U.S. patent application number 14/729979 was filed with the patent office on 2015-09-24 for cyclic amide derivative.
This patent application is currently assigned to MOCHIDA PHARMACEUTICAL CO., LTD.. The applicant listed for this patent is MOCHIDA PHARMACEUTICAL CO.., LTD.. Invention is credited to Muneyoshi MAKABE, Munetaka OHKOUCHI, Akihiro OKANO.
Application Number | 20150266839 14/729979 |
Document ID | / |
Family ID | 47072039 |
Filed Date | 2015-09-24 |
United States Patent
Application |
20150266839 |
Kind Code |
A1 |
OKANO; Akihiro ; et
al. |
September 24, 2015 |
CYCLIC AMIDE DERIVATIVE
Abstract
[Problem] To provide a GPR40 activating agent having, as an
active ingredient, a novel compound having a GPR40 agonist action,
a salt of the compound, a solvate of the salt or the compound, or
the like, particularly, an insulin secretagogues and a prophylactic
and/or therapeutic agent against diabetes, obesity, or the like.
[Means of Solving the Problem] A compound of Formula (III):
##STR00001## (where f is 0 to 2; g is 1 to 4; j is 0 to 3; k is 0
to 2; n is 0 to 2; p is 0 to 4; his 0 to 3; q1 id 0 to 3; q2 is 0
or 1; r1 is 0 to 2 (with the proviso that q1+q2+r1 is 0 to 5);
J.sub.1a is --CR.sup.11a--, N; J.sub.2 is --CR.sup.12aR.sup.12b--,
--CR.sup.12c--; T is --CH.sub.2--, O, --S(O).sub.i-- (i is an
integer of 0 to 2) or --NR.sup.7--; X is O, S, or --NR.sup.7--;
ring A''' is a benzene ring, a pyridine ring; ring B' is a benzene
ring, a pyridine ring, a pyrimidine ring; and R.sup.1 to R.sup.14
are specific groups), a salt of the compound, or a solvate of the
salt or the compound.
Inventors: |
OKANO; Akihiro; (Tokyo,
JP) ; OHKOUCHI; Munetaka; (Tokyo, JP) ;
MAKABE; Muneyoshi; (Tokyo, JP) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
MOCHIDA PHARMACEUTICAL CO.., LTD. |
Tokyo |
|
JP |
|
|
Assignee: |
MOCHIDA PHARMACEUTICAL CO.,
LTD.
Tokyo
JP
|
Family ID: |
47072039 |
Appl. No.: |
14/729979 |
Filed: |
June 3, 2015 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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14114017 |
Oct 25, 2013 |
9072758 |
|
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PCT/JP2012/059915 |
Apr 11, 2012 |
|
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14729979 |
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Current U.S.
Class: |
514/222.5 ;
514/222.2; 514/249; 514/342; 514/372; 544/3; 544/8; 546/271.1;
548/213 |
Current CPC
Class: |
C07D 285/16 20130101;
A61K 9/2018 20130101; C07D 417/14 20130101; A61K 31/425 20130101;
A61K 31/4985 20130101; A61K 31/541 20130101; A61K 9/485 20130101;
A61P 43/00 20180101; C07D 417/12 20130101; A61P 3/04 20180101; A61K
31/549 20130101; A61K 9/1652 20130101; A61K 31/54 20130101; A61P
3/00 20180101; A61K 31/4439 20130101; A61P 3/10 20180101; A61K
9/145 20130101; C07D 279/02 20130101; C07F 5/04 20130101; A61K
31/69 20130101; A61K 45/06 20130101; C07D 275/03 20130101; C07D
285/10 20130101 |
International
Class: |
C07D 275/03 20060101
C07D275/03; C07D 417/12 20060101 C07D417/12; A61K 31/4439 20060101
A61K031/4439; A61K 45/06 20060101 A61K045/06; A61K 31/549 20060101
A61K031/549; C07D 279/02 20060101 C07D279/02; A61K 31/541 20060101
A61K031/541; A61K 31/4985 20060101 A61K031/4985; A61K 31/425
20060101 A61K031/425; C07D 285/16 20060101 C07D285/16 |
Foreign Application Data
Date |
Code |
Application Number |
Apr 28, 2011 |
JP |
2011-102535 |
Aug 26, 2011 |
JP |
2011-185340 |
Oct 11, 2011 |
JP |
PCT/JP2011/073355 |
Feb 29, 2012 |
JP |
2012-044857 |
Claims
1. A compound of Formula (III): ##STR00600## (where n is an integer
of 0 to 2; p is an integer of 0 to 4; h is an integer of 0 to 3; j
is an integer of 0 to 3; k is an integer of 0 to 2; J.sub.1a is
--CR.sup.11a- or a nitrogen atom; J.sub.2 is
--CR.sup.12aR.sup.12b-- or --NR.sup.12c-- (with the proviso that
when J.sub.1a is a nitrogen atom, h is 0); X is an oxygen atom, a
sulfur atom, or --NR.sup.7--; a ring B' is a benzene ring, a
pyridine ring, or a pyrimidine ring; f is an integer of 0 to 2; g
is an integer of 1 to 4; q1 is an integer of 0 to 3; q2 is 0 or 1;
r1 is an integer of 0 to 2 (with the proviso that q1+q2+r1 is an
integer of 0 to 5); a ring A''' is a benzene ring or a pyridine
ring; T is --CH.sub.2--, an oxygen atom, --S(O).sub.i-- (i is an
integer of 0 to 2), or a group optionally selected from a
--NR.sup.7-- group; R.sup.1s are independently a group optionally
selected from a halogen atom, a C.sub.1-6 alkyl group that is
optionally substituted with 1 to 5 substituent(s) RI, a C.sub.2-6
alkenyl group that is optionally substituted with 1 to 5
substituent(s) RI, a C.sub.2-6 alkynyl group that is optionally
substituted with 1 to 5 substituent(s) RI, a C.sub.1-6 alkoxy group
that is optionally substituted with 1 to 5 substituent(s) RI, and a
cyano group; R.sup.2a and R.sup.2b are independently a group
optionally selected from a hydrogen atom, a halogen atom, a
C.sub.1-6 alkyl group, a C.sub.2-6 alkenyl group, a C.sub.2-6
alkynyl group, a C.sub.1-6 alkoxy group, and a cyano group;
R.sup.3, R.sup.4, R.sup.5, R.sup.6, and R.sup.7 are independently a
group optionally selected from a hydrogen atom, a C.sub.1-6 alkyl
group, a halogenated C.sub.1-6 alkyl group, a C.sub.2-6 alkenyl
group, and a C.sub.2-6 alkynyl group; R.sup.11as are independently
a group optionally selected from a hydrogen atom, a halogen atom, a
C.sub.1-6 alkyl group, a halogenated C.sub.1-6 alkyl group, a
C.sub.2-6 alkenyl group, a C.sub.2-6 alkynyl group, a C.sub.1-6
alkoxy group, a halogenated C.sub.1-6 alkoxy group, a C.sub.2-7
alkanoyl group, and a carboxy group that is optionally protected;
R.sup.12a and R.sup.12b are independently a group optionally
selected from a hydrogen atom, a halogen atom, a C.sub.1-6 alkyl
group, a halogenated C.sub.1-6 alkyl group, a C.sub.2-6 alkenyl
group, a C.sub.2-6 alkynyl group, a C.sub.1-6 alkoxy group, a
halogenated C.sub.1-6 alkoxy group, and a cyano group; R.sup.12cs
are independently a group optionally selected from a hydrogen atom,
a C.sub.1-6 alkyl group, and a halogenated C.sub.1-6 alkyl group;
R.sup.13s are independently a group optionally selected from a
halogen atom, --OH, a cyano group, a C.sub.1-10 alkyl group that is
optionally substituted with 1 to 5 substituent(s) RI, a C.sub.2-10
alkenyl group that is optionally substituted with 1 to 5
substituent(s) RI, a C.sub.2-10 alkynyl group that is optionally
substituted with 1 to 5 substituent(s) RI, a C.sub.1-10 alkoxy
group that is optionally substituted with 1 to 5 substituent(s) RI,
a C.sub.2-10 alkenyloxy group that is optionally substituted with 1
to 5 substituent(s) RI, a C.sub.2-10 alkynyloxy group that is
optionally substituted with 1 to 5 substituent(s) RI, --SH, a
--S(O).sub.iR.sup.a (i is an integer of 0 to 2) group, and a
--NR.sup.bR.sup.c group; R.sup.13a is a group optionally selected
from an aryl group that is optionally substituted with 1 to 5
substituent(s) RII, a heterocyclic group that is optionally
substituted with 1 to 5 substituent(s) RII, an aralkyl group that
is optionally substituted with 1 to 5 substituent(s) RII, a
heteroarylalkyl group that is optionally substituted with 1 to 5
substituent(s) RII, a non-aromatic heterocyclic alkyl group that is
optionally substituted with 1 to 5 substituent(s) RII, an aryloxy
group that is optionally substituted with 1 to 5 substituent(s)
RII, a heteroaryloxy group that is optionally substituted with 1 to
5 substituent(s) RII, a non-aromatic heterocyclic oxy group that is
optionally substituted with 1 to 5 substituent(s) RII, an
aralkyloxy group that is optionally substituted with 1 to 5
substituent(s) RII, a heteroarylalkyloxy group that is optionally
substituted with 1 to 5 substituent(s) RII, and a substituted
spiropiperidinylmethyl group; R.sup.14s are independently a group
optionally selected from a halogen atom, --OH, a cyano group, a
C.sub.1-6 alkyl group that is optionally substituted with 1 to 5
substituent(s) RI, a C.sub.2-6 alkenyl group that is optionally
substituted with 1 to 5 substituent(s) RI, a C.sub.2-6 alkynyl
group that is optionally substituted with 1 to 5 substituent(s) RI,
a C.sub.1-6 alkoxy group that is optionally substituted with 1 to 5
substituent(s) RI, --SH, a --S(O).sub.iR.sup.a (i is an integer of
0 to 2) group, and a --NR.sup.bR.sup.c group; R.sup.a is a
C.sub.1-6 alkyl group or a halogenated C.sub.1-6 alkyl group;
R.sup.b and R.sup.c are independently a group optionally selected
from a hydrogen atom, a C.sub.1-6 alkyl group, a halogenated
C.sub.1-6 alkyl group, a C.sub.2-6 alkenyl group, a C.sub.2-6
alkynyl group, a C.sub.2-7 alkanoyl group (the alkanoyl group is
optionally substituted with --OH or a C.sub.1-6 alkoxy group), a
C.sub.1-6 alkylsulfonyl group, an arylcarbonyl group, and a
heterocyclic carbonyl group, where R.sup.b and R.sup.c optionally
form together with a nitrogen atom to which R.sup.b and R.sup.c are
bonded, a 3- to 8-membered cyclic group, where in the cyclic group,
one or two carbon atom(s) is(are) optionally substituted with an
atom optionally selected from an oxygen atom, a sulfur atom, and a
nitrogen atom (the nitrogen atom is optionally substituted with a
C.sub.1-6 alkyl group that is optionally substituted with 1 to 5
substituent(s) RI) or with a carbonyl group, and the cyclic group
is further optionally substituted with 1 to 5 substituent(s) RII;
the substituents RI are optionally the same as or different from
each other and are each a group optionally selected from a halogen
atom, --OH, a cyano group, a C.sub.1-6 alkoxy group (the C.sub.1-6
alkoxy group is optionally substituted with 1 to 5 halogen atom(s),
1 to 5 --OH, 1 to 5 C.sub.1-6 alkoxy group(s), 1 to 5 aryl group(s)
(the aryl group is optionally substituted with 1 to 3 halogen
atom(s)), 1 to 5 heterocyclic group(s) (the heterocyclic group is
optionally substituted with 1 to 3 C.sub.1-6 alkyl group(s) or 1 to
3 oxo group(s)), 1 to 5 --S(O).sub.iR.sup.a (i is an integer of 0
to 2) group(s), 1 to 5 --SO.sub.2NR.sup.dR.sup.e group(s), 1 to 5
--CONR.sup.dR.sup.e group(s), or 1 to 5 --NR.sup.b1R.sup.c1
group(s)), a --NR.sup.b1R.sup.c1 group, and a heterocyclic oxy
group (the heterocyclic oxy group is optionally substituted with 1
to 3 C.sub.1-6 alkyl group(s) or 1 to 3 oxo group(s)); the
substituents RII are optionally the same as or different from each
other and are each a group optionally selected from the
substituents RI, a C.sub.1-6 alkyl group (the C.sub.1-6 alkyl group
is optionally substituted with 1 to 5 halogen atom(s), 1 to 5 --OH,
1 to 5 C.sub.1-6 alkoxy group(s), 1 to 5 --S(O).sub.iR.sup.a (i is
an integer of 0 to 2) group(s), 1 to 5 --NR.sup.b1R.sup.c1
group(s), 1 to 5 --SO.sub.2NR.sup.dR.sup.e group(s), or 1 to 5
--CONR.sup.dR.sup.e group(s)), a C.sub.2-6 alkenyl group, a
C.sub.2-7 alkanoyl group, an aralkyloxy group, a heterocyclic group
(the heterocyclic group is optionally substituted with 1 to 3
C.sub.1-6 alkyl group(s) or 1 to 3 oxo group(s)), a heterocyclic
carbonyl group (the heterocyclic carbonyl group is optionally
substituted with 1 to 3 C.sub.1-6 alkyl group(s) or 1 to 3 oxo
group(s)), a --S(O).sub.iR.sup.a (i is an integer of 0 to 2) group,
a --CONR.sup.dR.sup.e group, and a --CONR.sup.dR.sup.e1 group;
R.sup.d and R.sup.e are independently a hydrogen atom or a
C.sub.1-6 alkyl group (the C.sub.1-6 alkyl group is optionally
substituted with 1 to 5 halogen atom(s), 1 to 5 --OH, or 1 to 5
C.sub.1-6 alkoxy group(s)); R.sup.e1 is a C.sub.1-6 alkyl group
(the C.sub.1-6 alkyl group is optionally substituted with 1 to 5
--OH, 1 to 5 C.sub.1-6 alkoxy group(s), 1 to 5 aryl group(s) (the
aryl group is optionally substituted with 1 to 3 halogen atom(s)),
1 to 5 heterocyclic group(s) (the heterocyclic group is optionally
substituted with 1 to 3 C.sub.1-6 alkyl group(s) or 1 to 3 oxo
group(s)), 1 to 5 --S(O).sub.iR.sup.a (i is an integer of 0 to 2)
group(s), 1 to 5 --SO.sub.2NR.sup.dR.sup.e group(s), 1 to 5
--CONR.sup.dR.sup.e group(s), or 1 to 5 --NR.sup.b1R.sup.c1
group(s)); and R.sup.b1 and R.sup.c1 are independently a group
optionally selected from a hydrogen atom, a C.sub.1-6 alkyl group,
a C.sub.2-7 alkanoyl group, and a C.sub.1-6 alkylsulfonyl group,
where R.sup.b1 and R.sup.c1 optionally form together with a
nitrogen atom to which R.sup.b1 and R.sup.c1 are bonded, a 3- to
8-membered cyclic group, where in the cyclic group, one or two
carbon atom(s) is(are) optionally substituted with an atom
optionally selected from an oxygen atom, a sulfur atom, and a
nitrogen atom (the nitrogen atom is optionally substituted with a
C.sub.1-6 alkyl group) or with a carbonyl group), or a
pharmaceutically acceptable salt of the compound, or a
pharmaceutically acceptable solvate of the compound, or a
pharmaceutically acceptable solvate of the salt.
2. The compound according to claim 1 of Formula (III-1):
##STR00601## (where n, p, h, q1, q2, r1, the ring B', T, J.sub.1a,
J.sub.2, R.sup.1, R.sup.2a, R.sup.2b, R.sup.13, R.sup.13a, and
R.sup.14 are the same as defined in Formula (III); E is a group
optionally selected from Formulae (c1) to (c6): ##STR00602## or a
pharmaceutically acceptable salt of the compound, or a
pharmaceutically acceptable solvate of the compound, or a
pharmaceutically acceptable solvate of the salt.
3. The compound according to claim 1 or 2 of Formula (III-1)-1:
##STR00603## (where n, p, h, T, J.sub.2, R.sup.1, R.sup.2a
R.sup.2b, and J.sub.1a are the same as defined in Formula (III); q
is an integer of 0 to 4; s is an integer of 0 to 2 (with the
proviso that q+s is an integer of 0 to 5); a ring A' is an aryl
group or a heteroaryl group; V is a single bond or an oxygen atom;
R.sup.8s are independently a group optionally selected from a
C.sub.1-6 alkoxy group that is substituted with 1 to 5
substituent(s) M, a C.sub.2-6 alkenyloxy group that is substituted
with 1 to 5 substituent(s) M, a C.sub.2-6 alkynyloxy group that is
substituted with 1 to 5 substituent(s) M, a --CONR.sup.dR.sup.e1
group, an aralkyloxy group, a heterocyclic oxy group (the
heterocyclic oxy group is optionally substituted with 1 to 3
C.sub.1-6 alkyl group(s) or 1 to 3 oxo group(s)), a heterocyclic
group (the heterocyclic group is optionally substituted with 1 to 3
C.sub.1-6 alkyl group(s) or 1 to 3 oxo group(s)), and a
heterocyclic carbonyl group (the heterocyclic carbonyl group is
optionally substituted with 1 to 3 C.sub.1-6 alkyl group(s) or 1 to
3 oxo group(s)); the substituents M are independently a group
optionally selected from a halogen atom, --OH, a C.sub.1-6 alkoxy
group, an aryl group (the aryl group is optionally substituted with
1 to 3 halogen atom(s)), a heterocyclic group (the heterocyclic
group is optionally substituted with 1 to 3 --OH, 1 to 3 C.sub.1-6
alkyl group(s), or 1 to 3 oxo group(s)), a --S(O).sub.iR.sup.a (i
is an integer of 0 to 2) group, a --NR.sup.b1R.sup.c1 group, a
--SO.sub.2NR.sup.dR.sup.e group, and a --CONR.sup.dR.sup.e group;
R.sup.9s are independently a group optionally selected from a
halogen atom, --OH, a cyano group, a C.sub.1-6 alkyl group that is
optionally substituted with 1 to 5 substituent(s) RI, a C.sub.2-6
alkenyl group that is optionally substituted with 1 to 5
substituent(s) RI, a C.sub.2-6 alkynyl group that is optionally
substituted with 1 to 5 substituent(s) RI, a C.sub.1-6 alkoxy group
that is optionally substituted with 1 to 5 substituent(s) RI, a
C.sub.2-7 alkanoyl group, --SH, a --S(O).sub.iR.sup.a (i is an
integer of 0 to 2) group, a --NR.sup.b1R.sup.c1 group, and a
--CONR.sup.dR.sup.e group; (RI, R.sup.a, R.sup.d, R.sup.e,
R.sup.b1, R.sup.c1, and R.sup.e1 above are the same as defined in
Formula (III)); q1, r1, T, R.sup.13, and R.sup.14 are the same as
defined in Formula (III); q1+r1 is an integer of 0 to 4; and Ea is
a group optionally selected from groups of Formula (c1) or Formula
(c4): ##STR00604## or a pharmaceutically acceptable salt of the
compound, or a pharmaceutically acceptable solvate of the compound,
or a pharmaceutically acceptable solvate of the salt.
4. The compound according to claim 3, wherein T is --CH.sub.2-- or
an oxygen atom, Ea is Formula (c1), either of q or s is 1 or more,
or a pharmaceutically acceptable salt of the compound, or a
pharmaceutically acceptable solvate of the compound, or a
pharmaceutically acceptable solvate of the salt.
5. The compound according to claim 3 of Formula (III-1-A)-1:
##STR00605## (where n, p, h, q, q1, r1, s, V, J.sub.1a, J.sub.2,
R.sup.1, R.sup.2a, R.sup.2b, R.sup.8, R.sup.9, R.sup.13, and
R.sup.14 are the same as defined in Formula (III-1)-1; a ring A''
is a benzene ring, a pyridine ring, or a pyrimidine ring), or a
pharmaceutically acceptable salt of the compound, or a
pharmaceutically acceptable solvate of the compound, or a
pharmaceutically acceptable solvate of the salt.
6. The compound according to claim 3, wherein in Formula (III-1)-1
and Formula (III-1-A)-1, R.sup.8 s are independently a group
optionally selected from C.sub.1-6 alkoxy group that is substituted
with 1 to 5 substituent(s) M, a --CONR.sup.dR.sup.e1 group, and an
aralkyloxy group, the substituents M are independently a group
optionally selected from a halogen atom, --OH, a C.sub.1-6 alkoxy
group, a --S(O).sub.iR.sup.a (i is an integer of 0 to 2; and
R.sup.a is a C.sub.1-6 alkyl group or a halogenated C.sub.1-6 alkyl
group) group, a --NR.sup.b1R.sup.c1 group, a
--SO.sub.2NR.sup.dR.sup.e group, and a --CONR.sup.dR.sup.e group;
and R.sup.9s are independently a group optionally selected from a
halogen atom, --OH, a cyano group, a C.sub.1-6 alkyl group (the
C.sub.1-6 alkyl group is optionally substituted with 1 to 5 halogen
atom(s), 1 to 5 --OH, 1 to 5 C.sub.1-6 alkoxy group(s), 1 to 5
--S(O).sub.iR.sup.a (i is an integer of 0 to 2 and R.sup.a is a
C.sub.1-6 alkyl group or a halogenated C.sub.1-6 alkyl group)
group(s), or 1 to 5 --NR.sup.b1R.sup.c1 group(s)), a C.sub.2-6
alkenyl group, a C.sub.1-6 alkoxy group (the C.sub.1-6 alkoxy group
is optionally substituted with 1 to 5 halogen atom(s), 1 to 5 --OH,
1 to 5 C.sub.1-6 alkoxy group(s), or 1 to 5 --NR.sup.b1R.sup.c1
group(s)), a C.sub.2-7 alkanoyl group, a --S(O).sub.iR.sup.a (i is
an integer of 0 to 2 and R.sup.a is a C.sub.1-6 alkyl group or a
halogenated C.sub.1-6 alkyl group) group, a --NR.sup.b1R.sup.c1
group, and a --CONR.sup.dR.sup.e group, or a pharmaceutically
acceptable salt of the compound, or a pharmaceutically acceptable
solvate of the compound, or a pharmaceutically acceptable solvate
of the salt.
7. The compound according to claim 6, wherein in Formula (III-1)-1
and Formula (III-1-A)-1, R.sup.8 s are independently a C.sub.1-6
alkoxy group that is substituted with 1 to 5 substituent(s) M; the
substituents M are independently a group optionally selected from
--OH, a C.sub.1-6 alkoxy group, a --S(O).sub.iR.sup.a (i is an
integer of 0 to 2 and R.sup.a is a C.sub.1-6 alkyl group or a
halogenated C.sub.1-6 alkyl group) group, and a --NR.sup.b1R.sup.c1
group; R.sup.9s are independently a group optionally selected from
a halogen atom, a cyano group, a C.sub.1-6 alkyl group (the
C.sub.1-6 alkyl group is optionally substituted with 1 to 5 halogen
atom(s)), and a C.sub.1-6 alkoxy group, or a pharmaceutically
acceptable salt of the compound, or a pharmaceutically acceptable
solvate of the compound, or a pharmaceutically acceptable solvate
of the salt.
8. The compound according to claim 1, wherein when J.sub.1a is a
nitrogen atom, h is 0, and when J.sub.1a is CR.sup.11a and h is an
integer of 0 or 1, or a pharmaceutically acceptable salt of the
compound, or a pharmaceutically acceptable solvate of the compound,
or a pharmaceutically acceptable solvate of the salt.
9. A compound selected from the following compound group:
5-(4-(((R)-4-(6-(3-hydroxy-3-methylbutoxy)-2-methylpyridin-3-yl)-2,3-dihy-
dro-1H-inden-1-yl)oxy)phenyl)-1-oxo-1,2-thiazolidin-3-one (A);
5-(4-(((R)-4-(6-(3-hydroxy-3-methylbutoxy)-2-methylpyridin-3-yl)-2,3-dihy-
dro-1H-inden-1-yl)oxy)phenyl)-1-oxo-1,2-thiazolidin-3-one (A)-a;
5-(4-(((R)-4-(6-(3-hydroxy-3-methylbutoxy)-2-methylpyridin-3-yl)-2,3-dihy-
dro-1H-inden-1-yl)oxy)phenyl)-1-oxo-1,2-thiazolidin-3-one (A)-b;
5-[4-[[(1R)-4-[6-(3-hydroxy-3-methylbutoxy)-2,6-dimethylphenyl]-2,3-dihyd-
ro-1H-inden-1-yl]oxy]phenyl]-1-oxo-1,2-thiazolidin-3-one (A);
5-[4-[[(1R)-4-[6-(3-hydroxy-3-methylbutoxy)-2,6-dimethylphenyl]-2,3-dihyd-
ro-1H-inden-1-yl]oxy]phenyl]-1-oxo-1,2-thiazolidin-3-one (A)-a;
5-[4-[[(1R)-4-[6-(3-hydroxy-3-methylbutoxy)-2,6-dimethylphenyl]-2,3-dihyd-
ro-1H-inden-1-yl]oxy]phenyl]-1-oxo-1,2-thiazolidin-3-one (A)-b;
4-(((1R)-1-(4-(1-oxo-1,2-thiazolidin-3-one-5-yl)phenoxy)-2,3-dihydro-1H-i-
nden-4-yl)oxy)benzonitrile (A);
4-(((1R)-1-(4-(1-oxo-1,2-thiazolidin-3-one-5-yl)phenoxy)-2,3-dihydro-1H-i-
nden-4-yl)oxy)benzonitrile (A)-a;
4-(((1R)-1-(4-(1-oxo-1,2-thiazolidin-3-one-5-yl)phenoxy)-2,3-dihydro-1H-i-
nden-4-yl)oxy)benzonitrile (A)-b;
4-(((1R)-1-(4-(1,1-dioxo-1,2,6-thiadiazinan-3-one-5-yl)phenoxy)-2,3-dihyd-
ro-1H-inden-4-yl)oxy)benzonitrile;
5-(4-(((R)-4-phenoxy-2,3-dihydro-1H-inden-1-yl)oxy)phenyl)-1-oxo-1,2-thia-
zolidin-3-one;
5-(4-((7-(trifluoromethyl)-2,3-dihydrobenzofuran-3-yl)oxy)phenyl)-1-oxo-1-
,2-thiazolidin-3-one;
5-(4-(((R)-4-bromo-2,3-dihydro-1H-inden-1-yl)oxy)phenyl)-1-oxo-1,2-thiazo-
lidin-3-one (A);
5-(4-(((R)-4-(2,6-dimethyl-4-(3-(methylsulfonyl)propoxy)phenyl)-2,3-dihyd-
ro-1H-inden-1-yl)oxy)phenyl)-1-oxo-1,2-thiazolidin-3-one (A);
4-(((1R)-1-(4-(1,1-dioxo-3-oxo-1,2-thiazinan-5-yl)phenoxy)-2,3-dihydro-1H-
-inden-4-yl)oxy)benzonitrile;
5-(4-(((R)-4-bromo-2,3-dihydro-1H-inden-1-yl)oxy)phenyl)-1,1-dioxo-1,2-th-
iazinan-3-one;
5-(4-(((R)-4-(4-(3-hydroxy-3-methylbutoxy)-2,6-dimethylphenyl)-2,3
dihydro-1H-inden-1-yl)oxy)phenyl)-1,1-dioxo-1,2-thiazinan-3-one;
5-(4-(((R)-4-(6-(3-hydroxy-3-methylbutoxy)-2-methylpyridin-3-yl)-2,3-dihy-
dro-1H-inden-1-yl)oxy)phenyl)-1,2-thiazinan-3-one 1,1-dioxide;
5-(4-(((R)-4-(2,6-dimethylphenyl)-2,3-dihydro-1H-inden-1-yl)oxy)phenyl)-1-
,2-thiazinan-3-one 1,1-dioxide;
5-(4-(((R)-4-(2-(trifluoromethyl)phenyl)-2,3-dihydro-1H-inden-1-yl)oxy)ph-
enyl)-1,2-thiazinan-3-one 1,1-dioxide;
5-(4-(((R)-4-(4-(2-ethoxyethoxy)-2,6-dimethylphenyl)-2,3-dihydro-1H-inden-
-1-yl)oxy)phenyl)-1,2-thiazinan-3-one 1,1-dioxide;
5-(4-(((R)-4-(4-(3-hydroxy-3-methylbutoxy)-2,6-dimethylphenyl)-2,3-dihydr-
o-1H-inden-1-yl)oxy)phenyl)-1,2-thiazinan-3-one 1,1-dioxide (C);
5-(4-(((R)-4-(4-(3-hydroxy-3-methylbutoxy)-2,6-dimethylphenyl)-2,3-dihydr-
o-1H-inden-1-yl)oxy)phenyl)-1,2-thiazinan-3-one 1,1-dioxide (D);
5-(4-(((R)-4-(4-(2-ethoxyethoxy)-2,6-dimethylphenyl)-2,3-dihydro-1H-inden-
-1-yl)oxy)phenyl)-1,2-thiazinan-3-one 1,1-dioxide (C);
5-(4-(((R)-4-(2,6-dimethylphenyl)-2,3-dihydro-1H-inden-1-yl)oxy)phenyl)-1-
,2-thiazinan-3-one 1,1-dioxide (C);
5-(4-(((R)-4-(2-(trifluoromethyl)phenyl)-2,3-dihydro-1H-inden-1-yl)oxy)ph-
enyl)-1,2-thiazinan-3-one 1,1-dioxide (C);
5-(4-(((R)-4-(2,6-dimethyl-4-(3-(methylsulfonyl)propoxy)phenyl)-2,3-dihyd-
ro-1H-inden-1-yl)oxy)phenyl)-1,2-thiazinan-3-one 1,1-dioxide (C);
5-(4-(((R)-4-(4-methoxy-2,6-dimethylphenyl)-2,3-dihydro-1H-inden-1-yl)oxy-
)phenyl)-1,2-thiazinan-3-one 1,1-dioxide (C);
5-(4-(((R)-4-(4-(3-hydroxy-3-methylbutoxy)-2,6-dimethylphenyl)-2,3-dihydr-
o-1H-inden-1-yl)oxy)-2-methylphenyl)-1,2-thiazinan-3-one
1,1-dioxide;
5-(4-(((R)-4-phenoxy-2,3-dihydro-1H-inden-1-yl)oxy)phenyl)-1,2-thiazinan--
3-one 1,1-dioxide;
5-(4-(((R)-4-phenoxy-2,3-dihydro-1H-inden-1-yl)oxy)phenyl)-1,2-thiazinan--
3-one 1,1-dioxide (C);
4-(((1R)-1-(4-(1,1-dioxide-3-oxo-1,2-thiazinan-5-yl)phenoxy)-2,3-dihydro--
1H-inden-4-yl)oxy)benzonitrile (C);
3-hydroxy-5-(4-(((R)-4-((6-(3-hydroxy-3-methylbutoxy)-2-methylpyridin-3-y-
l)oxy)-2,3-dihydro-1H-inden-1-yl)oxy)phenyl)-4,5-dihydroisothiazole
1-oxide (A);
3-hydroxy-5-(4-(((R)-4-((6-(3-hydroxy-3-methylbutoxy)-2-methylpyridin-3-y-
l)oxy)-2,3-dihydro-1H-inden-1-yl)oxy)phenyl)-4,5-dihydroisothiazole
1-oxide (A)-a;
3-hydroxy-5-(4-(((R)-4-((6-(3-hydroxy-3-methylbutoxy)-2-methylpyridin-3-y-
l)oxy)-2,3-dihydro-1H-inden-1-yl)oxy)phenyl)-4,5-dihydroisothiazole
1-oxide (A)-b;
3-hydroxy-5-(4-(((R)-4-((6-methoxypyridin-3-yl)oxy)-2,3-dihydro-1H-inden--
1-yl)oxy)phenyl)-4,5-dihydroisothiazole 1-oxide (A);
3-hydroxy-5-(4-(((R)-4-((6-methoxypyridin-3-yl)oxy)-2,3-dihydro-1H-inden--
1-yl)oxy)phenyl)-4,5-dihydroisothiazole 1-oxide (A)-a;
3-hydroxy-5-(4-(((R)-4-((6-methoxypyridin-3-yl)oxy)-2,3-dihydro-1H-inden--
1-yl)oxy)phenyl)-4,5-dihydroisothiazole 1-oxide (A)-b;
3-hydroxy-5-(4-(((R)-4-(m-tolyloxy)-2,3-dihydro-1H-inden-1-yl)oxy)phenyl)-
-4,5-dihydroisothiazole 1-oxide (A);
3-hydroxy-5-(4-(((R)-4-(m-tolyloxy)-2,3-dihydro-1H-inden-1-yl)oxy)phenyl)-
-4,5-dihydroisothiazole 1-oxide (A)-a;
3-hydroxy-5-(4-(((R)-4-(m-tolyloxy)-2,3-dihydro-1H-inden-1-yl)oxy)phenyl)-
-4,5-dihydroisothiazole 1-oxide (A)-b;
5-(4-(((R)-4-(6-(2-ethoxyethoxy)-2-methylpyridin-3-yl)-2,3-dihydro-1H-ind-
en-1-yl)oxy)phenyl)-3-hydroxy-4,5-dihydroisothiazole 1-oxide (A);
5-(4-(((R)-4-(6-(2-ethoxyethoxy)-2-methylpyridin-3-yl)-2,3-dihydro-1H-ind-
en-1-yl)oxy)phenyl)-3-hydroxy-4,5-dihydroisothiazole 1-oxide (A)-a;
5-(4-(((R)-4-(6-(2-ethoxyethoxy)-2-methylpyridin-3-yl)-2,3-dihydro-1H-ind-
en-1-yl)oxy)phenyl)-3-hydroxy-4,5-dihydroisothiazole 1-oxide (A)-b;
3-hydroxy-5-(4-(((R)-4-((2-methylpyridin-3-yl)oxy)-2,3-dihydro-1H-inden-1-
-yl)oxy)phenyl)-4,5-dihydroisothiazole 1-oxide (A);
3-hydroxy-5-(4-(((R)-4-((2-methylpyridin-3-yl)oxy)-2,3-dihydro-1H-inden-1-
-yl)oxy)phenyl)-4,5-dihydroisothiazole 1-oxide (A)-a;
3-hydroxy-5-(4-(((R)-4-((2-methylpyridin-3-yl)oxy)-2,3-dihydro-1H-inden-1-
-yl)oxy)phenyl)-4,5-dihydroisothiazole 1-oxide (A)-b;
5-(4-(((R)-4-bromo-2,3-dihydro-1H-inden-1-yl)oxy)phenyl)-isothiazolidine--
3-one 1-oxide (A)-a;
5-(4-(((R)-4-bromo-2,3-dihydro-1H-inden-1-yl)oxy)phenyl)-isothiazolidin-3-
-one 1-oxide (A)-b;
5-(4-(((R)-4-(4-(2-ethoxyethoxy)-2,6-dimethylphenyl)-2,3-dihydro-1H-inden-
-1-yl)oxy)phenyl)-3-hydroxy-4,5-dihydroisothiazole 1-oxide (A)-a;
5-(4-(((R)-4-(4-(2-ethoxyethoxy)-2,6-dimethylphenyl)-2,3-dihydro-1H-inden-
-1-yl)oxy)phenyl)-3-hydroxy-4,5-dihydroisothiazole 1-oxide (A)-b;
5-(4-(((R)-4-(2,6-dimethyl-4-(3-(methylsulfonyl)propoxy)phenyl)-2,3-dihyd-
ro-1H-inden-1-yl)oxy)phenyl)-3-hydroxy-4,5-dihydroisothiazole
1-oxide (A)-a;
5-(4-(((R)-4-(2,6-dimethylphenyl)-2,3-dihydro-1H-inden-1-yl)oxy)ph-
enyl)-3-hydroxy-4,5-dihydroisothiazole 1-oxide (A)-a;
3-hydroxy-5-(4-(((R)-4-(4-methoxy)-2,6-dimethylphenyl)-2,3-dihydro-1H-ind-
en-1-yl)oxy)phenyl)-4,5-dihydroisothiazole 1-oxide (A)-a;
3-hydroxy-5-(4-(((R)-4-(2-methyl-6-(3-(methylsulfonyl)propoxy)pyridin-3-y-
l)-2,3-dihydro-1H-inden-1-yl)oxy)phenyl)-4,5-dihydroisothiazole
1-oxide (A)-a;
3-hydroxy-5-(4-(((R)-4-(6-methoxy)-2-methylpyridin-3-yl)-2,3-dihyd-
ro-1H-inden-1-yl)oxy)phenyl)-4,5-dihydroisothiazole 1-oxide (A)-a;
3-hydroxy-5-(4-(((R)-4-(2-(trifluoromethyl)phenyl)-2,3-dihydro-1H-inden-1-
-yl)oxy)phenyl)-4,5-dihydroisothiazole 1-oxide (A)-a;
3-hydroxy-5-(4-(((R)-4-(2-trifluoromethyl)pyridin-3-yl)-2,3-dihydro-1H-in-
den-1-yl)oxy)phenyl)-4,5-dihydroisothiazole 1-oxide (A)-a;
3-hydroxy-5-(4-(((R)-4-(o-tolyl)-2,3-dihydro-1H-inden-1-yl)oxy)phenyl)-4,-
5-dihydroisothiazole 1-oxide (A)-a;
5-(4-(((R)-4-(5-fluoro-2-methylphenyl)-2,3-dihydro-1H-inden-1-yl)oxy)phen-
yl)-3-hydroxy-4,5-dihydroisothiazole 1-oxide (A)-a;
5-(4-(((1R)-4-(2-fluoro-6-methoxyphenyl)-2,3-dihydro-1H-inden-1-yl)oxy)ph-
enyl)-3-hydroxy-4,5-dihydroisothiazole 1-oxide (A)-a; and
5-(4-(((R)-4-(2-ethoxy-5-fluorophenyl)-2,3-dihydro-1H-inden-1-yl)oxy)phen-
yl)-3-hydroxy-4,5-dihydroisothiazole 1-oxide (A)-a, or a
pharmaceutically acceptable salt of the compound, or a
pharmaceutically acceptable solvate of the compound or a
pharmaceutically acceptable solvate of the salt, an optical isomer
of the compound, a pharmaceutically acceptable salt of the isomer,
a pharmaceutically acceptable solvate of the isomer or a
pharmaceutically acceptable solvate of the salt of the isomer.
10. A compound selected from the following compound group:
5-(4-(((R)-4-(6-(3-hydroxy-3-methylbutoxy)-2-methylpyridin-3-yl)-2,3-dihy-
dro-1H-inden-1-yl)oxy)phenyl)-1-oxo-1,2-thiazolidin-3-one (A)-a;
4-(((1R)-1-(4-(1-oxo-1,2-thiazolidin-3-one-5-yl)phenoxy)-2,3-dihydro-1H-i-
nden-4-yl)oxy)benzonitrile (A)-a;
4-(((1R)-1-(4-(1,1-dioxo-1,2,6-thiadiazinan-3-one-5-yl)phenoxy)-2,3-dihyd-
ro-1H-inden-4-yl)oxy)benzonitrile;
5-(4-(((R)-4-(6-(3-hydroxy-3-methylbutoxy)-2-methylpyridin-3-yl)-2,3-dihy-
dro-1H-inden-1-yl)oxy)phenyl)-1,2-thiazinan-3-one 1,1-dioxide;
5-(4-(((R)-4-(4-(3-hydroxy-3-methylbutoxy)-2,6-dimethylphenyl)-2,3-dihydr-
o-1H-inden-1-yl)oxy)phenyl)-1,2-thiazinan-3-one 1,1-dioxide (C);
5-(4-(((R)-4-(4-(2-ethoxyethoxy)-2,6-dimethylphenyl)-2,3-dihydro-1H-inden-
-1-yl)oxy)phenyl)-1,2-thiazinan-3-one 1,1-dioxide (C);
5-(4-(((R)-4-(2-(trifluoromethyl)phenyl)-2,3-dihydro-1H-inden-1-yl)oxy)ph-
enyl)-1,2-thiazinan-3-one 1,1-dioxide (C);
5-(4-(((R)-4-(6-(2-ethoxyethoxy)-2-methylpyridin-3-yl)-2,3-dihydro-1H-ind-
en-1-yl)oxy)phenyl)-3-hydroxy-4,5-dihydroisothiazole 1-oxide (A)-a;
5-(4-(((R)-4-(4-(2-ethoxyethoxy)-2,6-dimethylphenyl)-2,3-dihydro-1H-inden-
-1-yl)oxy)phenyl)-3-hydroxy-4,5-dihydroisothiazole 1-oxide (A)-b;
5-(4-(((R)-4-(2,6-dimethyl-4-(3-(methylsulfonyl)propoxy)phenyl)-2,3-dihyd-
ro-1H-inden-1-yl)oxy)phenyl)-3-hydroxy-4,5-dihydroisothiazole
1-oxide (A)-a;
3-hydroxy-5-(4-(((R)-4-(2-(trifluoromethyl)phenyl)-2,3-dihydro-1H--
inden-1-yl)oxy)phenyl)-4,5-dihydroisothiazole 1-oxide (A)-a; and
5-(4-(((1R)-4-(2-fluoro-6-methoxyphenyl)-2,3-dihydro-1H-inden-1-yl)oxy)ph-
enyl)-3-hydroxy-4,5-dihydroisothiazole 1-oxide (A)-a, or a
pharmaceutically acceptable salt of the compound, or a
pharmaceutically acceptable solvate of the compound or a
pharmaceutically acceptable solvate of the salt, an optical isomer
of the compound, a pharmaceutically acceptable salt of the isomer,
a pharmaceutically acceptable solvate of the isomer or a
pharmaceutically acceptable solvate of the salt of the isomer.
11.
5-(4-(((R)-4-(6-(3-hydroxy-3-methylbutoxy)-2-methylpyridin-3-yl)-2,3--
dihydro-1H-inden-1-yl)oxy)phenyl)-1-oxo-1,2-thiazolidin-3-one
(A)-a, or a pharmaceutically acceptable salt of the compound, or a
pharmaceutically acceptable solvate of the compound or a
pharmaceutically acceptable solvate of the salt, an optical isomer
of the compound, a pharmaceutically acceptable salt of the isomer,
a pharmaceutically acceptable solvate of the isomer or a
pharmaceutically acceptable solvate of the salt of the isomer.
12.
4-(((1R)-1-(4-(1-oxo-1,2-thiazolidin-3-one-5-yl)phenoxy)-2,3-dihydro--
1H-inden-4-yl)oxy)benzonitrile (A)-a, or a pharmaceutically
acceptable salt of the compound, or a pharmaceutically acceptable
solvate of the compound or a pharmaceutically acceptable solvate of
the salt, an optical isomer of the compound, a pharmaceutically
acceptable salt of the isomer, a pharmaceutically acceptable
solvate of the isomer or a pharmaceutically acceptable solvate of
the salt of the isomer.
13.
4-(((1R)-1-(4-(1,1-dioxo-1,2,6-thiadiazinan-3-one-5-yl)phenoxy)-2,3-d-
ihydro-1H-inden-4-yl)oxy)benzonitrile, or a pharmaceutically
acceptable salt of the compound, or a pharmaceutically acceptable
solvate of the compound or a pharmaceutically acceptable solvate of
the salt, an optical isomer of the compound, a pharmaceutically
acceptable salt of the isomer, a pharmaceutically acceptable
solvate of the isomer or a pharmaceutically acceptable solvate of
the salt of the isomer.
14.
5-(4-(((R)-4-(6-(3-hydroxy-3-methylbutoxy)-2-methylpyridin-3-yl)-2,3--
dihydro-1H-inden-1-yl)oxy)phenyl)-1,2-thiazinan-3-one 1,1-dioxide,
or a pharmaceutically acceptable salt of the compound, or a
pharmaceutically acceptable solvate of the compound or a
pharmaceutically acceptable solvate of the salt, an optical isomer
of the compound, a pharmaceutically acceptable salt of the isomer,
a pharmaceutically acceptable solvate of the isomer or a
pharmaceutically acceptable solvate of the salt of the isomer.
15.
5-(4-(((R)-4-(4-(3-hydroxy-3-methylbutoxy)-2,6-dimethylphenyl)-2,3-di-
hydro-1H-inden-1-yl)oxy)phenyl)-1,2-thiazinan-3-one 1,1-dioxide
(C), or a pharmaceutically acceptable salt of the compound, or a
pharmaceutically acceptable solvate of the compound or a
pharmaceutically acceptable solvate of the salt, an optical isomer
of the compound, a pharmaceutically acceptable salt of the isomer,
a pharmaceutically acceptable solvate of the isomer or a
pharmaceutically acceptable solvate of the salt of the isomer.
16.
5-(4-(((R)-4-(4-(2-ethoxyethoxy)-2,6-dimethylphenyl)-2,3-dihydro-1H-i-
nden-1-yl)oxy)phenyl)-1,2-thiazinan-3-one 1,1-dioxide (C), or a
pharmaceutically acceptable salt of the compound, or a
pharmaceutically acceptable solvate of the compound or a
pharmaceutically acceptable solvate of the salt, an optical isomer
of the compound, a pharmaceutically acceptable salt of the isomer,
a pharmaceutically acceptable solvate of the isomer or a
pharmaceutically acceptable solvate of the salt of the isomer.
17.
5-(4-(((R)-4-(2-(trifluoromethyl)phenyl)-2,3-dihydro-1H-inden-1-yl)ox-
y)phenyl)-1,2-thiazinan-3-one 1,1-dioxide (C), or a
pharmaceutically acceptable salt of the compound, or a
pharmaceutically acceptable solvate of the compound or a
pharmaceutically acceptable solvate of the salt, an optical isomer
of the compound, a pharmaceutically acceptable salt of the isomer,
a pharmaceutically acceptable solvate of the isomer or a
pharmaceutically acceptable solvate of the salt of the isomer.
18.
5-(4-(((R)-4-(6-(2-ethoxyethoxy)-2-methylpyridin-3-yl)-2,3-dihydro-1H-
-inden-1-yl)oxy)phenyl)-3-hydroxy-4,5-dihydroisothiazole 1-oxide
(A)-a, or a pharmaceutically acceptable salt of the compound, or a
pharmaceutically acceptable solvate of the compound or a
pharmaceutically acceptable solvate of the salt, an optical isomer
of the compound, a pharmaceutically acceptable salt of the isomer,
a pharmaceutically acceptable solvate of the isomer or a
pharmaceutically acceptable solvate of the salt of the isomer.
19.
5-(4-(((R)-4-(4-(2-ethoxyethoxy)-2,6-dimethylphenyl)-2,3-dihydro-1H-i-
nden-1-yl)oxy)phenyl)-3-hydroxy-4,5-dihydroisothiazole 1-oxide
(A)-b, or a pharmaceutically acceptable salt of the compound, or a
pharmaceutically acceptable solvate of the compound or a
pharmaceutically acceptable solvate of the salt, an optical isomer
of the compound, a pharmaceutically acceptable salt of the isomer,
a pharmaceutically acceptable solvate of the isomer or a
pharmaceutically acceptable solvate of the salt of the isomer.
20.
5-(4-(((R)-4-(2,6-dimethyl-4-(3-(methylsulfonyl)propoxy)phenyl)-2,3-d-
ihydro-1H-inden-1-yl)oxy)phenyl)-3-hydroxy-4,5-dihydroisothiazole
1-oxide (A)-a, or a pharmaceutically acceptable salt of the
compound, or a pharmaceutically acceptable solvate of the compound
or a pharmaceutically acceptable solvate of the salt, an optical
isomer of the compound, a pharmaceutically acceptable salt of the
isomer, a pharmaceutically acceptable solvate of the isomer or a
pharmaceutically acceptable solvate of the salt of the isomer.
21.
3-Hydroxy-5-(4-(((R)-4-(2-(trifluoromethyl)phenyl)-2,3-dihydro-1H-ind-
en-1-yl)oxy)phenyl)-4,5-dihydroisothiazole 1-oxide (A)-a, or a
pharmaceutically acceptable salt of the compound, or a
pharmaceutically acceptable solvate of the compound or a
pharmaceutically acceptable solvate of the salt, an optical isomer
of the compound, a pharmaceutically acceptable salt of the isomer,
a pharmaceutically acceptable solvate of the isomer or a
pharmaceutically acceptable solvate of the salt of the isomer.
22.
5-(4-(((1R)-4-(2-fluoro-6-methoxyphenyl)-2,3-dihydro-1H-inden-1-yl)ox-
y)phenyl)-3-hydroxy-4,5-dihydroisothiazole 1-oxide (A)-a, or a
pharmaceutically acceptable salt of the compound, or a
pharmaceutically acceptable solvate of the compound or a
pharmaceutically acceptable solvate of the salt, an optical isomer
of the compound, a pharmaceutically acceptable salt of the isomer,
a pharmaceutically acceptable solvate of the isomer or a
pharmaceutically acceptable solvate of the salt of the isomer.
23. A pharmaceutical composition comprising: the compound as
claimed in any one of claims 1, 9, or 10, or a pharmaceutically
acceptable salt of the compound, or a pharmaceutically acceptable
solvate of the compound or a pharmaceutically acceptable solvate of
the salt.
24. (canceled)
25. (canceled)
26. (canceled)
27. A pharmaceutical composition, characterized by comprising: the
compound as claimed in claim 1, a pharmaceutically acceptable salt
of the compound, a pharmaceutically acceptable solvate of the
compound, or a pharmaceutically acceptable solvate of the salt; and
one or more compounds selected from the group consisting of a PPAR
gamma agonist, a biguanide agent, a sulfonylurea, a rapid-acting
insulin secretagogue, an alpha-glucosidase inhibitor, insulin or an
insulin derivative, GLP-1 or a GLP-1 agonist, a DPP-IV inhibitor,
an alpha-2 antagonist, an SGLT2 inhibitor, an omega-3 fatty acid,
an HMG-CoA reductase inhibitor, an HMG-CoA synthase inhibitor, a
cholesterol absorption inhibitor, an acyl-CoA-cholesterol
acyltransferase (ACAT) inhibitor, a CETP inhibitor, a squalene
synthase inhibitor, an antioxidant, a PPAR alpha agonist, a PPAR
delta agonist, an LXR agonist, an FXR agonist, an MTTP inhibitor, a
squalene epoxidase inhibitor, a bile acid absorption inhibitor, a
CB-1 receptor antagonist, a monoamine reuptake inhibitor, a
serotonin reuptake inhibitor, a lipase inhibitor, a neuropeptide Y
(NPY) receptor antagonist, a peptide YY (PYY) receptor antagonist,
and an adrenergic beta-3 receptor agonist.
28. The pharmaceutical composition according to claim 27, wherein
the DPP-IV inhibitor is a compound selected from sitagliptin,
vildagliptin, alogliptin, saxagliptin, linagliptin, and
teneligliptin, or a pharmaceutically acceptable salt of the
compound.
29. The pharmaceutical composition according to claim 27, wherein
the DPP-IV inhibitor is sitagliptin or a pharmaceutically
acceptable salt of sitagliptin.
30. A method for treating or preventing diabetes, comprising:
administering to a patient an effective amount of the compound as
claimed in any one of claims 1, 9, or 10, or a pharmaceutically
acceptable salt of the compound, or a pharmaceutically acceptable
solvate of the compound or a pharmaceutically acceptable solvate of
the salt.
31. A method for treating or preventing diabetes, comprising:
administering to a patient an effective amount of the compound as
claimed in claim 1, a pharmaceutically acceptable salt of the
compound, a pharmaceutically acceptable solvate of the compound, or
a pharmaceutically acceptable solvate of the salt; and one or more
compounds selected from the group consisting of a PPAR gamma
agonist, a biguanide agent, a sulfonylurea, a rapid-acting insulin
secretagogue, an alpha-glucosidase inhibitor, insulin or an insulin
derivative, GLP-1 or a GLP-1 agonist, a DPP-IV inhibitor, an
alpha-2 antagonist, an SGLT2 inhibitor, an omega-3 fatty acid, an
HMG-CoA reductase inhibitor, an HMG-CoA synthase inhibitor, a
cholesterol absorption inhibitor, an acyl-CoA-cholesterol
acyltransferase (ACAT) inhibitor, a CETP inhibitor, a squalene
synthase inhibitor, an antioxidant, a PPAR alpha agonist, a PPAR
delta agonist, an LXR agonist, an FXR agonist, an MTTP inhibitor, a
squalene epoxidase inhibitor, a bile acid absorption inhibitor, a
CB-1 receptor antagonist, a monoamine reuptake inhibitor, a
serotonin reuptake inhibitor, a lipase inhibitor, a neuropeptide Y
(NPY) receptor antagonist, a peptide YY (PYY) receptor antagonist,
and an adrenergic beta-3 receptor agonist.
32. The method of claim 31, wherein the DPP-IV inhibitor is a
compound selected from sitagliptin, vildagliptin, alogliptin,
saxagliptin, linagliptin, and teneligliptin, or a pharmaceutically
acceptable salt of the compound.
33. The method of claim 31, wherein the DPP-IV inhibitor is
sitagliptin or a pharmaceutically acceptable salt of sitagliptin.
Description
TECHNICAL FIELD
[0001] The present invention relates to a compound for modulating
the functions of G protein-coupled receptor 40 (GPR40). In
particular, the present invention relates to a compound
characterized by having a saturated cyclic amide structure having
--S(O).sub.n--NH--CO-- (n is an integer of 0 to 2) bonded to a ring
B (hereinafter, called the cyclic amide structure) of Formula (I),
a salt of the compound, a solvate of the compound or the salt, a
pharmaceutical composition containing the compound as an active
ingredient, prophylactic and/or therapeutic agents against
GPR40-involving diseases, especially diabetes, and an insulin
secretagogue.
BACKGROUND ART
[0002] Diabetes is categorized into Type 1 diabetes
(insulin-dependent diabetes) and Type 2 diabetes
(non-insulin-dependent diabetes), and borderline type diabetes
(glucose tolerance disorders) has also attracted attention as a
pre-diabetic condition in recent years. Type 1 diabetes is
characterized by a partial or complete inability to produce
insulin, which is a blood glucose regulating hormone. Type 2
diabetes is characterized by induced peripheral insulin resistance
and impaired insulin secretion. Borderline type diabetes is a
pathological condition exhibiting impaired glucose tolerance (IGT)
or impaired fasting glucose (IFG), associated with a risk of
developing Type 2 diabetes or diabetes complications.
[0003] Diabetes is caused by several predisposing factors. It is a
disease characterized by high glucose levels in blood plasma in
fasting and postprandial states or during an oral glucose tolerance
test or by chronic hyperglycemia, in general. Controlling chronic
hyperglycemia is essential in clinical management and treatment of
diabetes. In particular, reduced insulin secretion from beta cells
of the pancreas can induce an abrupt increase in postprandial blood
glucose levels in Type 2 diabetes or borderline type diabetes. An
international large-scale clinical trial has revealed that it is
essential to control postprandial hyperglycemia in impaired glucose
tolerance for suppressing the development and progress of not only
diabetes but also hypertension and cardiovascular diseases (JAMA,
290, 486-494 (2003) (Non-Patent Document 1)). On the basis of these
findings, the International Diabetes Federation published new
guidelines for diabetes treatment (postprandial blood glucose
control guidelines) in 2007, which recommend control of
postprandial blood glucose levels as essential for Type 1 and 2
diabetic patients to alleviate diabetes and reduce risk of
complications. As a practical step, an increased administration of
an alpha-glucosidase inhibitor (voglibose) that is a drug for
alleviating excessive postprandial blood glucose levels associated
with diabetes, has been approved in Japan as a prophylactic agent
against diabetes, aiming to "inhibit the development of Type 2
diabetes from impaired glucose tolerance". As described above,
there has been increasing awareness of the needs of
nonpharmacological and pharmacological treatments against diabetes
and borderline type diabetes, targeting the control of postprandial
blood glucose levels in recent years.
[0004] Diabetes is treated mainly through diet regulation and
exercise. When these fail to alleviate symptoms, pharmacological
treatment is needed. Various types of drugs are available as
prophylactic or therapeutic agents against diabetes. Among them,
examples of insulin secretagogues include sulfonylurea agents
(e.g., glibenclamide, glimepiride) and rapid-acting insulin
secretagogues (e.g., nateglinide, mitiglinide), all of which
stimulate beta cells of the pancreas so as to accelerate insulin
secretion. These drugs are, however, known for their
ineffectiveness (primary failure, secondary failure) and side
effects such as induced hypoglycemic effects. Analogs (e.g.,
exenatide, liraglutide) of glucagon-like peptide-1 (GLP-1), which
are hormones accelerating glucose-responsive insulin secretion in
beta cells of the pancreas, have become available as novel insulin
secretagogues, but they are administered by injection and known for
their side effects of transient gastrointestinal tract disorders.
Other examples of insulin secretagogues include dipeptidyl
peptidase IV (DPP-IV) inhibitors (e.g., sitagliptin, vildagliptin,
alogliptin), which inhibit the degradation of intrinsic GLP-1, but
they are known for their side effects of epipharyngitis, headache,
and infections. Alpha-glucosidase inhibitors (e.g., acarbose,
voglibose) inhibit the degradation and digestion of carbohydrate
and thus limit an abrupt increase in postprandial blood glucose
levels, but they need to be taken immediately before meals and are
known for their side effects such as distension and diarrhea and
serious liver disorders. Biguanides (e.g., metformin, buformin) are
insulin resistance improving agents enhancing insulin sensitivity
and thereby alleviating hyperglycemia, but are known to potentially
induce side effects such as lactic acidosis, nausea, and vomiting.
Thiazolidinedione derivatives (e.g., pioglitazone, rosiglitazone)
are peroxisome proliferator-activated receptor (PPAR) gamma
agonists. The derivatives increase insulin sensitivity in adipose
tissue, the liver, and skeletal muscles and thereby alleviate
chronic hyperglycemia, but are known to cause edema, weight gain,
and serious side effects of liver disorders. Side effects of these
drugs do not always occur, but remain as a major obstacle to high
satisfaction with treatment. Therefore, the demand has been
increasing for insulin secretagogues, particularly orally
administrable insulin secretagogues, entailing few issues and side
effects caused by conventional prophylactic and therapeutic agents
as described above and inhibiting postprandial hyperglycemia
without inducing hypoglycemia.
[0005] Fatty acid plays an important role in insulin use in the
liver and skeletal muscles, glucose-responsive insulin secretion
from the pancreas, and inflammation associated with fat
accumulation in adipose tissue. A strong correlation is known
between increased levels of fatty acid in blood plasma and the
development of diabetes, metabolic syndrome, obesity, and
adiposity.
[0006] GPR40, one of the G-protein-coupled receptors, is
categorized in the free fatty acid receptor (FFAR) family and
activated by C.sub.6-22 saturated or unsaturated fatty acid. It is
disclosed that high expression of GPR40 is observed in beta cells
of the pancreas where the receptor is involved in insulin secretion
caused by fatty acid (Nature, 422, 173-176 (2003) (Non-Patent
Document 2)). Non-fatty-acid low-molecular-weight compounds having
a GPR40 agonist action have been found in recent years, and it is
disclosed that thiazolidinediones, which are insulin sensitivity
improving agents, and MEDICA 16, which is a hypolipidemic agent,
also exhibit agonist actions (Biochem. Biophys. Res. Comm., 301,
406-410 (2003) (Non-Patent Document 3)).
[0007] In the pancreatic islets of Langerhans isolated from GPR40
knockout mice, the glucose-responsive insulin secretagogue action
of fatty acid is lower than the case with normal mice. Accordingly,
substances having a GPR40 agonist action like fatty acid are
expected to have the effect of inhibiting postprandial
hyperglycemia based on the glucose-responsive insulin secretagogue
action in the pancreas. Therefore, substances having a GPR40
agonist action are considered to be effective as prophylactic and
therapeutic agents against diabetes or borderline type
diabetes.
[0008] Studies have been progressed on compounds having a GPR40
activating action as insulin secretagogues or therapeutic agents
against diabetes. Technologies related to compounds having a GPR40
agonist action are disclosed, for example, in WO 2004/041266
pamphlet (Patent Document 1), WO 2005/086661 pamphlet (Patent
Document 2), WO 2007/123225 pamphlet (Patent Document 3), WO
2008/001931 pamphlet (Patent Document 4), WO 2009/054390 pamphlet
(Patent Document 5), WO 2009/054423 pamphlet (Patent Document 6),
WO 2009/054479 pamphlet (Patent Document 7), WO 2011/046851
pamphlet (Patent Document 8), WO 2010/143733 pamphlet (Patent
Document 9), WO 2007/033002 pamphlet (Patent Document 10), WO
2009/048527 pamphlet (Patent Document 11), WO 2009/111056 pamphlet
(Patent Document 12), WO 2005/051890 pamphlet (Patent Document 13),
WO 2004/022551 pamphlet (Patent Document 14), WO 2004/011446
pamphlet (Patent Document 15), WO 2008/030520 pamphlet (Patent
Document 16), WO 2011/066183 pamphlet (Patent Document 17), WO
2010/091176 pamphlet (Patent Document 18), WO 2010/085525 pamphlet
(Patent Document 19), WO 2009/039943 pamphlet (Patent Document 20),
WO 2005/063729 pamphlet (Patent Document 21), and WO 2008/130514
pamphlet (Patent Document 22). These documents, however, do not
disclose or suggest any compounds having a saturated cyclic amide
structure bonded to a benzene ring or the like.
[0009] A technique related to a compound having a
5-aryl-3-isothiazolidinone ring is disclosed in WO 2005/035551
pamphlet (Patent Document 23). The compound disclosed in Patent
Document 23, however, is a compound having an inhibitory effect on
protein tyrosine phosphatase 1B (PTP1B), and its structure of a
linker moiety is fundamentally different from that of the compounds
according to the present invention. Another compound group having a
5-aryl-3-isothiazolidinone ring is disclosed in WO 2008/033931
pamphlet (Patent Document 24) as a compound having an inhibitory
effect on PTP1B. The compound disclosed in Patent Document 24,
however, has a fundamental framework different from that of the
compounds according to the present invention.
[0010] Techniques related to compounds having a
5-aryl-1,2,5-thiadiazolidin-3-one ring are disclosed in WO
2003/082841 pamphlet (Patent Document 25), WO 2005/035551 pamphlet
(Patent Document 24), WO 2007/067612 pamphlet (Patent Document 26),
WO 2007/067613 pamphlet (Patent Document 27), WO 2007/067614
pamphlet (Patent Document 28), WO 2007/089857 pamphlet (Patent
Document 29), WO 2007/115058 pamphlet (Patent Document 30), and WO
2009/109999 pamphlet (Patent Document 31). The compounds disclosed
in Patent Documents 24 to 31, however, are compounds having an
inhibitory effect on PTP1B, and their fundamental structures of
linker moieties are different from that of the compounds according
to the present invention.
[0011] The compound having a 5-aryl-1,2,5-thiadiazolidin-3-one ring
is also disclosed in WO 2008/022771 pamphlet (Patent Document 32).
The compound disclosed in Patent Document 32, however, is a
compound having an inhibitory effect on sphingomyelin and having an
amide structure on its linker moiety, and is different from that of
the compounds according to the present invention.
[0012] A technique related to the compound having a
5-aryl-1,2,6-thiadiazinan-3-one ring and a
5-aryl-1,2-thiazinan-3-one ring is disclosed in Synlett, 834-838
(2005) (Non-Patent Document 4). The compound disclosed in
Non-Patent Document 4, however, has a fundamental framework
different from that of the compounds according to the present
invention and does not disclose or suggest any compounds having a
GPR40 agonist action like the present invention.
[0013] WO 2008/066131 pamphlet (Patent Document 33) and WO
2009/147990 pamphlet (Patent Document 34) disclose compounds having
a 3-hydroxy-5-arylisoxazolyl group as compounds having a G
protein-coupled receptor 120 (GPR120) agonist action. These
documents, however, do not disclose or suggest any compounds having
a GPR40 agonist action or a saturated cyclic amide structure bonded
to a benzene ring or the like as in the present invention.
[0014] WO 2011/052756 pamphlet (Patent Document 35) and WO
2011/078371 pamphlet (Patent Document 36) have recently disclosed
compounds having a 3-hydroxy-5-arylisoxazole group or a
3-hydroxy-5-arylisothiazole group as compounds having a GPR40
activating action.
[0015] In the development of drugs, various strict criteria must be
met in terms of absorption, distribution, metabolism, excretion,
and other factors as well as targeted pharmacological actions.
There are various things to consider, for example, interaction with
other drugs, desensitization or durability, digestive tract
absorption after oral administration, speed to reach the small
intestine, absorption speed and first pass effect, organ barriers,
protein binding, drug metabolizing enzyme induction or inhibition,
excretion route and clearance in the body, and application methods
(application sites, methods, purposes). It is difficult to find a
drug that meets all the criteria.
[0016] Several compounds are reported to have a GPR40 agonist
action, but none of them has been marketed so far. Such agonists
could also involve the above-mentioned general issues in the
development phase of drugs. More specifically, they have problems
in usefulness and safety, such as low metabolism stability and
difficulty in systemic exposure by oral administration, unfavorable
pharmacokinetic effects including absorption and persistence
properties, an activity of inhibiting the human ether-a-go-go
related gene (hERG) channel, possibly resulting in arrhythmia, an
activity of inducing or inhibiting drug metabolizing enzymes (e.g.,
cytochrome P450), or side effects caused by CNS from penetration
through blood-brain barrier. Therefore, required is a compound that
solves these issues as much as possible and still has high
efficacy.
[0017] Moreover, required as a GPR40 agonist is a compound with
fewer issues or side effects as described above than the
aforementioned conventional drugs that have been used to prevent or
treat diabetes (particularly Type 2 diabetes or borderline type
diabetes).
PRIOR ART DOCUMENTS
Patent Documents
[0018] Patent Document 1: WO 2004/041266 pamphlet [0019] Patent
Document 2: WO 2005/086661 pamphlet [0020] Patent Document 3: WO
2007/123225 pamphlet [0021] Patent Document 4: WO 2008/001931
pamphlet [0022] Patent Document 5: WO 2009/054390 pamphlet [0023]
Patent Document 6: WO 2009/054423 pamphlet [0024] Patent Document
7: WO 2009/054479 pamphlet [0025] Patent Document 8: WO 2011/046851
pamphlet [0026] Patent Document 9: WO 2010/143733 pamphlet [0027]
Patent Document 10: WO 2007/033002 pamphlet [0028] Patent Document
11: WO 2009/048527 pamphlet [0029] Patent Document 12: WO
2009/111056 pamphlet [0030] Patent Document 13: WO 2005/051890
pamphlet [0031] Patent Document 14: WO 2004/022551 pamphlet [0032]
Patent Document 15: WO 2004/011446 pamphlet [0033] Patent Document
16: WO 2008/030520 pamphlet [0034] Patent Document 17: WO
2011/066183 pamphlet [0035] Patent Document 18: WO 2010/091176
pamphlet [0036] Patent Document 19: WO 2010/085525 pamphlet [0037]
Patent Document 20: WO 2009/039943 pamphlet [0038] Patent Document
21: WO 2005/063729 pamphlet [0039] Patent Document 22: WO
2008/130514 pamphlet [0040] Patent Document 23: WO 2005/035551
pamphlet [0041] Patent Document 24: WO 2008/033931 pamphlet [0042]
Patent Document 25: WO 2003/082841 pamphlet [0043] Patent Document
26: WO 2007/067612 pamphlet [0044] Patent Document 27: WO
2007/067613 pamphlet [0045] Patent Document 28: WO 2007/067614
pamphlet [0046] Patent Document 29: WO 2007/089857 pamphlet [0047]
Patent Document 30: WO 2007/115058 pamphlet [0048] Patent Document
31: WO 2009/109999 pamphlet [0049] Patent Document 32: WO
2008/022771 pamphlet [0050] Patent Document 33: WO 2008/066131
pamphlet [0051] Patent Document 34: WO 2009/147990 pamphlet [0052]
Patent Document 35: WO 2011/052756 pamphlet [0053] Patent Document
36: WO 2011/078371 pamphlet
Non-Patent Documents
[0053] [0054] Non-Patent Document 1: JAMA, 290, 486-494 (2003)
[0055] Non-Patent Document 2: Nature, 422, 173-176 (2003) [0056]
Non-Patent Document 3: Biochem. Biophys. Res. Comm., 301, 406-410
(2003) [0057] Non-Patent Document 4: Synlett, 834-838 (2005)
SUMMARY OF THE INVENTION
Problem to be Solved by the Invention
[0058] In view of such medical circumstances related to diabetes,
prophylactic and therapeutic drugs are required that accelerate
insulin secretion, particularly glucose-responsive insulin
secretion, through activation of GPR40, and thus exhibit the action
of lowering blood glucose levels, particularly inhibiting
postprandial hyperglycemia.
[0059] Particularly required are orally administrable GPR40
activating agents, insulin secretagogues, prophylactic and/or
therapeutic agents against GPR40-involving diseases (particularly
prophylactic and/or therapeutic agents against diabetes or obesity)
all of which have high safety, excellent efficacy, and high
selectivity with respect to other members of the FFAR family or
similar receptors.
[0060] In particular, there are issues to be addressed as issues
with the conventional techniques described above. More
specifically, there are the following issues to be addressed with
prophylactic and therapeutic agents against diabetes:
ineffectiveness (primary failure, secondary failure) and side
effects such as induced hypoglycemic effects caused by sulfonylurea
agents and rapid-acting insulin secretagogues; transient
gastrointestinal tract disorders caused by GLP-1 analogs; side
effects of epipharyngitis, headache, and infections caused by
DPP-IV inhibitors; side effects such as distension and diarrhea and
serious liver disorders caused by alpha-glucosidase inhibitors;
side effects such as lactic acidosis, nausea, and vomiting caused
by biguanides; edema, weight gain, and serious liver disorders
caused by thiazolidinedione derivatives; and so on. Other issues to
be addressed include solubility, improvement in metabolism
stability, enhancement of absorption properties, improvement in
pharmacokinetic effects, reduction in the activity of inhibiting
hERG, reduction in the activity of inducing or inhibiting drug
metabolizing enzymes (e.g., cytochrome P450), and reduction in
central penetration. Consequently, there are needs for insulin
secretagogues and prophylactic and/or therapeutic agents against
GPR40-involving diseases (particularly prophylactic and/or
therapeutic agents against diabetes or obesity) all of which solve
at least one of the issues, to be orally administrable to mammals
including human beings, and clinically usable in particular.
Means for Solving the Problem
[0061] As a result of assiduous research for solving the above
problems by obtaining a compound having high safety and/or
excellent efficacy and modulating the functions of GPR40, the
inventors of the present invention have found that a derivative
having a cyclic amide structure of Formula (I) has a GPR40 agonist
action. The compound of the present invention has an excellent
glucose-responsive insulin secretagogue action and has a strong
hyperglycemia-inhibiting action during glucose load.
Effects of the Invention
[0062] The present invention provides: a compound characterized by
having a cyclic amide structure of Formula (I), a salt of the
compound, or a solvate of the compound or the salt; and a
pharmaceutical composition characterized by containing as an active
ingredient, the compound, a pharmaceutically acceptable salt of the
compound, or a solvate of the compound or the pharmaceutically
acceptable salt.
[0063] The compound of the present invention is a compound having a
GPR40 agonist action, or a compound having an action of lowering a
blood glucose level, particularly an action of inhibiting
postprandial hyperglycemia, by activating GPR40 to accelerate an
insulin secretion, particularly a glucose-responsive insulin
secretion. The pharmaceutical composition containing the compound
of the present invention as an active ingredient can be orally
administrated and is expected as an insulin secretagogue or a
prophylactic agent and/or a therapeutic agent for a GPR40-involving
disease, particularly diabetes (particularly Type 2 diabetes or
borderline type diabetes) or obesity and adiposity.
[0064] The group of the compounds of the present invention has at
least one of characteristics such as having advantageous
solubility, having high metabolism stability, having excellent oral
absorption properties, having a small activity of inhibiting the
hERG channel, and having small central penetration, and thus is
highly useful.
[0065] Particularly, among the compounds of the present invention,
a compound having a 1-oxo-1,2-thiazolidin-3-one ring has such
unexpected advantages as having a longer half-life in blood and
having a reduced activity of inhibiting cytP-450 (CYP2C9) in
comparison with a compound having an isothiazole-3-ol 1-oxide ring.
In addition, it has been unexpectedly found that a compound having
a 1,2-thiazinane-3-on 1,1-dioxide ring has a higher kinetic
solubility and exhibits a more attenuated activity of inhibiting
cytP-450 (CYP2C9) in comparison with a compound having an
isothiazole-3-ol 1-oxide ring.
MODES FOR CARRYING OUT THE INVENTION
[0066] The present invention provides: a compound of Formula (I),
characterized by having the cyclic amide structure shown in the
following aspects, a salt of the compound, or a solvate of the
compound or the salt; and a pharmaceutical composition or GPR40
activating agent, characterized by containing the compound, the
salt, or the solvate as an active ingredient.
[0067] [Aspects of the Present Invention]
[1] Aspect [1] of the present invention
[0068] A first aspect of the present invention is
a compound of Formula (I):
##STR00002##
[0069] (where n is an integer of 0 to 2; p is an integer of 0 to 4;
h is an integer of 0 to 3; j is an integer of 0 to 3; k is an
integer of 0 to 2;
a ring A is a C.sub.6-14 aryl group which is optionally substituted
with 1 to 5 L(s), a 3- to 14-membered heterocyclic group which is
optionally substituted with 1 to 5 L(s), a C.sub.5-7 cycloalkyl
group which is optionally substituted with 1 to 5 L(s), a C.sub.5-7
cycloalkenyl group which is optionally substituted with 1 to 5
L(s), a 6- to 14-membered spiro ring group which is optionally
substituted with 1 to 5 L(s), or a 2-phenylamino-2-oxoacetyl group
which is optionally substituted with 1 to 5 L(s); a ring B is a
C.sub.6-14 aryl group or a 5- to 14-membered heteroaryl group; X is
an oxygen atom, a sulfur atom, or --NR.sup.7--; J.sub.1 is
--CR.sup.11aR.sup.11b- or --NR.sup.11c--; J.sub.2 is
--CR.sup.12aR.sup.12b- or --NR.sup.12c-- (with the proviso that
when J.sub.1 is --NR.sup.11c--, h is 0); R.sup.1s are independently
a group optionally selected from a halogen atom, a C.sub.1-6 alkyl
group which is optionally substituted with 1 to 5 substituent(s)
RI, a C.sub.2-6 alkenyl group which is optionally substituted with
1 to 5 substituent(s) RI, a C.sub.2-6 alkynyl group which is
optionally substituted with 1 to 5 substituent(s) RI, a C.sub.1-6
alkoxy group which is optionally substituted with 1 to 5
substituent(s) RI, and a cyano group; R.sup.2a and R.sup.2b are
independently a group optionally selected from a hydrogen atom, a
halogen atom, a C.sub.1-6 alkyl group, a C.sub.2-6 alkenyl group, a
C.sub.2-6 alkynyl group, a C.sub.1-6 alkoxy group, and a cyano
group; R.sup.3, R.sup.4, R.sup.5, R.sup.6, and R.sup.7 are
independently a group optionally selected from a hydrogen atom, a
C.sub.1-6 alkyl group, a halogenated C.sub.1-6 alkyl group, a
C.sub.2-6 alkenyl group, and a C.sub.2-6 alkynyl group; R.sup.11a
and R.sup.11b are independently a group optionally selected from a
hydrogen atom, a halogen atom, a C.sub.1-6 alkyl group, a
halogenated C.sub.1-6 alkyl group, a C.sub.2-6 alkenyl group, a
C.sub.2-6 alkynyl group, a C.sub.1-6 alkoxy group, a halogenated
C.sub.1-6 alkoxy group, a C.sub.2-7 alkanoyl group, and a carboxy
group which is optionally protected; R.sup.12a and R.sup.12b are
independently a group optionally selected from a hydrogen atom, a
halogen atom, a C.sub.1-6 alkyl group, a halogenated C.sub.1-6
alkyl group, a C.sub.2-6 alkenyl group, a C.sub.2-6 alkynyl group,
a C.sub.1-6 alkoxy group, a halogenated C.sub.1-6 alkoxy group, and
a cyano group; R.sup.11c and R.sup.12c are independently a group
optionally selected from a hydrogen atom, a C.sub.1-6 alkyl group,
and a halogenated C.sub.1-6 alkyl group; with the proviso that in
the cyclic amide structure moiety, there is not one of the
substituents (R.sup.2b, R.sup.11b, R.sup.11c, R.sup.12b, or
R.sup.12c) on an atom to which the ring B is bonded; Ls are
independently a group optionally selected from a halogen atom,
--OH, an oxo group, a cyano group, a C.sub.1-10 alkyl group which
is optionally substituted with 1 to 5 substituent(s) RI, a
C.sub.2-10 alkenyl group which is optionally substituted with 1 to
5 substituent(s) RI, a C.sub.2-10 alkynyl group which is optionally
substituted with 1 to 5 substituent(s) RI, a C.sub.1-10 alkoxy
group which is optionally substituted with 1 to 5 substituent(s)
RI, a C.sub.2-10 alkenyloxy group which is optionally substituted
with 1 to 5 substituent(s) RI, a C.sub.2-10 alkynyloxy group which
is optionally substituted with 1 to 5 substituent(s) RI, an aryl
group which is optionally substituted with 1 to 5 substituent(s)
RII, a heterocyclic group which is optionally substituted with 1 to
5 substituent(s) RII, an aralkyl group which is optionally
substituted with 1 to 5 substituent(s) RII, a heteroarylalkyl group
which is optionally substituted with 1 to 5 substituent(s) RII, a
non-aromatic heterocyclic alkyl group which is optionally
substituted with 1 to 5 substituent(s) RII, an aryloxy group which
is optionally substituted with 1 to 5 substituent(s) RII, a
heteroaryloxy group which is optionally substituted with 1 to 5
substituent(s) RII, a non-aromatic heterocyclic oxy group which is
optionally substituted with 1 to 5 substituent(s) RII, an
aralkyloxy group which is optionally substituted with 1 to 5
substituent(s) RII, a heteroarylalkyloxy group which is optionally
substituted with 1 to 5 substituent(s) RII, --SH, --SF.sub.5, a
--S(O).sub.iR.sup.a (i is an integer of 0 to 2) group, a
--NR.sup.bR.sup.c group, and a substituted spiropiperidinylmethyl
group;
[0070] R.sup.a is a C.sub.1-6 alkyl group or a halogenated
C.sub.1-6 alkyl group; R.sup.b and R.sup.c are independently a
group optionally selected from a hydrogen atom, a C.sub.1-6 alkyl
group, a halogenated C.sub.1-6 alkyl group, a C.sub.2-6 alkenyl
group, a C.sub.2-6 alkynyl group, a C.sub.2-7 alkanoyl group (the
alkanoyl group is optionally substituted with --OH or a C.sub.1-6
alkoxy group), a C.sub.1-6 alkylsulfonyl group, an arylcarbonyl
group, and a heterocyclic carbonyl group, where R.sup.b and R.sup.c
optionally form together with a nitrogen atom to which they are
bonded, a 3- to 8-membered cyclic group, where in the cyclic group,
one or two carbon atom(s) is(are) optionally substituted with an
atom optionally selected from an oxygen atom, a sulfur atom, and a
nitrogen atom (the nitrogen atom is optionally substituted with a
C.sub.1-6 alkyl group which is optionally substituted with 1 to 5
substituent(s) RI) or with a carbonyl group, and the cyclic group
is optionally further substituted with 1 to 5 substituent(s)
RII;
where the substituents RI may be the same as or different from each
other and be each a group optionally selected from a halogen atom,
--OH, a cyano group, a C.sub.1-6 alkoxy group (the C.sub.1-6 alkoxy
group is optionally substituted with 1 to 5 halogen atom(s), 1 to 5
--OH, 1 to 5 C.sub.1-6 alkoxy group(s), 1 to 5 aryl group(s) (the
aryl group is optionally substituted with 1 to 3 halogen atom(s)),
1 to 5 heterocyclic group(s) (the heterocyclic group is optionally
substituted with 1 to 3 C.sub.1-6 alkyl group(s) or 1 to 3 oxo
group(s)), 1 to 5 --S(O).sub.iR.sup.a (i is an integer of 0 to 2)
group(s), 1 to 5 --SO.sub.2NR.sup.dR.sup.e group(s), 1 to 5
--CONR.sup.dR.sup.e group(s), or 1 to 5 --NR.sup.b1R.sup.c1
group(s)), a --NR.sup.b1R.sup.c1 group, and a heterocyclic oxy
group (the heterocyclic oxy group is optionally substituted with 1
to 3 C.sub.1-6 alkyl group(s) or 1 to 3 oxo group(s)); the
substituents RII may be the same as or different from each other
and be each a group optionally selected from the substituents RI, a
C.sub.1-6 alkyl group (the C.sub.1-6 alkyl group is optionally
substituted with 1 to 5 halogen atom(s), 1 to 5 --OH, 1 to 5
C.sub.1-6 alkoxy group(s), 1 to 5 --S(O).sub.iR.sup.a (i is an
integer of 0 to 2) group(s), 1 to 5 --NR.sup.b1R.sup.c1 group(s), 1
to 5 --SO.sub.2NR.sup.dR.sup.e group(s), or 1 to 5
--CONR.sup.dR.sup.e group(s)), a C.sub.2-6 alkenyl group, a
C.sub.2-7 alkanoyl group, an aralkyloxy group, a heterocyclic group
(the heterocyclic group is optionally substituted with 1 to 3
C.sub.1-6 alkyl group(s) or 1 to 3 oxo group(s)), a heterocyclic
carbonyl group (the heterocyclic carbonyl group is optionally
substituted with 1 to 3 C.sub.1-6 alkyl group(s) or 1 to 3 oxo
group(s)), a --S(O).sub.iR.sup.a (i is an integer of 0 to 2) group,
a --CONR.sup.dR.sup.e group, and a --CONR.sup.dR.sup.e1 group;
R.sup.d and R.sup.e are independently a hydrogen atom or a
C.sub.1-6 alkyl group (the C.sub.1-6 alkyl group is optionally
substituted with 1 to 5 halogen atom(s), 1 to 5 --OH, or 1 to 5
C.sub.1-6 alkoxy group(s)); R.sup.e1 is a C.sub.1-6 alkyl group
(the C.sub.1-6 alkyl group is substituted with 1 to 5 --OH, 1 to 5
C.sub.1-6 alkoxy group(s), 1 to 5 aryl group(s) (the aryl group is
optionally substituted with 1 to 3 halogen atom(s)), 1 to 5
heterocyclic group(s) (the heterocyclic group is optionally
substituted with 1 to 3 C.sub.1-6 alkyl group(s) or 1 to 3 oxo
group(s)), 1 to 5 --S(O).sub.iR.sup.a (i is an integer of 0 to 2)
group(s), 1 to 5 --SO.sub.2NR.sup.dR.sup.e group(s), 1 to 5
--CONR.sup.dR.sup.e group(s), or 1 to 5 --NR.sup.b1R.sup.c1
group(s)); R.sup.b1 and R.sup.c1 are independently a group
optionally selected from a hydrogen atom, a C.sub.1-6 alkyl group,
a C.sub.2-7 alkanoyl group, and a C.sub.1-6 alkylsulfonyl group,
where R.sup.b1 and R.sup.c1 optionally form together with a
nitrogen atom to which they are bonded, a 3- to 8-membered cyclic
group, where in the cyclic group, one or two carbon atom(s) is(are)
optionally substituted with an atom optionally selected from an
oxygen atom, a sulfur atom, and a nitrogen atom (the nitrogen atom
is optionally substituted with a C.sub.1-6 alkyl group) or with a
carbonyl group (with the proviso that there are excluded a compound
which is
5-[4-[2-(2-phenyl-4-oxazolyl)ethoxy]phenyl]-1,1-dioxo-1,2,5-thiadiazolidi-
n-3-one; a compound in which a saturated cyclic amide structure
having --S(O).sub.n--NH--CO-- is 1,1-dioxo-1,2-thiazolidin-3-one,
the ring B is a benzene ring, the ring B is bonded to J.sub.1, k is
1, and in the ring B, a linker moiety containing X and the cyclic
amide structure are positioned at a p-position; and a compound in
which the cyclic amide structure is
1,1-dioxo-1,2,5-thiadiazolidin-3-one, the ring B is bonded to
J.sub.1, and in the ring B, the cyclic amide structure is bonded to
an atom adjacent to an atom to which a linker containing X is
bonded)), or a pharmaceutically acceptable salt of the compound, or
a pharmaceutically acceptable solvate of the compound, or a
pharmaceutically acceptable solvate of the salt.
[0071] Each group in Formula (I) according to Aspect [1] is
specifically described below.
[0072] In the explanation of the compound according to the present
invention, for example, "C.sub.1-6" indicates that the number of
constituent carbon atoms, which is the number of carbon atoms in a
linear, branched, or cyclic group unless otherwise indicated, is 1
to 6. The number of constituent carbon atoms includes the total
number of carbon atoms in a group having a linear or branched group
substituted with a cyclic group or a cyclic group substituted with
a linear or branched group. Therefore, as for an acyclic group,
"C.sub.1-6" means a "linear or branched chain with the number of
constituent carbon atoms of 1 to 6". As for a cyclic group,
"C.sub.1-6" means a "cyclic group with the number of
ring-constituting carbon atoms of 1 to 6". As for a group having an
acyclic group and a cyclic group, "C.sub.1-6" means a "group with
the total number of carbon atoms of 1 to 6".
[0073] The "alkyl group" is a linear, branched, or cyclic alkyl
group. For example, examples of the "C.sub.1-6 alkyl group" include
methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl,
tert-butyl, pentyl, isopentyl, neopentyl, tert-pentyl,
1-methylbutyl, 2-methylbutyl, 1,2-dimethylpropyl, 1-ethylpropyl,
hexyl, isohexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl,
1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl,
1,3-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl,
1-ethylbutyl, 2-ethylbutyl, 1,1,2-trimethylpropyl,
1,2,2-trimethylpropyl, 1-ethyl-1-methylpropyl,
1-ethyl-2-methylpropyl, cyclopropyl, cyclobutyl, cyclopentyl,
cyclohexyl, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl,
1-cyclopropylethyl, 2-cyclopropylethyl, 2-cyclobutylethyl, and
2-methylcyclopropyl. Examples of the "C.sub.1-10 alkyl group"
include, in addition to the groups mentioned as the "C.sub.1-6
alkyl group", heptyl, 1-methylhexyl, octyl, 2-ethylhexyl,
1,1-dimethylhexyl, nonyl, decyl, cycloheptyl, cyclohexylmethyl,
2-cyclohexylethyl, 4-methylcyclohexyl, 4,4-dimethylcyclohexyl, and
3,3,5,5-tetramethylcyclohexyl. The cyclic alkyl group is also
expressed as "cycloalkyl group". Examples of the "C.sub.5-7
cycloalkyl group" include cyclopentyl, cyclohexyl, and
cycloheptyl.
[0074] The "alkenyl group" is a linear, branched, or cyclic alkenyl
group. For example, examples of the "C.sub.2-6 alkenyl group"
include vinyl, allyl, isopropenyl, 2-methylallyl, butenyl,
pentenyl, isopentenyl, hexenyl, 1-cyclopropen-1-yl,
2-cyclopropen-1-yl, 1-cyclobuten-1-yl, 1-cyclopenten-1-yl,
2-cyclopenten-1-yl, 3-cyclopenten-1-yl, 1-cyclohexen-1-yl,
2-cyclohexen-1-yl, 3-cyclohexen-1-yl, 2,4-cyclopentadien-1-yl, and
2,5-cyclohexadien-1-yl. Examples of the "C.sub.2-10 alkenyl group"
include, in addition to the groups mentioned as the "C.sub.2-6
alkenyl group", heptenyl, octenyl, nonenyl, decenyl,
1-cyclohepten-1-yl, 1-cyclohexen-1-ylmethyl,
4-methyl-1-cyclohexen-1-yl, 4,4-dimethyl-1-cyclohexen-1-yl, and
3,3,5,5-tetramethyl-1-cyclohexen-1-yl. The cyclic alkenyl group is
also expressed as "cycloalkenyl group". Examples of the "C.sub.5-7
cycloalkenyl group" include 1-cyclopenten-1-yl, 2-cyclopenten-1-yl,
3-cyclopenten-1-yl, 1-cyclohexen-1-yl, 2-cyclohexen-1-yl,
3-cyclohexen-1-yl, and 1-cyclohepten-1-yl.
[0075] The "alkynyl group" is a linear, branched, or cyclic alkynyl
group. For example, examples of the "C.sub.2-6 alkynyl group"
include ethynyl, 1-propynyl, 2-propynyl, butynyl, pentynyl, and
hexynyl. Examples of the "C.sub.2-10 alkynyl group" include, in
addition to the groups mentioned as the "C.sub.2-6 alkynyl group",
heptynyl, octynyl, nonynyl, and decynyl.
[0076] The "alkoxy group" is a linear, branched, or cyclic alkoxy
group and comprehensively a group of RO-- (as for the C.sub.1-6
alkoxy group, R is the C.sub.1-6 alkyl group listed above). For
example, examples of the "C.sub.1-6 alkoxy group" include methoxy,
ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy,
tert-butoxy, pentyloxy, isopentyloxy, neopentyloxy, tert-pentyloxy,
1-methylbutoxy, 2-methylbutoxy, 1,2-dimethylpropoxy,
1-ethylpropoxy, hexyloxy, isohexyloxy, 1-methylpentyloxy,
2-methylpentyloxy, 3-methylpentyloxy, 1,1-dimethylbutyloxy,
1,2-dimethylbutyloxy, 2,2-dimethylbutyloxy, 1,3-dimethylbutyloxy,
2,3-dimethylbutyloxy, 3,3-dimethylbutoxy, 1-ethylbutyloxy,
2-ethylbutyloxy, 1,1,2-trimethylpropyloxy,
1,2,2-trimethylpropyloxy, 1-ethyl-1-methylpropyloxy,
1-ethyl-2-methylpropyloxy, cyclopropyloxy, cyclobutyloxy,
cyclopentyloxy, cyclohexyloxy, cyclopropylmethoxy,
cyclobutylmethoxy, cyclopentylmethoxy, 1-cyclopropylethoxy,
2-cyclopropylethoxy, 2-cyclobutylethoxy, and
2-methylcyclopropyloxy. Examples of the "C.sub.1-10 alkoxy group"
include, in addition to the groups mentioned as the "C.sub.1-6
alkoxy group", heptyloxy, octyloxy, 2-ethylhexyloxy, nonyloxy,
decyloxy, cycloheptyloxy, cyclohexylmethoxy, 2-cyclohexylethoxy,
4-methylcyclohexyloxy, 4,4-dimethylcyclohexyloxy, and
3,3,5,5-tetramethylcyclohexyloxy.
[0077] The "alkenyloxy group" is the "alkenyl group" which is
substituted with an oxygen atom, denoting a linear, branched, or
cyclic alkenyloxy group. For example, examples of the "C.sub.2-6
alkenyloxy group" include vinyloxy, allyloxy, isopropenyloxy,
2-methylallyloxy, butenyloxy, pentenyloxy, isopentenyloxy,
hexenyloxy, 1-cyclopropen-1-yloxy, 2-cyclopropen-1-yloxy,
1-cyclobuten-1-yloxy, 1-cyclopenten-1-yloxy, 2-cyclopenten-1-yloxy,
3-cyclopenten-1-yloxy, 1-cyclohexen-1-yloxy, 2-cyclohexen-1-yloxy,
3-cyclohexen-1-yloxy, 2,4-cyclopentadien-1-yloxy, and
2,5-cyclohexadien-1-yloxy. Examples of the "C.sub.2-10 alkenyloxy
group" include, in addition to the groups mentioned as the
"C.sub.2-6 alkenyloxy group", heptenyloxy, octenyloxy, nonenyloxy,
decenyloxy, 1-cyclohepten-1-yloxy, 1-cyclohexen-1-ylmethoxy,
4-methyl-1-cyclohexen-1-yloxy, 4,4-dimethyl-1-cyclohexen-1-yloxy,
and 3,3,5,5-tetramethyl-1-cyclohexen-1-yloxy.
[0078] The "alkynyloxy group" is the "alkynyl group" which is
substituted with an oxygen atom, denoting a linear, branched, or
cyclic alkynyloxy group. For example, examples of the "C.sub.2-6
alkynyloxy group" include ethynyloxy, 1-propynyloxy, 2-propynyloxy,
butynyloxy, pentynyloxy, and hexynyloxy. Examples of the
"C.sub.2-10 alkynyloxy group" include, in addition to the groups
mentioned as the "C.sub.2-6 alkynyloxy group", heptynyloxy,
octynyloxy, nonynyloxy, and decynyloxy.
[0079] Examples of the "aryl group" include a monocyclic or
ring-fused C.sub.6-14 aryl groups, for example, phenyl, 1-naphthyl,
2-naphthyl, anthryl, phenanthryl, and acenaphthyl, or a fused aryl
group which is partly hydrogenated such as (1-, 2-, 4-, or
5-)indanyl, indenyl, and tetrahydronaphthyl. The fused aryl group
which is partly hydrogenated means a monovalent group obtained by
removing any hydrogen atom from a fused ring which is partly
hydrogenated, and the hydrogen atom to be removed is optionally a
hydrogen atom in an aromatic ring moiety or a hydrogen atom in a
hydrogenated moiety of the fused ring. For example,
tetrahydronaphthyl includes 1,2,3,4-tetrahydronaphthalene (-1-yl,
-2-yl, -3-yl,-4-yl, -5-yl, -6-yl, -7-yl, -8-yl), and the like.
[0080] Examples of the "heterocyclic group" include a "heteroaryl
group" and a saturated or unsaturated "non-aromatic heterocyclic
group". The term "cyclic" used for these groups means a monovalent
group obtained by removing any hydrogen atom from a ring having a
3- to 14-membered, preferably a 3- to 12-membered, monocyclic ring
or fused ring containing, in addition to carbon atoms, at least one
(preferably 1 to 4) heteroatom(s) optionally selected from N, O,
and S.
[0081] The "heteroaryl group" can be monocyclic or ring-fused, and
the monocyclic heteroaryl group preferably has 5 to 7 ring members
and examples of the "heteroaryl group" include pyrrolyl, furyl,
thienyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl,
isothiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,3-oxadiazolyl,
1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, furazanyl,
1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl,
tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl,
1,2,3-triazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl,
2H-1,2,3-thiadiazinyl, 4H-1,2,4-thiadiazinyl,
6H-1,3,4-thiadiazinyl, 1,4-diazepinyl, and 1,4-oxazepinyl.
[0082] The ring-fused heteroaryl group preferably has 8 to 14 ring
members and includes a monovalent group obtained by removing any
hydrogen atom from a fused ring formed by fusing the 5- to
7-membered heterocyclic ring and a monocyclic aryl group or a
monocyclic heteroaryl group, and the like. The hydrogen atom is
optionally removed from any of the fused rings.
[0083] Specifically, indolyl, isoindolyl, benzofuranyl,
isobenzofuranyl, benzothienyl, isobenzothienyl, benzoxazolyl,
1,2-benzisoxazolyl, benzothiazolyl, 1,2-benzisothiazolyl,
1H-benzimidazolyl, 1H-indazolyl, 1H-benzotriazolyl,
2,1,3-benzothiadiazinyl, chromenyl, isochromenyl,
4H-1,4-benzoxazinyl, 4H-1,4-benzothiazinyl, quinolyl, isoquinolyl,
cinnolinyl, quinazolinyl, quinoxalinyl, phthalazinyl,
benzoxazepinyl, benzoazepinyl, benzodiazepinyl, naphthyridinyl,
purinyl, pteridinyl, carbazolyl, carbolinyl, acridinyl,
phenoxazinyl, phenothiazinyl, phenazinyl, phenoxathiinyl,
thianthrenyl, phenanthridinyl, phenanthrolinyl, indolizinyl,
thieno[3,2-c]pyridyl, thiazolo[5,4-c]pyridyl,
pyrrolo[1,2-b]pyridazinyl, pyrazolo[1,5-a]pyridyl,
imidazo[1,2-a]pyridyl, imidazo[1,5-a]pyridyl,
imidazo[1,2-b]pyridazinyl, imidazo[1,5-a]pyrimidinyl,
1,2,4-triazolo[4,3-a]pyridyl, 1,2,4-triazolo[4,3-b]pyridazinyl,
1H-pyrazolo[3,4-b]pyridyl, 1,2,4-triazolo[1,5-a]pyrimidinyl,
dibenzofuranyl, and the like are mentioned.
[0084] A ring-fused heteroaryl group, etc. which is partly
hydrogenated, such as indolinyl, dihydrobenzofuranyl,
dihydroisobenzofuranyl, dihydrobenzoxazolyl, dihydrobenzothiazolyl,
chromanyl, isochromanyl, 3,4-dihydro-2H-1,4-benzoxazinyl,
3,4-dihydro-2H-1,4-benzothiazinyl, tetrahydroquinolyl,
tetrahydroisoquinolyl, tetrahydroquinoxalinyl, 1,3-benzodioxanyl,
1,4-benzodioxanyl, 1,3-benzodioxolyl, tetrahydrobenzoxazepinyl,
tetrahydrobenzoazepinyl, and
6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridyl is also mentioned. The
ring-fused heteroaryl group, etc. which is partly hydrogenated is
preferably one having 8 to 14 ring members, namely a monovalent
group obtained by removing any hydrogen atom from a ring which is
partly hydrogenated in the fused ring formed by fusing the 5- to
7-membered heterocyclic ring and a monocyclic aryl group or a
monocyclic heteroaryl group. The hydrogen atom to be removed is
optionally a hydrogen atom in the aryl group or in the heterocyclic
moiety or a hydrogen atom in the hydrogenated moiety. In the case
of tetrahydroquinolyl, examples of the partly hydrogenated
ring-fused heteroaryl group include 5,6,7,8-tetrahydroquinolyl and
1,2,3,4-tetrahydroquinolyl. Depending on the position in these
groups from which the hydrogen atom is removed, -2-yl, -3-yl,
-4-yl, -5-yl, -6-yl, -7-yl, and -8-yl are exemplified in the case
of 5,6,7,8-tetrahydroquinolyl, and in the case of
1,2,3,4-tetrahydroquinolyl, -1-yl, -2-yl, -3-yl, -4-yl, -5-yl,
-6-yl, -7-yl, and -8-yl are exemplified.
[0085] Examples of the "non-aromatic heterocyclic group" include a
3- to 8-membered saturated or unsaturated non-aromatic heterocyclic
group, for example, aziridinyl, azetidinyl, oxiranyl, oxetanyl,
thietanyl, pyrrolidinyl, tetrahydrofuryl, thiolanyl, pyrazolinyl,
pyrazolidinyl, piperidinyl, dihydropyranyl, tetrahydropyranyl
(oxanyl), tetrahydrothiopyranyl, piperazinyl, dioxanyl, oxazolinyl,
isoxazolinyl, oxazolidinyl, isoxazolidinyl, thiazolinyl,
isothiazolinyl, thiazolidinyl, isothiazolidinyl, oxadiazolinyl,
oxadiazolidinyl, morpholinyl, thiomorpholinyl, quinuclidinyl, and
oxepanyl, and the "non-aromatic heterocyclic group" means a
monovalent group obtained by removing any hydrogen atom from the
ring.
[0086] Examples of the "heterocyclic group (the heterocyclic group
is optionally substituted with 1 to 3 C.sub.1-6 alkyl group(s) or 1
to 3 oxo group(s))" include, in addition to the groups mentioned as
the "heterocyclic group", a group in which the cyclic group is
substituted with 1 to 3 "C.sub.1-6 alkyl group(s)" or 1 to 3 oxo
group(s) at any position. For example, methylpyrrolyl, methylfuryl,
methylthienyl, methylimidazolyl, methylpyrazolyl, methyloxazolyl,
methylisoxazolyl, methylthiazolyl, methylisothiazolyl,
methylpyridyl, methylpyrimidinyl, methylaziridinyl,
methylazetidinyl, methyloxiranyl, methyloxetanyl, methylthietanyl,
methylpyrrolidinyl, methyltetrahydrofuryl, methylthiolanyl,
methylpyrazolinyl, methylpyrazolidinyl, methylpiperidinyl,
methyltetrahydropyranyl, methylpiperazinyl, methyloxazolinyl,
methylisoxazolinyl, methyloxazolidinyl, methylisoxazolidinyl,
methylthiazolinyl, methylisothiazolinyl, methylthiazolidinyl,
methylisothiazolidinyl, methyloxadiazolinyl, methyloxadiazolidinyl,
methylmorpholinyl, methylthiomorpholinyl, methylquinuclidinyl,
methyloxepanyl, oxopyrrolidinyl, 1,1-dioxidetetrahydrothiopyranyl,
and the like are mentioned.
[0087] The "aralkyl group" is a group in which a linear or branched
alkyl group of the "C.sub.1-6 alkyl group" is substituted with the
"aryl group", and examples of the "aralkyl group" include benzyl,
phenethyl, 3-phenylpropyl, 1-naphthylmethyl, 2-naphthylmethyl,
2-(1-naphthyl)ethyl, 2-(2-naphthyl)ethyl, 1-indanylmethyl,
2-indanylmethyl, 1,2,3,4-tetrahydronaphthalen-1-ylmethyl, and
1,2,3,4-tetrahydronaphthalen-2-ylmethyl.
[0088] The "heteroarylalkyl group" is a group in which a linear or
branched alkyl group of the "C.sub.1-6 alkyl group" is substituted
with the "heteroaryl group", and examples of the "heteroarylalkyl
group" include those substituted with the "monocyclic heteroaryl
group", such as pyrrolylmethyl, furylmethyl, thienylmethyl,
imidazolylmethyl, pyrazolylmethyl, oxazolylmethyl,
isoxazolylmethyl, thiazolylmethyl, isothiazolylmethyl,
1,2,3-triazolylmethyl, 1,2,4-triazolylmethyl,
1,2,3-oxadiazolylmethyl, 1,2,4-oxadiazolylmethyl,
1,3,4-oxadiazolylmethyl, furazanylmethyl, 1,2,3-thiadiazolylmethyl,
1,2,4-thiadiazolylmethyl, 1,3,4-thiadiazolylmethyl,
tetrazolylmethyl, pyridylmethyl, pyridazinylmethyl,
pyrimidinylmethyl, pyrazinylmethyl, 1,2,3-triazinylmethyl,
1,2,4-triazinylmethyl, 1,3,5-triazinylmethyl,
2H-1,2,3-thiadiazinylmethyl, 4H-1,2,4-thiadiazinylmethyl,
6H-1,3,4-thiadiazinylmethyl, 1,4-diazepinylmethyl, and
1,4-oxazepinylmethyl, and
[0089] those substituted with the "ring-fused heteroaryl group",
such as indolylmethyl, isoindolylmethyl, benzofuranylmethyl,
isobenzofuranylmethyl, benzothienylmethyl, isobenzothienylmethyl,
benzoxazolylmethyl, 1,2-benzisoxazolylmethyl, benzothiazolylmethyl,
1,2-benzisothiazolylmethyl, 1H-benzimidazolylmethyl,
1H-indazolylmethyl, 1H-benzotriazolylmethyl,
2,1,3-benzothiadiazinylmethyl, chromenylmethyl, isochromenylmethyl,
4H-1,4-benzoxazinylmethyl, 4H-1,4-benzothiazinylmethyl,
quinolylmethyl, isoquinolylmethyl, cinnolinylmethyl,
quinazolinylmethyl, quinoxalinylmethyl, phthalazinylmethyl,
benzoxazepinylmethyl, benzoazepinylmethyl, benzodiazepinylmethyl,
naphthyridinylmethyl, purinylmethyl, pteridinylmethyl,
carbazolylmethyl, carbolinylmethyl, acridinylmethyl,
phenoxazinylmethyl, phenothiazinylmethyl, phenazinylmethyl,
phenoxathiinylmethyl, thianthrenylmethyl, phenanthridinylmethyl,
phenanthrolinylmethyl, indolizinylmethyl,
thieno[3,2-c]pyridylmethyl, thiazolo[5,4-c]pyridylmethyl,
pyrrolo[1,2-b]pyridazinylmethyl, pyrazolo[1,5-a]pyridylmethyl,
imidazo[1,2-a]pyridylmethyl, imidazo[1,5-a]pyridylmethyl,
imidazo[1,2-b]pyridazinylmethyl, imidazo[1,5-a]pyrimidinylmethyl,
1,2,4-triazolo[4,3-a]pyridylmethyl,
1,2,4-triazolo[4,3-b]pyridazinylmethyl,
1H-pyrazolo[3,4-b]pyridylmethyl,
1,2,4-triazolo[1,5-a]pyrimidinylmethyl, indolinylmethyl,
dihydrobenzofuranylmethyl, chromanylmethyl,
tetrahydroquinolylmethyl, tetrahydroisoquinolylmethyl,
1,4-benzodioxanylmethyl, and 1,3-benzodioxolylmethyl.
[0090] The "non-aromatic heterocyclic alkyl group" is a group in
which a linear or branched alkyl group of the "C.sub.1-6 alkyl
group" is substituted with the "non-aromatic heterocyclic group",
and examples of the "non-aromatic heterocyclic alkyl group" include
aziridinylmethyl, azetidinylmethyl, oxiranylmethyl, oxetanylmethyl,
thietanylmethyl, pyrrolidinylmethyl, tetrahydrofurylmethyl,
thiolanylmethyl, pyrazolinylmethyl, pyrazolidinylmethyl,
piperidinylmethyl, dihydropyranylmethyl, tetrahydropyranylmethyl,
tetrahydrothiopyranylmethyl, piperazinylmethyl, dioxanylmethyl,
oxazolinylmethyl, isoxazolinylmethyl, oxazolidinylmethyl,
isoxazolidinylmethyl, thiazolinylmethyl, isothiazolinylmethyl,
thiazolidinylmethyl, isothiazolidinylmethyl, oxadiazolinylmethyl,
oxadiazolidinylmethyl, morpholinylmethyl, thiomorpholinylmethyl,
quinuclidinylmethyl, and oxepanylmethyl.
[0091] The "aryloxy group" is the "aryl group" which is substituted
with an oxygen atom, and specifically, a group in which the group
mentioned as the "aryl group" is substituted with an oxygen atom is
mentioned. For example, examples of the "aryloxy group" include
phenoxy, 1-naphthyloxy, 2-naphthyloxy, 2-anthryloxy,
phenanthryloxy, 1-indanyloxy, 2-indanyloxy,
1,2,3,4-tetrahydronaphthalen-1-yloxy,
1,2,3,4-tetrahydronaphthalen-2-yloxy, and
1,2,3,4-tetrahydronaphthalen-8-yloxy.
[0092] The "heterocyclic oxy group" is the "heterocyclic group"
which is substituted with an oxygen atom, and a "heteroaryloxy
group" or a "non-aromatic heterocyclic oxy group" is mentioned.
Specifically, a group in which the group mentioned as the
"heterocyclic group" is substituted with an oxygen atom is
mentioned.
[0093] The "heteroaryloxy group" is the "heteroaryl group" which is
substituted with an oxygen atom, and specifically, a group in which
the group mentioned as the "heteroaryl group" is substituted with
an oxygen atom is mentioned. For example, examples of the
"heteroaryloxy group" include pyrrolyloxy, furyloxy, thienyloxy,
imidazolyloxy, pyrazolyloxy, oxazolyloxy, isoxazolyloxy,
thiazolyloxy, isothiazolyloxy, (2-, 3-, or 4-)pyridyloxy,
pyridazinyloxy, pyrimidinyloxy, pyrazinyloxy, indolyloxy,
quinolyloxy, isoquinolyloxy, indolinyloxy, dihydrobenzofuranyloxy,
chromanyloxy, tetrahydroquinolyloxy, tetrahydroisoquinolyloxy,
1,4-benzodioxanyloxy, and 1,3-benzodioxolyloxy.
[0094] The "non-aromatic heterocyclic oxy group" is the
"non-aromatic heterocyclic group" which is substituted with an
oxygen atom, and specifically, a group in which the group mentioned
as the "non-aromatic heterocyclic group" is substituted with an
oxygen atom is mentioned. Examples of the "non-aromatic
heterocyclic oxy group" include 3- to 8-membered saturated or
unsaturated non-aromatic heterocyclic oxy groups such as
aziridinyloxy, azetidinyloxy, oxiranyloxy, oxetanyloxy,
thietanyloxy, pyrrolidinyloxy, tetrahydrofuryloxy, thiolanyloxy,
pyrazolinyloxy, pyrazolidinyloxy, (1-, 2-, 3-, or
4-)piperidinyloxy, dihydropyranyloxy, (2-, 3-, or
4-)tetrahydropyranyloxy ((2-, 3-, or 4-)oxanyloxy),
tetrahydrothiopyranyloxy, piperazinyloxy, dioxanyloxy,
oxazolinyloxy, isoxazolinyloxy, oxazolidinyloxy, isoxazolidinyloxy,
thiazolinyloxy, isothiazolinyloxy, thiazolidinyloxy,
isothiazolidinyloxy, oxadiazolinyloxy, oxadiazolidinyloxy,
morpholinyloxy, thiomorpholinyloxy, quinuclidinyloxy, and
oxepanyloxy.
[0095] Examples of the "heterocyclic oxy group (the heterocyclic
oxy group is optionally substituted with 1 to 3 C.sub.1-6 alkyl
group(s) or 1 to 3 oxo group(s))" include, in addition to the
groups mentioned as the "heterocyclic oxy group", a group in which
the cyclic group is substituted with 1 to 3 "C.sub.1-6 alkyl
group(s)" or 1 to 3 oxo group(s) at any position. The "heterocyclic
oxy group" can also be expressed as a group in which the
"heterocyclic group (the heterocyclic group is optionally
substituted with 1 to 3 C.sub.1-6 alkyl group(s) or 1 to 3 oxo
group(s))" is substituted with an oxygen atom, and specifically, a
group in which the groups mentioned as the "heterocyclic group (the
heterocyclic group is optionally substituted with 1 to 3 C.sub.1-6
alkyl group(s) or 1 to 3 oxo group(s))" are substituted with an
oxygen atom, is mentioned.
[0096] The "aralkyloxy group" is the "aralkyl group" which is
substituted with an oxygen atom, and specifically, a group in which
the groups mentioned as the "aralkyl group" are substituted with an
oxygen atom is mentioned. For example, examples of the "aralkyloxy
group" include benzyloxy, phenethyloxy, 3-phenylpropoxy,
1-naphthylmethoxy, 2-naphthylmethoxy, 2-(1-naphthyl)ethoxy,
2-(2-naphthyl)ethoxy, 1-indanylmethoxy, 2-indanylmethoxy,
1,2,3,4-tetrahydronaphthalene-1-ylmethoxy, and
1,2,3,4-tetrahydronaphthalene-2-ylmethoxy.
[0097] The "heteroarylalkyloxy group" is the "heteroarylalkyl
group" which is substituted with an oxygen atom, and specifically,
a group in which the groups mentioned as the "heteroarylalkyl
group" are substituted with an oxygen atom is mentioned. For
example, a "monocyclic heteroarylalkyl group" substituted with an
oxygen atom, such as pyrrolylmethoxy, furylmethoxy, thienylmethoxy,
imidazolylmethoxy, pyrazolylmethoxy, oxazolylmethoxy,
isoxazolylmethoxy, thiazolylmethoxy, isothiazolylmethoxy,
1,2,3-triazolylmethoxy, 1,2,4-triazolylmethoxy,
1,2,3-oxadiazolylmethoxy, 1,2,4-oxadiazolylmethoxy,
1,3,4-oxadiazolylmethoxy, furazanylmethoxy,
1,2,3-thiadiazolylmethoxy, 1,2,4-thiadiazolylmethoxy,
1,3,4-thiadiazolylmethoxy, tetrazolylmethoxy, pyridylmethoxy,
pyridazinylmethoxy, pyrimidinylmethoxy, pyrazinylmethoxy,
1,2,3-triazinylmethoxy, 1,2,4-triazinylmethoxy,
1,3,5-triazinylmethoxy, 2H-1,2,3-thiadiazinylmethoxy,
4H-1,2,4-thiadiazinylmethoxy, 6H-1,3,4-thiadiazinylmethoxy,
1,4-diazepinylmethoxy, 1,4-oxazepinylmethoxy, and the like, and
[0098] a "ring-fused heteroarylalkyl group" which is optionally
partly hydrogenated and is substituted with an oxygen atom, such as
indolylmethoxy, isoindolylmethoxy, benzofuranylmethoxy,
isobenzofuranylmethoxy, benzothienylmethoxy,
isobenzothienylmethoxy, benzoxazolylmethoxy,
1,2-benzisoxazolylmethoxy, benzothiazolylmethoxy,
1,2-benzisothiazolylmethoxy, 1H-benzimidazolylmethoxy,
1H-indazolylmethoxy, 1H-benzotriazolylmethoxy,
2,1,3-benzothiadiazinylmethoxy, chromenylmethoxy,
isochromenylmethoxy, 4H-1,4-benzoxazinylmethoxy,
4H-1,4-benzothiazinylmethoxy, quinolylmethoxy, isoquinolylmethoxy,
cinnolinylmethoxy, quinazolinylmethoxy, quinoxalinylmethoxy,
phthalazinylmethoxy, benzoxazepinylmnethoxy, benzoazepinylmethoxy,
benzodiazepinylmethoxy, naphthyridinylmethoxy, purinylmethoxy,
pteridinylmethoxy, carbazolylmethoxy, carbolinylmethoxy,
acridinylmethoxy, phenoxazinylmethoxy, phenothiazinylmethoxy,
phenazinylmethoxy, phenoxathiinylmethoxy, thianthrenylmethoxy,
phenanthridinylmethoxy, phenanthrolinylmethoxy, indolizinylmethoxy,
thieno[3,2-c]pyridylmethoxy, thiazolo[5,4-c]pyridylmethoxy,
pyrrolo[1,2-b]pyridazinylmethoxy, pyrazolo[1,5-a]pyridylmethoxy,
imidazo[1,2-a]pyridylmethoxy, imidazo[1,5-a]pyridylmethoxy,
imidazo[1,2-b]pyridazinylmethoxy, imidazo[1,5-a]pyrimidinylmethoxy,
1,2,4-triazolo[4,3-a]pyridylmethoxy,
1,2,4-triazolo[4,3-b]pyridazinylmethoxy,
1H-pyrazolo[3,4-b]pyridylmethoxy,
1,2,4-triazolo[1,5-a]pyrimidinylmethoxy, indolinylmethoxy,
dihydrobenzofuranylmethoxy, chromanylmethoxy,
tetrahydroquinolylmethoxy, tetrahydroisoquinolylmethoxy,
1,4-benzodioxanylmethoxy, 1,3-benzodioxolylmethoxy, and the like,
are mentioned.
