Quinoline Derivatives and Quinazoline Derivatives Inhibiting Autophosphrylation of Flt3 and Medicinal Compositions Containing the Same

1 . A method for treating or preventing a disease, wherein the inhibition of autophosphorylation of FMS-like tyrosine kinase 3 (Flt3), its somatic cell variant (Flt3-ITD), or a combination thereof is therapeutically or prophylactically effective, comprising administering a compound represented by formula (I) or a pharmaceutically acceptable salt or solvate thereof together with a pharmaceutically acceptable carrier, to a mammal:

wherein

X represents CH or N,

Z represents O or S,

R 1 , R 2 , and R 3 , which may be the same or different, represent

a hydrogen atom,

hydroxyl,

halogen,

nitro,

cyano,

amino,

C 1-6 alkyl,

C 2-6 alkenyl,

C 2-6 alkynyl,

C 1-6 alkoxy,

—(C═O)OR C wherein R C represents a hydrogen atom or C 1-4 alkyl, or

—(C═O)NR d R e wherein R d and R e , which may be the same or different, represent a hydrogen atom or C 1-4 alkyl,

the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, and C 1-6 alkoxy groups, which may be represented by R 1 , R 2 , and R 3 , are optionally substituted by hydroxyl; a halogen atom; C 1-6 alkoxy; C 1-6 alkylcarbonyl; carboxyl; C 1-6 alkoxycarbonyl; —(C═O)—NR 10 R 11 wherein R 10 and R 1 , which may be the same or different, represent a hydrogen atom or C 1-4 alkyl optionally substituted by hydroxyl, or R 10 and R 11 may combine with a nitrogen atom attached thereto to form a saturated five- or six-membered heterocyclic group; amino in which one or two hydrogen atoms on the amino group are optionally substituted by C 1-6 alkyl or a saturated or unsaturated three- to eight-membered carbocyclic or heterocyclic group, and the C 1-6 alkyl group is further optionally substituted by hydroxyl, C 1-6 alkoxy, or a saturated or unsaturated three- to eight-membered carbocyclic or heterocyclic group; 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, an oxygen atom, a halogen atom, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 alkoxycarbonyl, or a saturated or unsaturated three- to eight-membered carbocyclic or heterocyclic group, the C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl groups are further optionally substituted by hydroxyl, C 1-6 alkoxy, or a saturated or unsaturated three- to eight-membered carbocyclic or heterocyclic group, and, when the carbocyclic or heterocyclic group is substituted by two C 1-6 alkyl groups, the two alkyl groups may combine together to form an alkylene chain, or the carbocyclic or heterocyclic group may be a bicyclic group condensed with another saturated or unsaturated five- to seven-membered carbocyclic or heterocyclic group;

one or two hydrogen atoms on the amino group, which may be represented by R 1 , R 2 , and R 3 , are optionally substituted by C 1-6 alkyl which is further optionally substituted by hydroxyl or C 1-6 alkoxy;

R 4 represents a hydrogen atom;

all of R 5 , R 6 , R 7 , and R 8 represent a hydrogen atom, or any one or two of R 5 , R 6 , R 7 , and R 8 represent a halogen atom, C 1-4 alkyl, C 1-4 alkoxy, nitro, amino, or hydroxyl with all the remaining groups representing a hydrogen atom, and

R 9 represents C 1-4 alkyl substituted by a substituent selected from the group consisting of a saturated three- to nine-membered carbocyclic group optionally substituted by C 1-4 alkyl, C 1-4 alkoxy, or hydroxyl; i-propyl optionally substituted by C 1-4 alkyl, C 1-4 alkoxy, or hydroxyl; t-butyl optionally substituted by C 1-4 alkyl, C 1-4 alkoxy, or hydroxyl; C 1-4 alkoxy; and —NR a R b wherein R a and R b , which may be the same or different, represent a hydrogen atom or C 1-4 alkyl optionally substituted by hydroxyl, or R a and R b may combine with a nitrogen atom attached thereto to form a saturated five- or six-membered heterocyclic group, or R 9 represents a saturated three- to nine-membered carbocyclic group optionally substituted by one to three C 1-4 alkyl groups.

