U.S. patent application number 11/410344 was filed with the patent office on 2006-08-24 for method of treating hyperproliferative disorders using heterocyclic inhibitors of mek.
This patent application is currently assigned to ARRAY BIOPHARMA INC.. Invention is credited to Jim Blake, Eli Wallace, Hong Woon Yang.
Application Number | 20060189668 11/410344 |
Document ID | / |
Family ID | 34218110 |
Filed Date | 2006-08-24 |
United States Patent
Application |
20060189668 |
Kind Code |
A1 |
Wallace; Eli ; et
al. |
August 24, 2006 |
Method of treating hyperproliferative disorders using heterocyclic
inhibitors of MEK
Abstract
Disclosed are methods of inhibiting MEK activity, comprising
administering to a mammal an effective amount of a compound of
Formula I or IV ##STR1## or a solvate or pharmaceutically
acceptable salt thereof, wherein R.sup.1, R.sup.2, R.sup.7,
R.sup.8, R.sup.9, R.sup.10, W and Y are as defined in the
specification. Also disclosed are methods of treating
hyperproliferative diseases, such as cancer and inflammation, in
mammals, said method comprising administering to a mammal an
effective amount of a compound of Formula I or IV.
Inventors: |
Wallace; Eli; (Lyons,
CO) ; Yang; Hong Woon; (Superior, CO) ; Blake;
Jim; (Longmont, CO) |
Correspondence
Address: |
HOGAN & HARTSON LLP
ONE TABOR CENTER
1200 17TH STREET, SUITE 1500
DENVER
CO
80202
US
|
Assignee: |
ARRAY BIOPHARMA INC.
BOULDER
CO
|
Family ID: |
34218110 |
Appl. No.: |
11/410344 |
Filed: |
April 24, 2006 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
10654580 |
Sep 3, 2003 |
|
|
|
11410344 |
Apr 24, 2006 |
|
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Current U.S.
Class: |
514/379 |
Current CPC
Class: |
C07D 471/04 20130101;
A61P 29/00 20180101; A61P 43/00 20180101; C07D 261/20 20130101;
A61P 35/00 20180101 |
Class at
Publication: |
514/379 |
International
Class: |
A61K 31/42 20060101
A61K031/42 |
Claims
1. A method of treating a hyperproliferative disorder in a mammal
comprising administrating to said mammal one or more compounds of
Formula I ##STR68## or a solvate or pharmaceutically acceptable
salt thereof, wherein: R.sup.1, R.sup.2, R.sup.7, R.sup.8, R.sup.9,
and R.sup.10 are independently hydrogen, halogen, cyano, nitro,
trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido,
--OR.sup.3, --C(O)R.sup.3, --C(O)OR.sup.3, NR.sup.4C(O)OR.sup.6,
--OC(O)R.sup.3, --NR.sup.4SO.sub.2R.sup.6,
--SO.sub.2NR.sup.3R.sup.4, --NR.sup.4C(O)R.sup.3,
--C(O)NR.sup.3R.sup.4, --NR.sup.5C(O)NR.sup.3R.sup.4,
--NR.sup.5C(NCN)NR.sup.3R.sup.4, --NR.sup.3R.sup.4,
C.sub.1-C.sub.10 alkyl, C.sub.2-C.sub.10 alkenyl, C.sub.2-C.sub.10
alkynyl, C.sub.3-C.sub.10 cycloalkyl, C.sub.3-C.sub.10
cycloalkylalkyl, --S(O).sub.j(C.sub.1-C.sub.6 alkyl),
--S(O).sub.j(CR.sup.4R.sup.5).sub.m-aryl, aryl, arylalkyl,
heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl,
--O(CR.sup.4R.sup.5).sub.m-aryl,
--NR.sup.4(CR.sup.4R.sup.5).sub.m-aryl,
--O(CR.sup.4R.sup.5).sub.m-heteroaryl,
--NR.sup.4(CR.sup.4R.sup.5).sub.m-heteroaryl,
--O(CR.sup.4R.sup.5).sub.m-heterocyclyl or
--NR.sup.4(CR.sup.4R.sup.5).sub.m-heterocyclyl, wherein any of said
alkyl, alkenyl, alkynyl, cycloalkyl, aryl, arylalkyl, heteroaryl,
heteroarylalkyl, heterocyclyl and heterocyclylalkyl portions are
optionally substituted with one or more groups independently
selected from oxo, halogen, cyano, nitro, trifluoromethyl,
difluoromethoxy, trifluoromethoxy, azido,
--NR.sup.4SO.sub.2R.sup.6, --SO.sub.2NR.sup.3R.sup.4,
--C(O)R.sup.3, --C(O)OR.sup.3, --OC(O)R.sup.3,
--NR.sup.4C(O)OR.sup.6, --NR.sup.4C(O)R.sup.3,
--C(O)NR.sup.3R.sup.4, --NR.sup.3R.sup.4,
--NR.sup.5C(O)NR.sup.3R.sup.4, --NR.sup.5C(NCN)NR.sup.3R.sup.4,
--OR.sup.3, aryl, heteroaryl, arylalkyl, heteroarylalkyl,
heterocyclyl, and heterocyclylalkyl; R.sup.3 is hydrogen,
trifluoromethyl, C.sub.1-C.sub.10 alkyl, C.sub.2-C.sub.10 alkenyl,
C.sub.2-C.sub.10 alkynyl, C.sub.3-C.sub.10 cycloalkyl,
C.sub.3-C.sub.10 cycloalkylalkyl, aryl, arylalkyl, heteroaryl,
heteroarylalkyl, heterocyclyl, heterocyclylalkyl, phosphate or an
amino acid residue, wherein any of said alkyl, alkenyl, alkynyl,
cycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl,
heterocyclyl and heterocyclylalkyl portions are optionally
substituted with one or more groups independently selected from
oxo, halogen, cyano, nitro, trifluoromethyl, difluoromethoxy,
trifluoromethoxy, azido, --NR'SO.sub.2R'''', --SO.sub.2NR'R'',
--C(O)R', C(O)OR', --OC(O)R', --NR'C(O)OR'''', --NR'C(O)R'',
--C(O)NR'R'', --SR', --S(O)R'''', --SO.sub.2R'''', --NR'R'',
--NR'C(O)NR''R''', --NR'C(NCN)NR''R''', --OR', aryl, heteroaryl,
arylalkyl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl, or
R.sup.3 and R.sup.4 together with the atom to which they are
attached form a 4 to 10 membered carbocyclic, heteroaryl or
heterocyclic ring, wherein any of said carbocyclic, heteroaryl and
heterocyclic rings are optionally substituted with one or more
groups independently selected from halogen, cyano, nitro,
trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido,
--NR'SO.sub.2R'''', --SO.sub.2NR'R'', --C(O)R', --C(O)OR',
--OC(O)R', --NR'C(O)OR, --NR'C(O)R'''', --C(O)NR'R'',
--SO.sub.2R'''', --NR'R'', --NR'C(O)NR''R''', --NR'C(NCN)NR''R''',
--OR, aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl,
and heterocyclylalkyl; R', R'' and R''' are independently hydrogen,
lower alkyl, lower alkenyl, aryl or arylalkyl, and R'''' is lower
alkyl, lower alkenyl, aryl or arylalkyl, or any two of R', R'',
R''' or R'''' together with the atom to which they are attached
form a 4 to 10 membered carbocyclic, heteroaryl or heterocyclic
ring, wherein any of said alkyl, alkenyl, aryl, arylalkyl
carbocyclic rings, heteroaryl rings or heterocyclic rings are
optionally substituted with one or more groups independently
selected from halogen, cyano, nitro, trifluoromethyl,
difluoromethoxy, trifluoromethoxy, azido, aryl, heteroaryl,
arylalkyl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl;
R.sup.4 and R.sup.5 are independently hydrogen or C.sub.1-C.sub.6
alkyl, or R.sup.4 and R.sup.5 together with the atom to which they
are attached form a 4 to 10 membered carbocyclic, heteroaryl or
heterocyclic ring, wherein said alkyl or any of said carbocyclic,
heteroaryl and heterocyclic rings are optionally substituted with
one or more groups independently selected from halogen, cyano,
nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido,
--NR'SO.sub.2R'''', --SO.sub.2NR'R'', --C(O)R'''', --C(O)OR',
--OC(O)R', --NR'C(O)OR'''', --NR'C(O)R'', --C(O)NR'R'',
--SO.sub.2R'''', --NR'R'', --NR'C(O)NR''R''', --NR'C(NCN)NR''R''',
--OR', aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl,
and heterocyclylalkyl; R.sup.6 is trifluoromethyl, C.sub.1-C.sub.10
alkyl, C.sub.3-C.sub.10 cycloalkyl, aryl, arylalkyl, heteroaryl,
heteroarylalkyl, heterocyclyl, or heterocyclylalkyl, wherein any of
said alkyl, cycloalkyl, aryl, arylalkyl, heteroaryl,
heteroarylalkyl, heterocyclyl and heterocyclylalkyl portions are
optionally substituted with one or more groups independently
selected from oxo, halogen, cyano, nitro, trifluoromethyl,
difluoromethoxy, trifluoromethoxy, azido, --NR'SO.sub.2R'''',
--SO.sub.2NR'R'', --C(O)R', --C(O)OR', --OC(O)R', --NR'C(O)OR'''',
--NR'C(O)R'', --C(O)NR'R'', --SO.sub.2R'''', --NR'R',
--NR'C(O)NR''R''', --NR'C(NCN)NR''R''', --OR', aryl, heteroaryl,
arylalkyl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl; W
is heteroaryl, heterocyclyl, --C(O)OR.sup.3, --C(O)NR.sup.3R.sup.4,
--C(O)NR.sup.4OR.sup.3, --C(O)R.sup.4OR.sup.3,
--C(O)(C.sub.3-C.sub.10 cycloalkyl), --C(O)(C.sub.1-C.sub.10
alkyl), --C(O)(aryl), --C(O)(heteroaryl), --C(O)(heterocyclyl),
CR.sup.3OR.sup.3, or --CONH(SO.sub.2)CH.sub.3, wherein any of said
heteroaryl, heterocyclyl, --C(O)OR.sup.3, --C(O)NR.sup.3R.sup.4,
--C(O)NR.sup.4OR.sup.3, --C(O)R.sup.4OR.sup.3,
--C(O)(C.sub.3-C.sub.10 cycloalkyl), --C(O)(C.sub.1-C.sub.10alkyl),
--C(O)(aryl), --C(O)(heteroaryl), --C(O)(heterocyclyl), and
CR.sup.3OR.sup.3 are optionally substituted with one or more groups
independently selected from --NR.sup.3R.sup.4, --OR.sup.3,
--R.sup.2, C.sub.1-C.sub.10 alkyl, C.sub.2-C.sub.10 alkenyl, and
C.sub.2-C.sub.10 alkynyl, wherein any of said C.sub.1-C.sub.10
alkyl, C.sub.2-C.sub.10 alkenyl, and C.sub.2-C.sub.10 alkynyl are
optionally substituted with 1 or more groups independently selected
from --NR.sup.3R.sup.4 and --OR.sup.3; m is 0, 1, 2, 3, 4 or 5; and
j is 1 or 2.
2. The method of claim 1, wherein R.sup.1 is halogen.
3. The method of claim 2, wherein R.sup.1 is 2-Cl.
4. The method of claim 1, wherein R.sup.7 is alkyl, NR.sup.3R.sup.4
or H.
5. The method of claim 4, wherein R.sup.7 is Me, NH.sub.2 or H.
6. The method of claim 1, wherein R.sup.8 is halogen.
7. The method of claim 6, wherein R.sup.8 is Br or Cl.
8. The method of claim 1, wherein R.sup.9 is halogen.
9. The method of claim 8, wherein R.sup.9 is F.
10. The method of claim 1, wherein W is --C(O)OR.sup.3,
--C(O)NR.sup.4OR.sup.3, or --CONH(SO.sub.2)CH.sub.3.
11. The method of claim 10, wherein W is --C(O)OH,
--C(O)NHOCH.sub.2-(cyclopropyl), --C(O)NHO(CH.sub.2).sub.2OH, or
--CONH(SO.sub.2)CH.sub.3.
12. The method of claim 1, wherein said compound is ##STR69##
13. The method of claim 1, wherein said compound is ##STR70##
14. The method of claim 1, wherein said compound is ##STR71##
15. The compound of claim 1, wherein said compound is ##STR72##
16. The method of claim 1, wherein said compound is ##STR73##
17. The method of claim 1, having the formula ##STR74##
18. The method of claim 1, wherein said compound is ##STR75##
19. The method of claim 1, wherein said compound is ##STR76##
20. The method of claim 1, wherein said hyperproliferative disorder
is cancer.
21. A method of treating a hyperproliferative disorder in a mammal
comprising administrating to said mammal one or more compounds of
Formula IV ##STR77## or a solvate or pharmaceutically acceptable
salt thereof, wherein: R.sup.1, R.sup.2, R.sup.7, R.sup.8, R.sup.9,
and R.sup.10 are independently hydrogen, halogen, cyano, nitro,
trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido,
--OR.sup.3, --C(O)R.sup.3, --C(O)OR.sup.3, NR.sup.4C(O)OR.sup.6,
--OC(O)R.sup.3, --NR.sup.4SO.sub.2R.sup.6,
--SO.sub.2NR.sup.3R.sup.4, --NR.sup.4C(O)R.sup.3,
--C(O)NR.sup.3R.sup.4, --NR.sup.5C(O)NR.sup.3R.sup.4,
--NR.sup.5C(NCN)NR.sup.3R.sup.4, --NR.sup.3R.sup.4,
C.sub.1-C.sub.10 alkyl, C.sub.2-C.sub.10 alkenyl, C.sub.2-C.sub.10
alkynyl, C.sub.3-C.sub.10 cycloalkyl, C.sub.3-C.sub.10
cycloalkylalkyl, --S(O).sub.j(C.sub.1-C.sub.6 alkyl),
--S(O).sub.j(CR.sup.4R.sup.5).sub.m-aryl, aryl, arylalkyl,
heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl,
--O(CR.sup.4R.sup.5).sub.m-aryl,
--NR.sup.4(CR.sup.4R.sup.5).sub.m-aryl,
--O(CR.sup.4R.sup.5).sub.m-heteroaryl,
--NR.sup.4(CR.sup.4R.sup.5).sub.m-heteroaryl,
--O(CR.sup.4R.sup.5).sub.m-heterocyclyl or
--NR.sup.4(CR.sup.4R.sup.5).sub.m-heterocyclyl, wherein any of said
alkyl, alkenyl, alkynyl, cycloalkyl, aryl, arylalkyl, heteroaryl,
heteroarylalkyl, heterocyclyl and heterocyclylalkyl portions are
optionally substituted with one or more groups independently
selected from oxo, halogen, cyano, nitro, trifluoromethyl,
difluoromethoxy, trifluoromethoxy, azido,
--NR.sup.4SO.sub.2R.sup.6, --SO.sub.2NR.sup.3R.sup.4,
--C(O)R.sup.3, --C(O)OR.sup.3, --OC(O)R.sup.3,
--NR.sup.4C(O)OR.sup.6, --NR.sup.4C(O)R.sup.3,
--C(O)NR.sup.3R.sup.4, --NR.sup.3R.sup.4,
--NR.sup.5C(O)NR.sup.3R.sup.4, --NR.sup.5C(NCN)NR.sup.3R.sup.4,
--OR.sup.3, aryl, heteroaryl, arylalkyl, heteroarylalkyl,
heterocyclyl, and heterocyclylalkyl; R.sup.3 is hydrogen,
trifluoromethyl, C.sub.1-C.sub.10 alkyl, C.sub.2-C.sub.10 alkenyl,
C.sub.2-C.sub.10 alkynyl, C.sub.3-C.sub.10 cycloalkyl,
C.sub.3-C.sub.10 cycloalkylalkyl, aryl, arylalkyl, heteroaryl,
heteroarylalkyl, heterocyclyl, heterocyclylalkyl, phosphate or an
amino acid residue, wherein any of said alkyl, alkenyl, alkynyl,
cycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl,
heterocyclyl and heterocyclylalkyl portions are optionally
substituted with one or more groups independently selected from
oxo, halogen, cyano, nitro, trifluoromethyl, difluoromethoxy,
trifluoromethoxy, azido, --NR'SO.sub.2R'''', --SO.sub.2NR'R'',
--C(O)R', --C(O)OR', --OC(O)R', --NR'C(O)OR'''', --NR'C(O)R'',
--C(O)NR'R'', --SR', --S(O)R'''', --SO.sub.2R'''', --NR'R'',
--NR'C(O)NR''R''', --NR'C(NCN)NR''R''', --OR', aryl, heteroaryl,
arylalkyl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl, or
R.sup.3 and R.sup.4 together with the atom to which they are
attached form a 4 to 10 membered saturated, unsaturated, or
partially saturated heterocyclic ring, wherein any of said
saturated, unsaturated, or partially saturated heterocyclic rings
are optionally substituted with one or more groups independently
selected from halogen, cyano, nitro, trifluoromethyl,
difluoromethoxy, trifluoromethoxy, azido, --NR'SO.sub.2R'''',
--SO.sub.2NR'R'', --C(O)R', --C(O)OR', --OC(O)R', --NR'C(O)OR'''',
--NR'C(O)R'', --C(O)NR'R'', --SO.sub.2R'''', --NR'R'',
--NR'C(O)NR''R''', --NR'C(NCN)NR''R''', --OR', aryl, heteroaryl,
arylalkyl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl;
R', R'' and R''' are independently hydrogen, lower alkyl, lower
alkenyl, aryl or arylalkyl, and R'''' is lower alkyl, lower
alkenyl, aryl or arylalkyl, or any two of R', R'', R''' or R''''
together with the atom to which they are attached form a 4 to 10
membered saturated, unsaturated, or partially saturated
heterocyclic ring, wherein any of said alkyl, alkenyl, aryl,
arylalkyl saturated, unsaturated, or partially saturated
heterocyclic rings are optionally substituted with one or more
groups independently selected from halogen, cyano, nitro,
trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido, aryl,
heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl, and
heterocyclylalkyl; R.sup.4 and R.sup.5 are independently hydrogen
or C.sub.1-C.sub.6 alkyl; R.sup.6 is trifluoromethyl,
C.sub.1-C.sub.10 alkyl, C.sub.3-C.sub.10 cycloalkyl, aryl,
arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, or
heterocyclylalkyl, wherein any of said alkyl, cycloalkyl, aryl,
arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl and
heterocyclylalkyl portions are optionally substituted with one or
more groups independently selected from oxo, halogen, cyano, nitro,
trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido,
--NR'SO.sub.2R'''', --SO.sub.2NR'R'', --C(O)R', --C(O)OR',
--OC(O)R', --NR'C(O)OR'''', --NR'C(O)R'', --C(O)NR'R'',
--SO.sub.2R'''', NR'R', --NR'C(O)NR''R''', --NR'C(NCN)NR''R''',
--OR', aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl,
and heterocyclylalkyl; W is heteroaryl, heterocyclyl,
--C(O)OR.sup.3, --C(O)NR.sup.3R.sup.4, --C(O)NR.sup.4OR.sup.3,
--C(O)R.sup.4OR.sup.3, --C(O)(C.sub.3-C.sub.10 cycloalkyl),
--C(O)(C.sub.1-C.sub.10 alkyl), --C(O)(aryl), --C(O)(heteroaryl),
--C(O)(heterocyclyl), or CR.sup.3OR.sup.3, wherein any of said
heteroaryl, heterocyclyl, --C(O)OR.sup.3, --C(O)NR.sup.3R.sup.4,
--C(O)NR.sup.4OR.sup.3, --C(O)R.sup.4OR.sup.3,
--C(O)(C.sub.3-C.sub.10 cycloalkyl), --C(O)(C.sub.1-C.sub.10
alkyl), --C(O)(aryl), --C(O)(heteroaryl), --C(O)(heterocyclyl) and
CR.sup.3OR.sup.3 are optionally substituted with one or more groups
independently selected from --NR.sup.3R.sup.4, --OR.sup.3,
--R.sup.2, C.sub.1-C.sub.10 alkyl, C.sub.2-C.sub.10 alkenyl, and
C.sub.2-C.sub.10 alkynyl, wherein any of said C.sub.1-C.sub.10
alkyl, C.sub.2-C.sub.10 alkenyl, and C.sub.2-C.sub.10 alkynyl are
optionally substituted with 1 or more groups independently selected
from --NR.sup.3R.sup.4 and --OR.sup.3; m is 0, 1, 2,3, 4 or 5; and
j is 1 or 2.
22. The method of claim 21, wherein R.sup.1 is halogen.
23. The method of claim 22 wherein R.sup.1 is 2-Cl.
24. The method of claim 21, wherein R.sup.7 is alkyl.
25. The method of claim 24, wherein R.sup.7 is methyl.
26. The method of claim 21, wherein R.sup.9 is halogen.
27. The method of claim 26, wherein R.sup.9 is F.
28. The method of claim 21, wherein W is --C(O)OR.sup.3 or
--C(O)NR.sup.4OR.sup.3.
29. The method of claim 28, wherein W is --COOH or
--C(O)NHO(CH.sub.2).sub.2OH.
30. The method of claim 21, wherein said compound is ##STR78##
31. The method of claim 21, wherein said compound is ##STR79##
32. The method of claim 21, wherein said compound is ##STR80##
33. The method of claim 21, wherein said hyperproliferative
disorder is cancer.
34. A method of inhibiting MEK activity in a mammal, comprising
administrating to said mammal one or more compounds of Formula I
##STR81## or a solvate or pharmaceutically acceptable salt thereof,
wherein: R.sup.1, R.sup.2, R.sup.7, R.sup.8, R.sup.9, and R.sup.10
are independently hydrogen, halogen, cyano, nitro, trifluoromethyl,
difluoromethoxy, trifluoromethoxy, azido, --OR.sup.3,
--C(O)R.sup.3, --C(O)OR.sup.3, NR.sup.4C(O)OR.sup.6,
--OC(O)R.sup.3, --NR.sup.4SO.sub.2R.sup.6,
--SO.sub.2NR.sup.3R.sup.4, --NR.sup.4C(O)R.sup.3,
C(O)NR.sup.3R.sup.4, --NR.sup.5C(O)NR.sup.3R.sup.4,
--NR.sup.5C(NCN)NR.sup.3R.sup.4, --NR.sup.3R.sup.4,
--C.sub.1-C.sub.10 alkyl, C.sub.2-C.sub.10 alkenyl,
C.sub.2-C.sub.10 alkynyl, C.sub.3-C.sub.10 cycloalkyl,
C.sub.3-C.sub.10 cycloalkylalkyl, --S(O).sub.j(C.sub.1-C.sub.6
alkyl), --S(O).sub.j(CR.sup.4R.sup.5).sub.m-aryl, aryl, arylalkyl,
heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl,
--O(CR.sup.4R.sup.5).sub.m-aryl,
--NR.sup.4(CR.sup.4R.sup.5).sub.m-aryl,
--O(CR.sup.4R.sup.5).sub.m-heteroaryl,
--NR.sup.4(CR.sup.4R.sup.5).sub.m-heteroaryl,
--O(CR.sup.4R.sup.5).sub.m-heterocyclyl or
--NR.sup.4(CR.sup.4R.sup.5).sub.m-heterocyclyl, wherein any of said
alkyl, alkenyl, alkynyl, cycloalkyl, aryl, arylalkyl, heteroaryl,
heteroarylalkyl, heterocyclyl and heterocyclylalkyl portions are
optionally substituted with one or more groups independently
selected from oxo, halogen, cyano, nitro, trifluoromethyl,
difluoromethoxy, trifluoromethoxy, azido,
--NR.sup.4SO.sub.2R.sup.6, --SO.sub.2NR.sup.3R.sup.4,
--C(O)R.sup.3, --C(O)OR.sup.3, --OC(O)R.sup.3,
--NR.sup.4C(O)OR.sup.6, --NR.sup.4C(O)R.sup.3, R.sup.4,
--NR.sup.3R.sup.4, --NR.sup.5C(O)NR.sup.3R.sup.4,
--NR.sup.5C(NCN)NR.sup.3R.sup.4, --OR.sup.3, aryl, heteroaryl,
arylalkyl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl;
R.sup.3 is hydrogen, trifluoromethyl, C.sub.1-C.sub.10 alkyl,
C.sub.2-C.sub.10 alkenyl, C.sub.2-C.sub.10 alkynyl,
C.sub.3-C.sub.10 cycloalkyl, C.sub.3-C.sub.10 cycloalkylalkyl,
aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl,
heterocyclylalkyl, phosphate or an amino acid residue, wherein any
of said alkyl, alkenyl, alkynyl, cycloalkyl, aryl, arylalkyl,
heteroaryl, heteroarylalkyl, heterocyclyl and heterocyclylalkyl
portions are optionally substituted with one or more groups
independently selected from oxo, halogen, cyano, nitro,
trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido,
--NR'SO.sub.2R'''', --SO.sub.2NR'R'', --C(O)R', C(O)OR', --OC(O)R',
--NR'C(O)OR'''', --NR'C(O)R'', --C(O)NR'R'', --SR', --S(O)R'''',
--SO.sub.2R'''', --NR'R'', --NR'C(O)NR''R''', --NR'C(NCN)NR''R''',
--OR', aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl,
and heterocyclylalkyl, or R.sup.3 and R.sup.4 together with the
atom to which they are attached form a 4 to 10 membered
carbocyclic, heteroaryl or heterocyclic ring, wherein any of said
carbocyclic, heteroaryl and heterocyclic rings are optionally
substituted with one or more groups independently selected from
halogen, cyano, nitro, trifluoromethyl, difluoromethoxy,
trifluoromethoxy, azido, --NR'SO.sub.2R'''', --SO.sub.2NR'R'',
--C(O)R', --C(O)OR', --OC(O)R', --NR'C(O)OR, --NR'C(O)R'',
--C(O)NR'R'', --SO.sub.2R'''', --NR'R'', --NR'C(O)NR''R''',
--NR'C(NCN)NR''R''', --OR', aryl, heteroaryl, arylalkyl,
heteroarylalkyl, heterocyclyl, and heterocyclylalkyl; R', R'' and
R''' are independently hydrogen, lower alkyl, lower alkenyl, aryl
or arylalkyl, and R'''' is lower alkyl, lower alkenyl, aryl or
arylalkyl, or any two of R', R'', R''' or R'''' together with the
atom to which they are attached form a 4 to 10 membered
carbocyclic, heteroaryl or heterocyclic ring, wherein any of said
alkyl, alkenyl, aryl, arylalkyl carbocyclic rings, heteroaryl rings
or heterocyclic rings are optionally substituted with one or more
groups independently selected from halogen, cyano, nitro,
trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido, aryl,
heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl, and
heterocyclylalkyl; R.sup.4 and R.sup.5 are independently hydrogen
or C.sub.1-C.sub.6 alkyl, or R.sup.4 and R.sup.5 together with the
atom to which they are attached form a 4 to 10 membered
carbocyclic, heteroaryl or heterocyclic ring, wherein said alkyl or
any of said carbocyclic, heteroaryl and heterocyclic rings are
optionally substituted with one or more groups independently
selected from halogen, cyano, nitro, trifluoromethyl,
difluoromethoxy, trifluoromethoxy, azido, --NR'SO.sub.2R'''',
--SO.sub.2NR'R'', --C(O)R'''', --C(O)OR', --OC(O)R',
--NR'C(O)OR'''', --NR'C(O)R'', --C(O)NR'R'', --SO.sub.2R'''',
--NR'R'', --NR'C(O)NR''R''', --NR'C(NCN)NR''R''', --OR', aryl,
heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl, and
heterocyclylalkyl; R.sup.6 is trifluoromethyl, C.sub.1-C.sub.10
alkyl, C.sub.3-C.sub.10 cycloalkyl, aryl, arylalkyl, heteroaryl,
heteroarylalkyl, heterocyclyl, or heterocyclylalkyl, wherein any of
said alkyl, cycloalkyl, aryl, arylalkyl, heteroaryl,
heteroarylalkyl, heterocyclyl and heterocyclylalkyl portions are
optionally substituted with one or more groups independently
selected from oxo, halogen, cyano, nitro, trifluoromethyl,
difluoromethoxy, trifluoromethoxy, azido, --NR'SO.sub.2R'''',
--SO.sub.2NR'R'', --C(O)R', --C(O)OR', --OC(O)R', --NR'C(O)OR'''',
--NR'C(O)R'', --C(O)NR'R'', --SO.sub.2R'''', --NR'R',
--NR'C(O)NR''R''', --NR'C(NCN)NR''R''', --OR', aryl, heteroaryl,
arylalkyl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl; W
is heteroaryl, heterocyclyl, --C(O)OR.sup.3, --C(O)NR.sup.3R.sup.4,
--C(O)NR.sup.4OR.sup.3, --C(O)R.sup.4OR.sup.3,
--C(O)(C.sub.3-C.sub.10 cycloalkyl), --C(O)(C.sub.1-C.sub.10
alkyl), --C(O)(aryl), --C(O)(heteroaryl), --C(O)(heterocyclyl),
CR.sup.3OR.sup.3, or --CONH(SO.sub.2)CH.sub.3, wherein any of said
heteroaryl, heterocyclyl, --C(O)OR.sup.3, --C(O)NR.sup.3R.sup.4,
--C(O)NR.sup.4OR.sup.3, --C(O)R.sup.4OR.sup.3,
--C(O)(C.sub.3-C.sub.10 cycloalkyl), --C(O)(C.sub.1-C.sub.10
alkyl), --C(O)(aryl), --C(O)(heteroaryl), --C(O)(heterocyclyl), and
CR.sup.3OR.sup.3 are optionally substituted with one or more groups
independently selected from --NR.sup.3R.sup.4, --OR.sup.3,
--R.sup.2, C.sub.1-C.sub.10 alkyl, C.sub.2-C.sub.10 alkenyl, and
C.sub.2-C.sub.10 alkynyl, wherein any of said C.sub.1-C.sub.10
alkyl, C.sub.2-C.sub.10 alkenyl, and C.sub.2-C.sub.10 alkynyl are
optionally substituted with 1 or more groups independently selected
from --NR.sup.3R.sup.4 and --OR.sup.3; m is 0, 1, 2, 3, 4 or 5; and
j is 1 or 2.