[0099] The "spiro ring group" is a 6- to 18-membered mono
spiro-cyclic group in which two cyclic groups share one atom as a
spiro atom to be spiro-fused. Each cyclic group forming a spiro
ring is a carbon ring group (such as a cyclic alkyl group and a
partly hydrogenated fused aryl group) or a heterocyclic group (such
as a non-aromatic heterocyclic group and a partly hydrogenated
ring-fused heteroaryl group) and may be a monocyclic ring or a
fused ring. The number of members of the spiro ring group is
preferably 6 to 14, and when each cyclic group forming the spiro
ring is monocyclic, the cyclic groups are independently preferably
a 3- to 7-membered cyclic group. Each cyclic group forming the
spiro ring may independently have, in the ring, 1 to 3 double
bond(s), preferably 1 double bond. Examples of the "spiro ring
group" include spiro[4,4]nona-(1- or 2-)ene-2-yl, spiro[4,5]dec-(1-
or 2-)ene-2-yl, spiro[4,5]dec-(6- or 7-)ene-7-yl,
spiro[5,5]undec-2-yl, spiro[5,5]undec-(1- or 2-)ene-2-yl,
spiro[inden-1,4'-piperidin]-1'-yl,
spiro[indolin-3,4'-piperidin]-1'-yl, and
spiro[isobenzofuran-1(3H),4'-piperidin]-1'-yl. These spiro rings
are optionally substituted with, for example, 1 to 5 halogen
atom(s), 1 to 5 --OH group(s), 1 to 5 C.sub.1-6 alkyl group(s), 1
to 5 halogenated C.sub.1-6 alkyl group(s), 1 to 5 C.sub.1-6 alkoxy
group(s), or 1 to 5 oxo group(s) which may be the same as or
different from each other.
[0100] The "substituted spiropiperidinylmethyl group" is a methyl
group to which a substituted spiropiperidinyl group defined by
Formula (SP):
##STR00003##
(where Rx and Rxa are independently a group selected from a
hydrogen atom, a fluorine atom, a chlorine atom, a C.sub.1-3 alkyl
group, a trifluoromethyl group, and a methoxy group;
X.sub.1 is --CH(Ry)CH.sub.2--, --C(Ry)=CH--, --N(Rz)CH.sub.2--, or
--C(O)CH.sub.2--;
[0101] Ry is a hydrogen atom or a C.sub.1-3 alkyl group; and Rz is
a hydrogen atom, a C.sub.1-3 alkyl group, or a phenyl group) is
bonded, or a methyl group to which Formula (SP'):
##STR00004##
(where R.sup.6as are independently a halogen atom or a C.sub.1-3
alkyl group; xa is an integer of 0 to 8; R.sup.7a is an oxygen atom
or --CH.sub.2--, R.sup.8a is an oxygen atom, --CH.sub.2--, or
--C(O)--, or R.sup.7a and R.sup.8a together optionally form
--CH.dbd.CH-- (with the proviso that R.sup.7a and R.sup.8a are not
simultaneously an oxygen atom); Y.sup.1a is .dbd.CR.sup.9a- or a
nitrogen atom, Y.sup.2a is .dbd.CR.sup.9b- or a nitrogen atom,
Y.sup.3a is .dbd.CR.sup.9c- or a nitrogen atom, and Y.sup.4a is
.dbd.CR.sup.9d- or a nitrogen atom; and R.sup.9a, R.sup.9b,
R.sup.9c, and R.sup.9d are independently a hydrogen atom, a halogen
atom, or a C.sub.1-6 alkyl group (with the proviso that 2 or more
of Y.sup.1a to Y.sup.4a are not simultaneously a nitrogen atom)) is
bonded.
[0102] Specifically, the "substituted spiropiperidinylmethyl group"
is Formula (SP)--CH.sub.2--:
##STR00005##
(where each definition is the same as defined in Formula (SP)), or
Formula (SP')--CH.sub.2--:
##STR00006##
(where each definition is the same as defined in Formula
(SP')).
[0103] More specific examples of the "substituted
spiropiperidinylmethyl group" as Formula (SP)--CH.sub.2-- include
spiro[indan-1,4'-piperidin]-1'-ylmethyl,
(1'H-spiro[inden-1,4'-piperidin]-1'-yl)methyl,
1,2-dihydro-1'H-spiro [indol-3,4'-piperidin]-1'-ylmethyl,
(1-methyl-1,2-dihydro-1'H-spiro[indol-3,4'-piperidin]-1'-yl)methyl,
{1-(1-methylethyl)-1,2-dihydro-1'H-spiro[indol-3,4'-piperidin]-1'-yl}meth-
yl,
(1-phenyl-1,2-dihydro-1'H-spiro[indol-3,4'-piperidin]-1'-yl)methyl,
(2,3-dihydro-1'H-spiro[inden-1,4'-piperidin]-1'-ylmethyl,
(7-chloro-1-methyl-1,2-dihydro-1'H-spiro[indol-3,4'-piperidin]-1'-yl)meth-
yl,
(5-fluoro-1-methyl-1,2-dihydro-1'-spiro[indol-3,4'-piperidin]-1'-yl)me-
thyl,
(5-methoxy-1-methyl-1,2-dihydro-1'H-spiro[indol-3,4'-piperidin]-1'-y-
l)methyl,
(1,5-dimethyl-1,2-dihydro-1'H-spiro[indol-3,4'-piperidin]-1'-yl)-
methyl,
[1-methyl-5-(trifluoromethyl)-1,2-dihydro-1'H-spiro[indol-3,4'-pip-
eridin]-1'-yl]methyl, and
(3-oxo-2,3-dihydro-1'H-spiro[inden-1,4'-piperidin]-1'-yl)methyl.
[0104] As the explanation for the substituted spiropiperidinyl
group or the examples for the substituent in Formula
(SP)--CH.sub.2--, the description in WO 2011/046851 pamphlet,
particularly Formula (3) in p.8 or the structural formulae and the
chemical names in Example 1 to Example 39, and the like can be
referred to.
[0105] Specific examples of the "substituted spiropiperidinylmethyl
group" as Formula (SP')--CH.sub.2-- include
(spiro[isobenzofuran-1(3H),4'-piperidin]-1-yl)methyl, (spiro
[benzofuran-3 (2H),4'-piperidin]-1-yl)methyl,
(3-oxospiro[6-azaisobenzofuran-1(3H),4'-piperidin]-1-yl)methyl,
(spiro[5-fluoroisobenzofuran-1(3H),4'-piperidin]-1-yl)methyl,
(spiro[6-fluoroisobenzofuran-1(3H),4'-piperidin]-1-yl)methyl,
(spiro[5-fluoro-6-azaisobenzofuran-1(3H),4'-piperidin]-1-yl)methyl,
(spiro[6-azaisobenzofuran-1(3H),4'-piperidin]-1-yl)methyl,
(spiro[5-fluoroisobenzofuran-1(3H),4'-piperidin]-1-yl)methyl,
(spiro[6-fluoroisobenzofuran-1(3H),4'-piperidin]-1-yl)methyl,
(spiro[5-fluoro-6-azaisobenzofuran-1(3H),4'-piperidin]-1-yl)methyl,
and
(7-fluoro-1H-spiro[fluoro[3,4-c]pyridin-3,4'-piperidin]-1-yl)methyl.
[0106] As the explanation for the substituted spiropiperidinyl
group or the examples for the substituent in Formula
(SP')--CH.sub.2--, each definition, explanation, and Example for a
spiropiperidine ring below disclosed as Formula [II](for the
definition for the substituent and the like, each definition in
Formula [I] in p.4-5 is to be referred to) in p.9 of WO 2002/088989
pamphlet, can be referred to.
##STR00007##
(R.sup.6s are the same as or different from each other and are a
halogen atom or a C.sub.1-3 alkyl group; x is an integer of 0 or 1
to 8; R.sup.7 is an oxygen atom or --CH.sub.2--, or R.sup.7 and
R.sup.8 together form --CH.dbd.CH--; R.sup.8 is an oxygen atom,
--CH.sub.2--, or --C(O)--, or R.sup.7 and R.sup.8 together form
--CH.dbd.CH--, with the proviso that R.sup.7 and R.sup.8 are not
simultaneously an oxygen atom; Y.sup.1 is .dbd.CR.sup.9a-- or a
nitrogen atom, Y.sup.2 is .dbd.CR.sup.9b-- or a nitrogen atom,
Y.sup.3 is .dbd.CR.sup.9c- or a nitrogen atom, and Y.sup.4 is
.dbd.CR.sup.9d- or a nitrogen atom; and R.sup.9a, R.sup.9b,
R.sup.9c, and R.sup.9d are the same as or different from each other
and are a hydrogen atom, a halogen atom, or a C.sub.1-6 alkyl
group, with the proviso that 2 or more of Y.sup.1 to Y.sup.4 are
not simultaneously a nitrogen atom).
[0107] Specific examples of the substituted spiropiperidinyl group
include spiropiperidines used in Examples of WO 2002/088989
pamphlet and more specific examples thereof include spiro
[isobenzofuran-1(3H),4'-piperidine],
spiro[benzofuran-3(2H),4'-piperidine],
spiro[6-azaisobenzofuran-1(3H),4'-piperidine],
3-oxospiro[4-azaisobenzofuran-1(3H),4'-piperidine], and
3-oxospiro[6-azaisobenzofuran-1(3H),4'-piperidine].
[0108] As the subordinate concept of the spiropiperidines disclosed
in WO 2002/088989 pamphlet and as specific examples for the
halogenated spiropiperidine ring, further, Examples in EP 1595867
and WO 2011/037771 pamphlet can be referred to. More specific
examples of the substituted spiropiperidinyl group include
spiro[5-fluoroisobenzofuran-1(3H),4'-piperidine],
spiro[6-fluoroisobenzofuran-1 (3H),4'-piperidine],
spiro[5-fluoro-6-azaisobenzofuran-1(3H),4'-piperidine],
spiro[6-fluoro-5-azaisobenzofuran-1(3H),4'-piperidine], and
7-fluoro-1H-spiro[fluoro[3,4-c]pyridin-3,4'-piperidine.
[0109] In the present invention, as a preferred aspect of various
compounds having a substituted spiropiperidinyl group of Formula
(SP') as a substructure: xa is preferably 0; R.sup.7a and R.sup.8a
together form --R.sup.7a--R.sup.8a-- which is any one of
--OCH.sub.2--, --CH.sub.2O--, --CH.sub.2--CH.sub.2--,
--CH.dbd.CH--, and --OC(O)--, more preferably --OCH.sub.2-- or
--CH.sub.2--CH.sub.2--; Y.sup.1a is .dbd.CR.sup.9a- or a nitrogen
atom, Y.sup.2a is .dbd.CR.sup.9b- or a nitrogen atom, Y.sup.3a is
.dbd.CR.sup.9-- or a nitrogen atom, and Y.sup.4a is .dbd.CR.sup.9d-
or a nitrogen atom; and R.sup.9a, R.sup.9b, R.sup.9c, and R.sup.9d
are independently a hydrogen atom, a halogen atom, or a C.sub.1-6
alkyl group (with the proviso that 2 or more of Y.sup.1a to
Y.sup.4a are not simultaneously a nitrogen atom).
[0110] Examples of the "halogen atom" include a fluorine atom, a
chlorine atom, a bromine atom, and an iodine atom.
[0111] The "halogenated C.sub.1-6 alkyl group" is a group in which
the "C.sub.1-6 alkyl group" is optionally substituted with 1 to 5
halogen atom(s). For example, trifluoromethyl, trifluoroethyl,
tetrafluoroethyl, pentafluoroethyl, and the like are mentioned.
[0112] The "halogenated C.sub.1-6 alkoxy" is a group in which the
"C.sub.1-6 alkoxy" is optionally substituted with 1 to 5 halogen
atom(s). For example, trifluoromethoxy, trifluoroethoxy,
tetrafluoroethoxy, pentafluoroethoxy, and the like are
mentioned.
[0113] Examples of the protective group for the "carboxy which is
optionally protected" include: an alkyl ester-based protective
group such as methyl, ethyl, tert-butyl, benzyl, diphenylmethyl,
and trityl; and a silyl ester-based protective group such as
trimethylsilyl and tert-butyldimethylsilyl.
[0114] The "C.sub.2-7 alkanoyl group" means a "linear, branched, or
cyclic C.sub.2-7 alkylcarbonyl group" and is expressed as R--CO--
(R is the "C.sub.1-6 alkyl group"). Examples thereof include
acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl,
pivaloyl, hexanoyl, heptanoyl, cyclopropylcarbonyl,
cyclobutylcarbonyl, cyclopentylcarbonyl, cyclohexylcarbonyl,
cyclopropylmethylcarbonyl, and 2-methylcyclopropylcarbonyl.
[0115] Examples of the "C.sub.2-7 alkanoyl group (the alkanoyl
group is optionally substituted with --OH or a C.sub.1-6 alkoxy
group)" include, in addition to the groups mentioned as the
"C.sub.2-7 alkanoyl group", a group in which the alkanoyl group is
substituted with --OH or a C.sub.1-6 alkoxy group at any position
and specific examples thereof include hydroxyacetyl and
methoxyacetyl.
[0116] The "arylcarbonyl group" is a group in which a carbonyl
group is bonded to the "aryl group", and examples thereof include
C.sub.6-14 arylcarbonyl such as benzoyl and naphthylcarbonyl.
[0117] The "heterocyclic carbonyl group" means a "heterocyclic
carbonyl group", and examples thereof include the "heterocyclic
group" (for example, a heteroaryl group, a saturated or unsaturated
non-aromatic heterocyclic group, and the like) to which a carbonyl
group is bonded, including a carbonyl group to which the
"monocyclic heteroaryl group" is bonded, such as pyrrolylcarbonyl,
furylcarbonyl, thienylcarbonyl, imidazolylcarbonyl,
pyrazolylcarbonyl, oxazolylcarbonyl, isoxazolylcarbonyl,
thiazolylcarbonyl, isothiazolylcarbonyl, 1,2,3-triazolylcarbonyl,
1,2,4-triazolylcarbonyl, 1,2,3-oxadiazolylcarbonyl,
1,2,4-oxadiazolylcarbonyl, 1,3,4-oxadiazolylcarbonyl,
furazanylcarbonyl, 1,2,3-thiadiazolylcarbonyl,
1,2,4-thiadiazolylcarbonyl, 1,3,4-thiadiazolylcarbonyl,
tetrazolylcarbonyl, pyridylcarbonyl, pyridazinylcarbonyl,
pyrimidinylcarbonyl, pyrazinylcarbonyl, 1,2,3-triazinylcarbonyl,
1,2,4-triazinylcarbonyl, 1,3,5-triazinylcarbonyl,
2H-1,2,3-thiadiazinylcarbonyl, 4H-1,2,4-thiadiazinylcarbonyl,
6H-1,3,4-thiadiazinylcarbonyl, 1,4-diazepinylcarbonyl, and
1,4-oxazepinylcarbonyl; a carbonyl group to which the "ring-fused
heteroaryl group" which is optionally partly hydrogenated is
bonded, such as indolylcarbonyl, isoindolylcarbonyl,
benzofuranylcarbonyl, isobenzofuranylcarbonyl,
benzothienylcarbonyl, isobenzothienylcarbonyl,
benzoxazolylcarbonyl, 1,2-benzisoxazolylcarbonyl,
benzothiazolylcarbonyl, 1,2-benzisothiazolylcarbonyl,
1H-benzimidazolylcarbonyl, 1H-indazolylcarbonyl,
1H-benzotriazolylcarbonyl, 2,1,3-benzothiadiazinylcarbonyl,
chromenylcarbonyl, isochromenylcarbonyl,
4H-1,4-benzoxazinylcarbonyl, 4H-1,4-benzothiazinylcarbonyl,
quinolylcarbonyl, isoquinolylcarbonyl, cinnolinylcarbonyl,
quinazolinylcarbonyl, quinoxalinylcarbonyl, phthalazinylcarbonyl,
benzoxazepinylcarbonyl, benzoazepinylcarbonyl,
benzodiazepinylcarbonyl, naphthyridinylcarbonyl, purinylcarbonyl,
pteridinylcarbonyl, carbazolylcarbonyl, carbolinylcarbonyl,
acridinylcarbonyl, phenoxazinylcarbonyl, phenothiazinylcarbonyl,
phenazinylcarbonyl, phenoxathiinylcarbonyl, thianthrenylcarbonyl,
phenanthridinylcarbonyl, phenanthrolinylcarbonyl,
indolizinylcarbonyl, thieno[3,2-c]pyridylcarbonyl,
thiazolo[5,4-c]pyridylcarbonyl, pyrrolo[1,2-b]pyridazinylcarbonyl,
pyrazolo[1,5-a]pyridylcarbonyl, imidazo[1,2-a]pyridylcarbonyl,
imidazo[1,5-a]pyridylcarbonyl, imidazo[1,2-b]pyridazinylcarbonyl,
imidazo[1,5-a]pyrimidinylcarbonyl,
1,2,4-triazolo[4,3-a]pyridylcarbonyl,
1,2,4-triazolo[4,3-b]pyridazinylcarbonyl,
1H-pyrazolo[3,4-b]pyridylcarbonyl,
1,2,4-triazolo[1,5-a]pyrimidinylcarbonyl, indolinylcarbonyl,
dihydrobenzofuranylcarbonyl, chromanylcarbonyl,
tetrahydroquinolylcarbonyl, tetrahydroisoquinolylcarbonyl,
1,4-benzodioxanylcarbonyl, and 1,3-benzodioxolylcarbonyl, and
[0118] a carbonyl group to which the "saturated or unsaturated
non-aromatic heterocyclic group" is bonded, such as
aziridinylcarbonyl, azetidinylcarbonyl, pyrrolidinylcarbonyl,
tetrahydrofurylcarbonyl, piperidinylcarbonyl,
tetrahydropyranylcarbonyl, piperazinylcarbonyl, and
morpholinylcarbonyl.
[0119] The "non-aromatic heterocyclic carbonyl group" is the
"heterocyclic carbonyl group" in which the "heterocyclic group" is
a "non-aromatic heterocyclic group", that is, a group in which a
carbonyl group is bonded to the "non-aromatic heterocyclic group".
Specifically, a carbonyl group to which the "saturated or
unsaturated non-aromatic heterocyclic group" mentioned as the
"heterocyclic carbonyl group" is bonded is mentioned.
[0120] In the "--COOR.sup.f group", R.sup.f is a hydrogen atom or a
C.sub.1-6 alkyl group and means a carboxy group or an
alkoxycarbonyl group. Specifically, for example, carboxy,
methoxycarbonyl, ethoxycarbonyl, and the like are mentioned.
[0121] In the "--S(O).sub.iR.sup.a group", i is an integer of 0 to
2, and R.sup.a is a group optionally selected from a C.sub.1-6
alkyl group and a halogenated C.sub.1-6 alkyl group. When i is 0,
examples of the "--S(O).sub.iR.sup.a group" include a "C.sub.1-6
alkylthio group" and a "halogenated C.sub.1-6 alkylthio group",
when i is 1, examples of the "--S(O).sub.iR.sup.a group" include a
"C.sub.1-6 alkylsulfinyl group" and a "halogenated C.sub.1-6
alkylsulfinyl group", and when i is 2, examples of the
"--S(O).sub.iR.sup.a group" include a "C.sub.1-6 alkylsulfonyl
group" and a "halogenated C.sub.1-6 alkylsulfonyl group".
[0122] The "C.sub.1-6 alkylthio group" means a linear, branched, or
cyclic C.sub.1-6 alkylthio group, and examples thereof include
methylthio, ethylthio, propylthio, isopropylthio, butylthio,
isobutylthio, sec-butylthio, tert-butylthio, pentylthio,
isopentylthio, neopentylthio, tert-pentylthio, 1-methylbutylthio,
2-methylbutylthio, 1,2-dimethylpropylthio, 1-ethylpropylthio,
hexylthio, isohexylthio, 1-methylpentylthio, 2-methylpentylthio,
3-methylpentylthio, 1,1-dimethylbutylthio, 1,2-dimethylbutylthio,
2,2-dimethylbutylthio, 1,3-dimethylbutylthio,
2,3-dimethylbutylthio, 3,3-dimethylbutylthio, I-ethylbutylthio,
2-ethylbutylthio, 1,1,2-trimethylpropylthio,
1,2,2-trimethylpropylthio, 1-ethyl-1-methylpropylthio,
1-ethyl-2-methylpropylthio, cyclopropylthio, cyclobutylthio,
cyclopentylthio, cyclohexylthio, cyclopropylmethylthio,
cyclobutylmethylthio, cyclopentylmethylthio,
1-cyclopropylethylthio, 2-cyclopropylethylthio,
2-cyclobutylethylthio, and 2-methylcyclopropylthio. The
"halogenated C.sub.1-6 alkylthio group" is a group in which the
"C.sub.1-6 alkylthio group" is optionally substituted with 1 to 5
halogen atom(s), and examples thereof include
trifluoromethylthio.
[0123] The "C.sub.1-6 alkylsulfinyl group" means a linear,
branched, or cyclic C.sub.1-6 alkylsulfinyl group, and examples
thereof include methylsulfinyl, ethylsulfinyl, propylsulfinyl,
isopropylsulfinyl, cyclopropylsulfinyl, cyclopropylmethylsulfinyl,
and 2-methylcyclopropylsulfinyl. The "halogenated C.sub.1-6
alkylsulfinyl group" is a group in which the "C.sub.1-6
alkylsulfinyl group" is optionally substituted with 1 to 5 halogen
atom(s), and examples thereof include trifluoromethylsulfinyl.
[0124] The "C.sub.1-6 alkylsulfonyl group" means a linear,
branched, or cyclic C.sub.1-6 alkylsulfonyl group, and examples
thereof include methylsulfonyl, ethylsulfonyl, propylsulfonyl,
isopropylsulfonyl, cyclopropylsulfonyl, cyclopropylmethylsulfonyl,
and 2-methylcyclopropylsulfonyl. The "halogenated C.sub.1-6
alkylsulfonyl group" is a group in which the "C.sub.1-6
alkylsulfonyl group" is optionally substituted with 1 to 5 halogen
atom(s), and examples thereof include trifluoromethylsulfonyl.
[0125] The "--SO.sub.2NR.sup.dR.sup.e group", in which R.sup.d and
R.sup.e are independently a hydrogen atom or a C.sub.1-6 alkyl
group (the C.sub.1-6 alkyl group is optionally substituted with 1
to 5 halogen atom(s), 1 to 5 --OH, or 1 to 5 C.sub.1-6 alkoxy
group(s)), means, in addition to a sulfamoyl group in which 1 or 2
hydrogen atom(s) on a nitrogen atom of the sulfamoyl group is(are)
optionally substituted with the "C.sub.1-6 alkyl group", a
sulfamoyl group substituted with a C.sub.1-6 alkyl group (the
C.sub.1-6 alkyl group is optionally substituted with 1 to 5 halogen
atom(s), 1 to 5 --OH, or 1 to 5 C.sub.1-6 alkoxy group(s)).
Specifically, for example, a sulfamoyl group, a methylsulfamoyl
group, an ethylsulfamoyl group, a propylsulfamoyl group, an
isopropylsulfamoyl group, a cyclopropylsulfamoyl group, a
butylsulfamoyl group, an isobutylsulfamoyl group, a pentylsulfamoyl
group, an isopentylsulfamoyl group, a hexylsulfamoyl group, an
isohexylsulfamoyl group, a dimethylsulfamoyl group, a
diethylsulfamoyl group, a dipropylsulfamoyl group, a
di-isopropylsulfamoyl group, a dibutylsulfamoyl group, a
dipentylsulfamoyl group, an ethylmethylsulfamoyl group, a
methylpropylsulfamoyl group, an ethylpropylsulfamoyl group, a
butylmethylsulfamoyl group, a butylethylsulfamoyl group, a
butylpropylsulfamoyl group, a trifluoromethylsulfamoyl group, a
hydroxymethylsulfamoyl group, a 2-hydroxyethylsulfamoyl group, a
3-hydroxypropylsulfamoyl group, a 3-hydroxybutylsulfamoyl group, a
3-hydroxy-3-methylbutylsulfamoyl group, a
2,3-dihydroxypropylsulfamoyl group, a
3-hydroxy-2-hydroxymethylpropylsulfamoyl group, a
3-hydroxy-2-hydroxymethyl-2 methylpropylsulfamoyl group, a
2-methoxyethylsulfamoyl group, a 2-ethoxyethylsulfamoyl group, a
2-methoxy-3-hydroxypropylsulfamoyl group, and the like are
mentioned.
[0126] The "--CONR.sup.dR.sup.e group", in which R.sup.d and
R.sup.e are independently a hydrogen atom or a C.sub.1-6 alkyl
group (the C.sub.1-6 alkyl group is optionally substituted with 1
to 5 halogen atom(s), 1 to 5 --OH, or 1 to 5 C.sub.1-6 alkoxy
group(s)), means, in addition to a carbamoyl group in which 1 or 2
hydrogen atom(s) on a nitrogen atom of the carbamoyl group is(are)
optionally substituted with the "C.sub.1-6 alkyl group", a
carbamoyl group substituted with a C.sub.1-6 alkyl group (the
C.sub.1-6 alkyl group is optionally substituted with 1 to 5 halogen
atom(s), 1 to 5 --OH, or 1 to 5 C.sub.1-6 alkoxy group(s)).
Specifically, for example, a carbamoyl group, a methylcarbamoyl
group, an ethylcarbamoyl group, a propylcarbamoyl group, an
isopropylcarbamoyl group, a cyclopropylcarbamoyl group, a
butylcarbamoyl group, an isobutylcarbamoyl group, a pentylcarbamoyl
group, an isopentylcarbamoyl group, a hexylcarbamoyl group, an
isohexylcarbamoyl group, a dimethylcarbamoyl group, a
diethylcarbamoyl group, a dipropylcarbamoyl group, a
di-isopropylcarbamoyl group, a dibutylcarbamoyl group, a
dipentylcarbamoyl group, an ethylmethylcarbamoyl group, a
methylpropylcarbamoyl group, an ethylpropylcarbamoyl group, a
butylmethylcarbamoyl group, a butylethylcarbamoyl group, a
butylpropylcarbamoyl group, a trifluoromethylcarbamoyl group, a
hydroxymethylcarbamoyl group, a 2-hydroxyethylcarbamoyl group, a
3-hydroxypropylcarbamoyl group, a 3-hydroxybutylcarbamoyl group, a
3-hydroxy-3-methylbutylcarbamoyl group, a
2,3-dihydroxypropylcarbamoyl group, a
3-hydroxy-2-hydroxymethylpropylcarbamoyl group, a
3-hydroxy-2-hydroxymethyl-2 methylpropylcarbamoyl group, a
2-methoxyethylcarbamoyl group, a 2-ethoxyethylcarbamoyl group, a
2-methoxy-3-hydroxypropylcarbamoyl group, and the like are
mentioned.
[0127] In the "--CONR.sup.dR.sup.e1 group", R.sup.d is a hydrogen
atom or a C.sub.1-6 alkyl group (the C.sub.1-6 alkyl group is
optionally substituted with 1 to 5 halogen atom(s), 1 to 5 --OH, or
1 to 5 C.sub.1-6 alkoxy group(s)), and R.sup.e1 is a C.sub.1-6
alkyl group (the C.sub.1-6 alkyl group is substituted with 1 to 5
--OH, 1 to 5 C.sub.1-6 alkoxy group(s), 1 to 5 aryl group(s) (the
aryl group is optionally substituted with 1 to 3 halogen atom(s)),
1 to 5 heterocyclic group(s) (the heterocyclic group is optionally
substituted with 1 to 3 C.sub.1-6 alkyl group(s) or 1 to 3 oxo
group(s)), 1 to 5 --S(O).sub.iR.sup.a group(s) (i is an integer of
0 to 2), 1 to 5 --SO.sub.2NR.sup.dR.sup.e group(s), 1 to 5
--CONR.sup.dR.sup.e group(s), or 1 to 5 --NR.sup.b1R.sup.c1
group(s). That is to say, the "--CONR.sup.dR.sup.e1 group" means,
in addition to a carbamoyl group in which one hydrogen atom on a
nitrogen atom of the carbamoyl group is substituted with R.sup.e1,
a carbamoyl group in which another hydrogen atom on the nitrogen
atom of the carbamoyl group is substituted with a C.sub.1-6 alkyl
group (the C.sub.1-6 alkyl group is optionally substituted with 1
to 5 halogen atom(s), 1 to 5 --OH, or 1 to 5 C.sub.1-6 alkoxy
group(s)). Specifically, for example, a hydroxymethylcarbamoyl
group, a 2-hydroxyethylcarbamoyl group, a 3-hydroxypropylcarbamoyl
group, a 3-hydroxybutylcarbamoyl group, a
3-hydroxy-3-methylbutylcarbamoyl group, a
2,3-dihydroxypropylcarbamoyl group, a
3-hydroxy-2-hydroxymethylpropylcarbamoyl group, a
3-hydroxy-2-hydroxymethyl-2 methylpropylcarbamoyl group, a
2-methoxyethylcarbamoyl group, a 2-ethoxyethylcarbamoyl group, a
2-methoxy-3-hydroxypropylcarbamoyl group, a
3-methylsulfonyl-propylcarbamoyl group, a
2-(morpholin-4-yl)ethylcarbamoyl group, a
2-(4-methylpiperazin-1-yl)ethylcarbamoyl group, a
2-(2-oxopyrrolidin-1-yl)ethylcarbamoyl group, a
3-(2-oxopyrrolidin-1-yl)propylcarbamoyl group, a
(5-oxopyrrolidin-2-yl)methylcarbamoyl group, a
3-(2-oxooxazolidin-3-yl)propylcarbamoyl group, a
(3-methyloxetan-3-yl)methylcarbamoyl group, a
3-(methylsulfonylamino)propylcarbamoyl group, and the like are
mentioned.
[0128] In the "--NR.sup.bR.sup.c group", R.sup.b and R.sup.c are
independently a group optionally selected from a hydrogen atom, a
C.sub.1-6 alkyl group, a halogenated C.sub.1-6 alkyl group, a
C.sub.2-6 alkenyl group, a C.sub.2-6 alkynyl group, a C.sub.2-7
alkanoyl group (the alkanoyl group is optionally substituted with
--OH or a C.sub.1-6 alkoxy group), a C.sub.1-6 alkylsulfonyl group,
an arylcarbonyl group, and a heterocyclic carbonyl group. R.sup.b
and R.sup.c optionally form, together with a nitrogen atom to which
they are bonded, a 3- to 8-membered cyclic group, where in the
cyclic group, one or two carbon atom(s) is(are) optionally
substituted with an atom optionally selected from an oxygen atom, a
sulfur atom, and a nitrogen atom (the nitrogen atom is optionally
substituted with a C.sub.1-6 alkyl group which is optionally
substituted with 1 to 5 substituent(s) RI) or with a carbonyl
group, and the cyclic group is optionally further substituted with
1 to 5 substituent(s) RII. Examples of the "--NR.sup.bR.sup.c
group" include amino, "mono/di C.sub.1-6 alkylamino", "halogenated
mono/di C.sub.1-6 alkylamino", "mono/di C.sub.2-6 alkenylamino",
"mono/di C.sub.2-6 alkynylamino", "C.sub.2-7 alkanoylamino which is
optionally substituted with --OH or C.sub.1-6 alkoxy", "C.sub.1-6
alkylsulfonylamino", "arylcarbonylamino", and "heterocyclic
carbonylamino".
[0129] In the "--NR.sup.b1R.sup.c1 group", R.sup.b1 and R.sup.c1
are independently a group optionally selected from a hydrogen atom,
a C.sub.1-6 alkyl group, a C.sub.2-7 alkanoyl group, and a
C.sub.1-6 alkylsulfonyl group. R.sup.b1 and R.sup.c1 optionally
form, together with a nitrogen atom to which they are bonded, a 3-
to 8-membered cyclic group, where in the cyclic group, one carbon
atom is optionally substituted with an atom optionally selected
from an oxygen atom, a sulfur atom, and a nitrogen atom (the
nitrogen atom is optionally substituted with a C.sub.1-6 alkyl
group) or with a carbonyl group. Examples of the
"--NR.sup.b1R.sup.c1 group" include amino, "mono/di C.sub.1-6
alkylamino", "C.sub.2-7 alkanoylamino", and "C.sub.1-6
alkylsulfonylamino".
[0130] The "mono/di C.sub.1-6 alkylamino" means an amino group, 1
or 2 hydrogen atom(s) of which is(are) substituted with a linear,
branched, or cyclic "C.sub.1-6 alkyl group". Specifically,
methylamino, ethylamino, propylamino, isopropylamino, butylamino,
isobutylamino, pentylamino, isopentylamino, hexylamino,
isohexylamino, cyclopropylamino, cyclobutylamino, cyclopentylamino,
cyclohexylamino, 1-cyclopropylmethylamino, 1-cyclobutylmethylamino,
1-cyclopentylmethylamino, 1-cyclohexylmethylamino, dimethylamino,
diethylamino, dipropylamino, diisopropylamino, dibutylamino,
dipentylamino; ethylmethylamino, propylmethylamino,
propylethylamino, butylmethylamino, butylethylamino,
butylpropylamino, N-cyclopropyl-N-methylamino,
N-cyclobutyl-N-methylamino, N-cyclopentyl-N-methylamino,
N-cyclohexyl-N-methylamino, and the like are mentioned.
[0131] The "halogenated mono/di C.sub.1-6 alkylamino" is a group in
which the "mono/di C.sub.1-6 alkylamino" is substituted with 1 to 5
halogen atom(s). For example, trifluoromethylamino and the like are
mentioned.
[0132] The "mono/di C.sub.2-6 alkenylamino" means an amino group, 1
or 2 hydrogen atom(s) of which is(are) substituted with a linear,
branched, or cyclic "C.sub.2-6 alkenyl group". Specifically,
vinylamino, allylamino, isopropenylamino, 2-methylallylamino,
butenylamino, pentenylamino, hexenylamino, 1-cyclopropen-1-ylamino,
2-cyclopropen-1-ylamino, 1-cyclobuten-1-ylamino,
1-cyclopenten-1-ylamino, 2-cyclopenten-1-ylamino,
3-cyclopenten-1-ylamino, 1-cyclohexen-1-ylamino,
2-cyclohexen-1-ylamino, 3-cyclohexen-1-ylamino,
2,4-cyclopentadien-1-ylamino, 2,5-cyclohexadien-1-ylamino,
divinylamino, diallylamino, diisopropenylamino,
di(2-methylallyl)amino, dibutenylamino, dipentenylamino,
dihexenylamino, di(1-cyclopropen-1-yl)amino,
di(2-cyclopropen-1-yl)amino, di(1-cyclobuten-1-yl)amino,
di(1-cyclopenten-1-yl)amino, di(2-cyclopenten-1-yl)amino,
di(3-cyclopenten-1-yl)amino, di(1-cyclohexen-1-yl)amino,
di(2-cyclohexen-1-yl)amino, di(3-cyclohexen-1-yl)amino,
di(2,4-cyclopentadien-1-yl)amino, di(2,5-cyclohexadien-1-yl)amino,
and the like are mentioned.
[0133] The "mono/di C.sub.2-6 alkynylamino" means an amino group, 1
or 2 hydrogen atom(s) of which is(are) substituted with a linear,
branched, or cyclic "C.sub.2-6 alkynyl group". Specifically,
ethynylamino, 1-propynylamino, 2-propynylamino, butynylamino,
pentynylamino, hexynylamino, diethynylamino, di(1-propynyl)amino,
di(2-propynyl)amino, dibutynylamino, dipentynylamino,
dihexynylamino, and the like are mentioned.
[0134] The "C.sub.2-7 alkanoylamino which is optionally substituted
with --OH or C.sub.1-6 alkoxy" means an amino group, a hydrogen
atom of which is substituted with a linear, branched, or cyclic
"C.sub.2-7 alkanoyl group (the alkanoyl group is optionally
substituted with --OH or a C.sub.1-6 alkoxy group)". Specifically,
acetamide, propionamide, butylamide, isobutylamide, valeramide,
isovaleramide, pivalamide, hexanamide, heptanamide,
cyclopropanecarboxamide, cyclobutanecarboxamide,
cyclopentanecarboxamide, cyclohexanecarboxamide,
2-methylcyclopropanecarboxamide, hydroxyacetylamino,
methoxyacetylamino, and the like are mentioned.
[0135] The "C.sub.1-6 alkylsulfonylamino" means an amino group, a
hydrogen atom of which is substituted with a linear, branched, or
cyclic C.sub.1-6 alkylsulfonyl group. Specifically,
methylsulfonylamino, ethylsulfonylamino, propylsulfonylamino,
isopropylsulfonylamino, cyclopropylsulfonylamino,
cyclopropylmethylsulfonylamino, 2-methylcyclopropylsulfonylamino,
and the like are mentioned.
[0136] The "arylcarbonylamino" means an amino group, a hydrogen
atom of which is substituted with the "arylcarbonyl group".
Specifically, C.sub.6-14 arylcarbonylamino such as benzamide and
naphthamide is mentioned.
[0137] The "heterocyclic carbonylamino" means an amino group, a
hydrogen atom of which is substituted with the "heterocyclic
carbonyl group". Specifically, pyrrolecarboxamide,
furancarboxamide, thiophenecarboxamide, imidazolecarboxamide,
pyrazolecarboxamide, pyridinecarboxamide, indolecarboxamide,
quinolinecarboxamide, piperidinecarboxamide, and the like are
mentioned.
[0138] With regard to "R.sup.b and R.sup.c optionally form,
together with a nitrogen atom to which they are bonded, a 3- to
8-membered cyclic group" and "R.sup.b1 and R.sup.c1 optionally
form, together with a nitrogen atom to which they are bonded, a 3-
to 8-membered cyclic group", the 3- to 8-membered cyclic group
specifically means, for example, a monovalent cyclic group obtained
by removing a hydrogen atom which is bonded to a nitrogen atom from
a ring that has a nitrogen atom in addition to carbon atoms in a 3-
to 8-membered saturated or unsaturated non-aromatic heterocyclic
group that is one of the "non-aromatic heterocyclic groups". For
example, aziridinyl, azetidinyl, pyrrolidinyl, pyrazolinyl,
pyrazolidinyl, piperidinyl, piperazinyl, oxazolinyl, isoxazolinyl,
oxazolidinyl, isoxazolidinyl, thiazolinyl, isothiazolinyl,
thiazolidinyl, isothiazolidinyl, oxadiazolinyl, oxadiazolidinyl,
morpholinyl, thiomorpholinyl, 2-oxopyrrolidinyl, and the like are
mentioned. As for R.sup.b and R.sup.c, and R.sup.b1 and R.sup.c1,
with regard to "where in the cyclic group, one carbon atom is
substituted with an oxygen atom, a sulfur atom, or a carbonyl
group", examples of the cyclic group include, among the
above-mentioned cyclic groups, oxazolinyl, isoxazolinyl,
oxazolidinyl, isoxazolidinyl, thiazolinyl, isothiazolinyl,
thiazolidinyl, isothiazolidinyl, morpholinyl, thiomorpholinyl, and
2-oxopyrrolidinyl.
[0139] As for R.sup.b and R.sup.c, with regard to "where the
nitrogen atom is substituted with a C.sub.1-6 alkyl group which is
optionally substituted with 1 to 5 substituent(s) RI", examples of
the cyclic group include 4-methylpiperazin-1-yl,
4-ethylpiperazin-1-yl, 4-propylpiperazin-1-yl, and
4-trifluoromethylpiperazin-1-yl.
[0140] As for R.sup.b1 and R.sup.c1, with regard to "where the
nitrogen atom is substituted with a C.sub.1-6 alkyl group",
examples of the cyclic group include 4-methylpiperazin-1-yl,
4-ethylpiperazin-1-yl, and 4-propylpiperazin-1-yl.
[0141] As for R.sup.b and R.sup.c, with regard to "where the cyclic
group is further substituted with 1 to 5 substituent(s) RII",
examples of the cyclic group include
4,4-difluoropiperidin-1-yl.
[0142] The "substituent RI" is a group optionally selected from a
halogen atom, --OH, a cyano group, a C.sub.1-6 alkoxy group (the
C.sub.1-6 alkoxy group is optionally substituted with 1 to 5
halogen atom(s), 1 to 5 --OH, 1 to 5 C.sub.1-6 alkoxy group(s), 1
to 5 aryl group(s) (the aryl group is optionally substituted with 1
to 3 halogen atom(s)), 1 to 5 heterocyclic group(s) (the
heterocyclic group is optionally substituted with 1 to 3 C.sub.1-6
alkyl group(s) or 1 to 3 oxo group(s)), 1 to 5 --S(O).sub.iR.sup.a
(i is an integer of 0 to 2) group(s), 1 to 5
--SO.sub.2NR.sup.dR.sup.e group(s), 1 to 5 --CONR.sup.dR.sup.e
group(s), or 1 to 5 --NR.sup.b1R.sup.c1 group(s)), a
--NR.sup.b1R.sup.c1 group, and a heterocyclic oxy group (the
heterocyclic oxy group is optionally substituted with 1 to 3
C.sub.1-6 alkyl group(s) or 1 to 3 oxo group(s)).
[0143] The "substituent RII" is a group optionally selected from
the same groups as in the case of the "substituent RI", a C.sub.1-6
alkyl group (the C.sub.1-6 alkyl group is optionally substituted
with 1 to 5 halogen atom(s), 1 to 5 --OH, 1 to 5 C.sub.1-6 alkoxy
group(s), 1 to 5 --S(O).sub.iR.sup.a (i is an integer of 0 to 2)
group(s), 1 to 5 --NR.sup.b1R.sup.c1 group(s), 1 to 5
--SO.sub.2NR.sup.dR.sup.e group(s), or 1 to 5 --CONR.sup.dR.sup.e
group(s)), a C.sub.2-6 alkenyl group, a C.sub.2-7 alkanoyl group,
an aralkyloxy group, a heterocyclic group (the heterocyclic group
is optionally substituted with 1 to 3 C.sub.1-6 alkyl group(s) or 1
to 3 oxo group(s)), a heterocyclic carbonyl group (the heterocyclic
carbonyl group is optionally substituted with 1 to 3 C.sub.1-6
alkyl group(s) or 1 to 3 oxo group(s)), a --S(O).sub.iR.sup.a (i is
an integer of 0 to 2) group, a --CONR.sup.dR.sup.e group, and a
--CONR.sup.dR.sup.e1 group.
[0144] Here, R.sup.a, R.sup.d, R.sup.e, R.sup.b1, R.sup.c1, and
R.sup.e1 are the same as defined above as R.sup.a, R.sup.d,
R.sup.e, R.sup.b1, R.sup.c1, and R.sup.e1 respectively in the
"--S(O).sub.iR.sup.a group", the "--SO.sub.2NR.sup.dR.sup.e group",
the "--CONR.sup.dR.sup.e group", the "--CONR.sup.dR.sup.e1 group",
and the "--NR.sup.b1R.sup.c1 group".
[0145] The "C.sub.1-6 alkyl group which is optionally substituted
with 1 to 5 substituent(s) RI" is a "C.sub.1-6 alkyl group which is
optionally substituted with 1 to 5 group(s) optionally selected
from a halogen atom, --OH, a cyano group, a C.sub.1-6 alkoxy group
(the C.sub.1-6 alkoxy group is optionally substituted with 1 to 5
halogen atom(s), 1 to 5 --OH, 1 to 5 C.sub.1-6 alkoxy group(s), 1
to 5 aryl group(s) (the aryl group is optionally substituted with 1
to 3 halogen atom(s)), 1 to 5 heterocyclic group(s) (the
heterocyclic group is optionally substituted with 1 to 3 C.sub.1-6
alkyl group(s) or 1 to 3 oxo group(s)), 1 to 5 --S(O).sub.iR.sup.a
(i is an integer of 0 to 2) group(s), 1 to 5 --NR.sup.b1R.sup.c1
group(s), 1 to 5 --SO.sub.2NR.sup.dR.sup.e group(s), or 1 to 5
--CONR.sup.dR.sup.e group(s)), a --NR.sup.b1R.sup.c1 group, and a
heterocyclic oxy group (the heterocyclic oxy group is optionally
substituted with 1 to 3 C.sub.1-6 alkyl group(s) or 1 to 3 oxo
group(s)), and specific examples thereof include the following.
[0146] For example, a "C.sub.1-6 alkyl group which is optionally
substituted with 1 to 5 halogen atom(s)" includes, in addition to
the "C.sub.1-6 alkyl group", a group in which the alkyl group is
optionally substituted with 1 to 5 halogen atom(s). Specifically,
in addition to methyl, ethyl, propyl, isopropyl, butyl, isobutyl,
sec-butyl, and tert-butyl, for example, trifluoromethyl,
trifluoroethyl, tetrafluoroethyl, pentafluoroethyl, and the like
are mentioned.
[0147] For example, a "C.sub.1-6 alkyl group which is optionally
substituted with 1 to 5 --OH" includes, in addition to the
"C.sub.1-6 alkyl group", a group in which the alkyl group is
optionally substituted with 1 to 5 hydroxy, and there are many
regioisomers depending on a substitution position. Specifically, in
addition to methyl, ethyl, propyl, isopropyl, butyl, isobutyl,
sec-butyl, and tert-butyl, for example, hydroxymethyl,
2-hydroxyethyl, 1-hydroxyethyl, 3-hydroxy-1-propyl,
2-hydroxy-1-propyl, 1-hydroxy-1-propyl, 2,3-dihydroxy-1-propyl,
1-hydroxy-1-methyl-1-ethyl, 2-hydroxy-1-methyl-1-ethyl,
4-hydroxy-1-butyl, 3-hydroxy-1-butyl, 2-hydroxy-1-butyl,
1-hydroxy-1-butyl, 3-hydroxy-2-methylpropyl,
2-hydroxy-2-methylpropyl, 3-hydroxy-2-hydroxymethylpropyl,
2-hydroxy-1,1-dimethyl-1-ethyl, 1-hydroxy-2-methylpropyl,
5-hydroxy-1-pentyl, 4-hydroxy-1-pentyl, 3-hydroxy-1-pentyl,
2-hydroxy-1-pentyl, 1-hydroxy-1-pentyl, 4-hydroxy-3-methylbutyl,
4-hydroxy-2-methylbutyl, 4-hydroxy-1-methylbutyl,
3-hydroxy-3-methylbutyl, 3-hydroxy-2-methylbutyl,
3-hydroxy-1-methylbutyl, 2-hydroxy-3-methylbutyl,
2-hydroxy-2-methylbutyl, 2-hydroxy-1-methylbutyl,
3-hydroxy-2,2-dimethylpropyl, 3-hydroxy-1,1-dimethylpropyl,
3-hydroxy-2-hydroxymethyl-2-methylpropyl, 6-hydroxy-1-hexyl,
4-hydroxy-1,1-dimethyl-1-butyl, 4-hydroxy-3,3-dimethyl-1-butyl,
2-hydroxycyclopropyl, 4-hydroxycyclohexyl, and the like are
mentioned.
[0148] For example, a "C.sub.1-6 alkyl group which is optionally
substituted with 1 to 5 C.sub.1-6 alkoxy group(s)" includes, in
addition to the "C.sub.1-6 alkyl group", a group in which the alkyl
group is optionally substituted with 1 to 5 of the "C.sub.1-6
alkoxy groups". Specifically, in addition to methyl, ethyl, propyl,
isopropyl, butyl, isobutyl, sec-butyl, and tert-butyl, for example,
methoxymethyl, methoxyethyl, methoxypropyl, ethoxyethyl, and the
like are mentioned.
[0149] For example, a "C.sub.1-6 alkyl group which is optionally
substituted with 1 to 5 C.sub.1-6 alkoxy group(s) which is
optionally substituted with 1 to 5 halogen atom(s)" includes, in
addition to the "C.sub.1-6 alkyl group" and the "C.sub.1-6 alkyl
group which is optionally substituted with 1 to 5 C.sub.1-6 alkoxy
group(s)", a group in which the alkyl group is optionally
substituted with 1 to 5 of the "C.sub.1-6 alkoxy groups" which is
optionally substituted with 1 to 5 halogen atom(s). Specifically,
in addition to methyl, ethyl, propyl, isopropyl, butyl, isobutyl,
sec-butyl, tert-butyl, methoxymethyl, methoxyethyl, and
methoxypropyl, for example, trifluoromethoxymethyl,
trifluoromethoxyethyl, trifluoromethoxypropyl, and the like are
mentioned.
[0150] The alkyl group is optionally substituted with 2 to 5 groups
optionally selected from two or more kinds of a halogen atom, --OH,
a cyano group, a C.sub.1-6 alkoxy group (the C.sub.1-6 alkoxy group
is optionally substituted with 1 to 5 halogen atom(s), 1 to 5 --OH,
1 to 5 C.sub.1-6 alkoxy group(s), 1 to 5 aryl group(s) (the aryl
group is optionally substituted with 1 to 3 halogen atom(s)), 1 to
5 heterocyclic group(s) (the heterocyclic group is optionally
substituted with 1 to 3 C.sub.1-6 alkyl group(s) or 1 to 3 oxo
group(s)), 1 to 5 --S(O).sub.iR.sup.a (i is an integer of 0 to 2)
group(s), 1 to 5 --NR.sup.b1R.sup.c1 group(s), 1 to 5
--SO.sub.2NR.sup.dR.sup.e group(s), or 1 to 5 --CONR.sup.dR.sup.e
group(s)), a --NR.sup.b1R.sup.c1 group, and a heterocyclic oxy
group (the heterocyclic oxy group is optionally substituted with 1
to 3 C.sub.1-6 alkyl group(s) or 1 to 3 oxo group(s)). For example,
a C.sub.1-6 alkyl group which is substituted with one --OH and one
C.sub.1-6 alkoxy group, such as 2-hydroxy-3-methoxypropyl and
3-hydroxy-2-methoxypropyl, and the like are mentioned.
[0151] Similarly, the "C.sub.2-6 alkenyl group which is optionally
substituted with 1 to 5 substituent(s) RI" includes, in addition to
the "C.sub.2-6 alkenyl group", a group in which the alkenyl group
is optionally substituted with 1 to 5 group(s) optionally selected
from a halogen atom, --OH, a cyano group, a C.sub.1-6 alkoxy group
(the C.sub.1-6 alkoxy group is optionally substituted with 1 to 5
halogen atom(s), 1 to 5 --OH, 1 to 5 C.sub.1-6 alkoxy group(s), 1
to 5 aryl group(s) (the aryl group is optionally substituted with 1
to 3 halogen atom(s)), 1 to 5 heterocyclic group(s) (the
heterocyclic group is optionally substituted with 1 to 3 C.sub.1-6
alkyl group(s) or 1 to 3 oxo group(s)), 1 to 5 --S(O).sub.iR.sup.a
(i is an integer of 0 to 2) group(s), 1 to 5 --NR.sup.b1R.sup.c1
group(s), 1 to 5 --SO.sub.2NR.sup.dR.sup.e group(s), or 1 to 5
--CONR.sup.dR.sup.e group(s)), a --NR.sup.b1R.sup.c1 group, and a
heterocyclic oxy group (the heterocyclic oxy group is optionally
substituted with 1 to 3 C.sub.1-6 alkyl group(s) or 1 to 3 oxo
group(s)). Specifically, in addition to vinyl, allyl, isopropenyl,
2-methylallyl, butenyl, pentenyl, and hexenyl, for example,
trifluorovinyl, 2-hydroxyvinyl, 2-methoxyvinyl,
2-trifluoromethoxyvinyl, and the like are mentioned.
[0152] The "C.sub.2-6 alkynyl group which is optionally substituted
with 1 to 5 substituent(s) RI" includes, in addition to the
"C.sub.2-6 alkynyl group", a group in which the alkynyl group is
optionally substituted with 1 to 5 group(s) optionally selected
from a halogen atom, --OH, a cyano group, a C.sub.1-6 alkoxy group
(the C.sub.1-6 alkoxy group is optionally substituted with 1 to 5
halogen atom(s), 1 to 5 --OH, 1 to 5 C.sub.1-6 alkoxy group(s), 1
to 5 aryl group(s) (the aryl group is optionally substituted with 1
to 3 halogen atom(s)), 1 to 5 heterocyclic group(s) (the
heterocyclic group is optionally substituted with 1 to 3 C.sub.1-6
alkyl group(s) or 1 to 3 oxo group(s)), 1 to 5 --S(O).sub.iR.sup.a
(i is an integer of 0 to 2) group(s), 1 to 5 --NR.sup.bR.sup.c
group(s), 1 to 5 --SO.sub.2NR.sup.dR.sup.e group(s), or 1 to 5
--CONR.sup.dR.sup.e group(s)), a --NR.sup.b1R.sup.c1 group, and a
heterocyclic oxy group (the heterocyclic oxy group is optionally
substituted with 1 to 3 C.sub.1-6 alkyl group(s) or 1 to 3 oxo
group(s)). Specifically, in addition to ethynyl, 1-propynyl,
2-propynyl, butynyl, pentynyl, and hexynyl, for example,
fluoroethynyl, 2-hydroxyethynyl, 2-methoxyethynyl,
2-trifluoromethoxyethynyl, and the like are mentioned.
[0153] The "C.sub.1-6 alkoxy group which is optionally substituted
with 1 to 5 substituent(s) RI" includes, in addition to the
"C.sub.1-6 alkoxy group", a group in which the alkoxy group is
optionally substituted with 1 to 5 group(s) optionally selected
from a halogen atom, --OH, a cyano group, a C.sub.1-6 alkoxy group
(the C.sub.1-6 alkoxy group is optionally substituted with 1 to 5
halogen atom(s), 1 to 5 --OH, 1 to 5 C.sub.1-6 alkoxy group(s), 1
to 5 aryl group(s) (the aryl group is optionally substituted with 1
to 3 halogen atom(s)), 1 to 5 heterocyclic group(s) (the
heterocyclic group is optionally substituted with 1 to 3 C.sub.1-6
alkyl group(s) or 1 to 3 oxo group(s)), 1 to 5 --S(O).sub.iR.sup.a
(i is an integer of 0 to 2) group(s), 1 to 5 --NR.sup.b1R.sup.c1
group(s), 1 to 5 --SO.sub.2NR.sup.dR.sup.e group(s), or 1 to 5
--CONR.sup.dR.sup.e group(s)), a --NR.sup.b1R.sup.c1 group, and a
heterocyclic oxy group (the heterocyclic oxy group is optionally
substituted with 1 to 3 C.sub.1-6 alkyl group(s) or 1 to 3 oxo
group(s)). Specifically, in addition to methoxy, ethoxy, propoxy,
isopropoxy, butoxy, isobutoxy, sec-butoxy, and tert-butoxy, for
example, trifluoromethoxy, hydroxymethoxy, 2-hydroxyethoxy,
3-hydroxypropoxy, 3-hydroxybutoxy, 3-hydroxy-3-methylbutoxy,
2,3-dihydroxypropoxy, 3-hydroxy-2-hydroxymethylpropoxy,
3-hydroxy-2-hydroxymethyl-2 methylpropoxy, 2-methoxyethoxy,
2-ethoxyethoxy, 2-trifluoromethoxyethoxy,
2-methoxy-3-hydroxypropoxy, 2-hydroxy-3-methoxypropoxy, and the
like are mentioned.
[0154] The "aryl group which is optionally substituted with 1 to 5
substituent(s) RII" is a group in which any hydrogen atom in the
"aryl group" is optionally substituted with 1 to 5 substituent(s)
RII. That is to say, the "aryl group which is optionally
substituted with 1 to 5 substituent(s) RII" includes, in addition
to the "aryl group", an "aryl group which is substituted with 1 to
5 group(s) optionally selected from a halogen atom, --OH, a cyano
group, a C.sub.1-6 alkoxy group (the C.sub.1-6 alkoxy group is
optionally substituted with 1 to 5 halogen atom(s), 1 to 5 --OH, 1
to 5 C.sub.1-6 alkoxy group(s), 1 to 5 aryl group(s) (the aryl
group is optionally substituted with 1 to 3 halogen atom(s)), 1 to
5 heterocyclic group(s) (the heterocyclic group is optionally
substituted with 1 to 3 C.sub.1-6 alkyl group(s) or 1 to 3 oxo
group(s)), 1 to 5 --S(O).sub.iR.sup.a (i is an integer of 0 to 2)
group(s), 1 to 5 --SO.sub.2NR.sup.dR.sup.e group(s), 1 to 5
--CONR.sup.dR.sup.e group(s), or 1 to 5 --NR.sup.b1R.sup.c1
group(s)), a --NR.sup.b1R.sup.c1 group, a heterocyclic oxy group
(the heterocyclic oxy group is optionally substituted with 1 to 3
C.sub.1-6 alkyl group(s) or 1 to 3 oxo group(s)), a C.sub.1-6 alkyl
group (the C.sub.1-6 alkyl group is optionally substituted with 1
to 5 halogen atom(s), 1 to 5 --OH, 1 to 5 C.sub.1-6 alkoxy
group(s), 1 to 5 --S(O).sub.iR.sup.a (i is an integer of 0 to 2)
group(s), 1 to 5 --SO.sub.2NR.sup.dR.sup.e group(s), 1 to 5
--CONR.sup.dR.sup.e group(s), or 1 to 5 --NR.sup.b1R.sup.c1
group(s)), a C.sub.2-6 alkenyl group, a C.sub.2-7 alkanoyl group,
an aralkyloxy group, a heterocyclic group (the heterocyclic group
is optionally substituted with 1 to 3 C.sub.1-6 alkyl group(s) or 1
to 3 oxo group(s)), a heterocyclic carbonyl group (the heterocyclic
carbonyl group is optionally substituted with 1 to 3 C.sub.1-6
alkyl group(s) or 1 to 3 oxo group(s)), a --S(O).sub.iR.sup.a (i is
an integer of 0 to 2) group, a --CONR.sup.dR.sup.e group, and a
--CONR.sup.dR.sup.e group".
[0155] Specifically, in addition to the "aryl group", for example,
an "aryl group which is optionally substituted with 1 to 5 halogen
atom(s)", an "aryl group which is substituted with 1 to 5 group(s)
optionally selected from the "C.sub.1-6 alkoxy group" (the
C.sub.1-6 alkoxy group is optionally substituted with 1 to 5
halogen atom(s), 1 to 5 --OH, 1 to 5 C.sub.1-6 alkoxy group(s), 1
to 5 aryl group(s) (the aryl group is optionally substituted with 1
to 3 halogen atom(s)), 1 to 5 heterocyclic group(s) (the
heterocyclic group is optionally substituted with 1 to 3 C.sub.1-6
alkyl group(s) or 1 to 3 oxo group(s)), 1 to 5 --S(O).sub.iR.sup.a
(i is an integer of 0 to 2) group(s), 1 to 5
--SO.sub.2NR.sup.dR.sup.e group(s), 1 to 5 --CONR.sup.dR.sup.e
group(s), or 1 to 5 --NR.sup.b1R.sup.c1 group(s))", an "aryl group
which is substituted with 1 to 5 group(s) optionally selected from
the "C.sub.1-6 alkyl group" (the C.sub.1-6 alkyl group is
optionally substituted with 1 to 5 halogen atom(s), 1 to 5 --OH, 1
to 5 C.sub.1-6 alkoxy group(s), 1 to 5 --S(O).sub.iR.sup.a (i is an
integer of 0 to 2) group(s), 1 to 5 --SO.sub.2NR.sup.dR.sup.e
group(s), 1 to 5 --CONR.sup.dR.sup.e group(s), or 1 to 5
--NR.sup.b1R.sup.c1 group(s))", and the like are mentioned.
[0156] The aryl group is optionally substituted with 2 to 5 groups
optionally selected from two or more kinds of a halogen atom, --OH,
a cyano group, a C.sub.1-6 alkoxy group (the C.sub.1-6 alkoxy group
is optionally substituted with 1 to 5 halogen atom(s), 1 to 5 --OH,
1 to 5 C.sub.1-6 alkoxy group(s), 1 to 5 aryl group(s) (the aryl
group is optionally substituted with 1 to 3 halogen atom(s)), 1 to
5 heterocyclic group(s) (the heterocyclic group is optionally
substituted with 1 to 3 C.sub.1-6 alkyl group(s) or 1 to 3 oxo
group(s)), 1 to 5 --S(O).sub.iR.sup.a (i is an integer of 0 to 2)
group(s), 1 to 5 --SO.sub.2NR.sup.dR.sup.e group(s), 1 to 5
--CONR.sup.dR.sup.e group(s), or 1 to 5 --NR.sup.b1R.sup.c1
group(s)), a --NR.sup.b1R.sup.c1 group, a heterocyclic oxy group
(the heterocyclic oxy group is optionally substituted with 1 to 3
C.sub.1-6 alkyl group(s) or 1 to 3 oxo group(s)), a C.sub.1-6 alkyl
group (the C.sub.1-6 alkyl group is optionally substituted with 1
to 5 halogen atom(s), 1 to 5 --OH, 1 to 5 C.sub.1-6 alkoxy
group(s), 1 to 5 --S(O).sub.iR.sup.a (i is an integer of 0 to 2)
group(s), 1 to 5 --SO.sub.2NR.sup.dR.sup.e group(s), 1 to 5
--CONR.sup.dR.sup.e group(s), or 1 to 5 --NR.sup.b1R.sup.c1
group(s)), a C.sub.2-6 alkenyl group, a C.sub.2-7 alkanoyl group,
an aralkyloxy group, a heterocyclic group (the heterocyclic group
is optionally substituted with 1 to 3 C.sub.1-6 alkyl group(s) or 1
to 3 oxo group(s)), a heterocyclic carbonyl group (the heterocyclic
carbonyl group is optionally substituted with 1 to 3 C.sub.1-6
alkyl group(s) or 1 to 3 oxo group(s)), a --S(O).sub.iR.sup.a (i is
an integer of 0 to 2) group, a --CONR.sup.dR.sup.e group, and a
--CONR.sup.dR.sup.e1 group. Specifically, for example, an "aryl
group which is optionally substituted with 1 or 2 of the "C.sub.1-6
alkyl groups" and 1 or 2 of the "C.sub.1-6 alkoxy groups" (the
C.sub.1-6 alkoxy group is optionally substituted with 1 to 5
halogen atom(s), 1 to 5 --OH, 1 to 5 C.sub.1-6 alkoxy group(s), 1
to 5 aryl group(s) (the aryl group is optionally substituted with 1
to 3 halogen atom(s)), 1 to 5 heterocyclic group(s) (the
heterocyclic group is optionally substituted with 1 to 3 C.sub.1-6
alkyl group(s) or 1 to 3 oxo group(s)), 1 to 5 --S(O)R.sup.a (i is
an integer of 0 to 2) group(s), 1 to 5 --SO.sub.2NR.sup.dR.sup.e
group(s), 1 to 5 --CONR.sup.dR.sup.e group(s), or 1 to 5
--NR.sup.b1R.sup.c1 group(s))" and the like are mentioned. More
preferably, for example, an "aryl group which is optionally
substituted with 1 or 2 of the "C.sub.1-6 alkyl groups" and one of
the "C.sub.1-6 alkoxy group" (the C.sub.1-6 alkoxy group is
optionally substituted with 1 or 2 --OH, 1 or 2 C.sub.1-6 alkoxy
group(s), 1 or 2 non-aromatic heterocyclic group(s) (the
heterocyclic group is optionally substituted with a C.sub.1-6 alkyl
group), 1 or 2 --S(O).sub.iR.sup.a (i is an integer of 0 to 2)
group(s), or 1 or 2 --NR.sup.b1R.sup.c1 group(s))", and the like
are mentioned.
[0157] Examples of the "aryl group which is optionally substituted
with 1 to 5 substituent(s) RII" more specifically include, in
addition to phenyl, (1- or 2-)naphthyl, indanyl, and
tetrahydronaphthyl, (2-, 3-, or 4-)fluorophenyl, (2-, 3-, or
4-)chlorophenyl, (2,6-, 2,5-, 2,4-, 2,3-, or 3,5-)difluorophenyl,
4-chloro-2-fluorophenyl, (2-, 3-, or 4-)hydroxyphenyl, (2-, 3-, or
4-)cyanophenyl, (2,6-, 2,5-, 2,4-, 2,3-, 3,4-, or
3,5-)dicyanophenyl, (2-, 3-, or 4-)methoxyphenyl, (2-, 3-, or
4-)ethoxyphenyl, (2-, 3-, or 4-)propoxyphenyl, (2-, 3-, or
4-)isopropoxyphenyl, (2-, 3-, or 4-)trifluoromethoxyphenyl, (2-,
3-, or 4-)methylphenyl, (2-, 3-, or 4-)ethylphenyl, (2-, 3-, or
4-)propylphenyl, (2-, 3-, or 4-)isopropylphenyl, (2-, 3-, or
4-)isobutylphenyl, (2-, 3-, or 4-)tert-butylphenyl, (2-, 3-, or
4-)trifluoromethylphenyl, (2,6-, 2,5-, 2,4-, 2,3-, or
3,5-)dimethoxyphenyl, (2,6-, 2,5-, 2,4-, or 2,3-)dimethylphenyl,
3,5-ditrifluoromethylphenyl, (4- or 5-)fluoro-(2- or
3-)methylphenyl, 3-fluoro-4-methylphenyl, 2-chloro-(4- or
5-)methylphenyl, (4- or 5-)fluoro-2-trifluoromethylphenyl, (4- or
5-)chloro-2-trifluoromethylphenyl, 2-(fluoro- or
chloro-)5-trifluoromethylphenyl, (4- or 5-)fluoro-(2- or
3-)methoxyphenyl, 2-fluoro-(3-, 4-, or 5-)methoxyphenyl, (4- or
5-)chloro-(2- or 3-)methoxyphenyl, 2-chloro-(3-, 4-, or
5-)methoxyphenyl, (4- or 5-)fluoro-2-ethoxyphenyl, (4- or
5-)chloro-2-ethoxyphenyl, 3-(fluoro- or chloro-)4-ethoxyphenyl,
2-methoxy-5-methylphenyl, 4-methoxy-2-methylphenyl,
4-methoxy-(2,6-, 2,5-, or 2,3-)dimethylphenyl, (2-, 3-, or
4-)hydroxymethylphenyl, 4-cyano-3-hydroxymethylphenyl, (3- or
4-)(2-hydroxyethyl)phenyl, (3- or
4-)(3-hydroxy-3-methylbutoxy)phenyl,
4-(2-hydroxyethoxy)-2-methylphenyl,
4-(2,3-dihydroxypropoxy)-2-methylphenyl,
4-(3-hydroxy-3-methylbutoxy)-2-methylphenyl,
3-(3-hydroxy-3-methylbutoxy)-2-methylphenyl,
4-(2-hydroxyethoxy)-(2,6-, 2,5-, or 2,3-)dimethylphenyl,
4-(3-hydroxypropoxy)-2-methylphenyl, 4-(3-hydroxypropoxy)-(2,6-,
2,5-, or 2,3-)dimethylphenyl, 4-(2,3-dihydroxypropoxy)-(2,6-, 2,5-,
or 2,3-)dimethylphenyl, 4-((2R)-2,3-dihydroxypropoxy)-(2,6-, 2,5-,
or 2,3-)dimethylphenyl, 4-((2S)-2,3-dihydroxypropoxy)-(2,6-, 2,5-,
or 2,3-)dimethylphenyl,
4-(3-hydroxy-2-hydroxymethylpropoxy)-2-methylphenyl,
4-(3-hydroxy-2-hydroxymethyl-2-methylpropoxy)-2-methylphenyl,
4-(3-hydroxybutoxy)-2-methylphenyl,
4-((3S)-3-hydroxybutoxy)-2-methylphenyl,
4-((3R)-3-hydroxybutoxy)-2-methylphenyl,
4-(3-hydroxy-2-hydroxymethylpropoxy)-(2,6-, 2,5-, or
2,3-)dimethylphenyl,
4-(3-hydroxy-2-hydroxymethyl-2-methylpropoxy)-(2,6-, 2,5-, or
2,3-)dimethylphenyl, 4-(3-hydroxybutoxy)-(2,6-, 2,5-, or
2,3-)dimethylphenyl, 4-((3S)-3-hydroxybutoxy)-(2,6-, 2,5-, or
2,3-)dimethylphenyl, 4-((3R)-3-hydroxybutoxy)-(2,6-, 2,5-, or
2,3-)dimethylphenyl, 4-(3-hydroxy-3-methylbutoxy)-(2,6-, 2,5-, or
2,3-)dimethylphenyl, 4-(3-aminopropoxy)-2-methylphenyl,
4-(3-aminopropoxy)-(2,6-, 2,5-, or 2,3-)dimethylphenyl,
4-(2-(2-oxo-1-pyrrolidinyl)ethoxy)-2-methylphenyl,
4-(2-(2-oxo-1-pyrrolidinyl)ethoxy)-(2,6-, 2,5-, or
2,3-)dimethylphenyl,
4-(3-(2-oxo-1-pyrrolidinyl)propoxy)-2-methylphenyl,
4-(3-(2-oxo-1-pyrrolidinyl)propoxy)-(2,6-, 2,5-, or
2,3-)dimethylphenyl,
4-(5-oxo-2-pyrrolidinyl)methoxy-2-methylphenyl,
4-(5-oxo-2-pyrrolidinyl)methoxy-(2,6-, 2,5-, or
2,3-)dimethylphenyl, 4-(2-ethoxy-ethoxy)-2-methylphenyl,
4-(2-ethoxy-ethoxy)-(2,6-, 2,5-, or 2,3-)dimethylphenyl,
4-(2-methylsulfonyl-ethoxy)-2-methylphenyl,
4-(2-methylsulfonyl-ethoxy)-(2,6-, 2,5-, or 2,3-)dimethylphenyl,
4-(3-methylsulfonyl-propoxy)phenyl,
4-(3-methylsulfonyl-propoxy)-2-methylphenyl,
4-(3-methylsulfonyl-propoxy)-(2,6-, 2,5-, or 2,3-)dimethylphenyl,
4-((1,1-dioxidetetrahydro-2H-thiopyran-4-yl)oxy)-2-methylphenyl,
4-((1,1-dioxidetetrahydro-2H-thiopyran-4-yl)oxy)-(2,6-, 2,5-, or
2,3-)dimethylphenyl,
4-((4-hydroxy-1,1-dioxidetetrahydro-2H-thiopyran-4-yl)methoxy)-2-methylph-
enyl,
[0158]
4-((4-hydroxy-1,1-dioxidetetrahydro-2H-thiopyran-4-yl)methoxy)-(2,6-
-, 2,5-, or 2,3-)dimethylphenyl,
4-((3-methyloxetan-3-yl)methoxy)-2-methylphenyl,
4-((3-methyloxetan-3-yl)methoxy)-(2,6-, 2,5-, or
2,3-)dimethylphenyl, 4-(2-acetylamino-ethoxy)-2-methylphenyl,
4-(2-acetylamino-ethoxy)-(2,6-, 2,5-, or 2,3-)dimethylphenyl,
4-(3-acetylamino-propoxy)-2-methylphenyl,
4-(3-acetylamino-propoxy)-(2,6-, 2,5-, or 2,3-)dimethylphenyl,
4-(2-methylsulfonylamino-ethoxy)-2-methylphenyl,
4-(2-methylsulfonylamino-ethoxy)-(2,6-, 2,5-, or
2,3-)dimethylphenyl,
4-(3-methylsulfonylamino-propoxy)-2-methylphenyl,
4-(3-methylsulfonylamino-propoxy)-(2,6-, 2,5-, or
2,3-)dimethylphenyl, 4-(2-carbamoyl-ethoxy)-2-methylphenyl,
4-(2-carbamoyl-ethoxy)-(2,6-, 2,5-, or 2,3-)dimethylphenyl,
4-(3-carbamoyl-propoxy)-2-methylphenyl,
4-(3-carbamoyl-propoxy)-(2,6-, 2,5-, or 2,3-)dimethylphenyl,
4-(2-methylcarbamoyl-ethoxy)-2-methylphenyl,
4-(2-methylcarbamoyl-ethoxy)-(2,6-, 2,5-, or 2,3-)dimethylphenyl,
4-(3-methylcarbamoyl-propoxy)-2-methylphenyl,
4-(3-methylcarbamoyl-propoxy)-(2,6-, 2,5-, or 2,3-)dimethylphenyl,
4-(2-dimethylcarbamoyl-ethoxy)-2-methylphenyl,
4-(2-dimethylcarbamoyl-ethoxy)-(2,6-, 2,5-, or 2,3-)dimethylphenyl,
4-(3-dimethylcarbamoyl-propoxy)-2-methylphenyl,
4-(3-dimethylcarbamoyl-propoxy)-(2,6-, 2,5-, or
2,3-)dimethylphenyl, 4-(2-sulfamoyl-ethoxy)-2-methylphenyl,
4-(2-sulfamoyl-ethoxy)-(2,6-, 2,5-, or 2,3-)dimethylphenyl,
4-(3-sulfamoyl-propoxy)-2-methylphenyl,
4-(3-sulfamoyl-propoxy)-(2,6-, 2,5-, or 2,3-)dimethylphenyl,
4-(2-methylsulfamoyl-ethoxy)-2-methylphenyl,
4-(2-methylsulfamoyl-ethoxy)-(2,6-, 2,5-, or 2,3-)dimethylphenyl,
4-(3-methylsulfamoyl-propoxy)-2-methylphenyl,
4-(3-methylsulfamoyl-propoxy)-(2,6-, 2,5-, or 2,3-)dimethylphenyl,
4-(2-dimethylsulfamoyl-ethoxy)-2-methylphenyl,
4-(2-dimethylsulfamoyl-ethoxy)-(2,6-, 2,5-, or 2,3-)dimethylphenyl,
4-(3-dimethylsulfamoyl-propoxy)-2-methylphenyl,
4-(3-dimethylsulfamoyl-propoxy)-(2,6-, 2,5-, or
2,3-)dimethylphenyl,
[0159] 3-fluoro-4-(3-hydroxy-3-methylbutoxy)-2-methylphenyl,
3-fluoro-4-(3-hydroxy-3-methylbutoxy)-(2,6- or 2,5-)dimethylphenyl,
3-fluoro-4-(3-methylsulfonyl-propoxy)-2-methylphenyl,
3-fluoro-4-(3-methylsulfonyl-propoxy)-(2,6- or
2,5-)dimethylphenyl,
[0160] 4-(3-hydroxy-3-methylbutoxy)-2-hydroxymethylphenyl,
4-(3-hydroxy-3-methylbutoxy)-6-methyl-2-hydroxymethylphenyl,
[0161] 4-(3-methylsulfonyl-propoxy)-2-hydroxymethylphenyl,
4-(3-methylsulfonyl-propoxy)-6-methyl-2-hydroxymethylphenyl, (2-,
3-, or 4-)vinylphenyl, (2-, 3-, or 4-)acetylphenyl, (2-, 3-, or
4-)benzyloxyphenyl, 2-benzyloxy-(3-, 4-, 5-, or 6-)fluorophenyl,
4-benzyloxy-(2- or 3-)fluorophenyl, 4-benzyloxy-(2- or
3-)methylphenyl, (2-, 3-, or 4-)methylsulfonylphenyl, (2-, 3-, or
4-)carbamoylphenyl, (2-, 3-, or 4-)N-methylcarbamoylphenyl, (2-,
3-, or 4-)N,N-dimethylcarbamoylphenyl, (2-, 3-, or
4-)(N-(2-hydroxyethyl)carbamoyl)phenyl, (2-, 3-, or
4-)(N-(2-methoxyethyl)carbamoyl)phenyl, (2-, 3-, or
4-)(N-(2-hydroxyethyl)-N-methylcarbamoyl)phenyl, (2-, 3-, or
4-)(N-(2-methoxyethyl)-N-methylcarbamoyl)phenyl, (2-, 3-, or
4-)(N-(2-methylsulfonyl-ethyl)carbamoyl)phenyl, (2-, 3-, or
4-)(N-(2-methylsulfonyl-ethyl)-N-methylcarbamoyl)phenyl,
4-cyano-3-carbamoylphenyl, 3-cyano-4-carbamoylphenyl, (2-, 3-, or
4-)(pyrrolidine-1-yl)carbonylphenyl, (2-, 3-, or
4-)morpholinophenyl, 4-cyano-3-morpholinophenyl, (2-, 3-, or
4-)(2-oxooxazolidin-3-yl)phenyl,
4-cyano-3-(2-oxooxazolidin-3-yl)phenyl, (4-, 5-, 6-, or
7-)fluoro-1-indanyl, (4-, 5-, 6-, or 7-)chloro-1-indanyl, (4-, 5-,
6-, or 7-)bromo-1-indanyl, (4-, 5-, 6-, or
7-)trifluoromethyl-1-indanyl, (4-, 5-, 6-, or 7-)fluoro-2-indanyl,
(4-, 5-, 6-, or 7-)chloro-2-indanyl, (4-, 5-, 6-, or
7-)bromo-2-indanyl, (4-, 5-, 6-, or 7-)trifluoromethyl-2-indanyl,
(2-, 3-, 4-, 5-, 6-, 7-, or 8-)fluoro-naphthalene-1-yl, (2-, 3-,
4-, 5-, 6-, 7-, or 8-)chloro-naphthalene-1-yl, and (2-, 3-, 4-, 5-,
6-, 7-, or 8-)methyl-naphthalene-1-yl.
[0162] The "heterocyclic group which is optionally substituted with
1 to 5 substituent(s) RII" is a group in which any hydrogen atom in
the "heterocyclic group" is optionally substituted with 1 to 5
substituent(s) RII. Namely, the "heterocyclic group which is
optionally substituted with 1 to 5 substituent(s) RII" is, in
addition to the unsubstituted "heteroaryl group" and the
"non-aromatic heterocyclic group" both exemplified above as a
"heterocyclic group" (these rings are each a monovalent group
obtained by removing any hydrogen atom from a ring having a
monocyclic ring or a fused ring that is a 3- to 14-membered ring,
or preferably a 3- to 12-membered ring, containing, in addition to
carbon atoms, at least one hetero atom (preferably 1 to 4 atom(s))
optionally selected from N, O, and S): a "heterocyclic group which
is substituted with 1 to 5 group(s) optionally selected from a
halogen atom, --OH, a cyano group, a C.sub.1-6 alkoxy group (the
C.sub.1-6 alkoxy group is optionally substituted with 1 to 5
halogen atom(s), 1 to 5 --OH, 1 to 5 C.sub.1-6 alkoxy group(s), 1
to 5 aryl group(s) (the aryl group is optionally substituted with 1
to 3 halogen atom(s)), 1 to 5 heterocyclic group(s) (the
heterocyclic group is optionally substituted with 1 to 3 C.sub.1-6
alkyl group(s) or 1 to 3 oxo group(s)), 1 to 5 --S(O).sub.iR.sup.a
(i is an integer of 0 to 2) group(s), 1 to 5
--SO.sub.2NR.sup.dR.sup.e group(s), 1 to 5 --CONR.sup.dR.sup.e
group(s), or 1 to 5 --NR.sup.b1R.sup.c1 group(s)), a
--NR.sup.b1R.sup.c1 group, a heterocyclic oxy group (the
heterocyclic oxy group is optionally substituted with 1 to 3
C.sub.1-6 alkyl group(s) or 1 to 3 oxo group(s)), a C.sub.1-6 alkyl
group (the C.sub.1-6 alkyl group is optionally substituted with 1
to 5 halogen atom(s), 1 to 5 --OH, 1 to 5 C.sub.1-6 alkoxy
group(s), 1 to 5 --S(O).sub.iR.sup.a (i is an integer of 0 to 2)
group(s), 1 to 5 --SO.sub.2NR.sup.dR.sup.e group(s), 1 to 5
--CONR.sup.dR.sup.e group(s), or 1 to 5 --NR.sup.b1R.sup.c1
group(s)), a C.sub.2-6 alkenyl group, a C.sub.2-7 alkanoyl group,
an aralkyloxy group, a heterocyclic group (the heterocyclic group
is optionally substituted with 1 to 3 C.sub.1-6 alkyl group(s) or 1
to 3 oxo group(s)), a heterocyclic carbonyl group (the heterocyclic
carbonyl group is optionally substituted with 1 to 3 C.sub.1-6
alkyl group(s) or 1 to 3 oxo group(s)), a --S(O).sub.iR.sup.a (i is
an integer of 0 to 2) group, a --CONR.sup.dR.sup.e group, and a
--CONR.sup.dR.sup.e1 group".
[0163] Specific examples of the "heterocyclic group which is
optionally substituted with 1 to 5 substituent(s) RII" include, in
addition to the "heterocyclic group", a "heterocyclic group
optionally substituted with 1 to 5 halogen atom(s)", a
"heterocyclic group substituted with 1 to 5 group(s) optionally
selected from the "C.sub.1-6 alkoxy group" (the C.sub.1-6 alkoxy
group is optionally substituted with 1 to 5 halogen atom(s), 1 to 5
--OH, 1 to 5 C.sub.1-6 alkoxy group(s), 1 to 5 aryl group(s) (the
aryl group is optionally substituted with 1 to 3 halogen atom(s)),
1 to 5 heterocyclic group(s) (the heterocyclic group is optionally
substituted with 1 to 3 C.sub.1-6 alkyl group(s) or 1 to 3 oxo
group(s)), 1 to 5 --S(O).sub.iR.sup.a (i is an integer of 0 to 2)
group(s), 1 to 5 --SO.sub.2NR.sup.dR.sup.e group(s), 1 to 5
--CONR.sup.dR.sup.e group(s), or 1 to 5 --NR.sup.b1R.sup.c1
group(s))", and a "heterocyclic group substituted with 1 to 5
group(s) optionally selected from the "C.sub.1-6 alkyl group" (the
C.sub.1-6 alkyl group is optionally substituted with 1 to 5 halogen
atom(s), 1 to 5 --OH, 1 to 5 C.sub.1-6 alkoxy group(s), 1 to 5
--S(O).sub.iR.sup.a (i is an integer of 0 to 2) group(s), 1 to 5
--SO.sub.2NR.sup.dR.sup.e group(s), 1 to 5 --CONR.sup.dR.sup.e
group(s), or 1 to 5 --NR.sup.b1R.sup.c1 group(s))". More specific
examples thereof include a "heteroaryl group substituted with 1 to
5 group(s) optionally selected from the "C.sub.1-6 alkyl group"
(the C.sub.1-6 alkyl group is optionally substituted with 1 to 5
halogen atom(s), 1 to 5 --OH, 1 to 5 C.sub.1-6 alkoxy group(s), 1
to 5 --S(O).sub.iR.sup.a (i is an integer of 0 to 2) group(s), 1 to
5 --SO.sub.2NR.sup.dR.sup.e group(s), 1 to 5 --CONR.sup.dR.sup.e
group(s), or 1 to 5 --NR.sup.b1R.sup.c1 group(s))" and a
"heteroaryl group substituted with 1 to 5 groups(s) optionally
selected from the "C.sub.1-6 alkoxy group" (the C.sub.1-6 alkoxy
group is optionally substituted with 1 to 5 halogen atom(s), 1 to 5
--OH, 1 to 5 C.sub.1-6 alkoxy group(s), 1 to 5 aryl group(s) (the
aryl group is optionally substituted with 1 to 3 halogen atom(s)),
1 to 5 heterocyclic group(s) (the heterocyclic group is optionally
substituted with 1 to 3 C.sub.1-6 alkyl group(s) or 1 to 3 oxo
group(s)), 1 to 5 --S(O).sub.iR.sup.a (i is an integer of 0 to 2)
group(s), 1 to 5 --SO.sub.2NR.sup.dR.sup.e group(s), 1 to 5
--CONR.sup.dR.sup.e group(s), or 1 to 5 --NR.sup.b1R.sup.c1
group(s))".
[0164] Furthermore, the heterocyclic group is optionally
substituted with 2 to 5 groups optionally selected from 2 or more
kinds of a halogen atom, --OH, a cyano group, a C.sub.1-6 alkoxy
group (the C.sub.1-6 alkoxy group is optionally substituted with 1
to 5 halogen atom(s), 1 to 5 --OH, 1 to 5 C.sub.1-6 alkoxy
group(s), 1 to 5 aryl group(s) (the aryl group is optionally
substituted with 1 to 3 halogen atom(s)), 1 to 5 heterocyclic
group(s) (the heterocyclic group is optionally substituted with 1
to 3 C.sub.1-6 alkyl group(s) or 1 to 3 oxo group(s)), 1 to 5
--S(O).sub.iR.sup.a (i is an integer of 0 to 2) group(s), 1 to 5
--SO.sub.2NR.sup.dR.sup.e group(s), 1 to 5 --CONR.sup.dR.sup.e
group(s), or 1 to 5 --NR.sup.b1R.sup.c1 group(s)), a
--NR.sup.b1R.sup.c1 group, a heterocyclic oxy group (the
heterocyclic oxy group is optionally substituted with 1 to 3
C.sub.1-6 alkyl group(s) or 1 to 3 oxo group(s)), a C.sub.1-6 alkyl
group (the C.sub.1-6 alkyl group is optionally substituted with 1
to 5 halogen atom(s), 1 to 5 --OH, 1 to 5 C.sub.1-6 alkoxy
group(s), 1 to 5 --S(O).sub.iR.sup.a (i is an integer of 0 to 2)
group(s), 1 to 5 --SO.sub.2NR.sup.dR.sup.e group(s), 1 to 5
--CONR.sup.dR.sup.e group(s), or 1 to 5 --NR.sup.b1R.sup.c1
group(s)), a C.sub.2-6 alkenyl group, a C.sub.2-7 alkanoyl group,
an aralkyloxy group, a heterocyclic group (the heterocyclic group
is optionally substituted with 1 to 3 C.sub.1-6 alkyl group(s) or 1
to 3 oxo group(s)), a heterocyclic carbonyl group (the heterocyclic
carbonyl group is optionally substituted with 1 to 3 C.sub.1-6
alkyl group(s) or 1 to 3 oxo group(s)), a --S(O).sub.iR.sup.a (i is
an integer of 0 to 2) group, a --CONR.sup.dR.sup.e group, and a
--CONR.sup.dR.sup.e1 group. Specific examples thereof include a
"heterocyclic group optionally substituted with 1 or 2 "C.sub.1-6
alkyl group(s)" and 1 or 2 "C.sub.1-6 alkoxy group(s)" (the
C.sub.1-6 alkoxy group is optionally substituted with 1 to 5
halogen atom(s), 1 to 5 --OH, 1 to 5 C.sub.1-6 alkoxy group(s), 1
to 5 aryl group(s) (the aryl group is optionally substituted with 1
to 3 halogen atom(s)), 1 to 5 heterocyclic group(s) (the
heterocyclic group is optionally substituted with 1 to 3 C.sub.1-6
alkyl group(s) or 1 to 3 oxo group(s)), 1 to 5 --S(O).sub.iR.sup.a
(i is an integer of 0 to 2) group(s), 1 to 5
--SO.sub.2NR.sup.dR.sup.e group(s), 1 to 5 --CONR.sup.dR.sup.e
group(s), or 1 to 5 --NR.sup.b1R.sup.c1 group(s))". More preferred
examples thereof include a "heteroaryl group optionally substituted
with 1 or 2 "C.sub.1-6 alkyl group(s)" and one "C.sub.1-6 alkoxy
group" (the C.sub.1-6 alkoxy group is optionally substituted with 1
or 2 --OH, 1 or 2 C.sub.1-6 alkoxy group(s), 1 or 2 non-aromatic
heterocyclic group(s) (the heterocyclic group is optionally
substituted with a C.sub.1-6 alkyl group), 1 or 2
--S(O).sub.iR.sup.a (i is an integer of 0 to 2) group(s), or 1 or 2
--NR.sup.b1R.sup.c1 group(s))".
[0165] The "heteroaryl group" in the "heterocyclic group which is
optionally substituted with 1 to 5 substituent(s) RII" may be
monocyclic or ring-fused. The monocyclic heteroaryl group
preferably has a 5- to 7-membered ring, and examples thereof
include those groups described in the definition of the "heteroaryl
group", such as pyrrolyl, furyl, thienyl, imidazolyl, pyrazolyl,
oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, 1,2,3-triazolyl,
1,2,4-triazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl,
1,3,4-oxadiazolyl, furazanyl, 1,2,3-thiadiazolyl,
1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, tetrazolyl, pyridyl,
pyridazinyl, pyrimidinyl, pyrazinyl, 1,2,3-triazinyl,
1,2,4-triazinyl, 1,3,5-triazinyl, 2H-1,2,3-thiadiazinyl,
4H-1,2,4-thiadiazinyl, 6H-1,3,4-thiadiazinyl, 1,4-diazepinyl, and
1,4-oxazepinyl. The ring-fused heteroaryl group preferably has an
8- to 14-membered ring, and examples thereof include a monovalent
group obtained by removing any hydrogen atom from a fused ring
formed by fusing the 5- to 7-membered heterocyclic ring and a
monocyclic aryl group (such as a benzene ring) or a monocyclic
heteroaryl group. The hydrogen atom is optionally removed from any
of the fused rings.
[0166] Specific examples include those groups described in the
definition of the "heteroaryl group", such as indolyl, isoindolyl,
benzofuranyl, isobenzofuranyl, benzothienyl, isobenzothienyl,
benzoxazolyl, 1,2-benzisoxazolyl, benzothiazolyl,
1,2-benzisothiazolyl, 1H-benzimidazolyl, 1H-indazolyl,
1H-benzotriazolyl, 2,1,3-benzothiadiazinyl, chromenyl,
isochromenyl, 4H-1,4-benzoxazinyl, 4H-1,4-benzothiazinyl, quinolyl,
isoquinolyl, cinnolinyl, quinazolinyl, quinoxalinyl, phthalazinyl,
benzoxazepinyl, benzoazepinyl, benzodiazepinyl, naphthyridinyl,
purinyl, pteridinyl, carbazolyl, carbolinyl, acridinyl,
phenoxazinyl, phenothiazinyl, phenazinyl, phenoxathiinyl,
thianthrenyl, phenanthridinyl, phenanthrolinyl, indolizinyl,
thieno[3,2-c]pyridyl, thiazolo[5,4-c]pyridyl,
pyrrolo[1,2-b]pyridazinyl, pyrazolo[1,5-a]pyridyl,
imidazo[1,2-a]pyridyl, imidazo[1,5-a]pyridyl,
imidazo[1,2-b]pyridazinyl, imidazo[1,5-a]pyrimidinyl,
1,2,4-triazolo[4,3-a]pyridyl, 1,2,4-triazolo[4,3-b]pyridazinyl,
1H-pyrazolo[3,4-b]pyridyl, 1,2,4-triazolo[1,5-a]pyrimidinyl, and
dibenzofuranyl. Specific examples thereof also include a ring-fused
heteroaryl group which is partly hydrogenated, such as indolinyl,
dihydrobenzofuranyl, dihydroisobenzofuranyl, dihydrobenzoxazolyl,
dihydrobenzothiazolyl, chromanyl, isochromanyl,
3,4-dihydro-2H-1,4-benzoxazinyl, 3,4-dihydro-2H-1,4-benzothiazinyl,
tetrahydroquinolyl, tetrahydroisoquinolyl, tetrahydroquinoxalinyl,
1,4-benzodioxanyl, 1,3-benzodioxolyl, tetrahydrobenzoxazepinyl,
tetrahydrobenzoazepinyl, and
6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridyl. The ring-fused
heteroaryl group which is partly hydrogenated preferably has an 8-
to 12-membered ring, namely a monovalent group obtained by removing
any hydrogen atom from a fused ring which is partly hydrogenated
and formed by fusing the 5- to 7-membered heterocyclic ring and a
monocyclic aryl group (such as a benzene ring) or a monocyclic
heteroaryl group. Any of the hydrogen atom in the aryl group or in
the heterocyclic moiety and of the hydrogen atom in the
hydrogenated moiety is optionally removed. In the case of
tetrahydroquinolyl, examples of the partly hydrogenated ring-fused
heteroaryl group include 5,6,7,8-tetrahydroquinolyl and
1,2,3,4-tetrahydroquinolyl. Depending on the position in these
groups from which any hydrogen atom is removed, -2-yl, -3-yl,
-4-yl, -5-yl, -6-yl, -7-yl, and -8-yl are exemplified in the case
of 5,6,7,8-tetrahydroquinolyl, and in the case of
1,2,3,4-tetrahydroquinolyl, -1-yl, -2-yl, -3-yl, -4-yl, -5-yl,
-6-yl, -7-yl, and -8-yl are exemplified.
[0167] Examples of the "non-aromatic heterocyclic group" in the
"heterocyclic group which is optionally substituted with 1 to 5
substituent(s) RII" include a 3- to 8-membered saturated or
unsaturated non-aromatic heterocyclic group. Specific examples
thereof include aziridinyl, azetidinyl, oxiranyl, oxetanyl,
thietanyl, pyrrolidinyl, tetrahydrofuryl, thiolanyl, pyrazolinyl,
pyrazolidinyl, piperidinyl, dihydropyranyl, tetrahydropyranyl
(oxanyl), tetrahydrothiopyranyl, piperazinyl, dioxanyl, oxazolinyl,
isoxazolinyl, oxazolidinyl, isoxazolidinyl, thiazolinyl,
isothiazolinyl, thiazolidinyl, isothiazolidinyl, oxadiazolinyl,
oxadiazolidinyl, morpholinyl, thiomorpholinyl, quinuclidinyl, and
oxepanyl. The "non-aromatic heterocyclic group" means a monovalent
group obtained by removing any hydrogen atom from the ring.
[0168] Specific examples of the "heterocyclic group which is
optionally substituted with 1 to 5 substituent(s) RII" include
pyrrolyl, furyl, thienyl, pyrazolyl, isoxazolyl, pyridyl,
pyrimidinyl, indolyl, 1H-benzimidazolyl, quinolyl, dibenzofuranyl,
dihydrobenzofuranyl, dihydroisobenzofuranyl, chromanyl,
1,3-benzodioxanyl, 1,4-benzodioxanyl, piperidinyl, dihydropyranyl,
and tetrahydropyranyl (oxanyl). Further specific examples thereof
include 2-pyrrolyl, 3-pyrrolyl, 2-furyl, 3-furyl, 2-thienyl,
3-thienyl, 1-pyrazolyl, 3-pyrazolyl, 4-pyrazolyl, 5-pyrazolyl,
3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-pyridyl, 3-pyridyl,
4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 1-indolyl,
2-indolyl, 3-indolyl, 4-indolyl, 5-indolyl, 6-indolyl, 7-indolyl,
1H-benzimidazol-1-yl, 1H-benzimidazol-2-yl, 1H-benzimidazol-4-yl,
1H-benzimidazol-5-yl, 1H-benzimidazol-6-yl, 1H-benzimidazol-7-yl,
2-quinolyl, 3-quinolyl, 4-quinolyl, 5-quinolyl, 6-quinolyl,
7-quinolyl, 8-quinolyl, 1-dibenzofuranyl, 2-dibenzofuranyl,
3-dibenzofuranyl, 4-dibenzofuranyl, 1,4-benzodioxazine-2-yl,
1,4-benzodioxazine-3-yl, 1,4-benzodioxazine-5-yl,
1,4-benzodioxazine-6-yl, piperidin-1-yl, piperidin-2-yl,
piperidin-3-yl, piperidin-4-yl, 3,6-dihydro-2H-pyran-4-yl, and
4-tetrahydropyranyl(4-oxanyl). Any hydrogen atom of the groups is
optionally substituted with 1 to 5 substituent(s) Rll. Specific
examples thereof include (3-, 4-, or 5-)chlorothiophen-2-yl, (2-,
4-, or 5-)chlorothiophen-3-yl, (3-, 4-, or 5-)acetylthiophen-2-yl,
1-methylpyrazol-4-yl, 3,5-dimethylisoxazol-4-yl, (2-, 4-, 5-, or
6-)fluoropyridin-3-yl, (2-, 4-, 5-, or 6-)chloropyridin-3-yl, (2-,
4-, 5-, or 6-)hydroxypyridin-3-yl, (3-, 4-, 5-, or
6-)cyanopyridin-2-yl, (2-, 4-, 5-, or 6-)cyanopyridin-3-yl, (2- or
3-)cyanopyridin-4-yl, (3-, 4-, 5-, or 6-)methoxypyridin-2-yl, (2-,
4-, 5-, or 6-)methoxypyridin-3-yl, (2- or 3-)methoxypyridin-4-yl,
(2-, 4-, 5-, or 6-)ethoxypyridin-3-yl, (2-, 4-, 5-, or
6-)cyclopropylmethoxypyridin-3-yl, (3-, 4-, 5-, or
6-)methylpyridin-2-yl, (2-, 4-, 5-, or 6-)methylpyridin-3-yl, (2-
or 3-)methylpyridin-4-yl, (2-, 4-, 5-, or
6-)trifluoromethylpyridin-3-yl, 6-(3-hydroxybutoxyl)pyridin-3-yl,
6-(3-hydroxy-3-methylbutoxy)pyridin-3-yl,
6-(2-ethoxyethoxyl)pyridin-3-yl,
6-(3-methylsulfonyl-propoxy)pyridin-3-yl, (2,4-, 2,5-, 2,6-, 4,5-,
4,6-, or 5,6-)dimethylpyridin-3-yl, (2,4-, 2,5-, 2,6-, 4,5-, 4,6-,
or 5,6-)dimethoxypyridin-3-yl, 6-isopropyl-(2-, 4-, or
5-)chloropyridin-3-yl, 6-methoxy-(2-, 4-, or 5-)methylpyridin-3-yl,
6-(2-hydroxyethoxy)-(2- or 4-)methylpyridin-3-yl,
6-(3-hydroxypropoxy)-(2- or 4-)methylpyridin-3-yl,
6-(2,3-dihydroxypropoxy)-(2- or 4-)methylpyridin-3-yl,
6-((2R)-2,3-dihydroxypropoxy)-(2- or 4-)methylpyridin-3-yl,
6-((2S)-2,3-dihydroxypropoxy)-(2- or 4-)methylpyridyl-3-yl,
6-((3S)-3-hydroxybutoxy)-(2- or 4-)methylpyridyl-3-yl,
6-((3R)-3-hydroxybutoxy)-(2- or 4-)methylpyridyl-3-yl,
6-(3-hydroxy-3-methylbutoxy)-(2- or 4-)methylpyridin-3-yl,
6-(3-hydroxy-2-hydroxymethylpropoxy)-(2- or
4-)methylpyridin-3-yl,
[0169] 6-(3-hydroxy-2-hydroxymethyl-2-methylpropoxy)-(2- or
4-)methylpyridin-3-yl, 6-(3-hydroxybutoxy)-(2- or
4-)methylpyridin-3-yl, 6-(2-ethoxyethoxy)-(2- or
4-)methylpyridin-3-yl, 6-(2-methylsulfonylethoxy)-(2- or
4-)methylpyridin-3-yl, 6-(3-methylsulfonyl-propoxy)-(2- or
4-)methylpyridin-3-yl,
6-((1,1-dioxidetetrahydro-2H-thiopyran-4-yl)oxy)-(2- or
4-)methylpyridin-3-yl,
6-((4-hydroxy-1,1-dioxidetetrahydro-2H-thiopyran-4-yl)methoxy)-(2-
or 4-)methylpyridin-3-yl, 6-((3-methyloxetane-3-yl)methoxy)-(2- or
4-)methylpyridin-3-yl, 6-(2-hydroxyethoxy)-(2,4-, 2,5-, or
4,5-)dimethylpyridin-3-yl, 6-(3-hydroxypropoxy)-(2,4-, 2,5-, or
4,5-)dimethylpyridin-3-yl, 6-(2,3-dihydroxypropoxy)-(2,4-, 2,5-, or
4,5-)dimethylpyridin-3-yl,
6-(3-hydroxy-2-hydroxymethylpropoxy)-(2,4-, 2,5-, or
4,5-)dimethylpyridin-3-yl,
6-(3-hydroxy-2-hydroxymethyl-2-methylpropoxy)-(2,4-, 2,5-, or
4,5-)dimethylpyridin-3-yl, 6-(3-hydroxybutoxy)-(2,4-, 2,5-, or
4,5-)dimethylpyridin-3-yl, 6-(3-hydroxy-3-methylbutoxy)-(2,4-,
2,5-, or 4,5-)dimethylpyridin-3-yl, 6-(2-ethoxyethoxy)-(2,4-, 2,5-,
or 4,5-)dimethylpyridin-3-yl, 6-(2-methylsulfonylethoxy)-(2,4-,
2,5-, or 4,5-)dimethylpyridin-3-yl,
6-(3-methylsulfonyl-propoxy)-(2,4-, 2,5-, or
4,5-)dimethylpyridin-3-yl,
6-((1,1-dioxidetetrahydro-2H-thiopyran-4-yl)oxy)-(2,4-, 2,5-, or
4,5-)dimethylpyridin-3-yl,
6-((4-hydroxy-1,1-dioxidetetrahydro-2H-thiopyran-4-yl)methoxy)-(2,4-,
2,5-, or 4,5-)dimethylpyridin-3-yl,
6-((3-methyloxetane-3-yl)methoxy)-(2,4-, 2,5-, or
4,5-)dimethylpyridin-3-yl, 6-(3-hydroxy-3-methylbutoxy)-(2- or
4-)methoxypyridin-3-yl, 6-(2-aminoethoxy)-(2- or
4-)methylpyridin-3-yl, 6-(2-aminoethoxy)-(2,4-, 2,5-, or
4,5-)dimethylpyridin-3-yl, 6-(3-aminopropoxy)-(2- or
4-)methylpyridin-3-yl, 6-(3-aminopropoxy)-(2,4-, 2,5-, or
4,5-)dimethylpyridin-3-yl, 6-(2-acetylamino-ethoxy)-(2- or
4-)methylpyridin-3-yl, 6-(2-acetylamino-ethoxy)-(2,4-, 2,5-, or
4,5-)dimethylpyridin-3-yl, 6-(3-acetylamino-propoxy)-(2- or
4-)methylpyridin-3-yl, 6-(3-acetylamino-propoxy)-(2,4-, 2,5-, or
4,5-)dimethylpyridin-3-yl, 6-(2-methylsulfonylamino-ethoxy)-(2- or
4-)methylpyridin-3-yl, 6-(2-methylsulfonylamino-ethoxy)-(2,4-,
2,5-, or 4,5-)dimethylpyridin-3-yl,
6-(3-methylsulfonylamino-propoxy)-(2- or 4-)methylpyridin-3-yl,
6-(3-methylsulfonylamino-propoxy)-(2,4-, 2,5-, or
4,5-)dimethylpyridin-3-yl, 6-(2-carbamoyl-ethoxy)-(2- or
4-)methylpyridin-3-yl, 6-(2-carbamoyl-ethoxy)-(2,4-, 2,5-, or
4,5-)dimethylpyridin-3-yl, 6-(3-carbamoyl-propoxy)-(2- or
4-)methylpyridin-3-yl,
[0170] 6-(3-carbamoyl-propoxy)-(2,4-, 2,5-, or
4,5-)dimethylpyridin-3-yl, 6-(2-methylcarbamoyl-ethoxy)-(2- or
4-)methylpyridin-3-yl, 6-(2-methylcarbamoyl-ethoxy)-(2,4-, 2,5-, or
4,5-)dimethylpyridin-3-yl, 6-(3-methylcarbamoyl-propoxy)-(2- or
4-)methylpyridin-3-yl, 6-(3-methylcarbamoyl-propoxy)-(2,4-, 2,5-,
or 4,5-)dimethylpyridin-3-yl, 6-(2-dimethylcarbamoyl-ethoxy)-(2- or
4-)methylpyridin-3-yl, 6-(2-dimethylcarbamoyl-ethoxy)-(2,4-, 2,5-,
or 4,5-)dimethylpyridin-3-yl, 6-(3-dimethylcarbamoyl-propoxy)-(2-
or 4-)methylpyridin-3-yl, 6-(3-dimethylcarbamoyl-propoxy)-(2,4-,
2,5-, or 4,5-)dimethylpyridin-3-yl, 6-(2-sulfamoyl-ethoxy)-(2- or
4-)methylpyridin-3-yl, 6-(2-sulfamoyl-ethoxy)-(2,4-, 2,5-, or
4,5-)dimethylpyridin-3-yl, 6-(3-sulfamoyl-propoxy)-(2- or
4-)methylpyridin-3-yl, 6-(3-sulfamoyl-propoxy)-(2,4-, 2,5-, or
4,5-)dimethylpyridin-3-yl, 6-(2-methylsulfamoyl-ethoxy)-(2- or
4-)methylpyridin-3-yl, 6-(2-methylsulfamoyl-ethoxy)-(2,4-, 2,5-, or
4,5-)dimethylpyridin-3-yl, 6-(3-methylsulfamoyl-propoxy)-(2- or
4-)methylpyridin-3-yl, 6-(3-methylsulfamoyl-propoxy)-(2,4-, 2,5-,
or 4,5-)dimethylpyridin-3-yl, 6-(2-dimethylsulfamoyl-ethoxy)-(2- or
4-)methylpyridin-3-yl, 6-(2-dimethylsulfamoyl-ethoxy)-(2,4-, 2,5-,
or 4,5-)dimethylpyridin-3-yl, 6-(3-dimethylsulfamoyl-propoxy)-(2-
or 4-)methylpyridin-3-yl, 6-(3-dimethylsulfamoyl-propoxy)-(2,4-,
2,5-, or 4,5-)dimethylpyridin-3-yl,
6-(2-(2-oxo-1-pyrrolidinyl)ethoxy)-(2- or 4-)methylpyridin-3-yl,
6-(2-(2-oxo-1-pyrrolidinyl)ethoxy)-(2,4-, 2,5-, or
4,5-)dimethylpyridin-3-yl, 6-(3-(2-oxo-1-pyrrolidinyl)propoxy)-(2-
or 4-)methylpyridin-3-yl,
6-(3-(2-oxo-1-pyrrolidinyl)propoxy)-(2,4-, 2,5-, or
4,5-)dimethylpyridin-3-yl, 6-(1-piperidinyl)pyridin-3-yl,
6-(4-morpholino)pyridin-3-yl, 6-(4-morpholino)-(2,4-, 2,5-, or
4,5-)dimethylpyridin-3-yl, 6-acetylpyridin-3-yl,
6-benzyloxypyridin-3-yl, 6-methylsulfonylpyridin-3-yl,
6-carbamoylpyridin-3-yl, (2- or 4-)methoxypyrimidin-5-yl,
2-(3-hydroxy-3-methylbutoxy)-4-methylpyrimidin-5-yl,
2-(3-methylsulfonyl-propoxy)-4-methylpyrimidin-5-yl,
2-(3-hydroxy-3-methylbutoxy)-4,6-dimethylpyrimidin-5-yl,
2-(3-methylsulfonyl-propoxy)-4,6-dimethylpyrimidin-5-yl,
[0171] 2-(4-morpholino)-4,6-dimethylpyrimidin-5-yl,
2-ethyl-6,7-difluoro-1H-benzimidazol-1-yl,
2-ethoxy-6,7-difluoro-1H-benzimidazol-1-yl, (2-, 4-, 5-, 6-, 7-, or
8-) methylquinoline-3-yl, 6-(1-piperidinyl)pyridin-3-yl,
1-methylpiperidin-4-yl, and 4,4-difluoropiperidin-1-yl.
[0172] The "aralkyl group which is optionally substituted with 1 to
5 substituent(s) RII" is the "aralkyl group" in which any hydrogen
atom is optionally substituted with 1 to 5 substituent(s) RII. That
is to say, the "aralkyl group which is optionally substituted with
1 to 5 substituent(s) RII" includes, in addition to the
unsubstituted groups exemplified as the "aralkyl group": "an
aralkyl group which is substituted with 1 to 5 group(s) optionally
selected from a halogen atom, --OH, a cyano group, a C.sub.1-6
alkoxy group (the C.sub.1-6 alkoxy group is optionally substituted
with 1 to 5 halogen atom(s), 1 to 5 --OH, 1 to 5 C.sub.1-6 alkoxy
group(s), 1 to 5 aryl group(s) (the aryl group is optionally
substituted with 1 to 3 halogen atom(s)), 1 to 5 heterocyclic
group(s) (the heterocyclic group is optionally substituted with 1
to 3 C.sub.1-6 alkyl group(s) or 1 to 3 oxo group(s)), 1 to 5
--S(O).sub.iR.sup.a (i is an integer of 0 to 2) group(s), 1 to 5
--SO.sub.2NRdR.sup.e group(s), 1 to 5 --CONR.sup.dR.sup.e group(s),
or 1 to 5 --NR.sup.b1R.sup.c1 group(s)), a --NR.sup.b1R.sup.c1
group, a heterocyclic oxy group (the heterocyclic oxy group is
optionally substituted with 1 to 3 C.sub.1-6 alkyl group(s) or 1 to
3 oxo group(s)), a C.sub.1-6 alkyl group (the C.sub.1-6 alkyl group
is optionally substituted with 1 to 5 halogen atom(s), 1 to 5 --OH,
1 to 5 C.sub.1-6 alkoxy group(s), 1 to 5 --S(O).sub.iR.sup.a (i is
an integer of 0 to 2) group(s), 1 to 5 --SO.sub.2NR.sup.dR.sup.e
group(s), 1 to 5 --CONR.sup.dR.sup.e group(s), or 1 to 5
--NR.sup.b1R.sup.c1 group(s)), a C.sub.2-6 alkenyl group, a
C.sub.2-7 alkanoyl group, an aralkyloxy group, a heterocyclic group
(the heterocyclic group is optionally substituted with 1 to 3
C.sub.1-6 alkyl group(s) or 1 to 3 oxo group(s)), a heterocyclic
carbonyl group (the heterocyclic carbonyl group is optionally
substituted with 1 to 3 C.sub.1-6 alkyl group(s) or 1 to 3 oxo
group(s)), a --S(O).sub.iR.sup.a (i is an integer of 0 to 2) group,
a --CONR.sup.dR.sup.e group, and a --CONR.sup.dR.sup.e1 group". The
substituent(s) of the aralkyl group may be substituted with either
the aryl moiety or the alkyl moiety. Specific examples thereof
include, in addition to unsubstituted benzyl, phenethyl,
1-naphthylmethyl, or 2-naphthylmethyl: (2-, 3-, or 4-)fluorobenzyl,
(2-, 3-, or 4-)chlorobenzyl, (2-, 3-, or 4-)hydroxybenzyl, (2-, 3-,
or 4-)methoxybenzyl, (2-, 3-, or 4-)trifluoromethoxybenzyl, (2-,
3-, or 4-)methylbenzyl, (2-, 3-, or 4-)trifluoromethylbenzyl,
(2,6-, 2,5-, 2,4-, or 2,3-)dimethylbenzyl,
3,5-ditrifluoromethylbenzyl,
4-(2-hydroxyethoxy)-2,6-dimethylbenzyl,
4-(2,3-dihydroxypropoxy)-2,6-dimethylbenzyl, and
4-(3-hydroxy-3-methylbutoxy)-2,6-dimethylbenzyl.
