U.S. patent application number 11/763524 was filed with the patent office on 2007-10-25 for chemical compounds.
Invention is credited to Mui Cheung, Philip Anthony Harris, Masaichi Hasegawa, Satoru Ida, Kazuya Kano, Naohiko Nishigaki, Hideyuki Sato, James Marvin Veal, Yoshiaki Washio, Rob I. West.
Application Number | 20070249600 11/763524 |
Document ID | / |
Family ID | 26943640 |
Filed Date | 2007-10-25 |
United States Patent
Application |
20070249600 |
Kind Code |
A1 |
Cheung; Mui ; et
al. |
October 25, 2007 |
CHEMICAL COMPOUNDS
Abstract
Benzimidazole derivatives, which are useful as TIE-2 and/or
VEGFR2 inhibitors are described herein. The described invention
also includes methods of making such benzimidazole derivatives as
well as methods of using the same in the treatment of
hyperproliferative diseases.
Inventors: |
Cheung; Mui; (Durham,
NC) ; Harris; Philip Anthony; (Durham, NC) ;
Hasegawa; Masaichi; (Tsukuba-shi, JP) ; Ida;
Satoru; (Keita, NE) ; Kano; Kazuya;
(Tsukuba-shi, JP) ; Nishigaki; Naohiko;
(Tsukuba-shi, JP) ; Sato; Hideyuki; (Tsukuba-shi,
JP) ; Veal; James Marvin; (Apex, NC) ; Washio;
Yoshiaki; (Tsukuba-shi, JP) ; West; Rob I.;
(Stevenage, GB) |
Correspondence
Address: |
GLAXOSMITHKLINE;CORPORATE INTELLECTUAL PROPERTY, MAI B475
FIVE MOORE DR., PO BOX 13398
RESEARCH TRIANGLE PARK
NC
27709-3398
US
|
Family ID: |
26943640 |
Appl. No.: |
11/763524 |
Filed: |
June 15, 2007 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10433128 |
Nov 12, 2003 |
7238813 |
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PCT/US01/44553 |
Nov 28, 2001 |
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11763524 |
Jun 15, 2007 |
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60253868 |
Nov 29, 2000 |
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60310939 |
Aug 8, 2001 |
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Current U.S.
Class: |
514/234.5 ;
514/254.06; 514/267; 514/303; 514/338; 514/363; 514/367; 514/395;
544/119; 544/251; 544/370; 546/118; 546/273.4; 548/140; 548/163;
548/304.7; 548/307.7; 548/309.1 |
Current CPC
Class: |
C07D 401/12 20130101;
C07D 417/12 20130101; C07D 471/14 20130101; C07D 403/12 20130101;
C07D 233/56 20130101; C07D 409/12 20130101; C07D 235/32 20130101;
A61P 43/00 20180101; A61P 35/00 20180101; C07D 471/04 20130101;
C07D 231/12 20130101; C07D 405/12 20130101; C07D 235/30 20130101;
C07D 263/58 20130101; C07D 249/08 20130101; C07D 413/12 20130101;
C07D 417/14 20130101; C07D 413/14 20130101; C07D 277/82 20130101;
C07D 487/04 20130101; C07D 405/14 20130101 |
Class at
Publication: |
514/234.5 ;
514/254.06; 514/267; 514/303; 514/338; 514/363; 514/367; 514/395;
544/119; 544/251; 544/370; 546/118; 546/273.4; 548/140; 548/163;
548/304.7; 548/307.7; 548/309.1 |
International
Class: |
A61K 31/4184 20060101
A61K031/4184; A61K 31/41 20060101 A61K031/41; A61K 31/428 20060101
A61K031/428; A61K 31/437 20060101 A61K031/437; A61K 31/4439
20060101 A61K031/4439; A61K 31/496 20060101 A61K031/496; A61K
31/519 20060101 A61K031/519; A61K 31/5377 20060101 A61K031/5377;
C07D 235/30 20060101 C07D235/30; C07D 277/82 20060101 C07D277/82;
C07D 401/12 20060101 C07D401/12; C07D 403/06 20060101 C07D403/06;
C07D 413/06 20060101 C07D413/06; C07D 417/10 20060101 C07D417/10;
C07D 471/04 20060101 C07D471/04; C07D 487/14 20060101
C07D487/14 |
Claims
1. A compound of Formula (I): ##STR282## or a salt or solvate
thereof: wherein: E is aryl substituted by R.sup.1 and R.sup.2, or
R.sup.1 and R.sup.2 together with the atoms of E to which they are
attached form a cycloalkyl, aryl, or heterocyclic ring fused to E;
A is aryl, heteroaryl, or heterocyclic; X is S, O, S(O).sub.2,
S(O), C(H).sub.2, C(H)(OH), or C(O); Z is O or S; p is 0 or 1; q is
0 or 1; the dotted line bonds "---" attached to Q and N' represent
a single bond or a double bond wherein when q is 0 the dotted line
bond "---" attached to Q is a single bond and the dotted line bond
attached to N' is a double bond, and when q is 1 the dotted line
bond "---" attached to Q is a double bond and the dotted line bond
attached to N' is a single bond; and the dotted line within the 6
membered ring containing D, M, and T represents appropriate
aromatic bonds; D is CH, T is CR.sup.8, M is C and Q is
N(R.sup.7).sub.p, wherein p is 0 and q is 1; or D is CH, T is
CR.sup.8, M is C and Q is N(R.sup.7).sub.p, wherein p is 1 and q is
0; or R.sup.1 is C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 haloalkyl,
aryl, heteroaryl, heterocyclic, halogen, C.sub.1-C.sub.6 alkoxy,
C.sub.1-C.sub.6 haloalkoxy, aralkyl, aralkoxy, aryloxy,
C.sub.1-C.sub.6 alkylsulfanyl, C.sub.1-C.sub.6 haloalkylsulfanyl,
C.sub.1-C.sub.6 alkylsulfenyl, C.sub.1-C.sub.6 alkylsulfonyl,
--NO.sub.2, --NR.sup.4R.sup.5, --C(O)OR.sup.6, --CN,
--C(O)NR.sup.4R.sup.5, --S(O).sub.2NR.sup.4R.sup.5, or cyanoalkyl;
R.sup.2 is hydrogen, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6
haloalkyl, aryl, heteroaryl, heterocyclic, aralkyl, aralkoxy,
aryloxy, halogen, C.sub.1-C.sub.6 alkoxy, C.sub.1-C.sub.6
haloalkoxy, C.sub.1-C.sub.6 alkylsulfanyl, C.sub.1-C.sub.6
haloalkylsulfanyl, C.sub.1-C.sub.6 alkylsulfenyl, C.sub.1-C.sub.6
alkylsulfonyl, oxo, hydroxy, --NO.sub.2, --NR.sup.4R.sup.5,
--C(O)OR.sup.6, --CN, --C(O)NR.sup.4R.sup.5,
--S(O).sub.2NR.sup.4R.sup.5, or cyanoalkyl; R.sup.3 is hydrogen,
C.sub.1-C.sub.6 alkyl, aryl, aralkyl, aralkoxy, heteroaryl,
heterocyclic, --RR.sup.6, --RNR.sup.4R.sup.5, --C(O)R.sup.6,
--C(O)NR.sup.4R.sup.5, --C(O)OR.sup.6, --C(O)ROR.sup.6,
--C(O)RC(O)OR.sup.6, --C(O)RR.sup.6, --C(O)RR'R.sup.6,
--C(O)ROR'OR''O R.sup.6, --C(O)ROR'OR.sup.6,
--C(O)RNR.sup.4R.sup.5, --C(O)RNR.sup.4C(O)R.sup.6,
--C(O)RNR.sup.4C(O)OR.sup.6, --C(O)ORNR.sup.4R.sup.5,
--S(O).sub.2R.sup.6, or --S(O).sub.2NR.sup.4R.sup.5; or R.sup.3 is
C.sub.1-C.sub.6 alkylene or C.sub.1-C.sub.6 alkylene substituted
with oxo, and is linked together with the nitrogen to which it is
attached and to one of the benzimidazole nitrogens to form a
heterocylic compound fused to the benzimidazole; R, R', and R'',
are each independently selected from C.sub.1-C.sub.6 alkylene,
arylene, heteroarylene, C.sub.3-C.sub.7 cycloalkylene, or
heterocyclylene; R''' is C.sub.1-C.sub.6 alkyl, aryl, heteroaryl,
aralkyl, C.sub.3-C.sub.7 cycloalkyl, or heterocyclic; R.sup.4 and
R.sup.5 are each independently selected from hydrogen,
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 haloalkyl,
C.sub.1-C.sub.6alkylsulfanyl, C.sub.1-C.sub.6alkylsulfenyl,
C.sub.1-C.sub.6alkylsulfonyl, aryl, heteroaryl, aralkyl,
heterocyclic, C.sub.3-C.sub.7 cycloalkyl, --C(O)OR.sup.6,
--C(O)NR'''R''', --C(O)NR'''H, --C(O)NH.sub.2, or
--S(O).sub.2NR'''R'''; R.sup.6 is hydrogen, C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.6 haloalkyl, aryl, heteroaryl, aralkyl, heterocyclic,
or C.sub.3-C.sub.7 cycloalkyl; R.sup.7 is hydrogen, C.sub.1-C.sub.6
alkyl, --S(O).sub.2R.sup.6, --RNR.sup.4R.sup.5--RR.sup.6, or
aralkyl; and R.sup.8 is hydrogen or halogen; and when R.sup.1 is
Cl, R.sup.2 is hydrogen or Cl, R.sup.3 is --C(O)OCH.sub.3, E and A
are phenyl, D is CH, T is CH, M is C, Q is N(R.sup.7).sub.p, where
R.sup.7 is H, wherein either p or q is 0 and the other is 1, and Z
is O, then X is O, S(O), S(O).sub.2, CH2, CH(OH), or C(O).
2. A compound as claimed in claim 1, wherein the compound is a
compound of formula (III): ##STR283## or salt or solvate
thereof.
3. A compound as claimed in claim 1, wherein E is aryl substituted
with R.sup.1 and R.sup.2.
4. A compound as claimed in claim 1, wherein E is phenyl
substituted with R.sup.1 and R.sup.2.
5. A compound as claimed in claim 1, wherein E is phenyl and
R.sup.1 and R.sup.2 together with the phenyl ring atoms with which
they are attached form a cycloalkyl ring fused to E.
6. A compound as claimed in claim 10, wherein the cycloalkyl ring
is cyclopentyl.
7. A compound as claimed in claim 1, wherein E is phenyl and
R.sup.1 and R.sup.2 together with the phenyl ring atoms with which
they are attached form an aryl ring fused to E.
8. A compound as claimed in claim 7, wherein the aryl ring is
phenyl.
9. A compound as claimed in claim 1, wherein A is phenyl, 2-pyridyl
or 3-pyridyl.
10. A compound as claimed in claim 1, wherein A is phenyl.
11. A compound as claimed in claim 1, wherein the group A is linked
to the side chain --NHC(Z)NHE and to the linker group X of the
benzimidazole core through a (-1,3-) or a (-1,4-) linkage.
12. A compound as claimed in claim 1, wherein A is a phenyl group
linked through a (-1,4-) or (-1,3-) linkage.
13. A compound as claimed in claim 1, wherein X is C(O) or O.
14. A compound as claimed in claim 1, wherein X is O.
15. A compound as claimed in claim 1, wherein X is S.
16. A compound as claimed in claim 1, wherein Z is O.
17. A compound as claimed in claim 1, wherein Z is S.
18. A compound as claimed in claim 1, wherein R.sup.1 is
C.sub.1-C.sub.6 alkyl, aryloxy, C.sub.1-C.sub.6 alkoxy,
C.sub.1-C.sub.6 haloalkyl, C.sub.1-C.sub.6 haloalkylsulfanyl,
C.sub.1-C.sub.6 alkylsulfanyl, --C(O)OR.sup.6, halogen, --CN, or
--NO.sub.2.
19. A compound as claimed in claim 1, wherein R.sup.1 is
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 haloalkyl,
C.sub.1-C.sub.6alkoxy, halogen, or --NO.sub.2.
20. A compound as claimed in claim 1, wherein R.sup.1 is
C.sub.1-C.sub.6 haloalkyl.
21. A compound as claimed in claim 1, wherein R.sup.1 is
--CF.sub.3.
22. A compound as claimed in claim 1, wherein R.sup.1 is
C.sub.1-C.sub.6 alkyl.
23. A compound as claimed in claim 1, wherein R.sup.1 is
--C(CH.sub.3).sub.3.
24. A compound as claimed in claim 1, wherein R.sup.2 is hydrogen,
halogen, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy, or
C.sub.1-C.sub.6 haloalkyl.
25. A compound as claimed in claim 1, wherein R.sup.2 is hydrogen
or halogen.
26. A compound as claimed in claim 1, wherein R.sup.2 is
halogen.
27. A compound as claimed in claim 1, wherein R.sup.2 is
fluorine.
28. A compound as claimed in claim 1, wherein R.sup.1 is
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy, aryloxy,
C.sub.1-C.sub.6 haloalkyl, C.sub.1-C.sub.6 haloalkylsulfanyl,
C.sub.1-C.sub.6 alkylsulfanyl, C(O)OR.sup.6, halogen, --CN, or
--NO.sub.2 and R.sup.2 is hydrogen, halogen, C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.6 alkoxy, or C.sub.1-C.sub.6 haloalkyl.
29. A compound as claimed in claim 1, wherein R.sup.1 is
C.sub.1-C.sub.6 haloalkyl and R.sup.2 is hydrogen or halogen.
30. A compound as claimed in claim 1, wherein R.sup.1 is --CF.sub.3
and R.sup.2 is fluorine.
31. A compound as claimed in claim 1, wherein D is CH, T is
CR.sup.8, M is C and Q is N(R.sup.7).sub.p, wherein p is 0, q is 1,
R.sup.7 is hydrogen, methyl, or S(O).sub.2R.sup.6.
32. A compound as claimed in claim 1, wherein D is CH, T is
CR.sup.8, wherein R.sup.8 is hydrogen or --Br, M is C and Q is
N(R.sup.7).sub.p, wherein p is 1, q is 0, R.sup.7 is hydrogen,
methyl, --S(O).sub.2R.sup.6, --RNR.sup.4R.sup.5, --RR.sup.6 or
aralkyl.
33. A compound as claimed in claim 1, wherein D is CH, T is
CR.sup.8, wherein R.sup.8 is hydrogen, M is C and Q is
N(R.sup.7).sub.p, wherein either p or q is 0, the other is 1 and
R.sup.7 is hydrogen.
34. A compound as claimed in claim 1, wherein D is CH, T is
CR.sup.8, wherein R.sup.8 is hydrogen or --Br, M is C and Q is S or
O; wherein q is 0.
35. A compound as claimed in claim 1, wherein R.sup.3 is
--C(O)R.sup.6, --C(O)NR.sup.4R.sup.5, --C(O)OR.sup.6,
--C(O)ROR.sup.6, --C(O)RC(O)OR.sup.6, --C(O)ROR'OR''OR.sup.6,
--C(O)ROR'OR.sup.6, --C(O)RNR.sup.4R.sup.5,
--C(O)RNR.sup.4C(O)R.sup.6, --C(O)RNR.sup.4C(O)OR.sup.6,
--SO.sub.2R.sup.6, or --SO.sub.2NR.sup.4R.sup.5.
36. A compound as claimed in claim 1, wherein R.sup.3 is
--C(O)R.sup.6, --C(O)NR.sup.4R.sup.5, or --C(O)OR.sup.6.
37. A compound as claimed in claim 1, wherein R.sup.3 is
--C(O)OR.sup.6.
38. A compound as claimed in claim 1, wherein R.sup.3 is
--C(O)OR.sup.6 and R.sup.6 is methyl.
39. A compound as claimed in claim 1, wherein A is phenyl; X is O;
Z is O; R.sup.1 is C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6 alkoxy,
C.sub.1-C.sub.6 haloalkyl, or --NO.sub.2; R.sup.2 is hydrogen,
halogen, C.sub.1-C.sub.6 alkyl, or C.sub.1-C.sub.6 alkoxy; and
R.sup.3 is --C(O)R.sup.6, --C(O)NR.sup.4R.sup.5, --C(O)OR.sup.6,
--C(O)ROR.sup.6--C(O)RC(O)OR.sup.6, --C(O)ROR'OR''OR.sup.6,
--C(O)ROR'OR.sup.6, --C(O)RNR.sup.4R.sup.5,
--C(O)RNR.sup.4C(O)R.sup.6, --C(O)RNR.sup.4C(O)OR.sup.6,
--SO.sub.2R.sup.6, or --SO.sub.2NR.sup.4R.sup.5.
40. A compound as claimed in claim 1, wherein A is phenyl; X is O;
Z is 0; R.sup.1 is C.sub.1-C.sub.6 alkyl, or C.sub.1-C.sub.6
haloalkyl; R.sup.2 is hydrogen or halogen; and R.sup.3 is
--C(O)R.sup.6, --C(O)NR.sup.4R.sup.5, or --C(O)OR.sup.6.
41. A compound as claimed in claim 1, wherein A is phenyl; X is O;
Z is O; R.sup.1 is C.sub.1-C.sub.6 haloalkyl; R.sup.2 is halogen;
and R.sup.3 is --C(O)OR.sup.6.
42. A compound as claimed in claim 1, wherein A is phenyl; X is S;
Z is O; R.sup.1 is C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6 alkoxy,
C.sub.1-C.sub.6 haloalkyl, or --NO.sub.2; R.sup.2 is hydrogen,
halogen, C.sub.1-C.sub.6 alkyl, or C.sub.1-C.sub.6 alkoxy; and
R.sup.3 is --C(O)R.sup.6, --C(O)NR.sup.4R.sup.5, --C(O)OR.sup.6,
--C(O)ROR.sup.6--C(O)RC(O)OR.sup.6, --C(O)ROR'OR''OR.sup.6,
--C(O)ROR'OR.sup.6, --C(O)RNR.sup.4R.sup.5,
--C(O)RNR.sup.4C(O)R.sup.6, --C(O)RNR.sup.4C(O)OR.sup.6,
--SO.sub.2R.sup.6, or --SO.sub.2NR.sup.4R.sup.5.
43. A compound as claimed in claim 1, wherein A is phenyl; X is S;
Z is O; R.sup.1 is C.sub.1-C.sub.6 alkyl, or C.sub.1-C.sub.6
haloalkyl; R.sup.2 is hydrogen or halogen; and R.sup.3 is
--C(O)R.sup.6, or --C(O)OR.sup.6.
44. A compound as claimed in claim 1, wherein A is phenyl; X is S;
Z is O; R.sup.1 is C.sub.1-C.sub.6 haloalkyl; R.sup.2 is halogen;
and R.sup.3 is --C(O)OR.sup.6.
45. A compound as claimed in claim 1, wherein A is pyridyl; X is O;
Z is O; R.sup.1 is C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6 alkoxy,
C.sub.1-C.sub.6 haloalkyl, or --NO.sub.2; R.sup.2 is hydrogen,
halogen, C.sub.1-C.sub.6 alkyl, or C.sub.1-C.sub.6 alkoxy; and
R.sup.3 is --C(O)R.sup.6, --C(O)NR.sup.4R.sup.5, --C(O)OR.sup.6,
--C(O)ROR.sup.6, --C(O)RC(O)OR.sup.6, --C(O)ROR'OR''OR.sup.6,
--C(O)ROR'OR.sup.6, --C(O)RNR.sup.4R.sup.5,
--C(O)RNR.sup.4C(O)R.sup.6, --C(O)RNR.sup.4C(O)OR.sup.6,
--SO.sub.2R.sup.6, or --SO.sub.2NR.sup.4R.sup.5.
46. A compound as claimed in claim 1, wherein A is pyridyl; X is O;
Z is O; R.sup.1 is C.sub.1-C.sub.6 alkyl, or C.sub.1-C.sub.6
haloalkyl; R.sup.2 is hydrogen or halogen; and R.sup.3 is
--C(O)R.sup.6, or --C(O)OR.sup.6.
47. A compound as claimed in claim 1, wherein A is pyridyl; X is O;
Z is O; R.sup.1 is C.sub.1-C.sub.6 haloalkyl; R.sup.2 is halogen;
and R.sup.3 is --C(O)OR.sup.6.
48. A compound as claimed in claim 1, wherein A is pyridyl; X is S;
Z is O; R.sup.1 is C.sub.1-6alkyl, C.sub.1-C.sub.6 alkoxy,
C.sub.1-C.sub.6 haloalkyl, or --NO.sub.2; R.sup.2 is hydrogen,
halogen, C.sub.1-C.sub.6 alkyl, or C.sub.1-C.sub.6 alkoxy; and
R.sup.3 is --C(O)R.sup.6, --C(O)NR.sup.4R.sup.5, --C(O)OR.sup.6,
--C(O)ROR.sup.6, --C(O)RC(O)OR.sup.6, --C(O)ROR'OR''OR.sup.6,
--C(O)ROR'OR.sup.6, --C(O)RNR.sup.4R.sup.5,
--C(O)RNR.sup.4C(O)R.sup.6, --C(O)RNR.sup.4C(O)OR.sup.6,
--SO.sub.2R.sup.6, or --SO.sub.2NR.sup.4R.sup.5.
49. A compound as claimed in claim 1, wherein A is pyridyl; X is S;
Z is O; R.sup.1 is C.sub.1-C.sub.6 alkyl, or C.sub.1-C.sub.6
haloalkyl; R.sup.2 is hydrogen or halogen; and R.sup.3 is
--C(O)R.sup.6, or --C(O)OR.sup.6.
50. A compound as claimed in claim 1, wherein A is pyridyl; X is S;
Z is O; R.sup.1 is C.sub.1-C.sub.6 haloalkyl; R.sup.2 is halogen;
and R.sup.3 is --C(O)OR.sup.6.
51. A compound as claimed in claim 1, selected from the group
consisting of: methyl
N-(5-(4-((3-chlorophenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl-
)carbamate; methyl
N-(5-(4-((3-(trifluoromethyl)phenyl)aminocarbonylamino)phenylthio)-1H-ben-
zimidazol-2-yl)carbamate; methyl
N-(5-(4-((3,5-di(trifluoromethyl)phenyl)aminocarbonylamino)
phenylthio)-1H -benzimidazol-2-yl)carbamate; methyl
N-(5-(4-((3-bromophenyl)aminocarbonylamino)phenylthio)-1H-benzimidazol-2--
yl)carbamate; methyl
N-(5-(4-((3,5-dimethoxyphenyl)aminocarbonylamino)phenylthio)-1H-benzimida-
zol-2-yl)carbamate; methyl
N-(5-(4-((2-methyl-5-nitrophenyl)aminocarbonylamino)phenylthio)-1H-benzim-
idazol-2-yl)carbamate; methyl
N-(5-(4-((3-ethylphenyl)aminocarbonylamino)phenylthio)-1H-benzimidazol-2--
yl)carbamate; methyl
N-(5-(4-((2-fluoro-5-nitrophenyl)aminocarbonylamino)phenylthio)-1H-benzim-
idazol-2-yl)carbamate; methyl
N-(5-(4-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenylthi-
o)-1H-benzimidazol-2-yl)carbamate; methyl
N-(5-(4-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)
phenoxy)-1H-benzimidazol-2-yl)carbamate; methyl
N-(5-(4-((3-ethylphenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)-
carbamate; methyl
N-(5-(4-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)
phenylsulfonyl)-1H-benzimidazol-2-yl)carbamate; methyl
N-(5-(4-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)
phenylsulfinyl)-1H-benzimidazol-2-yl)carbamate; methyl
(5-(3-((3-chlorophenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)c-
arbamate; methyl
N-(5-(3-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)--
1H -benzimidazol-2-yl)carbamate; methyl
N-(5-(3-((3-ethylphenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)-
carbamate; ethyl
N-(5-(4-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)--
1H-benzimidazol-2-yl)carbamate; t-butyl
N-(5-(4-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)--
1H -benzimidazol-2-yl)carbamate; methyl
N-(5-(4-((3-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1H-benzim-
idazol-2-yl)carbamate; methyl
N-(5-(3-((3-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1H-benzim-
idazol-2-yl)carbamate; methyl
N-(5-(4-((3-t-butylphenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-y-
l)carbamate;
2-amino-5-(4-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phen-
oxy)-1H-benzimidazole;
(6-(4-((2-Fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1--
(methanesulfonyl)-1H-benzimidazol-2-ylamine;
6-(4-((2-Fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1-(-
4-(methyl)phenylsulfonyl)-1H-benzimidazol-2-ylamine;
N-(5-(4-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)--
1H-benzimidazol-2-yl)acetamide;
N-(5-(4-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)--
1H-benzimidazol-2-yl)cyclopentamide;
N-(5-(4-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)--
1H-benzimidazol-2-yl)(2-furyl)formamide;
N-(5-(4-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)--
1H-benzimidazol-2-yl)-4-methylpentamide;
N-(5-(4-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)--
1H-benzimidazol-2-yl)-2-(N-acetylamino)acetamide;
N-(5-(4-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)--
1H-benzimidazol-2-yl)-2-aminoacetamide;
N-(5-(4-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)--
1H-benzimidazol-2-yl)-2-methoxyacetamide;
3-(N-(5-(4-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenox-
y)-1H-benzimidazol-2-yl)carbamoyl)propionic acid;
N-(5-(4-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)--
1H-benzimidazol-2-yl)(2-(2-(methoxy)ethoxy)ethoxy)acetamide;
N-(5-(4-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)--
1H-benzimidazol-2-yl)(2-(methoxy)ethoxy)acetamide;
N-(5-(4-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)--
1H-benzimidazol-2-yl)-2-(N-(t-butoxycarbony)amino)acetamide;
N-(5-(2-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)-5-pyridy-
loxy)-1H -benzimidazol-2-yl)acetamide; methyl
N-(5-(5-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)-2-pyridy-
loxy)-1H-benzimidazol-2-yl)carbamate; methyl
N-(5-(5-((3-(trifluoromethyl)phenyl)aminocarbonylamino)-2-pyridyloxy)-1H--
benzimidazol-2-yl)acetamide; and methyl
N-(5-(5-((3-ethylphenyl)aminocarbonylamino)-2-pyridyloxy)-1H-benzimidazol-
-2-yl)carbamate; or a salt or solvate thereof.
52. A compound as claimed in claim 1, selected from the group
consisting of: methyl
N-(5-(4-((3-bromophenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)-
carbamate; methyl
N-(5-(4-((3-(trifluoromethylthio)phenyl)aminocarbonylamino)phenoxy)-1H-be-
nzimidazol-2-yl)carbamate; methyl
N-(5-(4-((2,5-dimethoxyphenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-
-2-yl)carbamate; methyl
N-(5-(4-((2-chloro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)--
1H-benzimidazol-2-yl)carbamate; methyl
N-(5-(4-((4-chloro-3-trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1-
H-benzimidazol-2-yl)carbamate; methyl
N-(5-(4-((2,5-dichlorophenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol--
2-yl)carbamate; methyl
N-(5-(4-((2-fluoro-5-nitrophenyl)aminocarbonylamino)phenoxy)-1H-benzimida-
zol-2-yl)carbamate; methyl
N-(5-(4-((2-methyl-5-nitrophenyl)aminocarbonylamino)phenoxy)-1H-benzimida-
zol-2-yl)carbamate; methyl
N-(5-(4-(3-methylthiophenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-
-yl)carbamate; methyl
N-(5-(4-(3-cyanophenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)c-
arbamate; methyl
N-(5-(4-((3-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)--
1H -benzimidazol-2-yl)carbamate; methyl
N-(5-(4-((2-chloro-5-(trifluoromethyl)phenyl)aminocarbonylamino)
phenylthio)-1H-benzimidazol-2-yl)carbamate; methyl
N-(5-(3-((2-chloro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)--
1H-benzimidazol-2-yl)carbamate; methyl
N-(5-(4-((3-ethoxycarbonylphenyl)aminocarbonylamino)phenoxy)-1H-benzimida-
zol-2-yl)carbamate; methyl
N-(5-(4-((3-carboxyphenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-y-
l)carbamate; methyl
N-(5-(4-((2-fluoro-5-methylphenyl)aminocarbonylamino)phenoxy)-1H-benzimid-
azol-2-yl)carbamate; methyl
N-(5-(4-((2,5-difluorophenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol--
2-yl)carbamate; methyl
N-(5-(4-((2,5-dichlorophenyl)aminocarbonylamino)phenylthio)-1H-benzimidaz-
ol-2-yl)carbamate; methyl
N-(5-(3-((3-(trifluoromethylthio)phenyl)aminocarbonylamino)phenoxy)-1H-be-
nzimidazol-2-yl)carbamate; methyl
N-(5-(3-((3-bromophenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)-
carbamate; methyl
N-(5-(3-((3-(phenoxy)phenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-
-yl)carbamate; methyl
N-(5-(3-((4-chlorophenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl-
)carbamate; methyl
N-(5-(4-((4-methoxyphenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-y-
l)carbamate; methyl
N-(5-(4-((4-fluorophenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl-
)carbamate; methyl
N-(6-(4-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)
phenoxy)-1-methyl-1H-benzimidazol-2-yl)carbamate; methyl
N-(5-(4-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)
phenoxy)-1-methyl-1H-benzimidazol-2-yl)carbamate; methyl
N-(6-(4-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)
phenoxy)-1-(2-(dimethylamino)ethyl)-1H-benzimidazol-2-yl)carbamate;
methyl
N-(6-(4-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)
phenoxy)-1-(2-(4-morpholino)ethyl)-1H-benzimidazol-2-yl)carbamate;
methyl
N-(5-(4-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)ph-
enylcarbonyl)-1H -benzimidazol-2-yl)carbamate; methyl
N-(5-(4-((2,5-dichlorophenyl)aminocarbonylamino)phenylsulfinyl)-1H-benzim-
idazol-2-yl)carbamate; 2-(dimethylamino)ethyl
N-(5-(4-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)--
1H-benzimidazol-2-yl)carbamate; benzyl
N-(5-(4-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)--
1H-benzimidazol-2-yl)carbamate;
5-(4-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1-(-
methanesulfonyl)-1H-benzimidazol-2-ylamine;
N-(5-(4-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)--
1H-benzimidazol-2-yl)methanesulfonamide;
5-(4-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1-(-
4-(methyl)phenylsulfonyl)-1H-benzimidazol-2-ylamine;
N-(5-(4-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)--
1H-benzimidazol-2-yl)-4-methylbenzenesulfonamide;
N-(5-(4-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)--
1H-benzimidazol-2-yl)-4-(4-methyl-1-piperazinomethyl)benzamide;
N-(5-(4-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)--
1H-benzimidazol-2-yl)-3-(pyridine-3-yl)propionamide;
N-(5-(4-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)--
1H-benzimidazol-2-yl)-5-benzimidazolecarboxamide;
N-(5-(4-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)--
1H-benzimidazol-2-yl)-4-(pyrrol-1-yl)benzamide;
N-(5-(4-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)--
1H-benzimidazol-2-yl)-4-(1H-imidazol-1-yl)benzamide;
N-(5-(4-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)--
1H-benzimidazol-2-yl)-4-(dimethylamino)butylamide;
N-(5-(4-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)--
1H-benzimidazol-2-yl)-3-pyridinecarboxamide;
N-(5-(4-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)--
1H-benzimidazol-2-yl)-2-tetrahydrofurancarboxamide;
N-(5-(4-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)--
1H-benzimidazol-2-yl)(1H-indole-3-carboxamide);
N-(5-(4-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)--
1H-benzimidazol-2-yl)(5-(1-pyrrolidino)tetrazol-2-yl)acetamide;
N-(5-(4-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)--
1H-benzimidazol-2-yl)(1-methyl-1H-imidazol-4-yl)acetamide;
N-(5-(4-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)--
1H-benzimidazol-2-yl)(1H-imidazole-4-carboxamide);
N-(5-(4-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)--
1H-benzimidazol-2-yl)benzamide;
N-(5-(4-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)--
1H-benzimidazol-2-yl)-2-thiophenecarboxamide;
N-(5-(4-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)--
1H-benzimidazol-2-yl)(4-methyl-1-piperazino)acetamide;
N-(5-(4-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)--
1H-benzimidazol-2-yl)(dimethylamino)acetamide;
6-(4-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-3,4-
-dihydro-1,4a-diazacarbazol-2-one;
7-(4-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-3,4-
-dihydro-1,4a-diazacarbazol-2-one;
2-(2-(4-methyl-1-piperazino)ethylamino)-5-(4-((2-fluoro-5-(trifluoromethy-
l)phenyl)aminocarbonylamino)phenoxy)-1H-benzimidazole;
2-(2-(dimethylamino)ethylamino)-5-(4-((2-Fluoro-5-(trifluoromethyl)phenyl-
)aminocarbonylamino)phenoxy)-1H-benzimidazole;
2-(3-(4-methyl-1-piperazino)propylamino)-5-(4-((2-fluoro-5-(trifluorometh-
yl)phenyl)aminocarbonylamino)phenoxy)-1H-benzimidazole; methyl
N-(5-(5-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)-1-oxo-2--
pyridyloxy)-1H-benzimidazol-2-yl)carbamate;
N-(6-(2-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)-5-pyridy-
loxy)-3-benzyl-1H-benzimidazol-2-yl)acetamide; methyl
N-(5-(5-((2-chloro-5-(trifluoromethyl)phenyl)aminocarbonylamino)-2-pyridy-
loxy)-1H-benzimidazol-2-yl)carbamate; methyl
N-(5-(5-((2,5-dichlorophenyl)aminocarbonylamino)-2-pyridyloxy)-1H-benzimi-
dazol-2-yl)carbamate;
6-(6-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)-3-pyridylox-
y)-1-benzyl-1H-benzimidazol-2-ylamine; and
N-(6-(6-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)-3-pyridy-
loxy)-1-benzyl-1H-benzimidazol-2-yl)methanesulfonamide; or a salt
or solvate thereof.
53. A compound as claimed in claim 1, selected from the group
consisting of: methyl
N-(5-(3-((2-(trifluoromethoxy)phenyl)aminocarbonylamino)phenoxy)-1H-benzi-
midazol-2-yl)carbamate; methyl
N-(5-(3-((4-(trifluoromethylthio)phenyl)aminocarbonylamino)phenoxy)-1H-be-
nzimidazol-2-yl)carbamate; methyl
N-(5-(3-((2-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1H-benzim-
idazol-2-yl)carbamate; methyl
N-(5-(3-((4-chloro-3-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)--
1H-benzimidazol-2-yl)carbamate; methyl
N-(5-(3-((3-iodophenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)c-
arbamate; methyl
N-(5-(3-((2,5-dichlorophenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol--
2-yl)carbamate; methyl
N-(5-(4-((3-phenoxyphenyl)aminocarbonylamino)phenylthio)-1H-benzimidazol--
2-yl)carbamate; methyl
N-(5-(4-((3-phenoxyphenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-y-
l)carbamate; methyl
N-(5-(3-((2-phenoxyphenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-y-
l)carbamate; methyl
N-(5-(3-((4-phenoxyphenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-y-
l)carbamate; methyl
N-(5-(3-((5-indanyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)carb-
amate; methyl
N-(5-(4-((5-indanyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)carb-
amate; methyl
N-(5-(3-((1-naphtyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)carb-
amate; methyl
N-(5-(3-((2,3-dimethylphenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol--
2-yl)carbamate;
1-(5-(4-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)--
1H-benzimidazol-2-yl)-3-(2-fluoro-5-(trifluoromethyl)phenyl)urea;
1-(5-(4-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)--
1H-benzimidazol-2-yl)-3-(4-chlorophenyl)urea;
1-(5-(4-((2-fluoro-5-(trifluoromethy)phenyl)aminocarbonylamino)phenoxy)-1-
H-benzimidazol-2-yl)-3-(4-(N,N-dimethylamino)phenyl)urea;
N-(5-(4-((5-carbamoyl-2-methylphenyl)aminocarbonylamino)phenoxy)-1H-benzi-
midazol-2-yl)(2-furyl)formamide; methyl
N-(5-(3-((2,3-dichlorophenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol--
2-yl)carbamate; methyl
N-(5-(3-((2,3-dimethylphenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol--
2-yl)carbamate;
1-(5-(4-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)--
1H-benzimidazol-2-yl)-3-(2,3-dimethylphenyl)urea; methyl
N-(5-(4-((3-chlorophenyl)aminothiocarbonylamino)phenoxy)-1H-benzimidazol--
2-yl)carbamate; methyl
N-(5-(4-((3-methoxyphenyl)aminothiocarbonylamino)phenoxy)-1H-benzimidazol-
-2-yl)carbamate; and methyl
N-(5-(4-((3-(trifluoromethyl)phenyl)aminothiocarbonylamino)phenoxy)-1H-be-
nzimidazol-2-yl)carbamate; or a salt or solvate thereof.
54. A pharmaceutical composition, comprising: a therapeutically
effective amount of a compound as claimed in claim 1, or a salt or
solvate thereof and one or more of pharmaceutically acceptable
carriers, diluents and excipients.
55. A pharmaceutical composition, comprising: a therapeutically
effective amount of a compound as claimed in claim 51, or a salt or
solvate thereof and one or more of pharmaceutically acceptable
carriers, diluents and excipients.
56. A pharmaceutical composition, comprising: a therapeutically
effective amount of a compound as claimed in claim 52, or a salt or
solvate thereof and one or more of pharmaceutically acceptable
carriers, diluents and excipients.
57. A pharmaceutical composition, comprising: a therapeutically
effective amount of a compound as claimed in claim 53, or a salt or
solvate thereof and one or more of pharmaceutically acceptable
carriers, diluents and excipients.
Description
BACKGROUND OF THE INVENTION
[0001] The present invention relates to benzimidazole derivatives,
compositions and medicaments containing the same, as well as
processes for the preparation and use of such compounds,
compositions and medicaments. Such benzimidazole derivatives are
useful in the treatment of diseases associated with inappropriate
or pathological angiogenesis.
[0002] The process of angiogenesis is the development of new blood
vessels, generally capillaries, from pre-existing vasculature.
Angiogenesis is defined as involving (i) activation of endothelial
cells; (ii) increased vascular permeability; (iii) subsequent
dissolution of the basement membrane and extravisation of plasma
components leading to formation of a provisional fibrin gel
extracellular matrix; (iv) proliferation and mobilization of
endothelial cells; (v) reorganization of mobilized endothelial
cells to form functional capillaries; (vi) capillary loop
formation; and (vii) deposition of basement membrane and
recruitment of perivascular cells to newly formed vessels. Normal
angiogenesis is activated during tissue growth, from embryonic
development through maturity, and then enters a period of relative
quiescence during adulthood. Normal angiogensesis is also activated
during wound healing, and at certain stages of the female
reproductive cycle. Inappropriate or pathological angiogenesis has
been associated with several disease states including various
retinopathies; ischemic disease; atherosclerosis; chronic
inflammatory disorders; and cancer. The role of angiogenesis in
disease states is discussed, for instance, in Fan et al, Trends in
Pharmacol Sci. 16:54-66; Shawver et al, DDT Vol. 2, No. 2 February
1997; Folkmann, 1995, Nature Medicine 1:27-31.
[0003] In cancer the growth of solid tumors has been shown to be
angiogenesis dependent. (See Folkmann, J., J. Nat'l. Cancer Inst.,
1990, 82, 4-6.) Consequently, the targeting of pro-angiogenic
pathways is a strategy being widely pursued in order to provide new
therapeutics in these areas of great, unmet medical need. The role
of tyrosine kinases involved in angiogenesis and in the
vascularization of solid tumors has drawn interest. Until recently
most interest in this area has focused on growth factors such as
vascular endothelial growth factor (VEGF) and its receptors termed
vascular endothelial growth factor receptor(s) (VEGFR). VEGF, a
polypeptide, is mitogenic for endothelial cells in vitro and
stimulates angiogenic responses in vivo. VEGF has also been linked
to inappropriate or pathological angiogenesis (Pinedo, H. M. et al
The Oncologist, Vol. 5, No. 90001, 1-2, April 2000). VEGFR(s) are
protein tyrosine kinases (PTKs). PTKs catalyze the phosphorylation
of specific tyrosyl residues in proteins involved in the regulation
of cell growth and differentiation. (A. F. Wilks, Progress in
Growth Factor Research, 1990, 2, 97-111; S. A. Courtneidge, Dev.
Suppl., 1993, 57-64; J. A. Cooper, Semin. Cell Biol., 1994, 5(6),
377-387; R. F. Paulson, Semin. Immunol., 1995, 7(4), 267-277; A. C.
Chan, Curr. Opin. Immunol., 1996, 8(3), 394-401).
[0004] Three PTK receptors for VEGF have been identified: VEGFR-1
(Flt-1); VEGFR-2 (Flk-1 or KDR) and VEGFR-3 (Flt-4). These
receptors are involved in angiogenesis and participate in signal
transduction (Mustonen, T. et al J. Cell Biol. 1995:129:895-898).
Of particular interest is VEGFR-2, which is a transmembrane
receptor PTK expressed primarily in endothelial cells. Activation
of VEGFR-2 by VEGF is a critical step in the signal transduction
pathway that initiates tumor angiogenesis. VEGF expression may be
constitutive to tumor cells and can also be upregulated in response
to certain stimuli. One such stimuli is hypoxia, where VEGF
expression is upregulated in both tumor and associated host
tissues. The VEGF ligand activates VEGFR-2 by binding with its
extracellular VEGF binding site. This leads to receptor
dimerization of VEGFRs and autophosphorylation of tyrosine residues
at the intracellular kinase domain of VEGFR-2. The kinase domain
operates to transfer a phosphate from ATP to the tyrosine residues,
thus providing binding sites for signaling proteins downstream of
VEGFR-2 leading ultimately to initiation of angiogenesis (McMahon,
G., The Oncologist, Vol. 5, No. 90001, 3-10, April 2000).
[0005] Angiopoieten 1 (Angl), a ligand for the endothelium-specific
receptor tyrosine kinase TIE-2 is a novel angiogenic factor (Davis
et al, Cell, 1996, 87:1161-1169; Partanen et al, Mol. Cell. Biol,
12:1698-1707 (1992); U.S. Pat. Nos. 5,521,073; 5,879,672;
5,877,020; and 6,030,831). The acronym TIE represents "tyrosine
kinase containing Ig and EGF homology domains". TIE is used to
identify a class of receptor tyrosine kinases, which are
exclusively expressed in vascular endothelial cells and early
hemopoietic cells. Typically, TIE receptor kinases are
characterized by the presence of an EGF-like domain and an
immunoglobulin (IG) like domain, which consists of extracellular
folding units, stabilized by intra-chain disulfide bonds (Partanen
et al Curr. Topics Microbiol. Immunol., 1999, 237:159-172). Unlike
VEGF, which functions during the early stages of vascular
development, Ang1 and its receptor TIE-2 function in the later
stages of vascular development, i.e., during vascular remodeling
(remodeling refers to formation of a vascular lumen) and maturation
(Yancopoulos et al, Cell, 1998, 93:661-664; Peters, K. G., Circ.
Res., 1998, 83(3):342-3; Suri et al, Cell 87, 1171-1180
(1996)).
[0006] Consequently, inhibition of TIE-2 would be expected to serve
to disrupt remodeling and maturation of new vasculature initiated
by angiogenesis thereby disrupting the angiogenic process.
Furthermore, inhibition at the kinase domain binding site of
VEGFR-2 would block phosphorylation of tyrosine residues and serve
to disrupt initiation of angiogenesis. Presumably then, inhibition
of TIE-2 and/or VEGFR-2 should prevent tumor angiogenesis and serve
to retard or eradicate tumor growth. Accordingly, a treatment for
cancer or other disorder associated with inappropriate angiogenesis
could be provided.
[0007] The present inventors have discovered novel benzimidazole
compounds, which are inhibitors of TIE-2 and/or VEGFR-2 kinase
activity. Such benzimidazole derivatives are useful in the
treatment of disorders, including cancer, associated with
inappropriate angiogenesis.
BRIEF SUMMARY OF THE INVENTION
[0008] In one aspect of the present invention, there is provided a
compound of Formula (I): ##STR1## or a salt, solvate, or
physiologically functional derivative thereof: wherein: E is aryl
substituted by R.sup.1 and R.sup.2, or [0009] unsubstituted
heteroaryl, or [0010] heteroaryl substituted with R.sup.1, or
[0011] heteroaryl substituted by R.sup.1 and R.sup.2, or [0012]
R.sup.1 and R.sup.2 together with the atoms of E to which they are
attached form a cycloalkyl, aryl, or heterocyclic ring fused to E;
A is aryl, heteroaryl, or heterocyclic; X is S, O, S(O).sub.2,
S(O), C(H).sub.2, C(H)(OH), or C(O); Z is O or S; p is 0 or 1; q is
0 or 1; the dotted line bonds "---" attached to Q and N' represent
a single bond or a double bond wherein when q is 0 the dotted line
bond "---" attached to Q is a single bond and the dotted line bond
attached to N' is a double bond, and when q is 1 the dotted line
bond "---" attached to Q is a double bond and the dotted line bond
attached to N' is a single bond; and the dotted line within the 6
membered ring containing D, M, and T represents appropriate
aromatic bonds; D is CH, T is CR.sup.8, M is C and Q is
N(R.sup.7).sub.p, wherein p is 0 and q is 1; or D is CH, T is
CR.sup.8, M is C and Q is N(R.sup.7).sub.p, wherein p is 1 and q is
0; or D is CH, T is CR.sup.8, M is C and Q is S or O; wherein q is
0; D is N, T is CR.sup.8, M is C and Q is N(R.sup.7).sub.p, wherein
either p or q is 0 and the other is 1; or D is CH, T is N, M is C
and Q is N(R.sup.7).sub.p, wherein either p or q is 0 and the other
is 1; or D is CH, T is CR.sup.8, M is N and Q is CH, wherein q is
0; R.sup.1 is C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 haloalkyl,
aryl, heteroaryl, heterocyclic, halogen, C.sub.1-C.sub.6 alkoxy,
C.sub.1-C.sub.6 haloalkoxy, aralkyl, aralkoxy, aryloxy,
C.sub.1-C.sub.6 alkylsulfanyl, C.sub.1-C.sub.6 haloalkylsulfanyl,
C.sub.1-C.sub.6 alkylsulfenyl, C.sub.1-C.sub.6 alkylsulfonyl,
--NO.sub.2, --NR.sup.4R.sup.5, --C(O)OR.sup.6, --CN,
--C(O)NR.sup.4R.sup.5, --S(O).sub.2NR.sup.4R.sup.5, or cyanoalkyl;
R.sup.2 is hydrogen, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6
haloalkyl, aryl, heteroaryl, heterocyclic, aralkyl, aralkoxy,
aryloxy, halogen, C.sub.1-C.sub.6 alkoxy, C.sub.1-C.sub.6
haloalkoxy, C.sub.1-C.sub.6 alkylsulfanyl, C.sub.1-C.sub.6
haloalkylsulfanyl, C.sub.1-C.sub.6 alkylsulfenyl, C.sub.1-C.sub.6
alkylsulfonyl, oxo, hydroxy, --NO.sub.2, --NR.sup.4R.sup.5,
--C(O)OR.sup.6, --CN, --C(O)NR.sup.4R.sup.5,
--S(O).sub.2NR.sup.4R.sup.5, or cyanoalkyl; R.sup.3 is hydrogen,
C.sub.1-C.sub.6 alkyl, aryl, aralkyl, aralkoxy, heteroaryl,
heterocyclic, --RR.sup.6, --RNR.sup.4R.sup.5, --C(O)R.sup.6,
--C(O)NR.sup.4R.sup.5, --C(O)OR.sup.6, --C(O)ROR.sup.6,
--C(O)RC(O)OR.sup.6, --C(O)RR.sup.6, --C(O)RR'R.sup.6,
--C(O)ROR'OR''OR.sup.6, --C(O)ROR'OR.sup.6, --C(O)RNR.sup.4R.sup.5,
--C(O)RNR.sup.4C(O)R.sup.6, --C(O)RNR.sup.4C(O)OR.sup.6,
--C(O)ORNR.sup.4R.sup.5, --S(O).sub.2R.sup.6, or
--S(O).sub.2NR.sup.4R.sup.5; or R.sup.3 is C.sub.1-C.sub.6 alkylene
or C.sub.1-C.sub.6 alkylene substituted with oxo, and is linked
together with the nitrogen to which it is attached and to one of
the benzimidazole nitrogens to form a heterocylic compound fused to
the benzimidazole; R, R', and R'', are each independently selected
from C.sub.1-C.sub.6 alkylene, arylene, heteroarylene,
C.sub.3-C.sub.7 cycloalkylene, or heterocyclylene; R''' is
C.sub.1-C.sub.6 alkyl, aryl, heteroaryl, aralkyl, C.sub.3-C.sub.7
cycloalkyl, or heterocyclic; R.sup.4 and R.sup.5 are each
independently selected from hydrogen, C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.6 haloalkyl, C.sub.1-C.sub.6 alkylsulfanyl,
C.sub.1-C.sub.6 alkylsulfenyl, C.sub.1-C.sub.6 alkylsulfonyl, aryl,
heteroaryl, aralkyl, heterocyclic, C.sub.3-C.sub.7 cycloalkyl,
--C(O)OR.sup.6, --C(O)NR'''R''', --C(O)NR'''H, --C(O)NH.sub.2, or
--S(O).sub.2NR'''R'''; R.sup.6 is hydrogen, C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.6 haloalkyl, aryl, heteroaryl, aralkyl, heterocyclic,
or C.sub.3-C.sub.7 cycloalkyl; R.sup.7 is hydrogen, C.sub.1-C.sub.6
alkyl, --S(O).sub.2R.sup.6, --RNR.sup.4R.sup.5, --RR.sup.6 R.sup.8
is hydrogen or halogen; and when R.sup.1 is Cl, R.sup.2 is hydrogen
or Cl, R.sup.3 is --C(O)OCH.sub.3, E and A are phenyl, D is CH, T
is CH, M is C, Q is N(R.sup.7).sub.p, where R.sup.7 is H, wherein
either p or q is 0 and the other is 1, and Z is O, then X is O,
S(O), S(O).sub.2, CH2, CH(OH), or C(O).