35. A method of treating a hyperproliferative disorder in a mammal
comprising administrating to said mammal one or more compounds of
Formula IV ##STR82## or a solvate or pharmaceutically acceptable
salt thereof, wherein: R.sup.1, R.sup.2, R.sup.7, R.sup.8, R.sup.9,
and R.sup.10 are independently hydrogen, halogen, cyano, nitro,
trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido,
--OR.sup.3, --C(O)R.sup.3, --C(O)OR.sup.3, NR.sup.4C(O)OR.sup.6,
--OC(O)R.sup.3, --NR.sup.4SO.sub.2R.sup.6,
--SO.sub.2NR.sup.3R.sup.4, --NR.sup.4C(O)R.sup.3,
--C(O)NR.sup.3R.sup.4, --NR.sup.5C(O)NR.sup.3R.sup.4,
--NR.sup.5C(NCN)NR.sup.3R.sup.4, --NR.sup.3R.sup.4,
C.sub.1-C.sub.10 alkyl, C.sub.2-C.sub.10 alkenyl, C.sub.2-C.sub.10
alkynyl, C.sub.3-C.sub.10 cycloalkyl, C.sub.3-C.sub.10
cycloalkylalkyl, --S(O).sub.j(C.sub.1-C.sub.6 alkyl),
--S(O).sub.j(CR.sup.4R.sup.5).sub.m-aryl, aryl, arylalkyl,
heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl,
--O(CR.sup.4R.sup.5).sub.m-aryl,
--NR.sup.4(CR.sup.4R.sup.5).sub.m-aryl,
--O(CR.sup.4R.sup.5).sub.m-heteroaryl,
--NR.sup.4(CR.sup.4R.sup.5).sub.m-heteroaryl,
--O(CR.sup.4R.sup.5).sub.m-heterocyclyl or
--NR.sup.4(CR.sup.4R.sup.5).sub.m-heterocyclyl, wherein any of said
alkyl, alkenyl, alkynyl, cycloalkyl, aryl, arylalkyl, heteroaryl,
heteroarylalkyl, heterocyclyl and heterocyclylalkyl portions are
optionally substituted with one or more groups independently
selected from oxo, halogen, cyano, nitro, trifluoromethyl,
difluoromethoxy, trifluoromethoxy, azido,
--NR.sup.4SO.sub.2R.sup.6, --SO.sub.2NR.sup.3R.sup.4,
--C(O)R.sup.3, --C(O)OR.sup.3, --OC(O)R.sup.3,
--NR.sup.4C(O)OR.sup.6, --NR.sup.4C(O)R.sup.3,
--C(O)NR.sup.3R.sup.4, --NR.sup.3R.sup.4,
--NR.sup.5C(O)NR.sup.3R.sup.4, --NR.sup.5C(NCN)NR.sup.3R.sup.4,
--OR.sup.3, aryl, heteroaryl, arylalkyl, heteroarylalkyl,
heterocyclyl, and heterocyclylalkyl; R.sup.3 is hydrogen,
trifluoromethyl, C.sub.1-C.sub.10 alkyl, C.sub.2-C.sub.10 alkenyl,
C.sub.2-C.sub.10 alkynyl, C.sub.3-C.sub.10 cycloalkyl,
C.sub.3-C.sub.10 cycloalkylalkyl, aryl, arylalkyl, heteroaryl,
heteroarylalkyl, heterocyclyl, heterocyclylalkyl, phosphate or an
amino acid residue, wherein any of said alkyl, alkenyl, alkynyl,
cycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl,
heterocyclyl and heterocyclylalkyl portions are optionally
substituted with one or more groups independently selected from
oxo, halogen, cyano, nitro, trifluoromethyl, difluoromethoxy,
trifluoromethoxy, azido, --NR'SO.sub.2R'''', --SO.sub.2NR'R'',
--C(O)R', --C(O)OR', --OC(O)R', --NR'C(O)OR'''', --NR'C(O)R'',
--C(O)NR'R'', --SR', --S(O)R'''', --SO.sub.2R'''', --NR'R'''',
--NR'C(O)NR''R''', --NR'C(NCN)NR''R''', --OR', aryl, heteroaryl,
arylalkyl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl, or
R.sup.3 and R.sup.4 together with the atom to which they are
attached form a 4 to 10 membered saturated, unsaturated, or
partially saturated heterocyclic ring, wherein any of said
saturated, unsaturated, or partially saturated heterocyclic rings
are optionally substituted with one or more groups independently
selected from halogen, cyano, nitro, trifluoromethyl,
difluoromethoxy, trifluoromethoxy, azido, --NR'SO.sub.2R'''',
--SO.sub.2NR'R'', --C(O)R', --C(O)OR', --OC(O)R', --NR'C(O)OR'''',
--NR'C(O)R'', --C(O)NR'R'', --SO.sub.2R'''', --NR'R'',
--NR'C(O)N''R''R''', --NR'C(NCN)NR''R''', --OR', aryl, heteroaryl,
arylalkyl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl;
R', R'' and R''' are independently hydrogen, lower alkyl, lower
alkenyl, aryl or arylalkyl, and R'''' is lower alkyl, lower
alkenyl, aryl or arylalkyl, or any two of R', R'', R''' or R''''
together with the atom to which they are attached form a 4 to 10
membered saturated, unsaturated, or partially saturated
heterocyclic ring, wherein any of said alkyl, alkenyl, aryl,
arylalkyl saturated, unsaturated, or partially saturated
heterocyclic rings are optionally substituted with one or more
groups independently selected from halogen, cyano, nitro,
trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido, aryl,
heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl, and
heterocyclylalkyl; R.sup.4 and R.sup.5 are independently hydrogen
or C.sub.1-C.sub.6 alkyl; R.sup.6 is trifluoromethyl,
C.sub.1-C.sub.10 alkyl, C.sub.3-C.sub.10 cycloalkyl, aryl,
arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, or
heterocyclylalkyl, wherein any of said alkyl, cycloalkyl, aryl,
arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl and
heterocyclylalkyl portions are optionally substituted with one or
more groups independently selected from oxo, halogen, cyano, nitro,
trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido,
--NR'SO.sub.2R'''', --SO.sub.2NR'R'', --C(O)R', --C(O)OR',
--OC(O)R', --NR'C(O)OR'''', --NR'C(O)R'', --C(O)NR'R'',
--SO.sub.2R'''', NR'R', --NR'C(O)NR''R'', --NR'C(NCN)NR''R''',
--OR', aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl,
and heterocyclylalkyl; W is heteroaryl, heterocyclyl,
--C(O)OR.sup.3, --C(O)NR.sup.3R.sup.4, --C(O)NR.sup.4OR.sup.3,
--C(O)R.sup.4OR.sup.3, --C(O)(C.sub.3-C.sub.10 cycloalkyl),
--C(O)(C.sub.1-C.sub.10 alkyl), --C(O)(aryl), --C(O)(heteroaryl),
--C(O)(heterocyclyl), or CR.sup.3OR.sup.3, wherein any of said
heteroaryl, heterocyclyl, --C(O)OR.sup.3, --C(O)NR.sup.3R.sup.4,
--C(O)NR.sup.4OR.sup.3, --C(O)R.sup.4OR.sup.3,
--C(O)(C.sub.3-C.sub.10 cycloalkyl), --C(O)(C.sub.1-C.sub.10alkyl),
--C(O)(aryl), --C(O)(heteroaryl), --C(O)(heterocyclyl) and
CR.sup.3OR.sup.3 are optionally substituted with one or more groups
independently selected from --NR.sup.3R.sup.4, --OR.sup.3,
--R.sup.2, C.sub.1-C.sub.10 alkyl, C.sub.2-C.sub.10 alkenyl, and
C.sub.2-C.sub.10 alkynyl, wherein any of said C.sub.1-C.sub.10
alkyl, C.sub.2-C.sub.10 alkenyl, and C.sub.2-C.sub.10 alkynyl are
optionally substituted with 1 or more groups independently selected
from --NR.sup.3R.sup.4 and --OR.sup.3; m is 0, 1, 2,3, 4 or 5; and
j is 1 or 2.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is a divisional application of U.S.
application Ser. No. 10/654,580, which is incorporated herein by
reference in its entirety.
BACKGROUND OF THE INVENTION
[0002] 1. Field of the Invention
[0003] This invention relates to a series of novel heterocyclic
compounds that are useful in the treatment of hyperproliferative
diseases, such as cancer and inflammation, in mammals. This
invention also relates to a method of using such compounds in the
treatment of hyperproliferative diseases in mammals, especially
humans, and to pharmaceutical compositions containing such
compounds.
[0004] 2. Description of the State of the Art
[0005] Cell signaling through growth factor receptors and protein
kinases is an important regulator of cell growth, proliferation and
differentiation. In normal cell growth, growth factors, through
receptor activation (i.e. PDGF or EGF and others), activate MAP
kinase pathways. One of the most important and most well understood
MAP kinase pathways involved in normal and uncontrolled cell growth
is the Ras/Raf kinase pathway. Active GTP-bound Ras results in the
activation and indirect phosphorylation of Raf kinase. Raf then
phosphorylates MEK1 and 2 on two serine residues (S218 and S222 for
MEK1 and S222 and S226 for MEK2) (Ahn et al., Methods in
Enzymology, 2001, 332, 417-431). Activated MEK then phosphorylates
its only known substrates, the MAP kinases, ERK1 and 2. ERK
phosphorylation by MEK occurs on Y204 and T202 for ERK1 and Y185
and T183 for ERK2 (Ahn et al., Methods in Enzymology, 2001, 332,
417-431). Phosphorylated ERK dimerizes and then translocates to the
nucleus where it accumulates (Khokhlatchev et al., Cell, 1998, 93,
605-615). In the nucleus, ERK is involved in several important
cellular functions, including but not limited to nuclear transport,
signal transduction, DNA repair, nucleosome assembly and
translocation, and mRNA processing and translation (Ahn et al.,
Molecular Cell, 2000, 6, 1343-1354). Overall, treatment of cells
with growth factors leads to the activation of ERK1 and 2 which
results in proliferation and, in some cases, differentiation (Lewis
et al., Adv. Cancer Res., 1998, 74, 49-139).
[0006] In proliferative diseases, genetic mutations and/or
overexpression of the growth factor receptors, downstream signaling
proteins, or protein kinases involved in the ERK kinase pathway
lead to uncontrolled cell proliferation and, eventually, tumor
formation. For example, some cancers contain mutations which result
in the continuous activation of this pathway due to continuous
production of growth factors. Other mutations can lead to defects
in the deactivation of the activated GTP-bound Ras complex, again
resulting in activation of the MAP kinase pathway. Mutated,
oncogenic forms of Ras are found in 50% of colon and >90%
pancreatic cancers as well as many others types of cancers (Kohl et
al., Science, 1993, 260, 1834-1837). Recently, bRaf mutations have
been identified in more than 60% of malignant melanoma (Davies, H.
et al., Nature, 2002, 417, 949-954). These mutations in bRaf result
in a constitutively active MAP kinase cascade. Studies of primary
tumor samples and cell lines have also shown constitutive or
overactivation of the MAP kinase pathway in cancers of pancreas,
colon, lung, ovary and kidney (Hoshino, R. et al., Oncogene, 1999,
18, 813-822). Hence, there is a strong correlation between cancers
and an overactive MAP kinase pathway resulting from genetic
mutations.
[0007] As constitutive or overactivation of MAP kinase cascade
plays a pivotal role in cell proliferation and differentiation,
inhibition of this pathway is believed to be beneficial in
hyperproliferative diseases. MEK is a key player in this pathway as
it is downstream of Ras and Raf. Additionally, it is an attractive
therapeutic target because the only known substrates for MEK
phosphorylation are the MAP kinases, ERK1 and 2. Inhibition of MEK
has been shown to have potential therapeutic benefit in several
studies. For example, small molecule MEK inhibitors have been shown
to inhibit human tumor growth in nude mouse xenografts,
(Sebolt-Leopold et al., Nature-Medicine, 1999, 5 (7), 810-816;
Trachet et al., AACR Apr. 6-10, 2002, Poster #5426; Tecle, H., IBC
2.sup.nd International Conference of Protein Kinases, Sep. 9-10,
2002), block static allodynia in animals (WO 01/05390 published
Jan. 25, 2001) and inhibit growth of acute myeloid leukemia cells
(Milella et al., J. Clin. Invest., 2001, 108 (6), 851-859).
[0008] Small molecule inhibitors of MEK have been disclosed. At
least thirteen patent applications have appeared in the last
several years: U.S. Pat. No. 5,525,625 filed Jan. 24, 1995; WO
98/43960 published Oct. 8, 1998; WO 99/01421 published Jan. 14,
1999; WO 99/01426 published Jan. 14, 1999; WO 00/41505 published
Jul. 20, 2000; WO 00/42002 published Jul. 20, 2000; WO 00/42003
published Jul. 20, 2000; WO 00/41994 published Jul. 20, 2000; WO
00/42022 published Jul. 20, 2000; WO 00/42029 published Jul. 20,
2000; WO 00/68201 published Nov. 16, 2000; WO 01/68619 published
Sep. 20, 2001; and WO 02/06213 published Jan. 24, 2002.
SUMMARY OF THE INVENTION
[0009] This invention provides for novel heterocyclic compounds,
and pharmaceutically acceptable salts and prodrugs thereof, that
are useful in the treatment of hyperproliferative diseases.
Specifically, one aspect of the present invention relates to
compounds of Formula I that act as MEK inhibitors. Also provided is
a method for treatment of cancer. Also provided are formulations
containing compounds of Formula I and methods of using the
compounds to treat a patient in need thereof. In addition, there
are described processes for preparing the inhibitory compounds of
Formula I.
[0010] Accordingly, the present invention provides compounds of the
Formula I: ##STR2##
[0011] and pharmaceutically accepted salts, prodrugs and solvates
thereof, where:
[0012] R.sup.1, R.sup.2, R.sup.7, R.sup.8, R.sup.9, and R.sup.10
are independently hydrogen, halogen, cyano, nitro, trifluoromethyl,
difluoromethoxy, trifluoromethoxy, azido, --OR.sup.3,
--C(O)R.sup.3, --C(O)OR.sup.3, NR.sup.4C(O)OR.sup.6,
--OC(O)R.sup.3, --NR.sup.4SO.sub.2R.sup.6,
--SO.sub.2NR.sup.3R.sup.4, --NR.sup.4C(O)R.sup.3,
--C(O)NR.sup.3R.sup.4, --NR.sup.5C(O)NR.sup.3R.sup.4,
--NR.sup.5C(NCN)NR.sup.3R.sup.4, --NR.sup.3R.sup.4,
C.sub.1-C.sub.10 alkyl, C.sub.2-C.sub.10 alkenyl, C.sub.2-C.sub.10
alkynyl, C.sub.3-C.sub.10 cycloalkyl, C.sub.3-C.sub.10
cycloalkylalkyl, --S(O).sub.j(C.sub.1-C.sub.6 alkyl),
--S(O).sub.j(CR.sup.4R.sup.5).sub.m-aryl, aryl, arylalkyl,
heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl,
--O(CR.sup.4R.sup.5).sub.m-aryl, --NR.sup.4
(CR.sup.4R.sup.5).sub.m-aryl,
--O(CR.sup.4R.sup.5).sub.m-heteroaryl,
--NR.sup.4(CR.sup.4R.sup.5).sub.m-heteroaryl,
--O(CR.sup.4R.sup.5).sub.m-heterocyclyl or
--NR.sup.4(CR.sup.4R.sup.5).sub.m-heterocyclyl, wherein any of said
alkyl, alkenyl, alkynyl, cycloalkyl, aryl, arylalkyl, heteroaryl,
heteroarylalkyl, heterocyclyl and heterocyclylalkyl portions are
optionally substituted with one or more groups independently
selected from oxo, halogen, cyano, nitro, trifluoromethyl,
difluoromethoxy, trifluoromethoxy, azido,
--NR.sup.4SO.sub.2R.sup.6, --SO.sub.2NR.sup.3R.sup.4,
--C(O)R.sup.3, --C(O)OR.sup.3, --OC(O)R.sup.3,
--NR.sup.4C(O)OR.sup.6, --NR.sup.4C(O)R.sup.3,
--C(O)NR.sup.3R.sup.4, --NR.sup.3R.sup.4,
--NR.sup.5C(O)NR.sup.3R.sup.4, --NR.sup.5C(NCN)NR.sup.3R.sup.4,
--OR.sup.3, aryl, heteroaryl, arylalkyl, heteroarylalkyl,
heterocyclyl, and heterocyclylalkyl;
[0013] R.sup.3 is hydrogen, trifluoromethyl, C.sub.1-C.sub.10
alkyl, C.sub.2-C.sub.10 alkenyl, C.sub.2-C.sub.10 alkynyl,
C.sub.3-C.sub.10 cycloalkyl, C.sub.3-C.sub.10 cycloalkylalkyl,
aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl,
heterocyclylalkyl, phosphate, or an amino acid residue, wherein any
of said alkyl, alkenyl, alkynyl, cycloalkyl, aryl, arylalkyl,
heteroaryl, heteroarylalkyl, heterocyclyl and heterocyclylalkyl
portions are optionally substituted with one or more groups
independently selected from oxo, halogen, cyano, nitro,
trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido,
--NR'SO.sub.2R'''', --SO.sub.2NR'R'', --C(O)R', C(O)OR', --OC(O)R',
--NR'C(O)OR'''', --NR'C(O)R'', --C(O)NR'R'', --SR', --S(O)R'''',
--SO.sub.2R'''', --NR'R'', --NR'C(O)NR''R''', --NR'C(NCN)NR''R''',
--OR', aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl,
and heterocyclylalkyl,
[0014] or R.sup.3 and R.sup.4 together with the atom to which they
are attached form a 4 to 10 membered carbocyclic, heteroaryl or
heterocyclic ring, wherein any of said carbocyclic, heteroaryl or
heterocyclic rings are optionally substituted with one or more
groups independently selected from halogen, cyano, nitro,
trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido,
--NR'SO.sub.2R'''', --SO.sub.2NR'R'', --C(O)R', --C(O)OR',
--OC(O)R', --NR'C(O)OR'''', --NR'C(O)R'', --C(O)NR'R'',
--SO.sub.2R'''', --NR'R'', --NR'C(O)NR''R''', --NR'C(CN)NR''R''',
--OR', aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl,
and heterocyclylalkyl;
[0015] R', R'' and R''' independently are hydrogen, lower alkyl,
lower alkenyl, aryl or arylalkyl, and
[0016] R'''' is lower alkyl, lower alkenyl, aryl or arylalkyl,
[0017] or any two of R', R'', R''' or R'''' together with the atom
to which they are attached form a 4 to 10 membered carbocyclic,
heteroaryl or heterocyclic ring, wherein any of said alkyl,
alkenyl, aryl, arylalkyl carbocyclic rings, heteroaryl rings or
heterocyclic rings are optionally substituted with one or more
groups independently selected from halogen, cyano, nitro,
trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido, aryl,
heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl, and
heterocyclylalkyl;
[0018] R.sup.4 and R.sup.5 independently are hydrogen or
C.sub.1-C.sub.6 alkyl, or
[0019] R.sup.4 and R.sup.5 together with the atom to which they are
attached form a 4 to 10 membered carbocyclic, heteroaryl or
heterocyclic ring, wherein said alkyl or any of said carbocyclic,
heteroaryl and heterocyclic rings are optionally substituted with
one or more groups independently selected from halogen, cyano,
nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido,
--NR'SO.sub.2R'''', --SO.sub.2NR'R'', --C(O)R'''', --C(O)OR',
--OC(O)R', --NR'C(O)OR'''', --NR'C(O)R'', --C(O)NR'R'',
--SO.sub.2R'''', --NR'R'', --NR'C(O)NR''R''', --NR'C(NCN)NR''R''',
--OR', aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl,
and heterocyclylalkyl;
[0020] R.sup.6 is trifluoromethyl, C.sub.1-C.sub.10 alkyl,
C.sub.3-C.sub.10 cycloalkyl, aryl, arylalkyl, heteroaryl,
heteroarylalkyl, heterocyclyl, or heterocyclylalkyl, wherein any of
said alkyl, cycloalkyl, aryl, arylalkyl, heteroaryl,
heteroarylalkyl, heterocyclyl and heterocyclylalkyl portions are
optionally substituted with one or more groups independently
selected from oxo, halogen, cyano, nitro, trifluoromethyl,
difluoromethoxy, trifluoromethoxy, azido, --NR'SO.sub.2R'''',
--SO.sub.2NR'R'', --C(O)R', --C(O)OR', --OC(O)R', --NR'C(O)OR'''',
--NR'C(O)R'', --C(O)NR'R'', --SO.sub.2R'''', --NR'R',
--NR'C(O)NR''R''', --NR'C(NCN)NR''R''', --OR', aryl, heteroaryl,
arylalkyl, heteroarylalkyl, heterocyclyl, and
heterocyclylalkyl;
[0021] W is heteroaryl, heterocyclyl, --C(O)OR.sup.3,
--C(O)NR.sup.3R.sup.4, --C(O)NR.sup.4OR.sup.3,
--C(O)R.sup.4OR.sup.3, --C(O)(C.sub.3-C.sub.10 cycloalkyl),
--C(O)(C.sub.1-C.sub.10alkyl), --C(O)(aryl), --C(O)(heteroaryl),
--C(O)(heterocyclyl), CR.sup.3OR.sup.3, or
--CONH(SO.sub.2)CH.sub.3, wherein any of said heteroaryl,
heterocyclyl, --C(O)OR.sup.3, --C(O)NR.sup.3R.sup.4,
--C(O)NR.sup.4OR.sup.3, --C(O)R.sup.4OR.sup.3,
--C(O)(C.sub.3-C.sub.10 cycloalkyl), --C(O)(C.sub.1-C.sub.10
alkyl), --C(O)(aryl), --C(O)(heteroaryl), --C(O)(heterocyclyl), and
CR.sup.3OR.sup.3 are optionally substituted with one or more groups
independently selected from --NR.sup.3R.sup.4, --OR.sup.3,
--R.sup.2, C.sub.1-C.sub.10 alkyl, C.sub.2-C.sub.10 alkenyl, and
C.sub.2-C.sub.10 alkynyl, wherein any of said C.sub.1-C.sub.10
alkyl, C.sub.2-C.sub.10 alkenyl, and C.sub.2-C.sub.10 alkynyl are
optionally substituted with 1 or more groups independently selected
from --NR.sup.3R.sup.4 and --OR.sup.3;
[0022] m is 0, 1, 2, 3, 4 or 5;
[0023] j is 1 or 2; and
[0024] Y is a linker.
[0025] In another embodiment, this invention relates to compounds
of the general Formula II: ##STR3##
[0026] where R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6,
R.sup.7, R.sup.8, R.sup.9, R.sup.10, R', R'', R''', R'''', W, Y, m
and j are as defined above, and
[0027] R.sup.11 is hydrogen, halogen, cyano, nitro,
trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido,
--OR.sup.3, --C(O)R.sup.3, --C(O)OR.sup.3, NR.sup.4C(O)OR.sup.6,
--OC(O)R.sup.3, --NR.sup.4SO.sub.2R.sup.6,
--SO.sub.2NR.sup.3R.sup.4, --NR.sup.4C(O)R.sup.3,
--C(O)NR.sup.3R.sup.4, --NR.sup.5C(O)NR.sup.3R.sup.4,
--NR.sup.5C(NCN)NR.sup.3R.sup.4, --NR.sup.3R.sup.4,
C.sub.1-C.sub.10 alkyl, C.sub.2-C.sub.10 alkenyl, C.sub.2-C.sub.10
alkynyl, C.sub.3-C.sub.10 cycloalkyl, C.sub.3-C.sub.10
cycloalkylalkyl, --S(O).sub.j(C.sub.1-C.sub.6 alkyl),
--S(O).sub.j(CR.sup.4R.sup.5).sub.m-aryl, aryl, arylalkyl,
heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl,
--O(CR.sup.4R.sup.5).sub.m-aryl,
--NR.sup.4(CR.sup.4R.sup.5).sub.m-aryl,
--O(CR.sup.4R.sup.5).sub.m-heteroaryl,
--NR.sup.4(CR.sup.4R.sup.5).sub.m-heteroaryl,
--O(CR.sup.4R.sup.5).sub.m-heterocyclyl or
--NR.sup.4(CR.sup.4R.sup.5).sub.m-heterocyclyl, wherein any of said
alkyl, alkenyl, alkynyl, cycloalkyl, aryl, arylalkyl, heteroaryl,
heteroarylalkyl, heterocyclyl and heterocyclylalkyl portions are
optionally substituted with one or more groups independently
selected from oxo, halogen, cyano, nitro, trifluoromethyl,
difluoromethoxy, trifluoromethoxy, azido,
--NR.sup.4SO.sub.2R.sup.6, --SO.sub.2NR.sup.3R.sup.4,
--C(O)R.sup.3, --C(O)OR.sup.3, --OC(O)R.sup.3,
--NR.sup.4C(O)OR.sup.6, --NR.sup.4C(O)R.sup.3,
--C(O)NR.sup.3R.sup.4, --NR.sup.3R.sup.4,
--NR.sup.5C(O)NR.sup.3R.sup.4, --NR.sup.5C(NCN)NR.sup.3R.sup.4,
--OR.sup.3 aryl, heteroaryl, arylalkyl, heteroarylalkyl,
heterocyclyl, and heterocyclylalkyl.
[0028] In another embodiment, this invention relates to compounds
of the general Formula III: ##STR4##
[0029] where R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6,
R.sup.7, R.sup.8, R.sup.9, R.sup.10, R', R'', R''', R'''', W, Y, m
and j are as defined above.
[0030] In another embodiment, this invention relates to compounds
of the general Formula IV: ##STR5##
[0031] where R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6,
R.sup.7, R.sup.8, R.sup.9, R.sup.10, R', R'', R'''', R'''', W, Y, m
and j are as defined above.
[0032] In another embodiment, this invention relates to compounds
of the general Formula V: ##STR6##
[0033] where R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6,
R.sup.7, R.sup.8, R.sup.9, R.sup.10, R.sup.11, R', R'', R''',
R'''', W, Y, m and j are as defined above.
[0034] In a further aspect the present invention provides
compositions that inhibit MEK comprising compounds of Formulas
I-V.
[0035] The invention is also directed to pharmaceutically
acceptable prodrugs, pharmaceutically active metabolites, and
pharmaceutically acceptable salts of compounds of Formula I-V.
Methods of making the compounds of Formula I-V are also
described.
[0036] In a further aspect the present invention provides a method
of using the compounds of this invention to treat diseases or
medical conditions mediated by MEK. For example, this invention
provides a method for treatment of a hyperproliferative disorder in
a mammal comprising administrating to said mammal one or more
compounds of Formulas I-V or a pharmaceutically acceptable salt or
prodrug thereof in an amount effective to treat said
hyperproliferative disorder.
