Protein kinase inhibitors
View Patent ↗The present invention relates to novel kinase inhibitors. Compounds of this class have been found to be effective inhibitors of protein kinases, including members of PDGFR and VEGFR families.
1. A compound of the Formula 1:
wherein m is an integer from 0 to 1;
n is an integer from 0 to 2;
R 1 is selected from alkyl, heteroalkyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl, wherein the aryl and heteroaryl may be further substituted by the groups selected from:
1) Halogen,
2) Alkoxyl,
3) Amino,
4) —N(H)C(O)O-alkyl,
5) —N(H)SO 2 -aryl,
6) —N(H)SO 2 -heteroaryl,
7) —N(H)CON(H)-aryl,
8) and —N(H)CON(H)-heteroaryl;
R 2a , R 2b , R 2c , R 2d , R 2e , R 2f are independently selected from hydrogen, alkyl, heteroalkyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl; R 2a and R 2b , R 2c and R 2d , or R 2e and R 2f can be fused to form a 3 to 8 membered cycloalkyl or heterocyclyl ring system;
X is selected CH 2 , O, S(O) n , and NR 3 ;
R 3 is selected from hydrogen, alkyl, heteroalkyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, .C(O)R 4 , —C(O)OR 4 , S(O) 2 R 4 , C(O)NR 4 R 5 , —S(O) 2 NR 4 R 5 , and —C(S)NR 4 R 5 ; and
R 4 and R 5 are independently selected from alkyl, heteroalkyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl, or R 4 and R 5 can be fused to form a 3 to 8 membered heterocyclyl ring system.
2. The compound according to claim 1 , wherein Formula 1 is selected from the group consisting of:
3. A compound of claim 1 wherein R 1 is selected from the group consisting of:
4. The compound according to claim 1 wherein R 1 is selected from the group consisting of:
5. A compound selected from the group consisting of:
Compound
Structure
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
61
62
63
64
65
66
67
68
69
70
71
72
73
74
6. The compound according to claim 5 , wherein the compound is selected from the group consisting of compounds 1, 2, 18, 24, 25, 31, 32, 60 and 61.
7. The compound according to claim 5 , wherein the compound is selected from the group consisting of compounds 3, 5, 6, 7, 8, 9, 10, 12, 15, 26, 29, 34, 37, 40, 49 and 51.
8. The compound according to claim 5 , wherein the compound is selected from the group consisting of compounds 14, 16, 17, 20, 21, 23, 30, 33, 36, 39, 41, 44, 45, 46, 47, 50, 55, 57, 58, 59, 62, 63, 64, 66, 67, 68, 69, 72 and 73.
9. The compound according to claim 5 , wherein the compound is selected from the group consisting of compounds 11, 13, 19, 27, 28, 35, 43, 48, 54, 56 and 74.
10. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier or diluent.
11. A method of modulating a target kinase function comprising administering a pharmaceutical composition of claim 10 .
12. The method according to claim 11 , wherein the target kinase function is a function of kinase selected from the group consisting of PDGFR, FGFR, and VEGFR.
13. The method according to claim 12 , wherein the kinase is cFMS, Flt3, KDR, FGFR1 or Tie2.
14. A method of treating a patient, comprising the step of administering a compound according to claim 1 to the patient, thereby modulating the function of a protein kinase.
15. The method according to claim 14 , wherein the protein kinase is selected from the group consisting of PDGFR, FGFR and VEGFR.
16. The method according to claim 14 , wherein the protein kinase is selected from the group consisting of cFMS, Flt3, KDR, FGFR1 and Tie2.
17. A probe comprising a compound of claim 1 and a detectable label or affinity tag for said compound.
18. The probe according to claim 17 , wherein the detectable label is selected from a fluorescent moiety, a chemiluminescent moiety, a paramagnetic contrast agent, a metal chelate, a radioactive isotope-containing moiety, and biotin.
19. A method of modulating target kinase function comprising contacting a cell with a compound of claim 1 in an amount sufficient to modulate the target kinase function, whereby the target kinase activity and signaling is modulated.
20. A process for preparing a compound of formula i-e, comprising the steps of:
(a) alkylation of R 1 NH 2 with bromoacetonitrile to provide intermediate i-a
(b) condensation of i-a with i-b in the presence of an acid to provide intermediate i-c
(c) treatment of intermediate i-c with a base to provide intermediate i-d
(d) treatment of intermediate i-d with formamidine acetate in an alcohol to provide a compound of formula i-e