[0013] In a second aspect of the present invention, there is
provided a compound of Formula (I): ##STR2## or a salt, solvate, or
physiologically functional derivative thereof: wherein: E is
unsubstituted heteroaryl, or [0014] heteroaryl substituted with
R.sup.1, or [0015] heteroaryl substituted by R.sup.1 and R.sup.2; A
is aryl, heteroaryl, or heterocyclic; X is S, O, S(O).sub.2, S(O),
CH.sub.2, CH(OH), or C(O); Z is O or S; p is 0 or 1; q is 0 or 1;
the dotted line bonds "---" attached to Q and N' represent a single
bond or a double bond wherein when q is 0 the dotted line bond
"---" attached to Q is a single bond and the dotted line bond
attached to N' is a double bond, and when q is 1 the dotted line
bond "---" attached to Q is a double bond and the dotted line bond
attached to N' is a single bond; and the dotted line within the 6
membered ring containing D, M, and T represents appropriate
aromatic bonds; D is CH, T is CR.sup.8, M is C and Q is
N(R.sup.7).sub.p, wherein p is 0 and q is 1; or D is CH, T is
CR.sup.8, M is C and Q is N(R.sup.7).sub.p, wherein p is 1 and q is
0; or D is CH, T is CR.sup.8, M is C and Q is S or O; wherein q is
0; D is N, T is CR.sup.8, M is C and Q is N(R.sup.7).sub.p, wherein
either p or q is 0 and the other is 1; or D is CH, T is N, M is C
and Q is N(R.sup.7).sub.p, wherein either p or q is 0 and the other
is 1; or D is CH, T is CR.sup.8, M is N and Q is CH, wherein q is
0; R.sup.1 is C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 haloalkyl,
aryl, heteroaryl, heterocyclic, halogen, C.sub.1-C.sub.6 alkoxy,
C.sub.1-C.sub.6 haloalkoxy, aralkyl, aralkoxy, aryloxy,
C.sub.1-C.sub.6 alkylsulfanyl, C.sub.1-C.sub.6 haloalkylsulfanyl,
C.sub.1-C.sub.6 alkylsulfenyl, C.sub.1-C.sub.6 alkylsulfonyl,
--NO.sub.2, --NR.sup.4R.sup.5, --C(O)OR.sup.6, --CN,
--C(O)NR.sup.4R.sup.5, --S(O).sub.2NR.sup.4R.sup.5, or cyanoalkyl;
R.sup.2 is hydrogen, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6
haloalkyl, aryl, heteroaryl, heterocyclic, aralkyl, aralkoxy,
aryloxy, halogen, C.sub.1-C.sub.6 alkoxy, C.sub.1-C.sub.6
haloalkoxy, C.sub.1-C.sub.6 alkylsulfanyl, C.sub.1-C.sub.6
haloalkylsulfanyl, C.sub.1-C.sub.6 alkylsulfenyl, C.sub.1-C.sub.6
alkylsulfonyl, oxo, hydroxy, --NO.sub.2, --NR.sup.4R.sup.5,
--C(O)OR.sup.6, --CN, --C(O)NR.sup.4R.sup.5,
--S(O).sub.2NR.sup.4R.sup.5, or cyanoalkyl; R.sup.3 is hydrogen,
C.sub.1-C.sub.6 alkyl, aryl, aralkyl, aralkoxy, heteroaryl,
heterocyclic, --RR.sup.6, --RNR.sup.4R.sup.5, --C(O)R.sup.6,
--C(O)NR.sup.4R.sup.5, --C(O)OR.sup.6, --C(O)ROR.sup.6,
--C(O)RC(O)OR.sup.6, --C(O)RR.sup.6, --C(O)RR'R.sup.6,
--C(O)ROR'OR''OR.sup.6, --C(O)ROR'OR.sup.6, --C(O)RNR.sup.4R.sup.5,
--C(O)RNR.sup.4C(O)R.sup.6, --C(O)RNR.sup.4C(O)OR.sup.6,
--C(O)ORNR.sup.4R.sup.5, --S(O).sub.2R.sup.6, or
--S(O).sub.2NR.sup.4R.sup.5; or R.sup.3 is C.sub.1-C.sub.6 alkylene
or C.sub.1-C.sub.6 alkylene substituted with oxo, and is linked
together with the nitrogen to which it is attached and to one of
the benzimidazole nitrogens to form a heterocylic compound fused to
the benzimidazole; R, R', and R'', are each independently selected
from C.sub.1-C.sub.6 alkylene, arylene, heteroarylene,
C.sub.3-C.sub.7 cycloalkylene, or heterocyclylene; R''' is
C.sub.1-C.sub.6 alkyl, aryl, heteroaryl, aralkyl, C.sub.3-C.sub.7
cycloalkyl, or heterocyclic; R.sup.4 and R.sup.5 are each
independently selected from hydrogen, C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.6 haloalkyl, C.sub.1-C.sub.6 alkylsulfanyl,
C.sub.1-C.sub.6 alkylsulfenyl, C.sub.1-C.sub.6 alkylsulfonyl, aryl,
heteroaryl, aralkyl, heterocyclic, C.sub.3-C.sub.7 cycloalkyl,
--C(O)OR.sup.6, --C(O)NR'''R''', --C(O)NR'''H, --C(O)NH.sub.2, or
--S(O).sub.2NR'''R'''; R.sup.6 is hydrogen, C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.6 haloalkyl, aryl, heteroaryl, aralkyl, heterocyclic,
or C.sub.3-C.sub.7 cycloalkyl; R.sup.7 is hydrogen, C.sub.1-C.sub.6
alkyl, --S(O).sub.2R.sup.6, --RNR.sup.4R.sup.5, --RR.sup.6; and
R.sup.8 is hydrogen or halogen.
[0016] In a third aspect of the present invention, there is
provided a compound of Formula (II): ##STR3## or a salt, solvate,
or physiologically functional derivative thereof: wherein: A is
aryl, heteroaryl, or heterocyclic; X is S, O, S(O).sub.2, S(O),
CH.sub.2, CH(OH), or C(O); Z is O or S; p is 0 or 1; q is 0 or 1;
the dotted line bonds "---" attached to Q and N' represent a single
bond or a double bond wherein when q is 0 the dotted line bond
"---" attached to Q is a single bond and the dotted line bond
attached to N' is a double bond, and when q is 1 the dotted line
bond "---" attached to Q is a double bond and the dotted line bond
attached to N' is a single bond; and the dotted line within the 6
membered ring containing D, M, and T represents appropriate
aromatic bonds; D is CH, T is CR.sup.8, M is C and Q is
N(R.sup.7).sub.p, wherein p is 0 and q is 1; or D is CH, T is
CR.sup.8, M is C and Q is N(R.sup.7).sub.p, wherein p is 1 and q is
0; or D is CH, T is CR.sup.8, M is C and Q is S or O; wherein q is
0; D is N, T is CR.sup.8, M is C and Q is N(R.sup.7).sub.p, wherein
either p or q is 0 and the other is 1; or D is CH, T is N, M is C
and Q is N(R.sup.7).sub.p, wherein either p or q is 0 and the other
is 1; or D is CH, T is CR.sup.8, M is N and Q is CH, wherein q is
0; R.sup.1 is C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 haloalkyl,
aryl, heteroaryl, heterocyclic, halogen, C.sub.1-C.sub.6 alkoxy,
C.sub.1-C.sub.6 haloalkoxy, aralkyl, aralkoxy, aryloxy,
C.sub.1-C.sub.6 alkylsulfanyl, C.sub.1-C.sub.6 haloalkylsulfanyl,
C.sub.1-C.sub.6 alkylsulfenyl, C.sub.1-C.sub.6 alkylsulfonyl,
--NO.sub.2, --NR.sup.4R.sup.5, --C(O)OR.sup.6, --CN,
--C(O)NR.sup.4R.sup.5, --S(O).sub.2NR.sup.4R.sup.5, or cyanoalkyl;
R.sup.2 is hydrogen, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6
haloalkyl, aryl, heteroaryl, heterocyclic, aralkyl, aralkoxy,
aryloxy, halogen, C.sub.1-C.sub.6 alkoxy, C.sub.1-C.sub.6
haloalkoxy, C.sub.1-C.sub.6 alkylsulfanyl, C.sub.1-C.sub.6
haloalkylsulfanyl, C.sub.1-C.sub.6 alkylsulfenyl, C.sub.1-C.sub.6
alkylsulfonyl, oxo, hydroxy, --NO.sub.2, --NR.sup.4R.sup.5,
--C(O)OR.sup.6, --CN, --C(O)NR.sup.4R.sup.5,
--S(O).sub.2NR.sup.4R.sup.5, or cyanoalkyl; or R.sup.1 and R.sup.2
together with the phenyl ring atoms to which they are attached form
a cyloalkyl or aryl ring fused to the phenyl ring; R.sup.3 is
hydrogen, C.sub.1-C.sub.6 alkyl, aryl, aralkyl, aralkoxy,
heteroaryl, heterocyclic, --RR.sup.6, --RNR.sup.4R.sup.5,
--C(O)R.sup.6, --C(O)NR.sup.4R.sup.5, --C(O)OR.sup.6,
--C(O)ROR.sup.6, --C(O)RC(O)OR.sup.6, --C(O)RR.sup.6, --C(O)RR'
R.sup.6, --C(O)ROR'OR''OR.sup.6, --C(O)ROR'OR.sup.6,
--C(O)RNR.sup.4R.sup.5, --C(O)RNR.sup.4C(O)R.sup.6,
--C(O)RNR.sup.4C(O)OR.sup.6, --C(O)ORNR.sup.4R.sup.5,
--S(O).sub.2R.sup.6, or --S(O).sub.2NR.sup.4R.sup.5; or R.sup.3 is
C.sub.1-C.sub.6 alkylene or C.sub.1-C.sub.6 alkylene substituted
with oxo, and is linked together with the nitrogen to which it is
attached and to one of the benzimidazole nitrogens to form a
heterocylic compound fused to the benzimidazole; R, R', and R'',
are each independently selected from C.sub.1-C.sub.6 alkylene,
arylene, heteroarylene, C.sub.3-C.sub.7 cycloalkylene, or
heterocyclylene; R''' is C.sub.1-C.sub.6 alkyl, aryl, heteroaryl,
aralkyl, C.sub.3-C.sub.7 cycloalkyl, or heterocyclic; R.sup.4 and
R.sup.5 are each independently selected from hydrogen,
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 haloalkyl, C.sub.1-C.sub.6
alkylsulfanyl, C.sub.1-C.sub.6 alkylsulfenyl, C.sub.1-C.sub.6
alkylsulfonyl, aryl, heteroaryl, aralkyl, heterocyclic,
C.sub.3-C.sub.7 cycloalkyl, --C(O)OR.sup.6, --C(O)NR'''R''',
--C(O)NR'''H, --C(O)NH.sub.2, or --S(O).sub.2NR'''R'''; R.sup.6 is
hydrogen, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 haloalkyl, aryl,
heteroaryl, aralkyl, heterocyclic, or C.sub.3-C.sub.7 cycloalkyl;
R.sup.7 is hydrogen, C.sub.1-C.sub.6 alkyl, --S(O).sub.2R.sup.6,
--RNR.sup.4R.sup.5, --RR.sup.6 R.sup.8 is hydrogen or halogen; and
when R.sup.1 is Cl, R.sup.2 is H or Cl, R.sup.3 is --C(O)OCH.sub.3,
A is phenyl, D is CH, T is CH, M is C and Q is N(R.sup.7).sub.p,
where R.sup.7 is H, wherein either p or q is 0 and the other is 1
and Z is O, then X is O, S(O), .dbd.S(O).sub.2, CH2, CH(OH) or
C(O).
[0017] In a fourth aspect of the present invention, there is
provided a compound of Formula (III): ##STR4## or a salt, solvate,
or physiologically functional derivative thereof: wherein: A is
aryl, heteroaryl, or heterocyclic; X is S, O, S(O).sub.2, S(O),
CH.sub.2, CH(OH), or C(O); Z is O or S; p is 0 or 1; q is 0 or 1,
wherein either p or q is 0, and the other is 1; the dotted line
bonds "---" attached to N' and N'' represent a single bond or a
double bond wherein when q is 0 the dotted line bond "---" attached
to N' is a single bond and the dotted line bond attached to N'' is
a double bond, and when q is 1 the dotted line bond "---" attached
to N' is a double bond and the dotted line bond attached to N'' is
a single bond; R.sup.1 is C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6
haloalkyl, aryl, heteroaryl, heterocyclic, halogen, C.sub.1-C.sub.6
alkoxy, C.sub.1-C.sub.6 haloalkoxy, aralkyl, aralkoxy, aryloxy,
C.sub.1-C.sub.6 alkylsulfanyl, C.sub.1-C.sub.6 haloalkylsulfanyl,
C.sub.1-C.sub.6 alkylsulfenyl, C.sub.1-C.sub.6 alkylsulfonyl,
--NO.sub.2, --NR.sup.4R.sup.5, --C(O)OR.sup.6, --CN,
--C(O)NR.sup.4R.sup.5, --S(O).sub.2NR.sup.4R.sup.5, or cyanoalkyl;
R.sup.2 is hydrogen, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6
haloalkyl, aryl, heteroaryl, heterocyclic, aralkyl, aralkoxy,
aryloxy, halogen, C.sub.1-C.sub.6 alkoxy, C.sub.1-C.sub.6
haloalkoxy, C.sub.1-C.sub.6 alkylsulfanyl, C.sub.1-C.sub.6
haloalkylsulfanyl, C.sub.1-C.sub.6 alkylsulfenyl, C.sub.1-C.sub.6
alkylsulfonyl, oxo, hydroxy, --NO.sub.2, --NR.sup.4R.sup.5,
--C(O)OR.sup.6, --CN, --C(O)NR.sup.4R.sup.5,
--S(O).sub.2NR.sup.4R.sup.5, or cyanoalkyl; or R.sup.1 and R.sup.2
together with the phenyl ring atoms to which they are attached form
a cyloalkyl or aryl ring fused to the phenyl ring; R.sup.3 is
hydrogen, C.sub.1-C.sub.6 alkyl, aryl, aralkyl, aralkoxy,
heteroaryl, heterocyclic, --RR.sup.6, --RNR.sup.4R.sup.5,
--C(O)R.sup.6, --C(O)NR.sup.4R.sup.5, --C(O)OR.sup.6,
--C(O)ROR.sup.6, --C(O)RC(O)OR.sup.6, --C(O)RR.sup.6,
--C(O)RR'R.sup.6, --C(O)ROR'OR''OR.sup.6, --C(O)ROR'OR.sup.6,
--C(O)RNR.sup.4R.sup.5, --C(O)RNR.sup.4C(O)R.sup.6,
--C(O)RNR.sup.4C(O)OR.sup.6, --C(O)ORNR.sup.4R.sup.5,
--S(O).sub.2R.sup.6, or --S(O).sub.2NR.sup.4R.sup.5; or R.sup.3 is
C.sub.1-C.sub.6 alkylene or C.sub.1-C.sub.6 alkylene substituted
with oxo, and is linked together with the nitrogen to which it is
attached and to one of the benzimidazole nitrogens to form a
heterocylic compound fused to the benzimidazole; R, R', and R'',
are each independently selected from C.sub.1-C.sub.6 alkylene,
arylene, heteroarylene, C.sub.3-C.sub.7 cycloalkylene, or
heterocyclylene; R''' is C.sub.1-C.sub.6 alkyl, aryl, heteroaryl,
aralkyl, C.sub.3-C.sub.7 cycloalkyl, or heterocyclic; R.sup.4 and
R.sup.5 are each independently selected from hydrogen,
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 haloalkyl, C.sub.1-C.sub.6
alkylsulfanyl, C.sub.1-C.sub.6 alkylsulfenyl, C.sub.1-C.sub.6
alkylsulfonyl, aryl, heteroaryl, aralkyl, heterocyclic,
C.sub.3-C.sub.7 cycloalkyl, --C(O)OR.sup.6, --C(O)NR'''R''';
--C(O)NR'''H, --C(O)NH.sub.2, or --S(O).sub.2NR'''R'''; R.sup.6 is
hydrogen, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 haloalkyl, aryl,
heteroaryl, aralkyl, heterocyclic, or C.sub.3-C.sub.7 cycloalkyl;
R.sup.7 is hydrogen, C.sub.1-C.sub.6 alkyl, --S(O).sub.2R.sup.6,
--RNR.sup.4R.sup.5, --RR.sup.6 R.sup.8 is hydrogen or halogen; and
when R.sup.1 is Cl, R.sup.2 is H or Cl, R.sup.3 is --C(O)OCH.sub.3,
A is phenyl, and Z is O, then X is O, S(O), .dbd.S(O).sub.2,
CH.sub.2, CH(OH), or C(O).
[0018] In a fifth aspect of the present invention, there is
provided a compound of formula (IV) ##STR5## or a salt, solvate, or
physiologically functional derivative thereof: wherein: E is
unsubstituted heteroaryl, or
[0019] heteroaryl substituted with R.sup.1, or
[0020] heteroaryl substituted by R.sup.1 and R.sup.2;
A is aryl, heteroaryl, or heterocyclic;
X is S, O, S(O).sub.2, S(O), CH.sub.2, CH(OH), or C(O);
Z is O or S;
p is 0 or 1;
q is 0 or 1;
[0021] the dotted line bonds "---" attached to N' and N'' represent
a single bond or a double bond wherein when q is 0 the dotted line
bond "---" attached to N' is a single bond and the dotted line bond
attached to N'' is a double bond, and when q is 1 the dotted line
bond "---" attached to N' is a double bond and the dotted line bond
attached to N'' is a single bond;
[0022] R.sup.1 is C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 haloalkyl,
aryl, heteroaryl, heterocyclic, halogen, C.sub.1-C.sub.6 alkoxy,
C.sub.1-C.sub.6 haloalkoxy, aralkyl, aralkoxy, aryloxy,
C.sub.1-C.sub.6 alkylsulfanyl, C.sub.1-C.sub.6 haloalkylsulfanyl,
C.sub.1-C.sub.6 alkylsulfenyl, C.sub.1-C.sub.6 alkylsulfonyl,
--NO.sub.2, --NR.sup.4R.sup.5, --C(O)OR.sup.6, --CN,
--C(O)NR.sup.4R.sup.5, --S(O).sub.2NR.sup.4R.sup.5, or
cyanoalkyl;
[0023] R.sup.2 is hydrogen, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6
haloalkyl, aryl, heteroaryl, heterocyclic, aralkyl, aralkoxy,
aryloxy, halogen, C.sub.1-C.sub.6 alkoxy, C.sub.1-C.sub.6
haloalkoxy, C.sub.1-C.sub.6 alkylsulfanyl, C.sub.1-C.sub.6
haloalkylsulfanyl, C.sub.1-C.sub.6 alkylsulfenyl, C.sub.1-C.sub.6
alkylsulfonyl, oxo, hydroxy, --NO.sub.2, --NR.sup.4R.sup.5,
--C(O)OR.sup.6, --CN, --C(O)NR.sup.4R.sup.5,
--S(O).sub.2NR.sup.4R.sup.5, or cyanoalkyl;
[0024] R.sup.3 is hydrogen, C.sub.1-C.sub.6 alkyl, aryl, aralkyl,
aralkoxy, heteroaryl, heterocyclic, --RR.sup.6, --RNR.sup.4R.sup.5,
--C(O)R.sup.6, --C(O)NR.sup.4R.sup.5, --C(O)OR.sup.6,
--C(O)ROR.sup.6, --C(O)RC(O)OR.sup.6, --C(O)RR.sup.6, --C(O)RR'
R.sup.6, --C(O)ROR'OR''OR.sup.6, --C(O)ROR'OR.sup.6,
--C(O)RNR.sup.4R.sup.5, --C(O)RNR.sup.4C(O)R.sup.6,
--C(O)RNR.sup.4C(O)OR.sup.6, --C(O)ORNR.sup.4R.sup.5,
--S(O).sub.2R.sup.6, or --S(O).sub.2NR.sup.4R.sup.5; or
R.sup.3 is C.sub.1-C.sub.6 alkylene or C.sub.1-C.sub.6 alkylene
substituted with oxo, and is linked together with the nitrogen to
which it is attached and to one of the benzimidazole nitrogens to
form a heterocylic compound fused to the benzimidazole;
R, R', and R'', are each independently selected from
C.sub.1-C.sub.6 alkylene, arylene, heteroarylene, C.sub.3-C.sub.7
cycloalkylene, or heterocyclylene;
R''' is C.sub.1-C.sub.6 alkyl, aryl, heteroaryl, aralkyl,
C.sub.3-C.sub.7 cycloalkyl, or heterocyclic;
[0025] R.sup.4 and R.sup.5 are each independently selected from
hydrogen, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 haloalkyl,
C.sub.1-C.sub.6 alkylsulfanyl, C.sub.1-C.sub.6 alkylsulfenyl,
C.sub.1-C.sub.6 alkylsulfonyl, aryl, heteroaryl, aralkyl,
heterocyclic, C.sub.3-C.sub.7 cycloalkyl, --C(O)OR.sup.6,
--C(O)NR'''R''', --C(O)NR'''H, --C(O)NH.sub.2, or
--S(O).sub.2NR'''R''';
R.sup.6 is hydrogen, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6
haloalkyl, aryl, heteroaryl, aralkyl, heterocyclic, or
C.sub.3-C.sub.7 cycloalkyl;
R.sup.7 is hydrogen, C.sub.1-C.sub.6 alkyl, --S(O).sub.2R.sup.6,
--RNR.sup.4R.sup.5, --RR.sup.6; and
R.sup.8 is hydrogen or halogen.
[0026] In a sixth aspect of the present invention, there is
provided a pharmaceutical composition including a therapeutically
effective amount of a compound of formula (I), or a salt, solvate,
or a physiologically functional derivative thereof and one or more
of pharmaceutically acceptable carriers, diluents and
excipients.
[0027] In a seventh aspect of the present invention, there is
provided a method of treating a disorder in a mammal, said disorder
being mediated by inappropriate TIE-2 activity, including:
administering to said mammal a therapeutically effective amount of
a compound of formula (I) or a salt, solvate or a physiologically
functional derivative thereof.
[0028] In an eighth aspect of the present invention, there is
provided a compound of formula (I), or a salt, solvate, or a
physiologically functional derivative thereof for use in
therapy.
[0029] In a ninth aspect of the present invention, there is
provided the use of a compound of formula (I), or a salt, solvate,
or a physiologically functional derivative thereof in the
preparation of a medicament for use in the treatment of a disorder
mediated by inappropriate TIE-2 activity.
[0030] In a tenth aspect of the present invention, there is
provided a method of treating a disorder in a mammal, said disorder
being mediated by inappropriate TIE-2 activity, including:
administering to said mammal therapeutically effective amounts of
(i) a compound of formula (I), or a salt, solvate or
physiologically functional derivative thereof and (ii) an agent to
inhibit growth factor receptor function.
[0031] In an eleventh aspect of the present invention, there is
provided a method of treating a disorder in a mammal, said disorder
being characterized by inappropriate angiogenesis, including:
administering to said mammal a therapeutically effective amount of
a compound of formula (I), or a salt, solvate or physiologically
functional derivative thereof.
DETAILED DESCRIPTION
[0032] As used herein, the term "effective amount" means that
amount of a drug or pharmaceutical agent that will elicit the
biological or medical response of a tissue, system, animal or human
that is being sought, for instance, by a researcher or clinician.
Furthermore, the term "therapeutically effective amount" means any
amount which, as compared to a corresponding subject who has not
received such amount, results in improved treatment, healing,
prevention, or amelioration of a disease, disorder, or side effect,
or a decrease in the rate of advancement of a disease or disorder.
The term also includes within its scope amounts effective to
enhance normal physiological function.
[0033] As used herein, the term "alkyl" refers to a straight or
branched chain hydrocarbon having from one to twelve carbon atoms,
optionally substituted with substituents selected from the group
consisting of C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy,
C.sub.1-C.sub.6 alkylsulfanyl, C.sub.1-C.sub.6 alkylsulfenyl,
C.sub.1-C.sub.6 alkylsulfonyl, oxo, hydroxy, mercapto, amino
optionally substituted by alkyl, carboxy, carbamoyl optionally
substituted by alkyl, aminosulfonyl optionally substituted by
alkyl, nitro, cyano, halogen, or C.sub.1-C.sub.6 perfluoroalkyl,
multiple degrees of substitution being allowed. Examples of "alkyl"
as used herein include, but are not limited to, methyl, ethyl,
n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, n-pentyl,
isopentyl, and the like.
[0034] As used herein, the term "C.sub.1-C.sub.6 alkyl" refers to
an alkyl group as defined above containing at least 1, and at most
6, carbon atoms. Examples of branched or straight chained
"C.sub.1-C.sub.6 alkyl" groups useful in the present invention
include, but are not limited to, methyl, ethyl, n-propyl,
isopropyl, isobutyl, n-butyl, t-butyl, n-pentyl, and isopentyl.
[0035] As used herein, the term "alkylene" refers to a straight or
branched chain divalent hydrocarbon radical having from one to ten
carbon atoms, optionally substituted with substituents selected
from the group which includes lower alkyl, lower alkoxy, lower
alkylsulfanyl, lower alkylsulfenyl, lower alkylsulfonyl, oxo,
hydroxy, mercapto, amino optionally substituted by alkyl, carboxy,
carbamoyl optionally substituted by alkyl, aminosulfonyl optionally
substituted by alkyl, nitro, cyano, halogen and lower
perfluoroalkyl, multiple degrees of substitution being allowed.
Examples of "alkylene" as used herein include, but are not limited
to, methylene, ethylene, n-propylene, n-butylene, and the like.
[0036] As used herein, the term "C.sub.1-C.sub.6 alkylene" refers
to an alkylene group, as defined above, which contains at least 1,
and at most 6, carbon atoms respectively. Examples of
"C.sub.1-C.sub.6 alkylene" groups useful in the present invention
include, but are not limited to, methylene, ethylene, and
n-propylene.
[0037] As used herein, the term "halogen" refers to fluorine (F),
chlorine (Cl), bromine (Br), or iodine (I).
[0038] As used herein, the term "C.sub.1-C.sub.6 haloalkyl" refers
to an alkyl group as defined above containing at least 1, and at
most 6, carbon atoms substituted with at least one halogen, halogen
being as defined herein. Examples of branched or straight chained
"C.sub.1-C.sub.6 haloalkyl" groups useful in the present invention
include, but are not limited to, methyl, ethyl, propyl, isopropyl,
isobutyl and n-butyl substituted independently with one or more
halogens, e.g., fluoro, chloro, bromo and iodo.
[0039] As used herein, the term "C.sub.3-C.sub.7 cycloalkyl" refers
to a non-aromatic cyclic hydrocarbon ring having from three to
seven carbon atoms and which optionally includes a C.sub.1-C.sub.6
alkyl linker through which it may be attached. The C.sub.1-C.sub.6
alkyl group is as defined above. Exemplary "C.sub.3-C.sub.7
cycloalkyl" groups include, but are not limited to, cyclopropyl,
cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.
[0040] As used herein, the term "C.sub.3-C.sub.7 cycloalkylene"
refers to a non-aromatic alicyclic divalent hydrocarbon radical
having from three to seven carbon atoms, optionally substituted
with substituents selected from the group which includes lower
alkyl, lower alkoxy, lower alkylsulfanyl, lower alkylsulfenyl,
lower alkylsulfonyl, oxo, hydroxy, mercapto, amino optionally
substituted by alkyl, carboxy, carbamoyl optionally substituted by
alkyl, aminosulfonyl optionally substituted by alkyl, nitro, cyano,
halogen, lower perfluoroalkyl, multiple degrees of substitution
being allowed. Examples of "cycloalkylene" as used herein include,
but are not limited to, cyclopropyl-1,1-diyl, cyclopropyl-1,2-diyl,
cyclobutyl-1,2-diyl, cyclopentyl-1,3-diyl, cyclohexyl-1,4-diyl,
cycloheptyl-1,4-diyl, or cyclooctyl-1,5-diyl, and the like.
[0041] As used herein, the term "heterocyclic" or the term
"heterocyclyl" refers to a three to twelve-membered heterocyclic
ring having one or more degrees of unsaturation containing one or
more heteroatomic substitutions selected from S, SO, SO.sub.2, O,
or N, optionally substituted with substituents selected from the
group consisting of C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6
haloalkyl, C.sub.1-C.sub.6 alkoxy, C.sub.1-C.sub.6 alkylsulfanyl,
C.sub.1-C.sub.6 haloalkylsulfanyl, C.sub.1-C.sub.6 alkylsulfenyl,
C.sub.1-C.sub.6 alkylsulfonyl, oxo, hydroxy, mercapto, amino
optionally substituted by alkyl, carboxy, carbamoyl optionally
substituted by alkyl, aminosulfonyl optionally substituted by
alkyl, nitro, cyano, halogen, or C.sub.1-C.sub.6 perfluoroalkyl,
multiple degrees of substitution being allowed. Such a ring may be
optionally fused to one or more other "heterocyclic" ring(s) or
cycloalkyl ring(s). Examples of "heterocyclic" moieties include,
but are not limited to, tetrahydrofuran, pyran, 1,4-dioxane,
1,3-dioxane, piperidine, pyrrolidine, morpholine,
tetrahydrothiopyran, tetrahydrothiophene, and the like.
[0042] As used herein, the term "heterocyclylene" refers to a three
to twelve-membered heterocyclic ring diradical having one or more
degrees of unsaturation containing one or more heteroatoms selected
from S, SO, SO.sub.2, O, or N, optionally substituted with
substituents selected from the group which includes lower alkyl,
lower alkoxy, lower alkylsulfanyl, lower alkylsulfenyl, lower
alkylsulfonyl, oxo, hydroxy, mercapto, amino optionally substituted
by alkyl, carboxy, carbamoyl optionally substituted by alkyl,
aminosulfonyl optionally substituted by alkyl, nitro, cyano,
halogen and lower perfluoroalkyl, multiple degrees of substitution
being allowed. Such a ring may be optionally fused to one or more
benzene rings or to one or more of another "heterocyclic" rings or
cycloalkyl rings. Examples of "heterocyclylene" include, but are
not limited to, tetrahydrofuran-2,5-diyl, morpholine-2,3-diyl,
pyran-2,4-diyl, 1,4-dioxane-2,3-diyl, 1,3-dioxane-2,4-diyl,
piperidine-2,4-diyl, piperidine-1,4-diyl, pyrrolidine-1,3-diyl,
morpholine-2,4-diyl, and the like.
[0043] As used herein, the term "aryl" refers to an optionally
substituted benzene ring or to an optionally substituted benzene
ring system fused to one or more optionally substituted benzene
rings to form, for example, anthracene, phenanthrene, or napthalene
ring systems. Exemplary optional substituents include
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy, C.sub.1-C.sub.6
alkylsulfanyl, C.sub.1-C.sub.6 alkylsulfenyl, C.sub.1-C.sub.6
alkylsulfonyl, oxo, hydroxy, mercapto, amino optionally substituted
by alkyl, carboxy, tetrazolyl, carbamoyl optionally substituted by
alkyl, aminosulfonyl optionally substituted by alkyl, acyl, aroyl,
heteroaroyl, acyloxy, aroyloxy, heteroaroyloxy, alkoxycarbonyl,
nitro, cyano, halogen, C.sub.1-C.sub.6 perfluoroalkyl, heteroaryl,
or aryl, multiple degrees of substitution being allowed. Examples
of "aryl" groups include, but are not limited to, phenyl,
2-naphthyl, 1-naphthyl, biphenyl, as well as substituted
derivatives thereof.
[0044] As used herein, the term "arylene" refers to a benzene ring
diradical or to a benzene ring system diradical fused to one or
more optionally substituted benzene rings, optionally substituted
with substituents selected from the group which includes lower
alkyl, lower alkoxy, lower alkylsulfanyl, lower alkylsulfenyl,
lower alkylsulfonyl, oxo, hydroxy, mercapto, amino optionally
substituted by alkyl, carboxy, tetrazolyl, carbamoyl optionally
substituted by alkyl, aminosulfonyl optionally substituted by
alkyl, acyl, aroyl, heteroaroyl, acyloxy, aroyloxy, heteroaroyloxy,
alkoxycarbonyl, nitro, cyano, halogen, lower perfluoroalkyl,
heteroaryl and aryl, multiple degrees of substitution being
allowed. Examples of "arylene" include, but are not limited to,
benzene-1,4-diyl, naphthalene-1,8-diyl, anthracene-1,4-diyl, and
the like.
[0045] As used herein, the term "aralkyl" refers to an aryl or
heteroaryl group, as defined herein, attached through a
C.sub.1-C.sub.6 alkyl linker, wherein C.sub.1-C.sub.6 alkyl is as
defined herein. Examples of "aralkyl" include, but are not limited
to, benzyl, phenylpropyl, 2-pyridylmethyl, 3-isoxazolylmethyl,
5-methyl, 3-isoxazolylmethyl, and 2-imidazoyl ethyl.
[0046] As used herein, the term "heteroaryl" refers to a monocyclic
five to seven membered aromatic ring, or to a fused bicyclic
aromatic ring system comprising two of such monocyclic five to
seven membered aromatic rings. These heteroaryl rings contain one
or more nitrogen, sulfur, and/or oxygen heteroatoms, where N-oxides
and sulfur oxides and dioxides are permissible heteroatom
substitutions and may be optionally substituted with up to three
members selected from a group consisting of C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.6 haloalkyl, C.sub.1-C.sub.6 alkoxy, C.sub.1-C.sub.6
alkylsulfanyl, C.sub.1-C.sub.6 haloalkylsulfanyl, C.sub.1-C.sub.6
alkylsulfenyl, C.sub.1-C.sub.6 alkylsulfonyl, oxo, hydroxy,
mercapto, amino optionally substituted by alkyl, carboxy,
tetrazolyl, carbamoyl optionally substituted by alkyl,
aminosulfonyl optionally substituted by alkyl, acyl, aroyl,
heteroaroyl, acyloxy, aroyloxy, heteroaroyloxy, alkoxycarbonyl,
nitro, cyano, halogen, C.sub.1-C.sub.6 perfluoroalkyl, heteroaryl,
or aryl, multiple degrees of substitution being allowed. Examples
of "heteroaryl" groups used herein include furanyl, thiophenyl,
pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl,
oxazolyl, isoxazolyl, oxadiazolyl, oxo-pyridyl, thiadiazolyl,
isothiazolyl, pyridyl, pyridazyl, pyrazinyl, pyrimidyl, quinolinyl,
isoquinolinyl, benzofuranyl, benzothiophenyl, indolyl, indazolyl,
and substituted versions thereof.
[0047] As used herein, the term "heteroarylene" refers to a five-
to seven-membered aromatic ring diradical, or to a polycyclic
heterocyclic aromatic ring diradical, containing one or more
nitrogen, oxygen, or sulfur heteroatoms, where N-oxides and sulfur
monoxides and sulfur dioxides are permissible heteroaromatic
substitutions, optionally substituted with substituents selected
from the group consisting of: lower alkyl, lower alkoxy, lower
alkylsulfanyl, lower alkylsulfenyl, lower alkylsulfonyl, oxo,
hydroxy, mercapto, amino optionally substituted by alkyl, carboxy,
tetrazolyl, carbamoyl optionally substituted by alkyl,
aminosulfonyl optionally substituted by alkyl, acyl, aroyl,
heteroaroyl, acyloxy, aroyloxy, heteroaroyloxy, alkoxycarbonyl,
nitro, cyano, halogen, lower perfluoroalkyl, heteroaryl, or aryl,
multiple degrees of substitution being allowed. For polycyclic
aromatic ring system diradicals, one or more of the rings may
contain one or more heteroatoms. Examples of "heteroarylene" used
herein are furan-2,5-diyl, thiophene-2,4-diyl,
1,3,4-oxadiazole-2,5-diyl, 1,3,4-thiadiazole-2,5-diyl,
1,3-thiazole-2,4-diyl, 1,3-thiazole-2,5-diyl, pyridine-2,4-diyl,
pyridine-2,3-diyl, pyridine-2,5-diyl, pyrimidine-2,4-diyl,
quinoline-2,3-diyl, and the like.
[0048] As used herein, the term "alkoxy" refers to the group
R.sub.aO--, where R.sub.a is alkyl as defined above and the term
"C.sub.1-C.sub.6 alkoxy" refers to an alkoxy group as defined
herein wherein the alkyl moiety contains at least 1, and at most 6,
carbon atoms. Exemplary C.sub.1-C.sub.6 alkoxy groups useful in the
present invention include, but are not limited to, methoxy, ethoxy,
n-propoxy, isopropoxy, n-butoxy, and t-butoxy.
[0049] As used herein, the term "haloalkoxy" refers to the group
R.sub.aO--, where R.sub.a is haloalkyl as defined above and the
term "C.sub.1-C.sub.6 haloalkoxy" refers to an haloalkoxy group as
defined herein wherein the haloalkyl moiety contains at least 1,
and at most 6, carbon atoms. Exemplary C.sub.1-C.sub.6 haloalkoxy
groups useful in the present invention include, but are not limited
to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, and t-butoxy
substituted with one or more halo groups, for instance
trifluoromethoxy.
[0050] As used herein the term "aralkoxy" refers to the group
R.sub.bR.sub.aO--, where R.sub.a is alkyl and R.sub.b is aryl as
defined above.
[0051] As used herein the term "aryloxy" refers to the group
R.sub.aO--, where R.sub.a is aryl as defined above.
[0052] As used herein, the term "alkylsulfanyl" refers to the group
R.sub.aS--, where R.sub.a is alkyl as defined above and the term
"C.sub.1-C.sub.6 alkylsulfanyl" refers to an alkylsulfanyl group as
defined herein wherein the alkyl moiety contains at least 1, and at
most 6, carbon atoms.
[0053] As used herein, the term "haloalkylsulfanyl" refers to the
group R.sub.aS--, where R.sub.a is haloalkyl as defined above and
the term "C.sub.1-C.sub.6 haloalkylsulfanyl" refers to a
haloalkylsulfanyl group as defined herein wherein the alkyl moiety
contains at least 1, and at most 6, carbon atoms.
[0054] As used herein, the term "alkylsulfenyl" refers to the group
R.sub.aS(O)--, where R.sub.a is alkyl as defined above and the term
"C.sub.1-C.sub.6 alkylsulfenyl" refers to an alkylsulfenyl group as
defined herein wherein the alkyl moiety contains at least 1, and at
most 6, carbon atoms.
[0055] As used herein, the term "alkylsulfonyl" refers to the group
R.sub.aSO.sub.2--, where R.sub.a is alkyl as defined above and the
term "C.sub.1-C.sub.6 alkylsulfonyl"refers to an alkylsulfonyl
group as defined herein wherein the alkyl moiety contains at least
1, and at most 6, carbon atoms.
[0056] As used herein, the term "oxo" refers to the group
.dbd.O
[0057] As used herein, the term "mercapto" refers to the group
--SH.
[0058] As used herein, the term "carboxy" refers to the group
--COOH.
[0059] As used herein, the term "cyano" refers to the group
--CN.
[0060] As used herein the term "cyanoalkyl" refers to the group
--CNR.sub.a, wherein R.sub.a is alkyl as defined above. Exemplary
"cyanoalkyl" groups useful in the present invention include, but
are not limited to, cyanomethyl, cyanoethyl, and
cyanoisopropyl.
[0061] As used herein, the term "aminosulfonyl" refers to the group
--SO.sub.2NH.sub.2.
[0062] As used herein, the term "carbamoyl" refers to the group
--C(O)NH.sub.2.
[0063] As used herein, the term "sulfanyl" shall refer to the group
--S--.
[0064] As used herein, the term "sulfenyl" shall refer to the group
--S(O)--.
[0065] As used herein, the term "sulfonyl" shall refer to the group
--S(O).sub.2-- or --SO.sub.2--.
[0066] As used herein, the term "acyl" refers to the group
R.sub.aC(O)--, where R.sub.a is alkyl, cycloalkyl, or heterocyclyl
as defined herein.
[0067] As used herein, the term "aroyl" refers to the group
R.sub.aC(O)--, where R.sub.a is aryl as defined herein.
[0068] As used herein, the term "heteroaroyl" refers to the group
R.sub.aC(O)--, where R.sub.a is heteroaryl as defined herein.
[0069] As used herein, the term "alkoxycarbonyl" refers to the
group R.sub.aOC(O)--where R.sub.a is alkyl as defined herein.
[0070] As used herein, the term "acyloxy" refers to the group
R.sub.aC(O)O--, where R.sub.a is alkyl, cycloalkyl, or heterocyclyl
as defined herein.
[0071] As used herein, the term "aroyloxy" refers to the group
R.sub.aC(O)O--, where R.sub.a is aryl as defined herein.
[0072] As used herein, the term "heteroaroyloxy" refers to the
group R.sub.aC(O)O--, where R.sub.a is heteroaryl as defined
herein.
[0073] As used herein, the term "optionally" means that the
subsequently described event(s) may or may not occur, and includes
both event(s), which occur, and events that do not occur.
[0074] As used herein, the term "physiologically functional
derivative" refers to any pharmaceutically acceptable derivative of
a compound of the present invention, for example, an ester or an
amide, which upon administration to a mammal is capable of
providing (directly or indirectly) a compound of the present
invention or an active metabolite thereof. Such derivatives are
clear to those skilled in the art, without undue experimentation,
and with reference to the teaching of Burger's Medicinal Chemistry
And Drug Discovery, 5.sup.th Edition, Vol 1: Principles and
Practice, which is incorporated herein by reference to the extent
that it teaches physiologically functional derivatives.
[0075] As used herein, the term "solvate" refers to a complex of
variable stoichiometry formed by a solute (in this invention, a
compound of formula (I) or formula (II) or a salt or
physiologically functional derivative thereof) and a solvent. Such
solvents for the purpose of the invention may not interfere with
the biological activity of the solute. Examples of suitable
solvents include, but are not limited to, water, methanol, ethanol
and acetic acid. Preferably the solvent used is a pharmaceutically
acceptable solvent. Examples of suitable pharmaceutically
acceptable solvents include, without limitation, water, ethanol and
acetic acid. Most preferably the solvent used is water.
[0076] As used herein, the term "substituted" refers to
substitution with the named substituent or substituents, multiple
degrees of substitution being allowed unless otherwise stated.
[0077] Certain of the compounds described herein may contain one or
more chiral atoms, or may otherwise be capable of existing as two
enantiomers. Accordingly, the compounds of this invention include
mixtures of enantiomers as well as purified enantiomers or
enantiomerically enriched mixtures. Also included within the scope
of the invention are the individual isomers of the compounds
represented by formulae (I) and (II) above as well as any wholly or
partially equilibrated mixtures thereof. The present invention also
covers the individual isomers of the compounds represented by the
formulas above as mixtures with isomers thereof in which one or
more chiral centers are inverted. Also, it is understood that all
tautomers and mixtures of tautomers of the compounds of formulae
(I) or (II) are included within the scope of the compounds of
formulae (I) and (II).
[0078] It is to be understood that reference to compounds of
formula (I) and formula (II) above, following herein, refers to
compounds within the scope of formula (I) and formula (II) as
defined above with respect to E, X, Z, A, D, M, T, Q, R.sup.1,
R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7, or R.sup.8
unless specifically limited otherwise. It is also understood that
the following embodiments, including uses and compositions,
although recited with respect to formula (I) are also applicable to
formulae (II), (III), and (IV).
[0079] In one embodiment, E is aryl substituted with R.sup.1 and
R.sup.2. In a preferred embodiment, E is phenyl substituted with
R.sup.1 and R.sup.2. In another embodiment, E is unsubstituted
heteroaryl, heteroaryl substituted with R.sup.1, or heteroaryl
substituted with R.sup.1 and R.sup.2. In a preferred embodiment, E
is heteroaryl substituted with R.sup.1 or heteroaryl substituted
with R.sup.1 and R.sup.2. In a more preferred embodiment, E is
heteroaryl substituted with R.sup.1, wherein R.sup.1 is preferably
C.sub.1-C.sub.6 alkyl, more preferably --C(CH.sub.3).sub.3, i.e.
tert-butyl. In another preferred embodiment, E is selected from
##STR6## either unsubstituted, substituted by R.sup.1 or
substituted by R.sup.1 and R.sup.2.
[0080] It is understood that E is attached to the indicated linking
group of Formula (I) through the bond of E having an unfilled
valence and being indicated by "\". The appropriate attachments are
further illustrated in the working examples recited below.
[0081] In another embodiment, E is phenyl and R.sup.1 and R.sup.2
together with the phenyl ring atoms with which they are attached
form a cycloalkyl, preferably cyclopentyl, or aryl, preferably
phenyl fused to E.
[0082] In one embodiment, the compound of formula (I) is a compound
of formula (III): ##STR7## or salt, solvate, or physiologically
functional derivative thereof.
[0083] In one embodiment, the compound of formula (I) is a compound
of formula (IV): ##STR8## wherein E is unsubstituted heteroaryl,
heteroaryl substituted with R.sup.1, or heteroaryl substituted with
R.sup.1 and R.sup.2, or a salt, solvate, or physiologically
functional derivative thereof.
[0084] In one embodiment, R.sup.1 is C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.6 alkoxy, aryloxy, C.sub.1-C.sub.6 haloalkyl,
C.sub.1-C.sub.6 haloalkylsulfanyl, C.sub.1-C.sub.6 alkylsulfanyl,
--C(O)OR.sup.6, halogen, --CN, or --NO.sub.2. In a preferred
embodiment, R.sup.1 is C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6
haloalkyl, C.sub.1-C.sub.6 alkoxy, --NO.sub.2, or halogen. In a
more preferred embodiment, R.sup.1 is --NO.sub.2, --OCH.sub.3,
--CH.sub.2CH.sub.3, --C(CH.sub.3).sub.3, --CF.sub.3, --F, --Cl, and
--Br. In another preferred embodiment, R.sup.1 is C.sub.1-C.sub.6
haloalkyl, preferably --CF.sub.3. In still another preferred
embodiment, R.sup.1 is C.sub.1-C.sub.6 alkyl, preferably
--C(CH.sub.3).sub.3.
[0085] In one embodiment, R.sup.2 is hydrogen, halogen,
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy, or C.sub.1-C.sub.6
haloalkyl. In a preferred embodiment, R.sup.2 is hydrogen or
halogen. In a more preferred embodiment, R.sup.2 is hydrogen, --F,
--Cl, or --Br. In a most preferred embodiment, R.sup.2 is
fluorine.
[0086] In one embodiment, R.sup.1 is C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.6 alkoxy, aryloxy, C.sub.1-C.sub.6 haloalkyl,
C.sub.1-C.sub.6 haloalkylsulfanyl, C.sub.1-C.sub.6 alkylsulfanyl,
--C(O)OR.sup.6, halogen, --CN, or NO.sub.2 and R.sup.2 is hydrogen,
halogen, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy, or
C.sub.1-C.sub.6 haloalkyl. In a preferred embodiment, R.sup.1 is
C.sub.1-C.sub.6 haloalkyl and R.sup.2 is hydrogen or halogen. In a
more preferred embodiment, R.sup.1 is NO.sub.2, --OCH.sub.3,
--CH.sub.2CH.sub.3, --C(CH.sub.3).sub.3, --CF.sub.3, --F, --Cl, and
--Br and R.sup.2 is hydrogen, --F, --Cl, or --Br. In a most
preferred embodiment, R.sup.1 is --CF.sub.3 and R.sup.2 is
fluorine.