[0037] In a further aspect the present invention provides treating
or preventing an MEK-mediated condition, comprising administering
to a human or animal in need thereof a pharmaceutical composition
comprising a compound of Formula I-V or a
pharmaceutically-acceptable salt or in vivo cleavable prodrug
thereof in an amount effective to treat or prevent said
MEK-mediated condition.
[0038] The inventive compounds may further be used advantageously
in combination with other known therapeutic agents.
[0039] The invention also relates to pharmaceutical compositions
comprising an effective amount of an agent selected from compounds
of Formulas I-V or a pharmaceutically acceptable prodrug,
pharmaceutically active metabolite, or pharmaceutically acceptable
salt thereof.
[0040] Additional advantages and novel features of this invention
shall be set forth in part in the description that follows, and in
part will become apparent to those skilled in the art upon
examination of the following specification or may be learned by the
practice of the invention. The advantages of the invention may be
realized and attained by means of the instrumentalities,
combinations, compositions, and methods particularly pointed out in
the appended claims.
BRIEF DESCRIPTION OF THE FIGURES
[0041] The accompanying drawings, which are incorporated herein and
form a part of the specification, illustrate non-limiting
embodiments of the present invention, and together with the
description, serve to explain the principles of the invention.
[0042] In the Figures:
[0043] FIG. 1 shows a reaction scheme for the synthesis of compound
10a.
[0044] FIG. 2 shows a reaction scheme for the synthesis of compound
12a.
[0045] FIG. 3 shows a reaction scheme for the synthesis of compound
13a.
[0046] FIG. 4 shows a reaction scheme for the synthesis of compound
12b.
[0047] FIG. 5 shows a reaction scheme for the synthesis of compound
19.
[0048] FIG. 6 shows a reaction scheme for the synthesis of compound
21.
[0049] FIG. 7 shows a reaction scheme for the synthesis of compound
30.
[0050] FIG. 8 shows a reaction scheme for the synthesis of compound
31.
[0051] FIG. 9 shows a reaction scheme for the synthesis of compound
33a.
[0052] FIG. 10 shows a reaction scheme for the synthesis of
compounds 36-38.
[0053] FIG. 11 shows a reaction scheme for the synthesis of
compound 39.
[0054] FIG. 12 shows a reaction scheme for the synthesis of
compounds 44a and 44b.
[0055] FIG. 13 shows a reaction scheme for the synthesis of
compounds 47a and 47b.
[0056] FIG. 14 shows a reaction scheme for the synthesis of
compounds 53a, 53b and 54a.
[0057] FIG. 15 shows a reaction scheme for the synthesis of
compounds 57a and 57b.
[0058] FIG. 16 shows a reaction scheme for the synthesis of
compound 63.
[0059] FIG. 17 shows a reaction scheme for the synthesis of
compounds 73a and 73b.
[0060] FIG. 18 shows a reaction scheme for the synthesis of
compound 74.
DETAILED DESCRIPTION OF THE INVENTION
[0061] The inventive compounds of the Formulas I-V and the
pharmaceutically acceptable salts and prodrugs thereof of this
invention are useful in the treatment of hyperproliferative
diseases. Specifically, one aspect the present invention relates to
compounds of Formula I-V that act as MEK inhibitors. In general,
one aspect of the invention relates to compounds having the general
Formula I: ##STR7##
[0062] and pharmaceutically accepted salts, prodrugs and solvates
thereof, where:
[0063] R.sup.1, R.sup.2, R.sup.7, R.sup.8, R.sup.9, and R.sup.10
are independently hydrogen, halogen, cyano, nitro, trifluoromethyl,
difluoromethoxy, trifluoromethoxy, azido, --OR.sup.3,
--C(O)R.sup.3, --C(O)OR.sup.3, NR'C(O)OR.sup.6, --OC(O)R.sup.3,
--NR.sup.4SO.sub.2R.sup.6, --SO.sub.2NR.sup.3R.sup.4,
--NR.sup.4C(O)R.sup.3, --C(O)NR.sup.3R.sup.4,
--NR.sup.5C(O)NR.sup.3R.sup.4, --NR.sup.5C(CN)NR.sup.3R.sup.4,
--NR.sup.3R.sup.4, C.sub.1-C.sub.10 alkyl, C.sub.2-C.sub.10
alkenyl, C.sub.2-C.sub.0 alkynyl, C.sub.3-C.sub.10 cycloalkyl,
C.sub.3-C.sub.10 cycloalkylalkyl, --S(O).sub.j(C.sub.1-C.sub.6
alkyl), --S(O).sub.j(CR.sup.4R.sup.5).sub.m-aryl, aryl, arylalkyl,
heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl,
--O(CR.sup.4R.sup.5).sub.m-aryl, --NR.sup.4
(CR.sup.4R.sup.5).sub.m-aryl,
--O(CR.sup.4R.sup.5).sub.m-heteroaryl,
--NR.sup.4(CR.sup.4R.sup.5).sub.m-heteroaryl,
--O(CR.sup.4R.sup.5).sub.m-heterocyclyl or
--NR.sup.4(CR.sup.4R.sup.5).sub.m-heterocyclyl, wherein any of said
alkyl, alkenyl, alkynyl, cycloalkyl, aryl, arylalkyl, heteroaryl,
heteroarylalkyl, heterocyclyl and heterocyclylalkyl portions are
optionally substituted with one or more groups independently
selected from oxo, halogen, cyano, nitro, trifluoromethyl,
difluoromethoxy, trifluoromethoxy, azido,
--NR.sup.4SO.sub.2R.sup.6, --SO.sub.2NR.sup.3R.sup.4,
--C(O)R.sup.3, --C(O)OR.sup.3, --OC(O)R.sup.3,
--NR.sup.4C(O)OR.sup.6, --NR.sup.4C(O)R.sup.3,
--C(O)NR.sup.3R.sup.4, --NR.sup.3R.sup.4,
--NR.sup.5C(O)NR.sup.3R.sup.4, --NR.sup.5C(NCN)NR.sup.3R.sup.4,
--OR.sup.3, aryl, heteroaryl, arylalkyl, heteroarylalkyl,
heterocyclyl, and heterocyclylalkyl;
[0064] R.sup.3 is hydrogen, trifluoromethyl, C.sub.1-C.sub.10
alkyl, C.sub.2-C.sub.10 alkenyl, C.sub.2-C.sub.10 alkynyl,
C.sub.3-C.sub.10 cycloalkyl, C.sub.3-C.sub.10 cycloalkylalkyl,
aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl,
heterocyclylalkyl, phosphate, or an amino acid residue, wherein any
of said alkyl, alkenyl, alkynyl, cycloalkyl, aryl, arylalkyl,
heteroaryl, heteroarylalkyl, heterocyclyl and heterocyclylalkyl
portions are optionally substituted with one or more groups
independently selected from oxo, halogen, cyano, nitro,
trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido,
--NR'SO.sub.2R'''', --SO.sub.2NR'R'', --C(O)R', C(O)OR', --OC(O)R',
--NR'C(O)OR'''', --NR'C(O)R'', --C(O)NR'R'', --SR', --S(O)R'''',
--SO.sub.2R'''', --NR'R'', --NR'C(O)NR''R'''', --NR'C(NCN)NR''R''',
--OR, aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl,
and heterocyclylalkyl,
[0065] or R.sup.3 and R.sup.4 together with the atom to which they
are attached form a 4 to 10 membered carbocyclic, heteroaryl or
heterocyclic ring, wherein any of said carbocyclic, heteroaryl or
heterocyclic rings are optionally substituted with one or more
groups independently selected from halogen, cyano, nitro,
trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido,
--NR'SO.sub.2R'''', --SO.sub.2NR'R'', --C(O)R', --C(O)OR',
--OC(O)R', --NR'C(O)OR'''', --NR'C(O)R'', --C(O)NR'R'',
--SO.sub.2R'''', --NR'R'', --NR'C(O)NR''R''', --NR'C(NCN)NR''R''',
--OR', aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl,
and heterocyclylalkyl;
[0066] R', R'' and R''' independently are hydrogen, lower alkyl,
lower alkenyl, aryl or arylalkyl, and
[0067] R'''' is lower alkyl, lower alkenyl, aryl or arylalkyl,
[0068] or any two of R', R'', R''' or R'''' together with the atom
to which they are attached form a 4 to 10 membered carbocyclic,
heteroaryl or heterocyclic ring, wherein any of said alkyl,
alkenyl, aryl, arylalkyl carbocyclic rings, heteroaryl rings or
heterocyclic rings are optionally substituted with one or more
groups independently selected from halogen, cyano, nitro,
trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido, aryl,
heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl, and
heterocyclylalkyl;
[0069] R.sup.4 and R.sup.5 independently are hydrogen or
C.sub.1-C.sub.6 alkyl, or
[0070] R.sup.4 and R.sup.5 together with the atom to which they are
attached form a 4 to 10 membered carbocyclic, heteroaryl or
heterocyclic ring, wherein said alkyl or any of said carbocyclic,
heteroaryl and heterocyclic rings are optionally substituted with
one or more groups independently selected from halogen, cyano,
nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido,
--NR'SO.sub.2R'''', --SO.sub.2NR'R'', --C(O)R', --C(O)OR',
--OC(O)R', --NR'C(O)OR'''', --NR'C(O)R'', --C(O)NR'R'',
--SO.sub.2R'''', --NR'R'', --NR'C(O)NR''R''', --NR'C(NCN)NR''R''',
--OR', aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl,
and heterocyclylalkyl;
[0071] R.sup.6 is trifluoromethyl, C.sub.1-C.sub.10 alkyl,
C.sub.3-C.sub.10 cycloalkyl, aryl, arylalkyl, heteroaryl,
heteroarylalkyl, heterocyclyl, or heterocyclylalkyl, wherein any of
said alkyl, cycloalkyl, aryl, arylalkyl, heteroaryl,
heteroarylalkyl, heterocyclyl and heterocyclylalkyl portions are
optionally substituted with one or more groups independently
selected from oxo, halogen, cyano, nitro, trifluoromethyl,
difluoromethoxy, trifluoromethoxy, azido, --NR'SO.sub.2R'''',
--SO.sub.2NR'R'', --C(O)R', --C(O)OR', --OC(O)R', --NR'C(O)OR'''',
--NR'C(O)R'', --C(O)NR'R'', --SO.sub.2R'''', --NR'R',
--NR'C(O)NR''R'', --NR'C(NCN)NR''R'', --OR, aryl, heteroaryl,
arylalkyl, heteroarylalkyl, heterocyclyl, and
heterocyclylalkyl;
[0072] heteroaryl, heterocyclyl, --C(O)OR.sup.3,
--C(O)NR.sup.3R.sup.4, --C(O)NR.sup.4OR.sup.3,
--C(O)R.sup.4OR.sup.3, --C(O)(C.sub.3-C.sub.10 cycloalkyl),
--C(O)(C.sub.1-C.sub.10 alkyl), --C(O)(aryl), --C(O)(heteroaryl),
--C(O)(heterocyclyl), CR.sup.3OR.sup.3, or
--CONH(SO.sub.2)CH.sub.3, wherein any of said heteroaryl,
heterocyclyl, --C(O)OR.sup.3, --C(O)NR.sup.3R.sup.4,
--C(O)NR.sup.4OR.sup.3, --C(O)R.sup.4OR.sup.3,
--C(O)(C.sub.3-C.sub.10 cycloalkyl), --C(O)(C.sub.1-C.sub.10alkyl),
--C(O)(aryl), --C(O)(heteroaryl), --C(O)(heterocyclyl), and
CR.sup.3OR.sup.3 are optionally substituted with one or more groups
independently selected from --NR.sup.3R.sup.4, --OR.sup.3,
--R.sup.2, C.sub.1-C.sub.10 alkyl, C.sub.2-C.sub.10 alkenyl, and
C.sub.2-C.sub.10 alkynyl, wherein any of said C.sub.1-C.sub.10
alkyl, C.sub.2-C.sub.10 alkenyl, and C.sub.2-C.sub.10 alkynyl are
optionally substituted with 1 or more groups independently selected
from --NR.sup.3R.sup.4 and --OR.sup.3;
[0073] m is 0, 1, 2, 3, 4 or 5;
[0074] j is 1 or 2; and
[0075] Y is a linker.
[0076] A "linker" is a molecular entity that connects two or more
molecular entities through covalent or non-covalent interactions.
Examples of linkers include, but are not limited to, NR.sup.3, O,
S, S(O), S(O).sub.2, C(O), and CH.sub.2, where R.sup.3 is as
defined above.
[0077] FIGS. 1-6 show non-limiting examples of the synthesis of
compounds of this invention having the general Formula I.
[0078] In addition to compounds of the general Formula I, this
invention further includes compounds of the general Formula II:
##STR8##
[0079] where R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6,
R.sup.7, R.sup.8, R.sup.9, R.sup.10, R', R'', R''', R'''', W, Y, m
and j are as defined above, and
[0080] R.sup.11 is hydrogen, halogen, cyano, nitro,
trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido,
--OR.sup.3, --C(O)R.sup.3, --C(O)OR.sup.3, NR.sup.4C(O)OR.sup.6,
--OC(O)R.sup.3, --NR.sup.4SO.sub.2R.sup.6,
--SO.sub.2NR.sup.3R.sup.4, --NR.sup.4C(O)R.sup.3,
--C(O)NR.sup.3R.sup.4, --NR.sup.5C(O)NR.sup.3R.sup.4,
--NR.sup.5C(NCN)NR.sup.3R.sup.4, --NR.sup.3R.sup.4,
C.sub.1-C.sub.10 alkyl, C.sub.2-C.sub.10 alkenyl, C.sub.2-C.sub.10
alkynyl, C.sub.3-C.sub.10 cycloalkyl, C.sub.3-C.sub.10
cycloalkylalkyl, --S(O).sub.j(C.sub.1-C.sub.6 alkyl),
--S(O).sub.j(CR.sup.4R.sup.5).sub.m-aryl, aryl, arylalkyl,
heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl,
--O(CR.sup.4R.sup.5).sub.m-aryl, --NR.sup.4(CR.sup.4R.sup.5)
m-aryl, --O(CR.sup.4R.sup.5).sub.m-heteroaryl,
--NR.sup.4(CR.sup.4R.sup.5).sub.m-heteroaryl,
--O(CR.sup.4R.sup.5).sub.m-heterocyclyl or
--NR.sup.4(CR.sup.4R.sup.5).sub.m-heterocyclyl, wherein any of said
alkyl, alkenyl, alkynyl, cycloalkyl, aryl, arylalkyl, heteroaryl,
heteroarylalkyl, heterocyclyl and heterocyclylalkyl portions are
optionally substituted with one or more groups independently
selected from oxo, halogen, cyano, nitro, trifluoromethyl,
difluoromethoxy, trifluoromethoxy, azido,
--NR.sup.4SO.sub.2R.sup.6, --SO.sub.2NR.sup.3R.sup.4,
--C(O)R.sup.3, --C(O)OR.sup.3, --OC(O)R.sup.3,
--NR.sup.4C(O)OR.sup.6, --NR.sup.4C(O)R.sup.3,
--C(O)NR.sup.3R.sup.4, --NR.sup.3R.sup.4,
--NR.sup.5C(O)NR.sup.3R.sup.4, --NR.sup.5C(NCN)NR.sup.3R.sup.4,
--OR.sup.3, aryl, heteroaryl, arylalkyl, heteroarylalkyl,
heterocyclyl, and heterocyclylalkyl.
[0081] FIGS. 7-13 show non-limiting examples of the synthesis of
compounds of this invention having the general Formula II. FIG. 18
shows the synthesis of a phosphate prodrug of a compound having the
general Formula II.
[0082] In another embodiment, this invention relates to compounds
of the general Formula III: ##STR9##
[0083] where R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6,
R.sup.7, R.sup.8, R.sup.9, R.sup.10, R', R', R'''', R'''', W, Y, m
and j are as defined above.
[0084] FIG. 14 shows a non-limiting example of the synthesis of
compounds of this invention having the general Formula III.
[0085] In another embodiment, this invention relates to compounds
of the general Formula IV: ##STR10##
[0086] where R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6,
R.sup.7, R.sup.8, R.sup.9, R.sup.10, R', R'', R''', R'''', W, Y, m
and j are as defined above.
[0087] FIG. 15 shows a non-limiting example of the synthesis of
compounds of this invention having the general Formula IV.
[0088] In another embodiment, this invention relates to compounds
of the general Formula V: ##STR11##
[0089] where R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6,
R.sup.7, R.sup.8, R.sup.9, R.sup.10, R.sup.11, R', R'', R''',
R'''', W, Y, m and j are as defined above. FIGS. 16-17 show
non-limiting examples of the synthesis of compounds of this
invention having the general Formula V.
[0090] The terms "C.sub.1-C.sub.10 alkyl", "alkyl" and "lower
alkyl" as used herein refer to a saturated linear or branched-chain
monovalent hydrocarbon radical having one to ten carbon atoms,
wherein the alkyl radical may be optionally substituted
independently with one or more substituents described below.
Examples of alkyl groups include, but are not limited to, methyl,
ethyl, n-propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl,
pentyl, isopentyl, neopentyl, tert-pentyl, hexyl, 2-hexyl, 3-hexyl,
3-methylpentyl, heptyl, octyl, and the like.
[0091] The terms "C.sub.2-C.sub.10 alkenyl", "lower alkenyl" and
"alkenyl" refer to linear or branched-chain monovalent hydrocarbon
radical having two to 10 carbon atoms and at least one double bond,
and include, but is not limited to, ethenyl, propenyl,
1-but-3-enyl, 1-pent-3-enyl, 1-hex-5-enyl and the like, wherein the
alkenyl radical may be optionally substituted independently with
one or more substituents described herein, and includes radicals
having "cis" and "trans" orientations, or alternatively, "E" and
"Z" orientations.
[0092] The terms "C.sub.2-C.sub.10 alkynyl," "lower alkynyl" and
"alkynyl" refer to a linear or branched monovalent hydrocarbon
radical of two to twelve carbon atoms containing at least one
triple bond. Examples include, but are not limited to, ethynyl,
propynyl, butynyl, pentyn-2-yl and the like, wherein the alkynyl
radical may be optionally substituted independently with one or
more substituents described herein.
[0093] The term "allyl" refers to a radical having the formula
RC.dbd.CHCHR, wherein R is alkyl, alkenyl, alkynyl, cycloalkyl,
heterocycloalkyl, aryl, heteroaryl, or any substituent as defined
herein, wherein the allyl may be optionally substituted
independently with one or more substituents described herein.
[0094] The terms "carbocycle," "carbocyclyl," "cycloalkyl" or
"C.sub.3-C.sub.10 cycloalkyl" refer to saturated or partially
unsaturated cyclic hydrocarbon radical having from three to ten
carbon atoms. The term "cycloalkyl" includes monocyclic and
polycyclic (e.g., bicyclic and tricyclic) cycloalkyl structures,
wherein the polycyclic structures optionally include a saturated or
partially unsaturated cycloalkyl fused to a saturated or partially
unsaturated cycloalkyl or heterocycloalkyl ring or an aryl or
heteroaryl ring. Examples of cycloalkyl groups include, but are not
limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,
cycloheptyl, and the like. The cycloalkyl may be optionally
substituted independently in one or more substitutable positions
with various groups. For example, such cycloalkyl groups may be
optionally substituted with, for example, C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.6 alkoxy, halogen, hydroxy, cyano, nitro, amino,
mono(C.sub.1-C.sub.6)alkylamino, di(C.sub.1-C.sub.6)alkylamino,
C.sub.2-C.sub.6alkenyl, C.sub.2-C.sub.6alkynyl, C.sub.1-C.sub.6
haloalkyl, C.sub.1-C.sub.6 haloalkoxy, amino(C.sub.1-C.sub.6)alkyl,
mono(C.sub.1-C.sub.6)alkylamino(C.sub.1-C.sub.6)alkyl or
di(C.sub.1-C.sub.6)alkylamino(C.sub.1-C.sub.6)alkyl.
[0095] The term "heteroalkyl" refers to saturated linear or
branched-chain monovalent hydrocarbon radical of one to twelve
carbon atoms, wherein at least one of the carbon atoms is replaced
with a heteroatom selected from N, O, or S, and wherein the radical
may be a carbon radical or heteroatom radical (i.e., the heteroatom
may appear in the middle or at the end of the radical). The
heteroalkyl radical may be optionally substituted independently
with one or more substituents described herein. The term
"heteroalkyl" encompasses alkoxy and heteroalkoxy radicals.
[0096] The terms "heterocycloalkyl," "heterocycle" or "hetercyclyl"
refer to a saturated or partially unsaturated carbocyclic radical
of 3 to 8 ring atoms in which at least one ring atom is a
heteroatom selected from nitrogen, oxygen and sulfur, the remaining
ring atoms being C, where one or more ring atoms may be optionally
substituted independently with one or more substituent described
below. The radical may be a carbon radical or heteroatom radical.
The term further includes fused ring systems which include a
heterocycle fused to an aromatic group. "Heterocycloalkyl" also
includes radicals where heterocycle radicals are fused with
aromatic or heteroaromatic rings. Examples of heterocycloalkyl
rings include, but are not limited to, pyrrolidinyl,
tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl,
tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl,
piperidino, morpholino, thiomorpholino, thioxanyl, piperazinyl,
homopiperazinyl, azetidinyl, oxetanyl, thietanyl, homopiperidinyl,
oxepanyl, thiepanyl, oxazepinyl, diazepinyl, thiazepinyl,
1,2,3,6-tetrahydropyridinyl, 2-pyrrolinyl, 3-pyrrolinyl, indolinyl,
2H-pyranyl, 4H-pyranyl, dioxanyl, 1,3-dioxolanyl, pyrazolinyl,
dithianyl, dithiolanyl, dihydropyranyl, dihydrothienyl,
dihydrofuranyl, pyrazolidinylimidazolinyl, imidazolidinyl,
3-azabicyco[3.1.0]hexanyl, 3-azabicyclo[4.1.0]heptanyl,
azabicyclo[2.2.2]hexanyl, 3H-indolyl and quinolizinyl. Spiro
moieties are also included within the scope of this definition. The
foregoing groups, as derived from the groups listed above, may be
C-attached or N-attached where such is possible. For instance, a
group derived from pyrrole may be pyrrol-1-yl (N-attached) or
pyrrol-3-yl (C-attached). Further, a group derived from imidazole
may be imidazol-1-yl (N-attached) or imidazol-3-yl (C-attached). An
example of a heterocyclic group wherein 2 ring carbon atoms are
substituted with oxo (.dbd.O) moieties is
1,1-dioxo-thiomorpholinyl. The heterocycle groups herein are
unsubstituted or, as specified, substituted in one or more
substitutable positions with various groups. For example, such
heterocycle groups may be optionally substituted with, for example,
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy, halogen, hydroxy,
cyano, nitro, amino, mono(C.sub.1-C.sub.6)alkylamino,
di(C.sub.1-C.sub.6)alkylamino, C.sub.2-C.sub.6alkenyl,
C.sub.2-C.sub.6alkynyl, C.sub.1-C.sub.6 haloalkyl, C.sub.1-C.sub.6
haloalkoxy, amino(C.sub.1-C.sub.6)alkyl,
mono(C.sub.1-C.sub.6)alkylamino(C.sub.1-C.sub.6)alkyl or
di(C.sub.1-C.sub.6)alkylamino(C.sub.1-C.sub.6)alkyl.
[0097] The term "aryl" refers to a monovalent aromatic carbocyclic
radical having a single ring (e.g., phenyl), multiple rings (e.g.,
biphenyl), or multiple condensed rings in which at least one is
aromatic, (e.g., 1,2,3,4-tetrahydronaphthyl, naphthyl), which is
optionally mono-, di-, or trisubstituted with, e.g., halogen, lower
alkyl, lower alkoxy, trifluoromethyl, aryl, heteroaryl, and
hydroxy.
[0098] The term "heteroaryl" refers to a monovalent aromatic
radical of 5-, 6-, or 7-membered rings which includes fused ring
systems (at least one of which is aromatic) of 5-10 atoms
containing at least one and up to four heteroatoms selected from
nitrogen, oxygen, or sulfur. Examples of heteroaryl groups are
pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl,
pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl,
oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl,
indolyl, benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl,
indolizinyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl,
pteridinyl, purinyl, oxadiazolyl, triazolyl, thiadiazolyl,
thiadiazolyl, furazanyl, benzofurazanyl, benzothiophenyl,
benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl,
naphthyridinyl, and furopyridinyl. Spiro moieties are also included
within the scope of this definition. Heteroaryl groups are
optionally mono-, di-, or trisubstituted with, e.g., halogen, lower
alkyl, lower alkoxy, haloalkyl, aryl, heteroaryl, and hydroxy.
[0099] The term "halogen" represents fluorine, bromine, chlorine,
and iodine.
[0100] The term "arylalkyl" means an alkyl moiety (as defined
above) substituted with one or more aryl moiety (also as defined
above). More preferred arylalkyl radicals are
aryl-C.sub.1-3-alkyls. Examples include benzyl, phenylethyl, and
the like.
[0101] The term "heteroarylalkyl" means an alkyl moiety (as defined
above) substituted with a heteroaryl moiety (also as defined
above). More preferred heteroarylalkyl radicals are 5- or
6-membered heteroaryl-C.sub.1-3-alkyls. Examples include
oxazolylmethyl, pyridylethyl and the like.
[0102] The term "heterocyclylalkyl" means an alkyl moiety (as
defined above) substituted with a heterocyclyl moiety (also defined
above). More preferred heterocyclylalkyl radicals are 5- or
6-membered heterocyclyl-C.sub.1-3-alkyls. Examples include
tetrahydropyranylmethyl.
[0103] The term "cycloalkylalkyl" means an alkyl moiety (as defined
above) substituted with a cycloalkyl moiety (also defined above).
More preferred heterocyclyl radicals are 5- or 6-membered
cycloalkyl-C.sub.1-3-alkyls. Examples include
cyclopropylmethyl.
[0104] The term "Me" means methyl, "Et" means ethyl, "Bu" means
butyl and "Ac" means acetyl.
[0105] In general, the various moieties or functional groups of the
compounds of Formulas I-V may be optionally substituted by one or
more substituents. Examples of substituents suitable for purposes
of this invention include, but are not limited to, oxo, halogen,
cyano, nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy,
azido, --NR.sup.4SO.sub.2R.sup.6, --SO.sub.2NR.sup.3R.sup.4,
--C(O)R.sup.3, --C(O)OR.sup.3, --OC(O)R.sup.3,
--NR.sup.4C(O)OR.sup.6, --NR.sup.4C(O)R.sup.3,
--C(O)NR.sup.3R.sup.4, --NR.sup.3R.sup.4,
--NR.sup.5C(O)NR.sup.3R.sup.4, --NR.sup.5C(NCN)NR.sup.3R.sup.4,
--OR.sup.3, aryl, heteroaryl, arylalkyl, heteroarylalkyl,
heterocyclyl, and heterocyclylalkyl, where R.sup.3, R.sup.4,
R.sup.5 and R.sup.6 are as defined herein.
[0106] It is to be understood that in instances where two or more
radicals are used in succession to define a substituent attached to
a structure, the first named radical is considered to be terminal
and the last named radical is considered to be attached to the
structure in question. Thus, for example, the radical arylalkyl is
attached to the structure in question by the alkyl group.
[0107] In the compounds of the present invention, where terms such
as (CR.sup.4R.sup.5).sub.m or (CR.sup.4R.sup.5).sub.t are used,
R.sup.4 and R.sup.5 may vary with each iteration of m or t above 1.
For instance, where m or t is 2, the terms (CR.sup.4R.sup.5).sub.m
or (CR.sup.4R.sup.5), may equal --CH.sub.2CH.sub.2-- or
--CH(CH.sub.3)C(CH.sub.2CH.sub.3)(CH.sub.2CH.sub.2CH.sub.3)-- or
any number of similar moieties falling within the scope of the
definitions of R.sup.4 and R.sup.5.
