Inhibitors of protein tyrosine kinase activity
This invention relates to compounds that inhibit protein tyrosine kinase activity. In particular the invention relates to compounds that inhibit the protein tyrosine kinase activity of growth factor receptors, resulting in the inhibition of receptor signaling, for example, the inhibition of VEGF receptor signaling. The invention also provides compounds, compositions and methods for treating cell proliferative diseases and conditions and opthalmological diseases, disorders and conditions.
1. A compound of Formula (I):
or pharmaceutically acceptable salts thereof, wherein,
D is selected from the group consisting of an aromatic, heteroaromatic, cycloalkyl or heterocyclic ring system, each of which is substituted with 1 to 5 independently selected R 38 ;
M is
wherein
* represents the point of attachment to D; and
† represents the point of attachment to Z;
Z is —O—;
Ar is a 5 to 7 membered aromatic ring system, which is optionally substituted with 0 to 4 R 2 groups; and
G is selected from the group consisting of
wherein
each R 38 is —C 1 -C 6 alkyl-heterocycle, wherein said heterocycle is optionally substituted with halo, hydroxy, oxo, nitro, halohydrocarbyl, hydrocarbyl, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, aralkyl, alkoxy, aryloxy, amino, acylamino, alkylcarbamoyl, arylcarbamoyl, aminoalkyl, acyl, carboxy, hydroxyalkyl, alkanesulfonyl, arenesulfonyl, alkanesulfonamido, arenesulfonamido, aralkylsulfonamido, alkylcarbonyl, acyloxy, cyano, and ureido groups, and;
R 2 at each occurrence is independently selected from —H and halogen;
each R 3 is independently selected from the group consisting of —H and R 4 ;
R 4 is (C 1 -C 6 )alkyl;
each R 13 is independently selected from the group consisting of —H, —C(O)NR 3 R 3 and C 1 -C 6 alkyl;
Q is a three- to ten-membered ring system, optionally substituted with between zero and four of R 20 ;
each R 20 is independently selected from the group consisting of —H, halogen, trihalomethyl, —OR 3 , —S(O) 0-2 R 3 , —S(O) 2 NR 3 R 3 , —C(O)OR 3 , —C(O)NR 3 R 3 , —(CH 2 ) 0-5 (heteroaryl), C 1 -C 6 alkyl, —(CH 2 ) n P(═O)(C 1 -C 6 alkyl) 2 , wherein n is an integer ranging from 0 to 6.
2. The compound according to claim 1 , wherein D is an aromatic or heteroaromatic ring system, each of which is substituted with 1 or 2 independently selected R 38 groups.
3. The compound according to claim 1 , wherein D is a 5- or 6-membered heteroaromatic ring system, each of which is substituted with 1 or 2 independently selected R 38 groups.
4. The compound according to claim 1 , wherein D is a 6-membered aromatic or 6-membered heteroaromatic ring system, each of which is substituted with 1 or 2 independently selected R 38 groups.
5. The compound according to claim 1 , wherein D is a 6-membered aromatic ring system, substituted with 1 or 2 independently selected R 38 groups.
6. The compound according to claim 1 , wherein D is a 6-membered heteroaromatic ring system, substituted with 1 or 2 independently selected R 38 groups.
7. The compound according to claim 1 , wherein D is a 5-membered heteroaromatic ring system, substituted with 1 or 2 R 38 groups.
8. The compound according to claim 1 , wherein D is phenyl, pyridyl, imidazolyl or tetrahydropyridyl, each of which is substituted with 1 or 2 independently selected R 38 groups.
9. The compound according to claim 1 , wherein Ar is selected from the group consisting of phenyl, pyrazine, pyridazine, pryimidine and pyridine, wherein each of said phenyl, pyrazine, pyridazine, pryimidine and pyridine is optionally substituted with 0 to 4 R 2 groups.
10. The compound according to claim 1 , wherein G is selected from the group consisting of
11. The compound according to claim 1 , wherein Q is selected from the group consisting of phenyl, cyclopropyl, isoxazolyl, cyclohexyl, thiazolyl, tetrahydrofuran, pyrazolyl, cyclobutyl and cyclopentyl, optionally substituted with between zero and two R 20 .
12. The compound according to claim 1 , wherein each R 20 is independently selected from the group consisting of —P(═O)(Me) 2 , methyl, halo (for example F), trihalomethyl, methoxy, —C(O)NH 2 , heteroaryl, —COOH, —SO 2 HN 2 , —C(O)NH 2 , —COOMe, —C(O)N(H)(Me), —C(O)N(Me) 2 and —SO 2 Me.
13. The compound according to claim 1 , wherein
D is phenyl, pyridyl, imidazolyl or tetrahydropyridyl, each of which is substituted with 1 or 2 independently selected R 38 groups;
and
Ar is phenyl optionally substituted with 0 to 4 halo.
14. The compound according to claim 1 , wherein
D is pyridyl substituted with C 1 -C 6 alkyl-heterocycle, wherein said heterocycle is substituted with one oxo;
Ar is phenyl optionally substituted with one F; and
G is
15. The compound according to claim 1 , wherein
Ar is phenyl optionally substituted with 0 to 4 F; and
Q is phenyl optionally substituted with 1 or 2 independently selected R 20 , wherein each R 20 is independently selected from the group consisting of —P(═O)(Me) 2 , methyl, halo, trihalomethyl, methoxy, —C(O)NH 2 , heteroaryl, —COOH, —SO 2 HN 2 , —C(O)NH 2 , —COOMe, —C(O)N(H)(Me), —C(O)N(Me) 2 and —SO 2 Me, or Q is pyrazolyl substituted with methyl, or Q is cyclopropyl, cyclobutyl or tetrahydrofuran.
16. The compound according to claim 1 , wherein
D is pyridyl substituted with —C 1 -C 6 alkyl-(heterocycle substituted with one oxo);
Ar is phenyl optionally substituted with one F;
G is
wherein
R 13 is H; and
Q is cyclopropyl.
17. The compound according to claim 1 , wherein D is pyridyl;
Ar is phenyl optionally substituted with one F;
G is
wherein
R 13 is H; and
Q is cyclopropyl.
18. The compound according to claim 1 , wherein D is pyridyl substituted with —C 1 -C 6 alkyl-(heterocycle optionally substituted with one or two oxo);
Ar is phenyl optionally substituted with one F;
G is
wherein
R 13 is H; and
Q is cyclopropyl.
19. The compound according to claim 1 , wherein
D is pyridyl substituted with
Ar is phenyl optionally substituted with 0 to 4 R 2 groups;
G is
wherein
R 13 is H; and
Q is cyclopropyl.
20. A composition comprising a compound according to claim 1 .