U.S. patent application number 12/356097 was filed with the patent office on 2009-05-28 for raf inhibitors and uses thereof.
This patent application is currently assigned to ARQULE, INC.. Invention is credited to Syed M. Ali, Mark A. Ashwell, Chris J. Brassard, Rebecca J. Carazza, Anton Filikov, Dennis S. France, Patrick M. Hutchins, Jean-Marc Lapierre, Jeff S. Link, Yanbin Liu, Nivedita D. Namdev, Robb B. Nicewonger, Manish Tandon, Hui Wu.
Application Number | 20090136499 12/356097 |
Document ID | / |
Family ID | 38521225 |
Filed Date | 2009-05-28 |
United States Patent
Application |
20090136499 |
Kind Code |
A1 |
Lapierre; Jean-Marc ; et
al. |
May 28, 2009 |
RAF Inhibitors and Uses Thereof
Abstract
The present invention provides imidazooxazole and
imidazothiazole compounds and their synthesis. The compounds of the
present invention are capable of inhibiting the activity of RAF
kinase, such as B-RAF.sup.V600E. The compounds are useful for the
treatment of cell proliferative disorders such as cancer.
Inventors: |
Lapierre; Jean-Marc;
(Pelham, NH) ; Namdev; Nivedita D.; (Westford,
MA) ; Ashwell; Mark A.; (Carlisle, MA) ;
France; Dennis S.; (Cambridge, MA) ; Wu; Hui;
(Malden, MA) ; Hutchins; Patrick M.; (Denver,
CO) ; Tandon; Manish; (Framingham, MA) ; Liu;
Yanbin; (Acton, MA) ; Link; Jeff S.;
(Londonderry, NH) ; Ali; Syed M.; (North Andover,
MA) ; Brassard; Chris J.; (Somerville, MA) ;
Nicewonger; Robb B.; (Tyngsboro, MA) ; Filikov;
Anton; (Stoneham, MA) ; Carazza; Rebecca J.;
(Winchester, MA) |
Correspondence
Address: |
BROMBERG & SUNSTEIN LLP
125 SUMMER STREET
BOSTON
MA
02110-1618
US
|
Assignee: |
ARQULE, INC.
Woburn
MA
|
Family ID: |
38521225 |
Appl. No.: |
12/356097 |
Filed: |
January 20, 2009 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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11785163 |
Apr 16, 2007 |
7501430 |
|
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12356097 |
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60792314 |
Apr 17, 2006 |
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Current U.S.
Class: |
424/133.1 ;
514/210.21; 514/233.2; 514/275; 544/122; 544/331 |
Current CPC
Class: |
C07D 513/04 20130101;
A61P 35/00 20180101; A61P 43/00 20180101 |
Class at
Publication: |
424/133.1 ;
544/331; 514/275; 514/233.2; 544/122; 514/210.21 |
International
Class: |
A61K 39/395 20060101
A61K039/395; C07D 513/04 20060101 C07D513/04; A61K 31/506 20060101
A61K031/506; A61K 31/5377 20060101 A61K031/5377; C07D 498/04
20060101 C07D498/04; A61P 35/00 20060101 A61P035/00 |
Claims
1-33. (canceled)
34. A compound of Formula II, or pharmaceutically acceptable salts
thereof: ##STR00466## wherein X is O, S(O).sub.p; m is an integer
from 1 to 3; n is an integer from 1 to 3; p is an integer from 0 to
2; Z is hydrogen, a bond, --C(O)--, --C(O)NR.sub.11--,
--S(O).sub.2--, --C(O)NH--S(O).sub.2--, or CH(OH)--CH.sub.2--Y--,
wherein Y is CH.sub.2, O, S, NH, or a bond; R.sub.1 is halogen,
--CN, --NO.sub.2, --OH, --NR.sub.6R.sub.7, NR.sub.8--C(O)R.sub.9,
--(CH.sub.2).sub.0-3--C(O)NR.sub.6R.sub.7,
--NR.sub.8SO.sub.2R.sub.9, --NR.sub.8C(O)NR.sub.6R.sub.7,
--NR.sub.8C(S)NR.sub.6R.sub.7, --OSO.sub.2NR.sub.5R.sub.7,
--C(N--OH)NH.sub.2, --C(N--OH)R.sub.8, --CH.sub.2OR.sub.8,
--OC(O)NR.sub.6R.sub.7, --SR.sub.9, or
--C(O)NR.sub.8SO.sub.2R.sub.9; R.sub.2 is hydrogen, halogen, --CN,
--NO.sub.2, --OH, --NR.sub.6R.sub.7, NR.sub.8--C(O)R.sub.9,
--(CH.sub.2).sub.0-3--C(O)NR.sub.6R.sub.7,
--NR.sub.8SO.sub.2R.sub.9, --NR.sub.8C(O)NR.sub.6R.sub.7,
--NR.sub.8C(S)NR.sub.6R.sub.7, --OSO.sub.2NR.sub.5R.sub.7,
--C(N--OH)NH.sub.2, --C(N--OH)R.sub.8, --CH.sub.2OR.sub.8,
--OC(O)NR.sub.6R.sub.7, --SR.sub.9, or
--C(O)NR.sub.8SO.sub.2R.sub.9, and R.sub.1 and R.sub.2, taken
together, may form a ring; R.sub.3 and R.sub.4 are independently
hydrogen, substituted or unsubstituted, branched or unbranched
(C.sub.1-C.sub.6)alkyl, --COOH, --COOR.sub.8, or
--C(O)NR.sub.10R.sub.11; each R.sub.6 and each R.sub.7 are
independently hydrogen, substituted or unsubstituted alkyl,
substituted or unsubstituted aryl, or substituted or unsubstituted
heterocyclyl, and R.sub.6 and R.sub.7, taken together, may form a
ring; each R.sub.8 is independently hydrogen, or substituted or
unsubstituted, branched or unbranched (C.sub.1-C.sub.6)alkyl; each
R.sub.9 is independently substituted or unsubstituted alkyl,
substituted or unsubstituted aryl, substituted or unsubstituted
heterocyclyl, or substituted or unsubstituted heteroaryl; R.sub.10
is substituted or unsubstituted, branched or unbranched
(C.sub.1-C.sub.6)alkyl, or substituted or unsubstituted aryl;
R.sub.11 is hydrogen, substituted or unsubstituted alkyl,
substituted or unsubstituted aryl, substituted or unsubstituted
heterocyclyl, or substituted or unsubstituted heteroaryl, and
R.sub.11, taken together with R.sub.10, may form a ring; R.sub.12
is substituted or unsubstituted alkyl, substituted or unsubstituted
aryl, substituted or unsubstituted heterocyclyl, or substituted or
unsubstituted heteroaryl; and R.sub.13 is independently selected
from the group consisting of hydrogen, C.sub.1-C.sub.9 alkyl,
C.sub.1-C.sub.9 fluoro-substituted alkyl, C.sub.3-C.sub.8
cycloalkyl, C.sub.3-C.sub.8 fluoro-substituted cycloalkyl, aryl,
halogen-substituted aryl, heteroaryl, and halogen-substituted
heteroaryl.
35. The compound of claim 34 wherein R.sub.3 and R.sub.4 are
hydrogen.
36. The compound of claim 34 wherein R.sub.13 is hydrogen.
37. The compound of claim 34 wherein m+n=4, if m is not equal to n,
then the preferred configuration is R.
38. The compound of claim 34 wherein Z is --S(O).sub.2--.
39. The compound of claim 34 wherein m is an integer from 1 to 2; n
is an integer from 1 to 2; Z is --C(O)--, --C(O)NR.sub.11--,
--S(O).sub.2--; and R.sup.3, R.sup.4 and R.sup.13 are hydrogen.
40. The compound of claim 34 or 38 wherein, R.sub.12 is a
heteroaromatic group having one, two or three aromatic rings
containing from 1 to 4 heteroatoms in the aromatic ring or a
non-aromatic 3 to 7 membered monocyclic heterocyclic ring structure
or 8 to 11 membered bicyclic heterocyclic ring structure.
41. A pharmaceutical composition comprising a compound as defined
in claim 34 or a pharmaceutically acceptable salt thereof together
with one or more pharmaceutically acceptable carriers or
excipients.
42. The pharmaceutical composition of claim 41 further comprising a
second chemotherapeutic agent.
43. The pharmaceutical composition of claim 42, wherein said second
chemotherapeutic agent is selected from the group consisting of
tamoxifen, raloxifene, anastrozole, exemestane, letrozole,
cisplatin, carboplatin, paclitaxel, cyclophosphamide, lovastatin,
minosine, gemcitabine, araC, 5-fluorouracil, methotrexate,
docetaxel, goserelin, vincristin, vinblastin, nocodazole,
teniposide, etoposide, epothilone, navelbine, camptothecin,
daunonibicin, dactinomycin, mitoxantrone, amsacrine, doxorubicin,
epirubicin, idarubicin imatanib, gefitinib, erlotinib, sorafenib,
sunitinib malate, trastuzumab, rituximab, cetuximab, and
bevacizumab.
44. A method of treating a cell proliferative disorder, said method
comprising administering to a subject having cells with said cell
proliferative disorder a therapeutically effective amount of a
compound of formula II as claimed in claim 1, or a pharmaceutically
acceptable salt thereof, or a prodrug or metabolite thereof, in
combination with a pharmaceutically acceptable carrier, wherein
said cells with said cell proliferative disorder contain DNA
encoding a RAF, and wherein said cell proliferative disorder is
treated.
45. The method of claim 44 wherein R.sub.3 and R.sub.4 are
hydrogen.
46. The method of claim 44 wherein R.sub.13 is hydrogen.
47. The method of claim 45 wherein m+n=4, if m is not equal to n,
then the configuration is R.
48. The method of claim 45 wherein Z is --S(O).sub.2-- and
R.sub.-12 is 4-chlorophenyl, 4-fluorophenyl, 4-cyanophenyl, methyl,
or cyclopropyl.
49. The method of claim 44 wherein the compound is selected from
the group consisting of
3-{5-[2-({(3R)-1-[(4-chlorophenyl)sulfonyl]piperidin-3-yl}amino)pyrimidin-
-4-yl]imidazo[2,1-b][1,3]thiazol-6-yl}phenyl carbamate,
3-{5-[2-({(3R)-1-[(4-chlorophenyl)sulfonyl]piperidin-3-yl}amino)pyrimidin-
-4-yl]imidazo[2,1-b][1,3]thiazol-6-yl}phenyl sulfamate,
3-{5-[2-({(3R)-1-[(4-chlorophenyl)sulfonyl]piperidin-3-yl}amino)pyrimidin-
-4-yl]imidazo[2,1-b][1,3]oxazol-6-yl}phenyl sulfamate,
3-{5-[2-({(3R)-1-[(4-chlorophenyl)sulfonyl]piperidin-3-yl}amino)
pyrimidin-4-yl]imidazo[2,1-b][1,3]oxazol-6-yl}phenyl carbamate,
(1E)-1-(3-{5-[2-({(3R)-1-[(4-chlorophenyl)sulfonyl]piperidin-3-yl}amino)p-
yrimidin-4-yl]imidazo[2,1-b][1,3]thiazol-6-yl}phenyl)ethanone
oxime,
2-chloro-5-{5-[2-({(3R)-1-[(4-chlorophenyl)sulfonyl]piperidin-3-yl}amino)-
pyrimidin-4-yl]imidazo[2,1-b][1,3]thiazol-6-yl}phenol,
3-{5-[2-({(3R)-1-[(4-chlorophenyl)sulfonyl]piperidin-3-yl}amino)pyrimidin-
-4-yl]imidazo[2,1-b][1,3]oxazol-6-yl}phenol,
4-{[(3R)-3-({4-[6-(3-hydroxyphenyl)imidazo[2,1-b][1,3]thiazol-5-yl]pyrimi-
din-2-yl}amino)piperidin-1-yl]sulfonyl}benzonitrile,
4-{[(3R)-3-({4-[6-(3-hydroxyphenyl)imidazo[2,1-b][1,3]thiazol-5-yl]pyrimi-
din-2-yl}amino)piperidin-1-yl]sulfonyl}benzoic acid,
3-{[(3R)-3-({4-[6-(3-hydroxyphenyl)imidazo[2,1-b][1,3]thiazol-5-yl]pyrimi-
din-2-yl}amino)piperidin-1-yl]sulfonyl}phenol,
2-{5-[2-({(3R)-1-[(4-chlorophenyl)sulfonyl]piperidin-3-yl}amino)pyrimidin-
-4-yl]imidazo[2,1-b][1,3]thiazol-6-yl}benzene-1,4-diol,
3-[5-(2-{[(3R)-1-(methylsulfonyl)piperidin-3-yl]amino}pyrimidin-4-yl)
imidazo[2,1-b][1,3]thiazol-6-yl]phenol,
3-{5-[2-({1-[(4-fluorophenyl)sulfonyl]piperidin-4-yl}amino)pyrimidin-4-yl-
]imidazo[2,1-b][1,3]thiazol-6-yl}phenol,
3-{5-[2-({1-[(4-chlorophenyl)sulfonyl]piperidin-4-yl}amino)pyrimidin-4-yl-
]imidazo[2,1-b][1,3]thiazol-6-yl}phenol,
N-ethyl-4-({4-[6-(3-hydroxyphenyl)imidazo[2,1-b][1,3]thiazol-5-yl]pyrimid-
in-2-yl}amino)piperidine-1-carboxamide,
3-{5-[2-({(3R)-1-[(4-chlorophenyl)sulfonyl]piperidin-3-yl}amino)pyrimidin-
-4-yl]imidazo[2,1-b][1,3]thiazol-6-yl}phenol,
4-{[4-({4-[6-(3-hydroxyphenyl)
imidazo[2,1-b][1,3]oxazol-5-yl]pyrimidin-2-yl}amino)piperidin-1-yl]sulfon-
yl}benzonitrile,
4-{[4-({4-[6-(3-hydroxyphenyl)imidazo[2,1-b][1,3]oxazol-5-yl]pyrimidin-2--
yl}amino)piperidin-1-yl]sulfonyl}benzamide,
4-{[(3R)-3-({4-[6-(3-hydroxyphenyl)imidazo[2,1-b][1,3]oxazol-5-yl]pyrimid-
in-2-yl}amino)piperidin-1-yl]sulfonyl}benzonitrile,
3-{5-[2-({1-[(4-chlorophenyl)sulfonyl]piperidin-4-yl}amino)pyrimidin-4-yl-
]imidazo[2,1-b][1,3]oxazol-6-yl}-phenol,
3-{5-[2-({1-[(4-fluorophenyl)sulfonyl]piperidin-4-yl}amino)pyrimidin-4-yl-
]imidazo[2,1-b][1,3]oxazol-6-yl}phenol,
5-{5-[2-({(3R)-1-[(4-chlorophenyl)sulfonyl]piperidin-3-yl}amino)pyrimidin-
-4-yl]imidazo[2,1-b][1,3]thiazol-6-yl}-2-fluorophenol,
3-{5-[2-({(3R)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]piperidin-3-yl}amin-
o)pyrimidin-4-yl]imidazo[2,1-b][1,3]thiazol-6-yl}phenol,
3-[5-(2-{[(3R)-1-(3-thienylsulfonyl)piperidin-3-yl]amino}pyrimidin-4-yl)i-
midazo[2,1-b][1,3]thiazol-6-yl]phenol,
3-[5-(2-{[(3R)-1-(2-thienylsulfonyl)piperidin-3-yl]amino}pyrimidin-4-yl)i-
midazo[2,1-b][1,3]thiazol-6-yl]phenol,
3-[5-(2-{[(3R)-1-(phenylsulfonyl)piperidin-3-yl]amino}pyrimidin-4-yl)imid-
azo[2,1-b][1,3]thiazol-6-yl]phenol,
3-{5-[2-{(3R)-1-[(1-methyl-1H-pyrazol-3-yl)sulfonyl]piperidin-3-yl}amino)-
pyrimidin-4-yl]imidazo[2,1-b][1,3]thiazol-6-yl}phenol,
3-[5-(2-{[(3R)-1-(4H-1,2,4-triazol-3-ylsulfonyl)piperidin-3-yl]amino}pyri-
midin-4-yl)imidazo[2,1-b][1,3]thiazol-6-yl]phenol,
3-[5-(2-{[(3R)-1-(2-thienylsulfonyl)piperidin-3-yl]amino}pyrimidin-4-yl)i-
midazo[2,1-b][1,3]oxazol-6-yl]phenol,
3-[5-(2-{[(3R)-1-(phenylsulfonyl)piperidin-3-yl]amino}pyrimidin-4-yl)imid-
azo[2,1-b][1,3]oxazol-6-yl]phenol,
3-[5-(2-{[1-(cyclopropylsulfonyl)piperidin-4-yl]amino}pyrimidin-4-yl)
imidazo[2,1-b][1,3]thiazol-6-yl]phenol,
3-[5-(2-{[1-(methylsulfonyl)piperidin-4-yl]amino}pyrimidin-4-yl)imidazo[2-
,1-b][1,3]thiazol-6-yl]phenol,
3-[5-(2-{[1-(cyclopropylsulfonyl)piperidin-4-yl]amino}pyrimidin-4-yl)imid-
azo[2,1-b][1,3]oxazol-6-yl]phenol,
3-[5-(2-{[1-(methylsulfonyl)piperidin-4-yl]amino}pyrimidin-4-yl)imidazo[2-
,1-b][1,3]oxazol-6-yl]phenol,
5-[5-(2-{[1-(cyclopropylsulfonyl)piperidin-4-yl]amino}pyrimidin-4-yl)imid-
azo[2,1-b][1,3]thiazol-6-yl]-2-fluorophenol, and
3-[5-(2-{[(3R)-1-(cyclopropylsulfonyl)piperidin-3-yl]amino}pyrimidin-4-yl-
)imidazo[2,1-b][1,3]oxazol-6-yl]phenol.
50. The method of claim 44 wherein said cells with said cell
proliferative disorder contain DNA encoding a RAF, and wherein the
RAF is A-RAF, B-RAF, or C-RAF.
51. The method of claim 50 wherein the RAF is B-RAF.
52. The method of claim 51 wherein the B-RAF is selected from the
group consisting of wild-type B-RAF, a B-RAF mutant and
B-RAF.sup.V600E.
53. The method of claim 44 wherein the cells have a constitutively
enhanced RAF activity.
54. The method of claim 44, wherein said compound or a
pharmaceutically acceptable salt thereof, or a prodrug or
metabolite thereof, is administered in combination with a second
chemotherapeutic agent.
55. The method of claim 54, wherein said second chemotherapeutic
agent is selected from the group consisting of tamoxifen,
raloxifene, anastrozole, exemestane, letrozole, cisplatin,
carboplatin, paclitaxel, cyclophosphamide, lovastatin, minosine,
gemcitabine, araC, 5-fluorouracil, methotrexate, docetaxel,
goserelin, vincristin, vinblastin, nocodazole, teniposide,
etoposide, epothilone, navelbine, camptothecin, daunonibicin,
dactinomycin, mitoxantrone, amsacrine, doxorubicin, epirubicin,
idarubicin imatanib, gefitinib, erlotinib, sorafenib, sunitinib
malate, trastuzumab, rituximab, cetuximab, and bevacizumab.
56. The use of claim 44 wherein said cell proliferative disorder is
melanoma, a papillary thyroid cancer or Congenital Nevi.
Description
CROSS-REFERENCE TO RELATED APPLICATION
[0001] This application claims the benefit of U.S. Provisional
Application No. 60/792,314, filed Apr. 17, 2006, the contents of
which are incorporated herein by reference in their entirety.
BACKGROUND OF THE INVENTION
[0002] There are three RAF isoforms in humans: A-RAF, B-RAF and
C-RAF (Marais and Marshall. Cancer Surv. 27:101-125 (1996)). These
serine/threonine protein kinases are components of a conserved
signaling pathway downstream of the membrane-bound small G protein
RAS, which is activated by growth factors, hormones, and cytokines
(Robinson and Cobb, Curr. Opin. Cell Biol. 9:180-186 (1997)). RAS
stimulates RAF activation, which then leads to activation of the
MEK kinase and subsequently the ERK kinase. Depending on the
cellular context, this pathway mediates diverse biological
functions such as cell growth, survival and differentiation
predominantly through the regulation of transcription, metabolism
and cytoskeletal rearrangements.
[0003] The RAS-RAF signaling pathway has long been associated with
human cancers because oncogenic mutations in the ras gene occur in
at least 15% of all human cancers (Davies, H. et al., Nature
417:949-954 (2002)), and the downstream kinase ERK is
hyperactivated in 30% of cancers (Allen, et al., Semin. Oncol.
30:105-116 (2003)). However, for more than a decade, the RAF
proteins had been considered to be important in cancer only because
of their position downstream of RAS. This view was changed
radically when activating mutations of B-RAF were found at a high
frequency in human cancer, implicating B-RAF as a critical
initiator and promoter of malignancy (Davies, H. et al., Nature
417:949-954 (2002)).
[0004] Activating mutations in the B-RAF protooncogene underlie 70%
of melanomas, 50% of papillary thyroid cancers and 10% of colon
cancers (Tuveson, et al., Cancer Cell 4:95-98 (2003); and Xing,
Endocrine-Related Cancer: 12:245-262 (2005). Approximately 90% of
these mutations occur as a single-nucleotide substitution that
converts a valine to glutamate at amino acid 600 (V600E) in the
kinase domain of B-RAF. This mutation increases the basal kinase
activity of B-RAF, resulting in the activation of the MEK and ERK
proteins that ultimately leads to uncontrolled tumor cell growth.
Significantly, B-RAF and RAS mutations are usually mutually
exclusive in the same tumor types, suggesting that these genes are
on the same oncogenic signaling pathway and that RAS acts to
activate B-RAF in these tumors.
[0005] Recent studies have found that knockdown of mutant B-RAF by
small interference RNA in human melanoma cells inhibits both MEK
and ERK kinases, causing growth arrest and ultimately promoting
apoptosis (Sharma, et al., Cancer Res. 65:2412-2421 (2005); and
Wellbrock et al., Cancer Res. 64:2338-2342 (2004)). In addition,
data obtained from a short-hairpin RNA xenograft models targeting
mutant B-RAF have shown that tumor regression resulting from B-RAF
suppression is inducible, reversible, and tightly regulated
(Hoeflich et al., Cancer Res. 66:999-1006 (2006). Taken together,
gain-of-function B-RAF signaling is strongly associated with in
vivo tumorigenicity, confirming B-RAF as an important target for
cancer therapeutics.
[0006] The references cited herein are not admitted to be prior art
to the claimed invention.
SUMMARY OF THE INVENTION
[0007] The present invention provides a compound of formula I or
pharmaceutically acceptable salts thereof
##STR00001##
[0008] wherein
[0009] X is O, S(O).sub.p;
[0010] p is an integer from 0 to 2;
[0011] R.sub.1 is halogen, --CN, --NO.sub.2, --OH,
--O--(C.sub.1-C.sub.8 substituted or unsubstituted alkyl),
--O--(C.sub.1-C.sub.8 fluoroalkyl),
--(CH.sub.2).sub.0-3--CO.sub.2H, --(CH.sub.2).sub.0-3--C(O)O-alkyl,
-(C.sub.1-C.sub.8 substituted or unsubstituted alkyl),
--(C.sub.1-C.sub.8 fluoroalkyl), --(C.sub.3-C.sub.8 cycloalkyl),
--(C.sub.3-C.sub.8 fluorocycloalkyl), O-aryl(substituted or
unsubstituted), --O-heteroaryl (substituted or unsubstituted),
--NR.sub.6R.sub.7, --N.sub.8--C(O)R.sub.9,
--NR.sub.8--C(O)-fluoroalkyl, --NR.sub.8--C(O)-- aryl(substituted
or unsubstituted), --(CH.sub.2).sub.0-3--C(O)NR.sub.6R.sub.7,
--NR.sub.8SO.sub.2R.sub.9, --NR.sub.9C(O)NR.sub.6R.sub.7,
--NR.sub.8C(S)NR.sub.6R.sub.7, --OSO.sub.2NR.sub.6R.sub.7,
--C(N--OH)NH.sub.2, --C(N--OH)R.sub.8, --CH.sub.2OR.sub.9,
--OC(O)NR.sub.6R.sub.7, --SR.sub.9, or
--C(O)NR.sub.8SO.sub.2R.sub.9;
[0012] R.sub.2 is hydrogen, halogen, --CN, --NO.sub.2, --OH,
--O--(C.sub.1-C.sub.8 substituted or unsubstituted alkyl),
--O--(C.sub.1-C.sub.8 fluoroalkyl),
--(CH.sub.2).sub.0-3--CO.sub.2H, --(CH.sub.2).sub.0-3--C(O)O-alkyl,
--(C.sub.1-C.sub.8 substituted or unsubstituted alkyl),
--(C.sub.1-C.sub.8 fluoroalkyl), --(C.sub.3-C.sub.8 cycloalkyl),
--(C.sub.3-C.sub.8 fluorocycloalkyl), O-aryl(substituted or
unsubstituted), --O-heteroaryl (substituted or unsubstituted),
--NR.sub.6R.sub.7, --NR.sub.9--C(O)R.sub.9,
--NR.sub.9--C(O)-fluoroalkyl, --NR.sub.8--C(O)-aryl (substituted or
unsubstituted), --(CH.sub.2).sub.0-3--C(O)NR.sub.6R.sub.7,
--NR.sub.8SO.sub.2R.sub.9, --NR.sub.8C(O)NR.sub.6R.sub.7,
--NR.sub.8C(S)NR.sub.6R.sub.7, --OSO.sub.2NR.sub.6R.sub.7,
--C(N--OH)NH.sub.2, --C(N--OH)R.sub.8, --CH.sub.2OR.sub.8,
--OC(O)NR.sub.6R.sub.7, --SR.sub.9, or
--C(O)NR.sub.8SO.sub.2R.sub.9, and R.sub.1, R.sub.2, taken
together, may form a ring;
[0013] R.sub.3 and R.sub.4 are independently hydrogen, substituted
or unsubstituted lower alkyl, --COOH, --COO.sub.8, or
--C(O)NR.sub.10R.sub.11;
[0014] R.sub.5 is selected from the group consisting of
C.sub.1-C.sub.10 alkyl, C.sub.3-C.sub.10 cycloalkyl, heterocyclyl,
and aryl; wherein said C.sub.1-C.sub.10 alkyl, C.sub.3-C.sub.10
cycloalkyl, heterocyclyl, and aryl groups may be substituted with
one or more substituents independently selected from the group
consisting of: hydroxyl group, --COOH, oxo, fluorine, thiol, cyano,
nitro, --NR.sub.6R.sub.7, C.sub.1-C.sub.6 alkylthio, arylthio,
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.8 fluoro-substituted alkyl,
C.sub.1-C.sub.6 alkoxy, C.sub.1-C.sub.8 fluoro-substituted alkoxy,
--O-aryl, --OC(.dbd.O)-alkyl, --OC(.dbd.O)-aryl, C.sub.3-C.sub.8
cycloalkyl, C.sub.3-C.sub.8 fluoro-substituted cycloalkyl,
C.sub.3-C.sub.8 cycloalkyloxy, C.sub.3-C.sub.8 fluoro-substituted
cycloalkyloxy, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl,
aryl, --C(.dbd.O)--NR.sub.8R.sub.9, C.sub.1-C.sub.6 alkylcarbonyl,
C.sub.3-C.sub.8 cycloalkylcarbonyl, heterocyclylcarbonyl,
--C(.dbd.O)-aryl, --C(.dbd.O)--O-aryl, C.sub.1-C.sub.6
alkoxycarbonyl, C.sub.1-C.sub.6 fluoro-substituted alkoxycarbonyl,
C.sub.3-C.sub.8 cycloalkyloxycarbonyl, heterocyclyloxycarbonyl,
C.sub.1-C.sub.6 alkylsulfonyl, arylsulfonyl, and heterocyclyl;
[0015] wherein when R.sub.5 is aryl, said one or more substitutents
further include chlorine, bromine and iodine; and
[0016] wherein when R.sub.5 is a heterocycle having an endocyclic
nitrogen atom or endocyclic nitrogen atoms, said endocyclic
nitrogen atom or endocyclic nitrogen atoms may be substituted with
one or more substituents independently selected from the group
consisting of: hydrogen, C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.8
cycloalkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, aryl,
--C(.dbd.O)--NR.sub.8R.sub.9, C.sub.1-C.sub.6 alkylcarbonyl,
--C(.dbd.O)-aryl, --C(.dbd.O)--O-aryl, C.sub.1-C.sub.6
alkoxycarbonyl, C.sub.1-C.sub.6 alkylsulfonyl, arylsulfonyl, and
heterocyclyl;
[0017] each R.sub.6 and each R.sub.7 are independently hydrogen,
substituted or unsubstituted alkyl, substituted or unsubstituted
aryl, or substituted or unsubstituted heterocyclyl, and R.sub.6 and
R.sub.7, taken together, may form a ring;
[0018] each R.sub.8 is independently hydrogen, or substituted or
unsubstituted lower alkyl;
[0019] each R.sub.9 is independently substituted or unsubstituted
alkyl, substituted or unsubstituted aryl, substituted or
unsubstituted heterocyclyl, or substituted or unsubstituted
heteroaryl;
[0020] R.sub.10 is substituted or unsubstituted lower alkyl, or
substituted or unsubstituted aryl;
[0021] R.sub.11, is hydrogen, substituted or unsubstituted alkyl,
substituted or unsubstituted aryl, or substituted or unsubstituted
heterocyclyl, or substituted or unsubstituted heteroaryl, and
R.sub.11, taken together with R.sub.10, may form a ring; and
[0022] R.sub.13 is selected from the group consisting of hydrogen,
C.sub.1-C.sub.8 alkyl, C.sub.1-C.sub.8 fluoro-substituted alkyl,
C.sub.3-C.sub.8 cycloalkyl, C.sub.3-C.sub.8 fluoro-substituted
cycloalkyl, aryl, halogen-substituted aryl, heteroaryl, and
halogen-substituted heteroaryl.
[0023] In an embodiment, R.sub.5 is
##STR00002##
wherein m is an integer from 1 to 3; n is an integer from 1 to 3; Z
is hydrogen, a bond, --C(O)--, --C(O)NR.sub.11--, --S(O).sub.2--,
--C(O)NH--S(O).sub.2--, or CH(OH)--CH.sub.2--Y--, wherein Y is
CH.sub.2, O, S, NH, or a bond; and R.sub.12 is substituted or
unsubstituted alkyl, substituted or unsubstituted aryl, substituted
or unsubstituted heterocyclyl, or substituted or unsubstituted
heteroaryl.
[0024] In an embodiment, R.sub.3 and R.sub.4 are hydrogen.
[0025] In an embodiment, R.sub.13 is hydrogen.
[0026] In an embodiment, m+n=4, if m is not equal to n, then the
preferred configuration is R.
[0027] In an embodiment, Z is --S(O).sub.2-- and R.sub.12 is
4-chlorophenyl, 4-fluorophenyl, 4-cyanophenyl, methyl, or
cyclopropyl.
[0028] In an embodiment, R.sub.1 is
--(CH.sub.2).sub.0-3--C(O)NR.sub.6R.sub.7,
--NR.sub.8SO.sub.2R.sub.9, --NR.sub.8C(O)NR.sub.6R.sub.7,
--NR.sub.8C(S)NR.sub.6R.sub.7, --OSO.sub.2NR.sub.6R.sub.7,
--C(N--OH)NH.sub.2, --C(N--OH)R.sub.1, --CH.sub.2OR.sub.8,
--OC(O)NR.sub.6R.sub.7, --SR.sub.9, or
--C(O)NR.sub.8SO.sub.2R.sub.9; and R.sub.2 is hydrogen,
--(CH.sub.2).sub.0-3--C(O)NR.sub.6R.sub.7,
--NR.sub.8SO.sub.2R.sub.9, --NR.sub.8C(O)NR.sub.6R.sub.7,
--NR.sub.8C(S)NR.sub.6R.sub.7, --OSO.sub.2NR.sub.6R.sub.7,
--C(N--OH)NH.sub.2, --C(N--OH)R.sub.8, --CH.sub.2OR.sub.8,
--OC(O)NR.sub.6R.sub.7, --SR.sub.9, or
--C(O)NR.sub.8SO.sub.2R.sub.9, and R.sub.1 and R.sub.2, taken
together, may form a ring.
[0029] The present invention also provides a pharmaceutical
composition comprising a compound of formula I or a
pharmaceutically acceptable salt thereof together with one or more
pharmaceutically acceptable carriers or excipients. In an
embodiment, the pharmaceutical composition further comprises a
second chemotherapeutic agent.
[0030] The present invention further provides a method of treating
a cell proliferative disorder. The method comprises administering
to a subject in need thereof a therapeutically effective amount of
a compound of formula I, or a pharmaceutically acceptable salt
thereof, or a prodrug or metabolite thereof, in combination with a
pharmaceutically acceptable carrier, wherein said cell
proliferative disorder is treated.
[0031] In an embodiment, the cells with proliferative disorder
contain DNA encoding a RAF, mutant or wild type. In a further
embodiment, the cells have a constitutively enhanced RAF activity.
The RAF can be A-RAF, B-RAF, or C-RAF. In an embodiment, B-RAF is a
mutant, more specifically, B-RAF.sup.V600E.
[0032] The cell proliferative disorder can be a precancerous
condition, or a cancer. In an embodiment, the cell proliferative
disorder is melanoma, papillary thyroid cancers, colon cancer, or
Congenital Nevi.
[0033] The present invention further provides a method of
modulating B-RAF activity. The method comprises contacting a cell
containing B-RAF gene with an effective amount of a compound of
formula II, or a pharmaceutically acceptable salt thereof, or a
prodrug, metabolite, analog or derivative thereof, wherein said
contacting results in said inhibiting B-RAF activity. In an
embodiment, The B-RAF activity is the kinase activity of B-RAF. In
an embodiment, the B-RAF is B-RAF.sup.V600E.
[0034] Other features and advantages of the present invention are
apparent from the additional descriptions provided herein including
the different examples. The provided examples illustrate different
components and methodology useful in practicing the present
invention. The examples do not limit the claimed invention. Based
on the present disclosure the skilled artisan can identify and
employ other components and methodology useful for practicing the
present invention.
BRIEF DESCRIPTION OF THE DRAWINGS
[0035] FIG. 1: Synthesis of compounds of formula XI.
[0036] FIG. 2: Preparation of the guanidinium salts of formula
IX.
[0037] FIG. 3: Transformation of intermediate XI to compounds of
formulas XII to XV.
[0038] FIG. 4: Preparation of phenols of formula XVII and
carboxylic acids of formula XIX.
[0039] FIG. 5: Effects of compounds on Phospho-MEK in cancer cells.
A375 cells were treated with 0, 12, 37, 111, 333 and 1000 nM of
indicated compounds for 1 hr. The levels of Phospho-MEK and
total-MEK were accessed by immunoblotting.
[0040] FIG. 6: Effects of compounds on Phospho-ERK in cancer cells.
A375 cells were treated with 0, 12, 37, 111, 333 and 1000 nM of
indicated compounds for 1 hr. The levels of Phospho-ERK and
total-ERK were accessed by immunoblotting.
DETAILED DESCRIPTION OF THE INVENTION
1. The Compounds
[0041] The present invention provides imidazooxazole and/or
imidazothiazole compounds and their synthesis.
[0042] In an embodiment, the present invention provides compounds
of formula I and their synthesis.
##STR00003##
[0043] wherein
[0044] X is O, S(O).sub.p;
[0045] p is an integer from 0 to 2;
[0046] R.sub.1 is halogen, --CN, --NO.sub.2, --OH,
--O--(C.sub.1-C.sub.8 substituted or unsubstituted alkyl),
--O--(C.sub.1-C.sub.8 fluoroalkyl),
--(CH.sub.2).sub.0-3--CO.sub.2H, --(CH.sub.2).sub.0-3--C(O)O-alkyl,
--(C.sub.1-C.sub.8 substituted or unsubstituted alkyl),
--(C.sub.1-C.sub.9 fluoroalkyl), --(C.sub.3-C.sub.8 cycloalkyl),
--(C.sub.3-C.sub.8 fluorocycloalkyl), O-aryl(substituted or
unsubstituted), --O-heteroaryl (substituted or unsubstituted),
--NR.sub.6R.sub.7, --NR.sub.8--C(O)R.sub.9,
--NR.sub.8--C(O)-fluoroalkyl, --NR.sub.8--C(O)-- aryl(substituted
or unsubstituted), --(CH.sub.2).sub.0-3--C(O)NR.sub.6R.sub.7,
--NR.sub.9SO.sub.2R.sub.9, --NR.sub.5C(O)NR.sub.6R.sub.7,
--NR.sub.8C(S)NR.sub.6R.sub.7, --OSO.sub.2NR.sub.6R.sub.7,
--C(N--OH)NH.sub.2, --C(N--OH)R.sub.8, --CH.sub.2OR.sub.8,
--OC(O)NR.sub.6R.sub.7, --SR.sub.9, or
--C(O)NR.sub.8SO.sub.2R.sub.9;
[0047] R.sub.2 is hydrogen, halogen, --CN, --NO.sub.2, --OH,
--O--(C.sub.1-C.sub.8 substituted or unsubstituted alkyl),
--O--(C.sub.1-C.sub.8 fluoroalkyl),
--(CH.sub.2).sub.0-3--CO.sub.2H, --(CH.sub.2).sub.0-3--C(O)O-alkyl,
--(C.sub.1-C.sub.8 substituted or unsubstituted alkyl),
--(C.sub.1-C.sub.8 fluoroalkyl), --(C.sub.3-C.sub.8 cycloalkyl),
--(C.sub.3-C.sub.8 fluorocycloalkyl), O-aryl(substituted or
unsubstituted), --O-heteroaryl (substituted or unsubstituted),
--NR.sub.6R.sub.7, --NR.sub.8--C(O)R.sub.9,
--NR.sub.8--C(O)-fluoroalkyl, --NR.sub.8--C(O)-aryl(substituted or
unsubstituted), --(CH.sub.2).sub.0-3--C(O)NR.sub.6R.sub.7,
--NR.sub.8SO.sub.2R.sub.9, --NR.sub.8C(O)NR.sub.6R.sub.7,
--NR.sub.8C(S)NR.sub.6R.sub.7, --OSO.sub.2NR.sub.6R.sub.7,
--C(N--OH)NH.sub.2, --C(N--OH)R.sub.5, --CH.sub.2OR.sub.8,
--OC(O)NR.sub.6R.sub.7, --SR.sub.9, or C(O)NR.sub.8SO.sub.2R.sub.9,
and R.sub.1, R.sub.2, taken together, may form a ring;
[0048] R.sub.3 and R.sub.4 are independently hydrogen, substituted
or unsubstituted lower alkyl, --COOH, --COORS, or
--C(O)NR.sub.10R.sub.11;
[0049] R.sub.5 is independently selected from the group consisting
of C.sub.1-C.sub.10 alkyl, C.sub.3-C.sub.10 cycloalkyl,
heterocyclyl, and aryl; wherein said C.sub.1-C.sub.10 alkyl,
C.sub.3-C.sub.10 cycloalkyl, heterocyclyl, and aryl groups may be
substituted with one or more substituents independently selected
from the group consisting of: hydroxyl group, --COOH, oxo,
fluorine, thiol, cyano, nitro, --NR.sub.6R.sub.7, C.sub.1-C.sub.6
alkylthio, arylthio, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.8
fluoro-substituted alkyl, C.sub.1-C.sub.6 alkoxy, C.sub.1-C.sub.8
fluoro-substituted alkoxy, --O-aryl, --OC(.dbd.O)-alkyl,
--OC(.dbd.O)-aryl, C.sub.3-C.sub.8 cycloalkyl, C.sub.3-C.sub.8
fluoro-substituted cycloalkyl, C.sub.3-C.sub.8 cycloalkyloxy,
C.sub.3-C.sub.8 fluoro-substituted cycloalkyloxy, C.sub.2-C.sub.6
alkenyl, C.sub.2-C.sub.6 alkynyl, aryl,
--C(.dbd.O)--NR.sub.8R.sub.9, C.sub.1-C.sub.6 alkylcarbonyl,
C.sub.3-C.sub.8 cycloalkylcarbonyl, heterocyclylcarbonyl,
--C(.dbd.O)-aryl, --C(.dbd.O)--O-aryl, C.sub.1-C.sub.6
alkoxycarbonyl, C.sub.1-C.sub.6 fluoro-substituted alkoxycarbonyl,
C.sub.3-C.sub.8 cycloalkyloxycarbonyl, heterocyclyloxycarbonyl,
C.sub.1-C.sub.6 alkylsulfonyl, arylsulfonyl, and heterocyclyl;
[0050] wherein when R.sub.5 is aryl, said one or more substitutents
further include chlorine, bromine and iodine; and
[0051] wherein when R.sub.5 is a heterocycle having an endocyclic
nitrogen atom or endocyclic nitrogen atoms, said endocyclic
nitrogen atom or endocyclic nitrogen atoms may be substituted with
one or more substituents independently selected from the group
consisting of: hydrogen, C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.8
cycloalkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, aryl,
--C(.dbd.O)--NR.sub.8R.sub.9, C.sub.1-C.sub.6 alkylcarbonyl,
--C(.dbd.O)-aryl, --C(.dbd.O)--O-aryl, C.sub.1-C.sub.6
alkoxycarbonyl, C.sub.1-C.sub.6 alkylsulfonyl, arylsulfonyl, and
heterocyclyl;
[0052] each R.sub.6 and each R.sub.7 are independently hydrogen,
substituted or unsubstituted alkyl, substituted or unsubstituted
aryl, or substituted or unsubstituted heterocyclyl, and R.sub.6 and
R.sub.7, taken together, may form a ring;
[0053] each R.sub.8 is independently hydrogen, or substituted or
unsubstituted lower alkyl;
[0054] each R.sub.9 is independently substituted or unsubstituted
alkyl, substituted or unsubstituted aryl, substituted or
unsubstituted heterocyclyl, or substituted or unsubstituted
heteroaryl;
[0055] R.sub.10 is substituted or unsubstituted lower alkyl, or
substituted or unsubstituted aryl;
[0056] R.sub.11 is hydrogen, substituted or unsubstituted alkyl,
substituted or unsubstituted aryl, or substituted or unsubstituted
heterocyclyl, or substituted or unsubstituted heteroaryl, and
R.sub.11, taken together with R.sub.10, may form a ring; and
[0057] R.sub.13 is independently selected from the group consisting
of hydrogen, C.sub.1-C.sub.8 alkyl, C.sub.1-C.sub.8
fluoro-substituted alkyl, C.sub.3-C.sub.8 cycloalkyl,
C.sub.3-C.sub.8 fluoro-substituted cycloalkyl, aryl,
halogen-substituted aryl, heteroaryl, and halogen-substituted
heteroaryl.
[0058] The present invention also provides for compounds of formula
II and their synthesis.