[0108] The compounds of this invention may possess one or more
asymmetric centers; such compounds can therefore be produced as
individual (R)- or (S)-stereoisomers or as mixtures thereof. Unless
indicated otherwise, the description or naming of a particular
compound in the specification and claims is intended to include
both individual enantiomers, diastereomers mixtures, racemic or
otherwise, thereof. Accordingly, this invention also includes all
such isomers, including diastereomeric mixtures and pure
enantiomers of the Formulas I-V. Diastereomeric mixtures can be
separated into their individual diastereomers on the basis of their
physical chemical differences by methods known to those skilled in
the art, for example, by chromatography or fractional
crystallization. Enantiomers can be separated by converting the
enantiomer mixture into a diastereomeric mixture by reaction with
an appropriate optically active compound (e.g., alcohol),
separating the diastereomers and converting (e.g., hydrolyzing) the
individual diastereomers to the corresponding pure enantiomers. The
methods for the determination of stereochemistry and the separation
of stereoisomers are well known in the art (see discussion in
Chapter 4 of "Advanced Organic Chemistry", 4th edition, J. March,
John Wiley and Sons, New York, 1992).
[0109] This invention also encompasses pharmaceutical compositions
containing a compound of Formula I-V and methods of treating
proliferative disorders, or abnormal cell growth, by administering
compounds of the present invention. Compounds of the present
invention having free amino, amido, hydroxy or carboxylic groups
can be converted into pharmaceutically acceptable prodrugs.
[0110] A "pharmaceutically acceptable prodrug" is a compound that
may be converted under physiological conditions or by solvolysis to
the specified compound or to a pharmaceutically acceptable salt of
such compound. Prodrugs include compounds wherein an amino acid
residue, or a polypeptide chain of two or more (e.g., two, three or
four) amino acid residues is covalently joined through an amide or
ester bond to a free amino, hydroxy or carboxylic acid group of
compounds of the present invention. The amino acid residues include
but are not limited to the 20 naturally occurring amino acids
commonly designated by three letter symbols and also includes
4-hydroxyproline, hydroxylysine, demosine, isodemosine,
3-methylhistidine, norvaline, beta-alanine, gamma-aminobutyric
acid, cirtulline, homocysteine, homoserine, ornithine and
methionine sulfone. One preferred prodrug of this invention is a
compound of Formula I-V covalently joined to a phosphate residue.
Another preferred prodrug of this invention is a compound of
Formula I-V covalently joined to a valine residue.
[0111] Additional types of prodrugs are also encompassed. For
instance, free carboxyl groups can be derivatized as amides or
alkyl esters. Free hydroxy groups may be derivatized using groups
including but not limited to phosphate esters, hemisuccinates,
dimethylaminoacetates, and phosphoryloxymethyloxycarbonyls, as
outlined in Advanced Drug Delivery Reviews, 1996, 19, 115.
Carbamate prodrugs of hydroxy and amino groups are also included,
as are carbonate prodrugs, sulfonate esters and sulfate esters of
hydroxy groups. Derivatization of hydroxy groups as (acyloxy)methyl
and (acyloxy)ethyl ethers wherein the acyl group may be an alkyl
ester, optionally substituted with groups including but not limited
to ether, amine and carboxylic acid functionalities, or where the
acyl group is an amino acid ester as described above, are also
encompassed. Prodrugs of this type are described in J. Med. Chem.,
1996, 39, 10. Free amines can also be derivatized as amides,
sulfonamides or phosphonamides. All of these prodrug moieties may
incorporate groups including but not limited to ether, amine and
carboxylic acid functionalities.
[0112] In addition, the invention also includes solvates,
pharmaceutically active metabolites, and pharmaceutically
acceptable salts of compounds of Formulas I-V.
[0113] The term "solvate" refers to an aggregate of a molecule with
one or more solvent molecules.
[0114] A "pharmaceutically active metabolite" is a
pharmacologically active product produced through metabolism in the
body of a specified compound or salt thereof. Metabolites of a
compound may be identified using routine techniques known in the
art and their activities determined using tests such as those
described herein.
[0115] Prodrugs and active metabolites of a compound may be
identified using routine techniques known in the art. Various forms
of prodrugs are known in the art. For examples of such prodrug
derivatives, see, for example, a) Design of Prodrugs, edited by H.
Bundgaard, (Elsevier, 1985) and Methods in Enzymology, Vol. 42, p.
309-396, edited by K. Widder, et al. (Academic Press, 1985); b) A
Textbook of Drug Design and Development, edited by
Krogsgaard-Larsen and H. Bundgaard, Chapter 5 "Design and
Application of Prodrugs," by H. Bundgaard p. 113-191 (1991); c) H.
Bundgaard, Advanced Drug Delivery Reviews, 8, 1-38 (1992); d) H.
Bundgaard, et al., Journal of Pharmaceutical Sciences, 77:285
(1988); and e) N. Kakeya, et al., Chem. Pharm. Bull., 32: 692
(1984), each of which is specifically incorporated herein by
reference.
[0116] A "pharmaceutically acceptable salt" as used herein, unless
otherwise indicated, includes salts that retain the biological
effectiveness of the free acids and bases of the specified compound
and that are not biologically or otherwise undesirable. A compound
of the invention may possess a sufficiently acidic, a sufficiently
basic, or both functional groups, and accordingly react with any of
a number of inorganic or organic bases, and inorganic and organic
acids, to form a pharmaceutically acceptable salt. Examples of
pharmaceutically acceptable salts include those salts prepared by
reaction of the compounds of the present invention with a mineral
or organic acid or an inorganic base, such salts including
sulfates, pyrosulfates, bisulfates, sulfites, bisulfites,
phosphates, monohydrogenphosphates, dihydrogenphosphates,
metaphosphates, pyrophosphates, chlorides, bromides, iodides,
acetates, propionates, decanoates, caprylates, acrylates, formates,
isobutyrates, caproates, heptanoates, propiolates, oxalates,
malonates, succinates, suberates, sebacates, fumarates, maleates,
butyn-1,4-dioates, hexyne-1,6-dioates, benzoates, chlorobenzoates,
methylbenzoates, dinitrobenzoates, hydroxybenzoates,
methoxybenzoates, phthalates, sulfonates, xylenesulfonates,
phenylacetates, phenylpropionates, phenylbutyrates, citrates,
lactates, .gamma.-hydroxybutyrates, glycollates, tartrates,
methanesulfonates, propanesulfonates, naphthalene-1-sulfonates,
naphthalene-2-sulfonates, and mandelates. Since a single compound
of the present invention may include more than one acidic or basic
moieties, the compounds of the present invention may include mono,
di or tri-salts in a single compound.
[0117] If the inventive compound is a base, the desired
pharmaceutically acceptable salt may be prepared by any suitable
method available in the art, for example, treatment of the free
base with an acidic compound, particularly an inorganic acid, such
as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid,
phosphoric acid and the like, or with an organic acid, such as
acetic acid, maleic acid, succinic acid, mandelic acid, fumaric
acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid,
salicylic acid, a pyranosidyl acid, such as glucuronic acid or
galacturonic acid, an alpha hydroxy acid, such as citric acid or
tartaric acid, an amino acid, such as aspartic acid or glutamic
acid, an aromatic acid, such as benzoic acid or cinnamic acid, a
sulfonic acid, such as p-toluenesulfonic acid or ethanesulfonic
acid, or the like.
[0118] If the inventive compound is an acid, the desired
pharmaceutically acceptable salt may be prepared by any suitable
method, for example, treatment of the free acid with an inorganic
or organic base. Preferred inorganic salts are those formed with
alkali and alkaline earth metals such as lithium, sodium,
potassium, barium and calcium. Preferred organic base salts
include, for example, ammonium, dibenzylammonium, benzylammonium,
2-hydroxyethylammonium, bis(2-hydroxyethyl)ammonium,
phenylethylbenzylamine, dibenzyl-ethylenediamine, and the like
salts. Other salts of acidic moieties may include, for example,
those salts formed with procaine, quinine and N-methylglucosamine,
plus salts formed with basic amino acids such as glycine,
ornithine, histidine, phenylglycine, lysine and arginine.
[0119] The inventive compounds may be prepared using the reaction
routes and synthesis schemes as described below, employing the
techniques available in the art using starting materials that are
readily available or can be synthesized using methods known in the
art.
[0120] Illustrations of the preparation of compounds of the present
invention are shown in Schemes 1-11. ##STR12## ##STR13## ##STR14##
##STR15## ##STR16## ##STR17## ##STR18## ##STR19## ##STR20##
[0121] Scheme 1 illustrates one method of preparing compounds of
the Formula I. Carboxylic acid 102 can be prepared from arene 101
by deprotonation at low temperature (-100 to -60.degree. C.) in the
appropriate ethereal solvent such as THF or diethyl ether followed
by carbon dioxide quench, which can be performed with solid dry
ice. The deprotonation can be accomplished with LDA in THF at
-78.degree. C. One quench method comprises adding the aryllithium
THF solution via cannula to a saturated solution of dry carbon
dioxide in THF at -78.degree. C. and then warming to room
temperature. Aniline 103 can be prepared by deprotonation of an
appropriate 2-substituted aniline with KHMDS, LiHMDS, NaHMDS or LDA
at low temperature (-100 to -60.degree. C.) in an appropriate
ethereal solvent such as THF or diethyl ether, followed by addition
of carboxylic acid 102 and warming to room temperature. In one
embodiment, deprotonation is accomplished with LDA at -78.degree.
C. in THF, followed by addition of carboxylic acid 102 and warming
to room temperature. Ester 104 can be prepared by standard methods
including, but not limited to, Fisher esterification (MeOH,
H.sub.2SO.sub.4), reaction with TMSCHN.sub.2 or TMSCl in MeOH.
Acetylene derivative 105 is prepared by Sonagashria coupling of
bromide 104 using an appropriately substituted acetylene, CuI, an
amine base, palladium catalyst and organic solvent such as DME,
THF, or DMF at temperatures between 25 and 100.degree. C. Suitable
palladium catalysts include, but are not limited to,
PdCl.sub.2(dppf), Pd(Ph.sub.3P).sub.4, and Pd.sub.2 dba.sub.3/dppf.
Suitable amine bases include, but are not limited, to Et.sub.3N,
Hunig's base, and diisopropyl amine. In one embodiment, the Pd(0)
mediated coupling to prepare acetylene 105 is accomplished with
Pd(PPh.sub.3).sub.2Cl.sub.2, CuI, diisopropyl amine, and the
appropriate substituted acetylene in THF at room temperature.
Hydrolysis of acetylene 105 to prepare ketone 106 can be
accomplished by standard methods including but not limited to
H.sub.2SO.sub.4, TFA, trifluorosulfonamide, FeCl.sub.3, or
HgSO.sub.4/H.sub.2SO.sub.4. Benzisoxazole 107 can be prepared in a
two step procedure from ketone 106. Addition of the potassium salt
of acetone oxime in suitable organic solvent such as THF or
Et.sub.2O at temperatures ranging from -78 to 5.degree. C. is
followed by acid catalyzed cyclization. The acetone oxime addition
is most easily performed by addition of a THF solution of ketone
106 to the salt at 0.degree. C. The cyclization can be accomplished
with a variety of acidic aqueous conditions at a range of
temperatures. In one embodiment cyclization is accomplished by
treatment of the isopropylideneaminooxybenzoic acid methyl ester
with 5% aqueous HCl in MeOH at reflux. Halogenation to form
benzisoxazole 108 is accomplished using standard procedures such as
NCS or NBS in DMF. Hydrolysis of ester 108 to form carboxylic acid
109 can be performed under standard conditions. The acid can be
converted to hydroxamate 110 or amide 112 by standard coupling
procedures including but not limited to EDCI/HOBt, PyBOP, or DIC
and the appropriate hydroxylamine or amine. Alternatively,
hydroxamate 110 or amide 112 can be prepared in two steps by
initial conversion to the acid chloride by standard methods
followed by addition of the hydroxylamine or amine. Acyl
sulfonamide 111 can be synthesized by preparing an activated ester
of carboxylic acid 109 followed by treatment with the appropriate
sulfonamide and tertiary amine base in a suitable organic solvent
such as THF. In one embodiment, acyl sulfonamide 111 is prepared by
treatment of carboxylic acid 109 with CDI at elevated temperature
(50.degree. C.) in THF followed treatment with the appropriate
sulfonamide and DBU.
[0122] Scheme 2 illustrates an alternative method for synthesizing
compounds of the Formula I. Nitrile 113 can be prepared by
palladium mediated coupling of bromide 104 with zinc cyanide in
suitable organic solvent such as DMA, NMP or DMF at elevated
temperatures ranging from 50 to 120.degree. C. Several palladium
catalysts may be employed including but not limited to
Pd(PPh.sub.3).sub.4, PdCl.sub.2(dppf), or Pd.sub.2 dba.sub.3 with
ligands such as dppe, dppp, dppf or BINAP. In one embodiment,
nitrile 113 is prepared from bromide 104 by treatment with zinc
cyanide, Pd.sub.2 dba.sub.3, and dppf in NMP at 120.degree. C.
Amino benzisoxazole 114 can be prepared in a two step procedure
from nitrile 113 by the addition of the potassium salt of acetone
oxime in suitable organic solvent such as THF or Et.sub.2O at
temperatures ranging from -78 to 5.degree. C. followed by acid
catalyzed cyclization. In one embodiment the acetone oxime addition
can be performed by addition of a THF solution of nitrile 113 to
the salt at 0.degree. C. in THF followed by warming to room
temperature. The cyclization can be accomplished under a variety of
acidic conditions at a range of temperatures. In one embodiment the
cyclization method comprises treatment of the oxime addition
product in MeOH with 2 M HCl in Et.sub.2O. Halogenation to form
benzisoxazole 115 is accomplished using standard procedures such as
NCS or NBS in DMF. Compound 116 is prepared in a two step procedure
comprising hydrolysis of ester 115 under standard conditions to
form the corresponding carboxylic acid, followed by conversion of
the carboxylic acid to hydroxamate 116 by standard coupling
procedures, including but not limited, to EDCI/HOBt, PyBOP, or DIC
and the appropriate hydroxylamine.
[0123] Scheme 3 illustrates one method of synthesizing compounds of
the Formula II. 4,6-Dichloronicotinic acid 118 can be prepared from
4,6-dihydroxynicotinic acid ethyl ester 117 in two steps. In the
first step, 4,6-dihydroxynicotinic acid ethyl ester 117 is
chlorinated using an appropriate reagent such as POCl.sub.3, oxalyl
chloride or thionyl chloride. In one embodiment, chlorination is
accomplished with POCl.sub.3 and Et.sub.3N at elevated
temperatures. Hydrolysis of the resulting dichloroethyl ester to
provide compound 118 can be performed under standard conditions.
Aniline 119 can be prepared by deprotonation of the properly
substituted aniline with KHMDS, LiHMDS, NaHMDS or LDA at low
temperature (-100 to -60.degree. C.) in appropriate ethereal
solvent such as THF or diethyl ether followed by addition of
carboxylic acid 118 and warming to room temperature. In one
embodiment, deprotonation is accomplished with LiHMDS at
-78.degree. C. in THF, followed by addition of carboxylic acid 118
and warming to room temperature. Amino pyridine 120 is prepared in
three steps from aniline 119. In the first step, the tert-butyl
ester is prepared by treating the acid 119 with
2-tert-butyl-1,3-diisopropylisourea in THF at temperatures ranging
from 25 to 75.degree. C. In the second step, sodium azide is added
to the tert-butyl ester in DMF at 80.degree. C. The amino pyridine
120 is prepared by reduction of the azide under standard conditions
including but not limited to Zn dust/AcOH, Pt/C or PtO.sub.2 in the
presence of H.sub.2 gas, Ph.sub.3P or SnCl.sub.2/MeOH. In one
embodiment, the azide reduction is accomplished by treatment with
Zn dust in a mixture of methylene chloride and acetic acid.
Imidazopyridine 121 where Z=F is prepared in two steps from amino
pyridine 120. In the first step, fluorination is accomplished by
treatment of the amino pyridine 120 with SELECTFLUOR.TM. in a
mixture of MeOH and water or pH 7 phosphate buffer. Cyclization to
form imidazopyridine 121 (Z=H or F) can be accomplished by
treatment with chloro or bromo acetaldehyde in suitable organic
solvent such as DMF or EtOH at elevated temperatures (50 to
120.degree. C.). In one embodiment, cyclization is realized by
treatment with chloroacetaldehyde in EtOH at 70.degree. C.
Alternatively, aniline 119 can be converted to dichloroester 122 in
two steps. In the first step, chlorination is performed under
standard conditions such as NCS in DMF. In the second step,
esterification can be achieved by standard methods including but
not limited to Fisher esterification (MeOH, H.sub.2SO.sub.4),
reaction with TMSCHN.sub.2 or TMSCl in MeOH. Aminopyridine 123 can
be prepared as described above for aminopyridine 120 with the
exception that the sodium azide addition can be accomplished at
room temperature. Cyclization (achieved as described above for
imidazopyridine 121) followed by standard basic saponification
gives imidazopyridine 124. Hydroxamate 125 can be prepared from
either imidazopyridine 121 or 124 using standard coupling
procedures including but not limited to EDCI/HOBt, PyBOP, or DIC
and the appropriate hydroxylamine. Alternatively, hydroxamate 125
can be prepared in two steps by initial conversion to the acid
chloride by standard methods followed by addition of the
hydroxylamine.
[0124] Scheme 4 illustrates an alternative method of preparing
compounds of Formula II. An appropriately functionalized
2-aminopyridine 126 in a suitable organic solvent such as
dichloromethane or dichloroethane is reacted with a Lewis acid such
as zinc bromide and condensation product (127) as disclosed by
Katritzky et al. (J. Org. Chem., 2003, 68, 4935-4937: J. Org.
Chem., 1990, 55, 3209-3213) to provide the
3-dialkyamino-imidazo[1,2-a]pyridine ring system 128. Condensation
products 127 (i.e., condensation of a glyoxal, benzotriazole and a
secondary amine) can be generated using benzotriazole, glyoxal and
any appropriate secondary amine including, but not limited to
dimethylamine, diethylamine, pyrrolidine, piperidine, morpholine,
1-methylpiperazine, N-methyl allylamine, diallyamine, and N-methyl
benzylamine. The ester 128 is hydrolyzed by standard saponification
methods, and the resulting acid can be converted to hydroxamate 129
by standard coupling procedures including but not limited to
EDCI/HOBt, PyBOP, or DIC and the appropriate hydroxylamine.
Alternatively, hydroxamate 129 can be prepared in two steps by
initial conversion of the carboxylic acid to the acid chloride or
activated ester by standard methods followed by addition of the
hydroxylamine.
[0125] Scheme 5 illustrates an alternative method of preparing
compounds of the Formula II. The preparation of 3-aminomethyl
imidazo[1,2-a]pyridines 131 using the modified Mannich reaction
procedure developed by Kercher et al. (manuscript in preparation)
is illustrated. The reaction is generally carried out by combining
37% aqueous formaldehyde and a suitable amine in 6:1
acetonitrile/water. Several secondary amines can be employed
including but not limited to pyrrolidine, piperadine, morpholine,
dimethylamine, N-BOC-piperazine and 1-methylpiperazine. The
solution of amine and formaldehyde is stirred for approximately
half an hour after which time scandium triflate and the appropriate
imidazo[1,2-a]pyridine 130 are sequentially added. The Mannich
reaction is preferentially catalyzed by a group IIIA lanthanide
triflate, preferably scandium triflate, though alternatively it may
be performed using an excess of protic acid (AcOH or HCl) or
elevated temperatures.
[0126] Scheme 6 illustrates an alternative method of preparing
compounds of Formula II. In Scheme 6, the preparation of
3-aminomethyl imidazo[1,2-a]pyridines 134 via reductive alkylation
is illustrated. In step 1, the 3-aminomethyl imidazo[1,2-a]pyridine
133 is prepared from the appropriate
3-formyl-imidazo[1,2-a]pyridine 132 and a suitable amine using
standard reduction methods such as Na(CN)BH.sub.3, Na(OAc).sub.3BH,
NMe.sub.4BH(OAc).sub.3 with or without the addition of acetic acid
in a suitable nonreactive organic solvent such as methylene
chloride, acetonitrile or tetrahydrofuran. The reductive amination
is generally accomplished by treatment of the aldehyde derivative
132 with the amine and acetic acid in tetrahydrofuran at room
temperature followed by the addition of Na(OAc).sub.3BH. In cases
where R''=H, the corresponding secondary amine 133 can optionally
be protected, for example with an acid labile protecting group such
as tert-butyl carbamate (BOC) to facilitate handling in subsequent
steps. In step 2, the ester is hydrolyzed by standard
saponification methods, and the resulting acid can be converted to
hydroxamate 134 by standard coupling procedures including but not
limited to EDCl/HOBt, PyBOP, or DIC and the appropriate
hydroxylamine. Alternatively, hydroxamate 134 can be prepared in
two steps by initial conversion of the carboxylic acid to the acid
chloride or activated ester by standard methods followed by
addition of the hydroxylamine. Protecting groups, if present, are
removed after coupling.
[0127] Scheme 7 illustrates one method of preparing compounds of
Formula III. In Scheme 7 the preparation of
3-alkyl-[1,2,4]triazolo[4,3-a]pyridine derivatives is illustrated.
Compound 136 is prepared from compound 135 in a two step process. A
suitably functionalized 2-chloropyridine derivative 135 is
converted to the 2-hydrazinopyridine by reaction with hydrazine.
The reaction is generally accomplished by reaction of hydrazine
with 2-chloropyridine derivative 135 in an unreactive organic
solvent such as DMF or DMA at elevated temperature (50 to
100.degree. C.). The 2-hydrazinopyridine is then acylated with the
appropriate carboxylic acid halide such as fluoride, chloride or
bromide, or the appropriate carboxylic acid anhydride or mixed
anhydride in a suitable unreactive organic solvent such as
dichloromethane, and in the presence of a suitable base such as
triethylamine, diisopropylethylamine or pyridine, to provide
intermediate 136. Acylation of the 2-hydrazinopyridine can
alternatively be accomplished by standard peptide coupling
procedures with the appropriate carboxylic acid and appropriate
coupling reagent, including but not limited to EDCl/HOBt, PyBOP, or
DIC. The intermediate 136 is converted to
3-alkyl-[1,2,4]triazolo[4,3-a]pyridine 137 by treatment with an
excess of phosphorus oxychloride in refluxing dichloromethane. The
ester 137 is hydrolyzed by standard saponification methods, and the
resulting acid 138 can be converted to hydroxamate 139 by standard
peptide coupling procedures including but not limited to EDCl/HOBt,
PyBOP, or DIC and the appropriate hydroxylamine. Alternatively,
hydroxamate 139 can be prepared in two steps by initial conversion
of the carboxylic acid to the acid chloride or activated ester by
standard methods followed by addition of the hydroxylamine.
[0128] Scheme 8 illustrates one method of preparing compounds of
the Formula IV. In Scheme 8, the synthesis of
3-methyl-benzo[c]isoxazole derivatives is illustrated. Compound 141
is prepared from compound 140 in a two step process. Methyl ester
140 is treated with sodium azide in 3:1 acetone/water at elevated
temperature (reflux) to effect nucleophilic substitution. The
4-azido derivative is then isolated and heated in water at reflux
to effect cyclization to the benzo[c]isoxazole ring system 141. The
ester 141 is hydrolyzed by standard saponification methods, and the
resulting carboxylic acid can be converted to hydroxamate 142 by
standard peptide coupling procedures including but not limited to
EDCl/HOBt, PyBOP, or DIC and the appropriate hydroxylamine.
Alternatively, hydroxamate 142 can be prepared in two steps by
initial conversion of the carboxylic acid to the acid chloride or
activated ester by standard methods followed by addition of the
hydroxyl amine.
[0129] Scheme 9 illustrates one method of preparing compounds of
Formula V. 2-Chloro-4-methyl-5-nitropyridine 143 can be converted
to amino pyridine 144 in a three step sequence. In the first step,
Sonagashria coupling using TMS-acetylene, CuI, amine base,
palladium catalyst and organic solvent such as DME, THF, or DMF at
temperatures from 25 to 100.degree. C. gives the nitroacetylenic
pyridine. Suitable palladium catalysts include, but are not limited
to, PdCl.sub.2(dppf), Pd(Ph.sub.3P).sub.4,
Pd(PPh.sub.3).sub.2Cl.sub.2 and Pd.sub.2 dba.sub.3/dppf. Suitable
amine bases include, but are not limited to, Et.sub.3N, Hunig's
base, and diisopropyl amine. The amino pyridine 144 is then
prepared by removal of the TMS group under standard conditions such
as K.sub.2CO.sub.3 in MeOH, followed by reduction of the nitro
group using either Zn dust/AcOH, Fe or SnCl.sub.21MeOH. For Z=H,
amino pyridine 144 is used directly in the cyclization reaction.
When Z=Cl, aminopyridine 144 is halogenated under standard
conditions with NCS in DMF and then carried forward to the
cyclization. When Z=F, the 2-chloro-3-aminopyridine intermediate is
treated with KF, Kryptofix in DMSO to prepare amino pyridine 145.
Cyclization to give pyrazolo[1,5-a]pyridine 146 is accomplished by
treating aminopyridine 145 with O-(4-nitrophenyl)-hydroxylamine in
a suitable organic solvent such as DMF at room temperature in
presence of a base such as K.sub.2CO.sub.3. Carboxylic acid 149 can
be prepared, for example, using one the following routes. One route
involves palladium mediated cross-coupling with appropriately
substituted bromobenzene and amino-pyrazolo[1,5-a]pyridine 146. In
this case, the cross-coupling can be accomplished with palladium
catalyst and organic solvent such as DME, THF, dioxane, and toluene
at temperatures from 60 to 120.degree. C. Suitable palladium
catalysts include, but are not limited to, Pd(OAc).sub.2,
PdCl.sub.2(dppf), Pd.sub.2(bda).sub.3, and Pd(dba).sub.2. Suitable
ligands include, but are not limited to, BINAP, DPPF, and
(o-tol).sub.3P. Suitable amine bases include, but are not limited
to, NaOt-Bu, KOt-Bu, and Cs.sub.2CO.sub.3. The second route
involves S.sub.NAr reaction with amino-pyrazolo[1,5-a]pyridine 146
and the appropriately substituted 2-fluoronitro-benzene. In this
case, the coupling can be accomplished by mixing the two components
in a suitable organic solvent such as xylenes, toluene, DMSO or DMF
at elevated temperatures (80 to 150.degree. C.). Optionally, a base
can be employed in the S.sub.NAr coupling such as K.sub.2CO.sub.3
or Cs.sub.2CO.sub.3. The carboxylic acid 149 is then prepared by
functionalization of the aromatic ring followed by oxidation. In
the first case, functionalization involves halogenation under
standard conditions with either NCS or NBS in DMF. In the second
case, functionalization involves Sandmeyer chemistry to convert the
nitroarene into the desired arene or arylhalide (nitro group
reduction; diazonation; halogentation or protonation). In both
routes, the last step to prepare carboxylic acid 149 is oxidation
of the toluyl moiety. This can be achieved using standard methods
including but not limited to KMnO.sub.4, NaOCl/RuCl.sub.3 or
Na.sub.2Cr.sub.2O.sub.7/HCl. The resulting carboxylic acid 149 can
be converted to hydroxamate 150 by standard peptide coupling
procedures including but not limited to EDCI/HOBt, PyBOP, or DIC
and the appropriate hydroxylamine. Alternatively, hydroxamate 150
can be prepared in two steps by initial conversion of the
carboxylic acid to the acid chloride or activated ester by standard
methods followed by addition of the hydroxylamine.
[0130] The invention also relates to a pharmaceutical composition
for the treatment of a hyperproliferative disorder in a mammal
which comprises a therapeutically effective amount of a compound of
the present invention, or a pharmaceutically acceptable salt,
prodrug or hydrate thereof, and a pharmaceutically acceptable
carrier. In one embodiment, said pharmaceutical composition is for
the treatment of cancer such as brain, lung, squamous cell,
bladder, gastic, pancreatic, breast, head, neck, renal, kidney,
ovarian, prostate, colorectal, esophageal, testicular,
gynecological or thyroid cancer. In another embodiment, said
pharmaceutical composition is for the treatment of a non-cancerous
hyperproliferative disorder such as benign hyperplasia of the skin
(e.g., psoriasis), restenosis, or prostate (e.g., benign prostatic
hypertrophy (BPH)).
[0131] The invention also relates to a pharmaceutical composition
for the treatment of pancreatitis or kidney disease (including
proliferative glomerulonephritis and diabetes-induced renal
disease) or the treatment of pain in a mammal which comprises a
therapeutically effective amount of a compound of the present
invention, or a pharmaceutically acceptable salt, prodrug or
hydrate thereof, and a pharmaceutically acceptable carrier.
[0132] The invention also relates to a pharmaceutical composition
for the prevention of blastocyte implantation in a mammal which
comprises a therapeutically effective amount of a compound of the
present invention, or a pharmaceutically acceptable salt, prodrug
or hydrate thereof, and a pharmaceutically acceptable carrier.
