction, examples thereof
include aluminum chloride, aluminum triflate, bismuth triflate,
ytterbium triflate and BF.sub.3.OEt.sub.2.
Preparation Method VII Conversion and Modification of Functional
Groups
[0697] To the functional groups PR.sup.1 to PR.sup.10 in the
Formula (I) of the present invention, various substituent groups
can be introduced based on a method of converting and modifying a
functional group that is well known to a skilled person in the
pertinent art. Hereinbelow, representative examples of functional
group conversion will be explained. Further, although the following
reaction scheme is specific in that examples of PR.sup.8 and
PR.sup.9 are given for the tetracyclic compound that is already
constructed, it can be also carried out to an intermediate during
any steps explained in Preparation methods I to VI above or to a
final compound. Further, it can be carried out at any substitution
position of PR.sup.1 to PR.sup.4 and R.sup.6 to PR.sup.10.
[0698] In the following formula, Q.sup.1 and Q.sup.2 represent any
substituent group which constitutes PR.sup.1 to PR.sup.4 and
R.sup.6 to PR.sup.10.
##STR00009##
Step VII-1
[0699] It is a step of deprotecting a protecting group for an
aromatic hydroxyl group. As an example of the protecting group, a
methyl group, a t-butyl group, a benzyl group, a substituted benzyl
group, a t-butyldimethylsilyl group, a tetrahydropyranyl group and
the like can be used. Preferably, it is a methyl group. As for the
deprotection, examples thereof include a method described in
"Protective Groups in Organic Synthesis" (Greene and Wuts, 4.sup.th
edition, John Wiley & Sons 2007), and it can be appropriately
used according to the type of each protecting group. When a methyl
group is used as a protecting group, various reaction conditions
can be used selectively for the deprotection depending on
reactivity. Examples thereof include heating in the presence of
pyridine hydrochloric acid salt, heating in the presence of a
solvent with dodecane thiol and sodium methylate and heating in the
presence of a solvent with anhydrous lithium halide, boron
tribromide, TMSI and the like.
Step VII-2
[0700] It is one of the methods for introducing a substituent group
based on formation of ether bond with an aromatic hydroxyl group.
For the formation of an ether bond, Mitsunobu reaction described in
a known literature (Mitsunobu, et. al., Synthesis, Vol. 1, page 1,
1981) or a similar method can be used. Specifically, the reaction
is carried out in the presence of a phosphorus compound and an azo
compound in a solvent under the condition of a reaction temperature
of -78.degree. C. to boiling point of the solvent. As for the
phosphorus compound, examples thereof include PPh.sub.3 and
tri-n-butylphosphine. As for the azo compound, examples thereof
include DEAD, TMAD and diisopropyl azodicarboxylic acid. Also, by
using them in any combination, the target compound can be
obtained.
Step VII-3
[0701] It is a step of carrying out trifluoromethane sulfonylation
on an aromatic hydroxyl group. The reaction is carried out by
reacting with a reacting reagent such as trifluoromethanesulfonic
acid and the like in the presence of a base with or without a
solvent under the condition of a reaction temperature of
-20.degree. C. to boiling point of the solvent. As for the base
used for the reaction, TEA, DIPEA, pyridine, 2,6-lutidine,
dimethylaminopyridine and the like can be used. Preferably,
pyridine is used without any solvent. The obtained
trifluoromethanesulfonic acid ester VIId is a good leaving group
and can be used for various derivatization.
Step VII-4
[0702] It is a step of obtaining sulfamic acid ester by carrying
out sulfamoylation on an aromatic hydroxyl group. The reaction is
carried out by reacting with a reacting reagent such as sulfamoyl
chloride and the like in the presence of a base with a solvent
under the condition of a reaction temperature of -20.degree. C. to
boiling point of the solvent. As for the base used for the
reaction, sodium hydride, TEA, DIPEA, pyridine, 2,6-lutidine,
dimethylaminopyridine and the like can be used. Preferably, it is
sodium hydride. The obtained sulfamic acid ester VIIe is a
substrate for the thiaFries rearrangement of Step VII-5 and can be
used for various derivatization.
Step VII-5
[0703] This step corresponds to rearrangement of a sulfamoyl group
to a neighboring position in the presence of a Lewis acid catalyst
under the condition of a reaction temperature of 0.degree. C. to
boiling point of the solvent when the neighboring position of the
sulfamic acid ester is unsubstituted (i.e., C--H), i.e., a reaction
called thiaFries rearrangement. As for the catalyst used for the
reaction, aluminum chloride, aluminum triflate, bismuth triflate,
ytterbium triflate, BF.sub.3.OEt.sub.2 and the like can be used.
Preferably, it is aluminum chloride.
Step VII-6
##STR00010##
[0705] It is another step of introducing a substituent group based
on formation of an ether bond. According to the present step, a
reagent having an appropriate leaving group such as alkyl halide
and the like is subjected to nucleophilic reaction with the
hydroxyl group of compound VIIb in the presence of an appropriate
base to form an ether bond. As for the base, examples thereof
include an inorganic base such as sodium carbonate, potassium
carbonate, cesium carbonate, sodium hydride, potassium hydride,
calcium hydride and the like or an organic base such as pyridine,
TEA, DIPEA and the like.
[0706] Further, by using aryl halide, aryl borate and the like as a
reagent having a leaving group, formation of an diaryl ether bond
can be also achieved and used. When reactivity is not satisfactory,
a catalyst such as copper powder, copper acetate, copper iodide and
the like or a ligand such as phenanthroline,
trans-1,2-cyclohexanediamine and the like can be used.
##STR00011##
Step VII-7
[0707] It is a reaction for forming a bond between aryl and a
hetero atom by using compound VIIg having a leaving group. The
reaction is carried out in an appropriate solvent inert to the
reaction, in the presence of a base. As for the leaving group LG, a
halogen, triflate and the like can be used. As for the solvent,
examples thereof include toluene, xylene, n-hexane, cyclohexane,
DMF, DMA, EtOAc, DMSO, NMP, THF, DME, dioxane, acetonitrile and the
like and a mixture thereof. As for the base to be used for the
reaction, examples thereof include t-BuONa, t-BuOK, LiHMDS, NaHMDS,
KHMDS, potassium phosphate, sodium carbonate, potassium carbonate
and cesium carbonate. This step can be also carried out by using a
catalyst and a ligand. As for the catalyst and a ligand (or a
catalyst-ligand complex), palladium acetate, Pd.sub.2(dba).sub.3,
.pi.-allylpalladium chloride dimer, PdCl.sub.2(CH.sub.3CN).sub.2,
PdCl.sub.2(PPh.sub.3).sub.2, trialkylproazaphosphatrane,
{P(t-Bu).sub.3PdBr}.sub.2, PPh.sub.3, P(o-tol).sub.3, BINAP, DPPF,
P(t-Bu).sub.3, DavePhos, JohnPhos, c-Hexyl JohnPhos, S-Phos,
X-Phos, t-ButylX-Phos, Xantphos, 4,5-bis[bis
(3,5-bistrifluoromethylphenyl)phosphanyl]-9,9-dimethyl-9H-xanthene,
1,3-diallyldihydroimidazolium salt and the like can be used, for
example.
Step VII-8
[0708] When the reaction product of Step VII-7 is thio ether VIIh,
it is possible to obtain sulfoxide or sulfone compound VIIj by
oxidation with m-chloro perbenzoic acid, oxone, TEMPO and the
like.
Step VII-9
##STR00012##
[0710] It is a reaction for forming a bond between aryl and
SP.sup.2 carbon or a bond between aryl and SP.sup.3 carbon in which
compound VIIg having a leaving group is used. The reaction is
carried out in an appropriate solvent inert to the reaction, in the
presence of a base. As for the leaving group LG, a halogen,
triflate and the like can be used. As for the solvent, examples
thereof include toluene, xylene, n-hexane, cyclohexane, DMF, DMA,
EtOAc, DMSO, NMP, THF, DME, dioxane, acetonitrile, water,
isopropanol and the like and a mixture thereof. As for the base to
be used for the reaction, examples thereof include t-BuONa, t-BuOK,
LiHMDS, NaHMDS, KHMDS, potassium phosphate, sodium carbonate,
potassium carbonate, cesium carbonate, TEA and DIPEA. This step can
be also carried out by using a catalyst and a ligand. As for the
catalyst and a ligand (or a catalyst-ligand complex), palladium
acetate, Pd.sub.2(dba).sub.3, .pi.-allylpalladium chloride dimer,
PdCl.sub.2(CH.sub.3CN).sub.2, PdCl.sub.2(PPh.sub.3).sub.2,
trialkylproazaphosphatrane, {P(t-Bu).sub.3PdBr}.sub.2, PPh.sub.3,
P(o-tol).sub.3, BINAP, DPPF, P(t-Bu).sub.3, DavePhos, JohnPhos,
c-Hexyl JohnPhos, S-Phos, X-Phos, t-ButylX-Phos, Xantphos,
4,5-bis[bis
(3,5-bistrifluoromethylphenyl)phosphanyl]-9,9-dimethyl-9H-xanthene,
1,3-diallyldihydroimidazolium salt and the like can be used, for
example.
##STR00013##
Step VII-10
[0711] It is a carboxylation reaction using compound VIIg having a
leaving group. The reaction is carried out by reacting with formic
acid (or a synthetic equivalent thereof) in an appropriate solvent
inert to the reaction, in the presence of a base and a catalyst. As
for the leaving group LG, a halogen, triflate and the like can be
used. The solvent and the catalyst can be selected and used in the
same manner as Step VII-9.
Step VII-11
[0712] It is an amidation reaction using carboxylic acid VIIm.
Specifically, the reaction can be carried out by dehydrating
condensation reaction using various amines such as ammonia, primary
amines, secondary amines, hydrazines, substituted hydrazines and
the like. The reaction is carried out in the presence of an acid
halogenating agent or a dehydrating condensing agent in an aprotic
solvent under the condition of a reaction temperature of
-20.degree. C. to boiling point of the solvent, with or without an
active esterifying agent and a base.
[0713] As for the acid halogenating agent, examples thereof include
oxalyl chloride and thionyl chloride. As for the dehydrating
condensing agent, examples thereof include
1,3-dicyclohexylcarbodiimide (DCC),
2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline (EEDQ), bromo-tris
(pyrrolidino)-phosphonium hexafluorophosphate (PyBrOP), EDC and
(benzotriazolyloxy)tripyrrolidino-phosphonium=hexafluorophosphate
(PyBOP). As for the active esterifying agent, examples thereof
include HOBt, di(N-succinimidyl) carbonate and carbonyl
diimidazole. As for the base, examples thereof include TEA, DIPEA
and DBU. As for the solvent, examples thereof include DMF, DMA,
DCM, acetone, THF, dioxane, DME, ethyl acetate, MeCN, and a mixture
thereof.
Step VII-12
##STR00014##
[0715] It is a step of forming a bond between aryl and SP carbon
using compound VIIo having a leaving group. The reaction is carried
out by reacting terminal alkyne in an appropriate solvent in the
presence of a base and a catalyst with or without a catalytic
amount of a copper reagent, and the reaction is referred to as
Sonogashira reaction. The reagents and the condition for the
reaction are as defined in Step IV-1 and Step IV-3. As a variant of
Sonogashira reaction, examples thereof include a method disclosed
in Tetrahedron, 63(43), 10671-10683; 2007. Specifically, by having
secondary amines and the like in a reaction system and using
propargyl bromide as an alkyne, a propargyl amine can be
introduced.
Step VII-13
##STR00015##
[0717] It is a reaction of forming a bond between aryl and CN by
using compound VIIo having a leaving group. The reaction can be
carried out by adding CN.sup.- source in an appropriate solvent in
the presence of a copper, zinc or palladium catalyst, with or
without a ligand, in view of the reaction condition shown in
Organic Letters, 10(23), 5325-5328; 2008, Tetrahedron Letters,
49(32), 4693-4694; 2008 and Bioorganic & Medicinal Chemistry,
16(13), 6489-6500; 2008. As for the CN.sup.--source, copper (I)
cyanide, zinc (II) cyanide, iron (III) hexacyanide, sodium cyanide,
potassium cyanide and the like can be used.
Synthesis of Starting Materials
[0718] Some of the starting materials for the present invention are
novel compounds, and they can be easily synthesized in the same
manner as known reacting compounds or according to the method well
known to a skilled person in the art.
[0719] Hereinabove, examples of a method of preparing the compounds
having the Formula (I) according to the present invention are
described. However, separation and purification of the target
compounds that are described in detail in each reaction step can be
performed by applying common chemical treatments such as
extraction, concentration, removal by distillation,
crystallization, filtration, recrystallization, various
chromatography, etc.
Pharmaceutical of the Present Invention
[0720] The pharmaceutical composition of the present invention
comprises a pharmaceutically acceptable carrier, in addition to the
compound that is selected as being useful for the invention. In the
present specification, the term "pharmaceutically acceptable
carrier" means one or more type of appropriate solid or liquid
vehicle, diluent or an encapsulating material which is suitable for
administration to mammals. In the present specification, the term
"acceptable" means that it does not cause any reaction to
substantially reduce the pharmaceutical efficacy of a composition
under normal condition for use, and the components of the
composition and the subject compound can be mixed well with each
other. The pharmaceutically acceptable carrier should have
substantially high purity and substantially low toxicity so that it
can be suitably administered to a subject to be treated, preferably
an animal, and more preferably a mammal.
[0721] As the materials which can be used as a pharmaceutically
acceptable carrier, examples thereof include sugars such as
lactose, glucose, sucrose, and the like; starch such as corn
starch, potato starch and the like; cellulose and cellulose
derivatives such as sodium carboxy methyl cellulose, ethyl
cellulose, methyl cellulose and the like; tragacanth rubber powder;
malt; gelatin; talc; solid lubricating agent such as stearic acid
or magnesium stearate and the like; calcium sulfate; vegetable oils
such as peanut oil, cotton seed oil, sesame oil, olive oil, corn
oil, plant oil, cacao oil, and the like; polyhydric alcohols such
as propylene glycol, glycerin, sorbitol, mannitol, polyethylene
glycol and the like; alginic acid; an emulsifying agent such as
TWEEN; humectant such as lecithin and the like; colorant; flavor;
tabletting agent; stabilizer, anti-oxidant; preservative;
pyrogen-free water; aqueous isotonic solution and phosphate buffer
solution.
[0722] When the pharmaceutical composition of the present invention
is used as an ALK inhibitor or a therapeutic or prophylactic agent
for a proliferative disorder, or used against depression or
cognitive function disorder, as an administration route, oral,
rectal, parenteral (intravenous, intramuscular, subcutaneous),
intracisternal, intravaginal, intraperitoneal, intrabladder,
topical (drop, powder, ointment, gel or cream) administration or
administration via inhalation (mouth or nasal spray) and the like
can be considered. As for the administration form, examples thereof
include a tablet, a capsule, a granule, powder, a pill, an aqueous
or non-aqueous oral solution and suspension, and a parenteral
solution which is filled in a container suitable to be divided into
several small dosages. In addition, the administration form can be
modified for various administration routes including subcutaneous
transplant which gives controlled release of a drug compound.
[0723] The aforementioned preparation is prepared according to a
method generally known in the art by using additives such as a
vehicle, a lubricating agent (i.e., coating agent), a binding
agent, a disintegrating agent, a stabilizing agent, a corrigent for
taste and smell, a diluent and the like.
[0724] As a vehicle, examples thereof include starch such as
starch, potato starch, corn starch, lactose, crystalline cellulose
and calcium hydrogen phosphate.
[0725] As a coating agent, examples thereof include ethyl
cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose,
shellac, talc, carnauba wax and paraffin.
[0726] As a binding agent, examples thereof include polyvinyl
pyrrolidone, Macrogol and the compounds described above as a
vehicle.
[0727] As a disintegrating agent, examples thereof include the
compounds described as a vehicle in the above and a chemically
modified starch or cellulose such as sodium croscarmellose, sodium
carboxymethyl starch and crosslinked polyvinyl pyrrolidone.
[0728] As a stabilizing agent, examples thereof include paraoxy
benzoic acid esters such as methyl paraben, propyl paraben and the
like; alcohols such as chlorobutanol, benzyl alcohol, phenylethyl
alcohol and the like; benzalkonium chloride; phenols such as
phenol, cresol and the like; thimerosal; dehydroacetic acid; and
sorbic acid.
[0729] As a corrigent for taste and smell, examples thereof include
a sweetener, an acid tasting agent, a flavor and the like that are
commonly used in the art.
[0730] Further, as a solvent to prepare a liquid preparation,
examples thereof include ethanol, phenol, chlorocresol, purified
water and distilled water.
[0731] As a surface active agent or an emulsifying agent, examples
thereof include polysorbate 80, polyoxyl 40 stearate and
lauromacrogol.
[0732] When the pharmaceutical composition of the present invention
is used as an ALK inhibitor or a therapeutic or prophylactic agent
for a proliferative disorder, or used against depression or
cognitive function disorder, the use amount of the compounds of the
present invention or salts or solvates thereof varies depending on
symptom, age, body weight, relative health state of a subject,
administration of other drug compounds, administration method and
the like. For example, the amount which is generally effective for
a patient (i.e., warm-blooded animal, in particular human) is, in
an effective component (i.e., the compound of the present invention
that is represented by the Formula (I)), preferably 0.001 to 1000
mg per 1 kg body weight per day, more preferably 0.01 to 300 mg per
1 kg body weight per day in case of an orally administered agent,
and dosage per day is preferably in the range of 1 to 800 mg for an
adult patient with normal body weight. In case of a parenterally
administered agent, it is preferably 0.001 to 1000 mg per 1 kg body
weight per day, and more preferably, 0.01 to 300 mg per 1 kg body
weight per day. It is preferable to administer them once a day or
in divided dosages a day, depending on symptom of a subject to be
treated.
EXAMPLE
[0733] Hereinbelow, the present invention will be explained in
greater detail in view of the following examples. However, the
present invention is not limited by the examples. NMR analysis
[0734] NMR analysis was carried out by using JNM-EX270 (270 MHz,
manufactured by JEOL), JNM-GSX400 (400 MHz, manufactured by JEOL),
or 400 MR (400 MHz, manufactured by Varian). NMR data was expressed
in ppm (parts per million; 6), while it was compared with the
deuterium lock signal obtained from a sample solvent.
Mass Spectrum
[0735] The measurement was carried out by using JMS-DX303 or
JMS-SX/SX102A (both manufactured by JEOL).
High Performance Liquid Chromatography-Mass Spectrum Data
(LC-MS)
[0736] Measurement was carried out by using Micromass (ZMD,
manufactured by Micromass) equipped with 996-600E gradient high
performance liquid chromatography (manufactured by Waters) or
Micromass (ZQ, manufactured by Micromass) equipped with 2525
gradient high performance liquid chromatography (manufactured by
Waters).
[0737] One of the following conditions that are described in the
Table 1 below was taken as a condition for high performance liquid
chromatography.
TABLE-US-00001 TABLE 1 Analysis Flow Rate Detection Condition
Apparatus Column used Column Temperature Mobile phase, Gradient
(mL/min) Wavelength A ZMD Cadenza CD-C18 35 deg. A) 0.05% TFA, H2O
B) 0.05% 1.5 210-400 nm (Intakt) 3.0 mm I.D. .times. TFA, MeCN PDA
total 30 mm, 3 um (A/B): 95/5 => 0/100(3.5 min) => 0/100(1
min) B ZMD Cadenza CD-C18 35 deg. A) 0.05% TFA, H2O B) 0.05% 1.0
210-400 nm (Intakt) 3.0 mm I.D. .times. TFA, MeCN PDA total 30 mm,
3 um (A/B): 95/5 => 0/100(9.5 min) => 0/100(2.5 min) C ZQ
Chromolith Flash RP- Room Temp. A) 10 mM AcONH4, H2O B) MeOH 2.0
210-400 nm 18e (Merck KGaA) (A/B): 95/5 => 0/100(3 min) =>
PDA total 4.6 mm I.D. .times. 25 mm 0/100(2 min) D ZQ Chromolith
Flash RP- Room Temp. A) 10 mM AcONH4, H2O B) MeCN 2.0 210-400 nm
18e (Merck KGaA) (A/B): 95/5 => 0/100(3 min) => PDA total 4.6
mm I.D. .times. 25 mm 0/100(2 min) F ZQ Cadenza CD-C18 35 deg. A)
0.05% TFA, H2O B) 0.05% 1.5 210-400 nm (Intakt) 3.0 mm I.D. .times.
TFA, MeCN PDA total 30 mm, 3 um (A/B): 95/5 => 0/100(3.5 min)
=> 0/100(1 min) H ZQ Cadenza CD-C18 35 deg. A) 0.05% TFA, H2O B)
0.05% 1.0 210-400 nm (Intakt) 3.0 mm I.D. .times. TFA, MeCN PDA
total 30 mm, 3 um (A/B): 95/5 => 0/100(9.5 min) => 0/100(2.5
min) I ZQ Ascentis Express C18 Room Temp. A) 10 mM AcONH4, H2O B)
MeOH 1.0 210-400 nm (Sigma Aldrich) (A/B): 95/5 => 0/100(9.5
min) => PDA total 2.1 mm I.D. .times. 50 mm 0/100(1 min) S ZQ
Sunfire C18 (Waters) Room Temp. A) 0.05% TFA, H2O B) 0.05% 4.0
200-400 nm 4.5 mm I.D. .times. 50 mm, 5 um TFA, MeCN PDA total
(A/B): 90/10 => 5/95(3.5 min) => 90/10(1 min) => 90/10(0.5
min) T ZQ Sunfire C18 (Waters) Room Temp. A) 0.05% TFA, H2O B)
0.05% 4.0 200-400 nm 4.5 mm I.D. .times. 50 mm, 5 um TFA, MeCN PDA
total (A/B): 90/10 => 5/95(2 min) => 5/95(1.5 min) =>
90/10(1.0 min) => 90/10(0.5 min) U ZQ WAKOsil 3C18 AR, (Wako
Room Temp. A) 0.05% TFA, H2O B) 0.05% 2.0 210-400 nm Pure Chemical
Industries, TFA, MeCN PDA total Ltd.) 4.6 mm I.D. .times. 30 mm
(A/B): 90/10 => 90/10(0.2 min) => 5/95(3.1 min) =>
5/95(1.4 min) W ZMD Sunfire C18 (Waters) Room Temp. A) 0.05% TFA,
H2O B) 0.05% 4.0 200-400 nm 4.5 mm I.D. .times. 50 mm, 5 um TFA,
MeCN PDA total (A/B): 90/10 => 5/95(3.5 min) => 90/10(1 min)
=> 90/10(0.5 min) Y ZMD Sunfire C18 (Waters) Room Temp. A) 0.05%
TFA, H2O B) 0.05% 2.0 210-400 nm 4.5 mm I.D. .times. 50 mm, 7 um
TFA, MeCN PDA total (A/B): 90/10 => 0/100(3.5 min) => 0/100(1
min)
Microwave Reaction
[0738] The reaction was carried out by using a snap cap reaction
vial together with an Explorer.TM. (manufactured by CEM Microwave
Technology) or an initiator (manufactured by Biotage). Maximum
output setting includes cooling of the reaction vessel by air in
order to avoid temperature increase caused by microwave
irradiation.
[0739] Commercially available reagents were obtained and used
without any further purification. The room temperature indicates
the temperature range of between about 20 to 25.degree. C. All the
non-aqueous reaction was carried out in anhydrous solvent under
nitrogen or argon atmosphere. For concentration under reduced
pressure or removal of a solvent by distillation, a rotary
evaporator was used.
[0740] For preparing the compounds, when there is a possibility of
having an undesirable side reaction, a functional group was
protected using a protecting group to produce a target molecule,
and the protecting group was removed later, if desired. Selection,
addition and removal of a protecting group were carried out
according to the method described in the literature [Greene and
Wuts, "Protective Groups in Organic Synthesis" (4.sup.th edition,
John Wiley & Sons 2007)], for example.
Example 1
[0741] Compound A2
7-Methoxy-1,1-dimethyl-3,4-dihydro-1H-naphthalen-2-one
##STR00016##
[0743] 7-Methoxy-3,4-dihydro-1H-naphthalen-2-one (Compound A1, 209
g, 1.18 mol), tetrabutylammonium hydrogen sulfate (40 g, 0.118 mol)
and methyl iodide (162 g, 2.60 mol) were suspended in THF (500 ml)
at room temperature. Under stirring, the mixture was added with 50%
aqueous solution of potassium hydroxide (400 g) over 5 min. Reflux
occurred as the inner temperature rapidly increases. Once the inner
temperature stopped to increase, stirring was continued for 45 min.
The reaction solution was diluted with distilled water (1 L) and
extracted twice with CPME (1.5 L). The combined organic layer was
washed (distilled water 1 L.times.3), dried over anhydrous sodium
sulfate, and concentrated under reduced pressure. The resulting
crude product was recrystallized with MeOH (1 L) and distilled
water (500 ml) to obtain the title compound as a colorless
needle-like crystal (177 g, 73%).
[0744] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta.: 1.43 (6H, s),
2.65 (2H, t, 12 Hz), 3.02 (2H, t, 12 Hz), 3.79 (3H, s), 6.74 (1H,
m), 6.87 (1H, m), 7.24 (1H, m).
[0745] LCMS: m/z 205 [M+H].sup.+
Example 2
[0746] Compound A3-1, Compound A3-2
3-Bromo-8-methoxy-6,6-dimethyl-6,11-dihydro-5H-benzo[b]carbazole
1-Bromo-8-methoxy-6,6-dimethyl-6,11-dihydro-5H-benzo[b]carbazole
##STR00017##
[0748] 7-Methoxy-1,1-dimethyl-3,4-dihydro-1H-naphthalen-2-one
(Compound A2, 66.2 g, 324 mmol) and 3-bromophenylhydrazine
hydrochloric acid salt (71.0 g, 318 mmol) were dissolved in AcOH
(350 ml) and refluxed under stirring for 6 hr. The reaction solvent
was removed by distillation under reduced pressure to obtain the
crude product as a mixture of the title compound A3-1 and A3-2.
Example 3
[0749] Compound A4
3-Bromo-8-methoxy-6,6-dimethyl-5,6-dihydrobenzo[b]carbazol-11-one
##STR00018##
[0751] The crude product obtained from the above (i.e., mixture of
A3-1 and A3-2) was dissolved in a mixture solvent of THF (450 ml)
and distilled water (50 ml), added once with DDQ (115 g, 509 mmol),
and then stirred at room temperature for 1 hr. The reaction mixture
was diluted with CPME 3 L, and the organic layer was washed three
times with 0.5 N aqueous solution of sodium hydroxide (1 L) and
twice with distilled water (1 L) in order and dried over anhydrous
sodium sulfate. The organic layer was concentrated to 500 ml under
reduced pressure. The precipitated product was collected by
filtration and washed with a small amount of CPME to obtain the
title compound as a yellow crystal (48 g, 40%).
[0752] .sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta.: 1.73 (6H, s),
3.90 (3H, s), 7.06-7.09 (1H, m), 7.32-7.38 (2H, m), 7.65-7.66 (1H,
m), 8.09-8.17 (2H, m), 12.32 (1H, br. s).
[0753] LCMS: m/z 370, 372 [M+H].sup.+
Example 4
[0754] Compound AA1
4-Methoxy-2-(3-trimethylsilanylprop-2-ynyl)-benzoic acid methyl
ester
##STR00019##
[0756] To the THF (16 ml) solution of
2-bromomethyl-4-methoxy-benzoic acid methyl ester (961 mg, 4.09
mmol), triphenylphosphine (107 mg, 0.1 eq.), cesium carbonate (1.87
g, 1.4 eq.), copper iodide (59 mg, 0.076 eq.) and tris
(dibenzylideneacetone) dipalladium (86 mg, 0.023 eq.) were added,
degassed, flushed with nitrogen gas, added with
trimethylsilylacetylene (734 .mu.l, 1.3 eq.), and then stirred
overnight at 55.degree. C. To the reaction solution, saturated
aqueous solution of ammonium chloride was added followed by
extraction with ethyl acetate. The organic layer was washed with
brine and dried over magnesium sulfate. The drying agent was
removed by filtration and the residues obtained after concentration
under reduced pressure were purified by silica gel column
chromatography (ethyl acetate/hexane) to obtain the title compound
(brown oily substance, 606 mg, 54%).
[0757] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta.: 7.93 (1H, d,
J=8.8 Hz), 7.33 (1H, d, J=2.6 Hz), 6.78 (1H, dd, J=8.8, 2.6 Hz),
4.09 (2H, s), 3.86 (3H, s), 3.84 (3H, s), 0.14 (9H, s).
[0758] LCMS: m/z 277 [M+H].sup.+
[0759] HPLC retention time: 3.30 min (analysis condition U)
Example 5
[0760] Compound AA2
2-(1,1-Dimethyl-3-trimethylsilanylprop-2-ynyl)-4-methoxy-benzoic
acid methyl ester
##STR00020##
[0762] To the toluene (4 ml) solution of
4-methoxy-2-(3-trimethylsilanyl-prop-2-ynyl)-benzoic acid methyl
ester (Compound AA1, 273 mg, 0.988 mmol), sodium bis
(trimethylsilyl) amide (2.1 ml, 1.9 m solution, 4 eq.) and
iodomethane (308 .mu.l, 5 eq.) were added at -78.degree. C. After
allowing the reaction temperature to increase to the room
temperature, the mixture was stirred for 2 hr. To the reaction
solution, saturated aqueous solution of ammonium chloride was added
followed by extraction with ethyl acetate. The organic layer was
washed with brine and dried over magnesium sulfate. The drying
agent was removed by filtration and the residues obtained after
concentration under reduced pressure were purified by silica gel
column chromatography (ethyl acetate/hexane) to obtain the title
compound (yellow oily substance, 226 mg, 75%).
[0763] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta.: 7.45 (1.0H, d,
J=8.4 Hz), 7.09 (1.1H, d, J=2.6 Hz), 6.75 (1H, m), 3.84 (3H, s),
3.82 (3H, s), 1.70 (6H, s), 0.14 (9H, s)
[0764] LCMS: m/z 305 [M+H].sup.+
[0765] HPLC retention time: 3.38 min (analysis condition U)
Example 6
[0766] Compound AA3
2-(1,1-Dimethylprop-2-ynyl)-4-methoxy-benzoic acid methyl ester
##STR00021##
[0768] To the THF (18 ml) solution of
2-(1,1-dimethyl-3-trimethylsilanylprop-2-ynyl)-4-methoxy-benzoic
acid methyl ester (Compound AA2, 912 mg, 3 mmol),
tetrabutylammonium fluoride (2.061 g, 2.6 eq.) was added, and then
stirred for 3 hr at room temperature. To the reaction solution,
saturated aqueous solution of ammonium chloride was added followed
by extraction with ethyl acetate. The organic layer was washed with
brine and dried over magnesium sulfate. The drying agent was
removed by filtration and the residues obtained after concentration
under reduced pressure were purified by silica gel column
chromatography (ethyl acetate/hexane) to obtain the title compound
(yellow oily substance, 524 mg, 75%).
[0769] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta.: 7.44 (1H, d,
J=8.4 Hz), 7.05 (1H, d, J=2.3 Hz), 6.76 (1H, dd, J=8.4, 2.3 Hz),
3.84 (3H, s), 3.82 (3H, s), 1.73 (6H, s)
[0770] LCMS: m/z 223 [M+H].sup.+
[0771] HPLC retention time: 2.55 min (analysis condition U)
Example 7
[0772] Compound AA4
2-[1-(6-Cyano-1-methanesulfonyl-1H-indol-2-yl)-1-methylethyl]-4-methoxy-be-
nzoic acid methyl ester
##STR00022##
[0774] To the DMF (2 ml) solution of
2-(1,1-dimethylprop-2-ynyl)-4-methoxy-benzoic acid methyl ester
(Compound AA3, 134 mg, 0.577 mmol) and
N-(2-bromo-5-cyanophenyl)methanesulfonamide (Compound AA5, 167 mg,
1.05 eq.), copper iodide (9 mg, 0.08 eq.) and TEA (129 .mu.l, 1.6
eq.) were added, degassed and flushed with nitrogen gas, added with
dicholorobis (triphenylphosphine) palladium (20 mg, 0.05 eq.), and
then degassed and flushed again with nitrogen gas. After stirring
for 2 hr at 90.degree. C., the reaction solution was added with
water, extracted with ethyl acetate. The organic layer was washed
with an brine and dried over magnesium sulfate. The drying agent
was removed by filtration and the residues obtained after
concentration under reduced pressure were purified by silica gel
column chromatography (ethyl acetate/hexane) to obtain the title
compound (white solid, 152 mg, 62%).
[0775] .sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta.: 8.19 (1H, dd,
J=0.6, 0.6 Hz), 7.84 (1H, dd, J=8.0, 0.6 Hz), 7.67 (1H, dd, J=8.0,
1.3 Hz), 7.13 (1H, d, J=8.4 Hz), 6.99 (1H, s), 6.96 (1H, br.s),
6.85 (1H, dd, J=8.4, 2.5 Hz), 3.78 (3H, s), 3.12 (3H, s), 3.09 (3H,
br. s), 1.89 (6H, s).
[0776] LCMS: m/z 427 [M+H].sup.+
[0777] HPLC retention time: 2.77 min (analysis condition U)
Example 8
[0778] Compound AA5
N-(2-Bromo-5-cyanophenyl)methanesulfonamide
##STR00023##
[0780] To a mixture of 3-amino-4-bromo-benzonitrile (1.98 g, 10
mmol), TEA (5.06 g, 50 mmol), and methylene chloride (50 ml), mesyl
chloride (2.71 ml, 35 mmol) was added at 0.degree. C. and the
mixture was stirred at room temperature for 30 min. Water was added
to the reaction solution, which was then extracted with
dichloromethane. The organic layer was dried over sodium sulfate.
The drying agent was removed by filtration and the residues
obtained after concentration under reduced pressure were added with
tetrahydrofuran (100 ml), water (400 l) and sodium hydride (540 mg,
15.5 mmol), and stirred at room temperature for 16 hr. To the
reaction solution, saturated aqueous solution of ammonium chloride
(200 ml) was added followed by extraction with ethyl acetate. The
organic layer was dried over sodium sulfate. The drying agent was
removed by filtration and the residues obtained after concentration
under reduced pressure were purified by silica gel column
chromatography (hexane/ethyl acetate) to obtain the title compound
(2.48 g, 90%).
[0781] .sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta.: 9.82 (1H, s),
7.87 (1H, d, J=4 Hz), 7.75 (1H, d, J=8 Hz), 7.70 (1H, dd, J=8 Hz, 4
Hz), 3.14 (3H, s)
[0782] HPLC retention time: 1.63 min (analysis condition U)
Example 9
[0783] Compound AA6
2-(1-Hydroxy-1-methylethyl)-1H-indole-6-carbonitrile
##STR00024##
[0785] To N-(2-bromo-5-cyanophenyl)methanesulfonamide (Compound
AA5, 230 mg, 1 mmol), 3-methyl-2-butyn-3-ol (0.15 ml, 1.5 mmol),
X-Phos (72 mg, 15% mol), PdCl.sub.2(CH.sub.3CN).sub.2 (13 mg, 5%
mol) and cesium carbonate (390 mg, 2 mmol), DMA (2 ml) was added,
and the mixture was stirred at 100.degree. C. for 3 hr. Water and 5
N hydrochloric acid solution were added to the reaction solution,
which was then extracted with ethyl acetate. The organic layer was
dried over sodium sulfate. The drying agent was removed by
filtration and the residues obtained after concentration under
reduced pressure were purified by silica gel column chromatography
(hexane/ethyl acetate) to obtain the title compound (130 mg,
75%).
[0786] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta.: 8.76 (1H, s),
7.68 (1H, s), 7.60 (1H, d, J=8 Hz), 7.32 (1H, dd, J=8 Hz, 4 Hz),
6.37 (1H, m), 1.93 (1H, s), 1.70 (6H, s)
[0787] LCMS: m/z 201 [M+H].sup.+
[0788] HPLC retention time: 2.12 min (analysis condition U)
Example 10
[0789] Compound A5-1
3-Bromo-8-hydroxy-6,6-dimethyl-5,6-dihydrobenzo[b]carbazol-11-one
##STR00025##
[0791] Under the same conditions as the method for synthesizing
Compound A6, the title compound was synthesized from Compound
A4.
[0792] .sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta.: 12.30 (1H, s),
10.21 (1H, s), 8.06-8.11 (1H, m), 8.01-8.05 (1H, m), 7.62-7.66 (1H,
m), 7.32-7.37 (1H, m), 7.08-7.12 (1H, m), 6.84-6.90 (1H, m), 1.69
(6H, s).
[0793] LCMS: m/z 356, 358 [M+H].sup.+
[0794] HPLC retention time: 2.30 min (analysis condition U)
Example 11
[0795] Compound A5-2
8-Methoxy-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonit-
rile
##STR00026##
[0797] (Method 1)
3-Bromo-8-methoxy-6,6-dimethyl-5,6-dihydrobenzo[b]carbazol-11-one
(Compound A4, 10.45 g, 28.2 mmol) and copper (I) cyanide (5.0 g,
50.2 mmol) were dissolved in NMP (100 ml), followed by stirring at
170.degree. C. for 17 hr. The reaction mixture was suspended in
ethyl acetate (500 mL) and distilled water (200 mL). The insoluble
matters were removed by Celite filtration and washed twice with
ethyl acetate (300 mL.times.2). The organic layer was washed once
with an aqueous solution of disodium EDTA (200 mL) and twice with
saturated brine (200 mL) in order, and dried over anhydrous sodium
sulfate. The organic layer was concentrated under reduced pressure
to yield a product, which was suspended and washed with a small
amount of CPME to obtain the title compound as a colorless crystal
(6.58 g, 73%).
[0798] (Method 2) To the THF (5.6 ml) solution of
2-[1-(6-cyano-1-methanesulfonyl-1H-indol-2-yl)-1-methylethyl]-4-methoxy-b-
enzoic acid methyl ester (Compound AA4, 138 mg, 0.324 mmol),
tetrabutylammonium fluoride (514 mg, 6 eq.) was added, and the
mixture was stirred at room temperature overnight. Thereafter, 2 M
aqueous solution of sodium hydroxide (5.6 ml) was added to the
mixture, which was then stirred for 4 hr, added with 1 M HCl, and
extracted with ethyl acetate. The organic layer was washed with
brine and dried over magnesium sulfate. The drying agent was
removed by filtration and the residues obtained after concentration
under reduced pressure were dissolved in ethyl acetate (10 ml) and
added with e 4 M HCl and ethyl acetate solution (10 ml) followed by
stirring at room temperature for 30 min. The residues obtained
after concentration of the reaction solution under reduced pressure
were purified by silica gel column chromatography (ethyl
acetate/hexane) to obtain the title compound (89.2 mg, 62%).
[0799] (Method 3) To nitrobenzene (5 ml) and aluminum chloride (400
mg, 3 mmol), 4-methoxybenzoyl chloride (400 mg, 2.3 mmol) was
added. After stirring for 30 min at room temperature,
2-(1-hydroxy-1-methyl-ethyl)-1H-indole-6-carbonitrile (Compound
AA6, 200 mg, 1 mmol) was added followed by stirring at room
temperature for 3 hr. Water was added to the reaction solution,
which was then extracted with ethyl acetate. The organic layer was
dried over sodium sulfate. The drying agent was removed by
filtration and the residues obtained after concentration under
reduced pressure were purified by silica gel column chromatography
(hexane/ethyl acetate) to obtain the title compound (127 mg,
40%).
[0800] .sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta.: 1.71 (6H, s),
3.89 (3H, s), 7.07-7.09 (1H, m), 7.34 (1H, s), 7.58-7.60 (1H, m),
7.99 (1H, s), 8.14-8.16 (1H, m), 8.30-8.32 (1H, m), 12.32 (1H, br.
s),
[0801] LCMS: m/z 317 [M+H].sup.+
[0802] HPLC retention time: 2.56 min (analysis condition U)
Example 12
[0803] Compound A6
8-Hydroxy-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonit-
rile
##STR00027##
[0805]
8-Methoxy-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-c-
arbonitrile (Compound A5-2, 6.58 g, 20.8 mmol) was dissolved in
pyridine hydrochloric acid salt (25.0 g), and stirred at
170.degree. C. for 13 hr. The reaction mixture was partitioned in
ethyl acetate (400 mL) and distilled water (400 mL), and the
aqueous layer was extracted one more time with ethyl acetate (400
mL). The combined organic layer was washed twice with distilled
water (100 mL) and once with saturated brine (100 mL) in order, and
dried over anhydrous sodium sulfate. The organic layer was
concentrated under reduced pressure to yield a product, which was
suspended and washed with a small amount of CPME to obtain the
title compound as a colorless crystal (5.91 g, 93%).
[0806] .sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta.: 1.73 (6H, s),
6.87-6.90 (1H, m), 7.11 (1H, s), 7.57-7.59 (1H, m), 7.97 (1H, s),
8.04-8.06 (1H, m), 8.29-8.31 (1H, m), 10.27 (1H, s), 12.66 (1H, br.
s),
[0807] LCMS: m/z 303 [M+H].sup.+
Example 13
[0808] Compound A7-1
4-(3-Cyano-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yloxy)-p-
iperidine-1-carboxylic acid tert-butyl ester
##STR00028##
[0810]
8-Hydroxy-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-c-
arbonitrile (Compound A6, 30 mg, 0.099 mmol) was dissolved in THF
(1 mL), added with 4-hydroxy-piperidine-1-carboxylic acid
tert-butyl ester (40 mg, 2 eq.), triphenylphosphine (52 mg, 2 eq.),
and diisopropyl azodicarboxlyate (43 .mu.L, 2 eq.) in order, and
stirred at room temperature for 4 hr. The reaction solution was
poured to water, and then extracted with ethyl acetate. The organic
layer was washed with saturated brine and dried over sodium
sulfate. The drying agent was removed by filtration and the
residues obtained after concentration under reduced pressure were
purified by silica gel column chromatography (ethyl acetate/hexane)
to obtain the title compound (37 mg, 76%).
[0811] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta.: 9.44 (1H, s),
8.77 (1H, d, J=7.8 Hz), 8.62 (1H, d, J=8.2 Hz), 8.00 (1H, s), 7.81
(1H, d, J=8.2 Hz), 7.34 (1H, s), 7.26 (1H, d, J=7.8 Hz), 4.85-4.93
(1H, m), 3.96-4.04 (2H, m), 3.60-3.70 (2H, m), 2.19-2.32 (2H, m),
1.89-2.15 (8H, m), 1.74 (9H, s)
[0812] LCMS: m/z 430 [M+H].sup.+
[0813] HPLC retention time: 4.09 min (analysis condition W)
Example 14
[0814] Compound A7-2
6,6-Dimethyl-11-oxo-8-[2-(2-oxo-imidazolidin-1-yl)-ethoxy]-6,11-dihydro-5H-
-benzo[b]carbazole-3-carbonitrile
##STR00029##
[0816] Under the same conditions as the method for synthesizing
Compound A7-1, the title compound was prepared from Compound A6 and
1-(2-hydroxy-ethyl)-imidazolidin-2-one.
[0817] LCMS: m/z 415 [M+H].sup.+
[0818] HPLC retention time: 2.96 min (analysis condition W)
Example 15
[0819] Compound A7-3
[2-(3-Cyano-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yloxy)--
ethyl]-carbamic acid tert-butyl ester
##STR00030##
[0821] Under the same conditions as the method for synthesizing
Compound A7-1, the title compound was prepared from Compound A6 and
(2-hydroxy-ethyl)-carbamic acid tert-butyl ester.
[0822] LCMS: m/z 346 [M+H].sup.+
[0823] HPLC retention time: 2.40 min (analysis condition W)
Example 16
[0824] Compound A7-4
6,6-Dimethyl-8-(2-methylsulfanyl-ethoxy)-11-oxo-6,11-dihydro-5H-benzo[b]ca-
rbazole-3-carbonitrile
##STR00031##
[0826] Under the same conditions as the method for synthesizing
Compound A7-1, the title compound was prepared from Compound A6 and
2-methylthioethanol.
[0827] LCMS: m/z 451 [M+H].sup.+
[0828] HPLC retention time: 4.23 min (analysis condition W)
Example 17
[0829] Compound A7-5
6,6-Dimethyl-8-(2-methylsulfanyl-ethoxy)-5-(2-methylsulfanyl-ethyl)-11-oxo-
-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile
##STR00032##
[0831] The title compound was obtained as a by-product of the
synthesis of Compound A7-4.
[0832] LCMS: m/z 377 [M+H].sup.+
[0833] HPLC retention time: 3.75 min (analysis condition W)
Example 18
[0834] Compound A7-6
6,6-Dimethyl-11-oxo-8-(tetrahydro-pyran-4-yloxy)-6,11-dihydro-5H-benzo[b]c-
arbazole-3-carbonitrile
##STR00033##
[0836] Under the same conditions as the method for synthesizing
Compound A7-1, the title compound was prepared from Compound A6 and
tetrahydropyran-4-ol.
[0837] .sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta.: 12.72 (1H,
br.s), 8.32 (1H, d, 8.5H z), 8. (1H, d, 8.5 Hz), 8.01 (1H, s), 7.61
(1H, d, 8.5 Hz), 7.38 (1H, s), 7.15 (1H, d, 8.5 Hz), 4.86-4.81 (1H,
m), 3.93-3.88 (2H, m), 3.58-3.52 (2H, m), 2.06-2.00 (2H, m), 1.85
(6H, s), 1.69-1.60 (2H, m)
[0838] LCMS: m/z 387 [M+H].sup.+
[0839] HPLC retention time: 3.47 min (analysis condition W)
Example 19
[0840] Compound A7-7
6,6-Dimethyl-11-oxo-8-(pyridin-4-ylmethoxy)-6,11-dihydro-5H-benzo[b]carbaz-
ole-3-carbonitrile
##STR00034##
[0842] Under the same conditions as the method for synthesizing
Compound A7-1, the title compound was prepared from Compound A6 and
pyridin-4-yl-methanol.
[0843] LCMS: m/z 394 [M+H].sup.+
[0844] HPLC retention time: 2.56 min (analysis condition W)
Example 20
[0845] Compound A7-8
8-(2-Methoxyethoxy)-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole--
3-carbonitrile
##STR00035##
[0847] Under the same conditions as the method for synthesizing
Compound A7-1, the title compound was prepared from Compound A6 and
2-methoxyethanol.
[0848] .sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta.: 11.69 (1H, br.
s), 8.27 (1H, d, 7.9 Hz), 8. (1H, d, 8.5 Hz), 7.95 (1H, s), 7.55
(1H, d, 7.9 Hz), 7.32 (1H, d, 2.4 Hz), 7.05 (1 H, d, 8.5 Hz), 4.22
(2H, t, 4.3 Hz), 3.67 (2H, t, 4.3 Hz), 1.72 (6H, s)
[0849] LCMS: m/z 361 [M+H].sup.+
[0850] HPLC retention time: 3.38 min (analysis condition W)
Example 21
[0851] Compound A7-9
8-[2-(2-Methoxyethoxy)ethoxy]-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]-
carbazole-3-carbonitrile
##STR00036##
[0853] Under the same conditions as the method for synthesizing
Compound A7-1, the title compound was prepared from Compound A6 and
2-(2-methoxyethoxy)ethanol.
[0854] LCMS: m/z 405 [M+H].sup.+
[0855] HPLC retention time: 3.32 min (analysis condition W)
Example 22
[0856] Compound A7-10
6,6-Dimethyl-8-(3-methyloxetan-3-ylmethoxy)-11-oxo-6,11-dihydro-5H-benzo[b-
]carbazole-3-carbonitrile
##STR00037##
[0858] Under the same conditions as the method for synthesizing
Compound A7-17, the title compound was prepared from Compound A6
and 3-chloromethyl-3-methyloxetane.
[0859] LCMS: m/z 387 [M+H].sup.+
[0860] HPLC retention time: 2.23 min (analysis condition S)
[0861] Compound A7-11-1
[2-(3-Cyano-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yloxy)e-
thyl]ethyl-carbamic acid tert-butyl ester
##STR00038##
[0863] Under the same conditions as the method for synthesizing
Compound A7-1, the title compound was prepared from Compound A6 and
ethyl-(2-hydroxy-ethyl)-carbamic acid tert-butyl ester.
[0864] LCMS: m/z 474 [M+H].sup.+
[0865] HPLC retention time: 2.93 min (analysis condition U)
Example 24
[0866] Compound A7-11-2
8-(2-Ethylaminoethoxy)-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazo-
le-3-carbonitrile
##STR00039##
[0868] Under the same conditions as the method for synthesizing
Compound A8-1, the title compound was prepared from Compound
A7-11-1.
[0869] LCMS: m/z 374 [M+H].sup.+
[0870] HPLC retention time: 1.35 min (analysis condition U)
Example 25
[0871] Compound A7-12
8-(2-Hydroxyethoxy)-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole--
3-carbonitrile
##STR00040##
[0873] Under the same conditions as the method for synthesizing
Compound A7-17, the title compound was prepared from Compound A6
and 2-bromo-ethanol.
[0874] LCMS: m/z 437 [M+H].sup.+
[0875] HPLC retention time: 2.93 min (analysis condition U)
Example 26
[0876] Compound A7-13-1
6,6-Dimethyl-11-oxo-8-(2-phenyl-[1,3]dioxan-5-yloxy)-6,11-dihydro-5H-benzo-
[b]carbazole-3-carbonitrile
##STR00041##
[0878] Under the same conditions as the method for synthesizing
Compound A7-1, the title compound was prepared from Compound A6 and
2-phenyl-[1,3]dioxan-5-ol.
[0879] LCMS: m/z 465 [M+H].sup.+
[0880] HPLC retention time: 4.10 min (analysis condition W)
Example 27
[0881] Compound A7-13-2
8-(2-Hydroxy-1-hydroxymethylethoxy)-6,6-dimethyl-11-oxo-6,11-dihydro-5H-be-
nzo[b]carbazole-3-carbonitrile
##STR00042##
[0883] Anhydrous ferric trichloride (56 mg, 5 eq.) was added to the
dichloromethane (2 mL) suspension of
6,6-dimethyl-11-oxo-8-(2-phenyl-[1,3]dioxan-5-yloxy)-6,11-dihydro-5H-benz-
o[b]carbazole-3-carbonitrile (Compound A7-13-1, 13 mg, 0.028 mmol),
and stirred at room temperature for 1 hr. The reaction solution was
added to water, and then extracted with ethyl acetate. The organic
layer was washed with saturated brine and dried over sodium
sulfate. The drying agent was removed by filtration and the
residues obtained after concentration under reduced pressure were
purified by high performance liquid chromatography to obtain the
title compound (7 mg, 46%).
[0884] LCMS: m/z 377 [M+H].sup.+
[0885] HPLC retention time: 2.70 min (analysis condition W)
Example 28
[0886] Compound A7-14-1
8-((S)-2,2-Dimethyl-[1,3]dioxolan-4-ylmethoxy)-6,6-dimethyl-11-oxo-6,11-di-
hydro-5H-benzo[b]carbazole-3-carbonitrile
##STR00043##
[0888] Under the same conditions as the method for synthesizing
Compound A7-17, the title compound was prepared from Compound A6
and toluene-4-sulfonic acid
(R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethyl ester.
[0889] LCMS: m/z 417 [M+H].sup.+
[0890] HPLC retention time: 3.47 min (analysis condition Y)
Example 29
[0891] Compound A7-14-2
8-((R)-2,3-Dihydroxy-propoxy)-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]-
carbazole-3-carbonitrile
##STR00044##
[0893] To the solution of THF and water (4: 1, 1 mL) of
8-(2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-6,6-dimethyl-11-oxo-6,11-dihyd-
ro-5H-benzo[b]carbazole-3-carbonitrile (Compound A14-1, 30 mg, 0.07
mmol), camphor sulfonic acid (36 mg, 0.14 mmol) was added at room
temperature. After stirring at room temperature for 38 hr, the
mixture was extracted with ethyl acetate. The organic layer was
dried over sodium sulfate. The drying agent was removed by
filtration and the residues obtained after concentration under
reduced pressure were purified by silica gel column chromatography
(dichloromethane/methanol) to obtain the title compound (white
solid, 28 mg, 72%).
[0894] .sup.1H-NMR (300 MHz, DMSO-d.sub.6) .sigma.ppm; 12.7 (s,
1H), 8.31 (d, 1H, J=8.01 Hz), 8.15 (d, 1H, J=8.77 Hz), 8.00 (s,
1H), 7.60 (d, 1H, J=8.01 Hz), 7.12 (s, 1H), 7.09 (d, 1H, J=8.77
Hz), 4.46 (m, 1H), 4.15 (m, 3H), 3.78 (m, 1H), 1.76 (s, 6H), 1.38
(s, 3H), 1.32 (s, 3H)
[0895] LCMS: m/z 377 [M+H].sup.+
[0896] HPLC retention time: 1.80 min (analysis condition U)
Example 30
[0897] Compound A7-14-3
8-((S)-2,2-Dimethyl-[1,3]dioxolan-4-ylmethoxy)-5,6,6-trimethyl-11-oxo-6,11-
-dihydro-5H-benzo[b]carbazole-3-carbonitrile
##STR00045##
[0899] Under the same conditions as the method for synthesizing
Compound B3-4, the title compound was prepared as a crude product
from Compound A7-14-1.
Example 31
[0900] Compound A7-14-4
8-((R)-2,3-Dihydroxy-propoxy)-5,6,6-trimethyl-11-oxo-6,11-dihydro-5H-benzo-
[b]carbazole-3-carbonitrile
##STR00046##
[0902] Under the same conditions as the method for synthesizing
Compound A7-14-2, the title compound was prepared from Compound
A7-14-3 (303 mg, 98%).
[0903] LCMS: m/z 484 [M+H].sup.+
[0904] HPLC retention time: 2.08 min (analysis condition D)
Example 32
[0905] Compound A7-15-1
8-[(4R,5S)-5-(Tert-butyl-dimethyl-silanyloxymethyl)-2,2-dimethyl-[1,3]diox-
olan-4-ylmethoxy]-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3--
carbonitrile
##STR00047##
[0907] Under the same conditions as the method for synthesizing
Compound A7-1, the title compound was prepared from Compound A6 and
[(4R,5R)-5-(tert-butyl-dimethyl-silanyloxymethyl)-2,2-dimethyl-[1,3]dioxo-
lan-4-yl]-methanol.
[0908] LCMS: m/z 516 [M+H].sup.+
[0909] HPLC retention time: 3.97 min (analysis condition Y)
Example 33
[0910] Compound A7-15-2
6,6-Dimethyl-11-oxo-8-((2R,3R)-2,3,4-trihydroxy-butoxy)-6,11-dihydro-5H-be-
nzo[b]carbazole-3-carbonitrile
##STR00048##
[0912] Under the same conditions as the method for synthesizing
Compound A7-14-2, the title compound was prepared from Compound
A7-15-1.
[0913] LCMS: m/z 407 [M+H].sup.+
[0914] HPLC retention time: 1.73 min (analysis condition U)
Example 34
[0915] Compound A7-16
6,6-Dimethyl-8-(1-methyl-piperidin-4-yloxy)-11-oxo-6,11-dihydro-5H-benzo[b-
]carbazole-3-carbonitrile
##STR00049##
[0917] Under the same conditions as the method for synthesizing
Compound A7-1, the title compound was prepared from Compound A6 and
1-methylpiperidin-4-ol.
[0918] .sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta.: 12.75 (1H, s),
8.32 (1H, d, J=7.9 Hz), 8.14 (1H, d, J=9.8 Hz), 8.00 (1H, s), 7.60
(1H, d, J=7.9 Hz), 7.34 (1H, s), 7.11 (1H, d, J=9.1 Hz), 4.62 (1H,
m), 2.64 (2H, m), 2.23 (2H, m), 2.21 (s, 3H), 1.99 (2H, m), 1.77
(s, 6H), 1.73 (2H, m).
[0919] LCMS: m/z 400 [M+H].sup.+
[0920] HPLC retention time: 1.42 min (analysis condition S)
Example 35
[0921] Compound A7-17
8-(2-Diethylamino-ethoxy)-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carb-
azole-3-carbonitrile
##STR00050##
[0923]
8-Hydroxy-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-c-
arbonitrile (Compound A6, 25 mg, 0.083 mmol) was dissolved in
N,N-dimethylacetamide (1 mL), added with 2-chloroethyldiethylamine
(16 mg, 1.1 eq.) and cesium carbonate (54 mg, 2 eq.) in order and
stirred at 100.degree. C. for 4 hr. The reaction solution was
poured over water and extracted with ethyl acetate. The organic
layer was washed with saturated brine and dried over sodium
sulfate. The drying agent was removed by filtration and the
residues obtained after concentration under reduced pressure were
purified by amino silica gel column chromatography (ethyl
acetate/hexane) to obtain the title compound (11 mg, 32%).
[0924] .sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta.: 8.32 (1H, d,
J=8.2 Hz), 8.15 (1H, d, J=8.7 Hz), 8.01 (1H, s), 7.61 (1H, d, J=8.2
Hz), 7.35 (1H, d, J=1.8 Hz), 7.09 (1H, dd, J=8.7, 1.8 Hz), 4.19
(2H, t, J=5.9 Hz), 2.83 (2H, t, J=5.9 Hz), 2.58 (4H, q, J=7.0 Hz),
1.78 (6H, s), 1.00 (6H, t, J=7.0 Hz)
[0925] LCMS: m/z 402 [M+H].sup.+
[0926] HPLC retention time: 2.52 min (analysis condition W)
Example 36
[0927] Compound A7-18
N-[2-(3-Cyano-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yloxy-
)-ethyl]-acetamide
##STR00051##
[0929] Under the same conditions as the method for synthesizing
Compound A7-17, the title compound was prepared from Compound A6
and 2-chloroethylacetamide.
[0930] LCMS: m/z 388 [M+H].sup.+
[0931] HPLC retention time: 2.91 min (analysis condition W)
Example 37
[0932] Compound A7-19
[2-(3-Cyano-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yloxy)--
ethyl]-carbamic acid ethyl ester
##STR00052##
[0934] Under the same conditions as the method for synthesizing
Compound A7-17, the title compound was prepared from Compound A6
and ethyl-2-chloroethylcarbamate.
[0935] LCMS: m/z 418 [M+H].sup.+
[0936] HPLC retention time: 3.35 min (analysis condition W)
Example 38
[0937] Compound A7-20
[2-(3-Cyano-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yloxy)--
ethyl]-urea
##STR00053##
[0939] Under the same conditions as the method for synthesizing
Compound A7-17, the title compound was prepared from Compound A6
and 2-chloroethylurea.
[0940] LCMS: m/z 399 [M+H].sup.+
[0941] HPLC retention time: 2.80 min (analysis condition W)
Example 39
[0942] Compound A7-21
6,6-Dimethyl-8-(oxetan-3-yloxy)-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-
-carbonitrile
##STR00054##
[0944] Under the same conditions as the method for synthesizing
Compound A7-17, the title compound was prepared from Compound A6
and toluene-4-sulfonic acid oxetan-3-yl ester.
[0945] LCMS: m/z 359 [M+H].sup.+
[0946] HPLC retention time: 2.00 min (analysis condition S)
Example 40
[0947] Compound A7-22
6,6-Dimethyl-11-oxo-8-(pyrimidin-2-yloxy)-6,11-dihydro-5H-benzo[b]carbazol-
e-3-carbonitrile
##STR00055##
[0949] Under the same conditions as the method for synthesizing
Compound A7-17, the title compound was prepared from Compound A6
and 2-bromopyrimidine.
[0950] LCMS: m/z 381 [M+H].sup.+
[0951] HPLC retention time: 2.00 min (analysis condition S)
Example 41
[0952] Compound A7-23
(3-Cyano-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yloxy)-eth-
yl acetate ester
##STR00056##
[0954] Under the same conditions as the method for synthesizing
Compound A7-17, the title compound was prepared from Compound A6
and 3-chloro-propionic acid ethyl ester.
[0955] LCMS: m/z 389 [M+H].sup.+
[0956] HPLC retention time: 3.37 min (analysis condition U)
Example 42
[0957] Compound A7-24
8-(2-Bromo-ethoxy)-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-
-carbonitrile
##STR00057##
[0959] Under the same conditions as the method for synthesizing
Compound A7-1, the title compound was prepared from Compound A6 and
2-bromoethanol.
[0960] .sup.1H-NMR (270 MHz, DMSO-d.sub.6) .delta.: 12.75 (1H,
br.s), 8.32 (1H, d, J=8.2 Hz), 8.17 (1H, d, J=8.6 Hz), 8.01 (1H,
s), 7.61 (1H, dd, J=8.2, 1.4 Hz), 7.40 (1H, d, J=2.2 Hz), 7.12 (1H,
dd, J=8.6, 2.2 Hz), 4.50 (2H, t, J=5.3 Hz), 3.88 (2H, t, J=5.3 Hz),
1.77 (6H, s).
[0961] LCMS: m/z 409, 411 [M+H].sup.+
[0962] HPLC retention time: 2.48 min (analysis condition S)
Example 43
[0963] Compound A7-25
6,6-Dimethyl-11-oxo-8-(piperidin-4-ylmethoxy)-6,11-dihydro-5H-benzo[b]carb-
azole-3-carbonitrile hydrochloric acid salt
##STR00058##
[0965] Under nitrogen atmosphere,
3-cyano-8-hydroxy-6,6-dimethyl-5,6-dihydro-benzo[b]carbazol-11-one
(Compound A6, 85 mg, 0.28 mmol) and triphenylphosphine (150 mg, 2
eq.) were added with THF (2 ml), and then further added dropwise
with 4-hydroxymethyl-piperidine-1-carboxylic acid tert-butyl ester
(120 mg, 2 eq.) and 2.19 N toluene solution of diethyl
azodicarboxylic acid (0.26 mL, 2 eq.). The resultant was stirred at
room temperature for 12 hr under nitrogen atmosphere. The residues
obtained after concentrating the reaction solution under reduced
pressure were purified by silica gel column chromatography (ethyl
acetate/dichloromethane) to obtain
4-(3-cyano-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yloxyme-
thyl)-piperidine-1-carboxylic acid tert-butyl ester (white powder,
120 mg).
[0966] To the resulting compound, 4 N hydrochloric acid and dioxane
solution was added under cooling. After stirring at room
temperature for 2 hr, the solvent was removed under nitrogen
stream. Then, the residues were washed with diethyl ether and then
subjected to azeotropic treatment with toluene, followed by drying
under vacuum and filtration to obtain the title compound (79
mg).
[0967] LCMS: m/z 399 [M+H].sup.+
[0968] HPLC retention time: 2.22 min (analysis condition C)
Example 44
[0969] Compound A8-1
6,6-Dimethyl-11-oxo-8-(piperidin-4-yloxy)-6,11-dihydro-5H-benzo[b]carbazol-
e-3-carbonitrile
##STR00059##
[0971] THF (0.5 mL) and TFA (0.5 mL) were added to
4-(3-cyano-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yloxy)--
piperidine-1-carboxylic acid tert-butyl ester (Compound A7-1, 35
mg, 0.072 mmol), and the mixture was stirred at room temperature
until Compound A7-1 disappears. The reaction solution was
concentrated under reduced pressure and the residue was desalinated
by using anion exchanger PL StratoSpheres (trademark) PL-HCO3 MP to
obtain the title compound (37 mg, 76%).
[0972] .sup.1H-NMR (400 MHz, CD.sub.3OD) .delta.: 8.38 (1H, d,
J=7.9 Hz), 8.24 (1H, d, J=8.5 Hz), 7.85 (1H, s), 7.53 (1H, d, J=7.9
Hz), 7.27 (1H, s), 7.09 (1H, d, J=8.5 Hz), 4. 67-4.76 (1H, m),
3.07-3.20 (2H, m), 2.77-2.87 (2H, m), 2.03-2.15 (2H, m), 1.80 (6H,
s), 1.69-1.77 (2H, m)
[0973] LCMS: m/z 386 [M+H].sup.+
[0974] HPLC retention time: 2.51 min (analysis condition W)
Example 45
[0975] Compound A8-2
8-(2-Amino-ethoxy)-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-
-carbonitrile
##STR00060##
[0977] Under the same conditions as the method for synthesizing
Compound A8-1, the title compound was prepared from Compound
A7-3.
[0978] LCMS: m/z 346 [M+H].sup.+
[0979] HPLC retention time: 2.40 min (analysis condition W)
Example 46
[0980] Compound A8-3
8-(2-Methanesulfonyl-ethoxy)-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]c-
arbazole-3-carbonitrile
##STR00061##
[0982] Under the same conditions as the method for synthesizing
Compound B3-8, the title compound was prepared from Compound
A7-5.
[0983] LCMS: m/z 409 [M+H].sup.+
[0984] HPLC retention time: 3.13 min (analysis condition W)
Example 47
[0985] Compound A8-4
8-(2-Methanesulfinyl-ethoxy)-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]c-
arbazole-3-carbonitrile
##STR00062##
[0987] The title compound was obtained as a by-product of the
synthesis of Compound A8-3.
[0988] LCMS: m/z 393 [M+H].sup.+
[0989] HPLC retention time: 2.87 min (analysis condition W)
Example 48
[0990] Compound A8-5
5,6,6-Trimethyl-11-oxo-8-(tetrahydro-pyran-4-yloxy)-6,11-dihydro-5H-benzo[-
b]carbazole-3-carbonitrile
##STR00063##
[0992] Under the same conditions as the method for synthesizing
Compound A10-1, the title compound was prepared from Compound
A7-6.
[0993] LCMS: m/z 401 [M+H].sup.+
[0994] HPLC retention time: 2.72 min (analysis condition S)
Example 49
[0995] Compound A8-6-1
2-Bromo-8-methoxy-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3--
carbonitrile
##STR00064##
[0997]
8-Methoxy-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-c-
arbonitrile (Compound A5-2, 50 mg, 0.158 mmol) was dissolved in
CH.sub.3CN (1 mL), added with NBS (56 mg, 2 eq.), and stirred at
80.degree. C. overnight. The reaction solution was added to water,
and then extracted with ethyl acetate. The organic layer was washed
with saturated brine and dried over sodium sulfate. The drying
agent was removed by filtration and the residues obtained after
concentration under reduced pressure were added with MeOH and the
solid remained after dissolution was filtered to obtain the target
compound (yellow powder, 20 mg, 38%).
[0998] .sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta.: 12.92 (1H, s),
8.50 (1H, s), 8.16 (1H, d, J=8.5 Hz), 8.14 (1H, s), 7.36 (1H, d,
J=2.4 Hz), 7.11 (1H, dd, J=8.5, 2.4 Hz), 3.92 (3H, s), 1.78 (6H,
s).
[0999] LCMS: m/z 395, 397 [M+H].sup.+
[1000] HPLC retention time: 2.57 min (analysis condition S)
Example 50
[1001] Compound A8-6-2
2-Bromo-8-hydroxy-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3--
carbonitrile
##STR00065##
[1003] Under the same conditions as the method for synthesizing
Compound A6, the title compound was prepared from Compound
A8-6-1.
[1004] .sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta.: 8.46 (1H, s),
8.10 (1H, s), 8.05 (1H, d, J=8.6 Hz), 7.13 (1H, d, J=2.1 Hz), 6.89
(1H, dd, J=8.5, 2.1 Hz), 1.71 (6H, s).
[1005] LCMS: m/z 381, 383 [M+H].sup.+
[1006] HPLC retention time: 2.10 min (analysis condition S)
Example 51
[1007] Compound A8-6-3
2-Bromo-8-(2-diethylamino-ethoxy)-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benz-
o[b]carbazole-3-carbonitrile
##STR00066##
[1009] Under the same conditions as the method for synthesizing
Compound A7-17, the title compound was prepared from Compound
A8-6-2.
[1010] .sup.1H-NMR (400 MHz, CD.sub.3OD) .delta.: 8.53 (1H, d,
J=0.5 Hz), 8.20 (1H, d, J=8.7 Hz), 7.88 (1H, d, J=0.5 Hz), 7.28
(1H, d, J=2.3 Hz), 7.05 (1H, dd, J=8.9, 2.5 Hz), 4.24 (2H, t, J=5.7
Hz), 2.96 (2H, t, J=5.7 Hz), 2.70 (4H, q, J=7.1 Hz), 1.79 (6H, s),
1.12 (6H, t, J=7.2 Hz).
[1011] LCMS: m/z 480, 482 [M+H].sup.+
[1012] HPLC retention time: 1.73 min (analysis condition S)
Example 52
[1013] Compound A8-7
(3-Cyano-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yloxy)-ace-
tic acid
##STR00067##
[1015]
(3-Cyano-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-ylo-
xy)-ethyl acetate ester (Compound A7-23, 180 mg, 0.464 mmol) and
potassium hydroxide (130 mg, 2.32 mmol) were dissolved in THF (10
ml) and water (1.8 mL), and stirred at 70.degree. C. for 2 hr.
After cooling to room temperature, the mixture was extracted with
dichloromethane. Water layer () was adjusted to be acidic by using
1 N hydrochloric acid, and the precipitated solid was filtered and
washed several times with water to obtain the title compound (white
solid, 130 mg, 78%).
[1016] .sup.1H-NMR (300 MHz, DMSO) .sigma.ppm 13.09 (s, 1H), 8.31
(d, 1H, J=8.1 Hz), 8.11 (d, 1H, J=8.4 Hz), 8.01 (s, 1H), 7.58 (d,
1H, J=7.8 Hz), 7.25 (d, 1H, J=2.1 Hz), 6.97 (d, 1H, J=8.4 Hz), 4.51
(s, 2H), 1.73 (s, 6H)
[1017] LCMS: m/z 361 [M+H].sup.+
[1018] HPLC retention time: 2.97 min (analysis condition U)
Example 53
[1019] Compound A8-8
6,6-Dimethyl-8-(2-morpholin-4-yl-ethoxy)-11-oxo-6,11-dihydro-5H-benzo[b]ca-
rbazole-3-carbonitrile
##STR00068##
[1021] Under the same conditions as the method for synthesizing
Compound A8-17, the title compound was prepared from Compound A7-24
and morpholine.
[1022] .sup.1H-NMR (500 MHz, CD.sub.3OD+CDCl.sub.3) a ppm; 8.4 (d,
1H, J=8.2 Hz), 8.3 (d, 1H, J=8.7 Hz), 7.8 (s, 1H), 7.5 (dd, 1H,
J=1.1 Hz, J=8.2 Hz), 7.2 (d, 1H, J=2.3 Hz), 7.0 (dd, 1H, J=2.2 Hz,
J=8.7 Hz), 4.2 (t, 2H, J=5.3 Hz), 3.7 (t, 4H, J=4.5 Hz), 2.9 (t,
2H, J=5.3 Hz), 2.6 (t, 4H, J=4.5 Hz), 1.8 (s, 6H)
[1023] LCMS: m/z 416 [M+H].sup.+
[1024] HPLC retention time: 2.40 min (analysis condition U)
Example 54
[1025] Compound A8-9
8-[2-(1,1-Dioxothiomorpholino)-ethoxy]-6,6-dimethyl-11-oxo-6,11-dihydro-5H-
-benzo[b]carbazole-3-carbonitrile
##STR00069##
[1027] Under the same conditions as the method for synthesizing
Compound A7-17, the title compound was prepared from Compound A7-24
and thiomorpholine-1,1-dioxide.
[1028] .sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta.: 12.72 (1H, s),
8.31 (1H, d, 8.5 Hz), 8.15 (1H, d, 8.5 Hz), 8.00 (1H, s), 7.60 (1H,
d, 8.5 Hz), 7.36 (1H, d, 1.8 Hz), 7.10 (1H, dd, 1.8, 8.5), 4.25
(2H, t, 5.5 Hz), 3.06-3.33 (8H, m), 2.97 (2H, t, 5.5), 1.77 (6H,
s)
[1029] LCMS: m/z 464 [M+H].sup.+
[1030] HPLC retention time: 2.70 min (analysis condition W)
Example 55
[1031] Compound A8-10
8-(2-Tert-butylamino-ethoxy)-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]c-
arbazole-3-carbonitrile
##STR00070##
[1033] Under the same conditions as the method for synthesizing
Compound A7-17, the title compound was prepared from Compound A7-24
and tert-butylamine.
[1034] .sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta.: 12.71 (1H, s),
8.32 (1H, d, 7.9 Hz), 8.15 (1H, d, 9.1 Hz), 8.07 (1 d, 1.8 Hz),
7.60 (1H, dd, 1.8, 7.9 Hz), 7.35 (1H, d, 2.4 Hz), 7.09 (1H, dd,
2.4, 9.1 Hz), 4.16 (2H, t, 6.1 Hz), 2.91 (2H, t, 6.1 Hz), 1.77 (6H,
s), 1.08 (9H, s)
[1035] LCMS: m/z 402 [M+H].sup.+
[1036] HPLC retention time: 2.55 min (analysis condition W)
Example 56
[1037] Compound A8-11
8-(2-Sec-butylamino-ethoxy)-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]ca-
rbazole-3-carbonitrile
##STR00071##
[1039] Under the same conditions as the method for synthesizing
Compound A8-17, the title compound was prepared from Compound A7-24
and sec-butylamine.
[1040] LCMS: m/z 402 [M+H].sup.+
[1041] HPLC retention time: 1.88 min (analysis condition U)
Example 57
[1042] Compound A8-12
8-[2-(2-Hydroxy-1,1-dimethyl-ethylamino)-ethoxy]-6,6-dimethyl-11-oxo-6,11--
dihydro-5H-benzo[b]carbazole-3-carbonitrile
##STR00072##
[1044] Under the same conditions as the method for synthesizing
Compound A8-17, the title compound was prepared from Compound A7-24
and 2-amino-2-methyl-propan-1-ol.
[1045] .sup.1H-NMR (300 MHz, DMSO-d.sub.6) .sigma.ppm; 12.65 (brs,
1H), 8.31 (d, 1H, J=8.0 Hz), 8.15 (d, 1H, J=8.8 Hz), 7.99 (s, 1H),
7.59 (d, 1H, J=8.0 Hz), 7.34 (d, 1H, J=2.3 Hz), 7.08 (dd, 1H, J=2.2
Hz, J=8.8 Hz), 4.58 (brs, 1H), 4.16 (t, 2H, J=5.7 Hz), 3.20 (s,
2H), 2.88 (t, 2H, J=5.7 Hz), 1.76 (s, 6H), 0.97 (s, 6H)
[1046] LCMS: m/z 418 [M+H].sup.+
[1047] HPLC retention time: 2.47 min (analysis condition U)
Example 58
[1048] Compound A8-13
8-[2-(4-Ethyl-piperazin-1-yl)-ethoxy]-6,6-dimethyl-11-oxo-6,11-dihydro-5H--
benzo[b]carbazole-3-carbonitrile
##STR00073##
[1050] Under the same conditions as the method for synthesizing
Compound A8-17, the title compound was prepared from Compound A7-24
and 1-ethyl-piperazine.
[1051] LCMS: m/z 443 [M+H].sup.+
[1052] HPLC retention time: 1.68 min (analysis condition U)
Example 59
[1053] Compound A8-14
8-(2-Imidazol-1-yl-ethoxy)-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]car-
bazole-3-carbonitrile
##STR00074##
[1055] Under the same conditions as the method for synthesizing
Compound A7-1, the title compound was prepared from Compound A6 and
2-imidazol-1-yl-ethanol.
[1056] .sup.1H-NMR (300 MHz, DMSO-d.sub.6) a ppm; 12.71 (s, 1H),
8.31 (d, 1H, J=8.3 Hz), 8.14 (d, 1H, J=8.8 Hz), 7.99 (s, 1H), 7.73
(s, 1H), 7.60 (d, 1H, J=8.3 Hz), 7.34 (s, 1H), 7.29 (s, 1H), 7.09
(d, 1H, J=8.8 Hz), 6.91 (s, 1H), 4.20 (s, 4H), 1.76 (s, 6H)
[1057] LCMS: m/z 387 [M+H].sup.+
[1058] HPLC retention time: 1.77 min (analysis condition U)
Example 60
[1059] Compound A8-15
8-{2-[Bis-(2-hydroxy-ethyl)-amino]-ethoxy}-6,6-dimethyl-11-oxo-6,11-dihydr-
o-5H-benzo[b]carbazole-3-carbonitrile
##STR00075##
[1061] According to the same method as the method for synthesizing
Compound A7-17, the title compound was prepared from Compound A7-24
and 2-(2-hydroxy-ethylamino)-ethanol.
[1062] LCMS: m/z 434 [M+H].sup.+
[1063] HPLC retention time: 2.40 min (analysis condition U)
Example 61
[1064] Compound A8-16
1-[2-(3-Cyano-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yloxy-
)-ethyl]-piperidine-4-carboxylic acid amide
##STR00076##
[1066] Under the same conditions as the method for synthesizing
Compound A8-17, the title compound was prepared from Compound A7-24
and piperidine-4-carboxylic acid amide.
[1067] LCMS: m/z 457 [M+H].sup.+
[1068] HPLC retention time: 1.28 min (analysis condition S)
Example 62
[1069] Compound A8-17
6,6-Dimethyl-11-oxo-8-[2-(3-oxo-piperazin-1-yl)-ethoxy]-6,11-dihydro-5H-be-
nzo[b]carbazole-3-carbonitrile
##STR00077##
[1071] To DMF solution (5 mL) of
8-(2-bromo-ethoxy)-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole--
3-carbonitrile (Compound A7-24, 30 mg, 0.07 mmol), piperazin-2-one
(44.9 mg, 0.35 mmol) and N,N-diisopropylethylamine (0.061 mL, 0.35
mmol) were added at room temperature and stirred at 80.degree. C.
for 18 hr. After cooling to room temperature, the mixture was
extracted with ethyl acetate washed with saturated brine. The
organic layer was dried over magnesium sulfate. The drying agent
was removed by filtration and the residues obtained after
concentration under reduced pressure were purified by preparative
TLC (dichloromethane/methanol) to obtain the title compound (white
solid, 24 mg, 80%).
[1072] .sup.1H-NMR (300 MHz, DMSO-d.sub.6) .sigma.ppm; 12.71 (s,
1H), 8.32 (d, 1H, J=8.4 Hz), 8.15 (d, 1H, J=8.8 Hz), 8.00 (s, 1H),
7.75 (s, 1H), 7.60 (d, 1H, J=8.4 Hz), 7.37 (d, 1H, J=2.3 Hz), 7.09
(dd, 1H, J=2.3 Hz, J=8.8 Hz), 4.27 (t, 2H, J=5.7 Hz), 3.19 (m, 2H),
3.08 (s, 2H), 2.83 (t, 2H, J=5.7 Hz), 2.70 (t, 2H, J=5.7 Hz), 1.8
(s, 6H)
[1073] LCMS: m/z 429 [M+H].sup.+
[1074] HPLC retention time: 1.29 min (analysis condition S)
Example 63
[1075] Compound A8-18
Morpholine-4-sulfonic
acid[2-(3-cyano-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yl-
oxy)-ethyl]-amide
##STR00078##
[1077] The title compound was obtained as a by-product of the
synthesis of Compound C1-2.
[1078] LCMS: m/z 495 [M+H].sup.+
[1079] HPLC retention time: 2.00 min (analysis condition S)
Example 64
[1080] Compound A8-19
4-Methyl-piperazine-1-sulfonic
acid[2-(3-cyano-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yl-
oxy)-ethyl]-amide
##STR00079##
[1082] The title compound was obtained as a by-product of the
synthesis of Compound C.sub.1-4.
[1083] .sup.1H-NMR (300 MHz, DMSO-d.sub.6) .delta.: 1.77 (6H, s),
2.16 (3H, s), 2.34 (4H, m), 3.08 (4H, m), 3.35 (2H, m), 4.19 (2H,
t, 5.34 Hz), 7.09 (1H, dd, 8.77 Hz, 2.99 Hz), 7.37 (1H, bs, 1.91
Hz), 7.59 (2H, m), 8.01 (1H, s), 8.16 (1H, d, 8.40 Hz), 8.32 (1H,
d, 8.01 Hz), 12.7 (1H, s).
[1084] LCMS: m/z 501 [M+H].sup.+
[1085] HPLC retention time: 1.43 min (analysis condition S)
Example 65
[1086] Compound A8-20
6,6-Dimethyl-8-(1-oxetan-3-yl-piperidin-4-ylmethoxy)-11-oxo-6,11-dihydro-5-
H-benzo[b]carbazole-3-carbonitrile
##STR00080##
[1088]
6,6-Dimethyl-11-oxo-8-(piperidin-4-ylmethoxy)-6,11-dihydro-5H-benzo-
[b]carbazole-3-carbonitrile hydrochloric acid salt (Compound A7-25,
30 mg, 0.075 mmol) and oxetan-3-one (38 mg, 7 eq.) were dissolved
in acetic acid (0.2 ml), THF (1 ml) and methanol (1 ml), added with
sodium cyanoborohydride (33 mg, 7 eq.) at room temperature, and
stirred overnight. The reaction solution was added with water, and
then extracted with ethyl acetate. The solution was dried over
sodium sulfate and the solvent was removed under vacuum and the
resulting residues were purified by preparative TLC (chloroform: 2
N ammonia methanol=9: 1) to obtain the target compound (15 mg).
[1089] LCMS: m/z 456 [M+H].sup.+
[1090] HPLC retention time: 2.78 min (analysis condition C)
Example 66
[1091] Compound A8-21
6,6-Dimethyl-8-[2-(1-oxetan-3-yl-piperidin-4-yl)-ethoxy]-11-oxo-6,11-dihyd-
ro-5H-benzo[b]carbazole-3-carbonitrile
##STR00081##
[1093] Under the same conditions as the method for synthesizing
Compound A7-25, and Compound A8-20, the title compound was prepared
from Compound A6 and 4-(2-hydroxy-ethyl)-piperidine-1-carboxylic
acid tert-butyl ester (15 mg).
[1094] LCMS: m/z 470 [M+H].sup.+
[1095] HPLC retention time: 2.85 min (analysis condition C)
Example 67
[1096] Compound A9-1
N-[2-(3-Cyano-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yloxy-
)-ethyl]-methanesulfonamide
##STR00082##
[1098] Trifluoroacetic acid salt of
8-(2-amino-ethoxy)-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole--
3-carbonitrile (Compound A8-2, 19 mg, 0.044 mmol) was suspended in
dichloromethane (0.5 mL), added with diisopropylethylamine (0.0157
mL, 2 eq.) and methanesulfonyl chloride (0.0034 mL, 1 eq.), and
then stirred at room temperature for 2 hr. The reaction solution
was added to water, and then extracted with dichloromethane. After
washing with saturated brine, the organic layer was dried over
sodium sulfate. The drying agent was removed by filtration and the
residues obtained after concentration under reduced pressure were
separated by silica gel preparative TLC (ethyl acetate 100%) to
obtain the target compound (5.5 mg, 29%).
[1099] .sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta.: 8.47 (1H, d,
J=8.2 Hz), 8.32 (1H, d, J=8.7 Hz), 8.16 (1H, s), 7.76 (1H, d, J=8.2
Hz), 7.53-7.46 (2H, m), 7.26 (1H, d, J=8.7 Hz), 4.39-4.33 (2H, m),
3.58-3.51 (2H, m), 3.12 (3H, s), 1.93 (6H, s)
[1100] LCMS: m/z 424 [M+H].sup.+
[1101] HPLC retention time: 3.10 min (analysis condition W)
Example 68
[1102] Compound A9-2
N-[2-(3-Cyano-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yloxy-
)-ethyl]-2,2,2-trifluoro-acetamide
##STR00083##
[1104] The title compound was obtained as a by-product of the
synthesis of Compound A9-1.
[1105] LCMS: m/z 442 [M+H].sup.+
[1106] HPLC retention time: 3.45 min (analysis condition W)
Example 69
[1107] Compound A9-3-1
8-{2-(Tert-butyloxycarbonylaminosulfonyl)amino-ethoxy}-6,6-dimethyl-11-oxo-
-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile
##STR00084##
[1109] Trifluoroacetic acid salt of
8-(2-amino-ethoxy)-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole--
3-carbonitrile (Compound A8-2, 20 mg, 0.044 mmol) was dissolved in
pyridine (0.5 mL), added with
N-(tert-butoxycarbonyl)-N-[4-(dimethyl
azaniumylidene)-1,4-dihydropyridin-1-yl sulfonyl]azanide (13.5 mg,
1 eq.), and then stirred at room temperature for 14 hr. The
reaction solution was added to water, and then extracted with ethyl
acetate. After washing with saturated brine, the organic layer was
dried over sodium sulfate. The drying agent was removed by
filtration and the residues obtained after concentration under
reduced pressure were separated by silica gel preparative TLC
(ethyl acetate) to obtain the title compound (16.1 mg, 68%).
[1110] .sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta.: 12.74 (1H, s),
10.94 (1H, s), 8.33 (1H, d, J=8.5 Hz), 8.16 (1H, d, J=9.1 Hz), 8.02
(1H, s), 7.84 (1H, br.s), 7.62 (1H, d, J=7.9 Hz), 7.36 (1H, s),
7.10 (1H, d, J=7.9 Hz). 4.24-4.18 (2H, in), 1.78 (6H, s), 1.32 (9H,
s)
[1111] LCMS: m/z 525 [M+H].sup.+
[1112] HPLC retention time: 3.48 min (analysis condition W)
Example 70
[1113] Compound A9-3-2
8-{2-(Methylaminosulfonyl)amino-ethoxy}-6,6-dimethyl-11-oxo-6,11-dihydro-5-
H-benzo[b]carbazole-3-carbonitrile
##STR00085##
[1115] Under the same conditions as the method for synthesizing
Compound A8-1, the title compound was prepared from Compound
A9-3-1.
[1116] LCMS: m/z 425 [M+H].sup.+
[1117] HPLC retention time: 2.95 min (analysis condition W)
Example 71
[1118] Compound A9-4
8-(1-Methanesulfonyl-piperidin-4-yloxy)-6,6-dimethyl-11-oxo-6,11-dihydro-5-
H-benzo[b]carbazole-3-carbonitrile
##STR00086##
[1120] According to the same method as the method for synthesizing
Compound A7-17, the title compound was prepared from Compound A8-1
and methanesulfonyl chloride.
[1121] .sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta.: 12.72 (1H, s),
8.30 (1H, d, J=8.5 Hz), 8.14 (1H, d, J=8.5 Hz), 8.00 (1H, s), 7.59
(1H, d, J=7.9 Hz), 7.38 (1H, s), 7.13 (1H, d, J=8.5 Hz), 4.81 (1H,
s), 3.39-3.38 (2H, m), 3.19-3.13 (2H, m), 2.93 (3H, s), 2.11-2.04
(2H, m), 1.83-1.75 (8H, m).
[1122] LCMS: m/z 464 [M+H].sup.+
[1123] HPLC retention time: 3.41 min (analysis condition U)
Example 72
[1124] Compound A9-5
8-[1-(2-Methoxy-ethyl)-piperidin-4-yloxy]-6,6-dimethyl-11-oxo-6,11-dihydro-
-5H-benzo[b]carbazole-3-carbonitrile
##STR00087##
[1126] Under the same conditions as the method for synthesizing
Compound A9-1, the title compound was prepared from Compound A8-1
and 1-bromo-2-methoxy-ethane.
[1127] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta.: 8.48-8.53 (1H,
m), 8.32-8.38 (1H, m), 7.74-7.77 (1H, m), 7.50-7.55 (1H, m),
7.07-7.10 (1H, m), 6.95-7.00 (1H, m), 4.43-4.51 (1H, m), 3.53 (2H,
t, J=5.6 Hz), 3.36 (3H, s), 2.77-2.87 (2H, m), 2.62 (2H, t, J=5.6
Hz), 2.35-2.47 (2H, m), 2.02-2.12 (2H, m), 1.78-1.95 (2H, m), 1.82
(6H, s).
[1128] LCMS: m/z 444 [M+H].sup.+
[1129] HPLC retention time: 2.00 min (analysis condition U)
Example 73
[1130] Compound A9-6-2
8-[1-(2-Hydroxy-ethyl)-piperidin-4-yloxy]-6,6-dimethyl-11-oxo-6,11-dihydro-
-5H-benzo[b]carbazole-3-carbonitrile
##STR00088##
[1132] According to the same method as the method for synthesizing
Compound A7-17, the title compound was prepared from Compound A8-1
and (2-bromoethoxy)-tert-butyldimethylsilane, followed by treatment
with tetrabutylammonium fluoride.
[1133] LCMS: m/z 430 [M+H].sup.+
[1134] HPLC retention time: 1.45 min (analysis condition S)
Example 74
[1135] Compound A9-7
8-[1-(2-Fluoro-ethyl)-piperidin-4-yloxy]-6,6-dimethyl-11-oxo-6,11-dihydro--
5H-benzo[b]carbazole-3-carbonitrile
##STR00089##
[1137] According to the same method as the method for synthesizing
Compound A7-17, the title compound was prepared from Compound A8-1
and methanesulfonic acid 2-fluoroethyl ester.
[1138] .sup.1H-NMR (300 MHz, DMSO-d.sub.6) .delta.: 1.67 (2H, m),
1.76 (6H, s), 2.01 (2H, m), 2.37 (2H, t, 11.0 Hz), 2.61 (1H, t,
4.20 Hz), 2.70 (1H, t, 4.58), 2.78 (2H, m), 4.46 (1H, t, 4.58 Hz),
4.62 (2H, t, 5.34 Hz), 7.10 (1H, dd, 9.16 Hz, 2.29 Hz), 7.34 (1H,
bs, 1.53 Hz), 7.60 (1H, dd, 8.40 Hz, 1.53 Hz), 7.99 (1H, s), 8.13
(1H, d, 8.39 Hz), 8.30 (1H, d, 8.39 Hz), 12.7 (1H, s).
[1139] LCMS: m/z 432 [M+H].sup.+
[1140] HPLC retention time: 1.52 min (analysis condition S)
Example 75
[1141] Compound A9-8
8-(1-Acetyl-piperidin-4-yloxy)-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b-
]carbazole-3-carbonitrile
##STR00090##
[1143] According to the same method as the method for synthesizing
Compound A7-17, the title compound was prepared from Compound A8-1
and acetyl chloride.
[1144] LCMS: m/z 428 [M+H].sup.+
[1145] HPLC retention time: 1.91 min (analysis condition S)
Example 76
[1146] Compound A9-9
2-(3-Cyano-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yloxy)-a-
cetamide
##STR00091##
[1148] Under the same conditions as the method for synthesizing
Compound A7-17, the title compound was prepared from Compound A6
and 2-bromo-acetamide.
[1149] LCMS: m/z 360 [M+H].sup.+
[1150] HPLC retention time: 2.83 min (analysis condition U)
Example 77
[1151] Compound A9-10
2-(3-Cyano-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yloxy)-N-
-methyl-acetamide
##STR00092##
[1153]
(3-Cyano-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-ylo-
xy)-acetic acid (Compound A8-7, 30 mg, 0.0838 mmol), methylamine
hydrochloric acid salt (28.1 mg, 0.417 mmol), EDC (32 mg, 0.167
mmol) and HOBT (0.023 mg, 0.167 mmol) were dissolved in DMF (1 mL),
and added with diisopropylethylamine (0.145 mL, 0.833 mmol) at room
temperature. After stirring at room temperature for 18 hr, water
was added and the extraction was carried out with ethyl acetate.
After washing with saturated brine, the organic layer was dried
over magnesium sulfate. The drying agent was removed by filtration
and the residues obtained after concentration under reduced
pressure were dissolved in dichloromethane, added with diethyl
ether, and the precipitated title compound was obtained (white
solid, 19.7 mg, 63%).
[1154] .sup.1H-NMR (300 MHz, DMSO) a ppm 12.73 (s, 1H), 8.33 (d,
1H, J=8.1 Hz), 8.17 (d, 1H, J=8.7 Hz), 8.13 (s, 1H), 8.00 (s, 1H),
7.62 (d, 1H, J=8.1 Hz), 7.39 (d, 1H, J=2.4 Hz), 7.11 (dd, 1H, J=8.7
Hz, 2.4 Hz), 4.64 (s, 2H), 3.17 (d, 1H, J=5.4 Hz), 2.69 (d, 1H,
J=4.5 Hz), 1.76 (s, 6H)
[1155] LCMS: m/z 374 [M+H].sup.+
[1156] HPLC retention time: 2.43 min (analysis condition U)
Example 78
[1157] Compound A9-11
2-(3-Cyano-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yloxy)-N-
-(2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-acetamide
##STR00093##
[1159] Under the same conditions as the method for synthesizing
Compound A9-10, the title compound was prepared from Compound A8-7
and C-(2,2-dimethyl-[1,3]dioxolan-4-yl)-methylamine.
[1160] LCMS: m/z 474 [M+H].sup.+
[1161] HPLC retention time: 2.20 min (analysis condition U)
Example 79
[1162] Compound A9-12
2-(3-Cyano-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yloxy)-N-
-(2,3-dihydroxy-propyl)-acetamide
##STR00094##
[1164] Under the same conditions as the method for synthesizing
Compound A7-14-2, the title compound was prepared from Compound
A9-11.
[1165] LCMS: m/z 434 [M+H].sup.+
[1166] HPLC retention time: 1.72 min (analysis condition U)
Example 80
[1167] Compound A9-13
2-Methyl-acrylic acid
2-[2-(3-cyano-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-ylox-
y)-acetylamino]-ethyl ester
##STR00095##
[1169] Under the same conditions as the method for synthesizing
Compound A9-10, the title compound was prepared from Compound A8-7
and 2-methyl-acrylic acid 2-amino-ethyl ester.
[1170] LCMS: m/z 472 [M+H].sup.+
[1171] HPLC retention time: 3.30 min (analysis condition U)
Example 81
[1172] Compound A9-14
2-(3-Cyano-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yloxy)-N-
-(2-hydroxy-ethyl)-acetamide
##STR00096##
[1174] 2-Methyl-acrylic acid
2-[2-(3-cyano-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-ylox-
y)-acetylamino]-ethyl ester (Compound A9-13, 40 mg, 0.085 mmol) was
dissolved in a mixture solvent of methanol (2 mL) and water (2 mL),
added with potassium hydroxide (48 mg, 0.85 mmol), and then stirred
at room temperature for 18 hr. After the neutralization with 1 N
hydrochloric acid, the reaction solution was concentrated under
reduced pressure. The resulting residues were purified by amino
silica gel to obtain the title compound (white solid, 8.9 mg,
26%).
[1175] .sup.1H-NMR (300 MHz, DMSO) a ppm 12.75 (s, 1H), 8.32 (d,
1H, J=8.1 Hz), 8.17-8.13 (m, 2 Hz), 7.99 (s, 1H), 7.60 (d, 1H,
J=8.1 Hz), 7.38 (d, 1H, J=1.8 Hz), 7.11 (dd, 1H, J=2.1 Hz, 8.7 Hz),
4.72 (t, 1H, J=5.7 Hz), 4.65 (s, 1H), 3.48 (dd, 2H, J=12.0 Hz, 6.0
Hz), 3.26 (dd, 2H, J=12.0 Hz, 6.0 Hz), 1.76 (s, 6H)
[1176] LCMS: m/z 404 [M+H].sup.+
[1177] HPLC retention time: 2.83 min (analysis condition U)
Example 82
[1178] Compound A9-15-1
4-[2-(3-Cyano-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yloxy-
)-acetyl]-piperazine-1-carboxylic acid tert-butyl ester
##STR00097##
[1180]
(3-Cyano-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-ylo-
xy)-acetic acid (Compound A8-7, 30 mg, 0.083 mmol),
piperazine-1-carboxylic acid tert-butyl ester (31 mg, 2 eq.), and
HOBt (30 mg, 3 eq.) were dissolved in 0.5 ml DMF, added with EDC
(48 mg, 3 eq.), and stirred at room temperature overnight.
Thereafter, the solvent was removed under reduced pressure and the
resulting residues were purified by preparative TLC to obtain the
title compound (20 mg).
[1181] LCMS: m/z 527, 471, 427[M-H].sup.-
[1182] HPLC retention time: 2.77 min (analysis condition C)
Example 83
[1183] Compound A9-15-2
6,6-Dimethyl-11-oxo-8-(2-oxo-2-piperazin-1-yl-ethoxy)-6,11-dihydro-5H-benz-
o[b]carbazole-3-carbonitrile hydrochloric acid salt
##STR00098##
[1185]
4-[2-(3-Cyano-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol--
8-yloxy)-acetyl]-piperazine-1-carboxylic acid tert-butyl ester
(Compound A9-15-1, 20 mg) was added with 4 N hydrochloric acid and
dioxane solution (1 ml), and stirred in an water bath at 10.degree.
C. for 4 hr. Water was added to the reaction solution and the
resulting precipitates were filtered and dried to obtain the title
compound (15 mg, white powder).
[1186] LCMS: m/z 429 [M+H].sup.+
[1187] HPLC retention time: 0.81 min (analysis condition I)
Example 84
[1188] Compound A9-16
2-(3-Cyano-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yloxy)-N-
-(2-cyano-ethyl)-acetamide
##STR00099##
[1190]
(3-Cyano-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-ylo-
xy)-acetic acid (Compound A8-7, 30 mg, 0.083 mmol),
3-aminopropionitrile (12 mg, 2 eq.) and HOBt (30 mg, 3 eq.) were
dissolved in 0.5 ml DMF, added with EDC (48 mg, 3 eq.), and stirred
at room temperature overnight. Thereafter, the solvent was removed
under reduced pressure and the resulting residues were purified by
preparative TLC to obtain the title compound (23 mg).
[1191] LCMS: m/z 411 [M+H].sup.+
[1192] HPLC retention time: 2.27 min (analysis condition C)
Example 85
[1193] Compound A9-17
2-(3-Cyano-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yloxy)-N-
-(2-cyano-ethyl)-N-methyl-acetamide
##STR00100##
[1195]
(3-Cyano-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-ylo-
xy)-acetic acid (Compound A8-7, 30 mg, 0.083 mmol),
N-methyl-3-aminopropionitrile (14 mg, 2 eq.) and HOBt (30 mg, 3
eq.) were dissolved in 0.5 ml DMF, added with EDC (48 mg, 3 eq.),
and stirred at room temperature overnight. Thereafter, the solvent
was removed under reduced pressure and the resulting residues were
purified by preparative TLC to obtain the title compound (7
mg).
[1196] LCMS: m/z 411 [M+H].sup.+
[1197] HPLC retention time: 2.33 min (analysis condition C)
Example 86
[1198] Compound A10
8-(Tert-butyl-dimethyl-silanyloxy)-6,6-dimethyl-11-oxo-6,11-dihydro-5H-ben-
zo[b]carbazole-3-carbonitrile
##STR00101##
[1200] The DMF solution of
8-methoxy-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carboni-
trile (Compound A6, 100 mg, 0.331 mmol), imidazole (67.5 mg, 3 eq.)
and tert-butylchlorodimethylsilane (92.4 mg, 1.5 eq.) was stirred
overnight at room temperature. To the reaction solution, saturated
aqueous solution of sodium hydrogen carbonate was added followed by
extraction with tert-butylmethyl ether. The organic layer was
washed with brine and dried over sodium sulfate. The drying agent
was removed by filtration and the residues obtained after
concentration under reduced pressure were purified by silica gel
column chromatography (ethyl acetate/hexane) to obtain the target
compound (white solid, 170 mg, 100%).
[1201] LCMS: m/z 417 [M+H].sup.+
[1202] HPLC retention time: 3.38 min (analysis condition S)
Example 87
[1203] Compound A10-1
8-Methoxy-5,6,6-trimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbo-
nitrile
##STR00102##
[1205] To the THF solution of triphenylphosphine (260 mg, 3 eq.),
azodicarboxylic acid diisopropyl ester (0.195 ml, 3 eq.) was added
and the mixture was stirred at room temperature for 1 hr.
Thereafter,
8-(tert-butyldimethylsilanyloxy)-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benz-
o[b]carbazole-3-carbonitrile (Compound A10, 138 mg, 0.331 mmol) and
methanol (1 ml) were added and stirred overnight. The reaction
solution was purified by HPLC to obtain the target compound (44.8
mg, 41%).
[1206] .sup.1H-NMR (270 MHz, DMSO-d.sub.6) .delta.: 8.44 (1H, d,
J=8.1 Hz), 8.33 (1H, s), 8.14 (1H, d, J=8.7 Hz), 7.66 (1H, dd,
J=8.2, 1.1 Hz), 7.39 (1H, d, J=2.3 Hz), 7.09 (1H, dd, J=8.7, 2.3
Hz), 4.17 (3H, s), 3.92 (3H, s), 1.88 (6H, s).
[1207] LCMS: m/z 331 [M+H].sup.+
[1208] HPLC retention time: 2.35 min (analysis condition S)
Example 88
[1209] Compound A10-2
8-(1-Methanesulfonyl-piperidin-4-yloxy)-5,6,6-trimethyl-11-oxo-6,11-dihydr-
o-5H-benzo[b]carbazole-3-carbonitrile
##STR00103##
[1211] Under the same conditions as the method for synthesizing
Compound B3-4, the title compound was prepared from Compound
A9-4.
[1212] LCMS: m/z 478 [M+H].sup.+
[1213] HPLC retention time: 2.68 min (analysis condition U)
Example 89
[1214] Compound B1
Trifluoro-methanesulfonic acid
3-cyano-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yl
ester
##STR00104##
[1216]
8-Hydroxy-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-c-
arbonitrile (Compound A6, 550 mg, 0.189 mmol) was dissolved in
pyridine (18 mL), added with anhydrous trifluoromethanesulfonic
acid (0.758 ml, 3 eq.), and stirred at room temperature for 30 min.
The reaction solution was added to water and then extracted with
dichloromethane. The organic layer was dried over magnesium
sulfate. The drying agent was removed by filtration and the
residues obtained after concentration under reduced pressure were
purified by silica gel column chromatography (ethyl acetate/hexane)
to obtain the target compound (white powder, 641 mg, 81%).
[1217] .sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta.: 12.89 (1H, br.
s), 8.36 (1H, d, J=8.8 Hz), 8.31 (1H, dd, J=8.1, 0.7 Hz), 8.11 (1H,
d, J=2.3 Hz), 8.04 (1H, dd, J=1.5, 0.7 Hz), 7.65-7.60 (2H, m). 1.76
(6H, s)
[1218] LCMS: m/z 435 [M+H].sup.+
[1219] HPLC retention time: 3.10 min (analysis condition U)
Example 90
[1220] Compound B2-1
8-(4-Isopropyl-piperazin-1-yl)-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b-
]carbazole-3-carbonitrile
##STR00105##
[1222] Trifluoro-methanesulfonic acid
3-cyano-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yl
ester (Compound B1, 40 mg, 0.0921 mmol) was dissolved in NMP (1 ml)
and added with 1-isopropylpiperazine (236 mg, 20 eq.). The mixture
was stirred at 120.degree. C. for 3 hr. After cooling to room
temperature, purification was carried out by HPLC to obtain the
target compound (white powder, 12.8 mg, 34%).
[1223] .sup.1H-NMR (270 MHz, DMSO-d.sub.6) .delta.: 8.30 (1H, d,
8.1 Hz), 8.03 (1H, d, 8.6 Hz), 7.98 (1H, s), 7.56 (1H, d, 8.6 Hz),
7.21 (1H, s), 7.04 (1H, d, 9.1 Hz), 3.40-3.37 (4H, m), 2.73-2.65
(1H, m), 2.61-2.58 (4H, m), 1.75 (6H, s), 1.02 (6H, d, 6.6 Hz)
[1224] LCMS: m/z 413 [M+H].sup.+
Example 91
[1225] Compound B2-2
8-[4-(2-Hydroxy-ethyl)-piperazin-1-yl]-6,6-dimethyl-11-oxo-6,11-dihydro-5H-
-benzo[b]carbazole-3-carbonitrile
##STR00106##
[1227] According to the same method as the method for synthesizing
Compound B2-1, the title compound was prepared from Compound B1 and
N-(2-hydroxyethyl)piperazine.
[1228] .sup.1H-NMR (270 MHz, DMSO-d.sub.6) .delta.: 8.30 (1H, d,
8.1 Hz), 8.03 (1H, d, 8.7 Hz), 7.99 (1H, s), 7.58 (1H, d, 7.9 Hz),
7.21 (1H, s), 7.04 (1H, d, 8.7 Hz), 4.50-4.46 (1H, br m), 3.59-3.53
(2H, m), 3.39-3.35 (4H, m), 2.59-2.56 (4H, m), 2.45 (2H, t, 6.1
Hz), 1.76 (6H, s)
[1229] LCMS: m/z 415 [M+H].sup.+
[1230] HPLC retention time: 1.27 min (analysis condition S)
Example 92
[1231] Compound B2-3
6,6-Dimethyl-8-morpholin-4-yl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-c-
arbonitrile
##STR00107##
[1233] Under the same conditions as the method for synthesizing
Compound B2-1, the title compound was prepared from Compound B1 and
morpholine.
[1234] .sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta.: 12.62 (1H, br.
s), 8.29 (1H, d, 8.2 Hz), 8.04 (1H, d, 9.0 Hz), 7.96 (1H, s), 7.56
(1H, d, 8.2 Hz), 7.22 (1H, s), 7.04 (1H, d, 9.0 Hz), 3.77-3.75 (4H,
m), 3.35-3.30 (4H, m), 1.74 (6H, s)
[1235] LCMS: m/z 372 [M+H].sup.+
[1236] HPLC retention time: 2.45 min (analysis condition U)
Example 93
[1237] Compound B2-4
6,6-Dimethyl-11-oxo-8-(4-pyrrolidin-1-yl-piperidin-1-yl)-6,11-dihydro-5H-b-
enzo[b]carbazole-3-carbonitrile
##STR00108##
[1239] Under the same conditions as the method for synthesizing
Compound B2-1, the title compound was prepared from Compound B1 and
4-pyrrolidin-1-yl-piperidine.
[1240] .sup.1H-NMR (270 MHz, DMSO-d.sub.6) .delta.: 8.30 (1H, d,
8.1 Hz), 8.01 (1H, d, 8.7 Hz), 7.97 (1H, s), 7.56 (1H, d, 8.6 Hz),
7.20 (1H, s), 3.94-3.90 (2H, m), 3.30-3.28 (4H, m), 2.95 (2H, t,
11.8 Hz), 2.24-2.20 (1H, m), 1.95-1.91 (2H, m), 1.75 (6H, s),
1.70-1.66 (4H, m), 1.54-1.52 (2H, m)
[1241] LCMS: m/z 439 [M+H].sup.+
Example 94
[1242] Compound B2-5-1
4-(3-Cyano-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yl)-pipe-
razine-1-carboxylic acid tert-butyl ester
##STR00109##
[1244] Under the same conditions as the method for synthesizing
Compound B2-1, the title compound was prepared from Compound B1 and
piperazine-1-carboxylic acid tert-butyl ester.
[1245] LCMS: m/z 471 [M+H].sup.+
[1246] HPLC retention time: 2.67 min (analysis condition S)
Example 95
[1247] Compound B2-5-2
6,6-Dimethyl-11-oxo-8-piperazin-1-yl-6,11-dihydro-5H-benzo[b]carbazole-3-c-
arbonitrile
##STR00110##
[1249] Under the same conditions as the method for synthesizing
Compound A8-1, the title compound was prepared from Compound
B2-5-1.
[1250] .sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta.: 8.32 (1H, d,
8.5 Hz), 8.03 (1H, d, 9.1 Hz), 7.99 (1H, s), 7.59 (1H, dd, 8.2, 1.5
Hz), 7.20 (1H, d, 2.4 Hz), 7.04 (1H, dd, 8.8, 2.1 Hz), 3.32-3.30
(4H, m), 2.88-2.87 (4H, m), 1.77 (6H, s)
[1251] LCMS: m/z 371 [M+H].sup.+
Example 96
[1252] Compound B2-6
6,6-Dimethyl-11-oxo-8-piperidin-1-yl-6,11-dihydro-5H-benzo[b]carbazole-3-c-
arbonitrile
##STR00111##
[1254] Under the same conditions as the method for synthesizing
Compound B2-1, the title compound was prepared from Compound B1 and
piperidine.
[1255] LCMS: m/z 370 [M+H].sup.+
[1256] HPLC retention time: 2.40 min (analysis condition U)
Example 97
[1257] Compound B2-7-1
8-(4-Hydroxy-piperidin-1-yl)-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]c-
arbazole-3-carbonitrile
##STR00112##
[1259] Under the same conditions as the method for synthesizing
Compound B2-1, the title compound was prepared from Compound B1 and
piperidin-4-ol.
