Compound having TGFβ inhibitory activity and medicinal composition containing the same

1. A compound represented by formula (I) or a pharmaceutically acceptable salt or solvate thereof:

wherein

X represents CH,

Z represents —O— or —S—,

R and R′, which may be the same or different, represent

1) a hydrogen atom,

2) a halogen atom, or

OR″ wherein R″ represents a hydrogen atom, or —(CH 2 )m-R a wherein R a represents a hydrogen atom, a halogen atom, hydroxyl, a saturated or unsaturated three- to six-membered carbocyclic or heterocyclic group, C 1-4 alkoxy, C 1-4 alkoxycarbonyl, or —NR b R c wherein R b and R c , which may be the same or different, represent a hydrogen atom or C 1-6 alkyl, in which the C 1-6 alkyl group is optionally substituted by hydroxyl, an oxygen atom, amino, a nitrogen atom, or C 1-4 alkyl, and R b and R c 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 C 1-4 alkyl optionally substituted by hydroxyl, hydroxyl, an oxygen atom, aminocarbonyl, C 1-4 alkoxy, C 1-4 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, —(CH 2 )m-, is optionally substituted by hydroxyl, an oxygen atom, —OR d group, wherein R d represents C 1-4 alkyl or C 1-4 alkylcarbonyl, or C 1-4 alkyl optionally substituted by hydroxyl or a halogen atom and

A represents

a group of formula (b1):

wherein

R 25 to R 27 , which may be the same or different, represent

a hydrogen atom,

a halogen atom,

C 1-6 alkyl,

C 1-8 alkoxy,

C 1-4 alkylcarbonyl

C 1-4 alkylthio, or

phenylcarbonyl,

R 25 and R 26 , and R 26 and R 27 each may combine with a carbon atom attached thereto to form a saturated or unsaturated five- or six-membered carbocyclic or heterocyclic group,

R 28 represents

a hydrogen atom,

a halogen atom,

nitro,

cyano,

C 1-6 alkyl in which the alkyl group is optionally substituted by hydroxyl; phenyl; amino optionally substituted by C 1-4 alkyl; C 1-4 alkylcarbonyloxy; or a saturated or unsaturated six-membered heterocyclic group optionally substituted by C 1-4 alkyl,

C 1-8 alkoxy,

C 1-4 alkylcarbonyl,

C 2-6 alkenyl optionally substituted by a saturated or unsaturated six-membered carbocyclic group,

C 2-6 alkynyl optionally substituted by C 1-2 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 C 1-4 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; C 1-4 alkoxy; phenyloxy; C 1-4 alkylcarbonyl; amino optionally substituted by C 1-4 alkyl or C 1-4 alkylcarbonyl; aminocarbonyl optionally substituted by C 1-4 alkyl; or C 1-4 alkyl optionally substituted by hydroxyl or a halogen atom.

2. The compound according to claim 1 , represented by formula (II), or a pharmaceutically acceptable salt or solvate thereof:

wherein

X, Z, and A are as defined in claim 1 ,

R 1 and R 2 , which may be the same or different, represent a hydrogen atom, or —(CH 2 )m-R a wherein R a represents a hydrogen atom, a halogen atom, hydroxyl, a saturated or unsaturated three- to six-membered carbocyclic or heterocyclic group, C 1-4 alkoxy, C 1-4 alkoxycarbonyl, or —NR b R c wherein R b and R c , which may be the same or different, represent a hydrogen atom or C 1-6 alkyl, in which the C 1-6 alkyl group is optionally substituted by hydroxyl, an oxygen atom, amino, a nitrogen atom, or C 1-4 alkyl, and R b and R c 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 C 1-4 alkyl, optionally substituted by hydroxyl, hydroxyl, an oxygen atom, aminocarbonyl, C 1-4 alkoxy, C 1-4 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, —(CH 2 )m-, is optionally substituted by hydroxyl, an oxygen atom, —OR d group, wherein R d represents C 1-4 alkyl or C 1-4 alkylcarbonyl, or C 1-4 alkyl optionally substituted by hydroxyl or a halogen atom.

3. The compound according to claim 2 , wherein

R 1 and R 2 , which may be the same or different, represent any group selected from the group consisting of

a hydrogen atom,

C 1-6 alkyl optionally substituted by phenyl, and groups of formulae (i) to (vi):

(i) a group of formula (i):

wherein

R 51 and R 52 , which may be the same or different, represent

a hydrogen atom, or

C 1-8 alkyl optionally substituted by hydroxyl, an oxygen atom, amino, or a nitrogen atom,

R 51 and R 52 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 C 1-4 alkyl optionally substituted by hydroxyl, hydroxyl, an oxygen atom, aminocarbonyl, C 1-4 alkoxy, C 1-4 alkoxycarbonyl, or a saturated or unsaturated five- or six-membered heterocyclic group, and the heterocyclic group optionally formed by allowing R 51 to combine with R 52 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 —OR e group wherein R e represents C 1-4 alkyl or C 1-4 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

R 53 and R 54 , which may be the same or different, represent

a hydrogen atom, or

C 1-6 alkyl optionally substituted by hydroxyl,

R 53 and R 54 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 C 1-4 alkyl optionally substituted by hydroxyl, or a saturated or unsaturated five- or six-membered heterocyclic group, and the heterocyclic group optionally formed by allowing R 53 to combine with R 54 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

R 55 represents C 1-4 alkyl and

t is an integer of 0 (zero) to 3, and

(vi) a group of formula (vi):

wherein

R 56 , R 57 and R 58 , which may be the same or different, represent

a hydrogen atom,

C 1-4 alkoxycarbonyl, or

C 1-4 alkyl optionally substituted by hydroxyl or a halogen atom, and

u is an integer of 0 (zero) to 4.

