U.S. patent application number 11/754653 was filed with the patent office on 2008-12-04 for benzimidazole thiophene compounds.
Invention is credited to Mui Cheung, Hamilton Dickson, Kyle Allen Emmitte, Keith Hornberger, Kevin Kuntz, Tara Renae Rheault, Stephon Smith.
Application Number | 20080300247 11/754653 |
Document ID | / |
Family ID | 40088999 |
Filed Date | 2008-12-04 |
United States Patent
Application |
20080300247 |
Kind Code |
A1 |
Kuntz; Kevin ; et
al. |
December 4, 2008 |
Benzimidazole Thiophene Compounds
Abstract
The present invention provides benzimidazole thiophene compounds
pharmaceutical compositions containing the same, processes for
preparing the same and their use as pharmaceutical agents.
Inventors: |
Kuntz; Kevin; (Durham,
NC) ; Emmitte; Kyle Allen; (Durham, NC) ;
Rheault; Tara Renae; (Durham, NC) ; Smith;
Stephon; (Durham, NC) ; Hornberger; Keith;
(Durham, NC) ; Dickson; Hamilton; (Durham, NC)
; Cheung; Mui; (King of Prussia, PA) |
Correspondence
Address: |
GLAXOSMITHKLINE;CORPORATE INTELLECTUAL PROPERTY, MAI B482
FIVE MOORE DR., PO BOX 13398
RESEARCH TRIANGLE PARK
NC
27709-3398
US
|
Family ID: |
40088999 |
Appl. No.: |
11/754653 |
Filed: |
May 29, 2007 |
Current U.S.
Class: |
514/234.5 ;
514/254.06; 514/274; 514/318; 514/322; 544/139; 544/316; 544/370;
546/194; 546/199 |
Current CPC
Class: |
C07D 413/14 20130101;
C07D 409/14 20130101; A61P 7/00 20180101; A61P 35/00 20180101; C07D
409/04 20130101 |
Class at
Publication: |
514/234.5 ;
514/254.06; 514/274; 514/318; 514/322; 544/139; 544/316; 544/370;
546/194; 546/199 |
International
Class: |
A61K 31/5377 20060101
A61K031/5377; A61K 31/454 20060101 A61K031/454; A61K 31/4545
20060101 A61K031/4545; A61P 35/00 20060101 A61P035/00; C07D 401/14
20060101 C07D401/14; C07D 409/14 20060101 C07D409/14; C07D 413/14
20060101 C07D413/14; C07D 403/14 20060101 C07D403/14; A61P 7/00
20060101 A61P007/00; A61K 31/496 20060101 A61K031/496; A61K 31/513
20060101 A61K031/513 |
Claims
1. A compound of formula (I): ##STR00374## wherein: R.sup.1 is
selected from H, halo, alkyl, haloalkyl, --OR.sup.7, --CN,
--C(O)NR.sup.7R.sup.8, --S(O).sub.2R.sup.7,
--R.sup.5--S(O).sub.2R.sup.7, --NR.sup.7R.sup.8,
--NR.sup.7C(O)R.sup.8, Ph, and Het.sup.1; Ph is phenyl optionally
substituted 1 or 2 times with halo, alkyl, haloalkyl, --OR.sup.7,
--CN, --S(O).sub.2R.sup.7 or --NR.sup.7R.sup.8; Het.sup.1 is a 5-6
membered heteroaryl having 1, 2 or 3 heteroatoms selected from N, O
and S, optionally substituted 1 or 2 times with a substituent
selected from halo, alkyl, haloalkyl, OR.sup.7, --CN,
--S(O).sub.2R.sup.7, --NR.sup.7R.sup.8, Het.sup.2,
--R.sup.5--Het.sup.2, NR.sup.7--Het.sup.2, and oxo; Het.sup.2 is a
5-6 membered heterocycle having 1 or 2 heteroatoms selected from N,
O and S, optionally substituted 1 or 2 times with a substituent
selected from alkyl, OR.sup.7, --NR.sup.7R.sup.8,
--C(O)NR.sup.7R.sup.8, --S(O).sub.2R.sup.7, and oxo; R.sup.2 is
selected from H, halo, alkyl, haloalkyl, OR.sup.7, --CN,
--C(O)NR.sup.7R.sup.8, --S(O).sub.2R.sup.7,
--R.sup.5--S(O).sub.2R.sup.7, --S(O).sub.2NR.sup.7R.sup.8,
--R.sup.5--S(O).sub.2NR.sup.7R.sup.8, --NR.sup.7R.sup.8, and
--NR.sup.7C(O)R.sup.8; R.sup.3 is H, alkyl or haloalkyl; Z.sup.1,
Z.sup.2 and Z.sup.3 are each the same or different and are
independently C, CH or N, wherein at least one of Z.sup.1, Z.sup.2
and Z.sup.3 is C or CH; d is 0, 1 or 2; each R.sup.4 is the same or
different and is independently halo, alkyl or haloalkyl; Y.sup.1 is
--O-- or --N(R.sup.7)--; a is 0 or 1; each R.sup.5 is the same or
different and is independently C.sub.1-3alkylene; Ring A is a 5-6
membered heterocycle having 1 or 2 heteroatoms selected from N, O
and S; b is 0, 1 or 2; each R.sup.6 is the same or different and is
independently selected from halo, alkyl, haloalkyl, alkenyl, --CN,
--R.sup.5--CN, --CO.sub.2R.sup.7, --R.sup.5--CO.sub.2R.sup.7,
--C(O)NR.sup.7R.sup.8, --R.sup.5--C(O)NR.sup.7R.sup.8, --OR.sup.7,
--R.sup.5--OR.sup.7, --S(O).sub.2R.sup.7,
--R.sup.5--S(O).sub.2R.sup.7, --S(O).sub.2NR.sup.7R.sup.8,
--R.sup.5--S(O).sub.2NR.sup.7R.sup.8, --NR.sup.7R.sup.8,
--R.sup.5--NR.sup.7R.sup.8, --NR.sup.7C(O)R.sup.8,
--NR.sup.7S(O).sub.2R.sup.8, --NR.sup.7C(O)NR.sup.7R.sup.8,
--NR.sup.7C(O).sub.2R.sup.8 and oxo; each R.sup.7 and each R.sup.8
are the same or different and are each independently selected from
H, alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, cycloalkyl and
cycloalkenyl; or a pharmaceutically acceptable salt thereof.
2. The compound according to claim 1, wherein R.sup.1 is selected
from H, halo, alkyl, haloalkyl, --OR.sup.7, --S(O).sub.2R.sup.7 and
Het.sup.1.
3. The compound according to claim 1, wherein R.sup.2 is selected
from H, halo, alkyl, haloalkyl, --OR.sup.7, --CN,
--S(O).sub.2R.sup.7 and --R.sup.5--S(O).sub.2R.sup.7.
4. The compound according to claim 1, wherein R.sup.3 is alkyl or
halo alkyl.
5. The compound according to claim 1, wherein Z.sup.1, and Z.sup.3
are each C or CH.
6. The compound according to claim 1, wherein d is 0 or 1.
7. The compound according to claim 1, wherein each R.sup.4 is the
same or different and is halo, C.sub.1-3alkyl or
C.sub.1-3haloalkyl.
8. The compound according to claim 1, wherein Y.sup.1 is --O-- or
--N(H)--.
9. The compound according to claim 1, wherein a is 0.
10. The compound according to claim 1, wherein Ring A is a 6
membered heterocycle having 1 N atom and optionally 1 more
heteroatom selected from N, O and S.
11. The compound according to claim 1, wherein b is 0 or 1.
12. The compound according to claim 1, wherein each R.sup.6 is the
same or different and is independently selected from halo, alkyl,
haloalkyl, --CN, --CO.sub.2R.sup.7, --R.sup.5--CO.sub.2R.sup.7,
--C(O)NR.sup.7R.sup.8, --OR.sup.7, --R.sup.5--OR.sup.7,
--S(O).sub.2R.sup.7, --R.sup.5--S(O).sub.2R.sup.7,
--NR.sup.7R.sup.8, --R.sup.5--NR.sup.7R.sup.8, and oxo.
13. A compound according to claim 1, having the stereochemistry
depicted in formula (I-1): ##STR00375## wherein * indicates a
chiral carbon and all variables are as defined in claim 1.
14. A compound of formula (XL): ##STR00376## wherein: R.sup.1 is
selected from H, halo, alkyl, haloalkyl, --OR.sup.7, --CN,
--C(O)NR.sup.7R.sup.8, --S(O).sub.2R.sup.7,
--R.sup.5--S(O).sub.2R.sup.7 and Het.sup.1; Het.sup.1 is a 5-6
membered heteroaryl having 1, 2 or 3 heteroatoms selected from N, O
and S, optionally substituted I or 2 times with a substituent
selected from alkyl, haloalkyl, --OR.sup.7, --CN,
--S(O).sub.2R.sup.7, --NR.sup.7R.sup.8 and oxo; R.sup.2 is selected
from H, halo, alkyl, haloalkyl, --OR.sup.7, --CN,
--C(O)NR.sup.7R.sup.8, --S(O).sub.2R.sup.7,
-R.sup.5--S(O).sub.2R.sup.7, --S(O).sub.2NR.sup.7R.sup.8,
--R.sup.5--S(O).sub.2NR.sup.7R.sup.8, --NR.sup.7R.sup.8, and
--NR.sup.7C(O)R.sup.8; R.sup.3 is alkyl; * indicates a chiral
carbon; R.sup.4 is H or halo; each R.sup.5 is the same or different
and is independently C.sub.1-3alkylene; Ring A is a 5-6 membered
heterocycle having 1 or 2 heteroatoms selected from N, O and S; b
is 0 or 1; each R.sup.6 is the same or different and is
independently selected from halo, alkyl, haloalkyl,
--CO.sub.2R.sup.7, --R.sup.5--CO.sub.2R.sup.7, --OR.sup.7,
--R.sup.5--OR.sup.7, --S(O).sub.2R.sup.7,
--R.sup.5--S(O).sub.2R.sup.7, --NR.sup.7R.sup.8,
--R.sup.5--NR.sup.7R.sup.8 and oxo; each R.sup.7 and each R.sup.8
are the same or different and are each independently selected from
H, alkyl and haloalkyl; or a pharmaceutically acceptable salt
thereof.
15. (canceled)
16. 3-[((1 R)-1 -{2-Chloro-3-[(1
-methyl-4-piperidinyl)oxy]phenyl}ethyl)oxy]-5-[5-(1-methyl-1H-pyrazol-4-y-
l)-1 H-benzimidazol-1-yl]-2-thiophenecarboxamide ##STR00377##
17. A pharmaceutical composition comprising a compound according to
claim 1 and a pharmaceutically acceptable carrier, diluent or
excipient.
18. The pharmaceutical composition according to claim 17 further
comprising a chemotherapeutic agent.
19. A method for treating a susceptible neoplasm in a mammal in
need thereof, said method comprising administering to the mammal a
therapeutically effective amount of a compound according to claim
1.
20. The method according to claim 19, wherein said susceptible
neoplasm is selected from the group consisting of breast cancer,
colon cancer, small cell lung cancer, non-small cell lung cancer,
prostate cancer, endometrial cancer, gastric cancer, melanoma,
ovarian cancer, pancreatic cancer, squamous cell carcinoma,
carcinoma of the head and neck, esophageal carcinoma,
hepatocellular carcinoma, and hematologic malignancies.
21. A method for treating breast cancer in a human in need thereof,
said method comprising administering to the human a therapeutically
effective amount of a compound according to claim 1.
22. A method for treating breast cancer in a human in need thereof,
said method comprising administering to the human a therapeutically
effective amount of a compound according to claim 16.
23. A method for treating ovarian cancer in a human in need
thereof, said method comprising administering to the human a
therapeutically effective amount of a compound according to claim
1.
24. A method for treating ovarian cancer in a human in need
thereof, said method comprising administering to the human a
therapeutically effective amount of a compound according to claim
16.
25. A method for treating non-small cell lung cancer in a human in
need thereof, said method comprising administering to the human a
therapeutically effective amount of a compound according to claim
1.
26. A method for treating non-small cell lung cancer in a human in
need thereof, said method comprising administering to the human a
therapeutically effective amount of a compound according to claim
16.
27. A method for treating colon cancer in a human in need thereof,
said method comprising administering to the human a therapeutically
effective amount of a compound according to claim 1.
28. A method for treating colon cancer in a human in need thereof,
said method comprising administering to the human a therapeutically
effective amount of a compound according to claim 16.
29. A method for treating a hematologic malignancy in a human in
need thereof, said method comprising administering to the human a
therapeutically effective amount of a compound according to claim
1.
30. A method for treating a hematologic malignancy in a human in
need thereof, said method comprising administering to the human a
therapeutically effective amount of a compound according to claim
16.
31. A method for treating a condition characterized by
inappropriate cellular proliferation in a mammal in need thereof,
said method comprising administering to the mammal a
therapeutically effective amount of a compound according to claim
1.
32. A process for preparing a compound according to claim 1 wherein
Y.sup.1 is O, said process comprising the steps of: reacting the
compound of formula (VII): ##STR00378## wherein R.sup.10 is
selected from alkyl and suitable carboxylic acid protecting groups;
and all other variables are as defined in claim 1, with ammonia to
prepare a compound of formula (I).
33. A process for preparing a compound according to claim 1 wherein
Y.sup.1 is NH, said process comprising the steps of: reacting the
compound of formula (XXXIII): ##STR00379## wherein all variables
are as defined in claim 1, with a compound of formula (XXXIV):
##STR00380## to prepare a compound of formula (I).
34. A compound selected from the group consisting of
3-({(1R)-1-[2-Chloro-3-(4-piperidinyloxy)phenyl]ethyl}oxy)-5-[5-(1-methyl-
-1H-pyrazol-4-yl)-1H-benzimidazol-1-yl]-2-thiophenecarboxamide;
3-[((1
R)-1-(2-Chloro-3-[(1-methyl-4-piperidinyl)oxy]phenyl}ethyl)oxy]5-[5-(1-me-
thyl-1H-pyrazol-4-yl)-1H-benzimidazol-1-yl]-2-thiophenecarboxamide;
3-({(1R)-1-[2-Chloro-3-(4-piperidinyloxy)phenyl]ethyl}oxy)-5-[5-(2-methyl-
-4-pyridinyl)-1H-benzimidazol-1-yl]-2-thiophenecarboxamide; and a
pharmaceutically acceptable salts thereof.
35.
3-[((1R)-1-{2-Chloro-3-[(1-methyl-4-piperidinyl)oxy]phenyl}ethyl)oxy]-
-5-[5-(1-methyl-1H-pyrazol-4-yl)-1H-benzimidazol-1-yl]-2-thiophenecarboxam-
ide ##STR00381## or a pharmaceutically acceptable salt thereof.
36. A pharmaceutical composition comprising a compound according to
claim 16 and a pharmaceutically acceptable carrier, diluent or
excipient.