[1260] .sup.1H-NMR (270 MHz, DMSO-d.sub.6) .delta.: 8.30 (1H, d,
8.1 Hz), 8.01 (1H, d, 8.7 Hz), 7.97 (1H, s), 7.56 (1H, d, 7.7 Hz),
7.19 (1H, s), 7.04 (1H, d, 10.6 Hz), 4.76-4.71 (1H, br m),
3.81-3.75 (3H, m), 3.08 (2H, t, 10.2 Hz), 1.86-1.82 (2H, m), 1.75
(6H, s), 1.49-1.42 (2H, m)
[1261] LCMS: m/z 386 [M+H].sup.+
Example 98
[1262] Compound B2-7-2
6,6-Dimethyl-11-oxo-8-(4-oxo-piperidin-1-yl)-6,11-dihydro-5H-benzo[b]carba-
zole-3-carbonitrile
##STR00113##
[1264]
8-(4-Hydroxy-piperidin-1-yl)-6,6-dimethyl-11-oxo-6,11-dihydro-5H-be-
nzo[b]carbazole-3-carbonitrile (Compound B2-7-1, 210 mg, 0.545
mmol), was dissolved in the DCM (2 mL) and DMF (0.6 mL) mixture
solvent, added with 1,1,1-triacetoxy-1,1-dihydro-1,2-benzoiodoxol-3
(1H)-one (300 mg, 1.3 eq.), and the mixture was stirred at room
temperature for 2 hr. To the reaction solution, 0.25 mol/L aqueous
solution of sodium thiosulfate, saturated sodium bicarbonate
solution and CPME were added followed by further stirring at room
temperature for 1 hr. The reaction solution was filtered and the
filtrate was subjected to liquid seperation. The organic layer was
washed with saturated brine and dried over sodium sulfate. The
drying agent was removed by filtration and the residues obtained
after concentration under reduced pressure were purified by silica
gel column chromatography (ethyl acetate/hexane) to obtain the
target compound (yellowish white powder, 109 mg, 52%).
[1265] LCMS: m/z 384 [M+H].sup.+
[1266] HPLC retention time: 2.17 min (analysis condition U)
Example 99
[1267] Compound B2-8
8-(4-Methanesulfonyl-piperazin-1-yl)-6,6-dimethyl-11-oxo-6,11-dihydro-5H-b-
enzo[b]carbazole-3-carbonitrile
##STR00114##
[1269] Under the same conditions as the method for synthesizing
Compound B2-1, the title compound was prepared from Compound B1 and
1-methanesulfonylpiperazine.
[1270] .sup.1H-NMR (270 MHz, DMSO-d.sub.6) .delta.: 12.66 (1H,
br.s), 8.31 (1H, d, J=8.2 Hz), 8.06 (1H, d, J=8.7 Hz), 7.99 (1H,
s), 7.59 (1H, d, J=8.2 Hz), 7.30 (1H, d, J=1.8 Hz), 7.09 (1H, dd,
J=8.7, 1.8 Hz), 3.53 (4H, t, J=4.8 Hz), 3.27 (4H, t, J=4.8 Hz),
2.94 (3H, s), 1.77 (6H, s).
[1271] LCMS: m/z 449 [M+H].sup.+
[1272] HPLC retention time: 1.98 min (analysis condition S)
Example 100
[1273] Compound B2-9
8-(3-Methanesulfonyl-pyrrolidin-1-yl)-6,6-dimethyl-11-oxo-6,11-dihydro-5H--
benzo[b]carbazole-3-carbonitrile
##STR00115##
[1275] Under the same conditions as the method for synthesizing
Compound B2-1, the title compound was prepared from Compound B1 and
3-methanesulfonylpyrrolidine.
[1276] LCMS: m/z 434 [M+H].sup.+
[1277] HPLC retention time: 1.83 min (analysis condition S)
Example 101
[1278] Compound B2-10
8-(1,1-Dioxothiomorpholino)-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]ca-
rbazole-3-carbonitrile
##STR00116##
[1280] Trifluoro-methanesulfonic acid
3-cyano-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yl
ester (Compound B1, 30 mg, 0.069 mmol) was dissolved in 1,4-dioxane
(1 mL), added with thiomorpholine 1,1-dioxide (19 mg, 2 eq.),
Pd.sub.2(dba).sub.3 (6.3 mg, 0.1 eq.), BINAP (8.6 mg, 0.2 eq.) and
K.sub.3PO.sub.4 (29 mg, 2 eq.), and stirred at 100.degree. C.
overnight. The reaction solution was added to water, and then
extracted with ethyl acetate. The organic layer was washed with
saturated brine and dried over sodium sulfate. The drying agent was
removed by filtration and the residues obtained after concentration
under reduced pressure were purified by silica gel column
chromatography (ethyl acetate/hexane) to obtain the target compound
(white powder, 2.1 mg, 7%).
[1281] .sup.1H-NMR (270 MHz, DMSO-d.sub.6) .delta.: 8.29 (1H, d,
J=8.6 Hz), 8.07 (1H, d, J=8.9 Hz), 8.00 (1H, s), 7.55 (1H, dd,
J=8.5, 1.7 Hz), 7.34 (1H, d, J=2.0 Hz), 7.15 (1H, dd, J=9.1, 2.7
Hz), 4.01 (4H, s), 3.16 (4H, s), 1.77 (6H, s).
[1282] LCMS: m/z 420 [M+H].sup.+
[1283] HPLC retention time: 1.80 min (analysis condition S)
Example 102
[1284] Compound B2-11
8-(4-Cyclopentyl-2-oxo-piperazin-1-yl)-6,6-dimethyl-11-oxo-6,11-dihydro-5H-
-benzo[b]carbazole-3-carbonitrile
##STR00117##
[1286] Under the same conditions as the method for synthesizing
Compound B2-10, the title compound was prepared from Compound B1
and 4-cyclopentylpiperazin-2-one.
[1287] LCMS: m/z 453 [M+H].sup.+
[1288] HPLC retention time: 1.30 min (analysis condition S)
Example 103
[1289] Compound B2-12
6,6-Dimethyl-8-(4-morpholin-4-yl-piperidin-1-yl)-11-oxo-6,11-dihydro-5H-be-
nzo[b]carbazole-3-carbonitrile
##STR00118##
[1291] Under the same conditions as the method for synthesizing
Compound B2-1, the title compound was prepared from Compound B1 and
4-piperidin-4-yl morpholine.
[1292] .sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta.: 12.73 (1H, s),
8.27-8.31 (1H, m), 7.98-8.02 (1H, m), 7.95-7.97 (1H, m), 7.53-7.58
(1H, m), 7.17-7.21 (1H, m), 6.99-7.05 (1H, m), 3.97-4.05 (2H, m),
3.53-3.59 (4H, m), 2.80-2.90 (2H, m), 2.43-2.51 (4H, m), 2.31-2.40
(1H, m), 1.83-1.92 (2H, m), 1.74 (6H, s), 1.39-1.52 (2H, m)
[1293] LCMS: m/z 455 [M+H].sup.+
[1294] HPLC retention time: 1.73 min (analysis condition U)
Example 104
[1295] Compound B2-13
8-(4,4-Difluoro-1,4'-bipiperidin-1'-yl)-6,6-dimethyl-11-oxo-6,11-dihydro-5-
H-benzo[b]carbazole-3-carbonitrile
##STR00119##
[1297] Under the same conditions as the method for synthesizing
Compound B3-32, the title compound was prepared from Compound
B2-7-2 and 4,4-difluoropiperidine hydrochloric acid salt.
[1298] .sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta.: 12.59 (1H, s),
8.25-8.32 (1H, m), 7.97-8.02 (1H, m), 7.96 (1H, s), 7.52-7.59 (1H,
m), 7.16-7.21 (1H, m), 6.99-7.05 (1H, mz), 4.00-4.09 (2H, m),
3.55-3.62 (2H, m), 2.79-2.90 (2H, m), 2.55-2.67 (4H, m), 1.78-1.98
(5H, m), 1.74 (6H, s), 1.44-1.58 (2H, m)
[1299] LCMS: m/z 489 [M+H].sup.+
[1300] HPLC retention time: 1.88 min (analysis condition U)
Example 105
[1301] Compound B2-14
8-[4-((2R,6S)-2,6-Dimethyl-morpholin-4-yl)-piperidin-1-yl]-6,6-dimethyl-11-
-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile
##STR00120##
[1303] Under the same conditions as the method for synthesizing
Compound B3-32, the title compound was prepared from Compound
B2-7-2 and (2R,6S)-2,6-dimethylmorpholine.
[1304] .sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta.: 12.60 (1H, s),
8.25-8.31 (1H, m), 7.97-8.02 (1H, m), 7.95 (1H, s), 7.51-7.58 (1H,
m), 7.18 (1H, s), 6.99-7.05 (1H, m), 3.96-4. 06 (2H, m), 3.45-3.55
(2H, m), 2.80-2.91 (2H, m), 2.72-2.79 (2H, m), 2.29-2.41 (1H, m),
1.70-1.90 (10H, m), 1.40-1.53 (2H, m), 1.03 (6H, d, 6.3 Hz)
[1305] LCMS: m/z 483 [M+H].sup.+
[1306] HPLC retention time: 1.83 min (analysis condition U)
Example 106
[1307] Compound B2-15
8-((3R,5S)-3,5-Dimethylpiperazin-1-yl)-6,6-dimethyl-11-oxo-6,11-dihydro-5H-
-benzo[b]carbazole-3-carbonitrile
##STR00121##
[1309] Under the same conditions as the method for synthesizing
Compound B2-1, the title compound was prepared from Compound B1 and
2,6-dimethylpiperazine.
[1310] LCMS: m/z 399 [M+H].sup.+
[1311] HPLC retention time: 1.76 min (analysis condition U)
Example 107
[1312] Compound B2-16-1
(S)-4-(3-Cyano-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yl)--
3-methyl-piperazine-1-carboxylic acid tert-butyl ester
##STR00122##
[1314] Under the same conditions as the method for synthesizing
Compound B2-10, the title compound was prepared from Compound B1
and (S)-3-methylpiperazine-1-carboxylic acid tert-butyl ester.
[1315] LCMS: m/z 485 [M+H].sup.+
[1316] HPLC retention time: 3.97 min (analysis condition W)
Example 108
[1317] Compound B2-16-2
6,6-Dimethyl-8-((S)-2-methyl-piperazin-1-yl)-11-oxo-6,11-dihydro-5H-benzo[-
b]carbazole-3-carbonitrile
##STR00123##
[1319] Under the same conditions as the method for synthesizing
Compound A8-1, the title compound was prepared from Compound
2-16-1.
[1320] LCMS: m/z 385 [M+H].sup.+
[1321] HPLC retention time: 2.43 min (analysis condition W)
Example 109
[1322] Compound B2-16-3
8-((S)-4-Cyclobutyl-2-methyl-piperazin-1-yl)-6,6-dimethyl-11-oxo-6,11-dihy-
dro-5H-benzo[b]carbazole-3-carbonitrile
##STR00124##
[1324] Under the same conditions as the method for synthesizing
Compound B3-32, the title compound was prepared from Compound
B2-16-2 and cyclobutanone.
[1325] .sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta.: 8.31 (1H, d, 8
Hz), 8.03 (1H, d, 12 Hz), 7.98 (1H, s), 7.59 (1H, d, 12 Hz), 7.13
(1H, s), 6.98 (1H, d, 8 Hz), 4.35-4.28 (1H, m), 3.70 (1H, d, 12
Hz), 3.02 (1H, ddd, 12, 12, 4 Hz), 2.87 (1H, d, 8 Hz), 2.74-2.67
(2H, m), 2.08-1.99 (2H, m), 1.92-1.64 (10H, m), 1.70-1.62 (2H, m),
1.12 (3H, d, 8 Hz)
[1326] LCMS: m/z 439 [M+H].sup.+
[1327] HPLC retention time: 2.59 min (analysis condition W)
Example 110
[1328] Compound B2-17
8-(2-Diethylamino-ethylsulfanyl)-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo-
[b]carbazole-3-carbonitrile
##STR00125##
[1330] Trifluoro-methanesulfonic acid
3-cyano-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yl
ester (Compound B1, 25 mg, 0.057 mmol) was dissolved in
dimethoxyethane (0.5 mL), added with 2-diethylaminoethanethiol
hydrochloric acid salt (19.6 mg, 2 eq.), Pd.sub.2(dba).sub.3 (2.6
mg, 0.05 eq.), Xantphos (3.3 mg, 0.1 eq.) and DIPEA (0.06 mg, 6
eq.), and the mixture was stirred at 160.degree. C. for 30 min. The
reaction solution was added to water, extracted with ethyl acetate,
and dried over magnesium sulfate. The drying agent was removed by
filtration and the residues obtained after concentration under
reduced pressure were purified by silica gel column chromatography
(dichloromethane/methanol) to obtain the target compound (white
amorphous, 22.4 mg, 93%).
[1331] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta.: 9.60 (1H, s),
8.53-8.48 (1H, m), 8.32 (1H, d, J=8.4 Hz), 7.77 (1H, s), 7.53-7.50
(2H, m), 7.38-7.35 (1H, m), 3.18-3.12 (2H, m), 2.81-2.75 (2H, m),
2.65-2.57 (4H, m), 1.76 (6H, s), 1.08-1.04 (6H, m)
[1332] LCMS: m/z 418 [M+H].sup.+
[1333] HPLC retention time: 2.10 min (analysis condition U)
Example 111
[1334] Compound B2-18
8-(2-Diisopropylamino-ethylsulfanyl)-6,6-dimethyl-11-oxo-6,11-dihydro-5H-b-
enzo[b]carbazole-3-carbonitrile
##STR00126##
[1336] Under the same conditions as the method for synthesizing
Compound B2-17, the title compound was prepared from Compound B1
and 2-diisopropylaminoethanethiol hydrochloric acid salt.
[1337] LCMS: m/z 446 [M+H].sup.+
[1338] HPLC retention time: 2.22 min (analysis condition U)
Example 112
[1339] Compound B2-19
8-(2-Dimethylamino-ethylsulfanyl)-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benz-
o[b]carbazole-3-carbonitrile
##STR00127##
[1341] Under the same conditions as the method for synthesizing
Compound B2-17, the title compound was prepared from Compound B1
and 2-dimethylaminoethanethiol hydrochloric acid salt.
[1342] LCMS: m/z 390 [M+H].sup.+
[1343] HPLC retention time: 1.98 min (analysis condition U)
Example 113
[1344] Compound B2-20
3-(3-Cyano-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yl
sulfanyl)-propionic acid
##STR00128##
[1346] Under the same conditions as the method for synthesizing
Compound B2-17, the title compound was prepared from Compound B1
and 3-mercaptopropionic acid.
[1347] LCMS: m/z 391 [M+H].sup.+
[1348] HPLC retention time: 2.45 min (analysis condition U)
Example 114
[1349] Compound B2-21
8-(2,3-Dihydroxy-propylsulfanyl)-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo-
[b]carbazole-3-carbonitrile
##STR00129##
[1351] Under the same conditions as the method for synthesizing
Compound B2-17, the title compound was prepared from Compound B1
and 3-mercaptopropane-1,2-diol.
[1352] LCMS: m/z 393 [M+H].sup.+
[1353] HPLC retention time: 2.15 min (analysis condition U)
Example 115
[1354] Compound B2-22-1
4-(3-Cyano-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yl)-3,6--
dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester
##STR00130##
[1356] To trifluoro-methanesulfonic acid
3-cyano-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yl
ester (Compound B1, 7.80 g, 18.0 mmol),
4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine--
1-carboxylic acid tert-butyl ester (6.11 g, 19.8 mmol, 1.1 eq.),
Pd(PPh.sub.3).sub.2Cl.sub.2 (630 mg, 0.898 mmol, 0.05 eq.), and
sodium carbonate (5.71 g, 53.9 mmol, 3.0 eq.), DME (125 ml) and
water (25 ml) were added. The mixture was subjected to reduced
pressure under ultrasonication treatment, followed by flushing with
nitrogen gas. This procedure was repeated five times and then
degassed. After further stirring at 80.degree. C. for 2 hr under
nitrogen atmosphere, the mixture was cooled to room temperature,
added with water (250 ml), and further stirred for 30 min. The
precipitates were filtered and washed with water (50 ml). They were
further washed with CH.sub.3CN (50 ml) to obtain the target
compound as a crude product (gray powder, 7.54 g, 90%).
[1357] LCMS: m/z 468 [M+H].sup.+
[1358] HPLC retention time: 2.90 min (analysis condition S)
Example 116
[1359] Compound B2-22-2
6,6-Dimethyl-11-oxo-8-(1,2,3,6-tetrahydro-pyridin-4-yl)-6,11-dihydro-5H-be-
nzo[b]carbazole-3-carbonitrile
##STR00131##
[1361] Under the same conditions as the method for synthesizing
Compound A8-1, the title compound was prepared from Compound
B2-22-1.
[1362] LCMS: m/z 368 [M+H].sup.+
[1363] HPLC retention time: 1.47 min (analysis condition S)
Example 117
[1364] Compound B2-23
6,6-Dimethyl-8-(1-methyl-1H-pyrazol-4-yl)-11-oxo-6,11-dihydro-5H-benzo[b]c-
arbazole-3-carbonitrile
##STR00132##
[1366] Under the same conditions as the method for synthesizing
Compound B2-22-1, the title compound was prepared from Compound B1
and
1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole.
[1367] LCMS: m/z 367 [M+H].sup.+
[1368] HPLC retention time: 2.42 min (analysis condition U)
Example 118
[1369] Compound B2-24
6,6-Dimethyl-11-oxo-8-vinyl-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitri-
le
##STR00133##
[1371] Under nitrogen atmosphere, trifluoro-methanesulfonic acid
3-cyano-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yl
ester (Compound B1, 1.00 g, 2.302 mmol) was added with n-propanol
(20 mL), potassium vinyltrifluoroborate (854 mg, 3.0 eq.),
dichloro-((bis-diphenylphosphino)ferrocenyl)palladium (217 mg, 0.1
eq.) and triethylamine (1.11 ml, 3.0 eq.) in order and the
resultant was stirred at 60.degree. C. for 4 hr. Upon the
completion of the reaction, water was added to the reaction
solution. The resulting precipitates were filtered and washed with
distilled water, and the residues were dried to obtain the title
compound (666 mg, 80%).
[1372] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta.: 8.90 (1H, s),
8.55 (1H, d, J=7.9 Hz), 8.40 (1H, d, J=8.5 Hz), 7.79 (1H, s),
7.58-7.61 (3H, m), 6.85 (1H, dd, J=17.7, 11.0 Hz), 5.95 (1H, d,
J=17.1 Hz), 5.46 (1H, d, J=11.0 Hz), 1.84 (6H, s)
[1373] LCMS: m/z 313 [M+H].sup.+
[1374] HPLC retention time: 3.75 min (analysis condition W)
Example 119
[1375] Compound B2-25-1
4-(3-Cyano-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yl
methyl)-piperidine-1-carboxylic acid tert-butyl ester
##STR00134##
[1377] 4-Methylene-piperidine-1-carboxylic acid tert-butyl ester
(409 mg, 2.07 mmol, 1.2 eq.) was dissolved in THF (2 ml), added
under nitrogen atmosphere with 9-BBN (0.5 M THF solution, 4.83 ml,
2.42 mmol, 1.4 eq.) and then stirred at 60.degree. C. for 1 hr.
Thereafter, 9-BBN (0.5 M THF solution, 5.52 ml, 2.77 mmol, 1.6 eq.)
was further added and the mixture was stirred at 60.degree. C. for
1 hr. The resulting mixture was cooled to room temperature, added
with cesium fluoride (1.31 g, 8.60 mmol, 5.0 eq.), and stirred at
room temperature for 30 min.
[1378] To the solution obtained from the above, DMF (18 ml)
suspension comprising trifluoro-methanesulfonic acid
3-cyano-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yl
ester (Compound B1, 750 mg, 1.73 mmol) and
dichloro-((bisdiphenylphosphino)ferrocenyl)palladium (70.5 mg,
0.0863 mmol, 0.05 eq.) was added, and the mixture was stirred at
100.degree. C. for 3 hr. After cooling to the room temperature,
water (50 ml) was added, followed by extraction with ethyl acetate.
The organic layer was washed with saturated brine and dried over
sodium sulfate. The drying agent was removed by filtration and the
residues obtained after concentration under reduced pressure were
purified by silica gel column chromatography (ethyl acetate/hexane)
to obtain
4-(3-cyano-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yl
methyl)-piperidine-1-carboxylic acid tert-butyl ester (yellow
powder, 763 mg, 91%).
[1379] LCMS: m/z 484 [M+H].sup.+
[1380] HPLC retention time: 2.97 min (analysis condition S)
Example 120
[1381] Compound B2-25-2
6,6-Dimethyl-11-oxo-8-piperidin-4-yl
methyl-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile
##STR00135##
[1383] Under the same conditions as the method for synthesizing
Compound A8-1, the title compound was prepared from Compound
B2-25-1.
[1384] LCMS: m/z 384 [M+H].sup.+
[1385] HPLC retention time: 1.40 min (analysis condition S)
Example 121
[1386] Compound B2-26-1
Tert-butyl
4-((3-cyano-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazo-
l-8-yl)methyl)piperidin-1-yl sulfonylcarbamic acid
##STR00136##
[1388] Under the same conditions as the method for synthesizing
Compound A9-1, the title compound was prepared from Compound
B2-25-2 and
N-(tert-butoxycarbonyl)-N-[4-(dimethylazaniumylidene)-1,4-dihydropyridin--
1-yl sulfonyl]azanide (CAS No. 872496-91-8).
[1389] LCMS: m/z 563 [M+H].sup.+
[1390] HPLC retention time: 2.63 min (analysis condition S)
Example 122
[1391] Compound B2-26-2
4-(3-Cyano-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yl
methyl)-piperidine-1-sulfonic acid amide
##STR00137##
[1393] Under the same conditions as the method for synthesizing
Compound A8-1, the title compound was prepared from Compound
B2-26-1.
[1394] LCMS: m/z 463 [M+H].sup.+
[1395] HPLC retention time: 2.10 min (analysis condition S)
Example 123
[1396] Compound B2-27
8-(1-Isopropyl-piperidin-4-yl
methyl)-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitr-
ile
##STR00138##
[1398] Under the same conditions as the method for synthesizing
Compound B3-32, the title compound was prepared from Compound
B2-25-2 and acetone.
[1399] .sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta.: 12.80 (1H, s),
8.32 (1H, d, 7.9 Hz), 8.12 (1H, d, 7.9 Hz), 8.01 (1H, s), 7.65 (1H,
s), 7.61 (1H, d, 9.1 Hz), 7.30 (1H, d, 7.9 Hz), 2.75 (2H, d, 11.0
Hz), 2.65 (3H, q, 6.5 Hz), 2.04 (2H, t, 11.0 Hz), 1.77 (6H, s),
1.60-1.57 (3H, m), 1.22 (2H, t, 11.6 Hz), 0.94 (6H, d, 6.7 Hz)
[1400] LCMS: m/z 426 [M+H].sup.+
Example 124
[1401] Compound B2-28
3-Cyano-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-carboxylic
acid
##STR00139##
[1403] Under nitrogen atmosphere, to the dimethyl formamide (3 ml)
solution comprising trifluoro-methanesulfonic acid
3-cyano-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yl
ester (Compound B1, 150 mg, 0.345 mmol), lithium formate
monohydrate (90 mg, 5.0 eq.), 4,5-bis
(diphenylphosphino)-9,9-dimethylxanthene (Xantphos) (20 mg, 0.1
eq.), Pd.sub.2(dba).sub.3 (32 mg, 0.1 eq.), lithium chloride (88
mg, 6.0 eq.), N,N-diisopropylethylamine (241 .mu.l, 4.0 eq.), and
acetic anhydride (131 .mu.l, 4.0 eq.) were added, and the mixture
was stirred at 80.degree. C. for 15 hr. Upon the completion of the
reaction, ethyl acetate was added to the reaction solution. The
organic layer was washed in order with 1 M hydrochloric acid,
distilled water, and brine. The organic layer was dried over sodium
sulfate. The drying agent was removed by filtration and the
residues obtained after concentration under reduced pressure were
purified by silica gel column chromatography (ethyl acetate/hexane)
to obtain the title compound (88 mg, 76%).
[1404] .sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta.: 13.17 (1H, s),
8.35 (1H, d, J=7.9 Hz), 8.34 (1H, s), 8.23 (1H, d, J=7.9 Hz), 8.07
(1H, s), 8.02 (1H, d, J=9.1 Hz), 7.64 (1H, d, J=7.9 Hz), 1.80 (6H,
s)
[1405] LCMS: m/z 331 [M+H].sup.+
[1406] HPLC retention time: 3.08 min (analysis condition W)
Example 125
[1407] Compound B2-29
8-Formyl-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitr-
ile
##STR00140##
[1409] To the THF (24 ml) and distilled water (6 ml) suspension of
6,6-dimethyl-11-oxo-8-vinyl-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitr-
ile (Compound B2-24, 600 mg, 1.920 mmol), t-butanol solution of
osmium tetraoxide (192 .mu.l, 0.1 eq.) and sodium meta periodate
(821 mg, 2.0 eq.) were added and the mixture was stirred at room
temperature for 3 hr. Aqueous solution of sodium thiosulfate (0.3
M) was added to the solution, which was then extracted with an
ethyl acetate. The organic layer was washed with 10% aqueous
solution of disodium ethylenediamine tetraacetic acid. The organic
layer was dried over sodium sulfate. The drying agent was removed
by filtration and the residues obtained after concentration under
reduced pressure were purified by silica gel column chromatography
(ethyl acetate/hexane) to obtain the title compound (470 mg,
77%).
[1410] .sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta.: 12.95 (1H, s),
10.20 (1H, s), 8.48 (1H, s), 8.42 (1H, d, J=8.5 Hz), 8.36 (1H, d,
J=8.5 Hz), 8.07 (1H, s), 8.02 (1H, d, J=7.9 Hz), 7.67 (1H, d, J=7.9
Hz), 1.85 (6H, s)
[1411] LCMS: m/z 315 [M+H].sup.+
[1412] HPLC retention time: 3.38 min (analysis condition W)
Example 126
[1413] Compound B3-1
5,6,6-Trimethyl-8-morpholin-4-yl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole--
3-carbonitrile
##STR00141##
[1415] Under the same conditions as the method for synthesizing
Compound A10-1, the title compound was prepared from Compound
B2-3.
[1416] LCMS: m/z 386 [M+H].sup.+
[1417] HPLC retention time: 2.62 min (analysis condition U)
Example 127
[1418] Compound B3-2-1
Tert-butyl
4-(3-cyano-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-
-8-yl)piperazin-1-yl sulfonylcarbamic acid
##STR00142##
[1420] Under the same conditions as the method for synthesizing
Compound A9-1, the title compound was prepared from Compound B2-5-2
and
N-(tert-butoxycarbonyl)-N-[4-(dimethylazaniumylidene)-1,4-dihydropyridin--
1-yl sulfonyl]azanide (CAS No. 872496-91-8).
[1421] LCMS: m/z 550 [M+H].sup.+
[1422] HPLC retention time: 2.39 min (analysis condition S)
Example 128
[1423] Compound B3-2-2
4-(3-Cyano-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yl)-pipe-
razine-1-sulfonic acid amide
##STR00143##
[1425] Under the same conditions as the method for synthesizing
Compound A8-1, the title compound was prepared from Compound
B3-2-1.
[1426] LCMS: m/z 450 [M+H].sup.+
[1427] HPLC retention time: 1.82 min (analysis condition S)
Example 129
[1428] Compound B3-3
4-(3-Cyano-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yl)-pipe-
razine-1-sulfonic acid dimethylamide
##STR00144##
[1430] Under the same conditions as the method for synthesizing
Compound A9-1, the title compound was prepared from Compound B2-5-2
and dimethylsulfamoyl chloride.
[1431] LCMS: m/z 478 [M+H].sup.+
[1432] HPLC retention time: 2.45 min (analysis condition S)
Example 130
[1433] Compound B3-4
4-(3-Cyano-5,6,6-trimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yl)-p-
iperazine-1-sulfonic acid dimethylamide
##STR00145##
[1435] To the DMF suspension of
4-(3-cyano-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yl)-pip-
erazine-1-sulfonic acid amide (Compound B3-2-2, 20 mg, 0.04 mmol)
and sodium hydride (21.4 mg, 12 eq.), iodomethane (28 .mu.l, 10
eq.) was added and stirred at room temperature overnight. Water was
added to the reaction solution, followed by filtration to obtain
the target compound (25.8 mg, 100%).
[1436] .sup.1H-NMR (270 MHz, DMSO-d.sub.6) .delta.: 8.43 (1H, d,
J=8.2 Hz), 8.31 (1H, s), 8.03 (1H, d, J=8.9 Hz), 7.64 (1H, dd,
J=8.1, 1.3 Hz), 7.30 (1H, d, J=2.0 Hz), 7.08 (1H, dd, J=8.9, 2.0
Hz), 4.16 (3H, s), 3.43-3.53 (4H, t, J=4.7 Hz), 3.26-3.41 (4H, s),
2.82 (6H, s), 1.87 (6H, s).
[1437] LCMS: m/z 492 [M+H].sup.+
[1438] HPLC retention time: 2.69 min (analysis condition S)
Example 131
[1439] Compound B3-5
8-(4-Cyclopropyl-piperazin-1-yl)-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo-
[b]carbazole-3-carbonitrile
##STR00146##
[1441] The title compound was obtained as a by-product of the
synthesis of Compound F5-36.
[1442] LCMS: m/z 411 [M+H].sup.+
[1443] HPLC retention time: 1.31 min (analysis condition S)
Example 132
[1444] Compound B3-6
8-(4-Cyclobutyl-piperazin-1-yl)-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[-
b]carbazole-3-carbonitrile
##STR00147##
[1446] Under the same conditions as the method for synthesizing
Compound B3-32, the title compound was prepared from Compound
B2-5-2 and cyclobutanone.
[1447] .sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta.: 8.29 (1H, d,
J=8.2 Hz), 8.01 (1H, d, J=8.8 Hz), 7.96 (1H, s), 7.55 (1H, d, J=8.2
Hz), 7.19 (1H, d, J=2.2 Hz), 7.03 (1H, dd, J=2.4, 8.8 Hz),
2.71-2.75 (1H, m), 2.37-2.39 (4H, m), 1.98-2.00 (2H, m), 1.77-1.85
(2H, m), 1.74 (6H, s), 1.63-1.68 (2H, m).
[1448] LCMS: m/z 425 [M+H].sup.+
[1449] HPLC retention time: 1.80 min (analysis condition U)
Example 133
[1450] Compound B3-7
6,6-Dimethyl-8-(4-oxetan-3-yl-piperazin-1-yl)-11-oxo-6,11-dihydro-5H-benzo-
[b]carbazole-3-carbonitrile
##STR00148##
[1452] Under the same conditions as the method for synthesizing
Compound B3-32, the title compound was prepared from Compound
B2-5-2 and 3-oxetanone.
[1453] .sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta.: 8.29 (1H, dd,
J=8.2, 0.59 Hz), 8.02 (1H, d, J=9.0 Hz), 7.97 (1H, d, J=0.59 Hz),
7.56 (1H, dd, J=8.0, 1.4 Hz), 7.22 (1H, d, J=2.3 Hz), 7.04 (1H, dd,
J=8.8, 2.2 Hz), 4.56-4.59 (2H, m), 4.47-4.50 (2H, m), 3.43-3.48
(1H, m), 3.39-3.42 (4H, m), 2.40-2.42 (4H, m), 1.74 (6H, s)
[1454] LCMS: m/z 427 [M+H].sup.+
[1455] HPLC retention time: 1.67 min (analysis condition U)
Example 134
[1456] Compound B3-8
8-(2-Diethylamino-ethanesulfonyl)-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benz-
o[b]carbazole-3-carbonitrile
##STR00149##
[1458]
8-(2-Diethylamino-ethylsulfanyl)-6,6-dimethyl-11-oxo-6,11-dihydro-5-
H-benzo[b]carbazole-3-carbonitrile (Compound B2-17, 16.8 mg, 0.0402
mmol) was dissolved in methanol (1.5 mL), added with oxone (54.3
mg, 2.2 eq.) which had been dissolved in water (0.5 mL), and then
stirred at room temperature for 2 hr. The reaction solution was
concentrated, extracted with ethyl acetate, washed with saturated
sodium hydrogen carbonate, and dried over magnesium sulfate. The
drying agent was removed by filtration and the residues obtained
after concentration under reduced pressure were purified by silica
gel column chromatography (dichloromethane/methanol) to obtain the
target compound (white solid, 5.8 mg, 32%).
[1459] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta.: 9.29 (1H, s),
8.61 (1H, d, J=8.2 Hz), 8.52 (1H, d, J=8.0 Hz), 8.21 (1H, s), 8.01
(1H, d, J=8.2 Hz), 7.81 (1H, s), 7.61 (1H, d, J=8.2 Hz), 3.33 (2H,
t, J=7.4 Hz), 2.95 (2H, t, J=7.4 Hz), 2.41 (4H, q, J=7.2 Hz), 1.86
(6H, s), 0.89 (4H, t, J=7.1 Hz)
[1460] LCMS: m/z 450 [M+H].sup.+
[1461] HPLC retention time: 2.05 min (analysis condition U)
Example 135
[1462] Compound B3-9
8-(2-Diisopropylamino-ethanesulfonyl)-6,6-dimethyl-11-oxo-6,11-dihydro-5H--
benzo[b]carbazole-3-carbonitrile
##STR00150##
[1464] Under the same conditions as the method for synthesizing
Compound B3-8, the title compound was prepared from Compound
B2-18.
[1465] LCMS: m/z 478 [M+H].sup.+
[1466] HPLC retention time: 2.18 min (analysis condition U)
Example 136
[1467] Compound B3-10
8-(2-Dimethylamino-ethanesulfonyl)-6,6-dimethyl-11-oxo-6,11-dihydro-5H-ben-
zo[b]carbazole-3-carbonitrile
##STR00151##
[1469] Under the same conditions as the method for synthesizing
Compound B3-8, the title compound was prepared from Compound
B2-19.
[1470] LCMS: m/z 422 [M+H].sup.+
[1471] HPLC retention time: 2.03 min (analysis condition U)
Example 137
[1472] Compound B3-11
3-(3-Cyano-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-sulfonyl-
)-propionic acid
##STR00152##
[1474] Under the same conditions as the method for synthesizing
Compound B3-8, the title compound was prepared from Compound
B2-20.
[1475] LCMS: m/z 423 [M+H].sup.+
[1476] HPLC retention time: 2.28 min (analysis condition U)
Example 138
[1477] Compound B3-12
8-(2,3-Dihydroxy-propane-1-sulfonyl)-6,6-dimethyl-11-oxo-6,11-dihydro-5H-b-
enzo[b]carbazole-3-carbonitrile
##STR00153##
[1479] Under the same conditions as the method for synthesizing
Compound B3-8, the title compound was prepared from Compound
B2-21.
[1480] LCMS: m/z 425 [M+H].sup.+
[1481] HPLC retention time: 2.17 min (analysis condition U)
Example 139
[1482] Compound B3-13-1
4-(3-Cyano-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yl)-pipe-
ridine-1-carboxylic acid tert-butyl ester
##STR00154##
[1484]
4-(3-Cyano-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-y-
l)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester
(Compound B2-22-1, 16.2 g, 34.6 mmol) was dissolved in THF (800 ml)
and methanol (230 ml), added with 10 wt % Pd/C (3.2 g), and stirred
under hydrogen atmosphere for 19 hr. The solid was filtered through
Celite, eluted with a mixture solvent (400 ml; THF/methanol=4/1),
and concentrated under reduced pressure. The residues were
dissolved in ethyl acetate (400 ml), and then washed with 1%
aqueous solution of N-acetylcysteine, saturated aqueous solution of
NaHCO.sub.3 and saturated brine. The organic layer was dried over
sodium sulfate. The drying agent was removed by filtration and the
residues were concentrated under reduced pressure to obtain the
title compound as a crude product (white powder, 14.0 g, 86%).
[1485] LCMS: m/z 470 [M+H].sup.+
[1486] HPLC retention time: 2.88 min (analysis condition S)
Example 140
[1487] Compound B3-13-2
6,6-Dimethyl-11-oxo-8-piperidin-4-yl-6,11-dihydro-5H-benzo[b]carbazole-3-c-
arbonitrile
##STR00155##
[1489] Under the same conditions as the method for synthesizing
Compound A8-1, the title compound was prepared from Compound
B3-13-1.
[1490] LCMS: m/z 370 [M+H].sup.+
[1491] HPLC retention time: 1.30 min (analysis condition S)
Example 141
[1492] Compound B3-14
8-(1,2-Dihydroxy-ethyl)-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbaz-
ole-3-carbonitrile
##STR00156##
[1494] To the THF (1 ml) solution of
6,6-dimethyl-11-oxo-8-vinyl-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitr-
ile (Compound B2-24, 20 mg, 0.064 mmol), t-butanol solution of
osmium tetraoxide (19 .mu.l, 0.3 eq.) and 50% aqueous solution of
N-methylmorpholine-N-oxide (30 .mu.l, 2.0 eq.) were added and the
mixture was stirred at room temperature for 3 hr. To the reaction
solution, 10% aqueous solution of disodium ethylenediamine
tetraacetic acid was added, followed by extraction with ethyl
acetate. The organic layer was dried over sodium sulfate. The
drying agent was removed by filtration and the residues obtained
after concentration under reduced pressure were purified by high
performance liquid chromatography to obtain the title compound (21
mg, 63%).
[1495] .sup.1H-NMR (400 MHz, CD.sub.3OD) .delta.: 8.41 (1H, d,
J=7.9 Hz), 8.29 (1H, d, J=7.9 Hz), 7.87 (1H, s), 7.86 (1H, s), 7.57
(1H, d, J=7.9 Hz), 7.52 (1H, d, J=6.7 Hz), 4.85 (1H, dd, J=7.0, 4.6
Hz), 3.73 (1H, dd, J=11.3, 4.6 Hz), 3.68 (1H, dd, J=11.3, 7.0 Hz),
1.83 (6H, s)
[1496] LCMS: m/z 347 [M+H].sup.+
[1497] HPLC retention time: 2.68 min (analysis condition W)
Example 142
[1498] Compound B3-15
6,6-Dimethyl-8-(morpholine-4-carbonyl)-11-oxo-6,11-dihydro-5H-benzo[b]carb-
azole-3-carbonitrile
##STR00157##
[1500] To the tetrahydrofuran (1 ml) solution of
3-cyano-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-carboxylic
acid (Compound B2-28, 15 mg, 0.045 mmol), morpholine (6 .mu.l, 1.5
eq.), hexafluorophosphoric acid uronium
2-(1H-7-azabenzotriazol-1-yl)-1,1,3,3-tetramethylmethane aminium
(HATU) (26 mg, 1.5 eq.), and N,N-diisopropylethylamine (24 .mu.l,
3.0 eq.) were added and the mixture was stirred at room temperature
for 3 hr. The reaction solution was filtered to remove insoluble
matters and the residues obtained after concentration under reduced
pressure were purified by high performance liquid chromatography to
obtain the title compound (11 mg, 55%).
[1501] .sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta.: 12.85 (1H, s),
8.33 (1H, d, J=8.5 Hz), 8.27 (1H, d, J=7.9 Hz), 8.03 (1H, s), 7.92
(1H, s), 7.63 (1H, d, J=8.5 Hz), 7.54 (1H, d, J=7.9 Hz), 3.52-3.77
(6H, m), 3.30-3.42 (2H, m), 1.79 (6H, s)
[1502] LCMS: m/z 400 [M+H].sup.+
[1503] HPLC retention time: 2.96 min (analysis condition W)
Example 143
[1504] Compound B3-16
8-(4-Methanesulfonyl-piperazin-1-carbonyl)-6,6-dimethyl-11-oxo-6,11-dihydr-
o-5H-benzo[b]carbazole-3-carbonitrile
##STR00158##
[1506] Under the same conditions as the method for synthesizing
Compound B3-15, the title compound was prepared from Compound B2-28
and 1-methanesulfonylpiperazine.
[1507] LCMS: m/z 477 [M+H].sup.+
[1508] HPLC retention time: 3.03 min (analysis condition W)
Example 144
[1509] Compound B3-17
8-(4-Hydroxy-piperidin-1-carbonyl)-6,6-dimethyl-11-oxo-6,11-dihydro-5H-ben-
zo[b]carbazole-3-carbonitrile
##STR00159##
[1511] Under the same conditions as the method for synthesizing
Compound B3-15, the title compound was prepared from Compound B2-28
and piperidin-4-ol.
[1512] LCMS: m/z 414 [M+H].sup.+
[1513] HPLC retention time: 2.75 min (analysis condition W)
Example 145
[1514] Compound B3-18
3-Cyano-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-carboxylic
acid (2-hydroxy-1-hydroxymethyl-ethyl)-amide
##STR00160##
[1516] Under the same conditions as the method for synthesizing
Compound B3-15, the title compound was prepared from Compound B2-28
and 2-aminopropane-1,3-diol.
[1517] LCMS: m/z 404 [M+H].sup.+
[1518] HPLC retention time: 2.60 min (analysis condition W)
Example 146
[1519] Compound B3-19
3-Cyano-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-carboxylic
acid (2-methanesulfonyl-ethyl)-amide
##STR00161##
[1521] Under the same conditions as the method for synthesizing
Compound B3-15, the title compound was prepared from Compound B2-28
and 2-methanesulfonylethylamine.
[1522] LCMS: m/z 436 [M+H].sup.+
[1523] HPLC retention time: 2.87 min (analysis condition W)
Example 147
[1524] Compound B3-20
3-Cyano-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-carboxylic
acid (1,1-dioxo-tetrahydro-thiophen-3-yl)-amide
##STR00162##
[1526] Under the same conditions as the method for synthesizing
Compound B3-15, the title compound was prepared from Compound B2-28
and (1,1-dioxotetrahydrothiophen-3-yl)amine
[1527] LCMS: m/z 448 [M+H].sup.+
[1528] HPLC retention time: 1.70 min (analysis condition S)
Example 148
[1529] Compound B3-21
3-Cyano-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-carboxylic
acid ((R)-2,3-dihydroxy-propyl)-amide
##STR00163##
[1531] Under the same conditions as the method for synthesizing
Compound B3-15, the title compound was prepared from Compound B2-28
and (R)-(+)-3-amino-1,2-propanediol.
[1532] LCMS: m/z 404 [M+H].sup.+
[1533] HPLC retention time: 1.38 min (analysis condition S)
Example 149
[1534] Compound B3-22
3-Cyano-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-carboxylic
acid bis-(2-hydroxy-ethyl)-amide
##STR00164##
[1536] Under the same conditions as the method for synthesizing
Compound B3-15, the title compound was prepared from Compound B2-28
and N,N-diethanolamine.
[1537] LCMS: m/z 418 [M+H].sup.+
[1538] HPLC retention time: 1.35 min (analysis condition S)
Example 150
[1539] Compound B3-23
3-Cyano-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-carboxylic
acid oxetan-3-yl amide
##STR00165##
[1541] Under the same conditions as the method for synthesizing
Compound B3-15, the title compound was prepared from Compound B2-28
and oxetan-3-yl amine.
[1542] LCMS: m/z 386 [M+H].sup.+
[1543] HPLC retention time: 1.63 min (analysis condition S)
Example 151
[1544] Compound B3-24
3-Cyano-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-carboxylic
acid (2-hydroxy-ethoxy)-amide
##STR00166##
[1546] Under the same conditions as the method for synthesizing
Compound B3-15, the title compound was prepared from Compound B2-28
and 2-aminooxy-ethanol.
[1547] LCMS: m/z 390 [M+H].sup.+
[1548] HPLC retention time: 1.54 min (analysis condition S)
Example 152
[1549] Compound B3-25-1
2-[(3-Cyano-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-carbony-
l)-amino]-ethyl}-carbamic acid tert-butyl ester
##STR00167##
[1551] Under the same conditions as the method for synthesizing
Compound B3-15, the title compound was prepared from Compound B2-28
and (2-amino-ethyl)-carbamic acid tert-butyl ester.
[1552] LCMS: m/z 473 [M+H].sup.+
[1553] HPLC retention time: 2.08 min (analysis condition S)
Example 153
[1554] Compound B3-25-2
3-Cyano-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-carboxylic
acid (2-amino-ethyl)-amide
##STR00168##
[1556] Under the same conditions as the method for synthesizing
Compound A8-1, the title compound was prepared from Compound
B3-25-1.
[1557] LCMS: m/z 373 [M+H].sup.+
[1558] HPLC retention time: 1.19 min (analysis condition S)
Example 154
[1559] Compound B3-25-3
3-Cyano-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-carboxylic
acid (2-methanesulfonylamino-ethyl)-amide
##STR00169##
[1561] Under the same conditions as the method for synthesizing
Compound A9-1, the title compound was prepared from Compound
B3-25-2.
[1562] LCMS: m/z 451 [M+H].sup.+
[1563] HPLC retention time: 1.62 min (analysis condition S)
Example 155
[1564] Compound B3-26
3-Cyano-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-carboxylic
acid (2-hydroxy-ethyl)-methyl-amide
##STR00170##
[1566] Under the same conditions as the method for synthesizing
Compound B3-15, the title compound was prepared from Compound B2-28
and 2-methylamino-ethanol.
[1567] LCMS: m/z 388 [M+H].sup.+
[1568] HPLC retention time: 1.53 min (analysis condition S)
Example 156
[1569] Compound B3-27-1
Tert-butyl
N-(2-(3-cyano-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carba-
zol-8carboxamide)ethyl)sulfamoylcarbamic acid
##STR00171##
[1571] Under the same conditions as the method for synthesizing
Compound A9-1, the title compound was prepared from Compound
B3-25-2 and
N-(tert-butoxycarbonyl)-N-[4-(dimethylazaniumylidene)-1,4-dihydropyridin--
1-yl sulfonyl]azanide (CAS No. 872496-91-8).
[1572] LCMS: m/z 552 [M+H].sup.+
[1573] HPLC retention time: 2.03 min (analysis condition S)
Example 157
[1574] Compound B3-27-2
3-Cyano-6,6-dimethyl-11-oxo-N-(2-(sulfamoylamino)ethyl)-6,11-dihydro-5H-be-
nzo[b]carbazol-8-carboxamide
##STR00172##
[1576] Under the same conditions as the method for synthesizing
Compound A8-1, the title compound was prepared from Compound
B3-27-1.
[1577] LCMS: m/z 452 [M+H].sup.+
[1578] HPLC retention time: 1.57 min (analysis condition S)
Example 158
[1579] Compound B3-28
8-[4-(2-Hydroxy-ethyl)-piperazin-1-carbonyl]-6,6-dimethyl-11-oxo-6,11-dihy-
dro-5H-benzo[b]carbazole-3-carbonitrile
##STR00173##
[1581] Under the same conditions as the method for synthesizing
Compound B3-15, the title compound was prepared from Compound B2-28
and 2-piperazin-1-yl ethanol.
[1582] LCMS: m/z 443 [M+H].sup.+
[1583] HPLC retention time: 1.75 min (analysis condition U)
Example 159
[1584] Compound B3-29
8-(4-Tert-butyl-piperazin-1-carbonyl)-6,6-dimethyl-11-oxo-6,11-dihydro-5H--
benzo[b]carbazole-3-carbonitrile
##STR00174##
[1586] Under the same conditions as the method for synthesizing
Compound B3-15, the title compound was prepared from Compound B2-28
and 1-tert-butylpiperazine.
[1587] LCMS: m/z 455 [M+H].sup.+
[1588] HPLC retention time: 1.88 min (analysis condition U)
Example 160
[1589] Compound B3-30
8-[4-(2-Methoxy-ethyl)-piperazin-1-carbonyl]-6,6-dimethyl-11-oxo-6,11-dihy-
dro-5H-benzo[b]carbazole-3-carbonitrile
##STR00175##
[1591] Under the same conditions as the method for synthesizing
Compound B3-15, the title compound was prepared from Compound B2-28
and 1-(2-methoxyethyl)piperazine.
[1592] LCMS: m/z 457 [M+H].sup.+
[1593] HPLC retention time: 1.83 min (analysis condition U)
Example 161
[1594] Compound B3-31-1
4-(3-Cyano-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-carbonyl-
)-piperazine-1-carboxylic acid tert-butyl ester
##STR00176##
[1596] Under the same conditions as the method for synthesizing
Compound B3-15, the title compound was prepared from Compound B2-28
and piperazine-1-carboxylic acid tert-butyl ester.
[1597] LCMS: m/z 499 [M+H].sup.+
[1598] HPLC retention time: 2.63 min (analysis condition U)
Example 162
[1599] Compound B3-31-2
6,6-Dimethyl-11-oxo-8-(piperazin-1-carbonyl)-6,11-dihydro-5H-benzo[b]carba-
zole-3-carbonitrile
##STR00177##
[1601] Under the same conditions as the method for synthesizing
Compound A8-1, the title compound was prepared from Compound
B3-31-1.
[1602] LCMS: m/z 399 [M+H].sup.+
[1603] HPLC retention time: 1.78 min (analysis condition U)
Example 163
[1604] Compound B3-32
6,6-Dimethyl-8-morpholin-4-yl
methyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile
##STR00178##
[1606] To the THF (1 ml) solution of Compound B2-29 (30 mg, 0.095
mmol), morpholine (6 .mu.l, 1.5 eq.) and sodium
triacetoxyborohydride (81 mg, 2.0 eq.) were added and stirred at
room temperature for 1 hr. The reaction solution was filtered to
remove insoluble matters, and the residues obtained after
concentration under reduced pressure were purified by high
performance liquid chromatography to obtain the title compound (19
mg, 50%).
[1607] .sup.1H-NMR (400 MHz, CD.sub.3OD) .delta.: 8.41 (1H, d, 7.9
Hz), 8.27 (1H, d, 8.5 Hz), 7.87 (1 s), 7.81 (1H, s), 7.56 (1H, d,
8.5 Hz), 7.49 (1H, d, 7.9 Hz), 3.71 (4H, t, 4.6 Hz), 3.68 (2H, s),
2.51 (4H, t, 4.6 Hz), 1.82 (6H, s)
[1608] LCMS: m/z 386 [M+H].sup.+
[1609] HPLC retention time: 2.41 min (analysis condition W)
Example 164
[1610] Compound B3-33
6,6-Dimethyl-8-(4-methyl-piperazin-1-yl
methyl)-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile
##STR00179##
[1612] Under the same conditions as the method for synthesizing
Compound B3-32, the title compound was prepared from Compound B2-29
and 1-methylpiperazine.
[1613] .sup.1H-NMR (400 MHz, CD.sub.3OD) .delta.: 8.41 (1H, d, 7.9
Hz), 8.26 (1H, d, 7.9 Hz), 7.88 (1 s), 7.81 (1H, s), 7.56 (1H, d,
7.9 Hz), 7.48 (1H, d, 7.9 Hz), 3.70 (2H, s), 2.42-2.78 (8H, m),
2.31 (3H, s), 1.82 (6H, s)
[1614] LCMS: m/z 399 [M+H].sup.+
[1615] HPLC retention time: 2.30 min (analysis condition W)
Example 165
[1616] Compound B3-34
8-[4-(1,1-Dioxide-4-thiomorpholinyl)methyl]-6,6-dimethyl-11-oxo-6,11-dihyd-
ro-5H-benzo[b]carbazole-3-carbonitrile
##STR00180##
[1618] Under the same conditions as the method for synthesizing
Compound B3-32, the title compound was prepared from Compound B2-29
and thiomorpholine 1,1-dioxide.
[1619] LCMS: m/z 434 [M+H].sup.+
[1620] HPLC retention time: 2.75 min (analysis condition W)
[1621] Compound B3-35
8-(4-Methanesulfonyl-piperazin-1-yl
methyl)-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitr-
ile
##STR00181##
[1623] Under the same conditions as the method for synthesizing
Compound B3-32, the title compound was prepared from Compound B2-29
and 1-methanesulfonylpiperazine.
[1624] .sup.1H-NMR (400 MHz, CD.sub.3OD) .delta.: 8.41 (1H, d, 8.5
Hz), 8.28 (1H, d, 7.9 Hz), 7.87 (1 s), 7.80 (1H, s), 7.56 (1H, d,
8.5 Hz), 7.50 (1H, d, 7.9 Hz), 3.73 (2H, s), 3.24-3.28 (4H, m),
2.85 (3H, s), 2.59-2.65 (4H, m), 1.82 (6H, s)
[1625] LCMS: m/z 463 [M+H].sup.+
[1626] HPLC retention time: 2.47 min (analysis condition W)
Example 167
[1627] Compound B3-36
4-(3-Cyano-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yl
methyl)-piperazine-1-sulfonic acid dimethylamide
##STR00182##
[1629] Under the same conditions as the method for synthesizing
Compound B3-32, the title compound was prepared from Compound B2-29
and piperazine-1-sulfonic acid dimethylamide.
[1630] .sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta.: 12.79 (1H, s),
8.32 (1H, d, 7.9 Hz), 8.18 (1H, d, 7.9 Hz), 8.00 (1s), 7.77 (1H,
s), 7.60 (1H, d, 7.9 Hz), 7.46 (1H, d, 7.9 Hz), 3.67 (2H, s),
3.18-3.23 (4H, m), 2.76 (6H, s), 2.45-2.50 (4H, m), 1.77 (6H,
s)
[1631] LCMS: m/z 492 [M+H].sup.+
[1632] HPLC retention time: 2.58 min (analysis condition W)
[1633] Compound B3-37
6,6-Dimethyl-11-oxo-8-[(2,2,2-trifluoro-ethylamino)-methyl]-6,11-dihydro-5-
H-benzo[b]carbazole-3-carbonitrile
##STR00183##
[1635] Under the same conditions as the method for synthesizing
Compound B3-32, the title compound was prepared from Compound B2-29
and 2,2,2-trifluoroethylamine.
[1636] LCMS: m/z 398 [M+H].sup.+
[1637] HPLC retention time: 2.73 min (analysis condition W)
Example 169
[1638] Compound B3-38
8-Hydroxymethyl-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-ca-
rbonitrile
##STR00184##
[1640] The by-product obtained from the synthesis of Compound B3-37
was purified by high performance liquid chromatography to obtain
the target compound.
[1641] LCMS: m/z 317 [M+H].sup.+
[1642] HPLC retention time: 2.91 min (analysis condition W)
Example 170
[1643] Compound B4-1
8-(1-Cyclobutyl-piperidin-4-yl)-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[-
b]carbazole-3-carbonitrile
##STR00185##
[1645] Under the same conditions as the method for synthesizing
Compound B3-32, the title compound was prepared from Compound
B3-13-2 and cyclobutanone.
[1646] .sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta.: 12.73 (1H, s),
8.28-8.33 (1H, m), 8.09-8.14 (1H, m), 7.99 (1H, s), 7.72 (1H, s),
7.56-7.62 (1H, m), 7.34-7.41 (1H, m), 3.52-3.64 (2H, m), 2.85-2.95
(2H, m), 2.56-2.75 (2H, m), 1.91-2.04 (2H, m), 1.56-1.84 (14H,
m)
[1647] LCMS: m/z 424 [M+H].sup.+
[1648] HPLC retention time: 1.87 min (analysis condition U)
Example 171
[1649] Compound B4-2
8-(1-Methanesulfonyl-piperidin-4-yl)-6,6-dimethyl-11-oxo-6,11-dihydro-5H-b-
enzo[b]carbazole-3-carbonitrile
##STR00186##
[1651] Under the same conditions as the method for synthesizing
Compound A9-1, the title compound was prepared from Compound
B3-13-2 and mesyl chloride.
[1652] .sup.1H-NMR (270 MHz, DMSO-d.sub.6) .delta.: 12.77 (1H, s),
8.31 (1H, d, 8.6 Hz), 8.15 (1H, d, 8.2 Hz), 8.00 (1H, s), 7.77 (1H,
s), 7.59 (1H, d, 7.3 Hz), 7.42 (1H, d, 8.6 Hz), 3.74-3.70 (1H, m),
2.93 (3H, s), 2.86-2.77 (4H, m), 1.93-1.87 (4H, m), 1.77 (6.0H,
s)
[1653] LCMS: m/z 448 [M+H].sup.+
[1654] HPLC retention time: 2.37 min (analysis condition S)
Example 172
[1655] Compound B4-3-1
Tert-butyl
4-(3-cyano-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-
-8-yl)piperidin-1-yl sulfonylcarbamic acid
##STR00187##
[1657] Under the same conditions as the method for synthesizing
Compound A9-1, the title compound was prepared from Compound
B3-13-2 and
N-(tert-butoxycarbonyl)-N-[4-(dimethylazaniumylidene)-1,4-dihydropyridine-
-1-yl-sulfonyl]azanide.
[1658] LCMS: m/z 549 [M+H].sup.+
[1659] HPLC retention time: 2.72 min (analysis condition S)
Example 173
[1660] Compound B4-3-2
4-(3-Cyano-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yl)-pipe-
ridine-1-sulfonic acid amide
##STR00188##
[1662] Under the same conditions as the method for synthesizing
Compound A8-1, the title compound was prepared from Compound
B4-3-1.
[1663] .sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta.: 12.78 (1H, s),
8.29 (1H, d, 7.9 Hz), 8.14 (1H, d, 8.5 Hz), 7.97 (1H, s), 7.76 (1H,
s), 7.55 (1H, d, 8.5 Hz), 7.41 (1H, d, 7.9 Hz), 6.79 (2H, s), 3.63
(2H, d, 12.2 Hz), 2.80-2.73 (1H, m), 2.70-2.64 (2H, m), 1.96-1.93
(2H, m), 1.87-1.81 (2H, m), 1.77 (6H, s)
[1664] LCMS: m/z 449 [M+H].sup.+
[1665] HPLC retention time: 2.03 min (analysis condition S)
Example 174
[1666] Compound B4-4
4-(3-Cyano-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yl)-pipe-
ridine-1-sulfonic acid methylamide
##STR00189##
[1668] Under the same conditions as the method for synthesizing
Compound A9-1, the title compound was prepared from Compound
B3-13-2 and 2-oxooxazolidine-3-sulfonic acid methylamide.
[1669] LCMS: m/z 463 [M+H].sup.+
[1670] HPLC retention time: 2.40 min (analysis condition S)
Example 175
[1671] Compound B4-5
4-(3-Cyano-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yl)-pipe-
ridine-1-sulfonic acid dimethylamide
##STR00190##
[1673] Under the same conditions as the method for synthesizing
Compound A9-1, the title compound was prepared from Compound
B3-13-2 and dimethylsulfamoyl chloride.
[1674] LCMS: m/z 477 [M+H].sup.+
[1675] HPLC retention time: 2.65 min (analysis condition S)
Example 176
[1676] Compound B4-6
6,6-Dimethyl-8-(1-methyl-piperidin-4-yl)-11-oxo-6,11-dihydro-5H-benzo[b]ca-
rbazole-3-carbonitrile
##STR00191##
[1678] Under the same conditions as the method for synthesizing
Compound A9-1, the title compound was prepared from Compound
B3-13-2 and iodomethane.
[1679] LCMS: m/z 384 [M+H].sup.+
[1680] HPLC retention time: 1.50 min (analysis condition S)
Example 177
[1681] Compound B4-7
8-(1-Isopropyl-piperidin-4-yl)-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b-
]carbazole-3-carbonitrile
##STR00192##
[1683] Under the same conditions as the method for synthesizing
Compound B3-32, the title compound was prepared from Compound
B3-13-2 and acetone.
[1684] .sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta.: 12.77 (1H, s),
8.32 (1H, d, 7.9 Hz), 8.13 (1H, d, 7.9 Hz), 8.01 (1H, s), 7.73 (1H,
s), 7.61 (1H, d, 9.1 Hz), 7.39 (1H, d, 9.8 Hz), 2.93 (2H, d, 11.0
Hz), 2.77-2.71 (1H, m), 2.67-2.62 (1H, m), 2.25 (2H, t, 10.1 Hz),
1.80-1.73 (10H, m), 1.02 (6H, d, 6.7 Hz)
[1685] LCMS: m/z 412 [M+H].sup.+
[1686] HPLC retention time: 1.60 min (analysis condition S)
Example 178
[1687] Compound B4-8
6,6-Dimethyl-8-(1-oxetan-3-yl-piperidin-4-yl)-11-oxo-6,11-dihydro-5H-benzo-
[b]carbazole-3-carbonitrile
##STR00193##
[1689] Under the same conditions as the method for synthesizing
Compound B3-32, the title compound was prepared from Compound
B3-13-2 and oxetan-3-one.
[1690] .sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta.: 12.74 (1H, s),
8.32 (1H, d, 7.9 Hz), 8.13 (1H, d, 7.9 Hz), 8.00 (1H, s), 7.74 (1H,
s), 7.61 (1H, d, 9.8 Hz), 7.40 (1H, d, 7.9 Hz), 4.56 (2H, t, 6.7
Hz), 4.46 (2H, t, 6.1 Hz), 3.46-3.39 (1H, m), 2.85-2.82 (2H, m),
2.71-2.64 (1H, m), 1.92-1.86 (2H, m), 1.82-1.79 (4H, m), 1.77 (6H,
s)
[1691] LCMS: m/z 426 [M+H].sup.+
[1692] HPLC retention time: 1.53 min (analysis condition S)
[1693] Sulfuric Acid Salt of Compound B4-8
[1694]
6,6-Dimethyl-8-(1-oxetan-3-yl-piperidin-4-yl)-11-oxo-6,11-dihydro-5-
H-benzo[b]carbazole-3-carbonitrile was dissolved at 80.degree. C.
in a mixture of 5 volumes of DMA and 1.4 volumes of 2 N sulfuric
acid. After cooling to room temperature, 15 volumes of acetone were
added dropwise, and the precipitated solids were filtered and dried
to obtain sulfuric acid salt of
6,6-dimethyl-8-(1-oxetan-3-yl-piperidin-4-yl)-11-oxo-6,11-dihydro-5H-benz-
o[b]carbazole-3-carbonitrile.
[1695] .sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta.: 12.81 (1H, s),
10.26 (1H, br. s), 8.33 (1H, d, 8.3 Hz), 8.21 (1H, d, 8.3 Hz), 8.04
(1H, s), 7.75 (1H, s), 7.63 (1H, d, 8.3 Hz), 7.41 (1H, d, 8.3 Hz),
4.85-4.70 (4H, m), 4.50-4.40 (1H, br. s), 3.60-3.00 (6H, br. m),
2.20-2.10 (2H, m), 2.05-1.90 (2H, m), 1.79 (6H, s)
[1696] LCMS: m/z 426 [M+H].sup.+
Example 179
[1697] Compound B4-9
4-(3-Cyano-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yl)-pipe-
ridine-1-carboxylic acid ethylamide
##STR00194##
[1699] Under the same conditions as the method for synthesizing
Compound A9-1, the title compound was prepared from Compound
B-3-13-2 and ethylisocyanate.
[1700] LCMS: m/z 441 [M+H].sup.+
[1701] HPLC retention time: 2.20 min (analysis condition S)
Example 180
[1702] Compound B4-10
8-[1-(Imidazole-1-sulfonyl)-piperidin-4-yl]-6,6-dimethyl-11-oxo-6,11-dihyd-
ro-5H-benzo[b]carbazole-3-carbonitrile
##STR00195##
[1704] According to the method disclosed in Journal of Organic
Chemistry, 2003, page 115,
6,6-dimethyl-11-oxo-8-piperidin-4-yl-6,11-dihydro-5H-benzo[b]carbazole-3--
carbonitrile (Compound B3-13-2, 10 mg, 0.027 mmol) was reacted with
3-(imidazole-1-sulfonyl)-1-methyl-3H-imidazol-1-ium (19 mg, 2 eq.).
After removing the solvent, the residues were purified by liquid
chromatography to obtain the title compound (3 mg).
[1705] LCMS: m/z 500 [M+H].sup.+
[1706] HPLC retention time: 2.80 min (analysis condition C)
Example 181
[1707] Compound CC1
3-Methoxy-5,5-dimethyl-6-oxo-5,6,7,8-tetrahydro-naphthalen-2-sulfonyl
chloride
##STR00196##
[1709] To the dichloromethane (2 ml) solution of
7-methoxy-1,1-dimethyl-3,4-dihydro-1H-naphthalen-2-one (Compound
A2, 200 mg, 0.980 mmol), chlorosulfonic acid (110 .mu.l, 1.70 eq.)
was added and the mixture was stirred at room temperature for 2 hr.
To the reaction solution, oxalyl chloride (297 .mu.l, 3.0 eq.) and
N,N-dimethyl formamide (45 .mu.l, 0.6 eq.) were added in three
divided portions, and the mixture was stirred at room temperature
for 30 min. The reaction solution was concentrated under reduced
pressure to obtain the title compound (295 mg). Since the title
compound is unstable, its structure was identified in the next
step.
Example 182
[1710] Compound CC2-1
7-Methoxy-1,1-dimethyl-6-(pyrrolidine-1-sulfonyl)-3,4-dihydro-1H-naphthale-
n-2-one
##STR00197##
[1712] The THF (4 ml) solution of
3-methoxy-5,5-dimethyl-6-oxo-5,6,7,8-tetrahydro-naphthalen-2-sulfonyl
chloride (Compound CC1, 295 mg, 0.974 mmol) was cooled to 0.degree.
C., and the tetrafuran (1 ml) solution combining pyrrolidine (121
.mu.l, 1.5 eq.) and triethylamine (272 .mu.l, 2 eq.) was added
dropwise thereto over 2 min. The mixture was stirred at 0.degree.
C. until Compound CC-1 disappears. The reaction solution was added
with distilled water and extracted with ethyl acetate. The organic
layer was washed with 10% aqueous solution of disodium
ethylenediamine tetraacetic acid. The organic layer was washed with
brine and dried over sodium sulfate. The drying agent was removed
by filtration and the residues obtained after concentration under
reduced pressure were purified by silica gel column chromatography
(ethyl acetate/hexane) to obtain the title compound (246 mg,
75%).
[1713] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta.: 7.76 (1H, s),
6.93 (1H, s), 3.95 (3H, s), 3.37-3.46 (4H, m), 3.09 (0.0H, t, J=6.9
Hz), 2.69 (0.0H, t, J=6.9 Hz), 1.82-1.91 (4H, m), 1.47 (6H, s)
[1714] LCMS: m/z 338 [M+H].sup.+
[1715] HPLC retention time: 3.21 min (analysis condition W)
Example 183
[1716] Compound CC2-2
7-Methoxy-1,1-dimethyl-6-(4-methyl-piperazine-1-sulfonyl)-3,4-dihydro-1H-n-
aphthalen-2-one
##STR00198##
[1718] Under the same conditions as the method for synthesizing
Compound CC2-1, the title compound was prepared from Compound CC
and N-methylpiperazine.
[1719] LCMS: m/z 367 [M+H].sup.+
[1720] HPLC retention time: 2.22 min (analysis condition Y)
Example 184
[1721] Compound CC3-1
8-Methoxy-6,6-dimethyl-9-(pyrrolidine-1-sulfonyl)-6,11-dihydro-5H-benzo[b]-
carbazole-3-carbonitrile
##STR00199##
[1723] Under the same conditions as the method for synthesizing
Compound E2-1, the title compound was prepared from Compound
CC2-1.
[1724] LCMS: m/z 436 [M+H].sup.+
[1725] HPLC retention time: 3.76 min (analysis condition W)
Example 185
[1726] Compound CC3-2
3-Bromo-8-methoxy-6,6-dimethyl-9-(4-methyl-piperazine-1-sulfonyl)-6,11-dih-
ydro-5H-benzo[b]carbazole
##STR00200##
[1728] Under the same conditions as the method for synthesizing
Compound A3-1, the title compound was prepared from Compound
CC2-2.
[1729] LCMS: m/z 519 [M+H].sup.+
[1730] HPLC retention time: 2.99 min (analysis condition Y)
Example 186
[1731] Compound CC4-1
8-Methoxy-6,6-dimethyl-11-oxo-9-(pyrrolidine-1-sulfonyl)-6,11-dihydro-5H-b-
enzo[b]carbazole-3-carbonitrile
##STR00201##
[1733] Under the same conditions as the method for synthesizing
Compound A4, the title compound was prepared from Compound
CC3-1.
[1734] .sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta.: 12.86 (1H, s),
8.60 (1H, s), 8.30 (1H, d, J=8.5 Hz), 8.01 (1H, s), 7.60 (1H, s),
7.59 (1H, d, J=8.5 Hz), 4.09 (3H, s), 3.21-3.42 (4H, m), 1.72-1.90
(10H, m)
[1735] LCMS: m/z 450 [M+H].sup.+
[1736] HPLC retention time: 3.40 min (analysis condition W)
Example 187
[1737] Compound CC4-2
3-Bromo-8-methoxy-6,6-dimethyl-9-(4-methyl-piperazine-1-sulfonyl)-5,6-dihy-
dro-benzo[b]carbazol-11-one
##STR00202##
[1739] Under the same conditions as the method for synthesizing
Compound A4, the title compound was prepared from Compound
CC3-2.
[1740] LCMS: m/z 532, 534 [M+H].sup.+
[1741] HPLC retention time: 2.18 min (analysis condition U)
Example 188
[1742] Compound CC-4-3
8-Methoxy-6,6-dimethyl-9-(4-methyl-piperazine-1-sulfonyl)-11-oxo-6,11-dihy-
dro-5H-benzo[b]carbazole-3-carbonitrile
##STR00203##
[1744] Under the same conditions as the method for synthesizing
Compound A5-2, the title compound was prepared from Compound
CC4-2.
[1745] LCMS: m/z 479 [M+H].sup.+
[1746] HPLC retention time: 1.93 min (analysis condition U)
Example 189
[1747] Compound C1-1
Dimethyl-sulfamic acid
3-cyano-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yl
ester
##STR00204##
[1749]
8-Hydroxy-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-c-
arbonitrile (Compound A6, 50 mg, 0.165 mmol) was dissolved in DMF
(1.5 mL), added with sodium hydride (13 mg, 2.0 eq.) and
dimethylsulfamoyl chloride (0.02 mL, 1.2 eq.), and then stirred at
room temperature for 1 hr. Water was added to the reaction
solution, which was then extracted with ethyl acetate. The organic
layer was washed with saturated brine and dried over sodium
sulfate. The drying agent was removed by filtration and the
residues were concentrated under reduced pressure to obtain the
target compound (yellowish white powder, 62 mg, 92%).
[1750] .sup.1H-NMR (270 MHz, DMSO-d.sub.6) .delta.: 12.87 (1H, s),
8.40-8.30 (2H, m), 8.05 (1H, s), 7.82 (1H, d, J=1.8 Hz), 7.64 (1H,
d, J=7.9 Hz), 7.50 (1H, dd, J=8.5, 2.4 Hz), 2.96 (6H, s), 1.81 (6H,
s)
[1751] LCMS: m/z 410 [M+H].sup.+
[1752] HPLC retention time: 2.38 min (analysis condition S)
Example 190
[1753] Compound C1-2
Morpholine-4-sulfonic acid
3-cyano-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yl
ester
##STR00205##
[1755] According to the same method as the method for synthesizing
Compound A8-17, the title compound was prepared as a crude product
from Compound A6 and Compound A8-18-0.
Example 191
[1756] Compound C1-4
4-Methyl-piperazine-1-sulfonic acid
3-cyano-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yl
ester
##STR00206##
[1758] According to the same method as the method for synthesizing
Compound A8-17, the title compound was prepared as a crude product
from Compound A6 and Compound A8-19-0.
Example 192
[1759] Compound C2-1
3-Cyano-8-hydroxy-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-9--
sulfonic acid dimethylamide
##STR00207##
[1761] To dimethyl-sulfamic acid
3-cyano-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yl
ester (Compound C1-1, 250 mg, 0.610 mmol), aluminum chloride (1.0
M, nitromethane solution (1.8 mL, 3.0 eq.)) was added and the
mixture was stirred at 160.degree. C. for 10 min under irradiation
with microwave. Water was added to the reaction solution, which was
then extracted with dichloromethane. The organic layer was washed
with saturated brine and dried over sodium sulfate. The drying
agent was removed by filtration and the residues obtained after
concentration under reduced pressure were purified by silica gel
column chromatography (dichloromethane/methanol) to obtain the
target compound (yellowish white powder, 99 mg, 40%).
[1762] .sup.1H-NMR (270 MHz, DMSO-d.sub.6) .delta.: 12.78 (1H, s),
11.72 (1H, s), 8.50 (1H, s), 8.32 (1H, d, J=8.5 Hz), 8.02 (1H, s),
7.62 (1H, d, J=7.9 Hz), 7.25 (1H, s), 2.80 (6H, s), 1.75 (6H,
s).
[1763] LCMS: m/z 410 [M+H].sup.+
[1764] HPLC retention time: 2.00 min (analysis condition S)
[1765] Compound C2-2
8-Hydroxy-6,6-dimethyl-11-oxo-9-(pyrrolidine-1-sulfonyl)-6,11-dihydro-5H-b-
enzo[b]carbazole-3-carbonitrile
##STR00208##
[1767] Under the same conditions as the method for synthesizing
Compound E3-2, the title compound was prepared from Compound
CC4-1.
[1768] LCMS: m/z 436 [M+H].sup.+
[1769] HPLC retention time: 3.32 min (analysis condition W)
Example 194
[1770] Compound C2-3
8-Hydroxy-6,6-dimethyl-9-(morpholine-4-sulfonyl)-11-oxo-6,11-dihydro-5H-be-
nzo[b]carbazole-3-carbonitrile
##STR00209##
[1772] Under the same conditions as the method for synthesizing
Compound C2-1, the title compound was prepared from Compound
C1-2.
[1773] LCMS: m/z 452 [M+H].sup.+
[1774] HPLC retention time: 1.89 min (analysis condition S)
Example 195
[1775] Compound C2-4
8-Hydroxy-6,6-dimethyl-9-(4-methyl-piperazine-1-sulfonyl)-11-oxo-6,11-dihy-
dro-5H-benzo[b]carbazole-3-carbonitrile
##STR00210##
[1777] Under the same conditions as the method for synthesizing
Compound E3-2, the title compound was prepared from Compound
CC4-3.
[1778] LCMS: m/z 465 [M+H].sup.+
[1779] HPLC retention time: 1.87 min (analysis condition U)
Example 196
[1780] Compound C3-1
Trifluoro-methanesulfonic acid
3-cyano-9-dimethylsulfamoyl-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]c-
arbazol-8-yl ester
##STR00211##
[1782] Under the same conditions as the method for synthesizing
Compound B1, the title compound was prepared from Compound
C2-1.
[1783] .sup.1H-NMR (270 MHz, DMSO-d.sub.6) .delta.: 13.05 (1H, s),
8.67 (1H, s), 8.32 (1H, d, J=8.2 Hz), 8.06 (2H, m), 7.67 (1H, dd,
J=7.9, 1.3 Hz), 2.79 (6H, s), 1.84 (6H, s).
[1784] LCMS: m/z 542 [M+H].sup.+
[1785] HPLC retention time: 2.67 min (analysis condition S)
Example 197
[1786] Compound C3-2
Trifluoro-methanesulfonic acid
3-cyano-6,6-dimethyl-11-oxo-9-(pyrrolidine-1-sulfonyl)-6,11-dihydro-5H-be-
nzo[b]carbazol-8-yl ester
##STR00212##
[1788] Under the same conditions as the method for synthesizing
Compound B1, the title compound was prepared from Compound
C2-2.
[1789] LCMS: m/z 568 [M+H].sup.+
[1790] HPLC retention time: 4.00 min (analysis condition W)
Example 198
[1791] Compound C4-1
3-Cyano-8-(2-methoxy-ethoxy)-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]c-
arbazole-9-sulfonic acid dimethylamide
##STR00213##
[1793] Under the same conditions as the method for synthesizing
Compound A7-17, the title compound was prepared from Compound C2-1
and 1-bromo-2-methoxy-ethane.
[1794] .sup.1H-NMR (300 MHz, DMSO-d.sub.6) .sigma.ppm; 12.8 (s,
1H), 8.58 (s, 1H), 8.31 (d, 1H, J=8.4 Hz), 8.03 (s, 1H), 7.62 (m,
2H), 4.47 (m, 2H), 3.75 (m, 2H), 3.32 (s, 3H), 2.27 (s, 6H), 1.83
(s, 6H)
[1795] LCMS: m/z 468 [M+H].sup.+
[1796] HPLC retention time: 2.68 min (analysis condition U)
Example 199
[1797] Compound C4-2
3-Cyano-8-(2-diethylamino-ethoxy)-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benz-
o[b]carbazole-9-sulfonic acid dimethylamide
##STR00214##
[1799] Under the same conditions as the method for synthesizing
Compound A7-17, the title compound was prepared from Compound
C2-1.
[1800] .sup.1H-NMR (270 MHz, DMSO-d.sub.6) .delta.: 8.57 (1H, s),
8.29 (1H, d, J=8.4 Hz), 8.02 (1H, s), 7.70-7.60 (2H, m), 4.37 (2H,
t, J=6.3 Hz), 2.84 (2H, m), 2.80 (6H, s), 2.64-2.53 (4H, m), 1.83
(6H, s), 0.98 (6H, t, J=7.1 Hz).
[1801] LCMS: m/z 509 [M+H].sup.+
[1802] HPLC retention time: 1.55 min (analysis condition S)
Example 200
[1803] Compound C4-3
3-Cyano-8-methoxy-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-9--
sulfonic acid dimethylamide
##STR00215##
[1805] Under the same conditions as the method for synthesizing
Compound A7-17, the title compound was prepared from Compound C2-1
and iodomethane.
[1806] LCMS: m/z 424 [M+H].sup.+
[1807] HPLC retention time: 2.17 min (analysis condition S)
Example 201
[1808] Compound C4-4
3-Cyano-6,6-dimethyl-11-oxo-8-(piperidin-4-yl
oxy)-6,11-dihydro-5H-benzo[b]carbazole-9-sulfonic acid
dimethylamide
##STR00216##
[1810] Under the same conditions as the method for synthesizing
Compound A7-1 and Compound A8-1, the title compound was prepared
from Compound C2-1 and 4-hydroxy-piperidine-1-carboxylic acid
tert-butyl ester.
[1811] LCMS: m/z 493 [M+H].sup.+
[1812] HPLC retention time: 1.49 min (analysis condition S)
Example 202
[1813] Compound C4-5
3-Cyano-6,6-dimethyl-8-(2-morpholin-4-yl-ethoxy)-11-oxo-6,11-dihydro-5H-be-
nzo[b]carbazole-9-sulfonic acid dimethylamide
##STR00217##
[1815] Under the same conditions as the method for synthesizing
Compound A7-1, the title compound was prepared from Compound C2-1
and 2-morpholin-4-yl-ethanol.
[1816] LCMS: m/z 523 [M+H].sup.+
[1817] HPLC retention time: 1.64 min (analysis condition S)
Example 203
[1818] Compound C4-6
3-Cyano-8-[2-(1,1-dioxo-thiomorpholin-4-yl)-ethoxy]-6,6-dimethyl-11-oxo-6,-
11-dihydro-5H-benzo[b]carbazole-9-sulfonic acid dimethylamide
##STR00218##
[1820] Under the same conditions as the method for synthesizing
Compound A7-1, the title compound was prepared from Compound C2-1
and 2-(1,1-dioxothiomorpholino)ethanol.
[1821] LCMS: m/z 571 [M+H].sup.+
[1822] HPLC retention time: 1.75 min (analysis condition S)
Example 204
[1823] Compound C4-7
3-Cyano-8-(1-ethyl-piperidin-4-yl
oxy)-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-9-sulfonic
acid dimethylamide
##STR00219##
[1825] Under the same conditions as the method for synthesizing
Compound A7-1, the title compound was prepared from Compound C2-1
and 1-ethyl-piperidin-4-ol.
[1826] LCMS: m/z 521 [M+H].sup.+
[1827] HPLC retention time: 1.52 min (analysis condition S)
Example 205
[1828] Compound C4-8
3-Cyano-8-(4-isopropyl-piperazin-1-yl)-6,6-dimethyl-11-oxo-6,11-dihydro-5H-
-benzo[b]carbazole-9-sulfonic acid dimethylamide
##STR00220##
[1830] Under the same conditions as the method for synthesizing
Compound B2-1, the title compound was prepared from Compound
C3-1.
[1831] .sup.1H-NMR (270 MHz, DMSO-d.sub.6) .delta.: 8.61 (1H, s),
8.30 (1H, d, J=8.1 Hz), 8. 04 (1H, s), 7.87 (1H, s), 7.62 (1H, dd,
J=8.2, 1.8 Hz), 3.17-3.06 (2H, m), 2.75-2.70 (6H, s), 2.67-2.58
(2H, m), 1.81 (6H, s), 1.02 (6H, d, J=6.4 Hz).
[1832] LCMS: m/z 520 [M+H].sup.+
[1833] HPLC retention time: 1.52 min (analysis condition S)
Example 206
[1834] Compound C4-9
3-Cyano-8-[4-(2-hydroxy-ethyl)-piperazin-1-yl]-6,6-dimethyl-11-oxo-6,11-di-
hydro-5H-benzo[b]carbazole-9-sulfonic acid dimethylamide
##STR00221##
[1836] Under the same conditions as the method for synthesizing
Compound B2-1, the title compound was prepared from Compound C3-1
and 2-piperazin-1-yl-ethanol.
[1837] LCMS: m/z 522 [M+H].sup.+
[1838] HPLC retention time: 1.40 min (analysis condition S)
Example 207
[1839] Compound C4-10
3-Cyano-6,6-dimethyl-8-morpholin-4-yl-11-oxo-6,11-dihydro-5H-benzo[b]carba-
zole-9-sulfonic acid dimethylamide
##STR00222##
[1841] Under the same conditions as the method for synthesizing
Compound B2-1, the title compound was prepared from Compound C3-1
and morpholine.
[1842] LCMS: m/z 479 [M+H].sup.+
[1843] HPLC retention time: 2.22 min (analysis condition S)
Example 208
[1844] Compound C4-11
4-(3-Cyano-9-dimethylsulfamoyl-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b-
]carbazol-8-yl)-piperazine-1-carboxylic acid tert-butyl ester
##STR00223##
[1846] Under the same conditions as the method for synthesizing
Compound B2-1, the title compound was prepared from Compound C3-1
and piperazine-1-carboxylic acid tert-butyl ester.
[1847] LCMS: m/z 578 [M+H].sup.+
[1848] HPLC retention time: 2.72 min (analysis condition S)
Example 209
[1849] Compound C4-12
3-Cyano-6,6-dimethyl-11-oxo-8-piperazin-1-yl-6,11-dihydro-5H-benzo[b]carba-
zole-9-sulfonic acid dimethylamide
##STR00224##
[1851] Under the same conditions as the method for synthesizing
Compound A8-1, the title compound was prepared from C.sub.4-11.
[1852] .sup.1H-NMR (270 MHz, CD.sub.3OD) .delta.: 8.78 (1H, s),
8.39 (1H, dd, J=8.2, 0.7 Hz), 7.88 (1H, m), 7.75 (1.1H, s), 7.55
(1H, dd, J=8.2, 1.5 Hz), 3.15 (4H, m), 3.04 (4H, m), 2.82 (s, 6H),
1.85 (6H, s)
[1853] LCMS: m/z 478 [M+H].sup.+
[1854] HPLC retention time: 1.43 min (analysis condition S)
Example 210
[1855] Compound C4-13
6,6-Dimethyl-11-oxo-9-(pyrrolidine-1-sulfonyl)-8-(4-pyrrolidin-1-yl-piperi-
din-1-yl)-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile
##STR00225##
[1857] Under the same conditions as the method for synthesizing
Compound B2-1, the title compound was prepared from Compound C3-2
and 4-(1-pyrrolidyl)-piperidine.
[1858] .sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta.: 12.83 (1H, s),
8.64 (1H, s), 8.32 (1H, d, 8.2 Hz), 8.03 (1H, s), 7.80 (1H, s),
7.63 (1H, d, 8.2 Hz), 2.87-2.94 (4H, m), 1.94-1.99 (4H, m), 1.80
(6H, s), 1.58-1.76 (10H, m)
[1859] LCMS: m/z 572 [M+H].sup.+
[1860] HPLC retention time: 2.81 min (analysis condition W)
Example 211
[1861] Compound C4-14
8-(2-Diethylamino-ethoxy)-6,6-dimethyl-9-(morpholine-4-sulfonyl)-11-oxo-6,-
11-dihydro-5H-benzo[b]carbazole-3-carbonitrile
##STR00226##
[1863] Under the same conditions as the method for synthesizing
Compound A7-17, the title compound was prepared from Compound
C2-3.
[1864] LCMS: m/z 551 [M+H].sup.+
[1865] HPLC retention time: 1.46 min (analysis condition S)
[1866] Compound C4-15
6,6-Dimethyl-9-(morpholine-4-sulfonyl)-11-oxo-8-(tetrahydro-pyran-4-yloxy)-
-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile
##STR00227##
[1868] Under the same conditions as the method for synthesizing
Compound A7-1, the title compound was prepared from Compound C2-3
and tetrahydropyran-4-ol.
[1869] LCMS: m/z 536 [M+H].sup.+
[1870] HPLC retention time: 2.05 min (analysis condition S)
Example 213
[1871] Compound C4-16
6,6-Dimethyl-9-(4-methyl-piperazine-1-sulfonyl)-11-oxo-8-(tetrahydro-pyran-
-4-yl oxy)-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile
##STR00228##
[1873] Under the same conditions as the method for synthesizing
Compound A7-1, the title compound was prepared from Compound C2-4
and tetrahydropyran-4-ol.
[1874] LCMS: m/z 549 [M+H].sup.+
[1875] HPLC retention time: 2.03 min (analysis condition U)
Example 214
[1876] Compound C4-17
8-(2-Diethylamino-ethoxy)-6,6-dimethyl-9-(4-methyl-piperazine-1-sulfonyl)--
11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile
##STR00229##
[1878] Under the same conditions as the method for synthesizing
Compound A7-1, the target compound was prepared from Compound
C2-3.
[1879] LCMS: m/z 564 [M+H].sup.+
[1880] HPLC retention time: 1.20 min (analysis condition S)
Example 215
[1881] Compound C5
3-Cyano-8-methoxy-5,6,6-trimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-
-9-sulfonic acid dimethylamide
##STR00230##
[1883] The title compound was obtained as a by-product of the
synthesis of Compound C.sub.4-3.
[1884] LCMS: m/z 438 [M+H].sup.+
[1885] HPLC retention time: 2.29 min (analysis condition S)
Example 216
[1886] Compound D0-1-1
7-Methoxy-1,1-dimethyl-6-nitro-3,4-dihydro-1H-naphthalen-2-one
##STR00231##
[1888] Tetrabutylammonium nitrate (2.47 g, 1.07 eq.) was dissolved
in dichloromethane, and added with trifluoromethanesulfonic
anhydride (1.33 ml, 1.07 eq.) at 0.degree. C. The mixture was
stirred for 1 hr, added with DCM solution of
7-methoxy-1,1-dimethyl-3,4-dihydro-1H-naphthalen-2-one (Compound
A2, 1.55 g, 7.59 mmol), and then stirred at 0.degree. C. for 2 hr
and 30 min. The reaction solution was added to saturated aqueous
solution of sodium hydrogen carbonate and then extracted with ethyl
acetate. The organic layer was washed with brine and dried over
sodium sulfate. The drying agent was removed by filtration and the
residues obtained after concentration under reduced pressure were
purified by silica gel column chromatography (ethyl acetate/hexane)
to obtain the title compound (pale yellow solid, 1.144 g, 60%).
[1889] .sup.1H-NMR (270 MHz, DMSO-d.sub.6) .delta.: 7.79 (1H, s),
7.28 (1H, s), 3.95 (3H, s), 3.06 (2H, t, J=6.9 Hz), 2.64 (2H, t,
J=6.9 Hz), 1.41 (6H, s).
[1890] HPLC retention time: 2.03 min (analysis condition S)
Example 217
[1891] Compound D0-1-2
7-Methoxy-1,1-dimethyl-8-nitro-3,4-dihydro-1H-naphthalen-2-one
##STR00232##
[1893] The title compound was obtained as a by-product of the
synthesis of Compound D0-1-1.
[1894] .sup.1H-NMR (270 MHz, DMSO-d.sub.6) .delta.: 7.44 (1H, d,
J=8.6 Hz), 7.23 (1H, d, J=8.6 Hz), 3.84 (3H, s), 3.07 (2H, t, J=6.9
Hz), 2.65 (2H, t, J=6.9 Hz), 1.35 (6H, s)
[1895] HPLC retention time: 2.15 min (analysis condition S)
Example 218
[1896] Compound D0-2-1
3-Bromo-8-methoxy-6,6-dimethyl-9-nitro-6,11-dihydro-5H-benzo[b]carbazole
##STR00233##
[1898] Under the same conditions as the method for synthesizing
Compound A3-1, the title compound was prepared from Compound
D0-1-1.
[1899] LCMS: m/z 401, 403 [M+H].sup.+
[1900] HPLC retention time: 3.07 min (analysis condition S)
Example 219
[1901] Compound D0-2-2
3-Bromo-8-methoxy-6,6-dimethyl-7-nitro-6,11-dihydro-5H-benzo[b]carbazole
##STR00234##
[1903] Under the same conditions as the method for synthesizing
Compound A3-1, the title compound was prepared from Compound
D0-1-2.
[1904] LCMS: m/z 401, 403 [M+H].sup.+
[1905] HPLC retention time: 3.10 min (analysis condition S)
Example 220
[1906] Compound D0-3-1
3-Bromo-8-methoxy-6,6-dimethyl-9-nitro-5,6-dihydro-benzo[b]carbazol-11-one
##STR00235##
[1908] Under the same conditions as the method for synthesizing
Compound A4, the title compound was prepared from Compound
D0-2-1.
[1909] LCMS: m/z 415, 417 [M+H].sup.+
[1910] HPLC retention time: 3.07 min (analysis condition S)
Example 221
[1911] Compound D0-3-2
3-Bromo-8-methoxy-6,6-dimethyl-7-nitro-5,6-dihydro-benzo[b]carbazol-11-one
##STR00236##
[1913] Under the same conditions as the method for synthesizing
Compound A4, the title compound was prepared from Compound
D0-2-2.
[1914] LCMS: m/z 415, 417 [M+H].sup.+
[1915] HPLC retention time: 2.72 min (analysis condition S)
Example 222
[1916] Compound D0-4-1
8-Methoxy-6,6-dimethyl-9-nitro-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3--
carbonitrile
##STR00237##
[1918] Under the same conditions as the method for synthesizing
Compound A5-2, the title compound was prepared from Compound
D0-3-1.
[1919] LCMS: m/z 362 [M+H].sup.+
[1920] HPLC retention time: 2.35 min (analysis condition S)
Example 223
[1921] Compound D0-4-2
8-Methoxy-6,6-dimethyl-7-nitro-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3--
carbonitrile
##STR00238##
[1923] Under the same conditions as the method for synthesizing
Compound A5-2, the title compound was prepared from Compound
D0-3-2.
[1924] LCMS: m/z 362 [M+H].sup.+
[1925] HPLC retention time: 2.35 min (analysis condition S)
Example 224
[1926] Compound D0-5-1
8-Hydroxy-6,6-dimethyl-9-nitro-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3--
carbonitrile
##STR00239##
[1928] Under the same conditions as the method for synthesizing
Compound A6, the title compound was prepared from Compound
D0-4-1.
[1929] LCMS: m/z 348 [M+H].sup.+
[1930] HPLC retention time: 2.28 min (analysis condition S)
Example 225
[1931] Compound D0-5-2
8-Hydroxy-6,6-dimethyl-7-nitro-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3--
carbonitrile
##STR00240##
[1933] Under the same conditions as the method for synthesizing
Compound A6, the title compound was prepared from Compound
D0-4-2.
[1934] LCMS: m/z 348 [M+H].sup.+
[1935] HPLC retention time: 2.23 min (analysis condition S)
Example 226
[1936] Compound D1
6,6-Dimethyl-8-(1-methyl-piperidin-4-yloxy)-9-nitro-11-oxo-6,11-dihydro-5H-
-benzo[b]carbazole-3-carbonitrile
##STR00241##
[1938] Under the same conditions as the method for synthesizing
Compound A7-1, the title compound was prepared from Compound D0-5-1
and 1-methylpiperidin-4-ol.
[1939] LCMS: m/z 445 [M+H].sup.+
[1940] HPLC retention time: 1.64 min (analysis condition S)
Example 227
[1941] Compound D2
9-Amino-6,6-dimethyl-8-(1-methyl-piperidin-4-yl
oxy)-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile
##STR00242##
[1943] 6,6-Dimethyl-8-(1-methyl-piperidin-4-yl
oxy)-9-nitro-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile
(Compound D1, 83 mg, 0.19 mmol) was dissolved in ethanol, added
with aqueous solution of ammonium acetate and aqueous solution of
titanium (III) chloride, and then the mixture was stirred at room
temperature for 45 min. The reaction solution was added to
saturated aqueous solution of sodium hydrogen carbonate and then
extracted with ethyl acetate. The organic layer was washed with
brine and dried over sodium sulfate. The drying agent was removed
by filtration and the residues were concentrated under reduced
pressure to obtain the title compound (yellow solid, 60 mg,
78%).
[1944] .sup.1H-NMR (270 MHz, DMSO-d.sub.6) .delta.: 12.61 (1H, br.
s), 8.28-8.34 (1H, m), 7.94-8.00 (1H, m), 7.57 (1H, dd, J=8.2, 1.4
Hz), 7.46 (1H, s), 7.19 (1H, s), 4.93 (1.8H, s), 4.65 (1.0H, s),
4.06-4.15 (1H, m), 3.34 (5.7H, s), 3.16-3.18 (2H, m), 2.55-2.67
(2H, m), 2.17-2.33 (5H, m), 1.89-2.07 (2H, m), 1.65-1.81 (8H,
m)
[1945] LCMS: m/z 415 [M+H].sup.+
[1946] HPLC retention time: 1.12 min (analysis condition S)
Example 228
[1947] Compound D3-1
N-[3-Cyano-6,6-dimethyl-8-(1-methyl-piperidin-4-yl
oxy)-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-9-yl]-methanesulfonamide
##STR00243##
[1949] Under the same conditions as the method for synthesizing
Compound A9-1, the title compound was prepared from Compound D2 and
methanesulfonyl chloride.
[1950] LCMS: m/z 493 [M+H].sup.+
[1951] HPLC retention time: 1.43 min (analysis condition S)
Example 229
[1952] Compound D3-2
3-Cyano-6,6-dimethyl-11-oxo-8-(1-methylpiperidin-4-yl
oxy)-6,11-dihydro-5H-benzo[b]carbazole-9-sulfonic acid
dimethylamide
##STR00244##
[1954] Under the same conditions as the method for synthesizing
Compound A9-1, the title compound was prepared from Compound D2 and
dimethylsulfamoyl chloride.
[1955] .sup.1H-NMR (270 MHz, CD.sub.3OD) .delta.: 8.34-8.42 (2. OH,
m), 7.85 (1.0H, s), 7.47-7.58 (1.0H, m), 7.32 (1.0H, s), 4.73-4.89
(1H, m), 2.75-2.91 (8H, m), 2.38-2.52 (2H, m), 2.34 (3H, s),
2.06-2.21 (2H, m), 1.87-2.05 (2H, m), 1.80 (6H, s).
[1956] LCMS: m/z 522 [M+H].sup.+
[1957] HPLC retention time: 1.66 min (analysis condition S)
Example 230
[1958] Compound D3-3
N-[3-Cyano-6,6-dimethyl-8-(1-methyl-piperidin-4-yl
oxy)-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-9-yl]-2-dimethylamino-acetam-
ide
##STR00245##
[1960] Under the same conditions as the method for synthesizing
Compound A9-10, the title compound was prepared from Compound D2
and N,N-dimethylglycine.
[1961] LCMS: m/z 500 [M+H].sup.+
[1962] HPLC retention time: 1.31 min (analysis condition S)
Example 231
[1963] Compound E1
6-Bromo-7-methoxy-1,1-dimethyl-3,4-dihydro-1H-naphthalen-2-one
##STR00246##
[1965] 7-Methoxy-1,1-dimethyl-3,4-dihydro-1H-naphthalen-2-one
(Compound A2, 2.0 g, 9.791 mmol) was dissolved in CH.sub.3CN (40
mL), added with NBS (1.92 g, 1.1 eq.), and the mixture was stirred
at room temperature for 2.5 hr. The reaction solution was added to
water (40 mL), and the precipitated solid was filtered to obtain
the title compound (white powder, 2.55 g, 92%).
[1966] .sup.1H-NMR (270 MHz, CDCl.sub.3) .delta.: 7.36 (1H, s),
6.84 (1H, s), 3.91 (3H, s), 3.02 (2H, t, J=6.8 Hz), 2.66 (2H, t,
J=6.8 Hz), 1.42 (6H, s).
[1967] LCMS: m/z 283, 285 [M+H].sup.+
[1968] HPLC retention time: 2.67 min (analysis condition S)
Example 232
[1969] Compound E2-1
9-Bromo-8-methoxy-6,6-dimethyl-6,11-dihydro-5H-benzo[b]carbazole-3-carboni-
trile
##STR00247##
[1971]
6-Bromo-7-methoxy-1,1-dimethyl-3,4-dihydro-1H-naphthalen-2-one
(Compound E1, 7.89 g, 27.85 mmol) and 3-hydrazino-benzonitrile
(4.45 g, 1.2 eq.) were dissolved in TFA (250 mL), and stirred at
100.degree. C. for 2 hr. TFA was removed under reduced pressure and
the residues were added with saturated aqueous solution of
NaHCO.sub.3 (500 mL), followed by extraction with ethyl acetate.
The organic layer was washed with saturated brine and dried over
sodium sulfate. The drying agent was removed by filtration and the
residues obtained after concentration under reduced pressure were
added with ethyl acetate. After stirring at room temperature, the
precipitated solid was separated by filtration (Compound E2-2). The
filtrate was concentrated under reduced pressure to obtain the
title compound as a mixture with E2-2 (yellowish white powder, 2.65
g).
[1972] LCMS: m/z 381, 383 [M+H].sup.+
[1973] HPLC retention time: 3.03 min (analysis condition S)
Example 233
[1974] Compound E2-2
9-Bromo-8-methoxy-6,6-dimethyl-6,11-dihydro-5H-benzo[b]carbazole-1-carboni-
trile
##STR00248##
[1976] The title compound was obtained as a by-product of the
synthesis of Compound E2-1.
[1977] .sup.1H-NMR (270 MHz, DMSO-d.sub.6) .delta.: 11.70 (1H, s),
7.69 (1H, dd, J=8.1, 0.8 Hz), 7.55 (1H, s), 7.48 (1H, dd, J=7.4,
0.8 Hz), 7.27 (1H, s), 7.22 (1H, dd, J=8.1, 7.4 Hz), 4.23 (2H, s),
3.91 (3H, s), 1.70 (6H, s).
[1978] LCMS: m/z 381, 383 [M+H].sup.+
[1979] HPLC retention time: 2.92 min (analysis condition S)
Example 234
[1980] Compound E2-3, Compound E2-4
3,9-Dibromo-8-methoxy-6,6-dimethyl-6,11-dihydro-5H-benzo[b]carbazole
1,9-Dibromo-8-methoxy-6,6-dimethyl-6,11-dihydro-5H-benzo[b]carbazole
##STR00249##
[1982] Under the same conditions as the method for synthesizing
Compound A4, the title compound was prepared (as a mixture) from
Compound E1.
Example 235
[1983] Compound E3-1-1
9-Bromo-8-methoxy-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3--
carbonitrile
##STR00250##
[1985] Under the same conditions as the method for synthesizing
Compound A4, the title compound was prepared from Compound
E2-1.
[1986] .sup.1H-NMR (270 MHz, DMSO-d.sub.6) .delta.: 12.82 (1H, s),
8.30 (2H, s+d), 8.03 (1H, s), 7.61 (1H, dd, J=8.2, 1.4 Hz), 7.49
(1H, s), 4.04 (3H, s), 1.81 (6H, s).
[1987] LCMS: m/z 395, 397 [M+H].sup.+
[1988] HPLC retention time: 2.77 min (analysis condition S)
Example 236
[1989] Compound E3-1-2
9-Bromo-8-methoxy-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-1--
carbonitrile
##STR00251##
[1991] The title compound was obtained as a by-product of the
synthesis of Compound E3-1-1.
[1992] .sup.1H-NMR (270 MHz, DMSO-d.sub.6) .delta.: 12.84 (1H, s),
8.31 (1H, s), 7.86 (1H, dd, J=8.2, 0.9 Hz), 7.70 (1H, d, J=7.1 Hz),
7.47 (1H, s), 7.43 (1H, t, J=7.8 Hz), 4.04 (3H, s), 1.81 (6H,
s).
[1993] LCMS: m/z 395, 397 [M+H].sup.+
[1994] HPLC retention time: 2.42 min (analysis condition S)
Example 237
[1995] Compound E3-1-3
3,9-Dibromo-8-methoxy-6,6-dimethyl-5,6-dihydro-benzo[b]carbazol-11-one
##STR00252##
[1997] Under the same conditions as the method for synthesizing
Compound A4, the title compound was prepared from Compound E2-3 and
Compound E2-4 (mixture).
[1998] .sup.1H-NMR (270 MHz, DMSO-d.sub.6) .delta.: 12.42 (1H, s),
8.28 (1H, s), 8.09 (1H, d, J=8.2 Hz), 7.68 (1H, d, J=1.6 Hz), 7.47
(1H, s), 7.39 (1H, dd, J=8.3, 1.7 Hz), 4.03 (3H, s), 1.78 (6H,
s).
[1999] LCMS: m/z 448, 450, 452 [M+H].sup.+
[2000] HPLC retention time: 2.93 min (analysis condition S)
[2001] Compound E3-2
9-Bromo-8-hydroxy-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3--
carbonitrile
##STR00253##
[2003]
9-Bromo-8-methoxy-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carba-
zole-3-carbonitrile (Compound E3-1-1, 1.0 g, 2.53 mmol) was
dissolved in NMP (10 mL), added with NaOMe (683 mg, 5 eq.) and
1-dodecanethiol (3.0 mL, 5 eq.), and stirred at 160.degree. C. for
1 hr. The reaction solution was added to 0.5N aqueous solution of
hydrochloric acid, and then extracted with ethyl acetate. The
organic layer was washed with saturated brine and dried over sodium
sulfate. The drying agent was removed by filtration and the
residues obtained after concentration under reduced pressure were
added with MeOH, and the solid remaining after dissolution was
filtered to obtain the title compound (yellow powder, 1.88 g,
65%).
[2004] .sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta.: 12.77 (1H, s),
11.13 (1H, d, J=2.4 Hz), 8.31 (1H, dd, J=7.9, 2.4 Hz), 8.25 (1H, d,
J=3.0 Hz), 8.01 (1H, s), 7.61 (1H, d, J=7.9 Hz), 7.28 (1H, d, J=2.4
Hz), 1.74 (6H, s).
[2005] LCMS: m/z 381, 383 [M+H].sup.+
[2006] HPLC retention time: 2.40 min (analysis condition S)
Example 239
[2007] Compound E3-3
9-Bromo-8-isopropoxy-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-
-3-carbonitrile
##STR00254##
[2009] Under the same conditions as the method for synthesizing
Compound A7-17, the title compound was prepared from Compound E3-2
and 2-bromopropane.
[2010] .sup.1H-NMR (270 MHz, DMSO-d.sub.6) .delta.: 12.77 (1H, s),
8.29 (2H, s+d), 8.01 (1H, s), 7.60 (1H, d, J=8.1 Hz), 7.50 (1H, s),
5.03 (1H, m), 1.79 (6H, s), 1.36 (6H, d, J=5.9 Hz).
[2011] LCMS: m/z 423, 425 [M+H].sup.+
[2012] HPLC retention time: 2.98 min (analysis condition S)
Example 240
[2013] Compound E4-1
8-Methoxy-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3,9-dicarb-
onitrile
##STR00255##
[2015] Under the same conditions as the method for synthesizing
Compound A5-2, the title compound was prepared from Compound
E3-1-1.
[2016] .sup.1H-NMR (270 MHz, DMSO-d.sub.6) .delta.: 12.88 (1H, br.
s), 8.43 (1H, s), 8.30 (1H, d, J=8.2 Hz), 8.05 (1H, d, J=0.5 Hz),
7.65-7.62 (2H, m), 4.11 (3H, s), 1.84 (6H, s).
[2017] LCMS: m/z 342 [M+H].sup.+
[2018] HPLC retention time: 2.23 min (analysis condition S)
Example 241
[2019] Compound E4-2-1
9-(3-Hydroxy-3-methyl-but-1-ynyl)-8-methoxy-6,6-dimethyl-11-oxo-6,11-dihyd-
ro-5H-benzo[b]carbazole-3-carbonitrile
##STR00256##
[2021]
9-Bromo-8-methoxy-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carba-
zole-3-carbonitrile (Compound E3-1-1, 50 mg, 0.13 mmol), bis
(acetonitrile)dichloropalladium (II) (1.64 mg, 0.05 eq.), XPhos
(9.05 mg, 0.15 eq.), cesium carbonate (185 mg, 4.5 eq.) and
3-methyl-1-butyn-1-ol (18.6 .mu.l, 1.5 eq.) were dissolved in
acetonitrile and stirred at 85.degree. C. for 2 hr. The reaction
solution was added to water, and then extracted with ethyl acetate.
The organic layer was washed with brine and dried over sodium
sulfate. The drying agent was removed by filtration and the
residues obtained after concentration under reduced pressure were
purified by HPLC to obtain the title compound (brown solid, 21.3
mg, 42%).
[2022] .sup.1H-NMR (270 MHz, DMSO-d.sub.6) .delta.: 8.29 (1H, d,
J=8.1 Hz), 8.11 (1H, s), 8.00 (1H, s), 7.57 (1H, d, J=8.1 Hz), 7.40
(1H, s), 5.50 (1H, s), 3.95 (3H, s), 2.54 (1H, s), 1.79 (6H, s),
1.49 (6H, s).
[2023] LCMS: m/z 399 [M+H].sup.+
[2024] HPLC retention time: 2.10 min (analysis condition S)
Example 242
[2025] Compound E4-2-2
9-Ethynyl-8-methoxy-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole--
3-carbonitrile
##STR00257##
[2027]
9-(3-Hydroxy-3-methyl-but-1-ynyl)-8-methoxy-6,6-dimethyl-11-oxo-6,1-
1-dihydro-5H-benzo[b]carbazole-3-carbonitrile (Compound E4-2-1,
21.3 mg, 0.05 mmol) and sodium hydride (3.2 mg, 1.5 eq.) were
dissolved in THF, and the mixture was stirred overnight at
50.degree. C. Water was added to the reaction solution and the
residues obtained after concentration under reduced pressure were
purified by HPLC to obtain the title compound (brown solid, 9.6 mg,
31%).
[2028] .sup.1H-NMR (270 MHz, DMSO-d.sub.6) .delta.: 8.26 (1H, d,
J=8.2 Hz), 8.16 (1H, s), 7.97 (1H, s), 7.53 (1H, d, J=8.2 Hz), 7.41
(1H, s), 4.32 (1H, s), 4.00 (3H, s), 1.79 (6H, s).
[2029] LCMS: m/z 341 [M+H].sup.+
[2030] HPLC retention time: 2.27 min (analysis condition S)
Example 243
[2031] Compound E4-3
8-Methoxy-6,6-dimethyl-11-oxo-9-vinyl-6,11-dihydro-5H-benzo[b]carbazole-3--
carbonitrile
##STR00258##
[2033]
9-Bromo-8-methoxy-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carba-
zole-3-carbonitrile (Compound E3-1-1, 50 mg, 0.13 mmol), [1,1'-bis
(diphenylphosphino)ferrocene]palladium (II) dichloride
dichloromethane complex (1: 1) (10.3 mg, 0.1 eq.), TEA (53 .mu.l, 3
eq.) and potassium vinyltrifluoroborate (51 mg, 3 eq.) were
dissolved in n-propanol and the mixture was stirred at 60.degree.
C. for 5 days. The reaction solution was added to water and then
extracted with ethyl acetate. The organic layer was washed with
brine and dried over sodium sulfate. The drying agent was removed
by filtration and the residues obtained after concentration under
reduced pressure were purified by silica gel column chromatography
(ethyl acetate/hexane) to obtain the title compound (brown powder,
25 mg, 19%).
[2034] LCMS: m/z 343 [M+H].sup.+
[2035] HPLC retention time: 2.55 min (analysis condition S)
Example 244
[2036] Compound E4-4
9-(2-Diethylamino-ethylsulfanyl)-8-methoxy-6,6-dimethyl-11-oxo-6,11-dihydr-
o-5H-benzo[b]carbazole-3-carbonitrile
##STR00259##
[2038] Under the same conditions as the method for synthesizing
Compound B2-17, the title compound was prepared from Compound
E3-1-1.
[2039] LCMS: m/z 448 [M+H].sup.+
[2040] HPLC retention time: 2.05 min (analysis condition U)
Example 245
[2041] Compound E4-5
9-Isopropylsulfanyl-8-methoxy-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]-
carbazole-3-carbonitrile
##STR00260##
[2043] Under the same conditions as the method for synthesizing
Compound B2-17, the title compound was prepared from Compound
E3-1-1 and sodium salt of propane-2-thiol.
[2044] LCMS: m/z 391 [M+H].sup.+
[2045] HPLC retention time: 2.98 min (analysis condition U)
Example 246
[2046] Compound E4-6
8-Methoxy-6,6-dimethyl-9-(4-methylpiperazin-1-yl)-11-oxo-6,11-dihydro-5H-b-
enzo[b]carbazole-3-carbonitrile
##STR00261##
[2048] Under the same conditions as the method for synthesizing
Compound B2-10, the title compound was prepared from Compound
E3-1-1 and 1-methylpiperazine.
