US2011207736A1PendingUtilityA1
Compounds that modulate egfr activity and methods for treating or preventing conditions therewith
Assignee: GATEKEEPER PHARMACEUTICALS INCPriority: Dec 23, 2009Filed: Dec 22, 2010Published: Aug 25, 2011
Est. expiryDec 23, 2029(~3.4 yrs left)· nominal 20-yr term from priority
C07D 285/135C07D 401/14C07D 487/04C07D 401/12C07D 403/12C07D 239/95C07D 495/04A61P 35/00C07D 473/18C07D 417/12C07D 471/04
47
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Claims
Abstract
Provided are compounds and methods for treating or preventing kinase-mediated disorders therewith.
Claims
exact text as granted — not AI-modified1 . A compound of Formula IV:
or a pharmaceutically acceptable salt or ester thereof, wherein:
X is oxygen, sulfur, carbonyl, —NR 6 , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl;
X 2b is oxygen, sulfur, NH, or NR 30 ;
each R 1 is independently C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, or C 1 -C 6 haloalkoxy;
(i) one of R 2 , R 2a , and R 2b is piperidine, pyrrolidine, piperazine, or morpholine that is optionally substituted with C 1 -C 6 alkyl; or C 3 -C 6 alkyl or C 3 -C 6 cycloalkyl containing at least one nitrogen; and the other two of R 2 , R 2a , and R 2b are hydrogen or C 1 -C 6 alkyl; or (ii) R 2 and one of R 2a and R 2b join to form a piperidine, pyrrolidine, or morpholine that is optionally substituted with C 1 -C 6 alkyl; or C 3 -C 6 cycloalkyl containing at least one nitrogen; and the other of R 2a and R 2b is hydrogen or C 1 -C 6 alkyl;
one of R 3 , R 4 , and R 5 is Z, and the other two of R 3 , R 4 , and R 5 are hydrogen;
each R 6 is independently hydrogen or C 1 -C 6 alkyl;
R 7 is hydrogen, C 1 -C 6 alkyl, or C 2 -C 6 alkenyl;
R 8 is C 1 -C 6 alkyl that is substituted with halogen, cyano, —C(O)R 9 , or —OC(O)R 9 ; C 2 -C 6 alkenyl that is optionally substituted with halogen or —NR 9 2 ; C 2 -C 6 alkynyl; C 3 -C 6 cycloalkyl that is substituted with cyano or —C(O)R 9 ; C 4 -C 6 cycloalkenyl that is optionally substituted with halogen; or C 4 -C 9 heterocycloalkenyl that is optionally substituted with halogen, C 1 -C 6 alkyl, or carbonyl;
each R 9 is independently C 1 -C 6 alkyl;
R 10 is hydrogen or C 1 -C 6 alkyl;
R 11 is C 2 -C 6 alkenyl;
R 12 is C 2 -C 6 alkenyl substituted with cyano or —C(O)OR 9 ;
R 30 is halogen or C 1 -C 6 alkyl;
Z is C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl that is substituted with cyano or acetyl, —(CH 2 ) n NR 7 C(O)R 8 , —(CH 2 ) n C(O)(CH 2 ) n R 8 , —(CH 2 ) n OC(O)R 8 ,
(NH) m (SO 2 )R 11 , —CHR 11 OC(O)R 11 , —OR 12 , —(CH 2 ) n C(OH)R 12 ,
n is an integer from 0 to 6; and
m is 0 or 1;
R 17 is N, CH, or CR 30 ;
R 18 is O or S; and
G is N, CH, or CR 30 .
2 . The compound of claim 1 , wherein:
is
3 . The compound of claim 1 , wherein
is
4 . The compound of claim 1 , wherein Z is —(CH 2 ) n NR 7 C(O)R 8 ; R 7 is hydrogen; and R 8 is C 2 -C 6 alkenyl.
5 . The compound of claim 1 , wherein Z is
6 . The compound of claim 1 , wherein:
X is oxygen; R 1 is C 1 -C 6 alkoxy; R 2 is piperazine that is substituted at the N position with C 1 -C 6 alkyl; R 2a and R 2b are hydrogen; one of R 3 , R 4 , and R 5 is Z, and the other two of R 3 , R 4 , and R 5 are hydrogen; R 7 is hydrogen or C 1 -C 6 alkyl; R 8 is C 2 -C 6 alkenyl; and Z is —(CH 2 ) n NR 7 C(O)R 8 .