[0173] The "heteroarylalkyl group which is optionally substituted
with 1 to 5 substituent(s) RII" is the "heteroarylalkyl group" in
which any hydrogen atom is optionally substituted with 1 to 5
substituent(s) RII. That is to say, the "heteroarylalkyl group
which is optionally substituted with 1 to 5 substituent(s) RII"
includes, in addition to the unsubstituted groups exemplified as
the "heteroarylalkyl group": "a heteroarylalkyl group which is
substituted with 1 to 5 group(s) optionally selected from a halogen
atom, --OH, a cyano group, a C.sub.1-6 alkoxy group (the C.sub.1-6
alkoxy group is optionally substituted with 1 to 5 halogen atom(s),
1 to 5 --OH, 1 to 5 C.sub.1-6 alkoxy group(s), 1 to 5 aryl group(s)
(the aryl group is optionally substituted with 1 to 3 halogen
atom(s)), 1 to 5 heterocyclic group(s) (the heterocyclic group is
optionally substituted with 1 to 3 C.sub.1-6 alkyl group(s) or 1 to
3 oxo group(s)), 1 to 5 --S(O).sub.iR.sup.a (i is an integer of 0
to 2) group(s), 1 to 5 --SO.sub.2NR.sup.dR.sup.e group(s), 1 to 5
--CONR.sup.dR.sup.e group(s), or 1 to 5 --NR.sup.b1R.sup.c1
group(s)), a --NR.sup.b1R.sup.c1 group, a heterocyclic oxy group
(the heterocyclic oxy group is optionally substituted with 1 to 3
C.sub.1-6 alkyl group(s) or 1 to 3 oxo group(s)), a C.sub.1-6 alkyl
group (the C.sub.1-6 alkyl group is optionally substituted with 1
to 5 halogen atom(s), 1 to 5 --OH, 1 to 5 C.sub.1-6 alkoxy
group(s), 1 to 5 --S(O).sub.iR.sup.a (i is an integer of 0 to 2)
group(s), 1 to 5 --SO.sub.2NR.sup.dR.sup.e group(s), 1 to 5
--CONR.sup.dR.sup.e group(s), or 1 to 5 --NR.sup.b1R.sup.c1
group(s)), a C.sub.2-6 alkenyl group, a C.sub.2-7 alkanoyl group,
an aralkyloxy group, a heterocyclic group (the heterocyclic group
is optionally substituted with 1 to 3 C.sub.1-6 alkyl group(s) or 1
to 3 oxo group(s)), a heterocyclic carbonyl group (the heterocyclic
carbonyl group is optionally substituted with 1 to 3 C.sub.1-6
alkyl group(s) or 1 to 3 oxo group(s)), a --S(O).sub.iR.sup.a (i is
an integer of 0 to 2) group, a --CONR.sup.dR.sup.e group, and a
--CONR.sup.dR.sup.e1 group". The substituent(s) of the
heteroarylalkyl group may be substituted with either the heteroaryl
moiety or the alkyl moiety. Specific examples thereof include, in
addition to unsubstituted pyrrolylmethyl, furylmethyl,
pyridylmethyl, or quinolylmethyl: (2-, 4-, 5-, or
6-)chloropyridin-3-ylmethyl, (2-, 4-, 5-, or
6-)hydroxypyridin-3-ylmethyl, (2-, 4-, 5-, or
6-)methoxypyridin-3-ylmethyl, (2-, 4-, 5-, or
6-)methylpyridin-3-ylmethyl, (2,4-, 2,5-, 2,6-, 4,5-, or
4,6-)dimethylpyridin-3-ylmethyl,
6-(2-hydroxyethoxy)-2,4-dimethylpyridin-3-ylmethyl,
6-(2,3-dihydroxypropoxy)-2,4-dimethylpyridin-3-ylmethyl, and
6-(3-hydroxy-3-methylbutoxy)-2,4-dimethylpyridin-3-ylmethyl.
[0174] The "non-aromatic heterocyclic alkyl group which is
optionally substituted with 1 to 5 substituent(s) RII" is the
"non-aromatic heterocyclic alkyl group" in which any hydrogen atom
is optionally substituted with 1 to 5 substituent(s) RII. That is
to say, the "non-aromatic heterocyclic alkyl group which is
optionally substituted with 1 to 5 substituent(s) RII" includes, in
addition to the unsubstituted groups exemplified as the
"non-aromatic heterocyclic alkyl group": "a non-aromatic
heterocyclic alkyl group which is substituted with 1 to 5 group(s)
optionally selected from a halogen atom, --OH, a cyano group, a
C.sub.1-6 alkoxy group (the C.sub.1-6 alkoxy group is optionally
substituted with 1 to 5 halogen atom(s), 1 to 5 --OH, 1 to 5
C.sub.1-6 alkoxy group(s), 1 to 5 aryl group(s) (the aryl group is
optionally substituted with 1 to 3 halogen atom(s)), 1 to 5
heterocyclic group(s) (the heterocyclic group is optionally
substituted with 1 to 3 C.sub.1-6 alkyl group(s) or 1 to 3 oxo
group(s)), 1 to 5 --S(O).sub.iR.sup.a (i is an integer of 0 to 2)
group(s), 1 to 5 --SO.sub.2NR.sup.dR.sup.e group(s), 1 to 5
--CONR.sup.dR.sup.e group(s), or 1 to 5 --NR.sup.b1R.sup.c1
group(s)), a --NR.sup.b1R.sup.c1 group, a heterocyclic oxy group
(the heterocyclic oxy group is optionally substituted with 1 to 3
C.sub.1-6 alkyl group(s) or 1 to 3 oxo group(s)), a C.sub.1-6 alkyl
group (the C.sub.1-6 alkyl group is optionally substituted with 1
to 5 halogen atom(s), 1 to 5 --OH, 1 to 5 C.sub.1-6 alkoxy
group(s), 1 to 5 --S(O).sub.iR.sup.a (i is an integer of 0 to 2)
group(s), 1 to 5 --SO.sub.2NR.sup.dR.sup.e group(s), 1 to 5
--CONR.sup.dR.sup.e group(s), or 1 to 5 --NR.sup.b1R.sup.c1
group(s)), a C.sub.2-6 alkenyl group, a C.sub.2-7 alkanoyl group,
an aralkyloxy group, a heterocyclic group (the heterocyclic group
is optionally substituted with 1 to 3 C.sub.1-6 alkyl group(s) or 1
to 3 oxo group(s)), a heterocyclic carbonyl group (the heterocyclic
carbonyl group is optionally substituted with 1 to 3 C.sub.1-6
alkyl group(s) or 1 to 3 oxo group(s)), a --S(O).sub.iR.sup.a (i is
an integer of 0 to 2) group, a --CONR.sup.dR.sup.e group, and a
--CONR.sup.dR.sup.e1 group". The substituent(s) of the non-aromatic
heterocyclic alkyl group may be substituted with either the
non-aromatic heterocyclic moiety or the alkyl moiety. Specific
examples thereof include, in addition to unsubstituted
pyrrolidinylmethyl, tetrahydrofurylmethyl, piperidinylmethyl, or
tetrahydropyranylmethyl: (2-, 3-, or 4-)chloropiperidin-1-ylmethyl,
(2-, 3-, or 4-)hydroxypiperidin-1-ylmethyl, (2-, 3-, or
4-)cyanopiperidin-1-ylmethyl, (2-, 3-, or
4-)methoxypiperidin-1-ylmethyl, (2-, 3-, or
4-)methylpiperidin-1-ylmethyl, (2,3-, 2,4-, 2,5-, 2,6-, 3,4-, or
3,5-)dimethylpiperidin-1-ylmethyl,
4-(2-hydroxyethoxy)-2,6-dimethylpiperidin-1-ylmethyl,
4-(2,3-dihydroxypropoxy)-2,6-dimethylpiperidin-1-ylmethyl, and
4-(3-hydroxy-3-methylbutoxy)-2,6-dimethylpiperidin-1-ylmethyl.
[0175] The "aryloxy group which is optionally substituted with 1 to
5 substituent(s) RII" is the "aryloxy group" in which any hydrogen
atom is optionally substituted with 1 to 5 substituent(s) RII. The
"aryloxy group which is optionally substituted with 1 to 5
substituent(s) RII" is also the "aryl group which is optionally
substituted with 1 to 5 substituent(s) RII" which is substituted
with an oxygen atom. That is to say, the "aryloxy group which is
optionally substituted with 1 to 5 substituent(s) RII" includes, in
addition to the unsubstituted groups exemplified as the "aryloxy
group": "an aryloxy group which is substituted with 1 to 5 group(s)
optionally selected from a halogen atom, --OH, a cyano group, a
C.sub.1-6 alkoxy group (the C.sub.1-6 alkoxy group is optionally
substituted with 1 to 5 halogen atom(s), 1 to 5 --OH, 1 to 5
C.sub.1-6 alkoxy group(s), 1 to 5 aryl group(s) (the aryl group is
optionally substituted with 1 to 3 halogen atom(s)), 1 to 5
heterocyclic group(s) (the heterocyclic group is optionally
substituted with 1 to 3 C.sub.1-6 alkyl group(s) or 1 to 3 oxo
group(s)), 1 to 5 --S(O).sub.iR.sup.a (i is an integer of 0 to 2)
group(s), 1 to 5 --SO.sub.2NR.sup.dR.sup.e group(s), 1 to 5
--CONR.sup.dR.sup.e group(s), or 1 to 5 --NR.sup.b1R.sup.c1
group(s)), a --NR.sup.b1R.sup.c1 group, a heterocyclic oxy group
(the heterocyclic oxy group is optionally substituted with 1 to 3
C.sub.1-6 alkyl group(s) or 1 to 3 oxo group(s)), a C.sub.1-6 alkyl
group (the C.sub.1-6 alkyl group is optionally substituted with 1
to 5 halogen atom(s), 1 to 5 --OH, 1 to 5 C.sub.1-6 alkoxy
group(s), 1 to 5 --S(O).sub.iR.sup.a (i is an integer of 0 to 2)
group(s), 1 to 5 --SO.sub.2NR.sup.dR.sup.e group(s), 1 to 5
--CONR.sup.dR.sup.e group(s), or 1 to 5 --NR.sup.b1R.sup.c1
group(s)), a C.sub.2-6 alkenyl group, a C.sub.2-7 alkanoyl group,
an aralkyloxy group, a heterocyclic group (the heterocyclic group
is optionally substituted with 1 to 3 C.sub.1-6 alkyl group(s) or 1
to 3 oxo group(s)), a heterocyclic carbonyl group (the heterocyclic
carbonyl group is optionally substituted with 1 to 3 C.sub.1-6
alkyl group(s) or 1 to 3 oxo group(s)), a --S(O).sub.iR.sup.a (i is
an integer of 0 to 2) group, a --CONR.sup.dR.sup.e group, and a
--CONR.sup.dR.sup.e1 group". Specific examples thereof include a
group in which the group exemplified specifically as the "aryl
group which is optionally substituted with 1 to 5 substituent(s)
RII" is substituted with an oxygen atom, such as, in addition to
unsubstituted phenoxy, 1-naphthyloxy, 2-naphthyloxy, 1-indanyloxy,
or 2-indanyloxy: (2-, 3-, or 4-)fluorophenoxy, (2-, 3-, or
4-)chlorophenoxy, (2-, 3-, or 4-)hydroxyphenoxy, (2-, 3-, or
4-)cyanophenoxy, (2-, 3-, or 4-)methoxyphenoxy, (2-, 3-, or
4-)trifluoromethoxyphenoxy, (2-, 3-, or 4-)methylphenoxy, (2-, 3-,
or 4-)trifluoromethylphenoxy, (2,6-, 2,5-, 2,4-, or
2,3-)dimethylphenoxy, (3- or 4-)(2-hydroxyethyl)phenoxy,
4-(2-hydroxyethoxyl)phenoxy, 4-(2,3-dihydroxypropoxyl)phenoxy, (3-
or 4-)(3-hydroxy-3-methylbutoxy)phenoxy, (3- or
4-)(2-ethoxy-ethoxy)phenoxy, (3- or
4-)(3-methylsulfonyl-propoxy)phenoxy,
4-(3-hydroxy-3-methylbutoxy)-2-methylphenoxy,
4-(2-ethoxy-ethoxy)-2-methylphenoxy,
4-(3-methylsulfonyl-propoxy)-2-methylphenoxy,
4-(2-hydroxyethoxy)-2,6-dimethylphenoxy,
4-(2,3-dihydroxypropoxy)-2,6-dimethylphenoxy,
4-(3-hydroxy-3-methylbutoxy)-2,6-dimethylphenoxy,
4-(2-ethoxy-ethoxy)-2,6-dimethylphenoxy,
4-(3-methylsulfonyl-propoxy)-2,6-dimethylphenoxy,
4-methylsulfonylphenoxy, and 4-(4-morpholino)phenoxy.
[0176] The "heteroaryloxy group which is optionally substituted
with 1 to 5 substituent(s) RII" is the "heteroaryloxy group" in
which any hydrogen atom is optionally substituted with 1 to 5
substituent(s) RII. The "heteroaryloxy group which is optionally
substituted with 1 to 5 substituent(s) RII" is also a group in
which a group having the "heteroaryl group" in the "heterocyclic
group which is optionally substituted with 1 to 5 substituent(s)
RII" is substituted with an oxygen atom. That is to say, the
"heteroaryloxy group which is optionally substituted with 1 to 5
substituent(s) RII" includes, in addition to the unsubstituted
groups exemplified as the "heteroaryloxy group": "a heteroaryloxy
group which is substituted with 1 to 5 group(s) optionally selected
from a halogen atom, --OH, a cyano group, a C.sub.1-6 alkoxy group
(the C.sub.1-6 alkoxy group is optionally substituted with 1 to 5
halogen atom(s), 1 to 5 --OH, 1 to 5 C.sub.1-6 alkoxy group(s), 1
to 5 aryl group(s) (the aryl group is optionally substituted with 1
to 3 halogen atom(s)), 1 to 5 heterocyclic group(s) (the
heterocyclic group is optionally substituted with 1 to 3 C.sub.1-6
alkyl group(s) or 1 to 3 oxo group(s)), 1 to 5 --S(O).sub.iR.sup.a
(i is an integer of 0 to 2) group(s), 1 to 5
--SO.sub.2NR.sup.dR.sup.e group(s), 1 to 5 --CONR.sup.dR.sup.e
group(s), or 1 to 5 --NR.sup.b1R.sup.c1 group(s)), a
--NR.sup.b1R.sup.c1 group, a heterocyclic oxy group (the
heterocyclic oxy group is optionally substituted with 1 to 3
C.sub.1-6 alkyl group(s) or 1 to 3 oxo group(s)), a C.sub.1-6 alkyl
group (the C.sub.1-6 alkyl group is optionally substituted with 1
to 5 halogen atom(s), 1 to 5 --OH, 1 to 5 C.sub.1-6 alkoxy
group(s), 1 to 5 --S(O).sub.iR.sup.a (i is an integer of 0 to 2)
group(s), 1 to 5 --SO.sub.2NR.sup.dR.sup.e group(s), 1 to 5
--CONR.sup.dR.sup.e group(s), or 1 to 5 --NR.sup.b1R.sup.c1
group(s)), a C.sub.2-6 alkenyl group, a C.sub.2-7 alkanoyl group,
an aralkyloxy group, a heterocyclic group (the heterocyclic group
is optionally substituted with 1 to 3 C.sub.1-6 alkyl group(s) or 1
to 3 oxo group(s)), a heterocyclic carbonyl group (the heterocyclic
carbonyl group is optionally substituted with 1 to 3 C.sub.1-6
alkyl group(s) or 1 to 3 oxo group(s)), a --S(O).sub.iR.sup.a (i is
an integer of 0 to 2) group, a --CONR.sup.dR.sup.e group, and a
--CONR.sup.dR.sup.e1 group". Specific examples thereof include a
group in which a group having the "heteroaryl group" among the
groups exemplified specifically as the "heterocyclic group which is
optionally substituted with 1 to 5 substituent(s) RII" is
substituted with an oxygen atom, such as, in addition to
pyrrolyloxy, furyloxy, thienyloxy, (2-, 3-, or 4-)pyridyloxy,
pyrimidinyloxy, or quinolyloxy: (2-, 4-, 5-, or
6-)chloropyridin-3-yloxy, (2- or 3-)chloropyridin-4-yloxy, (2-, 4-,
5-, or 6-)hydroxypyridin-3-yloxy, (2- or 3-)hydroxypyridin-4-yloxy,
(3-, 4-, 5-, or 6-)cyanopyridin-2-yloxy, (2-, 4-, 5-, or
6-)cyanopyridin-3-yloxy, (2- or 3-)cyanopyridin-4-yloxy, (2-, 4-,
5-, or 6-)methoxypyridin-3-yloxy, (2- or 3-)methoxypyridin-4-yloxy,
(2-, 4-, 5-, or 6-)methylpyridin-3-yloxy, (2- or
3-)methylpyridin-4-yloxy, (2,4-, 2,5-, 2,6-, 4,5-, or
4,6-)dimethylpyridin-3-yloxy, (2,3-, 2,5-, 2,6-, or
3,5-)dimethylpyridin-4-yloxy, 6-methoxy-(2-, 4-, or
5-)methylpyridin-3-yloxy, 6-(2-hydroxyethoxyl)pyridin-3-yloxy,
6-(2,3-dihydroxypropoxyl)pyridin-3-yloxy,
6-(3-hydroxy-3-methylbutoxy)pyridin-3-yloxy,
6-(2-ethoxyethoxyl)pyridin-3-yloxy,
6-(3-methylsulfonyl-propoxy)pyridin-3-yloxy,
6-(3-hydroxy-3-methylbutoxy)-(2- or 4-)methylpyridin-3-yloxy,
6-(2-ethoxyethoxy)-(2- or 4-)methylpyridin-3-yloxy,
6-(3-methylsulfonyl-propoxy)-(2- or 4-)methylpyridin-3-yloxy,
6-(2-hydroxyethoxy)-2,4-dimethylpyridin-3-yloxy,
6-(2,3-dihydroxypropoxy)-2,4-dimethylpyridin-3-yloxy,
6-(3-hydroxy-3-methylbutoxy)-2,4-dimethylpyridin-3-yloxy,
6-(2-ethoxyethoxy)-2,4-dimethylpyridin-3-yloxy,
6-(3-methylsulfonyl-propoxy)-2,4-dimethylpyridin-3-yloxy, and
6-(4-morpholino)-pyridin-3-yloxy.
[0177] The "non-aromatic heterocyclic oxy group which is optionally
substituted with 1 to 5 substituent(s) RII" is the "non-aromatic
heterocyclic oxy group" in which any hydrogen atom is optionally
substituted with 1 to 5 substituent(s) RII. That is to say, the
"non-aromatic heterocyclic oxy group which is optionally
substituted with 1 to 5 substituent(s) RII" includes, in addition
to the unsubstituted groups exemplified as the "non-aromatic
heterocyclic oxy group": "a non-aromatic heterocyclic oxy group
which is substituted with 1 to 5 group(s) optionally selected from
a halogen atom, --OH, a cyano group, a C.sub.1-6 alkoxy group (the
C.sub.1-6 alkoxy group is optionally substituted with 1 to 5
halogen atom(s), 1 to 5 --OH, 1 to 5 C.sub.1-6 alkoxy group(s), 1
to 5 aryl group(s) (the aryl group is optionally substituted with 1
to 3 halogen atom(s)), 1 to 5 heterocyclic group(s) (the
heterocyclic group is optionally substituted with 1 to 3 C.sub.1-6
alkyl group(s) or 1 to 3 oxo group(s)), 1 to 5 --S(O).sub.iR.sup.a
(i is an integer of 0 to 2) group(s), 1 to 5
--SO.sub.2NR.sup.dR.sup.e group(s), 1 to 5 --CONR.sup.dR.sup.e
group(s), or 1 to 5 --NR.sup.b1R.sup.c1 group(s)), a
--NR.sup.b1R.sup.c1 group, a heterocyclic oxy group (the
heterocyclic oxy group is optionally substituted with 1 to 3
C.sub.1-6 alkyl group(s) or 1 to 3 oxo group(s)), a C.sub.1-6 alkyl
group (the C.sub.1-6 alkyl group is optionally substituted with 1
to 5 halogen atom(s), 1 to 5 --OH, 1 to 5 C.sub.1-6 alkoxy
group(s), 1 to 5 --S(O).sub.iR.sup.a (i is an integer of 0 to 2)
group(s), 1 to 5 --SO.sub.2NR.sup.dR.sup.e group(s), 1 to 5
--CONR.sup.dR.sup.e group(s), or 1 to 5 --NR.sup.b1R.sup.c1
group(s)), a C.sub.2-6 alkenyl group, a C.sub.2-7 alkanoyl group,
an aralkyloxy group, a heterocyclic group (the heterocyclic group
is optionally substituted with 1 to 3 C.sub.1-6 alkyl group(s) or 1
to 3 oxo group(s)), a heterocyclic carbonyl group (the heterocyclic
carbonyl group is optionally substituted with 1 to 3 C.sub.1-6
alkyl group(s) or 1 to 3 oxo group(s)), a --S(O).sub.iR.sup.a (i is
an integer of 0 to 2) group, a --CONR.sup.dR.sup.e group, and a
--CONR.sup.dR.sup.e1 group". For example, a 3- to 8-membered
saturated or unsaturated non-aromatic heterocyclic oxy group
optionally substituted with 1 to 5 substituent(s) RII is included.
Examples thereof include, in addition to pyrrolidinyloxy,
tetrahydrofuryloxy, piperidinyloxy, dihydropyranyloxy, or
tetrahydropyranyloxy(oxanyloxy): (2- or 3-)fluorooxane-4-yloxy, (2-
or 3-)chlorooxane-4-yloxy, (2- or 3-)hydroxyoxane-4-yloxy, (2- or
3-)methoxyoxane-4-yloxy, (2- or 3-)trifluoromethoxyoxane-4-yloxy,
(2- or 3-)methyloxane-4-yloxy, (2- or
3-)trifluoromethyloxane-4-yloxy, (2,3-, 2,5-, 2,6-, or
3,5-)dimethyloxane-4-yloxy, 1-methylpiperidin-4-yloxy, and (1,2- or
1,3-)dimethylpiperidin-4-yloxy.
[0178] The "aralkyloxy group which is optionally substituted with 1
to 5 substituent(s) RII" is the "aralkyloxy group" in which any
hydrogen atom is optionally substituted with 1 to 5 substituent(s)
RII. That is to say, the "aralkyloxy group which is optionally
substituted with 1 to 5 substituent(s) RII" includes, in addition
to the unsubstituted groups exemplified as the "aralkyloxy group":
"an aralkyloxy group which is substituted with 1 to 5 group(s)
optionally selected from a halogen atom, --OH, a cyano group, a
C.sub.1-6 alkoxy group (the C.sub.1-6 alkoxy group is optionally
substituted with 1 to 5 halogen atom(s), 1 to 5 --OH, 1 to 5
C.sub.1-6 alkoxy group(s), 1 to 5 aryl group(s) (the aryl group is
optionally substituted with 1 to 3 halogen atom(s)), 1 to 5
heterocyclic group(s) (the heterocyclic group is optionally
substituted with 1 to 3 C.sub.1-6 alkyl group(s) or 1 to 3 oxo
group(s)), 1 to 5 --S(O).sub.iR.sup.a (i is an integer of 0 to 2)
group(s), 1 to 5 --SO.sub.2NR.sup.dR.sup.e group(s), 1 to 5
--CONR.sup.dR.sup.e group(s), or 1 to 5 --NR.sup.b1R.sup.c1
group(s)), a --NR.sup.b1R.sup.c1 group, a heterocyclic oxy group
(the heterocyclic oxy group is optionally substituted with 1 to 3
C.sub.1-6 alkyl group(s) or 1 to 3 oxo group(s)), a C.sub.1-6 alkyl
group (the C.sub.1-6 alkyl group is optionally substituted with 1
to 5 halogen atom(s), 1 to 5 --OH, 1 to 5 C.sub.1-6 alkoxy
group(s), 1 to 5 --S(O).sub.iR.sup.a (i is an integer of 0 to 2)
group(s), 1 to 5 --SO.sub.2NR.sup.dR.sup.e group(s), 1 to 5
--CONR.sup.dR.sup.e group(s), or 1 to 5 --NR.sup.b1R.sup.c1
group(s)), a C.sub.2-6 alkenyl group, a C.sub.2-7 alkanoyl group,
an aralkyloxy group, a heterocyclic group (the heterocyclic group
is optionally substituted with 1 to 3 C.sub.1-6 alkyl group(s) or 1
to 3 oxo group(s)), a heterocyclic carbonyl group (the heterocyclic
carbonyl group is optionally substituted with 1 to 3 C.sub.1-6
alkyl group(s) or 1 to 3 oxo group(s)), a --S(O).sub.iR.sup.a (i is
an integer of 0 to 2) group, a --CONR.sup.dR.sup.e group, and a
--CONR.sup.dR.sup.e1 group". The substituent(s) of the aralkyloxy
group may be substituted with the aryl moiety or the alkyl moiety.
Specific examples thereof include, in addition to benzyloxy,
phenethyloxy, 1-naphthylmethoxy, or 2-naphthylmethoxy: (2-, 3-, or
4-)fluorobenzyloxy, (2-, 3-, or 4-)chlorobenzyloxy, (2-, 3-, or
4-)hydroxybenzyloxy, (2-, 3-, or 4-)methoxybenzyloxy, (2-, 3-, or
4-)trifluoromethoxybenzyloxy, (2-, 3-, or 4-)methylbenzyloxy, (2-,
3-, or 4-)trifluoromethylbenzyloxy, (2-, 3-, or
4-)methoxyphenethyloxy, (2,6-, 2,5-, 2,4-, or
2,3-)dimethylbenzyloxy, 4-(2-hydroxyethoxy)-2,6-dimethylbenzyloxy,
4-(2,3-dihydroxypropoxy)-2,6-dimethylbenzyloxy, and
4-(3-hydroxy-3-methylbutoxy)-2,6-dimethylbenzyloxy.
[0179] The "heteroarylalkyloxy group which is optionally
substituted with 1 to 5 substituent(s) RII" is the
"heteroarylalkyloxy group" in which any hydrogen atom is optionally
substituted with 1 to 5 substituent(s) RII. That is to say, the
"heteroarylalkyloxy group which is optionally substituted with 1 to
5 substituent(s) RII" includes, in addition to the unsubstituted
groups exemplified as the "heteroarylalkyloxy group": "a
heteroarylalkyloxy group which is substituted with 1 to 5 group(s)
optionally selected from a halogen atom, --OH, a cyano group, a
C.sub.1-6 alkoxy group (the C.sub.1-6 alkoxy group is optionally
substituted with 1 to 5 halogen atom(s), 1 to 5 --OH, 1 to 5
C.sub.1-6 alkoxy group(s), 1 to 5 aryl group(s) (the aryl group is
optionally substituted with 1 to 3 halogen atom(s)), 1 to 5
heterocyclic group(s) (the heterocyclic group is optionally
substituted with 1 to 3 C.sub.1-6 alkyl group(s) or 1 to 3 oxo
group(s)), 1 to 5 --S(O).sub.iR.sup.a (i is an integer of 0 to 2)
group(s), 1 to 5 --SO.sub.2NR.sup.dR.sup.e group(s), 1 to 5
--CONR.sup.dR.sup.e group(s), or 1 to 5 --NR.sup.b1R.sup.c1
group(s)), a --NR.sup.b1R.sup.c1 group, a heterocyclic oxy group
(the heterocyclic oxy group is optionally substituted with 1 to 3
C.sub.1-6 alkyl group(s) or 1 to 3 oxo group(s)), a C.sub.1-6 alkyl
group (the C.sub.1-6 alkyl group is optionally substituted with 1
to 5 halogen atom(s), 1 to 5 --OH, 1 to 5 C.sub.1-6 alkoxy
group(s), 1 to 5 --S(O).sub.iR.sup.a (i is an integer of 0 to 2)
group(s), 1 to 5 --SO.sub.2NR.sup.dR.sup.e group(s), 1 to 5
--CONR.sup.dR.sup.e group(s), or 1 to 5 --NR.sup.b1R.sup.c1
group(s)), a C.sub.2-6 alkenyl group, a C.sub.2-7 alkanoyl group,
an aralkyloxy group, a heterocyclic group (the heterocyclic group
is optionally substituted with 1 to 3 C.sub.1-6 alkyl group(s) or 1
to 3 oxo group(s)), a heterocyclic carbonyl group (the heterocyclic
carbonyl group is optionally substituted with 1 to 3 C.sub.1-6
alkyl group(s) or 1 to 3 oxo group(s)), a --S(O).sub.iR.sup.a (i is
an integer of 0 to 2) group, a --CONR.sup.dR.sup.e group, and a
--CONR.sup.dR.sup.e1 group". The substituent(s) of the
heteroarylalkyloxy group may be substituted with either the
heteroaryl moiety or the alkyl moiety. Specific examples thereof
include, in addition to pyrrolylmethoxy, furylmethoxy,
pyridylmethoxy, or quinolylmethoxy: (2-, 4-, 5-, or
6-)chloropyridin-3-ylmethoxy, (2-, 4-, 5-, or
6-)hydroxypyridin-3-ylmethoxy, (2-, 4-, 5-, or
6-)methoxypyridin-3-ylmethoxy, (2-, 4-, 5-, or
6-)methylpyridin-3-ylmethoxy, (2,4-, 2,5-, 2,6-, 4,5-, or
4,6-)dimethylpyridin-3-ylmethoxy,
6-(2-hydroxyethoxy)-2,4-dimethylpyridin-3-ylmethoxy,
6-(2,3-dihydroxypropoxy)-2,4-dimethylpyridin-3-ylmethoxy, and
6-(3-hydroxy-3-methylbutoxy)-2,4-dimethylpyridin-3-ylmethoxy.
[0180] In the compound of Formula (I), in the cyclic amide
structure moiety, proton tautomerism shown by the formula below can
be generated. The abundance ratio of this structure can vary
depending on whether the compound of Formula (I) is in the solid
state or in the dissolved state in a liquid. The tautomer generated
by the cyclic amide moiety is included in Formula (I).
##STR00008##
[0181] Namely, in Formula (I), for example, a proton tautomer as
shown below is supposed and such a tautomer is also included in the
range of the present compound.
##STR00009##
[0182] For example, when in the cyclic amide structure of Formula
(I), n is 1, h is 0, J.sub.1 is CR.sup.11a, R.sup.2a, R.sup.2b, and
R.sup.11a are a hydrogen atom, and the ring B is bonded to J.sub.1,
the tautomerism as shown below is supposed and such a tautomer is
also included in the range of the present compound.
##STR00010##
[0183] The description of any specific types of tautomers in any
structural formulae of the present specification is not intended to
limit the present invention, but is intended to represent the whole
set of tautomers that are applicable.
[0184] Specifically, for example, a tautomer, namely, [0185]
5-[4-[[3-[4-(2-ethoxyethoxy)-2,6-dimethylphenyl]phenyl]methoxy]phenyl]-1--
oxo-2-isothiazoline-3-ol, of the compounds described as
5-[4-[[3-[4-(2-ethoxyethoxy)-2,6-dimethylphenyl]phenyl]methoxy]phenyl]-1--
oxo-1,2-thiazolidin-3-one among compounds of Example 1 is also
categorized as a compound of Example 1. In addition, a tautomer,
namely, [0186]
5-(4-((3-(2,6-dimethyl-4-(2-ethoxyethoxyl)phenyl)phenyl)methoxy)phenyl)-4-
-isothiazoline-3-one 1-oxide, of the compounds described as
5-(4-((3-(2,6-dimethyl-4-(2-ethoxyethoxyl)phenyl)phenyl)methoxy)phenyl)is-
othiazol-3-ol 1-oxide among compounds of Step 6 of Example 1, which
are a reaction intermediate, is also categorized as a compound of
Step 6 of Example 1.
[0187] [1-1] In the compound of Formula (I) according to Aspect
[1], Ls are independently a group optionally selected from a
halogen atom, --OH, an oxo group, a cyano group, a C.sub.1-10 alkyl
group which is optionally substituted with 1 to 5 substituent(s)
RI, a C.sub.2-10 alkenyl group which is optionally substituted with
1 to 5 substituent(s) RI, a C.sub.2-10 alkynyl group which is
optionally substituted with 1 to 5 substituent(s) RI, a C.sub.1-10
alkoxy group which is optionally substituted with 1 to 5
substituent(s) RI, a C.sub.2-10 alkenyloxy group which is
optionally substituted with 1 to 5 substituent(s) RI, a C.sub.2-10
alkynyloxy group which is optionally substituted with 1 to 5
substituent(s) RI, an aryl group which is optionally substituted
with 1 to 5 substituent(s) RII, a heterocyclic group which is
optionally substituted with 1 to 5 substituent(s) RII, an aralkyl
group which is optionally substituted with 1 to 5 substituent(s)
RII, a heteroarylalkyl group which is optionally substituted with 1
to 5 substituent(s) RII, a non-aromatic heterocyclic alkyl group
which is optionally substituted with 1 to 5 substituent(s) RII, an
aryloxy group which is optionally substituted with 1 to 5
substituent(s) RII, a heteroaryloxy group which is optionally
substituted with 1 to 5 substituent(s) RII, a non-aromatic
heterocyclic oxy group which is optionally substituted with 1 to 5
substituent(s) RII, an aralkyloxy group which is optionally
substituted with 1 to 5 substituent(s) RII, a heteroarylalkyloxy
group which is optionally substituted with 1 to 5 substituent(s)
RII, --SH, --SF.sub.5, a --S(O).sub.iR.sup.a (i is an integer of 0
to 2) group, a --NR.sup.bR.sup.c group, and a substituted
spiropiperidinylmethyl group; and the substituent(s) RI, the
substituent(s) RII, i, R.sup.a, R.sup.b, and R.sup.c are the same
as defined in Aspect [1].
[0188] [1-1-a] Preferable examples of Ls include a group optionally
selected from a halogen atom, a cyano group, a C.sub.1-10 alkyl
group which is optionally substituted with 1 to 5 substituent(s)
RI, a C.sub.2-10 alkenyl group which is optionally substituted with
1 to 5 substituent(s) RI, a C.sub.2-10 alkynyl group which is
optionally substituted with 1 to 5 substituent(s) RI, a C.sub.1-10
alkoxy group which is optionally substituted with 1 to 5
substituent(s) RI, a C.sub.2-10 alkenyloxy group which is
optionally substituted with 1 to 5 substituent(s) RI, a C.sub.2-10
alkynyloxy group which is optionally substituted with 1 to 5
substituent(s) RI, an aryl group which is optionally substituted
with 1 to 5 substituent(s) RII, a heterocyclic group which is
optionally substituted with 1 to 5 substituent(s) RII, an aralkyl
group which is optionally substituted with 1 to 5 substituent(s)
RII, a heteroarylalkyl group which is optionally substituted with 1
to 5 substituent(s) RII, a non-aromatic heterocyclic alkyl group
which is optionally substituted with 1 to 5 substituent(s) RII, an
aryloxy group which is optionally substituted with 1 to 5
substituent(s) RII, a heteroaryloxy group which is optionally
substituted with 1 to 5 substituent(s) RII, a non-aromatic
heterocyclic oxy group which is optionally substituted with 1 to 5
substituent(s) RII, an aralkyloxy group which is optionally
substituted with 1 to 5 substituent(s) RII, a heteroarylalkyloxy
group which is optionally substituted with 1 to 5 substituent(s)
RII, a --NR.sup.bR.sup.c group, and a substituted
spiropiperidinylmethyl group (the substituent(s) RI and the
substituent(s) RII are the same as defined in Aspect [1]).
[0189] [1-1-b] More preferable examples of Ls include a group
optionally selected from a halogen atom, a cyano group, a
C.sub.1-10 alkyl group which is optionally substituted with 1 to 5
substituent(s) RI, a C.sub.2-10 alkenyl group which is optionally
substituted with 1 to 5 substituent(s) RI, a C.sub.1-10 alkoxy
group which is optionally substituted with 1 to 5 substituent(s)
RI, a C.sub.2-10 alkenyloxy group which is optionally substituted
with 1 to 5 substituent(s) RI, an aryl group which is optionally
substituted with 1 to 5 substituent(s) RII, a heterocyclic group
which is optionally substituted with 1 to 5 substituent(s) RII, an
aralkyl group which is optionally substituted with 1 to 5
substituent(s) RII, a heteroarylalkyl group which is optionally
substituted with 1 to 5 substituent(s) RII, a non-aromatic
heterocyclic alkyl group which is optionally substituted with 1 to
5 substituent(s) RII, an aryloxy group which is optionally
substituted with 1 to 5 substituent(s) RII, a heteroaryloxy group
which is optionally substituted with 1 to 5 substituent(s) RII, a
non-aromatic heterocyclic oxy group which is optionally substituted
with 1 to 5 substituent(s) RII, an aralkyloxy group which is
optionally substituted with 1 to 5 substituent(s) RII, a
heteroarylalkyloxy group which is optionally substituted with 1 to
5 substituent(s) RII, a --NR.sup.bR.sup.c group, and a substituted
spiropiperidinylmethyl group (the substituent(s) RI and the
substituent(s) RII are the same as defined in Aspect [1]).
[0190] [1-1-c] Further preferable examples of Ls include a group
optionally selected from a halogen atom, a cyano group, a
C.sub.1-10 alkyl group which is optionally substituted with 1 to 5
substituent(s) RI, a C.sub.2-10 alkenyl group which is optionally
substituted with 1 to 5 substituent(s) RI, a C.sub.1-10 alkoxy
group which is optionally substituted with 1 to 5 substituent(s)
RI, a C.sub.2-10 alkenyloxy group which is optionally substituted
with 1 to 5 substituent(s) RI, an aryl group which is optionally
substituted with 1 to 5 substituent(s) RII, a heterocyclic group
which is optionally substituted with 1 to 5 substituent(s) RII, an
aralkyl group which is optionally substituted with 1 to 5
substituent(s) RII, a non-aromatic heterocyclic alkyl group which
is optionally substituted with 1 to 5 substituent(s) RII, an
aryloxy group which is optionally substituted with 1 to 5
substituent(s) RII, a heteroaryloxy group which is optionally
substituted with 1 to 5 substituent(s) RII, a non-aromatic
heterocyclic oxy group which is optionally substituted with 1 to 5
substituent(s) RII, an aralkyloxy group which is optionally
substituted with 1 to 5 substituent(s) RII, and a substituted
spiropiperidinylmethyl group (the substituent(s) RI and the
substituent(s) RII are the same as defined in Aspect [1]).
[0191] [1-1-d] Most preferable examples of Ls include a group
optionally selected from a halogen atom, a cyano group, a
C.sub.1-10 alkyl group (the C.sub.1-10 alkyl group is optionally
substituted with 1 to 5 halogen atom(s), 1 to 5 --OH, or 1 to 5
C.sub.1-4 alkoxy group(s)), a C.sub.2-10 alkenyl group (the
C.sub.2-10 alkenyl group is optionally substituted with 1 to 5
halogen atom(s), 1 to 5 --OH, or 1 to 5 C.sub.1-4 alkoxy group(s)),
a C.sub.1-10 alkoxy group (the C.sub.1-10 alkoxy group is
optionally substituted with 1 to 5 halogen atom(s), 1 to 5 --OH, or
1 to 5 C.sub.1-4 alkoxy group(s)), a C.sub.2-10 alkenyloxy group
(the C.sub.2-10 alkenyloxy group is optionally substituted with 1
to 5 halogen atom(s), 1 to 5 --OH, or 1 to 5 C.sub.1-4 alkoxy
group(s)), an aryl group which is optionally substituted with 1 to
5 substituent(s) RIIa, a heterocyclic group which is optionally
substituted with 1 to 5 substituent(s) RIIa, an aralkyl group which
is optionally substituted with 1 to 5 substituent(s) RIIa, a
non-aromatic heterocyclic alkyl group which is optionally
substituted with 1 to 5 substituent(s) RII, an aryloxy group which
is optionally substituted with 1 to 5 substituent(s) RIIa, a
heteroaryloxy group which is optionally substituted with 1 to 5
substituent(s) RIIa, a non-aromatic heterocyclic oxy group which is
optionally substituted with 1 to 5 substituent(s) RIIa, an
aralkyloxy group which is optionally substituted with 1 to 5
substituent(s) RIIa, and a substituted spiropiperidinylmethyl group
(the substituent(s) RIIa are the same as or different from each
other and are each a group optionally selected from a halogen atom,
a cyano group, a C.sub.1-6 alkoxy group (the C.sub.1-6 alkoxy group
is optionally substituted with 1 to 5 halogen atom(s), 1 to 5 --OH,
or 1 to 5 C.sub.1-4 alkoxy group(s), 1 to 5 non-aromatic
heterocyclic group(s) (the heterocyclic group is optionally
substituted with 1 or 2 C.sub.1-4 alkyl group(s) or 1 or 2 oxo
group(s)), or 1 to 5 --S(O).sub.iR.sup.a (i is an integer of 0 to
2) group(s)), a --NR.sup.b1R.sup.c1 group, a non-aromatic
heterocyclic oxy group (the heterocyclic oxy group is optionally
substituted with 1 or 2 oxo group(s)), a C.sub.1-6 alkyl group (the
C.sub.1-6 alkyl group is optionally substituted with 1 to 5 halogen
atom(s), 1 to 5 --OH, or 1 to 5 C.sub.1-4 alkoxy group(s)), a
C.sub.2-6 alkenyl group, a C.sub.2-7 alkanoyl group, an aralkyloxy
group, a non-aromatic heterocyclic carbonyl group (the heterocyclic
carbonyl group is optionally substituted with 1 to 2 oxo group(s)),
a --S(O).sub.iR.sup.a (i is an integer of 0 to 2) group, a
--CONR.sup.dR.sup.e group, and a --CONR.sup.d3R.sup.e3 group
(R.sup.d3 is a hydrogen atom or a C.sub.1-4 alkyl group; and
R.sup.e3 is a C.sub.1-6 alkyl group (the C.sub.1-6 alkyl group is
substituted with 1 to 5 group(s) optionally selected from --OH, a
C.sub.1-6 alkoxy group, a non-aromatic heterocyclic group (the
heterocyclic group is optionally substituted with 1 to 2 C.sub.1-4
alkyl group(s) or 1 to 2 oxo group(s)), and a --S(O).sub.iR.sup.a
(i is an integer of 0 to 2) group))). Substitution with one to
three substituent(s) RIIa is preferable.
[0192] More specific examples of Ls include the groups specifically
exemplified above as the "halogen atom", the "C.sub.1-6 alkyl group
which is optionally substituted with 1 to 5 substituent(s) RI", the
"C.sub.1-6 alkoxy group which is optionally substituted with 1 to 5
substituent(s) RI", the "aryl group which is optionally substituted
with 1 to 5 substituent(s) RII", the "heterocyclic group which is
optionally substituted with 1 to 5 substituent(s) RII", the
"aralkyl group which is optionally substituted with 1 to 5
substituent(s) RII", the "heteroarylalkyl group which is optionally
substituted with 1 to 5 substituent(s) RII", the "non-aromatic
heterocyclic alkyl group which is optionally substituted with 1 to
5 substituent(s) RII", the "aryloxy group which is optionally
substituted with 1 to 5 substituent(s) RII", the "heteroaryloxy
group which is optionally substituted with 1 to 5 substituent(s)
RII", the "non-aromatic heterocyclic oxy group which is optionally
substituted with 1 to 5 substituent(s) RII", the "aralkyloxy group
which is optionally substituted with 1 to 5 substituent(s) RII",
the "heteroarylalkyloxy group which is optionally substituted with
1 to 5 substituent(s) RII", the substituted spiropiperidinylmethyl
group", and the like.
[0193] [1-2] In the compound of Formula (I) according to Aspect
[1], R.sup.1's are independently a group optionally selected from a
halogen atom, a C.sub.1-6 alkyl group which is optionally
substituted with 1 to 5 substituent(s) RI, a C.sub.2-6 alkenyl
group which is optionally substituted with 1 to 5 substituent(s)
RI, a C.sub.2-6 alkynyl group which is optionally substituted with
1 to 5 substituent(s) RI, a C.sub.1-6 alkoxy group which is
optionally substituted with 1 to 5 substituent(s) RI (the
substituents RI are the same as or different from each other and
are the same as defined as the substituent(s) RI above), and a
cyano group.
[0194] [1-2-a] Preferable examples of R.sup.1's include a halogen
atom, a C.sub.1-4 alkyl group which is optionally substituted with
1 to 5 substituent(s) RI, a C.sub.1-4 alkoxy group which is
optionally substituted with 1 to 5 substituent(s) RI (the
substituents RI are the same as or different from each other and
are the same as defined as the substituent(s) RI above), and a
cyano group.
[0195] [1-2-b] More preferable examples of R.sup.1's include a
halogen atom, a C.sub.1-4 alkyl group which is optionally
substituted with 1 to 5 halogen atom(s), a C.sub.1-4 alkoxy group
which is optionally substituted with 1 to 5 halogen atom(s), and a
cyano group. Specific examples of R.sup.1 include a fluorine atom,
a chlorine atom, a bromine atom, methyl, ethyl, propyl, isopropyl,
butyl, isobutyl, sec-butyl, tert-butyl, trifluoromethyl, methoxy,
ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy,
tert-butoxy, trifluoromethoxy, and cyano.
[0196] [1-3] In the compound of Formula (I) according to Aspect
[1], R.sup.2a and R.sup.2b are independently a group optionally
selected from a hydrogen atom, a halogen atom, a C.sub.1-6 alkyl
group, a C.sub.2-6 alkenyl group, a C.sub.2-6 alkynyl group, a
C.sub.1-6 alkoxy group, and a cyano group.
[0197] [1-3-a] Preferable examples of R.sup.2a and R.sup.2b
independently include a hydrogen atom, a halogen atom, and a
C.sub.1-4 alkyl group, and specific examples thereof include a
hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom,
and methyl.
[0198] [1-3-b] More preferably, any one of R.sup.2a and R.sup.2b is
a hydrogen atom, and further preferably, both of R.sup.2a and
R.sup.2b are each a hydrogen atom.
[0199] [1-4] In the compound of Formula (I) according to Aspect
[1], R.sup.3, R.sup.4, R.sup.5, R.sup.6, and R.sup.7 are
independently a group optionally selected from a hydrogen atom, a
C.sub.1-6 alkyl group, a halogenated C.sub.1-6 alkyl group, a
C.sub.2-6 alkenyl group, and a C.sub.2-6 alkynyl group.
[0200] [1-4-a]R.sup.3, R.sup.4, R.sup.5, R.sup.6, and R.sup.7 are
preferably a hydrogen atom.
[0201] [1-5] In the compound of Formula (I) according to Aspect
[1], R.sup.11a and R.sup.11b are independently a group optionally
selected from a hydrogen atom, a halogen atom, a C.sub.1-6 alkyl
group, a halogenated C.sub.1-6 alkyl group, a C.sub.2-6 alkenyl
group, a C.sub.2-6 alkynyl group, a C.sub.1-6 alkoxy group, a
halogenated C.sub.1-6 alkoxy group, a C.sub.2-7 alkanoyl group, and
a carboxy group which is optionally protected.
[0202] [1-5-a] Preferable examples of R.sup.11a and R.sup.11b
independently include a hydrogen atom, a halogen atom, a C.sub.1-4
alkyl group, a halogenated C.sub.1-4 alkyl group, a C.sub.2-5
alkanoyl group, and a carboxy group. More specifically, R.sup.11a
and R.sup.11b are independently a hydrogen atom, a fluorine atom, a
chlorine atom, a bromine atom, methyl, ethyl, propyl, isopropyl,
butyl, isobutyl, sec-butyl, tert-butyl, trifluoromethyl, acetyl,
carboxy, or the like, more preferably a hydrogen atom.
[0203] [1-6] In the compound of Formula (I) according to Aspect
[1], R.sup.12a and R.sup.12b are independently a group optionally
selected from a hydrogen atom, a halogen atom, a C.sub.1-6 alkyl
group, a halogenated C.sub.1-6 alkyl group, a C.sub.2-6 alkenyl
group, a C.sub.2-6 alkynyl group, a C.sub.1-6 alkoxy group, a
halogenated C.sub.1-6 alkoxy group, and a cyano group.
[0204] [1-6-a] Preferable examples of R.sup.12a and R.sup.12b
independently include a hydrogen atom, a halogen atom, a C.sub.1-4
alkyl group, a halogenated C.sub.1-4 alkyl group, and a cyano
group. Specifically, R.sup.12a and R.sup.12b are a hydrogen atom, a
fluorine atom, a chlorine atom, a bromine atom, methyl, ethyl,
propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl,
trifluoromethyl, cyano, or the like.
[0205] [1-6-b] More preferably, any one of R.sup.12a and R.sup.12b
is a hydrogen atom, and further preferably, both of R.sup.12a and
R.sup.12b are each a hydrogen atom.
[0206] [1-7] In the compound of Formula (I) according to Aspect
[1], R.sup.11c and R.sup.12c are independently a group optionally
selected from a hydrogen atom, a C.sub.1-6 alkyl group, and a
halogenated C.sub.1-6 alkyl group.
[0207] [1-7-a] Preferable examples of R.sup.11c and R.sup.12c
independently include a hydrogen atom and a C.sub.1-4 alkyl group.
More specifically, R.sup.11c and R.sup.12c are independently a
hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom,
methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl,
tert-butyl, or the like. More preferably, R.sup.11c and R.sup.12c
are each a hydrogen atom.
[0208] [1-8] In the compound of Formula (I) according to Aspect
[1], X is an oxygen atom, a sulfur atom, or --NR.sup.7-- (R.sup.7
is the same as defined as R.sup.7 above).
[0209] [1-8-a] Preferably, X is an oxygen atom or --NH--.
[0210] [1-8-b] More preferably, X is an oxygen atom.
[0211] [1-9] In the compound of Formula (I) according to Aspect
[1],j is an integer of 0 to 3, while k is an integer of 0 to 2.
Preferably, j is 0 or 1, while k is 0. When the ring A is a
monocyclic ring or a spiro ring, more preferably, j is 1, while k
is 0. When the ring A is a fused ring, more preferably, j is 0,
while k is 0.
[0212] [1-10] In the compound of Formula (I) according to Aspect
[1], the ring B is a C.sub.6-14 aryl group or a 5- to 14-membered
heteroaryl group, preferably a benzene ring, a pyridine ring, a
pyrimidine ring, or Formula (BB1) or Formula (BB2):
##STR00011##
[0213] (where p and R.sup.1 are the same as defined in Formula (I);
G is a carbon atom or a nitrogen atom; W.sub.1 is a single bond, an
oxygen atom, a sulfur atom, --CH.sub.2--, --CF.sub.2--, --CO--,
--SO--, or --SO.sub.2-; W.sub.2 is a single bond or --CH.sub.2--;
W.sub.3 is none or --CH.sub.2--; and is a single bond with a cyclic
amide structure moiety). The ring B is more preferably a benzene
ring, a pyridine ring, Formula (BB1), or Formula (BB2), further
preferably a benzene ring.
[0214] Preferable aspects of p and R.sup.1 in Formula (BB1) and
Formula (BB2) are the same as the preferable aspects described in
the below Aspect [1-11] and the above Aspects [1-2-a] to
[1-2-b].
[0215] [1-10-a] In Formula (BB1) or Formula (BB2), G is preferably
a carbon atom.
[0216] [1-10-b] In Formula (BB1), W.sub.1 is preferably an oxygen
atom, a sulfur atom, or --CH.sub.2--. When W.sub.3 is --CH.sub.2--,
W.sub.2 is preferably --CH.sub.2--.
[0217] [1-10-c] In Formula (BB2), W.sub.1 is preferably a single
bond, an oxygen atom, a sulfur atom, or --CH.sub.2--. When W.sub.3
is --CH.sub.2--, W.sub.2 is preferably --CH.sub.2--.
[0218] [1-11] In the compound of Formula (I) according to Aspect
[1], p is an integer of 0 to 4. p is preferably 0 or 1.
[0219] [1-12] In the compound of Formula (I) according to Aspect
[1], n is an integer of 0 to 2; h is an integer of 0 to 3; J.sub.1
is --CR.sup.11aR.sup.11b- or --NR.sup.11c-; and J.sub.2 is
--CR.sup.12aR.sup.12b- or --NR.sup.12c-- (with the proviso that
when J.sub.1 is --NR.sup.11c-, h is 0). n is preferably 1 or 2.
When J.sub.1 is --CR.sup.11aR.sup.11b- and h is 0, n is more
preferably 1. When J.sub.1 is --NR.sup.11c- and h is 0, n is more
preferably 2. When h is an integer of 1 to 3, n is more preferably
2.
[0220] [1-13] In the compound of Formula (I) according to Aspect
[1], the ring A is a C.sub.6-14 aryl group which is optionally
substituted with 1 to 5 L(s), a 3- to 14-membered heterocyclic
group which is optionally substituted with 1 to 5 L(s), a C.sub.5-7
cycloalkyl group which is optionally substituted with 1 to 5 L(s),
a C.sub.5-7 cycloalkenyl group which is optionally substituted with
1 to 5 L(s), a 6- to 14-membered spiro ring group which is
optionally substituted with 1 to 5 L(s), or a
2-phenylamino-2-oxoacetyl group which is optionally substituted
with 1 to 5 L(s).
[0221] [1-13-a] Preferably, the ring A is phenyl which is
optionally substituted with 1 to 5 L(s), a C.sub.6-14 fused aryl
group which is optionally substituted with 1 to 5 L(s) and partly
hydrogenated, a 5- to 7-membered monocyclic heteroaryl group which
is optionally substituted with 1 to 5 L(s), an 8- to 14-membered
ring-fused heteroaryl group which is optionally substituted with 1
to 5 L(s), an 8- to 14-membered ring-fused heteroaryl group which
is optionally substituted with 1 to 5 L(s) and partly hydrogenated,
a 3- to 8-membered non-aromatic heterocyclic group which is
optionally substituted with 1 to 5 L(s), a C.sub.5-7 cycloalkenyl
group which is optionally substituted with 1 to 5 L(s), or a 7- to
13-membered spiro ring group which is optionally substituted with 1
to 5 L(s).
[0222] [1-13-b] More preferably, the ring A is phenyl which is
optionally substituted with 1 to 5 L(s), indanyl which is
optionally substituted with 1 to 5 L(s), 1,2,3,4-tetrahydronaphthyl
which is optionally substituted with 1 to 5 L(s), thienyl which is
optionally substituted with 1 to 5 L(s), thiazolyl which is
optionally substituted with 1 to 5 L(s), phthalazinyl which is
optionally substituted with 1 to 5 L(s),
1,2,3,4-tetrahydro-4-isoquinolyl which is optionally substituted
with 1 to 5 L(s), 1,2,3,4-tetrahydro-4-quinolyl which is optionally
substituted with 1 to 5 L(s), dihydrobenzofuranyl which is
optionally substituted with 1 to 5 L(s), chromanyl which is
optionally substituted with 1 to 5 L(s), pyrrolidinyl which is
optionally substituted with 1 to 5 L(s), piperidinyl which is
optionally substituted with 1 to 5 L(s), a cyclohexenyl group which
is optionally substituted with 1 to 5 L(s), or a 7- to 13-membered
spiro ring group which is optionally substituted with 1 to 5
L(s).
[0223] [1-13-b-1] Further preferably, the ring A is phenyl which is
optionally substituted with 1 to 5 L(s), thienyl which is
optionally substituted with 1 to 5 L(s), thiazolyl which is
optionally substituted with 1 to 5 L(s), phthalazinyl which is
optionally substituted with 1 to 5 L(s),
1,2,3,4-tetrahydro-4-isoquinolyl which is optionally substituted
with 1 to 5 L(s), 1,2,3,4-tetrahydro-4-quinolyl which is optionally
substituted with 1 to 5 L(s), pyrrolidinyl which is optionally
substituted with 1 to 5 L(s), piperidinyl which is optionally
substituted with 1 to 5 L(s), a cyclohexenyl group which is
optionally substituted with 1 to 5 L(s), or a 7- to 13-membered
spiro ring group which is optionally substituted with 1 to 5
L(s).
[0224] [1-13-b-2] Most preferably, the ring A is phenyl which is
optionally substituted with 1 to 5 L(s), thienyl which is
optionally substituted with 1 to 5 L(s), thiazolyl which is
optionally substituted with 1 to 5 L(s), pyrrolidinyl which is
optionally substituted with 1 to 5 L(s), piperidinyl which is
optionally substituted with 1 to 5 L(s), a cyclohexenyl group which
is optionally substituted with 1 to 5 L(s), or a 7- to 13-membered
spiro ring group which is optionally substituted with 1 to 5
L(s).
[0225] [1-13-c] The ring A in Formula (I) according to Aspect [1]
is preferably phenyl that is optionally substituted with 1 to 5
L(s). More preferable examples of the ring A include Partial
Structural Formula (A):
##STR00012##
[0226] (where q and r are independently an integer of 0 to 4; s is
an integer of 0 to 2 (with the proviso that q+s is an integer of 0
to 5);
the ring A' is an aryl group or a heteroaryl group; V is a single
bond or an oxygen atom; R.sup.8s are independently a group
optionally selected from a C.sub.1-6 alkoxy group which is
substituted with 1 to 5 substituent(s) M, a C.sub.2-6 alkenyloxy
group that is substituted with 1 to 5 substituent(s) M, a C.sub.2-6
alkynyloxy group that is substituted with 1 to 5 substituent(s) M,
a --CONR.sup.dR.sup.e1 group, an aralkyloxy group, a heterocyclic
oxy group (the heterocyclic oxy group is optionally substituted
with 1 to 3 C.sub.1-6 alkyl group(s) or 1 to 3 oxo group(s)), a
heterocyclic group (the heterocyclic group is optionally
substituted with 1 to 3 C.sub.1-6 alkyl group(s) or 1 to 3 oxo
group(s)), and a heterocyclic carbonyl group (the heterocyclic
carbonyl group is optionally substituted with 1 to 3 C.sub.1-6
alkyl group(s) or 1 to 3 oxo group(s)); R.sup.8s are independently
preferably a group optionally selected from a C.sub.1-6 alkoxy
group that is substituted with 1 to 5 substituent(s) M, a
--CONR.sup.dR.sup.e1 group, and an aralkyloxy group; R.sup.8s are
independently more preferably a C.sub.1-6 alkoxy group that is
substituted with 1 to 5 substituent(s) M; the substituents M are
independently a group optionally selected from a halogen atom,
--OH, a C.sub.1-6 alkoxy group, an aryl group (the aryl group is
optionally substituted with 1 to 3 halogen atom(s)), a heterocyclic
group (the heterocyclic group is optionally substituted with 1 to 3
--OH, 1 to 3 C.sub.1-6 alkyl group(s), or 1 to 3 oxo group(s)), a
--S(O).sub.iR.sup.a (i is an integer of 0 to 2) group, a
--NR.sup.b1R.sup.c1 group, a --SO.sub.2NR.sup.dR.sup.e group, and a
--CONR.sup.dR.sup.e group; the substituents M are independently
preferably a group optionally selected from a halogen atom, --OH, a
C.sub.1-6 alkoxy group, a --S(O).sub.iR.sup.a (i is an integer of 0
to 2 and R.sup.a is a C.sub.1-6 alkyl group or a halogenated
C.sub.1-6 alkyl group) group, a --NR.sup.b1R.sup.c1 group, a
--SO.sub.2NR.sup.dR.sup.e group, and a --CONR.sup.dR.sup.e group;
the substituents M are independently more preferably a group
optionally selected from --OH, a C.sub.1-6 alkoxy group, a
--S(O).sub.iR.sup.a (i is an integer of 0 to 2 and R.sup.a is a
C.sub.1-6 alkyl group or a halogenated C.sub.1-6 alkyl group)
group, and a --NR.sup.b1R.sup.c1 group; R.sup.9s and R.sup.10s are
independently a group optionally selected from a halogen atom,
--OH, a cyano group, a C.sub.1-6 alkyl group that is optionally
substituted with 1 to 5 substituent(s) RI, a C.sub.2-6 alkenyl
group that is optionally substituted with 1 to 5 substituent(s) RI,
a C.sub.2-6 alkynyl group that is optionally substituted with 1 to
5 substituent(s) RI, a C.sub.1-6 alkoxy group that is optionally
substituted with 1 to 5 substituent(s) RI, a C.sub.2-7 alkanoyl
group, --SH, a --S(O).sub.iR.sup.a (i is an integer of 0 to 2)
group, a --NR.sup.b1R.sup.c1 group, and a --CONR.sup.dR.sup.e
group; R.sup.9s are independently preferably a group optionally
selected from a halogen atom, --OH, a cyano group, a C.sub.1-6
alkyl group (the C.sub.1-6 alkyl group is optionally substituted
with 1 to 5 halogen atom(s), 1 to 5 --OH, 1 to 5 C.sub.1-6 alkoxy
group(s), 1 to 5 --S(O).sub.iR.sup.a (i is an integer of 0 to 2 and
Ra is a C.sub.1-6 alkyl group or a halogenated C.sub.1-6 alkyl
group) group(s), or 1 to 5 --NR.sup.b1R.sup.c1 group(s)), a
C.sub.2-6 alkenyl group, a C.sub.1-6 alkoxy group (the C.sub.1-6
alkoxy group is optionally substituted with 1 to 5 halogen atom(s),
1 to 5 --OH, 1 to 5 C.sub.1-6 alkoxy group(s), or 1 to 5
--NR.sup.b1R.sup.c1 group(s)), a C.sub.2-7 alkanoyl group, a
--S(O).sub.iR.sup.a (i is an integer of 0 to 2 and R.sup.a is a
C.sub.1-6 alkyl group or a halogenated C.sub.1-6 alkyl group)
group, a --NR.sup.b1R.sup.c1 group, and a --CONR.sup.dR.sup.e
group; R.sup.9s are independently more preferably a group
optionally selected from a halogen atom, a cyano group, a C.sub.1-6
alkyl group (the C.sub.1-6 alkyl group is optionally substituted
with 1 to 5 halogen atom(s)), and a C.sub.1-6 alkoxy group; the
figures of 1 to 6 or 1' to 6' indicate where the ring A'-V-- or
each substituent is bonded; and R.sup.a, R.sup.d, R.sup.e,
R.sup.b1, R.sup.c1, and R.sup.e1 are the same as defined in Formula
(I)).
[0227] In Formula (A), the binding positions of the ring A'-V-- and
R.sup.10s are any positions at which they can be optionally bonded
in the benzene ring, and the binding positions of R.sup.8s and
R.sup.9s are any positions at which they can be optionally bonded
in the ring A'.
[0228] In Formula (A), preferably, the ring A' is a benzene ring, a
pyridine ring, or a pyrimidine ring. Namely, preferable examples of
Formula (A) include Formula (A)-1:
##STR00013##
[0229] (where q, r, s, V, R.sup.8s, R.sup.9s, and R.sup.10s are the
same as defined in Formula (A); and the ring A'' is a benzene ring,
a pyridine ring, or a pyrimidine ring).
[0230] [1-13-c-1] Preferable examples of Formula (A) include
Formula (A1) or Formula (A2):
##STR00014##
[0231] (where q, r, s, the ring A', R.sup.8s, R.sup.9s, and
R.sup.10s are the same as defined in Formula (A) described in
Aspect [1-13-c]; and the broken lines and the figures 3 and 4 or
the figures 3' and 4' indicate where the ring A', the ring A'-O--,
or R.sup.8s are bonded).
[0232] Here, when the position of the single bond of the phenyl
group (the binding position with the linker moiety containing X) is
determined as 1-position, the binding position of the ring A' in
Formula (A1) is 3-position or 4-position, preferably 3-position. In
the case that the ring A' is a 6-membered ring, when the binding
position with the phenyl group of the ring A' is determined as
1'-position, the binding position of R.sup.8 in Formula (A1) is
preferably 3'-position or 4'-position.
[0233] When the position of the single bond of the phenyl group
(the binding position with the linker moiety containing X) is
determined as 1-position, the binding position of the ring A'-O--
in Formula (A2) is 3-position or 4-position, preferably 3-position.
In the case that the ring A' is a 6-membered ring, when the binding
position with the phenyl group-O-- of the ring A' is determined as
1'-position, the binding position of R.sup.8 in Formula (A2) is
preferably 3'-position or 4'-position.
[0234] In Formula (A1) or Formula (A2), preferably, the ring A' is
a benzene ring, a pyridine ring, or a pyrimidine ring. Namely,
preferable examples of Formula (A1) or Formula (A2) include Formula
(A1)-1 or Formula (A2)-1:
##STR00015##
[0235] (where q, r, s, R.sup.8s, R.sup.9s, and R.sup.10s are the
same as defined in Formula (A) described in Aspect [1-13-c]; the
ring A'' is the same as defined in Formula (A)-1 described in
Aspect [1-13-c]; and the broken lines and the figures 3 and 4 or
the figures 3' and 4' indicate where the ring A'', the ring
A''-O--, or R.sup.8s are bonded).
[0236] Here, when the position of the single bond of the phenyl
group (the binding position with the linker moiety containing X) is
determined as 1-position, the binding position of the ring A'' or
the ring A''-O-- in Formula (A1)-1 or Formula (A2)-1 is preferably
3-position. When the binding position with the phenyl group or the
phenyl group-O-- of the ring A'' is determined as 1'-position, the
binding position of R.sup.8 in Formula (A1)-1 or Formula (A2)-1 is
preferably 4'-position.
[0237] [1-13-c-1-1] More specifically, Formula (A) is preferably
the above Partial Structural Formula (A1) or Formula (A1)-1.
[0238] [1-13-c-2] In Formula (A), Formula (A1), or Formula (A2),
more specifically, the ring A' is preferably benzene, naphthalene,
pyridine, pyrimidine, thiophene, quinoline, benzimidazole, or
dibenzofuran, more preferably benzene, pyridine, pyrimidine,
thiophene, or quinoline. Further preferably, the ring A' is
benzene, pyridine, or pyrimidine, that is, the ring A'' (Formula
(A)-1, Formula (A1)-1, or Formula (A2)-1). Most preferably, the
ring A' and the ring A'' are benzene or pyridine.
[0239] [1-13-c-3] More specifically, Formula (A) is more preferably
the above Partial Structural Formula (A), Formula (A)-1, Formula
(A1), Formula (A2), Formula (A1)-1, or Formula (A2)-1 in which s is
0 or 1. Preferably, any one of q and s is 1 or more.
[0240] [1-13-c-3-1] More preferably, Formula (A) is Formula (A1a)
or Formula (A1b) when s is 1 in Formula (A1)-1, and Formula (A) is
Formula (Ale) when s is 0 in Formula (A1)-1:
##STR00016##
[0241] (where q, r, R.sup.8, R.sup.9 and R.sup.10 are the same as
defined in the above Formula (A) described in Aspect [1-13-c]; and
G.sub.1, G.sub.2, G.sub.3, and G.sub.4 are a .dbd.CH-- group, a
.dbd.CR.sup.9-- group, or a nitrogen atom (with the proviso that
when G.sub.1 is a nitrogen atom, G.sub.2 and G.sub.3 are a
.dbd.CH-- group or a .dbd.CR.sup.9-- group)).
[0242] In Formula (A1a), Formula (A1b), or Formula (A1c), when the
position of the single bond of the phenyl group (the binding
position with the linker moiety containing X) is determined as
1-position, R.sup.10 can be bonded at 2-position, 4-position,
5-position, or 6-position. The binding position of R.sup.9 is any
positions at which it can be optionally bonded in the ring
including G.sub.1 or G.sub.4.
[0243] Formula (A) is more preferably Formula (A1a) or Formula
(A1c).
[0244] [1-13-c-3-2] In Formula (A1a), preferably, G.sub.1 is a
.dbd.CH-- group or a .dbd.CR.sup.9 group; and G.sub.2 and G.sub.3
are independently a .dbd.CH-- group, a .dbd.CR.sup.9-- group, or a
nitrogen atom. More preferably, G.sub.1 and G.sub.3 are
independently a .dbd.CH-- group or a .dbd.CR.sup.9-- group; and
G.sub.2 is a .dbd.CH-- group, a .dbd.CR.sup.9-- group, or a
nitrogen atom.
[0245] In Formula (A1c), preferably, G.sub.1 is a .dbd.CH-- group
or a .dbd.CR.sup.9-- group; and G.sub.2 and G.sub.3 are
independently a .dbd.CH-- group, a .dbd.CR.sup.9-- group or a
nitrogen atom. More preferably, G.sub.1 and G.sub.3 are
independently a .dbd.CH-- group or a .dbd.CR.sup.9-- group; and
G.sub.2 is a .dbd.CH-- group, a .dbd.CR.sup.9-- group, or a
nitrogen atom.
[0246] [1-13-c-4] More specifically, Formula (A) is preferably
Formula (A), Formula (A)-1, Formula (A1), Formula (A2), Formula
(A1)-1, Formula (A2)-1, Formula (A1a), Formula (A1b), or Formula
(A1c) in which r is 0 or 1. When r is not 0, at least one of the
binding positions of R.sup.10 is preferably 2-position, and when r
is 1, the binding position of R.sup.10 is preferably
2-position.
[0247] [1-13-c-5] More specifically, Formula (A) is preferably
Formula (A), Formula (A)-1, Formula (A1), Formula (A2), Formula
(A1)-1, Formula (A2)-1, Formula (A1a), Formula (A1b), or Formula
(A1c) in which q is an integer of 0 to 3, more preferably Formula
(A), Formula (A)-1, Formula (A1), Formula (A2), Formula (A1)-1,
Formula (A2)-1, Formula (A1a), Formula (A1b), or Formula (A1c) in
which q is an integer of 1 to 3. Preferably, any one of q and s is
1 or more.
[0248] [1-13-c-5-1] In Formula (A1a), when the binding position of
the ring containing G.sub.1 with 3-position of the phenyl group is
determined as 1'-position, the binding position of R.sup.9 when q
is 1 is preferably 2'-position (with the proviso that the case
where G.sub.1 is a nitrogen atom is excluded) or 6'-position. The
binding positions of R.sup.9s when q is 2 are preferably
2'-position and 6'-position, 2'-position and 5'-position, or
5'-position and 6'-position (with the proviso that the case where
the binding position is a nitrogen atom is excluded), and more
preferably, 2'-position and 6'-position or 2'-position and
5'-position. The binding positions of R.sup.9 when q is 3 are
preferably 2'-position, 5'-position, and 6'-position (with the
proviso that the case where the binding position is a nitrogen atom
is excluded).
[0249] In Formula (A1c), when the binding position of the ring
containing G.sub.1 with 3-position of the phenyl group is
determined as 1'-position, the binding position of R.sup.9 when q
is 1 is preferably 2'-position (with the proviso that the case
where G.sub.1 is a nitrogen atom is excluded) or 6'-position. The
binding positions of R.sup.9s when q is 2 are preferably
2'-position and 6'-position, 2'-position and 5'-position,
2'-position and 4'-position, 4'-position and 6'-position, or
5'-position and 6'-position (with the proviso that the case where
the binding position is a nitrogen atom is excluded), and more
preferably, 2'-position and 6'-position, 2'-position and
5'-position, or 2'-position and 4'-position. The binding positions
of R.sup.9s when q is 3 are preferably 2'-position, 5'-position and
6'-position, or 2'-position, 4'-position and 6'-position, or
2'-position, 4'-position and 5'-position (with the proviso that the
case where the binding position is a nitrogen atom is
excluded).
[0250] [1-13-c-6] In Formula (Ala), r is preferably 0 or 1. When r
is 1, the binding position of R.sup.10 is preferably 2-position.
When G.sub.1 is a .dbd.CH-- group or a .dbd.CR.sup.9-- group,
G.sub.2 is a .dbd.CH-- group or a nitrogen atom, G.sub.3 is a
.dbd.CH-- group, and q is 1 or 2, the binding position(s) of
R.sup.9(s) is more preferably 2'-position and/or 6'-position.
[0251] In Formula (A1c), r is preferably 0 or 1. When r is 1, the
binding position of R.sup.10 is preferably 2-position. When G.sub.1
is a .dbd.CH-- group or a .dbd.CR.sup.9-- group, G.sub.2 is a
.dbd.CH-- group or a nitrogen atom, G.sub.3 is a .dbd.CH-- group,
and q is 1 or 2, the binding position(s) of R.sup.9(s) is more
preferably 2'-position and/or 6'-position.
[0252] [1-13-c-7] In Formula (A), Formula (A)-1, Formula (A1),
Formula (A2), Formula (A1)-1, Formula (A2)-1, Formula (A1a), or
Formula (A1b), R.sup.8s are independently a C.sub.1-6 alkoxy group
which is substituted with 1 to 5 substituent(s) Ma, a C.sub.2-6
alkenyloxy group which is substituted with 1 to 5 substituent(s)
Ma, a C.sub.2-6 alkynyloxy group which is substituted with 1 to 5
substituent(s) Ma, a --CONR.sup.dR.sup.e2 group, an aralkyloxy
group, a non-aromatic heterocyclic oxy group (the heterocyclic oxy
group is optionally substituted with 1 to 2 oxo group(s)), or a
non-aromatic heterocyclic carbonyl group (the heterocyclic carbonyl
group is optionally substituted with 1 to 2 oxo group(s)); the
substituents Ma are independently a halogen atom, --OH, a C.sub.1-6
alkoxy group, a non-aromatic heterocyclic group (the heterocyclic
group is optionally substituted with 1 to 3 --OH, 1 to 3 C.sub.1-6
alkyl group(s), or 1 to 3 oxo group(s)), a --S(O).sub.iR.sup.a (i
is an integer of 0 to 2) group, a --NR.sup.b1R.sup.c1 group, a
--SO.sub.2NR.sup.dR.sup.e group, and a --CONR.sup.dR.sup.e group;
and Re.sup.2 is a C.sub.1-6 alkyl group (the C.sub.1-6 alkyl group
is optionally substituted with 1 to 5 halogen atom(s), 1 to 5 --OH,
1 to 5 C.sub.1-6 alkoxy group(s), 1 to 5 non-aromatic heterocyclic
group(s) (the heterocyclic group is optionally substituted with 1
to 3 --OH, 1 to 3 C.sub.1-6 alkyl group(s), or 1 to 3 oxo
group(s)), 1 to 5 --S(O).sub.iR.sup.a (i is an integer of 0 to 2)
group(s), 1 to 5 --SO.sub.2NR.sup.dR.sup.e group(s), 1 to 5
--CONR.sup.dR.sup.e group(s), or 1 to 5 --NR.sup.b1R.sup.c1
group(s)).
[0253] [1-13-c-7-1] More preferable examples of R.sup.8 include a
C.sub.1-6 alkoxy group (the alkoxy group is substituted with 1 to 5
group(s) optionally selected from --OH, a C.sub.1-6 alkoxy group, a
non-aromatic heterocyclic group (the heterocyclic group is
optionally substituted with 1 to 2 --OH, 1 to 2 C.sub.1-4 alkyl
group(s), or 1 to 2 oxo group(s)), a --S(O).sub.iR.sup.a (i is an
integer of 0 to 2) group, a --NR.sup.b2R.sup.c2 group, a
--SO.sub.2NR.sup.dR.sup.e group, and a --CONR.sup.dR.sup.e group),
a --CONR.sup.d3R.sup.e3 group, an aralkyloxy group, a non-aromatic
heterocyclic oxy group (the heterocyclic oxy group is optionally
substituted with 1 to 2 oxo group(s)), and a non-aromatic
heterocyclic carbonyl group (the heterocyclic carbonyl group is
optionally substituted with 1 to 2 oxo group(s)); R.sup.b2 and
R.sup.c2 are independently a group optionally selected from a
hydrogen atom, a C.sub.1-6 alkyl group, a C.sub.2-7 alkanoyl group
(the alkanoyl group is optionally substituted with --OH or a
C.sub.1-6 alkoxy group), and a C.sub.1-6 alkylsulfonyl group, where
R.sup.b2 and R.sup.c2 optionally form, together with a nitrogen
atom to which they are bonded, a 3- to 8-membered cyclic group, and
in the cyclic group, one carbon atom is optionally substituted with
a carbonyl group; and R.sup.d3 is a hydrogen atom or a C.sub.1-4
alkyl group, and R.sup.e3 is a C.sub.1-6 alkyl group (the C.sub.1-6
alkyl group is substituted with 1 to 5 group(s) optionally selected
from --OH, a C.sub.1-6 alkoxy group, a non-aromatic heterocyclic
group (the heterocyclic group is optionally substituted with 1 to 2
--OH, 1 to 2 C.sub.1-4 alkyl group(s), or 1 to 2 oxo group(s)), and
a --S(O).sub.iR.sup.a (i is an integer of 0 to 2).
[0254] [1-13-c-7-2] Further preferable examples of R.sup.8 include
a C.sub.1-6 alkoxy group (the alkoxy group is substituted with 1 to
5 --OH, 1 to 5 methoxy, 1 to 5 ethoxy, 1 to 5
4-hydroxy-1,1-dioxidotetrahydro-2H-thiopyran-4-yl, 1 to 5
3-methyloxetane-3-yl, 1 to 5 methylsulfonyl, 1 to 5 ethylsulfonyl,
1 to 5 --NH.sub.2, 1 to 5 acetylamino, 1 to 5 methylsulfonylamino,
1 to 5 2-oxo-1-pyrrolidinyl, 1 to 5 5-oxo-2-pyrrolidinyl, 1 to 5
sulfamoyl, 1 to 5 methylsulfamoyl, 1 to 5 dimethylsulfamoyl, 1 to 5
carbamoyl, 1 to 5 methylcarbamoyl, or 1 to 5 dimethylcarbamoyl), a
--CONR.sup.d4R.sup.c4 group (R.sup.d4 is a hydrogen atom or a
C.sub.1-4 alkyl group; and R.sup.e4 is a C.sub.1-6 alkyl group (the
C.sub.1-6 alkyl group is substituted with 1 to 5 --OH, 1 to 5
methoxy, 1 to 5 ethoxy, 1 to 5
4-hydroxy-1,1-dioxidotetrahydro-2H-thiopyran-4-yl, 1 to 5
3-methyloxetane-3-yl, 1 to 5 methylsulfonyl, 1 to 5 ethylsulfonyl,
1 to 5 --NH.sub.2, 1 to 5 acetylamino, 1 to 5 methylsulfonylamino,
1 to 5 2-oxo-1-pyrrolidinyl, 1 to 5 5-oxo-2-pyrrolidinyl, 1 to 5
sulfamoyl, 1 to 5 methylsulfamoyl, 1 to 5 dimethylsulfamoyl, 1 to 5
carbamoyl, 1 to 5 methylcarbamoyl, or 1 to 5 dimethylcarbamoyl),
benzyloxy, (1,1-dioxidotetrahydro-2H-thiopyran-4-yl)oxy, and
(pyrrolidine-1-yl)carbonyl. The substitution number of --OH,
methoxy, ethoxy, 4-hydroxy-1,1-dioxidotetrahydro-2H-thiopyran-4-yl,
3-methyloxetane-3-yl, methylsulfonyl, ethylsulfonyl, --NH.sub.2,
acetylamino, methylsulfonylamino, 2-oxo-1-pyrrolidinyl,
5-oxo-2-pyrrolidinyl, sulfamoyl, methylsulfamoyl,
dimethylsulfamoyl, carbamoyl, methylcarbamoyl, or dimethylcarbamoyl
in the C.sub.1-6 alkoxy group as R.sup.8 or the C.sub.1-6 alkyl
group as R.sup.e4 is particularly preferably 1 to 2.
[0255] More specifically, R.sup.8 is 2-hydroxyethoxy,
3-hydroxypropoxy, 3-hydroxybutoxy, 3-hydroxy-3-methylbutoxy,
2,3-dihydroxypropoxy, (2R)-2,3-dihydroxypropoxy,
(2S)-2,3-dihydroxypropoxy, (3S)-3-hydroxybutoxy,
(3R)-3-hydroxybutoxy, 3-hydroxy-2-hydroxymethylpropoxy,
3-hydroxy-2-hydroxymethyl-2-methylpropoxy, 2-ethoxyethoxy,
(4-hydroxy-1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methoxy,
(3-methyloxetane-3-yl)methoxy, 2-methylsulfonyl-ethoxy,
3-methylsulfonyl-propoxy, 2-ethylsulfonyl-ethoxy,
3-ethylsulfonyl-propoxy, 2-aminoethoxy, 3-aminopropoxy,
2-acetylamino-ethoxy, 3-acetylamino-propoxy,
2-methylsulfonylamino-ethoxy, 3-methylsulfonylamino-propoxy,
2-(2-oxo-1-pyrrolidinyl)ethoxy, 3-(2-oxo-1-pyrrolidinyl)propoxy,
(5-oxo-2-pyrrolidinyl)methoxy, 2-sulfamoyl-ethoxy,
3-sulfamoyl-propoxy, 2-methylsulfamoyl-ethoxy,
3-methylsulfamoyl-propoxy, 2-dimethylsulfamoyl-ethoxy,
3-dimethylsulfamoyl-propoxy, 2-carbamoyl-ethoxy,
3-carbamoyl-propoxy, 2-methylcarbamoyl-ethoxy,
3-methylcarbamoyl-propoxy, 2-dimethylcarbamoyl-ethoxy,
3-dimethylcarbamoyl-propoxy, N-(2-hydroxyethyl)carbamoyl,
N-(2-methoxyethyl)carbamoyl, N-(2-hydroxyethyl)-N-methylcarbamoyl,
N-(2-methoxyethyl)-N-methylcarbamoyl,
N-(2-methylsulfonyl-ethyl)carbamoyl,
N-(2-methylsulfonyl-ethyl)-N-methylcarbamoyl,
(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)oxy, benzyloxy,
(pyrrolidine-1-yl)carbonyl, or the like.
[0256] The C.sub.1-6 alkoxy group or the heterocyclic oxy group
which are substituted with a group of A in Formula (I) or the like
in WO 2010/143733 pamphlet, particularly the C.sub.1-6 alkoxy
groups substituted with (2) to (8) which are shown in [9](c) in pp.
25 and 26 or the heterocyclic oxy group shown in [9](e), and these
groups shown in Examples can also be referred to as specific
examples of R.sup.8 of the present specification. Similarly,
formulae and the corresponding groups shown in Examples in the
pamphlets below can also be referred to as specific examples of
R.sup.8 of the present specification.
WO 2008/001931 pamphlet, a group of R.sup.1--X--O-- in Formula (I);
WO 2010/123017 pamphlet, a group of R.sup.7 in Formula (I); WO
2010/123016 pamphlet, a group of R.sup.10 in Formula (I); WO
2009/054423 pamphlet, groups of A and B in Formula (II).
[0257] [1-13-c-8] In Formula (A), Formula (A)-1, Formula (A1),
Formula (A2), Formula (A1)-1, Formula (A2)-1, Formula (A1a),
Formula (A1b), or Formula (A1c), preferable examples of R.sup.9s
independently include a halogen atom, a cyano group, a C.sub.1-4
alkyl group (the C.sub.1-4 alkyl group is optionally substituted
with 1 to 5 halogen atom(s) or 1 to 5 --OH), a C.sub.2-4 alkenyl
group, a C.sub.1-4 alkoxy group (the C.sub.1-4 alkoxy group is
optionally substituted with 1 to 5 halogen atom(s)), a C.sub.2-5
alkanoyl group, a --S(O).sub.iR.sup.a (R.sup.a is a C.sub.1-4 alkyl
group) group, a --CONR.sup.dR.sup.e (R.sup.d and R.sup.e are
independently a hydrogen atom or a C.sub.1-4 alkyl group) group,
and a --NR.sup.b1R.sup.c1 group (R.sup.b1 and R.sup.c1 form,
together with a nitrogen atom to which they are bonded, a 3- to
8-membered cyclic group; and in the cyclic group, one or two carbon
atom(s) is(are) optionally substituted with an atom optionally
selected from an oxygen atom, a sulfur atom, and a nitrogen atom or
with a carbonyl group).
[0258] More preferably, R.sup.9s are independently a halogen atom,
a cyano group, a C.sub.1-4 alkyl group (the C.sub.1-4 alkyl group
is optionally substituted with 1 to 5 halogen atom(s) or 1 to 5
--OH), a C.sub.2-3 alkenyl group, a C.sub.1-4 alkoxy group (the
C.sub.1-4 alkoxy group is optionally substituted with 1 to 5
halogen atom(s)), a C.sub.2-3 alkanoyl group, a --S(O).sub.iR.sup.a
(R.sup.a is a C.sub.1-2 alkyl group) group, a --CONR.sup.dR.sup.e
(R.sup.d and R.sup.e are independently a hydrogen atom or a
C.sub.1-2 alkyl group) group, or a --NR.sup.b1R.sup.c1 group
(R.sup.b1 and R.sup.c1 form, together with a nitrogen atom to which
they are bonded, a 3- to 6-membered cyclic group; and in the cyclic
group, one or two carbon atom(s) is(are) optionally substituted
with an oxygen atom, a nitrogen atom, or a carbonyl group). Further
preferably, R.sup.9s are independently a halogen atom, a cyano
group, a C.sub.1-4 alkyl group which is optionally substituted with
1 to 5 halogen atom(s), or a C.sub.1-4 alkoxy group which is
optionally substituted with 1 to 5 halogen atom(s).
[0259] More specific examples of R.sup.9 include a fluorine atom, a
chlorine atom, a bromine atom, cyano, methyl, ethyl, propyl,
isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, trifluoromethyl,
hydroxymethyl, 2-hydroxyethyl, methoxy, ethoxy, propoxy,
isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy,
cyclopropylmethoxy, trifluoromethoxy, trifluoroethoxy, vinyl,
acetyl, methylsulfonyl, carbamoyl, methylcarbamoyl,
dimethylcarbamoyl, 1-piperidinyl, 4-morpholinyl, and
2-oxooxazolidin-3-yl. More preferable examples of R.sup.9 include a
fluorine atom, cyano, methyl, ethyl, methoxy, and ethoxy.
[0260] The amino group, the C.sub.1-6 alkylthio group, the
C.sub.1-6 alkyl group, the C.sub.3-10 cycloalkyl group, or the
C.sub.1-6 alkoxy group which are substituted with a group of A in
Formula (I) or the like in WO 2010/143733 pamphlet, particularly
the C.sub.1-6 alkyl group and the halogenated C.sub.1-6 alkyl group
which are shown in [9](b) in pp. 25 and 26 or the C.sub.1-6 alkoxy
group which is optionally substituted with (1) shown in [9](c), and
the corresponding groups shown in Examples can also be referred to
as specific examples of R.sup.9 of the present specification.
Similarly, formulae and the corresponding groups shown in Examples
in the pamphlets below can also be referred to as specific examples
of R.sup.9 of the present specification.
WO 2008/001931 pamphlet, groups of R.sup.2, R.sup.3, R.sup.4, and
R.sup.5 in Formula (I); WO 2010/123017 pamphlet, groups of R.sup.5,
R.sup.6, R.sup.7, and R.sup.Y in Formula (I); WO 2010/123016
pamphlet, groups of R.sup.8, R.sup.9, R.sup.10, and R.sup.Y in
Formula (I); WO 2009/054423 pamphlet, groups of R.sup.3, R.sup.4,
A, and B in Formula (II) and Formula (III).
[0261] [1-13-c-9] In Formula (A), Formula (A)-1, Formula (A1),
Formula (A2), Formula (A1)-1, Formula (A2)-1, Formula (A1a),
Formula (A1b), or Formula (A1c), preferable examples of R.sup.10s
independently include a halogen atom, a C.sub.1-4 alkyl group which
is optionally substituted with 1 to 5 halogen atom(s), and a
C.sub.1-4 alkoxy group which is optionally substituted with 1 to 5
halogen atom(s). More specific examples of R.sup.10 include a
fluorine atom, a chlorine atom, a bromine atom, methyl, ethyl,
propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl,
trifluoromethyl, methoxy, ethoxy, propoxy, isopropoxy, butoxy,
isobutoxy, sec-butoxy, tert-butoxy, and trifluoromethoxy. More
preferable examples of R.sup.10 include a fluorine atom, methyl,
ethyl, methoxy, and ethoxy.
[0262] [1-13-c-10] The preferable aspects of q, s, the ring A',
R.sup.8, and R.sup.9 of the Partial Structural Formula (A'):
##STR00017##
[0263] (where q, s, the ring A', R.sup.8, and R.sup.9 are the same
as defined in Formula (A) in Aspect [1-13-c]) in Formula (A),
Formula (A1), and Formula (A2) are the same as the preferable
aspects described in Aspects [1-13-c-2], [1-13-c-3], [1-13-c-5],
[1-13-c-7], [1-13-c-7-1], [1-13-c-7-2], or [1-13-c-8]. Examples of
the preferable aspect of Formula (A') include the same groups as
the groups having an aryl group or a heteroaryl group among the
preferable aspects of L described in Aspect [1-1-d]. Specific
examples of Formula (A') include specific examples of the "aryl
group which is optionally substituted with 1 to 5 substituent(s)
RII" or the same groups as the groups having a heteroaryl group
among specific examples of the "heterocyclic group which is
optionally substituted with 1 to 5 substituent(s) RII" that are
described in Aspect [1]. More specific examples of Formula (A')
include the same groups as the groups having benzene, naphthalene,
pyridine, pyrimidine, thiophene, quinoline, benzimidazole, or
dibenzofuran.
[0264] Specific examples of the ring A'' moiety having
(R.sup.8).sub.s and (R.sup.9).sub.q in Formula (A)-1, Formula
(A1)-1, and Formula (A2)-1 include the same groups as the groups
having a benzene ring, a pyridine ring, or a pyrimidine ring among
specific examples of the "aryl group which is optionally
substituted with 1 to 5 substituent(s) RII" and specific examples
of the "heterocyclic group which is optionally substituted with 1
to 5 substituent(s) RII" that are described in Aspect [1].
[0265] Specific examples of the ring moiety having R.sup.8 and
(R.sup.9).sub.q in Formula (A1a), Formula (A1b), and Formula (A1c)
include the groups having a benzene ring, a pyridine ring, or a
pyrimidine ring and having any group of R.sup.8 at the p-position
or the m-position or not having any group of R.sup.8 among specific
examples of the "aryl group which is optionally substituted with 1
to 5 substituent(s) RII" and specific examples of the "heterocyclic
group which is optionally substituted with 1 to 5 substituent(s)
RII" that are described in Aspect [1]. For example in Formula
(Ala), specific examples of the ring moiety having R.sup.8 and
(R.sup.9).sub.q include a phenyl group having any group of R.sup.8
at 4-position (such as 4-(3-hydroxy-3-methylbutoxy)phenyl) and a
3-pyridinyl group having any group of R.sup.8 at 6-position (such
as 6-(3-methylsulfonyl-propoxy)pyridin-3-yl) and further include
also a group having simultaneously any groups of R.sup.9 (such as
4-(2-ethoxy-ethoxy)-2,6-dimethylphenyl and
6-((1,1-dioxidetetrahydro-2H-thiopyran-4-yl)oxy)-2-methylpyridin-3-yl).
[0266] Specific examples of the ring A' moiety having
(R.sup.8).sub.s and (R.sup.9).sub.q of the present specification
also include the groups of A in Formula (I) or the like in WO
2010/143733 pamphlet and the groups of Q in Formula (V) in WO
2007/033002 pamphlet, particularly the groups having a cyclic group
among the corresponding groups shown in Examples of these
pamphlets. Similarly, also the corresponding groups shown in
formulae and Examples in the pamphlets below can be referred to as
the specific examples of the ring A' moiety having (R.sup.8).sub.s
and (R.sup.9).sub.q of the present specification.
WO 2008/001931 pamphlet, phenyl groups having R.sup.1--X--O--,
R.sup.2, R.sup.3, R.sup.4, and R.sup.5 in Formula (I); WO
2010/123017 pamphlet, 6-membered cyclic groups having R.sup.5,
R.sup.6, and R.sup.7 in Formula (I); WO 2010/123016 pamphlet,
6-membered cyclic groups having R.sup.8, R.sup.9, and R.sup.10 in
Formula (I); WO 2009/054423 pamphlet, groups of Formula (II) and
Formula (III).
[0267] That is, 4-(3-methylsulfonyl-propoxy)-2,6-dimethylphenyl,
4-((1,1-dioxidetetrahydro-2H-thiopyran-4-yl)oxy)-2,6-dimethylphenyl,
2-(4-morpholino)-4,6-dimethylpyrimidin-5-yl,
2-ethyl-6,7-difluoro-1H-benzimidazol-1-yl,
2-ethoxy-6,7-difluoro-1H-benzimidazol-1-yl, and the like are
mentioned.
[0268] [1-13-c-11] Preferable examples of the ring A in Formula
(I), Formula (A), Formula (A)-1, Formula (A1), Formula (A1)-1, or
Formula (A1c) include Formula (A1)-1-1:
##STR00018##
[0269] (where W, Y, and Z are .dbd.CH-- or a nitrogen atom (with
the proviso that 0 or 1 of W, Y, and Z is a nitrogen atom, and when
R.sup.9c is a fluorine atom, Z is .dbd.CH--);
R.sup.9c is a hydrogen atom, a fluorine atom, a chlorine atom, a
trifluoromethyl group, or a C.sub.1-6 alkoxy group; R.sup.9d is a
hydrogen atom, a fluorine atom, a chlorine atom, --OH, a C.sub.1-4
alkyl group, a C.sub.1-3 alkoxy group, or a C.sub.1-2 alkylthio
group; R.sup.10a is a C.sub.1-10 alkyl group (the C.sub.1-10 alkyl
group is optionally substituted with 1 to 4 halogen atom(s), 1 to 4
--OH, or 1 to 4 C.sub.1-4 alkoxy group (the C.sub.1-4 alkoxy group
is optionally substituted with 1 to 4 halogen atom(s), 1 to 4 --OH,
or 1 to 4 C.sub.1-2 alkoxy group)), a C.sub.2-10 alkenyl group (the
C.sub.2-10 alkenyl group is optionally substituted with 1 to 4
halogen atom(s), 1 to 4 --OH, or 1 to 4 C.sub.1-4 alkoxy group(s)
(the C.sub.1-4 alkoxy group is optionally substituted with 1 to 4
halogen atom(s), 1 to 4 --OH, or 1 to 4 C.sub.1-2 alkoxy
group(s))), a C.sub.1-10 alkoxy group (the C.sub.1-10 alkoxy group
is optionally substituted with 1 to 4 halogen atom(s), 1 to 4 --OH,
or 1 to 4 C.sub.1-2 alkoxy group(s)), or a C.sub.2-10 alkenyloxy
group (the C.sub.2-10 alkenyloxy group is optionally substituted
with 1 to 4 halogen atom(s), 1 to 4 --OH, or 1 to 4 C.sub.1-2
alkoxy group(s)); and R.sup.10b, R.sup.10c, and R.sup.10d are
independently a hydrogen atom, a fluorine atom, a chlorine atom, a
C.sub.1-4 alkyl group, or a C.sub.1-4 alkoxy group).
[0270] In Formula (A1)-1-1, preferable examples of R.sup.10a
include Formula (R.sup.10a'):
##STR00019##
[0271] (where R.sup.10a1, R.sup.10a2, and R.sup.10a3 are
independently a hydrogen atom, a fluorine atom, or a C.sub.1-4
alkyl group; at least two of R.sup.10a1, R.sup.10a2, and R.sup.10a3
are other than a hydrogen atom; and R.sup.10a1, R.sup.10a2, and
R.sup.10a3 optionally form, together with a carbon atom to which
they are bonded, a 3- to 8-membered cyclic group). Preferably, all
of R.sup.10a1, R.sup.10a2, and R.sup.10a3 are a methyl group, or
R.sup.10a1, R.sup.10a2, and R.sup.10a3 form a cyclopropyl
group.
[0272] In Formula (A1)-1-1, W, Y, and Z are preferably .dbd.CH--,
R.sup.9c is preferably a fluorine atom or a butoxy group, R.sup.9d
is preferably a methoxy group, and R.sup.10b, R.sup.10c, and
R.sup.10d are preferably a hydrogen atom.
[0273] Specific examples of Formula (A1)-1-1 include
6-(1,1-dimethylethyl)-2'-fluoro-5'-methoxy-1,1'-biphenyl-3-yl and
2'-butoxy-6-(1,1-dimethylethyl)-5'-methoxy-1,1'-biphenyl-3-yl.
[0274] [1-13-c-12] Preferable examples of the ring A in Formula
(I), Formula (A), Formula (A)-1, Formula (A1), or Formula (A1)-1
include Formula (A1)-1-2:
##STR00020##
(where W, Y, Z, R.sup.9c, R.sup.9d, R.sup.10a, R.sup.10b,
R.sup.10c, and R.sup.10d are the same as defined in Formula
(A1)-1-1 described in Aspect [1-13-c-11]).
[0275] In Formula (A1)-1-2, an alkyl chain or an alkenyl chain of
R.sup.10a is a linear, branched, or cyclic chain and also includes
a linear chain or branched chain group substituted with a cyclic
group and a cyclic group substituted with a linear chain or
branched chain group. When R.sup.10a is a C.sub.1-10 alkyl group,
specific examples of R.sup.10a include Formula (R.sup.10a)
described in Aspect [1-13-c-11]. More specific examples of
R.sup.10a include 1,1-dimethylethyl(tert-butyl),
2,2-dimethylcyclopentyl, 5,5-dimethylcyclopent-1-enyl,
2,2-dimethyl-1-hydroxypropyl, and 2,2-dimethyl-1-methoxypropyl.
Specific examples of R.sup.10a of the present specification also
include a group of A in Formula I in WO 2009/048527 pamphlet, a
group of A in Formula I and Formula III in WO 2009/111056 pamphlet,
and a group of A in Formula I'A in WO 2010/045258 pamphlet,
particularly the corresponding groups shown in Examples.
[0276] In Formula (A1)-1-2, W and Z are preferably .dbd.CH--,
R.sup.9c is preferably a fluorine atom, R.sup.9d is preferably a
methoxy group, R.sup.10b and R.sup.10d are preferably a hydrogen
atom, and R.sup.10c is preferably a hydrogen atom or a fluorine
atom.
[0277] Specific examples of Formula (A1)-1-2 include
2-(1,1-dimethylethyl)-2'-fluoro-5'-methoxy-1,1'-biphenyl-4-yl,
2-(2,2-dimethylcyclopentyl)-2'-fluoro-5'-methoxy-1,1'-biphenyl-4-yl,
and
2-(2,2-dimethyl-1-methoxypropyl)-2'-fluoro-5'-methoxy-1,1'-biphenyl-4-yl.
[0278] [1-13-d] The ring A in Formula (I) according to Aspect [I]
is preferably Partial Structural Formula (AA):
##STR00021##
[0279] (where f is an integer of 0 to 2; g is an integer of 1 to 4;
q1 is an integer of 0 to 3; q2 is 0 or 1; r1 is an integer of 0 to
2 (with the proviso that q1+q2+r1 is an integer of 0 to 5); the
ring A''' is a benzene ring or a pyridine ring;
T is --CH.sub.2--, an oxygen atom, --S(O).sub.i-- (i is an integer
of 0 to 2), or --NR.sup.7--(R.sup.7 is the same as R.sup.7 defined
in Formula (I)); R.sup.13s are independently a group optionally
selected from a halogen atom, --OH, a cyano group, a C.sub.1-10
alkyl group which is optionally substituted with 1 to 5
substituent(s) RI, a C.sub.2-10 alkenyl group which is optionally
substituted with 1 to 5 substituent(s) RI, a C.sub.2-10 alkynyl
group which is optionally substituted with 1 to 5 substituent(s)
RI, a C.sub.1-10 alkoxy group which is optionally substituted with
1 to 5 substituent(s) RI, a C.sub.2-10 alkenyloxy group which is
optionally substituted with 1 to 5 substituent(s) RI, a C.sub.2-10
alkynyloxy group which is optionally substituted with 1 to 5
substituent(s) RI, --SH, a --S(O).sub.iR.sup.a (i is an integer of
0 to 2) group, and a --NR.sup.bR.sup.c group; R.sup.13a is a group
optionally selected from an aryl group which is optionally
substituted with 1 to 5 substituent(s) RII, a heterocyclic group
which is optionally substituted with 1 to 5 substituent(s) RII, an
aralkyl group which is optionally substituted with 1 to 5
substituent(s) RII, a heteroarylalkyl group which is optionally
substituted with 1 to 5 substituent(s) RII, a non-aromatic
heterocyclic alkyl group which is optionally substituted with 1 to
5 substituent(s) RII, an aryloxy group which is optionally
substituted with 1 to 5 substituent(s) RII, a heteroaryloxy group
which is optionally substituted with 1 to 5 substituent(s) RII, a
non-aromatic heterocyclic oxy group which is optionally substituted
with 1 to 5 substituent(s) RII, an aralkyloxy group which is
optionally substituted with 1 to 5 substituent(s) RII, a
heteroarylalkyloxy group which is optionally substituted with 1 to
5 substituent(s) RII, and a substituted spiropiperidinylmethyl
group; R.sup.14s are independently a group optionally selected from
a halogen atom, --OH, a cyano group, a C.sub.1-6 alkyl group which
is optionally substituted with 1 to 5 substituent(s) RI, a
C.sub.2-6 alkenyl group which is optionally substituted with 1 to 5
substituent(s) RI, a C.sub.2-6 alkynyl group which is optionally
substituted with 1 to 5 substituent(s) RI, a C.sub.1-6 alkoxy group
which is optionally substituted with 1 to 5 substituent(s) RI,
--SH, a --S(O).sub.iR.sup.a (i is an integer of 0 to 2) group, and
a --NR.sup.bR.sup.c group; and R.sup.a, R.sup.b, R.sup.c, the
substituent RI, and the substituent RII are the same as defined in
Formula (I)). In Formula (AA), the binding positions of the linker
moiety containing X and R.sup.14s are any positions at which they
can be optionally bonded in the ring containing T, and the binding
positions of R.sup.13 and R.sup.13a are any positions at which they
can be optionally bonded in the ring A'''.
[0280] [1-13-d-1] Specific examples of Formula (AA) include Formula
(AA)-1:
##STR00022##
[0281] (where f, g, q1, r1, the ring A''', T, R.sup.13, and
R.sup.14 are the same as defined in Formula (AA) described in
Aspect [1-13-d]; and q, s, the ring A', V, R.sup.8, and R.sup.9 are
the same as defined in Formula (A) described in Aspect [1-13-c]).
In Formula (AA)-1, the binding positions of the linker moiety
containing X and R.sup.14s are any positions at which they can be
optionally bonded in the ring containing T; the binding positions
of the ring A'-V-- and R.sup.13 are any positions at which they can
be optionally bonded in the ring A'''; and the binding positions of
R.sup.8 and R.sup.9 are any positions at which they can be
optionally bonded in the ring A'.
[0282] The Formula (AA)-1 is preferably a Formula (AA)-1 in which
the ring A' is a benzene ring, a pyridine ring, or a pyrimidine
ring. That is, preferable examples of Formula (AA)-1 include
Formula (AA)-1-1:
##STR00023##
[0283] (where f, g, q1, r1, the ring A''', T, R.sup.13, and
R.sup.14 are the same as defined in Formula (AA) described in
Aspect [1-13-d]; q, s, V, R.sup.8, and R.sup.9 are the same as
defined in Formula (A) described in Aspect [1-13-c]; and the ring
A'' is the same as defined in Formula (A)-1 described in Aspect
[1-13-c]).
[0284] [1-13-d-2] In Formula (AA), Formula (AA)-1, or Formula
(AA)-1-1, the ring A''' is preferably a benzene ring.
[0285] [1-13-d-3] In Formula (AA), Formula (AA)-1, or Formula
(AA)-1-1, f is preferably 0 or 1, more preferably 0. g is
preferably 2 or 3, more preferably 2. Preferably, f is 0 and g is 2
or 3, and more preferably, f is 0 and g is 2.
[0286] [1-13-d-4] Specific examples of Formula (AA) include Formula
(AA1):
##STR00024##
[0287] (where q1, q2, r1, T, R.sup.13, R.sup.13a, and R.sup.14 are
the same as defined in Formula (AA) described in Aspect [1-13-d];
and the figures 1 to 7 indicate the binding position of a
substituent in the ring).
[0288] [1-13-d-4-1] In Formula (AA1), when the binding position of
the linker moiety containing X is determined as 1-position, the
substitution position of R.sup.13a is preferably 4-position or
5-position, more preferably 4-position.
[0289] [1-13-d-5] More specifically, Formula (AA), Formula (AA)-1,
Formula (AA)-1-1, or Formula (AA1) is preferably Formula
(AA1)-1:
##STR00025##
[0290] (where q1, r1, T, R.sup.13, and R.sup.14 are the same as
defined in Formula (AA) described in Aspect [1-13-d]; and q, s, the
ring A', V, R.sup.8, and R.sup.9 are the same as defined in Formula
(A) described in Aspect [1-13-c]).
[0291] [1-13-d-5-1] Specific examples of Formula (AA1)-1 include
Formula (AA1a)-1:
##STR00026##
[0292] (where q1, r1, R.sup.13, and R.sup.14 are the same as
defined in Formula (AA) described in Aspect [1-13-d]; and q, s, the
ring A', V, R.sup.8, and R.sup.9 are the same as defined in Formula
(A) described in Aspect [1-13-c]).
[0293] The Formula (AA1a)-1 is preferably a Formula (AA1a)-1 in
which the ring A' is a benzene ring, a pyridine ring, or a
pyrimidine ring. That is, preferable examples of Formula (AA1a)-1
include Formula (AA1a)-1-1:
##STR00027##
[0294] (where q1, r1, R.sup.13, and R.sup.14 are the same as
defined in Formula (AA) described in Aspect [1-13-d]; q, s, V,
R.sup.8, and R.sup.9 are the same as defined in Formula (A)
described in Aspect [1-13-c]; and the ring A'' is the same as
defined in Formula (A)-1 described in Aspect [1-13-c]).
[0295] [1-13-d-6] In Formula (AA), Formula (AA)-1, Formula
(AA)-1-1, Formula (AA1), or Formula (AA1)-1, T is preferably
--CH.sub.2-- or an oxygen atom.
[0296] [1-13-d-7] More specific examples of Formula (AA) or Formula
(AA1) include Formula (AA1b):
##STR00028##
[0297] (where q1, q2, r1, R.sup.13, R.sup.13a, and R.sup.14 are the
same as defined in Formula (AA) described in Aspect [1-13-d]; and
the figures 1 to 7 indicate the binding position of a substituent
in the ring).
[0298] [1-13-d-7-1] More specific examples of Formula (AA1)-1 or
Formula (AA1b) include Formula (AA1b)-1:
##STR00029##
[0299] (where q1, r1, R.sup.13, and R.sup.14 are the same as
defined in Formula (AA) described in Aspect [1-13-d]; and q, s, the
ring A', V, R.sup.8, and R.sup.9 are the same as defined in Formula
(A) described in Aspect [1-13-c]).
[0300] [1-13-d-8] In Formula (AA), Formula (AA)-1, Formula
(AA)-1-1, Formula (AA1), Formula (AA1)-1, Formula (AA1a)-1, Formula
(AA1a)-1-1, Formula (AA1b), or Formula (AA1b)-1, q1 is preferably 0
or 1, more preferably 0.
[0301] [1-13-d-9] In Formula (AA), Formula (AA1), or Formula
(AA1b), q2 is preferably 1.
[0302] [1-13-d-10] In Formula (AA), Formula (AA)-1, Formula
(AA)-1-1, Formula (AA1), Formula (AA1)-1, Formula (AA1a)-1, Formula
(AA1a)-1-1, Formula (AA1b), or Formula (AA1b)-1, r1 is preferably 0
or 1, more preferably 0.
[0303] [1-13-d-11] In Formula (AA), Formula (AA1), or Formula
(AA1b), preferable examples of R.sup.13a include a group optionally
selected from an aryl group which is optionally substituted with 1
to 5 substituent(s) RII, a heterocyclic group which is optionally
substituted with 1 to 5 substituent(s) RII, an aralkyl group which
is optionally substituted with 1 to 5 substituent(s) RII, a
non-aromatic heterocyclic alkyl group which is optionally
substituted with 1 to 5 substituent(s) RII, an aryloxy group which
is optionally substituted with 1 to 5 substituent(s) RII, a
heteroaryloxy group which is optionally substituted with 1 to 5
substituent(s) RII, a non-aromatic heterocyclic oxy group which is
optionally substituted with 1 to 5 substituent(s) RII, an
aralkyloxy group which is optionally substituted with 1 to 5
substituent(s) RII, and a substituted spiropiperidinylmethyl group
(the substituent RII is the same as defined in Aspect [1]).
[0304] [1-13-d-11-1] In Formula (AA), Formula (AA1), or Formula
(AA1b), more preferable examples of R.sup.13a include a group
optionally selected from an aryl group which is optionally
substituted with 1 to 5 substituent(s) RIIa, a heterocyclic group
which is optionally substituted with 1 to 5 substituent(s) RIIa, an
aralkyl group which is optionally substituted with 1 to 5
substituent(s) RIIa, a non-aromatic heterocyclic alkyl group which
is optionally substituted with 1 to 5 substituent(s) RIIa, an
aryloxy group which is optionally substituted with 1 to 5
substituent(s) RIIa, a heteroaryloxy group which is optionally
substituted with 1 to 5 substituent(s) RIIa, a non-aromatic
heterocyclic oxy group which is optionally substituted with 1 to 5
substituent(s) RIIa, an aralkyloxy group which is optionally
substituted with 1 to 5 substituent(s) RIIa, and a substituted
spiropiperidinylmethyl group (the substituent RIIa is the same as
defined in Aspect [1-1-d]). The number of substitutions by the
substituent RIIa is preferably 1 to 3.
[0305] [1-13-d-11-2] In Formula (AA), Formula (AA1), or Formula
(AA1b), more specific examples of R.sup.13a include the groups
specifically exemplified as the "aryl group which is optionally
substituted with 1 to 5 substituent(s) RII", the "heterocyclic
group which is optionally substituted with 1 to 5 substituent(s)
RII", the "aralkyl group which is optionally substituted with 1 to
5 substituent(s) RII", the "heteroarylalkyl group which is
optionally substituted with 1 to 5 substituent(s) RII", the
"non-aromatic heterocyclic alkyl group which is optionally
substituted with 1 to 5 substituent(s) RII", the "aryloxy group
which is optionally substituted with 1 to 5 substituent(s) RII",
the "heteroaryloxy group which is optionally substituted with 1 to
5 substituent(s) RII", the "non-aromatic heterocyclic oxy group
which is optionally substituted with 1 to 5 substituent(s) RII",
the "aralkyloxy group which is optionally substituted with 1 to 5
substituent(s) RII", the "heteroarylalkyloxy group which is
optionally substituted with 1 to 5 substituent(s) RII", the
"substituted spiropiperidinylmethyl group", and the like.
[0306] Specific examples of R.sup.13a of the present specification
also include the groups of A in Formula (II) in WO 2010/143733
pamphlet and the groups of Q in Formula (V) in WO 2007/033002
pamphlet, particularly the groups having a cyclic group among the
corresponding groups shown in Examples of these pamphlets.
[0307] [1-13-d-11-3] Specific examples of R.sup.13a include, in
addition to the Partial Structural Formula (A') described in Aspect
[1-13-c-10], a group in which Formula (A') is substituted with an
oxygen atom, a C.sub.1-6 alkyl group, or a C.sub.1-6 alkoxy group.
Particularly, when R.sup.13a is a group of Formula (A') or a group
in which Formula (A') is substituted with an oxygen atom (Formula
(A')-O--), R.sup.13a can be Formula (A')-V--. For example, a
Formula (AA) in which R.sup.13a is Formula (A') can be a Formula
(AA)-1 in which V is a single bond. A Formula (AA) in which
R.sup.13a is Formula (A')-O-- can be a Formula (AA)-1 in which V is
an oxygen atom.
[0308] In Formula (AA)-1, Formula (AA1)-1, Formula (AA1a)-1, or
Formula (AA1b)-1, more specific examples of the Formula (A')-V--
moiety when V is a single bond include the specific groups of the
Partial Structural Formula (A') described in Aspect [1-13-c-10],
that is, the same groups as specific examples of the "aryl group
which is optionally substituted with 1 to 5 substituent(s) RII", or
the groups having a heteroaryl group among specific examples of the
"heterocyclic group which is optionally substituted with 1 to 5
substituent(s) RII" that are described in Aspect [1]. More specific
examples of the Formula (A')-V-- moiety when V is an oxygen atom
include the groups in which the specific groups of the Partial
Structural Formula (A') described in Aspect [1-13-c-10] are
substituted with an oxygen atom, that is, the groups in which the
same groups as specific examples of the "aryl group which is
optionally substituted with 1 to 5 substituent(s) RII", or the
groups having a heteroaryl group among specific examples of the
"heterocyclic group which is optionally substituted with 1 to 5
substituent(s) RII", are substituted with an oxygen atom.