[2049] .sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta.: 8.25 (1H, d,
J=7.8 Hz), 7.93 (1H, s), 7.65 (1H, s), 7.50 (1H, d, J=6.8 Hz), 7.25
(1H, s), 3.93 (3H, s), 3.02 (4H, br), 2.22 (3H, s), 1.73 (6H,
s).
[2050] LCMS: m/z 415 [M+H].sup.+
[2051] HPLC retention time: 1.80 min (analysis condition U)
Example 247
[2052] Compound E4-7-1
4-(3-Cyano-8-methoxy-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol--
9-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl
ester
##STR00262##
[2054] To
9-bromo-8-methoxy-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]ca-
rbazole-3-carbonitrile (Compound E3-1-1, 300 mg, 0.759 mmol),
4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine--
1-carboxylic acid tert-butyl ester (282 mg, 0.911 mmol, 1.2 eq.),
Pd(PPh.sub.3).sub.2Cl.sub.2 (26.6 mg, 0.0379 mmol, 0.05 eq.) and
sodium carbonate (241 mg, 2.28 mmol, 3.0 eq.), DME (5 ml) and water
(1 ml) were added. The mixture was subjected to reduced pressure
under ultrasonication treatment, followed by flushing with nitrogen
gas. This procedure was repeated five times and then degassed. The
mixture was stirred at 80.degree. C. for 80 min under nitrogen
atmosphere. Pd(PPh.sub.3).sub.2Cl.sub.2 (26.6 mg, 0.0379 mmol, 0.05
eq.) was added and the mixture was further stirred at 80.degree. C.
for 20 min. Then, the mixture was cooled to room temperature, and
added with water and ethyl acetate. The insoluble matters were
filtered through Celite. The organic layer was dried over sodium
sulfate. The drying agent was removed by filtration, followed by
concentration under reduced pressure to obtain the title compound
as a crude product (gray powder).
[2055] LCMS: m/z 498 [M+H].sup.+
[2056] HPLC retention time: 2.85 min (analysis condition S)
Example 248
[2057] Compound E4-7-2
8-Methoxy-6,6-dimethyl-11-oxo-9-(1,2,3,6-tetrahydro-pyridin-4-yl)-6,11-dih-
ydro-5H-benzo[b]carbazole-3-carbonitrile
##STR00263##
[2059] Under the same conditions as the method for synthesizing
Compound A8-1, the title compound was prepared from Compound
B4-4-1.
[2060] LCMS: m/z 368 [M+H].sup.+
[2061] HPLC retention time: 1.27 min (analysis condition S)
Example 249
[2062] Compound E4-8-1
4-(3-Cyano-8-methoxy-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol--
9-yl)-piperidine-1-carboxylic acid tert-butyl ester
##STR00264##
[2064] Under the same conditions as the method for synthesizing
Compound B3-13-1, the title compound was prepared from Compound
B4-7-1.
[2065] LCMS: m/z 500 [M+H].sup.+
[2066] HPLC retention time: 4.18 min (analysis condition W)
Example 250
[2067] Compound E4-8-2
8-Methoxy-6,6-dimethyl-11-oxo-9-piperidin-4-yl-6,11-dihydro-5H-benzo[b]car-
bazole-3-carbonitrile
##STR00265##
[2069] Under the same conditions as the method for synthesizing
Compound A8-1, the title compound was prepared from Compound
B4-8-1.
[2070] LCMS: m/z 400 [M+H].sup.+
[2071] HPLC retention time: 1.35 min (analysis condition S)
Example 251
[2072] Compound E4-9-1
4-(3-Cyano-8-isopropoxy-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbaz-
ol-9-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl
ester
##STR00266##
[2074] Under the same conditions as the method for synthesizing
Compound E4-7-1, the title compound was prepared from Compound
E3-3.
[2075] LCMS: m/z 526 [M+H].sup.+
[2076] HPLC retention time: 3.13 min (analysis condition S)
Example 252
[2077] Compound E4-9-2
8-Isopropoxy-6,6-dimethyl-11-oxo-9-(1,2,3,6-tetrahydro-pyridin-4-yl)-6,11--
dihydro-5H-benzo[b]carbazole-3-carbonitrile
##STR00267##
[2079] Under the same conditions as the method for synthesizing
Compound A8-1, the title compound was prepared from Compound
E4-9-1.
[2080] LCMS: m/z 426 [M+H].sup.+
[2081] HPLC retention time: 1.40 min (analysis condition S)
Example 253
[2082] Compound E4-10
9-Cyclopropyl-8-methoxy-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbaz-
ole-3-carbonitrile
##STR00268##
[2084] Under the same conditions as the method for synthesizing
Compound E4-7-1, the title compound was prepared from Compound
E3-1-1 and potassium cyclopropyltrifluoroborate.
[2085] LCMS: m/z 357 [M+H].sup.+
[2086] HPLC retention time: 2.62 min (analysis condition S)
Example 254
[2087] Compound E4-11
3-Cyano-8-methoxy-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-9-c-
arboxylic acid
##STR00269##
[2089] Under the same conditions as the method for synthesizing
Compound B2-28, the title compound was prepared from Compound
E3-1-1.
[2090] LCMS: m/z 361 [M+H].sup.+
[2091] HPLC retention time: 1.68 min (analysis condition S)
Example 255
[2092] Compound E5-1
9-Ethyl-8-methoxy-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3--
carbonitrile
##STR00270##
[2094] The ethyl acetate suspension of
8-methoxy-6,6-dimethyl-11-oxo-9-vinyl-6,11-dihydro-5H-benzo[b]carbazole-3-
-carbonitrile (Compound E4-3, 25 mg, 0.07 mmol) and palladium
carbon (25 mg) were stirred at room temperature for 1 hr under
hydrogen atmosphere. The reaction solution was filtered through
Celite. The filtrate was concentrated under reduced pressure and
the resulting residues were purified by high performance liquid
chromatography to obtain the title compound (white solid, 3.2 mg,
13%).
[2095] LCMS: m/z 345 [M+H].sup.+
[2096] HPLC retention time: 2.62 min (analysis condition S)
Example 256
[2097] Compound E5-2
9-(2-Diethylamino-ethanesulfonyl)-8-methoxy-6,6-dimethyl-11-oxo-6,11-dihyd-
ro-5H-benzo[b]carbazole-3-carbonitrile
##STR00271##
[2099] Under the same conditions as the method for synthesizing
Compound B3-8, the title compound was prepared from Compound
E4-4.
[2100] LCMS: m/z 480 [M+H].sup.+
[2101] HPLC retention time: 1.97 min (analysis condition U)
Example 257
[2102] Compound E5-3
8-Methoxy-6,6-dimethyl-11-oxo-9-(propane-2-sulfonyl)-6,11-dihydro-5H-benzo-
[b]carbazole-3-carbonitrile
##STR00272##
[2104] Under the same conditions as the method for synthesizing
Compound B3-8, the title compound was prepared from Compound
E4-5.
[2105] LCMS: m/z 423 [M+H].sup.+
[2106] HPLC retention time: 2.40 min (analysis condition U)
Example 258
[2107] Compound E5-4
9-(1-Isopropyl-piperidin-4-yl)-8-methoxy-6,6-dimethyl-11-oxo-6,11-dihydro--
5H-benzo[b]carbazole-3-carbonitrile
##STR00273##
[2109] Under the same conditions as the method for synthesizing
Compound B3-32, the title compound was prepared from Compound
E4-8-2 and acetone.
[2110] LCMS: m/z 442 [M+H].sup.+
[2111] HPLC retention time: 1.48 min (analysis condition S)
Example 259
[2112] Compound E5-5
8-Methoxy-6,6-dimethyl-9-(1-oxetan-3-yl-1,2,3,6-tetrahydro-pyridin-4-yl)-1-
1-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile
##STR00274##
[2114] Under the same conditions as the method for synthesizing
Compound B3-32, the title compound was prepared from Compound
E4-7-2 and oxetan-3-one.
[2115] LCMS: m/z 454 [M+H].sup.+
[2116] HPLC retention time: 1.32 min (analysis condition S)
Example 260
[2117] Compound E5-6
8-Isopropoxy-6,6-dimethyl-9-(1-oxetan-3-yl-1,2,3,6-tetrahydro-pyridin-4-yl-
)-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile
##STR00275##
[2119] Under the same conditions as the method for synthesizing
Compound B3-32, the title compound was prepared from Compound
E4-9-2 and oxetan-3-one.
[2120] .sup.1H-NMR (270 MHz, DMSO-d.sub.6) .delta.: 12.71 (1H, s),
8.31 (1H, d, J=8.2 Hz), 7.99 (1H, s), 7.94 (1H, s), 7.58 (1H, d,
J=7.6 Hz), 7.33 (1H, s), 5.84 (1.0H, m), 4.95 (1H, m), 4.56 (4H,
dt, J=17.4, 6.3 Hz), 3.56 (1H, m), 3.01 (2H, br), 1.78 (6H, s),
1.34 (6H, d, J=5.9 Hz).
[2121] LCMS: m/z 482 [M+H].sup.+
[2122] HPLC retention time: 1.43 min (analysis condition S)
Example 261
[2123] Compound E5-7
9-(4-Isopropyl-piperazin-1-carbonyl)-8-methoxy-6,6-dimethyl-11-oxo-6,11-di-
hydro-5H-benzo[b]carbazole-3-carbonitrile
##STR00276##
[2125] Under the same conditions as the method for synthesizing
Compound B3-15, the title compound was prepared from Compound E4-11
and 1-isopropylpiperazine.
[2126] LCMS: m/z 471 [M+H].sup.+
[2127] HPLC retention time: 1.18 min (analysis condition S)
Example 262
[2128] Compound E5-8
8-Methoxy-6,6-dimethyl-9-(morpholine-4-carbonyl)-11-oxo-6,11-dihydro-5H-be-
nzo[b]carbazole-3-carbonitrile
##STR00277##
[2130] Under the same conditions as the method for synthesizing
Compound B3-15, the title compound was prepared from Compound E4-11
and morpholine.
[2131] LCMS: m/z 430 [M+H].sup.+
[2132] HPLC retention time: 1.68 min (analysis condition S)
Example 263
[2133] Compound E6-1
(3-Cyano-8-methoxy-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-9--
yl)-propionic acid methyl ester
##STR00278##
[2135] To the mixture of
9-ethynyl-8-methoxy-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-
-3-carbonitrile (Compound E4-2, 27 mg, 0.079 mmol), palladium (II)
chloride (2.0 mg, 0.14 eq.), copper (II) chloride (25.0 mg, 2.2
eq.), and sodium acetate (14.1 mg, 2.13 eq.), methanol (1.5 mL) was
added, and then the mixture was stirred at room temperature for 2
days under carbon monoxide atmosphere. The mixture was extracted
with water and ethyl acetate and the insoluble matters were
filtered off. The organic layer was washed with brine and dried
over magnesium sulfate. The residues obtained after filtration and
concentration under reduced pressure were washed with
dichloromethane to obtain the title compound (13.9 mg, 44%).
[2136] LCMS: m/z 399 [M+H].sup.+
[2137] HPLC retention time: 2.81 min (analysis condition F)
Example 264
[2138] Compound E6-2
(3-Cyano-8-methoxy-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-9--
yl)-propynoic acid
##STR00279##
[2140]
(3-Cyano-8-methoxy-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carb-
azol-9-yl)-propynoic acid methyl ester (Compound E6-1, 15.2 mg,
0.038 mmol) was dissolved in a mixture solvent of methanol (1.5 mL)
and THF (0.5 mL), added with 2 N aqueous solution of potassium
hydroxide (5 drops), and then stirred at room temperature
overnight. 0.5 N Hydrochloric acid was added to the reaction
solution, which was then extracted with ethyl acetate. The organic
layer was washed with brine and dried over magnesium sulfate. The
solids obtained after filtration and concentration under reduced
pressure were washed with dichloromethane and purified by HPLC to
obtain the title compound (white solid, 9.6 mg, 66%).
[2141] LCMS: m/z 385 [M+H].sup.+
[2142] HPLC retention time: 2.35 min (analysis condition F)
Example 265
[2143] Compound E6-3
9-(3-Hydroxy-3-methyl-butyl)-8-methoxy-6,6-dimethyl-11-oxo-6,11-dihydro-5H-
-benzo[b]carbazole-3-carbonitrile
##STR00280##
[2145]
9-(3-Hydroxy-3-methyl-but-1-ynyl)-8-methoxy-6,6-dimethyl-11-oxo-6,1-
1-dihydro-5H-benzo[b]carbazole-3-carbonitrile (Compound E4-2-1,
21.0 mg, 0.0527 mmol) was dissolved in ethanol (15 mL) and
N,N-dimethylacetamide (2 mL), added with 10% Pd/C (6.7 mg), and
then stirred at room temperature overnight under hydrogen
atmosphere. The reaction solution was filtered and concentrated
under reduced pressure. The resulting residues were diluted with
ethyl acetate, washed with brine, dried over magnesium sulfate,
filtered, and concentrated under reduced pressure. The resulting
solid was washed with dichloromethane to obtain the title compound
(yellow powder, 16.9 mg, 80%).
[2146] LCMS: m/z 403 [M+H].sup.+
[2147] HPLC retention time: 5.39 min (analysis condition H)
Example 266
[2148] Compound F1-1
4-(9-Bromo-3-cyano-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8--
yl oxy)-piperidine-1-carboxylic acid tert-butyl ester
##STR00281##
[2150] According to the same method as the method for synthesizing
Compound A7-17, the title compound was prepared from Compound E3-2
and 4-trifluoromethanesulfonyloxy-piperidine-1-carboxylic acid
tert-butyl ester.
[2151] LCMS: m/z 564, 566 [M+H].sup.+
[2152] HPLC retention time: 3.30 min (analysis condition S)
Example 267
[2153] Compound F1-2
9-Bromo-6,6-dimethyl-11-oxo-8-(piperidin-4-yl
oxy)-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile
##STR00282##
[2155] Under the same conditions as the method for synthesizing
Compound A8-1, the title compound was prepared from Compound
F1-1.
[2156] LCMS: m/z 464, 466 [M+H].sup.+
[2157] HPLC retention time: 1.52 min (analysis condition S)
Example 268
[2158] Compound F1-3
9-Bromo-8-(1-methanesulfonyl-piperidin-4-yloxy)-6,6-dimethyl-11-oxo-6,11-d-
ihydro-5H-benzo[b]carbazole-3-carbonitrile
##STR00283##
[2160] Under the same conditions as the method for synthesizing
Compound A9-1, the title compound was prepared from Compound F1-2
and methanesulfonyl chloride.
[2161] LCMS: m/z 542, 544 [M+H].sup.+
[2162] HPLC retention time: 2.57 min (analysis condition S)
Example 269
[2163] Compound F1-4
9-Bromo-6,6-dimethyl-11-oxo-8-(tetrahydro-pyran-4-yl
oxy)-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile
##STR00284##
[2165] Under the same conditions as the method for synthesizing
Compound A7-1, the title compound was prepared from Compound E3-2
and tetrahydropyran-4-ol.
[2166] LCMS: m/z 465, 467 [M+H].sup.+
[2167] HPLC retention time: 2.70 min (analysis condition S)
Example 270
[2168] Compound F2
Trifluoro-methanesulfonic acid
9-bromo-3-cyano-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yl
ester
##STR00285##
[2170] Under the same conditions as the method for synthesizing
Compound B1, the title compound was prepared from Compound
E3-2.
[2171] .sup.1H-NMR (270 MHz, DMSO-d.sub.6) .delta.: 12.99 (1H, s),
8.51 (1H, s), 8.31 (1H, dd, J=8.2, 0.7 Hz), 8.17 (1H, s), 8.07 (1H,
s), 7.67 (1H, dd, J=8.2, 1.4 Hz), 1.81 (6H, s).
[2172] LCMS: m/z 513, 515 [M+H].sup.+
[2173] HPLC retention time: 3.13 min (analysis condition S)
Example 271
[2174] Compound F3-1
9-Bromo-6,6-dimethyl-8-(1-oxetan-3-yl-piperidin-4-yl
oxy)-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile
##STR00286##
[2176] Under the same conditions as the method for synthesizing
Compound B3-32, the title compound was prepared from Compound F1-2
and oxetan-3-one.
[2177] .sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta.: 8.29 (1H, d, 8
Hz), 8.29 (1H, s), 8.01 (1H, s), 7.60 (1H, d, 8 Hz), 7.55 (1H, s),
5.00-4.95 (1H, m), 4.55 (2H, dd, 8, 8 Hz), 4.44 (2H, dd, 8, 8 Hz),
2.52-2.46 (1H, m), 2.33-2.29 (2H, m), 1.96-1.94 (2H, m), 1.79 (8H,
br. s)
[2178] LCMS: m/z 519, 521 [M+H].sup.+
[2179] HPLC retention time: 2.78 min (analysis condition W)
Example 272
[2180] Compound F3-2
9-Bromo-6,6-dimethyl-11-oxo-8-(4-pyrrolidin-1-yl-piperidin-1-yl)-6,11-dihy-
dro-5H-benzo[b]carbazole-3-carbonitrile
##STR00287##
[2182] Under the same conditions as the method for synthesizing
Compound B2-1, the title compound was prepared from Compound F2 and
4-pyrrolidin-1-yl-piperidine.
[2183] LCMS: m/z 517, 519 [M+H].sup.+
[2184] HPLC retention time: 1.70 min (analysis condition S)
Example 273
[2185] Compound F3-3
9-Bromo-8-(4-methanesulfonyl-piperazin-1-yl)-6,6-dimethyl-11-oxo-6,11-dihy-
dro-5H-benzo[b]carbazole-3-carbonitrile
##STR00288##
[2187] Under the same conditions as the method for synthesizing
Compound B2-1, the title compound was prepared from Compound F2 and
1-methanesulfonylpiperazine.
[2188] LCMS: m/z 527, 529 [M+H].sup.+
[2189] HPLC retention time: 2.48 min (analysis condition S)
Example 274
[2190] Compound F3-4
9-Bromo-6,6-dimethyl-8-morpholin-4-yl-11-oxo-6,11-dihydro-5H-benzo[b]carba-
zole-3-carbonitrile
##STR00289##
[2192] Under the same conditions as the method for synthesizing
Compound B2-1, the title compound was prepared from Compound F2 and
morpholine.
[2193] LCMS: m/z 450, 452 [M+H].sup.+
[2194] HPLC retention time: 2.65 min (analysis condition S)
Example 275
[2195] Compound F3-5
9-Bromo-8-[4-(2-hydroxy-ethyl)-piperazin-1-yl]-6,6-dimethyl-11-oxo-6,11-di-
hydro-5H-benzo[b]carbazole-3-carbonitrile
##STR00290##
[2197] Under the same conditions as the method for synthesizing
Compound B2-1, the title compound was prepared from Compound F2 and
2-piperazin-1-yl ethanol.
[2198] .sup.1H-NMR (270 MHz, DMSO-d.sub.6) .delta.: 8.26 (2.0H,
s+d), 7.97 (1H, s), 7.54 (1H, d, J=8.7 Hz), 7.43 (1H, s), 4.45 (1H,
t, J=5.4 Hz), 3.55 (2H, q, J=5.8 Hz), 3.17 (4H, br), 2.66 (2H, br),
1.76 (6H, s).
[2199] LCMS: m/z 493, 495 [M+H].sup.+
[2200] HPLC retention time: 1.43 min (analysis condition S)
Example 276
[2201] Compound F3-6-1
[1-(9-Bromo-3-cyano-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-
-yl)-piperidin-4-yl]-carbamic acid tert-butyl ester
##STR00291##
[2203] Under the same conditions as the method for synthesizing
Compound B2-1, the title compound was prepared from Compound F2 and
piperidin-4-yl-carbamic acid tert-butyl ester.
[2204] LCMS: m/z 563, 565 [M+H].sup.+
[2205] HPLC retention time: 3.05 min (analysis condition S)
Example 277
[2206] Compound F3-6-2
8-(4-Amino-piperidin-1-yl)-9-bromo-6,6-dimethyl-11-oxo-6,11-dihydro-5H-ben-
zo[b]carbazole-3-carbonitrile
##STR00292##
[2208] Under the same conditions as the method for synthesizing
Compound A8-1, the title compound was prepared from Compound
F3-6-1.
[2209] LCMS: m/z 463, 465 [M+H].sup.+
[2210] HPLC retention time: 1.47 min (analysis condition S)
[2211] Compound F3-7
9-Bromo-8-(4-hydroxy-piperidin-1-yl)-6,6-dimethyl-11-oxo-6,11-dihydro-5H-b-
enzo[b]carbazole-3-carbonitrile
##STR00293##
[2213] Under the same conditions as the method for synthesizing
Compound B2-1, the title compound was prepared from Compound F2 and
piperidin-4-ol.
[2214] LCMS: m/z 464, 466 [M+H].sup.+
[2215] HPLC retention time: 2.25 min (analysis condition S)
Example 279
[2216] Compound F3-8
9-Bromo-8-(4-isopropyl-piperazin-1-yl)-6,6-dimethyl-11-oxo-6,11-dihydro-5H-
-benzo[b]carbazole-3-carbonitrile
##STR00294##
[2218] Under the same conditions as the method for synthesizing
Compound B2-1, the title compound was prepared from Compound F2 and
1-isopropylpiperazine.
[2219] LCMS: m/z 491, 493 [M+H].sup.+
[2220] HPLC retention time: 1.58 min (analysis condition S)
Example 280
[2221] Compound F3-9
9-Bromo-6,6-dimethyl-11-oxo-8-piperazin-1-yl-6,11-dihydro-5H-benzo[b]carba-
zole-3-carbonitrile
##STR00295##
[2223] Under the same conditions as the method for synthesizing
Compound B2-1, the title compound was prepared from Compound F2 and
piperazine.
[2224] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 8.30-8.24 (2H, m), 8.00
(1H, s), 7.63-7.58 (1H, m), 7.37 (1H, s), 3.10-3.01 (4H, m),
2.91-2.85 (4H, m), 1.76 (6H, s)
[2225] LCMS: m/z 449, 451 [M+H].sup.+
[2226] HPLC retention time: 1.45 min (analysis condition S)
Example 281
[2227] Compound F3-10
4-(9-Bromo-3-cyano-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8--
yl)-piperazine-1-carboxylic acid tert-butyl ester
##STR00296##
[2229] Under the same conditions as the method for synthesizing
Compound B2-1, the title compound was prepared from Compound F2 and
piperazine-1-carboxylic acid tert-butyl ester.
[2230] LCMS: m/z 549, 551 [M+H].sup.+
[2231] HPLC retention time: 4.61 min (analysis condition W)
Example 282
[2232] Compound F3-11
9-Bromo-6,6-dimethyl-8-(4-morpholin-4-yl-piperidin-1-yl)-11-oxo-6,11-dihyd-
ro-5H-benzo[b]carbazole-3-carbonitrile
##STR00297##
[2234] Under the same conditions as the method for synthesizing
Compound B2-1, the title compound was prepared from Compound F2 and
4-piperidin-4-yl morpholine.
[2235] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 8.30-8.24 (2H, m), 8.00
(1H, s), 7.59 (1H, d, J=8.2 Hz), 7.42 (1H, s), 3.66-3.45 (6H, m),
2.80 (2H, t, J=11.1 Hz), 2.38-2.28 (1H, m), 1.96-1.87 (2H, m), 1.75
(6H, s), 1.66-1.56 (2H, m)
[2236] LCMS: m/z 533, 535 [M+H].sup.+
[2237] HPLC retention time: 1.53 min (analysis condition S)
Example 283
[2238] Compound F4-1-1
9-Ethynyl-6,6-dimethyl-8-(1-oxetan-3-yl-piperidin-4-yl
oxy)-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile
##STR00298##
[2240] Under the same conditions as the method for synthesizing
Compound F5-43, the title compound was prepared from Compound
F3-1.
[2241] .sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta.: 8.30 (1H, d, 8
Hz), 8.17 (1H, s), 8.01 (1H, s), 7.60 (1H, d, 8 Hz), 7.50 (1H, s),
4.87-4.83 (1H, m), 4.55 (2H, dd, 4, 4 Hz), 4.45 (2H, dd, 4, 4 Hz),
3.44 (1H, ddd, 4, 4, 4 Hz), 2.33-2.24 (2H, m), 1.99-1.91 (2H, m),
1.78 (8H, br. s)
[2242] LCMS: m/z 466 [M+H].sup.+
[2243] HPLC retention time: 2.67 min (analysis condition W)
Example 284
[2244] Compound F4-1-2
9-Ethyl-6,6-dimethyl-8-(1-oxetan-3-yl-piperidin-4-yl
oxy)-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile
##STR00299##
[2246] Under the same conditions as the method for synthesizing
Compound B3-13-1, the title compound was prepared from Compound
F4-1-1.
[2247] LCMS: m/z 470 [M+H].sup.+
[2248] HPLC retention time: 2.74 min (analysis condition W)
Example 285
[2249] Compound F4-2
N-[1-(9-Bromo-3-cyano-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-
-8-yl)-piperidin-4-yl]-methanesulfonamide
##STR00300##
[2251] Under the same conditions as the method for synthesizing
Compound A9-1, the title compound was prepared from Compound F3-6-2
and methanesulfonyl chloride.
[2252] LCMS: m/z 541, 543 [M+H].sup.+
[2253] HPLC retention time: 2.37 min (analysis condition S)
Example 286
[2254] Compound F4-3
9-Bromo-6,6-dimethyl-8-(4-oxetan-3-yl-piperazin-1-yl)-11-oxo-6,11-dihydro--
5H-benzo[b]carbazole-3-carbonitrile
##STR00301##
[2256] Under the same conditions as the method for synthesizing
Compound B3-32, the title compound was prepared from Compound F3-9
and 1-oxetan-3-one.
[2257] .sup.1H-NMR (270 MHz, DMSO-d.sub.6) .delta.: 12.83 (1H, br.
s), 8.31-8.32 (1H, m), 8.27-8.29 (1H, m), 8.01-8.04 (1H, m),
7.59-7.64 (1H, m), 7.48 (1H, s), 4.59 (2H, dd, J=6.3, 6.3 Hz), 4.48
(2H, dd, J=6.3, 6.3 Hz), 3.52 (1H, t, J=6.3 Hz), 3.12-3.25 (4H, m),
2.44-2.54 (4H, m), 1.78 (6H, s).
[2258] LCMS: m/z 505, 507 [M+H].sup.+
[2259] HPLC retention time: 1.45 min (analysis condition S)
[2260] Hydrochloric Acid Salt of Compound F4-3
[2261]
9-Bromo-6,6-dimethyl-8-(4-oxetan-3-yl-piperazin-1-yl)-11-oxo-6,11-d-
ihydro-5H-benzo[b]carbazole-3-carbonitrile was added with DMSO and
6 N hydrochloric acid (1.05 eq.) and dissolved therein. After
freeze-drying, crystallization was performed by using ethanol
comprising 25% water to obtain monohydrochloric acid salt of
9-bromo-6,6-dimethyl-8-(4-oxetan-3-yl-piperazin-1-yl)-11-oxo-6,11-dihydro-
-5H-benzo[b]carbazole-3-carbonitrile.
[2262] .sup.1H-NMR (270 MHz, DMSO-d.sub.6) .delta.: 12.91 (1H,
br.s), 11.70 (1H, br. s), 8.32-8.29 (2H, m), 8.04 (1H, s),
7.64-7.62 (1H, m), 7.52 (1H, s), 4.89-4.62 (4H, br. m), 3.66-3.39
(1H, m), 3.31-3.05 (8H, br. m), 1.81 (6H, s)
[2263] LCMS: m/z 505, 507 [M+H].sup.+
Example 287
[2264] Compound F4-4
9-Bromo-8-{4-[2-(2-methoxy-ethoxy)-ethyl]-piperazin-1-yl}-6,6-dimethyl-11--
oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile
##STR00302##
[2266] Under the same conditions as the method for synthesizing
Compound A7-17, the title compound was prepared from Compound F3-9
and 1-bromo-2-(2-methoxyethoxy)ethane.
[2267] LCMS: m/z 551, 553 [M+H].sup.+
[2268] HPLC retention time: 2.80 min (analysis condition W)
Example 288
[2269] Compound F4-5
9-Bromo-6,6-dimethyl-11-oxo-8-[4-(tetrahydro-pyran-4-yl)-piperazin-1-yl]-6-
,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile
##STR00303##
[2271] Under the same conditions as the method for synthesizing
Compound B3-32, the title compound was prepared from Compound F3-9
and tetrahydropyran-4-one.
[2272] LCMS: m/z 533, 535 [M+H].sup.+
[2273] HPLC retention time: 2.67 min (analysis condition W)
Example 289
[2274] Compound F4-6
9-Bromo-6,6-dimethyl-11-oxo-8-[4-(tetrahydro-thiopyran-4-yl)-piperazin-1-y-
l]-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile
##STR00304##
[2276] Under the same conditions as the method for synthesizing
Compound B3-32, the title compound was prepared from Compound F3-9
and tetrahydrothiopyran-4-one.
[2277] LCMS: m/z 549, 551 [M+H].sup.+
[2278] HPLC retention time: 2.86 min (analysis condition W)
Example 290
[2279] Compound F4-7
9-Bromo-8-[4-(1,1-dioxo-hexahydro-1.lamda.6-thiopyran-4-yl)-piperazin-1-yl-
]-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile
##STR00305##
[2281] Under the same conditions as the method for synthesizing
Compound B3-8, the title compound was prepared from Compound
F4-6.
[2282] LCMS: m/z 581, 583 [M+H].sup.+
[2283] HPLC retention time: 2.66 min (analysis condition W)
Example 291
[2284] Compound F4-8
9-Bromo-8-(4-cyclopropylmethyl-piperazin-1-yl)-6,6-dimethyl-11-oxo-6,11-di-
hydro-5H-benzo[b]carbazole-3-carbonitrile
##STR00306##
[2286] Under the same conditions as the method for synthesizing
Compound A7-17, the title compound was prepared from Compound F3-9
and bromomethylcyclopropane.
[2287] LCMS: m/z 503, 505 [M+H].sup.+
[2288] HPLC retention time: 2.81 min (analysis condition W)
Example 292
[2289] Compound F4-9
9-Bromo-8-(4-cyclopropyl-piperazin-1-yl)-6,6-dimethyl-11-oxo-6,11-dihydro--
5H-benzo[b]carbazole-3-carbonitrile
##STR00307##
[2291] Under the same conditions as the method for synthesizing
Compound B3-32, the title compound was prepared from Compound F3-9
and (1-ethoxy-cyclopropoxy)-trimethyl-silane.
[2292] .sup.1H-NMR (270 MHz, DMSO-d.sub.6) .delta.: 8.22-8.30 (2H,
m), 8.00 (1H, s), 7.56 (1H, d, J=7.9 Hz), 7.43 (1H, s), 3.30 (1H,
d, J=5.8 Hz), 3.11 (4H, s), 2.75 (4H, s), 1.75 (6H, s), 0.47 (2H,
d, J=5.8 Hz), 0.34 (2H, d, J=5.8 Hz)
[2293] LCMS: m/z 489, 491 [M+H].sup.+
[2294] HPLC retention time: 1.68 min (analysis condition S)
Example 293
[2295] Compound F4-10
9-Bromo-8-(4-cyclobutyl-piperazin-1-yl)-6,6-dimethyl-11-oxo-6,11-dihydro-5-
H-benzo[b]carbazole-3-carbonitrile
##STR00308##
[2297] Under the same conditions as the method for synthesizing
Compound B3-32, the title compound was prepared from Compound F3-9
and cyclobutanone.
[2298] .sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta.: 8.23-8.29 (2H,
m), 8.00 (1H, s), 7.55 (1H, d, 7.9 Hz), 7.45 (1H, s), 4.04-4.15
(1H, m), 3.10-3.20 (4H, m), 2.39-2.48 (4H, m), 1.97-2.06 (2H, m),
1.78-1.88 (2H, m), 1.77 (6H, s), 1.61-1.72 (2H, m)
[2299] LCMS: m/z 503, 505 [M+H].sup.+
[2300] HPLC retention time: 2.78 min (analysis condition W)
Example 294
[2301] Compound F5-1
9-Ethynyl-8-(4-methanesulfonyl-piperazin-1-yl)-6,6-dimethyl-11-oxo-6,11-di-
hydro-5H-benzo[b]carbazole-3-carbonitrile
##STR00309##
[2303] Under the same conditions as the method for synthesizing
Compound F5-43, the title compound was prepared from Compound
F3-3.
[2304] .sup.1H-NMR (270 MHz, DMSO-d.sub.6) .delta.: 12.78 (1H, s),
8.31 (1H, dd, J=8.1, 0.7 Hz), 8.19 (1H, s), 8.02 (1H, dd, J=1.4,
0.7 Hz), 7.61 (1H, dd, J=8.2, 1.4 Hz), 7.33 (1H, s), 4.55 (1H, s),
3.43 (4H, br), 2.98 (3H, s), 1.79 (6H, s).
[2305] LCMS: m/z 473 [M+H].sup.+
[2306] HPLC retention time: 2.27 min (analysis condition S)
Example 295
[2307] Compound F5-2
N-[1-(3-Cyano-9-ethynyl-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbaz-
ol-8-yl)-piperidin-4-yl]-methanesulfonamide
##STR00310##
[2309] Under the same conditions as the method for synthesizing
Compound F5-43, the title compound was prepared from Compound
F4-2.
[2310] .sup.1H-NMR (270 MHz, DMSO-d.sub.6) .delta.: 12.98 (1H, s),
8.30 (1H, d, J=8.1 Hz), 8. (1H, s), 8.02 (1H, s), 7.61 (1H, d,
J=7.9 Hz), 7.23 (2H, s+d), 4.55 (1H, s), 3.79 (2H, brd), 2.95 (4H,
br), 1.96 (2H, brd), 1.78 (3H, s), 1.65 (2H, brd).
[2311] LCMS: m/z 487 [M+H].sup.+
[2312] HPLC retention time: 2.15 min (analysis condition S)
Example 296
[2313] Compound F5-3
6,6-Dimethyl-11-oxo-8-(4-pyrrolidin-1-yl-piperidin-1-yl)-6,11-dihydro-5H-b-
enzo[b]carbazole-3,9-dicarbonitrile
##STR00311##
[2315] Under the same conditions as the method for synthesizing
Compound A5-2, the target compound was prepared from Compound
F3-2.
[2316] .sup.1H-NMR (270 MHz, DMSO-d.sub.6) .delta.: 8.33 (1H, d,
J=1.3 Hz), 8.27 (1H, dd, J=7.7, 1.3 Hz), 8.00 (1H, s), 7.57 (1H, d,
J=7.7 Hz), 7.40 (1H, s), 3.74 (2H, m), 3.19-3.33 (1H, m), 2.98-3.12
(2H, m), 2.35-2.62 (2H, m), 2.11-2.29 (2H, m), 1.89-2.06 (2H, m),
1.78 (6H, s), 1.54-1.70 (6H, m).
[2317] LCMS: m/z 464 [M+H].sup.+
[2318] HPLC retention time: 1.55 min (analysis condition S)
Example 297
[2319] Compound F5-4
9-Ethynyl-6,6-dimethyl-11-oxo-8-(4-pyrrolidin-1-yl-piperidin-1-yl)-6,11-di-
hydro-5H-benzo[b]carbazole-3-carbonitrile
##STR00312##
[2321] Under the same conditions as the method for synthesizing
Compound E4-2-1 and Compound E4-2-2, the title compound was
prepared from Compound F3-2.
[2322] .sup.1H-NMR (270 MHz, DMSO-d.sub.6) .delta.: 8.29 (1H, d,
J=8.2 Hz), 8.14 (1H, s), 8.00 (1H, s), 7.58 (1H, dd, J=8.1, 1.3
Hz), 7.24 (1H, s), 4.50 (1H, s), 3.70-3.83 (2H, m), 3.34-3.48 (1H,
m), 2.83-2.98 (2H, m), 2.45-2.58 (2H, m), 2.10-2.23 (2H, m),
1.90-2.03 (2H, m), 1.76 (6H, s), 1.51-1.74 (6H, m).
[2323] LCMS: m/z 463 [M+H].sup.+
[2324] HPLC retention time: 1.60 min (analysis condition S)
Example 298
[2325] Compound F5-5
9-Ethynyl-6,6-dimethyl-8-morpholin-4-yl-11-oxo-6,11-dihydro-5H-benzo[b]car-
bazole-3-carbonitrile
##STR00313##
[2327] Under the same conditions as the method for synthesizing
Compound E4-2-1 and Compound E4-2-2, the title compound was
prepared from Compound F3-4.
[2328] .sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta.: 12.82 (1H, s),
8.31 (1H, d, J=7.9 Hz), 8.18 (1H, s), 8.02 (1H, s), 7.61 (1H, d,
J=7.9 Hz), 7.28 (1H, s), 4.53 (1H, s), 3.80 (4 H, s), 3.36 (4H, s),
1.79 (6H, s).
[2329] LCMS: m/z 396 [M+H].sup.+
[2330] HPLC retention time: 2.32 min (analysis condition S)
Example 299
[2331] Compound F5-6
9-(3-Dimethylamino-prop-1-ynyl)-6,6-dimethyl-8-morpholin-4-yl-11-oxo-6,11--
dihydro-5H-benzo[b]carbazole-3-carbonitrile
##STR00314##
[2333] Under the same conditions as the method for synthesizing
Compound E4-2-1, the title compound was prepared from Compound F3-4
and 3-dimethylaminopropyne.
[2334] .sup.1H-NMR (270 MHz, CDCl.sub.3) .delta.: 8.52 (1H, d,
J=7.8 Hz), 8.47 (1H, s), 7.76 (1H, s), 7.56 (1H, d, J=7.8 Hz), 7.03
(1H, s), 3.92 (4H, m), 3.55 (2H, s), 3.39 (4H, m), 2.37 (6H, s),
1.83 (6H, s)
[2335] LCMS: m/z 453 [M+H].sup.+
Example 300
[2336] Compound F5-7
6,6-Dimethyl-8-morpholin-4-yl-9-(3-morpholin-4-yl-prop-1-ynyl)-11-oxo-6,11-
-dihydro-5H-benzo[b]carbazole-3-carbonitrile
##STR00315##
[2338] To
9-bromo-6,6-dimethyl-8-morpholin-4-yl-11-oxo-6,11-dihydro-5H-ben-
zo[b]carbazole-3-carbonitrile (Compound F3-4, 30 mg, 0.067 mmol),
3-bromopropyne (0.01 ml, 0.13 mmol), morpholine (0.029 ml, 0.33
mmol), X-Phos (4.8 mg, 15% mol), PdCl.sub.2 (CH.sub.3CN).sub.2 (0.9
mg, 5% mol) and cesium carbonate (87 mg, 0.27 mmol), acetonitrile
(2 ml) was added and the mixture was stirred at 80.degree. C. for 2
hr. The reaction solution was added to water, and then extracted
with dichloromethane. The organic layer was dried over sodium
sulfate. The drying agent was removed by filtration and the
residues obtained after concentration under reduced pressure were
purified by silica gel column chromatography
(dichloromethane/methanol) to obtain the target compound (pale
brown solid, 18 mg, 64%).
[2339] .sup.1H-NMR (270 MHz, DMSO-d.sub.6) .delta.: 8.29 (1H, d,
J=7.8 Hz), 8.14 (1H, s), 8.00 (1H, s), 7.59 (1H, d, J=7.8 Hz), 7.27
(1H, s), 3.79 (4H, m), 3.64 (4H, m), 3.61 (2H, s), 3.33 (4H, m),
2.56 (4H, m), 1.77 (6H, s)
[2340] LCMS: m/z 495 [M+H].sup.+
Example 301
[2341] Compound F5-8
6,6-Dimethyl-8-morpholin-4-yl-11-oxo-9-pent-1-ynyl-6,11-dihydro-5H-benzo[b-
]carbazole-3-carbonitrile
##STR00316##
[2343] Under the same conditions as the method for synthesizing
Compound E4-2-1, the title compound was prepared from Compound F3-4
and 1-pentyne.
[2344] LCMS: m/z 438 [M+H].sup.+
[2345] HPLC retention time: 2.88 min (analysis condition S)
Example 302
[2346] Compound F5-9
9-(3-Methoxy-prop-1-ynyl)-6,6-dimethyl-8-morpholin-4-yl-11-oxo-6,11-dihydr-
o-5H-benzo[b]carbazole-3-carbonitrile
##STR00317##
[2348] Under the same conditions as the method for synthesizing
Compound E4-2-1, the title compound was prepared from Compound F3-4
and 3-methoxypropyne.
[2349] .sup.1H-NMR (270 MHz, DMSO-d.sub.6) .delta.: 8.30 (1H, d,
J=7.8 Hz), 8.15 (1H, s), 8.01 (1H, s), 7.60 (1H, d, J=7.8 Hz), 7.28
(1H, s), 4.41 (2H, s), 3.79 (4H, m), 3.37 (3H, s), 3.34 (4H, m),
1.78 (6H, s)
[2350] LCMS: m/z 440 [M+H].sup.+
Example 303
[2351] Compound F5-10
9-[3-(4-Cyclopropyl-piperazin-1-yl)-prop-1-ynyl]-6,6-dimethyl-8-morpholin--
4-yl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile
##STR00318##
[2353] Under the same conditions as the method for synthesizing
Compound F5-7, the title compound was prepared from Compound F3-4
and 3-bromopropyne and 4-cyclopropylpiperazine.
[2354] LCMS: m/z 534 [M+H].sup.+
[2355] HPLC retention time: 1.40 min (analysis condition S)
Example 304
[2356] Compound F5-11
6,6-Dimethyl-9-(1-methyl-1H-pyrazol-4-yl)-8-morpholin-4-yl-11-oxo-6,11-dih-
ydro-5H-benzo[b]carbazole-3-carbonitrile
##STR00319##
[2358] Under the same conditions as the method for synthesizing
Compound E4-7-1, the title compound was prepared from Compound F3-4
and
1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole.
[2359] .sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta.: 8.29 (1H, d,
J=7.8 Hz), 8.22 (1H, s), 8.09 (1H, s), 7.99 (1H, s), 7.95 (1H, s),
7.56-7.61 (1H, m), 7.36 (1H, s), 3.90 (3H, s), 3.73 (4H, s), 2.95
(4H, s), 1.77 (6H, s).
[2360] LCMS: m/z 452 [M+H].sup.+
[2361] HPLC retention time: 2.18 min (analysis condition U)
Example 305
[2362] Compound F5-12
9-Cyclopropyl-6,6-dimethyl-8-morpholin-4-yl-11-oxo-6,11-dihydro-5H-benzo[b-
]carbazole-3-carbonitrile
##STR00320##
[2364] Under the same conditions as the method for synthesizing
Compound E4-7-1, the title compound was prepared from Compound F3-4
and potassium cyclopropyltrifluoroborate.
[2365] .sup.1H-NMR (270 MHz, CD.sub.3OD+CDCl.sub.3) .delta.: 8.45
(1H, d, J=7.8 Hz), 7.83 (2H, m), 7.54 (1H, d, J=7.8 Hz), 7.20 (1H,
s), 3.96 (4H, m), 3.24 (4H, m), 2.25 (1H, m), 1.80 (6H, s), 1.09
(2H, m), 0.93 (2H, m)
[2366] LCMS: m/z 412 [M+H].sup.+
Example 306
[2367] Compound F5-13
6,6-Dimethyl-8-morpholin-4-yl-11-oxo-9-vinyl-6,11-dihydro-5H-benzo[b]carba-
zole-3-carbonitrile
##STR00321##
[2369] Under the same conditions as the method for synthesizing
Compound B2-24, the title compound was prepared from Compound F3-4
and potassium vinyltrifluoroborate.
[2370] LCMS: m/z 398 [M+H].sup.+
[2371] HPLC retention time: 2.67 min (analysis condition U)
Example 307
[2372] Compound F5-14
9-Ethynyl-8-(4-isopropyl-piperazin-1-yl)-6,6-dimethyl-11-oxo-6,11-dihydro--
5H-benzo[b]carbazole-3-carbonitrile
##STR00322##
[2374] Under the same conditions as the method for synthesizing
Compound F5-43, the title compound was prepared from Compound
F3-8.
[2375] .sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta.: 12.73 (1H, s),
8.31 (1H, d, J=9.1 Hz), 8.16 (1H, d, J=1.2 Hz), 8.00 (1H, s), 7.60
(1H, d, J=7.9 Hz), 7.25 (1H, s), 4.50 (1H, d, J=1.8 Hz), 2.72 (1H,
m), 2.65 (4H, s), 1.78 (6H, s), 1.04 (6H, d, J=5.5 Hz).
[2376] LCMS: m/z 437 [M+H].sup.+
[2377] HPLC retention time: 1.48 min (analysis condition S)
Example 308
[2378] Compound F5-15-1
4-(3-Cyano-9-cyclopropyl-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carba-
zol-8-yl)-piperazine-1-carboxylic acid tert-butylester
##STR00323##
[2380] Under the same conditions as the method for synthesizing
Compound E4-7-1, the title compound was prepared from Compound
F3-10 and potassium cyclopropyltrifluoroborate.
[2381] .sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta.: 8.55 (1H, s),
8.28-8.25 (1H, m), 7.98-7.95 (1H, m), 7.62 (1H, s), 7.32 (1H, s),
3.56-3.53 (4 h, m), 3.09-3.07 (4H, m), 2.22-2.18 (1H, m), 1.73 (6H,
br s), 1.44 (9H, s), 1.08-1.05 (2H, m), 0.77-0.76 (2H, m)
[2382] LCMS: m/z 511 [M+H].sup.+
[2383] HPLC retention time: 4.50 min (analysis condition W)
Example 309
[2384] Compound F5-15-2
9-Cyclopropyl-6,6-dimethyl-11-oxo-8-piperazin-1-yl-6,11-dihydro-5H-benzo[b-
]carbazole-3-carbonitrile
##STR00324##
[2386] Under the same conditions as the method for synthesizing
Compound A8-1, the title compound was prepared from Compound
F5-15-1.
[2387] LCMS: m/z 411 [M+H].sup.+
[2388] HPLC retention time: 2.67 min (analysis condition W)
Example 310
[2389] Compound F5-16
9-Ethynyl-6,6-dimethyl-8-(4-oxetan-3-yl-piperazin-1-yl)-11-oxo-6,11-dihydr-
o-5H-benzo[b]carbazole-3-carbonitrile
##STR00325##
[2391] Under the same conditions as the method for synthesizing
Compound F5-43, the title compound was prepared from Compound
F4-3.
[2392] .sup.1H-NMR (270 MHz, DMSO-d.sub.6) .delta.: 12.77 (1H, br.
s), 8.31 (1H, d, J=8.2 Hz), 8.16 (1H, s), 8.02 (1H, s), 7.61 (1H,
dd, J=8.2, 1.3 Hz), 7.27 (1H, s), 4.59 (2H, dd, J=6.6, 6.6 Hz),
4.51 (1H, s), 4.49 (2H, dd, J=6.6, 6.6 Hz), 3.51 (1H, t, J=6.6 Hz),
3.35-3.43 (4H, m), 2.43-2.50 (4H, s), 1.78 (6H, s).
[2393] LCMS: m/z 451 [M+H].sup.+
[2394] HPLC retention time: 1.40 min (analysis condition S)
Example 311
[2395] Compound F5-17
6,6-Dimethyl-8-(4-oxetan-3-yl-piperazin-1-yl)-11-oxo-6,11-dihydro-5H-benzo-
[b]carbazole-3,9-dicarbonitrile
##STR00326##
[2397] According to the same method as the method for synthesizing
Compound A5-2, the title compound was prepared from Compound
F4-3.
[2398] .sup.1H-NMR (270 MHz, DMSO-d.sub.6) .delta.: 12.84 (1H, br.
s), 8.36 (1H, s), 8.32-8.29 (1H, d, 8.08 Hz), 8.04 (1H, s),
7.65-7.62 (1H, d, 8.08 Hz), 7.44 (1H, s), 4.62-4.57 (2H, m),
4.52-4.47 (2H, m), 3.81-3.78 (2H, t, 4.61 Hz), 3.57-3.50 (1H, m),
3.43 (4H, m) 2.51 (4H, m), 1.80 (6H, s)
[2399] LCMS: m/z 452 [M+H].sup.+
Example 312
[2400] Compound F5-18
9-(3-Methoxy-prop-1-ynyl)-6,6-dimethyl-8-(4-oxetan-3-yl-piperazin-1-yl)-11-
-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile
##STR00327##
[2402] Under the same conditions as the method for synthesizing
Compound E4-2-1, the title compound was prepared from Compound F4-3
and 3-methoxypropyne.
[2403] .sup.1H-NMR (270 MHz, DMSO-d.sub.6) .delta.: 12.77 (1H, br.
s), 8.32-8.29 (1H, d, 8.08 Hz), 8.13 (1H, s), 8.01 (1H, s),
7.62-7.59 (1H, d, 8.08 Hz), 7.27 (1H, s), 4.62-4.57 (2H, m),
4.52-4.47 (2H, m), 4.39 (2H, s), 3.53-3.47 (1H, m), 3.38 (4H, m),
3.36 (3H, s), 2.51 (4H, m), 1.77 (6H, s)
[2404] LCMS: m/z 495 [M+H].sup.+
Example 313
[2405] Compound F5-19
9-(3-Dimethylamino-prop-1-ynyl)-6,6-dimethyl-8-(4-oxetan-3-yl-piperazin-1--
yl)-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile
##STR00328##
[2407] Under the same conditions as the method for synthesizing
Compound E4-2-1, the title compound was prepared from Compound F4-3
and dimethyl-prop-2-ynylamine.
[2408] LCMS: m/z 508 [M+H].sup.+
[2409] HPLC retention time: 1.07 min (analysis condition S)
Example 314
[2410] Compound F5-20
6,6-Dimethyl-8-(4-oxetan-3-yl-piperazin-1-yl)-9-[3-(4-oxetan-3-yl-piperazi-
n-1-yl)-prop-1-ynyl]-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitri-
le
##STR00329##
[2412] Under the same conditions as the method for synthesizing
Compound F5-7, the title compound was prepared from Compound F4-3,
3-bromopropyne and 4-oxetan-3-yl-piperazine.
[2413] .sup.1H-NMR (270 MHz, DMSO-d.sub.6) .delta.: 8.30 (1H, d,
J=7.8 Hz), 8.12 (1H, s), 8.00 (1H, s), 7.59 (1H, d, J=7.8 Hz), 7.26
(1H, s), 4.60-4.42 (8H, m), 3.61 (2H, s), 3.60-3.30 (6H, m),
2.60-2.30 (12H, m), 1.77 (6H, s)
[2414] LCMS: m/z 605 [M+H].sup.+
Example 315
[2415] Compound F5-21
9-Cyclopentylethynyl-6,6-dimethyl-8-(4-oxetan-3-yl
piperazin-1-yl)-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile
##STR00330##
[2417] Under the same conditions as the method for synthesizing
Compound E4-2-1, the title compound was prepared from Compound F4-3
and cyclopentylacetylene.
[2418] LCMS: m/z 519 [M+H].sup.+
[2419] HPLC retention time: 1.80 min (analysis condition S)
Example 316
[2420] Compound F5-22
6,6-Dimethyl-8-(4-oxetan-3-yl-piperazin-1-yl)-11-oxo-9-prop-1-ynyl-6,11-di-
hydro-5H-benzo[b]carbazole-3-carbonitrile
##STR00331##
[2422] Under the same conditions as the method for synthesizing
Compound E4-2-1, the title compound was prepared from Compound F4-3
and propyne.
[2423] .sup.1H-NMR (400 MHz, CD.sub.3OD) .delta.: 8.37 (1H, d,
J=8.2 Hz), 8.18 (1H, s), 7.84 (1H, s), 7.53 (1H, d, J=8.2 Hz), 7.19
(1H, s), 4.70-4.77 (2H, m), 4.62-4.68 (2H, m), 3.57-3.63 (1H, m),
3.38-3.45 (4H, m), 2.54-2.61 (4H, m), 2.10 (3H, s), 1.79 (6H,
s)
[2424] LCMS: m/z 465 [M+H].sup.+
[2425] HPLC retention time: 1.90 min (analysis condition U)
Example 317
[2426] Compound F5-23
9-(3-Hydroxy-prop-1-ynyl)-6,6-dimethyl-8-(4-oxetan-3-yl-piperazin-1-yl)-11-
-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile
##STR00332##
[2428] Under the same conditions as the method for synthesizing
Compound E4-2-1, the TMS complex of the title compound was prepared
from Compound F4-3 and trimethylprop-2-ynyloxysilane. By treating
the resulting TMS complex with tetrabutylammonium fluoride, the
title compound was obtained.
[2429] LCMS: m/z 481 [M+H].sup.+
[2430] HPLC retention time: 1.30 min (analysis condition S)
Example 318
[2431] Compound F5-24
6,6-Dimethyl-9-(4-methyl-pent-1-ynyl)-8-(4-oxetan-3-yl-piperazin-1-yl)-11--
oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile
##STR00333##
[2433] Under the same conditions as the method for synthesizing
Compound E4-2-1, the title compound was prepared from Compound F4-3
and 4-methylpent-1-yne.
[2434] .sup.1H-NMR (270 MHz, DMSO-d.sub.6) .delta.: 12.75 (1H, br.
s), 8.32-8.29 (1H, d, 8.08 Hz), 8.08 (1H, s), 8.01 (1H, s),
7.62-7.59 (1H, m), 7.23 (1H, s), 4.61-4.57 (2H, m), 4.51-4.46 (2H,
m), 3.51-3.47 (1H, m), 3.37 (4H, m), 2.46 (4H, m), 2.41-2.39 (2H,
d, 5.94 Hz), 1.92-1.80 (1H, m), 1.77 (6H, s), 1.04 (3H, s), 1.01
(3H, s)
[2435] LCMS: m/z 507 [M+H].sup.+
Example 319
[2436] Compound F5-25
9-Cyclopropylethynyl-6,6-dimethyl-8-(4-oxetan-3-yl-piperazin-1-yl)-11-oxo--
6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile
##STR00334##
[2438] Under the same conditions as the method for synthesizing
Compound E4-2-1, the title compound was prepared from Compound F4-3
and ethynylcyclopropane.
[2439] .sup.1H-NMR (270 MHz, DMSO-d.sub.6) .delta.: 12.74 (1H, br.
s), 8.32-8.29 (1H, d, 8.08 Hz), 8.05 (1H, s), 8.00 (1H, s),
7.62-7.58 (1H, m), 7.21 (1H, s), 4.62-4.57 (2H, m), 4.51-4.47 (2H,
m), 3.53-3.48 (1H, m), 3.34 (4H, m), 2.46 (4H, m), 1.76 (6H, s),
1.64-1.58 (1H, m), 0.97-0.89 (2H, m), 0.76-0.70 (2H, m)
[2440] LCMS: m/z 491 [M+H].sup.+
Example 320
[2441] Compound F5-26
6,6-Dimethyl-9-(3-morpholin-4-yl-prop-1-ynyl)-8-(4-oxetan-3-yl-piperazin-1-
-yl)-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile
##STR00335##
[2443] Under the same conditions as the method for synthesizing
Compound F5-7, the title compound was prepared from Compound F4-3,
3-bromopropyne and morpholine.
[2444] .sup.1H-NMR (270 MHz, DMSO-d.sub.6) .delta.: 8.29 (1H, d,
J=7.8 Hz), 8.13 (1H, s), 8.02 (1H, s), 7.59 (1H, d, J=7.8 Hz), 7.25
(1H, s), 4.61-4.48 (4H, m), 3.64-3.32 (11H, m), 2.60-2.40 (8H, m),
1.78 (6H, s)
[2445] LCMS: m/z 550 [M+H].sup.+
Example 321
[2446] Compound F5-27
6,6-Dimethyl-8-(4-oxetan-3-yl-piperazin-1-yl)-11-oxo-9-pent-1-ynyl-6,11-di-
hydro-5H-benzo[b]carbazole-3-carbonitrile
##STR00336##
[2448] Under the same conditions as the method for synthesizing
Compound E4-2-1, the title compound was prepared from Compound F4-3
and 1-pentyne. .sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta.: 12.72
(1H, br. s), 8.28 (1H, d, 8.1 Hz), 8.06 (1H, s), 7.98 (1H, s), 7.58
(1H, d, 8.1 Hz), 7.21 (1H, s), 4.60-4.43 (4H, m), 3.53-3.44 (1H,
m), 3.39-3.32 (2H, m), 1.75 (6H, s), 1.60-1.53 (4H, m), 1.01 (3H,
t, 7.3 Hz)
[2449] LCMS: m/z 493 [M+H].sup.+
[2450] HPLC retention time: 2.17 min (analysis condition U)
Example 322
[2451] Compound F5-28
6,6-Dimethyl-9-(5-methyl-hex-1-ynyl)-8-(4-oxetan-3-yl-piperazin-1-yl)-11-o-
xo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile
##STR00337##
[2453] Under the same conditions as the method for synthesizing
Compound E4-2-1, the title compound was prepared from Compound F4-3
and 5-methylhex-1-yne.
[2454] LCMS: m/z 521 [M+H].sup.+
[2455] HPLC retention time: 2.37 min (analysis condition U)
Example 323
[2456] Compound F5-29
9-(3-Diethylamino-prop-1-ynyl)-6,6-dimethyl-8-(4-oxetan-3-yl-piperazin-1-y-
l)-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile
##STR00338##
[2458] Under the same conditions as the method for synthesizing
Compound E4-2-1, the title compound was prepared from Compound F4-3
and 3-diethylaminopropyne.
[2459] LCMS: m/z 536 [M+H].sup.+
[2460] HPLC retention time: 1.13 min (analysis condition S)
Example 324
[2461] Compound F5-30
9-[3-(Benzyl-ethyl-amino)-prop-1-ynyl]-6,6-dimethyl-8-(4-oxetan-3-yl-piper-
azin-1-yl)-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile
##STR00339##
[2463] Under the same conditions as the method for synthesizing
Compound E4-2-1, the title compound was prepared from Compound F4-3
and 3-benzyl-3-ethylaminopropyne.
[2464] LCMS: m/z 584 [M+H].sup.+
[2465] HPLC retention time: 1.32 min (analysis condition S)
Example 325
[2466] Compound F5-31
9-[3-(1,1-Dioxo-1.lamda.6-thiomorpholin-4-yl)-prop-1-ynyl]-6,6-dimethyl-8--
(4-oxetan-3-yl-piperazin-1-yl)-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3--
carbonitrile
##STR00340##
[2468] Under the same conditions as the method for synthesizing
Compound E4-2-1, the title compound was prepared from Compound F4-3
and 3-(1,1-dioxo-.lamda.6-thiomorpholin-4-yl)-propyne.
[2469] LCMS: m/z 598 [M+H].sup.+
[2470] HPLC retention time: 1.35 min (analysis condition S)
Example 326
[2471] Compound F5-32
9-Isopropenyl-6,6-dimethyl-8-(4-oxetan-3-yl-piperazin-1-yl)-11-oxo-6,11-di-
hydro-5H-benzo[b]carbazole-3-carbonitrile
##STR00341##
[2473] Under the same conditions as the method for synthesizing
Compound E4-7-1, the title compound was prepared from Compound F4-3
and 2-isopropenyl-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane.
[2474] .sup.1H-NMR (270 MHz, CD.sub.3OD+CDCl.sub.3) .delta.: 8.44
(1H, d, J=7.8 Hz), 8.09 (1H, s), 7.83 (1H, s), 7.54 (1H, d, J=7.8
Hz), 7.18 (1H, s), 5.24-5.20 (2H, m), 4.81-4.68 (4H, m), 3.66 (1H,
m), 3.30 (4H, m), 2.57 (4H, m), 2.21 (3H, s), 1.82 (6H, s)
[2475] LCMS: m/z 467 [M+H].sup.+
Example 327
[2476] Compound F5-33
6,6,9-Trimethyl-8-(4-oxetan-3-yl-piperazin-1-yl)-11-oxo-6,11-dihydro-5H-be-
nzo[b]carbazole-3-carbonitrile
##STR00342##
[2478] Under the same conditions as the method for synthesizing
Compound F5-47, the title compound was prepared from Compound
F4-3.
[2479] .sup.1H-NMR (270 MHz, DMSO-d.sub.6) .delta.: 12.71 (1H, br.
s), 8.33-8.31 (1H, d, 8.08 Hz), 8.01 (1H, s), 7.97 (1H, s),
7.62-7.59 (1H, m), 7.32 (1H, s), 4.61-4.57 (2H, m), 4.51-4.47 (2H,
m), 3.55-3.49 (1H, m), 3.05 (4H, m), 2.47 (4H, m), 2.33 (3H, s),
1.76 (6H, s)
[2480] LCMS: m/z 441 [M+H].sup.+
Example 328
[2481] Compound F5-34
9-Cyclopropyl-6,6-dimethyl-8-(4-oxetan-3-yl-piperazin-1-yl)-11-oxo-6,11-di-
hydro-5H-benzo[b]carbazole-3-carbonitrile
##STR00343##
[2483] Under the same conditions as the method for synthesizing
Compound B3-32, the title compound was prepared from Compound
F5-15-2 and oxetan-3-one.
[2484] .sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta.: 8.32-8.29 (1H,
m), 8.00-7.99 (1H, m), 7.62-7.58 (2H, m), 7.32-7.31 (1H, m),
4.61-4.57 (2H, m), 4.52-4.49 (2H, m), 3.53 (1H, br. s), 3.18 (4H,
br. s), 1.75 (6H, s), 1.25-1.23 (1H, m), 1.09-1.04 (2H, m),
0.79-0.75 (2H, m)
[2485] LCMS: m/z 467 [M+H].sup.+
[2486] HPLC retention time: 2.74 min (analysis condition W)
Example 329
[2487] Compound F5-35
6,6-Dimethyl-9-(1-methyl-1H-pyrazol-4-yl)-8-(4-oxetan-3-yl-piperazin-1-yl)-
-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile
##STR00344##
[2489] Under the same conditions as the method for synthesizing
Compound E4-7-1, the title compound was prepared from Compound F4-3
and
1-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole.
[2490] LCMS: m/z 507 [M+H].sup.+
[2491] HPLC retention time: 1.75 min (analysis condition U)
Example 330
[2492] Compound F5-36-1
4-[3-Cyano-6,6-dimethyl-11-oxo-8-(4-pyrrolidin-1-yl-piperidin-1-yl)-6,11-d-
ihydro-5H-benzo[b]carbazol-9-yl]-3,6-dihydro-2H-pyridine-1-carboxylic
acid tert-butyl ester
##STR00345##
[2494] Under the same conditions as the method for synthesizing
Compound E4-7-1, the title compound was prepared from Compound
F3-2.
[2495] LCMS: m/z 621 [M+H].sup.+
[2496] HPLC retention time: 2.58 min (analysis condition U)
Example 331
[2497] Compound F5-36-2
6,6-Dimethyl-11-oxo-8-(4-pyrrolidin-1-yl-piperidin-1-yl)-9-(1,2,3,6-tetrah-
ydro-pyridin-4-yl)-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile
##STR00346##
[2499] Under the same conditions as the method for synthesizing
Compound A8-1, the title compound was prepared from Compound
F5-36-1.
[2500] LCMS: m/z 520 [M+H].sup.+
[2501] HPLC retention time: 1.82 min (analysis condition U)
Example 332
[2502] Compound F5-37
8-(4-Cyclopropyl-piperazin-1-yl)-9-ethynyl-6,6-dimethyl-11-oxo-6,11-dihydr-
o-5H-benzo[b]carbazole-3-carbonitrile
##STR00347##
[2504] Under the same conditions as the method for synthesizing
Compound F5-43, the title compound was prepared from Compound
F4-9.
[2505] .sup.1H-NMR (270 MHz, DMSO-d.sub.6) .delta.: 12.76 (1H, br.
s), 8.31 (1H, d, J=8.1 Hz), 8.15 (1H, s), 8.01 (1H, s), 7.61 (1H,
dd, J=8.1, 1.5 Hz), 7.24 (1H, s), 4.52 (1H, s), 3.28-3.36 (4H, m),
3.17 (1H, d, J=5.3 Hz), 2.70-2.77 (4H, m), 1.76 (6H, s), 0.47 (2H,
d, J=5.3 Hz), 0.36 (2H, d, J=5.3 Hz).
[2506] LCMS: m/z 435 [M+H].sup.+
[2507] HPLC retention time: 1.57 min (analysis condition S)
Example 333
[2508] Compound F5-38
8-(4-Cyclopropyl-piperazin-1-yl)-6,6-dimethyl-11-oxo-9-prop-1-ynyl-6,11-di-
hydro-5H-benzo[b]carbazole-3-carbonitrile
##STR00348##
[2510] Under the same conditions as the method for synthesizing
Compound E4-2-1, the title compound was prepared from Compound F4-9
and propyne.
[2511] .sup.1H-NMR (270 MHz, DMSO-d.sub.6) .delta.: 12.76 (1H, br.
s), 8.31-8.28 (1H, d, 8.08 Hz), 8.06 (1H, s), 8.00 (1H, s),
7.60-7.57 (1H, m), 7.19 (1H, s), 3.29 (4H, m), 2.74 (4H, m), 2.55
(1H, m), 2.13 (3H, s), 1.75 (6H, s), 0.51-0.43 (2H, m), 0.38-0.32
(2H, m)
[2512] LCMS: m/z 449 [M+H].sup.+
Example 334
[2513] Compound F5-39
8-(4-Cyclopropyl-piperazin-1-yl)-6,6-dimethyl-11-oxo-9-phenyl-6,11-dihydro-
-5H-benzo[b]carbazole-3-carbonitrile
##STR00349##
[2515] Under the same conditions as the method for synthesizing
Compound E4-7-1, the title compound was prepared from Compound F4-9
and phenylboric acid.
[2516] LCMS: m/z 487 [M+H].sup.+
[2517] HPLC retention time: 2.15 min (analysis condition U)
Example 335
[2518] Compound F5-40
8-(4-Cyclopropyl-piperazin-1-yl)-6,6-dimethyl-11-oxo-9-pyridin-3-yl-6,11-d-
ihydro-5H-benzo[b]carbazole-3-carbonitrile
##STR00350##
[2520] Under the same conditions as the method for synthesizing
Compound E4-7-1, the title compound was prepared from Compound F4-9
and pyridine-3-boric acid.
[2521] LCMS: m/z 488 [M+H].sup.+
[2522] HPLC retention time: 1.53 min (analysis condition U)
Example 336
[2523] Compound F5-41
8-(4-Cyclopropyl-piperazin-1-yl)-6,6-dimethyl-11-oxo-9-thiophene-2-yl-6,11-
-dihydro-5H-benzo[b]carbazole-3-carbonitrile
##STR00351##
[2525] Under the same conditions as the method for synthesizing
Compound E4-7-1, the title compound was prepared from Compound F4-9
and thiophene-2-boric acid.
[2526] LCMS: m/z 493 [M+H].sup.+
[2527] HPLC retention time: 2.13 min (analysis condition U)
[2528] Compound F5-42
8-(4-Cyclopropyl-piperazin-1-yl)-6,6,9-trimethyl-11-oxo-6,11-dihydro-5H-be-
nzo[b]carbazole-3-carbonitrile
##STR00352##
[2530] Under the same conditions as the method for synthesizing
Compound F5-47, the title compound was prepared from Compound
F4-9.
[2531] .sup.1H-NMR (270 MHz, DMSO-d.sub.6) .delta.: 12.71 (1H, br.
s), 8.33-8.30 (1H, d, 8.08 Hz), 8.00 (1H, s), 7.96 (1H, s),
7.61-7.58 (1H, m), 7.29 (1H, s), 2.97 (4H, m), 2.73 (4H, m), 2.56
(1H, m), 2.34 (3H, s), 1.76 (6H, s), 1.64-1.58 (1H, m), 0.50-0.44
(2H, m), 0.37-0.32 (2H, m)
[2532] LCMS: m/z 425 [M+H].sup.+
Example 338
[2533] Compound F5-43
8-(4-Cyclobutyl-piperazin-1-yl)-9-ethynyl-6,6-dimethyl-11-oxo-6,11-dihydro-
-5H-benzo[b]carbazole-3-carbonitrile
##STR00353##
[2535] Under nitrogen atmosphere, to the MeCN (8 ml) suspension of
9-bromo-8-(4-cyclobutyl-piperazin-1-yl)-6,6-dimethyl-11-oxo-6,11-dihydro--
5H-benzo[b]carbazole-3-carbonitrile (Compound F4-10, 200 mg, 0.397
mmol), ethynyltriisopropylsilane (268 mg, 3.0 eq.),
2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (Xphos) (39
mg, 0.2 eq.), Pd(CH.sub.3CN).sub.2Cl.sub.2 (11 mg, 0.1 eq.) and
cesium carbonate (518 mg, 4.0 eq.) were added and the mixture was
stirred and heated under reflux condition until the reaction is
completed. Upon the completion of the reaction, distilled water was
added to the reaction solution, which was then extracted with ethyl
acetate. The organic layer was washed with brine and dried over
sodium sulfate. The drying agent was removed by filtration and the
residues obtained after concentration under reduced pressure were
purified by silica gel column chromatography (ethyl
acetate/methanol) to obtain
8-(4-cyclobutyl-piperazin-1-yl)-6,6-dimethyl-11-oxo-9-[(triisopropylsilan-
yl)-ethynyl]-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile (179
mg, 74%).
[2536] To the THF (6 ml) solution of the obtained compound (179 mg,
0.295 mmol), 1 M THF solution (710 l) of tetrabutylammonium
fluoride was added and the mixture was stirred until the reaction
is completed. Upon the completion of the reaction, ethyl acetate
was added to the reaction solution, which was then washed with
distilled water and dried over sodium sulfate. The drying agent was
removed by filtration and the residues obtained after concentration
under reduced pressure were washed with a mixture solvent of
ethanol and distilled water to obtain the title compound (67 mg,
92%).
[2537] .sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta.: 12.85 (1H, s),
8.31 (1H, d, 7.9 Hz), 8.20 (1H, s), 8.03 (1H, s), 7.62 (1H, d, 7.9
Hz), 7.35 (1H, s), 4.62 (1H, s), 3.94-4.03 (2H, m), 3.79-3.89 (1H,
m), 3.48-3.54 (2H, m), 3.27-3.38 (2H, m), 2.96-3.16 (2H, m),
2.30-2.41 (2H, m), 2.16-2.26 (2H, m), 1.72-1.85 (8H, m)
[2538] LCMS: m/z 449 [M+H].sup.+
[2539] HPLC retention time: 2.69 min (analysis condition W)
Example 339
[2540] Compound F5-44
8-(4-Cyclobutyl-piperazin-1-yl)-6,6-dimethyl-11-oxo-9-prop-1-ynyl-6,11-dih-
ydro-5H-benzo[b]carbazole-3-carbonitrile
##STR00354##
[2542] Under the same conditions as the method for synthesizing
Compound E4-2-1, the title compound was prepared from Compound
F4-10 under propyne gas atmosphere.
[2543] .sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta.: 12.71 (1H, s),
8.30 (1H, d, 7.9 Hz), 8.06 (1H, s), 8.00 (1H, s), 7.59 (1H, d, 7.9
Hz), 7.20 (1H, s), 2.75-2.83 (1H, m), 2.40-2.48 (4H, m), 2.11 (3H,
s), 1.97-2.06 (2H, m), 1.76 (6H, s), 1.62-1.71 (2H, m)
[2544] LCMS: m/z 463 [M+H].sup.+
[2545] HPLC retention time: 2.80 min (analysis condition W)
Example 340
[2546] Compound F5-45
9-Cyclobutylethynyl-8-(4-cyclobutyl-piperazin-1-yl)-6,6-dimethyl-11-oxo-6,-
11-dihydro-5H-benzo[b]carbazole-3-carbonitrile
##STR00355##
[2548] Under the same conditions as the method for synthesizing
Compound E4-2-1, the title compound was prepared from Compound
F4-10 and ethynylcyclobutane.
[2549] LCMS: m/z 503 [M+H].sup.+
[2550] HPLC retention time: 1.85 min (analysis condition S)
Example 341
[2551] Compound F5-46
8-(4-Cyclobutyl-piperazin-1-yl)-9-cyclopropyl-6,6-dimethyl-11-oxo-6,11-dih-
ydro-5H-benzo[b]carbazole-3-carbonitrile
##STR00356##
[2553] Under the same conditions as the method for synthesizing
Compound B3-32, the title compound was prepared from Compound
F5-15-2 and cyclobutanone.
[2554] .sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta.: 8.23 (1H, d, 8
Hz), 7.92 (1H, br. s), 7.59 (1H, s), 7.47 (1H, br. d, 8 Hz), 7.28
(1H, s), 3.12 (4H, br. s), 2.80 (1H, dddd, 8, 8, 8, 8 Hz),
2.20-2.13 (1H, m), 2.01 (2H, br. s), 1.86-1.68 (10H, m), 1.05 (2H,
d, 8 Hz), 0.76 (2H, d, 4 Hz)
[2555] LCMS: m/z 465 [M+H].sup.+
[2556] HPLC retention time: 2.79 min (analysis condition W)
[2557] Hydrochloric Acid Salt of Compound F5-46
[2558]
8-(4-Cyclobutyl-piperazin-1-yl)-9-cyclopropyl-6,6-dimethyl-11-oxo-6-
,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile was added with DMSO
and 6 N hydrochloric acid (1.05 eq.) and dissolved therein. After
freeze-drying, crystallization was performed by using ethanol
comprising 25% water to obtain monohydrochloric acid salt of
8-(4-cyclobutyl-piperazin-1-yl)-9-cyclopropyl-6,6-dimethyl-11-oxo-6,11-di-
hydro-5H-benzo[b]carbazole-3-carbonitrile.
[2559] .sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta.: 12.81 (1H, s),
10.64 (1H, br. s), 8.32-8.29 (1H, m), 8.01 (1H, s), 7.67 (1H, s),
7.61-7.60 (1H, m), 7.33 (1H, s), 4.00-3.39 (6H, m), 3.28-3.02 (3H,
m), 2.45-2.05 (5H, m), 1.83-1.77 (8H, m), 1.09-1.07 (2H, m),
0.81-0.80 (2H, m)
[2560] LCMS: m/z 465 [M+H].sup.+
Example 342
[2561] Compound F5-47
8-(4-Cyclobutyl-piperazin-1-yl)-6,6,9-trimethyl-11-oxo-6,11-dihydro-5H-ben-
zo[b]carbazole-3-carbonitrile
##STR00357##
[2563] Under nitrogen atmosphere, to the N,N-dimethyl formamide
(1.5 ml) solution of
9-bromo-8-(4-cyclobutyl-piperazin-1-yl)-6,6-dimethyl-11-oxo-6,11-dihydro--
5H-benzo[b]carbazole-3-carbonitrile (Compound F4-10, 50 mg, 0.099
mmol), trimethyl boroxine (12 mg, 0.1 eq.), tetrakis
triphenylphosphine palladium (39 mg, 0.2 eq.), and potassium
carbonate (41 mg, 3.0 eq.) were added, and the mixture was stirred
at 100.degree. C. for 24 hr. Upon the completion of the reaction,
distilled water was added to the reaction solution, which was then
extracted with ethyl acetate. The organic layer was washed with
brine and dried over sodium sulfate. The drying agent was removed
by filtration and the residues obtained after concentration under
reduced pressure were purified by silica gel column chromatography
(ethyl acetate/methanol) to obtain the title compound (25 mg,
58%).
[2564] .sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta.: 12.67 (1H, s),
8.31 (1H, d, 7.9 Hz), 7.98 (1H, s), 7.95 (1H, s), 7.59 (1H, d, 7.9
Hz), 7.30 (1H, s), 2.96-3.04 (4H, m), 2.76-2.84 (1H, m), 2.39-2.48
(4H, m), 2.32 (3H, s), 1.78-1.87 (2H, m), 1.75 (6H, s), 1.63-1.71
(2H, m)
[2565] LCMS: m/z 439 [M+H].sup.+
[2566] HPLC retention time: 2.66 min (analysis condition W)
Example 343
[2567] Compound F5-48
8-(4-Cyclobutyl-piperazin-1-yl)-9-isopropenyl-6,6-dimethyl-11-oxo-6,11-dih-
ydro-5H-benzo[b]carbazole-3-carbonitrile
##STR00358##
[2569] Under the same conditions as the method for synthesizing
Compound E4-7-1, the title compound was prepared from Compound
F4-10 and
2-isopropenyl-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane.
[2570] LCMS: m/z 465 [M+H].sup.+
[2571] HPLC retention time: 1.63 min (analysis condition S)
Example 344
[2572] Compound F5-49
9-Ethynyl-6,6-dimethyl-8-(4-morpholin-4-yl-piperidin-1-yl)-11-oxo-6,11-dih-
ydro-5H-benzo[b]carbazole-3-carbonitrile
##STR00359##
[2574] Under the same conditions as the method for synthesizing
Compound F5-43, the title compound was prepared from Compound
F3-11.
[2575] LCMS: m/z 479 [M+H].sup.+
[2576] HPLC retention time: 1.90 min (analysis condition U)
Example 345
[2577] Compound F5-50
6,6-Dimethyl-8-(4-morpholin-4-yl-piperidin-1-yl)-11-oxo-9-prop-1-ynyl-6,11-
-dihydro-5H-benzo[b]carbazole-3-carbonitrile
##STR00360##
[2579] Under the same conditions as the method for synthesizing
Compound E4-2-1, the title compound was prepared from Compound
F3-11 and propyne gas.
[2580] .sup.1H-NMR (270 MHz, CD.sub.3OD+CDCl.sub.3) .delta.: 8.40
(1H, d, J=7.8 Hz), 8.24 (1H, s), 7.84 (1H, s), 7.54 (1H, d, J=7.8
Hz), 7.14 (1H, s), 4.01-3.96 (2H, m), 3.78 (4H, m), 2.88-2.84 (2H,
m), 2.68 (4H, m), 2.16-1.73 (5H, m), 2.16 (3H, s), 1.80 (6H, s)
[2581] LCMS: m/z 493 [M+H].sup.+
[2582] Compound F5-51
6,6,9-Trimethyl-8-(4-morpholin-4-yl-piperidin-1-yl)-11-oxo-6,11-dihydro-5H-
-benzo[b]carbazole-3-carbonitrile
##STR00361##
[2584] Under the same conditions as the method for synthesizing
Compound F5-47, the title compound was prepared from Compound
F3-11
[2585] .sup.1H-NMR (270 MHz, DMSO-d.sub.6) .delta.: 12.70 (1H, br.
s), 8.33-8.30 (1H, d, 8.08 Hz), 8.00 (1H, s), 7.95 (1H, s),
7.61-7.58 (1H, m), 7.28 (1H, s), 3.60 (4H, m), 3.32-3.26 (2H, m),
2.79-2.69 (2H, m), 2.32 (3H, s), 1.95-1.90 (2H, m), 1.74 (6H, s),
1.65-1.52 (2H, m),
[2586] LCMS: m/z 469 [M+H].sup.+
[2587] Methanesulfonic Acid Salt of Compound F5-51
[2588]
6,6,9-Trimethyl-8-(4-morpholin-4-yl-piperidin-1-yl)-11-oxo-6,11-dih-
ydro-5H-benzo[b]carbazole-3-carbonitrile was added with DMSO and 2
N methanesulfonic acid (1.05 eq.) and dissolved therein. After
freeze-drying, crystallization was performed with ethanol to obtain
methanesulfonic acid salt of
6,6,9-trimethyl-8-(4-morpholin-4-yl-piperidin-1-yl)-11-oxo-6,11-dihydro-5-
H-benzo[b]carbazole-3-carbonitrile.
[2589] .sup.1H-NMR (270 MHz, DMSO-d.sub.6) .delta.: 12.72 (1H,
br.s), 9.60 (1H, br. s), 8.33-8.31 (1H, d, 9.8 Hz), 8.01 (1H, s),
7.99 (1H, s), 7.61-7.59 (1H, m), 7.31 (1H, s), 4.07-4.04 (2H, m),
3.73-3.67 (2H, m), 3.55-3.40 (8H, m), 3.32-3.26 (1H, m), 2.70-2.60
(2H, m), 2.34 (3H, s), 2.30 (3H, s), 1.95-1.90 (2H, m), 1.75 (6H,
s)
[2590] LCMS: m/z 469 [M+H].sup.+
Example 347
[2591] Compound F6-1
9-(1-Isopropyl-1,2,3,6-tetrahydro-pyridin-4-yl)-6,6-dimethyl-11-oxo-8-(4-p-
yrrolidin-1-yl-piperidin-1-yl)-6,11-dihydro-5H-benzo[b]carbazole-3-carboni-
trile
##STR00362##
[2593] Under the same conditions as the method for synthesizing
Compound B3-32, the title compound was prepared from Compound
F5-36-2 and acetone.
[2594] .sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta.: 12.68 (1H, br.
s), 8.30 (1H, d, 8.1 Hz), 7.98 (1H, s), 7.82 (1H, s), 7.58 (1H, d,
8.1 Hz), 7.20 (1H, s), 5.85 (1H, s), 3.56-3.44 (2H, m), 3.21-3.14
(2H, m), 2.77-2.66 (5H, m), 2.12-2.09 (1H, m), 1.98-1.88 (2H, m),
1.74 (6H, s), 1.70-1.63 (1H, m), 1.58-1.45 (2H, m), 1.09-1.00 (6H,
m)
[2595] LCMS: m/z 563 [M+H].sup.+
[2596] HPLC retention time: 1.90 min (analysis condition U)
Example 348
[2597] Compound F6-2
9-(1-Methanesulfonyl-1,2,3,6-tetrahydro-pyridin-4-yl)-6,6-dimethyl-11-oxo--
8-(4-pyrrolidin-1-yl-piperidin-1-yl)-6,11-dihydro-5H-benzo[b]carbazole-3-c-
arbonitrile
##STR00363##
[2599] Under the same conditions as the method for synthesizing
Compound A9-1, the title compound was prepared from Compound
F5-36-2.
[2600] LCMS: m/z 598 [M+H].sup.+
[2601] HPLC retention time: 1.52 min (analysis condition S)
[2602] Compound F6-3
9-[3-(4-Cyclopropyl-piperazin-1-yl)-propyl]-6,6-dimethyl-8-morpholin-4-yl--
11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile
##STR00364##
[2604] Under the same conditions as the method for synthesizing
Compound B3-13-1, the title compound was prepared from Compound
F5-10.
[2605] LCMS: m/z 538 [M+H].sup.+
[2606] HPLC retention time: 1.32 min (analysis condition S)
Example 350
[2607] Compound F6-4
9-Ethyl-6,6-dimethyl-8-(4-oxetan-3-yl-piperazin-1-yl)-11-oxo-6,11-dihydro--
5H-benzo[b]carbazole-3-carbonitrile
##STR00365##
[2609] Under the same conditions as the method for synthesizing
Compound B3-13-1, the title compound was prepared from Compound
F5-16.
[2610] .sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta.: 12.70 (1H, br.
s), 8.29 (1H, d, 8.0 Hz), 8.03-7.94 (2H, m), 7.59-7.55 (1H, m),
7.38 (1H, s), 4.59-4.47 (4H, m), 3.53-5.47 (1H, m), 3.03-2.97 (2H,
m), 2.73-2.62 (2H, m), 1.74 (6H, s), 1.29-1.98 (3H, m)
[2611] LCMS: m/z 455 [M+H].sup.+
[2612] HPLC retention time: 1.92 min (analysis condition U)
[2613] Hydrochloric Acid Salt of Compound F6-4
[2614]
9-Ethyl-6,6-dimethyl-8-(4-oxetan-3-yl-piperazin-1-yl)-11-oxo-6,11-d-
ihydro-5H-benzo[b]carbazole-3-carbonitrile was added with DMSO and
6 N hydrochloric acid (1.05 eq.) and dissolved therein. After
freeze-drying, crystallization was performed with ethanol
comprising 25% water to obtain monohydrochloric acid salt of
9-ethyl-6,6-dimethyl-8-(4-oxetan-3-yl-piperazin-1-yl)-11-oxo-6,11-dihydro-
-5H-benzo[b]carbazole-3-carbonitrile.
[2615] .sup.1H-NMR (270 MHz, DMSO-d.sub.6) .delta.: 12.83 (1H,
br.s), 11.59 (1H, br. s), 8.33-8.31 (1H, m), 8.09 (1H, s), 8.02
(1H, s), 7.63-7.61 (1H, m), 7.39 (1H, s), 4.91-4.60 (4H, br. m),
3.58-3.40 (1H, m), 3.31-3.05 (8H, br. m), 2.73 (2H, q, J=7.3), 1.81
(6H, s), 1.29 (3H, t, J=7.3)
[2616] LCMS: m/z 455 [M+H].sup.+
Example 351
[2617] Compound F6-5
9-(3-Methoxy-propyl)-6,6-dimethyl-8-(4-oxetan-3-yl-piperazin-1-yl)-11-oxo--
6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile
##STR00366##
[2619] Under the same conditions as the method for synthesizing
Compound B3-13-1, the title compound was prepared from Compound
F5-18.
[2620] .sup.1H-NMR (270 MHz, DMSO-d.sub.6) .delta.: 12.73 (1H, br.
s), 8.33-8.30 (1H, d, 8.08 Hz), 8.01 (1H, s), 8.00 (1H, s),
7.62-7.59 (1H, d, 8.08 Hz), 7.42 (1H, s), 4.61-4.56 (2H, m),
4.51-4.46 (2H, m), 3.53-3.47 (1H, m), 3.42-3.37 (2H, m), 3.02 (4H,
m), 2.75-2.68 (2H, m), 2.51 (4H, m), 1.93-1.82 (2H, m), 1.76 (6H,
s)
[2621] LCMS: m/z 499 [M+H].sup.+
Example 352
[2622] Compound F6-6
6,6-Dimethyl-8-(4-oxetan-3-yl-piperazin-1-yl)-9-[3-(4-oxetan-3-yl-piperazi-
n-1-yl)-propyl]-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile
##STR00367##
[2624] Under the same conditions as the method for synthesizing
Compound B3-13-1, the title compound was prepared from Compound
F5-20.
[2625] LCMS: m/z 609 [M+H].sup.+
[2626] HPLC retention time: 1.00 min (analysis condition S)
Example 353
[2627] Compound F6-7
9-(2-Cyclopentyl-ethyl)-6,6-dimethyl-8-(4-oxetan-3-yl-piperazin-1-yl)-11-o-
xo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile
##STR00368##
[2629] Under the same conditions as the method for synthesizing
Compound B3-13-1, the title compound was prepared from Compound
F5-21.
[2630] LCMS: m/z 523 [M+H].sup.+
[2631] HPLC retention time: 1.92 min (analysis condition S)
Example 354
[2632] Compound F6-8
6,6-Dimethyl-8-(4-oxetan-3-yl-piperazin-1-yl)-11-oxo-9-propyl-6,11-dihydro-
-5H-benzo[b]carbazole-3-carbonitrile
##STR00369##
[2634] Under the same conditions as the method for synthesizing
Compound B3-13-1, the title compound was prepared from Compound
F5-22.
[2635] .sup.1H-NMR (270 mHz DMSO-d.sub.6) .delta.: 12.75 (1H, s),
8.30 (1H, d, J=8.2 Hz), 8.01-7.97 (2H, m), 7.59 (1H, d, J=7.1 Hz),
7.38 (1H, s), 4.51 (4H, dt, J=27.7, 6.3 Hz), 3.55-3.49 (1H, m),
3.02-2.96 (4H, m), 2.63 (2H, t, J=7.3 Hz), 2.47-2.41 (4H, m), 1.73
(6H, s), 1.70-1.61 (2H, m), 0.94 (3H, t, J=7.4 Hz).
[2636] LCMS: m/z 469 [M+H].sup.+
[2637] HPLC retention time: 1.57 min (analysis condition S)
Example 355
[2638] Compound F6-9
8-[4-(4-Hydroxy-butyl)-piperazin-1-yl]-6,6-dimethyl-11-oxo-9-propyl-6,11-d-
ihydro-5H-benzo[b]carbazole-3-carbonitrile
##STR00370##
[2640] The title compound was obtained as a by-product of the
synthesis of Compound F6-8.
[2641] LCMS: m/z 485 [M+H].sup.+
[2642] HPLC retention time: 1.61 min (analysis condition S)
Example 356
[2643] Compound F6-10
9-(3-Hydroxy-propyl)-6,6-dimethyl-8-(4-oxetan-3-yl-piperazin-1-yl)-11-oxo--
6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile
##STR00371##
[2645] Under the same conditions as the method for synthesizing
Compound B3-13-1, the title compound was prepared from Compound
F5-23.
[2646] LCMS: m/z 499 [M+H].sup.+
[2647] HPLC retention time: 1.42 min (analysis condition S)
Example 357
[2648] Compound F6-11
6,6-Dimethyl-9-(3-morpholin-4-yl-propyl)-8-(4-oxetan-3-yl-piperazin-1-yl)--
11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile
##STR00372##
[2650] Under the same conditions as the method for synthesizing
Compound B3-13-1, the title compound was prepared from Compound
F5-26.
[2651] LCMS: m/z 554 [M+H].sup.+
[2652] HPLC retention time: 1.50 min (analysis condition U)
Example 358
[2653] Compound F6-12
6,6-Dimethyl-8-(4-oxetan-3-yl-piperazin-1-yl)-11-oxo-9-pentyl-6,11-dihydro-
-5H-benzo[b]carbazole-3-carbonitrile
##STR00373##
[2655] Under the same conditions as the method for synthesizing
Compound B3-13-1, the title compound was prepared from Compound
F5-27.
[2656] LCMS: m/z 497 [M+H].sup.+
[2657] HPLC retention time: 2.25 min (analysis condition U)
Example 359
[2658] Compound F6-13
9-(3-Isopropoxy-prop-1-ynyl)-6,6-dimethyl-8-(4-oxetan-3-yl-piperazin-1-yl)-
-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile
##STR00374##
[2660] Under the same conditions as the method for synthesizing
Compound A7-17, the title compound was prepared from Compound F5-23
and 2-bromopropane.
[2661] .sup.1H-NMR (270 MHz, CD.sub.3OD+CDCl.sub.3) .delta.: 8.40
(1H, d, J=7.8 Hz), 8.32 (1H, s), 7.84 (1H, s), 7.53 (1H, d, J=7.8
Hz), 7.18 (1H, s), 4.80-4.68 (4H, m), 4.46 (2H, s), 3.95 (1H, m),
3.64 (1H, m), 3.46 (4H, m), 2.62 (4H, m), 1.82 (6H, s), 1.24 (6H,
d, J=7.0 Hz)
[2662] LCMS: m/z 523 [M+H].sup.+
Example 360
[2663] Compound F6-14
9-Isopropyl-6,6-dimethyl-8-(4-oxetan-3-yl-piperazin-1-yl)-11-oxo-6,11-dihy-
dro-5H-benzo[b]carbazole-3-carbonitrile
##STR00375##
[2665] Under the same conditions as the method for synthesizing
Compound B3-13-1, the title compound was prepared from Compound
F5-32.
[2666] .sup.1H-NMR (270 MHz, CD.sub.3OD+CDCl.sub.3) .delta.: 8.44
(1H, d, J=7.8 Hz), 8.27 (1H, s), 7.84 (1H, s), 7.54 (1H, d, J=7.8
Hz), 7.36 (1H, s), 4.82-4.70 (4H, m), 3.68 (1H, m), 3.45 (1H, m),
3.13-3.09 (4H, m), 2.64-2.62 (4H, m), 1.81 (6H, s), 1.31 (6H, d,
J=7.0 Hz)
[2667] LCMS: m/z 469 [M+H].sup.+
Example 361
[2668] Compound F6-15
8-(4-Cyclopropyl-piperazin-1-yl)-9-ethyl-6,6-dimethyl-11-oxo-6,11-dihydro--
5H-benzo[b]carbazole-3-carbonitrile
##STR00376##
[2670] Under the same conditions as the method for synthesizing
Compound B3-13-1, the title compound was prepared from Compound
F5-37.
[2671] LCMS: m/z 439 [M+H].sup.+
[2672] HPLC retention time: 1.98 min (analysis condition U)
Example 362
[2673] Compound F6-16
8-(4-Cyclopropyl-piperazin-1-yl)-6,6-dimethyl-11-oxo-9-propyl-6,11-dihydro-
-5H-benzo[b]carbazole-3-carbonitrile
##STR00377##
[2675] Under the same conditions as the method for synthesizing
Compound B3-13-1, the title compound was prepared from Compound
F5-38.
[2676] LCMS: m/z 453 [M+H].sup.+
[2677] HPLC retention time: 1.63 min (analysis condition S)
Example 363
[2678] Compound F6-17
8-(4-Cyclobutyl-piperazin-1-yl)-9-ethyl-6,6-dimethyl-11-oxo-6,11-dihydro-5-
H-benzo[b]carbazole-3-carbonitrile
##STR00378##
[2680] Under the same conditions as the method for synthesizing
Compound B3-13-1, the title compound was prepared from Compound
F5-43.
[2681] .sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta.: 12.80 (1H, s),
8.32 (1H, d, 7.9 Hz), 8.10 (1H, s), 8.02 (1H, s), 7.62 (1H, d, 7.9
Hz), 7.38 (1H, s), 3.78-3.88 (1H, m), 3.79-3.89 (1H, m), 3.48-3.54
(2H, m), 3.40-3.47 (2H, m), 3.30-3.39 (2H, m), 3.02-3.24 (4H, m),
2.73 (2H, q, 7.3 Hz), 2.30-2.41 (2H, m), 2.17-2.26 (2H, m),
1.71-1.86 (8H, m), 1.29 (3H, t, 7.3 Hz)
[2682] LCMS: m/z 453 [M+H].sup.+
[2683] HPLC retention time: 2.76 min (analysis condition W)
[2684] Methanesulfonic Acid Salt of Compound F6-17
[2685]
8-(4-Cyclobutyl-piperazin-1-yl)-9-ethyl-6,6-dimethyl-11-oxo-6,11-di-
hydro-5H-benzo[b]carbazole-3-carbonitrile was dissolved in 6
volumes of DMF at room temperature and added dropwise with aqueous
solution of methanesulfonic acid (2 M, 1.05 eq.). The resulting
solution was added dropwise to 60 volumes of acetonitrile, and the
precipitated solid was filtered and dried to obtain
monomethanesulfonic acid salt of
8-(4-cyclobutyl-piperazin-1-yl)-9-ethyl-6,6-dimethyl-11-oxo-6,11-dihydro--
5H-benzo[b]carbazole-3-carbonitrile.
[2686] .sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta.: 12.75 (1H, s),
8.31 (1H, J=8.4 Hz), 8.07 (1H, s), 8.01 (1H, s), 7.59 (1H, d, J=7.9
Hz), 7.38 (1H, s), 3.58-2.84 (10H, m), 2.71 (2H, q, J=7.5 Hz), 2.34
(3H, s), 2.20-2.04 (4H, m), 1.76-1.68 (8H, m), 1.26 (3H, t, J=7.5
Hz)
[2687] FABMS: m/z 453 [M+H].sup.+
Example 364
[2688] Compound F6-18
8-(4-Cyclobutyl-piperazin-1-yl)-6,6-dimethyl-11-oxo-9-propyl-6,11-dihydro--
5H-benzo[b]carbazole-3-carbonitrile
##STR00379##
[2690] Under the same conditions as the method for synthesizing
Compound B3-13-1, the title compound was prepared from Compound
F5-44.
[2691] .sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta.: 12.69 (1H, s),
8.31 (1H, d, 7.9 Hz), 8.01 (1H, s), 7.99 (1H, s), 7.60 (1H, d, 7.9
Hz), 7.39 (1H, s), 2.92-3.02 (4H, m), 2.75-2.84 (1H, m), 2.65 (2H,
t, 7.3 Hz), 2.38-2.48 (4H, m), 1.96-2.06 (2H, m), 1.78-1.87 (2H,
m), 1.75 (6H, s), 1.62-1.73 (4H, m), 0.97 (3H, t, 7.3 Hz)
[2692] LCMS: m/z 467 [M+H].sup.+
[2693] HPLC retention time: 2.96 min (analysis condition W)
[2694] Compound F6-19
8-(4-Cyclobutyl-piperazin-1-yl)-9-isopropyl-6,6-dimethyl-11-oxo-6,11-dihyd-
ro-5H-benzo[b]carbazole-3-carbonitrile
##STR00380##
[2696] Under the same conditions as the method for synthesizing
Compound B3-13, the title compound was prepared from Compound
F5-48.
[2697] LCMS: m/z 467 [M+H].sup.+
[2698] HPLC retention time: 1.67 min (analysis condition S)
Example 366
[2699] Compound F6-20
9-Ethyl-6,6-dimethyl-8-(4-morpholin-4-yl-piperidin-1-yl)-11-oxo-6,11-dihyd-
ro-5H-benzo[b]carbazole-3-carbonitrile
##STR00381##
[2701] Under the same conditions as the method for synthesizing
Compound B3-13-1, the title compound was prepared from Compound
F5-49.
[2702] .sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta.: 12.70 (1H, s),
8.32 (1H, d, J=7.9 Hz), 8.04 (1H, s), 8.00 (1H, s), 7.61 (1H, d,
J=8.5 Hz), 7.34 (1H, s), 3.64-3.57 (4H, m), 3.27-3.18 (2H, m),
2.82-2.66 (4H, m), 2.39-2.28 (1H, m), 1.96-1.87 (2H, m), 1.76 (6H,
s), 1.69-1.53 (2H, m), 1.29 (3H, t, J=7.3 Hz)
[2703] LCMS: m/z 483 [M+H].sup.+
[2704] HPLC retention time: 1.98 min (analysis condition U)
[2705] Hydrochloric Acid Salt of Compound F6-20
[2706]
9-Ethyl-6,6-dimethyl-8-(4-morpholin-4-yl-piperidin-1-yl)-11-oxo-6,1-
1-dihydro-5H-benzo[b]carbazole-3-carbonitrile was dissolved in a
mixture solution of methylethyl ketone (10 volumes), water (4
volumes) and acetic acid (3 volumes) at 60.degree. C. To the
dissolved solution, hydrochloric acid (2 N) was added dropwise (1
volume). After stirring at 60.degree. C. for 30 min, ethanol (25
volume) was added dropwise. The precipitated solid was filtered and
dried to obtain monohydrochloric acid salt of
9-ethyl-6,6-dimethyl-8-(4-morpholin-4-yl-piperidin-1-yl)-11-oxo-6,11-dihy-
dro-5H-benzo[b]carbazole-3-carbonitrile.
[2707] .sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta.: 12.78 (1H, s),
10.57 (1H, br. s), 8.30 (1H, J=8.4 Hz), 8.05 (1H, s), 7.99 (1H, s),
7.59 (1H, d, J=7.9 Hz), 7.36 (1H, s), 4.02-3.99 (2H, m), 3.84-3.78
(2H, m), 3.51-3.48 (2H, m), 3.15-3.13 (1H, s), 2.83-2.73 (2H, s),
2.71-2.67 (2H, s), 2.23-2.20 (2H, m), 1.94-1.83 (2H, m), 1.75 (6H,
s), 1.27 (3H, t, J=7.5 Hz)
[2708] FABMS: m/z 483 [M+H].sup.+
Example 367
[2709] Compound F6-21
6,6-Dimethyl-8-(4-morpholin-4-yl-piperidin-1-yl)-11-oxo-9-propyl-6,11-dihy-
dro-5H-benzo[b]carbazole-3-carbonitrile
##STR00382##
[2711] Under the same conditions as the method for synthesizing
Compound B3-13-1, the title compound was prepared from Compound
F5-50.
[2712] .sup.1H-NMR (270 MHz, CD.sub.3OD+CDCl.sub.3) .delta.: 8.41
(1H, d, J=7.8 Hz), 8.14 (1H, s), 7.84 (1H, s), 7.53 (1H, d, J=7.8
Hz), 7.31 (1H, s), 3.77 (4H, m), 3.32 (2H, m), 2.86-2.66 (8H, m),
2.43-2.05 (3H, m), 1.79 (6H, s), 1.79-1.66 (4H, m), 1.02 (3H, t,
J=7.3 Hz)
[2713] LCMS: m/z 497 [M+H].sup.+
Example 368
[2714] Compound G2
8-Methoxy-10,10-dimethyl-10,11-dihydro-5H-1,11-diaza-benzo[B]fluorene
##STR00383##
[2716] 2-Hydrazinopyridine (1.3 g, 11.8 mmol) and
7-methoxy-1,1-dimethyl-3,4-dihydro-1H-naphthalen-2-one (Compound
A2, 2.4 g, 11.8 mmol) were dissolved in NMP (60 mL), and stirred at
190.degree. C. for 48 hr. The reaction solution was diluted with
ethyl acetate, washed with water and dried over magnesium sulfate.
The drying agent was removed by filtration and the residues
obtained after concentration under reduced pressure were purified
by silica gel column chromatography (hexane/ethyl acetate) to
obtain the target compound (white solid, 101 mg, 3%).
[2717] .sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta.: 11.53 (1H, s),
8.16-8.12 (1H, m), 7.84 (1H, d, J=7.8 Hz), 7.23 (1H, d, J=8.4 Hz),
7.11 (1H, s), 7.03-6.98 (1H, m), 6.85-6.81 (1H, m), 3.96 (2H, s),
3.77 (3H, s), 1.64 (6H, s)
[2718] LCMS: m/z 279 [M+H].sup.+
[2719] HPLC retention time: 2.08 min (analysis condition U)
Example 369
[2720] Compound G3
8-Methoxy-10,10-dimethyl-10,11-dihydro-1,11-diaza-benzo[b]fluoren-5-one
##STR00384##
[2722] Under the same conditions as the method for synthesizing
Compound A4, the title compound was prepared from Compound G2.
[2723] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta.: 12.95 (1H, br.
s), 8.78 (1H, d, J=7.8 Hz), 8.52 (1H, d, J=4.9 Hz), 8.41 (1H, d,
J=8.8 Hz), 7.37 (1H, dd, J=7.7, 5.0 Hz), 7.15 (1H, s), 7.04-7.00
(1H, m), 3.94 (3H, s), 1.98 (6H, s)
[2724] LCMS: m/z 293 [M+H].sup.+
[2725] HPLC retention time: 2.13 min (analysis condition U)
Example 370
[2726] Compound G4
8-Hydroxy-10,10-dimethyl-10,11-dihydro-1,11-diaza-benzo[b]fluoren-5-one
##STR00385##
[2728] Under the same conditions as the method for synthesizing
Compound E3-2, the title compound was prepared from Compound
G3.
[2729] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta.: 8.66 (1H, d,
J=7.7 Hz), 8.29 (1H, d, J=4.9 Hz), 8.23 (1H, d, J=13.8 Hz), 7.29
(1H, dd, J=7.7, 5.0 Hz), 7.12 (1H, s), 6.93 (1H, d, J=8.6 Hz), 1.71
(6H, s)
[2730] LCMS: m/z 279 [M+H].sup.+
[2731] HPLC retention time: 1.72 min (analysis condition U)
Example 371
[2732] Compound G5
Trifluoro-methanesulfonic acid
10,10-dimethyl-5-oxo-10,11-dihydro-5H-1,11-diaza-benzo[b]fluoren-8-yl
ester
##STR00386##
[2734] Under the same conditions as the method for synthesizing
Compound B1, the title compound was prepared from Compound G4.
[2735] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta.: 8.81 (1H, d,
J=7.8 Hz), 8.60-8.52 (2H, m), 7.55 (1H, s), 7.46-7.40 (2H, m), 2.01
(6H, s)
[2736] LCMS: m/z 411 [M+H].sup.+
[2737] HPLC retention time: 1.75 min (analysis condition U)
Example 372
[2738] Compound G6
10,10-Dimethyl-8-(4-pyrrolidin-1-yl-piperidin-1-yl)-10,11-dihydro-1,11-dia-
za-benzo[b]fluoren-5-one
##STR00387##
[2740] Under the same conditions as the method for synthesizing
Compound B2-1, the title compound was prepared from Compound G5 and
4-pyrrolidin-1-yl-piperidine.
[2741] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta.: 13.12 (1H, s),
8.78 (1H, d, J=7.8 Hz), 8.49 (1H, d, J=4.9 Hz), 8.29 (1H, d, J=8.8
Hz), 7.34 (1H, dd, J=7.7, 5.0 Hz), 7.06-6.98 (2H, m), 3.96-3.88
(2H, m), 3.02-3.92 (2H, m), 2.69-2.60 (4H, m), 2.32-2.23 (1H, m),
2.09-2.00 (4H, m), 1.92 (6H, s), 1.26-1.19 (4H, m)
[2742] LCMS: m/z 415 [M+H].sup.+
[2743] HPLC retention time: 1.57 min (analysis condition U)
Example 373
[2744] Compound H1
6-Acetyl-7-methoxy-1,1-dimethyl-3,4-dihydro-1H-naphthalen-2-one
##STR00388##
[2746] To the dichloromethane (70 ml) solution of
7-methoxy-1,1-dimethyl-3,4-dihydro-1H-naphthalen-2-one (Compound
A2, 3 g, 14.7 mmol), acetic anhydride (1.7 ml, 1.2 eq.) and
aluminum chloride-nitrobenzene solution (1 M, 44 ml, 3 eq.) was
added at 0.degree. C., and stirred for 3 hr. Thereafter, the
reaction solution was added with saturated aqueous solution of
sodium hydrogen carbonate and extracted twice with dichloromethane.
The organic layer was washed with brine and dried over magnesium
sulfate. The drying agent was removed by filtration and the
residues obtained after concentration under reduced pressure were
purified by silica gel column chromatography (ethyl acetate/hexane)
to obtain the title compound as a crude product.
Example 374
[2747] Compound H2-1
1-(3-Bromo-8-methoxy-6,6-dimethyl-6,11-dihydro-5H-benzo[b]carbazol-9-yl)-e-
thanone
##STR00389##
[2749] Under the same conditions as the method for synthesizing
Compound A3-1, the title compound was prepared from Compound H1 and
(3-bromo-phenyl)-hydrazine.
[2750] LCMS: m/z 398 [M+H].sup.+
[2751] HPLC retention time: 3.97 min (analysis condition Y)
Example 375
[2752] Compound H2-2
1-(1-Bromo-8-methoxy-6,6-dimethyl-6,11-dihydro-5H-benzo[b]carbazol-9-yl)-e-
thanone
##STR00390##
[2754] The title compound was obtained as a by-product of the
synthesis of Compound H2-1.
[2755] LCMS: m/z 398 [M+H].sup.+
[2756] HPLC retention time: 3.97 min (analysis condition Y)
Example 376
[2757] Compound H3
9-Acetyl-3-bromo-8-methoxy-6,6-dimethyl-5,6-dihydro-benzo[b]carbazol-11-on-
e
##STR00391##
[2759] Under the same conditions as the method for synthesizing
Compound A4, the title compound was prepared from Compound H2.
[2760] .sup.1H-NMR (300 MHz, DMSO-d.sub.6) .delta.: 1.80 (6H, s),
2.58 (3H, s), 4.06 (3H, s), 7.38 (1H, dd, 8.39 Hz, 1.91 Hz), 7.51
(1H, s), 7.67 (1H, bs, 1.53 Hz), 8.10 (1H, d, 8.39 Hz), 8.41 (1H,
s), 12.3 (1H, s)
[2761] LCMS: m/z 412, 414 [M+H].sup.+
[2762] HPLC retention time: 2.73 min (analysis condition U)
Example 377
[2763] Compound H4
9-Acetyl-8-methoxy-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-
-carbonitrile
##STR00392##
[2765] According to the same method as the method for synthesizing
Compound A5-2, the title compound was prepared from Compound
H3.
[2766] .sup.1H-NMR (300 MHz, DMSO-d.sub.6) .delta.: 1.83 (6H, s),
2.58 (3H, s), 4.07 (3H, s), 7.53 (1H, s), 7.61 (1H, d, 8.01 Hz),
8.03 (1H, s), 8.31 (1H, d, 8.77 Hz), 8.42 (1H, s), 12.8 (1H,
s).
[2767] LCMS: m/z 359 [M+H].sup.+
[2768] HPLC retention time: 2.47 min (analysis condition U)
[2769] Compound H5
9-Acetyl-8-hydroxy-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-
-carbonitrile
##STR00393##
[2771] Under the same conditions as the method for synthesizing
Compound A6, the title compound was prepared from Compound H4.
[2772] .sup.1H-NMR (300 MHz, DMSO-d.sub.6) .delta.: 1.77 (6H, s),
2.75 (3H, s), 7.43 (1H, s), 7.63 (1H, d, 8.01 Hz), 8.02 (1H, s),
8.32 (1H, d, 8.01 Hz), 8.67 (1H, s), 12.2 (1H, s), 12.8 (1H,
s).
[2773] LCMS: m/z 345 [M+H].sup.+
[2774] HPLC retention time: 2.27 min (analysis condition S)
Example 379
[2775] Compound H6-1
9-Acetyl-6,6-dimethyl-11-oxo-8-(tetrahydro-pyran-4-yl
oxy)-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile
##STR00394##
[2777] Under the same conditions as the method for synthesizing
Compound A7-1, the title compound was prepared from Compound H5 and
tetrahydropyran-4-ol.
