U.S. patent application number 13/544130 was filed with the patent office on 2012-11-01 for prodrugs of compounds that inhibit trpv1 receptor.
Invention is credited to Erol K. Bayburt, Brian S. Brown, Jerome F. Daanen, Arthur R. Gomtsyan, John R. Koenig, Chih-Hung Lee, Kennan C. Marsh, Robert G. Schmidt, JR., Weili Wang.
Application Number | 20120277190 13/544130 |
Document ID | / |
Family ID | 37668287 |
Filed Date | 2012-11-01 |
United States Patent
Application |
20120277190 |
Kind Code |
A1 |
Gomtsyan; Arthur R. ; et
al. |
November 1, 2012 |
PRODRUGS OF COMPOUNDS THAT INHIBIT TRPV1 RECEPTOR
Abstract
Compounds of formula (I) ##STR00001## wherein A, R.sub.1,
R.sub.2, and R.sub.3 are defined in the specification, and which
are useful as therapeutic compounds particularly for treating
disorders or conditions associated with inflammation, pain, bladder
overactivity, urinary incontinence, and other disorders caused by
or exacerbated by TRPV1.
Inventors: |
Gomtsyan; Arthur R.; (Vernon
Hills, IL) ; Bayburt; Erol K.; (Gurnee, IL) ;
Koenig; John R.; (Chicago, IL) ; Marsh; Kennan
C.; (Lake Forest, IL) ; Schmidt, JR.; Robert G.;
(Waukegan, IL) ; Lee; Chih-Hung; (Vernon Hills,
IL) ; Wang; Weili; (Buffalo Grove, IL) ;
Daanen; Jerome F.; (Racine, WI) ; Brown; Brian
S.; (Evanston, IL) |
Family ID: |
37668287 |
Appl. No.: |
13/544130 |
Filed: |
July 9, 2012 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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11588713 |
Oct 27, 2006 |
8232309 |
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13544130 |
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60730991 |
Oct 28, 2005 |
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Current U.S.
Class: |
514/80 ;
514/234.5; 514/322; 514/406; 544/140; 546/199; 548/113;
548/361.1 |
Current CPC
Class: |
C07D 403/12 20130101;
A61P 29/00 20180101; C07D 231/56 20130101; A61P 13/02 20180101;
A61P 13/00 20180101; C07D 405/12 20130101; A61P 13/10 20180101;
A61P 43/00 20180101; A61P 25/00 20180101; A61P 25/04 20180101; C07F
9/65038 20130101 |
Class at
Publication: |
514/80 ; 544/140;
514/234.5; 548/361.1; 514/406; 546/199; 514/322; 548/113 |
International
Class: |
A61K 31/5377 20060101
A61K031/5377; C07D 231/56 20060101 C07D231/56; A61K 31/416 20060101
A61K031/416; A61P 13/10 20060101 A61P013/10; A61K 31/454 20060101
A61K031/454; C07F 9/09 20060101 C07F009/09; A61K 31/675 20060101
A61K031/675; A61P 25/00 20060101 A61P025/00; C07D 413/06 20060101
C07D413/06; C07D 401/12 20060101 C07D401/12 |
Claims
1. A compound of formula (I) ##STR00041## or a pharmaceutically
acceptable salt, prodrug, salt of a prodrug or a combination
thereof, wherein A is ##STR00042## R.sub.1 is alkyl, cycloalkyl,
alkenyl; halogen or haloalkyl; R.sub.2 is hydrogen or
heterocyclealkyl wherein the heterocycle moiety of the
heterocyclealkyl is unsubstituted or substituted with 1, 2, 3 or 4
substituents selected from the group consisting of alkyl,
-alkyl-OR.sub.B, and -alkyl-N(R.sub.B).sub.2; R.sub.3 is
##STR00043## wherein R.sub.4 is --C(O)--O--(CH.sub.2).sub.mR.sub.5,
--C(O)(CH.sub.2).sub.n--R.sub.6, --(CH.sub.2).sub.r--R.sub.7,
--C(O)R.sub.8, or --CH.sub.2C(H)(OH)R.sub.9 when R.sub.2 is
hydrogen; or R.sub.4 is hydrogen when R.sub.2 is heterocyclealkyl;
wherein the heterocycle moiety of the heterocyclealkyl is
unsubstituted or substituted with 1, 2, 3 or 4 substituents
selected from the group consisting of alkyl, -alkyl-OR.sub.B, and
-alkyl-N(R.sub.B).sub.2; m is 1, 2, or 3; n is 1, 2 or 3; r is 1, 2
or 3; t is 0, 1, 2, 3 or 4; u is 0, 1, 2 or 3; R.sub.5 is alkyl,
--O--P(O)(OR.sub.A)(OR.sub.A), --P(O)(OR.sub.A)(OR.sub.A),
--OR.sub.A, --OC(O)(R.sub.A), heterocycle, --C(O)OR.sub.A,
--C(O)N(R.sub.B).sub.2, --C(O)(R.sub.A), --NR.sub.AR.sub.B, or
--N(R.sub.B)C(O)OR.sub.A, R.sub.6 is alkyl, --OC(O)(R.sub.A),
--OR.sub.A, --C(O)OR.sub.A, --NR.sub.AR.sub.B,
--OP(O)(OR.sub.A)(OR.sub.A), or --P(O)(OR.sub.A)(OR.sub.A); R.sub.7
is alkoxy, heterocycle, --OC(O)(R.sub.A), --OC(O)(hydroxyalkyl),
--OP(O)(OR.sub.A)(OR.sub.A), or --P(O)(OR.sub.A)(OR.sub.A), R.sub.8
is heterocycle or N(R.sub.8a)(R.sub.8b) wherein R.sub.8a and
R.sub.8b are independently hydrogen or alkyl; R.sub.9 is
alkoxyalkyl, --C(O)OR.sub.A, -alkyl-N(R.sub.B)C(O)OR.sub.A, or
heterocyclealkyl; R.sub.10 is alkyl; each occurence of R.sub.11 are
independently hydrogen, alkyl or aryl, or two R.sub.11 groups that
are attached to a single carbon atom together form a cycloalkyl
ring; R.sub.A is hydrogen, alkyl, alkoxyalkyl, aryl or arylalkyl;
R.sub.B is hydrogen or alkyl; the heterocycle and the heterocycle
moiety of the heterocyclealkyl, represented by R.sub.5, R.sub.7,
R.sub.8, and R.sub.9, are each independently substituted with 0, 1,
2 or 3 substituents independently selected from the group
consisting of alkyl, haloalkyl, alkoxy, haloalkoxy, --C(O)OH,
-alkyl-C(O)OH, and --N(Z.sub.A)(Z.sub.B); Z.sub.A and Z.sub.B are
each independently hydrogen, alkyl, --C(O)alkyl, formyl, aryl, or
arylalkyl; and the aryl and the aryl moiety of the arylalkyl,
represented by R.sub.A, Z.sub.A and Z.sub.B are each independently
substituted with 0, 1, 2 or 3 substituents selected from the group
consisting of alkyl, haloalkyl, alkoxy and haloalkoxy.
2. The compound of claim 1, wherein A is ##STR00044##
3. The compound of claim 2, wherein R.sub.1 is alkyl, cycloalkyl,
alkenyl; halogen or haloalkyl; R.sub.2 is hydrogen; R.sub.3 is
##STR00045## and R.sub.4 is --(CH.sub.2).sub.r--R.sub.7.
4. The compound of claim 2, wherein R.sub.1 is alkyl, cycloalkyl,
halogen or haloalkyl; R.sub.2 is hydrogen; R.sub.3 is ##STR00046##
and R.sub.4 is .sup.-C(O)(CH.sub.2).sub.n.sup.-R.sub.6.
5. The compound of claim 2, wherein R.sub.1 is alkyl, cycloalkyl,
halogen or haloalkyl; R.sub.2 is hydrogen; R.sub.3 is ##STR00047##
and R.sub.4 is --CH.sub.2C(H)(OH)R.sub.9.
6. The compound of claim 2, wherein R.sub.1 is alkyl, cycloalkyl,
halogen or haloalkyl; R.sub.2 is hydrogen; R.sub.3 is ##STR00048##
and R.sub.4 is --C(O)R.sub.8.
7. The compound of claim 2, wherein R.sub.1 is alkyl, cycloalkyl,
halogen or haloalkyl; R.sub.2 is heterocyclealkyl; R.sub.3 is
##STR00049## and R.sub.4 is hydrogen.
8. The compound of claim 2, wherein R.sub.1 is alkyl, cycloalkyl,
halogen or haloalkyl; R.sub.2 is hydrogen; R.sub.3 is ##STR00050##
and R.sub.4 is --C(O)--O--(CH.sub.2).sub.mR.sub.5.
9. The compound of claim 8 wherein R.sub.5 is
--O--P(O)(OR.sub.A)(OR.sub.A).
10. The compound of claim 8 wherein R.sub.5 is
--P(O)(OR.sub.A)(OR.sub.A).
11. The compound of claim 8 wherein R.sub.5 is --OR.sub.A.
12. The compound of claim 8 wherein R.sub.5 is
--OC(O)(R.sub.A).
13. The compound of claim 8 wherein R.sub.5 is heterocycle.
14. The compound of claim 8 wherein R.sub.5 is --C(O)OR.sub.A.
15. The compound of claim 8 wherein R.sub.5 is selected from the
group consisting of --C(O)R.sub.A, --N(R.sub.B)C(O)OR.sub.A,
--NR.sub.AR.sub.B, and --C(O)N(R.sub.B).sub.2.
16. The compound of claim 2, wherein R.sub.1 is alkyl, cycloalkyl,
halogen or haloalkyl; R.sub.2 is hydrogen; R.sub.3 is ##STR00051##
and R.sub.4 is --C(O)R.sub.8.
17. The compound of claim 2, wherein R.sub.1 is alkyl, cycloalkyl,
halogen or haloalkyl; R.sub.2 is hydrogen; R.sub.3 is ##STR00052##
and R.sub.4 is --CH.sub.2C(H)(OH)R.sub.9.
18. The compound of claim 2, wherein R.sub.1 is alkyl, cycloalkyl,
halogen or haloalkyl; R.sub.2 is hydrogen; R.sub.3 is ##STR00053##
and R.sub.4 is selected from the group consisting of
--C(O)--O--(CH.sub.2).sub.mR.sub.5,
--C(O)(CH.sub.2).sub.n--R.sub.6, and
--(CH.sub.2).sub.r--R.sub.7.
19. The compound of claim 2, wherein R.sub.1 is alkyl, cycloalkyl,
halogen or haloalkyl; R.sub.2 is heterocyclealkyl; R.sub.3 is
##STR00054## and R.sub.4 is hydrogen.
20. The compound of claim 1, wherein A is ##STR00055##
21. The compound of claim 20, wherein R.sub.1 is alkyl, cycloalkyl,
halogen or haloalkyl; R.sub.2 1S hydrogen; R.sub.3 is ##STR00056##
and R.sub.4 is --(CH.sub.2).sub.r--R.sub.7.
22. The compound of claim 20 wherein R.sub.1 is alkyl, cycloalkyl,
halogen or haloalkyl; R.sub.2 is hydrogen; R.sub.3 is ##STR00057##
and R.sub.4 is --C(O)(CH.sub.2).sub.n--R.sub.6.
23. The compound of claim 20 wherein R.sub.1 is alkyl, cycloalkyl,
halogen or haloalkyl; R.sub.2 is hydrogen; R.sub.3 is ##STR00058##
and R.sub.4 is --CH.sub.2C(H)(OH)R.sub.9.
24. The compound of claim 20 wherein R.sub.1 is alkyl, cycloalkyl,
halogen or haloalkyl; R.sub.2 is hydrogen; R.sub.3 is ##STR00059##
and R.sub.4 is --C(O)R.sub.8.
25. The compound of claim 20 wherein R.sub.1 is alkyl, cycloalkyl,
halogen or haloalkyl; R.sub.2 is heterocyclealkyl; R.sub.3 is
##STR00060## and R.sub.4 is hydrogen.
26. The compound of claim 20 wherein R.sub.1 is alkyl, cycloalkyl,
halogen or haloalkyl; R.sub.2 is hydrogen; R.sub.3 is ##STR00061##
and R.sub.4 is --C(O)--O--(CH.sub.2).sub.mR.sub.5.
27. The compound of claim 26 wherein R.sub.5 is
--O--P(O)(OR.sub.A)(OR.sub.A).
28. The compound of claim 26 wherein R.sub.5 is
--P(O)(OR.sub.A)(OR.sub.A).
29. The compound of claim 26 wherein R.sub.5 is --OR.sub.A.
30. The compound of claim 26 wherein R.sub.5 is
--OC(O)(R.sub.A).
31. The compound of claim 26 wherein R.sub.5 is heterocycle.
32. The compound of claim 26 wherein R.sub.5 is --C(O)OR.sub.A,
33. The compound of claim 26 wherein R.sub.5 is selected from the
group consisting of --C(O)R.sub.A, --N(R.sub.B)C(O)OR.sub.A,
--NR.sub.AR.sub.B, and --C(O)N(R.sub.B).sub.2.
34. The compound of claim 1, wherein A is ##STR00062##
35. The compound of claim 1, wherein A is ##STR00063##
36. The compound of claim 1, wherein A is ##STR00064##
37. The compound selected from the group consisting of
N-[(1R)-5-tert-butyl-2,3-dihydro-1H-inden-1-yl]-N'-[1-(2-morphol
in-4-ylethyl)-1H-indazol-4-yl]urea;
2-{4-[({[(1R)-5-tert-butyl-2,3-dihydro-1H-inden-1-yl]amino}carbonyl)amino-
]-1H-indazol-1-yl}-2-oxoethyl acetate;
N-[(1R)-5-tert-butyl-2,3-dihydro-1H-inden-1-yl]-N'-1H-indazol-4-yl-N-(2-m-
orpholin-4-ylethyl)urea;
N-{1-[(benzyloxy)acetyl]-1H-indazol-4-yl}-N'-[(1R)-5-tert-butyl-2,3-dihyd-
ro-1H-inden-1-yl]urea;
N-[(1R)-5-tert-butyl-2,3-dihydro-1H-inden-1-yl]-N'-[1-(methoxyacetyl)-1H--
indazol-4-yl]urea;
4-{4-[({[(1R)-5-tert-butyl-2,3-dihydro-1H-inden-1-yl]amino}carbonyl)amino-
]-1H-indazol-1-yl1-4-oxobutanoic acid;
N-[(1R)-5-tert-butyl-2,3-dihydro-1H-inden-1-yl]-N't1-(N,N-dimethylglycyl)-
-1H-indazol-4-yl]urea trifluoroacetic acid salt;
N-[(1R)-5-tert-butyl-2,3-dihydro-1H-inden-1-yl]-N'-(1-glycoloyl-1H-indazo-
l-4-yl)urea;
N-[(1R)-5-tert-butyl-2,3-dihydro-1H-inden-1-yl]-N'-1H-indazol-4-yl-N-(2-p-
iperidin-1-ylethyl)urea;
5-{4-[({[(1R)-5-tert-butyl-2,3-dihydro-1H-inden-1-yl]amino}carbonyl)amino-
]-1H-indazol-1-yl}-5-oxopentanoic acid; 2-(phosphonooxy)ethyl
4-[({[(1R)-5-tert-butyl-2,3-dihydro-1H-inden-1-yl]amino}carbonyl)amino]-1-
H-indazole-1-carboxylate; 2-(benzyloxy)ethyl
4-[({[(1R)-5-tert-butyl-2,3-dihydro-1H-inden-1-yl]amino}carbonyl)amino]-1-
H-indazole-1-carboxylate; 2-hydroxyethyl
4-[({[(1R)-5-tert-butyl-2,3-dihydro-1H-inden-1-yl]amino}carbonyl)amino]-1-
H-indazole-1-carboxylate; 2-[(di-tert-butoxyphosphoryl)oxy]ethyl
4-[({[(1R)-5-tert-butyl-2,3-dihydro-1H-inden-1-yl]amino}carbonyl)amino]-1-
H-indazole-1-carboxylate; 3-(benzyloxy)propyl
4-[({[(1R)-5-tert-butyl-2,3-dihydro-1H-inden-1-yl]amino}carbonyl)amino]-1-
H-indazole-1-carboxylate; 3-hydroxypropyl
4-[({[(1R)-5-tert-butyl-2,3-dihydro-1H-inden-1-yl]amino}carbonyl)amino]-1-
H-indazole-1-carboxylate; 3-[(di-tert-butoxyphosphoryl)oxy]propyl
4-[({[(1R)-5-tert-butyl-2,3-dihydro-1H-inden-1-yl]amino}carbonyl)amino]-1-
H-indazole-1-carboxylate; 3-(phosphonooxy)propyl
4-[({[(1R)-5-tert-butyl-2,3-dihydro-1H-inden-1-yl]amino}carbonyl)amino]-1-
H-indazole-1-carboxylate;
N-[(1R)-5-tert-butyl-2,3-dihydro-1H-inden-1-yl]-/V[1-(hydroxymethyl)-1H-i-
ndazol-4-yl)urea;
{4-[({[(1R)-5-tert-butyl-2,3-dihydro-1H-inden-1-yl]amino}carbonyl)amino]--
1H-indazol-1-yl}methyl acetate;
{4-[({[(1R)-5-tert-butyl-2,3-dihydro-1H-inden-1-yl]amino}carbonyl)am
ino]-1H-indazol-1-yl}methyl 3-hydroxypropanoate;
{[bis(benzyloxy)phosphoryl]oxy}methyl
4-[({[(1R)-5-tert-butyl-2,3-dihydro-1H-inden-1-yl]amino}carbonyl)amino]-1-
H-indazole-1-carboxylate; (phosphonooxy)methyl
4-[({[(1R)-5-tert-butyl-2,3-dihydro-1H-inden-1-yl]amino}carbonyl)amino]-1-
H-indazole-1-carboxylate; dibenzyl
3-{4-[({[(1R)-5-tert-butyl-2,3-dihydro-1H-inden-1-yl]amino}carbonyl)amino-
]-1H-indazol-1-yl}-3-oxopropyl phosphate;
3-{4-[({[(1R)-5-tert-butyl-2,3-dihydro-1H-inden-1-yl]amino}carbonyl)amino-
]-1H-indazol-1-yl}-3-oxopropyl dihydrogen phosphate;
[bis(benzyloxy)phosphoryl]methyl
4-[({[(1R)-5-tert-butyl-2,3-dihydro-1H-inden-1-yl]amino}carbonyl)amino]-1-
H-indazole-1-carboxylate;
[({4-[({[(1R)-5-tert-butyl-2,3-dihydro-1H-inden-1-yl]amino}carbonyl)amino-
]-1H-indazol-1-yl}carbonyl)oxy]methylphosphonic acid;
[({4-[({[(1R)-5-tert-butyl-2,3-dihydro-1H-inden-1-yl]amino}carbonyl)amino-
]-1H-indazol-1-yl}carbonyl)oxy]methylphosphonie acid triethylamine
salt; 2-methoxyethyl
4-[({[(1R)-5-tert-butyl-2,3-dihydro-1H-inden-1-yl]amino}carbonyl)amino]-1-
H-indazole-1-carboxylate; (2,2-dimethyl-1,3-dioxolan-4-yl)methyl
4-[({[(1R)-5-tert-butyl-2,3-dihydro-1H-inden-1-yl]amino}carbonyl)amino]-1-
H-indazole-1-carboxylate; (2-oxo-1,3-dioxolan-4-yl)methyl
4-[({[(1R)-5-tert-butyl-2,3-dihydro-1H-inden-1-yl]amino}carbonyl)amino]-1-
H-indazole-1-carboxylate; 2-(benzyloxy)ethyl
4-[({[(1R)-5-tert-butyl-2,3-dihydro-1H-inden-1-yl]amino}carbonyl)amino]-1-
H-indazole-1-carboxylate; 2-hydroxyethyl
4-[({[(1R)-5-tert-butyl-2,3-dihydro-1H-inden-1-yl]amino}carbonyl)amino]-1-
H-indazole-1-carboxylate; 2-(benzyloxy)-2-oxoethyl
4-[({[(1R)-5-tert-butyl-2,3-dihydro-1H-inden-1-yl]amino}carbonyl)amino]-1-
H-indazole-1-carboxylate; 2-{[(benzyloxy)carbonyl]amino}ethyl
4-[({[(1R)-5-tert-butyl-2,3-dihydro-1H-inden-1-yl]amino}carbonyl)amino]-1-
H-indazole-1-carboxylate;
[({4-[({[(1R)-5-tert-butyl-2,3-dihydro-1H-inden-1-yl]amino}carbonyl)amino-
]-1H-indazol-1-yl}carbonyl)oxy]acetic acid; 2-aminoethyl
4-[({[(1R)-5-tert-butyl-2,3-dihydro-1H-inden-1-yl]amino}carbonyl)amino]-1-
H-indazole-1-carboxylate hydrochloride; 2-ethoxy-2-oxoethyl
4-[({[(1R)-5-tert-butyl-2,3-dihydro-1H-inden-1-yl]amino}carbonyl)amino]-1-
H-indazole-1-carboxylate; (diethoxyphosphoryl)methyl
4-[({[(1R)-5-tert-butyl-2,3-dihydro-1H-inden-1-yl]amino}carbonyl)amino]-1-
H-indazole-1-carboxylate; 2-(diethylamino)-2-oxoethyl
4-[({[(1R)-5-tert-butyl-2,3-dihydro-1H-inden-1-yl]amino}carbonyl)amino]-1-
H-indazole-1-carboxylate; 2-oxopropyl
4-[({[(1R)-5-tert-butyl-2,3-dihydro-1H-inden-1-yl]amino}carbonyl)amino]-1-
H-indazole-1-carboxylate; 2-(acetyloxy)ethyl
4-[({[(1R)-5-tert-butyl-2,3-dihydro-1H-inden-1-yl]amino}carbonyl)amino]-1-
H-indazole-1-carboxylate; 2-(dimethoxyphosphoryl)ethyl
4-[({[(1R)-5-tert-butyl-2,3-dihydro-1H-inden-1-yl]amino}carbonyl)amino]-1-
H-indazole-1-carboxylate; [bis(benzyloxy)phosphoryl]methyl
4-[({[(1R)-5-tert-butyl-2,3-dihydro-1H-inden-1-yl]amino}carbonyl)amino]-1-
H-indazole-1-carboxylate;
[({4-[({[(1R)-5-tert-butyl-2,3-dihydro-1H-inden-1-yl]amino}carbonyl)amino-
]-1H-indazol-1-yl}carbonyl)oxy]methylphosphonic acid;
[({4-[({[(1R)-5-tert-butyl-2,3-dihydro-1H-inden-1-yl]amino}carbonyl)amino-
]-1H-indazol-1-yl}carbonyl)oxy]methylphosphonate, triethylamine
salt;
[({4-[({[(1R)-5-tert-butyl-2,3-dihydro-1H-inden-1-yl]amino}carbonyl)amino-
]-1H-indazol-1-yl}carbonyl)oxy]methylphosphonic acid,
diethylaminoethanol salt;
[({4-[({[(1R)-5-tert-butyl-2,3-dihydro-1H-inden-1-yl]amino}carbonyl-
)amino]-1H-indazol-1-yl}carbonyl)oxy]methylphosphonic acid,
triethanolamine salt;
[({4-[({[(1R)-5-tert-butyl-2,3-dihydro-1H-inden-1-yl]amino}carbonyl)amino-
]-1H-indazol-1-yl}carbonyl)oxy]methylphosphonic acid, piperazine
salt;
[({4-[({[(1R)-5-tert-butyl-2,3-dihydro-1H-inden-1-yl]amino}carbonyl)amino-
]-1H-indazol-1-yl}carbonyl)oxy]methylphosphonic acid,
N-methyl-D-glucamine salt;
N-[(1R)-5-tert-butyl-2,3-dihydro-1H-inden-1-yl]-N'-[1-(2-hydroxy-3--
methoxypropyl)-1H-indazol-4-yl]urea;
N-[(1R)-5-tert-butyl-2,3-dihydro-1H-inden-1-yl]-N'-[2-(2-hydroxy-3-methox-
ypropyl)-2H-indazol-4-yl]urea; methyl
3-{4-[({[(1R)-5-tert-butyl-2,3-dihydro-1H-inden-1-yl]amino}carbonyl)amino-
]-1H-indazol-1-yl}-2-hydroxypropanoate; methyl
3-{4-[({[(1R)-5-tert-butyl-2,3-dihydro-1H-inden-1-yl]amino}carbonyl)amino-
]-2H-indazol-2-yl}-2-hydroxypropanoate; tert-butyl
3-{4-[({[(1R)-5-tert-butyl-2,3-dihydro-1H-inden-1-yl]amino}carbonyl)amino-
]-1H-indazol-1-yl}-2-hydroxypropylcarbamate;
3-{4-[({[(1R)-5-tert-butyl-2,3-dihydro-1H-inden-1-yl]amino}carbonyl)amino-
]-1H-indazol-1-yl}-2-hydroxypropanoic acid;
3-{4-[({[(1R)-5-tert-butyl-2,3-dihydro-1H-inden-1-yl]amino}carbonyl)amino-
]-2H-indazol-2-yl}-2-hydroxypropanoic acid;
N-[(1R)-5-tert-butyl-2,3-dihydro-1H-inden-1-yl]-N't2-(2-hydroxy-3-morphol-
in-4-ylpropyl)-2H-indazol-4-yl]urea;
N-[(1R)-5-tert-butyl-2,3-dihydro-1H-inden-1-yl]-N'-[1-(2-hydroxy-3-morpho-
lin-4-ylpropyl)-1H-indazol-4-yl]urea;
N-[(1R)-5-tert-butyl-2,3-dihydro-1H-inden-1-yl]-N'-{1-[(4-methylpiperazin-
-1-yl)carbonyl]-1H-indazol-4-yl}urea;
N-[(1R)-5-tert-butyl-2,3-dihydro-1H-inden-1-yl]-N'-{2-[(4-methylpiperazin-
-1-yl)carbonyl]-2H-indazol-4-yl}urea;
N-[(1R)-5-tert-butyl-2,3-dihydro-1H-inden-1-yl]-N'-[1-(N,N-dimethylglycyl-
)-1H-indazol-4-yl]urea;
N-[(1R)-5-tert-butyl-2,3-dihydro-1H-inden-1-yl]-N'-[1-(N,N-dimethylglycyl-
)-1H-indazol-4-yl]urea, hydrochloride salt;
((R)-1-(5-tert-butyl-2,3-dihydro-1H-inden-1-yl)-3-(1-(2-(2-methoxyethoxy)-
acetyl)-1H-indazol-4-yl)urea;
1-((R)-5-tert-butyl-2,3-dihydro-1H-inden-1-yl)-3-(1-(3,5,5-trimethylhexan-
oyl)-1H-indazol-4-yl)urea; 2-ethylhexyl
4-(3-((R)-5-tert-butyl-2,3-dihydro-1H-inden-1-yl)ureido)-1H-indazole-1-ca-
rboxylate;
(R)-1-(1-(2-(2-butoxyethoxy)acetyl)-1H-indazol-4-yl)-3-(5-tert--
butyl-2,3-dihydro-1H-inden-1-yl)urea; methyl
4-(3-(7-fluoro-2,2-dimethylchroman-4-yl)ureido)-1H-indazole-1-carboxylate-
;
1-(7-fluoro-2,2-dimethylchroman-4-yl)-3-(1-(2-methoxyethyl)-1H-indazol-4-
-yl)urea; 3-(dimethylamino)propyl
4-(3-(4-cyclopropyl-5-fluoro-2,3-dihydro-1H-inden-1-yl)ureido)-1H-indazol-
e-1-carboxylate;
1-(4-cyclopropyl-2,3-dihydro-1H-inden-1-yl)-3-(1-(2-(dimethylamino)acetyl-
)-1H-indazol-4-yl)urea trifluoroacetate;
1-(5-cyclopropyl-2,3-dihydro-1H-inden-1-yl)-3-(1-(2-(dimethylamino)acetyl-
)-1H-indazol-4-yl)urea hydrochloride;
1-(1-(2-(dimethylamino)acetyl)-1H-indazol-4-yl)-3-(4-(3,3-dimethylbutyl)--
5-fluoro-2,3-dihydro-1H-inden-1-yl)urea;
(R)-1-(4-cyclopropyl-5-fluoro-2,3-dihydro-1H-inden-1-yl)-3-(1-(2-(dimethy-
lamino)acetyl)-1H-indazol-4-yl)urea;
(R)-1-(5-tert-butyl-2,3-dihydro-1H-inden-1-yl)-3-(1-(2-(methylamino)acety-
l)-1H-indazol-4-yl)urea hydrochloride;
4-[3-(7-trifluoromethyl-chroman-4-yl)-ureido]-indazole-1-carboxylic
acid methyl ester;
1-(1-(2-(dimethylamino)acetyl)-1H-indazol-4-yl)-3-(7-(trifluoromethyl)chr-
oman-4-yl)urea; methyl
4-({[(8-tert-butyl-3,4-dihydro-2H-chromen-4-yl)amino]carbonyl}amino)-1H-i-
ndazole-1-carboxylate; and
1-(8-tert-butylchroman-4-yl)-3-(1-(2-(dimethylamino)acetyl)-1H-indazol-4--
yl)urea hydrochloride.
38. A pharmaceutical composition comprising a therapeutically
effective amount of one or more compound of formula (I) as
described in claim 1, or a therapeutically acceptable salt,
solvate, or combination thereof, and a pharmaceutically acceptable
carrier.
39. A method of treating or preventing disorders that may be
ameliorated by inhibiting TRPV1 activity in a mammal comprising
administering a therapeutically effective amount of one or more
compounds of formula (I) according to claim 1 or a pharmaceutically
acceptable salt thereof.
40. A compound of formula (I) according according to claim 1 for
use in the manufacture of a medicament for the treatment or
prevention of a disease or condition that may be ameliorated by
inhibiting TRPV1 activity.
41. A compound according to claim 36 wherein the disease or
disorder is associated with pain, inflammation, urinary
incontinence and bladder dysfunction.
42. A method of treating or preventing a disease or disorders
associated with neuropathic pain, inflammatory pain, or both, which
method comprises administering a therapeutically effective amount
of a compound of formula (I) according to claim 1 or a
pharmaceutically acceptable salt thereof.
43. A method of treating or preventing a disease or disorder
associated with bladder overactivity or urinary incontinence, or
both, which method comprises administering a therapeutically
effective amount of a compound of formula (I) according to claim 1
or a pharmaceutically acceptable salt thereof.
44. The compound of claim 2 of formula (II), ##STR00065##
45. The compound of claim 2 of formula (III), ##STR00066##
46. The compound of claim 20 of formula (IV), ##STR00067##
47. The compound of claim 20 of formula (V), ##STR00068##
Description
[0001] This application claims priority to the provisional
application Ser. No. 60/730,991 filed on Oct. 28, 2005.
FIELD OF INVENTION
[0002] The present invention relates to prodrugs of urea containing
compounds, pharmaceutically acceptable salts and pharmaceutical
compositions thereof, which are useful for treating pain, bladder
overactivity, urinary incontinence, and other disorders caused by
or exacerbated by vanilloid receptor activity. The compounds of the
present invention have better physicochemical properties permitting
more active drug to be available.
BACKGROUND OF THE INVENTION
[0003] Nociceptors are primary sensory afferent (C and AS fibers)
neurons that are activated by a wide variety of noxious stimuli
including chemical, mechanical, thermal, and proton (pH<6)
modalities. The lipophillic vanilloid, capsaicin, activates primary
sensory fibers via a specific cell surface capsaicin receptor,
cloned as TRPV1. The intradermal administration of capsaicin is
characterized by an initial burning or hot sensation followed by a
prolonged period of analgesia. The analgesic component of TRPV1
receptor activation is thought to be mediated by a
capsaicin-induced desensitization of the primary sensory afferent
terminal. Thus, the long lasting anti-nociceptive effects of
capsaicin have prompted the clinical use of capsaicin analogs as
analgesic agents. Further, capsazepine, a capsaicin receptor
antagonist can reduce inflammation-induced hyperalgesia in animal
models. TRPV1 receptors are also localized on sensory afferents,
which innervate the bladder. Capsaicin or resiniferatoxin has been
shown to ameliorate incontinence symptoms upon injection into the
bladder.
[0004] The TRPV1 receptor has been called a "polymodal detector" of
noxious stimuli since it can be activated in several ways. The
receptor channel is activated by capsaicin and other vanilloids and
thus is classified as a ligand-gated ion channel. TRPV1 receptor
activation by capsaicin can be blocked by the competitive TRPV1
receptor antagonist, capsazepine. The channel can also be activated
by protons and heat. Under mildly acidic conditions (pH 6-7), the
affinity of capsaicin for the receptor is increased, whereas at
pH<6, direct activation of the channel occurs. In addition, when
membrane temperature reaches 43.degree. C., the channel is opened.
Thus heat can directly gate the channel in the absence of ligand.
The capsaicin analog, capsazepine, which is a competitive
antagonist of capsaicin, blocks activation of the channel in
response to capsaicin, acid, or heat.
[0005] The channel is a nonspecific cation conductor. Both
extracellular sodium and calcium enter through the channel pore,
resulting in cell membrane depolarization. This depolarization
increases neuronal excitability, leading to action potential firing
and transmission of a noxious nerve impulse to the spinal cord. In
addition, depolarization of the peripheral terminal can lead to
release of inflammatory peptides such as, but not limited to,
substance P and CGRP, leading to enhanced peripheral sensitization
of tissue.
[0006] Recently, two groups have reported the generation of a
"knock-out" mouse lacking the TRPV1 receptor (TRPV1 (-/-)).
Electrophysiological studies of sensory neurons (dorsal root
ganglia) from these animals revealed a marked absence of responses
evoked by noxious stimuli including capsaicin, heat, and reduced
pH. These animals did not display any overt signs of behavioral
impairment and showed no differences in responses to acute
non-noxious thermal and mechanical stimulation relative to
wild-type mice. The TRPV1 (-/-) mice also did not show reduced
sensitivity to nerve injury-induced mechanical or thermal
nociception. However, the TRPV1 knock-out mice were insensitive to
the noxious effects of intradermal capsaicin, exposure to intense
heat (50-55.degree. C.), and failed to develop thermal hyperalgesia
following the intradermal administration of carrageenan.
[0007] The compounds of the present invention are novel TRPV1
antagonists and have utility in for treating pain, bladder
overactivity, urinary incontinence, and other disorders associated
with pain that are caused by or exacerbated by vanilloid receptor
activity.
