COMPOUND HAVING TGFBETA INHIBITORY ACTIVITY AND PHARMACEUTICAL COMPOSITION COMPRISING THE SAME
First Claim
Patent Images
1. A compound represented by formula (I) or a pharmaceutically acceptable salt or solvate thereof:
-
whereinX represents or N,Z represents —
O—
, —
NH—
, —
S—
, or —
C(═
O)—
,R and R′
, which may be the same or different, represent1) a hydrogen atom,2) a halogen atom, or3) C1-6 alkyl optionally substituted by hydroxyl, a halogen atom, ora saturated or unsaturated five- or six-membered heterocyclic group,4) C2-6 alkenyl optionally substituted by an oxygen atom or C1-4 alkoxy,5) amino in which one or two hydrogen atoms on the amino group are optionally substituted by C1-6 alkyl, and the C1-6 alkyl group is optionally substituted by hydroxyl or a saturated or unsaturated five- or six-membered carbocyclic or heterocyclic group,6) —
C(═
O)—
NH2 wherein one or two hydrogen atoms on the aminocarbonyl group are optionally substituted by C1-6 alkyl,7) —
OR″
wherein R″
represents a hydrogen atom, or —
(CH2)m—
Ra wherein Ra represents a hydrogen atom, a halogen atom, hydroxyl, a saturated or unsaturated three- to six-membered carbocyclic or heterocyclic group, C1-4 alkoxy, C1-4 alkoxycarbonyl, or —
NRbRc wherein Rb and Rc, which may be the same or different, represent a hydrogen atom or C1-6 alkyl, in which the C1-6 alkyl group is optionally substituted by hydroxyl, an oxygen atom, amino, a nitrogen atom, or C1-4 alkyl, and Rb and Rc may combine with a nitrogen atom attached thereto to form a saturated or unsaturated five- or six-membered heterocyclic group, which may further comprise one or more heteroatoms, and in which the heterocyclic group is optionally substituted by C1-4 alkyl optionally substituted by hydroxyl, hydroxyl, an oxygen atom, aminocarbonyl, C1-4 alkoxy, C1-4 alkoxycarbonyl, or a saturated or unsaturated five- or six-membered heterocyclic group, and the heterocyclic group may condense with another saturated or unsaturated five- or six-membered carbocyclic or heterocyclic group to form a bicyclic group;
m is an integer of 1 to 6; and
the alkyl chain part in this group, —
(CH2)m—
, is optionally substituted by hydroxyl, an oxygen atom, —
ORd group, wherein Rd represents C1-4 alkyl or C1-4 alkylcarbonyl, or C1-4 alkyl optionally substituted by hydroxyl or a halogen atom, or8) a saturated or unsaturated five- or six-membered heterocyclic group, andA represents any group selected from the group consisting of formulae (a) to (c);
(a) a group of formula (a);
whereinR3 to R6, which may be the same or different, representa hydrogen atom,hydroxyl,a halogen atom,C1-6 alkyl,C1-10 alkoxy optionally substituted by a halogen atom or phenyl,C2-6 alkenylcarbonyloxy,C1-4 alkylcarbonyl,C1-4 alkylthio, orphenyl optionally substituted by a halogen atom,R3 and R4, R4 and R5, and R5 and R6 each may combine with a carbon atom attached thereto to form a saturated or unsaturated five- or six-membered carbocyclic or heterocyclic group in which the carbocyclic or heterocyclic group is optionally substituted by a hydrogen atom, a halogen atom, hydroxyl, or C1-4 alkyl,G represents—
C(═
O)—
R7,—
CH2—
N(—
R11)R12, or—
C(—
R13)(═
NR14),whereinR7 representsa hydrogen atom,C1-8 alkyl optionally substituted by C1-4 alkoxy, an oxygen atom, or a saturated or unsaturated five- or six-membered carbocyclic group,C2-6 alkenyl optionally substituted by a saturated or unsaturated five- or six-membered carbocyclic group,a saturated or unsaturated five- or six-membered carbocyclic group or heterocyclic group in which the carbocyclic or heterocyclic group is optionally substituted by hydroxyl, C1-4 alkyl, or C1-4 alkoxy, and the C1-4 alkoxy group is optionally substituted by a halogen atom or a saturated or unsaturated five- or six-membered heterocyclic group,group —
O—
R8, orgroup —
N(—
R9)R10 whereinR8 representsC1-10 alkyl optionally substituted by a saturated or unsaturated five- or six-membered carbocyclic group,C2-8 alkenyl, ora saturated or unsaturated five- or six-membered carbocyclic group in which the carbocyclic group is optionally substituted by a halogen atom,R9 and R10, and R11 and R12, which may be the same or different, each representa hydrogen atom,C1-6 alkyl,a saturated or unsaturated five- or six-membered carbocyclic group in which the carbocyclic group is optionally substituted by a halogen atom, ornaphthyl optionally substituted by a halogen atom,R9 and R10, or R11 and R12 may combine with a nitrogen atom attached thereto to form a saturated or unsaturated five- or six-membered heterocyclic group which may further comprise one or more heteroatoms and in which the heterocyclic group is optionally substituted by C1-4 alkyl optionally substituted by hydroxyl, or a saturated or unsaturated five- or six-membered heterocyclic group,R13 representsa hydrogen atom orC1-4 alkyl,R14 representsa hydrogen atom,hydroxyl,C1-4 alkoxy optionally substituted by a saturated or unsaturated six-membered carbocyclic group,C2-6 alkenyloxy,phenyloxy, oramino optionally substituted by a saturated or unsaturated six-membered heterocyclic group,(b) a group of formula (b);
whereinany one of J, L, and M represents a nitrogen atom with the remaining two representing a carbon atom,R15 to R19, which may be the same or different, representa hydrogen atom,a halogen atom,nitro,cyano,C1-6 alkyl in which the alkyl group is optionally substituted by hydroxyl;
phenyl;
amino optionally substituted by C1-4 alkyl;
C1-4 alkylcarbonyloxy;
or a saturated or unsaturated six-membered heterocyclic group optionally substituted by C1-4 alkyl,C1-8 alkoxy,C1-4 alkylcarbonyl,C2-6 alkenyl optionally substituted by a saturated or unsaturated five- or six-membered carbocyclic group,C2-6 alkynyl optionally substituted by C1-4 alkylsilyl,C1-4 alkylthio,a saturated or unsaturated three- to eight-membered carbocyclic oxy group,a saturated or unsaturated six-membered carbocyclic carbonyl or heterocyclic carbonyl group optionally substituted by C1-4 alkyl, ora saturated or unsaturated three- to eight-membered carbocyclic or heterocyclic group in which the carbocyclic or heterocyclic group is optionally substituted by hydroxyl;
cyano;
a halogen atom;
C1-4 alkoxy;
phenyloxy;
C1-4 alkylcarbonyl;
amino optionally substituted by C1-4 alkyl or C1-4 alkylcarbonyl;
aminocarbonyl optionally substituted by C1-4 alkyl;
or C1-4 alkyl optionally substituted by hydroxyl or a halogen atom,R15 and R16, R16 and R17, R17 and R18, and R18 and R19 each may combine with a carbon atom attached thereto to form a saturated or unsaturated five- or six-membered carbocyclic or heterocyclic group, and the carbocyclic or heterocyclic group is optionally substituted by C1-4 alkyl,provided that, among R17 to R19, those in which J, L, or M attached thereto is a nitrogen atom are absent, and(c) a group of formula (c);
whereinR20 to R24, which may be the same or different, representa hydrogen atom,a halogen atom,C1-10 alkyl optionally substituted by hydroxyl, a saturated or unsaturated five- or six-membered carbocyclic or heterocyclic group,C1-8 alkoxy,C2-6 alkenyl optionally substituted by C1-4 alkyl, C1-4 alkoxy, an oxygen atom or phenyl,phenylcarbonyl optionally substituted by C1-4 alkyl,amino optionally substituted by phenyl,nitro, ora saturated or unsaturated five- or six-membered carbocyclic or heterocyclic group in which the carbocyclic or heterocyclic group is optionally substituted by C1-6 alkyl,R20 and R21, or R23 and R24 may combine with a carbon atom attached thereto to form a saturated or unsaturated five- or six-membered carbocyclic or heterocyclic group, andR21 and R22, or R22 and R23 may combine with a carbon atom attached thereto to form a saturated or unsaturated five- or six-membered carbocyclic or heterocyclic group in which the carbocyclic or heterocyclic group is optionally substituted by a halogen atom, C1-4 alkyl, C1-4 alkylcarbonyl, C1-6 alkoxycarbonyl, or an oxygen atom, and the carbocyclic or heterocyclic group may condense with another saturated or unsaturated five- or six-membered carbocyclic or heterocyclic group to form a tricyclic group together with the six-membered carbocyclic ring of formula (c).