##STR00004##
[0059] wherein
[0060] X is O, S(O).sub.p;
[0061] m is an integer from 1 to 3;
[0062] n is an integer from 1 to 3;
[0063] p is an integer from 0 to 2;
[0064] Z is hydrogen, a bond, --C(O)--, --C(O)NR.sub.11--,
--S(O).sub.2--, --C(O)NH--S(O).sub.2--, or CH(OH)--CH.sub.2--Y--,
wherein Y is CH.sub.2, O, S, NH, or a bond;
[0065] R.sub.1 is halogen, --CN, --NO.sub.2, --OH,
--O--(C.sub.1-C.sub.8 substituted or unsubstituted alkyl),
--O--(C.sub.1-C.sub.8 fluoroalkyl),
--(CH.sub.2).sub.0-3--CO.sub.2H, --(CH.sub.2).sub.0-3--C(O)O-alkyl,
--(C.sub.1-C.sub.8 substituted or unsubstituted alkyl),
--(C.sub.1-C.sub.8 fluoroalkyl), --(C.sub.3-C.sub.8 cycloalkyl),
--(C.sub.3-C.sub.8 fluorocycloalkyl), O-aryl(substituted or
unsubstituted), --O-heteroaryl (substituted or unsubstituted),
--NR.sub.6R.sub.7, --NR.sub.9--C(O)R.sub.9,
--NR.sub.9--C(O)-fluoroalkyl, --NR.sub.8--C(O)-- aryl(substituted
or unsubstituted), --(CH.sub.2).sub.0-3--C(O)NR.sub.6R.sub.7,
--NR.sub.8SO.sub.2R.sub.9, --NR.sub.8C(O)NR.sub.6R.sub.7,
--NR.sub.8C(S)NR.sub.6R.sub.7, --OSO.sub.2NR.sub.6R.sub.7,
--C(N--OH)NH.sub.2, --C(N--OH)R.sub.9, --CH.sub.2O %,
--OC(O)NR.sub.6R.sub.7, --SR.sub.9, or
C(O)NR.sub.8SO.sub.2R.sub.9;
[0066] R.sub.2 is hydrogen, halogen, --CN, --NO.sub.2, --OH,
--O--(C.sub.1-C.sub.8 substituted or unsubstituted alkyl),
--O--(C.sub.1-C.sub.9 fluoroalkyl),
--(CH.sub.2).sub.0-3--CO.sub.2H, --(CH.sub.2).sub.0-3--C(O)O-alkyl,
--(C.sub.1-C.sub.8 substituted or unsubstituted alkyl),
--(C.sub.1-C.sub.8 fluoroalkyl), --(C.sub.3-C.sub.8 cycloalkyl),
--(C.sub.3-C.sub.8 fluorocycloalkyl), O-aryl(substituted or
unsubstituted), --O-heteroaryl (substituted or unsubstituted),
--NR.sub.6R.sub.7, --NR.sub.9--C(O)R.sub.9,
--NR.sub.8--C(O)-fluoroalkyl, --NR.sub.9--C(O)-aryl (substituted or
unsubstituted), --(CH.sub.2).sub.0-3--C(O)NR.sub.6R.sub.7,
--NR.sub.8SO.sub.2R.sub.9, --NR.sub.8C(O)NR.sub.6R.sub.7,
--NR.sub.8C(S)NR.sub.6R.sub.7, --OSO.sub.2NR.sub.6R.sub.7,
--C(N--OH)NH.sub.2, --C(N--OH)R.sub.8, --CH.sub.2Os,
--OC(O)N.sub.6R.sub.7, --SR.sub.9, or
--C(O)NR.sub.8SO.sub.2R.sub.9, and R.sub.1, R.sub.2, taken
together, may form a ring;
[0067] R.sub.3 and R.sub.4 are independently hydrogen, substituted
or unsubstituted lower alkyl, --COOH, --COOR.sub.8, or
--C(O)NR.sub.10R.sub.11;
[0068] each R.sub.6 and each R.sub.7 are independently hydrogen,
substituted or unsubstituted alkyl, substituted or unsubstituted
aryl, or substituted or unsubstituted heterocyclyl, and R.sub.6 and
R.sub.7, taken together, may form a ring;
[0069] each R.sub.8 is independently hydrogen, or substituted or
unsubstituted lower alkyl;
[0070] each R.sub.9 is independently substituted or unsubstituted
alkyl, substituted or unsubstituted aryl, substituted or
unsubstituted heterocyclyl, or substituted or unsubstituted
heteroaryl;
[0071] R.sub.10 is substituted or unsubstituted lower alkyl, or
substituted or unsubstituted aryl;
[0072] R.sub.11 is hydrogen, substituted or unsubstituted alkyl,
substituted or unsubstituted aryl, or substituted or unsubstituted
heterocyclyl, or substituted or unsubstituted heteroaryl, and
R.sub.11, taken together with R.sub.10, may form a ring;
[0073] R.sub.12 is substituted or unsubstituted alkyl, substituted
or unsubstituted aryl, substituted or unsubstituted heterocyclyl,
or substituted or unsubstituted heteroaryl; and
[0074] R.sub.13 is independently selected from the group consisting
of hydrogen, C.sub.1-C.sub.8 alkyl, C.sub.1-C.sub.8
fluoro-substituted alkyl, C.sub.3-C.sub.8 cycloalkyl,
C.sub.3-C.sub.8 fluoro-substituted cycloalkyl, aryl,
halogen-substituted aryl, heteroaryl, and halogen-substituted
heteroaryl.
[0075] In an embodiment, R.sub.1 is
--(CH.sub.2).sub.0-3--C(O)NR.sub.6R.sub.7,
--NR.sub.9SO.sub.2R.sub.5, --NR.sub.8C(O)NR.sub.6R.sub.7,
--NR.sub.9C(S)NR.sub.6R.sub.7, --OSO.sub.2NR.sub.6R.sub.7,
--C(N--OH)NH.sub.2, --C(N--OH)R.sub.5, --CH.sub.2OR.sub.9,
--OC(O)NR.sub.6R.sub.7, --SR.sub.9, or C(O)NR.sub.8SO.sub.2R.sub.9;
and R.sub.2 is hydrogen, --(CH.sub.2).sub.0-3--C(O)NR.sub.6R.sub.7,
--NR.sub.8SO.sub.2R.sub.9, --NR.sub.8C(O)NR.sub.6R.sub.7,
--NR.sub.8C(S)NR.sub.6R.sub.7, --OSO.sub.2NR.sub.6R.sub.7,
--C(N--OH)NH.sub.2, --C(N--OH)R.sub.8, --CH.sub.2OR.sub.8,
--OC(O)NR.sub.6R.sub.7, --SR.sub.9, or
--C(O)NR.sub.8SO.sub.2R.sub.9, and R.sub.1, R.sub.2, taken
together, may form a ring.
[0076] The term "alkyl" refers to radicals containing carbon and
hydrogen, without unsaturation. Alkyl radicals can be straight or
branched. Exemplary alkyl radicals include, without limitation,
methyl, ethyl, propyl, isopropyl, hexyl, t-butyl, sec-butyl and the
like. Alkyl groups may be denoted by a range, thus, for example, a
(C.sub.1-C.sub.6) alkyl group is an alkyl group having from one to
six carbon atoms in the straight or branched alkyl backbone.
Substituted and unsubstituted alkyl groups may independently be
(C.sub.1-C.sub.5) alkyl, (C.sub.1-C.sub.6) alkyl,
(C.sub.1-C.sub.10) alkyl, (C.sub.3-C.sub.10) alkyl, or
(C.sub.5-C.sub.10) alkyl. Unless expressly stated, the term "alkyl"
does not include "cycloalkyl." The term "lower alkyl" refers to
unbranched or branched (C.sub.1-C.sub.6) alkyl.
[0077] A "cycloalkyl" group refers to a cyclic alkyl group having
the indicated number of carbon atoms in the "ring portion," where
the "ring portion" may consist of one or more ring structures
either as fused, spiro, or bridged ring structures. For example, a
C.sub.3 to C.sub.6 cycloalkyl group (e.g., (C.sub.3-C.sub.6)
cycloalkyl) is a ring structure having between 3 and 6 carbon atoms
in the ring. When no range is given, then cycloalkyl has between
three and nine carbon atoms ((C.sub.3-C.sub.9) cycloalkyl) in the
ring portion. Exemplary cycloalkyl groups include, but are not
limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,
cycloheptyl, and adamantyl. Preferred cycloalkyl groups have three,
four, five, six, seven, eight, nine, or from three to nine carbon
atoms in the ring structure.
[0078] The term substituted alkyl and substituted cycloalkyl, refer
to alkyl and cycloalkyl groups, as defined above, substituted with
one or more substituents independently selected from the group
consisting of fluorine, aryl, heteroaryl, --O--(C.sub.1-C.sub.6)
alkyl, and --NR5R6, where R5 and R6 are independently selected from
the group consisting of hydrogen and --(C.sub.1-C.sub.6) alkyl.
[0079] The term "aryl" refers to an aromatic carbocyclic group,
having one, two, or three aromatic rings. Exemplary aryl groups
include, without limitation, phenyl, naphthyl, and the like. Aryl
groups include one, two, or three aromatic rings structures fused
with one or more additional nonaromatic carbocyclic or hetercyclic
rings having from 4-9 members. Examples of fused aryl groups
include benzocyclobutanyl, indanyl, tetrahydronapthylenyl,
1,2,3,4-tetrahydrophenanthrenyl, tetrahydroanthracenyl,
1,4-dihydro-1,4-methanonaphthalenyl, benzodioxolyl.
[0080] The term "heteroaryl" refers to a heteroaromatic
(heteroaryl) group having one, two, or three aromatic rings
containing from 1-4 heteroatoms (such as nitrogen, sulfur, or
oxygen) in the aromatic ring. Heteroaryl groups include one, two,
or three aromatic rings structures containing from 1-4 heteroatoms
fused with one or more additional nonaromatic rings having from 4-9
members. Heteroaryl groups containing a single type of hetroatom in
the aromatic ring are denoted by the type of hetero atom they
contain, thus, nitrogen-containing heteroaryl, oxygen-containing
heteroaryl and sulfur-containing heteroaryl denote heteroaromatic
groups containing one or more nitrogen, oxygen or sulfur atoms
respectively. Exemplary heteroaryl groups include, without
limitation, pyridyl, pyrimidinyl, triazolyl, quinolyl,
quinazolinyl, thiazolyl, benzo[b]thiophenyl, furanyl, imidazolyl,
indolyl, and the like.
[0081] The terms "heterocyclyl" or "heterocycle" refers to either
saturated or unsaturated, stable non-aromatic ring structures that
may be fused, spiro or bridged to form additional rings. Each
heterocycle consists of one or more carbon atoms and from one to
four heteroatoms selected from the group consisting of nitrogen,
oxygen and sulfur. "Heterocyclyl" or "heterocycle" include stable
non-aromatic 3-7 membered monocyclic heterocyclic ring structures
and 8-11 membered bicyclic heterocyclic ring structures. A
heterocyclyl radical may be attached at any endocyclic carbon or
nitrogen atom that results in the creation of a stable structure.
Preferred heterocycles include 3-7 membered monocyclic heterocycles
(more preferably 5-7-membered monocyclic heterocycles) and 8-10
membered bicyclic heterocycles. Examples of such groups include
piperidinyl, piperazinyl, pyranyl, pyrrolidinyl, morpholmyl,
thiomorpholinyl, oxopiperidinyl, oxopyrrolidinyl, oxoazepinyl,
azepinyl, isoxozolyl, tetrahydropyranyl, tetrahydrofuranyl,
dioxolyl, dioxinyl, oxathiofyl, dithiolyl, sulfolanyl, dioxanyl,
dioxolanyl, tetahydrofurodihydrofuranyl,
tetrahydropyranodihydro-furanyl, dihydropyranyl,
tetrahydrofurofuranyl, tetrahydropyranofuran, quinuclidinyl
(1-azabicyclo[2.2.2]octanyl) and tropanyl
(8-methyl-8-azabicyclo[3.2.1]octanyl).
[0082] All stereoisomers of the compounds of the instant invention
are contemplated, either in a mixture or in pure or substantially
pure form, including crystalline forms of racemic mixtures and
crystalline forms of individual isomers. The definition of the
compounds according to the invention embraces all possible
stereoisomers (e.g., the R and S configurations for each asymmetric
center) and their mixtures. It very particularly embraces the
racemic forms and the isolated optical isomers having a specified
activity. The racemic forms can be resolved by physical methods,
such as, for example, fractional crystallization, separation or
crystallization of diastereomeric derivatives, separation by chiral
column chromatography or supercritical fluid chromatography. The
individual optical isomers can be obtained from the racemates by
conventional methods, such as, for example, salt formation with an
optically active acid followed by crystallization. Furthermore, all
geometric isomers, such as E- and Z-configurations at a double
bond, are within the scope of the invention unless otherwise
stated. Certain compounds of this invention may exist in tautomeric
forms. All such tautomeric forms of the compounds are considered to
be within the scope of this invention unless otherwise stated. The
present invention also includes one or more regioisomeric mixtures
of an analog or derivative.
[0083] As used herein, the term "salt" is a pharmaceutically
acceptable salt and can include acid addition salts including
hydrochlorides, hydrobromides, phosphates, sulphates, hydrogen
sulphates, alkylsulphonates, arylsulphonates, acetates, benzoates,
citrates, maleates, fumarates, succinates, lactates, and tartrates;
alkali metal cations such as Na.sup.+, K.sup.+, Li.sup.+, alkali
earth metal salts such as M.sup.2+ or Ca.sup.2+, or organic amine
salts.
[0084] As used herein, the term "metabolite" means a product of
metabolism of a compound of the present invention, or a
pharmaceutically acceptable salt, analog or derivative thereof,
that exhibits a similar activity in vivo to said compound of the
present invention.
[0085] As used herein, the term "prodrug" means a compound of the
present invention covalently linked to one or more pro-moieties,
such as an amino acid moiety or other water solubilizing moiety. A
compound of the present invention may be released from the
pro-moiety via hydrolytic, oxidative, and/or enzymatic release
mechanisms. In an embodiment, a prodrug composition of the present
invention exhibits the added benefit of increased aqueous
solubility, improved stability, and improved pharmacokinetic
profiles. The pro-moiety may be selected to obtain desired prodrug
characteristics. For example, an amino acid moiety or other water
solubilizing moiety such as phosphate within R.sub.4, may be
selected based on solubility, stability, bioavailability, and/or in
vivo delivery or uptake. In an embodiment of the present invention,
the compound is a compound of formula I or formula II wherein
R.sub.3 and R.sub.4 are hydrogen.
[0086] In another embodiment of the present invention, the compound
is a compound of formula I or formula II wherein R.sub.1 is 3-OH
and R.sub.2 is hydrogen.
[0087] In another embodiment of the present invention, the compound
is a compound of formula I or formula II wherein R.sub.13 is
hydrogen.
[0088] In another embodiment of the present invention, the compound
is a compound of formula II wherein m+n=4, m is not equal to n, and
the configuration is R. As used herein, the configuration of a
molecule is the permanent geometry that results from the spatial
arrangement of its atoms. The configuration can be either R or S
and is defined according to the UIPAC rules. When more than one
stereogenic atoms are present in a molecule, each one will be
defined as of configuration R or S.
[0089] In another embodiment of the present invention, the compound
is a compound of formula I or formula II wherein Z is
--S(O).sub.2-- and R.sub.12 is 4-chlorophenyl, 4-fluorophenyl or
4-cyanophenyl.
[0090] In an embodiment of the present invention, the compound is
one of compounds #1-316 listed in table 2. In a further embodiment
of the present invention, thecompound is one of compounds #1-289
listed in table 2. In an embodiment of the present invention, the
compound is one of compounds #290-316 listed in table 2. In an
embodiment of the present invention, the compound is one of
compounds #317-401 listed in table 2.
[0091] In an embodiment of the present invention, the compound is
3-{5-[2-({(3R)-1-[(4-chlorophenyl)sulfonyl]piperidin-3-yl}amino)pyrimidin-
-4-yl]imidazo[2,1-b][1,3]thiazol-6-yl}phenyl carbamate,
3-{5-[2-({(3R)-1-[(4-chlorophenyl)sulfonyl]piperidin-3-yl}amino)pyrimidin-
-4-yl]imidazo[2,1-b][1,3]thiazol-6-yl}phenyl sulfamate,
3-{5-[2-({(3R)-1-[(4-chlorophenyl)sulfonyl]piperidin-3-yl}amino)pyrimidin-
-4-yl]imidazo[2,1-b][1,3]oxazol-6-yl}phenyl sulfamate,
3-{5-[2-({(3R)-1-[(4-chlorophenyl)sulfonyl]piperidin-3-yl}amino)pyrimidin-
-4-yl]imidazo[2,1-b][1,3]oxazol-6-yl}phenyl carbamate,
(1E)-1-(3-{5-[2-({(3R)-1-[(4-chlorophenyl)sulfonyl]piperidin-3-yl}amino)p-
yrimidin-4-yl]imidazo[2,1-b][1,3]thiazol-6-yl}phenyl)ethanone
oxime,
2-chloro-5-{5-[2-({(3R)-1-[(4-chlorophenyl)sulfonyl]piperidin-3-yl}amino)-
pyrimidin-4-yl]imidazo[2,1-b][1,3]thiazol-6-yl}phenol,
3-{5-[2-({(3R)-1-[(4-chlorophenyl)sulfonyl]piperidin-3-yl}amino)pyrimidin-
-4-yl]imidazo[2,1-b][1,3]oxazol-6-yl}phenol,
4-([(3R)-3-({4-[6-(3-hydroxyphenyl)imidazo[2,1-b][1,3]thiazol-5-yl]pyrimi-
din-2-yl)amino)piperidin-1-yl]sulfonyl}benzonitrile,
4-{[(3R)-3-({4-[6-(3-hydroxyphenyl)imidazo[2,1-b][1,3]thiazol-5-yl]pyrimi-
din-2-yl}amino)piperidin-1-yl]sulfonyl}benzoic acid,
3-{[(3R)-3-({4-[6-(3-hydroxyphenyl)imidazo[2,1-b][1,3]thiazol-5-yl]pyrimi-
din-2-yl}amino)piperidin-1-yl]sulfonyl}phenol,
2-{5-[2-({(3R)-1-[(4-chlorophenyl)sulfonyl]piperidin-3-yl}amino)pyrimidin-
-4-yl]imidazo[2,1-b][1,3]thiazol-6-yl}benzene-1,4-diol,
3-[5-(2-{[(3R)-1-(methylsulfonyl)piperidin-3-yl]amino}pyrimidin-4-yl)imid-
azo[2,1-b][1,3]thiazol-6-yl]phenol,
3-{5-[2-({1-[(4-fluorophenyl)sulfonyl]piperidin-4-yl}amino)pyrimidin-4-yl-
]imidazo[2,1-b][1,3]thiazol-6-yl}phenol,
3-{5-[2-({1-[(4-chlorophenyl)sulfonyl]piperidin-4-yl}amino)pyrimidin-4-yl-
]imidazo[2,1-b][1,3]thiazol-6-yl}phenol,
N-ethyl-4-({4-[6-(3-hydroxyphenyl)imidazo[2,1-b][1,3]thiazol-5-yl]pyrimid-
in-2-yl}amino)piperidine-1-carboxamide,
3-{5-[2-({(3R)-1-[(4-chlorophenyl)sulfonyl]piperidin-3-yl}amino)pyrimidin-
-4-yl]imidazo[2,1-b][1,3]thiazol-6-yl}phenol,
4-{[4-({4-[6-(3-hydroxyphenyl)imidazo[2,1-b][1,3]oxazol-5-yl]pyrimidin-2--
yl}amino)piperidin-1-yl]sulfonyl}benzonitrile,
4-{[4-({4-[6-(3-hydroxyphenyl)imidazo[2,1-b][1,3]oxazol-5-yl]pyrimidin-2--
yl}amino)piperidin-1-yl]sulfonyl}benzamide,
4-{[(3R)-3-({4-[6-(3-hydroxyphenyl)idazo[2,1-b][1,3]oxazol-5-yl]pyrimidin-
-2-yl}amino)piperidin-1-yl]sulfonyl}benzonitrile,
3-{5-[2-({1-[(4-chlorophenyl)sulfonyl]piperidin-4-yl}amino)pyrimidin-4-yl-
]imidazo[2,1-b][1,3]oxazol-6-yl}phenol,
3-{5-[2-({1-[(4-fluorophenyl)sulfonyl]piperidin-4-yl}amino)pyrimidin-4-yl-
]imidazo[2,1-b][1,3]oxazol-6-yl}phenol,
5-{5-[2-({(3R)-1-[(4-chlorophenyl)sulfonyl]piperidin-3-yl}amino)pyrimidin-
-4-yl]imidazo[2,1-b][1,3]triazol-6-yl}-2-fluorophenol,
3-{5-[2-({(3R)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]piperidin-3-yl}amin-
o)pyrimidin-4-yl]imidazo[2,1-b][1,3]thiazol-6-yl}phenol,
3-[5-(2-{[(3R)-1-(3-thienylsulfonyl)piperidin-3-yl]amino}pyrimidin-4-yl)i-
midazo[2,1-b][1,3]thiazol-6-yl]phenol,
3-[5-(2-{[(3R)-1-(2-thienylsulfonyl)piperidin-3-yl]amino}pyrimidin-4-yl)i-
midazo[2,1-b][1,3]thiazol-6-yl]phenol,
3-[5-(2-{[(3R)-1-(phenylsulfonyl)piperidin-3-yl]amino}pyrimidin-4-yl)imid-
azo[2,1-b][1,3]thiazol-6-yl]phenol,
3-(5-[2-({(3R)-1-[(1-methyl-1H-pyrazol-3-yl)sulfonyl]piperidin-3-yl}amino-
)pyrimidin-4-yl]imidazo[2,1-b][1,3]thiazol-6-yl)phenol,
3-[5-(2-{[(3R)-1-(4H-1,2,4-triazol-3-ylsulfonyl)piperidin-3-yl]amino}pyri-
midin-4-yl)imidazo[2,1-b][1,3]thiazol-6-yl]phenol,
3-[5-(2-{[(3R)-1-(2-thienylsulfonyl)piperidin-3-yl]amino}pyrimidin-4-yl)i-
midazo[2,1-b][1,3]oxazol-6-yl]phenol,
3-[5-(2-{[(3R)-1-(phenylsulfonyl)piperidin-3-yl]amino}pyrimidin-4-yl)imid-
azo[2,1-b][1,3]oxazol-6-yl]phenol,
3-[5-(2-{[1-(cyclopropylsulfonyl)piperidin-4-yl]amino}pyrimidin-4-yl)imid-
azo[2,1-b][1,3]thiazol-6-yl]phenol,
3-[5-(2-{[1-(methylsulfonyl)piperidin-4-yl]amino}pyrimidin-4-yl)imidazo[2-
,1-b][1,3]thiazol-6-yl]phenol,
3-[5-(2-{[1-(cyclopropylsulfonyl)piperidin-4-yl]amino}pyrimidin-4-yl)imid-
azo[2,1-b][1,3]oxazol-6-yl]phenol,
3-[5-(2-{[1-(methylsulfonyl)piperidin-4-yl]amino}pyrimidin-4-yl)imidazo[2-
,1-b][1,3]oxazol-6-yl]phenol,
5-[5-(2-{[1-(cyclopropylsulfonyl)piperidin-4-yl]amino}pyrimidin-4-yl)imid-
azo[2,1-b][1,3]thiazol-6-yl]-2-fluorophenol, or
3-[5-(2-{[(3R)-1-(cyclopropylsulfonyl)piperidin-3-yl]amino}pyrimidin-4-yl-
)imidazo[2,1-b][1,3]oxazol-6-yl]phenol.
[0092] In a further embodiment of the present invention, the
compound is
3-{5-[2-({(3R)-1-[(4-chlorophenyl)sulfonyl]piperidin-3-yl}amino)pyrimidin-
-4-yl]imidazo[2,1-b][1,3]thiazol-6-yl}phenyl carbamate,
3-{5-[2-({(3R)-1-[(4-chlorophenyl)sulfonyl]piperidin-3-yl}amino)pyrimidin-
-4-yl]imidazo[2,1-b][1,3]thiazol-6-yl}phenyl sulfamate,
3-{5-[2-({(3R)-1-[(4-chlorophenyl)sulfonyl]piperidin-3-yl}amino)pyrimidin-
-4-yl]imidazo[2,1-b][1,3]oxazol-6-yl}phenyl sulfamate,
3-{5-[2-({(3R)-1-[(4-chlorophenyl)sulfonyl]piperidin-3-yl}amino)pyrimidin-
-4-yl]imidazo[2,1-b][1,3]oxazol-6-yl}phenyl carbamate, or
(1E)-1-(3-{5-[2-({(3R)-1-[(4-chlorophenyl)sulfonyl]piperidin-3-yl}amino)p-
yrimidin-4-yl]imidazo[2,1-b][1,3]thiazol-6-yl}phenyl)ethanone
oxime.
[0093] In an alternative embodiment of the present invention, the
compound is
3-[5-(2-{[1-(cyclopropylsulfonyl)piperidin-4-yl]amino}pyrimidin-4-yl)i-
midazo[2,1-b][1,3]thiazol-6-yl]phenol,
3-[5-(2-{[1-(methylsulfonyl)piperidin-4-yl]amino}pyrimidin-4-yl)imidazo[2-
,1-b][1,3]thiazol-6-yl]phenol,
3-[5-(2-{[1-(cyclopropylsulfonyl)piperidin-4-yl]amino}pyrimidin-4-yl)imid-
azo[2,1-b][1,3]oxazol-6-yl]phenol,
3-[5-(2-{[1-(methylsulfonyl)piperidin-4-yl]amino}pyrimidin-4-yl)imidazo[2-
,1-b][1,3]oxazol-6-yl]phenol,
5-[5-(2-{[1-(cyclopropylsulfonyl)piperidin-4-yl]amino}pyrimidin-4-yl)imid-
azo[2,1-b][1,3]thiazol-6-yl]-2-fluorophenol, or
3-[5-(2-{[(3R)-1-(cyclopropylsulfonyl)piperidin-3-yl]amino}pyrimidin-4-yl-
)imidazo[2,1-b][1,3]oxazol-6-yl]phenol.
2. Methods and Intermediates for Preparing Compounds of the
Invention
[0094] Standard synthetic methods and procedures for the
preparation of organic molecules and functional group
transformations and manipulations including the use of protective
groups can be obtained from the relevant scientific literature or
from standard reference textbooks in the field. Although not
limited to any one or several sources, recognized reference
textbooks of organic synthesis include: Smith, M. B.; March, J.
March's Advanced Organic Chemistry: Reactions, Mechanisms, and
Structure, 5.sup.th ed.; John Wiley & Sons: New York, 2001; and
Greene, T. W.; Wuts, P. G. M. Protective Groups in Organic
Synthesis, 3R.sup.d; John Wiley & Sons: New York, 1999. The
following descriptions of synthetic methods are designed to
illustrate, but not limit, general procedures for the preparation
of compounds of the invention.
[0095] Compounds of the invention can be prepared in a variety of
ways, some of which are known in the art. In general, the compounds
of the present invention can be prepared from commercially
available starting materials, compounds known in the literature, or
from readily-prepared intermediates, by employing standard
synthetic methods and procedures known to those skilled in the art,
or which will be apparent to the skilled artisan in light of the
teachings herein. Standard synthetic methods and procedures for the
preparation of organic molecules and functional group
transformations and manipulations can be obtained from the relevant
scientific literature or from standard textbooks in the field. The
description of the synthesis of some compounds of the present
invention can also be found in PCT patent publications WO
2004/110990, and WO 2006/010082, and WO 2006/044869.
[0096] A method for preparing imidazooxazole and imidazothiazole
compounds of the invention is described in the Examples below and
illustrated in FIG. 1. In FIG. 1, step a, a suitably substituted
.alpha.-haloketone III is reacted with an optionally substituted
2-aminooxazole IV. This reaction is typically conducted in inert
organic solvent such as acetonitrile or similar at room
temperature. The product (not shown) is typically isolated from the
reaction mixture as a solid hydrogen bromide salt by filtration.
The cyclization of the hydrogen bromide intermediate to yield the
imidazooxazole compound V is conveniently performed by the addition
of a dehydrating reagent, such as titanium tetrachloride. This
reaction, following appropriate pH modification of the resulting
reaction mixture, provides V. In the case of the imidazothiazole
compounds, step b, a suitably substituted .alpha.-haloketone III is
reacted with an optionally substituted 2-aminothiazole IV. This
reaction is typically conducted in a solvent such as ethanol at
reflux to yield compound V directly. The compounds V are purified
by chromatography or by trituration in an inert solvent such as
diethylether. Acetylation of compounds V (step c) is typically done
in acetic anhydride, using concentrated sulfuric acid in catalytic
amount, providing compounds VI. The compounds VI are typically
purified by chromatography. The ketones VI are converted to the
enaminones VIII by reaction with DMF-DME at high temperature or by
mean of microwave activation (step d). Typically, the solid
enaminones VIII can be purified by chromatography or by trituration
in an inert solvent such as diethylether. The enaminones VIII are
cyclized to intermediate X (step f) by reaction with the
guanidinium salt IX in a suitable solvent such as ethanol, at
elevated temperature, typically reflux and using a base such as
sodium ethoxide. The compounds X can be purified by chromatography
or by trituration in an inert solvent such as diethylether. The BOC
protective group is suitably removed using HCl solution, typically
4N in dioxane, to yield the compounds XI (step g). Compounds XI are
typically hydrogen chloride salts and can be used without
purification.
[0097] The preparation of the guanidinium hydrochloride is
illustrated in FIG. 2. Typically, an amine such as tert-butyl
4-aminopiperidine-1-carboxylate is reacted with pyrazole
carboxamidine hydrochloride in an appropriate solvent such as DMF
at elevated temperature, in the presence of a tertiary amine such
as Hunig's base. The product IX is purified by repetitive
trituration in an inert solvent such as diethylether.
[0098] The functionalization of the amine XI is illustrated in FIG.
3. Typically, compounds XI are reacted with an appropriately
substituted isocyanate (step h) in an inert solvent such as
tetrahydrofuran, in the presence of a tertiary amine such as
triethylamine, at room temperature or at an elevated temperature.
The compounds XII are purified by chromatography or by trituration
in an inert solvent such as diethylether. Sulfonamides XIII are
prepared by reacting compounds XI with an appropriately substituted
sulfonyl chloride in an inert solvent such as methylene chloride,
in the presence of a tertiary amine such as Hunig's base, at room
temperature or at elevated temperature (step i). Compounds XIII are
purified by chromatography or by trituration in an inert solvent
such as diethylether. Compounds XIV can be prepared using any
coupling reagent and a carboxylic acid or by using an acyl halide.
For example, compounds XI are reacted with a suitably substituted
acid chloride in the presence of a tertiary amine such as
triethylamine, in an inert solvent such as methylene chloride, at
room temperature or elevated temperature (step j). Compounds XIV
are purified by chromatography or by trituration in an inert
solvent such as diethylether. In another example, compounds XI are
reacted with a suitably substituted carboxylic acid using HBTU as a
coupling reagent in the presence of DMAP and triethylamine, in an
inert solvent such as DMF, at room temperature or elevated
temperature (step k). Compounds XIV are purified by chromatography
or by trituration in an inert solvent such as diethylether.
Compounds XV are prepared by reacting compounds XI with an
appropriately substituted aldehyde in the presence of a reducing
agent such as Me.sub.4NBH(OAc).sub.3 in an inert solvent such as
DCE, at room temperature or elevated temperature (step 1).
Compounds XV are purified by chromatography or by trituration in an
inert solvent such as diethylether.
[0099] The preparation of compounds XVIII and XIX is illustrated in
FIG. 4. Compounds XVI are reacted with excess boron tribromide in
an inert solvent such as methylene chloride, at low temperature,
typically -78.degree. C. After all starting material has been
consumed, the reaction is carefully quench with an alcohol,
typically methanol, at low temperature (from -78.degree. C. to
0.degree. C.). The product XVII is purified by chromatography or by
trituration in an inert solvent such as diethylether. Compounds XIX
are prepared by reacting compounds XVIII with an hydroxide,
typically lithium hydroxide, in an appropriate solvent such as
tetrahydrofuran, at room temperature or elevated temperature.
Compounds XIX are purified by chromatography or by trituration in
an inert solvent such as diethylether.
3. Methods of Treatment
[0100] The compounds of the present invention can be used for the
treatment and or prevention of cell proliferative disorder such as
cancer. The compounds of the present invention are capable of
inhibiting the RAF protein kinases. Thus, the compounds can be used
for the treatment of cell proliferative disorder characterized by
aberrant RAS-RAF signaling. In an embodiment, the cells of cell
proliferative disorder such as cancer harbor a mutated B-RAF. In a
further embodiment, the mutated B-RAF is a B-RAF with the V600E
mutation (B-RAF.sup.V600E). The cell proliferative disorder can be
melanomas, papillary thyroid cancers, colon cancers.
[0101] The present invention also provides a method of treating any
other conditions characterized by a B-RAF.sup.V600E, e.g.,
Congenital Nevi (commonly known as moles or freckles) possessing
the B-RAF.sup.V600E, with the imidazooxazole and/or imidazothiazole
compounds. In a further embodiment, the present invention may be
used prophylactically (e.g., topically applied to the skin) to
prevent such nevi to develop into malignant melanomas.
[0102] As used herein, a "subject" can be any mammal, e.g. a human,
a primate, mouse, rat, dog, cat, cow, horse, pig, sheep, goat,
camel. In a preferred aspect, the subject is a human.
[0103] As used herein, a "subject in need thereof" is a subject
having a cell proliferative disorder, or a subject having an
increased risk of developing a cell proliferative disorder relative
to the population at large. In one aspect, a subject in need
thereof has a precancerous condition. In a preferred aspect, a
subject in need thereof has cancer.
[0104] As used herein, the term "cell proliferative disorder"
refers to conditions in which unregulated or abnormal growth, or
both, of cells can lead to the development of an unwanted condition
or disease, which may or may not be cancerous. In one aspect, a
cell proliferative disorder includes a non-cancerous condition,
e.g. rheumatoid arthritis; inflammation; autoimmune disease;
lymphoproliferative conditions; acromegaly; rheumatoid spondylitis;
osteoarthritis; gout, other arthritic conditions; sepsis; septic
shock; endotoxic shock; gram-negative sepsis; toxic shock syndrome;
asthma; adult respiratory distress syndrome; chronic obstructive
pulmonary disease; chronic pulmonary inflammation; inflammatory
bowel disease; Crohn's disease; psoriasis; eczema; ulcerative
colitis; pancreatic fibrosis; hepatic fibrosis; acute and chronic
renal disease; irritable bowel syndrome; pyresis; restenosis;
cerebral malaria; stroke and ischemic injury; neural trauma;
Alzheimer's disease; Huntington's disease; Parkinson's disease;
acute and chronic pain; allergic rhinitis; allergic conjunctivitis;
chronic heart failure; acute coronary syndrome; cachexia; malaria;
leprosy; leishmaniasis; Lyme disease; Reiter's syndrome; acute
synovitis; muscle degeneration, bursitis; tendonitis;
tenosynovitis; herniated, ruptures, or prolapsed intervertebral
disk syndrome; osteopetrosis; thrombosis; restenosis; silicosis;
pulmonary sarcosis; bone resorption diseases, such as osteoporosis;
graft-versus-host reaction; Multiple Sclerosis; lupus;
fibromyalgia; AIDS and other viral diseases such as Herpes Zoster,
Herpes Simplex I or II, influenza virus and cytomegalovirus; and
diabetes mellitus. In another aspect, a cell proliferative disorder
includes a precancer or a precancerous condition. In another
aspect, a cell proliferative disorder includes cancer. Various
cancers to be treated include but are not limited to breast cancer,
lung cancer, colorectal cancer, pancreatic cancer, ovarian cancer,
prostate cancer, renal carcinoma, hepatoma, brain cancer, melanoma,
multiple myeloma, chronic myelogenous leukemia, hematologic tumor,
and lymphoid tumor, including metastatic lesions in other tissues
or organs distant from the primary tumor site. Cancers to be
treated include but are not limited to sarcoma, carcinoma, and
adenocarcinoma. In one aspect, a "precancer cell" or "precancerous
cell" is a cell manifesting a cell proliferative disorder that is a
precancer or a precancerous condition. In another aspect, a "cancer
cell" or "cancerous cell" is a cell manifesting a cell
proliferative disorder that is a cancer. Any reproducible means of
measurement may be used to identify cancer cells or precancerous
cells. In a preferred aspect, cancer cells or precancerous cells
are identified by histological typing or grading of a tissue sample
(e.g., a biopsy sample). In another aspect, cancer cells or
precancerous cells are identified through the use of appropriate
molecular markers.
[0105] A "cell proliferative disorder of the colon" is a cell
proliferative disorder involving cells of the colon. In a preferred
aspect, the cell proliferative disorder of the colon is colon
cancer. In a preferred aspect compositions of the present invention
may be used to treat colon cancer or cell proliferative disorders
of the colon. In one aspect, colon cancer includes all forms of
cancer of the colon. In another aspect, colon cancer includes
sporadic and hereditary colon cancers. In another aspect, colon
cancer includes malignant colon neoplasms, carcinoma in situ,
typical carcinoid tumors, and atypical carcinoid tumors. In another
aspect, colon cancer includes adenocarcinoma, squamous cell
carcinoma, and adenosquamous cell carcinoma. In another aspect,
colon cancer is associated with a hereditary syndrome selected from
the group consisting of hereditary nonpolyposis colorectal cancer,
familial adenomatous polyposis, Gardner's syndrome, Peutz-Jeghers
syndrome, Turcot's syndrome and juvenile polyposis. In another
aspect, colon cancer is caused by a hereditary syndrome selected
from the group consisting of hereditary nonpolyposis colorectal
cancer, familial adenomatous polyposis, Gardner's syndrome,
Peutz-Jeghers syndrome, Turcot's syndrome and juvenile
polyposis.
[0106] In one aspect, cell proliferative disorders of the colon
include all forms of cell proliferative disorders affecting colon
cells. In one aspect, cell proliferative disorders of the colon
include colon cancer, precancerous conditions of the colon,
adenomatous polyps of the colon and metachronous lesions of the
colon. In one aspect, a cell proliferative disorder of the colon
includes adenoma. In one aspect, cell proliferative disorders of
the colon are characterized by hyperplasia, metaplasia, and
dysplasia of the colon. In another aspect, prior colon diseases
that may predispose individuals to development of cell
proliferative disorders of the colon include prior colon cancer. In
another aspect, current disease that may predispose individuals to
development of cell proliferative disorders of the colon include
Crohn's disease and ulcerative colitis. In one aspect, a cell
proliferative disorder of the colon is associated with a mutation
in a gene selected from the group consisting of p53, ras, FAP and
DCC. In another aspect, an individual has an elevated risk of
developing a cell proliferative disorder of the colon due to the
presence of a mutation in a gene selected from the group consisting
of p53, ras, FAP and DCC.
[0107] A "cell proliferative disorder of the skin" is a cell
proliferative disorder involving cells of the skin. In one aspect,
cell proliferative disorders of the skin include all forms of cell
proliferative disorders affecting skin cells. In one aspect, cell
proliferative disorders of the skin include a precancer or
precancerous condition of the skin, benign growths or lesions of
the skin, melanoma, malignant melanoma and other malignant growths
or lesions of the skin, and metastatic lesions in tissue and organs
in the body other than the skin. In another aspect, cell
proliferative disorders of the skin include hyperplasia,
metaplasia, and dysplasia of the skin.
[0108] In one aspect, a cancer that is to be treated has been
staged according to the American Joint Committee on Cancer (AJCC)
TNM classification system, where the tumor (T) has been assigned a
stage of TX, T1, T1mic, T1a, T1b, T1c, T2, T3, T4, T4a, T4b, T4c,
or T4d; and where the regional lymph nodes (N) have been assigned a
stage of NX, N0, N1, N2, N2a, N2b, N3, N3a, N3b, or N3c; and where
distant metastasis (M) has been assigned a stage of MX, M0, or M1.
In another aspect, a cancer that is to be treated has been staged
according to an American Joint Committee on Cancer (AJCC)
classification as Stage I, Stage IIA, Stage IIB, Stage IIIA, Stage
IIIB, Stage IIIC, or Stage IV. In another aspect, a cancer that is
to be treated has been assigned a grade according to an AJCC
classification as Grade GX (e.g., grade cannot be assessed), Grade
1, Grade 2, Grade 3 or Grade 4. In another aspect, a cancer that is
to be treated has been staged according to an AJCC pathologic
classification (pN) of pNX, pN0, PN0 (I-), PN0 (I+), PN0 (mol-),
PN0 (mol+), PN1, PN1(mi), PN1a, PN1b, PN1c, pN2, pN2a, pN2b, pN3,
pN3a, pN3b, or pN3c.
[0109] In one aspect, a cancer that is to be treated includes a
tumor that has been determined to be less than or equal to about 2
centimeters in diameter. In another aspect, a cancer that is to be
treated includes a tumor that has been determined to be from about
2 to about 5 centimeters in diameter. In another aspect, a cancer
that is to be treated includes a tumor that has been determined to
be greater than or equal to about 3 centimeters in diameter. In
another aspect, a cancer that is to be treated includes a tumor
that has been determined to be greater than 5 centimeters in
diameter. In another aspect, a cancer that is to be treated is
classified by microscopic appearance as well differentiated,
moderately differentiated, poorly differentiated, or
undifferentiated. In another aspect, a cancer that is to be treated
is classified by microscopic appearance with respect to mitosis
count (e.g., amount of cell division) or nuclear pleiomorphism
(e.g., change in cells). In another aspect, a cancer that is to be
treated is classified by microscopic appearance as being associated
with areas of necrosis (e.g., areas of dying or degenerating
cells). In one aspect, a cancer that is to be treated is classified
as having an abnormal karyotype, having an abnormal number of
chromosomes, or having one or more chromosomes that are abnormal in
appearance. In one aspect, a cancer that is to be treated is
classified as being aneuploid, triploid, tetraploid, or as having
an altered ploidy. In one aspect, a cancer that is to be treated is
classified as having a chromosomal translocation, or a deletion or
duplication of an entire chromosome, or a region of deletion,
duplication or amplification of a portion of a chromosome.
[0110] In one aspect, a cancer that is to be treated is evaluated
by DNA cytometry, flow cytometry, or image cytometry. In one
aspect, a cancer that is to be treated has been typed as having
10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90% of cells in the
synthesis stage of cell division (e.g., in S phase of cell
division). In one aspect, a cancer that is to be treated has been
typed as having a low S-phase fraction or a high S-phase
fraction.
[0111] As used herein, a "normal cell" is a cell that cannot be
classified as part of a "cell proliferative disorder." In one
aspect a normal cell lacks unregulated or abnormal growth, or both,
that can lead to the development of an unwanted condition or
disease. Preferably, a normal cell possesses normally functioning
cell cycle checkpoint control mechanisms.
[0112] As used herein, "contacting a cell" refers to a condition in
which a compound or other composition of matter is in direct
contact with a cell, or is close enough to induce a desired
biological effect in a cell.
[0113] As used herein, "candidate compound" refers to a compound of
the present invention that has been or will be tested in one or
more in vitro or in vivo biological assays, in order to determine
if that compound is likely to elicit a desired biological or
medical response in a cell, tissue, system, animal or human that is
being sought by a researcher or clinician. In one aspect, a
candidate compound is a compound of formula II; in another aspect,
a candidate compound is a compound of formula I. In a preferred
aspect, the biological or medical response is treatment of cancer.
In another aspect the biological or medical response is treatment
or prevention of a cell proliferative disorder. In one aspect, in
vitro or in vivo biological assays include, but are not limited to,
enzymatic activity assays, electrophoretic mobility shift assays,
reporter gene assays, in vitro cell viability assays.
[0114] As used herein, "monotherapy" refers to administration of a
single active or therapeutic compound to a subject in need thereof.
Preferably, monotherapy will involve administration of a
therapeutically effective amount of an active compound. For
example, cancer monotherapy with
3-{5-[2-({(3R)-1-[(4-chlorophenyl)sulfonyl]piperidin-3-yl}amino)pyrimidin-
-4-yl]imidazo[2,1-b][1,3]thiazol-6-yl}phenol comprises
administration of a therapeutically effective amount of
3-{5-[2-({(3R)-1-[(4-chlorophenyl)sulfonyl]piperidin-3-yl}amino)pyrimidin-
-4-yl]imidazo[2,1-b][1,3]thiazol-6-yl}phenol, or a pharmaceutically
acceptable salt, prodrug, metabolite, analog or derivative thereof,
to a subject in need of treatment of cancer. Monotherapy may be
contrasted with combination therapy, in which a combination of
multiple active compounds is administered, preferably with each
component of the combination present in a therapeutically effective
amount. In one aspect, montherapy with a compound of the present
invention is more effective than combination therapy in inducing a
desired biological effect.
[0115] As used herein, "treating" describes the management and care
of a patient for the purpose of combating a disease, condition, or
disorder and includes the administration of a compound of the
present invention to prevent the onset of the symptoms or
complications, alleviating the symptoms or complications, or
eliminating the disease, condition or disorder.
[0116] In one aspect, treating cancer results in a reduction in
size of a tumor. A reduction in size of a tumor may also be
referred to as "tumor regression." Preferably, after treatment,
tumor size is reduced by 5% or greater relative to its size prior
to treatment; more preferably, tumor size is reduced by 10% or
greater; more preferably, reduced by 20% or greater; more
preferably, reduced by 30% or greater; more preferably, reduced by
40% or greater; even more preferably, reduced by 50% or greater;
and most preferably, reduced by greater than 75% or greater. Size
of a tumor may be measured by any reproducible means of
measurement. In a preferred aspect, size of a tumor may be measured
as a diameter of the tumor.