[0309] [1-13-d-12] In Formula (AA), Formula (AA)-1, Formula
(AA)-1-1, Formula (AA1), Formula (AA1)-1, Formula (AA1a)-1, Formula
(AA1a)-1-1, Formula (AA1b), or Formula (AA1b)-1, preferable
examples of R.sup.13 include a group optionally selected from a
halogen atom, a cyano group, a C.sub.1-6 alkyl group which is
optionally substituted with 1 to 5 substituent(s) RI, a C.sub.2-6
alkenyl group which is optionally substituted with 1 to 5
substituent(s) RI, a C.sub.2-6 alkynyl group which is optionally
substituted with 1 to 5 substituent(s) RI, a C.sub.1-6 alkoxy group
which is optionally substituted with 1 to 5 substituent(s) RI, a
C.sub.2-6 alkenyloxy group which is optionally substituted with 1
to 5 substituent(s) RI, a C.sub.2-6 alkynyloxy group which is
optionally substituted with 1 to 5 substituent(s) RI, and a
--NR.sup.bR.sup.c group (the substituent RI is the same as defined
in Aspect [1]).
[0310] [1-13-d-12-1] In Formula (AA), Formula (AA)-1, Formula
(AA)-1-1, Formula (AA1), Formula (AA1)-1, Formula (AA1a)-1, Formula
(AA1a)-1-1, Formula (AA1b), or Formula (AA1b)-1, more preferable
examples of R.sup.13 include a group optionally selected from a
halogen atom, a cyano group, a C.sub.1-6 alkyl group (the C.sub.1-6
alkyl group is optionally substituted with 1 to 5 halogen atom(s),
1 to 5 --OH, or 1 to 5 C.sub.1-4 alkoxy group(s)), a C.sub.2-6
alkenyl group (the C.sub.2-6 alkenyl group is optionally
substituted with 1 to 5 halogen atom(s), 1 to 5 --OH, or 1 to 5
C.sub.1-4 alkoxy group(s)), a C.sub.1-6 alkoxy group (the C.sub.1-6
alkoxy group is optionally substituted with 1 to 5 halogen atom(s),
1 to 5 --OH, or 1 to 5 C.sub.1-4 alkoxy group(s)), and a C.sub.2-6
alkenyloxy group (the C.sub.2-6 alkenyloxy group is optionally
substituted with 1 to 5 halogen atom(s), 1 to 5 --OH, or 1 to 5
C.sub.1-4 alkoxy group(s)).
[0311] [1-13-d-12-2] In Formula (AA), Formula (AA)-1, Formula
(AA)-1-1, Formula (AA1), Formula (AA1)-1, Formula (AA1a)-1, Formula
(AA1a)-1-1, Formula (AA1b), or Formula (AA1b)-1, specific examples
of R.sup.13 include the groups specifically exemplified as the
cyano group, the "halogen atom", the "C.sub.1-6 alkyl group which
is optionally substituted with 1 to 5 substituent(s) RI", the
"C.sub.1-6 alkoxy group which is optionally substituted with 1 to 5
substituent(s) RI", and the like. More specific examples of
R.sup.13 include a fluorine atom, a chlorine atom, a bromine atom,
cyano, methyl, ethyl, trifluoromethyl, methoxy, ethoxy, and
trifluoromethoxy.
[0312] [1-13-d-13] In Formula (AA), Formula (AA)-1, Formula
(AA)-1-1, Formula (AA1), Formula (AA1)-1, Formula (AA1a)-1, Formula
(AA1a)-1-1, Formula (AA1b), or Formula (AA1b)-1, preferable
examples of R.sup.14 include a halogen atom and a C.sub.1-4 alkyl
group which is optionally substituted with 1 to 5 halogen atom(s).
More specific examples of R.sup.14 include a fluorine atom, a
chlorine atom, a bromine atom, methyl, ethyl, propyl, isopropyl,
butyl, isobutyl, sec-butyl, tert-butyl, and trifluoromethyl.
[0313] [1-13-d-14] In Formula (AA)-1, Formula (AA)-1-1, Formula
(AA1)-1, Formula (AA1a)-1, Formula (AA1a)-1-1, or Formula (AA1b)-1,
preferable aspects of the ring A', the ring A'', R.sup.8, and
R.sup.9 are the same as the preferable aspects described in Aspects
[1-13-c-2], [1-13-c-7], [1-13-c-7-1][1-13-c-7-2], or [1-13-c-8].
The ring A' moiety having (R.sup.8).sub.s and (R.sup.9).sub.q can
be Formula (A') described in Aspect [1-13-c-10] and the preferable
aspects of the ring A' moiety having (R.sup.8).sub.s and
(R.sup.9).sub.q are the same as the preferable aspects described in
Aspect [1-13-c-10].
[0314] [1-13-d-15] In Formula (AA)-1, Formula (AA)-1-1, Formula
(AA1)-1, Formula (AA1a)-1, Formula (AA1a)-1-1, or Formula (AA1b)-1,
s is preferably 0 or 1. q is preferably an integer of 0 to 3, more
preferably an integer of 0 to 2, further preferably 1 or 2.
Preferably, any one of q and s is 1 or more. [1-13-d-15-1] In
Formula (AA)-1, Formula (AA)-1-1, Formula (AA1)-1, Formula
(AA1a)-1, Formula (AA1a)-1-1, or Formula (AA1b)-1, when s is 1, the
binding position of R.sup.8 in the ring A' is preferably the
m-position or the p-position, more preferably the p-position,
relative to the binding position of V.
[0315] [1-13-e] Preferable examples of the ring A in Formula (I)
include the Partial Structural Formula (A)-IV:
##STR00030##
[0316] (where q, r, s, the ring A', R.sup.8, R.sup.9, and R.sup.10
are the same as defined in Formula (A) described in Aspect
[1-13-c]; and the ring A1 is a 5- or 6-membered heterocyclic
group). In Formula (A)-IV, the binding positions of R.sup.10s are
any positions at which they can be optionally bonded in the ring
A1, and the binding positions of R.sup.8s and R.sup.9s are any
positions at which they can be optionally bonded in the ring
A'.
[0317] [1-13-e-1] In Formula (A)-IV, the ring A1 is a 5- or
6-membered non-aromatic heterocyclic group or a 5- or 6-membered
heteroaryl group, and specifically, the ring A1 is preferably
pyrrolidine, piperidine, furan, thiophene, imidazole, oxazole,
thiazole, pyrazole, isoxazole, 1,2,3-triazole, or 1,2,4-oxadiazole.
More preferably, the ring A1 is pyrrolidine, piperidine, furan,
thiophene, oxazole, or thiazole, further preferably pyrrolidine,
piperidine, thiophene, or thiazole.
[0318] [1-13-e-2] The ring A in Formula (I), or Formula (A)-IV is
preferably the Partial Structural Formula (A1)-IV:
##STR00031##
[0319] (where q, r, s, the ring A', R.sup.8, R.sup.9, and R.sup.10
are the same as defined in Formula (A) described in Aspect
[1-13-c]; and g1 is 1 or 2). In Formula (A1)-IV, the binding
positions of R.sup.10s are any positions at which they can be
optionally bonded in the pyrrolidine or piperidine ring, and the
binding positions of R.sup.8s and R.sup.9s are any positions at
which they can be optionally bonded in the ring A'.
[0320] [1-13-e-3] Preferable examples of the ring A in Formula (I),
or Formula (A)-IV include the Partial Structural Formula
(A2)-IV:
##STR00032##
[0321] (where q, s, the ring A', R.sup.8, and R.sup.9 are the same
as defined in Formula (A) described in Aspect [1-13-c]; Z.sub.1 is
--CR.sup.10e-- or a nitrogen atom; Z.sub.2 is a sulfur atom or an
oxygen atom; Z.sub.3 is --CR.sup.10f- or a nitrogen atom; R.sup.10e
and R.sup.10f are independently a hydrogen atom, a C.sub.1-6 alkyl
group, or a methoxy group (with the proviso that at least one of
Z.sub.1 and Z.sub.3 is --CR.sup.10e- or --CR.sup.10f-)). In Formula
(A2)-IV, the binding positions of R.sup.8s and R.sup.9s are any
positions at which they can be optionally bonded in the ring A'.
Here, in Formula (A2)-IV, the ring A' may be a substituted
spiropiperidinylmethyl group in addition to the above
description.
[0322] Specific examples of Formula (A2)-IV include Formula (A3)-IV
described in Aspect [1-13-e-7] below and Formula (A4)-IV described
in Aspect [1-13-e-8] below. Specific examples of Formula (A2)-IV of
the present specification also include groups corresponding to
Formula (A2)-IV of the present specification in WO 2005/086661
pamphlet, WO 2005/051890 pamphlet, WO 2004/022551 pamphlet, and WO
2004/011446 pamphlet (such as a 5-membered ring group and the like
as examples of W in [0195] in p. 25 of WO 2005/086661 pamphlet),
particularly the corresponding groups shown in Examples of these
pamphlets.
[0323] [1-13-e-4] In Formula (A)-IV, Formula (A1)-IV, or Formula
(A2)-IV, more specifically, the ring A' is preferably benzene,
pyridine, or pyrimidine. More preferably, the ring A' is benzene or
pyridine, further preferably benzene.
[0324] [1-13-e-5] In Formula (A)-IV, Formula (A1)-IV, or Formula
(A2)-IV, more specifically, s is preferably 0 or 1, and when s is 1
and the ring A' is a 6-membered ring, the substitution position of
R.sup.8 is preferably p-position. q is more preferably an integer
of 0 to 2, further preferably 1 or 2. Most preferably, s is 0 or 1
and q is 2.
[0325] [1-13-e-6] In Formula (A)-IV or Formula (A1)-IV, more
specifically, r is preferably 0.
[0326] [1-13-e-7] The ring A in Formula (I), Formula (A)-IV, or
Formula (A2)-IV is preferably the Partial Structural Formula
(A3)-IV:
##STR00033##
[0327] (where q and R.sup.9 are the same as defined in Formula (A)
described in Aspect [1-13-c]; and R.sup.10f is the same as defined
in Formula (A2)-IV described in Aspect [1-13-e-3]).
[0328] In Formula (A3)-IV, preferably, R.sup.9 is a group
optionally selected from a halogen atom, a cyano group, a C.sub.1-6
alkyl group (the C.sub.1-6 alkyl group is optionally substituted
with 1 to 5 halogen atom(s)), and a C.sub.1-6 alkoxy group (the
C.sub.1-6 alkoxy group is optionally substituted with 1 to 5
halogen atom(s)). q is preferably an integer of 0 to 2. R.sup.10f
is preferably a hydrogen atom or a C.sub.1-6 alkyl group, more
preferably a hydrogen atom or a methyl group.
[0329] Specific examples of Formula (A3)-IV include
4-methyl-2-(4-trifluoromethylphenyl)thiazol-5-yl and
4-methyl-2-(4-butoxy-3-chlorophenyl)thiazol-5-yl. Specific examples
of Formula (A3)-IV of the present specification also include groups
of the same formula as Formula (A3)-IV of the present specification
in WO 2008/030520 pamphlet, that is, the corresponding groups in
groups of Formula VIIC in p. 8, particularly the corresponding
groups shown in Examples.
[0330] [1-13-e-8] The ring A in Formula (I), Formula (A)-IV, or
Formula (A2)-IV is preferably the Partial Structural Formula
(A4)-IV:
##STR00034##
[0331] (where Z.sub.1, Z.sub.2, and Z.sub.3 are the same as defined
in Formula (A2)-IV described in Aspect [1-13-e-3](with the proviso
that R.sup.10e and R.sup.10f are independently a hydrogen atom, a
methyl group, or a methoxy group); X.sub.2 is --CH.sub.2CH.sub.2--,
--CH.dbd.CH--, or --N(R.sub.z1)CH.sub.2--; and R.sub.z1 is a
hydrogen atom or a C.sub.1-3 alkyl group).
[0332] In Formula (A4)-IV, preferably, Z.sub.1 is --CR.sup.10e-,
R.sup.10e is a hydrogen atom or a methyl group, Z.sub.2 is a sulfur
atom, Z.sub.3 is --CR.sup.10f-, and R.sup.10f is a hydrogen atom.
X.sub.2 is --CH.dbd.CH-- or --N(R.sub.z1) CH.sub.2-- and R.sub.z1
is a methyl group.
[0333] Specific examples of Formula (A4)-IV include 5-(spiro
[inden-1,4'-piperidin]-1'-ylmethyl)-2-thienyl,
4-methyl-5-(spiro[inden-1,4'-piperidin]-1'-ylmethyl)-2-thienyl, and
5-(1-methylspiro[indolin-3,4'-piperidin]-1'-ylmethyl)-2-thienyl.
Specific examples of Formula (A4)-IV of the present specification
also include groups of the same formula as Formula (A4)-IV of the
present specification in WO 2011/066183 pamphlet, particularly the
corresponding groups shown in Examples.
[0334] [1-13-e-9] In Formula (A)-IV, Formula (A1)-IV, or Formula
(A2)-IV, more preferable examples of R.sup.8 include a C.sub.1-6
alkoxy group (the C.sub.1-6 alkoxy group is substituted with 1 to 5
--OH, 1 to 5 methoxy, 1 to 5 ethoxy, 1 to 5 methylsulfonyl, 1 to 5
sulfamoyl, 1 to 5 methylsulfamoyl, 1 to 5 dimethylsulfamoyl, 1 to 5
carbamoyl, 1 to 5 methylcarbamoyl, 1 to 5 dimethylcarbamoyl, 1 to 5
--NH.sub.2, 1 to 5 acetylamino, 1 to 5 methylsulfonylamino, 1 to 5
2-oxo-1-pyrrolidinyl, 1 to 5 5-oxo-2-pyrrolidinyl, or 1 to 5
3-methyloxetane-3-yl), a --CONR.sup.d4R.sup.c4 group (R.sup.d4 is a
hydrogen atom or a C.sub.1-4 alkyl group; and R.sup.e4 is a
C.sub.1-6 alkyl group (the C.sub.1-6 alkyl group is substituted
with 1 to 5 --OH, 1 to 5 methoxy, 1 to 5 ethoxy, 1 to 5
methylsulfonyl, 1 to 5 sulfamoyl, 1 to 5 methylsulfamoyl, 1 to 5
dimethylsulfamoyl, 1 to 5 carbamoyl, 1 to 5 methylcarbamoyl, 1 to 5
dimethylcarbamoyl, 1 to 5 --NH.sub.2, 1 to 5 acetylamino, 1 to 5
methylsulfonylamino, 1 to 5 2-oxo-1-pyrrolidinyl, 1 to 5
5-oxo-2-pyrrolidinyl, or 1 to 5 3-methyloxetane-3-yl),
(1,1-dioxidetetrahydro-2H-thiopyran-4-yl)oxy, and
(pyrrolidine-1-yl)carbonyl. The substitution number of --OH,
methoxy, ethoxy, methylsulfonyl, sulfamoyl, methylsulfamoyl,
dimethylsulfamoyl, carbamoyl, methylcarbamoyl, dimethylcarbamoyl,
--NH.sub.2, acetylamino, methylsulfonylamino, 2-oxo-1-pyrrolidinyl,
5-oxo-2-pyrrolidinyl, or 3-methyloxetane-3-yl is preferably 1 to
2.
[0335] More specific examples of R.sup.8 include 2-hydroxyethoxy,
3-hydroxypropoxy, 3-hydroxybutoxy, 3-hydroxy-3-methylbutoxy,
2,3-dihydroxypropoxy, (2R)-2,3-dihydroxypropoxy,
(2S)-2,3-dihydroxypropoxy, (3S)-3-hydroxybutoxy,
(3R)-3-hydroxybutoxy, 3-hydroxy-2-hydroxymethylpropoxy,
3-hydroxy-2-hydroxymethyl-2-methylpropoxy, 2-aminoethoxy,
3-aminopropoxy, 2-(2-oxo-1-pyrrolidinyl)ethoxy,
3-(2-oxo-1-pyrrolidinyl)propoxy, (5-oxo-2-pyrrolidinyl)methoxy,
2-ethoxyethoxy, 2-methylsulfonylethoxy, 3-methylsulfonyl-propoxy,
(1,1-dioxidetetrahydro-2H-thiopyran-4-yl)oxy,
(4-hydroxy-1,1-dioxidetetrahydro-2H-thiopyran-4-yl)methoxy,
(3-methyloxetane-3-yl)methoxy, 2-acetylamino-ethoxy,
2-acetylamino-ethoxy, 3-acetylamino-propoxy,
2-methylsulfonylamino-ethoxy, 3-methylsulfonylamino-propoxy,
2-carbamoyl-ethoxy, 3-carbamoyl-propoxy, 2-methylcarbamoyl-ethoxy,
3-methylcarbamoyl-propoxy, 2-dimethylcarbamoyl-ethoxy,
3-dimethylcarbamoyl-propoxy, 2-sulfamoyl-ethoxy,
3-sulfamoyl-propoxy, 2-methylsulfamoyl-ethoxy,
3-methylsulfamoyl-propoxy, 2-dimethylsulfamoyl-ethoxy,
3-dimethylsulfamoyl-propoxy, N-(2-hydroxyethyl)carbamoyl,
N-(2-methoxyethyl)carbamoyl, N-(2-hydroxyethyl)-N-methylcarbamoyl,
N-(2-methoxyethyl)-N-methylcarbamoyl,
N-(2-methylsulfonyl-ethyl)carbamoyl,
N-(2-methylsulfonyl-ethyl)-N-methylcarbamoyl, and
(pyrrolidine-1-yl)carbonyl.
[0336] [1-13-e-10] In Formula (A)-IV, Formula (A1)-IV, Formula
(A2)-IV, or Formula (A3)-IV, preferable examples of R.sup.9 and
R.sup.10 independently include a halogen atom, a cyano group, a
C.sub.1-4 alkyl group (the C.sub.1-4 alkyl group is optionally
substituted with 1 to 5 halogen atom(s) or 1 to 5 --OH), a
C.sub.1-4 alkoxy group which is optionally substituted with 1 to 5
halogen atom(s), a C.sub.2-4 alkenyl group, a C.sub.2-5 alkanoyl
group, a --S(O).sub.iR.sup.a (i is 2; and R.sup.a is a C.sub.1-4
alkyl group) group, a --CONR.sup.dR.sup.e (R.sup.d and R.sup.e are
independently a hydrogen atom or a C.sub.1-4 alkyl group) group,
and a --NR.sup.b1R.sup.c1 group (R.sup.b1 and R.sup.c1 form,
together with a nitrogen atom to which they are bonded, a 3- to
8-membered cyclic group; and in the cyclic group, one or two carbon
atom(s) is(are) optionally substituted with an oxygen atom, a
nitrogen atom, or a carbonyl group).
[0337] More specific examples of R.sup.9 and R.sup.10 include a
fluorine atom, a chlorine atom, a bromine atom, cyano, methyl,
ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl,
trifluoromethyl, hydroxymethyl, 2-hydroxyethyl, methoxy, ethoxy,
trifluoromethoxy, trifluoroethoxy, vinyl, acetyl, methylsulfonyl,
carbamoyl, methylcarbamoyl, dimethylcarbamoyl, 1-piperidinyl,
4-morpholinyl, and 2-oxooxazolidin-3-yl. More preferable examples
of R.sup.9, R.sup.9a, and R.sup.9b include a fluorine atom, methyl,
and methoxy, and more preferable examples of R.sup.10 include
methyl.
[0338] [1-13-e-11] In Formula (A)-IV, Formula (A1)-IV, or Formula
(A2)-IV, preferable aspects of the ring A' moiety having
(R.sup.8).sub.s and (R.sup.9).sub.q are the same groups as the
groups having an aryl group or a heteroaryl group among the
preferable aspects of L described in Aspect [1-1-d]. Specific
examples of the ring A' moiety having (R.sup.8).sub.s and
(R.sup.9).sub.q include the same groups as specific examples of the
"aryl group which is optionally substituted with 1 to 5
substituent(s) RII" or the groups having a heteroaryl group among
specific examples of the "heterocyclic group which is optionally
substituted with 1 to 5 substituent(s) RII" that are described in
Aspect [11]. More specific examples thereof include the same groups
as the groups having benzene, naphthalene, pyridine, pyrimidine,
thiophene, quinoline, or dibenzofuran.
[0339] [1-13-f] The ring A in Formula (I) is preferably Partial
Structural Formula (A)-V:
##STR00035##
[0340] (where q, r, s, R.sup.8, R.sup.9, and R.sup.10 are the same
as defined in Formula (A) described in Aspect [1-13-c]; n1 is an
integer of 0 to 4; n2 is an integer of 1 to 4, n3 is an integer of
0 to 2 (with the proviso that n2+n3 is an integer of 2 to 4);
X.sub.3s are independently --CR.sub.v1R.sub.v2-- or --NR.sub.v3--;
R.sub.v1, R.sub.v2, and R.sub.v3 are independently a hydrogen atom,
R.sup.8, or R.sup.9; and the broken lines in the ring are a single
bond or a double bond). In Formula (A)-V, the binding positions of
R.sup.8, R.sup.9, and R.sup.10 are any positions at which they can
be optionally bonded in the ring. Here, in Formula (A)-V, R.sup.9
and R.sup.10 may be, in addition to the above description, --OH or
an oxo group, and R.sup.8 may be, in addition to the above
description, --NHR.sub.v4 (R.sub.v4 is a C.sub.1-6 alkyl group (the
C.sub.1-6 alkyl group is optionally substituted with 1 to 5
group(s) optionally selected from --OH, a C.sub.1-6 alkoxy group, a
non-aromatic heterocyclic group (the heterocyclic group is
optionally substituted with 1 to 2 C.sub.1-4 alkyl group(s) or 1 to
2 oxo group(s)), and a --S(O).sub.iR.sup.a (i is an integer of 0 to
2) group) or a C.sub.2-7 alkanoyl group (the C.sub.2-7 alkanoyl
group is optionally substituted with 1 to 5 group(s) optionally
selected from --OH, a C.sub.1-6 alkoxy group, a non-aromatic
heterocyclic group (the heterocyclic group is optionally
substituted with 1 to 2 C.sub.1-4 alkyl group(s) or 1 to 2 oxo
group(s)), and a --S(O).sub.iR.sup.a (i is an integer of 0 to 2)
group)). These substituents are the same as or different from each
other and are optionally substituted with 1 to 5 group(s) in the
spiro ring.
[0341] [1-13-f-1] In Formula (A)-V, X.sub.3 is preferably
--CR.sub.v1R.sub.v2-- (R.sub.v1 and R.sub.v2 are the same as
defined in Formula (A)-V).
[0342] [1-13-f-2] In Formula (A)-V, preferably, n1 is an integer of
0 to 4, n2 is an integer of 1 to 3, and n3 is 1 or 2. More
preferably, n1 is 2 or 3, n2 is 1 or 2, and n3 is 1.
[0343] [1-13-f-3] In Formula (A)-V, preferably, q is an integer of
0 to 2 and r is an integer of 0 to 2. More preferably, q and r are
0.
[0344] [1-13-f-4] In Formula (A)-V, s is preferably 0 or 1. More
preferably, s is 0.
[0345] [1-13-f-5] More preferable examples of Formula (A)-V include
Formula (A1)-V: (A)-V
##STR00036##
[0346] (where n1, n2, and the broken lines are the same as defined
in Formula (A)-V). In Formula (A1)-V, most preferably, n1 is 2 or 3
and n2 is 1 or 2.
[0347] Specific examples of Formula (A)-V or Formula (A1)-V include
spiro[4,5]dec-6-ene-7-yl, spiro[5,5]undec-2-yl,
spiro[5,5]undec-1-ene-2-yl, and spiro[5,5]undec-2-ene-2-yl.
[0348] Specific examples of Formula (A)-V or Formula (A1)-V of the
present specification also include groups of the same formula as
Formula (A)-V or Formula (A1)-V of the present specification in WO
2009/054479 pamphlet, that is, the groups of the spiro ring AB in
the item 2 in pp. 4 and 5, particularly the corresponding groups
shown in Examples.
[0349] [1-13-f-6] In Formula (A)-V, preferable examples of R.sup.9
and R.sup.10 independently include a halogen atom, a C.sub.1-4
alkyl group which is optionally substituted with 1 to 5 halogen
atom(s), a C.sub.1-4 alkoxy group which is optionally substituted
with 1 to 5 halogen atom(s), an --OH group, and an oxo group. More
specific examples of R.sup.9 and R.sup.10 include a fluorine atom,
a chlorine atom, a bromine atom, methyl, ethyl, propyl, isopropyl,
butyl, isobutyl, sec-butyl, tert-butyl, trifluoromethyl, methoxy,
ethoxy, trifluoromethoxy, trifluoroethoxy, and --OH. More
preferable examples of R.sup.9 include a fluorine atom, methyl,
methoxy, and --OH, and more preferable examples of R.sup.10 include
methyl and --OH.
[0350] Specific examples of Formula (A)-V of the present
specification also include the corresponding groups of the spiro
ring AB substituted with a substituent (an --OH group, a C.sub.1-6
alkyl group, a C.sub.1-6 alkoxy group, or an oxo group) in a
formula of Formula [Ia] of WO 2009/054479 pamphlet) as a group
substituted with R.sup.9 or R.sup.10 in Formula (A)-V, particularly
the corresponding groups shown in Examples.
[0351] [1-13-f-7] In Formula (A)-V, preferable examples of R.sup.8s
independently include a C.sub.1-6 alkoxy group (the C.sub.1-6
alkoxy group is substituted with 1 to 5 group(s) optionally
selected from --OH, a C.sub.1-6 alkoxy group, a non-aromatic
heterocyclic group (the heterocyclic group is optionally
substituted with 1 to 2 C.sub.1-4 alkyl group(s) or 1 to 2 oxo
group(s)), and a --S(O).sub.iR.sup.a (i is an integer of 0 to 2)
group), a --CONR.sup.d3R.sup.e3 group (R.sup.d3 is a hydrogen atom
or a C.sub.1-4 alkyl group; and R.sup.e3 is a C.sub.1-6 alkyl group
(the C.sub.1-6 alkyl group is substituted with 1 to 5 group(s)
optionally selected from --OH, a C.sub.1-6 alkoxy group, a
non-aromatic heterocyclic group (the heterocyclic group is
optionally substituted with 1 to 2 C.sub.1-4 alkyl group(s) or 1 to
2 oxo group(s)), and a --S(O).sub.iR.sup.a (i is an integer of 0 to
2) group)), an aralkyloxy group, a non-aromatic heterocyclic oxy
group (the heterocyclic oxy group is optionally substituted with 1
to 2 oxo group(s)), a non-aromatic heterocyclic carbonyl group (the
heterocyclic carbonyl group is optionally substituted with 1 to 2
oxo group(s)), and --NHR.sub.v4 (R.sub.v4 is a C.sub.1-6 alkyl
group (the C.sub.1-6 alkyl group is optionally substituted with 1
to 5 group(s) optionally selected from --OH, a C.sub.1-6 alkoxy
group, a non-aromatic heterocyclic group (the heterocyclic group is
optionally substituted with 1 to 2 C.sub.1-4 alkyl group(s) or 1 to
2 oxo group(s)), and a --S(O).sub.iR.sup.a (i is an integer of 0 to
2) group) or a C.sub.2-7 alkanoyl group (the C.sub.2-7 alkanoyl
group is optionally substituted with 1 to 5 group(s) optionally
selected from --OH, a C.sub.1-6 alkoxy group, a non-aromatic
heterocyclic group (the heterocyclic group is optionally
substituted with 1 to 2 C.sub.1-4 alkyl group(s) or 1 to 2 oxo
group(s)), and a --S(O).sub.iR.sup.a (i is an integer of 0 to 2)
group)). More specific examples of R.sup.8 include a C.sub.1-6
alkoxy group which is substituted with 1 to 2 --OH, 1 to 2 methoxy,
1 to 2 ethoxy, 1 to 2 2-oxo-1-pyrrolidinyl, 1 to 2
5-oxo-2-pyrrolidinyl, 1 to 2 3-methyloxetane-3-yl, or 1 to 2
methylsulfonyl; a --CONR.sup.d4R.sup.e4 group (R.sup.d4 is a
hydrogen atom or a C.sub.1-4 alkyl group; and R.sup.e4 is a
C.sub.1-6 alkyl group (the C.sub.1-6 alkyl group is substituted
with 1 to 5 --OH, 1 to 5 methoxy, 1 to 5 ethoxy, 1 to 5
2-oxo-1-pyrrolidinyl, 1 to 5 5-oxo-2-pyrrolidinyl, 1 to 5
3-methyloxetane-3-yl, or 1 to 5 methylsulfonyl)), an aralkyloxy
group, (1,1-dioxidetetrahydro-2H-thiopyran-4-yl)oxy,
(pyrrolidine-1-yl)carbonyl, and --NHR.sub.v4 (R.sub.v4 is a
C.sub.1-6 alkyl group (the C.sub.1-6 alkyl group is optionally
substituted with 1 to 2 --OH, 1 to 2 ethoxy, 1 to 2
2-oxo-1-pyrrolidinyl, 1 to 2 5-oxo-2-pyrrolidinyl, 1 to 2
3-methyloxetane-3-yl, or 1 to 2 methylsulfonyl) or a C.sub.2-7
alkanoyl group (the C.sub.2-7 alkanoyl group is optionally
substituted with 1 to 2 --OH, 1 to 2 ethoxy, 1 to 2
2-oxo-1-pyrrolidinyl, 1 to 2 5-oxo-2-pyrrolidinyl, 1 to 2
3-methyloxetane-3-yl, or 1 to 2 methylsulfonyl)).
[0352] [1-13-f-8] The ring A in Formula (I) is preferably Partial
Structural Formula (AA)-V:
##STR00037##
[0353] (where R.sup.13a is the same as defined in Formula (AA)
described in Aspect [1-13-d]; r is the same as defined in Formula
(A) described in Aspect [1-13-c]; R.sup.10 is the same as defined
in Formula (A)-V described in Aspect [1-13-f]; n4 is an integer of
1 to 3; and the broken lines are a single bond, a double bond, or
the binding position of R.sup.13a).
[0354] [1-13-f-9] The preferable aspects of R.sup.13a in Formula
(AA)-V are the same as the preferable aspects described in Aspects
[1-13-d-11] to [1-13-d-11-3]. More preferably, R.sup.13a is a group
of Formula (A')-V--.
[0355] [1-13-f-10] Preferable examples of the ring A in Formula (I)
or Formula (AA)-V include Formula (AA1)-V:
##STR00038##
[0356] (where q, r, s, the ring A', V, R.sup.8, and R.sup.9 are the
same as defined in Formula (A) described in Aspect [1-13-c];
R.sup.10 and the broken line are the same as defined in Formula
(A)-V described in Aspect [1-13-f]; and n4 is the same as defined
in Formula (AA)-V).
[0357] [1-13-f-11] In Formula (AA)-V or Formula (AA1)-V, n4 is
preferably 1 or 2, more preferably 2.
[0358] [1-13-f-12] In Formula (AA)-V or Formula (AA1)-V, r is
preferably an integer of 0 to 2. In Formula (AA1)-V, q is
preferably an integer of 0 to 3, more preferably an integer of 0 to
2. s is preferably 0 or 1. More preferably, any one of q and s is 1
or more.
[0359] [1-13-f-13] In Formula (AA1)-V, the preferable aspects of
the ring A', R.sup.8, and R.sup.9 are the same as the preferable
aspects described in Aspects [1-13-c-2], [1-13-c-7] to
[1-13-c-7-2], and [1-13-c-8]. The preferable aspects of the ring A'
moiety having (R.sup.8).sub.s and (R.sup.9).sub.q are the same as
the preferable aspects described in Aspect [1-13-c-10].
[0360] In Formula (AA)-V or Formula (AA1)-V, the preferable aspects
of R.sup.10 are the same as the preferable aspects described in
Aspect [1-13-f-6].
[0361] [1-13-g] The ring A in Formula (I) is preferably Partial
Structural Formula (A)-VI:
##STR00039##
[0362] (where R.sub.x, R.sub.xa, and X.sub.1 are the same as
defined in Formula (SP) described as the "substituted
spiropiperidinyl group" in Aspect [1]; and R.sub.xb is a group
selected from a hydrogen atom, a fluorine atom, a chlorine atom,
C.sub.1-3 alkyl, trifluoromethyl, and methoxy).
[0363] [1-13-g-1] In Formula (A)-VI, preferably, at least any one
of R.sub.x and R.sub.xa is a hydrogen atom. More preferably,
R.sub.xa is a hydrogen atom and R.sub.x is a group selected from a
hydrogen atom, a fluorine atom, methyl, trifluoromethyl, and
methoxy, or R.sub.xa is a hydrogen atom or a chlorine atom and
R.sub.x is a hydrogen atom, or both of R.sub.x and R.sub.xa are a
hydrogen atom.
[0364] In Formula (A)-VI, R.sub.xb is preferably a group selected
from a hydrogen atom, methyl, trifluoromethyl, and methoxy, more
preferably a hydrogen atom.
[0365] In Formula (A)-VI, X.sub.1 is preferably
--CH(R.sub.y)CH.sub.2--, --C(R.sub.y).dbd.CH--, or
--N(R.sub.z)CH.sub.2, more preferably --C(R.sub.y).dbd.CH-- or
--N(R.sub.z)CH.sub.2.
[0366] In Formula (A)-VI, R.sub.y is preferably a hydrogen atom or
methyl, more preferably a hydrogen atom.
[0367] In Formula (A)-VI, R.sub.z is preferably a hydrogen atom or
C.sub.1-3 alkyl, more preferably methyl.
[0368] Specifically, in Aspect [1-13-g], examples of Partial
Structural Formula (SP)--CH.sub.2--:
##STR00040##
in Formula (A)-VI include a group selected from any of
spiro[indan-1,4'-piperidin]-1'-ylmethyl,
(1'H-spiro[inden-1,4'-piperidin]-1'-yl)methyl,
1,2-dihydro-1'H-spiro [indol-3,4'-piperidin]-1'-ylmethyl,
(1-methyl-1,2-dihydro-1'H-spiro[indol-3,4'-piperidin]-1'-yl)methyl,
{1-(1-methylethyl)-1,2-dihydro-1'H-spiro
[indol-3,4'-piperidin]-1'-yl}methyl,
(1-phenyl-1,2-dihydro-1'H-spiro[indol-3,4'-piperidin]-1'-yl)methyl,
(2,3-dihydro-1'H-spiro[inden-1,4'-piperidin]-1'-ylmethyl,
(7-chloro-1-methyl-1,2-dihydro-1'H-spiro
[indol-3,4'-piperidin]-1'-yl)methyl,
(5-fluoro-1-methyl-1,2-dihydro-1'H-spiro
[indol-3,4'-piperidin]-1'-yl)methyl,
(5-methoxy-1-methyl-1,2-dihydro-1'H-spiro
[indol-3,4'-piperidin]-1'-yl)methyl,
(1,5-dimethyl-1,2-dihydro-1'H-spiro[indol-3,4'-piperidin]-1'-yl)methyl,
[1-methyl-5-(trifluoromethyl)-1,2-dihydro-1'H-spiro[indol-3,4'-piperidin]-
-1'-yl)methyl, and (3-oxo-2,3-dihydro-1'H-spiro
[inden-1,4'-piperidin]-1'-yl)methyl.
[0369] [1-13-g-2] Preferable examples of the ring A in Formula (I)
include Partial Structural Formula (AA)-VI:
##STR00041##
[0370] (where q, s, R.sup.8, and R.sup.9 are the same as defined in
Formula (A) described in Aspect [1-13-c]; R.sub.xb is the same as
defined in Formula (A)-VI described in Aspect [1-13-g]; and the
broken lines indicate the binding position of a piperidinylmethyl
group).
[0371] The preferable aspects of q, s, R.sup.8, and R.sup.9 in
Formula (AA)-VI are the same as the preferable aspects described in
Aspects [1-13-c-3], [1-13-c-5], [1-13-c-7] to [1-13-c-7-2], or
[1-13-c-8].
[0372] [1-13-h] The ring A in Formula (I) is preferably Partial
Structural Formula (A)-VII:
##STR00042##
[0373] (where T is the same as defined in Formula (AA) described in
Aspect [1-13-d]; R.sub.x, R.sub.xa, and X.sub.1 are the same as
defined in Formula (SP) described as the "substituted
spiropiperidinyl group" in Aspect [1]; R.sub.xb is the same as
defined in Formula (A)-VI described in Aspect [1-13-g]; R.sub.xc is
a group selected from a hydrogen atom, a fluorine atom, a chlorine
atom, C.sub.1-3 alkyl, trifluoromethyl, and methoxy; and the broken
lines and the figures 4 and 5 indicate the binding position of the
substituted spiropiperidinylmethyl group).
[0374] [1-13-h-1] Preferable examples of the ring A in Formula (I)
include Partial Structural Formula (AA)-VII:
##STR00043##
[0375] (where T is the same as defined in Formula (AA) described in
Aspect [1-13-d]; q, s, R.sup.8, and R.sup.9 are the same as defined
in Formula (A) described in Aspect [1-13-c]; R.sub.xb is the same
as defined in Formula (A)-VI described in Aspect [1-13-g]; R.sub.xc
is the same as defined in Formula (A)-VII described in Aspect
[1-13-h]; and the broken lines indicate the binding position of the
piperidinylmethyl group).
[0376] The preferable aspects of q, s, R.sup.8, and R.sup.9 in
Formula (AA)-VII are the same as the preferable aspects described
in Aspects [1-13-c-3], [1-13-c-5], [1-13-c-7] to [1-13-c-7-2], or
[1-13-c-8].
[0377] [1-13-i] Preferable examples of the ring A in Formula (I)
include phthalazinyl which is optionally substituted with 1 to 5
L(s).
[0378] Specific examples of phthalazinyl which is optionally
substituted with 1 to 5 L(s) include 4-chloro-1-phthalazinyl,
4-trifluoromethyl-1-phthalazinyl, 4-cyano-1-phthalazinyl, and
4-cyclopropylmethoxy-1-phthalazinyl.
[0379] Specific examples of the ring A of the present specification
also include the groups of G in Formula (I) and the like in WO
2010/091176 pamphlet, particularly the corresponding groups shown
in Examples.
[0380] [1-13-j] Preferable examples of the ring A in Formula (I)
include Partial Structural Formula (A)-VIII:
##STR00044##
[0381] (where r2 is an integer of 0 to 4; n5 is 1 or 2;
D is --CO--CR.sup.14bR.sup.14c-- or --(CR.sup.14bR.sup.14c).sub.m
(m is 1 or 2)-; E is --CR.sup.14dR.sup.14c-;
[0382] L.sub.1 is a group optionally selected from a C.sub.1-10
alkyl group (the C.sub.1-10 alkyl group is optionally substituted
with 1 to 5 halogen atom(s)), an aryl group (the aryl group is
optionally substituted with 1 to 5 halogen atom(s), 1 to 5
C.sub.1-6 alkyl group(s), or 1 to 5 halogenated C.sub.1-6 alkyl
group(s)), a heterocyclic group (the heterocyclic group is
optionally substituted with 1 to 5 halogen atom(s), 1 to 5
C.sub.1-6 alkyl group(s), or 1 to 5 halogenated C.sub.1-6 alkyl
group(s)), an aralkyl group (the aralkyl group is optionally
substituted with 1 to 5 halogen atom(s), 1 to 5 C.sub.1-6 alkyl
group(s), or 1 to 5 halogenated C.sub.1-6 alkyl group(s)), a
heteroarylalkyl group (the heteroarylalkyl group is optionally
substituted with 1 to 5 halogen atom(s), 1 to 5 C.sub.1-6 alkyl
group(s), or 1 to 5 halogenated C.sub.1-6 alkyl group(s)), a
C.sub.2-7 alkanoyl group, and a --S(O).sub.iR.sup.a (i is an
integer of 0 to 2; and Ra is the same as defined in Formula (I))
group; R.sup.14as are independently a halogen atom, a C.sub.1-6
alkyl group (the C.sub.1-6 alkyl group is optionally substituted
with 1 to 5 halogen atom(s)), or a C.sub.1-6 alkoxy group (the
C.sub.1-6 alkoxy group is optionally substituted with 1 to 5
halogen atom(s)); and R.sup.14b, R.sup.14c, R.sup.14d, and
R.sup.14e are independently a hydrogen atom, a halogen atom, or a
C.sub.1-6 alkyl group (the C.sub.1-6 alkyl group is optionally
substituted with 1 to 5 halogen atom(s)); and R.sup.14c and
R.sup.14e optionally form, together with a carbon atom to which
they are bonded, a 5- to 6-membered aryl group or heteroaryl group
(ring B1)).
[0383] In Formula (A)-VIII, L.sub.1 is preferably a group
optionally selected from a C.sub.1-4 alkyl group (the C.sub.1-4
alkyl group is optionally substituted with 1 to 5 halogen atom(s)),
a heteroaryl group (the heteroaryl group is optionally substituted
with 1 to 5 halogen atom(s), 1 to 5 C.sub.1-4 alkyl group(s), or 1
to 5 halogenated C.sub.1-4 alkyl group(s)), and a
--S(O).sub.iR.sup.a (i is an integer of 0 to 2; and R.sup.a is the
same as defined in Formula (I)) group.
[0384] Specific examples of Formula (A)-VIII include
1,2,3,4-tetrahydro-1-oxo-2-(2,2,2-trifluoroethyl)-4-isoquinolyl,
2-cyclopropylmethyl-1,2,3,4-tetrahydro-1-oxo-4-isoquinolyl,
1,2,3,4-tetrahydro-2-(2-methylpropyl)-1-oxo-4-isoquinolyl,
1-(5-fluoro-2-pyridinyl)-3-piperidinyl,
1-(5-trifluoromethyl-2-pyridinyl)-3-piperidinyl,
1,2,3,4-tetrahydro-1-methylsulfonyl-4-quinolyl,
8-fluoro-1,2,3,4-tetrahydro-1-methylsulfonyl-4-quinolyl,
1,2,3,4-tetrahydro-1-(2,2,2-trifluoroethyl)-4-quinolyl, and
8-fluoro-1,2,3,4-tetrahydro-1-(2,2,2-trifluoroethyl)-4-quinolyl.
[0385] Specific examples of the ring A and Formula (A)-VIII of the
present specification also include the cyclic group containing D
and E in Formula (I) and the like in WO 2010/085525 pamphlet,
particularly the corresponding groups shown in Examples.
[0386] [1-13-k] Preferable examples of the ring A in Formula (I)
include a 2-phenylamino-2-oxoacetyl group which is optionally
substituted with 1 to 5 L(s) and more preferable examples thereof
include Partial Structural Formula (A)-IX:
##STR00045##
[0387] (where R.sub.x3 is a group optionally selected from a
hydrogen atom, a halogen atom, a C.sub.1-8 alkyl group (the
C.sub.1-8 alkyl group is optionally substituted with 1 to 5 halogen
atom(s)), a trifluoromethoxy group, a phenyl group, and a
--COOR.sup.f group; R.sub.x1 and R.sub.x5 are independently a group
optionally selected from a hydrogen atom, a halogen atom, a
C.sub.1-6 alkyl group (the C.sub.1-6 alkyl group is optionally
substituted with 1 to 5 halogen atom(s)), a phenyl group, and a
--COOR.sup.f group;
R.sub.x2 and R.sub.x4 are independently a group optionally selected
from a hydrogen atom, a halogen atom, a C.sub.1-6 alkyl group (the
C.sub.1-6 alkyl group is optionally substituted with 1 to 5 halogen
atom(s)), and a --COOR group; and R.sup.f is a hydrogen atom or a
C.sub.1-6 alkyl group).
[0388] In Formula (A)-IX, R.sub.x3 is preferably a hydrogen atom, a
halogen atom, a C.sub.1-6 alkyl group, a trifluoromethyl group, a
methoxycarbonyl group, or a phenyl group. R.sub.x1 and R.sub.x5 are
preferably independently a hydrogen atom, a halogen atom, a methyl
group, a trifluoromethyl group, a methoxycarbonyl group, or a
phenyl group. R.sub.x2 and R.sub.x4 are preferably independently a
hydrogen atom, a halogen atom, or a trifluoromethyl group.
[0389] Specific examples of Formula (A)-IX include
2-((2-bromo-4-isopropylphenyl)amino)-2-oxoacetyl,
2-((4-isopropyl-2-(trifluoromethyl)phenyl)amino)-2-oxoacetyl,
2-((2,4-bis(trifluoromethyl)phenyl)amino)-2-oxoacetyl, and
2-((4-bromo-3-chlorophenyl)amino)-2-oxoacetyl.
[0390] Specific examples of the ring A and Formula (A)-IX of the
present specification also include the groups of the same formula
as Formula (A)-IX of the present specification in Formula (I) in WO
2009/039943 pamphlet, particularly the corresponding groups shown
in Examples.
[0391] [1-13-1] In the preferable Aspects [1-13-e-8], [1-13-g], and
[1-13-h] of the ring A in Formula (I), an aspect in which each
spiropiperidine ring (SP) is replaced with the above-described
another spiropiperidine ring (SP') is also a preferable aspect.
[0392] Accordingly, it can be understood that examples of the
preferable aspect of the ring A in Formula (I) of the present
invention include, in addition to Aspects [1-13-e-8], [1-13-g], and
[1-13-h], [1-13-e-8a], [1-13-ga], and [1-13-ha] below. [1-13-e-8a]
The ring A in Formula (I) is preferably Partial Structural Formula
(A5)-IVa:
##STR00046##
[0393] (where Z.sub.1, Z.sub.2, and Z.sub.3 are the same as defined
in Formula (A2)-IV described in Aspect [1-13-e-3]; and R.sup.6a,
R.sup.7a, R.sup.8a, xa, and Y.sup.1a to Y.sup.4a are the same as
defined in the above Formula (SP')).
[0394] In Formula (A5)-IVa, preferably, Z.sub.1 is --CR.sup.10e,
R.sup.10e is a hydrogen atom or a methyl group, Z.sub.2 is a sulfur
atom, Z.sub.3 is --CR.sup.10f-, and R.sup.10f is a hydrogen atom.
X.sub.2 is --CH.dbd.CH-- or --N(R.sub.z1)CH.sub.2--, and R.sub.z1
is a methyl group.
[0395] Specific examples of Formula (A5)-IVa include
5-(spiro[isobenzofuran-1(3H),4'-piperidin]-1'-ylmethyl)-2-thienyl,
5-(spiro[benzofuran-3 (2H),4'-piperidin]-1'-ylmethyl)-2-thienyl,
5-(spiro[6-azaisobenzofuran-1(3H),4'-piperidin]-1'-ylmethyl)-2-thienyl,
5-(3-oxospiro[4-azaisobenzofuran-1(3H),4'-piperidin]-1'-ylmethyl)-2-thien-
yl,
5-(3-oxospiro[6-azaisobenzofuran-1(3H),4'-piperidin]-1'-ylmethyl)-2-th-
ienyl,
5-(spiro[5-fluoroisobenzofuran-1(3H),4'-piperidin]-1'-ylmethyl)-2-t-
hienyl,
5-(spiro[6-fluoroisobenzofuran-1(3H),4'-piperidin]-1'-ylmethyl)-2--
thienyl,
5-(spiro[5-fluoro-6-azaisobenzofuran-1(3H),4'-piperidin]-1'-ylmet-
hyl)-2-thienyl,
5-(spiro[6-fluoro-5-azaisobenzofuran-1(3H),4'-piperidin]-1'-ylmethyl)-2-t-
hienyl, and 5-(7-fluoro-1H-spiro
[fluoro[3,4-c]pyridin-3,4'-piperidin]-1'-ylmethyl)-2-thienyl.
[0396] [1-13-ga] The ring A in Formula (I) is preferably Formula
(A)-VIa:
##STR00047##
[0397] (where R.sub.xb is a group selected from a hydrogen atom, a
fluorine atom, a chlorine atom, C.sub.1-3 alkyl, trifluoromethyl,
and methoxy, more preferably, a hydrogen atom; and R.sup.6a,
R.sup.7a, R.sup.8a, xa, and Y.sup.1a to Y.sup.4a are the same as
defined in Formula (SP')).
[0398] Specific examples of the ring A include rings in which
Partial Structural Formula (SP')--CH.sub.2--:
##STR00048##
in Formula (A)-VIa is (spiro[isobenzofuran-1(3H),
4'-piperidin]-1-yl)methyl, (spiro [benzofuran-3(2H),
4'-piperidin]-1-yl)methyl, (3-oxospiro[6-azaisobenzofuran-1(3H),
4'-piperidin]-1-yl)methyl, (spiro[5-fluoroisobenzofuran-1(3H),
4'-piperidin]-1-yl)methyl, (spiro[6-fluoroisobenzofuran-1(3H),
4'-piperidin]-1-yl)methyl,
(spiro[5-fluoro-6-azaisobenzofuran-1(3H),
4'-piperidin]-1-yl)methyl, (spiro[6-azaisobenzofuran-1(3H),
4'-piperidin]-1-yl)methyl, (spiro[5-fluoroisobenzofuran-1(3H),
4'-piperidin]-1-yl)methyl, (spiro[6-fluoroisobenzofuran-1(3H),
4'-piperidin]-1-yl)methyl,
(spiro[5-fluoro-6-azaisobenzofuran-1(3H),
4'-piperidin]-1-yl)methyl, or
(7-fluoro-1H-spiro[fluoro[3,4-c]pyridin-3,4'-piperidin]-1-yl)methyl.
[0399] [1-13-ha] The ring A in Formula (I) is preferably Partial
Structural Formula (A)-VIIa:
##STR00049##
[0400] (where T is the same as defined in Formula (AA) described in
Aspect [1-13-d]; the definitions of R.sup.6a, R.sup.7a, R.sup.8a,
xa, and Y.sup.1a to Y.sup.4a correspond to the definitions of
R.sup.6, R.sup.7, R.sup.8, x, and Y.sup.1 to Y.sup.4 respectively
in Formula [II] in WO 2002/088989 pamphlet; R.sub.xb is a group
selected from a hydrogen atom, a fluorine atom, a chlorine atom,
C.sub.1-3 alkyl, trifluoromethyl, and methoxy, preferably a
hydrogen atom; R.sub.xc is a group selected from a hydrogen atom, a
fluorine atom, a chlorine atom, C.sub.1-3 alkyl, trifluoromethyl,
and methoxy, preferably a hydrogen atom; and the broken lines and
the figures 4 and 5 indicate the binding position of the
substituted spiropiperidinylmethyl group).
[0401] Specific examples of the ring A include rings in which
Partial Structural Formula (SP')--CH.sub.2--:
##STR00050##
in Formula (A)-VIIa is (spiro [isobenzofuran-1(3H),
4'-piperidin]-1-yl)methyl, (spiro [benzofuran-3 (2H),
4'-piperidin]-1-yl)methyl, (3-oxospiro[6-azaisobenzofuran-1(3H),
4'-piperidin]-1-yl)methyl, (spiro[5-fluoroisobenzofuran-1(31H),
4'-piperidin]-1-yl)methyl, (spiro[6-fluoroisobenzofuran-1(3H),
4'-piperidin]-1-yl)methyl,
(spiro[5-fluoro-6-azaisobenzofuran-1(3H),
4'-piperidin]-1-yl)methyl, (spiro[6-azaisobenzofuran-1(3H),
4'-piperidin]-1-yl)methyl, (spiro[5-fluoroisobenzofuran-1(3H),
4'-piperidin]-1-yl)methyl, (spiro[6-fluoroisobenzofuran-1(3H),
4'-piperidin]-1-yl)methyl,
(spiro[5-fluoro-6-azaisobenzofuran-1(3H),
4'-piperidin]-1-yl)methyl, or (7-fluoro-1H-spiro
[fluoro[3,4-c]pyridin-3,4'-piperidin]-1-yl)methyl.
[0402] [1-14] The group having the ring B and the cyclic amide
structure of Formula (I) according to Aspect [1] is Partial
Structural Formula (B):
##STR00051##
[0403] (where n, p, h, the ring B, J.sub.1, J.sub.2, R.sup.1,
R.sup.2a, and R.sup.2b are the same as defined in Formula (I)
described in Aspect [1]).
[0404] [1-14-a] In Formula (B), when the ring B is a monocyclic
ring, the ring B is preferably bonded to J.sub.1.
[0405] [1-14-a-1] In Formula (B), when the ring B is a benzene
ring, a pyridine ring, or a pyrimidine ring, Formula (B) is
preferably Formula (B)-1:
##STR00052##
[0406] (where n, p, h, J.sub.2, R.sup.1, R.sup.2a, and R.sup.2b are
the same as defined in Formula (I) described in Aspect [1]; the
ring B' is a benzene ring, a pyridine ring, or a pyrimidine ring;
and J.sup.1a is CR.sup.11a or a nitrogen atom).
[0407] [1-14-a-2] More preferable examples of Formula (B) include
Formula (B1) and Formula (B2):
##STR00053##
[0408] (where n, p, h, J.sub.2, R.sup.1, R.sup.2a, and R.sup.2b are
the same as defined in Formula (I); and the ring B' and J.sub.1a
are the same as defined in Formula (B)-1). When the binding
position with the linker moiety containing X is determined as
1-position, in Formula (B1), R.sup.1 can be bonded at 2-position,
3-position, 5-position, and 6-position, and in Formula (B2),
R.sup.1 can be bonded at 2-position, 4-position, 5-position, and
6-position.
[0409] [1-14-a-3] Formula (B) or Formula (B)-1 is preferably
Formula (B1).
[0410] [1-14-a-4] More preferable examples of Formula (B) or
Formula (B)-1 include Formula (B1a) and Formula (B1b):
##STR00054##
[0411] (where n, p, h, J.sub.2, R.sup.1, R.sup.2a, and R.sup.2b are
the same as defined in Formula (I); and J.sub.1a is the same as
defined in Formula (B)-1).
[0412] [1-14-a-5] Further preferable examples of Formula (B) or
Formula (B)-1 include Formula (B1a).
[0413] [1-14-b] When in Formula (B), the ring B is Formula (BB) or
Formula (BB2), Formula (B) is Formula (BB1)-1 or Formula
(BB2)-1:
##STR00055##
[0414] (where n, p, h, J.sub.1, J.sub.2, R.sup.1, R.sup.2a, and
R.sup.2b are the same as defined in Formula (I) described in Aspect
[1]; and G, W.sub.1, W.sub.2, and W.sub.3 are the same as in
Formula (BB1) and Formula (BB2) described in Aspect [1-10]).
Specifically, Formula (B) is preferably Formula (BB1)-1a, Formula
(BB1)-1b, Formula (BB2)-1a, or Formula (BB2)-1b:
##STR00056##
[0415] (where n, p, h, J.sub.1, J.sub.2, R.sup.1, R.sup.2a, and
R.sup.2b are the same as defined in Formula (I) described in Aspect
[1]; J.sub.1a is the same as defined in Formula (B)-1; and G,
W.sub.1, W.sub.2, and W.sub.3 are the same as in Formula (BB1) and
Formula (BB2) described in Aspect [1-10]).
[0416] When J.sub.2 is --CR.sup.12aR.sup.12b-, a structure in which
Formula (BB1) or Formula (BB2) is bonded to J.sub.2 adjacent to S
in the cyclic amide structure, is also preferred.
[0417] [1-14-c] When the ring A is Formula (A) described in Aspect
[1-13-c] and the ring A'-V-- is bonded at the m-position relative
to the binding position with the linker moiety containing X,
specifically when the ring A is Formula (A1a), Formula (A1b),
Formula (A1c), or Formula (A1)-1-1 described in Aspect [1-13-c-3-1]
or Aspect [1-13-c-11], in Formula (B)-1, an isothiazolyl group is
preferably bonded at the p-position relative to the binding
position with the linker moiety containing X. When the ring A is
Formula (AA1) described in Aspect [1-13-d-4] and R.sup.13a is
bonded at 4-position, or the ring A is Formula (AA1b) described in
Aspect [1-13-d-7] and R.sup.13a is bonded at 7-position,
specifically also when the ring A is Formula (AA1)-1, Formula
(AA1a)-1, Formula (AA1a)-1-1, or Formula (AA1b)-1 described in
Aspects [1-13-d-5] to [1-13-d-7-1], in Formula (B)-1, an
isothiazolyl group is preferably bonded at the p-position relative
to the binding position with the linker moiety containing X.
Further, also when the ring A is Formula (A)-IV, Formula (A1)-IV,
Formula (A2)-IV, Formula (A3)-IV, or Formula (A4)-IV described in
Aspects [1-13-e] to [1-13-e-8], Formula (A)-V, Formula (A1)-V,
Formula (AA)-V, or Formula (AA1)-V described in Aspects [1-13-f] to
[1-13-f-10], or Formula (A)-VI or Formula (AA)-VI described in
Aspects [1-13-g] to [1-13-g-2], in Formula (B)-1, an isothiazolyl
group is preferably bonded at the p-position relative to the
binding position with the linker moiety containing X.
[0418] [1-14-c-1] When the ring A is Formula (A) described in
Aspect [1-13-c] and the ring A'-V-- is bonded at the p-position
relative to the binding position with the linker moiety containing
X, specifically when the ring A is Formula (A1)-1-2 described in
Aspect [1-13-c-12], in Formula (B)-1, an isothiazolyl group is
preferably bonded at the m-position relative to the binding
position with the linker moiety containing X.
[0419] [1-14-d] In Formula (B), Formula (B)-1, Formula (B1),
Formula (B2), Formula (B1a), Formula (B1b), Formula (BB1)-1,
Formula (BB2)-1, Formula (BB1)-1a, Formula (BB1)-1b, Formula
(BB2)-1a, or Formula (BB2)-1b, R.sup.1 is preferably a halogen
atom, a C.sub.1-4 alkyl group which is optionally substituted with
1 to 5 halogen atom(s), a C.sub.1-4 alkoxy group which is
optionally substituted with 1 to 5 halogen atom(s), or a cyano
group, and more specifically, R.sup.1 is preferably a fluorine
atom, a chlorine atom, a bromine atom, methyl, ethyl, propyl,
isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, trifluoromethyl,
methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy,
sec-butoxy, tert-butoxy, trifluoromethoxy, or cyano. p is
preferably 0 or 1, more preferably 0.
[0420] In Formula (B), Formula (B)-1, Formula (B1), Formula (B2),
Formula (B1a), Formula (B1b), Formula (BB1)-1, Formula (BB2)-1,
Formula (BB1)-1a, Formula (BB1)-1b, Formula (BB2)-1a, or Formula
(BB2)-1b, R.sup.2a and R.sup.2b are preferably a hydrogen atom, a
halogen atom, or a C.sub.1-4 alkyl group. More specifically,
R.sup.2a and R.sup.2b are preferably a hydrogen atom, a fluorine
atom, a chlorine atom, a bromine atom, or methyl, and more
preferably, any one of R.sup.2a and R.sup.2b is a hydrogen atom.
Further preferably, both of R.sup.2a and R.sup.2b are a hydrogen
atom.
[0421] In Formula (B), Formula (B)-1, Formula (B1), Formula (B2),
Formula (B1a), Formula (B1b), Formula (BB1)-1, Formula (BB2)-1,
Formula (BB1)-1a, Formula (BB1)-1b, Formula (BB2)-1a, or Formula
(BB2)-1b, h is preferably 0 or 1 and n is preferably 1 or 2. When
J.sub.1a is CR.sup.11a and h is 0, n is more preferably 1. When
J.sub.1a is a nitrogen atom and h is 0, n is more preferably 2.
When h is an integer of 1 to 3, n is more preferably 2.
[0422] [1-14-e] The cyclic amide structure bonded to the ring B in
Formula (I), Formula (B), Formula (BB1)-1, or Formula (BB2)-1 is
Partial Structural Formula (B-Het):
##STR00057##
[0423] (where n, h, J.sub.1, J.sub.2, R.sup.2a, and R.sup.2b are
the same as defined in Formula (I) described in Aspect [1]). In
Formula (B-Het), the ring B can be bonded at any position in the
ring, specifically to a carbon atom to which R.sup.2a and R.sup.2b
are bonded, J.sub.1, or J.sub.2.
[0424] In Formula (I) or Formula (B), Formula (B-Het) is preferably
Formula (B-Het)-1 or (B-Het)-2:
##STR00058##
[0425] (where n, h, J.sub.1, J.sub.2, R.sup.2a, and R.sup.2b are
the same as defined in Formula (I) described in Aspect [1]; and
J.sub.1a is the same as defined in Formula (B)-1).
[0426] [1-14-e-1] More preferable examples of Formula (B-Het) or
Formula (B-Het)-1 include Formula (B-Het)-1a, Formula (B-Het)-1b,
Formula (B-Het)-1c, Formula (B-Het)-1d, Formula (B-Het)-1e, and
Formula (B-Het)-1f:
##STR00059##
[0427] (where n, R.sup.2a, R.sup.2b, R.sup.11a, R.sup.12a,
R.sup.12b, and R.sup.12c are the same as defined in Formula (I)
described in Aspect [1]; and h1 is 1 or 2).
[0428] More preferable examples of Formula (B-Het) or Formula
(B-Het)-2 include Formula (B-Het)-2a, Formula (B-Het)-2b, Formula
(B-Het)-2c, Formula (B-Het)-2d, Formula (B-Het)-2e, Formula
(B-Het)-2f, Formula (B-Het)-3c, and Formula (B-Het)-3f:
##STR00060## ##STR00061##
[0429] (where n, R.sup.2a, R.sup.2b, R.sup.11a, R.sup.11b,
R.sup.12a, R.sup.12b, R.sup.11c, and R.sup.12c are the same as
defined in Formula (I) described in Aspect [1]; and h1 is 1 or
2).
[0430] In Formula (I) according to Aspect [1], a compound in which
the cyclic amide structure bonded to the ring B (that is, Formula
(B-Het)) is Formula (B-Het)-1a is Formula (I)-1a. Similarly, the
compound having Formula (B-Het)-1b is Formula (I)-1b; the compound
having Formula (B-Het)-1c is Formula (I)-1c; the compound having
Formula (B-Het)-1d is Formula (I)-1d; the compound having Formula
(B-Het)-1e is Formula (I)-1e; the compound having Formula
(B-Het)-1f is Formula (I)-1f; the compound having Formula
(B-Het)-2a is Formula (I)-2a; the compound having Formula
(B-Het)-2b is Formula (I)-2b; the compound having Formula
(B-Het)-2c is Formula (I)-2c; the compound having Formula
(B-Het)-2d is Formula (I)-2d; the compound having Formula
(B-Het)-2e is Formula (I)-2e; the compound having Formula
(B-Het)-2f is Formula (I)-2f; the compound having Formula
(B-Het)-3c is Formula (I)-3c; and the compound having Formula
(B-Het)-3f is Formula (I)-3f.
[0431] In Formula (B-Het)-1a, n is preferably 1 or 2, and
specifically, Formula (B-Het)-1a is Formula (B-Het)-1a1 or Formula
(B-Het)-1a2:
##STR00062##
[0432] (where R.sup.2a, R.sup.2b, and R.sup.11a are the same as
defined in Formula (I)).
[0433] [1-14-e-2] In each formula used for a compound in each
aspect of Aspect [1], the Formula (B-Het) moiety can be accordingly
selected from, for example, Formulae (het1) to (het9):
##STR00063##
[0434] The Formula (B-Het) moiety is particularly preferably
Formulae (het1) to (het5) above.
[0435] [1-15] In a combination of j, k, X, R.sup.3, R.sup.4,
R.sup.3, and R.sup.6, in Formula (I), the linker moiety containing
X bonded to the ring A and the ring B is Partial Structural Formula
(C):
##STR00064##
[0436] (where j, k, X, R.sup.3, R.sup.4, R.sup.5, and R.sup.6 are
the same as defined in Formula (I) described in Aspect [1]; and is
a single bond with the ring A).
[0437] Preferable specific examples of Formula (C) include Formula
(c1) to Formula (c6).
##STR00065##
[0438] [1-15-a] More preferably, Formula (C) is Formula (c1),
Formula (c2), Formula (c4), or Formula (c5).
[0439] [1-15-b] When the ring A is a monocyclic ring or a spiro
ring, that is, when the ring A is a phenyl group, a monocyclic
heterocyclic group, a cycloalkyl group, a cycloalkenyl group, or a
spiro ring group, specifically, when the ring A is Formula (A),
Formula (A)-1, Formula (A1), Formula (A2), Formula (A1)-1, Formula
(A2)-1, Formula (A1a), Formula (A1b), Formula (A1c), Formula
(A1)-1-1, or Formula (A1)-1-2 described in Aspects [1-13-c] to
[1-13-c-12], Formula (A)-IV, Formula (A1)-IV, Formula (A2)-IV,
Formula (A3)-IV, or Formula (A4)-IV described in Aspects [1-13-e]
to [1-13-e-8], Formula (A)-V, Formula (A1)-V, Formula (AA)-V, or
Formula (AA1)-V described in Aspects [1-13-f] to [1-13-f-10],
Formula (A)-VI or Formula (AA)-VI described in Aspects [1-13-g] to
[1-13-g-2], or Formula (A5)-IVa or Formula (A)-VIa described in
Aspect [1-13-e-8a] or [1-13-ga], Formula (C) is further preferably
Formula (c2) or Formula (c5), most preferably Formula (c2).
[0440] [1-15-c] When the ring A is a fused ring, that is, when the
ring A is a ring-fused aryl group, a partly hydrogenated ring-fused
aryl group, a ring-fused heteroaryl group, a partly hydrogenated
ring-fused heteroaryl group, or a ring-fused non-aromatic
heterocyclic group, specifically when the ring A is Formula (AA),
Formula (AA)-1, Formula (AA)-1-1, Formula (AA1), Formula (AA1)-1,
Formula (AA1a)-1, Formula (AA1a)-1-1, Formula (AA1b), or Formula
(AA1b)-1 described in Aspects [1-13-d] to [1-13-d-7-1], Formula
(A)-VII or Formula (AA)-VII described in Aspect [1-13-h] or
[1-13-h-i], a phthalazinyl group described in Aspect [1-13-i],
Formula (A)-VIII described in Aspect [1-13-j], or Formula (A)-VIIa
described in Aspect [1-13-ha], Formula (C) is further preferably
Formula (c1) or Formula (c4), most preferably Formula (c1).
[0441] [1-15-d] When the ring A is a 2-phenylamino-2-oxoacetyl
group, specifically when the ring A is Formula (A)-IX described in
Aspect [1-13-k], the linker moiety is preferably --NR.sup.7--, more
preferably Formula (c4).
[0442] [1-16] The compound of Formula (I) according to Aspect [1]
is preferably a compound of Formula (I)-1:
##STR00066##
[0443] (where n, p, h, j, k, the ring A, X, J.sub.2, R.sup.1,
R.sup.2a, R.sup.2b, R.sup.3, R.sup.4, R.sup.5, and R.sup.6 are the
same as defined in Formula (I) described in Aspect [1]; and the
ring B' and J.sub.1a are the same as defined in Formula (B)-1
described in Aspect [1-14-a-1](with the proviso that a compound
that is
5-[4-[2-(2-phenyl-4-oxazolyl)ethoxy]phenyl]-1,1-dioxo-1,2,5-thiadiazolidi-
n-3-one; a compound in which a saturated cyclic amide structure
having --S(O).sub.n--NH--CO-- is 1,1-dioxo-1,2-thiazolidin-3-one,
the ring B' is a benzene ring, k is 1, and in the ring B', the
linker moiety containing X and the cyclic amide structure are at
the p-position; and a compound in which the cyclic amide structure
is 1,1-dioxo-1,2,5-thiadiazolidin-3-one, and in the ring B', the
cyclic amide structure is bonded to an atom adjacent to an atom to
which the linker containing X is bonded, are excluded)).
[0444] More specifically, the preferable aspects of n, p, h, j, k,
the ring A, the ring B', X, J.sub.1a, J.sub.2, R.sup.1, R.sup.2a,
R.sup.2b, R.sup.3, R.sup.4, R.sup.5, and R.sup.6 are the same as
the preferable aspects described in any one of Aspects [1-1] to
[1-15] and subordinate Aspects thereof. The preferable aspects of
the partial structure of Formula (I)-1 corresponding to the ring A,
Partial Structural Formula (B)-1, Partial Structural Formula
(B-Het)-1, or Partial Structural Formula (C) that are described in
any one of Aspects [1-13], [1-14], and [1-15], and subordinate
Aspects thereof are the same as described in any one of Aspects
[1-13], [1-14], and [1-15], and subordinate Aspects thereof.
[0445] [1-16-1] The compound of Formula (I)-1 according to Aspect
[1-16] is preferably a compound in which the ring A is Formula (A),
that is, a compound of Formula (II):
##STR00067##
[0446] (where n, p, h, j, k, X, J.sub.2, R.sup.1, R.sup.2a,
R.sup.2b, R.sup.3, R.sup.4, R.sup.5, and R.sup.6 are the same as
defined in Formula (I) described in Aspect [1]; the ring B' and
J.sub.1a are the same as defined in Formula (B)-1 described in
Aspect [1-14-a-1]; q, r, s, the ring A', V, R.sup.8, R.sup.9, and
R.sup.10 are the same as defined in Formula (A) described in Aspect
[1-13-c](with the proviso that a compound in which the saturated
cyclic amide structure having --S(O).sub.n--NH--CO-- is
1,1-dioxo-1,2-thiazolidin-3-one, the ring B' is a benzene ring, k
is 1, and in the ring B', the linker moiety containing X and the
cyclic amide structure are at the p-position is excluded)).
[0447] More specifically, the preferable aspects of n, p, q, r, s,
h, j, k, the ring A', the ring B', X, V, J.sub.1a, J.sub.2,
R.sup.1, R.sup.2a, R.sup.2b, R.sup.3, R.sup.4, R.sup.5, R.sup.6,
R.sup.8, R.sup.9, and R.sup.10 are the same as the preferable
aspects described in any one of Aspects [1-1] to [1-15] and
subordinate Aspects thereof. The preferable aspects of the partial
structure of Formula (II) corresponding to Partial Structural
Formula (A), Partial Structural Formula (B)-1, Partial Structural
Formula (B-Het)-1, or Partial Structural Formula (C) described in
any one of Aspects [1-13-c], [1-14], and [1-15], and subordinate
Aspects thereof are the same as described in any one of Aspects
[1-13-c], [1-14], and [1-15], and subordinate Aspects thereof.
[0448] The compound of Formula (II) is preferably a compound of
Formula (II) in which the ring A' is a benzene ring, a pyridine
ring, or a pyrimidine ring, that is, a compound in which the ring A
is Formula (A)-1 in Formula (I), which is a compound of Formula
(II)-1:
##STR00068##
[0449] (where n, p, h, j, k, X, J.sub.2, R.sup.1, R.sup.2a,
R.sup.2b, R.sup.3, R.sup.4, R.sup.5, and R.sup.6 are the same as
defined in Formula (I) described in Aspect [1]; the ring B' and
J.sub.1a are the same as defined in Formula (B)-1 described in
Aspect [1-14-a-1]; q, r, s, the ring A'', V, R.sup.8, R.sup.9, and
R.sup.10 are the same as defined in Formula (A) or Formula (A)-1
described in Aspect [1-13-c](with the proviso that a compound in
which the saturated cyclic amide structure having
--S(O).sub.n--NH--CO-- is 1,1-dioxo-1,2-thiazolidin-3-one, the ring
B' is a benzene ring, k is 1, and in the ring B', the linker moiety
containing X and the cyclic amide structure are at the p-position
is excluded)).
[0450] More specifically, the preferable aspects of n, p, q, r, s,
h, j, k, the ring A'', the ring B', X, V, J.sub.1a, J.sub.2,
R.sup.1, R.sup.2a, R.sup.2b, R.sup.3, R.sup.4, R.sup.5, R.sup.6,
R.sup.8, R.sup.9, and R.sup.10 are the same as the preferable
aspects described in any one of Aspects [1-1] to [1-15] and the
subordinate Aspects thereof. The preferable aspects of the partial
structure of Formula (II)-1 corresponding to Partial Structural
Formula (A)-1, Partial Structural Formula (B)-1, Partial Structural
Formula (B-Het)-1, or Partial Structural Formula (C) described in
any one of Aspects [1-13-c], [1-14], and [1-15], and the
subordinate Aspects thereof are the same as described in any one of
Aspects [1-13-c], [1-14], and [1-15], and subordinate Aspects
thereof.
[0451] In Formula (II) or Formula (II)-1, X is preferably an oxygen
atom or --NH--, more preferably an oxygen atom. In Formula (II) or
Formula (II)-1, j is preferably 1. k is preferably 0. In Formula
(II) or Formula (II)-1, more preferably, X is an oxygen atom and k
is 0. Further preferably, X is an oxygen atom, j is 1, and k is
0.
[0452] In Formula (II) or Formula (II)-1, in the ring B', the
linker moiety containing X and the cyclic amide structure are
preferably at the p-position, that is, the partial structure has
preferably Formula (B1). The ring B' is preferably a benzene
ring.
[0453] In Formula (II) or Formula (II)-1, preferably, any one of q
and s is 1 or more, more preferably, s is 1.
[0454] In Formula (II) or Formula (II)-1, preferably, X is an
oxygen atom, k is 0, and any one of q and s is 1 or more, more
preferably, X is an oxygen atom, k is 0, and s is 1.
[0455] [1-16-1a] In the compound of Formula (II), compounds
produced by optionally combining the groups of Partial Structural
Formula (A) (on the left of the left wavy line), Partial Structural
Formula (B) (on the right of the right wavy line), Partial
Structural Formula (C) (between the two wavy lines) in Formula (II)
can be produced optionally.
##STR00069##
More specifically, Partial Structural Formula (A) is a group
optionally selected from Formula (A)-1, Formula (A1), Formula (A2),
Formula (A1)-1, Formula (A2)-1, Formula (A1a), Formula (A1b),
Formula (A1c), Formula (A1)-1-1, and Formula (A1)-1-2 described in
Aspects [1-13-c] to [1-13-c-12]. Partial Structural Formula (B)-1
is a group optionally selected from Formula (B1), Formula (B2),
Formula (B1a), and Formula (B1b) described in Aspects [1-14-a-2]
and [1-14-a-4], and Partial Structural Formula (C) can be a group
optionally selected from Formula (c1) to Formula (c6) described in
Aspect [1-15]. An optional combination of each formula forms part
of the compound of Formula (I) according to the present
invention.
[0456] In the compound of Formula (II), preferably, Partial
Structural Formula (A) is Formula (A2)-1 in which the ring A''-O--
is bonded at 3-position, Formula (A1a), Formula (A1b), or Formula
(A1c), Partial Structural Formula (B)-1 is Formula (B1a) or Formula
(B1b), and Partial Structural Formula (C) is Formula (c2) or
Formula (c5). More preferably, Partial Structural Formula (A) is
Formula (A2)-1 in which the ring A''-O-- is bonded at 3-position,
Formula (A1a), or Formula (A1c), Partial Structural Formula (B)-1
is Formula (B1a), and Partial Structural Formula (C) is Formula
(c2). Further preferably, Partial Structural Formula (B-Het)-1 in
Partial Structural Formula (B)-1 is Formula (B-Het)-1a, Formula
(B-Het)-1b, Formula (B-Het)-1c, Formula (B-Het)-1d, Formula
(B-Het)-1e, or Formula (B-Het)-1f described in Aspect [1-14-e-1].
An optional combination of each formula forms part of the
preferable compound of Formula (I) according to the present
invention.
[0457] [1-16-1-a] The compound of Formula (II) or Formula (II)-1
according to Aspect [1-16-1] is preferably a compound of Formula
(II)-1a:
##STR00070##
[0458] (where n, p, j, k, X, R.sup.1, R.sup.2a, R.sup.2b, R.sup.3,
R.sup.4, R.sup.5, R.sup.6, and R.sup.11a are the same as defined in
Formula (I); the ring B' is the same as defined in Formula (B)-1
described in Aspect [1-14-a-1]; and q, r, s, the ring A'', V,
R.sup.8, R.sup.9, and R.sup.10 are the same as defined in Formula
(A) or Formula (A)-1 described in Aspect [1-13-c](with the proviso
that a compound in which the saturated cyclic amide structure
having --S(O).sub.n--NH--CO-- is 1,1-dioxo-1,2-thiazolidin-3-one,
the ring B' is a benzene ring, k is 1, and in the ring B', the
linker moiety containing X and the cyclic amide structure are at
the p-position is excluded)), a salt of the compound, or a solvate
of the compound or the salt.
[0459] More specifically, the preferable aspects of n, p, q, r, s,
j, k, the ring A'', the ring B', X, V, R.sup.1, R.sup.2a, R.sup.2b,
R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.8, R.sup.9, R.sup.10, and
R.sup.11a are the same as the preferable aspects described in any
one of Aspects [1-1] to [1-15] and subordinate Aspects thereof. The
preferable aspects of the partial structure of Formula (II)-1a
corresponding to Partial Structural Formula (A)-1, Partial
Structural Formula (B)-1, Partial Structural Formula (B-Het)-1a, or
Partial Structural Formula (C) described in any one of Aspects
[1-13-c], [1-14], and [1-15], and subordinate Aspects thereof are
the same as described in any one of Aspects [1-13-c], [1-14], and
[1-15], and subordinate Aspects thereof.
[0460] In Formula (II)-1a, X is preferably an oxygen atom or
--NH--, more preferably an oxygen atom. In Formula (II)-1a, j is
preferably 1. k is preferably 0. In Formula (II)-1a, more
preferably, x is an oxygen atom and k is 0. Further preferably, X
is an oxygen atom, j is 1, and k is 0.
[0461] In Formula (II)-1a, in the ring B', the linker moiety
containing X and the cyclic amide structure are preferably at the
p-position. The ring B' is preferably a benzene ring.
[0462] In Formula (II)-1a, preferably, any one of q and s is 1 or
more, and more preferably, s is 1.
[0463] In Formula (II)-1a, preferably, X is an oxygen atom, k is 0,
and any one of q and s is 1 or more, and more preferably, X is an
oxygen atom, k is 0, and s is 1.
[0464] [1-16-1-b] The compound of Formula (II) or Formula (II)-1
according to Aspect [1-16-1] is preferably a compound of Formula
(II)-1b:
##STR00071##
[0465] (where p, j, k, X, R.sup.1, R.sup.2a, R.sup.2b, R.sup.3,
R.sup.4, R.sup.5, and R.sup.6 are the same as defined in Formula
(I) described in Aspect [1]; the ring B' is the same as defined in
Formula (B)-1 described in Aspect [1-14-a-1]; and q, r, s, the ring
A'', V, R.sup.8, R.sup.9, and R.sup.10 are the same as defined in
Formula (A) or Formula (A)-1 described in Aspect [1-13-c]), or a
salt of the compound, or a solvate of the compound or the salt.
[0466] More specifically, the preferable aspects of p, q, r, s, j,
k, the ring A'', the ring B', X, V, R, R.sup.2a, R.sup.2b, R.sup.3,
R.sup.4, R.sup.5, R.sup.6, R.sup.8, R.sup.9, and R.sup.10 are the
same as the preferable aspects described in any one of Aspects
[1-1] to [1-15] and subordinate Aspects thereof. The preferable
aspects of the partial structure of Formula (II)-1b corresponding
to Partial Structural Formula (A)-1, Partial Structural Formula
(B)-1, Partial Structural Formula (B-Het)-1b, or Partial Structural
Formula (C) described in any one of Aspects [1-13-c], [1-14], and
[1-15], and subordinate Aspects thereof are the same as described
in any one of Aspects [1-13-c], [1-14], and [1-15], and subordinate
Aspects thereof.
[0467] In Formula (II)-1b, X is preferably an oxygen atom or
--NH--, more preferably an oxygen atom. In Formula (II)-1b, j is
preferably 1. k is preferably 0. In Formula (II)-1b, more
preferably, X is an oxygen atom and k is 0. Further preferably, X
is an oxygen atom, j is 1, and k is 0.
[0468] In Formula (II)-1b, in the ring B', the linker moiety
containing X and the cyclic amide structure are preferably at the
p-position. The ring B' is preferably a benzene ring.
[0469] In Formula (II)-1b, preferably, any one of q and s is 1 or
more, and more preferably, s is 1.
[0470] In Formula (II)-1b, preferably, X is an oxygen atom, k is 0,
and any one of q and s is 1 or more, and more preferably, X is an
oxygen atom, k is 0, and s is 1.
[0471] [1-16-1-c] The compound of Formula (II) or Formula (II)-1
according to Aspect [1-16-1] is preferably a compound of Formula
(II)-1c:
##STR00072##
[0472] (where p, j, k, X, R.sup.1, R.sup.2a, R.sup.2b, R.sup.3,
R.sup.4, R.sup.5, R.sup.6, R.sup.11a, R.sup.12a, and R.sup.12b are
the same as defined in Formula (I); the ring B' is the same as
defined in Formula (B)-1 described in Aspect [1-14-a-1]; and q, r,
s, the ring A'', V, R.sup.8, R.sup.9, and R.sup.10 are the same as
defined in Formula (A) or Formula (A)-1 described in Aspect
[1-13-c]), a salt of the compound, or a solvate of the compound or
the salt.
[0473] More specifically, the preferable aspects of p, q, r, s, j,
k, the ring A'', the ring B', X, V, R.sup.1, R.sup.2a, R.sup.2b,
R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.8, R.sup.9, R.sup.10,
R.sup.11a, R.sup.12a, and R.sup.12b are the same as the preferable
aspects described in any one of Aspects [1-1] to [1-15] and
subordinate Aspects thereof. The preferable aspects of the partial
structure of Formula (II)-1c corresponding to Partial Structural
Formula (A)-1, Partial Structural Formula (B)-1, Partial Structural
Formula (B-Het)-1c, or Partial Structural Formula (C) described in
any one of Aspects [1-13-c], [1-14], and [1-15], and subordinate
Aspects thereof are the same as described in any one of Aspects
[1-13-c], [1-14], and [1-15], and subordinate Aspects thereof.
[0474] In Formula (II)-1c, X is preferably an oxygen atom or
--NH--, more preferably an oxygen atom. In Formula (II)-1c, j is
preferably 1. k is preferably 0. In Formula (II)-1c, more
preferably, x is an oxygen atom and k is 0. Further preferably, X
is an oxygen atom, j is 1, and k is 0.
[0475] In Formula (II)-1c, in the ring B', the linker moiety
containing X and the cyclic amide structure are preferably at the
p-position. The ring B' is preferably a benzene ring.
[0476] In Formula (II)-1c, preferably, any one of q and s is 1 or
more, and more preferably, s is 1.
[0477] In Formula (II)-1c, preferably, X is an oxygen atom, k is 0,
and any one of q and s is 1 or more, and more preferably, X is an
oxygen atom, k is 0, and s is 1.
[0478] [1-16-1-d] The compound of Formula (II) or Formula (II)-1
according to Aspect [1-16-1] is preferably a compound of Formula
(II)-1d:
##STR00073##
[0479] (where p, j, k, X, R.sup.1, R.sup.2a, R.sup.2b, R.sup.3,
R.sup.4, R.sup.5, R.sup.6, R.sup.11a, and R.sup.12c are the same as
defined in Formula (I); the ring B' is the same as defined in
Formula (B)-1 described in Aspect [1-14-a-1]; and q, r, s, the ring
A'', V, R.sup.8, R.sup.9, and R.sup.10 are the same as defined in
Formula (A) or Formula (A)-1 described in Aspect [1-13-c]), a salt
of the compound, or a solvate of the compound or the salt.
[0480] More specifically, the preferable aspects of p, q, r, s, j,
k, the ring A'', the ring B', X, V, R.sup.1, R.sup.2a, R.sup.2b,
R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.8, R.sup.9, R.sup.10,
R.sup.11a, and R.sup.12c are the same as the preferable aspects
described in any one of Aspects [1-1] to [1-15] and subordinate
Aspects thereof. The preferable aspects of the partial structure of
Formula (II)-1d corresponding to Partial Structural Formula (A)-1,
Partial Structural Formula (B)-1, Partial Structural Formula
(B-Het)-1d, or Partial Structural Formula (C) described in any one
of Aspects [1-13-c], [1-14], and [1-15], and subordinate Aspects
thereof are the same as described in any one of Aspects [1-13-c],
[1-14], and [1-15], and subordinate Aspects thereof.
[0481] In Formula (II)-1d, X is preferably an oxygen atom or
--NH--, more preferably an oxygen atom. In Formula (II)-1d, j is
preferably 1. k is preferably 0. In Formula (II)-1d, more
preferably, x is an oxygen atom and k is 0. Further preferably, X
is an oxygen atom, j is 1, and k is 0.
[0482] In Formula (II)-1d, in the ring B', the linker moiety
containing X and the cyclic amide structure are preferably at the
p-position. The ring B' is preferably a benzene ring.
[0483] In Formula (II)-1d, preferably, any one of q and s is 1 or
more, and more preferably, s is 1.
[0484] In Formula (II)-1d, preferably, x is an oxygen atom, k is 0,
and any one of q and s is 1 or more, and more preferably, X is an
oxygen atom, k is 0, and s is 1.
[0485] [1-16-1-e] The compound of Formula (II) or Formula (II)-1
according to Aspect [1-16-1] is preferably a compound of Formula
(II)-1e:
##STR00074##
[0486] (where p, j, k, X, R.sup.1, R.sup.2a, R.sup.2b, R.sup.3,
R.sup.4, R.sup.5, R.sup.6, R.sup.11a, and R.sup.12c are the same as
defined in Formula (I); the ring B' is the same as defined in
Formula (B)-1 described in Aspect [1-14-a-1]; q, r, s, the ring
A'', V, R.sup.8, R.sup.9, and R.sup.10 are the same as defined in
Formula (A) or Formula (A)-1 described in Aspect [1-13-c]; and h1
is the same as defined in Formula (B-Het)-1e described in Aspect
[1-14-d]), a salt of the compound, or a solvate of the compound or
the salt.
[0487] More specifically, the preferable aspects of p, q, r, s, j,
k, the ring A'', the ring B', X, V, R.sup.1, R.sup.2a, R.sup.2b,
R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.8, R.sup.9, R.sup.10,
R.sup.11a, R.sup.12c, and h1 are the same as the preferable aspects
described in any one of Aspects [1-1] to [1-15] and subordinate
Aspects thereof. The preferable aspects of the partial structure of
Formula (II)-1e corresponding to Partial Structural Formula (A)-1,
Partial Structural Formula (B)-1, Partial Structural Formula
(B-Het)-1e, or Partial Structural Formula (C) described in any one
of Aspects [1-13-c], [1-14], and [1-15], and subordinate Aspects
thereof are the same as described in any one of Aspects [1-13-c],
[1-14], and [1-15], and subordinate Aspects thereof.
[0488] [1-16-1-f] The compound of Formula (II) or Formula (II)-1
according to Aspect [1-16-1] is preferably a compound of Formula
(II)-1f:
##STR00075##
[0489] (where p, j, k, X, R.sup.1, R.sup.2a, R.sup.2b, R.sup.3,
R.sup.4, R.sup.5, R.sup.6, R.sup.11a, R.sup.12a, and R.sup.12b are
the same as defined in Formula (I); the ring B' is the same as
defined in Formula (B)-1 described in Aspect [1-14-a-1]; q, r, s,
the ring A'', V, R.sup.8, R.sup.9, and R.sup.10 are the same as
defined in Formula (A) or Formula (A)-1 described in Aspect
[1-13-c]; and h1 is the same as defined in Formula (B-Het)-1f
described in Aspect [1-14-d]), a salt of the compound, or a solvate
of the compound or the salt.
[0490] More specifically, the preferable aspects of p, q, r, s, j,
k, the ring A'', the ring B', X, V, R.sup.1, R.sup.2a, R.sup.2b,
R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.8, R.sup.9, R.sup.10,
R.sup.11a, R.sup.12a, R.sup.12b, and h1 are the same as the
preferable aspects described in any one of Aspects [1-1] to [1-15]
and subordinate Aspects thereof. The preferable aspects of the
partial structure of Formula (II)-1f corresponding to Partial
Structural Formula (A)-1, Partial Structural Formula (B)-1, Partial
Structural Formula (B-Het)-1f, or Partial Structural Formula (C)
described in any one of Aspects [1-13-c], [1-14], and [1-15], and
subordinate Aspects thereof are the same as described in any one of
Aspects [1-13-c], [1-14], and [1-15], and subordinate Aspects
thereof.
[0491] [1-16-1-1] The compound of Formula (II) or Formula (II)-1
according to Aspect [1-16-1] is preferably Formula (II-1)-1:
##STR00076##
[0492] (where n, p, h, J.sub.2, R.sup.1, R.sup.2a, and R.sup.2b are
the same as defined in Formula (I); the ring B' and J.sub.1a are
the same as defined in Formula (B)-1 described in Aspect
[1-14-a-1]; q, r, s, the ring A'', R.sup.8, R.sup.9, and R.sup.10
are the same as defined in Formula (A) or Formula (A)-1 described
in Aspect [1-13-c]; the broken lines are the same as defined in
Formula (A1)-1 described in Aspect [1-13-c-1]; and E is a group
optionally selected from Formula (c1) to Formula (c6) shown as
specific examples of Formula (C) described in Aspect [1-15]).
[0493] More specifically, the preferable aspects of n, p, q, r, s,
h, the ring A'', the ring B', J.sub.1a, J.sub.2, R.sup.1, R.sup.2a,
R.sup.2b, R.sup.8, R.sup.9, R.sup.10, the broken lines, and E are
the same as the preferable aspects described in any one of Aspects
[1-1] to [1-15] and subordinate Aspects thereof. The preferable
aspects of the partial structure of Formula (II-1)-1 corresponding
to Partial Structural Formula (A1)-1 or Partial Structural Formula
(B1) described in any one of Aspects [1-13-c-1] and [1-14-a-2] are
the same as described in any one of Aspects [1-13-c] and [1-14],
and subordinate Aspects thereof.
[0494] In Formula (II-1)-1, E is preferably Formula (c2) or Formula
(c5), more preferably Formula (c2).
[0495] In Formula (II-1)-1, the ring B' is preferably a benzene
ring.
[0496] In Formula (II-1)-1, E and the ring A'' are preferably at
the m-position.
[0497] In Formula (II-1)-1, preferably, any one of q and s is 1 or
more, and more preferably, s is 1.
[0498] In Formula (II-1)-1, preferably, E is Formula (c2), any one
of q and s is 1 or more, and more preferably, E is Formula (c2) and
s is 1.
[0499] [1-16-1-1-a] The compound of Formula (II-1)-1 is more
preferably Formula (II-1)-1a:
##STR00077##
[0500] (where n, p, R.sup.1, R.sup.2a, R.sup.2b, and R.sup.11a are
the same as defined in Formula (I); the ring B' is the same as
defined in Formula (B)-1 described in Aspect [1-14-a-1]; q, r, s,
the ring A'', R.sup.8, R.sup.9, and R.sup.10 are the same as
defined in Formula (A) or Formula (A)-1 described in Aspect
[1-13-c]; the broken lines are the same as defined in Formula
(A1)-1 described in Aspect [1-13-c-1]; and E is a group optionally
selected from Formula (c1) to Formula (c6) shown as specific
examples of Formula (C) described in Aspect [1-15]).
[0501] More specifically, the preferable aspects of n, p, q, r, s,
the ring A'', the ring B', R.sup.1, R.sup.2a, R.sup.2b, R.sup.8,
R.sup.9, R.sup.10, R.sup.11a, the broken lines, and E are the same
as the preferable aspects described in any one of Aspects [1-1] to
[1-15] and subordinate Aspects thereof. The preferable aspects of
the partial structure of Formula (II-1)-1a corresponding to Partial
Structural Formula (A1)-1, Partial Structural Formula (B1), or
Partial Structural Formula (B-Het)-1a described in any one of
Aspects [1-13-c-1] and [1-14], and subordinate Aspects thereof are
the same as described in any one of Aspects [1-13-c] and [1-14],
and subordinate Aspects thereof.
[0502] In Formula (II-1)-1a, E is preferably Formula (c2) or
Formula (c5), more preferably Formula (c2).
[0503] In Formula (II-1)-1a, the ring B' is preferably a benzene
ring.
[0504] In Formula (II-1)-1a, E and the ring A'' are preferably at
the m-position.
[0505] In Formula (II-1)-1a, preferably, any one of q and s is 1 or
more, and more preferably, s is 1.
[0506] In Formula (II-1)-1a, preferably, E is Formula (c2), any one
of q and s is 1 or more, and more preferably, E is Formula (c2) and
s is 1.
[0507] [1-16-1-1-b] The compound of Formula (II-1)-1 is more
preferably Formula (II-1)-1b:
##STR00078##
[0508] (where p, R.sup.1, R.sup.2a, and R.sup.2b are the same as
defined in Formula (I); the ring B' is the same as defined in
Formula (B)-1 described in Aspect [1-14-a-1]; q, r, s, the ring
A'', R.sup.8, R.sup.9, and R.sup.10 are the same as defined in
Formula (A) or Formula (A)-1 described in Aspect [1-13-c]; the
broken lines are the same as defined in Formula (A1)-1 described in
Aspect [1-13-c-1]; and E is a group optionally selected from
Formula (c1) to Formula (c6) shown as specific examples of Formula
(C) described in Aspect [1-15]).
[0509] More specifically, the preferable aspects of p, q, r, s, the
ring A'', the ring B', R.sup.1, R.sup.2a, R.sup.2b, R.sup.8,
R.sup.9, R.sup.10, the broken lines, and E are the same as the
preferable aspects described in any one of Aspects [1-1] to [1-15]
and subordinate Aspects thereof. The preferable aspects of the
partial structure of Formula (II-1)-1b corresponding to Partial
Structural Formula (A1)-1, Partial Structural Formula (B1), or
Partial Structural Formula (B-Het)-1b described in any one of
Aspects [1-13-c-1] and [1-14], and subordinate Aspects thereof are
the same as described in any one of Aspects [1-13-c] and [1-14],
and subordinate Aspects thereof.
[0510] In Formula (II-1)-1b, E is preferably Formula (c2) or
Formula (c5), more preferably Formula (c2).
[0511] In Formula (II-1)-1b, the ring B' is preferably a benzene
ring.
[0512] In Formula (II-1)-1b, E and the ring A'' are preferably at
the m-position.
[0513] In Formula (II-1)-1b, preferably, any one of q and s is 1 or
more, and more preferably, s is 1.
[0514] In Formula (II-1)-1b, preferably, E is Formula (c2), any one
of q and s is 1 or more, and more preferably, E is Formula (c2) and
s is 1.
[0515] [1-16-1-1-c] The compound of Formula (II-1)-1 is more
preferably Formula (II-1)-1c:
##STR00079##
[0516] (where p, R.sup.1, R.sup.2a, R.sup.2b, R.sup.11a, R.sup.12a,
and R.sup.12b are the same as defined in Formula (I); the ring B'
is the same as defined in Formula (B)-1 described in Aspect
[1-14-a-1]; q, r, s, the ring A'', R.sup.8, R.sup.9, and R.sup.10
are the same as defined in Formula (A) or Formula (A)-1 described
in Aspect [1-13-c]; the broken lines are the same as defined in
Formula (A1)-1 described in Aspect [1-13-c-1]; and E is a group
optionally selected from Formula (c1) to Formula (c6) shown as
specific examples of Formula (C) described in Aspect [1-15]).
[0517] More specifically, the preferable aspects of p, q, r, s, the
ring A'', the ring B', R.sup.1, R.sup.2a, R.sup.2b, R.sup.8,
R.sup.9, R.sup.10, R.sup.11a, R.sup.12a, R.sup.12b, the broken
lines, and E are the same as the preferable aspects described in
any one of Aspects [1-1] to [1-15] and subordinate Aspects
thereof.
[0518] The preferable aspects of the partial structure of Formula
(II-1)-1c corresponding to Partial Structural Formula (A1)-1,
Partial Structural Formula (B1), or Partial Structural Formula
(B-Het)-1c described in any one of Aspects [1-13-c-1] and [1-14],
and subordinate Aspects thereof are the same as described in any
one of Aspects [1-13-c] and [1-14], and subordinate Aspects
thereof.
[0519] In Formula (II-1)-1c, E is preferably Formula (c2) or
Formula (c5), more preferably Formula (c2).
[0520] In Formula (II-1)-1c, the ring B' is preferably a benzene
ring.
[0521] In Formula (II-1)-1c, E and the ring A'' are preferably at
the m-position.
[0522] In Formula (II-1)-1c, preferably, any one of q and s is 1 or
more, and more preferably, s is 1.
[0523] In Formula (II-1)-1c, preferably, E is Formula (c2), any one
of q and s is 1 or more, and more preferably, E is Formula (c2) and
s is 1.
[0524] [1-16-1-1-d] The compound of Formula (II-1)-1 is more
preferably Formula (II-1)-1d:
##STR00080##
[0525] (where p, R.sup.1, R.sup.2a, R.sup.2b, R.sup.11a, and
R.sup.12c are the same as defined in Formula (I); the ring B' is
the same as defined in Formula (B)-1 described in Aspect
[1-14-a-1]; q, r, s, the ring A'', R.sup.8, R.sup.9, and R.sup.10
are the same as defined in Formula (A) or Formula (A)-1 described
in Aspect [1-13-c]; the broken lines are the same as defined in
Formula (A1)-1 described in Aspect [1-13-c-1]; and E is a group
optionally selected from Formula (c1) to Formula (c6) shown as
specific examples of Formula (C) described in Aspect [1-15]).
[0526] More specifically, the preferable aspects of p, q, r, s, the
ring A'', the ring B', R.sup.1, R.sup.2a, R.sup.2b, R.sup.8,
R.sup.9, R.sup.10, R.sup.11a, R.sup.12c, the broken lines, and E
are the same as the preferable aspects described in any one of
Aspects [1-1] to [1-15] and subordinate Aspects thereof. The
preferable aspects of the partial structure of Formula (II-1)-1d
corresponding to Partial Structural Formula (A1)-1, Partial
Structural Formula (B1), or Partial Structural Formula (B-Het)-1d
described in any one of Aspects [1-13-c-1] and [1-14], and
subordinate Aspects thereof are the same as described in any one of
Aspects [1-13-c] and [1-14], and subordinate Aspects thereof.
[0527] In Formula (II-1)-1d, E is preferably Formula (c2) or
Formula (c5), more preferably Formula (c2).
[0528] In Formula (II-1)-1d, the ring B' is preferably a benzene
ring.
[0529] In Formula (II-1)-1d, E and the ring A'' are preferably at
the m-position.
[0530] In Formula (II-1)-1d, preferably, any one of q and s is 1 or
more, and more preferably, s is 1.
[0531] In Formula (II-1)-1d, preferably, E is Formula (c2), any one
of q and s is 1 or more, and more preferably, E is Formula (c2) and
s is 1.
[0532] [1-16-1-1-e] The compound of Formula (II-1)-1 is more
preferably Formula (II-1)-1e:
##STR00081##
[0533] (where p, R.sup.1, R.sup.2a, R.sup.2b, R.sup.11a, and
R.sup.12c are the same as defined in Formula (I); the ring B' is
the same as defined in Formula (B)-1 described in Aspect
[1-14-a-1]; q, r, s, the ring A'', R.sup.8, R.sup.9, and R.sup.10
are the same as defined in Formula (A) or Formula (A)-1 described
in Aspect [1-13-c]; h1 is the same as defined in Formula (B-Het)-1e
described in Aspect [1-14-d]; the broken lines are the same as
defined in Formula (A1)-1 described in Aspect [1-13-c-1]; and E is
a group optionally selected from Formula (c1) to Formula (c6) shown
as specific examples of Formula (C) described in Aspect
[1-15]).
[0534] More specifically, preferable aspects of p, q, r, s, the
ring A'', the ring B', R.sup.1, R.sup.2a, R.sup.2b, R.sup.8,
R.sup.9, R.sup.10, R.sup.11a, R.sup.12c, h1, the broken lines, and
E are the same as the preferable aspects described in any one of
Aspects [1-1] to [1-15] and subordinate Aspects thereof. Preferable
aspects of the partial structure of Formula (II-1)-1e corresponding
to Partial Structural Formula (A1)-1, Partial Structural Formula
(B1), or Partial Structural Formula (B-Het)-1e described in any one
of Aspects [1-13-c-] and [1-14], and subordinate Aspects thereof
are the same as described in any one of Aspects [1-13-c] and
[1-14], and subordinate Aspects thereof.
[0535] [1-16-1-1-f] The compound of Formula (II-1)-1 is more
preferably Formula (II-1)-1f:
##STR00082##
[0536] (where p, R.sup.1, R.sup.2a, R.sup.2b, R.sup.11a, R.sup.12a,
and R.sup.12b are the same as defined in Formula (I); the ring B'
is the same as defined in Formula (B)-1 described in Aspect
[1-14-a-1]; q, r, s, the ring A'', R.sup.8, R.sup.9, and R.sup.10
are the same as defined in Formula (A) or Formula (A)-1 described
in Aspect [1-13-c]; h1 is the same as defined in Formula (B-Het)-1f
described in Aspect [1-14-d]; the broken lines are the same as
defined in Formula (A1)-1 described in Aspect [1-13-c-1]; and E is
a group optionally selected from Formula (c1) to Formula (c6) shown
as specific examples of Formula (C) described in Aspect
[1-15]).
[0537] More specifically, preferable aspects of p, q, r, s, the
ring A, the ring B', R.sup.1, R.sup.2a, R.sup.2b, R.sup.8, R.sup.9,
R.sup.10, R.sup.11a, R.sup.12a, R.sup.12b, h1, the broken lines,
and E are the same as the preferable aspects described in any one
of Aspects [1-1] to [1-15] and subordinate Aspects thereof.
Preferable aspects of the partial structure of Formula (II-1)-1f
corresponding to Partial Structural Formula (A1)-1, Partial
Structural Formula (B1), or Partial Structural Formula (B-Het)-1f
described in any one of Aspects [1-13-c-1] and [1-14], and
subordinate Aspects thereof are the same as described in any one of
Aspects [1-13-c] and [1-14], and subordinate Aspects thereof.
[0538] [1-16-1-2] The compound of Formula (II-1)-1 according to
Aspect [1-16-1-1] is more preferably Formula (II-1-A):
##STR00083##
[0539] (where n, p, h, J.sub.2, R.sup.1, R.sup.2a, and R.sup.2b are
the same as defined in Formula (I); J.sub.1a is the same as defined
in Formula (B)-1 described in Aspect [1-14-a-1]; q, r, R.sup.8,
R.sup.9, and R.sup.10 are the same as defined in Formula (A)
described in Aspect [1-13-c]; and G.sub.2 is the same as defined in
Formula (Ala) described in Aspect [1-13-c-3-1]).
[0540] More specifically, preferable aspects of n, p, q, r, h,
J.sub.1a, J.sub.2, R.sup.1, R.sup.2a, R.sup.2b, R.sup.8, R.sup.9,
R.sup.10 and G.sub.2 are the same as the preferable aspects
described in any one of Aspects [1-1] to [1-15] and subordinate
Aspects thereof. Preferable aspects of the partial structure of
Formula (II-1-A) corresponding to Partial Structural Formula (A1a)
or Partial Structural Formula (B1a) described in Aspect
[1-13-c-3-1] or [1-14-a-4] are the same as described in any one of
Aspects [1-13-c] and [1-14], and subordinate Aspects thereof.
[0541] [1-16-1-2a] In Formula (II-1-A), preferably, r is 0 or 1 and
R.sup.10 is a C.sub.1-4 alkyl group. Preferably, q is an integer of
1 to 3 and R.sup.9 is a halogen atom or a C.sub.1-4 alkyl group.
R.sup.8 is preferably a C.sub.1-6 alkoxy group (the alkoxy group is
substituted with 1 to 5 --OH, 1 to 5 ethoxy, 1 to 5 methylsulfonyl,
1 to 5 sulfamoyl, 1 to 5 methylsulfamoyl, 1 to 5 dimethylsulfamoyl,
1 to 5 carbamoyl, 1 to 5 methylcarbamoyl, 1 to 5 dimethylcarbamoyl,
1 to 5 --NH.sub.2, 1 to 5 acetylamino, 1 to 5 methylsulfonylamino,
1 to 5 2-oxo-1-pyrrolidinyl, or 1 to 5 3-methyloxetane-3-yl) or
(1,1-dioxidetetrahydro-2H-thiopyran-4-yl)oxy. More preferably,
R.sup.8 is a C.sub.1-6 alkoxy group (the alkoxy group is
substituted with 1 to 5 --OH, 1 to 5 ethoxy, 1 to 5 methylsulfonyl,
1 to 5 --NH.sub.2, 1 to 5 acetylamino, 1 to 5 methylsulfonylamino,
1 to 5 2-oxo-1-pyrrolidinyl, or 1 to 5 3-methyloxetane-3-yl) or
(1,1-dioxidetetrahydro-2H-thiopyran-4-yl)oxy. Further preferably,
R.sup.8 is a C.sub.1-6 alkoxy group (the alkoxy group is
substituted with 1 to 2 --OH, 1 to 2 ethoxy, 1 to 2 methylsulfonyl,
or 1 to 2 --NH.sub.2).
[0542] [1-16-1-2-a] The compound of Formula (II-1-A) according to
Aspect [1-16-1-2] is more preferably Formula (II-1-A)-a:
##STR00084##
[0543] (where n, p, R.sup.1, R.sup.2a, R.sup.2b, and R.sup.11a are
the same as defined in Formula (I); q, r, R.sup.8, R.sup.9 and
R.sup.10 are the same as defined in Formula (A) described in Aspect
[1-13-c]; and G.sub.2 is the same as defined in Formula (Ala)
described in Aspect [1-13-c-3-1]).
[0544] More specifically, preferable aspects of n, p, q, r,
R.sup.1, R.sup.2a, R.sup.2b, R.sup.8, R.sup.9, R.sup.10, R.sup.11a
and G.sub.2 are the same as the preferable aspects described in any
one of Aspects [1-1] to [1-15] and subordinate Aspects thereof.
Preferable aspects of the partial structure of Formula (II-1-A)-a
corresponding to Partial Structural Formula (A1a), Partial
Structural Formula (B1a), or Partial Structural Formula (B-Het)-1a
described in any one of Aspects [1-13-c-3-1] and [1-14], and
subordinate Aspects thereof are the same as described in any one of
Aspects [1-13-c] and [1-14], and subordinate Aspects thereof.
Preferable aspects of q, r, R.sup.8, R.sup.9, and R.sup.10 are the
same as described in Aspect [1-16-1-2a].
[0545] [1-16-1-2-b] The compound of Formula (II-1-A) according to
Aspect [1-16-1-2] is more preferably Formula (II-1-A)-b:
##STR00085##
[0546] (where p, R.sup.1, R.sup.2a, and R.sup.2b are the same as
defined in Formula (I); q, r, R.sup.8, R.sup.9, and R.sup.10 are
the same as defined in Formula (A) described in Aspect [1-13-c];
and G.sub.2 is the same as defined in Formula (A1a) described in
Aspect [1-13-c-3-1]).
[0547] More specifically, preferable aspects of p, q, r, R.sup.1,
R.sup.2a, R.sup.2b, R.sup.8, R.sup.9, R.sup.10, and G.sub.2 are the
same as the preferable aspects described in any one of Aspects
[1-1] to [1-15] and subordinate Aspects thereof. Preferable aspects
of the partial structure of Formula (II-1-A)-b corresponding to
Partial Structural Formula (A1a), Partial Structural Formula (B1a),
or Partial Structural Formula (B-Het)-1b described in any one of
Aspects [1-13-c-3-1] and [1-14], and subordinate Aspects thereof
are the same as described in any one of Aspects [1-13-c] and
[1-14], and subordinate Aspects thereof. Preferable aspects of q,
r, R.sup.8, R.sup.9, and R.sup.10 are the same as described in
Aspect [1-16-1-2a].
[0548] [1-16-1-2-c] The compound of Formula (II-1-A) according to
Aspect [1-16-1-2] is more preferably Formula (II-1-A)-c:
##STR00086##
[0549] (where p, R.sup.1, R.sup.2a, R.sup.2b, R.sup.11a, R.sup.12a,
and R.sup.12b are the same as defined in Formula (I); q, r,
R.sup.8, R.sup.9, and R.sup.10 are the same as defined in Formula
(A) described in Aspect [1-13-c]; and G.sub.2 is the same as
defined in Formula (Ala) described in Aspect [1-13-c-3-1]).
[0550] More specifically, preferable aspects of p, q, r, R.sup.1,
R.sup.2a, R.sup.2b, R.sup.8, R.sup.9, R.sup.10, R.sup.11a,
R.sup.12a, R.sup.12b, and G.sub.2 are the same as the preferable
aspects described in any one of Aspects [1-1] to [1-15] and
subordinate Aspects thereof. Preferable aspects of the partial
structure of Formula (II-1-A)-c corresponding to Partial Structural
Formula (A1a), Partial Structural Formula (B1a), or Partial
Structural Formula (B-Het)-1c described in any one of Aspects
[1-13-c-3-1] and [1-14], and subordinate Aspects thereof are the
same as described in any one of Aspects [1-13-c] and [1-14], and
subordinate Aspects thereof. Preferable aspects of q, r, R.sup.8,
R.sup.9, and R.sup.10 are the same as described in Aspect
[1-16-1-2a].
[0551] [1-16-1-2-d] The compound of Formula (II-1-A) according to
Aspect [1-16-1-2] is more preferably Formula (II-1-A)-d:
##STR00087##
[0552] (where p, R.sup.1, R.sup.2a, R.sup.2b, R.sup.11a, and
R.sup.11c are the same as defined in Formula (I); q, r, R.sup.8,
R.sup.9, and R.sup.10 are the same as defined in Formula (A)
described in Aspect [1-13-c]; and G.sub.2 is the same as defined in
Formula (Ala) described in Aspect [1-13-c-3-1]).
[0553] More specifically, preferable aspects of p, q, r, R.sup.1,
R.sup.2a, R.sup.2b, R.sup.8, R.sup.9, R.sup.10, R.sup.11a,
R.sup.12c and G.sub.2 are the same as the preferable aspects
described in any one of Aspects [1-1] to [1-15] and subordinate
Aspects thereof. Preferable aspects of the partial structure of
Formula (II-A-1)-d corresponding to Partial Structural Formula
(A1a), Partial Structural Formula (B1a), or Partial Structural
Formula (B-Het)-1d described in any one of Aspects [1-13-c-3-1] and
[1-14], and subordinate Aspects thereof are the same as described
in any one of Aspects [1-13-c] and [1-14], and subordinate Aspects
thereof. Preferable aspects of q, r, R.sup.8, R.sup.9, and R.sup.10
are the same as described in Aspect [1-16-1-2a].
[0554] [1-16-1-2-e] The compound of Formula (II-1-A) according to
Aspect [1-16-1-2] is more preferably Formula (II-1-A)-e:
##STR00088##
[0555] (where p, R.sup.1, R.sup.2a, R.sup.2b, R.sup.11a, and
R.sup.12c are the same as defined in Formula (I); q, r, R.sup.8,
R.sup.9, and R.sup.10 are the same as defined in Formula (A)
described in Aspect [1-13-c]; h1 is the same as defined in Formula
(B-Het)-1e described in Aspect [1-14-d]; and G.sub.2 is the same as
defined in Formula (A1a) described in Aspect [1-13-c-3-1]).
[0556] More specifically, preferable aspects of p, q, r, R.sup.1,
R.sup.2a, R.sup.2b, R.sup.8, R.sup.9, R.sup.10, R.sup.11a,
R.sup.12c, h1, and G.sub.2 are the same as the preferable aspects
described in any one of Aspects [1-1] to [1-15] and subordinate
Aspects thereof. Preferable aspects of the partial structure of
Formula (II-1-A)-e corresponding to Partial Structural Formula
(A1a), Partial Structural Formula (B1a), or Partial Structural
Formula (B-Het)-1e described in any one of Aspects [1-13-c-3-1] and
[1-14], and subordinate Aspects thereof are the same as described
in any one of Aspects [1-13-c] and [1-14], and subordinate Aspects
thereof. Preferable aspects of q, r, R.sup.8, R.sup.9, and R.sup.10
are the same as described in Aspect [1-16-1-2a].
[0557] [1-16-1-2-f] The compound of Formula (II-1-A) according to
Aspect [1-16-1-2] is more preferably Formula (II-1-A)-f:
##STR00089##
[0558] (where p, R.sup.1, R.sup.2a, R.sup.2b, R.sup.11a, R.sup.12a,
and R.sup.12b are the same as defined in Formula (I); q, r,
R.sup.8, R.sup.9, and R.sup.10 are the same as defined in Formula
(A) described in Aspect [1-13-c]; h1 is the same as defined in
Formula (B-Het)-1f described in Aspect [1-14-d]; and G.sub.2 is the
same as defined in Formula (A1a) described in Aspect
[1-13-c-3-1]).
[0559] More specifically, preferable aspects of p, q, r, R.sup.1,
R.sup.2a, R.sup.2b, R.sup.8, R.sup.9, R.sup.10, R.sup.11a,
R.sup.12a, R.sup.12b, h1, and G.sub.2 are the same as the
preferable aspects described in any one of Aspects [1-1] to [1-15]
and subordinate Aspects thereof. Preferable aspects of the partial
structure of Formula (II-1-A)-f corresponding to Partial Structural
Formula (A1a), Partial Structural Formula (B1a), or Partial
Structural Formula (B-Het)-1f described in any one of Aspects
[1-13-c-3-1] and [1-14], and subordinate Aspects thereof are the
same as described in any one of Aspects [1-13-c] and [1-14], and
subordinate Aspects thereof. Preferable aspects of q, r, R.sup.8,
R.sup.9, and R.sup.10 are the same as described in Aspect
[1-16-1-2a].