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Abstract
The present invention provides compounds represented by formula (I) and pharmaceutically acceptable salts and solvates thereof:
wherein X represents CH or N; Z represents —O—, —NH— or —C(═O)—; R and R′ represent a hydrogen atom, hydroxyl, a halogen atom, optionally substituted alkyl, optionally substituted alkenyl optionally substituted alkoxy, amino, aminocarbonyl, or an optionally substituted heterocyclic group; and A represents an optionally substituted specific carbocyclic or heterocyclic group. The compounds according to the present invention have excellent TGFβ inhibitory activity.
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Citations
61 Claims
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1. A compound represented by formula (I) or a pharmaceutically acceptable salt or solvate thereof:
-
wherein X represents or N, Z represents —
O—
, —
NH—
, —
S—
, or —
C(═
O)—
,R and R′
, which may be the same or different, represent1) a hydrogen atom, 2) a halogen atom, or 3) C1-6 alkyl optionally substituted by hydroxyl, a halogen atom, or a saturated or unsaturated five- or six-membered heterocyclic group, 4) C2-6 alkenyl optionally substituted by an oxygen atom or C1-4 alkoxy, 5) amino in which one or two hydrogen atoms on the amino group are optionally substituted by C1-6 alkyl, and the C1-6 alkyl group is optionally substituted by hydroxyl or a saturated or unsaturated five- or six-membered carbocyclic or heterocyclic group, 6) —
C(═
O)—
NH2 wherein one or two hydrogen atoms on the aminocarbonyl group are optionally substituted by C1-6 alkyl,7) —
OR″
wherein R″
represents a hydrogen atom, or —
(CH2)m—
Ra wherein Ra represents a hydrogen atom, a halogen atom, hydroxyl, a saturated or unsaturated three- to six-membered carbocyclic or heterocyclic group, C1-4 alkoxy, C1-4 alkoxycarbonyl, or —
NRbRc wherein Rb and Rc, which may be the same or different, represent a hydrogen atom or C1-6 alkyl, in which the C1-6 alkyl group is optionally substituted by hydroxyl, an oxygen atom, amino, a nitrogen atom, or C1-4 alkyl, and Rb and Rc may combine with a nitrogen atom attached thereto to form a saturated or unsaturated five- or six-membered heterocyclic group, which may further comprise one or more heteroatoms, and in which the heterocyclic group is optionally substituted by C1-4 alkyl optionally substituted by hydroxyl, hydroxyl, an oxygen atom, aminocarbonyl, C1-4 alkoxy, C1-4 alkoxycarbonyl, or a saturated or unsaturated five- or six-membered heterocyclic group, and the heterocyclic group may condense with another saturated or unsaturated five- or six-membered carbocyclic or heterocyclic group to form a bicyclic group;
m is an integer of 1 to 6; and
the alkyl chain part in this group, —
(CH2)m—
, is optionally substituted by hydroxyl, an oxygen atom, —
ORd group, wherein Rd represents C1-4 alkyl or C1-4 alkylcarbonyl, or C1-4 alkyl optionally substituted by hydroxyl or a halogen atom, or8) a saturated or unsaturated five- or six-membered heterocyclic group, and A represents any group selected from the group consisting of formulae (a) to (c); (a) a group of formula (a); wherein R3 to R6, which may be the same or different, represent a hydrogen atom, hydroxyl, a halogen atom, C1-6 alkyl, C1-10 alkoxy optionally substituted by a halogen atom or phenyl, C2-6 alkenylcarbonyloxy, C1-4 alkylcarbonyl, C1-4 alkylthio, or phenyl optionally substituted by a halogen atom, R3 and R4, R4 and R5, and R5 and R6 each may combine with a carbon atom attached thereto to form a saturated or unsaturated five- or six-membered carbocyclic or heterocyclic group in which the carbocyclic or heterocyclic group is optionally substituted by a hydrogen atom, a halogen atom, hydroxyl, or C1-4 alkyl, G represents —
C(═
O)—
R7,—
CH2—
N(—
R11)R12, or—
C(—
R13)(═
NR14),wherein R7 represents a hydrogen atom, C1-8 alkyl optionally substituted by C1-4 alkoxy, an oxygen atom, or a saturated or unsaturated five- or six-membered carbocyclic group, C2-6 alkenyl optionally substituted by a saturated or unsaturated five- or six-membered carbocyclic group, a saturated or unsaturated five- or six-membered carbocyclic group or heterocyclic group in which the carbocyclic or heterocyclic group is optionally substituted by hydroxyl, C1-4 alkyl, or C1-4 alkoxy, and the C1-4 alkoxy group is optionally substituted by a halogen atom or a saturated or unsaturated five- or six-membered heterocyclic group, group —
O—
R8, orgroup —
N(—
R9)R10wherein R8 represents C1-10 alkyl optionally substituted by a saturated or unsaturated five- or six-membered carbocyclic group, C2-8 alkenyl, or a saturated or unsaturated five- or six-membered carbocyclic group in which the carbocyclic group is optionally substituted by a halogen atom, R9 and R10, and R11 and R12, which may be the same or different, each represent a hydrogen atom, C1-6 alkyl, a saturated or unsaturated five- or six-membered carbocyclic group in which the carbocyclic group is optionally substituted by a halogen atom, or naphthyl optionally substituted by a halogen atom, R9 and R10, or R11 and R12 may combine with a nitrogen atom attached thereto to form a saturated or unsaturated five- or six-membered heterocyclic group which may further comprise one or more heteroatoms and in which the heterocyclic group is optionally substituted by C1-4 alkyl optionally substituted by hydroxyl, or a saturated or unsaturated five- or six-membered heterocyclic group, R13 represents a hydrogen atom or C1-4 alkyl, R14 represents a hydrogen atom, hydroxyl, C1-4 alkoxy optionally substituted by a saturated or unsaturated six-membered carbocyclic group, C2-6 alkenyloxy, phenyloxy, or amino optionally substituted by a saturated or unsaturated six-membered heterocyclic group, (b) a group of formula (b); wherein any one of J, L, and M represents a nitrogen atom with the remaining two representing a carbon atom, R15 to R19, which may be the same or different, represent a hydrogen atom, a halogen atom, nitro, cyano, C1-6 alkyl in which the alkyl group is optionally substituted by hydroxyl;
phenyl;
amino optionally substituted by C1-4 alkyl;
C1-4 alkylcarbonyloxy;
or a saturated or unsaturated six-membered heterocyclic group optionally substituted by C1-4 alkyl,C1-8 alkoxy, C1-4 alkylcarbonyl, C2-6 alkenyl optionally substituted by a saturated or unsaturated five- or six-membered carbocyclic group, C2-6 alkynyl optionally substituted by C1-4 alkylsilyl, C1-4 alkylthio, a saturated or unsaturated three- to eight-membered carbocyclic oxy group, a saturated or unsaturated six-membered carbocyclic carbonyl or heterocyclic carbonyl group optionally substituted by C1-4 alkyl, or a saturated or unsaturated three- to eight-membered carbocyclic or heterocyclic group in which the carbocyclic or heterocyclic group is optionally substituted by hydroxyl;