37. A pharmaceutical composition comprising a compound according to
claim 35 and a pharmaceutically acceptable carrier, diluent or
excipient.
38. The method according to claim 19, wherein said susceptible
neoplasm is selected from the group consisting of breast cancer,
colon cancer, non-small cell lung cancer, gastric cancer, melanoma,
ovarian cancer, pancreatic cancer, carcinoma of the head and neck
and hematologic malignancies.
39. The method according to claim 19, wherein said mammal is a
human.
40. A method for treating gastric cancer in a human in need
thereof, said method comprising administering to the human a
therapeutically effective amount of a compound according to claim
16.
41. A method for treating melanoma in a human in need thereof, said
method comprising administering to the human a therapeutically
effective amount of a compound according to claim 16.
42. A method for treating pancreatic cancer in a human in need
thereof, said method comprising administering to the human a
therapeutically effective amount of a compound according to claim
16.
43. A method for treating carcinoma of the head and neck in a human
in need thereof, said method comprising administering to the human
a therapeutically effective amount of a compound according to claim
16.
44. A method for treating Non-Hodgkins lymphoma in a human in need
thereof, said method comprising administering to the human a
therapeutically effective amount of a compound according to claim
16.
45. A method for treating leukemia in a human in need thereof, said
method comprising administering to the human a therapeutically
effective amount of a compound according to claim 16.
46. A method for treating breast cancer in a human in need thereof,
said method comprising administering to the human a therapeutically
effective amount of a compound according to claim 35.
47. A method for treating colon cancer in a human in need thereof,
said method comprising administering to the human a therapeutically
effective amount of a compound according to claim 35.
48. A method for treating non-small cell lung cancer in a human in
need thereof, said method comprising administering to the human a
therapeutically effective amount of a compound according to claim
35.
49. A method for treating gastric cancer in a human in need
thereof, said method comprising administering to the human a
therapeutically effective amount of a compound according to claim
35.
50. A method for treating melanoma in a human in need thereof, said
method comprising administering to the human a therapeutically
effective amount of a compound according to claim 35.
51. A method for treating ovarian cancer in a human in need
thereof, said method comprising administering to the human a
therapeutically effective amount of a compound according to claim
35.
52. A method for treating pancreatic cancer in a human in need
thereof, said method comprising administering to the human a
therapeutically effective amount of a compound according to claim
35.
53. A method for treating carcinoma of the head and neck in a human
in need thereof, said method comprising administering to the human
a therapeutically effective amount of a compound according to claim
35.
54. A method for treating Non-Hodgkins lymphoma in a human in need
thereof, said method comprising administering to the human a
therapeutically effective amount of a compound according to claim
35.
55. A method for treating leukemia in a human in need thereof, said
method comprising administering to the human a therapeutically
effective amount of a compound according to claim 35.
Description
BACKGROUND OF THE INVENTION
[0001] The present invention relates to novel benzimidazole
thiophene compounds, pharmaceutical formulations comprising these
compounds, and the use of these compounds in therapy.
[0002] Polo-like kinases ("PLK") are evolutionary conserved
serine/threonine kinases that play critical roles in regulating
processes in the cell cycle. PLK plays a role in the entry into and
the exit from mitosis in diverse organisms from yeast to mammalian
cells. PLK includes PLK1, PLK2, PLK3 and PLK4.
[0003] Overexpression of PLK1 appears to be strongly associated
with neoplastic cells (including cancers). A published study has
shown high levels of PLK1RNA expression in >80% of lung and
breast tumors, with little to no expression in adjacent normal
tissue. Several studies have shown correlations between PLK
expression, histological grade, and prognosis in several types of
cancer. Significant correlations were found between percentages of
PLK-positive cells and histological grade of ovarian and
endometrial cancer (P<0.001). These studies noted that PLK is
strongly expressed in invading endometrial carcinoma cells and that
this could reflect the degree of malignancy and proliferation in
endometrial carcinoma. Using RT-PCR analysis, PLK overexpression
was detected in 97% of esophageal carcinomas and 73% of gastric
carcinomas as compared to the corresponding normal tissues.
Further, patients with high levels of PLK overexpression in
esophageal carcinoma represented a significantly poorer prognosis
group than those with low levels of PLK overexpression. In head and
neck cancers, elevated mRNA expression of PLK1 was observed in most
tumors; a Kaplan-Meier analysis showed that those patients with
moderate levels of PLK1expression survived longer than those with
high levels of PLK1 expression. Analysis of patients with non-small
cell lung carcinoma showed similar outcomes related to PLK1
expression.
[0004] PCT Publication No. WO2004/014899 to SmithKHne Beecham
discloses novel benzimidazole thiophene compounds of formula
(I):
##STR00001##
[0005] wherein:
[0006] R.sup.1 is selected from the group consisting of H, alkyl,
alkenyl, alkynyl, --C(O)R.sup.7, --CO.sub.2R.sup.7,
--C(O)NR.sup.7R.sup.8, --C(O)N(R.sup.7)OR.sup.8,
--C(O)N(R.sup.7)--R.sup.2--OR.sup.8, --C(O)N(R.sup.7)--Ph,
--C(O)N(R.sup.7)--R.sup.2--Ph, --C(O)N(R.sup.7)C(O)R.sup.8,
--C(O)N(R.sup.7)CO.sub.2R.sup.8;
--C(O)M(R.sup.7)C(O)NR.sup.7R.sup.8,
--C(O)N(R.sup.7)S(O).sub.2R.sup.8, --R.sup.2--OR.sup.7,
--R.sup.2--O--C(O)R.sup.7, --C(S)R.sup.7, --C(S)NR.sup.7R.sup.8,
--C(S)N(R.sup.7)--Ph, --C(S)N(R.sup.7)--R.sup.2--Ph,
--R.sup.2--SR.sup.7, --C(.dbd.NR.sup.7)NR.sup.7R.sup.8,
--C(.dbd.NR.sup.7)N(R.sup.8)--Ph,
--C(.dbd.NR.sup.7)N(R.sup.8)--R.sup.2--Ph,
--R.sup.2--NR.sup.7R.sup.8, --CN, --OR.sup.7, --S(O).sub.fR.sup.7,
--S(O).sub.2NR.sup.7R.sup.8, --S(O).sub.2N(R.sup.7)--Ph,
--S(O).sub.2N(R.sup.7)--R.sup.2--Ph, --NR.sup.7R.sup.8,
N(R.sup.7)--Ph, --N(R.sup.7)--R.sup.2--Ph,
--N(R.sup.7)--SO.sub.2R.sup.8 and Het;
[0007] Ph is phenyl optionally substituted from 1 to 3 times with a
substituent selected from the group consisting of halo, alkyl,
--OH, --R.sup.2--OH, --O-- alkyl, --R.sup.2--O-alkyl, --HH.sub.2,
--N(H)alkyl, --N(alkyl).sub.2, --CN and --N.sub.3;
[0008] Het is a 5-7 membered heterocycle having 1, 2, 3 or 4
heteroatoms selected from N, O and S, or a 5-6 membered heteroaryl
having 1, 2, 3 or 4 heteroatoms selected from N, O and S, each
optionally substituted from 1 to 2 times with a substituent
selected from the group consisting of halo, alkyl, oxo, --OH,
--R.sup.2--GH, --O--alkyl, --R.sup.2--O-alkyl, --NH.sub.2,
--N(H)alkyl, --N(alkyl).sub.2, --CN and --N.sub.3;
[0009] Q.sup.1 Is a group of formula:
--(R.sup.2).sub.a--(Y.sup.1).sub.b--(R.sup.2).sub.c--R.sup.3
[0010] a, b and c are the same or different and are each
independently 0 or 1 and at least one of a or b is 1;
[0011] n is 0, 1, 2, 3 or 4;
[0012] Q.sup.2 is a group of formuia:
--(R.sup.2).sub.aa--(Y.sup.2).sub.bb--(R.sup.2).sub.cc--R.sup.4
[0013] or two adjacent Q.sup.2 groups are selected from the group
consisting of alkyl, alkenyl, --OR.sup.7, --S(O).sub.fR.sup.7 and
--NR.sup.7R.sup.8 and together with the carbon atoms to which they
are bound, they form a C.sub.5-6cycloalkyi, C.sub.5-6cycloalkenyl,
phenyl, 5-7 membered heterocyccle having 1 or 2heteroatoms selected
from N, O and S, or 5-6 membered heteroaryl having 1 or 2
heteroatoms selected from N, O and S;
[0014] aa, bb and cc are the same or different and are each
independently 0 or 1;
[0015] each Y.sup.1 and Y.sup.2 is the same or different and is
independently selected from the group consisting of --O--,
--S(O).sub.f--, --N(R.sup.7)--, --C(O)--, --OC(O)--, --CO.sub.2--,
--C(O)N(R.sup.7)--, --C(O)N(R.sup.7)S(O).sub.2--,
--OC(O)N(R.sup.7)--, --OS(O).sub.2--, --S(O).sub.2N(R.sup.7)--,
--S(O).sub.2N(R.sup.7)C(O)--, --N(R.sup.7)S(O).sub.2--,
--N(R.sup.7)C(O)--, --N(R.sup.7)CO.sub.2-- and
--N(R.sup.7)C(O)N(R.sup.7)--;
[0016] each R.sup.2 is the same or different and is independently
selected from the group consisting of alkylene, alkenylene and
alkynylene;
[0017] each R.sup.3 and R.sup.4 is the same or different and is
each independently selected from the group consisting of H, halo,
alkyl, alkenyl, alkynyl, --C(O)R.sup.7, --C(O)NR.sup.7R.sup.8,
--CO.sub.2R.sup.7, --C(S)R.sup.7, --C(S)NR.sup.7R.sup.8,
--C(.dbd.NR.sup.7)R.sup.8, --C(.dbd.NR.sup.7)NR.sup.7R.sup.8,
--CR.sup.7.dbd.N--OR.sup.7, --OR.sup.7, --S(O).sub.fR.sup.7,
--S(O).sub.2NR.sup.7R.sup.8, --NR.sup.7R.sup.8,
--N(R.sup.7)C(O)R.sup.8, --N(R.sup.7)S(O).sub.2R.sup.8, --NO.sub.2,
--CN, --N.sub.3 and a group of formula (ii):
##STR00002##
[0018] wherein:
[0019] Ring A is selected from the group consisting of
C.sub.5-10cycloalkyl, C.sub.5-10cycyloalkenyl, aryl, 5-10 membered
heterocycle having 1, 2 or 3 heteroatoms selected from N, O and S
and 5-10 membered heteroaryl having 1, 2 or 3 heteroatoms selected
from N, O and S
[0020] each d is 0 or 1;
[0021] e is 0, 1, 2, 3 or 4;
[0022] each R.sup.6 is the same or different and is independently
selected from the group consisting of H, halo, alkyl, alkenyl,
alkynyl, cycloalkyl, cycloalkenyl, Ph, Het, --CH(OH)--R.sup.2--OH,
--C(O)R.sup.7, --CO.sub.2R.sup.7, --CO.sub.2--R.sub.2--Ph,
--CO.sub.2--R.sup.2-Het, --C(O)NR.sup.7R.sup.8,
--C(O)N(R.sup.7)C(O)R.sup.7, --C(O)N(R.sup.7)CO.sub.2R.sup.7,
--C(O)N(R.sup.7)C(O)NR.sup.7R.sup.8,
--C(O)N(R.sup.7)S(O).sub.2R.sup.7, --C(S)R.sup.7,
--C(S)NR.sup.7R.sup.8, --C(.dbd.NR.sup.7)R.sup.8,
--C(.dbd.NR.sup.7)NR.sup.7R.sup.8, --CR.sup.7.dbd.N--OR.sup.8,
.dbd.O, --OR.sup.7, --OC(O)R.sup.7, --OC(O)Ph, --OC(O)Het,
--OC(O)NR.sup.7R.sup.8, --O--R.sup.2--S(O).sub.2R.sup.7,
--S(O).sub.fR.sup.7, --S(O).sub.2NR.sup.7R.sup.8, --S(O).sub.2Ph,
--S(O).sub.2Het, --NR.sup.7R.sup.8, --N(R.sup.7)C(O)R.sup.8,
--N(R.sup.7)CO.sub.2R.sup.8,
--N(R.sup.7)--R.sup.2--CO.sub.2R.sup.8,
--N(R.sup.7)C(O)NR.sup.7R.sup.8,
--N(R.sup.7)--R.sup.2--C(O)NR.sup.7R.sup.8, --N(R.sup.7)C(O)Ph,
--N(R.sup.7)C(O)Het, --N(R.sup.7)Ph, --N(R.sup.7)Het,
--N(R.sup.7)C(O)NR.sup.7--R.sup.2--NR.sup.7R.sup.8,
--N(R.sup.7)C(O)N(R.sup.7)Ph, --N(R.sup.7)C(O)N(R.sup.7)Het,
--N(R.sup.7)C(O)N(R.sup.7)--R.sup.2-Het,
--N(R.sup.7)S(O).sub.2R.sup.8,
--N(R.sup.7)--R.sup.2--S(O).sub.2R.sup.8, --NO.sub.2, --CN and
--N.sub.3;
[0023] wherein when Q.sup.1 is defined where b is 1 and c is 0,
R.sup.3 is not halo, --C(O)R.sup.7, --C(O)NR.sup.7R.sup.8,
--CO.sub.2R.sup.7, --C(S)R.sup.7, --C(S)NR.sup.7R.sup.8,
--C(.dbd.NR.sup.7)R.sup.8, --C(.dbd.NR.sup.7)NR.sup.7R.sup.8,
--CR.sup.7.dbd.N--OR.sup.7, --OR.sup.7, --S(O).sub.fR.sup.7,
--S(O).sub.2NR.sup.7R.sup.8, --NR.sup.7R.sup.8,
--N(R.sup.7)C(O)R.sup.8, --N(R.sup.7)S(O).sub.2R.sup.8, --NO.sub.2,
--CN or --N.sub.3;
[0024] wherein when Q.sup.2 is defined where bb is 1 and cc is 0,
R.sup.4 is not halo, --C(O)R.sup.7, --C(O)NR.sup.7R.sup.8,
--CO.sub.2R.sup.7, --C(S)R.sup.7, --C(S)NR.sup.7R.sup.8,
--C(.dbd.NR.sup.7)R.sup.8, --C(.dbd.NR.sup.7)NR.sup.7R.sup.8,
--CR.sup.7.dbd.N--OR.sup.7, --OR.sup.7, --S(O).sub.fR.sup.7,
--S(O).sub.2NR.sup.7R.sup.8, --NR.sup.7R.sup.8,
--N(R.sup.7)C(O)R.sup.8, --N(R.sup.7)S(O).sub.2R.sup.8, --NO.sub.2,
--CN or --N.sub.3;
[0025] R.sup.5 is selected from the group consisting of H, halo,
alkyl, cycloalkyl, OR.sup.7, --S(O).sub.fR.sup.7,
--NR.sup.7R.sup.8, --NHC(O)R.sup.7, --NHC(O)NR.sup.7R.sup.8 and
--NHS(O).sub.2R.sup.7;
[0026] f is 0, 1 or 2; and
[0027] each R.sup.7 and each R.sup.8 are the same or different and
are each independently selected from the group consisting of H,
alkyl, alkenyl, alkynyl, cycloalkyl and cycloalkenyl;
[0028] wherein when R.sup.1 is --CO.sub.2CH.sub.3 and n is 0,
Q.sup.1 is not --OH;
[0029] or a pharmaceutically acceptable salt, solvate or
physiologically functional derivative thereof.