[0117] In another aspect, treating cancer results in a reduction in
tumor volume. Preferably, after treatment, tumor volume is reduced
by 5% or greater relative to its size prior to treatment; more
preferably, tumor volume is reduced by 10% or greater; more
preferably, reduced by 20% or greater; more preferably, reduced by
30% or greater; more preferably, reduced by 40% or greater; even
more preferably, reduced by 50% or greater; and most preferably,
reduced by greater than 75% or greater. Tumor volume may be
measured by any reproducible means of measurement.
[0118] In another aspect treating cancer results in a decrease in
number of tumors. Preferably, after treatment, tumor number is
reduced by 5% or greater relative to number prior to treatment;
more preferably, tumor number is reduced by 10% or greater; more
preferably, reduced by 20% or greater, more preferably, reduced by
30% or greater; more preferably, reduced by 40% or greater, even
more preferably, reduced by 50% or greater; and most preferably,
reduced by greater than 75%. Number of rumors may be measured by
any reproducible means of measurement. In a preferred aspect,
number of tumors may be measured by counting tumors visible to the
naked eye or at a specified magnification. In a preferred aspect,
the specified magnification is 2.times., 3.times., 4.times.,
5.times., 10.times., or 50.times..
[0119] In another aspect, treating cancer results in a decrease in
number of metastatic lesions in other tissues or organs distant
from the primary tumor site. Preferably, after treatment, the
number of metastatic lesions is reduced by 5% or greater relative
to number prior to treatment; more preferably, the number of
metastatic lesions is reduced by 10% or greater; more preferably,
reduced by 20% or greater; more preferably, reduced by 30% or
greater; more preferably, reduced by 40% or greater; even more
preferably, reduced by 50% or greater; and most preferably, reduced
by greater than 75%. The number of metastatic lesions may be
measured by any reproducible means of measurement. In a preferred
aspect, the number of metastatic lesions may be measured by
counting metastatic lesions visible to the naked eye or at a
specified magnification. In a preferred aspect, the specified
magnification is 2.times., 3.times., 4.times., 5.times., 10.times.,
or 50.times..
[0120] In another aspect, treating cancer results in an increase in
average survival time of a population of treated subjects in
comparison to a population receiving carrier alone. Preferably, the
average survival time is increased by more than 30 days; more
preferably, by more than 60 days; more preferably, by more than 90
days; and most preferably, by more than 120 days. An increase in
average survival time of a population may be measured by any
reproducible means. In a preferred aspect an increase in average
survival time of a population may be measured, for example, by
calculating for a population the average length of survival
following initiation of treatment with an active compound. In
another preferred aspect, an increase in average survival time of a
population may also be measured, for example, by calculating for a
population the average length of survival following completion of a
first round of treatment with an active compound.
[0121] In another aspect, treating cancer results in an increase in
average survival time of a population of treated subjects in
comparison to a population of untreated subjects. Preferably, the
average survival time is increased by more than 30 days; more
preferably, by more than 60 days; more preferably, by more than 90
days; and most preferably, by more than 120 days. An increase in
average survival time of a population may be measured by any
reproducible means. In a preferred aspect, an increase in average
survival time of a population may be measured, for example, by
calculating for a population the average length of survival
following initiation of treatment with an active compound. In
another preferred aspect, an increase in average survival time of a
population may also be measured, for example, by calculating for a
population the average length of survival following completion of a
first round of treatment with an active compound.
[0122] In another aspect, treating cancer results in increase in
average survival time of a population of treated subjects in
comparison to a population receiving monotherapy with a drug that
is not a compound of the present invention, or a pharmaceutically
acceptable salt, prodrug, metabolite, analog or derivative thereof.
Preferably, the average survival time is increased by more than 30
days; more preferably, by more than 60 days; more preferably, by
more than 90 days; and most preferably, by more than 120 days. An
increase in average survival time of a population may be measured
by any reproducible means. In a preferred aspect, an increase in
average survival time of a population may be measured, for example,
by calculating for a population the average length of survival
following initiation of treatment with an active compound. In
another preferred aspect, an increase in average survival time of a
population may also be measured, for example, by calculating for a
population the average length of survival following completion of a
first round of treatment with an active compound.
[0123] In another aspect, treating cancer results in a decrease in
the mortality rate of a population of treated subjects in
comparison to a population receiving carrier alone. In another
aspect, treating cancer results in a decrease in the mortality rate
of a population of treated subjects in comparison to an untreated
population. In a further aspect, treating cancer results a decrease
in the mortality rate of a population of treated subjects in
comparison to a population receiving monotherapy with a drug that
is not a compound of the present invention, or a pharmaceutically
acceptable salt, prodrug, metabolite, analog or derivative thereof.
Preferably, the mortality rate is decreased by more than 2%; more
preferably, by more than 5%; more preferably, by more than 10%; and
most preferably, by more than 25%. In a preferred aspect, a
decrease in the mortality rate of a population of treated subjects
may be measured by any reproducible means. In another preferred
aspect, a decrease in the mortality rate of a population may be
measured, for example, by calculating for a population the average
number of disease-related deaths per unit time following initiation
of treatment with an active compound. In another preferred aspect,
a decrease in the mortality rate of a population may also be
measured; for example, by calculating for a population the average
number of disease-related deaths per unit time following completion
of a first round of treatment with an active compound.
[0124] In another aspect, treating cancer results in a decrease in
tumor growth rate. Preferably, after treatment, tumor growth rate
is reduced by at least 5% relative to number prior to treatment;
more preferably, tumor growth rate is reduced by at least 10%; more
preferably, reduced by at least 20%; more preferably, reduced by at
least 30%; more preferably, reduced by at least 40%; more
preferably, reduced by at least 50%; even more preferably, reduced
by at least 50%; and most preferably, reduced by at least 75%.
Tumor growth rate may be measured by any reproducible means of
measurement. In a preferred aspect, tumor growth rate is measured
according to a change in tumor diameter per unit time.
[0125] In another aspect, treating cancer results in a decrease in
tumor regrowth. Preferably, after treatment, tumor regrowth is less
than 5%; more preferably, tumor regrowth is less than 10%; more
preferably, less than 20%; more preferably, less than 30%; more
preferably, less than 40%; more preferably, less than 50%; even
more preferably, less than 50%; and most preferably, less than 75%.
Tumor regrowth may be measured by any reproducible means of
measurement. In a preferred aspect, tumor regrowth is measured, for
example, by measuring an increase in the diameter of a tumor after
a prior tumor shrinkage that followed treatment. In another
preferred aspect, a decrease in tumor regrowth is indicated by
failure of tumors to reoccur after treatment has stopped.
[0126] In another aspect, treating or preventing a cell
proliferative disorder results in a reduction in the rate of
cellular proliferation. Preferably, after treatment, the rate of
cellular proliferation is reduced by at least 5%; more preferably,
by at least 10%; more preferably, by at least 20%; more preferably,
by at least 30%; more preferably, by at least 40%; more preferably,
by at least 50%; even more preferably, by it least 50%; and most
preferably, by at least 75%. The rate of cellular proliferation may
be measured by any reproducible means of measurement. In a
preferred aspect, the rate of cellular proliferation is measured,
for example, by measuring the number of dividing cells in a tissue
sample per unit time.
[0127] In another aspect, treating or preventing a cell
proliferative disorder results in a reduction in the proportion of
proliferating cells. Preferably, after treatment, the proportion of
proliferating cells is reduced by at least 5%; more preferably, by
at least 10%; more preferably, by at least 20%; more preferably, by
at least 30%; more preferably, by at least 40%; more preferably, by
at least 50%; even more preferably, by at least 50%; and most
preferably, by at least 75%. The proportion of proliferating cells
may be measured by any reproducible means of measurement. In a
preferred aspect, the proportion of proliferating cells is
measured, for example, by quantifying the number of dividing cells
relative to the number of nondividing cells in a tissue sample. In
another preferred aspect, the proportion of proliferating cells is
equivalent to the mitotic index.
[0128] In another aspect, treating or preventing a cell
proliferative disorder results in a decrease in size of an area or
zone of cellular proliferation. Preferably, after treatment, size
of an area or zone of cellular proliferation is reduced by at least
5% relative to its size prior to treatment; more preferably,
reduced by at least 10%; more preferably, reduced by at least 20%;
more preferably, reduced by at least 30%; more preferably, reduced
by at least 40%; more preferably, reduced by at least 50%; even
more preferably, reduced by at least 50%; and most preferably,
reduced by at least 75%. Size of an area or zone of cellular
proliferation may be measured by any reproducible means of
measurement. In a preferred aspect, size of an area or zone of
cellular proliferation may be measured as a diameter or width of an
area or zone of cellular proliferation.
[0129] In another aspect, treating or preventing a cell
proliferative disorder results in a decrease in the number or
proportion of cells having an abnormal appearance or morphology.
Preferably, after treatment, the number of cells having an abnormal
morphology is reduced by at least 5% relative to its size prior to
treatment; more preferably, reduced by at least 10%; more
preferably, reduced by at least 20%; more preferably, reduced by at
least 30%; more preferably, reduced by at least 40%; more
preferably, reduced by at least 50%; even more preferably, reduced
by at least 50%; and most preferably, reduced by at least 75%. An
abnormal cellular appearance or morphology may be measured by any
reproducible means of measurement. In one aspect, an abnormal
cellular morphology is measured by microscopy, e.g., using an
inverted tissue culture microscope. In one aspect, an abnormal
cellular morphology takes the form of nuclear pleiomorphism.
[0130] As used herein, the term "selectively" means tending to
occur at a higher frequency in one population than in another
population. In one aspect, the compared populations are cell
populations. In a preferred aspect, a compound of the present
invention, or a pharmaceutically acceptable salt, prodrug,
metabolite, analog or derivative thereof, acts selectively on a
cancer or precancerous cell but not on a normal cell. In another
preferred aspect, a compound of the present invention, or a
pharmaceutically acceptable salt, prodrug, metabolite, analog or
derivative thereof, acts selectively to modulate one molecular
target (e.g., B-RAF). In another preferred aspect, the invention
provides a method for selectively inhibiting the activity of an
enzyme, such as a kinase. Preferably, an event occurs selectively
in population A relative to population B if it occurs greater than
two times more frequently in population A as compared to population
B. More preferably, an event occurs selectively if it occurs
greater than five times more frequently in population A. More
preferably, an event occurs selectively if it occurs greater than
ten times more frequently in population A; more preferably, greater
than fifty times; even more preferably, greater than 100 times; and
most preferably, greater than 1000 times more frequently in
population A as compared to population B. For example, cell death
would be said to occur selectively in cancer cells if it occurred
greater than twice as frequently in cancer cells as compared to
normal cells.
[0131] In a preferred aspect, a compound of the present invention
or a pharmaceutically acceptable salt, prodrug, metabolite, analog
or derivative thereof, modulates the activity of a molecular target
(e.g., B-RAF). In one aspect, modulating refers to stimulating or
inhibiting an activity of a molecular target. Preferably, a
compound of the present invention modulates the activity of a
molecular target if it stimulates or inhibits the activity of the
molecular target by at least 2-fold relative to the activity of the
molecular target under the same conditions but lacking only the
presence of said compound. More preferably, a compound of the
present invention modulates the activity of a molecular target if
it stimulates or inhibits the activity of the molecular target by
at least 5-fold, at least 10-fold, at least 20-fold, at least
50-fold, at least 100-fold relative to the activity of the
molecular target under the same conditions but lacking only the
presence of said compound. The activity of a molecular target may
be measured by any reproducible means. The activity of a molecular
target may be measured in vitro or in vivo. For example, the
activity of a molecular target may be measured in vitro by an
enzymatic activity assay or a DNA binding assay, or the activity of
a molecular target may be measured in vivo by assaying for
expression of a reporter gene.
[0132] In one aspect, a compound of the present invention, or a
pharmaceutically acceptable salt, prodrug, metabolite, analog or
derivative thereof, does not significantly modulate the activity of
a molecular target if the addition of the compound does not
stimulate or inhibit the activity of the molecular target by
greater than 10% relative to the activity of the molecular target
under the same conditions but lacking only the presence of said
compound.
[0133] As used herein, the term "isozyme selective" means
preferential inhibition or stimulation of a first isoform of an
enzyme in comparison to a second isoform of an enzyme (e.g.,
preferential inhibition or stimulation of a kinase isozyme alpha in
comparison to a kinase isozyme beta). Preferably, a compound of the
present invention demonstrates a minimum of a four-fold
differential, preferably a ten fold differential, more preferably a
fifty fold differential, in the dosage required to achieve a
biological effect. Preferably, a compound of the present invention
demonstrates this differential across the range of inhibition, and
the differential is exemplified at the IC.sub.50, i.e., a 50%
inhibition, for a molecular target of interest.
[0134] In a preferred embodiment, administering a compound of the
present invention, or a pharmaceutically acceptable salt, prodrug,
metabolite, analog or derivative thereof, to a cell or a subject in
need thereof results in modulation (i.e., stimulation or
inhibition) of an activity of RAF. As used herein, an activity of
RAF refers to any biological function or activity that is carried
out by RAF. For example, a function of RAF includes phosphorylation
of downstream target proteins.
[0135] In a preferred embodiment, administering a compound of the
present invention, or a pharmaceutically acceptable salt, prodrug,
metabolite, analog or derivative thereof, to a cell or a subject in
need thereof results in modulation (i.e., stimulation or
inhibition) of an activity of ERK 1 or ERK 2, or both. As used
herein, an activity of ERK 1 or ERK 2 refers to any biological
function or activity that is carried out by ERK 1 or ERK 2. For
example, a function of ERK 1 or ERK 2 includes phosphorylation of
downstream target proteins.
[0136] In one aspect, activating refers to placing a composition of
matter (e.g., protein or nucleic acid) in a state suitable for
carrying out a desired biological function. In one aspect, a
composition of matter capable of being activated also has an
unactivated state. In one aspect, an activated composition of
matter may have an inhibitory or stimulatory biological function,
or both.
[0137] In one aspect, elevation refers to an increase in a desired
biological activity of a composition of matter (e.g., a protein or
a nucleic acid). In one aspect, elevation may occur through an
increase in concentration of a composition of matter.
[0138] As used herein, "a cell cycle checkpoint pathway" refers to
a biochemical pathway that is involved in modulation of a cell
cycle checkpoint. A cell cycle checkpoint pathway may have
stimulatory or inhibitory effects, or both, on one or more
functions comprising a cell cycle checkpoint. A cell cycle
checkpoint pathway is comprised of at least two compositions of
matter, preferably proteins, both of which contribute to modulation
of a cell cycle checkpoint. A cell cycle checkpoint pathway may be
activated through an activation of one or more members of the cell
cycle checkpoint pathway. Preferably, a cell cycle checkpoint
pathway is a biochemical signaling pathway.
[0139] As used herein, "cell cycle checkpoint regulator" refers to
a composition of matter that can function, at least in part, in
modulation of a cell cycle checkpoint. A cell cycle checkpoint
regulator may have stimulatory or inhibitory effects, or both, on
one or more functions comprising a cell cycle checkpoint. In one
aspect, a cell cycle checkpoint regulator is a protein. In another
aspect, a cell cycle checkpoint regulator is not a protein.
[0140] In one aspect, treating cancer or a cell proliferative
disorder results in cell death, and preferably, cell death results
in a decrease of at least 10% in number of cells in a population.
More preferably, cell death means a decrease of at least 20%; more
preferably, a decrease of at least 30%; more preferably, a decrease
of at least 40%; more preferably, a decrease of at least 50%; most
preferably, a decrease of at least 75%. Number of cells in a
population may be measured by any reproducible means. In one
aspect, number of cells in a population is measured by fluorescence
activated cell sorting (FACS). In another aspect, number of cells
in a population is measured by immunofluorescence microscopy. In
another aspect, number of cells in a population is measured by
light microscopy. In another aspect, methods of measuring cell
death are as shown in Li et al, (2003) Proc Natl Acad Sci USA.
100(5): 2674-8. In an aspect, cell death occurs by apoptosis.
[0141] In a preferred aspect, an effective amount of a compound of
the present invention, or a pharmaceutically acceptable salt,
prodrug, metabolite, analog or derivative thereof is not
significantly cytotoxic to normal cells. A therapeutically
effective amount of a compound is not significantly cytotoxic to
normal cells if administration of the compound in a therapeutically
effective amount does not induce cell death in greater than 10% of
normal cells. A therapeutically effective amount of a compound does
not significantly affect the viability of normal cells if
administration of the compound in a therapeutically effective
amount does not induce cell death in greater than 10% of normal
cells. In an aspect, cell death occurs by apoptosis.
[0142] In one aspect, contacting a cell with a compound of the
present invention, or a pharmaceutically acceptable salt, prodrug,
metabolite, analog or derivative thereof, induces or activates cell
death selectively in cancer cells. Preferably, administering to a
subject in need thereof a compound of the present invention, or a
pharmaceutically acceptable salt, prodrug, metabolite, analog or
derivative thereof, induces or activates cell death selectively in
cancer cells. In another aspect, contacting a cell with a compound
of the present invention, or a pharmaceutically acceptable salt,
prodrug, metabolite, analog or derivative thereof, induces cell
death selectively in one or more cells affected by a cell
proliferative disorder. Preferably, administering to a subject in
need thereof a compound of the present invention, or a
pharmaceutically acceptable salt, prodrug, metabolite, analog or
derivative thereof, induces cell death selectively in one or more
cells affected by a cell proliferative disorder. In a preferred
aspect, the present invention relates to a method of treating or
preventing cancer by administering a compound of the present
invention, or a pharmaceutically acceptable salt, prodrug,
metabolite, analog or derivative thereof to a subject in need
thereof, where administration of the compound of the present
invention, or a pharmaceutically acceptable salt, prodrug,
metabolite, analog or derivative thereof results in one or more of
the following: accumulation of cells in G1 and/or S phase of the
cell cycle, cytotoxicity via cell death in cancer cells without a
significant amount of cell death in normal cells, antitumor
activity in animals with a therapeutic index of at least 2, and
activation of a cell cycle checkpoint. As used herein, "therapeutic
index" is the maximum tolerated dose divided by the efficacious
dose.
[0143] One skilled in the art may refer to general reference texts
for detailed descriptions of known techniques discussed herein or
equivalent techniques. These texts include Ausubel et al., Current
Protocols in Molecular Biology, John Wiley and Sons, Inc. (2005);
Sambrook et al., Molecular Cloning, A Laboratory Manual (3d ed.),
Cold Spring Harbor Press, Cold Spring Harbor, N.Y. (2000); Coligan
et al, Current Protocols in Immunology, John Wiley & Sons,
N.Y.; Enna et al, Current Protocols in Pharmacology, John Wiley
& Sons, N.Y.; Fingl et al, The Pharmacological Basis of
Therapeutics (1975), Remington's Pharmaceutical Sciences, Mack
Publishing Co., Easton, Pa., 18th edition (1990). These texts can,
of course, also be referred to in making or using an aspect of the
invention.
[0144] In additional aspects, a compound of the present invention,
or a pharmaceutically acceptable salt, prodrug, metabolite, analog
or derivative thereof, may be administered in combination with a
second chemotherapeutic agent. The second chemotherapeutic agent
can be a taxane, an aromatase inhibitor, an anthracycline, a
microtubule targeting drug, a topoisomerase poison drug, a targeted
monoclonal or polyconal antibody, an inhibitor of a molecular
target or enzyme (e.g., a kinase inhibitor), or a cytidine analogue
drug. In preferred aspects, the chemotherapeutic agent can be, but
not restricted to, tamoxifen, raloxifene, anastrozole, exemestane,
letrozole, HERCEPTIN.RTM. (trastuzumab), GLEEVEC.RTM. (imatanib),
TAXOL.RTM. (paclitaxel), cyclophosphamide, lovastatin, minosine,
araC, 5-fluorouracil (5-FU), methotrexate (MTX), TAXOTERE.RTM.
(docetaxel), ZOLADEX.RTM. (goserelin), vincristin, vinblastin,
nocodazole, teniposide, etoposide, GEMZAR.RTM. (gemcitabine),
epothilone, navelbine, camptothecin, daunonibicin, dactinomycin,
mitoxantrone, amsacrine, doxorubicin (adriamycin), epirubicin or
idarubicin or agents listed in
www.cancerorg/docroot/cdg/cdg.sub.--0.asp. In another aspect, the
second chemotherapeutic agent can be a cytokine such as G-CSF
(granulocyte colony stimulating factor). In another aspect, a
compound of the present invention, or a pharmaceutically acceptable
salt, prodrug, metabolite, analog or derivative thereof, may be
administered in combination with radiation therapy. In yet another
aspect, a compound of the present invention, or a pharmaceutically
acceptable salt, prodrug, metabolite, analog or derivative thereof,
may be administered in combination with standard chemotherapy
combinations such as, but not restricted to, CMF (cyclophosphamide,
methotrexate and 5-fluorouracil), CAF (cyclophosphamide, adriamycin
and 5-fluorouracil), AC (adriamycin and cyclophosphamide), FEC
(5-fluorouracil, epirubicin, and cyclophosphamide), ACT or ATC
(adriamycin, cyclophosphamide, and paclitaxel), or CMFP
(cyclophosphamide, methotrexate, 5-fluorouracil and
prednisone).
[0145] A compound of the present invention, or a pharmaceutically
acceptable salt, prodrug, metabolite, analog or derivative thereof,
can be incorporated into pharmaceutical compositions suitable for
administration. Such compositions typically comprise the compound
(i.e. including the active compound), and a pharmaceutically
acceptable excipient or carrier. As used herein, "pharmaceutically
acceptable excipient" or "pharmaceutically acceptable carrier" is
intended to include any and all solvents, dispersion media,
coatings, antibacterial and antifungal agents, isotonic and
absorption delaying agents, and the like, compatible with
pharmaceutical administration. Suitable carriers are described in
the most recent edition of Remington's Pharmaceutical Sciences, a
standard reference text in the field. Preferred examples of such
carriers or diluents include, but are not limited to, water,
saline, ringer's solutions, dextrose solution, and 5% human serum
albumin. Pharmaceutically acceptable carriers include solid
carriers such as lactose, terra alba, sucrose, talc, gelatin, agar,
pectin, acacia, magnesium stearate, stearic acid and the like.
Exemplary liquid carriers include syrup, peanut oil, olive oil,
water and the like. Similarly, the carrier or diluent may include
time-delay material known in the art, such as glyceryl monostearate
or glyceryl distearate, alone or with a wax, ethylcellulose,
hydroxypropylmethylcellulose, methylmethacrylate or the like. Other
fillers, excipients, flavorants, and other additives such as are
known in the art may also be included in a pharmaceutical
composition according to this invention. Liposomes and non-aqueous
vehicles such as fixed oils may also be used. The use of such media
and agents for pharmaceutically active substances is well known in
the art. Except insofar as any conventional media or agent is
incompatible with the active compound, use thereof in the
compositions is contemplated. Supplementary active compounds can
also be incorporated into the compositions.
[0146] In one aspect, a compound of the present invention, or a
pharmaceutically acceptable salt, prodrug, metabolite, analog or
derivative thereof, is administered in a suitable dosage form
prepared by combining a therapeutically effective amount (e.g., an
efficacious level sufficient to achieve the desired therapeutic
effect through inhibition of tumor growth, killing of tumor cells,
treatment or prevention of cell proliferative disorders, etc.) of a
compound of the present invention, or a pharmaceutically acceptable
salt, prodrug, metabolite, analog or derivative thereof, (as an
active ingredient) with standard pharmaceutical carriers or
diluents according to conventional procedures (i.e., by producing a
pharmaceutical composition of the invention). These procedures may
involve mixing, granulating, and compressing or dissolving the
ingredients as appropriate to attain the desired preparation.
4. The Pharmaceutical Compositions and Formulations
[0147] A pharmaceutical composition of the invention is formulated
to be compatible with its intended route of administration.
Examples of routes of administration include parenteral, e.g.,
intravenous, intradermal, subcutaneous, oral (e.g., inhalation),
transdermal (topical), and transmucosal administration. Solutions
or suspensions used for parenteral, intradermal, or subcutaneous
application can include the following components: a sterile diluent
such as water for injection, saline solution, fixed oils,
polyethylene glycols, glycerine, propylene glycol or other
synthetic solvents; antibacterial agents such as benzyl alcohol or
methyl parabens; antioxidants such as ascorbic acid or sodium
bisulfite; chelating agents such as ethylenediaminetetraacetic
acid; buffers such as acetates, citrates or phosphates, and agents
for the adjustment of tonicity such as sodium chloride or dextrose.
The pH can be adjusted with acids or bases, such as hydrochloric
acid or sodium hydroxide. The parenteral preparation can be
enclosed in ampoules, disposable syringes or multiple dose vials
made of glass or plastic.
[0148] A compound or pharmaceutical composition of the invention
can be administered to a subject in many of the well-known methods
currently used for chemotherapeutic treatment. For example, for
treatment of cancers, a compound of the invention may be injected
directly into tumors, injected into the blood stream or body
cavities or taken orally or applied through the skin with patches.
The dose chosen should be sufficient to constitute effective
treatment but not so high as to cause unacceptable side effects.
The state of the disease condition (e.g., cancer, precancer, and
the like) and the health of the patient should preferably be
closely monitored during and for a reasonable period after
treatment.
[0149] The term "therapeutically effective amount," as used herein,
refers to an amount of a pharmaceutical agent to treat, ameliorate,
or prevent an identified disease or condition, or to exhibit a
detectable therapeutic or inhibitory effect. The effect can be
detected by any assay method known in the art. The precise
effective amount for a subject will depend upon the subject's body
weight, size, and health; the nature and extent of the condition;
and the therapeutic or combination of therapeutics selected for
administration. Therapeutically effective amounts for a given
situation can be determined by routine experimentation that is
within the skill and judgment of the clinician. In a preferred
aspect, the disease or condition to be treated is cancer. In
another aspect, the disease or condition to be treated is a cell
proliferative disorder.
[0150] For any compound, the therapeutically effective amount can
be estimated initially either in cell culture assays, e.g., of
neoplastic cells, or in animal models, usually rats, mice, rabbits,
dogs, or pigs. The animal model may also be used to determine the
appropriate concentration range and route of administration. Such
information can then be used to determine useful doses and routes
for administration in humans. Therapeutic/prophylactic efficacy and
toxicity may be determined by standard pharmaceutical procedures in
cell cultures or experimental animals, e.g., ED.sub.50 (the dose
therapeutically effective in 50% of the population) and LD.sub.50
(the dose lethal to 50% of the population). The dose ratio between
toxic and therapeutic effects is the therapeutic index, and it can
be expressed as the ratio, LD.sub.50/ED.sub.50. Pharmaceutical
compositions that exhibit large therapeutic indices are preferred.
The dosage may vary within this range depending upon the dosage
form employed, sensitivity of the patient and the route of
administration.
[0151] Dosage and administration are adjusted to provide sufficient
levels of the active agent(s) or to maintain the desired effect.
Factors which may be taken into account include the severity of the
disease state, general health of the subject, age, weight, and
gender of the subject, diet, time and frequency of administration,
drug combination(s), reaction sensitivities, and tolerance/response
to therapy. Long-acting pharmaceutical compositions may be
administered every 3 to 4 days, every week, or once every two weeks
depending on half-life and clearance rate of the particular
formulation.
[0152] The pharmaceutical compositions containing active compounds
of the present invention may be manufactured in a manner that is
generally known, e.g., by means of conventional mixing, dissolving,
granulating, dragee-making, levigating, emulsifying, encapsulating,
entrapping, or lyophilizing processes. Pharmaceutical compositions
may be formulated in a conventional manner using one or more
pharmaceutically acceptable carriers comprising excipients and/or
auxiliaries that facilitate processing of the active compounds into
preparations that can be used pharmaceutically. Of course, the
appropriate formulation is dependent upon the route of
administration chosen.
[0153] Pharmaceutical compositions suitable for injectable use
include sterile aqueous solutions (where water soluble) or
dispersions and sterile powders for the extemporaneous preparation
of sterile injectable solutions or dispersion. For intravenous
administration, suitable carriers include physiological saline,
bacteriostatic water, Cremophor EL.TM. (BASF, Parsippany, N.J.) or
phosphate buffered saline (PBS). In all cases, the composition must
be sterile and should be fluid to the extent that easy
syringeability exists. It must be stable under the conditions of
manufacture and storage and must be preserved against the
contaminating action of microorganisms such as bacteria and fungi.
The carrier can be a solvent or dispersion medium containing, for
example, water, ethanol, polyol (for example, glycerol, propylene
glycol, and liquid polyethylene glycol, and the like), and suitable
mixtures thereof. The proper fluidity can 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 dispersion
and by the use of surfactants. Prevention of the action of
microorganisms can be achieved by various antibacterial and
antifungal agents, for example, parabens, chlorobutanol, phenol,
ascorbic acid, thimerosal, and the like. In many cases, it will be
preferable to include isotonic agents, for example, sugars,
polyalcohols such as manitol, sorbitol, sodium chloride in the
composition. Prolonged absorption of the injectable compositions
can be brought about by including in the composition an agent which
delays absorption, for example, aluminum monostearate and
gelatin.
[0154] Sterile injectable solutions can be prepared by
incorporating the active compound in the required amount in an
appropriate solvent with one or a combination of ingredients
enumerated above, as required, followed by filtered sterilization.
Generally, dispersions are prepared by incorporating the active
compound into a sterile vehicle that contains a basic dispersion
medium and the required other ingredients from those enumerated
above. In the case of sterile powders for the preparation of
sterile injectable solutions, methods of preparation are vacuum
drying and freeze-drying that yields a powder of the active
ingredient plus any additional desired ingredient from a previously
sterile-filtered solution thereof.
[0155] Oral compositions generally include an inert diluent or an
edible pharmaceutically acceptable carrier. They can be enclosed in
gelatin capsules or compressed into tablets. For the purpose of
oral therapeutic administration, the active compound can be
incorporated with excipients and used in the form of tablets,
troches, or capsules. Oral compositions can also be prepared using
a fluid carrier for use as a mouthwash, wherein the compound in the
fluid carrier is applied orally and swished and expectorated or
swallowed. Pharmaceutically compatible binding agents, and/or
adjuvant materials can be included as part of the composition. The
tablets, pills, capsules, troches and the like can contain any of
the following ingredients, or compounds of a similar nature: a
binder such as microcrystalline cellulose, gum tragacanth or
gelatin; an excipient such as starch or lactose, a disintegrating
agent such as alginic acid, Primogel, or corn starch; a lubricant
such as magnesium stearate or Sterotes; a glidant such as colloidal
silicon dioxide; a sweetening agent such as sucrose or saccharin;
or a flavoring agent such as peppermint, methyl salicylate, or
orange flavoring.
[0156] For administration by inhalation, the compounds are
delivered in the form of an aerosol spray from pressured container
or dispenser, which contains a suitable propellant, e.g., a gas
such as carbon dioxide, or a nebulizer.
[0157] Systemic administration can also be by transmucosal or
transdermal means. For transmucosal or transdermal administration,
penetrants appropriate to the barrier to be permeated are used in
the formulation. Such penetrants are generally known in the art,
and include, for example, for transmucosal administration,
detergents, bile salts, and fusidic acid derivatives. Transmucosal
administration can be accomplished through the use of nasal sprays
or suppositories. For transdermal administration, the active
compounds are formulated into ointments, salves, gels, or creams as
generally known in the art.
[0158] In one aspect, the active compounds are prepared with
pharmaceutically acceptable carriers that will protect the compound
against rapid elimination from the body, such as a controlled
release formulation, including implants and microencapsulated
delivery systems. Biodegradable, biocompatible polymers can be
used, such as ethylene vinyl acetate, polyanhydrides, polyglycolic
acid, collagen, polyorthoesters, and polylactic acid. Methods for
preparation of such formulations will be apparent to those skilled
in the art. The materials can also be obtained commercially from
Alza Corporation and Nova Pharmaceuticals, Inc. Liposomal
suspensions (including liposomes targeted to infected cells with
monoclonal antibodies to viral antigens) can also be used as
pharmaceutically acceptable carriers. These can be prepared
according to methods known to those skilled in the art for example,
as described in U.S. Pat. No. 4,522,811.
[0159] It is especially advantageous to formulate oral or
parenteral compositions in dosage unit form for ease of
administration and uniformity of dosage. Dosage unit form as used
herein refers to physically discrete units suited as unitary
dosages for the subject to be treated; each unit containing a
predetermined quantity of active compound calculated to produce the
desired therapeutic effect in association with the required
pharmaceutical carrier. The specification for the dosage unit forms
of the invention are dictated by and directly dependent on the
unique characteristics of the active compound and the particular
therapeutic effect to be achieved.
[0160] In therapeutic applications, the dosages of the
pharmaceutical compositions used in accordance with the invention
vary depending on the agent, the age, weight, and clinical
condition of the recipient patient, and the experience and judgment
of the clinician or practitioner administering the therapy, among
other factors affecting the selected dosage. Generally, the dose
should be sufficient to result in slowing, and preferably
regressing, the growth of the tumors and also preferably causing
complete regression of the cancer. Dosages can range from about
0.01 mg/kg per day to about 3000 mg/kg per day. In preferred
aspects, dosages can range from about 1 mg/kg per day to about 1000
mg/kg per day. In an aspect, the dose will be in the range of about
0.1 mg/day to about 50 g/day; about 0.1 mg/day to about 25 g/day;
about 0.1 mg/day to about 10 g/day; about 0.1 mg to about 3 g/day;
or about 0.1 mg to about 1 g/day, in single, divided, or continuous
doses (which dose may be adjusted for the patient's weight in kg,
body surface area in m.sup.2, and age in years). An effective
amount of a pharmaceutical agent is that which provides an
objectively identifiable improvement as noted by the clinician or
other qualified observer. For example, regression of a tumor in a
patient may be measured with reference to the diameter of a tumor.
Decrease in the diameter of a tumor indicates regression.
Regression is also indicated by failure of tumors to reoccur after
treatment has stopped. As used herein, the term "dosage effective
manner" refers to amount of an active compound to produce the
desired biological effect in a subject or cell.
[0161] The pharmaceutical compositions can be included in a
container, pack, or dispenser together with instructions for
administration.
[0162] All patents, patent applications and references cited herein
are incorporated by reference herein in their entirety.
EXAMPLES
[0163] Examples are provided below to further illustrate different
features of the present invention. The examples also illustrate
useful methodology for practicing the invention. These examples do
not limit the claimed invention.
Example 1
Preparation of
3-{5-[2-({(3R)-1-[(4-chlorophenyl)sulfonyl]piperidin-3yl}amino)pyrimidin--
4-yl]imidazo[2,1-b][1,3]thiazol-6-yl}phenol
1a: Preparation of 6-(3-methoxyphenyl)-imidazo[2,1-b]thiazole
##STR00005##
[0165] To a mixture of 2-aminothiazole (2.7 g, 26.7 mmol) and
2-bromo-3'-methoxyacetophenone (6.0 g, 0.0262 mol) was added
absolute ethanol (100 ml). The reaction was allowed to reflux with
vigorous stirring for 18 hours (checked by HPLC). The reaction
mixture was reduced to half its original volume in vacuo. The
remaining liquid was poured onto ice and the solution made basic by
the addition of ammonium hydroxide solution (30%). The resulting
fine solid was filtered and washed with water resulting in a dark
yellow solid product. The solid product was dried in a vacuum oven
at 50.degree. C. to provide
6-(3-methoxyphenyl)-imidazo[2,1-b]thiazole (5.0 g, 81%). 400 MHz
.sup.1H NMR (DMSO-d.sub.6) .delta. 8.18 (s, 1H), 7.88 (d, J=4.4 Hz,
1H), 7.36-7.42 (m, 2H), 7.28 (t, J=8.1 Hz, 1H), 7.22 (d, J=4.4 Hz,
1H), 6.82 (ddd, J=8.1, 2.6, 1.1 Hz, 1H), 3.80 (s, 3H). LCMS: 231
[M+H].
1b: Preparation of
1-[6-(3-methoxyphenyl)imidazo[2,1-b][1,3]thiazol-5-yl]ethanone
##STR00006##
[0167] To a mixture of 6-(3-methoxyphenyl)-imidazo[2,1-b]thiazole
(14.3 g, 62 mmol) and acetic anhydride (250 ml) was added 1 ml of
concentrated sulfuric acid. The reaction mixture was heated at
140.degree. C. for 4 hours. The reaction mixture was then poured
onto 500 ml of ice, and diluted with 500 ml of water and the
resulting mixture was extracted three times with 300 ml each of
ethyl acetate. The combined extracts were washed with three
portions of 100 ml of water and one portion of 200 ml of saturated
aqueous sodium chloride solution. The organic phase was dried with
magnesium sulfate, filtered and concentrated in vacuo, to give a
brown oil (17.95 g). The product,
-[6-(3-methoxyphenyl)imidazo[2,1-b][1,3]thiazol-5-yl]ethanone, was
used directly in the next step. 400 MHz .sup.1H NMR (DMSO-d.sub.6)
.delta. 8.43 (d, J=4.4 Hz, 1H), 7.55 (d, J=4.4 Hz, 1H), 7.42 (t,
J=8.2 Hz, 1H), 7.16-7.2 (m, 2H), 7.04-7.1 (m, 1H), 3.81 (s, 3H),
2.13 (s, 3H). LCMS: 273 [M+H].
1c: Preparation of
3-(dimethylamino)-1-[6-(3-methoxyphenyl)imidazo[2,1-b][1,3]thiazol-5-yl]p-
rop-2-en-1-one
##STR00007##
[0169] A 100 ml round bottom flask was charged with the
1-[6-(3-methoxyphenyl)imidazo[2,1-b][1,3]thiazol-5-yl]ethanone
(17.95 g, 62 mmol) and dimethylformamide dimethylacetal (120 ml).
The mixture was refluxed for 72 hours and then cooled to room
temperature. The mixture was concentrated in vacuo and the residue
was purified by flash chromatography (ethyl acetate), giving a pale
yellow solid (16.82 g). 300 MHz .sup.1H NMR (DMSO-d.sub.6) .delta.:
8.40 (d, J=4.4 Hz, 1H), 7.59 (d, J=12.5 Hz, 1H), 7.41 (d, J=4.4 Hz,
1H), 7.37 (t, J=7.7 Hz, 1H), 7.17-7.21 (m, 2H), 6.99-7.03 (m, 1H),
5.15 (d, J=12.5 Hz, 1H), 3.79 (s, 3H), 3.04 (s, 3H), 2.44 (s,
3H).
1d: Preparation of tert-butyl
(3R)-3-{[(Z)-amino(imino)methyl]amino}piperidine-1-carboxylate
hydrochloride
##STR00008##
[0171] To a mixture of tert-butyl
(3R)-3-aminopiperidine-1-carboxylate (10 g, 49.9 mmol) and pyrazole
carboxamidine hydrochloride (7.31 g, 49.9 mmol) was added Hunig's
base (8.72 ml, 49.9 mmol) and DMF (30 ml). The reaction was heated
at 70.degree. C. for 18 hours. The reaction was then cooled to room
temperature and quenched by adding 700 ml of diethyl ether and
stirring at room temperature for 24 hours. Product separated out as
a white solid, which was filtered, washed, and dried (13 g, 94%).
400 MHz .sup.1H NMR (DMSO-d.sub.6) .delta.: 7.67 (d, J=8.8 HZ, 1H),
6.9-7.6 (br. s, 4H), 3.55 (br.s, 2H), 2.8-3.6 (m, 4H), 2.8-2.9 (m,
1H), 1.6-1.7 (m, 1H), 1.39 (s, 9H), 1.2-1.3 (m, 1H). LCMS: 243
[M+H].
1e: Preparation of tert-butyl
(3R)-3-({4-[6-(3-methoxyphenyl)imidazo[2,1-b][1,3]thiazol-5-yl]pyrimidin--
2-yl}amino)piperidine-1-carboxylate
##STR00009##
[0173] A mixture of
3-(dimethylamino)-1-[6-(3-methoxyphenyl)imidazo[2,1-b][1,3]thiazol-5-yl]p-
rop-2-en-1-one (5.0 g, 15.3 mmol) and tert-butyl
(3R)-3-{[(Z)-amino(imino)methyl]amino}piperidine-1-carboxylate
hydrochloride (5.28 g, 18.95 mmol) was diluted with 60 ml of
absolute ethanol and treated with 1.15 eq. of a 21% w/w solution of
sodium ethoxide in ethanol (6.56 ml) to form a reaction mixture.
The reaction mixture was heated to reflux for 24 hours. Volatiles
were removed in vacuo and the residue was taken up in 250 ml of
ethyl acetate and 250 ml of water. The phases were separated and
the aqueous phase was extracted with 250 ml of ethyl acetate. The
combined organic extracts were washed with 250 ml each of water,
and then with a saturated sodium chloride solution (250 ml). The
organic phase was dried with magnesium sulfate, filtered and
concentrated in vacuo, to give a yellow oil. The product was
purified by flash chromatography on silica gel (ethyl
acetate/hexanes, 50%) to yield 7.2 g of a pale yellow solid (93%).
300 MHz .sup.1H NMR (DMSO-d.sub.6 at 80.degree. C.) .delta.: 8.69
(d, J=3.5 Hz, 1H), 8.10 (d, J=5.3 Hz, 1H), 7.32-7.41 (m, 2H),
7.12-7.18 (m, 2H), 6.91-7.02 (m, 2H), 6.41 (d, J=5.3 Hz, 1H), 3.94
(br. d, J=7.0, 1H), 3.74-3.88 (m, 1H), 3.78 (s, 3H), 3.67 (br. d,
J=13.2, 1H), 2.86-3.02 (m, 2H), 1.90-2.06 (m, 1H), 1.70-1.84 (m,
1H), 1.38-1.64 (m, 2H), 1.34 (s, 9H). LCMS: 507 [M+H].
1f: Preparation of
4-[6-(3-methoxyphenyl)imidazo[2,1-b][1,3]thiazol-5-yl]-N-[(3R)-piperidin--
3-yl]pyrimidin-2-amine hydrochloride
##STR00010##
[0175] The tert-butyl
(3R)-3-({4-[6-(3-methoxyphenyl)imidazo[2,1-b][1,3]thiazol-5-yl]pyrimidin--
2-yl}amino)piperidine-1-carboxylate (21 g, 41.5 mmol) was dissolved
in 250 ml of dioxane and treated with 75 ml of anhydrous a four
molar HCl in dioxane at room temperature. The reaction mixture was
stirred at room temperature for three hours. The mixture was then
diluted with 350 ml of ether and stirred until product separated as
a solid. Solid product was filtered and washed with ether. The
solid was dissolved in MeOH (200 ml) and concentrated to dryness
(this was done twice). The product was dried at high vacuum to
yield 20.275 g of yellow solid (tris HCl salt) (90%).
M.p.=220-225.degree. C.; 300 MHz .sup.1H NMR (DMSO-d.sub.6 at
80.degree. C.) .delta.: 9.6-9.3 (br. s, 2H), 8.9-8.4 (br. s, 2H),
8.82 (s, 1H), 8.11 (d, J=5.8 Hz, 1H), 7.50 (d, J=4.7 Hz, 1H), 7.39
(t, J=7.98 Hz, 1H), 7.2-7.1 (m, 2H), 7.08-7.0 (m, 1H), 6.49 (d,
J=5.8 Hz, 1H), 4.4-4.3 (m, 1H), 3.79 (s, 3H), 3.39 (d, J=10.2 Hz,
1H), 3.16 (br. s, 1H), 3.05-2.7 (m, 2H), 2.2-1.6 (m, 3H), 1.55-1.2
(m, 1H). LCMS: 407 [M+H]; calc. for C.sub.21H.sub.22N.sub.6OS 3.3
HCl 0.05 dioxane 0.3 methanol: C, 47.75; H, 5.01; N, 15.54. found
C, 47.73; H, 5.26; N, 15.55.
