IGF-1R inhibitor
View Patent ↗The present invention provides a type I insulin-like growth factor receptor (IGF-1R) inhibitor comprising, as an active ingredient, an indazole derivative represented by Formula (I): {wherein R 1 represents —NR 4 R 5 [wherein R 4 represents a hydrogen atom or the like, R 5 represents substituted or unsubstituted lower alkyl, —C(═O)R 6 (wherein R 6 represents substituted or unsubstituted lower alkyl, substituted or unsubstituted aryl or the like), or the like], or the like, and R 2 and R 3 may be the same or different and each represents a hydrogen atom, hydroxy, substituted or unsubstituted lower alkoxy, or the like} or a pharmaceutically acceptable salt thereof, and the like.
1. An indazole derivative represented by Formula (IIIb):
{wherein R 4 represents a hydrogen atom or substituted or unsubstituted lower alkyl,
R 5 represents a hydrogen atom, substituted or unsubstituted lower alkyl, a substituted or unsubstituted heterocyclic group, —C(═S)NH 2 , —C(═O)R 6 [wherein R 6 represents a hydrogen atom, substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkoxy, substituted or unsubstituted aryl, a substituted or unsubstituted heterocyclic group, or —NR 7a R 7b (wherein R 7a and R 7b may be the same or different and each represents a hydrogen atom, substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkoxy, substituted or unsubstituted aryl, or a substituted or unsubstituted heterocyclic group, or R 7a and R 7b are combined together with the adjacent nitrogen atom thereto to form a substituted or unsubstituted heterocyclic group)] or —S(O) 2 R 8 (wherein R 8 represents substituted or unsubstituted lower alkyl or substituted or unsubstituted aryl), or R 4 and R 5 are combined together with the adjacent nitrogen atom thereto to form nitro, a substituted or unsubstituted heterocyclic group, —N═CH—R 18 (wherein R 18 represents substituted or unsubstituted aryl, or a substituted or unsubstituted heterocyclic group), or —N═CH—NR 9a R 9b (wherein R 9a and R 9b may be the same or different and each represents a hydrogen atom or lower alkyl), and
R 11a and R 11b have the same meanings as R 7a and R 7b defined above, respectively},
or a pharmaceutically acceptable salt thereof.
2. The indazole derivative or the pharmaceutically acceptable salt thereof according to claim 1 , wherein R 11a and R 11b are combined together with the adjacent nitrogen atom thereto to form a substituted or unsubstituted heterocyclic group.
3. The indazole derivative or the pharmaceutically acceptable salt thereof according to claim 1 , wherein R 11a and R 11b may be the same or different and each is substituted or unsubstituted lower alkyl.
4. The indazole derivative or the pharmaceutically acceptable salt thereof according to claim 1 , wherein R 4 is a hydrogen atom and R 5 is —C(═O)R 6d (wherein R 6d represents a substituted or unsubstituted heterocyclic group).
5. The indazole derivative or the pharmaceutically acceptable salt thereof according to claim 2 , wherein R 4 is a hydrogen atom and R 5 is —C(═O)R 6d (wherein R 6d represents a substituted or unsubstituted heterocyclic group).
6. The indazole derivative or the pharmaceutically acceptable salt thereof according to claim 3 , wherein R 4 is a hydrogen atom and R 5 is —C(═O)R 6d (wherein R 6d represents a substituted or unsubstituted heterocyclic group).
7. The indazole derivative or the pharmaceutically acceptable salt thereof according to claim 5 , wherein R 6d methylthiophen-2-yl.
8. The indazole derivative or the pharmaceutically acceptable salt thereof according to claim 4 , wherein R 11a and R 11b are combined together with the adjacent nitrogen atom thereto to form a substituted or unsubstituted piperazinyl.
9. The indazole derivative or the pharmaceutically acceptable salt thereof according to claim 8 , wherein R 6d is 3-methylthiophen-2-yl.