7 . The compound of claim 1 , wherein the compound has the formula:
8 . The compound of claim 1 , wherein the compound has the formula:
9 . The compound of claim 1 , wherein the compound has the formula:
10 . The compound of claim 1 , wherein the compound is:
or a pharmaceutically acceptable salt or ester thereof.
11 . A pharmaceutical composition comprising the compound of claim 1 and a pharmaceutically acceptable excipient.
12 . A kit comprising the compound of claim 1 and instructions for use of the compound in treating a disease or disorder in a subject in need thereof.
13 . The kit of claim 12 , wherein the disease or disorder comprises a cancer or a proliferative disorder.
14 . A method for inhibiting a kinase, comprising contacting the kinase with an effective amount of the compound of claim 1 .
15 . The method of claim 14 , wherein the kinase comprises EGFR, Jak3, Blk, Bmx, Btk, HER2 (ErbB2), HER4 (ErbB4), Itk, Tec, or Txk.
16 . The method of claim 15 , wherein the EGFR is a mutant EGFR.
17 . The method of claim 16 , wherein the EGFR mutation comprises G719S, G719C, G719A, L858R, L861Q, an exon 19 deletion mutation or an exon 20 insertion mutation.
18 . The method of claim 17 , wherein the EGFR mutation further comprises an EGFR T790M, T854A or D761Y resistance mutation.
19 . A method for treating or preventing a disease that is mediated by a kinase comprising administering an effective amount of the compound of claim 1 to a subject in need thereof.
20 . The method of claim 19 , wherein the kinase comprises EGFR, Jak3, Blk, Bmx, Btk, HER2 (ErbB2), HER4 (ErbB4), Itk, Tec, or Txk.
21 . The method of claim 19 , wherein the disease comprises a cancer or a proliferation disease.
22 . The method of claim 19 , wherein the subject is a human.
23 . A compound of Formula VIII:
or a pharmaceutically acceptable salt or ester thereof, wherein:
X is oxygen, sulfur, carbonyl, —NR 6 , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl;
Y is hydrogen, halogen, or C 1 -C 6 alkyl;
each R 1 is independently C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, or C 1 -C 6 haloalkoxy;
(i) one of R 2 , R 2a , and R 2b is piperidine, pyrrolidine, or morpholine that is optionally substituted with C 1 -C 6 alkyl; or C 3 -C 6 alkyl or C 3 -C 6 cycloalkyl containing at least one nitrogen; and the other two of R 2 , R 2a , and R 2b are hydrogen or C 1 -C 6 alkyl; or (ii) R 2 and one of R 2a and R 2b join to form a piperidine, pyrrolidine, or morpholine that is optionally substituted with C 1 -C 6 alkyl; or C 3 -C 6 cycloalkyl containing at least one nitrogen; and the other of R 2a and R 2b is hydrogen or C 1 -C 6 alkyl;
one of R 3 , R 4 , and R 5 is Z, and the other two of R 3 , R 4 , and R 5 are hydrogen;
each R 6 is independently hydrogen or C 1 -C 6 alkyl;
R 7 is hydrogen, C 1 -C 6 alkyl, or C 2 -C 6 alkenyl;
R 8 is C 1 -C 6 alkyl that is substituted with halogen, cyano, —C(O)R 9 , or —OC(O)R 9 ; C 2 -C 6 alkenyl that is optionally substituted with halogen or —NR 9 2 ; C 2 -C 6 alkynyl; C 3 -C 6 cycloalkyl that is substituted with cyano or —C(O)R 9 ; C 4 -C 6 cycloalkenyl that is optionally substituted with halogen; or C 4 -C 9 heterocycloalkenyl that is optionally substituted with halogen, C 1 -C 6 alkyl, or carbonyl;
each R 9 is independently C 1 -C 6 alkyl;
R 10 is hydrogen or C 1 -C 6 alkyl;
R 11 is C 2 -C 6 alkenyl;
R 12 is C 2 -C 6 alkenyl substituted with cyano or —C(O)OR 9 ;
Z is C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl that is substituted with cyano or acetyl, —(CH 2 ) n NR 7 C(O)R 8 , —(CH 2 ) n C(O)(CH 2 ) n R 8 , —(CH 2 ) n OC(O)R 8 ,
—(NH) m (SO 2 )R 11 , —CHR 11 OC(O)R 11 , —OR 12 , —(CH 2 ) n C(OH)R 12 ,
n is an integer from 0 to 6; and
m is 0 or 1.
