Agent for removing undifferentiated iPS cells

1. A method of removing iPS cells, comprising adding a compound of formula (1):

or a salt thereof, wherein Q 1 is optionally-substituted C 6-10 aryl, optionally-substituted C 6-10 aryloxy, optionally-substituted C 6-10 arylthio, optionally-substituted C 3-10 cycloalkyl, or optionally-substituted 5- to 10-membered heteroaryl;

R 1 and R 2 are independently hydrogen atom, halogen atom, or C 1-6 alkyl which may be optionally substituted with the same or different 1 to 3 halogen atoms;

W 1 is C 1-4 alkylene which may be optionally substituted with 1 to 3 fluorine atoms or C 3-7 cycloalkyl;

W 2 -Q 2 is —NR 3a C(O)-Q 2 , —NR 3a C(O)OCH 2 -Q 2 , —NR 3a C(O)OCH 2 -Q 2 , —NR 3a C(O)NR 3b -Q 2 , —NR 3a C(O)NR 3b CH 2 -Q 2 , —NR 3a C(O)CH 2 O-Q 2 , —NR 3a C(O)CH 2 -Q 2 , —NR 3a C(O)CH 2 CH 2 -Q 2 , —C(O)NR 3a -Q 2 , —C(O)NR 3a CH 2 -Q 2 , —C(O)NR 3a CH 2 CH 2 -Q 2 , or NR 3a C(O)—CR 3 c=CR 3d -Q 2 wherein R 3a and R 3b are independently hydrogen atom or C 1-6 alkyl; R 3c and R 3d are independently hydrogen atom, fluorine atom, or C 1-6 alkyl; and

ring Q 2 is optionally-substituted C 6-10 aryl or optionally-substituted 5- to 10-membered heteroaryl into a culture solution containing iPS cells or a culture solution containing a cell mass formed from iPS cells.

2. The method according to claim 1 , wherein Q 1 is phenyl which may be optionally substituted with the same or different 1 to 4 groups selected from the group consisting of

(1) halogen atom,

(2) C 1-6 alkyl which may be optionally substituted with the same or different 1 to 3 groups selected from the group consisting of halogen atom, hydroxy, and C 1-6 alkoxy,

(3) C 1-6 alkoxy which may be optionally substituted with the same or different 1 to 3 groups selected from the group consisting of halogen atom, hydroxy, C 1-6 alkoxy, and phenyl,

(4) amino which may be optionally substituted with the same or different 1 to 2 C 1-6 alkyl groups,

(5) C 6-10 aryl which may be optionally substituted with the same or different 1 to 4 groups selected from the group consisting of halogen atom, C 1-6 alkyl, and C 1-6 alkoxy,

(6) C 6-10 aryloxy which may be optionally substituted with the same or different 1 to 4 groups selected from the group consisting of halogen atom, C 1-6 alkyl, and C 1-6 alkoxy,

(7) 5- to 10-membered heteroaryl which may be optionally substituted with the same or different 1 to 4 groups selected from the group consisting of halogen atom, C 1-6 alkyl, and C 1-6 alkoxy, and

(8) C 1-6 alkoxycarbonyl.

3. The method according to claim 1 , wherein Q 1 is phenyl which may be optionally substituted with the same or different 1 to 4 groups selected from the group consisting of halogen atom, and C 1-6 alkyl which may be optionally substituted with the same or different 1 to 3 halogen atoms.

4. The method according to claim 1 , wherein W 2 -Q 2 is —NHC(O)-Q 2 , —NHC(O)—CH═CH-Q 2 , —C(O)NH-Q 2 , or —NHC(O)CH 2 O-Q 2 .

5. The method according to claim 1 , wherein W 1 is methylene.

6. The method according to claim 1 , wherein ring Q 2 is

(1) phenyl which may be optionally substituted with the same or different 1 to 4 groups selected from the group consisting of

(a) halogen atom,

(b) C 1-6 alkyl which may be optionally substituted with the same or different 1 to 3 groups selected from the group consisting of halogen atom, hydroxy, and C 1-6 alkoxy,

(c) C 1-6 alkoxy which may be optionally substituted with the same or different 1 to 3 groups selected from the group consisting of halogen atom, hydroxy, and C 1-6 alkoxy,

(d) C 3-7 cycloalkyl,

(e) C 2-6 alkenyl,

(f) cyano,

(g) amino which may be optionally substituted with the same or different 1 to 2 C 1-6 alkyl groups, and

