US2009069360A1PendingUtilityA1
Organic Compounds
Est. expiryMar 16, 2026(expired)· nominal 20-yr term from priority
A61P 9/04A61P 35/00A61P 3/10A61P 43/00A61P 9/10A61P 29/00A61P 25/06A61P 27/02A61P 25/00C07D 401/04A61P 17/02A61K 31/506C07D 401/14
48
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Claims
Abstract
The present invention relates to the discovery that certain compounds inhibit, regulate and/or modulate tyrosine and serine/threonine kinase and kinase-like proteins, such as RAF kinase, a serine/threonine kinase that functions in the MAP kinase signaling pathway, and is concerned with compositions which contain these compounds, and methods of using them to treat tyrosine and serine/threonine kinase and kinase-like dependent diseases, such as angiogenesis, cancer and cardiac hypertrophy.
Claims
exact text as granted — not AI-modified1 . A compound of formula (I)
or a pharmaceutical acceptable salt, ester or prodrug thereof for use as a pharmaceutical
wherein
each of A 1 , A 2 , A 3 , A 4 is independent selected from N or C—R 3 where R 3 represents H or a substituent moiety of C and where at least one of A 1 , A 2 and A 4 is N;
X is a linking moiety selected from N—H, substituted amino, O or S;
R 1 is a substituent of the aromatic ring and n is an integer from 0 to 4;
Y and D are independently selected from O, S, CH 2 , NH, R 6 -substituted C, or R 6 -substituted N,
R 6 is a substituent of the ring which contains Y and D and r is an integer from 0 to the maximum number of available valencies of the ring;
R 2 is a substituted or unsubstituted moiety selected from hydrocarbyl and heterocyclic;
T is selected from H, halogen, O—R 9 , S—R 8 , SO—R 8 , SO 2 —R 8 , SO 2 —N(R 8 ) 2 , SO 2 —NR 10 and SO 2 -halogen, where R 8 is selected from hydrogen, substituted or unsubstituted alkyl, cycloalkyl, heterocyclyl or aryl; and R 9 is substituted or unsubstituted alkyl, cycloalkyl, or aryl, and NR 10 represents a heterocyclic ring including the nitrogen; and p is an integer from 0 to 5.
2 . A compound of formula (I)
or a pharmaceutically acceptable salt, ester or prodrug thereof
wherein
each of A 1 , A 2 , A 3 , A 4 is independently selected from N or C—R 3 where R 3 represents H or a substituent moiety of C and where at least one of A 1 , A 2 and A 4 is N;
X is a linking moiety selected from N—H, substituted amino, O or S;
R 1 is a substituent of the aromatic ring and n is an integer from 0 to 4;
Y and D are independently selected from O, S, CH 2 , NH, R 8 -substituted C, or R 8 -substituted N,
R 6 is a substituent of the ring which contains Y and D and r is an integer from 0 to the maximum number of available valencies of the ring;
R 2 is a substituted or unsubstituted moiety selected from hydrocarbyl and heterocyclic;
T is selected from H, halogen, OR 9 , S—R 8 , SO—R 8 SO 2 —R 8 , SO 2 —N(R 8 ) 2 , SO 2 —NR 10 and SO 2 — halogen, where R 8 is selected from hydrogen, substituted or unsubstituted alkyl, cycloalkyl, heterocyclyl or aryl; and R 9 is substituted or unsubstituted alkyl, cycloalkyl, or aryl, and NR 10 represents a heterocyclic ring including the nitrogen; and p is an integer from 0 to 5
and wherein the compound is not:
3 . A compound of claim 1 wherein A 1 and A 2 are N, and A 3 and A 4 are C—R 3 .
4 . (canceled)
5 . A compound of claim 1 wherein X is N—H.
6 . (canceled)
7 . (canceled)
8 . A compound of claim 1 wherein n is 1.
9 . A compound of claim 1 wherein Y is CH 2 .
10 . A compound of claim 1 wherein D is CH 2 .
11 . (canceled)
12 . (canceled)
13 . A compound as claimed in claim 1 wherein R 2 is selected from substituted or unsubstituted phenyl, imidazolyl, pyrrolyl, oxazolyl and isoxazolyl.
14 . A compound as claimed in claim 1 wherein R 2 phenyl.
15 . A compound as claimed in claim 1 wherein p is 1.
16 . A compound as claimed in claim 1 wherein p is 1 and T is located para- to the linking group X.
17 . A compound as claimed in claim 1 wherein T is selected from halogen, O-alkyl, O-alkyl-halogen, SO 2 —R 8 , SO 2 —NHR 8 , SO 2 —NR 10 and SO 2 -halogen.
18 . (canceled)
19 . (canceled)
20 . (canceled)
21 . A compound as claimed in claim 17 wherein T is a moiety selected from the formulae (i) to (x):
where q is an integer from 1 to 4 and s is an integer from 0 to 4
22 . (canceled)
23 . A compound as claimed in claim 1 selected from compounds of the formulae
(II), (III) and (IV):
24 . A compound as claimed in claim 23 wherein X is NH.