1g: Preparation of
N-{(3R)-1-[(4-chlorophenyl)sulfonyl]piperidin-3-yl}-4-[6-(3-methoxyphenyl-
)imidazo[2,1-b][1,3]thiazol-5-yl]pyrimidin-2-amine
##STR00011##
[0177] The
4-[6-(3-methoxyphenyl)imidazo[2,1-b][1,3]thiazol-5-yl]-N-[(3R)--
piperidin-3-yl]pyrimidin-2-amine hydrochloride (6.81 g, 14.2 mmol)
in methylene chloride (DCM) (60 ml) was cooled to 0.degree. C. and
was treated with Hunig's base (9.9 ml, 56.8 mmol). The mixture was
kept at 0.degree. C. for 30 minutes then the 4-chlorophenylsulfonyl
chloride (3.3 g, 15.6 mmol) was added. The reaction mixture was
stirred at room temperature overnight. The mixture was diluted with
methylene chloride (100 ml) and was washed water (100 ml) and a
saturated aqueous sodium chloride solution (100 ml). The organic
phase was dried over sodium sulfate and concentrated in vacuo. The
crude product was purified by flash chromatography using a gradient
(ethyl acetate/hexanes, 40-100%), affording 6.98 g (85%) of the
title compound as a pale yellow solid. 400 MHz .sup.1H NMR
(DMSO-d.sub.6 at 60.degree. C.) .delta.: 8.42 (br. s, 1H), 8.12 (d,
J=5.1 Hz, 1H), 7.8-7.75 (m, 2H), 7.7-7.65 (m, 2H), 7.43-7.39 (m,
10H), 7.36 (d, J=7.8 Hz, 1H), 7.18-7.1 (m, 2H), 7.05-6.98 (m, 1H),
6.42 (d, J=5.1 Hz, 1H), 4.0-3.9 (m, 1H), 3.78 (s, 3H), 3.74 (d,
J=11.7 Hz, 1H), 3.48 (d, J=11.7 Hz, 1H), 2.5-2.4 (m, 1H), 2.33 (t,
J=5.3 Hz, 1H), 1.95-1.8 (m, 2H), 1.65-1.5 (m, 1H), 1.45-1.4 (m,
1H). LCMS: 581 [M+H].
1h: Preparation of
3-{5-[2-({(3R)-1-[(4-chlorophenyl)sulfonyl]piperidin-3-yl}amino)pyrimidin-
-4-yl]imidazo[2,1-b][1,3]thiazol-6-yl}phenol
##STR00012##
[0179] The
N-{(3R)-1-[(4-chlorophenyl)sulfonyl]piperidin-3-yl}-4-[6-(3-met-
hoxy-phenyl)imidazo[2,1-b][1,3]thiazol-5-yl]pyrimidin-2-amine (6.98
g, 12.03 mmol) in methylene chloride (100 ml) was cooled to
-78.degree. C. and slowly treated with 1 molar solution of boron
tribromide in methylene chloride (65 ml). The reaction mixture was
kept at -78.degree. C. for one hour then was allowed to warm to
room temperature for two hours. The mixture was quenched by the
addition of methanol (25 ml) at 0.degree. C. and was stirred at
room temperature for an additional hour. The mixture was diluted
with methylene chloride (500 ml) and washed with three portions of
100 ml of saturated sodium bicarbonate solution, two portions of
100 ml of water and two portions of 100 ml of saturated sodium
chloride solution. The organic phase was dried over sodium sulfate
and concentrated in vacuo, giving a yellow foam. The crude product
was re-crystallized from methanol as a yellow solid (4.85 g, 71%).
M.p.=174-177.degree. C. 400 MHz .sup.1H NMR (DMSO-d.sub.6 at
60.degree. C.) .delta.: 9.4 (br. s, 1H), 8.70 (br. s, 1H), 8.12 (d,
J=5.5 Hz, 1H), 7.8-7.7 (m, 2H), 7.7-7.65 (m, 2H), 7.40 (d, J=4.7
Hz, 1H), 7.25 (t, J=8.0 Hz, 1H), 7.15 (d, J=7.4 Hz, 1H), 7.0-6.95
(m, 1H), 6.85-6.8 (m, 1H), 6.44 (d, J=5.5 Hz, 1H), 3.95 (br. s,
1H), 3.72 (dd, J=10.6 3.1 Hz, 1H), 3.40 (m, 10H), 2.5-2.4 (m, 1H),
2.35 (t, J=10.2 Hz, 1H), 2.0-1.8 (m, 2H), 1.65-1.5 (m, 1H),
1.46-1.32 (m, 1H). LCMS: 567 [M+H]. Calc. for
C.sub.26H.sub.23N.sub.6O.sub.3S.sub.2Cl 0.5 water 1.0 methanol: C,
53.33; H, 4.64; N, 13.82. found C, 53.32; H, 4.64; N, 13.82.
Example 2
Preparation of 2-amino-oxazole
##STR00013##
[0181] To a solution of cyanamide (19.8 ml of 50% w/w in water,
0.25 mol) in THF (60 ml) was added the hydroxyacetaldehyde (15 g,
0.25 mol) in 24 ml of water. The reaction mixture was treated at
0.degree. C. with a solution of sodium hydroxide 2 M (25.2 ml, 0.05
mol). The mixture was allowed to warm to room temperature and
stirred for 24 hrs. The volatiles were removed in vacuo (THF) and
the remaining aqueous solution was extracted with four portions of
200 ml of ethyl acetate. The organic extracts were dried over
sodium sulfate and concentrated in vacuo, yielding 14.968 g (71.3%)
of a white solid. 400 MHz .sup.1H NMR (CDCl.sub.3) .delta.: 7.13
(s, 1H), 6.74 (s, 1H), 5.26 (br. s, 2H). Calc. for
C.sub.3H.sub.4N.sub.2O: C, 42.86; H, 4.80; N, 33.32. found C,
43.01; H, 4.87; N, 33.11.
Example 3
Preparation of
N-[4-(dimethylamino)phenyl]-4-({4-[6-(4-fluorophenyl)-imidazo[2,1-b][1,3]-
oxazol-5-yl]pyrimidin-2-yl}amino)piperidine-1-carboxamide
3a: Preparation of
1-(4-fluorophenyl)-2-(2-imino-1,3-oxazol-3(2H)-yl)ethanone
hydrobromide
##STR00014##
[0183] A solution of 2-amino-oxazole (14.9 g, 0.179 mol) in
acetonitrile (100 ml) was slowly added over a period of 20 minutes
to a solution of 2-bromo-1-(4-fluorophenyl)ethanone (57.6 g, 0.36
mol) in THF (150 ml). The reaction mixture was stirred at room
temperature for 24 hrs then cooled to 0.degree. C. A precipitate
formed and was filtered off. The solid was washed with three
portions of 30 ml of cold acetonitrile and dried at 50.degree. C.
under vacuum, yielding 38.75 g (72%) of an off-white solid.
M.p.=218-221.degree. C.; 300 MHz .sup.1H NMR (DMSO-d.sub.6)
.delta.: 9.80 (br. s, 1H), 8.16-8.11 (m, 2H), 8.00 (s, 1H), 7.62
(s, 1H), 7.52-7.46 (m, 2H), 5.80 (s, 2H); LCMS: 221 [M+H]. Calc.
for C, 1H.sub.9N.sub.2O.sub.2F 1.05 HBr, 0.14 ACN: C, 43.58; H,
3.39; N, 9.64. found C, 43.63; H, 3.38; N, 9.65.
3b: Preparation of 6-(4-fluorophenyl)-imidazo[2,1-b]oxazole
##STR00015##
[0185] The 1-(4-fluorophenyl)-2-(2-iminooxazol-3-yl)-ethanone
hydrobromide salt (10.0 g, 0.32 mol) was introduced in a two-neck
flask, fitted with a condenser, and flushed with nitrogen.
Anhydrous toluene (100 ml) was added and the mixture was cooled to
-10.degree. C. TiCl.sub.4 (17.5 ml, 0.16 mol) was added over a
period of 30 minutes. The reaction becomes deep red and a dark
precipitate was formed. The reaction mixture was allowed to warm to
room temperature. The mixture was then brought to reflux and kept a
reflux for 5.5 hrs. The reaction mixture was cooled to room
temperature overnight. The toluene was decanted and iced water (60
ml) was added to the residue (caution!), which turned from dark
brown to beige. The resulting suspension was transferred to a large
beaker and treated with saturated aqueous sodium carbonate solution
until pH 8. A saturated aqueous sodium chloride solution was added
(200 ml), followed by 600 ml of ethyl acetate and the mixture was
stirred vigorously for one hour. The organic phase was separated
and the aqueous phase was further extracted with two portions of
600 ml of ethyl acetate. The organic extracts were dried over
sodium sulfate and concentrated in vacuo, yielding 6.84 g of a pale
yellow solid. 400 MHz .sup.1H NMR (CDCl.sub.3) .delta.: 7.78-7.72
(m, 2H), 7.37 (d, J=1.8 Hz, 1), 7.31 (d, J=1.8 Hz, 1), 7.24 (s,
1H), 7.10-7.00 (m, 2H).
3c: Preparation of
1-[6-(4-fluorophenyl)imidazo[2,1-b][1,3]oxazol-5-yl]ethanone
##STR00016##
[0187] A solution of 6-(4-fluorophenyl)-imidazo[2,1-b]oxazole (2.5
g, 0.0124 mol) in acetic anhydride (60 ml) was heated to
140.degree. C. and then treated with concentrated sulfuric acid (5
drops). After 15 minute at that temperature, HPLC showed clean
conversion and the reaction mixture was quenched by the addition of
ice cold water (150 ml). The mixture was extracted with ethyl
acetate (3.times.150 ml). The combined extracts were washed with a
saturated aqueous sodium chloride solution (300 ml), dried over
magnesium sulfate and concentrated in vacuo as a brown solid.
Trituration from a mixture of hexanes/ethyl:acetate (1:1) provided
2.2 g (72.6%) of a pale yellow solid. M.p.=173.degree. C.; 300 MHz
.sup.1H NMR (DMSO-d.sub.6) .delta. 8.25-8.19 (m, 2H), 7.75-7.68 (m,
2H), 7.35-7.25 (m, 2H), 2.15 (s, 3H). LCMS: 245 [M+H].
3d: Preparation of
3-(dimethylamino)-1-[6-(4-fluorophenyl)imidazo[2,1-b][1,3]oxazol-5-yl]pro-
p-2-en-1-one
##STR00017##
[0189] A solution of
1-[6-(4-fluorophenyl)imidazo[2,1-b][1,3]oxazol-5-yl]ethanone
(0.0374 g, 0.000153 mol) in N,N-dimethylformamide dimethyl acetal
(3.0 ml) was heated to 100.degree. C. for 24 hrs. HPLC showed
complete consumption of the starting material. The volatiles were
removed in vacuo, yielding a brown solid (0.046 g, quantitative).
M.p.=187-189.degree. C.; 300 MHz .sup.1H NMR (CDCl.sub.3)
.delta.8.03 (s, 1H), 7.72-7.64 (m, 3H), 7.46 (s, 1H), 7.13-7.10 (m,
2H), 5.19 (d, J=12.5 Hz, 1H), 3.07 (bs, 3H), 2.55 (bs, 31H). LCMS:
300 [M+H]. Calc. for C.sub.16H.sub.14FN.sub.3O.sub.2: C, 64.21; H,
4.71; N, 14.04. found C, 64.22; H, 4.31; N, 14.10.
3e: Preparation of tert-butyl
4-{[amino(imino)methyl]amino}piperidine-1-carboxylate
hydrochloride
##STR00018##
[0191] To a mixture of tert-butyl 4-aminopiperidine-1-carboxylate
(8.93 g, 44.6 mmol) and pyrazole carbox-amidine hydrochloride
(6.536 g, 44.6 mmol) was added Hunig's base (7.77 ml, 44.6 mmol)
and DMF (25 ml). The reaction was heated at 60.degree. C. for 15
hours. The reaction was then cooled to room temperature and
quenched by adding 400 ml of diethyl ether and stirring at room
temperature for 2 hours. Product separated out as a white solid,
which was filtered, washed and dried (10.9 g, 88%).
M.p.=169-172.degree. C.; 400 MHz .sup.1H NMR (DMSO-d.sub.6)
.delta.: 8.09 (d, J=8.8 HZ, 1H), 6.9-7.9 (br. s, 3H), 3.83 (d,
J=13.6 Hz, 2H), 3.63 (m, 1H), 2.88 (m, 2H), 1.80 (m, 2H), 1.40 (s,
9H), 1.25 (m, 2H); LCMS: 243 [M+H]; calc. for
C.sub.11H.sub.22N.sub.4O.sub.2 1.06 HCl 0.2H.sub.2O: C, 46.39; H,
8.31; N, 19.68. found C, 46.43; H, 8.31; N, 20.68.
3f: Preparation of tert-butyl
4-({4-[6-(4-fluorophenyl)imidazo[2,1-b][1,3]oxazol-5-yl]pyrimidin-2-yl}am-
ino)piperidine-1-carboxylate
##STR00019##
[0193] A mixture of
3-(dimethylamino)-1-[6-(4-fluorophenyl)imidazo[2,1-b][1,3]oxazol-5-yl]pro-
p-2-en-1-one (4.24 g, 14.2 mmol) and tert-butyl
4-{[amino(imino)methyl]amino}-piperidine-1-carboxylate
hydrochloride (5.92 g, 21.2 mmol) was diluted with 40 ml of
absolute ethanol and treated with 1.35 eq. of a 21% w/w solution of
sodium ethoxide in ethanol (7.2 ml) to form a reaction mixture. The
reaction mixture was heated to reflux for 15 hours. Volatiles were
removed in vacuo and the residue was taken up in 200 ml of ethyl
acetate, washed twice with 100 ml each of water, and then with a
saturated sodium chloride solution (100 ml). The organic phase was
dried with magnesium sulfate, filtered and concentrated in vacuo,
to give a brown solid. The product was purified by flash
chromatography on silica gel (gradient 50%-75% ethyl
acetate/hexanes) to yield 4.436 g of a tan solid (65%).
M.p.=175.degree. C.; 300 MHz .sup.1H NMR (CDCl.sub.3) .delta.: 8.06
(s, 1H), 8.04 (s, 1H), 7.65-7.60 (m, 2H), 7.48 (d, J=1.6 Hz, 1H),
7.17-7.13 (m, 2H), 6.52 (d, J=5.6 Hz, 1H), 5.1 (br. s, 1H), 4.2-3.9
(m, 3H), 2.2-2.0 9M, 2H), 16.-1.4 (m, 4H), 1.48 (s, 9H). LCMS: 479
[M+H]; calc. for C.sub.25H.sub.27FN.sub.6O.sub.3 0.25H.sub.2O: C,
62.11; H, 5.74; N, 17.39. found C, 62.43; H, 5.37; N, 17.35.
3g: Preparation of
4-[6-(4-fluorophenyl)imidazo[2,1-b][1,3]oxazol-5-yl]-N-piperidin-4-ylpyri-
midin-2-amine hydrochloride
##STR00020##
[0195] A solution of tert-butyl
4-({4-[6-(4-fluorophenyl)imidazo[2,1-b][1,3]oxazol-5-yl]pyrimidin-2-yl}am-
ino)piperidine-1-carboxylate (3.2 g, 0.0067 mol) in dioxane (35 ml)
was treated with HCl 4 M in dioxane (5 ml). The reaction mixture
was stirred at room temperature for 4 hrs. The volatiles were
removed in vacuo, giving 2.951 g (98%) of a yellow solid.
M.p.=217-220.degree. C.; 300 MHz .sup.1H NMR (DMSO-d.sub.6)
.delta.: 9.55-9.25 (br. m, 2H), 9.03 (br. s, 1H), 8.31 (s, 1H),
8.06 (br., 1H), 7.67 (t, J=7.1 Hz, 2H), 7.38 (t, J=8.8 Hz, 2H),
6.50 (d, J=6.0 Hz, 1H), 4.22 (br s, 1H), 3.5-3.3 (m, 2H), 3.25-2.9
(m, 2H), 2.16 (br. d, J=11.5 Hz, 2H), 2.0-1.8 (m, 2H). LCMS: 379
[M+H]; calc. for C.sub.20H.sub.19FN.sub.6O 3.0 HCl 0.3 dioxane: C,
49.47; H, 4.78; N, 16.34. found C, 49.30; H, 4.77; N, 16.51.
3h: Preparation of
N-[4-(dimethylamino)phenyl]-4-({4-[6-(4-fluorophenyl)-imidazo[2,1-b][1,3]-
oxazol-5-yl]pyrimidin-2-yl}amino)piperidine-1-carboxamide
##STR00021##
[0197] The
4-[6-(4-fluorophenyl)imidazo[2,1-b][1,3]oxazol-5-yl]-N-piperidi-
n-4-ylpyrimidin-2-amine (bis HCl salt) (100 mg, 0.222 mmol) in
tetrahydrofuran (5 ml) was treated with Hunig's base (240 ul),
followed by 4-dimethylaminophenyl wasocyanate (44 mg). The reaction
mixture was stirred at room temperature for 18 hours. The mixture
was quenched by the addition of water (15 ml) and extracted with
ethyl acetate (10 ml). The organic phase was washed with one
portion of 10 ml of saturated sodium chloride solution, dried over
sodium sulfate and concentrated in vacuo. The product was purified
by trituration in ether, giving 116 mg of a pale yellow solid
(97%). M.p.=225-227.degree. C. 400 MHz .sup.1H NMR (DMSO-d.sub.6)
.delta.: 8.73 (br. s, 1H), 8.24 (s, 1H), 8.18 (br. s, 1H), 8.10 (d,
J=5.5 Hz, 1H), 7.67-7.61 (m, 2H), 7.38-7.29 (m, 2H), 7.26-7.19 (m,
2H), 6.70-6.61 (m, 2H), 6.35 (br. s, 1H), 4.08 (d, J=13.3 Hz, 2H),
4.00-3.90 (m, 1H), 2.93 (t, J=1.5 Hz, 2H), 2.82 (s, 6H), 1.93 (d,
J=10.5 Hz, 2H), 1.50-1.35 (m, 2H). LCMS: 541 [M+H]. Calc. for
C.sub.29H.sub.29N.sub.8O.sub.2F 0.35 ether: C, 64.45; H, 5.78; N,
19.78. found C, 64.41; H, 5.58; N, 19.79.
Example 4
Preparation of
4-[6-(4-fluorophenyl)imidazo[2,1-b][1,3]oxazol-5-yl]-N-[1-(4-methoxybenzo-
yl)piperidin-4-yl]pyrimidin-2-amine
##STR00022##
[0199] The
4-[6-(4-fluorophenyl)imidazo[2,1-b][1,3]oxazol-5-yl]-N-piperidi-
n-4-ylpyrimidin-2-amine (his HCl salt) (100 mg, 0.222 mmol) in
dichloromethane (5 ml) was treated with triethylamine (500 ul). The
mixture was cooled to 0.degree. C. and treated with 4-methoxy
benzoyl chloride (36 mg, 0.2 mmole). The reaction mixture was
stirred at room temperature for 18 hours. The mixture was diluted
with dichloromethane (10 ml) and washed with a soln. of sodium
bicarbonate (3.times.15 ml) and water (15 ml). The organic phase
was washed with one portion of 10 ml of saturated sodium chloride
solution, dried over sodium sulfate and concentrated in vacuo. The
product was purified by trituration in ether, giving 75 mg of a
pale yellow solid (70%). M.p.=196-197.degree. C. 400 MHz .sup.1H
NMR (CDCl.sub.3) .delta.: 8.06-8.02 (m, 2H), 7.65-7.58 (m, 2H),
7.49 (d, J=1.6 Hz, 1H), 7.44-7.38 (m, 2H), 7.17-7.11 (m, 2H),
6.95-6.90 (m, 2H), 6.54 (d, J=5.5 Hz, 1H), 4.20-4.10 (m, 1H), 3.84
(s, 3H), 3.30-3.12 (m, 2H), 2.25-2.10 (m, 2H), 1.85-1.50 (m, 4H).
LCMS: 513 [M+H]. Calc. for C.sub.28H.sub.25N.sub.6O.sub.3F 0.03
ether 0.52 water: C, 64.38; H, 5.07; N, 16.03. found C, 64.43; H,
5.01; N, 16.04.
Example 5
Preparation of
N-{2-[4-({4-[6-(4-fluorophenyl)imidazo[2,1-b][1,3]oxazol-5-yl]pyrimidin-2-
-yl}amino)piperidin-1-yl]-2-oxoethyl}acetamide
##STR00023##
[0201] The
4-[6-(4-fluorophenyl)imidazo[2,1-b][1,3]oxazol-5-yl]-N-piperidi-
n-4-ylpyrimidin-2-amine (bis HCl salt) (100 mg, 0.222 mmol) in
dimethylformamide (4 ml) was treated with triethylamine (220 ul)
and stirred until all solids dissolve. The mixture was treated
sequentially with the acetamido glycine (26 mg), HBTU (84 mg) and
DMAP (27 mg). The reaction mixture was stirred at room temperature
for 15 hours. The mixture was partitioned into ethyl acetate (10
ml) and water (10 ml). The phases were separated and the organic
phase was washed with a saturated sodium carbonate solution (10
ml), water (10 ml) and a saturated sodium chloride solution (10
ml). The organic phase was dried over sodium sulfate and
concentrated in vacuo. The crude product was purified by
preparative chromatography plate (15% methanol/ethyl acetate),
giving 78 mg of a pale yellow solid (74%). M.p.=235-237.degree. C.
400 MHz .sup.1H NMR (DMSO-d.sub.6) .delta.: 8.73 (br. s, 1H), 8.18
(br. s, 1H), 8.10 (d, J=5.5 Hz, 1H), 7.98 (t, J=5.7 Hz, 1H),
7.66-7.6 (m, 2H), 7.38-7.28 (m, 3H), 6.36 (br. s, 1H), 4.26 (d,
J=13.3 Hz, 1H), 4.05-3.87 (m, 3H), 3.82 (d, J=13.3 Hz, 1H), 3.15
(t, J=11.5 Hz, 1H), 2.83 (t, J=11.5 Hz, 1H), 2.0-1.9 (m, 2H), 1.87
(s, 3H), 1.5-1.2 (m, 2H). LCMS: 478 [M+H]. Calc. for
C.sub.24H.sub.24N.sub.7O.sub.3F 0.44 water: C, 59.38, H, 5.17; N,
20.20. found C, 59.38; H, 4.93; N, 20.47.
Example 6
Preparation of
N-[1-(4-fluorobenzyl)piperidin-3-yl]-4-[6-(4-fluorophenyl)-imidazo[2,1-b]-
[1,3]thiazol-5-yl]pyrimidin-2-amine
##STR00024##
[0203] The racemic
4-[6-(4-fluorophenyl)imidazo[2,1-b][1,3]thiazol-5-yl]-N--[piperidin-3-yl]-
pyrimidin-2-amine hydrochloride (70 mg g, 0.15 mmol) was dissolved
in a 80/20 mixture of DCE and DMF (1.2 ml) and treated with three
equivalent of triethylamine (63 uL). The 4-fluorobenzaldehyde (19
mg, 0.15 mmol) was added, followed by a 0.2 M solution of
Me.sub.4NBH(OAc).sub.3 in 80/20 DCE/DMF (1.2 ml). The mixture was
stirred at room temperature for 18 hours. The mixture was washed
with a 1N sodium hydroxide solution (2 ml). Concentration in vacuo
followed by purification on reverse phase HPLC provides the title
compound as a pale yellow solid (42.4 mg, 56%).
M.p.=131-133.degree. C. 400 MHz .sup.1H NMR (DMSO-d.sub.6) .delta.:
8.73 (br. s, 1H), 8.06 (d, J=5.1 Hz, 1H), 7.64-7.58 (m, 2H), 7.44
(d, J=4.7 Hz, 1H), 7.35-7.31 (m, 2H), 7.30-7.23 (m, 2H), 7.07 (t,
J=8.8 Hz, 2H), 7.00 (br. s, 1H), 6.29 (d, J=5.1 Hz, 1H), 4.00-3.90
(m, 1H), 3.49 (s, 2H), 2.96-2.90 (m, 1H), 2.69-2.62 (m, 1H),
2.08-1.94 (m, 2H), 1.93-1.85 (m, 1H), 1.76-1.67 (m, 1H), 1.61-1.48
(m, 1H), 1.42-1.30 (m, 1H). LCMS: 503 [M+H].
Example 7
Preparation of
N.about.1.about.-(3-{5-[2-({(3R)-1-[(4-chlorophenyl)sulfonyl]piperidin-3--
yl}amino)pyrimidin-4-yl]imidazo[2,1-b][1,3]thiazol-6-yl}phenyl)glycinamide
7a: Preparation of
4-[6-(3-aminophenyl)imidazo[2,1-b][1,3]thiazol-5-yl]-N-{(3R)-1-[(4-chloro-
phenyl)sulfonyl]piperidin-3-yl}pyrimidin-2-amine
##STR00025##
[0205]
N-{(3R)-1-[(4-chlorophenyl)sulfonyl]piperidin-3-yl}-4-[6-(3-nitroph-
enyl)imidazo[2,1-b][1,3]thiazol-5-yl]pyrimidin-2-amine (1.05 g,
1.76 mmol) was dissolved in ethanol 95% (10 ml) and water (2.5 ml).
The solution was treated with irn powder (1 g, 17.6 mmol) and
concentrated HCl (200 uL). The reaction mixture was stirred at
100.degree. C. for one hour. The mixture was cooled down and
diluted with ethanol (100 ml). The heterogenous mixture was
filtered over Celite and the volatiles were removed in vacuo. The
residue was taken up in EtOAc (150 ml) and the organic phase was
washed with a saturated aqueous NaHCO.sub.3 solution (2.times.100
ml), water (100 ml) and a saturated aqueous NaCl solution (100 ml).
After drying over sodium sulfate and concentration, the solid was
triturated in ether, giving the title compound as a yellow powder,
0.835 g (84%). M.p.=226-228.degree. C. 400 MHz .sup.1H NMR
(DMSO-d.sub.6) .delta.: 8.73 (br. s, 1H), 8.10 (d, J=5.6 Hz, 1H),
7.77 (d, J=8.5 Hz, 2H), 7.67 (d, J=8.5 Hz, 2H), 7.36 (d, J=4.4 Hz,
1H), 7.09 (t, J=7.7 Hz, 1H), 7.02 (d, J=7.3 Hz, 1H), 6.81 (s, 1H),
6.69 (d, J=7.6 Hz, 1H), 6.65 (d, J=7.9 Hz, 1H), 6.49 (d, J=5.3 Hz,
1H), 5.01 (br. s, 2H), 4.02-3.88 (m, 1H), 3.73 (dd, J=11.1, 3.5 Hz,
1H), 3.47 (d, J=11.7 Hz, 1H), 2.60-2.46 (m, 1H), 2.39 (t, J=10.2
Hz, 1H), 1.98-1.80 (m, 2H), 1.68-1.51 (m, 1H), 1.47-1.32 (m, 1H).
LCMS: 566 [M+H]. Calc. for C.sub.26H.sub.24N.sub.7O.sub.2S.sub.2Cl:
C, 55.16; H, 4.27; N, 17.32. found C, 54.98; H, 3.85; N, 17.23.
7b: Preparation of tert-butyl
{2-[(3-{5-[2-({(3R)-1-[(4-chlorophenyl)sulfonyl]piperidin-3-yl}amino)pyri-
midin-4-yl]imidazo[2,1-b][1,3]thiazol-6-yl}phenyl)amino]-2-oxoethyl}carbam-
ate
##STR00026##
[0207] The
4-[6-(3-aminophenyl)imidazo[2,1-b][1,3]thiazol-5-yl]-N-{(3R)-1--
[(4-chlorophenyl)-sulfonyl]piperidin-3-yl}pyrimidin-2-amine (0.1 g,
0.177 mmol) and N-(tert-butoxycarbonyl)glycine (34 mg, 0.194 mmol)
were dissolved in DCM (5 ml) and treated with Hunig's base (92 uL,
0.53 mmol) and 2-chloro-1,3-dimethyl-1H-imidazol-3-ium chloride (33
mg, 0.194 mmol). The mixture was kept at room temperature for 90
minutes then was diluted with DCM (10 ml). The organic phase was
washed with water (2.times.10 ml) and with an aqueous sodium
chloride solution (10 ml). The organic phase was dried over sodium
sulfate and concentrated in vacuo, giving a yellow oil. The product
was purified by flash chromatography (gradient 70%-100%
EtoAc/hexanes), affording the title compound as a pale yellow solid
(71 mg). 400 MHz .sup.1H NMR (DMSO-d.sub.6) .delta.: 9.86 (s, 1H),
8.73 (br. s, 1H), 8.11 (d, J=5.5 Hz, 1H), 7.84 (s, 1H), 7.79-7.75
(m, 2H), 7.70-7.65 (m, 3H), 7.45-7.37 (m, 2H), 7.26 (d, J=7.4 Hz,
1H), 7.13 (d, J=8.2 Hz, 1H), 6.82 (br. s, 1H), 6.42 (d, J=6.9 Hz,
1H), 4.00-3.90 (m, 1H), 3.78-3.70 (m, 3), 3.52-3.44 (m, 1H), 3.18
(s, 2H), 2.34 (t, J=10.2 Hz, 1H), 1.94-1.81 (m, 2H), 1.65-1.52 (m,
1H), 1.39 (s, 9H). LCMS: 723 [M+H].
7c: Preparation of
N-(3-{5-[2-({(3R)-1-[(4-chlorophenyl)sulfonyl]piperidin-3-yl}amino)-pyrim-
idin-4-yl]imidazo[2,1-b][1,3]thiazol-6-yl}phenyl)glycinamide
hydrochloride
##STR00027##
[0209] The tert-butyl
{2-[(3-{5-[2-({(3R)-1-[(4-chlorophenyl)sulfonyl]piperidin-3-yl}amino)-pyr-
imidin-4-yl]imidazo[2,1-b][1,3]thiazol-6-yl}phenyl)amino]-2-oxoethyl}carba-
mate (71 mg, 0.098 mmol) was dissolved in dioxane (3 ml) and
treated with a 4N HCl solution in dioxane (1 ml). The mixture was
stirred at room temperature for 3 hours. The volatiles were removed
in vacuo and the residue was triturated in ether. Filtration
afforded the title compound as a yellow solid (65 mg).
M.p.=208-212.degree. C. 400 MHz .sup.1H NMR (DMSO-d.sub.6) .delta.:
10.69 (s, 1H), 8.18 (br. s, 3H), 8.13 (d, J=5.9 Hz, 1H), 7.88 (t,
J=1.6 Hz, 1H), 7.79-7.75 (m, 2H), 7.71-7.66 (m, 3H), 7.48-7.43 (m,
2H), 7.34 (d, J=7.8 Hz, 1H), 6.45 (d, J=5.9 Hz, 1H), 5.15 (br. s,
3H), 4.04-3.95 (m, 1H), 3.79 (d, J=5.5 Hz, 2H), 3.70 (dd, J=11.3,
4.3 Hz, 1H), 3.48-3.41 (m, 1H), 2.57-2.48 (m, 1H), 2.42 (t, J=10.6
Hz, 1H), 1.95-1.82 (m, 2H), 1.67-1.54 (m, 1H), 1.48-1.37 (m, 1H).
LCMS: 623 [M+H]. Calc. for C.sub.28H.sub.27N.sub.8O.sub.3S.sub.2Cl
2.52 HCl: C, 47.03; H, 4.16; N, 15.67. found C, 47.04; H, 3.97; N,
15.46.
Example 8
Preparation of
N-(3-{5-[2-({(3R)-1-[(4-chlorophenyl)sulfonyl]piperidin-3-yl}amino)pyrimi-
din-4-yl]imidazo[2,1-b][1,3]thiazol-6-yl}phenyl)acetamide
##STR00028##
[0211] The
4-[6-(3-aminophenyl)imidazo[2,1-b][1,3]thiazol-5-yl]-N-{(3R)-1--
[(4-chlorophenyl)-sulfonyl]piperidin-3-yl}pyrimidin-2-amine (0.1 g,
0.177 mmol) was dissolved in DCM (5 ml) and treated sequentially
with Hunig's base (46 uL, 0.265 mmol) and acetyl chloride (15 uL,
0.212 mmol). The mixture was kept at room temperature for two hours
then was diluted with DCM (10 ml). The organic phase was washed
with water (2.times.10 ml) and with an aqueous sodium chloride
solution (10 ml). The organic phase was dried over sodium sulfate
and concentrated in vacuo, giving a yellow foam. The product was
triturated in ether and filtered off, giving the title compound as
a yellow solid (97 mg). M.p.=169-174.degree. C. 400 MHz .sup.1H NMR
(DMSO-d.sub.6) .delta.: 9.89 (s, 1H), 8.72 (br. s, 1H), 8.12 (d,
J=5.1 Hz, 1H), 7.82 (s, 1H), 7.80-7.75 (m, 2H), 7.70-7.64 (m, 3H),
7.41 (d, J=4.3 Hz, 1H), 7.37 (t, J=7.8 Hz, 1H), 7.24 (d, J=7.8 Hz,
1H), 7.13 (d, J=7.4 Hz, 1H), 6.42 (d, J=5.5 Hz, 1H), 4.00-3.90 (m,
1H), 3.74 (d, J=8.6 Hz, 1H), 3.48 (d, J=11.7 Hz, 1H), 2.54-2.43 (m,
1H), 2.34 (t, J=10.2 Hz, 1H), 2.05 (s, 3H), 1.94-1.81 (m, 2H),
1.65-1.53 (m, 1H), 1.44-1.34 (m, 1H). LCMS: 608 [M+H]. Calc. for
C.sub.28H.sub.26N.sub.7O.sub.3S.sub.2Cl 0.38 water 0.41 dioxane: C,
54.68; H, 4.65; N, 15.06. found C, 54.68; H, 4.32; N, 15.05.
Example 9
Preparation of
(2R)-3-[(3R)-3-([4-[6-(3-hydroxyphenyl)imidazo[2,1-b][1,3]thiazol-5-yl]py-
rimidin-2-yl]amino)piperidin-1-yl]propane-1,2-diol
9a: Preparation of
N-((3R)-1-{[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]methyl}piperidin-3-yl)-4--
[6-(3-methoxyphenyl)imidazo[2,1-b][1,3]thiazol-5-yl]pyrimidin-2-amine
##STR00029##
[0213] The
4-[6-(3-methoxyphenyl)imidazo[2,1-b][1,3]thiazol-5-yl]-N-[(3R)--
piperidin-3-yl]-pyrimidin-2-amine hydrochloride (310 mg, 0.7 mmol)
was dissolved in DNF (15 ml) and was treated successively with
Hunig's base (240 uL, 1.4 mmol), potassium carbonate (192 mg, 0.7
mmol) and terabutylammonium iodide (26 mg, 0.07 mmol). The mixture
was heated to 130.degree. C. and the
[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]methyl
4-methyl-benzenesulfonate (0.2 g, 0.7 mmol) was added in three
portions. The mixture was kept at 130.degree. C. for 5 hours, at
which point no more starting material appears by HPLC. The
volatiles were removed in vacuo and the residue was taken up in
ether (100 ml). The organic phase was washed with water (2.times.20
ml) and with an aqueous sodium chloride solution (20 ml). The
organic phase was dried over sodium sulfate and concentrated in
vacuo, giving a yellow oil. The product was purified by flash
chromatography (5:4:0.5 hexanes/EtOAc, MeOH), affording the title
compound as an off-white solid (231 mg, 64%). M.p.=73-75.degree. C.
400 MHz .sup.1H NMR (DMSO-d.sub.6) .delta.: 8.71 (br. s, 1H), 8.07
(d, J=5.1 Hz, 1H), 7.42 (d, J=4.4 Hz, 1H), 7.36 (t, J=7.9 Hz, 1H),
7.19-7.11 (m, 2H), 7.04-6.92 (m, 2H), 6.36 (d, J=5.1 Hz, 1H), 4.19
(quintet, J=6.2 Hz, 1H), 3.99 (dd, J=8.1, 6.2 Hz, 1H), 3.96-3.87
(m, 1H), 3.77 (s, 3H), 3.52 (t, J=7.5 Hz, 1H), 3.15 (s, 2H), 3.05
(d, J=9.9 Hz, 1H), 2.69 (d, J=10.3 Hz, 1H), 2.15 (t, J=9.4 Hz, 1H),
2.04 (t, J=9.5 Hz, 1H), 1.90-1.82 (m, 1H), 1.75-1.65 (m, 1H),
1.59-1.48 (m, 1H), 1.40-1.25 (m, 1H), 1.29 (s, 3H), 1.21 (s, 3H).
LCMS: 521 [M+H].
9b: Preparation of
(2R)-3-[(3R)-3-({4-[6-(3-methoxyphenyl)imidazo[2,1-b][1,3]thiazol-5-yl]py-
rimidin-2-yl}amino)piperidin-1-yl]propane-1,2-diol
##STR00030##
[0215] The
N-((3R)-1-{[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]methyl}piperidi-
n-3-yl)-4-[6-(3-methoxyphenyl)imidazo[2,1-b][1,3]thiazol-5-yl]pyrimidin-2--
amine (150 mg, 0.288 mmol) was dissolved in MeOH (10 ml) and water
(1.2 ml) and treated with trifluoroacetic acid (90 uL). The mixture
was stirred at 50.degree. C. overnight (18 hours). The mixture was
neutralized with potassium carbonate (160 mg) and the volatiles
were removed in vacuo. The product was purified by flash
chromatography (6:1 EtOAc/MeOH), affording the title compound as an
off-white solid (120 mg, 87%). M.p.=106-108.degree. C. 400 MHz
.sup.1H NMR (DMSO-d.sub.6) .delta.: 8.72 (br. s, 1H), 8.08 (d,
J=5.5 Hz, 1H), 7.44 (d, J=4.4 Hz, 1H), 7.36 (t, J=7.9 Hz, 1H),
7.16-7.10 (m, 2H), 7.06-6.97 (m, 2H), 6.36 (d, J=5.5 Hz, 1H),
4.40-4.15 (m, 1H), 4.02-3.90 (m, 1H), 3.77 (s, 3H), 3.68-3.56 (m,
2H), 3.40-3.28 (m, 2H), 3.05-2.95 (m, 1H), 2.80-2.64 (m, 1H), 2.42
(br. s, 1H), 2.32 (br. s, 1H), 2.14 (br. s, 1H), 1.90-1.80 (m, 1H),
1.75-1.65 (m, 1H), 1.60-1.45 (m, 1H), 1.45-1.30 (m, 1H). LCMS: 481
[M+H].
9c: Preparation of
(2R)-3-[(3R)-3-({4-[6-(3-hydroxyphenyl)imidazo[2,1-b][1,3]thiazol-5-yl]py-
rimidin-2-yl}amino)piperidin-1-yl]propane-1,2-diol
##STR00031##
[0217] The
(2R)-3-[(3R)-3-({4-[6-(3-methoxyphenyl)imidazo[2,1-b][1,3]thiaz-
ol-5-yl]pyrimidin-2-yl}amino)piperidin-1-yl]propane-1,2-diol (150
mg, 0.312 mmol) in methylene chloride (10 ml) was cooled to
-78.degree. C. and slowly treated with 1 molar solution of boron
tribromide in methylene chloride (2.5 ml). The reaction mixture was
kept at -78.degree. C. for one hour then was allowed to warm to
room temperature for 18 hours. The mixture was quenched by the
addition of methanol (5 ml) at -78.degree. C. and was stirred at
room temperature for an additional hour. The mixture was
concentrated in vacuo and the crude product was purified by flash
chromatography (6:1 EtOAc/MeOH+drops of aq. NH.sub.4OH), affording
the title compound as a pale yellow solid (71 mg, 49%).
M.p.=185-187.degree. C. 400 MHz .sup.1H NMR (DMSO-d.sub.6) .delta.:
9.39 (s, 1H), 8.72 (br. s, 1H), 8.12 (d, J=5.1 Hz, 1H), 7.43 (d,
J=4.4 Hz, 1H), 7.32 (br. s, 1H), 7.26-7.20 (m, 1H), 7.00-6.95 (m,
2H), 6.84-6.81 (m, 1H), 6.45 (d, J=5.5 Hz, 1H), 5.28-5.03 (br. s,
1H), 4.90-4.65 (br. s, 1H), 4.34-4.22 (m, 1H), 3.98-3.84 (m, 1H),
3.47-3.38 (m, 1H), 3.35-3.25 (m, 1H), 3.15-2.65 (m, 4H), 2.10-1.88
(m, 2H), 1.87-1.72 (m, 2H), 1.65-1.40 (m, 2H). LCMS: 467 [M+H].
[0218] In addition to those examples of compounds prepared by the
methods of this invention set forth above, the following
non-limiting list of compounds prepared by the methods of this
invention is set forth in Table I.
Example 10
Preparation of
4-[6-(4-fluorophenyl)imidazo[2,1-b][1,3]oxazol-5-yl]-N-[(3
.mu.L-1-(morpholin-4-ylcarbonyl)piperidin-3-yl]pyrimidin-2-amine
##STR00032##
[0220] To a solution of
4-[6-(4-fluorophenyl)imidazo[2,1-b][1,3]oxazol-5-yl]-N-[(3R)-piperidin-3--
yl]pyrimidin-2-amine (200 mg, 0.45 mmol) and Hunig's base (145
.mu.L, 0.90 mmol) in 10 mL DCM was added a solution of triphosgene
(660 mg; 2.25 mmol) in 10 mL DCM dropwise over 10 min with
stirring. The mixture was allowed to stir at ambient temperature
for 1.5 hr. The reaction mixture was then concentrated under
reduced pressure. The residue was diluted with 20 mL ether and
concentrated under reduced pressure yielding
(3R)-3-({4-[6-(4-fluorophenyl)imidazo[2,1-b][1,3]oxazol-5-yl]pyrimidin-2--
yl}amino)piperidine-1-carbonyl chloride as an off-white solid (190
mg). The solid was diluted in 10 mL DCM. To the resulting solution
was added morpholine (60 .mu.L, 0.67 mmol) and triethylamine (70
.mu.L, 0.50 mmol). The mixture was allowed to stir at ambient
temperature for 20 hr. The reaction mixture was then concentrated
under reduced pressure and the residue purified by flash
chromatography on silica gel (1:4, ethyl acetate:hexanes) to yield
4-[6-(4-fluorophenyl)imidazo[2,1-b][1,3]oxazol-5-yl]-N-[(3R)-1-(morpholin-
-4-ylcarbonyl)piperidin-3-yl]pyrimidin-2-amine as an off-white
solid (50.2 mg, 23%). 400 MHz .sup.1H NMR (DMSO-d.sub.6) .delta.:
8.75 (s, 1H), 8.20 (s, 1H), 8.11 (d, J=5.2 Hz, 1H), 7.62-7.66 (m,
2H), 7.30-7.34 (m, 2H), 6.37 (s, 1H), 3.76 (m, 2H), 3.53 (m, 4H),
3.15 (m, 2H), 3.09 (m, 2H), 2.75 (m, 2H), 2.62 (m, 1H), 1.99 (s,
1H), 1.78 (br.s, 1H), 1.50-1.54 (m, 2H). LCMS: 492 [M+H].
Example 11
Preparation of
5-{5-[2-({(3R)-1-[(4-chlorophenyl)sulfonyl]piperidin-3-yl}amino)pyrimidin-
-4-yl]imidazo[2,1-b][1,3]thiazol-6-yl}-2-fluorophenol
11a Preparation of
2-bromo-1-(4-fluoro-3-methoxy-phenyl)-ethanone
##STR00033##
[0222] To a mixture of copper (II) bromide (5.31 g, 23.8 mmol) in
ethyl acetate (20 ml), heated to 60.degree. C. was added in a
dropwise fashion, a solution of 3-fluoro-4-methoxyacetophenone (2.0
g, 11.9 mmol) in chloroform (20 ml). The reaction mixture was kept
at reflux for 4.5 hours. The mixture was allowed to cool to room
temperature and filtered. The volatiles were removed in vacuo,
providing a brown oil which was purified by flash chromatography
(gradient 5% to 10% ethyl acetate in hexanes). The title compound
was obtained as an off-white solid (2.4 g, 82%). 400 MHz .sup.1H
NMR (DMSO-d.sub.6) .delta. 7.72-7.66 (m, 2H), 7.42 (dd, J=11.0, 8.2
Hz, 1H), 4.97 (s, 2H), 3.93 (s, 31H). LCMS: 248 [M+H].
11b Preparation of
6-(4-fluoro-3-methoxy-phenyl)-imidazo[2,1-b]thiazole
##STR00034##
[0224] To a mixture of 2-aminothiazole (0.976 g, 9.74 mmol) and
2-bromo-1-(4-fluoro-3-methoxy-phenyl)-ethanone (2.4 g, 9.74 mmol)
was added absolute ethanol (100 ml). The reaction was allowed to
reflux with vigorous stirring for 18 hours (checked by HPLC). The
reaction mixture was reduced to half its original volume in vacuo.