[0087] In one embodiment Z is S or O. In one embodiment, Z is S. In
a preferred embodiment, Z is O.
[0088] In one embodiment, A is aryl or heteroaryl. In a preferred
embodiment, A is phenyl, 2-pyridyl or 3-pyridyl. In a more
preferred embodiment A is phenyl.
[0089] In one embodiment, X is S, O, S(O).sub.2, S(O), CH.sub.2,
CH(OH), or C(O). In a preferred embodiment, X is O or C(O). In a
more preferred embodiment, X is O. In another embodiment, X is
S.
[0090] The side chain --NHC(Z)NHE of the compounds of formula (I)
and formula (II) may be linked to any suitable position of the
group A. Similarly, the linker group X linking the benzimidazole
core to the group A may be linked to any suitable position of the
group A. Preferably the group A is linked to the side chain
--NHC(Z)NHE and to the linker group X of the benzimidazole core
through a (-1,3-) or (-1,4-) linkage. In one preferred embodiment,
the group A is linked through a (-1,4-) linkage. In another
preferred embodiment, the group A is linked through a (-1,3-)
linkage.
[0091] The two dotted line bonds represented by "---", which are
attached to Q and N' in the five-membered heterocyclic core of
Formula I, may represent a single bond or a double bond. When q is
0, the dotted line bond "---" attached to Q is a single bond and
the dotted line bond attached to N' is a double bond as illustrated
following: ##STR9##
[0092] When q is 1, the dotted line bond "---" attached to Q is a
double bond and the dotted line bond attached to N' is a single
bond as illustrated following: ##STR10##
[0093] The dotted line within the 6 membered ring containing D, M,
and T of Formula I, represents the appropriate aromatic bonds.
[0094] In a preferred embodiment, D is CH, T is CR.sup.8, M is C
and Q is N(R.sup.7).sub.p, wherein p is 0, q is 1, R.sup.7 is
hydrogen, methyl, or S(O).sub.2R.sup.6 or D is CH, T is CR.sup.8,
wherein R.sup.8 is hydrogen or --Br, M is C and Q is
N(R.sup.7).sub.p, wherein p is 1, q is 0, R.sup.7 is hydrogen,
methyl, --S(O).sub.2R.sup.6, --RNR.sup.4R.sup.5, --RR.sup.6 or
aralkyl. In a more preferred embodiment, D is CH, T is CR.sup.8,
wherein R.sup.8 is hydrogen, M is C and Q is N(R.sup.7).sub.p,
wherein either p or q is 0, the other is 1 and R.sup.7 is
hydrogen.
[0095] In another embodiment, D is CH, T is CR.sup.8, wherein
R.sup.8 is hydrogen or --Br, M is C and Q is S or O; wherein q is
0. In a further embodiment, D is N, T is CR.sup.8, wherein R.sup.8
is hydrogen or --Br, M is C and Q is N(R.sup.7).sub.p, wherein
either p or q is 0, the other is 1, R.sup.7 is hydrogen, methyl, or
S(O).sub.2R.sup.6. In an alternative embodiment, D is CH, T is N, M
is C and Q is N(R.sup.7).sub.p, wherein either p or q is 0, the
other is 1, R.sup.7 is hydrogen, methyl, or S(O).sub.2R.sup.6. In a
further alternative embodiment, D is CH, T is CR.sup.8, wherein
R.sup.8 is hydrogen or --Br, M is N and Q is CH, wherein q is
0.
[0096] In one embodiment, R.sup.3 is --C(O)R.sup.6,
--C(O)NR.sup.4R.sup.5, --C(O)OR.sup.6, --C(O)ROR.sup.6,
--C(O)RC(O)OR.sup.6, --C(O)ROR'OR''OR.sup.6, --C(O)ROR'OR.sup.6,
--C(O)RNR.sup.4R.sup.5, --C(O)RNR.sup.4C(O)R.sup.6,
--C(O)RNR.sup.4C(O)OR.sup.6, --SO.sub.2R.sup.6, or
--SO.sub.2NR.sup.4R.sup.5; In a preferred embodiment, R.sup.3 is
--C(O)R.sup.6, --C(O)NR.sup.4R.sup.5, or --C(O)OR.sup.6. In a more
preferred embodiment, R.sup.3 is --C(O)OR.sup.6. In a most
preferred embodiment, R.sup.3 is --C(O)OR.sup.6 and R.sup.6 is
methyl.
[0097] In one embodiment, A is phenyl; X is O; Z is O; R.sup.1 is
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy, C.sub.1-C.sub.6
haloalkyl, or NO.sub.2; R.sup.2 is hydrogen, halogen,
C.sub.1-C.sub.6 alkyl, or C.sub.1-C.sub.6 alkoxy; and R.sup.3 is
--C(O)R.sup.6, --C(O)NR.sup.4R.sup.5, --C(O)OR.sup.6,
--C(O)ROR.sup.6, --C(O)RC(O)OR.sup.6, --C(O)ROR'OR''OR.sup.6,
--C(O)ROR'OR.sup.6, --C(O)RNR.sup.4R.sup.5,
--C(O)RNR.sup.4C(O)R.sup.6, C(O)RNR.sup.4C(O)OR.sup.6,
--SO.sub.2R.sup.6, or --SO.sub.2NR.sup.4R.sup.5. In a preferred
embodiment, A is phenyl; X is O; Z is O; R.sup.1 is C.sub.1-C.sub.6
alkyl or C.sub.1-C.sub.6 haloalkyl; R.sup.2 is hydrogen or halogen;
and R.sup.3 is --C(O)R.sup.6, --C(O)NR.sup.4R.sup.5, or
--C(O)OR.sup.6. In a more preferred embodiment, A is phenyl; X is
O; Z is O; R.sup.1 is C.sub.1-C.sub.6 haloalkyl; R.sup.2 is
halogen; and R.sup.3 is --C(O)OR.sup.6.
[0098] In one embodiment, A is phenyl; X is S; Z is O; R.sup.1 is
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy, C.sub.1-C.sub.6
haloalkyl, or NO.sub.2; R.sup.2 is hydrogen, halogen,
C.sub.1-C.sub.6 alkyl, or C.sub.1-C.sub.6 alkoxy; and R.sup.3 is
--C(O)R.sup.6, --C(O)NR.sup.4R.sup.5, --C(O)OR.sup.6,
--C(R)ROR.sup.6, --C(O)RC(O)OR.sup.6, --C(O)ROR'OR''OR.sup.6,
--C(O)ROR'OR.sup.6, --C(O)RNR.sup.4R.sup.5,
--C(O)RNR.sup.4C(O)R.sup.6, --C(O)RNR.sup.4C(O)OR.sup.6,
--SO.sub.2R.sup.6, or --SO.sub.2NR.sup.4R.sup.5. In a preferred
embodiment, A is phenyl; X is S; Z is O; R.sup.1 is C.sub.1-C.sub.6
alkyl or C.sub.1-C.sub.6 haloalkyl; R.sup.2 is hydrogen or halogen;
and R.sup.3 is --C(O)R.sup.6 or --C(O)OR.sup.6. In a more preferred
embodiment, A is phenyl; X is S; Z is O; R.sup.1 is C.sub.1-C.sub.6
haloalkyl; R.sup.2 is halogen; and R.sup.3 is --C(O)OR.sup.6.
[0099] In one embodiment, A is pyridyl; X is O; Z is O; R.sup.1 is
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy, C.sub.1-C.sub.6
haloalkyl, or NO.sub.2; R.sup.2 is hydrogen, halogen,
C.sub.1-C.sub.6 alkyl, or C.sub.1-C.sub.6 alkoxy; and R.sup.3 is
--C(O)R.sup.6, --C(O)NR.sup.4R.sup.5, --C(O)OR.sup.6,
--C(O)ROR.sup.6, --C(R)RC(O)OR.sup.6, --C(O)ROR'OR''OR.sup.6,
--C(O)ROR'OR.sup.6, --C(O)RNR.sup.4R.sup.5,
--C(O)RNR.sup.4C(O)R.sup.6, --C(O)RNR.sup.4C(O)OR.sup.6,
--SO.sub.2R.sup.6, or --SO.sub.2NR.sup.4R.sup.5. In a preferred
embodiment, A is pyridyl; X is O; Z is O; R.sup.1 is
C.sub.1-C.sub.6 alkyl or C.sub.1-C.sub.6 haloalkyl; R.sup.2 is
hydrogen or halogen; and R.sup.3 is --C(O)R.sup.6 or
--C(O)OR.sup.6. In a more preferred embodiment, A is pyridyl; X is
O; Z is O; R.sup.1 is C.sub.1-C.sub.6 haloalkyl; R.sup.2 is
halogen; and R.sup.3 is --C(O)OR.sup.6.
[0100] In one embodiment, A is pyridyl; X is S; Z is O; R.sup.1 is
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy, C.sub.1-C.sub.6
haloalkyl, or NO.sub.2; R.sup.2 is hydrogen, halogen,
C.sub.1-C.sub.6 alkyl, or C.sub.1-C.sub.6 alkoxy; and R.sup.3 is
--C(O)R.sup.6, --C(O)NR.sup.4R.sup.5, --C(O)OR.sup.6,
--C(O)ROR.sup.6, --C(R)RC(O)OR.sup.6, --C(O)ROR'OR''OR.sup.6,
--C(O)ROR'OR'', --C(O)RNR.sup.4R.sup.5, --C(O)RNR.sup.4C(O)R.sup.6,
--C(O)RNR.sup.4C(O)OR.sup.6, --SO.sub.2R.sup.6, or
--SO.sub.2NR.sup.4R.sup.5. In a preferred embodiment, A is pyridyl;
X is S; Z is O; R.sup.1 is C.sub.1-C.sub.6 alkyl or C.sub.1-C.sub.6
haloalkyl; R.sup.2 is hydrogen or halogen; and R.sup.3 is
--C(O)R.sup.6 or --C(O)OR.sup.6. In a more preferred embodiment, A
is pyridyl; X is S; Z is O; R.sup.1 is C.sub.1-C.sub.6 haloalkyl;
R.sup.2 is halogen; and R.sup.3 is --C(O)OR.sup.6.
[0101] In one embodiment, the compound is a compound of formula
(IV) where E is unsubstituted heteroaryl, heteroaryl substituted by
R.sup.1, or heteroaryl substituted by R.sup.1 and R.sup.2, A is
phenyl; X is O; Z is O; R.sup.1 is C.sub.1-C.sub.6 alkyl, aryl,
C.sub.3-C.sub.7 cycloalkyl, heterocyclyl, C.sub.1-C.sub.6
haloalkyl, or C.sub.1-C.sub.6 alkylsulfanyl; R.sup.2 is hydrogen,
halogen, C.sub.1-C.sub.6 alkyl, or C.sub.1-C.sub.6 haloalkyl; and
R.sup.3 is --C(O)R, --C(O)NR.sup.4R.sup.5, --C(O)OR.sup.6,
--C(O)ROR.sup.6, --C(O)RC(O)OR.sup.6, --C(O)ROR'OR''OR.sup.6,
--C(O)ROR'OR.sup.6, --C(O)RNR.sup.4R.sup.5,
--C(O)RNR.sup.4C(O)R.sup.6, --C(O)RNR.sup.4C(O)OR.sup.6,
--SO.sub.2R.sup.6, or --SO.sub.2NR.sup.4R.sup.5. In a preferred
embodiment, E is heteroaryl substituted by R.sup.1 or heteroaryl
substituted by R.sup.1 and R.sup.2, A is phenyl; X is O; Z is O;
R.sup.1 is C.sub.1-C.sub.6 alkyl; R.sup.2 is hydrogen or halogen;
and R.sup.3 is --C(O)R.sup.6, --C(O)ROR'OR.sup.6, or
--C(O)OR.sup.6. In a more preferred embodiment, E is heteroaryl
substituted by R.sup.1, A is phenyl; X is O; Z is O; R.sup.1 is
--C(CH.sub.3).sub.3; and R.sup.3 is --C(O)R.sup.6.
[0102] Specific examples of compounds of the present invention
include the following: [0103] Methyl
N-(5-(4-((3-chlorophenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl-
)carbamate; [0104] Methyl
N-(5-(4-((3-(trifluoromethyl)phenyl)aminocarbonylamino)phenylthio)-1H
-benzimidazol-2-yl)carbamate; [0105] Methyl
N-(5-(4-((3,5-di(trifluoromethyl)phenyl)aminocarbonylamino)
phenylthio)-1H-benzimidazol-2-yl)carbamate; [0106] Methyl
N-(5-(4-((3-bromophenyl)aminocarbonylamino)phenylthio)-1H-benzimidazol-2--
yl)carbamate; [0107] Methyl
N-(5-(4-((3,5-dimethoxyphenyl)aminocarbonylamino)phenylthio)-1H-benzimida-
zol-2-yl)carbamate; [0108] Methyl
N-(5-(4-((2-methyl-5-nitrophenyl)aminocarbonylamino)phenylthio)-1H-benzim-
idazol-2-yl)carbamate; [0109] Methyl
N-(5-(4-((3-ethylphenyl)aminocarbonylamino)phenylthio)-1H-benzimidazol-2--
yl)carbamate; [0110] Methyl
N-(5-(4-((2-fluoro-5-nitrophenyl)aminocarbonylamino)phenylthio)-1H-benzim-
idazol-2-yl)carbamate; [0111] Methyl
N-(5-(4-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenylthi-
o)-1H-benzimidazol-2-yl)carbamate; [0112] Methyl
N-(5-(4-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)
phenoxy)-1H-benzimidazol-2-yl)carbamate; [0113] Methyl
N-(5-(4-((3-ethylphenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)-
carbamate; [0114] Methyl
N-(5-(4-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)
phenylsulfonyl)-1H-benzimidazol-2-yl)carbamate; [0115] Methyl
N-(5-(4-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)
phenylsulfinyl)-1H-benzimidazol-2-yl)carbamate; [0116] Methyl
(5-(3-((3-chlorophenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)c-
arbamate; [0117] Methyl
N-(5-(3-((2-Fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)--
1H-benzimidazol-2-yl)carbamate; [0118] Methyl
N-(5-(3-((3-ethylphenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)-
carbamate; [0119] Ethyl
N-(5-(4-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)--
1H-benzimidazol-2-yl)carbamate; [0120] T-butyl
N-(5-(4-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)--
1H-benzimidazol-2-yl)carbamate; [0121] Methyl
N-(5-(4-((3-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1H-benzim-
idazol-2-yl)carbamate; [0122] Methyl
N-(5-(3-((3-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1H-benzim-
idazol-2-yl)carbamate; [0123] Methyl
N-(5-(4-((3-t-butylphenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-y-
l)carbamate; [0124]
2-Amino-5-(4-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phen-
oxy)-1H-benzimidazole; [0125]
(6-(4-((2-Fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1--
(methanesulfonyl)-1H-benzimidazol-2-ylamine; [0126]
6-(4-((2-Fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1-(-
4-(methyl)phenylsulfonyl)-1H-benzimidazol-2-ylamine; [0127]
N-(5-(4-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)--
1H -benzimidazol-2-yl)acetamide; [0128]
N-(5-(4-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)--
1H -benzimidazol-2-yl)cyclopentamide; [0129]
N-(5-(4-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)--
1H -benzimidazol-2-yl)(2-furyl)formamide; [0130]
N-(5-(4-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)--
1H -benzimidazol-2-yl)-4-methylpentamide; [0131]
N-(5-(4-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)--
1H -benzimidazol-2-yl)-2-(N-acetylamino)acetamide; [0132]
N-(5-(4-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)--
1H -benzimidazol-2-yl)-2-aminoacetamide; [0133]
N-(5-(4-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)--
1H -benzimidazol-2-yl)-2-methoxyacetamide; [0134]
3-(N-(5-(4-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenox-
y)-1H-benzimidazol-2-yl)carbamoyl)propionic acid; [0135]
N-(5-(4-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)--
1H -benzimidazol-2-yl)(2-(2-(methoxy)ethoxy)ethoxy)acetamide;
[0136]
N-(5-(4-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)--
1H -benzimidazol-2-yl)(2-(methoxy)ethoxy)acetamide; [0137]
N-(5-(4-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)--
1H -benzimidazol-2-yl)-2-(N-(t-butoxycarbony)amino)acetamide;
[0138]
N-(5-(2-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)-5-pyridy-
l oxy)-1H-benzimidazol-2-yl)acetamide; [0139] Methyl
N-(5-(5-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)-2-pyridy-
loxy)-1H-benzimidazol-2-yl)carbamate; [0140] Methyl
N-(5-(5-((3-(trifluoromethyl)phenyl)aminocarbonylamino)-2-pyridyloxy)-1H--
benzimidazol-2-yl)carbamate; and [0141] Methyl
N-(5-(5-((3-ethylphenyl)aminocarbonylamino)-2-pyridyloxy)-1H-benzimidazol-
-2-yl)carbamate; or a salt, solvate, or physiologically functional
derivative thereof.
[0142] Further specific Examples of compounds of the present
invention include: [0143] Methyl
N-(5-(4-((3-bromophenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)-
carbamate; [0144] Methyl
N-(5-(4-((3-(trifluoromethylthio)phenyl)aminocarbonylamino)phenoxy)-1H
-benzimidazol-2-yl)carbamate; [0145] Methyl
N-(5-(4-((2,5-dimethoxyphenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-
-2-yl)carbamate; [0146] Methyl
N-(5-(4-((2-chloro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)--
1H-benzimidazol-2-yl)carbamate; [0147] Methyl
N-(5-(4-((4-chloro-3-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)--
1H-benzimidazol-2-yl)carbamate; [0148] Methyl
N-(5-(4-((2,5-dichlorophenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol--
2-yl)carbamate; [0149] Methyl
N-(5-(4-((2-fluoro-5-nitrophenyl)aminocarbonylamino)phenoxy)-1H-benzimida-
zol-2-yl)carbamate; [0150] Methyl
N-(5-(4-((2-methyl-5-nitrophenyl)aminocarbonylamino)phenoxy)-1H-benzimida-
zol-2-yl)carbamate; [0151] Methyl
N-(5-(4-(3-methylthiophenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-
-yl)carbamate; [0152] Methyl
N-(5-(4-(3-cyanophenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)c-
arbamate; [0153] Methyl
N-(5-(4-((3-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)--
1H-benzimidazol-2-yl)carbamate; [0154] Methyl
N-(5-(4-((2-chloro-5-(trifluoromethyl)phenyl)aminocarbonylamino)
phenylthio)-1H-benzimidazol-2-yl)carbamate; [0155] Methyl
N-(5-(3-((2-chloro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)--
1H-benzimidazol-2-yl)carbamate; [0156] Methyl
N-(5-(4-((3-ethoxycarbonylphenyl)aminocarbonylamino)phenoxy)-1H-benzimida-
zol-2-yl)carbamate; [0157] Methyl
N-(5-(4-((3-carboxyphenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-y-
l) carbamate; [0158] Methyl
N-(5-(4-((2-fluoro-5-methylphenyl)aminocarbonylamino)phenoxy)-1H-benzimid-
azol-2-yl)carbamate; [0159] Methyl
N-(5-(4-((2,5-difluorophenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol--
2-yl)carbamate; [0160] Methyl
N-(5-(4-((2,5-dichlorophenyl)aminocarbonylamino)phenylthio)-1H-benzimidaz-
ol-2-yl)carbamate; [0161] Methyl
N-(5-(3-((3-(trifluoromethylthio)phenyl)aminocarbonylamino)phenoxy)-1H
-benzimidazol-2-yl)carbamate; [0162] Methyl
N-(5-(3-((3-bromophenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)-
carbamate; [0163] Methyl
N-(5-(3-((3-(phenoxy)phenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-
-yl)carbamate; [0164] Methyl
N-(5-(3-((4-chlorophenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl-
)carbamate; [0165] Methyl
N-(5-(4-((4-methoxyphenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-y-
l)carbamate; [0166] Methyl
N-(5-(4-((4-fluorophenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl-
)carbamate; [0167] Methyl
N-(6-(4-((6-fluoro-3-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)--
benzthiazol-2-yl)carbamate; [0168] Methyl
N-(4-bromo-6-(4-((6-fluoro-3-(trifluoromethyl)phenyl)aminocarbonylamino)
phenoxy)benzthiazol-2-yl)carbamate; [0169] Methyl
N-(6-(4-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)
phenoxy)-1-methyl-1H-benzimidazol-2-yl)carbamate; [0170] Methyl
N-(5-(4-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)
phenoxy)-1-methyl-1H-benzimidazol-2-yl)carbamate; [0171] Methyl
N-(5-(4-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)
phenoxy)-3a-aza-2-indolyl)carbamate; [0172] Methyl
N-(5-(4-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)
phenoxy)-3,4-diazaindolin-2-yl)carbamate; [0173] Methyl
N-(6-(4-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)
phenoxy)-1-(2-(dimethylamino)ethyl)-1H-benzimidazol-2-yl)carbamate
[0174] Methyl
N-(6-(4-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)
phenoxy)-1-(2-(4-morpholino)ethyl)-1H-benzimidazol-2-yl)carbamate;
[0175] Methyl
N-(5-(4-((2-chloro-5-(trifluoromethyl)phenyl)aminocarbonylamino)
phenoxy)-3,4-diaza-1H-indole-2-yl)carbamate; [0176] Methyl
N-(6-(4-((2-chloro-5-(trifluoromethyl)phenyl)aminocarbonylamino)
phenoxy)-3,4-diaza-1H-indole-2-yl)carbamate; [0177] Methyl
N-(5-(4-((2,5-dichlorophenyl)aminocarbonylamino)phenoxy)-3,4-diaza-1H-ind-
ole-2-yl)carbamate; [0178] Methyl
N-(6-(4-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)
phenoxy)-3,4-diaza-1H-indole-2-yl)carbamate; [0179] Methyl
N-(6-(4-((2-chloro-5-(trifluoromethyl)phenyl)aminocarbonylamino)
phenoxy)benzthiazol-2-yl)carbamate; [0180]
6-(4-((2-Fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-3,4-
-dihydro-1,4-a,5-triazacarbazol-2-one; [0181] Methyl
N-(5-(4-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenylcar-
bonyl)-1H -benzimidazol-2-yl)carbamate; [0182] Methyl
N-(5-(4-((2,5-dichlorophenyl)aminocarbonylamino)phenylsulfinyl)-1H-benzim-
idazol-2-yl)carbamate; [0183] 2-(Dimethylamino)ethyl
N-(5-(4-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)--
1H-benzimidazol-2-yl)carbamate; [0184] Benzyl
N-(5-(4-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)--
1H-benzimidazol-2-yl)carbamate; [0185]
5-(4-((2-Fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1-(-
methanesulfonyl)-1H-benzimidazol-2-ylamine; [0186]
N-(5-(4-((2-Fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)--
1H-benzimidazol-2-yl)methanesulfonamide; [0187]
5-(4-((2-Fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1-(-
4-(methyl)phenylsulfonyl)-1H-benzimidazol-2-ylamine; [0188]
N-(5-(4-((2-Fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)--
1H -benzimidazol-2-yl)-4-methylbenzenesulfonamide; [0189]
N-(6-(4-((2-Fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)
phenoxy)benzthiazol-2-yl)methanesulfonamide; [0190]
N-(5-(4-((2-Fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)--
1H -benzimidazol-2-yl)-4-(4-methyl-1-piperazinomethyl)benzamide;
[0191]
N-(5-(4-((2-Fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)--
1H -benzimidazol-2-yl)-3-(pyridine-3-yl)propionamide; [0192]
N-(5-(4-((2-Fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)--
1H -benzimidazol-2-yl)-5-benzimidazolecarboxamide; [0193]
N-(5-(4-((2-Fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)--
1H -benzimidazol-2-yl)-4-(pyrrol-1-yl)benzamide; [0194]
N-(5-(4-((2-Fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)--
1H -benzimidazol-2-yl)-4-(1H-imidazol-1-yl)benzamide; [0195]
N-(5-(4-((2-Fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)--
1H -benzimidazol-2-yl)-4-(dimethylamino)butylamide; [0196]
N-(5-(4-((2-Fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)--
1H -benzimidazol-2-yl)-3-pyridinecarboxamide; [0197]
N-(5-(4-((2-Fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)--
1H -benzimidazol-2-yl)-2-tetrahydrofurancarboxamide; [0198]
N-(5-(4-((2-Fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)--
1H -benzimidazol-2-yl) (1H-indole-3-carboxamide); [0199]
N-(5-(4-((2-Fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)--
1H -benzimidazol-2-yl)(5-(1-pyrrolidino)tetrazol-2-yl)acetamide;
[0200]
N-(5-(4-((2-Fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)--
1H -benzimidazol-2-yl)(1-methyl-1H-imidazol-4-yl)acetamide; [0201]
N-(5-(4-((2-Fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)--
1H -benzimidazol-2-yl)(1H-imidazole-4-carboxamide); [0202]
N-(5-(4-((2-Fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)--
1H -benzimidazol-2-yl)benzamide; [0203]
N-(5-(4-((2-Fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)--
1H -benzimidazol-2-yl)-2-thiophenecarboxamide; [0204]
N-(5-(4-((2-Fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)--
1H -benzimidazol-2-yl)(4-methyl-1-piperazino)acetamide; [0205]
N-(5-(4-((2-Fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)--
1H -benzimidazol-2-yl)(dimethylamino)acetamide; [0206]
6-(4-((2-Fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-3,4-
-dihydro-1,4a-diazacarbazol-2-one; [0207]
7-(4-((2-Fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-3,4-
-dihydro-1,4a-diazacarbazol-2-one; [0208]
2-(2-(4-Methyl-1-piperazino)ethylamino)-5-(4-((2-Fluoro-5-(trifluoromethy-
l)phenyl)aminocarbonylamino)phenoxy)-1H-benzimidazole; [0209]
2-(2-(Dimethylamino)ethylamino)-5-(4-((2-Fluoro-5-(trifluoromethyl)phenyl-
)aminocarbonylamino)phenoxy)-1H-benzimidazole; [0210]
2-(3-(4-Methyl-1-piperazino)propylamino)-5-(4-((2-Fluoro-5-(trifluorometh-
yl)phenyl)aminocarbonylamino)phenoxy)-1H-benzimidazole; [0211]
Methyl
N-(5-(5-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)-1-oxo-2--
pyridyloxy)-1H-benzimidazol-2-yl)carbamate; [0212]
N-(6-(2-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)-5-pyridy-
loxy)-1-benzyl-1H-benzimidazol-2-yl)acetamide; [0213] Methyl
N-(5-(5-((2-chloro-5-(trifluoromethyl)phenyl)aminocarbonylamino)-2-pyridy-
loxy)-1H-benzimidazol-2-yl)carbamate; [0214] Methyl
N-(5-(5-((2,5-dichlorophenyl)aminocarbonylamino)-2-pyridyloxy)-1H-benzimi-
dazol-2-yl)carbamate; [0215]
6-(6-((2-Fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)-3-pyridylox-
y)-1-benzyl-1H-benzimidazol-2-ylamine; [0216]
N-(6-(6-((2-Fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)-3-pyridy-
loxy)-1-benzyl-1H-benzimidazol-2-yl)methanesulfonamide; and [0217]
Methyl
N-(6-(4-((2-Fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)ph-
enoxy)benzoxazol-2-yl)carbamate; or a salt, solvate, or
physiologically functional derivative thereof.
[0218] Additional further specific Examples of compounds of the
present invention include: [0219] Methyl
N-(5-(3-((2-(trifluoromethoxy)phenyl)aminocarbonylamino)phenoxy)-1H-benzi-
midazol-2-yl)carbamate; [0220] Methyl
N-(5-(3-((4-(trifluoromethylthio)phenyl)aminocarbonylamino)phenoxy)-1H-be-
nzimidazol-2-yl)carbamate; [0221] Methyl
N-(5-(3-((2-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1H-benzim-
idazol-2-yl)carbamate; [0222] Methyl
N-(5-(3-((4-chloro-3-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)--
1H-benzimidazol-2-yl)carbamate; [0223] Methyl
N-(5-(3-((3-iodophenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)c-
arbamate; [0224] Methyl
N-(5-(3-((2,5-dichlorophenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol--
2-yl)carbamate; [0225] Methyl
N-(5-(4-((3-phenoxyphenyl)aminocarbonylamino)phenylthio)-1H-benzimidazol--
2-yl)carbamate; [0226] Methyl
N-(5-(4-((3-phenoxyphenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-y-
l)carbamate; [0227] Methyl
N-(5-(3-((2-phenoxyphenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-y-
l)carbamate; [0228] Methyl
N-(5-(3-((4-phenoxyphenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-y-
l)carbamate; [0229] Methyl
N-(5-(3-((5-indanyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)carb-
amate; [0230] Methyl
N-(5-(4-((5-indanyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)carb-
amate; [0231] Methyl
N-(5-(4-((5-tert-butylisoxazole-3-yl)aminocarbonylamino)phenoxy)-1H-benzi-
midazol-2-yl)carbamate; [0232] Methyl
N-(5-(3-((5-tert-butylisoxazole-3-yl)aminocarbonylamino)phenoxy)-1H-benzi-
midazol-2-yl)carbamate; [0233] Methyl
N-(5-(4-((5-tert-butylisoxazole-3-yl)aminocarbonylamino)phenylthio)-1H
-benzimidazol-2-yl)carbamate; [0234] Methyl
N-(5-(3-((3-phenyl-1,2,4-thiadiazol-5-yl)aminocarbonylamino)phenoxy)-1H-b-
enzimidazol-2-yl)carbamate; [0235] Methyl
N-(5-(3-((1-naphtyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)carb-
amate; [0236] Methyl
N-(5-(3-((2,3-dimethylphenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol--
2-yl)carbamate; [0237]
1-(5-(4-((2-Fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)--
1H-benzimidazol-2-yl)-3-(2-fluoro-5-(trifluoromethyl)phenyl)urea;
[0238]
1-(5-(4-((2-Fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)--
1H-benzimidazol-2-yl)-3-(4-chlorophenyl)urea; [0239]
1-(5-(4-((2-Fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)--
1H-benzimidazol-2-yl)-3-(4-(N,N-dimethylamino)phenyl)urea; [0240]
1-(6-(4-((4-Chloro-3-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)b-
enzthiazol-2-yl)-3-(butyl)urea; [0241]
1-(6-(4-((2-Fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)b-
enzthiazol-2-yl)-3-(butyl)urea; [0242]
N-(5-(4-((5-Methylisoxazol-3-yl)aminocarbonylamino)phenoxy)-1H-benzimidaz-
ol-2-yl)acetamide; [0243]
N-(5-(4-((Thiazol-2-yl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)a-
cetamide; [0244]
N-(5-(4-((1,3,4-Thiadiazol-2-yl)aminocarbonylamino)phenoxy)-1H-benzimidaz-
ol-2-yl)acetamide; [0245]
N-(5-(4-((4-Methylthiazol-2-yl)aminocarbonylamino)phenoxy)-1H-benzimidazo-
l-2-yl)acetamide; [0246]
N-(5-(4-((5-Methylthiazol-2-yl)aminocarbonylamino)phenoxy)-1H-benzimidazo-
l-2-yl)acetamide; [0247]
N-(5-(4-((5-Methyl-1,3,4-thiadiazol-2-yl)aminocarbonylamino)phenoxy)-1H-b-
enzimidazol-2-yl)acetamide; [0248]
N-(5-(4-((5-Ethyl-1,3,4-thiadiazol-2-yl)aminocarbonylamino)phenoxy)-1H-be-
nzimidazol-2-yl)acetamide; [0249]
N-(5-(4-((5-Cyclopropyl-1,3,4-thiadiazol-2-yl)aminocarbonylamino)phenoxy)-
-1H -benzimidazol-2-yl)acetamide; [0250]
N-(5-(4-((4-tert-Butyl-thiazol-2-yl)aminocarbonylamino)phenoxy)-1H-benzim-
idazol-2-yl)acetamide; [0251]
N-(5-(4-((5-tert-Butyl-1,3,4-thiadiazol-2-yl)aminocarbonylamino)phenoxy)--
1H-benzimidazol-2-yl)acetamide; [0252]
N-(5-(4-((4,5-Dimethylthiazol-2-yl)aminocarbonylamino)phenoxy)-1H-benzimi-
dazol-2-yl)acetamide; [0253]
N-(5-(4-((5-Morpholino-1,3,4-triazol-2-yl)aminocarbonylamino)phenoxy)-1H--
benzimidazol-2-yl)acetamide; [0254]
N-(5-(4-((5-Methylisoxazol-3-yl)aminocarbonylamino)phenoxy)-1H-benzimidaz-
ol-2-yl)(2-(methoxy)ethoxy)acetamide; [0255]
N-(5-(4-((Thiazol-2-yl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)(-
2-(methoxy)ethoxy)acetamide; [0256]
N-(5-(4-((1,3,4-Thiadiazol-2-yl)aminocarbonylamino)phenoxy)-1H-benzimidaz-
ol-2-yl)(2-(methoxy)ethoxy)acetamide; [0257]
N-(5-(4-((4-Methylthiazol-2-yl)aminocarbonylamino)phenoxy)-1H-benzimidazo-
l-2-yl)(2-(methoxy)ethoxy)acetamide; [0258]
N-(5-(4-((5-Methylthiazol-2-yl)aminocarbonylamino)phenoxy)-1H-benzimidazo-
l-2-yl)(2-(methoxy)ethoxy)acetamide; [0259]
N-(5-(4-((5-Methyl-1,3,4-thiadiazol-2-yl)aminocarbonylamino)phenoxy)-1H-b-
enzimidazol-2-yl)(2-(methoxy)ethoxy)acetamide; [0260]
N-(5-(4-((5-Ethyl-1,3,4-thiadiazol-2-yl)aminocarbonylamino)phenoxy)-1H-be-
nzimidazol-2-yl)(2-(methoxy)ethoxy)acetamide; [0261]
N-(5-(4-((5-Cyclopropyl-1,3,4-thiadiazol-2-yl)aminocarbonylamino)phenoxy)-
-1H -benzimidazol-2-yl)(2-(methoxy)ethoxy)acetamide; [0262]
N-(5-(4-((4-tert-Butyl
thiazol-2-yl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)(2-(methoxy-
)ethoxy)acetamide; [0263]
N-(5-(4-((5-tert-Butyl1,3,4-thiadiazol-2-yl)aminocarbonylamino)phenoxy)-1-
H-benzimidazol-2-yl)(2-(methoxy)ethoxy)acetamide; [0264]
N-(5-(4-((5-Ethylthio-1,3,4-thiadiazol-2-yl)aminocarbonylamino)phenoxy)-1-
H-benzimidazol-2-yl)(2-(methoxy)ethoxy)acetamide; [0265]
N-(5-(4-((5-Propylthio-1,3,4-thiadiazol-2-yl)aminocarbonylamino)phenoxy)--
1H-benzimidazol-2-yl)(2-(methoxy)ethoxy)acetamide; [0266]
N-(5-(4-((4,5-Dimethylthiazol-2-yl)aminocarbonylamino)phenoxy)-1H-benzimi-
dazol-2-yl)(2-(methoxy)ethoxy)acetamide; [0267]
N-(5-(4-((5-Morpholino-1,3,4-triazol-2-yl)aminocarbonylamino)phenoxy)-1H--
benzimidazol-2-yl)(2-(methoxy)ethoxy)acetamide; [0268]
N-(5-(4-((5-Methylisoxazol-3-yl)aminocarbonylamino)phenoxy)-1H-benzimidaz-
ol-2-yl)(2-furyl)formamide; [0269]
N-(5-(4-((Thiazol-2-yl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)(-
2-furyl)formamide; [0270]
N-(5-(4-((1,3,4-Thiadiazol-2-yl)aminocarbonylamino)phenoxy)-1H-benzimidaz-
ol-2-yl)(2-furyl)formamide; [0271]
N-(5-(4-((4-Methylthiazol-2-yl)aminocarbonylamino)phenoxy)-1H-benzimidazo-
l-2-yl)(2-furyl)formamide; [0272]
N-(5-(4-((5-Methylthiazol-2-yl)aminocarbonylamino)phenoxy)-1H-benzimidazo-
l-2-yl)(2-furyl)formamide; [0273]
N-(5-(4-((5-Methyl-1,3,4-thiadiazol-2-yl)aminocarbonylamino)phenoxy)-1H-b-
enzimidazol-2-yl)(2-furyl)formamide; [0274]
N-(5-(4-((5-Ethyl-1,3,4-thiadiazol-2-yl)aminocarbonylamino)phenoxy)-1H-be-
nzimidazol-2-yl)(2-furyl)formamide; [0275]
N-(5-(4-((5-Cycloproyl-1,3,4-thiadiazol-2-yl)aminocarbonylamino)phenoxy)--
1H -benzimidazol-2-yl)(2-furyl)formamide; [0276]
N-(5-(4-((4-tert-Butylthiazol-2-yl)aminocarbonylamino)phenoxy)-1H-benzimi-
dazol-2-yl)(2-furyl)formamide; [0277]
N-(5-(4-((5-tert-Butyl-1,3,4-thiadiazol-2-yl)aminocarbonylamino)phenoxy)--
1H-benzimidazol-2-yl)(2-furyl)formamide; [0278]
N-(5-(4-((5-Ethylthio-1,3,4-thiadiazol-2-yl)aminocarbonylamino)phenoxy)-1-
H-benzimidazol-2-yl)(2-furyl)formamide; [0279]
N-(5-(4-((4,5-Dimethylthiazol-2-yl)aminocarbonylamino)phenoxy)-1H-benzimi-
dazol-2-yl)(2-furyl)formamide; [0280]
N-(5-(4-((5-Morpholino-1,3,4-triazol-2-yl)aminocarbonylamino)phenoxy)-1H--
benzimidazol-2-yl)(2-furyl)formamide; [0281]
N-(5-(4-((5-Methylthio-1,3,4-thiadiazol-2-yl)aminocarbonylamino)phenoxy)--
1H-benzimidazol-2-yl)acetamide; [0282]
N-(5-(4-((5-Methylthio-1,3,4-thiadiazol-2-yl)aminocarbonylamino)phenoxy)--
1H-benzimidazol-2-yl)(2-(methoxy)ethoxy)acetamide; [0283]
N-(5-(4-((5-Methylthio-1,3,4-thiadiazol-2-yl)aminocarbonylamino)phenoxy)--
1H-benzimidazol-2-yl)(2-furyl)formamide; [0284]
N-(5-(4-((5-Carbamoyl-2-methylphenyl)aminocarbonylamino)phenoxy)-1H-benzi-
midazol-2-yl)(2-furyl)formamide; [0285] Methyl
N-(5-(3-((2,3-dichlorophenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol--
2-yl)carbamate; [0286] Methyl
N-(5-(3-((2,3-dimethylphenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol--
2-yl)carbamate; [0287]
1-(5-(4-((2-Fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)--
1H-benzimidazol-2-yl)-3-(2,3-dimethylphenyl)urea; [0288] Methyl
N-(5-(4-((3-chlorophenyl)aminothiocarbonylamino)phenoxy)-1H-benzimidazol--
2-yl)carbamate; [0289] Methyl
N-(5-(4-((3-methoxyphenyl)aminothiocarbonylamino)phenoxy)-1H-benzimidazol-
-2-yl)carbamate; and [0290] Methyl
N-(5-(4-((3-(trifluoromethyl)phenyl)aminothiocarbonylamino)phenoxy)-1H
-benzimidazol-2-yl)carbamate; or a salt, solvate, or
physiologically functional derivative thereof.
[0291] Typically, the salts of the present invention are
pharmaceutically acceptable salts. Salts encompassed within the
term "pharmaceutically acceptable salts" refer to non-toxic salts
of the compounds of this invention. Salts of the compounds of the
present invention may comprise acid addition salts derived from a
nitrogen on a substituent in the compound of formula (I).
Representative salts include the following salts: acetate,
benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate,
borate, bromide, calcium edetate, camsylate, carbonate, chloride,
clavulanate, citrate, dihydrochloride, edetate, edisylate,
estolate, esylate, fumarate, gluceptate, gluconate, glutamate,
glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide,
hydrochloride, hydroxynaphthoate, iodide, isethionate, lactate,
lactobionate, laurate, malate, maleate, mandelate, mesylate,
methylbromide, methylnitrate, methylsulfate, monopotassium maleate,
mucate, napsylate, nitrate, N-methylglucamine, oxalate, pamoate
(embonate), palmitate, pantothenate, phosphate/diphosphate,
polygalacturonate, potassium, salicylate, sodium, stearate,
subacetate, succinate, tannate, tartrate, teoclate, tosylate,
triethiodide, trimethylammonium and valerate. Other salts, which
are not pharmaceutically acceptable, may be useful in the
preparation of compounds of this invention and these form a further
aspect of the invention.
[0292] While it is possible that, for use in therapy,
therapeutically effective amounts of a compound of formula (I), as
well as salts, solvates and physiological functional derivatives
thereof, may be administered as the raw chemical, it is possible to
present the active ingredient as a pharmaceutical composition.
Accordingly, the invention further provides pharmaceutical
compositions, which include therapeutically effective amounts of
compounds of the formula (I) and salts, solvates and physiological
functional derivatives thereof, and one or more pharmaceutically
acceptable carriers, diluents, or excipients. The compounds of the
formula (I) and salts, solvates and physiological functional
derivatives thereof, are as described above. The carrier(s),
diluent(s) or excipient(s) must be acceptable in the sense of being
compatible with the other ingredients of the formulation and not
deleterious to the recipient thereof. In accordance with another
aspect of the invention there is also provided a process for the
preparation of a pharmaceutical formulation including admixing a
compound of the formula (I), or salts, solvates and physiological
functional derivatives thereof, with one or more pharmaceutically
acceptable carriers, diluents or excipients.
[0293] Pharmaceutical formulations may be presented in unit dose
forms containing a predetermined amount of active ingredient per
unit dose. Such a unit may contain, for example, 0.5 mg to 1 g,
preferably 1 mg to 700 mg, more preferably 5 mg to 100 mg of a
compound of the formula (I), depending on the condition being
treated, the route of administration and the age, weight and
condition of the patient, or pharmaceutical formulations may be
presented in unit dose forms containing a predetermined amount of
active ingredient per unit dose. Preferred unit dosage formulations
are those containing a daily dose or sub-dose, as herein above
recited, or an appropriate fraction thereof, of an active
ingredient. Furthermore, such pharmaceutical formulations may be
prepared by any of the methods well known in the pharmacy art.
[0294] Pharmaceutical formulations may be adapted for
administration by any appropriate route, for example by the oral
(including buccal or sublingual), rectal, nasal, topical (including
buccal, sublingual or transdermal), vaginal or parenteral
(including subcutaneous, intramuscular, intravenous or intradermal)
route. Such formulations may be prepared by any method known in the
art of pharmacy, for example by bringing into association the
active ingredient with the carrier(s) or excipient(s).
[0295] Pharmaceutical formulations adapted for oral administration
may be presented as discrete units such as capsules or tablets;
powders or granules; solutions or suspensions in aqueous or
non-aqueous liquids; edible foams or whips; or oil-in-water liquid
emulsions or water-in-oil liquid emulsions.
[0296] For instance, for oral administration in the form of a
tablet or capsule, the active drug component can be combined with
an oral, non-toxic pharmaceutically acceptable inert carrier such
as ethanol, glycerol, water and the like. Powders are prepared by
comminuting the compound to a suitable fine size and mixing with a
similarly comminuted pharmaceutical carrier such as an edible
carbohydrate, as, for example, starch or mannitol. Flavoring,
preservative, dispersing and coloring agent can also be
present.
[0297] Capsules are made by preparing a powder mixture, as
described above, and filling formed gelatin sheaths. Glidants and
lubricants such as colloidal silica, talc, magnesium stearate,
calcium stearate or solid polyethylene glycol can be added to the
powder mixture before the filling operation. A disintegrating or
solubilizing agent such as agar-agar, calcium carbonate or sodium
carbonate can also be added to improve the availability of the
medicament when the capsule is ingested.
[0298] Moreover, when desired or necessary, suitable binders,
lubricants, disintegrating agents and coloring agents can also be
incorporated into the mixture. Suitable binders include starch,
gelatin, natural sugars such as glucose or beta-lactose, corn
sweeteners, natural and synthetic gums such as acacia, tragacanth
or sodium alginate, carboxymethylcellulose, polyethylene glycol,
waxes and the like. Lubricants used in these dosage forms include
sodium oleate, sodium stearate, magnesium stearate, sodium
benzoate, sodium acetate, sodium chloride and the like.
Disintegrators include, without limitation, starch, methyl
cellulose, agar, bentonite, xanthan gum and the like. Tablets are
formulated, for example, by preparing a powder mixture, granulating
or slugging, adding a lubricant and disintegrant and pressing into
tablets. A powder mixture is prepared by mixing the compound,
suitably comminuted, with a diluent or base as described above, and
optionally, with a binder such as carboxymethylcellulose, an
aliginate, gelatin, or polyvinyl pyrrolidone, a solution retardant
such as paraffin, a resorption accelerator such as a quaternary
salt and/or an absorption agent such as bentonite, kaolin or
dicalcium phosphate. The powder mixture can be granulated by
wetting with a binder such as syrup, starch paste, acadia mucilage
or solutions of cellulosic or polymeric materials and forcing
through a screen. As an alternative to granulating, the powder
mixture can be run through the tablet machine and the result is
imperfectly formed slugs broken into granules. The granules can be
lubricated to prevent sticking to the tablet forming dies by means
of the addition of stearic acid, a stearate salt, talc or mineral
oil. The lubricated mixture is then compressed into tablets. The
compounds of the present invention can also be combined with a free
flowing inert carrier and compressed into tablets directly without
going through the granulating or slugging steps. A clear or opaque
protective coating consisting of a sealing coat of shellac, a
coating of sugar or polymeric material and a polish coating of wax
can be provided. Dyestuffs can be added to these coatings to
distinguish different unit dosages.
[0299] Oral fluids such as solution, syrups and elixirs can be
prepared in dosage unit form so that a given quantity contains a
predetermined amount of the compound. Syrups can be prepared by
dissolving the compound in a suitably flavored aqueous solution,
while elixirs are prepared through the use of a non-toxic alcoholic
vehicle. Suspensions can be formulated by dispersing the compound
in a non-toxic vehicle. Solubilizers and emulsifiers such as
ethoxylated isostearyl alcohols and polyoxy ethylene sorbitol
ethers, preservatives, flavor additive such as peppermint oil or
natural sweeteners or saccharin or other artificial sweeteners, and
the like can also be added.
[0300] Where appropriate, dosage unit formulations for oral
administration can be microencapsulated. The formulation can also
be prepared to prolong or sustain the release as for example by
coating or embedding particulate material in polymers, wax or the
like.
[0301] The compounds of formula (I), and salts, solvates and
physiological functional derivatives thereof, can also be
administered in the form of liposome delivery systems, such as
small unilamellar vesicles, large unilamellar vesicles and
multilamellar vesicles. Liposomes can be formed from a variety of
phospholipids, such as cholesterol, stearylamine or
phosphatidylcholines.
[0302] The compounds of formula (I) and salts, solvates and
physiological functional derivatives thereof may also be delivered
by the use of monoclonal antibodies as individual carriers to which
the compound molecules are coupled. The compounds may also be
coupled with soluble polymers as targetable drug carriers. Such
polymers can include polyvinylpyrrolidone, pyran copolymer,
polyhydroxypropyl methacrylamide-phenol,
polyhydroxyethylaspartamidephenol, or polyethyleneoxidepolylysine
substituted with palmitoyl residues. Furthermore, the compounds may
be coupled to a class of biodegradable polymers useful in achieving
controlled release of a drug, for example, polylactic acid,
polepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters,
polyacetals, polydihydropyrans, polycyanoacrylates and cross-linked
or amphipathic block copolymers of hydrogels.
[0303] Pharmaceutical formulations adapted for transdermal
administration may be presented as discrete patches intended to
remain in intimate contact with the epidermis of the recipient for
a prolonged period of time. For example, the active ingredient may
be delivered from the patch by iontophoresis as generally described
in Pharmaceutical Research, 3(6), 318 (1986).
[0304] Pharmaceutical formulations adapted for topical
administration may be formulated as ointments, creams, suspensions,
lotions, powders, solutions, pastes, gels, sprays, aerosols or
oils.
[0305] For treatments of the eye or other external tissues, for
example mouth and skin, the formulations are preferably applied as
a topical ointment or cream. When formulated in an ointment, the
active ingredient may be employed with either a paraffinic or a
water-miscible ointment base. Alternatively, the active ingredient
may be formulated in a cream with an oil-in-water cream base or a
water-in-oil base.
[0306] Pharmaceutical formulations adapted for topical
administrations to the eye include eye drops wherein the active
ingredient is dissolved or suspended in a suitable carrier,
especially an aqueous solvent.
[0307] Pharmaceutical formulations adapted for topical
administration in the mouth include lozenges, pastilles and mouth
washes.