4. The compound according to claim 3 , wherein formula (i) is represented by formula (i-a):

5. The compound according to claim 3 or 4 , wherein

R 1 and R 2 , which may be the same or different, represent any group selected from the group consisting of

a hydrogen atom,

C 1-6 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):

6. The compound according to claim 5 , wherein one of R 1 and R 2 is selected from C 1-6 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, and

a halogen atom.

8. The compound according to claim 1 , wherein

R′ is selected from the group consisting of

a hydrogen atom, and

a halogen atom.

9. The compound according to claim 1 , wherein

A represents a group of formula (b1) and, in formula (b1),

R 25 represents a hydrogen atom,

R 26 represents a hydrogen atom, a halogen atom, or C 1-4 alkyl,

R 27 represents a hydrogen atom, a halogen atom, C 1-4 alkyl, C 1-4 alkoxy, or C 1-4 alkylthio,

R 26 and R 27 may combine with a carbon atom attached thereto to form an unsaturated six-membered carbocyclic or heterocyclic group, and

R 28 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; C 1-4 alkoxy; phenyloxy; C 1-4 alkylcarbonyl; amino optionally substituted by C 1-4 alkyl or C 1-4 alkylcarbonyl; aminocarbonyl optionally substituted by C 1-4 alkyl; or C 1-4 alkyl optionally substituted by hydroxyl or a halogen atom.

10. The compound according to claim 1 , wherein when one of R 1 and R 2 is selected from C 1-6 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), (iii-a), and (iv-a) according to claim 5 ,

A is selected from groups of formula.

11. The compound according to claim 1 or pharmaceutically acceptable salt or solvate thereof, wherein formula (I) is represented by formula (600):

wherein

X represents CH,

Z represents —O—, or —S—,

R 601 and R 602 , which may be the same or different, represent any group selected from the group consisting of

a hydrogen atom,

C 1-6 alkyl,

benzyl, and

groups of formulae (i), (ii-a), (iii-a), (iv-a), (v), and (vi),

(i) a group of formula (i):

wherein

R 51 and R 52 , which may be the same or different, represent

a hydrogen atom, or

C 1-8 alkyl optionally substituted by hydroxyl, an oxygen atom, amino, or a nitrogen atom,

R 51 and R 52 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 C 1-4 alkyl, optionally substituted by hydroxyl, hydroxyl, an oxygen atom, aminocarbonyl, C 1-4 alkoxy, C 1-4 alkoxycarbonyl, or a saturated or unsaturated five- or six-membered heterocyclic group, and the heterocyclic group optionally formed by allowing R 51 to combine with R 52 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 —OR e group wherein R e represents C 1-4 alkyl or C 1-4 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

R 53 and R 54 , which may be the same or different, represent

a hydrogen atom, or

C 1-6 alkyl optionally substituted by hydroxyl, and

R 53 and R 54 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 C 1-4 alkyl, optionally substituted by hydroxyl, or a saturated or unsaturated five- or six-membered heterocyclic group, and the heterocyclic group optionally formed by allowing R 53 to combine with R 54 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

R 55 represents C 1-4 alkyl and

t is an integer of 0 (zero) to 3, and

(vi) a group of formula (vi):

wherein

R 56 , R 57 and R 58 , which may be the same or different, represent

a hydrogen atom,

C 1-4 alkoxycarbonyl, or

C 1-4 alkyl optionally substituted by hydroxyl or a halogen atom, and

u is an integer of 0 (zero) to 4,

R 625 represents a hydrogen atom,

R 626 represents a hydrogen atom, a halogen atom, or C 1-4 alkyl,

R 627 represents a hydrogen atom, a halogen atom, C 1-4 alkyl, C 1-4 alkoxy, or C 1-4 alkylthio,

R 626 and R 627 may combine with a carbon atom attached thereto to form an unsaturated six-membered carbocyclic or heterocyclic group,

R 628 represents

a hydrogen atom,

a halogen atom,

nitro,

cyano,

C 1-6 alkyl in which the alkyl group is optionally substituted by hydroxyl; phenyl; amino optionally substituted by C 1-4 alkyl; C 1-4 alkylcarbonyloxy; or a saturated or unsaturated six-membered heterocyclic group optionally substituted by C 1-4 alkyl,

C 18 alkoxy,

C 1-4 alkylcarbonyl,

C 2-6 alkenyl optionally substituted by a saturated or unsaturated six-membered carbocyclic group,

C 2-6 alkynyl optionally substituted by C 1-2 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 C 1-4 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; C 1-4 alkoxy; phenyloxy; C 1-4 alkylcarbonyl; amino optionally substituted by C 1-4 alkyl or C 1-4 alkylcarbonyl; aminocarbonyl optionally substituted by C 1-4 alkyl; or C 1-4 alkyl optionally substituted by hydroxyl or a halogen atom.

12. The compound according to claim 11 , wherein R 628 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; C 1-4 alkoxy; phenyloxy; C 1-4 alkylcarbonyl; amino optionally substituted by C 1-4 alkyl or C 1-4 alkylcarbonyl; aminocarbonyl optionally substituted by C 1-4 alkyl; or C 1-4 alkyl optionally substituted by hydroxyl or a halogen atom.

13. 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.