SUMMARY OF THE PRESENT INVENTION
[0008] The present invention discloses prodrugs of urea containing
compounds, pharmaceutically acceptable salts and pharmaceutical
compositions thereof. More particularly, the present invention is
directed to compounds of formula (1),
##STR00002##
or a pharmaceutically acceptable salt, prodrug, salt of a prodrug
or a combination thereof, wherein
[0009] A is
##STR00003##
[0010] R.sub.1 is alkyl, cycloalkyl, alkenyl; halogen or
haloalkyl;
[0011] R.sub.2 is hydrogen or heterocyclealkyl wherein the
heterocycle moiety of the heterocyclealkyl is unsubstituted or
substituted with 1, 2, 3 or 4 substituents selected from the group
consisting of alkyl, -alkyl-OR.sub.B, and
-alkyl-N(R.sub.B).sub.2;
[0012] R.sub.3 is
##STR00004##
[0013] wherein [0014] R.sup.4 is
--C(O)--O--(CH.sub.2).sub.mR.sub.5,
--C(O)(CH.sub.2).sub.n--R.sub.6, --(CH.sub.2).sub.r--R.sub.7,
--C(O)R.sub.8, or --CH.sub.2C(H)(OH)R.sub.9 when R.sub.2 is
hydrogen; or [0015] R.sub.4 is hydrogen when R.sub.2 is
heterocyclealkyl; wherein the heterocycle moiety of the
heterocyclealkyl is unsubstituted or substituted with 1, 2, 3 or 4
substituents selected from the group consisting of alkyl,
-alkyl-OR.sub.B, and -alkyl-N(R.sub.B).sub.2;
[0016] m is 1, 2, or 3;
[0017] n is 1, 2 or 3;
[0018] r is 1, 2 or 3;
[0019] t is 0, 1, 2, 3 or 4;
[0020] u is 0, 1, 2 or 3;
[0021] R.sub.5 is alkyl, --O--P(O)(OR.sub.A)(OR.sub.A),
--P(O)(OR.sub.A)(OR.sub.A), --OR.sub.A, --OC(O)(R.sub.A),
heterocycle, --C(O)OR.sub.A, --C(O)N(R.sub.B).sub.2,
--C(O)(R.sub.A), --NR.sub.AR.sub.B, or -N(R.sub.B)C(O)OR.sub.A,
[0022] R.sub.6 is alkyl, --OC(O)(R.sub.A), --OR.sub.A,
--C(O)OR.sub.A, --NR.sub.AR.sub.B, --OP(O)(OR.sub.A)(OR.sub.A), or
--P(O)(OR.sub.A)(OR.sub.A);
[0023] R.sub.7 is alkoxy, heterocycle, --OC(O)(R.sub.A),
--OC(O)(hydroxyalkyl), --OP(O)(OR.sub.A)(OR.sub.A), or
--P(O)(OR.sub.A)(OR.sub.A),
[0024] R.sub.8 is heterocycle or N(R.sub.8a)(R.sub.8b) wherein
R.sub.8a and R.sub.8b are independently hydrogen or alkyl;
[0025] R.sub.9 is alkoxyalkyl, --C(O)OR.sub.A,
-alkyl-N(R.sub.B)C(O)OR.sub.A, or heterocyclealkyl;
[0026] R.sub.10 is alkyl;
[0027] each occurence of R.sub.11 are independently hydrogen, alkyl
or aryl, or two R.sub.11 groups that are attached to a single
carbon atom together form a cycloalkyl ring;
[0028] R.sub.A is hydrogen, alkyl, alkoxyalkyl, aryl or
arylalkyl;
[0029] R.sub.B is hydrogen or alkyl;
[0030] the heterocycle and the heterocycle moiety of the
heterocyclealkyl, represented by R.sub.5, R.sub.7, R.sub.8, and
R.sub.9, are each independently substituted with 0, 1, 2 or 3
substituents independently selected from the group consisting of
alkyl, haloalkyl, alkoxy, haloalkoxy, --C(O)OH, -alkyl-C(O)OH, and
--N(Z.sub.A)(Z.sub.B);
[0031] Z.sub.A and Z.sub.B are each independently hydrogen, alkyl,
--C(O)alkyl, formyl, aryl, or arylalkyl; and
[0032] the aryl and the aryl moiety of the arylalkyl, represented
by R.sub.A, Z.sub.A and Z.sub.B are each independently substituted
with 0, 1, 2 or 3 substituents selected from the group consisting
of alkyl, haloalkyl, alkoxy and haloalkoxy.
[0033] The compounds of the present invention are useful for
treating pain, bladder overactivity, urinary incontinence, and
other disorders caused by or exacerbated by vanilloid receptor
activity.
[0034] Also described are pharmaceutical compositions comprising a
therapeutically effective amount of one or more compounds of
formula (I), or a therapeutically acceptable salt, solvate, or
combination thereof, and a pharmaceutically acceptable carrier.
[0035] One particular embodiment of the present invention describes
a method of treating a disease or preventing disorders that may be
ameliorated by inhibiting vanilloid receptor subtype 1 activity in
a mammal comprising administering a therapeutically effective
amount of one or more compounds of formula (I) or a
pharmaceutically acceptable salt thereof.
[0036] The compounds of formula (I) may be used in the manufacture
of a medicament for the treatment or prevention of a disease or
disorder that may be ameliorated by inhibiting vanilloid receptor
subtype 1 activity.
[0037] Furthermore, the disclosed compounds of formula (I) are
useful in treating a disease or a disorder, wherein the disease or
disorder is associated with pain, inflammation, urinary
incontinence and bladder dysfunction.
[0038] The disclosed methods of treating or preventing disease or
disorder associated with pain wherein the pain is neuropathic pain,
inflammatory pain, or both, which method comprises administering a
therapeutically effective amount of a compound of formula (I) or a
pharmaceutically acceptable salt thereof.
[0039] There is also disclosed methods of treating or preventing a
disease or disorder associated with bladder overactivity or urinary
incontinence, or both, which method comprises administering a
therapeutically effective amount of a compound of formula (I)
according to claim 1 or a pharmaceutically acceptable salt
thereof.
DETAILED DESCRIPTION OF THE INVENTION
[0040] Compounds of the invention have the formula (I) as described
above. In general, the compounds of formula (I) can include, but
are not limited to, compounds in which A is
##STR00005##
[0041] More particularly, compounds of formula (I) contain A which
is
##STR00006##
[0042] In another series of embodiments, compounds of formula (I)
contain A which is
##STR00007##
[0043] In a further series of embodiments, compounds of formula (I)
contain A which is
##STR00008##
[0044] In yet another series of embodiments, compounds of formula
(I) contain A which is
##STR00009##
[0045] Lastly in yet another series of embodiments, compounds of
formula (1) contain A which is
##STR00010##
[0046] For each substructure as defined by ring A, there exist the
following embodiments which further define the scope of the
compounds of the present invention. These further embodiments are
contemplated to apply to each series of compounds of the present
invention defined under ring A.
[0047] In one embodiment there is described compounds of formula
(I) wherein R.sub.1 is alkyl, cycloalkyl, halogen or haloalkyl,
R.sub.2 is hydrogen or heterocyclealkyl, R.sub.3 is selected from
the groups
##STR00011##
and R.sub.4 is selected form the group consisting of
--C(O)--O--(CH.sub.2).sub.mR.sub.5,
--C(O)(CH.sub.2).sub.n--R.sub.6, --(CH.sub.2).sub.r--R.sub.7,
--C(O)R.sub.8, or --CH.sub.2C(H)(OH)R.sub.9 when R.sub.2 is
hydrogen.
[0048] Compounds of the invention include those wherein R.sub.1 is
alkyl, cycloalkyl, halogen or haloalkyl, preferably alkyl, R.sub.2
is hydrogen, R.sub.3 is
##STR00012##
and R.sub.4 is --(CH.sub.2).sub.r--R.sub.7, in which R.sub.7
selected from the group consisting of heterocycle,
--OC(O)(R.sub.A), --OC(O)(hydroxyalkyl), and
--P(O)(OR.sub.A)(OR.sub.A). Preferred compounds include those in
which R.sub.7 is --OC(O)(R.sub.A), and R.sub.A is hydrogen or those
in which R.sub.7 is --OC(O)(hydroxyalkyl).
[0049] Other compounds of the present invention include those
wherein R.sub.1 is alkyl, cycloalkyl, halogen or haloalkyl,
preferably alkyl, R.sub.2 is hydrogen, R.sub.3 is
##STR00013##
and R.sub.4 is --C(O)(CH.sub.2).sub.n--R.sub.6, wherein R.sub.6 is
selected from the group consisting of is --OC(O)(R.sub.A),
--OR.sub.A, --C(O)OR.sub.A, --NR.sub.AR.sub.B,
--OP(O)(OR.sub.A)(OR.sub.A) or --P(O)(OR.sub.A)(OR.sub.A). Examples
of compounds of the present invention are those in which R.sub.A is
hydrogen, alkyl, aryl or arylalkyl.
[0050] Other compounds of the present invention include those
wherein R.sub.1 is alkyl, cycloalkyl, halogen or haloalkyl,
preferably alkyl, R.sub.2 is hydrogen, R.sub.3 is
##STR00014##
and R.sub.4 is --CH.sub.2C(H)(OH)R.sub.9, wherein R.sub.9 is
selected from the group consisting of alkoxyalkyl, --C(O)OR.sub.A,
-alkyl-N(R.sub.B)C(O)OR.sub.A, and heterocyclealkyl. Examples of
compounds of the present invention are those in which R.sub.9 is
alkoxyalkyl, --C(O)OR.sub.A, and heterocyclealkyl, and R.sub.A is
hydrogen, alkyl, aryl or arylalkyl.
[0051] Other compounds included in the present invention are those
in which R.sub.1 is alkyl, cycloalkyl, halogen or haloalkyl,
preferably alkyl, R.sub.2 is hydrogen, R.sub.3 is
##STR00015##
and R.sub.4 is --C(O)R.sub.8 , wherein R.sub.8 is heterocycle or
N(R.sub.8a)(R.sub.8b). Examples of compounds of the present
invention are those in which R.sub.8 is heterocycle.
[0052] Other compounds included in the present invention are those
in which R.sub.1 is alkyl, cycloalkyl, halogen or haloalkyl,
preferably alkyl, R.sub.2 is heterocyclealkyl, R.sub.3 is
##STR00016##
and R.sub.4 is hydrogen. Examples of the present invention comprise
compounds in which the heterocycle moiety of the heterocyclealkyl
is unsubstituted. However, compounds in which the heterocycle
moiety of the heterocyclealkyl is substituted with 1, 2, 3 or 4
substituents selected from the group consisting of alkyl,
-alkyl-OR.sub.B, and -alkyl-N(R.sub.B).sub.2, are also comprised in
the present invention.
[0053] Other compounds included in the present invention are those
in which R.sub.1 is alkyl, cycloalkyl, halogen or haloalkyl,
R.sub.2 is heterocyclealkyl, R.sub.3 is
##STR00017##
and R.sub.4 is hydrogen.
[0054] Compounds of the present invention include those wherein
R.sub.1 is alkyl, cycloalkyl, halogen or haloalkyl, preferably
alkyl, R.sub.2 is hydrogen, R.sub.3 is
##STR00018##
and R.sub.4 is --C(O)--O--(CH.sub.2).sub.mR.sub.5, wherein R.sub.5
is selected from the group consisting of
--O--P(O)(OR.sub.A)(OR.sub.A), --P(O)(OR.sub.A)(OR.sub.A),
--OR.sub.A, --OC(O)(R.sub.A), heterocycle, --C(O)OR.sub.A,
--C(O)N(R.sub.B).sub.2, --C(O)(R.sub.A), and
--N(R.sub.B)C(O)OR.sub.A. Examples of these compounds include those
in which R.sub.5 is --O--P(O)(OR.sub.A)(OR.sub.A), and R.sub.A is
independently selected from the group consisting of hydrogen,
alkyl, aryl or arylalkyl. Other examples include those compounds in
which R.sub.5 is --P(O)(OR.sub.A)(OR.sub.A), and R.sub.A is
independently selected from the group consisting of hydrogen,
alkyl, aryl or arylalkyl. Examples of compounds include those in
which R.sub.5 is OR.sub.A and R.sub.A is independently selected
from the group consisting of hydrogen, alkyl, aryl or arylalkyl.
Other examples include those in which R.sub.5 is heterocycle.
Examples include compounds in which R.sub.5 is OC(O)(R.sub.A), and
R.sub.A is independently selected from the group consisting of
hydrogen, alkyl, aryl or arylalkyl. Other examples include those
compounds in which R.sub.5 is --C(O)OR.sub.A, and R.sub.A is
independently selected from the group consisting of hydrogen,
alkyl, aryl or arylalkyl. Other compounds included in the examples
of the present invention are those in which R.sub.5 is
--C(O)N(R.sub.B).sub.2, and R.sub.B is selected between hydrogen
and alkyl. Other compounds included in the examples of the present
invention are those in which R.sub.5 is --N(R.sub.B)C(O)OR.sub.A
wherein R.sub.B is selected between hydrogen and alkyl, and R.sub.A
is independently selected from the group consisting of hydrogen,
alkyl, aryl or arylalkyl.
[0055] Other compounds of the present invention are those in which
R.sub.1 is alkyl, cycloalkyl, halogen or haloalkyl, preferably
alkyl, R.sub.2 is hydrogen, R.sub.3 is
##STR00019##
and R.sup.4 is --C(O)R.sub.8, in which R.sub.8 is heterocycle or
N(R.sub.8a)(R.sub.8b) wherein R.sup.8a and R.sub.8b are
independently hydrogen or alkyl. Examples of the present invention
include compounds in which Rg is heterocycle.
[0056] Other compounds of the present invention are those in which
R.sub.1 is alkyl, cycloalkyl, halogen or haloalkyl, preferably
alkyl, R.sub.2 is hydrogen, R.sub.3 is
##STR00020##
and R.sub.4 is --CH.sub.2C(H)(OH)R.sub.9, wherein R.sub.9 is
selected from the group consisting of alkoxyalkyl, --C(O)OR.sub.A,
-alkyl-N(R.sub.B)C(O)OR.sub.A, and heterocyclealkyl. Examples of
the present invention include compounds in which R.sub.9 is
alkoxyalkyl. Other examples include compounds in which R.sub.9 is
--C(O)OR.sub.A and R.sub.A is alkyl. Other examples include
compounds in which R.sub.9 is heterocyclealkyl.
[0057] Other compounds of the present invention include compounds
in which R.sub.1 is alkyl, cycloalkyl, halogen or haloalkyl,
preferably alkyl, R.sub.2 is hydrogen, R.sub.3 is
##STR00021##
and R4 is --C(O)--O--(CH.sub.2).sub.mR.sub.5. Other compounds
included in the invention are those in which, R.sub.1 is alkyl,
cycloalkyl, halogen or haloalkyl, preferably alkyl, R.sub.2 is
hydrogen, R.sub.3 is
##STR00022##
and R.sub.4 is --(O)(CH.sub.2).sub.n--R.sub.6. Other compounds
included in the invention are those in which, R.sub.1 is alkyl,
cycloalkyl, halogen or haloalkyl, preferably alkyl, R.sub.2 is
hydrogen, R.sub.3 is
##STR00023##
and R.sub.4 is and --(CH.sub.2).sub.n--R.sub.7. Other compounds
included in the present invention have R.sub.1 is alkyl or alkenyl,
preferably alkyl, R.sub.2 is heterocyclealkyl, R.sub.3 is
##STR00024##
and R.sub.4 is hydrogen.
[0058] Furthermore, compounds of formula (II) are considered within
the scope of the present invention,
##STR00025##
wherein R.sub.1, R.sub.2, R.sub.3 and t are defined in compounds of
formula (I).
[0059] Other compounds of the present invention include compounds
of formula (III)
##STR00026##
wherein R.sub.1, R.sub.2, R.sub.3 and t are defined in compounds of
formula (I).
[0060] Other compounds of the present invention include compounds
of formula (IV)
##STR00027##
wherein R.sub.1, R.sub.2, R.sub.3 and t are defined in compounds of
formula (I).
[0061] Other compounds of the present invention include compounds
of formula (V)
##STR00028##
wherein R.sub.1, R.sub.2, R.sub.3 and t are defined in compounds of
formula (I).
[0062] The following compounds are contemplated to be within the
scope of the present invention:
##STR00029##
[0063] It is contemplated that any of the embodiments described
above may be combined and the scope of the compounds of the present
invention defined under formula (I) is described by any such
combinations. Compounds and compositions of the invention are
useful for modulating the effects of vanilloid receptor activity,
and more particularly the receptor type TRPV1. In particular, the
compounds and compositions of the invention can be used for
treating and preventing disorders modulated by TRPV1. Typically,
such disorders can be ameliorated by selectively modulating the
TRPV1 receptor in a mammal, preferably by administering a compound
or composition of the invention, either alone or in combination
with another active agent, for example, as part of a therapeutic
regimen. The compounds of the invention, including but not limited
to those specified in the examples, possess an affinity for
TRPV1's. As TRPV1 ligands, the compounds of the invention can be
useful for the treatment and prevention of a number of diseases or
conditions mediated by the TRPV1 activity.
[0064] For example, TRPV1 have been shown to play a significant
role in the release of inflammatory peptides such as, but not
limited to, substance P and CGRP, leading to enhanced peripheral
sensitization of tissue. As such, TRPV1 ligands are suitable for
the treatment of disorders associated with pain and inflammation.
Further, capsazepine, a capsaicin receptor antagonist can reduce
inflammation-induced hyperalgesia in animal models.
[0065] TRPV1 receptors are also localized on sensory afferents,
which innervate the bladder. Capsaicin or resiniferatoxin has been
shown to ameliorate incontinence symptoms upon injection into the
bladder. Therefore, TRPV1 ligands are suitable for the treatment of
disorders associated with urinary incontinence and bladder
dysfunction.
Definition of Terms.
[0066] As used throughout this specification and the appended
claims, the following terms have the following meanings:
[0067] The term "alkenyl" as used herein, means a straight or
branched chain hydrocarbon containing from 2 to 10 carbons and
containing at least one carbon-carbon double bond formed by the
removal of two hydrogens. Representative examples of alkenyl
include, but are not limited to, ethenyl, 2-propenyl,
2-methyl-2-propenyl, 3-butenyl, 4-pentenyl, 5-hexenyl, 2-heptenyl,
2-methyl-1-heptenyl, and 3-decenyl.
[0068] The term "alkoxy" as used herein, means an alkyl group, as
defined herein, appended to the parent molecular moiety through an
oxygen atom. Representative examples of alkoxy include, but are not
limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy,
tert-butoxy, pentyloxy, and hexyloxy.
[0069] The term "alkoxyalkyl" as used herein, means an alkoxy
group, as defined herein, appended to the parent molecular moiety
through an alkyl group, as defined herein. Representative examples
of alkoxyalkyl include, but are not limited to, tert-butoxymethyl,
2-ethoxyethyl, 2-methoxyethyl, and methoxymethyl.
[0070] The term "alkyl" as used herein, means a straight or
branched chain hydrocarbon containing from 1 to 10 carbon atoms.
Representative examples of alkyl include, but are not limited to,
methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl,
tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, 3-methylhexyl,
2,2-dimethylpentyl, 2,3-dimethylpentyl, n-heptyl, n-octyl, n-nonyl,
and n-decyl.
[0071] The term "aryl" as used herein, means phenyl or a bicyclic
aryl. The bicyclic aryl is naphthyl, or a phenyl fused to a
monocyclic cycloalkyl, or a phenyl fused to a monocyclic
cycloalkenyl. The phenyl and the bicyclic aryl groups of the
present invention are unsubstituted or substituted. The bicyclic
aryl is attached to the parent molecular moiety through any carbon
atom contained within the bicyclic aryl. Representative examples of
the aryl groups include, but are not limited to, dihydroindenyl,
indenyl, naphthyl, dihydronaphthalenyl, 1,3-benzodioxolyl,
2,3-dihydro-1,4-benzodioxin-6-yl, and
5,6,7,8-tetrahydronaphthalenyl.
[0072] The term "arylalkyl" as used herein, means an aryl group, as
defined herein, appended to the parent molecular moiety through an
alkyl group, as defined herein. Representative examples of
arylalkyl include, but are not limited to, benzyl, 2-phenylethyl,
3-phenylpropyl, and 2-naphth-2-ylethyl.
[0073] The term "halo" or "halogen" as used herein, means --Cl,
--Br, --I or --F.
[0074] The term "haloalkoxy" as used herein, means an alkoxy group
as defined herein, wherein one to six hydrogen atoms are replaced
by halogens. Representative examples of haloalkoxy include, but are
not limited to, chloromethoxy, 2-fluoroethoxy, trifluoromethoxy,
2-chloro-3-fluoropentyloxy, and pentafluoroethoxy.
[0075] The term "haloalkyl" as used herein, means an alkyl group as
defined herein, wherein one to six hydrogen atoms are replaced by
halogens. Representative examples of haloalkyl include, but are not
limited to, chloromethyl, 2-fluoroethyl trifluoromethyl,
pentafluoroethyl, and 2-chloro-3-fluoropentyl.
[0076] The term "heterocycle" or "heterocyclic" as used herein,
means a monocyclic three-, four-, five-, six-, seven- or
eight-membered ring containing at least one heteroatom
independently selected from the group consisting of O, N, and S.
The three- or four-membered ring contains zero or one double bond,
and one heteroatom selected from the group consisting of O, N and
S. The five-membered ring contains zero or one double bond and one,
two or three heteroatoms selected from the group consisting of O, N
and S. The six-membered ring contains zero, one or two double bonds
and one, two or three heteroatoms selected from the group
consisting of O, N and S. The seven-membered ring contains zero,
one, two, or three double bonds and one, two or three heteroatoms
selected from the group consisting of O, N and S. The monocyclic
heterocycle is unsubstituted or substituted and is connected to the
parent molecular moiety through any carbon atom or any nitrogen
atom contained within the monocyclic heterocycle. Representative
examples of monocyclic heterocycle include, but are not limited to,
azetidinyl, azepanyl, aziridinyl, diazepanyl, 1,3-dioxanyl,
1,3-dioxolan-4-yl, 1,3-dithiolanyl, 1,3-dithianyl, imidazolinyl,
imidazolidinyl, isothiazolinyl, isothiazolidinyl, isoxazolinyl,
isoxazolidinyl, morpholinyl, oxadiazolinyl, oxadiazolidinyl,
oxazolinyl, oxazolidinyl, piperazinyl, piperidinyl, pyranyl,
pyrazolinyl, pyrazolidinyl, pyrrolinyl, pyrrolidinyl,
tetrahydrofuranyl, tetrahydrothienyl, thiadiazolinyl,
thiadiazolidinyl, thiazolinyl, thiazolidinyl, thiomorpholinyl,
1,1-dioxidothiomorpholinyl (thiomorpholine sulfone), thiopyranyl,
and trithianyl.
[0077] The term "heterocyclealkyl" as used herein, means a
heterocycle group, as defined herein, appended to the parent moiety
through an alkyl group, as defined herein. Examples of
heterocyclealkyl of the present invention include, but not limited
to, 2-morpholin-4-yl-ethyl and 2-piperidin-1-yl-ethyl.
[0078] The term "hydroxy" as used herein, means an --OH group.
[0079] The term "hydroxyalkyl" as used herein, means at least one
hydroxy group, as defined herein, appended to the parent molecular
moiety through an alkyl group, as defined herein.
[0080] Representative examples of hydroxyalkyl include, but are not
limited to, hydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl,
2,3-dihydroxypentyl, and 2-ethyl-4-hydroxyheptyl.
[0081] The term "oxo" as used herein, means .dbd.O.
[0082] Compounds of the present invention may exist as
stereoisomers wherein, asymmetric or chiral centers are present.
These stereoisomers are "R" or "S" depending on the configuration
of substituents around the chiral carbon atom. The terms "R" and
"S" used herein are configurations as defined in IUPAC 1974
Recommendations for Section E, Fundamental Stereochemistry, Pure
Appl. Chem., 1976, 45: 13-30. The present invention contemplates
various stereoisomers and mixtures thereof and these are
specifically included within the scope of this invention.
Stereoisomers include enantiomers and diastereomers, and mixtures
of enantiomers or diastereomers. Individual stereoisomers of
compounds of the present invention may be prepared synthetically
from commercially available starting materials that contain
asymmetric or chiral centers or by preparation of racemic mixtures
followed by resolution which is well known to those of ordinary
skill in the art. These methods of resolution are exemplified by
(1) attachment of a mixture of enantiomers to a chiral auxiliary,
separation of the resulting mixture of diastereomers by
recrystallization or chromatography and liberation of the optically
pure product from the auxiliary, (2) direct separation of the
mixture of optical enantiomers on chiral chromatographic columns,
or fractional recrystalization of salt of the compounds of the
present invention with chrial carboxylic acids followed by
neutralization to obtain the pure steroisomer of the compound of
the present invention.
[0083] The compounds and processes of the present invention will be
better understood by reference to the following Examples, which are
intended as an illustration of and not a limitation upon the scope
of the invention. Further, all citations herein are incorporated by
reference.
[0084] Compounds of the invention were named by ACD/ChemSketch
version 5.01 (developed by Advanced Chemistry Development, Inc.,
Toronto, ON, Canada) or were given names consistent with ACD
nomenclature. Alternatively, compounds were assigned names using
ChemDraw Ultra 9.0 (or higher version) (Cambridgesoft). The
practice of assigning names to chemical compounds from structures,
and of assigning chemical structures from given chemical names is
well known to those of ordinary skill in the art.
Preparation of Compounds of the Present Invention
[0085] The compounds of this invention can be prepared by a variety
of synthetic procedures. Representative procedures are shown in,
but are not limited to, Schemes 1-11.
##STR00030##
[0086] As outlined in Scheme 1, ketone containing compounds of
formula (3) may be converted into compounds of formula (8) which
are used in the synthesis of compounds of formula (I). Compounds of
formula (3) when heated in the presence of a compound of formula
(4) or similar chiral amine containing compound in toluene under
Dean-Stark conditions with or without a catalytic amount of acid,
followed by treatement with reducing conditions such as but not
limited to sodium borohydride in ethanol will provide a compounds
of formula (5). Compounds of formula (5) when treated with an
atmosphere of hydrogen in the presence of a palladium catalyst such
as palladium on carbon in solvents such as but not limited to
methanol or ethanol with our without a catalytic amount of an acid
such as acetic acid will provide compounds of formula (8) wherein
R.sub.1 is as defined in formula (I).
[0087] Alternatively, compounds of formula (3) when treated with an
hydroxylamine or O-substituted hydroxylamines such as, but not
limited to methoxyamine, in the presence of a solvent such as, but
not limited to, pyridine or mixtures of ethanol and pyridine at a
temperature from about room temperature to about 50.degree. C. will
provide oximes of formula (6). Oximes of formula (6) can be reduced
in the presence of an atmosphere of hydrogen gas from about 40 to
about 60 psi and a catalyst such as, but not limited to palladium
on carbon at a temperature from about 50.degree. C. to about
70.degree. C. to provide compounds of formula (7). Compounds of
formula (7) made through this method exist as a mixture of
enantiomers that may be resolved by fractional crystallization when
converted to salt with chiral carboxylic acid. Chiral carboxylic
acids useful in forming salts with compounds of formula (7) include
chiral amino acids such as, but not limited to,
N-acetyl-(D)-leucine and N-tert-butyloxycarbonyl phenylalanine. The
fractional crystallization of compounds of formula (7) with chiral
carboxylic acids will provide after neutralization the individual
isomers of (R) or the (S) form of the amine of formula (8).
##STR00031##
[0088] Ureas of general formula (14) wherein R.sub.1 and R.sub.2
are as defined in formula (I) can be prepared as described in
Scheme 2. Indazoles of general formula (10), prepared using the
procedures as described in Example 56C, when treated with a
compound of formula (11), in solvents such as but not limited to
acetonitrile will provide a compound of formula (12). Compounds of
formula (12) when treated with compounds of formula (9) in the
presence of a base such as but not limited to diisopropylethylamine
will provide ureas of formula (13). Typical solvents include but
are not limited to acetonitrile or N,N-dimethylformamide. Ureas of
general formula (13) when treated with sodium hydroxide or
potassium hydroxide will provide indazoles of general formula (14).
Typical solvents include but are not limited to methanol, ethanol
and mixtures of solvents such as N,N-dimethylformamide and
methanol. Compounds of formula (13) and of formula (14) described
in Scheme 2 are drawn to represent chiral compounds which are the
product of using the chiral compound of formula (9). Alternatively,
the use of racemic compounds of formula (7) in this synthetic
pathway will produce racemic mixtures of compounds of formula (13)
and racemic mixtures of compounds of formula (14).
[0089] Alternatively, compounds of formula (10) can be treated with
phosgene or triphosgene and 4-dimethylaminopyridine in a solvent
such as, but not limited to, dichloromethane, followed by treatment
with amines of general formula (9) in a solvent such as, but not
limited to, toluene or tetrahydrofuran or a combination thereof to
provide ureas of general formula (13) wherein R.sub.2 is hydrogen
or heterocyclealkyl.
[0090] It is also known to one skilled in the art that compounds of
formula (10) can be treated with trichloroacetyl chloride and a
base such as, but not limited to, triethylamine in a solvent such
as dichloromethane to provide trichloroacetamides, which in turn
can be treated with amines of formula (9) and a non-nucleophilic
base such as, but not limited to,
1,8-diazabicyclo[5.4.0]undec-7-ene in a solvent such as, but not
limited to, acetonitrile, to provide ureas of general formula (13)
wherein R.sub.2 is hydrogen or heterocyclealkyl. Compounds of
formula (9) wherein R.sub.2 is heterocyclealkyl can be obtained
from amines of formula (8) by treatment with halides of formula
R.sub.2X wherein X is Cl, Br or I, in the presence of a base such
as but not limited to sodium carbonate or potassium carbonate,
optioanally in the presence of catalytic amount of
tetrabutylammonium iodide. The reaction is generally performed in
solvents such as but not limited to N,N-dimethylformamide,
methanol, ethanol, and mixtures thereof.
[0091] Compounds of formula (13) wherein R.sub.2 is
heterocyclealkyl can also be prepared from compounds of formula
(13) wherein R.sub.2 is hydrogen employing the reaction conditions
for the transformation of compounds of formula (8) to compounds of
formula (9).
##STR00032##
[0092] Compounds of formula (16) and (17) wherein r, R.sub.iand
R.sub.7 are as defined in formula (1) can be obtained from
compounds of formula (15) by treatment with halides of formula
R.sub.7(CH.sub.2).sub.rX, wherein X is Cl, Br or I, in the presence
of a base such as but not limited to potassium carbonate, sodium
carbonate or sodium hydride, and optionally in the presence of
tetrabutyl ammonium iodide. The reaction is generally conducted in
a solvent such as, but not limited to N,N-dimethylformamide, and at
a temperature from about room temperature to about 100.degree. C.
The two regioisomers obtained can be separated using purification
techniques such as but not limited to column chromatography on
silica gel.
[0093] The compounds of formula (15), (16) and (17) are drawn to
represent chiral compounds in this Scheme are for clarity purposes
only. The same synthetic strategy may be carried out with the
racemic compound of formula (15), which will produce the racemic
mixtures of compounds of formula (16) and of formula (17).
Similarly, the following schemes also are depicting using a chiral
starting material but alternatively when carried out using a
racemic mixture of a starting material or the opposite enantiomer
will produce a racemic mixture of products or the opposite
enantiomeric product, respectively.
##STR00033##
[0094] Compounds of formula (18) wherein n, R.sub.1 and R.sub.6 are
as defined in formula (1) can be synthesized as outlined in Scheme
4. Acyl chlorides of formula R.sub.6(CH.sub.2).sub.nCOCl, or
anhydrides such as, but not limited to, glutaric anhydride,
succinic anhydride or acetic anhydride, purchased or prepared using
methodologies known to one skilled in the art, and an amine such
as, but not limited to triethylamine, pyridine or mixture thereof,
when treated with imidazoles of formula (15), provides compounds of
formula (18). The reaction can be conducted with or without a
solvent at about room temperature, for a period of about 1 hour to
about 5 days. Example of a solvent that can be employed includes,
but not limited to, tetrahydrofuran.
[0095] Alternatively, compounds of formula (18) can also be
obtained from compounds of formula (15) by treatment with acids of
formula R.sub.6(CH.sub.2).sub.nCOOH, purchased or prepared by known
methodologies, in the presence of a coupling agent such as, but not
limited to, N,N'-dicyclohexylcarbodiimide. The reaction can be
conducted at ambient temperature and in a solvent such as, but not
limited to, dichloromethane, tetrahydrofuran,
N,N-dimethylformamide, or mixture thereof.
##STR00034##
[0096] Compounds of formula (15) can be transformed to compounds of
formula (19) and (20) wherein R.sub.1 and R.sub.8 are as defined in
formula (1) as shown in Scheme 5.
[0097] Treatment of compounds of formula (15) and carbonyl
chlorides of formula R.sub.8COCl wherein R.sub.8 is either
N(R.sub.8a)(R.sub.8b) or a heterocycle wherein the ring nitrogen
atom is attached to the carbonyl moiety of the carbonyl chloride,
followed by separation of the two regioisomers employing known
purification technique such as but not limited to column
chromatograph on silica gel, furnished compounds of formula (19) or
(20). The reaction can be performed in a solvent such as but not
limited to N,N-dimethylformamide, and in the presence of a base
such as but not limited to sodium hydride. Treatment of compounds
of formula (15) with carbonyl chlorides of formula R.sub.8COCl
wherein the carbonyl moiety is appended to the carbon atom of the
heterocycle ring afford compounds of formula (19) under the
forgoing reaction conditions.
[0098] Carbonyl chlorides of formula R.sub.8COCl can be purchased
or prepared from acids of formula R.sub.8COOH with thionyl chloride
in the presence of catalytic amount of N,N-dimethylformamide, at a
temperature of about room temperature, in a solvent such as, but
not limited to, dichloromethane.
##STR00035##
[0099] Compounds of formula (24) wherein R.sub.1, R.sub.5 and m are
as defined in formula (I) can be prepared as outlined in Scheme
6.
[0100] Compounds of formula (15) when treated with compounds of
formula (21) or (23) and a base such as but not limited to
potassium tert-butoxide, in a solvent such as, but not limited to,
N,N-dimethylformamide, at a temperature from about 0.degree. C. to
about room temperature, provides compounds of formula (24).
[0101] Alternatively, compounds of formula (24) can be obtained by
treating compounds of formula (15) with chloroformates of formula
R.sub.5(CH.sub.2)m0C(O)C1 (purchased or prepared by known
methodologies) in the presence of a base such as but not limited to
4-methylmorpholine, in a solvent such as, but not limited to,
tetrahydrofuran.
[0102] Compounds of formula (21) or (23) can be prepared from
alcohols of formula (20), by treatment with 4-nitrophenyl
chloroformate or carbonate of formula (22) respectively, in the
presence of a base such as, but not limited to, triethylamine or
pyridine, in a solvent such as, but not limited to, dichloromethane
or acetonitrile.
##STR00036##
[0103] Compounds of formula (25) or (26) wherein R.sub.1 and
R.sub.9 are as defined in formula (I), can be prepared from
compounds of formula (15), by treatment with substituted oxiranes
(prepared by known methodologies or purchased) and a base such as,
but not limited to, sodium tert-butoxide, sodium carbonate or
potassium carbonate. The two regioisomers obtained can be separated
by column chromatography or other purification techniques known to
one skilled in the art. The reaction can be conducted at an
elevated temperature from about 70.degree. C. to about 120.degree.
C., in a solvent such as, but not limited to, methanol, ethanol, or
acetonitrile.
[0104] It is understood that Schemes 2-7 depicting chiral compounds
is done only for illustrative purposes only, and that the use of a
racemic mixture of one starting material or the opposite enantiomer
will produce a racemic mixture of products or the opposite
enantiomeric product, respectively.
##STR00037##
[0105] More specifically, compounds of the present invention which
contain an amino-indane moiety may be prepared as outlined in
Scheme 8. For example, chloropropionyl chloride when treated with
aluminum chloride in a solvent such as but not limited to methylene
chloride followed by the addition of a compound of formula (28)
will provide a compound of formula (29). Compounds of formula (29)
when treated with concentrated sulfuric acid or poly phosphoric
acid followed by heating will provide compounds of formula (30).
Compounds of formula (30) when treated according to the procedure
outlined in Scheme 1 will provide amines of formula (31).
Furthermore compounds of formula (31) when treated according to the
procedures outlined in Scheme 2 will provide compounds of formula
(32). Compounds of formula (32) when treated according to the
procedures outlined in Scheme 3-5 will provide compounds of formula
(33) which are representative of compounds of the present
invention.
##STR00038##
[0106] As outlined in Scheme 9, compounds of formula (34) when
treated with a ketone substituted with R.sub.11, wherein each
occurance of R.sub.11 are independently hydrogen, alkyl or aryl, or
two R.sub.11 groups that are attached to a single carbon atom or
two adjacent carbon atoms together form a cycloalkyl ring; and a
base such as but not limited to pyrrolidine in a solvent such as
but not limited to toluene heated to reflux containing a Dean-Stark
trap will provide compounds of formula (35). Compounds of formula
(35) when treated according to the procedures outlined in Schemes
1-5 will provide compounds of formula (33), which are
representative of compounds of the present invention.