[0133] The invention also relates to a pharmaceutical composition
for treating a disease related to vasculogenesis or angiogenesis in
a mammal which comprises a therapeutically effective amount of a
compound of the present invention, or a pharmaceutically acceptable
salt, prodrug or hydrate thereof, and a pharmaceutically acceptable
carrier. In one embodiment, said pharmaceutical composition is for
treating a disease selected from the group consisting of tumor
angiogenesis, chronic inflammatory disease such as rheumatoid
arthritis, atherosclerosis, inflammatory bowel disease, skin
diseases such as psoriasis, eczema, and scleroderma, diabetes,
diabetic retinopathy, retinopathy of prematurity, age-related
macular degeneration, hemangioma, glioma, melanoma, Kaposi's
sarcoma and ovarian, breast, lung, pancreatic, prostate, colon and
epidermoid cancer.
[0134] The invention also relates to a method of treating a
hyperproliferative disorder in a mammal that comprises
administering to said mammal a therapeutically effective amount of
a compound of the present invention, or a pharmaceutically
acceptable salt, prodrug or hydrate thereof. In one embodiment,
said method relates to the treatment of cancer such as brain, lung,
squamous cell, bladder, gastric, pancreatic, breast, head, neck,
renal, kidney, ovarian, prostate, colorectal, esophageal,
testicular, gynecological or thyroid cancer. In another embodiment,
said method relates to the treatment of a non-cancerous
hyperproliferative disorder such as benign hyperplasia of the skin
(e.g., psoriasis), restenosis, or prostate (e.g., benign prostatic
hypertrophy (BPH)).
[0135] The invention also relates to a method for the treatment of
a hyperproliferative disorder in a mammal that comprises
administering to said mammal a therapeutically effective amount of
a compound of the present invention, or a pharmaceutically
acceptable salt, prodrug or hydrate thereof, in combination with an
anti-tumor agent selected from the group consisting of mitotic
inhibitors, alkylating agents, anti-metabolites, intercalating
antibiotics, growth factor inhibitors, cell cycle inhibitors,
enzyme inhibitors, topoisomerase inhibitors, biological response
modifiers, anti-hormones, angiogenesis inhibitors, and
anti-androgens.
[0136] The invention also relates to a method of treating
pancreatitis or kidney disease in a mammal that comprises
administering to said mammal a therapeutically effective amount of
a compound of the present invention, or a pharmaceutically
acceptable salt, prodrug or hydrate thereof.
[0137] The invention also relates to a method of preventing
blastocyte implantation in a mammal that comprises administering to
said mammal a therapeutically effective amount of a compound of the
present invention, or a pharmaceutically acceptable salt, prodrug
or hydrate thereof.
[0138] The invention also relates to a method of treating diseases
related to vasculogenesis or angiogenesis in a mammal that
comprises administering to said mammal a therapeutically effective
amount of a compound of the present invention, or a
pharmaceutically acceptable salt, prodrug or hydrate thereof. In
one embodiment, said method is for treating a disease selected from
the group consisting of tumor angiogenesis, chronic inflammatory
disease such as rheumatoid arthritis, atherosclerosis, inflammatory
bowel disease, skin diseases such as psoriasis, eczema, and
scleroderma, diabetes, diabetic retinopathy, retinopathy of
prematurity, age-related macular degeneration, hemanglioma, glioma,
melanoma, Kaposi's sarcoma and ovarian, breast, lung, pancreatic,
prostate, colon and epidermoid cancer.
[0139] Patients that can be treated with compounds of the present
invention, or pharmaceutically acceptable salts, prodrugs and
hydrates of said compounds, according to the methods of this
invention include, for example, patients that have been diagnosed
as having psoriasis, restenosis, atherosclerosis, BPH, lung cancer,
bone cancer, CMML, pancreatic cancer, skin cancer, cancer of the
head and neck, cutaneous or intraocular melanoma, uterine cancer,
ovarian cancer, rectal cancer, cancer of the anal region, stomach
cancer, colon cancer, breast cancer, testicular, gynecologic tumors
(e.g., uterine sarcomas, carcinoma of the fallopian tubes,
carcinoma of the endometrium, carcinoma of the cervix, carcinoma of
the vagina or carcinoma of the vulva), Hodgkin's disease, cancer of
the esophagus, cancer of the small intestine, cancer of the
endocrine system (e.g., cancer of the thyroid, parathyroid or
adrenal glands), sarcomas of soft tissues, cancer of the urethra,
cancer of the penis, prostate cancer, chronic or acute leukemia,
solid tumors of childhood, lymphocytic lymphomas, cancer of the
bladder, cancer of the kidney or ureter (e.g., renal cell
carcinoma, carcinoma of the renal pelvis), or neoplasms of the
central nervous system (e.g., primary CNS lymphoma, spinal axis
tumors, brain stem gliomas or pituitary adenomas).
[0140] This invention also relates to a pharmaceutical composition
for inhibiting abnormal cell growth in a mammal which comprises an
amount of a compound of the present invention, or a
pharmaceutically acceptable salt or solvate or prodrug thereof, in
combination with an amount of a chemotherapeutic, wherein the
amounts of the compound, salt, solvate, or prodrug, and of the
chemotherapeutic are together effective in inhibiting abnormal cell
growth. Many chemotherapeutics are presently known in the art. In
one embodiment, the chemotherapeutic is selected from the group
consisting of mitotic inhibitors, alkylating agents,
anti-metabolites, intercalating antibiotics, growth factor
inhibitors, cell cycle inhibitors, enzymes, topoisomerase
inhibitors, biological response modifiers, anti-hormones,
angiogenesis inhibitors, and anti-androgens.
[0141] This invention further relates to a method for inhibiting
abnormal cell growth in a mammal or treating a hyperproliferative
disorder which method comprises administering to the mammal an
amount of a compound of the present invention, or a
pharmaceutically acceptable salt or solvate or prodrug thereof, in
combination with radiation therapy, wherein the amounts of the
compound, salt, solvate, or prodrug, is in combination with the
radiation therapy effective in inhibiting abnormal cell growth or
treating the hyperproliferative disorder in the mammal. Techniques
for administering radiation therapy are known in the art, and these
techniques can be used in the combination therapy described herein.
The administration of the compound of the invention in this
combination therapy can be determined as described herein.
[0142] It is believed that the compounds of the present invention
can render abnormal cells more sensitive to treatment with
radiation for purposes of killing and/or inhibiting the growth of
such cells. Accordingly, this invention further relates to a method
for sensitizing abnormal cells in a mammal to treatment with
radiation which comprises administering to the mammal an amount of
a compound of the present invention or pharmaceutically acceptable
salt or solvate or prodrug thereof, which amount is effective in
sensitizing abnormal cells to treatment with radiation. The amount
of the compound, salt, or solvate in this method can be determined
according to the means for ascertaining effective amounts of such
compounds described herein.
[0143] The invention also relates to a method of and to a
pharmaceutical composition of inhibiting abnormal cell growth in a
mammal which comprises an amount of a compound of the present
invention, or a pharmaceutically acceptable salt or solvate
thereof, a prodrug thereof, or an isotopically-labeled derivative
thereof, and an amount of one or more substances selected from
anti-angiogenesis agents, signal transduction inhibitors, and
antiproliferative agents.
[0144] Anti-angiogenesis agents, such as MMP-2
(matrix-metalloproteinase 2) inhibitors, MMP-9
(matrix-metalloproteinase 9) inhibitors, and COX-II (cyclooxygenase
II) inhibitors, can be used in conjunction with a compound of the
present invention and pharmaceutical compositions described herein.
Examples of useful COX-II inhibitors include CELEBREX.TM.
(alecoxib), valdecoxib, etoricoxib, lumiracoxib and rofecoxib.
Examples of useful matrix metalloproteinase inhibitors are
described in WO 96/33172 (published Oct. 24, 1996), WO 96/27583
(published Mar. 7, 1996), European Patent Application No.
97304971.1 (filed Jul. 8, 1997), European Patent Application No.
99308617.2 (filed Oct. 29, 1999), WO 98/07697 (published Feb. 26,
1998), WO 98/03516 (published Jan. 29, 1998), WO 98/34918
(published Aug. 13, 1998), WO 98/34915 (published Aug. 13, 1998),
WO 98/33768 (published Aug. 6, 1998), WO 98/30566 (published Jul.
16, 1998), European Patent Publication 606,046 (published Jul. 13,
1994), European Patent Publication 931,788 (published Jul. 28,
1999), WO 90/05719 (published May 31, 1990), WO 99/52910 (published
Oct. 21, 1999), WO 99/52889 (published Oct. 21, 1999), WO 99/29667
(published Jun. 17, 1999), PCT International Application No.
PCT/IB98/01113 (filed Jul. 21, 1998), European Patent Application
No. 99302232.1 (filed Mar. 25, 1999), Great Britain Patent
Application No. 9912961.1 (filed Jun. 3, 1999), U.S. Provisional
Application No. 60/148,464 (filed Aug. 12, 1999), U.S. Pat. No.
5,863,949 (issued Jan. 26, 1999), U.S. Pat. No. 5,861,510 (issued
Jan. 19, 1999), and European Patent Publication 780,386 (published
Jun. 25, 1997), all of which are incorporated herein in their
entireties by reference. Preferred MMP-2 and MMP-9 inhibitors are
those that have little or no activity inhibiting MMP-1. More
preferred, are those that selectively inhibit MMP-2 and/or MMP-9
relative to the other matrix-metalloproteinases (i.e., MMP-1,
MMP-3, MMP-4, MMP-5, MMP-6, MMP-7, MMP-8, MAP-10, MMP-11, MMP-12,
and MMP-13).
[0145] The terms "abnormal cell growth" and "hyperproliferative
disorder" are used interchangeably in this application.
[0146] "Abnormal cell growth," as used herein, unless otherwise
indicated, refers to cell growth that is independent of normal
regulatory mechanisms (e.g., loss of contact inhibition). This
includes, for example, the abnormal growth of: (1) tumor cells
(tumors) that proliferate by expressing a mutated tyrosine kinase
or overexpression of a receptor tyrosine kinase; (2) benign and
malignant cells of other proliferative diseases in which aberrant
tyrosine kinase activation occurs; (3) any tumors that proliferate
by receptor tyrosine kinases; (4) any tumors that proliferate by
aberrant serine/threonine kinase activation; and (5) benign and
malignant cells of other proliferative diseases in which aberrant
serine/theroine kinase activation occurs.
[0147] The term "treating," as used herein, unless otherwise
indicated, means reversing, alleviating, inhibiting the progress
of, or preventing the disorder or condition to which such term
applies, or one or more symptoms of such disorder or condition. The
term "treatment," as used herein, unless otherwise indicated,
refers to the act of treating as "treating" is defined immediately
above.
[0148] The amount of a given agent that will correspond to such an
amount will vary depending upon factors such as the particular
compound, disease condition and its severity, the identity (e.g.,
weight) of the mammal in need of treatment, but can nevertheless be
routinely determined by one skilled in the art. "Treating" is
intended to mean at least the mitigation of a disease condition in
a mammal, such as a human, that is affected, at least in part, by
the activity of MEK, and includes, but is not limited to,
preventing the disease condition from occurring in a mammal,
particularly when the mammal is found to be predisposed to having
the disease condition but has not yet been diagnosed as having it;
modulating and/or inhibiting the disease condition; and/or
alleviating the disease condition.
[0149] In order to use a compound of the Formula I-V or a
pharmaceutically acceptable salt or prodrug thereof, for the
therapeutic treatment (including prophylactic treatment) of mammals
including humans, it is normally formulated in accordance with
standard pharmaceutical practice as a pharmaceutical composition.
According to this aspect of the invention there is provided a
pharmaceutical composition that comprises a compound of the Formula
I-V, or a pharmaceutically acceptable salt or prodrug thereof, as
defined hereinbefore in association with a pharmaceutically
acceptable diluent or carrier.
[0150] The compositions of the invention may be in a form suitable
for oral use (for example as tablets, lozenges, hard or soft
capsules, aqueous or oily suspensions, emulsions, dispersible
powders or granules, syrups or elixirs), for topical use (for
example as creams, ointments, gels, or aqueous or oily solutions or
suspensions), for administration by inhalation (for example as a
finely divided powder or a liquid aerosol), for administration by
insufflation (for example as a finely divided powder) or for
parenteral administration (for example as a sterile aqueous or oily
solution for intravenous, subcutaneous, or intramuscular dosing or
as a suppository for rectal dosing). For example, compositions
intended for oral use may contain, for example, one or more
coloring, sweetening, flavoring and/or preservative agents.
[0151] Suitable pharmaceutically-acceptable excipients for a tablet
formulation include, for example, inert diluents such as lactose,
sodium carbonate, calcium phosphate or calcium carbonate,
granulating and disintegrating agents such as corn starch or
algenic acid; binding agents such as starch; lubricating agents
such as magnesium stearate, stearic acid or talc; preservative
agents such as ethyl or propyl p-hydroxybenzoate, and
anti-oxidants, such as ascorbic acid. Tablet formulations may be
uncoated or coated either to modify their disintegration and the
subsequent absorption of the active ingredient within the
gastrointestinal tract, or to improve their stability and/or
appearance, in either case, using conventional coating agents and
procedures well known in the art.
[0152] Compositions for oral use may be in the form of hard gelatin
capsules in which the active ingredient is mixed with an inert
solid diluent, for example, calcium carbonate, calcium phosphate or
kaolin, or as soft gelatin capsules in which the active ingredient
is mixed with water or an oil such as peanut oil, liquid paraffin,
or olive oil.
[0153] Aqueous suspensions generally contain the active ingredient
in finely powdered form together with one or more suspending
agents, such as sodium carboxymethylcellulose, methylcellulose,
hydroxypropylmethylcellulose, sodium alginate,
polyvinyl-pyrrolidone, gum tragacanth and gum acacia; dispersing or
wetting agents such as lecithin or condensation products of an
alkylene oxide with fatty acids (for example polyoxethylene
stearate), or condensation products of ethylene oxide with long
chain aliphatic alcohols, for example heptadecaethyleneoxycetanol,
or condensation products of ethylene oxide with partial esters
derived from fatty acids and a hexitol such as polyoxyethylene
sorbitol monooleate, or condensation products of ethylene oxide
with partial esters derived from fatty acids and hexitol
anhydrides, for example polyethylene sorbitan monooleate. The
aqueous suspensions may also contain one or more preservatives
(such as ethyl or propyl p-hydroxybenzoate, anti-oxidants (such as
ascorbic acid), coloring agents, flavoring agents, and/or
sweetening agents (such as sucrose, saccharine or aspartame).
[0154] Oily suspensions may be formulated by suspending the active
ingredient in a vegetable oil (such as arachis oil, olive oil,
sesame oil or coconut oil) or in a mineral oil (such as liquid
paraffin). The oily suspensions may also contain a thickening agent
such as beeswax, hard paraffin or cetyl alcohol. Sweetening agents
such as those set out above, and flavoring agents may be added to
provide a palatable oral preparation. These compositions may be
preserved by the addition of an anti-oxidant such as ascorbic
acid.
[0155] Dispersible powders and granules suitable for preparation of
an aqueous suspension by the addition of water generally contain
the active ingredient together with a dispersing or wetting agent,
suspending agent and one or more preservatives. Suitable dispersing
or wetting agents and suspending agents are exemplified by those
already mentioned above. Additional excipients such as sweetening,
flavoring and coloring agents may also be present.
[0156] The pharmaceutical compositions of the invention may also be
in the form of oil-in-water emulsions. The oily phase may be a
vegetable oil, such as olive oil or arachis oil, or a mineral oil,
such as for example liquid paraffin or a mixture of any of these.
Suitable emulsifying agents may be, for example,
naturally-occurring gums such as gum acacia or gum tragacanth,
naturally-occurring phosphatides such as soya bean, lecithin,
esters or partial esters derived from fatty acids and hexitol
anhydrides (for example sorbitan monooleate) and condensation
products of the said partial esters with ethylene oxide such as
polyoxyethylene sorbitan monooleate. The emulsions may also contain
sweetening, flavoring and preservative agents.
[0157] Syrups and elixirs may be formulated with sweetening agents
such as glycerol, propylene glycol, sorbitol, aspartame or sucrose,
and may also contain a demulcent, preservative, flavoring and/or
coloring agent.
[0158] The pharmaceutical compositions may also be in the form of a
sterile injectable aqueous or oily suspension, which may be
formulated according to known procedures using one or more of the
appropriate dispersing or wetting agents and suspending agents,
which have been mentioned above. A sterile injectable preparation
may also be a sterile injectable solution or suspension in a
non-toxic parenterally-acceptable diluent or solvent, for example a
solution in 1,3-butanediol.
[0159] Suppository formulations may be prepared by mixing the
active ingredient with a suitable non-irritating excipient which is
solid at ordinary temperatures but liquid at the rectal temperature
and will therefore melt in the rectum to release the drug. Suitable
excipients include, for example, cocoa butter and polyethylene
glycols.
[0160] Topical formulations, such as creams, ointments, gels and
aqueous or oily solutions or suspensions, may generally be obtained
by formulating an active ingredient with a conventional, topically
acceptable, vehicle or diluent using conventional procedures well
known in the art.
[0161] Compositions for administration by insufflation may be in
the form of a finely divided powder containing particles of average
diameter of, for example, 30 .mu.m or much less, the powder itself
comprising either active ingredient alone or diluted with one or
more physiologically acceptable carriers such as lactose. The
powder for insufflation is then conveniently retained in a capsule
containing, for example, 1 to 50 mg of active ingredient for use
with a turbo-inhaler device, such as is used for insufflation of
the known agent sodium cromoglycate.
[0162] Compositions for administration by inhalation may be in the
form of a conventional pressurized aerosol arranged to dispense the
active ingredient either as an aerosol containing finely divided
solid or liquid droplets. Conventional aerosol propellants such as
volatile fluorinated hydrocarbons or hydrocarbons may be used and
the aerosol device is conveniently arranged to dispense a metered
quantity of active ingredient.
[0163] For further information on formulations, see Chapter 25.2 in
Volume 5 of Comprehensive Medicinal Chemistry (Corwin Hansch;
Chairman of Editorial Board), Pergamon Press 1990, which is
specifically incorporated herein by reference.
[0164] The amount of a compound of this invention that is combined
with one or more excipients to produce a single dosage form will
necessarily vary depending upon the subject treated, the severity
of the disorder or condition, the rate of administration, the
disposition of the compound and the discretion of the prescribing
physician. However, an effective dosage is in the range of about
0.001 to about 100 mg per kg body weight per day, preferably about
0.5 to about 35 mg/kg/day, in single or divided doses. For a 70 kg
human, this would amount to about 0.05 to 7 g/day, preferably about
0.05 to about 2.5 g/day. In some instances, dosage levels below the
lower limit of the aforesaid range may be more than adequate, while
in other cases still larger doses may be employed without causing
any harmful side effect, provided that such larger doses are first
divided into several small doses for administration throughout the
day. For further information on routes of administration and dosage
regimes, see Chapter 25.3 in Volume 5 of Comprehensive Medicinal
Chemistry (Corwin Hansch; Chairman of Editorial Board), Pergamon
Press 1990, which is specifically incorporated herein by
reference.
[0165] The size of the dose for therapeutic or prophylactic
purposes of a compound of Formula I-V will naturally vary according
to the nature and severity of the conditions, the age and sex of
the animal or patient and the route of administration, according to
well known principles of medicine.
[0166] The compounds of this invention may be used alone in
combination with other drugs and therapies used in the treatment of
disease states which would benefit from the inhibition of MEK. For
example, a compound of this invention may be applied in combination
with one or more other anti-tumor substances, including, but not
limited to, mitotic inhibitors such as vinblastine; alkylating
agents such as cisplatin, carboplatin and cyclophosphamide;
anti-metabolites such as 5-fluorouracil, cytosine arabinside and
hydroxyurea; or, for example, one of the preferred anti-metabolites
disclosed in European Patent Application No. 239362 such as
N-(5-[N-(3,4-dihydro-2-methyl-4-oxoquinazolin-6-ylmethyl)-N-methylamin-
o]-2-thenoyl)-L-glutamic acid; growth factor inhibitors; signal
transduction inhibitors, such as agents that can inhibit EGFR
(epidermal growth factor receptor) responses, such as EGRF
antibodies, EGF antibodies and molecules that are EGFR inhibitors
such as the compounds ZD-1839 (AstraZeneca) and BIBX-1382
(Boehringer Ingelheim); VEGF inhibitors such as SU-6668 (Sugen Inc.
of South San Francisco, Calif., USA) or the anti-VEGF monoclonal
antibody of Genentech, Inc. of South San Francisco, Calif.; cell
cycle inhibitors; intercalating antibiotics such as adriamycin and
bleomycin; enzymes, for example, interferon; and anti-hormone such
as anti-estrogens such as Nolvadex.TM. (tamoxifen); or, for example
anti-androgens such as Casodex.TM.
(4'-cyano-3-(4-fluorophenylsulphonyl)-2-hydroxy-2-methyl-3'-(trifluoromet-
hyl)propionanilide). Such conjoint treatment may be achieved by way
of the simultaneous, sequential or separate dosing of the
individual components of treatment.
[0167] Although the compounds of Formula I-V are primarily of value
as therapeutic agents for use in warm-blooded animals (including
man), they are also useful whenever it is required to inhibit the
effects of MEK. Thus, they are useful as pharmacological standards
for use in the development of new biological tests and in the
search for new pharmacological agents.
[0168] The activity of the compounds of the present invention may
be determined by the following procedure. N-terminal 6 His-tagged,
constitutively active MEK-1 (2-393) is expressed in E. coli and
protein is purified by conventional methods (Ahn et al., Science
1994, 265, 966-970). The activity of MEK1 is assessed by measuring
the incorporation of .gamma.-.sup.33P-phosphate from
.gamma.-.sup.33P-ATP onto N-terminal His tagged ERK2, which is
expressed in E. Coli and is purified by conventional methods, in
the presence of MEK-1. The assay is carried out in 96-well
polypropylene plate. The incubation mixture (100 .mu.L) comprises
of 25 mM Hepes, pH 7.4, 10 mM MgCl.sub.2, 5 mM
.beta.-glycerolphosphate, 100 .mu.M Na-orthovanadate, 5 mM DTT, 5
nM MEK1, and 1 .mu.M ERK2. Inhibitors are suspended in DMSO, and
all reactions, including controls are performed at a final
concentration of 1% DMSO. Reactions are initiated by the addition
of 10 .mu.M ATP (with 0.5 .mu.Ci .gamma.-.sup.33P-ATP/well) and
incubated at ambient temperature for 45 minutes. Equal volume of
25% TCA is added to stop the reaction and precipitate the proteins.
Precipitated proteins are trapped onto glass fiber B filterplates,
and excess labeled ATP washed off using a Tomtec MACH III
harvestor. Plates are allowed to air-dry prior to adding 30
.mu.L/well of Packard Microscint 20, and plates are counted using a
Packard TopCount. In this assay, compounds of the invention
exhibited an IC.sub.50 of less than 50 micromolar.
[0169] Representative compounds of the present invention, which are
encompassed by the present invention include, but are not limited
to the compounds of the examples and their pharmaceutically
acceptable acid or base addition salts or prodrugs thereof. The
examples presented below are intended to illustrate particular
embodiments of the invention, and are not intended to limit the
scope of the specification or the claims in any way.
[0170] The disclosures in this application of all articles and
references, including patents, are incorporated herein by
reference.
EXAMPLES
[0171] In order to illustrate the invention, the following examples
are included. However, it is to be understood that these examples
do not limit the invention and are only meant to suggest a method
of practicing the invention. Persons skilled in the art will
recognize that the chemical reactions described may be readily
adapted to prepare a number of other MEK inhibitors of the
invention, and alternative methods for preparing the compounds of
this invention are deemed to be within the scope of this invention.
For example, the synthesis of non-exemplified compounds according
to the invention may be successfully performed by modifications
apparent to those skilled in the art, e.g., by appropriately
protecting interfering groups, by utilizing other suitable reagents
known in the art other than those described, and/or by making
routine modifications of reaction conditions. Alternatively, other
reactions disclosed herein or known in the art will be recognized
as having applicability for preparing other compounds of the
invention.
[0172] In the examples described below, unless otherwise indicated
all temperatures are set forth in degrees Celsius. Reagents were
purchased from commercial suppliers such as Aldrich Chemical
Company, Lancaster, TCI or Maybridge, and were used without further
purification unless otherwise indicated. Tetrahydrofuran (THF),
N,N-dimethylformamide (DMF), dichloromethane, toluene, dioxane and
1,2-difluoroethane were purchased from Aldrich in Sure seal bottles
and used as received.
[0173] The reactions set forth below were done generally under a
positive pressure of nitrogen or argon or with a drying tube
(unless otherwise stated) in anhydrous solvents, and the reaction
flasks were typically fitted with rubber septa for the introduction
of substrates and reagents via syringe. Glassware was oven dried
and/or heat dried.
[0174] Column chromatography was done on a Biotage system
(Manufacturer: Dyax Corporation) having a silica gel column or on a
silica SepPak cartridge (Waters).
[0175] .sup.1H-NMR spectra were recorded on a Bruker instrument
operating at 300 MHz or on a Varian instrument operating at 400
MHz. .sup.1H-NMR spectra were obtained as CDCl.sub.3 solutions
(reported in ppm), using chloroform as the reference standard (7.25
ppm). Other NMR solvents were used as needed. When peak
multiplicities are reported, the following abbreviations are used:
s (singlet), d (doublet), t (triplet), m (multiplet), br
(broadened), dd (doublet of doublets), dt (doublet of triplets).
Coupling constants, when given, are reported in Hertz (Hz).
Example 1
[0176] ##STR21##
Synthesis of
6-(4-bromo-2-chlorophenylamino)-7-fluoro-3-methylbenzo[d]isoxazole-5-carb-
oxylic acid (9a)
[0177] The reaction scheme for the synthesis of compound 9a is
shown in FIG. 1.
[0178] Step A: Preparation of 5-bromo-2,3,4-trifluorobenzoic acid
(2): To a solution of 1-bromo-2,3,4-trifluorobenzene (1) (5.0 mL,
41.7 mmol) in THF (120 mL) was added lithium diisopropylamine (2.0
M solution, 21 mL, 42 mmol) at -78.degree. C. After stirring for 1
hour at -78.degree. C., the mixture was added to a solution of
CO.sub.2 in THF (1 L). The dry-ice bath was removed and the
reaction mixture stirred overnight at room temperature. The
reaction mixture was quenched with 10% aqueous HCl (835 mL),
concentrated, and washed with ether (250 mL). The combined organics
were washed with 5% aqueous NaOH (300 mL) and water (100 mL, pH
12). The aqueous layer was acidified (pH 0) with concentrated HCl.
The resulting suspension was extracted with ether (2.times.300 mL),
dried over MgSO.sub.4, filtered, concentrated under reduced
pressure to afford 7.70 g (72% yield) of the desired product
(2).
[0179] Step B: Preparation of
5-bromo-2-(2-chlorophenylamino)-3,4-difluorobenzoic acid (3): To a
solution of lithium diisopropylamine (49.0 mL, 2 M in THF/heptane)
in THF (40 mL) was added 2-chlorophenylamine (6.50 mL, 60.6 mmol)
at -78.degree. C. After vigorous stirring for 10 minutes, a
solution of 5-bromo-2,3,4-trifluoro-benzoic acid (2) (7.70 g, 30.2
mmol) in THF (60 mL) was added. The dry-ice bath was removed and
the reaction mixture stirred for 4 hours at room temperature. The
mixture was concentrated, treated with 10% aqueous HCl (75 mL), and
extracted with EtOAc. The combined organic extracts were dried over
MgSO.sub.4, filtered, and concentrated. Purification by trituration
with boiling CH.sub.2Cl.sub.2 gave 7.24 g (66%) of the desired acid
(3) as a yellow solid
[0180] Step C: Preparation of
5-bromo-2-(2-chlorophenylamino)-3,4-difluorobenzoic acid methyl
ester (4): To a solution of
5-bromo-2-(2-chlorophenylamino)-3,4-difluorobenzoic acid (3) (4.50
g, 12.4 mmol) in a 3:1 mixture of THF:MeOH (32 mL) was added
(trimethylsilyl)-diazomethane (8.10 ml of a 2 M solution in
hexanes) at room temperature. After stirring for 2 hours, the
reaction mixture was quenched with acetic acid, diluted with EtOAc,
and washed with water. The organic layer was dried (MgSO.sub.4) and
concentrated under reduced pressure to give 4.35 g (93%) of the
desired methyl ester (4).