2 . The method according to claim 1 , wherein the disease where the inhibition of autophosphorylation of Flt3, Flt3-ITD, or a combination thereof is therapeutically or prophylactically effective is hematopoietic malignancy.

3 . The method according to claim 2 , wherein the hematopoietic malignancy is acute myelocytic leukemia or myelodysplastic syndrome.

4 . The method according to claim 1 , wherein the disease where the inhibition of autophosphorylation of Flt3, Flt3-ITD, or a combination thereof is therapeutically or prophylactically effective is an immunological disease caused by abnormal proliferation of B cells, dendritic cells, or natural killer cells.

5 . The method according to claim 1 , which is used in the treatment or prevention of diseases where the inhibition of autophosphorylation of Flt3 is therapeutically or prophylactically effective.

6 . The method according to claim 5 , wherein the disease where the inhibition of autophosphorylation of Flt3 is therapeutically or prophylactically effective is hematopoietic malignancy.

7 . The method according to claim 6 , wherein the hematopoietic malignancy is acute myelocytic leukemia or myelodysplastic syndrome.

8 . The method according to claim 5 , wherein the disease where the inhibition of autophosphorylation of Flt3 is therapeutically or prophylactically effective is an immunological disease caused by abnormal proliferation of B cells, dendritic cells, or natural killer cells.

9 . The method according to claim 1 , which is used in the treatment or prevention of diseases where the inhibition of autophosphorylation of Flt3-ITD is therapeutically or prophylactically effective.

10 . The method according to claim 9 , wherein the disease where the inhibition of autophosphorylation of Flt3-ITD is therapeutically or prophylactically effective is hematopoietic malignancy.

11 . The method according to claim 10 , wherein the hematopoietic malignancy is acute myelocytic leukemia or myelodysplastic syndrome.

12 . The method according to claim 9 , wherein the disease where the inhibition of autophosphorylation of Flt3-ITD is therapeutically or prophylactically effective is an immunological disease caused by abnormal proliferation of B cells, dendritic cells, or natural killer cells.

13 . The method according claim 1 , wherein X represents CH and Z represents O.

14 . The method according to claim 1 , wherein R 1 represents a hydrogen atom and R 2 and R 3 , which may be the same or different, represent optionally substituted C 1-6 alkoxy.

15 . The method according to claim 1 , wherein R 1 represents a hydrogen atom, R 2 and R 3 , which may be the same or different, represent —O—(CH 2 )p-R 12 wherein p is an integer of 0 to 6, —(CH 2 )p- is optionally substituted by C 1-6 alkyl, hydroxyl, or a halogen atom, and R 12 represents a hydrogen atom; hydroxyl; a halogen atom; C 1-6 alkoxy; C 1-6 alkylcarbonyl; carboxyl; C 1-6 alkoxycarbonyl; —(C═O)—NR 13 R 14 wherein R 13 and R 14 , which may be the same or different, represent a hydrogen atom or C 1-4 alkyl optionally substituted by hydroxyl, or R 13 and R 14 may combine with a nitrogen atom attached thereto to form a saturated five- or six-membered heterocyclic group; amino in which one or two hydrogen atoms on the amino group are optionally substituted by C 1-6 alkyl or a saturated or unsaturated three- to eight-membered carbocyclic or heterocyclic group, and the C 1-6 alkyl group is further optionally substituted by hydroxyl, C 1-6 alkoxy, or a saturated or unsaturated three- to eight-membered carbocyclic or heterocyclic group; 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, an oxygen atom, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 alkoxycarbonyl, or a saturated or unsaturated three- to eight-membered carbocyclic or heterocyclic group, the C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl groups are further optionally substituted by hydroxyl, C 1-6 alkoxy, or a saturated or unsaturated three- to eight-membered carbocyclic or heterocyclic group, and, when the carbocyclic or heterocyclic group is substituted by two C 1-6 alkyl groups, the two alkyl groups may combine together to form an alkylene chain, or the carbocyclic or heterocyclic group may be a bicyclic group condensed with another saturated or unsaturated five- to seven-membered carbocyclic or heterocyclic ring.