[0030] Also disclosed are pharmaceutical compositions containing
these compounds, processes for their preparation and methods for
treatment of conditions mediated by PLK using these compounds.
BRIEF SUMMARY OF THE INVENTION
[0031] According to a first aspect of the invention there is
provided compounds of formula (I):
##STR00003##
[0032] wherein:
[0033] R.sup.1 is selected from H, halo, alkyl, haloalkyl,
--OR.sup.7, --CN, --C(O)NR.sup.7R.sup.8, --S(O).sub.2R.sup.7,
--R.sup.5--S(O).sub.2R.sup.7, --NR.sup.7R.sup.8,
--NR.sup.7C(O)R.sup.8, Ph, and Het.sup.1; [0034] Ph is phenyl
optionally substituted 1 or 2 times with halo, alkyl, haloalkyl,
--OR.sup.7, --CN, --S(O).sub.2R.sup.7 and --NR.sup.7R.sup.8; [0035]
Het.sup.1 is a 5-6 membered heteroaryl having 1, 2 or 3 heteroatoms
selected from M, O and S, optionally substituted 1 or 2 times with
a substituent selected from halo, alkyl, haloalkyl, --OR.sup.7,
--CN, --S(O).sub.2R.sup.7, --NR.sup.7R.sup.8, Het.sup.2,
--R.sup.5-Het.sup.2, NR.sup.7-Het.sup.2, and oxo; [0036] Het.sup.2
is a 5-6 membered heterocycle having 1 or 2 heteroatoms selected
from H, O and S, optionally substituted 1 or 2 times with a
substituent selected from alkyl, --OR.sup.7, --NR.sup.7R.sup.8,
--C(O)NR.sup.7R.sup.8, --S(O).sub.2R.sup.7, and oxo;
[0037] R.sup.2 is selected from H, halo, alkyl, haloalkyl,
--OR.sup.7, --CN, --C(O)NR.sup.7R.sup.8, --S(O).sub.2R.sup.7,
--R.sup.5--S(O).sub.2R.sup.7, --S(O).sub.2NR.sup.7R.sup.8,
--R.sup.5--S(O).sub.2NR.sup.7R.sup.8, --NR.sup.7R.sup.8, and
--NR.sup.7C(O)R.sup.8;
[0038] R.sup.3 Is H, alkyl or haloalkyl;
[0039] Z.sup.1, Z.sup.2 and Z.sup.3 are each the same or different
and are independently C, CH or N, wherein at least one of Z.sup.1,
Z.sup.2 and Z.sup.3 is C or CH;
[0040] d is 0, 1 or 2;
[0041] each R.sup.4 is the same or different and is independently
halo, alkyl or haloalkyl;
[0042] Y.sup.1 is --O-- or --N(R.sup.7)--;
[0043] a is 0 or 1;
[0044] each R.sup.5 is the same or different and is independently
C.sub.1-3alkylene;
[0045] Ring A is a 5-6 membered heterocycle having 1 or 2
heteroatoms selected from N, O and S;
[0046] b is 0, 1 or 2;
[0047] each R.sup.6 is the same or different and Is independently
selected from halo, alkyl, haloalkyl, alkenyl, --CN, --R.sup.5--CN,
--CO.sub.2R.sup.7, --R.sup.5--CO.sub.2R.sup.7,
--C(O)NR.sup.7R.sup.8, --R.sup.5--C(O)NR.sup.7R.sup.8, --OR.sup.7,
--R.sup.5--OR.sup.7, --S(O).sub.2R.sup.7,
--R.sup.5--S(O).sub.2R.sup.7, --S(O).sub.2NR.sup.7R.sup.8,
--R.sup.5--S(O).sub.2NR.sup.7R.sup.8, --NR.sup.7R.sup.8,
--R.sup.5--NR.sup.7R.sup.8, --NR.sup.7C(O)R.sup.8,
--NR.sup.7S(O).sub.2R.sup.8, --NR.sup.7C(O)NR.sup.7R.sup.8,
--NR.sup.7C(O).sub.2R.sup.8 and oxo;
[0048] each R.sup.7 and each R.sup.8 are the same or different and
are each independently selected from H, alkyl, haloalkyi, alkenyl,
haloalkenyl, alkynyl, cycloalkyl and cycloalkenyl;
[0049] and pharmaceutjcaily acceptable salts thereof.
[0050] In second aspect, there Is provided an enantiometrically
enriched compound of formula (I) having the stereochemistry
depicted in formula (I-1).
##STR00004##
[0051] wherein * indicates a chiral carbon and all variables are as
defined above.
[0052] In third aspect, there is provided compounds of formula
(XL)
##STR00005##
[0053] wherein:
[0054] R.sup.1 is selected from H, halo, alkyl, haloalkyl,
--OR.sup.7, --CN, --C(O)NR.sup.7R.sup.8, --S(O).sub.2R.sup.7,
--R.sup.5--S(O).sub.2R.sup.7 and Het.sup.1; [0055] Het.sup.1 is a
5-6 membered heteroaryl having 1, 2 or 3 heteroatoms selected from
H, O and S, optionally substituted 1 or 2 times with a substituent
selected from alkyl, haloalkyl, --OR.sup.7, --CN,
--S(O).sub.2R.sup.7, --NR.sup.7R.sup.8 and oxo;
[0056] R.sup.2 is selected from H, halo, alkyl, haloalkyl,
--OR.sup.7, --CN, --C(O)NR.sup.7R.sup.8, --S(O).sub.2R.sup.7,
--R.sup.5--S(O).sub.2R.sup.7, --S(O).sub.2NR.sup.7R.sup.8,
--R.sup.5--S(O).sub.2NR.sup.7R.sup.8, --NR.sup.7R.sup.8, and
--NR.sup.7C(O)R.sup.8;
[0057] R.sup.3 is alkyl;
[0058] * indicates a chiral carbon;
[0059] R.sup.4 is H or halo;
[0060] each R.sup.5 is the same or different and is independently
C.sub.1-3alkylene;
[0061] Ring A is a 5-6 membered heterocycle having 1 or 2
heteroatoms selected from N, O and S;
[0062] b is 0 or 1;
[0063] each R.sup.6 is the same or different and is independently
selected from halo, alkyl, haloalkyl, --CO.sub.2R.sup.7,
--R.sup.5--CO.sub.2R.sup.7, --OR.sup.7, --R.sup.5--OR.sup.7,
--S(O).sub.2R.sup.7, --R.sup.5--S(O).sub.2R.sup.7,
--NR.sup.7R.sup.8, --R.sup.5--NR.sup.7R.sup.8 and oxo;
[0064] each R.sup.7 and each R.sup.8 are the same or different and
are each independently selected from H, alkyl and haloalkyl;
[0065] and pharmaceutically acceptable salts thereof.
[0066] In s fourth aspect of the Invention there is provided a
pharmaceutical composition comprising a compound of formula (I),
(I-1) or (XL) or a pharmaceutically acceptable salt thereof. In one
embodiment, the pharmaceutical composition further comprises a
pharmaceutically acceptable carrier, diluent or excipient.
[0067] In a fifth aspect of the invention, there is provided a
method for treating a condition mediated by PLK in a mammal in need
thereof. The method comprises administering to the mammal a
therapeutically effective amount of a compound of formula (I),
(I-1) or (XL) or a pharmaceutically acceptable salt thereof.
[0068] In a sixth aspect of the invention, there is provided a
method for treating a susceptible neoplasm in a mammal in need
thereof. The method comprises administering to the mammal a
therapeutically effective amount of a compound of formula (I),
(I-1) or (XL) or a pharmaceutically acceptable salt thereof. The
susceptible neoplasm may be selected from the group consisting of
breast cancer, colon cancer, lung cancer (including small cell lung
cancer and non-small cell lung cancer), prostate cancer,
endometrial cancer, gastric cancer, melanoma, ovarian cancer,
pancreatic cancer, squamous cell carcinoma, carcinoma of the head
and neck, esophageal carcinoma, hepatocellular carcinoma, renal
cell cancer, sarcoma (including cancers of connective tissue),
bladder cancer, glioma and hematologic malignancies such as
lymphoma including aggressive lymphomas and non-Hodgkins lymphoma,
and leukemia including acute leukemias. In one particular aspect,
there Is provided a method of treating breast cancer in a mammal in
need thereof, which comprises administering to the mammal a
therapeutically effective amount of a compound of formula (I),
(I-1) or (XL) or a pharmaceutically acceptable salt thereof. In one
particular aspect, there is provided a method of treating ovarian
cancer in a mammal in need thereof, which comprises administering
to the mammal a therapeutically effective amount of a compound of
formula (I), (I-1) or (XL) or a pharmaceutically acceptable salt
thereof. In one particular aspect, there is provided a method of
treating non-small cell lung cancer in a mammal in need thereof,
which comprises administering to the mammal a therapeutically
effective amount of a compound of formula (I), (I-1) or (XL) or a
pharmaceutically acceptable salt thereof, in one particular aspect,
there is provided a method of treating prostate cancer in a mammal
in need thereof, which comprises administering to the mammal a
therapeutically effective amount of a compound of formula (I),
(I-1) or (XL) or a pharmaceuticaliy acceptable salt thereof, in one
particular aspect, there is provided a method of treating a
hematologic malignancy in a mammal in need thereof, which comprises
administering to the mammal a therapeutically effective amount of a
compound of formula (I), (I-1) or (XL) or a pharmaceutically
acceptable salt thereof.
[0069] In a seventh aspect of the invention, there is provided a
method for treating a condition characterized by Inappropriate
cellular proliferation. The method comprises contacting the cell
with a therapeutically effective amount of a compound of formula
(I), (I-1) or (XL) or a pharmaceutically acceptable salt
thereof.
[0070] In an eighth aspect, the present invention provides a method
for inhibiting proliferation of a cell. The method comprises
contacting the cell with an amount of a compound of formula (I),
(I-1) or (XL) or a pharmaceutically acceptable salt thereof.
[0071] In another aspect, the present invention provides a method
for inhibiting mitosis in a cell. The method comprises
administering to the cell an amount of a compound of formula (I),
(I-1) or (XL) or a pharmaceutically acceptable salt thereof.
[0072] In another aspect, the present invention provides a process
for preparing a compound of formula (I) wherein Y.sup.1 is O, or a
pharmaceutically acceptable salt thereof. The process comprises the
steps of:
[0073] a) reacting the compound of formula (VII):
##STR00006## [0074] wherein R.sup.10 is selected from alkyl and
suitable carboxylic acid protecting groups; and all other variables
are as defined in claim 1,
[0075] with ammonia to prepare a compound of formula (I);
[0076] b) optionally separating the compound of formula (I) info
enantiomers of formula (I);
[0077] c) optionally converting the compound of formula (I) to a
pharmaceutically acceptable salt thereof; and
[0078] d) optionally converting the compound of formula (I) or a
pharmaceutically acceptable salt thereof to a different compound of
formula (I) or a pharmaceutically acceptable salt thereof.
[0079] In another aspect, the present invention provides a process
for preparing a compound of formula (I) wherein Y.sup.1 is NH, or a
pharmaceutically acceptable salt thereof. The process comprises the
steps of:
[0080] a) reacting the compound of formula (XXXIII):
##STR00007##
[0081] wherein all variables are as defined above,
[0082] with a compound of formula (XXXIV):
##STR00008##
[0083] to prepare a compound of formula (I);
[0084] b) optionally separating the compound of formula (I) into
enantiomers;
[0085] c) optionally converting the compound of formula (I) to a
pharmaceutically acceptable salt thereof; and
[0086] d) optionally converting the compound of formula (I) or a
pharmaceutically acceptable salt thereof to a different compound of
formula (I) or a pharmaceutically acceptable salt thereof.
[0087] In another aspect, the present invention provides a compound
of formula (I), (I-1) or (XL) or a pharmaceutically acceptable salt
thereof for use in therapy.
[0088] In yet another aspect, the present invention provides a
compound of formula (I), (I-1) or (XL) or a pharmaceutically
acceptable salt thereof for use in the treatment of a condition
mediated by PLK in a mammal in need thereof.
[0089] In yet another aspect, the present invention provides a
compound of formula (I), (I-1) or (XL) or a pharmaceutically
acceptable salt thereof for use in the treatment of a susceptible
neoplasm, such as breast cancer, colon cancer, small cell lung
cancer, non-small cell lung cancer, prostate cancer, endometrial
cancer, gastric cancer, melanoma, ovarian cancer, pancreatic
cancer, squamous cell carcinoma, carcinoma of the head and neck,
esophageal carcinoma, hepatocellular carcinoma, renal cell cancer,
sarcoma, bladder cancer, glioma and hematologic malignancies, in a
mammal. In one particular aspect, there is provided a compound of
formula (I), (I-1) or (XL) or a pharmaceutically acceptable salt
thereof, for use in the treatment of breast cancer, ovarian cancer,
non-small cell long cancer, prostate cancer, or a hematologic
malignancy in a mammal.
[0090] in another aspect, the present invention provides a compound
of formula (I), (I-1) or (XL) or a pharmaceutically acceptable salt
thereof, for use in the treatment of a condition characterized by
inappropriate cellular proliferation.
[0091] In yet another aspect, the present invention provides a
compound of formula (I), (I-1) or (XL) or a pharmaceutically
acceptable salt thereof, for use in inhibiting proliferation of a
cell.
[0092] In yet another aspect, the present invention provides a
compound of formula (I), (I-1) or (XL) or a pharmaceutically
acceptable salt thereof, for use in inhibiting mitosis in a
cell,
[0093] In yet another aspect, the present invention provides the
use of a compound of formula (I), (I-1) or (XL) or a
pharmaceutically acceptable salt thereof, for the preparation of a
medicament for the treatment of condition mediated by PLK in a
mammal.
[0094] In yet another aspect, the present invention provides the
use of a compound of formula (I), (I-1) or (XL) or a
pharmaceutically acceptable salt thereof, for the preparation of a
medicament for the treatment of a susceptible neoplasm, such as
breast cancer, colon cancer, small cell lung cancer, non-small cell
lung cancer, prostate cancer, endometrial cancer, gastric cancer,
melanoma, ovarian cancer, pancreatic cancer, squamous cell
carcinoma, carcinoma of the head and neck, esophageal carcinoma,
hepatocellular carcinoma, renal cell cancer, sarcoma, bladder
cancer, glioma and hematologic malignancies, in a mammal.