##STR00039##
[0107] As shown in Scheme 10, compounds of formula (37), wherein
R.sub.1 and t are defined in formula(I) when treated with propargyl
bromide in the presence of a base such as but not limited to
potassium carbonate in a solvent such as but not limited to
acetonitrile will provide compounds of formula (39). Compounds of
formula (39) when treated with N-chlorosuccinimide and silver
acetate in a solvent such as but not limited to acetone with
heating will provide compounds of formula (40). Compounds of
formula (40) when treated with ethylene glycol at reflux will
provide compounds of formula (41). Compounds of formula (41) when
treated according to the procedures outlined in Schemes 1-5 will
provide compounds of formula (42)
##STR00040##
[0108] As outlined in Scheme 11, compounds of formula (43) wherein
R.sub.1 and t are defined in formula (I), when treated with a base
such as cesium carbonate in acetonitrile or sodium hydride in DMF
followed by the treatment with methyl 3-bromopropionate will
provide compounds of formula (44). Compounds of formula (44) when
treated with sodium, lithium or potassium hydroxide in an aqueous
alcoholic solvent will provide compounds of formula (45). Compounds
of formula (45) when heated in the presence of polyphosphoric acid
will provide compounds of formula (46). Compounds of formula (46)
when treated according to conditions outlined in Schemes 1-5 will
provide compounds of formula (47), which are representative of
compounds of the present invention.
[0109] It is understoond that the schemes described herein are for
illustrative purposes and that routine experimentation, including
appropriate manipulation of the sequence of the synthetic route,
protection of any chemical functionality that are not compatible
with the reaction conditions and the removal of such protecting
groups are included in the scope of the invention.
[0110] It is understood that Schemes 8-11 depicting racemic
mixtures of compounds is done only for illustrative purposes only,
and that the use of a single enantiomeric starting material will
produce a single enantiomeric product.
[0111] The following Examples are intended as an illustration of
and not a limitation upon the scope of the invention as defined in
the appended claims.
EXAMPLE 2
N-[(1R)-5-tert-butyl-2,3-dihydro-1H-inden-1-yl]-N'-[1-(2-morpholin-4-yleth-
yl)-1H-indazol-4-yl]urea
[0112] To a solution of compound from Example 56J (150 mg, 0.43
mmol) in 2 ml dimethylformamide was added potassium carbonate (180
mg, 1.3 mmol) and 4-(2-chloro-ethyl)-morpholine hydrochloride (121
mg, 0.65 mmol). The reaction was stirred for eleven days at ambient
temperature. At this point, a catalytic amount (10 mg) of
tetrabutylammonium iodide was added, and the reaction continued for
16 hours longer. The reaction mixture was diluted with water and
filtered. The filtercake was then purified by chromatography on
silica gel, using 5% ethanol/ethyl acetate as solvent, to give 92
mg of the title compound. .sup.1H NMR (300 MHz, DMSO-d.sub.6)
.delta. ppm 8.56 (s, 1H), 8.02 (s, 1H), 7.70 (d, J=7.12 Hz, 1H),
7.17-7.32 (m, 5H), 6.68 (d, J=7.80 Hz, 1H), 5.15 (m, 1H), 4.46 (t,
J=6.61 Hz, 2 14), 3.44-3.53 (m, 4H), 2.87-2.79 (m, 4H), 2.38-2.52
(m, 5H), 1.76-1.90 (m, 1H), 1.28 (s, 9H). MS (ESI) m/e 462
(M+H).sup.+ Calcd. For C.sub.27H.sub.35N.sub.5O.sub.2.0.4H.sub.2O:
C, 69.17; H, 7.70; N, 14.94; Found C, 69.39; H, 7.78; N, 14.95.
EXAMPLE 3
2-{4-[({[(1R)-5-tert-butyl-2,3-dihydro-1H-inden-1-yl]amino}carbonyl)amino]-
-1H-indazol-1-yl}-2-oxoethyl acetate
[0113] To a solution of compound from Example 56J (1.05 g, 3 mmol)
in 10 ml pyridine and 1.5 ml triethylamine was added acetoxyacetyl
chloride (0.54 ml, 0.68 g, 5 mmol). The reaction was stirred at
ambient temperature for four days and the solvent was removed under
reduced pressure. The residue was purified twice by chromatography
on silica gel, using 25% to 40% ethyl acetate/hexane, to give 0.26
g of the title compound. .sup.1H NMR (300 MHz, DMSO-d.sub.6)
.delta. ppm 8.46 (s, 1H) 8.90 (s, 1H), 7.91 (d, J=7.80 Hz, 1H),
7.80 (d, J=8.14 Hz, 1H), 7.54 (t, J=8.14 Hz, 1H), 7.25-7.37 (m,
3H), 6.71 (d, J=8.14 Hz, 1H), 5.49 (s, 2H), 5.17 (m, 1H), 2.89-3.10
(m, 1H), 2.74-2.88 (m, 1H), 2.36-2.52 (m, 1H), 2.19 (s, 3H),
1.71-1.96 (m, 1H), 1.27 (s, 9H). MS (ESI) m/e 489 (M+H).sup.+.
Calcd. For C.sub.25H.sub.28N.sub.4O.sub.4: C, 66.95; H, 6.29; N,
12.49; Found C, 66.74; H, 6.43; N, 12.28.
EXAMPLE 4
methyl
4-({[[(1R)-5-tert-butyl-2,3-dihydro-1H-inden-1-yl](2-morpholin-4-yl-
ethyl)amino]carbonyl}amino)-1H-indazole-1-carboxylate
EXAMPLE 4A
N-[(1R)-5-tert-butyl-2,3-dihydro-1H-inden-1-yl]-N-(2-morpholin-4-ylethyl)a-
mine
[0114] 4-(2-Chloro-ethyl)-morpholine hydrochloride (0.56 g, 3
mmol), compound from Example 56K (1.08 g, 3 mmol), and sodium
carbonate (1.06 g, 10 mmol) were suspended in 5 ml of ethanol and
heated to reflux for four hours. The reaction mixture was then
cooled, stirred for two days at ambient temperature, and diluted
with water. The aqueous solution was extracted with diethyl ether,
and the combined organic layers were dried with magnesium sulfate.
The solvent was removed under vacuum to give 0.85 g crude title
compound as an oil that was used without further purification.
EXAMPLE 4B
methyl
4-({[[(1R)-5-tert-butyl-2,3-dihydro-1H-inden-1-yl](2-morpholin-4-yl-
ethyl)amino]carbonyl}amino)-1H-indazole-1-carboxylate
Step A
[0115] The product of Example 56C (1.9 g, 10 mmol) and
disuccinimidylcarbonate (2.8 g, 11 mmol) in acetonitrile (100 mL)
was stirred for 48 hours under nitrogen atmosphere. The solid was
isolated by filtration, washed with acetonitrile (10 mL) and dried
under vacuum at ambient temperature to give an off-white solid
(2.56 g, 77%).
Step B:
[0116] Example 4A (0.85 g 2.8 mmol) and intermediate from Step A of
Example 4B (0.66 g, 2 mmol) were dissolved in 5 ml
dimethylformamide, and diisopropylethylamine (0.39 g, 0.52 ml, 3
mmol). The reaction was stirred at ambient temperature for 16
hours, then diluted with water and filtered. The solid collected
was purified via flash chromatography using a gradient of 35% to
50% ethyl acetate in hexanes. After evaporation of solvent, the
purified product was further dried by the addition of toluene
followed by evaporation under vacuum, giving 0.70 g of title
compound. .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. ppm 8.27 (s,
1H), 7.83 (d, J=8.48 Hz, 1H), 7.55 (t, J=8.14 Hz, 1H), 7.37 (d,
J=7.46 Hz, 1H), 7.11-7.33 (m, 4H), 5.76 (t, J=7.97 Hz, 1H), 4.04
(s, 3H),3.47-3.51 (m, 4H), 3.11-3.42 (m, 4H), 2.96-3.02 (m, 1H),
2.71-2.89 (m, 1H), 2.33-2.47 (m, 5H), 2.30 (s, toluene, 1.2H),
1.89-2.14 (m, 1H), 1.29 (s, 9H). MS (ESI) m/e 520 (M+H).sup.+.
Calcd. For C.sub.29H.sub.37N.sub.5O4.0.4toluene.0.3H.sub.2O: C,
67.97; H, 7.32; N, 12.46; Found C, 68.07; H, 7.05; N, 12.41.
EXAMPLE 5
N-[(1R)-5-tert-butyl-2,3-dihydro-1H-inden-1-yl]-N'-1H-indazol-4-yl-N-(2-mo-
rpholin-4-ylethyl)urea
[0117] Example 4B (0.49 g, 0.94 mmol) was dissolved in a minimum
amount of methanol. 1 ml of 5M sodium hydroxide in methanol was
added, and the reaction stirred at ambient temperature for one
hour. The reaction mixture was then diluted with water, and the
product collected by filtration. Tituration with diethyl ether
followed by drying under vacuum gave 0.35 g of the title compound.
.sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. ppm 12.94 (s, 1H), 9.38
(s, 1H), 7.80 (s, 1H), 6.83-7.53 (m, 6H), 5.73 (t, J=7.97 Hz, 1H),
3.48-3.51 (m, 4H), 3.38-3.48 (m, 1H), 3.18-3.24 (m, 1H), 2.96-3.01
(m, 1H), 2.80-2.86 (m, 1H), 2.40-2.56(m, 7H), 1.96-2.03 (m, 1H),
1.30 (s, 9H). MS (ESI) m/e 462 (M+H).sup.+. Calcd. For
C.sub.27H.sub.35N.sub.5O.sub.2.0.3tetrahydrofuran.0.1H.sub.2O: C,
69.74; H, 7.93; N, 14.42; Found C, 69.70; H, 7.73; N, 14.30.
EXAMPLE 6
N-{1-[(benzyloxy)acetyl]-1H-indazol-4-yl}-N'-[(1R)-5-tert-butyl-2,3-dihydr-
o-1H-inden-1-yl]urea
[0118] To a solution of compound from Example 56J (1.05 g, 3 mmol)
in 10 ml pyridine and 1.5 ml triethylamine was added
benzyloxy-acetyl chloride (1 ml, 1.11 g, 6 mmol). The reaction was
stirred at ambient temperature for three days and the solvent was
removed under reduced pressure. The residue was dissolved in ethyl
acetate, washed with water, the organic layer dried with magnesium
sulfate, and the solvent removed under reduced pressure. The
residue was purified by chromatography on silica gel, using 2%
methanol in methylene chloride, then titurated with 1:1
ether:hexanes, to give 1.19 g of the title compound. .sup.1H NMR
(300 MHz, DMSO-d.sub.6) .delta. ppm 8.86 (s, 1H), 8.39 (s, 1H),
7.86-7.94 (m, 2H), 7.54 (t, J=8.14 Hz, 1H), 7.30-7.45 (m, 6H), 7.27
(s, 2H), 6.70 (d, J=7.80 Hz, 1H), 5.16 (m, 1H), 5.02 (s, 2H), 4.71
(s, 2H), 2.91-3.01 (m, 1H), 2.77-2.88 (m, 1H), 2.41-2.49 (m, 1H),
1.85 (dd, J=12.55, 7.80 Hz, 1H), 1.28 (s, 9H). MS (ESI) m/e 497
(M+H).sup.+. Calcd. For C.sub.30H.sub.32N.sub.4O.sub.3: C, 72.56;
H, 6.49; N, 11.28; Found C, 72.42; H, 6.52; N, 11.02.
EXAMPLE 7
N-[(1R)-5-tert-butyl-2,3-dihydro-1H-inden-1-yl]-N'-[1-(methoxyacetyl)-1H-i-
ndazol-4-yl]urea
[0119] The title compound was prepared using the procedure as
described in Example 6, substituting methyloxy-acetyl chloride for
benzyloxy-acetyl chloride. .sup.1H NMR (300 MHz, DMSO-d.sub.6)
.delta. ppm 8.86 (s, 1H), 8.40 (s, 1H), 7.88 (dd, J=10.51, 8.14 Hz,
2H), 7.53 (t, J=8.14 Hz, 1H), 7.24-7.32 (m, 3H), 6.70 (d, J=7.80
Hz, 1H), 5.16 (q, J=7.23 Hz, 1H), 4.90 (s, 2H), 3.45 (s, 3H), 2.96
(m, 1H), 2.82 (m, 1H), 2.41-2.48 (m, 1H), 1.79-1.91 (m, 1H), 1.28
(s, 9H). MS (ESI) m/e 421 (M+H).sup.+. Calcd. For
C.sub.24H.sub.28N.sub.4O.sub.3.0.2H.sub.2O: C, 67.97; H, 6.75; N,
13.21; Found C, 68.03; H, 6.68; N, 13.13.
EXAMPLE 8
4-{4-[({[(1R)-5-tert-butyl-2,3-dihydro-1H-inden-1-yl]amino}carbonyl)amino]-
-1H-indazol-1-yl}-4-oxobutanoic acid
[0120] To a solution of Example 56J (2.09 g, 6 mmol) in 50 ml
tetrahydrofuran and 6 ml triethylamine was added succinic anyhdride
(1.20 g 12 mmol). The reaction was stirred 7 days at ambient
temperature, then diluted with water and ethyl acetate, made acidic
with 1N aqueous HCl, and extracted with ethyl acetate. The combined
organic layers were dried with magnesium sulfate and the solvent
removed under reduced pressure to give 2.95 g of the title
compound. .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. ppm 12.21 (s,
1H), 8.87 (s, 1H), 8.42 (s, 1H), 7.88 (m, 2H), 7.50 (t, J=8.14 Hz,
1H), 7.04-7.37 (m, 3H), 6.72 (d, J=7.80 Hz, 1H), 5.17 (m, 1H), 4.03
(q, Ethyl acetate), 3.37-3.42 (m, 2H), 2.89-3.06 (m, 1H), 2.75-2.89
(m, 1H), 2.67-2.71 (m, 2H), 2.33-2.46 (m, 1H), 1.99 (t, Ethyl
acetate), 1.67-1.95 (m, 1H), 1.28 (s, 9H), 1.17 (t, Ethyl acetate).
MS (ESI) m/e 449 (M+H).sup.+. Calcd. For
C.sub.25H.sub.28N.sub.4O.sub.4.0.4ethyl acetate.1.2H.sub.2O: C,
63.22; H, 6.70; N, 11.09; Found C, 63.06; H, 6.26; N, 10.94.
EXAMPLE 9
N-[(1R)-5-tert-butyl-2,3-dihydro-1H-inden-1-yl]-N'-[1-(N,N-dimethylglycyl)-
-1H-indazol-4-yl]urea, trifluoroacetic acid salt
[0121] To a solution of Example 56J (3.48 g, 10 mmol) in 33 ml
pyridine and 10 ml triethylamine was added dimethylamino-acetyl
chloride hydrochloride (4.74 g, 30 mmol). The reaction was stirred
at ambient temperature for two days and the solvent was removed
under reduced pressure. The residue was dissolved in ethyl acetate,
washed with water and saturated aqueous sodium bicarbonate, the
organic layer dried with magnesium sulfate, and the solvent removed
under reduced pressure. The crude product obtained was purified
using reverse-phase HPLC (acetonitrile-water with 0.1%
trifluoroacetic acid as eleuent) to give the title compound.
.sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. ppm 8.98 (s, 1H), 8.54
(s, 1H), 7.85-7.92 (m, 2H), 7.60 (t, J=8.14 Hz, 1H), 7.26-7.33 (m,
3H), 6.75 (d, J=7.80 Hz, 1H), 5.17 (m, 1H), 4.99 (s, 2H), 3.23-3.37
(s, 1H, under H.sub.2O), 2.96 (s, 6H), 2.91-3.01 (m, 1H), 2.77-2.88
(m, 1H), 1.82-1.91 (m, 1H), 1.28 (s, 9H). MS (ESI) m/e 434
(M+14).sup.+. Calcd. For
C.sub.25H.sub.31N.sub.5O.sub.2.1.2trifluoroacetic acid: C, 57.70; H
5.69; N, 12.28; Found C, 57.63; H, 5.51; N, 12.27.
EXAMPLE 10
N-[(1R)-5-tert-butyl-2,3-dihydro-1H-inden-1-yl]-N'-(1-glycoloyl-1H-indazol-
-4-yl)urea
[0122] Example 6 (1.06 g, 2.1 mmol) was dissolved in 10 ml
tetrahydrofuran and was then subjected to hydrogenolysis over
palladium hydroxide (1.10 g of 20% Pd(OH).sub.2 on carbon, wet).
The reaction was stirred at ambient temperature for 16 hours under
a 50 psi hydrogen atmosphere. Filtration and removal of solvent
under vacuum gave 0.54 g of title compound. .sup.1H NMR (300 MHz,
DMSO-d.sub.6) .delta. ppm 8.85 (s, 1H), 8.39 (s, 1H), 7.88 (t,
J=7.80 Hz, 2H), 7.52 (t, J=8.14 Hz, 1H), 7.25-7.37 (m, 3H), 6.70
(d, J=7.80 Hz, 1H), 5.43 (t, J=6.44 Hz, 1H), 5.16 (q, J=7.35 Hz,
1H), 4.87 (d, J=6.44 Hz, 2H), 2.66-3.07 (m, 2H), 2.35-2.48 (m, 1H),
1.78-1.94 (m, 1H), 1.22-1.32 (m, 9H). MS (ESI) m/e 407
(M+H).sup.+
EXAMPLE 11
N-[(1R)-5-tert-butyl-2,3-dihydro-1H-inden-1-yl]-N'-1H-indazol-4-yl-N-(2-pi-
peridin-1-ylethyl)urea
EXAMPLE 11A
((R)-5-tert-Butyl-indan-1-yl)-(2-piperidin-1-yl-ethyl)-amine
[0123] The title compound was prepared using the procedure as
described in Example 4A, substituting 1-(2-chloro-ethyl)-piperidine
hydrochloride for 4-(2-chloro-ethyl)-morpholine hydrochloride. The
crude compound was used without further purification.
EXAMPLE 11B
methyl
4-({[[(1R)-5-tert-butyl-2,3-dihydro-1H-inden-1-yl](2-piperidin-1-yl-
ethyl)amino]carbonyl}amino)-1H-indazole-1-carboxylate
[0124] The title compound was prepared using the procedure as
described in Example 4B, substituting Example 11A for Example 4A.
The crude product was purified using reverse-phase HPLC
(acetonitrile-water with 0.1% trifluoroacetic acid as eleuent) to
give 0.32 g of the desired compound. .sup.1H NMR (300 MHz,
DMSO-d.sub.6) .delta. ppm 9.16 (s, 1H), 8.97 (s, 1H), 8.34 (s, 1H),
7.86 (d, J=8.48 Hz, 1H), 7.46-7.65 (m, 1H), 7.30-7.42 (m, 2H), 7.23
(d, J=7.80 Hz, 1H), 5.73 (t, J=7.80 Hz, 1H), 4.04 (s, 3H),
2.65-3.89 (m, 11H), 2.49-2.65 (m, 1H), 1.30-1.89 (m, 6H), 1.30 (s,
9H). MS (ESI) m/e 518 (M+H).sup.+.
EXAMPLE 11C
N-[(1R)-5-tert-butyl-2,3-dihydro-1H-inden-1-yl]-N'-1H-indazol-4-yl-N-(2-pi-
peridin-1-ylethyl)urea
[0125] The title compound was prepared using the procedure as
described in Example 5, substituting Example 11B for Example 4B.
.sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. ppm 12.89 (br s, 1H),
10.06 (br s, 1H), 7.86 (s, 1H), 7.03-7.41 (m, 6H), 5.77 (t, J=7.97
Hz, 1H), 3.25-3.44 (m, 2H), 3.06-3.22 (m, 1H), 2.89-3.05 (m, 1H),
2.69-2.89 (m, 1H), 2.32-2.48 (m, 6H), 1.83-2.06 (m, 1H), 1.30-1.57
(m, 6H), 1.29 (s, 9H). MS (ESI) m/e 460 (M+H).sup.+. Calcd. For
C.sub.28H.sub.37N.sub.5O.0.1H.sub.2O.0.33NaCl: C, 69.96; H, 7.80;
N, 14.57; Found C, 69.90; H, 7.80; N, 14.37.
EXAMPLE 12
5-{4-[({[(1R)-5-tert-butyl-2,3-dihydro-1H-inden-1-yl]amino}carbonyl)amino]-
-1H-indazol-1-yl}-5-oxopentanoic acid
[0126] To a solution of Example 56J (0.52 g, 1.5 mmol) in 7 ml
tetrahydrofuran and 1.5 ml triethylamine was added glutaric
anyhdride (0.34 g 3 mmol). The reaction was stirred 5 days at
ambient temperature, then was diluted with water and ethyl acetate,
made acidic with IN aqueous HCl, and extracted with ethyl acetate.
The combined organic layers were dried with magnesium sulfate and
the solvent removed under reduced pressure. The residue was found
to contain a large amount of glutaric acid, which was removed by
tituration with water to give 0.61 g of the title compound. .sup.1H
NMR (300 MHz, DMSO-d.sub.6) .delta. ppm 12.10 (br s, 1H), 8.85 (s,
1H), 8.39 (s, 1H), 7.90 (d, J=4.75 Hz, 1H), 7.87 (d, J=5.42 Hz,
1H), 7.50 (t, J=8.14 Hz, 1H), 7.23-7.35 (m, 2H), 6.71 (d, J=8.14
Hz, 1H), 5.09-5.27 (m, 1H), 3.15-3.27 (t, J=7.46 Hz, 2H), 2.89-3.06
(m, 1H), 2.73-2.89 (m, 1H), 2.41-2.48 (m, 1H), 2.37 (t, J=7.29 Hz,
2H), 1.88-2.00 (m, 2H), 1.77-1.89 (m, 1H), 1.28 (s, 9H). MS (ESI)
m/e 463 (M+H).sup.+. Calcd. For
C.sub.26H.sub.30N.sub.4O.sub.4.0.4H.sub.2O: C, 66.48; H, 6.61; N,
11.93; Found C, 66.43; H, 6.38; N, 11.82.
EXAMPLE 13
2-(phosphonooxy)ethyl
4-[({[(1R)-5-tert-butyl-2,3-dihydro-1H-inden-1-yl]amino}carbonyl)amino]-1-
H-indazole-1-carboxylate
[0127] To Example 14D (0.37 g, 0.6 mmol) in a 250 ml round bottom
flask was added acetonitrile (40 ml) and 0.1% trifluoroacetic acid
in water (40 ml) and the reaction was stirred at room temperature
for 4 days. Every 24 hours 0.5 ml of trifluoroacetic acid was
added. After four days, the reaction was concentrated to give a
white powder in 84% yield. .sup.1H NMR (DMSO-d.sub.6, 300 MHz);
.delta. 1.28 (s, 9H), 1.74-1.91 (m, 2H), 2.41-2.54 (m, 1H),
2.77-3.38 (m, 2H), 4.18-4.23 (m, 2H), 4.60-4.63 (m, 2H), 5.13-5.20
(m, 1H), 6.68 (d, J=7.8 Hz, 1H), 7.24-7.28 (m, 2H), 7.50 (t,
J=8.41, 16.18 Hz, 1H), 7.71 (d, J=8.48 Hz, 1H), 7.90 (d, J=8.27 Hz,
1H), 8.41 (s, 1H), 8.84 (s, 1H). MS (DCl/NH.sub.3) m/z 517; Calc
for C.sub.24H.sub.29N.sub.4O.sub.7P: C, 55.04; H, 5.74; N, 10.70.
Found: C, 55.18; H, 5.50; N, 10.52.
EXAMPLE 14
2-[(di-tert-butoxyphosphoryl)oxy]ethyl
4-[({[(1R)-5-tert-butyl-2,3-dihydro-1H-inden-1-yl]amino}carbonyl)amino]-1-
H-indazole-1-carboxylate
EXAMPLE 14A
Carbonic acid 2-benzyloxy-ethyl ester 4-nitro-phenyl ester
[0128] To a 250 ml round bottom flask was added 2-benzyloxyethanol
(7.54 g, 49.60 mmol) (Aldrich), 4-nitrophenyl chloroformate (10 g,
49.60 mmol) (Aldrich), dichloromethane (100 ml) followed by the
addition of pyridine (5.89 g, 79.10 mmol) and the reaction was
stirred at room temperature for 12 hours. The reaction was diluted
with 200 ml of dichloromethane was washed with 1N HCl (100 ml), sat
NaHCO.sub.3 (100 ml), dried (Na.sub.2SO.sub.4) and concentrated in
vacuo. The reaction was purified on SiO.sub.2 and eluted with
hexane/ethyl acetate 4/1 to provide a yellow solid (11.20 g) in 71%
yield. .sup.1H NMR (CDCl.sub.3, 300 MHz); .delta. ppm 3.70-3.80 (m,
2H), 4.30-4.57 (m, 2H), 4.61 (s, 2H), 7.26-7.40 (m, 7H), 8.26 (d,
J=8.82 Hz, 2H); DCl/NH.sub.3 m/z 318.00.
EXAMPLE 14B
2-(benzyloxy)ethyl
4-[({[(1R)-5-tert-butyl-2,3-dihydro-1H-inden-1-yl]amino}carbonyl)amino]-1-
H-indazole-1-carboxylate
[0129] To a 250 ml round bottom flask was added Example 56J (5.0 g,
14.40 mmol), anhydrous N,N-dimethylformamide (40 ml) and 1M in
tetrahydrofuran potassium tert-butoxide (17.30 ml) and the reaction
was stirred at room temperature for 1 hour. To the reaction mixture
was added Example 14A (5.50 g, 17.70 mmol) at 0.degree. C. and the
reaction was stirred for 12 hours while allowing to warm to room
temperature. The reaction was poured into a separatory funnel and
extracted with ethyl acetate (200 ml) and washed with H.sub.2O (100
ml), brine (100 ml), dried (Na.sub.2SO.sub.4) and concentrated in
vacuo. The mixture was purified on SiO.sub.2 eluting with
hexane/ethyl acetate 1/1 to provide a white solid (6.78 g) in 74%
yield. .sup.1H NMR (DMSO-d.sub.6, 300 MHz); .delta. ppm 1.27 (s,
9H), 1.74-1.84 (m, 1H), 2.50-2.60 (m, 1H), 2.73-2.93 (m, 3H), 3.61
(t, J=4.41, 9.16 Hz, 2H), 3.75-3.82 (m, 4H), 5.35-5.37 (m, 1H),
7.13-7.38 (m, 7H), 7.70-7.73 (m, 2H), 7.90-7.94 (m, 1H), 8.32 (s,
1H); MS (DCl/NH.sub.3) m/z 527.00.
EXAMPLE 14C
2-hydroxyethyl
4-[({[(1R)-5-tert-butyl-2,3-dihydro-1H-inden-1-yl]amino}carbonyl)amino]-1-
H-indazole-1-carboxylate
[0130] In a 250 ml Parr shaker flask was added Example 14B (6.0 g,
11.40 mmol), 20% Pd/C, and ethanol (100 ml). The vessel was
pressurized to 60 psi with H.sub.2 gas and shaken at room
temperature for 6 hours. The reaction was filter and concentrated
in vacuo. The material was purified on SiO.sub.2 with
dichloromethane/CH.sub.3OH (98/2) to give a white solid (4.18 g) in
84%. .sup.1H NMR (DMSO-d.sub.6, 300 MHz); .delta. ppm 1.32 (s, 9H),
1.86-1.93 (m, 2H), 2.57-2.63 (m, 1H), 2.84-2.92 (m, 1H), 2.96-3.01
(m, 1H), 3.92-3.95 (m, 2H), 4.55-4.58 (m, 2H), 5.27-5.32 (t,
J=7.12, 14.58, 1H), 7.28-7.31 (m, 2H), 7.52 (t, J=7.80, 16.28, 1H),
7.73 (d, J=7.72 Hz, 1H), 7.87 (d, J=8.48 Hz, 1H), 8.38 (s, 1H); MS
(DCI/NH.sub.3) m/z 437.00.
EXAMPLE 14D
2-[(di-tert-butoxyphosphoryl)oxy]ethyl
4-[({[(1R)-5-tert-butyl-2,3-dihydro-1H-inden-1-yl]amino}carbonyl)amino]-1-
H-indazole-1-carboxylate
[0131] To Example 14C (1.60 g, 3.70 mmol) was added methylene
chloride (25 ml), tetrahydrofuran (25 ml), tetrazole (0.77 g, 11.0
mmol), 4-(dimethylamino)pyridine (0.18 g, 1.50 mmol) and
di-tert-butyl diisopropyl-phosphoramidite (2.04 g, 7.30 mmol)
(Aldrich) and the reaction was stirred at room temperature for 2
hours. The reaction was then cooled to 0.degree. C. and 30%
hydrogen peroxide was added and the mixture was stirred for 2 hours
at room temperature. The reaction was poured into a separatory
funnel and washed with water, sat NaHCO.sub.3, dried over
Na.sub.2SO.sub.4 and concentrated in vacuo. The mixture was
purified by HPLC with acetonitrile and 0.1% trifluoroacetic acid
buffer to give a white solid in 48% yield. .sup.1H NMR (CD.sub.3OD,
300 MHz); .delta. ppm 1.32 (s, 9H), 1.45 (s,18H), 1.83-1.95 (m,2H),
2.52.66 (m, 1H), 2.82-2.90 (m, 1H), 3.92-3.06 (m, 1H), 4.35-4.40
(m, 2H), 4.73-4.84 (m, 2H), 5.29 (t, J=7.26, 14.68 Hz, 1H),
7.28-7.31 (m, 2H), 7.52 (t, J=8.13, 16.27 Hz, 1H), 7.54 (d, J=8.14
Hz, 1H), 7.76 (d, J=7.80 Hz, 1H), 8.37 (s, 1H); MS (DCUNH.sub.3)
m/z 629.00; Calc for C.sub.32H.sub.245N.sub.4O.sub.7P: C, 60.44; H,
7.26; N, 8.81. Found: C, 60.45; H, 7.26; N, 8.68.
EXAMPLE 15
3-(phosphonooxy)propyl
4-[({[(1R)-5-tert-butyl-2,3-dihydro-1H-inden-1-yl]amino}carbonyl)amino]-1-
H-indazole-1-carboxylate
EXAMPLE 15A
Carbonic acid 3-benzyloxy-propyl ester 4-nitro-phenyl ester
[0132] To a 250 ml round bottom flask was added 3-benzyloxypropanol
(8.24 g, 49.60 mmol) (Aldrich), 4-nitrophenyl chloroformate (10 g,
49.60 mmol) (Aldrich), dichloromethane (100 ml) followed by the
addition of pyridine (5.89 g, 79.10 mmol) and the reaction was
stirred at room temperature for 12 hours. The reaction was diluted
with 200 ml of dichloromethane was washed with 1N HCl (100 ml), sat
NaHCO.sub.3 (100 ml), dried (Na.sub.2SO.sub.4) and concentrated in
vacuo. The reaction was purified on SiO.sub.2 and eluted with
hexane/ethyl acetate 4/1 to provide a yellow oil (8.26) in 50%
yield. .sup.1H NMR (CDCl.sub.3, 300 MHz); .delta. ppm 2.03-2.11 (m,
2H), 3.62 (t, J=6.0, 12.0 Hz, 2H), 4.43 (t, J=6.0, 12.0 Hz, 2H),
4.53 (s, 2H), 7.26-7.37 (m, 7H), 8.26(d, J=9.0 Hz, 2H); MS
(DCl/NH.sub.3) m/z 332.0.
EXAMPLE 15B
3-(benzyloxy)propyl
4-[({[(1R)-5-tert-butyl-2,3-dihydro-1H-inden-1-yl]amino}carbonyl)amino]-1-
H-indazole-1-carboxylate
[0133] To a 250 ml round bottom flask was added Example 56J (7.35
g, 21.10 mmol), anhydrous N,N-dimethylformamide (60 ml) and
potassium tert-butoxide (1M in tetrahydrofuran, 25.32 ml) and the
reaction mixture was stirred at room temperature for 1 hour. To the
reaction mixture was added Example 15A (7.0 g, 21.10 mmol) at
0.degree. C., stirred for 12 hours while allowing to warm to room
temperature. The reaction mixture was poured into a separatory
funnel and extracted with ethyl acetate (500 ml) and washed with
H.sub.2O (200 ml), brine (200 ml), dried (Na.sub.2SO.sub.4) and
concentrated in vacuo. The mixture was purified on silica gel and
eluted with hexane/ethyl acetate 1/1 to provide a white solid (4.96
g) in 43% yield. .sup.1H NMR (CDCl.sub.3, 300 MHz); .delta. 1.27
(s, 9H), 1.72-1.87 (m, 1H), 2.07-2.21 (m, 2H), 2.51-2.61 (m, 1H),
2.73-2.94 (m, 3H), 3.64 (t, J=5.77, 16.95 Hz, 2H), 4.49-4.68 (m,
4H), 5.34-5.39 (m, 1H), 7.13-7.38 (m, 7H), 7.70-7.73 (m, 2H),
7.90-7.94 (m, 1H), 8.32 (s, 1H). DCI/NH.sub.3 m/z 540.00.
EXAMPLE 15C
3-hydroxypropyl
4-[({[(1R)-5-tert-butyl-2,3-dihydro-1H-inden-1-yl]amino}carbonyl)amino]-1-
H-indazole-1-carboxylate
[0134] In a 250 ml Parr shaker flask was added product of Example
15B (2.2 g, 4.10 mmol), 20% Pd/C and ethanol (100 ml). The vessel
was pressurized to 60 psi with H.sub.2 gas and shaken at room
temperature for 6 hours. The reaction was filtered and concentrated
in vacuo. The material was purified on SiO.sub.2 with
dichloromethane/CH.sub.3OH (98/2) to give a white solid (1.57 g) in
85%. .sup.1H NMR (CDCl.sub.3, 300 MHz); .delta. ppm 1.28 (s, 9H),
1.81-2.08 (m, 2H), 2.41-2.52 (m, 3H), 2.77-2.87 (m, 1H), 2.91-3.01
(m, 1H), 3.55-3.68 (m, 2H), 4.49 (t, J=4.43, 11.82 Hz,
2H),5.13-5.20 (m, 1H), 7.22-7.27 (m, 2H), 7.50 (t, J=8.14, 16.28
Hz, 1H),6.67 (d, J=9.13 Hz, 1H), 7.89 (d, J=8.14 Hz, 1H), 8.39 (s,
1H); MS (DCl/NH.sub.3) m/z 451.00.
EXAMPLE 15D
3-[(di-tert-butoxyphosphoryl)oxy]propyl
4-[({[(1R)-5-tert-butyl-2,3-dihydro-1H-inden-1-yl]amino}carbonyl)amino]-1-
H-indazole-1-carboxylate
[0135] To the product from Example 15C (1.49 g, 330 mmol) was added
methylene chloride (50 ml), tetrazole (0.70 g, 9.90 mmol),
4-(dimethylamino)pyridine (0.16 g, 1.30 mmol) and di-tert-butyl
diisopropyl-phosphoramidite (3.15 g, 9.90 mmol) (Aldrich) and the
reaction was stirred at room temperature for 2 hours. The reaction
was then cooled to 0.degree. C. and 30% hydrogen peroxide was added
and the mixture was stirred for 2 hours at room temperature. The
reaction was poured into a seperatory funnel and washed with water,
sat NaHCO.sub.3, dried over Na.sub.2SO.sub.4 and concentrated in
vacuo. The mixture was purified on SiO.sub.2 with hexane/ethyl
acetate (1/1) to give a white solid (2.12 g) in 97% yield. .sup.1H
NMR (CDCl.sub.3, 300 MHz); .delta. ppm 1.22 (s, 9H), 1.30(s, 18H),
2.17-2.27 (m, 1H), 2.58-2.65 (m,1H), 2.81-2.94 (m, 1H), 3.20-3.51
(m, 2H), 3.72-3.78 (m, 2H), 4.12-4.18 (m, 2H), 4.59 (t, J=6,78,
13.22, 2H), 5.42 (t, J=7.46, 12.24 Hz, 1H), 7.19-7.32 (m, 2H), 7.45
(t, J=8.14, 16.24 Hz, 1H), 7.76 (d, J=8.48 Hz, 1H), 7.95 (d, J=7.80
Hz, 1H), 8.47 (s, 1H); MS (DCl/NH.sub.3) m/z 642.00.