[2778] LCMS: m/z 429 [M+H].sup.+
[2779] HPLC retention time: 2.48 min (analysis condition U)
Example 380
[2780] Compound H6-2
9-Acetyl-8-(2-diethylamino-ethoxy)-6,6-dimethyl-11-oxo-6,11-dihydro-5H-ben-
zo[b]carbazole-3-carbonitrile
##STR00395##
[2782] Under the same conditions as the method for synthesizing
Compound A7-17, the title compound was prepared from Compound
H5.
[2783] LCMS: m/z 444 [M+H].sup.+
[2784] HPLC retention time: 2.05 min (analysis condition U)
Example 381
[2785] Compound H7
Trifluoro-methanesulfonic acid
9-acetyl-3-cyano-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-y-
l ester
##STR00396##
[2787] Under the same conditions as the method for synthesizing
Compound B1, the title compound was prepared from Compound H5.
[2788] .sup.1H-NMR (300 MHz, DMSO-d.sub.6) .delta.: 1.83 (6H, s),
2.74 (3H, s), 7.68 (1H, dd, 8.01 Hz, 1.53 Hz), 8.08 (2H, s), 8.33
(1H, d, 8.77 Hz), 8.79 (1H, s), 12.9 (1H, s).
Example 382
[2789] Compound H8-1
9-Acetyl-6,6-dimethyl-11-oxo-8-(4-pyrrolidin-1-yl-piperidin-1-yl)-6,11-dih-
ydro-5H-benzo[b]carbazole-3-carbonitrile
##STR00397##
[2791] Under the same conditions as the method for synthesizing
Compound B2-1, the title compound was prepared from Compound H7 and
4-pyrrolidin-1-yl-piperidine. .sup.1H-NMR (300 MHz, DMSO-d.sub.6)
.delta.: 1.65 (2H, m), 1.69 (4H, s), 1.79 (6H, s), 1.95 (2H, m),
2.18 (1H, m), 2.54 (4H, s), 2.59 (3H, s), 2.93 (2H, t, 11.8 Hz),
3.37 (2H, m), 7.36 (1H, s), 7.60 (1H, d, 8.01), 8.01 (1H, s), 8.13
(1H, s), 8.30 (1H, d, 8.39), 12.7 (1H, s).
[2792] LCMS: m/z 481 [M+H].sup.+
[2793] HPLC retention time: 2.03 min (analysis condition U)
Example 383
[2794] Compound H8-2
9-Acetyl-8-(4-isopropyl-piperazin-1-yl)-6,6-dimethyl-11-oxo-6,11-dihydro-5-
H-benzo[b]carbazole-3-carbonitrile
##STR00398##
[2796] Under the same conditions as the method for synthesizing
Compound B2-1, the title compound was prepared from Compound
H7.
[2797] LCMS: m/z 455 [M+H].sup.+
[2798] HPLC retention time: 2.02 min (analysis condition U)
Example 384
[2799] Compound H8-3
9-Acetyl-6,6-dimethyl-8-morpholin-4-yl-11-oxo-6,11-dihydro-5H-benzo[b]carb-
azole-3-carbonitrile
##STR00399##
[2801] Under the same conditions as the method for synthesizing
Compound B2-1, the title compound was prepared from Compound H7 and
morpholine.
[2802] LCMS: m/z 414 [M+H].sup.+
[2803] HPLC retention time: 2.11 min (analysis condition S)
Example 385
[2804] Compound H8-4
9-Acetyl-6,6-dimethyl-8-(4-morpholin-4-yl-piperidin-1-yl)-11-oxo-6,11-dihy-
dro-5H-benzo[b]carbazole-3-carbonitrile
##STR00400##
[2806] Under the same conditions as the method for synthesizing
Compound B2-1, the title compound was prepared from Compound H7 and
4-piperidin-4-yl-morpholine.
[2807] LCMS: m/z 497 [M+H].sup.+
[2808] HPLC retention time: 1.45 min (analysis condition S)
Example 386
[2809] Compound H8-5
9-Acetyl-6,6-dimethyl-11-oxo-8-piperazin-1-yl-6,11-dihydro-5H-benzo[b]carb-
azole-3-carbonitrile
##STR00401##
[2811] Under the same conditions as the method for synthesizing
Compound B2-1, the title compound was prepared from Compound H7 and
piperazine.
[2812] LCMS: m/z 413 [M+H].sup.+
[2813] HPLC retention time: 1.71 min (analysis condition U)
Example 387
[2814] Compound H9-1
9-Acetyl-8-(4-cyclobutyl-piperazin-1-yl)-6,6-dimethyl-11-oxo-6,11-dihydro--
5H-benzo[b]carbazole-3-carbonitrile
##STR00402##
[2816] Under the same conditions as the method for synthesizing
Compound B3-32, the title compound was prepared from Compound H8-5
and cyclobutanone.
[2817] LCMS: m/z 467 [M+H].sup.+
[2818] HPLC retention time: 1.82 min (analysis condition U)
Example 388
[2819] Compound H9-2
9-Acetyl-6,6-dimethyl-11-oxo-8-[4-(tetrahydro-pyran-4-yl)-piperazin-1-yl]--
6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile
##STR00403##
[2821] Under the same conditions as the method for synthesizing
Compound B3-32, the title compound was prepared from Compound H8-5
and tetrahydropyran-4-one.
[2822] LCMS: m/z 497 [M+H].sup.+
[2823] HPLC retention time: 1.76 min (analysis condition U)
Example 389
[2824] Compound H9-3
9-Acetyl-8-[4-(1,1-dimethyl-prop-2-ynyl)-piperazin-1-yl]-6,6-dimethyl-11-o-
xo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile
##STR00404##
[2826] To the anhydrous THF solution (0.5 mL) of
9-acetyl-6,6-dimethyl-11-oxo-8-piperazin-1-yl-6,11-dihydro-5H-benzo[b]car-
bazole-3-carbonitrile (Compound H8-5, 25 mg, 0.06 mmol),
3-chloro-3-methyl-but-1-yne (0.013 mL, 0.12 mmol), copper (I)
chloride (0.6 mg, 0.006 mmol) and triethylamine (0.017 mL, 0.12
mmol) were added at room temperature. After stirring for 30 min,
the mixture was added with water and extracted with ethyl acetate.
The organic layer was dried over magnesium sulfate. The drying
agent was removed by filtration and the residues obtained after
concentration under reduced pressure were purified by amino silica
gel column chromatography (dichloromethane/methanol) to obtain the
title compound (white solid, 9.8 mg, 35%).
[2827] LCMS: m/z 479 [M+H].sup.+
[2828] HPLC retention time: 1.88 min (analysis condition U)
Example 390
[2829] Compound I1-1
6-Chloro-7-methoxy-1,1-dimethyl-3,4-dihydro-1H-naphthalen-2-one
##STR00405##
[2831] 7-Methoxy-1,1-dimethyl-3,4-dihydro-1H-naphthalen-2-one
(Compound A2, 3.37 g, 16.5 mmol) was dissolved in CH.sub.3CN (82
mL), added with NCS (2.42 g, 1.1 eq.) and stirred at 90.degree. C.
for 1.5 hr. The reaction solution was extracted with ethyl acetate.
The organic layer was washed with saturated brine and dried over
sodium sulfate. The drying agent was removed and the target
compound was obtained after concentration under reduced pressure
(yellow oily substance, 4.45 g).
[2832] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta.: 7.16 (1H, s),
6.85 (1H, s), 3.90 (3H, s), 3.00 (2H, t, J=6.8 Hz), 2.65 (2H, t,
J=6.8 Hz), 1.42 (6H, s).
[2833] LCMS: m/z 239 [M+H].sup.+
[2834] HPLC retention time: 2.80 min (analysis condition U)
Example 391
[2835] Compound I1-2
9-Chloro-8-methoxy-6,6-dimethyl-6,11-dihydro-5H-benzo[b]carbazole-3-carbon-
itrile
##STR00406##
[2837]
6-Chloro-7-methoxy-1,1-dimethyl-3,4-dihydro-1H-naphthalen-2-one
(Compound I1-1, 4.45 g, 16.5 mmol) and 3-hydrazinobenzonitrile
(2.63 g, 1.2 eq.) were dissolved in TFA (91 mL), and stirred at
90.degree. C. for 3 hr. According to the concentration under
reduced pressure, TFA was removed and the residues were added with
saturated aqueous solution of NaHCO.sub.3, followed by extraction
with ethyl acetate. The organic layer was washed with saturated
brine and dried over sodium sulfate. The drying agent was removed
by filtration and the residues obtained after concentration under
reduced pressure were added with ethyl acetate. After stirring at
room temperature, the precipitated solid was separated by
filtration. The filtrate was concentrated under reduced pressure to
obtain the title compound as a mixture with I1-3 (red powder, 6.46
g).
Example 392
[2838] Compound I1-3
9-Chloro-8-methoxy-6,6-dimethyl-6,11-dihydro-5H-benzo[b]carbazole-1-carbon-
itrile
##STR00407##
[2840] The title compound was obtained as a by-product of the
synthesis of Compound I1-2.
[2841] .sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta.: 11.66 (1H, s),
7.65-7.69 (1H, m), 7.44-7.48 (1H, m), 7.39 (1H, s), 7.29 (1H, s),
7.17-7.23 (1H, m), 4.21 (2H, s), 3.91 (3H, s), 1.69 (6H, s).
[2842] LCMS: m/z 337 [M+H].sup.+
[2843] HPLC retention time: 3.15 min (analysis condition U)
Example 393
[2844] Compound I2-1
2-(4-Chloro-3-methoxy-phenyl)-2-methyl-propionitrile
##STR00408##
[2846] 1-Chloro-4-fluoro-2-methoxy-benzene (4.3 g, 26.78 mmol) and
isobutyronitrile (9.61 mL, 4.0 eq.) were dissolved in toluene (9.0
mL), added with KHMDS (80 mL, 0.5 M toluene solution) and stirred
at 65.degree. C. for 2 hr. The reaction solution was cooled to room
temperature, added with aqueous solution of 1 N hydrochloric acid
and then extracted with MTBE. The organic layer was washed with
saturated brine and dried over magnesium sulfate. The drying agent
was removed by filtration and the residues obtained after
concentration under reduced pressure were purified by silica gel
column chromatography (hexane/ethyl acetate) to obtain the title
compound (1.72 g, 31%).
[2847] .sup.1H-NMR (270 MHz, CDCl.sub.3) .delta.: 7.37 (1H, d,
J=8.4 Hz), 7.05 (1H, d, J=2.1 Hz), 6.97 (1H, dd, J=8.2, 2.1 Hz),
3.95 (3H, s), 1.73 (6H, s).
[2848] HPLC retention time: 2.33 min (analysis condition S)
Example 394
[2849] Compound I2-2
4-(4-Chloro-3-methoxy-phenyl)-4-methyl-3-oxo-pentanoic acid ethyl
ester
##STR00409##
[2851] Under the same conditions as the method for synthesizing
Compound K3, the title compound was prepared from Compound
I2-1.
[2852] .sup.1H-NMR (270 MHz, DMSO-d.sub.6) .delta.: 7.42 (1H, d,
J=8.1 Hz), 6.92 (1H, d, J=2.1 Hz), 6.86 (1H, dd, J=8.2, 2.3 Hz),
4.01 (2H, q, J=7.1 Hz), 3.87 (3H, s), 3.43 (2H, s), 1.44 (6H, s),
1.12 (3H, t, J=7.2 Hz).
[2853] LCMS: m/z 299, 301 [M+H].sup.+
[2854] HPLC retention time: 2.52, 3.05 min (analysis condition
S)
Example 395
[2855] Compound I2-3
4-(4-Chloro-3-methoxy-phenyl)-2-(4-cyano-2-nitro-phenyl)-4-methyl-3-oxo-pe-
ntanoic acid ethyl ester
##STR00410##
[2857] Under the same conditions as the method for synthesizing
Compound K4, the title compound was obtained as a crude product
from Compound I2-2.
Example 396
[2858] Compound I2-4
2-[1-(4-Chloro-3-methoxy-phenyl)-1-methyl-ethyl]-6-cyano-1H-indole-3-carbo-
xylic acid ethyl ester
##STR00411##
[2860] Under the same conditions as the method for synthesizing
Compound K5, the title compound was obtained from Compound
I2-3.
[2861] LCMS: m/z 397, 399 [M+H].sup.+
[2862] HPLC retention time: 2.83 min (analysis condition S)
Example 397
[2863] Compound I3
9-Chloro-8-methoxy-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-
-carbonitrile
##STR00412##
[2865] (Method 1) Under the same conditions as the method for
synthesizing Compound A.sup.4, the title compound was obtained from
Compound I1-2.
[2866] (Method 2) Under the same conditions as the method for
synthesizing Compound L8-1, the title compound was obtained from
Compound I2-4.
[2867] .sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta.: 12.79 (1H, s),
8.27-8.31 (1H, m), 8.12 (1H, s), 8.00-8.02 (1H, m), 7.58-7.63 (1H,
m), 7.51 (1H, s), 4.03 (3H, s), 1.80 (6H, s).
[2868] LCMS: m/z 351 [M+H].sup.+
[2869] HPLC retention time: 2.87 min (analysis condition U)
Example 398
[2870] Compound I4
9-Chloro-8-hydroxy-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-
-carbonitrile
##STR00413##
[2872] Under the same conditions as the method for synthesizing
Compound E3-2, the title compound was prepared from Compound
I3.
[2873] LCMS: m/z 337 [M+H].sup.+
[2874] HPLC retention time: 2.47 min (analysis condition U)
Example 399
[2875] Compound I5
Trifluoro-methanesulfonic acid
9-chloro-3-cyano-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-y-
l ester
##STR00414##
[2877] Under the same conditions as the method for synthesizing
Compound B1, the title compound was prepared from Compound I4.
[2878] LCMS: m/z 469 [M+H].sup.+
[2879] HPLC retention time: 3.40 min (analysis condition U)
Example 400
[2880] Compound I6-1
9-Chloro-6,6-dimethyl-11-oxo-8-(4-pyrrolidin-1-yl-piperidin-1-yl)-6,11-dih-
ydro-5H-benzo[b]carbazole-3-carbonitrile
##STR00415##
[2882] Under the same conditions as the method for synthesizing
Compound B2-1, the title compound was prepared from Compound I5 and
4-pyrrolidin-1-yl-piperidine.
[2883] LCMS: m/z 473 [M+H].sup.+
[2884] HPLC retention time: 2.25 min (analysis condition U)
Example 401
[2885] Compound I6-2
9-Chloro-8-(4-isopropyl-piperazin-1-yl)-6,6-dimethyl-11-oxo-6,11-dihydro-5-
H-benzo[b]carbazole-3-carbonitrile
##STR00416##
[2887] Under the same conditions as the method for synthesizing
Compound B2-1, the title compound was prepared from Compound
I5.
[2888] LCMS: m/z 447 [M+H].sup.+
[2889] HPLC retention time: 2.30 min (analysis condition U)
Example 402
[2890] Compound I6-3
9-Chloro-6,6-dimethyl-8-morpholin-4-yl-11-oxo-6,11-dihydro-5H-benzo[b]carb-
azole-3-carbonitrile
##STR00417##
[2892] Under the same conditions as the method for synthesizing
Compound B2-1, the title compound was prepared from 15 and
morpholine.
[2893] .sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta.: 12.79 (1H, s),
8.28 (1H, d, 8.0 Hz), 8.09 (1H, s), 8.00 (1H, s), 7.59 (1H, d, 8.0
Hz), 7.45 (1H, s), 3.75-3.81 (4H, m), 3.13-3.19 (4H, m), 1.76 (6H,
s)
[2894] LCMS: m/z 406 [M+H].sup.+
[2895] HPLC retention time: 2.88 min (analysis condition U)
Example 403
[2896] Compound I6-4
9-Chloro-6,6-dimethyl-8-(4-morpholin-4-yl-piperidin-1-yl)-11-oxo-6,11-dihy-
dro-5H-benzo[b]carbazole-3-carbonitrile
##STR00418##
[2898] Under the same conditions as the method for synthesizing
Compound B2-1, the title compound was prepared from Compound I5 and
4-piperidin-4-yl-morpholine.
[2899] .sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta.: 12.75 (1H, s),
8.28 (1H, d, 8.0 Hz), 8.07 (1H, s), 8.00 (1H, s), 7.59 (1H, d, 8.0
Hz), 7.41 (1H, s), 3.55-3.62 (4H, m), 3.47-3.56 (4H, m), 2.75-2.86
(2H, m), 2.45-2.55 (4H, m), 2.28-2.39 (1H, m), 1.86-1.96 (2H, m),
1.76 (6H, s), 1.52-1.66 (2H, m)
[2900] LCMS: m/z 489 [M+H].sup.+
[2901] HPLC retention time: 1.97 min (analysis condition U)
Example 404
[2902] Compound I6-5-1
[1-(9-Chloro-3-cyano-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol--
8-yl)-piperidin-4-yl]-carbamic acid tert-butyl ester
##STR00419##
[2904] Under the same conditions as the method for synthesizing
Compound B2-1, the title compound was prepared from Compound I5 and
piperidin-4-yl-carbamic acid tert-butyl ester.
[2905] LCMS: m/z 519 [M+H].sup.+
[2906] HPLC retention time: 3.27 min (analysis condition U)
Example 405
[2907] Compound I6-5-2
8-(4-Amino-piperidin-1-yl)-9-chloro-6,6-dimethyl-11-oxo-6,11-dihydro-5H-be-
nzo[b]carbazole-3-carbonitrile
##STR00420##
[2909] Under the same conditions as the method for synthesizing
Compound A8-1, the title compound was prepared from Compound
I6-5-1.
[2910] LCMS: m/z 419 [M+H].sup.+
[2911] HPLC retention time: 2.12 min (analysis condition U)
Example 406
[2912] Compound I6-6
9-Chloro-6,6-dimethyl-11-oxo-8-piperazin-1-yl-6,11-dihydro-5H-benzo[b]carb-
azole-3-carbonitrile
##STR00421##
[2914] Under the same conditions as the method for synthesizing
Compound B2-1, the title compound was prepared from Compound I5 and
piperazine.
[2915] LCMS: m/z 405 [M+H].sup.+
[2916] HPLC retention time: 1.87 min (analysis condition U)
Example 407
[2917] Compound I7-1
N-[1-(9-Chloro-3-cyano-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazo-
l-8-yl)-piperidin-4-yl]-methanesulfonamide
##STR00422##
[2919] Under the same conditions as the method for synthesizing
Compound A9-1, the title compound was prepared from Compound
I6-5-2.
[2920] LCMS: m/z 497 [M+H].sup.+
[2921] HPLC retention time: 2.62 min (analysis condition U)
Example 408
[2922] Compound I7-2
9-Chloro-6,6-dimethyl-8-(4-oxetan-3-yl-piperazin-1-yl)-11-oxo-6,11-dihydro-
-5H-benzo[b]carbazole-3-carbonitrile
##STR00423##
[2924] Under the same conditions as the method for synthesizing
Compound B2-1, the title compound was prepared from Compound I5 and
1-oxetan-3-yl-piperazine.
[2925] .sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta.: 12.78 (1H, s),
8.27-8.31 (1H, m), 8.07-8.09 (1H, s), 7.99-8.02 (1H, m), 7.59-7.62
(1H, m), 7.44-7.46 (1H, s), 4.54-4.60 (2H, m), 4.44-4.51 (2H, m),
3.47-3.55 (1H, m), 3.16-3.24 (4H, m), 2.40-2.55 (4H, m), 1.77 (6H,
s)
[2926] LCMS: m/z 461 [M+H].sup.+
[2927] HPLC retention time: 2.13 min (analysis condition U)
Example 409
[2928] Compound I7-3
9-Chloro-8-(4-cyclopropyl-piperazin-1-yl)-6,6-dimethyl-11-oxo-6,11-dihydro-
-5H-benzo[b]carbazole-3-carbonitrile
##STR00424##
[2930] Under the same conditions as the method for synthesizing
Compound B2-1, the title compound was prepared from Compound I5 and
1-cyclopropylpiperazine.
[2931] LCMS: m/z 445 [M+H].sup.+
[2932] HPLC retention time: 1.97 min (analysis condition U)
Example 410
[2933] Compound I7-4
9-Chloro-8-(4-cyclobutyl-piperazin-1-yl)-6,6-dimethyl-11-oxo-6,11-dihydro--
5H-benzo[b]carbazole-3-carbonitrile
##STR00425##
[2935] Under the same conditions as the method for synthesizing
Compound B3-32, the title compound was prepared from Compound I6-6
and cyclobutanone.
[2936] .sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta.: 12.78 (1H, s),
8.29 (1H, d, 8.5 Hz), 8.08 (1H, s), 8.01 (1H, s), 7.60 (1H, d, 8.5
Hz), 7.44 (1H, s), 3.17-3.15 (4H, m), 2.83-2.76 (1H, m), 2.47-2.44
(4H, m), 2.04-1.97 (2H, m), 1.82 (2H, t, 9.8 Hz), 1.77 (6H, s),
1.70-1.63 (2H, m)
[2937] LCMS: m/z 459, 461 [M+H].sup.+
[2938] HPLC retention time: 1.63 min (analysis condition S)
Example 411
[2939] Compound J2
6-Methoxy-1,1-dimethyl-3,4-dihydro-1H-naphthalen-2-one
##STR00426##
[2941] Under the same conditions as the method for synthesizing
Compound A2, the title compound was prepared from
6-methoxy-3,4-dihydro-H-naphthalen-2-one and iodomethane.
[2942] LCMS: m/z 205 [M+H].sup.+
[2943] HPLC retention time: 1.54 min (analysis condition S)
Example 412
[2944] Compound J3-1
9-Methoxy-6,6-dimethyl-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile
##STR00427##
[2946] Under the same conditions as the method for synthesizing
Compound E2-1, the title compound was prepared from Compound J2 and
3-hydrazino-benzonitrile.
[2947] LCMS: m/z 303 [M+H].sup.+
[2948] HPLC retention time: 2.73 min (analysis condition S)
Example 413
[2949] Compound J3-2
9-Methoxy-6,6-dimethyl-6,11-dihydro-5H-benzo[b]carbazole-1-carbonitrile
##STR00428##
[2951] Compound J3-2 was obtained as a by-product of the synthesis
of Compound J3-1.
[2952] LCMS: m/z 303 [M+H].sup.+
[2953] HPLC retention time: 2.67 min (analysis condition S)
Example 414
[2954] Compound J4
9-Methoxy-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonit-
rile
##STR00429##
[2956] Under the same conditions as the method for synthesizing
Compound A4, the title compound was prepared from Compound J3-1 and
Compound J3-2 (mixture).
[2957] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 12.79 (1H, s), 8.33 (1H,
d, J=8.2 Hz), 8.02 (1H, s), 7.81 (1H, d, J=8.6 Hz), 7.69 (1H, d,
J=3.0 Hz), 7.63 (1H, dd, J=8.3, 1.4 Hz), 7.28 (1H, dd, J=8.7, 3.0
Hz), 3.87 (3H, s), 1.74 (6H, s).
[2958] LCMS: m/z 317 [M+H].sup.+
[2959] HPLC retention time: 2.25 min (analysis condition S)
Example 415
[2960] Compound J5
9-Hydroxy-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonit-
rile
##STR00430##
[2962] Under the same conditions as the method for synthesizing
Compound A6, the title compound was prepared from Compound J4.
[2963] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 12.75 (1H, s), 9.77 (1H,
s), 8.32 (1H, dd, J=8.2, 0.7 Hz), 8.01 (1H, s), 7.68 (1H, d, J=8.6
Hz), 7.62 (1H, dd, J=8.2, 1.4 Hz), 7.58 (1H, d, J=2.8 Hz), 7.10
(1H, dd, J=8.6, 2.8 Hz), 1.72 (6H, s).
[2964] LCMS: m/z 303 [M+H].sup.+
[2965] HPLC retention time: 1.75 min (analysis condition S)
Example 416
[2966] Compound J6
Trifluoro-methanesulfonic acid
3-cyano-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-9-yl
ester
##STR00431##
[2968] Under the same conditions as the method for synthesizing
Compound B1, the title compound was prepared from Compound J5.
[2969] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 12.95 (1H, s), 8.31 (1H,
d, J=8.2 Hz), 8.15 (2H, m), 8.05 (1H, s), 7.87 (1H, dd, J=9.0, 2.7
Hz), 7.65 (1H, d, J=8.2 Hz), 1.80 (6H, s).
[2970] LCMS: m/z 435 [M+H].sup.+
[2971] HPLC retention time: 2.75 min (analysis condition S)
Example 417
[2972] Compound J7-1
9-Isopropoxy-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbo-
nitrile
##STR00432##
[2974] Under the same conditions as the method for synthesizing
Compound A7-1, the title compound was prepared from Compound J4 and
isopropanol.
[2975] LCMS: m/z 345 [M+H].sup.+
[2976] HPLC retention time: 3.87 min (analysis condition W)
Example 418
[2977] Compound J7-2-1
4-(3-Cyano-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-9-yl
oxy)-piperidine-1-carboxylic acid tert-butyl ester
##STR00433##
[2979] Under the same conditions as the method for synthesizing
Compound A7-1, the title compound was prepared from Compound
J5.
[2980] LCMS: m/z 486 [M+H].sup.+
[2981] HPLC retention time: 4.15 min (analysis condition W)
Example 419
[2982] Compound J7-2-2
6,6-Dimethyl-11-oxo-9-(piperidin-4-yloxy)-6,11-dihydro-5H-benzo[b]carbazol-
e-3-carbonitrile
##STR00434##
[2984] Under the same conditions as the method for synthesizing
Compound A8-1, the title compound was prepared from Compound
J7-2-1.
[2985] LCMS: m/z 386 [M+H].sup.+
[2986] HPLC retention time: 2.48 min (analysis condition W)
Example 420
[2987] Compound J7-2-3
6,6-Dimethyl-9-(1-oxetan-3-yl-piperidin-4-yl
oxy)-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile
##STR00435##
[2989] Under the same conditions as the method for synthesizing
Compound B3-32, the title compound was prepared from Compound
J7-2-2 and oxetan-3-one.
[2990] LCMS: m/z 442 [M+H].sup.+
[2991] HPLC retention time: 2.61 min (analysis condition W)
Example 421
[2992] Compound J7-3
6,6-Dimethyl-11-oxo-9-(4-pyrrolidin-1-yl-piperidin-1-yl)-6,11-dihydro-5H-b-
enzo[b]carbazole-3-carbonitrile
##STR00436##
[2994] Under the same conditions as the method for synthesizing
Compound B2-10, the title compound was prepared from Compound J6
and 4-pyrrolidin-1-yl-piperidine.
[2995] .sup.1H-NMR (270 MHz, DMSO-d.sub.6) .delta.: 13.12 (1H, s),
8.32 (1H, d, J=8.1 Hz), 8.01 (1H, s), 7.72 (1H, d, J=8.7 Hz), 7.68
(1H, d, J=2.6 Hz), 7.62 (1H, dd, J=8.2, 1.2 Hz), 7.38 (1H, dd,
J=9.1, 2.8 Hz), 3.90 (2H, d, J=11.5 Hz), 2.76 (2H, t, J=12.2 Hz),
2.14 (2H, d, J=10.9 Hz), 1.91 (4H, br), 1.74 (6H, s).
[2996] LCMS: m/z 439 [M+H].sup.+
[2997] HPLC retention time: 1.35 min (analysis condition S)
Example 422
[2998] Compound J7-4
9-(4-Isopropyl-piperazin-1-yl)-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b-
]carbazole-3-carbonitrile
##STR00437##
[3000] Under the same conditions as the method for synthesizing
Compound B2-10, the title compound was prepared from Compound J6
and 1-isopropyl-piperazine. .sup.1H-NMR (270 MHz, DMSO-d.sub.6)
.delta.: 12.80 (1H, s), 8.33 (1H, d, J=7.6 Hz), 8. 02 (1H, s), 7.66
(3H, m), 7.33 (1H, d, J=8.2 Hz), 3.21 (4H, br), 2.66 (5H, m), 1.72
(6H, s), 1.02 (6H, d, J=6.3 Hz).
[3001] LCMS: m/z 413 [M+H].sup.+
[3002] HPLC retention time: 1.38 min (analysis condition S)
Example 423
[3003] Compound J7-5
6,6-Dimethyl-11-oxo-9-pyrrolidin-1-yl-6,11-dihydro-5H-benzo[b]carbazole-3--
carbonitrile
##STR00438##
[3005] Under the same conditions as the method for synthesizing
Compound B2-10, the title compound was prepared from Compound J6
and pyrrolidine.
[3006] .sup.1H-NMR (270 MHz, DMSO-d.sub.6) .delta.: 8.24 (1H, d,
J=8.1 Hz), 7.91 (1H, s), 7.59 (1H, d, J=8.6 Hz), 7.45 (1H, d, J=7.9
Hz), 7.30 (1H, d, J=2.6 Hz), 6.85 (1H, dd, J=8.6, 2.8 Hz), 3.31
(4H, t, J=6.3 Hz), 1.99 (4H, t, J=6.2 Hz), 1.67 (6H, s).
[3007] LCMS: m/z 356 [M+H].sup.+
[3008] HPLC retention time: 2.38 min (analysis condition S)
Example 424
[3009] Compound J7-6
6,6-Dimethyl-11-oxo-9-((S)-2-pyrrolidin-1-yl
methyl-pyrrolidin-1-yl)-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile
##STR00439##
[3011] Under the same conditions as the method for synthesizing
Compound B2-10, the title compound was prepared from Compound J6
and (S)-2-pyrrolidin-1-yl methyl-pyrrolidine.
[3012] LCMS: m/z 439 [M+H].sup.+
[3013] HPLC retention time: 1.50 min (analysis condition S)
Example 425
[3014] Compound J7-7
6,6-Dimethyl-11-oxo-9-piperazin-1-yl-6,11-dihydro-5H-benzo[b]carbazole-3-c-
arbonitrile
##STR00440##
[3016] Under the same conditions as the method for synthesizing
Compound B2-10, the title compound was prepared from Compound J6
and piperazine.
[3017] LCMS: m/z 371 [M+H].sup.+
[3018] HPLC retention time: 1.31 min (analysis condition S)
Example 426
[3019] Compound J7-8
9-(3-Hydroxy-3-methyl-but-1-ynyl)-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benz-
o[b]carbazole-3-carbonitrile
##STR00441##
[3021] Under the same conditions as the method for synthesizing
Compound E4-2-1, the title compound was prepared from Compound
J6.
[3022] LCMS: m/z 369 [M+H].sup.+
[3023] HPLC retention time: 2.16 min (analysis condition S)
Example 427
[3024] Compound J7-9
9-Ethynyl-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonit-
rile
##STR00442##
[3026] Under the same conditions as the method for synthesizing
Compound E4-2-2, the title compound was prepared from Compound
J7-8.
[3027] .sup.1H-NMR (270 MHz, DMSO-d.sub.6) .delta.: 8.31 (1H, d,
J=8.1 Hz), 8.23 (1H, d, J=1.8 Hz), 8.02 (1H, d, J=1.3 Hz), 7.93
(1H, d, J=8.2 Hz), 7.78 (1H, dd, J=8.2, 1.8 Hz), 7.61 (1H, dd,
J=8.1, 1.3 Hz), 4.31 (1H, s), 1.77 (6H, s).
[3028] LCMS: m/z 311 [M+H].sup.+
[3029] HPLC retention time: 2.40 min (analysis condition S)
Example 428
[3030] Compound J7-10-1
4-(3-Cyano-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-9-yl)-3,6--
dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester
##STR00443##
[3032] Under the same conditions as the method for synthesizing
Compound B2-22-1, the title compound was prepared from Compound
J6.
[3033] LCMS: m/z 468 [M+H].sup.+
[3034] HPLC retention time: 2.90 min (analysis condition S)
Example 429
[3035] Compound J7-10-2
6,6-Dimethyl-11-oxo-9-(1,2,3,6-tetrahydro-pyridin-4-yl)-6,11-dihydro-5H-be-
nzo[b]carbazole-3-carbonitrile
##STR00444##
[3037] Under the same conditions as the method for synthesizing
Compound A8-1, the title compound was prepared from Compound
J7-10-1.
[3038] LCMS: m/z 368 [M+H].sup.+
[3039] HPLC retention time: 1.27 min (analysis condition S)
Example 430
[3040] Compound J7-11-1
9-(Piperidin-4-ylmethyl)-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carba-
zole-3-carbonitrile
##STR00445##
[3042] Under the same conditions as the method for synthesizing
Compound B2-25-1 and Compound B2-25-2, the title compound was
prepared from Compound J6.
[3043] LCMS: m/z 384 [M+H].sup.+
[3044] HPLC retention time: 1.42 min (analysis condition S)
Example 431
[3045] Compound J7-11-2
9-(1-Isopropyl-piperidin-4-ylmethyl)-6,6-dimethyl-11-oxo-6,11-dihydro-5H-b-
enzo[b]carbazole-3-carbonitrile
##STR00446##
[3047] Under the same conditions as the method for synthesizing
Compound B3-32, the title compound was prepared from Compound
J7-11-1 and acetone.
[3048] .sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta.: 12.79 (1H, s),
8.33 (1H, d, 7.9 Hz), 8.01 (1H, s), 7.98 (1H, d, 1.8 Hz), 7.79 (1H,
d, 7.9 Hz), 7.61 (1H, d, 7.9 Hz), 7.51-7.49 (1H, m), 2.74 (2H, d,
11.0 Hz), 2.64-2.60 (3H, m), 2.04 (2H, t, 10.7 Hz), 1.77 (6H, s),
1.60-1.51 (3H, m), 1.23-1.14 (2H, m), 0.94 (6H, d, 6.7 Hz)
[3049] LCMS: m/z 426 [M+H].sup.+
Example 432
[3050] Compound J7-12
4-(3-Cyano-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-9-yl
oxy)-butyric acid
##STR00447##
[3052]
9-Hydroxy-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-c-
arbonitrile (Compound J5, 30 mg, 0.099 mmol), 4-bromo-butyric acid
methyl ester (24.9 .mu.l, 0.198 mmol) and cesium carbonate (64.5
mg, 0.198 mmol) were dissolved in DMA (0.20 ml) and stirred at room
temperature for 4 hr. Water was added to the reaction solution,
which was then extracted with diethyl ether. The organic layer was
washed with saturated brine and dried over anhydrous magnesium
sulfate. The yellow solid obtained after concentration under
reduced pressure was purified by silica gel column chromatography
(methylene chloride/MeOH) to obtain
4-(3-cyano-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-9-yl
oxy)-butyric acid methyl ester as an intermediate. The intermediate
was dissolved in MeOH (0.50 ml), added with aqueous solution of
sodium hydroxide (6 mol/l) and stirred at room temperature for 30
min. The reaction solution was added with hydrochloric acid (3
mol/), extracted with diethyl ether. The organic layer was washed
with saturated brine and dried over anhydrous magnesium sulfate.
After concentration under reduced pressure, white solid was
obtained, which was then washed with methylene chloride to obtain
the title compound (19.0 mg, 70%).
[3053] LCMS: m/z 389 [M+H].sup.+
[3054] HPLC retention time: 2.39 min (analysis condition F)
Example 433
[3055] Compound J7-13
5-(3-Cyano-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-9-yl
oxy)-pentanoic acid
##STR00448##
[3057] Under the same conditions as the method for synthesizing
Compound J7-12, Compound J5 and 5-bromo-pentanoic acid methyl ester
were reacted to obtain the target compound (19.5 mg, 64%).
[3058] LCMS: m/z 403 [M+H].sup.+
[3059] HPLC retention time: 2.49 min (analysis condition F)
Example 434
[3060] Compound J7-14
6-(3-Cyano-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-9-yl
oxy)-hexanoic acid
##STR00449##
[3062] Under the same conditions as the method for synthesizing
Compound J7-12, Compound J5 and 6-bromo-hexanoic acid ethyl ester
were reacted to obtain the target compound (19.6 mg, 66%).
[3063] LCMS: m/z 417 [M+H].sup.+
[3064] HPLC retention time: 2.61 min (analysis condition F)
Example 435
[3065] Compound J7-15
3-[2-(3-Cyano-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-9-yl
oxy)-ethoxy]-propionic acid
##STR00450##
[3067] Under the same conditions as the method for synthesizing
Compound A7-1, Compound JJ2 and 3-(2-hydroxy-ethoxy)-propionic acid
tert-butyl ester were reacted to obtain
3-[2-(3-bromo-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-9-yl
oxy)-ethoxy]-propionic acid tert-butyl ester.
[3068] The resultant was dissolved in DMA (0.30 ml), added with
copper cyanide (25.5 mg, 0.285 mmol), and stirred at 200.degree. C.
for 1 hr under irradiation with microwave. The reaction solution
was diluted with ethyl acetate, washed with saturated brine and
dried over anhydrous magnesium sulfate. The residues obtained after
concentration under reduced pressure were dissolved in methylene
chloride (0.75 ml). The solution was added with TFA (250 l) and
stirred at room temperature for 5 min. Thereafter, the residues
obtained from the reaction solution after concentration under
reduced pressure were purified by silica gel column chromatography
(methylene chloride/MeOH) to obtain the title compound (5.6 mg,
14%).
[3069] LCMS: m/z 419 [M+H].sup.+
[3070] HPLC retention time: 2.31 min (analysis condition F)
Example 436
[3071] Compound J7-16
6,6-Dimethyl-11-oxo-9-(pyridin-4-ylmethoxy)-6,11-dihydro-5H-benzo[b]carbaz-
ole-3-carbonitrile
##STR00451##
[3073] Under the same conditions as the method for synthesizing
Compound A7-1, the title compound was prepared from Compound J5 and
pyridin-4-yl-methanol (pale yellow solid, 6.1 mg, 31%).
[3074] LCMS: m/z 394 [M+H].sup.+
[3075] HPLC retention time: 1.97 min (analysis condition F)
Example 437
[3076] Compound J7-17
6,6-Dimethyl-11-oxo-9-(pyridin-3-yl
methoxy)-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile
##STR00452##
[3078] Under the same conditions as the method for synthesizing
Compound JJ3-1, the title compound was prepared from Compound J5
and pyridin-3-yl-methanol (pale yellow solid, 7.9 mg, 38%).
[3079] LCMS: m/z 394 [M+H].sup.+
[3080] HPLC retention time: 1.99 min (analysis condition F)
Example 438
[3081] Compound J8-1
6,6-Dimethyl-9-(4-oxetan-3-yl-piperazin-1-yl)-11-oxo-6,11-dihydro-5H-benzo-
[b]carbazole-3-carbonitrile
##STR00453##
[3083] Under the same conditions as the method for synthesizing
Compound B3-32, the title compound was prepared from Compound J7-7
and oxetan-3-one.
[3084] LCMS: m/z 427 [M+H].sup.+
[3085] HPLC retention time: 1.31 min (analysis condition S)
[3086] Compound J8-2
9-(4-Cyclopropyl-piperazin-1-yl)-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo-
[b]carbazole-3-carbonitrile
##STR00454##
[3088] Under the same conditions as the method for synthesizing
Compound B3-32, the title compound was prepared from Compound J7-7
and (1-ethoxycyclopropoxy)trimethylsilane.
[3089] LCMS: m/z 411 [M+H].sup.+
[3090] HPLC retention time: 1.39 min (analysis condition S)
Example 440
[3091] Compound J8-3
9-(1-Methanesulfonyl-1,2,3,6-tetrahydro-pyridin-4-yl)-6,6-dimethyl-11-oxo--
6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile
##STR00455##
[3093] Under the same conditions as the method for synthesizing
Compound A9-1, the title compound was prepared from Compound
J7-10-2.
[3094] .sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta.: 12.81 (1H, s),
8.33 (1H, d, 7.9 Hz), 8.26 (1H, d, 2.4 Hz), 8.01 (1H, s), 7.88-7.81
(2H, m), 7.61 (1H, d, 7.9 Hz), 6.36 (1H, s), 3.93 (2H, d, 3.0 Hz),
3.45 (2H, t, 5.8 Hz), 2.97 (3H, s), 2.73-2.70 (2H, m), 1.78 (6H,
s)
[3095] LCMS: m/z 446 [M+H].sup.+
[3096] HPLC retention time: 2.15 min (analysis condition S)
[3097] Compound J8-4
9-(1-Isopropyl-1,2,3,6-tetrahydro-pyridin-4-yl)-6,6-dimethyl-11-oxo-6,11-d-
ihydro-5H-benzo[b]carbazole-3-carbonitrile
##STR00456##
[3099] Under the same conditions as the method for synthesizing
Compound B3-32, the title compound was prepared from Compound
J7-10-2 and acetone.
[3100] .sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta.: 12.82 (1H, s),
8.33 (1H, d, 7.9 Hz), 8.22 (1H, d, 1.8 Hz), 8.02 (1H, s), 7.84 (1H,
d, 8.5 Hz), 7.78 (1H, dd, 8.2, 2.1 Hz), 7.62 (1H, d, 7.9 Hz), 6.32
(1H, t, 3.7 Hz), 3.23-3.20 (2H, m), 2.83-2.76 (1H, m), 2.72 (2H, t,
5.5 Hz), 2.56-2.54 (2H, m), 1.78 (6H, s), 1.06 (6H, d, 6.7 Hz)
[3101] LCMS: m/z 410 [M+H].sup.+
[3102] HPLC retention time: 1.38 min (analysis condition S)
Example 442
[3103] Compound J8-5
6,6-Dimethyl-9-(1-oxetan-3-yl-1,2,3,6-tetrahydro-pyridin-4-yl)-11-oxo-6,11-
-dihydro-5H-benzo[b]carbazole-3-carbonitrile
##STR00457##
[3105] Under the same conditions as the method for synthesizing
Compound B3-32, the title compound was prepared from Compound
J7-10-2 and oxetan-3-one.
[3106] .sup.1H-NMR (270 MHz, DMSO-d.sub.6) .delta.: 12.81 (1H, br.
s), 8.34 (1H, d, J=8.2 Hz), 8.22 (1H, d, J=1.8 Hz), 8.03 (1H, s),
7.76-7.90 (2H, m), 7.64 (1H, dd, J=8.2, 1.8 Hz), 6.25-6.34 (1H, m),
4.60 (2H, dd, J=6.6, 6.0 Hz), 4.52 (2H, dd, J=6.6, 6.0 Hz), 3.57
(1H, t, J=6.0 Hz), 3.03 (2H, m), 2.55 (4H, m), 1.77 (6H, s).
[3107] LCMS: m/z 424 [M+H].sup.+
[3108] HPLC retention time: 1.34 min (analysis condition S)
Example 443
[3109] Compound J8-6
9-(1-Cyclopropyl-1,2,3,6-tetrahydro-pyridin-4-yl)-6,6-dimethyl-11-oxo-6,11-
-dihydro-5H-benzo[b]carbazole-3-carbonitrile
##STR00458##
[3111] Under the same conditions as the method for synthesizing
Compound B3-32, the title compound was prepared from Compound
J7-10-2 and (1-ethoxycyclopropoxy)trimethylsilane.
[3112] LCMS: m/z 408 [M+H].sup.+
[3113] HPLC retention time: 1.36 min (analysis condition S)
Example 444
[3114] Compound J9-1
4-(3-Cyano-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-9-yl)-pipe-
ridine-1-carboxylic acid tert-butyl ester
##STR00459##
[3116] Under the same conditions as the method for synthesizing
Compound B3-13-1, the title compound was prepared from Compound
J7-10-1.
[3117] LCMS: m/z 414, 470 [M+H].sup.+
[3118] HPLC retention time: 2.83 min (analysis condition S)
Example 445
[3119] Compound J9-2
6,6-Dimethyl-11-oxo-9-piperidin-4-yl-6,11-dihydro-5H-benzo[b]carbazole-3-c-
arbonitrile
##STR00460##
[3121] Under the same conditions as the method for synthesizing
Compound A8-1, the title compound was prepared from Compound
J9-1.
[3122] LCMS: m/z 370 [M+H].sup.+
[3123] HPLC retention time: 1.30 min (analysis condition S)
Example 446
[3124] Compound J9-3
9-(1-Isopropyl-piperidin-4-yl)-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b-
]carbazole-3-carbonitrile
##STR00461##
[3126] Under the same conditions as the method for synthesizing
Compound A9-1, the title compound was prepared from Compound J9-2
and 2-bromopropane.
[3127] .sup.1H-NMR (270 MHz, DMSO-d.sub.6) .delta.: 12.83 (1H, s),
8.34 (2H, d, J=8.1 Hz), 8.05 (2H, m), 7.82 (1H, d, J=8.1 Hz), 7.61
(2H, m), 3.02 (2H, br), 2.42 (2H, br), 1.76 (6H, s), 1.06 (6H, d,
J=6.4 Hz).
[3128] LCMS: m/z 412 [M+H].sup.+
[3129] HPLC retention time: 1.45 min (analysis condition S)
Example 447
[3130] Compound J9-4
6,6-Dimethyl-9-(1-oxetan-3-yl-piperidin-4-yl)-11-oxo-6,11-dihydro-5H-benzo-
[b]carbazole-3-carbonitrile
##STR00462##
[3132] Under the same conditions as the method for synthesizing
Compound B3-13-1, the title compound was prepared from Compound
J8-5.
[3133] LCMS: m/z 426 [M+H].sup.+
[3134] HPLC retention time: 1.26 min (analysis condition S)
Example 448
[3135] Compound J9-5
9-(1-Cyclopropyl-piperidin-4-yl)-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo-
[b]carbazole-3-carbonitrile
##STR00463##
[3137] Under the same conditions as the method for synthesizing
Compound B3-13-1, the title compound was prepared from Compound
J8-6.
[3138] LCMS: m/z 410 [M+H].sup.+
[3139] HPLC retention time: 1.43 min (analysis condition S)
Example 449
[3140] Compound JJ1
3-Bromo-9-methoxy-6,6-dimethyl-5,6-dihydro-benzo[b]carbazol-11-one
##STR00464##
[3142] 6-Methoxy-1,1-dimethyl-3,4-dihydro-1H-naphthalen-2-one
(Compound J2, 2.15 g, 10.5 mmol) and 3-bromophenylhydrazine
hydrochloric acid salt (3.11 g, 1.3 eq.) were dissolved in acetic
acid (12 mL), and stirred at 100.degree. C. for 2.5 hr under
nitrogen atmosphere. After cooling, the reaction solution was added
with ethyl acetate, washed with water, saturated aqueous solution
of sodium hydrogen carbonate, and saturated brine, and dried over
magnesium sulfate. After the filtration, it was concentrated under
reduced pressure. The resulting residues were dissolved in THF (30
mL) and water (3 mL), added with DDQ (5.96 g, 2.5 eq.) at 0.degree.
C., and then stirred at room temperature overnight. The reaction
solution was added with MTBE, washed with 0.5 N aqueous solution of
sodium hydroxide and saturated brine, and dried over magnesium
sulfate. After filtration and the concentration under reduced
pressure, the resulting residues were washed with MTBE to obtain
the title compound (brown solid, 1.80 g, 46%).
[3143] .sup.1H-NMR (270 MHz, DMSO-d.sub.6) .delta.: 12.4 (1H, s),
8.12 (1H, d, J=8.6 Hz), 7.79 (1H, d, J=8.9 Hz), 7.67-7.68 (2H, m),
7.40 (1H, dd, J=1.7, 8.6 Hz), 7.26 (1H, dd, J=2.6, 8.9 Hz), 3.86
(3H, s), 1.72 (6H, s),
[3144] LCMS: m/z 370 [M+H].sup.+
[3145] HPLC retention time: 6.45 min (analysis condition H)
Example 450
[3146] Compound JJ2
3-Bromo-9-hydroxy-6,6-dimethyl-5,6-dihydro-benzo[b]carbazol-11-one
##STR00465##
[3148]
3-Bromo-9-methoxy-6,6-dimethyl-5,6-dihydro-benzo[b]carbazol-11-one
(Compound JJ, 1.50 g, 4.05 mmol) and pyridinium chloride (15.2 g,
32.5 eq.) were stirred at 160.degree. C. for 12 hr under nitrogen
atmosphere. After cooling, water and ethyl acetate were added and
the resulting suspension was filtered. The organic layer was washed
with water and saturated brine and dried over magnesium sulfate.
After filtration and the concentration under reduced pressure, the
resulting residues were washed with MTBE to obtain the title
compound (brown solid, 1.47 g, 100%).
[3149] .sup.1H-NMR (270 MHz, DMSO-d.sub.6) .delta.: 12.4 (1H, s),
9.71 (1H, s), 8.11 (1H, d, J=8.2 Hz), 7.64-7.68 (2H, m), 7.57 (1H,
d, J=3.0 Hz), 7.38 (1H, dd, J=1.7, 8.2 Hz), 7.07 (1H, dd, J=3.0,
8.6 Hz), 1.69 (6H, s),
[3150] LCMS: m/z 356 [M+H].sup.+
[3151] HPLC retention time: 2.52 min (analysis condition F)
Example 451
[3152] Compound JJ3-1
3-Bromo-9-((S)-2,2-dimethyl-[1,3]dioxolan-4-yl
methoxy)-6,6-dimethyl-5,6-dihydro-benzo[b]carbazol-11-one
##STR00466##
[3154] Under nitrogen atmosphere,
3-bromo-9-hydroxy-6,6-dimethyl-5,6-dihydro-benzo[b]carbazol-11-one
(Compound JJ2, 356 mg, 1.00 mmol) and triphenylphosphine (317 mg,
1.2 eq.) were added with THF (3 ml), followed by dropwise addition
of ((S)-2,2-dimethyl-[1,3]dioxolan-4-yl)-methanol (148 .mu.l, 1.2
eq.) and diisopropyl azodicarboxylic acid (252 .mu.l, 1.3 eq.). The
mixture was then stirred at 50.degree. C. for 2 hr. After cooling,
the reaction solution was added with ethyl acetate, washed with
brine and dried over magnesium sulfate. After filtration and the
concentration under reduced pressure, the resulting residues were
purified by silica gel column chromatography (ethyl
acetate/dichloromethane) to yield the solid, which was then washed
with dichloromethane to obtain the title compound (white powder,
241.6 mg, 51%).
[3155] .sup.1H-NMR (270 MHz, DMSO-d.sub.6) .delta.: 12.4 (1H, s),
8.12 (1H, d, J=8.2 Hz), 7.79 (1H, d, J=8.9 Hz), 7.67-7.69 (2H, m),
7.40 (1H, dd, J=1.8, 8.2 Hz), 7.28 (1H, dd, J=3.0, 8.9 Hz),
4.41-4.48 (1H, m), 4.06-4.17 (2H, m), 3.79-3.85 (1H, m), 1.72 (3H,
s), 1.38 (3H, s), 1.33 (3H, s),
[3156] LCMS: m/z 470 [M+H].sup.+
[3157] HPLC retention time: 3.08 min (analysis condition F)
Example 452
[3158] Compound JJ3-2
3-Bromo-9-((R)-2,3-dihydroxy-propoxy)-6,6-dimethyl-5,6-dihydro-benzo[b]car-
bazol-11-one
##STR00467##
[3160]
3-Bromo-9-((S)-2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-6,6-dimethyl-
-5,6-dihydro-benzo[b]carbazol-11-one (Compound JJ3-1, 18.7 mg,
0.0398 mmol) was dissolved in methanol (1 mL) and THF (0.3 mL),
added with 1N hydrochloric acid (5 drops) and stirred at 50.degree.
C. for 1 hr. After cooling, the reaction solution was concentrated
under reduced pressure, and the resulting residues were added with
dichloromethane, and the solid was separated by filtration to
obtain the title compound (yellow powder, 16.8 mg, 98%).
[3161] .sup.1H-NMR (270 MHz, DMSO-d.sub.6) .delta.: 12.43 (1H, s),
8.12 (1H, d, J=8.6 Hz), 7.78 (1H, d, J=8.9 Hz), 7.67-7.70 (2H, m),
7.40 (2H, dd, J=1.8, 8.6 Hz), 7.27 (2H, dd, J=2.8, 8.9 Hz), 4.43
(2H, brs), 4.12 (1H, dd, J=9.9, 4.3 Hz), 3.96 (1H, dd, J=9.7, 6.1
Hz), 3.85 (1H, dd, J=9.9, 5.6 Hz), 3.48 (2H, d, J=5.6 Hz), 1.72
(6H, s),
[3162] LCMS: m/z 430 [M+H].sup.+
[3163] HPLC retention time: 2.02 min (analysis condition F)
Example 453
[3164] Compound JJ4-1
3-Bromo-9-((S)-2,2-dimethyl-[1,3]dioxolan-4-yl
methoxy)-5,6,6-trimethyl-5,6-dihydro-benzo[b]carbazol-11-one
##STR00468##
[3166] To the mixture of
3-bromo-9-((S)-2,2-dimethyl-[1,3]dioxolan-4-yl
methoxy)-6,6-dimethyl-5,6-dihydro-benzo[b]carbazol-11-one (Compound
JJ3-1, 33.2 mg, 0.0706 mmol) and sodium hydride (60% in oil, 6.4
mg, 2.3 eq.), DMA (0.55 mL) and methyl iodide (0.015 mL, 3.4 eq.)
were added under nitrogen atmosphere at 0.degree. C., and the
mixture was stirred at room temperature overnight. The reaction
solution was added with water and extracted with ethyl acetate. The
organic layer was washed with brine and dried over magnesium
sulfate. After filtration and the concentration under reduced
pressure, the resulting solid was washed with MTBE to obtain the
title compound (white solid, 31.2 mg, 91%).
[3167] LCMS: m/z 484 [M+H].sup.+
[3168] HPLC retention time: 3.34 min (analysis condition F)
Example 454
[3169] Compound JJ4-2
3-Bromo-9-((R)-2,3-dihydroxy-propoxy)-5,6,6-trimethyl-5,6-dihydro-benzo[b]-
carbazol-11-one
##STR00469##
[3171] Under the same conditions as the method for synthesizing
Compound JJ3-2, the title compound was prepared from Compound JJ4-1
(yellow solid, 13.3 mg, 83%).
[3172] LCMS: m/z 444 [M+H].sup.+
[3173] HPLC retention time: 2.47 min (analysis condition F)
Example 455
[3174] Compound JJ5
(3-Bromo-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-9-yl
oxy)-acetic acid
##STR00470##
[3176] Under the same conditions as the method for synthesizing
Compound A7-1,
(3-bromo-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-9-yl
oxy)-acetic acid methyl ester was prepared from Compound JJ2 and
hydroxy-acetic acid methyl ester. The resultant was dissolved in
MeOH (0.35 ml), added with aqueous solution of sodium hydroxide (6
mol/l), and stirred at room temperature for 10 min. The reaction
solution was added with hydrochloric acid (3 mol/l), extracted with
diethyl ether and dried over anhydrous magnesium sulfate. After the
concentration under reduced pressure, white solid was obtained,
which was then washed with methylene chloride to obtain the title
compound (11.2 mg, 48%).
[3177] LCMS: m/z 414 [M+H].sup.+
[3178] HPLC retention time: 2.50 min (analysis condition F)
Example 456
[3179] Compound JJ6
4-(3-Bromo-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-9-yl
oxy)-butyric acid
##STR00471##
[3181]
3-Bromo-9-hydroxy-6,6-dimethyl-5,6-dihydro-benzo[b]carbazol-11-one
(Compound JJ2, 20 mg, 0.056 mmol), 4-bromo-butyric acid methyl
ester (7.0 .mu.l, 0.056 mmol) and cesium carbonate (36.6 mg, 0.112
mmol) were dissolved in DMA (0.09 ml), and then stirred at room
temperature for 1 hr. Thereafter, 4-bromo-butyric acid methyl ester
(7.0 .mu.l, 0.056 mmol) was added thereto and the mixture was
stirred at room temperature for 3 hr, followed by further stirring
at 45.degree. C. for 30 min. The reaction solution was added with
water, extracted with diethyl ether and dried over anhydrous
magnesium sulfate. After the concentration under reduced pressure,
the resulting residues were purified by silica gel column
chromatography (ethyl acetate/hexane) to obtain
4-(3-bromo-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-9-yl
oxy)-butyric acid methyl ester. This compound was dissolved in MeOH
(0.50 ml), added with aqueous solution of sodium hydroxide (6
mol/l), and then stirred at room temperature for 10 min. The
reaction solution was added with hydrochloric acid (3 mol/),
extracted with diethyl ether, and dried over anhydrous magnesium
sulfate and concentrated under reduced pressure to obtain white
solid. This white solid was washed with methylene chloride to
obtain the title compound (6.1 mg, 25%).
[3182] LCMS: m/z 442 [M+H].sup.+
[3183] HPLC retention time: 2.65 min (analysis condition F)
Example 457
[3184] Compound JJ7-1
3-Bromo-9-[(4R,5R)-5-(tert-butyl-dimethyl-silanyloxymethyl)-2,2-dimethyl-[-
1,3]dioxolan-4-yl
methoxy]-6,6-dimethyl-5,6-dihydro-benzo[b]carbazol-11-one
##STR00472##
[3186] Under the same conditions as the method for synthesizing
Compound A7-1, the title compound (white solid, 111.5 mg, 65%) was
prepared from Compound JJ2 and
[(4R,5R)-5-(tert-butyl-dimethyl-silanyloxymethyl)-2,2-dimethyl-[1,3]dioxo-
lan-4-yl]-methanol.
[3187] LCMS: m/z 614 [M+H].sup.+
[3188] HPLC retention time: 4.04 min (analysis condition F)
Example 458
[3189] Compound JJ7-2
3-Bromo-6,6-dimethyl-9-((2R,3R)-2,3,4-trihydroxy-butoxy)-5,6-dihydro-benzo-
[b]carbazol-11-one
##STR00473##
[3191]
3-Bromo-9-[(4R,5R)-5-(tert-butyl-dimethyl-silanyloxymethyl)-2,2-dim-
ethyl-[1,3]dioxolan-4-yl
methoxy]-6,6-dimethyl-5,6-dihydro-benzo[b]carbazol-11-one (Compound
JJ7-1, 13.7 mg, 0.0223 mmol) was dissolved in THF (0.15 mL) and
methanol (0.1 mL), added with 0.5 M sulfuric acid (0.05 mL), and
then stirred at 60.degree. C. for 3 hr. After cooling, the reaction
solution was added with saturated aqueous solution of sodium
hydrogen carbonate and extracted with ethyl acetate. The organic
layer was washed with brine and dried over magnesium sulfate. After
filtration and the concentration under reduced pressure, the
resulting solid was washed with dichloromethane to obtain the title
compound (white solid, 8.4 mg, 82%).
[3192] LCMS: m/z 460 [M+H].sup.+
[3193] HPLC retention time: 2.18 min (analysis condition F)
Example 459
[3194] Compound JJ8-1
9-[(4R,5R)-5-(Tert-butyl-dimethyl-silanyloxymethyl)-2,2-dimethyl-[1,3]diox-
olan-4-yl
methoxy]-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-
-carbonitrile
##STR00474##
[3196] According to the same method as the method for synthesizing
Compound A5-2, the title compound (11.1 mg, 50%) was prepared from
Compound JJ7-1 and
[(4R,5R)-5-(tert-butyl-dimethyl-silanyloxymethyl)-2,2-dimethyl-[1,3]dioxo-
lan-4-yl]-methanol.
[3197] LCMS: m/z 561 [M+H].sup.+
[3198] HPLC retention time: 3.84 min (analysis condition F)
Example 460
[3199] Compound JJ8-2
6,6-Dimethyl-11-oxo-9-((2R,3R)-2,3,4-trihydroxy-butoxy)-6,11-dihydro-5H-be-
nzo[b]carbazole-3-carbonitrile
##STR00475##
[3201] Under the same conditions as the method for synthesizing
Compound JJ7-2, the title compound was prepared from
9-[(4R,5R)-5-(tert-butyl-dimethyl-silanyloxymethyl)-2,2-dimethyl-[1,3]dio-
xolan-4-yl
methoxy]-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole--
3-carbonitrile (Compound JJ8-1) (white solid, 7.8 mg, 97%).
[3202] LCMS: m/z 407 [M+H].sup.+
[3203] HPLC retention time: 1.92 min (analysis condition F)
Example 461
[3204] Compound JJ9-1
9-((R)-2,3-Dihydroxy-propoxy)-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]-
carbazole-3-carbonitrile
##STR00476##
[3206]
3-Bromo-9-((S)-2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-6,6-dimethyl-
-5,6-dihydro-benzo[b]carbazol-11-one (Compound JJ3-1, 49.5 mg,
0.105 mmol) and copper cyanide (90%, 35.3 mg, 3.4 eq.) were added
with DMA (0.5 mL), and the mixture was irradiated with microwave at
200.degree. C. for 1 hr under nitrogen atmosphere. After cooling,
the reaction solution was added with water and extracted with ethyl
acetate. The insoluble matters were separated off by filtration,
and the organic layer was washed with brine and dried over
magnesium sulfate. After filtration and the concentration under
reduced pressure, the resulting residues were purified by
preparative TLC (methanol/dichloromethane) to obtain the title
compound (white solid, 8.5 mg, 22%).
[3207] LCMS: m/z 377 [M+H].sup.+
[3208] HPLC retention time: 2.02 min (analysis condition F)
Example 462
[3209] Compound JJ9-2
9-((S)-2,2-Dimethyl-[1,3]dioxolan-4-yl
methoxy)-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonit-
rile
##STR00477##
[3211] The title compound was obtained as a by-product of the
synthesis of Compound JJ9-1 (white solid, 24.8 mg, 57%).
[3212] LCMS: m/z 417 [M+H].sup.+
[3213] HPLC retention time: 2.81 min (analysis condition F)
Example 463
[3214] Compound JJ9-3
9-((S)-2,2-Dimethyl-[1,3]dioxolan-4-yl
methoxy)-5,6,6-trimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbo-
nitrile
##STR00478##
[3216] Under the same conditions as the method for synthesizing
Compound JJ4-1, the title compound was prepared from
9-((S)-2,2-dimethyl-[1,3]dioxolan-4-yl
methoxy)-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonit-
rile (Compound JJ9-2) (17.0 mg, 84%).
[3217] LCMS: m/z 431 [M+H].sup.+
[3218] HPLC retention time: 3.00 min (analysis condition F)
Example 464
[3219] Compound JJ9-4
9-((R)-2,3-Dihydroxy-propoxy)-5,6,6-trimethyl-11-oxo-6,11-dihydro-5H-benzo-
[b]carbazole-3-carbonitrile
##STR00479##
[3221] Under the same conditions as the method for synthesizing
Compound JJ3-2, the title compound was prepared from
9-((S)-2,2-dimethyl-[1,3]dioxolan-4-yl
methoxy)-5,6,6-trimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbo-
nitrile (JJ9-3) (white solid, 12.1 mg, 90%).
[3222] LCMS: m/z 391 [M+H].sup.+
[3223] HPLC retention time: 2.13 min (analysis condition F)
Example 465
[3224] Compound JJ10-1
9-Benzyloxy-3-bromo-6,6-dimethyl-5,6-dihydro-benzo[b]carbazol-11-one
##STR00480##
[3226] Under the same conditions as the method for synthesizing
Compound A7-17, the title compound was prepared from Compound JJ2
and benzyl bromide (18.2 mg, 61%).
[3227] LCMS: m/z 446 [M+H].sup.+
[3228] HPLC retention time: 2.68 min (analysis condition D)
Example 466
[3229] Compound JJ10-2
5-Benzyl-9-benzyloxy-3-bromo-6,6-dimethyl-5,6-dihydro-benzo[b]carbazol-11--
one
##STR00481##
[3231] The title compound was obtained as a by-product of the
synthesis of Compound JJ10-1 (5.3 mg, 21%).
[3232] LCMS: m/z 536 [M+H].sup.+
[3233] HPLC retention time: 3.17 min (analysis condition D)
Example 467
[3234] Compound JJ10-3
3-Bromo-9-(4-methoxy-benzyloxy)-6,6-dimethyl-5,6-dihydro-benzo[b]carbazol--
11-one
##STR00482##
[3236] Under the same conditions as the method for synthesizing
Compound A7-1, the title compound was prepared by reacting Compound
JJ2 and (4-methoxyphenyl)-methanol (7.5 mg, 28%).
[3237] LCMS: m/z 476 [M+H].sup.+
[3238] HPLC retention time: 2.70 min (analysis condition D)
Example 468
[3239] Compound K2
2-(3-Bromo-4-methoxy-phenyl)-2-methyl-propionitrile
##STR00483##
[3241] To the THF suspension of potassium tert-butoxide (15.35 g, 3
eq.), (3-bromo-4-methoxyphenyl)acetonitrile (Compound K1, 10 g,
0.044 mmol) was added, and then stirred at 0.degree. C. for 1 hr.
Then, iodomethane (8.26 ml, 3 eq.) was added and the mixture was
stirred at room temperature for 1 hr. To the reaction solution,
saturated aqueous solution of ammonium chloride and water were
added followed by extraction with ethyl acetate. The organic layer
was washed with brine and dried over sodium sulfate. The drying
agent was removed by filtration and the residues obtained after
concentration under reduced pressure were purified by silica gel
column chromatography (ethyl acetate/hexane) to obtain the title
compound (colorless oily substance, 11.24 g, 100%).
[3242] .sup.1H-NMR (270 MHz, DMSO-d.sub.6) .delta.: 7.69 (1H, d,
J=2.5 Hz), 7.50 (1H, dd, J=8.6, 2.5 Hz), 7.16 (1H, d, J=8.6 Hz),
3.86 (3H, s), 1.67 (6H, s).
[3243] HPLC retention time: 2.30 min (analysis condition S)
Example 469
[3244] Compound K3
4-(3-Bromo-4-methoxy-phenyl)-4-methyl-3-oxo-pentanoic acid ethyl
ester
##STR00484##
[3246] To the THF suspension of zinc (5.72 g, 2 eq.),
methanesulfonic acid (25.6 .mu.l, 0.01 eq.) was added, and then
stirred at 80.degree. C. for 10 min. Then, the THF solution of
2-(3-bromo-4-methoxy-phenyl)-2-methyl-propionitrile (10 g, 39.35
mmol) was added, followed by addition of bromoethyl acetate (11.07
ml, 1.6 eq.) over 1 hr. The mixture was further stirred for 30 min.
To the reaction solution, 4 M hydrochloric acid was added, and
stirred at room temperature overnight. After extraction with ethyl
acetate, the organic layer was washed with brine and dried over
sodium sulfate. The drying agent was removed by filtration and the
residues obtained after concentration under reduced pressure were
purified by silica gel column chromatography (ethyl acetate/hexane)
to obtain the title compound (orange oily substance, 9.74 g,
72%).
[3247] .sup.1H-NMR (270 MHz, CDCl.sub.3) .delta.: 7.46 (1H, d,
J=2.5 Hz), 7.16 (1H, dd, J=8.6, 2.5 Hz), 6.89 (1H, d, J=8.6 Hz),
4.17-4.08 (2H, m), 3.90 (3H, s), 3.26 (2H, s), 1.49 (6H, s), 1.23
(3H, t, J=7.2 Hz).
[3248] LCMS: m/z 343, 345 [M+H].sup.+
[3249] HPLC retention time: 2.64 min (analysis condition S)
Example 470
[3250] Compound K4
4-(3-Bromo-4-methoxy-phenyl)-2-(4-cyano-2-nitro-phenyl)-4-methyl-3-oxo-pen-
tanoic acid ethyl ester
##STR00485##
[3252] 4-(3-Bromo-4-methoxy-phenyl)-4-methyl-3-oxo-pentanoic acid
ethyl ester (Compound K3, 10.3 g, 30.01 mmol) was dissolved in DMF
(80 mL), added with cesium carbonate (24.4 g, 2.5 eq.) and
4-chloro-3-nitro-benzonitrile (7.12 g, 1.3 eq.), and then stirred
at 45.degree. C. for 4 hr. The reaction solution was added to 1 N
aqueous solution of hydrochloric acid, and extracted with ethyl
acetate. The organic layer was washed with saturated brine and
dried over sodium sulfate. The drying agent was removed by
filtration, and after concentration under reduced pressure the
title compound was obtained as a crude product (yellow oily
substance).
[3253] LCMS: m/z 489, 491 [M+H].sup.+
[3254] HPLC retention time: 2.85, 3.20 min (analysis condition
S)
Example 471
[3255] Compound K5
2-[1-(3-Bromo-4-methoxy-phenyl)-1-methyl-ethyl]-6-cyano-1H-indole-3-carbox-
ylic acid ethyl ester
##STR00486##
[3257]
4-(3-Bromo-4-methoxy-phenyl)-2-(4-cyano-2-nitro-phenyl)-4-methyl-3--
oxo-pentanoic acid ethyl ester (Compound K4), which had been
obtained from the above, was dissolved in THF (140 mL) and water
(70 mL), added with Na.sub.2S.sub.2O.sub.4 (26.13 g, 5.0 eq.) and
stirred at 50.degree. C. overnight. The reaction solution was added
to saturated brine and extracted with ethyl acetate. The organic
layer was washed with 1 M aqueous solution of potassium carbonate
and saturated brine in order, and dried over sodium sulfate. The
drying agent was removed by filtration and the residues obtained
after concentration under reduced pressure were purified by
crystallization in MeCN (80 ml) to obtain the title compound
(yellow solid, 8.20 g, 62%).
[3258] .sup.1H-NMR (270 MHz, DMSO-d.sub.6) .delta.: 12.15 (1H, s),
8.07 (1H, d, J=8.4 Hz), 7.94 (1H, s), 7.51 (1H, dd, J=8.5, 1.2 Hz),
7.33 (1H, d, J=2.1 Hz), 7.03 (1H, dd, J=8.7, 2.4 Hz), 6.96 (1H, d,
J=8.4 Hz), 3.97 (2H, q, J=7.3 Hz), 3.78 (3H, s), 1.80 (6H, s), 1.09
(3H, t, J=7.2 Hz).
[3259] LCMS: m/z 441, 443 [M+H].sup.+
[3260] HPLC retention time: 2.85 min (analysis condition S)
Example 472
[3261] Compound K6
8-Bromo-9-methoxy-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3--
carbonitrile
##STR00487##
[3263] Phosphorus pentoxide-methanesulfonic acid (12 mL) was added
with
2-[1-(3-bromo-4-methoxy-phenyl)-1-methyl-ethyl]-6-cyano-1H-indole-3-carbo-
xylic acid ethyl ester (Compound K5, 1.0 g, 2.27 mmol), and the
mixture was stirred at room temperature for 20 min. The reaction
solution was diluted with MeCN (20 mL), poured into water (20 mL),
and the precipitated solid was filtered to obtain the title
compound (yellow solid, 763 mg, 85%).
[3264] .sup.1H-NMR (270 MHz, DMSO-d.sub.6) .delta.: 12.84 (1H, s),
8.32 (1H, d, J=8.1 Hz), 8. (1H, s), 8.03 (1H, s), 7.77 (1H, s),
7.64 (1H, dd, J=8.2, 1.4 Hz), 3.97 (3H, s), 1.75 (6H, s).
[3265] LCMS: m/z 395, 397 [M+H].sup.+
[3266] HPLC retention time: 2.58 min (analysis condition S)
Example 473
[3267] Compound K7-1
9-Methoxy-6,6-dimethyl-11-oxo-8-(4-pyrrolidin-1-yl-piperidin-1-yl)-6,11-di-
hydro-5H-benzo[b]carbazole-3-carbonitrile
##STR00488##
[3269] Under the same conditions as the method for synthesizing
Compound B2-1, the title compound was prepared from Compound K6 and
4-pyrrolidin-1-yl-piperidine.
[3270] LCMS: m/z 469 [M+H].sup.+
[3271] HPLC retention time: 1.37 min (analysis condition S)
Example 474
[3272] Compound K7-2
9-Methoxy-6,6-dimethyl-8-(4-morpholin-1-yl-piperidin-1-yl)-11-oxo-6,11-dih-
ydro-5H-benzo[b]carbazole-3-carbonitrile
##STR00489##
[3274] Under the same conditions as the method for synthesizing
Compound B2-1, the title compound was prepared from Compound K6 and
4-piperidin-4-yl-morpholine.
[3275] .sup.1H-NMR (270 MHz, DMSO-d.sub.6) .delta.: 12.70 (1H, s),
8.31 (1H, d, J=8.2 Hz), 7.99 (1H, s), 7.63 (1H, s), 7.60 (1H, dd,
J=8.2, 1.2 Hz), 7.16 (1H, s), 3.89 (3H, s), 3.64 (2H, brd), 2.72
(2H, brd), 1.91 (2H, brd), 1.73 (6H, s), 1.57 (2H, brd).
[3276] LCMS: m/z 485 [M+H].sup.+
[3277] HPLC retention time: 1.33 min (analysis condition S)
Example 475
[3278] Compound K7-3
9-Methoxy-6,6-dimethyl-11-oxo-8-piperazin-1-yl-6,11-dihydro-5H-benzo[b]car-
bazole-3-carbonitrile
##STR00490##
[3280] Under the same conditions as the method for synthesizing
Compound B2-1, the target compound was prepared from Compound K6
and piperazine.
[3281] LCMS: m/z 401 [M+H].sup.+
[3282] HPLC retention time: 1.31 min (analysis condition S)
Example 476
[3283] Compound K7-4
9-Methoxy-6,6-dimethyl-8-morpholin-4-yl-11-oxo-6,11-dihydro-5H-benzo[b]car-
bazole-3-carbonitrile
##STR00491##
[3285] Under the same conditions as the method for synthesizing
Compound B2-1, the title compound was prepared from Compound K6 and
morpholine.
[3286] LCMS: m/z 402 [M+H].sup.+
[3287] HPLC retention time: 2.10 min (analysis condition S)
Example 477
[3288] Compound K8
8-(4-Cyclobutyl-piperazin-1-yl)-9-methoxy-6,6-dimethyl-11-oxo-6,11-dihydro-
-5H-benzo[b]carbazole-3-carbonitrile
##STR00492##
[3290] Under the same conditions as the method for synthesizing
Compound B3-32, the title compound was prepared from Compound K7-3
and cyclobutanone.
[3291] .sup.1H-NMR (270 MHz, DMSO-d.sub.6) .delta.: 12.70 (1H, br.
s), 8.31 (1H, d, J=8.2 Hz), 8.00 (1H, s), 7.64 (1H, s), 7.61 (1H,
dd, J=8.1, 1.3 Hz), 7.16 (1H, s), 3.88 (3H, s), 3.60 (1H, t, J=6.2
Hz), 3.10-3.25 (4H, m), 2.77 (1H, t, J=7.1 Hz), 2.35-2.51 (4H, m),
1.74 (6H, s), 1.58-2.08 (6H, m).
[3292] LCMS: m/z 455 [M+H].sup.+
[3293] HPLC retention time: 1.45 min (analysis condition S)
Example 478
[3294] Compound K9-1
9-Hydroxy-6,6-dimethyl-11-oxo-8-(4-pyrrolidin-1-yl-piperidin-1-yl)-6,11-di-
hydro-5H-benzo[b]carbazole-3-carbonitrile
##STR00493##
[3296] The title compound was obtained as a by-product of the
synthesis of Compound K7-1.
[3297] LCMS: m/z 455 [M+H].sup.+
[3298] HPLC retention time: 1.22 min (analysis condition S)
Example 479
[3299] Compound K9-2
9-Hydroxy-6,6-dimethyl-8-(4-morpholin-4-yl-piperidin-1-yl)-11-oxo-6,11-dih-
ydro-5H-benzo[b]carbazole-3-carbonitrile
##STR00494##
[3301] Under the same conditions as the method for synthesizing
Compound E3-2, the title compound was prepared from Compound
K7-2.
[3302] .sup.1H-NMR (270 MHz, DMSO-d.sub.6) .delta.: 12.65 (1H, s),
9.61 (1H, s), 8.30 (1H, d, J=8.2 Hz), 7.98 (1H, s), 7.59-7.56 (2H,
m), 7.10 (1H, s), 3.71 (2H, brd, J=11.2 Hz), 3.60 (4H, m), 2.66
(2H, m), 1.88 (2H, brd, J=9.7 Hz), 1.71 (6H, s), 1.57 (2H,
brd).
[3303] LCMS: m/z 471 [M+H].sup.+
[3304] HPLC retention time: 1.20 min (analysis condition S)
Example 480
[3305] Compound K9-3
8-(4-Cyclobutyl-piperazin-1-yl)-9-hydroxy-6,6-dimethyl-11-oxo-6,11-dihydro-
-5H-benzo[b]carbazole-3-carbonitrile
##STR00495##
[3307] Under the same conditions as the method for synthesizing
Compound E3-2, the title compound was prepared from Compound
K8.
[3308] .sup.1H-NMR (270 MHz, DMSO-d.sub.6) .delta.: 12.66 (1H, br.
s), 9.67 (1H, s), 8.31 (1H, d, J=8.2 Hz), 7.98 (1H, s), 7.56-7.60
(2H, m), 7.09 (1H, s), 3.10-3.24 (4H, m), 2.77 (1H, t, J=7.5 Hz),
2.37-2.49 (4H, m), 1.52-2.07 (6H, m), 1.72 (6H, s).
[3309] LCMS: m/z 441 [M+H].sup.+
[3310] HPLC retention time: 1.31 min (analysis condition S)
[3311] Compound K9-4
9-Hydroxy-6,6-dimethyl-8-morpholin-4-yl-11-oxo-6,11-dihydro-5H-benzo[b]car-
bazole-3-carbonitrile
##STR00496##
[3313] Under the same conditions as the method for synthesizing
Compound E3-2, the title compound was prepared from Compound
K7-4.
[3314] LCMS: m/z 388 [M+H].sup.+
[3315] HPLC retention time: 1.67 min (analysis condition S)
Example 482
[3316] Compound K10-1
9-Isopropoxy-6,6-dimethyl-8-(4-morpholin-4-yl-piperidin-1-yl)-11-oxo-6,11--
dihydro-5H-benzo[b]carbazole-3-carbonitrile
##STR00497##
[3318] Under the same conditions as the method for synthesizing
Compound A7-17, the title compound was prepared from Compound K9-2
and 2-bromopropane.
[3319] .sup.1H-NMR (270 MHz, DMSO-d.sub.6) .delta.: 12.68 (1H, s),
8.30 (1H, d, J=8.1 Hz), 7.99 (1H, s), 7.60 (2H, m), 7.14 (1H, s),
4.72-4.63 (2H, m), 3.71 (2H, brd, J=10.7 Hz), 3.59 (6H, m), 2.68
(2H, t, J=12.9 Hz), 2.27 (2H, brd), 1.90 (2H, brd), 1.73 (6H, s),
1.56 (2H, br), 1.34 (6H, d, J=5.9 Hz).
[3320] LCMS: m/z 513 [M+H].sup.+
[3321] HPLC retention time: 1.48 min (analysis condition S)
[3322] Compound K10-2
8-(4-Cyclobutyl-piperazin-1-yl)-9-isopropoxy-6,6-dimethyl-11-oxo-6,11-dihy-
dro-5H-benzo[b]carbazole-3-carbonitrile
##STR00498##
[3324] Under the same conditions as the method for synthesizing
Compound A7-17, the title compound was prepared from Compound K9-3
and 2-iodopropane.
[3325] .sup.1H-NMR (270 MHz, DMSO-d.sub.6) .delta.: 8.29 (1H, d,
J=8.1 Hz), 7.98 (1H, s), 7.56-7.63 (2H, m), 7.14 (1H, s), 4.62-4.74
(1H, m), 3.10-3.26 (4H, m), 2.69-2.85 (1H, m), 2.35-2.48 (4H, m),
1.57-2.08 (6H, m), 1.73 (6H, s), 1.32 (6H, d, J=6.1 Hz).
[3326] LCMS: m/z 483 [M+H].sup.+
[3327] HPLC retention time: 1.65 min (analysis condition S)
Example 484
[3328] Compound K10-3
9-(2-Methoxy-ethoxy)-6,6-dimethyl-8-morpholin-4-yl-11-oxo-6,11-dihydro-5H--
benzo[b]carbazole-3-carbonitrile
##STR00499##
[3330] Under the same conditions as the method for synthesizing
Compound A7-17, the title compound was prepared from Compound K9-4
and 1-bromo-2-methoxyethane.
[3331] .sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta.: 12.67 (1H, s),
8.30 (1H, d, 7.9 Hz), 7.98 (1H, s), 7.64 (1, s), 7.58 (1H, d, 7.9
Hz), 7.16 (1H, s), 4.18-4.22 (2H, m), 3.72-3.80 (6H, m), 3.35 (3H,
s), 3.18-3.24 (4H, s), 1.74 (1H, s)
[3332] LCMS: m/z 446 [M+H].sup.+
[3333] HPLC retention time: 3.23 min (analysis condition W)
Example 485
[3334] Compound K10-4
9-[2-(2-Methoxy-ethoxy)-ethoxy]-6,6-dimethyl-8-morpholin-4-yl-11-oxo-6,11--
dihydro-5H-benzo[b]carbazole-3-carbonitrile
##STR00500##
[3336] Under the same conditions as the method for synthesizing
Compound A7-17, the title compound was prepared from Compound K9-4
and 1-bromo-2-(2-methoxyethoxy)ethane.
[3337] LCMS: m/z 490 [M+H].sup.+
[3338] HPLC retention time: 3.16 min (analysis condition W)
Example 486
[3339] Compound K10-5
6,6-Dimethyl-8-morpholin-1-yl-11-oxo-9-[(S)-(tetrahydro-furan-3-yl)oxy]-6,-
11-dihydro-5H-benzo[b]carbazole-3-carbonitrile
##STR00501##
[3341] Under the same conditions as the method for synthesizing
Compound A7-17, the title compound was prepared from Compound K9-4
and 3-mesyloxytetrahydrofurane.
[3342] LCMS: m/z 458 [M+H].sup.+
[3343] HPLC retention time: 3.20 min (analysis condition W)
Example 487
[3344] Compound K10-6
9-Isopropoxy-6,6-dimethyl-8-morpholin-4-yl-11-oxo-6,11-dihydro-5H-benzo[b]-
carbazole-3-carbonitrile
##STR00502##
[3346] Under the same conditions as the method for synthesizing
Compound A7-17, the title compound was prepared from Compound K9-4
and 2-bromopropane.
[3347] .sup.1H-NMR (270 MHz, DMSO-d.sub.6) .delta.: 12.70 (1H, br.
s), 8.32-8.29 (1H, d, 8.08 Hz), 8.00 (1H, s), 7.63 (1H, s),
7.62-7.59 (1H, d, 8.08 Hz), 7.16 (1H, s), 4.75-4.66 (1H, m), 3.77
(4H, m) 3.19 (4H, m), 1.74 (6H, s), 1.35 (3H, s), 1.33 (3H, s)
[3348] LCMS: m/z 430 [M+H].sup.+
Example 488
[3349] Compound K10-7
9-(2-Hydroxy-ethoxy)-6,6-dimethyl-8-morpholin-4-yl-11-oxo-6,11-dihydro-5H--
benzo[b]carbazole-3-carbonitrile
##STR00503##
[3351] Under the same conditions as the method for synthesizing
Compound A7-17, the title compound was prepared from Compound K9-4
and 2-bromoethanol.
[3352] .sup.1H-NMR (270 MHz, DMSO-d.sub.6) .delta.: 12.71 (1H, br.
s), 8.33-8.30 (1H, d, 8.08 Hz), 8.00 (1H, s), 7.63 (1H, s),
7.62-7.59 (1H, d, 8.08 Hz), 7.16 (1H, s), 4.13-4.09 (2H, t, 4.61
Hz), 3.81-3.78 (2H, t, 4.61 Hz), 3.78 (4H, m) 3.23 (4H, m), 1.75
(6H, s)
[3353] LCMS: m/z 432 [M+H].sup.+
Example 489
[3354] Compound L2-1
(4-Isopropoxy-3-methoxy-phenyl)-ethyl acetate ester
##STR00504##
[3356] (4-Hydroxy-3-methoxy-phenyl)-ethyl acetate ester (Compound
L1-1, 3.0 g, 14.27 mmol) was dissolved in DMF (70 mL), added with
2-iodopropane (2.9 mL, 2.0 eq.) and potassium carbonate (3.94 g,
2.0 eq.), and stirred at 80.degree. C. overnight. The reaction
solution was added to water and extracted with ethyl acetate. The
organic layer was washed with saturated brine and dried over sodium
sulfate. The drying agent was removed by filtration and the
residues obtained after concentration under reduced pressure were
purified by silica gel column chromatography (ethyl acetate/hexane)
to obtain the target compound (yellow oily substance, 2.61 g,
73%).
[3357] .sup.1H-NMR (270 MHz, DMSO-d.sub.6) .delta.: 6.88 (2H, m),
6.74 (1H, dd, J=8.1, 2.1 Hz), 4.52-4.43 (1H, m), 4.07 (2H, q, J=7.1
Hz), 3.72 (3H, s), 3.56 (2H, s), 1.23 (6H, d, J=6.1 Hz), 1.18 (3H,
t, J=7.1 Hz).
[3358] LCMS: m/z 253 [M+H].sup.+
[3359] HPLC retention time: 2.18 min (analysis condition S)
Example 490
[3360] Compound L2-2
(4-Isopropoxy-3-methoxy-phenyl)-acetic acid isopropyl ester
##STR00505##
[3362] (4-Hydroxy-3-methoxy-phenyl)-acetic acid (Compound L1-2, 1.5
g, 8.23 mmol) was dissolved in DMF (30 mL), added with
2-iodopropane (3.3 mL, 4.0 eq.) and potassium carbonate (4.55 g,
4.0 eq.), and stirred at 80.degree. C. overnight. The reaction
solution was added to water and extracted with ethyl acetate. The
organic layer was washed with saturated brine and dried over sodium
sulfate. The drying agent was removed by filtration and the
residues obtained after concentration under reduced pressure were
purified by silica gel column chromatography (ethyl acetate/hexane)
to obtain the target compound (yellow oily substance, 1.21 g,
55%).
[3363] .sup.1H-NMR (270 MHz, DMSO-d.sub.6) .delta.: 6.87 (2H, s+d),
6.73 (1H, dd, J=8.1, 2.1 Hz), 4.94-4.84 (1H, m), 4.52-4.43 (1H, m),
3.72 (3H, s), 3.52 (2H, s), 1.23 (6H, d, J=6.1 Hz), 1.18 (6H, d,
J=6.1 Hz).
[3364] LCMS: m/z 267 [M+H].sup.+
[3365] HPLC retention time: 2.40 min (analysis condition S)
Example 491
[3366] Compound L3-1
2-(4-Isopropoxy-3-methoxy-phenyl)-2-methyl-propionic acid ethyl
ester
##STR00506##
[3368] Under the same conditions as the method for synthesizing
Compound K2, the title compound was prepared from Compound
L2-1.
[3369] .sup.1H-NMR (270 MHz, DMSO-d.sub.6) .delta.: 6.90-6.76 (3H,
m), 4.53-4.44 (1H, m), 4.06 (2H, q, J=7.1 Hz), 3.73 (3H, s), 1.47
(6H, s), 1.23 (6H, d, J=6.1 Hz), 1.12 (3H, t, J=7.0 Hz).
[3370] LCMS: m/z 281 [M+H].sup.+
[3371] HPLC retention time: 2.57 min (analysis condition S)
Example 492
[3372] Compound L3-2
2-(4-Isopropoxy-3-methoxy-phenyl)-2-methyl-propionic acid isopropyl
ester
##STR00507##
[3374] Under the same conditions as the method for synthesizing
Compound K2, the title compound was prepared from Compound
L2-2.
[3375] .sup.1H-NMR (270 MHz, DMSO-d.sub.6) .delta.: 6.88 (1H, d,
J=8.2 Hz), 6.79 (2H, m), 4. 94-4.84 (1H, m), 4.53-4.44 (1H, m),
3.72 (3H, s), 1.45 (6H, s), 1.23 (6H, d, J=6.1 Hz), 1.12 (6H, d,
J=6.3 Hz).
[3376] LCMS: m/z 295 [M+H].sup.+
[3377] HPLC retention time: 2.75 min (analysis condition S)
Example 493
[3378] Compound L4
2-(4-Isopropoxy-3-methoxy-phenyl)-2-methyl-propionic acid
##STR00508##
[3380] 2-(4-Isopropoxy-3-methoxy-phenyl)-2-methyl-propionic acid
ethyl ester (Compound L3-1, 1.45 g, 5.17 mmol) was dissolved in THF
(13 mL) and EtOH (13 mL), added with 1 N aqueous solution of sodium
hydroxide (10.3 mL, 2.0 eq.), and stirred at 80.degree. C.
overnight. The reaction solution was added to water and extracted
with ethyl acetate. The aqueous layer was acidified by using 1 N
aqueous solution of hydrochloric acid, extracted with ethyl
acetate, washed with saturated brine and dried over sodium sulfate.
The drying agent was removed by filtration and the residues
obtained after concentration under reduced pressure were purified
by silica gel column chromatography (ethyl acetate/hexane) to
obtain the target compound (white solid, 1.10 g, 84%).
[3381] .sup.1H-NMR (270 MHz, DMSO-d.sub.6) .delta.: 12.26 (1H, s),
6.90-6.80 (3H, m), 4.49 (1H, m), 3.73 (3H, s), 1.45 (6H, s), 1.23
(6H, d, J=6.1 Hz).
[3382] LCMS: m/z 253 [M+H].sup.+
[3383] HPLC retention time: 1.83 min (analysis condition S)
Example 494
[3384] Compound L5
4-(4-Isopropoxy-3-methoxy-phenyl)-4-methyl-3-oxo-pentanoic acid
ethyl ester
##STR00509##
[3386] 2-(4-Isopropoxy-3-methoxy-phenyl)-2-methyl-propionic acid
(Compound L4, 1.4 g, 5.55 mmol) was added with thionyl chloride (10
mL), and then stirred at room temperature for 5 hr. According to
the concentration under reduced pressure, unreacted thionyl
chloride was removed to obtain corresponding acid chloride. To MeCN
(40 mL), malonic acid monoethyl ester potassium salt (1.98 g, 2.1
eq.), triethylamine (2.47 mL, 3.2 eq.), and magnesium chloride
(1.32 g, 2.5 eq.) were added and the mixture was stirred at room
temperature for 2 hr. To the reaction solution, MeCN (15 mL)
solution of the acid chloride prepared from the above was added
dropwise. Upon the completion of the dropwise addition, the mixture
was further stirred at room temperature for overnight. MeCN was
removed by distillation and concentrated under reduced pressure,
and the resulting residues were added with 1 N aqueous solution of
hydrochloric acid, extracted with toluene, washed with saturated
brine, and dried over sodium sulfate. The drying agent was removed
by filtration and the residues obtained after concentration under
reduced pressure were purified by silica gel column chromatography
(ethyl acetate/hexane) to obtain the target compound (yellow oily
substance, 1.45 g, 81%).
[3387] .sup.1H-NMR (270 MHz, DMSO-d.sub.6) .delta.: 6.94 (1H, d,
J=8.2 Hz), 6.76 (2H, m), 4.56-4.47 (1H, m), 4.00 (2H, q, J=7.1 Hz),
3.74 (3H, s), 3.38 (2H, s), 1.41 (6H, s), 1.24 (6H, d, J=6.1 Hz),
1.12 (3H, t, J=7.3 Hz).
[3388] LCMS: m/z 323 [M+H].sup.+
[3389] HPLC retention time: 2.45, 3.03 min (analysis condition
S)
Example 495
[3390] Compound L6
2-(4-Cyano-2-nitro-phenyl)-4-(4-isopropoxy-3-methoxy-phenyl)-4-methyl-3-ox-
o-pentanoic acid ethyl ester
##STR00510##
[3392] Under the same conditions as the method for synthesizing
Compound K4, the title compound was prepared from Compound L5.
[3393] .sup.1H-NMR (270 MHz, DMSO-d.sub.6) .delta.: 8.35 (1H, d,
J=1.8 Hz), 8.14 (1H, dd, J=8.2, 1.9 Hz), 7.67 (1H, d, J=8.2 Hz),
6.68 (1H, d, J=8.4 Hz), 6.59 (1H, dd, J=8.4, 2.0 Hz), 6.45 (1H, d,
J=2.1 Hz), 5.44 (1H, s), 4.43 (1H, m), 4.09 (2H, q, J=7.1 Hz), 3.53
(3H, s), 1.59 (3H, s), 1.35 (3H, s), 1.24 (6H, d.times.2), 1.13
(3H, t, J=7.1 Hz).
[3394] LCMS: m/z 469 [M+H].sup.+
[3395] HPLC retention time: 2.85, 3.10 min (analysis condition
S)
Example 496
[3396] Compound L7
6-Cyano-2-[1-(4-isopropoxy-3-methoxy-phenyl)-1-methyl-ethyl]-1H-indole-3-c-
arboxylic acid ethyl ester
##STR00511##
[3398] Under the same conditions as the method for synthesizing
Compound K5, the title compound was prepared from Compound L6.
[3399] .sup.1H-NMR (270 MHz, DMSO-d.sub.6) .delta.: 12.04 (1H, s),
8.05 (1H, d, J=8.4 Hz), 7.93 (1H, s), 7.49 (1H, dd, J=8.4, 1.5 Hz),
6.79 (2H, m), 6.54 (1H, dd, J=8.3, 1.9 Hz), 4.43 (1H, t, J=6.1 Hz),
3.94 (2H, q, J=7.0 Hz), 3.65 (3H, s), 1.81 (6H, s), 1.21 (6H, d,
J=5.9 Hz), 1.05 (3H, t, J=7.1 Hz).
[3400] LCMS: m/z 421 [M+H].sup.+
[3401] HPLC retention time: 2.82 min (analysis condition S)
[3402] Compound L8-1
9-Hydroxy-8-methoxy-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole--
3-carbonitrile
##STR00512##
[3404]
6-Cyano-2-[1-(4-isopropoxy-3-methoxy-phenyl)-1-methyl-ethyl]-1H-ind-
ole-3-carboxylic acid ethyl ester (Compound L7, 1.25 g, 2.97 mmol)
was dissolved in MeCN (18 mL), added with methanesulfonic acid
(3.75 mL), and then stirred at 50.degree. C. for 8 hr. Hexane was
added to the reaction solution, and the precipitated solid was
filtered to obtain the title compound (yellow solid, 185 mg,
19%).
[3405] .sup.1H-NMR (270 MHz, DMSO-d.sub.6) .delta.: 12.67 (1H, s),
8.30 (1H, d, J=8.2 Hz), 7.99 (1H, s), 7.59 (2H, m), 7.28 (1H, s),
3.93 (3H, s), 1.75 (6H, s).
[3406] LCMS: m/z 333 [M+H].sup.+
[3407] HPLC retention time: 1.73 min (analysis condition S)
Example 498
[3408] Compound L8-2
9-Isopropoxy-8-methoxy-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazo-
le-3-carbonitrile
##STR00513##
[3410] To the filtrate obtained from the synthesis of Compound
L8-1, water was added and the extraction was carried out with ethyl
acetate. The resultant was washed with saturated brine and dried
over sodium sulfate. The drying agent was removed by filtration and
the concentration was performed under reduced pressure to obtain
the target compound (red amorphous, 830 mg, 75%).
[3411] .sup.1H-NMR (270 MHz, DMSO-d.sub.6) .delta.: 12.72 (1H, s),
8.31 (1H, d, J=8.4 Hz), 8.01 (1H, d, J=0.7 Hz), 7.66 (1H, s), 7.61
(1H, dd, J=8.2, 1.4 Hz), 7.33 (1H, s), 4.65 (1H, m), 3.93 (3H, s),
1.77 (6H, s), 1.32 (6H, d, J=6.1 Hz).
[3412] LCMS: m/z 375 [M+H].sup.+
[3413] HPLC retention time: 2.38 min (analysis condition S)
Example 499
[3414] Compound L9
8-Hydroxy-9-isopropoxy-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazo-
le-3-carbonitrile
##STR00514##
[3416] Under the same conditions as the method for synthesizing
Compound E3-2, the title compound was prepared from Compound
L8-2.
[3417] .sup.1H-NMR (270 MHz, DMSO-d.sub.6) .delta.: 12.69 (1H, s),
9.69 (1H, s), 8.30 (1H, d, J=8.1 Hz), 7.99 (1H, s), 7.65 (1H, s),
7.60 (1H, dd, J=8.2, 1.2 Hz), 7.17 (1H, s), 4.64 (1H, m), 1.69 (6H,
s), 1.32 (6H, d, J=6.1 Hz).
[3418] LCMS: m/z 361 [M+H].sup.+
[3419] HPLC retention time: 2.20 min (analysis condition S)
Example 500
[3420] Compound L10-1
8-(1-Cyclobutyl-piperidin-4-yloxy)-9-isopropoxy-6,6-dimethyl-11-oxo-6,11-d-
ihydro-5H-benzo[b]carbazole-3-carbonitrile
##STR00515##
[3422] Under the same conditions as the method for synthesizing
Compound A7-1, the title compound was prepared from Compound L9 and
1-cyclobutylpiperidin-4-ol. .sup.1H-NMR (270 MHz, CDCl.sub.3)
.delta.: 9.31 (1H, br. s), 8.54-8.50 (1H, d, 8.08 Hz), 7.90 (1H,
s), 7.77 (1H, s), 7.59-7.55 (1H, m), 7.09 (1H, s), 4.70-4.61 (1H,
m), 4.52-4.43 (1H, m), 2.79-2.73 (1H, m), 2.70-2.60 (2H, m),
2.25-2.16 (2H, m), 2.09-1.99 (4H, m), 1.98-1.88 (4H, m), 1.77 (6H,
s), 1.72-1.58 (2H, m), 1.39 (3H, s), 1.37 (3H, s)
[3423] LCMS: m/z 498 [M+H].sup.+
Example 501
[3424] Compound L10-2
8-((R)-1-Cyclobutyl-pyrrolidin-3-yl
oxy)-9-isopropoxy-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-
-carbonitrile
##STR00516##
[3426] Under the same conditions as the method for synthesizing
Compound A7-1, the title compound was prepared from Compound L9 and
(S)-1-cyclobutylpyrrolidin-3-ol.
[3427] .sup.1H-NMR (270 MHz, CDCl.sub.3) .delta.: 10.63 (1H, br.
s), 8.51-8.48 (1H, d, 8.08 Hz), 7.89 (1H, s), 7.85 (1H, s),
7.55-7.51 (1H, m), 6.99 (1H, s), 5.03-4.97 (1H, m), 4.71-4.62 (1H,
m), 3.07-292 (2H, m), 2.84-2.73 (2H, m), 2.64-2.53 (1H, m),
2.36-2.23 (2H, m), 2.10-1.97 (2H, m), 1.83-1.67 (2H, m), 1.78 (6H,
s), 1.53-1.46 (2H, m), 1.39 (3H, s), 1.37 (3H, s)
[3428] LCMS: m/z 484 [M+H].sup.+
Example 502
[3429] Compound M1
7-Methoxy-3,4-dihydro-2H-spiro[cyclopentane-1,1'-naphthalen]-2-one
##STR00517##
[3431] To the THF (300 ml) solution of
7-methoxy-3,4-dihydro-1H-naphthalen-2-one (Compound A1, 0.5 g, 2.84
mmol), sodium hydride (36.4 mg, 2.2 eq.) was added at 0.degree. C.
After stirring for 20 min, 1,4-dibromobutane (0.74 ml, 1.2 eq.) was
added dropwise thereto, and the mixture was stirred at 80.degree.
C. for 4 hr. To the reaction solution, saturated aqueous solution
of ammonium chloride was added followed by extraction with ethyl
acetate. The organic layer was washed with saturated aqueous
solution of ammonium chloride and dried over magnesium sulfate. The
drying agent was removed by filtration and the residues obtained
after concentration under reduced pressure were purified by silica
gel column chromatography (ethyl acetate/hexane) to obtain the
title compound (yellow solid, 0.31 g, 47%).
[3432] .sup.1H-NMR (CDCl.sub.3, 300 MHz) .delta.: 1.79-1.92 (6H,
m), 2.42-2.27 (m, 2H), 3.03 (t, 2H, J=6.5 Hz), 3.81 (t, 2H, J=6.5
Hz), 3.81 (s, 3H), 6.73 (dd, 1H, J=2.7 Hz, 8.0 Hz), 6.83 (d, 1H,
J=2.7 Hz), 7.09 (d, 1H, J=8.0 Hz)
[3433] LCMS: m/z 231 [M+H].sup.+
Example 503
[3434] Compound M2
3-Bromo-8-methoxy-5,11-dihydrospiro[benzo[b]carbazole-6,1'-cyclopentane]
##STR00518##
[3436] Under the same conditions as the method for synthesizing
Compound A3-1, the title compound was prepared from Compound M1 and
(3-bromo-phenyl)-hydrazine.
[3437] LCMS: m/z 380, 382 [M+H].sup.+
[3438] HPLC retention time: 2.90 min (analysis condition Y)
Example 504
[3439] Compound M3
3-Bromo-8-methoxyspiro[benzo[b]carbazole-6,1'-cyclopentan]-11
(5H)-one
##STR00519##
[3441] Under the same conditions as the method for synthesizing
Compound A4, the title compound was prepared from Compound M2.
[3442] .sup.1H-NMR (CDCl.sub.3, 300 MHz) .delta.: 2.11-2.51 (8H,
m), 3.91 (s, 3H), 6.98 (dd, 1H, J=2.3 Hz, 8.8 Hz), 7.01 (d, 1H,
J=2.3 Hz), 7.41 (dd, 1H, J=1.5 Hz, 8.4 Hz), 7.57 (d, 1H, J=1.5 Hz),
8.30 (d, 1H, J=8.4 Hz), 8.35 (d, 1H, J=8.8 Hz), 8.69 (s, 1H)
[3443] LCMS: m/z 396, 398 [M+H].sup.+
Example 505
[3444] Compound M4
8-Methoxy-11-oxo-5,11-dihydrospiro[benzo[b]carbazole-6,1'-cyclopentane]-3--
carbonitrile
##STR00520##
[3446] Under the same conditions as the method for synthesizing
Compound A5-2, the title compound was prepared from Compound
M3.
[3447] .sup.1H-NMR (DMSO-d.sub.6, 300 MHz) .delta.: 2.14-2.37 (m,
8H), 3.90 (s, 3H), 7.05-7.10 (m, 2H), 7.60 (dd, 1H, J=1.5 Hz, 8.4
Hz), 7.95 (s, 1H), 8.13 (d, 1H, J=9.5 Hz), 8.30 (d, 1H, J=8.4 Hz),
12.24 (s, 1H)
[3448] LCMS: m/z 343 [M+H].sup.+
Example 506
[3449] Compound M5
8-Hydroxy-11-oxo-5,11-dihydrospiro[benzo[b]carbazole-6,1'-cyclopentane]-3--
carbonitrile
##STR00521##
[3451] Under the same conditions as the method for synthesizing
Compound A6, the title compound was prepared from Compound M4.
[3452] .sup.1H-NMR (DMSO-d.sub.6, 300 MHz) .delta.: 2.06-2.39 (m,
8H), 6.87 (dd, 1H, J=1.9 Hz, 8.8 Hz), 6.90 (d, 1H, J=1.9 Hz), 7.57
(dd, 1H, J=1.1 Hz, 8.0 Hz), 7.95 (s, 1H), 8.02 (d, 1H, J=8.8 Hz),
8.30 (d, 1H, J=8.0 Hz), 10.29 (s, 1H), 12.25 (s, 1H)
[3453] LCMS: m/z 329 [M+H].sup.+
Example 507
[3454] Compound M6-1
(S)-8-((2,2-Dimethyl-1,3-dioxolan-4-yl)methoxy)-11-oxo-5,11-dihydrospiro[b-
enzo[b]carbazole-6,1'-cyclopentane]-3-carbonitrile
##STR00522##
[3456] Under the same conditions as the method for synthesizing
Compound A7-17, the title compound was prepared as a crude product
from Compound M5 and toluene-4-sulfonic acid
(R)-2,2-dimethyl-[1,3]dioxolan-4-yl methyl ester.
Example 508
[3457] Compound M6-2
(R)-8-(2,3-Dihydroxypropoxy)-11-oxo-5,11-dihydrospiro[benzo[b]carbazole-6,-
1'-cyclopentane]-3-carbonitrile
##STR00523##
[3459] Under the same conditions as the method for synthesizing
Compound A7-14-2, the title compound was prepared from Compound
M6-1.
[3460] LCMS: m/z 403 [M+H].sup.+
[3461] HPLC retention time: 2.88 min (analysis condition U)
Example 509
[3462] Compound N1
7-Methoxy-2',3,3',4,5',6'-hexahydro-2H-spiro[naphthalene-1,4'-pyran]-2-one
##STR00524##
[3464] To the THF (300 ml) solution of
7-methoxy-3,4-dihydro-1H-naphthalen-2-one (Compound A1, 20 g, 0.11
mol), sodium hydride (9.9 g, 3.7 eq.) was added at 0.degree. C.
After stirring for 10 min, 1-bromo-2-(2-bromo-ethoxy)-ethane (19
ml, 12 eq.) was added dropwise thereto, and the mixture was stirred
at 80.degree. C. for 3 hr. To the reaction solution, saturated
aqueous solution of ammonium chloride was added and the extraction
was carried out twice with ethyl acetate. The organic layer was
dried over magnesium sulfate. The drying agent was removed by
filtration and the residues obtained after concentration under
reduced pressure were purified by silica gel column chromatography
(ethyl acetate/hexane) to obtain the title compound (white solid,
13 g, 51%).
[3465] .sup.1H-NMR (300 MHz, CDCl.sub.3) .delta.: 2.07 (4H, m),
2.70 (t, 2H, 6.8 Hz), 3.12 (t, 2H, 6.8 Hz), 3.81 (s, 3H), 3.89 (m,
4H), 6.75 (dd, 1H, 2.6 Hz, 8.3 Hz), 6.9 (d, 1H, 2.6 Hz), 7.0 (d,
1H, 8.3 Hz)
[3466] LCMS: m/z 247 [M+H].sup.+
Example 510
[3467] Compound N2-1, Compound N2-2
3-Bromo-8-methoxy-2',
3',5,5',6',11-hexahydrospiro[benzo[b]carbazole-6,4'-pyran]
1-Bromo-8-methoxy-2',3',5,5',6',11-hexahydrospiro[benzo[b]carbazole-6,4'-p-
yran]
##STR00525##
[3469] Under the same conditions as the method for synthesizing
Compound A3-1, the title compound was prepared as a mixture from
Compound N1.
Example 511
[3470] Compound N3
3-Bromo-8-methoxy-2',3',5',6'-tetrahydrospiro[benzo[b]carbazole-6,4'-pyran-
]-11 (5H)-one
##STR00526##
[3472] Under the same conditions as the method for synthesizing
Compound A4, the title compound was prepared from Compound
N2-1.
[3473] .sup.1H-NMR (300 MHz, DMSO-d.sub.6) .delta.: 1.9 (2H, m),
2.4 (m, 2H), 3.9 (s, 3H), 4.0 (m, 2H), 4.2 (m, 2H), 7.1 (dd, 1H,
2.2 Hz, 8.7 Hz), 7.3 (m, 2H), 7.8 (d, 1H, 2.2 Hz), 8.1 (d, 2H, 8.7
Hz), 11.8 (s, 1H)
[3474] LCMS: m/z 413 (M+1).sup.+
Example 512
[3475] Compound N4
8-Methoxy-11-oxo-2',3',5,5',6',11-hexahydrospiro[benzo[b]carbazole-6,4'-py-
ran]-3-carbonitrile
##STR00527##
[3477] Under the same conditions as the method for synthesizing
Compound A5-2, the title compound was prepared from Compound
N3.
[3478] .sup.1H-NMR (300 MHz, DMSO-d.sub.6) .delta.: 1.9 (m, 2H),
2.4 (m, 2H), 3.9 (s, 3H), 4.0 (m, 2H), 4.1 (m, 2H), 7.1 (dd, 1H,
2.2 Hz, 8.7 Hz), 7.4 (d, 1H, 2.2 Hz), 7.6 (dd, 1H, 1.5 Hz, 8.3 Hz),
8.0 (s, 1H), 8.1 (d, 1H, 8.7 Hz), 8.3 (d, 1H, 8.3 Hz), 12.2 (s,
1H)
[3479] LCMS: m/z 359 [M+H].sup.+
[3480] HPLC retention time: 2.80 min (analysis condition U)
Example 513
[3481] Compound N5
8-Hydroxy-11-oxo-2',3',5,5',6',11-hexahydrospiro[benzo[b]carbazole-6,4'-py-
ran]-3-carbonitrile
##STR00528##
[3483] Under the same conditions as the method for synthesizing
Compound A6, the title compound was prepared from Compound N4.
[3484] .sup.1H-NMR (300 MHz, DMSO-d.sub.6) d ppm 2.0 (m, 2H), 2.3
(m, 2H), 4.0 (m, 2H), 4.1 (m, 2H), 6.9 (dd, 1H, 1.9 Hz, 8.3 Hz),
7.3 (d, 1H, 1.9 Hz), 7.6 (dd, 1H, 1.5 Hz, 8.3 Hz), 8.0 (s, 1H), 8.1
(d, 1H, 8.3 Hz), 8.3 (d, 1H, 8.3 Hz), 10.3 (s, 1H), 12.2 (s,
1H)
[3485] LCMS: m/z 345 [M+H].sup.+
[3486] HPLC retention time: 2.37 min (analysis condition U)
Example 514
[3487] Compound N6-1-1
(S)-8-((2,2-Dimethyl-1,3-dioxolan-4-yl)
methoxy)-11-oxo-2',3',5,5',6',11-hexahydrospiro[benzo[b]carbazole-6,4'-py-
ran]-3-carbonitrile
##STR00529##
[3489] Under the same conditions as the method for synthesizing
Compound A7-1, the title compound was prepared from Compound N6-2
and (S)-2,2-dimethyl-4-p-tolyloxymethyl-[1,3]dioxolane.