cyano;
a halogen atom;
C1-4 alkoxy;
phenyloxy;
C1-4 alkylcarbonyl;
amino optionally substituted by C1-4 alkyl or C1-4 alkylcarbonyl;
aminocarbonyl optionally substituted by C1-4 alkyl;
or C1-4 alkyl optionally substituted by hydroxyl or a halogen atom,R15 and R16, R16 and R17, R17 and R18, and R18 and R19 each may combine with a carbon atom attached thereto to form a saturated or unsaturated five- or six-membered carbocyclic or heterocyclic group, and the carbocyclic or heterocyclic group is optionally substituted by C1-4 alkyl, provided that, among R17 to R19, those in which J, L, or M attached thereto is a nitrogen atom are absent, and (c) a group of formula (c); wherein R20 to R24, which may be the same or different, represent a hydrogen atom, a halogen atom, C1-10 alkyl optionally substituted by hydroxyl, a saturated or unsaturated five- or six-membered carbocyclic or heterocyclic group, C1-8 alkoxy, C2-6 alkenyl optionally substituted by C1-4 alkyl, C1-4 alkoxy, an oxygen atom or phenyl, phenylcarbonyl optionally substituted by C1-4 alkyl, amino optionally substituted by phenyl, nitro, or a saturated or unsaturated five- or six-membered carbocyclic or heterocyclic group in which the carbocyclic or heterocyclic group is optionally substituted by C1-6 alkyl, R20 and R21, or R23 and R24 may combine with a carbon atom attached thereto to form a saturated or unsaturated five- or six-membered carbocyclic or heterocyclic group, and R21 and R22, or R22 and R23 may combine with a carbon atom attached thereto to form a saturated or unsaturated five- or six-membered carbocyclic or heterocyclic group in which the carbocyclic or heterocyclic group is optionally substituted by a halogen atom, C1-4 alkyl, C1-4 alkylcarbonyl, C1-6 alkoxycarbonyl, or an oxygen atom, and the carbocyclic or heterocyclic group may condense with another saturated or unsaturated five- or six-membered carbocyclic or heterocyclic group to form a tricyclic group together with the six-membered carbocyclic ring of formula (c). - View Dependent Claims (2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 54, 55, 56, 57, 58, 59, 60)
wherein X, Z, and A are as defined in claim 1, R1 and R2, which may be the same or different, represent a hydrogen atom, or —
(CH2)m—
Ra wherein Ra represents a hydrogen atom, a halogen atom, hydroxyl, a saturated or unsaturated three- to six-membered carbocyclic or heterocyclic group, C1-4 alkoxy, C1-4 alkoxycarbonyl, or —
NRbRc wherein Rb and Rc, which may be the same or different, represent a hydrogen atom or C1-6 alkyl, in which the C1-6 alkyl group is optionally substituted by hydroxyl, an oxygen atom, amino, a nitrogen atom, or C1-4 alkyl, and Rb and Rc may combine with a nitrogen atom attached thereto to form a saturated or unsaturated five- or six-membered heterocyclic group, which may further comprise one or more heteroatoms, and in which the heterocyclic group is optionally substituted by C1-4 alkyl, optionally substituted by hydroxyl, hydroxyl, an oxygen atom, aminocarbonyl, C1-4 alkoxy, C1-4 alkoxycarbonyl, or a saturated or unsaturated five- or six-membered heterocyclic group, and the heterocyclic group may condense with another saturated or unsaturated five- or six-membered carbocyclic or heterocyclic group to form a bicyclic group;
m is an integer of 1 to 6; and
the alkyl chain part in this group, —
(CH2)m—
, is optionally substituted by hydroxyl, an oxygen atom, —
ORd group, wherein Rd represents C1-4 alkyl or C1-4 alkylcarbonyl, or C1-4 alkyl optionally substituted by hydroxyl or a halogen atom.
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3. The compound according to claim 2, wherein
R1 and R2, which may be the same or different, represent any group selected from the group consisting of a hydrogen atom, C1-6 alkyl optionally substituted by phenyl, and groups of formulae (i) to (vi): -
(i) a group of formula (i); wherein R51 and R52, which may be the same or different, represent a hydrogen atom, or C1-8 alkyl optionally substituted by hydroxyl, an oxygen atom, amino, or a nitrogen atom, R51 and R52 may combine with a nitrogen atom attached thereto to form a saturated or unsaturated five- or six-membered heterocyclic group which may further comprise one or more heteroatoms, and in which the heterocyclic group is optionally substituted by C1-4 alkyl optionally substituted by hydroxyl, hydroxyl, an oxygen atom, aminocarbonyl, C1-4 alkoxy, C1-4 alkoxycarbonyl, or a saturated or unsaturated five- or six-membered heterocyclic group, and the heterocyclic group optionally formed by allowing R51 to combine with R52 may condense with another saturated or unsaturated five- or six-membered carbocyclic or heterocyclic group to form a bicyclic group, p is an integer of 2 to 4, and the alkyl chain part in this group is optionally substituted by hydroxyl, or —
ORe group wherein Re represents C1-4 alkyl or C1-4 alkylcarbonyl,(ii) a group of formula (ii); wherein q is an integer of 1 to 4, (iii) a group of formula (iii); wherein Hal represents a halogen atom, and r represents an integer of 2 to 4, (iv) a group of formula (iv); wherein R53 and R54, which may be the same or different, represent a hydrogen atom, or C1-6 alkyl optionally substituted by hydroxyl, R53 and R54 may combine with a nitrogen atom attached thereto to form a saturated or unsaturated five- or six-membered heterocyclic group which may further comprise one or more heteroatoms and in which the heterocyclic group is optionally substituted by C1-4 alkyl optionally substituted by hydroxyl, or a saturated or unsaturated five- or six-membered heterocyclic group, and the heterocyclic group optionally formed by allowing R53 to combine with R54 may condense with another saturated or unsaturated five- or six-membered carbocyclic or heterocyclic group to form a bicyclic group, and s is an integer of 0 to 3, (v) a group of formula (v); wherein R55 represents C1-4 alkyl and t is an integer of 0 (zero) to 3, and (vi) a group of formula (vi); wherein R56, R57 and R58, which may be the same or different, represent a hydrogen atom, C1-4 alkoxycarbonyl, or C1-4 alkyl optionally substituted by hydroxyl or a halogen atom, and u is an integer of 0 (zero) to 4.