16 . The method according to claim 1 , wherein all of R 5 , R 6 , R 7 , and R 8 represent a hydrogen atom; or R 6 represents a fluorine atom, and R 5 , R 7 , and R 8 represent a hydrogen atom; or R 5 represents a halogen atom, C 1-4 alkyl, C 1-4 alkoxy, nitro, or amino, and R 6 , R 7 , and R 8 represent a hydrogen atom; or R 5 and R 7 represent a halogen atom, C 1-4 alkyl, C 1-4 alkoxy, nitro, or amino, and R 6 and R 8 represent a hydrogen atom.

17 . The method according to claim 1 , wherein R 9 represents —(CH 2 )s-R 51 wherein s is an integer of 1 to 4, and R 51 represents a saturated three- to seven-membered carbocyclic group; i-propyl optionally substituted by hydroxyl; t-butyl optionally substituted by hydroxyl; C 1-4 alkoxy; or —NR 52 R 53 wherein R 52 and R 53 , which may be the same or different, represent a hydrogen atom, or C 1-4 alkyl optionally substituted by hydroxyl, or R 52 and R 53 may combine with a nitrogen atom attached thereto to form a saturated five- or six-membered heterocyclic group, or R 9 represents a saturated five- to seven-membered carbocyclic group optionally substituted by one to three C 1-4 alkyl groups.

18 . The method according to claim 1 , wherein

X represents CH or N,

Z represents O or S,

R 1 , R 2 , and R 3 , which may be the same or different, represent

a hydrogen atom,

hydroxyl,

a halogen atom,

nitro,

amino,

C 1-6 alkyl,

C 2-6 alkenyl,

C 2-6 alkynyl, or

C 1-6 alkoxy,

the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, and C 1-6 alkoxy groups, which may be represented by R 1 , R 2 , and R 3 , are optionally substituted by hydroxyl; a halogen atom; C 1-6 alkoxy; C 1-6 alkylcarbonyl; carboxyl; C 1-6 alkoxycarbonyl; —(C═O)—NR 10 R 11 wherein R 10 and R 11 , which may be the same or different, represent a hydrogen atom or C 1-4 alkyl optionally substituted by hydroxyl, or R 10 and R 11 may combine with a nitrogen atom attached thereto to form a saturated five- or six-membered heterocyclic group; amino in which one or two hydrogen atoms on the amino group are optionally substituted by C 1-6 alkyl or a saturated or unsaturated three- to eight-membered carbocyclic or heterocyclic group, and the C 1-6 alkyl group is further optionally substituted by hydroxyl, C 1-6 alkoxy, or a saturated or unsaturated three- to eight-membered carbocyclic or heterocyclic group; 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, an oxygen atom, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 alkoxycarbonyl, or a saturated or unsaturated three- to eight-membered carbocyclic or heterocyclic group, the C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl groups are further optionally substituted by hydroxyl, C 1-6 alkoxy, or a saturated or unsaturated three- to eight-membered carbocyclic or heterocyclic group, and, when the carbocyclic or heterocyclic group is substituted by two C 1-6 alkyl groups, the two alkyl groups may combine together to form an alkylene chain, or the carbocyclic or heterocyclic group may be a bicyclic group condensed with another saturated or unsaturated five- to seven-membered carbocyclic or heterocyclic ring;

one or two hydrogen atoms on the amino group, which may be represented by R 1 , R 2 , and R 3 , are optionally substituted by C 1-6 alkyl which is further optionally substituted by hydroxyl or C 1-6 alkoxy;

R 4 represents a hydrogen atom;

all of R 5 , R 6 , R 7 , and R 8 represent a hydrogen atom, or any one or two of R 5 , R 6 , R 7 , and R 8 represent a halogen atom, C 1-4 alkyl, C 1-4 alkoxy, nitro, or amino with all the remaining groups representing a hydrogen atom, and

R 9 represents C 1-4 alkyl substituted by a substituent selected from the group consisting of a saturated three- to seven-membered carbocyclic group; i-propyl optionally substituted by hydroxyl; t-butyl optionally substituted by hydroxyl; C 1-4 alkoxy; and —NR a R b wherein R a and R b , which may be the same or different, represent a hydrogen atom or C 1-4 alkyl optionally substituted by hydroxyl, or R a and R b may combine with a nitrogen atom attached thereto to form a saturated five- or six-membered heterocyclic group, or R 9 represents a saturated five- to seven-membered carbocyclic group optionally substituted by one to three C 1-4 alkyl groups.