[0095] In yet another aspect, the present invention provides the
use of a compound of formula (I), (I-1) or (XL) or a
pharmaceutically acceptable salt thereof, for the preparation of a
medicament for the treatment of breast cancer, ovarian cancer, non
small cell lung cancer, prostate cancer or a hematologic malignancy
in a mammal.
[0096] In yet another aspect, the present invention provides the
use of a compound of formula (I), (I-1) or (XL) or a
pharmaceutically acceptable salt thereof, for the treatment of a
condition characterized by inappropriate cellular proliferation In
a mammal.
[0097] In yet another aspect, the present invention provides the
use a compound of formula (I), (I-1) or (XL) or a pharmaceutically
acceptable salt thereof, for the preparation of a medicament for
Inhibiting proliferation of a cell
[0098] In yet another aspect, the present invention provides the
use of a compound of formula (I), (I-1) or (XL) or a
pharroaceutically acceptable salt thereof, for the preparation of a
medicament for inhibiting mitosis in a cell.
[0099] In yet another aspect, the present invention provides a
pharmaceutical composition comprising a compound of formula (I),
(I-1) or (XL) or a pharmaceutically acceptable salt thereof, for
use in the treatment of a susceptible neoplasm, such as breast
cancer, colon cancer, small cell lung cancer, non-small cell lung
cancer, prostate cancer, endometrial cancer, gastric cancer,
melanoma, ovarian cancer, pancreatic cancer, squamous cell
carcinoma, carcinoma of the head and neck, esophageal carcinoma,
hepatocellular carcinoma, renal cell cancer, sarcoma, bladder
cancer, glioma and hematologic malignancies, in a mammal.
DETAILED DESCRIPTION OF THE INVENTION
[0100] As used herein, "compound(s) of formula (I)" means any
compound having the structural formula (I) as defined by the
variable definitions provided, solvates, including hydrates
thereof, and amorphous and crystal forms, including polymorphic
forms thereof, in the case of compounds of formula (I) which
possess one or more chiral centres, the compounds may be in the
form of a racemic mixture, or one or more isomerically enriched or
pure stereoisomers, including enantiomers and disastereomers
thereof. Stereoisomerism of the compounds is discussed in further
detail below. "Compound(s) of formula (I)" includes the racemic
form as well as the enriched or pure enantiomers and diastereomers
(e.g., compounds of formula (I-1). Where a compound of the
Invention contains an alkenyl or alkenylene group, cis. (E) and
trans (Z) isomerism may also occur. In such embodiments,
"compound(s) of formula (I)" includes the individual cis/trans
isomers of the compound, which will be indicated using
conventional, cis/trans nomenclature. It should also be understood
that compounds of formula (I) may exist in tautomeric forms other
than that shown in the formula and alternative tautomeric forms are
also Included within "compound(s) of formula (I)."
[0101] Similarly, "compound(s) of formula (XL)" means any compound
having the structural formula (XL) as defined by the variable
definitions provided, solvates, including hydrates thereof, and
amorphous and crystal forms, Including polymorphic forms, thereof.
"Compound(s) of formula (XL)" includes the racemic form as well as
the enriched or pure enantiomers and diasteriomers. "Compound(s) of
formula (XL)" also includes the individual cis/trans isomers of the
compound of the invention. It should also be understood that
compounds of formula (XL) may exist in tautomeric forms other than
that shown in the formula and alternative tautomeric forms are also
included within "compound(s) of formula (XL)."As used herein,
"compound(s) of the invention" refers to compounds of formula (I),
compounds of formula (I-1) and compounds of formula (XL) (each as
defined above) or a pharmaceutically acceptable sail thereof.
[0102] Also, with respect to isolatable intermediates such as for
example, compounds of formula (V) and (VII) (among others described
below) the phrase "a compound of formula (number)" means a compound
having that formula and pharmaceutically acceptable salts
thereof.
[0103] As used herein, the terms "alkyl" (and "alkylene") refer to
straight or branched hydrocarbon chains containing from 1 to 8
carbon atoms. Examples of "alky" as used herein include, but are
not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl,
isobutyl, tert-butyl and n-pentyl. Examples of "alkylene" as used
herein include, but are not limited to, methylene, ethylene,
propylene, isopropylene, butylene, and isobutylene,
[0104] The term "haloalkyl" refers to alkyl (as defined above)
substituted one or more times with a halogen. Thus, the term
"haloalkyl" includes perhaloalkyls such as trifluoromethyl, as well
as trifluoroethyl, among other halogenated alkyls.
[0105] As used herein, the term "alkenyl" (and "alkenylene") refers
to straight or branched hydrocarbon chains containing from 2 to 8
carbon atoms (unless a different number of atoms is specified) and
at least one and up to three carbon-carbon double bonds. Examples
of "alkenyl" as used herein include, but are not limited to ethenyl
and propenyl. Examples of "alkenylene" as used herein include, but
are not limited to ethenylene and propenyiene.
[0106] The term "haloalkenyl" refers to alkenyl (as defined above)
substituted one or more times with a halogen.
[0107] As used herein, the term "alkynyl" refers to straight or
branched hydrocarbon chains containing from 2 to 8 carbon atoms
(unless a different number of atoms is specified) and at least one
and up to three carbon-carbon triple bonds. Examples of "alkynyl"
as used herein Include, but are not limited lo ethynyl and
propynyl.
[0108] As used herein, the term "cydoalkyl" refers to a
non-aromatic monocyclic carbocyclic ring having from 3 to 8 carbon
atoms (unless a different number of atoms is specified) and no
carbon-carbon double bonds. "Cycloalkyl" includes by way of example
cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and
cyclooctyl. "Cycloalkyl" also includes substituted cycloalkyl. The
cycloalkyl may optionally be substituted on any available carbon
with one or more (e.g., 1, 2 or 3) substituents which may be the
same or different and are independently selected from the group
consisting of halo, C.sub.1-3alkyl and C.sub.1-3haloalkyl.
Preferred cycloalkyl groups include C.sub.3-6cycloalkyl and
substituted C.sub.3-8cycloalkyl.
[0109] As used herein, the term "cycloalkenyl" refers to a
non-aromatic monocyclic carbocyclic ring having from 3 to 8 carbon
atoms (unless a different number of atoms is specified) and up to 3
carbon-carbon double bonds. "Cycloalkenyl" includes by way of
example cyclobutenyl, cyclopentenyl and cyclohexenyl.
"Cycloaikenyl" also includes substituted cycloalkenyl. The
cycloalkenyl may optionally be substituted on any available carbon
with one or more (e.g., 1, 2or 3) substituents which may be the
same or different and are independently selected from the group
consisting of halo, C.sub.1-3alkyl and C.sub.1-3haloalkyl.
[0110] The term "halo" or "halogen" refers to fluorine, chlorine,
bromine and iodine.
[0111] The term "oxo" as used herein refers to the group .dbd.O
attached directly to a carbon atom of a hydrocarbon ring (i.e.,
cycloalkenyl, aryl, heterocycle or heteroaryl ring) or attached
directly to a N or S to yield -N-oxides, sulfones and sulfoxides
wherein the N or S are atoms of a heterocyclic or heteroaryl
ring.
[0112] The terms "heterocycle" and "heterocyclic" are synonomous
and refer to monocyclic saturated or unsaturated non-aromatic
groups and fused bicyclic saturated or unsaturated non-aromatic
groups, having the specified number of members and including 1, 2
or 3 heteroatoms selected from N, O and S (unless a different
number of heteroatoms is specified), in all embodiments wherein the
heterocycle includes 2 or more heteroatoms, the heteroatoms may be
the same or different and are independently selected from N, O and
S. In ail embodiments wherein the compound of formula (I) includes
two or more heterocyclic groups, the heterocyclic groups may be the
same or different and are Independently selected. Examples of
particular heterocyclic groups include but are not limited to
tetrahydrofuran, dihydropyran, tetrahydropyran, pyran, thietane,
1,4-dioxane, 1,3-dioxane, 1,3-dioxalane, piperidine, piperazine,
tetrahydropyrimidine, pyrrolidine, morpholine, thiomorpholine,
thiazolidlne, oxazolidine, tetrahydrothiopyran,
tetrahydrothiophene, and the like.
[0113] The term "heteroaryi" refers to aromatic monocyclic groups
and aromatic fused bicycHc groups and fused bicyclic groups which
have both aromatic and non-aromatic rings, each having the
specified number of members and including 1, 2, 3, or 4 heteroatoms
selected from N, O and S (unless a different number of heteroatoms
is specified). In all embodiments wherein the heteroaryl includes 2
or more heteroatoms, the heteroatoms may be the same or different
and are independently selected from N, O and S. In all embodiments
wherein the compound of formula (I) includes two or more heteroaryl
groups, the heteroaryl groups may be the same or different and are
Independently selected. Examples of particular heteroaryl groups
Include but are not limited to furan, thiophene, pyrrole,
imidazole, pyrazole, triazole, tetrazole, thiazole, oxazole,
isoxazole, oxadiazoie, thiadiazole, isothiazole, pyridine,
pyridazine, pyrazine, pyrimidine, quinoline, isoquinoiine,
benzofuran, benzothiophene, indole, and indazole.
[0114] The term "members" (and variants thereof e.g., "membered")
in the context of heterocyclic and heteroaryl groups refers to the
total atoms, carbon and heteroatoms N, O and/or S, which form the
ring. Thus, an example of a 6-membered heterocyclic ring is
piperidine and an example of a 6-membered heteroaryl ring is
pyridine.
[0115] As used herein, the term "optionally" means that the
subsequently described event(s) may or may not occur, and includes
both event(s) that occur and events that do not occur.
[0116] The present invention provides compounds of formula (I):
##STR00009##
[0117] wherein:
[0118] R.sup.1 is selected from H, halo, alkyl, haloalkyl,
--OR.sup.7, --CN, --C(O)NR.sup.7R.sup.8, --S(O).sub.2R.sup.7,
--R.sup.5--S(O).sub.2R.sup.7, --NR.sup.7R.sup.8,
--NR.sup.7C(O)R.sup.8, Ph, and Het.sup.1; [0119] Ph is phenyl
optionally substituted 1 or 2 times with halo, alkyl, haloalkyl,
--OR.sup.7, --CN, --S(O).sub.2R.sup.7 and --NR.sup.7R.sup.8; [0120]
Het.sup.1 is a 5-6 membered heteroaryl having 1, 2 or 3 heteroatoms
selected from N, O and S, optionally substituted 1 or 2 times with
a substituent selected from halo, alkyl, haloalkyi, --OR.sup.7,
--CN, --S(O).sub.2R.sup.7, --NR.sup.7R.sup.8, Het.sup.2,
--R.sup.5-Het.sup.2, NR.sup.7-Het.sup.2, and oxo; [0121] Het.sup.2
is a 5-6 membered heterocycle having 1 or 2 heteroatoms selected
from N, O and S, optionally substituted 1 or 2 times with a
substituent selected from alkyl, --OR.sup.7, --NR.sup.7R.sup.8,
--C(O)NR.sup.7R.sup.8, --S(O).sub.2R.sup.7, and oxo;
[0122] R.sup.2 is selected from H, halo, alkyl, haloalkyl,
--OR.sup.7, --CN, --C(O)NR.sup.7R.sup.8, --S(O).sub.2R.sup.7,
--R.sup.5--S(O).sub.2R.sup.7, --S(O).sub.2NR.sup.7R.sup.8,
--R.sup.5--S(O).sub.2NR.sup.7R.sup.8, NR.sup.7R.sup.8, and
--NR.sup.7C(O)R.sup.8;
[0123] R.sup.3 is H, alkyl or haloalkyl;
[0124] Z.sup.1, Z.sup.2 and Z.sup.3 are each the same or different
and are Independently C, CH or N, wherein at least one of Z.sup.1,
Z.sup.2 and Z.sup.3 is C or CH;
[0125] d is 0, 1 or 2; each R.sup.4 is the same or different and is
independently halo, alkyl or haloalkyl;
[0126] Y.sup.1 is --O-- or --N(R.sup.7)--;
[0127] a is 0 or 1;
[0128] each R.sup.5 is the same or different and is Independently
C.sub.1-3alkylene;
[0129] Ring A is a 5-8 membered heterocycle having 1 or 2
heteroatoms selected from N, O and S;
[0130] b is 0, 1 or 2;
[0131] each R.sup.6 is the same or different and is independently
selected from halo, alkyl, haloalkyl, alkenyl, --CN, --R.sup.5--CN,
--CO.sub.2R.sup.7, --R.sup.5--CO.sub.2R.sup.7,
--C(O)NR.sup.7R.sup.8, --R.sup.5--C(O)NR.sup.7R.sup.8, --OR.sup.7,
--R.sup.5--OR.sup.7, --S(O).sub.2R.sup.7,
--R.sup.5--S(O).sub.2R.sup.7, --S(O).sub.2NR.sup.7R.sup.8,
--R.sup.5--S(O).sub.2NR.sup.7R.sup.8, -13 NR.sup.7R.sup.8,
--R.sup.5--NR.sup.7R.sup.8, --NR.sup.7C(O)R.sup.8,
--NR.sup.7S(O).sub.2R.sup.8, --NR.sup.7C(O)NR.sup.7R.sup.8,
--NR.sup.7C(O).sub.2R.sup.8 and oxo;
[0132] each R.sup.7 and each R.sup.8 are the same or different and
are each independently selected from H, alkyl, haloalkyl, alkenyl,
haloalkenyl, alkynyl, cycloalkyl and cycloalkenyl;
[0133] and pharmaceutically acceptable salts thereof.
[0134] In one embodiment, the compounds of the Invention are
defined wherein R.sup.1 is selected from H, halo, alkyl, haloalkyl,
--OR.sup.7, --S(O).sub.2R.sup.7 and Het.sup.1, or any subset
thereof. In another embodiment, R.sup.1 is selected from H, halo,
alkyl, --OR.sup.7 and Het.sup.1, or any subset thereof, in a
further embodiment, R.sup.1 is selected from H, halo, --O-alkyl,
--O-haloalkyl and Het.sup.1, or any subset thereof. In another
embodiment, R.sup.1 is selected from H, halo, --O-C.sub.1-3alkyl
and Het.sup.1, or any subset thereof, in on particular embodiment,
R.sup.1 is halo. In one particular embodiment, R.sup.1 is
--O-C.sub.1-3alkyl. In one particular embodiment, R.sup.1 is
Het.sup.1,
[0135] In one embodiment, the compounds of the invention are
defined wherein R.sup.2 is selected from H, halo, alkyl, haloalkyl,
--OR.sup.7, --CN, --S(O).sub.2R.sup.7 and
--R.sup.5--S(O).sub.2R.sup.7, or any subset thereof, in another
embodiment, R.sup.2 is selected from H, halo, alkyl, --OR.sup.7,
--CN and --R.sup.5--S(O).sub.2R.sup.7, or any subset thereof. In
another embodiment, R.sup.2 is selected from H, halo,
C.sub.1-3alkyl, --O-C.sub.1-3alkyl, --O-C.sub.1-3haloalkyl, and
--R.sup.5--S(O).sub.2-alkyl, or any subset thereof. In one
particular embodiment, R.sup.2 is H. In one particular embodiment,
R.sup.2 is halo. In one particular embodiment, R.sup.2 is
--O-C.sub.1-3alkyl or --O-C.sub.1-3haloalkyl.