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4. The compound according to claim 3, wherein formula (i) is represented by formula (i-a):
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5. The compound according to claim 3 or 4, wherein
R1 and R2, which may be the same or different, represent any group selected from the group consisting of a hydrogen atom, C1-6 alkyl, benzyl, groups of formulae (i), (v), and (vi) according to claim 3, and groups of formulae (ii-a), (iii-a), and (iv-a): -
formula (ii-a); formula (iii-a); wherein r1 is an integer of 2 to 4, and formula (iv-a);
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6. The compound according to claim 5, wherein one of R1 and R2 is selected from C1-6 alkyl, and the other substituent is selected from the group consisting of
a hydrogen atom, benzyl, groups of formulae (i), (v), and (vi) according to claim 3, and groups of formulae (ii-a), (iii-a), and (iv-a) according to claim 5. -
7. The compound according to claim 1, wherein
at least one of R and R′ - is selected from the group consisting of
a hydrogen atom, a halogen atom, C1-4 alkyl optionally substituted by hydroxyl, a halogen atom, or a saturated or unsaturated five- or six-membered heterocyclic group, C2-4 alkenyl optionally substituted by an oxygen atom or C1-4 alkoxy, amino in which one or two hydrogen atoms on the amino group are optionally substituted by C1-4 alkyl, and the C1-4 alkyl group is optionally substituted by hydroxyl or a saturated or unsaturated five- or six-membered heterocyclic group, —
C(═
O)—
NH2, anda saturated or unsaturated five- or six-membered heterocyclic group.
- is selected from the group consisting of
-
8. The compound according to claim 1, wherein
R′ - is selected from the group consisting of
a hydrogen atom, a halogen atom, C1-4 alkyl optionally substituted by hydroxyl, a halogen atom, or a saturated or unsaturated five- or six-membered heterocyclic group, C2-4 alkenyl optionally substituted by an oxygen atom or C1-4 alkoxy, amino in which one or two hydrogen atoms on the amino group are optionally substituted by C1-4 alkyl, and the C1-4 alkyl group is optionally substituted by hydroxyl or a saturated or unsaturated five- or six-membered heterocyclic group, —
C(═
O)—
NH2, anda saturated or unsaturated five- or six-membered heterocyclic group.
- is selected from the group consisting of
-
9. The compound according to claim 1, wherein formula (a), which A may represent, represents any group selected from the group consisting of formulae (a1) to (a3):
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(1) a group of formula (a1); wherein R3, R4 and R6, which may be the same or different, represent a hydrogen atom, a halogen atom, C1-6 alkyl, C1-10 alkoxy optionally substituted by a halogen atom or phenyl, C2-6 alkenylcarbonyloxy, C1-4 alkylcarbonyl, or phenyl optionally substituted by a halogen atom, R5 is as defined in claim 1, R3 and R4, R4 and R5, and R5 and R6 each may combine with a carbon atom attached thereto to form a saturated or unsaturated five- or six-membered carbocyclic or heterocyclic group, and R7 is as defined in claim 1, (2) a group of formula (a2); wherein R3 to R6 are as defined in formula (a1), R11 and R12 are as defined in claim 1, and (3) a group of formula (a3); wherein R3a to R6a, which may be the same or different, represent a hydrogen atom, a halogen atom, or C1-6 alkyl, and R13 and R14 are as defined in claim 1.
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10. The compound according to claim 9, wherein A represents a group of formula (a1) and at least one of R3 to R6 in formula (a1) is selected from groups other than a hydrogen atom.
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11. The compound according to claim 9 or 10, wherein A represents a group of formula (a1) and R7 in formula (a1) represents a hydrogen atom, C1-4 alkyl, or phenyl in which the phenyl group is optionally substituted by hydroxyl, C1-4 alkyl, or C1-4 alkoxy.
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12. The compound according to claim 9 or 10, wherein A represents a group of formula (a1) and R7 in formula (a1) represents group —
- O—
R8 or group —
N(—
R9)R10.
- O—
-
13. The compound according to claim 12, wherein R8 represents unsubstituted C1-8 alkyl;
- C1-4 alkyl substituted by phenyl;
C2-8 alkenyl;
or phenyl optionally substituted by a halogen atom.
- C1-4 alkyl substituted by phenyl;
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14. The compound according to claim 12, wherein
at least one of R9 and R10 represents a hydrogen atom and the other substituent represents a hydrogen atom, C1-6 alkyl, a saturated or unsaturated five- or six-membered carbocyclic group in which the carbocyclic group is optionally substituted by a halogen atom, or naphthyl optionally substituted by a halogen atom, or R9 and R10 combine with a nitrogen atom attached thereto to form a saturated five- or six-membered heterocyclic group in which the heterocyclic group may further comprise at least one heteroatom. -
15. The compound according to claim 9, wherein A represents a group of formula (a1) and R5 in formula (a1) is selected from groups other than a hydrogen atom.
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16. The compound according to claim 10, wherein R and R′
- are selected from —
OR″
wherein R″
represents C1-6 alkyl.
- are selected from —
-
17. The compound according to claim 9, wherein A represents a group of formula (a2) and R11 and R12 in formula (a2) combine with a nitrogen atom attached thereto to form a saturated or unsaturated five- or six-membered heterocyclic group in which the heterocyclic group may further comprise one or more heteroatoms and is optionally substituted by C1-4 alkyl optionally substituted by hydroxyl;
- or a saturated five- or six-membered heterocyclic group.
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18. The compound according to claim 17, wherein A represents a group of formula (a2) and, in formula (a2),
R3, R4, and R6 represent a hydrogen atom, hydroxyl, or a halogen atom, and R5 represents C1-4 alkyl. -
19. The compound according to claim 9, wherein
A represents a group of formula (a3) and, in formula (a3), R13 represents methyl, and R14 represents hydroxyl; - C1-4 alkoxy optionally substituted by phenyl;
C2-6 alkenyloxy;
phenyloxy;
or amino optionally substituted by a six-membered unsaturated heterocyclic group.
- C1-4 alkoxy optionally substituted by phenyl;
-
20. The compound according to claim 9 or 19, wherein A represents a group of formula (a3), and, in formula (a3),
R3a and R6a represents a hydrogen atom, and R4a and R5a represent C1-6 alkyl. -
21. The compound according to claim 1, wherein A is selected from groups of formula (a) or (b).
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22. The compound according to claim 1, wherein formula (b), which A may represent, represents any group selected from the group consisting of formulae (b1) to (b3):
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(4) a group of formula (b1); wherein R25 to R27, which may be the same or different, represent a hydrogen atom, a halogen atom, C1-6 alkyl, C1-8 alkoxy, C1-4 alkylcarbonyl, C1-4 alkylthio, or phenylcarbonyl, R25 and R26, and R26 and R27 each may combine with a carbon atom attached thereto to form a saturated or unsaturated five- or six-membered carbocyclic or heterocyclic group, R28 represents a hydrogen atom, a halogen atom, nitro, cyano, C1-6 alkyl in which the alkyl group is optionally substituted by hydroxyl;
phenyl;
amino optionally substituted by C1-4 alkyl;
C1-4 alkylcarbonyloxy;
or a saturated or unsaturated six-membered heterocyclic group optionally substituted by C1-4 alkyl,C1-8 alkoxy, C1-4 alkylcarbonyl, C2-6 alkenyl optionally substituted by a saturated or unsaturated six-membered carbocyclic group, C2-6 alkynyl optionally substituted by C1-2 alkylsilyl, a saturated or unsaturated three- to eight-membered carbocyclic oxy group, a saturated or unsaturated six-membered carbocyclic carbonyl or heterocyclic carbonyl group optionally substituted by C1-4 alkyl, or a saturated or unsaturated three- to eight-membered carbocyclic or heterocyclic group in which the carbocyclic or heterocyclic group is optionally substituted by hydroxyl;
cyano;
a halogen atom;
C1-4 alkoxy;
phenyloxy;
C1-4 alkylcarbonyl;
amino optionally substituted by C1-4 alkyl or C1-4 alkylcarbonyl;
aminocarbonyl optionally substituted by C1-4 alkyl;
or C1-4 alkyl optionally substituted by hydroxyl or a halogen atom,(5) a group of formula (b2); wherein R29 to R32, which may be the same or different, represent a hydrogen atom, a halogen atom, or C1-6 alkyl optionally substituted by hydroxyl, R29 and R30, and R31 and R32 each may combine with a carbon atom attached thereto to form a saturated or unsaturated five- or six-membered carbocyclic or heterocyclic group in which the carbocyclic or heterocyclic group is optionally substituted by a halogen atom or C1-4 alkyl, and (6) a group of formula (b3); wherein R33 to R36, which may be the same or different, represent a hydrogen atom, a halogen atom, or C1-6 alkyl optionally substituted by hydroxyl, R33 and R34, R34 and R35, and R35 and R36 each may combine with a carbon atom attached thereto to form a saturated or unsaturated five- or six-membered carbocyclic or heterocyclic group in which the carbocyclic or heterocyclic group is optionally substituted by a halogen atom or C1-4 alkyl.
