Substituted pyrazolo[1,5-A]pyrimidines as tyrosine kinase inhibitors
View Patent ↗The present invention relates to compounds which inhibit, regulate and/or modulate tyrosine kinase signal transduction, compositions which contain these compounds, and methods of using them to treat tyrosine kinase-dependent diseases and conditions, such as angiogenesis, cancer, tumor growth, atherosclerosis, age related macular degeneration, diabetic retinopathy, macular edema, retinal ischemia, inflammatory diseases, and the like in mammals.
1. A compound of formula I
wherein
m is independently 0,1 or 2;
R 1 is:
1) C 2 -C 6 alkenyl,
2) C 2 -C 6 alkynyl,
3) C 2 -C 8 alkyl,
4) (C═O)NR a R b ,
5) (C═O)R c
6) (C═O)OR c , or
7) heterocyclyl, said heterocyclyl is substituted with at least one substituent selected from:
a) C 0 -C 6 alkyl-(C═O)NR a R b ,
b) C 0 -C 6 alkyl-SO m R d ,
c) C 0 -C 6 alkyl-CO 2 R c ,
d) C 1 -C 6 alkyl-OR c ,
e) C 1 -C 6 alkyl-NR a R b , and
f) C 0 -C 6 alkyl-(C═O)—C 0 -C 6 alkyl-OR c ;
R 2 , R 3 and R 5 are hydrogen;
R 4 is selected from:
1) C 6-10 aryl,
2) C 5-10 heterocyclyl, provided that R 4 is not pyrididonyl,
said aryl and heterocyclyl optionally substituted with at least one substituent selected from R b ;
R a and R b independently are independently selected from:
1) H,
2) C 1 -C 6 alkyl,
3) C 2 -C 6 alkenyl,
4) C 2 -C 6 alkynyl,
5) C 3 -C 10 cycloalkyl,
6) C 6 - 10 aryl,
7) C 5 - 10 heterocyclyl,
9) C 0 -C 6 alkyl-SOmR d ,
10) C 0 -C 6 alkyl-CO 2 R c ,
11) C 0 -C 6 alkyl-OR c ,
13) C 0 -C 6 alkyl-(C═O)-C 0 -C 6 alkyl-OR c ,
said alkyl, aryl and heterocyclyl are optionally substituted with at least one substituent selected from R d ,
R c independently is:
1) H,
2) unsubstituted or substituted C 1 -C 6 alkyl,
3) unsubstituted or substituted C 2 -C 6 alkenyl,
4) unsubstituted or substituted C 2 -C 6 alkynyl,
5) unsubstituted or substituted C 3 -C 10 cycloalkyl,
6) unsubstituted or substituted C 6 - 10 aryl, or
7) unsubstituted or substituted C 5 - 10 heterocyclyl;
said substitution being at least one substituent selected from R b ;
R d independently is:
1) unsubstituted or substituted C 1 -C 6 alkyl,
2) unsubstituted or substituted C 2 -C 6 alkenyl,
3) unsubstituted or substituted C 2 -C 6 alkynyl,
4) unsubstituted or substituted C 3 -C 10 cycloalkyl,
5) unsubstituted or substituted C 6 - 10 aryl, or
6) unsubstituted or substituted C 5 - 10 heterocyclyl;
said substitution being at least one substituent selected from R b ;
or a pharmaceutically acceptable salt or stereoisomer thereof.
2. The compound of claim 1 , wherein R 4 is aryl, which is optionally substituted with at least one substituent selected from R b ; or a pharmaceutically acceptable salt or stereoisomer thereof.
3. A compound selected from:
6-(4-methoxy-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid ethyl ester;
6-(4-methoxy-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid;
6-(4-methoxy-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid amide;
6-(4-methoxy-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carbonitrile;
ethyl 5- [6-(4-methoxyphenyl)pyrazolo[1,5-a]pyrimidin-3-yl]nicotinate;
5-[6-(4-methoxyphenyl)pyrazolo [1,5-a]pyrimidin-3 -yl]-N-methylnicotinamide;
N-ethyl-5-[6-(4-methoxyphenyl)pyrazolo[1,5-a]pyrimidin-3-yl]nicotinamide;
N-cyclopropyl-5-[6-(4-methoxyphenyl) pyrazolo[1,5-a]pyrimidin-3-yl]nicotinamide;
5-[6-(4-methoxyphenyl)pyrazolo[1,5-a]pyrimidin-3-yl]-N-propylnicotinamide;
5-[6-(3-methoxyphenyl)pyrazolo[1,5-a]pyrimidin-3-yl]-N-methylnicotinamide;
N-ethyl-5-[6-(3-methoxyphenyl)pyrazolo[1,5-a]pyrimidin-3-yl]nicotinamide;
5-[6-(3-methoxyphenyl)pyrazolo[1,5-a]pyrimidin-3-yl]-N-propylnicotinamide;
N-cyclopropyl-5-(6-pyridin-4-ylpyrazolo[1,5-a]pyrimidin-3-yl)nicotinamide;
N-propyl-5-(6-pyridin-4-ylpyrazolo[1,5-a]pyrimidin-3-yl)nicotinamide;
or a pharmaceutically acceptable salt or stereoisomer thereof.
4. The compound according to claim 3 selected from:
5-[6-(4-methoxyphenyl)pyrazolo[1,5-a]pyrimidin-3-yl]-N-methylnicotinamide
or a pharmaceutically acceptable salt or stereoisomer thereof.
5. The compound according to claim 3 selected from:
N-ethyl-5-[6-(4-methoxyphenyl)pyrazolo[1,5-a]pyrimidin-3-yl]nicotinamide
or a pharmaceutically acceptable salt or stereoisomer thereof.
6. The compound according to claim 3 selected from:
N-cyclopropyl-5-(6-pyridin-4-ylpyrazolo[1,5-a]pyrimidin-3-yl)nicotinamide
or a pharmaceutically acceptable salt or stereoisomer thereof.
7. A pharmaceutical composition which is comprised of a compound in accordance with claim 1 and a pharmaceutically acceptable carrier.