[3490] LCMS: m/z 459 [M+H].sup.+
[3491] HPLC retention time: 2.93 min (analysis condition Y)
Example 515
[3492] Compound N6-1-2
(R)-8-(2,3-Dihydroxypropoxy)-11-oxo-2',3',5,5',6',11-hexahydrospiro[benzo[-
b]carbazole-6,4'-pyran]-3-carbonitrile
##STR00530##
[3494] Under the same conditions as the method for synthesizing
Compound A7-14-2, the title compound was prepared from Compound
N6-1-1.
[3495] LCMS: m/z 419 [M+H].sup.+
[3496] HPLC retention time: 1.52 min (analysis condition S)
Example 516
[3497] Compound N6-2
11-Oxo-8-(piperidin-4-yloxy)-2',3',5,5',6',11-hexahydrospiro[benzo[b]carba-
zole-6,4'-pyran]-3-carbonitrile
##STR00531##
[3499] Under the same conditions as the method for synthesizing
Compound A7-1 and Compound A8-1, the title compound was prepared
from Compound N5.
[3500] LCMS: m/z 428 [M+H].sup.+
[3501] HPLC retention time: 1.38 min (analysis condition S)
Example 517
[3502] Compound N6-3
8-(3-Morpholinoethoxy)-11-oxo-2',3',5,5',6',11-hexahydrospiro[benzo[b]carb-
azole-6,4'-pyran]-3-carbonitrile
##STR00532##
[3504] Under the same conditions as the method for synthesizing
Compound A8-17, the title compound was prepared from Compound
N5.
[3505] LCMS: m/z 458 [M+H].sup.+
[3506] HPLC retention time: 1.33 min (analysis condition S)
Example 518
[3507] Compound N6-4
8-(3-Morpholinopropoxy)-11-oxo-2',3',5,5',6',11-hexahydrospiro[benzo[b]car-
bazole-6,4'-pyran]-3-carbonitrile
##STR00533##
[3509] Under the same conditions as the method for synthesizing
Compound A8-17, the title compound was prepared from Compound
N5.
[3510] LCMS: m/z 472 [M+H].sup.+
[3511] HPLC retention time: 1.41 min (analysis condition S)
Example 519
[3512] Compound N6-5
3-Cyano-8-[2-(1,1-dioxo-thiomorpholin-4-yl)-ethoxy]-6,6-dimethyl-11-oxo-6,-
11-dihydro-5H-benzo[b]carbazole-9-sulfonic acid dimethylamide
##STR00534##
[3514] Under the same conditions as the method for synthesizing
Compound A8-17, the title compound was prepared from Compound
N5.
[3515] LCMS: m/z 506 [M+H].sup.+
[3516] HPLC retention time: 1.53 min (analysis condition S)
Example 520
[3517] Compound N6-6
8-(1-Ethylpiperidin-4-yloxy)-11-oxo-2',3',5,5',6',11-hexahydrospiro[benzo[-
b]carbazole-6,4'-pyran]-3-carbonitrile
##STR00535##
[3519] Under the same conditions as the method for synthesizing
Compound A7-1, the title compound was prepared from Compound
N6-2.
[3520] .sup.1H-NMR (300 MHz, DMSO-d.sub.6) .delta.: 1.02 (3H, t,
7.25 Hz), 1.18 (2H, m), 1.71 (2H, m), 1.97 (4H, m), 2.27 (2H, m),
2.38 (3H, m), 2.71 (2H, m), 4.03 (2H, m), 4.21 (2H, m), 4.66 (1H,
s), 7.13 (1H, dd, 8.77 Hz, 1.91 Hz), 7.39 (1H, bs, 1.91 Hz), 7.60
(1H, d, 8.40 Hz), 8.07 (1H, s), 8.15 (1H, d, 8.40 Hz), 8.37 (1H, d,
8.01 Hz), 12.2 (1 H, s).
[3521] LCMS: m/z 456 [M+H].sup.+
[3522] HPLC retention time: 1.48 min (analysis condition S)
Example 521
[3523] Compound N7
Trifluoromethanesulfonic acid
3-cyano-11-oxo-2',3',5,5',6',11-hexahydrospiro[benzo[b]carbazole-6,4'-pyr-
an]-8-yl
##STR00536##
[3525] Under the same conditions as the method for synthesizing
Compound B1, the title compound was prepared from Compound N5.
[3526] LCMS: m/z 477 [M+H].sup.+
[3527] HPLC retention time: 3.58 min (analysis condition Y)
Example 522
[3528] Compound N8-1
11-Oxo-8-(4-(pyrrolidin-1-yl)piperidin-1-yl)-2',3',5,5',6',11-hexahydrospi-
ro[benzo[b]carbazole-6,4'-pyran]-3-carbonitrile
##STR00537##
[3530] Under the same conditions as the method for synthesizing
Compound B2-1, the title compound was prepared from Compound N7 and
4-pyrrolidin-1-yl-piperidine.
[3531] LCMS: m/z 481 [M+H].sup.+
[3532] HPLC retention time: 1.75 min (analysis condition U)
Example 523
[3533] Compound N8-2
8-(4-Morpholinopiperidin-1-yl)-11-oxo-2',3',5,5',6',11-hexahydrospiro[benz-
o[b]carbazole-6,4'-pyran]-3-carbonitrile
##STR00538##
[3535] Under the same conditions as the method for synthesizing
Compound B2-1, the title compound was prepared from Compound N7 and
4-piperidin-4-yl-morpholine.
[3536] LCMS: m/z 497 [M+H].sup.+
[3537] HPLC retention time: 1.70 min (analysis condition U)
Example 524
[3538] Compound O1
6-Bromo-7-methoxy-2',3,3',4,5',6'-hexahydro-2H-spiro[naphthalene-1,4'-pyra-
n]-2-one
##STR00539##
[3540] Under the same conditions as the method for synthesizing
Compound E-1, the title compound was prepared from Compound N1.
[3541] .sup.1H-NMR (300 MHz, DMSO-d.sub.6) .delta.: 2.01 (4H, m),
2.66 (2H, t, 6.87 Hz), 3.08 (2H, t, 6.87 Hz), 3.62 (2H, m), 3.78
(2H, m), 3.87 (3H, s), 7.00 (1H, s), 7.43 (1H, s)
Example 525
[3542] Compound O2
9-Bromo-8-methoxy-2',3',5,5',6',11-hexahydrospiro[benzo[b]carbazole-6,4'-p-
yran]-3-carbonitrile
##STR00540##
[3544] Under the same conditions as the method for synthesizing
Compound E2-1, the title compound was prepared as a crude product
from Compound O1.
Example 526
[3545] Compound O3
9-Bromo-8-methoxy-11-oxo-2',3',5,5',6',11-hexahydrospiro[benzo[b]carbazole-
-6,4'-pyran]-3-carbonitrile
##STR00541##
[3547] Under the same conditions as the method for synthesizing
Compound A4, the title compound was prepared from Compound O2.
[3548] .sup.1H-NMR (300 MHz, DMSO-d.sub.6) .delta.: 1.95 (2H, d,
14.87 Hz), 2.55 (2H, m), 4.04 (2H, m), 4.09 (3H, s), 4.22 (2H, m),
7.51 (1H, s), 7.63 (1H, dd, 8.01 Hz, 1.53 Hz), 8.09 (1H, s), 8.30
(1H, s), 8.36 (1H, d, 8.01 Hz), 12.3 (1H, s).
[3549] LCMS: m/z 437,439 [M+H].sup.+
[3550] HPLC retention time: 2.65 min (analysis condition U)
Example 527
[3551] Compound O4
9-Fluoro-8-methoxy-11-oxo-2',3',5,5',6',11-hexahydrospiro[benzo[b]carbazol-
e-6,4'-pyran]-3-carbonitrile
##STR00542##
[3553] Under the same conditions as the method for synthesizing
Compound O5-3, the title compound was prepared from Compound
O3.
[3554] LCMS: m/z 377 [M+H].sup.+
[3555] HPLC retention time: 2.29 min (analysis condition S)
Example 528
[3556] Compound O5-1
9-Fluoro-8-hydroxy-11-oxo-2',3',5,5',6',11-hexahydrospiro[benzo[b]carbazol-
e-6,4'-pyran]-3-carbonitrile
##STR00543##
[3558] Under the same conditions as the method for synthesizing
Compound E3-2, the title compound was prepared from Compound
O4.
[3559] LCMS: m/z 363 [M+H].sup.+
[3560] HPLC retention time: 1.88 min (analysis condition S)
Example 529
[3561] Compound O5-2
Trifluoromethanesulfonic acid
3-cyano-9-fluoro-11-oxo-2',3',5,5',6',11-hexahydrospiro[benzo[b]carbazole-
-6,4'-pyran]-8-yl
##STR00544##
[3563] Under the same conditions as the method for synthesizing
Compound B1, the title compound was prepared from Compound
O5-1.
[3564] LCMS: m/z 495 [M+H].sup.+
[3565] HPLC retention time: 3.47 min (analysis condition Y)
Example 530
[3566] Compound O5-3
9-Fluoro-11-oxo-8-(4-(pyrrolidin-1-yl)piperidin-1-yl)-2',3',5,5',6',11-hex-
ahydrospiro[benzo[b]carbazole-6,4'-pyran]-3-carbonitrile
##STR00545##
[3568] To the THF (0.9 ml) solution of
9-bromo-6-tetrahydropyran-8-pyrrolidinopiperidin-11-oxo-6,11-dihydro-5H-b-
enzo[b]carbazole-3-carbonitrile (Compound O8-1, 90 mg, 0.161 mmol),
THF solution of n-butyl lithium (2 M solution, 0.241 ml, 3 eq.) was
added at -78.degree. C. After stirring for 30 min, THF (1 ml)
solution of N-fluorobenzenesulfonimide (152 mg, 3 eq.) was added
dropwise thereto. After rising to room temperature, the mixture was
stirred for 18 hr. To the reaction solution, water was added and
the extraction was carried out with ethyl acetate. The organic
layer was washed with brine and dried over magnesium sulfate. The
drying agent was removed by filtration and the residues obtained
after concentration under reduced pressure were purified by high
performance chromatography to obtain the target compound (white
solid, 0.44 mg, 0.5%).
[3569] .sup.1H-NMR (CDCl.sub.3+CD.sub.3OD, 300 MHz) .delta.:
1.75-1.94 (m, 11H), 2.02-2.01 (m, 2H), 2.30-2.27 (m, 1H), 2.75-2.72
(m, 2H), 2.90-3.00 (m, 2H), 3.61-3.47 (m, 4H), 4.01-3.90 (m, 4H),
7.08 (dd, 1H, J=1, 2 Hz, 8.4 Hz), 7.29 (dd, 1H, J=1, 5 Hz, 8.1 Hz),
7.68 (d, 1H, J=12.9 Hz), 7.72 (s, 1H), 8.22 (d, 1H, J=8.4 Hz)
[3570] LCMS: m/z 499 [M+H].sup.+
[3571] HPLC retention time: 1.95 min (analysis condition U)
Example 531
[3572] Compound O5-4
8-(4-Cyclobutylpiperazin-1-yl)-9-fluoro-11-oxo-2',3',5,5',6',11-hexahydros-
piro[benzo[b]carbazole-6,4'-pyran]-3-carbonitrile
##STR00546##
[3574] Under the same conditions as the method for synthesizing
Compound B2-1, the title compound was prepared from Compound O5-2
and 1-cyclobutylpiperazine.
[3575] LCMS: m/z 485 [M+H].sup.+
[3576] HPLC retention time: 1.97 min (analysis condition U)
Example 532
[3577] Compound O6-1
9-Bromo-8-hydroxy-11-oxo-2',3',5,5',6',11-hexahydrospiro[benzo[b]carbazole-
-6,4'-pyran]-3-carbonitrile
##STR00547##
[3579] Under the same conditions as the method for synthesizing
Compound A6, the title compound was prepared from Compound O3.
[3580] LCMS: m/z 423, 425 [M+H].sup.+
[3581] HPLC retention time: 2.30 min (analysis condition U)
Example 533
[3582] Compound O6-2
Trifluoromethanesulfonic acid
9-bromo-3-cyano-11-oxo-2',3',5,5',6',11-hexahydrospiro[benzo[b]carbazole--
6,4'-pyran]-8-yl
##STR00548##
[3584] Under the same conditions as the method for synthesizing
Compound B1, the title compound was prepared from Compound
O6-1.
[3585] LCMS: m/z 555, 557 [M+H].sup.+
[3586] HPLC retention time: 3.13 min (analysis condition U)
Example 534
[3587] Compound O7-1
9-Bromo-11-oxo-8-(piperazin-1-yl)-2',3',5,5',6',11-hexahydrospiro[benzo[b]-
carbazole-6,4'-pyran]-3-carbonitrile
##STR00549##
[3589] Under the same conditions as the method for synthesizing
Compound B2-1, the title compound was prepared from Compound O6-2
and piperazine.
[3590] LCMS: m/z 491, 493 [M+H].sup.+
[3591] HPLC retention time: 1.88 min (analysis condition U)
Example 535
[3592] Compound O7-2
4-(9-Bromo-3-cyano-11-oxo-2',3',5,5',6',11-hexahydrospiro[benzo[b]carbazol-
e-6,4'-pyran]-8-yl)piperazine-1-carboxylic acid tert-butyl
##STR00550##
[3594] To the dichloromethane (5 mL) solution of
9-bromo-11-oxo-8-(piperazin-1-yl)-2',3',5,5',6',11-hexahydrospiro[benzo[b-
]carbazole-6,4'-pyran]-3-carbonitrile (Compound 07-1, 250 mg, 0.509
mmol) and mono-tert-butyl ester carbonic anhydride (122 mg, 0.560
mmol), triethylamine (0.21 mL, 1.53 mmol) was added at 0.degree.
C., and stirred at room temperature for 1 hr. The reaction mixture
was concentrated under reduced pressure and the residues were
purified by silica gel column chromatography
(methanol/dichloromethane) to obtain the target compound as a white
solid (212 mg, 70%).
[3595] .sup.1H-NMR (300 MHz, DMSO-d.sub.6) d ppm: 1.44 (9H, s),
1.97 (2H, m), 2.44 (2H, m), 1.35 (4H, m), 3.54 (4H, m), 4.06 (2H,
m), 4.18 (2H, m), 7.57 (1H, s), 7.63 (1H, dd, 8.01 Hz, 1.52 Hz),
8.08 (1H, d, 1.52 Hz), 8.31 (1H, s), 8.36 (1H, d, 8.01 Hz), 12.3
(1H, s)
[3596] LCMS: m/z 591, 593 [M+H].sup.+
[3597] HPLC retention time: 3.23 min (analysis condition T)
Example 536
[3598] Compound O7-3
Tert-butyl
4-(3-cyano-11-oxo-9-(prop-1-ynyl)-2',3',5,5',6',11-hexahydrospi-
ro[benzo[b]carbazole-6,4'-pyran]-8-yl)piperazine-1-carboxylic
acid
##STR00551##
[3600] Under the same conditions as the method for synthesizing
Compound O9-1, the title compound was prepared from Compound
O7-2.
[3601] LCMS: m/z 551 [M+H].sup.+
[3602] HPLC retention time: 3.92 min (analysis condition Y)
Example 537
[3603] Compound O7-4
11-Oxo-8-(piperazin-1-yl)-9-(prop-1-ynyl)-2',3',5,5',6',11-hexahydrospiro[-
benzo[b]carbazole-6,4'-pyran]-3-carbonitrile
##STR00552##
[3605] Under the same conditions as the method for synthesizing
Compound A8-1, the title compound was prepared from Compound
O7-3.
[3606] LCMS: 451 m/z [M+H].sup.+
[3607] HPLC retention time: 1.87 min (analysis condition U)
Example 538
[3608] Compound O7-5
4-(3-Cyano-9-ethynyl-11-oxo-2',3',5,5',6',11-hexahydrospiro[benzo[b]carbaz-
ole-6,4'-pyran]-8-yl)piperazine-1-carboxylic acid tert-butyl
##STR00553##
[3610] LCMS: m/z 537 [M+H].sup.+
[3611] HPLC retention time: 3.82 min (analysis condition Y)
Example 539
[3612] Compound O8-1
9-Bromo-11-oxo-8-(4-(pyrrolidin-1-yl)piperidin-1-yl)-2',3',5,5',6',11-hexa-
hydrospiro[benzo[b]carbazole-6,4'-pyran]-3-carbonitrile
##STR00554##
[3614] Under the same conditions as the method for synthesizing
Compound B2-1, the title compound was prepared from Compound O6-2
and 4-pyrrolidin-1-yl-piperidine.
[3615] LCMS: m/z 559, 561 [M+H].sup.+
[3616] HPLC retention time: 2.05 min (analysis condition U)
Example 540
[3617] Compound O8-2
9-Bromo-8-(4-cyclobutylpiperazin-1-yl)-11-oxo-2',3',5,5',6',11-hexahydrosp-
iro[benzo[b]carbazole-6,4'-pyran]-3-carbonitrile
##STR00555##
[3619] Under the same conditions as the method for synthesizing
Compound B2-1, the title compound was prepared from Compound O6-2
and 1-cyclobutylpiperazine.
[3620] LCMS: m/z 547 [M+H].sup.+
[3621] HPLC retention time: 1.61 min (analysis condition S)
Example 541
[3622] Compound O8-3
9-Bromo-8-(4-morpholinopiperidin-1-yl)-11-oxo-2',3',5,5',6',11-hexahydrosp-
iro[benzo[b]carbazole-6,4'-pyran]-3-carbonitrile
##STR00556##
[3623] Under the same conditions as the method for synthesizing
Compound B2-1, the title compound was prepared from Compound O6-2
and 4-piperidin-4-yl-morpholine.
[3624] LCMS: m/z 575, 577 [M+H].sup.+
[3625] HPLC retention time: 1.95 min (analysis condition U)
Example 542
[3626] Compound O8-4
9-Bromo-8-(4-(oxetan-3-yl)piperazin-1-yl)-11-oxo-2',3',5,5',6',11-hexahydr-
ospiro[benzo[b]carbazole-6,4'-pyran]-3-carbonitrile
##STR00557##
[3628] Under the same conditions as the method for synthesizing
Compound B3-32, the title compound was prepared from Compound O7-1
and oxetan-3-one.
[3629] LCMS: m/z 547, 549 [M+H].sup.+
[3630] HPLC retention time: 1.43 min (analysis condition S)
Example 543
[3631] Compound O8-5
9-Bromo-8-(4-tert-butylpiperazin-1-yl)-11-oxo-2',3',5,5',6',11-hexahydrosp-
iro[benzo[b]carbazole-6,4'-pyran]-3-carbonitrile
##STR00558##
[3633] Under the same conditions as the method for synthesizing
Compound B2-1, the title compound was prepared from Compound O6-2
and 1-tert-butylpiperazine.
[3634] LCMS: 547, 549 m/z [M+H].sup.+
[3635] HPLC retention time: 2.07 min (analysis condition U)
Example 544
[3636] Compound O9-1
11-Oxo-9-(prop-1-ynyl)-8-(4-(pyrrolidin-1-yl)piperidin-1-yl)-2',3',5,5',6'-
,11-hexahydrospiro[benzo[b]carbazole-6,4'-pyran]-3-carbonitrile
##STR00559##
[3638]
9-Bromo-11-oxo-8-(4-(pyrrolidin-1-yl)piperidin-1-yl)-2',3',5,5',6',-
11-hexahydrospiro[benzo[b]carbazole-6,4'-pyran]-3-carbonitrile
(Compound O8-1, 100 mg, 0.170 mmol), tin tributyl(1-propynyl)
(0.082 mL, 0.268 mmol), bis(acetonitrile) palladium dichloride (II)
(2.64 mg, 0.00895 mmol), X-Phos (12.8 mg, 0.0269 mmol), and cesium
carbonate (262.4 mg, 0.806 mmol) were suspended in acetonitrile (1
mL), and then stirred at 80.degree. C. for 2 hr. The reaction
mixture was cooled to room temperature followed by addition of
water and extracted with ethyl acetate. The organic layer was
washed with saturated brine and dried over anhydrous magnesium
sulfate. The drying agent was removed by filtration and the
residues obtained after concentration under reduced pressure were
purified by silica gel column chromatography
(dichloromethane/methanol) to obtain the target compound (pale
yellow solid, 3.8 mg, 4.1%).
[3639] .sup.1H-NMR (300 MHz, DMSO) .sigma.ppm 12.20 (bs, 1H), 8.35
(d, 1H, J=8.1 Hz), 8.06 (s, 1H), 8.06 (d, 1H, J=10.8 Hz), 7.58 (d,
1H, J=8.4 Hz), 7.29 (s, 1H), 4.25-4.23 (m, 2H), 4.02-3.98 (m, 2H),
3.78 (d, 2H, J=11.4 Hz), 2.93 (t, 2H, J=11.1 Hz), 2.55 (s, 1H),
2.45-2.28 (m, 2H), 2.24-2.05 (m, 4H), 2.08-1.81 (m, 4H), 1.75-1.50
(m, 7H)
[3640] LCMS: m/z 519 [M+H].sup.+
[3641] HPLC retention time: 1.98 min (analysis condition U)
Example 545
[3642] Compound O9-2
9-Ethynyl-11-oxo-8-(4-(pyrrolidin-1-yl)piperidin-1-yl)-2',3',5,5',6',11-he-
xahydrospiro[benzo[b]carbazole-6,4'-pyran]-3-carbonitrile
##STR00560##
[3644] Under the same conditions as the method for synthesizing
Compound F5-43, the title compound was prepared from Compound
O8-1.
[3645] LCMS: m/z 505 [M+H].sup.+
[3646] HPLC retention time: 1.92 min (analysis condition U)
Example 546
[3647] Compound O9-3
11-Oxo-8-(4-(pyrrolidin-1-yl)piperidin-1-yl)-2',3',5,5',6',11-hexahydrospi-
ro[benzo[b]carbazole-6,4'-pyran]-3,9-dicarbonitrile
##STR00561##
[3649] Under the same conditions as the method for synthesizing
Compound A5-2, the title compound was prepared from Compound
O8-1.
[3650] LCMS: 506 m/z [M+H].sup.+
[3651] HPLC retention time: 1.87 min (analysis condition U)
Example 547
[3652] Compound O9-4
9-(3-Hydroxy-3-methylbut-1-ynyl)-11-oxo-8-(4-(pyrrolidin-1-yl)piperidin-1--
yl)-2',3',5,5',6',11-hexahydrospiro[benzo[b]carbazole-6,4'-pyran]-3-carbon-
itrile
##STR00562##
[3654] Under the same conditions as the method for synthesizing
Compound E4-2-1, the title compound was prepared from Compound
O8-1.
[3655] LCMS: m/z 563 [M+H].sup.+
[3656] HPLC retention time: 1.92 min (analysis condition U)
Example 548
[3657] Compound O9-5
8-(4-Cyclobutylpiperazin-1-yl)-11-oxo-9-(prop-1-ynyl)-2',3',5,5',6',11-hex-
ahydrospiro[benzo[b]carbazole-6,4'-pyran]-3-carbonitrile
##STR00563##
[3659] Under the same conditions as the method for synthesizing
Compound O9-1, the title compound was prepared from Compound
O8-2.
[3660] .sup.1H-NMR (300 MHz, DMSO-d.sub.6) .delta.: 1.6 (m, 2H),
1.8 (m, 2H), 1.9 (m, 4H), 2.1 (s, 3H), 2.4 (m, 6H), 2.8 (m, 1H),
3.4 (m, 4H), 4.0 (m, 2H), 4.1 (m, 2H), 7.3 (s, 1H), 7.6 (d, 1H, 8.0
Hz), 8.0 (m, 2H), 8.3 (d, 1H, 8.0 Hz), 12.2 (s, 1H)
[3661] LCMS: m/z 505 [M+H].sup.+
[3662] HPLC retention time: 2.03 min (analysis condition U)
Example 549
[3663] Compound O9-6
8-(4-Cyclobutylpiperazin-1-yl)-9-ethynyl-11-oxo-2',3',5,5',6',11-hexahydro-
spiro[benzo[b]carbazole-6,4'-pyran]-3-carbonitrile
##STR00564##
[3665] Under the same conditions as the method for synthesizing
Compound F5-43, the title compound was prepared from Compound
O8-2.
[3666] .sup.1H-NMR (300 MHz, DMSO-d.sub.6) .delta.: 1.66 (2H, m),
1.83 (2H, t, 8.77 Hz), 1.99 (4H, m), 2.41 (6H, m), 2.79 (1H, t,
7.63 Hz), 3.35 (4H, m), 4.01 (2H, m), 4.27 (2H, m), 4.51 (1H, s),
7.33 (1H, s), 7.54 (1H, m), 8.03 (1H, s), 8.16 (1H, s), 8.32 (1H,
d, 8.40 Hz), 12.3 (1H, s).
[3667] LCMS: m/z 491 [M+H].sup.+
[3668] HPLC retention time: 1.95 min (analysis condition U)
Example 550
[3669] Compound O9-7
8-(4-Morpholinopiperidin-1-yl)-11-oxo-9-(prop-1-ynyl)-2',3',5,5',6',11-hex-
ahydrospiro[benzo[b]carbazole-6,4'-pyran]-3-carbonitrile
##STR00565##
[3671] Under the same conditions as the method for synthesizing
Compound O9-1, the title compound was prepared from Compound
O8-3.
[3672] .sup.1H-NMR (300 MHz, DMSO-d.sub.6) .delta.: 1.57 (2H, m),
1.95 (4H, m), 2.14 (3H, s), 2.37 (3H, m), 3.35 (4H, m), 2.83 (2H,
t, 12.6 Hz), 3.56 (4H, s), 3.86 (2H, d, 11.8 Hz), 4.04 (2H, m),
4.17 (2H, m), 7.31 (1H, s), 7.61 (1H, d, 8.01 Hz), 8.06 (1H, s),
8.07 (1H, s), 8.36 (1H, d, 8.01 Hz), 12.3 (1H, s).
[3673] LCMS: m/z 535 [M+H].sup.+
[3674] HPLC retention time: 1.95 min (analysis condition U)
Example 551
[3675] Compound O9-8
9-Ethynyl-8-(4-morpholinopiperidin-1-yl)-11-oxo-2',3',5,5',6',11-hexahydro-
spiro[benzo[b]carbazole-6,4'-pyran]-3-carbonitrile
##STR00566##
[3677] Under the same conditions as the method for synthesizing
Compound F5-43, the title compound was prepared from compound
08-3.
[3678] LCMS: m/z 521 [M+H].sup.+
[3679] HPLC retention time: 1.90 min (analysis condition U)
Example 552
[3680] Compound O9-9
8-(4-(Oxetan-3-yl)piperazin-1-yl)-11-oxo-9-(prop-1-ynyl)-2',3',5,5',6',11--
hexahydrospiro[benzo[b]carbazole-6,4'-pyran]-3-carbonitrile
##STR00567##
[3682] Under the same conditions as the method for synthesizing
Compound B3-32, the title compound was prepared from Compound O7-4
and oxetan-3-one.
[3683] LCMS: m/z 507 [M+H].sup.+
[3684] HPLC retention time: 1.43 min (analysis condition S)
Example 553
[3685] Compound O10-1-1
Tert-butyl 4-(3-cyano-9-ethyl-11-oxo-2',3',5,5a,
5',6',11,11a-octahydrospiro[benzo[b]carbazole-6,4'-pyran]-8-yl)piperazine-
-1-carboxylic acid
##STR00568##
[3687] Under the same conditions as the method for synthesizing
Compound B3-13-1, the title compound was prepared from Compound
O7-5.
[3688] LCMS: m/z 541 [M+H].sup.+
[3689] HPLC retention time: 3.08 min (analysis condition S)
Example 554
[3690] Compound O10-1-2
9-Ethyl-11-oxo-8-(piperazin-1-yl)-2',3',5,5',6',11-hexahydrospiro[benzo[b]-
carbazole-6,4'-pyran]-3-carbonitrile
##STR00569##
[3692] Under the same conditions as the method for synthesizing
Compound A8-1, the title compound was prepared from Compound
O10-1-1.
[3693] LCMS: m/z 441 [M+H].sup.+
[3694] HPLC retention time: 1.42 min (analysis condition S)
Example 555
[3695] Compound O10-2
9-Ethyl-8-(4-morpholinopiperidin-1-yl)-11-oxo-2',3',5,5',6',11-hexahydrosp-
iro[benzo[b]carbazole-6,4'-pyran]-3-carbonitrile
##STR00570##
[3697] According to the same method as the method for synthesizing
Compound B3-13-1, the title compound was prepared from Compound
O9-8.
[3698] .sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta.: 8.23-8.21 (1H,
m), 8.02-8.00 (1H, m), 7.88-7.86 (1H, m), 7.39-7.36 (2H, m),
4.63-4.59 (2H, m), 3.89-3.85 (2H, m), 3.60-3.56 (6H, m), 3.22-3.19
(4H, m), 2.76-2.68 (4H, m), 2.37-2.32 (3H, m), 1.92-1.88 (2H, m),
1.75-1.72 (2H, m), 1.61-1.57 (2H, m), 1.27-1.25 (3H, m)
[3699] LCMS: m/z 525 [M+H].sup.+
[3700] HPLC retention time: 1.48 min (analysis condition S)
Example 556
[3701] Compound O10-3
9-Ethyl-8-(4-(oxetan-3-yl)piperazin-1-yl)-11-oxo-2',3',5,5',6',11-hexahydr-
ospiro[benzo[b]carbazole-6,4'-pyran]-3-carbonitrile
##STR00571##
[3703] Under the same conditions as the method for synthesizing
Compound B3-32, the title compound was prepared from Compound
O10-1-2 and oxetan-3-one.
[3704] .sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta.: 12.26 (1H, s),
8.39 (1H, d, 7.9 Hz), 8.09-8.07 (2H, m), 7.63 (1H, d, 8.5 Hz), 7.51
(1H, s), 4.60-4.50 (4H, m), 4.20-4.09 (4H, m), 3.56-3.51 (1H, m),
3.07-3.05 (4H, m), 2.76-2.70 (2H, m), 2.44-2.40 (2H, m), 2.02-1.98
(2H, m), 1.29-1.26 (4H, m)
[3705] LCMS: m/z 497 [M+H].sup.+
[3706] HPLC retention time: 1.42 min (analysis condition S)
Example 557
[3707] Compound O10-4
8-(4-Cyclobutylpiperazin-1-yl)-9-ethyl-11-oxo-2',3',5,5',6',11-hexahydrosp-
iro[benzo[b]carbazole-6,4'-pyran]-3-carbonitrile
##STR00572##
[3709] Under the same conditions as the method for synthesizing
Compound B3-32, the title compound was prepared from Compound
O10-1-2 and cyclobutanone.
[3710] LCMS: m/z 495 [M+H].sup.+
[3711] HPLC retention time: 1.57 min (analysis condition S)
Example 558
[3712] Compound P1 (intermediate)
8-Methoxy-6,6-dimethyl-2-nitro-6,11-dihydro-5H-benzo[b]carbazole
##STR00573##
[3713] Under the same conditions as the method for synthesizing
Compound A3-1, the title compound was prepared from Compound A2 and
4-nitrophenylhydrazine.
[3714] LCMS: m/z 323 [M+H].sup.+
[3715] HPLC retention time: 4.08 min (analysis condition W)
Example 559
[3716] Compound P2 (intermediate)
8-Methoxy-6,6-dimethyl-2-nitro-5,6-dihydro-benzo[b]carbazol-11-one
##STR00574##
[3718] Under the same conditions as the method for synthesizing
Compound A4, the title compound was prepared from Compound P1.
[3719] .sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta.: 12.85 (1H, s),
9.03 (1H, d, J=1.9 Hz), 8.17-8.20 (2H, m), 7.71 (1H, d, J=9.1 Hz),
7.38 (1H, d, J=2.4 Hz), 7.12 (1H, dd, J=8.5, 2.4 Hz), 3.93 (3H, s),
1.79 (6H, s)
[3720] LCMS: m/z 337 [M+H].sup.+
[3721] HPLC retention time: 3.55 min (analysis condition W)
Example 560
[3722] Compound P3 (intermediate)
8-Hydroxy-6,6-dimethyl-2-nitro-5,6-dihydro-benzo[b]carbazol-11-one
##STR00575##
[3724] Under the same conditions as the method for synthesizing
Compound A6, the title compound was prepared from Compound P2.
[3725] LCMS: m/z 323 [M+H].sup.+
[3726] HPLC retention time: 3.11 min (analysis condition W)
Example 561
[3727] Compound P4 (intermediate)
4-(6,6-Dimethyl-2-nitro-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-8-yl
oxy)-piperidine-1-carboxylic acid tert-butyl ester
##STR00576##
[3729] Under the same conditions as the method for synthesizing
Compound A7-1, the title compound was prepared from Compound
P3.
[3730] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta.: 9.40 (1H, s),
9.37 (1H, s), 8.41 (1H, d, J=8.5 Hz), 8.24 (1H, d, J=11.0 Hz), 7.51
(1H, d, J=8.5 Hz), 7.13 (1H, s), 7.03 (1H, d, J=9.1 Hz), 4.61-4.71
(1H, m), 3.69-3.84 (2H, m), 3.35-3.49 (2H, m), 1.94-2.10 (2H, m),
1.75-1.93 (8H, m), 1.50 (9H, s)
[3731] LCMS: m/z 506 [M+H].sup.+
[3732] HPLC retention time: 4.17 min (analysis condition W)
Example 562
[3733] Compound P5
2-Amino-6,6-dimethyl-8-(piperidin-4-yloxy)-5,6-dihydro-benzo[b]carbazol-11-
-one
##STR00577##
[3735] Under the same conditions as the method for synthesizing
Compound A8-1, the title compound was prepared from Compound
P6.
[3736] .sup.1H-NMR (400 MHz, CD.sub.3OD) .delta.: 8.23 (1H, d,
J=8.5 Hz), 7.68 (1H, d, J=2.4 Hz), 7.26 (1H, d, J=8.5 Hz), 7.24
(1H, d, J=2.4 Hz), 7.06 (1H, dd, J=8.5, 2.4 Hz), 6.80 (1H, dd,
J=8.5, 2.4 Hz), 4.64-4.71 (1H, m), 3.06-3.15 (2H, m), 2.73-2.83
(2H, m), 2.02-2.13 (2H, m), 1.67-1.82 (8H, m)
[3737] LCMS: m/z 506 [M+H].sup.+
[3738] HPLC retention time: 4.17 min (analysis condition W)
[3739] Compound P6 (intermediate)
4-(2-Amino-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-8-yl
oxy)-piperidine-1-carboxylic acid tert-butyl ester
##STR00578##
[3741] To the ethanol (8 ml) suspension of
4-(6,6-dimethyl-2-nitro-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-8-yl
oxy)-piperidine-1-carboxylic acid tert-butyl ester (Compound P4,103
mg, 0.204 mmol), iron powder (228 mg, 20 eq.), ammonium chloride
(109 mg, 10 eq.), and distilled water (4 ml) were added and the
mixture was stirred at 90.degree. C. for 30 min. Upon the
completion of the reaction, insoluble matters were filtered off,
and the filtrate was extracted with ethyl acetate. The organic
layer was washed with brine and dried over sodium sulfate. The
drying agent was removed by filtration and the residues obtained
after concentration under reduced pressure were purified by silica
gel column chromatography (ethyl acetate/hexane) to obtain the
title compound (115 mg, 57%).
[3742] LCMS: m/z 476 [M+H].sup.+
[3743] HPLC retention time: 2.82 min (analysis condition W)
Example 564
[3744] Compound P7 (intermediate)
4-(2-Methanesulfonylamino-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carb-
azole-8-yl oxy)-piperidine-1-carboxylic acid tert-butyl ester
##STR00579##
[3746] To the pyridine (2 ml) solution of
4-(2-amino-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-8-yl
oxy)-piperidine-1-carboxylic acid tert-butyl ester (Compound P6, 50
mg, 0.105 mmol), mesyl chloride (9 .mu.l, 1.2 eq.) was added and
stirred at room temperature for 30 min. Upon the completion of the
reaction, the reaction solution was concentrated under reduced
pressure to obtain the title compound as an unpurified product.
[3747] LCMS: m/z 554 [M+H].sup.+
[3748] HPLC retention time: 3.60 min (analysis condition W)
Example 565
[3749] Compound P8
N-[6,6-Dimethyl-11-oxo-8-(piperidin-4-yloxy)-6,11-dihydro-5H-benzo[b]carba-
zole-2-yl]-methanesulfonamide
##STR00580##
[3751] Under the same conditions as the method for synthesizing
Compound A8-1, the title compound was prepared from Compound
P7.
[3752] .sup.1H-NMR (400 MHz, CD.sub.3OD) .delta.: 8.25 (1H, d,
J=8.5 Hz), 8.16 (1H, d, J=1.8 Hz), 7.46 (1H, d, J=9.1 Hz),
7.27-7.29 (2H, m), 7.09 (1H, dd, J=9.1, 1.8 Hz), 4.67-4.75 (1H, m),
3.09-3.18 (2H, m), 2.95 (3H, s), 2.77-2.87 (2H, m), 1.70-1.84 (8H,
m)
[3753] LCMS: m/z 454 [M+H].sup.+
[3754] HPLC retention time: 2.22 min (analysis condition W)
Example 566
[3755] Compound Q3 (intermediate)
2-Fluoro-8-methoxy-6,6-dimethyl-6,11-dihydro-5H-benzo[b]carbazole-3-carbon-
itrile
##STR00581##
[3757] Under the same conditions as the method for synthesizing
Compound A3-1, the title compound was prepared from Compound A2 and
3-cyano-4-fluorophenylhydrazine.
[3758] LCMS: m/z 321 [M+H].sup.+
[3759] HPLC retention time: 4.13 min (analysis condition W)
Example 567
[3760] Compound Q4 (intermediate)
2-Fluoro-8-methoxy-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-
-carbonitrile
##STR00582##
[3762] Under the same conditions as the method for synthesizing
Compound A4, the title compound was prepared from Compound Q3.
[3763] .sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta.: 12.89 (1H, s),
8.16 (1H, d, J=8.5 Hz), 8.07 (1H, d, J=4.9 Hz), 8.04 (1H, d, J=9.8
Hz), 7.36 (1H, d, J=2.4 Hz), 7.10 (1H, dd, J=8.5, 2.4 Hz), 3.91
(3H, s), 1.78 (3H, s)
[3764] LCMS: m/z 335 [M+H].sup.+
[3765] HPLC retention time: 3.61 min (analysis condition W)
Example 568
[3766] Compound Q5 (intermediate)
2-Fluoro-8-hydroxy-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-
-carbonitrile
##STR00583##
[3768] Under the same conditions as the method for synthesizing
Compound A6, the title compound was prepared from Compound Q4.
[3769] LCMS: m/z 321 [M+H].sup.+
[3770] HPLC retention time: 3.16 min (analysis condition W)
Example 569
[3771] Compound Q6 (intermediate)
4-(3-Cyano-2-fluoro-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole--
8-yl oxy)-piperidine-1-carboxylic acid tert-butyl ester
##STR00584##
[3773] Under the same conditions as the method for synthesizing
Compound A7-1, the title compound was prepared from Compound
Q5.
[3774] LCMS: m/z 504 [M+H].sup.+
[3775] HPLC retention time: 4.25 min (analysis condition W)
Example 570
[3776] Compound Q7
8-(2-Diethylamino-ethoxy)-2-fluoro-6,6-dimethyl-11-oxo-6,11-dihydro-5H-ben-
zo[b]carbazole-3-carbonitrile
##STR00585##
[3778] Under the same conditions as the method for synthesizing
Compound A7-17, the title compound was prepared from Compound
Q5.
[3779] .sup.1H-NMR (400 MHz, CD.sub.3OD) .delta.: 8.25 (1H, d,
J=8.5 Hz), 8.09 (1H, d, J=9.8 Hz), 7.83 (1H, d, J=5.5 Hz), 7.30
(1H, d, J=2.4 Hz), 7.09 (1H, dd, J=8.5, 2.4 Hz), 4.26 (2H, t, J=5.7
Hz), 2.98 (2H, t, J=5.7 Hz), 2.72 (4H, q, J=7.2 Hz), 1.81 (6H, s),
1.13 (6H, t, J=7.2 Hz)
[3780] LCMS: m/z 420 [M+H].sup.+
[3781] HPLC retention time: 2.65 min (analysis condition W)
Example 571
[3782] Compound Q8
2-Fluoro-6,6-dimethyl-11-oxo-8-(piperidin-4-yloxy)-6,11-dihydro-5H-benzo[b-
]carbazole-3-carbonitrile
##STR00586##
[3784] Under the same conditions as the method for synthesizing
Compound A8-1, the title compound was prepared from Compound
Q6.
[3785] .sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta.: 8.11 (1H, d,
J=8.5 Hz), 7.98 (1H, d, J=5.5 Hz), 7.96 (1H, d, J=9.8 Hz), 7.29
(1H, s), 7.08 (1H, d, J=8.5 Hz), 4.58-4.69 (1H, m), 2.93-3.05 (2H,
m), 2.60-2.69 (2H, m), 1.94-2.03 (2H, m), 1.74 (6H, s), 1.45-1.57
(2H, m)
[3786] LCMS: m/z 404 [M+H].sup.+
[3787] HPLC retention time: 2.67 min (analysis condition W)
Example 572
[3788] Compound R2
2-Fluoro-3-hydrazinylbenzonitrile
##STR00587##
[3790] 3-Amino-2-fluoro-benzonitrile (100 mg, 0.735 mmol) was
dissolved in water (0.94 mL), added with conc. hydrochloric acid
(0.74 mL) at 0.degree. C., and then further added with an aqueous
solution (0.294 mL) of sodium nitrite (61 mg, 0.882 mmol). The
resulting mixture was stirred at 0.degree. C. for 1 hr. To the
reaction mixture, conc. hydrochloric acid solution (0.94 mL) of tin
chloride (321 mg, 1.69 mmol) was added and stirred at room
temperature for 1 hr. Thereafter, the reaction solution was
neutralized with aqueous solution of sodium hydroxide, and
extracted with dichloromethane. The organic layer was washed with
saturated brine and dried over anhydrous magnesium sulfate. The
drying agent was removed by filtration and the residues were
obtained after concentration under reduced pressure to give the
target compound as a crude product.
Example 573
[3791] Compound R3
4-Fluoro-8-methoxy-6,6-dimethyl-6,11-dihydro-5H-benzo[b]carbazole-3-carbon-
itrile
##STR00588##
[3793] Under the same conditions as the method for synthesizing
Compound E2-1, the title compound was prepared as a crude product
from Compound A2 and Compound R2.
Example 574
[3794] Compound R4
4-Fluoro-8-methoxy-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-
-carbonitrile
##STR00589##
[3796] Under the same conditions as the method for synthesizing
Compound A4, the title compound was prepared from Compound R3.
[3797] LCMS: m/z 335 [M+H].sup.+
[3798] HPLC retention time: 2.70 min (analysis condition U)
Example 575
[3799] Compound R5
4-Fluoro-8-hydroxy-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-
-carbonitrile
##STR00590##
[3801] Under the same conditions as the method for synthesizing
Compound A6, the title compound was prepared from Compound R4.
[3802] LCMS: m/z 321 [M+H].sup.+
[3803] HPLC retention time: 2.32 min (analysis condition U)
Example 576
[3804] Compound R6
8-(2-Diethylamino-ethoxy)-4-fluoro-6,6-dimethyl-11-oxo-6,11-dihydro-5H-ben-
zo[b]carbazole-3-carbonitrile
##STR00591##
[3806] Under the same conditions as the method for synthesizing
Compound A7-17, the title compound was prepared from Compound
R5.
[3807] LCMS: m/z 420 [M+H].sup.+
[3808] HPLC retention time: 1.51 min (analysis condition S)
Example 577
[3809] Compound R7
Trifluoromethanesulfonic acid
3-cyano-4-fluoro-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-8--
yl
##STR00592##
[3811] Under the same conditions as the method for synthesizing
Compound B1, the title compound was prepared from Compound R5.
[3812] LCMS: m/z 453 [M+H].sup.+
[3813] HPLC retention time: 3.82 min (analysis condition Y)
Example 578
[3814] Compound R8-1
4-Fluoro-6,6-dimethyl-11-oxo-8-(4-pyrrolidin-1-yl-piperidin-1-yl)-6,11-dih-
ydro-5H-benzo[b]carbazole-3-carbonitrile
##STR00593##
[3816] Under the same conditions as the method for synthesizing
Compound B2-1, the title compound was prepared from Compound R7 and
4-pyrrolidin-1-yl-piperidine.
[3817] LCMS: m/z 457 [M+H].sup.+
[3818] HPLC retention time: 2.10 min (analysis condition U)
Example 579
[3819] Compound R8-2
4-Fluoro-8-(4-isopropyl-piperazin-1-yl)-6,6-dimethyl-11-oxo-6,11-dihydro-5-
H-benzo[b]carbazole-3-carbonitrile
##STR00594##
[3821] Under the same conditions as the method for synthesizing
Compound B2-1, the title compound was prepared from Compound
R7.
[3822] LCMS: m/z 431 [M+H].sup.+
[3823] HPLC retention time: 2.07 min (analysis condition U)
Example 580
[3824] Compound R9-1
8-((S)-2,2-Dimethyl-[1,3]dioxolan-4-ylmethoxy)-4-fluoro-6,6-dimethyl-11-ox-
o-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile
##STR00595##
[3826] Under the same conditions as the method for synthesizing
Compound A7-1, the title compound was prepared as a crude product
from Compound R5 and
(R)-(-)-2,2-dimethyl-1,3-dioxolan-4-methanol.
Example 581
[3827] Compound R9-2
8-((R)-2,3-Dihydroxy-propoxy)-4-fluoro-6,6-dimethyl-11-oxo-6,11-dihydro-5H-
-benzo[b]carbazole-3-carbonitrile
##STR00596##
[3829] Under the same conditions as the method for synthesizing
Compound A7-14-2, the title compound was prepared from Compound
R9-1 (9.9 mg, 80%).
[3830] LCMS: m/z 395 [M+H].sup.+
[3831] HPLC retention time: 2.38 min (analysis condition C)
Example 582
[3832] Compound S1-1
3-Chloro-8-methoxy-6,6-dimethyl-5,6-dihydrobenzo[b]carbazol-11-one
##STR00597##
[3834] Under the same conditions as the method for synthesizing
Compound A3-1 and Compound A4, the title compound was prepared as a
crude product from Compound A2 and (3-chlorophenyl)-hydrazine
hydrochloric acid salt.
Example 583
[3835] Compound S1-2
3-Chloro-8-methoxy-2,6,6-trimethyl-5,6-dihydro-benzo[b]carbazol-11-one
##STR00598##
[3837] 7-Methoxy-1,1-dimethyl-3,4-dihydro-1H-naphthalen-2-one
(Compound A2, 99.1 mg, 0.485 mmol) and
(3-chloro-4-methyl-phenyl)hydrazine hydrochloric acid salt (100.4
mg, 1.1 eq.) were dissolved in TFA (1 mL) and the mixture was
irradiated with microwave at 80.degree. C. for 10 min under
nitrogen atmosphere. After cooling, the reaction solution was added
with ethyl acetate, washed with water, saturated aqueous solution
of sodium hydrogen carbonate and saturated brine and dried over
magnesium sulfate. After filtration and concentration under reduced
pressure, the residues obtained therefrom were dissolved in THF (2
mL) and water (0.2 mL), added with DDQ (125.7 mg, 1.1 eq.), and
stirred at room temperature overnight. The reaction solution was
added with the mixture solvent of hexane and ethyl acetate, and the
starting-point components were removed by dry type silica gel
column. The eluent was concentrated under reduced pressure, and the
resulting residues were purified by preparative TLC
(methanol/dichloromethane) to obtain the title compound (19.4 mg,
12%).
[3838] .sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta.: 12.2 (1H, s),
8.15 (1H, d, J=8.8 Hz), 8.12 (1H, s), 7.52 (1H, s), 7.32 (1H, s),
7.07 (1H, dd, J=2.4, 8.8 Hz), 3.90 (3H, s), 2. (3H, s), 1.73 (6H,
s),
[3839] LCMS: m/z 340 [M+H].sup.+
[3840] HPLC retention time: 2.80 min (analysis condition F)
Example 584
[3841] Compound S1-3
3-Chloro-4-fluoro-8-methoxy-6,6-dimethyl-5,6-dihydro-benzo[b]carbazol-11-o-
ne
##STR00599##
[3843] According to the same method as the method for synthesizing
Compound A3-1, the title compound was prepared from Compound A2 and
(3-chloro-2-fluoro-phenyl)-hydrazine.
[3844] LCMS: m/z 344,346 [M+H].sup.+
[3845] HPLC retention time: 2.68 min (analysis condition S)
Example 585
[3846] Compound S1-4
9-Bromo-3-chloro-8-methoxy-6,6-dimethyl-5,6-dihydro-benzo[b]carbazol-11-on-
e
##STR00600##
[3848]
6-Bromo-7-methoxy-1,1-dimethyl-3,4-dihydro-1H-naphthalen-2-one
(Compound E1, 0.2 g, 0.71 mmol) and 3-chlorophenylhydrazine
hydrochloric acid salt (0.17 g, 1.3 eq.) were dissolved in acetic
acid (0.5 mL). Under nitrogen atmosphere, the reaction solution was
stirred at 90.degree. C. for 8 hr. After cooling to room
temperature, the reaction solution was added with ethyl acetate,
washed with water, saturated aqueous solution of sodium hydrogen
carbonate and saturated brine and dried over magnesium sulfate.
After filtration and concentration under reduced pressure, the
residues obtained therefrom were dissolved in THF (3 mL) comprising
10% water, added with DDQ (227 mg, 3 eq.) at room temperature, and
the mixture was stirred at room temperature for 2 hr. The reaction
solution was added with the mixture liquid of THF/diethyl ether (1:
1) and washed with 0.5 N aqueous solution of sodium hydroxide and
saturated brine. After drying with sodium sulfate, the mixture was
filtered and the resulting residues obtained after concentration
under reduced pressure were washed with the mixture liquid of
hexane/diethyl ether (1: 1) to obtain the title compound (brown
powder, 86 mg).
[3849] LCMS: m/z 404, 406, 408 [M+H].sup.+
[3850] HPLC retention time: 3.02 min (analysis condition C)
Example 586
[3851] Compound 52-1
3-Chloro-8-hydroxy-6,6-dimethyl-5,6-dihydrobenzo[b]carbazol-11-one
##STR00601##
[3853] Under the same conditions as the method for synthesizing
Compound A6, the title compound was prepared from Compound
S1-1.
[3854] LCMS: m/z 312 [M+H].sup.+
[3855] HPLC retention time: 4.18 min (analysis condition H)
Example 587
[3856] Compound S2-2
3-Chloro-8-hydroxy-2,6,6-trimethyl-5,6-dihydro-benzo[b]carbazol-11-one
##STR00602##
[3858]
3-Chloro-8-methoxy-2,6,6-trimethyl-5,6-dihydro-benzo[b]carbazol-11--
one (Compound S1-2, 18.9 mg, 0.0556 mmol) and pyridinium chloride
(220 mg, 34 eq.) were stirred at 185.degree. C. for 2.5 hr. After
cooling, the reaction solution was added with water and ethyl
acetate, and the organic layer was washed with water and saturated
brine, dried over magnesium sulfate, filtered and concentrated
under reduced pressure to obtain the title compound as a crude
product.
Example 588
[3859] Compound S2-3
3-Chloro-4-fluoro-8-hydroxy-6,6-dimethyl-5,6-dihydro-benzo[b]carbazol-11-o-
ne
##STR00603##
[3861]
3-Chloro-4-fluoro-8-methoxy-6,6-dimethyl-5,6-dihydro-benzo[b]carbaz-
ol-11-one (Compound 51-3, 220.0 mg, 0.640 mmol) and pyridinium
chloride (800 mg, 6.922 mmol) were mixed with each other, heated to
160.degree. C., and then stirred for 20 hr. The reaction solution
was added with water. As a result, black solid was obtained as a
precipitate, which was then filtered and subjected to purification
by silica gel column chromatography (ethyl acetate/hexane) to
obtain the title compound (139.4 mg, 66%).
[3862] LCMS: m/z 330 [M+H].sup.+
[3863] HPLC retention time: 2.60 min (analysis condition F)
Example 589
[3864] Compound S2-4
9-Bromo-3-chloro-8-hydroxy-6,6-dimethyl-5,6-dihydro-benzo[b]carbazol-11-on-
e
##STR00604##
[3866] Under the same conditions as the method for synthesizing
Compound A6, the title compound was prepared from Compound
S1-4.
[3867] LCMS: m/z 390, 392, 394 [M+H].sup.+
[3868] HPLC retention time: 2.75 min (analysis condition C)
Example 590
[3869] Compound S3
3-Chloro-8-(2-diethylaminoethoxy)-6,6-dimethyl-5,6-dihydro-benzo[b]carbazo-
l-11-one (CH5263231-000)
##STR00605##
[3871]
3-Chloro-8-hydroxy-6,6-dimethyl-5,6-dihydro-benzo[b]carbazol-11-one
(Compound S2-1, 10 mg, 0.03207 mmol) was dissolved in DMF (0.1 mL),
added with (2-chloroethyl)diethylamine (5.5 mg, 0.03207 mmol) and
cesium carbonate (20.9 mg, 0.06414 mmol), and stirred at 80.degree.
C. for 2 hr. The reaction solution was added to water and extracted
with ethyl acetate. The organic layer was dried over magnesium
sulfate. The residues obtained after concentration under reduced
pressure were purified by NH silica gel column chromatography
(ethyl acetate/hexane) to obtain the title compound (11.6 mg,
76%).
[3872] LCMS: m/z 411 [M+H].sup.+
[3873] HPLC retention time: 4.49 min (analysis condition H)
Example 591
[3874] Compound S4
3-Chloro-2,6,6-trimethyl-8-((2R,3R)-2,3,4-trihydroxy-butoxy)-5,6-dihydro-b-
enzo[b]carbazol-11-one
##STR00606##
[3876] Crude product of Compound S2-2 was dissolved in THF (0.4 mL)
under nitrogen atmosphere, together with THF (0.2 mL) solution of
triphenylphosphine (18.9 mg, 1.3 eq.) and
[(4R,5R)-5-(tert-butyl-dimethyl-silanyloxymethyl)-2,2-dimethyl-[1,3]dioxo-
lan-4-yl]-methanol (17 mg, 1.2 eq.). DEAD (40% toluene solution,
0.0031 mL, 1.2 eq.) was added to the solution, which was then
stirred at room temperature for 40 min and at 40.degree. C. for 4
hr. The reaction solution was added with triphenylphosphine (18.9
mg, 1.3 eq.) and DEAD (40% toluene solution, 0.002 mL, 0.8 eq.) and
stirred at 40.degree. C. overnight. The reaction solution was added
with ethyl acetate, washed with water and saturated brine, dried
over magnesium sulfate, and filtered. The residues obtained after
concentration under reduced pressure were purified by praparative
TLC (ethyl acetate/hexane) to obtain the crude product of
8-[(4R,5R)-5-(tert-butyl-dimethyl-silanyloxymethyl)-2,2-dimethyl-[1,3]dio-
xolan-4-yl
methoxy]-3-chloro-2,6,6-trimethyl-5,6-dihydro-benzo[b]carbazol--
11-one (12.6 mg).
[3877] The resultant was dissolved in THF (0.15 mL) and methanol
(0.03 mL) under nitrogen atmosphere, added with 0.5 M sulfuric acid
(0.05 mL) and stirred at 60.degree. C. for 3 hr. After cooling,
diethyl ether was added and sodium hydrogen carbonate (8.4 mg) and
water were further added thereto. The organic layer was washed with
saturated brine. The aqueous layer was extracted with ethyl
acetate, and the combined organic layer was dried over magnesium
sulfate, and filtered. The solid obtained from the concentration
under reduced pressure was washed with dichloromethane to obtain
the target compound (white solid, 5.3 mg, 22%).
[3878] .sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta.: 12.18 (1H, s),
8.14 (1H, d, J=8.8 Hz), 8.12 (1H, s), 7.52 (1H, s), 7.31 (1H, d,
J=2.4 Hz), 7.06 (1H, dd, J=2.4, 8.8 Hz), 4.78 (1H, d, J=5.9 Hz),
4.60 (1H, d, J=5.9 Hz), 4.52 (1H, t, J=5.4 Hz), 4.18-4.22 (1H, m),
4.02-4.06 (1H, m), 3.85-3.95 (1H, m), 3.50-3.60 (2H, m), 3.40-3.46
(1H, m), 2.45 (3H, s), 1.73 (3H, s),
[3879] LCMS: m/z 430 [M+H].sup.+
[3880] HPLC retention time: 2.27 min (analysis condition F)
Example 592
[3881] Compound S5
3-Chloro-8-ethoxy-4-fluoro-6,6-dimethyl-5,6-dihydro-benzo[b]carbazol-11-on-
e
##STR00607##
[3883] The title compound was obtained as a by-product of the
synthesis of Compound S6.
[3884] LCMS: m/z 358 [M+H].sup.+
[3885] HPLC retention time: 3.16 min (analysis condition F)
Example 593
[3886] Compound S6
3-Chloro-8-((R)-2,3-dihydroxy-propoxy)-4-fluoro-6,6-dimethyl-5,6-dihydro-b-
enzo[b]carbazol-11-one
##STR00608##
[3888]
3-Chloro-4-fluoro-8-hydroxy-6,6-dimethyl-5,6-dihydro-benzo[b]carbaz-
ol-11-one (Compound S2-3, 20.0 mg, 0.061 mmol) was dissolved in THF
(0.25 mL), added with
((S)-2,2-dimethyl-[1,3]dioxolan-4-yl)-methanol (9.8 .mu.L, 0.079
mmol), triphenylphosphine (20.7 mg, 0.079 mmol) and diethyl
azodicarboxylic acid (35.9 .mu.l, 0.079 mmol), and then stirred at
40.degree. C. for 5 hr. The reaction solution was concentrated
under reduced pressure, and the resulting residues were purified by
silica gel column chromatography (ethyl acetate/hexane) to obtain
the intermediate, 3-chloro-8-((S)-2,2-dimethyl-[1,3]dioxolan-4-yl
methoxy)-4-fluoro-6,6-dimethyl-5,6-dihydro-benzo[b]carbazol-11-one.
This compound was dissolved in THF (0.10 mL) and MeOH (0.08 ml),
added with sulfuric acid (0.5 M, 0.045 ml), and then stirred at
60.degree. C. for 1 hr. The reaction solution was added with
saturated aqueous solution of sodium hydrogen carbonate, extracted
with ethyl acetate and dried over anhydrous magnesium sulfate. The
yellow solid obtained after concentration under reduced pressure
was washed with methylene chloride/hexane solvent and filtered to
obtain the title compound (4.3 mg, 18%).
[3889] LCMS: m/z 404 [M+H].sup.+
[3890] HPLC retention time: 2.34 min (analysis condition F)
Example 594
[3891] Compound S7-1
3-Chloro-9-bromo-8-((S)-2,2-dimethyl-[1,3]dioxolan-4-yl
methoxy)-6,6-dimethyl-5,6-dihydro-benzo[b]carbazol-11-one
##STR00609##
[3893] Under nitrogen atmosphere,
9-bromo-3-chloro-8-hydroxy-6,6-dimethyl-5,6-dihydro-benzo[b]carbazol-11-o-
ne (Compound S2-4, 76 mg, 0.2 mmol) and triphenylphosphine (69 mg,
1.3 eq.) were added with THF (2 ml), and
((S)-2,2-dimethyl-[1,3]dioxolan-4-yl)-methanol (35 mg, 1.3 eq.) and
2.19 N toluene solution (118 .mu.L, 1.3 eq.) of diethyl
azodicarboxylic acid were added dropwise thereto, followed by
stirring at 50.degree. C. for 2 hr. After cooling, the reaction
solution was added with ethyl acetate, washed with brine, dried
over sodium sulfate and filtered. The residues obtained after
concentration under reduced pressure were purified by silica gel
column chromatography (ethyl acetate/dichloromethane) to give a
solid, which was then washed with dichloromethane to obtain the
title compound (brown powder, 53 mg).
[3894] LCMS: m/z 504, 506, 508 [M+H].sup.+
[3895] HPLC retention time: 3.17 min (analysis condition C)
Example 595
[3896] Compound S7-2
9-Bromo-3-chloro-8-((R)-2,3-dihydroxy-propoxy)-6,6-dimethyl-5,6-dihydro-be-
nzo[b]carbazol-11-one
##STR00610##
[3898]
3-Chloro-9-bromo-8-((S)-2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-6,6-
-dimethyl-5,6-dihydro-benzo[b]carbazol-11-one (Compound S7-1, 56
mg, 0.11 mmol) was dissolved in methanol (5 mL), added with 1 N
hydrochloric acid (0.2 ml), and stirred at 50.degree. C. for 2 hr.
After cooling, the reaction solution was concentrated under reduced
pressure and the resulting residues were added with methanol to
obtain a precipitated solid, which was then filtered to obtain the
title compound (white powder, 26 mg).
[3899] LCMS: m/z 464, 466, 468 [M+H].sup.+
[3900] HPLC retention time: 2.77 min (analysis condition C)
Example 596
[3901] Compound S7-3
3-Chloro-9-bromo-8-((S)-2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-6,6-dimeth-
yl-5,6-dihydro-benzo[b]carbazol-11-one
##STR00611##
[3903] Under nitrogen atmosphere,
9-bromo-3-chloro-8-hydroxy-6,6-dimethyl-5,6-dihydro-benzo[b]carbazol-11-o-
ne (Compound S2-4, 112 mg, 0.29 mmol) and triphenylphosphine (227
mg, 3 eq.) were added with THF (2 ml), and
((R)-2,2-dimethyl-[1,3]dioxolan-4-yl)-methanol (114 mg, 3 eq.) and
2.19 N toluene solution (0.4 mL, 3 eq.) of diethyl azodicarboxylic
acid were added dropwise thereto, followed by stirring at
40.degree. C. for 12 hr under nitrogen atmosphere. The residues
obtained from the reaction solution after concentration under
reduced pressure were purified by silica gel column chromatography
(ethyl acetate/dichloromethane) to obtain the title compound (white
powder, 100 mg).
[3904] LCMS: m/z 504, 506, 508 [M+H].sup.+
[3905] HPLC retention time: 3.15 min (analysis condition C)
Example 597
[3906] Compound S7-4
9-Bromo-3-chloro-8-((S)-2,3-dihydroxy-propoxy)-6,6-dimethyl-5,6-dihydro-be-
nzo[b]carbazol-11-one
##STR00612##
[3908] Under the same conditions as the method for synthesizing
Compound S7-2, the title compound was prepared from Compound
S7-3.
[3909] LCMS: m/z 464, 466, 468 [M+H].sup.+
[3910] HPLC retention time: 2.77 min (analysis condition C)
Example 598
[3911] Compound S8-1
9-Hydroxy-3-chloro-8-((S)-2,2-dimethyl-[1,3]dioxolan-4-yl
methoxy)-6,6-dimethyl-5,6-dihydro-benzo[b]carbazol-11-one
##STR00613##
[3913] 9-Bromo-3-chloro-8-((S)-2,2-dimethyl-[1,3]dioxolan-4-yl
methoxy)-6,6-dimethyl-5,6-dihydro-benzo[b]carbazol-11-one (Compound
S7-1, 30 mg, 0.06 mmol) was dissolved in the mixture solvent of
water dioxane (1: 1) (0.5 mL), added with tris(benzylidenacetone
dipalladium)chloroform complex (3.1 mg, 0.05 eq.),
2-di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl (2.5 mg, 0.1
eq.) and KOH (0.5 N aqueous solution 180 .mu.L, 1.5 eq.), and
stirred at 60.degree. C. for 12 hr. After cooling, the reaction
solution was concentrated under reduced pressure, and the resulting
residues were purified by HPLC to obtain the title compound (white
solid, 4.6 mg).
[3914] LCMS: m/z 442, 444 [M+H].sup.+
[3915] HPLC retention time: 2.78 min (analysis condition C)
Example 599
[3916] Compound S8-2
3-Chloro-8-((R)-2,3-dihydroxy-propoxy)-9-hydroxy-6,6-dimethyl-5,6-dihydro--
benzo[b]carbazol-11-one
##STR00614##
[3918] Under the same conditions as the method for synthesizing
Compound S7-2, the title compound was prepared from Compound
S8-1.
[3919] LCMS: m/z 402, 404 [M+H].sup.+
[3920] HPLC retention time: 0.90 min (analysis condition I)
Example 600
[3921] Compound S9-1
8-Hydroxy-6,6-dimethyl-11-oxo-9-(1H-tetrazol-5-yl)-6,11-dihydro-5H-benzo[b-
]carbazole-3-carbonitrile
##STR00615##
[3923]
9-Bromo-3-chloro-8-methoxy-6,6-dimethyl-5,6-dihydro-benzo[b]carbazo-
l-11-one (Compound S1-4, 150 mg, 0.37 mMol) was dissolved in NMP,
added with CuCN (100 mg, 3 eq.), and stirred at 210.degree. C. for
1.5 hr under irradiation with microwave. After cooling, the
reaction solution was added with water and ethyl acetate, and the
precipitated solid was filtered to remove the solvent. The obtained
residues were dissolved in DMF (1 ml), added with sodium azide (100
mg, 8 eq.) and ammonium chloride (5 mg), and then stirred at
120.degree. C. for 24 hr in a sealed tube. After adding water, the
insoluble matters were filtered and purified by HPLC to obtain the
title compound (6.5 mg).
[3924] LCMS: m/z 371 [M+H].sup.+
[3925] HPLC retention time: 2.22 min (analysis condition C)
Example 601
[3926] Compound S9-2
3-Chloro-8-hydroxy-6,6-dimethyl-9-(1H-tetrazol-5-yl)-5,6-dihydro-benzo[b]c-
arbazol-11-one
##STR00616##
[3928] The title compound was obtained as an intermediate for the
synthesis of Compound S9-1.
[3929] LCMS: m/z 380, 382 [M+H].sup.+
[3930] HPLC retention time: 2.38 min (analysis condition C)
Example 602
[3931] Compound S10
3-Chloro-8-((R)-2,3-dihydroxy-propoxy)-9-(3-hydroxy-3-methyl-but-1-ynyl)-6-
,6-dimethyl-5,6-dihydro-benzo[b]carbazol-11-one
##STR00617##
[3933] To the mixture of
9-bromo-3-chloro-8-((S)-2,2-dimethyl-[1,3]dioxolan-4-yl
methoxy)-6,6-dimethyl-5,6-dihydro-benzo[b]carbazol-11-one (Compound
S7-1, 50 mg, 0.1 mmol), bis(acetonitrile) palladium (II) dichloride
(2.6 mg, 0.01 eq.), cesium carbonate (195 mg, 6 eq.) and
2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (14.3 mg,
0.03 eq.), acetonitrile (2 mL) was added and stirred at 80.degree.
C. for 12 hr. Tar-like residues obtained after concentration under
reduced pressure were purified by silica gel column chromatography
(ethyl acetate/hexane) to obtain
3-chloro-8-((S)-2,2-dimethyl-[1,3]dioxolan-4-yl
methoxy)-9-(3-hydroxy-3-methyl-but-1-ynyl)-6,6-dimethyl-5,6-dihydro-benzo-
[b]carbazol-11-one (brown powder, 105 mg).
[3934] The resulting
3-chloro-8-((S)-2,2-dimethyl-[1,3]dioxolan-4-yl
methoxy)-9-(3-hydroxy-3-methyl-but-1-ynyl)-6,6-dimethyl-5,6-dihydro-benzo-
[b]carbazol-11-one (20 mg, 0.04 mmol) was dissolved in methanol (3
mL), added with 1 N hydrochloric acid (1 ml), and stirred at room
temperature for 12 hr. After cooling, the reaction solution was
concentrated under reduced pressure, and the resulting residues
were washed with methylene chloride to obtain the title compound
(pale yellow powder, 5.2 mg).
[3935] LCMS: m/z 468, 470 [M+H].sup.+
[3936] HPLC retention time: 2.70 min (analysis condition C)
Example 603
[3937] Compound S11-1
3-Chloro-8-((R)-2,3-dihydroxy-propoxy)-6,6-dimethyl-11-oxo-6,11-dihydro-5H-
-benzo[b]carbazole-9-carbonitrile
##STR00618##
[3939]
3-Chloro-9-bromo-8-((S)-2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-6,6-
-dimethyl-5,6-dihydro-benzo[b]carbazol-11-one (Compound S7-2, 17
mg, 37 .mu.mol) was dissolved in DMA, added with CuCN (17 mg, 5
eq.), and stirred at 220.degree. C. for 2 hr under irradiation with
microwave. After cooling, the reaction solution was added with
ethyl acetate, and the precipitated solid was filtered to remove
the solvent. The resulting residues were purified by HPLC to obtain
the title compound (4 mg).
[3940] LCMS: m/z 409, 411 [M+H].sup.+
[3941] HPLC retention time: 2.65 min (analysis condition C)
Example 604
[3942] Compound S11-2
3-Chloro-8-hydroxy-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-9-
-carbonitrile
##STR00619##
[3944] The title compound was obtained as a by-product of the
synthesis of Compound S11-1.
[3945] LCMS: m/z 337, 339 [M+H].sup.+
[3946] HPLC retention time: 2.35 min (analysis condition C)
Example 605
[3947] Compound T1-1
3-Bromo-6,6-dimethyl-8-[(R)-(tetrahydro-furan-3-yl)
oxy]-5,6-dihydro-benzo[b]carbazol-11-one
##STR00620##
[3949] According to the same method as the method for synthesizing
Compound A7-1, the title compound was prepared from Compound A5-1
and (S)-tetrahydro-furan-3-ol.
[3950] LCMS: m/z 426 [M+H].sup.+
[3951] HPLC retention time: 2.08 min (analysis condition D)
Example 606
[3952] Compound T1-2
6,6-Dimethyl-11-oxo-8-[(R)-(tetrahydro-furan-3-yl)oxy]-6,11-dihydro-5H-ben-
zo[b]carbazole-3-carbonitrile
##STR00621##
[3954] According to the same method as the method for synthesizing
Compound A5-2, the title compound was prepared from Compound
T1-1.
[3955] LCMS: m/z 373 [M+H].sup.+
[3956] HPLC retention time: 1.98 min (analysis condition A)
Example 607
[3957] Compound T2-1
3-Bromo-6,6-dimethyl-8-[(S)-(tetrahydro-furan-3-yl)oxy]-5,6-dihydro-benzo[-
b]carbazol-11-one
##STR00622##
[3959] According to the same method as the method for synthesizing
Compound A7-1, the title compound was prepared from Compound A5-1
and (R)-tetrahydro-furan-3-ol.
[3960] LCMS: m/z 426 [M+H].sup.+
[3961] HPLC retention time: 6.12 min (analysis condition H)
Example 608
[3962] Compound T2-2
6,6-Dimethyl-11-oxo-8-[(S)-(tetrahydro-furan-3-yl)oxy]-6,11-dihydro-5H-ben-
zo[b]carbazole-3-carbonitrile
##STR00623##
[3964] According to the same method as the method for synthesizing
Compound A5-2, the title compound was prepared from Compound
T2-1.
[3965] LCMS: m/z 373 [M+H].sup.+
[3966] HPLC retention time: 2.00 min (analysis condition D)
Example 609
[3967] Compound T3-1
3-Bromo-6,6-dimethyl-8-(tetrahydro-pyran-4-yl
oxy)-5,6-dihydro-benzo[b]carbazol-11-one
##STR00624##
[3969] According to the same method as the method for synthesizing
Compound A7-1, the title compound was prepared from Compound A5-1
and tetrahydro-pyran-4-ol.
[3970] LCMS: m/z 440 [M+H].sup.+
[3971] HPLC retention time: 8.07 min (analysis condition H)
Example 610
[3972] Compound T3-2
3-Bromo-5,6,6-trimethyl-8-(tetrahydro-pyran-4-yl
oxy)-5,6-dihydro-benzo[b]carbazol-11-one
##STR00625##
[3974] According to the same method as the method for synthesizing
Compound A10-2, the title compound was prepared from Compound
T3-1.
[3975] LCMS: m/z 454 [M+H].sup.+
[3976] HPLC retention time: 6.88 min (analysis condition H)
Example 611
[3977] Compound T4-1
3-Bromo-6,6-dimethyl-8-(2-phenyl-[1,3]dioxan-5-yloxy)-5,6-dihydro-benzo[b]-
carbazol-11-one
##STR00626##
[3979] According to the same method as the method for synthesizing
Compound A7-1, the title compound was prepared from Compound A5-1
and 5-phenyl-[1,3]dioxan-2-ol.
[3980] LCMS: m/z 518 [M+H].sup.+
[3981] HPLC retention time: 2.68 min (analysis condition D)
Example 612
[3982] Compound T4-2
3-Bromo-8-(2-hydroxy-1-hydroxymethyl-ethoxy)-6,6-dimethyl-5,6-dihydro-benz-
o[b]carbazol-11-one
##STR00627##
[3984] According to the same method as the method for synthesizing
Compound A7-13-2, the title compound was prepared from Compound
T4-1.
[3985] LCMS: m/z 430 [M+H].sup.+
[3986] HPLC retention time: 4.64 min (analysis condition H)
Example 613
[3987] Compound T5-1
4-(3-Bromo-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-8-yl
oxy)-piperidine-1-carboxylic acid tert-butyl ester
##STR00628##
[3989] According to the same method as the method for synthesizing
Compound A7-1, the title compound was prepared from Compound A5-1
and 4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester.
[3990] LCMS: m/z 539 [M+H].sup.+
[3991] HPLC retention time: 2.72 min (analysis condition D)
Example 614
[3992] Compound T5-2
4-(3-Bromo-5,6,6-trimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-8-yl
oxy)-piperidine-1-carboxylic acid tert-butyl ester
##STR00629##
[3994] According to the same method as the method for synthesizing
Compound A10-1, the title compound was prepared from Compound
T5-1.
[3995] LCMS: m/z 553 [M+H].sup.+
[3996] HPLC retention time: 2.93 min (analysis condition D)
Example 615
[3997] Compound T5-3
3-Bromo-5,6,6-trimethyl-8-(piperidin-4-yloxy)-5,6-dihydro-benzo[b]carbazol-
-11-one
##STR00630##
[3999] According to the same method as the method for synthesizing
Compound A8-1, the title compound was prepared from Compound
T5-2.
[4000] LCMS: m/z 453 [M+H].sup.+
[4001] HPLC retention time: 1.98 min (analysis condition D)
Example 616
[4002] Compound T5-4
3-Bromo-8-(1-methanesulfonyl-piperidin-4-yloxy)-5,6,6-trimethyl-5,6-dihydr-
o-benzo[b]carbazol-11-one
##STR00631##
[4004] According to the same method as the method for synthesizing
Compound A9-7, the title compound was prepared from Compound T5-3
and methanesulfonyl chloride.
[4005] LCMS: m/z 531 [M+H].sup.+
[4006] HPLC retention time: 2.38 min (analysis condition D)
Example 617
[4007] Compound T5-5
8-(1-Acetyl-piperidin-4-yloxy)-3-bromo-6,6-dimethyl-5,6-dihydro-benzo[b]ca-
rbazol-11-one
##STR00632##
[4009] According to the same method as the method for synthesizing
Compound A9-1, the title compound was prepared from Compound T5-3
and acetic anhydride.
[4010] LCMS: m/z 482 [M+H].sup.+
[4011] HPLC retention time: 2.10 min (analysis condition D)
Example 618
[4012] Compound T6-1
3-Bromo-6,6-dimethyl-8-[1-(2,2,2-trifluoro-acetyl)-piperidin-4-yloxy]-5,6--
dihydro-benzo[b]carbazol-11-one
##STR00633##
[4014] According to the same method as the method for synthesizing
Compound A9-1, the title compound was prepared from Compound T6-2
and trifluoroacetic anhydride.
[4015] LCMS: m/z 535 [M+H].sup.+
[4016] HPLC retention time: 2.53 min (analysis condition D)
Example 619
[4017] Compound T6-2
3-Bromo-6,6-dimethyl-8-(piperidin-4-yloxy)-5,6-dihydro-benzo[b]carbazol-11-
-one
##STR00634##
[4019]
3-Bromo-6,6-dimethyl-8-[1-(2,2,2-trifluoro-acetyl)-piperidin-4-ylox-
y]-5,6-dihydro-benzo[b]carbazol-11-one (Compound T6-1, 28.0 mg,
52.3 mol) was dissolved in THF (1.00 mL) and methanol (0.50 mL),
added with aqueous solution of potassium hydroxide (1.00 mL, 20 wt
%), and stirred at room temperature for 1 hr. The reaction solution
was added to water, and extracted with mixture solution of
chloroform and methanol, and dried over sodium sulfate. Then, after
filtering and concentration under reduced pressure,
3-bromo-6,6-dimethyl-8-(piperidin-4-yloxy)-5,6-dihydro-benzo[b]carbazol-1-
1-one was obtained as a crude product.
[4020] LCMS: m/z 439 [M+H].sup.+
[4021] HPLC retention time: 1.83 min (analysis condition D)
Example 620
[4022] Compound T6-3
3-Bromo-8-(1-methanesulfonyl-piperidin-4-yloxy)-6,6-dimethyl-5,6-dihydro-b-
enzo[b]carbazol-11-one
##STR00635##
[4024] According to the same method as the method for synthesizing
Compound A9-1, the title compound was prepared from Compound T6-2
and mesyl chloride.
[4025] LCMS: m/z 517 [M+H].sup.+
[4026] HPLC retention time: 2.23 min (analysis condition D)
Example 621
[4027] Compound T6-4
8-(1-Acetyl-piperidin-4-yloxy)-3-bromo-5,6,6-trimethyl-5,6-dihydro-benzo[b-
]carbazol-11-one
##STR00636##
[4029] According to the same method as the method for synthesizing
Compound A9-1, the title compound was prepared from Compound T6-2
and acetic anhydride.
[4030] LCMS: m/z 496 [M+H].sup.+
[4031] HPLC retention time: 2.27 min (analysis condition D)
Example 622
[4032] Compound T7-1
3-Bromo-8-isopropoxy-6,6-dimethyl-5,6-dihydro-benzo[b]carbazol-11-one
##STR00637##
[4034] The title compound was obtained as a by-product of the
synthesis of Compound T4-1.
[4035] LCMS: m/z 398 [M+H].sup.+
[4036] HPLC retention time: 3.18 min (analysis condition F)
Example 623
[4037] Compound T7-2
3-Bromo-8-isopropoxy-5,6,6-trimethyl-5,6-dihydro-benzo[b]carbazol-11-one
##STR00638##
[4039] According to the same method as the method for synthesizing
Compound A10-2, the title compound was prepared from Compound
T7-1.
[4040] LCMS: m/z 413 [M+H].sup.+
[4041] HPLC retention time: 2.70 min (analysis condition D)
Example 624
[4042] Compound T8-1
3-Bromo-5,6,6-trimethyl-8-(2-phenyl-[1,3]dioxan-5-yl
oxy)-5,6-dihydro-benzo[b]carbazol-11-one
##STR00639##
[4044] According to the same method as the method for synthesizing
Compound A10-2, the title compound was prepared from Compound
T4-1.
[4045] LCMS: m/z 532 [M+H].sup.+
[4046] HPLC retention time: 2.90 min (analysis condition D)
Example 625
[4047] Compound T8-2
3-Bromo-8-(2-hydroxy-1-hydroxymethyl-ethoxy)-5,6,6-trimethyl-5,6-dihydro-b-
enzo[b]carbazol-11-one
##STR00640##
[4049] According to the same method as the method for synthesizing
Compound A7-13-2, the title compound was prepared from Compound
T4-1.
[4050] LCMS: m/z 444 [M+H].sup.+
[4051] HPLC retention time: 1.90 min (analysis condition D)
Example 626
[4052] Compound T9
N-[2-(3-Bromo-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-8-yl
oxy)-ethyl]-acetamide
##STR00641##
[4054] According to the same method as the method for synthesizing
Compound A7-17, the title compound was prepared from Compound A5-1
and (N-(2-chloro-ethyl)-acetamide.
[4055] LCMS: m/z 441 [M+H].sup.+
[4056] HPLC retention time: 1.92 min (analysis condition D)
Example 627
[4057] Compound T10
[4058] 3-Bromo-6,6-dimethyl-8-(oxetan-3-yl
oxy)-5,6-dihydro-benzo[b]carbazol-11-one
##STR00642##
[4059] According to the same method as the method for synthesizing
Compound A7-17, the title compound was prepared from Compound A5-1
and toluene-4-sulfonic acid oxetan-3-yl ester.
[4060] LCMS: m/z 412 [M+H].sup.+
[4061] HPLC retention time: 2.17 min (analysis condition D)
Example 628
[4062] Compound T11
3-Bromo-8-(4-hydroxy-tetrahydro-furan-3-yl
oxy)-6,6-dimethyl-5,6-dihydro-benzo[b]carbazol-11-one
##STR00643##
[4064] Under nitrogen atmosphere,
tetrahydro-furo[3,4-d][1,3,2]dioxathiol 2,2-dioxide (71.5 mg, 0.420
mmol) was dissolved in DMF (1.40 mL), added with
3-bromo-8-hydroxy-6,6-dimethyl-5,6-dihydro-benzo[b]carbazol-11-one
(Compound A5-1, 50.0 mg, 0.140 mmol) and cesium carbonate (228 mg,
0.700 mmol), and stirred at 80.degree. C. for 15 hr. Subsequently,
sulfuric acid (0.10 mL, 18 M), THF (3.00 mL) and water (0.50 mL)
were added to the mixture, which was then stirred at room
temperature for 24 hr and further at 60.degree. C. for 24 hr. The
reaction solution was added to water, extracted with ethyl acetate,
washed with water, saturated aqueous solution of sodium
bicarbonate, and saturated brine, and dried over sodium sulfate.
After filtering and concentration under reduced pressure, the
resulting residues were washed with dichloromethane and purified by
NH silica gel column chromatography (ethyl acetate/THF) to obtain
the target compound (44.7 mg, 72%).
[4065] LCMS: m/z 442 [M+H].sup.+
[4066] HPLC retention time: 1.98 min (analysis condition D)
Example 629
[4067] Compound T12-1
Acetic acid
(2S,3R,4S,5R,6R)-4,5-diacetoxy-6-(3-bromo-6,6-dimethyl-11-oxo-6,11-dihydr-
o-5H-benzo[b]carbazole-8-yl
oxymethyl)-2-methoxy-tetrahydro-pyran-3-yl ester
##STR00644##
[4069] According to the same method as the method for synthesizing
Compound A7-1, the title compound was prepared from Compound A5-1
and methyl 2,3,4-tri-O-acetyl-a-D-glucopyranoside.
[4070] LCMS: m/z 658 [M+H].sup.+
[4071] HPLC retention time: 2.38 min (analysis condition D)
Example 630
[4072] Compound T12-2
3-Bromo-6,6-dimethyl-8-((2R,3S,4S,5R,6S)-3,4,5-trihydroxy-6-methoxy-tetrah-
ydro-pyran-2-yl methoxy)-5,6-dihydro-benzo[b]carbazol-11-one
##STR00645##
[4074] Under nitrogen atmosphere, to acetic acid
(2S,3R,4S,5R,6R)-4,5-diacetoxy-6-(3-bromo-6,6-dimethyl-11-oxo-6,11-dihydr-
o-5H-benzo[b]carbazole-8-yl
oxymethyl)-2-methoxy-tetrahydro-pyran-3-yl ester (Compound T12-1,
34.0 mg, 51.63 .mu.mol), methanol solution (2.50 mL, 2 M) of
ammonia was added, and the mixture was stirred at room temperature
for 21 hr. The reaction solution was concentrated under reduced
pressure, and the resulting resides were washed with diethyl ether
to obtain the target compound (25.7 mg, 94%).
[4075] LCMS: m/z 532 [M+H].sup.+
[4076] HPLC retention time: 2.42 min (analysis condition D)
Example 631
[4077] Compound T13-1
(3-Bromo-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-8-yl
oxy)-acetic acid tert-butyl ester
##STR00646##
[4079] According to the same method as the method for synthesizing
Compound A7-17, the title compound was prepared from Compound A5-1
and bromo-acetic acid tert-butyl ester.
[4080] LCMS: m/z 470 [M+H].sup.+
[4081] HPLC retention time: 2.53 min (analysis condition D)
Example 632
[4082] Compound T13-2
(3-Bromo-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-8-yl
oxy)-acetic acid
##STR00647##
[4084] According to the same method as the method for synthesizing
Compound A8-1, the title compound was prepared from Compound
T13-1.
[4085] LCMS: m/z 414 [M+H].sup.+
[4086] HPLC retention time: 1.50 min (analysis condition D)
Example 633
[4087] Compound T13-3
2-(3-Bromo-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-8-yl
oxy)-N-(3-ethyl-3-hydroxy-pentyl)-acetamide
##STR00648##
[4089] Under nitrogen atmosphere,
(3-azide-1,1-diethyl-propoxy)-trimethyl-silane (16.6 mg, 72.42
.mu.mol) was dissolved in toluene (0.48 mL), added with
3-bromo-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-8-yl
oxy)-acetic acid (20.0 mg, 48.28 .mu.mol) and Molecular Sieves 4
angstrom, and the mixture was stirred at room temperature for 5
min. Thereafter, the mixture was added with trimethylphosphine
(10.2 .mu.L, 96.56 .mu.mol) and stirred at 80.degree. C. for 22 hr.
The reaction solution was added to hydrochloric acid (1 M),
extracted with ethyl acetate, washed with water, saturated aqueous
solution of sodium bicarbonate, saturated brine and dried over
sodium sulfate. After filtering and concentration under reduced
pressure, the resulting residues were purified by silica gel column
chromatography (methanol/dichloromethane) to obtain the target
compound (0.7 mg, 3%).
[4090] LCMS: m/z 527 [M+H].sup.+
[4091] HPLC retention time: 2.93 min (analysis condition D)
Example 634
[4092] Compound T13-4
4-[2-(3-Bromo-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-8-yl
oxy)-acetyl]-piperazine-1-carboxylic acid tert-butyl ester
##STR00649##
[4094] According to the same method as the method for synthesizing
Compound A9-10, the title compound was prepared from Compound T13-2
and 1-(tert-butoxycarbonyl)piperazine.
[4095] LCMS: m/z 582 [M+H].sup.+
[4096] HPLC retention time: 2.32 min (analysis condition D)
Example 635
[4097] Compound T13-5
3-Bromo-6,6-dimethyl-8-(2-oxo-2-piperazin-1-yl-ethoxy)-5,6-dihydro-benzo[b-
]carbazol-11-one hydrochloric acid salt
##STR00650##
[4099] According to the same method as the method for synthesizing
Compound A8-1, the title compound was prepared from Compound
T13-4.
[4100] LCMS: m/z 482 [M+H].sup.+
[4101] HPLC retention time: 1.75 min (analysis condition D)
Example 636
[4102] Compound T13-6
3-Bromo-8-[2-(4-methanesulfonyl-piperazin-1-yl)-2-oxo-ethoxy]-6,6-dimethyl-
-5,6-dihydro-benzo[b]carbazol-11-one
##STR00651##
[4104] According to the same method as the method for synthesizing
Compound A9-1, the title compound was prepared from Compound T13-5
and methanesulfonyl chloride.
[4105] LCMS: m/z 560 [M+H].sup.+
[4106] HPLC retention time: 2.00 min (analysis condition D)
Example 637
[4107] Compound T13-7
3-Bromo-6,6-dimethyl-8-{2-oxo-2-[4-(propane-2-sulfonyl)-piperazin-1-yl]-et-
hoxy}-5,6-dihydro-benzo[b]carbazol-11-one
##STR00652##
[4109] According to the same method as the method for synthesizing
Compound A9-1, the title compound was prepared from Compound T13-5
and isopropylsulfonyl chloride.
[4110] LCMS: m/z 588 [M+H].sup.+
[4111] HPLC retention time: 2.47 min (analysis condition D)
Example 638
[4112] Compound T13-8
8-[2-(4-Acetyl-piperazin-1-yl)-2-oxo-ethoxy]-3-bromo-6,6-dimethyl-5,6-dihy-
dro-benzo[b]carbazol-11-one
##STR00653##
[4114] According to the same method as the method for synthesizing
Compound A9-1, the title compound was prepared from Compound T13-5
and acetic anhydride.
[4115] LCMS: m/z 524 [M+H].sup.+
[4116] HPLC retention time: 1.85 min (analysis condition D)
Example 639
[4117] Compound T13-9
3-Bromo-6,6-dimethyl-8-[2-(4-oxetan-3-yl-piperazin-1-yl)-2-oxo-ethoxy]-5,6-
-dihydro-benzo[b]carbazol-11-one
##STR00654##
[4119] According to the same method as the method for synthesizing
Compound B3-32, the title compound was prepared from Compound T13-5
and 3-oxetanone.
[4120] LCMS: m/z 538 [M+H].sup.+
[4121] HPLC retention time: 1.88 min (analysis condition D)
Example 640
[4122] Compound T13-10
4-[2-(3-Bromo-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-8-yl-o-
xy)-acetyl]-piperazine-1-sulfonic acid methylamide
##STR00655##
[4124] According to the same method as the method for synthesizing
Compound A9-1, the title compound was prepared from Compound T13-5
and 2-oxo-oxazolidine-3-sulfonic acid methylamide.
[4125] LCMS: m/z 575 [M+H].sup.+
[4126] HPLC retention time: 2.29 min (analysis condition A)
Example 641
[4127] Compound T14-1
4-(3-Bromo-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-8-yl
oxymethyl)-piperidine-1-carboxylic acid tert-butyl ester
##STR00656##
[4129] According to the same method as the method for synthesizing
Compound A7-1, the title compound was prepared from Compound A5-1
and 1-(tert-butoxycarbonyl)-4-(hydroxymethyl)piperidine.
[4130] LCMS: m/z 553 [M+H].sup.+
[4131] HPLC retention time: 2.80 min (analysis condition D)
Example 642
[4132] Compound T14-2
3-Bromo-6,6-dimethyl-8-(piperidin-4-ylmethoxy)-5,6-dihydro-benzo[b]carbazo-
l-11-one hydrochloric acid salt
##STR00657##
[4134] According to the same method as the method for synthesizing
Compound A8-1, the title compound was prepared from Compound
T14-1.
[4135] LCMS: m/z 454 [M+H].sup.+
[4136] HPLC retention time: 1.90 min (analysis condition D)
Example 643
[4137] Compound T14-3
3-Bromo-6,6-dimethyl-8-(1-oxetan-3-yl-piperidin-4-ylmethoxy)-5,6-dihydro-b-
enzo[b]carbazol-11-one
##STR00658##
[4139] According to the same method as the method for synthesizing
Compound B3-32, the title compound was prepared from Compound T14-2
and 3-oxetanone.
[4140] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta.: 9.24 (1H, s),
8.37 (1H, d, 8.8 Hz), 8.30 (1H, d, 8.3 Hz), 7.57 (1H, d, 1.5 Hz),
7.41 (1H, dd, 8.3, 1.5 Hz), 7.08 (1H, d, 2.4 Hz), 6.98 (1H, dd,
8.8, 2.4 Hz) 4.60-4.95 (7H, m), 3.93 (2H, d, 5.9 Hz), 3.50 (1H, m),
2.83 (2H, d, 11.2 Hz), 1.89 (4H, m), 1.78 (6H, s),
[4141] LCMS: m/z 509 [M+H].sup.+
[4142] HPLC retention time: 2.10 min (analysis condition A)
Example 644
[4143] Compound T14-4
8-(1-Acetyl-piperidin-4-ylmethoxy)-3-bromo-6,6-dimethyl-5,6-dihydro-benzo[-
b]carbazol-11-one
##STR00659##
[4145] According to the same method as the method for synthesizing
Compound A9-1, the title compound was prepared from Compound T14-2
and acetic anhydride.
[4146] LCMS: m/z 495 [M+H].sup.+
[4147] HPLC retention time: 2.53 min (analysis condition A)
Example 645
[4148] Compound T14-5
3-Bromo-8-(1-methanesulfonyl-piperidin-4-ylmethoxy)-6,6-dimethyl-5,6-dihyd-
ro-benzo[b]carbazol-11-one
##STR00660##
[4150] According to the same method as the method for synthesizing
Compound A9-1, the title compound was prepared from Compound T14-2
and methanesulfonyl chloride.
[4151] LCMS: m/z 531 [M+H].sup.+
[4152] HPLC retention time: 2.30 min (analysis condition D)
Example 646
[4153] Compound T14-6
3-Bromo-6,6-dimethyl-8-[1-(propane-2-sulfonyl)-piperidin-4-ylmethoxy]-5,6--
dihydro-benzo[b]carbazol-11-one
##STR00661##
[4155] According to the same method as the method for synthesizing
Compound A9-1, the title compound was prepared from Compound T14-2
and isopropylsulfonyl chloride.
[4156] LCMS: m/z 559 [M+H].sup.+
[4157] HPLC retention time: 2.58 min (analysis condition D)
Example 647
[4158] Compound T14-7
3-[4-(3-Bromo-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-8-yl
oxymethyl)-piperidin-1-yl]-azetidine-1-carboxylic acid tert-butyl
ester
##STR00662##
[4160] According to the same method as the method for synthesizing
Compound B3-32, the title compound was prepared from Compound T14-2
and 3-oxo-azetidine-1-carboxylic acid tert-butyl ester.
[4161] LCMS: m/z 608 [M+H].sup.+
[4162] HPLC retention time: 2.29 min (analysis condition A)
Example 648
[4163] Compound T14-8
8-(1-Azetidin-3-yl-piperidin-4-ylmethoxy)-3-bromo-6,6-dimethyl-5,6-dihydro-
-benzo[b]carbazol-11-one
##STR00663##
[4165] According to the same method as the method for synthesizing
Compound A8-1, the title compound was prepared from Compound
T14-7.
[4166] LCMS: m/z 508 [M+H].sup.+
[4167] HPLC retention time: 1.90 min (analysis condition A)
Example 649
[4168] Compound T14-9
3-Bromo-8-[1-(1-methanesulfonyl-azetidin-3-yl)-piperidin-4-ylmethoxy]-6,6--
dimethyl-5,6-dihydro-benzo[b]carbazol-11-one
##STR00664##
[4170] According to the same method as the method for synthesizing
Compound A9-1, the title compound was prepared from Compound T14-8
and mesyl chloride.
[4171] LCMS: m/z 586 [M+H].sup.+
[4172] HPLC retention time: 2.06 min (analysis condition A)
Example 650
[4173] Compound T14-10
8-[1-(1-Acetyl-azetidin-3-yl)-piperidin-4-ylmethoxy]-3-bromo-6,6-dimethyl--
5,6-dihydro-benzo[b]carbazol-11-one
##STR00665##
[4175] According to the same method as the method for synthesizing
Compound A9-1, the title compound was prepared from Compound T14-8
and acetic anhydride.
[4176] LCMS: m/z 550 [M+H].sup.+
[4177] HPLC retention time: 2.53 min (analysis condition A)
Example 651
[4178] Compound T15-1
4-[2-(3-Bromo-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-8-yl
oxy)-ethyl]-piperidine-1-carboxylic acid tert-butyl ester
##STR00666##
[4180] According to the same method as the method for synthesizing
Compound A7-1, the title compound was prepared from Compound A5-1
and N-(tert-butoxycarbonyl)-4-piperidine ethanol.
[4181] LCMS: m/z 567 [M+H].sup.+
[4182] HPLC retention time: 2.29 min (analysis condition D)
Example 652
[4183] Compound T15-2
3-Bromo-6,6-dimethyl-8-(2-piperidin-4-yl-ethoxy)-5,6-dihydro-benzo[b]carba-
zol-11-one
##STR00667##
[4185] According to the same method as the method for synthesizing
Compound A8-1, the title compound was prepared from Compound
T15-1.
[4186] LCMS: m/z 467 [M+H].sup.+
[4187] HPLC retention time: 1.95 min (analysis condition D)
Example 653
[4188] Compound T15-3
3-Bromo-6,6-dimethyl-8-[2-(1-oxetan-3-yl-piperidin-4-yl)-ethoxy]-5,6-dihyd-
ro-benzo[b]carbazol-11-one
##STR00668##
[4190] According to the same method as the method for synthesizing
Compound B3-32, the title compound was prepared from Compound T15-2
and 3-oxetanone.
[4191] LCMS: m/z 523 [M+H].sup.+
[4192] HPLC retention time: 2.28 min (analysis condition D)
Example 654
[4193] Compound T16-1
4-(3-Bromo-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-8-yl
oxy)-1-oxa-8-aza-spiro[4.5]decane-8-carboxylic acid tert-butyl
ester
##STR00669##
[4195] According to the same method as the method for synthesizing
Compound A7-1, the title compound was prepared from Compound A5-1
and 3-hydroxy-1-oxa-8-aza-spiro[4.5]decane-8-carboxylic acid
tert-butyl ester.
[4196] LCMS: m/z 595 [M+H].sup.+
[4197] HPLC retention time: 3.08 min (analysis condition A)
Example 655
[4198] Compound T16-2
3-Bromo-6,6-dimethyl-8-(1-oxa-8-aza-spiro[4.5]decan-4-yl
oxy)-5,6-dihydro-benzo[b]carbazol-11-one
##STR00670##
[4200] According to the same method as the method for synthesizing
Compound A8-1, the title compound was prepared from Compound
T16-1.
[4201] LCMS: m/z 496 [M+H].sup.+
[4202] HPLC retention time: 1.99 min (analysis condition A)
Example 656
[4203] Compound T16-3
3-Bromo-8-(8-methanesulfonyl-1-oxa-8-aza-spiro[4.5]decan-4-yl
oxy)-6,6-dimethyl-5,6-dihydro-benzo[b]carbazol-11-one
##STR00671##
[4205] According to the same method as the method for synthesizing
Compound A9-1, the title compound was prepared from Compound T16-2
and mesyl chloride.
[4206] LCMS: m/z 573 [M+H].sup.+
[4207] HPLC retention time: 2.56 min (analysis condition A)
Example 657
[4208] Compound T16-4
3-Bromo-6,6-dimethyl-8-(8-oxetan-3-yl-1-oxa-8-aza-spiro[4.5]decan-4-yl
oxy)-5,6-dihydro-benzo[b]carbazol-11-one
##STR00672##
[4210] According to the same method as the method for synthesizing
Compound B3-32, the title compound was prepared from Compound T16-2
and 3-oxetanone.
[4211] LCMS: m/z 551 [M+H].sup.+
[4212] HPLC retention time: 2.01 min (analysis condition A)
Example 658
[4213] Compound T17-1
3,7,9-Tribromo-8-hydroxy-6,6-dimethyl-5,6-dihydro-benzo[b]carbazol-11-one
##STR00673##
[4215] Under nitrogen atmosphere,
4-[1,3]dithian-2-ylidene-piperidine-1-carboxylicacid tert-butyl
ester (100 g, 0.332 mmol) was dissolved in dichloromethane (2.50
mL), added with trifluoromethanesulfonic acid (30.8 .mu.L, 0.348
mmol) at -20.degree. C., and stirred at room temperature for 30
min. The reaction solution was cooled to -70.degree. C., and then
added dropwise with the dichloromethane (2.50 mL) solution of
3-bromo-8-hydroxy-6,6-dimethyl-5,6-dihydro-benzo[b]carbazol-11-one
(Compound A5-1, 177 mg, 0.498 mmol) and triethylamine (78.6 .mu.L,
0.564 mmol). Thereafter, triethylamine hydrotrifluoric acid salt
(262 .mu.L, 1.610 mmol) and 1,3-dibromo-5,5-dimethylhydantoin (460
mg, 1.610 mmol) were added thereto and stirred at -70.degree. C.
for 1 hr. The reaction solution was added to aqueous solution of
sodium hydroxide (1 M), extracted with ethyl acetate, washed with
water, saturated aqueous solution of sodium bicarbonate, saturated
brine and dried over sodium sulfate. After filtering and
concentration under reduced pressure, the resulting residues were
purified by silica gel column chromatography (ethyl acetate/hexane)
and aminosilica gel column chromatography (ethyl acetate/hexane) to
obtain the target compound (42.0 mg, 25%).
[4216] LCMS: m/z 511 [M+H].sup.+
[4217] HPLC retention time: 6.34 min (analysis condition B)
Example 659
[4218] Compound T17-2
3,7,9-Tribromo-8-((S)-2,2-dimethyl-[1,3]dioxolan-4-yl
methoxy)-6,6-dimethyl-5,6-dihydro-benzo[b]carbazol-11-one
##STR00674##
[4220] According to the same method as the method for synthesizing
Compound A7-1, the title compound was prepared from Compound A17-1
and (S)-(+)-2,2-dimethyl-1,3-dioxolan-4-methanol.
[4221] LCMS: m/z 625 [M+H].sup.+
[4222] HPLC retention time: 3.41 min (analysis condition A)
Example 660
[4223] Compound T17-3
3,7,9-Tribromo-8-((R)-2,3-dihydroxy-propoxy)-6,6-dimethyl-5,6-dihydro-benz-
o[b]carbazol-11-one
##STR00675##
[4225] According to the same method as the method for synthesizing
Compound A7-14-2, the title compound was prepared from Compound
T17-2.
[4226] LCMS: m/z 585 [M+H].sup.+
[4227] HPLC retention time: 2.44 min (analysis condition A)
Example 661
[4228] Compound T18-1
3-Bromo-8-((S)-2,2-dimethyl-[1,3]dioxolan-4-yl
methoxy)-6,6-dimethyl-5,6-dihydro-benzo[b]carbazol-11-one
##STR00676##
[4230]
3-Bromo-8-hydroxy-6,6-dimethyl-5,6-dihydro-benzo[b]carbazol-11-one
(Compound A5-1, 18.0 mg, 50.5 .mu.mol) was dissolved in DMF (0.18
mL), added with toluene-4-sulfonic acid
(R)-2,2-dimethyl-[1,3]dioxolan-4-yl methyl ester (14.5 mg, 0.0505
mmol) and potassium carbonate (10.0 mg, 0.07575 mmol), and the
mixture was stirred at 70.degree. C. for 3 days. The reaction
solution was added to water, extracted with ethyl acetate, and the
organic layer was dried over magnesium sulfate. The residues
obtained after concentration under reduced pressure were purified
by preparative TLC (methylene chloride/methanol) to obtain the
title compound (16.6 mg, 70%).
[4231] LCMS: m/z 470 [M+H].sup.+
[4232] HPLC retention time: 3.01 min (analysis condition F)
Example 662
[4233] Compound T18-2
3-Bromo-8-((R)-2,3-dihydroxy-propoxy)-6,6-dimethyl-5,6-dihydro-benzo[b]car-
bazol-11-one
##STR00677##
[4235] Under the same conditions as the method for synthesizing
Compound A7-14-2, the title compound was prepared from Compound
T18-1.
[4236] LCMS: m/z 430 [M+H].sup.+
[4237] HPLC retention time: 4.72 min (analysis condition H)
Example 663
[4238] Compound T19-1-1
3-Bromo-8-methoxy-5,6,6-trimethyl-5,6-dihydro-benzo[b]carbazol-11-one
##STR00678##
[4240] Under the same conditions as the method for synthesizing
Compound A10-1, the title compound was prepared from Compound
A4.
[4241] LCMS: m/z 384 [M+H].sup.+
[4242] HPLC retention time: 2.84 min (analysis condition D)
Example 664
[4243] Compound T19-1
3-Bromo-8-hydroxy-5,6,6-trimethyl-5,6-dihydro-benzo[b]carbazol-11-one
##STR00679##
[4245] Under the same conditions as the method for synthesizing
Compound A6, the title compound was prepared from Compound
T19-1-1.
[4246] LCMS: m/z 370 [M+H].sup.+
[4247] HPLC retention time: 2.40 min (analysis condition D)
Example 665
[4248] Compound T19-2
3-Bromo-8-(2-diethylaminoethoxy)-6,6-trimethyl-5,6-dihydro-benzo[b]carbazo-
l-11-one
##STR00680##
[4250] Under the same conditions as the method for synthesizing
Compound A7-17, the title compound was prepared from Compound A5-1
(9.8 mg, 36%).
[4251] LCMS: m/z 455 [M+H].sup.+
[4252] HPLC retention time: 1.96 min (analysis condition D)
Example 666
[4253] Compound T19-3
3-Bromo-8-(2-diethylaminoethoxy)-5,6,6-trimethyl-5,6-dihydro-benzo[b]carba-
zol-11-one
##STR00681##
[4255] Under the same conditions as the method for synthesizing
Compound A7-17, the title compound was prepared from Compound
T19-1.
[4256] LCMS: m/z 469 [M+H].sup.+
[4257] HPLC retention time: 2.09 min (analysis condition D)
Example 667
[4258] Compound T20
5-(3-Bromo-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yl
oxy)-pentanoic acid
##STR00682##
[4260] Under the same conditions as the method for synthesizing
Compound A7-17, Compound A5-1 and methyl 5-bromovalerate were
reacted, added with 1 N NaOH (140 L), and then stirred at room
temperature for 2 hr. The reaction mixture was added with 2 N HCl
(70 .mu.L), and concentrated under reduced pressure. The resulting
residues were purified by preparative TLC (methylene
chloride:methanol=15:1) to obtain 7 mg (55%).
[4261] LCMS: m/z 456 [M+H].sup.+
[4262] HPLC retention time: 5.88 min (analysis condition H)
Example 668
[4263] Compound T21
(R)-5-(3-Bromo-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yl
oxy)-4-hydroxy-pentanoic acid
##STR00683##
[4265] Under the same conditions as the method for synthesizing
Compound T20, the title compound was prepared from the reaction
between Compound A5-1 and toluene-4-sulfonic acid
(R)-5-oxo-tetrahydrofuran-2-yl methyl ester.
[4266] LCMS: m/z 471 [M+H].sup.+
[4267] HPLC retention time: 4.57 min (analysis condition H)
Example 669
[4268] Compound T22-0
[5-(Tert-butyldimethylsilanyloxymethyl)-2,2-dimethyl-[1,3]dioxolan-4-yl]-m-
ethanol
##STR00684##
[4270] To THF (50 mL), NaH (1.41 g, 0.032 mmol) was added at room
temperature, followed by addition of
((4R,5R)-5-hydroxymethyl-2,2-dimethyl-[1,3]dioxolan-4-yl)-methanol
(5.0 g, 0.031 mmol) at room temperature. The mixture was stirred at
room temperature for 1 hr. After that, TBSCl (5.11 g, 0.034 mmol)
was added at room temperature and stirred at room temperature
overnight. The reaction solution was added with saturated aqueous
solution of sodium hydrogen carbonate and extracted with ethyl
acetate. The organic layer was dried over magnesium sulfate. The
residues obtained after concentration under reduced pressure were
purified by silica gel column chromatography (ethyl acetate/hexane)
to obtain the title compound (8.21 g, 96%).
[4271] .sup.1H-NMR (270 MHz, DMSO-d.sub.6) .delta.: 3.64-4.98 (6H,
m), 2.37 (1H, m), 1.41 (3H, s), 1.40 (3H, s), 0.90 (9H, s), 0.08
(6H, s)
Example 670
[4272] Compound T22-1
3-Bromo-8-[(4R,5R)-5-(tert-butyldimethylsilanyloxymethyl)-2,2-dimethyl-[1,-
3]dioxolan-4-ylmethoxy]-6,6-dimethyl-5,6-dihydro-benzo[b]carbazol-11-one
##STR00685##
[4274] Under the same conditions as the method for synthesizing
Compound A7-1, the title compound was prepared from Compound A5-1
and
[5-(tert-butyldimethylsilanyloxymethyl)-2,2-dimethyl-[1,3]dioxolan-4-yl]--
methanol (Compound T22-0) (704 mg, 80%).
[4275] LCMS: m/z 614 [M+H].sup.+
[4276] HPLC retention time: 4.00 min (analysis condition F)
Example 671
[4277] Compound T22-1-1
3-Bromo-8-((1R,5R)-5-hydroxymethyl-2,2-dimethyl-[1,3]dioxolan-4-yl
methoxy)-6,6-dimethyl-5,6-dihydro-benzo[b]carbazol-11-one
##STR00686##
[4279] Under nitrogen atmosphere, to the DMF (0.4 mL) suspension of
3-bromo-8-[(1R,5R)-5-(tert-butyl-dimethyl-silanyloxymethyl)-2,2-dimethyl--
[1,3]dioxolan-4-yl
methoxy]-6,6-dimethyl-5,6-dihydro-benzo[b]carbazol-11-one (Compound
T22-1, 50.3 mg, 0.0818 mmol) and copper (I) iodide (34 mg), sodium
methoxide (1 M methanol solution, 0.82 mL, 0.818 mmol) was added
and the mixture was stirred for 6 hr and 45 min at ambient
temperature of 90.degree. C. After cooling to room temperature, the
reaction mixture was added with diethyl ether and ethyl acetate,
and the insoluble matters were removed by Celite filtration. The
concentrated residues were added with diethyl ether, hexane, ethyl
acetate and water, and then the mixture was extracted twice with
diethyl ether. The organic layer was washed with water and
subsequently with brine, dried over sodium sulfate and concentrated
under reduced pressure. The resulting crude product was purified by
preparative TLC (Merck60 F.sub.254, 0.5 mm) {solution for elution:
hexane/ethyl acetate (1: 2)} to obtain the title compound
(colorless oily substance, 22.6 mg, 55%).