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-
23. The compound according to claim 22, wherein A represents a group of formula (b1) and, in formula (b1),
R25 represents a hydrogen atom, R26 represents a hydrogen atom, a halogen atom, or C1-4 alkyl, R27 represents a hydrogen atom, a halogen atom, C1-4 alkyl, C1-4 alkoxy, or C1-4 alkylthio, and R26 and R27 may combine with a carbon atom attached thereto to form an unsaturated six-membered carbocyclic or heterocyclic group. -
24. The compound according to claim 1, wherein
A represents a group of formula (b1) and, in formula (b1), R25 represents a hydrogen atom, R26 represents a hydrogen atom, a halogen atom, or C1-4 alkyl, R27 represents a hydrogen atom, a halogen atom, C1-4 alkyl, C1-4 alkoxy, or C1-4 alkylthio, R26 and R27 may combine with a carbon atom attached thereto to form an unsaturated six-membered carbocyclic or heterocyclic group, and R28 represents a saturated or unsaturated four- to seven-membered carbocyclic or heterocyclic group in which the carbocyclic or heterocyclic group is optionally substituted by hydroxyl; - cyano;
a halogen atom;
C1-4 alkoxy;
phenyloxy;
C1-4 alkylcarbonyl;
amino optionally substituted by C1-4 alkyl or C1-4 alkylcarbonyl;
aminocarbonyl optionally substituted by C1-4 alkyl;
or C1-4 alkyl optionally substituted by hydroxyl or a halogen atom.
- cyano;
-
25. The compound according to claim 22, wherein A represents a group of formula (b2) and, in formula (b2),
R29 represents a hydrogen atom, R30 represents a hydrogen atom or C1-4 alkyl, and R31 and R32 combine with carbon atom attached thereto to from an unsaturated five- or six-membered carbocyclic or heterocyclic group in which the carbocyclic or heterocyclic group is optionally substituted by a halogen atom or C1-4 alkyl. -
26. The compound according to claim 22, wherein A represents a group of formula (b3) and, in formula (b3),
R33 and R34 represent a hydrogen atom, and R35 and R36 combine with a carbon atom attached thereto to form an unsaturated five- or six-membered carbocyclic or heterocyclic group. -
27. The compound according to claim 1, wherein when one of R1 and R2 is selected from C1-6 alkyl, and the other substituent is selected from the group consisting of
a hydrogen atom, benzyl, groups of formulae (i), (v), and (vi) according to claim 3, and groups of formulae (ii-a), (iii-a), and (iv-a) according to claim 5, A is selected from groups of formula (b1). -
28. The compound according to claim 1, wherein A represents a group of formula (c) and, in formula (c),
R21 and R22, or R22 and R23 combine with a carbon atom attached thereto to form a saturated or unsaturated five- or six-membered carbocyclic or heterocyclic group in which the carbocyclic or heterocyclic group is optionally substituted by a halogen atom, C1-4 alkyl, C1-4 alkylcarbonyl, C1-6 alkoxycarbonyl, or an oxygen atom and may condense with another saturated or unsaturated five- or six-membered carbocyclic or heterocyclic group to form, together with the six-membered carbocyclic ring in formula (c), a tricyclic group, and any one of or both R20 and R24 is selected from groups other than a hydrogen atom. -
29. The compound according to claim 1 or pharmaceutically acceptable salt or solvate thereof, wherein formula (I) is represented by formula (100):
-
wherein X represents CH or N, Z represents —
O—
, —
NH—
, —
S—
, or —
C(═
O)—
,R101 and R102, which may be the same or different, represent any group selected from the group consisting of a hydrogen atom, C1-6 alkyl, benzyl, and groups of formulae (i), (ii-a), (iii-a), (iv-a), (v), and (vi), (i) a group of formula (i); wherein R51 and R52, which may be the same or different, represent a hydrogen atom, or C1-8 alkyl optionally substituted by hydroxyl, an oxygen atom, amino, or a nitrogen atom, R51 and R52 may combine with a nitrogen atom attached thereto to form a saturated or unsaturated five- or six-membered heterocyclic group which may further comprise one or more heteroatoms and in which the heterocyclic group is optionally substituted by C1-4 alkyl, optionally substituted by hydroxyl, hydroxyl, an oxygen atom, aminocarbonyl, C1-4 alkoxy, C1-4 alkoxycarbonyl, or a saturated or unsaturated five- or six-membered heterocyclic group, and the heterocyclic group optionally formed by allowing R51 to combine with R52 may condense with another saturated or unsaturated five- or six-membered carbocyclic or heterocyclic group to form a bicyclic group, p is an integer of 2 to 4, and the alkyl chain part in this group is optionally substituted by hydroxyl, or —
ORe group wherein Re represents C1-4 alkyl or C1-4 alkylcarbonyl,(ii) a group of formula (ii-a); (iii) a group of formula (iii-a); wherein r1 represents an integer of 2 to 4, (iv) a group of formula (iv-a); wherein R53 and R54, which may be the same or different, represent a hydrogen atom, or C1-6 alkyl optionally substituted by hydroxyl, and R53 and R54 may combine with a nitrogen atom attached thereto to form a saturated or unsaturated five- or six-membered heterocyclic group which may further comprise one or more heteroatoms and in which the heterocyclic group is optionally substituted by C1-4 alkyl, optionally substituted by hydroxyl, or a saturated or unsaturated five- or six-membered heterocyclic group, and the heterocyclic group optionally formed by allowing R53 to combine with R54 may condense with another saturated or unsaturated five- or six-membered carbocyclic or heterocyclic group to form a bicyclic group, (v) a group of formula (v); wherein R55 represents C1-4 alkyl and t is an integer of 0 (zero) to 3, and (vi) a group of formula (vi); wherein R56, R57 and R58, which may be the same or different, represent a hydrogen atom, C1-4 alkoxycarbonyl, or C1-4 alkyl optionally substituted by hydroxyl or a halogen atom, and u is an integer of 0 (zero) to 4, R103, R104 and R106, which may be the same or different, represent a hydrogen atom, a halogen atom, C1-6 alkyl, C1-10 alkoxy optionally substituted by a halogen atom or phenyl, C2-6 alkenylcarbonyloxy, C1-4 alkylcarbonyl, or phenyl optionally substituted by a halogen atom, R105 represents hydroxyl, a halogen atom, C1-6 alkyl, C1-10 alkoxy optionally substituted by a halogen atom or phenyl, C2-6 alkenylcarbonyloxy, C1-4 alkylcarbonyl, C1-4 alkylthio, or phenyl optionally substituted by a halogen atom, R103 and R104, R104 and R105, and R105 and R106 each may combine with a carbon atom attached thereto to form a saturated or unsaturated five- or six-membered carbocyclic or heterocyclic group, R107 represents a hydrogen atom, C1-4 alkyl, or phenyl optionally substituted by hydroxyl, C1-4 alkyl, or C1-4 alkoxy.