The remaining liquid was poured onto ice and the solution made
basic by the addition of ammonium hydroxide solution (30%), until
pH is 8. The mixture was extracted with ethyl acetate (2.times.100
ml). The combined extracts were washed with water (100 ml) and
saturated aqueous sodium chloride solution (100 ml). The organic
phase was dried with sodium sulfate, filtered and concentrated in
vacuo, to give an orange solid. Purification by flash
chromatography (gradient 25%-50% ethyl actetate in hexanes)
afforded the title product as a pale yellow solid (1.59 g, 66%).
400 MHz .sup.1H NMR (DMSO-d.sub.6) .delta. 8.26 (s, 1H), 7.95 (d,
J=2.3 Hz, 1H), 7.61 (dd, J=8.6, 2.0 Hz, 1H), 7.39 (ddd, J=8.2, 4.3,
2.0 Hz, 1H); 7.28 (d, J=4.7 Hz, 1H), 7.22 (dd, J=11.3, 8.2 Hz, 1H),
3.91 (s, 3H). LCMS: 249 [M+H].
11c: Preparation of
1-[6-(4-fluoro-3-methoxyphenyl)imidazo[2,1-b][1,3]thiazol-5-yl]ethanone
##STR00035##
[0226] To a mixture of
6-(4-fluoro-3-methoxyphenyl)-imidazo[2,1-b]thiazole (1.0 g, 4.03
mmol) and acetic anhydride (25 ml), heated to 140.degree. C., was
added 43 .mu.l of concentrated sulfuric acid. The reaction mixture
was heated at 140.degree. C. for 1 hour. The reaction was monitored
by HPLC. After one hour, only 10% product was observed. Another 43
.mu.l of concentrated sulfuric acid was added and the mixture was
kept at 140.degree. C. for 4 hours. The reaction mixture was then
poured onto 50 ml of ice, and diluted with 50 ml of water and the
resulting mixture was extracted two times with 100 ml each of ethyl
acetate. The combined extracts were washed with two portions of 50
ml of water and two portions of 50 ml of saturated aqueous sodium
chloride solution. The organic phase was dried with sodium sulfate,
filtered and concentrated in vacuo, to give a brown solid. The
product,
-[6-(4-fluoro-3-methoxyphenyl)imidazo[2,1-b][1,3]thiazol-5-yl]ethanone,
was purified by flash chromatography (gradient 25%-50% ethyl
acetate in hexanes) and obtained as a pale yellow solid (1.12 g,
96%). 400 MHz .sup.1H NMR (DMSO-d.sub.6) .delta. 8.44 (d, J=4.3 Hz,
1H), 7.56 (d, J=4.3 Hz, 1H), 7.43 (dd, J=8.2, 2.0 Hz, 1H), 7.34
(dd, J=11.7, 8.6 Hz, 1H), 7.21 (ddd, J=8.2, 4.3, 2.0 Hz, 1H), 3.89
(s, 3H), 2.14 (s, 3H). LCMS: 291 [M+H].
11d: Preparation of
3-(dimethylamino)-1-[6-(4-fluoro-3-methoxyphenyl)imidazo[2,1-b][1,3]thiaz-
ol-5-yl]prop-2-en-1-one
##STR00036##
[0228] A 100 ml round bottom flask was charged with the
1-[6-(4-fluoro-3-methoxyphenyl)imidazo[2,1-b][1,3]thiazol-5-yl]ethanone
(1.12 g, 3.86 mmol) and dimethylformamide dimethylacetal (25 ml).
The mixture was refluxed for 20 hours and then cooled to room
temperature. The mixture was concentrated in vacuo and the residue
was purified by flash chromatography (ethyl acetate), giving a pale
yellow solid (1.138 g, 85%). 400 MHz .sup.1H NMR (DMSO-d.sub.6)
.delta.: 8.39 (d, J=4.7 Hz, 1H), 7.62 (d, J=12.5 Hz, 1H), 7.45-7.40
(m, 2H), 7.31 (dd, J 11.3, 8.2 Hz, 1H), 7.20 (ddd, J=8.2, 4.3, 2.0
Hz, 1H), 5.10 (d, J=12.5 Hz, 1H), 3.87 (s, 3H), 3.06 (br. s, 3H),
2.49 (br. s, 3H). LCMS: 346 [M+H].
11e: Preparation of tert-butyl
(3R)-3-({4-[6-(4-fluoro-3-methoxyphenyl)imidazo[2,1-b][1,3]thiazol-5-yl]p-
yrimidin-2-yl}amino)piperidine-1-carboxylate
##STR00037##
[0230] A mixture of
3-(dimethylamino)-1-[6-(4-fluoro-3-methoxyphenyl)imidazo[2,1-b][1,3]triaz-
ol-5-yl]prop-2-en-1-one (0.6 g, 1.74 mmol) and tert-butyl
(3R)-3-{[(Z)-amino(imino)methyl]amino}piperidine-1-carboxylate
hydrochloride (0.726 g, 2.61 mmol) was diluted with 13 ml of
absolute ethanol and treated with 1.35 eq. of a 21% w/w solution of
sodium ethoxide in ethanol (875 .mu.l) to form a reaction mixture.
The reaction mixture was heated to reflux for 24 hours. HPLC
revealed remaining starting enaminone. More tert-butyl
(3R)-3-{[(Z)-amino(imino)methyl]amino}piperidine-1-carboxylate
hydrochloride (0.243 g, 0.87 mmol) was added followed by a 21% w/w
solution of sodium ethoxide in ethanol (270 .mu.l). The mixture was
kept at reflux for an additional 15 hours. Volatiles were removed
in vacuo and the residue was taken up in 50 ml of ethyl acetate and
50 ml of water. The phases were separated and the aqueous phase was
extracted with 50 ml of ethyl acetate. The combined organic
extracts were washed with 100 ml of water, and then with a
saturated sodium chloride solution (100 ml). The organic phase was
dried with sodium sulfate, filtered and concentrated in vacuo, to
give a brown oil. The product was purified by flash chromatography
on silica gel (gradient 50% to 75% ethyl acetate in hexanes) to
yield 0.785 g of a pale yellow solid (86%). 400 MHz .sup.1H NMR
(DMSO-d.sub.6 at 60.degree. C.) .delta.: 8.72 (br. s, 1H), 8.13 (d,
J=5.5 Hz, 1H), 7.41 (d, J=4.7 Hz, 1H), 7.35 (dd, J=8.6, 2.0 Hz,
1H), 7.26 (dd, J=11.7, 8.6 Hz, 1H), 7.18-7.08 (m, 2H), 6.41 (d,
J=5.5 Hz, 1H), 4.00-3.90 (m, 1H), 3.84 (s, 3H), 3.85-3.75 (m, 1H),
3.72-3.63 (m, 1H), 3.00-2.88 (m, 2H), 2.04-1.94 (m, 1H), 1.82-1.73
(m, 1H), 1.62-1.50 (m, 1H), 1.50-1.38 (m, 1H), 1.34 (s, 9H). LCMS:
525 [M+H].
11f: Preparation of
4-[6-(4-fluoro-3-methoxyphenyl)imidazo[2,1-b][1,3]thiazol-5-yl]-N-[(3R)-p-
iperidin-3-yl]pyrimidin-2-amine hydrochloride
##STR00038##
[0232] The tert-butyl
(3R)-3-({4-[6-(4-fluoro-3-methoxyphenyl)imidazo[2,1-b][1,3]thiazol-5-yl]p-
yrimidin-2-yl}amino)piperidine-1-carboxylate (0.785 g, 1.50 mmol)
was dissolved in 15 ml of dioxane and treated with 7.5 ml of
anhydrous 4N HCl in dioxane at room temperature. The reaction
mixture was stirred at room temperature for two hours. The mixture
was then diluted with 25 ml of ether and stirred until product
separated as a solid. Solid product was filtered and washed with
ether. The solid was dissolved in MeOH (20 ml) and concentrated to
dryness twice. The product was dried at high vacuum to yield 0.709
g of yellow solid (bis HCl salt) (95%). 400 MHz .sup.1H NMR
(DMSO-d.sub.6 at 60.degree. C.) .delta.: 11.65 (br. s, 2H), 9.60
(br. s, 1H), 8.90 (br. s, 1H), 8.14 (d, J=6.3 Hz, 1H), 7.61 (m,
1H), 7.40 (dd, J=8.6, 2.0 Hz, 1H), 7.33 (dd, J=11.7, 8.6 Hz, 1H),
7.20 (ddd, J=8.2, 4.3, 2.0 Hz, 1H), 6.55 (d, J=6.3 Hz, 1H),
4.50-4.40 (m, 1H), 3.86 (s, 3H), 3.48-3.38 (m, 1H), 3.22-3.10 (m,
1H), 3.06-2.88 (m, 2H), 2.12-2.02 (m, 1), 2.00-1.84 (m, 2H),
1.78-1.64 (m, 1H). LCMS: 425 [M+H].
11g: Preparation of
N-{(3R)-1-[(4-chlorophenyl)sulfonyl]piperidin-3-yl}-4-[6-(4-fluoro-3-meth-
oxyphenyl)imidazo[2,1-b][1,3]thiazol-5-yl]pyrimidin-2-amine
##STR00039##
[0234] The
4-[6-(4-fluoro-3-methoxyphenyl)imidazo[2,1-b][1,3]thiazol-5-yl]-
-N-[(3R)-piperidin-3-yl]pyrimidin-2-amine hydrochloride (0.25 g,
0.50 mmol) in methylene chloride (DCM) (12 ml) was cooled to
0.degree. C. and was treated with Hunig's base (440 .mu.l, 2.5
mmol). The mixture was kept at 0.degree. C. for 30 minutes then the
4-chlorophenylsulfonyl chloride (0.128 g, 0.60 mmol) was added. The
reaction mixture was stirred at room temperature for one hour. The
mixture was diluted with methylene chloride (10 ml) and was washed
water (2.times.10 ml) and a saturated aqueous sodium chloride
solution (10 ml). The organic phase was dried over sodium sulfate
and concentrated in vacuo. The crude product was purified by flash
chromatography using a gradient (ethyl acetate/hexanes, 50-75%),
affording 0.281 g (94%) of the title compound as a pale yellow
solid. M.p.: 142-143.degree. C. 400 MHz .sup.1H NMR (DMSO-d.sub.6
at 60.degree. C.) .delta.: 8.71 (br. s, 1H), 8.15 (d, J=5.5 Hz,
1H), 7.80-7.74 (m, 2H), 7.70-7.64 (m, 2H), 7.42 (d, J=4.5 Hz, 1H),
7.36 (dd, J=8.6, 2.3 Hz, 1H), 7.27 (dd, J=11.3, 8.2 Hz, 1H),
7.19-7.12 (m, 2H), 6.43 (d, J=5.5 Hz, 1H), 4.00-3.90 (m, 1H), 3.84
(s, 3H), 3.77-3.70 (m, 1H), 3.52-3.44 (m, 1H), 2.56-2.42 (m, 1H),
2.34 (t, J=10.0 Hz, 1H), 1.95-1.80 (m, 2H), 1.66-1.52 (m, 1H),
1.45-1.33 (m, 1H). LCMS: 599 [M+H]. Calc. for
C.sub.27H.sub.24N.sub.6O.sub.3S.sub.2FCl 0.16 water 0.74 diethyl
ether: C, 53.94; H, 4.57; N, 12.60. found C, 53.94; H, 4.19; N,
12.59.
11h: Preparation of
3-{5-[2-({(3R)-1-[(4-chlorophenyl)sulfonyl]piperidin-3-yl}amino)pyrimidin-
-4-yl]imidazo[2,1-b][1,3]thiazol-6-yl}-2-fluorophenol
##STR00040##
[0236] The
N-{(3R)-1-[(4-chlorophenyl)sulfonyl]piperidin-3-yl}-4-[6-(4-flu-
oro-3-methoxy-phenyl)imidazo[2,1-b][1,3]thiazol-5-yl]pyrimidin-2-amine
(0.251 g, 0.42 mmol) in methylene chloride (8 ml) was cooled to
-78.degree. C. and slowly treated with 1 molar solution of boron
tribromide in methylene chloride (3.4 ml). The reaction mixture was
kept at -78.degree. C. for one hour then was allowed to warm to
room temperature for two hours. The mixture was quenched by the
addition of methanol (900 .mu.l) at -78.degree. C. and was stirred
at room temperature for an additional hour. The mixture was diluted
with methylene chloride (100 ml) and washed with three portions of
25 ml of saturated sodium bicarbonate solution, two portions of 25
ml of water and two portions of 25 ml of saturated sodium chloride
solution. The organic phase was dried over sodium sulfate and
concentrated in vacuo, giving a yellow solid. The crude product was
purified by flash chromatography using a gradient (ethyl
acetate/hexanes, 50-75%), affording 0.063 g of the title compound
as a pale yellow solid. M.p.=172-175.degree. C. 400 MHz .sup.1H NMR
(DMSO-d.sub.6 at 60.degree. C.) .delta.: 9.84 (s, 1H), 8.70 (br. s,
1H), 8.15 (d, J=5.5 Hz, 1H), 7.80-7.74 (m, 2H), 7.70-7.64 (m, 2H),
7.40 (d, J=4.3 Hz, 1H), 7.19 (dd, J=13.3, 8.6 Hz, 1H), 7.18 (d,
J=8.2 Hz, 1H), 7.13 (br. d, J=7.8 Hz, 1H), 6.99 (ddd, J=8.2, 4.3,
2.0 Hz, 1H), 6.42 (d, J=5.1 Hz, 1H), 4.00-3.90 (m, 1H), 3.76-3.69
(m, 1H), 3.51-3.43 (m, 1H), 2.58-2.42 (m, 1H), 2.35 (t, J=10.6 Hz,
1H), 1.94-1.80 (m, 2H), 1.66-1.50 (m, 1H), 1.45-1.32 (m, 1H). LCMS:
585 [M+H]. Calc. for C.sub.26H.sub.22N.sub.6O.sub.3S.sub.2FCl 0.89
diethyl ether: C, 53.51; H, 4.42; N, 12.67. found C, 53.76; H,
4.22; N, 12.66.
Example 12
Preparation of
5-[5-(2-{[1-(cyclopropylsulfonyl)piperidin-4-yl]amino}pyrimidin-4-yl)imid-
azo[2,1-b][1,3]thiazol-6-yl]-2-fluorophenol
12a: Preparation of tert-butyl
4-{(4-[6-(4-fluoro-3-methoxyphenyl)imidazo[2,1-b][1,3]thiazol-5-yl]pyrimi-
din-2-yl}amino)piperidine-1-carboxylate
##STR00041##
[0238] A mixture of
3-(dimethylamino)-1-[6-(4-fluoro-3-methoxyphenyl)imidazo[2,1-b][1,3]thiaz-
ol-5-yl]prop-2-en-1-one (0.537 g, 1.55 mmol) and tert-butyl
4-{[(Z)-amino(imino)methyl]amino}piperidine-1-carboxylate
hydrochloride (0.650 g, 2.33 mmol) was diluted with 13 ml of
absolute ethanol and treated with 1.35 eq. of a 21% w/w solution of
sodium ethoxide in ethanol (780 .mu.l) to form a reaction mixture.
The reaction mixture was heated to reflux for 24 hours. Volatiles
were removed in vacuo and the residue was taken up in 50 ml of
ethyl acetate and 50 ml of water. The phases were separated and the
aqueous phase was extracted with 50 ml of ethyl acetate. The
combined organic extracts were washed with 100 ml of water, and
then with a saturated sodium chloride solution (100 ml). The
organic phase was dried with sodium sulfate, filtered and
concentrated in vacuo, to give a brown oil. The product was
purified by flash chromatography on silica gel (gradient 50% to 75%
ethyl acetate in hexanes) to yield 0.713 g of a pale yellow solid
(88%). 400 MHz .sup.1H NMR (DMSO-d.sub.6 at 60.degree. C.) .delta.:
8.71 (br. s, 1H), 8.11 (d, J=5.5 Hz, 1H), 7.45 (d, J=4.3 Hz, 1H),
7.35 (dd, J=8.2, 2.0 Hz, 1H), 7.26 (dd, J=11.3, 8.2 Hz, 1H),
7.19-7.12 (m, 2H), 6.39 (d, J=5.1 Hz, 1H), 3.98-3.87 (m, 3H), 3.83
(s, 3H), 2.91 (t, J=11.5 Hz, 2H), 1.94-1.87 (m, 2H), 1.47-1.35 (m,
2H), 1.42 (s, 9H). LCMS: 525 [M+H].
12b: Preparation of
4-[6-(4-fluoro-3-methoxyphenyl)imidazo[2,1-b][1,3]thiazol-5-yl]-N-[piperi-
din-4-yl]pyrimidin-2-amine hydrochloride
##STR00042##
[0240] The tert-butyl
4-({4-[6-(4-fluoro-3-methoxyphenyl)imidazo[2,1-b][1,3]thiazol-5-yl]pyrimi-
din-2-yl}amino)piperidine-1-carboxylate (0.713 g, 1.36 mmol) was
dissolved in 15 ml of dioxane and treated with 7.5 ml of anhydrous
4N HCl in dioxane at room temperature (RT). The reaction mixture
was stirred at room temperature for two hours. The mixture was then
diluted with 25 ml of ether and stirred until product separated as
a solid. Solid product was filtered and washed with ether. The
solid was dissolved in MeOH (20 ml) and concentrated to dryness
twice. The product was dried at high vacuum to yield 0.652 g of
yellow solid (bis HCl salt) (96%). 400 MHz .sup.1H NMR
(DMSO-d.sub.6 at 60.degree. C.) .delta.: 9.32 (br. s, 1H), 8.10 (d,
J=4.7 Hz, 1H), 7.61 (d, J=4.3 Hz, 1H), 7.39 (dd, J=8.2, 2.0 Hz,
1H), 7.33 (dd, J=11.3, 8.2 Hz, 1H), 7.19 (ddd, J=8.2, 4.3, 2.0 Hz,
1H), 6.56 (d, J=6.7 Hz, 1H), 4.30-4.20 (m, 1H), 3.86 (s, 3H),
3.40-3.32 (m, 2H), 3.12-2.96 (m, 2H), 2.22-2.12 (m, 2H), 1.99-1.86
(m, 2H). LCMS: 425 [M+H].
12c: Preparation of
N-[1-(cyclopropylsulfonyl)piperidin-4-yl]-4-[6-(4-fluoro-3-methoxyphenyl)-
imidazo[2,1-b][1,3]thiazol-5-yl]pyrimidin-2-amine
##STR00043##
[0242] The
4-[6-(4-fluoro-3-methoxyphenyl)imidazo[2,1-b][1,3]thiazol-5-yl]-
-N-[piperidin-4-yl]pyrimidin-2-amine hydrochloride (0.25 g, 0.50
mmol) in methylene chloride (DCM) (12 ml) was cooled to 0.degree.
C. and was treated with Hunig's base (440 .mu.l, 2.5 mmol). The
mixture was kept at 0.degree. C. for 30 minutes then the
cyclopropyl-sulfonyl chloride (72 .mu.l, 0.60 mmol) was added. The
reaction mixture was stirred at room temperature for one hour. The
mixture was diluted with methylene chloride (10 ml) and was washed
water (2.times.10 ml) and a saturated aqueous sodium chloride
solution (10 ml). The organic phase was dried over sodium sulfate
and concentrated in vacuo. The crude product was purified by flash
chromatography using a gradient (ethyl acetate/hexanes, 30-75%),
affording 0.253 g (96%) of the title compound as a pale yellow
solid. M.p.: 146-148.degree. C.400 MHz .sup.1H NMR (DMSO-d.sub.6 at
60.degree. C.) .delta.: 8.72 (br. s, 1H), 8.13 (d, J=5.1 Hz, 1H),
7.45 (d, J=4.3 Hz, 1H), 7.35 (dd, J=8.6, 2.0 Hz, 1H), 7.26 (dd,
J=11.3, 8.2 Hz, 1H), 7.25 (br. S, 1H), 7.15 (ddd, J=8.2, 4.7, 2.0
Hz, 1H), 6.41 (d, J=5.1 Hz, 1H), 3.95-3.86 (m, 1H), 3.83 (s, 3H),
3.68-3.61 (m, 2H), 3.06-2.96 (m, 2H), 2.60-2.52 (m, 1H), 2.08-1.96
(m, 2H), 1.66-1.54 (m, 2H), 1.04-0.94 (m, 4H). LCMS: 529 [M+H].
Calc. for C.sub.24H.sub.25N.sub.6O.sub.3S.sub.2F 0.13 water 0.7
diethyl ether: C, 54.31; H, 5.25; N, 14.18. found C, 54.32; H,
4.89; N, 14.19.
12d: Preparation of
5-[5-(2-{[1-(cyclopropylsulfonyl)piperidin-4-yl]amino}pyrimidin-4-yl)imid-
azo[2,1-b][1,3]thiazol-6-yl]-2-fluorophenol
##STR00044##
[0244] The
N-[1-(cyclopropylsulfonyl)piperidin-4-yl]-4-[6-(4-fluoro-3-meth-
oxyphenyl)imidazo[2,1-b][1,3]thiazol-5-yl]pyrimidin-2-amine (0.226
g, 0.43 mmol) in methylene chloride (8 ml) was cooled to
-78.degree. C. and slowly treated with 1 molar solution of boron
tribromide in methylene chloride (3.4 ml). The reaction mixture was
kept at -78.degree. C. for one hour then was allowed to warm to
room temperature for two hours. The mixture was quenched by the
addition of methanol (900 .mu.l) at -78.degree. C. and was stirred
at room temperature for an additional hour. The mixture was diluted
with methylene chloride (100 ml) and washed with three portions of
25 ml of saturated sodium bicarbonate solution, two portions of 25
ml of water and two portions of 25 ml of saturated sodium chloride
solution. The organic phase was dried over sodium sulfate and
concentrated in vacuo, giving a yellow solid. The crude product was
purified by flash chromatography (ethyl acetate), affording 0.19 g
(86%) of the title compound as a beige solid. M.p.=224-225.degree.
C. 400 MHz .sup.1H NMR (DMSO-d.sub.6 at 60.degree. C.) .delta.:
9.82 (s, 1H), 8.67 (br. s, 1H), 8.12 (d, J=5.5 Hz, 1H), 7.43 (d,
J=4.3 Hz, 1H), 7.25-7.14 (m, 3H), 6.99 (ddd, J=8.2, 4.3, 2.0 Hz,
1H), 6.41 (d, J=5.1 Hz, 1H), 3.95-3.84 (m, 1H), 3.68-3.60 (m, 2H),
3.00 (td, J=11.9, 2.7 Hz, 2H), 2.59-2.52 (m, 1H), 2.06-1.98 (m,
2H), 1.66-1.54 (m, 2H), 1.04-0.92 (m, 4H). LCMS: 515 [M+H]. Calc.
for C.sub.23H.sub.23N.sub.6O.sub.3S.sub.2F 0.53 diethyl ether 0.17
water: C, 53.46; H, 4.93; N, 14.89. found C, 53.46; H, 4.60; N,
14.88.
Example 13
Preparation of
N-[(3R)-1-[(4-chlorophenyl)sulfonyl]piperidin-3-yl]-4-[6-(3-cyanophenyl)i-
midazo[2,1-b][1,3]thiazol-5-yl]pyrimidin-2-amine
13a: Preparation of 6-(3-cyanophenyl)-imidazo[2,1-b]thiazole
##STR00045##
[0246] To a mixture of 2-aminothiazole (3.29 g, 32.9 mmol) and
2-bromo-3'-cyano-acetophenone (7.37 g, 32.9 mmol) was added
absolute ethanol (250 mL). The reaction was allowed to reflux with
vigorous stirring for 20 hours. The reaction mixture was reduced to
half its original volume in vacuo. The remaining suspension was
poured onto ice-water (200 mL) and the resulting mixture was
basified by addition of ammonium hydroxide solution (30%, 100 mL).
Product was collected by filtration and washed with water (50 mL),
dried in a vacuum oven at 50.degree. C. to provide
6-(3-cyanophenyl)-imidazo[2,1-b]thiazole (6.0 g, 81%). It was used
with out further purification. LCMS: 226 [M+H].
13b: Preparation of
1-[6-(3-cyanophenyl)imidazo[2,1-b][1,3]thiazol-5-yl]ethanone
##STR00046##
[0248] To a mixture of 6-(3-cyanophenyl)-imidazo[2,1-b]thiazole
(5.50 g, 24.4 mmol) and acetic anhydride (50 mL) was added 0.6 mL
of concentrated sulfuric acid. The reaction mixture was heated at
135.degree. C. for 5 hours. After cooling to room temperature, the
reaction mixture was diluted with dichloromethane (100 mL), washed
with water (50 mL.times.2), saturated aqueous sodium bicarbonate
solution (50 mL.times.2), water (50 mL), dried over sodium sulfate,
filtered and concentrated in vacuo. Product was purified by flash
chromatography on silica gel eluting with 40% ethyl acetate in
hexane to yield 4.8 g (74%) of the title compound as a light yellow
solid. LCMS: 268 [M+H].
13c: Preparation of
3-(dimethylamino)-1-[6-(3-cyanophenyl)imidazo[2,1-b][1,3]thiazol-5-yl]pro-
p-2-en-1-one
##STR00047##
[0250] A 100 mL round bottom flask was charged with the
1-[6-(3-cyanophenyl)imidazo[2,1-b][1,3]thiazol-5-yl]ethanone (4.30
g, 16.1 mmol) and dimethylformamide dimethylacetal (40 mL). The
mixture was refluxed for 6 hours and then concentrated in vacuo to
provide a dark solid. LCMS: 323 [M+H]; purity: 90% by UV at 254 nm.
This crude was used for next step reaction without further
purification.
13d: Preparation of tert-butyl
(3R)-3-({4-[6-(3-cyanophenyl)imidazo[2,1-b][1,3]thiazol-5-yl]pyrimidin-2--
yl}amino)piperidine-1-carboxylate
##STR00048##
[0252] To a mixture of
3-(dimethylamino)-1-[6-(3-cyanoyphenyl)imidazo[2,1-b][1,3]thiazol-5-yl]pr-
op-2-en-1-one (.about.16 mmol, crude) and tert-butyl
(3R)-3-{[(Z)-amino(imino)methyl]amino}piperidine-1-carboxylate
hydrochloride (6.71 g, 24.15 mmol) in 20 mL of absolute ethanol was
added a solution of sodium ethoxide in ethanol (21% w/w, 6.8 mL).
The mixture was heated to reflux for 24 hours. Then 3.0 mL of
sodium ethoxide in ethanol (21% w/w) was added and the mixture was
stirred for further 18 hours. Volatiles were removed in vacuo and
the residue was taken up in 200 mL of dichloridementhane, washed
with water (100 mL.times.2), dried over sodium sulfate and
concentrated. The product was purified by flash chromatography on
silica gel (ethyl acetate/hexanes, 50%) to yield 4.7 g of a pale
yellow solid (59%). M.p.=108-110.degree. C.; 400 MHz .sup.1H NMR
(DMSO-d.sub.6 at 60.degree. C.) .delta.: 8.65 (bs, 1H), 8.15 (d,
J=5.2 Hz, 1H), 8.00-7.99 (m, 1H), 7.93-7.90 (m, 1H), 7.86-7.83 (m,
1H), 7.64 (t, J=7.6 Hz, 1H), 7.43 (d, J=4.4 Hz, 1H), 7.16 (d, J=6.8
Hz, 1H), 6.34 (d, J=4.8 Hz, 1H), 3.93 (bs, 1H), 3.80-3.73 (m, 1H),
3.73 (bs, 1H), 2.92 (bs, 2H), 1.98-1.94 (m, 1H), 1.77-1.74 (m, 1H),
1.59-1.51 (m, 1H), 1.47-1.31 (m, 1H), 1.31 (s, 9H). LCMS: 502
[M+H].
13e: Preparation of
4-[6-(3-cyanophenyl)imidazo[2,1-b][1,3]thiazol-5-yl]-N-[(3R)-piperidin-3--
yl]pyrimidin-2-amine hydrochloride
##STR00049##
[0254] The tert-butyl
(3R)-3-({4-[6-(3-cyanophenyl)imidazo[2,1-b][1,3]thiazol-5-yl]pyrimidin-2--
yl}amino)piperidine-1-carboxylate (2.90 g, 5.79 mmol) was dissolved
in 20 mL of ethyl acetate and treated with 30 mL of 3.0 M HCl in
ethyl acetate at room temperature (RT) overnight. Solid product was
filtered, washed with ethyl acetate and dried under vacuum
overnight to provide the title compound as a yellow solid. It was
used without further purification. LCMS: 402 [M+H].
13e: Preparation of
N-{(3R)-1-[(4-chlorophenyl)sulfonyl]piperidin-3-yl}-4-[6-(3-cyanophenyl)i-
midazo[2,1-b][1,3]thiazol-5-yl]pyrimidin-2-amine
##STR00050##
[0256] The
4-[6-(3-cyanophenyl)imidazo[2,1-b][1,3]thiazol-5-yl]-N-[(3R)-pi-
peridin-3-yl]pyrimidin-2-amine hydrochloride (.about.5.79 mmol) in
dichloromethane (DCM) (50 mL) was cooled to 0.degree. C. and
treated with triethylamine (4.0 mL, 28.9 mmol), then
4-chlorophenylsulfonyl chloride (1.34 g, 6.37 mmol) was added. The
reaction mixture was stirred at room temperature for 1 hour,
diluted with dichloromethane (100 mL), washed with water (50
mL.times.3), dried over sodium sulfate and concentrated in vacuo to
provide 3.22 g (97%) of the title compound as a yellow solid.
M.p.=144-146.degree. C.; 400 MHz .sup.1H NMR (DMSO-d.sub.6 at
60.degree. C.) .delta.: 8.65 (br. s, 1H), 8.17 (d, J=5.2 Hz, 1H),
8.01 (s, 1H), 7.94 (dd, J=0.8 and 7.6 Hz, 1H), 7.82-7.85 (m, 1H),
7.77-7.75 (m, 2H), 7.67-7.64 (m, 3H), 7.44 (d, J=4.4 Hz, 1H), 7.18
(d, J=7.2 Hz, 1H), 6.37 (d, J=4.8 Hz, 1H), 3.91 (bs, 1H), 3.72 (d,
J=10.8 Hz, 1H), 3.48 (d, J=10.8 Hz, 1H), 2.48-2.45 (m, 1H), 2.32
(t, J=10 Hz, 1H), 1.89-1.82 (m, 2H), 1.60-1.56 (m, 1H), 1.41-1.36
(m, 1H). LCMS: 576 [M+H].
Example 14
Preparation of
3-{5-[2-({(3R)-1-[(4-chlorophenyl)sulfonyl]piperidin-3-yl}amino)pyrimidin-
-4-yl]imidazo[2,1-b][1,3]thiazol-6-yl}-N'-hydroxybenzenecarboximidamide
##STR00051##
[0258] To a suspension of
N-{(3R)-1-[(4-chlorophenyl)sulfonyl]piperidin-3-yl}-4-[6-(3-cyano-phenyl)-
imidazo[2,1-b][1,3]thiazol-5-yl]pyrimidin-2-amine (0.050 g, 0.086
mmol) in 80% ethanol-water (2.5 mL) was added an aqueous solution
(0.50 mL) containing 6.65 mg of hydroxylamine hydrochloride (1.1
equivalents) and 4.61 mg of sodium carbonate (0.5 equivalents). The
resulting solution was heated at 80.degree. C. for 20 hours. Solid
was collected by filtration and treated with hot (80.degree. C.)
80% ethanol-water (2 mL.times.5). Solid was collected and dried
under vacuum at 45.degree. C. overnight to afford 25 mg (48%) of
the title compound as a yellow solid. M.p.=272-273.degree. C. 400
MHz .sup.1H NMR (DMSO-d.sub.6 at 60.degree. C.) .delta.: 9.52 (s,
1H), 8.70 (bs, 1H), 8.11 (d, J=5.2 Hz, 1H), 7.93 (s, 1H), 7.77-7.73
(m, 3H), 7.67-7.66 (m, 2H), 7.59 (d, J=6.8 Hz, 1H), 7.47-7.40 (m,
2H), 7.11 (d, J=7.6 Hz, 1H), 6.38 (d, J=4.4 Hz, 1H), 5.68 (s, 2H),
3.94 (br. s, 1H), 3.73 (d, J=8.4 Hz, 1H), 3.48 (d, J=10.8 Hz, 1H),
2.49-2.48 (m, 1H), 2.35 (t, J=8.8 Hz, 1H), 1.95-1.84 (m, 21),
1.60-1.5 (m, 1H), 1.46-1.30 (m, 1H). LCMS: 610 [M+H].
Example 15
Preparation of
3-(5-{2-[(R)-1-(4-chloro-benzenesulfonyl)-piperidin-3-ylamino]-pyrimidin--
4-yl}-imidazo[2,1-b]thiazol-6-yl)-benzamide
##STR00052##
[0260] To a solution of
N-{(3R)-1-[(4-chlorophenyl)sulfonyl]piperidin-3-yl}-4-[6-(3-cyano-phenyl)-
imidazo[2,1-b][1,3]thiazol-5-yl]pyrimidin-2-amine (0.50 g, 0.87
mmol) in dichloromethane (DCM) (10 mL) at -78.degree. C. was added
a solution of borane tribromide (BBr.sub.3) (1.74 mL, 1.0 M in
DCM). The mixture was stirred at -78.degree. C. for 0.5 hour, then
room temperature for one hour. The mixture was then cooled to
-78.degree. C. and methanol (1 mL) was added. The resulting mixture
was stirred at room temperature overnight. Solvent was removed in
vaco, the residue was treated with a 1:1 mixture of dichloromethane
and water (50 mL). Organic layer was separated, dried over sodium
sulfate and concentrated. Product was purified by flash
chromatography on silica gel eluting with 5% methanol in
dichloromethane to afford 0.019 g (4%) of the title compound as a
yellow solid. M.p.=168-170.degree. C. 400 MHz .sup.1H NMR
(DMSO-d.sub.6 at 60.degree. C.) .delta.: 8.70 (br. s, 1H), 8.10 (s,
1H), 8.10 (d, J=4.8 Hz, 1H), 7.94 (d, J=7.6 Hz, 1H), 7.94-7.80 (m,
1H), 7.77-7.65 (m, 4H), 7.53 (t, J=8.0 Hz, 1H), 7.42 (d, J=4.4 Hz,
1H), 7.25-7.13 (m, 2H), 7.15 (d, J=7.2 Hz, 1H), 6.34 (d, J=5.6 Hz,
1H), 3.92 (bs, 1H), 3.73 (d, J=8.4 Hz, 1H), 3.48 (d, J=11.2 Hz,
1H), 2.48-2.43 (m, 1H), 2.35 (t, J=10.8 Hz, 1H), 1.90-1.82 (m, 2M),
1.59-1.56 (m, 1H), 1.39-1.34 (m, 1H). LCMS: 595 [M+H].
Example 16
Preparation of
3-(5-{2-[(3R)-piperidin-3-ylamino]pyrimidin-4-yl}imidazo[2,1-b][1,3]thiaz-
ol-6-yl)benzamide
16a: Preparation of
(R)-3-{4-[6-(3-carbamoyl-phenyl)-imidazo[2,1-b]thiazol-5-yl]-pyrimidin-2--
ylamino}-piperidine-1-carboxylic acid tert-butyl ester
##STR00053##
[0262] To a solution of tert-butyl
(3R)-3-({4-[6-(3-cyanophenyl)imidazo[2,1-b][1,3]thiazol-5-yl]pyrimidin-2--
yl}amino)piperidine-1-carboxylate (0.204 g, 0.407 .mu.mmol) in
ethanol (5 mL) was added 25% aqueous sodium hydroxide (0.072 mL,
0.448 mmol). The mixture was heated at 75.degree. C. for 20 hours.
Solvent was removed to dryness. Residue was taken into
dichloromethane (20 mL), washed with water (5 mL), dried over
sodium sulfate and concentrated. Product was purified by flash
chromatography on silica gel eluting with 5% methanol in
dichloromethane to afford 0.175 g (83%) of the title compound as an
off-white solid. M.p.=161-165.degree. C. 400 MHz .sup.1H NMR
(DMSO-d.sub.6 at 60.degree. C.) .delta.: 8.70 (br. s, 1H), 8.14 (s,
114), 8.10 (d, J=5.6 Hz, 1H), 7.94 (d, J=8.0 Hz, 1H), 7.72 (d,
J=7.6 Hz, 1H). 7.54 (t, J=7.6 Hz, 1H), 7.44 (d, J=4.4 Hz, 1H),
7.30-7.14 (bs, 2H), 7.15 (d, J=6.8 Hz, 1H), 6.33 (d, J=5.2 Hz, 1H),
3.96 (bs, 1H), 3.81-3.77 (m, 1H), 3.68 (bs, 1H), 2.94-2.90 (m, 2H),
2.00-1.97 (m, 1H), 1.80-1.77 (m, 1H), 1.59-1.53 (m, 1H), 1.46-1.40
(m, 1H), 1.34 (s, 9H); LCMS: 520 [M+H].
16b: Preparation of
345-{2-[(3R)-piperidin-3-ylamino]pyrimidin-4-yl}imidazo[2,1-b][1,3]thiazo-
l-6-yl)benzamide
##STR00054##
[0264]
(R)-3-{4-[6-(3-carbamoyl-phenyl)-imidazo[2,1-b]thiazol-5-yl]-pyrimi-
din-2-ylamino}-piperidine-1-carboxylic acid tert-butyl ester (0.15
g, 0.289 mmol) was dissolved in 3 mL of ethyl acetate and treated
with 3 ml of 3.0 M HCl in ethyl acetate at room temperature (RT)
evernight. Solid product was filtered, washed ethyl acetate and
dried under vacuum overnight to provide 0.130 g (97%) of the title
compound as a yellow solid. M.p.=202-205.degree. C. 400 MHz .sup.1H
NMR (DMSO-d.sub.6 at 60.degree. C.) .delta.: 9.35 (br. s, 1H),
9.20-8.25 (bs, 3H), 8.12-8.09 (m, 2H), 7.98-7.968.0 (m, 1H),
7.74-7.72 (m, 1H), 7.57-7.52 (m, 2H), 7.25 (bs, 1H), 6.40 (d, J=6.0
Hz, 1H), 4.31 (br. s, 1H), 3.40 (d, J=9.2 Hz, 1H), 3.16-3.13 (m,
1H), 2.94-2.90 (m, 2H), 2.03-1.97 (m, 1H), 1.96-1.89 (m, 1H),
1.89-1.80 (bs, 1H), 1.66-1.60 (m, 1H); LCMS: 459 [M+H]. calc. for
C.sub.21H.sub.21N.sub.7OS 3.14 (HCl), 0.25 (EtOAc) C, 47.52; H,
4.74; N, 17.63. found C, 47.57; H, 4.44; N, 17.52; LCMS: 420
[M+H].
Example 17
Preparation of
3-{5-[2-([(3R)-1-[(4-chlorophenyl)sulfonyl]piperidin-3-yl]amino)pyrimidin-
-4-yl]imidazo[2,1-b][1,3]thiazol-6-yl}benzoic Acid
17a: Preparation of
3-(5-{2-[(R)-1-(4-Chloro-benzenesulfonyl)-piperidin-3-ylamino]-pyrimidin--
4-yl}-imidazo[2,1-b]thiazol-6-yl)-N-methoxy-N-methyl-benzamide
##STR00055##
[0266] To a solution of
N-{(3R)-1-[(4-chlorophenyl)sulfonyl]piperidin-3-yl}-4-[6-(3-cyano-phenyl)-
imidazo[2,1-b][1,3]thiazol-5-yl]pyrimidin-2-amine (1.43 g, 2.49
mmol) in ethanol (30 mL) was added 25% aqueous sodium hydroxide
(1.5 mL, 15.5 mmol). The mixture was heated at 75.degree. C. for 5
days. Solvent was removed to dryness. Residue was dissolved into a
mixture of dichloromethane (100 mL) and 0.5 N HCl (40 mL). Organic
layer was separated, dried over sodium sulfate and concentrated to
dryness. The residue was dried further under high vacuum for 24
hours. It was used without further purification.
[0267] The crude product was dissolved in N,N-dimethylformamide (30
mL). To the resulting solution was added
O-benzotriazole-1-yl-N,N,N',N'-tetramethyluronium
hexafluorophosphate (HBTU) (1.42 g, 3.74 mmol), triethylamine (1.04
mL, 7.47 mmol), lastly, a solution of N,O-dimethyl hydroxylamine
hydrochloride (0.365 S, 3.74 mmol). The mixture was stirred at room
temperature for 1 hour, diluted with dichloromethane (100 mL),
washed with water (50 mL.times.4), dried over sodium sulfate and
concentrated. Product was purified by flash chromatography on
silica gel (methanol:dichloromethane:ethylacetate=0.5:7:2) to
afford the title compound 0.976 g (62%, two steps) as a pale yellow
solid. M.p.=114-115.degree. C. 400 MHz .sup.1H NMR (DMSO-d.sub.6 at
60.degree. C.) .delta.: 8.70 (br. s, 1H), 8.11 (d, J=4.6 Hz, 1H),
7.77-7.74 (m, 3H), 7.71 (d, J=8.0 Hz, 1H), 7.68-7.62 (m, 3H), 7.53
(t, J=7.2 Hz, 1H), 7.41 (d, J=4.4 Hz, 1H), 7.14 (d, J=6.8 Hz, 1H),
6.40 (d, J=5.8 Hz, 1H), 3.93 (br. s, 1H), 3.73-3.71 (m, 1H), 3.54
(s, 3H), 3.48-3.45 (m, 10H), 3.25 (s, 3H), 2.48-2.43 (m, 1H), 2.33
(t, J=10.0 Hz, 1H), 1.89-1.82 (m, 2H), 1.59-1.56 (m, 1H), 1.41-1.32
(m, 1H).LCMS: 639 [M+H].
17b: Preparation of
3-{5-[2-({(3R)-1-[(4-chlorophenyl)sulfonyl]piperidin-3-yl}amino)pyrimidin-
-4-yl]imidazo[2,1-b][1,3]thiazol-6-yl}benzoic Acid
##STR00056##
[0269] To a solution of
3-(5-{2-[(R)-1-(4-chloro-benzenesulfonyl)-piperidin-3-ylamino]-pyrimidin--
4-yl}-imidazo[2,1-b]thiazol-6-yl)-N-methoxy-N-methyl-benzamide
(0.57 g, 0.089 mmol) in a mixture of methanol (1.0 mL) and
tetrahydrofuran (THF) (3.0 mL) was added a solution of lithium
hydroxide (0.075 g, 0.179 mmol.) in water (1.0 mL). The mixture was
stirred at room temperature for 48 hours. Solvent was removed to
dryness. Residue was dissolved into a mixture of dichloromethane
(20 mL) and 1.0 N HCl (1.0 mL). Organic layer was separated, washed
with water (5 mL.times.4), dried over sodium sulfate and
concentrated to dryness. The residue was dried further under high
vacuum at 45.degree. C. for 24 hours to provide 0.45 g (85%) as a
yellow solid. M.p.=190-195.degree. C. 400 MHz .sup.1H NMR
(DMSO-d.sub.6 at 60.degree. C.) .delta.: 8.70 (br. s, 1H), 8.16
(bs, 1H), 8.12 (d, J=5.2 Hz, 1H), 7.99 (d, J=8.0 Hz, 1H), 7.78-7.83
(m, 1H), 7.77-7.74 (m, 2H), 7.68-7.65 (m, 2H), 7.58 (t, J=8.0 Hz,
1H), 7.41 (d, J=4.4 Hz, 1H), 7.17 (d, J=6.8 Hz, 1H), 6.37 (d, J=5.2
Hz, 1H), 3.92 (br. s, 1H), 3.75-3.71 (m, 1H), 3.48-3.45 (m, 1H),
2.49-2.43 (m, 1H), 2.32 (t, J=10.4 Hz, 1H), 1.90-1.82 (m, 2H),
1.59-1.56 (m, 1H), 1.39-1.32 (m, 1H).LCMS: 596 [M+H].
