Tyrosine kinase inhibitors

1. A compound of Formula I

wherein

R 1 is selected from

hydrogen,

halogen,

substituted or unsubstituted C 1 -C 10 alkyl,

substituted or unsubstituted C 2 -C 10 alkenyl,

substituted or unsubstituted C 2 -C 10 alkynyl,

substituted or unsubstituted aryl,

substituted or unsubstituted C 3 -C 10 cycloalkyl,

—(CR a 2 ) n OR 4 , and

—(CR a 2 ) t C(O)OR 4 ;

said alkyl, alkenyl, alkynyl, aryl, and cycloalkyl, is optionally substituted with one or more of R 7 ;

R 2 is selected from

hydrogen,

substituted or unsubstituted aralkyl,

substituted or unsubstituted C 1 -C 10 alkyl,

substituted or unsubstituted aryl, and

substituted or unsubstituted C 3 -C 10 cycloalkyl;

R 3 is selected from

halogen,

—C(O)R 4 ,

unsubstituted C 1 -C 10 alkyl,

substituted or unsubstituted aryl,

substituted or unsubstituted C 3 -C 10 cycloalkyl,

substituted or unsubstituted C 2 -C 10 alkenyl, and

substituted or unsubstituted C 2 -C 10 alkynyl;

R 4 is independently selected from

hydrogen,

substituted or unsubstituted C 1 -C 10 alkyl,

substituted or unsubstituted aryl,

substituted or unsubstituted C 3 -C 10 cycloalkyl,

substituted or unsubstituted C 2 -C 10 alkenyl, and

substituted or unsubstituted C 2 -C 10 alkynyl;

R 6 is independently selected from

substituted or unsubstituted aryl,

substituted or unsubstituted cycloalkyl, and

halogen;

R 7 is independently selected from

hydrogen,

halogen,

substituted or unsubstituted C 1 -C 10 alkyl,

substituted or unsubstituted C 2 -C 10 alkenyl,

substituted or unsubstituted C 2 -C 10 alkynyl,

substituted or unsubstituted C 3 -C 10 cycloalkyl,

substituted or unsubstituted aryl,

—NO 2 ,

—NR 4 (CR a 2 ) n C(O)R 4 ,

—(CR a 2 ) n NR 4 2 ,

—(CR a 2 ) n NR 4 (CR a 2 ) n R 6 ,

—CN,

—(CR a 2 ) n C(O)R 4 ,

—(CR a 2 ) n C(O)(CR a 2 ) n OR 4 ,

—(CR a 2 ) n OR 4 ,

—(CR a 2 ) n R 6 ,

—(CR a 2 ) n C(O)OR 4 , and

—(CR a 2 ) n Si(R 4 ) 3 ;

R a is independently selected from

hydrogen,

substituted or unsubstituted C 1 -C 10 alkyl,

substituted or unsubstituted C 2 -C 10 alkenyl,

substituted or unsubstituted C 2 -C 10 alkynyl,

—OR 4 ,

—C(O)OR 4 ,

—NR 4 2 ,

substituted or unsubstituted aryl, and

substituted or unsubstituted C 3 -C 10 cycloalkyl;

n is independently 0 to 6;

t is 1 to 4;

or a pharmaceutically acceptable salt or stereoisomer thereof.

2. The compound according to claim 1 , wherein

R 1 is selected from

1) hydrogen,

2) halogen,

3) substituted or unsubstituted C 1 -C 6 alkyl,

4) substituted or unsubstituted C 2 -C 10 alkynyl,

5) substituted or unsubstituted aryl, and

6) substituted or unsubstituted C 3 -C 10 cycloalkyl,

said alkyl, alkynyl, aryl, and cycloalkyl is optionally substituted with one or more of R 7 ;

R 2 is selected from

1) substituted or unsubstituted aralkyl,

2) substituted or unsubstituted C 1 -C 6 alkyl,

3) substituted or unsubstituted aryl, and

4) substituted or unsubstituted C 3 -C 10 cycloalkyl;

R 3 is selected from

1) halogen,

2) —C(O)R 4 , and

3) unsubstituted C 1 -C 6 alkyl;

R 4 is independently selected from

hydrogen,

substituted or unsubstituted C 1 -C 6 alkyl,

substituted or unsubstituted aryl, and

substituted or unsubstituted C 3 -C 10 cycloalkyl;

or a pharmaceutically acceptable salt or stereoisomer thereof.