24 . The compound of claim 23 , wherein:
R 1 is C 1 -C 6 alkoxy; R 2 is piperazine that is substituted at the N position with C 1 -C 6 alkyl; R 2a and R 2b are hydrogen; one of R 3 , R 4 , and R 5 is Z, and the other two of R 3 , R 4 , and R 5 are hydrogen; R 7 is hydrogen or C 1 -C 6 alkyl; R 8 is C 2 -C 6 alkenyl; and Z is —(CH 2 ) n NR 7 C(O)R 8 .
25 . The compound of claim 23 , wherein Z is —(CH 2 ) n NR 7 C(O)R 8 ; R 7 is hydrogen; and R 8 is C 2 -C 6 alkenyl.
26 . The compound of claim 23 , wherein Z is
27 . The compound of claim 23 , wherein the compound is:
or a pharmaceutically acceptable salt or ester thereof.
28 . A pharmaceutical composition comprising the compound of claim 23 and a pharmaceutically acceptable excipient.
29 . A kit comprising the compound of claim 23 and instructions for use of the compound in treating a disease or disorder in a subject in need thereof.
30 . The kit of claim 29 , wherein the disease or disorder comprises a cancer or a proliferative disorder.
31 . A method for inhibiting a kinase, comprising contacting the kinase with an effective amount of the compound of claim 23 .
32 . The method of claim 31 , wherein the kinase comprises EGFR, Jak3, Blk, Bmx, Btk, HER2 (ErbB2), HER4 (ErbB4), Itk, Tec, or Txk.
33 . The method of claim 32 , wherein the EGFR is a mutant EGFR.
34 . The method of claim 33 , wherein the EGFR mutation comprises G719S, G719C, G719A, L858R, L861Q, an exon 19 deletion mutation or an exon 20 insertion mutation.
35 . The method of claim 34 , wherein the EGFR mutation further comprises an EGFR T790M, T854A or D761Y resistance mutation.
36 . A method for treating or preventing a disease that is mediated by a kinase comprising administering an effective amount of the compound of claim 23 to a subject in need thereof.
37 . The method of claim 36 , wherein the kinase comprises EGFR, Jak3, Blk, Bmx, Btk, HER2 (ErbB2), HER4 (ErbB4), Itk, Tec, or Txk.
38 . The method of claim 36 , wherein the disease comprises a cancer or a proliferation disease.
39 . The method of claim 36 , wherein the subject is a human.