Example 18
Preparation of
(1E)-1-(3-[5-[2-([(3R)-1-[(4-chlorophenyl)sulfonyl]piperidin-3-yl]amino)p-
yrimidin-4-yl]imidazo[2,1-b][1,3]thiazol-6-yl]phenyl)ethanone
oxime
18a: Preparation of
1-(3-{5-[2-({(3R)-1-[(4-chlorophenyl)sulfonyl]piperidin-3-yl}amino)pyrimi-
din-4-yl]imidazo[2,1-b][1,3]thiazol-6-yl}phenyl)ethanone
##STR00057##
[0271] To a solution of
3-(5-{2-[(R)-1-(4-chloro-benzenesulfonyl)-piperidin-3-ylamino]-pyrimidin--
4-yl}-imidazo[2,1-b]thiazol-6-yl)-N-methoxy-N-methyl-benzamide
(0.10 g, 0.157 mmol) in anhydrous tetrahydrofuran (THF) (3.0 mL) at
0.degree. C. was added a solution of methyl magnesium chloride (3.0
M in THF) (0.523 mL, 1.57 mmoL). The mixture was stirred for 3
hours, then quenched with saturated aqueous ammonium chloride
solution (1 mL). Product was extracted with 10 mL of
dichloromethane, washed with water (5 mL.times.2), dried over
sodium sulfate and concentrated. Product was purified by flash
chromatography on silica gel (40% dichloromethane in ethyl acetate)
to afford 0.085 g (91%) of the title compound as a pale yellow
solid. M.p.=124-127.degree. C. 400 MHz .sup.1H NMR (DMSO-d.sub.6 at
60.degree. C.) .delta.: 8.70 (br. s, 1H), 8.17 (m, 1H), 8.12 (d,
J=5.6 Hz, 1H), 7.9 (d, J=7.6 Hz, 1H), 7.86-7.84 (m, 1H), 7.77-7.74
(m, 2H), 7.67-7.65 (m, 2H), 7.62 (t, J=8.0 Hz, 1H), 7.42 (d, J=4.8
Hz, 1H), 7.15 (d, J=7.6 Hz, 1H), 6.38 (d, J=5.2 Hz, 1H), 3.93 (bs,
1H), 3.74-3.72 (m, 1H), 3.48-3.45 (m, 1H), 2.57 (s, 3H), 2.49-2.45
(m, 1H), 2.32 (t, J=10.4 Hz, 1H), 1.90-1.82 (m, 2H), 1.59-1.56 (m,
1H), 1.39-1.32 (m, 1H); LCMS: 594 [M+H].
18b: Preparation of
(1E)-1-(3-{5-[2-({(3R)-1-[(4-chlorophenyl)sulfonyl]piperidin-3-yl}amino)p-
yrimidin-4-yl]imidazo[2,1-b][1,3]thiazol-6-yl}phenyl)ethanone
oxime
##STR00058##
[0273] To a mixture of
1-(3-{5-[2-({(3R)-1-[(4-chlorophenyl)sulfonyl]piperidin-3-yl}amino)pyrimi-
din-4-yl]imidazo[2,1-b][1,3]thiazol-6-yl}phenyl)ethanone (0.10 g,
0.168 mmol) and hydroxylamine hydrochloride (0.0125 g, 0.188 mmol.)
in methanol (2.0 mL) was added 0.2 mL of acetic acid. The mixture
was heated at 50.degree. C. for 3 hours. After cooled to room
temperature, the mixture was diluted with dichloromethane (10 mL),
washed with saturated aqueous sodium bicarbonate (5 mL.times.3),
water (5 mL), dried over sodium sulfate and concentrated. Product
was purified by flash chromatography on silica gel
(methanol:dichloromethane:ethylacetate=0.5:7:2) to afford 0.069 g
(67%) of the title compound as an off-white solid.
M.p.=156-158.degree. C. 400 MHz .sup.1H NMR (DMSO-d.sub.6 at
60.degree. C.) .delta.: 11.08 (s, 1H), 8.70 (br. s, 1H), 8.11 (d,
J=4.8 Hz, 1H), 7.87 (s, 1H), 7.77-7.74 (m, 2H), 7.71-7.59 (m, 3H),
7.59-7.56 (m, 1H), 7.46 (t, J=7.6 Hz, 1H), 7.41 (d, J=4.4 Hz, 1H),
7.13 (d, J=7.6 Hz, 1H), 6.40 (d, J=5.2 Hz, 1H), 3.93 (br. s, 1H),
3.74-3.71 (m, 1H), 3.48-3.45 (m, 1H), 2.48-2.45 (m, 1H), 2.33 (t,
J=7.6 Hz, 1H), 2.15 (s, 3H), 1.89-1.82 (m, 2H), 1.59-1.56 (m, 1H),
1.39-1.34 (m, 1H); LCMS: 608 [M+H].
Example 19
Preparation of
3-{5-[2-([(3R)-1-[(4-chlorophenyl)sulfonyl]piperidin-3-yl]amino)pyrimidin-
-4-yl]imidazo[2,1-b][1,3]thiazol-6-yl}benzaldehyde oxime
19a: Preparation of
3-{5-[2-({(3R)-1-[(4-chlorophenyl)sulfonyl]piperidin-3-yl}amino)pyrimidin-
-4-yl]imidazo[2,1-b][1,3]thiazol-6-yl}benzaldehyde
##STR00059##
[0275] To a solution of
3-(5-{2-[(R)-1-(4-chloro-benzenesulfonyl)-piperidin-3-ylamino]-pyrimidin--
4-yl}-imidazo[2,1-b]thiazol-6-yl)-N-methoxy-N-methyl-benzamide
(0.05 g, 0.078 mmol) in anhydrous tetrahydrofuran (THF) (3.0 mL) at
0.degree. C. was added a solution of lithium aluminum hydride (LAH)
(2.0 M in THF) (0.078 mL, 0.15 mmol). The mixture was stirred at
0.degree. C. for 30 minutes, then quenched with methanol (0.5 mL),
diluted with dichloromethane (5 mL), washed with a solution of 10%
aqueous potassium sodium tartrate (5 mL), water (5 mL), dried over
sodium sulfate and concentrated. Product was purified by flash
chromatography on silica gel
(methanol:dichloromethane:ethylacetate=0.5:7:2) to afford 0.033 g
(73%) of the title compound as a pale yellow solid.
M.p.=124-126.degree. C.; 400 MHz .sup.1H NMR (DMSO-d.sub.6 at
60.degree. C.) .delta.: 10.06 (s, 1H), 8.70 (br. s, 1H), 8.14-8.12
(m, 2H), 7.96-7.91 (m, 2H), 7.77-7.74 (m, 2H), 7.70-7.64 (m, 3H),
7.43 (d, J=4.4 Hz, 1H), 7.15 (d, J=7.6 Hz, 1H), 6.39 (d, J=5.2 Hz,
1H), 3.93 (bs, 1H), 3.74-3.71 (m, 1H), 3.48-3.45 (m, 1H), 2.49-2.4
(m, 1H), 2.35 (t, J=10.8 Hz, 1H), 1.89-1.82 (m, 2H), 1.60-1.56 (m,
1H), 1.39-1.32 (m, 1H).LCMS: 580 [M+H].
19b: Preparation of
3-{5-[2-({(3R)-1-[(4-chlorophenyl)sulfonyl]piperidin-3-yl}amino)pyrimidin-
-4-yl]imidazo[2,1-b][1,3]thiazol-6-yl}benzaldehyde oxime
##STR00060##
[0277] To a mixture
3-{5-[2-({(3R)-1-[(4-chlorophenyl)sulfonyl]piperidin-3-yl}amino)pyrimidin-
-4-yl]imidazo[2,1-b][1,3]thiazol-6-yl}benzaldehyde (0.81 g, 0.14
mmol) and hydroxylamine hydrochloride (0.0107 g, 0.154 mmol.) in
methanol (2.0 mL) was added 0.2 mL of acetic acid. The mixture was
heated at 50.degree. C. for 2 hours. After cooled to room
temperature, the mixture was diluted with dichloromethane (10 mL),
washed with saturated aqueous sodium bicarbonate (5 mL.times.3),
water (5 mL), dried over sodium sulfate and concentrated. Product
was purified by flash chromatography on silica gel
(methanol:dichloromethane:ethylacetate=0.5:7:2) to afford 0.051 g
(61%) of the title compound as an off-white solid.
M.p.=238-240.degree. C. 400 MHz .sup.1H NMR (DMSO-d, at 60.degree.
C.) 11.14 (s, 1H), 8.70 (bs, 1H), 8.17 (s, 1H), 8.11 (d, J=5.6 Hz,
1H), 7.8 (s, 1H), 7.77-7.74 (m, 2H), 7.68-7.64 (m, 3H), 7.60-7.57
(m, 1H), 7.47 (t, J=7.6 Hz, 1H), 7.41 (d, J=4.4 Hz, 1H), 7.14 (d,
J=7.6 Hz, 1H), 6.40 (d, J=5.2 Hz, 1H), 3.93 (br. s, 1H), 3.74-3.71
(m, 1H), 3.48-3.45 (m, 1H), 2.5-2.4 (m, 1H), 2.33 (t, J=10.4 Hz,
1H), 1.89-1.82 (m, 2H), 1.59-1.56 (m, 1H), 1.40-1.32 (m, 1H). LCMS:
594 [M+H].
Example 20
Preparation of
(3-{5-[2-({(3R)-1-[(4-chlorophenyl)sulfonyl]piperidin-3-yl}amino)pyrimidi-
n-4-yl]imidazo[2,1-b][1,3]thiazol-6-yl}phenyl)methanol
##STR00061##
[0279] To a mixture
3-{5-[2-({(3R)-1-[(4-chlorophenyl)sulfonyl]piperidin-3-yl}amino)pyrimidin-
-4-yl]imidazo[2,1-b][1,3]thiazol-6-yl}benzaldehyde (0.20 g, 0.346
mmol) in anhydrous tetrahydrofuran (THF) (5.0 mL) at room
temperature was added a solution of lithium aluminum hydride (LAH)
(2.0 M in THF) (0.346 mL, 0.692 mmol). The mixture was stirred for
one hour, then quenched with methanol (1.0 mL), diluted with
dichloromethane (50 mL) and 30 mL of water. Organic layer was
separated and the water layer was extracted with dichloromethane
(50 mL.times.2). Organic layer was combined, dried over sodium
sulfate and concentrated. Product was purified by flash
chromatography on silica gel
(methanol:dichloromethane:ethylacetate=0.5:7:2) to afford 0.142 g
(71%) of the title compound as an off-white solid.
M.p.=150-155.degree. C. 400 MHz .sup.1H NMR (DMSO-d.sub.6 at
60.degree. C.) .delta.: 8.75 (bs, 1H), 8.12 (d, J=5.6 Hz, 1H),
7.77-7.74 (m, 2H), 7.67-7.65 (m, 2H), 7.56 (s, 1H), 7.44-7.36 (m,
4H), 7.11 (d, J=7.2 Hz, 1H), 6.39 (d, J=5.6 Hz, 1H), 5.07 (t, J=5.6
Hz, 1H), 4.55 (d, J=6.0 Hz, 2H), 3.29 (br. s, 1H), 3.73 (d, J=7.2
Hz, 1H), 3.48 (d, J=11.2 Hz, 1H), 2.5-2.43 (m, 1H), 2.35 (t, J=10.0
Hz, 1H), 1.91-1.82 (m, 2H), 1.60-1.57 (m, 1H), 1.40-1.32 (m, 1H).
LCMS: 581 [M+H].
Example 21
Preparation of
4-{6-[3-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl]imidazo[2,1-b][1,3]thiazol--
5-yl}-N-[(3R)-piperidin-3-yl]pyrimidin-2-amine
21a: Preparation of
(R)-3-(4-{6-[3-(5-methyl-[1,2,4]oxadiazol-3-yl)-phenyl]-imidazo[2,1-b]thi-
azol-5-yl}-pyrimidin-2-ylamino)-piperidine-1-carboxylic acid
tert-butyl ester
##STR00062##
[0281] To mixture of hydroxylamine hydrochloride (0.030 g, 0.439
mmol) and sodium carbonate (0.021 g, 0.200 mmol) in water (0.40 mL)
was added tert-butyl
(3R)-3-({4-[6-(3-cyanophenyl)imidazo[2,1-b][1,3]thiazol-5-yl]pyrimidin-2--
yl}amino)piperidine-1-carboxylate (0.200 g, 0.399 mmol) and ethanol
(1.6 mL). The resulting mixture was heated at 80.degree. C. for 4
hours and then solvent was removed. Residue was dried under vacuum
at 45.degree. C. overnight. It was used for next reaction without
further purification. The dried residue was dissolved in anhydrous
N,N-demethylformamide (DMF) and acetic anhydride (0.041 mL, 0.419
mmol) was added. The resulting mixture was heated at 120.degree. C.
for 3 hours, cooled to room temperature, diluted with
dichloromethane (10 mL), washed with water (5 mL.times.3), dried
over sodium sulfate and concentrated. Product was purified by flash
chromatography on silica gel eluting with 80% ethyl acetate in
hexane to afford 0.169 g (76%) of the title compound as a yellow
solid. M.p.=110-112.degree. C. 400 MHz .sup.1H NMR (DMSO-d.sub.6 at
60.degree. C.) .delta.: 8.72 (bs, 1H), 8.25-8.24 (m, 1H), 8.12 (d,
J=5.2 Hz, 1H), 8.06-8.03 (m, 1H), 7.83-7.80 (m, 1H), 7.66 (t, J=8.0
Hz, 1H), 7.44 (d, J=4.4 Hz, 1H), 7.17 (d, J=7.2 Hz, 1H), 6.44 (d,
J=5.6 Hz, 1H), 3.95 (bs, 1H), 3.81-3.78 (m, 1H), 3.68 (bs, 1H),
2.96 (bs, 2H), 2.00-1.97 (m, 1H), 1.82-1.77 (m, 1H), 1.64-1.56 (m,
1H), 1.50-1.40 (m, 1H), 1.34 (s, 9H); LCMS: 559 [M+H].
21b: Preparation of
4-{6-[3-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl]imidazo[2,1-b][1,3]thiazol--
5-yl}-N-[(3R)-piperidin-3-yl]pyrimidin-2-amine
##STR00063##
[0283]
((R)-3-(4-{6-[3-(5-Methyl-[1,2,4]oxadiazol-3-yl)-phenyl]-imidazo[2,-
1-b]thiazol-5-yl}-pyrimidin-2-ylamino)-piperidine-1-carboxylic acid
tert-butyl ester (0.15 g, 0.269 mmol) was dissolved in 2 mL of
ethyl acetate and treated with 2 ml of 3.0 M HCl in ethyl acetate
at room temperature (RT) overnight. Solid product was filtered,
washed ethyl acetate and dried under vacuum overnight to provide
0.135 g (100%) of the title compound as a yellow solid.
M.p.=203-207.degree. C. 400 MHz .sup.1H NMR (DMSO-d.sub.6 at
60.degree. C.) .delta. 9.35 (br. s, 1H), 8.21 (s, 1H), 8.12 (d,
J=6.0 Hz, 1H), 8.0 (d, J=7.6 Hz, 1H), 7.82-7.80 (m, 1H), 7.67 (t,
J=8.2 Hz, 1H), 7.54 (s, 10H), 6.90 (bs, 1H), 6.48 (d, J=5.6 Hz,
1H), 4.2 (br. s, 1H), 3.40 (d, J=10.8 Hz, 1H), 3.13 (d, 1H),
2.92-2.87 (m, 2H), 2.65 (s, 31), 2.00-1.97 (m, 1H), 1.96-1.89 (m,
1H), 1.89-1.80 (bs, 1H), 1.64-1.57 (m, 1H); LCMS: 459 [M+H]. calc.
for C.sub.23H.sub.22N.sub.8OS 2.3 HCl: C, 50.93; H, 4.52; N, 20.66.
found C, 50.93; H, 4.42; N, 19.30.
Example 22
Preparation of
3-{5-[2-({(3R)-1-[(4-chlorophenyl)sulfonyl]piperidin-3-yl}amino)pyrimidin-
-4-yl]imidazo[2,1-b][1,3]thiazol-6-yl}phenyl carbamate
##STR00064##
[0285] A solution of
3-{5-[2-({(3R)-1-[(4-chlorophenyl)sulfonyl]piperidin-3-yl}amino)pyrimidin-
-4-yl]imidazo[2,1-b][1,3]thiazol-6-yl}phenol (0.15 g, 0.26 mmol) in
anhydrous tetrahydrofuran (10 ml, dissolved by slow warming) was
treated with chlorosulfonyl isocyanate (34 ul, 1.5 eq) at room
temperature. After 30 min the mixture was again treated with
chlorosulfonyl isocyanate (34 ul, 1.5 eq) and stirred for 10 min.
Solvent was removed under reduced pressure and the residue was
purified by preparative HPLC (using TFA as modifier). Pure
fractions were collected and dried to give product as TFA salt
(0.03 g, 19%). M.p.=118-120.degree. C. 400 MHz .sup.1H NMR
(DMSO-d.sub.6 at 60.degree. C.) .delta.: 8.78 (br. s, 1H), 8.12 (d,
J=5.6 Hz, 1H), 7.78-7.75 (m, 2H), 7.68-7.66 (m, 2H), 7.31 (m, 1H),
7.40 (m, 1H), 7.25 (m, 1H), 7.15 (tt, J=2.0 and 7.4 Hz, 1H), 6.9
(br m, 1H), 6.48 (d, J=5.6 Hz, 1H), 3.97 (br. s, 1H), 3.72 (dd,
J=11.2 and 4.4 Hz, 1H), 3.46 (d, J=11.6 Hz, 1H), 2.51 (m, 1H), 2.36
(t, J=9.6 Hz, 1H), 1.91-1.83 (m, 2H), 1.65-1.5 (m, 1H), 1.44-1.38
(m, 1H). LCMS: 611 [M+H]. Calc. for
C.sub.27H.sub.24N.sub.7O.sub.4S.sub.2Cl 1.84 TFA: C, 44.94; H,
3.18; N, 11.96. found C, 44.93; H, 3.3; N, 11.46.
Example 23
Preparation of
3-{5-[2-({(3R)-1-[(4-chlorophenyl)sulfonyl]piperidin-3-yl}amino)pyrimidin-
-4-yl]imidazo[2,1-b][1,3]thiazol-6-yl}phenyl sulfamate
##STR00065##
[0287] A solution of
3-{(5-[2-({(3R)-1-[(4-chlorophenyl)sulfonyl]piperidin-3-yl}amino)pyrimidi-
n-4-yl]imidazo[2,1-b][1,3]thiazol-6-yl}phenol (0.10 g, 0.176 mmol)
in DMA (2.0 ml) was treated with sulfamoyl chloride (3-4 eq) in
portions and monitor reaction for completion. After the reaction
was complete dimethyl acetamide was removed under reduced pressure.
Residue was taken in methanol (2.0 ml) and purified by preparative
HPLC (using TFA as modifier). Pure fractions were collected and
dried to give product as TFA salt (0.06 g, 53%).
M.p.=133-35.degree. C. 400 MHz H NMR (DMSO-d.sub.6 at 60.degree.
C.) .delta.: 8.67 (br, 1H), 8.13 (d, J=5.2 Hz, 1H), 7.90 (brs, 2H),
7.77 (d, J=9.2 Hz 2H), 7.67 (d, J=9.2 Hz, 2H), 7.57 (m, 1H), 7.52
(m, 1H), 7.43 (d, J=4.4 Hz, 1H), 7.35-7.33 (m, 1H), 7.20 (m, 1H),
6.50 (d, J=5.2 Hz, 1H), 3.97 (br. s, 1H), 3.73 (m, 1H), 3.46 (d,
J=10.8 Hz, 1H), 2.52 (m, 1H), 2.35 (t, J=10.8 Hz, 1H), 1.91-1.83
(m, 2H), 1.59 (m, 1H), 1.43-1.35 (m, 1H). LCMS: 647 [M+H]. Calc.
for C.sub.26H.sub.24N.sub.7O.sub.5S.sub.3Cl.5.7 TFA: C, 34.66; H,
2.31; N, 7.56. found C, 35.08; H, 1.78; N, 9.36.
Example 24
Measurement of RAF Activity
[0288] Materials: The RAF kinases and the anti-phospho MEK1/2
antibody were from Upstate (Charlottesville, Va.). The RAF
substrate used was full length N-terminal GST-MEK-1, which was
expressed in E. coli and purified in-house by HPLC. All proteins
were aliquoted and stored at -80.degree. C. Superblock.TM. in
phosphate buffered saline (PBS) blocking reagent was form Pierce
(cat. #37515). ATP was from Roche (cat. # 19035722). Alkaline
Phosphatase-tagged goat anti-rabbit antibody was from Pierce (cat.
# 31340).
[0289] Methods: All RAF biochemical assays were performed using an
assay buffer containing 20 mM MOPS, 5 mM EGTA, 37.5 mM MgCl.sub.2,
1 mM DTT and 50 .mu.M ATP. There was 6.25 ng/well mutant B-RAF and
7.5 ng/well MEK-1 in the final assay conditions. Compounds were
serially diluted in assay buffer containing 1% DMSO and 20 .mu.L of
test compound at a concentration 3-fold more than the final
concentration, and were added to a polypropylene V-well reaction
plate. Vehicle control wells received buffer only with DMSO at
equivalent concentrations to the test wells. In rapid succession,
20 .mu.l of substrate was added (0.45 ng/.mu.l MEK-1), followed by
20 .mu.l of enzyme (0.375 ng/.mu.l mutant B-RAF). These reaction
plates were incubated at room temperature for 30 minutes. Capture
of MEK-1 was initiated by transferring 50 .mu.L of the reaction
mixture to a Nunc Maxisorp.TM. microplate that is designed for
non-specific protein capture. After 30 minute capture of MEK-1 at
room temperature, this plate was washed with TBST (6.times.200
.mu.L/well) to fully terminate the reaction. The plate was then
blocked for 1 hour by the addition of 100 .mu.l/well of
Superblock.TM. in phosphate buffered saline (PBS) blocking reagent.
Plate was again washed with TBST (6 times with 200 .mu.L/well),
followed by the addition of 70 .mu.L/well of Upstate anti-phospho
MEK 1/2 diluted 1:1000 in Pierce Superblock (PBS). After a 60
minute incubation, this plate was washed with TBST (6 times with
200 .mu.L/well), and 70 .mu.L of the secondary antibody (Pierce
Alkaline Phosphatase tagged goat anti-rabbit) prepared at 1:4000 in
Superblock, were added. After a 45 minute incubation at room
temperature, the wells of the microplate were washed with TBST (6
times with 200 .mu.L/well), and thereafter 100 .mu.l/well of
Attophos.TM. fluorescent alkaline phosphatase substrate was added
according to the manufacturer's instructions (JBL Scientific).
Fluorescence was read on a Perkin Elmer Envision multilabel reader,
using the following filters: Excitation Filter: CFP430 nM, Emission
Filter: Emission Filter 579 nM.
Example 25
[0290] Compounds of the present invention have been screened for
their ability to inhibit all isoforms, both wild-type and mutant of
RAF kinases (A-RAF, B-RAF and C-RAF) in general, and the mutant
B-RAF (V600E) in particular in human cancer cells. A375 is a human
melanoma cell line that harbors the most common B-RAF
mutation-V600E found in human cancers. The ability of compounds to
inhibit RAF kinases in this assay is correlated with the reduction
of MEK and ERK phosphorylation, and is therefore a direct indicator
of potential in vivo therapeutic activity.
[0291] Materials: A375 cells from ATCC were maintained at
37.degree. C., 5% CO.sub.2 in DMEM media supplemented with 10%
fetal bovine serum, penicillin/streptomycin and fungizone.
(Invitrogen)
[0292] Methods: Test compounds were dissolved and diluted 1:1000 in
DMSO. A375 cells were seeded in six-well tissue culture plates at
5-8.times.10.sup.5 per well and cultured at 37.degree. C. for 24 h.
Cells were incubated with compounds for one hour before being lysed
in EPage.TM. loading buffer (Invitrogen). Lysates were
electrophoresed on 8% EPage.TM. gels and transferred to
polyvinylidene difluoride membranes. After incubations with primary
and secondary antibodies, the immunostained proteins were detected
and quantitated by an Odyssey infrared imager (Li-cor). Analysis
was performed by non-linear regression to generate a dose response
curve. The calculated IC.sub.50 value was the concentration of the
test compound that causes a 50% decrease in phospho-MEK and
phospho-ERK levels. The primary antibodies used were anti-MEK
(Stressgen), anti-ERK (BD Biosciences), anti-phospho-ERK and
anti-phospho-MEK (Cell Signaling). The secondary antibodies used
were IRDYE800 anti-rabbit, IRDYE 800 anti-mouse (Rockland),
AlexaFluor680 anti-mouse and AlexaFluoro680 anti-rabbit
(Invitrogen).
[0293] Compounds of the present invention reduce the levels of
phospho-MEK and phospho-ERK through the inhibition of RAF kinases.
The RAF/MEK/ERK pathway inhibition data for certain compounds of
the present invention are shown in FIGS. 5 and 6.
Example 26
[0294] Compounds of the present invention have been tested for
activity against a variety of cancer cell lines. The ability of
compounds to inhibit cell growth in this assay is correlated with
the reduction of dehydrogenase enzyme activity found in
metabolically active cells.
[0295] Materials: A375, Colo-205, DLD1, SK-MEL-2, SK-MEL-28 and
SW480 cells from ATCC were maintained at 37.degree. C., 5% CO.sub.2
in DMEM media supplemented with 10% fetal bovine serum,
penicillin/streptomycin and fungizone (Invitrogen). NCM460
(Incell), a normal colon epithelial cell line, and human mammary
epithelial cells (Cambrex) were maintained at 37.degree. C., 5%
CO.sub.2 in DMEM and HEBM media (Cambrex), respectively.
[0296] Methods: Test compounds were dissolved and diluted to
300.times. in DMSO then diluted 1:40 in DMEM. Cells were seeded
into 96-well tissue culture plates at 2-5.times.10.sup.3 per well
and cultured at 37.degree. C. for 24 h. Cells were incubated with
test compounds for 72 hours followed by incubation with tetrazolium
compound
(3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl-
)-2H-tetrazolium, inner salt; MTS) and the electron coupling
reagent, phenazine methosulfate (PMS) for 4 hr. MTS was chemically
reduced by dehydrogenase in cells into formazan. The measurement of
the absorbance of the formazan was assessed using an ENVISION.TM.
(Perkin Elmer) microplate reader at 492 nm. The calculated
IC.sub.50 value is the concentration of the test compound that
causes a 50% decrease in the absorbance.
[0297] Compounds of the present invention inhibit the growth of a
variety of cancer cells. The data for certain compounds of the
invention are shown in Table 1.
TABLE-US-00001 TABLE 1 IC.sub.50 values of compound in various
normal and cancer cell lines (units in .mu.M) SKMEL2 DLD1 SW480
HMEC NCM460 A375 Colo205 SKMEL28 NRAS KRAS KRAS Compound # Normal
Normal B-RAF (V600E) B-RAF (V600E) B-RAF (V600E) (Q61R) (G13D)
(G12V) 289 1.24 4.17 0.15 0.18 0.67 0.99 3.08 2.97 105 2.72 6.68
0.31 0.38 0.48 1.1 4.73 1.28 267 1.07 2.05 0.27 0.19 0.38 0.87 1.76
2.13 112 2.24 4.71 0.27 0.33 0.86 0.91 3.33 2.74 268 0.72 2.54 0.37
0.36 0.8 1.33 4.03 4.4
TABLE-US-00002 TABLE 2 Exemplary compounds of the invention Melting
Mutant B- point RAF IC.sub.50 Cmpd (.degree. C.) (uM) or #
Structure IUPAC name or LCMS % inhibition 1 ##STR00066##
4-[6-(4-fluorophenyl)imidazo[2,1- b][1,3]thiazol-5-yl]-N-[1-
(methylsulfonyl)piperidin-3- yl]pyrimidin-2-amine 208-209 62 @ 10
uM 2 ##STR00067## 4-[6-(4-fluorophenyl)imidazo[2,1-
b][1,3]thiazol-5-yl]-N-{1-[(4- fluorophenyl)sulfonyl]piperidin-3-
yl}pyrimidin-2-amine 196-197 0.458 3 ##STR00068##
N-[1-(4-fluorobenzoyl)piperidin-3- yl]-4-[6-(4-
fluorophenyl)imidazo[2,1- b][1,3]thiazol-5-yl]pyrimidin-2- amine
226-228 45 @ 10 uM 4 ##STR00069## N-[1-(4-fluorobenzyl)piperidin-3-
yl]-4-[6-(4- fluorophenyl)imidazo[2,1-
b][1,3]thiazol-5-yl]pyrimidin-2- amine 131-133 55 @ 10 uM 5
##STR00070## N-(1-ethylpiperidin-3-yl)-4-[6-(4-
fluorophenyl)imidazo[2,1- b][1,3]thiazol-5-yl]pyrimidin-2- amine
115-117 54 @ 10 uM 6 ##STR00071## N-ethyl-3-({4-[6-(4-
fluorophenyl)imidazo[2,1- b][1,3]thiazol-5-yl]pyrimidin-2
yl}amino)piperidine-1- carboxamide 128-130 54 @ 10 uM 7
##STR00072## N-(4-fluorophenyl)-3-({4-[6-(4-
fluorophenyl)imidazo[2,1- b][1,3]thiazol-5-yl]pyrimidin-2-
yl}amino)piperidine-1- carboxamide 221-223 49 @ 10 uM 8
##STR00073## 4-[6-(4-fluorophenyl)imidazo[2,1-
b][1,3]thiazol-5-yl]-N-{(3R)-1-[(4-
fluorophenyl)sulfonyl]piperidin-3- yl}pyrimidin-2-amine 145-148
0.023 9 ##STR00074## 4-[6-(4-fluorophenyl)imidazo[2,1-
b][1,3]thiazol-5-yl]-N-{(3S)-1-[(4-
fluorophenyl)sulfonyl]piperidin-3- yl}pyrimidin-2-amine 141-143
2.94 10 ##STR00075## 4-[6-(4-fluorophenyl)imidazo[2,1-
b][1,3]thiazol-5-yl]-N-[(3S)- piperidin-3-yl]pyrimidin-2-amine
208-210 51 @ 10 uM 11 ##STR00076##
4-[6-(4-fluorophenyl)imidazo[2,1-
b][1,3]oxazol-5-yl]-N-{(3R)-1-[(4-
fluorophenyl)sulfonyl]piperidin-3- yl}pyrimidin-2-amine 135-138
0.207 12 ##STR00077## 4-[6-(4-fluorophenyl)imidazo[2,1-
b][1,3]oxazol-5-yl]-N-[(3R)- piperidin-3-yl]pyrimidin-2-amine
184-186 46 @ 10 uM 13 ##STR00078##
4-[6-(4-fluorophenyl)imidazo[2,1- b][1,3]oxazol-5-yl]-N-[(3S)-
piperidin-3-yl]pyrimidin-2-amine 202-205 30 @ 10 uM 14 ##STR00079##
4-[6-(4-fluorophenyl)imidazo[2,1-
b][1,3]oxazol-5-yl]-N-{(3S)-1-[(4-
fluorophenyl)sulfonyl]piperidin-3- yl}pyrimidin-2-amine 115-117
>3.0 15 ##STR00080## (3R)-3-({4-[6-(4- fluorophenyl)imidazo[2,1-
b][1,3]oxazol-5-yl]pyrimidin-2- yl}amino)-N-phenylpiperidine-1-
carboxamide 141-144 28 @ 10 uM 16 ##STR00081##
(3R)-N-butyl-3-({4-[6-(4- fluorophenyl)imidazo[2,1-
b][1,3]oxazol-5-yl]pyrimidin-2- yl}amino)piperidine-1- carboxamide
108-111 44 @ 10 uM 17 ##STR00082## (3R)-3-({4-[6-(4-
fluorophenyl)imidazo[2,1- b][1,3]oxazol-5-yl]pyrimidin-2-
yl}amino)-N-(4- methylphenyl)piperidine-1- carboxamide 129-132 16 @
10 uM 18 ##STR00083## (3R)-3-({4-[6-(4- fluorophenyl)imidazo[2,1-
b][1,3]oxazol-5-yl]pyrimidin-2- yl}amino)-N-(2-
phenylethyl)piperidine-1- carboxamide 105-108 18 @ 10 uM 19
##STR00084## (3R)-N-cyclohexyl-3-({4-[6-(4-
fluorophenyl)imidazo[2,1- b][1,3]oxazol-5-yl]pyrimidin-2-
yl}amino)piperidine-1- carboxamide 130-132 46 @ 10 uM 20
##STR00085## (3R)-N-benzyl-3-({4-[6-(4- fluorophenyl)imidazo[2,1-
b][1,3]oxazol-5-yl]pyrimidin-2- yl}amino)piperidine-1- carboxamide
116-120 24 @ 10 uM 21 ##STR00086## (3R)-3-({4-[6-(4-
fluorophenyl)imidazo[2,1- b][1,3]oxazol-5-yl]pyrimidin-2-
yl}amino)-N-(4- methoxyphenyl)piperidine-1- carboxamide 123-127 53
@ 10 uM 22 ##STR00087## (3R)-N-(4-fluorophenyl)-3-({4-[6-
(4-fluorophenyl)imidazo[2,1- b][1,3]oxazol-5-yl]pyrimidin-2-
yl}amino)piperidine-1- carboxamide 134-137 35 @ 10 uM 23
##STR00088## (3R)-3-({4-[6-(4- fluorophenyl)imidazo[2,1-
b][1,3]oxazol-5-yl]pyrimidin-2- yl}amino)-N-(tetrahydro-2H-
pyran-2-yl)piperidine-1- carboxamide 140-143 48 @ 10 uM 24
##STR00089## (3R)-N-[4- (dimethylamino)phenyl]-3-({4-[6-
(4-fluorophenyl)imidazo[2,1- b][1,3]oxazol-5-yl]pyrimidin-2-
yl}amino)piperidine-1- carboxamide 145-148 60 @ 10 uM 25
##STR00090## (3R)-3-({4-[6-(4- fluorophenyl)imidazo[2,1-
b][1,3]oxazol-5-yl]pyrimidin-2- yl}amino)-N-(2-
furylmethyl)piperidine-1- carboxamide 112-115 35 @ 10 uM 26
##STR00091## N-[(3R)-1-benzoylpiperidin-3-yl]-
4-[6-(4-fluorophenyl)imidazo[2,1- b][1,3]oxazol-5-yl]pyrimidin-2-
amine 131-133 0.195 27 ##STR00092##
4-[6-(4-fluorophenyl)imidazo[2,1- b][1,3]oxazol-5-yl]-N-[(3R)-1-(4-
methoxybenzoyl)piperidin-3- yl]pyrimidin-2-amine 155-156 4.89 28
##STR00093## N-[(3R)-1-(4- fluorobenzoyl)piperidin-3-yl]-4-[6-
(4-fluorophenyl)imidazo[2,1- b][1,3]oxazol-5-yl]pyrimidin-2- amine
184-185 0.184 29 ##STR00094## N-{(3R)-1-[(4-
chlorophenoxy)acetyl]piperidin-3- yl}-4-[6-(4-
fluorophenyl)imidazo[2,1- b][1,3]oxazol-5-yl]pyrimidin-2- amine
102-103 1.82 30 ##STR00095## 4-[6-(4-fluorophenyl)imidazo[2,1-
b][1,3]oxazol-5-yl]-N-[(3R)-1- (methoxyacetyl)piperidin-3-
yl]pyrimidin-2-amine 161-162 0.711 31 ##STR00096## N-[(3R)-1-
(cyclohexylcarbonyl)piperidin-3- yl]-4-[6-(4-
fluorophenyl)imidazo[2,1- b][1,3]oxazol-5-yl]pyrimidin-2- amine
129-131 2.95 32 ##STR00097## 4-[6-(4-fluorophenyl)imidazo[2,1-
b][1,3]oxazol-5-yl]-N-[(3R)-1- isonicotinoylpiperidin-3-
yl]pyrimidin-2-amine 196-198 0.362 33 ##STR00098##
4-[6-(4-fluorophenyl)imidazo[2,1- b][1,3]oxazol-5-yl]-N-[(3R)-1-(2-
furoyl)piperidin-3-yl]pyrimidin-2- amine 110-112 2.17 34
##STR00099## 4-[6-(4-fluorophenyl)imidazo[2,1-
b][1,3]oxazol-5-yl]-N-[(3R)-1- propionylpiperidin-3-yl]pyrimidin-
2-amine 173-174 1.58 35 ##STR00100##
N-[(3R)-1-(aminoacetyl)piperidin- 3-yl]-4-[6-(4-
fluorophenyl)imidazo[2,1- b][1,3]oxazol-5-yl]pyrimidin-2- amine
225-230 11 @ 10 uM 36 ##STR00101## N-[(3R)-1-(2-amino-2-
methylpropanoyl)piperidin-3-yl]-4- [6-(4-fluorophenyl)imidazo[2,1-
b][1,3]oxazol-5-yl]pyrimidin-2- amine 215-218 4.52 37 ##STR00102##
4-[6-(4-fluorophenyl)imidazo[2,1- b][1,3]oxazol-5-yl]-N-[(3R)-1-L-
prolylpiperidin-3-yl]pyrimidin-2- amine 210-212 >5.0 38
##STR00103## 4-[6-(4-fluorophenyl)imidazo[2,1-
b][1,3]oxazol-5-yl]-N-(3R)-1-(3- phenylpropanoyl)piperidin-3-
yl]pyrimidin-2-amine 94-95 2.9 39 ##STR00104## N-{(3R)-1-[4-
(dimethylamino)benzoyl]piperidin- 3-yl}-4-[6-(4-
fluorophenyl)imidazo[2,1- b][1,3]oxazol-5-yl]pyrimidin-2- amine
145-146 0.477 40 ##STR00105## 4-[6-(4-fluorophenyl)imidazo[2,1-
b][1,3]oxazol-5-yl]-N-[(3R)-1-(3- methylbutanoyl)piperidin-3-
yl]pyrimidin-2-amine 89-90 0.142 41 ##STR00106##
4-[6-(4-fluorophenyl)imidazo[2,1- b][1,3]oxazol-5-yl]-N-[(3R)-1-
(morpholin-4-ylcarbonyl)piperidin- 3-yl]pyrimidin-2-amine 102-105
38 @ 10 uM 42 ##STR00107## 4-[6-(4-fluorophenyl)imidazo[2,1-
b][1,3]oxazol-5-yl]-N-[(3R)-1- (phenylsulfonyl)piperidin-3-
yl]pyrimidin-2-amine 143-144 68 @ 10 uM 43 ##STR00108##
N-{(3R)-1-[(4- chlorophenyl)sulfonyl]piperidin-3- yl}-4-[6-(4-
fluorophenyl)imidazo[2,1- b][1,3]oxazol-5-yl]pyrimidin-2- amine
146-147 0.143 44 ##STR00109## 4-[6-(4-fluorophenyl)imidazo[2,1-
b][1,3]oxazol-5-yl]-N-{(3R)-1-[(4-
methoxyphenyl)sulfonyl]piperidin- 3-yl}pyrimidin-2-amine 233-234 45
@ 10 uM 45 ##STR00110## 4-[6-(4-fluorophenyl)imidazo[2,1-
b][1,3]oxazol-5-yl]-N-{(3R)-1-[(4-
methylphenyl)sulfonyl]piperidin-3- yl}pyrimidin-2-amine 194-195
0.59 46 ##STR00111## 4-[6-(4-fluorophenyl)imidazo[2,1-
b][1,3]oxazol-5-yl]-N-((3R)-1-{[3-
(trifluoromethyl)phenyl]sulfonyl} piperidin-3-yl)pyrimidin-2-amine
125-127 19 @ 10 uM 47 ##STR00112## N-{(3R)-1-[(3-chloro-4-
fluorophenyl)sulfonyl]piperidin-3- yl}-4-[6-(4-
fluorophenyl)imidazo[2,1- b][1,3]oxazol-5-yl]pyrimidin-2- amine
135-136 0.963 48 ##STR00113## 4-[6-(4-fluorophenyl)imidazo[2,1-
b][1,3]oxazol-5-yl]-N-{(3R)-1-[(4-