[0181] Step D: Preparation of
2-(2-chlorophenylamino)-3,4-difluoro-5-trimethylsilanylethynyl-benzoic
acid methyl ester (5): A mixture of
5-bromo-2-(2-chlorophenylamino)-3,4-difluorobenzoic acid methyl
ester (4) (101 mg, 0.268 mmol), TMS-acetylene (0.045 mL, 0.31
mmol), Pd(PPh.sub.3).sub.2Cl.sub.2 (18.7 mg, 0.0261 mmol), CuI (5.1
mg, 0.027 mmol), and i-Pr.sub.2NH (0.075 mL, 0.53 mmol) in THF (1.5
mL) was stirred for 16 hours at room temperature. The reaction
mixture was concentrated under reduced pressure, and diluted with
EtOAc. The organic layer was washed with saturated aqueous
NH.sub.4Cl and brine, dried over MgSO.sub.4, and concentrated.
Purification by flash column chromatography using the Biotage
system (100% hexane to 1% EtOAc in hexane) gave 81.3 mg (77% yield)
of the desired product (5).
[0182] Step E: Preparation of
5-acetyl-2-(2-chlorophenylamino)-3,4-difluorobenzoic acid methyl
ester (6): A mixture of
2-(2-chlorophenylamino)-3,4-difluoro-5-trimethylsilanylethynylbenzoic
acid methyl ester (5) (79.4 mg, 0.20 mmol), HgSO.sub.4 (59.8 mg,
2.0 mmol), and conc. H.sub.2SO.sub.4 (0.02 mL, 0.40 mmol) in 80%
aqueous acetone (2.5 mL), were refluxed for 48 hours. The reaction
was concentrated under reduced pressure, and diluted with EtOAc.
The organic layer was washed with water and brine, dried over
MgSO.sub.4 and concentrated to give 50.1 mg (73%) of the desired
product (6).
[0183] Step F: Preparation of 6-(2-chlorophenylamino)-7-fluoro
methylbenzo[d]isoxazole-5-carboxylic acid methyl ester (7): t-BuOK
(0.47 mL, 1.0 M in THF) was added to propan-2-one oxime (35 mg,
0.47 mmol). After stirring for 30 minutes, THF (0.5 mL) was added,
and the reaction mixture was cooled to -78.degree. C. A solution of
5-acetyl-2-(2-chlorophenylamino)-3,4-difluorobenzoic acid methyl
ester (6) (50.0 mg, 0.147 mmol) in THF (1 mL) was added. The
reaction mixture was slowly warmed to 0.degree. C. and stirred for
2 hours. The reaction mixture was quenched with saturated aqueous
NH.sub.4Cl, diluted with EtOAc and water. The aqueous layer was
separated and extracted with EtOAc. The combined organic extracts
were dried over MgSO.sub.4, filtered, and concentrated in vacuo to
give the
5-acetyl-2-(2-chloro-phenylamino)-3-fluoro-4-isopropylideneaminooxy-benzo-
ic acid methyl ester. The recovered oxime was suspended in a 1:1
mixture of 5% aqueous HCl and MeOH (30 ml) and heated to reflux.
After 1 hour, the reaction mixture was cooled to room temperature
and diluted with EtOAc. The organic layer was washed with water,
dried (MgSO.sub.4) and concentrated. Purification by flash column
chromatography using the Biotage system (40% methylene chloride in
hexanes) provided 17 mg (35% for two steps) of the desired product
(7).
[0184] Step G: Preparation of
6-(4-bromo-2-chlorophenylamino)-7-fluoro-3-methyl-benzo[d]isoxazole-5-car-
boxylic acid methyl ester (8a):
6-(2-Chlorophenylamino)-7-fluoro-3-methylbenzo[d]isoxazole-5-carboxylic
acid methyl ester (7) (18.6 mg, 0.0556 mmol) and N-bromosuccinimide
(12.0 mg, 0.0667 mmol) were stirred in DMF (1 mL) for 16 hours. The
reaction mixture was diluted with EtOAc, and washed with water
(2.times.). The organic layer was dried over MgSO.sub.4, filtered,
and concentrated. Purification by flash column chromatography using
the Biotage system (10% EtOAc in hexanes) provided 12.6 mg (55%) of
the desired product (8a).
[0185] Step H: Preparation of
6-(4-bromo-2-chlorophenylamino)-7-fluoro-3-methylbenzo[d]isoxazole-5-carb-
oxylic acid (9a): To a solution of
6-(4-bromo-2-chlorophenylamino)-7-fluoro-3-methylbenzo[d]isoxazole-5-carb-
oxylic acid methyl ester (8a) (200 mg, 0.48 mmol) in THF-water (3
mL/1.5 mL) was added aqueous LiOH (1 M, 1.00 mL) at room
temperature. After 15 hours, the reaction mixture was acidified to
pH 1 with aqueous HCl (1 M), diluted with water, and extracted with
EtOAc/THF. The organic layer was washed with water, dried over
MgSO.sub.4, filtered, and concentrated in vacuo to give 191.5 mg
(99%) of the crude acid (9a) which was used without further
purification. MS APCI (-) m/z 397, 399 (M+, Br, Cl pattern)
detected: .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 9.55 (s, 1H),
8.37 (s, 1H), 7.75 (s, 1H), 7.42 (d, 1H), 6.97 (t, 1H), 2.60 (s,
3H): .sup.19F NMR (376 MHz, DMSO-d.sub.6) -140.15 (s, 1F).
Example 2
[0186] ##STR22##
Synthesis of 6-(4-bromo-2-chlorophenylamino)-7-fluoro-3-methylbenzo
[d]isoxazole-5-carboxylic acid cyclopropylmethoxyamide (10a)
[0187] The reaction scheme for the synthesis of compound 10a is
shown in FIG. 1. To a solution of
6-(4-bromo-2-chlorophenylamino)-7-fluoro-3-methylbenzo[d]isoxazole-5-carb-
oxylic acid (9a) (50.0 mg, 0.125 mmol) in DMF (1 mL) was added HOBt
(24.6 mg, 0.161 mmol), Et.sub.3N (0.060 mL, 0.43 mmol),
O-cyclopropylmethyl-hydroxylamine (15.5 mg, 0.178 mmol), and
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCl)
(32.2 mg, 0.168 mmol) at room temperature. After 6 days, the
reaction mixture was diluted with EtOAc, washed with saturated
aqueous NH.sub.4Cl, brine, saturated aqueous NaHCO.sub.3, and
brine. The organic layer was dried over MgSO.sub.4, filtered,
concentrated in vacuo, and purified by flash column chromatography
using the Biotage system (0.5% MeOH in CH.sub.2Cl.sub.2) to give
27.6 mg (47% yield) of the desired product (10a). MS APCI (-) m/z
466, 468 (M+, Br, Cl pattern) detected: .sup.1H NMR (400 MHz,
CD.sub.3OD) .delta. 7.82 (s, 1H), 7.57 (d, 1H), 7.31 (dd, 1H), 6.74
(dd, 1H), 3.73 (d, 2H), 2.60 (s, 3H), 1.16 (m, 1H), 0.55 (m, 2H),
0.28 (m, 2H): .sup.19F NMR MHz, CD.sub.3OD)-140.96 (s, 1F).
Example 3
[0188] ##STR23##
Synthesis of
6-(4-bromo-2-chlorophenylamino)-7-fluoro-3-methylbenzo[d]isoxazole-5-carb-
oxylic acid (2-hydroxyethoxy)-amide (12a)
[0189] The reaction scheme for the synthesis of compound 12a is
shown in FIG. 2.
[0190] Step A: Preparation of
6-(4-bromo-2-chlorophenylamino)-7-fluoro-3-methyl-benzo[d]isoxazole-5-car-
boxylic acid (2-vinyloxyethoxy)-amide (11a): To a solution of
6-(4-bromo-2-chlorophenylamino)-7-fluoro-3-methylbenzo[d]isoxazole-5-carb-
oxylic acid (10a) (75.2 mg, 0.188 mmol) in DMF (1.5 mL) was added
HOBt (38.2 mg, 0.249 mmol), Et.sub.3N (0.080 mL, 0.571 mmol),
O-(2-vinyloxyethyl)hydroxylamine (28.5 mg, 0.276 mmol), and EDCI
(47.2 mg, 0.246 mmol) at room temperature. After 6 days, the
reaction mixture was diluted with EtOAc, washed with saturated
aqueous NH.sub.4Cl, brine, saturated aqueous NaHCO.sub.3, and
brine. The organic layer was dried over MgSO.sub.4, filtered,
concentrated in vacuo, and purified by flash column chromatography
using the Biotage system (3% MeOH in CH.sub.2Cl.sub.2) to give 57.8
mg (63%) of the desired product (11a).
[0191] Step B: Preparation of
6-(4-bromo-2-chlorophenylamino)-7-fluoro-3-methylbenzo[d]isoxazole-5-carb-
oxylic acid (2-hydroxyethoxy)-amide (12a): A solution of
6-(4-bromo-2-chlorophenylamino)-7-fluoro-3-methylbenzo[d]isoxazole-5-carb-
oxylic acid (2-vinyloxyethoxy) amide (11a) (55.4 mg, 0.114 mmol)
and aqueous HCl (1 M, 0.23 mL) in EtOH (3 mL) was stirred for 2
hours at room temperature. The pH of the reaction mixture was
adjusted to 6-7 with aqueous NaOH (2 N). The reaction was diluted
with EtOAc. The organic layer was washed with water, dried over
MgSO.sub.4, filtered, and concentrated in vacuo to give 50.2 mg
(96% yield) of the desired product (12a). MS APCI (-) m/z 456, 458
(M+, Br, Cl pattern) detected: .sup.1H NMR (400 MHz, CD.sub.3OD)
.delta. 7.87 (s, 1H), 7.57 (d, 1H), 7.31 (dd, 1H), 6.74 (dd, 1H),
4.01 (t, 2H), 3.74 (t, 2H), 2.60 (s, 3H): .sup.19F NMR (376 MHz,
CD.sub.3OD)-140.85 (s, 1F).
Example 4
[0192] ##STR24##
Synthesis of
N-[6-(4-bromo-2-chlorophenylamino)-7-fluoro-3-methylbenzo[d]isoxazole-5-c-
arbonyl]-methanesulfonamide (13a)
[0193] The reaction scheme for the synthesis of compound 13a is
shown in FIG. 3. A mixture of
6-(4-bromo-2-chlorophenylamino)-7-fluoro-3-methylbenzo[d]isoxazole-5-carb-
oxylic acid (9a) (41 mg, 0.102 mmol) and carbonyl diimidazole (23
mg, 0.140 mmol) in THF (1 mL) was stirred at 50.degree. C. in a
sealed tube reactor. The reaction mixture was cooled to room
temperature and methanesulfonamide (17 mg, 0.179 mmol) was added
followed by DBU (0.025 ml, 0.164 mmol). After stirring at
50.degree. C. for 1 hour, the reaction mixture was cooled to room
temperature, and diluted with EtOAc. The organic layer was washed
with water, 1 N HCl, and brine. The organic layer was dried
(MgSO.sub.4) and concentrated. Purification by flash column
chromatography using the Biotage system (7% MeOH in
CH.sub.2Cl.sub.2) provided 34 mg (65% yield) of the desired product
(13a). MS APCI (-) m/z 474, 476 (M+, Br, Cl pattern) detected:
.sup.1H NMR (400 MHz, CD.sub.3OD) .delta. 8.27 (s, 1H), 7.53 (s,
1H), 7.27 (d, 1H), 6.73 (t, 1H), 3.11 (s, 3H), 2.55 (s, 3H):
.sup.19F NMR (376 MHz, CD.sub.3OD)-141.84 (s, 1F).
Example 5
[0194] ##STR25##
Synthesis of
6-(2,4-dichloro-phenylamino)-7-fluoro-3-methylbenzo[d]isoxazole-5-carboxy-
lic acid (9b)
[0195] The reaction scheme for the synthesis of compound 9b is
shown in FIG. 1.
[0196] Step A: Preparation of
6-(2,4-dichlorophenylamino)-7-fluoro-3-methylbenzo[d]isoxazole-5-carboxyl-
ic acid methyl ester (8b):
6-(2-Chlorophenylamino)-7-fluoro-3-methylbenzo[d]isoxazole-5-carboxylic
acid methyl ester (7) (129 mg, 0.384 mmol) and N-chlorosuccinimide
(57 mg, 0.421 mmol) were stirred in DMF (5 mL) for 16 hours.
Concentrated HCl (3 .mu.L) was added and the reaction mixture
stirred 2 hours. The reaction mixture was diluted with EtOAc, and
washed with water (2.times.). The organic layer was dried over
MgSO.sub.4, filtered, and concentrated. Purification by flash
column chromatography using the Biotage system (5% EtOAc in
hexanes) provided 73 mg (52%) the desired product (8b).
[0197] Step B: Preparation of
6-(2,4-dichlorophenylamino)-7-fluoro-3-methylbenzo[d]isoxazole-5-carboxyl-
ic acid (9b): Compound 9b was prepared according to Step H of
Example 1 using
6-(2,4-dichlorophenylamino)-7-fluoro-3-methylbenzo[d]isoxazole-5-ca-
rboxylic acid methyl ester (8b) to provide 68 mg (98% yield) of the
desired product (9b). MS APCI (-) m/z 353, 355 (M+, Br, Cl pattern)
detected: .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 9.58 (s, 1H),
8.34 (s, 1H), 7.65 (d, 1H), 7.31 (dd, 1H), 7.04 (dd, 1H), 2.60 (s,
3H): .sup.19F NMR (376 MHz, DMSO-d.sub.6)-140.36 (s, 1F).
Example 6
[0198] ##STR26##
Synthesis of
6-(2,4-dichlorophenylamino)-7-fluoro-3-methylbenzo[d]isoxazole-5-carboxyl-
ic acid (2-hydroxyethoxy)amide (12b)
[0199] The reaction scheme for the synthesis of compound 12b, as
shown in FIG. 4, was carried out according to Steps A and B of
Example 3 using
6-(2,4-dichlorophenylamino)-7-fluoro-3-methylbenzo[d]isoxazole-5-carboxyl-
ic acid (9b) as the starting material to provide 29 mg (38% yield
for two steps) of 12b. MS APCI (-) m/z 412, 414 (M+, Br, Cl
pattern) detected: .sup.1H NMR (400 MHz, CD.sub.3OD) .delta. 7.87
(s, 1H), 7.45 (m, 1H), 7.19 (m, 1H), 6.80 (m, 1H), 4.02 (t, 2H),
3.75 (t, 2H), 2.60 (s, 3H): .sup.19F NMR (376 MHz,
CD.sub.3OD)-141.05 (s, 1F).
Example 7
[0200] ##STR27##
Synthesis of 3-amino-6-(4-bromo-2-chlorophenylamino)-7-fluorobenzo
[d]isoxazole-5-carboxylic acid (19)
[0201] The reaction scheme for the synthesis of compound 19 is
shown in FIG. 5.
[0202] Step A: Preparation of
2-(2-chlorophenylamino)-5-cyano-3,4-difluorobenzoic acid methyl
ester (15): A mixture of
5-bromo-2-(2-chlorophenylamino)-3,4-difluorobenzoic acid methyl
ester (14) (3.01 g, 7.99 mmol), 1,1'-bis(diphenylphosphino)
ferrocene (dppf) (93 mg, 0.162 mmol), Pd.sub.2 dba.sub.3 (73 mg,
0.080 mmol) and Zn(CN).sub.2 (573 mg, 4.78 mmol) in
1-methyl-2-pyrrolidinone (NMP: 4.5 mL) was heated in a sealed tube
reactor. After 20 hours, the reaction mixture was cooled to room
temperature, quenched by the addition of 8 mL 4:1:4 (volume)
mixture of saturated NH.sub.4Cl, concentrated NH.sub.4OH and water,
and extracted with a mixture of EtOAc:THF. The combined organic
extracts were washed with 4:1:4 (volume) mixture of saturated
NH.sub.4Cl, concentrated NH.sub.4OH and water, and brine. The
organic layer was dried (MgSO.sub.4) and concentrated. Purification
by flash column chromatography using the Biotage system (twice:
100% hexanes to 35% CH.sub.2Cl.sub.2 in hexanes, then 30%
CH.sub.2Cl.sub.2 in hexanes) provided 1.33 g (52%) of the desired
product (15).
[0203] Step B: Preparation of
3-amino-6-(2-chlorophenylamino)-7-fluorobenzo[d]isoxazole-5-carboxylic
acid methyl ester (17): t-BuOK (3.80 mL of a 1.0 M solution in THF)
was added to a stirred solution of acetone oxime (285 mg, 3.82
mmol) in THF (5 mL) at room temperature. The reaction mixture was
further diluted with THF (20 mL) and after 30 minutes cooled to
0.degree. C. A solution of
2-(2-chlorophenylamino)-5-cyano-3,4-difluorobenzoic acid methyl
ester (15) (600 mg, 1.86 mmol) in THF (5 mL) was added. The
reaction mixture was slowly warmed to room temperature. After 90
minutes, the reaction mixture was quenched with saturated
NH.sub.4Cl and diluted with EtOAc. The organic layer was washed
with saturated NH.sub.4Cl and brine, dried (MgSO.sub.4) and
concentrated. The residue (16) was diluted with MeOH (10 mL) and a
solution of 2 M HCl in diethyl ether (10 mL) was added. After 16
hours, the reaction mixture was diluted with EtOAc, washed with
water, saturated NaHCO.sub.3 and water. The organic layer was dried
(MgSO.sub.4) and concentrated. Purification by flash column
chromatography using the Biotage system (1.5% MeOH in
CH.sub.2Cl.sub.2) provided 399 mg (64%) of the desired product
(17).
[0204] Step C: Preparation of
3-amino-6-(4-bromo-2-chlorophenylamino)-7-fluorobenzo[d]isoxazole-5-carbo-
xylic acid methyl ester (18): Compound 18 was prepared according to
Step G of Example 1 using compound 17 as the starting material.
[0205] Step D: Preparation of
3-amino-6-(4-bromo-2-chlorophenylamino)-7-fluoro-benzo[d]isoxazole-5-carb-
oxylic acid (19): Compound 19 was prepared according to Step H of
Example 1 using
3-amino-6-(4-bromo-2-chlorophenylamino)-7-fluorobenzo[d]isoxazole-
-5-carboxylic acid methyl ester (18) as the starting material to
provide 188 mg (98% yield) of compound 19. MS APCI (-) m/z 398, 400
(M+, Br, Cl pattern) detected: .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta. 9.47 (s, 1H), 8.49 (s, 1H), 7.73 (m, 1H), 7.41 (dd, 1H),
6.92 (t, 1H), 6.76 (s, 2H): .sup.19F NMR (376 MHz,
DMSO-d.sub.6)-141.48 (s, 1F).
Example 8
[0206] ##STR28##
Synthesis of
3-amino-6-(4-bromo-2-chloro-phenylamino)-7-fluorobenzo[d]isoxazole-5-carb-
oxylic acid (2-hydroxyethoxy)-amide (21).
[0207] The reaction scheme for the synthesis of compound 21, as
shown in FIG. 6, was accomplished according to Steps A and B of
Example 3 using
3-amino-6-(4-bromo-2-chlorophenylamino)-7-fluorobenzo[d]isoxazole-5-carbo-
xylic acid (19) as the starting material to provide 16 mg (23%
yield for two steps) of compound 21. MS APCI (-) m/z 457, 459 (M+,
Br, Cl pattern) detected: .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta. 11.92 (s, 1H), 8.59 (s, 1H), 7.94 (s, 1H), 7.69 (s, 1H),
7.36 (d, 1H), 6.75 (dd, 1H), 6.71 (s, 2H), 4.73 (s, 1H), 3.87 (s,
2H), 3.59 (s, 2H): .sup.19F NMR (376 MHz, DMSO-d.sub.6)-140.64 (s,
1F).
Example 9
[0208] ##STR29##
Synthesis of
7-(4-bromo-2-chlorophenylamino)-8-chloroimidazo[1,2-a]pyridine-6-carboxyl-
ic acid (30)
[0209] The reaction scheme for the synthesis of compound 30 is
shown in FIG. 7
[0210] Step A: Preparation of 4,6-dichloronicotinic acid ethyl
ester (22): POCl.sub.3 (100 mL, 1092 mmol) was added to
4,6-dihydroxynicotinic acid ethyl ester (J. Heterocyclic Chem.
1983, 20, 1363) (20.0 g, 109 mmol). The resulting suspension was
cooled to 0.degree. C. and triethylamine (15.2 mL, 109 mmol) was
added dropwise at such a rate as to maintain the internal reaction
mixture temperature below 25.degree. C. Upon completion of
addition, the reaction mixture was warmed to room temperature and
then to 80.degree. C. After 4 hours, the reaction mixture was
cooled to room temperature and stirred for 16 hours. The reaction
mixture was carefully poured onto 2 L crushed ice. The mixture was
extracted with EtOAc and diethyl ether. The combined organic
extracts were washed with brine, dried (Na.sub.2SO.sub.4) and
concentrated. The dark brown liquid was purified by passing through
a plug of silica gel (CH.sub.2Cl.sub.2) to give the desired product
(22) as a low melting yellow solid (18.7 g, 78%).
[0211] Step B: Preparation of 4,6-dichloronicotinic acid (23):
Sodium hydroxide (40 mL, 6.25 M solution) was added to a stirred
solution of 4,6-dichloronicotinic acid ethyl ester (22) (25.95 g,
118 mmol) in 4:1:1 THF:MeOH:water (600 mL). After 30 minutes, the
reaction mixture was acidified to pH 2 with concentrated HCl,
diluted with 1:1 EtOAc:Et.sub.2O and washed with water and brine.
The organic layer was dried (Na.sub.2SO.sub.4) and concentrated.
The resulting off-white solid was twice concentrated from toluene
to give the desired product (23) as a white solid (21.73 g,
96%).
[0212] Step C: Preparation of
4-(4-bromo-2-chlorophenylamino)-6-chloronicotinic acid
hydrochloride salt (24): LiHMDS (261 mL of a 1 M solution in
hexanes) was added dropwise over 30 minutes to a solution of
4-bromo-2-chlorophenylamine (35.0 g, 172 mmol) in THF (80 mL) at
-78.degree. C. After 1 hour, 4,6-dichloronicotinic acid (23) (15.7
g, 81.7 mmol) was added dropwise over 30 minutes. The reaction
mixture was slowly warmed to room temperature and stirred 16 hours.
The reaction mixture was quenched with water, diluted with EtOAc
and acidified with 1 N HCl. The resulting precipitate was isolated
by filtration and washed with EtOAc. The solids were twice
concentrated from toluene, triturated with CH.sub.2Cl.sub.2 and
collected by filtration. The solids were further concentrated from
toluene (3.times.) followed by drying in vacuo to give the desired
product (24) containing a small amount of water (36.0 g).
[0213] Step D. Preparation of
4-(4-Bromo-2-chloro-phenylamino)-5,6-dichloro-nicotinic acid (25):
N-Chlorosuccinimide was (13.0 g, 99.0 mmol) added to a suspension
of 4-(4-bromo-2-chloro-phenylamino)-6-chloro-nicotinic acid (24)
(32.54 g, 89.9 mmol) in DMF (500 mL). The suspension was allowed to
stir at room temperature overnight. The reaction mixture was
diluted with saturated sodium bisulfite (200 mL) and water (1 L)
resulting in formation of a thick white precipitate which was
isolated by filtration and washed with water. The solids were
dissolved into THF. Two volumes of diethyl ether were added and the
organic solution washed with brine, dried over NaSO.sub.4,
filtered, and concentrated in vacuo to provide an orange solid. The
solid was triturated with diethyl ether to provide the desired
product as an off-white solid (25) (13.34 g, 37%). MS (APCI-) m/z
393, 395, 397 (M-; Cl, Br pattern) detected.
[0214] Step E. Preparation of
4-(4-Bromo-2-chloro-phenylamino)-5,6-dichloro-nicotinic acid methyl
ester (26): Trimethylsilyldiazomethane (2.0 M solution in hexanes,
37 mL, 74 mmol) was added slowly to a suspension of
4-(4-bromo-2-chloro-phenylamino)-5,6-dichloro-nicotinic acid (25)
(14.67 g, 37 mmol). After the addition was complete the resulting
slurry was diluted with hexanes (600 mL) and the solids isolated by
filtration washing with hexanes. The desired product was isolated
as an off-white solid (10.06 g). The hexanes washes were
concentrated and the solids passed through a plug of silica gel
eluting with dichloromethane. Concentration of the
product-containing fractions provided an additional 3.83 g desired
product (26) for a total of 13.89 g (91%). MS (APCI+) m/z 409, 411,
413 (M+; Cl, Br pattern) detected.
[0215] Step F. Preparation of
6-Azido-4-(4-bromo-2-chloro-phenylamino)-5-chloro-nicotinic acid
methyl ester (27): Sodium azide (4.4 g, 68 mmol) was added to a
suspension of
4-(4-bromo-2-chloro-phenylamino)-5,6-dichloro-nicotinic acid methyl
ester (26) (13.89 g, 33.8 mmol) in DMF (200 mL) and the mixture
allowed to stir at room temperature overnight. The solution was
diluted with water (600 mL) and the resulting white precipitate was
collected by filtration and washed with water. The solids were
dissolved into THF. Two volumes of diethyl ether were added and the
organic solution washed with brine, dried over NaSO.sub.4,
filtered, and concentrated in vacuo to the desired product (27) as
a light yellow solid (12.94 g, 92%).
[0216] Step G. Preparation of
6-Amino-4-(4-bromo-2-chloro-phenylamino)-5-chloro-nicotinic acid
methyl ester (28): Zinc powder (10 g, 155 mmol) was added
portionwise to a suspension of
6-azido-4-(4-bromo-2-chloro-phenylamino)-5-chloro-nicotinic acid
methyl ester (27) (12.94 g, 31 mmol) in 3:1 dichloromethane/acetic
acid (300 mL). After fifteen minutes the reaction mixture was
poured into 700 mL ethyl acetate, washed with water, saturated
sodium bicarbonate and brine. The organic solution was dried over
NaSO.sub.4, filtered, and concentrated in vacuo to provide the
desired product (28) as an off-white solid (11.85 g, 98%). MS
(APCI+) m/z 390, 392, 394 (M+; Cl, Br pattern) detected.
[0217] Step H. Preparation of
7-(4-Bromo-2-chloro-phenylamino)-8-chloro-imidazo[1,2-a]pyridine-6-carbox-
ylic acid methyl ester (29): Chloroacetaldehyde (50% aqueous
solution, 0.70 mL, 5.7 mmol) was added to a suspension of
6-amino-4-(4-bromo-2-chloro-phenylamino)-5-chloro-nicotinic acid
methyl ester (28) in DMF (7 mL) contained in a sealed tube. The
reaction mixture was heated at 80.degree. C. for four hours and
then allowed to cool to room temperature and stir overnight. The
dark brown solution was diluted with water (70 mL) the resulting
light brown precipitate was collected by filtration and washed with
water. The solids were dissolved into THF. Two volumes of ethyl
acetate were added and the organic solution washed with brine,
dried over NaSO.sub.4, filtered, and concentrated in vacuo to
provide a brown solid. The aqueous filtrate was extracted with
ethyl acetate and the organic extracts were dried over NaSO.sub.4,
filtered, and concentrated in vacuo. This material was combined
with the previously isolated brown solid and the combined material
subjected to column chromatography (dichloromethane, followed by
20:1 dichloromethane/methanol). The desired product (29) was
isolated as a light yellow solid (0.752 g, 64%). MS (APCI+) m/z
414, 416, 418 (M+; Cl, Br pattern) detected.
[0218] Step I. Preparation of
7-(4-Bromo-2-chloro-phenylamino)-8-chloro-imidazo[1,2-a]pyridine-6-carbox-
ylic acid (30): Sodium hydroxide (1.0 M aqueous solution, 14.6 mL,
14.6 mmol) was added to a solution of
7-(4-bromo-2-chloro-phenylamino)-8-chloro-imidazo[1,2-a]pyridine-6-carbox-
ylic acid methyl ester (29) in methanol (30 mL) and the solution
allowed to stir at room temperature overnight. Methanol was removed
by rotary evaporation and the solution diluted with water and
acidified to pH 2 by addition of 1.0 M HCl. The aqueous suspension
was extracted with 4:1 ethyl acetate/THF. The organic extracts were
washed with brine, dried over NaSO.sub.4, filtered, and
concentrated in vacuo to provide the desired product as a light
orange solid (30). MS (APCI+) m/z 400, 402, 404 (M+: Cl, Br
pattern) detected: .sup.1H NMR (400 MHz, methanol-d.sub.4) .delta.