-
-
30. The compound according to claim 29, wherein
Z represents — - O—
,at least one of R101 and R102 represents methyl, and R107 represents a hydrogen atom, methyl, ethyl, or phenyl optionally substituted by hydroxyl, C1-4 alkyl or C1-4 alkoxy.
- O—
-
31. The compound according to claim 1 or pharmaceutically acceptable salt or solvate thereof, wherein formula (I) is represented by formula (200):
-
wherein X represents CH or N, Z represents —
O—
, —
NH—
, —
S—
, or —
C(═
O)—
,R201 and R202, which may be the same or different, represent any group selected from the group consisting of a hydrogen atom, C1-6 alkyl, benzyl, and groups of formulae (i), (ii-a), (iii-a), (iv-a), (v), and (vi), (i) a group of formula (i); wherein R51 and R52, which may be the same or different, represent a hydrogen atom, or C1-8 alkyl optionally substituted by hydroxyl, an oxygen atom, amino, or a nitrogen atom, R51 and R52 may combine with a nitrogen atom attached thereto to form a saturated or unsaturated five- or six-membered heterocyclic group which may further comprise one or more heteroatoms and in which the heterocyclic group is optionally substituted by C1-4 alkyl, optionally substituted by hydroxyl, hydroxyl, an oxygen atom, aminocarbonyl, C1-4 alkoxy, C1-4 alkoxycarbonyl, or a saturated or unsaturated five- or six-membered heterocyclic group, and the heterocyclic group optionally formed by allowing R51 to combine with R52 may condense with another saturated or unsaturated five- or six-membered carbocyclic or heterocyclic group to form a bicyclic group, p is an integer of 2 to 4, and the alkyl chain part in this group is optionally substituted by hydroxyl, or —
ORe group wherein Re represents C1-4 alkyl or C1-4 alkylcarbonyl,(ii) a group of formula (ii-a); (iii) a group of formula (iii-a); wherein r1 represents an integer of 2 to 4, (iv) a group of formula (iv-a); wherein R53 and R54, which may be the same or different, represent a hydrogen atom, or C1-6 alkyl optionally substituted by hydroxyl, and R53 and R54 may combine with a nitrogen atom attached thereto to form a saturated or unsaturated five- or six-membered heterocyclic group which may further comprise one or more heteroatoms and in which the heterocyclic group is optionally substituted by C1-4 alkyl, optionally substituted by hydroxyl, or a saturated or unsaturated five- or six-membered heterocyclic group, and the heterocyclic group optionally formed by allowing R53 to combine with R54 may condense with another saturated or unsaturated five- or six-membered carbocyclic or heterocyclic group to form a bicyclic group, (v) a group of formula (v); wherein R55 represents C1-4 alkyl and t is an integer of 0 (zero) to 3, and (vi) a group of formula (vi); wherein R56, R57 and R58, which may be the same or different, represent a hydrogen atom, C1-4 alkoxycarbonyl, or C1-4 alkyl optionally substituted by hydroxyl or a halogen atom, and u is an integer of 0 (zero) to 4, R203 to R206, which may be the same or different, represent a hydrogen atom, hydroxyl, a halogen atom, C1-6 alkyl, C1-10 alkoxy optionally substituted by a halogen atom or phenyl, C2-6 alkenylcarbonyloxy, C1-4 alkylcarbonyl, C1-4 alkylthio, or phenyl optionally substituted by a halogen atom, R203 and R204, R204 and R205, and R205 and R206 each may combine with a carbon atom attached thereto to form a saturated or unsaturated five- or six-membered carbocyclic or heterocyclic group, provided that at least one of R203 to R206 is selected from a group other than a hydrogen atom, and R208 represents unsubstituted C1-8 alkyl;
C1-4 alkyl substituted by phenyl;
C2-8 alkenyl;
or phenyl optionally substituted by a halogen atom.
-
-
32. The compound according to claim 31, wherein
Z represents — - O—
, S—
, or —
C(═
O)—
, andR208 represents unsubstituted C1-8 alkyl;
methyl substituted by phenyl;
C2-8 alkenyl;
or phenyl.
- O—
-
33. The compound according to claim 1 or pharmaceutically acceptable salt or solvate thereof, wherein formula (I) is represented by formula (300):
-
wherein X represents CH or N, Z represents —
O—
, —
NH—
, —
S—
, or —
C(═
O)—
,R301 and R302, which may be the same or different, represent any group selected from the group consisting of a hydrogen atom, C1-6 alkyl, benzyl, and groups of formulae (i), (ii-a), (iii-a), (iv-a), (v), and (vi), (i) a group of formula (i); wherein R51 and R52, which may be the same or different, represent a hydrogen atom, or C1-8 alkyl optionally substituted by hydroxyl, an oxygen atom, amino, or a nitrogen atom, R51 and R52 may combine with a nitrogen atom attached thereto to form a saturated or unsaturated five- or six-membered heterocyclic group which may further comprise one or more heteroatoms and in which the heterocyclic group is optionally substituted by C1-4 alkyl, optionally substituted by hydroxyl, hydroxyl, an oxygen atom, aminocarbonyl, C1-4 alkoxy, C1-4 alkoxycarbonyl, or a saturated or unsaturated five- or six-membered heterocyclic group, and the heterocyclic group optionally formed by allowing R51 to combine with R52 may condense with another saturated or unsaturated five- or six-membered carbocyclic or heterocyclic group to form a bicyclic group, p is an integer of 2 to 4, and the alkyl chain part in this group is optionally substituted by hydroxyl, or —
ORe group wherein Re represents C1-4 alkyl or C1-4 alkylcarbonyl,(ii) a group of formula (ii-a); (iii) a group of formula (iii-a); wherein r1 represents an integer of 2 to 4, (iv) a group of formula (iv-a); wherein R53 and R54, which may be the same or different, represent a hydrogen atom, or C1-6 alkyl optionally substituted by hydroxyl, and R53 and R54 may combine with a nitrogen atom attached thereto to form a saturated or unsaturated five- or six-membered heterocyclic group which may further comprise one or more heteroatoms and in which the heterocyclic group is optionally substituted by C1-4 alkyl, optionally substituted by hydroxyl, or a saturated or unsaturated five- or six-membered heterocyclic group, and the heterocyclic group optionally formed by allowing R53 to combine with R54 may condense with another saturated or unsaturated five- or six-membered carbocyclic or heterocyclic group to form a bicyclic group, (v) a group of formula (v); wherein R55 represents C1-4 alkyl and t is an integer of 0 (zero) to 3, and (vi) a group of formula (vi); wherein R56, R57 and R58, which may be the same or different, represent a hydrogen atom, C1-4 alkoxycarbonyl, or C1-4 alkyl optionally substituted by hydroxyl or a halogen atom, and u is an integer of 0 (zero) to 4, R303 to R306, which may be the same or different, represent a hydrogen atom, hydroxyl, a halogen atom, C1-6 alkyl, C1-10 alkoxy optionally substituted by a halogen atom or phenyl, C2-6 alkenylcarbonyloxy, C1-4 alkylcarbonyl, C1-4 alkylthio, or phenyl optionally substituted by a halogen atom, R303 and R304, R304 and R305, and R305 and R306 each may combine with a carbon atom attached thereto to form a saturated or unsaturated five- or six-membered carbocyclic or heterocyclic group, provided that at least one of R303 to R306 is selected from a group other than a hydrogen atom, and at least one of R309 and R310 represents a hydrogen atom and the other substituent represents a hydrogen atom, C1-6 alkyl, a saturated or unsaturated five- or six-membered carbocyclic group in which the carbocyclic group is optionally substituted by a halogen atom, or naphthyl optionally substituted by a halogen atom, or R309 and R310 combine with a nitrogen atom attached thereto to form a saturated five- or six-membered heterocyclic group which may further comprise one or more heteroatoms.