[0136] In one embodiment of the present invention, the compounds of
the invention are defined wherein both R.sup.1 and R.sup.2 are the
same or different and are halo, in another embodiment, both R.sup.1
and R.sup.2 are the same or different and are selected from
--O-C.sub.1-3alkyl and --O-C.sub.1-3haloalkyl. In another
embodiment, R.sup.1 is Het.sup.1 and R.sup.2 is H.
[0137] In one embodiment, the compounds of the invention are
defined wherein Net.sup.1 is a 5-6 membered heteroaryl having 1, 2
or 3 heteroatoms selected from N, O and S, optionally substituted 1
or 2 times with a substituent selected from alkyl, haloalkyl,
NR.sup.7-Het.sup.2, and oxo. in another embodiment, Het.sup.1 is a
5-6membered heteroaryl having 1, 2 or 3 heteroatoms selected from
N, O and S, optionally substituted 1 or 2 times with a substituent
selected from C.sub.1-3alkyl, NH-Het.sup.2 and oxo. In another
embodiment, Het.sub.1 is a 5-6 membered heteroaryl having 1, 2 or 3
heteroatoms selected from N, O and S, optionally substituted 1 or 2
times with a substituent selected from C.sub.1-3alkyl and oxo. In a
further embodiment, Het.sub.1 is selected from pyridinyl, pyrazolyl
and oxadiazolyl, each optionally substituted 1 or 2 times with a
substituent selected from C.sub.1-3alkyl and oxo.
[0138] In one embodiment, the compounds of the invention are
defined wherein Het.sub.2is a 6 membered heterocyde having 1 or 2
heteroatoms selected from N, O and S, optionally substituted 1 or 2
times with a substituent selected from alkyl and oxo. In one
embodiment, Het.sub.2 is piperidyl, optionally substituted 1 or 2
times with a substituent selected from alkyl and oxo. In one
embodiment, Het.sub.2 is N-methyl piperidyl.
[0139] Specific examples of groups defining R.sup.1 include but are
not limited to H; F; Cl; --O-alkyl, such as --O--CH.sub.3;
--O-haloalkyl, such as --O--CF.sub.3; pyridyl or substituted
pyridyl such as methyl pyridyl and N-oxo pyridyl; pyrazolyl or
substituted pyrazolyl such as N-methyl pyrazolyl and H-oxo
pyrazolyl; and oxadiazolyl or substituted oxadiazolyl such as
methyl oxadlazolyl.
[0140] Specific examples of groups defining R.sup.2 include but are
not limited to H; F; Cl; Br; CN, --O-alkyl, such as --O--CH.sub.3;
--O-haloalkyl, such as --O--CF.sub.3; --SO.sub.2-alkyl such as
--SO.sub.2CH.sub.3; --CH.sub.2--SO.sub.2-alkyl such as
--CH.sub.2--SO.sub.2CH.sub.3.
[0141] In one embodiment, the compounds of the invention are
defined wherein R.sup.3 is alkyl or haloalkyl, or any subset
thereof. In one embodiment, R.sup.3 is C.sub.1-3alkyl or
C.sub.1-3haloalkyl; or any subset thereof. In one particular
embodiment, R.sup.3 Is C.sub.1-3alkyl. In one preferred embodiment,
R.sup.3 is methyl.
[0142] If Z.sup.1, Z.sub.2 or Z.sub.3 is C, it is understood that
R.sup.4 Is bound at that position. In one embodiment, the compounds
of the Invention are defined wherein Z.sup.1, Z.sub.2 and Z.sub.3
are each C or CH. In one embodiment, one of Z.sub.1, Z.sub.2 and
Z.sub.3 is N and the other two are C or CH. in one embodiment, both
Z.sup.1 and Z.sub.2 are N and Z.sub.3 is CH.
[0143] In one embodiment, the compounds of the invention are
defined wherein d is 0 or 1. In one particular embodiment, d is
1.
[0144] The substituent R.sup.4 may be bound to any suitable C. In
one embodiment, the compounds of the invention are defined wherein
each R.sup.4 is the same or different and is independently halo,
C.sub.1-3alkyl or G.sub.1-3haloalkyl, or any subset thereof. In one
embodiment, each R.sup.4 is halo. In one particular embodiment,
each R.sup.4 is Cl or F. In one particular embodiment, each R.sup.4
is Cl.
[0145] In one embodiment, the compounds of the invention are
defined wherein Y.sub.1 is --O-- or --N(H)--. In one particular
embodiment, Y.sub.1 is --O--.
[0146] In one embodiment, the compounds of the invention are
defined wherein a is 0. In one particular embodiment, the compounds
of the invention are defined wherein a is 1 and (R.sup.5).sub.a is
C.sub.1-3alkylene.
[0147] In one embodiment, the compounds of the invention are
defined wherein Ring A is a 6 membered heterocycle having 1 or 2
heteroatoms selected from N, O and S. in one embodiment, Ring A is
a 6 membered heterocycle having 1 N atom and optionally 1
additional heteroatom selected from N, O and S. Specific examples
of groups defining Ring A include but are not limited to
pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, and
piperazinyl. In one embodiment, Ring A is piperidinyl.
[0148] In one embodiment, the compounds of the invention are
defined wherein b is 0 or 1. In one embodiment, b is 0. In one
embodiment, b is 1.
[0149] In one embodiment, the compounds of the invention are
defined wherein each R.sup.6 is the same or different and is
independently selected from halo, alkyl, haloalkyl,
--R.sup.5-haloalkyl, --CN, --CO.sub.2R.sup.7,
--R.sup.5--CO.sub.2R.sup.7, --C(O)NR.sup.7R.sup.8, --OR.sup.7,
--R.sup.5--OR.sup.7, --S(O).sub.2R.sup.7,
--R.sup.5--S(O).sub.2R.sup.7, --NR.sup.7R.sup.8,
--R.sup.5--NR.sup.7R.sup.8, and oxo, or any subset thereof. In one
embodiment, each R.sup.6 is the same or different and is
independently selected from halo, alkyl, haloalkyl,
--CO.sub.2R.sup.7, --OR.sup.7, --S(O).sub.2R.sup.7,
--R.sup.5--S(O).sub.2R.sup.7, --NR.sup.7R.sup.8, and oxo, or any
subset thereof. In one embodiment, each R.sup.6 is the same or
different and is independently selected from alkyl, haloalkyl,
R.sup.5--S(O).sub.2R.sup.7, or any subset thereof. In one
particular embodiment, b is 1 and R.sup.6 is
R.sup.5--S(O).sub.2R.sup.7. In one particular embodiment, each
R.sup.6 is the same or different and is independently selected from
C.sub.1-3alkyl and trifluoromethyl. In one particular embodiment, b
is 1 and R.sup.6 is C.sub.1-3aJkyl.
[0150] In one embodiment, the moiety
##STR00010##
[0151] In one embodiment, the moiety
##STR00011##
[0152] In one embodiment, the moiety
##STR00012##
[0153] In one embodiment, the compounds of the invention are
defined wherein each R.sup.7 and each R.sup.8 are the same or
different and are each independently selected from H, alkyl,
haloalkyl and alkenyl, or any subset thereof. In one embodiment,
each R.sup.7 and each R.sup.8 are the same or different and are
each independently selected from H and alkyl. In one embodiment,
each R.sup.7 and each R.sup.8 are the same or different and are
each independently selected from H and C.sub.1-3alkyl.
[0154] Compounds of the invention exist in stereoisomers forms
(e.g. they contain one or more chiral or asymmetric carbon atoms).
The term "chiral" refers to a molecule that is not superimposable
on its mirror image. The term "chira;" refers to a molecule that is
superimposable on Its mirror image.
[0155] The term "stereoisomers" refers to compounds which are have
a common chemical constitution but differ in the arrangment of the
atoms or groups in space. Stereoisomers may be optical isomers or
geometric isomers. Optical isomers include both enantiomers and
diastereomers. An "enantiomer" is one of a pair of optical isomers
containing a chiral carbon atom whose molecular configuration have
left- and right-hand (chiral) forms. That is, "enantiomer" refers
to each of a pair of optical isomers of a compound which are
non-superimposabie mirror images of one another. A "diastereomer"
is one of a pair of optical isomers of a compound with two or more
centers of dissymmetry and whose molecules are not mirror images of
one another. The nomenclature of a chiral center is governed by the
(R)--(S) system. Whether a particular compound is designated as the
"R" or "S" enantiomer according to the system depends upon the
nature of the atoms or groups which are bound to the chiral
carbon.
[0156] Enantiomers differ in their behavior toward plane-polarized
light, that is, their optical activity. An enantiomer that rotates
plane-polarized light in a clockwise direction is said to be
dextrorotatory and is designated by the symbol "d" or "(+)" for
positive rotation. An enantiomer that rotates plane-polarized light
in the counterclockwise direction is said to be levorotatory and is
designated by the symbol "l" or "(-)" for negative rotation. There
is no correlation between the configuration of enantiomers and the
direction in which they rotate plane-polarized light. There is also
no necessary correlation between the (R) and (S) designation and
the direction of rotation of the plane-polarized light. The optical
activity, or direction of rotation of plane-polarized light, of an
enantiomer of a compound of the invention may be determined using
conventional techniques.
[0157] The compounds of the present invention may be in racemix
mixture, enantiomerically enriched or enantiomerically pure form.
The terms "racemate" and "racemic mixture" as used herein refer to
a mixture of the (R)-- and the (S)-- optical isomers (e.g.,
enantiomers) of a compound in equal, i.e. 50:50 proportion.
[0158] The term "enantiomericaily enriched" as used herein refers
to preparations comprising a mixture of optical isomers in which
the quantity of one enantiomer is higher than the quantity of the
other. Thus, "enantiomerically enriched" refers to mixtures of
optical isomers wherein the ratio of enantiomer is greater than
50:50, An enantiomerically enriched compound comprises greater than
50% by weight of one enantiomer relative to the other. For example
enantiomerically enriched
3-[((1R)-1-{2-Chloro-3-[(1-methyl-4-piperidinyl)oxy]phenyl}ethyl-
)oxy]-5-[5-(1-methyl-1H-pyrazol-4-yl)-1H-benzimidazol-1-yl]-2-thiophenecar-
boxamide refers to a composition comprising greater than 50% by
weight of the (R)-enantiomer relative to the (S)-enantiomer of the
compound. In one embodiment, an enantiomerically enriched compound
comprises at least 75% by weight of one enantiomer relative to the
other, in another embodiment, an enantiomerically enriched compound
comprises at least 80% by weight of one enantiomer relative to the
other, in one particular embodiment, an enantiomerically enriched
compound comprises at least 85% by weight of one enantiomer
relative to the other.
[0159] The term "enantiomerically pure" as used herein refers to
enantiomerically enriched compounds comprising at least 90% by
weight of one enantiomer relative to the other. In one embodiment,
an enantiomerically pure compound comprises at least 95% by weight
of one enantiomer relative to the other. In one particular
embodiment, an enantiomerically pure compound comprises at least
99% by weight of one enantiomer relative to the other.
[0160] In one embodiment, the present invention provides an
enantiomerically enriched compound of formula (I), having the
stereochemistry depicted in formula (I-1):
##STR00013##
[0161] wherein * Indicates a chiral carbon and ail variables are as
defined above, and pharmaceutically acceptable salts thereof. The
foregoing specific embodiments of the invention described above for
the variables defining compounds of the invention are equally
applicable to compounds of formula (I-1). in one embodiment, the
present invention provides and enantiomerically pure compound of
formula (I-1).
[0162] In one particular embodiment, the present invention provides
a compound of formula (XI):
##STR00014##
[0163] wherein:
[0164] R.sup.1 is selected from H, halo, alkyl, haloalkyl,
--OR.sup.7, --CN, --C(O)NR.sup.7R.sup.8, --S(O).sub.2R.sup.7,
--R.sup.5--S(O).sub.2R.sup.7 and Het.sub.1; [0165] Het.sub.1 is a
5-6 membered heteroaryl having 1, 2 or 3 heteroatoms selected from
H, O and S, optionally substituted 1 or 2 times with a substituent
selected from alkyl, haloalkyl, --OR.sup.7, --CN,
--S(O).sub.2R.sup.7. --NR.sup.7R.sup.8 and oxo;
[0166] R.sup.2 is selected from H, halo, alkyl, haloalkyl,
--OR.sup.7, --CN, --C(O)NR.sup.7R.sup.8, --S(O).sub.2R.sup.7,
--R.sup.5--S(O).sub.2R.sup.7, --S(O).sub.2NR.sup.7R.sup.8,
--R.sup.5--S(O).sub.2NR.sup.7R.sup.8, --NR.sup.7R.sup.8, and
--NR.sup.7C(O)R.sup.8;
[0167] R.sup.3 is alkyl;
[0168] * indicates a chiral carbon;
[0169] R.sup.4 is H or halo;
[0170] each R.sup.5 is the same or different and is independently
C.sub.1-3alkylene;
[0171] Ring A is a 5-6 membered heterocycie having 1 or 2
heteroatoms selected from N, O and S;
[0172] b is 0 or 1;
[0173] each R.sup.6 is the same or different and is independently
selected from halo, alkyl, haloalkyl, --CO.sub.2R.sub.7,
--R.sup.5--CO.sub.2R.sup.7, --OR.sup.7, --R.sup.5--OR.sup.7,
--S(O).sub.2R.sup.7, --R.sup.5--S(O).sub.2R.sup.7,
--NR.sup.7R.sup.8, --R.sup.5--NR.sup.7R.sup.8 and oxo;
[0174] each R.sup.7 and each R.sup.8 are the same or different and
are each independently selected from H, alkyl and haloalkyl;
[0175] or a pharmaceutically acceptable salt thereof.
[0176] The foregoing specific embodiments of the invention
described above for the variables defining compounds of the
Invention are equally applicable to compounds of formula (XL).
[0177] In one embodiment, the present invention provides an
enantiomerically enriched compound of formula (XL). In one
embodiment, the present invention provides an enantiomerically pure
compound of formula (XL).
[0178] It is to be understood that the present invention includes
ail combinations and subsets of the particular groups defined
hereinabove.
[0179] Specific examples of compounds within the scope of the
present invention include those recited in the Examples which
follow, racemic mixtures, all enantiomers, and pharmaceutically
acceptable salts thereof.