9.01 (s, 1H), 7.83 (s, 1H), 7.51 (s, 2H), 7.25 (d, 1H), 6.60 (d,
1H).
Example 10
[0219] ##STR30##
Synthesis of
7-(4-bromo-2-chlorophenylamino)-8-chloroimidazo[1,2-a]pyridine-6-carboxyl-
ic acid cyclopropylmethoxyamide (31)
[0220] FIG. 8 shows the reaction scheme for the synthesis of
compound 31, which was prepared according to the method of Example
2, using
7-(4-bromo-2-chlorophenylamino)-8-chloroimidazo[1,2-a]pyridine-6-carboxyl-
ic acid (30) as the starting material to provide 4.1 g (53% yield)
of compound 31. MS (APCI-) m/z 467, 469, 471 (M-: Cl, Br pattern)
detected: .sup.1H NMR (400 MHz, methanol-d.sub.4) .delta. 8.76 (s,
1H), 7.95 (d, 1H), 7.64 (d, 1H), 7.56 (d, 1H), 7.26 (dd, 1H), 6.56
(d, 1H), 3.57 (d, 2H), 1.10 (m, 1H), 0.54 (m, 2H), 0.24 (m,
2H).
[0221] The following compounds were synthesized in a similar manner
as shown in FIGS. 7, 8, and 9 using the appropriate aniline in Step
C of Example 9. ##STR31##
7-(4-Bromo-2-fluorophenylamino)-8-chloroimidazo[1,2-a]pyridine-6-carboxyli-
c acid cyclopropylmethoxyamide
[0222] MS ESI (+) m/z 453, 455, 457 (M+, Cl, Br pattern) detected.
.sup.1H NMR (400 MHz, CD.sub.3OD) .delta. 8.70 (s, 1H), 7.95 (s,
1H), 7.67 (s, 1H), 7.34 (m, 1H), 7.20 (m, 1H), 6.79 (m, 1H), 3.49
(m, 2H), 1.08 (m, 1H), 0.55 (m, 2H), 0.26 (m, 2H). .sup.19F NMR
(376 MHz, CD.sub.3OD) .delta.-127.4. ##STR32##
Synthesis of
8-chloro-7-(2-fluorophenylamino)-imidazo[1,2-a]pyridine-6-carboxylic
acid cyclopropylmethoxy-amide
[0223] MS ESI (+) m/z 375, 377 (M+, Cl pattern) detected. .sup.1H
NMR (400 MHz, CD.sub.3OD) .delta. 8.70 (s, 1H), 7.91 (s, 1H), 7.60
(s, 1H), 7.09 (m, 1H), 7.00 (m, 1H), 6.95 (m, 1H), 6.77 (m, 1H),
3.47 (d, 2H), 1.05 (m, 1H), 0.51 (m, 2H), 0.22 (m, 2H). .sup.19F
NMR (376 MHz, CD.sub.3OD) .delta.-132.1. ##STR33##
Synthesis of
7-(4-bromo-2-fluor-phenylamino)-8-chloroimidazo[1,2-a]pyridine-6-carboxyl-
ic acid (2-hydroxyethoxy)-amide
[0224] MS ESI (+) m/z 443, 445, 447 (M+, Cl, Br pattern) detected.
.sup.1H NMR (400 MHz, CD.sub.3OD) .delta. 8.74 (s, 1H), 7.91 (s,
1H), 7.61 (s, 1H), 7.32 (m, 1H), 7.16 (m, 1H), 6.68 (m, 1H), 3.84
(t, 2H), 3.66 (t, 2H). .sup.19F NMR-(376 MHz, CD.sub.3OD)
.delta.-128.9. ##STR34##
8-Chloro-7-(2-fluorophenylamino)-imidazo[1,2-a]pyridine-6-carboxylic
acid (2-hydroxyethoxy)-amide
[0225] MS ESI (+) m/z 365, 367 (M+, Cl pattern) detected. .sup.1H
NMR (400 MHz, CD.sub.3OD) .delta. 8.73 (s, 1H), 7.89 (s, 1H), 7.59
(s, 1H), 7.10 (m, 1H), 7.00 (m, 1H), 6.94 (m, 1H), 6.77 (m, 1H),
3.78 (t, 2H), 3.62 (t, 2H). .sup.19F NMR (376 MHz, CD.sub.3OD)
.delta.-131.9. ##STR35##
Synthesis of
8-chloro-7-(2,4-dichlorophenylamino)-imidazo[1,2-a]pyridine-6-carboxylic
acid (2-hydroxyethoxy) amide
[0226] MS APCI (-) m/z 413, 415, 417 (M-, Cl pattern) detected:
.sup.1H NMR (400 MHz, CD.sub.3OD) .delta. 8.78 (s, 1H), 7.90 (s,
1H), 7.87 (s, 1H), 7.10 (dd, 1H), 6.61 (d, 1H), 4.0 (m, 2H), 3.72
(m, 2H). ##STR36##
7-(4-Bromo-2-fluorophenylamino)-8-chloro-imidazo[1,2-a]pyridine-6-carboxyl-
ic acid
[0227] MS ESI (+) m/z 384, 386, 388 (M+, Cl, Br pattern) detected.
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 9.29 (s, 1H), 8.10 (s,
1H), 7.68 (s, 1H), 7.53 (m, 1H), 7.23 (m, 1H), 6.75 (m, 1H).
.sup.19F NMR (376 MHz, DMSO-d.sub.6) .delta.-127.9. ##STR37##
8-Chloro-7-(2-fluorophenylamino)-imidazo[1,2-a]pyridine-6-carboxylic
acid
[0228] MS ESI (+) m/z 306, 308 (M+, Cl pattern) detected. .sup.1H
NMR (400 MHz, DMSO-d.sub.6) .delta. 9.30 (s, 1H), 8.09 (s, 1H),
7.67 (s, 1H), 7.22 (dd, 1H), 7.06 (dd, 1H), 6.98 (m, 1H), 6.84 (m,
1H). .sup.19F NMR (376 MHz, DMSO-d.sub.6) .delta.-130.5.
##STR38##
8-Chloro-7-(4-chloro-2-fluorophenylamino)-imidazo[1,2-a]pyridine-6-carboxy-
lic acid
[0229] MS ESI (+) m/z 340, 342 (M+, Cl pattern) detected. .sup.1H
NMR (400 MHz, DMSO-d.sub.6) .delta. 9.29 (s, 1H), 8.10 (s, 1H).
7.68 (s, 1H), 7.43 (m, 1H), 7.12 (m, 1H), 6.83 (m, 1H). .sup.19F
NMR (376 MHz, DMSO-d.sub.6) .delta.-127.8. ##STR39##
8-Chloro-7-(4-chloro-2-fluorophenylamino)-imidazo[1,2-a]pyridine-6-carboxy-
lic acid cyclopropylmethoxyamide
[0230] MS ESI (+) m/z 409, 411 (M+, Cl pattern) detected. .sup.1H
NMR (400 MHz, CD.sub.3OD) .delta. 9.97 (br s, 1H), 8.82 (s, 1H).
7.73 (s, 1H), 7.71 (s, 1H), 7.18 (m, 1H), 6.97 (m, 1H), 6.56 (m,
1H), 6.47 (br s, 1H), 3.60 (m, 2H), 1.00 (m, 1H), 0.56 (m, 2H),
0.24 (m, 2H).
[0231] .sup.19F NMR (376 MHz, CD.sub.3OD) .delta.-128.7.
Example 11
[0232] ##STR40##
Synthesis of
7-(4-bromo-2-chlorophenylamino)-8-chloroimidazo[1,2-a]pyridine-6-carboxyl-
ic acid (2-hydroxyethoxy)-amide (33a)
[0233] The reaction scheme for the synthesis of compound 33a is
shown in FIG. 9, which was prepared according to Steps A and B of
Example 3 using
7-(4-bromo-2-chlorophenylamino)-8-chloroimidazo[1,2-a]pyridine-6-carboxyl-
ic acid (30) to provide 44 mg (40% yield for two steps) of the
desired product. MS (APCI+) m/z 459, 461, 463 (M+: Cl, Br pattern)
detected: .sup.1H NMR (400 MHz, methanol-d.sub.4) .delta. 8.90 (s,
1H), 8.08 (s, 1H), 7.93 (s, 1H), 7.69 (s, 1H), 7.45, (d, 1H), 7.06
(m, 1H), 3.86 (br s, 2H), 3.72 (br s, 2H).
Example 12
[0234] ##STR41##
Synthesis of
7-(4-bromo-2-chlorophenylamino)-8-chloro-3-(4-methylpiperazin-1-yl)-imida-
zo[1,2-a]pyridine-6-carboxylic acid cyclopropylmethoxyamide
(36)
[0235] The reaction scheme for the synthesis of compound 36 is
shown in FIG. 10.
[0236] Step A:
7-(4-Bromo-2-chlorophenylamino)-8-chloro-3-(4-methylpiperazin-1-yl)-imida-
zo[1,2-a]pyridine-6-carboxylic acid methyl ester (34): Preparation
was accomplished by modification of the procedure of Katritzky et
al. (J. Org. Chem., 2003, 68, 4935-4937: J. Org. Chem., 1990, 55,
3209-3213). Bis(benzotriazazole) adduct (formed with
1-methylpiperazine) (106 mg, 0.230 mmol) was added to a suspension
of 6-amino-4-(4-bromo-2-chlorophenylamino)-5-chloronicotinic acid
methyl ester (28) (30 mg, 0.076 mmol) in dichloroethylene (1 mL)
followed by the addition of ZnBr.sub.2 (52 mg, 0.230 mmol). The
reaction mixture was stirred at reflux for 10 hours and then at
room temperature for 16 hours. The reaction mixture was diluted
with CH.sub.2Cl.sub.2 and filtered. The filtrate was washed with
water. The aqueous layer was extracted with CH.sub.2Cl.sub.2. The
combined organic extracts were washed with brine, dried
(Na.sub.2SO.sub.4) and concentrated. Purification by flash column
chromatography using the Biotage system (60:1
CH.sub.2Cl.sub.2:MeOH) provided the desired product (34) as a
yellow solid (31 mg, 79%).
[0237] Step B:
7-(4-Bromo-2-chlorophenylamino)-8-chloro-3-(4-methylpiperazin-1-yl)-imida-
zo[1,2-a]pyridine-6-carboxylic acid cyclopropylmethoxyamide (36):
Sodium hydroxide (59 .mu.L, 1 M solution) was added to a suspension
of
7-(4-bromo-2-chlorophenylamino)-8-chloro-3-(4-methylpiperazin-1-yl)-imida-
zo[1,2-a]pyridine-6-carboxylic acid methyl ester (34) in MeOH (1
mL). After stirring 18 hours, the reaction mixture was concentrated
to dryness. The residue (35) was diluted with toluene and
concentrated (repeated), and 31 mg of the recovered yellow residue
(35) was carried forward without purification. The residue (35) was
suspended in CH.sub.2Cl.sub.2 (1 mL), cooled to 0.degree. C. and
oxalyl chloride (150 .mu.L of a 2 M solution in CH.sub.2Cl.sub.2)
was added. One drop of DMF was added and the reaction mixture
warmed to room temperature. After 10 minutes, concentration of the
mixture was followed by concentrating from toluene twice and then
drying in vacuo. The resulting yellow solid was suspended in
CH.sub.2Cl.sub.2 (1 mL), cooled to 0.degree. C. and
cyclopropylmethylhydroxylamine (16 mg, 0.180 mmol) was added. After
the reaction mixture was warmed to room temperature and stirred for
16 hours, it was diluted with EtOAc. The organic layer was washed
with saturated NaHCO.sub.3 and brine, dried (Na.sub.2SO.sub.4) and
concentrated. Purification by flash column chromatography using the
Biotage system (15:1 CH.sub.2Cl.sub.2:MeOH) provided the desired
product (36) as a pale yellow solid (12 mg, 37%). MS ESI (+) m/z
567, 569, 571 (M+, Cl, Br pattern) detected: .sup.1H NMR (400 MHz,
CD.sub.3OD) .delta. 8.35 (s, 1H), 7.55 (d, 1H), 7.38 (s, 1H), 7.25
(dd, 1H), 6.54 (d, 1H), 3.59 (d, 2H), 3.17 (t, 4H), 2.74 (m, 4H),
2.43 (s, 3H), 1.09 (m, 1H), 0.54 (m, 2H), 0.24 (m, 2H).
Example 13
[0238] ##STR42##
Synthesis of
7-(4-bromo-2-chlorophenylamino)-8-chloro-3-morpholin-4-yl-imidazo[1,2-a]--
pyridine-6-carboxylic acid cyclopropylmethoxyamide (37)
[0239] The reaction scheme for the synthesis of compound 37 is
shown in FIG. 10. Compound 37 was prepared according to Steps A and
B of Example 12 using
6-amino-4-(4-bromo-2-chlorophenylamino)-5-chloronicotinic acid
methyl ester (28) and the bis(benzotriazazole) adduct (formed with
morpholine) to provide 2 mg (8% yield for two steps) of the desired
product (37). MS ESI (+) m/z 554, 556, 558 (M+, Cl, Br pattern)
detected: .sup.1H NMR (400 MHz, CD.sub.3OD) .delta. 8.41 (s, 1H),
7.55 (d, 1H), 7.38 (s, 1H), 7.26 (dd, 1H), 6.54 (d, 1H), 3.91 (t,
4H), 3.59 (d, 2H), 3.11 (t, 4H), 1.08 (m, 1H), 0.54 (m, 2H), 0.24
(m, 2H).
Example 14
[0240] ##STR43##
Synthesis of
7-(4-bromo-2-chlorophenylamino)-8-chloro-3-dimethylaminoimidazo[1,2-a]pyr-
idine-6-carboxylic acid cyclopropylmethoxyamide (38)
[0241] The reaction scheme for the synthesis of compound 38 is
shown in FIG. 10. Compound 38 was prepared according to Steps A and
B of Example 12 using
6-amino-4-(4-bromo-2-chlorophenylamino)-5-chloronicotinic acid
methyl ester (28) and the bis(benzotriazazole) adduct (formed with
dimethylamine) providing 16 mg (37% yield for two steps) of the
desired product (38). MS ESI (+) m/z 512, 514, 516 (M+, Cl, Br
pattern) detected: .sup.1H NMR (400 MHz, CD.sub.3OD) .delta. 8.37
(s, 1H), 7.54 (d, 1H), 7.30 (s, 1H), 7.24 (dd, 1H), 6.52 (d, 1H),
3.59 (d, 2H), 2.86 (s, 6H), 1.07 (m, 1H), 0.53 (m, 2H), 0.23 (m,
2H).
Example 15
[0242] ##STR44##
Synthesis of
7-(4-bromo-2-chlorophenylamino)-8-chloro-3-piperidin-1-ylmethylimidazo[1,-
2-a]pyridine-6-carboxylic acid (2-hydroxyethoxy) amide (39)
[0243] The reaction scheme for the synthesis of compound 39 is
shown in FIG. 11. Compound 39 was prepared by a modification of the
procedure of Kercher et al. (manuscript in preparation). Piperidine
(4 .mu.L, 0.043 mmol) and 37% aqueous formaldehyde (5 .mu.L, 0.065
mmol) were dissolved in 6:1 MeCN:water (0.5 ml), and stirred 30
minutes.
7-(4-bromo-2-chlorophenylamino)-8-chloroimidazo[1,2-a]pyridine-6-carboxyl-
ic acid (2-hydroxyethoxy)amide (33a) (10 mg, 0.022 mmol) was added
followed by scandium triflate (1 mg, 0.002 mmol). After stirring 16
hours, additional scandium triflate (1 mg), piperidine (3.8 .mu.L)
and aqueous formaldehyde (3.8 .mu.L) were added. After about 60
hours, the reaction mixture was diluted with EtOAc and washed with
water, 10% K.sub.2CO.sub.3, and brine. The organic layer was dried
(Na.sub.2SO.sub.4) and concentrated. Purification by flash column
chromatography using the Biotage system (40:1 CH.sub.2Cl.sub.2:MeOH
to 20:1 CH.sub.2Cl.sub.2:MeOH to 9:1 CH.sub.2Cl.sub.2:MeOH)
provided the desired product (39) as a white solid (6 mg, 50%). MS
APCI (+) m/z 556, 558, 560 (M+, Cl, Br pattern) detected: .sup.1H
NMR (400 MHz, CD.sub.3OD) .delta. 8.83 (s, 1H), 7.56 (s, 1H), 7.54
(s, 1H), 7.27 (dd, 1H), 6.56 (d, 1H), 3.91 (m, 4H), 3.70 (m, 2H),
2.51 (broad s, 4H), 1.60 (broad s, 4H), 1.50 (broad s, 2H).
[0244] The following compounds were synthesized in a similar manner
as shown in FIG. 11. ##STR45##
7-(4-Bromo-2-chlorophenylamino)-8-chloro-3-morpholin-4-ylmethyl-imidazo[1,-
2-a]pyridine-6-carboxylic acid cyclopropylmethoxy-amide
[0245] The reaction scheme for the synthesis of
7-(4-bromo-2-chlorophenylamino)-8-chloro-3-morpholin-4-ylmethyl-imidazo[1-
,2-a]pyridine-6-carboxylic acid cyclopropylmethoxy-amide is similar
to that shown in FIG. 11 using
7-(4-bromo-2-chlorophenylamino)-8-chloroimidazo[1,2-a]pyridine-6-carboxyl-
ic acid (2-hydroxyethoxy)amide (33a) and morpholine to provide the
desired product. MS APCI (+) m/z 568, 570, 572 (M+, Cl, Br pattern)
detected; .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.76 (s, 1H),
8.04 (s, 1H), 7.56 (d, 1H), 7.21 (dd, 1H), 6.68 (d, 1H), 4.51 (s,
2H), 4.00 (m, 4H), 3.78 (d, 2H), 1.68 (m, 1H), 0.56 (m, 2H), 0.26
(m, 2H). ##STR46##
7-(4-Bromo-2-chlor-phenylamino)-8-chloro-3-dimethylaminomethyl-imidazo[1,2-
-a]pyridine-6-carboxylic acid cyclopropylmethoxyamide
[0246] The reaction scheme for the synthesis of
7-(4-bromo-2-chlor-phenylamino)-8-chloro-3-dimethylaminomethyl-imidazo[1,-
2-a]pyridine-6-carboxylic acid cyclopropylmethoxyamide was similar
to that shown in FIG. 11, using
7-(4-bromo-2-chlorophenylamino)-8-chloroimidazo[1,2-a]pyridine-6-carboxyl-
ic acid (2-hydroxyethoxy)amide (33a) and dimethylamine to provide
the desired product. MS APCI (+) m/z 528, 530, 532 (M+, Cl, Br
pattern) detected; .sup.1H NMR (400 MHz, CD.sub.3OD) .delta. 8.71
(s, 1H), 7.50 (d, 1H), 7.44 (s, 1H), 7.20 (dd, 1H), 6.55 (d, 1H),
3.80 (s, 2H), 3.74 (d, 2H), 2.04 (s, 6H), 1.18 (m, 1H), 0.51 (m,
2H), 0.27 (m, 2H). ##STR47##
4-[7-(4-Bromo-2-chlorophenylamino)-8-chloro-6-cyclopropylmethoxycarbamoyli-
midazo[1,2-a]pyridin-3-ylmethyl]-piperazine-1-carboxylic acid
tert-butyl ester
[0247] The reaction scheme for the synthesis of
4-[7-(4-bromo-2-chlorophenylamino)-8-chloro-6-cyclopropylmethoxycarbamoyl-
imidazo[1,2-a]pyridin-3-ylmethyl]-piperazine-1-carboxylic acid
tert-butyl ester was similar to that shown in FIG. 11, using
7-(4-bromo-2-chlorophenylamino)-8-chloroimidazo[1,2-a]pyridine-6-carboxyl-
ic acid (2-hydroxyethoxy)amide (33a) and piperazine-1-carboxylic
acid tert-butyl ester to provide the desired product. MS APCI (+)
m/z 669, 671, 673 (M+, Cl, Br pattern) detected; .sup.1H NMR (400
MHz, CDCl.sub.3) .delta. 8.80 (s, 1H), 8.00 (s, 1H), 7.56 (d, 1H),
7.27 (dd, 1H), 6.67 (d, 1H), 4.54 (s, 2H), 3.76 (d, 4H), 3.27 (m,
4H), 1.50 (s, 9H), 1.12 (m, 1H), 0.55 (m, 2H), 0.28 (m, 2H).
##STR48##
7-(4-Bromo-2-chlorophenylamino)-8-chloro-3-(4-methylpiperazin-1-ylmethyl)--
imidazo[1,2-a]pyridine-6-carboxylic acid
cyclopropylmethoxyamide
[0248] The reaction scheme for the synthesis of
7-(4-bromo-2-chlorophenylamino)-8-chloro-3-(4-methylpiperazin-1-ylmethyl)-
-imidazo[1,2-a]pyridine-6-carboxylic acid cyclopropylmethoxyamide
was similar to that shown in FIG. 11 using
7-(4-bromo-2-chlorophenylamino)-8-chloroimidazo[1,2-a]pyridine-6-carboxyl-
ic acid (2-hydroxyethoxy)amide (33a) and 1-methylpiperazine to
provide the desired product. MS APCI (+) m/z 581, 583, 585 (M+, Cl,
Br pattern) detected; .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.
8.90 (s, 1H), 7.57 (s, 1H), 7.56 (d, 1H), 7.22 (dd, 1H), 6.47 (d,
1H), 3.83 (s, 2H), 3.60 (d, 2H), 2.47 (m, 8H), 2.31 (s, 3H), 1.02
(m, 1H), 0.56 (m, 2H), 0.26 (m, 2H). ##STR49##
7-(4-Bromo-2-chlorophenylamino)-8-chloro-3-(4-methylpiperazin-1-ylmethyl)--
imidazo[1,2-a]pyridine-6-carboxylic acid
cyclopropylmethoxyamide
[0249]
7-(4-Bromo-2-chlorophenylamino)-8-chloro-3-(4-methylpiperazin-1-yl-
methyl)-imidazo[1,2-a]pyridine-6-carboxylic acid
cyclopropylmethoxyamide was prepared using
7-(4-bromo-2-chlorophenylamino)-8-chloroimidazo[1,2-a]pyridine-6-carboxyl-
ic acid (2-hydroxyethoxy)amide (33a) and 1-methyl-piperazine to
provide the desired product. MS APCI (+) m/z 581, 583, 585 (M+, Cl,
Br pattern) detected; .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.
8.90 (s, 1H), 7.57 (s, 1H), 7.56 (d, 1H), 7.22 (dd, 1H), 6.47 (d,
1H), 3.83 (s, 2H), 3.60 (d, 2H), 2.47 (m, 8H), 2.31 (s, 3H), 1.02
(m, 1H), 0.56 (m, 2H), 0.26 (m, 2H).
Example 16
[0250] ##STR50##
Synthesis of
7-(4-bromo-2-chlorophenylamino)-imidazo[1,2-a]pyridine-6-carboxylic
acid cyclopropylmethoxyamide (44a)
[0251] The reaction scheme for the synthesis of compound 44a is
shown in FIG. 12.
[0252] Step A: Preparation of
4-(4-bromo-2-chlorophenylamino)-6-chloronicotinic acid tert-butyl
ester (40): 2-tert-Butyl-1,3-diisopropylisourea (8.04 g, 40.1 mmol)
was added to a mixture of
4-(4-bromo-2-chlorophenylamino)-6-chloronicotinic acid
hydrochloride salt (24) (2.91 g, 7.31 mmol) in THF (165 mL). After
stirring for 2 hours at room temperature and 30 minutes at reflux,
the reaction mixture was cooled to room temperature and diluted
with EtOAc. The organic layer was washed with 10% K.sub.2CO.sub.3
and brine, dried (Na.sub.2SO.sub.4) and concentrated. The resulting
residue was dissolved in CH.sub.2Cl.sub.2 and filtered. The
filtrate was concentrated and purified by flash column
chromatography using the Biotage system (CH.sub.2Cl.sub.2) to give
the desired product (40) (3.28 g, 78%).
[0253] Step B: Preparation of
6-azido-4-(4-bromo-2-chlorophenyl-amino)nicotinic acid tert-butyl
ester (41): Sodium azide (1.51 g, 23.2 mmol) was added to a mixture
of 4-(4-bromo-2-chlorophenylamino)-6-chloronicotinic acid
tert-butyl ester (40) (3.23 g, 7.73 mmol) in DMF (60 mL). The
reaction mixture was heated to 80.degree. C. and stirred for 16
hours. After cooling to room temperature, the reaction was diluted
with EtOAc and washed with water, saturated NaHCO.sub.3 and brine.
The organic layer was dried (Na.sub.2SO.sub.4) and concentrated.
Purification by flash column chromatography using the Biotage
system (CH.sub.2Cl.sub.2) (repeated) provided the desired product
(41) (1.41 g; 43%).
[0254] Step C: Preparation of
6-amino-4-(4-bromo-2-chlorophenylamino)-nicotinic acid tert-butyl
ester (42): Compound 42 was prepared as described in Step G of
Example 9 using 6-azido-4-(4-bromo-2-chlorophenylamino)nicotinic
acid tert-butyl ester (41).
[0255] Step D: Preparation of
7-(4-bromo-2-chlorophenylamino)imidazo[1,2-a]pyridine-6-carboxylic
acid (43): Chloroacetaldehyde (12 .mu.L, 0.188 mmol) was added to a
mixture of 6-amino-4-(4-bromo-2-chlorophenylamino)-nicotinic acid
tert-butyl ester (42) (50 mg, 0.125 mmol) in EtOH (630 .mu.L).
After stirring the reaction mixture at 80.degree. C. for 5 hours,
an additional 12 .mu.L of chloroacetaldehyde were added and heating
was continued for 10 hours. The reaction mixture was cooled to room
temperature and diluted with EtOAc to give a cloudy semi-solution.
The organic layer was washed with water, saturated NaHCO.sub.3 and
brine. The organic layer contains a precipitate, which was
collected by filtration to give the desired product (43) (15 mg,
33%).
[0256] Step E: Preparation of
7-(4-bromo-2-chlorophenylamino)-imidazo[1,2-a]pyridine-6-carboxylic
acid cyclopropylmethoxyamide (44a): Oxalyl chloride (102 .mu.L of a
2.0 M solution in CH.sub.2Cl.sub.2) was added to a stirred
suspension of
7-(4-bromo-2-chlorophenylamino)imidazo[1,2-a]pyridine-6-carboxylic
acid (43) (15 mg, 0.041 mmol) in CH.sub.2Cl.sub.2 (1 mL) at
0.degree. C. One drop of DMF was added. The reaction mixture was
warmed to room temperature, stirred for 25 minutes, and then
concentrated. The residue was twice concentrated from toluene and
dried in vacuo. The residue was suspended in CH.sub.2Cl.sub.2 (1
mL), cooled to 0.degree. C. and cyclopropylmethylhydroxylamine (36
mg, 0.409 mmol) was added. The reaction mixture was warmed to room
temperature, stirred for 2 hours and diluted with EtOAc. The
organic layer was washed with saturated NaHCO.sub.3 and brine,
dried (Na.sub.2SO.sub.4) and concentrated. Purification by flash
column chromatography using the Biotage system (40:1
CH.sub.2Cl.sub.2:MeOH to 20:1 CH.sub.2Cl.sub.2:MeOH) provided the
desired product (44a) as a tan solid (6 mg, 31%). MS APCI (-) m/z
433, 435 (M-, Cl, Br pattern) detected: .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 8.68 (s, 1H), 7.69 (m, 1H), 7.67 (d, 1H),
7.52-7.44 (m, 3H), 7.08 (s, 1H), 3.83 (d, 2H), 0.90 (m, 1H), 0.62
(m, 2H), 0.35 (m, 2H).
