Imidazolylamide derivative
The present invention pertains to an imidazolylamide derivative represented by formula (1) that exhibits an exceptional suppressive effect on cancer cell sphere formation ability and that is useful as an antitumor agent that can be administered orally, or a pharmacologically acceptable salt thereof. [In the formula, ring Q 1 represents a C 6-10 aryl group or the like; m represents 0, 1, 2, 3, 4, or 5; R 3 , independently when multiple, represent(s) a halogen atom or the like; R 1 and R 2 independently represent a hydrogen atom or the like; W 1 represents a C 1-4 alkylene group (said group may be substituted by 1-3 fluorine atoms or C 3-7 cycloalkyls); W 2 represents —NR 4a C(O)— or the like (where R 4a represents a hydrogen atom or C 1-6 alkyl group); and ring Q 2 represents a C 6-10 arylgroup or the like]
1. A compound of Formula (1):
wherein Q 1 is C 6-10 aryl, C 6-10 aryloxy, C 6-10 arylthio, C 3-10 cycloalkyl, or 5- to 10-membered heteroaryl;
m is 0, 1, 2, 3, 4, or 5;
each R 3 is independently selected from:
(1) halogen,
(2) optionally-substituted C 1-6 alkyl,
(3) optionally-substituted C 1-6 alkoxy,
(4) optionally-substituted amino,
(5) optionally-substituted C 6-10 aryl,
(6) optionally-substituted C 6-10 aryloxy,
(7) optionally-substituted 5- to 10-membered heteroaryl,
(8) optionally-substituted C 1-6 alkoxy-carbonyl,
(9) optionally-substituted aminocarbonyl,
(10) optionally-substituted C 1-6 alkyl-carbonyl,
(11) optionally-substituted C 1-6 alkylsulfonyl,
(12) optionally-substituted C 1-6 alkyl-carbonylamino,
(13) optionally-substituted C 1-6 alkylsulfonylamino,
(14) optionally-substituted C 1-6 alkoxy-carbonylamino,
(15) optionally-substituted C 1-6 alkyl-carbonyloxy,
(16) hydroxy,
(17) cyano,
(18) optionally-substituted amino sulfonyl, and
(19) optionally-substituted C 3-10 cycloalkyl;
provided that when two R a s bind to any of the adjacent carbon atoms on Ring Q 1 , the R 3 groups may combine together with the carbon atoms to which they are attached to form a 5- to 8-membered saturated carbocyclic ring or non-aromatic heterocyclic ring, each of which is optionally substituted with 1 to 2 groups independently selected from the group consisting of halogen, C 1-6 alkyl, and C 1-6 alkoxy,
R 1 and R 2 are each independently hydrogen, halogen, or C 1-6 alkyl which is optionally substituted with 1 to 3 independently selected halogen atoms;
W 1 is C 1-4 alkylene which is optionally substituted with 1 to 3 fluorine atoms or C 3-7 cycloalkyl;
W 2 -Q 2 is —NHC(O)—CH═CH-Q 2 ;
Ring Q 2 is:
(1) phenyl which is optionally substituted with 1 to 4 groups independently selected from the group consisting of:
(a) cyano;
(b) C 1-6 alkyl which is optionally substituted with 1 to 3 groups independently selected halogen and hydroxy;
(c) amino which is optionally substituted with 1 to 2 independently selected C 1-6 alkyl groups, wherein each alkyl group is optionally substituted with 1 to 3 independently selected halogen atoms;
(d) C 1-6 alkyl-carbonylamino wherein the alkyl moiety of the alkyl-carbonylamino is optionally substituted with 1 to 3 groups independently selected from halogen, hydroxy, and C 1-6 alkoxy;
(e) C 1-6 alkoxy which is optionally substituted with 1 to 3 groups independently selected from halogen, hydroxy, and C 1-6 alkoxy,
(f) phenoxy which is optionally substituted with 1 to 4 groups independently selected from the group consisting of halogen, C 1-6 alkyl, and C 1-6 alkoxy, and
(g) halogen atom;
or
(2) pyridyl which is optionally substituted with 1 to 4 groups independently selected from the group consisting of:
(a) cyano,
(b) C 1-6 alkyl which is optionally substituted with 1 to 3 independently selected halogen atoms,
(c) amino which is optionally substituted with 1 to 2 independently selected C 1-6 alkyl groups, wherein each alkyl group is optionally substituted with 1 to 3 independently selected halogen atoms, and
(d) C 1-6 alkyl-carbonylamino wherein the alkyl moiety of the alkyl-carbonylamino is optionally substituted with 1 to 3 groups independently selected from halogen, hydroxy, and C 1-6 alkoxy;
or a pharmaceutically acceptable salt thereof.
2. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein Q 1 is phenyl.
3. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein m is 3 or 4.
4. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein each R 3 is independently selected from
(1) halogen,
(2) C 1-6 alkyl which is optionally substituted with 1 to 3 groups independently selected from the group consisting of halogen, hydroxy, and C 1-6 alkoxy,
(3) C 1-6 alkoxy which is optionally substituted with 1 to 3 groups independently selected from the group consisting of halogen, hydroxy, C 1-6 alkoxy, and phenyl,
(4) amino which is optionally substituted with 1 to 2 independently selected C 1-6 alkyl groups,
(5) C 6-10 aryl which is optionally substituted with 1 to 4 groups independently selected from the group consisting of halogen, C 1-6 alkyl, and C 1-6 alkoxy,
(6) C 6-10 aryloxy which is optionally substituted with 1 to 4 groups independently selected from the group consisting of halogen, C 1-6 alkyl, and C 1-6 alkoxy,
(7) 5- to 10-membered heteroaryl which is optionally substituted with 1 to 4 groups independently selected from the group consisting of halogen, C 1-6 alkyl, and C 1-6 alkoxy, and
(8) C 1-6 alkoxy-carbonyl.
5. The compound according to claim 4 , or a pharmaceutically acceptable salt thereof, wherein each R 3 is independently a halogen atom or C 1-6 alkyl which is optionally substituted with 1 to 3 independently selected halogen atoms.
6. The compound according to claim 4 , or a pharmaceutically acceptable salt thereof, wherein any or all of R 3 is fluorine.
7. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein W 1 is methylene.
8. The compound according to claim 7 , wherein Ring Q 2 is phenyl substituted with 1 to 3 groups independently selected from the group consisting of C 1-6 alkoxy which is optionally substituted with 1 to 3 groups independently selected from halogen, hydroxy, and C 1-6 alkoxy, and C 1-6 alkyl-carbonylamino, wherein the alkyl moiety of the alkyl-carbonylamino is optionally substituted with 1 to 3 groups independently selected from halogen, hydroxy, and C 1-6 alkoxy.
9. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein Ring Q 2 is phenyl substituted with 1 to 3 C 1-6 alkoxy groups, each of which is optionally substituted with 1 to 3 groups independently selected from halogen, hydroxy, and C 1-6 alkoxy.
10. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein both R 1 and R 2 are hydrogen.
11. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, which has the structure of Formula (1a):
wherein Ring Q 1a is trifluorophenyl or trifluoromethylphenyl;
Ring Q 2a is phenyl substituted with 1 to 3 groups independently selected from the group consisting of hydroxy, C 1-6 alkoxy which is optionally substituted with 1 to 3 groups independently selected from halogen, hydroxy, and C 1-6 alkoxy, and C 1-6 alkyl-carbonylamino, wherein the alkyl moiety of the alkyl-carbonylamino is optionally substituted with 1 to 3 groups independently selected from halogen, hydroxy, and C 1-6 alkoxy, and
W 2a -Q 2a is —NHC(O)—CH═CH-Q 2a ;
or a pharmaceutically acceptable salt thereof.
12. The compound according to claim 11 , or a pharmaceutically acceptable salt thereof, wherein Ring Q 1a is trifluorophenyl.
13. The compound according to claim 1 , which is selected from the following compounds:
(2E)-3-[4-(acetylamino)phenyl]-N-[1-(3-chlorobenzyl)-1H-imidazol-4-yl]prop-2-enamide,
(2E)-N-[1-(3-chlorobenzyl)-1H-imidazol-4-yl]-3-(pyridin-3-yl)prop-2-enamide,
(2E)-N-[1-(3-chlorobenzyl)-1H-imidazol-4-yl]-3-[4-cyano-3-(2-hydroxyethoxy)phenyl]prop-2-enamide,
(2E)-3-[4-(acetylamino)phenyl]-N-{1-[3-(trifluoromethyl)benzyl]-1H-imidazol-4-yl}prop-2-enamide,
(2E)-3-[3-(2-hydroxyethoxy)-4-methoxyphenyl]-N-{1 [3-(trifluoromethyl)benzyl]-1H-imidazol-4-yl}prop-2-enamide,
(2E)-N-[1-(3-chlorobenzyl)-1H-imidazol-4-yl]-3-[3-(2-hydroxyethoxy)-4-methoxyphenyl]prop-2-enamide,
(2E)-3-[4-(acetylamino)phenyl]-N-[1-(3,4,5-trifluorobenzyl)-1H-imidazol-4-yl]prop-2-enamide, and
(2E)-3-[4-(acetylamino)phenyl]-N-{1-[3-(trifluoromethoxy)benzyl]-1H-imidazol-4-yl}prop-2-enamide, or a pharmaceutically acceptable salt thereof.
14. The compound according to claim 1 , which is (2E)-3-[4-(acetylamino)phenyl]-N-{1-[3-(trifluoromethyl)benzyl]-1H-imidazol-4-yl}prop-2-enamide, or a pharmaceutically acceptable salt thereof.
15. A method for inhibiting the sphere-forming ability of cancer cells, comprising administering an effective amount of a compound according to claim 1 , or a pharmaceutically acceptable salt thereof, to a patient in need thereof.
16. A pharmaceutical composition, comprising a compound according to claim 1 , or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable additives.
17. A pharmaceutical composition, comprising a compound according to claim 11 , or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable additives.
18. A pharmaceutical composition, comprising a compound according to claim 13 , or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable additives.