[0180] One example of a preferred compound of the present invention
is
3-({(1R)-1-[2-chloro-3-(4-piperidmyloxy)phenyl]ethyl}oxy)-5-[5-(2-methyl--
4-pyridinyl)-1H-benzimidazol-1-yl]-2-thiophenecarboxamide and
pharmaceutically acceptable salts thereof.
[0181] One example of a preferred compound of the present Invention
is
3-({(1R)-1-[2-chloro-3-(4-piperidInyloxy)phenyl]ethyl}oxy)-5-[5-(1-methyl-
-1H-pyrazol-4-yl)-1H-benzsmidazol-1-yi]-2-thiophenecarboxamide and
pharmaceutically acceptable salts thereof.
[0182] One example of a preferred compound of the present invention
is
3-[((1R)-1-{2-chloro-3-[(1-methyl-4-piperidinyl)oxy]phenyl}ethyl)oxy]-5-[-
5-(1-methyl-1H-pyrazol-4-yl)-1H-benzimidazol-1-yl]-2-thiophenecarboxamide
and pharmaceutically acceptable salts thereof. In one preferred
embodiment,
3-[((1R)-1-{2-chloro-3-[(1-methyl-4-piperidinyl)oxy]phenyl}ethyl)oxy]-5-[-
5-(1-methyl-1H-pyrazol-4-yl)-1H-benzimidazol-1-yl]-2-thiophenecarboxamide
is in the form of the free base.
[0183] It will be appreciated by those skilled In the art that the
compounds of the invention may be utilized in the form of a
pharmaceutically acceptable salt thereof. The pharmaceutically
acceptable salts of the compounds of the invention (or the
enantiomerically enriched or pure forms thereof) include
conventional salts formed from pharmaceutically acceptable
inorganic or organic acids or bases as well as quaternary ammonium
salts. More specific examples of suitable acid salts include
hydrochloric, hydrobromlc, sulfuric, phosphoric, nitric,
perchloric, fumaric, acetic, trifluoroacetic, propionic, succinic,
glycolic, formic, lactic, maleic. tartaric, citric, palmoic,
malonic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic,
fumaric, toluenesulfonic, methanesulfonic (mesylate),
napnthalene-2-sulfonic, benzenesulfonic hydroxynaphthoic,
hydroiodic, malic, steroic, tannic and the like. In one embodiment,
the compounds of the invention are in the hydrochloride or citrate
salt form.
[0184] Other acids such as oxalic, while not in themselves
pharmaceutically acceptable, may be useful in the preparation of
salts useful as intermediates in obtaining the compounds of the
invention and their pharmaceutical acceptable salts. More specific
examples of suitable basic salts include sodium, lithium,
potassium, magnesium, aluminium, calcium, zinc,
N,N'-dibenzylethylenediamine, chloroprocaine, choline,
diethanolamlne, ethylenediamine, N-methylglucamine and procaine
salts.
[0185] The term "solvate" as used herein refers to a complex of
variable stoichiometry formed by a solute (a compound of formula
(I) or an enaniomehcally enriched or pure form thereof) and a
solvent. Solvents, by way of example, include water, methanol,
ethanol, or acetic acid. The compounds of formula (I) may be in the
form of a hydrate, including for example, a monohydrate or a
dihydrate.
[0186] Processes for preparing pharmaceutically acceptable salts
and solvates of the compounds of the invention are conventional in
the art. See, e.g., Burger's Medicinal Chemistry And Drug Discovery
5th Edition, Vol 1: Principles And Practice.
[0187] As will be apparent to those skilled in the art, in the
processes described below for the preparation of the compounds of
the invention, certain Intermediates, may alternatively be in the
form of pharmaceutically acceptable salts of the compound. Those
terms as applied to any intermediate employed in the process of
preparing the compounds of the invention have the same meanings as
noted above with respect to the compounds of the invention.
Processes for preparing pharmaceutically acceptable salts of such
intermediates are known in the art and are analogous to the process
for preparing pharmaceutically acceptable salts of the compounds of
the invention.
[0188] The compounds of the invention are typically inhibitors of
PLK, in particular, PLK1. By PLK inhibitor Is meant a compound
which exhibits pIC.sub.50 greater than 6 in the PLK Inhibition
assay described below in the examples or an IC.sub.50 less than 10
.mu.M in the Cell-Titer Glo or Methylene Blue Cell Growth
Inhibition assays described below in the examples; more
particularly a PLK inhibitor is a compound which exhibits a
pIC.sub.50 greater than 7 in the PLK inhibition assay or an
IC.sub.50 less than 1 .mu.M in the Cell-Titer Glo or Methylene Blue
Cell Growth Inhibition assay using the methods described in the
examples below.
[0189] The present invention further provides compounds of the
Invention for use in medical therapy in an animal, e.g. a mammal
such as a human. In particular, the present invention provides
compounds for use in the treatment of a condition mediated by PLK,
particularly PLK1. In one embodiment, the present invention
provides compounds for use in the treatment of a condition
attenuated by inhibition of PLK, particularly PLK1. The present
invention also provides compounds for use in the treatment of a
susceptible neoplasm. In particular, the present invention provides
compounds for use in the treatment of a variety of solid tumors
including but not limited to breast cancer, ovarian cancer,
non-small cell lung cancer and prostate cancer as well as
hematologic malignancies including but not limited to acute
leukemias and aggressive lymphomas and non-Hodgkins lymphomas.
"Acute leukemias" includes both acute myeloid leukemias and acute
lymphoid leukemias. See, M. Harris, et al., J Clin. Onc. (1999)
17(12):3835-3849. "Aggressive lymphomas" is a term of art. See, J.
Chan, Hematological Onc. (2001) 19:129-150.
[0190] The present invention provides compounds for use in treating
a condition characterized by inappropriate cellular proliferation.
The present invention also provides compounds for use in inhibiting
proliferation of a cell. The present invention also provides
compounds for use in inhibiting mitosis In a cell.
[0191] The present invention provides methods for the treatment of
several conditions or diseases, all of which comprise the step of
administering a therapeutically effective amount of a compound of
the invention. As used herein, the term "treatment" refers to
alleviating the specified condition, eliminating or reducing the
symptoms of the condition, slowing or eliminating the progression
of the condition and preventing or delaying the reoccurrence of the
condition in a previously afflicted subject.
[0192] As used herein, the term "therapeutically effective amount"
means an amount of a compound of the invention which is sufficient,
in the subject to which it is administered, to elicit the
biological or medical response of a cell culture, tissue, system,
animal (including human) that is being sought, for instance, by a
researcher or clinician. For example, a therapeutically effective
amount of a compound of the invention for the treatment of a
condition mediated by PLK, particularly PLK1, is an amount
sufficient to treat the PLK mediated condition in the subject.
Similarly, a therapeutically effective amount of a compound of the
invention for the treatment of a susceptible neoplasm is an amount
sufficient to treat the susceptible neoplasm in the subject, in one
embodiment of the present invention, the therapeutically effective
amount of a compound of the invention is an amount sufficient to
treat breast cancer in a human in need thereof, in one embodiment
of the present invention, a therapeutically effective amount of a
compound of the Invention is an amount sufficient to regulate,
modulate, bind or inhibit PLK, particularly PLK1.
[0193] The precise therapeutically effective amount of the
compounds of the invention will depend on a number of factors
including, but not limited to, the age and weight of the subject
being treated, the precise condition or disease requiring treatment
and its severity, the nature of the formulation, and the route of
administration, and will ultimately be at the discretion of the
attendant physician or veterinarian. Typically, the compound of the
invention will be given for treatment in the range of 0.1 to 200
mg/kg body weight of recipient (animal) per day, per dose or per
cycle of treatment and more usually in the range of 1 to 100 mg/kg
body weight per day, per dose or per cycle of treatment. Acceptable
dally dosages, may be from about 0.1 to about 2000 mg per day, per
dose or per cycle of treatment, and preferably from about 0.1 to
about 1000 mg per day. per dose or per cycle of treatment.
[0194] As one aspect, the present invention provides methods of
regulating, modulating, binding, or inhibiting PLK for the
treatment of conditions mediated by PLK, particularly PLK1.
"Regulating, modulating, binding or inhibiting PLK" refers to
regulating, modulating, binding or inhibiting PLK, particularly
PLK1activity, as well as regulating, modulating, binding or
inhibiting overexpression of PLK, particularly PLK1. Such
conditions Include certain neoplasms (including cancers and tumors)
which have been associated with PLK, particularly PLK1, and
conditions characterized by inappropriate cellular
proliferation.
[0195] The present invention provides a method for treating a
condition mediated by PLK, particularly PLK1 which comprises
administering to the animal a therapeutically effective amount of
the compound of the invention. This method and other methods of the
present invention are useful for the treatment of animals such as
mammals and in particular humans. Conditions which are mediated by
PLK are known in the art and include but are not limited to
neoplasms and conditions characterized by inappropriate cellular
proliferation.
[0196] The present invention also provides a method for treating a
susceptible neoplasm (cancer or tumor) in an animal such as a
mammal (e.g., a human) in need thereof, which method comprises
administering to the animal a therapeutically effective amount of
the compound of the invention. "Susceptible neoplasm" as used
herein refers to neoplasms which are susceptible to treatment with
a PLK, particularly PLK1, Inhibitor. Neoplasms which have been
associated with PLK and are therefore susceptible to treatment with
a PLK inhibitor are known in the art, and include both primary and
metastatic tumors and cancers. See e.g., M. Whitfield et al. (2006)
Nature Reviews/Cancer 6:99. For example, susceptible neoplasms
within the scope of the present invention include but are not
limited to breast cancer, colon cancer, lung cancer (including
small cell lung cancer and non-small cell lung cancer), prostate
cancer, endometrial cancer, gastric cancer, melanoma, ovarian
cancer, pancreatic cancer, squamous cell carcinoma, carcinoma of
the head and neck, esophageal carcinoma, hepatocellular carcinoma,
renal cell cancer, sarcoma (including cancers of connective
tissue), bladder cancer, glioma and hematologic malignancies such
as lymphoma including aggressive lymphomas and non-Hodgkins
lymphoma, and leukemia including acute leukemias. in one particular
embodiment, the present invention provides a method of treating
breast cancer in an animal, such as a mammal (e.g., a human) in
need thereof by administering a therapeutically effective amount of
a compound of the present invention. In another particular
embodiment, the present Invention provides a method of treating
ovarian cancer In an animal, such as a mammal (e.g., a human) in
need thereof by administering a therapeutically effective amount of
a compound of the present invention. In another particular
embodiment, the present invention provides a method of treating
non-small cell lung cancer in an animal, such as a mammal (e.g., a
human) in need thereof by administering a therapeutically effective
amount of a compound of the present invention. In another
particular embodiment, the present invention provides a method of
treating prostate cancer in an animal, such as a mammal (e.g., a
human) in need thereof by administering a therapeutically effective
amount of a compound of the present invention. In another
particular embodiment, the present invention provides a method of
treating hematologic malignancies including lymphoma, such as
aggressive lymphoma and non--Hodgkins lymphoma, and leukemia such
as acute leukemia in an animal, such as a mammal (e.g., a human) in
need thereof by administering a therapeutically effective amount of
a compound of the present invention.
[0197] The compounds of the invention can be used alone in the
treatment of such susceptible neoplasms or some compounds may be
used to provide additive or possibly synergistic effects with one
or more other compounds of the invention, or in combination with
certain existing chemotherapies and/or other anti-neoplastic
therapies. In addition, the compounds of the invention may in some
Instances be used to restore effectiveness of certain existing
chemotherapies and/or other anti--neoplastic therapies. As used
herein, "anti-neoplastic therapies" includes but Is not limited to
cytotoxic chemotherapy, cytostatic chemotherapy, hormonal therapy,
targeted kinase inhibitors, therapeutic monoclonal antibodies,
surgery and radiation therapy.
[0198] The present invention also provides a method for treating a
condition characterized by inappropriate cellular proliferation in
an animal, such as a mammal (e.g., a human) in need thereof. The
method comprises administering a therapeutically effective amount
of a compound of the present invention. By "inappropriate cellular
proliferation" is meant cellular proliferation resulting from
inappropriate cell growth, cellular proliferation resulting from
excessive cell division, cellular proliferation resulting from cell
division at an accelerated rate, cellular proliferation resulting
from inappropriate cell survival, and/or cellular proliferation in
a normal cell occurring at a normal rate, which is nevertheless
undesired. Conditions characterized by inappropriate cellular
proliferation include but are not limited to neoplasms, blood
vessel proliferative disorders, fibrotic disorders, mesangial cell
proliferative disorders and inflammatory/immune-mediated diseases.
Stood vessel proliferative disorders include arthritis and
restenosis. Fibrotic disorders include hepatic cirrhosis and
atherosclerosis. Mesangial cell proliferative disorders include
glomerulonephritis, malignant nephrosclerosis and glomerulopathies.
Inflammatory/immune-mediated disorders include psoriasis, chronic
wound healing, organ transplant rejection, thrombotic
microangiopathy syndromes, and neurodegenerative diseases.
Osteoarthritis and other osteoclast proliferation dependent
diseases of excess bone resorbtion are examples of conditions
characterized by inappropriate cellular proliferation in which the
cellular proliferation occurs in normal cells at a normal rate, but
is nevertheless undesired.
[0199] The present invention also provides a method for inhibiting
proliferation of a cell, which method comprises contacting the cell
with an amount of a compound of the invention sufficient to inhibit
proliferation of the cell. In one particular embodiment, the cell
Is a neoplastic cell. In one particular embodiment, the cell Is an
inappropriately proliferative cell. The term "inappropriately
proliferative cell" as used herein refers to cells that grow
inappropriately (abnormally), cells that divide excessively or at
an accelerated rate, cells that inappropriately (abnormally)
survive and/or normal cells that proliferate at a normal rate but
for which proliferation is undesired. Neoplastic cells (including
cancer cells) are an example of inappropriately proliferative cells
but are not the only inappropriately proliferative cells.
[0200] PLK is essential for cellular mitosis and accordingly, the
compounds of the invention are believed to be effective for
inhibiting mitosis, "inhibiting mitosis" refers to inhibiting the
entry into the M phase of the cell cycle, inhibiting the normal
progression of the M phase of the cell cycle once M phase has been
entered and inhibiting the normal exit from the M phase of the cell
cycle. Thus, the compounds of the present invention may inhibit
mitosis by inhibiting the cell's entry into mitosis, by inhibiting
the cell's progression through mitosis or by inhibiting the cell's
exit from mitosis. As one aspect, the present invention provides a
method for inhibiting mitosis in a cell, which method comprises
administering to the cell an amount of a compound of the invention
sufficient to inhibit mitosis, in one particular embodiment, the
cell is a neoplastic cell. In one particular embodiment, the cell
is an inappropriately proliferative cell.