(h) C 1-6 alkyl-carbonylamino,

(2) 5- to 10-membered heteroaryl which may be optionally substituted with the same or different 1 to 4 groups selected from the group consisting of (a) to (h) defined in the above (1), or

(3) a group of the following formula (11), (12), (13), (14), (15), or (16):

wherein ring Q 3 is optionally-substituted benzene ring, optionally-substituted pyridine ring, optionally-substituted pyrimidine ring, optionally-substituted pyridazine ring, or optionally-substituted pyrazine ring;

ring Q 4 is optionally-substituted 5-membered heteroaryl ring;

n and m are independently 0, 1, or 2, provided that n and m are not simultaneously 0;

X and Z are independently NR 5 , —NR 3e C(O)—, —C(O)NR 3e —, or O wherein R 5 is hydrogen atom, C 1-6 alkyl which may be optionally substituted with the same or different 1 to 3 halogen atoms, or C 1-6 alkylcarbonyl; R 3e is hydrogen atom or C 1-6 alkyl;

p is 1, 2, 3, 4, or 5;

R 4 is, independently when two or more exist, hydrogen atom, halogen atom, hydroxy, oxo, C 1-6 alkyl which may be optionally substituted with the same or different 1 to 3 halogen atoms, or C 1-6 alkoxy which may be optionally substituted with the same or different 1 to 3 halogen atoms.

7. The method according to claim 1 , wherein ring Q 2 is

(1) phenyl which may be optionally substituted with the same or different 1 to 2 groups selected from the group consisting of C 1-6 alkoxy which may be optionally substituted with hydroxy, and C 1-6 alkyl-carbonylamino,

(2) a group of the following formula (2):

wherein R 11 , R 12 , and R 13 are independently

(a) hydrogen atom,

(b) halogen atom,

(c) C 1-6 alkyl which may be optionally substituted with the same or different 1 to 3 fluorine atoms, or

(d) amino which may be optionally substituted with the same or different 1 to 2 C 1-6 alkyl groups, or

(3) a group of the following formula (21):

wherein X 1 is N or CR 14 ;

X 2 is N or CR 15 ;

X 3 is N or CR 16 ;

provided that X 1 , X 2 and X 3 are not simultaneously N;

R 14 , R 15 and R 16 are independently

(a) hydrogen atom,

(b) halogen atom,

(c) C 1-6 alkyl which may be optionally substituted with the same or different 1 to 3 halogen atoms, or

(d) C 1-6 alkoxy which may be optionally substituted with the same or different 1 to 3 halogen atoms;

n and m are independently 0, 1, or 2, provided that n and m are not simultaneously 0;

p is 1, 2, 3, 4, or 5;

R 4a is independently when two or more exist, hydrogen atom, halogen atom, or C 1-6 alkyl which may be optionally substituted with the same or different 1 to 3 halogen atoms.

8. The method according to claim 7 , wherein W 2 -Q 2 is —NHC(O)-Q 2 , or —C(O)NH-Q 2 ; and

ring Q 2 is a group of formula (2) or (21).

9. The method according to claim 7 , wherein R 11 and R 12 are hydrogen atom;

R 13 is hydrogen atom, C 1-4 alkyl which may be optionally substituted with 1 to 3 fluorine atoms, or amino;

R 14 , R 15 and R 16 are independently hydrogen atom or fluorine atom;

n is 1;

m is 0 or 1;

p is 1 or 2;

R 4a is independently when two or more exist, hydrogen atom or methyl.

10. The method according to claim 1 , wherein W 2 -Q 2 is —NHC(O)—CH═CH-Q 2 ; and

ring Q 2 is phenyl which may be optionally substituted with the same or different 1 to 2 groups selected from the group consisting of C 1-6 alkoxy which may be optionally substituted with hydroxy, and C 1-6 alkyl-carbonylamino.

11. The method according to claim 1 , wherein R 1 and R 2 are hydrogen atom.

12. The method according to claim 1 , wherein the compound of formula (1) is selected from the following compounds:

(2E)-3-[4-(acetylamino)phenyl]-N-(1-[3-(trifluoromethyl)benzyl]-1H-imidazol-4-yl)prop-2-enamide,

N-[1-(3-chlorobenzyl)-1H-imidazol-4-yl]-3,4-dimethoxybenzamide, and

6-(hydroxymethyl)-N—{1-[3-(trifluoromethyl)benzyl]-1H-imidazol-4-yl}nicotinamide;

or a salt thereof.