[0308] Pharmaceutical formulations adapted for rectal
administration may be presented as suppositories or as enemas.
[0309] Pharmaceutical formulations adapted for nasal administration
wherein the carrier is a solid include a coarse powder having a
particle size for example in the range 20 to 500 microns which is
administered in the manner in which snuff is taken, i.e. by rapid
inhalation through the nasal passage from a container of the powder
held close up to the nose. Suitable formulations wherein the
carrier is a liquid, for administration as a nasal spray or as
nasal drops, include aqueous or oil solutions of the active
ingredient.
[0310] Pharmaceutical formulations adapted for administration by
inhalation include fine particle dusts or mists, which may be
generated by means of various types of metered, dose pressurised
aerosols, nebulizers or insufflators.
[0311] Pharmaceutical formulations adapted for vaginal
administration may be presented as pessaries, tampons, creams,
gels, pastes, foams or spray formulations.
[0312] Pharmaceutical formulations adapted for parenteral
administration include aqueous and non-aqueous sterile injection
solutions which may contain anti-oxidants, buffers, bacteriostats
and solutes which render the formulation isotonic with the blood of
the intended recipient; and aqueous and non-aqueous sterile
suspensions which may include suspending agents and thickening
agents. The formulations may be presented in unit-dose or
multi-dose containers, for example sealed ampoules and vials, and
may be stored in a freeze-dried (lyophilized) condition requiring
only the addition of the sterile liquid carrier, for example water
for injections, immediately prior to use. Extemporaneous injection
solutions and suspensions may be prepared from sterile powders,
granules and tablets.
[0313] It should be understood that in addition to the ingredients
particularly mentioned above, the formulations may include other
agents conventional in the art having regard to the type of
formulation in question, for example those suitable for oral
administration may include flavouring agents.
[0314] A therapeutically effective amount of a compound of the
present invention will depend upon a number of factors including,
for example, the age and weight of the animal, the precise
condition requiring treatment and its severity, the nature of the
formulation, and the route of administration, and will ultimately
be at the discretion of the attendant physician or veterinarian
However, an effective amount of a compound of formula (I) for the
treatment of neoplastic growth, for example colon or breast
carcinoma, will generally be in the range of 0.1 to 100 mg/kg body
weight of recipient (mammal) per day and more usually in the range
of 1 to 10 mg/kg body weight per day. Thus, for a 70 kg adult
mammal, the actual amount per day would usually be from 70 to 700
mg and this amount may be given in a single dose per day or more
usually in a number (such as two, three, four, five or six) of
sub-doses per day such that the total daily dose is the same. An
effective amount of a salt or solvate, or physiologically
functional derivative thereof, may be determined as a proportion of
the effective amount of the compound of formula (I) per se. It is
envisaged that similar dosages would be appropriate for treatment
of the other conditions referred to above.
[0315] The compounds of the present invention and their salts and
solvates, and physiologically functional derivatives thereof, may
be employed alone or in combination with other therapeutic agents
for the treatment of the above-mentioned conditions. In particular,
in anti-cancer therapy, combination with other chemotherapeutic,
hormonal or antibody agents is envisaged as well as combination
with surgical therapy and radiotherapy. Combination therapies
according to the present invention thus comprise the administration
of at least one compound of formula (I) or a pharmaceutically
acceptable salt or solvate thereof, or a physiologically functional
derivative thereof, and the use of at least one other cancer
treatment method. Preferably, combination therapies according to
the present invention comprise the administration of at least one
compound of formula (I) or a pharmaceutically acceptable salt or
solvate thereof, or a physiologically functional derivative
thereof, and at least one other pharmaceutically active agent,
preferably an anti-neoplastic agent. The compound(s) of formula (I)
and the other pharmaceutically active agent(s) may be administered
together or separately and, when administered separately this may
occur simultaneously or sequentially in any order. The amounts of
the compound(s) of formula (I) and the other pharmaceutically
active agent(s) and the relative timings of administration will be
selected in order to achieve the desired combined therapeutic
effect.
[0316] The compounds of the Formula (I) or salts, solvates, or
physiologically functional derivatives thereof and at least one
additional cancer treatment therapy may be employed in combination
concomitantly or sequentially in any therapeutically appropriate
combination with such other anti-cancer therapies. In one
embodiment, the other anti-cancer therapy is at least one
additional chemotherapeutic therapy including administration of at
least one anti-neoplastic agent. The administration in combination
of a compound of formula (I) or salts, solvates, or physiologically
functional derivatives thereof with other anti-neoplastic agents
may be in combination in accordance with the invention by
administration concomitantly in (1) a unitary pharmaceutical
composition including both compounds or (2) separate pharmaceutical
compositions each including one of the compounds. Alternatively,
the combination may be administered separately in a sequential
manner wherein one anti-neoplastic agent is administered first and
the other second or vice versa. Such sequential administration may
be close in time or remote in time.
[0317] Anti-neoplastic agents may induce anti-neoplastic effects in
a cell-cycle specific manner, i.e., are phase specific and act at a
specific phase of the cell cycle, or bind DNA and act in a non
cell-cycle specific manner, i.e., are non-cell cycle specific and
operate by other mechanisms.
[0318] Anti-neoplastic agents useful in combination with the
compounds and salts, solvates or physiologically functional
derivatives thereof of formula I include the following:
[0319] (1) cell cycle specific anti-neoplastic agents include, but
are not limited to diterpenoids such as paclitaxel and its analog
docetaxel; vinca alkaloids such as vinblastine, vincristine,
vindesine, and vinorelbine; epipodophyllotoxins such as etoposide
and teniposide; fluoropyrimidines such as 5-fluorouracil and
fluorodeoxyuridine; antimetabolites such as allopurinol,
fludurabine, methotrexate, cladrabine, cytarabine, mercaptopurine
and thioguanine; and camptothecins such as 9-amino camptothecin,
irinotecan, CPT-11 and the various optical forms of
7-(4-methylpiperazino-methylene)-10,11-ethylenedioxy-20-camptoth-
ecin;
[0320] (2) cytotoxic chemotherapeutic agents including, but not
limited to, alkylating agents such as melphalan, chlorambucil,
cyclophosphamide, mechlorethamine, hexamethylmelamine, busulfan,
carmustine, lomustine, and dacarbazine; anti-tumour antibiotics
such as doxorubicin, daunomycin, epirubicin, idarubicin,
mitomycin-C, dacttinomycin and mithramycin; and platinum
coordination complexes such as cisplatin, carboplatin, and
oxaliplatin; and
[0321] (3) other chemotherapeutic agents include, but are not
limited to, anti-estrogens such as tamoxifen, toremifene,
raloxifene, droloxifene and iodoxyfene; progestrogens such as
megestrol acetate; aromatase inhibitors such as anastrozole,
letrazole, vorazole, and exemestane; antiandrogens such as
flutamide, nilutamide, bicalutamide, and cyproterone acetate; LHRH
agonists and antagagonists such as goserelin acetate and luprolide,
testosterone 5.alpha.-dihydroreductase inhibitors such as
finasteride; metalloproteinase inhibitors such as marimastat;
antiprogestogens; urokinase plasminogen activator receptor function
inhibitors; growth factor function inhibitors such as inhibitors of
the functions of hepatocyte growth factor; erb-B2, erb-B4,
epidermal growth factor receptor (EGFR), platelet derived growth
factor receptor (PDGFR), vascular endothelial growth factor
receptor (VEGFR, and TIE-2 (other than those VEGFR and TIE-2
inhibitors described in the present invention); and other tyrosine
kinase inhibitors such as inhibitors of CDK2 and CDK4
inhibitors.
[0322] The compounds of formula (I) and salts, solvates and
physiological functional derivatives thereof, are believed to have
anticancer activity as a result of inhibition of the protein kinase
TIE-2 and its effect on selected cell lines whose growth is
dependent on TIE-2 protein kinase activity.
[0323] The present invention thus also provides compounds of
formula (I) and pharmaceutically acceptable salts or solvates
thereof, or physiologically functional derivatives thereof, for use
in medical therapy, and particularly in the treatment of disorders
mediated by inappropriate TIE-2 activity.
[0324] The inappropriate TIE-2 activity referred to herein is any
TIE-2 activity that deviates from the normal TIE-2 activity
expected in a particular mammalian subject. Inappropriate TIE-2
activity may take the form of, for instance, an abnormal increase
in activity, or an aberration in the timing and or control of TIE-2
activity. Such inappropriate activity may result then, for example,
from overexpression or mutation of the protein kinase leading to
inappropriate or uncontrolled activation. Furthermore, it is also
understood that unwanted TIE-2 activity may reside in an abnormal
source, such as a malignancy. That is, the level of TIE-2 activity
does not have to be abnormal to be considered inappropriate, rather
the activity derives from an abnormal source. In a like manner, the
inappropriate angiogenesis referred to herein is any angiogenic
activity that deviates from the normal angiogenic activity expected
in a particular mammalian subject. Inappropriate angiogenesis may
take the form of, for instance, an abnormal increase in activity,
or an aberration in the timing and or control of angiogenic
activity. Such inappropriate activity may result then, for example,
from overexpression or mutation of a protein kinase leading to
inappropriate or uncontrolled activation. Furthermore, it is also
understood that unwanted angiogenic activity may reside in an
abnormal source, such as a malignancy. That is, the level of
angiogenic activity does not have to be abnormal to be considered
inappropriate, rather the activity derives from an abnormal
source.
[0325] The present invention is directed to methods of regulating,
modulating, or inhibiting TIE-2 for the prevention and/or treatment
of disorders related to unregulated TIE-2 activity. In particular,
the compounds of the present invention can also be used in the
treatment of certain forms of cancer. Furthermore, the compounds of
the present invention can be used to provide additive or
synergistic effects with certain existing cancer chemotherapies,
and/or be used to restore effectiveness of certain existing cancer
chemotherapies and radiation.
[0326] The compounds of the present invention are also useful in
the treatment of one or more diseases afflicting mammals which are
characterized by cellular proliferation in the area of disorders
associated with neo-vascularization and/or vascular permeability
including blood vessel proliferative disorders including arthritis
and restenosis; fibrotic disorders including hepatic cirrhosis and
atherosclerosis; mesangial cell proliferative disorders include
glomerulonephritis, diabetic nephropathy, malignant
nephrosclerosis, thrombotic microangiopathy syndromes, organ
transplant rejection and glomerulopathies; and metabolic disorders
include psoriasis, diabetes mellitus, chronic wound healing,
inflammation and neurodegenerative diseases.
[0327] A further aspect of the invention provides a method of
treatment of a mammal suffering from a disorder mediated by
inappropriate TIE-2 activity, including susceptible malignancies,
which includes administering to said subject an effective amount of
a compound of formula (I) or a pharmaceutically acceptable salt,
solvate, or a physiologically functional derivative thereof. In a
preferred embodiment, the disorder is cancer.
[0328] A further aspect of the invention provides a method of
treatment of a mammal suffering from cancer which includes
administering to said subject an effective amount of a compound of
formula (I) or a pharmaceutically acceptable salt or solvate
thereof, or a physiologically functional derivative thereof.
[0329] A further aspect of the present invention provides the use
of a compound of formula (I), or a pharmaceutically acceptable salt
or solvate thereof, or a physiologically functional derivative
thereof, in the preparation of a medicament for the treatment of a
disorder characterized by inappropriate TIE-2 activity. In a
preferred embodiment, the disorder is cancer.
[0330] A further aspect of the present invention provides the use
of a compound of formula (I), or a pharmaceutically acceptable salt
or solvate thereof, or a physiologically functional derivative
thereof, in the preparation of a medicament for the treatment of
cancer and malignant tumors.
[0331] The mammal requiring treatment with a compound of the
present invention is typically a human being.
[0332] In another embodiment, therapeutically effective amounts of
the compounds of formula (I) or salts, solvates or physiologically
derived derivatives thereof and agents which inhibit growth factor
receptor function may be administered in combination to a mammal
for treatment of a disorder mediated by inappropriate TIE-2
activity, for instance in the treatment of cancer. Such growth
factor receptors include, for example, EGFR, PDGFR, erbB2, erbB4,
VEGFR, and/or TIE-2. Growth factor receptors and agents that
inhibit growth factor receptor function are described, for
instance, in Kath, John C., Exp. Opin. Ther. Patents (2000)
10(6):803-818 and in Shawver et al DDT Vol 2, No. 2 Feb. 1997.
[0333] The compounds of the Formula (I) or salts, solvates, or
physiologically functional derivatives thereof and the agent for
inhibiting growth factor receptor function may be employed in
combination concomitantly or sequentially in any therapeutically
appropriate combination. The combination may be employed in
combination in accordance with the invention by administration
concomitantly in (1) a unitary pharmaceutical composition including
both compounds or (2) separate pharmaceutical compositions each
including one of the compounds. Alternatively, the combination may
be administered separately in a sequential manner wherein one is
administered first and the other second or vice versa. Such
sequential administration may be close in time or remote in
time.
[0334] In another aspect of the present invention, there is
provided a method of treating a disorder in a mammal, said disorder
being mediated by inappropriate angiogenesis, including:
administering to said mammal a therapeutically effective amount of
a compound of formula (I), or a salt, solvate or physiologically
functional derivative thereof. In one embodiment, the inappropriate
angiogenic activity is due to at least one of inappropriate VEGFR1,
VEGFR2, VEGFR3, or TIE-2 activity. In another embodiment, the
inappropriate angiogenesis is due to inappropriate VEGFR2 and TIE-2
activity. In a further embodiment, the method further includes
administering a therapeutically effective amount of a VEGFR2
inhibitor along with the compounds of formula (I) or salts,
solvates or physiologically functional derivatives thereof.
Preferably the disorder is cancer.
[0335] In another aspect of the present invention, there is
provided the use of a compound of formula (I), or a salt, solvate
or physiologically functional derivative thereof in the preparation
of a medicament for use in treating a disorder in a mammal, said
disorder being characterized by inappropriate angiogenesis. In one
embodiment, the inappropriate angiogenic activity is due to at
least one of inappropriate VEGFR1, VEGFR2, VEGFR3 or TIE-2
activity. In another embodiment, the inappropriate angiogenesis is
due to inappropriate VEGFR2 and TIE-2 activity. In a further
embodiment, the use further includes use of a VEGFR2 inhibitor to
prepare said medicament.
[0336] The combination of a compound of formula (I) or salts,
solvates, or physiologically functional derivatives thereof with a
VEGFR2 inhibitor may be employed in combination in accordance with
the invention by administration concomitantly in (1) a unitary
pharmaceutical composition including both compounds or (2) separate
pharmaceutical compositions each including one of the compounds.
Alternatively, the combination may be administered separately in a
sequential manner wherein one is administered first and the other
second or vice versa. Such sequential administration may be close
in time or remote in time.
[0337] The compounds of this invention may be made by a variety of
methods, including standard chemistry. Any previously defined
variable will continue to have the previously defined meaning
unless otherwise indicated. Illustrative general synthetic methods
are set out below and then specific compounds of the invention are
prepared in the Working Examples.
[0338] Compounds of general formula (I) may be prepared by methods
known in the art of organic synthesis as set forth in part by the
following synthesis schemes. In all of the schemes described below,
it is well understood that protecting groups for sensitive or
reactive groups are employed where necessary in accordance with
general principles of chemistry. Protecting groups are manipulated
according to standard methods of organic synthesis (T. W. Green and
P. G. M. Wuts (1991) Protecting Groups in Organic Synthesis, John
Wiley & Sons). These groups are removed at a convenient stage
of the compound synthesis using methods that are readily apparent
to those skilled in the art. The selection of processes as well as
the reaction conditions and order of their execution shall be
consistent with the preparation of compounds of Formula (I). Those
skilled in the art will recognize if a stereocenter exists in
compounds of Formula (I). Accordingly, the present invention
includes both possible stereoisomers and includes not only racemic
compounds but the individual enantiomers as well. When a compound
is desired as a single enantiomer, it may be obtained by
stereospecific synthesis or by resolution of the final product or
any convenient intermediate. Resolution of the final product, an
intermediate, or a starting material may be effected by any
suitable method known in the art. See, for example, Stereochemistry
of Organic Compounds by E. L. Eliel, S. H. Wilen, and L. N. Mander
(Wiley-Interscience, 1994).
[0339] Compounds of Formula (I), wherein R.sup.3 is
--C(O)OCH.sub.3, A is phenyl, and X and Z are oxygen, D and T are
CH, M is C, Q is N(R.sup.7).sub.p, either p or q is 1, and the
other is 0, can be prepared according to the synthetic sequence
shown in Scheme 1 and further detailed in the Examples section
following. 4-Acetamidophenol (1) in DMF is reacted with
5-chloro-2-nitroaniline (2) in the presence of 60% NaH to provide
5-(4-acetamidophenoxy)-2-nitroaniline (3). The nitroaniline (3) is
then refluxed with Na.sub.2S.sub.2O.sub.4 to provide
4-(4-acetamidophenoxy)phenylene-1,2-diamine (4). (It is understood
that reduction of nitro group of (3) can be effected in many ways,
for example by use of H.sub.2, Pd/C; Raney Nickel with hydrazine;
SnCl.sub.4 in HCl; etc.) Diamine (4) is refluxed with
1,3-bis(methoxycarbonyl)-2-methyl-2-thiopseudourea in ethanol and
the acetylated carbamate (5) is obtained. HCl is added to
deacetylate the carbamate (5) to give methyl
(5-(4-aminophenoxy)-1H-benzimidazol-2-yl)carbamate (7).
Alternatively, carbamate (7) may be prepared by refluxing
3,4,4'-triaminodiphenylether (6) with
1,3-bis(methoxycarbonyl)-2-methyl-2-thiopseudourea and then
treating with conc. HCl to give carbamate (7). Carbamate (7) is
then reacted with the appropriate phenyl isocyanate (8) to give the
resultant benzimidazole (9) of the present invention. It is
understood that R.sup.1 and R.sup.2 are as described above. When X
of Formula (I) is sulfur and Z of Formula (I) is oxygen, the final
compounds are obtained by following the same procedure using a
phenylthiol derivative of 1. When X of Formula (I) is sulfur, the
compound thus obtained can be oxidized with MCPBA
(meta-chloroperbenzoic acid) to give compounds containing sulfone
(SO.sub.2) or sulfine (SO) as X. Also, when
3-(3-substitutedphenyl)aminocarbonylamino)phenoxy derivatives of
Formula I are prepared, 3-acetamidophenol is utilized instead of
4-acetamidophenol. ##STR11##
[0340] Compounds of Formula (I), wherein A is phenyl, X and Z are
oxygen, D and T are CH, M is C, Q is N(R.sup.7).sub.p, either p or
q is 1, and the other is 0, R.sup.1 is CF.sub.3, R.sup.2 is F, and
R.sup.3 is a substituted carbonyl, can be prepared according to the
synthetic sequence shown in Scheme 2 and further detailed in the
Examples section following. 4-aminophenol (1) in DMF is reacted
with 5-chloro-2-nitroaniline (2) in the presence of 60% NaH to give
5-(4-aminophenoxy)-2-nitroaniline (3). The compound (3) is reacted
with 2-fluoro-5-trifluoromethylphenylisocyanate (4) to provide
5-(4-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-2-n-
itroaniline (5). The nitroaniline (5) is hydrogenated under an
H.sub.2 atmosphere in the presence of Pd/C to give the
corresponding diamine (6). Diamine (6) is reacted with cyanogen
bromide to give benzimidazole (7). Benzimidazole (7) may be reacted
with the appropriate carboxylic acid in the presence of
triethylamine and HBTU
(O-Benzotriazole-1-yl-N,N,N',N'-tetramethyluroniumhexafluorophosphate)
to give the corresponding benzimidazole (8). Benzimidazole (7) may
also be reacted with J'SO.sub.2Cl (J' is methyl or p-tolyl) to give
a couple of endo-sulfonated products (9, 10). J'SO.sub.2 moiety was
migrated to the exo site by heating (11). Further, benzimidazole
(7) may be reacted with isocyanate J''NCO to give diurea (12). When
X of Formula (I) is sulfur and Z of Formula (I) is oxygen, the
final compounds are obtained by following the same procedure except
that a phenylthiol derivative of 1 is used. When X of Formula (I)
is sulfur, the compound thus obtained can be oxidized with MCPBA
(meta-chloroperbenzoic acid) to give compounds containing sulfonyl
(--SO.sub.2) or sulfenyl (--SO) as X. Also, as indicated above
3-(3-substituted phenyl)aminocarbonylamino) phenoxy derivatives of
Formula I are prepared using 3-acetamidophenol instead of
4-acetamidophenol. The substituent J may be any substituent
attached to C(O) within the scope of the definition of R.sup.3 as
recited herein. The substituent J'' may be any substituent R.sup.5
as defined herein. ##STR12##
[0341] Compounds of Formula I, wherein A is pyridyl, D and T are
CH, M is C, Q is N(R.sup.7).sub.p, either p or q is 1, and the
other is 0, can be prepared according to the synthetic sequence
shown in Scheme 3 and further detailed in the Examples section
following. The terms A1 and A2 refer to N and C, or C and N,
respectively. 5-Hydroxybenzimdazole derivative (2) with or without
a protecting group L is coupled with halonitropyridine (1) in the
presence of base e.g. Cs.sub.2CO.sub.3 to give compound (3).
Subsequent hydrogenation over Pd--C provides aniline derivative
(4), followed by coupling with isocyanate (and deprotection if
needed) to afford urea (5).). The intermediate (4) can also be
provided by way of triamine (6). ##STR13## ##STR14##
[0342] Compounds of Formula I, wherein D is CH, T is C, M is C, Q
is N(R.sup.7).sub.p, R.sup.7 is CH.sub.3, p is 0 and q is 1, can be
prepared according to the synthetic sequence shown in Scheme 4 and
further detailed in the Examples section following.
4-(4-Nitrophenoxy)-2-nitroaniline (1) was coupled with
1-fluoro-4-nitrobenzene with NaH to give (2). Methylation,
hydrogenation proceeding through (3), and subsequent cyclization
with (4) afforded (5), followed by coupling with isocyanate (6) to
yield urea (7). ##STR15##
[0343] Compounds of Formula I, wherein D is CH, T is CH, M is C, Q
is N(R.sup.7).sub.p (p is 1; R.sup.7 is C.sub.1-C.sub.6 alkyl,
--RNR.sup.4R.sup.5 or --RR.sup.6), and q is 0, can be prepared
according to the synthetic sequence shown in Scheme 5 and further
detailed in the Examples section following.
N-alkyl-5-chloro-2-nitroaniline (3), derived from (1) or (2), was
coupled with 4-aminophenol to provide (4). Using methods similar to
those shown in the previous Schemes, hydrogenation, cyclization
through (5), and coupling with isocyanate afforded (6).
##STR16##
[0344] Compounds of Formula I, wherein D is CH, T is CH, M is C, Q
is O, and q is 0, can be prepared according to the synthetic
sequence shown in Scheme 6 and further detailed in the Examples
section following. 4-Aminophenol (1) was coupled with (2) to give
ether (3), which was coupled with isocyante to afford (4).
Hydrogenation and cyclization with BrCN to give (5), followed by
the reaction with CICOOMe gave oxazole derivative (6).
##STR17##
[0345] Compounds of Formula I, wherein D is CH, T is CH, M is C, Q
is S, and q is 0, can be prepared according to the synthetic
sequence shown in Scheme 7 and further detailed in the Examples
section following. 4-(4-Nitrophenoxy)aniline (2), derived from (1)
and 4-aminophenol, was cyclized with KSCN and Br.sub.2 in the
presence of acid to provide thiazole (3). Subsequent reaction with
CICO.sub.2Me or butylisocyante (BuNCO) to give (4), followed by
reduction with SnCl.sub.2 to give (5) and finally coupling with
isocyanate afforded (6). ##STR18##
[0346] Compounds of Formula I, wherein D is N, T is CH, M is C, Q
is N(R.sup.7).sub.p, R.sup.7 is H, either p or q is 1, and the
other is 0, can be prepared according to the synthetic sequence
shown in Scheme 8 and further detailed in the Examples section
following. 2-Amino-6-chloro-3-nitropyridine (1) was coupled with
4-acetylaminophenol (2) with K.sub.2CO.sub.3 to provide ether (3).
Using methods similar to those shown in the previous Schemes,
hydrogenation and cyclization to give (4), hydrolysis to give (5),
and coupling with isocyanate, were carried out to yield
pyridoimidazole (6). ##STR19##
[0347] Compounds of Formula I, wherein D is N, T is CH, M is C, Q
is N, q is 0, and R.sup.3 is COCH.sub.2CH.sub.2 linked together
with the nitrogen at Q, can be prepared according to the synthetic
sequence shown in Scheme 9 and further detailed in the Examples
section following. 2,6-Dichloro-3-nitropyridine (1) was aminated to
give (2) and coupled with 4-acetylaminophenol to give ether (3).
After hydrogenation, and subsequent cyclization with BrCN to give
(4), compound (4) was cyclized by ester hydrolysis through heating
to provide (5). Using methods similar to those shown in the
previous Schemes, hydrolysis to give (6) and coupling with
isocyanate yielded urea (7). ##STR20##
[0348] Compounds of Formula I, wherein D is CH, T is CH, M is N, Q
is CH, and q is 0, can be prepared according to the synthetic
sequence shown in Scheme 10 and further detailed in the Examples
section following. Ether (2), derived from 5-bromo-2-nitroaniline
(1), was cyclized with ClCH.sub.2CONHCO.sub.2Me to give
pyridoimidazole (3). Using methods similar to those shown in the
previous Schemes, hydrolysis to give (4) and coupling with
isocyanate yielded urea (5). ##STR21##
[0349] Compounds of Formula I, wherein D is CH, T is N, M is C, Q
is N(R.sup.7).sub.p, R.sup.7 is H, either p or q is 1, and the
other is 0, can be prepared according to the synthetic sequence
shown in Scheme 11 and further detailed in the Examples section
following. A nitro moiety was added to ethyl
N-(5-bromopyridine-3-yl)carbamate (1) to give (2), followed by
hydrolysis to give (3). Using methods similar to those shown in the
previous Schemes, coupling with phenol derivative gave (4),
hydrogenation and cyclization in the presence of acid gave (5),
hydrolysis gave (6), and coupling with isocyanate yielded
pyridoimidazole (7). ##STR22##
[0350] Compounds of Formula I, wherein X is CO, CH.sub.2, CH(OH), D
is CH, T is CH, M is C, Q is N(R.sup.7).sub.p, R.sup.7 is H, either
p or q is 1, and the other is 0, can be prepared according to the
synthetic sequence shown in Scheme 12 and further detailed in the
Examples section following. Friedel-Crafts condensation with the
halide of (1) and acetoanilide was carried out to give ketone (2).
Using methods similar to those shown in the previous Schemes,
reduction with zinc and cyclization gave (3), hydrolysis, and
coupling with isocyanate yielded pyridoimidazole (4). Also,
reduction with NaBH.sub.4 gave carbinol (5), followed by further
reduction with Et.sub.3SiH provided benzyl derivative (6).
##STR23##
[0351] J is as defined above.
[0352] According to Scheme 13,
amino-(4-methoxyphenyl)-methylpolystyrene resin was first loaded
with 4-chloro-2-fluoronitrobenzene in the presence of DIEA. The
chlorine of compound (1) was displaced with the oxygen of the
4-aminophenol using NaH as the base to arrive at (2). The free
amino group of (2) was then activated with p-nitrophenyl
chloroformate, the excess of which washed away before the amines
were added. For this step, the resin was split into 21 equal
batches and twenty (20) five-membered heteroaryl amines and one
substituted aniline were used to afford (3). The nitro group of (3)
was reduced with tin chloride to give diamine (4). Cyclization with
Fmoc-NCS resulted in the Fmoc-protected aminobenzimidazole (5).
Each resin batch was split again into four even portions. They were
deprotected and acylated with four different carboxylic acids.
Finally, the resin was treated with 23:2:75 (v/v/v)
TFA/H.sub.2O/DCM to yield 84 discrete benzimidazoles (7).
[0353] Certain embodiments of the present invention will now be
illustrated by way of example only. The physical data given for the
compounds exemplified is consistent with the assigned structure of
those compounds.
EXAMPLES
[0354] As used herein the symbols and conventions used in these
processes, schemes and examples are consistent with those used in
the contemporary scientific literature, for example, the Journal of
the American Chemical Society or the Journal of Biological
Chemistry. Standard single-letter or three-letter abbreviations are
generally used to designate amino acid residues, which are assumed
to be in the L-configuration unless otherwise noted. Unless
otherwise noted, all starting materials were obtained from
commercial suppliers and used without further purification.
Specifically, the following abbreviations may be used in the
examples and throughout the specification:
[0355] g (grams); mg (milligrams);
[0356] L (liters); mL (milliliters);
[0357] .mu.L (microliters); psi (pounds per square inch);
[0358] M (molar); mM (millimolar);
[0359] i. v. (intravenous); Hz (Hertz);
[0360] MHz (megahertz); mol (moles);
[0361] mmol (millimoles); rt (room temperature);
[0362] min (minutes); h (hours);
[0363] mp (melting point); TLC (thin layer chromatography);
[0364] T.sub.r (retention time); RP (reverse phase);
[0365] MeOH (methanol); i-PrOH (isopropanol);
[0366] TEA (triethylamine); TFA (trifluoroacetic acid);
[0367] TFAA (trifluoroacetic anhydride); THF (tetrahydrofuran);
[0368] DMSO (dimethylsulfoxide); AcOEt (ethyl acetate);
[0369] DME (1,2-dimethoxyethane); DCM (dichloromethane);
[0370] DCE (dichloroethane); DMF (N,N dimethylformamide);
[0371] DMPU (N,N'-dimethylpropyleneurea); CDI
(1,1-carbonyldiimidazole);
[0372] IBCF (isobutyl chloroformate); HOAc (acetic acid);
[0373] HOSu (N-hydroxysuccinimide); HOBT
(1-hydroxybenzotriazole);
[0374] mCPBA (meta-chloroperbenzoic acid; EDC
(ethylcarbodiimide
[0375] hydrochloride); BOC (tert-butyloxycarbonyl); FMOC
(9-fluorenylmethoxycarbonyl);
[0376] DCC (dicyclohexylcarbodiimide); CBZ (benzyloxycarbonyl);
[0377] Ac (acetyl); atm (atmosphere);
[0378] TMSE (2-(trimethylsilyl)ethyl); TMS (trimethylsilyl);
[0379] TIPS (triisopropylsilyl); TBS (t-butyldimethylsilyl);
[0380] DMAP (4-dimethylaminopyridine); BSA (bovine serum
albumin)
[0381] ATP (adenosine triphosphate); HRP (horseradish
peroxidase);
[0382] DMEM (Dulbecco's modified Eagle medium);
[0383] HPLC (high pressure liquid chromatography);
[0384] BOP (bis(2-oxo-3-oxazolidinyl)phosphinic chloride);
[0385] TBAF (tetra-n-butylammonium fluoride);
[0386] HBTU (O-Benzotriazole-1-yl-N,N,N',N'-tetramethyluronium
hexafluorophosphate).
[0387] HEPES (4-(2-hydroxyethyl)-1-piperazine ethane sulfonic
acid);
[0388] DPPA (diphenylphosphoryl azide);
[0389] EtOH (Ethanol)
[0390] fHNO.sub.3 (fumed HNO.sub.3);
[0391] DIC (1,3-Diisopropylcarbodiimide);
[0392] EDC (1-(3-(Dimethylamino)propyl)-3-ethylcarbodiimide
hydrochloride;
[0393] DIEA (N,N-Diisopropylethylamine); and
[0394] EDTA (ethylenediaminetetraacetic acid).
[0395] All references to ether are to diethyl ether; brine refers
to a saturated aqueous solution of NaCl. Unless otherwise
indicated, all temperatures are expressed in .degree. C. (degrees
Centigrade). All reactions are conducted under an inert atmosphere
at room temperature unless otherwise noted.
[0396] .sup.1H NMR spectra were recorded on a Varian VXR-300, a
Varian Unity-300, a Varian Unity-400 instrument, a Brucker
AVANCE-400, or a General Electric QE-300. Chemical shifts are
expressed in parts per million (ppm, 6 units). Coupling constants
are in units of hertz (Hz). Splitting patterns describe apparent
multiplicities and are designated as s (singlet), d (doublet), t
(triplet), q (quartet), quint (quintet), m (multiplet), br
(broad).
[0397] Low-resolution mass spectra (MS) were recorded on a JOEL
JMS-AX505HA, JOEL SX-102, or a SCIEX-APIiii spectrometer; LC-MS
were recorded on a micromass 2MD and Waters 2690; high resolution
MS were obtained using a JOEL SX-102A spectrometer. All mass
spectra were taken under electrospray ionization (ESI), chemical
ionization (CI), electron impact (EI) or by fast atom bombardment
(FAB) methods. Infrared (IR) spectra were obtained on a Nicolet 510
FT-IR spectrometer using a 1-mm NaCl cell. Most of the reactions
were monitored by thin-layer chromatography on 0.25 mm E. Merck
silica gel plates (60F-254), visualized with UV light, 5% ethanolic
phosphomolybdic acid or p-anisaldehyde solution. Flash column
chromatography was performed on silica gel (230-400 mesh,
Merck).
[0398] A further note on characterization, when R.sup.7 is H in a
compound of Formula (I) wherein Q is N(R.sup.7).sub.p, it is not
identifiable whether p or q is 1 due to the tautomerism.
Preparation of Intermediates
Intermediate 1
5-(4-Acetamidophenoxy)-2-nitroaniline
[0399] ##STR24##
[0400] To a solution of 4-acetamidophenol (7.56 g, 50 mmol) in DMF
(20 ml) was added 60% NaH (2.2 g) followed by
5-chloro-2-nitroaniline (9.06 g, 50 mmol). The mixture was heated
to 120.degree. C. overnight. After cooling, 800 ml of water was
added and the resultant solid was collected by filtration.
Desiccation in vacuo gave intermediate 1 as a brown solid (13.75 g,
96%): MS m/e 286 (M-1).
Intermediate 1A
5-(3-Acetamidophenoxy)-2-nitroaniline
[0401] ##STR25##
[0402] 3-Acetamidophenol was utilized instead of 4-acetamidophenol,
according to the same procedure for Intermediate 1 to prepare
Intermediate 1A: MS m/e 286 (M-1).
Intermediate 2
4-(4-Acetamidophenoxy)phenylene-1,2-diamine
[0403] ##STR26##
[0404] Na.sub.2S.sub.2O.sub.4 (28.2 g, 160 mmol) was added to a
solution of 5-(4-Acetamidophenoxy)-2-nitroaniline (Intermediate 1)
(13.7 g, 48 mmol) in EtOH (600 ml) and H.sub.2O (150 ml). The
yellow mixture was refluxed with vigorous stirring until the color
disappeared. After cooling, the mixture washed with brine and the
product was extracted with AcOEt. The AcOEt layer was dried over
MgSO.sub.4, filtered and evaporated to give intermediate 2 as a
brown film (10.2 g, 83%): MS m/e 258 (M+1).
Intermediate 2A
4-(3-Acetamidophenoxy)phenylene-1,2-diamine
[0405] ##STR27##
[0406] Intermediate 1A was treated instead of Intermediate 1 to
give Intermediate 2A: MS m/e 258 (M+1).
Intermediate 3
Methyl (5-(4-aminophenoxy)-1H-benzimidazol-2-yl)carbamate
[0407] ##STR28## Method A:
[0408] A mixture of 4-(4-Acetamidophenoxy)phenylene-1,2-diamine
(Intermediate 2) (750 mg, 2.9 mmol) and
1,3-bis(methoxycarbonyl)-2-methyl-2-thiopseudourea (600 mg) in ETOH
(13 ml) was refluxed overnight. After cooling to rt, diethyl ether
was added to form a solid (830 mg), which was collected by
filtration. 1N-HCl (150 ml) was poured to this acetylated version
of intermediate 3 (7.7 g, 23 mmol). The mixture was heated to
reflux (105.degree. C.) for 2 h. After cooling, aq. NH.sub.3 (30%,
20 ml) was added. The precipitate thus formed was collected by
filtration with suction and dried in vacuo. The solid material was
then suspended in MeOH (150 ml) and heated to 70.degree. C. for 30
min. with stirring to dissolve a minor by-product. After cooling,
the undissolved material was collected by filtration and dried in
vacuo to give intermediate 3 as a brown solid (6.75 g, 99%): MS m/e
299 (M+1).
Method B:
[0409] A mixture of 3,4,4'-triaminodiphenylether (12.6 g, 59 mmol)
and 1,3-bis(methoxycarbonyl)-2-methyl-2-thiopseudourea (26.7 g) was
refluxed overnight. After cooling, Et.sub.2O was added to form a
precipitate, which was then collected by filtration. The solid thus
obtained (4 g) was dissolved in MeOH (20 ml) and treated with
2N-HCl (20 ml) and then with conc.HCl (3 ml). Stirring was
continued overnight at rt. The mixture was evaporated to remove
MeOH. The resultant material was neutralized with aq. NaOH to give
intermediate 3 as an off-white solid: MS m/z 299 (M+1).
Intermediate 3A
Methyl (5-(3-aminophenoxy)-1H-benzimidazol-2-yl)carbamate
[0410] ##STR29##
[0411] Intermediate 3A was prepared following the Method A
procedure for the preparation of Intermediate 3 using Intermediate
2A instead of Intermediate 2: MS m/z 299 (M+1).
Intermediate 3B
Methyl (5-(4-aminophenylthio)-1H-benzimidazol-2-yl)carbamate
[0412] ##STR30##
[0413] Intermediate 3B was prepared following the Method A
procedure for the preparation of Intermediate 3 starting from
4-acetamidophenylthiol: MS m/z 315 (M+1).
Intermediate 3C
Benzyl(5-(4-(N,N'-bis(benzyloxycarbonyl)amidino)aminophenoxy)-1H-benzimida-
zol-2-yl)carbamate
[0414] ##STR31##
[0415] A mixture of 3,4,4'-triaminodiphenyl ether (5.0 g, 23.2
mmol) and 1,3-bis(benzyloxycarbonyl)-2-methyl-2-thiopseudourea
(16.5 g, 46.0 mmol) in dry MeOH (100 ml) was refluxed overnight.
The reaction mixture was cooled to room temperature and ether was
added. An off white solid was generated and collected by filtration
and washed with ether and dried in vacuo. 14.3 g of Intermediate 3C
was obtained as off white powder. Yield 89.9% .sup.1H NMR
(DMSO-d.sub.6) .delta. 11.82 (br, 1H), 11.40 (br, 1H), 7.51-7.27
(m, 20H), 7.03 (s, 1H), 6.93 (d, 2H), 6.80 (dd, 1H), 5.24 (s, 4H),
5.02 (s, 2H); MS m/e 685 (M+1).
Intermediate 3D
Benzyl (5-(4-aminophenoxy)-1H-benzimidazol-2-yl)carbamate
[0416] ##STR32##
[0417] 14.3 g of Intermediate 3C was dissolved in 300 ml of MeOH
and 300 ml of 2M HCl and stirred for 3 days at 50.degree. C. Then
MeOH was removed by evaporation and 2M of NaOH solution was added
to pH 9.0. The generated solid was collected by filtration and
washed with water and dried in vacuo. Yield 78.0% (7.61 g) .sup.1H
NMR (DMSO-d.sub.6) .delta. 7.48-7.33 (m, 8H), 7.01-6.94 (m, 3H),
6.89 (d, 2H), 6.78 (dd, 1H), 5.24 (s, 2H); MS m/e 375 (M+1).
Intermediate 4
5-(4-Aminophenoxy)-2-nitroaniline
[0418] ##STR33##
[0419] To a solution of 4-aminophenol (5.0 g, 46 mmol) in DMF (120
ml) was slowly added 60% NaH (2.0 g, 50 mmol), followed by
5-chloro-2-nitroaniline (8.7 g). The mixture was heated to
90.degree. C. and stirred overnight. The reaction mixture was
poured onto aq. NH.sub.4Cl to form a solid, which was collected by
filtration, washed with hexane and dried to give intermediate 4 as
a yellow solid (12.0 g, >99%): MS m/e 244 (M-1).
[0420] Intermediate 5
5-(4-((2-Fluoro-5-(trifluoromethyl)phenyl)aminocarbonylaminophenoxy)-2-nit-
roaniline
[0421] ##STR34##
[0422] A mixture of 2-fluoro-5-(trifluoromethyl)phenylisocyanate
(10.0 g, 48.8 mmol) and 5-(4-Aminophenoxy)-2-nitroaniline
(Intermediate 4)(11.6 g, 47.3 mmol) in dry THF (200 ml) was stirred
overnight at rt. After treatment with activated carbon, the solvent
was evaporated. Purification of the crude material by column
chromatography (hexane-AcOEt, 1:2) afforded intermediate 5 as a
yellow solid (21.6 g, >98%): MS m/e 449 (M-1).
Intermediate 6
4-(4-((2-Fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)
phenoxy)phenylene-1,2-diamine
[0423] ##STR35##
[0424] Pd/C (5%, 3.0 g) was introduced to a solution of
5-(4-((2-Fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-2-n-
itroaniline (Intermediate 5) (21.6 g, 48 mmol) in ethanol (200 ml)
under Ar. The starting material was hydrogenated under a H.sub.2
atmosphere for 3 days while being stirred. The reaction mixture was
then filtered through celite and evaporated to give intermediate 6
as a black film. This crude material was chromatographed through
silica gel (hexane-AcOEt, 4:1-3:1-2:1-1:1-0:1) to give purified
intermediate 6 (13.0 g, 64%): MS m/e 421 (M+1).
Intermediate 7
N-(5-(2-Nitro-5-pyridyloxy)-1H-benzimidazol-2-yl)acetamide
[0425] ##STR36##
[0426] To a mixture of 5-hydroxy-2-acetylaminobenzimidazole (382
mg, 2 mmol) and CS.sub.2CO.sub.3 (978 mg, 3 mmol) in DMF (20 ml)
was added 5-bromo-2-nitropyridine (550 mg, 2 mmol) at room
temperature. After 2 hours of stirring, the mixture was poured into
water and extracted with AcOEt. The organic solvent washed with
water and brine, then evaporated to obtain a crude product. It was
purified with silica gel column chromatography (CHCl.sub.3-MeOH).
The pure fractions were collected to provide intermediate 7, which
was then used for the subsequent reduction (314 mg, 50%).
Intermediate 8
N-(5-(2-Amino-5-pyridyloxy)-1H-benzimidazol-2-yl)acetamide
[0427] ##STR37##
[0428] N-(5-(2-Nitro-5-pyridyloxy)-1H-benzimidazol-2-yl)acetamide
(Intermediate 7) was hydrogenated under an H.sub.2 atmosphere with
Pd--C (10%) in MeOH. After the reaction was complete, the solid was
filtered off, and the filtrate was evaporated to give intermediate
8 (47 mg, 17%): .sup.1H NMR (DMSO-d.sub.6) .delta. 11.56 (brs, 1H)
7.51 (d, 1H), 7.32 (d, 1H), 7.05 (dd, 1H), 6.97 (d, 1H), 6.74 (dd,
1H), 6.70 (d, 1H), 5.02 (br s, 2H), 3.74 (s, 3H), 7.08 (d, 2H),
6.84 (d, 1H), 6.61 (d, 1H), 3.75 (s, 3H); MS m/e 284 (M+1).
Intermediate 8A
4-(4-Nitrophenoxy)-2-nitroaniline
[0429] ##STR38##
[0430] To a solution of 4-hydroxy-2-nitroaniline (3.08 g, 20.0
mmol) in DMF (30 mL) was added NaH (60% oily, 880 mg, 22.0 mmol)
followed by 1-fluoro-4-nitrobenzene (2.33 mL, 22.0 mmol). The
mixture was stirred at 90.degree. C. overnight. After cooling, the
mixture was extracted with ethyl acetate. The organic layer washed
with water and brine, dried over Na.sub.2SO.sub.4 then evaporated.
Sequence purification on SiO.sub.2 column chromatography gave the
title compound (4.56 g, 83%): MS m/e 274 (M-1).
Intermediate 8B
N-Methyl-4-(4-nitrophenoxy)-2-nitroaniline
[0431] ##STR39##
[0432] To a mixture of NaH (60% oily, 320 mg, 8.0 mmol) in DMF (30
mL) was added a solution of 4-(4-nitrophenoxy)-2-nitroaniline
(Intermediate 8A--2.00 g, 7.3 mmol) in DMF (30 mL) at 0.degree. C.
followed by an excess amount of MeI (2.0 mL). The mixture was
stirred at 0.degree. C. for 1.5 hrs then at room temperature
overnight. The mixture was extracted with ethyl acetate. The
organic layer washed with water and brine, dried over
Na.sub.2SO.sub.4 then evaporated. Sequence purification on
SiO.sub.2 column chromatography gave the title compound (2.10 g,
quant).): .sup.1H NMR (CDCl.sub.3-d.sub.1) .delta. 3.08 (d, 3H),
6.94 (d, 1H), 7.00 (d, 2H), 7.30 (dd, 1H), 7.97 (d, 1H), 8.08 (brs,
1H), 8.22 (d, 2H).
Intermediate 8C
Methyl (1-methyl-5-(4-aminophenoxy)-benzimidazol-2-yl)carbamate
[0433] ##STR40##
[0434] To a mixture of N-methyl-4-(4-nitrophenoxy)-2-nitroaniline
(Intermediate 8B--2.10 g, 2.27 mmol) in MeOH (100 mL) was added 5%
Pd--C (catalytic amount) and stirred at room temperature under
H.sub.2 atmosphere. After 7 hrs, the catalyst was removed by
filtration then the solvent was evaporated off. The residual
mixture was dissolved into MeOH (50 mL) and added
1,3-bis(methoxycarbonyl)-2-methyl-2-thiopseudourea (3.0 g, 14.5
mmol). The mixture was refluxed overnight. The solvent was removed
by evaporation and sequence purification on SiO.sub.2 column
chromatography gave title compound (87.3 mg, 4%): MS m/e 313
(M+1).
Intermediate 8D
N-methyl-5-chloro-2-nitroaniline
[0435] ##STR41##
[0436] To a solution of 5-chloro-2-nitroaniline (1.73 g, 10.0 mmol)
in DMF (40 mL) was added NaH (60% oily, 880 mg, 22.0 mmol) at
0.degree. C. followed by excess amount of MeI (3.0 mL). The mixture
was stirred at 0.degree. C. for 1 hr then at room temperature
overnight. The mixture was extracted with ethyl acetate. The
organic layer washed with water and brine, dried over
Na.sub.2SO.sub.4 then evaporated. Sequence purification on
SiO.sub.2 column chromatography gave the title compound (1.86 g,
quant): .sup.1H NMR (DMSO-d.sub.6) .delta. 2.95 (d, 3H), 6.69 (dd,
1H), 7.03 (d, 1H), 8.08 (d, 1H), 8.28 (br, 1H).
Intermediate 8E
N-(2-(dimethylamino)ethyl)-5-chloro-2-nitroaniline
[0437] ##STR42##
[0438] To a solution of 3-fluoro-4-nitro-1-chlorobenzene (1.75 g,
10.0 mmol) in DMSO (50 mL) was added K.sub.2CO.sub.3 (2.76 g, 20.0
mmol) followed by N,N-dimethylaminoethylamine (1.21 mL, 11.0 mmol)
at 0.degree. C. The mixture was stirred at 0.degree. C. for 5 min.
before being stirred at room temperature overnight. The mixture was
poured into water then extracted with ethyl acetate. The organic
layer washed with water and brine, dried over Na.sub.2SO.sub.4 then
evaporated. Sequence purification on SiO.sub.2 column
chromatography gave the title compound (2.29 g, 94%): MS m/e 244,
246 (M+1).
Intermediate 8F
N-(2-(4-morpholino)ethyl)-5-chloro-2-nitroaniline
[0439] ##STR43##
[0440] The title compound was prepared following the procedure for
Intermediate 8E using 2-(4-morpholino)ethylamine: MS m/e 286, 288
(M+1).
Intermediate 8G
4-(3-Methylamino-4-nitrophenoxy)aniline
[0441] ##STR44##
[0442] To a mixture of NaH (60% oily, 440 mg, 11.0 mmol) in DMF (30
mL) was added a solution of 4-aminophenol (1.20 g, 11.0 mmol) in
DMF (15 mL) followed by N-methyl-5-chloro-2-nitroaniline
(Intermediate 8D--2.02 g, 10.0 mmol) in DMF (20 mL). The mixture
was stirred at 90.degree. C. overnight. After cooling, the mixture
was extracted with ethyl acetate. The organic layer was washed with
water and brine, dried over Na.sub.2SO.sub.4 then evaporated.
Sequence purification on SiO.sub.2 column chromatography gave the
title compound (2.44 g, 94%): MS m/e 260 (M+1).