[4280] .sup.1H-NMR (270 MHz, CDCl.sub.3) .delta.: 8.44-8.38 (1H,
b), 8.39 (1H, d, 8.6 Hz), 8.31 (1H, d, 8.2 Hz), 7.60 (1H, d, 1.3
Hz), 7.44 (1H, dd, 8.2 Hz, 1.3 Hz), 7.12 (1H, d, 2.3 Hz), 7.02 (1H,
dd, 8.6 Hz, 2.3 Hz), 4.41-4.10 (4H, m), 4.00-3.88 (1H, m),
3.86-3.76 (1H, m), 1.78 (6H, s), 1.50 (3H, s), 1.49 (3H, s)
[4281] LCMS: m/z 500 [M+H].sup.+
[4282] HPLC retention time: 2.85 min (analysis condition C)
Example 672
[4283] Compound T22-1-2
Acetic acid
(3R,4R)-5-(3-bromo-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-
-yl oxymethyl)-2,2-dimethyl[1,3]dioxolan-4-yl methyl ester
##STR00687##
[4285] The title compound was obtained as a by-product of the
synthesis of T22-1-1 (white solid, 17.8 mg, 40%).
[4286] .sup.1H-NMR (270 MHz, CDCl.sub.3) .delta.: 8.92-8.80 (1H,
b), 8.40 (1H, d, 8.9 Hz), 8.31 (1H, d, 8.6 Hz), 7.58 (1H, d, 1.7
Hz), 7.43 (1H, dd, 8.6 Hz, 1.7 Hz), 7.14 (1H, d, 2.3 Hz), 7.02 (1H,
dd, 8.9 Hz, 2.3 Hz), 4.51-4.38 (1H, m), 4.34-4.16 (4H, m), 2.13
(3H, s), 1.78 (6H, s), 1.50 (6H, s)
[4287] LCMS: m/z 542 [M+H].sup.+
[4288] HPLC retention time: 3.00 min (analysis condition C)
Example 673
[4289] Compound T22-2
3-Bromo-6,6-dimethyl-8-((2R,3R)-2,3,4-trihydroxy-butoxy)-5,6-dihydro-benzo-
[b]carbazol-11-one
##STR00688##
[4291] Under the same conditions as the method for synthesizing
Compound A7-14-2, the title compound was prepared from Compound
T22-1 (2.83 g, 95%).
[4292] LCMS: m/z 460 [M+H].sup.+
[4293] HPLC retention time: 4.50 min (analysis condition H)
Example 674
[4294] Compound T22-3
3-Bromo-8-[(4R,5R)-5-(tert-butyldimethylsilanyloxymethyl)-2,2-dimethyl-[1,-
3]dioxolan-4-yl
methoxy]-5,6,6-trimethyl-5,6-dihydro-benzo[b]carbazol-11-one
##STR00689##
[4296] Under the same conditions as the method for synthesizing
Compound B3-4, the title compound was prepared from Compound
T22-1.
[4297] LCMS: m/z 628 [M+H].sup.+
[4298] HPLC retention time: 4.74 min (analysis condition F)
Example 675
[4299] Compound T22-4
3-Bromo-8-((2R,3R)-2,3-dihydroxy-pentyloxy)-5,6,6-trimethyl-5,6-dihydro-be-
nzo[b]carbazol-11-one
##STR00690##
[4301] Under the same conditions as the method for synthesizing
Compound A7-14-2, the title compound was prepared from Compound
T22-3.
[4302] LCMS: m/z 475 [M+H].sup.+
[4303] HPLC retention time: 4.86 min (analysis condition H)
Example 676
[4304] Compound T22-5
{3-Bromo-8-[(4R,5R)-5-(tert-butyldimethylsilanyloxymethyl)-2,2-dimethyl-[1-
,3]dioxolan-4-yl
methoxy]-6,6-dimethyl-11-oxo-6,11-dihydro-benzo[b]carbazol-5-yl}-acetic
acid methyl ester
##STR00691##
[4306] Under nitrogen atmosphere,
3-bromo-8-[(4R,5R)-5-(tert-butyldimethylsilanyloxymethyl)-2,2-dimethyl-[1-
,3]dioxolan-4-yl
methoxy]-6,6-dimethyl-5,6-dihydro-benzo[b]carbazol-11-one (Compound
T22-1, 40.0 mg, 65.2 .mu.mol) was dissolved in DMF (0.20 mL), added
at 0.degree. C. with methyl bromoacetate (30.5 .mu.L, 134.5
.mu.mol) and sodium hydride (4.5 mg, 132 .mu.mol), and then stirred
at room temperature for 2 hr. The residues obtained from the
reaction solution after concentration under reduced pressure were
purified by silica gel column chromatography (ethyl acetate/hexane)
to obtain the title compound (44.5 mg, 85%).
[4307] LCMS: m/z 686 [M+H].sup.+
[4308] HPLC retention time: 3.35 min (analysis condition D)
Example 677
[4309] Compound T22-6
{3-Bromo-8-[(4R,5R)-5-(tert-butyldimethylsilanyloxymethyl)-2,2-dimethyl-[1-
,3]dioxolan-4-yl
methoxy]-6,6-dimethyl-11-oxo-6,11-dihydro-benzo[b]carbazol-5-yl}-acetic
acid
##STR00692##
[4311]
{3-Bromo-8-[(4R,5R)-5-(tert-butyl-dimethyl-silanyloxymethyl)-2,2-di-
methyl-[1,3]dioxolan-4-ylmethoxy]-6,6-dimethyl-11-oxo-6,11-dihydro-benzo[b-
]carbazol-5-yl}-acetic acid methyl ester (Compound T22-5, 40 mg,
60.0 .mu.mol) was dissolved in the mixture solvent of methanol (120
l) and water (30 l), added with lithium hydroxide monohydrate (10
mg, 240 .mu.mol), and then stirred 40.degree. C. for 15 min. The
residues obtained from the reaction solution after concentration
under reduced pressure were purified by silica gel column
chromatography (methylene chloride/methanol) to obtain the target
compound (35.2 mg, 96%).
[4312] LCMS: m/z 672 [M+H].sup.+
[4313] HPLC retention time: 3.41 min (analysis condition D)
Example 678
[4314] Compound T22-7
[3-Bromo-6,6-dimethyl-11-oxo-8-((2R,3R)-2,3,4-trihydroxy-butoxy)-6,11-dihy-
dro-benzo[b]carbazol-5-yl]-acetic acid
##STR00693##
[4316] Under the same conditions as the method for synthesizing
Compound A7-14-2, the title compound was prepared from Compound
T22-6 (6.2 mg, 31%).
[4317] LCMS: m/z 518 [M+H].sup.+
[4318] HPLC retention time: 1.30 min (analysis condition D)
[4319] Compound T22-8
[3-Bromo-6,6-dimethyl-11-oxo-8-((2R,3R)-2,3,4-trihydroxy-butoxy)-6,11-dihy-
dro-benzo[b]carbazol-5-yl]-acetic acid methyl ester
##STR00694##
[4321]
[3-Bromo-6,6-dimethyl-11-oxo-8-((2R,3R)-2,3,4-trihydroxy-butoxy)-6,-
11-dihydro-benzo[b]carbazol-5-yl]-acetic acid (Compound T22-6, 15.0
mg, 29.0 .mu.mol) was dissolved in methanol (0.30 mL), added with
trimethylsilyldiazomethane (0.10 mL), and then stirred at room
temperature for 1 hr. The residues obtained from the reaction
solution after concentration under reduced pressure were purified
by silica gel column chromatography (methylene chloride/methanol)
to obtain the target compound (15.2 mg, 96%).
[4322] LCMS: m/z 532 [M+H].sup.+
[4323] HPLC retention time: 1.80 min (analysis condition D)
Example 680
[4324] Compound T23-1
3-Bromo-5-((R)-1,2-dihydroxyethyl)-8-methoxy-6,6-dimethyl-5,6-dihydro-benz-
o[b]carbazol-11-one
##STR00695##
[4326] Under the same conditions as the method for synthesizing
Compound T18-1 and Compound T18-2, the title compound was prepared
from Compound A5-1 and toluene-4-sulfonic acid
(R)-2,2-dimethyl-[1,3]dioxolan-4-yl methyl ester.
[4327] LCMS: m/z 366 [M+H].sup.+
[4328] HPLC retention time: 4.50 min (analysis condition H)
Example 681
[4329] Compound T23-2
3-Bromo-5-((S)-1,2-dihydroxyethyl)-8-methoxy-6,6-dimethyl-5,6-dihydro-benz-
o[b]carbazol-11-one
##STR00696##
[4331] Under the same conditions as the method for synthesizing
Compound T18-1 and Compound T18-2, the title compound was prepared
from Compound A4 and toluene-4-sulfonic acid
(S)-2,2-dimethyl-[1,3]dioxolan-4-yl methyl ester.
[4332] LCMS: m/z 366 [M+H].sup.+
[4333] HPLC retention time: 4.50 min (analysis condition H)
Example 682
[4334] Compound T24-1
3-Bromo-8-((S)-2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-5,6,6-trimethyl-5,6-
-dihydro-benzo[b]carbazol-11-one
##STR00697##
[4336] Under nitrogen atmosphere, to the DMF (1 mL) suspension of
3-bromo-8-((S)-2,2-dimethyl-[1,3]dioxolan-4-yl
methoxy)-6,6-dimethyl-5,6-dihydro-benzo[b]carbazol-11-one (Compound
T18-1, 112.2 mg, 0.239 mmol) and sodium hydride (60%) (19 mg, 0.477
mmol), cooled in an ice bath, methyl iodide (37 mL, 0.596 mmol) was
added. The reaction mixture was stirred at room temperature for 45
min, and then added with saturated aqueous solution of ammonium
chloride and saturated aqueous solution of sodium thiosulfate under
ice cooling. The mixture was extracted twice with ethyl
acetate/diethyl ether/hexane. The organic layer was washed with
water and subsequently with aqueous solution of ammonium chloride,
dried over sodium sulfate, and then concentrated under reduced
pressure. The resulting crude product was purified by flash column
chromatography {Merck Kieselgel60, solution for elution:
hexane/ethyl acetate (1: 1)} to obtain the title compound (white
solid, 107.3 mg, 93%).
[4337] .sup.1H-NMR (270 MHz, CDCl.sub.3) .delta.: 8.41 (1H, d, 8.6
Hz), 8.35 (1H, d, 8.9 Hz), 7.56 (1H, d, 1.7 Hz), 7.46 (1H, dd, 8.6
Hz, 1.7 Hz), 7.14 (1H, d, 2.3 Hz), 7.00 (1H, dd, 8.9 Hz, 2.3 Hz),
4.60-4.49 (1H, m), 4.20-3.90 (4H, m), 4.03 (3H, s), 1.88 (6H, s),
1.50 (3H, s), 1.43 (3H, s)
[4338] LCMS: m/z 484 [M+H].sup.+
[4339] HPLC retention time: 6.59 min (analysis condition B)
Example 683
[4340] Compound T24-2
3-Bromo-8-((R)-2,3-dihydroxy-propoxy)-5,6,6-trimethyl-5,6-dihydro-benzo[b]-
carbazol-11-one
##STR00698##
[4342] Under nitrogen atmosphere, to the THF (0.15 mL)-MeOH (0.1
mL) solution of 3-bromo-8-((S)-2,2-dimethyl-[1,3]dioxolan-4-yl
methoxy)-5,6,6-trimethyl-5,6-dihydro-benzo[b]carbazol-11-one
(Compound T24-1, 15.5 mg, 0.0320 mmol), 0.5 M aqueous solution of
sulfuric acid (128 .mu.L, 0.0640 mmol) was added at room
temperature. The reaction mixture was stirred at ambient
temperature of 55.degree. C. for 2 hr, cooled to room temperature,
and then added with diethyl ether and subsequently with sodium
hydrogen carbonate (11 mg). The mixture was extracted twice with
diethyl ether/ethyl acetate, and the organic layer was washed with
brine, dried over sodium sulfate and concentrated under reduced
pressure to obtain the title compound (white solid, 11.9 mg,
84%).
[4343] .sup.1H-NMR (270 MHz, CD.sub.3OD) .delta.: 8.26 (1H, d, 8.6
Hz), 8.20 (1H, d, 8.9 Hz), 7.77 (1H, d, 1.7 Hz), 7.42 (1H, dd, 8.6
Hz, 1.7 Hz), 7.33 (1H, d, 2.3 Hz), 7.09 (1H, dd, 8.9 Hz, 2.3 Hz),
4.26-3.96 (3H, m), 4.10 (3H, s), 3.74-3.66 (1H, m), 1.92 (6H,
s)
[4344] LCMS: m/z 444 [M+H].sup.+
[4345] HPLC retention time: 4.65 min (analysis condition B)
Example 684
[4346] Compound T25
3-Bromo-6,6-dimethyl-5,6-dihydro-benzo[b]carbazol-11-one
##STR00699##
[4348] Under the same conditions as the method for synthesizing
Compound A3-1 and Compound A4, the title compound was prepared from
3,4-dihydro-1H-naphthalen-2-one (560 mg).
[4349] LCMS: m/z 340 [M+H].sup.+
[4350] HPLC retention time: 4.57 min (analysis condition H)
Example 685
[4351] Compound T26-1
8-[(4R,5R)-5-(Tert-butyldimethylsilanyloxymethyl)-2,2-dimethyl-[1,3]dioxol-
an-4-yl
methoxy]-3-iodo-6,6-dimethyl-5,6-dihydro-benzo[b]carbazol-11-one
##STR00700##
[4353] Under nitrogen atmosphere,
3-bromo-8-[(4R,5R)-5-(tert-butyldimethylsilanyloxymethyl)-2,2-dimethyl-[1-
,3]dioxolan-4-yl
methoxy]-6,6-dimethyl-5,6-dihydro-benzo[b]carbazol-11-one (Compound
T22-1, 300 mg, 0.47 mmol), sodium iodide (147 mg, 0.94 mmol) and
copper iodide (9.40 mg, 0.047 mmol) were dissolved in dioxane (1.00
ml), added with
(1R,2R)--N,N,N',N'-tetramethyl-cyclohexane-1,2-diamine (15.4 .mu.l,
0.094 mmol), and then stirred at 110.degree. C. for 16 hr. The
residues obtained from the reaction solution after concentration
under reduced pressure were purified by silica gel column
chromatography (methylene chloride/methanol) to obtain the title
compound (220 mg, 70%).
[4354] LCMS: m/z 662 [M+H].sup.+
[4355] HPLC retention time: 3.40 min (analysis condition D)
Example 686
[4356] Compound T26-2
3-Iodo-6,6-dimethyl-8-((2R,3R)-2,3,4-trihydroxy-butoxy)-5,6-dihydro-benzo[-
b]carbazol-11-one
##STR00701##
[4358] Under the same conditions as the method for synthesizing
Compound A7-14-2, the title compound was prepared from Compound
T26-1 (17.0 mg, 90%).
[4359] LCMS: m/z 508 [M+H].sup.+
[4360] HPLC retention time: 1.77 min (analysis condition D)
Example 687
[4361] Compound T27-1
3-Bromo-9-(2-fluoro-4-methoxy-phenyl)-8-methoxy-6,6-dimethyl-5,6-dihydro-b-
enzo[b]carbazol-11-one
##STR00702##
[4363] To the mixture of
6-bromo-7-methoxy-1,1-dimethyl-3,4-dihydro-1H-naphthalen-2-one
(Compound E1, 410 mg, 1.44 mmol), tetrakistriphenylphosphine
palladium (80 mg, 0.05 eq.) and sodium carbonate (614 mg, 4 eq.),
toluene (3 mL) and water (1 ml) were added and then stirred at room
temperature and at 90.degree. C. for 3 hr. The mixture was
extracted by adding water and diethyl ether, and the organic layer
was washed with brine, and dried over magnesium sulfate. The
residues obtained after concentration under reduced pressure were
purified by silica gel column chromatography (ethyl acetate/hexane)
to obtain
6-(2-fluoro-4-methoxy-phenyl)-7-methoxy-1,1-dimethyl-3,4-dihydr-
o-1H-naphthalen-2-one (white solid, 320 mg).
[4364] Thus-obtained
6-(2-fluoro-4-methoxy-phenyl)-7-methoxy-1,1-dimethyl-3,4-dihydro-1H-napht-
halen-2-one (320 mg, 0.1 mmol) and 3-bromophenylhydrazine (0.29 g,
1.3 eq.) were dissolved in acetic acid (1 mL), and stirred under
nitrogen atmosphere at 90.degree. C. for 8 hr. After cooling, the
reaction solution was added with ethyl acetate, washed with water,
saturated aqueous solution of sodium hydrogen carbonate, and
saturated brine, dried over magnesium sulfate, and then filtered.
The residues obtained after concentration under reduced pressure
were dissolved in THF (3 mL) comprising 10% water, added with DDQ
(227 mg, 3 eq.) at room temperature, and stirred at room
temperature for 2 hr. To the reaction solution, the mixture
solution of THF/diethyl ether (1: 1) was added, and the reaction
solution was washed with 0.5 N aqueous solution of sodium hydroxide
and saturated brine, dried over sodium sulfate, and then filtered.
The residues obtained after concentration under reduced pressure
were purified by silica gel column chromatography (ethyl
acetate/hexane) to obtain the title compound (red solid, 75
mg).
[4365] LCMS: m/z 494, 496 [M+H].sup.+
[4366] HPLC retention time: 3.10 min (analysis condition C)
Example 688
[4367] Compound T27-2
3-Bromo-9-(2-fluoro-4-hydroxy-phenyl)-8-hydroxy-6,6-dimethyl-5,6-dihydro-b-
enzo[b]carbazol-11-one
##STR00703##
[4369] Under the same conditions as the method for synthesizing
Compound A6, the title compound was prepared from Compound
T27-1.
[4370] LCMS: m/z 464, 466 [M+H].sup.+
[4371] HPLC retention time: 2.68 min (analysis condition C)
Example 689
[4372] Compound U5
4-Bromo-8-methoxy-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbzaole-3--
carbonitrile
##STR00704##
[4374] 2-Bromo-3-nitro-benzonitrile (Compound U1, 678 mg, 2.987
mmol) was dissolved in ethanol (20.9 mL) and water (8.96 mL), added
with acetic acid (2.39 mL, 41.81 mmol) andiron (1.17 g, 20.91
mmol), and stirred at 60.degree. C. for 18 hr. The reaction
solution was poured into aqueous solution of sodium hydroxide (1
M), extracted with ethyl acetate, washed with water and saturated
brine, dried over sodium sulfate, and then filtered. After
concentration under reduced pressure, 3-amino-2-bromo-benzonitrile
(Compound U2) was obtained as a crude product.
[4375] The crude product obtained from the above was dissolved in
12 M aqueous solution of hydrochloric acid (4.00 mL), added slowly
at 0.degree. C. with aqueous solution in which sodium nitrite (247
mg, 3.584 mmol) is dissolved in water (3.58 mL), and then the
mixture was stirred at 0.degree. C. for 30 min. Under
light-shielding conditions, aqueous solution in which tin chloride
dihydrate (2.02 g, 8.961 mmol) is dissolved in 12 M aqueous
solution of hydrochloric acid (4.00 mL) was slowly added to the
reaction solution at 0.degree. C., and then the mixture was stirred
at 0.degree. C. for 1 hr. The reaction solution was poured into 5 M
aqueous solution of sodium hydroxide, extracted with ethyl acetate,
washed with saturated brine, dried over sodium sulfate, and
filtered. After concentration under reduced pressure,
2-bromo-3-hydrazino-benzonitrile (Compound U3) was obtained as a
crude product. Under nitrogen atmosphere, the above crude product
and 7-methoxy-1,1-dimethyl-3,4-dihydro-1H-naphthalen-2-one
(Compound A2, 462 mg, 2.260 mmol) were added with TFA (6.78 mL) and
stirred at 100.degree. C. for 2 hr. After cooling, the reaction
solution was poured into saturated aqueous solution of sodium
bicarbonate, extracted with ethyl acetate, washed with water and
saturated brine, dried over sodium sulfate, and filtered. After
concentration under reduced pressure,
4-bromo-8-methoxy-6,6-dimethyl-6,11-dihydro-5H-benzo[b]carbzaole-3-carbon-
itrile (Compound U4) was obtained as a crude product. The above
crude product was dissolved in THF (10.0 mL) and water (1.00 mL),
added with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (1.54 g, 6.780
mmol), and stirred at room temperature for 20 hr. The reaction
solution was poured into 1 M aqueous solution of sodium hydroxide,
extracted with cyclopentylmethyl ether, washed with 1 M aqueous
solution of sodium hydroxide, water and saturated brine, dried over
sodium sulfate, and filtered. The residues obtained after
concentration under reduced pressure were washed with
cyclopentylmethyl ether to obtain the title compound (460 mg,
52%).
[4376] LCMS: m/z 395 [M+H].sup.+
[4377] HPLC retention time: 2.25 min (analysis condition D)
Example 690
[4378] Compound U6
8-Hydroxy-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbzaole-3-carbonit-
rile
##STR00705##
[4380]
4-Bromo-8-methoxy-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbz-
aole-3-carbonitrile (Compound U5, 325 mg, 0.822 mmol) was added
with pyridine hydrochloride salt (3.80 g, 32.89 mmol) and stirred
at 160.degree. C. for 28 hr. The reaction solution was poured into
water, extracted with ethyl acetate, washed with water, dried over
sodium sulfate, and filtered. After concentration under reduced
pressure, the title compound was obtained as a crude product.
[4381] LCMS: m/z 381 [M+H].sup.+
[4382] HPLC retention time: 1.92 min (analysis condition D)
Example 691
[4383] Compound U7-1
4-Bromo-8-((R)-2,2-dimethyl-[1,3]dioxolan-4-yl
methoxy)-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbzaole-3-carbonit-
rile
##STR00706##
[4385] Under the same conditions as the method for synthesizing
Compound A7-1, the title compound was prepared from the reaction
between Compound U6 and
(R)-(-)-2,2-dimethyl-1,3-dioxolane-4-methanol (354 mg, 87%).
[4386] LCMS: m/z 495 [M+H].sup.+
[4387] HPLC retention time: 2.35 min (analysis condition D)
Example 692
[4388] Compound U7-2
4-Bromo-8-((S)-2,3-dihydroxy-propoxy)-6,6-dimethyl-11-oxo-6,11-dihydro-5H--
benzo[b]carbzaole-3-carbonitrile
##STR00707##
[4390] Under the same conditions as the method for synthesizing
Compound A7-14-2, the title compound was prepared from Compound
U7-1.
[4391] LCMS: m/z 455 [M+H].sup.+
[4392] HPLC retention time: 2.40 min (analysis condition C)
Example 693
[4393] Compound U8-2
8-((R)-2,3-Dihydroxy-propoxy)-5,6,6-trimethyl-11-oxo-6,11-dihydro-5H-benzo-
[b]carbzaole-3-carbonitrile
##STR00708##
[4395] Under the same conditions as the method for synthesizing
Compound U7-1 and Compound U7-2, the title compound was prepared
from the reaction between Compound U6 and
(S)-(+)-2,2-dimethyl-1,3-dioxolane-4-methanol (4.5 mg, 29%).
[4396] LCMS: m/z 455 [M+H].sup.+
[4397] HPLC retention time: 2.37 min (analysis condition C)
Example 694
[4398] Compound U8-3-1
8-((S)-2,2-Dimethyl-[1,3]dioxolan-4-yl
methoxy)-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3,4-dicarb-
onitrile
##STR00709##
[4400] Under nitrogen atmosphere,
4-bromo-8-((S)-2,2-dimethyl-[1,3]dioxolan-4-yl
methoxy)-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbzaole-3-carbonit-
rile (Compound U6, 20.0 mg, 40.37 .mu.mol) was dissolved in DMA
(0.35 mL), added with copper (I) cyanide (18.1 mg, 201.9 .mu.mol),
and stirred at 200.degree. C. for 1 hr under irradiation with
microwave. The reaction solution was poured into water, extracted
with ethyl acetate, washed with water and saturated brine, dried
over sodium sulfate, and then filtered. The residues obtained after
concentration under reduced pressure were purified by silica gel
column chromatography (ethyl acetate/hexane) to obtain the title
compound as a crude product.
[4401] LCMS: m/z 442 [M+H].sup.+
[4402] HPLC retention time: 2.30 min (analysis condition D)
[4403] Compound U8-3-2
8-((R)-2,3-Dihydroxy-propoxy)-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]-
carbazole-3,4-dicarbonitrile
##STR00710##
[4405] Under the same conditions as the method for synthesizing
Compound A7-14-2, the title compound was prepared from Compound
U8-3-1 (9.5 mg, 59%).
[4406] LCMS: m/z 402 [M+H].sup.+
[4407] HPLC retention time: 2.40 min (analysis condition D)
Example 696
[4408] Compound U8-4-1
8-((R)-2,2-Dimethyl-[1,3]dioxolan-4-yl
methoxy)-4-hydroxy-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbzaole--
3-carbonitrile
##STR00711##
[4410] Under the same conditions as the method for synthesizing
Compound U9, the title compound was prepared as a crude product
from Compound U8-1 (9.5 mg, 59%).
[4411] LCMS: m/z 433 [M+H].sup.+
[4412] HPLC retention time: 2.34 min (analysis condition A)
Example 697
[4413] Compound U8-4-2
8-((R)-2,3-Dihydroxy-propoxy)-4-hydroxy-6,6-dimethyl-11-oxo-6,11-dihydro-5-
H-benzo[b]carbzaole-3-carbonitrile
##STR00712##
[4415] Under the same conditions as the method for synthesizing
Compound A7-14-2, the title compound was prepared from Compound
U8-4-1 (crude product) (9.7 mg, 52%).
[4416] LCMS: m/z 393 [M+H].sup.+
[4417] HPLC retention time: 1.69 min (analysis condition A)
Example 698
[4418] Compound U8-4-3
8-((R)-2,3-Dihydroxy-propoxy)-4-methoxy-6,6-dimethyl-11-oxo-6,11-dihydro-5-
H-benzo[b]carbzaole-3-carbonitrile
##STR00713##
[4420] Under nitrogen atmosphere,
8-((R)-2,3-dihydroxy-propoxy)-4-hydroxy-6,6-dimethyl-11-oxo-6,11-dihydro--
5H-benzo[b]carbzaole-3-carbonitrile (Compound U8-4-2, 8.0 mg, 20.39
.mu.mol) was dissolved in methanol (2.0 mL) and chloroform (2.00
mL), added with trimethylsilyldiazomethane (diethyl ether solution,
2 M, 15.3 .mu.L, 30.58 .mu.mol) and diisopropylethylamine (0.05
mL), and then stirred at room temperature for 31 hr. The residues
obtained from the reaction solution after concentration under
reduced pressure were purified by silica gel column chromatography
(methanol/dichloromethane) to obtain the title compound (5.1 mg,
62%).
[4421] LCMS: m/z 407 [M+H].sup.+
[4422] HPLC retention time: 3.74 min (analysis condition A)
Example 699
[4423] Compound U8-5-1
8-((R)-2,2-Dimethyl-[1,3]dioxolan-4-yl
methoxy)-6,6-dimethyl-11-oxo-4-trifluoromethyl-6,11-dihydro-5H-benzo[b]ca-
rbzaole-3-carbonitrile
##STR00714##
[4425] Under nitrogen atmosphere,
4-bromo-8-((S)-2,2-dimethyl-[1,3]dioxolan-4-yl
methoxy)-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbzaole-3-carbonit-
rile (Compound U8-1, 25.0 mg, 50.47 .mu.mol) was dissolved in DMF
(0.75 mL), added with copper iodide (I) (48.0 mg, 252.3 .mu.mol)
and difluoro-fluorosulfonyl-acetic acid methyl ester (31.9 .mu.L,
252.3 .mu.mol), and then stirred at 100.degree. C. for 2 days. The
reaction solution was poured into hydrochloric acid (1 M),
extracted with ethyl acetate, washed with water, saturated aqueous
solution of sodium bicarbonate and saturated brine, dried over
sodium sulfate, and then filtered. The residues obtained after
concentration under reduced pressure were purified by silica gel
column chromatography (ethyl acetate/hexane) to obtain the title
compound as a crude product.
[4426] LCMS: m/z 485 [M+H].sup.+
[4427] HPLC retention time: 2.88 min (analysis condition A)
Example 700
[4428] Compound U8-5-2
8-((R)-2,3-Dihydroxy-propoxy)-6,6-dimethyl-11-oxo-4-trifluoromethyl-6,11-d-
ihydro-5H-benzo[b]carbzaole-3-carbonitrile
##STR00715##
[4430] Under the same conditions as the method for synthesizing
Compound A7-14-2, the title compound was prepared from Compound
U8-5-1 (4.0 mg, 30%).
[4431] LCMS: m/z 445 [M+H].sup.+
[4432] HPLC retention time: 2.17 min (analysis condition A)
Example 701
[4433] Compound U8-6-1
4-Cyclopropyl-8-((S)-2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-6,6-dimethyl--
11-oxo-6,11-dihydro-5H-benzo[b]carbzaole-3-carbonitrile
##STR00716##
[4435] Under nitrogen atmosphere,
2-cyclopropyl-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (13.2 mg,
78.73 82 mol) and potassium phosphate (212.27 mg, 212.0 .mu.mol)
were dissolved in water (0.20 mL), and the mixture was stirred at
room temperature for 15 min. To the reaction solution,
4-bromo-8-((S)-2,2-dimethyl-[1,3]dioxolan-4-yl
methoxy)-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbzaole-3-carbonit-
rile (Compound U8-1, 30.0 mg, 60.56 82 mol), palladium acetate
(1.36 mg, 6.056 82 mol), and tricyclohexylphosphine (toluene
solution, 20 wt %, 17.0 mg, 12.11 82 mol) were added and the
mixture was stirred at 80.degree. C. for 24 hr. The reaction
solution was poured into hydrochloric acid (1 M), extracted with
ethyl acetate, washed with saturated aqueous solution of sodium
bicarbonate and saturated brine, dried over sodium sulfate, and
then filtered. The residues obtained after concentration under
reduced pressure were purified by silica gel column chromatography
(ethyl acetate/hexane) to obtain the title compound (13.6 mg,
49%).
[4436] LCMS: m/z 457 [M+H].sup.+
[4437] HPLC retention time: 2.38 min (analysis condition D)
Example 702
[4438] Compound U8-6-2
4-Cyclopropyl-8-((R)-2,3-dihydroxy-propoxy)-6,6-dimethyl-11-oxo-6,11-dihyd-
ro-5H-benzo[b]carbzaole-3-carbonitrile
##STR00717##
[4440] Under the same conditions as the method for synthesizing
Compound A7-14-2, the title compound was prepared from Compound
U8-6-1.
[4441] LCMS: m/z 417 [M+H].sup.+
[4442] HPLC retention time: 2.42 min (analysis condition A)
Example 703
[4443] Compound U8-7-1
(S)-8-((2,2-Dimethyl-1,3-dioxolan-4-yl)methoxy)-4,6,6-trimethyl-11-oxo-6,1-
1-dihydro-5H-benzo[b]carbzaole-3-carbonitrile
##STR00718##
[4445] Under nitrogen atmosphere,
4-bromo-8-((S)-2,2-dimethyl-[1,3]dioxolan-4-yl
methoxy)-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbzaole-3-carbonit-
rile (Compound U8-1, 30.0 mg, 60.56 82 mol) and lithium chloride
(7.70 mg, 181.7 82 mol) were dissolved in DMF (1.00 mL), added with
tetramethyl tin (12.5 .mu.L, 90.84 82 mol),
tetrakistriphenylphosphine palladium (3.50 mg, 6.056 82 mol) and
tricyclohexylphosphine (toluene solution, 20 wt %, 17.0 mg, 3.028
82 mol), and the mixture was stirred at 100.degree. C. for 24 hr.
The reaction solution was poured into hydrochloric acid (1 M),
extracted with ethyl acetate, washed with water, saturated aqueous
solution of sodium bicarbonate and saturated brine, dried over
sodium sulfate, and then filtered. The residues obtained after
concentration under reduced pressure were purified by silica gel
column chromatography (ethyl acetate/hexane) to obtain
8-((S)-2,2-dimethyl-[1,3]dioxolan-4-yl
methoxy)-4,6,6-trimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbzaole-3-carbo-
nitrile as a crude product (20.9 mg, 80%).
Example 704
[4446] Compound U8-7-2
8-((R)-2,3-Dihydroxy-propoxy)-4,6,6-trimethyl-11-oxo-6,11-dihydro-5H-benzo-
[b]carbzaole-3-carbonitrile
##STR00719##
[4448] Under the same conditions as the method for synthesizing
Compound A7-14-2, the title compound was prepared from Compound
U8-7-1.
[4449] LCMS: m/z 391 [M+H].sup.+
[4450] HPLC retention time: 1.82 min (analysis condition A)
Example 705
[4451] Compound U8-8-1
3-Cyano-8-((S)-2,2-dimethyl-[1,3]dioxolan-4-yl
methoxy)-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-4-carboxyl-
ic acid amide
##STR00720##
[4453] Under nitrogen atmosphere,
4-bromo-8-((S)-2,2-dimethyl-[1,3]dioxolan-4-yl
methoxy)-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbzaole-3-carbonit-
rile (Compound U8-1, 30.0 mg, 60.56 82 mol), palladium acetate
(1.36 mg, 6.056 82 mol), 1,1'-bis(diphenylphosphino)ferrocene (3.36
mg, 6.056 82 mol), imidazole (4.12 mg, 60.56 mol) and
tert-potassium butoxy (10.2 mg, 90.84 mol) were dissolved in
formamide (3.00 mL) and the mixture was stirred at 180.degree. C.
for 5 min under irradiation with microwave. The reaction solution
was poured into water, extracted with ethyl acetate, washed with
water and saturated brine, dried over sodium sulfate, and then
filtered. The residues obtained after concentration under reduced
pressure were purified by silica gel column chromatography
(methanol/dichloromethane) to obtain the target compound (7.6 mg,
27%).
[4454] LCMS: m/z 460 [M+H].sup.+
[4455] HPLC retention time: 1.82 min (analysis condition A)
Example 706
[4456] Compound U8-8-2
3-Cyano-8-((R)-2,3-dihydroxy-propoxy)-6,6-dimethyl-11-oxo-6,11-dihydro-5H--
benzo[b]carbazole-4-carboxylic acid
##STR00721##
[4458] Under the same conditions as the method for synthesizing
Compound A7-14-2, the title compound was prepared from Compound
U8-8-1.
[4459] LCMS: m/z 421 [M+H].sup.+
[4460] HPLC retention time: 1.57 min (analysis condition A)
Example 707
[4461] Compound U8-8-3
3-Cyano-8-((R)-2,3-dihydroxy-propoxy)-6,6-dimethyl-11-oxo-6,11-dihydro-5H--
benzo[b]carbazole-4-carboxylic acid amide
##STR00722##
[4463] The title compound was obtained as a by-product of the
synthesis of Compound U8-8-2.
[4464] LCMS: m/z 420 [M+H].sup.+
[4465] HPLC retention time: 1.27 min (analysis condition A)
Example 708
[4466] Compound U9
4-Hydroxy-8-methoxy-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbzaole--
3-carbonitrile
##STR00723##
[4468] Under nitrogen atmosphere,
4-bromo-8-methoxy-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbzaole-3-
-carbonitrile (Compound U5, 10.0 mg, 25.30 82 mol), X-phos (1.07
mg, 2.530 82 mol), sodium hydroxide (4.36 mg, 75.90 82 mol) and
Pd.sub.2dba.sub.3.CHCl.sub.3 (1.31 mg, 1.265 82 mol) were dissolved
in dioxane (0.50 mL) and water (0.50 mL) and the mixture was
stirred at 100.degree. C. for 1 hr. The reaction solution was
poured into hydrochloric acid (1 M), extracted with ethyl acetate,
washed with saturated brine, dried over sodium sulfate, and then
filtered. The residues obtained after concentration under reduced
pressure were purified by silica gel column chromatography (ethyl
acetate/hexane) and washed with dichloromethane to obtain the title
compound (5.4 mg, 64%).
[4469] LCMS: m/z 333 [M+H].sup.+
[4470] HPLC retention time: 1.62 min (analysis condition D)
Example 709
[4471] Compound U10-1
4-((R)-2,3-Dihydroxy-propoxy)-8-methoxy-6,6-dimethyl-11-oxo-6,11-dihydro-5-
H-benzo[b]carbzaole-3-carbonitrile
##STR00724##
[4473] Under the same conditions as the method for synthesizing
Compound A7-1, the title compound was prepared from the reaction
between Compound U9 and
(S)-(+)-2,2-dimethyl-1,3-dioxolane-4-methanol.
[4474] LCMS: m/z 407 [M+H].sup.+
[4475] HPLC retention time: 2.06 min (analysis condition A)
Example 710
[4476] Compound U10-2
4-((S)-2,3-Dihydroxy-propoxy)-8-methoxy-6,6-dimethyl-11-oxo-6,11-dihydro-5-
H-benzo[b]carbzaole-3-carbonitrile
##STR00725##
[4478] Under the same conditions as the method for synthesizing
Compound A7-1, the title compound was prepared from the reaction
between Compound U9 and
(R)-(-)-2,2-dimethyl-1,3-dioxolane-4-methanol.
[4479] LCMS: m/z 407 [M+H].sup.+
[4480] HPLC retention time: 2.06 min (analysis condition A)
Example 711
[4481] Compound U11
4-Amino-8-methoxy-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbzaole-3--
carbonitrile
##STR00726##
[4483] Under nitrogen atmosphere,
4-bromo-8-methoxy-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbzaole-3-
-carbonitrile (Compound U5, 25.0 mg, 63.25 82 mol), copper iodide
(2.41 mg, 12.65 82 mol), sodium azide (20.6 mg, 316.3 82 mol),
(1S,2S)--N,N'-dimethyl-cyclohexane-1,2-diamine (2.70 mg, 18.98 82
mol), and sodium ascorbate (1.25 mg, 6.325 82 mol) were dissolved
in ethanol (0.70 mL) and water (0.30 mL) and the mixture was
stirred at 100.degree. C. for 2 hr. The reaction solution was
poured into aqueous solution of sodium hydroxide (1 M), extracted
with ethyl acetate, washed with water and saturated brine, dried
over sodium sulfate, and then filtered. The residues obtained after
concentration under reduced pressure were purified by silica gel
column chromatography (methanol/dichloromethane) to obtain the
title compound (5.6 mg, 27%).
[4484] LCMS: m/z 332 [M+H].sup.+
[4485] HPLC retention time: 2.16 min (analysis condition A)
Example 712
[4486] Compound V2
3-Fluoro-8-methoxy-6,6-dimethyl-6,11-dihydro-5H-benzo[b]carbazole
##STR00727##
[4488] Under nitrogen atmosphere, the acetic acid (1 mL) suspension
of 7-methoxy-1,1-dimethyl-3,4-dihydro-1H-naphthalen-2-one (Compound
A2, 101.0 mg, 0.495 mmol) and (3-fluoro-phenyl)-hydrazine
hydrochloric acid salt (Compound VI, 96.5 mg, 0.593 mmol) was
stirred at ambient temperature of 95.degree. for 3.75 hr. After
cooling to room temperature, the reaction mixture was added with
water (1 mL) and hexane/ethyl acetate (15: 1) (0.5 mL), and stirred
at room temperature for 15 min. The solid was filtered, washed with
hexane/ethyl acetate (15: 1), and then dried under reduced pressure
to obtain the title compound (beige powder, 72.7 mg, 50%).
[4489] .sup.1H-NMR (270 MHz, CDCl.sub.3) .delta.: 7.92-7.82 (1H,
b), 7.47 (1H, dd, 8.9 Hz, 5.6 Hz), 7.10-7.03 (2H, m), 6.95-6.81
(2H, m), 4.05 (2H, s), 3.86 (3H, s), 1.67 (6H, s)
Example 713
[4490] Compound V3
3-Fluoro-8-methoxy-6,6-dimethyl-5,6-dihydro-benzo[b]carbazol-11-one
##STR00728##
[4492] Under nitrogen atmosphere, to the THF (1.8 mL)-water (0.18
mL) solution of
3-fluoro-8-methoxy-6,6-dimethyl-6,11-dihydro-5H-benzo[b]carbazole
(Compound V2, 72.4 mg, 0.245 mmol), DDQ (122.4 mg, 0.539 mmol) was
added and the mixture was stirred at room temperature for 5 hr. The
reaction mixture was added with diethyl ether and 0.5 N aqueous
solution of sodium hydroxide (2 mL), and the resulting mixture was
extracted twice with diethyl ether. The organic layer was washed
twice with 0.5 N aqueous solution of sodium hydroxide (2 mL) and
subsequently twice with brine (2 mL), and dried over sodium
sulfate. After concentration under reduced pressure, hexane/ethyl
acetate (5: 1) and diethyl ether were added to the obtained crude
product, and the solid was triturated. After removing the
supernatant and drying under reduced pressure, the title compound
was obtained (yellow solid, 57.0 mg, 75%).
[4493] .sup.1H-NMR (270 MHz, CDCl.sub.3) .delta.: 8.54-8.44 (1H,
b), 8.43-8.33 (2H, m), 7.16-6.98 (4H, m), 3.93 (3H, s), 1.77 (6H,
s)
Example 714
[4494] Compound V4
3-Fluoro-8-hydroxy-6,6-dimethyl-5,6-dihydro-benzo[b]carbazol-11-one
##STR00729##
[4496] Mixture of
3-fluoro-8-methoxy-6,6-dimethyl-5,6-dihydro-benzo[b]carbazol-11-one
(Compound V3, 56.6 mg, 0.183 mmol) and pyridinium chloride (0.65 g)
was stirred at ambient temperature of 160.degree. C. for 12 hr. The
reaction mixture was cooled to room temperature, added with ethyl
acetate and water, and the resulting mixture was extracted four
times with ethyl acetate. The organic layer was washed with water
three times, dried over sodium sulfate, and concentrated under
reduced pressure. The obtained crude product was used for the next
step without further purification (brown solid, 61.6 mg, 100%).
[4497] .sup.1H-NMR (270 MHz, CD.sub.3OD) .delta.: 8.20 (1H, dd, 8.9
Hz, 5.3 Hz), 8.15 (1H, d, 9.6 Hz), 7.17 (1H, dd, 9.6 Hz, 2.3 Hz),
7.12 (1H, d, 2.3 Hz), 7.05-6.95 (1H, m), 6.88 (1H, dd, 8.9 Hz, 2.3
Hz), 1.74 (6H, s)
[4498] Compound V5-1
8-[(1R,5R)-5-(Tert-butyl-dimethyl-silanyloxymethyl)-2,2-dimethyl-[1,3]diox-
olan-4-ylmethoxy]-3-fluoro-6,6-dimethyl-5,6-dihydro-benzo[b]carbazol-11-on-
e
##STR00730##
[4500] Under nitrogen atmosphere, to the THF (1.5 mL) solution of
3-fluoro-8-hydroxy-6,6-dimethyl-5,6-dihydro-benzo[b]carbazol-11-one
(Compound V4, 0.183 mmol),
(4S,5R)-5-(tert-butyl-dimethyl-silanyloxymethyl)-2,2-dimethyl[1,3]dioxola-
n-4-ol (75.9 mg, 0.275 mmol) and triphenylphosphine (72 mg, 0.275
mmol), toluene solution (125 .mu.L, 0.275 mmol) of DEAD was added
dropwise at room temperature. The reaction mixture was stirred at
ambient temperature of 40.degree. C. for 7 hr. After cooling to
room temperature, the reaction mixture was concentrated under
reduced pressure, and the resulting crude product was purified by
preparative TLC (Merck 60 F254, 0.5 mm) {solution for elution:
hexane/ethyl acetate (3: 1)} to obtain the title compound (pale
orange amorphous, 54.1 mg, 53.4%).
[4501] .sup.1H-NMR (270 MHz, CDCl.sub.3) .delta.: 8.54-8.45 (1H,
b), 8.42-8.33 (2H, m), 7.17-6.99 (4H, m), 4.41-4.27 (2H, m),
4.25-4.15 (1H, m), 4.06-3.96 (1H, m), 3.96-3.88 (1H, m), 3.83-3.74
(1H, m), 1.76 (3H, s), 1.75 (3H, s), 1.48 (3H, s), 1.47 (3H, s),
0.87 (9H, s), 0.092 (6H, s)
Example 716
[4502] Compound V5-2
3-Fluoro-6,6-dimethyl-8-((3R,4R)-2,3,4-trihydroxy-butoxy)-5,6-dihydro-benz-
o[b]carbazol-11-one
##STR00731##
[4504] Under nitrogen atmosphere, to the THF (0.3 mL)-MeOH (0.1 mL)
solution of
8-[(1R,5R)-5-(tert-butyl-dimethyl-silanyloxymethyl)-2,2-dimethyl-[1,3]dio-
xolan-4-yl
methoxy]-3-fluoro-6,6-dimethyl-5,6-dihydro-benzo[b]carbazol-11--
one (Compound V5-1, 52.8 mg, 0.0954 mmol), 0.5 M aqueous solution
of sulfuric acid (0.19 mL, 0.0954 mmol) was added at room
temperature. The reaction mixture was stirred at ambient
temperature of 55.degree. C. for 4 hr, cooled to room temperature,
and then added with diethyl ether, sodium hydrogen carbonate (20
mg) and water in order. The mixture was extracted twice with
diethyl ether and subsequently twice with ethyl acetate, and the
organic layer was washed with brine, dried over sodium sulfate, and
concentrated under reduced pressure. The resulting crude product
was washed with dichloromethane, and dried under reduced pressure
to obtain the title compound (white powder, 29.9 mg, 78%).
[4505] .sup.1H-NMR (270 MHz, CD.sub.3OD) .delta.: 8.24 (1H, d, 8.9
Hz), 8.19 (1H, dd, 8.6 Hz, 5.3 Hz), 7.30 (1H, d, 2.3 Hz), 7.18 (1H,
dd, 9.2 Hz, 2.3 Hz), 7.09 (1H, dd, 8.9 Hz, 2.3 Hz), 7.06-6.96 (1H,
m), 4.32-4.22 (1H, m), 4.21-4.12 (1H, m), 4.11-4.02 (1H, m),
3.84-3.75 (1H, m), 3.74-3.61 (2H, m), 1.77 (6H, s)
[4506] LCMS: m/z 400 [M+H].sup.+
[4507] HPLC retention time: 4.02 min (analysis condition H)
Example 717
[4508] Compound W2
7-((S)-2,3-Dihydroxy-propoxy)-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]-
carbzaole-3-carbonitrile
##STR00732##
[4510] To the toluene suspension of sodium t-butoxide (700 mg, 2.5
eq.), 8-methoxy-3,4-dihydro-1H-naphthalen-2-one (Compound W1, 500
mg, 2.9 mmol) was added dropwise at 0.degree. C. After 15 minutes,
the solution turned into blackish green color. The mixture solution
was added dropwise with methyl iodide (1.03 g, 2.5 eq.) and stirred
at 15.degree. C. overnight. Brown solid precipitated. The reaction
solution was added to saturated aqueous solution of ammonium
chloride/diethyl ether under stirring and cooling. After that, the
solution was extracted with diethyl ether, and dried over sodium
sulfate. After removing the solvent under reduced pressure, the
resulting residues were purified by silica gel column
chromatography (ethyl acetate/hexane) to obtain
8-methoxy-1,1-dimethyl-3,4-dihydro-1H-naphthalen-2-one (350
mg).
[4511] Thus-obtained
8-methoxy-1,1-dimethyl-3,4-dihydro-1H-naphthalen-2-one (250 mg,
1.23 mmol) and 3-cyanophenylhydrazine (0.2 g, 1.2 eq.) were
dissolved in trifluoroacetic acid (1 mL), and stirred at
120.degree. C. for 1 hr under irradiation with microwave. After
cooling, the reaction solution was added with ethyl acetate, washed
with water, saturated aqueous solution of sodium hydrogen
carbonate, and saturated brine, dried over magnesium sulfate, and
filtered. The residues obtained after concentration under reduced
pressure were dissolved in THF (3 mL) comprising 10% water and
added at room temperature with DDQ (227 mg, 3 eq.). The mixture was
then stirred at room temperature for 2 hr. The reaction solution
was added with mixture solution of THF/diethyl ether (1: 1), washed
with 0.5 N aqueous solution of sodium hydroxide and saturated
brine, dried over sodium sulfate, and then filtered. The residues
obtained after concentration under reduced pressure were purified
by silica gel column chromatography (ethyl acetate/hexane) to
obtain
7-methoxy-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbzaole-3-carboni-
trile (brown solid, 54 mg).
[4512] LCMS: m/z 317 [M+H].sup.+
[4513] HPLC retention time: 1.00 min (analysis condition I)
Example 718
[4514] Compound W3
7-Hydroxy-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbzaole-3-carbonit-
rile
##STR00733##
[4516] Under the same conditions as Compound A6, the title compound
was prepared from Compound W2.
[4517] LCMS: m/z 316 [M+H].sup.+
[4518] HPLC retention time: 0.93 min (analysis condition I)
Example 719
[4519] Compound W4-1
7-((R)-2,2-Dimethyl-[1,3]dioxolan-4-yl
methoxy)-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbzaole-3-carbonit-
rile
##STR00734##
[4521] Under nitrogen atmosphere,
7-methoxy-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbzaole-3-carboni-
trile (Compound W3, 15 mg, 0.05 mmol) and triphenylphosphine (40
mg, 3 eq.) were added with THF (1 ml), further added dropwise with
((R)-2,2-dimethyl-[1,3]dioxolan-4-yl)-methanol (20 mg, 3 eq.) and
2.19 N toluene solution of diethyl azodicarboxylate (68 .mu.L, 3
eq.), and the mixture was stirred at 50.degree. C. for 2 hr. After
cooling, the reaction solution was added with ethyl acetate, washed
with brine, dried over sodium sulfate, and filtered. The residues
obtained after concentration under reduced pressure were purified
by preparative TLC (ethyl acetate/dichloromethane), and the
resulting solid was washed with dichloromethane to obtain the
target compound (brown powder, 5 mg).
[4522] LCMS: m/z 417 [M+H].sup.+
[4523] HPLC retention time: 1.04 min (analysis condition I)
Example 720
[4524] Compound W4-2
7-((S)-2,3-Dihydroxy-propoxy)-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]-
carbzaole-3-carbonitrile
##STR00735##
[4526] Under the same conditions as Compound S7-2, the title
compound was prepared from Compound W4-1.
[4527] LCMS: m/z 377 [M+H].sup.+
[4528] HPLC retention time: 0.88 min (analysis condition I)
Example 721
[4529] Compound X1
1,1-Spiro-4-piperidine-N-paratoluenesulfonyl-7-methoxy-3,4-dihydro-1H-naph-
thalen-2-one
##STR00736##
[4531] 7-Methoxy-3,4-dihydro-1H-naphthalen-2-one (Compound A1, 100
mg, 0.568 mmol) was dissolved in toluene (4 mL), added with NaH
(60% in oil, 68 mg, 3 eq.), and stirred at room temperature for 10
min. The mixture solution was added with
bis-(2-iodo-ethyl)-p-toluenesulfonamide (172 mg, 0.568 mmol), and
stirred at 70.degree. C. for 2 hr under nitrogen stream. After
cooling, the reaction solution was added to saturated aqueous
solution of ammonium chloride, extracted with ethyl acetate, washed
with saturated brine, and then dried over magnesium sulfate. The
residues obtained after concentration under reduced pressure were
purified by silica gel column chromatography (hexane: ethyl
acetate/3: 1) to obtain the title compound (colorless oily
substance, 62 mg, 33%).
[4532] LCMS: m/z 400 [M+H].sup.+
[4533] HPLC retention time: 2.02 min (analysis condition B)
Example 722
[4534] Compound X2
1,1-Spiro-4-piperidine-N-paratoluenesulfonyl-7-methoxy-3,4-dihydro-1H-naph-
thalen-2-one
##STR00737##
[4536]
1,1-Spiro-4-piperidine-N-paratoluenesulfonyl-7-methoxy-3,4-dihydro--
1H-naphthalen-2-one (Compound X1, 400 mg, 1.0 mmol) and
phenylhydrazine (217 mg, 1.5 eq.) were dissolved in acetic acid (6
mL), and the mixture was stirred at 120.degree. C. for 4 hr under
nitrogen atmosphere. After cooling, the reaction solution was added
to water, extracted with ethyl acetate, washed with saturated
brine, and then dried over magnesium sulfate. The residues obtained
after concentration under reduced pressure were purified by silica
gel column chromatography (hexane:ethyl acetate/4: 1) to obtain the
title compound (brown solid, 185 mg, 43%).
[4537] LCMS: m/z 473 [M+H].sup.+
[4538] HPLC retention time: 7.23 min (analysis condition B)
Example 723
[4539] Compound X3
6,6-Spiro-4-piperidine-N-paratoluenesulfonyl-8-methoxy-5,6-dihydro-benzo[b-
]carbazol-11-one
##STR00738##
[4541]
6,6-Spiro-4-piperidine-N-paratoluenesulfonyl-8-methoxy-5,6-dihydro--
5H-benzo[b]carbazole (Compound X2,400 mg, 0.848 mmol) and DDQ (770
mg, 4 eq.) were dissolved in THF (10 mL) and water (2 mL), and then
the mixture was stirred at 50.degree. C. for 5 hr. After cooling,
the reaction solution was added to saturated aqueous solution of
sodium hydrogen carbonate, extracted with ethyl acetate, washed
with saturated brine, and then dried over magnesium sulfate. The
residues obtained after concentration under reduced pressure were
purified by silica gel column chromatography (hexane: ethyl
acetate/3: 1) to give a solid, which was then washed with ethyl
ether to obtain the title compound (yellow solid, 86 mg, 21%).
[4542] .sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta.: 11.9 (1H, s),
8.22 (2H, m), 7.75 (2H, d), 7.60 (4H, m) 7.30 (2H, m), 7.11 (1H,
d), 3.81 (2H, m), 3.68 (3H, s), 3.62 (2H, m), 2.49 (3H, s), 2.21
(2H, m), 2.10 (2H, m),
[4543] LCMS: m/z 487 [M+H].sup.+
[4544] HPLC retention time: 6.05 min (analysis condition B)
Example 724
[4545] Compound X4
6,6-Spiro-4-piperidine-8-hydroxy-5,6-dihydro-benzo[b]carbazol-11-one
##STR00739##
[4547] Mixture of
6,6-spiro-4-piperidine-N-paratoluenesulfonyl-8-methoxy-5,6-dihydro-benzo[-
b]carbazol-11-one (Compound X3, 35 mg, 0.072 mmol) and pyridine
hydrochloride salt (800 mg) was stirred in a sealing tube at
160.degree. C. for 10 hr. After cooling, the reaction solution was
added to water, extracted with ethyl acetate, washed with saturated
brine, and then dried over magnesium sulfate. The residues obtained
after concentration under reduced pressure were purified by silica
gel column chromatography (dichloromethane:methanol/4: 1) to obtain
the title compound (yellow solid, 30 mg, 98%).
[4548] .sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta.: 8.20 (1H, m),
8.10 (1H, m), 7.53 (1H, m), 7.25 (3H, m), 6.80 (1H, m), 3.60 (2H,
m), 3.45 (2H, m), 2.52 (2H, m), 2.05 (2H, m).
[4549] LCMS: m/z 319 [M+H].sup.+
[4550] HPLC retention time: 2.86 min (analysis condition B)
Example 725
[4551] Compound X5
8-(2-Diethylaminoethoxy)-6,6-spiro-4-piperidine-8-hydroxy-5,6-dihydro-benz-
o[b]carbazol-11-one
##STR00740##
[4553]
6,6-Spiro-4-piperidine-8-hydroxy-5,6-dihydro-benzo[b]carbazol-11-on-
e (Compound X4, 30 mg, 0.094 mmol), diethylaminoethanol (22 mg, 2
eq.), triphenylphosphine (50 mg, 2 eq.) and DIAD (39 mg, 2 eq.)
were dissolved in THF (4 mL) and the mixture was stirred at room
temperature for 4 hr. The reaction solution was added to water,
extracted with ethyl acetate, washed with saturated brine, and then
dried over magnesium sulfate. The residues obtained after
concentration under reduced pressure were purified by silica gel
column chromatography (dichloromethane:methanol/4: 1) to obtain the
title compound (yellow oily substance, 6.8 mg, 17%).
[4554] LCMS: m/z 418 [M+H].sup.+
[4555] HPLC retention time: 2.75 min (analysis condition B)
Example 726
[4556] Compound Y2
2,3-Dichloro-8-methoxy-6,6-dimethyl-6,11-dihydro-5H-benzo[b]carbazole
##STR00741##
[4558] Under nitrogen atmosphere, the acetic acid (1 mL) suspension
of 7-methoxy-1,1-dimethyl-3,4-dihydro-1H-naphthalen-2-one (Compound
A2, 92.3 mg, 0.452 mmol) and (3,4-dichlorophenyl)hydrazine
hydrochloric acid salt (Compound Y1, 96.5 mg, 0.452 mmol) was
stirred at ambient temperature of 90.degree. C. for 3.5 hr. After
cooling to room temperature, the reaction mixture was added with
diethyl ether and water, and the resulting mixture was extracted
twice with diethyl ether. The organic layer was washed three times
with water, dried over sodium sulfate, and concentrated under
reduced pressure. The resulting crude product was purified by flash
column chromatography {Merck Kieselgel60, solution for elution:
hexane/ethyl acetate (4: 1)} to obtain the title compound (pale
yellow solid, 62.1 mg, 40%).
[4559] .sup.1H-NMR (270 MHz, CDCl.sub.3) .delta.: 7.92-7.84 (1H,
b), 7.62 (1H, s), 7.46 (1H, s), 7.05 (1H, d, 2.6), 6.84 (1H, dd,
8.6 Hz, 2.6 Hz), 4.01 (2H, s), 3.86 (3H, s), 1.67 (6H, s)
Example 727
[4560] Compound Y3
2,3-Dichloro-8-methoxy-6,6-dimethyl-5,6-dihydro-benzo[b]carbazol-11-one
##STR00742##
[4562] Under nitrogen atmosphere, to the 1,4-dioxane (1.7 mL)-water
(0.1 mL) solution of
2,3-dichloro-8-methoxy-6,6-dimethyl-6,11-dihydro-5H-benzo[b]carbazole
(Compound Y2, 61.0 mg, 0.176 mmol), DDQ (120 mg, 0.529 mmol) was
added and the mixture was stirred at room temperature for 16 hr and
15 min. The reaction mixture was purified by flash column
chromatography {Merck Kieselgel60, solution for elution:
hexane/ethyl acetate (2: 1)} to obtain the title compound (pale
orange solid, 16.7 mg, 26%).
[4563] .sup.1H-NMR (270 MHz, CDCl.sub.3) .delta.: 8.55 (1H, s),
8.42-8.36 (1H, b), 8.39 (1H, d, 8.6 Hz), 7.54 (1H, s), 7.08 (1H, d,
2.3 Hz), 7.03 (1H, dd, 8.6 Hz, 2.3 Hz), 3.93 (3H, s), 1.76 (6H,
s)
Example 728
[4564] Compound Y4
2,3-Dichloro-8-hydroxy-6,6-dimethyl-5,6-dihydro-benzo[b]carbazol-11-one
##STR00743##
[4566] Mixture of
2,3-dichloro-8-methoxy-6,6-dimethyl-5,6-dihydro-benzo[b]carbazol-11-one
(Compound Y3, 16.5 mg, 0.0457 mmol) and pyridinium chloride (0.2 g)
was stirred at ambient temperature of 160.degree. C. for 7 hr. The
reaction mixture was cooled to room temperature and added with
ethyl acetate and water. The mixture was extracted three times with
ethyl acetate. The organic layer was washed twice with water, dried
over sodium sulfate, and concentrated under reduced pressure. The
resulting crude product was used for the next step without further
purification (brown solid, 14.8 mg, 94%).
[4567] .sup.1H-NMR (270 MHz, CD.sub.3OD) .delta.: 8.34 (1H, s),
8.14 (1H, d, 8.6 Hz), 7.61 (1H, s), 7.10 (1H, d, 2.3 Hz), 6.89 (1H,
dd, 8.6 Hz, 2.3 Hz), 1.75 (1H, s)
Example 729
[4568] Compound Y5-1
8-[(1R,5R)-5-(Tert-butyldimethylsilanyloxymethyl)-2,2-dimethyl-[1,3]dioxol-
an-4-yl
methoxy]-2,3-dichloro-6,6-dimethyl-5,6-dihydro-benzo[b]carbazol-11-
-one
##STR00744##
[4570] Under nitrogen atmosphere, to the THF (0.3 mL) solution of
2,3-dichloro-8-hydroxy-6,6-dimethyl-5,6-dihydro-benzo[b]carbazol-11-one
(Compound Y4, 12.9 mg, 0.0373 mmol),
(4S,5R)-5-(tert-butyldimethylsilanyloxymethyl)-2,2-dimethyl-[1,3]dioxolan-
-4-ol (15.5 mg, 0.0559 mmol) and triphenylphosphine (14.7 mg,
0.0559 mmol), toluene solution (25.4 .mu.L, 0.0559 mmol) of DEAD
was added dropwise at room temperature. The reaction mixture was
stirred at ambient temperature of 40.degree. C. for 4 hr. After
cooling to room temperature, the reaction mixture was concentrated
under reduced pressure, and the resulting crude product was
purified by preparative TLC (Merck 60 F254, 0.5 mm) {solution for
elution: hexane/ethyl acetate (3: 1)} to obtain the title compound
(white solid, 15.1 mg, 67%).
[4571] .sup.1H-NMR (270 MHz, CDCl.sub.3) .delta.: 8.55 (1H, s),
8.44-8.37 (1H, b), 8.37 (1H, d, 8.6 Hz), 7.54 (1H, s), 7.15 (1H, d,
2.6 Hz), 7.03 (1H, dd, 8.6 Hz, 2.6 Hz), 4.41-4.26 (2H, m),
4.25-4.15 (1H, m), 4.06-3.86 (2H, m), 3.83-3.73 (1H, m), 1.76 (3H,
s), 1.75 (3H, s), 1.48 (3H, s), 1.47 (3H, s), 0.90 (9H, s), 0.092
(6H, s)
Example 730
[4572] Compound Y5-2
2,3-Dichloro-6,6-dimethyl-8-((3R,4R)-2,3,4-trihydroxy-butoxy)-5,6-dihydro--
benzo[b]carbazol-11-one
##STR00745##
[4574] Under nitrogen atmosphere, to the THF (0.2 mL)-MeOH (0.1 mL)
solution of
8-[(1R,5R)-5-(tert-butyldimethyl-silanyloxymethyl)-2,2-dimethyl-[1,3]diox-
olan-4-yl
methoxy]-2,3-dichloro-6,6-dimethyl-5,6-dihydro-benzo[b]carbazol--
11-one (Compound Y5-1, 14.6 mg, 0.0242 mmol), 0.5 M aqueous
solution of sulfuric acid (96.6 .mu.L, 0.0483 mmol) was added at
room temperature. The reaction mixture was stirred at ambient
temperature of 55.degree. C. for 3 hr, cooled to room temperature,
and then added with diethyl ether and sodium hydrogen carbonate (10
mg) in order. The mixture was extracted twice with diethyl ether,
and the organic layer was washed with water and brine, dried over
sodium sulfate, and concentrated under reduced pressure. The
resulting crude product was washed with dichloromethane, and dried
under reduced pressure to obtain the title compound (white solid,
8.3 mg, 76%).
[4575] .sup.1H-NMR (270 MHz, CD.sub.3OD) .delta.: 8.35 (1H, s),
8.24 (1H, d, 8.9 Hz), 7.62 (1H, s), 7.31 (1H, d, 2.3 Hz), 7.10 (1H,
dd, 8.9 Hz, 2.3 Hz), 4.31-4.23 (1H, m), 4.12-4.12 (1H, m),
4.11-4.02 (1H, m), 3.84-3.74 (1H, m), 3.73-3.61 (1H, m), 1.78 (6H,
s)
[4576] LCMS: m/z 450 [M+H].sup.+
[4577] HPLC retention time: 4.92 min (analysis condition H)
Example 731
[4578] Compound Z3
2-[1-(2-Bromo-5-methoxy-phenyl)-1-methylethyl]-benzo[b]thiophene
##STR00746##
[4580] 2-(2-Bromo-5-methoxyphenyl)-2-methyl-propinoic acid (1.5 g,
5.5 mmol) was dissolved in methylene chloride (15 mL), added with
oxalyl chloride (1.5 mL) and dimethylformamide (2 micro liter) at
room temperature, and the mixture was stirred at room temperature
for 30 min. After removing the solvent, the residues were dissolved
in toluene, added at room temperature with
2-[(triphenyl-5-phosphanyl)-methyl]-benzenethiol hydrobromide (2.56
g, 5.5 mmol) and triethylamine (2.27 mL), and then the mixture was
refluxed under heating for 30 min. Thereafter, the mixture was
cooled to 0.degree. C., added with lithium hexamethyldisilazide (1
M tetrahydrofuran solution, 5.5 mL), and refluxed under heating for
24 hr. The reaction mixture was extracted with ethyl acetate and
washed with water. The organic layer was dried over magnesium
sulfate. The residues obtained after concentration under reduced
pressure were purified by silica gel column chromatography (ethyl
acetate/hexane) to obtain the title compound (0.55 g, 28%).
[4581] .sup.1H-NMR (270 MHz, CDCl.sub.3) .delta.: 6.61 (1H, s),
3.37 (3H, s), 1.83 (6H, s)
Example 732
[4582] Compound Z4
2-(1-Benzo[b]thiophen-2-yl-1-methyl-ethyl)-4-methoxy-benzoic
acid
##STR00747##
[4584]
2-[1-(2-Bromo-5-methoxy-phenyl)-1-methylethyl]-benzo[b]thiophene
(Compound Z3, 40 mg, 0.11 mmol) was dissolved in tetrahydrofuran
(0.5 mL), cooled to -78.degree. C., added with n-butyl lithium
(1.57 M, hexane solution, 0.07 mL), and the mixture was stirred for
10 min. The reaction mixture was added with dry ice and then
maintained for 1 hr. After that, the mixture was added with 0.5 N
hydrochloric acid, extracted with ethyl acetate and washed with
water. The organic layer was dried over magnesium sulfate. The
residues obtained after concentration under reduced pressure were
purified by silica gel column chromatography (ethyl acetate/hexane)
to obtain the title compound (22 mg, 55%).
[4585] .sup.1H-NMR (270 MHz, CDCl.sub.3) .delta.: 7.46 (1H, d),
7.44 (1H, d), 6.92 (s, 1H), 6.70 (d, 1H), 3.84 (s, 3H), 1.89 (6H,
s)
Example 733
[4586] Compound Z5
8-Methoxy-6,6-dimethyl-6H-benzo[b]naphth[2,3-d]thiophen-11-one
##STR00748##
[4588] To
2-(1-benzo[b]thiophen-2-yl-1-methylethyl)-4-methoxy-benzoic acid
(Compound Z4, 68 mg, 0.22 mmol), polyphosphoric acid (3.5 g) was
added, and the mixture was stirred for 1 hr at 100.degree. C. under
heating. The mixture was added with water, extracted with ethyl
acetate and washed with water. The organic layer was dried over
magnesium sulfate. The residues obtained after concentration under
reduced pressure were purified by silica gel column chromatography
(ethyl acetate/hexane) to obtain the title compound (41 mg,
63%).
[4589] LCMS: m/z 309 [M+H].sup.+
[4590] HPLC retention time: 2.89 min (analysis condition C)
Example 734
[4591] Compound Z6
8-Hydroxy-6,6-dimethyl-6H-benzo[b]naphth[2,3-d]thiophen-11-one
##STR00749##
[4593] Under the same conditions as Compound A6, the title compound
was prepared from Compound Z5.
[4594] LCMS: m/z 295 [M+H].sup.+
[4595] HPLC retention time: 2.91 min (analysis condition F)
Example 735
[4596] Compound Z7
8-(2-Diethylamino-ethoxy)-6,6-dimethyl-6H-benzo[b]naphth[2,3-d]thiophen-11-
-one
##STR00750##
[4598] According to the same method as the method for synthesizing
Compound A7-17, the title compound was prepared from Compound
Z6.
[4599] LCMS: m/z 394 [M+H].sup.+
[4600] HPLC retention time: 5.06 min (analysis condition F)
Example 736
[4601] Compound Z9
2-Bromo-1,3-dihydroxytetrahydropyranbenzene
##STR00751##
[4603] To 4-bromo-benzene-1,3-diol (Compound Z8, 20 g, 105.8 mmol)
and 3,4-dihydro-2H-pyran (38.6 mL), pyridium paratoluenesulfonate
(266 mg) was added, and the mixture was stirred at 50.degree. C.
for 1 hr. The residues obtained after concentration under reduced
pressure were purified by silica gel column chromatography (ethyl
acetate/hexane) to obtain the title compound (31.82 mg, 84%).
[4604] LCMS: m/z 358 [M+H].sup.+
[4605] HPLC retention time: 3.15 min (analysis condition C)
Example 737
[4606] Compound Z10
3-(2,4-Dihydroxy-phenyl)-7-methoxy-1,1-dimethyl-3,4-dihydro-1H-naphthalen--
2-one
##STR00752##
[4608] To 7-methoxy-1,1-dimethyl-3,4-dihydro-1H-naphthalen-2-one
(Compound A2, 10 g), 2-bromo-1,3-dihydroxytetrahydropyranbenzene
(Compound Z9, 20.98 g), sodium t-butoxide (5.88 g), palladium
acetate (550 mg) and tri-t-butylphosphonium tetrafluoroborate (710
mg), toluene (40 mL) was added and the mixture was stirred and
heated at 70.degree. C. under nitrogen atmosphere for 6 hr. After
cooling, the reaction mixture was added with methanol (38 mL) and
trifluoroacetic acid (14.54 mL) at room temperature, and then
stirred at room temperature overnight. To the resulting residues,
methylene chloride and saturated dipotassium hydrogen phosphate
were added and the organic layer was washed with saturated brine.
Thereafter, the organic layer was dried over magnesium sulfate. The
residues obtained after concentration under reduced pressure were
purified by silica gel column chromatography (ethyl acetate/hexane)
to obtain the title compound (5.53 g, 36%).
[4609] LCMS: m/z 312 [M+H].sup.+
[4610] HPLC retention time: 2.39 min (analysis condition F)
Example 738
[4611] Compound Z11
Trifluoromethanesulfonic acid
8-methoxy-6,6-dimethyl-6,11-dihydro-benzo[b]naphth[2,3-d]furan-3-yl
ester
##STR00753##
[4613]
3-(2,4-Dihydroxy-phenyl)-7-methoxy-1,1-dimethyl-3,4-dihydro-TH-naph-
thalen-2-one (Compound Z10, 5.53 g) was dissolved in methylene
chloride (40 mL), and added with trifluoromethanesulfonic anhydride
(2.98 mL) at room temperature. After cooling to 5.degree. C.,
diisopropylethylamine (9.25 mL) and trifluoromethanesulfonic
anhydride (4.47 mL) were added thereto. To the reaction mixture,
methylene chloride and saturated dipotassium hydrogen phosphate
were added and the organic layer was washed with saturated brine.
Thereafter, the organic layer was dried over magnesium sulfate. The
residues obtained after concentration under reduced pressure were
purified by silica gel column chromatography (ethyl acetate/hexane)
to obtain the title compound (4.82 g, 64%).
[4614] LCMS: m/z 427 [M+H].sup.+
[4615] HPLC retention time: 8.95 min (analysis condition H)
Example 739
[4616] Compound Z12
Trifluoromethanesulfonic acid
8-methoxy-6,6-dimethyl-11-oxo-6,11-dihydro-benzo[b]naphth[2,3-d]furan-3-y-
l ester
##STR00754##
[4618] Trifluoromethanesulfonic acid
8-methoxy-6,6-dimethyl-6,11-dihydro-benzo[b]naphth[2,3-d]furan-3-yl
ester (Compound Z11, 4.82 g) was dissolved in acetonitrile (48 mL)
and water (24 mL), added with sodium chlorite (2.55 g) and
N-hydroxyphthalimide (369 mg), and then the mixture was stirred at
40.degree. C. for 1 hr. The reaction mixture was added with
methylene chloride and the organic layer was washed with saturated
brine. Thereafter, the organic layer was dried over magnesium
sulfate. The residues obtained after concentration under reduced
pressure were purified by silica gel column chromatography (ethyl
acetate/hexane) to obtain the title compound (2.80 g, 56%).
[4619] LCMS: m/z 441 [M+H].sup.+
[4620] HPLC retention time: 8.02 min (analysis condition H)
Example 740
[4621] Compound Z13
Trifluoromethanesulfonic acid
8-hydroxy-6,6-dimethyl-11-oxo-6,11-dihydro-benzo[b]naphth[2,3-d]furan-3-y-
l ester
##STR00755##
[4623] Under the same conditions as Compound A6, the title compound
was prepared as a crude product from Compound Z12.
Example 741
[4624] Compound Z14
Trifluoro-methanesulfonic acid
8-[(4R,5R)-5-(tert-butyl-dimethyl-silanyloxymethyl)-2,2-dimethyl-[1,3]dio-
xolan-4-yl methoxy]-6,6
dimethyl-11-oxo-6,11-dihydro-benzo[b]naphth[2,3-d]furan-3-yl
ester
##STR00756##
[4626] Under the same conditions as the method for synthesizing
Compound A7-1, the title compound was obtained as a crude product
from Compound Z13 and
[5-(tert-butyldimethylsilanyloxymethyl)-2,2-dimethyl-[1,3]dioxola-
n-4-yl]-methanol (Compound T22-0).
Example 742
[4627] Compound Z15
8-[(4R,5R)-5-(Tert-butyl-dimethyl-silanyloxymethyl)-2,2-dimethyl-[1,3]diox-
olan-4-yl
methoxy]-6,6-dimethyl-11-oxo-6,11-dihydro-benzo[b]naphth[2,3-d]f-
urane-3-carbonitrile
##STR00757##
[4629] Trifluoro-methanesulfonic acid
8-[(4R,5R)-5-(tert-butyl-dimethyl-silanyloxymethyl)-2,2-dimethyl-[1,3]dio-
xolan-4-yl methoxy]-6,6
dimethyl-11-oxo-6,11-dihydro-benzo[b]naphth[2,3-d]furan-3-yl ester
(Compound Z14, 24 mg) was dissolved in DMF (0.5 mL), added with
zinc (II) cyanide (8.2 mg) and palladium tetrakistriphenylphosphine
(2.0 mg), and the mixture was stirred under heating at 200.degree.
C. for 20 min with microwave irradiation. To the reaction mixture,
ethyl acetate was added and the organic layer was washed with
saturated brine. Thereafter, the organic layer was dried over
magnesium sulfate. The residues obtained after concentration under
reduced pressure were purified by silica gel column chromatography
(ethyl acetate/hexane) to obtain the title compound (15 mg).
[4630] LCMS: m/z 562 [M+H].sup.+
[4631] HPLC retention time: 4.14 min (analysis condition F)
Example 743
[4632] Compound Z16
6,6-Dimethyl-11-oxo-8-((2R,3R)-2,3,4-trihydroxy-butoxy)-6,11-dihydro-benzo-
[b]naphth[2,3-d]furane-3-carbonitrile
##STR00758##
[4634] Under the same conditions as Compound S7-2, the title
compound was prepared from Compound Z15.
[4635] LCMS: m/z 408 [M+H].sup.+
[4636] HPLC retention time: 4.51 min (analysis condition H)
Example 744
[4637] Compound K7-5
4-(3-Cyano-9-methoxy-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol--
8-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl
ester
##STR00759##
[4639] Under the same conditions as the method for synthesizing
Compound B2-22-1, the title compound was prepared from Compound K6
and
4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine--
1-carboxylic acid tert-butyl ester.
[4640] LCMS: m/z 498 [M+H].sup.+
[4641] HPLC retention time: 4.24 min (analysis condition W)
Example 745
[4642] Compound K7-6
9-Methoxy-6,6-dimethyl-11-oxo-8-(1,2,3,6-tetrahydro-pyridin-4-yl)-6,11-dih-
ydro-5H-benzo[b]carbazole-3-carbonitrile
##STR00760##
[4644] Under the same conditions as the method for synthesizing
Compound A8-1, the title compound was prepared from K7-5.
[4645] LCMS: m/z 398 [M+H].sup.+
[4646] HPLC retention time: 2.57 min (analysis condition W)
Example 746
[4647] Compound K8-1
8-(1-Cyclobutyl-1,2,3,6-tetrahydro-pyridin-4-yl)-9-methoxy-6,6-dimethyl-11-
-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile
##STR00761##
[4649] Under the same conditions as the method for synthesizing
Compound B3-32, the title compound was prepared from Compound K7-6
and cyclobutanone.
[4650] LCMS: m/z 452 [M+H].sup.+
[4651] HPLC retention time: 2.72 min (analysis condition W)
Example 747
[4652] Compound K8-2
8-(1-Cyclobutyl-piperidin-4-yl)-9-methoxy-6,6-dimethyl-11-oxo-6,11-dihydro-
-5H-benzo[b]carbazole-3-carbonitrile
##STR00762##
[4654] Under the same conditions as the method for synthesizing
Compound B3-13-1, the title compound was prepared from Compound
K8-1.
[4655] LCMS: m/z 454 [M+H].sup.+
[4656] HPLC retention time: 2.76 min (analysis condition W)
Example 748
[4657] Compound K9-5
8-(1-Cyclobutyl-piperidin-4-yl)-9-hydroxy-6,6-dimethyl-11-oxo-6,11-dihydro-
-5H-benzo[b]carbazole-3-carbonitrile
##STR00763##
[4659] Under the same conditions as the method for synthesizing
Compound E3-2, the title compound was prepared from Compound
K8-2.
[4660] LCMS: m/z 440 [M+H].sup.+
[4661] HPLC retention time: 2.57 min (analysis condition W)
Example 749
[4662] Compound K10-8
8-(1-Cyclobutyl-piperidin-4-yl)-9-isopropoxy-6,6-dimethyl-11-oxo-6,11-dihy-
dro-5H-benzo[b]carbazole-3-carbonitrile
##STR00764##
[4664] Under the same conditions as the method for synthesizing
Compound A7-17, the title compound was prepared from Compound K9-5
and isopropyl iodide.
[4665] LCMS: m/z 482 [M+H].sup.+
[4666] HPLC retention time: 1.74 min (analysis condition S)
[4667] The compounds described in the following Tables 2-3 were
synthesized from the intermediates of Compound K or Compound L by
alkylation of hydroxyl group according to Mitsunobu reaction used
for preparing Compound A7-1 or the method used for the synthesis of
Compound A7-17 (described in the Table).
TABLE-US-00002 TABLE 2 Exam- HPLC Reten- ple Comp. Condi- tion No.
No. Structure Compound Name tion Time m/z Method 750 K10-9
##STR00765## 6,6-Dimethyl-8-(4- morpholin-4-yl- piperidin-1-yl)-11-
oxo-9-(tetrahydro- pyran-4-yloxy)- 6,11-dihydro-5H-
benzo[b]carbazole- 3-carbonitrile U 1.85 555 A7-1 751 K10-10
##STR00766## 9-(2-Methoxy- ethoxy)-5-(2- methoxy-ethyl)-
6,6-dimethyl-8-(4- morpholin-4-yl- piperidin-1-yl)-11-
oxo-6,11-dihydro- 5H- benzo[b]carbazole- 3-carbonitrile S 1.50 587
A7-17 752 K10-11 ##STR00767## 9-(2-Methoxy- ethoxy)-6,6-
dimethyl-8-(4- morpholin-4-yl- piperidin-1-yl)-11-
oxo-6,11-dihydro- 5H- benzo[b]carbazole- 3-carbonitrile S 1.37 529
A7-17 753 K10-12 ##STR00768## 9-Ethoxy-6,6- dimethyl-8-(4-
morpholin-4-yl- piperidin-1-yl)-11- oxo-6,11-dihydro- 5H-
benzo[b]carbazole- 3-carbonitrile U 1.95 499 A7-17 754 K10-13
##STR00769## 6,6-Dimethyl-8-(4- morpholin-4-yl- piperidin-1-yl)-11-
oxo-9-(tetrahydro- furan-3-yloxy)- 6,11-dihydro-5H-
benzo[b]carbazole- 3-carbonitrile S 1.40 541 A7-1 755 K10-14
##STR00770## 9-(2-Diethylamino- ethoxy)-6,6- dimethyl-8-(4-
morpholin-4-yl- piperidin-1-yl)-11- oxo-6,11-dihydro- 5H-
benzo[b]carbazole- 3-carbonitrile S 1.13 570 A7-17 756 K10-15
##STR00771## 8-(4-Cyclobutyl- piperazin-1-yl)-9- (2-methoxy-
ethoxy)-6,6- dimethyl-11-oxo- 6,11-dihydro-5H- benzo[b]carbazole-
3-carbonitrile S 1.45 499 A7-17 757 K10-16 ##STR00772##
8-(4-Cyclobutyl- piperazin-1-yl)- 5,6,6-trimethyl-11-
oxo-9-(tetrahydro- furan-3-yloxy)- 6,11-dihydro-5H-
benzo[b]carbazole- 3-carbonitrile S 1.98 525 A7-1 758 K10-17
##STR00773## 8-(4-Cyclobutyl- piperazin-1-yl)-9- (1-ethyl-propoxy)-
5,6,6-trimethyl-11- oxo-6,11-dihydro- 5H-benzo[b]carbazole-
3-carbonitrile S 2.43 525 A7-1 759 K10-18 ##STR00774##
8-(4-Cyclobutyl- piperazin-1-yl)-6,6- dimethyl-11-oxo-9-
(tetrahydro-furan- 3-yloxy)-6,11- dihydro-5H- benzo[b]carbazole-
3-carbonitrile S 1.92 511 A7-1 760 K10-19 ##STR00775##
8-(4-Cyclobutyl- piperazin-1-yl)-6,6- dimethyl-11-oxo-9-
(tetrahydro-pyran- 4-yloxy)-6,11- dihydro-5H- benzo[b]carbazole-
3-carbonitrile U 1.97 525 A7-1 761 K10-20 ##STR00776##
8-(4-Cyclobutyl- piperazin-1-yl)-9- (1-ethyl-propoxy)-
6,6-dimethyl-11- oxo-6,11-dihydro- 5H- benzo[b]carbazole-
3-carbonitrile S 1.82 511 A7-1 762 L10-3 ##STR00777##
9-Isopropoxy-8-(2- methoxy-ethoxy)- 5-(2-methoxy- ethyl)-6,6-
dimethyl-11-oxo- 6,11-dihydro-5H- benzo[b]carbazole- 3-carbonitrile
S 2.68 477 A7-17 763 L10-4 ##STR00778## 9-Isopropoxy-8-(2-
methoxy-ethoxy)- 6,6-dimethyl-11- oxo-6,11-dihydro- 5H-
benzo[b]carbazole- 3-carbonitrile S 2.68 419 A7-17
TABLE-US-00003 TABLE 3 Exam- HPLC Reten- ple Comp. Condi- tion No.
No. Structure Compound Name tion Time m/z Method 764 L10-5
##STR00779## 8-(1-Cyclobutyl- piperidin-4- ylmethoxy)-9-
isopropoxy-6,6- dimethyl-11-oxo- 6,11-dihydro-5H-
benzo[b]carbazole- 3-carbonitrile S 1.65 512 A7-1 765 L10-6
##STR00780## 9-Isopropoxy-8-(1- isopropyl-piperidin-
4-ylmethoxy)-6,6- dimethyl-11-oxo- 6,11-dihydro-5H-
benzo[b]carbazole- 3-carbonitrile S 1.62 500 A7-1 766 L10-7
##STR00781## 8-(1-Cyclobutyl- piperidin-3-yloxy)- 9-isopropoxy-6,6-
dimethyl-11-oxo- 6,11-dihydro-5H- benzo[b]carbazole- 3-carbonitrile
S 1.65 498 A7-1 767 L10-8 ##STR00782## 9-Isopropoxy-8-(1-
isopropyl-piperidin- 3-yloxy)-6,6- dimethyl-11-oxo-
6,11-dihydro-5H- benzo[b]carbazole- 3-carbonitrile S 1.59 486 A7-1
768 L10-9 ##STR00783## 8-(2-Diethylamino- ethoxy)-9-
isopropoxy-6,6- dimethyl-11-oxo- 6,11-dihydro-5H-
benzo[b]carbazole- 3-carbonitrile U 2.07 460 A7-17 769 L10-10
##STR00784## 9-Isopropoxy-6,6- dimethyl-11-oxo-8-
(pyridin-4-yloxy)- 6,11-dihydro-5H- benzo[b]carbazole-
3-carbonitrile U 2.07 438 A7-17 770 L10-11 ##STR00785##
9-Isopropoxy-6,6- dimethyl-11-oxo-8- vinyloxy-6,11- dihydro-5H-
benzo[b]carbazole- 3-carbonitrile U 2.77 387 A7-17 771 L10-12
##STR00786## 9-Isopropoxy-6,6- dimethyl-11-oxo-8-
(tetrahydro-furan- 3-yloxy)-6,11- dihydro-5H- benzo[b]carbazole-
3-carbonitrile S 2.45 431 A7-1
[4668] The compounds described in the following Table 4 were
synthesized from the intermediates of Compound B according to the
method described in the Table.
TABLE-US-00004 TABLE 4 Exam- HPLC Reten- ple Comp. Condi- tion No.
No. Structure Compound Name tion Time m/z Method 772 B3-39
##STR00787## 8-((3R,5S)-4- Cyclobutyl-3,5- dimethyl-piperazin-1-
yl)-6,6-dimethyl-11- oxo-6,11-dihydro-5H- benzo[b]carbazole-3-
carbonitrile U 1.90 453 B3-32 773 B3-40 ##STR00788##
8-((3R,5S)-4-Ethyl- 3,5-dimethyl-piperazin- 1-yl)-6,6-dimethyl-11-
oxo-6,11-dihydro-5H- benzo[b]carbazole-3- carbonitrile U 1.82 427
B3-32 774 B2-30 ##STR00789## 6,6-Dimethyl-8-[4-(1-
methyl-piperidin-4-yl)- piperazin-1-yl]-11-oxo- 6,11-dihydro-5H-
benzo[b]carbazole-3- carbonitrile U 1.58 468 B2-1 775 B3-41
##STR00790## 8-(4- Cyclobutanecarbonyl- piperazin-1-yl)-6,6-
dimethyl-11-oxo-6,11- dihydro-5H- benzo[b]carbazole-3- carbonitrile
U 2.35 453 A9-10 776 B3-42 ##STR00791## 8-(4- Cyclopropanecarbonyl-
piperazin-1-yl)-6,6- dimethyl-11-oxo-6,11- dihydro-5H-
benzo[b]carbazole-3- carbonitrile U 2.22 439 A9-10
Example 777
[4669] Compound E6-4
9-Ethyl-8-hydroxy-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3--
carbonitrile
##STR00792##
[4671] Under the same conditions as the method for synthesizing
Compound E3-2, the title compound was prepared from Compound
E5-1.
[4672] LCMS: m/z 331 [M+H].sup.+
[4673] HPLC retention time: 3.42 min (analysis condition W)
Example 778
[4674] Compound E7
Trifuloro-methanesulfonic acid
3-cyano-9-ethyl-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yl
ester
##STR00793##
[4676] Under the same conditions as the method for synthesizing
Compound B1, the title compound was prepared from Compound
E6-4.
[4677] LCMS: m/z 463 [M+H].sup.+
[4678] HPLC retention time: 4.39 min (analysis condition W)
Example 779
[4679] Compound E8-1
9-Ethyl-6,6-dimethyl-11-oxo-8-piperazin-1-yl-6,11-dihydro-5H-benzo[b]carba-
zole-3-carbonitrile
##STR00794##
[4681] The title compound was prepared from Compound E7 and
piperazine in the same manner as the method for synthesizing
Compound B2-1.
[4682] LCMS: m/z 399 [M+H].sup.+
[4683] HPLC retention time: 1.88 min (analysis condition U)
[4684] Compound E8-2
9-Ethyl-6,6-dimethyl-8-((S)-3-methyl-piperazin-1-yl)-11-oxo-6,11-dihydro-5-
H-benzo[b]carbazole-3-carbonitrile
##STR00795##
[4686] Under the same conditions as the method for synthesizing
Compound B2-1, the title compound was prepared from Compound E7 and
2-(S)-methylpiperazine.
[4687] LCMS: m/z 413 [M+H].sup.+
[4688] HPLC retention time: 2.76 min (analysis condition W)
Example 781
[4689] Compound E8-3
8-((3R,5S)-3,5-Dimethyl-piperazin-1-yl)-9-ethyl-6,6-dimethyl-11-oxo-6,11-d-
ihydro-5H-benzo[b]carbazole-3-carbonitrile
##STR00796##
[4691] Under the same conditions as the method for synthesizing
Compound B2-1, the title compound was prepared from Compound E7 and
cis-2,6-dimethylpiperazine.
[4692] LCMS: m/z 427 [M+H].sup.+
[4693] HPLC retention time: 2.00 min (analysis condition U)
Example 782
[4694] Compound E8-4
8-(1-Cyclobutyl-1,2,3,6-tetrahydro-pyridin-4-yl)-9-ethyl-6,6-dimethyl-11-o-
xo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile
[4695] Compound 7 was converted in the same manner as Compound
B2-22-1 and Compound 2, and subsequently subjected to reductive
amination in the same manner as Compound B3-32 to obtain the title
compound.
##STR00797##
[4696] LCMS: m/z 450 [M+H].sup.+
[4697] HPLC retention time: 2.12 min (analysis condition U)
Example 783
[4698] Compound E9-1
8-((S)-4-Cyclobutyl-3-methyl-piperazin-1-yl)-9-ethyl-6,6-dimethyl-11-oxo-6-
,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile
##STR00798##
[4700] Under the same conditions as the method for synthesizing
Compound B3-32, the title compound was prepared from Compound E8-2
and cyclobutanone.
[4701] LCMS: m/z 467 [M+H].sup.+
[4702] HPLC retention time: 2.90 min (analysis condition W)
[4703] The compounds described in the following Table 5 were
prepared by acylation from Compound E8-1 in the same manner as the
method for synthesizing Compound A9-10.
TABLE-US-00005 TABLE 5 Reten- Example Comp. HPLC tion m/z No. No.
Structure Compound Name Condition Time 784 E9-2 ##STR00799## 8-(4-
Cyclopropanecarbonyl- piperazin-1-yl)-9-ethyl- 6,6-dimethyl-11-oxo-
6,11-dihydro-5H- benzo[b]carbazole-3- carbonitrile U 2.58 467 785
E9-3 ##STR00800## 8-(4- Cyclobutanecarbonyl-
piperazin-1-yl)-9-ethyl- 6,6-dimethyl-11-oxo- 6,11-dihydro-5H-
benzo[b]carbazole-3- carbonitrile U 2.74 481 786 E9-4 ##STR00801##
8-[4-(2- Dimethylamino-acetyl)- piperazin-1-yl]-9-ethyl-
6,6-dimethyl-11-oxo- 6,11-dihydro-5H- benzo[b]carbazole-3-
carbonitrile U 1.98 484 787 E9-5 ##STR00802##
9-Ethyl-8-(4-isobutyryl- piperazin-1-yl)-6,6- dimethyl-11-oxo-6,11-
dihydro-5H- benzo[b]carbazole-3- carbonitrile U 2.67 469 788 E9-6
##STR00803## 8-(4-Acetyl-piperazin- 1-yl)-9-ethyl-6,6-
dimethyl-11-oxo-6,11- dihydro-5H- benzo[b]carbazole-3- carbonitrile
U 2.35 441 789 E9-7 ##STR00804## 8-(4- Cyclopentanecarbonyl-
piperazin-1-yl)-9-ethyl- 6,6-dimethyl-11-oxo- 6,11-dihydro-5H-
benzo[b]carbazole-3- carbonitrile S 2.87 495 790 E9-8 ##STR00805##
8-(4- Cyclohexanecarbonyl- piperazin-1-yl)-9-ethyl-
6,6-dimethyl-11-oxo- 6,11-dihydro-5H- benzo[b]carbazole-3-
carbonitrile S 2.97 509
Example 791
[4704] Compound E9-9
8-[4-(1-Cyano-cyclohexyl)-piperazin-1-yl]-9-ethyl-6,6-dimethyl-11-oxo-6,11-
-dihydro-5H-benzo[b]carbazole-3-carbonitrile
##STR00806##
[4706]
9-Ethyl-6,6-dimethyl-11-oxo-8-piperazin-1-yl-6,11-dihydro-5H-benzo[-
b]carbazole-3-carbonitrile (45 mg) and cyclohexanone (25 mg) were
suspended in chloroform (2 ml), added with trimethylsilyl cyanide
(30 mg) and zinc iodide (5 mg), and the mixture was stirred at
60.degree. C. for 17 hrs. The reaction mixture was diluted with
ethyl acetate (20 ml) and the organic layer was washed with 1000
brine solution and concentrated under reduced pressure. The
resulting residues were purified by silica gel column
(dichloromethane/methanol (=99/1)) to obtain the title compound (12
mg, yield 30%).
[4707] LCMS: m/z 506 [M+H].sup.+
[4708] HPLC retention time: 3.00 min (analysis condition U)
[4709] The compounds described in the following Table 6 were
synthesized from Compound E8-1 or Compound PR10-1 in the same
manner as the method for Compound E9-9.
TABLE-US-00006 TABLE 6 Example Comp. HPLC Retention No. No.
Structure Compound Name Condition Time m/z 792 E9-10 ##STR00807##
8-[4-(1-Cyano- cyclobutyl)-piperazin- 1-yl]-9-ethyl-6,6-
dimethyl-11-oxo- 6,11-dihydro-5H- benzo[b]carbazole-3- carbonitrile
U 2.88 478 793 PR11-20 ##STR00808## 8-(4-Cyano-4-
hydroxy-piperazin-1- yl)-9-ethyl-6,6- dimethyl-11-oxo-
6,11-dihydro-5H- benzo[b]carbazole-3- carbonitrile Y 3.05 439 794
PR11-21 ##STR00809## 8-(4-Cyano-4- morpholine-4-yl-
piperidine-1-yl)-9- ethyl-6,6-dimethyl- 11-oxo-6,11-dihydro-
5H-benzo[b]carbazole- 3-carbonitrile Y 3.35 508
[4710] With respect to the compounds described in the following
Table 7, Compound F2 was subjected to amination in the same manner
as Compound B2-1. Subsequently, the preparation was carried out by
reductive amination in the same manner as the method for Compound
B3-32.
TABLE-US-00007 TABLE 7 Exam- HPLC Reten- ple Comp. Condi- tion No.
No. Structure Compound Name tion Time m/z Method 795 F3-12
##STR00810## 9-Bromo-8-((3R,5S)- 3,5-dimethyl- piperazin-1-yl)-6,6-
dimethyl-11-oxo-6,11- dihydro-5H- benzo[b]carbazole-3- carbonitrile
U 2.05 477, 479 B2-1 796 F4-11 ##STR00811## 9-Bromo-8-((3R,5S)-
4-cyclobutyl-3,5- dimethyl-piperazin-1- yl)-6,6-dimethyl-11-
oxo-6,11-dihydro-5H- benzo[b]carbazole-3- carbonitrile U 2.28 531,
533 B3-32
Example 797
[4711] Compound PR1
2-(4-Vinylphenyl)-2-methylpropanoic acid
##STR00812##
[4713] 2-(4-Bromophenyl)-2-methylpropanoic acid (30 g), PPh.sub.3
(5.0 g), potassium vinyltrifluoroborate (24.8 g), potassium
carbonate (51.2 g), and palladium acetate (1.43 g) were dissolved
in 1-propanol (198 ml) and distilled water (99 ml). After
deaeration, the mixture was stirred under reflux for 6 hrs under
nitrogen atmosphere. Insoluble matters were removed by filtration
and washed with 1-propanol (210 ml). The filtrate was then
concentrated under reduced pressure. Concentrated residues were
partitioned between CPME (300 ml) and distilled water (150 ml,
comprising 4.17 ml of ethylenediamine). The organic layer was
removed and the aqueous layer was adjusted to pH 5 by using 2 N
hydrochloric acid. The aqueous layer was extracted with a mixture
of isopropyl acetate (240 ml) and heptane (240 ml). The organic
layer was dried over anhydrous sodium sulfate and concentrated
under reduced pressure. Ethanol (300 ml) was added thereto for
suspending and washing the resultant. The solid was removed by
Celite filtration, and the filtrate was concentrated under reduced
pressure to obtain the title compound (21.7 g, 93%).
[4714] .sup.1H-NMR (400 MHz CDCl.sub.3) .delta. ppm 7.49-7.34 (4H,
m), 6.69 (1H, dd, J=17.6, 11.0 Hz), 5.72 (1H, d, J=17.6 Hz), 5.23
(1H, d, 11.0 Hz), 1.59 (s, 6H)
[4715] HPLC retention time: 2.05 min (analysis condition S)
Example 798
[4716] Compound PR2
2-(4-Ethylphenyl)-2-methylpropanoic acid
##STR00813##
[4718] 2-(4-Vinylphenyl)-2-methylpropanoic acid (58 g) was
dissolved in ethanol, and then stirred for 3 hrs under atmospheric
hydrogen pressure in the presence of 10% palladium carbon (5.8 g).
The catalyst was removed by filtration, and the filtrate was
concentrated to obtain a crude product, which was then suspended
and washed with hexane to give the title compound (56.5 g,
94.8%).
[4719] .sup.1H-NMR (270 MHz DMSO-d.sub.6) .delta. ppm 12.28 (1H,
s), 7.27-7.22 (2H, m), 7.18-7.14 (2H, m), 2.56 (2H, q, J=7.6 Hz),
1.45 (6H, s), 1.16 (3H, t, J=7.6 Hz)
[4720] LCMS: m/z 193 [M+H].sup.+
[4721] HPLC retention time: 2.18 min (analysis condition S)
Example 799
[4722] Compound PR3
2-(4-Ethyl-3-iodophenyl)-2-methylpropanoic acid
##STR00814##
[4724] 2-(4-Ethylphenyl)-2-methylpropanoic acid (58.1 g, 302.2
mmol) was dissolved in acetic acid (175 ml), added with
N-iodosuccinimide (71.4 g, 317.3 mmol, 1.05 eq.) and conc. sulfuric
acid (75 ml) at 0.degree. C. Thereafter, the mixture was stirred at
room temperature for 2 hrs. After cooling the reaction solution to
0.degree. C., 10% aqueous solution of sodium hydrogen sulfite (100
ml) was added and the mixture was stirred for 1 hr. H.sub.2O (450
ml) was added to the mixture and the precipitated solid was
filtered to obtain the title compound as a crude product. Ethanol
(150 ml) and 10% aqueous solution of sodium hydrogen sulfite (50
ml) were added to the crude product, and the mixture was dissolved
under heating at 50.degree. C. After confirming the dissolution,
the solution was cooled to room temperature, added with H.sub.2O
(300 ml), and then stirred at 0.degree. C. for 1 hr. The
precipitated solid was filtered to obtain the title compound (95.8
g, 99%).
[4725] .sup.1H-NMR (270 MHz DMSO-d.sub.6) .delta. ppm 12.46 (1H,
s), 7.70 (1H, d, J=1.8 Hz), 7.32 (1H, dd, J=8.1, 1.8 Hz), 7.26 (1H,
d, J=8.1 Hz), 2.64 (2H, q, J=7.5 Hz), 1.43 (6H, s), 1.12 (3H, t,
J=7.5 Hz)
[4726] HPLC retention time: 2.53 min (analysis condition S)
Example 800
[4727] Compound PR4
Tert-butyl 4-(4-ethyl-3-iodophenyl)-4-methyl-3-oxopentanoic
acid
##STR00815##
[4729] Mono-tert-butyl malonic acid (72.5 g) was dissolved in DME
(360 ml), added with TEA (189 ml) and magnesium chloride (29.63 g)
and the mixture was stirred for 2 hrs. In a separate vessel, CDI
(52.75 g) was added to the DME (360 ml) solution of
2-(4-ethyl-3-iodophenyl)-2-methylpropanoic acid (90 g) and stirred
at room temperature for 1 hr to prepare a solution. This solution
was then added dropwise to the aforementioned mixture, and the
resulting solution was washed with DME (90 ml) and stirred at
70.degree. C. for 3 hrs. The reaction mixture was diluted with
isopropyl acetate (225 ml) and heptane (225 ml), and the organic
layer was washed with 2 N hydrochloric acid (684 ml), 0.17 N
hydrochloric acid (540 ml), 15% aqueous solution of ammonium
chloride (540 ml), 1 N aqueous solution of sodium hydroxide (540
ml) and 15% brine (540 ml) in order. The organic layer was
concentrated under reduced pressure to obtain the title compound as
a crude product, which was used for the next step without further
purification.
[4730] .sup.1H-NMR (270 MHz DMSO-d.sub.6) .delta.: 7.64 (1H, d,
J=2.0 Hz), 7.30 (1H, d, J=8.1 Hz), 7.24 (1H, d, J=8.0, 2.0 Hz),
3.32 (2H, s), 2.65 (2H, q, J=7.4 Hz), 1.40 (6H, s), 1.34 (9H, s),
1.13 (3H, t, J=7.4 Hz)
Example 801
[4731] Compound PR5-1
Tert-butyl
6-cyano-2-(2-(4-ethyl-3-iodophenyl)propan-2-yl)-1H-indole-3-car-
boxylic acid
##STR00816##
[4733] 4-(4-Ethyl-3-iodophenyl)-4-methyl-3-oxopentanoic acid
tert-butyl (117.76 g) was dissolved in DMF (471 ml) and added with
cesium carbonate (276.5 g). DMF solution (176.6 ml) of
4-chloro-3-nitrobenzonitrile (63.9 g) was added dropwise thereto
(washed with DMF 58.8 ml), and the mixture was stirred at
35.degree. C. for 6 hrs. To the mixture, THF (588.8 ml), ethyl
acetate (588.8 ml), acetic acid (72.87 ml) and distilled water
(588.8 ml) were added for distribution, and the aqueous layer was
removed. The organic layer was added with THF (588.8 ml) and water
(588.8 ml), and under stirring sodium hydrosulfite (80%, 147.76 g)
was added in small portions and the mixture was stirred at room
temperature for 3 hrs. After removing the aqueous layer, the
organic layer was washed with 15% brine (588.8 ml). The organic
layer was added with 1 N hydrochloric acid (94.2 ml), stirred for 1
hr, and then added with 1 N aqueous solution of sodium hydroxide
(329.7 ml). The aqueous layer was removed and the organic layer was
concentrated under reduced pressure. The concentrated residues were
dissolved in ethanol (824.3 ml) and added dropwise with distilled
water (247.3 ml). The resulting precipitated crystals were filtered
and collected, washed with water: ethanol (=1: 2 mixture solution,
588.8 ml), and then dried to obtain the title compound (98.12 g,
two-step 63.5%).
[4734] .sup.1H-NMR (270 MHz DMSO-d.sub.6) .delta.: 12.04 (1H, br.
s), 8.01 (1H, d, J=8.4 Hz), 7.91 (1H, d, J=0.8 Hz), 7.55 (1H, d,
J=1.8 Hz), 7.49 (1H, dd, J=1.5, 8.4 Hz), 7.16 (1H, d, J=8.1 Hz),
7.07 (1H, dd, J=2.0, 8.1 Hz), 2.58 (2H, q, J=7.4 Hz), 1.79 (6H, s),
1.23 (9H, s), 1.06 (3H, t, J=7.4 Hz)
[4735] LCMS: m/z 459, 515 [M+H].sup.+
Example 802
[4736] Compound PR5-2
Methyl
6-cyano-2-(2-(4-ethyl-3-iodophenyl)propan-2-yl)-1H-indole-3-carboxy-
lic acid
##STR00817##
[4738] The title compound was prepared from monomethyl malonate and
2-(4-ethyl-3-iodophenyl)-2-methylpropanoic acid in the same manner
as the method for Compound PR4 and Compound PR5-1.
[4739] .sup.1H-NMR (270 MHz DMSO-D6) 6: 12.20 (s, 1H), 8.06-8.03
(m, 1H), 7.95-7.94 (m, 1H), 7.58-7.57 (m, 1H), 7.53-7.49 (m, 1H),
7.17-7.14 (m, 1H), 7.06-7.02 (m, 1H), 3.46 (s, 3H), 2.65-2.56 (q,
2H, J=7.5 Hz), 1.78 (s, 6H), 1.12-1.07 (t, 3H, J=7.5 Hz)
[4740] LCMS: m/z 473 [M+H].sup.+
Example 803
[4741] Compound PR6
Tert-butyl
6-cyano-2-(2-(4-ethyl-3-(4-morpholin-4-yl-piperidin-1-yl)phenyl-
)propan-2-yl)-1H-indole-3-carboxylic acid hydrochloric acid
salt
##STR00818##
[4743] Tert-butyl
6-cyano-2-(2-(4-ethyl-3-iodophenyl)propan-2-yl)-1H-indole-3-carboxylic
acid (390.5 g), 4-morpholin-4-yl piperidine (158 g), and
1,3-bis-(2,6-diisopropylphenyl)-imidazoyl-2-ylidene (allyl)
palladium (II) chloride (8.83 g) were dissolved in a mixture of
NaHMDS (1.9 M, THF solution 1.32 L) and DME (1.95 L) under nitrogen
stream, and the mixture was stirred at 40.degree. C. for 1 hr. The
reaction mixture was then partitioned between isopropyl acetate
(1.95 L) and 20% aqueous solution of ammonium chloride (1.95 L).
The organic layer was washed twice with 10% brine (1.56 L), and
then concentrated under reduced pressure. The resulting residues
were dissolved in a mixture of DME (3.9 L) and water (78.1 ml),
added with N-acetylcysteine (12.39 g), and stirred at 45.degree. C.
for 1 hr. After that, the insoluble matters were filtered and
washed with DME (1.95 L). The filtrate was concentrated under
reduced pressure. The resulting residues were dissolved in acetone
(5.5 L) and added with the solution in which pyridinium chloride
(96.5 g) is dissolved in acetone (195 ml) and ethanol (78 ml). The
precipitated solid was filtered, collected, washed with acetone
(1.95 L) and dried to obtain the title compound (373 g, 83%).
[4744] .sup.1H-NMR (400 MHz DMSO-D6) 6: 12.03 (1H, s), 10.75-10.88
(1H, m), 7.99 (1 H, d, J=8.3 Hz), 7.93 (1H, d, J=1.3 Hz), 7.46 (1H,
dd, J=1.3, 8.1 Hz), 7.10 (1H, d, J=7.9 Hz), 6.88 (1H, dd, J=1.7,
7.9 Hz), 6.79 (1H, d, J=1.7 Hz), 3.91-4.01 (2H, m), 3.76-3.87 (2H,
m), 3.37-3.46 (2H, m), 3.22 (1H, m), 2.94-3.11 (4H, m), 2.57 (2H,
q, J=7.5 Hz), 2.45-2.53 (2H, m), 2.09-2.16 (2H, m), 1.80 (6H, s),
1.71-1.77 (2H, m), 1.19 (9H, s), 1.14 (3H, t, J=7.5 Hz)
[4745] LCMS: m/z 557 [M+H].sup.+
Example 804
[4746] Compound PR7
6-Cyano-2-(2-(4-ethyl-3-(4-morpholin-4-yl-piperidin-1-yl)phenyl)propan-2-y-
l)-1H-indole-3-carboxylicacid
##STR00819##
[4748] Tert-butyl
6-cyano-2-(2-(4-ethyl-3-(4-morpholin-4-yl-piperidin-1-yl)phenyl)propan-2--
yl)-1H-indole-3-carboxylic acid hydrochloric acid salt (1400 g) was
suspended in TFE (7 L) under nitrogen stream, and added dropwise
with TMSCl (554 ml) at 8.degree. C. After stirring for 3 hrs, the
reaction solution was added with acetone (5.6 L) and aqueous
solution of NaOH (1 N, 4.39 L), and 10% aqueous solution of
K2HPO.sub.4 (1.4 L) was added thereto for neutralization. The
precipitated solid was filtered and collected, washed twice with a
mixture solution of water: acetone (=1: 1, 2.8 L), and dried to
obtain the title compound (1061 g, 96.6%).