[0560] [1-16-1-3] The compound of Formula (II-1)-1 according to
Aspect [1-16-1-] is more preferably Formula (II-1-B):
##STR00090##
[0561] (where n, p, h, J.sub.2, R.sup.1, R.sup.2a, and R.sup.2b are
the same as defined in Formula (I); J.sub.1a is the same as defined
in Formula (B)-1 described in Aspect [1-14-a-1]; q, r, R.sup.9, and
R.sup.10 are the same as defined in Formula (A) described in Aspect
[1-13-c]; and G.sub.2 is the same as defined in Formula (A1a)
described in Aspect [1-13-c-3-1]).
[0562] Specifically, preferable aspects of n, p, q, r, h, J.sub.1a,
J.sub.2, R.sup.1, R.sup.2a, R.sup.2b, R.sup.9, R.sup.10, and
G.sub.2 are the same as the preferable aspects described in any one
of Aspects [1-1] to [1-15] and subordinate Aspects thereof.
Preferable aspects of the partial structure of Formula (II-1-B)
corresponding to Partial Structural Formula (A1c) or Partial
Structural Formula (B1a) described in Aspect [1-13-c-3-1] or
[1-14-a-4] are the same as described in any one of Aspects [1-13-c]
and [1-14], and subordinate Aspects thereof.
[0563] [1-16-1-3a] In Formula (II-1-B), preferably, r is 0 or 1 and
R.sup.10 is a C.sub.1-4 alkyl group. Preferably, q is an integer of
1 to 3 and R.sup.9 is a halogen atom or a C.sub.1-4 alkyl
group.
[0564] [1-16-1-3-a] The compound of Formula (II-1-B) according to
Aspect [1-16-1-3] is more preferably Formula (II-1-B)-a:
##STR00091##
[0565] (where n, p, R.sup.1, R.sup.2a, R.sup.2b, and R.sup.11a are
the same as defined in Formula (I); q, r, R.sup.9, and R.sup.10 are
the same as defined in Formula (A) described in Aspect [1-13-c];
and G.sub.2 is the same as defined in Formula (Ala) described in
Aspect [1-13-c-3-1]).
[0566] More specifically, preferable aspects of n, p, q, r,
R.sup.1, R.sup.2a, R.sup.2b, R.sup.9, R.sup.10, R.sup.11a, and
G.sub.2 are the same as the preferable aspects described in any one
of Aspects [1-1] to [1-15] and subordinate Aspects thereof.
Preferable aspects of the partial structure of Formula (II-1-B)-a
corresponding to Partial Structural Formula (A1c), Partial
Structural Formula (B1a), or Partial Structural Formula (B-Het)-1a
described in any one of Aspects [1-13-c-3-1] and [1-14], and
subordinate Aspects thereof are the same as described in any one of
Aspects [1-13-c] and [1-14], and subordinate Aspects thereof.
Preferable aspects of q, r, R.sup.9, and R.sup.10 are the same as
described in Aspect [1-16-1-3a].
[0567] [1-16-1-3-b] The compound of Formula (II-1-B) according to
Aspect [1-16-1-3] is more preferably Formula (II-1-B)-b:
##STR00092##
[0568] (where p, R.sup.1, R.sup.2a, and R.sup.2b are the same as
defined in Formula (I); q, r, R.sup.9, and R.sup.10 are the same as
defined in Formula (A) described in Aspect [1-13-c]; and G.sub.2 is
the same as defined in Formula (A1a) described in Aspect
[1-13-c-3-1]).
[0569] More specifically, preferable aspects of p, q, r, R.sup.1,
R.sup.2a, R.sup.2b, R.sup.9, R.sup.10, and G.sub.2 are the same as
the preferable aspects described in any one of Aspects [1-1] to
[1-15] and subordinate Aspects thereof. Preferable aspects of the
partial structure of Formula (II-1-B)-b corresponding to Partial
Structural Formula (A1c), Partial Structural Formula (B1a), or
Partial Structural Formula (B-Het)-1b described in any one of
Aspects [1-13-c-3-1] and [1-14], and subordinate Aspects thereof
are the same as described in any one of Aspects [1-13-c] and
[1-14], and subordinate Aspects thereof. Preferable aspects of q,
r, R.sup.9, and R.sup.10 are the same as described in Aspect
[1-16-1-3a].
[0570] [1-16-1-3-c] The compound of Formula (II-1-B) according to
Aspect [1-16-1-3] is more preferably Formula (II-1-B)-c:
##STR00093##
[0571] (where p, R.sup.1, R.sup.2a, R.sup.2b, R.sup.11a, R.sup.12a,
and R.sup.12b are the same as defined in Formula (I); q, r,
R.sup.9, and R.sup.10 are the same as defined in Formula (A)
described in Aspect [1-13-c]; and G.sub.2 is the same as defined in
Formula (Ala) described in Aspect [1-13-c-3-1]).
[0572] More specifically, preferable aspects of p, q, r, R.sup.1,
R.sup.2a, R.sup.2b, R.sup.9, R.sup.10, R.sup.11a, R.sup.12a,
R.sup.12b and G.sub.2 are the same as the preferable aspects
described in any one of Aspects [1-1] to [1-15] and subordinate
Aspects thereof. Preferable aspects of the partial structure of
Formula (II-1-B)-c corresponding to Partial Structural Formula
(A1c), Partial Structural Formula (B1a), or Partial Structural
Formula (B-Het)-1c described in any one of Aspects [1-13-c-3-1] and
[1-14], and subordinate Aspects thereof are the same as described
in any one of Aspects [1-13-c] and [1-14], and subordinate Aspects
thereof. Preferable aspects of q, r, R.sup.9, and R.sup.10 are the
same as described in Aspect [1-16-1-3a].
[0573] [1-16-1-3-d] The compound of Formula (II-1-B) according to
Aspect [1-16-1-3] is more preferably Formula (II-1-B)-d:
##STR00094##
[0574] (where p, R.sup.1, R.sup.2a, R.sup.2b, R.sup.11a, and
R.sup.12c are the same as defined in Formula (I); q, r, R.sup.9,
and R.sup.10 are the same as defined in Formula (A) described in
Aspect [1-13-c]; and G.sub.2 is the same as defined in Formula
(A1a) described in Aspect [1-13-c-3-1]).
[0575] More specifically, preferable aspects of p, q, r, R.sup.1,
R.sup.2a, R.sup.2b, R.sup.9, R.sup.10, R.sup.11a, R.sup.12c, and
G.sub.2 are the same as the preferable aspects described in any one
of Aspects [1-1] to [1-15] and subordinate Aspects thereof.
Preferable aspects of the partial structure of Formula (II-1-B)-d
corresponding to Partial Structural Formula (A1c), Partial
Structural Formula (B1a), or Partial Structural Formula (B-Het)-1d
described in any one of Aspects [1-13-c-3-1] and [1-14], and
subordinate Aspects thereof are the same as described in any one of
Aspects [1-13-c] and [1-14], and subordinate Aspects thereof.
Preferable aspects of q, r, R.sup.9, and R.sup.10 are the same as
described in Aspect [1-16-1-3a].
[0576] [1-16-1-3-e] The compound of Formula (II-1-B) according to
Aspect [1-16-1-3] is more preferably Formula (II-1-B)-e:
##STR00095##
[0577] (where p, R.sup.1, R.sup.2a, R.sup.2b, R.sup.11a, and
R.sup.12c are the same as defined in Formula (I); q, r, R.sup.9 and
R.sup.10 are the same as defined in Formula (A) described in Aspect
[1-13-c]; h1 is the same as defined in Formula (B-Het)-1e described
in Aspect [1-14-d]; and G.sub.2 is the same as defined in Formula
(A1a) described in Aspect [1-13-c-3-1]).
[0578] More specifically, preferable aspects of p, q, r, R.sup.1,
R.sup.2a, R.sup.2b, R.sup.9, R.sup.10, R.sup.11a, R.sup.12c, h1,
and G.sub.2 are the same as the preferable aspects described in any
one of Aspects [1-1] to [1-15] and subordinate Aspects thereof.
Preferable aspects of the partial structure of Formula (II-1-B)-e
corresponding to Partial Structural Formula (A1c), Partial
Structural Formula (B1a), or Partial Structural Formula (B-Het)-1e
described in any one of Aspects [1-13-c-3-1] and [1-14], and
subordinate Aspects thereof are the same as described in any one of
Aspects [1-13-c] and [1-14], and subordinate Aspects thereof.
Preferable aspects of q, r, R.sup.9, and R.sup.10 are the same as
described in Aspect [1-16-1-3a].
[0579] [1-16-1-3-f] The compound of Formula (II-1-B) according to
Aspect [1-16-1-3] is more preferably Formula (II-1-B)-f:
##STR00096##
[0580] (where p, R.sup.1, R.sup.2a, R.sup.2b, R.sup.11a, R.sup.12a,
and R.sup.12b are the same as defined in Formula (I); q, r,
R.sup.9, and R.sup.10 are the same as defined in Formula (A)
described in Aspect [1-13-c]; h1 is the same as defined in Formula
(B-Het)-1f described in Aspect [1-14-d]; and G.sub.2 is the same as
defined in Formula (A1a) described in Aspect [1-13-c-3-1]).
[0581] More specifically, preferable aspects of p, q, r, R.sup.1,
R.sup.2a, R.sup.2b, R.sup.9, R.sup.10, R.sup.11a, R.sup.12a,
R.sup.12b h1, and G.sub.2 are the same as the preferable aspects
described in any one of Aspects [1-1] to [1-15] and subordinate
Aspects thereof. Preferable aspects of the partial structure of
Formula (II-1-B)-f corresponding to Partial Structural Formula
(A1c), Partial Structural Formula (B1a), or Partial Structural
Formula (B-Het)-1f described in any one of Aspects [1-13-c-3-1] and
[1-14], and subordinate Aspects thereof are the same as described
in any one of Aspects [1-13-c] and [1-14], and subordinate Aspects
thereof. Preferable aspects of q, r, R.sup.9, and R.sup.10 are the
same as described in Aspect [1-16-1-3a].
[0582] [1-16-1-4] As the compound of Formula (I) according to
Aspect [1] or of Formula (II) or Formula (II)-1 according to Aspect
[1-16-1], a preferable compound is Formula (II-B):
##STR00097##
[0583] (where n, p, h, J.sub.2, R.sup.1, R.sup.2a, and R.sup.2b are
the same as defined in Formula (I) described in Aspect [1];
J.sub.1a is the same as defined in Formula (B)-1 described in
Aspect [1-14-a-1]; and W, Y, Z, R.sup.9c, R.sup.9d, R.sup.10a1,
R.sup.10a2, R.sup.10a3, R.sup.10b, R.sup.10c, and R.sup.10d are the
same as defined in Formula (A1)-1-1 or Formula (R.sup.10a')
described in Aspect [1-13-c-11]).
[0584] More specifically, preferable aspects of n, p, h, J.sub.1a,
J.sub.2, R.sup.1, R.sup.2a, R.sup.2b, W, Y, Z, R.sup.9c, R.sup.9d,
R.sup.10a1, R.sup.10a2, R.sup.10a3, R.sup.10b, R.sup.10c, and
R.sup.10d are the same as the preferable aspects described in any
one of Aspects [1-1] to [1-15] and subordinate Aspects thereof.
[0585] [1-16-1-5] As the compound of Formula (I) according to
Aspect [1] or of Formula (II) or Formula (II)-1 according to Aspect
[1-16-1], a preferable compound is Formula (II-C):
##STR00098##
[0586] (where n, p, h, J.sub.2, R.sup.1, R.sup.2a, and R.sup.2b are
the same as defined in Formula (I) described in Aspect [1];
J.sub.1a is the same as defined in Formula (B)-1 described in
Aspect [1-14-a-1]; and W, Y, Z, R.sup.9c, R.sup.9d, R.sup.10a,
R.sup.10b, R.sup.10c, and R.sup.10d are the same as defined in
Formula (A1)-1-1 described in Aspect [1-13-c-11]).
[0587] More specifically, preferable aspects of n, p, h, J.sub.1a,
J.sub.2, R.sup.1, R.sup.2a, R.sup.2b, W, Y, Z, R.sup.9c, R.sup.9d,
R.sup.10a, R.sup.10b, R.sup.10c, and R.sup.10d are the same as the
preferable aspects described in any one of Aspects [1-1] to [1-15]
and subordinate Aspects thereof.
[0588] [1-16-2] As the compound of Formula (I) according to Aspect
[1], a preferable compound is a compound in which the ring A is
Formula (AA), that is, a compound of Formula (III):
##STR00099##
[0589] (where n, p, h, j, k, J.sub.2, X, R.sup.1, R.sup.2a,
R.sup.2b, R.sup.3, R.sup.4, R.sup.5, and R.sup.6 are the same as
defined in Formula (I); the ring B' and J.sub.1a are the same as
defined in Formula (B)-1 described in Aspect [1-14-a-1]; and f, g,
q1, q2, r1, the ring A''', T, R.sup.13, R.sup.13a, and R.sup.14 are
the same as defined in Formula (AA) described in Aspect [1-13-d]),
a salt of the compound, or a solvate of the compound or the
salt.
[0590] More specifically, preferable aspects of n, p, h, j, k, f,
g, q1, q2, r1, the ring A''', the ring B', J.sub.1a, J.sub.2, T, X,
R.sup.1, R.sup.2a, R.sup.2b, R.sup.3, R.sup.4, R.sup.5, R.sup.6,
R.sup.13, R.sup.13a, and R.sup.14 are the same as described in any
one of Aspects [1-1] to [1-15] and the subordinate Aspects
thereof.
[0591] In Formula (III), X is preferably an oxygen atom or --NH--,
more preferably an oxygen atom. In Formula (III), j is preferably
0, and k is preferably 0. In Formula (III), more preferably, X is
an oxygen atom, j is 0, and k is 0.
[0592] In Formula (III), the ring B' is preferably a benzene
ring.
[0593] In Formula (III), preferably, any one of q1 and q2 is 1 or
more and more preferably, q2 is 1.
[0594] In Formula (III), preferably, X is an oxygen atom, j is 0, k
is 0, and any one of q1 and q2 is 1 or more, and more preferably, X
is an oxygen atom, j is 0, k is 0, and q2 is 1.
[0595] When the definitions of the substituents are assembled once
more and are described in detail, Aspect [1-16-2] is a compound of
Formula (III):
##STR00100##
[0596] (where n is an integer of 0 to 2; p is an integer of 0 to 4;
h is an integer of 0 to 3; j is an integer of 0 to 3; k is an
integer of 0 to 2;
J.sub.1a is --CR.sup.11a-- or a nitrogen atom; J.sub.2 is
--CR.sup.12aR.sup.12b-- or --NR.sup.12c-- (with the proviso that
when J.sub.1a is a nitrogen atom, h is 0); X is an oxygen atom, a
sulfur atom, or --NR.sup.7--; the ring B' is a benzene ring, a
pyridine ring, or a pyrimidine ring; f is an integer of 0 to 2; g
is an integer of 1 to 4; q1 is an integer of 0 to 3; q2 is 0 or 1;
r1 is an integer of 0 to 2 (with the proviso that q1+q2+r1 is an
integer of 0 to 5); the ring A''' is a benzene ring or a pyridine
ring; T is a group optionally selected from --CH.sub.2--, an oxygen
atom, --S(O).sub.i-- (i is an integer of 0 to 2), and a
--NR.sup.7-- group; R.sup.1s are independently a group optionally
selected from a halogen atom, a C.sub.1-6 alkyl group that is
optionally substituted with 1 to 5 substituent(s) RI, a C.sub.2-6
alkenyl group that is optionally substituted with 1 to 5
substituent(s) RI, a C.sub.2-6 alkynyl group that is optionally
substituted with 1 to 5 substituent(s) RI, a C.sub.1-6 alkoxy group
that is optionally substituted with 1 to 5 substituent(s) RI, and a
cyano group; R.sup.2a and R.sup.2b are independently a group
optionally selected from a hydrogen atom, a halogen atom, a
C.sub.1-6 alkyl group, a C.sub.2-6 alkenyl group, a C.sub.2-6
alkynyl group, a C.sub.1-6 alkoxy group, and a cyano group;
R.sup.3, R.sup.4, R.sup.5, R.sup.6, and R.sup.7 are independently a
group optionally selected from a hydrogen atom, a C.sub.1-6 alkyl
group, a halogenated C.sub.1-6 alkyl group, a C.sub.2-6 alkenyl
group, and a C.sub.2-6 alkynyl group; R.sup.11as are independently
a group optionally selected from a hydrogen atom, a halogen atom, a
C.sub.1-6 alkyl group, a halogenated C.sub.1-6 alkyl group, a
C.sub.2-6 alkenyl group, a C.sub.2-6 alkynyl group, a C.sub.1-6
alkoxy group, a halogenated C.sub.1-6 alkoxy group, a C.sub.2-7
alkanoyl group, and a carboxy group that is optionally protected;
R.sup.12a and R.sup.12b are independently a group optionally
selected from a hydrogen atom, a halogen atom, a C.sub.1-6 alkyl
group, a halogenated C.sub.1-6 alkyl group, a C.sub.2-6 alkenyl
group, a C.sub.2-6 alkynyl group, a C.sub.1-6 alkoxy group, a
halogenated C.sub.1-6 alkoxy group, and a cyano group; R.sup.12cs
are independently a group optionally selected from a hydrogen atom,
a C.sub.1-6 alkyl group, and a halogenated C.sub.1-6 alkyl group;
R.sup.13s are independently a group optionally selected from a
halogen atom, --OH, a cyano group, a C.sub.1-10 alkyl group that is
optionally substituted with 1 to 5 substituent(s) RI, a C.sub.2-10
alkenyl group that is optionally substituted with 1 to 5
substituent(s) RI, a C.sub.2-10 alkynyl group that is optionally
substituted with 1 to 5 substituent(s) RI, a C.sub.1-10 alkoxy
group that is optionally substituted with 1 to 5 substituent(s) RI,
a C.sub.2-10 alkenyloxy group that is optionally substituted with 1
to 5 substituent(s) RI, a C.sub.2-10 alkynyloxy group that is
optionally substituted with 1 to 5 substituent(s) RI, --SH, a
--S(O).sub.iR.sup.a (i is an integer of 0 to 2) group, and a
--NR.sup.bR.sup.c group; R.sup.13a is a group optionally selected
from an aryl group that is optionally substituted with 1 to 5
substituent(s) RII, a heterocyclic group that is optionally
substituted with 1 to 5 substituent(s) RII, an aralkyl group that
is optionally substituted with 1 to 5 substituent(s) RII, a
heteroarylalkyl group that is optionally substituted with 1 to 5
substituent(s) RII, a non-aromatic heterocyclic alkyl group that is
optionally substituted with 1 to 5 substituent(s) RII, an aryloxy
group that is optionally substituted with 1 to 5 substituent(s)
RII, a heteroaryloxy group that is optionally substituted with 1 to
5 substituent(s) RII, a non-aromatic heterocyclic oxy group that is
optionally substituted with 1 to 5 substituent(s) RII, an
aralkyloxy group that is optionally substituted with 1 to 5
substituent(s) RII, a heteroarylalkyloxy group that is optionally
substituted with 1 to 5 substituent(s) RII, and a substituted
spiropiperidinylmethyl group; R.sup.14s are independently a group
optionally selected from a halogen atom, --OH, a cyano group, a
C.sub.1-6 alkyl group that is optionally substituted with 1 to 5
substituent(s) RI, a C.sub.2-6 alkenyl group that is optionally
substituted with 1 to 5 substituent(s) RI, a C.sub.2-6 alkynyl
group that is optionally substituted with 1 to 5 substituent(s) RI,
a C.sub.1-6 alkoxy group that is optionally substituted with 1 to 5
substituent(s) RI, --SH, a --S(O).sub.iR.sup.a (i is an integer of
0 to 2) group, and a --NR.sup.bR.sup.c group; R.sup.a is a
C.sub.1-6 alkyl group or a halogenated C.sub.1-6 alkyl group;
R.sup.b and R.sup.c are independently a group optionally selected
from a hydrogen atom, a C.sub.1-6 alkyl group, a halogenated
C.sub.1-6 alkyl group, a C.sub.2-6 alkenyl group, a C.sub.2-6
alkynyl group, a C.sub.2-7 alkanoyl group (the alkanoyl group is
optionally substituted with --OH or a C.sub.1-6 alkoxy group), a
C.sub.1-6 alkylsulfonyl group, an arylcarbonyl group, and a
heterocyclic carbonyl group, where R.sup.b and R.sup.c optionally
form together with a nitrogen atom to which they are bonded, a 3-
to 8-membered cyclic group, where in the cyclic group, one or two
carbon atom(s) is(are) optionally substituted with an atom
optionally selected from an oxygen atom, a sulfur atom, and a
nitrogen atom (the nitrogen atom is optionally substituted with a
C.sub.1-6 alkyl group that is optionally substituted with 1 to 5
substituent(s) RI) or with a carbonyl group, and the cyclic group
is further optionally substituted with 1 to 5 substituent(s) RII;
where the substituents RI may be the same as or different from each
other and be each a group optionally selected from a halogen atom,
--OH, a cyano group, a C.sub.1-6 alkoxy group (the C.sub.1-6 alkoxy
group is optionally substituted with 1 to 5 halogen atom(s), 1 to 5
--OH, 1 to 5 C.sub.1-6 alkoxy group(s), 1 to 5 aryl group(s) (the
aryl group is optionally substituted with 1 to 3 halogen atom(s)),
1 to 5 heterocyclic group(s) (the heterocyclic group is optionally
substituted with 1 to 3 C.sub.1-6 alkyl group(s) or 1 to 3 oxo
group(s)), 1 to 5 --S(O).sub.iR.sup.a (i is an integer of 0 to 2)
group(s), 1 to 5 --SO.sub.2NR.sup.dR.sup.e group(s), 1 to 5
--CONR.sup.dR.sup.e group(s), or 1 to 5 --NR.sup.b1R.sup.c1
group(s)), a --NR.sup.b1R.sup.c1 group, and a heterocyclic oxy
group (the heterocyclic oxy group is optionally substituted with 1
to 3 C.sub.1-6 alkyl group(s) or 1 to 3 oxo group(s)); the
substituents RII may be the same as or different from each other
and be each a group optionally selected from the substituents RI, a
C.sub.1-6 alkyl group (the C.sub.1-6 alkyl group is optionally
substituted with 1 to 5 halogen atom(s), 1 to 5 --OH, 1 to 5
C.sub.1-6 alkoxy group(s), 1 to 5 --S(O).sub.iR.sup.a (i is an
integer of 0 to 2) group(s), 1 to 5 --NR.sup.b1R.sup.c1 group(s), 1
to 5 --SO.sub.2NR.sup.dR.sup.e group(s), or 1 to 5
--CONR.sup.dR.sup.e group(s)), a C.sub.2-6 alkenyl group, a
C.sub.2-7 alkanoyl group, an aralkyloxy group, a heterocyclic group
(the heterocyclic group is optionally substituted with 1 to 3
C.sub.1-6 alkyl group(s) or 1 to 3 oxo group(s)), a heterocyclic
carbonyl group (the heterocyclic carbonyl group is optionally
substituted with 1 to 3 C.sub.1-6 alkyl group(s) or 1 to 3 oxo
group(s)), a --S(O).sub.iR.sup.a (i is an integer of 0 to 2) group,
a --CONR.sup.dR.sup.e group, and a --CONR.sup.dR.sup.e1 group;
R.sup.d and R.sup.e are independently a hydrogen atom or a
C.sub.1-6 alkyl group (the C.sub.1-6 alkyl group is optionally
substituted with 1 to 5 halogen atom(s), 1 to 5 --OH, or 1 to 5
C.sub.1-6 alkoxy group(s)); R.sup.e1 is a C.sub.1-6 alkyl group
(the C.sub.1-6 alkyl group is optionally substituted with 1 to 5
--OH, 1 to 5 C.sub.1-6 alkoxy group(s), 1 to 5 aryl group(s) (the
aryl group is optionally substituted with 1 to 3 halogen atom(s)),
1 to 5 heterocyclic group(s) (the heterocyclic group is optionally
substituted with 1 to 3 C.sub.1-6 alkyl group(s) or 1 to 3 oxo
group(s)), 1 to 5 --S(O).sub.iR.sup.a (i is an integer of 0 to 2)
group(s), 1 to 5 --SO.sub.2NR.sup.dR.sup.e group(s), 1 to 5
--CONR.sup.dR.sup.e group(s), or 1 to 5 --NR.sup.b1R.sup.c1
group(s)); and R.sup.b1 and R.sup.c1 are independently a group
optionally selected from a hydrogen atom, a C.sub.1-6 alkyl group,
a C.sub.2-7 alkanoyl group, and a C.sub.1-6 alkylsulfonyl group,
where R.sup.b1 and R.sup.c1 optionally form together with a
nitrogen atom to which they are bonded, a 3- to 8-membered cyclic
group, where in the cyclic group, one or two carbon atom(s) is(are)
optionally substituted with an atom optionally selected from an
oxygen atom, a sulfur atom, and a nitrogen atom (the nitrogen atom
is optionally substituted with a C.sub.1-6 alkyl group) or with a
carbonyl group), a salt of the compound, or a solvate of the
compound or the salt.
[0597] [1-16-2-0] In the compound of Formula (III) according to
Aspect [1-16-2], J.sub.1a and h are preferably in such a
relationship that when J.sub.1a is a nitrogen atom, h is 0 and when
J.sub.1a is CR.sup.11a, h is an integer of 0 to 1.
[0598] [1-16-2a] In the compound of Formula (III) according to
Aspect [1-16-2], compounds produced by optionally combining the
groups of Partial Structural Formula (AA) (on the left of the left
wavy line), Partial Structural Formula (B)-1 (on the right of the
right wavy line), and Partial Structural Formula (C) (between the
two wavy lines) in Formula (III):
##STR00101##
can be produced optionally.
[0599] More specifically, Partial Structural Formula (AA) is a
group optionally selected from Formula (AA)-1, Formula (AA)-1-1,
Formula (AA1), Formula (AA1)-1, Formula (AA1a)-1, Formula
(AA1a)-1-1, Formula (AA1b), and Formula (AA1b)-1 described in
Aspects [1-13-d-1] to [1-13-d-7-1]. Partial Structural Formula (B)
is a group optionally selected from Formula (B1), Formula (B2),
Formula (B1a), and Formula (B1b) described in Aspects [1-14-a-2]
and [1-14-a-4], and Partial Structural Formula (C) can be a group
optionally selected from Formula (c1) to Formula (c6) described in
Aspect [1-15]. An optional combination of each formula forms part
of the compound of Formula (I) according to the present
invention.
[0600] The cyclic amide structure bonded to the ring B' of Formula
(III) is Partial Structural Formula (B-Het)-1 described in Aspect
[1-14-e], and preferable examples of the cyclic amide structure
include Formula (B-Het)-1a, (B-Het)-1b, Formula (B-Het)-1c, Formula
(B-Het)-1d, Formula (B-Het)-1e, and Formula (B-Het)-1f described in
Aspect [1-14-e-1].
[0601] In Formula (III), a compound having Formula (B-Het)-1a is
Formula (III)-1a, a compound having Formula (B-Het)-1b is Formula
(III)-1b, a compound having Formula (B-Het)-1c is Formula (III)-1c,
a compound having Formula (B-Het)-1d is Formula (III)-1d, a
compound having Formula (B-Het)-1e is Formula (III)-1e, and a
compound having Formula (B-Het)-1f is Formula (III)-1f.
[0602] [1-16-2-1] The compound of Formula (III) according to Aspect
[1-16-2] is preferably Formula (III-1):
##STR00102##
[0603] (where n, p, h, J.sub.2, R.sup.1, R.sup.2a, and R.sup.2b are
the same as defined in Formula (I); the ring B' and J.sub.1a are
the same as defined in Formula (B)-1 described in Aspect
[1-14-a-1]; q1, q2, r1, T, R.sup.13, R.sup.13a, and R.sup.14 are
the same as defined in Formula (AA) described in Aspect [1-13-d];
and E is a group optionally selected from Formula (c1) to Formula
(c6) shown as specific examples of Formula (C) described in Aspect
[1-15]).
[0604] More specifically, preferable aspects of n, p, h, q1, q2,
r1, the ring B', T, J.sub.1a, J.sub.2, R.sup.1, R.sup.2a, R.sup.2b,
R.sup.13, R.sup.13a, R.sup.14, and E are the same as the preferable
aspects described in any one of Aspects [1-1] to [1-15] and
subordinate Aspects thereof.
[0605] In Formula (III-1), E is preferably Formula (c1) or Formula
(c4), and more preferably Formula (c1).
[0606] In Formula (III-1), the ring B' is preferably a benzene
ring.
[0607] In Formula (III-1), preferably, any one of q1 and q2 is 1 or
more, and more preferably, q2 is 1.
[0608] In Formula (III-1), preferably, E is Formula (c1) and any
one of q1 and q2 is 1 or more, and more preferably, E is Formula
(c1) and q2 is 1.
[0609] The cyclic amide structure bonded to the ring B' of Formula
(III-1) is Partial Structural Formula (B-Het)-1 described in Aspect
[1-14-e], and preferable examples of the cyclic amide structure
include Formula (B-Het)-1a, (B-Het)-1b, Formula (B-Het)-1c, Formula
(B-Het)-1d, Formula (B-Het)-1e, and Formula (B-Het)-1 f described
in Aspect [1-14-e-1]. In Formula (III-1), a compound having Formula
(B-Het)-1a is Formula (III-1)-1a, a compound having Formula
(B-Het)-1b is Formula (III-1)-1b, a compound having Formula
(B-Het)-1c is Formula (III-1)-1c, a compound having Formula
(B-Het)-1d is Formula (III-1)-1d, a compound having Formula
(B-Het)-1e is Formula (III-1)-1e, and a compound having Formula
(B-Het)-1f is Formula (III-1)-1f.
[0610] When the definitions of the substituents are assembled once
more and are described in detail, Aspect [1-16-2-1] is a compound
of Formula (III-1):
##STR00103##
[0611] (where n, p, h, q1, q2, r1, the ring B', T, J.sub.1a,
J.sub.2, R.sup.1, R.sup.2a, R.sup.2b, R.sup.13, R.sup.13a, and
R.sup.14 are the same as defined in Formula (III) according to
Aspect [1-16-2]; and E is a group optionally selected from Formula
(c1) to Formula (c6):
##STR00104##
that is a compound of Formula (III) according to Aspect [1-16-2], a
salt of the compound, or a solvate of the compound or the salt.
[0612] [1-16-2-1-a] In the compound of Formula (III-1) according to
Aspect [1-16-2-1], J.sub.1a and h are preferably in such a
relationship that when J.sub.1a is a nitrogen atom, h is 0 and when
J.sub.1a is CR.sup.11a, h is an integer of 0 to 1.
[0613] [1-16-2-2] The compound of Formula (III) according to Aspect
[1-16-2] or of Formula (III-1) according to Aspect [16-2-1] is
preferably Formula (III-1)-1:
##STR00105##
[0614] (where n, p, h, J.sub.2, R.sup.1, R.sup.2a, and R.sup.2b are
the same as defined in Formula (I); J.sub.1a is the same as defined
in Formula (B)-1 described in Aspect [1-14-a-1]; q, s, the ring A',
V, R.sup.8, and R.sup.9 are the same as defined in Formula (A)
described in Aspect [1-13-c]; q1, r1, T, R.sup.13 and R.sup.14 are
the same as defined in Formula (AA) described in Aspect [1-13-d];
and Ea is Formula (c1) or Formula (c4) shown as specific examples
of Formula (C) described in Aspect [1-15]).
[0615] More specifically, preferable aspects of n, p, h, q, q1, r1,
s, the ring A', V, T, J.sub.1a, J.sub.2, R.sup.1, R.sup.2a,
R.sup.2b, R.sup.8, R.sup.9, R.sup.13, R.sup.14, and Ea are the same
as the preferable aspects described in any one of Aspects [1-1] to
[1-15] and subordinate Aspects thereof.
[0616] In Formula (III-1)-1, Ea is preferably Formula (c1).
[0617] In Formula (III-1)-1, any one of q and s is preferably 1 or
more.
[0618] In Formula (III-1)-1, more preferably, Ea is Formula (c1)
and any one of q and s is 1 or more.
[0619] The cyclic amide structure bonded to the ring B of Formula
(III-1)-1 is Partial Structural Formula (B-Het)-1 described in
Aspect [1-14-e], and preferable examples of the cyclic amide
structure include Formula (B-Het)-1a, (B-Het)-1b, Formula
(B-Het)-1c, Formula (B-Het)-1d, Formula (B-Het)-1e, and Formula
(B-Het)-1f described in Aspect [1-14-e-1]. In Formula (III-1)-1, a
compound having Formula (B-Het)-1a is Formula (III-1)-1-1a, a
compound having Formula (B-Het)-1b is Formula (III-1)-1-1b, a
compound having Formula (B-Het)-1c is Formula (III-1)-1-1c, a
compound having Formula (B-Het)-1d is Formula (III-1)-1-d, a
compound having Formula (B-Het)-1e is Formula (III-1)-1-1e, and a
compound having Formula (B-Het)-1f is Formula (III-1)-1-1f.
[0620] When the definitions of the substituents are assembled once
more and are described in detail, Aspect [1-16-2-2] is a compound
of Formula (III-1)-1:
##STR00106##
[0621] (where n, p, h, T, J.sub.2, R.sup.1, R.sup.2a, R.sup.2b, and
J.sub.1a are the same as defined in Formula (III) according to
Aspect [1-16-2];
q is an integer of 0 to 4; s is an integer of 0 to 2 (with the
proviso that q+s is an integer of 0 to 5); the ring A' is an aryl
group or a heteroaryl group; V is a single bond or an oxygen atom;
R.sup.8s are independently a group optionally selected from a
C.sub.1-6 alkoxy group that is substituted with 1 to 5
substituent(s) M, a C.sub.2-6 alkenyloxy group that is substituted
with 1 to 5 substituent(s) M, a C.sub.2-6 alkynyloxy group that is
substituted with 1 to 5 substituent(s) M, a --CONR.sup.dR.sup.e1
group, an aralkyloxy group, a heterocyclic oxy group (the
heterocyclic oxy group is optionally substituted with 1 to 3
C.sub.1-6 alkyl group(s) or 1 to 3 oxo group(s)), a heterocyclic
group (the heterocyclic group is optionally substituted with 1 to 3
C.sub.1-6 alkyl group(s) or 1 to 3 oxo group(s)), and a
heterocyclic carbonyl group (the heterocyclic carbonyl group is
optionally substituted with 1 to 3 C.sub.1-6 alkyl group(s) or 1 to
3 oxo group(s)); the substituents M are independently a group
optionally selected from a halogen atom, --OH, a C.sub.1-6 alkoxy
group, an aryl group (the aryl group is optionally substituted with
1 to 3 halogen atom(s)), a heterocyclic group (the heterocyclic
group is optionally substituted with 1 to 3 --OH, 1 to 3 C.sub.1-6
alkyl group(s), or 1 to 3 oxo group(s)), a --S(O).sub.iR.sup.a (i
is an integer of 0 to 2) group, a --NR.sup.b1R.sup.c1 group, a
--SO.sub.2NR.sup.dR.sup.e group, and a --CONR.sup.dR.sup.e group;
R.sup.9s are independently a group optionally selected from a
halogen atom, --OH, a cyano group, a C.sub.1-6 alkyl group that is
optionally substituted with 1 to 5 substituent(s) RI, a C.sub.2-6
alkenyl group that is optionally substituted with 1 to 5
substituent(s) RI, a C.sub.2-6 alkynyl group that is optionally
substituted with 1 to 5 substituent(s) RI, a C.sub.1-6 alkoxy group
that is optionally substituted with 1 to 5 substituent(s) RI, a
C.sub.2-7 alkanoyl group, --SH, a --S(O).sub.iR.sup.a (i is an
integer of 0 to 2) group, a --NR.sup.b1R.sup.c1 group, and a
--CONR.sup.dR.sup.e group; (RI, R.sup.a, R.sup.d, R.sup.e,
R.sup.b1, R.sup.c1, and R.sup.e1 above are the same as defined in
Formula (III) according to Aspect [1-16-2]); q1, r1, T, R.sup.13,
and R.sup.14 are the same as defined in Formula (III) according to
Aspect [1-16-2]; q1+r1 is an integer of 0 to 4; and Ea is a group
optionally selected from groups of Formula (c1) or Formula
(c4):
##STR00107##
that is a compound of Formula (III) according to Aspect [1-16-2] or
a compound of Formula (III-1) according to Aspect [1-16-2-2], a
salt of the compound, or a solvate of the compound or the salt.
[0622] [1-16-2-2-a] In the compound of Formula (III-1)-1 according
to Aspect [1-16-2-2], J.sub.1a and h are preferably in such a
relationship that when J.sub.1a is a nitrogen atom, h is 0 and when
J.sub.1a is CR.sup.11a, h is an integer of 0 to 1.
[0623] [1-16-2-3] The compound of Formula (III-1)-1 according to
Aspect [1-16-2-2] is preferably Formula (III-1-A)-1:
##STR00108##
[0624] (where n, p, h, J.sub.2, R.sup.1, R.sup.2a, and R.sup.2b are
the same as defined in Formula (I); J.sub.1a is the same as defined
in Formula (B)-1 described in Aspect [1-14-a-1]; q, s, the ring
A'', V, R.sup.8, and R.sup.9 are the same as defined in Formula (A)
or Formula (A)-1 described in Aspect [1-13-c]; and q1, r1,
R.sup.13, and R.sup.14 are the same as defined in Formula (AA)
described in Aspect [1-13-d]).
[0625] More specifically, preferable aspects of n, p, h, q, q1, r1,
s, the ring A'', V, J.sub.1a, J.sub.2, R.sup.1, R.sup.2a, R.sup.2b,
R.sup.8, R.sup.9, R.sup.13, and R.sup.14 are the same as the
preferable aspects described in any one of Aspects [1-1] to [1-15]
and subordinate Aspects thereof.
[0626] In Formula (III-1-A)-1, any one of q and s is preferably 1
or more.
[0627] The cyclic amide structure bonded to the ring B of Formula
(III-1-A)-1 is Partial Structural Formula (B-Het)-1 described in
Aspect [1-14-e], and preferable examples of the cyclic amide
structure include Formula (B-Het)-1a, (B-Het)-1b, Formula
(B-Het)-1c, Formula (B-Het)-1d, Formula (B-Het)-1e, and Formula
(B-Het)-1f described in Aspect [1-14-e-1]. In Formula (III-1-A)-1,
a compound having Formula (B-Het)-1a is Formula (III-1-A)-1-1a, a
compound having Formula (B-Het)-1b is Formula (III-1-A)-1-1b, a
compound having Formula (B-Het)-1c is Formula (III-1-A)-1-1c, a
compound having Formula (B-Het)-1d is Formula (III-1-A)-1-1d, a
compound having Formula (B-Het)-1e is Formula (III-1-A)-1-1e, and a
compound having Formula (B-Het)-1f is Formula (III-1-A)-1-1 f.
[0628] When the definitions of the substituents are assembled once
more and are described in detail, Aspect [1-16-2-3] is a compound
of Formula (III-1-A)-1:
##STR00109##
[0629] (where n, p, h, q, q1, r1, s, V, J.sub.1a, J.sub.2, R.sup.1,
R.sup.2a, R.sup.2b, R.sup.8, R.sup.9, R.sup.13, and R.sup.14 are
the same as defined in Formula (III-1)-1 according to Aspect
[1-16-2-2]; and the ring A'' is a benzene ring, a pyridine ring, or
a pyrimidine ring) that is a compound of Formula (III-1)-1
according to Aspect [1-16-2-2], a salt of the compound, or a
solvate of the compound or the salt. [1-16-2-3-1] In the compound
of Formula (III-1-A)-1 according to Aspect [1-16-2-3], J.sub.1a and
h are preferably in such a relationship that when J.sub.1a is a
nitrogen atom, h is 0 and when J.sub.1a is CR.sup.11a, h is an
integer of 0 to 1.
[0630] [1-16-2-4] The compound of Formula (III-1)-1 according to
Aspect [1-16-2-2] is preferably Formula (III-1-B)-1:
##STR00110##
[0631] (where n, p, h, J.sub.2, R.sup.1, R.sup.2a, and R.sup.2b are
the same as defined in Formula (I); J.sub.1a is the same as defined
in Formula (B)-1 described in Aspect [1-14-a-1]; q, s, the ring
A'', V, R.sup.8, and R.sup.9 are the same as defined in Formula (A)
or Formula (A)-1 described in Aspect [1-13-c]; and q1, r1,
R.sup.13, and R.sup.14 are the same as defined in Formula (AA)
described in Aspect [1-13-d]).
[0632] More specifically, preferable aspects of n, p, h, q, q1, r1,
s, the ring A'', V, J.sub.1a, J.sub.2, R.sup.1, R.sup.2a, R.sup.2b,
R.sup.8, R.sup.9, R.sup.13, and R.sup.14 are the same as the
preferable aspects described in any one of Aspects [1-1] to [1-15]
and subordinate Aspects thereof.
[0633] In Formula (III-1-B)-1, any one of q and s is preferably 1
or more.
[0634] The cyclic amide structure bonded to the ring B of Formula
(III-1-B)-1 is Partial Structural Formula (B-Het)-1 described in
Aspect [1-14-e], and preferable examples of the cyclic amide
structure include Formula (B-Het)-1a, (B-Het)-1b, Formula
(B-Het)-1c, Formula (B-Het)-1d, Formula (B-Het)-1e, and Formula
(B-Het)-1f described in Aspect [1-14-e-1]. In Formula (III-1-B)-1,
a compound having Formula (B-Het)-1a is Formula (III-1-B)-1-1a, a
compound having Formula (B-Het)-1b is Formula (III-1-B)-1-1b, a
compound having Formula (B-Het)-1c is Formula (III-1-B)-1-1c, a
compound having Formula (B-Het)-1d is Formula (III-1-B)-1-1d, a
compound having Formula (B-Het)-1e is Formula (III-1-B)-1-1e, and a
compound having Formula (B-Het)-1f is Formula (III-1-A)-1-1f.
[0635] [1-16-2-5] In the compound of Formula (III-1)-1 according to
Aspect [1-16-2-2] and in Formula (III-1-A)-1 according to Aspect
[1-16-2-3], it is preferred that R.sup.8s are independently a group
optionally selected from a C.sub.1-6 alkoxy group that is
substituted with 1 to 5 substituent(s) M, a --CONR.sup.dR.sup.e1
group, and an aralkyloxy group; the substituents M are
independently a group optionally selected from a halogen atom,
--OH, a C.sub.1-6 alkoxy group, a --S(O).sub.iR.sup.a (i is an
integer of 0 to 2 and R.sup.a is a C.sub.1-6 alkyl group or a
halogenated C.sub.1-6 alkyl group) group, a --NR.sup.b1R.sup.c1
group, a --SO.sub.2NR.sup.dR.sup.e group, and a --CONR.sup.dR.sup.e
group; and R.sup.9s are independently a group optionally selected
from a halogen atom, --OH, a cyano group, a C.sub.1-6 alkyl group
(the C.sub.1-6 alkyl group is optionally substituted with 1 to 5
halogen atom(s), 1 to 5 --OH, 1 to 5 C.sub.1-6 alkoxy group(s), 1
to 5 --S(O).sub.iR.sup.a (i is an integer of 0 to 2 and R.sup.a is
a C.sub.1-6 alkyl group or a halogenated C.sub.1-6 alkyl group)
group(s), or 1 to 5 --NR.sup.b1R.sup.c1 group(s)), a C.sub.2-6
alkenyl group, a C.sub.1-6 alkoxy group (the C.sub.1-6 alkoxy group
is optionally substituted with 1 to 5 halogen atom(s), 1 to 5 --OH,
1 to 5 C.sub.1-6 alkoxy group(s), or 1 to 5 --NR.sup.b1R.sup.c1
group(s)), a C.sub.2-7 alkanoyl group, a --S(O).sub.iR.sup.a (i is
an integer of 0 to 2 and R.sup.a is a C.sub.1-6 alkyl group or a
halogenated C.sub.1-6 alkyl group) group, a --NR.sup.b1R.sup.c1
group, and a --CONR.sup.dR.sup.e group. [1-16-2-6] In the compound
of Formula (III-1)-1, and Formula (III-1-A)-1 that are quoted in
[1-16-2-5], it is more preferred that R.sup.8s are independently a
C.sub.1-6 alkoxy group that is substituted with 1 to 5
substituent(s) M; the substituents M are independently a group
optionally selected from --OH, a C.sub.1-6 alkoxy group, and a
--S(O).sub.iR.sup.a (i is an integer of 0 to 2 and R.sup.a is a
C.sub.1-6 alkyl group or a halogenated C.sub.1-6 alkyl group)
group; and R.sup.9s are independently a group optionally selected
from a halogen atom, a cyano group, a C.sub.1-6 alkyl group (the
C.sub.1-6 alkyl group is optionally substituted with 1 to 5 halogen
atom(s)), and a C.sub.1-6 alkoxy group.
[0636] [1-16-2-7] In the compound of Formula (III-1)-1 and the
compound of Formula (III-1-A)-1 that are quoted in Aspect
[1-16-2-5] and Aspect [1-16-2-6], J.sub.1a and h are preferably in
such a relationship that when J.sub.1a is a nitrogen atom, h is 0
and when J.sub.1a is CR.sup.11a, h is an integer of 0 to 1.
[0637] [1-16-3] As the compound of Formula (I) according to Aspect
[1], a preferable compound is a compound in which the ring A is
Formula (A1)-IV and Formula (C) is Formula (c2), that is, Formula
(IV-1):
##STR00111##
[0638] (where n, p, h, J.sub.2, R.sup.1, R.sup.2a, and R.sup.2b are
the same as defined in Formula (I) described in Aspect [1];
J.sub.1a is the same as defined in Formula (B)-1 described in
Aspect [1-14-a-1]; q, r, s, the ring A', R.sup.8, R.sup.9, and
R.sup.10 are the same as defined in Formula (A) described in Aspect
[1-13-c]; and g1 is the same as defined in Formula (A1)-IV
described in Aspect [1-13-e-2]).
[0639] More specifically, preferable aspects of n, p, h, q, r, s,
the ring A', J.sub.1a, J.sub.2, R.sup.1, R.sup.2a, R.sup.2b,
R.sup.8, R.sup.9, R.sup.10, and g1 are the same as the preferable
aspects described in any one of Aspects [1-1] to [1-15] and
subordinate Aspects thereof.
[0640] [1-16-3-1] As the compound of Formula (I) according to
Aspect [1], a preferable compound is a compound in which the ring A
is Formula (A3)-IV and Formula (C) is Formula (c2), that is,
Formula (IV-3):
##STR00112##
[0641] (where n, p, h, J.sub.2, R.sup.1, R.sup.2a, and R.sup.2b are
the same as defined in Formula (I) described in Aspect [1];
J.sub.1a is the same as defined in Formula (B)-1 described in
Aspect [1-14-a-1]; q and R.sup.9 are the same as defined in Formula
(A) described in Aspect [1-13-c]; and R.sup.10f is the same as
defined in Formula (A2)-IV described in Aspect [1-13-e-3]).
[0642] More specifically, preferable aspects of n, p, h, q,
J.sub.1a, J.sub.2, R.sup.1, R.sup.2a, R.sup.2b, R.sup.9, and
R.sup.10f are the same as the preferable aspects described in any
one of Aspects [1-1] to [1-15] and subordinate Aspects thereof.
[0643] [1-16-3-2] As the compound of Formula (I) according to
Aspect [1], a preferable compound is a compound in which the ring A
is Formula (A4)-IV and Formula (C) is Formula (c2), that is,
Formula (IV-4):
##STR00113##
[0644] (where n, p, h, J.sub.2, R.sup.1, R.sup.2a, and R.sup.2b are
the same as defined in Formula (I) described in Aspect [1];
J.sub.1a is the same as defined in Formula (B)-1 described in
Aspect [1-14-a-1]; and Z.sub.1, Z.sub.2, Z.sub.3, and X.sub.2 are
the same as defined in Formula (A4)-IV described in Aspect
[1-13-e-8]).
[0645] More specifically, preferable aspects of n, p, h, J.sub.1a,
J.sub.2, R.sup.1, R.sup.2a, R.sup.2b, Z.sub.1, Z.sub.2, Z.sub.3,
and X.sub.2 are the same as the preferable aspects described in any
one of Aspects [1-1] to [1-15] and subordinate Aspects thereof.
[0646] [1-16-4] As the compound of Formula (I) according to Aspect
[1], a preferable compound is a compound in which the ring A is
Formula (A)-V and Formula (C) is Formula (c2), that is, Formula
(V):
##STR00114##
[0647] (where n, p, h, J.sub.2, R.sup.1, R.sup.2a, and R.sup.2b are
the same as defined in Formula (I) described in Aspect [1];
J.sub.1a is the same as defined in Formula (B)-1 described in
Aspect [1-14-a-1]; q and s are the same as defined in Formula (A)
described in Aspect [1-13-c]); r is the same as defined in Formula
(AA) described in Aspect [1-13-d]; and R.sup.8, R.sup.9, R.sup.10,
n1, n2, n3, X.sub.3, and the broken lines are the same as defined
in Formula (A)-V described in Aspect [1-13-f]).
[0648] More specifically, preferable aspects of n, p, h, q, r, s,
J.sub.1a, J.sub.2, R.sup.1, R.sup.2a, R.sup.2b, R.sup.8, R.sup.9,
R.sup.10, n1, n2, n3, and X.sub.3 are the same as the preferable
aspects described in any one of Aspects [1-1] to [1-15] and
subordinate Aspects thereof.
[0649] [1-16-4-1] The compound of Formula (V) according to Aspect
[1-16-4] is further preferably Formula (V)-1:
##STR00115##
[0650] (where n, p, h, J.sub.2, R.sup.1, R.sup.2a, and R.sup.2b are
the same as defined in Formula (I) described in Aspect [1];
J.sub.1a is the same as defined in Formula (B)-1 described in
Aspect [1-14-a-1]; and n1 and n2 are the same as defined in Formula
(A)-V described in Aspect [1-13-f]).
[0651] More specifically, preferable aspects of n, p, h, J.sub.1a,
J.sub.2, n1, n2, R.sup.1, R.sup.2a, and R.sup.2b are the same as
the preferable aspects described in any one of Aspects [1-1] to
[1-15] and subordinate Aspects thereof.
[0652] [1-16-4-2] As the compound of Formula (I) according to
Aspect [1], a preferable compound is a compound in which the ring A
is Formula (AA1)-V and Formula (C) is Formula (c2), that is,
Formula (V-A):
##STR00116##
[0653] (where n, p, h, J.sub.2, R.sup.1, R.sup.2a, and R.sup.2b are
the same as defined in Formula (I) described in Aspect [1];
J.sub.1a is the same as defined in Formula (B)-1 described in
Aspect [1-14-a-1]; q, s, the ring A', V, R.sup.8, and R.sup.9 are
the same as defined in Formula (A) described in Aspect [1-13-c]); r
is the same as defined in Formula (AA) described in Aspect
[1-13-d]; R.sup.10 and the broken lines are the same as defined in
Formula (A)-V described in Aspect [1-13-f]; and n4 is the same as
defined in Formula (AA)-V described in Aspect [1-13-f-8]).
[0654] More specifically, preferable aspects of n, p, h, q, r, s,
the ring A', V, J.sub.1a, J.sub.2, R.sup.1, R.sup.2a, R.sup.2b,
R.sup.8, R.sup.9, R.sup.10, and n4 are the same as the preferable
aspects described in any one of Aspects [1-1] to [1-15] and
subordinate Aspects thereof.
[0655] [1-16-5] As the compound of Formula (I) according to Aspect
[1], a preferable compound is a compound in which the ring A is
Formula (A)-VI, that is, Formula (VI):
##STR00117##
[0656] (where X, n, p, h, J.sub.2, R.sup.1, R.sup.2a, R.sup.2b, and
the broken lines are the same as defined in Formula (I) described
in Aspect [1]; J.sub.1a is the same as defined in Formula (B)-1
described in Aspect [1-14-a-1]; and Rx, Rxa, Rxb, and X.sub.1
(including Ry and Rz) are the same as defined in Formula (A)-VI
described in Aspect [1-13-g]). Preferable aspects of X, n, p, h,
J.sub.1a, J.sub.2, R.sup.1, R.sup.2a, R.sup.2b, Rx, Rxa, Rxb, and
X.sub.1 are the same as the preferable aspects described in any one
of Aspects [1-1] to [1-15] and subordinate Aspects thereof.
[0657] Here, as preferable aspects and specific examples of the
Partial Structural Formula (A)-VI moiety having a substituted
spiropiperidinylmethyl group described in Aspect [1-13-g], the same
as the preferable aspects and specific examples described in
Aspects [1-13-g] and [1-13-g-1] can be mentioned.
[0658] [1-16-5-1] As the compound of Formula (I) according to
Aspect [1], a preferable compound is a compound in which the ring A
is Formula (AA)-VI, that is, Formula (VI-A):
##STR00118##
[0659] (where X, n, p, h, J.sub.2, R.sup.1, R.sup.2a, and R.sup.2b
are the same as defined in Formula (I) described in Aspect [1];
J.sub.1a is the same as defined in Formula (B)-1 described in
Aspect [1-14-a-1]; q, s, R.sup.8, and R.sup.9 are the same as
defined in Formula (A) described in Aspect [1-13-c]; Rxb is the
same as defined in Formula (A)-VI described in Aspect [1-13-g]; and
the broken lines are the binding position of an isothiazolyl group
or a piperidinylmethyl group).
[0660] More specifically, preferable aspects of X, n, p, h, q, s,
J.sub.1a, J.sub.2, R.sup.1, R.sup.2a, R.sup.2b, R.sup.8, R.sup.9,
and Rxb are the same as the preferable aspects described in any one
of Aspects [1-1] to [1-15] and subordinate Aspects thereof.
[0661] [1-17] As the compound of Formula (I) according to Aspect
[1], a preferable compound is Formula (I)-B1 or Formula (I)-B2:
##STR00119##
[0662] (where n, p, h, j, k, the ring A, X, J.sub.1, J.sub.2,
R.sup.1, R.sup.2a, R.sup.2b, R.sup.3, R.sup.4, R.sup.5, and R.sup.6
are the same as defined in Formula (I) described in Aspect [1]; and
G, W.sub.1, W.sub.2, and W.sub.3 are the same as in Formula (BB1)
or Formula (BB2) described in Aspect [1-10]).
[0663] More specifically, preferable aspects of n, p, h, j, k, the
ring A, X, J.sub.1, J.sub.2, R.sup.1, R.sup.2a, R.sup.2b, R.sup.3,
R.sup.4, R.sup.5, and R.sup.6 are the same as the preferable
aspects described in any one of Aspects [1-1] to [1-15] and
subordinate Aspects thereof. Preferable aspects of G, W.sub.1,
W.sub.2, and W.sub.3 are the same as the preferable aspects
described in Aspect [1-10] and subordinate Aspects thereof.
[0664] [1-17-a] As the compound of Formula (I)-B1 or Formula
(I)-B2, a preferable compound is a compound in which the ring A is
a C.sub.6-14 aryl group which is optionally substituted with 1 to 5
L(s) or a 3- to 14-membered heterocyclic group which is optionally
substituted with 1 to 5 L(s) and the linker moiety containing X is
Formula (c1) or Formula (c4) described in Aspect [1-15].
[0665] A more preferable compound thereof is a compound in which
the ring A is a phenyl group which is optionally substituted with 1
to 5 L(s), a phthalazinyl group which is optionally substituted
with 1 to 5 L(s), or Formula (A)-VIII described in Aspect [1-13-j]
and the linker moiety containing X is Formula (c1).
[0666] A further preferable compound thereof is a compound in which
the ring A is a phenyl group (the phenyl group is optionally
substituted with 1 to 3 halogen atom(s), 1 to 3 cyano group(s), 1
to 3 C.sub.1-6 alkyl group(s), 1 to 3 halogenated C.sub.1-6 alkyl
group(s), 1 to 3 C.sub.1-6 alkoxy group(s), or 1 to 3 --SF.sub.5),
a phthalazinyl group (the phthalazinyl group is optionally
substituted with 1 to 3 halogen atom(s), 1 to 3 cyano group(s), 1
to 3 C.sub.1-6 alkyl group(s), 1 to 3 halogenated C.sub.1-6 alkyl
group(s), 1 to 3 C.sub.1-6 alkoxy group(s), or 1 to 3 --SF.sub.5),
or Formula (A)-VIII and the linker moiety containing X is Formula
(c1).
[0667] [1-18] As described above, Aspects [1-1] to [1-17] and
subordinate Aspects thereof of the present invention, respective
preferable aspects described above, and the definitions of the
substituents can be optionally combined, so that the preferable
aspects of the compound of Formula (I) according to Aspect [1] can
be optionally provided.
[0668] [1-19] Examples of preferable compounds as the compound of
Formula (I) according to Aspect [1] include the following: [0669]
5-[4-[[3-[4-(2-ethoxyethoxy)-2,6-dimethylphenyl]phenyl]methoxy]phenyl]-1--
oxo-1,2-thiazolidin-3-one (Example 1); [0670]
5-[4-[[3-[4-(2-ethoxyethoxy)-3-fluoro-2,6-dimethylphenyl]phenyl]methoxy]p-
henyl]-1-oxo-1,2-thiazolidin-3-one (Example 2); [0671]
5-[4-[[3-[3-fluoro-4-(3-hydroxy-3-methylbutoxy)-2,6-dimethylphenyl]phenyl-
]methoxy]phenyl]-1-oxo-1,2-thiazolidin-3-one (Example 3); [0672]
5-[4-[[3-[4-(3-hydroxy-3-methylbutoxy)-2,6-dimethylphenyl]phenyl]methoxy]-
phenyl]-1-oxo-1,2-thiazolidin-3-one (Example 4); [0673]
5-[4-[[3-[2,4-dimethyl-6-(3-methylsulfonylpropoxyl)pyridin-3-yl]phenyl]me-
thoxy]phenyl]-1-oxo-1,2-thiazolidin-3-one (Example 5); [0674]
5-[4-[[3-[6-(3-hydroxy-3-methylbutoxy)-2,4-dimethylpyridin-3
yl]phenyl]methoxy]phenyl]-1-oxo-1,2-thiazolidin-3-one trifluoro
acetic acid salt (Example 6); [0675]
5-[4-[[3-[4-(3-hydroxy-3-methylbutoxy)-2,5-dimethylphenyl]phenyl]methoxy]-
phenyl]-1-oxo-1,2-thiazolidin-3-one (Example 7); [0676]
5-[4-[[3-[4-(3-hydroxypropoxy)-2,6-dimethylphenyl]phenyl]methoxy]phenyl]--
1-oxo-1,2-thiazolidin-3-one (Example 8); [0677]
5-[4-[[3-[4-[(2R)-2,3-dihydroxypropoxy]-2,6-dimethylphenyl]phenyl]methoxy-
]phenyl]-1-oxo-1,2-thiazolidin-3-one (Example 9); [0678]
5-[4-[[3-[4-[3-hydroxy-2-(hydroxymethyl)propoxy)-2,6-dimethylphenyl]pheny-
l]methoxy]phenyl]-1-oxo-1,2-thiazolidin-3-one (Example 10); [0679]
5-[4-[[3-[4-(3-aminopropoxy)-2,6-dimethylphenyl]phenyl]methoxy]phenyl]-1--
oxo-1,2-thiazolidin-3-one trifluoro acetic acid salt (Example 11);
[0680]
5-[4-[[3-[4-[(3R)-3-hydroxybutoxy]-2,6-dimethylphenyl]phenyl]methoxy]phen-
yl]-1-oxo-1,2-thiazolidin-3-one (Example 12); [0681]
5-[4-[[3-[2,6-dimethyl-4-(3-methylsulfonylpropoxyl)phenyl]phenyl]methoxy]-
phenyl]-1-oxo-1,2-thiazolidin-3-one (Example 13); [0682]
5-[4-[[3-(2,6-dimethylphenyl)phenyl]methoxy]phenyl]-1,1-dioxo-1,2,5-thiad-
iazolidin-3-one (Example 14); [0683]
5-[4-[[3-[2,6-dimethyl-4-(3-methylsulfonylpropoxyl)phenyl]phenyl]methoxy]-
phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one (Example 15); [0684]
5-[2-chloro-4-[[3-(2,6-dimethylphenyl)phenyl]methoxy]phenyl]-1,1-dioxo-1,-
2,5-thiadiazolidin-3-one (Example 16); [0685]
5-[4-[[3-(2,6-dimethylphenyl)phenyl]methoxy]-2-methylphenyl]-1,1-dioxo-1,-
2,5-thiadiazolidin-3-one (Example 17); [0686]
5-[4-[[3-(2,6-dimethylphenyl)phenyl]methoxy]phenyl]-4-methyl-1,1-dioxo-1,-
2,5-thiadiazolidin-3-one (Example 18); [0687]
5-[4-[[3-(2,6-dimethyl-4-(3-methylsulfonylpropoxyl)phenyl]phenyl]methoxy]-
phenyl]-1,1-dioxo-1,2-thiazolidin-3-one (Example 19); [0688]
5-[4-[[3-[6-(3-hydroxy-3-methylbutoxy)-2,4-dimethylpyridin-3-yl]phenyl]me-
thoxy]phenyl]-1,1-dioxo-1,2-thiazolidin-3-one (Example 20); [0689]
5-[4-[[3-(2,6-dimethylphenyl)phenyl]methoxy]phenyl]-1,1-dioxo-1,2,6-thiad-
iazinane-3-one (Example 21); [0690]
5-[4-[[3-(2,6-dimethylphenyl)phenyl]methoxy]phenyl]-1,1-dioxo-1,2-thiazin-
an-3-one (Example 22);
[0691] A compound selected from: [0692]
5-(4-(((R)-4-(6-(3-hydroxy-3-methylbutoxy)-2-methylpyridin-3-yl)-2,3-dihy-
dro-1H-inden-1-yl)oxy)phenyl)-1-oxo-1,2-thiazolidin-3-one (A)
(Example 23); [0693]
5-(4-(((R)-4-(6-(3-hydroxy-3-methylbutoxy)-2-methylpyridin-3-yl)-2,3-dihy-
dro-1H-inden-1-yl)oxy)phenyl)-1-oxo-1,2-thiazolidin-3-one (A)-a
(Example 23 (A)-a); [0694]
5-(4-(((R)-4-(6-(3-hydroxy-3-methylbutoxy)-2-methylpyridin-3-yl)-2,3-dihy-
dro-1H-inden-1-yl)oxy)phenyl)-1-oxo-1,2-thiazolidin-3-one (A)-b
(Example 23 (A)-b); [0695]
5-[4-[[(1R)-4-[6-(3-hydroxy-3-methylbutoxy)-2,6-dimethylphenyl]-2,3-dihyd-
ro-1H-inden-1-yl]oxy]phenyl]-1-oxo-1,2-thiazolidin-3-one (A)
(Example 24); [0696]
5-[4-[[(1R)-4-[6-(3-hydroxy-3-methylbutoxy)-2,6-dimethylphenyl]-2,-
3-dihydro-1H-inden-1-yl]oxy]phenyl]-1-oxo-1,2-thiazolidin-3-one
(A)-a (Example 24 (A)-a); [0697]
5-[4-[[(1R)-4-[6-(3-hydroxy-3-methylbutoxy)-2,6-dimethylphenyl]-2,3-dihyd-
ro-1H-inden-1-yl]oxy]phenyl]-1-oxo-1,2-thiazolidin-3-one (A)-b
(Example 24 (A)-b); [0698]
4-(((1R)-1-(4-(1-oxo-1,2-thiazolidin-3-one-5-yl)phenoxy)-2,3-dihydro-1H-i-
nden-4-yl)oxy)benzonitrile (A) (Example 25); [0699]
4-(((1R)-1-(4-(1-oxo-1,2-thiazolidin-3-one-5-yl)phenoxy)-2,3-dihydro-1H-i-
nden-4-yl)oxy)benzonitrile (A)-a (Example 25 (A)-a); [0700]
4-(((1R)-1-(4-(1-oxo-1,2-thiazolidin-3-one-5-yl)phenoxy)-2,3-dihydro-1H-i-
nden-4-yl)oxy)benzonitrile (A)-b (Example 25 (A)-b); [0701]
4-(((1R)-1-(4-(1,1-dioxo-1,2,6-thiadiazinan-3-one-5-yl)phenoxy)-2,3-dihyd-
ro-1H-inden-4-yl)oxy)benzonitrile (Example 26); [0702]
5-(4-(((R)-4-phenoxy-2,3-dihydro-1H-inden-1-yl)oxy)phenyl)-1-oxo-1,2-thia-
zolidin-3-one (Example 27); [0703]
5-(4-((7-(trifluoromethyl)-2,3-dihydrobenzofuran-3-yl)oxy)phenyl)-1-oxo-1-
,2-thiazolidin-3-one (Example 28); [0704]
5-(4-(((R)-4-bromo-2,3-dihydro-1H-inden-1-yl)oxy)phenyl)-1-oxo-1,2-thiazo-
lidin-3-one (Example 29); [0705]
5-(4-(((R)-4-(2,6-dimethyl-4-(3-(methylsulfonyl)propoxy)phenyl)-2,3-dihyd-
ro-1H-inden-1-yl)oxy)phenyl)-1-oxo-1,2-thiazolidin-3-one (Example
30); [0706]
5-[4-[[3-[2,6-dimethyl-4-(3-methylsulfonylpropoxyl)phenyl]phenyl]m-
ethoxy]phenyl]-1,1-dioxo-1,2-thiazinan-3-one (Example 31); [0707]
4-(((1R)-1-(4-(1,1-dioxo-3-oxo-1,2-thiazinan-5-yl)phenoxy)-2,3-dihydro-1H-
-inden-4-yl)oxy)benzonitrile (Example 32); [0708]
5-(4-(((R)-4-bromo-2,3-dihydro-1H-inden-1-yl)oxy)phenyl)-1,1-dioxo-1,2-th-
iazinan-3-one (Example 33); [0709]
5-(4-(((R)-4-(4-(3-hydroxy-3-methylbutoxy)-2,6-dimethylphenyl)-2,3-dihydr-
o-1H-inden-1-yl)oxy)phenyl)-1,1-dioxo-1,2-thiazinan-3-one (Example
34); [0710]
5-[4-[[3-[6-(3-hydroxy-3-methylbutoxy)-2,4-dimethylpyridin-3-yl]ph-
enyl]methoxy]phenyl]-1,1-dioxo-1,2-thiazinan-3-one (Example 35);
[0711]
5-(4-(((R)-4-(6-(3-hydroxy-3-methylbutoxy)-2-methylpyridin-3-yl)-2,3-dihy-
dro-1H-inden-1-yl)oxy)phenyl)-1,2-thiazinan-3-one 1,1-dioxide
(Example 36); [0712]
5-(4-(((R)-4-(2,6-dimethylphenyl)-2,3-dihydro-1H-inden-1-yl)oxy)phenyl)-1-
,2-thiazinan-3-one 1,1-dioxide (Example 37); [0713]
5-(4-(((R)-4-(2-(trifluoromethyl)phenyl)-2,3-dihydro-1H-inden-1-yl)oxy)ph-
enyl)-1,2-thiazinan-3-one 1,1-dioxide (Example 38); [0714]
5-(4-(((R)-4-(4-(2-ethoxyethoxy)-2,6-dimethylphenyl)-2,3-dihydro-1H-inden-
-1-yl)oxy)phenyl)-1,2-thiazinan-3-one 1,1-dioxide (Example 39);
[0715]
5-(4-(((R)-4-(4-(3-hydroxy-3-methylbutoxy)-2,6-dimethylphenyl)-2,3-dihydr-
o-1H-inden-1-yl)oxy)phenyl)-1,2-thiazinan-3-one 1,1-dioxide (C)
(Example 40); [0716]
5-(4-(((R)-4-(4-(3-hydroxy-3-methylbutoxy)-2,6-dimethylphenyl)-2,3-dihydr-
o-1H-inden-1-yl)oxy)phenyl)-1,2-thiazinan-3-one 1,1-dioxide (D)
(Example 41); [0717]
5-(4-(((R)-4-(4-(2-ethoxyethoxy)-2,6-dimethylphenyl)-2,3-dihydro-1H-inden-
-1-yl)oxy)phenyl)-1,2-thiazinan-3-one 1,1-dioxide (C) (Example 42);
[0718]
5-(4-(((R)-4-(2,6-dimethylphenyl)-2,3-dihydro-1H-inden-1-yl)oxy)phenyl)-1-
,2-thiazinan-3-one 1,1-dioxide (C) (Example 43); [0719]
5-(4-(((R)-4-(2-(trifluoromethyl)phenyl)-2,3-dihydro-1H-inden-1-yl)oxy)ph-
enyl)-1,2-thiazinan-3-one 1,1-dioxide (C) (Example 44); [0720]
5-(4-(((R)-4-(2,6-dimethyl-4-(3-(methylsulfonyl)propoxy)phenyl)-2,3-dihyd-
ro-1H-inden-1-yl)oxy)phenyl)-1,2-thiazinan-3-one 1,1-dioxide (C)
(Example 45); [0721]
5-(4-(((R)-4-(4-methoxy-2,6-dimethylphenyl)-2,3-dihydro-1H-inden-1-yl)oxy-
)phenyl)-1,2-thiazinan-3-one 1,1-dioxide (C) (Example 46); [0722]
5-(4-(((R)-4-(4-(3-hydroxy-3-methylbutoxy)-2,6-dimethylphenyl)-2,3-dihydr-
o-1H-inden-1-yl)oxy)-2-methylphenyl)-1,2-thiazinan-3-one
1,1-dioxide (Example 47); [0723]
5-(4-(((R)-4-phenoxy-2,3-dihydro-1H-inden-1-yl)oxy)phenyl)-1,2-thiazinan--
3-one 1,1-dioxide (Example 48); [0724]
5-(4-(((R)-4-phenoxy-2,3-dihydro-1H-inden-1-yl)oxy)phenyl)-1,2-thiazinan--
3-one 1,1-dioxide (C) (Example 49); [0725]
4-(((1R)-1-(4-(1,1-dioxide-3-oxo-1,2-thiazinan-5-yl)phenoxy)-2,3-dihydro--
1H-inden-4-yl)oxy)benzonitrile (C) (Example 50); [0726]
3-hydroxy-5-(4-(((R)-4-((6-(3-hydroxy-3-methylbutoxy)-2-methylpyridin-3-y-
l)oxy)-2,3-dihydro-1H-inden-1-yl)oxy)phenyl)-4,5-dihydroisothiazole
1-oxide (A) (Example 51); [0727]
3-hydroxy-5-(4-(((R)-4-((6-(3-hydroxy-3-methylbutoxy)-2-methylpyridin-3-y-
l)oxy)-2,3-dihydro-1H-inden-1-yl)oxy)phenyl)-4,5-dihydroisothiazole
1-oxide (A)-a (Example 51 (A)-a); [0728]
3-hydroxy-5-(4-(((R)-4-((6-(3-hydroxy-3-methylbutoxy)-2-methylpyridin-3-y-
l)oxy)-2,3-dihydro-1H-inden-1-yl)oxy)phenyl)-4,5-dihydroisothiazole
1-oxide (A)-b (Example 51 (A)-b); [0729]
3-hydroxy-5-(4-(((R)-4-((6-methoxypyridin-3-yl)oxy)-2,3-dihydro-1H-inden--
1-yl)oxy)phenyl)-4,5-dihydroisothiazole 1-oxide (A) (Example 52);
[0730]
3-hydroxy-5-(4-(((R)-4-((6-methoxypyridin-3-yl)oxy)-2,3-dihydro-1H-inden--
1-yl)oxy)phenyl)-4,5-dihydroisothiazole 1-oxide (A)-a (Example 52
(A)-a); [0731]
3-hydroxy-5-(4-(((R)-4-((6-methoxypyridin-3-yl)oxy)-2,3-dihydro-1H-
-inden-1-yl)oxy)phenyl)-4,5-dihydroisothiazole 1-oxide (A)-b
(Example 52 (A)-b); [0732]
3-hydroxy-5-(4-(((R)-4-(m-tolyloxy)-2,3-dihydro-1H-inden-1-yl)oxy)phenyl)-
-4,5-dihydroisothiazole 1-oxide (A) (Example 53); [0733]
3-hydroxy-5-(4-(((R)-4-(m-tolyloxy)-2,3-dihydro-1H-inden-1-yl)oxy)phenyl)-
-4,5-dihydroisothiazole 1-oxide (A)-a (Example 53 (A)-a); [0734]
3-hydroxy-5-(4-(((R)-4-(m-tolyloxy)-2,3-dihydro-1H-inden-1-yl)oxy)phenyl)-
-4,5-dihydroisothiazole 1-oxide (A)-b (Example 53 (A)-b); [0735]
5-(4-(((R)-4-(6-(2-ethoxyethoxy)-2-methylpyridin-3-yl)-2,3-dihydro-1H-ind-
en-1-yl)oxy)phenyl)-3-hydroxy-4,5-dihydroisothiazole 1-oxide (A)
(Example 54); [0736]
5-(4-(((R)-4-(6-(2-ethoxyethoxy)-2-methylpyridin-3-yl)-2,3-dihydro-1H-ind-
en-1-yl)oxy)phenyl)-3-hydroxy-4,5-dihydroisothiazole 1-oxide (A)-a
(Example 54 (A)-a); [0737]
5-(4-(((R)-4-(6-(2-ethoxyethoxy)-2-methylpyridin-3-yl)-2,3-dihydro-1H-ind-
en-1-yl)oxy)phenyl)-3-hydroxy-4,5-dihydroisothiazole 1-oxide (A)-b
(Example 54 (A)-b); [0738]
3-hydroxy-5-(4-(((R)-4-((2-methylpyridin-3-yl)oxy)-2,3-dihydro-1H-inden-1-
-yl)oxy)phenyl)-4,5-dihydroisothiazole 1-oxide (A) (Example 55);
[0739]
3-hydroxy-5-(4-(((R)-4-((2-methylpyridin-3-yl)oxy)-2,3-dihydro-1H-inden-1-
-yl)oxy)phenyl)-4,5-dihydroisothiazole 1-oxide (A)-a (Example 55
(A)-a); [0740]
3-hydroxy-5-(4-(((R)-4-((2-methylpyridin-3-yl)oxy)-2,3-dihydro-1H--
inden-1-yl)oxy)phenyl)-4,5-dihydroisothiazole 1-oxide (A)-b
(Example 55 (A)-b); [0741]
5-(4-(((R)-4-bromo-2,3-dihydro-1H-inden-1-yl)oxy)phenyl)-isothiazolidine--
3-one 1-oxide (A)-a (Example 56 (A)-a); [0742]
5-(4-(((R)-4-bromo-2,3-dihydro-1H-inden-1-yl)oxy)phenyl)-isothiazolidin-3-
-one 1-oxide (A)-b (Example 56 (A)-b); [0743]
5-(4-(((R)-4-(4-(2-ethoxyethoxy)-2,6-dimethylphenyl)-2,3-dihydro-1H-inden-
-1-yl)oxy)phenyl)-3-hydroxy-4,5-dihydroisothiazole 1-oxide (A)-a
(Example 57); [0744]
5-(4-(((R)-4-(4-(2-ethoxyethoxy)-2,6-dimethylphenyl)-2,3-dihydro-1H-inden-
-1-yl)oxy)phenyl)-3-hydroxy-4,5-dihydroisothiazole 1-oxide (A)-b
(Example 58); [0745]
5-(4-(((R)-4-(2,6-dimethyl-4-(3-(methylsulfonyl)propoxy)phenyl)-2,3-dihyd-
ro-1H-inden-1-yl)oxy)phenyl)-3-hydroxy-4,5-dihydroisothiazole
1-oxide (A)-a (Example 59); [0746]
5-(4-(((R)-4-(2,6-dimethylphenyl)-2,3-dihydro-1H-inden-1-yl)oxy)phenyl)-3-
-hydroxy-4,5-dihydroisothiazole 1-oxide (A)-a (Example 60); [0747]
3-hydroxy-5-(4-(((R)-4-(4-methoxy)-2,6-dimethylphenyl)-2,3-dihydro-1H-ind-
en-1-yl)oxy)phenyl)-4,5-dihydroisothiazole 1-oxide (A)-a (Example
61); [0748]
3-hydroxy-5-(4-(((R)-4-(2-methyl-6-(3-(methylsulfonyl)propoxy)pyri-
din-3-yl)-2,3-dihydro-1H-inden-1-yl)oxy)phenyl)-4,5-dihydroisothiazole
1-oxide (A)-a (Example 62); [0749]
3-hydroxy-5-(4-(((R)-4-(6-methoxy)-2-methylpyridin-3-yl)-2,3-dihydro-1H-i-
nden-1-yl)oxy)phenyl)-4,5-dihydroisothiazole 1-oxide (A)-a (Example
63); [0750]
3-hydroxy-5-(4-(((R)-4-(2-(trifluoromethyl)phenyl)-2,3-dihydro-1H--
inden-1-yl)oxy)phenyl)-4,5-dihydroisothiazole 1-oxide (A)-a
(Example 64); [0751]
3-hydroxy-5-(4-(((R)-4-(2-trifluoromethyl)pyridin-3-yl)-2,3-dihydr-
o-1H-inden-1-yl)oxy)phenyl)-4,5-dihydroisothiazole 1-oxide (A)-a
(Example 65); [0752]
3-hydroxy-5-(4-(((R)-4-(o-tolyl)-2,3-dihydro-1H-inden-1-yl)oxy)phenyl)-4,-
5-dihydroisothiazole 1-oxide (A)-a (Example 66); [0753]
5-(4-(((R)-4-(5-fluoro-2-methylphenyl)-2,3-dihydro-1H-inden-1-yl)oxy)phen-
yl)-3-hydroxy-4,5-dihydroisothiazole 1-oxide (A)-a (Example 67);
[0754]
5-(4-(((1R)-4-(2-fluoro-6-methoxyphenyl)-2,3-dihydro-1H-inden-1-yl)oxy)ph-
enyl)-3-hydroxy-4,5-dihydroisothiazole 1-oxide (A)-a (Example 68);
and [0755]
5-(4-(((R)-4-(2-ethoxy-5-fluorophenyl)-2,3-dihydro-1H-inden-1-yl)o-
xy)phenyl)-3-hydroxy-4,5-dihydroisothiazole 1-oxide (A)-a (Example
69), a pharmaceutically acceptable salt of the compound, a
pharmaceutically acceptable solvate of the compound or a
pharmaceutically acceptable solvate of the salt, an optical isomer
of the compound, a pharmaceutically acceptable salt of the isomer,
and a pharmaceutically acceptable solvate of the isomer or a
pharmaceutically acceptable solvate of the salt. Examples of the
above preferable compounds also include the compounds of Structural
Formulae 8 to 17 below in (Example 1P) to (Example 157P), a
pharmaceutically acceptable salt of the compound, a
pharmaceutically acceptable solvate of the compound or a
pharmaceutically acceptable solvate of the salt, an optical isomer
of the compound, a pharmaceutically acceptable salt of the isomer,
and a pharmaceutically acceptable solvate of the isomer or a
pharmaceutically acceptable solvate of the salt.
[0756] [1-19-1] In the compound of Formula (I) according to Aspect
[1] or of Formula (I)-1 according to Aspect [1-16],
##STR00120##
compounds produced by optionally combining the groups of Partial
Structural Formula (A)-(C) (on the left of the wavy line) and
Partial Structural Formula (B)-1 (on the right of the wavy line) in
Formula (I)-1 below can be produced optionally. More specifically,
Partial Structural Formula (B)-1 is a group optionally selected
from Formula (B1a-het1) to Formula (B1a-het5) or Formula (B2a-het1)
to Formula (B2a-het5) described below, and Partial Structural
Formula (A)-(C) is a group optionally selected from Formula (a-1)
to Formula (a-109) described below.
##STR00121## ##STR00122## ##STR00123## ##STR00124## ##STR00125##
##STR00126## ##STR00127## ##STR00128## ##STR00129## ##STR00130##
##STR00131## ##STR00132## ##STR00133## ##STR00134## ##STR00135##
##STR00136##
[0757] The compounds produced by combining these partial structural
formulae are exemplified as specific compounds of the compound of
Formula (I) or Formula (I)-1. For example, a compound of Formula
(a1-B1a-het1):
##STR00137##
produced by combining Formula (B1a-het1) with Formula (a-1) is
exemplified as the specific compound. In such a specific compound,
a compound in which the moiety corresponding to X is exchanged from
an oxygen atom to --NH-- or from --NH-- to an oxygen atom can also
be optionally produced, and the thus produced compound is also
exemplified as the specific compound.
[0758] [1-19-2] In the compound of Formula (I) according to Aspect
[1] or of Formula (I)-B1 or Formula (I)-B2 according to Aspect
[1-17], compounds produced by optionally combining the groups of
Partial Structural Formula (A)-(C) (on the left of the left wavy
line), Partial Structural Formula (BB1) or Formula (BB2) (between
the two wavy lines), Partial Structural Formula (B-Het) (on the
right of the right wavy line) in Formula (I)-B1 or Formula (I)-B2
can also be produced optionally:
##STR00138##
More specifically, Partial Structural Formula (B-Het) is a group
optionally selected from Formula (het1) to Formula (het9). Partial
Structural Formula (BB1) or Formula (BB2) is a group optionally
selected from Formula (b-1) to Formula (b-5), and Partial
Structural Formula (A)-(C) is a group optionally selected from
Formula (a-37) to Formula (a-40) exemplified in Aspect [1-19-1] or
Formula (a-94) to Formula (a-99) below.
##STR00139## ##STR00140## ##STR00141##
[0759] The compounds produced by combining these partial structural
formulae are exemplified as specific compounds of the compound of
Formula (I), Formula (I)-B1, or Formula (I)-B2. For example, a
compound of Formula (a94-b1-het6):
##STR00142##
produced by combining Formula (het6), Formula (b-1), and Formula
(a-94) is exemplified as the specific compound.
[0760] [2]A second aspect of the present invention is a
pharmaceutical composition containing the compound of Formula (I),
a pharmaceutically acceptable salt of the compound, or a
pharmaceutically acceptable solvate of the compound or a
pharmaceutically acceptable solvate of the salt.
[0761] [3]A third aspect of the present invention is a prophylactic
agent and/or a therapeutic agent for a GPR40-involving disease,
characterized by containing, as an active ingredient, at least one
of the compound of Formula (I), a pharmaceutically acceptable salt
of the compound, and a pharmaceutically acceptable solvate of the
compound and a pharmaceutically acceptable solvate of the salt.
[0762] [3-1] Specifically, the third aspect of the present
invention is a prophylactic agent and/or a therapeutic agent for
each disease of diabetes [more specifically, any one of or all of
Type 1 diabetes (insulin-dependent diabetes), Type 2 diabetes
(non-insulin-dependent diabetes), and borderline type diabetes
(impaired glucose tolerance (IGT) and/or impaired fasting glycemia
(IFG))], obesity, and adiposity, characterized by containing, as an
active ingredient, at least one of the compound of Formula (I), a
pharmaceutically acceptable salt of the compound, and a
pharmaceutically acceptable solvate of the compound and a
pharmaceutically acceptable solvate of the salt. An inhibitor of
Type 2 diabetes in the impaired glucose tolerance is also included
in examples of the above prophylactic agent and therapeutic agent.
A therapeutic agent for sulfonylurea secondary failure diabetes is
also included in the examples thereof, and by the therapeutic
agent, also in (administration-ineffective) diabetic patients who
cannot obtain a satisfactory hypoglycemic effect even by being
administrated with a sulfonylurea agent (such as glibenclamide and
glimepiride) or a rapid-acting insulin secretagogues (such as
mitiglinide), insulin secretion effect or hypoglycemic effect can
be obtained.
[0763] Here, in relationship between the blood glucose level and
the disease, the diabetes is characterized by exhibiting a fasting
blood glucose level of 126 mg/dL or more, or a casual blood glucose
level or a 2 hours value of the 75 g oral glucose tolerance test
(OGTT) of 200 mg/dL or more. The borderline type diabetes (also
called glucose tolerance disorders) refers to an impaired fasting
glycemia (IFG) in which the fasting blood glucose level is 110
mg/dL or more and less than 126 mg/dL and/or an impaired glucose
tolerance (IGT) in which a 2 hours value of the 75 g OGTT is 140
mg/dL or more and less than 200 mg/dL.
[0764] The insulin resistance refers to a pathological condition in
which insulin becomes unable to lower the blood glucose level in
the organism and is evaluated by a quantitative glucose clamp
technique or HOMA-IR in clinical practice. It is known that the
insulin resistance causes a hyperinsulinemia and becomes a risk of
a hypertension and a coronary artery disease.
[0765] The "adiposity" is defined by the Japan Society for the
Study of Obesity as "a pathological condition requiring medically a
weight reduction in the case where an obesity-derived or -related
health impairment is combined or such a combination is expected".
The "obesity" defined here is evaluated by measuring BMI (body mass
index, kg/m.sup.2). Generally, a body having a BMI of 25 or more is
diagnosed as obesity. Examples of the result of the therapy include
the reduction of BMI.
[0766] [4]A fourth aspect of the present invention is an insulin
secretagogue, characterized by containing, as an active ingredient,
at least one of the compound of Formula (I), a pharmaceutically
acceptable salt of the compound, and a pharmaceutically acceptable
solvate of the compound and a pharmaceutically acceptable solvate
of the salt.
[0767] [5]A fifth aspect of the present invention is a GPR40
activating agent containing one or more of the compound of Formula
(I), a pharmaceutically acceptable salt of the compound, and a
pharmaceutically acceptable solvate of the compound and a
pharmaceutically acceptable solvate of the salt.
[0768] In the second to fifth aspects and preferable aspects
thereof, more preferable substituents and a combination thereof in
Formula (I) are according to descriptions described in the first
aspect.
[0769] In each aspect as described in [1] to [5] of the present
invention, it is preferable to use a compound having a EC50 value
of preferably, 3 .mu.M or less, more preferably, 1 .mu.M or less,
further preferably, 300 nM or less, and most preferably, 100 nM or
less, when the GPR40 agonist action is measured by a method
accordingly selected (for example, the below described
pharmacological test example 1 (an agonist action on GPR40 of human
origin)).
[0770] In the above aspects of the present invention, the
"therapeutic agent" is not only for treating diseases or symptoms,
but also for improving diseases or symptoms.
[0771] In all of the above aspects, when the term "compound" is
used, the compound refers also to a "pharmaceutically acceptable
salt of the compound". In addition, there is the case where the
compound of the present invention has an asymmetric carbon, and
thus, the compound of the present invention includes a mixture of
various stereoisomers such as a geometric isomer, a tautomer, and
an optical isomer, and an isolated stereoisomer. The compound of
Formula (I) may have an axial asymmetry due to a steric hindrance
and an isomer caused by the axial asymmetry (axial chirality) is
also included in the compound of the Formula (I). The isolation and
the purification of such stereoisomers can be performed by a person
skilled in the art by an ordinary technique through an optical
resolution or an asymmetric synthesis using a preferential
crystallization or a column chromatography.
[0772] The compound of Formula (I) of the present invention may
form an acid addition salt or a salt with a base depending on the
type of the substituent. Such salt is not particularly limited so
long as the salt is a pharmaceutically acceptable salt. Specific
examples thereof include acid addition salts with: mineral acids
such as hydrochloric acid, hydrobromic acid, hydriodic acid,
sulfuric acid, nitric acid, and phosphoric acid; organic carboxylic
acids, for example, an aliphatic monocarboxylic acid such as formic
acid, acetic acid, propionic acid, butyric acid, valeric acid,
enanthic acid, capric acid, myristic acid, palmitic acid, stearic
acid, lactic acid, sorbic acid, and mandelic acid, an aromatic
monocarboxylic acid such as benzoic acid and salicylic acid, an
aliphatic dicarboxylic acid such as oxalic acid, malonic acid,
succinic acid, fumaric acid, maleic acid, malic acid, and tartaric
acid, an aliphatic tricarboxylic acid such as citric acid, cinnamic
acid, glycolic acid, pyruvic acid, oxylic acid, salicylic acid, and
N-acetylcysteine; organic sulfonic acids, for example, an aliphatic
sulfonic acid such as methanesulfonic acid, ethanesulfonic acid,
and 2-hydroxyethanesulfonic acid, and an aromatic sulfonic acid
such as benzenesulfonic acid and p-toluenesulfonic acid; and acidic
amino acids such as aspartic acid and glutamic acid, salts
(including, besides mono salts, disodium salts and dipotassium
salts) with a metal, for example, alkali metals such as lithium,
sodium, potassium, and cesium, and alkaline earth metals such as
magnesium, calcium, and barium, salts with a metal such as
aluminum, iron, copper, nickel, cobalt, and zinc, salts with an
organic base such as methylamine, ethylamine, tert-butylamine,
tert-octylamine, diethylamine, triethylamine, cyclohexylamine,
dibenzylamine, ethanolamine, diethanolamine, triethanolamine,
piperidine, morpholine, pyridine, lysine, arginine, ornithine,
ethylenediamine, N-methylglucamine, glucosamine, a phenylglycine
alkyl ester, and guanidine, and salts with glycine, histidine,
choline, and ammonium.
[0773] These salts can be obtained by an ordinary method including,
for example, mixing an equivalent of the compound of the present
invention with a solution containing a desired acid, base, or the
like, and collecting a desired salt by filtration or
distillation-off of a solvent. The compound of the present
invention or a salt of the compound can form a solvate with a
solvent such as water, ethanol, and glycerol.
[0774] The salt of the compound of the present invention includes a
mono-salt and a di-salt. The compound of the present invention can
form both of an acid addition salt and a salt with a base
simultaneously depending on the type of the substituent in the side
chains. Further, the present invention encompasses also hydrates,
various pharmaceutically acceptable solvates, and crystal
polymorphs of the compound of Formula (I) of the present invention.
Here, needless to say, the present invention is not limited to the
compounds described in Examples below and encompasses all of the
compounds of Formula (I) of the present invention and
pharmaceutically acceptable salts of the compounds.
[0775] The compound of the present invention may be labeled with an
isotope (such as .sup.3H, .sup.14C, and .sup.35S).
[0776] [Method for Producing the Compound of the Present
Invention]
[0777] Methods for producing the compound of Formula (I) of the
present invention will be described below.
[0778] The compound of Formula (I) of the present invention, a salt
of the compound, and a solvate of the compound or the salt can be
produced by a combination of commonly known chemical production
methods. Typical production methods will be described below.
[0779] In each Formula in the production methods below, each
definition of ring A, ring B, ring A', ring A'', ring A''', ring
B', X, V, T, J.sub.1, J.sub.1a, J.sub.2, R.sup.1, R.sup.2a,
R.sup.2b, R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7, R.sup.8,
R.sup.9, R.sup.10, R.sup.11a, R.sup.11b, R.sup.11c, R.sup.12a,
R.sup.12b, R.sup.12c, R.sup.13, R.sup.13a, R.sup.14, n, p, q, q1,
q2, r, r1, s, h, j, k, f g, g1, X.sub.3, n1, n2, n3, n4, Z.sub.1,
Z.sub.2, Z.sub.3, Rx, Rxa, Rxb, X.sub.1, and the like is the same
as each definition in Formula (I), Formula (A), Formula (A)-1,
Formula (AA), Formula (A1)-IV, Formula (A2)-IV, Formula (A)-V,
Formula (AA)-V, Formula (A)-VI, and Formula (B)-I described in the
first aspect above unless otherwise specified.
[0780] In the production methods, the definition of m is an integer
of 1 or 2.
[0781] In the production methods, the definition of h2 is an
integer of 0 to 2.
[0782] In the production methods, the definition of g-1 is an
integer of 0 to 3.
[0783] In the production methods, the definition of R' is a
C.sub.1-6 alkyl group such as a methyl group, an ethyl group, and a
t-butyl group unless otherwise specified.
[0784] In the production methods, the definition of R'' is a
hydrogen atom, a hydroxy group, or a C.sub.1-6 alkoxy group such as
a methoxy group and an ethoxy group unless otherwise specified.
[0785] In the production methods, each definition of Y, Y.sub.1,
and Y.sub.2 is a halogen atom, a nitro group, a protected imino
group (--NP.sup.1.sub.2), a formyl group, or an ester group unless
otherwise specified.
[0786] In the production methods, the definition of Z is a leaving
group including a hydroxy group, a halogen atom, and a sulfonyloxy
group such as a methanesulfonyloxy group, a p-toluenesulfonyloxy
group, and a trifluoromethanesulfonyloxy group unless otherwise
specified.
[0787] In the production methods, the definition of W is boronic
acid, a boronic ester, or a trifluoroborate salt unless otherwise
specified.
[0788] In the production methods, for the definitions of W.sup.1
and W.sup.2, W.sup.2 is boronic acid, a boronic ester, or a
trifluoroborate salt when W.sup.1 is a hydroxy group, a halogen
atom, or a trifluoromethanesulfonyloxy group, and W.sup.2 is a
hydroxy group, a halogen atom, or a trifluoromethanesulfonyloxy
group when W.sup.1 is boronic acid, a boronic ester, or a
trifluoroborate salt unless otherwise specified.
[0789] In the production methods, the definition of * is a chiral
center.
[0790] In the production methods, each definition of P.sup.1,
P.sup.2, P.sup.3, P.sup.4, and P.sup.5 is a protective group for a
hydroxy group (--OH), a thiol group (--SH), or an imino group
(--NH--) unless otherwise specified. Examples of the protective
group for a hydroxy group include an alkyl group such as a methyl
group; an alkoxyalkyl group such as a methoxymethyl group, a
methoxyethoxymethyl group, and a tetrahydropyranyl group; an
arylmethyl group such as a benzyl group and a triphenylmethyl
group; a silyl group such as a trimethylsilyl group, a
triethylsilyl group, and a t-butyldimethylsilyl group; an alkanoyl
group such as an acetyl group and a pivaloyl group; an aroyl group
such as a benzoyl group; an alkoxycarbonyl group such as a
t-butoxycarbonyl group; and an arylmethoxycarbonyl group such as a
benzyloxycarbonyl group. Examples of the protective group for a
thiol group include an alkyl group such as a methyl group; an
arylmethyl group such as a benzyl group and a triphenylmethyl
group; an alkanoyl group such as an acetyl group and a pivaloyl
group; and an aroyl group such as a benzoyl group. Examples of the
protective group for an imino group include an alkanoyl group such
as an acetyl group; an alkoxycarbonyl group such as a
methoxycarbonyl group, an ethoxycarbonyl group, and a
t-butoxycarbonyl group; an arylmethoxycarbonyl group such as a
benzyloxycarbonyl group, a para-methoxybenzyloxycarbonyl group, and
a para-nitrobenzyloxycarbonyl group; an arylmethyl group such as a
benzyl group, a para-methoxybenzyl group, a dimethoxybenzyl group,
and a triphenylmethyl group; and an aroyl group such as a benzoyl
group.
[0791] Deprotection methods of such protective groups are different
depending on the chemical properties of a protected reactive group
(a hydroxy group, a thiol group, or an imino group) and an employed
protective group. For example, an acyl-type protective group such
as an alkanoyl group, an alkoxycarbonyl group, and an aroyl group
can be hydrolyzed using a suitable base such as an alkali metal
hydroxide including lithium hydroxide, sodium hydroxide, and
potassium hydroxide for the deprotection. An alkoxyalkyl-type
protective group such as a methoxymethyl group, a
methoxyethoxymethyl group, and a tetrahydropyranyl group, a
substituted methoxycarbonyl-type protective group such as a
t-butoxycarbonyl group and a para-methoxybenzyloxycarbonyl group,
and a silyl-type protective group such as a triethylsilyl group and
a t-butyldimethylsilyl group can be removed using a suitable acid
such as acetic acid, hydrochloric acid, hydrobromic acid, sulfuric
acid, phosphoric acid, trifluoroacetic acid, and
trifluoromethanesulfonic acid or a combination of them. The
silyl-type protective group can also be removed using a suitable
fluorine ion (F.sup.-) generating reagent such as
tetrabutylammonium fluoride and hydrogen fluoride. An
arylmethoxycarbonyl group such as a benzyloxycarbonyl group, a
para-methoxybenzyloxycarbonyl group, and a
para-nitrobenzyloxycarbonyl group and an arylmethyl group such as a
benzyl group can be removed by hydrogenolysis using a palladium
carbon catalyst. A benzyl group can be removed by Birch reduction
using metallic sodium in liquid ammonia. A triphenylmethyl group
can be removed using a suitable acid such as acetic acid,
hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric
acid, trifluoroacetic acid, and trifluoromethanesulfonic acid or a
combination of them. It can also be removed by Birch reduction
using metallic sodium in liquid ammonia and removed by
hydrogenolysis using a palladium carbon catalyst.
[0792] During the production of the compound of Formula (I) of the
present invention, when it has a reactive group such as a hydroxy
group, an amino group, and a carboxy group, such a group may be
properly protected in any reaction step, and the protective group
may be removed in a suitable step.
[0793] Methods for introducing and removing such protective groups
are properly performed depending on the type of a group to be
protected or a protective group. For example, such introduction and
removal can be performed by methods described in [Protective Groups
in Organic Synthesis, edited by Greene et al., the fourth edition
(2007), John Wiley & Sons].
[0794] Required starting materials are commercially available or
can be easily obtained from commercial products by usual production
methods in organic chemistry.
[0795] Reaction conditions in the production methods are as follows
unless otherwise specified. The reaction temperature is in a range
from -78.degree. C. to the reflux temperature of a solvent, and the
reaction time is a time sufficient for a reaction. Examples of the
reaction inert solvent include, but are not limited to, an aromatic
hydrocarbon solvent such as toluene, benzene, and xylene; an
alcoholic solvent such as methanol, ethanol, and 2-propanol; a
polar solvent such as water, acetonitrile, N,N-dimethylformamide,
dimethyl sulfoxide, and 1,3-dimethyl-2-imidazolidinone; a basic
solvent such as triethylamine and pyridine; a halogenated solvent
such as chloroform, methylene chloride, and 1,2-dichloroethane; an
ether solvent such as 1,2-dimethoxyethane, cyclopentyl methyl
ether, diethyl ether, tetrahydrofuran, and dioxane; and a mixed
solvent of them. Such solvents are properly selected depending on
reaction conditions. Examples of the base include, but are not
limited to, an inorganic base such as sodium carbonate, potassium
carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide,
and sodium hydride; and an organic base such as triethylamine,
N,N-diisopropylethylamine, pyridine, N,N-dialkylaniline, lithium
diisopropylamide, and lithium bistrimethylsilylamide. Examples of
the acid include, but are not limited to, a mineral acid such as
hydrochloric acid, sulfuric acid, and nitric acid; and an organic
acid such as methanesulfonic acid and p-toluenesulfonic acid.
[0796] Hereinafter, production methods will be described, but the
present invention is not limited to these methods.
[0797] The compound of Formula (I) of the present invention can be
obtained by a production method suitable for the type of the ring
including a saturated amide structure having --S(O)n-NH--CO--. A
material compound for the compound is typically shown as Formula
(IX).
##STR00143##
In the formulae in the production method, <Het> generally
means a conversion part into the ring structure of a saturated
cyclic amide structure that is bonded to the ring B and has
--S(O)n-NH--CO-- (n is an integer of 0 to 2), examples of which
include W (for example, boronic acid, a boronic ester, and a
trifluoroborate salt) and Y (for example, a halogen atom, a nitro
group, a protected imino group (--NP.sup.1.sub.2), a formyl group,
and an ester group) in the production method, and a molecular chain
to form the saturated cyclic amide structure.
[0798] (1) Methods for producing the compound of Formula (I)-1a or
Formula (I)-2a of the present invention will be described
below.
[0799] <Production Method A>
[0800] <When R.sup.2a.dbd.R.sup.2b.dbd.H and R.sup.11a.dbd.H in
Formula (I)-1a above>
##STR00144##
<Step 1>
[0801] The compound of Formula (IX)-1a obtained in (Production
Method E) or (Production Method F) described later is subjected to
isothiazole ring formation reaction. In accordance with methods
known in literatures, for example, the methods described in
[Heterocyclic Compounds, New Edition, Applications, pp. 41-57
(2004), Kodansha Ltd.], [Chemische Berichte, vol. 94, p. 2950
(1961)], and [Chemische Berichte, vol. 96, p. 944 (1963)], a
compound of (I)-1a-1 can be produced by reacting the compound of
Formula (IX)-1a with a thiol (SH) source such as sodium
hydrosulfide and hydrogen sulfide gas in a reaction inert solvent
such as methanol, ethanol, and water or a mixed solvent of them at
a temperature from 0.degree. C. to a reflux temperature of the
solvent, and then by reacting the obtained thiol adduct in the
presence of a halogen such as iodine and bromine and in the
presence or absence of a base such as pyridine and potassium
carbonate in a reaction inert solvent such as methanol, ethanol,
ethyl acetate, and water or a mixed solvent of them at a
temperature from 0.degree. C. to a reflux temperature of the
solvent.
<Step 2>
[0802] The sulfur atom in the compound of Formula (I)-1a-1 is
oxidized. In accordance with methods known in literatures, for
example, the method described in [Jikken Kagaku Koza (Experimental
Chemistry Course), the fourth edition, vol. 20, Organic Synthesis
V, Oxidation Reaction, pp. 276-280 (1992), Maruzen Co., Ltd.], a
compound of Formula (I)-1a-2 can be produced by reacting the
compound of Formula (I)-1a-1 in the presence of a peracid or a
peroxide such as hydrogen peroxide water, m-chloroperbenzoic acid
(MCPBA), peracetic acid, trifluoroperacetic acid, Oxone (registered
trademark) (DuPont), and tert-butylhydroperoxide (TBHP) in a
reaction inert solvent including a halogenated solvent such as
dichloromethane and chloroform, an aromatic hydrocarbon solvent
such as toluene and benzene, and a polar solvent such as
acetonitrile, methanol, acetone, and water or in a mixed solvent of
them at a temperature from 0.degree. C. to a reflux temperature of
the solvent. In the oxidation reaction, selection of an oxidizing
agent and suitable selection of equivalent of a reagent, a reaction
temperature, a reaction time, a solvent, and the like can produce a
sulfoxide (n=1) and a sulfone (n=2) separately. Such sulfoxide and
sulfone can be separated by common techniques such as column
chromatography.
[0803] <Step 3>
[0804] The compound of Formula (I)-1a-2 is subjected to reduction.
In accordance with methods known in literatures, for example, the
method described in [Japan Institute of Heterocyclic Chemistry,
vol. 64, pp. 101-120 (2004)], the compound of Formula (I)-1a can be
produced by reacting the compound of Formula (I)-1a-2 in the
presence of a reducing agent such as lithium
tri(sec-butyl)borohydride (L-selectride), potassium
tri(sec-butyl)borohydride, lithium borohydride, and Raney nickel
(Raney-Ni)-formic acid or a reducing agent such as a hydride of a
metal or a metalloid and a complex compound of them in a reaction
inert solvent including an ether solvent such as tetrahydrofuran,
diethyl ether, and dioxane, an aromatic hydrocarbon solvent such as
toluene and benzene, and a polar solvent such as acetonitrile and
methanol or in a mixed solvent of them at a temperature from
-78.degree. C. to a reflux temperature of the solvent.
<Step 4>
[0805] In accordance with methods known in literatures, for
example, the method described in [Jikken Kagaku Koza (Experimental
Chemistry Course), the fourth edition, vol. 26, Organic Synthesis
VIII, Asymmetric Synthesis, Reduction, Sugar, and Labelled
Compound, pp. 23-68 (1992), Maruzen Co., Ltd.], the compound of
Formula (I)-1a-3 as an optically active compound of Formula (I)-1a
can be produced by reaction in the presence of the compound of
Formula (I)-1a-2 in the presence of, for example, optically active
dichloro
[bis(diphenylphosphino)binaphthyl][diphenylethylenediamine]ruthenium
and a basic reagent such as potassium hydroxide and potassium
t-butoxide in a hydrogen gas atmosphere using 2-propanol as a
solvent at a temperature from room temperature to a reflux
temperature of the solvent. Alternatively, the compound of Formula
(I)-1a-3 as an optically active compound can be produced by
reaction in the presence of a transition-metal complex such as
chlorotris(triphenylphosphine)rhodium(I), a reagent such as
optically active 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl, and a
hydrogen source such as hydrogen and formic acid-triethylamine
using a solvent such as ethanol at a temperature from room
temperature to a reflux temperature of the solvent.
[0806] In the production methods below, when an isothiazole ring is
subjected to reduction, a corresponding optically active compound
can be obtained by the reduction in accordance with <Step 4>
in <Production Method A>.
[0807] The compounds of Formula (II)-1a and Formula (III)-1a above
are included in the compound of Formula (I)-1a in (Production
Method A) and can be produced by a similar production method. In
Formula (II-B), Formula (II-C), Formula (IV-1), Formula (IV-3),
Formula (IV-4), Formula (V), Formula (V-A), Formula (VI), Formula
(VI-A), Formula (I)-B1, and Formula (I)-B2 above, the compound
having Formula (B-Het)-1a is also included in the compound of
Formula (I)-1a and can be produced by a similar production method
to (Production Method A). These compounds of Formula (I)-1a are
included in the compound of Formula (I).
[0808] Similarly, in the production methods in (Production Method
B) or later, the compounds of Formula (II)-1a and Formula (III)-1a
above and the compounds having Formula (B-Het)-1a in Formula
(II-B), Formula (II-C), Formula (IV-1), Formula (IV-3), Formula
(IV-4), Formula (V), Formula (V-A), Formula (VI), Formula (VI-A),
Formula (I)-B1, and Formula (I)-B2 above are included in the
compound of Formula (I)-1a and can be produced by a similar
production method, and these compounds of Formula (I)-1a are
included in the compound of Formula (I).
[0809] When n=0 in (Production Method A), a compound can be
produced without the oxidation step in <Step 2>.
[0810] Similarly, in the production methods in (Production Method
B) or later, it should be understood that when n is not specified
to 0, 1, or 2, an oxide (a sulfoxide or a sulfone derivative) in
which n=1 or 2 can be produced in accordance with the oxidation
reaction in <Step 2> in (Production Method A) in the
oxidation step shown in each reaction scheme or a compound (a
sulfenamide derivative) in which n=0 can be produced without the
oxidation step.
[0811] <Production Method B>
[0812] <When R.sup.2a.dbd.R.sup.2b.dbd.H and R.sup.11a.dbd.H in
Formula (I)-1a above>
##STR00145##
<Step 1>
[0813] A compound of Formula (B-I) is subjected to isothiazole ring
formation reaction. A compound of Formula (B-II) can be produced by
reacting the compound of Formula (B-I) (it is known in the art or
can be easily produced from a known compound as described later in
(Production Method E) and is a properly protected compound) in a
similar manner to that in <Step 1> in (Production Method
A).
<Step 2>
[0814] The compound of Formula (B-II) is protected with a
protective group P.sup.2. A compound of Formula (B-III) can be
produced by causing the compound of Formula (B-II) to react with
the protective group P.sup.2 by a method suitable for the type of
the protective group.
<Step 3>
[0815] The protective group P.sup.1 in the compound of Formula
(B-III) is deprotected. A compound of Formula (B-IV) can be
produced by deprotecting the protective group P.sup.1 in the
compound of Formula (B-III) by a method suitable for the type of
the protective group.
[0816] <Step 4>
[0817] The compound of Formula (B-IV) is subjected to substitution
reaction with a compound of Formula (B-V).
[0818] <When Z=halogen, methanesulfonyloxy group, or
p-toluenesulfonyloxy group>
[0819] In accordance with methods known in literatures, for
example, the methods described in [Jikken Kagaku Koza (Experimental
Chemistry Course), the fourth edition, vol. 20, Organic Synthesis
II, Alcohol and Amine, pp. 187-200 and 284-292 (1992), Maruzen Co.,
Ltd.] and [Jikken Kagaku Koza (Experimental Chemistry Course), the
fourth edition, vol. 20, Organic Synthesis VI, Hetero Element- or
Main Group Metal Element-Containing Compound, pp. 319-350 (1992),
Maruzen Co., Ltd.], a compound of Formula (B-VI) can be produced by
substitution reaction of the compound of Formula (B-IV) in the
presence of the compound of Formula (B-V) in the presence or
absence of a base such as triethylamine, pyridine, sodium hydride,
sodium hydroxide, and potassium carbonate in a reaction inert
solvent including a halogenated solvent such as dichloromethane and
chloroform, an ether solvent such as diethyl ether and
tetrahydrofuran, an aromatic hydrocarbon solvent such as toluene
and benzene, and a polar solvent such as N,N-dimethylformamide or
in a mixed solvent of them at a temperature from 0.degree. C. to a
reflux temperature of the solvent.
[0820] <When Z=hydroxy group, X.noteq.-NR.sup.7--, and
k=0>
[0821] In accordance with methods known in literatures, for
example, the method described in [Tetrahedron, vol. 67 (10), pp.
3140-3149 (2011)], a compound of Formula (B-VI) can be produced by
reacting the compound of Formula (B-IV) in the presence of the
compound of Formula (B-V) in the presence of a base such as
potassium tert-butoxide and a catalyst such as copper acetate in a
reaction inert solvent including an ether solvent such as diethyl
ether, tetrahydrofuran, and 1,4-dioxane and an aromatic hydrocarbon
solvent such as toluene and benzene or in a mixed solvent of them
at a temperature from 0.degree. C. to a reflux temperature of the
solvent.
[0822] <When Z=hydroxy group, X=nitrogen atom, and k=0>
[0823] In accordance with methods known in literatures, for
example, the methods described in [WO 2010/143733 pamphlet, p. 71,
[0179]: Step 2 in Reaction scheme 1], [Tetrahedron Letters, vol.
36, pp. 63733-6374 (1995)], and [Tetrahedron Letters, vol. 38, pp.
5831-5834 (1997)], a compound of Formula (B-VI) can be produced by
Mitsunobu reaction of the compound of Formula (B-IV) in the
presence of the compound of Formula (B-V) in the presence of an
organophosphorus compound such as triphenylphosphine and an azo
compound such as an azodicarboxylic acid ester and azodicarboxylic
amide in a reaction inert solvent including a halogenated solvent
such as dichloromethane and chloroform, an ether solvent such as
diethyl ether and tetrahydrofuran, an aromatic hydrocarbon solvent
such as toluene and benzene, and a polar solvent such as
N,N-dimethylformamide or in a mixed solvent of them at a
temperature from 0.degree. C. to a reflux temperature of the
solvent.
[0824] The compound of Formula (B-V) used in the step is known in
the art or can be produced from a corresponding known compound in
accordance with methods known in literatures as described later in
(Production Method J), (Production Method J-1), (Production Method
J-2), (Production Method J-3), (Production Method J-4), (Production
Method J-5), and (Production Method J-6). For example, it can be
produced from a corresponding compound in accordance with the
methods described in [WO 2005/063729 pamphlet, Reference Examples 2
and 3 and the like], [WO 2005/086661 pamphlet, Example 18 and the
like], [WO 2008/001931 pamphlet, Reaction Scheme 2, Reference
Examples 15-19, and the like], [WO 2009/039943 pamphlet, pp.
51-52], [WO 2009/054423 pamphlet, Production Examples 12, 24, 37,
and the like], [WO 2010/085525 pamphlet, Examples 2-5, 3-3, 4-4,
and the like], and [WO 2010/091176 pamphlet, Examples 1-3 and the
like]. Examples of the compound include compounds that are obtained
by properly protecting the compounds in Example 25-5 and the
like.
[0825] The compound that is shown as Formula (I) in WO 2009/039943
pamphlet and that has a similar formula to Formula (A)-IX in the
present application is represented by Formula III described in WO
2009/039943 pamphlet, p. 52 as Formula (B-V), and the compound is
reacted under the condition of <When Z #hydroxy group> above
to produce the compound of Formula (B-VI) (X=nitrogen atom).
[0826] <Step 5>
[0827] The sulfur atom in the compound of Formula (B-VI) is
oxidized. A compound of Formula (B-VII) can be produced by causing
the reaction of the compound of Formula (B-VI) in a similar manner
to that in <Step 2> in (Production Method A).
<Step 6>
[0828] The protective group P.sup.2 in the compound of Formula
(B-VII) is deprotected. A compound of Formula (I)-1a-2 can be
produced by deprotecting the protective group P.sup.2 in the
compound of Formula (B-VII) by a method suitable for the type of
the protective group.
<Step 7>
[0829] The compound of Formula (B-VI) is simultaneously subjected
to oxidization of the sulfur atom and deprotection. When the
protective group of P.sup.2 is a protective group capable of being
deprotected by a common oxidation method, a compound of Formula
(I)-1a-2 can be produced by reacting the compound of Formula (B-VI)
in a similar manner to that in <Step 2> in (Production Method
A).