Intermediate 8H
4-(3-(2-(Dimethylamino)ethylamino)-4-nitrophenoxy)aniline
[0443] ##STR45##
[0444] Intermediate 8H is prepared using a procedure similar to
Intermediate 8H. MS m/e 317 (M+1).
Intermediate 8I
4-(3-(2-(4-Morpholino)ethylamino)-4-nitrophenoxy)aniline
[0445] ##STR46##
[0446] The title compound was prepared following the procedure for
Intermediate 8H using Intermediate 8F. MS m/e 359 (M+1).
Intermediate 8J
Methyl (3-methyl-5-(4-aminophenoxy)-benzimidazol-2-yl)carbamate
[0447] ##STR47##
[0448] After hydrogenation of
4-(3-methylamino-4-nitrophenoxy)aniline (Intermediate 8G--519.2 mg,
2.0 mmol) with 5% Pd--C in MeOH (20 mL),
1,3-bis(methoxycarbonyl)-2-methyl-2-thiopseudourea (1.03 g, 5.0
mmol) and AcOH (2.0 mL) was added then stirred at 85.degree. C. for
5.5 hrs. After cooling, the mixture was added 2N HClaq. (25 mL)
then stirred at 65.degree. C. for 2 hrs. The mixture was passed
through celite pad to remove catalyst and the solvent was removed
by evaporation. The residue was extracted with ethyl acetate. The
organic layer washed with NH.sub.4OH(aq). and brine, dried over
Na.sub.2SO.sub.4 then evaporated. Sequence purification on
SiO.sub.2 column chromatography gave the title compound (529.1 mg,
85%): MS m/e 313 (M+1).
Intermediate 8K
Methyl
(3-(2-(N,N-dimethylamino)ethyl)-5-(4-aminophenoxy)-benzimidazol-2-y-
l)carbamate
[0449] ##STR48##
[0450] The title compound was prepared following the procedure for
Intermediate 8J using Intermediate 8H. MS m/e 370 (M+1).
Intermediate 8L
Methyl
(3-(2-(4-morpholino)ethyl)-5-(4-aminophenoxy)-benzimidazol-2-yl)car-
bamate
[0451] ##STR49##
[0452] The title compound was prepared following the procedure for
Intermediate 8J using Intermediate 8I. MS m/e 412 (M+1).
Intermediate 9
Ethyl N-(5-bromopyridine-3-yl)carbamate
[0453] ##STR50##
[0454] To a solution of 5-bromonicotinic acid (20.0 g, 99.0 mmol)
in ethanol (300 mL) was added DPPA (21.6 mL, 100.0 mmol) followed
by triethylamine (14.3 mL, 103.0 mmol) then refluxed overnight.
After cooling, a half amount of solvent was removed by evaporation.
The ethanol solution was extracted with ethyl acetate. The organic
layer washed with NaHCO.sub.3 (aq) and brine, dried over
Na.sub.2SO.sub.4 then evaporated. Sequence purification on
SiO.sub.2 column chromatography gave the title compound (4.55 g,
19%): MS m/e 245, 246 (M+1).
Intermediate 9A
5-Bromo-2-nitropyridine-3-ylamine
[0455] ##STR51##
[0456] To a mixture of concentrated H.sub.2SO.sub.4 (3.0 mL) and
fHNO.sub.3 (2.1 mL), 3-bromo-5-(ethoxycarbonyl)aminopyridine
(Intermediate 9--20.0 g, 99.0 mmol) was portionwise added at
0.degree. C. After stirring at 0.degree. C. for 5 min., the mixture
was stirred at room temperature overnight. The mixture was poured
into ice-water then basified with aqueous NH.sub.4OH. The mixture
was extracted with ethyl acetate. The organic layer washed with
aqueous NH.sub.4OH and brine, dried over Na.sub.2SO.sub.4 then
evaporated. Sequence purification on SiO.sub.2 column
chromatography gave 5-bromo-3-(ethoxycarbonyl)amino-2-nitropyridine
(1.57 g, 54%).
[0457] To a solution of
5-bromo-3-(ethoxycarbonyl)amino-2-nitropyridine (1.57 g, 5.4 mmol)
in ethanol (2.5 mL) was added KOH (813 mg, 14.5 mmol) in water
(12.5 mL) and stirred at 90.degree. C. for 1 hr then at room
temperature for 1 hr. The mixture was added water. The formed
precipitate was collected by filtration, washed with water then
dried under reduced pressure to give the title compound (1.08 g,
92%): MS m/e 216, 218 (M-1).
Intermediate 9B
3-Nitro-6-(4-acetamidophenoxy)pyridine-2-ylamine
[0458] ##STR52##
[0459] To a solution of 2-amino-6-chloro-3-nitropyridine (2.77 g,
16.0 mmol) in DMF (55 mL) was added 4-acethylaminophenol (2.67 g,
17.5 mmol) followed by K.sub.2CO.sub.3 (3.3 g, 5.0 mmol) and
stirred at room temperature for 2 hrs. The solvent was removed by
evaporation. To the residue, water was added to form a precipitate.
The solid was collected by filtration, washed with water and ethyl
acetate then dried under reduced pressure to give the title
compound (4.32 g, 94%): MS m/e 289 (M+1).
Intermediate 9C
2-Nitro-5-(4-(tert-butoxycarbonylamino)phenoxy)pyridine-3-ylamine
[0460] ##STR53##
[0461] To a solution of 5-bromo-2-nitropyridine-3-ylamine (436 mg,
2.0 mmol) in DMF (10 mL) was added Cs.sub.2CO.sub.3 (977 mg, 3.0
mmol) followed by 4-(t-butoxy carbonyl)aminophenol (459 mg, 2.2
mmol) in DMF (10 mL) at 0.degree. C. then stirred at room
temperature for 3 days. The mixture was extracted with ethyl
acetate. The organic layer washed with NaHCO.sub.3 (aq) and brine,
dried over Na.sub.2SO.sub.4 then evaporated. Sequence purification
on SiO.sub.2 column chromatography gave the title compound (624.2
mg, 90%): MS m/e 347 (M+1).
Intermediate 9D
Methyl (5-(4-aminophenoxy)-3,4-diazaindolin-2-yl)carbamate
[0462] ##STR54##
[0463] After hydrogenation of
3-nitro-6-(4-acetamidophenoxy)pyridine-2-ylamine (2.02 g, 7.0 mmol)
with 5% Pd--C in MeOH (70 mL), catalyst was removed by filtration.
To the MeOH solution,
1,3-bis(methoxycarbonyl)-2-methyl-2-thiopseudourea (1.73 g, 8.4
mmol) was added and stirred at 75.degree. C. After 8 days, AcOH (15
mL) was added and stirred at 80.degree. C. overnight. Additional
1,3-bis(methoxycarbonyl)-2-methyl-2-thiopseudourea (1.73 g, 8.4
mmol) was added then stirred at 80.degree. C. overnight. After
cooling, the mixture was poured into NaHCO.sub.3 (aq). Formed
precipitate was collected by filtration, washed with ethyl acetate
then dried under reduced pressure to give methyl
(5-(4-acetoamidophenoxy)-3,4-diazaindolin-2-yl)carbamate (983.0 mg,
41%). To a solution of methyl
(5-(4-acetoamidophenoxy)-3,4-diazaindolin-2-yl)carbamate (102.4 mg,
0.3 mmol) in water (3 mL) was added 2N HCl (aq) (3.0 mL) then
refluxed for 1 hr and stirred at room temperature for 1 hr. The
mixture was extracted with ethyl acetate. The organic layer washed
with NH.sub.4OH (aq), dried over Na.sub.2SO.sub.4 then evaporated.
Sequence purification on SiO.sub.2 column chromatography gave the
title compound (33.6 mg, 37%): MS m/e 342 (M+1).
Intermediate 9E
Methyl (6-(4-aminophenoxy)-3,4-diazaindolin-2-yl)carbamate
[0464] ##STR55##
[0465] The same procedure described in Intermediate 9D gave methyl
(5-(4-(tert-butoxycarbonyl)aminophenoxy)-3,7-diazaindolin-2-yl)carbamate.
To a solution of methyl
(5-(4-(tert-butoxycarbonyl)aminophenoxy)-3,7-diazaindolin-2-yl)carbamate
(160.8 mg, 0.4 mmol) in methanol (10 mL) was added 2N HCl (aq) (10
mL) then stirred at room temperature overnight. The solution was
removed by evaporation then the residue was extracted with ethyl
acetate. The organic layer washed with NaHCO.sub.3 (aq) and brine,
dried over Na.sub.2SO.sub.4 then evaporated. The residual solid
washed with ethyl acetate then dried under reduced pressure to give
the title compound (95.3 mg, 80%): MS m/e 300 (M+1).
Intermediate 9F
Ethyl 3-(6-Chrolo-3-nitropyridine-2-ylamino)propanoate
[0466] ##STR56##
[0467] To a solution of 2,6-dichloro-3-nitropyridine (4.83 g, 25.0
mmol) in acetonitrile (100 mL) was added .beta.-alanine
hydrochloride (4.61 g, 30.0 mmol) followed by K.sub.2CO.sub.3 (10.4
g, 75.0 mmol). After stirring at room temperature for 3 days, the
solvent was removed by evaporation. The residue was extracted with
ethyl acetate. The organic layer washed with water and brine, dried
over Na.sub.2SO.sub.4 then evaporated. Sequence purification on
SiO.sub.2 column chromatography gave the title compound (5.01 g,
73%): MS m/e 272, 274 (M-1).
Intermediate 9G
Ethyl
3-(6-(4-acetamidophenoxy)-3-nitropyridine-2-ylamino)propanoate
[0468] ##STR57##
[0469] To a solution of ethyl
3-(6-chrolo-3-nitropyridine-2-ylamino)propanoate (Intermediate
9F--2.72 g, 9.94 mmol) in DMF (30 mL) was added
4-acethylaminophenol (1.66 g, 11.0 mmol) followed by
K.sub.2CO.sub.3 (2.1 g, 14.9 mmol) then stirred at room temperature
for 1 hr. To the mixture, water was added to form precipitate. The
solid was collected by filtration, washed with water and ethyl
acetate then dried under reduced pressure to give the title
compound (3.79 g, 98%): MS m/e 389 (M+1).
Intermediate 9H
2-Amino-3-(2-(ethoxycarbonyl)ethyl)-5-(4-acetamidophenoxy)-3,4-diazaindoli-
dine
[0470] ##STR58##
[0471] After hydrogenation of ethyl
3-(6-(4-acetamidophenoxy)-3-nitropyridine-2-ylamino)propanoate
(Intermediate 9G--1.94 g, 5.0 mmol) with 5% Pd--C in MeOH (25 mL)
and evaporation, the residue was added ethanol (65 mL) and BrCN
(1.84 g, 17 mmol) and stirred at room temperature overnight. The
mixture was extracted with ethyl acetate. The organic layer washed
with NaHCO.sub.3 (aq) and brine, dried over Na.sub.2SO.sub.4 then
evaporated. The residue washed with ethyl acetate then MeOH then
dried under reduced pressure to give the title compound (800.0 mg,
42%): MS m/e 384 (M+1).
Intermediate 9I
3,4-Dihydro-6-(4-aminophenoxy)-1,4-a,5-triazacarbazol-2-one
[0472] ##STR59##
[0473] To a solution of
2-amino-3-(2-(ethoxycarbonyl)ethyl)-5-(4-acetamidophenoxy)-3,4-diazaindol-
idine (Intermediate 9H--200.0 mg, 0.52 mmol) in ethanol (10 mL) was
added conc.HCl (1.0 mL) and stirred at 85.degree. C. overnight.
After evaporation to remove ethanol, DMF (10 mL) was added to the
mixture then heated to 120.degree. C. for 2 hrs. After cooling, the
solvent was removed by evaporation then the residue washed with
MeOH. The result solid was added 2M HCl (12 mL) and stirred at room
temperature overnight. The mixture was basified with NH.sub.4OH
(aq). The formed precipitate was collected, washed with water then
dried under reduced pressure to give the title compound (103.4 mg,
67%): MS m/e 296 (M+1).
Intermediate 9J
5-(4-Acetamidophenoxy)pyridine-2-ylamine
[0474] ##STR60##
[0475] To a solution of 5-bromo2-nitropyridine (2.03 g, 10.0 mmol)
in DMF (30 mL) was added Cs.sub.2CO.sub.3 (4.9 g, 15.0 mmol)
followed by 4-acetylaminophenol (1.66 g, 11.0 mmol) in DMF (30 mL)
at 0.degree. C. then stirred at room temperature overnight. The
mixture was extracted with ethyl acetate. The organic layer washed
with water and brine, dried over Na.sub.2SO.sub.4 then evaporated.
Sequence purification on SiO.sub.2 column chromatography and
recrystallization from ethyl acetate gave
5-(4-acetamidophenoxy)-2-nitropyridine (1.62 g, 59%). Hydrogenation
of 5-(4-acetamidophenoxy)-2-nitropyridine (879.0 mg, 3.22 mmol)
with 5% Pd--C in MeOH (80 mL) gave the title compound (575.7 mg,
74%): MS m/e 244 (M+1).
Intermediate 9K
Methyl (5-(4-aminophenoxy)azaindolizine-2-yl)carbamate
[0476] ##STR61##
[0477] To a solution of 5-(4-acetamidophenoxy)pyridine-2-ylamine
(Intermediate 9J--170.2 mg, 0.7 mmol) in DMF (2 mL) was added
N-(methoxycarbonyl)chloroacetoamide (159.0 mg, 1.1 mmol). The
mixture was stirred at 80.degree. C. overnight. Additional
N-(methoxy carbonyl)chloroacetoamide (159.0 mg, 1.1 mmol) was added
and stirred at 80.degree. C. overnight. After cooling, the mixture
was extracted with ethyl acetate. The organic layer washed with
NaHCO.sub.3 (aq) and brine, dried over Na.sub.2SO.sub.4 then
evaporated. Sequence purification on SiO.sub.2 column
chromatography gave methyl
(5-(4-acetoamidophenoxy)azaindolizine-2-yl)carbamate (51.7 mg,
22%). To a solution of methyl
(5-(4-acetoamidophenoxy)azaindolizine-2-yl)carbamate (34.0 mg, 0.1
mmol) in water (2 mL) was added 2N HCl (aq) (2.0 mL) then refluxed
for 1 hr and stirred at room temperature for 1 hr. The mixture was
added NH.sub.4OH (aq). Formed precipitate was collected by
filtration, washed with water then dried under reduced pressure to
give the title compound (22.0 mg, 74%): MS m/e 299 (M+1).
Intermediate 10
4-(4-Nitrophenoxy)aniline
[0478] ##STR62##
[0479] To a mixture of NaH (60% oily, 880 mg, 22.0 mmol) in DMF (40
mL) was added a solution of 4-aminophenol (2.40 g, 22.0 mmol) in
DMF (30 mL) followed by 1-fluoro-4-nitrobenzene (2.12 mL, 20.0
mmol). The mixture was stirred at 90.degree. C. overnight. After
cooling, the mixture was extracted with ethyl acetate. The organic
layer washed with water and brine, dried over Na.sub.2SO.sub.4 then
evaporated. Sequence purification on SiO.sub.2 column
chromatography gave the title compound (4.60 g, quant): MS m/e 229
(M-1).
Intermediate 10A
6-(4-Nitrophenoxy)benzthiazole-2-ylamine
[0480] ##STR63##
[0481] See the procedure following for Intermediate 10B.
Intermediate 10B
4-Bromo-6-(4-nitrophenoxy)benzthiazole-2-ylamine
[0482] ##STR64##
[0483] To a solution of 4-(4-nitrophenoxy)aniline (Intermediate
10--1.15 g, 5.0 mmol) in AcOH (5 mL) was added KSCN (729 mg, 7.5
mmol). The mixture was cooled to 0.degree. C. and added a solution
of Br.sub.2 (256 .mu.L, 5.0 mmol) in AcOH (6 mL) then stirred at
room temperature overnight. The mixture was poured into H.sub.2O,
basified with NH.sub.4OH (aq), then extracted with ethyl acetate.
The organic layer washed with water and brine, dried over
Na.sub.2SO.sub.4 then evaporated. Sequence purification on
SiO.sub.2 column chromatography gave Intermediate 10A (941.5 mg,
66%): MS m/e 288 (M+1) and Intermediate 10B (223.7 mg, 12%): MS m/e
366, 368 (M+1).
Intermediate 10C
N-(6-(4-Nitrophenoxy)benzthiazole-2-yl)methanesulfonamide
[0484] ##STR65##
[0485] To a solution of Intermediate 10A (1.15 g, 4.0 mmol) in
pyridine (10 ml) was added mesyl chloride (1.55 ml, 20 mmol) at
0.degree. C. and stirred over night at 0.degree. C.-room
temperature. Then potassium carbonate (5.5 g, 40 mmol) in water (20
ml) and MeOH (20 ml) was added and stirred 4 days at 60.degree. C.
MeOH was removed by evaporated and desired compound was extracted
with AcOEt x3 and organic layer washed with water and brine and
dried over with MgSO.sub.4. And purified by column chromatography
(AcOEt-DCM, 1:1, 3:1) and crystallized from AcOEt-Hexane. 300 mg of
Intermediate 10C was obtained as yellow solid. Yield 20.5% MS m/e
366 (M+1).
Intermediate 10D
N-(6-(4-Aminophenoxy)benzthiazole-2-yl)methanesulfonamide
[0486] ##STR66##
[0487] To a solution of Intermediate 10C (100 mg, 0.27 mmol) in
acetic acid (1 ml) was added Zn (54 mg, 0.81 mmol) and stirred over
night at room temprature. Acetic acid was removed by evaporation
and residue was dissolved in DMF and filtrated. Filtrate was
purified by SPE(SCX) tube (washed with MeOH/DMF and eluted with
NH.sub.3/MeOH). NH3/MeOH eluent was collected and 72 mg of
Intermediate 10D was obtained. Yield 79.5% MS m/e 336 (M+1).
Intermediate 10E
Methyl (6-(4-nitrophenoxy)benzthiazole-2-yl)carbamate
[0488] ##STR67##
[0489] To a mixture of 5-(4-nitrophenoxy)benz-3-thiazole-2-ylamine
(430.5 mg, 1.5 mmol) in pyridine (6 mL) and DMF (9 mL) was dropwise
added an excess amount of ClCO.sub.2Me (ca 0.8 mL) at room
temperature. The mixture was added water. The formed precipitate
was collected by filtration, washed with water and MeOH and dried
under reduced pressure to give the title compound (503.7 mg, 97%):
MS m/e 346 (M+1).
Intermediate 10F
Methyl (4-bromo-6-(4-nitrophenoxy)benzthiazole-2-yl)carbamate
[0490] ##STR68##
[0491] The title compound was prepared following the procedure for
Intermediate 10E using Intermediate 10A. MS m/e 424, 426 (M+1)
Intermediate 10G
Methyl (6-(4-aminophenoxy)benzthiazole-2-yl)carbamate
[0492] ##STR69##
[0493] To a solution of methyl
(6-(4-nitrophenoxy)benzthiazole-2-yl)carbamate (Intermediate
10E--172.7 mg, 0.5 mmol) in DMF (5 mL) was added SnCl.sub.2 (474.0
mg, 2.5 mmol) and stirred at room temperature for 4 days. The
mixture was extracted with ethyl acetate, and the organic layer
washed with NaHCO.sub.3aq. and dried over Na.sub.2SO.sub.4 then
evaporated to remove solvent. The residue dissolved in small amount
of DMF was charged on SCX column chromatography then washed with
MeOH then eluted with NH.sub.3-MeOH to give the title compound
(69.2 mg, 44%): MS m/e 316 (M+1).
Intermediate 10H
Methyl (4-bromo-6-(4-aminophenoxy)benzthiazole-2-yl)carbamate
[0494] ##STR70##
[0495] To a solution of methyl
(4-bromo-6-(4-nitrophenoxy)benzthiazole-2-yl)carbamate
(Intermediate 10F--65.3 mg, 0.15 mmol) in AcOH (2 mL) was added Zn
powder (300 mg) and stirred at room temperature for 2 hrs. The
insoluble materials were removed by filtration. The solvent was
removed by evaporation. The residue was charged on SCX column
chromatography then washed with MeOH then eluted with NH.sub.3-MeOH
to give the title compound (39.6 mg, 65%): MS m/e 394, 396
(M+1).
Intermediate 11
4 (3-Benzyloxy-4-nitrophenoxy)aniline
[0496] ##STR71##
[0497] To a solution of 5-fluoro-2-notrophenol (9.43 g, 60.0 mmol)
in acetone (100 mL) was added K.sub.2CO.sub.3 (12.4 g, 90.0 mmol)
followed by benzylbromide (8.6 mL, 72.0 mmol) and acetone (60 mL)
then stirred at room temperature overnight. The mixture was
extracted with ethyl acetate, and the organic layer washed with
water and brine, dried over Na.sub.2SO.sub.4 then evaporated.
Sequence purification on SiO.sub.2 column chromatography gave
2-benzyloxy-4-nitro-1-fluorobenzene (11.97 g, 81%).
[0498] To a mixture of NaH (60% oily, 440.0 mg, 11.0 mmol) in DMF
(20 mL) was dropwise added 4-aminophenol (1.20 g, 11.0 mmol) in DMF
(15 mL) followed by 2-benzyloxy-4-nitro-1-fluorobenzene (2.47 g,
10.0 mmol) in DMF (15 mL). The mixture was stirred at room
temperature for 10 min then at 80.degree. C. overnight. After
cooling, the mixture was extracted with ethyl acetate. The organic
layer washed with water and brine, dried over Na.sub.2SO.sub.4 then
evaporated. Sequence purification on SiO.sub.2 column
chromatography gave the title compound (3.30 g, 98%): MS m/e 337
(M+1).
Intermediate 11A
N-(4-(3-Benzyloxy-4-nitrophenoxy)phenyl)
(2-fluoro-5-(trifluoromethyl)phenylamino)formamide
[0499] ##STR72##
[0500] To a mixture of 4-(3-benzyloxy-4-nitrophenoxy)aniline
(Intermediate 11--1.34 g, 4.0 mmol) in THF (40 mL) was added
5-fluoro-3-trifruolomethylphenyl isocyanate (636 .mu.L, 4.4 mmol)
and stirred at room temperature overnight. The mixture was added
MeOH then the solvent was removed by evaporation. The residue was
purified on SiO.sub.2 column chromatography gave the title compound
(2.17 g, quant): MS m/e 542 (M+1).
Intermediate 11B
6-(4-((2-Fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)
phenyloxy)benzoxazol-2-ylamine
[0501] ##STR73##
[0502] After hydrogenation of
N-(4-(3-benzyloxy-4-nitrophenoxy)phenyl)
(2-fluoro-5-(trifluoromethyl)phenylamino)formamide (Intermediate
11A--542 mg, 1.0 mmol) with 5% Pd--C in MeOH (10 mL), BrCN (800 mg,
7.6 mmol) was added and stirred at room temperature for 4 days. The
mixture was added NaHCO.sub.3 (aq) and stirred for 1 day. The
mixture was extracted with ethyl acetate. The organic layer washed
with NaHCO.sub.3 (aq) and brine, dried over Na.sub.2SO.sub.4 then
evaporated. Sequence purification on SiO.sub.2 column
chromatography gave the title compound (237 mg, 53%): MS m/e 447
(M+1).
Intermediate 11C
4-(4-(Acetamido)phenylcarbonyl)-1,2-dinitrobenzene
[0503] ##STR74##
[0504] A mixture of 3,4-dinitrobenzoyl chloride (4 mmol),
acetoanilide (540 mg, 4 mmol), and AlCl.sub.3 (1.6 g) in
CH.sub.2Cl.sub.2 was heated at 40.degree. C. for 24 h. The slurry
washed with HCl (aq) and the product was extracted with ether. It
washed with K.sub.2CO.sub.3 (aq), dried, and evaporated.
Purification by column-chromatography on silica-gel (hexane:
AcOEt=1:3) provided 87 mg of the title compound; MS m/e 328
(M-1).
Intermediate 11D
4-(4-Aminophenylcarbonyl)-1,2-dinitrobenzene
[0505] ##STR75##
[0506] Using the methods of Intermediate 2 and then Intermediate 3
(Method A), Intermediate 11D was prepared from Intermediate 11C; MS
m/e 311 (M+1).
Intermediate 12
4-Nitro-3-fluorophenyl tetrahydropyranyl ether
[0507] ##STR76##
[0508] To the mixture of 3-fluoro-4-nitrophenol (25 g, 0.160 mol)
and 3,4-dihydro-2H-pyran (14 g, 0.167 mol)in dichloromethane (200
ml), pyridinium p-toluenesulfonate (4.0 g, 16 mol) was added
portionly under ice-water bath. After overnight at room
temperature, the reaction mixture was pored to Si-column
chromatography. Eluting by Hexane Ethyl acetate (3:1), the desired
product was obtained at 35.5 g (92%) as light yellow solid.
Intermediate 12A
3-Benzylamino-4-nitrophenyl tetrahydropyranyl ether
[0509] ##STR77##
[0510] To the solution of Intermediate 12 (20 g, 0.083 mol) in DMSO
(150 ml), benzylamine (8.9 g, 0.083 mol) and K.sub.2CO.sub.3 (23 g)
were added at room temperature. NH.sub.2-TLC by eluted Hexane-AcOEt
showed reaction complete. Water was added to the mixture, then,
extracted by AcOEt at twice. All organic layer was evaporated. The
residue is used to the next reduction. MS m/e 329 (M+1).
Intermediate 12B
3-Benzylamino-4-nitrophenyl tetrahydropyranyl ether
[0511] ##STR78##
[0512] The product of Intermediate 12A was reduced in a usual
manner to give 2-benzylaminoaniline derivative (see Intermediate
2). To the suspension of crude diamino phenylene (26.3 g, 88 mmol)
derivatives in methanol (300 ml), bromocyamide (9.35 g, 1 equiv.)
was added at 0.degree. C. After 15 min, the ice-bath was removed
and stirred for 1 hr at room temperature. After evaporation of the
methanol solution, saturated NaHCO.sub.3 (300 ml) and AcOEt (100
ml) were added to the residue. Generated precipitates were filtered
and washed with water to give a crude powder (21.68 g). MS m/e 324
(M+1).
Intermediate 12C
N-(1-Benzyl-6-hydroxy-1H-benzimidazol-2-yl)acetamide
[0513] ##STR79##
[0514] To the suspension of Intermediate 12B (2 g, 6.1 mmol) in THF
(5 ml), acetic anhydride (2.3 ml) was added at room temperature.
After 3 hr at room temperature, THF was evaporated. Ice-water was
added to the residue, then conc. HCl and methanol were added
carefully at 0 C. After 30 min' stirring, the acidic solution was
neutralized by NaOH and NaHCO.sub.3. The generated precipitate was
collected, washed with Et.sub.2O, and dried to give the title
compound. MS m/e 282 (M+1).
Intermediate 12D
1-Benzyl-6-hydroxy-2-(tert-butoxycarbonylamino)-1H-benzimidazole
[0515] ##STR80##
[0516] 1-Benzyl-6-hydroxy-2-amino-1H-benzimidazole was treated with
BOC.sub.2O in pyridine, followed by hydrolysis with NaOH (aq) to
give the title compound; MS m/e 340 (M+1).
Intermediate 12E
Tert-Butyl
N-(1-benzyl-6-(6-aminopyridin-3-yloxy)-1H-benzimidazol-2-yl)
[0517] ##STR81##
[0518] Coupling of Intermediate 12D with 3-bromo-6-nitropyridine
and subsequent hydrogenation over Pd/C gave the title compound; MS
m/e 432 (M+1).
Intermediate 13A
1-(6-(4-Nitrophenoxy)benzthiazol-2-yl)-3-butylurea
[0519] ##STR82##
[0520] Intermediate 13A was prepared following a similar procedure
for Example 1 using Intermediate 10A. MS m/e 387 (M+1)
Intermediate 13B
1-(6-(4-Aminophenoxy)benzthiazol-2-yl)-3-butylurea
[0521] ##STR83##
[0522] Intermediate 13B was prepared following a similar procedure
for Intermediate 10D using Intermediate 13A. MS m/e 357 (M+1)
Intermediate 14A ##STR84##
Resin-Bound 5-Chloro-2-nitroaniline
[0523] Amino-(4-methoxyphenyl)-methylpolystyrene (loading 1.69
mmol/g, 7.00 g, 11.8 mmol) was soaked in DMSO in a peptide vessel
for 30 min. The solvent was then drained. DIEA (11.3 mL, 65.1 mmol)
in DMSO (88 mL) was added to the resin, followed by
4-chloro-2-fluoronitrobenzene (10.4 g, 59.2 mmol). The mixture was
shaken at room temperature for 19 h, at which point it was drained.
The resin washed with DMSO (3.times.), ETOH (3.times.), DMF
(3.times.), MeOH (3.times.) and DCM (3.times.). It was then dried
under vacuum overnight. A small sample (approx. 10 mg) was treated
with 23:2:75 (v/v/v) TFA/H.sub.2O/DCM (0.5 mL) for ca. 1 h. The
solution containing the released material was concentrated and
analyzed with LC/MS. UV (254 nm): 97% @ 5.65 min. MS: m/e 171
(M-1).
Intermediate 14B
Resin-bound 5-(4-Aminophenoxy)-2-nitroanillne
[0524] ##STR85##
[0525] 4-Aminophenol (4.71 g, 43.2 mmol) was dissolved in degassed
DMF (108 mL) and bubbled with Ar for 10 min in a dry, 300-mL
pear-shaped flask. Sodium hydride (60% in mineral, 1.78 g, 44.5
mmol) was added. The mixture was bubbled and stirred for an
additional 15 min. Resin-bound 5-chloro-2-nitroaniline 1 (4.3 g,
theoretically 5.75 mmol) was added to the now dark mixture. After
the evolution of gas had minimized, the flask was stoppered and
shaken at room temperature for ca. 4.5 days. The mixture was
filtered and the salts washed away with water. The black resin
washed with H.sub.2O (3.times.), 1:1 DMF/H.sub.2O (3.times.), DMF
(3.times.), MeOH (3.times.) and DCM (3.times.). The reaction was
repeated on the same resin batch the same way. After drying in
vacuo, a small sample (approx. 10 mg) was treated with 23:2:75
(v/v/v) TFA/H.sub.2O/DCM (0.5 mL) for ca. 1 h. The solution
containing the released material was concentrated and analyzed with
LC/MS. UV (254 nm): 90% @ 6.08 min. MS: m/e 244 (M-1).
Intermediate 14C (Library)
Resin-bound
5-(4-((Heteroaryl)aminocarbonylamino)phenoxy)-2-nitroaniline
[0526] ##STR86##
[0527] Intermediate 14B (approx. 224 mg, theoretically 0.273 mmol)
was rinsed with 1:1 (v/v) THF/DCM in a 25-mL Alltech tube.
p-Nitrophenyl chloroformate (551 mg, 2.73 mmol) and DIEA (476
.mu.L, 2.73 mmol) in 1:1 (v/v) THF/DCM (5.5 mL) was added. The
mixture was shaken for 18-22 h. After draining, the resin washed
with 1:1 (v/v) THF/DCM (3-4.times.). The heteroaryl amine (2.73
mmol) and DIEA (476 .mu.L, 2.73 mmol) in DMF (5.5 mL) were added.
(Twice the equivalent of DIEA was used for the amines that were
monohydrochloride salts.) The yellow mixtures were shaken for ca.
16 h. and then drained. The resin washed thoroughly with DMF
(3.times.), 10:90 DIEA/DMF (10.times.), DMF (3.times.), 1:1
DMF/H.sub.2O (3.times.), MeOH (3.times.), DCM (3.times.) to wash
away most of the p-nitrophenol that slowly leached away from the
resin. After drying, a small sample (approx. 5 mg) was treated with
23:2:75 (v/v/v) TFA/H.sub.2O/DCM (0.5 mL) for ca. 1 h. The solution
containing the released material was concentrated and analyzed with
LC/MS.
Intermediate 14D (Library)
Resin-Bound
4-(4-((Heteroaryl)aminocarbonylamino)phenoxy)-1,2-phenylenediamine
[0528] ##STR87##
[0529] Intermediate 14C (theoretically 0.273 mmol) was soaked in
NMP for at least 30 min in a 25-mL Alltech tube. Tin (II) chloride
dihydrate (1.85 g, 8.20 mmol) in NMP (8.20 mL) was added and the
mixture was shaken for ca. 5.5 days. After filtration, the resin
washed with NMP (3.times.), 30:70 ethylene diamine/NMP (10.times.),
NMP (3.times.), MeOH (3.times.) and DCM (3.times.). It was dried
under vacuum and a small sample (approx. 5 mg) was treated with
23:2:75 (v/v/v) TFA/H.sub.2O/DCM (0.5 mL) for ca. 1 h. The solution
containing the released material was concentrated and analyzed with
LC/MS.
Intermediate 14E (Library)
1-Resin-bound-2-(Fmoc-amino)-6-(4-((heteroaryl)aminocarbonylamino)phenoxy)-
-1H-benzimidazoles
[0530] ##STR88##
[0531] Intermediate 14D (theoretically 0.273 mmol) was rinsed with
DMF in a 25-mL Alltech tube. DIC (1.71 mL, 10.9 mmol) was added to
a solution of Fmoc-NCS (1.54 g, 5.47 mmol) in DMF (5.5 mL) and the
mixture was immediately added to the resin. The Alltech tube was
vortexed vigorously for ca. 6.75 days. The mixture was drained and
the precipitate formed during the reaction washed away with DCM.
The resin was then washed with DCM (3.times.), DMF (3.times.), 1:1
DMF/H.sub.2O (3.times.), MeOH (3.times.) and DCM (3.times.) and
dried in vacuo. A small sample (approx. 5 mg) was treated with
23:2:75 (v/v/v) TFA/H.sub.2O/DCM (0.5 mL) for ca. 1 h. The solution
containing the released material was concentrated and analyzed with
LC/MS.
Intermediate 14F (Library)
1-Resin-Bound-2-(R2-carbonylamino)-6-(4-((heteroaryl)aminocarbonylamino)ph-
enoxy)-1H-benzimidazoles
[0532] ##STR89##
[0533] Intermediate 14E (theoretically 0.0401 mmol) was treated
with 20% piperidine in DMF (1 mL) in a 6-mL Alltech tube for 30
min. The mixture was drained and the resin washed with DMF
(3.times.). The piperidine treatment and the succeeding DMF wash
were repeated for a second time.
[0534] Coupling Procedure A (for acetic acid and
4-dimethylaminobutyric acid hydrochloride): To a mixture of DIEA
(69.9 .mu.L, 0.400 mmol) and EDC (38.5 mg, 0.200 mmol) in DMF (0.67
mL) was added a solution of HOBt-H.sub.2O (30.7 mg, 0.200 mmol) and
the acid (0.200 mmol) also dissolved in DMF (1.33 mL). (The
equivalent of DIEA was doubled for the butyric acid coupling.) The
acid was activated for ca. 5 min. and then added to the deprotected
resin. The reaction mixture was vortexed for ca. 15 h. The solvent
was removed by vacuum and the resin washed with DMF (3.times.), 1:1
DMF/H.sub.2O (3.times.), MeOH (3.times.) and DCM (3.times.).
[0535] Coupling Procedure B (for 2-furoic and
2-(2-methoxyethoxy)acetic acids): To a solution of the acid (0.202
mmol) in DMF (0.67 mL) was added HOBt-H.sub.2O (30.9 mg, 0.202
mmol) in DMF (0.67 mL), DIEA (70.4 .mu.L, 0.404 mmol) and then HBTU
(75.1 mg, 0.198 mmol) in DMF (0.67 mL). The reaction mixture was
vortexed for ca. 20 h. After filtration, the resin was washed with
DMF (3.times.), 1:1 DMF/H.sub.2O (3.times.), MeOH (3.times.) and
DCM (3.times.).
Intermediate 15A
5-Amino-2-(3,4-diaminophenoxy)pyridine
[0536] ##STR90##
[0537] 2-Nitro-4-hydroxyaniline was reacted with
2-chloro-5-nitropyridine and K.sub.2CO.sub.3 in DMF at rt, followed
by hydrogenation over Pd/C in MeOH, afforded the title compound; MS
m/e 217 (M+1).
Intermediate 15B
Methyl
N-(5-(5-aminopyridine-2-yl)-1H-benzimidazol-2-yl)carbamate
[0538] ##STR91##
[0539] The title compound was obtained according to procedures for
Intermediate 3C and 3D, using the product of Intermediate 15A
instead of 3,4,4'-triaminodiphenylether; MS m/e 300 (M+1).
Example 1
Methyl
N-(5-(4-((3-chlorophenyl)aminocarbonylamino)phenoxy)-1H-benzimidazo-
l-2-yl)carbamate
[0540] ##STR92##
[0541] A mixture of methyl
(5-(4-aminophenoxy)-1H-benzimidazol-2-yl)carbamate (Intermediate 3)
(80 mg, 0.27 mmol) and 3-chlorophenylisocyanate (49 mg, 0.32 mmol)
in dry THF (2 ml) was heated to 45.degree. C. overnight. After
cooling, diethyl ether was added to form a precipitate. The solid
was collected by filtration to provide the title compound (83 mg,
69%): .sup.1H NMR (DMSO-d.sub.6) .delta.11.60 (brs, 2H), 9.00 (s,
1H), 8.83 (s, 1H), 7.70 (m, 1H), 7.42 (d, 2H), 7.38 (d, 1H),
7.32-7.24 (m, 2H), 7.01 (m, 2H), 6.93 (d, 2H), 6.80 (dd, 1H) 3.75
(s, 3H); MS m/e 452 (M+1).
[0542] Examples 2-11, 14-16, 19-21, 40-78, 81, and 86 were prepared
according to the procedures described above for Example 1.
Intermediates 3, 3A, and 3B, were used or other precursors as
indicated. The free bases obtained may be transformed into their
pharmaceutically acceptable salts (e.g. HCl salts) by standard
procedures known in the art.
Example 2
Methyl N-(5-(4-((3-(trifluoromethyl)phenyl)aminocarbonylamino)
phenylthio)-1H -benzimidazol-2-yl)carbamate
[0543] ##STR93##
[0544] .sup.1H NMR (DMSO-d.sub.6) .delta. 11.61 (brs, 1H), 9.01 (s,
1H), 8.85 (s, 1H), 7.76 (s, 1H), 7.08-7.52 (m, 8H), 6.90 (d, 1H),
6.53 (d, 1H), 5.35 (s, 1H), 3.71 (s, 3H); MS m/e 502 (M+1).
Example 3
Methyl N-(5-(4-((3,5-di(trifluoromethyl)phenyl)aminocarbonylamino)
phenylthio)-1H-benzimidazol-2-yl)carbamate
[0545] ##STR94##
[0546] .sup.1H NMR (DMSO-d.sub.6) .delta. 11.65 (brs, 1H), 10.00
(s, 1H), 9.45 (s, 1H), 8.07 (s, 2H), 7.59 (s, 1H), 7.31-7.48 (m,
4H), 7.05-7.20 (m, 4H), 3.72 (s, 3H); MS m/e 570 (M+1).
Example 4
Methyl
N-(5-(4-((3-bromophenyl)aminocarbonylamino)phenylthio)-1H-benzimida-
zol-2-yl)carbamate
[0547] ##STR95##
[0548] .sup.1H NMR (DMSO-d.sub.6) .delta. 11.61 (brs, 1H), 9.25 (s,
1H), 9.17 (s, 1H), 7.79 (s, 1H), 7.40 (d, 2H), 7.16-7.36 (m, 6H),
7.10 (d, 1H), 7.05 (d, 1H), 5.72 (s, 1H), 3.71 (s, 3H); MS m/e 513
(M+1).
Example 5
Methyl N-(5-(4-((3,5-dimethoxyphenyl)aminocarbonylamino)
phenylthio)-1H-benzimidazol-2-yl)carbamate
[0549] ##STR96##
[0550] .sup.1H NMR (DMSO-d.sub.6) .delta. 11.60 (brs, 1H), 9.13 (s,
1H), 9.05 (s, 1H), 7.40 (d, 2H), 7.05-7.36 (m, 5H), 6.64 (d, 2H),
6.09 (s, 1H), 5.72 (s, 1H), 3.71 (s, 3H), 3.67 (s, 6H); MS m/e 494
(M+1).
Example 6
Methyl N-(5-(4-((2-methyl-5-nitrophenyl)aminocarbonylamino)
phenylthio)-1H-benzimidazol-2-yl)carbamate
[0551] ##STR97##
[0552] .sup.1H NMR (DMSO-d.sub.6) .delta. 11.24 (brs, 1H), 9.32 (s,
1H), 8.93 (dd, 1H), 8.27 (s, 1H), 7.79 (dd, 1H), 7.48-7.38 (m, 5H),
7.22 (dd, 2H), 7.12 (dd, 1H), 3.75 (s, 3H), 2.35 (s, 3H); MS m/e
493 (M+1).
Example 7
Methyl
N-(5-(4-((3-ethylphenyl)aminocarbonylamino)phenylthio)-1H-benzimida-
zol-2-yl)carbamate
[0553] ##STR98##
[0554] .sup.1H NMR (DMSO-d.sub.6) .delta. 11.86 (brs, 1H), 8.72 (s,
1H), 8.58 (s, 1H), 7.46-7.34 (m, 4H), 7.29 (dd, 1H), 7.23-7.14 (m,
4H), 7.08 (dd, 1H), 6.81 (dd, 1H), 3.74 (s, 3H), 2.56 (q, 2H), 1.17
(t, 3H); MS m/e 462 (M+1).
Example 8
Methyl N-(5-(4-((2-fluoro-5-nitrophenyl)amino carbonylamino)
phenylthio)-1H-benzimidazol-2-yl)carbamate
[0555] ##STR99##
[0556] .sup.1H NMR (DMSO-d.sub.6) .delta. 11.81 (brs, 1H), 9.26 (s,
1H), 9.13 (dd, 1H), 8.99 (s, 1H), 7.90 (m, 1H), 7.54 (dd, 1H),
7.46-7.38 (m, 4H), 7.21 (dd, 2H), 7.12 (dd, 1H), 3.75 (s, 3H); MS
m/e 497 (M+1).
Example 9
Methyl
N-(5-(4-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)
phenylthio)-1H-benzimidazol-2-yl)carbamate
[0557] ##STR100##
[0558] .sup.1H NMR (DMSO-d.sub.6) .delta. 11.70 (brs, 2H), 9.25 (s,
1H), 8.89 (d, 1H), 8.60 (dd, 1H), 7.53-7.36 (m, 6H), 7.22 (d, 2H),
7.12 (dd, 1H), 3.75 (s, 3H); MS m/e 520 (M+1).
Example 9A
Methyl
N-(5-(4-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)
phenylthio)-1H-benzimidazol-2-yl)carbamate methanesulfonic acid
[0559] ##STR101##
[0560] .sup.1H NMR (DMSO-d.sub.6) .delta. 9.38 (s, 1H), 8.97 (s,
1H), 8.60 (s, 1H), 7.58-7.48 (m, 4H), 7.44-7.35 (m, 3H), 7.34 (d,
1H), 7.27 (dd, 1H), 3.85 (s, 3H), 2.34 (s, 3H); MS m/e 520
(M+1).
Example 9B
Methyl
N-(5-(4-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phe-
nylthio)-1H -benzimidazol-2-yl)carbamate sulfuric acid
[0561] ##STR102##
[0562] .sup.1H NMR (DMSO-d.sub.6) .delta. 9.38 (s, 1H), 8.96 (s,
1H), 8.60 (s, 1H), 7.58-7.48 (m, 4H), 7.44-7.34 (m, 4H), 7.26 (dd,
1H), 3.84 (s, 3H); MS m/e 520 (M+1).
Example 10
Methyl
N-(5-(4-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)
phenoxy)-1H-benzimidazol-2-yl)carbamate
[0563] ##STR103##
[0564] .sup.1H NMR (DMSO-d.sub.6) .delta.11.60 (brs, 2H), 9.13 (s,
1H), 8.85 (d, 1H), 8.62 (dd, 1H), 7.49 (m, 1H), 7.44 (d, 2H),
7.40-7.35 (m, 2H), 7.01 (d, 1H), 6.94 (d, 2H), 6.79 (dd, 1H) 3.74
(s, 3H); MS m/e 504 (M+1).
Example 11
Methyl
N-(5-(4-((3-ethylphenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-
-2-yl)carbamate
[0565] ##STR104##
[0566] .sup.1H NMR (DMSO-d.sub.6) .delta.11.60 (brs, 2H), 8.71 (s,
1H), 8.67 (s, 1H), 7.42 (d, 2H), 7.37 (d, 1H), 7.31-6.98 (m, 4H),
6.92 (d, 2H), 6.83-6.77 (m, 2H), 3.75 (s, 3H), 2.57 (q, 2H), 1.17
(t, 3H); MS m/e 446 (M+1).
Example 12
Methyl
N-(5-(4-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)
phenylsulfonyl)-1H-benzimidazol-2-yl)carbamate
[0567] ##STR105##
[0568] To a solution of methyl
N-(5-(4-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)
phenylthio)-1H-benzimidazol-2-yl)carbamate (Product of Example 9,
100 mg, 0.19 mmol) in acetic acid (2 ml) was added mCPBA (92 mg,
0.53 mmol) in DCM (1 ml) and stirred over night. Aqueous
NaHCO.sub.3 solution was added and off-white solid was generated.
Solid was collected by filtration and washed with water and dried
in vacuo. 80 mg of off-white compound was obtained: Yield 76.3%;
.sup.1H NMR (DMSO-d.sub.6) .delta.12.29 (brs, 1H), 11.60 (brs, 1H),
9.70 (s, 1H), 9.07 (d, 1H), 8.56 (dd, 1H), 7.95 (br, 1H), 7.85 (d,
2H), 7.66 (d, 2H), 7.64-7.61 (m, 1H), 7.59-7.47 (m, 2H), 7.45-7.40
(m, 1H), 3.78 (s, 3H); MS m/e 552 (M+1).
Example 13
Methyl
N-(5-(4-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)
phenylsulfinyl)-1H-benzimidazol-2-yl)carbamate
[0569] ##STR106##
[0570] Reduced amount of mCPBA in Example 12 also afforded the
title compound.
[0571] .sup.1H NMR (DMSO-d.sub.6) .delta.12.12 (brs, 1H), 11.49
(br, 1H), 9.46 (s, 1H), 8.96 (d, 1H), 8.58 (dd, 1H), 7.73 (s, 1H),
7.60 (s, 4H), 7.54-7.47 (m, 2H), 7.43-7.38 (m, 1H), 7.34 (dd, 1H),
3.76 (s, 3H); MS m/e 536 (M+1).
Example 14
Methyl
(5-(3-((3-Chlorophenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol--
2-yl)carbamate hydrochloride
[0572] ##STR107##
[0573] .sup.1H NMR (DMSO-d.sub.6) .delta. 10.70 (brs, 1H), 8.82 (s,
1H), 8.79 (s, 1H), 7.64 (m, 1H), 7.40 (d, 1H), 7.23 (m, 3H), 7.11
(m, 2H), 7.07 (m, 1H), 7.00 (d, 1H), 6.82 (dd, 1H), 6.57 (d, 1H),
3.75 (s, 3H); MS m/e 452 (M+1).
Example 15
Methyl
N-(5-(3-((2-Fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phe-
noxy)-1H-benzimidazol-2-yl)carbamate
[0574] ##STR108##
[0575] .sup.1H NMR (DMSO-d.sub.6) .delta. 11.67 (brs, 2H), 9.23 (s,
1H), 8.80 (s, 1H), 8.54 (d, 1H), 7.48 (t, 1H), 7.41 (m, 2H), 7.26
(t, 1H), 7.14 (d, 1H), 7.08 (d, 2H), 6.84 (d, 1H), 6.61 (d, 1H),
3.75 (s, 3H); MS m/e 504 (M+1).
Example 16
Methyl
N-(5-(3-((3-ethylphenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-
-2-yl)carbamate
[0576] ##STR109##
[0577] .sup.1H NMR (DMSO-d.sub.6) .delta. 11.62 (br, 2H), 8.71 (s,
1H), 8.50 (s, 1H), 7.40 (d, 1H), 7.25-7.15 (m, 5H), 7.09 (d, 2H),
6.81 (t, 2H), 6.55 (d, 1H), 3.75 (s, 3H), 2.54 (q, 2H), 1.15 (t,
3H); MS m/e 446 (M+1).
Example 17
Ethyl
N-(5-(4-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phen-
oxy)-1H-benzimidazol-2-yl)carbamate
[0578] ##STR110##
[0579] The title compound was prepared by heating a mixture of the
product of Example 10 and NaOEt in ethanol:
[0580] .sup.1H NMR (DMSO-d.sub.6) .delta. 11.50 (brs, 2H), 9.13 (s,
1H), 8.85 (s, 1H), 8.62 (d, 1H), 7.49 (t, 1H), 7.43 (d, 2H), 7.37
(m, 2H), 7.01 (s, 1H), 6.93 (d, 2H), 6.79 (d, 1H), 4.21 (q, 2H),
1.27 (t, 3H); MS m/e 518 (M+1).