EXAMPLE 15E
3-(phosphonooxy)propyl
4-[({[(1R)-5-tert-butyl-2,3-dihydro-1H-inden-1-yl]amino}carbonyl)amino]-1-
H-indazole-1-carboxylate
[0136] To the product from Example 15D (2.12 g, 3.30 mmol) in a 250
ml round bottom flask was added acetonitrile (40 ml) and 0.1%
trifluoroacetic acid in water (40 ml) and the reaction was stirred
at room temperature for 4 days. Every 24 hours 0.5 ml of
trifluoroacetic acid was added until day four. The reaction was
concentrated to give a white powder in 81% yield. .sup.1H NMR
(CDCl.sub.3, 300 MHz); .delta. ppm 1.32 (s, 9H), 1.88-1.92 (m, 1H),
2.22-2.26 (m, 2H), 2.57-2.63 (m, 1H), 2.84-2.90 (m, 1H), 2.96-3.32
(m, 1H), 4.21 (m, 2H), 4.65 (t, J=6.11, 12.55 Hz, 2H), 5.29 (t,
J=7.46, 14.58 Hz, 1H), 7.28-7.31 (m, 3H), 7.52 (t, J=8.14, 16.28
Hz, 1H), 7.73 (d, J=7.45 Hz, 1H), 7.83 (d, J=8.48 Hz, 1H), 8.36 (s,
1H); MS (DCl/NH.sub.3) m/z 531.00; Calc for
C.sub.25H.sub.31N.sub.4O.sub.7P: C, 54.45; H, 5.59; N, 9.92. Found:
C, 54.84; H, 5.88; N, 9.92.
EXAMPLE 16
N-[(1R)-5-tert-butyl-2,3-dihydro-1H-inden-1-yl]-N41-(hydroxymethyl)-[1H-in-
dazol-4-yl]urea
[0137] To a solution of compound from Example 56J (67 mg, 0.192
mmol) in 4 mL ethanol was added 0.5 mL of 37% aqueous formaldehyde
solution. The mixture was stirred at room temperature for 3 days,
and then was evaporated in vacuo. The crude product was purified by
silica gel chromatography (96:4 dichloromethane:methanol, eluant)
to afford a white solid, 24 mg (33%). .sup.1H NMR (d.sub.6-DMSO)
.delta. ppm 8.60 (s, 1H), 8.04 (s, 1H), 7.72 (dd; 1H; J=7.2, 0.8
Hz), 7.27 (m, 4H), 6.67 (d, 1H, J=8.0 Hz), 6.64 (t, 1H, J=7.5 Hz),
5.66 (d, 2H, J=7.5 Hz), 5.15 (q, 1H, J=7.5 Hz), 2.87 (m, 2H), 2.43
(m, 1H), 1.82 (m, 1H), 1.28 (s, 9H); MS (ESI.sup.+) m/z 379
(M+H).
EXAMPLE 17
{4-[({[(1R)-5-tert-butyl-2,3-dihydro-1H-inden-1-ylJam i no}
carbonyl)amino]-1H-indazol-1-yl}methyl acetate
[0138] The product from Example 16 (50 mg, 0.132 mmol) and acetic
anhydride (1 mL) were heated for 4 hours at 60.degree.. The mixture
was evaporated in vacuo and chromatographed on silica gel (65:35
hexane:ethyl acetate, eluant) to afford the desired product as a
white solid, 12 mg (22%). .sup.1H NMR (d.sub.6-DMSO) .delta. 8.67
(s, 1H), 8.16 (s, 1H), 7.75 (d, 1H, J=7.5 Hz), 7.27 (m, 5H), 6.67
(d, 1H, J=7.8 Hz), 6.34 (s, 2H), 5.15 (q, 1H, J=6.7 Hz), 2.85 (m,
2H), 2.42 (m, 1H), 2.02 (s, 3H), 1.85 (m, 1H), 1.28 (s, 9H); MS
(ESI.sup.+) m/z 421 (M+H), 443 (M+Na).
EXAMPLE 18
{4-[({[(1R)-5-tert-butyl-2,3-dihydro-1H-inden-1-yl]amino}carbonyl)amino]-1-
H-indazol-1-yl}methyl 3-hydroxypropanoate
EXAMPLE 18A
3-{[tert-butyl(diphenyl)silyl]oxy}propan-1-ol
[0139] To a solution of 1,3-propanediol (1.25 g, 16.4 mmol) in
N,N-dimethylformamide (50 mL) was added imidazole (2.23 g, 32.8
mmol) and tert-butyldiphenylsilyl chloride (4.97 g, 18.1 mmol). The
reaction was stirred for 3 days at room temperature, then was
diluted with ethyl acetate and was washed with water and brine.
Concentration in vacuo afforded the crude product as a thick
colorless oil which was used directly in the next step.
EXAMPLE 18B
3-{[tert-butyl(diphenyl)silyl]oxy}propanoic acid
[0140] Example 18A (.about.5.0 g, 16.4 mmol) was dissolved in
acetone (700 mL) and then chilled in ice. Jones reagent (10 mL,
prepared by dissolution of 26.72 g CrO.sub.3 in 23 mL conc.
H.sub.2SO.sub.4 and dilution to 100 mL with H.sub.2O) was added
slowly. The reaction mixture was stirred in the ice bath for 10
minutes, then the acetone was removed in vacuo. Ethyl acetate was
added, and this solution was washed several times with H.sub.2O and
once with brine. The solution was dried over Na.sub.2SO.sub.4 and
was then evaporated in vacuo to afford a crude yellow oil, 5.9 g
(quantitative). MS (ESI.sup./) m/z 351 (M+Na); MS (ESI.sup.-) m/z
327 (M-H).
EXAMPLE 18C
chloromethyl 3-{[tert-butyl(diphenyl)silyl]oxy}propanoate
[0141] The title compound was prepared from the compound of Example
18B using the procedure as described in Synth. Commun. 2003, 33,
1683. .sup.1H NMR (d.sub.6-DMSO) .delta. 7.58-7.64 (m, 4H),
7.37-7.48 (m, 6H), 5.88 (s, 2H), 3.80 (t, 2H, J=6.1 Hz), 2.68 (t,
2H, J=5.8 Hz), 0.96 (s, 9H).
EXAMPLE 18D
{4-[({[(1R)-5-tert-butyl-2,3-dihydro-1H-inden-1-yl]amino}carbonyl)amino]-1-
H-indazol-1-yl}methyl 3-hydroxypropanoate
[0142] To a solution of compound from Example 56J (500 mg, 1.44
mmol) in N,N-dimethylformamide (8 mL) was added 60% NaH (65 mg,
1.63 mmol). The reaction was stirred at room temperature for 10
minutes and was then treated with Example 18C (1.35 g, .about.40%
pure) in 3 mL N,N-dimethylformamide. The mixture was stirred
overnight at 60.degree. C. and was then evaporated in vacuo. To
this crude mixture in tetrahydrofuran (50 mL) in a polyethylene
bottle was added hydrogen fluoride-triethylamine complex (3 mL).
The reaction was stirred at room temperature for 5 hours and was
then evaporated in vacuo. Chromatography on silica gel (97:3
dichloromethane:methanol to 94:6 dichloromethane:methanol) afforded
the desired product as a white solid. .sup.1H NMR (d.sub.6-DMSO)
.delta. 8.68 (s, 1H), 8.16 (s, 1H), 7.75 (dd; 1H; J=7.5, 1.0 Hz),
7.27-7.37 (m, 5H), 6.68 (d, 1H, J=7.8 Hz), 6.35 (s, 2H), 5.15 (q,
1H, J=6.9 Hz), 4.69 (t, 1H, J=5.0 Hz), 3.60 (m, 2H), 2.73-3.01 (m,
2H), 2.44 (t, 2H, J=6.1 Hz), 1.78-1.92 (m, 2H), 1.28 (s, 9H); MS
(ESI.sup.+) m/z 451 (M+H).
EXAMPLE 19
(phosphonooxy)methyl
4-[({[(1R)-5-tert-butyl-2,3-dihydro-1H-inden-1-yl]amino}carbonyl)amino}-1-
H-indazole-1-carboxylate
EXAMPLE 19A
Thiocarbonic acid O-sec-butyl ester O-chloromethyl ester
[0143] Sodium methoxide (11.5 g 0.2 moles) of 95% was added to 200
ml of methanol and the solution was cooled to 0.degree. C.
Sec-butanethiol (21.4 ml, 0.2 mol) was then added dropwise and the
solution stirred for 2 hours. The solvent was removed and the
residue was evaporated from ether twice. 300 ml of diethyl ether
was added to the residue and the mixture was cooled to -78.degree.
C. Chloromethyl chloroformate (19 ml, 0.2 mol) in 75 ml of ether
was added dropwise and the reaction mixture was allowed to warm to
room temperature and then stirred for 18 hours. The reaction was
filtered through celite and washed with ether. The filtrate was
evaporated, resuspended in in ether and filtered through a silica
plug, and the solvent was evaporated to give 29 g of a clear
liquid. .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. ppm 0.94 (t,
J=7.29 Hz, 3H) 1.36-1.48 (m, 2H) 1.60-1.70 (m, 2H) 2.89-2.95 (m,
2H) 5.76 (s, 2H).
EXAMPLE 19B
Thiocarbonic acid O-sec-butyl ester O-iodomethyl ester
[0144] Example 19A (6.0 g 33 mmol) in 45 mL of acetone was combined
with (9.8 g 66 mmol) of sodium iodide and (0.3 g 3.3 mmol) of
sodium bicarbonate and heated at 40.degree. C. for 4 hours. 100 ml
of diethyl ether was added and the mixture was washed with 10%
sodium bicarbonate then 1% sodium thiosulfate until the organic
phase was clear. The organic phase was dried with sodium sulfate
and the solvent was evaporated. The residue was resuspended in
pentane and the organic layer was washed with 10% sodium
bicarbonate then 1% sodium thiosulfate. The organic phase was then
dried with magnesium sulfate and the solvent was evaporated to give
7.3 g of a clear oil. .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. ppm
0.93 (t, J=7.29 Hz, 3H) 1.35-1.48 (m, 2H) 1.58-1.70 (m, 2H)
2.88-2.94 (m, 2H) 5.99 (s, 2H).
EXAMPLE 19C
O-({[bis(benzyloxy)phosphoryl]oxy}methyl)O-(sec-butyl)thiocarbonate
[0145] The product of Example 19B (7.3 g, 27 mmoles) and
tetrabutylammonium dibenzylphosphate (13.8 g, 26.6 mmol)were mixed
in 20 ml of tetrahydrofuran and stirred at room temperature for 24
hours. The mixture was diluted with 100 mL of tetrahydrofuran,
filtered through celite and the solvent was evaporated. The residue
was resuspended in 200 mL of 20% ethyl acetate in hexane and the
precipitate was filtered and washed with an additional 100 mL of
20% ethyl acetate. The organic filtrates were combined and the
solvent was evaporated. Final product was obtained by flash
chromatography on silica using 20% ethyl acetate in hexane.
Fractions containing product were combined and the solvent was
removed to give 8.7 g (78%) of a colorless oil. .sup.1H NMR (300
MHz, CDCl.sub.3) .delta. ppm 0.91 (t, J=7.29 Hz, 3H) 1.31-1.45 (m,
2H) 1.55-1.65 (m, 2H) 2.80-2.90 (m, 2H) 5.07 (d, J=7.80 Hz, 4H)
5.65 (d, J=13.90 Hz, 2H) 7.34 (s, 10H).
EXAMPLE 19D
O-dibenzylphosphonooxymethyl chloroformate
[0146] 7.3 g (17 mmol) of the compound from Example 19C was cooled
to 4.degree. C. 1.7 mL (21 mmol) of sulfuryl chloride was added
dropwise. Reaction was stirred at 4.degree. C. for an additional 20
minutes, the cooling bath was removed and the mixture was allowed
to stir at room temperature for an additional 3 hours. Diethyl
ether was added and then was evaporated under vacuum. The remaining
oil was dried under high vacuum for 18 hours yielding 6.1 g
(quantitative) of a colorless oil. .sup.1H NMR (300 MHz,
CDCl.sub.3) .delta. ppm 5.08 (d, J=8.14 Hz, 4H) 5.62 (d, J=14.24
Hz, 2H) 7.35 (s, 10H).
EXAMPLE 19E
{[bis(benzyloxy)phosphoryl]oxy}methyl
4-[({[(1R)-5-tert-butyl-2,3-dihydro-1H-inden-1-yl]amino}carbonyl)amino]-1-
H-indazole-1-carboxylate
[0147] 1.6 g (4.6 mmol) of compound from Example 56J in 15 mL of
tetrahydrofuran was cooled to -40.degree. C. in an acetonitrile dry
ice bath. 1 mL (9.1 mmol) of 4-methylmorpholine was added, then 4.1
g (11 mmol) of compound from Example 19D was added dropwise. The
reaction was stirred at -40.degree. C. for 20 minutes then the ice
bath removed and the reaction allowed to warm to room temperature.
The mixture was diluted with 200 mL of diethyl ether, extracted 4
times with 25 mL of water, dried over magnesium sulfate, 2 mL of
dimethylformamide was added and the ether removed by rotory
evaporation leaving a clear oil which was purified by reverse phase
HPLC with 0.1% trifluoroacetic acid in water and acetonitrile as
mobile phases to provide 1.3 g of a white powder. .sup.1H NMR (400
MHz, DMSO-d.sub.6) .delta. ppm 1.31 (s, 9H) 1.88-1.98 (m, 1H)
2.48-2.57 (m, 1H) 2.87 (m, 1H) 2.97-3.05 (m, 1H) 5.16 (d, J=7.98
Hz, 4H) 5.26 (q, J=7.06 Hz, 1H) 6.05 (d, J=14.73 Hz, 2H) 6.79 (d,
J=7.67 Hz, 1H) 7.29-7.39 (m, 13H) 7.55 (t, J=8.13 Hz, 1H) 7.74 (d,
J=8.29 Hz, 1H) 8.01 (d, J=7.98 Hz, 1H) 8.53 (s, 1H) 8.97 (s, 1H).
MS(ESI) m/z 683.3 (M+H).sup.+.
EXAMPLE 19F
(phosphonooxy)methyl
4-[({[(1R)-5-tert-butyl-2,3-dihydro-1H-inden-1-yl]amino}carbonyl)amino]-1-
H-indazole-1-carboxylate
[0148] 1.3 g (1.9 mmol) of Example 19E in 150 mL of tetrahydrofuran
was added to 0.7 g of 20% Pd(OH).sub.2 on carbon, wet, under argon.
The vessel was charged to 60 psi with hydrogen and reacted for 3.2
hours with shaking. The catalyst was removed by filtration and the
solvent removed. The compound was purified by reverse phase HPLC
with 0.1% trifluoroacetic acid in water and acetonitrile as mobile
phases to obtain 0.3 g of title compound. .sup.1H NMR (300 MHz,
DMSO-d.sub.6) .delta. ppm 1.28 (s, 9H) 1.79-1.91 (m, 1H) 2.41-2.48
(m, 1H) 2.77-2.88 (m, 1H) 2.91-3.01 (m, 1H) 5.16 (q, J=7.35 Hz, 1H)
5.84 (d, J=14.24 Hz, 2H) 6.69 (d, .1=7.80 Hz, 1H) 7.25-7.33 (m, 3H)
7.52 (t, J=8.14 Hz, 1H) 7.72 (d, J=8.48 Hz, 1H) 7.90 (d, J=7.80 Hz,
1H) 8.44 (s, 1H) 8.86 (s, 1H)MS (DCl/NH.sub.3) m/z 503.2 (M
+H).sup.+.
EXAMPLE 20
3-{4-[({[(1R)-5-cert-butyl-2,3-dihydro-1H-inden-1-yl]amino}carbonyl)amino]-
-1H-indazol-1-yl}-3-oxopropyl dihydrogen phosphate
EXAMPLE 20A
3-{[bis(benzyloxy)phosphoryl]oxy}propanoic acid
[0149] The water was removed in vacuo from 3-hydroxy-propionic acid
and the residue dried twice from toluene. 0.8 g (8.9 mmol), and
dissolved in 10 mL of dry tetrahydrofuran. 1 ml (9 mmol) of
4-methyl-morpholine was added, then 10 mL of a 1 M solution of
tert-butyldimethylsilyl chloride in tetrahydrofuran was added and
the mixture stirred at room temperature for 10 minutes. 5 g (14.5
mmol) of dibenzyl diisopropylphosphoramidite and 1.2 g (17.1 mmol)
of tetrazole was premixed in 20 mL of tetrahydrofuran then added to
the reaction mixture and allowed to react at room temperature for
30 minutes. The mixture was cooled to 0.degree. C. in an ice bath,
then 3.5 mls of 35% aqueous hydrogen peroxide was added and the
mixture stirred for 30 minutes. 10 mL of 10% sodium bisulfite was
added slowly then 200 mL of diethyl ether. The organic phase was
washed three times with 10% potassium dihydrogen phosphate, dried
over magnesium sulfate and the was solvent evaporated. Product was
obtained by flash chromatography of the crude material on silica
using hexanes and ethyl acetate (70:30). .sup.1H NMR (300 MHz,
CDCl.sub.3) .delta. ppm 2.65 (t, J=6.10 Hz, 2H) 4.26 (q, J=6.44 Hz,
2H) 5.04 (d, J=8.14 Hz, 4H) 7.33 (s, 10H). MS (ESI) m/z 351.1 (M
+H).sup.+.
EXAMPLE 20B
dibenzyl
3-{4-[({[(1R)-5-tert-butyl-2,3-dihydro-1H-inden-1-yl]amino}carbon-
yl)amino]-1H-indazol-1-yl}-3-oxopropyl phosphate
[0150] 1.1 g (3.1 mmol) of Example 20A in 8 mL of dichloromethane
and 3.1 mL of a 1M solution of N,N'-dicyclohexylcarbodiimide in
dichloromethane were mixed and 1.0 g (2.9 mmol) of Example 56J in 8
mL of dimethylformamide was added. The mixture was allowed to react
at room temperature for 18 hours. 200 mL of diethyl ether was added
to the mixture and the organic phase was washed three times with
water, dried over magnesium sulfate and the solvent removed. The
product was isolated by flash chromatography on silica using
hexanes and ethyl acetate (80:20). .sup.1H NMR (300 MHz,
DMSO-d.sub.6) .delta. ppm 1.28 (s, 9H) 1.79-1.92 (m, 1H) 2.41-2.49
(m, 1H) 2.77-2.89 (m, 1H) 2.91-3.02 (m, 1H) 3.56 (t, J=5.93 Hz, 2H)
4.39-4.49 (m, 2H) 5.01 (d, J=8.14 Hz, 4H) 5.17 (q, J=7.23 Hz, 1H)
6.70 (d, J=7.80 Hz, 1H) 7.25-7.38 (m, 13H) 7.52 (t, J=8.14 Hz, 1H)
7.89 (t, J=8.14 Hz, 2H) 8.41 (s, 1H) 8.85 (s, 1H). MS(ESI) m/z
681.5 (M+H).sup.+.
EXAMPLE 20C
3-{4-[({[(1R)-5-tert-butyl-2,3-dihydro-1H-inden-1-yl]amino}carbonyl)amino]-
-1H-indazol-1-yl}-3-oxopropyl dihydrogen phosphate
[0151] 0.45 g (0.7 mmol) of Example 20B in 100 mL of
tetrahydrofuran was added to 0.7 g of 20% Pd(OH).sub.2 on carbon,
wet, under argon. The vessel was charged to 60 psi with hydrogen
and reacted for 3.2 hours with shaking. The catalyst was removed by
filtration and the solvent was evaporated. The compound was
purified by reverse phase HPLC with 0.1% trifluoroacetic acid in
water and acetonitrile as mobile phases to obtain 0.15 g of title
compound. .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. ppm 1.28 (s,
9H) 1.79-1.92 (m, 1H) 2.41-2.49 (m, 1H) 2.76-2.88 (n, 1H) 2.89-3.01
(m, 1H) 3.53 (t, J=6.27 Hz, 2H) 4.23-4.32 (m, 2H) 5.17 (q, J=7.12
Hz, 1H) 6.71 (d, J=7.80 Hz, 1H) 7.25-7.33 (m, 3H) 7.52 (t, J=8.14
Hz, 1H) 7.89 (t, J=7.46 Hz, 2H) 8.42 (d, J=0.68 Hz, 1H) 8.86 (s,
1H). MS(ESI) m/z 501.3 (M+H).sup.+.
EXAMPLE 21
[({4-[({[(1R)-5-tert-butyl-2,3-dihydro-1H-inden-1-yl]amino}carbonyl)amino]-
-1H-indazol-1-yl}carbonyl)oxy]methylphosphonic acid
EXAMPLE 21A
Hydroxymethyl-phosphonic acid dibenzyl ester
[0152] Charged an Emrys 5 mL process vial with 2.0 g (7.63 mmol)
dibenzyl phosphite, 229 mg (7.63 mmol) paraformaldehyde powder, and
0.11 mL (0.76 mmol) triethylamine. The white mixture was heated in
a microwave (Personal Chemistry) at 130.degree. for 5 minutes. The
crude oil was purified on silica gel, eluting with 50-100% ethyl
acetate in hexane to provide 947 mg (42% yield) of the title
compound, a colorless oil. MS (ESI) m/z: 181.1, 293.0 [M+H].sup.+
.sup.1H NMR (DMSO-d.sub.6) .delta.: 3.83 (m, 2H), 5.02 (d, 4H),
5.50 (m, 1H), 7.37 (m, 10H).
EXAMPLE 21B
(4-Nitro-phenoxycarbonyloxymethyl)-phosphonic acid dibenzyl
ester
[0153] Charged a round bottom flask with 20 mL dichloroethane, 947
mg (3.24 mmol) of Example 21A, 718 mg (3.56 mmol) 4-nitrophenyl
chloroformate, and 0.31 mL (3.89 mmol) pyridine. The reaction
mixture was stirred at 0.degree. C. for 40 minutes, treated with 50
mL ethyl acetate, filtered through a silica gel plug, rinsed with
ethyl acetate, and concentrated. The crude oil was purified on
silica gel with 30-70% ethyl acetate in hexane to provide 1.429 g
(97% yield) of the title compound. MS (ESI) m/z: 181.0, 351.1,
458.1 [M+H].sup.+ 1H NMR (DMSO-d.sub.6) .delta.: 4.71 (d, 2H), 5.11
(d, 4H), 7.39 (m, 10H), 7.48 (d, 2H), 8.29 (d, 2H).
EXAMPLE 21C
[bis(benzyloxy)phosphoryl]methyl
4-[({[(1R)-5-tert-butyl-2,3-dihydro-1H-inden-1-yl]amino}carbonyl)amino]-1-
H-indazole-1-carboxylate
[0154] Dissolved 990 mg (2.84 mmol) of Example 56J in 10 mL
N,N-dimethylformamide solution, added 3.12 mL (3.12 mmol) 1.0M
potassium tert-butoxide in tetrahydrofuran, stirred for 5 minutes
at ambient temperature, then added 1.429 g (3.12 mmol) of Example
21B in 10 mL N,N-dimethylformamide. After 15 minutes, the solution
was partitioned between 200 mL ethyl acetate and 200 mL H.sub.2O,
dried the organic layer with brine and Na.sub.2SO.sub.4, and
concentrated. The crude oil was purified on silica gel, eluting
with 50-100% ethyl acetate in hexane to obtain 1.622 g (86%) of
title compound as yellow foam. MS (ESI) m/z: 349.1, 667.30
[M+H].sup.+ 1H NMR (DMSO-d.sub.6) .delta.: 1.28 (s, 9H), 1.79-1.91
(m, 1H), 2.41-2.47 (m, 1H), 2.79-2.87 (m, 1H), 2.91-3.01 (m, 1H),
4.94 (d, 2H), 5.11-5.23 (m, 5H), 6.70 (d, 1H), 7.27 (s, 2H),
7.29-7.41 (m, 11H), 7.45 (t, 1H), 7.62 (d, 1H), 7.89 (d, 1H), 8.44
(s, 1H), 8.86 (s, 1H).
EXAMPLE 21D
[({4-[({[(1R)-5-tert-butyl-2,3-dihydro-1H-inden-1-yl]amino}carbonyl)amino]-
-1H-indazol-1-yl}carbonyl)oxy]methylphosphonic acid
[0155] 1.5 g (2.25 mmol) of the compound from Example 21C was added
to a mixture of 0.3 g 20% Pd(OH).sub.2/C and 150 mL methanol in a
stainless steel autoclave. The reactor was sealed and flushed with
nitrogen, and then it was pressurized with hydrogen (60 psi). The
mixture was stirred at ambient temperature for 90 minutes. Product
precipitated, added 150 mL tetrahydrofuran to redissolve, catalyst
was filtered off, washed with methanol and tetrahydrofuran, and the
filtrate was concentrated to provide 1.08 g (99%) of the title
compound. MS (ESI) m/z: 485.21 [M-H].sup.- 1H NMR (DMSO-d.sub.6)
.delta.: 1.28 (s, 9H), 1.81-1.88 (m, 1H), 2.42-2.48 (m, 1H),
2.79-2.87 (m, 1H), 2.91-3.01 (m, 1H), 4.56 (d, 2H), 5.16 (q, 1H),
6.69 (d, 1H), 7.27 (s, 2H), 7.31 (s, 1H), 7.50 (t, 1H), 7.72 (d,
1H), 7.89 (d, 1H), 8.43 (s, 1H), 8.85 (s, 1H).
EXAMPLE 22
[({4-[({[(1R)-5-tert-butyl-2,3-dihydro-1H-inden-1-yl]amino}carbonyl)amino}-
-1H-indazol-1-yl}carbonyl)oxy]methylphosphonic acid triethylamine
salt
[0156] Suspended 50.2 mg (103 .mu.mol) of compound from Example 21D
in 10 mL methanol, added 10.4 mg (103 .mu.mol) triethylamine,
stirred the colorless solution for 10 minutes at ambient
temperature, concentrated and vacuum dried. Obtained 61 mg (100%
yield) of the title compound as an off-white powder. .sup.1H NMR
(methanol-d.sub.4) .delta.: 1.29 (t, 9H), 1.32 (s, 9H), 1.90 (m,
1H), 2.59 (m, 1H), 2.89 (m, 1H), 3.00 (m, 1H), 3.16 (q, 6H), 4.54
(d, 2H), 5.29 (t, 1H), 7.28 (s, 2H), 7.31 (s, 1H), 7.52 (t, 1H),
7.74 (d, 1H), 7.97 (d, 1H), 8.36 (s, 1H). Anal Calcd for
C.sub.23H.sub.27N.sub.4O.sub.6P.1.0 triethylamine.0.7 methanol: C,
58.47; H, 7.40; N, 11.48. Found: C, 58.46; H, 7.38; N, 11.44.
EXAMPLE 23
2-methoxyethyl
4-[({[(1R)-5-tert-butyl-2,3-dihydro-1H-inden-1-yl]amino}carbonyl)amino]-1-
H-indazole-1-carboxylate
[0157] The title compound was prepared using the procedure as
described in Example 21C, substituting methoxyethoxychloroformate
for Example 21B. MS (ESI) m/z: 450.78 [M+H].sup.+ 1H NMR
(DMSO-d.sub.6) .delta.: 1.28 (s, 9H), 1.86 (m, 1H), 2.48 (m, 1H),
2.85 (m, 1H), 2.96 (m, 1H), 3.33 (S, 3H), 332 (m, 2H), 4.57 (m,
2H), 5.15 (q, 1H), 6.67 (d, 1H), 7.27 (s, 2H), 7.31 (s, 1H), 7.50
(t, 1H), 7.67 (d, 1H), 7.88 (d, 1H), 8.40 (s, 1H), 8.84 (s, 1H).
Anal Calcd for C.sub.25H.sub.30N.sub.4O.sub.4: C, 66.65; H, 6.71;
N, 12.44. Found: C, 66.22; H, 6.75; N, 12.25.
EXAMPLE 24
(2,2-dimethyl-1,3-dioxolan-4-yl)methyl
4-[({[(1R)-5-tert-butyl-2,3-dihydro-1H-inden-1-yl]amino}carbonyl)amino]-1-
H-indazole-1-carboxylate
EXAMPLE 24A
Carbonic acid 2,2-dimethyl[1,3]dioxolane-4-ylmethyl ester
2,5-dioxo-pyrrolidin-1-yl ester
[0158] To a solution of (2,2-dimethyl-[1,3]dioxolan-4-yl)-methanol
(0.4 g, 3.0 mmol) in acetonitrile (10 mL) was added carbonic acid
bis-(2,5-dioxo-pyrrolidin-1-yl) ester (1.15 g, 4.5 mmol) and
triethylamine (0.84 mL, 6.0 mmol). After stirring at ambient
temperature for 10 min, the mixture was concentrated at reduced
pressure, sat. NaHCO.sub.3 (50 mL) was added, and the solution was
extracted with ethyl acetate and organic phase was separated and
concentrated to obtain 1.0 g of crude product that was used without
further purification in the next step. MS (APCI) m/z: 273
[M+H].sup.+ 1H NMR (DMSO-d.sub.6) .delta.: 4.50 (m, 1H), 4.40-4.29
(m, 2H), 4.04 (m, 1H), 3.73 (dd, J=6.0 and 9.0 Hz, 1H), 2.80 (s,
4H), 1.35 (s, 3H), 1.30 (s, 3H).
EXAMPLE 24B
(2,2-dimethyl-1,3-dioxolan-4-yl)methyl
4-[({[(1R)-5-tert-butyl-2,3-dihydro-1H-inden-1-yl]amino}carbonyl)amino]-1-
H-indazole-1-carboxylate
[0159] The title compound was prepared using the procedure as
described in Example 21C, substituting Example 24A for Example 21B.
MS (ESI) m/z: 507.14 [M+H].sup.+ 1H NMR (DMSO-d.sub.6) .delta.:
1.28 (s, 9H), 1.30 (s, 3H), 1.35 (s, 3H), 1.86 (m, 1H), 2.48 (m,
1H), 2.85 (m, 1), 2.96 (m, 1H), 3.84 (dd, 1H), 4.10 (dd, 1H), 4.45
(m, 3H), 5.15 (q, 1H), 6.67 (d, 1H), 7.27 (s, 2H), 7.31 (s, 1H),
7.50 (t, 1H), 7.69 (d, 1H), 7.88 (d, 1H), 8.40 (s, 1H), 8.83 (s,
1H). Anal Calcd for C.sub.28H.sub.34N.sub.4O.sub.5.1.4H.sub.2O: C,
63.24; H, 6.97; N, 10.53. Found: C, 63.16; H, 6.60; N, 10.90.
EXAMPLE 25
(2-oxo-1,3-dioxolan-4-yl)methyl
4-[({[(1R)-5-tert-butyl-2,3-dihydro-1H-inden-1-yl]amino}carbonyl)amino]-1-
H-indazole-1-carboxylate
EXAMPLE 25A
Carbonic acid 2,5-dioxo-pyrrolidin-1-yl ester
2-oxo-[1,3]dioxolan-4-ylmethyl ester
[0160] The title compound was prepared using the procedure as
described in Example 24A, substituting
4-hydroxymethyl41,3]dioxolan-2-one for
(2,2-dimethyl-[1,3]dioxolan-4-yl)-methanol. MS (APCI) m/z: 259
[M+H].sup.+ 1H NMR (DMSO-d.sub.6) .delta.: 5.13 (m, 1H), 4.61 (m,
3H), 4.31 (dd, J=6.0 and 9.0 Hz, 1H), 2.80 (s, 4H).
EXAMPLE 25B
(2-oxo-1,3-dioxolan-4-yl)methyl
4-[({[(1R)-5-tert-butyl-2,3-dihydro-1H-inden-1-yl]amino}lcarbonyl)amino]--
1H-indazole-1-carboxylate
[0161] The title compound was prepared using the procedure as
described in Example 21C, substituting Example 25A for Example 21B.
MS (ESI) m/z: 492.93 [M+H].sup.+ 1H NMR (DMSO-d.sub.6) .delta.:
1.28 (s, 9H), 1.86 (m, 1H), 2.48 (m, 1H), 2.85 (m, 1H), 2.96 (m,
1H), 4.44 (dd, 1H), 4.66 (m, 3H), 5.15 (q, 1H), 5.24 (m, 1H), 6.68
(d, 1H), 7.27 (s, 2H), 7.31 (s, 1H), 7.51 (t, 1H), 7.64 (d, 1H),
7.89 (d, 1H), 8.42 (s, 1H), 8.85 (s, 1H). Anal Calcd for
C.sub.26H.sub.28N.sub.4O.sub.6.0.8H.sub.2O: C, 61.60; H, 5.89; N,
11.05. Found: C, 61.62; H, 5.66; N, 11.07.
EXAMPLE 26
2-hydroxyethyl
4-[({[(1R)-5-tert-butyl-2,3-dihydro-1H-inden-1-yl]amino}carbonyl)amino]-1-
H-indazole-1-carboxylate
EXAMPLE 26A
2-(benzyloxy)ethyl
4-[({[(1R)-5-tert-butyl-2,3-dihydro-1H-inden-1-yl]amino}carbonyl)amino]-1-
H-indazole-1-carboxylate
[0162] The title compound was prepared using the procedure as
described in Example 21C, substituting benzyloxyethoxychloroformate
for Example 21B MS (ESI) m/z: 525 [M-H].sup.+ 1H NMR (DMSO-d.sub.6)
.delta.: 1.28 (s, 9H), 1.86 (m, 1H), 2.44 (m, 1H), 2.82 (m, 1H),
2.95 (m, 1H), 3.82 (m, 2H), 4.61 (m, 2H), 4.96 (s, 1H), 5.15 (m,
1H), 6.67 (d, J=4.5 Hz,1H), 7.38-7.25 (m, 9H), 7.48 (t, J=4.5 Hz,
1H), 7.70 (d, J=6.0 Hz, 1H), 7.90 (d, J=6.0 Hz, 1H), 8.40 (s, 1H),
8.84 (s, 1H).
EXAMPLE 26B
2-hydroxyethyl
4-[({[(1R)-5-tert-butyl-2,3-dihydro-1H-inden-1-yl]amino}carbonyl)amino]-1-
H-indazole-1-carboxylate
[0163] Example 26A (0.41 g, 0.77 mmol) and 20% Pd(OH).sub.2/C (0.42
g, 0.6 mmol) in ethyl acetate (10 mL) was hydrogenated at ambient
temperature at 50 psi for 2 hours. The resulting mixture was
filtered through a nylon filter and concentrated to obtain the
title compound (0.29 g, 86%). MS (ESI) m/z: 437.0 [M+H].sup.+ 1HNMR
(DMSO-d.sub.6) .delta.: 1.28 (s, 9H), 1.86 (m, 1H), 2.48 (m, 1H),
2.85 (m, 1H), 2.95 (m, 1H), 3.82 (q, 2H), 4.46 (dd, 2H), 5.00 (t,
1H), 5.15 (q, 1H), 6.67 (d, 1H), 7.27 (s, 2H), 7.31 (s, 1H), 7.49
(t, 1H), 7.69 (d, 1H), 7.87 (d, 1H), 8.40 (s, 1H), 8.84 (s, 1H).
Anal Calcd for C.sub.24H.sub.28N.sub.4O.sub.4: C, 66.04; H, 6.47;
N, 12.84. Found: C, 65.63; H, 6.54; N, 11.94.
EXAMPLE 27
2-(benzyloxy)-2-oxoethyl
4-[({[(1R)-5-tert-butyl-2,3-dihydro-1H-inden-1-yl]amino}carbonyl)amino]-1-
H-indazole-1-carboxylate
EXAMPLE 27A
(2,5-Dioxo-pyrrolidin-1-yloxycarbonyloxy)-acetic acid benzyl
ester
[0164] The title compound was prepared using the procedure as
described in Example 24A, substituting hydroxy-acetic acid benzyl
ester for (2,2-dimethyl-[1,3]dioxolan-4-yl)-methanol.
EXAMPLE 27B
2-(benzyloxy)-2-oxoethyl
4-[({[(1R)-5-tert-butyl-2,3-dihydro-1H-inden-1-yl]amino}carbonyl)amino]-1-
H-indazole-1-carboxylate
[0165] The title compound was prepared using the procedure as
described in Example 21C, substituting the compound from Example
27A for the compound from Example 21B MS (ESI) m/z: 541.29
[M+H].sup.+ 1H NMR (DMSO-d.sub.6) .delta.: 1.28 (s, 9H), 1.86 (m,
1H), 2.47 (m, 1H), 2.85 (m, 1H), 2.96 (m, 1H), 5.17 (m, 3H), 5.25
(s, 2H), 6.69 (d, 1H), 7.27 (s, 2H), 7.31 (s, 1H), 7.38 (m, 5H),
7.51 (t, 1H), 7.68 (d, 1H), 7.88 (d, 1H), 8.45 (s, 1H), 8.87 (s,
1H). Anal Calcd for C.sub.31H.sub.32N.sub.4O.sub.5: C, 68.87; H,
5.97; N, 10.36. Found: C, 66.93; H, 5.05; N, 9.98.