19 . The method according to claim 1 , wherein said compound represented by formula (I) is represented by formula (Ia):

wherein

X represents CH or N,

Z represents O or S,

R 10l and R 104 represent a hydrogen atom,

R 102 and R 103 , which may be the same or different, represent

a hydrogen atom,

hydroxyl,

a halogen atom,

nitro,

cyano,

—NR 11 R 112 wherein R 111 and R 112 , which may be the same or different, represent a hydrogen atom or C 1-4 alkyl,

—(C═O)OR 113 wherein R 113 represents a hydrogen atom or C 1-4 alkyl,

—(C═O)NR 114 R 115 wherein R 114 and R 115 , which may be the same or different, represent a hydrogen atom or C 1-4 alkyl,

C 1-6 alkoxy,

C 1-6 alkyl,

C 1-6 alkenyl, or

C 1-6 alkynyl,

the C 1-6 alkoxy, C 1-6 alkyl, C 1-6 alkenyl, or C 1-6 alkynyl are optionally substituted by hydroxyl; a halogen atom; C 1-4 alkoxy; —NR 116 R 117 wherein R 116 and R 117 , which may be the same or different, represent a hydrogen atom or C 1-4 alkyl and the alkyl group is further optionally substituted by hydroxyl or C 1-4 alkoxy; or a saturated or unsaturated three- to eight-membered carbocylic or heterocyclic group in which the cyclic group is optionally substituted by hydroxyl, a halogen atom, C 1-4 alkyl, or C 1-4 alkoxy,

all of R 105 , R 106 , R 107 , and R 108 represent a hydrogen atom, or any one or two of R 105 , R 106 , R 107 , and R 108 represent hydroxyl, C 1-4 alkyl, C 1-4 alkoxy, amino, nitro, or a halogen atom with all the remaining groups representing a hydrogen atom,

R 109 represents —(CH 2 )n-R 110 wherein n is 2, 3, or 4, and R 110 represents i-propyl optionally substituted by C 1-4 alkyl, C 1-4 alkoxy, or hydroxyl; t-butyl optionally substituted by C 1-4 alkyl, C 1-4 alkoxy, or hydroxyl; or a three- to nine-membered saturated carbocyclic group optionally substituted by C 1-4 alkyl, C 1-4 alkoxy, or hydroxyl.

20 . The method according to claim 19 , wherein R 102 and R 103 , which may be the same or different, represent C 1-6 alkoxy and the C 1-6 alkoxy is optionally substituted by hydroxyl; a halogen atom; C 1-4 alkoxy; —NR 116 R 117 wherein R 116 and R 117 , which may be the same or different, represent a hydrogen atom or C 1-4 alkyl and the alkyl group is further optionally substituted by hydroxyl or C 1-4 alkoxy; or a saturated or unsaturated three- to eight-membered carbocylic or heterocyclic group in which the cyclic group is optionally substituted by hydroxyl, halogen atom, C 1-4 alkyl, or C 1-4 alkoxy.

21 . The method according to claim 20 , wherein R 102 and R 103 , which may be the same or different, represent C 1-6 alkoxy in which the alkoxy group is optionally substituted by a saturated or unsaturated three- to eight-membered carbocylic or heterocyclic group and the cyclic group is further optionally substituted by hydroxyl, a halogen atom, C 1-4 alkyl, or C 1-4 alkoxy.

22 . The method according to claim 21 , wherein R 102 and R 103 , which may be the same or different, represent C 1-4 alkoxy in which the alkoxy group is optionally substituted by a saturated five- to seven-membered heterocyclic group and the cyclic group is further optionally substituted by C 1-4 alkyl.

23 . The method according to claim 22 , wherein said substituted C 1-4 alkoxy group is a group represented by

24 . The method according to claim 23 , wherein n is 2.

25 . The method according to claim 22 , wherein said substituted C 1-4 alkoxy group is a group represented by

26 . The method according to claim 25 , wherein n is 2.

27 . The method according to claim 19 , wherein one of R 102 and R 103 represents unsubstituted C 1-6 alkoxy and the other represents substituted C 1-6 alkoxy.

28 . The method according to claim 27 , wherein R 102 represents unsubstituted C 1-6 alkoxy and R 103 represents substituted C 1-6 alkoxy.