Example 18
t-Butyl
N-(5-(4-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)ph-
enoxy)-1H-benzimidazol-2-yl)carbamate
[0581] ##STR111##
[0582] Utilizing the method described for preparing Intermediate 3,
but using 1,3-bis(tert-butoxycarbonyl)-2-methyl-2-thiopseudourea
instead of 1,3-bis(methoxycarbonyl)-2-methyl-2-thiopseudourea
afforded the title compound. .sup.1H NMR (DMSO-d.sub.6) .delta.
11.80 (brs, 1H), 10.94 (brs, 1H), 9.12 (s, 1H), 8.85 (s, 1H), 8.62
(dd, 1H), 7.50 (t, 1H), 7.42 (d, 2H), 7.37 (m, 2H), 7.00 (brs, 1H),
6.91 (d, 2H), 6.76 (dd, 1H), 1.51 (s, 9H); MS m/e 546 (M+1).
Example 19
Methyl
N-(5-(4-((3-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1H--
benzimidazol-2-yl)carbamate
[0583] ##STR112##
[0584] .sup.1H NMR (DMSO-d.sub.6) .delta. 11.80 (brs, 2H), 9.04 (s,
1H), 8.78 (s, 1H), 8.01 (s, 1H), 7.57 (d, 1H), 7.50 (t, 1H), 7.43
(d, 2H), 7.37 (d, 1H), 7.29 (d, 1H), 7.00 (s, 1H), 6.92 (d, 2H),
6.79 (dd, 1H), 3.74 (s, 3H); MS m/e 486 (M+1).
Example 20
Methyl
N-(5-(3-((3-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1H--
benzimidazol-2-yl)carbamate
[0585] ##STR113##
[0586] .sup.1H NMR (DMSO-d.sub.6) .delta. 11.60 (brs, 2H), 8.98 (s,
1H), 8.89 (s, 1H), 7.94 (s, 1H), 7.54 (d, 1H), 7.49 (t, 1H), 7.41
(d, 1H), 7.29 (d, 1H), 7.24 (t, 1H), 7.14 (s, 1H), 7.09 (d, 2H),
6.83 (dd, 1H), 6.59 (d, 1H), 3.75 (s, 3H); MS m/e 486 (M+1).
Example 21
Methyl
N-(5-(4-((3-t-butylphenyl)aminocarbonylamino)phenoxy)-1H-benzimidaz-
ol-2-yl)carbamate
[0587] ##STR114##
[0588] .sup.1H NMR (DMSO-d.sub.6) .delta.12.2-11.0 (brs, 2H), 8.61
(s, 1H), 8.59 (s, 1H), 7.45 (m, 3H), 7.36 (d, 1H), 7.27 (d, 1H),
7.19 (t, 1H), 6.99 (m, 2H), 6.91 (d, 2H), 6.78 (dd, 1H), 3.75 (s,
3H), 1.27 (s, 9H); MS m/e 474 (M+1).
Example 22
2-Amino-5-(4-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)pheno-
xy)-1H-benzimidazole
[0589] ##STR115##
[0590] The title compound was prepared from intermediates 4, 5, and
6 described above. To a solution of
4-(4-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonyl
amino)phenoxy)phenylene-1,2-diamine (Intermediate 6) (1.5 g, 3.6
mmol) in MeOH (20 ml) was added cyanogen bromide (490 mg, 4.6
mmol). The reaction mixture was stirred for 1 h and then washed
with aq. NaOH. The product was extracted with AcOEt, dried over
MgSO.sub.4 and the solvent evaporated. Purification with SCX Ion
exchange column chromatography (eluted first with MeOH then with
aq. NH.sub.3 in MeOH) yielded the title compound (1.53 g, 96%);
.sup.1H NMR (DMSO-d.sub.6) .delta. 10.63 (brs, 1H), 9.08 (s, 1H),
8.83 (s, 1H), 8.62 (d, 1H), 7.49 (t, 1H), 7.40 (d, 2H), 7.38 (m,
1H), 7.05 (d, 1H), 6.89 (d, 2H), 6.74 (s, 1H), 6.55 (d, 1H), 6.15
(s, 2H); MS m/e 446 (M+1).
Example 23
(6-(4-((2-Fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-3-(-
methanesulfonyl)-1H-benzimidazol-2-ylamine
[0591] ##STR116##
[0592] To a mixture of
2-amino-5-4-((2-fluoro-5-trifluoromethylphenyl)aminocarbonylamino)
phenoxy)-1H-benzimidazole (90 mg, 0.20 mmol) (prepared according to
similar procedures as described for Intermediates 4, 5, and 6 and
Example 22) and triethylamine (30 mg, 0.30 mmol) in DMF/CHCl.sub.3
(3 ml/1 ml) was added methanesulfonyl chloride (30 mg, 0.26 mmol).
After stirring for 3 h at rt, the reaction mixture washed with
water and extracted with CHCl.sub.3. The organic layer was dried
over MgSO.sub.4 and evaporated. The crude material was purified
with silica gel column chromatography (AcOEt) to give the title
compound (22.0 mg, 15%): .sup.1H NMR (DMSO-d.sub.6) .delta. 9.14
(s, 1H), 8.85 (s, 1H), 8.62 (d, 1H), 7.50 (t, 1H), 7.48 (d, 2H),
7.38 (m, 1H), 7.22 (d, 1H), 7.18 (s, 1H), 6.97 (d, 2H), 6.87 (s,
1H), 6.86 (d, 1H), 3.49 (s, 3H); MS m/e 524 (M+1).
Example 24
6-(4-((2-Fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1-(4-
-(methyl)phenylsulfonyl)-1H-benzimidazol-2-ylamine
[0593] ##STR117##
[0594] Example 24 was prepared according to procedures similar to
the one described above in Example 23. They can be transformed into
their pharmaceutically acceptable salts (e.g. HCl salts) by
standard procedures. .sup.1H NMR (DMSO-d.sub.6) .delta. 9.18 (s,
1H), 8.88 (d, 1H), 8.63 (dd, 1H), 7.85 (d, 2H), 7.51-7.46 (m, 5H),
7.43-7.36 (m, 1H), 7.25 (d, 1H), 7.14-7.11 (m, 3H), 6.94 (d, 2H),
6.84 (dd, 1H), 2.38 (s, 3H); MS m/e 600 (M+1).
Example 25
N-(5-(4-((2-Fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1-
H -benzimidazol-2-yl)acetamide
[0595] ##STR118##
[0596] To a mixture of
2-amino-5-4-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)pheno-
xy)-1H -benzimidazole (prepared according to similar procedures as
described for Intermediates 4, 5, and 6 and Example 22) (72 mg,
0.165 mmol), acetic acid (15 mg, 0.24 mmol) and triethylamine (50
mg) in DMF was added HBTU (91 mg, 0.24 mmol) and HOBT (20 mg). The
reaction mixture was stirred for 4 h, poured into water, washed and
extracted with AcOEt. The organic layer was dried over MgSO.sub.4
and evaporated. Purification of the residue by column
chromatography on silica gel (AcOEt as an eluant) afforded the
title compound (28 mg, 36%): .sup.1H NMR (DMSO-d.sub.6) .delta.
11.99 (brs, 1H), 11.51 (br, 1H), 9.15 (s, 1H), 8.87 (s, 1H), 8.62
(d, 1H), 7.50 (t, 1H), 7.43 (d, 2H), 7.38 (m, 2H), 7.04 (d, 1H),
6.93 (d, 2H), 6.80 (dd, 1H), 2.15 (s, 3H); MS m/e 488 (M+1).
[0597] Examples 26-35 and 87-102 were prepared according to
procedures similar to that described above. They can be transformed
into their pharmaceutically acceptable salts (e.g. HCl salts) by
standard procedures.
Example 26
N-(5-(4-((2-Fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1-
H -benzimidazol-2-yl)cyclopentamide
[0598] ##STR119##
[0599] .sup.1H NMR (DMSO-d.sub.6) .delta. 12.05 (brd, 1H), 11.51
(d, 1H), 9.13 (s, 1H), 8.85 (s, 1H), 8.62 (d, 1H), 7.50 (t, 1H),
7.43 (d, 2H), 7.39 (m, 2H), 6.99 (d, 1H), 6.93 (d, 2H), 6.80 (dd,
1H), 2.93 (quint, 1H), 1.88 (m, 2H), 1.70 (m, 4H), 1.57 (m, 2H); MS
m/e 542 (M+1).
Example 27
N-(5-(4-((2-Fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1-
H -benzimidazol-2-yl)(2-furyl)formamide
[0600] ##STR120##
[0601] .sup.1H NMR (DMSO-d.sub.6) .delta. 12.20 (brs, 2H), 9.16 (s,
1H), 8.88 (s, 1H), 8.62 (d, 1H), 7.95 (s, 1H), 7.45 (m, 5H), 7.39
(m, 1H), 7.05 (s, 1H), 6.96 (d, 2H), 6.86 (dd, 1H), 6.70 (m, 1H);
MS m/e 540 (M+1).
Example 28
N-(5-(4-((2-Fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1-
H -benzimidazol-2-yl)-4-methylpentamide
[0602] ##STR121##
[0603] .sup.1H NMR (DMSO-d.sub.6) .delta. 12.08 (brd, 1H), 11.51
(d, 1H), 9.13 (s, 1H), 8.85 (s, 1H), 8.62 (d, 1H), 7.50 (t, 1H),
7.43 (d, 2H), 7.38 (m, 2H), 7.05 (d, 1H), 6.93 (d, 2H), 6.80 (dd,
1H), 2.44 (t, 2H), 1.53 (m, 2H), 0.90 (d, 6H); MS m/e 544
(M+1).
Example 29
N-(5-(4-((2-Fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1-
H -benzimidazol-2-yl)-2-(N-acetylamino)acetamide
[0604] ##STR122##
[0605] .sup.1H NMR (DMSO-d.sub.6) .delta. 12.03 (brs, 1H), 11.58
(s, 1H), 9.14 (s, 1H), 8.85 (s, 1H), 8.62 (d, 1H), 8.29 (t, 1H),
7.52 (t, 1H), 7.44 (d, 2H), 7.42 (m, 1H), 7.39 (m, 1H), 7.05 (br,
1H), 6.94 (d, 2H), 6.82 (dd, 1H), 3.96 (d, 2H), 1.90 (s, 3H); MS
m/e 545 (M+1).
Example 30
N-(5-(4-((2-Fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1-
H -benzimidazol-2-yl)-2-aminoacetamide dihydrochloride
[0606] ##STR123##
[0607] .sup.1H NMR (DMSO-d.sub.6) .delta. 9.76 (s, 1H), 9.15 (d,
2H), 8.62 (d, 1H), 8.40 (br, 2H), 7.56 (d, 2H), 7.54 (d, 2H), 7.39
(m, 1H), 7.10 (s, 1H), 7.02 (m, 1H), 7.01 (d, 2H), 3.97 (m, 2H); MS
m/e 503 (M+1).
Example 31
N-(5-(4-((2-Fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1-
H -benzimidazol-2-yl)-2-methoxyacetamide
[0608] ##STR124##
[0609] .sup.1H NMR (DMSO-d.sub.6) .delta. 12.09 (brs, 1H), 11.41
(br, 1H), 9.13 (s, 1H), 8.86 (s, 1H), 8.62 (dd, 1H), 7.50 (m, 2H),
7.44 (d, 2H), 7.39 (m, 1H), 7.05 (br, 1H), 6.94 (d, 2H), 6.82 (dd,
1H), 4.14 (s, 2H), 3.39 (s, 3H); MS m/e 518 (M+1).
Example 32
3-(N-(5-(4-((2-Fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy-
)-1H-benzimidazol-2-yl)carbamoyl)propionic acid
[0610] ##STR125##
[0611] .sup.1H NMR (DMSO-d.sub.6) .delta. 12.10 (brs, 1H), 11.60
(brs, 1H), 9.22 (s, 1H), 8.92 (s, 1H), 8.61 (dd, 1H), 7.60-7.40 (m,
3H), 7.44 (d, 2H), 7.05 (brs, 1H), 6.93 (d, 2H), 6.80 (dd, 1H),
2.67 (t, 2H), 2.55 (t, 2H); MS m/e 546 (M+1).
Example 33
N-(5-(4-((2-Fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1-
H -benzimidazol-2-yl)(2-(2-(methoxy)ethoxy)ethoxy)acetamide
[0612] ##STR126##
[0613] .sup.1H NMR (DMSO-d.sub.6) .delta. 12.11 (brs, 1H), 11.29
(brs, 1H), 9.15 (s, 1H), 8.86 (d, 1H), 8.61 (dd, 1H), 7.43-7.50 (m,
5H), 6.98-7.14 (brm, 1H), 6.94 (d, 2H), 6.82 (dd, 1H), 4.23 (s,
2H), 3.68-3.70 (m, 2H), 3.56-3.61 (m, 4H), 3.49-3.47 (m, 2H), 3.24
(s, 3H); MS m/e 606 (M+1).
Example 34
N-(5-(4-((2-Fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1-
H -benzimidazol-2-yl)(2-(methoxy)ethoxy)acetamide
[0614] ##STR127##
[0615] .sup.1H NMR (DMSO-d.sub.6) .delta. 12.11 (brs, 1H), 11.28
(brs, 1H), 9.14 (s, 1H), 8.86 (d, 1H), 8.61 (dd, 1H), 7.38-7.52 (m,
5H), 6.98-7.14 (brs, 1H), 6.94 (d, 2H), 6.82 (dd, 1H), 4.22 (s,
2H), 3.68-3.71 (m, 2H), 3.51-3.54 (m, 2H), 3.30 (s, 3H); MS m/e 562
(M+1).
Example 35
N-(5-(4-((2-Fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1-
H -benzimidazol-2-yl)-2-(N-(t-butoxycarbony)amino)acetamide
[0616] ##STR128##
[0617] .sup.1H NMR (DMSO-d.sub.6) .delta. 12.06 (d, 1H), 11.56
(brs, 1H), 9.13 (s, 1H), 8.85 (s, 1H), 8.62 (s, 1H), 7.50 (t, 1H),
7.44 (d, 2H), 7.41 (m, 1H), 7.39 (m, 1H), 7.17 (t, 1H), 7.04 (br,
1H), 6.97 (d, 2H), 6.81 (dd, 1H), 3.82 (d, 2H), 1.40 (s, 9H); MS
m/e 603 (M+1).
Example 36
N-(5-(2-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)-5-pyridyl-
oxy)-1H-benzimidazol-2-yl)acetamide dihydrochloride
[0618] ##STR129##
[0619] The title compound was synthesized according to similar
procedures as described for Intermediates 7 and 8 and for Example 1
(13.0 mg 14%): .sup.1H NMR (DMSO-d.sub.6) .delta. 12.42 (brs, 1H),
10.64 (brs, 1H), 9.97 (s, 1H), 8.66 (dd, 1H), 8.11 (d, 1H),
7.68-7.61 (m, 1H), 7.60-7.48 (m, 3H), 7.47-7.41 (m, 1H), 7.17 (d,
1H), 7.04 (dd, 1H), 2.24 (s, 3H); MS m/e 489 (M+1).
[0620] The compounds of Examples 37 to 39 were prepared according
to procedures similar to that described for Example 36 above. They
can be transformed into their pharmaceutically acceptable salts
(e.g. HCl salts) by standard procedures.
Example 37
Methyl
N-(5-(5-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)-2--
pyridyloxy)-1H-benzimidazol-2-yl)carbamate
[0621] ##STR130##
[0622] .sup.1H NMR (DMSO-d.sub.6) .delta. 12.0-11.1 (brm, 2H), 9.21
(s, 1H), 8.96 (d, 1H), 8.58 (dd, 1H), 8.15 (d, 1H), 8.00 (dd, 1H),
7.52-7.48 (m, 1H), 7.41-7.38 (m, 2H), 7.11 (d, 1H), 6.94 (d, 1H),
6.82 (dd, 1H), 3.75 (s, 3H); MS m/e 505 (M+1).
Example 38
N-(5-(5-((3-(trifluoromethyl)phenyl)aminocarbonylamino)-2-pyridyloxy)-1H-b-
enzimidazol-2-yl)acetamide
[0623] ##STR131##
[0624] .sup.1H NMR (DMSO-d.sub.6) .delta. 11.70 (brs, 2H), 9.17 (s,
1H), 8.88 (s, 1H), 8.17 (d, 1H), 7.99 (s, 1H), 7.96 (d, 1H), 7.59
(d, 1H), 7.51 (t, 1H), 7.39 (d, 1H), 7.31 (d, 1H), 7.11 (s, 1H),
6.92 (d, 1H), 6.83 (dd, 1H), 3.75 (s, 3H); MS m/e 487 (M+1).
Example 39
Methyl
N-(5-(5-((3-ethylphenyl)aminocarbonylamino)-2-pyridyloxy)-1H-benzim-
idazol-2-yl)carbamate
[0625] ##STR132##
[0626] .sup.1H NMR (DMSO-d.sub.6) .delta. 11.82 (brs, 1H), 11.30
(brs, 1H), 8.71 (d, 2H), 8.15 (d, 1H), 7.95 (d, 1H), 7.38 (d, 1H),
7.31 (s, 1H), 7.24 (d, 1H), 7.17 (t, 1H), 7.09 (brs, 1H), 6.91 (d,
1H), 6.83-6.80 (m, 2H), 3.75 (s, 3H), 2.56 (q, 2H), 1.17 (t, 3H);
MS m/e 447 (M+1).
Example 40
Methyl
N-(5-(4-((3-bromophenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-
-2-yl)carbamate
[0627] ##STR133##
[0628] .sup.1H NMR (DMSO-d.sub.6) .delta. 12.2-11.0 (brs, 2H), 9.11
(s, 1H), 8.93 (s, 1H), 7.84 (t, 1H), 7.42 (d, 2H), 7.37 (d, 1H),
7.31 (d, 1H), 7.22 (t, 1H), 7.13 (d, 1H), 7.00 (d, 1H), 6.92 (d,
2H), 6.79 (dd, 1H), 3.74 (s, 3H); MS m/e 496 (M), 498 (M+2).
Example 41
Methyl
N-(5-(4-((3-(trifluoromethylthio)phenyl)aminocarbonylamino)phenoxy)-
-1H -benzimidazol-2-yl)carbamate
[0629] ##STR134##
[0630] .sup.1H NMR (DMSO-d.sub.6) .delta. 12.2-11.2 (brs, 2H), 8.96
(s, 1H), 8.73 (s, 1H), 7.98 (s, 1H), 7.55 (d, 1H), 7.46-7.42 (m,
1H), 7.43 (d, 2H), 7.37 (d, 1H), 7.29 (d, 1H), 7.00 (d, 1H), 6.92
(d, 2H), 6.79 (dd, 1H), 3.74 (s, 3H); MS m/e 518 (M+1).
Example 42
Methyl
N-(5-(4-((2,5-dimethoxyphenyl)aminocarbonylamino)phenoxy)-1H-benzim-
idazol-2-yl)carbamate
[0631] ##STR135##
[0632] .sup.1H NMR (DMSO-d.sub.6) .delta. 12.0-11.2 (brs, 2H), 9.31
(s, 1H), 8.20 (s, 1H), 7.85 (d, 1H), 7.42 (d, 2H), 7.36 (d, 1H),
6.99 (s, 1H), 6.91 (m, 3H), 6.78 (dd, 1H), 6.48 (dd, 1H), 3.82 (s,
3H), 3.74 (s, 3H), 3.68 (s, 3H). 6; MS m/e 478 (M+1).
Example 43
Methyl
N-(5-(4-((2-chloro-5-(trifluoromethylgphenyl)aminocarbonylamino)phe-
noxy)-1H-benzimidazol-2-yl)carbamate
[0633] ##STR136##
[0634] .sup.1H NMR (DMSO-d.sub.6) .delta. 12.0-11.2 (brs, 2H), 9.53
(s, 1H), 8.65 (d, 1H), 8.57 (s, 1H), 7.71 (d, 1H), 7.45 (d, 2H),
7.37 (m, 2H), 7.01 (s, 1H), 6.94 (d, 2H), 6.80 (dd, 1H), 3.75 (s,
3H); MS m/e 520 (M+1), 522 (M+3).
Example 44
Methyl
N-(5-(4-((4-chloro-3-(trifluoromethyl)phenyl)aminocarbonylamino)phe-
noxy)-1H-benzimidazol-2-yl)carbamate
[0635] ##STR137##
[0636] .sup.1H NMR (DMSO-d.sub.6) .delta. 12.0-11.2 (brs, 2H), 9.13
(s, 1H), 8.80 (s, 1H), 8.11 (d, 1H), 7.65-7.59 (m, 2H), 7.43 (d,
2H), 7.37 (d, 1H), 7.00 (d, 1H), 6.92 (d, 2H), 6.79 (dd, 1H), 3.74
(s, 3H); MS m/e 520 (M+1)), 522 (M+3).
Example 45
Methyl
N-(5-(4-((2,5-dichlorophenyl)aminocarbonylamino)phenoxy)-1H-benzimi-
dazol-2-yl)carbamate
[0637] ##STR138##
[0638] .sup.1H NMR (DMSO-d.sub.6) .delta. 12.2-11.2 (brs, 2H), 9.50
(s, 1H), 8.42 (s, 1H), 8.33 (m, 1H), 7.49 (d, 1H), 7.43 (d, 2H),
7.38 (d, 1H), 7.08 (dd, 1H), 7.01 (d, 1H), 6.94 (d, 2H), 6.80 (dd,
1H), 3.75 (s, 3H); MS m/e 486 (M+1).
Example 46
Methyl
N-(5-(4-((2-fluoro-5-nitrophenyl)aminocarbonylamino)phenoxy)-1H-ben-
zimidazol-2-yl)carbamate
[0639] ##STR139##
[0640] .sup.1H NMR (DMSO-d.sub.6) .delta. 12.2-11.2 (brs, 2H), 9.16
(m, 2H), 8.97 (s, 1H), 7.90 (m, 1H), 7.55 (t, 1H), 7.45 (d, 2H),
7.38 (d, 1H), 7.01 (d, 1H), 6.94 (d, 2H), 6.80 (dd, 1H), 3.75 (s,
3H); MS m/e 481 (M+1).
Example 47
Methyl
N-(5-(4-((2-methyl-5-nitrophenyl)aminocarbonylamino)phenoxy)-1H-ben-
zimidazol-2-yl)carbamate
[0641] ##STR140##
[0642] .sup.1H NMR (DMSO-d.sub.6) .delta. 12.2-11.2 (brs, 2H), 9.22
(s, 1H), 8.96 (d, 1H), 8.23 (s, 1H), 7.79 (dd, 1H), 7.47 (m, 1H),
7.46 (d, 2H), 7.38 (d, 1H), 7.01 (d, 1H), 6.94 (d, 2H), 6.80 (dd,
1H), 3.75 (s, 3H), 2.37 (s, 3H); MS m/e 477 (M+1).
Example 48
Methyl
N-(5-(4-(3-methylthiophenyl)aminocarbonylamino)phenoxy)-1H-benzimid-
azol-2-yl)carbamate
[0643] ##STR141##
[0644] .sup.1H NMR (DMSO-d.sub.6) .delta. 12.2-11.2 (brs, 2H), 8.67
(s, 1H), 8.64 (s, 1H), 7.46 (t, 1H), 7.41 (d, 2H), 7.36 (d, 1H),
7.21 (t, 1H), 7.13 (d, 1H), 6.99 (d, 1H), 6.92 (d, 2H), 6.84 (d,
1H), 6.78 (dd, 1H), 3.74 (s, 3H), 2.45 (s, 3H); MS m/e 464
(M+1).
Example 49
Methyl
N-(5-(4-(3-cyanophenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol--
2-yl)carbamate
[0645] ##STR142##
[0646] .sup.1H NMR (DMSO-d.sub.6) .delta. 12.2-11.2 (brs, 2H), 9.02
(s, 1H), 8.83 (s, 1H), 7.97 (s, 1H), 7.67 (d, 1H), 7.49 (t, 1H),
7.43 (d, 2H), 7.42 (t, 1H), 7.37 (d, 1H), 7.00 (d, 1H), 6.93 (d,
2H), 6.79 (dd, 1H), 3.74 (s, 3H); MS m/e 443 (M+1).
Example 50
Methyl
N-(5-(4-((3-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phe-
noxy)-1H-benzimidazol-2-yl)carbamate
[0647] ##STR143##
[0648] .sup.1H NMR (DMSO-d.sub.6) .delta. 12.2-11.2 (brs, 2H), 9.21
(s, 1H), 8.87 (s, 1H), 7.70 (s, 1H), 7.61 (d, 1H), 7.43 (d, 2H),
7.37 (d, 1H), 7.22 (d, 1H), 7.00 (d, 1H), 6.93 (d, 2H), 6.79 (dd,
1H), 3.74 (s, 3H); MS m/e 504 (M+1).
Example 51
Methyl
N-(5-(4-((2-chloro-5-(trifluoromethyl)phenyl)aminocarbonylamino)
phenylthio)-1H-benzimidazol-2-yl)carbamate hydrochloride
[0649] ##STR144##
[0650] .sup.1H NMR (DMSO-d.sub.6) .delta. 9.82 (s, 1H), 6.69 (s,
1H), 8.62 (d, 1H), 7.71 (d, 1H), 7.46 (d, 2H), 7.42-7.36 (m, 3H),
7.21 (d, 2H), 7.12 (dd, 1H), 3.75 (s, 3H); MS m/e 536 (M+1), 538
(M+3).
Example 52
Methyl
N-(5-(3-((2-chloro-5-(trifluoromethylgphenyl)aminocarbonylamino)phe-
noxy)-1H-benzimidazol-2-yl)carbamate hydrochloride
[0651] ##STR145##
[0652] .sup.1H NMR (DMSO-d.sub.6) .delta. 9.67 (s, 1H), 8.57 (s,
1H), 8.56 (s, 1H), 7.70 (d, 1H), 7.41 (d, 1H), 7.36 (dd, 1H), 7.27
(t, 1H), 7.18 (d, 1H), 7.09 (d, 1H), 7.03 (t, 1H), 6.84 (dd, 1H),
6.62 (dd, 1H), 3.75 (s, 3H); MS m/e 520 (M+1), 522 (M+3).
Example 53
Methyl
N-(5-(4-((3-ethoxycarbonylphenyl)aminocarbonylamino)phenoxy)-1H-ben-
zimidazol-2-yl)carbamate
[0653] ##STR146##
[0654] .sup.1H NMR (DMSO-d.sub.6) .delta. 12.0-11.2 (brs, 2H), 8.91
(s, 1H), 8.64 (s, 1H), 8.15 (t, 1H), 7.65 (d, 1H), 7.55 (d, 1H),
7.44-7.40 (m, 3H), 7.37 (d, 1H), 7.00 (s, 1H), 6.92 (d, 2H), 6.79
(dd, 1H), 4.31 (q, 2H), 3.74 (s, 3H), 1.32 (t, 3H); MS m/e 490
(M+1).
Example 54
Methyl
N-(5-(4-((3-carboxyphenyl)aminocarbonylamino)phenoxy)-1H-benzimidaz-
ol-2-yl)carbamate
[0655] ##STR147##
[0656] Hydrolysis of the product of Example 53 with NaOH gave the
title compound.
[0657] .sup.1H NMR (DMSO-d.sub.6) .delta. 12.2-11.2 (brs, 2H), 8.97
(brs, 1H), 8.77 (brs, 1H), 8.12 (s, 1H), 7.64 (d, 1H), 7.54 (d,
1H), 7.44 (d, 2H), 7.38 (m, 2H), 7.00 (d, 1H), 6.92 (d, 2H), 6.79
(dd, 1H), 3.74 (s, 3H); MS m/e 462 (M+1).
Example 55
Methyl
N-(5-(4-((2-fluoro-5-methylphenyl)aminocarbonylamino)phenoxy)-1H-be-
nzimidazol-2-yl)carbamate hydrochloride
[0658] ##STR148##
[0659] .sup.1H NMR (DMSO-d.sub.6) .delta. 9.56 (s, 1H), 8.66 (s,
1H), 7.96 (d, 1H), 7.58 (d, 1H), 7.51 (d, 2H), 7.12-7.06 (m, 3H),
7.01 (d, 2H), 6.79 (m, 1H), 3.86 (s, 3H), 2.27 (s, 3H); MS m/e 450
(M+1).
Example 56
Methyl
N-(5-(4-((2,5-difluorophenyl)aminocarbonylamino)phenoxy)-1H-benzimi-
dazol-2-yl)carbamate
[0660] ##STR149##
[0661] .sup.1H NMR (DMSO-d.sub.6) .delta. 12.0-11.0 (brs, 2H), 9.09
(s, 1H), 8.71 (s, 1H), 8.04 (m, 1H), 7.42 (d, 2H), 7.37 (d, 1H),
7.29 (m, 1H), 7.00 (d, 1H), 6.93 (d, 2H), 6.82 (m, 1H), 6.79 (dd,
1H), 3.74 (s, 3H); MS m/e 454 (M+1).
Example 57
Methyl
N-(5-(4-((2,5-dichlorophenyl)aminocarbonylamino)phenylthio)-1H-benz-
imidazol-2-yl)carbamate
[0662] ##STR150##
[0663] .sup.1H NMR (DMSO-d.sub.6) .delta. 12.2-11.2 (brs, 2H), 9.60
(s, 1H), 8.46 (s, 1H), 8.30 (d, 1H), 7.49 (d, 1H), 7.45-7.39 (m,
4H), 7.21 (d, 2H), 7.13 (dd, 1H), 7.09 (dd, 1H), 3.75 (s, 3H); MS
m/e 502 (M+1), 504 (M+3).
Example 58
Methyl
N-(5-(3-((3-(trifluoromethylthio)phenyl)aminocarbonylamino)phenoxy)-
-1H-benzimidazol-2-yl)carbamate
[0664] ##STR151##
[0665] .sup.1H NMR (DMSO-d.sub.6) .delta. 12.2-11.2 (brs, 2H), 9.02
(s, 1H), 8.94 (s, 1H), 7.90 (s, 1H), 7.52 (d, 1H), 7.44-7.40 (m,
2H), 7.30-7.21 (m, 2H), 7.12-7.07 (m, 3H), 6.84 (dd, 1H), 6.57 (d,
1H), 3.75 (s, 3H); MS m/e 518 (M+1).
Example 59
Methyl
N-(5-(3-((3-bromophenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-
-2-yl)carbamate
[0666] ##STR152##
[0667] .sup.1H NMR (DMSO-d.sub.6) .delta. 12.0-11.5 (brs, 2H), 7.78
(s, 1H), 7.41 (d, 1H), 7.30-7.00 (m, 9H), 6.83 (dd, 1H), 6.57 (dd,
1H), 3.75 (s, 3H); MS m/e 496 (M), 498 (M+2).
Example 60
Methyl
N-(5-(3-((3-(phenoxy)phenyl)aminocarbonylamino)phenoxy)-1H-benzimid-
azol-2-yl)carbamate
[0668] ##STR153##
[0669] .sup.1H NMR (DMSO-d.sub.6) .delta. 12.0-11.5 (brs, 2H), 8.94
(s, 1H), 8.91 (s, 1H), 7.39 (m, 3H), 7.30-7.21 (m, 2H), 7.19 (t,
1H), 7.11-7.00 (m, 7H), 6.83 (dd, 1H), 6.59 (d, 1H), 6.54 (d, 1H)
3.75 (s, 3H); MS m/e 510 (M+1).
Example 61
Methyl
N-(5-(3-((4-chlorophenyl)aminocarbonylamino)phenoxy)-1H-benzimidazo-
l-2-yl)carbamate
[0670] ##STR154##
[0671] .sup.1H NMR (DMSO-d.sub.6) .delta. 12.0-11.2 (brs, 2H), 8.94
(s, 1H), 8.91 (s, 1H), 7.44-7.40 (m, 3H), 7.29 (d, 2H), 7.23 (t,
1H), 7.14 (t, 1H), 7.07 (s, 2H), 6.82 (dd, 1H), 6.57 (dd, 1H), 3.75
(s, 3H). 6; MS m/e 452 (M+1).
Example 62
Methyl
N-(5-(4-((4-methoxyphenyl)aminocarbonylamino)phenoxy)-1H-benzimidaz-
ol-2-yl)carbamate
[0672] ##STR155##
[0673] .sup.1H NMR (DMSO-d.sub.6) .delta. 12.0-11.0 (brs, 2H), 8.53
(s, 1H), 8.42 (s, 1H), 7.40 (d, 2H), 7.36 (d, 1H), 7.34 (d, 2H),
6.99 (d, 1H), 6.90 (d, 2H), 6.86 (d, 2H), 6.78 (dd, 1H), 3.74 (s,
3H), 3.71 (s, 3H); MS m/e 448 (M+1).
Example 63
Methyl
N-(5-(4-((4-fluorophenyl)aminocarbonylamino)phenoxy)-1H-benzimidazo-
l-2-yl)carbamate
[0674] ##STR156##
[0675] .sup.1H NMR (DMSO-d.sub.6) .delta. 12.2-11.2 (brs, 2H), 8.66
(s, 1H), 8.61 (s, 1H), 7.46-7.40 (m, 5H), 7.36 (d, 1H), 7.11 (t,
2H), 7.00 (d, 1H), 6.91 (d, 2H), 6.78 (dd, 1H), 3.74 (s, 3H).
.delta.; MS m/e 436 (M+1).
Example 64
Methyl
N-(6-(4-((6-fluoro-3-(trifluoromethyl)phenyl)aminocarbonylamino)phe-
noxy)-benzthiazol-2-yl)carbamate
[0676] ##STR157##
[0677] This example was prepared according to the procedure of
Example 1 except that Intermediate 10G was used as a precursor in
lieu of Intermediate 1.
[0678] .sup.1H NMR (DMSO-d.sub.6) .delta. 12.05 (brs, 1H), 9.18 (s,
1H), 8.87 (d, 1H), 8.62 (dd, 1H), 7.66 (d, 1H), 7.60 (s, 1H), 7.50
(m, 1H), 7.47 (d, 2H), 7.38 (m, 1H), 7.07 (dd, 1H), 7.00 (d, 2H),
3.77 (s, 3H); MS m/e 521 (M+1).
Example 65
Methyl
N-(4-bromo-6-(4-((6-fluoro-3-(trifluoromethyl)phenyl)aminocarbonyla-
mino)phenoxy)benzthiazol-2-yl)carbamate hydrochloride
[0679] ##STR158##
[0680] This example was prepared according to the procedure of
Example 1 except that Intermediate 10H was used as a precursor in
lieu of Intermediate 1.
[0681] .sup.1H NMR (DMSO-d.sub.6) .delta. 12.39 (brs, 1H), 9.27
(brs, 1H), 8.91 (d, 1H), 8.62 (dd, 1H), 7.67 (d, 1H), 7.50 (d, 2H),
7.50 (m, 1H), 7.39 (m, 1H), 7.32 (d, 1H), 7.05 (d, 2H), 3.78 (s,
3H); MS m/e 599, 601 (M+1).
Example 66
Methyl
N-(6-(4-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)
phenoxy)-1-methyl-1H-benzimidazol-2-yl)carbamate
[0682] ##STR159##
[0683] This example was prepared according to the procedure of
Example 1 except that Intermediate 8J was used as a precursor in
lieu of Intermediate 1. .sup.1H NMR (DMSO-d.sub.6) .delta. 9.22
(brs, 1H), 8.92 (brs, 1H), 8.61 (d, 1H), 7.50 (m, 1H), 7.45 (d,
2H), 7.43-7.36 (m, 2H), 7.15 (d, 1H), 6.96 (d, 2H), 6.83 (dd, 1H),
3.62 (s, 3H), 3.46 (s, 3H); MS m/e 518 (M+1).
Example 67
Methyl
N-(5-(4-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)
phenoxy)-1-methyl-1H-benzimidazol-2-yl)carbamate
[0684] ##STR160##
[0685] This example was prepared according to the procedure of
Example 1 except that Intermediate 8C was used as a precursor in
lieu of Intermediate 1. .sup.1H NMR (chloroform-d.sub.1) .delta.
8.65 (brd, 1H), 7.43 (d, 2H), 7.22 (m, 1H), 7.14 (m, 1H), 7.12 (d,
1H), 6.99-6.90 (m, 4H), 3.78 (s, 3H), 3.59 (s, 3H); MS m/e 518
(M+1).
Example 68
Methyl
N-(5-(4-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)
phenoxy)-3a-aza-2-indolyl)carbamate
[0686] ##STR161##
[0687] This example was prepared according to the procedure of
Example 1 except that Intermediate 9K was used as a precursor in
lieu of Intermediate 1. .sup.1H NMR (DMSO-d.sub.6) .delta. 10.28
(brs, 1H), 9.26 (s, 1H), 8.95 (s, 1H), 8.60 (dd, 1H), 8.47 (d, 1H),
7.87 (s, 1H), 7.48 (m, 1H), 7.47 (d, 2H), 7.42 (d, 1H), 7.38 (m,
1H), 7.05 (dd, 1H), 7.02 (d, 2H), 3.68 (s, 3H); MS m/e 504
(M+1).
Example 69
Methyl
N-(5-(4-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)
phenoxy)-3,4-diazaindolin-2-yl)carbamate dihydrochloride
[0688] ##STR162##
[0689] This example was prepared according to the procedure of
Example 1 except that Intermediate 9D was used as a precursor in
lieu of Intermediate 1. .sup.1H NMR (DMSO-d.sub.6) .delta. 9.21 (s,
1H), 8.89 (d, 1H), 8.63 (dd, 1H), 7.79 (d, 1H), 7.49 (m, 1H), 7.47
(d, 2H), 7.38 (m, 1H), 7.05 (d, 2H), 6.73 (d, 1H), 3.76 (s, 3H); MS
m/e 505 (M+1).
Example 70
Methyl
N-(6-(4-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)
phenoxy)-1-(2-(dimethylamino)ethyl)-1H-benzimidazol-2-yl)carbamate
[0690] ##STR163##
[0691] This example was prepared according to the procedure of
Example 1 except that Intermediate 8K was used as a precursor in
lieu of Intermediate 1. .sup.1H NMR (chloroform-d.sub.1) .delta.
9.02 (brs, 1H), 8.59 (dd, 1H), 8.48 (brs, 1H), 7.38 (d, 2H), 7.17
(d, 1H), 7.13 (m, 1H), 7.03 (dd, 1H), 6.86 (d, 2H), 6.84 (d, 1H),
6.76 (dd, 1H), 4.06 (t, 2H), 3.79 (s, 3H), 2.70 (t, 2H), 2.32 (s,
6H); MS m/e 573 (M-1).
Example 71
Methyl
N-(6-(4-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)
phenoxy)-1-(2-(4-morpholino)ethyl)-1H-benzimidazol-2-yl)carbamate
[0692] ##STR164##
[0693] This example was prepared according to the procedure of
Example 1 except that Intermediate 8L was used as a precursor in
lieu of Intermediate 1. .sup.1H NMR (chloroform-d.sub.1) .delta.
8.66-8.59 (br, 2H), 8.15 (d, 1H), 7.38 (d, 2H), 7.19 (d, 1H), 7.18
(m, 1H), 7.07 (dd, 1H), 6.90 (d, 2H), 6.86 (d, 1H), 6.81 (dd, 1H),
4.09 (t, 2H), 3.82 (s, 3H), 3.64 (brs, 4H), 2.70 (t, 2H), 2.50
(brs, 4H); MS m/e 615 (M-1).
Example 72
Methyl
N-(5-(4-((2-chloro-5-(trifluoromethyl)phenyl)aminocarbonylamino)
phenoxy)-3,4-diaza-1H-indole-2-yl)carbamate dihydrochloride
[0694] ##STR165##
[0695] This example was prepared according to the procedure of
Example 1 except that Intermediate 9D was used as a precursor in
lieu of Intermediate 1. .sup.1H NMR (DMSO-d.sub.6) .delta. 9.60 (s,
1H), 8.65 (d, 1H), 8.61 (s, 1H), 7.80 (d, 1H), 7.72 (d, 1H), 7.48
(d, 2H), 7.37 (dd, 1H), 7.05 (d, 2H), 6.73 (d, 1H), 3.76 (s, 3H);
MS m/e 521(M+1), 523 (M+3).
Example 73
Methyl
N-(6-(4-((2-chloro-5-(trifluoromethyl)phenyl)aminocarbonylamino)
phenoxy)-3,4-diaza-1H-indole-2-yl)carbamate dihydrochloride
[0696] ##STR166##
[0697] This example was prepared according to the procedure of
Example 1 except that Intermediate 9E was used as a precursor in
lieu of Intermediate 1. .sup.1H NMR (DMSO-d.sub.6) .delta. 9.62 (s,
1H), 8.64 (d, 1H), 8.60 (s, 1H), 8.09 (d, 1H), 7.72 (d, 1H), 7.49
(d, 2H), 7.47 (d, 1H), 7.37 (dd, 1H), 7.01 (d, 2H), 3.78 (s, 3H);
MS m/e 521, 523 (M+1).
Example 74
Methyl
N-(5-(4-((2,5-dichlorophenyl)aminocarbonylamino)phenoxy)-3,4-diaza--
1H -indole-2-yl)carbamate dihydrochloride
[0698] ##STR167##
[0699] This example was prepared according to the procedure of
Example 1 except that Intermediate 9D was used as a precursor in
lieu of Intermediate 1. .sup.1H NMR (DMSO-d.sub.6) .delta. 9.56 (s,
1H), 8.46 (s, 1H), 8.34 (d, 1H), 7.80 (d, 1H), 7.51 (d, 1H), 7.47
(d, 2H), 7.09 (dd, 1H), 7.05 (d, 2H), 6.73 (d, 1H), 3.76 (s, 3H);
MS m/e 487 (M+1), 489 (M+3).
Example 75
Methyl
N-(6-(4-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)
phenoxy)-3,4-diaza-1H-indole-2-yl)carbamate dihydrochloride
[0700] ##STR168##
[0701] This example was prepared according to the procedure of
Example 1 except that Intermediate 9E was used as a precursor in
lieu of Intermediate 1. .sup.1H NMR (DMSO-d.sub.6) .delta. 9.22 (s,
1H), 8.89 (d, 1H), 8.61 (dd, 1H), 8.08 (s, 1H), 7.53-7.42 (m, 4H),
7.38 (m, 1H), 7.01 (d, 2H), 3.78 (s, 3H); MS m/e 505 (M+1).
Example 76
Methyl
N-(6-(4-((2-chloro-5-(trifluoromethyl)phenyl)aminocarbonylamino)
phenoxy)benzthiazol-2-yl)carbamate
[0702] ##STR169##
[0703] This example was prepared according to the procedure of
Example 1 except that Intermediate 10G was used as a precursor in
lieu of Intermediate 1.
[0704] .sup.1H NMR (DMSO-d.sub.6) .delta. 12.06 (s, 1H), 9.57 (s,
1H), 8.65 (d, 1H), 8.59 (s, 1H), 7.72 (d, 1H), 7.67 (d, 1H), 7.62
(d, 1H), 7.50 (t, 1H), 7.48 (t, 1H), 7.37 (dd, 1H), 7.09 (dd, 1H),
7.02 (t, 1H), 7.00 (t, 1H), 3.77 (s, 3H). 6; MS m/e 537 (M+1), 539
(M+3).
Example 77
6-(4-((2-Fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-3,4--
dihydro-1,4a,5-triazacarbazol-2-one
[0705] ##STR170##
[0706] This example was prepared according to the procedure of
Example 1 except that Intermediate 9I was used as a precursor in
lieu of Intermediate 3. .sup.1H NMR (DMSO-d.sub.6) .delta. 9.22 (d,
1H), 8.92 (s, 1H), 8.62 (d, 1H), 7.83 (d, 1H), 7.50 (m, 1H), 7.48
(d, 2H), 7.38 (m, 1H), 7.07 (d, 2H), 6.71 (d, 1H), 4.12 (t, 2H),
2.83 (t, 2H); MS m/e 501 (M+1).
Example 78
Methyl
N-(5-(4-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)
phenylcarbonyl)-1H-benzimidazol-2-yl)carbamate
[0707] ##STR171##
[0708] This example was prepared according to the procedure of
Example 1 except that Intermediate 11D was used as a precursor in
lieu of Intermediate 3.
[0709] .sup.1H NMR (DMSO-d.sub.6) .delta. 12.5-11.2 (brs, 2H), 9.59
(s, 1H), 9.04 (s, 1H), 8.62 (d, 1H), 7.83 (brs, 1H), 7.75 (d, 2H),
7.65 (d, 2H), 7.55-7.50 (m, 3H), 7.44 (m, 1H), 3.78 (s, 3H); MS m/e
516 (M+1).
Example 79
Methyl
N-(5-(4-((2,5-dichlorophenyl)aminocarbonylamino)phenylsulfinyl)-1H--
benzimidazol-2-yl)carbamate
[0710] ##STR172##
[0711] The title compound was prepared following the procedure for
Example 12 except that the product of Example 57 was used as a
precursor.
[0712] .sup.1H NMR (DMSO-d.sub.6) .delta. 12.4-11.3 (brs, 2H), 9.80
(s, 1H), 8.52 (s, 1H), 8.29 (d, 1H), 7.73 (s, 1H), 7.60 (s, 4H),
7.51 (m, 1H), 7.50 (d, 1H), 7.34 (dd, 1H), 7.11 (dd, 1H), 3.76 (s,
3H); MS m/e 518 (M+1).
Example 80
2-(Dimethylamino)ethyl
N-(5-(4-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)--
1H-benzimidazol-2-yl)carbamate
[0713] ##STR173##
[0714] Heating of a mixture of Example 10 and NaH,
2-(dimethylamino)ethanol gave the title compound:
[0715] .sup.1H NMR (DMSO-d.sub.6) .delta.11.62 (br, 2H), 9.13 (s,
1H), 8.85 (s, 1H), 8.62 (d, 1H), 7.54-7.34 (m, 5H), 7.01 (d, 1H),
6.93 (d, 2H), 6.78 (dd, 1H), 4.25 (dd, 2H), 2.54 (t, 2H), 2.20 (s,
6H); MS m/e 561 (M+1).
Example 81
Benzyl
N-(5-(4-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phe-
noxy)-1H-benzimidazol-2-yl)carbamate
[0716] ##STR174##
[0717] Following the method for Example 1 using Intermediate 3D
instead of Intermediate 3 afforded the title compound.
[0718] .sup.1H NMR (DMSO-d.sub.6) .delta.11.73 (br, 2H), 9.17 (s,
1H), 8.87 (s, 1H), 8.62 (d, 1H), 7.53-7.33 (m, 10H), 7.01 (d, 1H),
6.93 (d, 2H), 6.79 (dd, 1H), 5.24 (s, 2H); MS m/e 580 (M+1).
Example 82
5-(4-((2-Fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1-(m-
ethanesulfonyl)-1H-benzimidazol-2-ylamine
[0719] ##STR175##
[0720] To a mixture of
2-amino-5-(4-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)
phenoxy)-1H-benzimidazole (90 mg, 0.20 mmol) (prepared according to
similar procedures as described for Intermediates 4, 5, and 6 and
Example 22) and triethylamine (30 mg, 0.30 mmol) in DMF/CHCl.sub.3
(3 ml/1 ml) was added methanesulfonyl chloride (30 mg, 0.26 mmol).
After stirring for 3 h at rt, the reaction mixture washed with
water and extracted with CHCl.sub.3. The organic layer was dried
over MgSO.sub.4 and evaporated. The crude material was purified
with silica gel column chromatography (AcOEt) to give the product
of Example 23 (11.0 mg, 11%) and the title compound (34 mg, 25%):
.sup.1H NMR (DMSO-d.sub.6) .delta. 9.14 (s, 1H), 8.85 (s, 1H), 8.62
(d, 1H), 7.51 (d, 1H), 7.47 (d, 1H), 7.46 (d, 2H), 7.38 (m, 1H),
7.02 (brs, 2H), 6.97 (d, 2H), 6.82 (d, 1H), 6.70 (dd, 1H), 3.49 (s,
3H); MS m/e 524 (M+1).