[0201] The present invention also provides the use of a compound of
the invention for the preparation of a medicament for the treatment
of condition mediated by PLK, particularly PLK1, in an animal, such
as a mammal (e.g., a human), The present invention further provides
the use of a compound for the preparation of a medicament for the
treatment of a susceptible neoplasm in an animal, particularly a
mammal (e.g., a human), in particular, the present invention
provides the use of a compound for the preparation of a medicament
for the treatment of breast cancer. The present invention also
provides the use of a compound for the preparation of a medicament
for the treatment of ovarian cancer. The present invention provides
the use of a compound for the preparation of a medicament for the
treatment of non-small cell lung cancer. The present invention
provides the use of a compound for the preparation of a medicament
for the treatment of prostate cancer. The present Invention
provides the use of a compound for the preparation of a medicament
for the treatment of hematologic malignancies such as acute
leukemias, aggressive lymphomas and non-Hodgkins lymphomas. The
present invention further provides the use of a compound for the
preparation of a medicament for the treatment of a condition
characterized by inappropriate cellular proliferation. The present
invention further provides the use of a compound for the
preparation of a medicament for inhibiting proliferation of a cell.
The present invention further provides the use of a compound for
the preparation of a medicament for Inhibiting mitosis in a
cell.
[0202] While it Is possible that, for use in therapy, a
therapeutically effective amount of a compound of the invention may
be administered as the raw chemical, it is typically presented as
the active ingredient of a pharmaceutical composition or
formulation. Accordingly, the invention further provides a
pharmaceutical composition comprising a compound of the invention.
The pharmaceutical composition may further comprise one or more
pharmaceuticaiiy acceptable carriers, diluents, and/or excipients.
The carriers), diluent(s) and/or excipient(s) must be acceptable in
the sense of being compatible with the other Ingredients of the
formulation and not deleterious to the recipient thereof, in
accordance with another aspect of the invention there is also
provided a process for the preparation of a pharmaceutical
formulation including admixing a compound of the invention with one
or more pharmaceutically acceptable carriers, diluents and/or
exciplents.
[0203] Pharmaceutical formulations may be presented in unit dose
form containing a predetermined amount of active ingredient per
unit dose. Such a unit may contain a therapeutically effective dose
of the compound of the invention (in any form) or a fraction of a
therapeutically effective dose such that multiple unit dosage forms
might be administered at a given time to achieve the desired
therapeutically effective dose. Preferred unit dosage formulations
are those containing a dally dose or sub-dose, as herein above
recited, or an appropriate fraction thereof, of an active
ingredient (compound of the invention). Furthermore, such
pharmaceutical formulations may be prepared by any of the methods
well known in the pharmacy art.
[0204] Pharmaceutical formulations may be adapted for
administration by any appropriate route, for example by the oral
(including tablets, capsules, liquid-filed capsules, disintegrating
tablets, controlled release tablets, buccal, sublingual, etc.),
rectal, nasal, topical (including buccal, sublingual or
transdermal), vaginal or parenteral (including subcutaneous,
intramuscular, intravenous or intradermal) route. Such formulations
may be prepared by any method known in the art of pharmacy, for
example by bringing into association the active ingredient with the
carrier(s) or excipient(s).
[0205] Pharmaceutical formulations adapted for oral administration
may be presented as discrete units such as capsules or tablets;
powders or granules; solutions or suspensions in aqueous or
non-aqueous liquids; edible foams or whips; or oil-in-water liquid
emulsions or wafer-in-oil liquid emulsions. For instance, for oral
administration in the form of a tablet or capsule, the active drug
component can be combined with an oral, non-toxic pharmaceutically
acceptable inert carrier such as ethanol, glycerol, water and the
like. Powders are prepared by comminuting the compound to a
suitable fine size and mixing with a similarly comminuted
pharmaceutical carrier such as an edible carbohydrate, as, for
example, starch or mannitol. Flavoring, preservative, dispersing
and coloring agent can also be present.
[0206] Capsules are made by preparing a powder mixture as described
above, and filling formed gelatin sheaths. Glidants and lubricants
such as colloidal silica, talc, magnesium stearate, calcium
stearate or solid polyethylene glycol can be added to the powder
mixture before the filling operation. A disintegrating or
solubilizing agent such as agar-agar, calcium carbonate or sodium
carbonate can also be added to improve the availability of the
medicament when the capsule is ingested.
[0207] Moreover, when desired or necessary, suitable binders,
lubricants, disintegrating agents and coloring agents can also be
incorporated into the mixture. Suitable binders include starch,
gelatin, natural sugars such as glucose or beta-lactose, corn
sweeteners, natural and synthetic gums such as acacia, tragacanth
or sodium alginate, carboxymethylcellulose, polyethylene glycol,
waxes and the like. Lubricants used in these dosage forms Include
sodium oleate, sodium stearate, magnesium stearate, sodium
benzoate, sodium acetate, sodium chloride and the like.
Disintegrators include, without limitation, starch, methyl
cellulose, agar, bentonite, xanthan gum and the like. Tablets are
formulated, for example, by preparing a powder mixture, granulating
or slugging, adding a lubricant and disintegrant and pressing into
tablets. A powder mixture is prepared by mixing the compound,
suitably comminuted, with a diluent or base as described above, and
optionally, with a binder such as carboxymethylcellulose, an
aliginate, gelatin, or polyvinyl pyrrolidone, a solution retardant
such as paraffin, a resorption accelerator such as a quaternary
salt and/or an absorption agent such as bentonite, kaolin or
dicalcium phosphate. The powder mixture can be granulated by
wetting with a binder such as syrup, starch paste, acadia mucilage
or solutions of cellulosic or polymeric materials and forcing
through a screen. As an alternative to granulating, the powder
mixture can he run through the tablet machine and the result is
imperfectly formed slugs broken into granules. The granules can be
lubricated to prevent sticking to the tablet forming dies by means
of the addition of stearic acid, a stearate salt, talc or mineral
oil. The lubricated mixture is then compressed into tablets. The
compounds of the present invention can also be combined with a free
flowing inert carrier and compressed into tablets directly without
going through the granulating or slugging steps. A clear or opaque
protective coating consisting of a sealing coat of shellac, a
coating of sugar or polymeric material and a polish coating of wax
can be provided. Dyestuffs can be added to these coatings to
distinguish different unit dosages.
[0208] Oral fluids such as solution, syrups and elixirs can be
prepared in dosage unit form so that a given quantity contains a
predetermined amount of active ingredient. Syrups can be prepared
by dissolving the compound in a suitably flavored aqueous solution,
while elixirs are prepared through the use of a non-toxic alcoholic
vehicle. Suspensions can be formulated by dispersing the compound
in a non-toxic vehicle. Solubilizers and emulsifiers such as
ethoxylated isostearyl alcohols and polyoxy ethylene sorbitol
ethers, preservatives, flavor additive such as peppermint oil or
natural sweeteners or saccharin or other artificial sweeteners, and
the like can also be added.
[0209] Where appropriate, dosage unit formulations for oral
administration can be microencapsulated. The formulation can also
be prepared to prolong or sustain the release as for example by
coating or embedding particulate material in polymers, wax or the
like.
[0210] The compounds of the invention can also be administered in
the form of liposome delivery systems, such as small unilamellar
vesicles, large unilamellar vesicles and multilamellar vesicles.
Liposomes can be formed from a variety of phospholipids, such as
cholesterol, stearylamine or phosphatidylcholines.
[0211] The compounds of the invention may also be delivered by the
use of monoclonal antibodies as individual carriers to which the
compound molecules are coupled. The compounds may also be coupled
with soluble polymers as targetable drug carriers. Such polymers
can include peptides, polyvinylpyrrolidone, pyran copolymer,
polyhydroxypropylmethacrylamide-phenol,
polyhydroxyethylaspartamidephenol, or polyethyleneoxidepolylysine
substituted with palmitoyl residues. Furthermore, the compounds may
be coupled to a class of biodegradable polymers useful in achieving
controlled release of a drug, for example, polylactic acid,
polepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters,
polyacetals, polydihydropyrans, polycyanoacrylates and cross-linked
or amphipathic block copolymers of hydrogels.
[0212] Pharmaceutical formulations adapted for transdermal
administration may be presented as discrete patches intended to
remain in intimate contact with the epidermis of the recipient for
a prolonged period of time, For example, the active ingredient may
be delivered from the patch by iontophoresis as generally described
in Pharmaceutical Research, 3(6):318 (1986), Pharmaceutical
formulations adapted for topical administration may be formulated
as ointments, creams, suspensions, lotions, powders, solutions,
pastes, gels, sprays, aerosols or oils.
[0213] For treatments of the eye or other external tissues, for
example mouth and skin, the formulations are preferably applied as
a topical ointment or cream. When formulated in an ointment, the
active Ingredient may be employed with either a paraffinic or a
water--miscthle ointment base. Alternatively, the active ingredient
may be formulated In a cream with an oil-in-water cream base or a
water-in-oil base.
[0214] Pharmaceutical formulations adapted for topical
administrations to the eye include eye drops wherein the active
ingredient is dissolved or suspended in a suitable carrier,
especially an aqueous solvent.
[0215] Pharmaceutical formulations adapted for topical
administration in the mouth include lozenges, pastilles and mouth
washes.
[0216] Pharmaceutical formulations adapted for rectal
administration may be presented as suppositories or as enemas.
[0217] Pharmaceutical formulations adapted for nasal administration
wherein the carrier is a solid include a coarse powder having a
particle size for example In the range 20 to 500 microns which is
administered in the manner in which snuff is taken, i.e. by rapid
inhalation through the nasal passage from a container of the powder
held close up to the nose. Suitable formulations wherein the
carrier is a liquid, for administration as a nasal spray or as
nasal drops, include aqueous or oil solutions of the active
ingredient.
[0218] Pharmaceutical formulations adapted for administration by
inhalation include fine particle dusts or mists, which may be
generated by means of various types of metered, dose pressurised
aerosols, nebulizers or insufflators. Pharmaceutical formulations
adapted for vaginal administration may be presented as pessaries,
tampons, creams, gels, pastes, foams or spray formulations.
[0219] Pharmaceutical formulations adapted for parenteral
administration include aqueous and non-aqueous sterile injection
solutions which may contain anti-oxidants, buffers, bacteriostats
and solutes which render the formulation isotonic with the blood of
the intended recipient; and aqueous and non-aqueous sterile
suspensions which may include suspending agents and thickening
agents. The formulations may be presented in unit-dose or
multi-dose containers, for example sealed ampoules and vials, and
may be stored in a freeze-dried (lyophilized) condition requiring
only the addition of the sterile liquid carrier, for example water
for injections, immediately prior to use. Extemporaneous Injection
solutions and suspensions may be prepared from sterile powders,
granules and tablets.
[0220] It should be understood that in addition to the ingredients
particularly mentioned above, the formulations may include other
agents conventional in the art having regard to the type of
formulation in question, for example those suitable for oral
administration may include flavouring agents.
[0221] In the above-described methods of treatment and uses, a
compound of the invention may be employed alone, in combination
with one or more other compounds of the invention or in combination
with other therapeutic agents and/or In combination with other
antineoplastic therapies, in particular. In methods of treating
conditions mediated by PLK and methods of treating susceptible
neoplasms, combination with oilier chemotherapeulic agents is
envisaged as well as combination with surgical therapy and
radiation therapy. The term "chemotherapeutic" as used herein
refers to any chemical agent having a therapeutic effect on the
subject to which it is administered. "Chemotherapeutic" agents
include but are not limited to anti-neoplastic agents, analgesics
and anti-emetics. As used herein, "anti-neoplastic agents" include
both cytostatic and cytotoxic agents such as but not limited to
cytotoxic chemotherapy, hormonal therapy, targeted kinase
inhibitors and therapeutic monoclonal antibodies. Combination
therapies according to the present invention thus comprise the
administration of at least one compound of the invention and the
use of at least one other cancer treatment method. In one
embodiment, combination therapies according to the present
invention comprise the administration of at least one compound of
the invention and at least one other chemotherapeutic agent. In one
particular embodiment, the present invention comprises the
administration of at least one compound of the invention and at
least one anti-neoplastic agent. As an additional aspect, the
present invention provides the methods of treatment and uses as
described above, which comprise administering a compound of the
invention together with at least one chemotherapeutic agent, in one
particular embodiment, the chemotherapeutic agent is an
anti-neoplastic agent. In another embodiment, the present invention
provides a pharmaceutical composition as described above further
comprising at least one other chemotherapeutic agent, more
particularly, the chemotherapeutic agent is an anti-neoplastic
agent.
[0222] Typically, any chemotherapeutic agent that has activity
versus a susceptible neoplasm being treated may be utilized In
combination with the compounds of the invention, provided that the
particular agent is clinically compatible with therapy employing a
compound of the invention. Typical anti-neoplastic agents useful in
the present invention include, but are not limited to,
anti-microtubule agents such as diterpenoids and vinca alkaloids;
platinum coordination complexes; alkylating agents such as nitrogen
mustards, oxazaphosphor-ines, alkylsulfonates, nitrosoureas, and
triazenes; antibiotic agents such as anthracydins, actinomycins and
bleomycins; topoisomerase II inhibitors such as
epipodophyllotoxins; antimetabolites such as purine and pyrimidine
analogues and anti-folate compounds; topoisomerase I inhibitors
such as camptothedns; hormones and hormonal analogues; signal
transduction pathway inhibitors; non-receptor tyrosine kinase
anglogenesis inhibitors; immunotherapeutic agents; proapoptotic
agents; and cell cycle signaling inhibitors.
[0223] Anti-microtubule or antimitotic agents are phase specific
agents active against the microtubules of tumor cells during M or
the mitosis phase of the cell cycle. Examples of anti-microtubule
agents include, but are not limited to, diterpenoids and vinca
alkaloids. Examples of diterpenoids include, but are not limited
to, paclitaxel and its analog docetaxel. Examples of vinca
alkaloids include, but are not limited to, vinblastine,
vincristine, and vinorelbine. Platinum coordination complexes are
non-phase specific anti-neoplastic agents, which are interactive
with DNA. The platinum complexes enter tumor cells, undergo,
aquation and form infra- and interstrand crosslinks with DNA
causing adverse biological effects to the tumor. Examples of
platinum coordination complexes include, but are not limited to,
oxaliplatin, cisplatin and carboplatin.
[0224] Alkylating agents are non-phase specific anti--neoplastic
agents and strong electrophiles. Typically, alkylating agents form
covalent linkages, by alkylation, to DNA through nucleophilic
moieties of the DNA molecule such as phosphate, amino, and hydroxyl
groups. Such alkylation disrupts nucleic acid function leading to
cell death. Examples of alkylating agents include, but are not
limited to, nitrogen mustards such as cyclophosphamide, melphalan,
and chlorambucil; alkyl sulfonates such as busulfan; nitrosoureas
such as carmustine; and triazenes such as dacarbazine.
[0225] Antibiotic chemotherapeufic agents are non-phase specific
agents, which bind or Intercalate with DNA, Typically, such action
results in stable DNA complexes or strand breakage, which disrupts
ordinary function of the nucleic acids leading to cell death.