isopropylphenyl)sulfonyl]piperidin- 3-yl}pyrimidin-2-amine 199-200
3.02 49 ##STR00114## 4-[6-(4-fluorophenyl)imidazo[2,1-
b][1,3]oxazol-5-yl]-N-((3R)-1-{[4-
(trifluoromethoxy)phenyl]sulfonyl} piperidin-3-yl)pyrimidin-2-amine
164-165 32 @ 10 uM 50 ##STR00115## N-{(3R)-1-[(3-
chlorophenyl)sulfonyl]piperidin-3- yl}-4-[6-(4-
fluorophenyl)imidazo[2,1- b][1,3]oxazol-5-yl]pyrimidin-2- amine
165-166 35 @ 10 uM 51 ##STR00116## N-{(3R)-1-[(3,5-
dichlorophenyl)sulfonyl]piperidin- 3-yl}-4-[6-(4-
fluorophenyl)imidazo[2,1- b][1,3]oxazol-5-yl]pyrimidin-2- amine
173-174 25 @ 10 uM 52 ##STR00117##
4-[6-(4-fluorophenyl)imidazo[2,1-
b][1,3]oxazol-5-yl]-N-{(3R)-1-[(3-
fluorophenyl)sulfonyl]piperidin-3- yl}pyrimidin-2-amine 134-135 55
@ 10 uM 53 ##STR00118## 4-[6-(4-fluorophenyl)imidazo[2,1-
b][1,3]oxazol-5-yl]-N-{(3R)-1-[(2-
methylphenyl)sulfonyl]piperidin-3- yl}pyrimidin-2-amine 155-156 42
@ 10 uM 54 ##STR00119## N-{(3R)-1-[(2,6-
difluorophenyl)sulfonyl]piperidin- 3-yl}-4-[6-(4-
fluorophenyl)imidazo[2,1- b][1,3]oxazol-5-yl]pyrimdin-2- amine
192-193 47 @ 10 uM 55 ##STR00120## 4-{[(3R)-3-({4-[6-(4-
fluorophenyl)imidazo[2,1- b][1,3]oxazol-5-yl]pyrimidin-2-
yl}amino)piperidin-1- yl]sulfonyl}benzonitrile 144-145 0.63 56
##STR00121## N-((3R)-1-{(3,5- bis(trifluoromethyl)phenyl]
sulfonyl}piperidin-3-yl)-4-[6-(4- fluorophenyl)imidazo[2,1-
b][1,3]oxazol-5-yl]pyrimidin-2- amine 185-186 57 @ 10 uM 57
##STR00122## 4-[6-(4-fluorophenyl)imidazo[2,1-
b][1,3]oxazol-5-yl]-N-{(3R)-1-[(3-
methoxyphenyl)sulfonyl]piperidin- 3-yl}pyrimidin-2-amine 188-190 34
@ 10 uM 58 ##STR00123## 4-[6-(4-fluorophenyl)imidazo[2,1-
b][1,3]oxazol-5-yl]-N-((3R)-1-{[4-
(trifluoromethyl)phenyl]sulfonyl} piperidin-3-yl)pyrimidin-2-amine
153-154 0.403 59 ##STR00124## 4-{[(3R)-3-({4-[6-(4-
fluorophenyl)imidazo[2,1- b][1,3]oxazol-5-yl)pyrimidin-2-
yl}amino)piperidin-1- yl]sulfonyl}benzoic acid 300 0.576 60
##STR00125## 4-[6-(4-fluorophenyl)imidazo[2,1-
b][1,3]oxazol-5-yl]-N-{(3R)-1-[(4-
phenoxyphenyl)sulfonyl]piperidin- 3-yl}pyrimidin-2-amine 279-280 15
@ 10 uM 61 ##STR00126## N-{(3R)-1-[(5-chloro-2-
methoxyphenyl)sulfonyl]piperidin- 3-yl}-4-[6-(4-
fluorophenyl)imidazo[2,1- b][1,3]oxazol-5-yl]pyrimidin-2- amine
173-174 37 @ 10 uM 62 ##STR00127##
4-[6-(4-fluorophenyl)imidazo[2,1- b][1,3]thiazol-5-yl]-N-[(3R)-
piperidin-3-yl]pyrimidin-2-amine 191-194 45 @ 10 uM 63 ##STR00128##
3-(4-{[(3R)-3-({4-[6-(4- fluorophenyl)imidazo[2,1-
b][1,3]oxazol-5-yl]pyrimidin-2- yl}amino)piperidin-1-
yl]sulfonyl}phenyl)propanoic acid 268-269 0.441 64 ##STR00129##
N-(5-{[(3R)-3-({4-[6-(4- fluorophenyl)imidazo[2,1-
b][1,3]oxazol-5-yl]pyrimidin-2- yl}amino)piperidin-1-yl]sulfonyl}-
4-methyl-1,3-thiazol-2- yl)acetamide 176-177 58 @ 10 uM 65
##STR00130## N-{(3R)-1-[(2,4-dimethyl-1,3-
thiazol-5-yl)sulfonyl]piperidin-3- yl}-4-[6-(4-
fluorophenyl)imidazo[2,1- b][1,3]oxazol-5-yl]pyrimidin-2- amine
220-222 42 @ 10 uM 66 ##STR00131## N-{(3R)-1-[(1,2-dimethyl-1H-
imidazol-4-yl)sulfonyl]piperidin-3- yl}-4-[6-(4-
fluorophenyl)imidazo[2,1- b][1,3]oxazol-5-yl]pyrimidin-2- amine
141-143 70 @ 10 uM 67 ##STR00132## (3R)-3-({4-[6-(4-
fluorophenyl)imidazo[2,1- b][1,3]oxazol-5-yl]pyrimidin-2-
yl}amino)-N-[5-methyl-2- (trifluoromethyl)-3-
furyl]piperidine-1-carboxamide 120-122 29 @ 10 uM 68 ##STR00133##
(3R)-N-(cyclohexylmethyl)-3-({4- [6-(4-fluorophenyl)imidazo[2,1-
b][1,3]oxazol-5-yl]pyrimidin-2- yl}amino)piperidine-1- carboxamide
118-120 42 @ 10 uM 69 ##STR00134## (3R)-N-(2,4-dimethoxyphenyl)-3-
({4-[6-(4- fluorophenyl)imidazo[2,1-
b][1,3]oxazol-5-yl]pyrimidin-2- yl}amino)piperidine-1- carboxamide
113-116 42 @ 10 uM 70 ##STR00135## (3R)-N-(5-chloro-2-
methoxyphenyl)-3-({4-[6-(4- fluorophenyl)imidazo[2,1-
b][1,3]oxazol-5-yl]pyrimidin-2- yl}amino)piperidine-1- carboxamide
127-130 49 @ 10 uM 71 ##STR00136##
(3R)-N-[2-(4-fluorophenyl)ethyl]- 3-({4-[6-(4-
fluorophenyl)imidazo[2,1- b][1,3]oxazol-5-yl]pyrimidin-2-
yl}amino)piperidine-1- carboxamide 114-116 16 @ 10 uM 72
##STR00137## (3R)-3-({4-[6-(4- fluorophenyl)imidazo[2,1-
b][1,3]oxazol-5-yl]pyrimidin-2- yl}amino)-N-[(1R)-1-
phenylethyl]piperidine-1- carboxamide 121-122 53 @ 10 uM 73
##STR00138## (3R)-N-(3,4-difluorophenyl)-3-({4-
[6-(4-fluorophenyl)imidazo[2,1- b][1,3]oxazol-5-yl]pyrimidin-2-
yl}amino)piperidine-1- carboxamide 132-134 37 @ 10 uM 74
##STR00139## (3R)-N-(2-fluorophenyl)-3-({4-[6-
(4-fluorophenyl)imidazo[2,1- b][1,3]oxazol-5-yl]pyrimidin-2-
yl}amino)piperidine-1- carboxamide 112-115 35 @ 10 uM 75
##STR00140## (3R)-3-({4-[6-(4- fluorophenyl)imidazo[2,1-
b][1,3]oxazol-5-yl]pyrimidin-2- yl}amino)-N-(2-methoxy-4-
nitrophenyl)piperidine-1- carboxamide 154-156 >10 76
##STR00141## (3R)-N-(4-fluorobenzyl)-3-({4-[6-
(4-fluorophenyl)imidazo[2,1- b][1,3]oxazol-5-yl]pyrimidin-2-
yl}amino)piperidine-1- carboxamide 111-113 36 @ 10 uM 77
##STR00142## 4-[6-(3- methoxyphenyl)imidazo[2,1-
b][1,3]thiazol-5-yl]-N-[(3R)- piperidin-3-yl]pyrimidin-2-amine
220-225 1.81 78 ##STR00143## 4-[6-(3,4- difluorophenyl)imidazo[2,1-
b][1,3]thiazol-5-yl]-N-[(3R)- piperidin-3-yl]pyrimidin-2-amine
195-198 1.26 79 ##STR00144## 4-[6-(4-fluorophenyl)-2-
methylimidazo[2,1-b][1,3]thiazol- 5-yl]-N-[(3R)-piperidin-3-
yl]pyrimidin-2-amine 206-208 67 @ 10 uM 80 ##STR00145##
(3R)-N-benzyl-3-({4-[6-(3- methoxyphenyl)imidazo[2,1-
b][1,3]thiazol-5-yl]pyrimidin-2- yl}amino)piperidine-1- carboxamide
108-110 40 @ 10 uM 81 ##STR00146##
(3R)-N-(2-furylmethyl)-3-({4-[6-(3- methoxyphenyl)imidazo[2,1-
b][1,3]thiazol-5-yl]pyrimidin-2- yl}amino)piperidine-1- carboxamide
119-121 50 @ 10 uM 82 ##STR00147## N-{(3R)-1-[(4-
fluorophenyl)sulfonyl]piperidin-3- yl}-4-[6-(3-
methoxyphenyl)imidazo[2,1- b][1,3]thiazol-5-yl]pyrimidin-2- amine
143-144 0.192 83 ##STR00148## N-[(3R)-1-(4-
methoxybenzoyl)piperidin-3-yl]-4- [6-(3-methoxyphenyl)imidazo[2,1-
b][1,3]thiazol-5-yl]pyrimidin-2- amine 130-132 >3.0 84
##STR00149## (3R)-N-[4- (dimethylamino)phenyl]-3-({4-[6-
(3-methoxyphenyl)imidazo[2,1- b][1,3]thiazol-5-yl]pyrimidin-2-
yl}amino)piperidine-1- carboxamide 127-129 19 @ 10 uM 85
##STR00150## 4-[6-(3,4- difluorophenyl)imidazo[2,1-
b][1,3]thiazol-5-yl]-N-{(3R)-1-[(4-
fluorophenyl)sulfonyl]piperidin-3- yl}pyrimidin-2-amine 128-131
0.058 86 ##STR00151## (3R)-3-({4-[6-(3,4-
difluorophenyl)imidazo[2,1- b][1,3]thiazol-5-yl]pyrimidin-2-
yl}amino)-N-[4- (dimethylamino)phenyl]piperidine- 1-carboxamide
135-137 54 @ 10 uM 87 ##STR00152## (3R)-N-benzyl-3-({4-[6-(3,4-
difluorophenyl)imidazo[2,1- b][1,3]thiazol-5-yl]pyrimidin-2-
yl}amino)piperidine-1- carboxamide 107-110 53 @ 10 uM 88
##STR00153## (3R)-3-({4-[6-(3,4- difluorophenyl)imidazo[2,1-
b][1,3]thiazol-5-yl]pyrimidin-2- yl}amino)-N-(2-
furylmethyl)piperidine-1- carboxamide 101-102 54 @ 10 uM 89
##STR00154## 4-[6-(3,4- difluorophenyl)imidazo[2,1-
b][1,3]thiazol-5-yl]-N-[(3R)-1-(4- methoxybenzoyl)piperidin-3-
yl]pyrimidin-2-amine 121-122 40 @ 10 uM 90 ##STR00155##
(3R)-N-benzyl-3-({4-[6-(4- fluorophenyl)-2-
methylimidazo[2,1-b][1,3]thiazol- 5-yl]pyrimidin-2-
yl}amino)piperidine-1- carboxamide 135-137 34 @ 10 uM 91
##STR00156## 4-[6-(4-fluorophenyl)-2-
methylimidazo[2,1-b][1,3]thiazol- 5-yl]-N-{(3R)-1-[(4-
fluorophenyl)sulfonyl]piperidin-3- yl}pyrimidin-2-amine 245-246
0.352 92 ##STR00157## 4-[6-(4-fluorophenyl)-2-
methylimidazo[2,1-b][1,3]thiazal- 5-yl]-N-[(3R)-1-(4-
methoxybenzoyl)piperidin-3- yl]pyrimidin-2-amine 200-201 5 @ 10 uM
93 ##STR00158## (3R)-3-({4-[6-(4-fluorophenyl)-2-
methylimidazo[2,1-b][1,3]thiazol- 5-yl]pyrimidin-2-yl}amino)-N-(2-
furylmethyl)piperidine-1- carboxamide 113-115 61 @ 10 uM 94
##STR00159## (3R)-N-[4- (dimethylamino)phenyl]-3-({4-[6-
(4-fluorophenyl)-2- methylimidazo[2,1-b][1,3]thiazol-
5-yl]pyrimidin-2- yl}amino)piperidine-1- carboxamide 193-194
>3.0 95 ##STR00160## N-{(3R)-1-[(4-
chlorophenyl)sulfonyl]piperidin-3- yl}-4-[6-(3-
methoxyphenyl)imidazo[2,1- b][1,3]thiazol-5-yl]pyrimidin-2- amine
127-128 0.147 96 ##STR00161## N-{(3R)-1-[(4-
chlorophenyl)sulfonyl]piperidin-3- yl}-4-[6-(4-fluorophenyl)-2-
methylimidazo[2,1-b][1,3]thiazol- 5-yl]pyrimidin-2-amine 273-274
0.026 97 ##STR00162## 4-[6-(2-naphthyl)imidazo[2,1-
b][1,3]thiazol-5-yl]-N-[(3R)- piperidin-3-yl]pyrimidin-2-amine
202-205 0.314 98 ##STR00163## N-{(3R)-1-[(4-
chlorophenyl)sulfonyl]piperidin-3- yl}-4-[6-(4-
fluorophenyl)imidazo[2,1- b][1,3]thiazol-5-yl]pyrimidin-2- amine
154-155 0.036 99 ##STR00164## 4-[6-(2,3-dihydro-1,4-
benzodioxin-6-yl)imidazo[2,1- b][1,3]thiazol-5-yl]-N-[(3R)-
piperidin-3-yl]pyrimidin-2-amine 210-215 29 @ 10 uM 100
##STR00165## 4-[6-(4-chloro-3- methoxyphenyl)imidazo[2,1-
b][1,3]thiazol-5-yl]-N-{(3R)-1-[(4-
chlorophenyl)sulfonyl]piperidin-3- yl}pyrimidin-2-amine 149-151 40
@ 10 uM 101 ##STR00166## 2-chloro-5-{5-[2-({(3R)-1-[(4-
chlorophenyl)sulfonyl]piperidin-3- yl}amino)pyrimidin-4-
yl]imidazo[2,1-b][1,3]thiazol-6- yl}phenol 163-164 0.011 102
##STR00167## 4-[6-(2- methoxyphenyl)imidazo[2,1-
b][1,3]thiazol-5-yl]-N-[(3R)- piperidin-3-yl]pyrimidin-2-amine
237-239 1.26 103 ##STR00168## N-{(3R)-1-[(4-
chlorophenyl)sulfonyl]piperidin-3- yl}-4-[6-(3-
methoxyphenyl)imidazo[2,1- b][1,3]oxazol-5-yl]pyrimidin-2- amine
115-118 48 @ 10 uM 104 ##STR00169## 3-{5-[2-({(3R)-1-[(4-
chlorophenyl)sulfonyl]piperidin-3- yl}amino)pyrimidin-4-
yl]imidazo[2,1-b][1,3]oxazol-6- yl}phenol 205-210 0.038 105
##STR00170## N-{(3R)-1-[(4- chlorophenyl)sulfonyl]piperidin-3-
yl}-4-[6-(2- methoxyphenyl)imidazo[2,1-
b][1,3]thiazol-5-yl]pyrimidin-2- amine 151-153 0.25 106
##STR00171## 4-[6-(4- methoxyphenyl)imidazo[2,1-
b][1,3]thiazol-5-yl]-N-[(3R)- piperidin-3-yl]pyrimidin-2-amine
189-191 27 @ 10 uM 107 ##STR00172## 2-{5-[2-({(3R)-1-[(4-
chlorophenyl)sulfonyl]piperidin-3- yl}amino)pyrimidin-4-
yl]imidazo[2,1-b][1,3]thiazol-6- yl}phenol 154-155 0.033 108
##STR00173## N-[(3R)-1-(4- fluorobenzoyl)piperidin-3-yl]-4-[6-
(3-methoxyphenyl)imidazo[2,1- b][1,3]thiazol-5-yl]pyrimidin-2-
amine 88-90 73 @ 10 uM 109 ##STR00174## 4-[6-(3-
methoxyphenyl)imidazo[2,1- b][1,3]thiazol-5-yl]-N-[(3R)-1-(3-
methylbutanoyl)piperidin-3- yl]pyrimidin-2-amine 85-87 >3.0 110
##STR00175## 4-{5-[(2-({(3R)-1-[(4-
chlorophenyl)sulfonyl]piperidin-3- yl}amino)pyrimidin-4-
yl]imidazo[2,1-b][1,3]thiazol-6- yl}phenol 179-180 >5.0 111
##STR00176## 4-{[(3R)-3-({4-[6-(3- hydroxyphenyl)imidazo[2,1-
b][1,3]thiazol-5-yl]pyrimidin-2- yl}amino)piperidin-1-
yl]sulfonyl}benzonitrile 178-180 0.028 112 ##STR00177##
N-[(3R)-1-isonicotinoylpiperidin-3- yl]-4-[6-(3-
methoxyphenyl)imidazo[2,1- b][1,3]thiazol-5-yl]pyrimidin-2- amine
133-135 >5.0 113 ##STR00178## 3-[5-(2-{[(3R)-1-(4-
fluorobenzoyl)piperidin-3- yl]amino}pyrimidin-4-
yl)imidazo[2,1-b][1,3]thiazol-6- yl]phenol 155-157 3.84 114
##STR00179## N-{(3R)-1-[(4- chlorophenyl)sulfonyl]piperidin-3-
yl}-4-[6-(3,4- difluorophenyl)imidazo[2,1-
b][1,3]thiazol-5-yl]pyrimidin-2- amine 111-113 48 @ 3 uM 115
##STR00180## 4-[6-(3- methoxyphenyl)imidazo[2,1-
b][1,3]oxazol-5-yl]-N-[(3R)- piperidin-3-yl]pyrimidin-2-amine
172-175 >10 116 ##STR00181## 3-[5-(2-{[(3R)-1-(3-
methylbutanoyl)piperidin-3- yl]amino}pyrimidin-4-
yl)imidazo[2,1-b][1,3]thiazol-6- yl]phenol 146-148 52 @ 10 uM 117
##STR00182## 3-[5-(2-{[(3R)-1- isonicatinoylpiperidin-3-
yl]amino}pyrimidin-4- yl)imidazo[2,1-b][1,3]thiazol-6- yl]phenol
162-164 0.328 118 ##STR00183## 3-(4-{[(3R)-3-({4-[6-(3-
methoxyphenyl)imidazo[2,1- b][1,3]thiazol-5-yl]pyrimidin-2-
yl}amino)piperidin-1- yl]sulfonyl}phenyl)propanoic acid 146-148
0.229 119 ##STR00184## 4-{[(3R)-3-({4-[6-(3-
methoxyphenyl)imidazo[2,1- b][1,3]thiazol-5-yl]pyrimidin-2-
yl}amino)piperidin-1- yl]sulfonyl}benzoic acid >300 0.092 120
##STR00185## N-{(3R)-1-[(4- chlorophenyl)sulfonyl]piperidin-3-
yl}-4-[6-(3- nitrophenyl)imidazo[2,1-
b][1,3]thiazol-5-yl]pyrimidin-2- amine 185-187 55 @ 10 uM 121
##STR00186## 4-{[(3R)-3-({4-[6-(3- hydroxyphenyl)imidazo[2,1-
b][1,3]thiazol-5-yl]pyrimidin-2- yl}amino)piperidin-1-
yl]sulfonyl}benzoic acid >300 0.002 122 ##STR00187##
4-[6-(3-aminophenyl)imidazo[2,1-
b][1,3]thiazol-5-yl]-N-{(3R)-1-[(4-
chlorophenyl)sulfonyl]piperidin-3- yl}pyrimidin-2-amine 226-228
0.429 123 ##STR00188## N-(3-{5-[2-({(3R)-1-[(4-
chlorophenyl)sulfonyl]piperidin-3- yl}amino)pyrimidin-4-
yl]imidazo[2,1-b][1,3]thiazol-6- yl}phenyl)acetamide 169-174
0.215
124 ##STR00189## N~1~-(3-{5-[2-({(3R)-1-[(4-
chlorophenyl)sulfonyl]piperidin-3- yl}amino)pyrimidin-4-
yl]imidazo[2,1-b][1,3]thiazol-6- yl}phenyl)glycinamide 208-212 2.96
125 ##STR00190## 3-(5-{2-[(3R)-piperidin-3- ylamino]pyrimidin-4-
yl}imidazo[2,1-b][1,3]thiazol-6- yl)benzonitrile 205-207 19 @ 10 uM
126 ##STR00191## 3-{5-[2-({(3R)-1-[(4-
chlorophenyl)sulfonyl]piperidin-3- yl}amino)pyrimidin-4-
yl]imidazo[2,1-b][1,3]thiazol-6- yl}benzonitrile 144-146 0.71 127
##STR00192## 4-{5-[2-({(3R)-1-[(4-
chlorophenyl)sulfonyl]piperidin-3- yl}amino)pyrimidin-4-
yl]imidazo[2,1-b][1,3]thiazol-6- yl}benzoic acid 255-260 >3.0
128 ##STR00193## ethyl 2-ethoxy-4-(5-{2-[(3R)-
piperidin-3-ylamino]pyrimidin-4- yl}imidazo[2,1-b][1,3]thiazal-6-
yl)benzoate 195-197 24 @ 10 uM 129 ##STR00194##
4-{[(3R)-3-({4-[6-(3- cyanophenyl)imidazo[2,1-
b][1,3]thiazol-5-yl]pyrimidin-2- yl}amino)piperidin-1-
yl]sulfonyl}benzoic acid 245-247 >3.0 130 ##STR00195## ethyl
4-{5-[2-({(3R)-1-[(4- chlorophenyl)sulfonyl]piperidin-3-
yl}amino)pyrimidin-4- yl]imidazo[2,1-b][1,3]thiazol-6-yl}-
2-ethoxybenzoate 138-140 1.09 131 ##STR00196## N-{(3R)-1-[(4-
chlorophenyl)sulfonyl]piperidin-3- yl}-4-[6-(2-
nitrophenyl)imidazo[2,1- b][1,3]thiazol-5-yl]pyrimidin-2- amine
155-156 0.025 132 ##STR00197## 4-[6-(2-aminophenyl)imidazo[2,1-
b][1,3]thiazol-5-yl]-N-{(3R)-1-[(4-
chlorophenyl)sulfonyl]piperidin-3- yl}pyrimidin-2-amine 155-157
0.444 133 ##STR00198## 4-{5-[2-({(3R)-1-[(4-
chlorophenyl)sulfonyl]piperidin-3- yl}amino)pyrimidin-4-
yl]imidazo[2,1-b][1,3]thiazol-6- yl}-2-hydroxybenzoic acid 228-229
0.84 134 ##STR00199## 4-{5-[2-({(3R)-1-[(4-
chlorophenyl)sulfonyl]piperidin-3- yl}amino)pyrimidin-4-
yl]imidazo[2,1-b][1,3]thiazol-6- yl)benzene-1,2-diol 195-197 0.024
135 ##STR00200## N-{(3R)-1-[(4- chlorophenyl)sulfonyl]piperidin-3-
yl}-4-[6-(3,4- dimethoxyphenyl)imidazo[2,1-
b][1,3]thiazol-5-yl]pyrimidin-2- amine 168-170 0.696 136
##STR00201## 4-amino-N-(2-{5-[2-({(3R)-1-[(4-
chlorophenyl)sulfonyl]piperidin-3- yl}amino)pyrimidin-4-
yl]imidazo[2,1-b][1,3]thiazol-6- yl}phenyl)butanamide 206-208
>3.0 137 ##STR00202## 4-[6-(3- methoxyphenyl)imidazo[2,1-
b][1,3]thiazol-5-yl]-N-[(3S)- piperidin-3-yl]pyrimidin-2-amine
176-178 42 @ 10 uM 138 ##STR00203## N~1~-(2-{5-[2-({(3R)-1-[(4-
chlorophenyl)sulfonyl]piperidin-3- yl}amino)pyrimidin-4-
yl]imidazo[2,1-b][1,3]thiazol-6- yl]phenyl)-beta-alaninamide
203-204 82 @ 10 uM 139 ##STR00204## N-{(3S)-1-[(4-
chlorophenyl)sulfonyl]piperidin-3- methoxyphenyl)imidazo[2,1-
b][1,3]thiazol-5-yl]pyrimidin-2- amine 125-127 41 @ 10 uM 140
##STR00205## 3-{5-[(2-({(3S)-1-[(4-
chlorophenyl)sulfonyl]piperidin-3- yl)amino)pyrimidin-4-
yl]imidazo[2,1-b][1,3]thiazol-6- yl}phenol 158-160 0.953 141
##STR00206## N~1~-(2-{5-[2-({(3R)-1-[(4-
chlorophenyl)sulfonyl]piperidin-3- yl}amino)pyrimidin-4-
yl]imidazo[2,1-b][1,3]thiazol-6- yl}phenyl)glycinamide 198-200
0.814 142 ##STR00207## 4-[6-(3- methoxyphenyl)imidazo[2,1-
b][1,3]thiazol-5-yl]-N-{(3R)-[(3- methoxyphenyl)sulfonyl]piperidin-
3-yl}pyrimidin-2-amine 105-106 56 @ 10 uM 143 ##STR00208##
3-{[(3R)-3-({4-[6-(3- hydroxyphenyl)imidazo[2,1-
b][1,3]thiazol-5-yl]pyrimidin-2- yl}amino)piperidin-1-
yl]sulfonyl}phenol 170-172 0.019 144 ##STR00209## N-{(3R)-1-[(4-
chlorophenyl)sulfonyl]piperidin-3- yl}-4-[(6-(2,5-
dimethoxyphenyl)imidazo[2,1- b][1,3]thiazol-5-yl]pyrimidin-2- amine
128-131 69 @ 10 uM 145 ##STR00210## 2-{5-[2-({(3R)-1-[(4-
chlorophenyl)sulfonyl]piperidin-3- yl}amino)pyrimidin-4-
yl]imidazo[2,1-b][1,3]thiazol-6- yl}benzene-1,4-diol 185-187 0.092
146 ##STR00211## N-((3R)-1-{[(4R)-2,2-dimethyl-1,3-
dioxolan-4-yl]methyl}piperidin-3- yl)-4-[6-(3-
methoxyphenyl)imidazo[2,1- b][1,3]thiazol-5-yl]pyrimidin-2- amine
73-75 43 @ 10 uM 147 ##STR00212## (2R)-3-[(3R)-3-({4-[6-(3-
methoxyphenyl)imidazo[2,1- b][1,3]thiazol-5-yl]pyrimidin-2-
yl}amino)piperidin-1-yl]propane- 1,2-diol 106-108 >3.0 148
##STR00213## (2R)-3-[(3R)-3-({4-[6-(3- hydroxyphenyl)imidazo[2,1-
b][1,3]thiazol-5-yl]pyrimidin-2- yl}amino)piperidin-1-yl]propane-
1,2-diol 185-187 >3.0 149 ##STR00214## 4-[6-(3-
methoxyphenyl)imidazo[2,1- b][1,3]thiazol-5-yl]-N-{(3R)-1-[(4-
methoxyphenyl)sulfonyl]piperidin- 3-yl}pyrimidin-2-amine 105-107
0.188 150 ##STR00215## 3-{5-[2-({(3R)-1-[(4-
hydroxyphenyl)sulfonyl]piperidin- 3-yl}amino)pyrimidin-4-
yl]imidazo[2,1-b][1,3]thiazol-6- yl}phenol 185-187 0.009 151
##STR00216## 4-[6-(3- methoxyphenyl)imidazo[2,1-
b][1,3]thiazol-5-yl]-N-[(3R)-1- (methylsulfonyl)piperidin-3-
yl]pyrimidin-2-amine 118-120 0.85 152 ##STR00217##
3-[5-(2-{[(3R)-1- (methylsulfonyl)piperidin-3-
yl]amino}pyrimidin-4- yl)imidazo[2,1-b][1,3]thiazol-6- yl]phenol
172-175 0.116 153 ##STR00218## 4-[6-(4-fluorophenyl)imidazo[2,1-
b][1,3]thiazol-5-yl]-N-{1 -[(4- fluorophenyl)sulfonyl]piperidin-4-
yl}pyrimidin-2-amine 259-260 0.078 154 ##STR00219##
N-(1-ethylpiperidin-4-yl)-4-[6-(4- fluorophenyl)imidazo[2,1-
b][1,3]thiazol-5-yl]pyrimidin-2- amine 173-175 36 @ 10 uM 155
##STR00220## 4-[6-(4-fluorophenyl)imidazo[2,1-
b][1,3]thiazol-5-yl]-N-piperidin-4- ylpyrimidin-2-amine 282-286,
2.36 156 ##STR00221## N-ethyl-4-({4-[6-(4-
fluorophenyl)imidazo[2,1- b][1,3]oxazol-5-yl]pyrimidin-2-
yl}amino)piperidine-1- carboxamide 110-112 0.428 157 ##STR00222##
4-[6-(4-fluorophenyl)imidazo[2,1- b][1,3]oxazol-5-yl]-N-{1-[(4-
fluorophenyl)sulfonyl]piperidin-4- yl}pyrimidin-2-amine 222-223
0.675 158 ##STR00223## 4-[6-(4-fluorophenyl)imidazo[2,1-
b][1,3]oxazol-5-yl]-N-[1-(4- methoxybenzoyl)piperidin-4-
yl]pyrimidin-2-amine 196-197 0.465 159 ##STR00224##
N-(1-benzoylpiperidin-4-yl)-4-[6- (4-fluorophenyl)imidazo(2,1-
b][1,3]oxazol-5-yl]pyrimidin-2- amine 218-220 1.01 160 ##STR00225##
N-{1-[(4- chlorophenoxy)acetyl]piperidin-4- yl}-4-[6-(4-
fluorophenyl)imidazo[2,1- b][1,3]oxazol-5-yl]pyrimidin-2- amine
209-210 3.85 161 ##STR00226## 4-[6-(4-fluorophenyl)jmidazo[2,1-
b][1,3]oxazol-5-yl]-N-[1-(quinolin- 8-ylcarbonyl)piperidin-4-
yl]pyrimidin-2-amine 254-256 1.57 162 ##STR00227##
4-[6-(4-fluorophenyl)imidazo[2,1-
b][1,3]oxazol-5-yl]-N-[1-(piperidin- 4-ylcarbonyl)piperidin-4-
yl]pyrimidin-2-amine 209-212 1.32 163 ##STR00228##
4-[6-(4-fluorophenyl)imidazo[2,1- b][1,3]oxazol-5-yl]-N-[1-
(methoxyacetyl)piperidin-4- yl]pyrimidin-2-amine 204-207 53 @ 10 uM
164 ##STR00229## N-[1- (cyclohexylcarbonyl)piperidin-4-
yl]-4-[6-(4- fluorophenyl)imidazo[2,1-
b][1,3]oxazol-5-yl]pyrimidin-2- amine 135-136 38 @ 10 uM 165
##STR00230## 4-[6-(4-fluorophenyl)imidazo[2,1-
b][1,3]oxazol-5-yl]-N-(1- isonicotinoylpiperidin-4-
yl)pyrimidin-2-amine 210-211 33 @ 10 uM 166 ##STR00231##
4-[6-(4-fluorophenyl)imidazo[2,1- b][1,3]oxazol-5-yl]-N-[1-(2-
furoyl)piperidin-4-yl]pyrimidin-2- amine 105-107 76 @ 10 uM 167
##STR00232## N-cyclohexyl-4-({4-[6-(4- fluorophenyl)imidazo(2,1-
b][1,3]oxazol-5-yl]pyrimidin-2- yl}amino)piperidine-1- carboxamide
168-169 4.71 168 ##STR00233## N-butyl-4-({4-[6-(4-
fluorophenyl)imidazo[2,1- b][1,3]oxazol-5-yl]pyrimidin-2-
yl}amino)piperidine-1- carboxamide 155-156 1.11 169 ##STR00234##
4-({4-[6-(4- fluorophenyl)imidazo[2,1-
b][1,3]oxazol-5-yl]pyrimidin-2- yl}amino)-N-(2-
phenylethyl)piperidine-1- carboxamide 119-120 0.266 170
##STR00235## N-benzyl-4-({4-[6-(4- fluorophenyl)imidazo[2,1-
b][1,3]oxazol-5-yl]pyrimidin-2- yl}amino)piperidine-1- carboxamide
124-126 0.189 171 ##STR00236## 4-({4-[6-(4-
fluorophenyl)imidazo[2,1- b][1,3]oxazol-5-yl]pyrimidin-2-
yl}amino)-N-phenylpiperidine-1- carboxamide 182-183 4.73 172
##STR00237## 4-({4-[6-(4- fluorophenyl)imidazo[2,1-
b][1,3]oxazol-5-yl]pyrimidin-2- yl}amino)-N-(4-
methylphenyl)piperidine-1- carboxamide 180-182 1.98 173
##STR00238## 4-({4-[6-(4- fluorophenyl)imidazo[2,1-
b][1,3]oxazol-5-yl]pyrimidin-2- yl}amino)-N-(4-
methoxyphenyl)piperidine-1- carboxamide 153-154 2.56 174
##STR00239## N-(4-fluorophenyl)-4-({4-[6-(4-
fluorophenyl)imidazo[2,1- b][1,3]oxazol-5-yl]pyrimidin-2-
yl}amino)piperidine-1- carboxamide 192-193 4.73 175 ##STR00240##
N-[4-(dimethylamino)phenyl]-4- ({4-[6-(4- fluorophenyl)imidazo[2,1-
b][1,3]oxazol-5-yl]pyrimidin-2- yl}amino)piperidine-1- carboxamide
225-227 0.066 176 ##STR00241## 4-({4-[6-(4-
fluorophenyl)imidazo[2,1- b][1,3]oxazol-5-yl]pyrimidin-2-
yl}amino)-N-(2- furylmethyl)piperidine-1- carboxamide 118-121 0.082
177 ##STR00242## 4-({4-[6-(4- fluorophenyl)imidazo[2,1-
b][1,3]oxazol-5-yl]pyrimidin-2- yl}amino)-N-(tetrahydro-2H-
pyran-2-yl)piperidine-1- carboxamide 184-185 0.354 178 ##STR00243##
N-(3,5-dimethylisoxazol-4-yl)-4- ({4-[6-(4-
fluorophenyl)imidazo[2,1- b][1,3]oxazol-5-yl]pyrimidin-2-
yl}amino)piperidine-1- carboxamide 208-210 19 @ 10 uM 179
##STR00244## N-{1-[(4- fluorophenyl)acetyl]piperidin-4-
yl}-4-[6-(4- fluorophenyl)imidazo[2,1-
b][1,3]oxazol-5-yl]pyrimidin-2- amine 209-211 29 @ 10 uM 180
##STR00245## 4-[6-(4-fluorophenyl)imidazo[2,1-
b][1,3]oxazol-5-yl]-N-[1-(3- methylbutanoyl)piperidin-4-
yl]pyrimidin-2-amine 101-103 2.04 181 ##STR00246##
N-[1-(4-fluorobenzoyl)piperidin-4- yl]-4-[6-(4-
fluorophenyl)imidazo[2,1- b][1,3]oxazol-5-yl]pyrimidin-2- amine
204-206 2.7 182 ##STR00247## 4-({4-[6-(4- fluorophenyl)imidazo[2,1-
b][1,3]oxazol-5-yl]pyrimidin-2- yl}amino)-N-[4-
(trifluoromethyl)phenyl]piperidine- 1-carboxamide 209-211 45 @ 10
uM 183 ##STR00248## N-(cyclohexylmethyl)-4-({4-[6-(4-
fluorophenyl)imidazo[2,1- b][1,3]oxazol-5-yl]pyrimidin-2-
yl}amino)piperidine-1- carboxamide 127-130 3.61 184 ##STR00249##
N-[2-(4-fluorophenyl)ethyl]-4-({4- [6-(4-fluorophenyl)imidazo[2,1-
b][1,3]oxazol-5-yl]pyrimidin-2- yl}amino)piperidine-1- carboxamide
194-195 1.28 185 ##STR00250## N-(tert-butyl)-4-({4-[6-(4-
fluorophenyl)imidazo[2,1- b][1,3]oxazol-5-yl]pyrimidin-2-
yl}amino)piperidine-1- carboxamide 134-138 1.58 186 ##STR00251##
4-({4-[6-(4- fluorophenyl)imidazo[2,1-
b][1,3]oxazol-5-yl]pyrimidin-2- yl}amino)-N-[5-methyl-2-
(trifluoromethyl)-3- furyl]piperidine-1-carboxamide 195-200 16 @ 10
uM
187 ##STR00252## N-(2-fluorophenyl)-4-({4-(6-(4-
fluorophenyl)imidazo[2,1- b][1,3]oxazol-5-yl]pyrimidin-2-
yl}amino)piperidine-1- carboxamide 133-134 10 @ 10 uM 188
##STR00253## 4-[6-(4-fluorophenyl)imidazo[2,1-
b][1,3]oxazol-5-yl]-N-(1- propionylpiperidin-4-yl)pyrimidin-
2-amine 199-201 1.5 189 ##STR00254##
4-[6-(4-fluorophenyl)imidazo[2,1- b][1,3]oxazol-5-yl]-N-[1-(3-
phenylpropanoyl)piperidin-4- yl]pyrimidin-2-amine 144-146 1.94 190
##STR00255## N-[1-(aminoacetyl)piperidin-4-yl]-
4-[6-(4-fluorophenyl)imidazo[2,1- b][1,3]oxazol-5-yl]pyrimidin-2-
amine 204-205 1.15 191 ##STR00256## N-[1-(2-amino-2-
methylpropanoyl)piperidin-4-yl]-4- [6-(4-fluorophenyl)imidazo[2,1-
b][1,3]oxazol-5-yl]pyrimidin-2- amine 216-218 3.76 192 ##STR00257##
4-[6-(4-fluorophenyl)imidazo[2,1- b][1,3]oxazol-5-yl]-N-(1-L-
prolylpiperidin-4-yl)pyrimidin-2- amine 198-202 1.45 193
##STR00258## N-(3,4-difluorophenyl)-4-({4-[6-(4-
fluorophenyl)imidazo[2,1- b][1,3]oxazol-5-yl]pyrimidin-2-
yl}amino)piperidine-1- carboxamide 187-188 1.23 194 ##STR00259##
N-(4-fluorobenzyl)-4-({4-[6-(4- fluorophenyl)imidazo[2,1-
b][1,3]oxazol-5-yl]pyrimidin-2- yl}amino)piperidine-1- carboxamide
115-118 55 @ 10 uM 195 ##STR00260## 4-({4-[6-(4-
fluorophenyl)imidazo[2,1- b][1,3]oxazol-5-yl]pyrimidin-2-
yl}amino)-N-[(1S)-1- phenylethyl]piperidine-1- carboxamide 121-123
56 @ 10 uM 196 ##STR00261## (4S)-4-amino-5-[4-({4-[6-(4-
fluorophenyl)imidazo[2,1- b][1,3]oxazol-5-yl]pyrimidin-2-
yl}amino)piperidin-1-yl]-5- oxopentanoic acid 161-164 3.32 197
##STR00262## 4-[6-(4-fluorophenyl)imidazo[2,1-
b][1,3]oxazol-5-yl]-N-[1- (phenylsulfonyl)piperidin-4-
yl]pyrimidin-2-amine 266-268 0.168 198 ##STR00263##
4-[6-(4-fluorophenyl)imidazo[2,1- b][1,3]oxazol-5-yl]-N-{1-[(4-
methylphenyl)sulfonyl]piperidin-4- yl}pyrimidin-2-amine 247-248
0.218 199 ##STR00264## N-{1-[(4- chlorophenyl)sulfonyl]piperidin-4-
yl}-4-[6-(4- fluorophenyl)imidazo[2,1-
b][1,3]oxazol-5-yl]pyrimidin-2- amine 229-230 0.092 200
##STR00265## 4-[6-(4-fluorophenyl)imidazo[2,1-
b][1,3]oxazol-5-yl]-N-{1-[(4- methoxyphenyl)sulfonyl]piperidin-
4-yl}pyrimidin-2-amine 234-236 0.115 201 ##STR00266##
4-[6-(4-fluorophenyl)imidazo[2,1- b][1,3]oxazol-5-yl]-N-{1-[(4-
isopropylphenyl)sulfonyl]piperidin- 4-yl}pyrimidin-2-amine 235-237
0.42 202 ##STR00267## 4-[6-(4-fluorophenyl)imidazo[2,1-
b][1,3]oxazol-5-yl]-N-(1-{[3- (trifluoromethyl)phenyl]sulfonyl}
piperidin-4-yl)pyrimidin-2-amine 266-268 0.84 203 ##STR00268##
4-[6-(4-fluorophenyl)imidazo[2,1- b][1,3]oxazol-5-yl]-N-(1-{[4-
(trifluoromethoxy)phenyl]sulfonyl} piperidin-4-yl)pyrimidin-2-amine
230-232 0.521 204 ##STR00269## N-{1-[(3-chloro-4-
fluorophenyl)sulfonyl]piperidin-4- yl}-4-[6-(4-
fluorophenyl)imidazo[2,1- b][1,3]oxazol-5-yl]pyrimidin-2- amine
218-220 0.541 205 ##STR00270## N-{1-[(3,5-
dichlorophenyl)sulfonyl]piperidin- 4-yl}-4-[6-(4-
fluorophenyl)imidazo[2,1- b][1,3]oxazol-5-yl]pyrimidin-2- amine
218-220 0.981 206 ##STR00271## N-{1-[(3-
chlorophenyl)sulfonyl]piperidin-4- yl}-4-[6-(4-
fluorophenyl)imidazo[2,1- b][1,3]oxazol-5-yl]pyrimidin-2- amine
225-226 0.329 207 ##STR00272## N-(1-{[3,5-
bis(trifluoromethyl)phenyl] sulfonyl}piperidin-4-yl)-4-[6-(4-
fluorophenyl)imidazo[2,1- b][1,3]oxazol-5-yl]pyrimidin-2- amine
225-227 0.027 208 ##STR00273## 4-[6-(3- methoxyphenyl)imidazo[2,1-
b][1,3]thiazol-5-yl]-N-piperidin-4- ylpyrimidin-2-amine 255-260
2.93 209 ##STR00274## N-{1-[(4-amino-3,5,6- trichloropyridin-2-
yl)carbonyl]piperidin-4-yl}-4-[6-(4- fluorophenyl)imidazo[2,1-
b][1,3]oxazol-5-yl]pyrimidin-2- amine 275-276 49 @ 10 uM 210
##STR00275## N-[1-(2,6- dimethoxybenzoyl)piperidin-4-yl]-
4-[6-(4-fluorophenyl)imidazo[2,1- b][1,3]oxazol-5-yl]pyrimidin-2-
amine 253-254 38 @ 10 uM 211 ##STR00276## N-{2-[4-({4-[6-(4-
fluorophenyl)imidazo[2,1- b][1,3]oxazol-5-yl]pyrimidin-
2-yl}amino)piperidin-1-yl]-2- oxoethyl}acetamide 235-237 29 @ 10 uM
212 ##STR00277## N-[2-[4-({4-[6-(4- fluorophenyl)imidazo[2,1-
b][1,3]oxazol-5-yl]pyrimidin- 2-yl}amino)piperidin-1-yl]-1-
(hydroxymethyl)-2- oxoethyl]acetamide 155-157 43 @ 10 uM 213
##STR00278## N-ethyl-4-({4-[6-(3- methoxyphenyl)imidazo[2,1-
b][1,3]thiazol-5-yl]pyrimidin-2- yl}amino)piperidine-1- carboxamide
124-125 2.04 214 ##STR00279## N-{1-[(4-
fluorophenyl)sulfonyl]piperidin-4- yl}-4-[6-(3-
methoxyphenyl)imidazol[2,1- b][1,3]thiazol-5-yl]pyrimidin-2- amine
208-209 0.392 215 ##STR00280## 4-[6-(4-fluorophenyl)imidazo[2,1-
b][1,3]oxazol-5-yl]-N-(1-{[(4- methylpyrimidin-2-
yl)thio]acetyl}piperidin-4- yl)pyrimidin-2-amine 219-220 40 @ 10 uM
216 ##STR00281## N-[4-(dimethylamino)phenyl]-4- ({4-[6-(3-
methoxyphenyl)imidazo[2,1- b][1,3]thiazol-5-yl]pyrimidin-2-
yl}amino)piperidine-1- carboxamide 127-128 58 @ 10 uM 217
##STR00282## 4-[6-(3,4- difluorophenyl)imidazo[2,1-
b][1,3]thiazol-5-yl]-N-{1-[(4- fluorophenyl)sulfonyl]piperidin-4-
yl}pyrimidin-2-amine 258-259 48 @ 10 uM 218 ##STR00283##
4-({4-[6-(3,4- difluorophenyl)imidazo[2,1-
b][1,3]thiazol-5-yl]pyrimidin-2- yl}amino)-N-ethylpiperidine-1-
carboxamide 221-222 1.22 219 ##STR00284## 4-[6-(4-fluorophenyl)-2-
methylimidazo[2,1-b][1,3]thiazol- 5-yl]-N-{1-[(4-
fluorophenyl)sulfonyl]piperidin-4- yl}pyrimidin-2-amine 238-239
0.051 220 ##STR00285## N-ethyl-4-({4-[6-(4-fluorophenyl)-
2-methylimidazo[2,1- b][1,3]thiazol-5-yl]pyrimidin-2-
yl}amino)piperidine-1- carboxamide 217-218 0.428 221 ##STR00286##
4-[6-(3,4- difluorophenyl)imidazo[2,1-
b][1,3]thiazol-5-yl]-N-{1-[4- (dimethylamino)benzoyl]piperidin-
4-yl}pyrimidin-2-amine 148-149 42 @ 10 uM 222 ##STR00287## N-{1-[4-
(dimethylamino)benzoyl]piperidin- 4-yl}-4-[6-(4-