29 . The method according to claim 28 , wherein R 102 represents methoxy.

30 . The method according to claim 19 , wherein X represents CH.

31 . The method according to claim 19 , wherein Z represents O.

32 . The method according to claim 19 , wherein all of R 105 , R 106 , R 107 , and R 108 represent a hydrogen atom, or any one or two of R 105 , R 106 , R 107 , and R 108 represent C 1-4 alkyl, C 1-4 alkoxy, or a halogen atom with all the remaining groups representing a hydrogen atom.

33 . The method according to claim 32 , wherein R 105 represents methoxy and R 106 , R 107 , and R 108 represent a hydrogen atom.

34 . The method according to claim 32 , wherein R 105 represents methyl and R 106 , R 107 , and R 108 represent a hydrogen atom.

35 . The method according to claim 32 , wherein R 105 represents a halogen atom and R 106 , R 107 , and R 108 represent a hydrogen atom.

36 . The method according to claim 35 , wherein the halogen atom represents a chlorine or fluorine atom.

37 . The method according to claim 35 , wherein the halogen atom represents a fluorine atom.

38 . The method according to claim 32 , wherein all of R 105 , R 106 , R 107 , and R 108 represent a hydrogen atom.

39 . The method according to any claim 19 , wherein R 109 is a group represented by

40 . The pharmaceutical composition according to claim 39 , wherein n is 2.

41 . The method according to claim 19 , wherein R 109 is a group represented by

42 . The method according to claim 41 , wherein n is 2.

43 . The method according to claim 19 , wherein the compound represented by formula (Ia) is 1-(3,3-dimethyl-butyl)-3-{3-fluoro-4-[6-methoxy-7-(2-piperidin-1-yl-ethoxy)-quinolin-4-yloxy]-phenyl}-urea.

44 . The method according to claim 19 , wherein the compound represented by formula (Ia) is 1-(2-cyclopentyl-ethyl)-3-{3-fluoro-4-[6-methoxy-7-(2-piperidin-1-yl-ethoxy)-quinolin-4-yloxy]-phenyl}-urea.

45 . The method according to claim 19 , wherein the compound represented by formula (Ia) is 1-(2-cyclopentyl-ethyl)-3-{2-fluoro-4-[6-methoxy-7-(2-piperidin-1-yl-ethoxy)-quinolin-4-yloxy]-phenyl}-urea.

46 . The method according to claim 1 , wherein the compound represented by formula (I) is represented by formula (II):

wherein

R 15 and R 16 , which may be the same or different, represent —O—(CH 2 )r-R 22 wherein r is an integer of 0 to 6, —(CH 2 )r- is optionally substituted by C 1-6 alkyl, hydroxyl, or a halogen atom, and R 22 represents a hydrogen atom; hydroxyl; a halogen atom; C 1-6 alkoxy; C 1-6 alkylcarbonyl; carboxyl; C 1-6 alkoxycarbonyl; —(C═O)—NR 23 R 24 wherein R 23 and R 24 , which may be the same or different, represent a hydrogen atom or C 1-4 alkyl optionally substituted by hydroxyl, or R 23 and R 24 may combine with a nitrogen atom attached thereto to form a saturated five- or six-membered heterocyclic group; amino in which one or two hydrogen atoms on the amino group are optionally substituted by C 1-6 alkyl or a saturated or unsaturated three- to eight-membered carbocyclic or heterocyclic group, and the C 1-6 alkyl group is further optionally substituted by hydroxyl, C 1-6 alkoxy, or a saturated or unsaturated three- to eight-membered carbocyclic or heterocyclic group; 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, an oxygen atom, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 alkoxycarbonyl, or a saturated or unsaturated three- to eight-membered carbocyclic or heterocyclic group, the C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl groups are further optionally substituted by hydroxyl, C 1-6 alkoxy, or a saturated or unsaturated three- to eight-membered carbocyclic or heterocyclic group, and, when the carbocyclic or heterocyclic group is substituted by two C 1-6 alkyl groups, the two alkyl groups may combine together to form an alkylene chain, or the carbocyclic or heterocyclic group may be a bicyclic group condensed with another saturated or unsaturated five- to seven-membered carbocyclic or heterocyclic ring,

all of R 17 , R 18 , R 19 , and R 20 represent a hydrogen atom, or any one or two of R 17 , R 18 , R 19 , and R 20 represent a halogen atom, C 1-4 alkyl, C 1-4 alkoxy, nitro, or amino with all the remaining groups representing a hydrogen atom, and