EXAMPLE 28
2-{[(benzyloxy)carbonyl]amino}ethyl
4-[({[(1R)-5-tert-butyl-2,3-dihydro-1H-inden-1-yl]amino}carbonyl)amino]-1-
H-indazole-1-carboxylate
EXAMPLE 28A
Carbonic acid 2-benzyloxycarbonylamino-ethyl ester
2,5-dioxo-pyrrolidin-1-yl ester
[0166] The title compound was prepared using the procedure as
described in Example 24A, substituting (2-hydroxy-ethyl)-carbamic
acid benzyl ester for (2,2-dimethyl-[1,3]dioxolan-4-yl)-methanol.
MS (APCI) m/z: 337 [M+H].sup.+
EXAMPLE 28B
2-{[(benzyloxy)carbonyl]amino}ethyl
4-[({[(1R)-5-tert-butyl-2,3-dihydro-1H-inden-1-yl]amino}carbonyl)amino]-1-
H-indazole-1-carboxylate
[0167] The title compound was prepared using the procedure as
described in Example 21C, substituting compound from Example 28A
for the compound from Example 21B. MS (ESI) m/z: 570.33 [M+H].sup.+
1H NMR (DMSO-d.sub.6) .delta.: 1.28 (s, 9H), 1.85 (m, 1H), 2.48 (m,
1H), 2.85 (m, 1H), 2.95 (m, 1H), 3.45 (q, 2H), 4.47 (t, 2H), 5.01
(s, 2H), 5.15 (q, 1H), 6.67 (d, 1H), 7.27 (s, 2H), 7.32 (m, 6H),
7.47 (t, 1H), 7.55 (m, 1H), 7.65 (d, 1H), 7.87 (d, 1H), 8.39 (s,
1H), 8.83 (s, 1H). Anal Calcd for
C.sub.32H.sub.35N.sub.5O.sub.5.0.9H.sub.2O: C, 65.60; H, 6.33; N,
11.95. Found: C, 65.60; H, 5.97; N, 11.81.
EXAMPLE 29
[({4-[({[(1R)-5-tert-butyl
-2,3-dihydro-1H-inden-1-yl]amino}carbonyl)amino]-1H-indazol-1-yl}carbonyl-
)oxy]acetic acid
[0168] The title compound was prepared using the procedure as
described in Example 26B, substituting Example 27B for Example 26A.
MS (ESI) m/z: 451.20 [M+H].sup.+ 1H NMR (DMSO-d.sub.6) .delta.:
1.28 (s, 9H), 1.86 (m, 1H), 2.45 (m, 1H), 2.85 (m, 1H), 2.94 (m,
1H), 4.98 (s, 2H), 5.18 (q, 1H), 6.68 (d, 1H), 7.27 (s, 2H), 7.31
(s, 1H), 7.52 (t, 1H), 7.69 (d, 1H), 7.88 (d, 1H), 8.43 (s, 1H),
8.86 (s, 1H), 13.38 (br s, 1H). Anal Calcd for
C.sub.24H.sub.26N.sub.4O.sub.5.0.8H.sub.2O: C, 62.00; H, 5.98; N,
12.05. Found: C, 62.13; H, 5.78; N, 11.79.
EXAMPLE 30
2-aminoethyl
4-[({[(1R)-5-tert-butyl-2,3-dihydro-1H-inden-1-yl]amino}carbonyl)amino]-1-
H-indazole-1-carboxyl ate hydrochloride
[0169] A mixture of the product from Example 28B (0.53 g, 0.93
mmol) and 10% Pd/C (0.053 g, 0.047 mmol) in methanol (50 mL) and
conc. HCl (86 .mu.L, 1.02 mmol) was hydrogenated under 60 psi of
hydrogen gas at ambient temperature for I h. The resulting mixture
was filtered and concentrated to obtain title compound (0.47 g,
quantitative yield). .sup.1H NMR (DMSO-d.sub.6) .delta.: 1.28 (s,
9H), 1.84 (m, 1H), 2.46 (m, 1H), 2.85 (m, 1H), 2.94 (m, 1H), 4.65
(dd, 2H), 5.18 (q, 1H), 6.96 (d, 1H), 7.26 (s, 2H), 7.31 (s, 1H),
7.51 (t, 1H), 7.69 (d, 1H), 7.91 (d, 1H), 8.02 (br s, 2H), 8.59 (s,
1H), 9.19 (s, 1H). .sup.1H NMR (methanol-d.sub.4) 8: 1.32 (s, 9H),
1.91 (m, 1H), 2.59 (m, 1H), 2.90 (m, 1H), 3.00 (m, 1H), 3.45 (dd,
2H), 4.71 (dd, 2H), 5.30 (t, 1H), 7.28 (s, 2H), 7.32 (s, 1H), 7.57
(t, 1H), 7.67 (d, 1H), 7.90 (d, 1H), 8.48 (s, 1H). MS (ESI) m/z:
436.2 [M+H].sup.+ Anal Calcd for
C.sub.24H.sub.29N.sub.5O.sub.3.HCl.1.8 H2O: C, 57.15; H, 6.71; N,
13.88. Found: C, 57.21; H, 6.55; N, 13.60.
EXAMPLE 31
2-ethoxy-2-oxoethyl
4-[({[(1R)-5-tert-butyl-2,3-dihydro-1H-inden-1-yl]amino}carbonyl)amino]-1-
H-indazole-1-carboxylate
EXAMPLE 31A
(4-Nitro-phenoxycarbonyloxy)-acetic acid ethyl ester
[0170] The title compound was prepared using the procedure as
described in Example 21B, substituting hydroxy-acetic acid ethyl
ester for Example 21A. .sup.1H NMR (DMSO-d.sub.6) .delta.: 8.36 (m,
2H), 7.57 (m, 2H), 4.90 (s, 2H), 4.20 (q, J=7.5 Hz, 2H), 1.22 (t,
J=7.5 Hz, 3H).
EXAMPLE 31B
2-ethoxy-2-oxoethyl
4-[({[(1R)-5-tert-butyl-2,3-dihydro-1H-inden-1-yl]amino}carbonyl)amino]-1-
H-indazole-1-carboxylate
[0171] The title compound was prepared using the procedure as
described in Example 21C, substituting compound from Example 31A
for the compound from Example 21B. MS (ESI) m/z: 479.27 [M+H].sup.+
1H NMR (DMSO-d.sub.6) .delta.: 1.24 (t, 3H), 1.28 (s, 9H), 1.86 (m,
1H), 2.48 (m, 1H), 2.85 (m, 1H), 2.94 (m, 1H), 4.20 (q, 2H), 5.09
(s, 2H), 5.18 (q, 1H), 6.69 (d, 1H), 7.28 (s, 2H), 7.31 (s, 1H),
7.52 (t, 1H), 7.69 (d, 1H), 7.88 (d, 1H), 8.45 (s, 1H), 8.88 (s,
1H). Anal Calcd for C.sub.26H.sub.30N.sub.4O.sub.5.0.4H.sub.2O: C,
64.29; H, 6.39; N, 11.53. Found: C, 64.22; H, 6.23; N, 11.46.
EXAMPLE 32
(diethoxyphosphoryl)methyl
4-[({[(1R)-5-tert-butyl-2,3-dihydro-1H-inden-1-yl]amino}carbonyl)amino]-1-
H-indazole-1-carboxylate
EXAMPLE 32A
(4-Nitro-phenoxycarbonyloxymethyl)-phosphonic acid diethyl
ester
[0172] The title compound was prepared using the procedure as
described in Example 21B, substituting hydroxymethyl-phosphonic
acid diethyl ester for Example 21A. .sup.1H NMR (DMSO-d.sub.6)
.delta.: 8.38 (d, J=11.0 Hz, 2H), 7.60 (d, J-11.0 Hz, 2H), 4.63 (d,
7.5 Hz, 2H), 4.10 (m, 4H), 1.24 (t, J=6.0 Hz, 6H).
EXAMPLE 32B
(diethoxyphosphoryl)methyl
4-[({[(1R)-5-tert-butyl-2,3-dihydro-1H-inden-1-yl]amino}carbonyl)amino]-1-
H-indazole-1-carboxylate
[0173] The title compound was prepared using the procedure as
described in Example 21C, substituting Example 32A for Example 21B.
MS (ESI) m/z: 543.3 [M+H].sup.+. .sup.1H NMR (DMSO-d.sub.6)
.delta.: 1.26 (s, 6H), 1.28 (s, 9H), 1.86 (m, 1H), 2.47 (m, 1H),
2.85 (m, 1H), 2.96 (m, 1H), 4.15 (m, 4H), 4.84 (d, 2H), 5.15 (q,
1H), 6.70 (d, 1H), 7.27 (s, 2H), 7.31 (s, 1H), 7.52 (t, 1H), 7.67
(d, 1H), 7.88 (d, 1H), 8.44 (s, 1H), 8.87 (s, 1H). Anal Calcd for
C.sub.27H.sub.35N.sub.4O.sub.6P.0.4 H.sub.2O: C, 58.99; H, 6.56; N,
10.19. Found: C, 59.08; H, 6.40; N, 10.01.
EXAMPLE 33
2-(diethylamino)-2-oxoethyl
4-[({[(1R)-5-tert-butyl-2,3-dihydro-1H-inden-1-yl]amino}carbonyl)amino]-1-
H-indazole-1-carboxylate
EXAMPLE 33A
Carbonic acid diethylcarbamoylmethyl ester 4-nitro-phenyl ester
[0174] The title compound was prepared using the procedure as
described in Example 21B, substituting
N,N-diethyl-2-hydroxy-acetamide for Example 21A. .sup.1H NMR
(DMSO-d.sub.6) .delta.: 8.38 (d, J=11.0 Hz, 2H), 7.57 (d, J=11.0
Hz, 2H), 5.0 (s, 2H), 3.20 (m, 4H), 1.12 (m 6H).
EXAMPLE 33B
2-(diethylamino)-2-oxoethyl 4-[({[(1R)-5-tert-buty
l-2,3-dihydro-1H-inden-1-yl]amino}carbonyl)amino]-1H-indazole-1-carboxyla-
te
[0175] The title compound was prepared using the procedure as
described in Example 21C, substituting Example 33A for Example 21B.
MS (ESI) m/z: 506.32 [M+H].sup.+ 1H NMR (DMSO-d.sub.6) .delta.:
1.05 (t, 3H), 1.18 (t, 3H), 1.28 (s, 9H), 1.86 (m, 1H), 2.48 (m,
1H), 2.85 (m, 1H), 2.96 (m, 1H), 5.18 (m, 3H), 6.68 (d, 1H), 7.28
(s, 2H), 7.31 (s, 1H), 7.50 (t, 1H), 7.70 (d, 1H), 7.87 (d, 1H),
8.42 (s, 1H), 8.86 (s, 1H). Anal Calcd for
C.sub.28H.sub.35N.sub.5O.sub.4.0.7 H.sub.2O: C, 64.90; H, 7.08; N,
13.51. Found: C, 65.04; H, 7.13; N, 13.41.
EXAMPLE 34
2-oxopropyl
4-[({[(1R)-5-tert-butyl-2,3-dihydro-1H-inden-1-yl]amino}carbonyl)amino]-1-
H-indazole-1-carboxylate
EXAMPLE 34A
Carbonic acid 4-nitro-phenyl ester 2-oxo-propyl ester
[0176] The title compound was prepared using the procedure as
described in Example 21B, substituting 1-hydroxy-propan-2-one for
Example 21A. .sup.1H NMR (DMSO-d.sub.6) .delta.: 8.35 (d, J=11.0
Hz, 2H), 7.58 (d, J-11.0 Hz, 2H), 5.00 (m 2H), 2.16 (s, 3H).
EXAMPLE 34B
2-oxopropyl
4-[({[(1R)-5-tert-butyl-2,3-dihydro-1H-inden-1-yl]amino}carbonyl)amino]-1-
H-indazole-1-carboxylate
[0177] The title compound was prepared using the procedure as
described in Example 21C, substituting Example 34A for Example 21B.
MS (ESI) m/z: 449.17 [M+H].sup.+ 1H NMR (DMSO-d.sub.6) .delta.:
1.28 (s, 9H), 1.86 (m, 1H), 2.23 (s, 3H), 2.47 (m, 1H), 2.85 (m,
1H), 2.96 (m, 1H), 4.84 (d, 1H), 5.17 (q, 1H), 5.40 (d, 1H), 6.69
(d, 1H), 7.23 (d, 1H), 7.27 (s, 2H), 7.31 (s, 1H), 7.39 (t, 1H),
7.82 (d, 1H), 8.23 (s, 1H), 8.71 (s, 1H). Anal Calcd for
C.sub.25H.sub.28N.sub.4O.sub.4.0.3 H.sub.2O: C, 66.15; H, 6.35; N,
12.34. Found: C, 66.14; H, 6.25; N, 12.46.
EXAMPLE 35
2-(acetyloxy)ethyl
4-[({[(1R)-5-tert-butyl-2,3-dihydro-1H-inden-1-yl]amino}carbonyl)amino]-1-
H-indazole-1-carboxylate
EXAMPLE 35A
Acetic acid 2-(4-nitro-phenoxycarbonyloxy)-ethyl ester
[0178] The title compound was prepared using the procedure as
described in Example 21B, substituting acetic acid 2-hydroxy-ethyl
ester for Example 21A. .sup.1H NMR (DMSO-d.sub.6) .delta.: 8.38 (d,
J=11.0 Hz, 2H), 7.59 (d, J-11.0 Hz, 2H), 4.46 (m 2H), 4.12 (m, 2H),
2.05 (s, 3H).
EXAMPLE 35B
2-(acetyloxy)ethyl
4-[({[(1R)-5-tert-butyl-2,3-dihydro-1H-inden-1-yl]amino}carbonyl)amino]-1-
H-indazole-1-carboxylate
[0179] The title compound was prepared using the procedure as
described in Example 21C, substituting Example 35A for Example 21B.
MS (ESI) m/z: 479.27 [M+H].sup.+ 1H NMR (DMSO-d.sub.6) .delta.:
1.28 (s, 9H), 1.86 (m, 1H), 2.05 (s, 3H), 2.48 (m, 1H), 2.85 (m,
1H), 2.96 (m, 1H), 4.41 (m, 2H), 4.65 (m, 2H), 5.15 (q, 1H), 6.69
(d, 1H), 7.27 (s, 2H), 7.31 (s, 1H), 7.51 (t, 1H), 7.66 (d, 1H),
7.88 (d, 1H), 8.41 (s, 1H), 8.86 (s, 1H). Anal Calcd for
C.sub.26H.sub.30N.sub.4O.sub.5. 0.4 H.sub.2O: C, 64.29; H, 6.39; N,
11.53. Found: C, 64.29; H, 6.48; N, 11.24.
EXAMPLE 36
2-(dimethoxyphosphoryl)ethyl
4-[({[(1R)-5-tert-butyl-2,3-dihydro-1H-inden-1-yl]amino}carbonyl)amino]-1-
H-indazole-1-carboxylate
EXAMPLE 36A
[2-(4-Nitro-phenoxycarbonyloxy)-ethyl]-phosphonic acid dimethyl
ester
[0180] The title compound was prepared using the procedure as
described in Example 21B, substituting (2-hydroxy-ethyl)-phosphonic
acid dimethyl ester for Example 21A. MS (ESI) m/z: 320 [M+H].sup.+
1H NMR (DMSO-d.sub.6) .delta.: 8.35 (d, J=11.0 Hz, 2H), 7.56 (d,
J=11.0 Hz, 2H), 4.40 (m, 2H), 3.70 (s, 3H), 3.66 (s, 3H), 2.37 (m,
2H).
EXAMPLE 36B
2-(dimethoxyphosphoryl)ethyl
4-[({[(1R)-5-tert-butyl-2,3-dihydro-1H-inden-1-yl]amino}carbonyl)amino]-1-
H-indazole-1-carboxylate
[0181] The title compound was prepared using the procedure as
described in Example 21C, substituting Example 36A for Example 21B.
MS (ESI) m/z: 529.25 [M+H].sup.+ 1H NMR (DMSO-d.sub.6) .delta.:
1.28 (s, 9H), 1.85 (m, 1H), 2.42 (m, 3H), 2.85 (m, 1H), 2.94 (m,
1H), 3.64 (s, 3H), 3.68 (s, 3H), 4.60 (m, 2H), 5.15 (q, 1H), 6.68
(d, 1H), 7.27 (s, 2H), 7.31 (s, 1H), 7.50 (t, 1H), 7.71 (d, 1H),
7.87 (d, 1H), 8.40 (s, 1H), 8.84 (s, 1H). Anal Calcd for
C.sub.26H.sub.33N.sub.4O.sub.6P.0.5H.sub.2O: C, 58.09; H, 6.38; N,
10.42. Found: C, 58.16; H, 6.37; N, 10.30.
EXAMPLE 37
[bis(benzyloxy)phosphoryl]methyl
4-[({[(1R)-5-tert-butyl-2,3-dihydro-1H-inden-1-yl]amino}carbonyl)amino]-1-
H-indazole-1-carboxylate
EXAMPLE 37A
(4-Nitro-phenoxycarbonyloxymethyl)-phosphonic acid dibenzyl
ester
[0182] The title compound was prepared using the procedure as
described in Example 21B, substituting hydroxymethyl-phosphonic
acid dibenzyl ester for Example 21A. MS (ESI) m/z: 458 [M+H].sup.+
1HNMR (DMSO-d.sub.6) .delta.: 8.30 (d, J=11.0 Hz, 2H), 7.51 (d,
J=11.0 Hz, 2H), 7.37 (m, 10H), 5.13 (d, J=7.5 Hz, 4H), 4.72 (d
J=8.0 Hz, 2H).
EXAMPLE 37B
[bis(benzyloxy)phosphoryl]methyl
4-[({[(1R)-5-tert-butyl-2,3-dihydro-1H-inden-1-yl]amino}carbonyl)amino]-1-
H-indazole-1-carboxylate
[0183] The title compound was prepared using the procedure as
described in Example 21C, substituting Example 37A for the compound
from Example 21B. MS (ESI) m/z: 349.1, 667.30 [M+H4].sup.+ 1H NMR
(DMSO-d.sub.6) .delta.: 1.28 (s, 9H), 1.79-1.91 (m, 1H), 2.41-2.47
(m, 1H), 2.79-2.87 (m, 1H), 2.91-3.01 (m, 1H), 4.94 (d, 2H),
5.11-5.23 (m, 5H), 6.70 (d, 1H), 7.27 (s, 2H), 7.29-7.41 (m, 11H),
7.45 (t, 1H), 7.62 (d, 1H), 7.89 (d, 1H), 8.44 (s, 1H), 8.86 (s,
1H). Anal Calcd for C.sub.37H.sub.39N.sub.4O.sub.6P: C, 66.66; H,
5.90; N, 8.40. Found: C, 66.56; H, 5.76; N, 8.55.
EXAMPLE 38
[({4-{({[(1R)-5-tert-butyl-2,3-dihydro-1H-inden-1-yl]amino}carbonyl)amino]-
-1H-indazol-1-yl}carbonyl)oxy]methylphosphonic acid
[0184] The title compound was prepared using the procedure as
described in Example 26B, substituting Example 37B for Example 26A.
MS (ESI) m/z: 485.21 [M-H].sup.- 1H NMR (DMSO-d.sub.6) .delta.:
1.28 (s, 9H), 1.81-1.88 (m, 1H), 2.42-2.48 (m, 1H), 2.79-2.87 (m,
1H), 2.91-3.01 (m, 1H), 4.56 (d, 2H), 5.16 (q, 1H), 6.69 (d, 1H),
7.27 (s, 2H), 7.31 (s, 1H), 7.50 (t, 1H), 7.72 (d, 1H), 7.89 (d,
1H), 8.43 (s, 1H), 8.85 (s, 1H). .sup.1H NMR (methanol-d.sub.4) 6:
1.32 (s, 9H), 1.89 (m, 1H), 2.59 (m, 1H), 2.87 (m, 1H), 3.01 (m,
1H), 4.72 (d, 2H), 5.29 (t, 1H), 7.28 (s, 2H), 7.32 (s, 1H), 7.54
(t, 1H), 7.75 (d, 1H), 7.90 (d, 1H), 8.41 (s, 1H). Anal Calcd for
C.sub.23H.sub.27N.sub.4O.sub.6P.0.6H.sub.2O: C, 55.55; H, 5.72; N,
11.27. Found: C, 55.63; H, 5.77; N, 10.99.
EXAMPLE 39
[({4-[({[(1R)-5-tert-butyl-2,3-dihydro-1H-inden-1-yl]amino}carbonyl)amino]-
-1H-indazol-1-yl}carbonyl)oxy]methylphosphonate, triethylamine
salt
[0185] To a suspension of Example 38 (0.05 g, 0.1 mmol) in methanol
(10 mL) was added triethylamine (0.01 g, 0.1 mmol) and the mixture
stirred 10 minutes at ambient temperature, concentrated under
reduced pressure and drying in vacuum to provide 0.06 g (100%) of
title compound. .sup.1H NMR (methanol-d.sub.4) .delta.: 1.29 (t,
9H), 1.32 (s, 9H), 1.90 (m, 1H), 2.59 (m, 1H), 2.89 (m, 1H), 3.00
(m, 1H), 3.16 (q, 6H), 4.54 (d, 2H), 5.29 (t, 1H), 7.28 (s, 2H),
7.31 (s, 1H), 7.52 (t, 1H), 7.74 (d, 1H), 7.97 (d, 1H), 8.36 (s,
1H). Anal Calcd for C.sub.23H.sub.27N.sub.4O.sub.6P.1.0
triethylamine.0.7 methanol: C, 58.47; H, 7.40; N, 11.48. Found: C,
58.46; H, 7.38; N, 11.44.
EXAMPLE 40
[({4-[({[(1R)-5-tert-butyl-2,3-dihydro-1H-inden-1-yl]amino}carbonyl)amino]-
-1H-indazol-1-yl}carbonyl)oxy]methylphosphonic acid,
diethylaminoethanol salt
[0186] The title compound was prepared using the procedure as
described in Example 39, substituting diethylaminoethanol for
triethylamine. .sup.1H NMR (methanol-d.sub.4) .delta.: 1.30 (t,
6H), 1.32 (s, 9H), 1.90 (m, 1H), 2.59 (m, 1H), 2.89 (m, 1H), 3.00
(m, 1H), 3.20 (m, 6H), 3.83 (dd, 2H), 4.54 (d, 2H), 5.29 (t, 1H),
7.28 (s, 2H), 7.31 (s, 1H), 7.52 (t, 1H), 7.74 (d, 1H), 7.98 (d,
1H), 8.36 (s, 1H). Anal Calcd for
C.sub.23H.sub.27N.sub.4O.sub.6P.0.8 C.sub.6H.sub.5NO.0.65 methanol:
C, 56.85; H, 6.98; N, 11.19. Found: C, 56.85; H, 7.01; N,
11.23.
EXAMPLE 41
[({4-[({[(1R) -5-tert
-butyl-2,3-dihydro-1H-inden-1-yl]amino}carbonyl)amino]-1H-indazol-1-yl}ca-
rbonyl)oxy]methylphosphonic acid, triethanolamine salt
[0187] The title compound was prepared using the procedure as
described in Example 39, substituting triethanolamine for
triethylamine. .sup.1H NMR (methanol-d.sub.4) .delta.: 1.31 (s,
9H), 1.90 (m, 1H), 2.59 (m, 1H), 2.89 (m, 1H), 3.00 (m, 1H), 3.37
(m, 6H), 3.87 (dd, 6H), 4.54 (d, 2H), 5.29 (t, 1H), 7.28 (s, 2H),
7.31 (s, 1H), 7.52 (t, 1H), 7.74 (d, 1H), 7.98 (d, 1H), 8.36 (s,
1H). Anal Calcd for C.sub.23H.sub.27N.sub.4O.sub.6P.1.1
C.sub.6H.sub.15NO.sub.3.0.7 methanol: C, 54.08; H, 6.93; N, 10.61.
Found: C, 54.08; H, 6.82; N, 10.67.
EXAMPLE 42
[({4-[({[(1R)-5-tert-butyl-2,3-dihydro-1H-inden-1-yl]amino}carbonyl)amino]-
-1H-indazol-1-yl}carbonyl)oxy]methylphosphonic acid, piperazine
salt
[0188] The title compound was prepared using the procedure as
described in Example 39, substituting piperazine for triethylamine.
.sup.1H NMR (methanol-d.sub.4) .delta.: 1.32 (s, 9H), 1.90 (m, 1H),
2.59 (m, 1H), 2.89 (m, 1H), 3.01 (m, 1H), 3.04 (s, 8H), 4.54 (d,
2H), 5.29 (t, 1H), 7.29 (s, 2H), 7.31 (s, 1H), 7.52 (t, 1H), 7.74
(d, 1H), 7.97 (d, 1H), 8.37 (s, 1H). Anal Calcd for
C.sub.23H.sub.27N.sub.4O.sub.6P.0.9 C.sub.4H.sub.10N.sub.2.1.2
H.sub.2O: C, 54.56; H, 6.61; N, 13.87. Found: C, 54.58; H, 6.74; N,
13.76.
EXAMPLE 43
[({4-[({[(1R)-5-tert-butyl-2,3-dihydro-1H-inden-1-yl]amino}carbonyl)amino]-
-1H-indazol-1-yl}carbonyl)oxy]methylphosphonic acid,
N-methyl-D-glucamine salt
[0189] The title compound was prepared using the procedure as
described in Example 39, substituting N-methyl-D-glucamine for
triethylamine. .sup.1H NMR (methanol-d.sub.4) .delta.: 1.32 (s,
9H), 1.90 (m, 1H), 2.59 (m, 1H), 2.69 (s, 3H), 2.89 (m, 1H), 3.00
(m, 1H), 3.15 (d, 2H), 3.61-3.83 (m, 5H), 4.04 (m, 1H), 4.54 (d,
2H), 5.29 (t, 1H), 7.28 (s, 2H), 7.31 (s, 1H), 7.52 (t, 1H), 7.74
(d, 1H), 7.97 (d, 1H), 8.37 (s, 1H). Anal Calcd for
C.sub.23H.sub.27N.sub.4O.sub.6P.1.3
C.sub.7H.sub.17NO.sub.5.0.6H.sub.2O: C, 51.33; H, 6.75; N, 9.88.
Found: C, 51.45; H, 6.61; N, 9.78.
EXAMPLE 47
N-[(1R)-5-tert-butyl-2,3-dihydro-1H-inden-1-yl]-N'-[1-(2-hydroxy-3-methoxy-
propyl)-1H-indazol-4-yl]urea
[0190] A mixture of 2-methoxymethyl-oxirane (0.18 g, 4.0 mmol),
Example 56J (0.35 g, 1.0 mmol) and K.sub.2CO.sub.3 (0.14 g, 1.0
mmol) in ethanol (4.0 mL) were heated at 120.degree. C. for 10
minutes in the microwave (Personal Chemistry). After filtration,
concentration of the filtrate and chromatography (ethyl acetate,
100%) two regioisomers were obtained: title compound (0.17 g, 26%)
and compound described in Example 48 (0.11 g, 24%). MS (ESI) m/z:
437.14 [M+H].sup.+ 1H NMR (DMSO-d.sub.6) .delta.: 1.28 (s, 9H),
1.84 (m, 1H), 2.45 (m, 1H), 2.84 (m, 1H), 2.94 (m, 1H), 3.25 (s,
3H), 4.05 (q, 1H), 4.28 (dd, 1H), 4.34 (dd, 1H), 5.06 (d, 1H), 5.16
(q, 1H), 6.66 (d, 1H), 7.15 (d, 1H), 7.24 (d, 1H), 7.27 (s, 2H),
7.31 (s, 1H), 7.68 (d, 1H), 8.02 (s, 1H), 8.55 (s, 1H).
EXAMPLE 48
N-[(1R)-5-tert-butyl-2,3-dihydro-1H-inden-1-yl]-N'-[2-(2-hydroxy-3-methoxy-
propyl)-2H-indazol-4-yl]urea
[0191] The title compound was prepared and isolated as described in
Example 47 with yield of 0.11 g (24%). MS (ESI) m/z: 437.13
[M+H].sup.+ 1H NMR (DMSO-d.sub.6) .delta.: 1.28 (s, 9H), 1.82 (m,
1H), 2.44 (m, 1H), 2.84 (m, 1H), 2.94 (m, 1H), 3.22 (m, 1H), 3.29
(s, 3H), 4.05 (m, 1H), 4.31 (dd, 1H), 4.45 (dd, 1H), 5.13 (q, 1H),
5.27 (d, 1H), 6.56 (d, 1H), 7.13 (m, 2H), 7.26 (s, 2H), 7.30 (s,
1H), 7.52 (dd, 1H), 8.21 (s, 1H), 8.45 (s, 1H).
EXAMPLE 49
methyl
3-{4-[({[(IR)-5-tert-butyl-2,3-dihydro-1H-inden-1-yl]amino}carbonyl-
)amino]-1H-indazol-1-yl}-2-hydroxypropanoate
[0192] A mixture of oxirane-2-carboxylic acid methyl ester (0.51 g,
5.0 mmol), Example 56J (0.35 g, 1.0 mmol) and sodium tert-butoxide
(0.1 g, 1.0 mmol) in methanol (4.0 mL) was heated at 120.degree. C.
for 30 minutes in microwave (Personal Chemistry). After filtration,
concentration of the filtrate and chromatography (ethyl
acetate:dichloromethane 1:1 to 3:1) two regioisomers were obtained:
title compound (0.18 g, 40%) and compound described in Example 50
(0.12 g, 27%). MS (ESI) m/z: 451.12 [M+H].sup.+. .sup.1H NMR
(DMSO-d.sub.6) .delta.: 1.28 (s, 9H), 1.84 (m, 1H), 2.44 (m, 1H),
2.84 (m, 1H), 2.94 (m, 1H), 3.60 (s, 3H), 4.49-4.64 (m, 3H), 5.14
(q, 1H), 6.65 (d, 1H), 7.13 (d, 1H), 7.22 (d, 1H), 7.27 (s, 2H),
7.31 (s, 1H), 7.68 (d, 1H), 8.02 (s, 1H), 8.56 (s, 1H).
EXAMPLE 50
methyl
3-{4-[({[(1R)-5-tert-butyl-2,3-dihydro-1H-inden-1-yl]amino}carbonyl-
)amino]-2H-indazol-2-yl}-2-hydroxypropanoate
[0193] The title compound was prepared and isolated as described in
Example 49 with yield of 0.12 g (27%). MS (ESI) m/z: 451.11
[M+H].sup.+ 1H NMR (DMSO-d.sub.6) .delta.: 1.28 (s, 9H), 1.81 (m,
1H), 2.47 (m, 1H), 2.84 (m, 1H), 2.93 (m, 1H), 3.67 (s, 3H), 4.56
(m, 2H), 4.67 (m, 1H), 5.13 (q, 1H), 6.56 (d, 1H), 7.11 (d, 2H),
7.26 (s, 2H), 7.30 (s, 1H), 7.53 (t, 1H), 8.21 (s, 1H), 8.46 (s,
1H).
EXAMPLE 51
tert-butyl
3-{4-[({[(1R)-5-tert-butyl-2,3-dihydro-1H-inden-1-yl]amino}carb-
onyl)amino]-1H-indazol-1-yl}-2-hydroxypropylcarbamate
[0194] A mixture of oxiranylmethyl-carbamic acid tert-butyl ester
(0.35 g, 2.0 mmol), Example 56J (0.35 g, 1.0 mmol) and
K.sub.2CO.sub.3 (0.14 g, 1.0 mmol) in acetonitrile (4.0 mL) were
heated at 120.degree. C. for 15 minutes in the microwave (Personal
Chemistry). The reaction mixture was cooled, filtered and
concentrated. The crude material was purified on silica gel (ethyl
acetate/hexane 65/35 to 80/20) to provide the title compound (0.12
g, 23%). MS (ESI) m/z: 522.15 [M+H].sup.+ 1H NMR (DMSO-d.sub.6)
.delta.: 1.28 (s, 9H), 1.38 (s, 9H), 1.84 (m, 1H), 2.45 (m, 1H),
2.84 (m, 1H), 2.99 (m, 3H), 3.92 (m, 1H), 4.23 (dd, 1H), 4,29 (dd,
1H), 5.01 (d, 1H), 5.14 (q, 1H), 6.66 (d, 1H), 6.80 (t, 1H), 7.13
(d, 1H), 7.22 (d, 1H), 7.27 (s, 2H), 7.31 (s, 1H), 7.68 (d, 1H),
8.02 (s, 1H), 8.56 (s, 1H).
EXAMPLE 52
3-{4-[({[(1R)-5-tert-butyl-2,3-dihydro-1H-inden-1-yl]amino}carbonyl)amino]-
-1H-indazol-1-yl}-2-hydroxypropanoic acid
[0195] A solution of compound from Example 49 (0.31 g, 0.68 mmol)
in methanol (20 mL) was treated with 1IN NaOH (2 mL) for 16 hours.
The mixture was cooled in ice bath, treated with 1N HCl (2 mL) and
concentrated under reduced pressure. The residue was dissolved in
dimethyl sulfoxide-methanol, 1:1 (3 mL), filtered and the filtrated
purified by HPLC (eluted with water/acetonitrile 10 to 100%
contains 0.1% trifluoroacetic acid) (0.12 g, 27%). MS (ESI) m/z:
437.11 [M+H].sup.+ 1H NMR (DMSO-d.sub.6) .delta.: 1.28 (s, 9H),
1.84 (m, 1H), 2.45 (m, 1H), 2.84 (m, 1H), 2.94 (m, 1H), 4.40-4.62
(m, 3H), 5.14 (q, 1H), 6.65 (d, 1H), 7.15 (d, 1H), 7.22 (d, 1H),
7.27 (s, 2H), 7.31 (s, 1H), 7.68 (d, 1H), 8.03 (s, 1H), 8.56 (s,
1H).
EXAMPLE 53
3-{4-[({[(1R)-5-tert-butyl-2,3-dihydro-1H-inden-1-yl]amino}carbonyl)amino]-
-2H-indazol-2-yl}-2-hydroxypropanoic acid
[0196] The title compound was prepared using the procedure as
described in Example 52, substituting Example 50 for Example 49. MS
(ESI) m/z: 437.11 [M+H].sup.+ 1H NMR (DMSO-d.sub.6) .delta.: 1.28
(s, 9H), 1.82 (m, 1H), 2.45 (m, 1H), 2.84 (m, 1H), 2.93 (m, 1H),
4.44 (dd, 1H), 4.52 (dd, 1H), 4.65 (dd, 1H), 5.13 (q, 1H), 6.57 (d,
1H), 7.11 (d, 2H), 7.26 (s, 2H), 7.30 (s, 1H), 7.54 (t, 1H), 8.23
(s, 1H), 8.47 (s, 1H).
EXAMPLE 54
N-[(1R)-5-tert-butyl-2,3-dihydro-1H-inden-1-yl]-N'-[2-(2-hydroxy-3-morphol-
in-4-ylpropyl)-2H-indazol-4-yl]urea
[0197] Charged an Emrys 5 mL process vial with 350 mg (1.0 mmol)
Example 56J, 290 mg (2.0 mmol)
4-[(.+-.)-2,3-epoxypropyl]-morpholine, 139 mg (1.0 mmol)
K.sub.2CO.sub.3 and 4 mL ethanol. The mixture was heated in a
microwave at 120.degree. C. for 30 minutes, filtered, rinsed with
ethanol and concentrated. The .about.1:1 mixture of regioisomers
was purified on silica gel with 5-10% methanol in ethyl acetate to
obtain 0.32 g of the title compound and 0.45 g of the compound
described in Example 55. MS (ESI) m/z: 492.18 [M+H].sup.+ 1H NMR
(DMSO-d.sub.6) .delta.: 1.28 (s, 9H), 1.80 (m, 1H), 2.32 (dd, 2H),
2.42 (dd, 4H), 2.47 (m, 1H), 2.84 (m, 1H), 2.93 (m, 1H), 3.57 (dd,
4H), 4.08 (m, 1H), 4.23 (dd, 1H), 4.51 (dd, 1H), 5.07 (d, 1H), 5.13
(q, 1H), 6.57 (d, 1H), 7.12 (m, 2H), 7.26 (s, 2H), 7.30 (s, 1H),
7.51 (dd, 1H), 8.24 (s, 1H), 8.47 (s, 1H).