<Step 8>
[0830] The compound of Formula (I)-1a-2 is subjected to reduction.
The compound of Formula (I)-1a can be produced by causing the
reaction of the compound of Formula (I)-1a-2 in a similar manner to
that in <Step 3> in (Production Method A).
[0831] <Production Method C>
[0832] <When R.sup.2b.dbd.H and R.sup.11b.dbd.H in Formula
(I)-1a or Formula (I)-2a above>
##STR00146##
<Step 1>
[0833] A compound of Formula (C-I) obtained in (Production Method
H), (Production Method H-1), (Production Method H-2), or
(Production Method H-3) described later is subjected to
substitution reaction with a compound of Formula (C-II) (Formula
(G-III)a or Formula (I-I)) obtained in (Production Method I)
described later. In accordance with methods known in literatures,
for example, the methods described in [Jikken Kagaku Koza
(Experimental Chemistry Course), the fifth edition, vol. 18,
Synthesis of Organic Compound VI, Organic Synthesis Using Metal,
pp. 327-352 (2004), Maruzen Co., Ltd.] and [Journal of Medicinal
Chemistry, vol. 48 (20), pp. 6326-6339 (2005)], a compound of
Formula (I)-1a-2/Formula (I)-2a-2 can be produced by reacting the
compounds of Formula (C-I) and Formula (C-II) in the presence of
three reagents of a palladium catalyst, a phosphine reagent or an
alkylammonium halide reagent, and a base reagent using a reaction
inert solvent such as toluene, xylene, N,N-dimethylformamide, and
N,N-dimethylacetamide or a mixed solvent of them at a temperature
from 0.degree. C. to a reflux temperature of the solvent. Examples
of the palladium catalyst include palladium(II) acetate, tetrakis
triphenylphosphine palladium,
tris(dibenzylideneacetone)dipalladium,
bis(dibenzylideneacetone)palladium, and
[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II).
Examples of the phosphine reagent include triphenylphosphine,
tris(tert-butyl)phosphine, tris(o-tolyl)phosphine,
2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl,
2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl, and
dicyclohexylphosphino-2',4',6'-trisisopropylbiphenyl (Xphos).
Examples of the base reagent include sodium carbonate, cesium
carbonate, potassium carbonate, triethylamine,
N,N-diisopropylethylamine, and potassium phosphate. In the reaction
above, in place of the phosphine reagent, an alkylammonium halide
reagent such as tetramethylammonium chloride and tetrabutylammonium
chloride may be used.
[0834] Formula (C-II) used in this step is a compound of Formula
(G-III)a described later when n=0 and is a compound of Formula
(I-I) described later when n #0.
[0835] <Step 2>
[0836] The compound of Formula (I)-1a-2/Formula (I)-2a-2 is
subjected to reduction. The compound of Formula (I)-1a/Formula
(I)-2a can be produced by reacting the compound of Formula
(I)-1a-2/Formula (I)-2a-2 in a similar manner to that in <Step
3> in (Production Method A).
[0837] In the present specification, when n=1 in Formula
(I)-1a-2/Formula (I)-2a-2 and Formula (I)-1a/Formula (I)-2a above,
Formula (I)-1a-2/Formula (I)-2a-2 and Formula (I)-1a/Formula (I)-2a
include optical isomers. A compound derived from an enantiomer A
(I-I-A) that has a shorter column elution time when optically
active Formula (I-I) obtained in (Production Method I) described
later is separated by a chiral column is represented by Formula
(I)-1a-2 (A)/Formula (I)-2a-2 (A).
##STR00147##
[0838] Isomers (diastereomers) of Formula (I)-1a (A)/Formula (I)-2a
(A) that are obtained by reduction of the compound in a similar
manner to that in <Step 3> in (Production Method A) can be
separated through optical resolution using chiral column
chromatography or asymmetric synthesis by a person skilled in the
art based on conventional techniques.
##STR00148##
[0839] For example, each diastereomer can be obtained using
preparative chromatography as in Step 2 in Example 7 described
later. In the present invention, in the preparative chromatography
of a mixture of the diastereoisomers, a diastereomer having a
shorter elution time is represented as a, while a diastereomer
having a longer elution time is represented as b, and the
diastereomers are correspondingly represented by Formula (I)-1a
(A)-a/Formula (I)-2a (A)-a and Formula (I)-1a (A)-b/Formula (I)-2a
(A)-b. In the present specification, the diastereomers are
expressed as a compound name (A)-a and a compound name (A)-b for a
compound name.
[0840] A compound obtained from an enantiomer (B) (I-I-B) having a
longer elution time when Formula (I-I) is separated by chiral
column resolution is represented as Formula (I)-1a-2 (B)/Formula
(I)-2a-2 (B). A compound of Formula (I)-1a (B)/Formula (I)-2a (B)
that is obtained by reduction using the compound also includes
isomers (diastereomers), which are similarly represented by Formula
(I)-1a (B)-a/Formula (I)-2a (B)-a and Formula (I)-1a (B)-b/Formula
(I)-2a (B)-b. The diastereomers are expressed as a compound name
(B)-a and a compound name (B)-b for a compound name.
[0841] In the present specification, when n=2 in Formula
(I)-1a/Formula (I)-2a above, Formula (I)-1a/Formula (I)-2a includes
optical isomers. The isomers can be separated through optical
resolution using chiral column chromatography or asymmetric
synthesis by a person skilled in the art based on conventional
techniques.
[0842] <Production Method D>
[0843] <When R.sup.2a.noteq.H, R.sup.2b.dbd.H, and
R.sup.11a.dbd.H in Formula (I)-1a above>
##STR00149##
<Step 1>
[0844] The compound of Formula (B-VI)a obtained in <Step 4>
in (Production Method B) above is subjected to substitution
reaction on the isothiazole ring.
[0845] <When R.sup.2a=halogen atom>
[0846] In accordance with methods known in literatures, for
example, the method described in [Organic And Biomolecular
Chemistry, vol. 5 (3), pp. 643-471 (2007)], a compound of Formula
(B-VI)b can be produced by halogenation reaction of the compound of
Formula (B-VI)a in the presence of a corresponding halogenating
agent such as N-fluorodibenzenesulfonimide, N-chlorosuccinimide,
N-bromosuccinimide, and N-iodosuccinimide in a reaction inert
solvent including a halogenated solvent such as dichloromethane and
chloroform, an ether solvent such as diethyl ether and
tetrahydrofuran, an aromatic hydrocarbon solvent such as toluene
and benzene, and a polar solvent such as N,N-dimethylformamide or
in a mixed solvent of them at a temperature from -78.degree. C. to
a reflux temperature of the solvent.
[0847] <When R.sup.2a=cyano group>
[0848] In accordance with methods known in literatures, for
example, the method described in [Tetrahedron Letters, vol. 40
(47), pp. 8193-8195 (1999)], a compound of Formula (B-VI)b can be
produced by reacting the compound of Formula (B-VI)b
(R.sup.2a.dbd.I, Br) obtained in <When R.sup.2a=halogen atom>
in <Step 1> in (Production Method D) in the presence of a
corresponding cyanating agent such as zinc cyanide and potassium
ferrocyanide in the presence of a palladium catalyst such as
palladium(II) acetate, tetrakis triphenylphosphine palladium,
tris(dibenzylideneacetone)dipalladium, and
[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II), a
phosphine reagent such as triphenylphosphine,
tris(tert-butyl)phosphine, and tris(o-tolyl)phosphine, and an
organic or inorganic base such as triethylamine,
N,N-diisopropylethylamine, and potassium phosphate using a reaction
inert solvent such as toluene, xylene, N,N-dimethylformamide, and
N,N-dimethylacetamide or a mixed solvent of them at a temperature
from 0.degree. C. to a reflux temperature of the solvent. It can
also be produced in a similar method using tetramethylammonium
chloride, tetrabutylammonium chloride, or the like in place of the
phosphine reagent.
<Step 2>
[0849] The sulfur atom in the compound of Formula (B-VI)b is
oxidized. A compound of Formula (B-VII)b can be produced by causing
the reaction of the compound of Formula (B-VI)b in a similar manner
to that in <Step 2> in (Production Method A).
<Step 3>
[0850] The protective group P.sup.2 in the compound of Formula
(B-VII)b is deprotected. A compound of Formula (I)-1a-2 can be
produced by reacting the compound of Formula (B-VII)b in a similar
manner to that in <Step 6> in (Production Method B).
<Step 4>
[0851] The compound of Formula (B-VI)b is simultaneously subjected
to oxidation and deprotection of the protective group P.sup.2. A
compound of Formula (I)-1a-2 can be produced by reacting the
compound of Formula (B-VI)b in a similar manner to that in <Step
7> in (Production Method B).
<Step 5>
[0852] The compound of Formula (I)-1a-2 is subjected to reduction.
The compound of Formula (I)-1a can be produced by causing the
reaction of the compound of Formula (I)-1a-2 in a similar manner to
that in <Step 3> in (Production Method A).
[0853] (2) Next, methods for producing the compounds of Formula
(IX)-1a, Formula (B-I), and Formula (B-II) will be described.
[0854] The compounds of Formula (IX)-1a and Formula (B-I) can be
produced by the methods below.
[0855] <Production Method E>
##STR00150##
<Step 1>
[0856] A compound of Formula (E-I) is subjected to alkynylation. In
accordance with methods known in literatures, for example, the
methods described in [Jikken Kagaku Koza (Experimental Chemistry
Course), the fourth edition, vol. 19, Organic Synthesis I,
Hydrocarbon and Halogenated Compounds, pp. 318-335 (1992), Maruzen
Co., Ltd.] and [WO 2008/066131 pamphlet, Reference Example 1], a
compound of Formula (E-II) can be produced by reacting the compound
of Formula (E-I), which is known in the art or can be easily
produced from a known compound, in the presence of a corresponding
propiolic acid ester such as methyl propiolate and ethyl propiolate
and copper(II) oxide using a reaction inert solvent such as
toluene, xylene, N,N-dimethylformamide, and N,N-dimethylacetamide
or a mixed solvent of them at a temperature from 0.degree. C. to a
reflux temperature of the solvent.
[0857] The compound of Formula (E-II) can also be produced by
reaction in the presence of an ortho ester of a corresponding
propiolic acid such as 3,3,3-triethoxypropyne or a corresponding
propiolic acid ester such as methyl propiolate and ethyl propiolate
in the presence of copper(I) iodide or zinc bromide in the presence
of a palladium catalyst such as palladium(II) acetate, tetrakis
triphenylphosphine palladium,
tris(dibenzylideneacetone)dipalladium, and
[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II), a
phosphine reagent such as triphenylphosphine,
tris(tert-butyl)phosphine, and tris(o-tolyl)phosphine, and an
organic or inorganic base such as triethylamine,
N,N-diisopropylethylamine, potassium phosphate, and potassium
carbonate using a reaction inert solvent such as toluene, xylene,
N,N-dimethylformamide, and N,N-dimethylacetamide or a mixed solvent
of them at a temperature from 0.degree. C. to a reflux temperature
of the solvent.
<Step 2>
[0858] The compound of Formula (E-II) is hydrolyzed. In accordance
with methods known in literatures, for example, the method
described in [Jikken Kagaku Koza (Experimental Chemistry Course),
the fourth edition, vol. 22, Organic Synthesis IV, Acid, Amino
Acid, and Peptide, pp. 1-43 (1992), Maruzen Co., Ltd.], a compound
of Formula (E-III) can be produced by reacting the compound of
Formula (E-II) in the presence of a base such as lithium hydroxide,
sodium hydroxide, potassium hydroxide, lithium carbonate, sodium
carbonate, and potassium carbonate using a reaction inert solvent
such as water, methanol, ethanol, 2-propanol,
N,N-dimethylformamide, 1,4-dioxane, and tetrahydrofuran or a mixed
solvent of them at a temperature from 0.degree. C. to a reflux
temperature of the solvent.
<Step 3>
[0859] The compound of Formula (E-III) is subjected to amidation
reaction. In accordance with methods known in literatures, for
example, the method described in [Jikken Kagaku Koza (Experimental
Chemistry Course), the fourth edition, vol. 22, Organic Synthesis
IV, Acid, Amino Acid, and Peptide, pp. 191-309 (1992), Maruzen Co.,
Ltd.], a compound of Formula (B-I) can be produced by reacting the
compound of Formula (E-III) with aqueous ammonia or ammonia gas in
the presence of a condensing agent such as
1,3-dicyclohexylcarbodiimide (DCC),
1-ethyl-3-(3'-dimethylaminopropyl)carbodiimide hydrochloride
(WSC-HCl), benzotriazol-1-yloxytris(dimethylamino)phosphonium
hexafluorophosphate (BOP reagent),
bis(2-oxo-3-oxazolidinyl)phosphinic chloride (BOP-Cl),
2-chloro-1,3-dimethylimidazolinium hexafluorophosphate (CIP), and
4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride
(DMTMM) in a reaction inert solvent including a halogenated solvent
such as dichloromethane and chloroform, an ether solvent such as
diethyl ether and tetrahydrofuran, an aromatic hydrocarbon solvent
such as toluene and benzene, a polar solvent such as
N,N-dimethylformamide, or an alcoholic solvent such as methanol,
ethanol, and 2-propanol or in a mixed solvent of them in the
presence or absence of a base such as triethylamine and pyridine at
a temperature from 0.degree. C. to a reflux temperature of the
solvent. When the compound of Formula (E-III) is converted into an
acid chloride, in accordance with the methods described in [Jikken
Kagaku Koza (Experimental Chemistry Course), the fourth edition,
vol. 22, Organic Synthesis IV, Acid, Amino Acid, and Peptide, pp.
144-146 (1992), Maruzen Co., Ltd.] and the like, the compound of
Formula (B-I) can be produced by reacting the acid chloride in the
presence of a base such as triethylamine and pyridine in a reaction
inert solvent including a halogenated solvent such as
dichloromethane and chloroform, an ether solvent such as diethyl
ether and tetrahydrofuran, an aromatic hydrocarbon solvent such as
toluene and benzene, and a polar solvent such as
N,N-dimethylformamide or in a mixed solvent of them at a
temperature from 0.degree. C. to a reflux temperature of the
solvent.
<Step 4>
[0860] The protective group P.sup.1 in the compound of Formula
(B-I) is deprotected. A compound of Formula (E-IV) can be produced
by reacting the compound of Formula (B-I) in a similar manner to
that in <Step 3> in (Production Method B).
<Step 5>
[0861] The compound of Formula (E-IV) is subjected to substitution
reaction with a compound of Formula (B-V). A compound of Formula
(IX)-1a can be produced by causing the compound of Formula (E-IV)
to react with the compound of Formula (B-V) in a similar manner to
that in <Step 4> in (Production Method B).
<Step 6>
[0862] The compound of Formula (B-I) can also be produced from the
compound of Formula (E-II). Namely, in accordance with methods
known in literatures, for example, the method described in
[Tetrahedron, vol. 61 (48), pp. 11333-11344 (2001)], the compound
of Formula (E-II) can be produced by reaction in the presence of
ammonia using a reaction inert solvent such as water, methanol,
ethanol, 2-propanol, N,N-dimethylformamide, 1,4-dioxane, and
tetrahydrofuran or in a mixed solvent of them at a temperature from
-78.degree. C. to a reflux temperature of the solvent.
[0863] The compound of Formula (IX)-1a can also be produced by the
following method.
[0864] <Production Method F>
##STR00151##
<Step 1>
[0865] A compound of Formula (F-I) is subjected to substitution
reaction with a compound of Formula (B-V). A compound of Formula
(F-II) can be produced by reacting the compound of Formula (F-I),
which is known in the art or can be easily produced from a known
compound, with the compound of Formula (B-V) in a similar manner to
that in <Step 4> in (Production Method B).
<Step 2>
[0866] The compound of Formula (F-II) is subjected to alkynylation.
A compound of Formula (F-III) can be produced by causing the
reaction of the compound of Formula (F-II) in a similar manner to
that in <Step 1> in (Production Method E).
<Step 3>
[0867] The compound of Formula (F-III) is hydrolyzed. A compound of
Formula (F-IV) can be produced by causing the reaction of the
compound of Formula (F-III) in a similar manner to that in <Step
2> in (Production Method E).
<Step 4>
[0868] The compound of Formula (F-IV) is subjected to amidation
reaction. The compound of Formula (IX)-1a can be produced by
causing the reaction of the compound of Formula (F-IV) in a similar
manner to that in <Step 3> in (Production Method E).
<Step 5>
[0869] The compound of Formula (IX-Ia) can also be produced from
the compound of Formula (F-III) in a similar manner to that in
<Step 6> in <Production Method E>.
[0870] The compound of Formula (B-II) can also be produced by the
method below.
[0871] <Production Method G>
##STR00152##
<Step 1>
[0872] A compound of Formula (G-I) is subjected to boration
reaction.
[0873] <When W=boronic ester>
[0874] In accordance with methods known in literatures, for
example, the method described in [The Journal of Organic Chemistry,
vol. 60, pp. 7508-2665 (1995)], a boronic ester of Formula (G-II)
can be produced by reacting the compound of Formula (G-I), which is
known in the art or can be easily produced from a known compound,
in the presence of a diboronic ester such as bis(pinacolato)diboron
and bis(neopentylglycolato)diboron in the presence of a palladium
catalyst such as palladium(II) acetate, tetrakis triphenylphosphine
palladium, tris(dibenzylideneacetone)dipalladium, and
[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) in the
presence or absence of a phosphine reagent such as
triphenylphosphine, tris(tert-butyl)phosphine,
tris(o-tolyl)phosphine, and
2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl and an organic or
inorganic base such as triethylamine, N,N-diisopropylethylamine,
and potassium acetate using a reaction inert solvent such as
toluene, N,N-dimethylformamide, dimethyl sulfoxide, and 1,4-dioxane
or a mixed solvent of them at a temperature from 0.degree. C. to a
reflux temperature of the solvent. It can also be produced in a
similar method using tetramethylammonium chloride,
tetrabutylammonium chloride, or the like in place of the phosphine
reagent.
[0875] <When W=boronic acid>
[0876] In accordance with methods known in literatures, for
example, the method described in [Chemische Berichte, vol. 42, p.
3090 (1909)], a boronic acid of Formula (G-II) can be produced by
reacting the compound of Formula (G-I) using a reaction inert
solvent such as toluene, tetrahydrofuran, and 1,4-dioxane or a
mixed solvent of them in the presence of an alkyllithium such as
n-butyllithium and sec-butyllithium, a Grignard reagent such as
isopropyl magnesium chloride, or metal magnesium, with a trialkyl
borate such as trimethyl borate and triisopropyl borate at a
temperature from -78.degree. C. to room temperature, followed by
reaction with an acid such as hydrochloric acid and sulfuric acid
at a temperature from 0.degree. C. to a reflux temperature of the
solvent.
[0877] <When W=trifluoroborate salt>
[0878] In accordance with methods known in literatures, for
example, the method described in [Chemical Reviews, vol. 108, pp.
288-325 (2008)], a trifluoroborate salt of Formula (G-II) can be
produced by reacting the compound of Formula (G-II) (W=boronic
ester or boronic acid) obtained in <When W=boronic ester or
boronic acid> in <Step 1> in (Production Method G) in the
presence of potassium hydrogen difluoride (KHF.sub.2) using a
reaction inert solvent such as methanol, ethanol, and water or a
mixed solvent of them at a temperature from 0.degree. C. to a
reflux temperature of the solvent.
[0879] <When W=boronic acid N-methylimino diacetic acid (MIDA)
ester>
[0880] In accordance with methods known in literatures, for
example, the method described in [Journal of Organometallic
Chemistry, vol. 307 (1), pp. 1-6 (1986)], a boronic acid
N-methylimino diacetic acid (MIDA) ester of Formula (G-II) can be
produced by reacting the compound of Formula (G-II) (W=boronic
acid) obtained in <When W=boronic acid> in <Step 1> in
(Production Method G) in the presence of N-methyliminodiacetic acid
(MIDA) using a reaction inert solvent such as benzene, toluene,
xylene, and dimethyl sulfoxide or a mixed solvent of them at a
temperature from 0.degree. C. to a reflux temperature of the
solvent.
<Step 2>
[0881] The compound of Formula (G-II) is subjected to substitution
reaction with a compound of Formula (G-III). The compound of
Formula (B-II) can be produced by reacting the compound of Formula
(G-II) with the compound of Formula (G-III), which is known in the
art or can be easily produced from a known compound, in a similar
manner to that in <Step 1> in (Production Method C).
[0882] (3) Next, a method for producing the compound of Formula
(C-I) will be described.
[0883] <Production Method H>
##STR00153##
<Step 1>
[0884] A compound of Formula (H-I) is subjected to substitution
reaction with a compound of Formula (B-V). A compound of Formula
(H-II) can be produced by reacting the compound of Formula (H-I),
which is known in the art or can be easily produced from a known
compound, with the compound of Formula (B-V) in a similar manner to
that in <Step 4> in (Production Method B).
<Step 2>
[0885] The compound of Formula (H-II) is subjected to boration
reaction. The compound of Formula (C-I) can be produced by reacting
the compound of Formula (H-II) in a similar manner to that in
<Step 1> in (Production Method G).
<Step 3>
[0886] The compound of Formula (H-I) is subjected to boration
reaction. A compound of Formula (H-III) can be produced by reacting
the compound of Formula (H-I) in a similar manner to that in
<Step 1> in (Production Method G).
<Step 4>
[0887] The compound of Formula (H-III) is subjected to substitution
reaction with the compound of Formula (B-V). The compound of
Formula (C-I) can be produced by reacting the compound of Formula
(H-III) with the compound of Formula (B-V) in a similar manner to
that in <Step 4> in (Production Method B).
[0888] (4) Next, a method for producing the compound of Formula
(C-II) will be described.
[0889] <Production Method I>
[0890] <When n is 1 or 2 in Formula (C-II) above>
##STR00154##
[0891] The sulfur atom in a compound of Formula (G-III)a is
oxidized. A compound of Formula (I-I) (m=1 or 2) can be produced by
reacting the compound of Formula (G-III)a, which is known in the
art or can be easily produced from a known compound, in a similar
manner to that in <Step 2> in (Production Method A).
[0892] The compounds of Formula (G-III)a and Formula (I-I) are
included in the compound of Formula (C-II).
[0893] When m is 1 in Formula (I-I) above, the compound of Formula
(I-I) includes optically active isomers. The isomers can be
separated through optical resolution using column chromatography or
asymmetric synthesis by a person skilled in the art based on
conventional techniques. For example, each enantiomer can be
obtained using preparative chromatography as in Step 5 in Example 1
described later.
[0894] (5) Hereinafter, the method for producing the compound of
Formula (B-V) of the present invention will be described in further
detail. As typical examples, methods for producing a compound of
Formula (B-V)-II having Partial Structural Formula (A) above and a
compound of Formula (B-V)-III having Partial Structural Formula
(AA)-1 above will be described.
[0895] <Production Method J>
##STR00155##
[0896] A compound of Formula (J-I) is subjected to substitution
reaction on the ring.
[0897] <When V=single bond>
[0898] A compound of Formula (B-V)-II can be produced by reacting
the compound of Formula (J-I), which is known in the art or can be
easily produced from a known compound, with a compound of Formula
(J-II) (W.sup.2 is boronic acid, a boronic ester, or a
trifluoroborate salt when W.sup.1 is a halogen atom or a
trifluoromethanesulfonyloxy group, and vice versa) in a similar
manner to that in <Step 1> in (Production Method C).
[0899] <When V=oxygen atom>
[0900] In accordance with methods known in literatures, for
example, the method described in [Tetrahedron Letters, vol. 44, pp.
3863-3865 (2003)], the compound of Formula (B-V)-II can be produced
by reacting the compound of Formula (J-I) in the presence of a
compound of Formula (J-II) (W.sup.2 is boronic acid, a boronic
ester, or a trifluoroborate salt when W.sup.1 is a hydroxy group,
and vice versa) in the presence of a copper catalyst such as
copper(II) acetate and copper(II) trifluoroacetate and a base such
as triethylamine, N,N-diisopropylethylamine, and pyridine using a
reaction inert solvent such as dichloromethane, 1,4-dioxane,
tetrahydrofuran, and N,N-dimethylformamide or a mixed solvent of
them at a temperature from 0.degree. C. to a reflux temperature of
the solvent.
[0901] When R.sup.8 or R.sup.9 is an electron withdrawing group or
the ring A' is heteroaryl, the compound of Formula (B-V)-II can
also be produced by reacting a compound of Formula (J-I)
(W.sup.1=hydroxy group) with a compound of Formula (J-II)
(W.sup.2=halogen atom) in a similar manner to that in <Step
4> in (Production Method B).
[0902] The compound of Formula (J-II) used in this step is known in
the art or can be easily produced from a known compound.
Specifically, a halogenated derivative can be produced from a
corresponding compound in accordance with methods known in
literatures, for example, the methods described in [WO 2005/063729
pamphlet, Reference Example 1 and the like], [WO 2008/001931
pamphlet, <Step 4A> in Reaction Scheme 2, Reference Examples
1, 54, and the like], and [WO 2009/054423 pamphlet, Production
Example 37 and the like]. Furthermore, a boronic acid derivative
can be produced by boration reaction of the halogenated derivative
in a similar manner to that in <Step 1> in (Production Method
G).
[0903] <Production Method J-1><When j=1, R.sup.3,
R.sup.4.dbd.H, and Z.dbd.OH in Formula (B-V)-II above>
##STR00156##
<Step 1>
[0904] A compound of Formula (J1-I) is subjected to substitution
reaction on the ring.
[0905] <When V=single bond>
[0906] A compound of Formula (J1-II) can be produced by reacting
the compound of Formula (J1-I), which is known in the art or can be
easily produced from a known compound, with a compound of Formula
(J-II) in a similar manner to that in <When V=single bond> in
(Production Method J).
[0907] <When V=oxygen atom>
[0908] A compound of Formula (J1-II) can be produced by reacting
the compound of Formula (J1-I) with a compound of Formula (J-II) in
a similar manner to that in <When V=oxygen atom> in
(Production Method J).
<Step 2>
[0909] The compound of Formula (J1-II) is subjected to reduction.
In accordance with methods known in literatures, for example, the
method described in [Jikken Kagaku Koza (Experimental Chemistry
Course), the fourth edition, vol. 26, Organic Synthesis VIII,
Asymmetric Synthesis, Reduction, Sugar, and Labelled Compound, pp.
234-245 (1992), Maruzen Co., Ltd.], the compound of Formula
(B-V)-II-1 can be produced by reacting the compound of Formula
(J1-II) in the presence of sodium borohydride (when R''.dbd.H),
diisobutyl aluminum hydride (DIBAH), lithium aluminum hydride
(LAH), lithium triethoxyaluminum hydride (when R''.dbd.C.sub.1-6
alkoxy group), borane-tetrahydrofuran (BH.sub.3-THF),
borane-dimethyl sulfide (BH.sub.3-Me.sub.2S) (when R''.dbd.OH), or
the like using a reaction inert solvent including an ether solvent
such as diethyl ether, tetrahydrofuran, 1,2-dimethoxyethane, and
1,4-dioxane, a halogenated solvent such as dichloromethane,
chloroform, and 1,2-dichloroethane, or an alcoholic solvent such as
methanol and ethanol or a mixed solvent of them at a temperature
from 0.degree. C. to a reflux temperature of the solvent.
[0910] The compound of Formula (B-V)-II-1 can also be produced from
a corresponding compound in accordance with methods known in
literatures, for example, the methods described in [WO 2005/063729
pamphlet, Reference Examples 2, 3 and the like], [WO 2008/001931
pamphlet, Reaction Scheme 2, Reference Examples 15-19, and the
like], [WO 2008/130514 pamphlet, Method A, Method C, and the like],
[WO 2009/048527 pamphlet, Reaction Formulae 5 and 6, Example 66.6,
and the like], and [WO 2009/054423 pamphlet, Production Examples
12, 24, 37, and the like].
[0911] <Production Method J-2>
##STR00157##
[0912] A compound of Formula (J2-I) is subjected to substitution
reaction on the ring.
[0913] <When V=single bond>
[0914] The compound of Formula (B-V)-III can be produced by
reacting the compound of Formula (J2-I), which is known in the art
or can be easily produced from a known compound, with a compound of
Formula (J-II) in a similar manner to that in <When V=single
bond> in (Production Method J).
[0915] <When V=oxygen atom>
[0916] The compound of Formula (B-V)-III can be produced by
reacting the compound of Formula (J2-I) with a compound of Formula
(J-II) in a similar manner to that in <When V=oxygen atom> in
(Production Method J).
[0917] The compound of Formula (J2-I) includes optical isomers
because a carbon atom in the ring is an asymmetric carbon by
bonding the carbon atom to the linker moiety including Z. Such
isomers are known in the art or can be easily produced from a known
compound. Each enantiomer can be obtained through optical
resolution using column chromatography or asymmetric synthesis by a
person skilled in the art based on conventional techniques. For
example, the isomers are separated with an optical resolution
column, and each absolute configuration can be determined in
accordance with [Agric. Biol. Chem., vol. 46 (10), pp. 2579-2585
(1982)]. Furthermore, the enantiomers can be obtained in accordance
with the method described in [WO 2009/157418 pamphlet, Example 51
and Example 52]. Each enantiomer of Formula (B-V)-III (for example,
compounds in Example 25-5 described later) can be produced using
such an enantiomer.
[0918] <Production Method J-3>
[0919] <When j=0 and Z.dbd.OH in Formula (B-V)-III above>
##STR00158##
<Step 1>
[0920] A compound of Formula (J3-I) is subjected to substitution
reaction on the ring.
[0921] <When V=single bond>
[0922] A compound of Formula (J3-II) can be produced by reacting
the compound of Formula (J3-I), which is known in the art or can be
easily produced from a known compound, with a compound of Formula
(J-II) in a similar manner to that in <When V=single bond> in
(Production Method J).
[0923] <When V=oxygen atom>
[0924] A compound of Formula (J3-II) can be produced by reacting
the compound of Formula (J3-I) with a compound of Formula (J-II) in
a similar manner to that in <When V=oxygen atom> in
(Production Method J).
<Step 2>
[0925] The compound of Formula (J3-II) is subjected to reduction.
The compound of Formula (B-V)-III-1 can be produced by reacting the
compound of Formula (J3-II) with sodium borohydride, diisobutyl
aluminum hydride (DIBAH), or lithium aluminum hydride (LAH) in a
similar manner to that in <Step 2> in (Production Method
J-1).
[0926] The compound of Formula (B-V)-III-1 can also be produced
from a corresponding compound in accordance with methods known in
literatures, for example, the methods described in [WO 2005/063729
pamphlet, Reference Examples 2, 3 and the like], [WO 2008/001931
pamphlet, Reaction Scheme 2, Reference Examples 15-19, and the
like], and [WO 2009/054423 pamphlet, Production Examples 12, 24,
37, and the like].
[0927] (5-1) As another typical example of the compound of Formula
(B-V), a method for producing a compound of Formula (B-V)-IV having
Partial Structural Formula (A1)-IV:
##STR00159##
will be described.
[0928] <Production Method J-4>
[0929] <When the ring A is Partial Structural Formula (A1)-IV
above, j=1, R.sup.3, R.sup.4.dbd.H, and Z.dbd.OH in Formula (B-V)
above>
##STR00160##
[0930] An amino alcohol of Formula (J4-I) is subjected to
substitution reaction. In accordance with methods known in
literatures, for example, the method described in [WO 2006/021401
pamphlet], the compound of Formula (B-V)-IV can be produced by
reacting the compound of Formula (J4-I), which is known in the art
or can be easily produced from a known compound, with a compound of
Formula (J-II)a in the presence of potassium phosphate and copper
iodide using a reaction inert solvent including a polar solvent
such as dimethylaminoethanol and N,N-dimethylformamide, an ether
solvent such as diethyl ether, tetrahydrofuran,
1,2-dimethoxyethane, and 1,4-dioxane, or an alcoholic solvent such
as methanol and ethanol or a mixed solvent of them at a temperature
from 0.degree. C. to a reflux temperature of the solvent.
[0931] (5-2) As another typical example of the compound of Formula
(B-V), a method for producing a compound of Formula (B-V)-V having
Partial Structural Formula (AA1)-V:
##STR00161##
will be described.
[0932] <Production Method J-5>
[0933] <When the ring A is Partial Structural Formula (AA1)-V
above (when V=an oxygen atom), j=1, R.sup.3, R.sup.4.dbd.H, and
Z.dbd.OH in Formula (B-V) above>
##STR00162##
<Step 1>
[0934] A compound of Formula (J5-I) [in Formula, R'' is a C.sub.1-6
alkoxy group] is oxidized. In accordance with methods known in
literatures, for example, the method described in [Journal of
Organic Chemistry, vol. 43, pp. 2057 (1978)], a compound of Formula
(J5-11) can be produced by reacting the compound of Formula (J5-I),
which is known in the art or can be easily produced from a known
compound, with chromium trioxide (CrO.sub.3) in the presence of
3,5-dimethylpyrazole using a reaction inert solvent such as
methylene chloride, 1,2-dichloroethane, acetonitrile, and benzene
or a mixed solvent of them at a temperature from 0.degree. C. to a
reflux temperature of the solvent.
<Step 2>
[0935] [When the ring structure in Formula (J5-III) has a double
bond (.gamma.-hydroxy-.alpha.,.beta.-unsaturated ester)]
[0936] The compound of Formula (J5-II) is subjected to reduction. A
compound of Formula (J5-III) can be produced by causing the
compound of Formula (J5-II) to react with sodium borohydride and
cerium chloride in a similar manner to that in <Step 2> in
(Production Method J-1).
[0937] [When the ring structure in Formula (J5-III) is saturated
(.gamma.-hydroxy-.alpha.,.beta.-saturated ester)]
[0938] The compound of Formula (J5-II) is subjected to reduction. A
compound of Formula (J5-III) can be produced by causing the
compound of Formula (J5-II) to react with sodium borohydride in a
similar manner to that in <Step 2> in (Production Method
J-1).
<Step 3>
[0939] The compound of Formula (J5-III) is subjected to
substitution reaction with a compound of Formula (J-II)b. A
compound of Formula (J5-IV) can be produced by reacting the
compound of Formula (J-II)b, which is known in the art or can be
easily produced from a known compound, with the compound of Formula
(J5-III) in a similar manner to that in <Step 4> in
(Production Method B).
<Step 4>
[0940] [When the aliphatic ring structure has a double bond
(.gamma.-hydroxy-.alpha.,.beta.-unsaturated ester)]
[0941] The compound of Formula (J5-IV) is subjected to reduction.
The compound of Formula (B-V)-V can be produced by causing the
compound of Formula (J5-IV) to react with diisobutyl aluminum
hydride (DIBAH) in a similar manner to that in <Step 2> in
(Production Method J-1).
[0942] [When the aliphatic ring structure is saturated
(.gamma.-hydroxy-.alpha.,.beta.-saturated ester)]
[0943] The compound of Formula (J5-IV) is subjected to reduction.
The compound of Formula (B-V)-V can be produced by reacting the
compound of Formula (J5-IV) with lithium aluminum hydride (LAH) or
diisobutyl aluminum hydride (DIBAH) in a similar manner to that in
<Step 2> in (Production Method J-1).
[0944] (5-3) As another typical example of the compound of Formula
(B-V), a method for producing a compound of Formula (B-V)-VI having
Partial Structural Formula (AA)-VI:
##STR00163##
will be described.
[0945] <Production Method J-6>
[0946] <When the ring A is Partial Structural Formula (AA)-VI
above, j=1, R.sup.3, R.sup.4.dbd.H, and Z.dbd.OH in Formula (B-V)
above>
##STR00164##
<Step 1>
[0947] A compound of Formula (J6-I) [in Formula, R'' is a C.sub.1-6
alkoxy group] is subjected to reductive amination. In accordance
with methods known in literatures, for example, the method
described in [The Journal of Organic Chemistry, vol. 61, pp.
3849-3862 (1996)], a compound of Formula (J6-III) can be produced
by reacting the compound of Formula (J6-I), which is known in the
art or can be easily produced from a known compound, with a
compound of Formula (J6-II) in the presence of a reducing agent
such as sodium triacetoxyborohydride and sodium cyanoborohydride in
the presence or absence of a catalytic amount of acetic acid using
a reaction inert solvent such as dichloromethane,
1,2-dichloroethane, tetrahydrofuran, acetonitrile, and toluene or a
mixed solvent of them at a temperature from 0.degree. C. to a
reflux temperature of the solvent.
<Step 2>
[0948] The compound of Formula (J6-III) is subjected to reduction.
The compound of Formula (B-V)-VI can be produced by causing the
reaction of the compound of Formula (J6-III) in a similar manner to
that in <Step 2> in (Production Method J-1).
[0949] (3-1) The compound of Formula (C-I) can also be produced by
the methods below.
[0950] <Production Method H-1>
[0951] <When the ring A is Partial Structural Formula (A) above,
the ring B is the ring B', j=1, k=0, R.sup.3, R.sup.4.dbd.H, and
X.dbd.NR.sup.7 in Formula (C-I) above>
##STR00165##
[0952] A compound of Formula (H1-I) is subjected to reductive
amination. The compound of Formula (C-I)-II can be produced by
reacting the compound of Formula (H1-I) (the compound of Formula
(H1-I) is included in the compound of Formula (J1-II) and can be
easily produced from a known compound as shown in <Step 1> in
(Production Method J-1) above) with a compound of Formula (H1-II)
(it is known in the art or can be easily produced from a known
compound) in a similar manner to that in <Step 1> in
(Production Method J-6).
[0953] <Production Method H-2>
[0954] <When the ring A is Partial Structural Formula (AA1):
##STR00166##
the ring B is the ring B', j, k=0, and X.dbd.NH in Formula (C-I)
above>
##STR00167##
[0955] A compound of Formula (H2-I) is subjected to reductive
amination. In accordance with methods known in literatures, for
example, the method described in [WO 2006/128670 pamphlet], the
compound of Formula (C-I)-III can be produced by reacting the
compound of Formula (H2-I) (it is known in the art or can be easily
produced from a known compound as shown in <Step 1> in
(Production Method J-3) above and the like) with a compound of
Formula (H2-II) (it is known in the art or can be easily produced
from a known compound) (<Step 1>).
##STR00168##
[0956] The compound of Formula (C-I)-III can also be produced by
reacting, in accordance with methods known in literatures, for
example, the method described in [WO 2006/085149 pamphlet], the
compound of Formula (H2-I) with hydroxylamine hydrochloride to
afford an oxime, then by hydrogenating the oxime using hydrogen and
Pd--C to produce a compound of Formula (H2-II) (<Step 2>),
and by reacting the obtained compound of Formula (H2-II) with a
compound of Formula (H2-III) in accordance with methods known in
literatures, for example, the method described in [WO 2005/682859
pamphlet or Journal of the American Chemical Society, vol. 128
(29), pp. 9306-9307 (2006)](<Step 3>). Z.sub.1 in Formula
(H2-III) above is halogen, a methanesulfonyloxy group, or a
p-toluenesulfonyloxy group in Z above.
[0957] <Step 2> above can be carried out with reference to
known reaction conditions for reductive amination, for example, in
[WO 2006/083454 pamphlet, p. 62, Steps A and B in Preliminary
Example] and [WO 2010/143733 pamphlet, Reference Example 68].
<Step 3> above can be carried out in accordance with known
reaction conditions for substitution, for example, in [WO
2010/143733 pamphlet, [0184], Step 7].
[0958] <Production Method H-3>
[0959] <When the ring A is Partial Structural Formula (A)-V:
##STR00169##
the ring B is the ring B', j=1, k=0, R.sup.3, R.sup.4.dbd.H, and
X=oxygen atom in Formula (C-I) above>
##STR00170##
[0960] A compound of Formula (H3-I) is subjected to substitution
reaction with a compound of Formula (H3-II). The compound of
Formula (C-I)-V can be produced by reacting the compound of Formula
(H3-II), which is known in the art or can be easily produced from a
known compound, with the compound of Formula (H3-I) in a similar
manner to that in <Step 4> in (Production Method B) or in
accordance with the method described in [WO 2009/054479 pamphlet,
Step 1 or Step 1' in Production Method A1 (for example, Step 6 in
Example 41)]. For example, condensation is carried out in a solvent
at room temperature or under heating. Examples of the reagent
include 1,1'-(diazocarbonyl)dipiperidine and triphenylphosphine.
Examples of the solvent include an ether solvent such as
tetrahydrofuran.
[0961] The compound of Formula (H3-I) above is known in the art or
can be easily produced from a known compound with reference to, for
example, [WO 2009/054479 pamphlet, Production Method B, C, D, or
the like (paragraphs [0185] to [0264])].
[0962] Hereinafter, the methods for producing the compound of
Formula (H3-1) of the present invention will be described in
further detail.
[0963] <Production Method H-4>
[0964] <When n3=1, the broken line adjacent to the carbon atom
in the n3 moiety is a double bond, and the other broken lines are
single bonds in Formula (H3-I) above>
##STR00171##
<Step 1>
[0965] A compound of Formula (H4-I) is subjected to substitution
reaction with a compound of Formula (H4-II) (each X.sub.3a in
Formula (H4-II) is independently --CR.sub.V1aR.sub.V2a-- or
--NR.sub.V3a--, each of R.sub.V1a, R.sub.V2a, and R.sub.V3a is
independently a hydrogen atom, --OH, or --NH.sub.2, each definition
of Z.sub.1 and Z.sub.2 is the same as that of Z above, and Z.sub.1
and Z.sub.2 are preferably a halogen atom). A compound of Formula
(H4-III) can be produced by reacting the compound of Formula
(H4-I), which is known in the art or can be easily produced from a
known compound, with the compound of Formula (H4-II) in accordance
with the method described in [WO 2009/054479 pamphlet, Production
Method D1-1 (for example, Step 1 in Example 41 and Step 4 in
Example 104)]. For example, the condensation is carried out in a
solvent at room temperature or under heating in the presence of a
base. Examples of the base include potassium tert-butoxide and
sodium hydride. Examples of the solvent include an aromatic
hydrocarbon solvent such as toluene.
<Step 2>
[0966] A compound of Formula (H4-IV) can be produced from the
compound of Formula (H4-III) in accordance with the method
described in [WO 2009/054479 pamphlet, Steps 1 to 4 in Production
Method C1-1 (for example, Steps 2 to 4 in Example 41)].
<Step 3>
[0967] The compound of Formula (H3-I)-1 can be produced from the
compound of Formula (H4-IV) in accordance with the method described
in [WO 2009/054479 pamphlet, Step 5 in Production Method C1-1 (for
example, Step 5 in Example 41)].
[0968] <Production Method H-5>
[0969] <When the ring A is Partial Structural Formula
(A)-VI:
##STR00172##
the ring B is a benzene ring, a linker moiety including an
isothiazolyl group and X is placed at the p-position, j=1, k=0, and
R.sup.3, R.sup.4.dbd.H in Formula (C-1) above>
[0970] As shown in the scheme below, in accordance with Scheme I in
WO 2011/046851 pamphlet, pp. 8-9, a substituted benzyl bromide of
Formula (1) is reacted with a suitable substituted spiropiperidine
of Formula (SP) or its hydrochloric acid salt or trifluoroacetic
acid salt in the presence of a suitable base such as
diisopropylethylamine and cesium carbonate to give a compound of
Formula (4) in step 1a. The ester is properly reduced in step 2
with diisobutylaluminum hydride, lithium aluminum hydride, sodium
borohydride, or the like to give a substituted benzyl alcohol of
Formula (B-V). The compound of Formula (B-V) can be properly used
in, for example, (Production Method B), (Production Method E),
(Production Method F), and (Production Method H) above and
(Production Method L) below. The compound of Formula (B-V) can also
be obtained by reduction in step 1b instead of step 1a to give a
compound of Formula (2), followed by reaction with the compound of
Formula (SP) in step 1c in the same manner as in the above.
##STR00173## ##STR00174## ##STR00175##
[0971] Here, the compound of Formula (B-V) is further reacted with
a phenol derivative of Formula (B-IV) by Mitsunobu reaction in step
4a in the presence of a suitable phosphine such as
triphenylphosphine and triethylphosphine and an azodicarbonyl such
as ADDP or an azodicarboxylate such as DEAD, and then the product
is properly oxidized and deprotected in steps 6a and 6b to give a
compound of Formula (VI)-1a-2 (X=oxygen atom).
[0972] Another pathway may be employed. That is, the compound of
Formula (B-V) is derived to a benzyl bromide of Formula (B-V') in
step 3a with a suitable brominating agent such as phosphorus
tribromide, and then the benzyl bromide is reacted with the phenol
derivative of Formula (B-IV) above in step 4b to give the compound
of Formula (B-VI).
[0973] The compound of Formula (B-V') is also reacted with a
compound of Formula (H3-II) or a compound of Formula (H1-II) in
step 5a/b to give a corresponding compound of Formula (C-I)-VI
(X=oxygen atom or --NR.sub.7--). Alternatively, the compound of
Formula (C-I)-VI can be derived from the compound of Formula (B-V)
by oxidation with a suitable oxidizing agent such as Dess-Martin
reagent to give an aldehyde of Formula (5) in step 3b, followed by
oxidative amination with a compound of Formula (H1-II) in step 5c.
The compound of Formula (C-I)-VI (X=oxygen atom or --NR.sub.7--)
can also be derived from the compound of Formula (B-V) by direct
Mitsunobu reaction with a compound of Formula (H3-II) in step
5d.
[0974] The compound of Formula (C-I)-VI is reacted with a compound
of Formula (C-II) in step 7 to give a compound of Formula (VI)-1a-2
(X=oxygen atom or --NR.sub.7--).
[0975] A final compound of Formula (VI)-1a can be produced by
reduction of the obtained compound of Formula (VI)-1a-2 in a
similar manner to that in <Step 3> in (Production Method
A).
[0976] Through the synthetic route shown below, the compound of
Formula (B-VI) can also be obtained using a known or suitable
benzyl bromide derivative to give an intermediate, followed by
reaction with a substituted spiropiperidine of Formula (SP). Each
definition of substituents and reference signs is the same as in
the above.
##STR00176##
[0977] In particular, a method for producing a compound of Formula
(B-V) where X.sub.1 is --N(Rz)CH.sub.2-- can be with reference to
WO 2011/064851 pamphlet, pp. 10-11. In accordance with Scheme II in
the literature, a protected piperidine-4-carboaldehyde is reacted
with a phenylhydrazine that may be substituted at the 2-position
and/or 4-position to give a substituted
spiro[indoline-3,4'-piperidine]. The product is, as necessary,
further alkylated, and then is deprotected to give the compound of
Formula (SP) suited for the present invention.
[0978] WO 2011/046851 pamphlet discloses in pp. 29-31, as specific
known compounds of Formula (B-V) suitably used for Production
Method U of the present invention,
(4-(spiro[inden-1,4'-piperidin]-1'-ylmethyl)phenyl)methanol as well
as
[3-chloro-4-(spiro[inden-1,4'-piperidin]-1'-ylmethyl)phenyl]methanol,
[2-methoxy-4-(spiro
[inden-1,4'-piperidin]-1'-ylmethyl)phenyl]methanol,
[3-fluoro-4-(spiro[inden-1,4'-piperidin]-1'-ylmethyl)phenyl]methanol,
[4-(spiro
[inden-1,4'-piperidin]-1'-ylmethyl)-3-(trifluoromethyl)phenyl]m-
ethanol,
[3-chloro-4-[(1-methylspiro[indolin-3,4'-piperidin]-1'-yl)methyl]-
phenyl]methanol,
[4-(spiro[indan-1,4'-piperidin]-1'-ylmethyl)-3-(trifluoromethyl)phenyl]me-
thanol, and [4-(spiro
[indan-1,4'-piperidin]-1'-ylmethyl)phenyl]methanol.
[0979] As other usable compounds of Formula (B-V'), WO 2011/046851
pamphlet also discloses, in pp. 31-32, corresponding bromomethyl
derivatives as Prep No. 56-61.
[0980] Hereinbefore, the method for producing a compound
substituted with an isothiazole ring at the p position with respect
to the hetero atom X has been described. Furthermore, an m-isomer
that can be properly obtained or synthesized is used in place of
the starting material of Formula (1) or Formula (2) to produce a
corresponding compound substituted with the isothiazole ring at the
m position with respect to the hetero atom X in a similar
manner.
[0981] <Production Method H-5a>
[0982] It can be understood that another substituted
spiropiperidine of Formula (SP') is used in place of the
substituted spiropiperidine of Formula (SP) in each production
route in (Production Method H-5) to give each compound of Formula
(B-Va), Formula (B-Va'), Formula (C-1)-VIa, Formula (B-VIa), and
Formula (VIa)-1a-2 having the moiety of Formula (SP') that replaces
the moiety of Formula (SP) in each compound of Formula (B-V),
Formula (B-V'), Formula (C-1)-VI, Formula (B-VI), and Formula
(VI)-1a-2.
[0983] Furthermore, each compound of Formula (B-V), Formula (B-V'),
Formula (B-Va), and Formula (B-Va') described in (Production Method
H-5) and (Production Method H-5a) can be used as the compound of
Formula (B-V) in (Production Method B), (Production Method E),
(Production Method F), or (Production Method H) above, (Production
Method L) below, or the like in each step (for example, in <Step
4> in (Production Method B)).
[0984] <Production Method H-5b>
[0985] In place of the starting material of Formula (1) or Formula
(2) used in steps 1a, 1b, and 1c in (Production Method H-5) or
(Production Method H-5a), in accordance with the description of
scheme I or scheme III in pp. 5 to 10 in WO 2011/066183 pamphlet, a
corresponding bromomethyl-heteroarylcarboxylic acid derivative of
Formula (1) or a methyl alcohol of bromomethyl-heteroaryl of
Formula (2):
##STR00177##
(where each definition of Z.sub.1, Z.sub.2, and Z.sub.3 is the same
as that in Formula (A2) IV described in the aspect [1-13-e-3]) is
used to produce the compound in the aspect [1-13-e-8] or
[1-13-e-8a] having a 5-membered heteroaryl in the molecule.
[0986] (6) The compound of Formula (I)-1a can also be produced by
the methods below.
[0987] <Production Method K>
[0988] <When the ring A is Partial Structural Formula (AA)-1
above (that is Formula (III)-1a1), X=oxygen atom, R.sup.2b.dbd.H,
and R.sup.11a.dbd.H in Formula (I)-1a above>
##STR00178##
[0989] <Step 1>
[0990] A compound of Formula (H-III)a is subjected to substitution
reaction with a compound of Formula (K-I). A compound of Formula
(K-II) can be produced by reacting the compound of Formula (H-III)a
obtained in <Step 3> in (Production Method H) above with the
compound of Formula (K-I), which is known in the art or can be
easily produced from a known compound, in a similar manner to that
in <Step 4> in (Production Method B).
<Step 2>
[0991] The compound of Formula (K-II) is subjected to substitution
reaction with a compound of Formula (I-I)a. A compound of Formula
(K-III) can be produced by reacting the compound of Formula (K-II)
with the compound of Formula (I-I)a in a similar manner to that in
<Step 1> in (Production Method C).
<Step 3>
[0992] The compound of Formula (K-III) is subjected to substitution
reaction with a compound of Formula (J-II).
[0993] <When V=single bond>
[0994] A compound of Formula (III)-1a1-2 can be produced by
reacting the compound of Formula (K-III) with the compound of
Formula (J-II) in a similar manner to that in <Step 1> in
(Production Method C).
[0995] <When V=oxygen atom>
[0996] In accordance with methods known in literatures, for
example, the method described in [Tetrahedron Letters, vol. 49, pp.
1851-1855 (2008)], a compound of Formula (III)-1a1-2 can be
produced by reacting the compound of Formula (K-III) in the
presence of the compound of Formula (J-II) in the presence of a
copper catalyst such as copper(I) iodide, copper(I) bromide,
copper(I) chloride, and copper(I) oxide, a base such as potassium
phosphate, potassium carbonate, and sodium tert-butoxide, and an
additive such as 1-butylimidazole, 1-methylimidazole, and
2,2'-bipyridine using a reaction inert solvent such as toluene,
xylene, 1,4-dioxane, and N-methylpyrrolidone or a mixed solvent of
them at a temperature from 0.degree. C. to a reflux temperature of
the solvent.
[0997] In accordance with other methods known in literatures, for
example, the method described in [Journal of the American Chemical
Society, vol. 121, pp. 4369-4378 (1999)], the compound of Formula
(III)-1a1-2 can also be produced by reacting the compounds of
Formula (K-III) and Formula (J-II) in the presence of a palladium
catalyst such as palladium(II) acetate, tetrakis triphenylphosphine
palladium, tris(dibenzylideneacetone)dipalladium,
bis(dibenzylideneacetone)palladium, and
[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II), a
phosphine reagent such as (2-biphenyl)di-(tert-butyl)phosphine,
2-di-(tert-butyl)-2'-(N,N-dimethylamino)biphenyl, and
2-dicyclohexyl-2'-(N,N-dimethylamino)biphenyl, and a base such as
potassium phosphate, sodium hydride, and sodium tert-butoxide using
a reaction inert solvent such as dichloromethanc, 1,4-dioxane,
tetrahydrofuran, toluene, and N,N-dimethylformamide or a mixed
solvent of them at a temperature from 0.degree. C. to a reflux
temperature of the solvent.
<Step 4>
[0998] The compound of Formula (III)-1a1-2 is subjected to
reduction. The compound of Formula (III)-1a1 can be produced by
causing the reaction of the compound of Formula (III)-1a1-2 in a
similar manner to that in <Step 3> in (Production Method
A).
[0999] The compound of Formula (K-I) includes optical isomers
because a carbon atom is an asymmetric carbon by bonding the carbon
atom to Z. As with Formula (J2-I) above, such isomers are known in
the art or can be easily produced from a known compound. Each
enantiomer can be obtained through optical resolution using column
chromatography or asymmetric synthesis by a person skilled in the
art based on conventional techniques (for example,
(1S)-4-bromo-2,3-dihydro-1H-inden-1-ol). Each enantiomer of Formula
(K-II), Formula (K-III), Formula (III)-1a1-2, and Formula (III)-1a1
(for example, compounds in Example 23-3, Example 23-4, Example
23-5, and Example 23 described later) can be produced using such an
enantiomer.
[1000] <Production Method L>
[1001] <When R.sup.2b.dbd.H and R.sup.11a.dbd.H in Formula
(I)-1a>
##STR00179## ##STR00180##
<Step 1>
[1002] The sulfur atom of a compound of Formula (B-II) is oxidized.
A compound of Formula (L-I) can be produced by reacting the
compound of Formula (B-II) in a similar manner to that in <Step
2> in (Production Method A).
<Step 2>
[1003] The compound of Formula (L-I) is subjected to reduction. A
compound of Formula (L-II) can be produced by reacting the compound
of Formula (L-I) in a similar manner to that in <Step 3> in
(Production Method A).
<Step 3>
[1004] The compound of Formula (L-III) is protected with a
protective group P.sup.3. A compound of Formula (L-III) can be
produced by causing the reaction of the compound of Formula (L-II)
in a similar manner to that in <Step 2> in (Production Method
B).
<Step 4>
[1005] The protective group P.sup.1 in the compound of Formula
(L-III) is deprotected. A compound of Formula (L-IV) can be
produced by causing the reaction of the compound of Formula (L-III)
in a similar manner to that in <Step 3> in (Production Method
B).
<Step 5>
[1006] The compound of Formula (L-IV) is subjected to substitution
reaction with a compound of Formula (B-V). A compound of Formula
(L-V) can be produced by causing the reaction of the compound of
Formula (L-IV) in a similar manner to that in <Step 4> in
(Production Method B).
<Step 6>
[1007] The protective group P.sup.3 in the compound of Formula
(L-V) is deprotected. The compound of Formula (I)-1a can be
produced by causing the reaction of the compound of Formula (L-V)
in a similar manner to that in <Step 3> in (Production Method
B).
[1008] <Production Method L-1>
[1009] <When X=oxygen atom in Formula (I) above>
##STR00181## ##STR00182##
<Step 1>
[1010] A compound of Formula (G-II) can be produced by reaction in
a similar manner to that in <Step 1> in (Production Method
G).
<Step 2>
[1011] A compound of Formula (L-I)a can be produced by reaction in
a similar manner to that in <Step 2> in (Production Method
G).
<Step 3>
[1012] A compound of Formula (L-II)a can be produced by reaction in
a similar manner to that in <Step 2> in (Production Method
L).
<Step 4>
[1013] A compound of Formula (L-III)a can be produced by reaction
in a similar manner to that in <Step 3> in (Production Method
L).
<Step 5>
[1014] A compound of Formula (L-IV)a can be produced by reaction in
a similar manner to that in <Step 4> in (Production Method
L).
<Step 6>
[1015] A compound of Formula (L-V)a can be produced by reaction in
a similar manner to that in <Step 5> in (Production Method
L).
<Step 7>
[1016] The compound of Formula (I)-1a/Formula (I)-2a can be
produced by reaction in a similar manner to that in <Step 6>
in (Production Method L).
[1017] <Production Method M>
[1018] (When W=halogen atom and n=2 in Formula)
##STR00183##
[1019] <Step 1>
[1020] A compound of Formula (C-I) is reacted. In accordance with
methods known in literatures, for example, the method described in
[Tetrahedron Letters, vol. 26 (22), pp. 2667-2670 (1985)], a
compound of Formula (M-I) can be produced by reacting the compound
of Formula (C-I) above in the presence of a palladium catalyst such
as palladium diacetate, tetrakis triphenylphosphine palladium, and
tris dibenzylideneacetone dipalladium and a base such as potassium
carbonate, silver carbonate, and tributylamine using a reaction
inert solvent such as acetonitrile, dioxane, tetrahydrofuran,
benzene, toluene, dimethyl sulfoxide, and N,N-dimethylformamide or
a mixed solvent of them at a temperature from room temperature to a
reflux temperature of the solvent.
<Step 2>
[1021] The compound of Formula (M-I) is reacted. In accordance with
methods known in literatures, for example, the method described in
[Organic Letters, vol. 7 (22), pp. 5067-5069 (2005)], a compound of
Formula (M-II) can be produced by reacting the compound of Formula
(M-I) in the presence of a sulfur reagent such as sodium sulfite
using a reaction inert solvent such as ethanol and water or a mixed
solvent of them at a temperature from room temperature to a reflux
temperature of the solvent or at high temperature and high pressure
using a microwave reaction apparatus.
<Step 3>
[1022] The compound of Formula (M-II) is reacted. In accordance
with methods known in literatures, for example, the method
described in [Organic Letters, vol. 7 (22), pp. 5067-5069 (2005)],
a compound of Formula (M-III) can be produced by reacting the
compound of Formula (M-II) in the presence of a chlorinating
reagent such as phosphorus pentachloride using a reaction inert
solvent such as methylene chloride and DMF or a mixed solvent of
them at a temperature from room temperature to a reflux temperature
of the solvent and then by stopping the reaction with aqueous
ammonia.
<Step 4>
[1023] The compound of Formula (M-III) is protected with a
protective group P.sup.3. A compound of Formula (M-IV) can be
produced by causing the reaction of the compound of Formula (M-III)
in a similar manner to that in <Step 2> in (Production Method
B).
<Step 5>
[1024] The compound of Formula (M-II) is reacted. In accordance
with methods known in literatures, for example, the method
described in [Organic Letters, vol. 7 (22), pp. 5067-5069 (2005)],
a compound of Formula (M-IV) can be produced by reacting the
compound of Formula (M-II) in the presence of a chlorinating
reagent such as phosphorus pentachloride using a reaction inert
solvent such as methylene chloride and DMF or a mixed solvent of
them at a temperature from room temperature to a reflux temperature
of the solvent and then by stopping the reaction with a protected
secondary amine such as benzylamine and tosylamine.
<Step 6>
[1025] <When R.sup.2b.noteq.hydrogen atom>
[1026] The compound of Formula (M-IV) is subjected to substitution
reaction. In accordance with methods known in literatures, for
example, the method described in [Jikken Kagaku Koza (Experimental
Chemistry Course), the fifth edition, vol. 16, Synthesis of Organic
Compound IV, Carboxylic acid, Amino acid, and Peptide, pp. 1-70
(2005), Maruzen Co., Ltd.], a compound of Formula (M-V) can be
produced by reacting the compound of Formula (M-IV) with, for
example, a halogenated alkyl of R.sup.2bX in the presence of a base
such as sodium ethoxide, sodium methoxide, sodium hydride, lithium
hydride, lithium hydroxide, sodium hydroxide, potassium hydroxide,
lithium carbonate, sodium carbonate, and potassium carbonate using
a reaction inert solvent such as ethanol, water,
N,N-dimethylformamide, 1,4-dioxane, and tetrahydrofuran or a mixed
solvent of them at a temperature from 0.degree. C. to a reflux
temperature of the solvent.
<Step 7>
[1027] The compound of Formula (M-V) is subjected to ring formation
reaction. In accordance with methods known in literatures, for
example, the method described in [Organic Letters, vol. 7 (22), pp.
5067-5069 (2005)], a compound of Formula (M-VI) can be produced by
reacting the compound of Formula (M-V) in the presence of sodium
methoxide, sodium ethoxide, or the like using a reaction inert
solvent such as methanol and ethanol or a mixed solvent of them at
a temperature from room temperature to a reflux temperature of the
solvent.
<Step 8>
[1028] The protective group P.sup.3 in the compound of Formula
(M-VI) is deprotected. The compound of Formula (I)-1a can be
produced by reaction in a similar manner to that in <Step 3>
in (Production Method B).
[1029] (7) The methods for producing the compound of Formula (I)-1b
of the present invention will be described below.
[1030] <Production Method N>
[1031] (When n=2 in Formula)
##STR00184##
<Step 1>
[1032] A compound of Formula (N-I) can be produced by reacting the
compound of Formula (H-II) above (Y=protected imino group
(--NP.sup.1.sub.2)) in a similar manner to that in <Step 3>
in (Production Method B).
<Step 2>
[1033] The compound of Formula (N-I) is reacted. In accordance with
methods known in literatures, for example, the method described in
[Chemical & Pharmaceutical Bulletin, vol. 43 (5), pp. 820-841
(1995)], a compound of Formula (N-III) can be produced by
substitution reaction of the compound of Formula (N-I) in the
presence of a compound of Formula (N-II), which is known in the art
or can be easily produced from a known compound, in the presence or
absence of a base such as diisopropylethylamine, triethylamine,
pyridine, sodium hydride, sodium hydroxide, potassium carbonate,
and cesium carbonate in a reaction inert solvent including a
halogenated solvent such as dichloromethane and chloroform, an
ether solvent such as diethyl ether and tetrahydrofuran, an
aromatic hydrocarbon solvent such as toluene and benzene, and a
polar solvent such as N,N-dimethylformamide or in a mixed solvent
of them at a temperature from 0.degree. C. to a reflux temperature
of the solvent.
<Step 3>
[1034] The compound of Formula (N-III) is reacted. In accordance
with methods known in literatures, for example, the method
described in [WO 2007/110337 pamphlet], each compound of Formula
(N-IV) (n=0, 1, or 2) can be produced by reacting the compound of
Formula (N-IIII), for example, in the presence of a sulfur reagent
such as carbamic acid n-(chlorosulfonyl)-1,1-dimethylethyl ester
and in the presence or absence of a base such as
diisopropylethylamine, triethylamine, pyridine, sodium hydride,
sodium hydroxide, potassium carbonate, and cesium carbonate in a
reaction inert solvent including a halogenated solvent such as
dichloromethane and chloroform, an ether solvent such as diethyl
ether and tetrahydrofuran, an aromatic hydrocarbon solvent such as
toluene and benzene, and a polar solvent such as
N,N-dimethylformamide or in a mixed solvent of them at a
temperature from 0.degree. C. to a reflux temperature of the
solvent.
<Step 4>
[1035] The compound of Formula (N-IV) is deprotected. A compound of
Formula (N-V) can be produced by reaction in a similar manner to
that in <Step 3> in (Production Method B).
<Step 5>
[1036] The compound of Formula (N-V) is hydrolyzed. A compound of
Formula (N-VI) can be produced by reaction in a similar manner to
that in <Step 2> in (Production Method E).
<Step 6>
[1037] The compound of Formula (N-VI) is subjected to ring
formation reaction. The compound of Formula (I)-1b can be produced
by reaction in a similar manner to that in <Step 3> in
(Production Method E) (in the absence of ammonia).
<Step 7>
[1038] The compound of Formula (N-V) is subjected to ring formation
reaction. The compound of Formula (I)-1b can be produced by
reaction in a similar manner to that in <Step 7> in
(Production Method M).
[1039] The compounds of Formula (II)-1b and Formula (III)-1b above
are included in the compound of Formula (I)-1 b in (Production
Method N) and can be produced by a similar production method, and
these compounds of Formula (I)-1b are included in the compound of
Formula (I).
[1040] <Production Method O>
[1041] (When n=2 in Formula)
##STR00185## ##STR00186##
<Step 1>
[1042] A compound of Formula (O-I) is reacted. A compound of
Formula (O-II) can be produced by reacting the compound of Formula
(O-I), which is known in the art or can be easily produced from a
known compound, with a compound of Formula (N-II) in a similar
manner to that in <Step 2> in (Production Method N).
<Step 2>
[1043] The compound of Formula (O-II) is reacted. A compound of
Formula (O-III) can be produced by reaction in a similar manner to
that in <Step 3> in (Production Method N).
<Step 3>
[1044] The compound of Formula (O-III) is deprotected. A compound
of Formula (O-VI) can be produced by reaction in a similar manner
to that in <Step 3> in (Production Method B).
<Step 4>
[1045] The compound of Formula (O-VI) is subjected to ring
formation reaction.
[1046] A compound of Formula (O-V) can be produced by reaction in a
similar manner to that in <Step 7> in (Production Method
M).
<Step 5>
[1047] The protective group P.sup.1 in the compound of Formula
(O-V) is deprotected. A compound of Formula (O-VI) can be produced
by reaction in a similar manner to that in <Step 3> in
(Production Method B).
<Step 6>
[1048] The compound of Formula (O-VI) is subjected to substitution
reaction with a compound of Formula (B-V). A compound of Formula
(O-VII) can be produced by reaction in a similar manner to that in
<Step 4> in (Production Method B).
<Step 7>
[1049] The protective group P.sup.3 in the compound of Formula
(O-VII) is deprotected. The compound of Formula (I)-1b can be
produced by reaction in a similar manner to that in <Step 3>
in (Production Method B).
[1050] The compounds of Formula (II)-1b and Formula (III)-1b above
are included in the compound of Formula (I)-1b in (Production
Method O) and can be produced by a similar production method, and
these compounds of Formula (I)-1b are included in the compound of
Formula (I).
[1051] (7-1) The compounds of Formula (O-V) and Formula (O-VI) can
also be produced by the method below.
[1052] <Production Method P>
[1053] (When n=2 in Formula)
##STR00187##
<Step 1>
[1054] A compound of Formula (P-I) is subjected to ring formation
reaction. A compound of Formula (P-II) can be produced by reacting
the compound of Formula (P-I) that can be produced in accordance
with methods known in literatures, for example, the method
described in [Bioorganic & Medicinal Chemistry, vol. 16 (7),
pp. 3550-3556 (2008)] in a similar manner to that in <Step 7>
in (Production Method M).
<Step 2>
[1055] The compound of Formula (P-II) is subjected to substitution
reaction with a compound of Formula (G-II). [When W=halogen in
Formula] The compound of Formula (O-V) can be produced by using the
compound of Formula (P-II) and the compound of Formula (G-II) above
in accordance with methods known in literatures, for example, the
method described in [WO 2007/067615 pamphlet]. [When W=boronic acid
or boronic ester in Formula] The compound of Formula (O-V) can be
produced by using the compound of Formula (P-II) and the compound
of Formula (G-II) above in accordance with methods known in
literatures, for example, the method described in [Bioorganic &
Medicinal Chemistry, vol. 14 (17), pp. 5833-5849 (2006)].
<Step 3>
[1056] The compound of Formula (P-II) is subjected to substitution
reaction with a compound of Formula (H-III). The compound of
Formula (O-VI) can be produced by causing the compound of Formula
(P-II) to react with the compound of Formula (H-III) above in a
similar manner to that in <Step 2> in (Production Method
P).
[1057] (7-2) The compound of Formula (O-VII) can also be produced
by the method below.
[1058] <Production Method Q>
##STR00188##
[1059] A compound of Formula (C-I) that is easily obtained from a
known compound by the method in (Production Method H) is subjected
to substitution reaction with a compound of Formula (P-II). The
compound of Formula (O-VII) can be produced by reaction in a
similar manner to that in <Step 2> in (Production Method
P).
[1060] (8) The method for producing the compound of Formula (I)-1c
of the present invention will be described below.
[1061] <Production Method R>
[1062] <When R.sup.2a.dbd.R.sup.2b.dbd.H, R.sup.12b.dbd.H,
alkyl, alkenyl, or alkynyl in Formula (I)-c above>
[1063] (In Formula, n=2 and Y=formyl group or COR.sup.11a
group)
##STR00189##
<Step 1>
[1064] A compound of Formula (H-II) is reacted with a compound of
Formula (R-I). In accordance with methods known in literatures, for
example, the method described in [Synlett, vol. 5, pp. 843-838
(2005)], a compound of Formula (R-II) can be produced by reacting
the compound of Formula (H-II) that is easily obtained from a known
compound by the method in <Step 1> in (Production Method H)
with the compound of Formula (R-I) in the presence of a base such
as hexamethyldisilazane lithium and potassium tert-butoxide,
diethyl chlorophosphate, and the like in a reaction inert solvent
including an ether solvent such as diethyl ether and
tetrahydrofuran, an aromatic hydrocarbon solvent such as toluene
and benzene, and a polar solvent such as N,N-dimethylformamide or
in a mixed solvent of them at a temperature from -78.degree. C. to
a reflux temperature of the solvent.
<Step 2>
[1065] The compound of Formula (R-II) is reacted. In accordance
with methods known in literatures, for example, the method
described in [Heterocyclic Communications, vol. 3 (1), pp. 19-22
(1995)], a compound of Formula (R-III) can be produced by reacting
the compound of Formula (R-II) in the presence of a malonic acid
ester and a base such as sodium hydride, potassium tert-butoxide,
sodium methoxide, and sodium methoxide in a reaction inert solvent
including an ether solvent such as diethyl ether and
tetrahydrofuran, an aromatic hydrocarbon solvent such as toluene
and benzene, and a polar solvent such as N,N-dimethylformamide or
in a mixed solvent of them at a temperature from 0.degree. C. to a
reflux temperature of the solvent.
<Step 3>
[1066] The compound of Formula (R-III) is reacted. In accordance
with methods known in literatures, for example, the method
described in [Chemical & Pharmaceutical Bulletin, vol. 33 (12),
pp. 5316-5327 (1985)], a compound of Formula (R-IV) can be produced
by substitution reaction in the presence of the compound of Formula
(R-III) in the presence or absence of sodium chloride in a reaction
inert solvent including a polar solvent such as dimethyl sulfoxide
and N,N-dimethylformamide or in a mixed solvent of them at a
temperature from 0.degree. C. to a reflux temperature of the
solvent.
<Step 4>
[1067] The protective group P.sup.1 in the compound of Formula
(R-IV) is deprotected. A compound of Formula (R-V) can be produced
by reaction in a similar manner to that in <Step 3> in
(Production Method B).
<Step 5>
[1068] The compound of Formula (R-V) is subjected to ring formation
reaction. The compound of Formula (I)-1c can be produced by
reaction in a similar manner to that in <Step 7> in
(Production Method M).
[1069] The compounds of Formula (II)-1c and Formula (III)-1c above
are included in the compound of Formula (I)-1c in (Production
Method R) and can be produced by a similar production method, and
these compounds of Formula (I)-1c are included in the compound of
Formula (I). Similarly, in the production methods in (Production
Method S) or later, the compounds of Formula (II)-1c and Formula
(III)-1c are included in the compound of Formula (I)-1c and can be
produced by a similar production method, and these compounds of
Formula (I)-1c are included in the compound of Formula (I).
[1070] <Production Method S>
[1071] <When R.sup.2a and/or R.sup.2b.noteq.H and
R.sup.12b.dbd.H in Formula (I)-1c above>
[1072] (When n=2 in Formula)
##STR00190##
<Step 1>
[1073] A compound of Formula (R-IV) is subjected to substitution
reaction. A compound of Formula (S-I) can be produced by reaction
in a similar manner to that in <Step 6> in (Production Method
M).
<Step 2>
[1074] The protective group P.sup.1 in the compound of Formula
(S-I) is deprotected. A compound of Formula (S-II) can be produced
by reaction in a similar manner to that in <Step 3> in
(Production Method B).
<Step 3>
[1075] The compound of Formula (S-II) is subjected to ring
formation reaction. The compound of Formula (I)-c) can be produced
by reaction in a similar manner to that in <Step 7> in
(Production Method M).
[1076] <Production Method T>
[1077] <When R.sup.12b.dbd.H, alkyl, alkenyl, or alkynyl in
Formula (I)-1c above>
[1078] (In Formula, n=2 and Y=formyl group or COR.sup.11a
group)
##STR00191## ##STR00192##
<Step 1>
[1079] A compound of Formula (G-I) is reacted. A compound of
Formula (T-I) can be produced by reacting a compound of Formula
(G-I), which is known in the art or can be easily produced from a
known compound, with a compound of Formula (R-I) in a similar
manner to that in <Step 1> in (Production Method R).
<Step 2>
[1080] The compound of Formula (T-I) is reacted. A compound of
Formula (T-II) can be produced by reaction in a similar manner to
that in <Step 2> in (Production Method R).
<Step 3>
[1081] The compound of Formula (T-II) is reacted. A compound of
Formula (T-III) can be produced by reaction in a similar manner to
that in <Step 3> in (Production Method R).
[1082] <Step 4>
[1083] The protective group P.sup.2 in the compound of Formula
(T-III) is deprotected. A compound of Formula (T-IV) can be
produced by reaction in a similar manner to that in <Step 3>
in (Production Method B).
<Step 5>
[1084] The compound of Formula (T-IV) is subjected to ring
formation reaction. A compound of Formula (T-V) can be produced by
reaction in a similar manner to that in <Step 7> in
(Production Method M).
<Step 6>
[1085] The compound of Formula (T-V) is protected with a protective
group P.sup.3. A compound of Formula (T-VI) can be produced by
causing the reaction of the compound of Formula (T-V) in a similar
manner to that in <Step 2> in (Production Method B).
<Step 7>
[1086] The protective group P.sup.1 in the compound of Formula
(T-VI) is deprotected. A compound of Formula (T-VII) can be
produced by reaction in a similar manner to that in <Step 3>
in (Production Method B).
<Step 8>
[1087] The compound of Formula (T-VII) is subjected to substitution
reaction with a compound of Formula (B-V). A compound of Formula
(T-VIII) can be produced by reaction in a similar manner to that in
<Step 4> in (Production Method B).
<Step 9>
[1088] The protective group P.sup.3 in the compound of Formula
(T-VIII) is deprotected. The compound of Formula (I)-1c can be
produced by reaction in a similar manner to that in <Step 3>
in (Production Method B).
[1089] (8-1) The compound of Formula (I)-1c or Formula (I)-1f can
also be produced by the method below.
[1090] <Production Method U>
[1091] <When J.sub.1=J.sub.1a.dbd.CR.sup.11a,
J.sub.2=CR.sup.12aR.sup.12b, and h=1 to 3 in Formula (I) above,
that is, in the case of Formula (I)-1c or Formula (I)-1f>
[1092] (In Formula, n=2 and Y=halogen)
##STR00193## ##STR00194##
<Step 1>
[1093] A compound of Formula (G-II) is reacted. In accordance with
methods known in literatures, for example, the method described in
[Journal of Organic Chemistry, vol. 49 (16), pp. 2922-2925 (1984)],
a compound of Formula (U-II) can be produced by reacting a compound
of Formula (G-II), which is known in the art or can be easily
produced from a known compound, with various cyclic ethers of
Formula (G-I) (for example, ethylene oxide, oxetane, and
tetrahydrofuran) in the presence of a base such as n-butyllithium
and Grignard reagent, and a Lewis acid such as boron trifluoride
diethyl ether complex (BF.sub.3-Et.sub.2O) in a reaction inert
solvent including an ether solvent such as diethyl ether and
tetrahydrofuran, an aromatic hydrocarbon solvent such as toluene
and benzene, and a polar solvent such as N,N-dimethylformamide or
in a mixed solvent of them at a temperature from 0.degree. C. to a
reflux temperature of the solvent.
<Step 2>
[1094] The compound of Formula (U-II) is reacted. In accordance
with methods known in literatures, for example, the method
described in [Jikken Kagaku Koza (Experimental Chemistry Course),
the fifth edition, vol. 13, Synthesis of Organic Compound I,
Hydrocarbon and Halide, pp. 374-420 (2004), Maruzen Co., Ltd.], a
compound of Formula (U-III) can be produced by reacting the
compound of Formula (U-II) in the presence of a halogenating agent
such as phosphorus tribromide using a reaction inert solvent such
as diethyl ether and 1,4-dioxane or a mixed solvent of them at a
temperature from 0.degree. C. to a reflux temperature of the
solvent.
<Step 3>
[1095] The compound of Formula (U-III) is reacted. In accordance
with methods known in literatures, for example, the method
described in [Justus Liebigs Annalen der Chemie, vol. 586, pp.
158-164 (1954)], a compound of Formula (U-IV) can be produced by
reaction in the presence of the compound of Formula (U-III) in the
presence of a sulfur agent such as sodium sulfite, potassium
sulfite, sodium disulfite, and thiourea in a reaction inert solvent
including an alcoholic solvent such as methanol and ethanol and
water or in a mixed solvent of them at a temperature from 0.degree.
C. to a reflux temperature of the solvent.
<Step 4>
[1096] The compound of Formula (U-II) is reacted. In accordance
with, for example, the method described in [Organic Reaction, vol.
42 (1992)], a compound of Formula (U-IV) can be produced by
reacting the compound of Formula (U-II) with thioacetic acid in the
presence of an organophosphorus compound such as triphenylphosphine
and an azo compound such as an azodicarboxylic acid ester and
azodicarboxylic amide in a reaction inert solvent including a
halogenated solvent such as dichloromethane and chloroform, an
ether solvent such as diethyl ether and tetrahydrofuran, an
aromatic hydrocarbon solvent such as toluene and benzene, and a
polar solvent such as N,N-dimethylformamide and dimethyl sulfoxide
or in a mixed solvent of them at a temperature from 0.degree. C. to
a reflux temperature of the solvent to afford a compound and by
reacting the compound with chlorine in acetic acid as a solvent in
accordance with, for example, the method described in [Canadian
Journal of Chemistry, vol. 62 (3), pp. 610-614 (1984)].
<Step 5>
[1097] [When X4=OH or a salt such as ONa and OK]
[1098] The compound of Formula (U-III) is reacted. A compound of
Formula (U-IV) can be produced by reaction in a similar manner to
that in <Step 3> in (Production Method M).
[1099] [When X4=Cl]
[1100] The compound of Formula (U-III) is reacted. A compound of
Formula (U-IV) can be produced by reaction in a similar manner to
that in <Step 3> in (Production Method M) except that the
halogenation step is excluded.
<Step 6>
[1101] The compound of Formula (U-IV) is protected with a
protective group P.sup.3. A compound of Formula (U-V) can be
produced by causing the reaction of the compound of Formula (U-IV)
in a similar manner to that in <Step 2> in (Production Method
B).
<Step 7>
[1102] The compound of Formula (U-V) is reacted. For example, when
R.sup.11a.noteq.H and Y.sub.2=bromo, in accordance with methods
known in literatures, for example, the method described in [Journal
of Organic Chemistry, vol. 57 (10), pp. 2967-2970 (1992)], a
compound of Formula (U-VI) can be produced by reacting the compound
of Formula (U-V) with 2-bromopropanedioic acid-1,3-diethyl ester as
a brominating agent at a temperature from 0.degree. C. to a reflux
temperature of the solvent. When R.sup.11a.dbd.H and
Y.sub.2=halogen such as chloro and bromo, in accordance with, for
example, the method described in [Jikken Kagaku Koza (Experimental
Chemistry Course), the fifth edition, vol. 13, Synthesis of Organic
Compound I, Hydrocarbon and Halide, pp. 374-420 (2004), Maruzen
Co., Ltd.], a compound of Formula (U-VI) can be produced by
reaction in the presence of a halogenating agent such as
N-chlorosuccinimide and N-bromosuccinimide and
.alpha.,.alpha.'-azobisisobutyronitrile (AIBN) using a reaction
inert solvent such as carbon tetrachloride and chloroform or a
mixed solvent of them at a temperature from 0.degree. C. to a
reflux temperature of the solvent.
<Step 8>
[1103] The compound of Formula (U-VI) is subjected to substitution
reaction with a carboxylic acid methyl ester. In accordance with,
for example, the method described in [Tetrahedron, vol. 65 (28),
pp. 5462-5471 (2009)], a compound of Formula (U-VIII) can be
produced by using the compound of Formula (U-VI), indium bromide
(InBr.sub.3), and a silyl enolate of Formula (U-VIII).
<Step 9>
[1104] The protective group P.sup.3 in the compound of Formula
(U-IX) is deprotected. A compound of Formula (U-X) can be produced
by reaction in a similar manner to that in <Step 3> in
(Production Method B).
<Step 10>
[1105] The compound of Formula (U-X) is subjected to ring formation
reaction. A compound of Formula (U-XI) can be produced by reaction
in a similar manner to that in <Step 7> in (Production Method
M).
<Step 11>
[1106] The compound of Formula (U-XI) is protected with a
protective group P.sup.4. A compound of Formula (U-XII) can be
produced by causing the reaction of the compound of Formula (U-XI)
in a similar manner to that in <Step 2> in (Production Method
B).
<Step 12>
[1107] The protective group P.sup.1 in the compound of Formula
(U-XII) is deprotected. A compound of Formula (U-XIII) can be
produced by reaction in a similar manner to that in <Step 3>
in (Production Method B).
<Step 13>
[1108] The compound of Formula (U-XIII) is subjected to
substitution reaction with a compound of Formula (B-V). A compound
of Formula (U-XIV) can be produced by reaction in a similar manner
to that in <Step 4> in (Production Method B).
<Step 14>
[1109] The protective group P.sup.4 in the compound of Formula
(U-XIV) is deprotected. The compound of Formula (I)-1c (when h2=0)
or Formula (I)-1f (when h2=1 or 2) can be produced by reaction in a
similar manner to that in <Step 3> in (Production Method
B).
[1110] The compounds of Formula (II)-1f and Formula (III)-1f above
are included in the compound of Formula (I)-1f in (Production
Method U) and can be produced by a similar production method, and
these compounds of Formula (I)-1 f are included in the compound of
Formula (I).
[1111] In Formula (I) above, Formula (I)-1c and Formula (I)-1f
include optical isomers. The isomers can be separated through
optical resolution using chiral column chromatography or asymmetric
synthesis by a person skilled in the art based on conventional
techniques.
[1112] (9) The methods for producing the compound of Formula (I)-1d
of the present invention will be described below.
[1113] <Production Method V>
[1114] <When n=1 to 2, R.sup.2a.dbd.R.sup.2b.dbd.H,
Y.dbd.CH.dbd.CH--COOR', and n=2 in Formula (I)-1d above>
##STR00195##
<Step 1>
[1115] A compound of Formula (H-II) is reacted. In accordance with
methods known in literatures, for example, the method described in
[Journal of Organic Chemistry, vol. 50 (13), pp. 2259-2263 (1985)],
a compound of Formula (V-I) can be produced by reacting the
compound of Formula (H-II) that is easily obtained from a known
compound by the method in <Step 1> in (Production Method H)
in the presence of an amine such as ammonium acetate, an alkyl
ammonium, and aqueous ammonia, malonic acid, and the like in a
reaction inert solvent including a polar solvent such as ethanol,
butanol, and water or in a mixed solvent of them at a temperature
from 0.degree. C. to a reflux temperature of the solvent.
<Step 2>
[1116] The compound of Formula (V-I) is reacted. In accordance with
methods known in literatures, for example, the method described in
[Synlett, vol. 5, pp. 843-838 (2005)], a compound of Formula (V-II)
can be produced by reacting the compound of Formula (V-I) with a
sulfur agent such as an N-chlorosulfonylcarbamic acid ester in the
presence of a base such as sodium hydride, sodium hydroxide,
triethylamine, and pyridine in a reaction inert solvent including
an ether solvent such as diethyl ether and tetrahydrofuran, an
aromatic hydrocarbon solvent such as toluene and benzene, and a
polar solvent such as methanol, ethanol, and N,N-dimethylformamide
or in a mixed solvent of them at a temperature from -78.degree. C.
to a reflux temperature of the solvent.
<Step 3>
[1117] The protective groups P.sup.1 and P.sup.2 in the compound of
Formula (V-II) are deprotected. A compound of Formula (V-III) can
be produced by reaction in a similar manner to that in <Step
3> in (Production Method B).
<Step 4>
[1118] The compound of Formula (V-V) is subjected to ring formation
reaction. The compound of Formula (I)-1d can be produced by
reaction in a similar manner to that in <Step 7> in
(Production Method M).
[1119] The compounds of Formula (II)-1d and Formula (III)-1d above
are included in the compound of Formula (I)-1d in (Production
Method V) and can be produced by a similar production method, and
these compounds of Formula (I)-1 d are included in the compound of
Formula (I).
[1120] Similarly, in the production methods in (Production Method
W) or later, the compounds of Formula (II)-1d and Formula (III)-1d
above are included in the compound of Formula (I)-1d and can be
produced by a similar production method, and these compounds of
Formula (I)-1d are included in the compound of Formula (I).
[1121] <Production Method W>
[1122] <When n=2 and R.sup.11a.dbd.H>
##STR00196## ##STR00197##
<Step 1>
[1123] A compound of Formula (G-I) is reacted. A compound of
Formula (W-I) can be produced by reacting the compound of Formula
(G-I), which is known in the art or can be easily produced from a
known compound, in a similar manner to that in <Step 1> in
(Production Method V).
<Step 2>
[1124] The compound of Formula (W-I) is reacted. A compound of
Formula (W-II) can be produced by reaction in a similar manner to
that in <Step 4> in (Production Method V).
[1125] <Step 3>
[1126] <When R.sup.12c.noteq.hydrogen atom>
[1127] The compound of Formula (W-II) is reacted. In accordance
with methods known in literatures, for example, the method
described in [Synlett, vol. 5, pp. 697-699 (2002)], a compound of
Formula (W-III) can be produced by reacting the compound of Formula
(W-II) with a compound of R.sup.12cOH in the presence of an
organophosphorus compound such as triphenylphosphine and an azo
compound such as an azodicarboxylic acid ester and azodicarboxylic
amide in a reaction inert solvent including a halogenated solvent
such as dichloromethane and chloroform, an ether solvent such as
diethyl ether and tetrahydrofuran, an aromatic hydrocarbon solvent
such as toluene and benzene, and a polar solvent such as
N,N-dimethylformamide and dimethyl sulfoxide or in a mixed solvent
of them at a temperature from 0.degree. C. to a reflux temperature
of the solvent.
<Step 4>
[1128] <When R.sup.2a and/or R.sup.2b.noteq.hydrogen
atom>
[1129] The compound of Formula (W-III) is subjected to substitution
reaction. A compound of Formula (W-IV) can be produced by reaction
in a similar manner to that in <Step 6> in (Production Method
M).
<Step 5>
[1130] The protective groups P.sup.2 and P.sup.3 in the compound of
Formula (W-IV) are deprotected. A compound of Formula (W-V) can be
produced by causing the reaction of the compound of Formula (W-IV)
in a similar manner to that in <Step 3> in (Production Method
B).
<Step 6>
[1131] The compound of Formula (W-V) is subjected to ring formation
reaction. A compound of Formula (W-VI) can be produced by causing
the reaction of the compound of Formula (W-V) in a similar manner
to that in <Step 7> in (Production Method M).
<Step 7>
[1132] The compound of Formula (W-VI) is protected with a
protective group P.sup.4. A compound of Formula (W-VII) can be
produced by causing the reaction of the compound of Formula (W-VI)
in a similar manner to that in <Step 2> in (Production Method
B).
<Step 8>
[1133] The protective group P.sup.1 in the compound of Formula
(W-VII) is deprotected. A compound of Formula (W-VIII) can be
produced by reaction in a similar manner to that in <Step 3>
in (Production Method B).
<Step 9>
[1134] The compound of Formula (W-VIII) is subjected to
substitution reaction with a compound of Formula (B-V). A compound
of Formula (W-IX) can be produced by reaction in a similar manner
to that in <Step 4> in (Production Method B).
<Step 10>
[1135] The protective group P.sup.4 in the compound of Formula
(W-IX) is deprotected. The compound of Formula (I)-1d can be
produced by reaction in a similar manner to that in <Step 3>
in (Production Method B).
[1136] (9-1) The compound of Formula (I)-1d or Formula (I)-1e can
also be produced by the method below.
[1137] <Production Method X>
[1138] <When J.sub.1=J.sub.1a=CR.sup.11a, J.sub.2=NR.sup.12c,
and h=1 to 3 in Formula (I) above, that is, in the case of Formula
(I)-1d or Formula (I)-1e and when n=2 and R.sup.11a.dbd.H>
##STR00198## ##STR00199## ##STR00200##
<Step 1>
[1139] A compound of Formula (X-I) is protected with a protective
group P.sup.2. A compound of Formula (X-II) can be produced by
reacting the compound of Formula (X-I) that is obtained in
(Production Method Y) or (Production Method Z) described later in a
similar manner to that in <Step 2> in (Production Method
B).
<Step 2>
[1140] The compound of Formula (X-II) is reacted. A compound of
Formula (X-IV) can be produced from the compound of Formula (X-II)
and a compound of Formula (X-III) in accordance with, for example,
the method described in [Synlett, vol. 6, pp. 833-836 (2006)].
<Step 3>
[1141] <When R.sup.12c.noteq.hydrogen atom>
[1142] The compound of Formula (X-IV) is reacted. A compound of
Formula (X-V) can be produced by reaction in a similar manner to
that in <Step 3> in (Production Method W).
<Step 4>
[1143] The compound of Formula (X-V) is subjected to substitution
reaction. A compound of Formula (X-VI) can be produced by reaction
in a similar manner to that in <Step 2> in (Production Method
U).
<Step 5>
[1144] The compound of Formula (X-VI) is subjected to substitution
reaction. A compound of Formula (X-VII) can be produced from the
compound of Formula (X-VI) in accordance with, for example, the
method described in [Journal of the American Chemical Society, vol.
73, pp. 3987-3993 (1953)].
[1145] <Step 6>
[1146] The protective groups P.sup.3 and P.sup.4 in the compound of
Formula (X-VII) are deprotected. A compound of Formula (X-VIII) can
be produced by causing the reaction of the compound of Formula
(X-VII) in a similar manner to that in <Step 3> in
(Production Method B).
<Step 7>
[1147] The compound of Formula (X-VIII) is subjected to ring
formation reaction. A compound of Formula (X-IX) can be produced by
causing the reaction of the compound of Formula (X-VIII) in a
similar manner to that in <Step 7> in (Production Method
M).
<Step 8>
[1148] The compound of Formula (X-IX) is protected with a
protective group P.sup.5. A compound of Formula (X-X) can be
produced by causing the reaction of the compound of Formula (X-IX)
in a similar manner to that in <Step 2> in (Production Method
B).
<Step 9>
[1149] The protective group P.sup.1 in the compound of Formula
(X-X) is deprotected. A compound of Formula (X-XI) can be produced
by reaction in a similar manner to that in <Step 3> in
(Production Method B).
<Step 10>
[1150] The compound of Formula (X-XI) is subjected to substitution
reaction with a compound of Formula (B-V). A compound of Formula
(X-XII) can be produced by reaction in a similar manner to that in
<Step 4> in (Production Method B).
<Step 11>
[1151] The protective group P.sup.5 in the compound of Formula
(X-XII) is deprotected. The compound of Formula (I)-1d (when h2=0)
or Formula (I)-1e (when h2=1 or 2) can be produced by reaction in a
similar manner to that in <Step 3> in (Production Method
B).
[1152] The compounds of Formula (II)-1e and Formula (III)-1e above
are included in the compound of Formula (I)-1e in (Production
Method X) and can be produced by a similar production method, and
these compounds of Formula (I)-1e are included in the compound of
Formula (I).
[1153] (9-2) Next, methods for producing the compound of Formula
(X-I) will be described.
[1154] <Production Method Y>
[1155] <When h2=0 and Y=halogen atom in Formula (X-I)
above>
##STR00201##
<Step 1>
[1156] A compound of Formula (Y-I) is reacted. In accordance with
methods known in literatures, for example, the method described in
[Tetrahedron, vol. 57 (24), pp. 5243-5253 (2001)], a compound of
Formula (Y-II) can be produced by reacting the compound of Formula
(Y-I) in the presence of a base such as n-butyllithium and
dimethylformamide in a reaction inert solvent including an ether
solvent such as diethyl ether and tetrahydrofuran and an aromatic
hydrocarbon solvent such as hexane, toluene, and benzene or in a
mixed solvent of them at a temperature from 0.degree. C. to a
reflux temperature of the solvent.
<Step 2>
[1157] The compound of Formula (Y-II) is subjected to reduction.
The compound of Formula (X-I)a can be produced by reacting the
compound of Formula (Y-II) in a similar manner to that in <Step
2> in (Production Method J-1).
[1158] <Production Method Y-1>
[1159] <When h2=1 to 2 in Formula (X-I) above>
##STR00202##
[1160] A compound of Formula (Y1-I) is subjected to reduction. The
compound of Formula (X-I)b can be produced by reacting the compound
of Formula (Y1-I) in a similar manner to that in <Step 2> in
(Production Method J-1).
[1161] (9-3) The compound of Formula (V-II) can also be produced by
the method below.
[1162] <Production Method Z>
[1163] <Y.dbd.--CH.dbd.CH--COOR' in Formula>
##STR00203##
<Step 1>
[1164] A compound of Formula (Z-I) can be produced by using a
compound of Formula (G-I), which is known in the art or can be
easily produced from a known compound, by the method in <Step
1> and <Step 2> or <Step 3> in (Production Method
V).
<Step 2>
[1165] The protective group P.sup.1 in the compound of Formula
(Z-I) is deprotected. A compound of Formula (Z-II) can be produced
by reaction in a similar manner to that in <Step 3> in
(Production Method B).
<Step 3>
[1166] The compound of Formula (Z-II) is subjected to substitution
reaction with a compound of Formula (B-V). The compound of Formula
(V-II) can be produced by reaction in a similar manner to that in
<Step 4> in (Production Method B).
[1167] In Formula (I) above, Formulae (I)-1b, (I)-1c, (I)-1d,
(I)-1e, and (I)-1f include optical isomers. The isomers can be
separated through optical resolution using chiral column
chromatography, preferential crystallization using an optically
active salt, or asymmetric synthesis by a person skilled in the art
based on conventional techniques.
[1168] <Production Method AA>
[1169] <When n=1, 2>
##STR00204##
<Step 1>
[1170] A compound of Formula (AA-II) can be produced in a similar
manner to that in <Step 2> in (Production Method B) by
reacting a compound of Formula (AA-I), which is known in the art or
can be easily produced from a known compound (for example, a
phenylacetic acid derivative such as
4-hydroxy-.alpha.-methylphenylacetic acid (manufactured by Tokyo
Chemical Industry Co., Ltd.) when the ring B is a benzene ring, or
2,3-dihydro-6-hydroxy-3-benzofuran acetic acid,
3,4-dihydro-7-hydroxy-2H-1-benzopyran-4-acetic acid,
2,3-dihydro-6-hydroxy-benzo[b]thiophene-3-acetic acid, and the like
that can be produced in accordance with, for example, the method
described in WO 2006/083781 pamphlet when the ring B is a bicyclic
hetero ring such as a 2,3-dihydrobenzofuran ring, a
3,4-dihydro-2H-1-benzopyran ring, and a
2,3-dihydrobenzo[b]thiophene ring).
<Step 2>
[1171] The compound of Formula (AA-II) is subjected to substitution
reaction. A compound of Formula (AA-IV) can be produced by causing
the compound of Formula (AA-II) to react with a compound of Formula
(AA-III) in a similar manner to that in <Step 5> in
(Production Method X).
<Step 3>
[1172] The protective group P.sup.1 in the compound of Formula
(AA-IV) is deprotected. A compound of Formula (AA-V) can be
produced by causing the reaction of the compound of Formula (A-IV)
in a similar manner to that in <Step 3> in (Production Method
B).
<Step 4>
[1173] The compound of Formula (AA-V) is subjected to ring
formation reaction. A compound of Formula (I)-2a/Formula
(I)-2c/Formula (I)-2f can be produced by reacting the compound of
Formula (AA-V) in a similar manner to that in <Step 7> in
(Production Method M).
[1174] <Production Method BB>
[1175] <When n=2>
##STR00205##
<Step 1>
[1176] A compound of Formula (BB-II) can be produced by reacting a
compound of Formula (BB-I), which is known in the art or can be
easily produced from a known compound (for example, a benzyl
bromide derivative such as 4-(1-bromoethyl)-phenol when the ring B
is a benzene ring, and
3-(bromomethyl)-6-hydroxy-2,3-dihydrobenzofuran that can be derived
from 6-hydroxy-3(2H)-benzofuran in accordance with a method known
in a literature when the ring B is a bicyclic compound such as
2,3-dihydro-6-hydroxy-3-benzofuran ring), with a sulfur source such
as sodium sulfite and potassium sulfite in a similar manner to that
in <Step 3> in (Production Method U) (M is a metal such as Na
and K in Formula (BB-II)).
<Step 2>
[1177] The compound of Formula (BB-II) is subjected to halogenation
and sulfonylation, followed by sulfonamidation. A compound of
Formula (BB-III) can be produced by causing the reaction of the
compound of Formula (BB-II) in a similar manner to that in <Step
5> in (Production Method M).
<Step 3>
[1178] The compound of Formula (BB-III) is subjected to
substitution reaction. A compound of Formula (BB-V) can be produced
by causing the compound of Formula (BB-III) to react with a
compound of Formula (BB-IV) in a similar manner to that in <Step
5> in (Production Method X).
<Step 4>
[1179] The protective group P.sup.1 in the compound of Formula
(BB-V) is deprotected. A compound of Formula (BB-VI) can be
produced by causing the reaction of the compound of Formula (BB-V)
in a similar manner to that in <Step 3> in (Production Method
B).
<Step 5>
[1180] The compound of Formula (BB-VI) is subjected to ring
formation reaction. A compound of Formula (I)-3c/Formula (I)-3f can
be produced by reacting the compound of Formula (BB-VI) in a
similar manner to that in <Step 7> in (Production Method
M).
[1181] [Concomitant Drug Containing Compound of the Present
Invention]
[1182] The compound and pharmaceutical composition of the present
invention can be used in combination with other drugs or medicines
by a general method performed in medical practice. Particularly,
such combination is used for the prevention, progress delay, and
therapies of the mediating state of the GPR40 agonist, and is
further particularly used against at least one disease selected
from the group consisting of diabetes (Type 1 diabetes, Type 2
diabetes, and borderline type diabetes (impaired glucose tolerance
(IGT) and/or impaired fasting glycemia (IFG))), insulin resistance,
hyperinsulinemia, obesity, adiposity, and various diseases derived
from or related to these diseases.
[1183] Examples of an insulin sensitizer and an anti-diabetic drug
include 1) PPAR gamma agonists (specifically, pioglitazone,
rosiglitazone, troglitazone, ciglitazone, darglitazone,
englitazone, netoglitazone, etc.), 2) biguanide agents
(specifically, metformin, buformin, phenformin, etc.), 3)
sulfonylureas (specifically, tolbutamide, acetohexamide,
chlorpropamide, glibenclamide, gliclazide, glipizide, glimepiride,
glipentide, gliquidone, glisolamide, tolazamide, etc.), 4)
rapid-acting insulin secretagogues (specifically, nateglinide,
mitiglinide, repaglinide, etc.), 5) alpha-glucosidase inhibitors
(specifically, acarbose, voglibose, miglitol, camiglibose,
adiposin, emiglitate, pradimicin Q, salbostatin, etc.), 6) insulin
or insulin derivatives (specifically, insulin zinc suspensions,
insulin lispro, insulin aspart, regular insulin, NPII insulin,
insulin glargine, insulin detemir, mixed insulin, etc.), 7) GLP-1
or GLP-1 receptor agonists (specifically, exenatide, liraglutide,
lixisenatide, taspoglutide, albiglutide, dulaglutide, etc.), 8)
DPP-IV inhibitors (specifically, sitagliptin, vildagliptin,
alogliptin, saxagliptin, linagliptin, teneligliptin, anagliptin,
SYR-472, NVP-DPP-728, etc.), 9) alpha-2 antagonists (specifically,
midaglizole, isaglidole, deriglidole, idazoxan, efaroxan, etc.),
and 10) SGLT2 inhibitors (specifically, dapagliflozin,
ipragliflozin, tofogliflozin, empagliflozin, canagliflozin,
luseogliflozin, etc.). Examples of the insulin sensitizer and the
anti-diabetic drug also include a combination drug (specifically,
pioglitazone/metformin, pioglitazone/glimepiride,
mitiglinide/voglibose, alogliptin/pioglitazone,
alogliptin/metformin, etc.) containing as the components thereof,
two or more drugs among the above drugs.
[1184] Examples of the insulin sensitizer and the anti-diabetic
drug also include a hypolipidemic agent and a dyslipidemia
therapeutic agent. Examples of the hypolipidemic agent and the
dyslipidemia therapeutic agent include 1) omega-3 fatty acids
(specifically, ethyl icosapentate (EPA-E preparation),
docosahexaenoic acid (DHA), etc.), 2) HMG-CoA reductase inhibitors
(specifically, atorvastatin, simvastatin, pitavastatin,
itavastatin, fluvastatin, lovastatin, pravastatin, rivastatin,
rosuvastatin, etc.), 3) HMG-CoA synthase inhibitors, 4) cholesterol
absorption inhibitors (specifically, ezetimibe), 5)
acyl-CoA-cholesterol acyltransferase (ACAT) inhibitors, 6) CETP
inhibitors, 7) squalene synthase inhibitors, 8) antioxidants
(specifically, probucol, etc.), 9) PPAR alpha agonists
(specifically, clofibrate, etofibrate, fenofibrate, bezafibrate,
ciprofibrate, gemfibrozil, KRP-101, etc.), 10) PPAR delta agonists,
11) LXR agonists, 12) FXR agonists (specifically, INT-747, etc.),
13) MTTP inhibitors, 14) squalene epoxidase inhibitors, and 15)
bile acid absorption inhibitors (specifically, cholestyramine,
colestipol, etc).
[1185] Examples of the insulin sensitizer and the anti-diabetic
drug also include an anti-obesity agent. Specific examples of the
anti-obesity agent include 1) CB-1 receptor antagonists
(specifically, rimonabant, SR-147778, BAY-65-2520, etc.), 2)
monoamine reuptake inhibitors (specifically, sibutramine, mazindol,
etc.), 3) serotonin reuptake inhibitors (specifically, fluoxetine,
paroxetine, etc.), 4) lipase inhibitors (specifically, orlistat,
cetilistat, etc.), 5) neuropeptide Y (NPY) receptor antagonists
(specifically, S-2367, etc.), 6) peptide YY (PYY) receptor
antagonists, and 7) adrenergic beta-3 receptor agonists
(specifically, KRP-204, TRK-380/TAC-301, etc).
[1186] The therapies can be performed in combination with not only
other drugs, but also other therapies. Examples of the therapies
include the improvement of lifestyle through weight control,
exercise therapy, and diet therapy, and radiotherapy.
[1187] Against GPR40-involving diseases except for diabetes and
obesity, the therapies can be performed in combination with drugs
used in the respective fields.
[1188] Preferred examples of the concomitant drug include PPAR
gamma agonists (more preferably pioglitazone, rosiglitazone),
biguanide agents (more preferably metformin, buformin), sulfonyl
urea agents (more preferably glibenclamide, gliclazide,
glimepiride), rapid-acting insulin secretagogues (more preferably
nateglinide, mitiglinide, repaglinide), alpha-glucosidase
inhibitors (more preferably acarbose, voglibose, miglitol), insulin
or insulin derivatives, GLP-1 or GLP-1 receptor agonists (more
preferably exenatide, liraglutide), and DPP-IV inhibitors (more
preferably sitagliptin, vildagliptin, alogliptin, saxagliptin,
linagliptin, teneligliptin; further preferably sitagliptin,
vildagliptin, alogliptin, linagliptin).
[1189] The combined use of the concomitant drug and conventional
drugs against the diseases described above enables the dosage of
the conventional drugs to be reduced, which can reduce the side
effects of the conventional drugs. Needless to say, the combining
method using the drugs is not limited to the diseases, and the
drugs to be used in combination are not limited to the compounds
exemplified above.
[1190] To use the compound of the present invention in combination
with the drug to be used in combination, they may be individual
preparations or be a drug combination. In the form of individual
preparations, the compound and the drug can be taken at the same
time or can be administered at different times.
[1191] [Producing Preparations of Prophylactic or Therapeutic
Agents of the Present Invention]
[1192] The medicines of the present invention are administered in
the form of pharmaceutical compositions.
[1193] The pharmaceutical compositions of the present invention may
include at least the compound of Formula (I) or Formula (II) of the
present invention and are produced in combination with
pharmaceutically acceptable additives. More in detail, various
dosage forms can be prepared by appropriately combining the
compound of the present invention and, for example, excipients (for
example, lactose, white soft sugar, mannitol, microcrystalline
cellulose, silicic acid, corn starch, and potato starch), bonding
agents (for example, celluloses (hydroxypropylcellulose (HPC),
hcxydroxypropylmethylcellulose (HPMC), microcrystalline cellulose,
saccharide (lactose, mannitol, white soft sugar, sorbitol,
erythritol, and xylitol), starches (corn starch and potato starch),
gelatinized starch, dextrin, polyvinylpyrrolidone (PVP), macrogol,
polyvinyl alcohol (PVA)), lubricants (for example, magnesium
stearate, calcium stearate, talc, and carboxymethylcellulose),
disintegrants (for example, starches (corn starch and potato
starch), sodium carboxymethyl starch, carmellose, carmellose
calcium, croscarmellose sodium, and crospovidone), coating agents
(for example, celluloses (hydroxypropylcellulose (HPC),
hydroxypropylmethylcellulose (HPMC), aminoalkylmethacrylate
copolymers E, and methacrylic copolymers LD), plasticizers (for
example, triethyl citrate and macrogol), masking agents (for
example, titanium oxide), colorants, flavoring agents, antiseptics
(for example, benzalkonium chloride and p-hydroxybenzoate esters),
tonicity agents (for example, glycerin, sodium chloride, calcium
chloride, mannitol, and dextrose), pH regulators (for example,
sodium hydroxide, potassium hydroxide, sodium carbonate,
hydrochloric acid, sulfuric acid, and buffer solutions such as
phosphate buffer solutions), stabilizing agents (for example,
sugar, sugar alcohol, and xanthan gum), dispersants, antioxidants
(for example, ascorbic acid, butylated hydroxyanisole (BHA), propyl
gallate, and dl-alpha-tocopherol), buffer agents, preservatives
(for example, paraben, benzyl alcohol, and benzalkonium chloride),
perfumes (for example, vanillin, 1-menthol, and rose oil),
solubilizing agents (for example, polyoxyethylene hydrogenated
castor oil, polysorbate 80, polyethylene glycol, phospholipid
cholesterol, and triethanolamine), absorbefacients (for example,
sodium glycolate, sodium edetate, sodium caprate, acylcarnitines,
and limonene), gelators, suspending agents, emulsifiers, and
generally used suitable additives and solvents.
[1194] Examples of the various dosage forms include tablets,
capsules, granules, powderes, pills, aerosols, inhalants,
ointments, adhesive patches, suppositories, injections, troches,
liquids, spirits, suspensions, extracts, and elixirs. The dosage
forms can be administered to patients through oral administration,
subcutaneous injection, intramuscular injection, intranasal
administration, transdermal administration, intravenous injection,
intraarterial injection, perineural administration, epidural
administration, administration in subdural cavity, intraventricular
administration, rectal administration, inhalation, or the like.
[1195] The dosage of the compound of the present invention is
generally, 0.005 mg to 3.0 g, preferably, 0.05 mg to 2.5 g, and
more preferably, 0.1 mg to 1.5 g per day for adults, but can be
reduced or increased as needed depending on symptoms or
administration routes.
[1196] The compound can be administered as a whole at once or be
separately administered by being divided into two to six doses
through oral administration or parenteral administration, or can be
administered through repeated administration such as intravenous
infusion.
[1197] The present specification incorporates, as references, the
whole publications cited in the present specification, for example,
related-art documents, publications of unexamined applications,
patent publications, and other patent documents.
Pharmacological Test Examples
[1198] The present invention is specifically described below with
reference to test examples but is not limited to them.
[1199] The following pharmacological test examples 1 to 7 provide
methods for investigating the efficacy of the compound of the
present invention.
Pharmacological Test Example 1
Agonist Action on GPR40 of Human Origin
[1200] A CHO cell strain stably expressing GPR40 of human origin
was used to determine the agonist action of a title compound. This
cell strain was seeded in a clear bottom 96 well plate at
2.times.10.sup.4 cells/100 .mu.L/well. The cell strain was cultured
in a CO.sub.2 incubator overnight using a Ham's F-12 medium
containing a 10% fetal bovine serum, 100 U/mL penicillin, 0.1 mg/mL
streptomycin, and 400 .mu.g/mL Geneticin. Calcium 4 Assay Kit
(Molecular Devices) was used as a fluorescent calcium indicator.
One mL of 77 mg/mL probenecid (Invitrogen) was added to 100 mL of a
calcium indicator solution to prepare a solution (loading solution)
mixed with a 20 mM HEPES-containing Hanks' balanced salt solution
(HBSS) in equal proportions. To the cells from which the culture
solution was removed, 200 .mu.L of the loading solution was added,
and the cells were cultured in a CO.sub.2 incubator for 1 hour. The
title compound was diluted with a 20 mM HEPES-containing HBSS and
was added to the cells by 50 .mu.L, and the fluctuation of the
Ca.sup.2+ concentration was measured by an intracellular ion
analyzer. The EC.sub.50 value of the title compound was calculated
using the dose-response curve of fluorescence intensity variation.
Table 1 indicates the compound of the present invention having an
EC.sub.50 value of less than 0.3 .mu.M as A and the compound of the
present invention having an EC.sub.50 value of 0.3 .mu.M or more
and less than 3 .mu.M as B.
TABLE-US-00001 Compound of EC.sub.50 Examples values 1 A 2 A 3 A 4
A 5 A 6 A 7 A 8 A 9 A 10 A 11 A 12 A 13 A 14 A 15 B 16 A 17 A 18 B
19 A 20 B 21 A 22 A 23(A)-a A 23(A)-b B 24(A)-a A 24(A)-b A 25(A)-a
A 25(A)-b A 26 A 27 A 28 B 29 A 30 A 31 A 32 A 33 A 34 A 35 A 36 A
37 A 38 A 39 A 40 A 41 A 42 A 43 A 44 A 45 A 46 A 47 A 48 A 49 A 50
A 51(A)-a A 51(A)-b A 52(A)-a A 52(A)-b A 53(A)-a A 53(A)-b A
54(A)-a A 54(A)-b A 55(A)-a A 55(A)-b A 57 A 58 A 59 A 60 A 61 A 62
A 63 A 64 A 65 A 66 A 67 A 68 A 69 A
Pharmacological Test Example 2
Oral Glucose Tolerance Test
[1201] A reduction of blood glucose excursion of a subject compound
after glucose load is examined using male C57BL/6J mice or SD rats
fasted overnight. The subject compound is suspended with a solvent
(for example, 0.5% carboxymethylcellulose) and is orally
administered before glucose load. The solvent is singly
administered to the control group. Blood specimen collection is
performed before compound administration (pre-administration blood
collection), after compound administration and immediately before
glucose load, during glucose load, after 15, 30, 60, and 120
minutes, and the blood glucose level of the collected blood is
measured. The reduction of blood glucose excursion is obtained by
orally administering a dosage of 0.3 to 10 mg/kg of the preferable
compound of the compound of the present invention.
Pharmacological Test Example 3
Solubility Test
(1) DMSO Precipitation Solubility (Kinetic Solubility)
[1202] A 10 mM DMSO solution of the compound of the present
invention is added to a 50 mM phosphate buffer solution (pH 7.4) to
the final concentration of 100 .mu.M. The resultant solution is
incubated with stirring at 600 rpm for 1.5 hours at room
temperature, and then is filtered through a filter plate (4 .mu.m,
MultiScreen Solubility Filter Plate, Millipore). The absorbance of
the obtained filtrate is measured at the maximum absorption
wavelength using a plate reader (Powerscan IT, (Dainippon
Pharmaceutical)). In this process, DMSO solutions of known
concentration of the test compound (1, 3, 10, 30, and 100 .mu.M)
are prepared as standard solutions for a calibration curve. The
absorbance of each of the standard solutions is measured to
generate a calibration curve. The solubility (.mu.M) of the
compound is calculated using the absorbance values of the filtrate
and the standard solutions.