R 21 represents —(CH 2 )t-R 61 wherein t is an integer of 1 to 4 and R 61 represents a saturated three- to seven-membered carbocyclic group; i-propyl optionally substituted by hydroxyl; t-butyl optionally substituted by hydroxyl; C 1-4 alkoxy; or —NR 62 R 63 wherein R 62 and R 63 , which may be the same or different, represent a hydrogen atom, or C 1-4 alkyl optionally substituted by hydroxyl, or R 62 and R 63 may combine with a nitrogen atom attached thereto to form a saturated five- or six-membered heterocyclic group, or R 21 represents a saturated five- to seven-membered carbocyclic group optionally substituted by one to three C 1-4 alkyl groups.

47 . The method according to claim 46 , wherein R 15 and R 16 represent —O—(CH 2 )r-H wherein r is an integer of 1 to 4 and the —(CH 2 )r- part is unsubstituted, or any one of R 15 and R 16 represents —O—(CH 2 ) r —H wherein r is an integer of 1 to 4 and the —(CH 2 )r- part is unsubstituted with the other representing —O—(CH 2 )r-R 22 wherein r is an integer of 1 to 4, the —(CH 2 )r- part is unsubstituted, and R 22 represents optionally substituted amino or an optionally substituted saturated three- to eight-membered heterocyclic group,

all of R 17 , R 18 , R 19 , and R 20 represent a hydrogen atom, or any one or two of R 7 , R 18 , R 19 , and R 20 represent a halogen atom, C 1-4 alkyl, C 1-4 alkoxy, nitro, or amino with all the remaining groups representing a hydrogen atom, and

R 21 represents —(CH 2 )t-R 61 , wherein t is an integer of 1 to 4 and R 61 represents a saturated five- to seven-membered carbocyclic group; i-propyl; t-butyl optionally substituted by hydroxyl; C 1-4 alkoxy; or —NR 62 R 63 wherein R 62 and R 63 , which may be the same or different, represent C 1-4 alkyl, or R 21 represents a five- to seven-membered carbocyclic group optionally substituted by 1 to 3 C 1-4 alkyl groups.

48 . The method according to claim 46 , wherein R 15 and R 16 represent —O—(CH 2 )r-H wherein r is an integer of 1 to 4 and the —(CH 2 )r- part is unsubstituted, or any one of R 15 and R 16 represents —O—(CH 2 )r-H wherein r is an integer of 1 to 4 and the —(CH 2 )r- part is unsubstituted with the other representing —O—(CH 2 )r-R 22 wherein r is an integer of 1 to 4, the —(CH 2 )r- part is unsubstituted, and R 22 represents optionally substituted amino or an optionally substituted saturated three- to eight-membered heterocyclic group,

all of R 17 , R 18 , R 19 , and R 20 represent a hydrogen atom; or R 18 represents a fluorine atom, and R 7 , R 19 , and R 20 represent a hydrogen atom; or R 17 represents a halogen atom, C 1-4 alkyl, or C 1-4 alkoxy, and R 18 , R 19 , and R 20 represent a hydrogen atom; or R 17 and R 19 represent a halogen atom, C 1-4 alkyl, or C 1-4 alkoxy, and R 18 and R 20 represent a hydrogen atom, and

R 21 represents —(CH 2 )t-R 6 , wherein t is an integer of 2 or 3 and R 6 represents a saturated five- to seven-membered carbocyclic group or t-butyl, or R 21 represents a five- to seven-membered carbocyclic group optionally substituted by one to three C 1-4 alkyl groups.

49 - 50 . (canceled)

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

wherein X, Z, R 10l , R 102 , R 103 , R 104 , R 105 , R 106 , R 107 , R 108 , and R 109 are as defined in claim 19 .

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

wherein R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , and R 21 are as defined in claim 46 .

53 . A pharmaceutical composition comprising a compound according to claim 51 or 52 or a pharmaceutically acceptable salt or solvate thereof.