EXAMPLE 55
N-[(1R)-5-tert-butyl-2,3-dihydro-1H-inden-1-yl]-N'-[1-(2-hydroxy-3-morphol-
in-4-ylpropyl)-1H-indazol-4-yl]urea
[0198] The title compound was prepared and isolated as described in
Example 54 with yield of 0.45 g MS (ESI) m/z: 492.19 [M+H].sup.+ 1H
NMR (DMSO-d.sub.6) .delta.: 1.28 (s, 9H), 1.84 (m, 1H), 2.29 (dd,
2H), 2.36 (dd, 4H), 2.44 (m, 1H), 2.84 (m, 1H), 2.94 (m, 1H), 3.52
(dd, 4H), 4.08 (m, 1H), 4.23 (dd, 1H), 4.39 (dd, 1H), 4.85 (m, 1H),
5.14 (q, 1H), 6.71 (d, 1H), 7.15 (d, 1H), 7.21 (d, 1H), 7.27 (s,
2H), 7.31 (s, 1H), 7.67 (d, 1H), 8.02 (s, 1H), 8.59 (s, 1H).
EXAMPLE 56
N-[(1R)-5-tert-butyl-2,3-dihydro-1H-inden-1-yl]-N'-1H-indazol-4-ylurea
EXAMPLE 56A
4-nitro-1H-indazole
[0199] 2-Methyl-3-nitroaniline (20 g, 129.0 mmol) in acetic acid
(-200 mL) was treated with NaNO.sub.2 (20 g, 290.0 mmol) in water
(50 mL) at 4.degree. C. with mechanical stirring. The reaction
mixture was allowed to warm to room temperature and stir overnight.
The solvent was removed under reduced pressure. The residue was
treated with water (700 mL) and the mixture was filtered. The solid
was dried at 45.degree. C. in a vacuum oven overnight to provide
the title compound. .sup.1H NMR (DMSO-d.sub.6) .delta. 8.56 (s,
1H), 8.2-8.05 (dd, 2H), 7.6 (t, 1H).
EXAMPLE 56B
methyl 4-nitro-1H-indazole-1-carboxylate
[0200] NaH (0.3 g, 12.5 mmol) in N,N-dimethylformamide (5 mL) was
treated with Example 56A (1.33 g, 10 mmol) at 0.degree. C. The
reaction mixture was allowed to warm to room temperature and stir
for 1 hour. The mixture was treated with methyl chloroformate (0.9
mL,11.7 mol) and stirred at room temperature for 3 hours. The
mixture was treated with water and filtered to provide the title
compound as a solid. .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta.
4.19 (s, 3H), 7.9 (t, 1H), 8.38 (d, 1H), 8.62 (d, 1H), 8.85 (s,
1H).
EXAMPLE 56C
methyl 4-amino-1H-indazole-1-carboxylate
[0201] Example 56B (1.66 g, 7.5 mmol) and 10% Pd/C were combined in
ethanol (20 mL) and exposed to a hydrogen atmosphere. The reaction
mixture was heated at 80.degree. C. for 20 minutes, allowed to cool
to room temperature, and filtered through Celite. The filtrate was
evaporated to provide title compound. .sup.1H NMR (300 MHz,
DMSO-d.sub.6) .delta. 6.1 (s, 2H), 6.41 (dd, 1H), 7.21 (m, 2H),
8.42 (s, 1H).
EXAMPLE 56D
1-(4-tert-butylphenyl)-3-chloro-1-propanone
[0202] A solution of tert-butyl benzene (31 ml, 200 mmol) and
3-chloro-propionyl chloride (19 ml, 200 mmol) in methylene chloride
(75 ml) was added dropwise to a suspension of aluminum chloride
(29.33 g, 220 mmol) in methylene chloride (300 ml) at 0.degree. C.
The reaction mixture was allowed to warm to ambient temperature,
stirred for 16 hours, and quenched with water dropwise. The
reaction mixture was washed with water, dried with magnesium
sulfate, and the filtrate was evaporated under reduced pressure to
provide the title compound which was used without further
purification in the next step.
EXAMPLE 56E
5-tea-butyl-1-indanone
[0203] Example 56D (22.25 g, 99 mmol) was dissolved in concentrated
sulfuric acid (100 ml) and heated on a water bath at 95.degree. C.
for 2.5 hours. The reaction mixture was cooled, poured onto ice,
and extracted with diethyl ether. The combined organic extracts
were washed with saturated aqueous sodium bicarbonate, dried with
magnesium sulfate, and the filtrate was evaporated under reduced
pressure to provide the title compound which was used without
further purification in the next step.
EXAMPLE 56F
5-tert-butyl-1-indanone O-methyloxime
[0204] Example 56E (13.41 g, 71.23 mmol) and methoxyamine
hydrochloride (6.68 g, 80 mmol) were disolved in pyridine (75 ml)
and stirred at ambient temperature for 16 hours. The mixture was
evaporated under reduced pressure and the residue was partitioned
between water and diethyl ether. The combined organic layers were
washed with IN aqueous hydrochloric acid, dried with magnesium
sulfate, and the filtrate was evaporated under reduced pressure to
provide the title compound which was used without further
purification in the next step.
EXAMPLE 56G
5-tert-butyl-2,3-dihydro-1H-inden-1-ylamine
[0205] Example 56F (4.37 g, 20.2 mmol) and 10% palladium on carbon
(2.2 g) were combined in methanol (50 ml) and ammonia (10 ml) and
placed in a Parr apparatus which was charged with hydrogen to 60
psi. The reaction was shaken at 50.degree. C. for 16 hours. The
reaction mixture was filtered and the filtrate was evaporated under
reduced pressure. The residue was treated with diethyl ether (100
ml) and extracted with hydrochloric acid (1N, 3.times.50 ml). The
combined aqueous extracts were neutralized with sodium hydroxide (6
g) in water (25 ml) and extracted with diethyl ether. The organic
extracts were combined, dried with magnesium sulfate, and the
filtrate was evaporated under reduced pressure to provide the title
compound which was used without further purification in the next
step.
EXAMPLE 56H
(1R)-5-tert-butyl-2,3-dihydro-1H-inden-1-ylamine
[0206] Example 56G (11.70 g, 61.9 mmol, 44.4% ee),
N-acetyl-(D)-leucine (11.78 g 68.1 mmol) and methanol (120 mL) were
combined and heated at 65.degree. C. for 1 hour. The solution was
allowed to cool to ambient temperature. The solids were filtered
and washed with toluene. The solid was then resuspended in methanol
(125 mL) and brought to reflux. The solution was allowed to cool to
ambient temperature and the solids were filtered. The solid was
dried at 40.degree. C. under reduced pressure to provide the title
compound. The solid was treated with IN NaOH (100 mL) and extracted
with methyl-t-butyl ether. Organic phase was concentrated to obtain
free base (3.8 g, 98.7% ee, determined by chiral HPLC with
Chirobiotic column from Astec using mobile phase of 0.1% acetic
acid and 0.06% triethylamine in methanol) (98.7% ee)
EXAMPLE 56I
methyl
4-[({[(1R)-5-tert-butyl-2,3-dihydro-1H-inden-1-yl]amino}carbonyl)am-
ino]-1H-indazole-1-carboxylate
[0207] Example 56C (4.59 g, 24 mmol) in toluene (800 ml) was
treated with phosgene (20% in toluene, 25.4 ml, 48 mmol). The
mixture was heated at reflux for 3 hours, cooled, and the solvent
removed under vacuum. The residue in diethyl ether (800 ml) and
triethyl amine (20 ml) was filtered and then treated with Example
56H (3.78 g, 20 mmol). After stirring at ambient temperature for 16
hours, the solvent was removed under vacuum and the residue
triturated with a 1:1 mixture of diethyl ether and hexanes to
provide the title compound. .sup.1H NMR (DMSO-d.sub.6) .delta. 1.28
(s, 9H), 1.78-1.91 (m, 1H), 2.39-2.48 (m, 1H), 2.75-2.88 (m, 1H),
2.91-3.02 (m, 1H), 4.04 (s, 3H), 5.17 (m, 1H), 6.73 (d, 1H), 7.27
(s, 2H), 7.30 (m, 1H), 7.50 (m, 1H), 7.69 (d, 1H), 7.88 (d, 1H),
8.39 (s, 1H), 8.84 (s, 1H); MS (ESI+) 407 (M+H).sup.+; Elemental:
Calculated for C.sub.23H.sub.26N.sub.4O.sub.3: C, 67.96; H, 6.45;
N, 13.78; Found: C, 67.85; H, 6.51; N, 13.56.
EXAMPLE 56J
N-[(1R)-5-tert-butyl-2,3-dihydro-1H-inden-1-yl]-N'-1H-indazol-4-ylurea
[0208] Example 561 (5.67 g, 14 mmol) in tetrahydrofuran (20 ml) was
treated with A 5M solution of sodium hydroxide in methanol (8 ml,
40 mmol). After stirring for 30 minutes, the reaction mixture was
diluted with water and filtered. The solid was air-dried to obtain
desired compound. .sup.1H NMR (DMSO-d.sub.6) .delta. 1.27 (s, 9H),
1.75-1.88 (m, 1H), 2.40-2.48 (m, 1H), 2.76-2.88 (m, 1H), 2.90-3.01
(m, 1H), 5.15 (m, 1H), 6.84 (br, 1H), 7.05 (d, 1H), 7.20, (m, 1H),
7.26 (s, 2H), 7.31 (s, 1H), 7.69 (d, 1H), 8.17 (s, 1H), 8.83 (s,
1H); MS (ESI+): 349 (M+H).sup.+; Elemental: Calculated for
C.sub.21H.sub.24N.sub.4O.HCl: C, 65.53; H, 6.55; N, 14.56; Found:
C, 65.29; H, 6.63; N, 14.23.
EXAMPLE 56K
(1R)-5-tert-butyl-indan-1-ylamine tosylate salt
[0209] A solution of the product from Example 56H (1.9 g, 10 mmol)
in methanol (25 mL) was added to a solution of p-toluenesulfonic
acid (1.76 g, 10.5 mmol) in methanol (5 mL). The resultant solution
was distilled under reduced pressure to approximately 5 mL. The
internal temperature was adjusted to .about.65.degree. C., and
water (50 mL) was added while maintaining the internal temperature
at 60.degree. C. The product crystallized during the addition. The
mixture was held at .about.65.degree. C. for 1 h, then gradually
cooled to .about.20.degree. C. After stirring at .about.20.degree.
C. for 2 h, the suspension was filtered through a polypropylene pad
to collect the crude product The wetcake was washed with water and
dried to obtain title compound (2.81 g, 80%).
EXAMPLE 57
N-[(1R)-5-tert-butyl-2,3-dihydro-1H-inden-1-yl]-N'-{1-[(4-methylpiperazin--
1-yl)carbonyl]-1H-indazol-4-yl}urea
[0210] A solution of the product from Example 56J (240 mg, 0.69
mmol) in N,N-dimethylformamide (5 mL) was treated with 60% NaH (45
mg, 1.13 mmol) and stirred at room temperature for 15 min.
4-methylpiperazine carbonyl chloride (1.64 mmol) was then added,
and the reaction mixture was stirred overnight at 80.degree. C. It
was then cooled to room temperature and poured into H.sub.2O, and
the resulting precipitate was collected by filtration.
Chromatography on silica gel (eluted with 97:3
CH.sub.2Cl.sub.2-methanol) afforded the desired product. .sup.1H
NMR (d.sub.6-DMSO) .delta. 8.59 (s, 1H), 8.07 (s, 1H), 7.72 (d,
J=7.5 Hz, 1H), 7.28 (m, 3H), 7.17 (d, J=7.5 Hz, 1H), 6.66 (d, J=7.5
Hz, 1H), 5.17 (m, 1H), 4.44 (m, 2H), 3.48 (m, 2H), 3.02 (m, 4H),
2.90 (m, 1H), 2.81 (m, 1H), 2.53 (s, 3H), 2.42 (m, 1H), 1.80 (m,
1H), 1.27 (s, 9H). MS (DCI) m/z 475 (M+H).
C.sub.27H.sub.34N.sub.6O.sub.2.0.5H.sub.2O: C, 67.06; H, 7.29; N,
17.38; Found: C, 66.87; H, 7.22; N, 17.04.
EXAMPLE 58
N-[(1R)-5-tert-butyl-2,3-dihydro-1H-inden-1-yl]-N'-{2-[(4-methylpiperazin--
1-yl)carbonyl]-2H-indazol-4-yl urea
[0211] The title compound was prepared and isolated as described in
Example 57. .sup.1H NMR (d.sub.6-DMSO) .delta. 8.43 (s, 1H), 8.20
(s, 1H), 7.51 (d, J=1.0 and 7.5 Hz, 1H), 7.31 (s, 1H), 7.25 (m,
2H), 7.17 (m, 2H), 6.58 (d, J=7.5 Hz, 1H), 5.17 (m, 1H), 4.53 (m,
2H), 3.60 (m, 2H), 3.11 (m, 2H), 3.00 (m, 2H), 2.92 (m, 1H), 2.81
(m, 1H), 2.60 (s, 3H), 2.42 (m, 1H), 1.80 (m, 1H), 1.24 (s, 3H). MS
(DCI) m/z 475 (M+H). C.sub.27H.sub.34N.sub.6O.sub.2.0.8H.sub.2O: C,
66.32; H, 7.34; N, 17.19; Found: C, 66.62; H, 7.29; N, 16.78.
EXAMPLE 59
N-[(1R)-5-tert-butyl-2,3-dihydro-1H-inden-1-yl]-N'-[1-(N,N-dimethylglycyl)-
-1H-indazol-4-yl]urea
[0212] To a 200 mL round bottom flask was added
1-hydroxybenzotriazole (HOBT) (3.50 mmol, 0.47 g),
1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride (EDCI)
(3.50 mmol, 0.67 g), N,N-dimethylglycine (2.90 mmol, 0.30 g) and
methylene chloride (36 mL) and the reaction was stirred at room
temperature for 10 minutes. To the flask was then added Example 56J
(2.90 mmol, 1.10 g) in 4 mL of DMF and the reaction was stirred at
room temperature for 24 hours. The reaction was not complete after
24 hours so another equivalent of HOBT and EDCI was added and
stirred at room temperature for 24 hours. The reaction was diluted
with methylene chloride (100 mL) and the organic layer was washed
with saturated sodium bicarbonate (100 mL), dried (sodium sulfate)
and concentrated in vacuo. The material was purified on SiO.sub.2
and eluted with ethyl acetate to give a oily white solid in 62%.
.sup.1H NMR (DMSO-d.sub.6, 300 MHz); .delta. 1.28 (s, 9H),
1.79-1.91 (m, 1H), 2.38 (s, 6H), 2.73-3.01(m, 3H), 4.04 (s, 2H),
5.13-5.20 (m, 1H), 6.70 (d, J=7.8 Hz, 1H), 7.27-7.54 (m, 3H), 7.51
(t, J=8.14, 16.28, 1H), 7.88 (t, J=8.48, 13.91 Hz, 2H), 8.38 (s,
1H), 8.84 (s, 1H). DCl/NH.sub.3 m/z 434.
EXAMPLE 60
N-[(1R)-5-tert-butyl-2,3-dihydro-1H-inden-1-yl]-N.sup.711-(N,N-dimethylgly-
cyl)-1H-indazol-4-yl]urea, hydrochloride salt
[0213] The solid from Example 59 was taken up in ethyl
acetate/diethyl ether (1/10) (20 mL) and 2N HCl in diethyl ether
(2.0 eq) was added dropwise and the mixture was stirred for 5
minutes. The reaction was concentrated in vacuo to give the title
compound as a white solid. .sup.1H NMR (DMSO-d.sub.6, 300 MHz);
.delta.1.28 (s, 9H), 1.77-1.83 (m, 1H), 2.42-2.53 (m, 1H),
2.73-2.94 (m, 2H), 2.97 (s, 6H), 5.02 (s, 2H), 5.14-5.21 (m,1H),
7.25-7.35 (m, 4H), 7.58 (t, J=7.80, 15.94 Hz, 1H), 7.83 (d, J=8.14
Hz, 1H), 8.03 (d, J=8.14 Hz, 1H), 8.93(s, 1H), 9.77 (s, 1H). Calc
for C.sub.25H.sub.31N.sub.5O.sub.2.1.7HCl: C, 60.60; H, 6.65; N,
14. 13. Found: C, 60.91; H, 6.87; N, 13.85. MS (DCl/NH.sub.3) m/z
434.
EXAMPLE 61
(R)-1-(5-tert-Butyl-2,3-dihydro-1H-inden-1-yl)-3-(1-(2-(2-methoxyethoxy)ac-
etyl)-1H-indazol-4-yl)urea
EXAMPLE 61A
4-Nitrophenyl 2-(2-methoxyethoxy)acetate
[0214] 2-(2-methoxyethoxy)acetic acid (Alfa, 2.68 g, 20 mmol) was
dissolved in dichloromethane (60 mL), and oxalyl chloride (5.2 mL,
60 mmol) was added with a few drops of dimethylformamide. The
mixture was stirred for one hour, concentrated to a yellow slurry
and dichloromethane (40 mL) was added. 4-nitrophenol (Aldrich, 2.78
g, 20 mmol) was dissolved in pyridine (2.4 mL, 30 mmol) and
dichloromethane (60 mL), and then the (2-methoxyethoxy)acetyl
chloride solution was added and the mixture was stirred for one
hour. A solution of 1:1 ethyl acetate:hexane was added which
precipitated the salts, which were then filtered through a silica
gel plug. The filtrate was concentrated to a yellow oil and
chromatographed on silica gel with 0-to-60% ethyl acetate in
hexane. Obtained 4.33 g (85% yield) of Example 61A as a yellow
solid. .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. ppm 3.26 (s,
3H), 3.50 (m, 2H), 3.71 (m, 2H), 4.48 (s, 2H), 7.49 (d, J=9.15 Hz,
2H), 8.32 (d, J=9.15 Hz, 2H). MS (DCI) m/z 273.08
(M+NH.sub.4).sup.+.
EXAMPLE 61B
(R)-1-(5-tert-Butyl-2,3-dihydro-1H-inden-1-yl)-3-(1-(2-(2-methoxyethoxy)ac-
etyl)-1H-indazol-4-yl)urea
[0215] Example 56J (1.74 g, 5.0 mmol) was dissolved in
tetrahydrofuran (80 mL), and then potassium tert-butoxide (1.0 M in
THF, 5.5 mL, 5.5 mmol) was added. The solution stirred for 5
minutes, Example 61A (1.40 g, 5.5 mmol) was added in
tetrahydrofuran (20 mL), and the solution was stirred for another
15 minutes. Ethyl acetate was added, the salts precipitated, and
the mixture was filtered through a silica gel plug. The filtrate
was concentrated and chromatographed on silica gel using 0-to-35%
ethyl acetate in dichloromethane as the eluent. Obtained 1.227 g
(53% yield) of Example 61B as a solid. .sup.1H NMR (300 MHz,
DMSO-d.sub.6) .delta. ppm 1.28 (s, 9H), 1.85 (m, 1H), 2.45 (m, 1H),
2.82 (m, 1H), 2.96 (m, 1H), 3.27 (s, 3H), 3.53 (m, 2H), 3.75 (m,
2H), 4.98 (s, 2H), 5.16 (q, J=7.34 Hz, 1H), 6.69 (d, J=7.80 Hz,
1H), 7.27 (s, 2H), 7.31 (s, 1H), 7.52 (t, J=7.97 Hz, 1H), 7.86 (d,
J=8.14 Hz, 1H), 7.89 (d, J=7.79 Hz, 1H), 8.39 (s, 1H), 8.85 (s,
1H). MS (ESI) m/z 465.32 (M+H).sup.+. Calcd for
C.sub.26H.sub.32N.sub.4O.sub.4.0.22 Ethyl acetate.0.15 H.sub.2O: C,
66.34; H, 7.05; N, 11.51; Found: C, 66.32; H, 6.63; N, 11.45.
EXAMPLE 62
1-((R)-5-tert-Butyl-2,3-dihydro-1H-inden-1-yl)-3-(1-(3,5,5-trimethylhexano-
yl)-1H-indazol-4-yl)urea
EXAMPLE 62A
4-Nitrophenyl 3,5,5-trimethylhexanoate
[0216] Dissolved 4-nitrophenol (Aldrich, 1.39 g, 10 mmol) in
pyridine (1.2 mL, 15 mmol) and dichloromethane (50 mL), chilled to
0.degree. C., then added 3,5,5-trimethylhexanoyl chloride (Aldrich,
1.9 mL, 10 mmol), warmed to ambient temperature and stirred for 1.5
hours. Added ethyl acetate, precipitated salts, and filtered
through silica gel plug. Concentrated filtrate and chromatographed
on silica gel with 0-to-20% ethyl acetate in hexane. Obtained 2.79
g (100% yield) of Example 62A as an oil. .sup.1H NMR (300 MHz,
DMSO-d.sub.6) .delta. ppm 0.92 (s, 9H), 1.05 (d, J=6.78 Hz, 3H),
1.18 (dd, J=13.90, 6.44 Hz, 1H), 1.34 (dd, J=13.90, 4.07 Hz, 1H),
2.07 (m, 1H), 2.47 (dd, J=14.92, 7.80 Hz, 1H), 2.62 (dd, J=14.92,
6.11 Hz, 1H), 7.44 (d, J=9.16 Hz, 2H), 8.30 (d, J=9.16 Hz, 2H). MS
(DCI) m/z 297.1 (M+NH.sub.4).sup.+.
EXAMPLE 62B
1-((R)-5-tert-Butyl-2,3-dihydro-1H-inden-1-yl)-3-(1-(3,5,5-trimethylhexano-
yl)-1H-indazol-4-yl)urea
[0217] Dissolved Example 56J (1.394 g, 4.0 mmol) in tetrahydrofuran
(50 mL), added potassium tert-butoxide (1.0 M in THF, 4.0 mL, 4.0
mmol), stirred for 5 minutes, then added Example 62A (1.229 g, 4.4
mmol) in tetrahydrofuran (20 mL). After stirring for 15 minutes,
1:1 ethyl acetate:hexane was added, the salts precipitated, and
were filtered through a silica gel plug. Concentrated filtrate to a
foam and chromatographed on silica gel using 0-to-30% ethyl acetate
in hexane. Obtained 1.771 g (91% yield) of Example 62B as a foam.
.sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. ppm 0.88 (s, 9H), 1.02
(d, J=6.79 Hz, 3H), 1.19 (dd, J=6.78, 3.05 Hz, 1H), 1.28 (s, 9H),
1.36 (dd, J=14.07, 190 Hz, 1H), 1.84 (m, 1H), 2.23 (m, 1H), 2.45
(m, 1H), 2.82 (m, 1H), 2.95 (m, 1H), 3.05 (d, J=4.41 Hz, 1H), 3.08
(d, J=3.39 Hz, 1H), 5.16 (q, J=7.46 Hz, 1H), 6.69 (d, J=7.80 Hz,
1H), 7.27 (s, 2H), 7.31 (s, 1H), 7.50 (t, J=7.97 Hz, 1H), 7.88 (dd,
J=8.14, 3.05 Hz, 2H), 8.39 (s, 1H), 8.82 (s, 1H). MS (ESI) m/z
489.42 (M+H).sup.+. Calcd for C.sub.30H.sub.40N.sub.4O.sub.2.0.19
Ethyl acetate: C, 73.10; H, 8.28; N, 11.09; Found: C, 73.13; H,
8.12; N, 11.02.
EXAMPLE 63
2-Ethylhexyl
4-(3-((R)-5-tert-butyl-2,3-dihydro-1H-inden-1-yl)ureido)-1H-indazole-1-ca-
rboxylate
[0218] Dissolved Example 56J (1.045 g, 3.0 mmol) in
dimethylformamide (20 mL), added potassium tert-butoxide (1.0M in
THF, 3.0 mL, 3.0 mmol), stirred the solution for 5 minutes, then
added 2-ethylhexyl chloroformate (Aldrich, 0.65 mL, 3.3 mmol), and
stirred solution for 20 minutes. The solution was partitioned
between ethyl acetate (200 mL) and water (200 mL), the organic
layer was washed with brine and sodium sulfate and then
concentrated to an oil and chromatographed on silica gel with
0-to-50% ethyl acetate in hexane. Obtained 1.475 g (97% yield) of
Example 63 as a foam. .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta.
ppm 0.87 (m, 6H), 1.33 (m, 17H), 1.81 (m, 2H), 2.45 (m, 1H), 2.82
(m, 1H), 2.96 (m, 1H), 4.38 (dd, J=5.76, 1.70 Hz, 2H), 5.16 (q,
J=7.12 Hz, 1H), 6.70 (d, J=7.80 Hz, 1H), 7.27 (s, 2H), 7.31 (s,
1H), 7.50 (t, J=8.14 Hz, 1H), 7.66 (d, J=8.48 Hz, 1H), 7.89 (d,
J=7.79 Hz, 1H), 8.39 (s, 1H), 8.83 (s, 1H). MS (ESI) m/z 505.43
(M+H).sup.+. Calcd for C.sub.30H.sub.40N.sub.4O.sub.3.0.14 Ethyl
acetate: C, 71.00; H, 8.02; N, 10.84; Found: C, 71.23; H, 8.36; N,
10.53.
EXAMPLE 64
(R)-1-(1-(2-(2-Butoxyethoxy)acetyl)-1H-indazol-4-yl)-3-(5-tert-butyl-2,3-d-
ihydro-1H-inden-1-yl)urea
EXAMPLE 64A
4-Nitrophenyl 2-(2-butoxyethoxy)acetate
[0219] Dissolved 2-(2-butoxyethoxy)acetic acid (TCI, 3.654 g, 20.7
mmol) in dichloromethane (60 mL), added oxalyl chloride (5.4 mL,
62.2 mmol) and a few drops of dimethylformamide, stirred for 1
hour, concentrated to an oil and added dichloromethane (40 mL).
This solution was added to a solution of 4-nitrophenol (Aldrich,
2.88 g, 20.7 mmol) in pyridine (2.5 mL, 31.1 mmol) and
dichloromethane (60 mL) and stirred for 1.5 hours. Added 1:1 ethyl
acetate:hexane, precipitated the salts, and filtered through a
silica gel plug. Concentrated the filtrate to a yellow oil and
chromatographed on silica gel with 0-to-30% ethyl acetate in
hexane. Residue was dissolved in ethyl acetate (200 mL), washed
with 0.5 M potassium carbonate (200 mL), dried with brine and
sodium sulfate, and then evaporated. Recovered 5.63 g (91% yield)
of Example 64A as an oil. .sup.1H NMR (300 MHz, DMSO-d.sub.6)
.delta. ppm 0.87 (t, J=7.29 Hz, 3H), 1.30 (m, 2H), 1.48 (m, 2H),
3.40 (t, J=6.44 Hz, 2H), 3.54 (m, 2H), 3.71 (m, 2H), 4.48 (s, 2H),
7.49 (d, J=9.16 Hz, 2H), 8.32 (d, J=9.16 Hz, 2H). MS (DCI) m/z
315.14 (M+NH.sub.4).sup.+.
EXAMPLE 64B
(R)-1-(1-(2-(2-Butoxyethoxy)acetyl)-1H-indazol-4-yl)-3-(5-tert-butyl-2,3-d-
ihydro-1H-inden-1-yl)urea
[0220] Dissolved Example 56J (2.09 g, 6.0 mmol) in tetrahydrofuran
(100 mL), added potassium tert-butoxide (1.0 M in THF, 6.0 mL, 6.0
mmol), stirred solution for 5 minutes, and then added Example 64A
(1.96 g, 6.6 mmol) in tetrahydrofuran (40 mL), and stirred mixture
for 15 minutes. Added 1:1 ethyl acetate:hexane, precipitated the
salts, and filtered through silica gel plug. Concentrated filtrate
and chromatographed on silica gel with 0-to-30% ethyl acetate in
dichloromethane. Dissolved solid in ethyl acetate (250 mL), washed
with 0.5 M potassium carbonate (200 mL), dried with brine, filtered
through a silica gel plug, and concentrated the filtrate. Recovered
2.13 g (70% yield) of Example 64B as a solid. .sup.1H NMR (300 MHz,
DMSO-d.sub.6) .delta. ppm 0.82 (t, J=7.29 Hz, 3H), 1.28 (m, 11H),
1.41 (m, 2H), 1.86 (m, 1H), 2.45 (m, 1H), 2.82 (m, 1H), 2.96 (m,
1H), 3.38 (t, J=6.44 Hz, 2H), 3.56 (m, 2H), 3.75 (m, 2H), 4.99 (s,
2H), 5.16 (q, J=7.12 Hz, 1H), 6.70 (d, J=7.80 Hz, 1H), 7.27 (s,
2H), 7.31 (s, 1H), 7.52 (t, J=7.97 Hz, 1H), 7.86 (d, J=8.14 Hz,
1H), 7.90 (d, J=7.80 Hz, 1H), 8.39 (s, 1H), 8.86 (s, 1H). MS (ESI)
m/z 507.43 (M+H).sup.+. Calcd for
C.sub.29H.sub.38N.sub.4O.sub.4.0.25 Ethyl acetate: C, 68.16; H,
7.63; N, 10.60; Found: C, 68.16; H, 7.74; N, 10.61.
EXAMPLE 65
1-(7-fluoro-2,2-dimethylchroman-4-yl)-3-(1-(2-methoxyethyl)-1H-indazol-4-y-
l)urea
EXAMPLE 65A
7-fluoro-2,2-dimethylchroman-4-one
[0221] A mixture of 4-fluoro-2-hydroxyacetophenone (Aldrich, 1.54
g, 10 mmol), acetone (0.95 mL, 12.9 mmol), and pyrrolidine (0.83
mL, 9.94 mmol) was stirred in 3 mL toluene at room temperature for
1 h and at reflux (Dean-Stark trap) for 4 hours. After cooling to
room temperature, the mixture was diluted with ether (30 mL) and
was washed with 2N HCl (10 mL) and H.sub.2O (10 mL). Drying over
Na.sub.2SO.sub.4 and evaporation of volatiles in vacuo afforded the
crude title compound, which was used without further
purification.
EXAMPLE 65B
7-fluoro-2,2-dimethylchroman-4-amine
[0222] To a solution of Example 65A (415 mg, 2.14 mmol) in methanol
(12 mL) was added methoxylamine hydrochloride (0.179 g, 2.14 mmol)
and pyridine (0.87 mL, 10.8 mmol). The mixture was stirred
overnight at room temperature and was then evaporated in vacuo. The
residue was partitioned between ethyl acetate and H.sub.2O, and the
organic layer was dried over Na.sub.2SO.sub.4 and was evaporated in
vacuo. The residue thus obtained was dissolved in methanol (8 mL)
and was hydrogenated (balloon) over 10% Pd--C in the presence of 4
drops of concentrated HCl overnight at room temperature. The
catalyst was filtered off (Celite), and the filtrate was evaporated
in vacuo. The residue was taken up in ether (20 mL) and was
extracted with 1N HCl (3.times.10 mL). These acidic extracts were
then basified to pH 10 with 2N NaOH and were extracted with ethyl
acetate (3.times.10 mL). Drying over Na.sub.2SO.sub.4, followed by
evaporation in vacuo, yielded Example 65B, 158 mg (48%). .sup.1H
NMR (300 MHz, DMSO-d.sub.6) .delta. ppm 7.56 (m,1H), 6.66 (m, 1H),
6.48 (m, 1H), 3.81 (m, 1H), 2.02 (m, 2H), 1.35 (s, 3H), 1.20 (s,
3H). MS (ESI) m/z 196 (M+H).
EXAMPLE 65C
methyl
4-(3-(7-fluoro-2,2-dimethylchroman-4-yl)ureido)-1H-indazole-1-carbo-
xylate
[0223] Example 65B (158 mg, 0.81 mmol) was stirred with Example 66E
(269 mg, 0.81 mmol) and DIEA (0.21 mL, 1.21 mmol) in 2 mL DMF at
room temperature for 2 hours. The DMF was removed in vacuo, and the
residue was diluted with H.sub.2O. The precipitate thus formed was
collected by filtration and was air-dried to afford the title
compound, which was used without further purification.
EXAMPLE 65D
1-(7-fluoro-2,2-dimethylchroman-4-yl)-3-(1H-indazol-4-yl)urea
[0224] Example 65C (2.35 mmol, 0.57 mmol) was suspended in methanol
(5 mL) and was treated with 5N methanolic NaOH (0.6 mL, 3.0 mmol).
The mixture was stirred at room temperature for 30 minutes, and
poured into H.sub.2O (30 mL). The precipitate was collected by
filtration and was air-dried to afford the title compound, 68 mg
(34%). .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. ppm 13.02 (br,
1H), 8.72 (s, 1H), 8.31 (s, 1H), 7.67 (d, J=6.8 Hz, 1H), 7.36 (m,
1H), 7.22 (m, 1H), 7.09 (m, 1H), 6.59-6.72 (m, 3H), 4.97 (m, 1H),
2.22 (m, 1H), 1.78 (m, 1H), 1.42 (s, 3H), 1.30 (s, 3H). MS (ESI)
m/z 355 (M+H).
EXAMPLE 65E
1-(7-fluoro-2,2-dimethylchroman-4-yl)-3-(1-(2-methoxyethyl)-1H-indazol-4-y-
l)urea
[0225] A solution of Example 65D (500 mg, 1.41 mmol) in DMF (7 mL)
was treated with 60% sodium hydride (68 mg, 1.7 mmol) at room
temperature, and the mixture was stirred at this temperature for 1
hour. Bromoethyl methyl ether (0.15 mL, 1.6 mmol) was then added,
and the mixture was stirred overnight at room temperature. After
this time, most of the DMF was evaporated in vacuo, then water (50
mL) was added. The resulting sticky residue was collected by
filtration and was then chromatographed on silica gel (98:2
CH.sub.2Cl.sub.2--CH.sub.3OH) to afford the title compound, 131 mg
(23%). .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. ppm 8.73 (s,
1H), 8.07 (s, 1H), 7.69 (d, J=6.44 Hz, 1H), 7.32 (dd, J=15.09, 7.63
Hz, 1H), 7.18-7.26 (m, 2H), 6.71-6.79 (m, 2H), 6.61 (dd, J=10.85,
2.71 Hz, 1H), 4.96 (m, 1H), 4.51 (t, J=5.43 Hz, 2H), 3.75 (t,
J=5.43 Hz, 2H), 3.18 (s, 3H), 2.20 (dd, J=13.39, 6.27 Hz, 1H), 1.78
(dd, J=13.05, 11.02 Hz, 1H), 1.41 (s, 3H), 1.30 (s, 3H). MS
(ESI.sup.+) m/z 413 (M+H), 435 (M+Na).
EXAMPLE 66
3-(Dimethylamino)propyl
4-(3-(4-cyclopropyl-5-fluoro-2,3-dihydro-1H-inden-1-yl)ureido)-1H-indazol-
e-1-carboxylate
EXAMPLE 66A
4-Bromo-5-fluoro-2,3-dihydro-1H-inden-1-one
[0226] 5-Fluoro-1-indanone (Aldrich, 6.0 g, 40 mmol) was charged in
three portions to aluminum chloride (13.32 g, 100 mmol). After
mixing by mechanical stirrer for 40 minutes, bromine (2.5 mL, 48
mmol) was added over 15 minutes. The mixture was heated in a hot
water bath (internal temperature 45-50.degree. C.) for 2 hours.