[0257] The following compounds were synthesized in a similar manner
as shown in FIG. 12 using the appropriate aniline in Step C of
Example 9. ##STR51##
7-(4-Bromo-2-fluorophenylamino)-imidazo[1,2-a]pyridine-6-carboxylic
acid
[0258] MS ESI (+) m/z 350, 352 (M+, Br pattern) detected. (400 MHz,
DMSO-d.sub.6) .delta. 9.13 (s, 1H), 7.94 (d, 1H). 7.70 (dd, 1H),
7.67 (d, 1H), 7.59 (t, 1H), 7.47 (m, 1H), 6.84 (s, 1H). .sup.19F
NMR (376 MHz, DMSO-d.sub.6) .delta.-128.9. ##STR52##
7-(4-Bromo-2-fluorophenylamino)-imidazo[1,2-a]pyridine-6-carboxylic
acid cyclopropylmethoxyamide
[0259] MS ESI (+) m/z 419, 421 (M+, Br pattern) detected. .sup.1H
NMR (400 MHz, DMSO-d.sub.6) .delta. 11.91 (br s, 1H), 8.79 (s, 1H),
8.72 (br s, 1H), 7.81 (s, 2H), 7.64 (m, 1H), 7.50 (m, 1H), 7.45 (m,
1H), 7.39 (m, 1H), 6.90 (s, 1H), 3.74 (d, 2H), 1.14 (m, 1H), 0.55
(m, 2H), 0.29 (m, 2H). .sup.19F NMR (376 MHz, DMSO-d.sub.6)
.delta.-124.3. ##STR53##
7-(4-bromo-2-fluorophenylamino)-imidazo[1,2-a]pyridine-6-carboxylic
acid (2-hydroxyethoxy)-amide
[0260] MS ESI (+) m/z 409, 411 (M+, Br pattern) detected. .sup.1H
NMR (400 MHz, DMSO-d.sub.6) .delta. 12.02 (br s, 1H), 8.83 (s, 1H),
7.80 (s, 1H), 7.63 (s, 1H), 7.51 (m, 1H), 7.45 (m, 1H), 7.39 (m,
1H), 6.91 (s, 1H), 4.79 (br s, 1H), 3.94 (t, 2H), 3.64 (t, 2H).
.sup.19F NMR (376 MHz, DMSO-d.sub.6) .delta.-124.4.
Example 17
[0261] ##STR54##
Synthesis of
7-(4-bromo-2-chlorophenylamino)-8-fluoroimidazo[1,2-a]pyridine-6-carboxyl-
ic acid cyclopropylmethoxyamide (47a)
[0262] The reaction scheme for the synthesis of compound 47a is
shown in FIG. 13.
[0263] Step A: Preparation of
6-amino-4-(4-bromo-2-chlorophenylamino)-5-fluoronicotinic acid
tert-butyl ester (45):
1-Chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane
bis(tetrafluoroborate) (889 mg, 2.508 mmol) was added to a mixture
of 6-amino-4-(4-bromo-2-chlorophenylamino)nicotinic acid tert-butyl
ester (42) (1.00 g, 2.51 mmol) in 1:1 MeOH:water (25 mL). After
about 2 hours, the reaction mixture was diluted with EtOAc and
water. The layers were separated and the organic layer washed with
0.5 N HCl and brine. The aqueous washes were back extracted with
EtOAc. The combined organic extracts were dried (Na.sub.2SO.sub.4)
and concentrated. Purification by flash column chromatography using
the Biotage system (20:1 hexanes:EtOAc to 15:1 hexanes:EtOAc)
provided the desired product (45) as a yellow solid (75 mg,
7%).
[0264] Step B: Preparation of
7-(4-bromo-2-chlorophenylamino)-8-fluoroimidazo[1,2-a]pyridine-6-carboxyl-
ic acid (46): Chloroacetaldehyde (23 .mu.L, 0.360 mmol) was added
to a mixture of
6-amino-4-(4-bromo-2-chlorophenylamino)-5-fluoronicotinic acid
tert-butyl ester (45) (75 mg, 0.180 mmol) in EtOH (1 mL). After
stirring the reaction mixture at 70.degree. C. for 10 hours, an
additional 10 .mu.L chloro-acetaldehyde was added and heating was
continued for 33 hours. The reaction mixture was cooled to room
temperature and desired product (46) was collected by filtration.
The filtrate was diluted with EtOAc and washed with water,
saturated NaHCO.sub.3 and brine. The organic layer was dried
(Na.sub.2SO.sub.4) and concentrated to give additional product (46)
(51 mg, 74% combined recovery).
[0265] Step C: Preparation of
7-(4-bromo-2-chlorophenylamino)-8-fluoroimidazo[1,2-a]pyridine-6-carboxyl-
ic acid cyclopropylmethoxyamide (47a): Compound 47 was prepared as
described in Step E of Example 16 using
7-(4-bromo-2-chlorophenylamino)-8-fluoroimidazo[1,2-a]pyridine-6-carboxyl-
ic acid (46) to give 15 mg (24%) of the desired product (47a) as a
white solid. MS APCI (+) m/z 453, 455, 457 (M+, Cl, Br pattern)
detected: .sup.1H NMR (400 MHz, CD.sub.3OD) .delta. 8.66 (s, 1H),
7.93 (m, 1H), 7.61 (s, 1H), 7.56 (d, 1H), 7.32 (dd, 1H), 6.73 (q,
1H) 3.70 (d, 2H), 1.14 (m, 1H), 0.56 (m, 2H), 0.26 (m, 2H):
.sup.19F (400 MHz, CD.sub.3OD)-139.4 (s, 1F).
[0266] The following compounds were synthesized in a similar manner
as shown in FIG. 13. ##STR55##
7-(4-Bromo-2-chlorophenylamino)-8-fluoroimidazo[1,2-a]pyridine-6-carboxyli-
c acid (2-hydroxy-ethoxy)amide
[0267] MS APCI (+) m/z 443, 445, 447 (M+, Cl, Br pattern) detected;
.sup.1H NMR (400 MHz, CD.sub.3OD) .delta. 8.69 (s, 1H), 7.89 (m,
1H), 7.59 (s, 1H), 7.55 (d, 1H), 7.31 (dd, 1H), 6.72 (q, 1H), 4.01
(t, 2H), 3.76 (t, 2H); .sup.19F (400 MHz, CD.sub.3OD)-139.7 (s,
1F). ##STR56##
7-(4-Bromo-2-fluorophenylamino)-8-fluoroimidazo[1,2-a]pyridine-6-carboxyli-
c acid
[0268] MS ESI (+) m/z 368, 370 (M+, Br pattern) detected.
##STR57##
7-(4-Bromo-2-fluorophenylamino)-8-fluoroimidazo[1,2-a]pyridine-6-carboxyli-
c acid cyclopropylmethoxyamide
[0269] MS ESI (+) m/z 437, 439 (M+, Br pattern) detected. .sup.1H
NMR (400 MHz, CD.sub.3OD) .delta. 9.55 (br s, 1H), 8.57 (s, 1H).
7.68 (s, 2H), 7.65 (s, 1H), 7.28 (m, 1H), 7.14 (m, 1H), 6.78 (br s,
1H), 6.63 (m, 1H), 3.72 (m, 2H), 1.07 (m, 1H), 0.59 (m, 2H), 0.28
(m, 2H). .sup.19F NMR (376 MHz, CD.sub.3OD) .delta.-128.9,
-138.1.
Example 18
[0270] ##STR58##
Synthesis of
7-(4-bromo-2-chlorophenylamino)-8-chloro-3-methyl-[1,2,4]-triazolo-[4,3-a-
]pyridine-6-carboxylic acid cyclopropylmethoxyamide (53a)
[0271] The reaction scheme for the synthesis of compound 53a is
shown in FIG. 14.
[0272] Step A: Preparation of
4-(4-bromo-2-chlorophenylamino)-5-chloro-6-hydrazinonicotinic acid
ethyl ester (49):
4-(4-Bromo-2-chlorophenylamino)-5,6-dichloronicotinic acid ethyl
ester (48) was prepared by standard methods from
4-(4-bromo-2-chlorophenylamino)-5,6-dichloronicotinic acid.
Hydrazine monohydrate (0.59 mL, 12.16 mmol) was added to a solution
of 4-(4-bromo-2-chlorophenylamino)-5,6-dichloronicotinic acid ethyl
ester (48) (1.72 g, 4.05 mmol) in N,N-dimethylacetamide (20 mL).
After stirring at 90.degree. C. for 1 hour, the reaction mixture
was cooled to room temperature and diluted with EtOAc. The organic
layer was washed with water and brine, dried (Na.sub.2SO.sub.4) and
concentrated. Purification by flash column chromatography using the
Biotage system (20:1 CH.sub.2Cl.sub.2:EtOAc) provided the desired
product (49) (307 mg, 18%).
[0273] Step B: Preparation of
7-(4-bromo-2-chlorophenylamino)-8-chloro-3-methyl-[1,2,4]triazolo[4,3-a]p-
yridine-6-carboxylic acid ethyl ester (51a): Acetic anhydride (22
.mu.L, 0.238 mmol) was added to a solution of
4-(4-bromo-2-chlorophenylamino)-5-chloro-6-hydrazinonicotinic acid
ethyl ester (49) (0.100 g, 0.238 mmol) and triethylamine (66 .mu.L,
0.476 mmol) in CH.sub.2Cl.sub.2 (2.5 mL) at 0.degree. C., and then
the solution was warmed to room temperature to provide compound 50a
(not isolated). After 10 minutes, POCl.sub.3 (87 .mu.L, 0.952 mmol)
was added dropwise and the reaction mixture was warmed to room
temperature. After 16 hours, the reaction mixture was heated to
reflux and stirred for 3 days. The reaction mixture was cooled to
room temperature and concentrated. The residue was diluted with
EtOAc and saturated NaHCO.sub.3 was added and the mixture stirred
for 20 minutes. The layers were separated and the organic layer was
washed with brine. The aqueous washings were back extracted with
EtOAc. The combined organic extracts were dried (Na.sub.2SO.sub.4)
and concentrated. Purification by flash column chromatography using
the Biotage system (9:1 CH.sub.2Cl.sub.2:EtOAc) provided compound
51a (80 mg, 75%).
[0274] Step C: Preparation of
7-(4-bromo-2-chlorophenylamino)-8-chloro-3-methyl-[1,2,4]triazolo[4,3-a]p-
yridine-6-carboxylic acid (52a): Sodium hydroxide (715 .mu.L of a 1
M solution) was added to a solution of
7-(4-bromo-2-chlorophenylamino)-8-chloro-3-methyl-[1,2,4]triazolo[4,3-a]p-
yridine-6-carboxylic acid ethyl ester (51a) (79 mg, 179 mmol) in
3:1 THF:water (4.5 mL). After 16 hours, the reaction mixture was
poured into a separatory funnel, diluted with brine and acidified
with 1 N HCl to about pH 2. The aqueous layer was extracted with
1:1 EtOAc:THF. The combined organic extracts were dried
(Na.sub.2SO.sub.4) and concentrated and the residue (52a) was
carried forward without further purification.
[0275] Step D: Preparation of
7-(4-bromo-2-chlorophenylamino)-8-chloro-3-methyl-[1,2,4]triazolo[4,3-a]p-
yridine-6-carboxylic acid cyclopropylmethoxyamide (53a): Compound
53a was prepared as described in Example 2 using
7-(4-bromo-2-chlorophenylamino)-8-chloro-3-methyl-[1,2,4]triazolo[4,3-a]p-
yridine-6-carboxylic acid (52a) to give 2 mg (5%) of the desired
product. MS APCI (-) m/z 482, 484, 486 (M-, Cl, Br pattern)
detected.
Example 19
[0276] ##STR59##
Synthesis of
7-(4-bromo-2-chlorophenylamino)-8-chloro-3-methyl-[1,2,4]triazolo[4,3-a]p-
yridine-6-carboxylic acid (2-hydroxyethoxy)-amide (54a)
[0277] The reaction scheme for the synthesis of compound 54a is
shown in FIG. 14. Compound 54a was prepared as described herein
starting with
7-(4-bromo-2-chlorophenylamino)-8-chloro-3-methyl-[1,2,4]triazolo[4,3-a]p-
yridine-6-carboxylic acid (52a) to give 1 mg (2% for the two steps)
desired product (54a). MS APCI (-) m/z 472, 474, 476 (M-, Cl, Br
pattern) detected.
Example 20
[0278] ##STR60##
Synthesis of
3-benzyl-7-(4-bromo-2-chlorophenylamino)-8-chloro-[1,2,4]triazolo[4,3-a]p-
yridine-6-carboxylic acid cyclopropylmethoxyamide (53b)
[0279] The reaction scheme for the synthesis of compound 53b is
shown in FIG. 14.
[0280] Step A: Preparation of
3-benzyl-7-(4-bromo-2-chlorophenylamino)-8-chloro-[1,2,4]triazolo[4,3-a]p-
yridine-6-carboxylic acid methyl ester (51b): Phenylacetyl chloride
(152 .mu.L, 1.148 mmol) was added to a solution of
4-(4-bromo-2-chlorophenylamino)-5-chloro-6-hydrazinonicotinic acid
methyl ester (49) (0.233 g, 0.574 mmol) and triethylamine (160
.mu.L, 1.148 mmol) in CH.sub.2Cl.sub.2 (5.7 mL) at 0.degree. C.
After warming to room temperature, an additional 75 .mu.L
phenylacetyl chloride was added. After 6 hours, the reaction
mixture was concentrated and diluted with EtOAc. The organic layer
was washed with water and brine, dried (Na.sub.2SO.sub.4) and
concentrated. The residue (50b) was diluted with dichloroethylene
(2 mL) and POCl.sub.3 (465 .mu.L, 5.082 mmol) was added. After
stirring at reflux for 12 hours, the reaction mixture was cooled to
room temperature and concentrated. The residue was diluted with
EtOAc and saturated NaHCO.sub.3 was added and the mixture stirred
for 20 minutes. The resulting solid was collected by filtrate to
give the desired product (51b) (97 mg, 30%).
[0281] Step B: Preparation of
3-benzyl-7-(4-bromo-2-chlorophenylamino)-8-chloro-[1,2,4]triazolo[4,3-a]p-
yridine-6-carboxylic acid cyclopropylmethoxyamide (53b): Compound
53b was prepared as described in Step C of Example 18 and Example 2
using
3-benzyl-7-(4-bromo-2-chloro-phenylamino)-8-chloro-[1,2,4]triazolo[4,3-a]-
pyridine-6-carboxylic acid methyl ester (51b) as the starting
material to give 5 mg (4% for the two steps) of the desired product
(53b). MS APCI (-) m/z 558, 560, 562 (M-, Cl, Br pattern) detected:
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.22 (s, 1H), 7.30 (m,
6H), 6.50 (d, 1H), 4.53 (s, 2H), 3.49 (m, 2H), 0.94 (m, 1H), 0.51
(m, 2H), 0.19 (m, 2H).
Example 21
[0282] ##STR61##
Synthesis of
6-(2-chlorophenylamino)-7-fluoro-3-methylbenzo[c]isoxazole-5-carboxylic
acid (56)
[0283] The synthesis of compound 56 is shown in FIG. 15.
[0284] Step A: Preparation of
6-(2-chlorophenylamino)-7-fluoro-3-methyl-benzo[c]-isoxazole-5-carboxylic
acid methyl ester (55): Sodium azide (128 mg, 1.95 mmol) was added
to a mixture of
5-acetyl-2-(2-chlorophenylamino)-3,4-difluorobenzoic acid methyl
ester (6) (601 mg, 1.59 mmol) in 3:1 acetone:water (16 ml) and
heated to reflux. After 16 hours, the reaction mixture was cooled
to room temperature, and diluted with EtOAc and water. The organic
layer was washed with water, dried (MgSO.sub.4) and concentrated.
The resulting residue was diluted with water (8 mL) and heated to
reflux. After 5 hours, the mixture was cooled to room temperature
and diluted with EtOAc. The organic layer was washed with water,
dried (MgSO.sub.4) and concentrated. Purification by flash column
chromatography using the Biotage system (20% EtOAc in hexanes)
provided the desired product (55) (410 mg, 77%).
[0285] Step B: Preparation of
6-(2-chlorophenylamino)-7-fluoro-3-methylbenzo[c]-isoxazole-5-carboxylic
acid (56): To a solution of
6-(2-chlorophenylamino)-7-fluoro-3-methyl-benzo[c]-isoxazole-5-carboxylic
acid methyl ester (55) (100 mg, 0.299 mmol) in 6:1 THF:water (3.5
mL) was added LiOH (0.60 ml of a 1 M solution in water). After 1
hour, the reaction was acidified to pH 1 with 1 N HCl, diluted with
water and extracted with EtOAc. The combined organic extracts were
washed with water, dried (MgSO.sub.4) and concentrated to give the
desired product (56) (87 mg, 91%). MS APCI (-) m/z 319, 321 (M+, Cl
pattern) detected: .sup.1H NMR (400 MHz, CD.sub.3OD) .delta. 8.45
(s, 1H), 7.38 (dd, 1H), 7.20 (m, 1H), 6.91 (m, 2H), 2.88 (s, 3H):
.sup.19F NMR (376 MHz, CD.sub.3OD)-136.40 (s, 1F).
Example 22
[0286] ##STR62##
Synthesis of
6-(2-chlorophenylamino)-7-fluoro-3-methylbenzo[c]isoxazole-5-carboxylic
acid (2-hydroxyethoxy)amide (57a)
[0287] Compound 57a was prepared as shown in FIG. 15 using
6-(2-chlorophenylamino)-7-fluoro-3-methylbenzo[c]isoxazole-5-carboxylic
acid (56) to give 35 mg (44%) desired product. MS APCI (-) m/z 388,
390 (M+, Cl pattern) detected; .sup.1H NMR (400 MHz, CD.sub.3OD)
.delta. 7.73 (s, 1H), 7.36 (d, 1H), 7.17 (t, 1H), 6.89 (t, 1H),
6.81 (dd, 1H), 3.72(d, 2H), 2.87 (s, 3H), 1.15 (m, 1H), 0.54 (d,
2H), 0.26 (d, 2H); 19F NMR (376 MHz, CD.sub.3OD)-135.08 (s,
1F).
Example 23
[0288] ##STR63##
Synthesis of
6-(2-Chloro-phenylamino)-7-fluoro-3-methyl-benzo[c]isoxazole-5-carboxylic
acid cyclopropylmethoxy-amide (57b)
[0289] Compound 57b was prepared as shown in FIG. 15 and described
in Example 2 using
6-(2-chlorophenylamino)-7-fluoro-3-methylbenzo[c]isoxazole-5-carboxylic
acid (56) to give 35 mg (44%) desired product. MS APCI (-) m/z 388,
390 (M+, Cl pattern) detected; .sup.1H NMR (400 MHz, CD.sub.3OD)
.delta. 7.73 (s, 1H), 7.36 (d, 1H), 7.17 (t, 1H), 6.89 (t, 1H),
6.81 (dd, 1H), 3.72(d, 2H), 2.87 (s, 3H), 1.15 (m, 1H), 0.54 (d,
2H), 0.26 (d, 2H); 19F NMR (376 MHz, CD.sub.3OD)-135.08 (s,
1F).
Example 24
[0290] ##STR64##
Synthesis of
7-(4-bromo-2-chlorophenylamino)-8-chloro-3-methylaminomethyl-imidazo[1,2--
a]pyridine-6-carboxylic acid cyclopropylmethoxy-amide (63)
[0291] The synthesis of compound 63 is shown in FIG. 16.
[0292] Step A: Preparation of
7-(4-bromo-2-chlorophenylamino)-8-chloro-3-formyl-imidazo[1,2-a]pyridine--
6-carboxylic acid methyl ester (58): A suspension of
6-amino-4-(4-bromo-2-chlorophenylamino)-5-chloro-nicotinic acid
methyl ester (28) (1.06 g, 2.72 mmol) and 2-chloro-malonaldehyde
(587 mg, 5.43 mmol) was heated to 80.degree. C. for 45 minutes. The
solution was allowed to cool to room temperature, and then washed
with saturated aqueous NaHCO.sub.3, and brine. The organic layer
was dried over NaSO.sub.4, filtered, concentrated in vacuo, and
purified by column chromatography (20:1 methylene
chloride/methanol) to give the desired product as a dark yellow
solid. The solid was triturated with ethyl acetate and isolated by
filtration to provide the desired product as a yellow solid (0.436
g, 36%). MS (APCI+) m/z 442, 444, 446 (M+; Cl, Br pattern)
detected.
[0293] Step B: Preparation of
7-(4-bromo-2-chloro-phenylamino)-8-chloro-3-methylaminomethyl-imidazo[1,2-
-a]pyridine-6-carboxylic acid methyl ester (59): A suspension of
7-(4-bromo-2-chlorophenylamino)-8-chloro-3-formylimidazo[1,2-a]pyridine-6-
-carboxylic acid methyl ester (58) (25 mg, 0.056 mmol), acetic acid
(7 .mu.L, 0.11 mmol), and methylamine (2.0 M solution in THF, 56
.mu.L, 0.11 mmol) was stirred for 0.5 hours. Sodium
triacetoxyborohydride (36 mg, 0.17 mmol) was added and the solution
allowed to stir overnight. The reaction mixture was concentrated to
dryness and flashed (dichloromethane followed by 10:1
dichloromethane/methanol) to provide the desired product as a
yellow solid (12 mg, 46%). MS (APCI+) m/z 455, 457, 459 (M+; Cl, Br
pattern) detected.
[0294] Step C: Preparation of
7-(4-bromo-2-chlorophenylamino)-3-[(tert-butoxycarbonyl-methyl-amino)-met-
hyl]-8-chloroimidazo[1,2-a]pyridine-6-carboxylic acid methyl ester
(60): Di-tert-butyl dicarbonate (6 mg, 0.029 mmol) and
triethylamine (4 .mu.L, 0.029 mmol) were added to a solution of
7-(4-bromo-2-chlorophenylamino)-8-chloro-3-methyaminomethylimidazo[1,2-a]-
pyridine-6-carboxylic acid methyl ester (59) (12 mg, 0.026 mmol) in
dichloromethane. The solution was stirred at room temperature for
0.5 hr after which time HPLC analysis indicated the reaction had
gone to completion. The solution was rotovapped to dryness to
provide the desired product as a yellow foam (15 mg, quantitative).
MS (APCI+) m/z 557, 559, 561 (M+; Cl, Br pattern) detected.
[0295] Step D: Preparation of
7-(4-bromo-2-chlorophenylamino)-3-[(tert-butoxycarbonyl-methylamino)-meth-
yl]-8-chloroimidazo[1,2-a]pyridine-6-carboxylic acid (61): Sodium
hydroxide (1.0 M aqueous solution, 0.16 mL, 0.16 mmol) is added to
a solution of
7-(4-bromo-2-chlorophenylamino)-3-[(tert-butoxycarbonylmethylamino)-methy-
l]-8-chloroimidazo[1,2-a]pyridine-6-carboxylic acid methyl ester
(60) (15 mg, 0.026 mmol) in 4:1 MeOH/water (5 mL). When the
reaction was complete, the solution was diluted with water,
acidified to pH 3 by addition of 1.0 M aqueous HCl, and extracted
with ethyl acetate. The organic extracts were dried over
NaSO.sub.4, filtered, concentrated in vacuo to provide the desired
product as a white crystalline solid (12 mg, 84%). MS (APCI-) m/z
541, 543, 545 (M-; Cl, Br pattern) detected.
[0296] Step E: Preparation of
[7-(4-bromo-2-chlorophenylamino)-8-chloro-6-cyclopropylmethoxycarbamoylim-
idazo[1,2-a]pyridin-3-ylmethyl]-methylcarbamic acid tert-butyl
ester (62): EDCl (6 mg, 0.033 mmol) and HOBt (5 mg, 0.033 mmol)
were added to a solution of
7-(4-bromo-2-chlorophenylamino)-3-[(tert-butoxycarbonylmethylamino)-methy-
l]-8-chloro-imidazo[1,2-a]pyridine-6-carboxylic acid (61) in
dimethylacetamide (0.4 mL). The yellow solution was allowed to stir
at room temperature for 0.5 hours after which time
O-cyclopropylmethyl-hydroxylamine (6 mg, 0.066 mmol) and
triethylamine (6 .mu.L, 0.044 mmol) were added and the solution
allowed to stir overnight. The reaction mixture was diluted with
ethyl acetate, washed with water, saturated aqueous ammonium
chloride, saturated aqueous potassium carbonate and brine. The
organic phase was dried over NaSO.sub.4, filtered, concentrated in
vacuo to provide the desired product as a yellow residue (11.5 mg,
85%). MS (APCI+) m/z 612, 614, 616 (M+; Cl, Br pattern)
detected.
[0297] Step F: Preparation of
7-(4-bromo-2-chlorophenylamino)-8-chloro-3-methylaminomethylimidazo[1,2-a-
]pyridine-6-carboxylic acid cyclopropylmethoxyamide (63): A
solution of
[7-(4-bromo-2-chlorophenylamino)-8-chloro-6-cyclopropylmethoxy-carbamoyl--
imidazo[1,2-a]pyridin-3-ylmethyl]-methyl-carbamic acid tert-butyl
ester (62) in 1:1 dichloromethane/trifluoroacetic acid was stirred
for two hours. Solvent was removed under reduced pressure and the
residue redissolved into ethyl acetate. The organic solution was
washed with saturated aqueous potassium carbonate and brine. The
aqueous washes were back-extracted with ethyl acetate. The combined
organic extracts are dried over NaSO.sub.4, filtered, and
concentrated in vacuo to provide the desired product as a yellow
solid (8 mg, 83%). MS (APCI+) m/z 512, 514, 516 (M+; Cl, Br
pattern) detected. .sup.1H NMR (400 MHz, methanol-d.sub.4) .delta.
8.72 (s, 1H), 7.58 (s, 1H), 7.54 (s, 1H), 7.25 (d, 1H), 6.55 (d,
1H), 4.23 (s, 2H), 3.67 (d, 2H), 2.51 (s, 3H), 1.13 (m, 1H), 0.50
(d, 2H), 0.24 (d, 2H).
Example 25
[0298] ##STR65##
Synthesis of
6-(4-bromo-2-chlorophenylamino)-pyrazolo[1,5-a]pyridine-5-carboxylic
acid (2-hydroxyethoxy)amide (73a)
[0299] Compound 73a, where W.dbd.Br, Y.dbd.Cl, and X.dbd.H, can be
prepared as shown in FIG. 17.
Example 26
[0300] ##STR66##
Synthesis of
6-(4-bromo-2-chlorophenylamino)-7-fluoropyrazolo[1,5-a]pyridine-5-carboxy-
lic acid (2-hydroxyethoxy)-amide (73b)
[0301] Compound 73b, where W.dbd.Br, Y.dbd.Cl, and X.dbd.F, can be
prepared as shown in FIG. 17.
Example 27
[0302] ##STR67##
Synthesis of phosphoric acid
mono-(2-{[7-(4-bromo-2-chloro-phenylamino)-8-chloro-imidazo[1,2-a]pyridin-
e-6-carbonyl]-aminooxy}-ethyl)ester (74)
[0303] The synthesis of compound 74 is shown in FIG. 18.
7-(4-bromo-2-chlorophenylamino)-8-chloroimidazo[1,2-a]pyridine-6-carboxyl-
ic acid (2-hydroxyethoxy)-amide (33a) (100 mg, 0.234 mmol),
tetrazole (23 mg, 0.327 mmol) and di-tert-butyl
diisopropylphosphoramidite (0.096 mL, 0.304 mmol) were
dissolved/suspended in 30 mL of anhydrous DMF under an atmosphere
of dry N.sub.2. The reaction mixture was stirred for about 3 hours,
after which time the reaction was cooled to -78.degree. C. and
tert-butyl hydrogen peroxide (0.100 mL of 70% solution in water)
was added. The cooling bath was then taken away and the reaction
was slowly warmed up to room temperature and reacted over night.
The reaction mixture was then partitioned between a solution of
ethyl ether/ethyl acetate (5:1) and saturated aqueous NaHCO.sub.3.
The organic layer was saved and successively washed with 10%
aqueous sodium sulfite, 3 times with water and finally with brine.
The resulting organic layer was dried over MgSO.sub.4, filtered and
concentrated under vacuum. The residue was dissolved in 3 mL of a
solution of TFA/DCM (2:1) under an atmosphere of dry N.sub.2. The
reaction was stirred at room temperature for about 2 hours after
which time it was concentrated under vacuum and the resulting
residue was stirred in methanol for about 1 hour. The off-white
solid was collected via suction filtration, washed with methanol
followed by ethyl ether and then air-dried to give the desired
compound (74).
[0304] The foregoing description is considered as illustrative only
of the principles of the invention. Further, since numerous
modifications and changes will be readily apparent to those skilled
in the art, it is not desired to limit the invention to the exact
construction and process shown as described above. Accordingly, all
suitable modifications and equivalents may be resorted to falling
within the scope of the invention as defined by the claims that
follow.
[0305] The words "comprise," "comprising," "include," "including,"
and "includes" when used in this specification and in the following
claims are intended to specify the presence of stated features,
integers, components, or steps, but they do not preclude the
presence or addition of one or more other features, integers,
components, steps, or groups thereof.
* * * * *