3. The compound according to claim 2 ,

wherein

R 1 is selected from

substituted or unsubstituted C 1 -C 6 alkyl,

substituted or unsubstituted C 2 -C 10 alkynyl, and

substituted or unsubstituted aryl;

said alkyl, alkynyl, and aryl is optionally substituted with one or more of R 7 ;

R 2 is selected from

1) substituted or unsubstituted aralkyl, and

2) substituted or unsubstituted C 1 -C 6 alkyl;

R 3 is selected from

1) halogen, and

2) —C(O)R 4 ;

or a pharmaceutically acceptable salt or stereoisomer thereof.

4. A compound of Formula II

wherein

R 1 is selected from

1) hydrogen,

2) halogen,

3) substituted or unsubstituted C 1 -C 6 alkyl,

4) substituted or unsubstituted C 2 -C 10 alkynyl,

5) substituted or unsubstituted aryl, and

6) substituted or unsubstituted C 3 -C 10 cycloalkyl,

said alkyl, alkynyl, aryl, and cycloalkyl is optionally substituted with one or more of R 7 ;

R 2 is selected from

1) substituted or unsubstituted aralkyl, and

2) substituted or unsubstituted C 1 -C 6 alkyl;

R 4 is independently selected from

hydrogen,

substituted or unsubstituted C 1 -C 10 alkyl,

substituted or unsubstituted aryl,

substituted or unsubstituted C 3 -C 10 cycloalkyl,

substituted or unsubstituted C 2 -C 10 alkenyl, and

substituted or unsubstituted C 2 -C 10 alkynyl;

R 6 is independently selected from

substituted or unsubstituted aryl,

substituted or unsubstituted C 3 -C 10 cycloalkyl, and

halogen;

R 7 is independently selected from

hydrogen,

halogen,

substituted or unsubstituted C 1 -C 10 alkyl,

substituted or unsubstituted C 2 -C 10 alkenyl,

substituted or unsubstituted C 2 -C 10 alkynyl,

substituted or unsubstituted C 3 -C 10 cycloalkyl,

substituted or unsubstituted aryl,

—NO 2 ,

—NR 4 (CR a 2 ) n C(O)R 4 ,

—(CR a 2 ) n NR 4 2 ,

—(CR a 2 ) n NR 4 (CR a 2 ) n R 6 ,

—CN,

—(CR a 2 ) n C(O)R 4 ,

—(CR a 2 ) n C(O)(CR a 2 ) n OR 4 ,

—(CR a 2 ) n OR 4 ,

—(CR a 2 ) n R 6 ,

—(CR a 2 ) n C(O)OR 4 , and

—(CR a 2 ) n Si(R 4 ) 3 ;

R a is independently selected from

hydrogen,

substituted or unsubstituted C 1 -C 10 alkyl,

substituted or unsubstituted C 1 -C 10 alkenyl,

substituted or unsubstitute C 1 -C 10 alkynyl,

—OR 4 ,

—C(O)OR 4 ,

—NR 4 2 ,

substituted or unsubstituted aryl, and

substituted or unsubstituted C 3 -C 10 cycloalkyl;

n is independently 0 to 6;

t is 1 to 4;

or a pharmaceutically acceptable salt or stereoisomer thereof.

5. A compound selected from:

benzyl4-ethyl-2-formyl-1H-pyrrole-3-carboxylate;

benzyl4-ethyl-2-formyl-5-iodo-1H-pyrrole-3-carboxylate;

methyl4-ethyl-2-formyl-5-iodo-1H-pyrrole-3-carboxylate;

methyl4-ethyl-2,5-diiodo-1H-pyrrole-3-carboxylate;

methyl5-(4-fluorophenyl)-4-ethyl-2-formyl-1H-pyrrole-3-carboxylate;

methyl4-ethyl-2-formyl-5-thien-2-yl-1H-pyrrole-3-carboxylate;

methyl4-ethyl-2-formyl-5-[3-(trimethylsilyl)prop-1-ynyl]-1H-pyrrole-3-carboxylate;