-
-
34. The compound according to claim 33, wherein
Z represents — - O—
,at least one of R309 and R310 represents a hydrogen atom and the other substituent represents a hydrogen atom, C1-4 alkyl, a saturated or unsaturated six-membered carbocyclic group in which the carbocyclic group is optionally substituted by a halogen atom, or naphthyl, or R309 and R310 combine with a nitrogen atom attached thereto to form a saturated six-membered heterocyclic group which may further comprise one or more heteroatoms.
- O—
-
35. The compound according to claim 1 or pharmaceutically acceptable salt or solvate thereof, wherein formula (I) is represented by formula (400):
-
wherein X represents CH or N, Z represents —
O—
, —
NH—
, —
S—
, or —
C(═
O)—
,R401 and R402, which may be the same or different, represent any group selected from C1-6 alkyl, R403, R404, and R406 represent a hydrogen atom, hydroxyl, or a halogen atom, R405 represents C1-4 alkyl, R411 and R412 combine with a nitrogen atom attached thereto to form a saturated or unsaturated five- or six-membered heterocyclic group in which the heterocyclic group may further comprise one or more heteroatoms and is optionally substituted by C1-4 alkyl optionally substituted by hydroxyl;
or a saturated five- or six-membered heterocyclic group.
-
-
36. The compound according to claim 35, wherein
Z represents — - O—
,R401 and R402 represent methyl, R411 and R412 combine with a nitrogen atom attached thereto to form a saturated five- or six-membered heterocyclic group in which the heterocyclic group may further comprise one or more heteroatoms.
- O—
-
37. The compound according to claim 1 or pharmaceutically acceptable salt or solvate thereof, wherein formula (I) is represented by formula (500):
-
wherein X represents CH or N, Z represents —
O—
, —
NH—
, —
S—
, or —
C(═
O)—
,R501 and R502, which may be the same or different, represent any group selected from C1-6 alkyl, R503 and R506 represent a hydrogen atom, R504 and R505 represent C1-6 alkyl, and R513 represents C1-4 alkyl, and R514 represents hydroxyl;
C1-4 alkoxy optionally substituted by phenyl;
C2-6 alkenyloxy;
phenyloxy;
or amino optionally substituted by a six-membered unsaturated heterocyclic group.
-
-
38. The compound according to claim 37, wherein
Z represents — - O—
,R501 and R502 represent methyl, R503 and R506 represent a hydrogen atom, R504 and R505 represent methyl, and R513 represents methyl.
- O—
-
39. The compound according to claim 1 or pharmaceutically acceptable salt or solvate thereof, wherein formula (I) is represented by formula (600):
-
wherein X represents or N, Z represents —
O—
, —
NH—
, or —
S—
, or —
C(═
O)—
,R601 and R602, which may be the same or different, represent any group selected from the group consisting of a hydrogen atom, C1-6 alkyl, benzyl, and groups of formulae (i), (ii-a), (iii-a), (iv-a), (v), and (vi), (i) a group of formula (i); wherein R51 and R52, which may be the same or different, represent a hydrogen atom, or C1-8 alkyl optionally substituted by hydroxyl, an oxygen atom, amino, or a nitrogen atom, R51 and R52 may combine with a nitrogen atom attached thereto to form a saturated or unsaturated five- or six-membered heterocyclic group which may further comprise one or more heteroatoms and in which the heterocyclic group is optionally substituted by C1-4 alkyl, optionally substituted by hydroxyl, hydroxyl, an oxygen atom, aminocarbonyl, C1-4 alkoxy, C1-4 alkoxycarbonyl, or a saturated or unsaturated five- or six-membered heterocyclic group, and the heterocyclic group optionally formed by allowing R51 to combine with R52 may condense with another saturated or unsaturated five- or six-membered carbocyclic or heterocyclic group to form a bicyclic group, p is an integer of 2 to 4, and the alkyl chain part in this group is optionally substituted by hydroxyl, or —
ORe group wherein Re represents C1-4 alkyl or C1-4 alkylcarbonyl,(ii) a group of formula (ii-a); (iii) a group of formula (iii-a); wherein r1 represents an integer of 2 to 4, (iv) a group of formula (iv-a); wherein R53 and R54, which may be the same or different, represent a hydrogen atom, or C1-6 alkyl optionally substituted by hydroxyl, and R53 and R54 may combine with a nitrogen atom attached thereto to form a saturated or unsaturated five- or six-membered heterocyclic group which may further comprise one or more heteroatoms and in which the heterocyclic group is optionally substituted by C1-4 alkyl, optionally substituted by hydroxyl, or a saturated or unsaturated five- or six-membered heterocyclic group, and the heterocyclic group optionally formed by allowing R53 to combine with R54 may condense with another saturated or unsaturated five- or six-membered carbocyclic or heterocyclic group to form a bicyclic group, (v) a group of formula (v); wherein R55 represents C1-4 alkyl and t is an integer of 0 (zero) to 3, and (vi) a group of formula (vi); wherein R56, R57 and R58, which may be the same or different, represent a hydrogen atom, C1-4 alkoxycarbonyl, or C1-4 alkyl optionally substituted by hydroxyl or a halogen atom, and u is an integer of 0 (zero) to 4, R625 represents a hydrogen atom, R626 represents a hydrogen atom, a halogen atom, or C1-4 alkyl, R627 represents a hydrogen atom, a halogen atom, C1-4 alkyl, C1-4 alkoxy, or C1-4 alkylthio, R626 and R627 may combine with a carbon atom attached thereto to form an unsaturated six-membered carbocyclic or heterocyclic group, R628 represents a hydrogen atom, a halogen atom, nitro, cyano, C1-6 alkyl in which the alkyl group is optionally substituted by hydroxyl;
phenyl;
amino optionally substituted by C1-4 alkyl;
C1-4 alkylcarbonyloxy;
or a saturated or unsaturated six-membered heterocyclic group optionally substituted by C1-4 alkyl,C1-8 alkoxy, C1-4 alkylcarbonyl, C2-6 alkenyl optionally substituted by a saturated or unsaturated six-membered carbocyclic group, C2-6 alkynyl optionally substituted by C1-2 alkylsilyl, a saturated or unsaturated three- to eight-membered carbocyclic oxy group, a saturated or unsaturated six-membered carbocyclic carbonyl or heterocyclic carbonyl group optionally substituted by C1-4 alkyl, or a saturated or unsaturated three- to eight-membered carbocyclic or heterocyclic group in which the carbocyclic or heterocyclic group is optionally substituted by hydroxyl;
cyano;
a halogen atom;
C1-4 alkoxy;
phenyloxy;
C1-4 alkylcarbonyl;
amino optionally substituted by C1-4 alkyl or C1-4 alkylcarbonyl;
aminocarbonyl optionally substituted by C1-4 alkyl;
or C1-4 alkyl optionally substituted by hydroxyl or a halogen atom.