fluorophenyl)imidazo[2,1- b][1,3]oxazol-5-yl]pyrimidin-2- amine
175-177 45 @ 10 uM 223 ##STR00288## 4-[6-(3,4-
difluorophenyl)imidazo[2,1- b][1,3]thiazol-5-yl]-N-piperidin-4-
ylpyrimidin-2-amine 189-191 71 @ 10 uM 224 ##STR00289##
4-[6-(4-fluorophenyl)-2- methylimidazo[2,1-b][1,3]thiazol-
5-yl]-N-piperidin-4-ylpyrimidin-2- amine 267-268 70 @ 10 uM 225
##STR00290## N-[4-(dimethylamino)phenyl]-4-
({4-[6-(4-fluorophenyl)-2- methylimidazo[2,1-b][1,3]thiazol-
5-yl]pyrimidin-2- yl}amino)piperidine-1- carboxamide 228-230 38 @
10 uM 226 ##STR00291## 4-({4-[6-(3,4- difluorophenyl)imidazo[2,1-
b][1,3]thiazol-5-yl]pyrimidin-2- yl}amino)-N-[4-
(dimethylamino)phenyl]piperidine- 1-carboxamide 205-206 61 @ 10 uM
227 ##STR00292## N-{1-[(5-chloro-2-
methoxyphenyl)sulfonyl]piperidin- 4-yl}-4-[6-(4-
fluorophenyl)imidazo[2,1- b][1,3]oxazol-5-yl]pyrimidin-2- amine
156-158 27 @ 10 uM 228 ##STR00293## N-(5-{[4-({4-[6-(4-
fluorophenyl)imidazo[2,1- b][1,3]oxazol-5-yl]pyrimidin-2-
yl}amino)piperidin-1-yl]sulfonyl}- 4-methyl-1,3-thiazol-2-
yl)acetamide >300 40 @ 10 uM 229 ##STR00294## 4-{[4-({4-[6-(4-
fluorophenyl)imidazo[2,1- b][1,3]oxazol-5-yl]pyrimidin-2-
yl}amino)piperidin-1- yl]sulfonyl}benzoic acid 182-184 1.37 230
##STR00295## N-{1-[(2,4-dimethyl-1,3-thiazol-5-
yl)sulfonyl]piperidin-4-yl}-4-[6-(4- fluorophenyl)imidazo[2,1-
b][1,3]oxazol-5-yl]pyrimidin-2- amine 240-242 50 @ 10 uM 231
##STR00296## 4-[6-(4-fluorophenyl)imidazo[2,1-
b][1,3]oxazol-5-yl]-N-{1-[(3- methoxyphenyl)sulfonyl]piperidin-
4-yl}pyrimidin-2-amine 214-215 0.408 232 ##STR00297##
N-ethyl-4-({4-[6-(4- fluorophenyl)imidazo[2,1-
b][1,3]thiazol-5-yl]pyrimidin-2- yl}amino)-N-methylpiperldine-1-
carboxamide 104-107 56 @ 10 uM 233 ##STR00298##
N-benzyl-4-({4-[6-(3- methoxyphenyl)imidazo[2,1-
b][1,3]thiazol-5-yl]pyrimidin-2- yl}amino)piperidine-1- carboxamide
118-120 53 @ 10 uM 234 ##STR00299## N-(2-furylmethyl)-4-({4-[6-(3-
methoxyphenyl)imidazo[2,1- b][1,3]thiazol-5-yl]pyrimidin-2-
yl}amino)piperidine-1- carboxamide 127-128 0.825 235 ##STR00300##
4-[6-(4-fluorophenyl)imidazo[2,1- b][1,3]oxazol-5-yl]-N-{1-[(2-
methylphenyl)sulfonyl]piperidin-4- yl}pyrimidin-2-amine 263-265 30
@ 10 uM 236 ##STR00301## N-{1-[(2,6-
difluorophenyl)sulfonyl]piperidin- 4-yl}-4-[6-(4-
fluorophenyl)imidazo[2,1- b][1,3]oxazol-5-yl]pyrimidin-2- amine
252-255 30 @ 10 uM 237 ##STR00302##
4-[6-(4-fluorophenyl)imidazo[2,1- b][1,3]oxazol-5-yl]-N-{1-[(3-
fluorophenyl)sulfonyl]piperidin-4- yl}pyrimidin-2-amine 215-218 85
@ 5 uM 238 ##STR00303## 4-[6-(4-fluorophenyt)imidazo[2,1-
b][1,3]oxazol-5-yl]-N-{1-[(4- phenoxyphenyl)sulfonyl]piperidin-
4-yl}pyrimidin-2-amine 213-215 >10 239 ##STR00304##
4-[6-(4-fluorophenyl)imidazo[2,1- b][1,3]oxazol-5-yl]-N-(1-{[4-
(trifluoromethyl)phenyl]sulfonyl} piperidin-4-yl)pyrimidin-2-amine
231-233 52 @ 3 uM 240 ##STR00305## 4-{[4-({4-[6-(4-
fluorophenyl)imidazo[2,1- b][1,3]oxazol-5-yl]pyrimidin-2-
yl}amino)piperidin-1- yl]sulfonyl}benzonitrile 267-269 44 @ 10 uM
241 ##STR00306## N-benzyl-4-({4-[6-(4- fluorophenyl)-2-
methylimidazo[2,1-b][1,3]thiazol- 5-yl]pyrimidin-2-
yl}amino)piperidine-1- carboxamide 137-138 2.53 242 ##STR00307##
4-({4-[6-(4-fluorophenyl)-2- methylimidazo[2,1-b][1,3]-thiazol-
5-yl]pyrimidin-2-yl}amino)-N-(2- furylmethyl)piperidine-1-
carboxamide 178-179 67 @ 10 uM 243 ##STR00308## 4-({4-[6-(3,4-
difluorophenyl)imidazo[2,1- b][1,3]thiazol-5-yl]pyrimidin-2-
yl}amino)-N-(2- furylmethyl)piperidine-1- carboxamide 159-160 76 @
10 uM 244 ##STR00309## 4-[6-(2-naphthyl)imidazo[2,1-
b][1,3]thiazol-5-yl]-N-piperidin-4- ylpyrimidin-2-amine 210-215 47
@ 10 uM 245 ##STR00310## N-(1-{[4- (dimethylamino)phenyl]acetyl}
piperidin-4-yl)-4-[6-(3- methoxyphenyl)imidazo[2,1-
b][1,3]thiazol-5-yl]pyrimidin-2- amine 138-140 2.46 246
##STR00311## 4-[3-methyl-6-(4- methylphenyl)imidazo[2,1-
b][1,3]thiazol-5-yl]-N-piperidin-4- ylpyrimidin-2-amine 185-189
>10 247 ##STR00312## 4-[6-(4-nitrophenyl)imidazo[2,1-
b][1,3]thiazol-5-yl]-N-piperidin-4- ylpyrimidin-2-amine 203-206 9 @
3 uM 248 ##STR00313## N-{1-[(1,2-dimethyl-1H-imidazol-
4-yl)sulfonyl]piperidin-4-yl}-4-[6- (4-fluorophenyl)imidazo[2,1-
b][1,3]oxazol-5-yl]pyrimidin-2- amine 148-152 0.931 249
##STR00314## 4-[6-(2,3-dihydro-1,4- benzodioxin-6-yl)imidazo[2,1-
b][1,3]thiazol-5-yl]-N-piperidin-4- ylpyrimidin-2-amine 231-235 58
@ 10 uM 250 ##STR00315## 4-(6-biphenyl-4-ylimidazo[2,1-
b][1,3]thiazol-5-yl)-N-piperidin-4- ylpyrimidin-2-amine 195-198 2 @
3 uM 251 ##STR00316## N-benzyl-4-({4-[6-(3,4-
difluorophenyl)imidazo[2,1- b][1,3]thiazol-5-yl]pyrimidin-2-
yl}amino)piperidine-1- carboxamide 187-188 63 @ 10 uM 252
##STR00317## N-[4-(dimethylamino)phenyl]-4- ({4-[3-methyl-6-(4-
methylphenyl)imidazo[2,1- b][1,3]thiazol-5-yl]pyrimidin-2-
yl}amino)piperidine-1- carboxamide 133-135 >3.0 253 ##STR00318##
N-[4-(dimethylamino)phenyl]-4- ({4-[6-(4-nitrophenyl)imidazo[2,1-
b][1,3]thiazol-5-yl]pyrimidin-2- yl}amino)piperidine-1- carboxamide
185-188 >3.0 254 ##STR00319## 4-{[4-(6-biphenyl-4-ylimidazo[2,1-
b][1,3]thiazol-5-yl)pyrimidin-2- yl]amino}-N-[4-
(dimethylamino)phenyl]piperidine- 1-carboxamide 141-145 >3.0 255
##STR00320## N-{1-[(4- chlorophenyl)sulfonyl]piperidin-4-
yl}4-[6-(4- fluorophenyl)imidazo[2,1-
b][1,3]thiazol-5-yl]pyrimidin-2- amine 244-245 0.696 256
##STR00321## 4-({4-[6-(4- fluorophenyl)imidazo[2,1-
b][1,3]oxazol-5-yl]pyrimidin-2- yl}amino)piperidine-1- carboxamide
185-190 >1.0 257 ##STR00322## N-{1-[(4-
chlorophenyl)sulfonyl]piperidin-4- yl}-4-[6-(4-fluorophenyl)-2-
methylimidazo[2,1-b][1,3]thiazol- 5-yl]pyrimidin-2-amine 148-149
0.073 258 ##STR00323## 4-{[4-({4-[6-(4-fluorophenyl)-2-
methylimidazo[2,1-b][1,3]thiazol- 5-yl]pyrimidin-2-
yl}amino)piperidin-1- yl]sulfonyl}benzoic acid 195-196 0.322 259
##STR00324## N-(4-{5-(2-({1-[(4- chlorophenyl)sulfonyl]piperidin-4-
yl}amino)pyrimidin-4- yl}imidazo[2,1-b][1,3]thiazol-6-
yl}phenyl)acetamide 175-178 >3.0 260 ##STR00325##
4-[6-(2,3-dihydro-1,4- benzodioxin-6-yl)imidazo[2,1-
b][1,3]thiazol-5-yl]-N-{1-[(4- fluorophenyl)sulfonyl]piperidin-4-
yl}pyrimidin-2-amine 251-253 0.186 261 ##STR00326## 4-[6-(2-
methoxyphenyl)imidazo[2,1- b][1,3]thiazol-5-yl]-N-piperidin-4-
ylpyrimidin-2-amine 235-237 >3.0 262 ##STR00327## N-{1-[(4-
chlorophenyl)sulfonyl]piperidin-4- yl}-4-[6-(4-
methoxyphenyl)imidazo[2,1- b][1,3]thiazol-5-yl]pyridimin-2- amine
127-129 >3.0 263 ##STR00328## N{1-[(4-
chlorophenyl)sulfonyl]piperidin-4- yl}-4-[6-(3-
methoxyphenyl)imidazo[2,1- b][1,3]thiazol-5-yl]pyrimidin-2- amine
215-216 >5.0 264 ##STR00329## 4-{5-[2-({1-[(4-
chlorophenyl)sulfonyl]piperidin-4- yl}amino)pyrimidin-4-
yl]imidazo[2,1-b][1,3]thiazol-6- yl}phenol 188-190 5 @ 10 uM 265
##STR00330## N-{1-[(4- chlorophenyl)sulfonyl]piperidin-4-
difluorophenyl)imidazo[2,1- b][1,3]thiazol-5-yl]pyrimidin-2- amine
243-245 >3.0 266 ##STR00331## 3-{5-[2-({1-[(4-
fluorophenyl)sulfonyl]piperidin-4- yl}amino)pyrimidin-4-
yl]imidazo[2,1-b][1,3]thiazol-6- yl}phenol 175-179 0.029 267
##STR00332## 3-{5-[2-({1-[(4- chlorophenyl)sulfonyl]piperidin-4-
yl}amino)pyrimidin-4- yl]imidazo[2,1-b][1,3]thiazol-6- yl}phenol
160-170 0.031 268 ##STR00333## N-ethyl-4-({4-[6-(3-
hydroxyphenyl)imidazo[2,1- b][1,3]thiazol-5-yl]pyrimidin-2-
yl}amino)piperidine-1- carboxamide 170-172 0.009 269 ##STR00334##
3-{5-[2-({1-[(4- chlorophenyl)sulfonyl]piperidin-4-
yl}amino)pyrimidin-4- yl]imidazo[2,1-b][1,3]thiazol-6-
yl}benzonitrile 145-147 1.63 270 ##STR00335## 3-(4-{[4-({4-[6-(3-
methoxyphenyl)imidazo[2,1- b][1,3]thiazol-5-yl]pyrimidin-2-
yl}amino)piperidin-1- yl]sulfonyl}phenyl)prapanoic acid 159-160
0.316 271 ##STR00336## 3-{5-[2-(piperidin-4- ylamino)pyrimidin-4-
yl]imidazo[2,1-b][1,3]thiazol-6- yl}benzonitrile 218-220 58 @ 10 uM
272 ##STR00337## methyl 3-(4-{[4-({4-[6-(3-
hydroxyphenyl)imidazo[2,1- b][1,3]thiazol-5-yl]pyrimidin-2-
yl}amino)piperidin-1- yl]sulfonyl}phenyl)propanoate 155-157 0.01
273 ##STR00338## 3-(4-{[4-({4-[6-(3- hydroxyphenyl)imidazo[2,1-
b][1,3]thiazol-5-yl]pyrimidin-2- yl}amino)piperidin-1-
yl]sulfonyl}phenyl)propanoic acid 179-180 0.01 274 ##STR00339##
N-{1-[(4- chlorophenyl)sulfonyl]piperidin-4- yl)-4-[6-(2-
nitrophenyl)imidazo[2,1- b][1,3]thiazol-5-yl]pyrimidin-2- amine
258-260 0.722 275 ##STR00340## 4-[6-(4-fluorophenyl)imidazo[2,1-
b][1,3]thiazol-5-yl]-N-[(3S)- pyrrolidin-3-yl]pyrimidin-2-amine
230-232 30 @ 10 uM 276 ##STR00341## N-{(3S)-1-[(4-
chlorophenyl)sulfonyl]pyrrolidin-3- yl}-4-[6-(4-
fluorophenyl)imidazo[2,1- b][1,3]thiazol-5-yl]pyrimidin-2- amine
190-191 95 @ 10 uM 277 ##STR00342##
4-[6-(4-fluorophenyl)imidazo[2,1- b][1,3]thiazol-5-yl]-N-[(3R)-
pyrrolidin-3-yl]pyrimidin-2-amine 175-179 0.044 278 ##STR00343##
N-{(3R)-1-[(4- chlorophenyl)sulfonyl]pyrrolidin-3- yl}-4-[6-(4-
fluorophenyl)imidazo[2,1- b][1,3]thiazol-5-yl]pyrimidin-2- amine
191-192 10 @ 10 uM 279 ##STR00344## 4-[6-(3-
methoxyphenyl)imidazo[2,1- b][1,3]thiazol-5-yl]-N-[(3R)-
pyrrolidin-3-yl]pyrimidin-2-amine 171-173 36 @ 10 uM 280
##STR00345## N-{(3R)-1-[(4- chlorophenyl)sulfonyl]pyrrolidin-3-
yl)-4-[6-(3- methoxyphenyl)imidazo[2,1-
b][1,3]thiazol-5-yl]pyrimidin-2- amine 180-182 37 @ 10 uM 281
##STR00346## 4-{[(3R)-3-({4-[6-(3- methoxyphenyl)imidazo[2,1-
b][1,3]thiazol-5-yl]pyrimidin-2- yl}amino)pyrrolidin-1-
yl]sulfonyl}benzoic acid 68-70 >3.0 282 ##STR00347##
4-{[(3R)-3-({4-[6-(3- hydroxyphenyl)imidazo[2,1-
b][1,3]thiazol-5-yl]pyrimidin-2- yl}amino)pyrrolidin-1-
yl]sulfonyl}benzoic acid 210-212 0.522 283 ##STR00348##
3-{5-[2-({(3R)-1-[(4- chlorophenyl)sulfonyl]pyrrolidin-3-
yl}amino)pyrimidin-4- yl]imidazo[2,1-b][1,3]thiazol-6- yl}phenol
142-143 1.6 284 ##STR00349## 3-(5-{2-[(3R)-pyrrolidin-3-
ylamino]pyrimidin-4- yl}imidazo[2,1-b][1,3]thiazol-6-
yl)benzonitrile 186-188 61 @ 10 uM 285 ##STR00350##
3-{5-[2-({(3R)-1-[(4- chlorophenyl)sulfonyl]pyrrolidin-3-
yl}amino)pyrimidin-4- yl]imidazo[2,1-b][1,3]thiazol-6-
yl}benzonitrile 165-167 35 @ 10 uM 286 ##STR00351## N-{1-[(4-
chlorophenyl)sulfonyl]azetidin-3- yl}-4-[6-(4-
fluorophenyl)imidazo[2,1- b][1,3]thiazal-5-yl]pyrimidin-2- amine
129-130 3 287 ##STR00352## N-azetidin-3-yl-4-[6-(4-
fluorophenyl)imidazo[2,1- b][1,3]thiazol-5-yl]pyrimidin-2- amine
223-225 2.49 288 ##STR00353## 3-{5-[2-({(3R)-1-[(4-
chlorophenyl)sulfonyl]piperidin-3- yl}amino)pyrimidin-4-
yl]imidazo[2,1-b][1,3]thiazol-6- yl}phenol 174-177 0.002 289
##STR00354## N-[1-(4-fluorobenzoyl)piperidin-4- yl]-4-[6-(4-
fluorophenyl)imidazo[2,1- b][1,3]thiazol-5-yl]pyrimidin-2- amine
184-185 >10 290 ##STR00355## 4-[6-(4-fluorophenyl)imidazo[2,1-
b][1,3]thiazol-5-yl]-N-{1-[(4- fluorophenyl)sulfonyl}piperidin-4-
yl}pyrimidin-2-amine 256-257 0.078 291 ##STR00356##
N-(1-acetylpiperidin-4-yl)-4-[6-(4- fluorophenyl)imidazo[2,1-
b][1,3]thiazol-5-yl]pyrimidin-2- amine 201-203 41 @ 10 uM 292
##STR00357## N-(1-ethylpiperidin-4-yl)-4-[6-(4-
fluorophenyl)imidazo[2,1- b][1,3]thiazol-5-yl]pyrimidin-2- amine
173-175 36 @ 10 uM 293 ##STR00358##
N-[1-(4-fluorobenzyl)piperidin-4- yl]-4-[6-(4-
fluorophenyl)imidazo[2,1- b][1,3]thiazol-5-yl]pyrimidin-2- amine
503 [M + H] 14 @ 10 uM 294 ##STR00359## N-ethyl-4-({4-[6-(4-
fluorophenyl)imidazo[2,1- b][1,3]thiazol-5-yl]pyrimidin-2-
yl}amino)piperidine-1- carboxamide 210-212 0.041 295 ##STR00360##
N-(4-fluorophenyl)-4-({4-[6-(4- fluorophenyl)imidazo[2,1-
b][1,3]thiazol-5-yl]pyrimidin-2- yl}amino)piperidine-1- carboxamide
158-160 49 @ 10 uM 296 ##STR00361##
4-[6-(4-fluorophenyl)imidazo[2,1- b][1,3]thiazol-5-yl]-N-[1-
(methylsulfonyl)piperidin-4- yl]pyrimidin-2-amine 473 [M + H] NT
297 ##STR00362## 4-[6-(4-fluorophenyl)imidazo[2,1-
b][1,3]thiazol-5-yl]-N-piperidin-4- ylpyrimidin-2-amine 282-286 3
298 ##STR00363## N-(1-acetylpiperidin-4-yl)-4-[6-(4-
fluorophenyl)imidazo[2,1- b][1,3]oxazol-5-yl]pyrimidin-2- amine 214
59 @ 10 uM 299 ##STR00364## 4-[6-(4-fluorophenyl)imidazo[2,1-
b][1,3]oxazol-5-yl]-N-[1- (methylsulfonyl)piperidin-4-
yl]pyrimidin-2-amine 206-208 55 @ 10 uM 300 ##STR00365## 4-[6-(2,4-
difluorophenyl)imidazo[2,1- b][1,3]oxazol-5-yl]-N-piperidin-4-
ylpyrimidin-2-amine 212-215 65 @ 10 uM 301 ##STR00366##
4-[6-(2-chloro-4- fluorophenyl)imidazo[2,1-
b][1,3]oxazol-5-yl]-N-piperidin-4- ylpyrimidin-2-amine 216-218 39 @
10 uM 302 ##STR00367## N-(1-acetylpiperidin-4-yl)-4-[6-(2-
chlorophenyl)imidazo[2,1- b][1,3]oxazol-5-yl]pyrimidin-2- amine
155-163 39 @ 10 uM 303 ##STR00368##
N-(1-acetylpiperidin-4-yl)-4-[6-(2- methylphenyl)imidazo[2,1-
b][1,3]oxazol-5-yl]pyrimidin-2- amine 152-159 42 @ 10 uM 304
##STR00369## 4-[6-(2-methylphenyl)imidazo[2,1-
b][1,3]oxazol-5-yl]-N-piperidin-4- ylpyrimidin-2-amine 217-220 56 @
10 uM 305 ##STR00370## N-(1-acetylpiperidin-4-yl)-4-[6-(2-
chloro-4- fluorophenyl)imidazo[2,1- b][1,3]oxazol-5-yl]pyrimidin-2-
amine 143-145 47 @ 10 uM 306 ##STR00371## N-piperidin-4-yl-4-{6-[3-
(trifluoromethyl)phenyl]imidazo[2,
1-b][1,3]oxazol-5-yl}pyrimidin-2- amine 176-180 32 @ 10 uM 307
##STR00372## 4-[6-(2-chlorophenyl)imidazo[2,1-
b][1,3]oxazol-5-yl]-N-piperidin-4- ylpyrimidin-2-amine 216-220 55 @
10 uM 308 ##STR00373## 4-[6-(2-methylphenyl)imidazo[2,1-
b][1,3]oxazol-5-yl]-N-[1- (methylsulfonyl)piperidin-4-
yl]pyrimidin-2-amine 121-123 45 @ 10 uM 309 ##STR00374##
N-[1-(methylsulfonyl)piperidin-4- yl]-4-{6-[3-
(trifluoromethyl)phenyl]imidazo[2,
1-b][1,3]oxazol-5-yl}pyrimidin-2- amine 165-167 33 @ 10 uM 310
##STR00375## N-(1-acetylpiperidin-4-yl)-4-[6-
(2,4-difluorophenyl)imidazo[2,1- b][1,3]oxazol-5-yl]pyrimidin-2-
amine 255-258 33 @ 10 uM 311 ##STR00376##
4-[6-(2-chlorophenyl)imidazo[2,1- b][1,3]oxazol-5-yl]-N-[1-
(methylsulfonyl)piperidin-4- yl]pyrimidin-2-amine 145-148 61 @ 10
uM 312 ##STR00377## 4-[6-(2-chloro-4- fluorophenyl)imidazo[2,1-
b][1,3]oxazol-5-yl]-N-[1- (methylsulfonyl)piperidin-4-
yl]pyrimidin-2-amine 210-212 73 @ 10 uM 313 ##STR00378## 4-[6-(2,5-
dimethoxyphenyl)imidazo[2,1- b][1,3]thiazol-5-yl]-N-[(3R)-
piperidin-3-yl]pyrimidin-2-amine 195-200 3 314 ##STR00379## methyl
4-{[(3R)-3-({4-[6-(3- hydroxyphenyl)imidazo[2,1-
b][1,3]thiazol-5-yl]pyrimidin-2- yl}amino)piperidin-1-
yl]sulfonyl}benzoate 184-186 0.03
315 ##STR00380## 3-[5-(2-{[1- (cyclopropylsulfonyl)piperidin-4-
yl]amino}pyrimidin-4- yl)imidazo[2,1-b][1,3]thiazol-6- yl]phenol
166-171 0.011 316 ##STR00381## 1-(4-chlorophenoxy)-3-[4-({4-[6-
(3-methoxyphenyl)imidazo[2,1- b][1,3]thiazol-5-yl]pyrimidin-2-
yl}amino)piperidin-1-yl]propan-2- ol 109-111 3 317 ##STR00382##
4-{[4-({4-[6-(3- hydroxyphenyl)imidazo[2,1-
b][1,3]oxazol-5-yl]pyrimidin-2- yl}amino)piperidin-1-
yl]sulfonyl}benzonitrile 224-226 0.022 318 ##STR00383##
3-{5-[2-({1-[3-(4-chlorophenoxy)- 2-hydroxypropyl]piperidin-4-
yl}amino)pyrimidin-4- yl]imidazo[2,1-b][1,3]thiazol-6- yl}phenol
130-132 0.422 319 ##STR00384## 4-{[4-({4-[6-(3-
hydroxyphenyl)imidazo[2,1- b][1,3]oxazol-5-yl]pyrimidin-2-
yl}amino)piperidin-1- yl]sulfonyl}benzamide 242-250 0.018 320
##STR00385## 4-{[(3R)-3-({4-[6-(3- hydroxyphenyl)imidazo[2,1-
b][1,3]oxazol-5-yl]pyrimidin-2- yl}amino)piperidin-1-
yl]sulfonyl}benzonitrile 178-180 0.01 321 ##STR00386##
3-{5-[2-({1-[(4- chlorophenyl)sulfonyl]piperidin-4-
yl}amino)pyrimidin-4- yl]imidazo[2,1-b][1,3]oxazol-6- yl}phenol
175-177 0.126 322 ##STR00387## 3-{5-[2-({1-[(4-
fluorophenyl)sulfonyl]piperidin-4- yl}amino)pyrimidin-4-
yl]imidazo[2,1-b][1,3]oxazol-6- yl}phenol 173-176 0.046 323
##STR00388## N-[(4-chlorophenyl)sulfonyl]-4- ({4-[6-(3-
hydroxyphenyl)imidazo[2,1- b][1,3]oxazol-5-yl]pyrimidin-2-
yl}amino)piperidine-1- carboxamide 204-208 1.22 324 ##STR00389##
N-[(4-chlorophenyl)sulfonyl]-4- ({4-[6-(3-
methoxyphenyl)imidazo[2,1- b][1,3]oxazol-5-yl]pyrimidin-2-
yl}amino)piperidine-1- carboxamide 165-166 4 325 ##STR00390##
N-[(3R)-1- (cyclopropylsulfonyl)piperidin-3- yl]-4-[6-(3-
methoxyphenyl)imidazo[2,1- b][1,3]thiazol-5-yl]pyrimidin-2- amine
107-115 4 326 ##STR00391## 4-[6-(3- methoxyphenyl)imidazo[2,1-
b][1,3]thiazol-5-yl]-N-[1- (methylsulfonyl)piperidin-4-
yl]pyrimidin-2-amine 110-118 4 327 ##STR00392##
(3R)-N-(4-fluorophenyl)-3-({4-[6- (3-methoxyphenyl)imidazo[2,1-
b][1,3]thiazol-5-yl]pyrimidin-2- yl}amino)piperidine-1- carboxamide
120-122 4 328 ##STR00393## (3R)-N-cyclohexyl-3-({4-[6-(3-
methoxyphenyl)imidazo[2,1- b][1,3]thiazol-5-yl]pyrimidin-2-
yl}amino)piperidine-1- carboxamide 123-125 4 329 ##STR00394##
(3R)-N-(4-ethoxyphenyl)-3-({4-[6- (3-methoxyphenyl)imidazo[2,1-
b][1,3]thiazol-5-yl]pyrimidin-2- yl}amino)piperidine-1- carboxamide
122-124 4 330 ##STR00395## (3R)-3-({4-[6-(3-
methoxyphenyl)imidazo[2,1- b][1,3]thiazol-5-yl]pyrimidin-2-
yl}amino)-N-(4- (methylthio)phenyl]piperidine-1- carboxamide
128-130 4 331 ##STR00396## 3-{5-[2-({(3R)-1-[3-(4-
chlorophenoxy)-2- hydroxypropyl]piperidin-3- yl}amino)pyrimidin-4-
yl]imidazo[2,1-b][1,3]thiazol-6- yl}phenol 130-135 1.04 332
##STR00397## 3-[5-(2-{[1- (methylsulfonyl)piperidin-4-
yl]amino}pyrimidin-4- yl)imidazo[2,1-b][1,3]thiazol-6- yl]phenol
220-226 0.01 333 ##STR00398## 3-(5-{2-[(3R)-piperidin-3-
ylamino]pyrimidin-4- yl}imidazo[2,1-b][1,3]oxazol-6- yl)phenol
220-225 0.906 334 ##STR00399## (3R)-3-({4-[6-(3-
hydroxyphenyl)imidazo[2,1- b][1,3]thiazol-5-yl]pyrimidin-2-
yl}amino)-N-isopropylpiperidine- 1-carboxamide 170-172 0.65 335
##STR00400## (3R)-N-(4-fluorophenyl)-3-({4-[6-
(3-hydroxyphenyl)imidazo[2,1- b][1,3]thiazol-5-yl]pyrimidin-2-
yl}amino)piperidine-1- carboxamide 160-162 3.26 336 ##STR00401##
N-[(4-chloropheriyl)sulfonyl]-4- ({4-[6-(3-
hydroxyphenyl)imidazo[2,1- yl}amino)piperidine-1-
b][1,3]thiazol-5-yl]pyrimidin-2- yl}amino)piperidine-1- carboxamide
185-189 1.05 337 ##STR00402## 4-[6-(3- methoxyphenyl)imidazo[2,1-
b][1,3]oxazol-5-yl]-N-piperidin-4- ylpyrimidin-2-amine 230-232 3.21
338 ##STR00403## N-[1- (cyclopropylsulfonyl)piperidin-4-
yl]-4-[6-(3- methoxyphenyl)imidazo[2,1-
b][1,3]oxazol-5-yl]pyrimidin-2- amine 165-166 6.99 339 ##STR00404##
3-[5-(2-{[1- (cyclopropylsulfonyl)piperidin-4-
yl]amino}pyrimidin-4- yl)imidazo[2,1-b][1,3]oxazol-6- yl]phenol
152-154 0.046 340 ##STR00405## 4-[6-(3- methoxyphenyl)imidazo[2,1-
b][1,3]oxazol-5-yl]-N-[1- (methylsulfonyl)piperidin-4-
yl]pyrimidin-2-amine 206-207 10 341 ##STR00406##
(2R)-2,3-dihydroxypropyl 4- {[(3R)-3-({4-[6-(3-
hydroxyphenyl)imidazo[2,1- b][1,3]thiazol-5-yl]pyrimidin-2-
yl)amino)piperidin-1- yl]sulfonyl}benzoate 182-184 0.033 342
##STR00407## 3-[5-(2-{[1- (methylsulfonyl)piperidin-4-
yl]amino}pyrimidin-4- yl)imidazo[2,1-b][1,3]oxazol-6- yl]phenol
237-239 0.258 343 ##STR00408## (3R)-N-(4-hydroxyphenyl)-3-({4-
[6-(3-hydroxyphenyl)imidazo[2,1- b][1,3]thiazol-5-yl]pyrimidin-2-
yl}amino)piperidine-1- carboxamide 205-207 1.44 344 ##STR00409##
(3R)-3-({4-[6-(3- hydroxyphenyl)imidazo[2,1-
b][1,3]thiazol-5-yl]pyrimidin-2- yl}amino)-N-[4-
(methylthio)phenyl]piperidine-1- carboxamide 172-174 2.45 345
##STR00410## 3-{5-[2-({(3R)-1-[(4-
chlorophenyl)sulfonyl]piperidin-3- yl}amino)pyrimidin-4-
yl]imidazo[2,1-b][1,3]thiazol-6-yl}- N'-
hydroxybenzenecarboximidamide 272-273 30 346 ##STR00411##
N-(3-{5-[2-({(3R)-1-[(4- chlorophenyl)sulfonyl]piperidin-3-
yl}amino)pyrimidin-4- yl]imidazo[2,1-b][1,3]thiazol-6-
yl}phenyl)methanesulfonamide 170-172 0.88 347 ##STR00412##
1-(3-{5-[2-({(3R)-1-[(4- chlorophenyl)sulfonyl]piperidin-3-
yl}amino)pyrimidin-4- yl]imidazo[2,1-b][1,3]thiazol-6-
yl}phenyl)-3-ethylurea 165-167 0.546 348 ##STR00413##
N-{(3R)-1-[(4- chlorophenyl)sulfonyl]piperidin-3-
yl}-4-[6-(4-fluoro-3- methoxyphenyl)imidazo[2,1-
b][1,3]thiazol-5-yl]pyrimidin-2- amine 142-143 0.105 349
##STR00414## N-[1- (cyclopropylsulfonyl)piperidin-4-
yl]-4-[6-(4-fluoro-3- methoxyphenyl)imidazo[2,1-
b][1,3]thiazol-5-yl]pyrimidin-2- amine 146-148 2.6 350 ##STR00415##
3-{5-[2-({(3R)-1-[(4- chlorophenyl)sulfonyl]piperidin-3-
yl}amino)pyrimidin-4- yl]imidazo[2,1-b][1,3]thiazol-6- yl}benzamide
168-170 0.14 351 ##STR00416## 4-({4-[6-(3-
hydroxyphenyl)imidazo[2,1- b][1,3]thiazol-5-yl]pyrimidin-2-
yl}amino)-N-isopropylpiperidine- 1-carboxamide 280-290 0.94 352
##STR00417## 4-({4-[6-(3- hydroxyphenyl)imidazo[2,1-
b][1,3]thiazol-5-yl]pyrimidin-2- yl}amino)-N-methylpiperidine-1-
carboxamide 285-295 0.67 353 ##STR00418## 5-{5-[2-({(3R)-1-[(4-
chlorophenyl)sulfonyl]piperidin-3- yl}amino)pyrimidin-4-
yl]imidazo[2,1-b][1,3]thiazol-6-yl}- 2-fluorophenol 172-175 0.003
354 ##STR00419## 5-[5-(2-{[1- (cyclopropylsulfonyl)piperidin-4-
yl]amino}pyrimidin-4- yl)imidazo[2,1-b][1,3]thiazol-6-yl]-
2-fluorophenol 224-225 0.0003 355 ##STR00420## 4-({4-[6-(3-
hydroxyphenyl)imidazo[2,1- b][1,3]thiazol-5-yl]pyrimidin-2-
yl}amino)-N-propylpiperidine-1- carboxamide 235-240 1.79 356
##STR00421## N-cyclopentyl-4-({4-[6-(3- hydroxyphenyl)imidazo[2,1-
b][1,3]thiazol-5-yl]pyrimidin-2- yl}amino)piperidine-1- carboxamide
282-295 2.54 357 ##STR00422## N-butyl-4-({4-[6-(3-
hydroxyphenyl)imidazo[2,1- b][1,3]thiazol-5-yl]pyrimidin-2-
yl}amino)piperidine-1- carboxamide 265-270 3 358 ##STR00423##
4-(5-{2-[(3R)-piperidin-3- ylamino]pyrimidin-4-
yl}imidazo[2,1-b][1,3]thiazol-6- yl)benzonitrile 215-216 30 359
##STR00424## ethyl 4-(5-{2-[(3R)-piperidin-3- ylamino]pyrimidin-4-
yl}imidazo[2,1-b][1,3]thiazol-6- yl)benzoate 224-226 30 360
##STR00425## 4-{5-[2-({(3R)-1-[(4-
chlorophenyl)sulfonyl]piperidin-3- yl}amino)pyrimidin-4-
yl]imidazo[2,1-b](1,3]thiazol-6- yl}benzonitrile 241-244 2.47 361
##STR00426## ethyl 4-{5-[2-({(3R)-1-[(4-
chlorophenyl)sulfonyl]piperidin-3- yl}amino)pyrimidin-4-
yl]imidazo[2,1-b][1,3]thiazol-6- yl}benzoate 129-131 3.25 362
##STR00427## N-cyclohexyl-4-({4-[6-(3- hydroxyphenyl)imidazo[2,1-
b][1,3]thiazol-5-yl]pyrimidin-2- yl}amino)piperidane-1- carboxamide
190-200 3 363 ##STR00428## 3-{5-[2-({(3R)-1-[(4-
chlorophenyl)sulfonyl]piperidin-3- yl}amino)pyrimidin-4-
yl]imidazo[2,1-b][1,3]thiazol-6-yl}- N'-
hydroxybenzenecarboximidamide 177-179 8 364 ##STR00429##
3-{5-[2-({(3R)-1-[(4- chlorophenyl)sulfonyl]piperidin-3-
yl}amino)pyrimidin-4- yl]imidazo[2,1-b][1,3]thiazol-6- yl}phenyl
carbamate 118-120 0.007 365 ##STR00430##
4-{6-[3-(5-methyl-1,2,4-oxadiazol- 3-yl)phenyl]imidazo[2,1-
b][1,3]thiazol-5-yl}-N-[(3R)- piperidin-3-yl]pyrimidin-2-amine
203-207 0.03 366 ##STR00431## 3-{5-[2-({(3R)-1-[(1-methyl-1H-
imidazol-4-yl)sulfonyl]piperidin-3- yl}amino)pyrimidin-4-
yl}imidazo[2,1-b][1,3]thiazol-6- yl}phenol 183-191 0.011 367
##STR00432## 3-[5-(2-{[(3R)-1-(3- thienylsulfonyl)piperidin-3-
yl]amino}pyrimidin-4- yl)imidazo[2,1-b][1,3]thiazol-6- yl]phenol
180-185 0.003 368 ##STR00433## 3-[5-(2-{[(3R)-1-
(isopropylsulfonyl)piperidin-3- yl]amino}pyrimidin-4-
yl)imidazo[2,1-b][1,3]thiazol-6- yl]phenol 165-170 >3 369
##STR00434## 3-[5-(2-{[(3R)-1- (benzylsulfonyl)piperidin-3-
yl]amino}pyrimidin-4- yl)imidazo[2,1-b][1,3]thiazol-6- yl]phenol
165-170 >3 370 ##STR00435## 3-[5-(2-{[(3R)-1-
(propylsulfonyl)piperidin-3- yl]amino}pyrimidin-4-
yl)imidazo[2,1-b][1,3]thiazol-6- yl]phenol 150-155 1.2 371
##STR00436## 3-[5-(2-{[(3R)-1-(2- thienylsulfonyl)piperidin-3-
yl]amino}pyrimidin-4- yl)imidazo[2,1-b][1,3]thiazol-6- yl]phenol
158-168 0.003 372 ##STR00437## 3-[5-(2-{[(3R)-1-
(phenylsulfonyl)piperidin-3- yl]amino}pyrimidin-4-
yl)imidazo[2,1-b][1,3]thiazol-6- yl]phenol 180-185 0.003 373
##STR00438## 3-[5-(2-{[(3R)-1- (ethylsulfonyl)piperidin-3-
yl]amino}pyrimidin-4- yl)imidazo[2,1-b][1,3]thiazol-6- yl]phenol
162-170 >3 374 ##STR00439## N-(4-{[(3R)-3-({4-[6-(3-
hydraxyphenyl)imidazo[2,1- b][1,3]thiazol-5-yl]pyrimidin-2-
yl}amino)piperidin-1- yl]sulfonyl}phenyl)acetamide 180-192 0.001
375 ##STR00440## 3-{5-[2-({(3R)-1-[(2,2,2-
trifluoroethyl)sulfonyl]piperidin-3- yl)amino)pyrimidin-4-
yl]imidazo[2,1-b][1,3]thiazol-6- yl}phenol >300 >3 376
##STR00441## 3-{5-[2-({(3R)-1-[(1-methyl-1H-
pyrazol-3-yl)sulfonyl]piperidin-3- yl}amino)pyrimidin-4-
yl]imidazo[2,1-b][1,3]thiazol-6- yl)phenol 196-210 0.001 377
##STR00442## 3-{5-[2-({(3R)-1-[(4-
chlorophenyl)sulfonyl]piperidin-3- yl}amino)pyrimidin-4-
yl]imidazo[2,1-b][1,3]thiazol-6- yl}phenyl sulfamate 133-135 0.085
378 ##STR00443## (4-{5-[2-({(3R)-1-[(4-
chlorophenyl)sulfonyl]piperidin-3- yl}amino)pyrimidin-4-
yl]imidazo[2,1-b][1,3]thiazol-6- yl}phenyl)methanol 136-137 2.26
379 ##STR00444## 4-{5-[2-({(3R)-1-[(4-
chlorophenyl)sulfonyl]piperidin-3- yl}amino)pyrimidin-4-
yl]imidazo[2,1-b][1,3]thiazol-6- yl}benzamide 177-179 2.67 380
##STR00445## 3-{5-[2-({(3R)-1-[(4-
chlorophenyl)sulfonyl]piperidin-3- yl}amino)pyrimidin-4-
yl]imidazo[2,1-b][1,3]oxazol-6- yl}phenyl sulfamate 142-145 1.59
381 ##STR00446## 3-[5-(2-{[(3R)-1-(4H-1,2,4-triazol-
3-ylsulfonyl)piperidin-3- yl]amino}pyrimidin-4-
yl)imidazo[2,1-b][1,3]thiazol-6- yl]phenol 218-240 0.015 382
##STR00447## 3-{5-[2-({(3R)-1-[(4-
chlorophenyl)sulfonyl]piperidin-3- yl}amino)pyrimidin-4-
yl]imidazo[2,1-b][1,3]thiazol-6- yl}benzoic acid 190-195 1.19 383
##STR00448## 3-(5-{2-[(3R)-piperidin-3- ylamino]pyrimidin-4-
yl}imidazo[2,1-b][1,3]thiazol-6- yl)benzamide 202-205 3 384
##STR00449## 1-(3-{5-[2-({(3R)-1-[(4-
chlorophenyl)sulfonyl]piperidin-3- yl}amino)pyrimidin-4-
yl]imidazo[2,1-b][1,3]thiazol-6- yl}phenyl)ethanone 124-127 1.3 385
##STR00450## 4-{5-[2-({(3R)-1-[(4-
chlorophenyl)sulfonyl]piperidin-3- yl}amino)pyrimidin-4-
yl]imidazo[2,1-b][1,3]thiazol-6- yl}benzaldehyde 155-159 0.876 386
##STR00451## 3-{5-[2-({(3R)-1-[(4-
chlorophenyl)sulfonyl]piperidin-3- yl}amino)pyrimidin-4-
yl]imidazo[2,1-b][1,3]oxazol-6- yl}phenyl carbamate 144-147 0.109
387 ##STR00452## propyl 4-({4-[6-(3- hydroxyphenyl)imidazo[2,1-
b][1,3]thiazol-5-yl]pyrimidin-2- yl}amino)piperidine-1-carboxylate
135-143 >3 388 ##STR00453## 3-[5-(2-{[(3R)-1-(2-
thienylsulfonyl)piperidin-3- yl]amino}pyrimidin-4-
yl)imidazo[2,1-b][1,3]oxazol-6- yl]phenol 162-174 0.009 389
##STR00454## (1E)-1-(3-{5-[2-({(3R)-1-[(4-
chlorophenyl)sulfonyl]piperidin-3- yl}amino)pyrimidin-4-
yl]imidazo[2,1-b][1,3]thiazol-6- yl}phenyl)ethanone oxime 156-158
0.034 390 ##STR00455## 3-{5-[2-({(3R)-1-[(4-
chlorophenyl)sulfonyl]piperidin-3- yl}amino)pyrimidin-4-
yl]imidazo[2,1-b][1,3]thiazol-6- yl}benzaldehyde 124-126 0.28 391
##STR00456## 3-[5-(2-{[(3R)-1- (benzylsulfonyl)piperidin-3-
yl]amino}pyrimidin-4- yl)imidazo[2,1-b][1,3]oxazol-6- yl]phenol
222-227 >3 392 ##STR00457## 4-{5-[2-({(3R)-1-[(4-
chlorophenyl)sulfonyl]piperidin-3- yl}amino)pyrimidin-4-
yl]imidazo[2,1-b][1,3]thiazol-6- yl}benzaldehyde oxime 174-177
0.698 393 ##STR00458## 3-[5-(2-{[(3R)-1-
(propylsulfonyl)piperidin-3- yl]amino}pyrimidin-4-
yl)imidazo[2,1-b][1,3]oxazol-6- yl]phenol 144-155 0.33 394
##STR00459## methyl 4-({4-[6-(3- hydroxyphenyl)imidazo[2,1-
b][1,3]thiazol-5-yl]pyrimidin-2- yl}amino)piperidine-1-carboxylate
275-280 >3 395 ##STR00460## 3-{5-[2-({(3R)-1-[(4-
chlorophenyl)sulfonyl]piperidin-3- yl}amino)pyrimidin-4-
yl]imidazo[2,1-b][1,3]thiazol-6- yl}benzaldehyde oxime 238-240
0.018 396 ##STR00461## (3-{5-[2-({(3R)-1-[(4-
chlorophenyl)sulfonyl]piperidin-3- yl}amino)pyrimidin-4-
yl]imidazo[2,1-b][1,3]thiazol-6- yl}phenyl)methanol 150-155 1.6 397
##STR00462## 3-[5-(2-{[(3R)-1- (cyclopropylsulfonyl)piperidin-3-
yl]amino}pyrimidin-4- yl)imidazo[2,1-b][1,3]oxazol-6- yl]phenol
163-169 2.3 398 ##STR00463## 3-[5-(2-{[(3R)-1-
(phenylsulfonyl)piperidin-3- yl]amino}pyrimidin-4-
yl)imidazo[2,1-b][1,3]oxazol-6- yl]phenol 152-157 0.042 399
##STR00464## 3-[5-(2-{[(3R)-1-(3- thienylsulfonyl)piperidin-3-
yl]amino}pyrimidin-4- yl)imidazo[2,1-b][1,3]oxazol-6- yl]phenol
161-168 >3 400 ##STR00465## 1-(4-{5-[2-({(3R)-1-[(4-
chlorophenyl)sulfonyl]piperidin-3- yl}amino)pyrimidin-4-
yl]imidazo[2,1-b][1,3]thiazol-6- yl}phenyl)ethanone 137-139 1.3
[0298] Other embodiments are within the following claims. While
several embodiments have been shown and described, various
modifications may be made without departing from the spirit and
scope of the present invention.
* * * * *
References