4′-benzyl1-tert-butyl3′-ethyl-5′-formyl-1H,1′H-2,2′-bipyrrole-1,4′-dicarboxylate;

benzyl5-(3,5-dimethylisoxazol-4-yl)-4-ethyl-2-formyl-1H-pyrrole-3-carboxylate;

benzyl5-(1-benzofuran-2-yl)-4-ethyl-2-formyl-1H-pyrrole-3-carboxylate;

benzyl4-ethyl-2-formyl-5-(3-nitrophenyl)-1H-pyrrole-3-carboxylate;

benzyl4-ethyl-2-formyl-5-(5-methyl-2-furyl)-1H-pyrrole-3-carboxylate;

benzyl5-[3-(acetylamino)phenyl]-4-ethyl-2-formyl-1H-pyrrole-3-carboxylate;

benzyl4-ethyl-2-formyl-5-pyridin-4-yl-1H-pyrrole-3-carboxylate;

benzyl4-ethyl-2-formyl-5-phenyl-1H-pyrrole-3-carboxylate;

benzyl5-(3-cyanophenyl)-4-ethyl-2-formyl-1H-pyrrole-3-carboxylate;

benzyl4-ethyl-2-formyl-5-(3-methoxyphenyl)-1H-pyrrole-3-carboxylate;

benzyl4-ethyl-2-formyl-5-(5-formyl-2-furyl)-1H-pyrrole-3-carboxylate;

methyl4-ethyl-2-formyl-5-(phenylethynyl)-1H-pyrrole-3-carboxylate;

methyl5-{3-[benzyl(methyl)amino]prop-1-ynyl}-4-ethyl-2-formyl-1H-pyrrole-3-carboxylate;

benzyl5-(2-cyanophenyl)-4-ethyl-2-formyl-1H-pyrrole-3-carboxylate;

benzyl5-(4-cyanophenyl)-4-ethyl-2-formyl-1H-pyrrole-3-carboxylate;

benzyl4-ethyl-2-formyl-5-(4-nitrophenyl)-1H-pyrrole-3-carboxylate;

benzyl4-ethyl-2-formyl-5-(2-methoxyphenyl)-1H-pyrrole-3-carboxylate;

benzyl4-ethyl-2-formyl-5-(4-methoxyphenyl)-1H-pyrrole-3-carboxylate;

benzyl4-ethyl-2-formyl-5-(2-methylphenyl)-1H-pyrrole-3-carboxylate;

benzyl4-ethyl-2-formyl-5-(3-methyiphenyl)-1H-pyrrole-3-carboxylate;

benzyl5-(2-chlorophenyl)-4-ethyl-2-formyl-1H-pyrrole-3-carboxylate;

benzyl5-(3-chlorophenyl)-4-ethyl-2-formyl-1H-pyrrole-3-carboxylate;

methyl4-ethyl-2-formyl-5-[1-(3-hydroxypropyl)vinyl]-1H-pyrrole-3-carboxylate;

methyl4-ethyl-2-formyl-5-(5-hydroxypent-1-ynyl)-1H-pyrrole-3-carboxylate;

methyl4-ethyl-2-formyl-5-[(1-hydroxycyclohexyl)ethynyl]-1H-pyrrole-3-carboxylate;

methyl5-[3-(dimethylamino)prop-1-ynyl]-4-ethyl-2-formyl-1H-pyrrole-3-carboxylate;

methyl5-(3,3-dimethylbut-1-ynyl)-4-ethyl-2-formyl-1H-pyrrole-3-carboxylate;

methyl4-ethyl-2-formyl-5-(pyridin-2-ylethynyl)-1H-pyrrole-3-carboxylate;

methyl4-ethyl-2-formyl-5-(6-methoxypyridin-2-yl)-1H-pyrrole-3-carboxylate;

methyl4-ethyl-2-formyl-5-(3-methoxyprop-1-ynyl)-1H-pyrrole-3-carboxylate;

methyl5-[(2-bromophenyl)ethynyl]-4-ethyl-2-formyl-1H-pyrrole-3-carboxylate;

methyl5-[3-(1H-1,2,3-benzotriazol-1-yl)prop-1-ynyl]-4-ethyl-2-formyl-1H-pyrrole-3-carboxylate;

methyl4-ethyl-5-(2-ethylbutyl)-2-formyl-1H-pyrrole-3-carboxylate;

methyl4-ethyl-2-formyl-5-(4-methylpyridin-2-yl)-1H-pyrrole-3-carboxylate;

methyl4-ethyl-2-formyl-5-(6-methylpyridin-2-yl)-1H-pyrrole-3-carboxylate;

methyl5-(4-tert-butylphenyl)-4-ethyl-2-formyl-1H-pyrrole-3-carboxylate;

methyl5-(2,4-difluorophenyl)-4-ethyl-2-formyl-1H-pyrrole-3-carboxylate;

methyl4-ethyl-2-formyl-5-[3-(methoxycarbonyl)phenyl]-1H-pyrrole-3-carboxylate;

methyl4-ethyl-2-formyl-5-[4-(methoxycarbonyl)phenyl]-1H-pyrrole-3-carboxylate;

