US2009099165A1PendingUtilityA1
Protein Kinase Inhibitors
Est. expiryOct 14, 2023(expired)· nominal 20-yr term from priority
Inventors:Laurence HurleyDaruka MahadevanHaiyong HanDavid J. BearssHariprasad VankayalapatiSridevi BashyamRuben M. MunozSteven L. WarnerKimiko Della CroceDaniel D. Von HoffCory L. GrandJames Welsh
C07D 487/04A61K 45/06A61N 5/00C07D 403/14C07D 495/14C07D 495/04A61K 31/519C07D 491/048A61P 35/00C07D 405/14A61P 35/04
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Claims
Abstract
Protein kinase inhibitors are disclosed having utility in the treatment of protein kinase-mediated diseases and conditions, such as cancer. The compounds of this invention have the following structure: including steroisomers, prodrugs and pharmaceutically acceptable salts thereof, wherein A is a ring moiety selected from: and wherein R1, R2, R3, X, Z, L1, Cycl1, L2 and Cycl2 are as defined herein. Also disclosed are compositions containing a compound of this invention, as well as methods relating to the use thereof.
Claims
exact text as granted — not AI-modified1 . A compound having the following structure (I):
or a steroisomer, prodrug or pharmaceutically acceptable salt thereof, wherein
A is a ring moiety selected from:
X is NH, S or O;
Z is CH or N;
R 1 and R 2 are the same or different and are independently hydrogen, hydroxyl, halo, —CN, —NO 2 , —NH 2 , —R, —OR, —SCH 3 , —CF 3 , —C(═O)OR or —OC(═O)R, where R is alkyl or substituted alkyl;
R 3 is hydrogen, —NH 2 , alkyl, —CN, or —NO 2 , or R 3 is -L 3 -Cycl 3 wherein L 3 is a direct bond, S or NH, and Cycl 3 is a carbocycle, substituted carbocycle, heterocycle or substituted heterocycle;
L 1 is a direct bond, —NR′—, —OC(═S)NH— or —NHC(═S)O—, wherein R′ is H or alkyl;
Cycl 1 is a carbocycle, substituted carbocycle, heterocycle or substituted heterocycle;
L 2 is a direct bond or —C(═S)NH—, —NHC(═S)—, —NHC(═S)NH—, —C(═O)NH—, —NHC(═O)—, —NHC(═O)NH—, —(CH 2 ) n —, —NH(CH 2 ) n —, —(CH 2 ) n NH—, —NH(CH 2 ) n NH—, —C(═S)NH(CH 2 ) n —, —NHC(═S)(CH 2 ) n —, —(CH 2 ) n C(═S)NH(CH 2 ) n —,
(CH 2 ) n NHC(═S)(CH 2 ) n —, —NHC(═O)—, —S(═O) 2 —, —S(═O) 2 NH—, —NHS(═O) 2 —, wherein n is, at each occurrence the same or different and independently 1, 2, 3 or 4; and
Cycl 2 is a carbocycle, substituted carbocycle, heterocycle or substituted heterocycle.
2 . The compound of claim 1 , wherein ring moiety A is (I-A).
3 . The compound of claim 2 wherein L 1 is a direct bond.
4 . The compound of claim 3 wherein X is NH and Z is CH.
5 . The compound of claim 3 wherein R 1 and R 2 are selected from —OCH 3 , —OH, —Cl, —CF 3 or —OC(═O)CH 3 , and R 3 is hydrogen or —NH2.
6 . The compound of claim 3 wherein Cycl 1 is selected from:
7 . The compound of claim 3 wherein L 2 is selected from —C(═S)NH—, —C(═S)NHCH 2 —, —NHC(═S)NH—, —NHC(═O)—, and —NHC(═O)NH—.
8 . The compound of claim 3 wherein Cycl 2 is selected from:
where w is
9 . The compound of claim 2 , wherein L 1 is —NH— or —OC(═S)NH—.
10 . The compound of claim 9 , wherein X is NH and Z is CH.