More bromine (0.1 mL) was added via syringe, then heating continued
for another 30 minutes. The solution was poured onto a mixture of
12N hydrochloric acid (16 mL) and ice (80 g). The residual tar in
the flask was rinsed out with the quenched solution. The product
was extracted into ethyl acetate and the combined organic layers
were washed twice with water (60 mL), dried over sodium sulfate,
and concentrated. The product was isolated by flash chromatography
on silica gel with 10% ethyl acetate in heptane. Obtained 5.90 g
(64.5% yield) of Example 66A as a light yellow solid. .sup.1H NMR
(300 MHz, DMSO-d.sub.6) .delta. 2.73 (t, J=5.77 Hz, 2H), 3.04 (t,
J=5.77 Hz, 2H), 7.44 (t, J=8.48 Hz, 1H), 7.70 (dd, J=8.31, 4.92 Hz,
1H). MS (DCI) m/z 247.89 (M+NH.sub.4).sup.+.
EXAMPLE 66B
4-Bromo-5-fluoro-2,3-dihydro-1H-inden-1-one O-methyl oxime
[0227] Methoxylamine hydrochloride (1.92 g, 22.9 mmol) was added to
Example 66A (4.777 g, 20.9 mmol) in pyridine (30 mL) and stirred
for 3 hours at ambient temperature. Concentrated the mixture to a
slurry, added ethyl acetate (200 mL), washed with 1N hydrochloric
acid (200 mL), dried with brine, filtered through a silica gel
plug, and concentrated the filtrate. Obtained 5.186 g (96% yield)
of Example 66B. .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. ppm
2.86 (m, 2H), 2.99 (m, 2H), 3.90 (s, 3H), 7.29 (t, J=8.65 Hz, 1H),
7.57 (dd, J=8.48, 5.09 Hz, 1H). MS (DCI) m/z 259.83
(M+H).sup.+.
EXAMPLE 66C
4-Cyclopropyl-5-fluoro-2,3-dihydro-1H-inden-1-one O-methyl
oxime
[0228] Example 66B (1.29 g, 5.0 mmol) was added to a mixture of
cyclopropylboronic acid (Aldrich, 558 mg, 6.5 mmol), potassium
phosphate (3.71 g, 17.5 mmol), palladium(II) acetate (56 mg, 0.25
mmol) and tricyclohexylphosphine (140 mg, 0.5 mmol) in toluene (20
mL) with water (1 mL). Heated the mixture at 100.degree. C. for 1.5
hours on the microwave (Personal Chemistry). After cooling, the
mixture was filtered through celite and rinsed with ethyl acetate.
Concentrated the filtrate to an oil and chromatographed on silica
gel with 0-to-15% ethyl acetate in hexane. Obtained 1.03 g (94%
yield) of Example 66C. .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta.
ppm 0.81 (m, 2H), 0.93 (m, 2H), 1.76 (m, 1H), 2.82 (m, 2H), 3.06
(m, 2H), 3.87 (s, 3H), 7.03 (dd, J=11.19, 8.48 Hz, 1H), 7.39 (dd,
J=8.31, 4.92 Hz, 1H). MS (DCI) m/z 220.07 (M+H).sup.+.
EXAMPLE 66D
4-Cyclopropyl-5-fluoro-2,3-dihydro-1H-inden-1-amine
[0229] Example 66C (1.03 g, 4.7 mmol), Raney nickel (10 g), and 20%
ammonia in methanol (90 mL) were shaken under hydrogen (60 psi) for
4 hours at ambient temperature. The catalyst was removed by
filtration and the solvent evaporated under reduced pressure,
giving 828 mg (92% yield) of Example 66D as a light yellow oil.
.sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. ppm 0.73 (m, 2H), 0.88
(m, 2H), 1.59 (m, 1H), 1.73 (m, 1H), 1.85 (br s, 2H), 2.34 (m, 1H),
2.70 (m, 1H), 2.96 (ddd, J=16.02, 8.73, 3.05 Hz, 1H), 4.11 (t,
J=7.46 Hz, 1H), 6.88 (dd, J=11.36, 8.31 Hz, 1H), 7.14 (dd, J=8.14,
5.09 Hz, 1H). MS (DCI) m/z 192.0 (M+H).sup.+.
EXAMPLE 66E
Methyl
4-({[(2,5-dioxopyrrolidin-1-yl)oxy]carbonyl}amino)-1H-indazole-1-ca-
rboxylate
[0230] Example 56C (1.9 g, 10 mmol) and disuccinimidyl carbonate
(Fluka, 2.8 g, 11 mmol) were mixed in acetonitrile (100 mL) for 48
hours under nitrogen atmosphere. The solid was isolated by
filtration, washed with acetonitrile (10 mL) and dried under vacuum
at ambient temperature to give Example 66E (2.56 g, 77%). This
product was used without further purification.
EXAMPLE 66F
1-(4-Cyclopropyl-5-fluoro-2,3-dihydro-1H-inden-1-yl)-3-(1H-indazol-4-yl)ur-
ea
[0231] Example 66E (1.44 g, 4.33 mmol) was added to Example 66D
(828 mg, 4.33 mmol) in diisopropylethylamine (0.75 mL, 4.33 mmol)
and dimethylformamide (30 mL) at ambient temperature. After 1 hour
the mixture was diluted with water (100 mL), the resulting white
precipitate was filtered off, washed with water and air-dried.
Suspended the wet cake in triethylamine (1.2 mL, 8.66 mmol),
methanol (100 mL) and water (10 mL). Refluxed the mixture for 30
minutes, cooled to ambient temperature, diluted with water (300
mL), collected the precipitate by filtration, rinsed with water and
allowed to dry. The resulting filter cake was further dried to
constant weight, yielding 1.439 g (95% yield) of Example 66F as a
white solid.
[0232] .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. ppm 0.78 (m,
2H), 0.93 (m, 2H), 1.78 (m, 1H), 1.87 (m, 1H), 2.47 (m, 1H), 2.87
(m, 1H), 3.05 (m, 1H), 5.14 (q, J=7.46 Hz, 1H), 6.69 (d, J=7.80 Hz,
1H), 6.96 (dd, J=11.36, 8.31 Hz, 1H), 7.06 (d, J=8.48 Hz, 1H), 7.16
(dd, J=8.13, 4.74 Hz, 1H), 7.21 (t, J=8.14 Hz, 1H), 7.67 (d, J=7.12
Hz, 1H), 8.04 (s, 1H), 8.59 (s, 1H), 12.99 (s, 1H). MS (ESI) m/z
351.09 (M+H).sup.+. Calcd for C.sub.20H.sub.19FN.sub.4O: C, 68.56;
H, 5.47; N, 15.99; Found: C, 68.43; H, 5.41; N, 15.34.
EXAMPLE 66G
3-(Dimethylamino)propyl 2,5-dioxopyrrolidin-1-yl carbonate
[0233] To a flask containing dichloromethane (200 mL) was added
di-(N-succinimidyl)carbonate 5.50 g, 21.50 mmol) and
3-(dimethylamino)propan-1-ol (2.43 g, 23.60 mmol) and the mixture
was stirred at room temperature for 12 hours. The mixture was
concentrated in vacuo, purified on SiO.sub.2 eluting with 1%
CH.sub.3OH in CH.sub.2Cl.sub.2 to give Example 66G (3.7 g) in 70%
yield. MS(+APCI)m/z 245 (M+H).sup.+.
EXAMPLE 66H
3-(Dimethylamino)propyl
4-(3-(4-cyclopropyl-5-fluoro-2,3-dihydro-1H-inden-1-yl)ureido)-1H-indazol-
e-1-carboxylate trifluoroacetate
[0234] To a solution of Example 66F (0.24 g, 0.70 mmol) and Example
66G (0.335 g, 1.40 mmol) in N,N-dimethylformamide (10 mL) was added
a solution of 1N KO-t-Bu (0.8 mL, 0.80 mmol) and the mixture
stirred 12 hours at ambient temperature. The resulting solution was
concentrated and the residue was purified on reverse phase HPLC
eluting with acetonitrile/0.1% TFA in H.sub.2O to give Example 66H
(0.124 g) in 34%. .sup.1H NMR (300 MHz, CD.sub.3OD) .delta. ppm
0.80-0.84 (m, 2H), 0.92-0.97 (m, 2H), 1.60-1.82 (m, 1H), 1.86-2.12
(m, 2H), 2.28-2.38 (m, 1H), 2.60-2.72 (m, 1H), 2.97 (s, 6H), 3.40
(t, J=7.80, 15.26 Hz, 2H), 3.71 (t, J=6.44, 13.22 Hz, 1H), 4.21 (t,
J=6.10, 11.87 Hz, 1H), 4.61 (t, J=5.77, 11.87 Hz, 2H), 5.27 (t,
J=7.46, 14.58 Hz, 1H), 6.83-6.98 (m, 1H), 7.14-7.18 (m, 1H),
7.42-7.67 (m, 2H), 7.87-7.96 (m, 1H), 8.40 (d, J=1.02 Hz, 1H).
MS(+APCI)m/z 480 (M+H).sup.+. Calc for
C.sub.26H.sub.30N.sub.5O.sub.3F:1.0TFA:C, 56.66; H, 5.26; N, 11.80.
Found: C, 56.84; H, 5.43; N, 11.92.
EXAMPLE 67
1-(4-Cyclopropyl-2,3-dihydro-1H-inden-1-yl)-3-(1-(2-(dimethylamino)acetyl)-
-1H-indazol-4-yl)urea trifluoroacetate
EXAMPLE 67A
4-Bromo-2,3-dihydro-1H-inden-1-one O-methyl oxime
[0235] Methoxylamine hydrochloride (5.7 g, 68.2 mmol) was added to
4-bromo-1-indanone (Aldrich, 13.477 g, 63.9 mmol) in pyridine (50
mL) and stirred for 3 hours at ambient temperature. Concentrated
the mixture to a slurry, added ethyl acetate (200 mL), washed with
1N hydrochloric acid (200 mL), dried with brine, filtered through a
silica gel plug, and concentrated the filtrate. Obtained 15.248 g
(99% yield) of Example 67A. .sup.1H NMR (300 MHz, DMSO-d.sub.6)
.delta. ppm 2.83 (m, 2H), 2.96 (m, 2H), 3.91 (s, 3H), 7.25 (t,
J=7.80 Hz, 1H), 7.57 (dd, J=7.63, 0.84 Hz, 1H), 7.61 (dd, J=7.79,
1.01 Hz, 1H). MS (DCI) m/z 241.90 (M+H).sup.+.
EXAMPLE 67B
4-Cyclopropyl-2,3-dihydro-1H-inden-1-one O-methyl oxime
[0236] Example 67A (1.92 g, 8.0 mmol) was added to a mixture of
cyclopropylboronic acid (Aldrich, 893 mg, 10.4 mmol), potassium
phosphate (5.94 g, 28.0 mmol), palladium(II) acetate (90 mg, 0.4
mmol) and tricyclohexylphosphine (224 mg, 0.8 mmol) in toluene (32
mL) with water (1.6 mL). Heated the mixture at 100.degree. C. for 3
hours on the microwave (Personal Chemistry). After cooling, the
mixture was filtered through celite and rinsed with ethyl acetate.
Concentrated the filtrate to an oil and chromatographed on silica
gel with 0 to 10% ethyl acetate in hexane. Obtained 1.32 g (82%
yield) of Example 67B. .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta.
ppm 0.68 (m, 2H), 0.95 (m, 2H), 1.90 (m, 1H), 2.82 (m, 2H), 3.05
(m, 2H), 3.88 (s, 3H), 6.90 (d, J=7.46 Hz, 1H), 7.18 (t, J=7.63 Hz,
1H), 7.36 (d, J=7.80 Hz, 1H). MS (DCI) m/z 202.09 (M+H).sup.+.
EXAMPLE 67C
4-Cyclopropyl-2,3-dihydro-1H-inden-1-amine
[0237] Example 67B (1.32 g, 6.56 mmol), Raney nickel (6.0 g), and
20% ammonia in methanol (40 mL) were shaken under hydrogen (60 psi)
for 4 hours at ambient temperature. The catalyst was removed by
filtration and the solvent evaporated under reduced pressure,
giving 1.11 g (97% yield) of Example 67C. .sup.1H NMR (300 MHz,
DMSO-d.sub.6) .delta. ppm 0.61 (m, 2H), 0.90 (m, 2H), 1.58 (dq,
J=12.29, 8.45 Hz, 1H), 1.85 (m, 3H), 2.35 (rn, 1H), 2.70 (dt,
J=16.05, 7.97 Hz, 1H), 2.97 (ddd, J=15.85, 8.73, 3.22 Hz, 1H), 4.17
(t, .1-7.46 Hz, 1H), 6.66 (d, J=7.80 Hz, 1H), 7.09 (m, 2H). MS
(DCI) m/z 174.12 (M+H).sup.+.
EXAMPLE 67D
1-(4-Cyclopropyl-2,3-dihydro-1H-inden-1-yl)-3-(1H-indazol-4-yl)urea
[0238] Example 66E (2.13 g, 6.41 mmol) was added to Example 67C
(1.11 g, 6.41 mmol) in diisopropylethylamine (1.12 mL, 6.41 mmol)
and dimethylformamide (50 mL) at ambient temperature. After 1 hour
the mixture was diluted with water (200 mL), the resulting white
precipitate was filtered off, washed with water and air dried.
Obtained 2.44 g (98% yield) of methyl
4-(3-(4-cyclopropyl-2,3-dihydro-1H-inden-1-yl)ureido)-1H-indazole-1-carbo-
xylate as a white solid. Suspended 1.94 g of this intermediate in
triethylamine (1.4 mL, 10.0 mmol), methanol (150 mL) and water (15
mL). Refluxed the mixture for 30 minutes, cooled to ambient
temperature, diluted with water (500 mL), collected the white
precipitate by filtration, rinsed with water and air-dried. The wet
cake was freeze-dried to constant weight, yielding 1.60 g (97%
yield) of Example 67D. .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta.
ppm 0.66 (m, 2H), 0.94 (m, 2H), 1.84 (m, 1H), 1.91 (m, 1H), 2.48
(m, 1H), 2.87 (dt, J=15.94, 7.97 Hz, 1H), 3.07 (ddd, J=15.94, 8.81,
4.07 Hz, 1H), 5.20 (q, J=7.46 Hz, 1H), 6.70 (d, J=7.80 Hz, 1H),
6.78 (m, 1H), 7.06 (d, J=8.14 Hz, 1H), 7.13 (d, J=4.41 Hz, 2H),
7.22 (t, J=7.97 Hz, 1H), 7.68 (d, J=7.12 Hz, 1H), 8.04 (s, 1H),
8.58 (s, 1H), 12.99 (s, 1H). MS (ESI) m/z 333.08 (M+H).sup.+. Calcd
for C.sub.20H.sub.20N.sub.4O.0.23 H.sub.2O: C, 71.38; H, 6.13; N,
16.65; Found: C, 71.40; H, 5.95; N, 16.42.
EXAMPLE 67E
1-(4-Cyclopropyl-2,3-dihydro-1H-inden-1-yl)-3-(1-(2-(dimethylamino)acetyl)-
-1H-indazol-4-yl)urea trifluoroacetate
[0239] The title compound was prepared as described in Example 68E
substituting Example 67D (0.18 g, 0.50 mmol) for Example 68D and
HPLC purification (acetonitrile/0.1% TFA in H.sub.2O) instead of
HCl treatment. The material was recrystallized from THF (10 mL) to
give 0.056 g (25% yield). .sup.1H NMR (300 MHz, CD.sub.3OD) .delta.
ppm 0.63-0.67 (m, 2H), 0.90-0.96 (m, 2H), 1.83-1.93 (m, 2H),
2.53-2.64 (m, 1H), 2.79-2.89 (m, 1H), 2.96-3.05 (m, 1H), 3.31 (s,
6H), 5.06 (s, 2H), 5.27-5.28 (m, 1H), 6.96-7.01 (m, 2H), 7.24 (d,
J=7.67 Hz, 1H), 7.39 (t, J=8.28, 15.96 Hz, 1H), 7.57 (d, J=7.98 Hz,
1H), 7.75 (d, J=7.98 Hz, 1H), 8.53 (s, 1H). MS(+APCI)m/z 418
(M+H).sup.+. Calc for C.sub.24H.sub.27N.sub.5O.sub.2:1.0TFA:C,
58.75; H, 5.31; N,13.18. Found: C, 58.92; H, 5.18; N,13.26.
EXAMPLE 68
1-(5-Cyclopropyl-2,3-dihydro-1H-inden-1-yl)-3-(1-(2-(dimethylamino)acetyl)-
-1H-indazol-4-yl)urea hydrochloride
EXAMPLE 68A
5-Bromo-2,3-dihydro-1H-inden-1-one O-methyl oxime
[0240] Methoxylamine hydrochloride (6.75 g, 80.9 mmol) was added to
5-bromo-1-indanone (Aldrich, 15.517 g, 73.5 mmol) in pyridine (7 5
mL) and stirred overnight at ambient temperature. Concentrated the
mixture to a slurry, added ethyl acetate (200 mL), washed with IN
hydrochloric acid (200 mL), dried with brine, filtered through a
silica gel plug, and concentrated the filtrate. Obtained 17.56 g
(99% yield) of Example 68A as a beige solid. .sup.1H NMR (300 MHz,
DMSO-d.sub.6) .delta. ppm 2.80 (m, 2H), 3.01 (m, 2H), 3.89 (s, 3H),
7.47 (m, .sup.2H), 7.63 (m, 1H). MS (DCI) m/z 239.96
(M+H).sup.+.
EXAMPLE 68B
5-Cyclopropyl-2,3-dihydro-1H-inden-1-one O-methyl oxime
[0241] Example 68A (960 mg, 4.0 mmol) was added to a mixture of
cyclopropylboronic acid (Aldrich, 447 mg, 5.2 mmol), potassium
phosphate (2.97 g, 14.0 mmol), palladium(II) acetate (45 mg, 0.2
mmol) and tricyclohexylphosphine (112 mg, 0.4 mmol) in toluene (16
mL) with water (0.8 mL). Heated the mixture at 100.degree. C. for 3
hours on the microwave (Personal Chemistry). After cooling, the
mixture was filtered through celite and rinsed with ethyl acetate.
Concentrated the filtrate to an oil and chromatographed on silica
gel with 0-to-10% ethyl acetate in hexane. Obtained 657 mg (82%
yield) of Example 68B. .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta.
ppm 0.70 (m, 2H), 0.97 (m, 2H), 1.94 (m, 1H), 2.77 (m, 2H), 2.94
(m, 2H), 3.86 (s, 3H), 6.99 (d, J=8.14 Hz, 1H), 7.06 (s, 1H), 7.42
(d, J=7.80 Hz, 1H). MS (DCI) m/z 202.06 (M+H).sup.+.
EXAMPLE 68C
5-Cyclopropyl-2,3-dihydro-1H-inden-1-amine
[0242] Example 68B (629 mg, 3.13 mmol), Raney nickel (3.0 g), and
20% ammonia in methanol (40 mL) were shaken under hydrogen (60 psi)
for 6 hours at ambient temperature. The catalyst was removed by
filtration and the solvent evaporated under reduced pressure,
giving 509 mg (94% yield) of Example 68C. .sup.1H NMR (300 MHz,
DMSO-d.sub.6) .delta. ppm 0.60 (m, 2H), 0.88 (m, 2H), 1.54 (dq,
J=12.21, 8.59 Hz, 1H), 1.87 (m, 3H), 2.30 (m, 1H), 2.63 (m, 1H),
2.78 (ddd, J=15.77, 8.65, 3.05 Hz, 1H), 4.12 (t, J=7.46 Hz, 1H),
6.87 (m, 2H), 7.18 (d, J=7.46 Hz, 1H). MS (DCI) m/z 157.07
(M+H--NH.sub.3).sup.+.
EXAMPLE 68D
1-(5-Cyclopropyl-2,3-dihydro-1H-inden-1-yl)-3-(1H-indazol-4-yl)urea
[0243] Example 66E (977 mg, 2.94 mmol) was added to Example 68C
(509 mg, 2.94 mmol) in diisopropylethylamine (0.51 mL, 2.94 mmol)
and dimethylformamide (30 mL) at ambient temperature. After 1 hour
the mixture was diluted with water (100 mL), the resulting white
precipitate was filtered off, washed with water and air dried.
Suspended the wet cake in triethylamine (0.82 mL, 5.88 mmol),
methanol (75 mL) and water (5 mL). Refluxed the mixture for 30
minutes, cooled to ambient temperature, diluted with water (250
mL), collected the white precipitate by filtration, rinsed with
water and allowed to dry. The resulting filter cake was further
dried to constant weight, yielding 924 mg (95% yield) of Example
68D. .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. ppm 0.65 (m, 2H),
0.92 (m, 2H), 1.78 (m, 1H), 1.91 (m, 1H), 2.44 (m, 1H), 2.78 (m,
1H), 2.91 (m, 1H), 5.14 (q, J=7.46 Hz, 1H), 6.69 (d, J=7.80 Hz,
1H), 6.97 (m, 2H), 7.06 (d, J=8.14 Hz, 1H), 7.21 (m, 2H), 7.68 (d,
J=7.46 Hz, 1H), 8.05 (s, 1H), 8.60 (s, 1H), 12.99 (s, 1H). MS (ESI)
m/z 333.04 (M+H).sup.+. Calcd for C.sub.20H.sub.20N.sub.4O.0.3
H.sub.2O: C, 71.11; H, 6.15; N, 16.59; Found: C, 71.13; H, 6.04; N,
16.38.
EXAMPLE 68E
1-(5-Cyclopropyl-2,3-dihydro-1H-inden-1-yl)-3-(1-(2-(dimethylamino)acetyl)-
-1H-indazol-4-yl)urea hydrochloride
[0244] To a round bottom flask containing 40 mL of
CH.sub.2Cl.sub.2/DMF (10/1) was added Example 68D (0.30 g, 1.10
mmol), 1-hydroxybenzotriazole hydrate (0.18 g, 1.30 mmol),
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.256
g, 1.30 mmol), N,N-dimethylglycine (0.138 g, 1.30 mmol), and the
mixture was stirred at room temperature for 24 hours. The mixture
was diluted with CH.sub.2Cl.sub.2 (100 mL), washed with sat
NaHCO.sub.3, dried (Na.sub.2SO.sub.4) and concentrated in vacuo.
The material was purified on SiO.sub.2 eluting with ethyl acetate.
The material was taken up in ethyl acetate/diethyl ether (22 mL,
1/10) and 2M HCl in diethyl ether (2.0 eq) was added and the
solution stirred at room temperature for 5 minutes. The material
was concentrated in vacuo to give Example 68E as a white solid
(0.192 g) in 42%. .sup.1H NMR (300 MHz, CD.sub.3OD) .delta. ppm
0.62-0.66 (m, 2H), 0.91-0.96 (m, 2H), 1.84-1.93 (m, 2H), 2.54-2.62
(m, 1H), 2.79-2.87 (m, 1H), 2.94-3.01 (m, 1H), 3.11 (s, 6H), 5.02
(s, 2H), 5.25-5.29 (m, 1H), 6.93-6.96 (m, 2H), 7.23 (d, J=7.67 Hz,
1H), 7.37 (t, J=8.28, 15.96 Hz, 1H), 7.56 (d, J=7.98 Hz, 1H), 7.74
(d, J=7.98 Hz, 1H), 8.49 (s, 1H). MS(-FAPCI)m/z 418 (M+H).sup.+.
Calc for C.sub.24H.sub.27N.sub.5O.sub.2:1.4 HCl:C, 61.52; H, 6.11;
N,14.95. Found: C, 61.87; H, 6.15; N,14.82.
EXAMPLE 69
1-(1-(2-(Dimethylamino)acetyl)-1H-indazol-4-yl)-3-(4-(3,3-dimethylbutyl)-5-
-fluoro-2,3-dihydro-1H-inden-1-yl)urea
EXAMPLE 69A
4-(3,3-Dimethylbut-1-ynyl)-5-fluoro-2,3-dihydro-1H-inden-1-one
O-methyl oxime
[0245] Example 66B (1.29 g, 5.0 mmol) was added to a mixture of
3,3-dimethyl-1-butyne (Aldrich, 0.75 mL, 6.0 mmol),
Pd(Ph.sub.3P).sub.2Cl.sub.2 (175 mg, 0.25 mmol), copper(I) iodide
(48 mg, 0.25 mmol) and triphenylphosphine (262 mg, 1.0 mmol) in
triethylamine (7.5 mL) and dimethylformamide (2.5 mL). The mixture
was heated to 130.degree. C. for 20 minutes on the microwave
(Personal Chemistry). Additional 3,3-dimethyl-1-butyne (1.5 mL,
12.0 mmol) was added via syringe, then continued heating for
another 20 minutes. After cooling, the mixture was filtered through
celite, rinsed with ethyl acetate, and the filtrate concentrated to
an oil. The material was chromatographed on silica gel with 0 to
10% ethyl acetate in hexane, yielding 1.32 g of impure product.
Repeated chromatography on silica gel with 0 to 100%
dichloromethane in hexane, to give 1.089 g (84% yield) of Example
69A. .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. ppm 1.31 (s, 9H),
2.84 (m, 2H), 2.99 (m, 2H), 3.89 (s, 3H), 7.17 (dd, J=9.67, 8.65
Hz, 1H), 7.51 (dd, J=8.48, 5.09 Hz, 1H). MS (DCI) m/z 260.06
(M+H).sup.+.
EXAMPLE 69B
4-(3,3-Dimethylbutyl)-5-fluoro-2,3-dihydro-1H-inden-1-amine
[0246] Example 69A (1.065 g, 4.11 mmol), Raney nickel (10 g), and
20% ammonia in methanol (90 mL) were shaken under hydrogen (60 psi)
for 16 hours at ambient temperature. The catalyst was removed by
filtration and the solvent evaporated under reduced pressure,
giving 843 mg (88% yield) of
(Z)-4-(3,3-dimethylbut-1-enyl)-5-fluoro-2,3-dihydro-1H-inden-1-amine
as a green oil. This intermediate (700 mg, 3.0 mmol), Raney nickel
(7.17 g), and methanol (20 mL) were shaken under hydrogen (60 psi)
for 16 hours at 40.degree. C. The mixture was filtered and
retreated with catalyst (7.01 g) for 2 hours at 40.degree. C., then
14 hours at ambient temperature. The mixture was filtered through a
nylon membrane and the filtrate was concentrated to yield 389 mg
(55% yield) of Example 69B. .sup.1H NMR (300 MHz, DMSO-d.sub.6)
.delta. ppm 0.94 (s, 9H), 1.31 (m, 2H), 1.60 (m, 1H), 1.87 (br s,
2H), 2.34 (m, 1H), 2.63 (m, 1H), 2.84 (ddd, J=15.85, 8.73, 3.22 Hz,
1H), 4.14 (t, J=7.80 Hz, 1H), 6.91 (dd, J=10.51, 8.14 Hz, 1H), 7.14
(dd, .J=7.97, 4.92 Hz, 1H). MS (DCI) m/z 236.1 (M+H).sup.+.
EXAMPLE 69C
1-(4-(3,3-Dimethylbutyl)-5-fluoro-2,3-dihydro-1H-inden-1-yl)-3-(1H-indazol-
-4-yl)urea
[0247] Example 66E (549 mg, 1.65 mmol) was added to Example 69B
(389 mg, 1.65 mmol) along with diisopropylethylamine (0.29 mL, 1.65
mmol) in dimethylformamide (20 mL) at ambient temperature. After 1
hour, the mixture was partitioned between ethyl acetate (200 mL)
and water (200 mL), and the organic layer was dried with brine and
sodium sulfate, and then evaporated under reduced pressure. The
residue was chromatographed on silica gel with 10% methanol in
ethyl acetate to obtain methyl
4-(3-(4-(3,3-dimethylbutyl)-5-fluoro-2,3-dihydro-1H-inden-1-yl)ureido)-1H-
-indazole-1-carboxylate as a tan solid. This intermediate was
dissolved in triethylamine (0.46 mL, 3.31 mmol), methanol (50 mL)
and water (5 mL). The mixture was refluxed for 1 hour, concentrated
under reduced pressure and chromatographed on silica gel with 0 to
10% methanol in dichloromethane to give 413 mg (63% yield) of
Example 69C as a solid. .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta.
ppm 0.97 (s, 9H), 1.35 (m, 2H), 1.87 (m, 1H), 2.55 (m, 2H), 2.80
(dt, J=15.60, 7.80 Hz, 1H), 2.96 (ddd, J=16.28, 8.47, 4.41 Hz, 1H),
5.17 (q, J=7.12 Hz, 1H), 6.70 (d, J=7.80 Hz, 1H), 6.99 (dd,
J=10.18, 8.47 Hz, 1H), 7.07 (d, J=8.47 Hz, 1H), 7.18 (m, 1H), 7.21
(t, J=8.14 Hz, 1H), 7.67 (d, J=7.45 Hz, 1H), 8.04 (s, 1H), 8.59 (s,
1H), 12.99 (s, 1H). MS (ESI) m/z 395.23 (M+H).sup.+. Calcd for
C.sub.23H.sub.27FN.sub.4O.0.25 H.sub.2O.0.20 Methanol: C, 68.74; H,
7.04; N, 13.82; Found: C, 68.72; H, 7.09; N, 13.84.
EXAMPLE 69D
1-(1-(2-(Dimethylamino)acetyl)-1H-indazol-4-yl)-3-(4-(3,3-dimethylbutyl)-5-
-fluoro-2,3-dihydro-1H-inden-1-yl)urea hydrochloride
[0248] The title compound was prepared as described in Example 68E
substituting Example 69C (0.150 g, 0.40 mmol) for Example 68D. The
mixture was purified on SiO.sub.2 with ethyl acetate/methylene
chloride (1/1) to give a white solid. The material was taken up in
ethyl acetate/diethyl ether (22 mL, 1/10) and 2M HCl in diethyl
ether (2.0 eq) was added and stirred at room temperature for 5
minutes. The material was concentrated in vacuo to give Example 69D
(0.062 g) in 30% yield. .sup.1H NMR (300 MHz, CD.sub.3OD) .delta.
ppm 1.0 (s, 9H), 1.35-1.43 (m, 2H), 1.91-2.01 (m, 1H), 2.59-2.69
(m, 2H), 2.81-2.89 (m, 1H), 2.97-3.07 (m, 2H), 3.10 (s, 6H), 5.02
(s, 2H), 5.27-5.32 (m, 1H), 6.88-6.97 (m, 1H), 7.15-7.20 (m, 1H),
7.58 (t, J=8.13, 15.93 Hz, 1H), 7.72 (d, J=7.80 Hz, 1H), 8.02 (d,
J=8.14 Hz, 1H), 8.47 (d, J=1.02 Hz, 1H). MS(+APCI)m/z 480
(M+H).sup.+. Calc for C.sub.27H.sub.34N.sub.5O.sub.2F:1.1 HCl:1.0
H.sub.2O:C, 60.31; H, 6.95; N,13.02. Found: C, 60.57; H, 7.32;
N,12.83.
EXAMPLE 70
1-(4-cyclopropyl-5-fluoro-2,3-dihydro-1H-inden-1-yl)-3-(1-(2-(dimethylamin-
o)acetyl)-1H-indazol-4-yl)urea hydrochloride
[0249] The title compound was prepared as described in Example 68E,
substituting Example 66F (0.250 g, 0.70 mmol) for Example 68D. The
mixture was purified on SiO.sub.2 with 1% methanol in ethyl acetate
to give a solid. The material was taken up in ethyl acetate/diethyl
ether (44 mL, 1/10) and 2M HCl in diethyl ether (2.0 eq) was added
and stirred at room temperature for 5 minutes. The material was
concentrated in vacuo to give Example 70 (0.180 g) in 54%. .sup.1H
NMR (300 MHz, CD.sub.3OD) .delta. ppm 0.80-0.84 (m, 2H), 0.92-0.97
(m, 2H), 1.74-1.79 (m, 1H), 1.87-2.00 (m, 1H), 2.57-2.68 (m, 1H),
2.87-2.98 (m, 1H), 3.10-3.20 (m, 7H), 5.02 (s, 2H), 5.25-5.30 (m,
1H), 6.83-6.90 (m, 1H), 7.14-7.18 (m, 1H), 7.58 (t, J=8.14, 15.93
Hz, 1H), 7.71 (d, J=8.14 Hz, 1H), 8.03 (d, J=7.46 Hz, 1H), 8.46 (d,
J=0.68 Hz, 1H). MS(+APCI)m/z 436 (M+H).sup.+. Calc for
C.sub.24H.sub.22N.sub.5O.sub.2F:1.2HCl:C, 60.15; H, 5.72; N,14.61.
Found: C, 60.07; H, 5.76; N,14.28.
EXAMPLE 75
(R)-1-(5-tert-butyl-2,3-dihydro-1H-inden-1-yl)-3-(1-(2-(methylamino)acetyl-
)-1H-indazol-4-yl)urea hydrochloride
EXAMPLE 75A
(R)-benzyl
2-(4-(3-(5-tert-butyl-2,3-dihydro-1H-inden-1-yl)ureido)-1H-inda-
zol-1-yl)-2-oxoethyl(methyl)carbamate
[0250] The title compound was prepared as described in Example 68E
substituting Example 56J for Example 68D and
2-((benzyloxycarbonyl)(methyl)amino)acetic acid for
N,N-dimethylglycine. The mixture was purified on SiO.sub.2 eluting
with 5% CH.sub.3OH in CH.sub.2Cl.sub.2 to give Example 75A. .sup.1H
NMR (300 MHz, CD.sub.3OD) .delta. ppm 1.32 (s, 9H), 1.83-1.95 (m,
1H), 2.55-2.65 (m, 1H), 2.81-2.89 (m, 1H), 2.92-3.06 (m, 1H), 4.76
(s, 2H), 4.84 (s, 3H), 5.15 (s, 2H), 5.29 (t, J=7.46, 14.58 Hz,
1H), 7.24-7.42 (m, 8H), 7.51 (t, J=7.80, 15.94 Hz, 1H), 7.75 (d,
J=7.80 Hz, 1H), 8.01 (d, J=7.84 Hz, 1H), 8.34 (s, 1H). MS(+APCI)m/z
554 (M+H).sup.+.
EXAMPLE 75B
(R)-1-(5-tert-butyl-2,3-dihydro-1H-inden-1-yl)-3-(1-(2-(methylamino)acetyl-
)-1H-indazol-4-yl)urea hydrochloride
[0251] To a Parr flask containing methanol (100 mL) was added
Example 75A (0.85 g, 1.50 mmol), 10% Pd/C (0.20 g) and saturated
HCl in methanol (1.1 eq). A hydrogen atmosphere (60 psi) was
applied to the mixture and the vessel was shaken at room
temperature for 1 hour. The mixture was filtered, washed with
methanol (50 mL) and concentrated in vacuo to give Example 75B as a
white solid (0.46 g) in 73% yield. .sup.1H NMR (300 MHz,
CD.sub.3OD) .delta. ppm 1.31 (s, 9H), 1.82-1.98 (m, 1H), 2.54-2.72
(m, 1H), 2.80-2.88 (m, 1H), 2.91-3.07 (m, 1H), 3.83 (s, 3H), 3.91
(s, 2H), 5.25-5.33 (m, 1H), 7.17 (d, J=7.46 Hz, 1H), 7.24-7.34 (m,
4H), 7.59 (d, J=7.46 Hz, 1H), 8.01 (s, J=0.68 Hz, 1H). MS(+APCI)m/z
420 (M+H).sup.+. Calc for
C.sub.24H.sub.29N.sub.5O.sub.2:1.1HCl:0.40H.sub.2O:C, 61.75; H,
6.67; N,15.00. Found: C, 62.12; H, 7.07; N, 14.75.
EXAMPLE 76
1-(1-(2-(Dimethylamino)acetyl)-1H-indazol-4-yl)-3-(7-(trifluoromethyl)chro-
man-4-yl)urea
EXAMPLE 76A
3-(3-Trifluoromethyl-phenoxy)propanoic acid
[0252] Sodium hydroxide (4.24 g, 106 mmol) was dissolved in water
(50 ml). 3-Trifluoromethyl-phenol (5.19 g, 32 mmol) was dissolved
in 25 ml of the sodium hydroxide solution and heated to reflux.
3-Bromopropionic acid (9.79 g, 64 mmol) in the other 25 ml of
sodium hydroxide solution was added dropwise over 15 minutes. The
reflux was continued for 45 minutes more, with portions of 10M
sodium hydroxide solution added to maintain the pH of the solution
at appoximately pH 10. The reaction mixture was then cooled,
acidified with hydrochloric acid, and extracted with ethyl acetate.