methyl4-ethyl-2-formyl-5-[(1-hydroxycyclopentyl)ethynyl]-1H-pyrrole-3-carboxylate;

methyl4-ethyl-2-formyl-5-(3-hydroxy-3-methylbut-1-ynyl)-1H-pyrrole-3-carboxylate

methyl4-ethyl-2-formyl-5-(1-hexylvinyl)-1H-pyrrole-3-carboxylate;

methyl4-ethyl-2-formyl-5-(1,3-thiazol-2-yl)-1H-pyrrole-3-carboxylate;

methyl5-[1-(3-chloropropyl)vinyl]-4-ethyl-2-formyl-1H-pyrrole-3-carboxylate;

methyl5-(5-chloropent-1-ynyl)-4-ethyl-2-formyl-1H-pyrrole-3-carboxylate;

methyl4-ethyl-2-formyl-5-(3-hydroxy-3-phenylbut-1-ynyl)-1H-pyrrole-3-carboxylate;

methyl4-ethyl-2-formyl-5-(3-methylpyridin-2-yl)-1H-pyrrole-3-carboxylate;

methyl4-ethyl-2-formyl-5-isopentyl-1H-pyrrole-3-carboxylate;

methyl4-ethyl-2-formyl-5-(3-methylthien-2-yl)-1H-pyrrole-3-carboxylate;

methyl4-ethyl-2-formyl-5-isobutyl-1H-pyrrole-3-carboxylate;

methyl5-cyclohexyl-4-ethyl-2-formyl-1H-pyrrole-3-carboxylate;

methyl5-butyl-4-ethyl-2-formyl-1H-pyrrole-3-carboxylate;

methyl5-cyclopentyl-4-ethyl-2-formyl-1H-pyrrole-3-carboxylate;

methyl5-(cyclohexylmethyl)-4-ethyl-2-formyl-1H-pyrrole-3-carboxylate;

methyl5-sec-butyl-4-ethyl-2-formyl-1H-pyrrole-3-carboxylate;

methyl4-ethyl-2-formyl-5-(3-methoxy-2-methyl-3-oxopropyl)-1H-pyrrole-3-carboxylate;

methyl4-ethyl-2-formyl-5-phenyl-1H-pyrrole-3-carboxylate;

methyl4-ethyl-2-formyl-5-pyridin-4-yl-1H-pyrrole-3-carboxylate;

methyl4-ethyl-2-formyl-5-(4-nitrophenyl)-1H-pyrrole-3-carboxylate; and

methyl4-ethyl-2-formyl-5-(2-methoxyphenyl)-1H-pyrrole-3-carboxylate;

or a pharmaceutically acceptable salt or stereoisomer thereof.

6. The compound according claim 5 that is selected from methyl4-ethyl-2-formyl-5-iodo-1H-pyrrole-3-carboxylate

benzyl4-ethyl-2-formyl-5-phenyl-1H-pyrrole-3-carboxylate

methyl4-ethyl-2-formyl-5-[(1-hydroxycyclohexyl)ethynyl]-1H-pyrrole-3-carboxylate

methyl4-ethyl-2-formyl-5-(6-methoxypyridin-2-yl)-1H-pyrrole-3-carboxylate

and

methyl5-[1-(3-chloropropyl)vinyl]-4-ethyl-2-formyl-1H-pyrrole-3-carboxylate

or a pharmaceutically acceptable salt or stereoisomer thereof.

7. A trifluoroacetic acid salt of a compound of claim 5 which is selected from

methyl4-ethyl-2-formyl-5-(6-methoxypyridin-2-yl)-1H-pyrrole-3-carboxylate;

methyl4-ethyl-2-formyl-5-(4-methylpyridin-2-yl)-1H-pyrrole-3-carboxylate;

methyl4-ethyl-2-formyl-5-(6-methylpyridin-2-yl)-1H-pyrrole-3-carboxylate; and

benzyl4-ethyl-2-formyl-5-pyridin-4-yl-1H-pyrrole-3-carboxylate.

8. A pharmaceutical composition which is comprised of a compound in accordance with claim 1 and a pharmaceutically acceptable carrier.

9. A method of inhibiting the catalytic activity of IGF-1R in a mammal in need thereof comprising contacting the IGF-1R with a compound of claim 1 .

10. A method of treating cancer selected from the group consisting of brain cancer, prostate cancer, colorectal cancer, small cell lung cancer, non-small cell lung cancer, renal cell carcinoma and endometrial carcinoma in a mammal in need of such treatment comprising administering to said mammal a therapeutically effective amount of a compound of claim 1 .