Indazole derivatives useful as ERK inhibitors
View Patent ↗The present invention provides a compound of the Formula I: Formula I or a pharmaceutically acceptable salt, solvate or ester thereof, wherein R, R1, R2, R3, R4, X, m and n are as defined herein. The compounds are ERK inhibitors. Also disclosed are pharmaceutical compositions comprising the above compounds and methods of treating cancer using the same.
1. A compound of Formula I
or a pharmaceutically acceptable salt thereof, wherein:
R is H;
R 1 is selected from the group consisting of aryl, heterocyclyl and —C(═O)—NR 5 R 6 ;
R 2 is H or alkyl;
X is selected from the group consisting of —O—;
each R 3 independently is selected from the group consisting of alkyl, aryl, hydroxyl, and —S-alkyl, or wherein two R 3 groups together with the same carbon atom to which both are attached form ═O;
m is 0, 1, or 2;
n is 0 or 1;
R 4 is selected from the group consisting of H, alkyl, aryl, —C(═O)-aryl, and —C(═O)—O-alkyl;
R 5 , R 6 , and R 7 independently are H or alkyl;
R 8 and R 9 independently are H, alkyl or aryl; or R 8 and R 9 with the carbon atom to which they are attached form a heterocyclyl ring.
2. The compound of claim 1 wherein R 1 is heterocyclyl which is pyridyl.
3. The compound of claim 1 , wherein R 1 is —C(═O)—NR 5 R 6 wherein R 5 is H and R 6 is alkyl.
4. The compound of claim 3 , wherein said R 6 alkyl is unsubstituted or substituted with an aryl substituent.
5. The compound of claim 1 , wherein R 2 is H.
6. The compound of claim 1 , wherein m is 0.
7. The compound of claim 1 , wherein m is 1, and R 3 is selected from the group consisting of alkyl, aryl, hydroxyl, and —S-alkyl; wherein said R 3 alkyl is hydroxymethyl and said R 3 aryl is phenyl.
8. The compound of claim 1 , wherein m is 2, and the two R 3 groups together with the carbon atom to which both are attached form —C(═O)—.
9. The compound of claim 1 , wherein
is
10. The compound of claim 1 , wherein R 4 is alkyl, which is unsubstituted or substituted with at least one substitutent selected from the group consisting of aryl and heteroaryl.
11. The compound of claim 10 , wherein said R 4 is alkyl which is substituted with a heteroaryl selected from the group consisting of pyridyl, thiazolyl, and thiophenyl.
12. The compound of claim 1 , selected from the group consisting of:
N-[3-[6-(1-METHYLETHOXY)-3-PYRIDINYL]-1H-INDAZOL-5-YL]-4-(PHENYLMETHYL)-2-MORPHOLINECARBOXAMIDE;
N-[3-[6-(1-METHYLETHOXY)-3-PYRIDINYL]-1H-INDAZOL-5-YL]-2-MORPHOLINECARBOXAMIDE;
N-[3-(4-PYRIDINYL)-1H-INDAZOL-5-YL]-4-(4-THIAZOLYLMETHYL)-2-MORPHOLINECARBOXAMIDE;
N-[3-(4-PYRIDINYL)-1H-INDAZOL-5-YL]-4-(3-THIENYLMETHYL)-2-MORPHOLINECARBOXAMIDE;
4-[(2-FLUOROPHENYL)METHYL]-N-[3-(4-PYRIDINYL)-1H-INDAZOL-5-YL]-2-MORPHOLINECARBOXAMIDE;
N-[3-(4-PYRIDINYL)-1H-INDAZOL-5-YL]-4-(2-PYRIDINYLMETHYL)-2-MORPHOLINECARBOXAMIDE;
N-[3-(4-PYRIDINYL)-1H-INDAZOL-5-YL]-4-(2-PYRIDINYLMETHYL)-2-MORPHOLINECARBOXAMIDE;
4-[(2-BROMOPHENYL)METHYL]-N-[3-(4-PYRIDINYL)-1H-INDAZOL-5-YL]-2-MORPHOLINECARBOXAMIDE;