25 . A compound as claimed in claim 23 wherein R 2 is phenyl.
26 . (canceled)
27 . (canceled)
28 . A compound as claimed in claim 1 of the formula (V):
29 . (canceled)
30 . A compound as claimed in claim 1 or 2 selected from compounds for the formulae (VI), (VII) and (VIII):
31 . (canceled)
32 . A compound as claimed in claim 1 or 2 of the formula (IX)
33 . (canceled)
34 . (canceled)
35 . A compound as claimed in claim 1 of the formula (X)
wherein G represents R 8 , NHR 8 or NR 10 .
36 . (canceled)
37 . A compound as claimed in claim 1 of the formula (XI)
38 . A compound as claimed in claim 1 of the formula (XII)
39 . (canceled)
40 . (canceled)
41 . (canceled)
42 . The compound of any one of claim 1 for use in inhibiting IKK, PDGF-R, Kdr, c-Src, Her-1, Her-2, c-Kit, c-Abl, Ins-r, Tek, Flt-1, Flt-3, Flt-4, c-Abi, RAF Kinase, and FGFR-1, Eph receptors (e.g. EphB4), CDK1, CDK2 and RET activity in a warm-blooded animal.
43 . (canceled)
44 . A compound as claimed in claim 42 wherein said diseases are selected from one or more of angiogenesis, cancer, tumour growth, atherosclerosis, age related macular degeneration, diabetic retinopathy, inflammatory diseases, neurotraumatic diseases, chronic neurodegeneration, pain, migraine or cardiac hypertrophy, and melanoma.
45 . (canceled)
46 . A compound of claim 1 for use in the treatment of a disease characterized by an activated mutant B-RAF kinase.
47 . (canceled)
48 . (canceled)
49 . (canceled)
50 . (canceled)
51 . (canceled)
52 . The use as claimed in claim 46 wherein said compound is administered in combination with at least one other anticancer agent.
53 . (canceled)
54 . A pharmaceutical composition comprising a compound of any one of claim 1 .
55 . (canceled)
56 . (canceled)
57 . (canceled)
58 . (canceled)
59 . (canceled)
60 . A pharmaceutical composition of claim 54 additionally comprising a carrier.
61 . A pharmaceutical composition of claim 60 wherein said carrier is mannitol, a suspension in oil, or a solid carrier.
62 . (canceled)
63 . (canceled)
64 . (canceled)
65 . (canceled)
66 . (canceled)
67 . (canceled)
68 . A pharmaceutical composition comprising a compound of claim 1 and at least one anticancer agent.
69 . (canceled)
70 . (canceled)
71 . (canceled)
72 . (canceled)
73 . A method of treating melanoma, which method comprises
(a) testing melanoma tissue from a patient to determine whether the melanoma tissue expresses mutant RAF kinase or overexpresses a wild-type RAF kinase, and (b) treating the patient with an effective RAF kinase inhibiting amount of a RAF inhibiting compound as claimed in claim 1 if the melanoma is found to overexpresses a wild type RAF kinase or express an activating mutant B-RAF kinase.
74 . A method of treating melanoma, which method comprises
(a) testing melanoma tissue from a patient and determining whether the melanoma tissue overexpresses B-RAF kinase or C-RAF kinase activity, and (b) treating the patient with an effective RAF kinase inhibiting amount of a RAF inhibiting compound as claimed in claim 1 if the melanoma tissue is found to overexpress B-RAF kinase or C-RAF kinase activity.
75 . A method of treating melanoma, which method comprises
(a) testing melanoma tissue from a patient and determining whether the melanoma tissue expresses mutant B-RAF kinase or C-RAF kinase activity, and (b) treating the patient with an effective RAF kinase inhibiting amount of a RAF inhibiting compound as claimed in claim 1 if the melanoma tissue is found to express mutant B-RAF kinase.
76 . A method of treating a disease characterized by an activated mutant B-RAF kinase, which method comprises detecting a mutation in the B-RAF kinase gene or protein in a tissue sample from a patient and treating the patient with an effective B-RAF kinase inhibiting amount of a compound as claimed in claim 1 .
77 . (canceled)
78 . A process for the preparation of a compound of the formula
which process comprises the following reaction scheme:
where step 2 is optional and where carried out T′ is a precursor of T, and R 1′ is a precursor of R 1 or is R 1 and X, R 1 , R 2 , T and P are as defined in claim 1 .
79 . A process as claimed in claim 78 wherein X is NH.
80 . A process as claimed in claim 78 wherein R 2 is phenyl.
81 . A process as claimed in claim 78 wherein p is 1.
82 . A process as claimed in claim 78 wherein R 1′ is OH.
83 . A process as claimed in claim 78 wherein T represents SO 2 -G where G represents R 8 , NHR 8 or NR 10 and R 8 and R 10 are as defined in claim 1 .
84 . A process as claimed in claim 78 wherein T represents O—R 9 where R 9 is as defined in claim 1 .
85 . A process as claimed in claim 84 wherein X—R 2 -(T) p representsCited by (0)
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