Example 83
N-(5-(4-((2-Fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1-
H -benzimidazol-2-yl)methanesulfonamide
[0721] ##STR176##
[0722]
2-amino-5-(4-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylami-
no) phenoxy)-1H-benzimidazole (the product of Example 22-600 mg)
and methanesulfonyl chloride (5 equiv.) in pyridine was stirred at
room temperature for 2 days. The resulting mixture was treated with
K.sub.2CO.sub.3 (10 equiv.) and H.sub.2O (10 mL) and MeOH (10 mL),
and heated at 60 C for 7 days. The crude solid was collected by
filtration. Recrystallization from hot MeOH afforded the title
compound (280 mg, 40%);
[0723] .sup.1H NMR (DMSO-d.sub.6) .delta. 11.69 (br, 2H), 9.16 (s,
1H), 8.86 (s, 1H), 8.62 (d, 1H), 7.54-7.43 (m, 3H), 7.41-7.36 (m,
1H), 7.23 (d, 1H), 6.97 (d, 2H), 6.86 (d, 1H), 6.80 (dd, 1H), 2.92
(s, 3H); MS m/e 524 (M+1).
Example 84
5-(4-((2-Fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1-(4-
-(methyl)phenylsulfonyl)-1H-benzimidazol-2-ylamine
[0724] ##STR177##
[0725] The title compound was prepared following for Example 24.
The products of Example 24 and 84 are separated by
columnchromatography.
[0726] .sup.1H NMR (DMSO-d.sub.6) .delta. 9.16 (s, 1H), 8.86 (s,
1H), 8.62 (d, 1H), 7.93 (d, 2H), 7.62 (d, 1H), 7.53-7.42 (m, 5H),
7.41-7.36 (m, 1H), 7.25 (br, 2H), 6.96 (d, 2H), 6.70 (d, 1H) 6.66
(dd, 1H), 2.37 (s, 3H); MS m/e 600 (M+1).
Example 85
N-(5-(4-((2-Fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1-
H -benzimidazol-2-yl)-4-methylbenzenesulfonamide
[0727] ##STR178##
[0728] To a mixture of Intermediate 6 (105 mg, 0.25 mmol) and
N',N''-bis-p-tolyl sulfonyl-S-methylisothiourea (100 mg, 0.25 mmol;
prepared from p-toluene sulfonamide, cf. J. Org. Chem., 1998, 53,
3120-3122; Zh. Org. Khim., 1975,11, (3), 574-576) in THF (3 ml) was
added acetic acid (0.5 ml) and stirred for 4 days at 90.degree. C.
Reaction mixture was treated with SPE (NH.sub.2) tube (washed with
MeOH and eluted with NH.sub.3/MeOH). NH.sub.3/MeOH eluent was
collected and purified by column chromatography (hexane-AcOEt, 1:1)
and desired compound was obtained as off-white solid. (2.3 mg,
yield 1.53%)
[0729] .sup.1H NMR (DMSO-d.sub.6) .delta. 11.89 (br, 1H), 11.84
(br, 1H), 9.16 (s, 1H), 8.85 (s, 1H), 8.61 (d, 1H), 7.76 (d, 2H),
7.53-7.43 (m, 3H), 7.41-7.36 (m, 1H), 7.31 (d, 2H), 7.24 (d, 1H),
6.97 (d, 2H), 6.86 (d, 1H), 6.82 (dd, 1H), 2.33 (s, 3H); MS m/e 600
(M+1).
Example 86
N-(6-(4-((2-Fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)
phenoxy)benzthiazol-2-yl)methanesulfonamide
[0730] ##STR179##
[0731] A mixture of 2-fluoro-5-(trifluoromethyl)phenylisocyanate
(47.4 mg, 0.23 mmol) and Intermediate 10D (72 mg, 0.21 mmol) in THF
(3 ml) was stirred over night at 45.degree. C. The reaction mixture
was cooled to room temperature and ether was added and a pale brown
solid was generated. The solid was collected by filtration and
washed with ether and dried in vacuo. 55 mg of desired compound was
obtained. (50% yield)
[0732] .sup.1H NMR (DMSO-d.sub.6) .delta. 12.95 (br, 1H), 9.18 (s,
1H), 8.86 (s, 1H), 8.61 (d, 1H), 7.54-7.44 (m, 4H), 7.41-7.36 (m,
1H), 7.30 (d, 1H), 7.05 (dd, 1H), 6.99 (d, 2H), 2.99 (s, 3H); MS
m/e 541 (M+1).
[0733] Examples 87-102 were prepared according to procedure similar
to Example 25.
Example 87
N-(5-(4-((2-Fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1-
H -benzimidazol-2-yl)-4-(4-methyl-1-piperazinomethyl)benzamide
[0734] ##STR180##
[0735] .sup.1H NMR (DMSO-d.sub.6) .delta. 12.20 (brs, 2H), 9.15 (s,
1H), 8.86 (d, 1H), 8.62 (dd, 1H), 8.08 (d, 2H), 7.44-7.53 (m, 4H),
7.35-7.42 (m, 1H), 7.22-7.34 (brs, 1H), 7.08 (d, 1H), 6.96 (d, 2H),
6.86 (dd, 1H), 6.64-6.76 (brs, 1H), 3.54 (s, 2H), 2.25-2.48 (brs,
4H), 2.18 (s, 4H), 1.76 (s, 3H); MS m/e 663 (M+2).
Example 88
N-(5-(4-((2-Fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1-
H -benzimidazol-2-yl)-3-(pyridine-3-yl)propionamide
[0736] ##STR181##
[0737] .sup.1H NMR (DMSO-d.sub.6) .delta. 12.04 (brd, 1H), 11.57
(brd, 1H), 9.15 (s, 1H), 8.86 (d, 1H), 8.62 (dd, 1H), 8.50 (d, 1H),
8.40 (dd, 1H), 7.69 (d, 1H), 7.35-7.53 (m, 5H), 7.32 (dd, 1H), 7.03
(d, 1H), 6.93 (d, 2H), 6.80 (dd, 1H), 2.96 (t, 2H), 2.80 (t, 2H);
MS m/e 579 (M+1).
Example 89
N-(5-(4-((2-Fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1-
H -benzimidazol-2-yl)-5-benzimidazolecarboxamide
[0738] ##STR182##
[0739] .sup.1H NMR (DMSO-d.sub.6) .delta. 12.80 (brs, 1H), 12.40
(brs, 2H), 9.16 (s, 1H), 8.88 (s, 1H), 8.62 (d, 1H), 8.45 (brs,
1H), 8.39 (dd, 1H), 8.01 (d, 1H), 7.69 (brs, 1H), 7.44-7.53 (m,
4H), 7.36-7.41 (m, 1H), 7.09 (brs, 1H), 6.96 (d, 2H), 6.85 (dd,
1H); MS m/e 590 (M+1).
Example 90
N-(5-(4-((2-Fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1-
H -benzimidazol-2-yl)-4-(pyrrol-1-yl)benzamide
[0740] ##STR183##
[0741] .sup.1H NMR (DMSO-d.sub.6) .delta. 12.26 (brs, 2H), 9.17 (s,
1H), 8.88 (s, 1H), 8.62 (d, 1H), 8.22 (d, 2H), 7.77 (d, 2H), 7.54
(t, 2H), 7.42-7.52 (m, 4H), 7.36-7.41 (m, 1H), 7.08 (brs, 1H), 6.97
(d, 2H), 6.86 (dd, 1H), 6.33 (t, 2H); MS m/e 615 (M+1).
Example 91
N-(5-(4-((2-Fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1-
H -benzimidazol-2-yl)-4-(1H-imidazol-1-yl)benzamide
[0742] ##STR184##
[0743] .sup.1H NMR (DMSO-d.sub.6) .delta. 12.40 (brs, 2H), 9.17 (s,
1H), 8.86 (d, 1H), 8.62 (dd, 1H), 8.43 (s, 1H), 8.27 (d, 2H), 8.05
(d, 1H), 7.80-7.96 (m, 3H), 7.45-7.54 (m, 3H), 7.33-7.42 (m, 1H),
7.16 (s, 1H), 7.07 (brs, 1H), 6.98 (d, 2H), 6.88 (dd, 1H); MS m/e
616 (M+1).
Example 92
N-(5-(4-((2-Fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1-
H -benzimidazol-2-yl)-4-(dimethylamino)butylamide
[0744] ##STR185##
[0745] .sup.1H NMR (DMSO-d.sub.6) .delta.12.02 (br, 1H), 11.56 (br,
1H), 9.18 (s, 1H), 8.90 (s, 1H), 8.62 (s, 1H), 7.53-7.35 (m, 5H),
7.16-6.97 (m, 1H), 6.93 (d, 2H), 6.80 (dd, 1H), 2.45 (t, 2H), 2.24
(t, 2H), 2.13 (s, 6H), 1.75 (m, 2H); MS m/e 559 (M+1).
Example 93
N-(5-(4-((2-Fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1-
H -benzimidazol-2-yl)-3-pyridinecarboxamide
[0746] ##STR186##
[0747] .sup.1H NMR (DMSO-d.sub.6) .delta.12.41 (br, 2H), 9.26 (d,
1H), 9.16 (s, 1H), 8.87 (s, 1H), 8.74 (s, 1H), 8.62 (dd, 1H), 8.43
(m, 1H), 7.57-7.42 (m, 5H), 7.42-7.36 (m, 1H), 7.05 (d, 1H), 6.98
(d, 2H), 6.88 (dd, 1H); MS m/e 551 (M+1).
Example 94
N-(5-(4-((2-Fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1-
H -benzimidazol-2-yl)-2-tetrahydrofurancarboxamide
[0748] ##STR187##
[0749] .sup.1H NMR (DMSO-d.sub.6) .delta. 12.08 (br, 1H), 11.26
(br, 1H), 9.14 (s, 1H), 8.86 (s, 1H), 8.62 (d, 1H), 7.53-7.41 (m,
4H), 7.41-7.35 (m, 1H), 7.06 (br, 1H), 6.94 (d, 2H), 6.83 (dd, 1H),
4.53 (dd, 1H), 3.99 (q, 1H), 3.83 (q, 1H), 2.28-2.18 (m, 1H),
2.04-1.83 (m, 3H); MS m/e 544 (M+1).
Example 95
N-(5-(4-((2-Fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1-
H -benzimidazol-2-yl) (1H-indole-3-carboxamide)
[0750] ##STR188##
[0751] .sup.1H NMR (DMSO-d.sub.6) .delta. 12.25 (brs, 1H), 11.77
(s, 1H), 9.18 (s, 1H), 8.88 (d, 1H), 8.62 (dd, 1H), 7.70 (d, 1H),
7.60 (brs, 1H), 7.43-7.55 (m, 6H), 7.35-7.41 (m, 1H), 7.25 (t, 1H),
7.05-7.12 (m, 2H), 6.97 (d, 2H), 6.86 (dd, 1H); MS m/e 589
(M+1).
Example 96
N-(5-(4-((2-Fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1-
H-benzimidazol-2-yl)(5-(1-pyrrolidino)tetrazol-2-yl)acetamide
[0752] ##STR189##
[0753] .sup.1H NMR (DMSO-d.sub.6) .delta. 12.17 (brs, 2H), 9.14 (s,
1H), 8.85 (d, 1H), 8.61 (dd, 1H), 7.36-7.53 (m, 5H), 7.01 (d, 1H),
6.96 (d, 2H), 6.85 (dd, 1H), 5.49 (s, 2H), 3.30.3.40 (m, 4H,
overlap with d6-DMSO water peak), 1.88-1.97 (m, 4H); MS m/e 625
(M+1).
Example 97
N-(5-(4-((2-Fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1-
H -benzimidazol-2-yl)(1-methyl-1H-imidazol-4-yl)acetamide
[0754] ##STR190##
[0755] .sup.1H NMR (DMSO-d.sub.6) .delta. 12.10 (brs, 1H), 11.85
(brs, 1H), 9.39 (s, 1H), 9.07 (dd, 2H), 7.62-7.84 (m, 7H), 7.33 (s,
1H), 7.21 (d, 2H), 7.11 (dd, 1H), 3.99 (s, 5H); MS m/e 568
(M+1).
Example 98
N-(5-(4-((2-Fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1-
H -benzimidazol-2-yl)(1H-imidazole-4-carboxamide)
dihydrochloride
[0756] ##STR191##
[0757] .sup.1H NMR (DMSO-d.sub.6) .delta. 9.74 (s, 1H), 9.13 (s,
1H), 8.62 (d, 2H), 8.24 (s, 1H), 7.60 (d, 1H), 7.53 (d, 2H), 7.48
(d, 1H), 7.40 (m, 1H), 7.17 (d, 1H), 7.08 (m, 1H), 7.04 (d, 2H),
3.88 (s, 3H); MS m/e 540 (M+1).
Example 99
N-(5-(4-((2-Fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1-
H -benzimidazol-2-yl)benzamide
[0758] ##STR192##
[0759] .sup.1H NMR (DMSO-d.sub.6) .delta. 12.6-12.2 (brs, 2H), 9.15
(s, 1H), 8.87 (d, 1H), 8.62 (dd, 1H), 8.13 (d, 2H), 7.95 (s, 2H),
7.64-7.50 (m, 4H), 7.45 (d, 2H), 7.39 (brm, 1H), 6.97 (d, 2H), 6.86
(dd, 1H); MS m/e 550 (M+1).
Example 100
N-(5-(4-((2-Fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1-
H -benzimidazol-2-yl)-2-thiophenecarboxamide
[0760] ##STR193##
[0761] .sup.1H NMR (DMSO-d.sub.6) .delta. 12.23 (br, 2H), 9.16 (s,
1H), 8.86 (s, 1H), 8.62 (d, 1H), 8.02 (br, 1H), 7.84 (br, 1H),
7.54-7.34 (m, 5H), 7.20 (t, 1H), 7.03 (br, 1H), 6.97 (d, 2H), 6.86
(dd, 1H); MS m/e 556 (M+1).
Example 101
N-(5-(4-((2-Fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1-
H -benzimidazol-2-yl)(4-methyl-1-piperazino)acetamide
[0762] ##STR194##
[0763] .sup.1H NMR (DMSO-d.sub.6) .delta. 11.90-12.25 (brd, 1H),
10.90-11.30 (brs, 1H), 9.13 (s, 1H), 8.85 (d, 1H), 8.62 (dd, 1H),
7.33-7.53 (m, 5H), 6.97-7.18 (brd, 1H), 6.93 (d, 2H), 6.81 (dd,
1H), 3.26 (s, 2H), 2.54-2.62 (bs, 4H), 2.28-2.42 (bs, 4H), 2.16 (s,
3H); MS m/e 584 (M-1).
Example 102
N-(5-(4-((2-Fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1-
H -benzimidazol-2-yl)(dimethylamino)acetamide
[0764] ##STR195##
[0765] .sup.1H NMR (DMSO-d.sub.6) .delta. 12.10 (brs, 1H), 9.14 (s,
1H), 8.85 (d, 1H), 8.62 (dd, 1H), 7.35-7.53 (m, 6H), 6.96 (brs,
1H), 6.95 (d, 2H), 6.85 (dd, 1H), 3.60-3.80 (brs, 2H), 2.55-2.67
(brs, 6H); MS m/e 529 (M-1).
Example 103
[0766] ##STR196##
[0767] Prepared as described by the coupling reaction in Example 25
using 1-piperidine propionic acid. Using these reaction conditions,
elimination of piperidine followed by cyclization to the two
regioisomeric products in a 1:1 ratio occurred in situ without
isolation of the intermediates.
[0768] .sup.1H NMR (DMSO-d.sub.6) .delta. 11.45 (brs, 1H), 11.42
(brs, 1H), 9.12 (s, 2H), 8.84 (d, 2H), 8.61 (dd, 2H), 7.35-7.53 (m,
10H), 7.15 (d, 1H), 7.03 (d, 1H), 6.93 (d, 2H), 6.91 (d, 2H), 6.85
(dd, 1H), 6.80 (dd, 1H), 4.25 (t, 2H), 4.21 (t, 2H), 2.89 (t, 2H),
2.86 (t, 2H); MS m/e 500 (M+1).
[0769] The two regioisomers were separated by successive
recrystallizations from 2-butanone followed by methanol.
Example 103A
6-(4-((2-Fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-3,4--
dihydro-1,4a-diazacarbazol-2-one
[0770] ##STR197##
[0771] .sup.1H NMR (DMSO-d.sub.6) .delta. 9.16 (s, 1H), 8.88 (d,
1H), 8.61 (d, 1H), 7.35-7.53 (m, 5H), 7.15 (d, 1H), 6.93 (d, 2H),
6.80 (dd, 1H), 4.21 (t, 2H), 2.86 (t, 2H); MS m/e 500 (M+1).
Example 103B
7-(4-((2-Fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-3,4--
dihydro-1,4a-diazacarbazol-2-one
[0772] ##STR198##
[0773] .sup.1H NMR (DMSO-d.sub.6) .delta. 11.42 (brs, 1H), 9.17 (s,
1H), 8.90 (s, 1H), 8.61 (dd, 1H), 7.35-7.53 (m, 5H), 7.03 (d, 1H),
6.91 (d, 2H), 6.84 (dd, 1H), 4.25 (t, 2H), 2.89 (t, 2H); MS m/e 500
(M+1).
Example 104
2-(2-(4-Methyl-1-piperazino)ethylamino)-5-(4-((2-fluoro-5-(trifluoromethyl-
)phenyl)aminocarbonylamino)phenoxy)-1H-benzimidazole
[0774] ##STR199##
[0775] To a stirred solution of
N-(5-(4-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)--
1H-benzimidazol-2-yl)(N-4-methyl-1-piperazino)acetamide (the
product of Example 101, 150 mg, 0.26 mmol) in dry THF (10 ml) under
nitrogen was added dropwise a solution of lithium aluminium hydride
in THF (5 ml of a 1M solution, 5 mmol). The reaction was stirred at
room temperature for 5 h and then quenched by slow dropwise
addition of ethyl acetate, followed by methanol and water. The
resulting white precipitate was filtered off through a celite pad
and washed well with methanol. The filtered solution was evaporated
to dryness and partioned between ethyl acetate and water. The
aqueous phase was further extracted by ethyl acetate three times
and then combined ethyl acetate solutions were dried over magnesium
sulfate and concentrated to give the crude product as an oil.
Purification of the crude material by column chromatography
(eluting with AcOEt and incremental amounts of methanolic ammonia
up to 10%) afforded the product as an oil (86 mg, 58% yield).
[0776] .sup.1H NMR (DMSO-d.sub.6) .delta. 10.80 (brs, 1H), 9.10 (s,
1H), 8.84 (d, 1H), 8.61 (dd, 1H), 7.49 (t, 1H), 7.35-7.43 (m, 4H),
7.08 (d, 1H), 6.88 (d, 2H), 6.70 (d, 1H), 6.41 (brs, 1H), 2.25-2.45
(m, 4H), 2.15 (s, 4H), 1.76 (s, 7H); MS m/e 572 (M+1).
Example 105
2-(2-(Dimethylamino)ethylamino)-5-(4-((2-fluoro-5-(trifluoromethyl)phenyl)-
aminocarbonylamino)phenoxy)-1H-benzimidazole
[0777] ##STR200##
[0778] The title compound was prepared as described in Example 104
using the product of Example 102;
[0779] .sup.1H NMR (DMSO-d.sub.6) .delta. 10.75 (brs, 1H), 9.10 (s,
1H), 8.85 (d, 1H), 8.61 (dd, 1H), 7.49 (t, 1H), 7.34-7.44 (m, 4H),
7.08 (d, 1H), 6.88 (d, 2H), 6.55 (dd, 1H), 6.43 (brs, 1H), 3.53 (t,
2H, overlap with d6-DMSO water peak), 2.44 (t, 2H), 3.19 (s, 6H);
MS m/e 517 (M+1).
Example 106
2-(3-(4-methyl-1-piperazino)propylamino)-5-(4-((2-fluoro-5-(trifluoromethy-
l)phenyl)aminocarbonylamino)phenoxy)-1H-benzimidazole
[0780] ##STR201##
[0781] To a stirred solution of thiophosgene (1.47 g, 12.8 mmol) in
acetone (10 ml) and dichloromethane (10 ml), cooled in an ice bath
under nitrogen, was added dropwise a solution of
1-(3-aminopropyl)-4-methylpiperazine (1.0 g, 6.4 mmol) in acetone
(5 ml) and dichloromethane (5 ml) over 10 minutes. The reaction was
stirred at room temperature for 3 h and then diluted with
dichloromethane (50 ml) and washed with aqueous sodium bicarbonate
solution (25 ml). The aqueous phase was further extracted by
dichloromethane twice and then combined dichloromethane solutions
were dried over magnesium sulfate and concentrated to give a brown
oil (0.37 g, 1.86 mmol, 0.29% yield) which was used without
purification. The crude oil was dissolved in acetonitrile (30 ml)
and
4-(4-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)phen-
ylene-1,2-diamine (intermediate 6) (0.20 g, 0.47 mmol) was added.
The stirred reaction was heated to reflux for 24 hours. On cooling,
the reaction solution was decanted off to leave behind an insoluble
dark oil residue. The acetonitrile was evaporated off to give a
crude oil. Purification of the crude material was achieved by two
column chromatographic separations. The first eluting with
dichloromethane and incremental amounts of methanolic ammonia up to
15%, and the second eluting with AcOEt and incremental amounts of
methanolic ammonia up to 15%, to afford the product as an oil (79
mg, 28% yield) which solidified on standing.
[0782] .sup.1H NMR (DMSO-d.sub.6) .delta. 10.76 (brs, 1H), 9.09 (s,
1H), 8.83 (d, 1H), 8.61 (dd, 1H), 7.49 (t, 1H), 7.35-7.43 (m, 3H),
7.07 (d, 1H), 6.88 (d, 2H), 6.76 (d, 1H), 6.63 (brs, 1H), 6.56
(brs, 1H), 2.22-2.43 (m, 10H), 2.15 (s, 4H), 1.65-1.78 (m, 3H); MS
m/e 586 (M+1).
Example 107
Methyl
N-(5-(5-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)-1--
oxo-2-pyridyloxy)-1H-benzimidazol-2-yl)carbamate
[0783] ##STR202##
[0784] The title compound was prepared following the procedure for
Example 12 using the compound of Example 37.
[0785] .sup.1H NMR (DMSO-d.sub.6) .delta. 12.2-11.2 (brs, 2H), 9.42
(s, 1H), 9.06 (s, 1H), 8.68 (s, 1H), 8.53 (d, 1H), 7.53 (t, 1H),
7.45 (brs, 1H), 7.39 (d, 1H), 7.30 (d, 1H), 7.11 (d, 1H), 7.02 (s,
1H), 6.80 (d, 1H), 3.75 (s, 3H); MS m/e 521 (M+1).
Example 108
Methyl
N-(5-(5-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)-2--
pyridyloxy)-1H-benzimidazol-2-yl)carbamate dimethanesulfonic
acid
[0786] ##STR203##
[0787] The product of Example 37 was converted into the salt
form.
[0788] .sup.1H NMR (DMSO-d.sub.6) .delta. 9.31 (brs, 1H), 9.02 (d,
1H), 8.56 (dd, 1H), 8.21 (d, 1H), 8.05 (dd, 1H), 7.62 (d, 1H), 7.51
(m, 1H), 7.41 (m, 2H), 7.42 (m, 1H), 7.33 (d, 1H), 7.17 (dd, 1H),
7.08 (d, 1H), 3.89 (s, 6H); MS m/e 505 (M+1).
Example 109
Methyl
N-(5-(5-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)-2--
pyridyloxy)-1H-benzimidazol-2-yl)carbamate maleate
[0789] ##STR204##
[0790] The product of Example 37 was converted into the salt
form.
[0791] .sup.1H NMR (DMSO-d.sub.6) .delta. 9.21 (s, 1H), 8.95 (d,
1H), 8.57 (dd, 1H), 8.15 (d, 1H), 8.00 (dd, 1H), 7.51 (m, 1H), 7.41
(m, 2H), 7.13 (d, 1H), 6.95 (d, 1H), 6.86 (dd, 1H), 6.24 (s, 2H),
3.77 (s, 3H); MS m/e 505 (M+1).
Example 110
N-(6-(2-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)-5-pyridyl-
oxy)-1-benzyl-1H-benzimidazol-2-yl)acetamide
[0792] ##STR205##
[0793] Coupling of Intermediate 12C with 2-nitro-5-bromopyridine
and subsequent hydrogenation gave
N-(6-(2-amino-5-pyridyloxy)-1-benzyl-1H-benzimidazol-2-yl)acetamide.
Following the procedure for Example 1 provides the title
compound.
[0794] .sup.1H NMR (DMSO-d.sub.6) .delta. 10.62 (brs, 1H), 9.92 (s,
1H), 8.67 (dd, 1H), 8.02 (dd, 1H), 7.41-7.62 (m, 5H), 7.22-7.34 (m,
3H), 7.16 (brs, 2H), 6.91 (dd, 1H), 5.30 (s, 2H), 2.10 (s, 3H); MS
m/e 579 (M+1).
[0795] Examples 111 and 112 are prepared according to the procedure
for Example 1 using Intermediate 15B.
Example 111
Methyl-N-(5-(5-((2-chloro-5-(trifluoromethyl)phenyl)aminocarbonylamino)-2--
pyridyloxy)-1H-benzimidazol-2-yl)carbamate
[0796] ##STR206##
[0797] .sup.1H NMR (DMSO-d.sub.6) .delta. 12.2-11.2 (brs, 2H), 9.61
(s, 1H), 8.66 (s, 1H), 8.61 (d, 1H), 8.15 (d, 1H), 8.01 (dd, 1H),
7.72 (dd, 1H), 7.38 (m, 2H), 7.11 (d, 1H), 6.94 (d, 1H), 6.83 (dd,
1H), 3.76 (s, 3H); MS m/e 521 (M+1).
Example 112
Methyl
N-(5-(5-((2,5-dichlorophenyl)aminocarbonylamino)-2-pyridyloxy)-1H-b-
enzimidazol-2-yl)carbamate dihydrochloride
[0798] ##STR207##
[0799] .sup.1H NMR (DMSO-d.sub.6) .delta. 10.35 (s, 1H), 8.76 (s,
1H), 8.29 (d, 1H), 8.24 (d, 1H), 8.03 (dd, 1H), 7.63 (d, 1H), 7.50
(d, 1H), 7.35 (d, 1H), 7.16 (dd, 1H), 7.11-7.07 (m, 2H), 3.88 (s,
3H); MS m/e 487 (M+1).
Example 113
6-(6-((2-Fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)-3-pyridyloxy-
)-1-benzyl-1H-benzimidazol-2-ylamine
[0800] ##STR208##
[0801] The title compound was prepared according to the procedure
for Example 1 using Intermediate 12E, followed by acidic
hydrolysis.
[0802] .sup.1H NMR (DMSO-d.sub.6) .delta. 10.69 (brs, 1H), 9.87
(brs, 1H), 8.65 (dd, 1H), 7.92 (d, 1H), 7.51 (m, 2H), 7.41 (m, 2H),
7.31 (m, 2H), 7.23 (m, 1H), 7.18 (m, 1H), 7.12 (d, 1H), 6.89 (d,
1H), 6.67 (d, 1H), 6.56 (brs, 2H), 5.23 (s, 2H); MS m/e 537
(M+1).
Example 114
N-(6-(6-((2-Fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)-3-pyridyl-
oxy)-1-benzyl-1H-benzimidazol-2-yl)methanesulfonamide
[0803] ##STR209##
[0804] To the suspension of the product of Example 113 in dry THF,
BOC.sub.2O (2 eq.) was added at room temperature. The solution
becomes clear. After the reaction completion, the solvent was
removed then Si-column chromatograpy was performed by
CHCl.sub.3-MeOH (1-3%) as eluent.
5-(6-((2-fluloro-5-(trifluoromethyl)phenyl)aminocarbonylamino)-3--
pyridyloxy)-3-benzyl-1-tert-butoxycarbonyl-2-imino
benzimidazolidine was obtained as amorphous in good yield.
[0805] The compound (100 mg) was dissolved to pyridine, and
mesylchloride was dropped slowly (5-7 drops) to it at 0.degree. C.
After overnight stirring, the mixture was quenched to the ice-water
and extracted with AcOEt then solvent was removed. To the obtained
crude mixture. TFA (1 ml) was added. After stirring 30 min at room
temperature, TFA was removed. The obtained residue was charged to
the amino-column chromatography. 5-7% MeOH--CHCl.sub.3 eluent was
used to get the title compound.
[0806] .sup.1H NMR (DMSO-d.sub.6) .delta. 11.84 (brs, 1H), 10.64
(brs, 1H), 9.92 (brs, 1H), 8.66 (dd, 1H), 8.00 (brs, 1H), 7.48 (m,
4H), 7.33 (m, 5H), 7.17 (m, 1H), 5.86 (dd, 1H), 5.18 (s, 2H), 2.98
(s, 3H); MS m/e 615 (M+1).
Example 115
Methyl
N-(6-(4-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phe-
noxy)benzoxazol-2-yl)carbamate
[0807] ##STR210##
[0808] To a mixture of
5-(4-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonyl
amino)phenyloxy)benz-3-oxazol-2-ylamine (Intermediate 11B--67.0 mg,
0.15 mmol) in pyridine (2 mL) was dropwise added excess amount of
ClCO.sub.2Me (ca 0.23 mL) at room temperature. The mixture was
added water and stirred at room temperature overnight. The mixture
was extracted with ethyl acetate. The organic layer washed with
NaHCO.sub.3 (aq) and brine then dried over Na.sub.2SO.sub.4. After
evaporation, residual solid washed with MeOH and dried under
reduced pressure to give the title compound (46.1 mg, 61%):
[0809] .sup.1H NMR (DMSO-d.sub.6) .delta. 9.17 (brs, 1H), 8.86 (d,
1H), 8.62 (dd, 1H), 7.49 (m, 2H), 7.46 (d, 2H), 7.38 (m, 1H), 7.26
(brs, 1H), 6.99 (d, 2H), 6.92 (dd, 1H), 3.70 (s, 3H); MS m/e 505
(M+1).
[0810] The following compounds (Example 116-132) were prepared
according to the procedures described for Example 1.
Example 116
Methyl
N-(5-(3-((2-(trifluoromethoxy)phenyl)aminocarbonylamino)phenoxy)-1H
-benzimidazol-2-yl)carbamate
[0811] ##STR211##
[0812] .sup.1H NMR (DMSO-d.sub.6) .delta. 12.2-11.2 (brs, 2H), 9.39
(s, 1H), 8.42 (s, 1H), 8.19 (d, 1H), 7.41 (d, 1H), 7.36 (d, 1H),
7.31 (t, 1H), 7.26 (t, 1H), 7.09 (m, 1H), 6.83 (dd, 1H), 6.60 (dd,
1H), 3.75 (t, 3H); MS m/e 502 (M+1)
Example 117
Methyl
N-(5-(3-((4-(trifluoromethylthio)phenyl)aminocarbonylamino)phenoxy)-
-1H-benzimidazol-2-yl)carbamate
[0813] ##STR212##
[0814] .sup.1H NMR (DMSO-d.sub.6) .delta. 12.2-11.2 (brs, 2H), 9.17
(s, 1H), 9.04 (s, 1H), 7.58 (q, 4H), 7.41 (d, 1H), 7.24 (t, 1H),
7.15 (s, 1H), 7.08 (m, 2H), 6.83 (dd, 1H), 6.59 (dd, 1H), 3.75 (s,
3H); MS m/e 518 (M+1)
Example 118
Methyl
N-(5-(3-((2-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1H
-benzimidazol-2-yl)carbamate
[0815] ##STR213##
[0816] .sup.1H NMR (DMSO-d.sub.6) .delta. 12.2-11.2 (brs, 2H), 9.49
(s, 1H), 8.04 (s, 1H), 7.87 (d, 1H), 7.65 (d, 1H), 7.60 (t, 1H),
7.39 (d, 1H), 7.27-7.22 (m, 2H), 7.12-7.07 (m, 3H), 6.82 (dd, 1H),
6.60 (dd, 1H), 3.74 (s, 3H); MS m/e 486 (M+1)
Example 119
Methyl
N-(5-(3-((4-chloro-3-(trifluoromethyl)phenyl)aminocarbonylamino)phe-
noxy)-1H-benzimidazol-2-yl)carbamate
[0817] ##STR214##
[0818] .sup.1H NMR (DMSO-d.sub.6) .delta. 12.2-11.2 (brs, 2H), 9.29
(s, 1H), 9.08 (dd, 1H), 8.94 (d, 1H), 7.90 (m, 1H), 7.53 (t, 1H),
7.42 (d, 1H), 7.27 (t, 1H), 7.14 (d, 1H), 7.09 (m, 2H), 6.84 (dd,
1H), 6.62 (dd, 1H), 3.75 (s, 3H); MS m/e 520 (M+1)
Example 120
Methyl
N-(5-(3-((3-iodophenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol--
2-yl)carbamate
[0819] ##STR215##
[0820] .sup.1H NMR (DMSO-d.sub.6) .delta. 12.2-11.2 (brs, 2H), 8.87
(s, 1H), 8.79 (s, 1H), 7.94 (s, 1H), 7.41 (d, 1H), 7.31 (d, 2H),
7.23 (t, 1H), 7.11-7.03 (m, 4H), 6.83 (dd, 1H), 6.57 (d, 1H), 3.75
(s, 3H); MS m/e 544 (M+1)
Example 121
Methyl
N-(5-(3-((2,5-dichlorophenyl)aminocarbonylamino)phenoxy)-1H-benzimi-
dazol-2-yl)carbamate
[0821] ##STR216##
[0822] .sup.1H NMR (DMSO-d.sub.6) .delta. 12.2-11.2 (brs, 2H), 9.57
(s, 1H), 8.38 (s, 1H), 8.26 (d, 1H), 7.48 (d, 1H), 7.41 (d, 1H),
7.27 (t, 1H), 7.14 (d, 1H), 7.08 (m, 2H), 7.04 (s, 1H), 6.84 (dd,
1H), 6.62 (d, 1H), 3.75 (s, 1H); MS m/e 486 (M+1), 488 (M+3)
Example 122
Methyl
N-(5-(4-((3-phenoxyphenyl)aminocarbonylamino)phenylthio)-1H-benzimi-
dazol-2-yl)carbamate
[0823] ##STR217##
[0824] .sup.1H NMR (DMSO-d.sub.6) 6; 12.0-11.5 (brs, 2H), 9.00 (s,
1H), 8.94 (s, 1H), 7.41-7.38 (m, 6H), 7.27 (t, 1H), 7.25 (t, 1H),
7.20 (d, 2H), 7.16-7.08 (m, 3H), 7.03 (d, 2H), 6.60 (dd, 1H), 3.73
(s, 3H), MS m/e 526 (M+1)
Example 123
Methyl
N-(5-(4-((3-phenoxyphenyl)aminocarbonylamino)phenoxy)-1H-benzimidaz-
ol-2-yl)carbamate
[0825] ##STR218##
[0826] .sup.1H NMR (DMSO-d.sub.6) 6; 12.0-11.2 (brs, 2H), 8.76 (s,
1H), 8.60 (s, 1H), 7.42-7.35 (m, 5H), 7.27 (t, 1H), 7.25 (s, 1H),
7.17-7.10 (m, 2H), 7.03 (d, 2H), 6.98 (d, 1H), 6.90 (d, 2H), 6.78
(dd, 1H), 6.60 (dd, 1H), 3.75 (s, 3H), MS m/e 510 (M+1)
Example 124
Methyl
N-(5-(3-((2-phenoxyphenyl)aminocarbonylamino)phenoxy)-1H-benzimidaz-
ol-2-yl)carbamate
[0827] ##STR219##
[0828] .sup.1H NMR (DMSO-d.sub.6) .delta.; 12.0-11.2 (brs, 2H),
9.34 (s, 1H), 8.40 (s, 1H), 7.42-7.36 (m, 3H), 7.22 (t, 1H), 7.14
(t, 1H), 7.10-7.05 (m, 4H), 7.01 (d, 2H), 6.94 (td, 1H), 6.82 (m,
2H), 6.57 (d, 1H), 3.75 (s, 3H), MS m/e 510 (M+1)
Example 125
Methyl
N-(5-(3-((4-phenoxyphenyl)aminocarbonylamino)phenoxy)-1H-benzimidaz-
ol-2-yl)carbamate
[0829] ##STR220##
[0830] .sup.1H NMR (DMSO-d.sub.6) .delta.; 12.0-11.2 (brs, 2H),
8.90 (s, 1H), 8.78 (s, 1H), 7.43-7.40 (m, 3H), 7.36 (d, 1H), 7.34
(d, 1H), 7.22 (t, 1H), 7.16 (d, 1H), 7.08 (m, 3H), 6.97-6.93 (m,
4H), 6.83 (dd, 1H), 6.55 (dd, 1H), 3.75 (s, 3H), MS m/e 510
(M+1)
Example 126
Methyl
N-(5-(3-((5-indanyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-y-
l)carbamate
[0831] ##STR221##
[0832] .sup.1H NMR (DMSO-d.sub.6) .delta.; 12.0-11.2 (brs, 2H),
8.68 (s, 1H), 8.43 (s, 1H), 7.40 (d, 1H), 7.32 (s, 1H), 7.21 (t,
1H), 7.11 (t, 1H), 7.08 (m, 4H), 6.82 (dd, 1H), 6.55 (d, 1H), 3.75
(s, 3H), 2.79 (m, 4H), 1.98 (m, 2H), MS m/e 458 (M+1)
Example 127
Methyl
N-(5-(4-((5-indanyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-y-
l)carbamate
[0833] ##STR222##
[0834] .sup.1H NMR (DMSO-d.sub.6) .delta.; 12.0-11.2 (brs, 2H),
8.57 (s, 1H), 8.48 (s, 1H), 7.41 (d, 2H), 7.37 (m, 2H), 7.11 (m,
2H), 6.99 (d, 1H), 6.90 (d, 2H), 6.78 (dd, 1H), 3.75 (s, 3H), 2.80
(quint, 4H), 1.99 (m, 2H), MS m/e 458 (M+1)
Example 128
Methyl
N-(5-(4-((5-tert-butylisoxazole-3-yl)aminocarbonylamino)phenoxy)-1H-
-benzimidazol-2-yl)carbamate
[0835] ##STR223##
[0836] .sup.1H NMR (DMSO-d.sub.6) .delta. 11.8-11.4 (brs, 2H), 9.46
(s, 1H), 8.76 (s, 1H), 7.42 (d, 2H), 7.38 (d, 1H), 7.01 (d, 1H),
6.92 (d, 2H), 6.79 (dd, 1H), 6.48 (s, 1H), 3.74 (s, 3H), 1.29 (s,
9H); MS m/e 465 (M+1)
Example 129
Methyl
N-(5-(3-((5-tert-butylisoxazole-3-yl)aminocarbonylamino)phenoxy)-1H-
-benzimidazol-2-yl)carbamate
[0837] ##STR224##
[0838] .sup.1H NMR (DMSO-d.sub.6) .delta. 12.0-11.2 (brs, 2H), 9.40
(s, 1H), 8.88 (s, 1H), 7.40 (d, 1H), 7.25 (t, 1H), 7.13 (t, 1H),
7.07 (m, 2H), 6.82 (dd, 1H), 6.61 (dd, 1H), 6.46 (s, 1H), 3.75 (s,
3H), 1.27 (s, 9H); MS m/e 465 (M+1)
Example 130
Methyl
N-(5-(4-((5-tert-butylisoxazole-3-yl)aminocarbonylamino)phenylthio)-
-1H-benzimidazol-2-yl)carbamate
[0839] ##STR225##
[0840] .sup.1H NMR (DMSO-d.sub.6) .delta. 12.2-11.2 (brs, 2H), 9.49
(s, 1H), 8.89 (s, 1H), 7.42 (d, 2H), 7.40 (m, 2H), 7.20 (d, 2H),
7.11 (dd, 1H), 6.49 (s, 1H), 3.75 (s, 3H), 1.28 (s, 9H); MS m/e 481
(M+1)
Example 131
Methyl
N-(5-(3-((3-phenyl-1,2,4-thiadiazol-5-yl)aminocarbonylamino)phenoxy-
)-1H-benzimidazol-2-yl)carbamate
[0841] ##STR226##
[0842] .sup.1H NMR (DMF-d.sub.7) .delta. 12.4-11.2 (brs, 2H), 9.84
(brs, 1H), 8.22-8.20 (m, 2H), 7.50 (m, 4H), 7.38 (brs, 1H),
7.36-7.34 (m, 2H), 7.22 (brs, 1H), 6.92 (dd, 1H), 6.71 (m, 1H),
3.81 (s, 1H); MS m/e 502 (M+1)
Example 132
Methyl
N-(5-(3-((1-naphtyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-y-
l)carbamate
[0843] ##STR227##
[0844] .sup.1H NMR (DMSO-d.sub.6) .delta. 12.0-11.2 (brs, 2H), 9.14
(s, 1H), 8.70 (s, 1H), 8.08 (d, 1H), 7.95 (d, 1H), 7.92 (d, 1H),
7.62 (d, 1H), 7.55 (m, 2H), 7.45 (t, 1H), 7.41 (d, 1H), 7.26 (t,
1H), 7.16-7.14 (m, 2H), 7.10 (d, 1H), 6.84 (dd, 1H), 6.59 (d, 1H),
3.75 (s, 3H); MS m/e 468 (M+1)
[0845] The compound of Example 22 was treated with
2-fluoro-5-trifluoromethylphenyl, 4-chrolophenyl, and
N,N-dimethylaminophenyl isocyanate in THF to give compounds of
Example 133, 134, and 135 respectively.
Example 133
1-(5-(4-((2-Fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1-
H
-benzimidazol-2-yl)-3-(2-fluoro-5-(trifluoromethyl)phenyl)urea
[0846] ##STR228##
[0847] .sup.1H NMR (DMSO-d.sub.6) .delta.; 12.0-11.3 (brs, 1H),
10.7-10.1 (brs, 1H), 8.92 (s, 1H), 8.63 (s, 1H), 8.46 (d, 1H), 8.39
(d, 1H), 7.29 (m, 4H), 7.22 (d, 2H), 7.18-7.14 (m, 3H), 6.72 (d,
2H), 6.58 (dd, 1H), MS m/e 651 (M+1)
Example 134
1-(5-(4-((2-Fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1-
H -benzimidazol-2-yl)-3-(4-chlorophenyl)urea
[0848] ##STR229##
[0849] .sup.1H NMR (DMSO-d.sub.6) .delta.; 9.77 (brs, 1H), 9.14 (s,
1H), 8.86 (brs, 1H), 8.62 (d, 1H), 7.61 (d, 2H), 7.50 (m, 1H), 7.44
(d, 2H), 7.39 (m, 2H), 7.34 (d, 2H), 6.99 (d, 1H), 6.95 (d, 2H),
6.79 (dd, 1H), MS m/e 599 (M+1), 601 (M+3)
Example 135
1-(5-(4-((2-Fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1-
H -benzimidazol-2-yl)-3-(4-(N,N-dimethylamino)phenyl)urea
[0850] ##STR230##
[0851] .sup.1H NMR (DMSO-d.sub.6) .delta.; 9.30 (brs 1H), 9.13 (s,
1H), 8.85 (s, 1H), 8.62 (d, 1H), 7.50 (t, 1H), 7.43 (d, 2H), 7.37
(brm, 2H), 7.34 (d, 2H), 7.00 (s, 1H), 6.93 (d, 2H), 6.76 (d, 1H),
6.72 (d, 2H), 2.85 (s, 6H), MS m/e 608 (M+1)
Example 136
1-(6-(4-((4-Chloro-3-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)be-
nzthiazol-2-yl)-3-(butyl)urea
[0852] ##STR231##
[0853] The title compound and the next compound (Example 137) were
prepared according to the procedures described for Example 1, using
Intermediate 13B.
[0854] .sup.1H NMR (DMSO-d.sub.6) .delta.; 10.57 (s, 1H), 9.15 (s,
1H), 8.84 (s, 1H), 8.11 (d, 1H), 7.65-7.63 (m, 2H), 7.58 (d, 1H),
7.46 (d, 2H), 7.02 (dd, 1H), 6.98 (d, 2H), 6.72 (brs, 1H), 3.15 (q,
2H), 1.46 (quint, 2H), 1.31 (sextet, 2H), MS m/e 578 (M+1), 580
(M+3).
Example 137
1-(6-(4-((2-Fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)be-
nzthiazol-2-yl)-3-(butyl)urea
[0855] ##STR232##
[0856] .sup.1H NMR (DMSO-d.sub.6) .delta.; 10.58 (brs, 1H), 9.17
(s, 1H), 8.87 (s, 1H), 8.62 (dd, 1H), 7.59 (d, 1H), 7.54 (d, 1H),
7.52-7.47 (m, 1H), 7.47 (d, 2H), 7.39 (m, 1H), 7.03 (dd, 1H), 6.99
(d, 2H), 6.74 (brs, 1H), 3.15 (q, 2H), 1.47 (quint, 2H), 1.31
(sextet, 2H), MS m/e 562 (M+1).
Example 138
N-(5-(4-((5-Methylisoxazol-3-yl)aminocarbonylamino)phenoxy)-1H-benzimidazo-
l-2-yl)acetamide
[0857] ##STR233##
[0858] Intermediate 14F was treated with 23:2:75 (v/v/v)
TFA/H.sub.2O/DCM (1 mL) for ca. 1 h. The solution containing the
released material was collected. The resin washed with DCM
(3.times., 1 mL each). The washings were collected and combined
with the original filtrate. Evaporation of the solvent in vacuo
yielded a dark sticky solid. The cleaving was repeated two more
times and the materials obtained after each time were combined. The
crude material was dissolved in DMSO and purified with
reverse-phase preparative Gilson HPLC system to yield the desired
benzimidazole.
[0859] .sup.1H NMR (DMF-d.sub.7) .delta. 10.79 (br s, 1H), 10.40
(br s, 1H), 7.64 (d, J=8.8 Hz, 2H), 7.49 (br s, 1H), 7.15 (br s,
1H), 6.96 (d, J=8.8 Hz, 2H), 6.87 (dd, J=8.6, 2.5 Hz, 1H), 6.62 (s,
1H), 2.38 (s, 3H), 2.24 (s, 3H); MS m/e 407 (M+1).
[0860] The following compounds (Example 139-180) were prepared in a
combinatorial chemistry format using the same procedure as Example
138. In most cases, the benzimidazoles thus obtained were light
colored after HPLC purification.
Example 139
N-(5-(4-((Thiazol-2-yl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)ac-
etamide
[0861] ##STR234##
[0862] .sup.1H NMR (DMF-d.sub.7) .delta. 12.12 (br s, 1H), 11.61
(br s, 1H), 9.58 (br s, 1H), 7.60 (d, J=8.8 Hz, 2H), 7.50 (br s,
1H), 7.39 (d, J=3.5 Hz, 1H), 7.27-7.06 (m, 2H), 7.00 (d, J=8.8 Hz,
2H), 6.88 (dd, J=8.6, 2.5 Hz, 1H), 2.25 (s, 3H); MS m/e 409
(M+1).
Example 140
N-(5-(4-((1,3,4-Thiadiazol-2-yl)aminocarbonylamino)phenoxy)-1H-benzimidazo-
l-2-yl)acetamide
[0863] ##STR235##
[0864] .sup.1H NMR (DMF-d.sub.7) .delta. 12.12 (br s, 1H), 11.56
(br s, 1H), 9.80 (br s, 1H), 9.09 (s, 1H) 7.66 (m, 2H), 7.50 (br s,
1H), 7.19 (br s, 1H), 7.01 (d, J=8.8 Hz, 2H), 6.88 (dd, J=8.6, 2.3
Hz, 1H), 2.25 (s, 3H); MS m/e 410 (M+1).
Example 141
N-(5-(4-((4-Methylthiazol-2-yl)aminocarbonylamino)phenoxy)-1H-benzimidazol-
-2-yl)acetamide
[0865] ##STR236##
[0866] .sup.1H NMR (DMF-d.sub.7) .delta. 9.61 (s, 1H), 7.60 (d,
J=9.0 Hz, 2H), 7.50 (br s, 1H), 7.16 (br s, 1H), 7.00 (d, J=9.0 Hz,
2H), 6.88 (dd, J=8.6, 2.5 Hz, 1H), 6.65 (s, 1H), 2.24 (m, 6H); MS
m/e 423 (M+1).
Example 142
N-(5-(4-((5-Methylthiazol-2-yl)aminocarbonylamino)phenoxy)-1H-benzimidazol-
-2-yl)acetamide
[0867] ##STR237##
[0868] .sup.1H NMR (DMF-d.sub.7) .delta. 9.56 (s, 1H), 7.60 (d,
J=8.8 Hz, 2H), 7.51 (br s, 1H), 7.16 (br s, 1H), 7.04 (s, 1H), 6.99
(d, J=8.8 Hz, 2H), 6.88 (dd, J=8.5, 2.4 Hz, 1H), 2.35 (s, 3H), 2.25
(s, 3H); MS m/e 423 (M+1).
