Dihydroindolinone derivatives
Disclosed are dihydroindolone compounds which can modulate the activity of protein tyrosine kinases, a method for preparing the same, and pharmaceutical compositions comprising the same. Also disclosed are use of such compounds and pharmaceutical compositions thereof in the treatment and/or prophylaxis of protein tyrosine kinase associated diseases in an organism, particularly in the treatment and/or prophylaxis of tumors and fibroblast proliferation associated diseases.
1. A compound of Formula I or a pharmaceutically acceptable salt thereof:
Formula I
wherein:
R 1 , R 3 and R 4 are each independently hydrogen;
R 2 is selected from the group consisting of hydrogen and halogen;
R 5 , R 7 and R 17 are each independently hydrogen;
R 6 is selected from the group consisting of phenyl, phenyl substituted with di-C 1-8 alkylamino, and a 5- or 6-membered heterocycloalkyl having one nitrogen as a heteroatom, optionally substituted with C 1-8 alkyl or phenyl-C 1-8 alkyl, with the proviso that when R 6 is heterocycloalkyl, the heteroatom in R 6 is not connected to other groups in Formula I directly;
R 8 and R 9 may be the same or different, and are each independently selected from the group consisting of hydrogen and C 1-8 alkyl;
R 15 and R 16 may be the same or different, and are each independently C 1-8 alkyl;
n1, n2 and n3 are each independently an integer from 0 to 4; and
m is an integer from 0 to 2;
with the proviso that when R 2 is F, R 15 and R 16 are methyl group, R 8 and R 9 are hydrogen, n1+n2=0 or 1 and m=0, and R 6 can not be a piperidin-4-yl optionally substituted with C 1 -C 2 alkyl.
2. The compound of claim 1 , wherein R 1 , R 3 and R 4 are each independently hydrogen; R 2 is selected from the group consisting of hydrogen and halogen; R 5 , R 7 and R 17 are each independently hydrogen; R 6 is selected from the group consisting of phenyl, phenyl substituted with di-C 1-8 alkylamino, a 5- or 6-membered heterocycloalkyl having one nitrogen as a heteroatom, optionally substituted with C 1-8 alkyl, phenyl-C 1-8 alkyl, with the proviso that when R 6 is heterocycloalkyl, the heteroatom in R 6 is not connected to other groups in Formula I directly; R 8 and R 9 are each independently selected from the group consisting of hydrogen and C 1 -C 4 alkyl; and R 15 and R 16 are each independently C 1 -C 4 alkyl.
3. The compound of claim 1 , which is selected from a compound of Formula II or a pharmaceutically acceptable salt thereof:
wherein R 6 , R 8 , R 9 , n1, n2 and n3 and m have the same meanings as defined in the compound of Formula I of claim 1 .
4. The compound of claim 3 , wherein R 6 is selected from the group consisting of phenyl, phenyl substituted with di-C 1-8 alkylamino, a 5- or 6-membered heterocycloalkyl having one nitrogen as a heteroatom, optionally substituted with C 1-8 alkyl, phenyl-C 1-8 alkyl, with the proviso that when R 6 is heterocycloalkyl, the heteroatom in R 6 is not connected to other groups in Formula II directly; R 8 and R 9 are each independently selected from the group consisting of hydrogen and C 1 -C 4 alkyl; n1, n2 and n3 are each independently an integer from 0 to 2, and m is an integer from 0 to 1.
5. A compound or a salt thereof selected from the group consisting of:
No.