11 . The compound of claim 9 , wherein R 1 and R 2 are methoxy, and R 3 is hydrogen or —NH2.
12 . The compound of claim 9 , wherein Cycl 1 is selected from:
13 . The compound of claim 9 , wherein L 2 is selected from —NHCH 2 —, —NH—, —C(═S)NH—, —NHC(═S)—, —C(═S)NHCH 2 —, —NHC(═S)NH—, —NHC(═O)—, —NHC(═O)NH—; —S(═O) 2 —; and
14 . The compound of claim 9 , wherein Cycl 2 is selected from:
where w is —NH 2 , —NO 2 or:
15 . The compound of claim 9 having the following structure (II-2-6):
16 . The compound of claim 9 having the following structure (II-2-7):
17 . The compound of claim 1 , wherein ring moiety A is (I-B).
18 . The compound of claim 17 wherein L 1 is a direct bond.
19 . The compound of claim 18 wherein R 1 , R 2 and R 3 are hydrogen.
20 . The compound of claim 18 wherein Cycl 1 is:
21 . The compound of claim 18 wherein L 2 is selected from —C(═S)NH—, —C(═S)—, —C(═S)NHCH 2 — or —CH 2 —.
22 . The compound of claim 18 wherein Cycl 2 is selected from:
where w is
23 . The compound of claim 17 wherein L 1 is —NH— or —OC(═S)NH—.
24 . The compound of claim 23 wherein R 1 , R 2 and R 3 are hydrogen.
25 . The compound of claim 23 wherein Cycl 1 is selected from:
26 . The compound of claim 23 wherein L 2 is selected from —NHC(═S)NH—, —NHC(═O)—, —NH— or —NHCH 2 —.
27 . The compound of claim 23 wherein Cycl 2 is selected from:
where w is
28 . The compound of claim 23 having the following structure (III-1-3):
29 . The compound of claim 23 having the following structure (III-1-4):
30 . The compound of claim 23 having the following structure (III-1-5):
31 . The compound of claim 1 , wherein ring moiety A is (I-C).
32 . The compound of claim 31 wherein L 1 is a direct bond.
33 . The compound of claim 32 wherein R 1 and R 2 are methoxy and R 3 is hydrogen.
34 . The compound of claim 32 wherein Cycl 1 is:
35 . The compound of claim 32 wherein L 2 is —C(═S)NH—.
36 . The compound of claim 32 wherein Cycl 2 is:
where w is
37 . The compound of claim 31 wherein L 1 is —NH—.
38 . The compound of claim 37 wherein R 1 and R 2 are methoxy; and R 3 is hydrogen.
39 . The compound of claim 37 wherein Cycl 1 is:
40 . The compound of claim 37 wherein L 2 is selected from —NHC(═S)NH—, —NH— or —NHCH 2 —.
41 . The compound of claim 37 wherein Cycl 2 is selected from:
wherein w is L 4 -Cycl 4 , wherein L 4 is selected from —S(═O) 2 NH—, —NHC(═S)NHCH 2 —, —NHCH 2 — or —NHC(═S)NH—, and wherein Cycl 4 is:
42 . A composition comprising a compound of claim 1 in combination with a pharmaceutically acceptable excipient.
43 . A method for treating a protein kinase-mediated disease comprising administering to a subject in need thereof a therapeutically effective amount of a compound of claim 1 or a composition of claim 42 .
44 . The method of claim 43 , wherein the protein kinase-mediated disease is an aurora-2 kinase-mediated disease, a c-kit-mediated disease, a PDGFR-a-mediated disease, a c-ret-mediated disease or a c-met-mediated disease.
45 . The method of claim 44 wherein the protein-kinase mediated disease is cancer.
46 . The method of claim 45 wherein the cancer is a cancer of the pancreas, breast, ovary or colon.
47 . The method of claim 43 , further comprising administering to the patient a DNA-damaging anticancer agent.
48 . The method of claim 43 , further comprising administering radiation to the patient.Join the waitlist — get patent alerts
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