[4749] .sup.1H-NMR (270 MHz DMSO-D6) 6: 11.95 (1H, s), 11.92 (1H,
bs), 8.04 (1H, d, J=8.4 Hz), 7.89 (1H, d, J=1.3 Hz), 7.44 (1H,
J=dd, 1.3, 8.4 Hz), 7.00 (1H, d, J=8.4 Hz), 6.88 (1H, d, J=1.8 Hz),
6.71 (1H, dd, J=2.2, 7.9 Hz), 3.50-3.55 (4H, m), 2.92-2.96 (2H, m),
2.54 (2H, q, 7.5 Hz), 2.39-2.50 (6H, m), 2.15-2.22 (1H, m),
1.74-1.85 (8H, m), 1.43-1.52 (2H, m), 1.13 (3H, t, J=7.5 Hz)
[4750] LCMS: m/z 501 [M+H].sup.+
[4751] HPLC retention time: 1.53 min (analysis condition U)
Example 805
[4752] Compound F6-20
9-Ethyl-6,6-dimethyl-8-(4-morpholin-4-yl-piperidin-1-yl)-11-oxo-6,11-dihyd-
ro-5H-benzo[b]carbazole-3-carbonitrile
##STR00820##
[4754]
6-Cyano-2-(2-(4-ethyl-3-(4-morpholin-4-yl-piperidin-1-yl)phenyl)pro-
pan-2-yl)-1H-indole-3-carboxylic acid (500 g) was dissolved in a
mixture of DMA (9.4 L), acetic anhydride (270 ml) and DIPEA (1170
ml) under nitrogen stream. The mixture was stirred at 90.degree. C.
for 1 hr. After cooling to room temperature, the mixture was added
with methanol (3.525 L) and subsequently with distilled water
(5.875 L). The precipitated solid was filtered, collected, washed
twice with the mixture solution (methanol:water=3:5, 1.41 L), and
then dried to obtain the title compound (389.6 g, 85%).
[4755] .sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta.: 12.70 (1H, s),
8.32 (1H, d, J=7.9 Hz), 8.04 (1H, s), 8.00 (1H, s), 7.61 (1H, d,
J=8.5 Hz), 7.34 (1H, s), 3.64-3.57 (4H, m), 3.27-3.18 (2H, m),
2.82-2.66 (4H, m), 2.39-2.28 (1H, m), 1.96-1.87 (2H, m), 1.76 (6H,
s), 1.69-1.53 (2H, m), 1.29 (3H, t, J=7.3 Hz)
[4756] LCMS: m/z 483 [M+H].sup.+
[4757] HPLC retention time: 1.98 min (analysis condition U)
[4758] Hydrochloric Acid Salt of Compound F6-20
[4759]
9-Ethyl-6,6-dimethyl-8-(4-morpholin-4-yl-piperidin-1-yl)-11-oxo-6,1-
1-dihydro-5H-benzo[b]carbazole-3-carbonitrile (400 g) was dissolved
in a mixture solvent of methylethyl ketone (4.8 L), acetic acid
(1.44 L) and distilled water (1.68 L) at room temperature. The
resulting solution was added dropwise to the mixture of ethanol (12
L) and 2 N hydrochloric acid (0.8 L). The precipitated solid was
filtered, washed with ethanol (2 L), and dried to obtain
hydrochloric acid salt of Compound F6-20 (357 g).
[4760] .sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta.: 12.83 (1H, s),
10.78 (1H, s), 8.32 (1H, d, J=8.1 Hz), 8.06 (1H, s), 8.01 (1H, s),
7.61 (1H, d, J=8.1 Hz), 7.37 (1H, s), 4.02 (2H, m), 3.85 (2H, m),
3.51 (2H, m), 3.34 (1H, m), 3.32 (2H, m), 3.15 (2H, m), 2.81 (2H,
dd, J=11.98, 11.7 Hz), 2.72 (2H, q, J=7.5 Hz), 2.23 (2H, m), 1.89
(2H, m), 1.77 (6H, s), 1.29 (3H, t, J=7.5 Hz) FABMS: m/z 483.4
[M+H].sup.+
Example 806
[4761] Compound F6-22
9-Ethyl-6,6-dimethyl-10-(4-morpholin-4-yl-piperidin-1-yl)-11-oxo-6,11-dihy-
dro-5H-benzo[b]carbazole-3-carbonitrile
##STR00821##
[4763] From the filtrate solution obtained from the synthesis of
Compound F6-20, the title compound was obtained.
[4764] .sup.1H-NMR (400 MHz DMSO-D6) 6: 12.56 (1H, s), 8.32 (1H, d,
J=7.9 Hz), 7.96 (1H, s), 7.45-7.59 (3H, m), 3.55-3.62 (4H, m),
3.36-3.50 (2H, m), 2.75-2.86 (2H, m), 2.71 (2H, q, J=7.5 Hz),
2.45-2.56 (4H, m), 2.27-2.38 (1H, m), 1.73-1.84 (2H, m), 1.69 (6H,
s), 1.43-1.58 (2H, m), 1.21 (3H, t, J=7.5 Hz).
[4765] LCMS: m/z 483 [M+H].sup.+
[4766] HPLC retention time: 1.52 min (analysis condition U)
Example 807
[4767] Compound PR8
9-Ethyl-6,6-dimethyl-8-iodo-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-car-
bonitrile
##STR00822##
[4769] Tert-butyl
6-cyano-2-(2-(4-ethyl-3-iodophenyl)propan-2-yl)-1H-indole-3-carboxylic
acid (11 g) was dissolved in Eaton's reagent (200 g) and stirred at
room temperature for 30 min. The reaction solution was diluted with
acetonitrile (200 ml) and distilled water (400 ml). The
precipitated solid was collected by filtration, washed with
distilled water, and then dried. The crude product was dissolved in
DMA (45 ml), diluted with acetonitrile (20 ml) and distilled water
(18 ml), and re-precipitated to obtain the title compound (6.62 g,
70%).
[4770] .sup.1H-NMR (400 MHz DMSO-D6) 6: 12.79 (1H, s), 8.32-8.29
(2H, m), 8.06 (1H, s), 8.01 (1H, s), 7.62 (1H, dd, J=1.3, 7.9 Hz),
2.78 (2H, q, J=7.5 Hz), 1.75 (6H, s), 1.20 (3H, t, J=7.5 Hz)
[4771] LCMS: m/z 441 [M+H].sup.+
[4772] HPLC retention time: 3.17 min (analysis condition U)
Example 808
[4773] Compound PR9-1
8-(1,4-Dioxa-8-aza-spiro[4.5]dec-8-yl)-9-ethyl-6,6-dimethyl-11-oxo-6,11-di-
hydro-5H-benzo[b]carbazole-3-carbonitrile
##STR00823##
[4775] The dioxane solution (50 ml) of
9-ethyl-6,6-dimethyl-8-iodo-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-ca-
rbonitrile (5.0 g), 1,4-dioxa-8-aza-spiro[4.5]decane (2.08 ml),
Pd.sub.2(dba).sub.3 (520 mg), and S-Phos (963 mg) was flushed with
nitrogen gas, added with NaHMDS (1M, THF solution 40 ml), and
stirred at 60.degree. C. for 1 hr. The resulting mixture was
diluted with ethyl acetate (200 ml). The organic layer was washed
three times with 10% brine, and then concentrated under reduced
pressure to obtain the title compound as a crude product. This
crude product was used for the next step without further
purification.
[4776] LCMS: m/z 456 [M+H].sup.+
[4777] HPLC retention time: 2.78 min (analysis condition U)
Example 809
[4778] Compound PR9-2
9-Ethyl-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitri-
le
##STR00824##
[4780] As a by-product of Compound PR9-1, the target compound was
obtained according to silica gel column separation of Example
810.
[4781] LCMS: m/z 315 [M+H].sup.+
[4782] HPLC retention time: 2.77 min (analysis condition U)
Example 810
[4783] Compound PR10-1
9-Ethyl-6,6-dimethyl-11-oxo-8-(4-oxopiperidin-1-yl)-6,11-dihydro-5H-benzo[-
b]carbazole-3-carbonitrile
##STR00825##
[4785]
8-(1,4-Dioxa-8-aza-spiro[4.5]dec-8-yl)-9-ethyl-6,6-dimethyl-11-oxo--
6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile, which had been
prepared in Example 809, was dissolved in THF (10 ml), added with 5
N hydrochloric acid (50 ml), and the mixture was stirred for 17
hrs. The reaction mixture was neutralized with 5 N aqueous solution
of sodium hydroxide and diluted with ethyl acetate (200 ml). The
organic layer was washed with 10% brine, and then concentrated
under reduced pressure. The resulting residues were purified by
silica gel column (dichloromethane/methanol=99/1 to 90/10) to
obtain the title compound (2.9 g, two step yield 64%).
[4786] .sup.1H-NMR (400 MHz DMSO-D6) 6: 12.70 (1H, s), 8.32 (1H, d,
J=8.4), 8.07 (1H, s), 7.99 (1H, s), 7.60 (1H, dd, J=1.3, 7.9 Hz),
7.42 (1H, s), 3.28 (4H, t, J=5.7), 2.80 (q, 2H, J=7.5 Hz), 2.55
(4H, t, J=5.7), 1.75 (6H, s), 1.31 (3H, t, J=7.5 Hz)
[4787] LCMS: m/z 412 [M+H].sup.+
[4788] HPLC retention time: 2.57 min (analysis condition U)
Example 811
[4789] Compound PR11-1
9-Ethyl-6,6-dimethyl-11-oxo-8-[4-(3-oxo-piperazin-1-yl)-piperidin-1-yl]-6,-
11-dihydro-5H-benzo[b]carbazole-3-carbonitrile
##STR00826##
[4791]
9-Ethyl-6,6-dimethyl-11-oxo-8-(4-oxopiperidin-1-yl)-6,11-dihydro-5H-
-benzo[b]carbazole-3-carbonitrile (30 mg) and 2-ketopiperazine (10
mg) were dissolved in THF (2 ml), added with sodium triacetoxy
borohydride (30 mg), and the mixture was stirred at 30.degree. C.
for 6 hrs. The reaction mixture was diluted with ethyl acetate (20
ml). The organic layer was washed with 10% brine, and then
concentrated under reduced pressure. The resulting residues were
purified by silica gel column (dichloromethane/methanol=99/1 to
90/10) to obtain the title compound (11.5 mg, yield 32%).
[4792] LCMS: m/z 496 [M+H].sup.+
[4793] HPLC retention time: 1.90 min (analysis condition U)
[4794] Compound PR11-2
9-Ethyl-8-(4-hydroxy-piperidin-1-yl)-6,6-dimethyl-11-oxo-6,11-dihydro-5H-b-
enzo[b]carbazole-3-carbonitrile
##STR00827##
[4796] As a by-product of Compound PR11-1, the target compound was
obtained.
[4797] LCMS: m/z 414 [M+H].sup.+
[4798] HPLC retention time: 2.13 min (analysis condition S)
[4799] The compounds described in the following Tables 8-10 were
synthesized by introducing a corresponding amine to
9-ethyl-6,6-dimethyl-8-iodo-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-ca-
rbonitrile according to the method used for the synthesis of
Compound PR9-1. Although the relevant literatures are not entirely
known, some amines in which a tertiary alkyl group is attached to
the nitrogen atom were prepared according to the method described
in Journal of Medicinal Chemistry, 45 (14), 3143-3160, 2002.
Alternatively, the preparation was carried out by introducing a
corresponding amine to
9-ethyl-6,6-dimethyl-11-oxo-8-(4-oxopiperidin-1-yl)-6,11-dihydro-5H-benzo-
[b]carbazole-3-carbonitrile based on the method that is used for
the synthesis of Compound PR11-1 (i.e., reductive amination).
TABLE-US-00008 TABLE 8 Example Comp. HPLC Retention No. No.
Structure Compound Name Condition Time m/z 813 PR9-3 ##STR00828##
8-(4-tert-Butyl- piperazin-1-yl)-9- ethyl-6,6-dimethyl-
11-oxo-6,11- dihydro-5H- benzo[b]carbazole- 3-carbonitrile S 1.63
455 814 PR9-4 ##STR00829## 9-Ethyl-6,6- dimethyl-11-oxo-8-
(4-pyrrolidin-1-yl- piperidin-1-yl)- 6,11-dihydro-5H-
benzo[b]carbazole- 3-carbonitrile U 2.13 467 815 PR9-5 ##STR00830##
9-Ethyl-8-(4- isopropyl- piperazin-1-yl)-6,6- dimethyl-11-oxo-
6,11-dihydro-5H- benzo[b]carbazole- 3-carbonitrile U 2.08 441 816
PR9-6 ##STR00831## 9-Ethyl-6,6- dimethyl-8-(4- methyl-piperazin-
1-yl)-11-oxo-6,11- dihydro-5H- benzo[b]carbazole- 3-carbonitrile U
1.97 413 817 PR9-7 ##STR00832## 9-Ethyl-8-(4-ethyl-
piperazin-1-yl)-6,6- dimethyl-11-oxo- 6,11-dihydro-5H-
benzo[b]carbazole- 3-carbonitrile U 2.03 427 818 PR9-8 ##STR00833##
9-Ethyl-6,6- dimethyl-8- morpholin-4-yl-11- oxo-6,11-dihydro- 5H-
benzo[b]carbazole- 3-carbonitrile U 2.65 400 819 PR11-3
##STR00834## 8-[4-((2R,6S)-2,6- Dimethyl- morpholin-4-yl)-
piperidin-1-yl]-9- ethyl-6,6-dimethyl- 11-oxo-6,11- dihydro-5H-
benzo[b]carbazole- 3-carbonitrile S 1.65 511 820 PR11-4
##STR00835## 8- [1,4']Bipiperidinyl- 1'-yl-9-ethyl-6,6-
dimethyl-11-oxo- 6,11-dihydro-5H- benzo[b]carbazole- 3-carbonitrile
S 1.63 481 821 PR11-5 ##STR00836## 8-(4,4-Difluoro-
[1,4']bipiperidinyl- 1'-yl)-9-ethyl-6,6- dimethyl-11-oxo-
6,11-dihydro-5H- benzo[b]carbazole- 3-carbonitrile S 1.70 517 822
PR11-6 ##STR00837## 8-(4-Azetidin-1-yl- piperidin-1-yl)-9-
ethyl-6,6-dimethyl- 11-oxo-6,11- dihydro-5H- benzo[b]carbazole-
3-carbonitrile S 1.55 453 823 PR11-7 ##STR00838## 9-Ethyl-8-(4-
hydroxy- [1,4']bipiperidinyl- 1'-yl)-6,6-dimethyl- 11-oxo-6,11-
dihydro-5H- benzo[b]carbazole- 3-carbonitrile U 1.95 497 824 PR9-9
##STR00839## 8-(4-Cyclopropyl- 4-hydroxy- piperidin-1-yl)-9-
ethyl-6,6-dimethyl- 11-oxo-6,11- dihydro-5H- benzo[b]carbazole-
3-carbonitrile U 2.53 454 825 PR11-8 ##STR00840## 9-Ethyl-8-(4-
fluoro- [1,4']bipiperidinyl- 1'-yl)-6,6-dimethyl- 11-oxo-6,11-
dihydro-5H- benzo[b]carbazole- 3-carbonitrile U 2.13 499 826 PR9-10
##STR00841## 9-Ethyl-6,6- dimethyl-8-(3- morpholin-4-yl-
azetidin-1-yl)-11- oxo-6,11-dihydro- 5H- benzo[b]carbazole-
3-carbonitrile S 1.48 455
TABLE-US-00009 TABLE 9 Example Comp. HPLC Retention No. No.
Structure Compound Name Condition Time m/z 827 PR9-11 ##STR00842##
9-Ethyl-6,6- dimethyl-11-oxo-8- (3-piperidin-1-yl-
azetidin-1-yl)-6,11- dihydro-5H- benzo[b]carbazole- 3-carbonitrile
S 1.57 453 828 PR9-12 ##STR00843## 9-Ethyl-6,6- dimethyl-8-[4-(1-
methyl-piperidin-4- yl)-piperazin-1-yl]- 11-oxo-6,11- dihydro-5H-
benzo[b]carbazole- 3-carbonitrile U 1.70 496 829 PR9-13
##STR00844## 9-Ethyl-6,6- dimethyl-8-[4-(4- methyl-piperazin-
1-yl)-piperidin-1- yl]-1l-oxo-6,11- dihydro-5H- benzo[b]carbazole-
3-carbonitrile U 1.73 496 830 PR11-9 ##STR00845## 8-(4-Cyclopentyl-
piperazin-1-yl)-9- ethyl-6,6-dimethyl- 11-oxo-6,11- dihydro-5H-
benzo[b]carbazole- 3-carbonitrile U 2.12 467 831 PR11-10
##STR00846## 9-Ethyl-8-[4-(2- hydroxy- ethylamino)-
piperidin-1-yl]-6,6- dimethyl-11-oxo- 6,11-dihydro-5H-
benzo[b]carbazole- 3-carbonitrile U 1.90 457 832 PR-11-11
##STR00847## 9-Ethyl-8-[4-(3- hydroxy- propylamino)-
piperidin-1-yl]-6,6- dimethyl-11-oxo- 6,11-dihydro-5H-
benzo[b]carbazole- 3-carbonitrile S 1.90 471 833 PR9-14
##STR00848## 9-Ethyl-6,6- dimethyl-8-(4- methyl-4- morpholine-4-yl-
piperidin-1-yl)-11- oxo-6,11-dihydro- 5H- benzo[b]carbazole-
3-carbonitrile U 2.00 497 834 PR9-15 ##STR00849## 9-Ethyl-8-[4-(1-
ethyl-cyclobutyl)- piperazine-1-yl]- 6,6-dimethyl-11-
oxo-6,11-dihydro- 5H- benzo[b]carbazole- 3-carbonitrile Y 2.25 481
835 PR9-16 ##STR00850## 9-Ethyl-8-(4- ethyl-4- morpholine-4-yl-
piperidine-1-yl)- 6,6-dimethyl-11- oxo-6,11-dihydro- 5H-
benzo[b]carbazole- 3-carbonitrile Y 2.17 511 836 PR9-17
##STR00851## 9-Ethyl-8-(4- isopropyl-4- morpholine-4-yl-
piperidine-1-yl)- 6,6-dimethyl-11- oxo-6,11-dihydro- 5H-
benzo[b]carbazole- 3-carbonitrile U 2.12 525 837 PR9-18
##STR00852## 9-Ethyl-6,6- dimethyl-11-oxo-8- [4-(1-propyl-
cyclobutyl)- piperazine-1-yl]- 6,11-dihydro-5H- benzo[b]carbazole-
3-carbonitrile U 2.28 495 838 PR9-19 ##STR00853## 9-Ethyl-8-[4-(1-
isopropyl- cyclobutyl)- piperazine-1-yl]- 6,6-dimethyl-11-
oxo-6,11-dihydro- 5H- benzo[b]carbazole- 3-carbonitrile U 2.25 495
839 PR9-20 ##STR00854## 9-Ethyl-6,6- dimethyl-8-(2-
morpholine-4-yl- ethylamino)-11- oxo-6,11-dihydro- 5H-
benzo[b]carbazole- 3-carbonitrile Y 1.85 443 840 PR9-21
##STR00855## 9-Ethyl-6,6- dimethyl-11-oxo-6- (2-piperidine-1-yl-
ethylamino)-6,11- dihydro-5H- benzo[b]carbazole- 3-carbonitrile Y
1.85 441
TABLE-US-00010 TABLE 10 Ex- HPLC Re- ample Comp. Con- tention No.
No. Structure Compound Name dition Time m/z 841 PR11-12
##STR00856## 8-(4-Amino- piperidine-1-yl)-9- ethyl-6,6-dimethyl-
11-oxo-6,11-dihydro- 5H- benzo[b]carbazole-3- carbonitrile U 1.92
413 842 PR11-13 ##STR00857## 9-Ethyl-6,6- dimethyl-8-(4-
2,2,3,3,5,5,6,6-d8- morpholine-4-yl- piperidine-1-yl)-1 1-oxo-6,11-
dihydro-5H-benzo [b]carbazole-3- carbonitrile U 1.98 491 843 PR9-22
##STR00858## 9-Ethyl-8-[4-(2- methoxy-ethoxy)- piperidine-1-yl]6,6-
dimethyl-11-oxo- 6,11-dihydro-5H- benzo[b]carbazole-3- carbonitrile
Y 3.23 472 844 PR9-23 ##STR00859## 8-[4-(2-Ethoxy-
ethoxy)-piperidine-1- yl]-9-ethyl-6,6- dimethyl-11-oxo-
6,11-dihydro-5H- benzo[b]carbazole-3- carbonitrile Y 3.35 486 845
PR9-24 ##STR00860## 8-(4- Cyclopropylmethoxy- piperidine-1-yl)-9-
ethyl-6,6-dimethyl- 11-oxo-6,11-dihydro- 5H- benzo[b]carbazole-3-
carbonitrile Y 3.50 468 846 PR9-25 ##STR00861## 8-[4-(2-Ethoxy-
ethoxy)-piperidine-1- yl]-9-ethyl-6,6- dimethyl-11-oxo-
6,11-dihydro-5H- benzo[b]carbazole-3- carbonitrile Y 4.00 524 847
PR11-14 ##STR00862## 8-(4- Cyclopropylamino- piperidine-1-yl)-9-
ethyl-6,6-dimethyl- 11-oxo-6,11-dihydro- 5H- benzo[b]carbazole-3-
carbonitrile Y 2.33 495 848 PR11-15 ##STR00863## 8-(4-
Cyclopropylamino- piperidine-1-yl)-9- ethyl-6,6-dimethyl-
11-oxo-6,11-dihydro- 5H- benzo[b]carbazole-3- carbonitrile Y 2.15
481 849 PR11-16 ##STR00864## 8-[4- Cyclopropylmethoxy-
amino)-piperidine-1- yl]-9-ethyl-6,6- dimethyl-11-oxo-
6,11-dihydro-5H- benzo[b]carbazole-3- carbonitrile Y 2.15 467 850
PR11-17 ##STR00865## 8-(4- Cyclopropylamino- piperidine-1-yl)-9-
ethyl-6,6-dimethyl- 11-oxo-6,11-dihydro- 5H- benzo[b]carbazole-3-
carbonitrile Y 2.08 453 851 PR11-18 ##STR00866## 8-(4-
Cyclopropylamino- piperidine-1-yl)-9- ethyl-6,6-dimethyl-
11-oxo-6,11-dihydro- 5H- benzo[b]carbazole-3- carbonitrile Y 2.13
467 852 PR11-19 ##STR00867## 8-[4- Cyclohexylmethl-
amino)-piperidine-1- yl]-9-ethyl-6,6- dimethyl-11-oxo-
6,11-dihydro-5H- benzo[b]carbazole-3- carbonitrile Y 2.42 509
Example 853
[4800] Compound PR11-22
9-Ethyl-8-(4-hydroxyimino-piperidin-1-yl)-6,6-dimethyl-11-oxo-6,11-dihydro-
-5H-benzo[b]carbazole-3-carbonitrile
##STR00868##
[4802]
9-ethyl-6,6-dimethyl-11-oxo-8-(4-oxopiperidin-1-yl)-6,11-dihydro-5H-
-benzo[b]carbazole-3-carbonitrile (30 mg) and hydroxylamine
hydrochloric acid salt (10 mg) were dissolved in ethanol (5 ml) and
stirred at 60.degree. C. for 6 hrs. The reaction mixture was
diluted with ethyl acetate (20 ml). The organic layer was washed
with 10% brine and concentrated under reduced pressure. The
resulting residues were purified by silica gel column
(dichloromethane/methanol=99/1 to 90/10) to obtain the title
compound (23.5 mg, yield 74%).
[4803] LCMS: m/z 427 [M+H].sup.+
[4804] HPLC retention time: 3.08 min (analysis condition Y)
Example 854
[4805] Compound PR10-2
9-Ethyl-6,6-dimethyl-5-(2-morpholin-4-yl-ethyl)-8-(2-morpholin-4-yl-ethyla-
mino)-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile
##STR00869##
[4807]
9-Ethyl-6,6-dimethyl-8-(2-morpholin-4-yl-ethylamino)-11-oxo-6,11-di-
hydro-5H-benzo[b]carbazole-3-carbonitrile (10 mg) was dissolved in
DMF (1 ml), added with K2CO.sub.3 (10 mg) and
1-(2-chloroethyl)morpholine (8 mg), and then stirred at 90.degree.
C. for 17 hrs. The reaction mixture was diluted with ethyl acetate
(10 ml). The organic layer was washed with 10% brine and
concentrated under reduced pressure. The resulting residues were
purified by silica gel column (dichloromethane/methanol=99/1 to
90/10) to obtain the title compound (6.4 mg, yield 58%).
[4808] LCMS: m/z 556 [M+H].sup.+
[4809] HPLC retention time: 1.78 min (analysis condition Y)
Example 855
[4810] Compound F7
9-Ethyl-6,6-dimethyl-11-oxo-8-[4-(4-oxy-morpholin-4-yl)-piperidin-1-yl]-6,-
11-dihydro-5H-benzo[b]carbazole-3-carbonitrile
##STR00870##
[4812]
9-Ethyl-6,6-dimethyl-8-(4-morpholin-4-yl-piperidin-1-yl)-11-oxo-6,1-
1-dihydro-5H-benzo[b]carbazole-3-carbonitrile (400 mg) was
dissolved in trifuloroethanol (80 ml), added with 30% hydrogen
peroxide solution (0.8 ml), and the mixture was stirred at
60.degree. C. for 17 hrs. The reaction mixture was concentrated to
30 ml and diluted with water (20 ml). The precipitated matter was
collected by filtration and dried to obtain the title compound (375
mg, yield 90%).
[4813] LCMS: m/z 499 [M+H].sup.+
[4814] HPLC retention time: 2.05 min (analysis condition U)
Example 856
[4815] Compound FR1
6-Cyano-2-[1-(4-ethyl-3-iodophenyl)-1-methyl-ethyl]-benzofuran-3-carboxyli-
c acid tert-butyl ester
##STR00871##
[4817] 4-(4-Ethyl-3-iodo-phenyl)-4-methyl-3-oxo-pentanoic acid
tert-butyl ester (1.00 g, 2.40 mmol) was dissolved in NMP (4 ml),
added with cesium carbonate (1.56 g, 4.80 mmol, 2.0 eq.), and the
mixture was stirred for 5 min. The NMP solution (2 ml) of
4-chloro-3-nitro-benzonitrile (542 mg, 2.88 mmol, 1.2 eq.) was
added thereto, and the mixture was stirred at 50.degree. C. for 64
hrs under nitrogen atmosphere. After cooling to room temperature,
ethyl acetate (20 ml) was added and the organic layer was washed
with saturated aqueous solution of ammonium chloride (20 ml). The
organic layer was further washed with saturated brine and dried
over sodium sulfate. The drying agent was removed by filtration and
the residues obtained after concentration under reduced pressure
were purified by silica gel column chromatography (ethyl
acetate/hexane) to obtain the title compound (white amorphous, 320
mg, 26%).
[4818] LCMS: m/z 516 [M+H].sup.+
Example 857
[4819] Compound FR2
6-Cyano-2-{1-[4-ethyl-3-(4-morpholin-4-yl-piperidin-1-yl)-phenyl]-1-methyl-
-ethyl}-benzofuran-3-carboxylic acid tert-butyl ester
##STR00872##
[4821]
6-Cyano-2-[1-(4-ethyl-3-iodophenyl)-1-methyl-ethyl]-benzofuran-3-ca-
rboxylic acid tert-butyl ester was converted to obtain the title
compound in the same manner as the method for Compound PR6.
[4822] LCMS: m/z 558 [M+H].sup.+
Example 858
[4823] Compound FR3
6-Cyano-2-{1-[4-ethyl-3-(4-morpholin-4-yl-piperidin-1-yl)-phenyl]-1-methyl-
-ethyl}-benzofuran-3-carboxylic acid hydroiodic acid salt
##STR00873##
[4825] To obtain the title compound,
6-Cyano-2-{1-[4-ethyl-3-(4-morpholin-4-yl-piperidin-1-yl)-phenyl]-1-methy-
l-ethyl}-benzofuran-3-carboxylic acid tert-butyl ester was
deprotected by using trimethylsilyl iodide in the same manner as
the method for Compound PR7.
[4826] LCMS: m/z 502 [M+H].sup.+
Example 859
[4827] Compound FR4
9-Ethyl-6,6-dimethyl-8-(4-morpholin-4-yl-piperidin-1-yl)-11-oxo-6,11-dihyd-
ro-benzo[b]naphtho[2,3-d]furan-3-carbonitrile
##STR00874##
[4829]
6-Cyano-2-{1-[4-ethyl-3-(4-morpholin-4-yl-piperidin-1-yl)-phenyl]-1-
-methyl-ethyl}-benzofuran-3-carboxylic acid hydroiodic acid salt
was converted in the same method as Example 805 to obtain the
target compound.
[4830] LCMS: m/z 484 [M+H].sup.+
Example 860
[4831] Compound LB1
2-[4-Ethyl-3-(4-morpholin-4-yl-piperidin-1-yl)-phenyl]-2-methyl-propionic
acid
##STR00875##
[4833] The title compound was prepared from
2-(4-ethyl-3-iodophenyl)-2-methylpropanoic acid by carrying out
amination in the same manner as the method for synthesizing
Compound PR6.
[4834] LCMS: m/z 361 [M+H].sup.+
Example 861
[4835] Compound LB2
2-{1-[4-Ethyl-3-(4-morpholin-4-yl-piperidin-1-yl)-phenyl]-1-methyl-ethyl}--
6-iodo-1H-indole-3-carboxylic acid tert-butyl ester
##STR00876##
[4837]
2-[4-Ethyl-3-(4-morpholin-4-yl-piperidin-1-yl)-phenyl]-2-methyl-pro-
pionic acid was converted in the same manner as the method for
synthesizing Compound PR5-1 to obtain the title compound.
[4838] LCMS: m/z 658 [M+H].sup.+
[4839] HPLC retention time: 2.76 min (analysis condition U)
Example 862
[4840] Compound LB3
2-{1-[4-Ethyl-3-(4-morpholin-4-yl-piperidin-1-yl)-phenyl]-1-methyl-ethyl}--
6-iodo-1H-indole-3-carboxylic acid
##STR00877##
[4842]
2-{1-[4-Ethyl-3-(4-morpholin-4-yl-piperidin-1-yl)-phenyl]-1-methyl--
ethyl}-6-iodo-1H-indole-3-carboxylic acid tert-butyl ester was
deprotected in the same manner as the method for preparing Compound
PR7 to obtain the title compound.
[4843] LCMS: m/z 602 [M+H].sup.+
[4844] HPLC retention time: 2.17 min (analysis condition U)
Example 863
[4845] Compound LB4
9-Ethyl-3-iodo-6,6-dimethyl-8-(4-morpholin-4-yl-piperidin-1-yl)-5,6-dihydr-
o-benzo[b]carbazol-11-one
##STR00878##
[4847]
2-{1-[4-Ethyl-3-(4-morpholin-4-yl-piperidin-1-yl)-phenyl]-1-methyl--
ethyl}-6-iodo-1H-indole-3-carboxylic acid was converted in the same
manner as Example 805 to obtain the title compound.
[4848] LCMS: m/z 584 [M+H].sup.+
[4849] HPLC retention time: 2.25 min (analysis condition U)
[4850] The compounds described in the following Table 11 were
converted and prepared from
9-ethyl-3-iodo-6,6-dimethyl-8-(4-morpholin-4-yl-piperidin-1-yl)-5,6-dihyd-
ro-benzo[b]carbazol-11-one according to the method described in the
Table.
TABLE-US-00011 TABLE 11 Example Comp. HPLC Retention No. No.
Structure Compound Name Condition Time m/z Method 864 LB5-1
##STR00879## N-[9-Ethyl-6,6- dimethyl-8-(4- morpholine-4-yl-
piperidine-1-yl)-11- oxo-6,11-dihydro- 5H- benzo[b]carbazole-
3-yl]-benzamide Y 1.78 577 B2-10 865 LB5-2 ##STR00880## 9-Ethyl-3-
ethylsulfanyl-6,6- dimethyl-8-(4- morpholine-4-yl-
piperidine-1-yl)-5,6- dihydro- benzo[b]carbazole- 11-one Y 2.28 518
B2-17 866 LB5-3 ##STR00881## N-[9-Ethyl-6,6- dimethyl-8-(4-
morpholine-4-yl- piperidine-1-yl)-11- oxo-6,11-dihydro- 5H-
benzo[b]carbazole- 3-yl]-acetamide Y 1.50 515 B2-10
Example 867
[4851] Compound AZT1
Methanesulfonic acid (2-fluoropyridin-4-yl)methyl ester
##STR00882##
[4853] (2-Fluoropyridin-4-yl) methanol (1g) was dissolved in DCM
(40 ml), added with TEA (3.3 ml) and mesyl chloride (0.67 ml), and
the mixture was stirred at 0.degree. C. for 1 hr. The mixture was
concentrated and then purified by silica gel column (n-hexane/ethyl
acetate=4/1) to obtain the title compound (1.18 g, 77%).
[4854] .sup.1H-NMR (270 MHz DMSO-d.sub.6) .delta.: 3.21 (3H, s),
5.38 (2H, s), 7.22 (1H, s), 7.39 (1H, d, J=5.0), 8.29 (1H, d,
J=5.0)
Example 868
[4855] Compound AZ2
(2-Fluoropyridin-4-yl)acetonitrile
##STR00883##
[4857] To the DMF (28 ml) solution of methanesulfonic acid
(2-fluoropyridin-4-yl)methyl ester (1.16 g), sodium cyanide (0.42
g) was added and the mixture was stirred at 80.degree. C. for 1 hr.
The mixture was diluted with ethyl acetate (100 ml), and washed
with 15% brine and distilled water in order. The organic layer was
concentrated and purified by silica gel column (n-hexane/ethyl
acetate=5/1) to obtain the title compound (278 mg, 36%).
[4858] .sup.1H-NMR (270 MHz DMSO-d.sub.6) .delta.: 4.22 (2H, s),
7.18 (1H, s), 7.36 (1H, d, J=5.0), 8.27 (1H, d, J=5.0)
Example 869
[4859] Compound AZ3
(2-Fluoropyridin-4-yl).sub.2-methylpropionitrile
##STR00884##
[4861] The title compound was prepared from (2-fluoropyridin-4-yl)
acetonitrile in the same manner as the method for Compound K2.
[4862] .sup.1H-NMR (270 MHz DMSO-d.sub.6) .delta.: 1.72 (6H, s),
7.34 (1H, s), 7.53 (1H, d, J=5.3), 8.31 (1H, d, J=5.3)
Example 870
[4863] Compound AZ4
4-(2-Fluoropyridin-4-yl)-4-methyl-3-oxopentanoic acid ethyl
ester
##STR00885##
[4865] The title compound was prepared from (2-fluoropyridin-4-yl)
2-methylpropionitrile in the same manner as the method for Compound
K3.
[4866] .sup.1H-NMR (270 MHz DMSO-d.sub.6) .delta.: 1.13 (3H, t,
J=7.3), 1.48 (6H, s), 3.57 (2H, s), 4.01 (2H, q, J=7.3), 7.12 (1H,
s), 7.25 (1H, d, J=5.3), 8.22 (1H, d, J=5.3)
Example 871
[4867] Compound AZ5
6-Cyano-2-[1-(2-fluoropyridin-4-yl)-1-methyl-ethyl]-1H-indole-3-carboxylic
acid ethyl ester
##STR00886##
[4869] The title compound was prepared from
4-(2-fluoropyridin-4-yl)-4-methyl-3-oxopentanoic acid ethyl ester
in the same manner as the method for Compound K4 and Compound
K5.
[4870] LCMS: m/z 352 [M+H].sup.+
[4871] .sup.1H-NMR (270 MHz DMSO-d.sub.6) .delta.: 1.05 (3H, t,
J=7.3), 1.82 (6H, s), 3.98 (2H, q, J=7.3), 6.99-7.02 (2H, m), 7.16
(1H, dd, J=8.4, 1.5), 7.97 (1H, s), 8.05-8.11 (2H, m)
Example 872
[4872] Compound AZ6
6-Cyano-2-[1-(2-(4-morpholin-4-yl-piperidin-1-yl))pyridin-4-yl)-1-methyl-e-
thyl]-1H-indole-3-carboxylic acid ethyl ester
##STR00887##
[4874]
6-Cyano-2-[1-(2-fluoropyridin-4-yl)-1-methyl-ethyl]-1H-indole-3-car-
boxylic acid ethyl ester (110 mg) was dissolved in NMP (3.3 ml),
added with 4-morpholin-4-yl-piperidine (319 mg), and stirred in a
sealing tube at 120.degree. C. for 1 hr. The reaction mixture was
diluted with ethyl acetate (50 ml) and washed with 15% brine and
distilled water in order. The organic layer was concentrated and
purified by silica gel column (DCM/methanol=20/1) to obtain the
title compound (120 mg, 76%).
[4875] LCMS: m/z 502 [M+H].sup.+
Example 873
[4876] Compound AZ7-1
5,5-Dimethyl-3-(4-morpholin-4-yl-piperidin-1-yl)-11-oxo-6,11-dihydro-5H-py-
rido[4,3-b]carbazole-8-carboxylic acid amide
##STR00888##
[4878]
6-Cyano-2-[1-(2-(4-morpholin-4-yl-piperidin-1-yl))pyridin-4-yl)-1-m-
ethyl-ethyl]-1H-indole-3-carboxylic acid ethyl ester (110 mg) was
dissolved in Eaton's reagent (2.5 ml) and stirred at 55.degree. C.
for 17 hrs. The reaction mixture was neutralized with saturated
aqueous solution of sodium bicarbonate. The precipitated matters
were collected by filtration, and then washed with water to obtain
the title compound (72 mg, 70%).
[4879] LCMS: m/z 474 [M+H].sup.+
[4880] HPLC retention time: 1.17 min (analysis condition U)
[4881] .sup.1H-NMR (270 MHz DMSO-d.sub.6) .delta.: 1.38 (2H, m),
1.75 (6H, s), 1.88 (2H, m), 2.44 (5H, m), 2.94 (2H, m), 3.57 (4H,
m), 4.58 (2H, m), 7.10 (1H, s), 7.32 (1H, s), 7.75 (1 H, d, J=8.4),
8.00 (2H, m), 8.15 (1H, d, J=8.4), 8.85 (1H, s), 12.3 (1H, s)
Example 874
[4882] Compound AZ7-2
5,5-Dimethyl-3-(4-morpholin-4-yl-piperidin-1-yl)-11-oxo-6,11-dihydro-5H-py-
rido[4,3-b]carbazole-8-carbonitrile
##STR00889##
[4884]
5,5-Dimethyl-3-(4-morpholin-4-yl-piperidin-1-yl)-11-oxo-6,11-dihydr-
o-5H-pyrido[4,3-b]carbazole-8-carboxylic acid amide (54 mg) was
dissolved in DMF (1 ml), added with thionyl chloride (25 .mu.L),
and the mixture was stirred at room temperature for 1 hr. The
reaction mixture was diluted with water. The precipitated matters
were collected by filtration to obtain the title compound (25 mg,
49%).
[4885] LCMS: m/z 456 [M+H].sup.+
[4886] HPLC retention time: 1.55 min (analysis condition U)
[4887] .sup.1H-NMR (270 MHz DMSO-d.sub.6) .delta.: 1.36 (2H, m),
1.76 (6H, s), 1.89 (2H, m), 2.44 (5H, m), 2.95 (2H, m), 3.57 (4H,
m) 4.58 (2H, m), 7.10 (1H, s), 7.59 (1H, d, J=8.0), 7.99 (1H, s),
8.29 (1H, d, J=8.0), 8.86 (1H, s), 12.7 (1H, s)
[4888] The compounds described in the following Tables 12-13 were
synthesized by introducing a corresponding amino group to
6-cyano-2-[1-(2-fluoropyridin-4-yl)-1-methyl-ethyl]-1H-indole-3-carboxyli-
c acid ethyl ester and forming a ring according to the method that
is used for the synthesis of Compound AZ7-1. Furthermore, the
preparation was carried out by converting the substituent group at
position 3 from a carboxamide group to a cyano group according to
the method that is used for the synthesis of Compound AZ7-2.
TABLE-US-00012 TABLE 12 Ex- HPLC Re- ample Comp. Con- tention No.
No. Structure Compound Name dition Time m/z 875 AZ7-3 ##STR00890##
3-[4-((2R,6S)-2,6- Dimethyl-morpholine- 4-yl)-piperidine-1-
yl]-5,5-dimethyl-11- oxo-6,11-dihydro-5H- pyrido[4,3-
b]carbazole-8- carboxylic acid amide U 1.32 502 876 AZ7-4
##STR00891## 3-[4-((2R,6S)-2,6- Dimethyl-morpholine-
4-yl)-piperidine-1- yl]-5,5-dimethyl-11- oxo-6,11-dihydro-5H-
pyrido[4,3- b]carbazole-8- carbonitrile U 1.70 484 877 AZ7-5
##STR00892## 3-[1,4']Biperidinyl- 1'-yl-5,5-dimethyl-
11-oxo-6,11-dihydro- 5H-pyrido[4,3- b]carbazole-8- carboxylic acid
amide U 1.30 472 878 AZ7-6 ##STR00893## 5,5-Dimethyl-3-(4-
methyl-4-morpholine- 4-yl-piperidine-1-yl)- 11-oxo-6,11-dihydro-
5H-pyrido[4,3- b]carbazole-8- carboxylic acid amide Y 1.00 488 879
AZ7-7 ##STR00894## 5,5-Dimethyl-3-(4- methyl-4-morpholine-
4-yl-piperidine-1-yl)- 11-oxo-6,11-dihydro- 5H-pyrido[4,3-
b]carbazole-8- carbonitrile Y 1.62 470 880 AZ7-8 ##STR00895##
3-(4-Cyclobutyl- piperazine-1-yl)-5,5- dimethyl-11-oxo-
6,11-dihydro-5H- pyrido[4,3- b]carbazole-8- carboxylic acid amide Y
1.22 444 881 AZ7-9 ##STR00896## 3-(4-Cyclobutyl-
piperazine-1-yl)-5,5- dimethyl-11-oxo- 6,11-dihydro-5H- pyrido[4,3-
b]carbazole-8- carbonitrile Y 1.55 426 882 AZ7-10 ##STR00897##
3-[1,4']Biperidinyl- 1'-yl-5,5-dimethyl- 11-oxo-6,11-dihydro-
5H-pyrido[4,3- b]carbazole-8- carbonitrile Y 1.73 454 883 AZ7-11
##STR00898## 5,5-Dimethyl-3- morpholine-4-yl-11-
oxo-6,11-dihydro-5H- pyrido[4,3- b]carbazole-8- carboxylic acid
amide U 1.33 391 884 AZ7-12 ##STR00899## 5,5-Dimethyl-3-
morpholine-4-yl-11- oxo-6,11-dihydro-5H- pyrido[4,3- b]carbazole-8-
carbonitrile U 1.77 373 885 AZ7-13 ##STR00900## 3-[4-(1-Ethyl-
cyclobutyl)- piperazine-1-yl]5,5- dimethyl-11-oxo- 6,11-dihydro-5H-
pyrido[4,3- b]carbazole-8- carbonitrile Y 1.93 464 886 AZ7-14
##STR00901## 3-(4-Ethyl-4- morpholine-4-yl- piperidine-1-yl)-5,5-
dimethyl-11-oxo- 6,11-dihydro-5H- pyrido[4,3- b]carbazole-8-
carboxylic acid amide Y 1.18 502 887 AZ7-15 ##STR00902##
3-(4-Ethyl-4- morpholine-4-yl- piperidine-1-yl)-5,5-
dimethyl-11-oxo- 6,11-dihydro-5H- pyrido[4,3- b]carbazole-8-
carbonitrile Y 1.78 484 888 AZ7-16 ##STR00903## 3-[4-(1-Ethyl-
cyclobutyl)- piperazine-1-yl]5,5- dimethyl-11-oxo- 6,11-dihydro-5H-
pyrido[4,3- b]carbazole-8- carboxylic acid amide Y 1.25 472
TABLE-US-00013 TABLE 13 Example Comp. HPLC Retention No. No.
Structure Compound Name Condition Time m/z 889 AZ7-17 ##STR00904##
3-(4-Isopropyl- 4-morpholine-4- yl-piperidine-1- yl)-5,5-dimethyl-
11-oxo-6,11- dihydro-5H- pyrido[4,3- b]carbazole-8- carboxylic acid
amide U 1.27 516 890 AZ7-18 ##STR00905## 5,5-Dimethyl-3-
(4-morpholine-4- yl-4-propyl- piperidine-1-yl)- 11-oxo-6,11-
dihydro-5H- pyrido[4,3- b]carbazole-8- carboxylic acid amide U 1.36
516 891 AZ7-19 ##STR00906## 5,5-Dimethyl-3- (4-morpholine-4-
yl-4-propyl- piperidine-1-yl)- 11-oxo-6,11- dihydro-5H- pyrido[4,3-
b]carbazole-8- carbonitrile U 1.68 498 892 AZ7-20 ##STR00907##
3-(4-Isopropyl- 4-morpholine-4- yl-piperidine-1- yl)-5,5-dimethyl-
11-oxo-6,11- dihydro-5H- pyrido[4,3- b]carbazole-8- carbonitrile U
1.60 498 893 AZ7-21 ##STR00908## 5,5-Dimethyl- 11-oxo-3-[4-(1-
propyl- cyclobutyl)- piperazine-1-yl]- 6,11-dihydro-5H- pyrido[4,3-
b]carbazole-8- carboxylic acid amide U 1.58 486 894 AZ7-22
##STR00909## 5,5-Dimethyl- 11-oxo-3-[4-(1- propyl- cyclobutyl)-
piperazine-1-yl]- 6,11-dihydro-5H- pyrido[4,3- b]carbazole-8-
carbonitrile U 1.97 468
[4889] The compounds described in the following Table 14 were
synthesized from (2-chloro-3-fluoropyridin-4-yl)methanol according
to the method that is used for the synthesis of Compound AZ1 to
AZ7-2.
TABLE-US-00014 TABLE 14 Example Comp. HPLC Retention No. No.
Structure Compound Name Condition Time m/z 895 AZ7-23 ##STR00910##
4-Fluoro-5,5- dimethyl-3-(4- morpholin-4-yl- piperidin-1-yl)-11-
oxo-6,11-dihydro- 5H-pyrido[4,3- b]carbazole-8- carboxylic acid
amide U 1.37 492 896 AZ7-24 ##STR00911## 4-Fluoro-5,5-
dimethyl-3-(4- morpholin-4-yl- piperidin-1-yl)-11-
oxo-6,11-dihydro- 5H-pyrido[4,3- b]carbazole-8- carbonitrile U 1.14
474 897 AZ7-25 ##STR00912## 4-Fluoro-5,5- dimethyl-11-oxo-3-
[4-(3-oxo- piperazin-1-yl)- piperidin-1-yl]-6,11- dihydro-5H-
pyrido[4,3- b]carbazole-8- carboxylic acid amide U 1.32 505 898
AZ7-26 ##STR00913## 3- [1,4']Bipiperidinyl- 1'-yl-4-fluoro-5,5-
dimethyl-11-oxo- 6,11-dihydro-5H- pyrido[4,3- b]carbazole-8-
carboxylic acid amide U 1.45 490 899 AZ7-27 ##STR00914## 3-
[1,4']Bipiperidinyl- 1'-yl-4-fluoro-5,5- dimethyl-11-oxo-
6,11-dihydro-5H- pyrido[4,3- b]carbazole-8- carbonitrile U 1.87
472
Example 900
[4890] Compound BZ1
2-Cyano-4-hydrazinopyridine
##STR00915##
[4892] 4-Chloro-2-cyanopyridine (1 g) was dissolved in hydrazine
monohydrate (1 ml) and 1,4-dioxane (10 ml), and stirred overnight
under reflux. The reaction solution was diluted with water (30 ml)
and extracted repeatedly with ethyl acetate. The organic layer was
concentrated to obtain the title compound as a crude product, which
was used for the next step without further purification.
[4893] LCMS: m/z 135 [M+H].sup.+
Example 901
[4894] Compound BZ2-1
8-Methoxy-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[f]pyrido[4,3-b]indol-3-
-carbonitrile
##STR00916##
[4896] According to the method used for synthesizing Compound A3-1,
the intermediate was prepared from 2-cyano-4-hydrazinopyridine and
7-methoxy-1,1-dimethyl-3,4 dihydro-1H-naphthalen-2-one. Without any
purification, the intermediate was subjected to oxidation according
to the method used for synthesizing Compound A4 to obtain the title
compound.
[4897] LCMS: m/z 318 [M+H].sup.+
[4898] HPLC retention time: 2.10 min (analysis condition U)
Example 902
[4899] Compound BZ2-2
3-Chloro-8-methoxy-6,6-dimethyl-5,6-dihydro-benzo[f]pyrido[4,3-b]indol-11--
one
##STR00917##
[4901] According to the method used for synthesizing Compound A3-1,
the intermediate was prepared from 2-chloro-4-hydrazinopyridine and
7-methoxy-1,1-dimethyl-3,4 dihydro-1H-naphthalen-2-one. Without any
purification, the intermediate was subjected to oxidation according
to the method used for synthesizing Compound A4 to obtain the title
compound.
[4902] LCMS: m/z 327, 329 [M+H].sup.+
[4903] HPLC retention time: 1.80 min (analysis condition S)
Example 903
[4904] Compound CZ1
2-Bromo-8-methoxy-10,10-dimethyl-10,11-dihydro-1,11-diaza-benzo[b]fluoren--
5-one
##STR00918##
[4906] According to the method used for synthesizing Compound A3-1,
the intermediate was prepared from 2-bromo-6-hydrazinopyridine and
7-methoxy-1,1-dimethyl-3,4 dihydro-1H-naphthalen-2-one. Without any
purification, the intermediate was subjected to oxidation according
to the method used for synthesizing Compound A4 to obtain the title
compound.
[4907] LCMS: m/z 371, 373 [M+H].sup.+
[4908] HPLC retention time: 2.85 min (analysis condition U)
Example 904
[4909] Compound CZ2
8-Methoxy-10,10-dimethyl-5-oxo-10,11-dihydro-5H-1,11-diaza-benzo[b]fluoren-
e-2-carbonitrile
##STR00919##
[4911] According to the method 1 for Compound A5-2,
2-bromo-8-methoxy-10,10-dimethyl-10,11-dihydro-1,11-diaza-benzo[b]fluoren-
-5-one was subjected to cyanation to obtain the title compound.
[4912] LCMS: m/z 318 [M+H].sup.+
[4913] HPLC retention time: 2.35 min (analysis condition U)
Example 905
[4914] Compound CZ3
8-Hydroxy-10,10-dimethyl-5-oxo-10,11-dihydro-5H-1,11-diaza-benzo[b]fluoren-
e-2-carbonitrile
##STR00920##
[4916] According to the method used for synthesizing Compound A6,
8-methoxy-10,10-dimethyl-5-oxo-10,11-dihydro-5H-1,11-diaza-benzo[b]fluore-
ne-2-carbonitrile was subjected to demethylation to obtain the
title compound.
[4917] LCMS: m/z 304 [M+H].sup.+
[4918] HPLC retention time: 1.72 min (analysis condition S)
Example 906
[4919] Compound CZ4
Trifuloromethanesulfonic acid
2-cyano-10,10-dimethyl-5-oxo-10,11-dihydro-5H-1,11-diaza-benzo[b]fluoren--
8-yl ester
##STR00921##
[4921] According to the method used for synthesizing Compound B1,
8-hydroxy-10,10-dimethyl-5-oxo-10,11-dihydro-5H-1,11-diaza-benzo[b]fluore-
ne-2-carbonitrile was subjected to trifluoromethanesulfone
esterification to obtain the title compound.
[4922] LCMS: m/z 436 [M+H].sup.+
[4923] HPLC retention time: 3.32 min (analysis condition Y)
Example 907
[4924] Compound CZ5-1
10,10-Dimethyl-5-oxo-8-piperazin-1-yl-10,11-dihydro-5H-1,11-diaza-benzo[b]-
fluorene-2-carbonitrile
##STR00922##
[4926] According to the method used for synthesizing Compound B2-1,
trifuloromethanesulfonic acid
2-cyano-10,10-dimethyl-5-oxo-10,11-dihydro-5H-1,11-diaza-benzo[b]fluoren--
8-yl ester was introduced with piperazine to obtain the title
compound.
[4927] LCMS: m/z 372 [M+H].sup.+
[4928] HPLC retention time: 1.17 min (analysis condition S)
[4929] Compound CZ5-2
10,10-Dimethyl-8-(4-morpholin-4-yl-piperidin-1-yl)-5-oxo-10,11-dihydro-5H--
1,11-diaza-benzo[b]fluorene-2-carbonitrile
##STR00923##
[4931] According to the method used for synthesizing Compound B2-1,
trifuloromethanesulfonic acid
2-cyano-10,10-dimethyl-5-oxo-10,11-dihydro-5H-1,11-diaza-benzo[b]fluoren--
8-yl ester was introduced with 4-morpholin-4-yl piperidine to
obtain the title compound.
[4932] LCMS: m/z 456 [M+H].sup.+
[4933] HPLC retention time: 1.68 min (analysis condition U)
Example 909
[4934] Compound CZ6
8-(4-Cyclobutyl-piperazin-1-yl)-10,10-dimethyl-5-oxo-10,11-dihydro-5H-1,11-
-diaza-benzo[b]fluorene-2-carbonitrile
##STR00924##
[4936] According to the method used for synthesizing Compound
B3-32,
10,10-dimethyl-5-oxo-8-piperazin-1-yl-10,11-dihydro-5H-1,11-diaza-benzo[b-
]fluorene-2-carbonitrile was subjected to reductive amination with
cyclobutanone to obtain the title compound.
[4937] LCMS: m/z 426 [M+H].sup.+
[4938] HPLC retention time: 1.60 min (analysis condition U)
Example 910
[4939] Compound DZ1
6-Ethynyl-7-methoxy-1,1-dimethyl-3,4-dihydro-1H-naphthalen-2-one
##STR00925##
[4941]
6-Bromo-7-methoxy-1,1-dimethyl-3,4-dihydro-1H-naphthalen-2-one (1
g) was dissolved in acetonitrile (50 ml), added with
PdCl.sub.2(CH.sub.3CN).sub.2 (45 mg), X-phos (168 mg), CsCO.sub.3
(1.2 g) and trimethylsilylacetylene (0.9 ml), and the mixture was
stirred at 85.degree. C. for 2 hrs. The reaction mixture was
diluted with ethyl acetate (100 ml). The organic layer was washed
twice with 10% brine and concentrated under reduced pressure. The
resulting residues were dissolved in THF (10 ml), added with the
THF solution (4 ml) comprising tetrabutylammonium fluoride and
stirred at room temperature for 1 hr. The reaction mixture was
diluted with ethyl acetate (100 ml). The organic layer was washed
twice with 10% brine and concentrated under reduced pressure. The
resulting residues were purified by silica gel column
(n-hexane/ethyl acetate=9/1) to obtain the title compound (346 mg,
two step yield 43%).
[4942] LCMS: m/z 229 [M+H].sup.+
Example 911
[4943] Compound DZ2
6-Ethyl-7-methoxy-11-dimethyl-3,4-dihydro-1H-naphthalen-2-one
##STR00926##
[4945]
6-Ethynyl-7-methoxy-1,1-dimethyl-3,4-dihydro-1H-naphthalen-2-one
(346 mg) was dissolved in ethanol: THF (=2: 1 mixture solvent, 20
ml), added with 10% Pd/C (170 mg), and then the mixture was stirred
at room temperature for 1 hr under hydrogen atmosphere. The
catalyst was removed by filtration and the organic layer was
concentrated under reduced pressure to obtain the title compound
(322 mg, yield 91%).
[4946] LCMS: m/z 233 [M+H].sup.+
Example 912
[4947] Compound DZ3
2-Bromo-7-ethyl-8-methoxy-10,10-dimethyl-10,11-dihydro-1,11-diaza-benzo[b]-
fluoren-5-one
##STR00927##
[4949] According to the method used for synthesizing Compound A3-1,
the intermediate was prepared from 2-bromo-6-hydrazinopyridine and
6-ethyl-7-methoxy-1,1-dimethyl-3,4-dihydro-1H-naphthalen-2-one.
Without any purification, the intermediate was subjected to
oxidation according to the method used for synthesizing Compound A4
to obtain the title compound.
[4950] LCMS: m/z 399, 401 [M+H].sup.+
[4951] HPLC retention time: 3.35 min (analysis condition Y)
Example 913
[4952] Compound DZ4
7-Ethyl-8-methoxy-10,10-dimethyl-5-oxo-10,11-dihydro-5H-1,11-diaza-benzo[b-
]fluorene-2-carbonitrile
##STR00928##
[4954] According to the method 1 for Compound A5-2,
2-bromo-7-ethyl-8-methoxy-10,10-dimethyl-10,11-dihydro-1,11-diaza-benzo[b-
]fluoren-5-one was subjected to cyanation to obtain the title
compound.
[4955] LCMS: m/z 346 [M+H].sup.+
[4956] HPLC retention time: 3.05 min (analysis condition Y)
Example 914
[4957] Compound DZ5
7-Ethyl-8-hydroxy-10,10-dimethyl-5-oxo-10,11-dihydro-5H-1,11-diaza-benzo[b-
]fluorene-2-carbonitrile
##STR00929##
[4959] According to the method used for synthesizing Compound A5,
7-ethyl-8-methoxy-10,10-dimethyl-5-oxo-10,11-dihydro-5H-1,11-diaza-benzo[-
b]fluorene-2-carbonitrile was subjected to demethylation to obtain
the title compound.
[4960] LCMS: m/z 332 [M+H].sup.+
[4961] HPLC retention time: 2.60 min (analysis condition Y)
Example 915
[4962] Compound DZ6-1
Trifuloro-methanesulfonic acid
2-cyano-7-ethyl-10,10-dimethyl-5-oxo-10,11-dihydro-5H-1,11-diaza-benzo[b]-
fluoren-8-yl ester
##STR00930##
[4964] According to the method used for synthesizing Compound B1,
7-ethyl-8-hydroxy-10,10-dimethyl-5-oxo-10,11-dihydro-5H-1,11-diaza-benzo[-
b]fluorene-2-carbonitrile was subjected to trifluoromethanesulfone
esterification to obtain the title compound.
[4965] LCMS: m/z 464 [M+H].sup.+
[4966] HPLC retention time: 3.50 min (analysis condition Y)
[4967] The compounds described in the following Table 15 were
prepared from trifuloro-methanesulfonic acid
2-cyano-7-ethyl-10,10-dimethyl-5-oxo-10,11-dihydro-5H-1,11-diaza-benzo[b]-
fluoren-8-yl ester and corresponding amine according to the method
that is used for the synthesis of Compound B2-10. The compounds of
Example 919 and Example 920 were obtained as a by-product of the
reaction.
TABLE-US-00015 TABLE 15 Example Comp. HPLC Retention No. No.
Structure Compound Name Condition Time m/z 916 DZ7-1 ##STR00931##
8-(4-Cyclobutyl- piperazine-1-yl)-7-ethyl- 10,10-dimethyl-5-oxo-
10,11-dihydro-5H-1,11- diaza-benzo[b]fluorene- 2-carbonitrile Y
1.83 454 917 DZ7-2 ##STR00932## 7-Ethyl-10,10-dimethyl-
8-(4-morpholine-4-yl- piperidine-1-yl)-5-oxo-
10,11-dihydro-5H-1,11- diaza-benzo[b]fluorene- 2-carbonitrile Y
1.85 484 918 DZ7-3 ##STR00933## 7-Ethyl-10,10-dimethyl-
8-morpholine-4-yl-5- oxo-10,11-dihydro-5H- 1,11-diaza-
benzo[b]fluorene-2- carbonitrile Y 3.02 401 919 DZ7-4 ##STR00934##
7-Ethyl-10,10-dimethyl- 5-oxo-10,11-dihydro-5H- 1,11-diaza-
benzo[b]fluorene-2- carbonitrile Y 3.07 316 920 DZ7-5 ##STR00935##
7-Ethyl-10,10-dimethyl- 2-(morpholine-4- carbonyl)-8-morpholine-
4-yl-10,11-dihydro-1,11- diaza-benzo[b]fluorene- 5-one Y 2.70
489
Example 921
[4968] Compound DZ6-2
8-(2-Diethylamino-ethoxy)-11-(2-diethylamino-ethyl)-7-ethyl-10,10-dimethyl-
-5-oxo-10,11-dihydro-5H-1,11-diaza-benzo[b]fluorene-2-carbonitrile
##STR00936##
[4970] According to the method used for synthesizing Compound
A7-17,
7-ethyl-8-hydroxy-10,10-dimethyl-5-oxo-10,11-dihydro-5H-1,11-diaza-benzo[-
b]fluorene-2-carbonitrile was alkylated to obtain the title
compound.
[4971] LCMS: m/z 530 [M+H].sup.+
[4972] HPLC retention time: 1.38 min (analysis condition Y)
Example 922
[4973] Compound EZ1
2-(6-Methoxy-pyridin-2-yl)-2-methyl-propionic acid ethyl ester
##STR00937##
[4975] 2-Bromo-6-methoxypyridine (7.0 g), ethyl isobutyrate (4.75
g), tri t-butylphosphine (300 mg) and Pd.sub.2(dba).sub.3 (680 mg)
were dissolved in toluene (200 ml) under nitrogen atmosphere, added
with THF solution of LiHMDS (1.6 M, 24 ml), and the mixture was
stirred at 100.degree. C. for 6 hrs. The reaction mixture was
diluted with ethyl acetate (300 ml), and washed three times with
15% brine (200 ml). The organic layer was concentrated under
reduced pressure and the resulting residues were purified by silica
gel column (n-hexane/ethyl acetate=4/1) to obtain the title
compound (5.353 g, yield 60%).
[4976] LCMS: m/z 224 [M+H].sup.+
Example 923
[4977] Compound EZ2
2-(6-Methoxy-pyridin-2-yl)-2-methyl-propionic acid
##STR00938##
[4979] 2-(6-Methoxy-pyridin-2-yl)-2-methyl-propionic acid ethyl
ester (5.33 g) was dissolved in methanol (200 ml), added with 5 N
aqueous solution of potassium hydroxide (25 ml), and then stirred
under reflux. The reaction mixture was concentrated and neutralized
with 2N hydrochloric acid. The precipitated matters were collected
by filtration and dried to obtain the title compound (3.55 g).
[4980] LCMS: m/z 196 [M+H].sup.+
Example 924
[4981] Compound EZ3
4-(6-Methoxy-pyridin-2-yl)-4-methyl-3-oxo-pentanoic acid tert-butyl
ester
##STR00939##
[4983] The title compound was synthesized from
2-(6-methoxy-pyridin-2-yl)-2-methyl-propionic acid and
mono-tert-butyl malonic acid according to the method used for the
synthesis of Compound PR4. The resultant was used for the next step
without further purification.
Example 925
[4984] Compound EZ4-1
6-Cyano-2-[1-(6-methoxy-pyridin-2-yl)-1-methyl-ethyl]-1H-indole-3-carboxyl-
ic acid tert-butyl ester
##STR00940##
[4986] According to the method that is used for the preparation of
Compound PR5-1, the title compound was synthesized from
4-(6-methoxy-pyridin-2-yl)-4-methyl-3-oxo-pentanoic acid tert-butyl
ester and 4-chloro-3-nitrobenzonitrile
[4987] LCMS: m/z 392 [M+H].sup.+
Example 926
[4988] Compound EZ4-2
6-Cyano-2-[1-(6-methoxy-pyridin-2-yl)-1-methyl-ethyl]-benzofuran-3-carboxy-
lic acid tert-butyl ester
##STR00941##
[4990] According to the method that is used for the preparation of
Compound FR1, the title compound was synthesized from
4-(6-methoxy-pyridin-2-yl)-4-methyl-3-oxo-pentanoic acid tert-butyl
ester and 4-chloro-3-nitrobenzonitrile.
[4991] LCMS: m/z 393 [M+H].sup.+
Example 927
[4992] Compound EZ5-1
6-Cyano-2-[1-(6-methoxy-pyridin-2-yl)-1-methyl-ethyl]-1H-indole-3-carboxyl-
ic acid
##STR00942##
[4994] According to the method that is used for the preparation of
Compound PR7, the title compound was synthesized from
6-cyano-2-[1-(6-methoxy-pyridin-2-yl)-1-methyl-ethyl]-1H-indole-3-carboxy-
lic acid tert-butyl ester.
[4995] LCMS: m/z 336 [M+H].sup.+
Example 928
[4996] Compound EZ5-2
6-Cyano-2-[1-(6-methoxy-pyridin-2-yl)-1-methyl-ethyl]-benzofuran-3-carboxy-
lic acid
##STR00943##
[4998] According to the method that is used for the preparation of
Compound PR7, the title compound was synthesized from
6-cyano-2-[1-(6-methoxy-pyridin-2-yl)-1-methyl-ethyl]-benzofuran-3-carbox-
ylic acid tert-butyl ester.
[4999] LCMS: m/z 337 [M+H].sup.+
Example 929
[5000] Compound EZ6-1
2-Methoxy-11,11-dimethyl-5-oxo-10,11-dihydro-5H-pyrido[2,3-b]carbazole-8-c-
arboxylic acid amide
##STR00944##
[5002] According to the method that is used for the preparation of
Compound AZ7-1, the title compound was synthesized from
6-cyano-2-[1-(6-methoxy-pyridin-2-yl)-1-methyl-ethyl]-1H-indole-3-carboxy-
lic acid.
[5003] LCMS: m/z 336 [M+H].sup.+
[5004] HPLC retention time: 1.98 min (analysis condition S)
Example 930
[5005] Compound EZ6-2
2-Methoxy-11,11-dimethyl-5-oxo-5,11-dihydro-benzo[4,5]furo[3,2-g]quinoline-
-8-carboxylic acid amide
##STR00945##
[5007] According to the method that is used for the preparation of
Compound AZ7-1, the title compound was synthesized from
6-cyano-2-[1-(6-methoxy-pyridin-2-yl)-1-methyl-ethyl]-benzofuran-3-carbox-
ylic acid.
[5008] LCMS: m/z 337 [M+H].sup.+
[5009] HPLC retention time: 2.38 min (analysis condition S)
Example 931
[5010] Compound EZ7-1
2-Methoxy-11,11-dimethyl-5-oxo-10,11-dihydro-5H-pyrido[2,3-b]carbazole-8-c-
arbonitrile
##STR00946##
[5012] According to the method that is used for the preparation of
Compound AZ7-2, the title compound was synthesized from
2-methoxy-11,11-dimethyl-5-oxo-10,11-dihydro-5H-pyrido[2,3-b]carbazole-8--
carboxylic acid amide.
[5013] LCMS: m/z 318 [M+H].sup.+
[5014] HPLC retention time: 2.60 min (analysis condition S)
Example 932
[5015] Compound EZ7-2
2-Methoxy-11,11-dimethyl-5-oxo-5,11-dihydro-benzo[4,5]furo[3,2-g]quinoline-
-8-carbonitrile
##STR00947##
[5017] According to the method that is used for the preparation of
Compound AZ7-2, the title compound was synthesized from
2-methoxy-11,11-dimethyl-5-oxo-5,11-dihydro-benzo[4,5]furo[3,2-g]quinolin-
e-8-carboxylic acid amide.
[5018] LCMS: m/z 319 [M+H].sup.+
[5019] HPLC retention time: 3.18 min (analysis condition S)
Example 933
[5020] Compound EZ8-1
2-Hydroxy-11,11-dimethyl-5-oxo-10,11-dihydro-5H-pyrido[2,3-b]carbazole-8-c-
arbonitrile
##STR00948##
[5022] According to the method that is used for the preparation of
Compound A5,
2-methoxy-11,11-dimethyl-5-oxo-10,11-dihydro-5H-pyrido[2,3-b]carbazole-8--
carbonitrile was demethylated to synthesize the title compound.
[5023] LCMS: m/z 304 [M+H].sup.+
[5024] HPLC retention time: 1.70 min (analysis condition U)
Example 934
[5025] Compound EZ8-2
2-Hydroxy-11,11-dimethyl-5-oxo-5,11-dihydro-benzo[4,5]furo[3,2-g]quinoline-
-8-carbonitrile
##STR00949##
[5027] According to the method that is used for the preparation of
Compound A5,
2-methoxy-11,11-dimethyl-5-oxo-5,11-dihydro-benzo[4,5]furo[3,2-g]quinolin-
e-8-carbonitrile was demethylated to synthesize the title
compound.
[5028] LCMS: m/z 305 [M+H].sup.+
[5029] HPLC retention time: 2.17 min (analysis condition U)
[5030] The compounds described in the following Table 16 were
synthesized from
2-hydroxy-11,11-dimethyl-5-oxo-10,11-dihydro-5H-pyrido[2,3-b]carbazo-
le-8-carbonitrile or from
2-hydroxy-11,11-dimethyl-5-oxo-5,11-dihydro-benzo[4,5]furo[3,2-g]quinolin-
e-8-carbonitrile according to the method described in the
Table.
TABLE-US-00016 TABLE 16 Ex- HPLC Re- ample Comp. Con- tention No.
No. Structure Compound Name dition Time m/z Method 935 EZ9-1
##STR00950## Trifluoro- methanesulfonic acid 8-cyano-
11,11-dimethyl-5- oxo-10,11- dihydro-5H- pyrido[2,3-
b]carbazol-2-yl ester U 2.93 436 B1 936 EZ9-2 ##STR00951##
11,11-Dimethyl- 5-oxo-2- (tetrahydro-pyran- 4-yloxy)-10,11-
dihydro-5H- pyrido[2,3- b]carbazole-8- carbonitrile U 2.57 388 A7-1
937 EZ9-3 ##STR00952## 2-(2- Diethylamino- ethoxy)-11,11-
dimethyl-5-oxo- 10,11-dihydro-5H- pyrido[2,3- b]carbazole-8-
carbonitrile Y 1.63 403 A7-17 938 EZ9-4 ##STR00953## 2-(2-
Diethylamino- ethoxy)-10-(2- diethylamino- ethyl)-11,11-
dimethyl-5-oxo- 10,11-dihydro-5H- pyrido[2,3- b]carbazole-8-
carbonitrile Y 1.82 502 A7-17 939 EZ9-5 ##STR00954## 2-(2-
Diethylamino- ethoxy)-11,11- dimethyl-5-oxo- 5,11-dihydro-
benzo[4,5]furo[3,2- g]quinoline-8- carbonitrile Y 1.77 404
A7-17
[5031] The compounds described in the following Table 17 were
synthesized from Compound W3 and corresponding halide by alkylation
of hydroxyl group according to the method that is used for the
synthesis of Compound A7-17.
TABLE-US-00017 TABLE 17 Example Comp. HPLC Retention No. No.
Structure Compound Name Condition Time m/z 940 W4-3 ##STR00955##
7-(2-Dimethylamino- ethoxy)-6,6-dimethyl- 11-oxo-6,11-dihydro-
5H-benzo[b]carbazole- 3-carbonitrile 1 0.96 374.0 941 W4-4
##STR00956## 7-(3-Dimethylamino- propoxy)-6,6-dimethyl-
11-oxo-6,11-dihydro- 5H-benzo[b]carbazole- 3-carbonitrile 1 0.92
388.0
[5032] The compounds described in the following Table 18 were
synthesized according to the method shown below. Specifically,
Compound GT1-1 was prepared from Compound J2 and phenylhydrazine
according to the method that is used for the synthesis of Compound
A3 and Compound A4. Subsequently, in accordance with the
methylation carried out in the same manner as Compound A10-1,
Compound GT1-2 was prepared.
TABLE-US-00018 TABLE 18 Example Comp. HPLC Retention No. No.
Structure Compound Name Condition Time m/z Method 942 GT1- 1
##STR00957## 9-Methoxy-6,6- dimethyl-5,6- dihydro-
benzo[b]carbazol- 11-one A 2.36 292.0 A3 A4 943 GT1- 2 ##STR00958##
9-Methoxy-5,6,6- trimethyl-5,6- dihydro- benzo[b]carbazol- 11-one A
2.53 306.0 A10-1
[5033] The compounds described in the following Table 19 were
synthesized according to the method shown below. Specifically,
Compound GT2-1 was prepared from Compound A2 and phenylhydrazine
according to the method that is used for the synthesis of Compound
A3 and Compound A4.
[5034] Subsequently, by carrying out the alkylation in the same
manner as Compound A10-1, Compound GT2-2 and Compound GT2-8 were
prepared.
[5035] To obtain the compounds of the Table, chemical conversion of
Compound GT2-1 or the 5-alkylate of Compound GT2-1 was achieved by
using in combination the functional group modifications (e.g.,
demethylation according to the method used for the preparation of
Compound A6 and subsequent introduction of a functional group,
etc.) as explained before and described in the Table.
TABLE-US-00019 TABLE 19 Example Comp. HPLC Retention No. No.
Structure Compound Name Condition Time m/z Method 944 GT2-1
##STR00959## 8-Methoxy-6,6- dimethyl-5,6- dihydro-
benzo[b]carbazol- 11-one A 2.30 292.0 A3 A4 945 GT2-2 ##STR00960##
8-Methoxy-5,6,6- trimethyl-5,6- dihydro- benzo[b]carbazol- 11-one A
2.55 306.0 A10-1 946 GT2-3 ##STR00961## 8-(2- Diethylamino-
ethoxy)-5,6,6- trimethyl-5,6- dihydro- benzo[b]carbazol- 11-one A
1.90 391.0 A6 A7-17 A10-1 947 GT2-4 ##STR00962## 8-((R)-2,3-
Dihydroxy- propoxy)-5,6,6- trimethyl-5,6- dihydro-
benzo[b]carbazol- 11-one A 1.90 366.0 A6 A7-17 A10-1 948 GT2-5
##STR00963## 8-(2- Diethylamino- ethoxy)-6,6- dimethyl-5,6-
dihydro- benzo[b]carbazol- 11-one F 1.93 377.3 A6 A7-17 949 GT2-6
##STR00964## 8-(2- Diethylamino- ethoxy)-6,6- dimethyl-5-
propyl-5,6- dihydro- benzo[b]carbazol- 11-one A 2.09 419.0 A6 A7-17
A10-1 950 GT2-7 ##STR00965## 5-Benzyl-8-(2- diethylamino-
ethoxy)-6,6- dimethyl-5,6- dihydro- benzo[b]carbazol- 11-one B 4.83
467.3 A6 A7-17 A10-1 951 GT2-8 ##STR00966## 5-Ethyl-8- methoxy-6,6-
dimethyl-5,6- dihydro- benzo[b]carbazol- 11-one F 2.94 320.0 A10-1
952 GT2-9 ##STR00967## 8-(2- Diethylamino- ethoxy)-5-ethyl-
6,6-dimethyl-5,6- dihydro- benzo[b]carbazol- 11-one F 2.16 405.0 A6
A7-17 A10-1 953 GT2-10 ##STR00968## 8-(2- Diethylamino- ethoxy)-5-
isopropyl-6,6- dimethyl-5,6- dihydro- benzo[b]carbazol- 11-one A
2.02 419.0 A6 A7-17 A10-1 954 GT2-11 ##STR00969## 8-((R)-2,3-
Dihydroxy- propoxy)-6,6- dimethyl-5,6- dihydro- benzo[b]carbazol-
11-one C 2.17 352.2 A6 A7-17 A7- 14-2 955 GT2-12 ##STR00970## 5-
Methanesulfonyl- 8-methoxy-6,6- dimethyl-5,6- dihydro-
benzo[b]carbazol- 11-one C 2.81 370.1 A9-1 956 GT2-13 ##STR00971##
8-(2- Diethylamino- ethoxy)-5- methanesulfonyl- 6,6-dimethyl-5,6-
dihydro- benzo[b]carbazol- 11-one F 2.20 455.1 A6 A7-17 A9-1 957
GT2-14 ##STR00972## 8-(2- Diethylamino- ethoxy)-5-(2-
hydroxy-ethyl)- 6,6-dimethyl-5,6- dihydro- benzo[b]carbazol- 11-one
H 3.73 421.0 A6 A7-17 A10-1 958 GT2-15 ##STR00973## 6,6-Dimethyl-8-
((2R,3R)-2,3,4- trihydroxy- butoxy)-5,6- dihydro- benzo[b]carbazol-
11-one H 3.73 382.4 A7-1 A7- 14-2
[5036] The compounds described in the following Table 20 were
synthesized according to the method shown below. Specifically, by
using Compound A2 and phenylhydrazine having a corresponding
substituent group, 2 (or
3)-substituted-8-methoxy-6,6-dimethyl-6,11-dihydro-5H-benzo[b]carbazol-11-
-one was prepared according to the method that is used for the
synthesis of Compound A3 and Compound A4. Subsequently, to obtain
the compounds of the Table, chemical conversion of the above
compounds was achieved by using in combination the functional group
modifications as explained before and described in the Table.
TABLE-US-00020 TABLE 20 Exam- HPLC Reten- ple Comp. Condi- tion No.
No. Structure Compound Name tion Time m/z Method 959 GT3-1
##STR00974## 8-Methoxy-3,6,6- trimethyl-5,6- dihydro-
benzo[b]carbazol- 11-one A 2.39 306.0 A3 A4 960 GT3-2 ##STR00975##
8-(2-Diethylamino- ethoxy)-3,5,6,6- tetramethyl-5,6- dihydro-
benzo[b]carbazol- 11-one A 1.97 405.0 A6 A7-17 A10-1 961 GT3-3
##STR00976## 8-(2-Diethylamino- ethoxy)-6,6- dimethyl-3-nitro-
5,6-dihydro- benzo[b]carbazol- 11-one B 3.86 422.2 A6 A7-17 962
GT3-4 ##STR00977## 8-(2-Diethylamino- ethoxy)-6,6- dimethyl-3-
trifluoromethyl-5,6- dihydro- benzo[b]carbazol- 11-one A 2.03 445.0
A6 A7-17 963 GT3-5 ##STR00978## 8-(2-Diethylamino- ethoxy)-5-(2-
diethylamino- ethyl)-6,6- dimethyl-3-nitro- 5,6-dihydro-
benzo[b]carbazol- 11-one F 1.74 521.3 A6 A7-17 A10-1 964 GT3-6
##STR00979## 2,6,6-Trimethyl-8- ((2R,3R)-2,3,4- trihydroxy-butoxy)-
5,6-dihydro- benzo[b]carbazol- 11-one F 2.03 396.0 A6 A7-17 A7-
14-2 965 GT3-7 ##STR00980## 2-Fluoro-6,6- dimethyl-8-
((2R,3R)-2,3,4- trihydroxy-butoxy)- 5,6-dihydro- benzo[b]carbazol-
11-one F 1.99 400.0 A6 A7-17 A7-14-2 966 GT3-8 ##STR00981##
2-Chloro-6,6- dimethyl-8- ((2R,3R)-2,3,4- trihydroxy-butoxy)-
5,6-dihydro- benzo[b]carbazol- 11-one F 2.14 416.0 A6 A7-17 A7-
14-2 967 GT3-9 ##STR00982## 6,6-Dimethyl-11- oxo-8-((2R,3R)-
2,3,4-trihydroxy- butoxy)-6,11- dihydro-5H- benzo[b]carbazole-
2-carbonitrile F 1.90 407.4 A6 A7-17 A7- 14-2 968 GT3-10
##STR00983## 6,6-Dimethyl-3- trifluoromethoxy-8- ((2R,3R)-2,3,4-
trihydroxy-butoxy)- 5,6-dihydro- benzo[b]carbazol- 11-one F 2.31
466.4 A6 A7-17 A7- 14-2 969 GT3-11 ##STR00984## 8-((R)-2,3-
Dihydroxy- propoxy)-6,6- dimethyl-3- trifluoromethoxy- 5,6-dihydro-
benzo[b]carbazol- 11-one F 2.43 436.4 A6 A7-17 A7- 14-2 970 GT3-12
##STR00985## 8-((R)-2,3- Dihydroxy- propoxy)-3- methoxy-5,6,6-
trimethyl-5,6- dihydro- benzo[b]carbazol- 11-one B 3.79 396.5 A6
A7-17 A10-1 A7- 14-2 971 GT3-13 ##STR00986## 8-((R)-2,3- Dihydroxy-
propoxy)-3- methoxy-6,6- dimethyl-5,6- dihydro- benzo[b]carbazol-
11-one B 3.40 382.4 A6 A7-17 A7- 14-2
[5037] The compounds described in the following Table 21 were
synthesized according to the method shown below. Specifically, by
using Compound E1 and phenylhydrazine having a corresponding
substituent group,
9-bromo-1-chloro-8-methoxy-6,6-dimethyl-5,6-dihydro-benzo[b]carbazol-11-o-
ne or
9-bromo-8-methoxy-6,6-dimethyl-3-trifuloromethoxy-5,6-dihydro-benzo[-
b]carbazol-11-one was prepared according to the method used for the
synthesis of Compound A3 and Compound A4. Subsequently, to obtain
the compounds of the Table, chemical conversion of the above
compounds was achieved by using in combination the functional group
modifications as explained before and described in the Table.
TABLE-US-00021 TABLE 21 Exam- HPLC Reten- ple Comp. Condi- tion No.
No. Structure Compound Name tion Time m/z Method 972 GT4-1
##STR00987## 9-Bromo-8-((R)- 2,3-dihydroxy- propoxy)-6,6-
dimethyl-3- trifluoromethoxy- 5,6-dihydro- benzo[b]carbazol- 11-one
C 2.68 514.0 A6 A7-17 A7- 14-2 973 GT4-2 ##STR00988## 9-Bromo-1-
chloro-8-((R)-2,3- dihydroxy- propoxy)-6,6- dimethyl-5,6- dihydro-
benzo[b]carbazol- 11-one C 2.58 464.0 A6 A7-17 A7- 14-2
[5038] The compounds described in the following Tables 22-23 were
synthesized according to the method shown below. Specifically,
catalytic reduction of Compound GT3-3 was carried out according to
the method used for the preparation of Compound D2 to prepare
Compound GT5-1.
[5039] Reductive alkylation of Compound GT5-1 was carried out
according to the method used for the preparation of Compound B3-32
for the introduction of a methyl group or a benzyl group (Compound
GT5-2, Compound GT5-3).
[5040] Catalytic reduction of Compound GT5-3 was carried out
according to the method used for the preparation of Compound D2,
and then processed to prepare Compound GT5-4.
[5041] The resulting amino derivatives of Compound GT5-1 to 4 were
reacted with corresponding acyl chloride, isocynate, or
chloroformate according to the method used for the preparation of
Compound A9-1 to obtain the compounds of the Table.
TABLE-US-00022 TABLE 22 Exam- Reten- ple Comp. HPLC tion No. No.
Structure Compound Name Condition Time m/z Method 974 GT5-1
##STR00989## 3-Amino-8-(2- diethylamino- ethoxy)-6,6- dimethyl-5,6-
dihydro- benzo[b]carbazol- 11-one A 1.15 392.3 D2 975 GT5-2
##STR00990## 8-(2-Diethylamino- ethoxy)-3- dimethylamino-6,6-
dimethyl-5,6- dihydro- benzo[b]carbazol- 11-one A 1.18 420.2 B3-32
976 GT5-3 ##STR00991## 3-(Benzyl-methyl- amino)-8-(2- diethylamino-
ethoxy)-6,6- dimethyl-5,6- dihydro- benzo[b]carbazol- 11-one B 3.05
496.4 B3-32 977 GT5-4 ##STR00992## 8-(2-Diethylamino- ethoxy)-6,6-
dimethyl-3- methylamino-5,6- dihydro- benzo[b]carbazol- 11-one B
2.46 406.3 B3-32 D2 978 GT5-5 ##STR00993## Pentanoic acid [8-
(2-diethylamino- ethoxy)-6,6- dimethyl-11-oxo- 6,11-dihydro-5H-
benzo[b]carbazol- 3-yl]amide C 2.52 476.5 A9-1 979 GT5-6
##STR00994## N-[8-(2- Diethylamino- ethoxy)-6,6- dimethyl-11-oxo-
6,11-dihydro-5H- benzo[b]carbazol- 3-yl]-2,2-dimethyl- A 1.74 476.4
A9-1 propionamide 980 GT5-7 ##STR00995## [8-(2- Diethylamino-
ethoxy)-6,6- dimethyl-11-oxo- 6,11-dihydro-5H- benzo[b]carbazol-
3-yl]-carbamic acid 2-methoxy-ethyl A 1.55 494.3 A9-1 ester 981
GT5-8 ##STR00996## 1-[8-(2- Diethylamino- ethoxy)-6,6-
dimethyl-11-oxo- 6,11-dihydro-5H- benzo[b]carbazol-
3-yl]-3-phenyl-urea B 3.79 511.3 A9-1 982 GT5-9 ##STR00997##
N-[8-(2- Diethylamino- ethoxy)-6,6- dimethyl-11-oxo-
6,11-dihydro-5H- benzo[b]carbazol- 3-yl]-2-phenyl- acetamide B 3.81
510.4 A9-1 983 GT5-10 ##STR00998## N-[8-(2- Diethylamino-
ethoxy)-6,6- dimethyl-11-oxo- 6,11-dihydro-5H- benzo[b]carbazol-
3-yl]-3- trifluoromethyl- benzamide B 4.47 564.4 A9-1 984 GT5-11
##STR00999## 1-[8-(2- Diethylamino- ethoxy)-6,6- dimethyl-11-oxo-
6,11-dihydro-5H- benzo[b]carbazol- 3-yl]-3-(3- trifluoromethyl- B
4.55 579.4 A9-1 phenyl)-urea 985 GT5-12 ##STR01000## [8-(2-
Diethylamino- ethoxy)-6,6- dimethyl-11-oxo- 6,11-dihydro-5H-
benzo[b]carbazol- 3-yl]-carbamic acid 3-trifluoromethyl- H 5.17
580.1 A9-1 phenyl ester 986 GT5-13 ##STR01001## N-[8-(2-
Diethylamino- ethoxy)-6,6- dimethyl-11-oxo- 6,11-dihydro-5H-
benzo[b]carbazol- 3-yl]-2-phenoxy- acetamide C 2.57 526.1 A9-1 987
GT5-14 ##STR01002## 1-[8-(2- Diethylamino- ethoxy)-6,6-
dimethyl-11-oxo- 6,11-dihydro-5H- benzo[b]carbazol-
3-yl]-1-methyl-3- phenyl-urea B 3.83 525.6 A9-1
TABLE-US-00023 TABLE 23 Example Comp. HPLC Retention No. No.
Structure Compound Name Condition Time m/z Method 988 GT5-15
##STR01003## 1-[8-(2- Diethylamino- ethoxy)-6,6- dimethyl-11-oxo-
6,11-dihydro-5H- benzo[b]carbazol- 3-yl]-1-methyl-3-
(3-trifluoromethyl- phenyl)-urea B 4.58 593.4 A9-1 989 GT5-16
##STR01004## 3-Benzyl-1-[8-(2- diethylamino- ethoxy)-6,6-
dimethyl-11-oxo- 6,11-dihydro-5H- benzo[b]carbazol- 3-yl]-1-methyl-
urea B 3.81 539.4 A9-1 990 GT5-17 ##STR01005## N-[8-(2-
Diethylamino- ethoxy)-6,6- dimethyl-11-oxo- 6,11-dihydro-5H-
benzo[b]carbazol- 3-yl]-N-methyl-3- trifluoromethyl- benzamide B
415 578.3 A9-1 991 GT5-18 ##STR01006## N-[8-(2- Diethylamino-
ethoxy)-6,6- dimethyl-11-oxo- 6,11-dihydro-5H- benzo[b]carbazol-
3-yl]N-methyl-2- phenoxy- acetamide C 262 540.4 A9-1 992 GT5-19
##STR01007## 3-(4-tert-Butyl- phenyl)-1-[8-(2- diethylamino-
ethoxy)-6,6- dimethyl-11-oxo- 6,11-dihydro-5H- benzo[b]carbazol-
3-yl]-1-methyl- F 2.45 581.6 A9-1 urea 993 GT5-20 ##STR01008##
1-[8-(2- Diethylamino- ethoxy)-6,6- dimethyl-11-oxo-
6,11-dihydro-5H- benzo[b]carbazol- 3-yl]-3-(4- methoxy-phenyl)- B
377 555.4 A9-1 1-methyl-urea 994 GT5-21 ##STR01009## [8-(2-
Diethylamino- ethoxy)-6,6- dimethyl-11-oxo- 6,11-dihydro-5H-
benzo[b]carbazol- 3-yl]carbamic acid phenyl ester A 1.89 512.2
A9-1
[5042] The compounds described in the following Table 24 were
synthesized according to the method shown below. Specifically,
having Compound T22-1 as a starting material,
8-[(4R,5R)-5-(tert-butyl-dimethylsilanyloxymethyl)-2,2-dimethyl-[1,3]diox-
olan-4-yl
methoxy]-6,6-dimethyl-5,6-dihydro-11-oxo-benzo[b]carbazole-3-car-
boxylic acid was prepared according to the method that is used for
the preparation of Compound B2-28.
[5043] The resulting carboxylic acid was subjected to dehydrating
condensation with corresponding amine, alcohol according to the
method that is used for the preparation of Compound A9-10.
Subsequently, deprotection was carried out according to the method
used for the preparation of Compound T22-1-1 and Compound T22-1-2
to obtain the compounds described in the Table.
TABLE-US-00024 TABLE 24 Exam- HPLC Reten- ple Comp. Condi- tion No.
No. Structure Compound Name tion Time m/z Method 995 GT6-1
##STR01010## 6,6-Dimethyl-11-oxo-8-((2R,3R)-
2,3,4-trihydroxy-butoxy)-6,11- dihydro-5H-benzo[b]carbazole-
3-carboxylic acid phenylamide A 1.79 501.0 A9-10 996 GT6-2
##STR01011## 6,6-Dimethyl-11-oxo-8-((2R,3R)-
2,3,4-trihydroxy-butoxy)-6,11- dihydro-5H-benzo[b]carbazole-
3-carboxylic acid dimethylamide D 1.33 453.0 A9-10 997 GT6-3
##STR01012## 6,6-Dimethyl-11-oxo-8-((2R,3R)-
2,3,4-trihydroxy-butoxy)-6,11- dihydro-5H-benzo[b]carbazole-
3-carboxylic acid 2- hydroxy-ethyl ester A 1.40 470.0 A9-10 998
GT6-4 ##STR01013## 6,6-Dimethyl-11-oxo-8-((2R,3R)-
2,3,4-trihydroxy-butoxy)-6,11- dihydro-5H-benzo[b]carbazole-
3-carboxylic acid butylamide D 1.55 481.0 A9-10 999 GT6-5
##STR01014## 6,6-Dimethyl-11-oxo-8-((2R,3R)-
2,3,4-trihydroxy-butoxy)-6,11- dihydro-5H-benzo[b]carbazole-
3-carboxylic acid (2-methoxy-ethyl)-amide D 1.30 483.0 A9-10 1000
GT6-6 ##STR01015## 6,6-Dimethyl-11-oxo-8-((2R,3R)-
2,3,4-trihydroxy-butoxy)-6,11- dihydro-5H-benzo[b]carbazole-
3-carboxylic acid methylamide D 1.24 439.0 A9-10 1001 GT6-7
##STR01016## 6,6-Dimethyl-11-oxo-8-((2R,3R)-
2,3,4-trihydroxy-butoxy)-6,11- dihydro-5H-benzo[b]carbazole-
3-carboxylic acid benzylamide D 1.58 515.0 A9-10 1002 GT6-8
##STR01017## 6,6-Dimethyl-11-oxo-8-((2R,3R)-
2,3,4-trihydroxy-butoxy)-6,11- dihydro-5H-benzo[b]carbazole-
3-carboxylic acid amide D 1.18 425.0 A9-10 1003 GT6-9 ##STR01018##
6,6-Dimethyl-11-oxo-8-((2R,3R)- 2,3,4-trihydroxy-butoxy)-6,11-
dihyrdo-5H-benzo[b]carbazole- 3-carboxylic acid pyridin-4ylamide D
1.40 502.0 A9-10 1004 GT6-10 ##STR01019##
6,6-Dimethyl-11-oxo-8-((2R,3R)- 2,3,4-trihydroxy-butoxy)-6,11-
dihydro-5H-benzo[b]carbazole- 3-carboxylic acid D 1.01 426.0 E2-28
1005 GT6-11 ##STR01020## 6,6-Dimethyl-11-oxo-8-((2R,3R)-
2,3,4-trihydroxy-butoxy)-6-,11- dihydro-5H-benzo[b]carbazole-
3-carboxylic acid pyridin-2-ylamide D 1.52 502.0 A9-10 1006 GT6-12
##STR01021## 6,6-Dimethyl-11-oxo-8-((2R,3R)-
2,3,4-trihydroxy-butoxy)-6,11- dihydro-5H-benzo[b]carbazole-
3-carboxylic acid pyridin-3-ylamide D 1.34 502.0 A9-10 1007 GT6-13
##STR01022## 6,6-Dimethyl-11-oxo-8-((2R,3R)-
2,3,4-trihydroxy-butoxy)-6,11- dihydro-5H-benzo[b]carbazole-
3-carbolic acid phenethyl-amide D 1.67 529.0 A9-10 1008 GT6-14
##STR01023## N-[6,6-Dimethyl-11-oxo-8- ((2R,3R)-2,3,4-trihydroxy-
butoxy)-6,11-dihydro- 5H-benzo[b]carbazole-3- carbonyl]-
benzenesulfonamide D 1.23 565.0 A9-10
[5044] To the compounds described in the following Table 25, a
hydroxyl group was introduced from Compound T17-3 according to the
method described in JACS 2006, Vol. 128, page 10964. Subsequently,
deprotection was carried out according to the method used for
Compound A7-14-2 and Compound T22-2 to obtain the compounds shown
below.
TABLE-US-00025 TABLE 25 Exam- Reten- ple Comp. HPLC tion No. No.
Structure Compound Name Condition Time m/z 1009 GT7-1 ##STR01024##
8-((R)-2,3-Dihydroxy-propoxyl-3- hydroxy-6,6-dimethyl-5,6-dihydro-
benzo[b]carbazol-11-one B 259 368.4 1010 GT7-2 ##STR01025##
8-((R)-2,3-Dihydroxy-propoxy-3-
hydroxy-5,6,6-trimethyl-5,6-dihydro- benzo[b]carbazol-11-one C 1.90
382.4
[5045] The compounds described in the following Table 26 were
prepared by alkylation according to the method used for the
preparation of Compound A7-1 from Compound GT7-1 or Compound GT7-2,
or by carbamation according to the method used for the preparation
of A9-1.
TABLE-US-00026 TABLE 26 Exam- HPLC Reten- ple Comp. Condi- tion No.
No. Structure Compound Name tion Time m/z Method 1011 GT8-1
##STR01026## 8-((R)-2,3-Dihydroxy-propoxy)-
3-ethoxy-5,6,6-trimethyl-5,6- dihydro-benzo[b]carbazol-11- one C
2.43 410.5 A7-1 1012 GT8-2 ##STR01027##
8-((R)-2,3-Dihydroxy-propoxy)- 3-ethoxy-6,6-dimethyl-5,6-
dihydro-benzo[b]carbazol-11- one C 2.30 396.5 A7-1 1013 GT8-3
##STR01028## 8-((R)-2,3-Dihydroxy-propoxy)-
5,6,6-trimethyl-3-(oxetan-3- yloxy)-5,6-dihydro-benzo[b]
carbazol-11-one B 1.72 438.5 A7-1 1014 GT8-4 ##STR01029##
Phenyl-carbamic acid 8-((R)- 2,3-dihydroxy-propoxy)- 6,6-dimethyl-
11-oxo-6,11-dihydro-5H- benzo[b]carbazol-3-yl ester B 4.23 487.0
A9-1
Example 1015
[5046] Compound GT9-1
8-((R)-2,3-Dihydroxy-propoxy)-6,6-dimethyl-3-(2H-tetrazol-5-yl)-5,6-dihydr-
o-benzo[b]carbazol-11-one
##STR01030##
[5048]
8-((S)-2,2-Dimethyl-[1,3]dioxolan-4-ylmethoxy)-6,6-dimethyl-11-oxo--
6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile (20.0 mg, 0.048
mmol), ammonium chloride (1.28 mg, 0.024 mmol) and NaN.sub.3 (6.24
mg, 0.096 mmol) were dissolved in DMF, and the mixture was stirred
at 120.degree. C. for 14 hrs. NaN.sub.3 (6.24 mg, 0.096 mmol) was
further added to the mixture, which was then stirred at 120.degree.
C. for 30 hrs. The reaction solution was added with 1 N aqueous
solution of hydrochloric acid and extracted with ethyl acetate. The
organic layer was washed with saturated brine and concentrated
under reduced pressure. The resultant solid obtained after
concentration was washed with hexane: ethyl acetate=1: 1 to obtain
8-((S)-2,2-dimethyl-[1,3]dioxolan-4-yl
methoxy)-6,6-dimethyl-3-(2H-tetrazol-5-yl)-5,6-dihydro-benzo[b]carbazol-1-
1-one as a white solid.
[5049] The product was suspended in MeOH (1.0 ml), added with 1 N
aqueous solution of hydrochloric acid, and then stirred at
60.degree. C. for 1 hr and 30 min. After cooling to room
temperature, the reaction solution was concentrated under reduced
pressure, and the resulting solid was washed with DCM to obtain the
title compound as a pale yellow solid (13.4 mg, 66.3%).
[5050] LCMS: m/z 420 [M+H].sup.+
Example 1016
[5051] Compound GT9-2
8-((R)-2,3-Dihydroxy-propoxy)-6,6-dimethyl-3-thiophen-3-yl-5,6-dihydro-ben-
zo[b]carbazol-11-one
##STR01031##
[5053] 3-Bromo-8-((S)-2,2-dimethyl-[1,3]dioxolan-4-yl
methoxy)-6,6-dimethyl-5,6-dihydro-benzo[b]carbazol-11-one (20.0 mg,
0.043 mmol), thiophene-3-boronic acid (10.9 mg, 0.085 mmol),
K3PO.sub.4 (40 mg) and Pd (PPh.sub.3).sub.4 (9.9 mg, 0.0086 mmol)
were dissolved in DMA (0.8 ml) and water (0.2 ml), and stirred at
140.degree. C. for 10 min under microwave irradiation. The reaction
solution was diluted with ethyl acetate and washed with saturated
brine. The organic layer was concentrated under reduced pressure,
and the resulting residues were purified by column chromatography
(hexane/ethyl acetate) to obtain
8-((S)-2,2-dimethyl-[1,3]dioxolan-4-yl
methoxy)-6,6-dimethyl-3-thiphen-3-yl-5,6-dihydro-benzo[b]carbazol-11-one.
[5054] This product was suspended in MeOH (1.0 ml), added with 1 N
hydrochloric acid, and then stirred at 60.degree. C. for 1 hr and
30 min. The reaction solution was concentrated under reduced
pressure, and the resulting solid was washed with DCM to obtain the
title compound as a yellow solid (12.6 mg, 67.1%).
[5055] LCMS: m/z 434 [M+H].sup.+
[5056] Using the combination of Compound T18-1 and corresponding
boronic acid or the combination of
(S)-8-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)-6,6-dimethyl-3-(4,4,5,5-t-
etramethyl-1,3,2-dioxaborolan-2-yl)-5H-benzo[b]carbazol-11 (6H)-one
and corresponding bromide, the reaction was carried out in the same
manner as Compound GT9-2 to obtain the compounds of the following
Table 27.
TABLE-US-00027 TABLE 27 Exam- Reten- ple Comp. HPLC tion No. No.
Structure Compound Name Condition Time m/z 1017 GT9-3 ##STR01032##
8-((R)-2,3-Dihydroxy-propoxy)-6,6-
dimethyl-3-thiophen-2-yl-5,6-dihydro- benzo[b]carbazol-11-one B
4.59 494.0 1018 GT9-4 ##STR01033##
8-((R)-2,3-Dihydroxy-propoxy)-6,6- dimethyl-3-(1H-pyrazol-4-yl)-5,6
dihydro-benzo[b]carbazol-11-one B 4.04 418.0 1019 GT9-5
##STR01034## 8-((R)-2,3-Dihydroxy-propoxy)-6,6-
dimethyl-3-(2H-pyrazol-3-yl)-5,6- dihydro-benzo[b]carbazol-11-one A
1.51 418.0 1020 GT9-6 ##STR01035##
8-((R)-2,3-Dihydroxy-propoxy)-6,6-
dimethyl-3-thiazol-5-yl-5,6-dihydro- benzo[b]carbazol-11-one F 1.97
435.0 1021 GT9-7 ##STR01036## 8-((R)-2,3-Dihydroxy-propoxy)-3-(3H-
imidazol-4-yl)-6,6-dimethyl-5,6-dihydro- benzo[b]carbazol-11-one H
2.91 418.0
Example 1022
[5057] Compound GT10-1
8-((2R,3R)-2,3,4-Trihydroxybutoxy)-2',3',5',6'-tetrahydrospiro[benzo[b]car-
bazole-6,4'-pyran]-11 (5H)-one
##STR01037##
[5059] Preparation was carried out in the same manner as Compound
N6-1-2.
[5060] LCMS: m/z 434 [M+H].sup.+
[5061] HPLC retention time: 1.56 min (analysis condition A)
[5062] The compounds described in the following Table 28--were
synthesized according to the method shown below. Specifically, by
using the method for the preparation of Compound Z10, Z11, Z12 and
Z13, 8-hydroxy-6,6-dimethyl-6H-benzo[b]naphtho[2,3-d]furan-11-one
was prepared from Compound A2 and bromophenol. To the resulting
compound, a side chain or a synthetic equivalent thereof was
introduced according to Mitsunobu reaction that is used for the
preparation of Compound A7-1 or the method that is used for A7-17,
etc. After that, if necessary, functional group modification such
as deprotection, etc. was carried out to prepare the compounds
listed below.
TABLE-US-00028 TABLE 28 Exam- Reten- ple Comp. HPLC tion No. No.
Structure Compound Name Condition Time m/z 1023 GT11-1 ##STR01038##
(R)-5-(6,6-Dimethyl-11-oxo-6,11-
dihydro-benzo[b]naphtho[2,3-d]furan- 8-yloxy)-4-hydroxy-pentanoic
acid H 5.37 395.0 1024 GT11-2 ##STR01039##
(R)-5-(6,6-Dimethyl-11-oxo-6,11-
dihydro-benzo[b]naphtho[2,3-d]furan-
8-yloxymethyl)-pyrrolidin-2-one H 5.50 376.0 1025 GT11-3
##STR01040## 8-(3-Hydroxy-propoxy)-6,6-dimethyl-
6H-benzo[b]naphtho[2,3-d]furan-11- one H 5.97 337.0 1026 GT11-4
##STR01041## 8-(3-Ethyl-3-hydroxy-pentyloxy)-6,6-
dimethyl-6H-benzo[b]naphtho[2,3- d]furan-11-one H 9.29 393.0 1027
GT11-5 ##STR01042## (6,6-Dimethyl-11-oxo-6,11-dihydro-
benzo[b]naphtho[2,3-d]furan-8-yloxy)- acetic acid H 5.65 336.0 1028
GT11-6 ##STR01043## 4-(6,6-Dimethyl-11-oxo-6,11-dihydro-
benzo[b]naphtho[2,3-d]furan-8-yloxy)- butyric acid H 6.15 365.0
1029 GT11-7 ##STR01044## 5-(6,6-Dimethyl-11-oxo-6,11-dihydro-
benzo[b]naphtho[2,3-d]furan-8-yloxy)- pentanoic acid H 6.44 379.0
1030 GT11-8 ##STR01045## 6-(6,6-Dimethyl-11-oxo-6,11-dihydro-
benzo[b]naphtho[2,3-d]furan-8-yloxy)- hexanoic acid H 6.77 393.0
1031 GT11-9 ##STR01046## 2-(6,6-Dimethyl-11-oxo-6,11-dihydro-
benzo[b]naphtho[2,3-d]furan-8-yloxy)- N,N-diethyl-acetamide H 6.39
392.0 1032 GT11-10 ##STR01047## 6,6-Dimethyl-8-(2-morpholin-4-yl-
ethoxy)-6H-benzo[b]naphtho[2,3- d]furan-11-one H 4.45 392.0 1033
GT11-11 ##STR01048## 8-(2-Dimethylamino-ethoxy)-6,6-
dimethyl-6H-benzo[b]naphtho[2,3- d]furan-11-one H 4.59 350.0
TABLE-US-00029 TABLE 29 Example Comp. HPLC Retention No. No.
Structure Compound Name Condition Time m/z 1034 GT11-12
##STR01049## 8-((S)-2,3-Dihydroxy-propoxy)-6,6-
dimethyl-6H-benzo[b]naphtho[2,3- d]furan-11-one F 2.40 353.0 1035
GT11-13 ##STR01050## 8-((R)-2,3-Dihydroxy-propoxy)-6,6-
dimethyl-6H-benzo[b]naphtho[2,3- d]furan-11-one H 5.07 353.0 1036
GT11-14 ##STR01051## 6,6-Dimethyl-8-(2-pyrrolidin-1-yl-
ethoxy)-6H-benzo[b]naphtho[2,3- d]furan-11-one C 3.03 375.9 1037
GT11-15 ##STR01052## 6,6-Dimethyl-8-(2-piperidin-1-yl-
ethoxy)-6H-benzo[b]naphtho[2,3- d]furan-11-one C 3.15 389.9 1038
GT11-16 ##STR01053## 8-(3-Dimethylamino-propoxy)-6,6-
dimethyl-6H-benzo[b]naphtho[2,3- d]furan-11-one C 3.30 364.2 1039
GT11-17 ##STR01054## 8-(2-Azepan-1-yl-ethoxy)-6,6-dimethyl-
6H-benzo[b]naphtho[2,3-d]furan-11- one F 2.35 404.3 1040 GT11-18
##STR01055## (6,6-Dimethyl-11-oxo-6,11-dihydro-
benzo[b]naphtho[2,3-d]furan-8-yloxy)- acetic acid methyl ester D
2.38 351.0 1041 GT11-19 ##STR01056##
2-(6,6-Dimethyl-11-oxo-6,11-dihydro-
benzo[b]naphtho[2,3-d]furan-8-yloxy)-
N-(2-morpholin-4-yl-ethyl)-acetamide D 2.03 450.0 1042 GT11-20
##STR01057## 6,6-Dimethyl-8-(2-piperazin-1-yl-
ethoxy)-6H-benzo[b]naphtho[2,3- d]furan-11-one C 2.81 391.2 1043
GT11-21 ##STR01058## 8-[2-(4-Methanesulfonyl-piperazin-1-
yl)-ethoxy]-6,6-dimethyl-6H- benzo[b]naphtho[2,3-d]furan-11-one F
2.21 469.1 1044 GT11-22 ##STR01059##
2-(6,6-Dimethyl-11-oxo-6,11-dihydro-
benzo[b]naphtho[2,3-d]furan-8-yloxy)- acetamide D 1.95 336.0 1045
GT11-23 ##STR01060## 4-[2-(6,6-Dimethyl-11-oxo-6,11-
dihydro-benzo[b]naphtho[2,3-d]furan-
8-yloxy)-ethyl]-piperazine-1-carboxylic acidamide F 2.04 434.0 1046
GT11-24 ##STR01061## N-(2,3-Dihydroxy-propyl)-2-(6,6-
dimethyl-11-oxo-6,11-dihydro- benzo[b]naptho[2,3-d]furan-8-yloxy)-
acetamide D 1.82 410.0
TABLE-US-00030 TABLE 30 Example Comp. HPLC Retention No. No.
Structure Compound Name Condition Time m/z 1047 GT11-25
##STR01062## 8-[2-(4-Acetyl-piperazin-1-yl)-
ethoxy]-6,6-dimethyl-6H- benzo[b]naphtho [2,3-d]furan-11-one F 2.10
433.1 1048 GT11-26 ##STR01063## 4-[2-(6,6-Dimethyl-11-oxo-6,11-
dihydro-benzo[b]naphtho[2,3-d] furan-8-yloxy)-acetyl]-
piperazine-1-carboxylic acid tert-butyl ester D 2.53 505.0 1049
GT11-27 ##STR01064## 8-[2-(2-Hydroxy-ethoxy)-
ethoxy]-6,6-dimethyl-6H- benzo[b]naphtho[2,3- d]furan-11-one H 5.62
367.0 1050 GT11-28 ##STR01065## 8-{2-[2-(2-Hydroxy-ethoxy)-
ethoxy]-ethoxy}-6,6- dimethyl-6H-benzo[b]naphtho
[2,3-d]furan-11-one H 5.64 411.0 1051 GT11-29 ##STR01066##
8-(2-Imidazol-1-yl-ethoxy)-6,6- dimethyl-6H-benzo[b]
naphtho[2,3-d]furan-11-one F 2.05 373.1 1052 GT11-30 ##STR01067##
2-(6,6-Dimethyl-11-oxo- 6,11-dihydro-benzo[b]naphtho
[2,3-d]furan-8-yloxy)- N-(2-pyridin-4-yl-ethyl)- acetamide D 2.10
441.0 1053 GT11-31 ##STR01068## N-(2-Dimethylamino-ethyl)-
2-(6,6-dimethyl-11-oxo- 6,11-dihydro-benzo[b]naphtho
[2,3-d]furan-8-yloxy)- acetamide D 2.01 407.0 1054 GT11-32
##STR01069## 2-(6,6-Dimethyl-11-oxo- 6,11-dihydro-benzo[b]naphtho
[2,3-d]furan-8-yloxy)- N-[2-(2-hydroxy-ethoxy)- ethyl]-acetamide D
1.88 424.0 1055 GT11-33 ##STR01070## 6,6-Dimethyl-8-[2-(4-methyl-
piperazin-1-yl)-ethoxy]- 6H-benzo[b]naphtho [2,3-d]furan-11-one F
405.2 1056 GT11-34 ##STR01071## 6,6-Dimethyl-8-((2R,3R)-2,3,4-
trihydroxy-butoxy)-6H- benzo[b]naphtho [2,3-d]furan-11-one F 2.21
383.0 1057 GT11-35 ##STR01072## 8-((R)-2-Hydroxy-3-
piperidin-1-yl-propoxy)-6,6- dimethyl-6H- benzo[b]naphtho
[2,3-d]furan-11-one F 2.25 420.0 1058 GT11-36 ##STR01073##
6,6-Dimethyl-8-(2-oxo-2- piperazin-1-yl-ethoxy)-
6H-benzo[b]naphtho[2,3- d]furan-11-one D 1.92 405.0 1059 GT11-37
##STR01074## 8-{2-[4-(2-Hydroxy-acetyl)- piperazin-1-
yl]-ethoxy}-6,6-dimethyl-6H- benzo[b]naphtho [2,3-d]furan-11-one F
2.06 449.1 1060 GT11-38 ##STR01075##
8-((S)-2-Hydroxy-3-piperidin-1-yl- propoxy)-6,6-dimethyl-6H-
benzo[b]naptho[2,3-d]furan-11-one F 2.24 420.0 indicates data
missing or illegible when filed
TABLE-US-00031 TABLE 31 Example Comp. HPLC Retention No. No.