4-[(2-CHLOROPHENYL)METHYL]-N-[3-(4-PYRIDINYL)-1H-INDAZOL-5-YL]-2-MORPHOLINECARBOXAMIDE;
N-[3-(4-PYRIDINYL)-1H-INDAZOL-5-YL]-2-MORPHOLINECARBOXAMIDE;
4-[(2-METHYL-4-THIAZOLYL)METHYL]-N-[3-(4-PYRIDINYL)-1H-INDAZOL-5-YL]-2-MORPHOLINECARBOXAMIDE;
N-[3-(4-PYRIDINYL)-1H-INDAZOL-5-YL]-4-(3-PYRIDINYLMETHYL)-2-MORPHOLINECARBOXAMIDE;
4-(PHENYLMETHYL)-N-[3-(4-PYRIDINYL)-1H-INDAZOL-5-YL]-2-MORPHOLINECARBOXAMIDE;
4-[(4-CHLOROPHENYL)METHYL]-N-[3-(4-PYRIDINYL)-1H-INDAZOL-5-YL]-2-MORPHOLINECARBOXAMIDE;
4-[(3-METHOXYPHENYL)METHYL]-N-[3-(4-PYRIDINYL)-1H-INDAZOL-5-YL]-2-MORPHOLINECARBOXAMIDE;
4-[(3-CHLOROPHENYL)METHYL]-N-[3-(4-PYRIDINYL)-1H-INDAZOL-5-YL]-2-MORPHOLINECARBOXAMIDE;
4-[(4-CYANOPHENYL)METHYL]-N-[3-(4-PYRIDINYL)-1H-INDAZOL-5-YL]-2-MORPHOLINECARBOXAMIDE;
4-[(3-CYANOPHENYL)METHYL]-N-[3-(4-PYRIDINYL)-1H-INDAZOL-5-YL]-2-MORPHOLINECARBOXAMIDE;
4-[(2-CYANOPHENYL)METHYL]-N-[3-(4-PYRIDINYL)-1H-INDAZOL-5-YL]-2-MORPHOLINECARBOXAMIDE;
4-[(4-METHOXYPHENYL)METHYL]-N-[3-(4-PYRIDINYL)-1H-INDAZOL-5-YL]-2-MORPHOLINECARBOXAMIDE;
4-[[4-(METHYLTHIO)PHENYL]METHYL]-N-[3-(4-PYRIDINYL)-1H-INDAZOL-5-YL]-2-MORPHOLINECARBOXAMIDE;
4[(2-METHOXYPHENYL)METHYL]-N-[3-(4-PYRIDINYL)-1H-INDAZOL-5-YL]-2-MORPHOLINECARBOXAMIDE;
4-[(2-CHLORO-6-FLUOROPHENYL)METHYL]-N-[3-(4-PYRIDINYL)-1H-INDAZOL-5-YL]-2-MORPHOLINECARBOXAMIDE;
4-[(2-FLUORO-4-METHOXYPHENYL)METHYL]-N-[3-(4-PYRIDINYL)-1H-INDAZOL-5-YL]-2-MORPHOLINECARBOXAMIDE;
4-[[2-FLUORO-6-(TRIFLUOROMETHYL)PHENYL]METHYL]-N-[3-(4-PYRIDINYL)-1H-INDAZOL-5-YL]-2-MORPHOLINECARBOXAMIDE;
4-[(2-FLUORO-4,5-DIMETHOXYPHENYL)METHYL]-N-[3-(4-PYRIDINYL)-1H-INDAZOL-5-YL]-2-MORPHOLINECARBOXAMIDE;
4-[(4-CHLORO-2-FLUOROPHENYL)METHYL]-N-[3-(4-PYRIDINYL)-1H-INDAZOL-5-YL]-2-MORPHOLINECARBOXAMIDE;
4-[[2-FLUORO-3-(TRIFLUOROMETHYL)PHENYL]METHYL]-N-[3-(4-PYRIDINYL)-1H-INDAZOL-5-YL]-2-MORPHOLINECARBOXAMIDE;
4-[[2-FLUORO-5-(TRIFLUOROMETHYL)PHENYL]METHYL]-N-[3-(4-PYRIDINYL)-1H-INDAZOL-5-YL]-2-MORPHOLINECARBOXAMIDE;
4-[(2,3-DIFLUOROPHENYL)METHYL]-N-[3-(4-PYRIDINYL)-1H-INDAZOL-5-YL]-2-MORPHOLINECARBOXAMIDE;
4-[(2,6-DIFLUOROPHENYL)METHYL]-N-[3-(4-PYRIDINYL)-1H-INDAZOL-5-YL]-2-MORPHOLINECARBOXAMIDE;
4-[(2,4-DIFLUOROPHENYL)METHYL]-N-[3-(4-PYRIDINYL)-1H-INDAZOL-5-YL]-2-MORPHOLINECARBOXAMIDE;
4-[(2-FLUORO-5-METHOXYPHENYL)METHYL]-N-[3-(4-PYRIDINYL)-1H-INDAZOL-5-YL]-2-MORPHOLINECARBOXAMIDE;
4-[(3-CHLORO-2,6-DIFLUOROPHENYL)METHYL]-N-[3-(4-PYRIDINYL)-1H-INDAZOL-5-YL]-2-MORPHOLINECARBOXAMIDE;
4-[(2-CHLORO-3,6-DIFLUOROPHENYL)METHYL]-N-[3-(4-PYRIDINYL)-1H-INDAZOL-5-YL]-2-MORPHOLINECARBOXAMIDE;
4-[(3-CHLORO-4-FLUOROPHENYL)METHYL]-N-[3-(4-PYRIDINYL)-1H-INDAZOL-5-YL]-2-MORPHOLINECARBOXAMIDE;
4-[(3,5-DICHLOROPHENYL)METHYL]-N-[3-(4-PYRIDINYL)-1H-INDAZOL-5-YL]-2-MORPHOLINECARBOXAMIDE; and
4-[(2,5-DIFLUOROPHENYL)METHYL]-N-[3-(4-PYRIDINYL)-1H-INDAZOL-5-YL]-2-MORPHOLINECARBOXAMIDE;
or a pharmaceutically acceptable salt thereof.
13. A pharmaceutical composition comprising at least one compound of claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.