US 2001/0044451 A1Published application

Tyrosine kinase inhibitors

AssigneeMerck & Co., Inc.

InventorsMark E. Fraley, George D. Hartman, Randall W. Hungate

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Abstract

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, inflammatory diseases, and the like in mammals.

Claims32

Dependent claims

A compound of Formula I

26
or a pharmaceutically acceptable salt or stereoisomer thereof, wherein
Q is S,O, or -E=D-;
X, Y and Z are C or N, so long as only one of X, Y and Z is N;
a is 0 or 1;
b is 0 or 1;
s is 1 or 2;
t is 1,2, or 3;
m is 0, 1, or 2;
E=D is C═N, N═C, or C═C;
R1, R1a, R4 and R5 are independently selected from:
1) H,
2) (C═O)aObC1-C10 alkyl, optionally substituted with one to three substituents selected from R6,
3) (C═O)aObaryl, optionally substituted with one to three substituents selected from R6,
4) (C═O)aObC2-C10 alkenyl, optionally substituted with one to three substituents selected from R6,
5) (C═O)aObC2-C10 alkynyl, optionally substituted with one to three substituents selected from R6,
6) SOmC1-C10 alkyl, optionally substituted with one to three substituents selected from R6,
7) SOmaryl, optionally substituted with one to three substituents selected from R6,
8) CO2H,
9) halo,
10) CN,
11) OH,
12) ObC1-C6 perfluoroalkyl, and
13) (C═O)aNR7R8;
R2 and R3 are independently selected from the group consisting of:
1) H,
2) (C═O)OaC1-C10 alkyl,
3) (C═O)Oaaryl,
4) C1-C10 alkyl,
5) SOmC1-C10 alkyl,
6) SOmaryl,
7) (C═O)aObC2-C10 alkenyl,
8) (C═O)aObC2-C10 alkynyl, and
9) aryl, said alkyl, aryl, alkenyl and alkynyl is optionally substituted with one to three substituents selected from R6;
R6 is:
1) H,
2) (C═O)aObC1-C6 alkyl,
3) (C═O)aObaryl,
4) C2-C10 alkenyl,
5) C2-C10 alkynyl,
6) heterocyclyl,
7) CO2H,
8) halo,
9) CN,
10) OH,
11) oxo,
12) ObC1-C6 perfluoroalkyl, or
13) NR7R8;
R6a is:
1) H,
2) SOmaryl,
3) SOmC1-C6 alkyl,
4) (C═O)aObC1-C6 alkyl,
5) (C═O)aObaryl,
6) C2-C10 alkenyl,
7) C2-C10 alkynyl,
8) heterocyclyl,
9) CO2H,
10) halo,
11) CN,
12) OH,
13) oxo,
14) ObC1-C6 perfluoroalkyl, or
15) N(C1-C6 alkyl)2;
R7 and R8 are independently selected from:
1) H,
2) (C═O)ObC1-C10 alkyl, optionally substituted with one to three substituents selected from R6a,
3) (C═O)Obaryl, optionally substituted with one to three substituents selected from R6a,
4) C1-C10 alkyl, optionally substituted with one to three substituents selected from R6a,
5) aryl, optionally substituted with one to three substituents selected from R6a,
6) C2-C10 alkenyl, optionally substituted with one to three substituents selected from R6a,
7) C2-C10 alkynyl, optionally substituted with one to three substituents selected from R6a, and
8) heterocyclyl, or
R7 and R8 can be taken together with the nitrogen to which they are attached to form a 5-7 membered heterocycle containing, in addition to the nitrogen, one or two additional heteroatoms selected from N, O and S, said heterocycle optionally substituted with one to three substituents selected from R6a.

71 more elements

Dependencies are inferred from the claim text.

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Abstract

A compound of Formula I

26
or a pharmaceutically acceptable salt or stereoisomer thereof, wherein
Q is S,O, or -E=D-;
X, Y and Z are C or N, so long as only one of X, Y and Z is N;
a is 0 or 1;
b is 0 or 1;
s is 1 or 2;
t is 1,2, or 3;
m is 0, 1, or 2;
E=D is C═N, N═C, or C═C;
R1, R1a, R4 and R5 are independently selected from:
1) H,
2) (C═O)aObC1-C10 alkyl, optionally substituted with one to three substituents selected from R6,
3) (C═O)aObaryl, optionally substituted with one to three substituents selected from R6,
4) (C═O)aObC2-C10 alkenyl, optionally substituted with one to three substituents selected from R6,
5) (C═O)aObC2-C10 alkynyl, optionally substituted with one to three substituents selected from R6,
6) SOmC1-C10 alkyl, optionally substituted with one to three substituents selected from R6,
7) SOmaryl, optionally substituted with one to three substituents selected from R6,
8) CO2H,
9) halo,
10) CN,
11) OH,
12) ObC1-C6 perfluoroalkyl, and
13) (C═O)aNR7R8;
R2 and R3 are independently selected from the group consisting of:
1) H,
2) (C═O)OaC1-C10 alkyl,
3) (C═O)Oaaryl,
4) C1-C10 alkyl,
5) SOmC1-C10 alkyl,
6) SOmaryl,
7) (C═O)aObC2-C10 alkenyl,
8) (C═O)aObC2-C10 alkynyl, and
9) aryl, said alkyl, aryl, alkenyl and alkynyl is optionally substituted with one to three substituents selected from R6;
R6 is:
1) H,
2) (C═O)aObC1-C6 alkyl,
3) (C═O)aObaryl,
4) C2-C10 alkenyl,
5) C2-C10 alkynyl,
6) heterocyclyl,
7) CO2H,
8) halo,
9) CN,
10) OH,
11) oxo,
12) ObC1-C6 perfluoroalkyl, or
13) NR7R8;
R6a is:
1) H,
2) SOmaryl,
3) SOmC1-C6 alkyl,
4) (C═O)aObC1-C6 alkyl,
5) (C═O)aObaryl,
6) C2-C10 alkenyl,
7) C2-C10 alkynyl,
8) heterocyclyl,
9) CO2H,
10) halo,
11) CN,
12) OH,
13) oxo,
14) ObC1-C6 perfluoroalkyl, or
15) N(C1-C6 alkyl)2;
R7 and R8 are independently selected from:
1) H,
2) (C═O)ObC1-C10 alkyl, optionally substituted with one to three substituents selected from R6a,
3) (C═O)Obaryl, optionally substituted with one to three substituents selected from R6a,
4) C1-C10 alkyl, optionally substituted with one to three substituents selected from R6a,
5) aryl, optionally substituted with one to three substituents selected from R6a,
6) C2-C10 alkenyl, optionally substituted with one to three substituents selected from R6a,
7) C2-C10 alkynyl, optionally substituted with one to three substituents selected from R6a, and
8) heterocyclyl, or
R7 and R8 can be taken together with the nitrogen to which they are attached to form a 5-7 membered heterocycle containing, in addition to the nitrogen, one or two additional heteroatoms selected from N, O and S, said heterocycle optionally substituted with one to three substituents selected from R6a.

71 more elements