(2) Crystal solubility (Thermodynamic Solubility)
[1203] The compound of the present invention is added to water so
as to be 1 mg/mL. The resultant solution is incubated at 37.degree.
C. for 24 hours, and then is centrifuged. The obtained supernatant
is analyzed by HPLC to detect the peak at the maximum absorption
wavelength, and thus, the peak area is calculated. Similarly, DMSO
solutions of known concentration of the test compound (0.03, 0.1,
0.3, 1, 3, and 10 .mu.g/mL) are added as standard solutions for a
calibration curve. The peak area of each of the standard solutions
is measured. The solubility (.mu.g/mL) of the compound is
calculated using the peak areas of the obtained calibration
curve.
Pharmacological Test Example 4
Metabolic Stability Test
[1204] The 10 mM DMSO solution of the compound of the present
invention is added to a solution containing liver microsome (human,
mouse, or rat; XenoTech) and a NADPH generating systems (water
containing beta-NADP, Glucose-6-Phosphate, G-6-PDH(Y), and
MgCl.sub.2) to the final concentration of 1 .mu.M. The resultant
solution is incubated at 37.degree. C. for 20 minutes, and then the
reaction is terminated by adding acetonitrile. Similarly, samples
are collected at predetermined times during the incubation, and
then the reaction is terminated. Each reaction solution is
filtrated by centrifugation using a filter plate (MultiScreen
HTS-HV plate, Millipore). The test compound in the filtrate is
measured by high performance liquid chromatogram/mass spectrometry.
Similarly, a sample with a reaction time of 0 is measured as a
control. The compound concentration of the control is regarded as
100%, and the residual ratio of the compound in each reaction
solution is calculated. These residual ratios are plotted with
respect to the time, and the metabolic clearance (.mu.L/mg/min) is
calculated from the slope of the obtained regression line.
Pharmacological Test Example 5
hERG Inhibition Test by Patch-Clamp Technique
[1205] An effect against a human ether-a-go-go related gene (hERG)
channel is measured using a fully automatic patch-clamp system
(Patchliner (Nanion)). To confirm the hERG I.sub.Kr current of a
cell (hERG-HEK (Upstate)), the membrane potential is kept at -80
mV, and a depolarizing pulse is applied to the cell on a regular
basis. After the generated current became stable, a test compound
is added. The effect of the test compound against the hERG channel
is confirmed from the change in tail current induced by a
repolarizing pulse at -40 mV for 0.5 second subsequent to a
depolarizing pulse at 40 mV for 0.5 second. The stimulation is
performed at a frequency of once every 10 seconds. The measurement
is performed at room temperature. The hERG channel inhibition rate
is calculated as the reduction rate (suppression rate) of a tail
current two minutes after the application of the test compound
relative to the maximum tail current before the application.
[1206] The calculated suppression rate shows the possibility that
drug-induced QT prolongation followed by fatal side effects (such
as ventricular tachycardia and sudden death).
Pharmacological Test Example 6
Pharmacokinetics Study (Cassette Dosing PK)
[1207] The compound of the present invention is orally
administrated in a single dose to 7- or 8-week-old male C57BL/6J
Jcl mice or SD rats at 1 mg/kg (the vehicle is DMSO: Tween 80:
ultrapure water=1:1:8 and 10 mL/kg). After the administration, the
blood of the mouse is collected from the abdominal aorta after
0.25, 0.5, 1, and 2 hours, and the blood of the rat is collected
from the jugular vein after 0.5, 1, 2, and 4 hours. The blood is
centrifuged (3000 rpm, 15 minutes, and 4.degree. C.) to obtain
plasma, and the test compound in the plasma is measured by high
performance liquid chromatogram/mass spectrometry. Similarly,
standard solutions of known concentration of the test compound
(0.01, 0.02, 0.05, 0.1, 0.2, 0.5, and 1 .mu.g/mL) are measured to
generate a calibration curve. The concentration (.mu.g/mL) of the
compound in the plasma is calculated using the calibration curve,
and the maximum concentration in the plasma is indicated by Cmax
(.mu.g/mL).
Pharmacological Test Example 7
Safety Assessment Study
[1208] The compound of the present invention is orally
administrated in a single dose to mice or rats. No death is
confirmed and no noticeable behavior disorder is observed, and
therefore the safety of the compound of the present invention is
shown.
Pharmacological Test Example 8
Brain Penetration Study
[1209] Rats (male, SD, 7-9 weeks) are given single oral dose of
invention compounds at 1 mg/10 mL/kg (solvent: 0.5% CMC) after
overnight fasting. Blood samples are collected from jugular vein at
1 h after the administration and centrifuged (3,000 rpm, 15 min,
4.degree. C.) to give plasma.
Cerebral cortexes are obtained at the same time points as for blood
samples. Plasma concentrations (.mu.g/mL) of invention compounds
are measured by LC-MS/MS and quantitated using standard solution
(0.01, 0.02, 0.05, 0.1, 0.2, 0.5, 1 ug/mL) treated as well as
invention compounds samples. Cerebral cortexes are homogenized with
water, and after addition of methanol they are mixed and
centrifuged (14,000 rpm, 10 min, 4.degree. C.) to give supernatants
for measuring by LC-MS/MS. Cerebral cortex concentrations (g/mL) of
invention compounds are measured by LC-MS/MS and quantitated using
standard solution (0.01, 0.02, 0.05, 0.1, 0.2, 0.5, 1 ug/mL)
treated as well as invention compounds samples. Brain-to-plasma
ratio (B/P ratio) of invention compound is calculated from plasma
and cerebral cortex concentrations(.mu.g/mL). B/P ratio is a good
and common parameter for assessing extent of brain penetration,
therefore it is possible to compare the extent of brain penetration
among the invention compounds.
[1210] As a result, the compound of the present invention showed an
excellent GPR40 agonist action and reduced blood glucose excursion
in the single oral dose glucose tolerance test using normal mice or
rats. In the safety assessment study, no abnormality to indicates
low toxicity of the compound of the present invention.
[1211] By performing the tests described above, the compound of the
present invention is confirmed to have favorable properties in at
least one regard, such as solubility, metabolic stability,
pharmacokinetics, the avoidance of an hERG channel inhibition
action, and penetration through blood-brain barrier.
[1212] Accordingly, the compound of the present invention is
expected to be used as a GPR40 agonist for insulin secretagogues
and prophylactic and/or therapeutic agents against diabetes
(particularly, Type 2 diabetes or borderline type diabetes),
obesity, and adiposity.
Preparation Example
[1213] Hereinafter, Examples of the pharmaceutical compositions of
the present invention are described.
Preparation Example 1 Tablet
TABLE-US-00002 [1214] Compound of Example 2 100 g Lactose 137 g
Crystalline cellulose 30 g Hydroxypropylcellulose 15 g Sodium
carboxymethyl starch 15 g Magnesium stearate 3 g
[1215] The above components are weighed and then are uniformly
mixed. The mixture is formed into tablets having a weight of 150
mg.
Preparation Example 2 Film Coating
TABLE-US-00003 [1216] Hydroxypropylmethylcellulose 9 g Macrogol
6000 1 g Titanium oxide 2 g
[1217] The above components are weighed. Subsequently,
hydroxypropylmethylcellulose and macrogol 6000 are dissolved into
water to disperse titanium oxide. The resultant liquid is
film-coated on 300 g of the tablets of Preparation Example 1 to
obtain film-coated tablets.
Preparation Example 3 Capsules
TABLE-US-00004 [1218] Compound of Example 6 50 g Lactose 435 g
Magnesium stearate 15 g
[1219] The above components are weighed and then are uniformly
mixed. Adequate hard capsules are each filled with 300 mg of the
mixture by weight with a capsule inserter to produce capsules.
Preparation Example 4 Capsules
TABLE-US-00005 [1220] Compound of Example 8 100 g Lactose 63 g Corn
starch 25 g Hydroxypropylcellulose 10 g Talc 2 g
[1221] The above components are weighed, and then the compound of
Example 8, lactose, and corn starch are uniformly mixed. A
hydroxypropylcellulose aqueous solution is added to the resultant
mixture to produce granules by wet granulation. Talc is uniformly
mixed with the granules, and adequate hard capsules are each filled
with 200 mg of the mixture by weight to produce capsules.
Preparation Example 5 Powders
TABLE-US-00006 [1222] Compound of Example 11 200 g Lactose 790 g
Magnesium stearate 10 g
[1223] The above components are weighed and then are uniformly
mixed to produce 20% powdered drugs.
Preparation Example 6 Granules and Fine Granules
TABLE-US-00007 [1224] Compound of Example 13 100 g Lactose 200 g
Crystalline cellulose 100 g Partially gelatinized starch 50 g
Hydroxypropylcellulose 50 g
[1225] The above components are weighed, and the compound of
Example 13, lactose, crystalline cellulose, and partially
pregelatinized starch are uniformly mixed. A hydroxypropylcellulose
(HPC) aqueous solution is added to the resultant mixture to produce
granules or fine granules by wet granulation. The granules or fine
granules are dried to be formulation of granules or fine
granules.
EXAMPLES
[1226] Next, in order to describe the present invention further in
detail, there are described Examples which should not be construed
as limiting the scope of the present invention.
[1227] For the measurement of the nuclear magnetic resonance
spectrum (NMR), JEOL JNM-ECX400 FT-NMR (manufactured by JEOL Ltd.)
and JEOL JNM-ECX300 FT-NMR (manufactured by JEOL Ltd.) were used.
As the LC-MS, a Waters Fraction Lynx MS system (manufactured by
Waters Corporation) was used and as the column, a Sun Fire column
(4.6 mm.times.5 cm, 5 .mu.m) (manufactured by Waters Corporation)
was used. As a mobile phase, methanol: 0.05% acetic acid aqueous
solution=1:9 (0 min) to 10:0 (5 min) to 10:0 (7 min) (gradient
condition) or methanol: 0.05% trifluoroacetic acid aqueous
solution=1:9 (0 min) to 10:0 (5 min) to 10:0 (7 min) (gradient
condition) was used. As the UPLC/MS, a Waters UPLC-ZQ MS system
(manufactured by Waters Corporation) was used and as the column,
MGIII-H (2.1 mm.times.5 cm, 3 am) (manufactured by Shiseido Co.
Ltd.) was used. As a mobile phase, methanol: 0.05% trifluoroacetic
acid aqueous solution=5:95 (0 min) to 100:0 (1 min) to 100:0 (2
min) (gradient condition) was used. For the preparative isolation
system, gradient conditions appropriately changed depending on the
type of the compound were used. In the present invention, in the
preparative chromatography of a mixture of optical isomers of
5-substituted-isothiazol-3-ol 1-oxides [for example, (Example 1)
<Step 5>], an enantiomer having a shorter elution time is
expressed as A and an enantiomer having a longer elution time is
expressed as B, and in the preparative chromatography of a mixture
of optical isomers of 5-substituted-1,2-thiazinan-3-one
1,1-dioxides, an enantiomer having a shorter elution time is
expressed as C and an enantiomer having a longer elution time is
expressed as D [for example, (Example 40) <Step 1>].
[1228] In the preparative chromatography of a mixture of optical
isomers, a diastereomer having a shorter elution time is expressed
as a and a diastereomer having a longer elution time is expressed
as b [for example, (Example 23) <Step 6>]. In Structural
Formulae of the compounds described below, a mark * is affixed to
an asymmetric center of the enantiomer A, a mark C or D is affixed
to an asymmetric center of the enantiomer C or D, and a mark a or b
is affixed to an asymmetric center of a diastereomer a or b.
Reference Example 1
Synthesis of 4-hydroxyphenylboronic acid N-methyliminodiacetic acid
ester
[1229] A suspension of 4-hydroxyphenylboronic acid (10.3 g) and
N-methyliminodiacetic acid (11.0 g) in dimethyl sulfoxide (37
mL)--toluene (333 mL) was heated and refluxed for 1.5 hours. From
the resultant reaction mixture, toluene was distilled off under
reduced pressure and the reaction mixture was poured into water
(400 mL). The resultant reaction mixture was stirred for 1.5 hours.
The precipitate was filtered, washed with water, and then dried
under reduced pressure to give the title compound (16:4 g) as a
gray white solid.
Reference Example 2
Synthesis of
3'-(bromomethyl)-2,6-dimethyl-4-(3-(methylsulfonyl)propoxy)-1,1'-biphenyl
[1230] Concentrated sulfuric acid (1.4 g) was added dropwise to 48%
hydrobromic acid (15 ml) at room temperature and
[2',6'-dimethyl-4'-[3-(methylsulfonyl)propoxy]-[1,1'-biphenyl]-3-yl]metha-
nol (25 g) synthesized in accordance with the method described in
[WO 2008/001931 pamphlet] was divided into five portions and added
to the mixture. The reaction mixture was stirred at 60.degree. C.
for 2.5 hours and 48% hydrobromic acid (3.3 ml) was added to the
mixture. The mixture was further stirred for 1 hour at the same
temperature. After the reaction mixture was allowed to cool, water
was added to the reaction mixture. The mixture was extracted with
ethyl acetate. The obtained organic phase was washed with water,
then washed with brine, and dried over anhydrous sodium sulfate.
From the organic phase, the solvent was distilled off under reduced
pressure to give the title compound (27 g) as a pale yellow
solid.
Example 1
Synthesis of
5-[4-[[3-[4-(2-ethoxyethoxy)-2,6-dimethylphenyl]phenyl]methoxy]phenyl]-1--
oxo-1,2-thiazolidin-3-one
<Step 1> Synthesis of
1-bromo-2,6-dimethyl-4-(2-ethoxyethoxyl)benzene
[1231] In accordance with the method described in [WO 2005/063729
pamphlet, Reference Example 31], the title compound (12.8 g) was
obtained as a colorless oil from 4-bromo-3,5-dimethylphenol (10.0
g) and 2-chloroethyl ethyl ether (5.94 mL).
<Step 2> Synthesis of
(3-(2,6-dimethyl-4-(2-ethoxyethoxyl)phenyl)phenyl)methanol
[1232] To a mixed solution of the compound (6.40 g) obtained in
(Example 1) <Step 1> and 3-(hydroxymethyl)phenylboronic acid
(3.56 g) in 1,4-dioxane (70 mL)--water (7 mL),
bis(dibenzylideneacetone)palladium (1.35 g),
2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl (SPhos: 1.92 g),
and potassium phosphate monohydrate (10.8 g) were sequentially
added and the resultant reaction mixture was heated and stirred at
100.degree. C. for 4 hours. To the reaction mixture, water was
added and the mixture was extracted with ethyl acetate. The organic
phase was washed with brine and then dried over anhydrous sodium
sulfate. From the organic phase, the solvent was distilled off
under reduced pressure. The resultant residue was purified by
silica gel column chromatography (eluent; n-hexane:ethyl
acetate=80:20 to 75:25) to give the title compound (4.13 g) as a
colorless oil.
<Step 3> Synthesis of
4-((3-(2,6-dimethyl-4-(2-ethoxyethoxyl)phenyl)phenyl)methoxy)phenylboroni-
c acid N-methyliminodiacetic acid ester
[1233] To a solution of the compound (1.50 g) obtained in (Example
1) <Step 2>, the compound (1.49 g) obtained in (Reference
Example 1), and tri-n-butylphosphine (1.48 mL) in tetrahydrofuran
(50 mL), 1,1'-azobis(N,N-dimethylformamide) (1.03 g) was added
under ice-cooling and the resultant reaction mixture was stirred at
room temperature for 2 hours. From the reaction mixture, the
solvent was distilled off under reduced pressure and the resultant
residue was purified by silica gel column chromatography (eluent;
n-hexane:ethyl acetate) to give the title compound (2.37 g) as a
white amorphous solid.
<Step 4> Synthesis of 5-chloro-isothiazol-3-ol 1-oxide
[1234] To a suspension of 5-chloro-isothiazol-3-ol (31.8 g) in
dichloromethane (640 mL), m-chloroperbenzoic acid (content 65%)
(60.7 g) was added under ice-cooling and the resultant reaction
mixture was stirred at room temperature for 15 hours. The reaction
mixture was filtered and then the filtrate was concentrated under
reduced pressure. To the residue, dichloromethane was added and the
precipitate was filtered off. The filtrate was concentrated under
reduced pressure and the resultant residue was purified by silica
gel chromatography (eluent; n-hexane:ethyl acetate=67:33 to 60:40)
to give the title compound (26.0 g) as a white solid.
<Step 5> Optical resolution of (Rac)-5-chloro-isothiazol-3-ol
1-oxide
[1235] Optical resolution of the compound (30.5 g) obtained in
(Example 1) <Step 4> was conducted by preparative
chromatography (column: CHIRALPAK AS-H (5 cm.times.25 cm)
manufactured by Daicel Chemical Industries, Ltd., eluent; carbon
dioxide:methanol=86:14 (V/V), flow rate: 200 g/second, detection:
UV 238 nm) to give each enantiomer of the title compound.
[1236] Primary fraction (14.7 g, white solid, >99% ee, retention
time 4.8 minutes (enantiomer A: Example 1-5 (A)))
[1237] Secondary fraction (14.1 g, white solid, >98% ee,
retention time 5.3 minutes (enantiomer B: Example 1-5 (B)))
[1238] The optical purity and the retention time were determined
under the following conditions.
Column: CHIRALPAK AD-H (0.46 cm.times.25 cm) (manufactured by
Daicel Chemical Industries, Ltd.), Eluent: methanol:acetic
acid=100:0.1 (v/v), Flow rate: 1.0 mL/min,
Detection: UV 282 nm,
[1239] Column temperature: 40.degree. C.
[1240] Hereinafter, the compounds and derivatives of them
synthesized using the enantiomer A (Example 1-5 (A)) obtained in
(Example 1) <Step 5> is expressed as "name of the
compound+(A)" and the compounds and derivatives of them synthesized
using the enantiomer B (Example 1-5 (B)) obtained in (Example 1)
<Step 5> is expressed as "name of the compound+(B)".
<Step 6> Synthesis of 5-(4-((3-(2,6-dimethyl
4-(2-ethoxyethoxyl)phenyl)phenyl)methoxy)phenyl)isothiazol-3-ol
1-oxide (A)
[1241] To a solution of the compound (0.20 g) obtained in (Example
1) <Step 3> in 1,4-dioxane (3.7 mL), a 1M sodium hydroxide
aqueous solution (1.1 mL) was added and the resultant reaction
mixture was stirred at room temperature for 1.5 hours. To the
reaction mixture, the enantiomer A (Example 1-5 (A)) (74 mg)
obtained in (Example 1) <Step 5>,
2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl (SPhos: 31 mg), and
palladium acetate (8.4 mg) were sequentially added and the
resultant reaction mixture was heated and stirred at 90.degree. C.
for 3 hours. To the reaction mixture, a saturated aqueous ammonium
chloride solution was added and the mixture was extracted with
ethyl acetate. The organic phase was washed with brine and then
dried over anhydrous sodium sulfate. From the organic phase, the
solvent was distilled off under reduced pressure and the resultant
residue was purified by LC/MS to give the title compound (9.2 mg)
as a pale yellow amorphous solid.
<Step 7> Synthesis of
5-[4-[[3-[4-(2-ethoxyethoxy)-2,6-dimethylphenyl]phenyl]methoxy]phenyl]-1--
oxo-1,2-thiazolidin-3-one (A)
[1242] To a solution of the compound (50 mg) obtained in (Example
1) <Step 6> in absolute THF (1 mL), a solution of 1M
L-Selectride in tetrahydrofuran (0.31 mL) was added at 0.degree. C.
and the resultant reaction mixture was stirred at the same
temperature for 1.5 hours. To the reaction mixture, 1M hydrochloric
acid was added and the mixture was extracted with ethyl acetate.
The organic phase was washed with brine and then dried over
anhydrous sodium sulfate. From the organic phase, the solvent was
distilled off under reduced pressure and the resultant residue was
purified by silica gel column chromatography (eluent;
n-hexane:ethyl acetate) to give the title compound (4.6 mg) as a
white solid. The obtained compound by the reduction in this step is
a mixture of diastereomers having a new asymmetric center.
[1243] The compounds of Examples 2 to Example 4 below were
synthesized by the same method or a similar method in Example 1
from each corresponding raw material through a corresponding
substituted phenylboronic acid ester and further through a
corresponding substituted isothiazole.
Example 2
5-[4-[[3-[4-(2-ethoxyethoxy)-3-fluoro-2,6-dimethylphenyl]phenyl]methoxy]ph-
enyl]-1-oxo-1,2-thiazolidin-3-one (A)
Example 3
5-[4-[[3-[3-fluoro-4-(3-hydroxy-3-methylbutoxy)-2,6-dimethylphenyl]phenyl]-
methoxy]phenyl]-1-oxo-1,2-thiazolidin-3-one (A)
Example 4
5-[4-[[3-[4-(3-hydroxy-3-methylbutoxy)-2,6-dimethylphenyl]phenyl]methoxy]p-
henyl]-1-oxo-1,2-thiazolidin-3-one (A)
Example 5
Synthesis of optically active
5-[4-[[3-[2,4-dimethyl-6-(3-methylsulfonylpropoxyl)pyridin-3-yl]phenyl]me-
thoxy]phenyl]-1-oxo-1,2-thiazolidin-3-one (A)-a and (A)-b
<Step 1> Synthesis of
5-(4-((3-(2,4-dimethyl-6-(3-(methylsulfonyl)propoxy)pyridin-3-yl)phenyl)m-
ethoxy)phen yl)isothiazol-3-ol 1-oxide (A)
[1244] The title compound was synthesized by the same method or a
similar method in <Step 1> to <Step 6> in (Example 1)
from a corresponding raw material through a corresponding
substituted phenylboronic acid ester.
<Step 2> Synthesis of
5-[4-[[3-[2,4-dimethyl-6-(3-methylsulfonylpropoxyl)pyridin-3-yl]phenyl]me-
thoxy]phenyl]-1-oxo-1,2-thiazolidin-3-one (A)-a and (A)-b
[1245] To a solution of the compound (200 mg) obtained in (Example
5) <Step 1> in absolute THF (6 mL), a solution of 1M
L-Selectride in tetrahydrofuran (1.5 mL) was added at 0.degree. C.
and the resultant reaction mixture was stirred at the same
temperature for 1 hour. To the reaction mixture, 1M hydrochloric
acid was added and the mixture was extracted with ethyl acetate.
The organic phase was washed with brine and then dried over
anhydrous sodium sulfate. From the organic phase, the solvent was
distilled off under reduced pressure and the resultant residue was
purified by LC/MS to give each diastereomer of the title
compound.
[1246] Primary fraction (1.6 mg, pale yellow solid, retention time
5.25 minutes, diastereomer a: Example 5 (A)-a)
[1247] Secondary fraction (3.4 mg, pale yellow solid, retention
time 5.32 minutes, diastereomer b: Example 5 (A)-b)
[1248] Hereinafter, for example, the mixture of diastereomers that
are obtained by the reduction in Example 5 <Step 2> using the
enantiomer A (Example 5-1 (A)) obtained in Example 5 <Step 1>
can be separated into optically active diastereomers as shown in
Example 5 <Step 2>. For example, when a resolution column is
used, the primary fraction that is firstly eluted in the separation
condition is expressed as "name of the compound+a" as a
diastereomer a (Example 5 (A)-a) and the secondary fraction that is
eluted later is expressed as "name of the compound+b" as a
diastereomer b (Example 5 (A)-b).
[1249] For example, Example 5-1 (B), Example 5 (B)-a, and Example 5
(B)-b can similarly be obtained when the enantiomer B obtained in
Example 1 <Step 5> is used in Example 5 <Step 1>.
[1250] The compound of Example 6 below was synthesized by the same
method or a similar method in Example 5 form each corresponding raw
material through a corresponding substituted phenylboronic acid
ester and further through a corresponding substituted
isothiazole.
Example 6
5-[4-[[3-[6-(3-hydroxy-3-methylbutoxy)-2,4-dimethylpyridin-3-yl]phenyl]met-
hoxy]phenyl]-1-oxo-1,2-thiazolidin-3-one (A)-a trifluoroacetic acid
salt and (A)-b trifluoroacetic acid salt
[1251] Primary fraction (6.4 mg, colorless amorphous solid,
retention time 5.72 minutes, diastereomer a: Example 6 (A)-a)
[1252] Secondary fraction (8.1 mg, colorless oil, retention time
5.77 minutes, diastereomer b: Example 6 (A)-b)
Example 7
Synthesis of
5-[4-[[3-[4-(3-hydroxy-3-methylbutoxy)-2,5-dimethylphenyl]phenyl]methoxy]-
phenyl]-1-oxo-1,2-thiazolidin-3-one (A)-a and (A)-b
<Step 1> Synthesis of 3-hydroxy-5-(4-((4'
(3-hydroxy-3-methylbutoxy)-2',5'-dimethyl-[1,1'-biphenyl]-3-yl)methoxy)ph-
enyl)isothiazole 1-oxide (A)
[1253] The title compound was synthesized by the same method or a
similar method in <Step 1> to <Step 6> in (Example 1)
from a corresponding raw material through a corresponding
substituted phenylboronic acid ester.
<Step 2> Synthesis of
5-[4-[[3-[4-(3-hydroxy-3-methylbutoxy)-2,5-dimethylphenyl]phenyl]methoxy]-
phenyl]-1-oxo-1,2-thiazolidin-3-one (A)-a and (A)-b
[1254] To a solution of the compound (100 mg) obtained in (Example
7) <Step 1> in absolute THF (3 mL), a solution of 1M
L-Selectride in tetrahydrofuran (0.79 mL) was added at 0.degree. C.
and the resultant reaction mixture was stirred at the same
temperature for 1.5 hours. To the reaction mixture, 1M hydrochloric
acid was added and the mixture was extracted with ethyl acetate.
The organic phase was washed with brine and then dried over
anhydrous sodium sulfate. From the organic phase, the solvent was
distilled off under reduced pressure and the resultant residue was
separated and purified by LC/MS. Optical resolution of the
resultant solid was conducted by preparative chromatography
(column: CHIRALPAK IB (2 cm.times.25 cm) manufactured by Daicel
Chemical Industries, Ltd., eluent; hexane:ethanol:trifluoroacetic
acid=70:30:0.1 (V/V), flow rate: 17 mL/min) to give each
diastereomer of the title compound. The retention times were
determined by LC/MS.
[1255] Primary fraction (10 mg, colorless amorphous solid,
retention time 6.20 minutes, diastereomer a: Example 7 (A)-a)
[1256] Secondary fraction (21 mg, colorless amorphous solid,
retention time 6.10 minutes, diastereomer b: Example 7 (A)-b)
Example 8
Synthesis of
5-[4-[[3-[4-(3-hydroxypropoxy)-2,6-dimethylphenyl]phenyl]methoxy]phenyl]--
1-oxo-1,2-thiazolidin-3-one (A)
<Step 1> Synthesis of 1-bromo-4-(3-((tert-butyl
dimethylsilyl)oxy)propoxy)-2,6-dimethylbenzene
[1257] In accordance with the method in (Example 1) <Step 1>,
the title compound (7.60 g) was obtained as a colorless oil from
4-bromo-3,5-dimethylphenol (4.00 g) and
3-((tert-butyldimethylsilyl)oxy)propyl bromide (5.55 g).
<Step 2> Synthesis of
(3-(2,6-dimethyl-4-(3-(tert-butyldimethylsilyl)oxy)propoxyphenyl)phenyl)m-
ethanol
[1258] In accordance with the method in (Example 1) <Step 2>,
the title compound (1.34 g) was obtained as a brown oil from the
compound (3.60 g) obtained in (Example 8) <Step 1>.
<Step 3> Synthesis of
4-((3-(4-(3-((tert-butyldimethylsilyl)oxy)propoxy)-2,6-dimethylphenyl)phe-
nyl)methoxy)phenylboronic acid N-methyliminodiacetic acid ester
[1259] In accordance with the method in (Example 1) <Step 3>,
the title compound (1.21 g) was obtained as a pale yellow amorphous
solid from the compound (1.20 g) obtained in (Example 8) <Step
2>.
<Step 4> Synthesis of
5-(4-((3-(2,6-dimethyl-4-(3-hydroxypropoxyl)phenyl)phenyl)methoxy)phenyl)-
isothiazol-3-ol 1-oxide (A)
[1260] To a solution of the compound (0.20 g) obtained in (Example
8) <Step 3> in 1,4-dioxane (3.2 mL), a 1M sodium hydroxide
aqueous solution (0.9 mL) was added and the resultant reaction
mixture was stirred at room temperature for 1.5 hours. To the
reaction mixture, the enantiomer A (62 mg) obtained in (Example 1)
<Step 5>, 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl
(SPhos: 26 mg), and palladium acetate (7.1 mg) were sequentially
added and the resultant reaction mixture was heated and stirred at
100.degree. C. for 2 hours. To the reaction mixture, a saturated
aqueous ammonium chloride solution was added and the mixture was
extracted with ethyl acetate. The organic phase was washed with
brine and then dried over anhydrous sodium sulfate. From the
organic phase, the solvent was distilled off under reduced pressure
and the resultant residue was dissolved in ethanol (5.0 mL) and
tetrahydrofuran (5.0 mL). To the solution, concentrated
hydrochloric acid (4.1 mL) was added and the resultant reaction
mixture was stirred at room temperature for 8 hours. To the
reaction mixture, a saturated aqueous sodium hydrogen carbonate was
added to make the mixture weak acidic and the mixture was extracted
with ethyl acetate. The organic phase was washed with brine and
then dried over anhydrous sodium sulfate. From the organic phase,
the solvent was distilled off under reduced pressure and the
resultant residue was purified by LC/MS to give the title compound
(23 mg) as a pale yellow amorphous solid.
<Step 5> Synthesis of
5-[4-[[3-[4-(3-hydroxypropoxy)-2,6-dimethylphenyl]phenyl]methoxy]phenyl]--
1-oxo-1,2-thiazolidin-3-one (A)
[1261] In accordance with the method in (Example 1) <Step 7>,
the title compound (4.2 mg) was obtained as a pale yellow amorphous
solid from the compound (11 mg) obtained in (Example 8) <Step
4>. The title compound is a mixture of diastereomers.
[1262] The compounds of Example 9 to Example 10 below were
synthesized by the same method or a similar method in Example 8
form each corresponding raw material through a corresponding
substituted phenylboronic acid ester and further through a
corresponding substituted isothiazole.
Example 9
5-[4-[[3-[4-[(2R)-2,3-dihydroxypropoxy]-2,6-dimethylphenyl]phenyl]methoxy]-
phenyl]-1-oxo-1,2-thiazolidin-3-one (A)
Example 10
5-[4-[[3-[4-[3-hydroxy-2-(hydroxymethyl)propoxy]-2,6-dimethylphenyl]phenyl-
]methoxy]phenyl]-1-oxo-1,2-thiazolidin-3-one (A)
Example 11
Synthesis of
5-[4-[[3-[4-(3-aminopropoxy)-2,6-dimethylphenyl]phenyl]methoxy]phenyl]-1--
oxo-1,2-thiazolidin-3-one trifluoroacetic acid salt
<Step 1> Synthesis of
3-(4-bromo-3,5-dimethylphenoxy)propyl)carbamic acid tert-butyl
ester
[1263] In accordance with the method in (Example 1) <Step 3>,
the title compound (6.6 g) was obtained as a white solid from
4-bromo-3,5-dimethylphenol (5.00 g) and (3-hydroxypropyl)carbamic
acid tert-butyl ester (5.2 g).
<Step 2> Synthesis of
(3-((3'-formyl-2,6-dimethyl-[1,1'-biphenyl]-4-yl)oxy)propyl)carbamic
acid tert-butyl ester
[1264] In accordance with the method in (Example 1) <Step 2>,
the title compound (1.95 g) was obtained as a red oil from the
compound (2.3 g) obtained in (Example 11)<Step 1> and
3-formylphenylboronic acid (0.95 g).
<Step 3> Synthesis of
3-((3'-hydroxymethyl-2,6-dimethyl-[1,1'-biphenyl]-4-yl)oxy)propyl)carbami-
c acid tert-butyl ester
[1265] The compound (1.84 g) obtained in (Example 11) <Step
2> was dissolved in a solution of tetrahydrofuran (12.0 mL) and
methanol (6.0 mL). To the solution, sodium borohydride (0.18 g) was
gradually added under ice-cooling. The reaction mixture was allowed
to reach room temperature and stirred for 2 hours. To the reaction
mixture, a saturated aqueous ammonium chloride solution was added
to make the mixture pH 7 and the mixture was extracted with ethyl
acetate. The organic phase was washed with brine and then dried
over anhydrous sodium sulfate. From the organic phase, the solvent
was distilled off under reduced pressure and the resultant residue
was purified by silica gel column chromatography (eluent;
n-hexane:ethyl acetate=75:25 to 70:30) to give the title compound
(1.73 g) as an amorphous solid.
<Step 4> Synthesis of
(3-((2,6-dimethyl-3'-(4-(6-methyl-4,8-dioxo-1,3,6,2-dioxazaborocan-2-yl)p-
henoxy)methyl-[1,1'-biphenyl]-4-yl)oxy)propyl)carbamic acid
tert-butyl ester
[1266] In accordance with the method in Example 1 <Step 3>,
the title compound (2.09 g) was obtained as a white amorphous solid
from the compound (1.70 g) obtained in (Example 11) <Step
3>.
<Step 5> Synthesis of
(3-((2,6-dimethyl-3'-((4-(1-oxide-3-oxo-2,3-dihydroisothiazol-5-yl)phenox-
y)methyl-[1,1'-biphenyl]-4-yl)oxy)propyl)carbamic acid tert-butyl
ester (A)
[1267] In accordance with the method in Example 1 <Step 6>,
the title compound (45.6 mg) was obtained as a white amorphous
solid from the compound (100 mg) obtained in (Example 11) <Step
4> using the enantiomer A (Example 1-5 (A)) obtained in (Example
1) <Step 5>.
<Step 6> Synthesis of
5-(4-((4'-(3-aminopropoxy)-2',6'-dimethyl[1,1'-biphenyl]-3-yl)methoxy)phe-
nyl)isothiazol-3(2H)-one 1-oxide (A)
[1268] The compound (45 mg) obtained in (Example 11) <Step 5>
was dissolved in ethyl acetate (1.0 mL). To the solution, a
solution of 4M hydrogen chloride in ethyl acetate (1.0 mL) was
added and the resultant reaction mixture was stirred at room
temperature over night. The reaction mixture was concentrated under
reduced pressure and dried to give the title compound (49 mg) as a
yellow solid.
<Step 7> Synthesis of
5-[4-[[3-[4-[(3R)-3-hydroxybutoxy]-2,6-dimethylphenyl]phenyl]methoxy]phen-
yl]-1-oxo-1,2-thiazolidin-3-one (A)
[1269] In accordance with the method in (Example 1) <Step 7>,
the title compound (26 mg) was obtained as a colorless amorphous
solid from the compound (50 mg) obtained in (Example 11) <Step
6>. The obtained compound is a mixture of diastereomers.
Example 12
Synthesis of
5-[4-[[3-[4-[(3R)-3-hydroxybutoxy]-2,6-dimethylphenyl]phenyl]methoxy]phen-
yl]-1-oxo-1,2-thiazolidin-3-one (A)
<Step 1> Synthesis of (3R)-3-acetoxybutoxy
4-methylbenzenesulfonate
[1270] The hydroxy group in (3R)-3-hydroxybutoxy
4-methylbenzenesulfonate (35.0 g) that was synthesized in
accordance with the method in [Tetrahedron: Asymmetry, vol. 5 (1),
pp. 117-118 (1994)] was acetylated in a common procedure to give
the title compound (15.6 g) as a yellow oil.
<Step 2> Synthesis of
4-((3R)-3-acetoxybutoxy)-1-bromo-2,6-dimethylbenzene
[1271] In accordance with the method in (Example 1) <Step 1>,
the title compound (4.09 g) was obtained as a colorless oil from
4-bromo-3,5-dimethylphenol (5.00 g) and the compound (7.83 g)
obtained in (Example 12) <Step 1>.
<Step 3> Synthesis of
(3-(4-((3R)-3-acetoxybutoxy)-2,6-dimethylphenyl)phenyl)methanol
[1272] In accordance with the method in (Example 1) <Step 2>,
the title compound (1.36 g) was obtained as a brown oil from the
compound (2.00 g) obtained in (Example 12) <Step 2>.
<Step 4> Synthesis of
4-((3-(4-((3R)-3-acetoxybutoxy)-2,6-dimethylphenyl)phenyl)methoxy)phenylb-
oronic acid N-methyliminodiacetic acid ester
[1273] In accordance with the method in (Example 1) <Step 3>,
the title compound (1.83 g) was obtained as a white solid from the
compound (1.20 g) obtained in (Example 12) <Step 3>.
<Step 5> Synthesis of
5-(4-((3-(2,6-dimethyl-4-((3R)-3-hydroxybutoxy)phenyl)phenyl)methoxy)phen-
yl)isothiazol-3-ol 1-oxide (A)
[1274] To a solution of the compound (0.40 g) obtained in (Example
12) <Step 4> in 1,4-dioxane (7.0 mL), a 1M sodium hydroxide
aqueous solution (2.1 mL) was added and the resultant reaction
mixture was stirred at room temperature for 1.5 hours. To the
reaction mixture, the enantiomer A (137 mg) obtained in (Example 1)
<Step 5>, 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl
(SPhos: 57 mg), and palladium acetate (39 mg) were sequentially
added and the resultant reaction mixture was heated and stirred at
100.degree. C. for 2 hours. To the reaction mixture, a saturated
aqueous ammonium chloride solution was added and the mixture was
extracted with ethyl acetate. The organic phase was washed with
brine and then dried over anhydrous sodium sulfate. From the
organic phase, the solvent was distilled off under reduced pressure
and the resultant residue was dissolved in ethanol (5.0 mL). To the
solution, a 1M sodium hydroxide aqueous solution (4.9 mL) was added
and the resultant reaction mixture was stirred at room temperature
for 8 hours. To the reaction mixture, a saturated aqueous ammonium
chloride solution was added to make the mixture weak acidic and the
mixture was extracted with ethyl acetate. The organic phase was
washed with brine and then dried over anhydrous sodium sulfate.
From the organic phase, the solvent was distilled off under reduced
pressure and the resultant residue was purified by LC/MS to give
the title compound (29 mg) as a pale yellow amorphous solid.
<Step 6> Synthesis of
5-[4-[[3-[4-[(3R)-3-hydroxybutoxy]-2,6-dimethylphenyl]phenyl]methoxy]phen-
yl]-1-oxo-1,2-thiazolidin-3-one (A)
[1275] In accordance with the method in (Example 1) <Step 7>,
the title compound (5.2 mg) was obtained as a pale yellow amorphous
solid from the compound (11 mg) obtained in (Example 12) <Step
5>. The obtained compound is a mixture of diastereomers.
Example 13
Synthesis of 5-[4-[[3-[2,6-dimethyl
4-(3-methylsulfonylpropoxyl)phenyl]phenyl]methoxy]phenyl]-1-oxo-1,2-thiaz-
olidin-3-one (A)
<Step 1> Synthesis of (3-(2,6-dimethyl
4-((tert-butyldimethylsilyl)oxy)phenyl)phenyl)methanol
[1276] In accordance with the method in (Example 1) <Step 2>,
the title compound (10.4 g) was obtained as an orange solid from
1-bromo-4-((tert-butyldimethylsilyl)oxy)-2,6-dimethylbenzene (15.0
g) that was synthesized in accordance with the method described in
[WO 2005/063729 pamphlet].
<Step 2> Synthesis of
4-((3-(2,6-dimethyl-4-((tert-butyldimethyl
silyl)oxy)phenyl)phenyl)methoxy)phenylboronic acid
N-methyliminodiacetic acid ester
[1277] In accordance with the method in (Example 1) <Step 3>,
the title compound (0.24 g) was obtained as a pale yellow amorphous
solid from the compound (0.20 g) obtained in (Example 13) <Step
1>.
<Step 3> Synthesis of
4-((3-(2,6-dimethyl-4-hydroxyphenyl)phenyl)methoxy)phenylboronic
acid N-methyliminodiacetic acid ester
[1278] To a solution of the compound (4.18 g) obtained in (Example
13) <Step 2> in tetrahydrofuran (70 mL), a solution of 1M
tetrabutylammonium fluoride in tetrahydrofuran (14.6 mL) was added
under ice-cooling and the mixture was stirred under ice-cooling for
30 minutes. Water was added to the reaction mixture and the mixture
was extracted with ethyl acetate. The organic phase was washed with
brine and then dried over anhydrous sodium sulfate. From the
organic phase, the solvent was distilled off under reduced pressure
and the resultant residue was purified by silica gel column
chromatography (eluent; n-hexane:ethyl acetate=33:67 to 20:80) to
give the title compound (1.06 g) as a beige amorphous solid.
<Step 4> Synthesis of
4-((3-(2,6-dimethyl-4-(3-(methylsulfonyl)propoxy)phenyl)phenyl)methoxy)ph-
enylboronic acid N-methyliminodiacetic acid ester
[1279] In accordance with the method in (Example 1) <Step 1>,
the title compound (79 mg) was obtained as a white solid from the
compound (0.20 g) obtained in (Example 13) <Step 3> and
3-(methylsulfonyl)propyl 4-methylbenzenesulfonate (0.14 g)
synthesized in accordance with the method described in [WO
2007/018314 pamphlet].
<Step 5> Synthesis of 5-(4-((3-(2,6-dimethyl
4-(3-(methylsulfonyl)propoxy)phenyl)phenyl)methoxy)phenyl)isothiazol-3-ol
1-oxide (A)
[1280] In accordance with the method in (Example 1) <Step 6>,
the title compound (15 mg) was obtained as a beige solid from the
compound (76 mg) obtained in (Example 13) <Step 4> using the
enantiomer A (Example 1-5 (A)) obtained in (Example 1) <Step
5>.
<Step 6> Synthesis of 5-[4-[[3-[2,6-dimethyl
4-(3-methylsulfonylpropoxyl)phenyl]phenyl]methoxy]phenyl]-1-oxo-1,2-thiaz-
olidin-3-one (A)-a and (A)-b
[1281] In accordance with the method in (Example 7) <Step 2>,
each diastereomer of the title compound was obtained from the
compound (100 mg) obtained in (Example 13) <Step 5>. The
separation condition was as follows. Preparative chromatography
(column: CHIRALPAK IB (2 cm.times.25 cm) manufactured by Daicel
Chemical Industries, Ltd., eluent; hexane:ethanol:trifluoroacetic
acid=50:50:0.1 (V/V), flow rate: 17 mL/min). The retention times
were determined by LC/MS.
[1282] Primary fraction (7.8 mg, colorless amorphous solid,
retention time 5.62 minutes, diastereomer a: Example 13 (A)-a)
[1283] Secondary fraction (6.0 mg, colorless amorphous solid,
retention time 5.53 minutes, diastereomer b: Example 13 (A)-b)
Example 14
Synthesis of
5-[4-[[3-(2,6-dimethylphenyl)phenyl]methoxy]phenyl]-1,1-dioxo-1,2,5-thiad-
iazolidin-3-one
<Step 1> Synthesis of
(4-((2',6'-dimethyl-[1,1'-biphenyl]-3-yl)methoxy)phenyl)carbamic
acid tert-butyl ester
[1284] To a solution of
(2',6'-dimethyl-[1,1'-biphenyl]-3-yl)methanol (4.0 g),
4-hydroxycarbamic acid tert-butyl ester (5.91 g), and
tri-n-butylphosphine (6.97 mL) in tetrahydrofuran (80 mL),
1,1'-azobis(N,N-dimethylformamide) (4.87 g) was added under
ice-cooling and the resultant reaction mixture was stirred at room
temperature for 62 hours. The precipitated solid was filtered off
and the solvent in the filtrate was distilled off under reduced
pressure. To the resultant residue, water was added and the mixture
was extracted with ethyl acetate. The organic phase was washed with
brine and then dried over anhydrous sodium sulfate. From the
organic phase, the solvent was distilled off under reduced pressure
and the resultant residue was purified by silica gel column
chromatography (eluent; n-hexane:ethyl acetate=95:5) twice to give
the title compound (6.17 g) as a colorless amorphous solid.
<Step 2> Synthesis of
4-((2',6'-dimethyl-[1,1'-biphenyl]-3-yl)methoxy)aniline
[1285] The compound (6.15 g) obtained in (Example 14) <Step
1> was dissolved in ethyl acetate (27 mL). To the solution, a
solution of 4M hydrogen chloride in ethyl acetate (19 mL) was added
and the resultant reaction mixture was stirred at room temperature
over night. The reaction mixture was diluted with ethyl acetate. To
the mixture, a saturated aqueous sodium hydrogen carbonate solution
was added to make the mixture basic and the mixture was extracted
with ethyl acetate. The obtained organic phase was washed with
brine and then dried over anhydrous sodium sulfate. The organic
phase was concentrated under reduced pressure to give the title
compound (4.58 g) as a pale brown oil.
<Step 3> Synthesis of tert-butyl
2-((4-((2',6'-dimethyl-[1,1'-biphenyl]-3-yl)methoxy)phenyl)amino)acetate
[1286] To a solution of the compound (0.50 g) obtained in (Example
14) <Step 2> in N,N'-dimethylformamide (3.3 mL),
diisopropylethylamine (0.57 mL) and tert-butyl 2-bromoacetate (0.23
mL) were sequentially added and the resultant reaction mixture was
stirred at 60.degree. C. for 4 hours. The reaction mixture was
allowed to reach room temperature, then diluted with water, and
extracted with ethyl acetate. The obtained organic phase was washed
with brine and then dried over anhydrous sodium sulfate. From the
organic phase, the solvent was distilled off under reduced
pressure. The resultant residue was purified by silica gel column
chromatography (eluent; n-hexane:ethyl acetate=90:10) to give the
title compound (0.60 g) as a pale yellow oil.
<Step 4> Synthesis of tert-butyl
2-((N-(tert-butoxycarbonyl)sulfamoyl)(4-((2',6'-dimethyl-[1,1'-biphenyl]--
3-yl)methoxy)phenyl)amino)acetate
[1287] To a solution of tert-butanol (0.14 mL) in methylene
chloride (0.70 mL), chlorosulfonyl isocyanate (0.13 mL) was added
under ice-cooling. The resultant reaction mixture was stirred at
room temperature for 30 minutes to prepare a solution of
chlorosulfonyl carbamic acid tert-butyl ester in methylene
chloride. The mixed solution was added to a solution of the
compound (0.30 g) obtained in (Example 14) <Step 3> and
diisopropylethylamine (0.38 mL) in methylene chloride (0.70 mL)
under ice-cooling and the resultant reaction mixture was stirred at
room temperature for 4 hours. The reaction solution was diluted
with water and extracted with methylene chloride. The obtained
organic phase was washed with brine and then dried over anhydrous
sodium sulfate. From the organic phase, the solvent was distilled
off under reduced pressure to give a mixture (0.48 g) containing
the title compound as a colorless amorphous solid.
<Step 5> Synthesis of
2-((4-((2',6'-dimethyl-[1,1'-biphenyl]-3-yl)methoxy)phenyl)(sulfamoyl)ami-
no)acetic acid
[1288] To a solution of the compound (0.30 g) obtained in (Example
14) <Step 4> in methylene chloride (3.0 mL), trifluoroacetic
acid (0.8 mL) was added under ice-cooling and the resultant
reaction mixture was stirred at room temperature for 21 hours. To
the reaction solution, water was added and the mixture was
extracted with methylene chloride. The obtained organic phase was
washed with brine and then dried over anhydrous sodium sulfate.
From the organic phase, the solvent was distilled off under reduced
pressure to give the title compound (0.20 g) as a brown amorphous
solid.
<Step 6> Synthesis of
5-[4-[[3-(2,6-dimethylphenyl)phenyl]methoxy]phenyl]-1,1-dioxo-1,2,5-thiad-
iazolidin-3-one
[1289] To a solution of the compound (80.0 mg) obtained in (Example
14) <Step 5> in tetrahydrofuran (1.2 mL),
1-hydroxybenzotriazole monohydrate (27.8 mg) and
1-ethyl-3-(3'-dimethylaminopropyl)carbodiimide hydrochloride
(WSC-HCl: 34.8 mg) were sequentially added and the resultant
reaction mixture was stirred at room temperature for 10 minutes.
Subsequently, triethylamine (27.84 .mu.l) was added and the
resultant reaction mixture was stirred at room temperature for 15
hours. From the reaction mixture, the solvent was distilled off
under reduced pressure. To the residue, ethyl acetate was added.
The mixture was sequentially washed with 1M hydrochloric acid and
brine and then dried over anhydrous sodium sulfate. From the
organic phase, the solvent was distilled off under reduced
pressure. The resultant residue was purified by preparative TLC
(eluent; methylene chloride:methanol=20:1, 1% acetic acid). The
obtained compound was triturated with ether to give the title
compound (10.2 mg) as a brown solid.
Example 15
Synthesis of
5-[4-[[3-[2,6-dimethyl-4-(3-methylsulfonylpropoxyl)phenyl]phenyl]methoxy]-
phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one
<Step 1> Synthesis of
(4-((2',6'-dimethyl-4'-(3-methylsulfonyl)propoxy-[1,1'-biphenyl]-3-yl)met-
hoxy)phenyl)carbamic acid tert-butyl ester
[1290] In accordance with the method in (Example 14) <Step
1>, the title compound (1.54 g) was obtained as a white
amorphous solid from
{2',6'-dimethyl-4'-[3-(methylsulfonyl)propoxy]-[1,1'-biphenyl]-3-yl}metha-
nol (1.0 g) that was synthesized in accordance with the method
described in [WO 2008/001931 pamphlet].
<Step 2> Synthesis of
4-((2',6'-dimethyl-4'-(3-methylsulfonyl)propoxy-[1,1'-biphenyl]-3-yl)meth-
oxy)aniline
[1291] In accordance with the method in (Example 14) <Step
2>, the title compound (1.18 g) was obtained as a pale yellow
oil from the compound (1.53 g) synthesized in (Example 15) <Step
1>.
<Step 3> Synthesis of ethyl
2-((4-((2',6'-dimethyl-4'-[3-(methylsulfonyl)propoxy]-[1,1'-biphenyl]-3-y-
l)methoxy)phen yl)amino)acetate
[1292] In accordance with the method in (Example 14) <Step
3>, the title compound (0.40 g) was obtained as a pale yellow
oil from the compound (0.40 g) obtained in (Example 15) <Step
2> and ethyl 2-bromoacetate (95.6 l).
<Step 4> Synthesis of ethyl
2-((N-(tert-butoxycarbonyl)sulfamoyl)(4-((2',6'-dimethyl-4'-(3-(methylsul-
fonyl)propoxy)-[1,1'-biphenyl]-3-yl)methoxy)phenyl)amino)acetate
[1293] In accordance with the method in (Example 14) <Step
4>, the title compound (0.55 g) was obtained as a brown
amorphous solid from the compound (0.38 g) obtained in (Example 15)
<Step 3>.
<Step 5> Synthesis of ethyl
2-((4-((2',6'-dimethyl-4'-[3-(methylsulfonyl)propoxy]-[1,1'-biphenyl]-3-y-
l)methoxy)phen yl)(sulfamoyl)amino)acetate
[1294] In accordance with the method in (Example 14) <Step
5>, the title compound (0.47 g) was obtained as a brown
amorphous solid from the compound (0.53 g) obtained in (Example 15)
<Step 4>.
<Step 6> Synthesis of
5-[4-[[3-[2,6-dimethyl-4-(3-methylsulfonylpropoxyl)phenyl]phenyl]methoxy]-
phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one
[1295] To a solution of the compound (0.20 g) obtained in (Example
15) <Step 5> in ethanol (0.80 mL), a 2M sodium hydroxide
aqueous solution (0.33 mL) was added under ice-cooling and the
resultant reaction mixture was stirred for 30 minutes. To the
reaction solution, ethyl acetate and 1M hydrochloric acid were
added and the mixture was extracted with ethyl acetate. The organic
phase was dried over anhydrous sodium sulfate. From the organic
phase, the solvent was distilled off under reduced pressure and the
resultant residue was purified by LC/MS to give the title compound
(17 mg) as a pale beige solid.
Example 16
Synthesis of
5-[2-chloro-4-[[3-(2,6-dimethylphenyl)phenyl]methoxy]phenyl]-1,1-dioxo-1,-
2,5-thiadiazolidin-3-one
<Step 1> Synthesis of (2-chloro-4-hydroxyphenyl)carbamic acid
tert-butyl ester
[1296] To a solution of 4-amino-3-chlorophenol hydrochloride (1.0
g) and triethylamine (0.77 mL) in tetrahydrofuran (4.6 mL),
di-tert-butyl carbonate (1.39 mL) was slowly added dropwise and the
resultant reaction mixture was heated and refluxed for 8 hours. The
reaction mixture was allowed to reach room temperature and added to
a saturated aqueous ammonium chloride. The mixture was extracted
with ethyl acetate and the organic phase was dried over anhydrous
sodium sulfate. From the organic phase, the solvent was distilled
off under reduced pressure to give a mixture (1.42 g) containing
the title compound as a pale brown solid.
<Step 2> Synthesis of
(2-chloro-4-((2',6'-dimethyl-[1,1'-biphenyl]-3-yl)methoxy)phenyl)carbamic
acid tert-butyl ester
[1297] In accordance with the method in (Example 14) <Step
1>, a mixture (0.83 g) containing the title compound was
obtained as a colorless oil using the compound (0.69 g) obtained in
(Example 16) <Step 1>.
<Step 3> Synthesis of
2-chloro-4-((2',6'-dimethyl-[1,1'-biphenyl]-3-yl)methoxy)aniline
hydrochloride
[1298] To a solution of the compound (0.78 g) obtained in (Example
16) <Step 2> in ethyl acetate (3.0 mL), a solution of 4M
hydrogen chloride in ethyl acetate (2.23 mL) was added and the
resultant reaction mixture was stirred at room temperature for 3
hours. The precipitate was collected by filtration and dried under
reduced pressure to give the title compound (0.47 g) as a white
solid.
<Step 4> Synthesis of ethyl
2-((2-chloro-4-((2',6'-dimethyl-[1,1'-biphenyl]-3-yl)methoxy)phenyl)amino-
)acetate
[1299] In accordance with the method in (Example 14) <Step
3>, the title compound (357 mg) was obtained as a pale yellow
oil using the compound (0.40 g) obtained in (Example 16) <Step
3> and ethyl 2-bromoacetate (0.24 mL).
<Step 5> Synthesis of ethyl
2-((2-chloro-4-((2',6'-dimethyl-[1,1'-biphenyl]-3-yl)methoxy)phenyl)(sulf-
amoyl)amino)acetate
[1300] In accordance with the methods in (Example 14) <Step
4> and (Example 14)<Step 5>, a mixture (839 mg) containing
the title compound was obtained as a brown oil using the compound
(0.34 g) obtained in (Example 16) <Step 4>.
<Step 6> Synthesis of
5-[2-chloro-4-[[3-(2,6-dimethylphenyl)phenyl]methoxy]phenyl]-1,1-dioxo-1,-
2,5-thiadiazolidin-3-one
[1301] In accordance with the method in (Example 15) <Step
6>, the title compound (46 mg) was obtained as a pale brown
amorphous solid using the compound (0.80 g) obtained in (Example
16) <Step 5>.
Example 17
Synthesis of
5-[4-[[3-(2,6-dimethylphenyl)phenyl]methoxy]-2-methylphenyl]-1,1-dioxo-1,-
2,5-thiadiazolidin-3-one
<Step 1> Synthesis of (4-hydroxy-2-methylphenyl)carbamic acid
tert-butyl ester
[1302] In accordance with the method in (Example 16) <Step
1>, the title compound (1.71 g) was obtained as a pale brown
amorphous solid using 4-amino-3-methylphenol (1.0 g).
<Step 2> Synthesis of
(4-((2',6'-dimethyl-[1,1'-biphenyl]-3-yl)methoxy)-2-methylphenyl)carbamic
acid tert-butyl ester
[1303] In accordance with the method in (Example 16) <Step
2>, the title compound (0.70 g) was obtained as a colorless
amorphous solid using the compound (0.40 g) obtained in (Example
17) <Step 1>.
<Step 3> Synthesis of
4-((2',6'-dimethyl-[1,1'-biphenyl]-3-yl)methoxy)-2-methylaniline
hydrochloride
[1304] In accordance with the method in (Example 16) <Step
3>, the title compound (0.47 g) was obtained as a white solid
using the compound (0.65 g) obtained in (Example 17) <Step
2>.
<Step 4> Synthesis of ethyl
2-((4-((2',6'-dimethyl-[1,1'-biphenyl]-3-yl)methoxy)-2-methylphenyl)amino-
)acetate
[1305] In accordance with the method in (Example 16) <Step
4>, the title compound (0.31 g) was obtained as a brown oil
using the compound (0.40 g) obtained in (Example 17) <Step
3>.
<Step 5> Synthesis of ethyl
2-((4-((2',6'-dimethyl-[1,1'-biphenyl]-3-yl)methoxy)-2-methylphenyl)(sulf-
amoyl)amino)acetate
[1306] In accordance with the method in (Example 16) <Step
5>, a mixture (895 mg) containing the title compound was
obtained as a brown oil using the compound (0.30 g) obtained in
(Example 17) <Step 4>.
<Step 6> Synthesis of
5-[4-[[3-(2,6-dimethylphenyl)phenyl]methoxy]-2-methylphenyl]-1,1-dioxo-1,-
2,5-thiadiazolidin-3-one
[1307] In accordance with the method in (Example 15) <Step
6>, the title compound (27 mg) was obtained as a brown amorphous
solid using the compound (0.85 g) obtained in (Example 17) <Step
5>.
Example 18
Synthesis of
5-[4-[[3-(2,6-dimethylphenyl)phenyl]methoxy]phenyl]-4-methyl-1,1-dioxo-1,-
2,5-thiadiazolidin-3-one
<Step 1> Synthesis of ethyl
2-((4-((2',6'-dimethyl-[1,1'-biphenyl]-3-yl)methoxy)phenyl)amino)propiona-
te
[1308] In accordance with the method in (Example 14) <Step
3>, the title compound (0.56 g) was obtained as an orange oil
from a hydrochloride (0.50 g) of the compound obtained in (Example
14) <Step 2> and ethyl 2-bromopropionate (0.39 mL).
<Step 2> Synthesis of ethyl
2-((N-(tert-butoxycarbonyl)sulfamoyl)
(4-((2',6'-dimethyl-[1,1'-biphenyl]-3-yl)methoxy)phenyl)amino)propionate
[1309] In accordance with the method in (Example 14) <Step
4>, a mixture (753 mg) containing the title compound was
obtained as a brown amorphous solid using the compound (0.55 g)
obtained in (Example 18) <Step 1>.
<Step 3> Synthesis of ethyl
2-((4-((2',6'-dimethyl-[1,1'-biphenyl]-3-yl)methoxy)phenyl)(sulfamoyl)ami-
no)propionate
[1310] In accordance with the method in (Example 14) <Step
5>, a mixture (0.70 g) containing the title compound was
obtained as a brown amorphous solid using the compound (0.74 g)
obtained in (Example 18) <Step 2>.
<Step 4> Synthesis of
5-[4-[[3-(2,6-dimethylphenyl)phenyl]methoxy]phenyl]-4-methyl-1,1-dioxo-1,-
2,5-thiadiazolidin-3-one
[1311] In accordance with the method in (Example 15) <Step
6>, the title compound (5 mg) was obtained as a pale yellow
solid using the compound (0.30 g) obtained in (Example 18) <Step
3>.
Example 19
Synthesis of 5-[4-[[3-[2,6-dimethyl 4-(3-methyl
sulfonylpropoxy)phenyl]phenyl]methoxy]phenyl]-1,1-dioxo-1,2-thiazolidin-3-
-one
<Step 1> Synthesis of
5-(4-((2',6'-dimethyl-4'-(3-(methylsulfonyl)propoxy)-[1,1'-biphenyl]-3-yl-
)methoxy)phenyl)isothiazol-3(2H)-one 1,1-dioxide
[1312] To a solution of the compound (50 mg) obtained in (Example
13) <Step 5> in methanol (5.0 mL), water (0.5 mL) and OXONE
(registered trademark) (117 mg) were added and the resultant
reaction mixture was stirred at 40.degree. C. for 18 hours.
Subsequently, the mixture was stirred at 100.degree. C. for 23
hours. The reaction mixture was allowed to reach room temperature
and water was added. The mixture was extracted with ethyl acetate.
The organic phase was washed with brine and dried over anhydrous
sodium sulfate. From the organic phase, the solvent was distilled
off under reduced pressure to give a mixture (50.0 mg) containing
the title compound as a colorless solid.
<Step 2> Synthesis of
5-[4-[[3-[2,6-dimethyl-4-(3-methylsulfonylpropoxyl)phenyl]phenyl]methoxy]-
phenyl]-1,1-dioxo-1,2-thiazolidin-3-one
[1313] In accordance with the method in (Example 1) <Step 7>,
the title compound (6.0 mg) was obtained as a colorless solid using
the compound (50 mg) obtained in (Example 19) <Step 1>. The
obtained compound is a racemic mixture.
Example 20
Synthesis of
5-[4-[[3-[6-(3-hydroxy-3-methylbutoxy)-2,4-dimethylpyridin-3-yl]phenyl]me-
thoxy]phenyl]-1,1-dioxo-1,2-thiazolidin-3-one
[1314] To a solution of the compound (50 mg) obtained in (Example
6) in acetone (5 mL), water (0.5 mL) and OXONE (registered
trademark) (363 mg) were added and the resultant reaction mixture
was stirred at 90.degree. C. for 16 hours. The reaction mixture was
allowed to reach room temperature and water was added. The mixture
was extracted with ethyl acetate. The organic phase was washed with
brine and dried over anhydrous sodium sulfate. From the organic
phase, the solvent was distilled off under reduced pressure and the
resultant residue was purified by silica gel column chromatography
(eluent; methylene chloride:methanol=20:1) to give the title
compound (11 mg) as a colorless amorphous solid. The obtained
compound is a racemic mixture.
Example 21
Synthesis of
5-[4-[[3-(2,6-dimethylphenyl)phenyl]methoxy]phenyl]-1,1-dioxo-1,2,6-thiad-
iazinan-3-one
<Step 1> Synthesis of
4-((2',6'-dimethyl-[1,1'-biphenyl]-3-yl)methoxy)benzaldehyde
[1315] To a solution of
(2',6'-dimethyl-[1,1'-biphenyl]-3-yl)methanol (1.0 g),
4-hydroxybenzaldehyde (0.58 g), and triphenylphosphine (1.48 g) in
tetrahydrofuran (10 mL), a solution of 40%
diisopropylazodicarboxylic acid diisopropyl in toluene (1.09 mL)
was added under ice-cooling and the resultant reaction mixture was
stirred under ice-cooling for 3 hours. A solution of diisopropyl
azodicarboxylate in toluene (0.6 mL) was further added and the
resultant reaction mixture was stirred at room temperature for 12
hours. From the reaction mixture, the solvent was distilled off
under reduced pressure to give a residue and water was added to the
resultant residue. The mixture was extracted with an organic
solvent and the resultant organic phase was dried over anhydrous
sodium sulfate. From the organic phase, the solvent was distilled
off under reduced pressure and the resultant residue was purified
by silica gel column chromatography (eluent; n-heptane:ethyl
acetate=100:0 to 100:20) to give the title compound (1.2 g) as a
colorless oil.
<Step 2> Synthesis of ethyl
3-amino-3-(4-((2',6'-dimethyl-[1,1'-biphenyl]-3-yl)methoxy)phenyl)propion-
ate
[1316] A mixed solution of the compound (1 g) obtained in (Example
21) <Step 1>, ammonium acetate (0.73 g), and monoethyl
malonate (0.44 g) in ethanol (15 mL) was heated and refluxed for 20
hours. The reaction mixture was allowed to reach room temperature
and a 2M sodium hydroxide aqueous solution was added. The mixture
was extracted with ethyl acetate. The obtained organic phase was
dried over anhydrous sodium sulfate. From the organic phase, the
solvent was distilled off under reduced pressure and the resultant
residue was purified by silica gel column chromatography (eluent;
n-heptane:ethyl acetate=100:0 to 100:20) to give the title compound
(0.28 g) as a yellow oil.
<Step 3> Synthesis of ethyl
3-(4-((2',6'-dimethyl-[1,1'-biphenyl]-3-yl)methoxy)phenyl)-3-(sulfamoyl)p-
ropionate
[1317] In accordance with the method in (Example 14) <Step
4>, a mixture (8 mg) containing the title compound was obtained
as a pale yellow amorphous solid using the compound (200 mg)
obtained in (Example 21) <Step 2>.
<Step 4> Synthesis of
5-[4-[[3-(2,6-dimethylphenyl)phenyl]methoxy]phenyl]-1,1-dioxo-1,2,6-thiad-
iazinan-3-one
[1318] In accordance with the method in (Example 15) <Step
6>, the title compound (3.2 mg) was obtained as a pale yellow
solid using the compound (7.0 mg) obtained in (Example 21) <Step
3>. The title compound is a racemic mixture.
Example 22
Synthesis of
5-[4-[[3-(2,6-dimethylphenyl)phenyl]methoxy]phenyl]-1,1-dioxo-1,2-thiazin-
an-3-one
<Step 1> Synthesis of
N,N-bis(4-methoxybenzyl)methanesulfonamide
[1319] To a solution of methanesulfonamide (5 g) in
N,N-dimethylformamide (75 mL), potassium carbonate (29.1 g) was
added and the resultant reaction mixture was stirred at room
temperature for 5 hours. To the solution, p-methoxybenzyl chloride
(18.1 g) was added and the resultant reaction mixture was stirred
at room temperature for 19 hours. To the reaction solution, water
was added and the mixture was extracted with ethyl acetate. The
obtained organic phase was dried over anhydrous sodium sulfate.
From the organic phase, the solvent was distilled off under reduced
pressure to give the title compound (17.1 g) as a white solid.
<Step 2> Synthesis of
2-(4-((2',6'-dimethyl-[1,1'-biphenyl]-3-yl)methoxy)phenyl)-N,N-bis(4-meth-
oxybenzyl)ethenesulfonamide
[1320] To a solution of the compound (1.19 g) obtained in (Example
22) <Step 1> in tetrahydrofuran (5.5 mL), a solution of 1M
lithium hexamethyldisilazide in tetrahydrofuran (8.29 mL) was added
dropwise at -20.degree. C. After stirring the mixture at
-20.degree. C. for 1 hour, a solution of diethyl chlorophosphate
(0.51 mL) in tetrahydrofuran (3 mL) was added dropwise. After
stirring the mixture at -20.degree. C. for 1 hour, a solution of
the compound (0.75 g) obtained in (Example 21) <Step 1> in
tetrahydrofuran (3 mL) was added dropwise. After stirring the
mixture at room temperature for 19 hours, 1M hydrochloric acid and
water were sequentially added to the reaction solution and the
mixture was extracted with ethyl acetate. The obtained organic
phase was washed with brine and dried over anhydrous sodium
sulfate. From the organic phase, the solvent was distilled off
under reduced pressure and the resultant residue was purified by
silica gel column chromatography (eluent; n-hexane:ethyl
acetate=90:10 to 80:20) to give the title compound (890 mg) as a
colorless oil.
<Step 3> Synthesis of dimethyl
2-(2-(N,N-bis(4-methoxybenzyl)sulfamoyl)-1-(4-((2',6'-dimethyl-[1,1'-biph-
enyl]-3-yl)methoxy)phenyl)ethyl)malonate
[1321] To a solution of dimethyl malonate (0.54 g) in
tetrahydrofuran (6 mL), a solution of 28% sodium methoxide in
methanol (0.81 g) was added and the resultant reaction mixture was
stirred for 1 hour. Subsequently, a solution of the compound (0.87
g) obtained in (Example 22) <Step 2> in tetrahydrofuran (4
mL) was added and the resultant reaction mixture was heated and
refluxed for 17 hours. The reaction mixture was allowed to reach
room temperature and a 10% citric acid aqueous solution was added.
The mixture was extracted with ethyl acetate. The organic phase was
washed with brine and the resultant organic phase was dried over
anhydrous sodium sulfate. From the organic phase, the solvent was
distilled off under reduced pressure and the resultant residue was
purified by silica gel column chromatography (eluent;
n-hexane:ethyl acetate=85:15 to 70:30) to give the title compound
(730 mg) as a white amorphous solid.
<Step 4> Synthesis of methyl
4-(N,N-bis(4-methoxybenzyl)sulfamoyl)-3-(4-((2',6'-dimethyl-[1,1'-bipheny-
l]-3-yl)methoxy)phenyl)butanoate
[1322] To a solution of the compound (0.72 g) obtained in (Example
22) <Step 3> in N,N-dimethylformamide (6.0 mL), water (33.8
mg) and sodium chloride (54.92 mg) were added and the resultant
reaction mixture was heated and refluxed for 2.5 hours. The
reaction mixture was allowed to reach room temperature and water
was added. The mixture was extracted with ethyl acetate. The
organic phase was washed with brine and the resultant organic phase
was dried over anhydrous sodium sulfate. From the organic phase,
the solvent was distilled off under reduced pressure and the
resultant residue was purified by silica gel column chromatography
(eluent; n-hexane:ethyl acetate=85:15 to 70:30) to give the title
compound (358 mg) as a colorless oil.
<Step 5> Synthesis of methyl
3-(4-((2',6'-dimethyl-[1,1'-biphenyl]-3-yl)methoxy)phenyl)-4-sulfamoylbut-
anoate
[1323] To a solution of the compound (0.32 g) obtained in (Example
22) <Step 4> in methylene chloride (3.0 mL), trifluoroacetic
acid (0.60 mL) was added and the resultant reaction mixture was
stirred at room temperature for 15 hours. The reaction solution was
poured into a mixed solution of a 10% potassium carbonate aqueous
solution and ethyl acetate and the mixture was extracted with ethyl
acetate. The obtained organic phase was washed with brine and then
dried over anhydrous sodium sulfate. From the organic phase, the
solvent was distilled off under reduced pressure and the resultant
residue was purified by silica gel column chromatography (eluent;
n-hexane:ethyl acetate=75:25 to 65:35) to give the title compound
(150 mg) as a colorless oil.
<Step 6> Synthesis of
5-[4-[[3-(2,6-dimethylphenyl)phenyl]methoxy]phenyl]-1,1-dioxo-1,2-thiazin-
an-3-one
[1324] To a mixed solution of the compound (140 mg) obtained in
(Example 22) <Step 5> in methanol (2.0 mL) and
tetrahydrofuran (1.0 mL), a solution of 28% sodium methoxide in
methanol (57.7 Ing) was added and the resultant reaction mixture
was stirred for 1 hour. To the reaction solution, 1M hydrochloric
acid was added and the mixture was extracted with ethyl acetate.
The obtained organic phase was washed with brine and dried over
anhydrous sodium sulfate. From the organic phase, the solvent was
distilled off under reduced pressure and the resultant residue was
triturated with a mixed solution of n-hexane:ethyl acetate=2:1 to
give the title compound (93 mg) as a white solid. The title
compound is a racemic mixture.
Example 23
Synthesis of
5-(4-(((R)-4-(6-(3-hydroxy-3-methylbutoxy)-2-methylpyridin-3-yl)-2,3-dihy-
dro-1H-inden-1-yl)oxy)phenyl)-1-oxo-1,2-thiazolidin-3-one (A)
<Step 1> Synthesis of
4-(5-bromo-6-methylpyridin-2-yloxy)-2-methylbutan-2-ol
[1325] To a suspension of sodium hydride (containing about 40% of a
mineral oil, 0.38 g) in N,N-dimethylformamide (10 mL),
5-bromo-2-hydroxy-6-methylpyridine (1.00 g) and
3-hydroxy-3-methylbutyl 4-methylbenzenesulfonate (1.51 g) were
added under ice-cooling and the resultant reaction mixture was
stirred at 60.degree. C. for 2.5 hours. To the mixture,
3-hydroxy-3-methylbutyl 4-methylbenzenesulfonate (0.50 g) was
further added and the resultant reaction mixture was stirred at
60.degree. C. for 1.5 hours. Sodium hydride (containing about 40%
of a mineral oil, 40 mg) was further added. To the reaction
mixture, a saturated aqueous ammonium chloride solution was added
and the mixture was extracted with ethyl acetate. The organic phase
was washed with brine and then dried over anhydrous sodium sulfate.
From the organic phase, the solvent was distilled off under reduced
pressure and the resultant residue was purified by silica gel
column chromatography (eluent; n-hexane:ethyl acetate=50:50 to
33:67) to give the title compound (1.3 g) as a pale yellow oil.
<Step 2> Synthesis of
4-[5-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-6-methylpyridin-2-yl]oxy-2-me-
thylbutan-2-ol
[1326] To a solution of the compound (2.85 g) obtained in (Example
23) <Step 1> and bis(neopentyl glycolate)diboron (2.82 g) in
1,4-dioxane (45 mL), potassium acetate (3.06 g) and a
[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium
(II)--dichloromethane adduct (0.42 g) were added. The mixture was
degassed and then heated and refluxed for 16 hours. To the reaction
mixture, water (200 mL) was added and the mixture was extracted
with ethyl acetate (200 mL). The organic phase was washed with
brine (80 mL) and then dried over anhydrous sodium sulfate. From
the organic phase, the solvent was distilled off under reduced
pressure and the resultant residue was purified by silica gel
column chromatography (eluent; n-hexane:ethyl acetate=95:5 to
80:20) to give the title compound (2.2 g).
<Step 3> Synthesis of
4-(((1R)-4-bromo-2,3-dihydro-1H-inden-1-yloxy)phenylboronic acid
N-methyliminodiacetic acid ester
[1327] To a mixed solution of the compound (0.20 g) obtained in
(Reference Example 1), (1S)-4-bromo-2,3-dihydro-1H-inden-1-ol (153
mg) that was commercially available or could be obtained by a known
method, and tri-n-butylphosphine (0.50 mL) in tetrahydrofuran (3
mL), 1,1'-azobis(N,N-dimethylformamide) (0.35 g) was added under
ice-cooling. The resultant reaction mixture was stirred at room
temperature for 1.5 hours. From the reaction mixture, the solvent
was distilled off under reduced pressure and the resultant residue
was purified by silica gel column chromatography (eluent;
n-hexane:ethyl acetate=50:50 to 0:100). From the eluted solution,
the solvent was distilled off under reduced pressure to give a
crude product containing the title compound.
<Step 4> Synthesis of
5-(4-((1R)-4-bromo-2,3-dihydro-1H-inden-1-yloxy)phenyl)isothiazol-3-ol
1-oxide (A)
[1328] In accordance with the method in (Example 1) <Step 6>,
the title compound (24.6 mg) was obtained from the crude product
(178 mg) obtained in (Example 23) <Step 3>.
<Step 5> Synthesis of
3-hydroxy-5-(4-(((R)-4-(6-(3-hydroxy-3-methylbutoxy)-2-methylpyridin-3-yl-
)-2,3-dihydro-1H-inden-1-yl)oxy)phenyl)isothiazole 1-oxide (A)
[1329] A mixed solvent of the compound (50 mg) obtained in (Example
23) <Step 4>, the compound (49.4 mg) obtained in (Example 23)
<Step 2>, bis(dibenzylideneacetone)palladium (7.1 mg),
2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (XPhos: 11.8
mg), potassium carbonate (34.2 mg), 1,4-dioxane (1.0 mL), and water
(0.5 mL) was heated and refluxed for 4 hours. The reaction solution
was extracted with ethyl acetate and the organic phase was dried
over anhydrous sodium sulfate. From the organic phase, the solvent
was distilled off under reduced pressure and the resultant residue
was purified by silica gel column chromatography (eluent; ethyl
acetate:methanol=100:0 to 80:20). From the eluted solution, the
solvent was distilled off under reduced pressure to give the title
compound (12 mg) as a colorless amorphous solid.
<Step 6> Synthesis of
5-(4-(((R)-4-(6-(3-hydroxy-3-methylbutoxy)-2-methylpyridin-3-yl)-2,3-dihy-
dro-1H-inden-1-yl)oxy)phenyl)-1-oxo-1,2-thiazolidin-3-one (A)
[1330] In accordance with the method in (Example 7) <Step 2>,
the title compound was obtained from the compound (0.13 g) obtained
in (Example 23) <Step 5> and then each diastereomer of the
title compound was obtained.
[1331] Primary fraction (10.3 mg, white amorphous solid, retention
time 5.85 minutes (LC/MS), diastereomer a: Example 23 (A)-a)
[1332] Secondary fraction (3.3 mg, white amorphous solid, retention
time 5.77 minutes (LC/MS), diastereomer b: Example 23 (A)-b)
Example 24
Synthesis of
5-[4-[[(1R)-4-[6-(3-hydroxy-3-methylbutoxy)-2,6-dimethylphenyl]-2,3-dihyd-
ro-1H-inden-1-yl]oxy]phenyl]-1-oxo-1,2-thiazolidin-3-one (A)
<Step 1> Synthesis of
4-(4-bromo-3,5-dimethylphenoxy)-2-methylbutan-2-ol
[1333] A mixed solution of 3-hydroxy-3-methylbutyl
4-methylbenzenesulfonate (4.24 g) synthesized in accordance with
the method described in [WO 2009/067613 pamphlet, Example 308],
4-bromo-3,5-dimethylphenol (3.0 g), and potassium carbonate (3.09
g) in N,N-dimethylformamide (15 mL) was stirred at 80.degree. C.
for 3 hours. To the reaction mixture, ethyl acetate (200 mL) and
water (100 mL) were added and the mixture was extracted with ethyl
acetate. The organic phase was successively washed with water (50
mL) and brine (50 mL) and then dried over anhydrous sodium sulfate.
From the organic phase, the solvent was distilled off under reduced
pressure and the resultant residue was purified by silica gel
column chromatography (eluent; n-hexane:ethyl acetate=80:20 to
70:30). From the eluted solution, the solvent was distilled off
under reduced pressure to give the title compound (3.9 g).
<Step 2> Synthesis of
4-(4-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-3,5-dimethylphenoxy)-2-methyl-
butan-2-ol
[1334] In accordance with the method in (Example 23) <Step
2>, the title compound (2.65 g) was obtained using the compound
(3.90 g) obtained in (Example 24) <Step 1>.
<Step 3> Synthesis of
5-[4-[[(1R)-4-[6-(3-hydroxy-3-methylbutoxy)-2,6-dimethylphenyl]-2,3-dihyd-
ro-1H-inden-1-yl]oxy]phenyl]isothiazol-3-ol 1-oxide (A)
[1335] In accordance with the method in (Example 23) <Step
5>, the title compound (8 mg) was obtained as a pale yellow
solid using the compound (50 mg) obtained in (Example 23) <Step
4> and the compound (0.12 g) obtained in (Example 24) <Step
2>.
<Step 4> Synthesis of
5-[4-[[(1R)-4-[6-(3-hydroxy-3-methylbutoxy)-2,6-dimethylphenyl]-2,3-dihyd-
ro-1H-inden-1-yl]oxy]phenyl]-1-oxo-1,2-thiazolidin-3-one (A)
[1336] In accordance with the method in (Example 7) <Step 2>,
the title compound was obtained from the compound (0.17 g) obtained
in (Example 24) <Step 3> and then each diastereomer of the
title compound was obtained.
[1337] Primary fraction (34.3 mg, white amorphous solid, retention
time 6.17 minutes (LC/MS), diastereomer a: Example 24 (A)-a)
[1338] Secondary fraction (40.5 mg, white amorphous solid,
retention time 6.08 minutes (LC/MS), diastereomer b: Example 24
(A)-b)
Example 25
Synthesis of
4-(((1R)-1-(4-(1-oxo-1,2-thiazolidin-3-on-5-yl)phenoxy)-2,3-dihydro-1H-in-
den-4-yl)oxy)benzonitrile (A)
<Step 1> Synthesis of
2-(((S)-4-bromo-2,3-dihydro-1H-inden-1-yl)oxy)tetrahydro-2H-pyran
[1339] In methylene chloride (16.2 mL), 3,4-dihydro-2H-pyran (10.6
mL) was dissolved. To the solution, a solution of 4M hydrogen
chloride in 1,4-dioxane (31.1 .mu.L) was added and
(1S)-4-bromo-2,3-dihydro-1H-inden-1-ol (10.0 g) that was
commercially available or could be obtained by a known method was
added. The resultant reaction mixture was stirred at room
temperature for 3 hours. To the reaction mixture, a saturated
aqueous sodium hydrogen carbonate solution (60 mL) was added and
extracted with methylene chloride (60 mL). The organic phase was
washed with brine (60 mL) and dried over anhydrous sodium sulfate.
From the organic phase, the solvent was distilled off under reduced
pressure and the resultant residue was purified by silica gel
column chromatography (eluent; n-hexane:ethyl acetate=95:5). From
the eluted solution, the solvent was distilled off under reduced
pressure to give the title compound (15 g).
<Step 2> Synthesis of 5,5-dimethyl-2-((1
S)-1-((tetrahydro-2H-pyran-2-yl)oxy-2,3-dihydro-1H-inden-4-yl)-1,3,2-diox-
aborinane
[1340] To a solution of the compound (14.0 g) obtained in (Example
25) <Step 1> in 1,4-dioxane (213 mL),
5,5',5,5'-tetramethyl-2,2'-di(1,3,2-dioxaborinane) (17.3 g),
potassium acetate (18.8 g), and a
1,1'-bis(diphenylphosphino)ferrocene--palladium(II)
dichloride--dichloromethane complex (2.61 g) were sequentially
added and the resultant reaction mixture was heated and refluxed
for 3 hours. To the reaction mixture, water (300 mL) was added and
the mixture was filtered with Celite while washing the mixture with
ethyl acetate (250 mL). To the filtrate, brine (200 mL) was added
and the mixture was extracted with ethyl acetate (200 mL). The
organic phase was dried over anhydrous sodium sulfate. From the
organic phase, the solvent was distilled off under reduced pressure
and the resultant residue was purified by silica gel column
chromatography (eluent; n-hexane:ethyl acetate=70:30). From the
eluted solution, the solvent was distilled off under reduced
pressure to give the title compound (15.3 g) as an orange oil.
<Step 3> Synthesis of
((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy-2,3-dihydro-1H-inden-4-yl)boronic
acid
[1341] To a solution of the compound (8.20 g) obtained in (Example
25) <Step 2> in ethyl acetate (370 mL), water (1.10 L) was
added and the resultant reaction mixture was stirred at room
temperature for 16 hours. Liquid separation of the reaction mixture
was conducted and the organic phase was washed with brine (200 mL)
and dried over anhydrous sodium sulfate. From the organic phase,
the solvent was distilled off under reduced pressure and the
resultant residue was purified by silica gel column chromatography
(eluent; n-hexane:ethyl acetate=90:10 to 50:50). From the eluted
solution, the solvent was distilled off under reduced pressure to
give the title compound (3.00 g) as a yellowish white solid.
<Step 4> Synthesis of 4-(((1
S)-1-((tetrahydro-2H-pyran-2-yl)oxy)-2,3-dihydro-1H-inden-4-yl)oxy)benzon-
itrile
[1342] To a solution of the compound (0.50 g) obtained in (Example
25) <Step 3> in methylene chloride (16 mL),
4-hydroxybenzonitrile (0.19 g), copper(II) acetate (0.32 g), and
triethylamine (1.16 mL) were added and the resultant reaction
mixture was stirred in an oxygen atmosphere at room temperature for
3 days. The reaction mixture was filtered with Celite. From the
filtrate, the solvent was distilled off under reduced pressure and
the resultant residue was purified by silica gel column
chromatography. From the eluted solution, the solvent was distilled
off under reduced pressure to give the title compound (0.42 g) as a
colorless oil.
<Step 5> Synthesis of
(S)-4-((1-hydroxy-2,3-dihydro-1H-inden-4-yl)oxy)benzonitrile
[1343] The compound (0.40 g) obtained in (Example 25) <Step
4> was dissolved in a 1:1 mixed solvent (8.0 mL) of methanol and
tetrahydrofuran. To the solution, 1M hydrochloric acid (4.0 mL) was
added and the resultant reaction mixture was stirred at room
temperature for 18 hours. From the reaction mixture, the solvent
was distilled off under reduced pressure. To the residue, a 1M
sodium hydroxide aqueous solution was added to make the mixture
basic. The mixture was extracted with ethyl acetate. The organic
phase was washed with brine and then dried over anhydrous sodium
sulfate. From the organic phase, the solvent was distilled off
under reduced pressure to give the title compound (0.29 g) as a
colorless oil.
<Step 6> Synthesis of
(R)-4-((4-(4-cyanophenoxy)-2,3-dihydro-1H-inden-1-yl)oxy)phenylboronic
acid N-methyliminodiacetic acid ester
[1344] In accordance with the method in (Example 1) <Step 3>,
a mixture (330 mg) containing the title compound was obtained as a
white solid from the compound (0.3 g) obtained in (Example 25)
<Step 5>.
<Step 7> Synthesis of
4-(((1R)-1-(4-(3-hydroxy-1-oxidoisothiazol-5-yl)phenoxy)-2,3-dihydro-1H-i-
nden-4-yl)oxy)benzonitrile (A)
[1345] In accordance with the method in (Example 1) <Step 6>,
the title compound (92 mg) was obtained as a pale yellow solid from
the compound (0.2 g) obtained in (Example 25) <Step 6>.
<Step 8> Synthesis of
4-(((1R)-1-(4-(1-oxo-1,2-thiazolidin-3-on-5-yl)phenoxy)-2,3-dihydro-1H-in-
den-4-yl)oxy)benzonitrile (A)
[1346] In accordance with the method in (Example 7) <Step 2>,
the title compound was obtained from the compound (130 mg) obtained
in (Example 25) <Step 7> and then each diastereomer of the
title compound was obtained.
[1347] Primary fraction (25.3 mg, white solid, retention time 5.65
minutes (LC/MS), diastereomer a: Example 25 (A)-a)
[1348] Secondary fraction (31.4 mg, white solid, retention time
5.60 minutes (LC/MS), diastereomer b: Example 25 (A)-b)
Example 26
Synthesis of
4-(((1R)-1-(4-(1,1-dioxo-1,2,6-thiadiazinan-3-on-5-yl)phenoxy)-2,3-dihydr-
o-1H-inden-4-yl)oxy)benzonitrile
<Step 1> Synthesis of ethyl
3-(4-hydroxyphenyl)-3-(2,2,2-trifluoroacetamide) propionate
[1349] To a solution of ethyl 3-amino-3-(4-hydroxyphenyl)propionate
(1.0 g) that was commercially available or could be obtained by a
known method in methylene chloride (0.41 mL), trifluoroacetic
anhydride (0.70 mL) was added under 10.degree. C. and the resultant
reaction mixture was stirred at room temperature for 5 hours. To
the reaction mixture, pyridine (0.41 mL) was added at 10.degree. C.
or lower and the resultant reaction mixture was stirred at room
temperature for 1 hour. To the reaction mixture, trifluoroacetic
anhydride (0.70 mL) and pyridine (0.41 mL) were further added and
the resultant reaction mixture was stirred at room temperature for
15 hours. From the reaction mixture, the solvent was distilled off
under reduced pressure. The residue was diluted with ethyl acetate
(50 mL), then successively washed with 0.5M hydrochloric acid (50
ml) and water (50 mL), and dried over anhydrous sodium sulfate.
From the organic phase, the solvent was distilled off under reduced
pressure and the resultant residue was washed with hexane to give
the title compound (900 mg) as a yellow solid.
<Step 2> Synthesis of ethyl
3-(4-(((R)-4-(4-cyanophenoxy)-2,3-dihydro-1H-inden-1-yl)oxy)phenyl)-3-(2,-
2,2-trifluoroacetamide)propionate
[1350] In accordance with the method in (Example 23) <Step
3>, the title compound (680 mg) was obtained as a yellow oil
using the compound (0.40 g) obtained in (Example 26) <Step 1>
and the compound (0.33 g) obtained in (Example 25) <Step
5>.
<Step 3> Synthesis of ethyl
3-amino-3-(4-(((R)-4-(4-cyanophenoxy)-2,3-dihydro-1H-inden-1-yl)oxy)pheny-
l)propionate
[1351] The compound (0.45 g) obtained in (Example 26) <Step
2> was dissolved in ethanol (10 mL). To the solution, sodium
borohydride (63.2 mg) was added and the resultant reaction mixture
was stirred at room temperature for 16 hours. The reaction mixture
was diluted with water (50 mL) and extracted with ethyl acetate (50
mL). The obtained organic phase was dried over anhydrous sodium
sulfate. From the organic phase, the solvent was distilled off
under reduced pressure and the resultant residue was purified by
silica gel column chromatography (eluent; n-hexane:ethyl
acetate=0:100). From the eluted solution, the solvent was distilled
off under reduced pressure to give a mixture (290 mg) containing
the title compound as a colorless solid.
<Step 4> Synthesis of ethyl
3-(4-(((R)-4-(4-cyanophenoxy)-2,3-dihydro-1H-inden-1-yl)oxy)phenyl)-3-(su-
lfamoylamino)propionate
[1352] To a solution of chlorosulfonyl isocyanate in
tetrahydrofuran, aqueous tetrahydrofuran was added at 10.degree. C.
or lower. The reaction mixture was stirred at room temperature for
30 minutes to prepare a solution of sulfamoyl chloride in
tetrahydrofuran. A solution of the compound obtained in (Example
26) <Step 3> in tetrahydrofuran was prepared in another
container. To the container, pyridine (0.10 ml) was added and the
solution of sulfamoyl chloride in tetrahydrofuran was added
dropwise under 10.degree. C. The resultant reaction mixture was
stirred at room temperature for 19 hours. To the reaction mixture,
water (30 mL) was added. The mixture was extracted with ethyl
acetate (20 mL) twice. The obtained organic phase was washed with
water (20 mL) and dried over anhydrous sodium sulfate. From the
organic phase, the solvent was distilled off under reduced pressure
and the resultant residue was purified by silica gel column
chromatography. From the eluted solution, the solvent was distilled
off under reduced pressure to give the title compound.
<Step 5> Synthesis of
4-(((1R)-1-(4-(1,1-dioxo-1,2,6-thiadiazinan-3-on-5-yl)phenoxy)-2,3-dihydr-
o-1H-inden-4-yl)oxy)benzonitrile
[1353] The compound (15 mg) obtained in (Example 26) <Step 4>
was dissolved in ethanol (1.5 mL) and a 1M sodium hydroxide aqueous
solution (0.15 mL) was added to the solution. The resultant
reaction mixture was stirred at room temperature for 2 hours. To
the reaction mixture, a saturated aqueous ammonium chloride
solution (1 mL) and water (1 mL) were added. The mixture was
extracted with ethyl acetate (10 mL) and the organic phase was
dried over anhydrous sodium sulfate. From the organic phase, the
solvent was distilled off under reduced pressure and the resultant
residue was purified by silica gel column chromatography (eluent;
n-hexane:ethyl acetate=0:100). From the eluted solution, the
solvent was distilled off under reduced pressure to give the title
compound (7.5 mg) as a colorless amorphous solid.
[1354] Each compound of (Example 27) to (Example 28) below was
synthesized by the same method or a similar method in (Example 1)
or (Example 26).
Example 27
5-(4-(((R)-4-phenoxy-2,3-dihydro-1H-inden-1-yl)oxy)phenyl)-1-oxo-1,2-thiaz-
olidin-3-one
Example 28
5-(4-((7-(trifluoromethyl)-2,3-dihydrobenzofuran-3-yl)oxy)phenyl)-1-oxo-1,-
2-thiazolidin-3-one
Example 29
Synthesis of
5-(4-(((R)-4-bromo-2,3-dihydro-1H-inden-1-yl)oxy)phenyl)-1-oxo-1,2-thiazo-
lidin-3-one (A)
[1355] To a solution of 1N L-Selectride in tetrahydrofuran (14.8
mL), tetrabutylammonium chloride (4.1 g) was added under
ice-cooling and a solution of the compound (1 g) obtained in
(Example 23) <Step 4> in anhydrous THE (5 mL) was added
dropwise under 3.degree. C. The reaction mixture was allowed to
reach room temperature and stirred for 2 days. To the reaction
mixture, 1M hydrochloric acid was added. The mixture was extracted
with ethyl acetate. The organic phase was washed with brine and
then dried over anhydrous sodium sulfate. From the organic phase,
the solvent was distilled off under reduced pressure and the
resultant residue was purified by silica gel column chromatography
(eluent; n-hexane:ethyl acetate) to give the title compound (0.44
g) as a yellow solid. The reduced title compound in this step is a
mixture of diastereomers because the compound has a new asymmetric
center (carbon atom).
Example 30
Synthesis of 5-(4-(((R)-4-(2,6-dimethyl
4-(3-(methylsulfonyl)propoxy)phenyl)-2,3-dihydro-1H-inden-1-yl)oxy)phenyl-
)-1-oxo-1,2-thiazolidin-3-one (A)
<Step 1> Synthesis of
2-bromo-1,3-dimethyl-5-(3-(methylsulfonyl)propoxy)benzene
[1356] In accordance with the method in (Example 23) <Step
1>, the title compound (289 g) was obtained as a white solid
from 4-bromo-3,5-dimethylphenol (217 g) and
3-(methylsulfonyl)propyl 4-methylbenzenesulfonate (300 g).
<Step 2> Synthesis of
2-(2,6-dimethyl-4-(3-(methylsulfonyl)propoxy)phenyl)-5,5-dimethyl-1,3,2-d-
ioxaborinane
[1357] In accordance with the method in (Example 23) <Step
2>, the title compound (0.70 g) was obtained as a beige solid
from the compound (1.0 g) obtained in (Example 30) <Step
1>.
<Step 3> Synthesis of 5-(4-(((R)-4-(2,6-dimethyl
4-(3-(methylsulfonyl)propoxy)phenyl)-2,3-dihydro-1H-inden-1-yl)oxy)phenyl-
)-1-oxo-1,2-thiazolidin-3-one
[1358] To a solution of the compound (0.10 g) in (Example 29), the
compound (0.13 g) obtained in (Example 30) <Step 2>,
potassium carbonate (34 mg),
2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (XPhos: 23
mg), and bis(dibenzylideneacetone)palladium (14 mg) in 1,4-dioxane
(4 mL), water (2 mL) was added. The inside of the reaction system
was purged with nitrogen and the resultant reaction mixture was
heated and refluxed for 2 hours. To the reaction mixture, a
saturated aqueous ammonium chloride solution was added. The mixture
was extracted with ethyl acetate. The organic phase was washed with
brine and then dried over anhydrous sodium sulfate. From the
organic phase, the solvent was distilled off under reduced pressure
and the resultant residue was purified by silica gel column
chromatography (eluent; n-hexane:ethyl acetate) to give the title
compound (55 mg) as a pale yellow solid. The title compound is a
mixture of diastereomers because it has the asymmetric center as
with the compound in Example 29.
Example 31
Synthesis of 5-[4-[[3-[2,6-dimethyl
4-(3-methylsulfonylpropoxyl)phenyl]phenyl]methoxy]phenyl]-1,1-dioxo-1,2-t-
hiazinan-3-one
<Step 1> Synthesis of
N,N-bis((2-(trimethylsilyl)ethoxy)methyl)methanesulfonamide
[1359] Sodium hydride (4.6 g) was added to DMF (35 ml). To the
solution, a solution of methanesulfonamide (5.0 g) in DMF (15 ml)
was added dropwise. (2-(chlorotrimethoxy)ethyl)trimethylsilane
(18.6 ml) was added to the solution and the resultant reaction
mixture was stirred at room temperature for 2 hours. The reaction
mixture was poured into ice water and extracted with ethyl acetate.
The organic phase was washed with brine and then dried over
anhydrous sodium sulfate. From the organic phase, the solvent was
distilled off under reduced pressure and the resultant residue was
purified by silica gel column chromatography (eluent;
n-hexane:ethyl acetate) to give the title compound (7.4 g) as a
colorless oil.
<Step 2> Synthesis of
4-((2',6'-dimethyl-4'-(3-(methylsulfonyl)propoxy)-[1,1,1'-biphenyl]-3-yl)-
methoxy)benzaldehyde
[1360] To a solution of the compound (3.0 g) in (Reference Example
2) in DMF (40 ml), potassium carbonate (1.2 g) and
4-hydroxybenzaldehyde (0.94 g) were added at room temperature. The
inside of the reaction system was purged with nitrogen and the
mixture was heated and stirred at 80.degree. C. for 2 hours. After
the reaction mixture was allowed to cool to room temperature, water
was added to the reaction mixture. The mixture was extracted with
ethyl acetate. The organic phase was washed with brine and then
dried over anhydrous sodium sulfate. From the organic phase, the
solvent was distilled off under reduced pressure to give the title
compound (3.3 g) as a pale yellow oil.
<Step 3> Synthesis of
(E)-2-(4-((2',6'-dimethyl-4'-(3-(methylsulfonyl)propoxy)-[1,1'-biphenyl]--
3-yl)methoxy)phenyl)-N,N-bis((2-(trimethylsilyl)ethoxy)methyl)ethenesulfon-
amide
[1361] A solution of the compound (2.4 g) in (Example 31) <Step
1> in THF (7 ml) was cooled in an acetonitrile--dry ice bath. To
the solution, a solution of 1M lithium hexamethyldisilazane in THF
(14.6 ml) was added dropwise and the resultant reaction mixture was
stirred at the same temperature for 50 minutes. Next, diethyl
chlorophosphonate (1.1 ml) was added dropwise and the resultant
reaction mixture was further stirred for 90 minutes. Then, a
solution of the compound (3.0 g) in (Example 31) <Step 2> in
THF (10 ml) was added dropwise. The resultant reaction mixture was
stirred at the same temperature for 30 minutes, next stirred under
ice-cooling for 1 hour, then allowed to reach room temperature, and
stirred for 1 hour. To the reaction mixture, 1M hydrochloric acid
was added. The mixture was extracted with ethyl acetate. The
organic phase was washed with saturated aqueous sodium hydrogen
carbonate, then washed with a half saturated salt solution, and
dried over anhydrous sodium sulfate. From the organic phase, the
solvent was distilled off under reduced pressure and the resultant
residue was purified by silica gel column chromatography (eluent;
n-hexane:ethyl acetate) to give the title compound (6.0 g) as a
pale yellow oil.
<Step 4> Synthesis of dimethyl
2-(2-(N,N-bis(2-(trimethylsilyl)ethoxymethyl)sulfamoyl)-1-(4-((2',6'-dime-
thyl-4'-(3-(methylsulfonyl)propoxy)-[1,1'-biphenyl]-3-yl)methoxy)phenyl)et-
hyl)malonate
[1362] To a solution of dimethyl malonate (1.5 ml) in THF (10 ml),
a solution of 28% sodium methoxide in methanol (2.6 g) was added at
room temperature. The mixture was stirred for 10 minutes. To the
reaction mixture, a solution of the compound (3.5 g) in (Example
31) <Step 3> in THF (30 ml) was added and the resultant
reaction mixture was heated and refluxed for 65 hours. To the
reaction mixture, a saturated aqueous ammonium chloride solution
was added. The mixture was extracted with ethyl acetate. The
organic phase was washed with saturated aqueous sodium hydrogen
carbonate, then washed with brine, and dried over anhydrous sodium
sulfate. From the organic phase, the solvent was distilled off
under reduced pressure and the resultant residue was purified by
silica gel column chromatography (eluent; n-hexane:ethyl acetate)
to give the title compound (3.5 g) as a colorless oil.
<Step 5> Synthesis of methyl
4-(N,N-bis(2-(trimethylsilyl)-ethoxymethyl)sulfamoyl)-3-(4-((2',6'-dimeth-
yl-4'-(3-(methylsulfonyl)propoxy)-[1,1'-biphenyl]-3-yl)methoxy)phenyl)buta-
noate
[1363] To a solution of the compound (3.5 g) in (Example 31)
<Step 4> in DMF (35 ml), sodium chloride (0.22 g) and water
(0.14 ml) were added and the resultant reaction mixture was heated
and refluxed for 17 hours. To the reaction mixture, water was added
and the mixture was extracted with ethyl acetate. The organic phase
was washed with water, then washed with brine, and dried over
anhydrous sodium sulfate. From the organic phase, the solvent was
distilled off under reduced pressure to give the title compound
(3.0 g) as a colorless oil.
<Step 6> Synthesis of methyl
3-(4-((2',6'-dimethyl-4'-(3-(methylsulfonyl)propoxy)-[1,1'-biphenyl]-3-yl-
)methoxy)phenyl)-4-sulfamoylbutanoate
[1364] To a solution of the compound (1.5 g) in (Example 31)
<Step 5> in acetic acid (15 ml), water (7.5 ml) was added and
the resultant reaction mixture was heated and stirred at 80.degree.
C. for 3 hours. To the reaction mixture, water was added and the
mixture was extracted with ethyl acetate. The organic phase was
washed with water, then washed with brine, and dried over anhydrous
sodium sulfate. From the organic phase, the solvent was distilled
off under reduced pressure and the resultant residue was purified
by silica gel column chromatography (eluent; n-hexane:ethyl
acetate) to give the title compound (0.34 g) as a colorless
oil.
<Step 7> Synthesis of
5-[4-[[3-[2,6-dimethyl-4-(3-methylsulfonylpropoxyl)phenyl]phenyl]methoxy]-
phenyl]-1,1-dioxo-1,2-thiazinan-3-one
[1365] To a solution of the compound (20 mg) in (Example 31)
<Step 6> in methanol (0.40 ml), a solution of 28% sodium
methoxide in methanol (8.3 mg) was added at room temperature and
the resultant reaction mixture was stirred for 1 hour. To the
reaction mixture, 1M hydrochloric acid was added and the mixture
was extracted with ethyl acetate. The organic phase was washed with
saturated aqueous sodium hydrogen carbonate, then washed with
brine, and dried over anhydrous sodium sulfate. From the organic
phase, the solvent was distilled off under reduced pressure to give
the title compound (15 mg) as a colorless solid.
Example 32
Synthesis of
4-(((1R)-1-(4-(1,1-dioxo-3-oxo-1,2-thiazinan-5-yl)phenoxy)-2,3-dihydro-1H-
-inden-4-yl)oxy)benzonitrile
<Step 1> Synthesis of
(E)-2-(4-(benzyloxy)phenyl)-N,N-bis((2-(trimethylsilyl)ethoxy)methyl)ethe-
nesulfonamide
[1366] In accordance with the method in (Example 31) <Step
3>, the title compound (6.1 g) was obtained as a colorless solid
from the compound (7.5 g) obtained in (Example 31) <Step 1>
and 4-benzyloxybenzaldehyde (4.5 g).
<Step 2> Synthesis of dimethyl
2-(1-(4-(benzyloxy)phenyl)-2-(N,N-bis(2-(trimethylsilyl)-ethoxymethyl)sul-
famoyl)ethyl) malonate
[1367] In accordance with the method in (Example 31) <Step
4>, the title compound (2.5 g) was obtained as a colorless oil
from the compound (3.0 g) obtained in (Example 32) <Step
1>.
<Step 3> Synthesis of methyl
3-(4-(benzyloxy)phenyl)-4-(N,N-bis(2-(trimethylsilyl)-ethoxymethyl)sulfam-
oyl)butanoate
[1368] In accordance with the method in (Example 31) <Step
5>, the title compound (1.3 g) was obtained as a colorless oil
from the compound (2.4 g) obtained in (Example 32) <Step
2>.
<Step 4> Synthesis of methyl
4-(N,N-bis(2-(trimethylsilyl)-ethoxymethyl)sulfamoyl)-3-(4-hydroxyphenyl)-
butanoate
[1369] To a solution of the compound (20 mg) in (Example 32)
<Step 3> in methanol (1.0 ml), 10% palladium--carbon (2.0 mg)
was added and the resultant reaction mixture was stirred in a
hydrogen atmosphere for 16 hours. The inside of the reaction system
was purged with nitrogen. Then, the reaction mixture was filtered
with Celite. From the filtrate, the solvent was distilled off under
reduced pressure to give the title compound (17 mg).
<Step 5> Synthesis of methyl
4-(N,N-bis(2-(trimethylsilyl)-ethoxymethyl)sulfamoyl)-3-(4-(((R)-4-(4-cya-
nophenoxy)-2,3-dihydro-1H-inden-1-yl)oxy)phenyl)butanoate
[1370] A mixture of the compound (0.23 g) in (Example 25) <Step
5>, the compound (0.48 g) in (Example 32) <Step 4>,
molecular sieves 3A (0.50 g), and toluene (9.0 ml) was heated and
refluxed. To the mixture, cyanomethylenetributylphosphorane (1.2
ml) was added dropwise and the resultant reaction mixture was
heated and refluxed for 2.5 hours. After the reaction mixture was
allowed to cool to room temperature, the solvent was distilled off
under reduced pressure and the resultant residue was purified by
silica gel column chromatography (eluent; n-hexane:ethyl acetate)
to give the title compound (0.25 g) as a pale yellow viscous
oil.
<Step 6> Synthesis of
4-(((1R)-1-(4-(1,1-dioxo-3-oxo-1,2-thiazinan-5-yl)phenoxy)-2,3-dihydro-1H-
-inden-4-yl)oxy)benzonitrile
[1371] To a solution of the compound (30 mg) in (Example 32)
<Step 5> in THF (0.6 ml), a solution of 1M tetrabutylammonium
fluoride in THF (0.15 ml) was added at room temperature. The
resultant reaction mixture was stirred at room temperature for 30
minutes, then heated and refluxed for 1 hour, and stirred at room
temperature for 16 hours. The reaction mixture was filtered and
washed with ethyl acetate. To the obtained organic phase, 1M
hydrochloric acid was added and the mixture was extracted with
ethyl acetate. The organic phase was washed with water, then washed
with brine, and dried over anhydrous sodium sulfate. From the
organic phase, the solvent was distilled off under reduced pressure
and the resultant residue was purified by silica gel column
chromatography (eluent; methylene chloride:methanol) to give the
title compound (3.2 mg) as a pale brown solid.
Example 33
Synthesis of
5-(4-(((R)-4-bromo-2,3-dihydro-1H-inden-1-yl)oxy)phenyl)-1,1-dioxo-1,2-th-
iazinan-3-one
<Step 1> Synthesis of
(R)-4-((4-bromo-2,3-dihydro-1H-inden-1-yl)oxy)benzaldehyde
[1372] In accordance with the method in (Example 1) <Step 3>,
the title compound (5.5 g) was obtained as a colorless solid from
(S)-4-bromo-2,3-dihydro-1H-inden-1-ol (6.0 g) and
4-hydroxybenzaldehyde (3.5 g).
<Step 2> Synthesis of
(R,E)-2-(4-((4-bromo-2,3-dihydro-1H-inden-1-yl)oxy)phenyl)-N,N-bis((2-(tr-
imethylsilyl)ethoxy)methyl)ethenesulfonamide
[1373] In accordance with the method in (Example 31) <Step
3>, the title compound (8.2 g) was obtained as a yellow oil from
the compound (6.0 g) obtained in (Example 31) <Step 1> and
the compound (5.4 g) obtained in (Example 33) <Step 1>.
<Step 3> Dimethyl
2-(2-(N,N-bis(2-(trimethylsilyl)ethoxymethyl)sulfamoyl)-1-(4-(((R)-4-brom-
o-2,3-dihydro-1H-inden-1-yl)oxy)phenyl)ethyl)malonate
[1374] In accordance with the method in (Example 31) <Step
4>, the title compound (9.6 g) was obtained as a yellow oil from
the compound (8.2 g) obtained in (Example 33) <Step 2>.
<Step 4> Synthesis of methyl
4-(N,N-bis(2-(trimethylsilyl)ethoxymethyl)sulfamoyl)-3-(4-(((R)-4-bromo-2-
,3-dihydro-1H-inden-1-yl)oxy)phenyl)butanoate
[1375] In accordance with the method in (Example 31) <Step
5>, the title compound (5.9 g) was obtained as a colorless oil
from the compound (9.6 g) obtained in (Example 33) <Step
3>.
<Step 5> Synthesis of
5-(4-(((R)-4-bromo-2,3-dihydro-1H-inden-1-yl)oxy)phenyl)-1,1-dioxo-1,2-th-
iazinan-3-one
[1376] In accordance with the method in (Example 32) <Step
6>, the title compound (5.1 mg) was obtained as a pale brown
solid from the compound (30 mg) obtained in (Example 33) <Step
4>.
Example 34
Synthesis of
5-(4-(((R)-4-(4-(3-hydroxy-3-methylbutoxy)-2,6-dimethylphenyl)-2,3-dihydr-
o-1H-inden-1-yl)oxy)phenyl)-1,1-dioxo-1,2-thiazinan-3-one
[1377] In accordance with the method in (Example 30) <Step
3>, the title compound (6.0 mg) was obtained as a white solid
from the compound (17 mg) obtained in (Example 33) and the compound
(16 mg) obtained in (Example 24) <Step 2>.
Example 35
Synthesis of
5-[4-[[3-[6-(3-hydroxy-3-methylbutoxy)-2,4-dimethylpyridin-3-yl]phenyl]me-
thoxy]phenyl]-1,1-dioxo-1,2-thiazinan-3-one
<Step 1> Synthesis of
(E)-2-(4-((3-bromobenzyl)oxy)phenyl)-N,N-bis((2-(trimethylsilyl)ethoxy)me-
thyl)ethenesulfonamide
[1378] In accordance with the method in (Example 31) <Step
3>, the title compound (18 g) was obtained as a white solid from
4-[(3-bromobenzyl)oxy]benzaldehyde (11 g) and the compound (13.4 g)
obtained in (Example 31) <Step 1>.
<Step 2> Synthesis of dimethyl
2-(2-(N,N-bis((2-(trimethylsilyl)ethoxymethyl)sulfamoyl)-1-(4-((3-bromobe-
nzyl)oxy)phenyl)ethyl)malonate
[1379] In accordance with the method in (Example 31) <Step
4>, the title compound (23 g) was obtained as a colorless oil
from the compound (18 g) obtained in (Example 35)<Step
1>.
<Step 3> Synthesis of methyl
4-(N,N-bis(2-(trimethylsilyl)ethoxymethyl)sulfamoyl)-3-(4-((3-bromobenzyl-
)oxy)phenyl)butanoate
[1380] In accordance with the method in (Example 31) <Step
5>, the title compound (21 g) was obtained as a colorless oil
from the compound (23 g) obtained in (Example 35)<Step
2>.
<Step 4> Synthesis of methyl
3-(4-((3-bromobenzyl)oxy)phenyl)-4-sulfamoylbutanoate
[1381] In accordance with the method in (Example 31) <Step
6>, the title compound (0.32 g) was obtained as a colorless oil
from the compound (1.0 g) obtained in (Example 35) <Step
3>.
<Step 5> Synthesis of
5-(4-((3-bromobenzyl)oxy)phenyl)-1,2-thiazinan-3-one
1,1-dioxide
[1382] In accordance with the method in (Example 31) <Step
7>, the title compound (0.12 g) was obtained as a white solid
from the compound (0.16 g) obtained in (Example 35) <Step
4>.
<Step 6> Synthesis of
5-[4-[[3-[6-(3-hydroxy-3-methylbutoxy)-2,4-dimethylpyridin-3-yl]phenyl]me-
thoxy]phen yl]-1,1-dioxo-1,2-thiazinan-3-one
[1383] In accordance with the method in (Example 30) <Step
3>, the title compound (29 mg) was obtained as a white solid
from the compound (0.10 g) obtained in (Example 35) <Step 5>
and
4-((5-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-4,6-dimethylpyridin-2-yl)oxy-
)-2-methylbut an-2-ol (86 mg) synthesized by a similar method of
(Example 23) <Step 2>.
Example 36
Synthesis of
5-(4-(((R)-4-(6-(3-hydroxy-3-methylbutoxy)-2-methylpyridin-3-yl)-2,3-dihy-
dro-1H-inden-1-yl)oxy)phenyl)-1,2-thiazinan-3-one 1,1-dioxide
[1384] In accordance with the method in (Example 23) <Step
5>, the title compound (5.0 mg) was obtained as a white solid
from the compound (40 mg) obtained in (Example 33) and the compound
(31 mg) obtained in (Example 23) <Step 2>.
Example 37
Synthesis of
5-(4-(((R)-4-(2,6-dimethylphenyl)-2,3-dihydro-1H-inden-1-yl)oxy)phenyl)-1-
,2-thiazinan-3-one 1,1-dioxide
<Step 1> Synthesis of methyl
3-(4-(((R)-4-(2,6-dimethylphenyl)-2,3-dihydro-1H-inden-1-yl)oxy)phenyl)-4-
-(N,N-bis(2-(trimethylsilyl)ethoxymethylsulfamoyl)butanoate
[1385] In accordance with the method in (Example 23) <Step
5>, the title compound (100 mg) was obtained as a colorless
amorphous from the compound (40 mg) obtained in (Example 33)
<Step 4> and (2,6-dimethylphenyl)boronic acid (28 mg).