40 . A compound of Formula XII:
each R 1 is independently C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, or C 1 -C 6 haloalkoxy;
(i) one of R 2 , R 2a , and R 2b is piperidine, pyrrolidine, piperazine, or morpholine that is optionally substituted with C 1 -C 6 alkyl; or C 3 -C 6 alkyl or C 3 -C 6 cycloalkyl containing at least one nitrogen; and the other two of R 2 , R 2a , and R 2b are hydrogen or C 1 -C 6 alkyl; or (ii) R 2 and one of R 2a and R 2b join to form a piperidine, pyrrolidine, or morpholine that is optionally substituted with C 1 -C 6 alkyl; or C 3 -C 6 cycloalkyl containing at least one nitrogen; and the other of R 2a and R 2b is hydrogen or C 1 -C 6 alkyl;
one of R 3 , R 4 , and R 5 is Z, and the other two of R 3 , R 4 , and R 5 are hydrogen;
each R 6 is independently hydrogen or C 1 -C 6 alkyl;
R 7 is hydrogen, C 1 -C 6 alkyl, or C 2 -C 6 alkenyl;
R 8 is C 1 -C 6 alkyl that is substituted with halogen, cyano, —C(O)R 9 , or —OC(O)R 9 ; C 2 -C 6 alkenyl that is optionally substituted with halogen or —NR 9 2 ; C 2 -C 6 alkynyl; C 3 -C 6 cycloalkyl that is substituted with cyano or —C(O)R 9 ; C 4 -C 6 cycloalkenyl that is optionally substituted with halogen; or C 4 -C 9 heterocycloalkenyl that is optionally substituted with halogen, C 1 -C 6 alkyl, or carbonyl;
each R 9 is independently C 1 -C 6 alkyl;
R 10 is hydrogen or C 1 -C 6 alkyl;
R 11 is C 2 -C 6 alkenyl;
R 12 is C 2 -C 6 alkenyl substituted with cyano or —C(O)OR 9 ;
Z is C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl that is substituted with cyano or acetyl, —(CH 2 ) n NR 7 C(O)R 8 , —(CH 2 ) n C(O)(CH 2 ) n R 8 , —(CH 2 ) n OC(O)R 8 ,
—(NH) m (SO 2 )R 11 , —CHR 11 OC(O)R 11 , —OR 12 , —(CH 2 ) n C(OH)R 12 ,
n is an integer from 0 to 6;
m is 0 or 1;
X 1 is oxygen, sulfur, or —NR 6 ;
each G is independently N, CH, or CR 30 ; and
each R 27 is independently hydrogen, halogen, C 1 -C 3 alkyl, or C 1 -C 3 alkoxy.
41 . The compound of claim 40 , wherein at least one G is N.
42 . The compound of claim 40 , wherein Z is —(CH 2 ) n NR 7 C(O)R 8 ; R 7 is hydrogen; and R 8 is C 2 -C 6 alkenyl.
43 . The compound of claim 40 , wherein Z is
44 . The compound of claim 40 , wherein:
X 1 is oxygen, sulfur, or —NH; R 2 is piperidine that is substituted at the N position with C 1 -C 6 alkyl or piperazine that is substituted at the N position with C 1 -C 6 alkyl; R 2a and R 2b are hydrogen or C 1 -C 6 alkyl; one of R 3 , R 4 , and R 5 is Z, and the other two of R 3 , R 4 , and R 5 are hydrogen; R 7 is hydrogen or C 1 -C 6 alkyl; R 8 is C 2 -C 6 alkenyl; and Z is —(CH 2 ) n NR 7 C(O)R 8 .
45 . The compound of claim 40 , wherein the compound is:
or a pharmaceutically acceptable salt or ester thereof.
46 . A pharmaceutical composition comprising the compound of claim 40 and a pharmaceutically acceptable excipient.
47 . A kit comprising the compound of claim 40 and instructions for use of the compound in treating a disease or disorder in a subject in need thereof.
48 . The kit of claim 47 , wherein the disease or disorder comprises a cancer or a proliferative disorder.
49 . A method for inhibiting a kinase, comprising contacting the kinase with an effective amount of the compound of claim 40 .
50 . The method of claim 49 , wherein the kinase comprises EGFR, Jak3, Blk, Bmx, Btk, HER2 (ErbB2), HER4 (ErbB4), Itk, Tec, or Txk.
51 . The method of claim 50 , wherein the EGFR is a mutant EGFR.
52 . The method of claim 51 , wherein the EGFR mutation comprises G719S, G719C, G719A, L858R, L861Q, an exon 19 deletion mutation or an exon 20 insertion mutation.
53 . The method of claim 52 , wherein the EGFR mutation further comprises an EGFR T790M, T854A or D761Y resistance mutation.
54 . A method for treating or preventing a disease that is mediated by a kinase comprising administering an effective amount of the compound of claim 40 to a subject in need thereof.
55 . The method of claim 54 , wherein the kinase comprises EGFR, Jak3, Blk, Bmx, Btk, HER2 (ErbB2), HER4 (ErbB4), Itk, Tec, or Txk.
56 . The method of claim 54 , wherein the disease comprises a cancer or a proliferation disease.
57 . The method of claim 54 , wherein the subject is a human.Cited by (0)
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