Structure
Name
1
N-[(1-ethylpyrrolidin-2-yl)methyl]- 5-(5-fluoro-2-oxo-1,2-dihydroindole- 3-methylene)-2,4-dimethyl-1H- pyrrole-3-formamide
2
N-[(1-methylpyrrolidin-2-yl)ethyl]- 5-(5-fluoro-2-oxo-1,2-dihydroindole- 3-methylene)-2,4-dimethyl-1H- pyrrole-3-formamide
3
N-[(piperidin-2-yl)methyl-5-(5-fluoro- 2-oxo-1,2-dihydroindole-3- methylene)-2,4-dimethyl-1H-pyrrole-3- formamide
4
N-[(piperidin-4-yl)methyl-5-(5-fluoro- 2-oxo-1,2-dihydroindole-3- methylene)-2,4-dimethyl-1H-pyrrole-3- formamide
5
N-(pyrrolidin-3-yl)-5-(5-fluoro-2- oxo-1,2-dihydroindole-3-methylene)- 2,4-dimethyl-1H-pyrrole-3- formamide
6
N-(1-benzylpyrrolidin-3-yl)-5-(5- fluoro-2-oxo-1,2-dihydroindole-3- methylene)-2,4-dimethyl-1H- pyrrole-3-formamide
7
N-[4-(dimethylamino)phenyl]-5-(5- fluoro-2-oxo-1,2-dihydroindole-3- methylene)-2,4-dimethyl-1H-pyrrole- 3-formamide
8
N-{2-[4-(dimethylamino)anilino]-2- oxoethyl}-5-(5-fluoro-2-oxo-1,2- dihydroindole-3-methylene)-2,4- dimethyl-1H-pyrrole-3-formamide
9
N-{1-[4-(dimethylamino)anilino]-1- oxoprop-2-yl}-5-(5-fluoro-2-oxo-1,2- dihydroindole-3-methylene)-2,4- dimethyl-1H-pyrrole-3-formamide
10
N-{2-[2-(diethylamino)ethylamino]-2- oxoethyl}-5-(5-fluoro-2-oxo-1,2- dihydroindole-3-methylene)-2,4- dimethyl-1H-pyrrole-3-formamide
11
N-{2-[(1-ethylpyrrolidin-2-yl) methylamino]-2-oxoethyl}- 5-(5-fluoro-2-oxo-1,2- dihydroindole-3-methylene)-2,4- dimethyl-1H-pyrrole-3-formamide
12
N-{2-[(1-ethylpyrrolidin-2-yl) methylamino]-1-oxoprop-2-yl}- 5-(5-fluoro-2-oxo-1,2- dihydroindole-3-methylene)-2,4- dimethyl-1H-pyrrole-3-formamide
13
N-{2-[2-(1-methylpyrrolidin-2-yl) ethylamino]-2-oxoethyl}- 5-(5-fluoro-2-oxo-1,2- dihydroindole-3-methylene)-2,4- dimethyl-1H-pyrrole-3-formamide
14
N-{1-[2-(1-methylpyrrolidin-2-yl) ethylamino]-1-oxoprop-2-yl}- 5-(5-fluoro-2-oxo-1,2- dihydroindole-3-methylene)-2,4- dimethyl-1H-pyrrole-3-formamide
15
N-{2-[(1-benzylpyrrolidin-3-yl) amino]-2-oxoethyl}- 5-(5-fluoro-2-oxo-1,2- dihydroindole-3-methylene)-2,4- dimethyl-1H-pyrrole-3-formamide
16
N-{2-[(piperidin-2-yl) methylamino]-2-oxoethyl}- 5-(5-fluoro-2-oxo-1,2- dihydroindole-3-methylene)-2,4- dimethyl-1H-pyrrole-3-formamide
17
N-{2-[(piperidin-4-yl) methylamino]-2-oxoethyl}- 5-(5-fluoro-2-oxo-1,2- dihydroindole-3-methylene)-2,4- dimethyl-1H-pyrrole-3-formamide
6. A method for preparing the compound of claim 1 , comprising reacting an intermediate of Formula III with an intermediate of Formula IV:
wherein R 1 ˜R 9 , R 15 ˜R 17 , n1, n2, n3 and m have the same meanings as defined in Formula I of claim 1 .
7. A method for preparing the compound of claim 3 , comprising reacting an intermediate of Formula V with an intermediate of Formula VI:
wherein R 6 , R 8 , R 9 , n1, n2, n3 and m have the same meanings as defined in Formula II of claim 3 .
8. A pharmaceutical composition comprising the compound of claim 1 , and one or more pharmaceutically acceptable carriers, excipients and/or vehicles.
9. A method for treating cervical carcinoma, liver cancer, lung cancer, gastric cancer, breast cancer or colon cancer, comprising administering to a subject in need thereof a therapeutically effective amount of the compound of claim 1 .
10. A method for treating a fibroblast proliferation associated disease by inhibiting fibroblast proliferation in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of the compound of claim 1 , wherein the fibroblast proliferation associated disease is selected from the group consisting of hepatic fibrosis, chronic pancreatitis, scleroderma, renal glomerular fibrosis and multiple organ fibrosis supervened with radiochemotherapy and tissue transplantation.
11. The compound of claim 1 , wherein n1, n2 and n3 are each independently selected from 0, 1 or 2; and m is selected from 0 or 1.
12. The compound of claim 1 , wherein R 6 is phenyl substituted with di-C 1-8 alkylamino.
13. The compound of claim 1 , wherein R 6 is piperidin-2-yl, piperidin-4-yl, pyrrolidin-3-yl or pyrrolidin-2-yl that may be optionally substituted with C 1-4 alkyl or phenyl-C 1-8 alkyl.