-
-
40. The compound according to claim 39, wherein R628 represents a saturated or unsaturated four- to seven-membered carbocyclic or heterocyclic group in which the carbocyclic or heterocyclic group is optionally substituted by hydroxyl;
- cyano;
a halogen atom;
C1-4 alkoxy;
phenyloxy;
C1-4 alkylcarbonyl;
amino optionally substituted by C1-4 alkyl or C1-4 alkylcarbonyl;
aminocarbonyl optionally substituted by C1-4 alkyl;
or C1-4 alkyl optionally substituted by hydroxyl or a halogen atom.
- cyano;
-
41. The compound according to claim 1 or pharmaceutically acceptable salt or solvate thereof, wherein formula (I) is represented by formula (700):
-
wherein X represents N, Z represents —
O—
, —
NH—
, —
S—
, or —
C(═
O)—
,R701 and R702, which may be the same or different, represent any group selected from C1-6 alkyl, R729 represents a hydrogen atom, R730 represents a hydrogen atom or C1-4 alkyl, and R731 and R732 combine with a carbon atom attached thereto to form an unsaturated five- or six-membered carbocyclic or heterocyclic group in which the carbocyclic or heterocyclic group is optionally substituted by a halogen atom or C1-4 alkyl.
-
-
42. The compound according to claim 41, wherein
Z represents — - O— and
R701 and R702 represent methyl.
- O— and
-
43. The compound according to claim 1, represented by formula (800), or a pharmaceutically acceptable salt or solvate thereof:
-
wherein X represents N, Z represents —
O—
, —
NH—
, —
S—
, or —
C(═
O)—
,R801 and R802, which may be the same or different, represent any group selected from C1-6 alkyl, R833 and R834 represent a hydrogen atom, and R835 and R836 combine with a carbon atom attached thereto to form an unsaturated five- or six-membered carbocyclic or heterocyclic group.
-
-
44. The compound according to claim 43, wherein
Z represents — - O—
or —
S—
,R801 and R802 represent methyl, R835 and R836 combine with a carbon atom attached thereto to form phenyl.
- O—
-
45. The compound according to claim 1 or pharmaceutically acceptable salt or solvate thereof, wherein formula (I) is represented by formula (900):
-
wherein X represents N, Z represents —
O—
, —
NH—
, —
S—
, or —
C(═
O)—
,R901 and R902, which may be the same or different, represent any group selected from C1-6 alkyl R920, R921, R923, and R924, which may be the same or different, represent a hydrogen atom, a halogen atom, C1-10 alkyl optionally substituted by hydroxyl, a saturated or unsaturated five- or six-membered carbocyclic or heterocyclic group, C1-8 alkoxy, C2-6 alkenyl optionally substituted by C1-4 alkyl, C1-4 alkoxy, an oxygen atom or phenyl, phenylcarbonyl optionally substituted by C1-4 alkyl, amino optionally substituted by phenyl, nitro, or a saturated or unsaturated five- or six-membered carbocyclic or heterocyclic group in which the carbocyclic or heterocyclic group is optionally substituted by C1-6 alkyl, provided that at least one of R920 and R924 is selected from a group other than a hydrogen atom, R922 represents C1-10 alkyl optionally substituted by hydroxyl, a saturated or unsaturated six-membered carbocyclic or heterocyclic group, C1-8 alkoxy, amino optionally substituted by phenyl, nitro, or a saturated or unsaturated five- or six-membered carbocyclic or heterocyclic group in which the carbocyclic or heterocyclic group is optionally substituted by C1-6 alkyl, and R921 and R922, or R922 and R923 may combine with a carbon atom attached thereto to form a saturated or unsaturated five- or six-membered carbocyclic or heterocyclic group in which the carbocyclic or heterocyclic group is optionally substituted by a halogen atom, C1-4 alkyl, C1-4 alkylcarbonyl, C1-6 alkoxycarbonyl, or an oxygen atom, and the carbocyclic or heterocyclic group may condense with another saturated or unsaturated five- or six-membered carbocyclic or heterocyclic group to form a tricyclic group together with the six-membered carbocyclic ring of formula (c).
-
-
46. The compound according to claim 45, wherein
at least one of R920 and R924 is selected from a group other than a hydrogen atom, and R921 and R922, or R922 and R923 may combine with a carbon atom attached thereto to form a saturated or unsaturated five- or six-membered carbocyclic or heterocyclic group in which the carbocyclic or heterocyclic group is optionally substituted by a halogen atom, C1-4 alkyl, C1-4 alkylcarbonyl, C1-6 alkoxycarbonyl, or an oxygen atom. -
47. A pharmaceutical composition comprising as an active ingredient the compound according to claim 1 or a pharmaceutically acceptable salt or solvate thereof;
- and a pharmaceutically acceptable carrier.
-
54. A method for treating a disease for which TGFβ
- inhibition is effective therapeutically or prophylactically, comprising the step of administering a therapeutically or prophylactically effective amount of the compound according to claim 1 or a pharmaceutically acceptable salt or solvate thereof to a patient who should undergo therapy of a disease for which inhibition activity is effective therapeutically or prophylactically.
-
55. The method according to claim 54, wherein the disease for which TGFβ
- inhibition is effective therapeutically or prophylactically is a disease involving fibrosis of an organ or a tissue.
-
56. The method according to claim 54, wherein the disease for which TGFβ
- inhibition is effective therapeutically or prophylactically is chronic renal disease, acute renal disease, hepatic fibrosis, cirrhosis, pulmonary fibrosis, scleroderma, wound healing, arthritis, congestive cardiac disease, ulcer, ocular disorder, cornea disorder, diabetic nephropathy, peritoneal sclerosis, arterial sclerosis, peritoneal adhesion, or subdermal adhesion.
-
57. The method according to claim 54, wherein the disease for which TGFβ
- inhibition is effective therapeutically or prophylactically is a malignant tumor.
-
58. A method for amplifying cells in vitro, comprising the step of addition, into target cells in vitro, of the compound according to claim 1 or a pharmaceutically acceptable salt or solvate thereof in an amount effective for promoting cell amplification to amplify cells.
-
59. The method according to claim 58, wherein said target cells are hematopoietic stem cells.
-
60. A method for inhibiting the action of TGFβ
- on cells, comprising the step of applying an effective amount of the compound according to claim 1 to cells present in vitro or in vivo.
-
48-53. -53. (canceled)
-
61-63. -63. (canceled)
Specification
-
- Resources
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-
Current AssigneeKirin Beer Kabushiki Kaisha
-
Original AssigneeKirin Beer Kabushiki Kaisha
-
InventorsShimizu, Toshiyuki, Shimizu, Kiyoshi, Kimura, Kaname, Nakoji, Masayoshi, Kawakami, Kazuki
-
Application NumberUS12/471,520Publication NumberTime in Patent OfficeDaysField of SearchUS Class Current514/230.500CPC Class CodesA61P 1/04 for ulcers, gastritis or re...A61P 1/16 for liver or gallbladder di...A61P 11/00 Drugs for disorders of the ...A61P 13/12 of the kidneysA61P 17/00 Drugs for dermatological di...A61P 17/02 for treating wounds, ulcers...A61P 19/02 for joint disorders, e.g. a...A61P 19/04 for non-specific disorders ...A61P 27/02 Ophthalmic agentsA61P 3/10 for hyperglycaemia, e.g. an...A61P 35/00 Antineoplastic agentsA61P 41/00 Drugs used in surgical meth...A61P 43/00 Drugs for specific purposes...A61P 9/00 Drugs for disorders of the ...A61P 9/10 for treating ischaemic or a...C07D 215/233 only one oxygen atom which ...C07D 401/14 containing three or more he...