<Step 2> Synthesis of
3-(4-(((R)-4-(2,6-dimethylphenyl)-2,3-dihydro-1H-inden-1-yl)oxy)phenyl)-4-
-(N,N-bis(2-(trimethylsilyl)ethoxymethyl)sulfamoyl)butanoic
acid
[1386] To a mixed solution of the compound (70 mg) obtained in
(Example 37) <Step 1> in methanol (1.0 mL) and
tetrahydrofuran (1.0 mL), a 1M sodium hydroxide aqueous solution
(0.14 mL) was added and the resultant reaction mixture was stirred
at 65.degree. C. for 1 hour. To the reaction mixture, 1M
hydrochloric acid was added and the resultant reaction mixture was
extracted with ethyl acetate. The organic phase was washed with
water and brine and then dried over anhydrous sodium sulfate. From
the organic phase, the solvent was distilled off under reduced
pressure to give the title compound (58 mg) as a pale yellow
amorphous.
<Step 3> Synthesis of
3-(4-(((R)-4-(2,6-dimethylphenyl)-2,3-dihydro-1H-inden-1-yl)oxy)phenyl)-4-
-sulfamoyl butanoic acid
[1387] In accordance with the method in (Example 32) <Step
6>, the title compound (23 mg) was obtained as a pale yellow
amorphous from the compound (50 mg) obtained in (Example 37)
<Step 2>.
<Step 4> Synthesis of
5-(4-(((R)-4-(2,6-dimethylphenyl)-2,3-dihydro-1H-inden-1-yl)oxy)phenyl)-1-
,2-thiazinan-3-one 1,1-dioxide
[1388] In accordance with the method in (Example 14) <Step
6>, the title compound (11 mg) was obtained as a colorless
amorphous from the compound (20 mg) obtained in (Example 37)
<Step 3>.
Example 38
Synthesis of
5-(4-(((R)-4-(2-(trifluoromethyl)phenyl)-2,3-dihydro-1H-inden-1-yl)oxy)ph-
enyl)-1,2-thiazinan-3-one 1,1-dioxide
<Step 1> Synthesis of methyl
4-(N,N-bis(2-(trimethylsilyl)ethoxymethyl)sulfamoyl)-(3-(4-(((R)-4-(2-(tr-
ifluoromethyl)phenyl)-2,3-dihydro-1H-inden-1-yl)oxy)phenyl)butanoate
[1389] In accordance with the method in (Example 23) <Step
5>, the title compound (0.24 g) was obtained as a colorless oil
from the compound (0.30 g) obtained in (Example 33) <Step
4>.
<Step 2> Synthesis of
4-(N,N-bis(2-(trimethylsilyl)ethoxymethyl)sulfamoyl)-(3-(4-(((R)-4-(2-(tr-
ifluoromethyl)phenyl)-2,3-dihydro-1H-inden-1-yl)oxy)phenyl)butanoic
acid
[1390] In accordance with the method in (Example 37) <Step
2>, the title compound (0.19 g) was obtained as a colorless oil
from the compound (0.22 g) obtained in (Example 38) <Step
1>.
<Step 3> Synthesis of
4-sulfamoyl-3-(4-(((R)-4-(2-(trifluoromethyl)phenyl)-2,3-dihydro-1H-inden-
-1-yl)oxy)phenyl)butanoic acid
[1391] In accordance with the method in (Example 32) <Step
6>, the title compound (0.10 g) was obtained as a pale yellow
amorphous from the compound (0.19 g) obtained in (Example 38)
<Step 2>.
<Step 4> Synthesis of
5-(4-(((R)-4-(2-(trifluoromethyl)phenyl)-2,3-dihydro-1H-inden-1-yl)oxy)ph-
enyl)-1,2-thiazinan-3-one 1,1-dioxide
[1392] In accordance with the method in (Example 14) <Step
6>, the title compound (73 mg) was obtained as a colorless
amorphous from the compound (90 mg) obtained in (Example 38)
<Step 3>.
Example 39
Synthesis of
5-(4-(((R)-4-(4-(2-ethoxyethoxy)-2,6-dimethylphenyl)-2,3-dihydro-1H-inden-
-1-yl)oxy)phenyl)-1,2-thiazinan-3-one 1,1-dioxide
<Step 1> Synthesis of methyl
4-(N,N-bis(2-(trimethylsilyl)ethoxymethyl)sulfamoyl)-3-(4-(((R)-4-(4-(2-e-
thoxyethoxy)-2,6-dimethylphenyl)-2,3-dihydro-1H-inden-1-yl)oxy)phenyl)buta-
noate
[1393] In accordance with the method in (Example 23) <Step
5>, the title compound (0.28 g) was obtained as a colorless
amorphous from the compound (0.30 g) obtained in (Example 33)
<Step 4>.
<Step 2> Synthesis of
4-(N,N-bis(2-(trimethylsilyl)ethoxymethyl)sulfamoyl)-3-(4-(((R)-4-(4-(2-e-
thoxyethoxy)-2,6-dimethylphenyl)-2,3-dihydro-1H-inden-1-yl)oxy)phenyl)buta-
noic acid
[1394] In accordance with the method in (Example 37) <Step
2>, the title compound (0.25 g) was obtained as a brown
amorphous from the compound (0.25 g) obtained in (Example 39)
<Step 1>.
<Step 3> Synthesis of
3-(4-(((R)-4-(4-(2-ethoxyethoxy)-2,6-dimethylphenyl)-2,3-dihydro-1H-inden-
-1-yl)oxy)phenyl)-4-sulfamoyl butanoic acid
[1395] In accordance with the method in (Example 32) <Step
6>, the title compound (48 mg) was obtained as a pale brown
amorphous from the compound (0.22 g) obtained in (Example 39)
<Step 2>.
<Step 4> Synthesis of
5-(4-(((R)-4-(4-(2-ethoxyethoxy)-2,6-dimethylphenyl)-2,3-dihydro-1H-inden-
-1-yl)oxy)phenyl)-1,2-thiazinan-3-one 1,1-dioxide
[1396] In accordance with the method in (Example 14) <Step
6>, the title compound (36 mg) was obtained as a pale brown
amorphous from the compound (40 mg) obtained in (Example 39)
<Step 3>.
Example 40
5-(4-(((R)-4-(4-(3-hydroxy-3-methylbutoxy)-2,6-dimethylphenyl)-2,3-dihydro-
-1H-inden-1-yl)oxy)phenyl)-1,2-thiazinan-3-one 1,1-dioxide (C)
<Step 1> Optical resolution of methyl
3-(4-(((R)-4-bromo-2,3-dihydro-1H-inden-1-yl)oxy)phenyl)-4-(N,N-bis(2-(tr-
imethylsilyl) sulfamoyl)butanoate
[1397] Optical resolution of the compound obtained in (Example 33)
<Step 4> was performed by preparative chromatography (column:
CHIRALPAK AS-H (250 mm.times.4.6 mm) manufactured by Daicel
Chemical Industries, Ltd., eluent; carbon dioxide: 2-propanol
(containing 0.05% diethylamine)=95:5 to 60:40 (V/V), flow rate: 2.5
mL/minute, detection: UV 220 nm) to give each enantiomer of the
title compound.
[1398] Primary fraction (7.1 g, white solid, >99% ee, retention
time 5.2 minutes (enantiomer A: Example 1-5 (C)))
[1399] Secondary fraction (8.9 g, white solid, >98% ee,
retention time 5.6 minutes (enantiomer B: Example 1-5 (D)))
[1400] Hereinafter, the compounds and derivatives of them
synthesized using the enantiomer C (Example 40-1 (C)) obtained in
(Example 40) <Step 1> are expressed as "name of the
compound+(C)" and the compounds and derivatives of them synthesized
using the enantiomer D (Example 40-1 (D)) obtained in (Example 40)
<Step 1> are expressed as "name of the compound+(D)".
<Step 2> Synthesis of methyl
4-(N,N-bis(2-(trimethylsilyl)ethoxymethyl)sulfamoyl)-3-(4-(((R)-4-(4-(3-h-
ydroxy-3-methylbutoxy)-2,6-dimethylphenyl)-2,3-dihydro-1H-inden-1-yl)oxy)p-
henyl)butanoate (C)
[1401] In accordance with the method in (Example 23) <Step
5>, the title compound (1.6 g) was obtained as a colorless oil
from the enantiomer C (Example 40-1 (C)) (1.6 g) obtained in
(Example 40) <Step 1>.
<Step 3> Synthesis of
4-(N,N-bis(2-(trimethylsilyl)ethoxymethyl)sulfamoyl)-3-(4-(((R)-4-(4-(3-h-
ydroxy-3-methylbutoxy)-2,6-dimethylphenyl)-2,3-dihydro-1H-inden-1-yl)oxy)p-
henyl)butanoic acid (C)
[1402] In accordance with the method in (Example 37) <Step
2>, the title compound (1.4 g) was obtained as a pale yellow
amorphous from the compound (1.5 g) obtained in (Example 40)
<Step 2>.
<Step 4> Synthesis of
3-(4-(((R)-4-(4-(3-hydroxy-3-methylbutoxy)-2,6-dimethylphenyl)-2,3-dihydr-
o-1H-inden-1-yl)oxy)phenyl)-4-sulfamoyl butanoic acid (C)
[1403] In accordance with the method in (Example 32) <Step
6>, the title compound (0.4 g) was obtained as a colorless oil
from the compound (1.3 g) obtained in (Example 40) <Step
3>.
<Step 5> Synthesis of
5-(4-(((R)-4-(4-(3-hydroxy-3-methylbutoxy)-2,6-dimethylphenyl)-2,3-dihydr-
o-1H-inden-1-yl)oxy)phenyl)-1,2-thiazinan-3-one 1,1-dioxide (C)
[1404] In accordance with the method in (Example 14) <Step
6>, the title compound (0.18 g) was obtained as a colorless
amorphous from the compound (0.20 g) obtained in (Example 40)
<Step 4>.
Example 41
Synthesis of
5-(4-(((R)-4-(4-(3-hydroxy-3-methylbutoxy)-2,6-dimethylphenyl)-2,3-dihydr-
o-1H-inden-1-yl)oxy)phenyl)-1,2-thiazinan-3-one 1,1-dioxide (D)
<Step 1> Synthesis of methyl
4-(N,N-bis(2-(trimethylsilyl)ethoxymethyl)sulfamoyl)-(3-(4-(((R)-4-(4-(3--
hydroxy-3-methylbutoxy)-2,6-dimethylphenyl)-2,3-dihydro-1H-inden-1-yl)oxy)-
phenyl)butanoate (D)
[1405] In accordance with the method in (Example 23) <Step
5>, the title compound (1.6 g) was obtained as a colorless oil
from the enantiomer D (Example 40-1 (D)) (1.6 g) obtained in
(Example 40) <Step 1>.
<Step 2> Synthesis of
4-(N,N-bis(2-(trimethylsilyl)ethoxymethyl)sulfamoyl)-3-(4-(((R)-4-(4-(3-h-
ydroxy-3-methylbutoxy)-2,6-dimethylphenyl)-2,3-dihydro-1H-inden-1-yl)oxy)p-
henyl)butanoic acid (D)
[1406] In accordance with the method in (Example 37) <Step
2>, the title compound (1.7 g) was obtained as a colorless oil
from the compound (1.6 g) obtained in (Example 41) <Step
1>.
<Step 3> Synthesis of
3-(4-(((R)-4-(4-(3-hydroxy-3-methylbutoxy)-2,6-dimethylphenyl)-2,3-dihydr-
o-1H-inden-1-yl)oxy)phenyl)-4-sulfamoyl butanoic acid (D)
[1407] In accordance with the method in (Example 32) <Step
6>, the title compound (0.52 g) was obtained as a white solid
from the compound (1.7 g) obtained in (Example 41) <Step
2>.
<Step 4> Synthesis of
5-(4-(((R)-4-(4-(3-hydroxy-3-methylbutoxy)-2,6-dimethylphenyl)-2,3-dihydr-
o-1H-inden-1-yl)oxy)phenyl)-1,2-thiazinan-3-one 1,1-dioxide (D)
[1408] In accordance with the method in (Example 14) <Step
6>, the title compound (22 mg) was obtained as a white solid
from the compound (0.39 g) obtained in (Example 41) <Step
3>.
[1409] The compounds of Example 42 to Example 46 below were
synthesized by the same method as or a similar method to the method
in Example 41 by performing Step 1 to Step 4 using the compound of
the enantiomer C (Example 40-1 (C)) obtained in (Example 40)
<Step 1> and a corresponding substituted boronic acid ester
or boronic acid.
Example 42
5-(4-(((R)-4-(4-(2-ethoxyethoxy)-2,6-dimethylphenyl)-2,3-dihydro-1H-inden--
1-yl)oxy)phenyl)-1,2-thiazinan-3-one 1,1-dioxide (C)
Example 43
5-(4-(((R)-4-(2,6-dimethylphenyl)-2,3-dihydro-1H-inden-1-yl)oxy)phenyl)-1,-
2-thiazinan-3-one 1,1-dioxide (C)
Example 44
5-(4-(((R)-4-(2-(trifluoromethyl)phenyl)-2,3-dihydro-1H-inden-1-yl)oxy)phe-
nyl)-1,2-thiazinan-3-one 1,1-dioxide (C)
Example 45
5-(4-(((R)-4-(2,6-dimethyl-4-(3-(methylsulfonyl)propoxy)phenyl)-2,3-dihydr-
o-1H-inden-1-yl)oxy)phenyl)-1,2-thiazinan-3-one 1,1-dioxide (C)
Example 46
5-(4-(((R)-4-(4-methoxy-2,6-dimethylphenyl)-2,3-dihydro-1H-inden-1-yl)oxy)-
phenyl)-1,2-thiazinan-3-one 1,1-dioxide (C)
Example 47
Synthesis of
5-(4-(((R)-4-(4-(3-hydroxy-3-methylbutoxy)-2,6-dimethylphenyl)-2,3-dihydr-
o-1H-inden-1-yl)oxy)-2-methylphenyl)-1,2-thiazinan-3-one
1,1-dioxide
<Step 1> Synthesis of
(R)-4-((4-bromo-2,3-dihydro-1H-inden-1-yl)oxy)-2-methylbenzaldehyde
[1410] In accordance with the method in (Example 23) <Step
3>, the title compound (1.5 g) was obtained as a beige solid
from (1S)-4-bromo-2,3-dihydro-1H-inden-1-ol (1.6 g) that was
commercially available or could be obtained by a known method and
commercially available 4-hydroxy-2-methylbenzaldehyde (1.0 g).
<Step 2> Synthesis of
(R)-(E)-2-(4-((4-bromo-2,3-dihydro-1H-inden-1-yl)oxy)-2-methylphenyl)-N,N-
-bis(2-(trimethylsilyl)ethoxymethyl)ethenesulfonamide
[1411] In accordance with the method in (Example 31) <Step
3>, the title compound (1.8 g) was obtained as a yellow oil from
the compound (1.6 g) obtained in (Example 31) <Step 1> and
the compound (1.5 g) obtained in (Example 47) <Step 1>.
<Step 3> Synthesis of dimethyl
2-(1-(4-(((R)-4-bromo-2,3-dihydro-1H-inden-1-yl)oxy)-2-methylphenyl)-2-(N-
,N-bis(2-(trimethylsilyl)ethoxymethyl)sulfamoyl)ethyl)malonate
[1412] In accordance with the method in (Example 31) <Step
4>, the title compound (1.4 g) was obtained as a colorless oil
from the compound (1.8 g) obtained in (Example 47) <Step
2>.
<Step 4> Synthesis of methyl
3-(4-(((R)-4-bromo-2,3-dihydro-1H-inden-1-yl)oxy)-2-methylphenyl)-4-(N,N--
bis(2-(trimethylsilyl)ethoxymethyl)sulfamoyl)butanoate
[1413] In accordance with the method in (Example 31) <Step
5>, the title compound (0.44 g) was obtained as a colorless oil
from the compound (1.3 g) obtained in (Example 47) <Step
3>.
<Step 5> Synthesis of methyl
4-(N,N-bis(2-(trimethylsilyl)ethoxymethyl)sulfamoyl)-3-(4-(((R)-4-(4-(3-h-
ydroxy-3-methylbutoxy)-2,6-dimethylphenyl)-2,3-dihydro-1H-inden-1-yl)oxy)--
2-methylphenyl)butanoate
[1414] In accordance with the method in (Example 23) <Step
5>, the title compound (0.31 g) was obtained as a colorless oil
from the compound (0.40 g) obtained in (Example 47) <Step 4>
and the compound (0.19 g) obtained in (Example 24) <Step
2>.
<Step 6> Synthesis of
4-(N,N-bis(2-(trimethylsilyl)ethoxymethyl)sulfamoyl)-3-(4-(((R)-4-(4-(3-h-
ydroxy-3-methylbutoxy)-2,6-dimethylphenyl)-2,3-dihydro-1H-inden-1-yl)oxy)--
2-methylphenyl)butanoic acid
[1415] In accordance with the method in (Example 37) <Step
2>, the title compound (0.24 g) was obtained as a pale yellow
amorphous from the compound (0.30 g) obtained in (Example 47)
<Step 5>.
<Step 7> Synthesis of
3-(4-(((R)-4-(4-(3-hydroxy-3-methylbutoxy)-2,6-dimethylphenyl)-2,3-dihydr-
o-1H-inden-1-yl)oxy)-2-methylphenyl)-4-sulfamoyl butanoic acid
[1416] In accordance with the method in (Example 32) <Step
6>, the title compound (65 mg) was obtained as a pale yellow
amorphous from the compound (0.20 g) obtained in (Example 47)
<Step 6>.
<Step 8> Synthesis of
5-(4-(((R)-4-(4-(3-hydroxy-3-methylbutoxy)-2,6-dimethylphenyl)-2,3-dihydr-
o-1H-inden-1-yl)oxy)-2-methylphenyl)-1,2-thiazinan-3-one
1,1-dioxide
[1417] In accordance with the method in (Example 14) <Step
6>, the title compound (50 mg) was obtained as a pale yellow
amorphous from the compound (60 mg) obtained in (Example 47)
<Step 7>.
Example 48
Synthesis of
5-(4-(((R)-4-phenoxy-2,3-dihydro-1H-inden-1-yl)oxy)phenyl)-1,2-thiazinan--
3-one 1,1-dioxide
<Step 1> Synthesis of methyl
3-(4-(((R)-4-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-2,3-dihydro-1H-inden--
1-yl)oxy)phenyl)-4-(N,N-bis(2-(trimethylsilyl)ethoxymethyl)sulfamoyl)butan-
oate
[1418] In accordance with the method in (Example 23) <Step
1>, the title compound (5.0 g) was obtained as a yellow oil from
the compound (5.0 g) obtained in (Example 33)<Step 4>.
<Step 2> Synthesis of methyl
4-(N,N-bis(2-(trimethylsilyl)ethoxymethyl)sulfamoyl)-3-(4-(((R)-4-hydroxy-
-2,3-dihydro-1H-inden-1-yl)oxy)phenyl)butanoate
[1419] Under ice-cooling, to a mixed solution of acetone (10 mL)
and water (30 mL), sodium hydrogen carbonate (2.2 g) was added and
thereto, OXONE (2.0 g) was slowly added. To the resultant reaction
mixture, further acetone (80 mL) was added and thereto, a solution
of the compound (1.0 g) obtained in (Example 48) <Step 1> in
acetone (10 mL) was added, followed by stirring the resultant
reaction mixture for 1 hour. To the reaction mixture, a 10% sodium
hydrogen sulfite aqueous solution was added and 1M hydrochloric
acid was added. The reaction mixture was extracted with ethyl
acetate. The organic phase was washed with water, then washed with
brine, and dried over anhydrous sodium sulfate. From the organic
phase, the solvent was distilled off under reduced pressure to give
the title compound (0.80 g).
<Step 3> Synthesis of methyl
4-(N,N-bis(2-(trimethylsilyl)ethoxymethyl)sulfamoyl)-3-(4-(((R)-4-phenoxy-
-2,3-dihydro-1H-inden-1-yl)oxy)phenyl)butanoate
[1420] In accordance with the method in (Example 25) <Step
4>, the title compound (0.75 g) was obtained as a colorless oil
from the compound (0.80 g) obtained in (Example 48) <Step
2>.
<Step 4> Synthesis of
4-(N,N-bis(2-(trimethylsilyl)ethoxymethyl)sulfamoyl)-3-(4-(((R)-4-phenoxy-
-2,3-dihydro-1H-inden-1-yl)oxy)phenyl)butanoic acid
[1421] In accordance with the method in (Example 37) <Step
2>, the title compound (0.71 g) was obtained as a colorless oil
from the compound (0.80 g) obtained in (Example 48) <Step
3>.
<Step 5> Synthesis of
3-(4-(((R)-4-phenoxy-2,3-dihydro-1H-inden-1-yl)oxy)phenyl)-4-sulfamoyl
butanoic acid
[1422] In accordance with the method in (Example 32) <Step
6>, the title compound (0.19 g) was obtained as a white solid
from the compound (0.71 g) obtained in (Example 48) <Step
4>.
<Step 6> Synthesis of
5-(4-(((R)-4-phenoxy-2,3-dihydro-1H-inden-1-yl)oxy)phenyl)-1,2-thiazinan--
3-one 1,1-dioxide
[1423] In accordance with the method in (Example 14) <Step
6>, the title compound (24 mg) was obtained as a white solid
from the compound (0.11 g) obtained in (Example 48) <Step
5>.
Example 49
Synthesis of
5-(4-(((R)-4-phenoxy-2,3-dihydro-1H-inden-1-yl)oxy)phenyl)-1,2-thiazinan--
3-one 1,1-dioxide (C)
<Step 1> Synthesis of methyl
3-(4-(((R)-4-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-2,3-dihydro-1H-inden--
1-yl)oxy)phenyl)-4-(N,N-bis(2-(trimethylsilyl)ethoxymethyl)sulfamoyl)butan-
oate (C)
[1424] In accordance with the method in (Example 23) <Step
1>, the title compound (2.2 g) was obtained as a colorless oil
from the enantiomer C (Example 40-1 (C)) (2.5 g) obtained in
(Example 40) <Step 1>.
<Step 2> Synthesis of methyl
4-(N,N-bis(2-(trimethylsilyl)ethoxymethyl)sulfamoyl)-3-(4-(((R)-4-hydroxy-
-2,3-dihydro-1H-inden-1-yl)oxy)phenyl)butanoate (C)
[1425] In accordance with the method in (Example 48) <Step
2>, the title compound (2.0 g) was obtained as a colorless oil
from the compound (1.2 g) obtained in (Example 49) <Step
1>.
<Step 3> Synthesis of methyl
4-(N,N-bis(2-(trimethylsilyl)ethoxymethyl)sulfamoyl)-3-(4-(((R)-4-phenoxy-
-2,3-dihydro-1H-inden-1-yl)oxy)phenyl)butanoate (C)
[1426] In accordance with the method in (Example 25) <Step
4>, the title compound (0.95 g) was obtained as a colorless oil
from the compound (0.98 g) obtained in (Example 49) <Step
2>.
<Step 4> Synthesis of
4-(N,N-bis(2-(trimethylsilyl)ethoxymethyl)sulfamoyl)-3-(4-(((R)-4-phenoxy-
-2,3-dihydro-1H-inden-1-yl)oxy)phenyl)butanoic acid (C)
[1427] In accordance with the method in (Example 37) <Step
2>, the title compound (0.92 g) was obtained as a white solid
from the compound (0.95 g) obtained in (Example 49) <Step
3>.
<Step 5> Synthesis of
3-(4-(((R)-4-phenoxy-2,3-dihydro-1H-inden-1-yl)oxy)phenyl)-4-sulfamoyl
butanoic acid (C)
[1428] In accordance with the method in (Example 32) <Step
6>, the title compound (0.17 g) was obtained as a white solid
from the compound (0.92 g) obtained in (Example 49) <Step
4>.
<Step 6> Synthesis of
5-(4-(((R)-4-phenoxy-2,3-dihydro-1H-inden-1-yl)oxy)phenyl)-1,2-thiazinan--
3-one 1,1-dioxide (C)
[1429] In accordance with the method in (Example 14) <Step
6>, the title compound (67 mg) was obtained as a white solid
from the compound (0.17 g) obtained in (Example 49) <Step
5>.
Example 50
Synthesis of
4-(((1R)-1-(4-(1,1-dioxide-3-oxo-1,2-thiazinan-5-yl)phenoxy)-2,3-dihydro--
1H-inden-4-yl)oxy)benzonitrile (C)
<Step 1> Synthesis of methyl
3-(4-(((R)-4-(4-cyanophenoxy)-2,3-dihydro-1H-inden-1-yl)oxy)phenyl)-4-(N,-
N-bis(2-(tri methylsilyl)ethoxymethyl)sulfamoyl)butanoate (C)
[1430] In accordance with the method in (Example 25) <Step
4>, the title compound (0.55 g) was obtained as a colorless oil
from the compound (0.98 g) obtained in (Example 49) <Step
2>.
<Step 2> Synthesis of
3-(4-(((R)-4-(4-cyanophenoxy)-2,3-dihydro-1H-inden-1-yl)oxy)phenyl)-4-(N,-
N-bis(2-(trimethylsilyl)ethoxymethyl)sulfamoyl)butanoic acid
(C)
[1431] In accordance with the method in (Example 37) <Step
2>, the title compound (0.51 g) was obtained as a white solid
from the compound (0.55 g) obtained in (Example 50) <Step
1>.
<Step 3> Synthesis of
3-(4-(((R)-4-(4-cyanophenoxy)-2,3-dihydro-1H-inden-1-yl)oxy)phenyl)-4-sul-
famoyl butanoic acid (C)
[1432] In accordance with the method in (Example 32) <Step
6>, the title compound (0.18 g) was obtained as a white solid
from the compound (0.51 g) obtained in (Example 50) <Step
2>.
<Step 4> Synthesis of
4-(((1R)-1-(4-(1,1-dioxide-3-oxo-1,2-thiazinan-5-yl)phenoxy)-2,3-dihydro--
1H-inden-4-yl)oxy)benzonitrile (C)
[1433] In accordance with the method in (Example 14) <Step
6>, the title compound (0.12 g) was obtained as a white solid
from the compound (0.18 g) obtained in (Example 50) <Step
3>.
Example 51
Synthesis of
3-hydroxy-5-(4-(((R)-4-((6-(3-hydroxy-3-methylbutoxy)-2-methylpyridin-3-y-
l)oxy)-2,3-dihydro-1H-inden-1-yl)oxy)phenyl)-4,5-dihydroisothiazole
1-oxide (A)
<Step 1> Synthesis of
(S)-4-((6-(3-hydroxy-3-methylbutoxy)-2-methylpyridin-3-yl)oxy)-2,3-dihydr-
o-1H-inden-1-ol
[1434] (1S)-4-hydroxy-2,3-dihydro-1H-inden-1-ol (1.0 g) that was
commercially available or could be obtained by a known method and
the compound (2.5 g) obtained in (Example 23) <Step 2> were
dissolved in methylene chloride (50.0 mL) and to the resultant
reaction solution, molecular sieves 4A (powder; 2.0 g), copper(II)
acetate (1.5 g), and triethylamine (4.6 mL) were added. The
resultant reaction mixture was stirred in an oxygen atmosphere at
room temperature for 18 hours. To the reaction mixture, silica gel
(20 g) was added and the reaction mixture was filtered with Celite.
The filtrate was washed with ethyl acetate and from the filtrate,
the solvent was distilled off under reduced pressure. The resultant
residue was purified by silica gel column chromatography (eluent;
n-hexane: ethyl acetate=100:0 to 55:45) and was further purified by
silica gel column chromatography (NH silica, eluent; n-hexane:
ethyl acetate=100:0 to 55:45). From the eluted solution, the
solvent was distilled off under reduced pressure to give the title
compound (1.0 g) as a pale yellow oil.
<Step 2> Synthesis of
(R)-2-(4-((4-((6-(3-hydroxy-3-methylbutoxy)-2-methylpyridin-3-yl)oxy)-2,3-
-dihydro-1H-inden-1-yl)oxy)phenyl)-6-methyl-1,3,6,2-dioxaazaborocane-4,8-d-
ione
[1435] In accordance with the method in (Example 1) <Step 3>,
the title compound (0.68 g) was obtained as a pale orange amorphous
from the compound (1.0 g) obtained in (Example 51) <Step 1>
and the compound (0.73) obtained in (Reference Example 1).
<Step 3> Synthesis of
3-hydroxy-5-(4-(((R)-4-((6-(3-hydroxy-3-methylbutoxy)-2-methylpyridin-3-y-
l)oxy)-2,3-dihydro-1H-inden-1-yl)oxy)phenyl)isothiazole 1-oxide
(A)
[1436] In accordance with the method in (Example 1) <Step 6>,
the title compound (0.12 g) was obtained as a pale yellow solid
using the enantiomer A (Example 1-5 (A)) (79 mg) obtained in
(Example 1) <Step 5> from the compound (0.20 g) obtained in
(Example 51) <Step 2>.
<Step 4> Synthesis of
3-hydroxy-5-(4-(((R)-4-((6-(3-hydroxy-3-methylbutoxy)-2-methylpyridin-3-y-
l)oxy)-2,3-dihydro-1H-inden-1-yl)oxy)phenyl)-4,5-dihydroisothiazole
1-oxide (A)
[1437] To a solution of 1N L-Selectride in tetrahydrofuran (1.1
mL), tetrabutylammonium chloride (0.31 g) was added under
ice-cooling and thereto, a solution of the compound (0.1 g)
obtained in (Example 51) <Step 3> in anhydrous THF (0.35 mL)
was added dropwise at or below 3.degree. C. The reaction mixture
was allowed to reach room temperature and stirred for 1 day. To the
reaction mixture, 1M hydrochloric acid was added. The mixture was
extracted with ethyl acetate. The organic phase was washed with
brine and then dried over anhydrous sodium sulfate. From the
organic phase, the solvent was distilled off under reduced pressure
and the resultant residue was purified by silica gel column
chromatography (eluent; n-hexane: ethyl acetate) to give the title
compound. Optical resolution of the solid of the title compound was
performed by preparative chromatography (column: CHIRALPAK OJ-H (2
cm.times.25 cm) manufactured by Daicel Chemical Industries, Ltd.,
eluent; ethanol: trifluoroacetic acid=100:0.1 (V/V), flow rate: 2
mL/minute) to give each diastereomer of the title compound. The
retention time was determined by LC/MS.
[1438] Primary fraction (27 mg, retention time 5.87 minutes,
diastereomer a: Example 51 (A)-a)
[1439] Secondary fraction (21 mg, retention time 5.82 minutes,
diastereomer b: Example 51 (A)-b)
Example 52
Synthesis of
3-hydroxy-5-(4-(((R)-4-((6-methoxypyridin-3-yl)oxy)-2,3-dihydro-1H-inden--
1-yl)oxy)phenyl)-4,5-dihydroisothiazole 1-oxide (A)
<Step 1> Synthesis of
(S)-4-((6-methoxypyridin-3-yl)oxy)-2,3-dihydro-1H-inden-1-ol
[1440] A mixed solution of (1S)-4-hydroxy-2,3-dihydro-1H-inden-1-ol
(0.5 g) that was commercially available or could be obtained by a
known method, 2,2,6,6-tetramethyl-3,5-heptanedione (0.55 mL),
copper (I) iodide (0.16 g), cesium carbonate (2.7 g),
5-bromo-2-methoxypyridine (0.48 mL), and N-methylpyrrolidone (6.5
mL) was heated and stirred by a microwave at 100.degree. C. for 45
minutes. The reaction mixture was allowed to reach room
temperature, was filtered with Celite, and was washed with ethyl
acetate. To the reaction mixture, a saturated aqueous ammonium
chloride solution was added and the resultant reaction mixture was
extracted with ethyl acetate. The resultant extract was washed with
brine and then dried over anhydrous sodium sulfate. From the
resultant extract, the solvent was distilled off under reduced
pressure and the resultant residue was purified by silica gel
column chromatography (eluent; n-hexane: ethyl acetate=9:1 to 3:1),
followed by distillation-off of the solvent under reduced pressure
to give the title compound (0.42 g) as a brown oil.
<Step 2> Synthesis of
(R)-2-(4-((4-((6-methoxylpyridin-3-yl)oxy)-2,3-dihydro-1H-inden-1-yl)oxy)-
phenyl)-6-m ethyl-1,3,6,2-dioxaazaborocane-4,8-dione
[1441] In accordance with the method in (Example 1) <Step 3>,
the title compound (0.26 g) was obtained as a pale yellow amorphous
from the compound (0.20 g) obtained in (Example 52) <Step 1>
and the compound (0.23 g) obtained in (Reference Example 1).
<Step 3> Synthesis of
3-hydroxy-5-(4-(((R)-4-((6-methoxypyridin-3-yl)oxy)-2,3-dihydro-1H-inden--
1-yl)oxy)phenyl)isothiazole 1-oxide (A)
[1442] In accordance with the method in (Example 1) <Step 6>,
the title compound (0.10 g) was obtained as a white solid using the
enantiomer A (Example 1-5 (A)) (0.12 g) obtained in (Example 1)
<Step 5> from the compound (0.25 g) obtained in (Example
52)<Step 2>.
<Step 4> Synthesis of
3-hydroxy-5-(4-(((R)-4-((6-methoxypyridin-3-yl)oxy)-2,3-dihydro-1H-inden--
1-yl)oxy)phenyl)-4,5-dihydroisothiazole 1-oxide (A)
[1443] In accordance with the method in (Example 51) <Step
4>, the title compound was obtained from the compound (0.30 g)
obtained in (Example 52) <Step 3> and by the following
preparative chromatography, each diastereomer (primary fraction
(diastereomer-a):54 mg, secondary fraction (diastereomer-b):24 mg)
thereof was obtained.
Example 53
Synthesis of 3-hydroxy-5-(4-(((R)-4-(m-tolyloxy)-2,3-dihydro-I
H-inden-1-yl)oxy)phenyl)-4,5-dihydroisothiazole 1-oxide (A)
<Step 1> Synthesis of
(S)-4-(m-tolyloxy)-2,3-dihydro-1H-inden-1-ol
[1444] In accordance with the method in (Example 51) <Step
1>, the title compound (0.61 g) was obtained as a pale yellow
solid from (1S)-4-hydroxy-2,3-dihydro-1H-inden-1-ol (1.0 g) that
was commercially available and could be obtained by a known method
and m-tolylboronic acid (1.1 g).
<Step 2> Synthesis of
((R)-6-methyl-2-(4-((4-(m-tolyloxy)-2,3-dihydro-1H-inden-1-yl)oxy)phenyl)-
-1,3,6,2-dioxaazaborocane-4,8-dione
[1445] In accordance with the method in (Example 1) <Step 3>,
the title compound (0.75 g) was obtained as a beige amorphous from
the compound (0.60 g) obtained in (Example 53) <Step 1> and
the compound (0.61 g) obtained in (Reference Example 1).
<Step 3> Synthesis of
3-hydroxy-5-(4-(((R)-4-(m-tolyloxy)-2,3-dihydro-1H-inden-1-yl)oxy)phenyl)-
isothiazazole 1-oxide (A)
[1446] In accordance with the method in (Example 1) <Step 6>,
the title compound (0.16 g) was obtained as a pale yellow solid
using the enantiomer A (Example 1-5 (A)) (0.14 g) obtained in
(Example 1) <Step 5> from the compound (0.30 g) obtained in
(Example 53) <Step 2>.
<Step 4> Synthesis of
3-hydroxy-5-(4-(((R)-4-(m-tolyloxy)-2,3-dihydro-1H-inden-1-yl)oxy)phenyl)-
-4,5-dihydroisothiazole 1-oxide (A)
[1447] In accordance with the method in (Example 51) <Step
4>, the title compound was obtained from the compound (0.26 g)
obtained in (Example 53) <Step 3> and by the following
preparative chromatography, each diastereomer (primary fraction
(diastereomer-a):45 mg, secondary fraction (diastereomer-b):44 mg)
thereof was obtained.
Example 54
Synthesis of
5-(4-(((R)-4-(6-(2-ethoxyethoxy)-2-methylpyridin-3-yl)-2,3-dihydro-1H-ind-
en-1-yl)oxy)phenyl)-3-hydroxy-4,5-dihydroisothiazole 1-oxide
(A)
<Step 1> Synthesis of
3-bromo-6-(2-ethoxyethoxy)-2-methylpyridin
[1448] In accordance with the method in (Example 23) <Step
1>, the title compound (3.3 g) was obtained using
5-bromo-6-methylpyridine-2-ol (3.0 g) from 1-chloro-2-ethoxyethane
(1.9 mL).
<Step 2> Synthesis of
3-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-6-(2-ethoxyethoxy)-2-methylpyrid-
ine
[1449] In accordance with the method in (Example 23) <Step
2>, the title compound (3.1 g) was obtained as an oil from the
compound (5.0 g) obtained in (Example 54) <Step 1>.
<Step 3> Synthesis of
5-(4-(((R)-4-(6-(2-ethoxyethoxy)-2-methylpyridin-3-yl)-2,3-dihydro-1H-ind-
en-1-yl)oxy)phenyl)-3-hydroxy-4,5-dihydroisothiazole 1-oxide
(A)
[1450] To a solution of the compound (0.15 g) in (Example 29), the
compound (0.16 g) obtained in (Example 54) <Step 2>,
potassium carbonate (0.10 g),
2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (XPhos: 35
mg), and bis(dibenzylideneacetone)palladium (21 mg) in 1,4-dioxane
(6 mL), water (3 mL) was added. The inside of the reaction system
was purged with nitrogen and the resultant reaction mixture was
heated and refluxed for 4 hours. To the reaction mixture, a
saturated aqueous sodium hydrogen carbonate solution was added. The
mixture was extracted with ethyl acetate. The organic phase was
washed with water, then washed with brine, and dried over anhydrous
sodium sulfate. From the organic phase, the solvent was distilled
off under reduced pressure and the resultant residue was purified
by silica gel column chromatography (eluent; n-hexane: ethyl
acetate) to give the title compound. Optical resolution of the
solid of the title compound was performed by preparative
chromatography (column: CHIRALPAK OD-H (2 cm.times.25 cm)
manufactured by Daicel Chemical Industries, Ltd., eluent; hexane:
ethanol=1:1 (V/V), flow rate: 8 mL/minute) to give each
diastereomer of the title compound. The retention time was
determined by LC/MS.
[1451] Primary fraction (21 mg, retention time 5.92 minutes,
diastereomer a: Example 54 (A)-a)
[1452] Secondary fraction (31 mg, retention time 5.83 minutes,
diastereomer b: Example 54 (A)-b)
Example 55
Synthesis of
3-hydroxy-5-(4-(((R)-4-((2-methylpyridin-3-yl)oxy)-2,3-dihydro-1H-inden-1-
-yl)oxy)phenyl)-4,5-dihydroisothiazole 1-oxide
<Step 1> Synthesis of
(S)-4-((2-methylpyridin-3-yl)oxy)-2,3-dihydro-1H-inden-1-ol
[1453] In accordance with the method in (Example 51) <Step
1>, the title compound (1.0 g) was obtained as a brown solid
from (1S)-4-hydroxy-2,3-dihydro-1H-inden-1-ol (4.0 g) that was
commercially available or could be obtained by a known method and
(2-methylpyridin-3-yl)boronic acid (4.4 g).
<Step 2> Synthesis of
(R)-6-methyl-2-(4-((4-((2-methylpyridin-3-yl)oxy)-2,3-dihydro-1H-inden-1--
yl)oxy)phen yl)-1,3,6,2-dioxaazaborocane-4,8-dione
[1454] In accordance with the method in (Example 1) <Step 3>,
the title compound (0.35 g) was obtained as a colorless amorphous
from the compound (0.40 g) obtained in (Example 55) <Step 1>
and the compound (0.40 g) obtained in (Reference Example 1).
<Step 3> Synthesis of
3-hydroxy-5-(4-(((R)-4-((2-methylpyridine-3-yl)oxy)-2,3-dihydro-1H-inden--
1-yl)oxy)phenyl)isothiazole 1-oxide (A)
[1455] In accordance with the method in (Example 1) <Step 6>,
the title compound (0.13 g) was obtained as a white solid using the
enantiomer A (Example 1-5 (A)) (0.16 g) obtained in (Example 1)
<Step 5> from the compound (0.33 g) obtained in (Example
55)<Step 2>.
<Step 4> Synthesis of
3-hydroxy-5-(4-(((R)-4-(m-tolyloxy)-2,3-dihydro-1H-inden-1-yl)oxy)phenyl)-
-4,5-dihydroisothiazole 1-oxide (A)
[1456] In accordance with the method in (Example 51) <Step
4>, the title compound was obtained from the compound (0.10 g)
obtained in (Example 55) <Step 3> and by the following
preparative chromatography, each diastereomer (primary fraction
(diastereomer-a: Example 55 (A)-a):31 mg, secondary fraction
(diastereomer-b: Example 55 (A)-b):15 mg) thereof was obtained.
Example 56
Optical resolution of
5-(4-(((R)-4-bromo-2,3-dihydro-1H-inden-1-yl)oxy)phenyl)isothiazolidin-3--
one 1-oxide (A)
[1457] In accordance with the method in (Example 1) <Step 5>,
optical resolution of the compound in (Example 29) was
performed.
column: CHIRALCEL OD-3 manufactured by Daicel Chemical Industries,
Ltd., mobile phase; ethanol (containing 0.05% diethylamine):carbon
dioxide=5:95 to 40:60 The retention time was determined by
UPLC/MS.
[1458] Primary fraction (1.4 g, retention time 1.13 minutes,
diastereomer a: Example 56 (A)-a)
[1459] Secondary fraction (1.1 g, retention time 1.14 minutes,
diastereomer b: Example 56 (A)-b)
Example 57
Synthesis of
5-(4-(((R)-4-(4-(2-ethoxyethoxy)-2,6-dimethylphenyl)-2,3-dihydro-1H-inden-
-1-yl)oxy)phenyl)-3-hydroxy-4,5-dihydroisothiazole 1-oxide
(A)-a
[1460] In accordance with the method in (Example 30) <Step
3>, the title compound (48 mg) was obtained as a white solid
from the diastereomer a (Example 56 (A)-a)) obtained in (Example
56) (50 mg).
[1461] The compounds of (Example 58) to (Example 69) below were
synthesized in the same manner as in (Example 57) in accordance
with the method in (Example 30) <Step 3> and among them, the
compound of (Example 58) was synthesized from the diastereomer b
(Example 56 (A)-b) obtained in (Example 56) and the compounds of
(Example 59) to (Example 69) were synthesized using the
diastereomer a (Example 56 (A)-a)) obtained in (Example 56) and a
corresponding boronic acid or boronic acid ester.
Example 58
5-(4-(((R)-4-(4-(2-ethoxyethoxy)-2,6-dimethylphenyl)-2,3-dihydro-1H-inden--
1-yl)oxy)phenyl)-3-hydroxy-4,5-dihydroisothiazole 1-oxide (A)-b
Example 59
5-(4-(((R)-4-(2,6-dimethyl-4-(3-(methylsulfonyl)propoxy)phenyl)-2,3-dihydr-
o-1H-inden-1-yl)oxy)phenyl)-3-hydroxy-4,5-dihydroisothiazole
1-oxide (A)-a
Example 60
5-(4-(((R)-4-(2,6-dimethylphenyl)-2,3-dihydro-1H-inden-1-yl)oxy)phenyl)-3--
hydroxy-4,5-dihydroisothiazole 1-oxide (A)-a
Example 61
3-hydroxy-5-(4-(((R)-4-(4-methoxy)-2,6-dimethylphenyl)-2,3-dihydro-1H-inde-
n-1-yl)oxy)phenyl)-4,5-dihydroisothiazole 1-oxide (A)-a
Example 62
3-hydroxy-5-(4-(((R)-4-(2-methyl-6-(3-(methylsulfonyl)propoxy)pyridin-3-yl-
)-2,3-dihydro-1H-inden-1-yl)oxy)phenyl)-4,5-dihydroisothiazole
1-oxide (A)-a
Example 63
3-hydroxy-5-(4-(((R)-4-(6-methoxy-2-methylpyridin-3-yl)-2,3-dihydro-1H-ind-
en-1-yl)oxy)phenyl)-4,5-dihydroisothiazole 1-oxide (A)-a
Example 64
3-hydroxy-5-(4-(((R)-4-(2-(trifluoromethyl)phenyl)-2,3-dihydro-1H-inden-1--
yl)oxy)phenyl)-4,5-dihydroisothiazole 1-oxide (A)-a
Example 65
3-hydroxy-5-(4-(((R)-4-(2-(trifluoromethyl)pyridin-3-yl)-2,3-dihydro-1H-in-
den-1-yl)oxy)phenyl)-4,5-dihydroisothiazole 1-oxide (A)-a
Example 66
3-hydroxy-5-(4-(((R)-4-(o-tolyl)-2,3-dihydro-1H-inden-1-yl)oxy)phenyl)-4,5-
-dihydroisothiazole 1-oxide (A)-a
Example 67
5-(4-(((R)-4-(5-fluoro-2-methylphenyl)-2,3-dihydro-1H-inden-1-yl)oxy)pheny-
l)-3-hydroxy-4,5-dihydroisothiazole 1-oxide (A)-a
Example 68
5-(4-(((1R)-4-(2-fluoro-6-methoxyphenyl)-2,3-dihydro-1H-inden-1-yl)oxy)phe-
nyl)-3-hydroxy-4,5-dihydroisothiazole 1-oxide (A)-a
Example 69
5-(4-(((R)-4-(2-ethoxy-5-fluorophenyl)-2,3-dihydro-1H-inden-1-yl)oxy)pheny-
l)-3-hydroxy-4,5-dihydroisothiazole 1-oxide (A)-a
[1462] The compounds shown below, the compounds of Structural
Formulae 8 to 17 ((Example 1P) to (Example 157P)), compounds that
can be obtained in combination of Partial Structural Formulae shown
in the aspect [1-19-1] to the aspect [1-19-2], salts of them,
solvates of them, and optical isomers of them can also be easily
synthesized by using Production Methods above, the methods
described in Examples, methods known by a person skilled in the
art, or modified methods of them. [1463]
5-[4-[[3-[2,4-dimethyl-6-(3-methylsulfonylpropoxyl)pyridin-3-yl]phenyl]me-
thoxy]phenyl]-1,1-dioxo-1,2-thiazolidin-3-one; [1464]
5-[4-[[3-[2,4-dimethyl-6-(3-methylsulfonylpropoxyl)pyridin-3-yl]phenyl]me-
thoxy]phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one; [1465]
5-[4-[[3-[6-(3-hydroxy-3-methylbutoxy)-2,4-dimethylpyridin-3-yl]phenyl]me-
thoxy]phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one; [1466]
5-[2-chloro-4-[[3-[2,6-dimethyl-4-(3-methylsulfonylpropoxyl)phenyl]phenyl-
]methoxy]phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one; [1467]
5-[2-chloro-4-[[3-[2,4-dimethyl-6-(3-methylsulfonylpropoxyl)pyridin-3-yl]-
phenyl]methoxy]phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one; [1468]
5-[2-chloro-4-[[3-[6-(3-hydroxy-3-methylbutoxy)-2,4-dimethylpyridin-3-yl]-
phenyl]methoxy]phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one; [1469]
5-[4-[[3-[2,6-dimethyl-4-(3-methylsulfonylpropoxyl)phenyl]phenyl]methoxy]-
phenyl]-1,1-dioxo-1,2,6-thiadiazinan-3-one; [1470]
5-[4-[[3-[2,4-dimethyl-6-(3-methylsulfonylpropoxyl)pyridin-3-yl]phenyl]me-
thoxy]phenyl]-1,1-dioxo-1,2,6-thiadiazinan-3-one; [1471]
5-[4-[[3-[6-(3-hydroxy-3-methylbutoxy)-2,4-dimethylpyridin-3-yl]phenyl]me-
thoxy]phenyl]-1,1-dioxo-1,2,6-thiadiazinan-3-one (Example 14P);
[1472]
5-[4-[[3-[2,4-dimethyl-6-(3-methylsulfonylpropoxyl)pyridin-3-yl]phenyl]me-
thoxy]phenyl]-1,1-dioxo-1,2-thiazinan-3-one; and [1473]
5-(4-((3-(2,6-dimethylphenyl)phenyl)methoxy)phenyl)-1,1-dioxo-1,2-thiazol-
idin-3-one (Example 37P).
[1474] The structures of the final compounds synthesized in
(Example 1) to (Example 35) above and the structures of the
compounds in (Example 1P) to (Example 157P) are shown in the
figures below (Structural Formulae 1 to 12). LC/MS data and NMR
data (no mark: 400 MHz NMR, *: 300 MHz NMR) of these final
compounds of Examples are also shown in Tables below (Tables 2, 3,
7, and 8). The structures of the intermediate compounds synthesized
in Examples and the compounds of Reference Examples are shown in
the figures below (Structural Formulae 13 to 19) and LC/MS data of
these intermediate compounds and the compounds of Reference
Examples and NMR data (no mark: 400 MHz NMR, *: 300 MHz NMR) of
these intermediate compounds and the compounds of Reference
Examples are also shown in Tables below (Tables 4, 5, 6, 9, 10, 11,
and 12). Here, with respect to the intermediate compound, for
example, the compound obtained in Example 1<Step 1> is
expressed as "1-1".
TABLE-US-00008 Structural Formula 1 Example No. Structure 1
##STR00206## 2 ##STR00207## 3 ##STR00208## 4 ##STR00209## 5
##STR00210## 6 ##STR00211## 7 ##STR00212## 8 ##STR00213## 9
##STR00214## 10 ##STR00215## 11 ##STR00216## 12 ##STR00217## 13
##STR00218## 14 ##STR00219## 15 ##STR00220## 16 ##STR00221## 17
##STR00222## 18 ##STR00223## 19 ##STR00224## 20 ##STR00225## 21
##STR00226## 22 ##STR00227##
TABLE-US-00009 Structural Formula 2 ##STR00228## Example 23
##STR00229## Example 23(A)-a ##STR00230## Example 23(A)-b
##STR00231## Example 24 ##STR00232## Example 24(A)-a ##STR00233##
Example 24(A)-b ##STR00234## Example 25 ##STR00235## Example
25(A)-a ##STR00236## Example 25(A)-b ##STR00237## Example 26
##STR00238## Example 27 ##STR00239## Example 28
TABLE-US-00010 Structural Formula 3 ##STR00240## Example 29
##STR00241## Example 30 ##STR00242## Example 31 ##STR00243##
Example 32 ##STR00244## Example 33 ##STR00245## Example 34
##STR00246## Example 35 ##STR00247## Example 36 ##STR00248##
Example 37 ##STR00249## Example 38 ##STR00250## Example 39
##STR00251## Example 40
TABLE-US-00011 Structural Formula 4 ##STR00252## Example 41
##STR00253## Example 42 ##STR00254## Example 43 ##STR00255##
Example 44 ##STR00256## Example 45 ##STR00257## Example 46
##STR00258## Example 47 ##STR00259## Example 48 ##STR00260##
Example 49 ##STR00261## Example 50
TABLE-US-00012 Structural Formula 5 ##STR00262## Example 51
##STR00263## Example 51(A)-a ##STR00264## Example 51(A)-b
##STR00265## Example 52 ##STR00266## Example 52(A)-a ##STR00267##
Example 52(A)-b ##STR00268## Example 53 ##STR00269## Example
53(A)-a ##STR00270## Example 53(A)-b ##STR00271## Example 54
##STR00272## Example 54(A)-a ##STR00273## Example 54(A)-b
TABLE-US-00013 Structural Formula 6 ##STR00274## Example 55
##STR00275## Example 55(A)-a ##STR00276## Example 55(A)-b
##STR00277## Example 56(A)-a ##STR00278## Example 56(A)-b
##STR00279## Example 57 ##STR00280## Example 58 ##STR00281##
Example 59 ##STR00282## Example 60 ##STR00283## Example 61
TABLE-US-00014 Structural Formula 7 ##STR00284## Example 62
##STR00285## Example 63 ##STR00286## Example 64 ##STR00287##
Example 65 ##STR00288## Example 66 ##STR00289## Example 67
##STR00290## Example 68 ##STR00291## Example 69
TABLE-US-00015 Structural Formula 8 ##STR00292## Example 1P
##STR00293## Example 2P ##STR00294## Example 3P ##STR00295##
Example 4P ##STR00296## Example 5P ##STR00297## Example 6P
##STR00298## Example 7P ##STR00299## Example 8P ##STR00300##
Example 9P ##STR00301## Example 10P ##STR00302## Example 11P
##STR00303## Example 12P ##STR00304## Example 13P ##STR00305##
Example 14P ##STR00306## Example 15P ##STR00307## Example 16P
TABLE-US-00016 Structural Formula 9 ##STR00308## Example 17P
##STR00309## Example 18P ##STR00310## Example 19P ##STR00311##
Example 20P ##STR00312## Example 21P ##STR00313## Example 22P
##STR00314## Example 23P ##STR00315## Example 24P ##STR00316##
Example 25P ##STR00317## Example 26P ##STR00318## Example 27P
##STR00319## Example 28P ##STR00320## Example 29P ##STR00321##
Example 30P ##STR00322## Example 31P ##STR00323## Example 32P
TABLE-US-00017 Structural Formula 10 ##STR00324## Example 33P
##STR00325## Example 34P ##STR00326## Example 35P ##STR00327##
Example 36P ##STR00328## Example 37P ##STR00329## Example 38P
##STR00330## Example 39P ##STR00331## Example 40P ##STR00332##
Example 41P ##STR00333## Example 42P ##STR00334## Example 43P
##STR00335## Example 44P ##STR00336## Example 45P ##STR00337##
Example 46P ##STR00338## Example 47P ##STR00339## Example 48P
TABLE-US-00018 Structural Formula 11 ##STR00340## Example 49P
##STR00341## Example 50P ##STR00342## Example 51P ##STR00343##
Example 52P ##STR00344## Example 53P ##STR00345## Example 54P
##STR00346## Example 55P ##STR00347## Example 56P ##STR00348##
Example 57P
TABLE-US-00019 Structural Formula 12 ##STR00349## Example 58P
##STR00350## Example 59P ##STR00351## Example 60P ##STR00352##
Example 61P ##STR00353## Example 62P ##STR00354## Example 63P
##STR00355## Example 64P ##STR00356## Example 65P ##STR00357##
Example 66P ##STR00358## Example 67P ##STR00359## Example 68P
##STR00360## Example 69P ##STR00361## Example 70P ##STR00362##
Example 71P ##STR00363## Example 72P
TABLE-US-00020 Structural Formula 13 ##STR00364## Example 73P
##STR00365## Example 74P ##STR00366## Example 75P ##STR00367##
Example 76P ##STR00368## Example 77P ##STR00369## Example 78P
##STR00370## Example 79P ##STR00371## Example 80P ##STR00372##
Example 81P ##STR00373## Example 82P ##STR00374## Example 83P
##STR00375## Example 84P ##STR00376## Example 85P ##STR00377##
Example 86P ##STR00378## Example 87P
TABLE-US-00021 Structural Formula 14 ##STR00379## Example 88P
##STR00380## Example 89P ##STR00381## Example 90P ##STR00382##
Example 91P ##STR00383## Example 92P ##STR00384## Example 93P
##STR00385## Example 94P ##STR00386## Example 95P ##STR00387##
Example 96P ##STR00388## Example 97P ##STR00389## Example 98P
##STR00390## Example 99P ##STR00391## Example 100P ##STR00392##
Example 101P ##STR00393## Example 102P
TABLE-US-00022 Structural Formula 15 ##STR00394## Example 118P
##STR00395## Example 119P ##STR00396## Example 120P ##STR00397##
Example 121P ##STR00398## Example 122P ##STR00399## Example 123P
##STR00400## Example 124P ##STR00401## Example 125P ##STR00402##
Example 126P ##STR00403## Example 127P ##STR00404## Example 128P
##STR00405## Example 129P ##STR00406## Example 130P ##STR00407##
Example 131P ##STR00408## Example 132P
TABLE-US-00023 Structural Formula 16 ##STR00409## Example 133P
##STR00410## Example 134P ##STR00411## Example 135P ##STR00412##
Example 136P ##STR00413## Example 137P ##STR00414## Example 138P
##STR00415## Example 139P ##STR00416## Example 140P ##STR00417##
Example 141P ##STR00418## Example 142P
TABLE-US-00024 Structural Formula 17 ##STR00419## Example 143P
##STR00420## Example 144P ##STR00421## Example 145P ##STR00422##
Example 146P ##STR00423## Example 147P ##STR00424## Example 148P
##STR00425## Example 149P ##STR00426## Example 150P ##STR00427##
Example 151P ##STR00428## Example 152P ##STR00429## Example 153P
##STR00430## Example 154P ##STR00431## Example 155P ##STR00432##
Example 156P ##STR00433## Example 157P
TABLE-US-00025 Structural Formula 18 Example No. Substituted
Phenylboronic Ester 1 ##STR00434## 2 ##STR00435## 3 ##STR00436## 4
##STR00437## 5 ##STR00438## 6 ##STR00439## 7 ##STR00440## 8
##STR00441## 9 ##STR00442## Example No. Substituted Isothiazole 1
##STR00443## 2 ##STR00444## 3 ##STR00445## 4 ##STR00446## 5
##STR00447## 6 ##STR00448## 7 ##STR00449## 8 ##STR00450## 9
##STR00451##
TABLE-US-00026 Structural Formula 19 Example No. Substituted
Phenylboronic Ester 10 ##STR00452## 11 ##STR00453## 12 ##STR00454##
13 ##STR00455## Example No. Substituted Isothiazole 10 ##STR00456##
11 ##STR00457## 12 ##STR00458## 13 ##STR00459##
TABLE-US-00027 Structural Formula 20 No. Structure 14-1
##STR00460## 14-2 ##STR00461## 14-3 ##STR00462## 14-4 ##STR00463##
14-5 ##STR00464## 15-1 ##STR00465## 15-2 ##STR00466## 15-3
##STR00467## 15-4 ##STR00468## 15-5 ##STR00469## 16-1 ##STR00470##
16-2 ##STR00471## 16-3 ##STR00472## 16-4 ##STR00473## 16-5
##STR00474## 17-1 ##STR00475## 17-2 ##STR00476## 17-3 ##STR00477##
17-4 ##STR00478## 17-5 ##STR00479## 18-1 ##STR00480## 18-2
##STR00481##
TABLE-US-00028 Structural Formula 21 No. Structure 18-3
##STR00482## 19-1 ##STR00483## 21-1 ##STR00484## 21-2 ##STR00485##
21-3 ##STR00486## 22-1 ##STR00487## 22-2 ##STR00488## 22-3
##STR00489## 22-4 ##STR00490## 22-5 ##STR00491##
TABLE-US-00029 Structural Formula 22 ##STR00492## Example 23-1
##STR00493## Example 23-2 ##STR00494## Example 23-3 ##STR00495##
Example 23-4 ##STR00496## Example 23-5 ##STR00497## Example 24-1
##STR00498## Example 24-2 ##STR00499## Example 24-3 ##STR00500##
Example 25-1 ##STR00501## Example 25-2 ##STR00502## Example 25-3
##STR00503## Example 25-4 ##STR00504## Example 25-5 ##STR00505##
Example 25-6 ##STR00506## Example 25-7 ##STR00507## Example 26-1
##STR00508## Example 26-2 ##STR00509## Example 26-3 ##STR00510##
Example 26-4
TABLE-US-00030 Structural Formula 23 ##STR00511## Example 30-1
##STR00512## Example 30-2 ##STR00513## Example 31-1 ##STR00514##
Example 31-2 ##STR00515## Example 31-3 ##STR00516## Example 31-4
##STR00517## Example 31-5 ##STR00518## Example 31-6 ##STR00519##
Example 32-1 ##STR00520## Example 32-2 ##STR00521## Example
32-3
TABLE-US-00031 Structural Formula 24 ##STR00522## Example 32-4
##STR00523## Example 32-5 ##STR00524## Example 33-1 ##STR00525##
Example 33-2 ##STR00526## Example 33-3 ##STR00527## Example 33-4
##STR00528## Example 35-1 ##STR00529## Example 35-2 ##STR00530##
Example 35-3 ##STR00531## Example 35-4 ##STR00532## Example 35-5
##STR00533## Reference Example 2
TABLE-US-00032 Structural Formula 25 ##STR00534## Example 37-1
##STR00535## Example 37-2 ##STR00536## Example 37-3 ##STR00537##
Example 38-1 ##STR00538## Example 38-2 ##STR00539## Example 38-3
##STR00540## Example 39-1 ##STR00541## Example 39-2 ##STR00542##
Example 39-3 ##STR00543## Example 40-1A ##STR00544## Example 40-1B
##STR00545## Example 40-2A ##STR00546## Example 40-3A ##STR00547##
Example 40-4A ##STR00548## Example 41-1B ##STR00549## Example 41-2B
##STR00550## Example 41-3B
TABLE-US-00033 Structural Formula 26 ##STR00551## Example 42-1A
##STR00552## Example 42-2A ##STR00553## Example 42-3A ##STR00554##
Example 43-1A ##STR00555## Example 43-2A ##STR00556## Example 43-3A
##STR00557## Example 44-1A ##STR00558## Example 44-2A ##STR00559##
Example 44-3A ##STR00560## Example 45-1A ##STR00561## Example 45-2A
##STR00562## Example 45-3A ##STR00563## Example 46-1A ##STR00564##
Example 46-2A ##STR00565## Example 46-3A ##STR00566## Example 47-1
##STR00567## Example 47-2 ##STR00568## Example 47-3 ##STR00569##
Example 47-4 ##STR00570## Example 47-5
TABLE-US-00034 Structural Formula 27 ##STR00571## Example 47-6
##STR00572## Example 47-7 ##STR00573## Example 48-1 ##STR00574##
Example 48-2 ##STR00575## Example 48-3 ##STR00576## Example 48-4
##STR00577## Example 48-5 ##STR00578## Example 49-1A ##STR00579##
Example 49-2A ##STR00580## Example 49-3A ##STR00581## Example 49-4A
##STR00582## Example 49-5A ##STR00583## Example 50-1A ##STR00584##
Example 50-2A ##STR00585## Example 50-3A ##STR00586## Example 51-1
##STR00587## Example 51-2 ##STR00588## Example 51-3
TABLE-US-00035 Structural Formula 28 ##STR00589## Example 53-1
##STR00590## Example 53-2 ##STR00591## Example 53-3 ##STR00592##
Example 54-1 ##STR00593## Example 54-2 ##STR00594## Example 55-1
##STR00595## Example 55-2 ##STR00596## Example 55-3 ##STR00597##
Example 52-1 ##STR00598## Example 52-2 ##STR00599## Example
52-3
TABLE-US-00036 TABLE 2 Example ESI-MS Retention Time No. (M + 1)+
(Minute) 1 494 6.10 2 512 6.03 3 526 6.00 4 530* 5.98 5(A)-b 543
5.32 6(A)-b 509 5.77 7(A)-a 530* 6.20 8 480 5.79 9 496 5.33 10 510
5.42 11 479 3.90 12 494 5.97 13(A)-a 542 5.62 14 445* 5.72# 15 559
6.50 16 456& -- 17 436& -- 18 459* 5.65 19 558 5.82# 20 525
4.73# 21 437 6.20# 22 436 6.30 *(M + Na)+, #TFA system,
&EI-MS(M+)
TABLE-US-00037 TABLE 3 MS-ESI (m/z) Retention Time Example [M +
H].sup.+ (Minute) 23 521 5.77 5.85 23-(A)-a 521 5.85 23-(A)-b 521
5.77 24 556** 6.08 6.17 24-(A)-a 534 6.17 24-(A)-b 534 6.08 25 445
5.67 25-(A)-a 445 5.65 25-(A)-b 445 5.60 26 477# 5.72 27 442** 5.98
28 420**, # 5.30 29 428, 430** 5.80, 5.92 30 590** 5.60# 31 572
5.82# 32 497 5.82# 33 436, 438 6.05# 34 586** 6.31# 35 539 5.02#
*[M - H].sup.- **[M + Na].sup.+ #TFAsystem
TABLE-US-00038 TABLE 4 MS-ESI (m/z) Retention Time Example [M +
H].sup.+ (Minute) 36# 551 5.70 37## 484** 1.24 38## 524** 1.19 39##
572** 1.22 40## 586** 1.19 41## 586** 1.20 42## 572** 1.21 43##
484** 1.24 44# 502 6.22 45# 620** 5.87 46## 514** 1.24 47## 600**
1.21 48## 472** 1.19 49## 472** 1.19 50## 497** 1.11 51 537 5.87
5.97 51(A)-a 537 5.87 51(A)-b 537 5.82 52 451 5.78 5.85 52(A)-a 451
5.78 52(A)-b 451 5.70 53 456** 6.18 6.30 53a 456** 6.27 53b 456**
6.18 54## 507 1.11 54(A)-a 507 5.92 54(A)-b 507 5.83 55## 435 0.87
55(A)-a 435 5.28 55(A)-b 435 5.23 56(A)-a## 428, 430** 1.13
56(A)-b## 428, 430** 1.14 57## 542** 1.18 58## 542** 1.19 59##
590** 1.09 60## 454** 1.22 61## 484** 1.20 62## 555 1.00 63## 449
1.09 64## 494** 1.16 65## 495** 1.13 66## 440** 1.19 67## 458**
1.19 68## 474** 1.13 69## 488** 1.18 #TFA system ##UPLC *[M -
H].sup.- **[M + Na].sup.+
TABLE-US-00039 TABLE 5 Substituted Phenylboronic Ester Substituted
Isothiazole ESI-MS Retention Time ESI-MS Retention Time Example No.
(M + 1)+ (Minute) (M + 1)+ (Minute) 1 532 5.87 492 6.08# 2 550 6.03
510 6.07# 3 586* 5.98 524 6.02# 4 546 5.95# 528* 6.05 5 581 4.32#
541 4.54# 6 547 5.62 507 4.83 7 568* 6.02 528* 6.53 8 632 6.97# 478
5.77# 9 668* 6.97# 494 5.45# 10 588 6.07# 508 5.75 11 617 6.12 577
6.57 12 574 6.15 492 6.01# 13 580 5.49 540 5.78 *(M + Na)+, #TFA
system
TABLE-US-00040 TABLE 6 Retention Retention Retention ESI-MS Time
ESI-MS Time ESI-MS Time No. (M + 1) + (Minute) No. (M + 1) +
(Minute) No. (M + 1) + (Minute) 14-1 426* 6.72 14-2 304 5.57 14-3
418 6.72 14-4 619* 6.84 14-5 441 5.98 15-1 562* 6.18 15-2 440 4.82
15-3 526 5.95 15-4 727* 6.18 15-5 605 5.70 16-1 266* 5.05 16-2 460*
6.92 16-3 338 6.45 16-4 424 6.82 16-5 503 6.38 17-1 246* 4.53 17-2
440* 6.65 17-3 318 5.95 17-4 404 6.68 17-5 505* 6.37 18-1 404 6.56
18-2 605* 6.72 18-3 483 6.35 19-1 556 6.22# 21-1 339 6.45 21-2 404
4.42 21-3 505* 6.17 22-1 358* 5.40 22-2 634 7.06 22-3 788* 6.80
22-4 730* 6.92 22-5 468 6.13 *(M + Na) +, #: TFA system
TABLE-US-00041 TABLE 7 MS-ESI (m/z) Retention Time Example [M +
H].sup.+ (Minute) 23-1 296** 5.78 23-3 443*, # 5.75 23-5 519 6.08
24-1 309** 6.22 24-2 343** 5.94 24-3 532 6.46 25-3 285** 5.18 25-4
358** 6.15 25-5 234# 5.18 25-6 481* 5.57 25-7 443# 5.70 30-1 343,
345** 5.63 31-1 378** 6.52 31-2 475** 6.20 31-3 813** 7.03 31-4
944** 6.85 31-5 886** 6.87 31-6 626** 5.63 32-1 572** 7.06 32-2
704** 6.92 32-3 646** 7.03 32-4 556** 6.50 32-5 789** 7.05 33-1 --
6.13 33-2 678, 680** 7.37 33-3 808, 810** 7.24 33-4 750, 752** 7.26
35-1 650, 652** 7.23 35-2 782, 784** 7.03 35-3 724, 726** 7.10 35-4
464, 466** 5.55 35-5 432, 434** 5.78# Reference 433, 435** 5.93
Example 2 *[M - H].sup.- **[M + Na].sup.+ #TFA system
TABLE-US-00042 TABLE 8 MS-ESI (m/z) Retention Time Example [M +
H].sup.+ (Minute) 37-1## 776** 1.66 37-2## 762** 1.51 37-3## 502**
1.17 38-1## 816** 1.47 38-2## 802** 1.39 38-3## 542** 1.12 39-1##
864** 1.54 39-2## 850** 1.43 39-3## 590** 1.15 40-1A## 750, 752**
1.51 40-1B## 750, 752** 1.51 40-2A## 878** 1.46 40-3A## 864** 1.38
40-4A## 604** 1.12 41-1B## 878** 1.46 41-2B## 864** 1.39 41-3B##
604** 1.12 42-2A## 850** 1.42 42-3A## 590** 1.14 43-1A## 776** 1.61
43-2A## 762** 1.49 43-3A## 502** 1.16 44-1A## 816** 1.45 44-2A##
802** 1.38 44-3A## 542** 1.11 45-1A## 912** 1.35 45-2A## 898** 1.30
45-3A## 638** 1.03 46-1A## 806** 1.56 46-2A## 792** 1.45 46-3A##
532** 1.14 47-1# 353, 355** 6.37 47-2## 690, 692** 1.68 47-3## 820,
822** 1.45 47-4## 764, 766** 1.54 47-5## 892** 1.48 47-6## 879**
1.39 47-7## 618** 1.14 48-1## 730 (Boronic 1.33 acid + Na) 48-2##
688** 1.30 48-3## 764** 1.53 48-4## 750** 1.42 48-5## 490** 1.11
49-1A## 730 (Boronic 1.33 acid + Na) 49-2A## 688** 1.29 49-3A##
764** 1.50 49-4A## 750** 1.41 49-5A## 490** 1.11 50-1A## 789** 1.37
50-2A## 775** 1.32 50-3A## 515** 1.04 51-1 344 5.50 51-2 575 5.78
51-3 535 5.90 52-1 258 5.13 52-2 489 5.62 52-3# 449 5.82 53-1 223
(M - H.sub.2O + 1) 5.85 53-2 494** 6.10 53-3# 454** 6.27 54-1 260,
262 5.85 54-2## 294 0.53 55-1 242 4.28 55-2 473 5.20 55-3# 433 4.38
#TFA system ##UPLC *[M - H].sup.- **[M + Na].sup.+
TABLE-US-00043 TABLE 9 Example NMR data (.delta.: ppm) <400 MHz
(*300 MHz)> 1 (CDCl.sub.3) .delta.: 7.42 (1H, t, J = 8 Hz),
7.40-7.32 (1H, m), 7.20-7.13 (1H, m), 7.17 (2H, d, J = 9 Hz),
7.12-7.07 (1H, m), 6.98 (2H, d, J = 9 Hz), 6.68 (2H, s), 5.10 (2H,
s), 4.41 (1H, d, J = 7 Hz), 4.13 (2H, t, J = 5 Hz), 3.80 (2H, t, J
= 5 Hz), 3.62 (2H, q, J = 7 Hz), 3.55 (1H, d, J = 8 Hz), 2.91-2.84
(1H, m), 1.97 (6H, s), 1.25 (3H, t, J = 7 Hz). 12* (CDCl.sub.3)
.delta.: 7.50-7.33 (4H, m), 7.21-6.96 (4H, m), 6.68 (2H, s),
5.16-5.10 (2H, m), 4.53-4.39 (1H, m), 4.26-4.07 (3H, m), 3.70-3.52
(0.25H, m, isomer-1), 3.35-3.21 (0.75H, m, isomer-2), 3.02-2.83
(1H, m), 2.03-1.90 (2H, m), 2.00 (6H, s), 1.30 (3H, d, J = 6 Hz).
13 (DMSO-D.sub.6) .delta.: 11.00 (1H, s), 7.48-7.35 (2H, m), 7.22
(2H, d, J = 9 Hz), 7.14 (1H, s), 7.09-7.00 (3H, m), 6.70 (2H, s),
5.16 (2H, s), 4.51 (1H, d, J = 8 Hz), 4.08 (2H, t, J = 6 Hz),
3.52-3.39 (1H, m), 3.27 (2H, t, J = 8 Hz), 3.02 (3H, s), 2.80 (1H,
d, J = 17 Hz), 2.19-2.08 (2H, m), 1.90 (6H, s). 14* (DMSO-D.sub.6)
.delta.: 7.50-7.37 (2H, m), 7.22-6.88 (9H, m), 5.10 (2H, s), 3.90
(2H, s), 1.95 (6H, s). 16* (CDCl.sub.3) .delta.: 7.57-7.28 (3H, m),
7.20-6.95 (6H, m), 6.95-6.80 (1H, m), 5.07 (2H, s), 4.40 (2H, br
s), 1.99 (6H, s). 17* (CDCl.sub.3) .delta.: 7.48-7.28 (3H, m),
7.20-7.01 (5H, m), 6.89-6.77 (2H, m), 5.08 (2H, s), 4.29 (2H, br
s), 2.36 (3H, s), 2.00 (6H, s). 18* (CDCl.sub.3) .delta.: 7.50-7.31
(4H, m), 7.21-7.00 (7H, m), 5.14 (2H, s), 4.51 (1H, q, J = 7 Hz),
2.01 (6H, s), 1.45 (3H, d, J = 7 Hz). 19 (DMSO-D.sub.6) .delta.:
7.47-7.38 (2H, m), 7.20 (2H, d, J = 9 Hz), 7.16 (1H, s), 7.05 (1H,
dt, J = 7.2 Hz), 6.96 (2H, d, J = 9 Hz), 6.70 (2H, s), 5.14 (2H,
s), 4.33 (1H, t, J = 8 Hz), 4.08 (2H, t, J = 6 Hz), 3.30-3.24 (1H,
m), 3.02 (3H, s), 2.84 (1H, dd, J = 16, 8 Hz), 2.63 (2H, dd, J =
16, 8 Hz), 2.17-2.10 (2H, m), 1.92 (6H, s). 21 (DMSO-D.sub.6)
.delta.: 11.97 (1H, br s), 7.93 (1H, br s), 7.52-7.41 (2H, m), 7.37
(2H, d, J = 9 Hz), 7.20 (1H, s), 7.18-7.08 (4H, m), 7.03 (2H, d, J
= 9 Hz), 5.19 (2H, s), 4.76-4.66 (1H, m), 2.80-2.66 (1H, m),
2.64-2.54 (1H, m), 1.95 (6H, s). 22 (CDCl.sub.3) .delta.: 7.46 (1H,
t, J = 8 Hz), 7.40 (1H, d, J = 8 Hz), 7.22-7.08 (7H, m), 6.99 (2H,
d, J = 9 Hz), 5.13 (2H, s), 3.81-3.69 (1H, m), 3.66-3.59 (1H, m),
3.45 (1H, dd, J = 14, 12 Hz), 3.03-2.92 (1H, m), 2.82 (1H, dd, J =
17, 12 Hz), 2.01 (6H, s).
TABLE-US-00044 TABLE 10 Example NMR data (.delta.: ppm)<400 MHz
(*300 MHz)> 23 (A)-a 1H-NMR (CDCl.sub.3) .delta.: 7.47-7.27 (4H,
m), 7.22 (2H, d, J = 9 Hz), 7.16 (1H, d, J = 6 Hz), 7.04 (2H, d, J
= 9 Hz), 6.61 (1H, d, J = 8 Hz), 5.84-5.79 (1H, m), 4.56 (2H, t, J
= 6 Hz), 4.44 (1H, d, J = 8 Hz), 3.60 (1H, dd, J = 17.8 Hz),
2.92-2.80 (1H, m), 2.91 (1H, d, 17 Hz), 2.71-2.60 (1H, m),
2.60-2.49 (1H, m), 2.27 (3H, s), 2.19-2.09 (1H, m), 2.02 (2H, t, J
= 6 Hz), 1.32 (6H, s). 23 (A)-b 1H-NMR (CDCl.sub.3) .delta.: 7.62
(1H, s), 7.45-7.29 (5H, m), 7.16 (1H, d, J = 6 Hz), 7.09 (2H, d, J
= 9 Hz), 6.61 (1H, d, J = 8 Hz), 5.86-5.82 (1H, m), 4.56 (2H, t, J
= 6 Hz), 4.51 (1H, dd, J = 12.7 Hz), 3.30 (1H, dd, J = 17.12 Hz),
2.98 (1H, dd, J = 17.7 Hz), 2.94-2.81 (1H, m), 2.73-2.51 (2H, m),
2.28 (3H, s), 2.21-2.11 (1H, m), 2.02 (2H, t, J = 6 Hz), 1.32 (6H,
s). 25 (A)-a* .sup.1H-NMR (CDCl.sub.3) .delta.: 7.68 (1H, s), 7.60
(2H, d, J = 9 Hz), 7.33-7.28 (2H, m), 7.22 (2H, d, J = 9 Hz), 7.02
(2H, d, J = 9 Hz), 7.03-6.98 (1H, m), 6.97 (2H, d, J = 9 Hz), 5.79
(1H, dd, J = 7.5 Hz), 4.44 (1H, d, J = 8 Hz), 3.60 (1H, dd, J =
18.8 Hz), 3.01-2.88 (1H, m), 2.90 (1H, d, J = 18 Hz), 2.82-2.69
(1H, m), 2.61-2.51 (1H, m), 2.24-2.11 (1H, m). 26 1H-NMR
(CDCl.sub.3) .delta.: 7.62 (2H, d, J = 9 Hz), 7.38-7.30 (4H, m),
7.07 (2H, d, J = 9 Hz), 7.02 (1H, dd, J = 4.4 Hz), 6.99 (2H, d, J =
9 Hz), 5.86-5.79 (1H, m), 5.00-4.91 (1H, m), 4.65 (1H, d, J = 11
Hz), 3.09 (1H, dd, J = 17.4 Hz), 3.03-2.91 (1H, m), 2.91 (1H, dd, J
= 12, 17 Hz), 2.83-2.72 (1H, m), 2.67-2.55 (1H, m), 2.27-2.15 (1H,
m). 31 1H-NMR (CDCl3) .delta.: 7.48-7.34 (2H, m), 7.19-7.03 (4H,
m), 7.01-6.92 (2H, m), 6.64 (2H, s), 5.10 (2H, s), 4.18-4.06 (2H,
m), 3.80-3.56 (2H, m), 3.53-3.37 (1H, m), 3.31-3.22 (2H, m),
3.01-2.90 (1H, m), 2.97 (3H, s), 2.86-2.71 (1H, m), 2.42-2.29 (2H,
m), 1.97 (6H, s). 35 1H-NMR (DMSO-D6).delta.: 7.50-7.40 (2H, m),
7.23-7.16 (3H, m), 7.15-7.10 (1H, m), 6.93 (2H, d, J = 9 Hz), 6.55
(1H, s), 5.13 (2H, s), 4.37 (1H, s), 4.33 (2H, t, J = 7 Hz),
3.26-3.15 (1H, m), 2.94-2.79 (2H, m), 2.28-2.20 (1H, m), 2.19-2.09
(1H, m), 2.06 (3H, s), 1.90 (3H, s), 1.82 (2H, t, J = 7 Hz), 1.16
(6H, s). 36 .sup.1H-NMR (DMSO-D.sub.6) .delta.: 7.49 (1H, d, J = 8
Hz), 7.40 (1H, d, J = 8 Hz), 7.35-7.28 (1H, m), 7.24 (2H, d, J = 9
Hz), 7.18 (1H, d, J = 6 Hz), 6.98 (2H, d, 7 = 9 Hz), 6.65 (1H, d, J
= 8 Hz), 5.90-5.84 (1H, m), 4.39 (1H, s), 4.37 (2H, t, J = 7 Hz),
3.54-2.85 (3H, m), 2.84-2.44 (3H, m), 2.38-2.14 (2H, m), 2.21 (3H,
s), 2.06-1.92 (1H, m), 1.85 (2H, t, J = 7 Hz), 1.18 (6H, s).
TABLE-US-00045 TABLE 11 Example NMR data (.delta.: ppm) <*300
MHz> 40 .sup.1H-NMR (DMSO-D.sub.6) .delta.: 12.14 (1H, s),
7.39-7.28 (4H, m), 7.06-6.98 (3H, m), 6.70 (2H, s), 5.94-5.88 (1H,
m), 4.38 (1H, s), 4.07 (2H, t, J = 7 Hz), 3.84-3.42 (3H, m),
2.84-2.62 (2H, m), 2.61-2.35 (3H, m), 2.00-1.88 (1H, m), 1.90 (3H,
s), 1.87 (3H, s), 1.84 (2H, t, J = 7 Hz), 1.18 (6H, s). 42
.sup.1H-NMR (DMSO-D.sub.6) .delta.: 12.14 (1H, brs), 7.35-7.31 (4H,
m), 7.03-7.00 (3H, m), 6.72 (2H, s), 5.92-5.90 (1H, m), 4.09-4.07
(2H, m), 3.81-3.78 (1H, m), 3.70-3.67 (3H, m), 3.59-3.55 (1H, m),
3.51 (2H, q, J = 7 Hz), 2.85-2.64 (2H, m), 2.61-2.35 (3H, m),
1.98-1.88 (1H, m), 1.90 (3H, s), 1.87 (3H, s), 1.14 (3H, t, J = 7
Hz). 44* .sup.1H-NMR (DMSO-D.sub.6) .delta.: 12.12 (1H, s), 7.85
(1H, d, J = 8 Hz), 7.73 (1H, dd, J = 7, 7 Hz), 7.66-7.58 (1H, m),
7.47-7.26 (5H, m), 7.16 (1H, d, J = 7 Hz), 7.03 (2H, d, J = 8 Hz),
5.95-5.87 (1H, m), 3.79-3.45 (3H, m), 2.83-2.35 (5H, m), 2.04-1.85
(1H, m). 47 .sup.1H-NMR (*DMSO-D.sub.6) .delta.: 12.07 (1H, s),
7.39-7.22 (3H, m), 7.03-6.96 (1H, m), 6.94-6.85 (2H, m), 6.69 (2H,
s), 5.93-5.85 (1H, m), 4.35 (1H, s), 4.07 (2H, t, J = 7 Hz),
3.77-3.43 (3H, m), 2.86-2.22 (5H, m), 2.31 (3H, s), 1.97-1.77 (3H,
m), 1.90 (3H, s), 1.87 (3H, s), 1.18 (6H, s). 48 .sup.1H-NMR
(DMSO-D.sub.6) .delta.: 7.44-6.85 (12H, m), 5.85 (1H, dd, J = 6, 4
Hz), 3.30-2.46 (5H, m), 2.37-1.93 (4H, m). 51 (A)-a .sup.1H-NMR
(DMSO-D.sub.6) .delta.: 7.35 (1H, d, J = 9 Hz), 7.26 (2H, d, J = 9
Hz), 7.20-7.14 (1H, m), 7.12-7.03 (3H, m), 6.65 (1H, d, J = 9 Hz),
6.52 (1H, d, J = 8 Hz), 5.89 (1H, dd, J = 7, 4 Hz), 4.50 (1H, d, J
= 8 Hz), 4.38 (1H, s), 4.32 (2H, t, J = 7 Hz), 3.55-3.20 (1H, m),
3.06-2.93 (1H, m), 2.92-2.74 (2H, m), 2.70-2.55 (1H, m), 2.27 (3H,
s), 2.10-1.98 (1H, m), 1.83 (2H, t, J = 7 Hz), 1.17 (6H, s). 51
(A)-b .sup.1H-NMR (DMSO-D.sub.6) .delta.: 7.41 (2H, d, J = 9 Hz),
7.36 (1H, d, J = 9 Hz), 7.22-7.15 (1H, m), 7.11 (1H, d, J = 7 Hz),
7.07 (2H, d, J = 9 Hz), 6.65 (1H, d, J = 9 Hz), 6.53 (1H, d, J = 8
Hz), 5.92 (1H, dd, J = 7, 4 Hz), 4.79-4.69 (1H, m), 4.38 (1H, s),
4.32 (2H, t, J = 7 Hz), 3.53-2.39 (5H, m), 2.27 (3H, s), 2.11-2.00
(1H, m), 1.83 (2H, t, J = 7 Hz), 1.17 (6H, s). 54 (A)-a .sup.1H-NMR
(DMSO-D.sub.6) .delta.: 11.05 (1H, s), 7.51 (1H, d, J = 8 Hz), 7.40
(1H, d, J = 8 Hz), 7.32 (1H, t, J = 7 Hz), 7.27 (2H, d, J = 9 Hz),
7.21-7.17 (1H, m), 7.10 (2H, d, J = 9 Hz), 6.70 (1H, d, J = 8 Hz),
5.94-5.89 (1H, m), 4.54 (1H, d, J = 8 Hz), 4.39 (2H, t, J = 5 Hz),
3.71 (2H, t, J = 5 Hz), 3.54-3.40 (1H, m), 3.50 (2H, q, J = 7 Hz),
2.82 (1H, d, J = 17 Hz), 2.82-2.43 (3H, m), 2.20 (3H, s), 2.03-1.90
(1H, m), 1.13 (3H, t, J = 7 Hz). 56 (A)-a .sup.1H-NMR (CDCl.sub.3)
.delta.: 7.89 (1H, s), 7.48 (1H, d, J = 8 Hz), 7.42-7.33 (3H, m),
7.17-7.10 (1H, m), 7.07-7.02 (2H, m), 5.83 (1H, dd, J = 7, 5 Hz),
4.50 (1H, dd, J = 12, 7 Hz), 3.29 (1H, dd, J = 17, 12 Hz),
3.21-3.09 (1H, m), 3.03-2.89 (2H, m), 2.66-2.53 (1H, m), 2.28-2.15
(1H, m). 56 (A)-b .sup.1H-NMR (CDCl.sub.3) .delta.: 7.48 (1H, d, J
= 8 Hz), 7.33 (1H, d, J = 7 Hz), 7.21 (2H, d, J = 9 Hz), 7.17-7.09
(1H, m), 7.00 (2H, d, J = 9 Hz), 5.81 (1H, dd, J = 7, 4 Hz), 4.43
(1H, d, J = 8 Hz), 3.60 (1H, dd, J = 18, 8 Hz), 3.23-3.08 (1H, m),
3.02-2.82 (2H, m), 2.64-2.51 (1H, m), 2.25-2.13 (1H, m). 57
.sup.1H-NMR (DMSO-D.sub.6) .delta.: 11.10 (1H, s), 7.42 (2H, d, J =
9 Hz), 7.39-7.28 (2H, m), 7.09 (2H, d, J = 9 Hz), 7.03-6.99 (1H,
m), 6.72 (2H, s), 5.99-5.92 (1H, m), 4.79 (1H, dd, J = 12, 7 Hz),
4.10-4.05 (2H, m), 3.73-3.66 (2H, m), 3.51 (2H, q, J = 7 Hz), 3.23
(1H, dd, J = 17, 12 Hz), 2.86 (1H, dd, J = 17, 8 Hz), 2.63-2.36
(3H, m), 2.01-1.89 (1H, m), 1.91 (3H, s), 1.87 (3H, s), 1.14 (3H,
t, J = 7 Hz). 58 .sup.1H-NMR (DMSO-D.sub.6) .delta.: 11.04 (1H, s),
7.38-7.28 (2H, m), 7.26 (2H, d, J = 9 Hz), 7.10 (2H, d, J = 9 Hz),
7.00 (1H, d, J = 7 Hz), 6.72 (2H, s), 5.96-5.90 (1H, m), 4.54 (1H,
d, J = 7 Hz), 4.08 (2H, t, J = 5 Hz), 3.69 (2H, t, J = 5 Hz), 3.51
(2H, q, J = 7 Hz), 3.35-3.27 (1H, m), 2.82 (1H, d, J = 17 Hz),
2.62-2.37 (3H, m), 1.99-1.88 (1H, m), 1.90 (3H, s), 1.87 (3H, s),
1.14 (3H, t, J = 7 Hz). 59* .sup.1H-NMR (DMSO-D.sub.6) .delta.:
11.01 (1H, s), 7.39-7.29 (2H, m), 7.26 (2H, d, J = 9 Hz), 7.10 (2H,
d, J = 9 Hz), 7.00 (1H, dd, J = 7, 2 Hz), 6.72 (2H, s), 5.98-5.88
(1H, m), 4.53 (1H, d, J = 8 Hz), 4.09 (2H, t, J = 6 Hz), 3.52-3.38
(1H, m), 3.37-3.28 (1H, m), 3.34-3.28 (2H, m), 3.30-3.23 (1H, m),
3.03 (3H, s), 2.87-2.76 (1H, m), 2.63-2.50 (1H, m), 2.48-2.34 (1H,
m), 2.21-2.07 (2H, m), 1.95-1.82 (6H, m). 64 .sup.1H-NMR
(CDCl.sub.3) .delta.: 7.80-7.72 (1H, m), 7.59-7.53 (1H, m),
7.53-7.38 (3H, m), 7.34-7.23 (2H, m), 7.24-7.17 (2H, m), 7.04 (2H,
d, J = 9 Hz), 5.87-5.77 (1H, m), 4.44 (1H, d, J = 8 Hz), 3.60 (1H,
dd, J = 18, 8 Hz), 2.94-2.88 (1H, m), 2.91-2.63 (2H, m), 2.63-2.45
(1H, m), 2.21-2.05 (1H, m). 68 .sup.1H-NMR (CDCl.sub.3) .delta.:
7.48-7.41 (1H, m), 7.36-7.28 (2H, m), 7.21 (2H, d, J = 9 Hz),
7.15-7.08 (1H, m), 7.05 (2H, d, J = 9 Hz), 7.02-6.94 (1H, m),
6.91-6.83 (1H, m), 5.86-5.78 (1H, m), 4.44 (1H, d, J = 7 Hz), 3.93
(3H, s), 3.59 (1H, dd, J = 18, 8 Hz), 3.08-2.97 (1H, m), 2.96-2.80
(2H, m), 2.62-2.49 (1H, m), 2.23-2.08 (1H, m).
TABLE-US-00046 TABLE 12 Substituted Isothiazole Example NMR data
(.delta.: ppm) <400 MHz (*300 MHz)> 1-6 (DMSO-D.sub.6)
.delta.: 11.27 (1H, s), 7.80 (2H, d, J = 9 Hz), 7.51-7.40 (2H, m),
7.24-7.16 (3H, m), 7.08 (1H, d, J = 7 Hz), 7.07 (1H, s), 6.71 (2H,
s), 5.27 (2H, s), 4.10-4.05 (2H, m), 3.72-3.66 (2H, m), 3.51 (2H,
q, J = 7 Hz), 1.92 (6H, s), 1.14 (3H, t, J = 7 Hz) 12-5
(DMSO-D.sub.6) .delta.: 11.28 (1H, s), 7.83-7.76 (2H, m), 7.50-7.39
(2H, m), 7.24-7.16 (3H, m), 7.08 (2H, d, J = 9 Hz), 6.68 (2H, s),
5.26 (2H, s), 4.58-4.53 (1H, m), 4.09-3.95 (2H, m), 3.87-3.74 (1H,
m), 1.91 (6H, s), 1.81-1.68 (2H, m), 1.15-1.08 (3H, m) 13-5
(DMSO-D.sub.6) .delta.: 7.79 (2H, d, J = 9 Hz), 7.50-7.39 (2H, m),
7.23-7.16 (3H, m), 7.11-7.03 (2H, m), 6.71 (2H, s), 5.26 (2H, s),
4.08 (2H, t, J = 6 Hz), 3.31-3.24 (2H, m), 3.03 (3H, s), 2.19-2.09
(2H, m), 1.92 (6H, s)
TABLE-US-00047 TABLE 13 Substituted Boronic Ester Example NMR data
(.delta.: ppm) <400 MHz (*300 MHz)> 1-3 (CDCl.sub.3) .delta.:
7.45-7.35 (4H, m), 7.18 (1H, s), 7.11-7.06 (1H, m), 6.99 (2H, d, J
= 9 Hz), 6.69 (2H, s), 5.11 (2H, s), 4.16-4.12 (2H, m), 3.95 (2H,
d, J = 16 Hz), 3.80 (2H, t, J = 5 Hz), 3.75 (2H, d, J = 16 Hz),
3.62 (2H, q, J = 7 Hz), 2.53 (3H, s), 1.98 (6H, s), 1.25 (3H, t, J
= 7 Hz) 12-4 (CDCl.sub.3) .delta.: 7.47-7.35 (4H, m), 7.17 (1H, s),
7.08 (1H, d, J = 7 Hz), 6.99 (2H, d, J = 9 Hz), 6.63 (2H, s),
5.20-5.06 (2H, m), 5.12 (1H, s), 4.01 (2H, t, J = 6 Hz), 3.89 (2H,
d, J = 16 Hz), 3.74 (2H, d, J = 16 Hz), 2.54 (3H, s), 2.12-1.99
(2H, m), 2.05 (3H, s), 1.98 (6H, s), 1.32 (3H, d, J = 6 Hz) 13-4*
(DMSO-D.sub.6) .delta.: 7.50-7.37 (2H, m), 7.33 (2H, d, J = 9 Hz),
7.16 (1H, s), 7.10-7.02 (1H, m), 6.99 (2H, d, J = 9 Hz), 6.70 (2H,
s), 5.16 (2H, s), 4.30 (2H, d, J = 17 Hz), 4.14-3.97 (4H, m),
3.31-3.22 (2H, m), 3.03 (3H, s), 2.47 (3H, s), 2.20-2.07 (2H, m),
1.91 (6H, s)
TABLE-US-00048 TABLE 14 Example NMR data (.delta.: ppm) <400 MHz
(*300 MHz)> 14-3 (CDCl.sub.3) .delta.: 7.46-7.36 (2H, m),
7.21-7.12 (2H, m), 7.12-7.05 (3H, m), 6.84 (2H, d, J = 9 Hz), 6.55
(2H, d, J = 9 Hz), 5.03 (2H, s), 4.01 (1H, br s), 3.75 (2H, s),
2.01 (6H, s), 1.47 (9H, s). 14-5* (CDCl.sub.3) .delta.: 7.49-7.32
(4H, m), 7.22-7.05 (5H, m), 6.96 (2H, d, J = 9 Hz), 5.11 (2H, s),
5.00 (2H, br s), 4.45 (2H, s), 2.01 (6H, s). 18-3* (CDCl.sub.3)
.delta.: 7.49-7.28 (4H, m), 7.22-7.04 (5H, m), 7.00-6.91 (2H, m),
5.11 (2H, s), 4.95 (1H, q, J = 8 Hz), 4.25 (2H, q, J = 7 Hz), 2.01
(6H, s), 1.31 (3H, t, J = 7 Hz), 1.23 (4H, d, J = 8 Hz). 21-2*
(CDCl.sub.3) .delta.: 7.49-7.36 (2H, m), 7.27 (2H, d, J = 9 Hz),
7.22-7.06 (5H, m), 6.94 (2H, d, J = 9 Hz), 5.10 (2H, s), 4.38 (1H,
dd, J = 8, 6 Hz), 4.13 (2H, q, J = 7 Hz), 2.70-2.59 (2H, m), 2.01
(6H, s), 1.23 (3H, t, J = 7 Hz). 22-3* (CDCl.sub.3) .delta.:
7.49-7.37 (2H, m), 7.24-7.06 (11H, m), 6.90 (2H, d, J = 9 Hz), 6.83
(4H, d, J = 9 Hz), 5.08 (2H, s), 4.22 (2H, d, J = 15 Hz), 4.03-3.96
(1H, m), 4.03 (2H, d, J = 15 Hz), 3.85 (1H, d, 7 = 8 Hz), 3.80 (6H,
s), 3.70 (3H, s), 3.62-3.51 (1H, m), 3.55 (3H, s), 3.32 (1H, dd, J
= 14, 8 Hz), 2.03 (6H, s). 22-4* (CDCl.sub.3) .delta.: 7.51-7.37
(2H, m), 7.24-7.14 (6H, m), 7.14-7.08 (3H, m), 7.03 (2H, d, J = 9
Hz), 6.90 (2H, d, J = 9 Hz), 6.85 (4H, d, J = 9 Hz), 5.09 (2H, s),
4.31 (2H, d, J = 15 Hz), 4.11 (2H, d, J = 15 Hz), 3.81 (6H, s),
3.76-3.63 (1H, m), 3.56 (3H, s), 3.25 (1H, dd, J = 14, 8 Hz), 3.10
(1H, t, J = 5 Hz), 3.05 (1H, dd, J = 5, 2 Hz), 2.69 (1H, dd, J =
16, 9 Hz), 2.02 (6H, s). 22-5 (CDCl.sub.3) .delta.: 7.46 (1H, t, 7
= 8 Hz), 7.39 (1H, d, 7 = 8 Hz), 7.23-7.15 (4H, m), 7.15-7.08 (3H,
m), 6.96 (2H, d, J = 7 Hz), 5.10 (2H, s), 4.23 (2H, br s),
3.82-3.71 (1H, m), 3.63 (3H, s), 3.54 (1H, dd, J = 14, 7 Hz), 3.39
(1H, dd, J = 14, 8 Hz), 2.94 (1H, dd, J = 16, 7 Hz), 2.73 (1H, dd,
J = 16, 7 Hz), 2.02 (6H, s).
TABLE-US-00049 TABLE 15 Example NMR data (.delta.: ppm)<400 MHz
(*300 MHz)> 23-2* .sup.1H-NMR (CDCl.sub.3) .delta.: 7.92 (1H, d,
J = 8 Hz), 6.51 (1H, d, J = 8 Hz), 4.55 (2H, t, J = 6 Hz), 3.77
(4H, s), 2.64 (3H, s), 1.98 (2H, t, J = 6 Hz), 1.29 (6H, s), 1.03
(6H, s). 23-4 .sup.1H-NMR (DMSO-d.sub.6) 11.28 (1H, s), 7.83 (2H,
d, J = 9 Hz), 7.57 (1H, d, J = 8 Hz), 7.46-7.41 (1H, m), 7.27-7.19
(1H, m), 7.23 (2H, d, J = 9 Hz), 7.11 (1H, s), 6.10 (1H, dd, J = 7,
4 Hz), 3.11-2.97 (1H, m), 2.97-2.83 (1H, m), 2.71-2.58 (1H, m),
2.15-2.00 (1H, m) 25-1 .sup.1H-NMR (CDCl.sub.3) .delta.: 7.42-7.38
(3H, m), 7.28 (1H, d, J = 8 Hz), 7.09 (2H, dt, J = 14, 6 Hz), 5.37
(1H, t, J = 6 Hz), 5.21 (1H, dd, J = 7, 5 Hz), 4.86-4.81 (2H, m),
4.03-3.93 (2H, m), 3.63-3.54 (2H, m), 3.13-3.03 (2H, m), 2.86-2.77
(2H, m), 2.49-2.38 (2H, m), 2.21-2.13 (1H, m), 2.06-1.98 (1H, m),
1.91-1.78 (2H, m), 1.78-1.68 (2H, m), 1.68-1.47 (8H, m). 25-2
.sup.1H-NMR (CDCl.sub.3) .delta.: 7.72-7.68 (2H, m), 7.52 (1H, d, J
= 7 Hz), 7.40 (1H, d, J = 8 Hz), 7.24-7.16 (2H, m), 5.29 (1H, t, J
= 6 Hz), 5.13 (1H, dd, J = 7, 5 Hz), 4.87 (1H, t, J = 4 Hz), 4.83
(1H, dd, J = 5, 3 Hz), 4.08-3.94 (2H, m), 3.75 (4H, s), 3.75 (4H,
s), 3.62-3.54 (2H, m), 3.33-3.22 (2H, m), 3.04-2.94 (2H, m),
2.42-2.32 (2H, m), 2.16-2.07 (1H, m), 1.75-1.52 (13H, m), 1.02 (6H,
s), 1.01 (6H, s). 26-1* 1H-NMR (DMSO-d6) .delta.: 9.84 (1H, d, J =
9 Hz), 9.42 (1H, s), 7.14 (2H, d, J = 8 Hz), 6.70 (2H, d, J = 8
Hz), 5.17 (1H, ddd, J = 9 Hz, 9 Hz, 6 Hz), 4.09-3.98 (2H, m), 2.92
(1H, dd, J = 16 Hz, 9 Hz), 2.80 (1H, dd, J = 16 Hz, 6 Hz), 1.12
(3H, t, J = 7 Hz). 26-2* 1H-NMR (CDCl3) .delta.: 7.71 (1H, d, J = 9
Hz), 7.61 (2H, d, J = 9 Hz), 7.35-7.30 (2H, m), 7.26 (2H, d, J = 9
Hz), 7.04-6.95 (5H, m), 5.79 (1H, dd, J = 7 Hz, 4 Hz), 5.45-5.35
(1H, m), 4.15 (2H, q, J = 7 Hz), 3.04-2.86 (3H, m), 2.83-2.68 (1H,
m), 2.66-2.51 (1H, m), 2.29-2.12 (1H, m), 1.23 (3H, t, J = 7 Hz).
26-3* 1H-NMR (CD3OD) .delta.: 7.69 (2H, d, J = 9 Hz), 7.35-7.28
(4H, m), 7.06-6.96 (5H, m), 5.85 (1H, dd, J = 7 Hz, 4 Hz), 4.29
(1H, dd, J = 7 Hz, 8 Hz), 4.09 (2H, q, J = 7 Hz), 2.95-2.81 (1H,
m), 2.80-2.50 (4H, m), 2.18-2.04 (1H, m), 1.20 (3H, t, J = 7 Hz).
26-4* 1H-NMR (CDCl3) .delta.: 7.61 (2H, d, J = 9 Hz), 7.37-7.30
(4H, m), 7.06-6.95 (5H, m), 5.79 (1H, dd, J = 7 Hz, 4 Hz), 5.48
(1H, d, J = 7 Hz), 4.94-4.84 (1H, m), 4.43 (2H, s), 4.13 (2H, q, J
= 7 Hz), 3.03-2.84 (3H, m), 2.83-2.68 (1H, m), 2.66-2.50 (1H, m),
2.27-2.12 (1H, m), 1.24 (3H, t, J = 7 Hz). 30-2 1H-NMR (CDCl3)
.delta.: 6.48 (2H, s), 4.07 (2H, t, J = 6 Hz), 3.77 (4H, s),
3.28-3.18 (2H, m), 2.93 (3H, s), 2.36 (6H, s), 2.36-2.24 (2H, m),
1.09 (6H, s). 33-1 1H-NMR (CDCl3) .delta.: 9.90 (1H, s), 7.87 (2H,
d, J = 9 Hz), 7.50 (1H, d, J = 8 Hz), 7.37 (1H, d, J = 8 Hz), 7.15
(1H, t, J = 8 Hz), 7.09 (2H, d, J = 9 Hz), 5.96-5.89 (1H, m),
3.23-3.12 (1H, m), 3.03-2.92 (1H, m), 2.70-2.59 (1H, m), 2.29-2.18
(1H, m). 35-5 1H-NMR (DMSO-D6) .delta.: 12.15 (1H, s), 7.64 (1H,
s), 7.52 (1H, d, J = 8 Hz), 7.44 (1H, d, J = 8 Hz), 7.35 (1H, t, J
= 8 Hz), 7.30 (2H, d, J = 9 Hz), 6.98 (2H, d, J = 9 Hz), 5.11 (2H,
s), 3.84-3.73 (1H, m), 3.73-3.62 (1H, m), 3.62-3.49 (1H, m),
2.82-2.71 (1H, m), 2.71-2.60 (1H, m).
TABLE-US-00050 TABLE 16 Example NMR data (.delta.: ppm) <*300
MHz> 40-1A .sup.1H-NMR (CDCl.sub.3) .delta.: 7.46 (1H, d, J = 8
Hz), 7.32 (1H, d, J = 7 Hz), 7.16 (2H, d, J = 9 Hz), 7.14-7.08 (1H,
m), 6.91 (2H, d, J = 9 Hz), 5.76 (1H, dd, J = 7, 4 Hz), 4.71 (2H,
d, J = 10 Hz), 4.67 (2H, d, J = 10 Hz), 3.82-3.72 (1H, m),
3.61-3.33 (9H, m), 3.18-3.03 (2H, m), 2.97-2.87 (1H, m), 2.72 (1H,
dd, J = 16, 9 Hz), 2.62-2.50 (1H, m), 2.25-2.14 (1H, m), 0.93-0.84
(4H, m), 0.00 (18H, s). 40-1B .sup.1H-NMR (CDCl.sub.3) .delta.:
7.46 (1H, d, J = 8 Hz), 7.33 (1H, d, J = 8 Hz), 7.16 (2H, d, J = 9
Hz), 7.14-7.08 (1H, m), 6.91 (2H, d, J = 9 Hz), 5.76 (1H, dd, J =
7, 4 Hz), 4.72 (2H, d, J = 10 Hz), 4.67 (2H, d, J = 10 Hz),
3.82-3.69 (1H, m), 3.62-3.32 (9H, m), 3.19-3.04 (2H, m), 2.98-2.87
(1H, m), 2.72 (1H, dd, J = 16, 9 Hz), 2.61-2.50 (1H, m), 2.24-2.13
(1H, m), 0.95-0.83 (4H, m), 0.00 (18H, s). 40-2A .sup.1H-NMR
(CDCl.sub.3) .delta.: 7.40 (1H, d, J = 7 Hz), 7.34-7.28 (1H, m),
7.18 (2H, d, J = 9 Hz), 7.05 (1H, d, J = 6 Hz), 6.97 (2H, d, J = 9
Hz), 6.69 (2H, s), 5.82-5.77 (1H, m), 4.75-4.65 (4H, m), 4.21 (2H,
t, J = 6 Hz), 3.83-3.71 (1H, m), 3.63-3.34 (9H, m), 3.11 (1H, dd, J
= 16, 5 Hz), 2.79-2.63 (2H, m), 2.59-2.43 (3H, m), 2.17-2.07 (1H,
m), 2.02 (2H, t, J = 6 Hz), 1.98 (3H, s), 1.95 (3H, s), 1.34 (6H,
s), 0.95-0.86 (4H, m), 0.01 (18H, s). 40-3A .sup.1H-NMR
(CDCl.sub.3) .delta.: 7.38 (1H, d, J = 7 Hz), 7.31-7.27 (1H, m),
7.18 (2H, d, J = 9 Hz), 7.03 (1H, d, J = 7 Hz), 6.96 (2H, d, J = 9
Hz), 6.67 (2H, s), 5.81-5.76 (1H, m), 4.72 (2H, d, J = 10 Hz), 4.67
(2H, d, J = 10 Hz), 4.20 (2H, t, J = 6 Hz), 3.82-3.70 (1H, m),
3.62-3.32 (6H, m), 3.18 (1H, dd, J = 16, 5 Hz), 2.77 (1H, dd, J =
16, 10 Hz), 2.72-2.61 (1H, m), 2.59-2.41 (2H, m), 2.16-2.07 (1H,
m), 2.01 (2H, t, J = 6 Hz), 1.97 (3H, s), 1.93 (3H, s), 0.92-0.86
(4H, m), 0.00 (25H, s). 40-4A .sup.1H-NMR (CDCl.sub.3) .delta.:
7.39 (1H, d, J = 7 Hz), 7.34-7.27 (1H, m), 7.23 (2H, d, J = 9 Hz),
7.06-7.03 (1H, m), 7.01 (2H, d, J = 9 Hz), 6.68 (2H, s), 5.84-5.76
(1H, m), 4.36 (2H, s), 4.20 (2H, t, J = 6 Hz), 3.83-3.70 (1H, m),
3.58 (1H, dd, J = 15, 7 Hz), 3.45-3.37 (1H, m), 3.01 (1H, dd, J =
16, 7 Hz), 2.85-2.75 (1H, m), 2.74-2.62 (1H, m), 2.60-2.41 (1H, m),
2.16-2.07 (1H, m), 2.03-1.98 (2H, m), 1.97 (3H, s), 1.94 (3H, s),
1.33 (6H, s). 48-1 .sup.1H-NMR (CDCl.sub.3) .delta.: 7.78-7.74 (1H,
m), 7.45 (1H, d, J = 7 Hz), 7.25-7.20 (1H, m), 7.15 (2H, d, J = 9
Hz), 6.93 (2H, d, J = 9 Hz), 5.68 (1H, dd, J = 7, 4 Hz), 4.72 (2H,
d, J = 10 Hz), 4.67 (2H, d, J = 10 Hz), 3.80-3.70 (1H, m), 3.76
(4H, s), 3.62-3.25 (10H, m), 3.17-3.04 (2H, m), 2.72 (1H, dd, J =
16, 9 Hz), 2.56-2.43 (1H, m), 2.19-2.07 (1H, m), 1.02 (6H, s),
0.93-0.84 (4H, m), 0.00 (18H, s). 48-2 .sup.1H-NMR (CDCl.sub.3)
.delta.: 7.18-7.11 (1H, m), 7.15 (2H, d, J = 9 Hz), 7.00 (1H, d, J
= 8 Hz), 6.92 (2H, d, J = 9 Hz), 6.75 (1H, d, J = 8 Hz), 5.71 (1H,
dd, J = 6, 4 Hz), 4.75-4.63 (4H, m), 3.81-3.69 (1H, m), 3.61-3.34
(9H, m), 3.13-2.99 (2H, m), 2.90-2.79 (1H, m), 2.72 (1H, dd, J =
16, 9 Hz), 2.62-2.50 (1H, m), 2.27-2.16 (1H, m), 0.93-0.84 (4H, m),
0.00 (18H, s). 48-3 .sup.1H-NMR (CDCl.sub.3) .delta.: 7.36-6.85
(12H, m), 5.75 (1H, dd, J = 7, 4 Hz), 4.74-4.64 (4H, m), 3.82-3.71
(1H, m), 3.62-3.33 (9H, m), 3.14-2.96 (2H, m), 2.86-2.77 (1H, m),
2.73 (1H, dd, J = 16, 10 Hz), 2.60-2.49 (1H, m), 2.23-2.11 (1H, m),
0.94-0.84 (4H, m), 0.00 (18H, s). 48-4 .sup.1H-NMR (CDCl.sub.3)
.delta.: 7.37-6.85 (12H, m), 5.75 (1H, dd, J = 7, 5 Hz), 4.74-4.65
(4H, m), 3.81-3.71 (1H, m), 3.61-3.32 (6H, m), 3.18 (1H, dd, J =
16, 5 Hz), 3.07-2.95 (1H, m), 2.87-2.72 (2H, m), 2.61-2.49 (1H, m),
2.24-2.11 (1H, m), 0.96-0.84 (4H, m), 0.00 (18H, s). 48-5
.sup.1H-NMR (DMSO-D.sub.6) .delta.: 7.41-6.61 (12H, m), 6.82 (1H,
s), 6.76 (1H, s), 5.86-5.81 (1H, m), 3.69-1.91 (9H, m). 51-1
.sup.1H-NMR (*CDCl.sub.3) .delta.: 720-7.08 (3H, m), 6.58-6.45 (2H,
m), 5.35-5.24 (1H, m), 4.50 (2H, t, J = 6 Hz), 3.14-2.99 (1H, m),
2.87-2.66 (2H, m), 2.61-2.45 (1H, m), 2.35 (3H, s), 2.06-1.93 (3H,
m), 1.31 (6H, s). 51-2 .sup.1H-NMR (*CDCl.sub.3) .delta.: 7.47 (2H,
d, J = 9 Hz), 7.22-7.10 (3H, m), 7.04 (2H, d, J = 9 Hz), 6.59-6.50
(2H, m), 5.82 (1H, dd, J = 7, 4 Hz), 4.51 (2H, t, J = 6 Hz), 3.90
(2H, d, J = 16 Hz), 3.76 (2H, d, J = 16 Hz), 3.21-3.06 (1H, m),
3.01-2.87 (1H, m), 2.72-2.52 (1H, m), 2.59 (3H, s), 2.36 (3H, s),
2.30-2.21 (1H, m), 2.00 (2H, t, J = 6 Hz), 1.31 (6H, s). 51-3
.sup.1H-NMR (*DMSO-D.sub.6) .delta.: 11.28 (1H, s), 7.83 (2H, d, J
= 9 Hz), 7.36 (1H, d, J = 9 Hz), 7.24 (2H, d, J = 9 Hz), 7.21-7.10
(2H, m), 7.08 (1H, s), 6.66 (1H, d, J = 9 Hz), 6.59-6.50 (1H, m),
6.04 (1H, dd, J = 7, 4 Hz), 4.39 (1H, s), 4.33 (2H, t, J = 7 Hz),
3.11-259 (3H, m), 2.28 (3H, s), 2.17-2.01 (1H, m), 1.84 (2H, t, J =
7 Hz), 1.17 (6H, s).
* * * * *