Example 143
N-(5-(4-((5-Methyl-1,3,4-thiadiazol-2-yl)aminocarbonylamino)phenoxy)-1H-be-
nzimidazol-2-yl)acetamide
[0869] ##STR238##
[0870] .sup.1H NMR (DMF-d.sub.7) .delta. 12.12 (br s, 1H), 11.59
(br s, 1H), 9.70 (br s, 1H), 7.65 (m, 2H), 7.50 (br s, 1H), 7.21
(br s, 1H), 7.00 (d, J=8.8 Hz, 2H), 6.88 (dd, J=8.6, 2.3 Hz, 1H),
2.62 (s, 3H), 2.25 (s, 3H); MS m/e 424 (M+1).
Example 144
N-(5-(4-((5-Ethyl-1,3,4-thiadiazol-2-yl)aminocarbonylamino)phenoxy)-1H-ben-
zimidazol-2-yl)acetamide
[0871] ##STR239##
[0872] .sup.1H NMR (DMF-d.sub.7) .delta. 12.15 (br s, 1H), 11.59
(br s, 1H), 9.29 (s, 1H), 7.60 (d, J=8.8 Hz, 2H), 7.53 (br s, 1H),
7.19 (br s, 1H), 7.01 (d, J=8.8 Hz, 2H), 6.89 (dd, J=8.6, 2.3 Hz,
1H), 3.00 (q, J=7.6 Hz, 2H), 2.25 (s, 3H), 1.34 (t, J=7.6 Hz, 3H);
MS m/e 438 (M+1).
Example 145
N-(5-(4-((5-Cyclopropyl-1,3,4-thiadiazol-2-yl)aminocarbonylamino)phenoxy)--
1H-benzimidazol-2-yl)acetamide
[0873] ##STR240##
[0874] .sup.1H NMR (DMF-d.sub.7) .delta. 11.63 (br s, 1H), 9.28 (s,
1H), 7.59 (d, J=9.0 Hz, 2H), 7.53 (br d, J=8.4 Hz, 1H), 7.18 (br s,
1H), 7.01 (d, J=9.0 Hz, 2H), 6.89 (dd, J=8.6, 2.3 Hz, 1H), 2.38 (m,
1H), 2.25 (s, 3H), 1.16 (m, 2H), 0.99 (m, 2H); MS m/e 450
(M+1).
Example 146
N-(5-(4-((4-tert-Butylthiazol-2-yl)aminocarbonylamino)phenoxy)-1H-benzimid-
azol-2-yl)acetamide
[0875] ##STR241##
[0876] .sup.1H NMR (DMF-d.sub.7) .delta. 12.13 (br s, 1H), 9.50 (br
s, 1H), 7.60 (d, J=8.9 Hz, 2H), 7.46 (m, 1H), 7.21-7.13 (m, 1H),
7.01 (d, J=8.9 Hz, 2H), 6.89 (dd, J=8.6, 2.5 Hz, 1H), 6.68 (s, 1H),
2.25 (s, 3H), 1.27 (s, 9H); MS m/e 465 (M+1).
Example 147
N-(5-(4-((5-tert-Butyl-1,3,4-thiadiazol-2-yl)aminocarbonylamino)phenoxy)-1-
H-benzimidazol-2-yl)acetamide
[0877] ##STR242##
[0878] .sup.1H NMR (DMF-d.sub.7) .delta. 12.09 (br s, 1H), 11.57
(br s, 1H), 9.42 (s, 1H), 7.62 (d, J=8.8 Hz, 2H), 7.51 (br s, 1H),
7.17 (br s, 1H), 7.01 (d, J=8.8 Hz, 2H), 6.88 (dd, J=8.6, 2.3 Hz,
1H), 2.25 (s, 3H), 1.42 (s, 9H); MS m/e 466 (M+1).
Example 148
N-(5-(4-((4,5-Dimethylthiazol-2-yl)aminocarbonylamino)phenoxy)-1H-benzimid-
azol-2-yl)acetamide
[0879] ##STR243##
[0880] .sup.1H NMR (DMF-d.sub.7) .delta. 12.10 (br s, 1H), 11.58
(br s, 1H), 9.60 (br s, 1H), 7.60 (d, J=8.8 Hz, 2H), 7.50 (br s,
1H), 7.16 (br s, 1H), 6.99 (d, J=8.8 Hz, 2H), 6.87 (dd, J=8.6, 2.3
Hz, 1H), 2.24 (m, 6H), 2.13 (s, 3H); MS m/e 437 (M+1).
Example 149
N-(5-(4-((5-Morpholino-1,3,4-triazol-2-yl)aminocarbonylamino)phenoxy)-1H-b-
enzimidazol-2-yl)acetamide
[0881] ##STR244##
[0882] .sup.1H NMR (DMF-d.sub.7) .delta. 12.14 (br s, 1H), 11.60
(br s, 1H), 9.67 (s, 1H), 7.73 (d, J=9.1 Hz, 2H), 7.51 (br s, 1H),
7.38 (br s, 1H), 7.31-7.07 (m, 1H), 7.02 (d, J=9.1 Hz, 2H), 6.89
(dd, J=8.6, 2.3 Hz, 1H), 3.69 (m, 4H), 3.33 (m, 4H), 2.25 (s, 3H);
MS m/e 478 (M+1).
Example 150
N-(5-(4-((5-Methylisoxazol-3-yl)aminocarbonylamino)phenoxy)-1H-benzimidazo-
l-2-yl)(2-(methoxy)ethoxy)acetamide
[0883] ##STR245##
[0884] .sup.1H NMR (DMF-d.sub.7) .delta. 9.85 (s, 1H), 9.43 (s,
1H), 7.59 (d, J=8.9 Hz, 2H), 7.52 (br s, 1H), 7.17 (br s, 1H), 6.99
(d, J=9.1 Hz, 2H), 6.90 (dd, J=8.6, 2.3 Hz, 1H), 6.61 (s, 1H), 4.33
(s, 2H), 3.81 (m, 2H), 3.61 (m, 2H), 3.41 (s, 3H), 2.40 (s, 3H); MS
m/e 481 (M+1).
Example 151
N-(5-(4-((Thiazol-2-yl)aminocarbonylamindo)phenoxy)-1H-benzimidazol-2-yl)(-
2-(methoxy)ethoxy)acetamide
[0885] ##STR246##
[0886] .sup.1H NMR (DMF-d.sub.7) .delta. 12.10 (br s, 1H), 11.04
(br s, 1H), 9.54 (s, 1H), 7.61 (d, J=9.0 Hz, 2H), 7.53 (br s, 1H),
7.39 (d, J=3.5 Hz, 1H), 7.19 (br s, 1H), 7.13 (d, J=3.5 Hz), 7.02
(d, J=9.0 Hz, 2H), 6.91 (dd, J=8.6, 2.5 Hz, 1H), 4.32 (s, 2H), 3.81
(m, 2H), 3.61 (m, 2H), 3.41 (s, 3H); MS m/e 483 (M+1).
Example 152
N-(5-(4-((1,3,4-Thiadiazol-2-yl)aminocarbonylamino)phenoxy)-1H-benzimidazo-
l-2-yl)(2-(methoxy)ethoxy)acetamide
[0887] ##STR247##
[0888] .sup.1H NMR (DMF-d.sub.7) .delta. 12.23 (br s, 1H), 11.19
(br s, 1H), 9.45 (br s, 1H), 9.12 (s, 1H), 7.62 (d, J=9.1 Hz, 2H),
7.54 (br d, J=8.4 Hz, 1H), 7.19 (br s, 1H), 7.03 (d, J=9.1 Hz, 2H),
6.91 (dd, J=8.6, 2.3 Hz, 1H), 4.32 (s, 2H), 3.82 (m, 2H), 3.61 (m,
2H), 3.41 (s, 3H); MS m/e 484 (M+1).
Example 153
N-(5-(4-((4-Methylthiazol-2-yl)aminocarbonylamino)phenoxy)-1H-benzimidazol-
-2-yl)(2-(methoxy)ethoxy)acetamide
[0889] ##STR248##
[0890] .sup.1H NMR (DMF-d.sub.7) .delta. 12.20 (br s, 1H), 10.95
(br s, 1H), 9.38 (s, 1H), 7.60 (d, J=9.0 Hz, 2H), 7.53 (br d, J=8.2
Hz 1H), 7.18 (br s, 1H), 7.01 (d, J=9.0 Hz, 2H), 6.91 (dd, J=8.6,
2.3 Hz, 1H), 6.67 (s, 1H), 4.32 (s, 2H), 3.81 (m, 2H), 3.61 (m,
2H), 3.41 (s, 3H), 2.24 (s, 3H); MS m/e 497 (M+1).
Example 154
N-(5-(4-((5-Methylthiazol-2-yl)aminocarbonylamino)phenoxy)-1H-benzimidazol-
-2-yl)(2-(methoxy)ethoxy)acetamide
[0891] ##STR249##
[0892] .sup.1H NMR (DMF-d.sub.7) .delta. 9.35 (s, 1H), 7.59 (d,
J=9.1, 2H), 7.53 (br d, J=8.4, 1H), 7.18 (br s, 1H), 7.04 (app d
1H), 7.01 (d, J=9.1, 2H), 6.90 (dd, J=8.4, 2.3, 1H), 4.32 (s, 2H),
3.81 (m, 2H), 3.61 (m, 2H), 3.41 (s, 3H), 2.35 (app d, 3H); MS m/e
497 (M+1).
Example 155
N-(5-(4-((5-Methyl-1,3,4-thiadiazol-2-yl)aminocarbonylamino)phenoxy)-1H-be-
nzimidazol-2-yl)(2-(methoxy)ethoxy)acetamide
[0893] ##STR250##
[0894] .sup.1H NMR (DMF-d.sub.7) .delta. 12.23 (br s, 1H), 11.07
(br s, 1H), 9.32 (s, 1H), 7.61 (d, J=9.0 Hz, 2H), 7.55 (d, J=8.5
Hz, 1H), 7.20 (br s, 1H), 7.02 (d, J=9.0 Hz, 2H), 6.92 (dd, J=8.5,
2.5 Hz, 1H), 4.32 (s, 2H), 3.82 (m, 2H), 3.65 (m, 2H), 3.41 (s,
3H), 2.63 (s, 3H); MS m/e 498 (M+1).
Example 156
N-(5-(4-((5-Ethyl-1,3,4-thiadiazol-2-yl)aminocarbonylamino)phenoxy)-1H-ben-
zimidazol-2-yl)(2-(methoxy)ethoxy)acetamide
[0895] ##STR251##
[0896] .sup.1H NMR (DMF-d.sub.7) .delta. 12.14 (br s, 1H), 11.16
(br s, 1H), 9.38 (s, 1H), 7.62 (d, J=9.0 Hz, 2H), 7.51 (d, J=8.6
Hz, 1H), 7.19 (br s, 1H), 7.02 (d, J=9.0 Hz, 2H), 6.91 (dd, J=8.6,
2.3 Hz, 1H), 4.32 (s, 2H), 3.82 (m, 2H), 3.61 (m, 2H), 3.41 (s,
3H), 3.00 (q, J=7.6 Hz, 2H), 1.34 (t, J=7.6 Hz, 3H); MS m/e 512
(M+1).
Example 157
N-(5-(4-((5-Cyclopropyl-1,3,4-thiadiazol-2-yl)aminocarbonylamino)phenoxy)--
1H -benzimidazol-2-yl)(2-(methoxy)ethoxy)acetamide
[0897] ##STR252##
[0898] .sup.1H NMR (DMF-d.sub.7) .delta. 12.13 (br s, 1H), 11.24
(br s, 1H), 9.44 (s, 1H), 7.63 (d, J=8.8 Hz, 2H), 7.54 (d, J=8.6,
1H), 7.19 (br s, 1H), 7.02 (d, J=8.8 Hz, 2H), 6.91 (dd, J=8.6, 2.5
Hz, 1H), 4.32 (s, 2H), 3.81 (m, 2H), 3.61 (m, 2H), 3.41 (s, 3H),
2.38 (m, 1H), 1.15 (m, 2H), 1.00 (m, 2H); MS m/e 524 (M+1).
Example 158
N-(5-(4-((4-tert-Butylthiazol-2-yl)aminocarbonylamino)phenoxy)-1H-benzimid-
azol-2-yl)(2-(methoxy)ethoxy)acetamide
[0899] ##STR253##
[0900] .sup.1H NMR (DMF-d.sub.7) .delta. 9.54 (s, 1H), 7.61 (d,
J=8.8 Hz, 2H), 7.55 (br d, J=8.4 Hz, 1H), 7.20 (br s, 1H), 7.02 (d,
J=8.8 Hz, 2H), 6.92 (dd, J=8.4, 2.5 Hz, 1H), 6.69 (s, 1H), 4.33 (s,
2H), 3.82 (m, 2H), 3.61 (m, 2H), 3.41 (s, 3H), 1.28 (s, 9H); MS m/e
539 (M+1).
Example 159
N-(5-(4-((5-tert-Butyl-1,3,4-thiadiazol-2-yl)aminocarbonylamino)phenoxy)-1-
H-benzimidazol-2-yl)(2-(methoxy)ethoxy)acetamide
[0901] ##STR254##
[0902] .sup.1H NMR (DMF-d.sub.7) .delta. 12.20 (br s, 1H), 11.24
(br s, 1H), 9.59 (br s, 1H), 7.65 (d, J=8.9 Hz, 2H), 7.54 (br d,
J=8.4 Hz, 1H), 7.19 (br s, 1H), 7.02 (d, J=8.9 Hz, 2H), 6.91 (dd,
J=8.4, 2.3 Hz, 1H), 4.32 (s, 2H), 3.81 (m, 2H), 3.61 (m, 2H), 3.41
(s, 3H), 1.43 (s, 9H); MS m/e 540 (M+1).
Example 160
N-(5-(4-((5-Ethylthio-1,3,4-thiadiazol-2-yl)aminocarbonylamino)phenoxy)-1H-
-benzimidazol-2-yl)(2-(methoxy)ethoxy)acetamide
[0903] ##STR255##
[0904] .sup.1H NMR (DMF-d.sub.7) .delta. 9.76 (s, 1H), 7.64 (d,
J=8.8 Hz, 2H), 7.54 (d, J=8.6, 1H), 7.19 (br s, 1H), 7.02 (d, J=8.8
Hz, 2H), 6.91 (dd, J=8.6, 2.3 Hz, 1H), 4.32 (s, 2H), 3.81 (m, 2H),
3.61 (m, 2H), 3.41 (s, 3H), 3.25 (q, J=7.2 Hz, 2H) 1.39 (t, J=7.3
Hz, 3H); MS m/e 544 (M+1).
Example 161
N-(5-(4-((5-Propylthio-1,3,4-thiadiazol-2-yl)aminocarbonylamino)phenoxy)-1-
H-benzimidazol-2-yl)(2-(methoxy)ethoxy)acetamide
[0905] ##STR256##
[0906] .sup.1H NMR (DMF-d.sub.7) .delta. 12.19 (br s, 1H), 7.77 (m,
2H), 7.52 (br s, 1H), 7.19 (br s, 1H), 7.01 (d, J=8.8 Hz, 2H), 6.91
(dd, J=8.6, 2.3 Hz, 1H), 4.31 (s, 2H), 3.81 (m, 2H), 3.61 (m, 2H),
3.41 (s, 3H), 3.20 (t, J=7.1 Hz, 2H), 1.77 (m, 2H), 1.02 (t, J=7.3
Hz, 3H); MS m/e 558 (M+1).
Example 162
N-(5-(4-((4,5-Dimethylthiazol-2-yl)aminocarbonylamino)phenoxy)-1H-benzimid-
azol-2-yl)(2-(methoxy)ethoxy)acetamide
[0907] ##STR257##
[0908] .sup.1H NMR (DMF-d.sub.7) .delta. 9.57 (s, 1H), 7.60 (d,
J=9.1 Hz, 2H), 7.53 (br d, J=8.3, 1H), 7.18 (br s, 1H), 7.00 (d,
J=9.1 Hz, 2H), 6.90 (dd, J=8.3, 2.3 Hz, 1H), 4.32 (s, 2H), 3.81 (m,
2H), 3.61 (m, 2H), 3.41 (s, 3H), 2.24 (s, 3H), 2.14 (s, 3H); MS m/e
511 (M+1).
Example 163
N-(5-(4-((5-Morpholino-1,3,4-triazol-2-yl)aminocarbonylamino)phenoxy)-1H-b-
enzimidazol-2-yl)(2-(methoxy)ethoxy)acetamide
[0909] ##STR258##
[0910] .sup.1H NMR (DMF-d.sub.7) .delta. 11.22 (br s, 1H), 9.68 (s,
1H), 7.75 (d, J=9.0 Hz, 2H), 7.55 (d, J=8.7 Hz, 1H), 7.38 (br s,
1H), 7.22 (br s, 1H), 7.03 (d, J=9.0 Hz, 2H), 6.93 (dd, J=8.7, 2.5
Hz, 1H), 4.33 (s, 2H), 3.82 (m, 2H), 3.70 (m, 4H), 3.61 (m, 2H),
3.41 (s, 3H), 3.34 (m, 4H); MS m/e 552 (M+1).
Example 164
N-(5-(4-((5-Methylisoxazol-3-yl)aminocarbonylamino)phenoxy)-1H-benzimidazo-
l-2-yl)(2-furyl)formamide
[0911] ##STR259##
[0912] .sup.1H NMR (DMF-d.sub.7) .delta. 9.80 (s, 1H), 9.38 (s,
1H), 8.00 (s, 1H), 7.59 (m, 3H), 7.54 (d, J=8.6 Hz, 1H), 7.19 (d,
J=2.3 Hz, 1H), 7.02 (d, J=8.8 Hz, 2H), 6.92 (dd, J=8.6, 2.3 Hz,
1H), 6.75 (m, 1H), 6.62 (s, 1H), 2.41 (s, 3H); MS m/e 459
(M+1).
Example 165
N-(5-(4-((Thiazol-2-yl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)(2-
-furyl)formamide
[0913] ##STR260##
[0914] .sup.1H NMR (DMF-d.sub.7) .delta. 9.56 (br s, 1H), 8.00 (s,
1H), 7.62 (d, J=8.8 Hz, 2H), 7.58 (m, 1H), 7.54 (d, J=8.5 Hz, 1H),
7.39 (d, J=3.5 Hz, 1H), 7.20 (d, J=2.2 Hz, 1H), 7.13 (d, J=35 Hz,
1H), 7.04 (d, J=8.8 Hz, 2H), 6.93 (dd, J=8.5, 2.2 Hz, 1H), 6.75 (m,
1H); MS m/e 461 (M+1).
Example 166
N-(5-(4-((1,3,4-Thiadiazol-2-yl)aminocarbonylamino)phenoxy)-1H-benzimidazo-
l-2-yl)(2-furyl)formamide
[0915] ##STR261##
[0916] .sup.1H NMR (DMF-d.sub.7) .delta. 11.95 (br s, 1H), 9.56 (br
s, 1H), 9.12 (s, 1H), 8.00 (s, 1H), 7.65 (d, J=8.9 Hz, 2H), 7.59
(m, 1H), 7.55 (d, J=8.6 Hz, 1H), 7.21 (d, J=2.4 Hz, 1H), 7.05 (d,
J=8.9 Hz, 2H), 6.93 (dd, J=8.6, 2.4 Hz, 1H), 6.75 (m, 1H); MS m/e
462 (M+1).
Example 167
N-(5-(4-((4-Methylthiazol-2-yl)aminocarbonylamino)phenoxy)-1H-benzimidazol-
-2-yl)(2-furyl)formamide
[0917] ##STR262##
[0918] .sup.1H NMR (DMF-d.sub.7) .delta. 9.41 (s, 1H), 8.00 (s,
1H), 7.61 (d, =9.0 Hz, 2H), 7.58 (m, 1H), 7.54 (d, =8.7 Hz, 1H),
7.20 (d, J=2.4 Hz, 1H), 7.03 (d, J=9.0 Hz, 2H), 6.92 (dd, =8.7, 2.4
Hz, 1H), 6.75 (m, 1H), 6.67 (s, 1H), 2.24 (s, 3H); MS m/e 475
(M+1).
Example 168
N-(5-(4-((5-Methylthiazol-2-yl)aminocarbonylamino)phenoxy)-1H-benzimidazol-
-2-yl)(2-furyl)formamide
[0919] ##STR263##
[0920] .sup.1H NMR (DMF-d.sub.7) .delta. 9.48 (s, 1H), 8.00 (s,
1H), 7.61 (d, J=9.0 Hz, 2H), 7.58 (d, J=3.8 Hz, 1H), 7.54 (d, J=8.6
Hz, 1H), 7.19 (d, J=2.3 Hz, 1H), 7.03 (m, 3H), 6.93 (dd, J=8.6, 2.3
Hz, 1H), 6.75 (m, 1H), 2.35 (s, 3H); MS m/e 475 (M+1).
Example 169
N-(5-(4-((5-Methyl-1,3,4-thiadiazol-2-yl)aminocarbonylamino)phenoxy)-1H-be-
nzimidazol-2-yl)(2-furyl)formamide
[0921] ##STR264##
[0922] .sup.1H NMR (DMF-d.sub.7) .delta. 11.99 (br s, 1H), 9.45 (br
s, 1H), 8.00 (s, 1H), 7.63 (d, J=8.8 Hz, 2H), 7.59 (br d, J=3.3 Hz,
1H), 7.54 (d, J=8.6 Hz, 1H), 7.20 (d, J=2.3 Hz, 1H), 7.04 (d, J=8.8
Hz, 2H), 6.93 (dd, J=8.6, 2.3 Hz, 1H), 6.75 (m, 1H), 2.62 (s, 3H);
MS m/e 476 (M+1).
Example 170
N-(5-(4-((5-Ethyl-1,3,4-thiadiazol-2-yl)aminocarbonylamino)phenoxy)-1H-ben-
zimidazol-2-yl)(2-furyl)formamide
[0923] ##STR265##
[0924] .sup.1H NMR (DMF-d.sub.7) .delta. 11.93 (br s, 1H), 9.37 (br
s, 1H), 8.00 (s, 1H), 7.63 (d, J=9.1 Hz, 2H), 7.59 (br d, J=3.3 Hz,
1H), 7.54 (d, J=8.6 Hz, 1H), 7.20 (d, J=2.3 Hz, 1H), 7.04 (d, J=9.1
Hz, 2H), 6.93 (dd, J=8.6, 2.3 Hz, 1H), 6.75 (m, 1H), 3.00 (q, J=7.5
Hz, 2H), 1.33 (t, J=7.5 Hz, 3H); MS m/e 490 (M+1).
Example 171
N-(5-(4-((5-Cyclopropyl-1,3,4-thiadiazol-2-yl)aminocarbonylamino)phenoxy)--
1H -benzimidazol-2-yl)(2-furyl)formamide
[0925] ##STR266##
[0926] .sup.1H NMR (DMF-d.sub.7) .delta. 11.92 (br s, 1H), 9.42 (br
s, 1H), 8.00 (s, 1H), 7.62 (d, J=9.1 Hz, 2H), 7.59 (br d, J=3.3 Hz,
1H), 7.54 (d, J=8.6 Hz, 1H), 7.20 (d, J=2.3 Hz, 1H), 7.04 (d, J=9.1
Hz, 2H), 6.93 (dd, J=8.6, 2.3 Hz, 1H), 6.75 (m, 1H), 2.38 (m, 1H),
1.15 (m, 2H), 0.99 (m, 2H); MS m/e 502 (M+1).
Example 172
N-(5-(4-((4-tert-Butylthiazol-2-yl)aminocarbonylamino)phenoxy)-1H-benzimid-
azol-2-yl)(2-furyl)formamide
[0927] ##STR267##
[0928] .sup.1H NMR (DMF-d.sub.7) .delta. 10.60 (br s, 1H), 9.41 (br
s, 1H), 8.00 (s, 1H), 7.61 (d, J=8.8 Hz, 2H), 7.58 (br d, J=3.5 Hz,
1H), 7.55 (d, J=8.6 Hz, 1H), 7.20 (d, J=2.3 Hz, 1H), 7.04 (d, J=8.8
Hz, 2H), 6.93 (dd, J=8.6, 2.3 Hz, 1H), 6.75 (m, 1H), 6.69 (s, 1H),
1.27 (s, 9H); MS m/e 517 (M+1).
Example 173
N-(5-(4-((5-tert-Butyl-1,3,4-thiadiazol-2-yl)aminocarbonylamino)phenoxy)-1-
H-benzimidazol-2-yl)(2-furyl)formamide
[0929] ##STR268##
[0930] .sup.1H NMR (DMF-d.sub.7) .delta. 11.96 (br s, 1H), 9.39 (br
s, 1H), 8.00 (s, 1H), 7.64 (d, J=9.1 Hz, 2H), 7.59 (m, 1H), 7.54
(d, J=8.5 Hz, 1H), 7.20 (d, J=2.3 Hz, 1H), 7.04 (d, J=9.1 Hz, 2H),
6.93 (dd, J=8.5, 2.3 Hz, 1H), 6.75 (m, 1H), 1.43 (s, 9H); MS m/e
518 (M+1).
Example 174
N-(5-(4-((5-Ethylthio-1,3,4-thiadiazol-2-yl)aminocarbonylamino)phenoxy)-1H-
-benzimidazol-2-yl)(2-furyl)formamide
[0931] ##STR269##
[0932] .sup.1H NMR (DMF-d.sub.7) .delta. 12.20 (br s, 1H), 8.00 (s,
1H), 7.75 (m, 2H), 7.58 (br s, 1H), 7.54 (d, J=8.6 Hz, 1H), 7.20
(d, J=2.3 Hz, 1H), 7.04 (d, J=8.8 Hz, 2H), 6.93 (dd, J=8.6, 2.3 Hz,
1H), 6.75 (m, 1H), 3.25 (q, J=7.2 Hz, 2H), 1.40 (t, J=7.2 Hz, 3H);
MS m/e 522 (M+1).
Example 175
N-(5-(4-((4,5-Dimethylthiazol-2-yl)aminocarbonylamino)phenoxy)-1H-benzimid-
azol-2-yl)(2-furyl)formamide
[0933] ##STR270##
[0934] .sup.1H NMR (DMF-d.sub.7) .delta. 9.37 (br s, 1H), 8.00 (s,
1H), 7.60 (d, J=8.8 Hz, 2H), 7.58 (m, 1H), 7.54 (d, J=8.6 Hz, 1H),
7.19 (d, J=2.4 Hz, 1H), 7.03 (d, J=8.8 Hz, 2H), 6.93 (dd, J=8.6,
2.4 Hz, 1H), 6.75 (m, 1H), 2.24 (s, 3H), 2.14 (s, 3H); MS m/e 489
(M+1).
Example 176
N-(5-(4-((5-Morpholino-1,3,4-triazol-2-yl)aminocarbonylamino)phenoxy)-1H-b-
enzimidazol-2-yl)(2-furyl)formamide
[0935] ##STR271##
[0936] .sup.1H NMR (DMF-d.sub.7) .delta. 9.69 (s, 1H), 8.00 (s,
1H), 7.76 (d, J=8.9 Hz, 2H), 7.60 (br d, J=3.3 Hz, 1H), 7.56 (d,
J=8.6 Hz, 1H), 7.38 (br s, 1H), 7.23 (d, J=2.4 Hz, 1H), 7.05 (d,
J=8.9 Hz, 2H), 6.94 (dd, J=8.6, 2.4 Hz, 1H), 6.75 (m, 1H), 3.70 (m,
4H), 3.33 (m, 4H); MS m/e 530 (M+1).
Example 177
N-(5-(4-((5-Methylthio-1,3,4-thiadiazol-2-yl)aminocarbonylamino)phenoxy)-1-
H -benzimidazol-2-yl)acetamide
[0937] ##STR272##
[0938] .sup.1H NMR (DMF-d.sub.7) .delta. 12.11 (br s, 1H), 11.57
(br s, 1H), 10.58 (br s, 1H), 7.74 (m, 2H), 7.52 (br s, 1H),
7.30-7.07 (m, 1H), 7.00 (d, J=9.1 Hz, 2H), 6.88 (dd, J=8.6, 2.5 Hz,
1H), 2.95-2.72 (m, 3H), 2.24 (s, 3H); MS m/e 456 (M+1).
Example 178
N-(5-(4-((5-Methylthio-1,3,4-thiadiazol-2-yl)aminocarbonylamino)phenoxy)-1-
H-benzimidazol-2-yl) (2-(methoxy)ethoxy)acetamide
[0939] ##STR273##
[0940] .sup.1H NMR (DMF-d.sub.7) .delta. 12.20 (br s, 1H), 7.77 (m,
2H), 7.52 (br s, 1H), 7.18 (br s, 1H), 7.01 (d, J=9.1 Hz, 2H), 6.91
(dd, J=8.6, 2.5 Hz, 1H), 4.31 (s, 2H), 3.81 (m, 2H), 3.61 (m, 2H),
3.41 (s, 3H), 2.95-2.72 (m, 3H); MS m/e 530 (M+1).
Example 179
N-(5-(4-((5-Methylthio-1,3,4-thiadiazol-2-yl)aminocarbonylamino)phenoxy)-1-
H -benzimidazol-2-yl)(2-furyl)formamide
[0941] ##STR274##
[0942] .sup.1H NMR (DMF-d.sub.7) .delta. 12.12 (br s, 1H), 9.91 (br
s, 1H), 8.00 (s, 1H), 7.69 (m, 2H), 7.58 (m, 1H), 7.54 (d, J=8.6
Hz, 1H), 7.20 (d, J=2.3 Hz, 1H), 7.04 (d, J=9.1 Hz, 2H), 6.93 (dd,
J=8.6, 2.3 Hz, 1H), 6.75 (m, 1H), 2.95-2.72 (m, 3H); MS m/e 508
(M+1).
Example 180
N-(5-(4-((5-Carbamoyl-2-methylphenyl)aminocarbonylamino)phenoxy)-1H-benzim-
idazol-2-yl)(2-furyl)formamide
[0943] ##STR275##
[0944] This compound was prepared according to procedure for
Example 1381 by way of Intermediate 14F, although left-hand ring is
not heteroarylic.
[0945] .sup.1H NMR (DMF-d.sub.7) .delta. 12.26 (br s, 1H), 9.23 (s,
1H), 8.57 (d, J=1.8 Hz, 1H), 8.00 (s, 1H), 7.61-7.58 (m, 4H), 7.53
(d, J=8.6 Hz, 1H), 7.27 (d, J=7.8 Hz, 1H), 7.23 (br s, 1H), 7.19
(d, J=2.3 Hz, 1H), 7.02 (d, J=8.8 Hz, 2H), 6.92 (dd, J=8.6, 2.3 Hz,
1H), 6.74 (m, 1H), 2.34 (s, 3H); MS m/e 511 (M+1).
[0946] Examples 181-182 were prepared according to the procedures
described for Example 1 using intermediate 3A.
Example 181
Methyl
N-(5-(3-((2,3-dichlorophenyl)aminocarbonylamino)phenoxy)-1H-benzimi-
dazol-2-yl)carbamate
[0947] ##STR276##
[0948] .sup.1H NMR (DMSO-d.sub.6) .delta. 12.0-11.2 (brs, 2H), 9.53
(s, 1H), 8.40 (s, 1H), 8.10 (dd, 1H), 7.41 (d, 1H), 7.30-7.24 (m,
3H), 7.13-7.07 (m, 3H), 6.83 (dd, 1H), 6.62 (dd, 1H), 3.75 (s, 3H);
MS m/e 486 (M+1), 488 (M+3).
Example 182
Methyl
N-(5-(3-((2,3-dimethylphenyl)aminocarbonylamino)phenoxy)-1H-benzimi-
dazol-2-yl)carbamate
[0949] ##STR277##
[0950] .sup.1H NMR (DMSO-d.sub.6) .delta. 12.0-11.2 (brs, 2H), 8.98
(s, 1H), 7.86 (s, 1H), 7.48 (d, 1H), 7.40 (d, 1H), 7.22 (t, 1H),
7.10 (d, 1H), 7.07 (m, 2H), 7.00 (t, 1H), 6.88 (d, 1H), 6.82 (dd,
1H), 3.75 (s, 3H), 2.23 (s, 3H), 2.09 (s, 3H); MS m/e 446 (M+1)
Example 183
1-(5-(4-((2-Fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1-
H-benzimidazol-2-yl)-3-(2,3-dimethylphenyl)urea
[0951] ##STR278##
[0952] The compound of Example 22 was treated with
2,3-dimethylphenylisocyanate in THF to give the title compound.
[0953] .sup.1H NMR (DMSO-d.sub.6) .delta.; 11.5 (brs, 1H), 10.4
(brs, 1H), 9.6 (brs, 1H), 9.13 (s, 1H), 8.85 (s, 1H), 8.62 (d, 1H),
7.68 (d, 1H), 7.50 (t, 1H), 7.44 (d, 2H), 7.38 (m, 2H), 7.08 (t,
1H), 7.02 (brs, 1H), 6.94 (d, 2H), 6.94 (d, 1H), 6.79 (dd, 1H),
2.28 (s, 3H), 2.22 (s, 3H), MS m/e 593 (M+1)
[0954] The following compounds (Example 184-186) are synthesized
according to the similar procedure for Example 1 using
corresponding isothiocyanate in lieu of isocyanate.
Example 184
Methyl
N-(5-(4-((3-chlorophenyl)aminothiocarbonylamino)phenoxy)-1H-benzimi-
dazol-2-yl)carbamate
[0955] ##STR279##
[0956] .sup.1H NMR (DMSO-d.sub.6) .delta.; 12.0-11.2 (brs, 2H),
9.89 (s, 1H), 9.85 (s, 1H), 7.70 (t, 1H), 7.42-7.32 (m, 5H), 7.16
(d, 1H), 7.06 (d, 1H), 6.92 (d, 2H), 6.81 (dd, 1H), 3.75 (s, 3H);
MS m/e 468 (M+1), 470 (M+3).
Example 185
Methyl
N-(5-(4-((3-methoxyphenyl)aminothiocarbonylamino)phenoxy)-1H-benzim-
idazol-2-yl)carbamate
[0957] ##STR280##
[0958] .sup.1H NMR (DMSO-d.sub.6) .delta.; 12.0-11.2 (brs, 2H),
9.73 (s, 1H), 9.71 (s, 1H), 7.40 (m, 1H), 7.39 (d, 2H), 7.22 (t,
1H), 7.18 (s, 1H), 7.05 (s, 1H), 7.01 (d, 1H), 6.91 (d, 2H), 6.80
(dd, 1H), 6.70 (dd, 1H), 3.75 (s, 3H), 3.74 (s, 3H); MS m/e 464
(M+1).
Example 186
Methyl
N-(5-(4-((3-(trifluoromethyl)phenyl)aminothiocarbonylamino)phenoxy)-
-1H -benzimidazol-2-yl)carbamate
[0959] ##STR281##
[0960] .sup.1H NMR (DMSO-d.sub.6) .delta.; 12.0-11.2 (brs, 2H),
9.95 (s, 1H), 9.92 (s, 1H), 7.95 (s, 1H), 7.75 (d, 1H), 7.55 (t,
1H), 7.44 (d, 1H), 7.39 (m, 1H), 7.38 (d, 2H), 7.06 (s, 1H), 6.93
(d, 2H), 6.81 (dd, 1H), 3.75 (s, 3H); MS m/e 502 (M+1).
Biological Data
TIE-2 Enzyme Assay (TIE2-E)
[0961] The TIE-2 enzyme assay used the LANCE method (Wallac) and
GST-TIE2, baculovirus expressed recombinant constructs of the
intracellular domains of human TIE2 (amino acids 762-1104, GenBank
Accession # L06139) tagged by GST). The method measured the ability
of the purified enzymes to catalyse the transfer of the
.gamma.-phosphate from ATP onto tyrosine residues in a biotinylated
synthetic peptide, D1-15 (biotin-C6-LEARLVAYEGWVAGKKKamide). This
peptide phosphorylation was detected using the following procedure:
for enzyme preactivation, GST-TIE2 was incubated for 30 mins at
room temperature with 2 mM ATP, 5 mM MgCl.sub.2 and 12.5 mM DTT in
22.5 mM HEPES buffer (pH7.4). Preactivated GST-TIE2 was incubated
for 30 mins at room temperature in 96 well plates with 1 .mu.M
D1-15 peptide, 80 uM ATP, 10 mM MgCl.sub.2, 0.1 mg/ml BSA and the
test compound (diluted from a 10 mM stock in DMSO, final DMSO
concentration was 2.4%) in 1 mM HEPES (pH7.4). The reaction was
stopped by the addition of EDTA (final concentration 45 mM).
Streptavidin linked-APC (allophycocyanin, Molecular Probe) and
Europium-labeled anti-phosphorylated tyrosine antibody (Wallac)
were then added at the final concentration of 17 .mu.g/well and 2.1
.mu.g/well, respectively. The APC signal was measured using an ARVO
multilabel counter. (Wallac Berthold Japan). The percent inhibition
of activity was calculated relative to blank control wells. The
concentration of test compound that inhibits 50% of activity
(IC.sub.50) was interpolated using nonlinear regression
(Levernberg-Marquardt) and the equation, y=Vmax (1-x/(K+x))+Y2,
where "K" was equal to the IC.sub.50. The IC.sub.50 values were
converted to pIC.sub.50 values, i.e., -log IC.sub.50 in Molar
concentration. The results are represented in Table 1 below.
TIE-2 Autophosphorylation Assay (TIE2-C)
[0962] The TIE-2 autophosphorylation assay used an ELISA method and
a TIE2 intracellular domain/c-fms extracellular domain (TIE2/c-fms)
chimeric protein expressing mouse 3T3 cells. This assay measured
the autophosphorylation level of TIE2 protein expressed in cells.
The cells were cultured in high glucose DMEM (Sigma) containing 10%
serum at 37.degree. C. in a humidified 10% CO.sub.2, 90% air
incubator. The test compound (diluted from a 10 mM stock in DMSO,
final DMSO concentration was 0.1%) was incubated with TIE2/c-fms
expressing cells for 1 hr in serum free DMEM in 96 well plates
followed by the activation of TIE2/c-fms receptor using c-fms
ligand, MCSF (macrophage colony stimulating factor). The culture
media was removed by aspiration and the cells incubated for at
least 30 mins on ice with lysis buffer containing 137 mM NaCl, 2 mM
EDTA, 10% glycerol, 0.09 ml sodium ortho vanadate and complete
protease inhibitor cocktail (Roche) in 20 mM Tris-HCl (pH8.0). The
cell extracts were transferred into Rat anti-c-fms antibody coated
96 well plates and incubated for 12 hrs at 4.degree. C. The
extracts were removed by aspiration and the plate was incubated
with biotinylated anti-phosphotyrosine antibody, PT66 (Sigma) and
then with HRP (Horseradish Peroxidase)-labeled streptavidin
(PIERCE). The optical density at 450 nm derived from HRP catalyzed
TMB was measured with an ARVO multilabel counter. (Wallac Berthold
Japan). The percent inhibition of activity was calculated relative
to blank control wells. The concentration of test compound that
inhibits 50% of activity (IC.sub.50) was interpolated using
nonlinear regression (Levernberg-Marquardt) and the equation,
y=Vmax (1-x/(K+x))+Y2, where "K" was equal to the IC.sub.50. The
IC.sub.50 values were converted to pIC.sub.50 values, i.e., -log
IC.sub.50 in Molar concentration. The results are represented in
Table 1 below.
Tie2 Fluorescence Polarization Kinase Activity Assay: (TIE2-FP)
Activation of Recombinant Tie2 Activation:
[0963] Recombinant GST-Tie2 was activated by incubating the enzyme
in 20 mM Tris-HCl, pH 7.5, 12 mM MgCl.sub.2, 100 mM NaCl, 20 .mu.M
sodium vanidate, 1 mM DTT and 300 .mu.M ATP at room temperature for
2 hours. The activation mixture was then passed through a NAP-25
desalting column (Pharmacia Biotech cat. no. 17-0852-02) to remove
the free ATP. The activated enzyme was stored as aliquots at
-80.degree. C. in 20 mM Tris-HCl, pH 7.5 and 100 mM NaCl.
Assay Conditions:
[0964] The final assay conditions were 50 mM HEPES, pH 7.5, 5% DMSO
(when screening compounds), 200 .mu.M ATP, 5 mM MgCl.sub.2, 1 mM
DTT, 50 .mu.M sodium vanidate, 1 nM activated enzyme, and 200 .mu.M
peptide. IC.sub.50's of compounds were measured under subsaturating
ATP (200 .mu.M) and varing concentrations of activated Tie2 and
peptide substrate (RFWKYEFWR-OH; MW 1873 Da, TFA salt). Panvera
Anti-phosphotyrosine antibody (Cat#P2840) and PTK Green Tracer
(Cat#P2842) were used to detect the phosphorylated peptide.
Polarization was measured on a TECAN Polarion in 138-second cycles
for 30 minutes at room temperature. IC.sub.50's were then
determined from the % polarization using normal calculation
methods. Results are indicated below.
VEGF-R2 Enzyme Assay (VEGF-E)
[0965] The VEGF enzyme assay used the LANCE method (Wallac) and
GST-VEGFR2, baculovirus expressed recombinant constructs of the
intracellular domains of human TIE2 tagged by GST. The method
measured the ability of the purified enzymes to catalyse the
transfer of the .gamma.-phosphate from ATP onto tyrosine residues
in a biotinylated synthetic peptide,
(biotin-aminohexyl-EEEEYFELVAKKKK-NH.sub.2). This peptide
phosphorylation was detected using the following procedure:
GST-VEGFR2 was incubated for 40-60 mins at room temperature with 75
.mu.M ATP, 5 mM MgCl.sub.2, 0.1 mM DTT, 0.1 mg/mL BSA and the test
compound (diluted from a 10 mM stock in DMSO for desired
concentration) in 100 mM HEPES buffer. The reaction was stopped by
the addition of EDTA (final concentration 50 mM). Streptavidin
linked-APC (allophycocyanin, Molecular Probe) and Europium-labeled
anti-phosphorylated tyrosine antibody (Wallac) were then added at
the final concentration of 15 nM and 1 nM, respectively. The APC
signal was measured using an ARVO multilabel counter (Wallac
Berthold, Japan). The percent inhibition of activity was calculated
relative to blank control wells. The concentration of test compound
that inhibits 50% of activity (IC.sub.50) was interpolated using
nonlinear regression (Levernberg-Marquardt) and the equation,
y=Vmax(1-x/(K.sup.+ x))+Y2, where "K" was equal to the IC.sub.50.
The IC.sub.50 values were converted to pIC.sub.50 values, i.e.,
-log IC.sub.50 in Molar concentration. The results are represented
in Table 1 below.
VEGF-Driven Cellular Proliferation Assay: BrdU Incorporation Assay
(VEGF-C)
[0966] Human umbilical cord endothelial cells (HUVEC, Clonetics,
CC2519) were passaged in Type I collagen-coated 100-mm petridishes
in EGM-MV medium (Clonetics, CC3125) at 37.degree. C. in a
humidified 5% CO.sub.2, 95% air incubator. (HUVEC passaged more
than 6 times in vitro were discarded and not subjected to
assaying.) The cells were harvested using trypsin/EDTA, counted
using a haemocytometer and plated at 5000 cells/well in a Type
I-collagen coated 96-well plate (Becton Dickinson, 354407) in M199
medium (Gibco BRL, 12340-030) containing 5% FBS (Hyclone, A 1115-L)
and gentamicin (at 50 .mu.g/ml, Gibco BRL). After incubation
overnight at 37.degree. C., the media were replaced with 100 ul of
M199 serum-free medium containing compounds at various
concentrations with 0.6% DMSO and gentamicin. The compounds were
diluted in serum-free M199 medium from 10 mM stock solutions
prepared in 100% DMSO. After a 30 min incubation at 37.degree. C.,
the cells were fed with 100 .mu.l of serum-free M199 medium
containing gentamicin, 0.2% culture-grade bovine serum albumin
(BSA, Sigma A1993) and 20 ng/ml of VEGF (R&D systems, 293-VE)
or 0.6 ng/ml of basic FGF (R&D systems, 233-FB), and cultured
at 37.degree. C. for another 24 h. The cells were pulsed with
bromodeoxyuridine (BrdU at 10 .mu.M in serum-free M199) at
37.degree. C. for an additional 24 h. The incorporation of BrdU
into the proliferating HUVEC were analyzed using BrdU Cell
Proliferation ELISA (Roche Molecular Biochemicals, 1647229)
according to the manufacturer's protocols. The optical density at
450 nm was measured with a multilabel counter (ARVO SX, Wallac).
The percent inhibition of cell growth was calculated relative to
blank control wells. The concentration of test compound that
inhibits 50% of cell growth (IC.sub.50) was interpolated using
nonlinear regression (Levernberg-Marquardt) and the equation,
y=Vmax (1-x/(K+x))+Y2, where "K" was equal to the IC.sub.50. The
IC.sub.50 values were converted to pIC.sub.50 values, i.e., -log
IC.sub.50 in Molar concentration. The results are represented in
Table 1 below.
[0967] Test compounds are employed in free or salt form.
TABLE-US-00001 TABLE I Ex. No TIE2-E TIE2-C VEGF-E VEGF-C 1 +++ ++
+++ - 2 +++ +++ +++ + 3 ++ +++ - 4 +++ + ++ - 5 ++ +++ + - 6 +++ +
- 7 +++ - - 8 +++ +++ - 9 +++ +++ +++ - 10 +++ +++ +++ +++ 11 +++
++ +++ - 12 ++ +++ + - 13 +++ ++ ++ - 14 ++ ++ +++ ++ 15 +++ +++
+++ ++ 16 +++ +++ +++ 17 +++ +++ +++ +++ 18 +++ +++ +++ +++ 19 +++
+++ +++ - 20 +++ ++ +++ 21 +++ +++ - 22 +++ + +++ + 23 +++ +++ ++
24 +++ ++ +++ - 25 +++ +++ +++ +++ 26 +++ ++ +++ ++ 27 +++ +++ +++
++ 28 +++ +++ +++ ++ 29 +++ +++ +++ ++ 30 +++ +++ +++ ++ 31 +++ +++
+++ +++ 32 +++ ++ + 33 +++ +++ +++ +++ 34 +++ +++ +++ - 35 +++ ++
+++ + 36 +++ +++ - 37 +++ +++ +++ - 38 +++ +++ +++ - 39 ++ ++ ++ 40
+++ +++ +++ - 41 +++ +++ +++ - 42 +++ +++ +++ ++ 43 +++ +++ +++ +
44 +++ ++ +++ - 45 +++ +++ +++ - 46 +++ +++ +++ - 47 +++ +++ +++ -
48 +++ +++ +++ - 49 ++ ++ +++ - 50 +++ +++ +++ ++ 51 +++ +++ +++ -
52 +++ ++ +++ 55 +++ +++ +++ - 56 ++ +++ +++ - 57 +++ ++ 58 +++ 59
+++ 60 +++ 61 +++ 62 + +++ 63 - +++ 64 +++ +++ +++ +++ 65 +++ +++
+++ - 68 +++ +++ +++ +++ 69 +++ +++ +++ ++ 70 +++ ++ +++ + 71 +++
++ +++ + 72 +++ +++ +++ + 73 ++ ++ +++ 74 +++ +++ +++ - 75 ++ +++
+++ - 76 +++ +++ - 77 +++ +++ +++ ++ 78 +++ 79 ++ ++ 80 +++ +++ +++
+++ 81 +++ +++ +++ - 87 +++ +++ +++ ++ 88 +++ +++ +++ +++ 89 +++
+++ +++ ++ 90 +++ + +++ 91 +++ +++ +++ - 92 +++ +++ +++ +++ 93 +++
+++ +++ + 94 +++ +++ +++ + 95 +++ ++ +++ 96 +++ +++ +++ ++ 97 +++
+++ +++ +++ 98 +++ +++ +++ ++ 99 +++ ++ +++ 100 +++ +++ +++ 101 +++
+++ +++ +++ 102 +++ +++ +++ +++ 103 +++ +++ +++ + 104 ++ ++ +++ 105
++ + +++ 106 ++ ++ +++ 107 +++ ++ ++ 110 +++ ++ ++ 111 +++ +++ +++
- 112 ++ ++ ++ 113 +++ 115 +++ +++ +++ +++ 116 +++ 117 +++ 118 ++
119 +++ 120 +++ 121 ++ 123 ++ 124 +++ 125 +++ 127 +++ 128 +++ 129
+++ 130 +++ 133 +++ 134 +++ 136 +++ 137 +++ 146* ++ +++ 151* + ++
152* + + 153* + ++ 155* + ++ 156* ++ +++ 158* ++ +++ 159* +++ +++
163 + 184 + + +++ 185 ++ + 186 + ++ +++ + = pIC.sub.50 of 5.0-6.0;
++ = pIC.sub.50 of 6.0-7.0; +++ = pIC.sub.50 of >7.0; - = a
negative or inconclusive result; blank = not tested *Tie-2
activities run utilizing Tie2-FP assay described above.
* * * * *