The combined organic layers were extracted with saturated aqueous
sodium bicarbonate, and the aqueous layers acidified with
hydrochloric acid. The acidified aqueous layers were extracted with
diethyl ether. The ether layers were dried with magnesium sulfate,
and the solvent removed under vacuum to give 2.5 g of the crude
product which was used directly in the next step.
[0253] .sup.1H NMR (300 MHz, d.sub.6-DMSO) .delta. 12.40 (broad s,
1H), 7.51 (t, J 7.5 Hz, 1H), 7.24 (m, 3H), 4.23 (t, J 6.0 Hz, 2H),
2.71 (t, J 6.0 Hz, 2H).
EXAMPLE 76B
7-Trifluoromethyl-chroman-4-one
[0254] Polyphosphoric acid (10 mL) was heated in water bath and
Example 76A (.about.2.5 g) was added. After stirring for 30 minutes
this mixture was poured onto ice and extracted twice with diethyl
ether. The combined organic layers were washed with water, aqueous
NaHCO.sub.3, and water and concentrated. The residue was
chromatographed on silica gel, and eluted with 9:1ethyl acetate:
hexanes to afford the title compound (0.84 g, 12% for 2 steps) as a
solid. .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 7.96 (d, J 7.5
Hz, 1H), 7.40 (m, 2H), 4.62 (t, J 6.0 Hz, 2H), 2.88 (t, J 6.0 Hz,
2H). MS (DCl/NH.sub.3) m/e 234 (M+NH.sub.4).sup.+.
EXAMPLE 76C
7-Trifluoromethyl-chroman-4-one O-methyl-oxime
[0255] A solution of Example 76B (0.84 g, 3.88 mmol) and methoxyl
amine hydrochloride (0.65 g, 7.78 mmol, 2 eq.) in pyridine (10 mL)
was stirred for 18 hours at ambient temperature and concentrated
under reduced pressure. The residue was dissolved in diethyl ether
and washed sequentially with water, 1N HCl and water. The isolated
organic layer was concentrated and the residue chromatographed on
silica gel, eluting with 5:95 ethyl acetate:hexanes to afford the
title product (0.71 g, 74%). .sup.1H NMR (300 MHz, DMSO-d.sub.6)
.delta. 8.60 (d, J 7.5 Hz, 1H, major), 8.00 (d, J 7.5 Hz, 1H,
minor), 7.28 (m, 2H), 4.40 (t, J 6.0 Hz, 2H, major), 4.24 (t, J 6.0
Hz, 2H, minor), 3.98 (s, 3H, minor), 3.96 (s, 3H, major), 2.87 (t,
J 6.0 Hz, 2H, minor), 2.70 (t, J 6.0 Hz, 2H, major). MS
(DCI/NH.sub.3) m/e 246 (M+H).sup.+.
EXAMPLE 76D
7-Trifluoromethyl-chroman-4-ylamine
[0256] The title compound was prepared as described in Example 66D,
substituting Example 76C for Example 66C. .sup.1H NMR (300 MHz,
CDCl.sub.3) .delta. 7.43(d, 1H, J=8.1 Hz), 7.14(d, 1H, J=8.1 Hz),
7.06(s, 1H), 4.22-4.37 (m, 2H), 4.08 (t, 1H, J=5.4 Hz), 2.12-2.22
(m, 1H), 1.82-1.92 (m, 1H). MS (DCI) m/e 218 (M+H).sup.+.
EXAMPLE 76E
4-[3-(7-Trifluoromethyl-chroman-4-yl)-ureido]-indazole-1-carboxylic
acid methyl ester
[0257] The title compound was prepared as described in Example 65C,
substituting Example 76D for Example 65B. .sup.1H NMR (300 MHz,
DMSO-d.sub.6) .delta. 8.92 (s, 1H), 8.40 (s, 1H), 7.85 (d, 1H,
J=7.1 Hz), 7.71 (d, 1H, J=8.5 Hz), 7.54 (m, 2H), 7.26 (d, 1H, J=7.8
Hz), 7.14 (s, 1H), 6.95 (d, 1H, J=8.1 Hz), 5.03 (m, 1H), 4.38 (m,
1H), 4.27 (m, 1H), 4.03 (s, 3H), 2.19 (m, 1H), 2.09 (m, 1H). MS
(ESI) m/e 435 (M+H).sup.+.
EXAMPLE 76F
N-1H-indazol-4-yl-N'-[7-(trifluoromethyl)-3,4-dihydro-2H-chromen-4-yl]urea
[0258] The title compound was prepared as described in Example 65D,
substituting Example 76E for Example 65C. .sup.1H NMR (300 MHz,
DMSO-d.sub.6) .delta. 13.00 (broad s, 1H), 8.67 (s, 1H), 8.04 (s,
1H), 7.67 (d, J=7.5 Hz, 1H), 7.55 (d, J=7.5 Hz, 1H), 7.22 (m, 2H),
7.10 (m, 2H), 7.00 (d, J=7.5 Hz, 1H), 5.00 (m, 1H), 4.41-4.20 (m,
2H), 2.22-2.00 (m, 2H). S (ESI) m/e 377 (M+H).sup.+. Calcd. For
C.sub.18H.sub.15N.sub.4O.sub.2F.sub.3.0.7H.sub.2O: C, 55.59; H,
4.25; N, 14.40; Found: C, 55.51; H, 3.98; N, 14.65.
EXAMPLE 76G
1-(1-(2-(Dimethylamino)acetyl)-1H-indazol-4-yl)-3-(7-(trifluoromethyl)chro-
man-4-yl)urea
[0259] The title compound was prepared as described in Example 68E,
substituting Example 76F for Example 68D. The mixture was purified
on SiO.sub.2 eluting with 3% CH.sub.3OH in CH.sub.2Cl.sub.2 to give
the title compound as a solid (0.62 g) in 46% yield. .sup.1H NMR
(300 MHz, CD.sub.3OD) .delta. ppm 2.10-2.34 (m,1H), 2.23-2.34 (m,
1H), 3.11 (s, 6H), 4.32-4.42 (m, 2H), 5.03 (s, 2H), 5.12 (t,
J=5.77, 11.87 Hz, 1H), 7.08-7.10 (m, 1H), 7.17-7.20 (m, 1H),
7.52-7.63 (m, 2H)`, 7.72-7.75 (m, 1H), 7.98-8.05 (m, 1H), 8.50 (d,
J=1.01 Hz, 1H). MS(+APCI)m/z 462 (M+H).sup./. Calc for
C.sub.22H.sub.22N.sub.5O.sub.3F.sub.3:1.1HCl:C, 52.69; H, 4.64;
N,13.96. Found: C, 52.64; H, 4.88; N,13.76.
EXAMPLE 77
1-(8-Tert-butylchroman-4-yl)-3-(1-(2-(dimethylamino)acetyl)-1H-indazol-4-y-
l)urea hydrochloride
EXAMPLE 77A
1-Tert-butyl-2-(prop-2-ynyloxy)benzene
[0260] 2-Tert-butylphenol (15.02 g, 15.4 ml, 100 mmol), propargyl
bromide (14.3 ml of 80% in toluene, 128 mmol), and potassium
carbonate (17.66 g, 128 mmol) were stirred together in 200 ml of
acetonitrile at ambient temperature for 5 days. The solvent was
removed under reduced pressure, and the residue taken into water
and extracted with diethyl ether. The organic layers were combined,
dried with magnesium sulfate, and filtered. The solvent was
evaporated under reduced pressure to give 18.86 g of the title
compound which was used without further purification. .sup.1H NMR
(300 MHz, CDCl.sub.3) .delta. ppm 7.30 (dd, J=7.80, 1.70 Hz, 1H),
7.15-7.22 (m, 1H), 6.90-6.98 (m, 2H), 4.73 (d, J=2.37 Hz, 2H), 2.48
(t, J=2.37 Hz, 1H), 1.39 (s, 9H). MS (DCI) m/e 206
(M+NH.sub.4).sup.+.
EXAMPLE 77B
1-Tert-butyl-2-(3-chloroprop-2-ynyloxy)benzene
[0261] Example 77A (18.86 g, 100 mmol) was dissolved in 400 ml
acetone. N-chlorosuccinimide (16.02 g, 120 mmol) and silver acetate
(1.67 g, 10 mmol) were added, and the mixture heated to reflux for
4 hours. After cooling, the silver salts were removed by filtration
and the filtrate evaporated under reduced pressure. The residue was
taken up in diethyl ether, washed with water and saturated aqueous
sodium bicarbonate, dried with magnesium sulfate, and filtered. The
solvent removed under reduced pressure to give 26.13 g of Example
77B which was used without further purification. .sup.1H NMR (300
MHz, CDCl.sub.3) .delta. ppm 7.30 (dd, J=7.97, 1.53 Hz, 1H), 7.19
(td, J=7.71, 1.86 Hz, 1H), 6.91-6.97 (m, 2H), 4.73 (s, 2H), 1.38
(s, 9H). MS (DCI) m/e 223 (M+H).sup.+
EXAMPLE 77C
8-Tert-butylchroman-4-one
[0262] Example 77B (25.8 g) in 250 ml ethylene glycol was heated to
reflux for 4 hours. The mixture was cooled, poured into water, and
extracted with diethyl ether. The organic layers were combined,
washed with 1N sodium hydroxide and saturated ammonium carbonate
sequentially, dried with magnesium sulfate, and filtered. Removal
of solvent under reduced pressure gave a residue. The residues were
filtered through a pad of silica gel with 1:1 methylene
chloride:hexanes, and the filtrate evaporated under reduced
pressure to give 13.51 g of Example 77C. .sup.1H NMR (300 MHz,
CDCl.sub.3) .delta. ppm 7.81 (dd, J=7.80, 1.70 Hz, 1H), 7.47 (dd,
J=7.63, 1.86 Hz, 1H), 6.95 (t, J=7.80 Hz, 1H), 4.51-4.58 (m, 2H),
2.79-2.85 (m, 2H), 1.39 (s, 9H). MS (DCI) m/e 205 (M+H).sup.+
EXAMPLE 77D
8-Tert-butylchroman-4-one O-methyl oxime
[0263] Example 77C (13.51 g, 66 mmol) was dissolved in 100 ml
pyridine. Methoxylamine hydrochloride (10 g, 120 mmol) was added
and the mixture stirred at ambient temperature for 16 hours. The
pyridine was removed under reduced pressure, and the residue
partitioned between water and diethyl ether. The mixture was
extracted with diethyl ether, and the combined organic layers
washed with IN sodium hydroxide and 1N hydrochloric acid
sequentially, dried with magnesium sulfate, and filtered. The
solvent was removed under reduced pressure to give 14.44 g of
Example 77D which was used without further purification.
[0264] .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. ppm 7.79 (dd,
.J=7.80, 1.70 Hz, 1H), 7.21-7.27 (m, 1H), 6.87 (t, J=7.80 Hz, 1H),
4.18 (t, J=6.27 Hz, 2H), 3.98 (s, 3H), 2.91 (t, J=6.27 Hz, 2H),
1.36 (s, 9H). MS (DCI) m/e 234 (M+H).sup.+.
EXAMPLE 77E
8-Tert-butylchroman-4-amine
[0265] Example 77D (14.44 g, 61.9 mmol), 1.5 g of 10% palladium on
carbon, and 400 ml of 20% ammonia in methanol were shaken under
hydrogen at 60 psi and ambient temperature for 2.5 hours. The
catalyst was removed by filtration and the solvent evaporated under
reduced pressure, giving 13.50 g of Example 77E which was used
without further purification. .sup.1H NMR (300 MHz, CDCl.sub.3)
.delta. ppm 7.14-7.24 (m, 3H) 6.81-6.89 (m, 1H) 4.22-4.29 (m, 2H)
4.11 (t, J=5.09 Hz, 1H) 2.10-2.25 (m, 1H) 1.90 (td, J=9.16, 4.07
Hz, 1H) 1.34-1.37 (m, 9H). MS (DCI) m/e 206 (M+H).sup.+.
EXAMPLE 77F
Methyl
4-({[(8-tert-butyl-3,4-dihydro-2H-chromen-4-yl)amino]carbonyl}amino-
)-1H-indazole-1-carboxylate
[0266] Example 77E (12.32 g, 60 mmol), Example 66E (19.94 g, 60
mmol), and diisopropylethylamine (11.63 g, 16 ml, 90 mmol) were
dissolved in 100 ml of N,N-dimethylformamide. The mixture was
stirred at ambient temperature for 16 hours, and diluted with
water. The precipitate that formed was collected by filtration,
air-dried, and then suspended in diethyl ether and hexane and
filtered with a mixture of diethyl ether and hexanes to give 20.6 g
of the titled compound. .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta.
ppm 8.77 (s, 1H), 8.35 (s, 1H), 7.89 (d, J=7.46 Hz, 1H), 7.69 (d,
J=8.48 Hz, 1H), 7.46-7.55 (m, 1H), 7.16 (dd, J=8.14, 2.37 Hz, 2H),
6.83-6.93 (m, 2H), 4.86-4.92 (m, 1H), 4.32-4.40 (m, 1H), 4.09-4.20
(m, 1H), 4.03 (s, 3H), 2.09 (ddd, J=17.88, 8.90, 4.75 Hz, 2H), 1.34
(s, 9H). MS (ESI) m/e 423 (M+H).sup.+.
EXAMPLE 77G
N-(8-Tert-butyl-3,4-dihydro-2H-chromen-4-yl)-N'-1H-indazol-4-ylurea
[0267] Example 77F (20.6 g, 48 mmol) was dissolved in a mixture of
100 ml tetrahydrofuran and 75 ml methanol. Sodium hydroxide (5M in
methanol, 50 ml, 250 mmol) was added, and the mixture stirred at
ambient temperature for 30 minutes. The mixture was diluted with
water, and the precipitate that formed was collected by filtration,
giving 15.70 g of the titled compound. .sup.1H NMR (300 MHz,
DMSO-d.sub.6) .delta. ppm 13.00 (s, 1H), 8.51 (s, 1H), 8.01 (s,
1H), 7.69 (d, J=7.46 Hz, 1H), 7.13-7.25 (m, 3H), 7.06 (d, J=8.14
Hz, 1H), 6.83-6.94 (m, 2H), 4.84-4.91 (m, 1H), 4.37 (dt, J=10.85,
4.24 Hz, 1H), 4.06-4.19 (m, 1H), 1.99-2.14 (m, 2H), 1.35 (s, 9H).
MS (ESI) m/e 365 (M+H).sup.+.
EXAMPLE 77H
1-(8-Tert-butylchroman-4-yl)-3-(1-(2-(dimethylamino)acetyl)-1H-indazol-4-y-
l)urea hydrochloride
[0268] The title compound was prepared as described in Example 68E,
substituting 77G for Example 68D. The mixture was purified on
SiO.sub.2 eluting with ethyl acetate/CH.sub.2Cl.sub.2 (1/4)
followed by recrystallization from THF to give the title compound
as a solid in 67% yield. .sup.1H NMR (300 MHz, CD.sub.3OD) .delta.
ppm 1.37 (s, 9H), 2.09-2.16 (m, 1H), 2.20-2.28 (m, 1H), 3.10 (s,
6H), 4.21-4.27 (m, 1H), 4.32-4.37 (m, 1H), 5.02-5.04 (m, 3H), 6.82
(t, J=7.68, 15.35 Hz, 1H), 7.18 (d, J=15.95 Hz, 2H), 7.57 (t,
J=7.97, 15.02 Hz, 1H), 7.75 (d, J=7.98 Hz, 1H), 8.00 (d, J=8.29 Hz,
1H), 8.48 (s, 1H). MS(+APCI)m/z 450 (M+H).sup.+. Calc for
C.sub.25H.sub.31N.sub.5O.sub.3:1.2HCl:C, 60.87; H, 6.58; N,14.20.
Found: C, 60.93; H, 6.82; N,13.95.
COMPOSITIONS OF THE INVENTION
[0269] The invention also provides pharmaceutical compositions
comprising a therapeutically effective amount of a compound of
formula (I) in combination with a pharmaceutically acceptable
carrier. The compositions comprise compounds of the invention
formulated together with one or more non-toxic pharmaceutically
acceptable carriers. The pharmaceutical compositions can be
formulated for oral administration in solid or liquid form, for
parenteral injection or for rectal administration.
[0270] The term "pharmaceutically acceptable carrier," as used
herein, means a non-toxic, inert solid, semi-solid or liquid
filler, diluent, encapsulating material or formulation auxiliary of
any type. Some examples of materials which can serve as
pharmaceutically acceptable carriers are sugars such as lactose,
glucose and sucrose; starches such as corn starch and potato
starch; cellulose and its derivatives such as sodium carboxymethyl
cellulose, ethyl cellulose and cellulose acetate; powdered
tragacanth; malt; gelatin; talc; cocoa butter and suppository
waxes; oils such as peanut oil, cottonseed oil, safflower oil,
sesame oil, olive oil, corn oil and soybean oil; glycols; such a
propylene glycol; esters such as ethyl oleate and ethyl laurate;
agar; buffering agents such as magnesium hydroxide and aluminum
hydroxide; alginic acid; pyrogen-free water; isotonic saline;
Ringer's solution; ethyl alcohol, and phosphate buffer solutions,
as well as other non-toxic compatible lubricants such as sodium
lauryl sulfate and magnesium stearate, as well as coloring agents,
releasing agents, coating agents, sweetening, flavoring and
perfuming agents, preservatives and antioxidants can also be
present in the composition, according to the judgment of one
skilled in the art of formulations.
[0271] The pharmaceutical compositions of this invention can be
administered to humans and other mammals orally, rectally,
parenterally, intracisternally, intravaginally, intraperitoneally,
topically (as by powders, ointments or drops), bucally or as an
oral or nasal spray. The term "parenterally," as used herein,
refers to modes of administration, including intravenous,
intramuscular, intraperitoneal, intrasternal, subcutaneous,
intraarticular injection and infusion.
[0272] Pharmaceutical compositions for parenteral injection
comprise pharmaceutically acceptable sterile aqueous or nonaqueous
solutions, dispersions, suspensions or emulsions and sterile
powders for reconstitution into sterile injectable solutions or
dispersions. Examples of suitable aqueous and nonaqueous carriers,
diluents, solvents or vehicles include water, ethanol, polyols
(propylene glycol, polyethylene glycol, glycerol, and the like, and
suitable mixtures thereof), vegetable oils (such as olive oil) and
injectable organic esters such as ethyl oleate, or suitable
mixtures thereof Suitable fluidity of the composition may be
maintained, for example, by the use of a coating such as lecithin,
by the maintenance of the required particle size in the case of
dispersions, and by the use of surfactants.
[0273] These compositions can also contain adjuvants such as
preservative agents, wetting agents, emulsifying agents, and
dispersing agents. Prevention of the action of microorganisms can
be ensured by various antibacterial and antifungal agents, for
example, parabens, chlorobutanol, phenol, sorbic acid, and the
like. It also can be desirable to include isotonic agents, for
example, sugars, sodium chloride and the like. Prolonged absorption
of the injectable pharmaceutical form can be brought about by the
use of agents delaying absorption, for example, aluminum
monostearate and gelatin.
[0274] In some cases, in order to prolong the effect of a drug, it
is often desirable to slow the absorption of the drug from
subcutaneous or intramuscular injection. This can be accomplished
by the use of a liquid suspension of crystalline or amorphous
material with poor water solubility. The rate of absorption of the
drug can depend upon its rate of dissolution, which, in turn, may
depend upon crystal size and crystalline form. Alternatively, a
parenterally administered drug form can be administered by
dissolving or suspending the drug in an oil vehicle.
[0275] Suspensions, in addition to the active compounds, can
contain suspending agents, for example, ethoxylated isostearyl
alcohols, polyoxyethylene sorbitol and sorbitan esters,
microcrystalline cellulose, aluminum metahydroxide, bentonite,
agar-agar, tragacanth, and mixtures thereof.
[0276] If desired, and for more effective distribution, the
compounds of the invention can be incorporated into slow-release or
targeted-delivery systems such as polymer matrices, liposomes, and
microspheres. They may be sterilized, for example, by filtration
through a bacteria-retaining filter or by incorporation of
sterilizing agents in the form of sterile solid compositions, which
may be dissolved in sterile water or some other sterile injectable
medium immediately before use.
[0277] Injectable depot forms are made by forming microencapsulated
matrices of the drug in biodegradable polymers such as
polylactide-polyglycolide. Depending upon the ratio of drug to
polymer and the nature of the particular polymer employed, the rate
of drug release can be controlled. Examples of other biodegradable
polymers include poly(orthoesters) and poly(anhydrides) Depot
injectable formulations also are prepared by entrapping the drug in
liposomes or microemulsions which are compatible with body
tissues.
[0278] The injectable formulations can be sterilized, for example,
by filtration through a bacterial-retaining filter or by
incorporating sterilizing agents in the form of sterile solid
compositions which can be dissolved or dispersed in sterile water
or other sterile injectable medium just prior to use.
[0279] Injectable preparations, for example, sterile injectable
aqueous or oleaginous suspensions can be formulated according to
the known art using suitable dispersing or wetting agents and
suspending agents. The sterile injectable preparation also can be a
sterile injectable solution, suspension or emulsion in a nontoxic,
parenterally acceptable diluent or solvent such as a solution in
1,3-butanediol. Among the acceptable vehicles and solvents that can
be employed are water, Ringer's solution, U.S.P. and isotonic
sodium chloride solution. In addition, sterile, fixed oils are
conventionally employed as a solvent or suspending medium. For this
purpose any bland fixed oil can be employed including synthetic
mono- or diglycerides. In addition, fatty acids such as oleic acid
are used in the preparation of injectables.
[0280] Solid dosage forms for oral administration include capsules,
tablets, pills, powders, and granules. In such solid dosage forms,
one or more compounds of the invention is mixed with at least one
inert pharmaceutically acceptable carrier such as sodium citrate or
dicalcium phosphate and/or a) fillers or extenders such as
starches, lactose, sucrose, glucose, mannitol, and salicylic acid;
b) binders such as carboxymethylcellulose, alginates, gelatin,
polyvinylpyrrolidinone, sucrose, and acacia; c) humectants such as
glycerol; d) disintegrating agents such as agar-agar, calcium
carbonate, potato or tapioca starch, alginic acid, certain
silicates, and sodium carbonate; e) solution retarding agents such
as paraffin; f) absorption accelerators such as quaternary ammonium
compounds; g) wetting agents such as cetyl alcohol and glycerol
monostearate; h) absorbents such as kaolin and bentonite clay; and
i) lubricants such as talc, calcium stearate, magnesium stearate,
solid polyethylene glycols, sodium lauryl sulfate, and mixtures
thereof. In the case of capsules, tablets and pills, the dosage
form may also comprise buffering agents.
[0281] Solid compositions of a similar type may also be employed as
fillers in soft and hard-filled gelatin capsules using lactose or
milk sugar as well as high molecular weight polyethylene
glycols.
[0282] The solid dosage forms of tablets, dragees, capsules, pills,
and granules can be prepared with coatings and shells such as
enteric coatings and other coatings well-known in the
pharmaceutical formulating art. They can optionally contain
opacifying agents and can also be of a composition that they
release the active ingredient(s) only, or preferentially, in a
certain part of the intestinal tract in a delayed manner. Examples
of materials useful for delaying release of the active agent can
include polymeric substances and waxes.
[0283] Compositions for rectal or vaginal administration are
preferably suppositories which can be prepared by mixing the
compounds of this invention with suitable non-irritating carriers
such as cocoa butter, polyethylene glycol or a suppository wax
which are solid at ambient temperature but liquid at body
temperature and therefore melt in the rectum or vaginal cavity and
release the active compound.
[0284] Liquid dosage forms for oral administration include
pharmaceutically acceptable emulsions, microemulsions, solutions,
suspensions, syrups and elixirs. In addition to the active
compounds, the liquid dosage forms may contain inert diluents
commonly used in the art such as, for example, water or other
solvents, solubilizing agents and emulsifiers such as ethyl
alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl
alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol,
dimethylformamide, oils (in particular, cottonseed, groundnut,
corn, germ, olive, castor, and sesame oils), glycerol,
tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid
esters of sorbitan, and mixtures thereof.
[0285] Besides inert diluents, the oral compositions can also
include adjuvants such as wetting agents, emulsifying and
suspending agents, sweetening, flavoring, and perfuming agents.
[0286] Dosage forms for topical or transdermal administration of a
compound of this invention include ointments, pastes, creams,
lotions, gels, powders, solutions, sprays, inhalants or patches. A
desired compound of the invention is admixed under sterile
conditions with a pharmaceutically acceptable carrier and any
needed preservatives or buffers as may be required. Ophthalmic
formulation, eardrops, eye ointments, powders and solutions are
also contemplated as being within the scope of this invention. The
ointments, pastes, creams and gels may contain, in addition to an
active compound of this invention, animal and vegetable fats, oils,
waxes, paraffins, starch, tragacanth, cellulose derivatives,
polyethylene glycols, silicones, bentonites, silicic acid, talc and
zinc oxide, or mixtures thereof.
[0287] Powders and sprays can contain, in addition to the compounds
of this invention, lactose, talc, silicic acid, aluminum hydroxide,
calcium silicates and polyamide powder, or mixtures of these
substances. Sprays can additionally contain customary propellants
such as chlorofluorohydrocarbons.
[0288] Compounds of the invention also can be administered in the
form of liposomes. As is known in the art, liposomes are generally
derived from phospholipids or other lipid substances. Liposomes are
formed by mono- or multi-lamellar hydrated liquid crystals that are
dispersed in an aqueous medium. Any non-toxic, physiologically
acceptable and metabolizable lipid capable of forming liposomes may
be used. The present compositions in liposome form may contain, in
addition to the compounds of the invention, stabilizers,
preservatives, and the like. The preferred lipids are the natural
and synthetic phospholipids and phosphatidylcholines (lecithins)
used separately or together.
[0289] Methods to form liposomes are known in the art. See, for
example, Prescott, Ed., Methods in Cell Biology, Volume XIV,
Academic Press, New York, N.Y., (1976), p 33 et seq.
[0290] Dosage forms for topical administration of a compound of
this invention include powders, sprays, ointments and inhalants.
The active compound is mixed under sterile conditions with a
pharmaceutically acceptable carrier and any needed preservatives,
buffers or propellants. Ophthalmic formulations, eye ointments,
powders and solutions are also contemplated as being within the
scope of this invention. Aqueous liquid compositions of the
invention also are particularly useful.
[0291] The compounds of the invention can be used in the form of
pharmaceutically acceptable salts, esters, or amides derived from
inorganic or organic acids. The term "pharmaceutically acceptable
salts, esters and amides," as used herein, include salts,
zwitterions, esters and amides of compounds of formula (I) which
are, within the scope of sound medical judgment, suitable for use
in contact with the tissues of humans and lower animals without
undue toxicity, irritation, allergic response, and the like, are
commensurate with a reasonable benefit/risk ratio, and are
effective for their intended use.
[0292] The term "pharmaceutically acceptable salt" refers to those
salts which are, within the scope of sound medical judgment,
suitable for use in contact with the tissues of humans and lower
animals without undue toxicity, irritation, allergic response, and
the like, and are commensurate with a reasonable benefit/risk
ratio. Pharmaceutically acceptable salts are well-known in the art.
The salts can be prepared in situ during the final isolation and
purification of the compounds of the invention or separately by
reacting a free base function with a suitable organic acid.
[0293] Representative acid addition salts include, but are not
limited to acetate, adipate, alginate, citrate, aspartate,
benzoate, benzenesulfonate, bisulfate, butyrate, camphorate,
camphorsulfonate, digluconate, glycerophosphate, hemisulfate,
heptanoate, hexanoate, fumarate, hydrochloride, hydrobromide,
hydroiodide, 2-hydroxyethansulfonate (isethionate), lactate,
maleate, methanesulfonate, nicotinate, 2-naphthalenesulfonate,
oxalate, pamoate, pectinate, persulfate, 3-phenylpropionate,
picrate, pivalate, propionate, succinate, tartrate, thiocyanate,
phosphate, glutamate, bicarbonate, p-toluenesulfonate and
undecanoate.
[0294] Also, the basic nitrogen-containing groups can be
quaternized with such agents as lower alkyl halides such as methyl,
ethyl, propyl, and butyl chlorides, bromides and iodides; dialkyl
sulfates such as dimethyl, diethyl, dibutyl and diamyl sulfates;
long chain halides such as decyl, lauryl, myristyl and stearyl
chlorides, bromides and iodides; arylalkyl halides such as benzyl
and phenethyl bromides and others. Water or oil-soluble or
dispersible products are thereby obtained.
[0295] Examples of acids which can be employed to form
pharmaceutically acceptable acid addition salts include such
inorganic acids as hydrochloric acid, hydrobromic acid, sulphuric
acid and phosphoric acid and such organic acids as oxalic acid,
maleic acid, succinic acid, and citric acid.
[0296] Basic addition salts can be prepared in situ during the
final isolation and purification of compounds of this invention by
reacting a carboxylic acid-containing moiety with a suitable base
such as the hydroxide, carbonate or bicarbonate of a
pharmaceutically acceptable metal cation or with ammonia or an
organic primary, secondary or tertiary amine. Pharmaceutically
acceptable salts include, but are not limited to, cations based on
alkali metals or alkaline earth metals such as lithium, sodium,
potassium, calcium, magnesium, and aluminum salts, and the like,
and nontoxic quaternary ammonia and amine cations including
ammonium, tetramethylammonium, tetraethylammonium, methylamine,
dimethylamine, trimethylamine, triethylamine, diethylamine,
ethylamine and the such as. Other representative organic amines
useful for the formation of base addition salts include
ethylenediamine, ethanolamine, diethanolamine, piperidine, and
piperazine.
[0297] The term "pharmaceutically acceptable ester," as used
herein, refers to esters of compounds of the invention which
hydrolyze in vivo and include those that break down readily in the
human body to leave the parent compound or a salt thereof. Examples
of pharmaceutically acceptable, non-toxic esters of the invention
include C.sub.1-to-C.sub.6 alkyl esters and C.sub.5-to-C.sub.7
cycloalkyl esters, although C.sub.1-to-C.sub.4 alkyl esters are
preferred. Esters of the compounds of formula (I) can be prepared
according to conventional methods. Pharmaceutically acceptable
esters can be appended onto hydroxy groups by reaction of the
compound that contains the hydroxy group with acid and an
alkylcarboxylic acid such as acetic acid, or with acid and an
arylcarboxylic acid such as benzoic acid. In the case of compounds
containing carboxylic acid groups, the pharmaceutically acceptable
esters are prepared from compounds containing the carboxylic acid
groups by reaction of the compound with base such as triethylamine
and an alkyl halide, alkyl trifilate, for example with methyl
iodide, benzyl iodide, cyclopentyl iodide. They also can be
prepared by reaction of the compound with an acid such as
hydrochloric acid and an alkylcarboxylic acid such as acetic acid,
or with acid and an arylcarboxylic acid such as benzoic acid.
[0298] The term "pharmaceutically acceptable amide," as used
herein, refers to non-toxic amides of the invention derived from
ammonia, primary C.sub.1-to-C.sub.6 alkyl amines and secondary
C.sub.1-to-C.sub.6 dialkyl amines. In the case of secondary amines,
the amine can also be in the form of a 5- or 6-membered heterocycle
containing one nitrogen atom. Amides derived from ammonia,
C.sub.1-to-C.sub.3 alkyl primary amides and C.sub.1-to-C.sub.2
dialkyl secondary amides are preferred. Amides of the compounds of
formula (I) can be prepared according to conventional methods.
Pharmaceutically acceptable amides can be prepared from compounds
containing primary or secondary amine groups by reaction of the
compound that contains the amino group with an alkyl anhydride,
aryl anhydride, acyl halide, or aroyl halide. In the case of
compounds containing carboxylic acid groups, the pharmaceutically
acceptable esters are prepared from compounds containing the
carboxylic acid groups by reaction of the compound with base such
as triethylamine, a dehydrating agent such as dicyclohexyl
carbodiimide or carbonyl diimidazole, and an alkyl amine,
dialkylamine, for example with methylamine, diethylamine,
piperidine. They also can be prepared by reaction of the compound
with an acid such as sulfuric acid and an alkylcarboxylic acid such
as acetic acid, or with acid and an arylcarboxylic acid such as
benzoic acid under dehydrating conditions as with molecular sieves
added. The composition can contain a compound of the invention in
the form of a pharmaceutically acceptable prodrug.
[0299] The term "pharmaceutically acceptable prodrug" or "prodrug,"
as used herein, represents those prodrugs of the compounds of the
invention which are, within the scope of sound medical judgment,
suitable for use in contact with the tissues of humans and lower
animals without undue toxicity, irritation, allergic response, and
the like, commensurate with a reasonable benefit/risk ratio, and
effective for their intended use. Prodrugs of the invention can be
rapidly transformed in vivo to a parent compound of formula (I),
for example, by hydrolysis in blood. A thorough discussion is
provided in T. Higuchi and V. Stella, Pro-drugs as Novel Delivery
Systems, V. 14 of the A.C.S. Symposium Series, and in Edward B.
Roche, ed., Bioreversible Carriers in Drug Design, American
Pharmaceutical Association and Pergamon Press (1987).
[0300] The invention contemplates pharmaceutically active compounds
either chemically synthesized or formed by in vivo
biotransformation to compounds of formula (I).
METHODS OF THE INVENTION
[0301] Compounds and compositions of the invention are useful for
ameliorating or preventing disorders involving TRPV1 receptor
activation such as, but not limited to, inflammatory thermal
hyperalgesia, bladder overactivity, and urinary incontinence as
described by Nolano, M. et al., Pain, Vol. 81, pages 135-145,
(1999); Caterina, M. J. and Julius, D., Annu. Rev. Neurosci. Vol.
24, pages 487-517 (2001); Caterina, M. J. et al., Science Vol. 288
pages 306-313 (2000); Caterina, M. J. et al., Nature Vol. 389 pages
816-824 (1997); Fowler, C. Urology Vol. 55 pages 60-64 (2000); and
Davis, J. et al., Nature Vol. 405 pages 183-187.
[0302] The present invention also provides pharmaceutical
compositions that comprise compounds of the present invention. The
pharmaceutical compositions comprise compounds of the present
invention that may be formulated together with one or more
non-toxic pharmaceutically acceptable carriers.
In vivo Evaluation of TRPV1 Prodrugs
[0303] The pharmacokinetic behavior of prodrugs was evaluated in
male Sprague-Dawley derived rats (n=3/group). Each compound was
prepared as a 10 .mu.mol/ml solution in a vehicle of 10% DMSO in
PEG-400. Groups of three rats received a 10 .mu.mol/kg (1 ml/kg)
intravenous or oral dose of each compound. The intravenous dose was
administered in a jugular vein under light isoflurane anesthetic;
the oral dose was administered by gavage. Serial blood samples were
obtained from a tail vein of each rat 0.1 (IV only), 0.25, 0.5, 1,
1.5, 2, 4, 6 and 8 hours after dosing. Plasma was separated by
centrifugation and stored frozen until analysis.
[0304] The plasma concentrations of the administered prodrug and a
TRPV I antagonist compound were determined by HPLC-MS/MS. The
compounds were removed from the plasma using protein precipitation
with acetonitrile. Following centrifugation, the supernatant was
transferred to a clean container and evaporated to dryness with
nitrogen. The prodrug and parent compound were separated from
co-extracted contaminant using reverse phase HPLC, with MS/MS
detection and quantitation. Spiked standards were analyzed
simultaneously with the samples. The plasma drug concentration of
each sample was calculated by least squares linear regression
analysis (non-weighted) of the peak area ratio (parent/internal
standard) of the spiked plasma standards versus concentration.
[0305] Peak plasma concentrations (C.sub.max) and the time to peak
plasma concentration (T.sub.max) were read directly from the plasma
concentration data for each rat. The plasma concentration data were
submitted to multi-exponential curve fitting using WinNonlin
(WinNonlin-Professional.RTM., Version 3.2, Pharsight Corporation,
Mountain View, Calif.). All representative prodrug compounds
transformed to a TRPV1 antagonist compound. C. ranges varied from
2% to 100% compared to the 100% C. of the administered TRPV1
antagonist compound.
* * * * *