10. An indazole derivative selected from the group consisting of:
(E)-N-{2-[2-(1H-indazol-3-yl)vinyl]-5-(4-methylpiperazin-1-ylmethyl)phenyl}-3-methylthiophene-2-carboxamide,
(E)-N-{5-[4-(2-hydroxyethyl)piperazin-1-ylmethyl]-2-[2-(1H-indazol-3-yl)vinyl]phenyl}-3-methylthiophene-2-carboxamide,
(E)-N-{2-[2-(1H-indazol-3-yl)vinyl]-5-piperazin-1-ylmethyl}phenyl}-3-methylthiophene-2-carboxamide,
(E)-N-{2-[2-(1H-indazol-3-yl)vinyl]-5-[4-(2-methoxyacetyl)piperazin-1-ylmethyl]phenyl}-3-methylthiophene-2-carboxamide,
(E)-N-{2-[2-(1H-indazol-3-yl)vinyl]-5-[4-(2-hydroxyacetyl)piperazin-1-ylmethyl]phenyl}-3-methylthiophene-2-carboxamide,
(E)-N-{5-(4-acetylpiperazin-1-ylmethyl)-2-[2-(1H-indazol-3-yl)vinyl]phenyl}-3-methylthiophene-2-carboxamide,
(E)-N-{2-[2-(1H-indazol-3-yl)vinyl]-5-[4-(2-methoxyethyl)piperazin-1-ylmethyl]phenyl}-3-methylthiophene-2-carboxamide,
(E)-N-{5-[4-(3-hydroxypropyl)piperazin-1-ylmethyl]-2-[2-(1H-indazol-3-yl)vinyl]phenyl}-3-methylthiophene-2-carboxamide,
(E)-N-{5-[4-(2-hydroxy-2-methylpropyl)piperazin-1-ylmethyl]-2-[2-(1H-indazol-3-yl)vinyl]phenyl}-3-methylthiophene-2-carboxamide,
(E)-{2-[2-(1H-indazol-3-yl)vinyl]-5-[4-(3-oxobutyl)piperazin-1-ylmethyl]phenyl}-3-methylthiophene-2-carboxamide, and
(E)-N-{5-[4-(3-hydroxy-3-methylbutyl)piperidin-1-ylmethyl]-2-[2-(1H-indazol-3-yl)vinyl]phenyl}-3-methylthiophene-2-carboxamide,
or a pharmaceutically acceptable salt thereof.
11. An indazole derivative selected from the group consisting of:
(E)-N-{2-[2-(1H-indazol-3-yl)vinyl]-5-(4-methyl-3-oxopiperazin-1-ylmethyl)phenyl}-3-methylthiophene-2-carboxamide,
(R)-(E)-N-{2-[2-(1H-indazol-3-yl)vinyl]-5-(2-methylpiperazin-1-ylmethyl)phenyl}-3-methylthiophene-2-carboxamide, and
(S)-(E)-N-{2-[2-(1H-indazol-3-yl)vinyl]-5-(2-methylpiperazin-1-ylmethyl)phenyl}-3-methylthiophene-2-carboxamide,
or a pharmaceutically acceptable salt thereof.
12. An indazole derivative selected from the group consisting of:
(E)-N-{2-[2-(1H-indazol-3-yl)vinyl]-5-(piperazin-1-ylcarbonyl)phenyl}-3-methylthiophene-2-carboxamide,
(E)-N-{2-[2-(1H-indazol-3-yl)vinyl]-5-(4-methanesulfonylpiperazin-1-ylcarbonyl)phenyl}-3-methylthiophene-2-carboxamide,
(S)-(E)-N-{2-[2-(1H-indazol-3-yl)vinyl]-5-[4-(pyrrolidin-2-ylcarbonyl)piperazin-1-ylcarbonyl]phenyl}-3-methylthiophene-2-carboxamide, and
(E)-N-{5-[4-(2-hydroxyethyl)piperazin-1-ylcarbonyl]-2-[2-(1H-indazol-3-yl)vinyl]phenyl}-3-methylthiophene-2-carboxamide,
or a pharmaceutically acceptable salt thereof.
13. An indazole derivative selected from the group consisting of:
(E)-N-{-2-[2-(1H-indazol-3-yl)vinyl]-5-(N-propylcarbamoyl)phenyl}-3-methylthiophene-2-carboxamide,
(E)-N-{-2-[2-(1H-indazol-3-yl)vinyl]-5-[2-(morpholin-4-yl)ethylaminomethyl]phenyl}-3-methylthiophene-2-carboxamide, and
(E)-N-{-2-[2-(1H-indazol-3-yl)vinyl]-5-[N-(2-methoxyethyl)methylaminomethyl]phenyl}-3-methylthiophene-2-carboxamide, or a pharmaceutically acceptable salt thereof.
14. A method for inhibiting type I insulin-like growth factor receptor comprising administering to a mammal an effective amount of the indazole derivative or the pharmaceutically acceptable salt thereof described in any one of claims 1 to 4 , 5 , 6 and 7 to 13 .
15. A method for treating solid carcinoma selected from the group consisting of colon cancer and pancreatic cancer comprising administering to a mammal an effective amount of the indazole derivative or the pharmaceutically acceptable salt thereof described in any one of claims 1 to 4 , 5 , 6 and 7 to 13 .
16. A method for treating multiple myeloma comprising administering to a mammal an effective amount of the indazole derivative or the pharmaceutically acceptable salt thereof described in any one of claims 1 to 4 , 5 , 6 and 7 to 13 .