Structure Compound Name Condition Time m/z 1061 GT11-39
##STR01076## 8-[2-((R)-2,3-Dihydroxy- propylamino)-
ethoxy]-6,6-dimethyl-6H- benzo[b]naphtho [2,3-d]furan-11-one H 4.18
1062 GT11-40 ##STR01077## 8-((S)-4,5-Dihydroxy- pentyloxy)-6,6-
dimethyl-6H-benzo[b] naphtho[2,3-d]furan-11-one F 2.56 381.0 1063
GT11-41 ##STR01078## 4-[2-(6,6-Dimethyl-11-oxo-6,11-
dihydro-benzo[b]naphtho [2,3-d]furan- 8-yloxy)-ethyl]-
piperazin-2-one F 2.06 405.0 1064 GT11-42 ##STR01079##
2-(6,6-Dimethyl-11-oxo- 6,11-dihydro- benzo[b]naphtho[2,3-d]
furan-8-yloxy)- N-piperidin-4-yl-acetamide D 419.0 1065 GT11-43
##STR01080## N-{2-[Bis-(2-hydroxy- ethyl)-amino]-
ethyl}-2-(6,6-dimethyl-11-oxo- 6,11-dihydro-benzo[b]naphtho
[2,3-d]furan-8-yloxy)-acetamide D 1.83 467.0 1066 GT11-44
##STR01081## N-(3-Dimethylamino-propyl)- 2-(6,6-dimethyl-11-oxo-
6,11-dihydro-benzo[b]naphtho [2,3-d]furan-8-yloxy)- acetamide D
2.08 422.0 1067 GT11-45 ##STR01082## N-(2-Diethylamino-ethyl)-
2-(6,6-dimethyl-11-oxo-6,11- dihydro-benzo[b]naphtho
[2,3-d]furan-8-yloxy)- acetamide D 2.10 1068 GT11-46 ##STR01083##
6,6-Dimethyl-8-(pyrimidin- 2-yloxy)-6H-benzo[b]naphtho
[2,3-d]furan-11-one H 6.35 357.0 1069 GT11-47 ##STR01084##
8-(2-Ethylamino-ethoxy)- 6,6-dimethyl- 6H-benzo[b]naphtho
[2,3-d]furan-11-one F 2.15 350.0 1070 GT11-48 ##STR01085##
1-[2-(6,6-Dimethyl-11-oxo- 6,11-dihydro-benzo[b]naphtho
[2,3-d]furan-8-yloxy)-ethyl]- piperazin-2-one H 4.42 405.0 1071
GT11-49 ##STR01086## 4-[2-(6,6-Dimethyl-11-oxo-
6,11-dihydro-benzo[b] naphtho[2,3-d]furan- 8-yloxy)-ethyl]-1-
methyl-piperazin-2-one H 4.33 419.0 1072 GT11-50 ##STR01087##
2-(6,6-Dimethyl-11-oxo- 6,11-dihydro-benzo[b]naphtho
[2,3-d]furan-8-yloxy)- N-(2-piperazin-1-yl-ethyl)- acetamide A 3.99
448.0 1073 GT11-51 ##STR01088## 2-Dimethylamino-
N-[2-(6,6-dimethyl- 11-oxo-6,11-dihydro- benzo[b]naphtho[2,3-d]
furan-8-yloxy)- ethyl]-acetamide D 2.13 408.0 1074 GT11-52
##STR01089## 4-[2-(6,6-Dimethyl-11-oxo- 6,11-dihydro-benzo[b]naptho
[2,3-d]furan-8-yloxy)-ethyl]- 1,1-dimethyl-3-oxo- piperazin-1-ium;
chloride H 4.47 indicates data missing or illegible when filed
TABLE-US-00032 TABLE 32 Example Comp. HPLC Retention No. No.
Structure Compound Name Condition Time m/z 1075 GT12-53
##STR01090## 8-{2-[4-(2-Hydroxy-ethyl)-
piperazin-1-yl]-ethoxy}-6,6- dimethyl-6H-benzo[b]
naphtho[2,3-d]furan-11-one A 1.75 435.0 1076 GT12-54 ##STR01091##
1-[2-(6,6-Dimethyl-11-oxo- 6,11-dihydro-benzo[b]naphtho
[2,3-d]furan-8-yloxy)-ethyl]- 4-methyl-piperazin-2-one B 4.09 419.0
1077 GT12-55 ##STR01092## 6,6-Dimethyl-8-(3-piperazin-1-yl-
propoxy)-6H-benzo[b]naphtho[2,3- d]furan-11-one A 1.75 405.0 1078
GT12-56 ##STR01093## 8-{2-[4-((S)-2,3-Dihydroxy-
propyl)-piperazin-1-yl]-ethoxy}- 6,6-dimethyl-6H-benzo[b]naphtho
[2,3-d]furan-11-one A 1.72 465.0 1079 GT12-57 ##STR01094##
8-[2-(2-Hydroxy-1,1- dimethyl-ethylamino)-ethoxy]-
6,6-dimethyl-6H-benzo[b] naphtho[2,3-d]furan-11-one 2.57 394.0 1080
GT12-58 ##STR01095## 8-{2-[Bis-(2-hydroxy-ethyl)-
amino]-ethoxy}-6,6- dimethyl-6H-benzo[b]naphtho [2,3-d]furan-11-one
2.77 410.0 1081 GT12-59 ##STR01096##
8-[2-(3-Hydroxy-piperidin-1-yl)- ethoxy]-6,6-dimethyl-6H-
benzo[b]naphtho[2,3- d]furan-11-one 2.88 406.0 1082 GT12-60
##STR01097## 8-[2-(2-Hydroxymethyl- pyrrolidin-1-yl)-
ethoxy]-6,6-dimethyl-6H- benzo[b]naphtho [2,3-d]furan-11-one 2.82
406.0 1083 GT12-61 ##STR01098## 8-{2-[Ethyl-(2-hydroxy-
ethyl)-amino]- ethoxy}-6,6-dimethyl-6H- benzol[b]naphtho
[2,3-d]furan-11-one 2.85 394.0 1084 GT12-62 ##STR01099##
6,6-Dimethyl-8-(3-methyl- oxetan-3- ylmethoxy)-6H-
benzo[b]naphtho[2,3- d]furan-11-one 3.03 363.0 1085 GT12-63
##STR01100## 8-[2-(1-Hydroxymethyl- cycloperrtylamino)-ethoxy]-
6,6-dimethyl- 6H-benzo[b]naphtho [2,3-d]furan-11-one 2.72 420.0
1086 GT12-64 ##STR01101## 8-(4-Hydroxy-pyrrolidin-
2-ylmethoxy)-6,6-dimethyl-6H- benzo[b]naphtho[2,3-d] furan-11-one Y
2.96 378.0 1087 GT12-65 ##STR01102## 6,6-Dimethyl-8-(piperidin-
3-yloxy)-6H-benzo[b]naphtho [2,3-d]furan-11-one Y 3.03 362.0
indicates data missing or illegible when filed
[5063] The compounds described in the following Table 33 were
synthesized according to the method shown below. From Compound A2
and 2-bromophenol having a fluorine atom at corresponding position,
8-methoxy-6H-benzo[b]naphtho[2,3-d]furan-11-one having a fluorine
atom at corresponding position (Compound GT12-1, GT12-2, GT12-5 and
GT12-7) was prepared according to the method used for the
preparation of Compound Z10, Z11 and Z12. Further, demethylation
was carried out according to the method used for the preparation of
Compound A6 to obtain
8-hydroxy-6H-benzo[b]naphtho[2,3-d]furan-11-one which has a
fluorine atom at corresponding position. Thereafter, according to
Mitsunobu reaction used for the preparation of Compound A7-1 or the
alkylation method used for the preparation of Compound A7-17, a
corresponding side chain was introduced and, if necessary,
functional group modification such as deprotection, etc. was
carried out to prepare the compounds listed below.
TABLE-US-00033 TABLE 33 Example Comp. HPLC Retention No. No.
Structure Compound Name Condition Time m/z 1088 GT12-1 ##STR01103##
3-Fluoro-8-methoxy-6,6-dimethyl-6H-
benzo[b]naphtho[2,3-d]furan-11-one A 3.02 311.0 1089 GT12-2
##STR01104## 4-Fluoro-8-methoxy-6,6-dimethyl-6H-
benzo[b]naphtho[2,3-d]furan-11-one A 3.00 311.0 1090 GT12-3
##STR01105## 8-(2-Diethylamino-ethoxy)-3-fluoro-6,6-
dimethyl-6H-benzo[b]naphtho[2,3- d]furan-11-one B 4.48 396.0 1091
GT12-4 ##STR01106## 3-Fluoro-6,6-dimethyl-8-((2R,3R)-
2,3,4-trihydroxy-butoxy)-6H- benzo[b]naphtho[2,3-d]furan-11-one H
4.91 401.4 1092 GT12-5 ##STR01107##
2-Fluoro-8-methoxy-6,6-dimethyl-6H-
benzo[b]naphtho[2,3-d]furan-11-one 3.01 311.0 1093 GT12-6
##STR01108## 8-(2-Diethylamino-ethoxy)-2-fluoro-6,6-
dimethyl-6H-benzo[b]naphtho[2,3- d]furan-11-one 2.09 395.0 1094
GT12-7 ##STR01109## 1-Fluoro-8-methoxy-6,6-dimethyl-6H-
benzo[b]naphtho[2,3-d]furan-11-one B 6.26 311.0 1095 GT12-8
##STR01110## 8-((R)-2,3-Dihydroxy-propoxy)-2-
fluoro-6,6-dimethyl-6H- benzo[b]naphtho[2,3-d]furan-11-one 2.22
371.0 1096 GT12-9 ##STR01111##
8-(2-Diethylamino-ethoxy)-1-fluoro-6,6-
dimethyl-6H-benzo[b]naphtho[2,3- d]furan-11-one B 4.20 396.0 1097
GT12-10 ##STR01112## 8-((R)-2,3-Dihydroxy-propoxy)-3-
fluoro-6,6-dimethyl-6H- benzo[b]naphtho[2,3-d]furan-11-one B 371.0
1098 GT12-11 ##STR01113## 8-((R)-2,3-Dihydroxy-propoxy)-4-
fluoro-6,6-dimethyl-6H- benzo[d]naphtho[2,3-d]furan-11-one D 1.80
371.0 1099 GT12-12 ##STR01114## 8-((R)-2,3-Dihydroxy-propoxy)-1-
fluoro-6,6-dimethyl-6H- benzo[b]naphtho[2,3-d]furan-11-one D 1.85
371.0 indicates data missing or illegible when filed
[5064] The compounds described in the following Table 34 were
synthesized according to the method shown below.
8-Hydroxy-6H-benzo[b]naphtho[2,3-d]furan-11-one was transformed
into trifuloromethanesulfonic acid ester according to the method
used for the preparation of Compound BT. Subsequently, by carrying
out the method used for the preparation of Compound B2-1 or
Compound B2-18, Compound GT13-1, Compound GT13-2 and Compound
GT13-3 were prepared. Compound GT13-3 was oxidized according to the
method used for the preparation of Compound B3-8 to prepare
Compound 13-4.
TABLE-US-00034 TABLE 34 Example Comp. HPLC Retention No. No.
Structure Compound Name Condition Time m/z Method 1100 GT13-1
##STR01115## 6,6-Dimethyl-8-morpholin-4-yl-6H-
benzo[b]naphtho[2,3-d]furan-11-one F 3.04 348.2 B1, B2-1 1101
GT13-2 ##STR01116## 6,6-Dimethyl-8-(4-methyl-piperazin-1-
yl)-6H-benzo[b]naphtho[2,3-d]furan- 11-one F 2.13 361.3 B1, B2-1
1102 GT13-3 ##STR01117## 8-(2-Diisopropylamino-ethylsulfanyl)-
6,6-dimethyl-6H-benzo[b]naphtho[2,3- d]furan-11-one 3.45 422.0 1103
GT13-4 ##STR01118## 8-(2-Diisopropylamino-
ethanesulfonyl)-6,6-dimethyl-6H- benzo[b]naphtho[2,3-d]furan-11-one
3.23 454.0 indicates data missing or illegible when filed
[5065] The compounds described in the following Table 35 were
synthesized according to the method shown below. Specifically, a
side chain was introduced to Compound Z13 to prepare Compound
GT13-5 according to the method that is used for the preparation of
Compound A7-17. Further Compound GT13-5 or trifuloromethanesulfonic
acid ester of Compound Z14 was hydrolyzed to prepare Compound
GT13-6 and Compound GT13-7 according to the method used for the
preparation of Compound T20.
TABLE-US-00035 TABLE 35 Example Comp. HPLC Retention No. No.
Structure Compound Name Condition Time m/z Method 1104 GT13-5
##STR01119## Trifluoro-methanesulfonic acid
8-(2-diethylamino-ethoxy)- 6,6-dimethyl-11-oxo-6,11-
dihydro-benzo[b]naphtho [2,3-d]furan-3-yl ester H 5.37 526.0 A7-17
1105 GT13-6 ##STR01120## 8-(2-Diethylamino-ethoxy)-
3-hydroxy-6,6-dimethyl-6H- benzo[b]naphtho[2,3- d]furan-11-one B
3.40 384.0 T20 1106 GT13-7 ##STR01121## 3-Hydroxy-6,6-dimethyl-
8-((2R,3R)-2,3,4-trihydroxy- butoxy)-6H-benzo[b]naphtho
[2,3-d]furan-11-one F 1.87 399.0 T20
[5066] The compounds described in the following Table 36 were
prepared by subjecting Compound GT13-6 or GT13-7 to Mitsunobu
reaction that is used for the preparation of Compound A7-1 to
introduce a corresponding side chain or a synthetic equivalent.
After that, by carrying out deprotection, if necessary, the
compounds listed below were prepared.
TABLE-US-00036 TABLE 36 HPLC Re- Exam- Comp. Con- tention Me- ple
No. No. Structure Compound Name dition Time m/z thod 1107 GT13-8
##STR01122## 8-(2-Diethylamino- ethoxy)-3-methoxy- 6,6-dimethyl-6H-
benzo[b]naphtho[2,3- d]furan-11-one H 4.72 408.0 A7-1 1108 GT13-9
##STR01123## 3-Methoxy-6,6- dimethyl-8-((2R,3R)- 2,3,4-trihydroxy-
butoxy)-6H -benzo[b] naphtho[2,3-d] furan-11-one B 4.23 413.2 A7-1
1109 GT13-10 ##STR01124## 8-(2-Diethylamino- ethoxy)-3-ethoxy-
6,6-dimethyl-6H- benzo[b]naphtho [2,3-d]furan- 11-one H 5.10 422.0
A7-1 1110 GT13-11 ##STR01125## 8-(2-Diethylamino-
ethoxy)-6,6-dimethyl- 3-propoxy-6H-benzo [b]naphtho[2,3-d]
furan-1-one H 5.63 436.0 A7-1 1111 GT13-12 ##STR01126##
3-(2-Hydroxy- ethoxy)-6,6-dimethyl- 8-((2R,3R)-2,3,4-
trihydroxy-butoxy)- 6H-benzo[b]naphtho [2,3-d]furan-11-one F 1.83
443.0 A7-1 1112 GT13-13 ##STR01127## 3-(3-Hydroxy- propoxy)-6,6-
dimethyl-8- ((2R,3R)-2,3,4- trihydroxy-butoxy)- 6H-benzo[b]naphtho
[2,3-d]furan-11-one F 1.94 457.0 A7-1 1113 GT13-14 ##STR01128##
3-(4-Hydroxy- butoxy)-6,6-dimethyl- 8-((2R,3R)-2,3,4-
trihydroxy-butoxy)- 6H-benzo[b]naphtho [2,3-d]furan-11-one F 2.01
471.0 A7-1 1114 GT13-15 ##STR01129## 3-Isopropoxy-6,6-
dimethyl-8-((2R,3R)- 2,3,4-trihydroxy- butoxy)-6H-benzo
[b]naphtho[2,3-d] furan-11-one H 5.40 441.0 A7-1 1115 GT13-16
##STR01130## 3-(2-Methoxy- ethoxy)-6,6- dimethyl-8-((2R,3R)-
2,3,4-trihydroxy- butoxy)-6H-benzo [b]naphtho[2,3-d] furan-11-one F
2.17 457.0 A7-1 1116 GT13-17 ##STR01131## 3-(3-Methoxy-
propoxy)-6,6-dimethyl- 8-((2R,3R)-2,3,4- trihydroxy-butoxy)-6H-
benzo[b]naphtho[2,3-d] furan-11-one F 2.34 471.0 A7-1 1117 GT13-18
##STR01132## 3-(4-Methoxy- butoxy)-6,6- dimethyl-8- ((2R,3R)-2,3,4-
trihydroxy-butoxy)- 6H-benzo[b]naphtho [2,3-d]furan-11-one F 2.45
485.0 A7-1 1118 GT13-19 ##STR01133## 3-((S)-2,3-
Dihydroxy-propoxy)- 6,6-dimethyl-8- ((2R,3R)-2,3,4-
trihydroxy-butoxy)- 6H-benzo[b] naphtho[2,3-d] furan-11-one F 1.69
473.0 A7-1 A7- 14-1 1119 GT13-20 ##STR01134## 3-((R)-2,3-
Dihydroxy-propoxy)- 6,6-dimethyl-8- ((2R,3R)-2,3,4-
trihydroxy-butoxy)- 6H-benzo[b]naphtho [2,3-d]furan-11-one F 1.69
473.0 A7-1 A7- 14-1 ##STR01135##
[5067] The compounds described in the following Table 37 were
prepared from Compound GTT3-7 according to carbamation that is used
for the preparation of Compound A9-1.
TABLE-US-00037 TABLE 37 HPLC Re- Exam- Comp. Con- tention Me- ple
No. No. Structure Compound Name dition Time m/z thod 1120 GT13-21
##STR01136## (4-Methoxy-phenyl)- carbamic acid 6,6-
dimethyl-11-oxo-8- ((2R,3R)-2,3,4- trihydroxy-butoxy)-
6,11-dihydro- benzo[b]naphtho [2,3-d]furan-3-yl ester B 4.34 548.2
1121 GT13-22 ##STR01137## (3-Methoxy-phenyl)- carbamic acid 6,6-
dimethyl-11-oxo-8- ((2R,3R)-2,3,4- trihydroxy-butoxy)-
6,11-dihydro-benzo [b]naphtho[2,3-d] furan-3-yl ester B 4.69 548.2
1122 GT13-23 ##STR01138## (2-Methoxy-phenyl)- carbamic acid 6,6-
dimethyl-11-oxo-8- ((2R,3R)-2,3,4- trihydroxy-butoxy)-
6,11-dihydro-benzo [b]naphtho[2,3-d] furan-3-yl ester B 548.3 1123
GT13-24 ##STR01139## Phenyl-carbamic acid 6,6-dimethyl-11-
oxo-8-((2R,3R)-2,3,4- trihydroxy- butoxy)-6,11-dihydro-
benzo[b]naphtho [2,3-d]furan-3-yl ester B 4.67 518.2 1124 GT13-25
##STR01140## Cyclohexyl-carbamic acid 6,6-dimethyl-11-
oxo-8-((2R,3R)-2,3,4- trihydroxy-butoxy)- 6,11-dihydro-benzo
[b]naphtho[2,3-d] furan-3-yl ester B 4.94 524.2 1125 GT13-26
##STR01141## Benzyl-carbamic acid 6,6-dimethyl-11-
oxo-8-((2R,3R)-2,3,4- trihydroxy-butoxy)- 6,11-dihydro-benzo
[b]naphtho[2,3-d] furan-3-yl ester A 2.08 532.3 1126 GT13-27
##STR01142## Methyl-phenyl-carbamic acid 6,6-dimethyl-11-
oxo-8-((2R,3R)-2,3,4- trihydroxy-butoxy)-6,11-
dihydro-benzo[b]naphtho [2,3-d]furan-3-ylester B 4.88 532.3
indicates data missing or illegible when filed
[5068] The compounds described in the following Table 38 were
prepared from corresponding intermediates by alkylation and
carbamation based on the method described in the Table.
TABLE-US-00038 TABLE 38 HPLC Re- Exam- Comp. Con- tention Me- ple
No. No. Structure Compound Name dition Time m/z thod 1127 GT13-28
##STR01143## 3-(2-Diethylamino- ethoxy)-8-methoxy- 6,6-dimethyl-6H-
benzo[b]naphtho[2,3- d]furan-11-one H 4.65 408.0 A7-17 1128 GT13-29
##STR01144## 2-[8-((R)-2,3- Dihydroxy-propoxy)-
6,6-dimethyl-11-oxo- 6,11-dihydro-benzo [b]naphtho[2,3-d]
furan-3-yloxy]- N-phenyl-acetamide B 4.70 502.0 A7-17 A8-1 T13-3
1129 GT13-30 ##STR01145## (4-tert-Butyl-phenyl)- carbamic acid 8-
((R)-2,3-dihydroxy- propoxy)-6,6-dimethyl- 11-oxo-6,11-dihydro-
benzo[b]naphtho[2,3-d] furan-3-yl ester B 6.19 544.3 1130 GT13-31
##STR01146## (2-ferf-Butyl-phenyl)- carbamic acid 8-((R)-
2,3-dihydroxy-propoxy)- 6,6-dimethyl-11-oxo- 6,11-dihydro-benzo[b]
naphtho[2,3-d]furan- 3-yl ester B 5.74 544.3 1131 GT13-32
##STR01147## (5-tert-Butyl-2- methoxy-phenyl)- carbamic acid
8-((R)- 2,3-dihydroxy- propoxy)-6,6-dimethyl- 11-oxo-6,11-dihydro-
benzo[b]naphtho [2,3-d]furan- 3-yl ester B 6.52 574.3 1132 GT13-33
##STR01148## 6,6-Dimethyl-3- (pyrimidin-2-yloxy)- 8-((2R,3R)-2,3,4-
trihydroxy-butoxy)- 6H-benzo[b]naphtho [2,3-d]furan-11-one H 4.14
477.0 A7-17 indicates data missing or illegible when filed
Example 1133
[5069] Compound GT14-1
3-Chloro-8-((R)-2,3-dihydroxy-propoxy)-6,6-dimethyl-5,6-dihydro-benzo[f]py-
rido[4,3-b]indol-11-one
##STR01149##
[5071] Compound BZ2-2 was demethylated according to the method used
for the preparation of Compound A6, and subsequently introduced
with a substituent group and deprotected according to the method
used for the preparation of Compound A7-14-1 and A7-14-2.
[5072] LCMS: m/z 386 [M+H].sup.+
[5073] HPLC retention time: 3.02 min (analysis condition B)
Example 1134
[5074] Compound GT15-1
2-Iodo-3-(4-methoxy-benzyloxy)-pyridine
##STR01150##
[5076] 2-Iodo-pyridin-3-ol (50 mg, 0.226 mmol), K2CO.sub.3 (62 mg,
0.452 mmol) and DMF (2 ml) were added with para-methoxybenzyl
chloride (46 .mu.L, 0.339 mmol), and the mixture was stirred
overnight at 45.degree. C. The resultant was added with water, and
then extracted with ethyl acetate. The organic layer was washed
with saturated brine, and the resulting residues obtained after
concentration under reduced pressure were purified by silica gel
column (ethyl acetate/hexane) to obtain the title compound (21 mg,
27%).
[5077] LCMS: m/z 342 [M+H].sup.+
[5078] HPLC retention time: 3.44 min (analysis condition Y)
Example 1135
[5079] Compound GT15-2
7-Methoxy-3-[3-(4-methoxy-benzyloxy)-pyridin-2-yl]-1,1-dimethyl-3,4-dihydr-
o-1H-naphthalen-2-one
##STR01151##
[5081] Toluene (0.5 ml) was added to
7-methoxy-1,1-dimethyl-3,4-dihydro-1H-naphthalen-2-one (Compound
A2, 36 mg), 2-iodo-3-(4-methoxy-benzyloxy)-pyridine (Compound
GT15-1, 50 mg), sodium t-butoxide (35.3 mg), Pd.sub.2dba.sub.3
(13.5 mg) and Xantphos (17 mg), and the mixture was stirred and
heated at 80.degree. C. for 2.5 hrs under nitrogen atmosphere.
After cooling, the reaction mixture was diluted with ethyl acetate
and subjected to Celite filtration. The organic layer was washed
with saturated aqueous solution of sodium bicarbonate and saturated
brine, and then concentrated under reduced pressure. The resulting
residues were purified by silica gel column (ethyl acetate/hexane)
to obtain the title compound (27 mg, 44%).
[5082] LCMS: m/z 419 [M+H].sup.+
[5083] HPLC retention time: 3.31 min (analysis condition Y)
Example 1136
[5084] Compound GT15-3
8-Methoxy-10,10-dimethyl-5,10-dihydro-11-oxa-4-aza-benzo[b]fluorene
##STR01152##
[5086] To the mixture of
7-methoxy-3-[3-(4-methoxy-benzyloxy)-pyridin-2-yl]-1,1-dimethyl-3,4-dihyd-
ro-1H-naphthalen-2-one (Compound GT15-2, 21 mg) and ethyl acetate
(0.8 ml), sulfuric acid (0.2 ml) was added. The mixture was stirred
and heated at 70.degree. C. for 5 hrs. After cooling, the reaction
mixture was neutralized with 2 N aqueous solution of sodium
hydroxide. The mixture was diluted with ethyl acetate. The organic
layer was washed with saturated aqueous solution of sodium
bicarbonate and saturated brine, and then concentrated under
reduced pressure. The resulting residues were purified by silica
gel column (ethyl acetate/hexane) to obtain the title compound (7
mg, 50%).
[5087] LCMS: m/z 280 [M+H].sup.+
[5088] HPLC retention time: 2.71 min (analysis condition Y)
Example 1137
[5089] Compound GT15-4
8-Methoxy-10,10-dimethyl-10H-11-oxa-4-aza-benzo[b]fluoren-5-one
##STR01153##
[5091]
8-Methoxy-10,10-dimethyl-5,10-dihydro-11-oxa-4-aza-benzo[b]fluorene
(Compound GT15-3, 22 mg) was dissolved in MeCN (0.26 ml) and water
(0.13 ml), added with sodium chlorite (14 mg) and
N-hydroxyphthalimide (2.6 mg), and the mixture was stirred at
40.degree. C. for 1 hr. The reaction mixture was diluted with ethyl
acetate. The organic layer was washed with saturated aqueous
solution of sodium bicarbonate and saturated brine, and then
concentrated under reduced pressure. The resulting residues were
purified by silica gel column (ethyl acetate/hexane) to obtain the
title compound (16 mg, 70%).
[5092] LCMS: m/z 294 [M+H].sup.+
[5093] HPLC retention time: 2.85 min (analysis condition Y)
Example 1138
[5094] Compound GT15-5
8-Hydroxy-10,10-dimethyl-10H-11-oxa-4-aza-benzo[b]fluoren-5-one
##STR01154##
[5096] Mixture of
8-methoxy-10,10-dimethyl-10H-11-oxa-4-aza-benzo[b]fluoren-5-one
(Compound GT15-4, 25 mg) and pyridine hydrochloric acid salt (492
mg) was stirred and heated at 178.degree. C. overnight. The
reaction mixture was cooled, and added with water. The mixture was
neutralized with saturated aqueous solution of sodium bicarbonate
and extracted with DCM. The organic layer was washed with saturated
brine, and then concentrated under reduced pressure. The resulting
residues were purified by silica gel column (DCM/MeOH) to obtain
the title compound (13 mg, 54%).
[5097] LCMS: m/z 280 [M+H].sup.+
[5098] HPLC retention time: 2.30 min (analysis condition Y)
Example 1139
[5099] Compound GT15-6
8-[(4R,5R)-5-(Tert-butyl-dimethyl-silanyloxymethyl)-2,2-dimethyl-[1,3]diox-
olan-4-yl
methoxy]-10,10-dimethyl-10H-11-oxa-4-aza-benzo[b]fluoren-5-one
##STR01155##
[5101] In the same manner as Compound A7-1, the title compound was
synthesized from Compound GT15-5 and Compound T22-0 (29 mg,
50%).
[5102] LCMS: m/z 538 [M+H].sup.+
[5103] HPLC retention time: 3.64 min (analysis condition Y)
Example 1140
[5104] Compound GT15-7
10,10-Dimethyl-8-((2R,3R)-2,3,4-trihydroxy-butoxy)-10H-11-oxa-4-aza-benzo[-
b]fluoren-5-one
##STR01156##
[5106] To the mixture of
8-[(4R,5R)-5-(tert-butyl-dimethyl-silanyloxymethyl)-2,2-dimethyl-[1,3]dio-
xolan-4-yl
methoxy]-10,10-dimethyl-10H-11-oxa-4-aza-benzo[b]fluoren-5-one
(Compound GT15-6, 27 mg), MeOH (0.1 ml) and THF (0.3 ml), 0.5 N
sulfuric acid (0.1 ml) was added, and the mixture was stirred and
heated at 55 to 60.degree. C. for 4 hrs. The reaction mixture was
neutralized with saturated aqueous solution of sodium bicarbonate.
The resulting solid was filtered and washed with diethyl ether. The
filtrate was extracted with the mixture solution of DCM and MeOH
(DCM:MeOH=10:1). The organic layer was washed with saturated brine,
and dried over magnesium sulfate. The filtered solid and the
residues obtained after concentration under reduced pressure were
combined and purified by silica gel column (DCM/MeOH) to obtain the
title compound (5.4 mg, 28%).
[5107] LCMS: m/z 384 [M+H].sup.+
[5108] HPLC retention time: 2.02 min (analysis condition Y)
Example 1141
[5109] Compound GT15-8
7-Methoxy-3-(3-methoxymethoxy-pyridin-4-yl)-1,1-dimethyl-3,4-dihydro-1H-na-
phthalen-2-one
##STR01157##
[5111] To 7-methoxy-1,1-dimethyl-3,4-dihydro-1H-naphthalen-2-one
(Compound A2, 924 mg), 4-iodo-3-methoxymethoxy-pyridine (1 g),
sodium t-butoxide (906 mg), Pd.sub.2dba.sub.3 (173 mg) and S-Phos
(185 mg), toluene (19 ml) was added, and the mixture was stirred
and heated at 70.degree. C. for 2 hrs under nitrogen atmosphere.
The reaction mixture was diluted with ethyl acetate and filtered
through Celite. The organic layer was washed with saturated aqueous
solution of sodium bicarbonate and saturated brine, and then
concentrated under reduced pressure. The resulting residues were
purified by silica gel column (ethyl acetate/hexane) to obtain the
title compound (610 mg, 47%).
[5112] LCMS: m/z 342 [M+H].sup.+
[5113] HPLC retention time: 2.60 min (analysis condition Y)
Example 1142
[5114] Compound GT15-9
3-(3-Hydroxy-pyridin-4-yl)-7-methoxy-1,1-dimethyl-3,4-dihydro-1H-naphthale-
n-2-one
##STR01158##
[5116] Mixture of
7-methoxy-3-(3-methoxymethoxy-pyridin-4-yl)-1,1-dimethyl-3,4-dihydro-1H-n-
aphthalen-2-one (Compound GT15-8, 430 mg) and 4 N hydrochloric acid
dioxane solution (5 ml) was heated and stirred at room temperature
for 1.5 hrs. The reaction mixture was neutralized with 2 N aqueous
solution of sodium hydroxide. The resulting mixture was extracted
with the mixture of DCM and MeOH (DCM:MeOH=9:1). The residues
obtained after concentration under reduced pressure were purified
by silica gel column (DCM/MeOH) to obtain the title compound (280
mg, 75%).
[5117] LCMS: m/z 298 [M+H].sup.+
[5118] HPLC retention time: 2.41 min (analysis condition Y)
Example 1143
[5119] Compound GT15-10
8-Methoxy-10,10-dimethyl-5,10-dihydro-11-oxa-2-aza-benzo[b]fluorene
##STR01159##
[5121] Mixture of
3-(3-hydroxy-pyridin-4-yl)-7-methoxy-1,1-dimethyl-3,4-dihydro-1H-naphthal-
en-2-one (Compound GT15-9, 270 mg) and methanesulfonic acid (1 ml)
was stirred and heated at 110.degree. C. for 0.5 hrs. After
cooling, the reaction mixture was neutralized with 2 N aqueous
solution of sodium hydroxide. The resulting mixture was extracted
with the mixture of DCM and MeOH (DCM:MeOH=9: 1). The organic layer
was concentrated under reduced pressure, and the resulting residues
were purified by silica gel column (DCM/MeOH) to obtain the title
compound (110 mg, 43%).
[5122] LCMS: m/z 280 [M+H].sup.+
[5123] HPLC retention time: 2.53 min (analysis condition Y)
Example 1144
[5124] Compound GT15-11
8-Methoxy-10,10-dimethyl-10H-1l-oxa-2-aza-benzo[b]fluoren-5-one
##STR01160##
[5126]
8-Methoxy-10,10-dimethyl-5,10-dihydro-11-oxa-2-aza-benzo[b]fluorene
(Compound GT15-10, 20 mg) was dissolved in acetonitrile (0.2 ml)
and water (0.15 ml), added with sodium chlorite (16 mg) and
N-hydroxyphthalimide (2.3 mg), and the mixture was stirred at
40.degree. C. for 40 min. To the reaction mixture, ethyl acetate
was added. The organic layer was washed with saturated aqueous
solution of sodium bicarbonate and saturated brine, and then
concentrated under reduced pressure. The resulting residues were
purified by silica gel column (ethyl acetate/hexane) to obtain the
title compound (12 mg, 57%).
[5127] LCMS: m/z 294 [M+H].sup.+
[5128] HPLC retention time: 2.51 min (analysis condition Y)
Example 1145
[5129] Compound GT15-12
8-Hydroxy-10,10-dimethyl-10H-11-oxa-2-aza-benzo[b]fluoren-5-one
##STR01161##
[5131] DCM (0.34 ml) solution of
8-methoxy-10,10-dimethyl-10H-11-oxa-2-aza-benzo[b]fluoren-5-one
(Compound GT15-11, 10 mg) was cooled to -78.degree. C., added with
the DCM solution (0.17 ml) of 1.0 M BBr.sub.3, and the mixture was
stirred at room temperature overnight. To the reaction mixture,
water and saturated aqueous solution of sodium bicarbonate were
added, and the solid produced therefrom was filtered off. The
filtrate was extracted with the mixture solution of DCM and MeOH
(DCM:MeOH=9: 1). The organic layer was washed with saturated brine.
The filtered solid and the residues obtained after concentration
under reduced pressure were combined to obtain the title compound
(9.5 mg, 99%).
[5132] LCMS: m/z 280 [M+H].sup.+
[5133] HPLC retention time: 2.50 min (analysis condition Y)
Example 1146
[5134] Compound GT15-13
8-[(4R,5R)-5-(Tert-butyl-dimethyl-silanyloxymethyl)-2,2-dimethyl-[1,3]diox-
olan-4-yl
methoxy]-10,10-dimethyl-10H-1l-oxa-2-aza-benzo[b]fluoren-5-one
##STR01162##
[5136] Under the same conditions as the method for synthesizing
Compound A7-1, the title compound was prepared from Compound
GT15-12 and Compound T22-0 (38 mg, 66%).
[5137] LCMS: m/z 538 [M+H].sup.+
[5138] HPLC retention time: 3.55 min (analysis condition Y)
Example 1147
[5139] Compound GT15-14
10,10-Dimethyl-8-((2R,3R)-2,3,4-trihydroxy-butoxy)-10H-11-oxa-2-aza-benzo[-
b]fluoren-5-one
##STR01163##
[5141] Under the same conditions as the method for synthesizing
Compound GT15-7, the title compound was prepared from Compound
GT15-13 (2.1 mg, 84%).
[5142] LCMS: m/z 384 [M+H].sup.+
[5143] HPLC retention time: 1.70 min (analysis condition Y)
Example 1148
[5144] Compound GT15-15
3-Bromo-2-(4-methoxy-benzyloxy)-pyridine
##STR01164##
[5146] Under the same conditions as the method for synthesizing
Compound G15-1, the title compound was prepared from
3-bromo-pyridin-2-ol (740 mg, 88%).
[5147] LCMS: m/z 295 [M+H].sup.+
[5148] HPLC retention time: 2.86 min (analysis condition Y)
Example 1149
[5149] Compound GT15-16
7-Methoxy-3-[2-(4-methoxy-benzyloxy)-pyridin-3-yl]-1,1-dimethyl-3,4-dihydr-
o-1H-naphthalen-2-one
##STR01165##
[5151] To 7-methoxy-1,1-dimethyl-3,4-dihydro-1H-naphthalen-2-one
(Compound A2, 845 mg), 3-bromo-2-(4-methoxy-benzyloxy)-pyridine
(Compound GT15-15, 1.46 g), sodium t-butoxide (597 mg), palladium
acetate (18.6 mg) and tri-tert-butylphosphine tetrafluoroboric acid
(21 mg), toluene (10 ml) and THF (2 ml) were added and the mixture
was stirred and heated at 90.degree. C. for 2.5 hrs under nitrogen
atmosphere. After cooling, the reaction mixture was added with
saturated aqueous solution of ammonium chloride, and then extracted
with ethyl acetate. The organic layer was washed with saturated
brine, and the residues obtained after concentration under reduced
pressure were purified by silica gel column (ethyl acetate/hexane)
to obtain the title compound (140 mg, 8%).
[5152] LCMS: m/z 419 [M+H].sup.+
[5153] HPLC retention time: 3.50 min (analysis condition Y)
Example 1150
[5154] Compound GT15-17
8-Methoxy-10,10-dimethyl-10H-11-oxa-1-aza-benzo[b]fluoren-5-one
##STR01166##
[5156] Under the same conditions as the method for synthesizing
Compound GT15-3, the title compound was prepared from Compound
GT15-16 (49 mg, 52%).
[5157] LCMS: m/z 294 [M+H].sup.+
[5158] HPLC retention time: 3.39 min (analysis condition Y)
Example 1151
[5159] Compound GT15-18
8-Hydroxy-10,10-dimethyl-10H-11-oxa-1-aza-benzo[b]fluoren-5-one
##STR01167##
[5161] Under the same conditions as the method for synthesizing
Compound GT15-5, the title compound was prepared from Compound
GT15-17 (6.5 mg, 51%).
[5162] LCMS: m/z 280 [M+H].sup.+
[5163] HPLC retention time: 3.10 min (analysis condition Y)
Example 1152
[5164] Compound GT15-19
8-[(4R,5R)-5-(Tert-butyl-dimethyl-silanyloxymethyl)-2,2-dimethyl-[1,3]diox-
olan-4-yl
methoxy]-10,10-dimethyl-10H-1l-oxa-1-aza-benzo[b]fluoren-5-one
##STR01168##
[5166] Under the same conditions as the method for synthesizing
Compound A7-1, the title compound was prepared from Compound
GT15-18 and Compound T22-0 (4.5 mg, 11%).
[5167] LCMS: m/z 538 [M+H].sup.+
[5168] HPLC retention time: 3.88 min (analysis condition Y)
Example 1153
[5169] Compound GT15-20
10,10-Dimethyl-8-((2R,3R)-2,3,4-trihydroxy-butoxy)-10H-11-oxa-1-aza-benzo[-
b]fluoren-5-one
##STR01169##
[5171] Under the same conditions as the method for synthesizing
Compound GT15-7, the title compound was prepared from Compound
GT15-19 (7.9 mg, 51%).
[5172] LCMS: m/z 384 [M+H].sup.+
[5173] HPLC retention time: 2.57 min (analysis condition Y)
Example 1154
[5174] Compound GT15-21
8-Methoxy-10,10-dimethyl-5,10-dihydro-11-oxa-3-aza-benzo[b]fluorene
##STR01170##
[5176] To 7-methoxy-1,1-dimethyl-3,4-dihydro-1H-naphthalen-2-one
(Compound A2, 2.5 g), 3-bromo-4-chloro-pyridine (2 g), sodium
t-butoxide (3 g), Pd.sub.2dba.sub.3 (476 mg), and S-Phos (512 mg),
toluene (20 ml) was added, and the mixture was stirred and heated
at 100.degree. C. overnight under nitrogen atmosphere. After
cooling, the reaction mixture was diluted with ethyl acetate and
filtered through Celite. The organic layer was washed with
saturated aqueous solution of sodium bicarbonate and saturated
brine. Thereafter, the organic layer was dried over sodium sulfate.
The residues obtained after concentration under reduced pressure
were purified by silica gel column (ethyl acetate/hexane) to obtain
the title compound (112 mg, 4%).
[5177] LCMS: m/z 280 [M+H].sup.+
[5178] HPLC retention time: 2.46 min (analysis condition Y)
Example 1155
[5179] Compound GT15-22
8-Methoxy-10,10-dimethyl-10H-11-oxa-3-aza-benzo[b]fluoren-5-one
##STR01171##
[5181] Under the same conditions as the method for synthesizing
Compound GT15-3, the title compound was prepared from Compound
GT15-21 (49 mg, 52%).
[5182] LCMS: m/z 294 [M+H].sup.+
[5183] HPLC retention time: 2.30 min (analysis condition Y)
Example 1156
[5184] Compound GT15-23
8-Hydroxy-10,10-dimethyl-10H-11-oxa-3-aza-benzo[b]fluoren-5-one
##STR01172##
[5186] Under the same conditions as the method for synthesizing
Compound GT15-12, the title compound was prepared from Compound
GT15-22 (110 mg, 77%).
[5187] LCMS: m/z 280 [M+H].sup.+
[5188] HPLC retention time: 1.95 min (analysis condition Y)
Example 1157
[5189] Compound GT15-24
8-[(4R,5R)-5-(Tert-butyl-dimethyl-silanyloxymethyl)-2,2-dimethyl-[1,3]diox-
olan-4-yl
methoxy]-10,10-dimethyl-10H-1l-oxa-3-aza-benzo[b]fluoren-5-one
##STR01173##
[5191] Under the same conditions as the method for synthesizing
Compound A7-1, the title compound was prepared from Compound
GT15-23 and Compound T22-0 (38 mg, 49%).
[5192] LCMS: m/z 538 [M+H].sup.+
[5193] HPLC retention time: 3.40 min (analysis condition Y)
[5194] Compound GT15-25
10,10-Dimethyl-8-((2R,3R)-2,3,4-trihydroxy-butoxy)-10H-11-oxa-3-aza-benzo[-
b]fluoren-5-one
##STR01174##
[5196] Under the same conditions as the method for synthesizing
Compound GT15-7, the title compound was prepared from Compound
GT15-24 (17 mg, 72%).
[5197] LCMS: m/z 384 [M+H].sup.+
[5198] HPLC retention time: 1.48 min (analysis condition Y)
Example 1159
[5199] Compound GT16-1
2-(2-Bromo-4-methoxy-phenyl)-propan-2-ol
##STR01175##
[5201] To the mixture of 1-(2-bromo-4-methoxyphenyl)-ethanone (300
mg) dissolved in THF solution (3 ml), MeMgBr (3 M THF solution,
0.52 ml) was added at 0.degree. C. under nitrogen atmosphere. Then,
the mixture was stirred at room temperature for 6 hrs. The reaction
mixture was added with saturated aqueous solution of ammonium
chloride and extracted with ethyl acetate. The organic layer was
washed with saturated brine, and the residues obtained after
concentration under reduced pressure were purified by silica gel
column (ethyl acetate/hexane) to obtain the title compound (220 mg,
69%).
[5202] .sup.1H-NMR (CDCL.sub.3) .delta.: 7.55 (1H, d), 7.14 (1H,
d), 6.83 (1H, dd), 3.79 (3H, s), 2.72 (1H, s), 1.73 (6H, s)
Example 1160
[5203] Compound GT16-2
2-[1-(2-Bromo-4-methoxyphenyl)-1-methylethyl]benzofuran
##STR01176##
[5205] Mixture comprising 2-(2-bromo-4-methoxyphenyl)-propan-2-ol
(100 mg), 2,3-benzofuran (0.19 ml) and polyphosphoric acid (1 g)
was stirred and heated at 90.degree. C. for 30 min. The reaction
mixture was added with water and extracted with DCM. The residues
obtained after concentration under reduced pressure were purified
by silica gel column (DCM/hexane) to obtain the title compound (143
mg, 51%).
[5206] .sup.1H-NMR (CDCL.sub.3) .delta.: 7.4-7.5 (1H, m), 7.3-7.4
(2H, m), 7.1-7.25 (3H, m), 6.87 (1H, dd), 6.42 (1H, s) 3.79 (3H,
s), 1.84 (6H, s)
Example 1161
[5207] Compound GT16-3
2-(1-Benzofuran-2-yl-1-methyl-ethyl)-5-methoxy-benzoic acid
##STR01177##
[5209] To the mixture comprising
2-[1-(2-bromo-4-methoxyphenyl)-1-methylethyl]benzofuran (140 mg)
and THF (2 ml), n-butyl lithium (2.5 M solution, 0.17 ml) was added
at -78.degree. C. under nitrogen atmosphere. The mixture was
stirred for 20 min. The resulting reaction mixture was flushed with
carbon dioxide gas for 15 min. Then, the reaction mixture was added
with saturated aqueous solution of ammonium chloride and extracted
with ethyl acetate. The organic layer was washed with water and
saturated brine, and the residues obtained after concentration
under reduced pressure were purified by silica gel column
(DCM/MeOH) to obtain the title compound (68 mg, 54%).
[5210] LCMS: m/z 311 [M+H].sup.+
[5211] HPLC retention time: 2.92 min (analysis condition Y)
Example 1162
[5212] Compound GT16-4
9-Methoxy-6,6-dimethyl-6H-benzo[b]naphtho[2,3-d]furan-11-one
##STR01178##
[5214] To the DCM solution (1 ml) of
2-(1-benzofuran-2-yl-1-methylethyl)-5-methoxy benzoic acid (63 mg),
trifuloroacetic anhydride (0.03 ml) was added at room temperature
under nitrogen atmosphere. The mixture was stirred for 30 min. The
reaction mixture was then added with water and extracted with DCM.
The organic layer was dried over sodium sulfate. The residues
obtained after concentration under reduced pressure were purified
by silica gel column (DCM) to obtain the title compound (50 mg,
84%).
[5215] LCMS: m/z 293 [M+H].sup.+
[5216] HPLC retention time: 3.49 min (analysis condition Y)
Example 1163
[5217] Compound GT16-5
9-Hydroxy-6,6-dimethyl-6H-benzo[b]naphtho[2,3-d]furan-11-one
##STR01179##
[5219] Under the same conditions as the method for synthesizing
Compound A6, the title compound was prepared from Compound
GT16-4.
[5220] LCMS: m/z 279 [M+H].sup.+
[5221] HPLC retention time: 3.05 min (analysis condition Y)
Example 1164
[5222] Compound GT16-6
9-(2-Diethylamino-ethoxy)-6,6-dimethyl-6H-benzo[b]naphtho[2,3-d]furan-11-o-
ne
##STR01180##
[5224] Under the same conditions as the method for synthesizing
Compound A7-17, the title compound was prepared from Compound
GT16-5.
[5225] LCMS: m/z 378 [M+H].sup.+
[5226] HPLC retention time: 2.41 min (analysis condition Y)
Example 1165
[5227] Compound GT16-7
9-((S)-2,2-Dimethyl-[1,3]dioxolan-4-yl
methoxy)-6,6-dimethyl-6H-benzo[b]naphtho[2,3-d]furan-11-one
##STR01181##
[5229] Under the same conditions as the method for synthesizing
Compound A7-17, the title compound was prepared from Compound
GT16-5 and toluene-4-sulfonic acid
(R)-2,2-dimethyl-[1,3]dioxolan-4-yl methyl ester.
[5230] LCMS: m/z 393 [M+H].sup.+
[5231] HPLC retention time: 3.22 min (analysis condition Y)
Example 1166
[5232] Compound GT16-8
9-((R)-2,3-Dihydroxy-propoxy)-6,6-dimethyl-6H-benzo[b]naphtho[2,3-d]furan--
11-one
##STR01182##
[5234] Under the same conditions as the method for synthesizing
Compound A7-14-2, the title compound was prepared from Compound
GT16-7.
[5235] LCMS: m/z 353 [M+H].sup.+
[5236] HPLC retention time: 2.83 min (analysis condition Y)
Example 1167
[5237] Compound GT16-9
3-(6,6-Dimethyl-11-oxo-6,11-dihydro-benzo[b]naphtho[2,3-d]furan-9-yl)-benz-
oic acid
##STR01183##
[5239] In the same manner as Compound GT9-2, the title compound was
synthesized from Compound GT16-5.
[5240] LCMS: m/z 383 [M+H].sup.+
[5241] HPLC retention time: 7.11 min (analysis condition H)
Example 1168
[5242] Compound GT16-10
9-(4-Hydroxymethyl-phenyl)-6,6-dimethyl-6H-benzo[b]naphtho[2,3-d]furan-11--
one
##STR01184##
[5244] In the same manner as Compound GT9-2, the title compound was
synthesized from Compound GT16-5.
[5245] LCMS: m/z 369 [M+H].sup.+
[5246] HPLC retention time: 6.97 min (analysis condition H)
[5247] The compounds described in the following Table 39 were
synthesized according to the method shown below. Specifically,
Compound GT17-1 was prepared from
8-methoxy-1,1-dimethyl-3,4-dihydro-1H naphthalen-2-one and
bromophenol by following the method that is used for the
preparation of Compound Z10, Z11 and Z12. Compound GT17-1 was
demethylated according to the method used for the preparation of
Compound A.sup.6, and as a result
7-hydroxy-6,6-dimethyl-6H-benzo[b]naphtho[2,3-d]furan-11-one was
prepared. The resulting hydroxy compound was subjected to the
alkylation according to the method used for the preparation of
A7-1, or Mitsunobu reaction used for the preparation of Compound
A7-17 for introducing a corresponding side chain or a synthetic
equivalent thereof. Thereafter, if necessary, functional group
modification was carried out to prepare Compound GT17-2 and
Compound GT17-3.
TABLE-US-00039 TABLE 39 Example Comp. HPLC Retention No. No.
Structure Compound Name Condition Time m/z 1169 GT17-1 ##STR01185##
7-Methoxy-6,6-dimethyl-6H- benzo[b]naphtho[2,3-d]furan-11-one Y
13.42 293.0 1170 GT17-2 ##STR01186## 7-(2-Diethylamino-ethoxy)-6,6-
dimethyl-6H-benzo[b]naphtho[2,3- d]furan-11-one Y 9.92 378.0 1171
GT17-3 ##STR01187## 7-((R)-2,3-Dihydroxy-propoxy)-6,6-
dimethyl-6H-benzo[b]naphtho[2,3- d]furan-11-one Y 11.68 353.0
[5248] The compounds described in the following Table 40 were
synthesized according to the method shown below.
[5249] By using the method used for the preparation of Compound
Z10, Z11 and Z12, Compound GT18-1 was prepared from Compound M1 and
bromophenol. Further, according to the method used for the
preparation of Compound A6, Compound GT18-1 was demethylated to
prepare
8-hydroxy-1H-spiro[benzo[b]naphtho[2,3-d]furan-6,1'-cyclopentan]-11-one,
which was then introduced with a side chain based on the alkylation
that is used for the preparation of Compound A7-1. As a result,
Compound GT18-2 was prepared.
[5250] The following spiro compounds were prepared from
7-methoxy-3,4-dihydro-H-naphthalen-2-one and corresponding
dibromide in the same manner as above.
TABLE-US-00040 TABLE 40 Example Comp. HPLC Retention No. No.
Structure Compound Name Condition Time m/z 1172 GT18-1 ##STR01188##
8-methoxy-11H- spiro[benzo[b]naphtho[2,3-d]
furan-6,1'-cyclopentane]-11-one Y 10.00 319.0 1173 GT18-2
##STR01189## 8-(2-diethylamino-ethoxy)-11H-
spiro[benzo[b]naphtho[2,3-d] furan-6,1'-cyclopentane]-11-one C 2.19
404.0 1174 GT18-3 ##STR01190## 8-(2-diethylamino-ethoxy)-11H-
spiro[benzo[b]naphtho[2,3-d] furan-6,1'-cyclohexane]-11-one C 3.28
418.2 1175 GT18-4 ##STR01191## 8-((2R,3R)-2,3,4-
trihydroxybutoxy-11H- spiro[benzo[b]naphtho[2,3-d]
furan-6,1'-cyclohexane]-11-one A 2.26 423.2 1176 GT18-5
##STR01192## 8-methoxy-11H- spiro[benzo[b]naphtho[2,3-d]
furan-6,1'-cyclobutane]-11-one Y 9.00 305.0 1177 GT18-6
##STR01193## 8-(2-diethylamino-ethoxy)- 2',3',5',6'-tetrahydro-11H-
spiro[benzo[b]naphtho[2,3-d] furan-6,4'-pyran]-11-one B 4.05
420.3
Example 1178
[5251] Compound GT19-1
8-(2-Diethylamino-ethoxy)-6,6-dimethyl-3-trifuloromethyl-6H-benzo[B]naphth-
o[2,3-d]furan-11-one
##STR01194##
[5253] According to the method described before, the preparation
was carried out by using 7-methoxy-1,1-dimethyl-3,4-dihydro-1H
naphthalen-2-one and 2-bromo-5-trifulorophenol.
[5254] LCMS: m/z 446 [M+H].sup.+
[5255] HPLC retention time: 3.25 min (analysis condition C)
Example 1179
[5256] Compound GT19-2
8-(2-Diethylamino-ethoxy)-6,6-dimethyl-3-phenyl-6H-benzo[b]naphtho[2,3-d]f-
uran-11-one
##STR01195##
[5258] By carrying out Suzuki coupling of Compound GT23-5 and a
corresponding boronic acid reagent based on the method that is used
for the preparation of Compound GT9-2, the title compound was
prepared.
[5259] LCMS: m/z 454 [M+H].sup.+
[5260] HPLC retention time: 2.67 min (analysis condition F)
Example 1180
[5261] Compound GT20-1
8-Hydroxy-6,6-dimethyl-3-(2-phenyl-ethanesulfonyl)-5,6-dihydro-benzo[b]car-
bazol-11-one
##STR01196##
[5263]
3-Bromo-8-hydroxy-6,6-dimethyl-5,6-dihydro-benzo[b]carbazol-11-one
(72.2 mg, 0.203 mmol), 2-phenylethanethiol (0.0297 ml, 0.221 mmol),
Pd.sub.2dba.sub.3 (9.3 mg, 0.0102 mmol), Xantphos (11.6 mg, 0.020
mmol) and ethyl diisopropylamine (0.068 ml, 0.40 mmol) were
dissolved in dioxane (0.6 ml), and the mixture was stirred at
110.degree. C. for 16 hrs under nitrogen atmosphere. Water and
ethyl acetate were added to the mixture to give a suspension, which
was then filtered. The organic layer was washed with water and
saturated brine, and then concentrated under reduced pressure. The
resulting residues were purified by silica gel column (ethyl
acetate/hexane). The resulting residues were dissolved in THF (4
ml), and the supernatant liquid (2 ml) was taken and added with
water (1 ml) and OXONE (99 mg). The resulting mixture was stirred
at room temperature overnight. The reaction solution was
partitioned between water and ethyl acetate. The organic layer was
washed with brine, and then concentrated under reduced pressure.
The resulting residues were purified by silica gel column (ethyl
acetate/hexane) to obtain the title compound (37.1 mg).
[5264] LCMS: m/z 446 [M+H].sup.+
[5265] HPLC retention time: 2.51 min (analysis condition F)
Example 1181
[5266] Compound GT20-2
6,6-Dimethyl-3-(2-phenyl-ethanesulfonyl)-8-((2R,3R)-2,3,4-trihydroxy-butox-
y)-5,6-dihydro-benzo[b]carbazol-11-one and
[5267] Compound GT20-3
8-Isopropoxy-6,6-dimethyl-3-(2-phenyl-ethanesulfonyl)-5,6-dihydro-benzo[b]-
carbazol-11-one
##STR01197##
[5269]
8-Hydroxy-6,6-dimethyl-3-(2-phenyl-ethanesulfonyl)-5,6-dihydro-benz-
o[b]carbazol-11-one (30 mg, 0.0673 mmol),
[(4R,5R)-5-(tert-butyl-dimethyl-silanyloxymethyl)-2,2-dimethyl-[1,3]dioxo-
lan-4-yl]methanol (22.3 mg, 0.0808 mmol), and PPh.sub.3 (23 mg,
0.0875 mmol) were dissolved in THF (0.5 ml), added with DIAD
(0.0169 ml, 0.0808 mmol), and the mixture was stirred at 50.degree.
C. overnight. After cooling, the reaction solution was filtered and
concentrated under reduced pressure. The resulting residues were
purified by silica gel column (ethyl acetate/hexane). The resulting
residues were dissolved in THF (0.4 ml) and water (0.13 ml), added
with camphor sulfonic acid (28.1 mg, 0.121 mmol), and then
subjected to microwave irradiation at 80.degree. C. for 15 min
under nitrogen atmosphere. Ethyl acetate was added to the
resultant. The organic layer was washed with saturated aqueous
solution of sodium hydrocarbonate and saturated brine, and then
concentrated under reduced pressure. The resulting residues were
purified by thin layer chromatography (MeOH/DCM) to obtain Compound
GT20-2 (10.5 mg) and Compound GT20-3 (2.4 mg).
[5270] Compound GT20-2
[5271] LCMS: m/z 550 [M+H].sup.+
[5272] HPLC retention time: 2.20 min (analysis condition F)
[5273] Compound GT20-3
[5274] LCMS: m/z 488 [M+H].sup.+
[5275] HPLC retention time: 3.13 min (analysis condition F)
Example 1182
[5276] Compound GT20-4
3-Methanesulfonyl-6,6-dimethyl-8-((2R,3R)-2,3,4-trihydroxy-butoxy)-5,6-dih-
ydro-benzo[b]carbazol-11-one
##STR01198##
[5278] The DMA solution (0.6 ml) comprising Compound GT23-2 (59.6
mg, 0.167 mmol), sodium methanethiolate (77 mg, 1.10 mmol),
Pd.sub.2dba.sub.3 (23.7 mg, 0.0259 mmol) and Xantphos (29.7 mg,
0.0513 mmol) was subjected to microwave irradiation at 180.degree.
C. for 30 min under nitrogen atmosphere. The reaction solution was
partitioned between aqueous solution of potassium dihydrophosphoric
acid and ethyl acetate. The organic layer was washed with saturated
brine, and then concentrated under reduced pressure. The resulting
residues were purified by silica gel column (ethyl acetate/hexane
and MeOH/DCM). The resulting solids were dissolved in THF (1 ml)
and water (0.5 ml), and then added with OXONE (101.4 mg). The
resulting mixture was stirred at room temperature for 2 hrs. The
reaction solution was partitioned between water and ethyl acetate.
The organic layer was washed with saturated brine, and then
concentrated under reduced pressure. The resulting residues were
suspended and washed with MTBE. The resulting solid was dissolved
in THF (0.4 ml), and added with PPh.sub.3 (37 mg, 0.141 mmol),
[(4R,5R)-5-(tert-butyl-dimethyl-silanyloxymethyl)-2,2-dimethyl-[1,3]dioxo-
lan-4-yl]-methanol (39.0 mg, 0.141 mmol) and DEAD (2.2 M toluene
solution, 0.064 ml, 0.141 mmol), and the mixture was stirred at
40.degree. C. for 4 hrs under nitrogen atmosphere. The reaction
solution was partitioned between water and ethyl acetate. The
organic layer was washed with saturated brine, and then
concentrated under reduced pressure. The resulting residues were
purified by silica gel column (MeOH/DCM). Thus-obtained product was
dissolved in THF (0.25 ml) and MeOH (0.05 ml), added with 0.5 M
sulfuric acid (0.1 ml), and the mixture was stirred at 60.degree.
C. for 5 hrs. After cooling, the mixture was added with diethyl
ether and sodium hydrocarbonate (13 mg, 0.15 mmol). The separated
aqueous layer was filtered, concentrated under reduced pressure,
and suspended and purified with MeOH to obtain the title compound
as a white solid (10.4 mg, 14%).
[5279] LCMS: m/z 460 [M+H].sup.+
[5280] HPLC retention time: 1.71 min (analysis condition F)
Example 1183
[5281] Compound GT20-5
8-((R)-2,3-Dihydroxy-propoxy)-6,6-dimethyl-3-methylsulfanyl-5,6-dihydro-be-
nzo[b]carbazol-11-one
##STR01199##
[5283]
3-Bromo-8-((S)-2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-6,6-dimethyl-
-5,6-dihydro-benzo[b]carbazol-11-one (47.3 mg, 0.101 mmol), sodium
methanethiolate (34.6 mg, 0.493 mmol), Pd.sub.2(dba).sub.3 (13.1
mg, 0.0413 mmol), and Xantphos (17.9 mg, 0.0309 mmol) were
dissolved in DMA (0.5 ml) and subjected to microwave irradiation at
200.degree. C. for 30 min under nitrogen atmosphere. The resultant
was partitioned between aqueous solution of potassium
dihydrophosphoric acid and ethyl acetate. The organic layer was
washed with saturated brine, and then concentrated under reduced
pressure. The resulting residues were purified by thin layer
chromatography (ethyl acetate/DCM). The resulting solid was
dissolved in THF (0.23 ml) and MeOH (0.06 ml), and then added with
0.5 M sulfuric acid (0.12 ml). The resulting mixture was stirred at
60.degree. C. for 2 hrs. The reaction solution was diluted with
diethyl ether and neutralized with sodium hydrocarbonate (15.5 mg,
0.185 mmol). Thereafter, the solution was partitioned between brine
and ethyl acetate. The organic layer was concentrated under reduced
pressure. The resulting residues were added with diethyl ether. The
precipitated solid was filtered to obtain the title compound as a
white solid (15.8 mg, 39%).
[5284] LCMS: m/z 398 [M+H].sup.+
[5285] HPLC retention time: 4.46 min (analysis condition H)
Example 1184
[5286] Compound GT20-5
8-((R)-2,3-Dihydroxy-propoxy)-6,6-dimethyl-3-thiazol-2-yl-5,6-dihydro-benz-
o[b]carbazol-11-one
##STR01200##
[5288]
3-Bromo-8-((S)-2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-6,6-dimethyl-
-5,6-dihydrobenzo[b]carbazol-11-one (47 mg, 0.10 mmol), bis
(pinacolate)diborone (33 mg, 0.13 mmol), Pd (dppf).sub.2C.sub.2.
DCM (8.2 mg, 0.010 mmol) and potassium acetate (294 mg, 0.3 mmol)
were dissolved in dioxane (0.6 ml), and the mixture was stirred at
100.degree. C. overnight under nitrogen atmosphere. The resultant
was partitioned between aqueous solution of potassium
dihydrophosphoric acid and ethyl acetate. The organic layer was
washed with saturated brine, and then concentrated under reduced
pressure. The resulting residues were purified by silica gel column
(ethyl acetate/DCM) to obtain
8-((S)-2,2-dimethyl-[1,3]dioxolan-4-yl
methoxy)-6,6-dimethyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-5,-
6-dihydro-benzo[b]carbazol-11-one (30.2 mg). The product (11 mg)
was dissolved in DMA (0.4 ml), added with 2-bromothiazole (0.0038
ml, 0.0428 mmol), Pd (PPh.sub.3).sub.4 (5.3 mg, 0.00459 mmol),
potassium phosphate (27.4 mg, 0.129 mmol) and water (0.1 ml), and
the mixture was subjected to microwave irradiation at 140.degree.
C. for 7 min under nitrogen atmosphere. The resultant was
partitioned between aqueous solution of potassium dihydrophosphoric
acid and ethyl acetate. The organic layer was washed with saturated
brine, and then concentrated under reduced pressure. The resulting
residues were purified by thin layer chromatography (MeOH/DCM). The
resulting solid was dissolved in MeOH (1 ml), and then added with 1
N HCl (3 drops). The resulting mixture was stirred at 60.degree. C.
for 2 hrs. The reaction solution was concentrated under reduced
pressure, and the residues obtained therefrom were suspended and
washed with DCM/hexane (2/1) followed by drying to obtain the title
compound as a yellow solid (8.7 mg).
[5289] LCMS: m/z 435 [M+H].sup.+
[5290] HPLC retention time: 1.76 min (analysis condition A)
[5291] The compounds described in the following Table 41 were also
synthesized in the same manner.
TABLE-US-00041 TABLE 41 Example Comp. HPLC Retention No. No.
Structure Compound Name Condition Time m/z 1185 GT20-6 ##STR01201##
8-((R)-2,3-Dihydroxy- propoxy)-3-(1-methoxymethyl-
1H-midazol-2-yl)-6,6- dimethyl-5,6-dihydro- benzo[b]carbazol-11-one
B 2.63 462.0 1186 GT20-7 ##STR01202## 8-((R)-2,3-Dihydroxy-
propoxy)-3-(1H- imidazol-2-yl)-6,6- dimethyl-5,6-dihydro-
benzo[b]carbazol-11-one B 2.45 418.5
Example 1187
[5292] Compound GT20-8
8-((R)-2,3-Dihydroxy-propoxy)-3-methoxymethyl-6,6-dimethyl-5,6-dihydro-ben-
zo[b]carbazol-11-one and
[5293] Compound GT20-9
8-((R)-2,3-Dihydroxy-propoxy)-3-hydroxymethyl-6,6-dimethyl-5,6-dihydro-ben-
zo[b]carbazol-11-one
##STR01203##
[5295]
3-Bromo-8-((S)-2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-6,6-dimethyl-
-5,6-dihydrobenzo[b]carbazol-11-one (200.2 mg, 0.426 mmol),
palladium acetate (II) (19 mg, 0.0848 mmol), hexacarbonyl
molybdenum (115.5 mg, 0.438 mmol) and tris(o-tolyl)phosphine (52.5
mg, 0.172 mmol) were dissolved in THF (1.3 ml) and ethanol (0.075
ml), added with DBU (0.195 ml), and subjected to microwave
irradiation at 160.degree. C. for 15 min under nitrogen atmosphere.
The resulting reaction solution was partitioned between aqueous
solution of potassium dihydrophosphoric acid and ethyl acetate. The
organic layer was washed with saturated brine, and then
concentrated under reduced pressure. The resulting residues were
dissolved in ethanol (10 ml) and THF (3 ml), added with 2 N KOH (2
ml), and stirred at room temperature for 2 hrs, at 50.degree. C.
overnight and at 70.degree. C. for 2 hrs. The reaction solution was
partitioned between aqueous solution of potassium dihydrophosphoric
acid and ethyl acetate. The organic layer was washed with saturated
brine, and then concentrated under reduced pressure. The resulting
residues were suspended and purified with MTBE/hexane (1/1) (155.4
mg). The THF solution (1.5 ml) of the product (109 mg) was added
with TEA (0.052 ml, 0.373 mmol) and ethyl chloroformate (0.029 ml,
0.303 mmol) under ice cooling, and the mixture was stirred at
0.degree. C. for 2 hrs. Subsequently, ethanol (1 ml) and sodium
borohydride (75.7 mg, 2.0 mmol) were added to the mixture, which
was then stirred at room temperature for 2 hrs. The reaction
solution was partitioned between aqueous solution of potassium
dihydrophosphoric acid and ethyl acetate. The organic layer was
washed with saturated brine, and then concentrated under reduced
pressure. The resulting residues were purified by silica gel column
(MeOH/DCM) (35.2 mg). Thus-obtained solid (9.6 mg) was dissolved in
MeOH (1 ml), added with 1 N HCl (3 drops), and the mixture was
stirred at 60.degree. C. for 90 min. After cooling and
concentration under reduced pressure, the resultant was purified by
TLC (MeOH/DCM) to obtain Compound GT20-8 (6.2 mg, white solid) and
Compound GT20-9 (4.3 mg, white solid).
[5296] Compound GT20-8
[5297] LCMS: m/z 396 [M+H].sup.+
[5298] HPLC retention time: 1.66 min (analysis condition A)
[5299] Compound GT20-9
[5300] LCMS: m/z 382 [M+H].sup.+
[5301] HPLC retention time: 1.37 min (analysis condition A)
Example 1188
[5302] Compound GT21-1
8-[(E)-2-(2,2-Dimethyl-[1,3]dioxolan-4-yl)-vinyl]-6,6-dimethyl-6H-benzo[b]-
naphtho[2,3-d]furan-11-one
##STR01204##
[5304] To the DMF solution (4 ml) of trifuloro-methanesulfonic acid
6,6-dimethyl-1-oxo-6,11-dihydro-benzo[b]naphtho[2,3-d]furan-8-yl
ester (300 mg), 2,2-dimethyl-4-vinyl-[1,3]dioxolane (469 mg) and
PdCl.sub.2(PPh.sub.3).sub.2 (103 mg), sodium hydrocarbonate (184
mg) was added, and the mixture was stirred at 100.degree. C.
overnight under nitrogen atmosphere. The reaction mixture was
diluted with ethyl acetate. The organic layer was washed with
saturated aqueous solution of sodium bicarbonate and saturated
brine, and then concentrated under reduced pressure. The resulting
residues were purified by silica gel column (ethyl acetate/hexane)
to obtain the title compound (130 mg, 46%).
[5305] LCMS: m/z 389 [M+H].sup.+
[5306] HPLC retention time: 3.28 min (analysis condition Y)
Example 1189
[5307] Compound GT21-2
8-(3,4-Dihydroxy-butyl)-6,6-dimethyl-6H-benzo[b]naphtho[2,3-d]furan-11-one
##STR01205##
[5309] To the MeOH solution (5 ml) of
8-[(E)-2-(2,2-dimethyl-[1,3]dioxolan-4-yl)-vinyl]-6,6-dimethyl-6H-benzo[b-
]naphtho[2,3-d]furan-11-one (125 mg), 10% Pd--C (25 mg) was added
and the mixture was stirred overnight at room temperature under
hydrogen atmosphere. The catalyst was removed by filtration. The
residues obtained after concentration under reduced pressure were
purified by HPLC to obtain the title compound (35 mg, 31%).
[5310] LCMS: m/z 351 [M+H].sup.+
[5311] HPLC retention time: 1.79 min (analysis condition Y)
[5312] Compound GT21-3
8-Amino-6,6-dimethyl-6H-benzo[b]naphtho[2,3-d]furan-11-one
##STR01206##
[5314] To trifuloro-methanesulfonic acid
6,6-dimethyl-11-oxo-6,11-dihydro-benzo[b]naphtho[2,3-d]furan-8-yl
ester (100 mg), benzhydrylideneamine (0.05 ml), cesium carbonate
(110 mg), palladium acetate (2 mg) and BINAP (7 mg), THF (2 ml) was
added. The mixture was stirred and heated at 65.degree. C.
overnight under nitrogen atmosphere, and the reaction mixture was
diluted with ethyl acetate. The organic layer was washed with
saturated aqueous solution of sodium bicarbonate and saturated
brine, and then concentrated under reduced pressure. The resulting
residues were purified by silica gel column (ethyl acetate/hexane)
to obtain the title compound (16 mg, 23%).
[5315] LCMS: m/z 278 [M+H].sup.+
[5316] HPLC retention time: 2.52 min (analysis condition Y)
Example 1191
[5317] Compound GT21-4
8-[((S)-2,2-Dimethyl-[1,3]dioxolan-4-yl
methyl)-amino]-6,6-dimethyl-6H-benzo[b]naphtho[2,3-d]furan-11-one
##STR01207##
[5319] The mixture comprising
8-amino-6,6-dimethyl-6H-benzo[b]naphtho[2,3-d]furan-11-one (50 mg),
(R)-4-iodomethyl-2,2-dimethyl-[1,3]dioxolane (104 mg), potassium
carbonate (150 mg) and DMF (2 ml) was stirred and heated at
160.degree. C. for 2 days under nitrogen atmosphere. The reaction
mixture was diluted with ethyl acetate. The organic layer was
washed with water and saturated brine, and then concentrated under
reduced pressure. The resulting residues were purified by silica
gel column (ethyl acetate/hexane). To the compound (71 mg) obtained
therefrom, THF (1 ml) and conc. hydrochloric acid (8 drops) were
added and the mixture was stirred at room temperature for 1 hr. The
reaction mixture was added with saturated aqueous solution of
sodium bicarbonate and then diluted with ethyl acetate. The organic
layer was washed with saturated aqueous solution of sodium
bicarbonate and saturated brine, and then concentrated under
reduced pressure. The resulting residues were purified by silica
gel column (ethyl acetate/hexane) to obtain the title compound (34
mg, 51%).
[5320] LCMS: m/z 392 [M+H].sup.+
[5321] HPLC retention time: 3.11 min (analysis condition Y)
Example 1192
[5322] Compound GT21-5
8-((S)-2,3-Dihydroxy-propylamino)-6,6-dimethyl-6H-benzo[b]naphtho[2,3-d]fu-
ran-11-one
##STR01208##
[5324] In the same manner as Compound A7-14-2, Compound GT21-4 was
deprotected to obtain the title compound.
[5325] LCMS: m/z 352 [M+H].sup.+
[5326] HPLC retention time: 2.26 min (analysis condition Y)
Example 1193
[5327] Compound GT22-1
8-(2-Diethylamino-ethoxy)-6,6-dimethyl-3-propyl-6H-benzo[b]naphtho[2,3-d]f-
uran-11-one
##STR01209##
[5329] To the mixture of trifluoro-methanesulfonic acid
8-(2-diethylamino-ethoxy)-6,6-dimethyl-11-oxo-6,11-dihydro-benzo[b]naphth-
o[2,3-d]furan-3-yl ester (15 mg), which had been obtained in the
same manner as Compound A7-25, tris(1-methyl-3-oxo-1-butenyloxy)
iron (III) (1 mg), NMP (0.3 ml) and THF (0.3 ml), n-PrMgBr (0.88 M,
THF solution, 0.291 ml) and zinc chloride (0.5 M THF solution,
0.114 ml) were added at 0.degree. C. under nitrogen atmosphere, and
the mixture was stirred at 0.degree. C. for 10 min. The reaction
mixture was added with water and extracted with ethyl acetate. The
organic layer was washed with saturated brine, and then
concentrated under reduced pressure. The resulting residues were
purified by silica gel column (ethyl acetate/hexane) to obtain the
title compound (4.5 mg, 38%).
[5330] LCMS: m/z 420 [M+H].sup.+
[5331] HPLC retention time: 5.77 min (analysis condition H)
Example 1194
[5332] Compound GT22-2
8-(2-Diethylamino-ethoxy)-3-ethyl-6,6-dimethyl-6H-benzo[b]naphtho[2,3-d]fu-
ran-11-one
##STR01210##
[5334] In the same manner as Compound GT22-2, the title compound
was synthesized.
[5335] LCMS: m/z 406 [M+H].sup.+
[5336] HPLC retention time: 5.12 min (analysis condition B)
Example 1195
[5337] Compound GT23-1
3-Bromo-8-methoxy-6,6-dimethyl-6H-benzo[b]naphtho[2,3-d]furan-11-one
##STR01211##
[5339]
8-Methoxy-6,6-dimethyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-
-yl)-6H-benzo[b]naphtho[2,3-d]furan-11-one (10.3 mg), which had
been synthesized from Compound Z12 under the same conditions as the
method for synthesizing Compound GT20-5, was mixed with copper (II)
bromide (16.5 mg), MeOH (0.5 ml) and water (0.25 ml), and the
mixture was stirred and heated at 70.degree. C. for 2 hrs. DCM was
added to the reaction solution for extraction. The organic layer
was concentrated and purified by silica gel column to obtain the
title compound (9.4 mg).
[5340] LCMS: m/z 371 [M+H].sup.+
[5341] HPLC retention time: 7.55 min (analysis condition B)
Example 1196
[5342] Compound GT23-2
3-Bromo-8-hydroxy-6,6-dimethyl-6H-benzo[b]naphtho[2,3-d]furan-11-one
##STR01212##
[5344] In the same manner as Compound GT15-5,
3-bromo-8-methoxy-6,6-dimethyl-6H-benzo[b]naphtho[2,3-d]furan-11-one
was deprotected to obtain the title compound.
[5345] LCMS: m/z 357 [M+H].sup.+
[5346] HPLC retention time: 2.82 min (analysis condition A)
[5347] The compounds described in the following Table 42 were
synthesized from Compound GT23-2 according to the method given in
the Table.
TABLE-US-00042 TABLE 42 Example Comp. HPLC Retention No. No.
Structure Compound Name Condition Time m/z Method 1197 GT23-3
##STR01213## 3-Bromo-6,6-dimethyl- 8-((2R,3R)-
2,3,4-trihydroxy-butoxy)- 6H-benzo[b]naphtho [2,3-d]furan-11-one D
2.30 461.0 1198 GT23-4 ##STR01214## 3-Bromo-8- ((R)-2,3-dihydroxy-
propoxy)- 6,6-dimethyl-6H- benzo[b]naphtho [2,3-d]furan-11-one A
5.42 431.0 1199 GT23-5 ##STR01215## 3-Bromo-8-(2-diethylamino-
ethoxy)-6,6-dimethyl-6H- benzo[b]naphtho [2,3-d]furan-11-one H 5.37
456.0 A7-17 indicates data missing or illegible when filed
Example 1200
[5348] Compound GT24-1
8-((R)-2,3-Dihydroxy-propoxy)-3-iodo-6,6-dimethyl-6H-benzo[b]naphtho[2,3-d-
]furan-11-one
##STR01216##
[5350] To
3-bromo-8-((S)-2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-6,6-dimet-
hyl-6H-benzo[b]naphtho[2,3-d]furan-11-one (15 mg, 0.032 mmol), CuI
(6.2 mg, 0.032 mmol), NaI (9.6 mg, 0.064 mmol) and
trans-N,N'-dimethylcyclohexane-1,2-diamine (0.01 ml) were added and
the mixture was stirred for 48 hrs under nitrogen atmosphere. The
reaction solution was diluted with ethyl acetate. The organic layer
was washed with saturated brine, and then concentrated under
reduced pressure. The resulting residues were purified by silica
gel column (ethyl acetate/hexane) to obtain
8-((S)-2,2-dimethyl-[1,3]dioxolan-4-yl
methoxy)-3-iodo-6,6-dimethyl-6H-benzo[b]naphtho[2,3-d]furan-11-one
(16 mg, 97%), which was then deprotected according to the method of
A-14-2 to give the title compound.
[5351] LCMS: m/z 479 [M+H].sup.+
[5352] HPLC retention time: 4.26 min (analysis condition A)
Example 1201
[5353] Compound GT24-2
3-Iodo-6,6-dimethyl-8-((2R,3R)-2,3,4-trihydroxy-butoxy)-6H-benzo[b]naphtho-
[2,3-d]furan-11-one
##STR01217##
[5355] In the same manner as Compound GT24-1,
3-iodo-8-[(4R,5R)-5-(tert-butyl-dimethyl-silanyloxymethyl)-2,2-dimethyl-[-
1,3]dioxolan-4-yl
methoxy]-6,6-dimethyl-6H-benzo[b]naphtho[2,3-d]furan-11-one was
synthesized from
3-bromo-8-[(4R,5R)-5-(tert-butyl-dimethyl-silanyloxymethyl)-2,2-dimethyl--
[1,3]dioxolan-4-yl
methoxy]-6,6-dimethyl-6H-benzo[b]naphtho[2,3-d]furan-11-one.
Subsequently, according to the same method as Compound T22-2,
deprotection was carried out to obtain the title compound.
Example 1202
[5356] Compound GT25-1
6,6-Dimethyl-8-(4-methyl-piperazine-1-sulfonyl)-6H-benzo[b]naphtho[2,3-d]f-
uran-11-one
##STR01218##
[5358] By using the method for preparing Compound B1,
trifuloro-methanesulfonic acid
6,6-dimethyl-11-oxo-6,11-dihydro-benzo[b]naphtho[2,3-d]furan-8-yl
ester was prepared from
8-hydroxy-6,6-dimethyl-6H-benzo[b]naphtho[2,3-d]furan-11-one. This
trifuloromethanesulfonic acid ester (205 mg), (2R)-1-[(1R)-1-[bis
(1,1-dimethylethyl)phosphino]ethyl]-2-(dicyclohexylphosphino)ferrocene
(13 mg), palladium acetate (6 mg), 2-trimethylsilanyl-ethanethiol
(90 .mu.L) and potassium carbonate (85 mg) were reacted in DME to
obtain a product (120 mg). To the benzyl alcohol solution (90
.mu.L) of the product (50 mg), DCM solution of N-chlorosuccinimide
(90 mg) was added, and the mixture was stirred at room temperature.
The reaction solution was partitioned between water and ethyl
acetate, and the organic layer was concentrated under reduced
pressure. To the DCM solution of thus-obtained white solid,
N-methylpiperazine (10 .mu.L) was added and the mixture was
stirred. The residues obtained after removing the solvent by
distillation were purified by TLC to obtain the title compound as a
white solid (6 mg).
Example 1203
[5359] Compound GT26-1
(2-Bromo-5-methoxy-phenyl)-acetonitrile
##STR01219##
[5361] To the THF solution (1000 ml) of 2-bromo-5-methoxy-benzoic
acid methyl ester (20 g, 81.6 mmol), the THF suspension (50 ml) of
LAH (4.07 g, 102 mmol) was added under ice cooling. The mixture was
stirred for 30 min under ice cooling. The reaction solution was
partitioned between saturated aqueous solution of Na.sub.2SO.sub.4
and ethyl acetate. The organic layer was washed with saturated
brine and concentrated under reduced pressure. The resulting
residues were dissolved in DCM (200 ml), and added with TEA (12.51
ml, 89.76 mmol) and MsCl (6.63 ml, 85.68 mmol) under ice cooling,
followed by stirring overnight at room temperature. The reaction
mixture was diluted with DCM, and washed in order with 10% aqueous
solution of citric acid, saturated aqueous solution of NaHCO.sub.3
and saturated brine. The residues obtained after concentration
under reduced pressure were dissolved in DMF (100 ml), and added
with the DMF (500 ml) solution of NaCN (40 g, 81.6 mmol) under ice
cooling. After stirring for 2 hrs under ice cooling, the reaction
mixture was extracted with ether, washed with saturated brine and
dried over magnesium sulfate. The residues obtained after
concentration under reduced pressure were purified by silica gel
column (hexane:ethyl acetate=10:1) to obtain the title compound
(12.1 g, 67%).
[5362] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 3.82 (s, 3H), 6.77
(d, 1H), 7.07 (s, 1H), 7.47 (d, 1H)
Example 1204
1-(2-Bromo-5-methoxy-phenyl)-cyclopropane carbonitrile Compound
GT26-2
##STR01220##
[5364] 2-Bromo-5-methoxy-phenyl)-acetonitrile (12.2 g, 53.97 mmol)
was dissolved in toluene (50 ml), and added with tetrabutylammonium
bromide (3.55 g, 10.79 mmol), dibromoethane (7.05 ml, 80.95 mmol)
and 50% aqueous solution of NaOH (50 ml) at room temperature. The
mixture was stirred at room temperature for 4 hrs. The reaction
mixture was added with water and extracted with ethyl acetate. The
residues obtained after concentration under reduced pressure were
purified by silica gel column (hexane: ethyl acetate) to obtain the
title compound (11.18 g, 82%).
[5365] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 1.33 (t, 1H), 1.76
(t, 1H), 3.79 (s, 3H), 6.75-6.79 (m, 1H), 6.89 (d, 1H), 7.47 (d,
1H)
Example 1205
1-(2-Bromo-5-methoxy-phenyl)-cyclopropane carboxylic acid Compound
GT26-3
##STR01221##
[5367] 1-(2-Bromo-5-methoxy-phenyl)-cyclopropane carbonitrile (3.0
g, 11.9 mmol) was dissolved in ethylene glycol (30 ml). After
adding KOH (2.1 g, 33.3 mmol) thereto, the mixture was stirred and
heated at 180.degree. C. for 7 hrs. After cooling, the reaction
mixture was added with 1 N HCl (90 ml). The reaction mixture was
extracted with ether, washed with water and saturated brine and
dried over magnesium sulfate. After concentration under reduced
pressure, the title compound was obtained (12.3 g, 72%).
[5368] LCMS: m/z 272 [M+H].sup.+
[5369] HPLC retention time: 2.03 min (analysis condition Y)
Example 1206
[5370] Compound GT26-4
2-[1-(2-Bromo-5-methoxy-phenyl)-cyclopropyl]-benzofuran
##STR01222##
[5372] To the DCM solution (6 ml) of
1-(2-bromo-5-methoxy-phenyl)-cyclopropane carboxylic acid (0.3 g,
1.1 mmol), DMF (2 drops) and oxalyl chloride (0.23 ml, 2.5 mmol)
were added at room temperature, and the mixture was stirred at room
temperature for 2 hrs. The residues obtained from the reaction
solution after concentration under reduced pressure were dissolved
in toluene (6 ml), added with (2-hydroxybenzyl)triphenylphosphonium
bromide (0.605 g, 1.32 mmol) and TEA (0.46 ml, 3.3 mmol), and the
resulting mixture was stirred and heated at 100.degree. C.
overnight. The residues obtained after concentration under reduced
pressure were purified by silica gel column (hexane: DCM) to obtain
the title compound (0.309 g, 81%).
[5373] LCMS: m/z 343 [M+H].sup.+
[5374] HPLC retention time: 3.55 min (analysis condition Y)
Example 1207
[5375] Compound GT26-5
2-(1-Benzofuran-2-yl-cyclopropyl)-4-methoxy-benzoic acid
##STR01223##
[5377] To the THF solution (3 ml) of
2-[1-(2-bromo-5-methoxy-phenyl)-cyclopropyl]-benzofuran (0.259 g,
0.75 mmol), n-BuLi was added at -78.degree. C., and the mixture was
stirred at -78.degree. C. for 20 min. Thereafter, the mixture was
flushed with carbon dioxide gas. The reaction mixture was added
with saturated solution of NH.sub.4Cl and extracted with ethyl
acetate. The residues obtained after concentration under reduced
pressure were purified by silica gel column (DCM:MeOH) to obtain
the title compound (0.163 g, 70%).
[5378] LCMS: m/z 309 [M+H].sup.+
[5379] HPLC retention time: 2.67 min (analysis condition Y)
Example 1208
[5380] Compound GT26-6
8-Methoxy-11H-spiro[benzo[d]naphtho[2,3-b]furan-6,1'-cyclopropan]-11-one
##STR01224##
[5382] To the DCM solution (10 ml) of
2-(1-benzofuran-2-yl-cyclopropyl)-4-methoxy-benzoic acid (1.0 g,
3.24 mmol), trifuloroacetic acid anhydride (0.45 ml, 3.24 mmol) was
added at -78.degree. C., and the mixture was stirred at -78.degree.
C. for 10 min, at -50.degree. C. for 10 min, and at -30.degree. C.
for 20 min. Thereafter, the mixture was added with water and
extracted with DCM. The residues obtained after concentration under
reduced pressure were washed with DCM and hexane to obtain the
title compound (0.163 g, 70%).
[5383] LCMS: m/z 291 [M+H].sup.+
[5384] HPLC retention time: 2.90 min (analysis condition Y)
Example 1209
[5385] Compound GT26-7
8-(2-(Diethylamino)ethoxy)-11H-spiro[benzo[d]naphtho[2,3-b]furan-6,1'-cycl-
opropan]-11-one
##STR01225##
[5387] In the same manner as Compound A6 and Compound A7-17, the
title compound was obtained from
8-methoxy-11H-spiro[benzo[d]naphtho[2,3-b]furan-6,1'-cyclopropan]-11-one.
[5388] LCMS: m/z 376 [M+H].sup.+
[5389] HPLC retention time: 1.65 min (analysis condition Y)
Example 1210
[5390] Compound GT27-1
2-(2-Bromo-5-methoxy-phenyl)-2-ethyl-butyric acid
##STR01226##
[5392] (2-Bromo-5-methoxy-phenyl)-acetic acid methyl ester (3.51 g,
13.5 mmol) was dissolved in DMF (4.5 ml), and added with NaH (2.1
g, 67.7 mmol). Subsequently, 15-crown-5 (1.38 ml, 6.8 mmol) and EtI
(5.5 ml, 67.7 mmol) cooled to 0.degree. C. were added to the
mixture. The mixture was diluted with ethyl acetate and washed with
water and saturated brine. The residues obtained after
concentration under reduced pressure were purified by silica gel
column (hexane-ethyl acetate). Then, the resultant was dissolved in
ethanol (80 ml) and water (80 ml), added with KOH (91 g), and
stirred at 140.degree. C. The reaction solution was extracted with
ethyl acetate, and washed with water and saturated brine. After
concentration under reduced pressure, the target compound was
obtained (10.62 g, 78%).
[5393] LCMS: m/z 301 [M+H].sup.+
[5394] HPLC retention time: 3.07 min (analysis condition Y)
Example 1211
[5395] Compound GT27-2
2-(2-Bromo-5-methoxy-phenyl)-2-ethyl-butyric acid o-tolyl ester
##STR01227##
[5397] Compound GT27-1 (0.5 g, 1.66 mmol) was dissolved in DCM (10
ml), added with DMF (2 drops) and oxalyl chloride (0.28 ml, 3.32
mmol), and the mixture was stirred for 2 hrs. The reaction mixture
obtained after concentration under reduced pressure was dissolved
in toluene (5 ml), added with DMAP (406 mg, 3.32 mmol), and the
mixture was heated under reflux. The reaction mixture was extracted
with ethyl acetate, washed with 1 N HCl, and saturated brine. The
residues obtained after concentration under reduced pressure were
purified by silica gel column (hexane-ethyl acetate) to obtain the
target compound (0.36 g, 86%).
[5398] LCMS: m/z 393 [M+H].sup.+
[5399] HPLC retention time: 3.03 min (analysis condition Y)
Example 1212
[5400] Compound GT27-3
2-(2-Bromo-5-methoxy-phenyl)-2-ethyl-butyric acid
2-[(triphenyl-phosphanyl)-methyl]-phenyl ester bromate salt
##STR01228##
[5402] Compound GT27-2 (0.118 g, 0.302 mmol) was dissolved in
carbon tetrachloride (3 ml), added with N-bromosuccinimide (54 mg,
0.302 mmol), and the mixture was heated under reflux. The reaction
mixture was concentrated under reduced pressure and the resulting
residues were purified by silica gel column (ethyl acetate-hexane).
The product was dissolved in toluene (3 ml), added with PPh.sub.3
(77 mg, 0.302 mmol), and the mixture was heated under reflux. The
reaction mixture was concentrated under reduced pressure to obtain
the target compound (130 mg, 57%).
Example 1213
[5403] Compound GT27-4
2-[1-(2-Bromo-5-methoxy-phenyl)-1-ethyl-propyl]-benzofuran
##STR01229##
[5405] To the toluene solution (3 ml) of Compound GT27-3 (0.14 g,
0.137 mmol), toluene solution (0.16 ml, 0.164 mmol) of 1 M LiHMDS
was added. The mixture was heated and stirred for 4 hrs. The
reaction mixture was concentrated under reduced pressure and the
resulting residues were purified by silica gel column (ethyl
acetate: hexane) to obtain the title compound (28 mg, 35%).
[5406] LCMS: m/z 373 [M+H].sup.+
[5407] HPLC retention time: 2.73 min (analysis condition Y)
Example 1214
[5408] Compound GT27-5
8-(2-Diethylamino-ethoxy)-6,6-diethyl-6H-benzo[b]naphtho[2,3-d]furan-11-on-
e
##STR01230##
[5410] In the same manner as Compound A7-17, the title compound was
obtained from Compound GT27-4.
[5411] LCMS: m/z 407 [M+H].sup.+
[5412] HPLC retention time: 1.92 min (analysis condition Y)
[5413] Compound GT27-6
8-((R)-2,3-Dihydroxy-propoxy)-6,6-diethyl-6H
benzo[b]naphtho[2,3-d]furan-11-one
##STR01231##
[5415] In the same manner as Compound A7-14-1 and Compound A7-14-2,
the title compound was obtained from Compound GT27-4.
[5416] LCMS: m/z 381 [M+H].sup.+
[5417] HPLC retention time: 2.38 min (analysis condition Y)
[5418] The compounds described in the following Table 43 were
synthesized according to the method shown below. According to the
method used for the preparation of Compound Z10, Z11 and Z12,
3-chloro-8-methoxy-6H-benzo[b]naphtho[2,3-d]furan-11-one was
prepared from Compound A2 and 2-bromo-5-chlorophenol. Subsequently,
demethylation was carried out according to the method that is used
for the preparation of Compound A6, and thus
3-chloro-8-hydroxy-6H-benzo[b]naphtho[2,3-d]furan-11-one was
obtained. Thereafter, according to Mitsunobu reaction that is used
for the preparation of Compound A7-1 or the alkylation method that
is used for the preparation of A7-17, a corresponding side chain
was introduced and, if necessary, functional group modification
such as deprotection, etc. was carried out to prepare the compounds
listed below.
TABLE-US-00043 TABLE 43 Example Comp. HPLC Retention No. No.
Structure Compound Name Condition Time m/z 1216 GT28-1 ##STR01232##
3-Chloro-8-(2-diethylamino-ethoxy)-
6,6-dimethyl-6H-benzo[b]naphtho[2,3- d]furan-11-one F 2.52 412.0
1217 GT28-2 ##STR01233## 3-Chloro-6,6-dimethyl-8-((2R,3R)-
2,3,4-trihydroxy-butoxy)-6H- benzo[b]naphtho[2,3-d]furan-11-one H
5.39 417.0 1218 GT28-3 ##STR01234## 3-Chloro-8-((R)-2,3-dihydroxy-
propoxy)-6,6-dimethyl-6H- benzo[b]naphtho[2,3-d]furan-11-one H 5.77
387.0
Pharmacological Testing Method
1. Activity of Inhibiting ALK Enzyme
[5419] ALK-inhibiting activity was measured by following an
activity of inhibiting phosphorylation by biotinylated peptide
(EGPWLEEEEEAYGWMDF). For the detection of phosphorylation of the
biotinylated peptide, time-resolved fluorescence measurement was
performed using an anti-phosphorylated tyrosine antibody labeled
with europium cryptate and streptavidin conjugated to XL665, i.e.,
an allophycocyanin derivative. From the inhibition ratio compared
to the control group that does not comprise a test compound, 50%
inhibitory concentration (i.e., IC.sub.50 value) was
calculated.
2. Measurement of an Activity of Inhibiting Karpas-299 Cell
Growth
[5420] The test compounds were serially diluted with dimethyl
sulfoxide, further diluted with phosphate buffered saline which is
free of any Ca.sup.2, Mg.sup.2+ (.times.50 dilution), and 10 .mu.L
of the resulting solution was aliquoted in a 96-well plate. Human
lymphoma cell line KARPAS-299 was prepared in RPMI-1640 medium to
which 10% bovine fetal serum was added to give a cell suspension
with the cell density of 10,000 cells/190 .mu.L. The resulting cell
suspension was aliquoted to the plate (190 .mu.L per well) to which
the test compound had been already added, and the plate was kept in
a 5% carbon dioxide gas incubator at 37.degree. C. Ninety-six hours
later, 10 .mu.L of WST-8 (manufactured by Dojindo Laboratories) was
added to each well, and subsequently the absorbance was measured at
450 nm. From the ratio of inhibition on cell growth which had been
obtained from the addition of a test compound compared to the
control group with no addition, 50% growth inhibitory concentration
(i.e., IC.sub.50 value) of the test compound was calculated. The
results are summarized in Tables 44-49.
TABLE-US-00044 TABLE 44 Inhibitory activity ALK-inhibiting on
Karpas-299 cell Examples activity IC.sub.50(.mu.M) growth
IC.sub.50(.mu.M) .sup. 123(Compound B2-27) 0.00228 0.0138
177(Compound B4-7).sup. 0.00084 0.0105 178(Compound B4-8).sup.
0.00153 0.0214 304(Compound F5-11) 0.00081 0.0061 338(Compound
F5-43) 0.00032 0.0086 341(Compound F5-46) 0.01056 0.0289
364(Compound F6-18) 0.00177 0.0231 366(Compound F6-20) 0.0053
0.0093 372(Compound G6) .sup. 0.03074 0.1682 380(Compound H6-2)
0.00053 0.0062 .sup. 429(Compound J7-10-2) 0.00083 0.0303
543(Compound O8-5) 0.00032 0.03 550(Compound O9-7) 0.00090 0.0044
735(Compound Z7) 0.09385 1.1924 516(Compound N6-2) 0.003906748
0.0248 725(Compound X5) .sup. 0.687683357 2.8765 .sup. 882(Compound
AZ7-10) 0.000493765 0.005769 916(Compound DZ7-1) 0.001836659
0.357381 .sup. 937(Compound EZ9-3) 0.006473484 0.056914 .sup.
939(Compound EZ9-5) 0.399865279 13.421227 1175(Compound GT18-4)
0.093 2.012
TABLE-US-00045 TABLE 45 Example ALK-inhibiting No. Compound
activity IC.sub.50(.mu.M) 13 A7-1 0.052707597 14 A7-2 0.006159417
38 A7-20 0.026183852 39 A7-21 0.017713716 40 A7-22 0.030434111 41
A7-23 0.029469872 45 A8-2 0.008009528 47 A8-4 0.010253392 51 A8-6-3
0.097920152 52 A8-7 0.045959643 55 A8-10 0.00673264 57 A8-12
0.003594618 63 A8-18 0.016005139 65 A8-20 0.0029 67 A9-1 0.004943
70 A9-3-2 0.007649647 73 A9-6-2 0.001398207 74 A9-7 0.0034607 76
A9-9 0.017148495 78 A9-11 0.051123952 79 A9-12 0.017501168 83
A9-15-2 0.0035 84 A9-16 0.08468 90 B2-1 0.033572 100 B2-9
0.016225317 101 B2-10 0.039433518 102 B2-11 0.072607257 104 B2-13
0.001681324 109 B2-16-3 0.000980809 117 B2-23 0.005436966 118 B2-24
0.014834642 122 B2-26-2 0.007278245 124 B2-28 0.059632226 128
B3-2-2 0.003183521 130 B3-4 0.063798146 135 B3-9 0.01492317 137
B3-11 0.071084446 141 B3-14 0.011893599 142 B3-15 0.030133825 143
B3-16 0.027324427 146 B3-19 0.010369469 147 B3-20 0.026851192 149
B3-22 0.272356381 150 B3-23 0.023088404 151 B3-24 0.003610645 157
B3-27-2 0.002114607 158 B3-28 0.042375341 159 B3-29 0.006002322 165
B3-34 0.006783031 166 B3-35 0.003473067 168 B3-37 0.011859342 179
B4-9 0.002000975 187 CC4-2 0.096115639 189 C1-1 0.051102036 206
C4-9 0.005101172 210 C4-13 0.008752733 212 C4-15 0.009616778 226 D1
0.000991134 227 D2 0.003611773 228 D3-1 0.006279559 245 E4-5
0.009450575 256 E5-2 0.00133756 264 E6-2 0.006668071 265 E6-3
0.008113087 268 F1-3 0.005054399 277 F3-6-2 0.000167996 283 F4-1-1
0.001625048 286 F4-3 0.000951804 290 F4-7 0.001133931 293 F4-10
0.002098847 298 F5-5 0.002385717 300 F5-7 0.002575475 306 F5-13
0.002051837 314 F5-20 0.000996109 319 F5-25 0.000881378 322 F5-28
0.01227125 331 F5-36-2 0.001778367 334 F5-39 0.014824288
TABLE-US-00046 TABLE 46 Example ALK-inhibiting No. Compound
activity IC.sub.50(.mu.M) 340 F5-45 0.000579745 346 F5-51
0.002610782 350 F6-4 0.00715425 353 F6-7 0.020276801 355 F6-9
0.001092627 358 F6-12 0.015047658 359 F6-13 0.000399685 389 H9-3
0.002622129 403 I6-4 0.000391036 407 I7-1 0.001863642 421 J7-3
0.015290853 422 J7-4 0.004631153 423 J7-5 0.012009506 424 J7-6
0.001570404 426 J7-8 0.001170682 431 J7-11-2 0.01172814 435 J7-15
0.02319 437 J7-17 0.007091939 438 J8-1 0.012517614 443 J8-6 0.00396
455 JJ5 0.862941682 458 JJ7-2 0.028993627 461 JJ9-1 0.004337558 465
JJ10-1 0.492725332 472 K6 0.029284532 486 K10-5 0.000589765 501
L10-2 0.00160 508 M6-2 0.006136762 517 N6-3 0.03272871 519 N6-5
0.026853329 531 O5-4 0.00431 546 O9-3 0.00086 571 Q8 0.005719259
579 R8-2 0.000769618 591 S4 1.664818863 599 S8-2 0.04064 601 S9-2
0.000456356 607 T2-1 0.432812267 618 T6-1 0.614075453 621 T6-4
0.341433432 628 T11 0.271479209 630 T12-2 0.15422 633 T13-3 0.16211
637 T13-7 0.16821 639 T13-9 0.16189 645 T14-5 0.41327 650 T14-10
0.18923 654 T16-1 0.01951 657 T16-4 0.07941 668 T21 0.8521 671
T22-1-1 0.151061541 678 T22-7 2.8135 679 T22-8 0.583 686 T26-2
0.08320 702 U8-6-2 0.00260 704 U8-7-2 0.00604 706 U8-8-2 0.35976
707 U8-8-3 0.84884 709 U10-1 0.55215 711 U11 0.00193 720 W4-2
0.13445 730 Y5-2 0.554738402 751 K10-10 0.0085 753 K10-12 0.0022
755 K10-14 0.0118 758 K10-17 0.1422 760 K10-19 0.0015 762 L10-3
0.0099 770 L10-11 0.0231 776 B3-42 0.0042 786 E9-4 0.0004 790 E9-8
0.0075 796 F4-11 0.0003 822 PR11-6 0.0003 823 PR11-7 0.0003 824
PR9-9 0.0142 829 PR9-13 0.0007 832 PR11-11 0.0006 846 PR9-25
0.021743738 847 PR11-14 0.001890642
TABLE-US-00047 TABLE 47 Example ALK-inhibiting No. Compound
activity IC.sub.50(.mu.M) 849 PR11-16 0.000813047 864 LB5-1
0.424843491 866 LB5-3 2.398295 875 AZ7-3 0.113911239 892 AZ7-20
0.009369855 893 AZ7-21 0.142933634 920 DZ7-5 0.326374265 938 EZ9-4
0.300760062 949 GT2-6 1.3255 956 GT2-13 0.1617 960 GT3-2 5.9473 962
GT3-4 1.0829 963 GT3-5 4.224 967 GT3-9 0.8981 970 GT3-12 1.6214 972
GT4-1 0.29 973 GT4-2 0.104 981 GT5-8 2.9743 982 GT5-9 21.3078 983
GT5-10 3.2 994 GT5-21 1.2466 995 GT6-1 12.9519 996 GT6-2 12.9704
997 GT6-3 0.575 998 GT6-4 4.3855 999 GT6-5 3.9 1000 GT6-6 5.4 1001
GT6-7 3.7 1004 GT6-10 0.9 1005 GT6-11 1.4385 1007 GT6-13 0.7526
1008 GT6-14 4.8429 1013 GT8-3 0.93 1017 GT9-3 0.3785 1019 GT9-5
0.77 1030 GT11-8 5.9346 1031 GT11-9 7.7947 1034 GT11-12 2.076 1035
GT11-13 1.6274 1039 GT11-17 0.7938 1042 GT11-20 0.5083 1043 GT11-21
2.2822 1047 GT11-25 1.9038 1048 GT11-26 5.3708 1050 GT11-28 3.2813
1051 GT11-29 1.811 1052 GT11-30 4.0931 1054 GT11-32 7.0451 1059
GT11-37 2.7739 1060 GT11-38 1.1587 1061 GT11-39 1.0914 1065 GT11-43
3.7028 1066 GT11-44 3.1203 1072 GT11-50 3.3428 1073 GT11-51 2.547
1074 GT11-52 1.2588 1081 GT11-59 1.0586 1083 GT11-61 0.7928 1085
GT11-63 0.9013 1086 GT11-64 0.3127 1087 GT11-65 0.206 1090 GT12-3
0.8541 1096 GT12-9 5.7571 1102 GT13-3 0.4209 1105 GT13-6 0.3894
1113 GT13-14 0.1571 1114 GT13-15 0.7 1117 GT13-18 2.2 1118 GT13-19
0.5 1119 GT13-20 0.42 1125 GT13-26 0.028 1126 GT13-27 3.0645 1127
GT13-28 5.6311 1128 GT13-29 17.4641 1129 GT13-30 0.51 1130 GT13-31
0.54 1164 GT16-5 0.4149 1177 GT18-6 0.7527 1185 GT20-6 1.8
TABLE-US-00048 TABLE 48 Inhibitory activity Example on Karpas-299
cell No. Compound growth IC.sub.50(.mu.M) 15 A7-3 0.1138 17 A7-5
0.6268 19 A7-7 0.3293 21 A7-9 0.2037 22 A7-10 0.3031 25 A7-12
0.1119 46 A8-3 0.0866 56 A8-11 0.0677 58 A8-13 0.0226 60 A8-15
0.2322 61 A8-16 0.0345 62 A8-17 0.1269 64 A8-19 0.0726 66 A8-21
0.1050 68 A9-2 0.1372 72 A9-5 0.0523 93 B2-4 0.0365 138 B3-12
1.4358 154 B3-25-3 0.7298 155 B3-26 1.3613 160 B3-30 0.2282 163
B3-32 0.0652 167 B3-36 0.0390 174 B4-4 0.0812 229 D3-2 0.9700 230
D3-3 0.1320 244 E4-4 0.1090 257 E5-3 0.1895 260 E5-6 0.0527 273
F3-3 0.0162 287 F4-4 0.0071 289 F4-6 0.0291 291 F4-8 0.0221 292
F4-9 0.0650 294 F5-1 0.0091 297 F5-4 0.0018 301 F5-8 0.0297 302
F5-9 0.0043 303 F5-10 0.0135 309 F5-15-2 0.0098 310 F5-16 0.0042
315 F5-21 0.0663 316 F5-22 0.0066 323 F5-29 0.0076 325 F5-31 0.0727
326 F5-32 0.0240 335 F5-40 0.0256 336 F5-41 0.1491 339 F5-44 0.0060
348 F6-2 0.0295 351 F6-5 0.0274 352 F6-6 0.0364 357 F6-11 0.0776
359 F6-13 0.0079 420 J7-2-3 0.0295 434 J7-14 0.5567 446 J9-3 0.0532
467 JJ10-3 6.0632 488 K10-7 0.0518 518 N6-4 0.1224 562 P5 27.7670
605 T1-1 1.8669 636 T13-6 1.2901 640 T13-10 1.3775 642 T14-2 0.6324
646 T14-6 1.9418 649 T14-9 1.08 656 T16-3 2.25 672 T22-1-2 1.7820
680 T23-1 4.2526 681 T23-2 7.0799 688 T27-2 0.9970 689 U5 0.1217
695 U8-3-2 0.6773 698 U8-4-3 1.10 700 U8-5-2 0.3573 708 U9 0.4070
710 U10-2 0.94
TABLE-US-00049 TABLE 49 Inhibitory activity Example on Karpas-299
cell No. Compound growth IC.sub.50(.mu.M) 764 L10-5 0.019 766 L10-7
0.037 767 L10-8 0.024 769 L10-10 0.159 773 B3-40 0.022 787 E9-5
0.041 792 E9-9 0.004 793 PR11-20 0.020313 794 PR11-21 0.06439 827
PR9-11 0.036 839 PR9-20 0.018772 844 PR9-23 0.020492 845 PR9-24
0.067888 850 PR11-17 0.005766 852 PR11-19 0.034632 865 LB5-2
1.287666 878 AZ7-6 1.126471 896 AZ7-24 0.054 935 EZ9-1 16.635 941
W4-4 0.116 976 GT5-3 1.868 979 GT5-6 8.231 980 GT5-7 17.135 984
GT5-11 1.957 985 GT5-12 19.989 986 GT5-13 1.332 987 GT5-14 3.787
990 GT5-17 2.359 991 GT5-18 4.255 993 GT5-20 6.081 1020 GT9-6 2.655
1115 GT13-16 7.875 1123 GT13-24 3.951 1124 GT13-25 5.511 1131
GT13-32 2.501 1132 GT13-33 10.887
* * * * *
References