13. The method of claim 1 , which comprises adding the compound of formula (1), or a salt thereof, into a culture solution containing iPS cells.

14. The method of claim 1 , which comprises adding the compound of formula (1), or a salt thereof, into a culture solution containing a cell mass formed from iPS cells.

15. A method of preparing an iPS cell-derived cell population free of iPS cells, which comprises contacting an iPS cell-derived cell population with the compound of formula (1):

or a salt thereof, wherein:

Q 1 is optionally-substituted C 6-10 aryl, optionally-substituted C 6-10 aryloxy, optionally-substituted C 6-10 arylthio, optionally-substituted C 3-10 cycloalkyl, or optionally-substituted 5- to 10-membered heteroaryl;

R 1 and R 2 are independently hydrogen atom, halogen atom, or C 1-6 alkyl which may be optionally substituted with the same or different 1 to 3 halogen atoms;

W 1 is C 1-4 alkylene which may be optionally substituted with 1 to 3 fluorine atoms or C 3-7 cycloalkyl;

W 2 -Q 2 is —NR 3a C(O)-Q 2 , —NR 3a C(O)OCH 2 -Q 2 , —NR 3a C(O)OCH 2 -Q 2 , —NR 3a C(O)NR 3b -Q 2 , —NR 3a C(O)NR 3b CH 2 -Q 2 , —NR 3a C(O)CH 2 O-Q 2 , —NR 3a C(O)CH 2 -Q 2 , —NR 3a C(O)CH 2 CH 2 -Q 2 , —C(O)NR 3a -Q 2 , —C(O)NR 3a CH 2 -Q 2 , —C(O)NR 3a CH 2 CH 2 -Q 2 , or NR 3a C(O)—CR 3 c=CR 3d -Q 2 wherein R 3a and R 3b are independently hydrogen atom or C 1-6 alkyl; R 3c and R 3d are independently hydrogen atom, fluorine atom, or C 1-6 alkyl; and

ring Q 2 is optionally-substituted C 6-10 aryl or optionally-substituted 5- to 10-membered heteroaryl.

16. A method of preparing an iPS cell-derived cell population free of cells maintaining pluripotency, which comprises:

(1) inducing differentiation of a cell population containing iPS cells, and

(2) contacting the cell population obtained in step (1) with the compound of formula (1):

or a salt thereof, wherein:

Q 1 is optionally-substituted C 6-10 aryl, optionally-substituted C 6-10 aryloxy, optionally-substituted C 6-10 arylthio, optionally-substituted C 3-10 cycloalkyl, or optionally-substituted 5- to 10-membered heteroaryl;

R 1 and R 2 are independently hydrogen atom, halogen atom, or C 1-6 alkyl which may be optionally substituted with the same or different 1 to 3 halogen atoms;

W 1 is C 1-4 alkylene which may be optionally substituted with 1 to 3 fluorine atoms or C 3-7 cycloalkyl;

W 2 -Q 2 is —NR 3a C(O)-Q 2 , —NR 3a C(O)OCH 2 -Q 2 , —NR 3a C(O)OCH 2 -Q 2 , —NR 3a C(O)NR 3b -Q 2 , —NR 3a C(O)NR 3b CH 2 -Q 2 , —NR 3a C(O)CH 2 O-Q 2 , —NR 3a C(O)CH 2 -Q 2 , —NR 3a C(O)CH 2 CH 2 -Q 2 , —C(O)NR 3a -Q 2 , —C(O)NR 3a CH 2 -Q 2 , —C(O)NR 3a CH 2 CH 2 -Q 2 , or NR 3a C(O)—CR 3 c=CR 3d -Q 2 wherein R 3a and R 3b are independently hydrogen atom or C 1-6 alkyl; R 3c and R 3d are independently hydrogen atom, fluorine atom, or C 1-6 alkyl; and

ring Q 2 is optionally-substituted C 6-10 aryl or optionally-substituted 5- to 10-membered heteroaryl.

17. An iPS cell-derived cell population free of iPS cells, prepared by the method according to claim 15 .

18. The cell population according to claim 17 containing cells for transplantation.

19. A pharmaceutical composition comprising cells in the cell population according to claim 17 as an active ingredient.