Examples of antibiotic anti-neoplastic agents include, but are not
limited to, actinomycins such as dactinomycin, anthracyclins such
as daunorubicin and doxorubicin; and bleomycins. Topoisomerase II
inhibitors include, but are not limited to,
epipodopbyliotoxins.
[0226] Epipodophyllotoxins are phase specific anti-neoplastic
agents derived from the mandrake plant. Epipodophyllotoxins
typically affect cells in the S and G.sub.2phases of the cell cycle
by forming a ternary complex with topoisomerase II and DMA causing
DMA strand breaks. The strand breaks accumulate and cell death
follows. Examples of epipodophyllotoxins include, but are not
limited to, etoposide and teniposide.
[0227] Antimetabolite neoplastic agents are phase specific
anti--neoplastic agents that act at S phase (DNA synthesis) of the
cell cycle by inhibiting DMA synthesis or by inhibiting purine or
pyrimidine base synthesis and thereby limiting DNA synthesis.
Consequently, S phase does not proceed and cell death follows.
Examples of antimetabolite anti-neoplastic agents include, but are
not limited to, fluorouracil, methotrexate, cytarabine,
mecaptopurine and thioguanine.
[0228] Camptotheeins, including, camptothecin and camptothecin
derivatives are available or under development as Topoisomerase I
inhibitors. Camptotheeins cytotoxic activity is believed to be
related to its Topoisomerase 1 inhibitory activity. Examples of
camptotheeins include, but are not limited to irinotecan,
topotecan, and the various optical forms of
7-(4-methylpiperazino-methylene)-10,11-ethylenedioxy-20-camptoth-
ecin. Hormones and hormonal analogues are useful compounds for
treating cancers in which there is a relationship between the
hormone(s) and growth and/or lack of growth of the cancer. Examples
of hormones and hormonal analogues believed to be useful in the
treatment of neoplasms include, but are not limited to,
adrenocorti-costeroids such as prednisone and prednisolone which
are useful in the treatment of malignant lymphoma and acute
leukemia in children; aminoglutethimide and other aromatase
inhibitors such as anastrozole, letrazole, vorazole, and exemestane
useful in the treatment of adrenocortical carcinoma and hormone
dependent breast carcinoma containing estrogen receptors;
progestrins such as megestrol acetate useful in the treatment of
hormone dependent breast cancer and endometrial carcinoma;
estrogens, androgens, and anti-androgens such as flutamide,
nilutamide, bicalutamide, cyproterone acetate and
5.alpha.-reductases such as finasteride and dutasterlde, useful in
the treatment of prostatic carcinoma and benign prostatic
hypertrophy; anti-estrogens such as tamoxifen, toremifene,
raloxifene, droloxifene and iodoxyfene useful in the treatment of
hormone dependent breast carcinoma; and gonadotropin-releasing
hormone (GnRH) and analogues thereof, such as goserelin acetate and
leuprolide, which stimulate the release of leutinizing hormone (LH)
and/or follicle stimulating hormone (FSH) with short-term or
intermittent use but lead to suppression of LH and FSH with
long-term use indicated for the treatment prostatic carcinoma, and
hormone dependent breast carcinoma.
[0229] Signal transduction pathway inhibitors are those inhibitors
which block or inhibit a chemical process which evokes an
intracellular change. As used herein this change is cell
proliferation, survival, anglogenesis or differentiation. Signal
tranduction inhibitors useful in the present invention include
inhibitors of receptor tyrosine kinases, non-receptor tyrosine
kinases, SH2/SH3 domain blockers, serine/threonine kinases,
phosphotidyl inositol-3 kinases, myo-inositol signaling, and Ras
oncogenes.
[0230] Several protein tyrosine kinases catalyse the
phosphorylation of specific tyrosyl residues in various proteins
involved in the regulation of cell growth. Such protein tyrosine
kinases can be broadly classified as receptor or non-receptor
kinases.
[0231] Receptor tyrosine kinases are transmembrane proteins having
an extracellular ligand binding domain, a transmembrane domain, and
a tyrosine kinase domain. Receptor tyrosine kinases are involved in
the regulation of cell growth and are sometimes termed growth
factor receptors. Inappropriate or uncontrolled activation of many
of these kinases, i.e. aberrant kinase growth factor receptor
activity, for example by over-expression or mutation, has been
shown to result in uncontrolled cell growth. Accordingly, the
aberrant activity of such kinases has been linked to malignant
tissue growth. Consequently, inhibitors of such kinases could
provide cancer treatment methods. Growth factor receptors include,
for example, epidermal growth factor receptor (EGFr, ErbB2 and
ErbB4,), platelet derived growth factor receptor (PDGFr), vascular
endothelial growth factor receptor (VEGFR), tyrosine kinase with
immunoglobulin-iike and epidermal growth factor homology domains
(TIE-2), Insulin growth factor-I receptor (IGF-I), macrophage
colony stimulating factor (cfms), BTK, ckit, cmet, fibroblast
growth factor (FGF) receptors, Trk receptors (TrkA, TrkB, and
TrkC), ephrin (eph) receptors, and the RET protooncogene. Several
inhibitors of growth factor receptors are under development and
include ligand antagonists, antibodies, tyrosine kinase inhibitors,
anti-sense oligonucleotides and aptamers. Growth factor receptors
and agents that inhibit growth factor receptor function are
described, for instance, in Kath, John C, Exp. Opin. Ther. Patents
(2000) 10(6):803-318; Shawver et al DDT Vol 2, No. 2 February 1897:
and Lofts, F. J. et al, "Growth Factor Receptors as Targets", New
Molecular Targets for Cancer Chemotherapy, Ed. Workman, Paul and
Kerr, David, CRC Press 1894, London,
[0232] Tyrosine kinases, which are not growth factor receptor
kinases are termed non-receptor tyrosine kinases. Non-receptor
tyrosine kinases useful in the present invention, which are targets
or potential targets of anti-neoplastic drugs, include cSrc, Lck,
Fyn, Yes, Jak, cAbl, FAK (Focal adhesion kinase), Brutons tyrosine
kinase, and Bcr-Abl. Such non-receptor kinases and agents which
inhibit non-receptor tyrosine kinase function are described in
Sinh, S. and Corey, S. J., (1999) Journal of Hematotherapy and Stem
Ceil Research 8 (5): 485-80; and Bolen, J. B., Brugge, J. S.,
(1997) Annual Review of Immunology. 15: 371-404.
[0233] SH2/SH3 domain blockers are agents that disrupt SH2 or SH3
domain binding in a variety of enzymes or adaptor proteins
including, PI3-K p85subunit, Src family kinases, adaptor molecules
(She, Crk, Nck, Grb2) and Ras-GAP. SH2/SH3 domains as targets for
anti-cancer drugs are discussed in Smithgall, T. E. (1995), Journal
of Pharmacological and Toxicological Methods. 34(3) 125-32.
[0234] Inhibitors of Serine/Threonine Kinases including MAP kinase
cascade blockers which include blockers of Raf kinases (Rafk),
Mitogen or Extracellular Regulated Kinase (MEKs), and Extracellular
Regulated Kinases (ERKs); and Protein kinase C family member
blockers including blockers of subtypes of PKCs (alpha, beta,
gamma, epsilon, mu, lambda, iota, zeta), lkB kinase family (IKKa,
IKKb), PKB family kinases, Akt kinase family members, and TGF beta
receptor kinases. Such Serine/Threonine kinases and inhibitors
thereof are described in Yamamoto, T., Taya, S., Kaibuchi, K.,
(1999), Journal of Biochemistry. 126 (5) 739-803; Brodt, P, Samani,
A., and Navab, R. (2000), Biochemical Pharmacology, 60. 1101-1107;
Massague, J., Weis-Garcia, F. (1996) Cancer Surveys. 27:41-84;
Philip, P. A., and Harris, A. L. (1995), Cancer Treatment and
Research. 78: 3-27, Lackey, K. et al Bioorganic and Medicinal
Chemistry Letters, (10), 2000, 223-228; and Martinez-Iacaci. L, et
al, Int. J. Cancer (2000), 88(1), 44-52.
[0235] Inhibitors of Phosphotidyl Inositol-3 Kinase family members
including blockers of PI3-kinase, ATM, DNA-PK, and Ku are also
useful in combination with the present invention. Such kinases are
discussed in Abraham, R. T. (1998), Current Opinion in Immunology.
8 (3) 412-8; Canman, C. E., Lim, D. S. (1998), Oncogene 17 (25)
3301-3308; Jackson, S. P. (1997), International Journal of
Biochemistry and Cell Biology. 29 (7):935-8; and Zhong, H. et al,
Cancer Res, (2000) 60(6), 1541-1545.
[0236] Also useful in combination with the present invention are
Myo-inositol signaling Inhibitors such as phospholipase C blockers
and Myoinositol analogues. Such signal inhibitors are described in
Powis, G., and Kozikowski A., (1994) New Molecular Targets for
Cancer Chemotherapy ed., Paul Workman and David Kerr.. CRC Press
1994, London.
[0237] Another group of signal transduction pathway inhibitors
useful in combination with the present invention are inhibitors of
Ras Oncogene. Such inhibitors include inhibitors of
farnesyltransferase, geranyl-geranyl transferase, and CAAX
proteases as well as anti-sense oligonucleotides, ribozymes and
immunotherapy. Such inhibitors have been shown to block Ras
activation in cells containing wild type mutant Ras, thereby acting
as antiproliferation agents. Ras oncogene inhibition is discussed
In Scharovsky, O. G., Rozados, V. R., Gervasoni, S. I. Matar, P.
(2000), Journal of Biomedical Science. 7(4) 292-8; Ashby, M. N.
(1998), Current Opinion in Upidology. 9(2)99-102; and BioChim,
Biophys. Acta, (1989) 1423(3): 19-30.
[0238] As mentioned above, antibodies to receptor kinase ligand
binding may also serve as signal transduction inhibitors. This
group of signal transduction pathway inhibitors includes the use of
humanized antibodies to the extracellular ligand binding domain of
receptor tyrosine kinases. For example, Imclone C225 EGFR specific
antibody (see Green, M. C. et al, Monoclonal Antibody Therapy for
Solid Tumors, Cancer Treat. Rev., (2000), 26(4), 269-286);
Herceptin.RTM. ErbB2 antibody (see Tyrosine Kinase Signaling in
Breast Cancer:ErbB Family Receptor Tyrosine Kinases, Breast Cancer
Res., 2000, 2(3), 176-183); and 2CB VEGFR2 specific antibody (see
Brekken, R. A. et al, Selective Inhibition of VEGFR2 Activity by a
Monoclonal Anti-VEGF Antibody Blocks Tumor Growth in Mice, Cancer
Res. (2000) 60, 5117-5124).
[0239] Receptor kinase angiogenesis inhibitors may also find use in
the present invention, inhibitors of angiogenesis related VEGFR and
TIE2 are discussed above in regard to signal transduction
inhibitors (both receptors are receptor tyrosine kinases). Other
inhibitors may be used in combination with the compounds of the
present invention. For example, anti-VEGF antibodies, which do not
recognize VEGFR (the receptor tyrosine kinase), but bind to the
ligand; small molecule inhibitors of integrin (alpha, beta.sub.3)
that will inhibit angiogenesis; endostatin and angiostatin
(non-RTK) may also prove useful in combination with PLK
inhibitors.
[0240] Agents used in immunotherapeutic regimens may also be useful
in combination with the compounds of the invention.
[0241] Agents used in proapoptotic regimens (e.g., bcl-2 antisense
oligonucleotides) may also be used in the combination of the
present invention. Members of the Bcl-2 family of proteins block
apoptosis. Upregulation of bcl-2 has therefore been linked to
chemoresistance. Studies have shown that the epidermal growth
factor (EGF) stimulates anti-apoptotlc members of the bcl-2family
(i.e., mcl-1). Therefore, strategies designed to downregulate the
expression of bcl-2 in tumors have demonstrated clinical benefit
and are now in Phase II/III trials, namely Genta's G3139 bcl-2
antisense oligonucleotide. Such proapoptotic strategies using the
antisense oligonucleotide strategy for bcl-2 are discussed in Water
J S et al., J. Clin. Oncol. 18:1812-1823 (2000); and Kitada S et
al., Antisense Res. Dev. 4:71-79 (1994).
[0242] Cell cycle signaling inhibitors inhibit molecules involved
in the control of the cell cycle. Cyclin dependent kinases (CDKs)
and their interaction with cyclins control progression through the
eukaryotic cell cycle. The coordinated activation and inactivation
of different cyclin/CDK complexes is necessary for normal
progression through the cell cycle. Several inhibitors of cell
cycle signaling are under development. For instance, examples of
cyclin dependent kinases, including CDK2, CDK4, and CDK6 and
inhibitors for the same are described in, for instance, Rosania, et
al., Exp. Opin. Ther. Patents 10(2):215-230 (2000).
[0243] In one embodiment, the methods of the present invention
comprise administering to the animal a compound of the invention in
combination with a signal transduction pathway inhibitor,
particularly gefitinlb (IRESSA.RTM.).
[0244] The methods and uses employing these combinations may
comprise the administration of the compound of the invention and
the other chemotherapeutic/anti-neoplastic agent either
sequentially in any order or simultaneously in separate or combined
pharmaceutical compositions. When combined in the same formulation
it will be appreciated that the two compounds must be stable and
compatible with each other and the other components of the
formulation and may be formulated for administration. When
formulated separately they may be provided in any convenient
formulation, in such a manner as are known for such compounds in
the art.
[0245] When a compound of the Invention is used in combination with
a chemotherapeutic agent, the dose of each compound may differ from
that when the compound is used alone. Appropriate doses will be
readily appreciated by those skilled in the art. The appropriate
dose of the compound(s) of the invention and the other
therapeutically active agent(s) and the relative timings of
administration will be selected in order to achieve the desired
combined therapeutic effect, and are within the expertise and
discretion of the attendent clinician.
[0246] The compounds of the invention may be conveniently prepared
by the process outlined in Scheme 1 below.
##STR00015##
[0247] wherein:
[0248] Y.sup.1 is O;
[0249] R.sup.10 is selected alkyl and suitable carboxylic acid
protecting groups; and
[0250] all other variables are as defined above.
[0251] Generally, the process for preparing the compounds of the
invention (all formulas and ail variables having been defined
above) comprises the steps of:
[0252] a) reacting the compound of formula (IV) with a compound of
formula (III) to prepare a compound of formula (V);
[0253] b) reacting the compound of formula (V) with a compound of
formula (VI) to prepare a compound of formula (VII);
[0254] c) reacting the compound of formula (VII) with ammonia to
prepare a compound of formula (I);
[0255] d) optionally separating the compound of formula (I) into
enantiomers of formula (I);
[0256] e) optionally converting the compound of formula (I) to a
pharmaceutically acceptable salt thereof; and
[0257] f) optionally converting the compound of formula (I) or a
pharmaceutically acceptable salt thereof to a different compound of
formula (I) or a pharmaceutically acceptable salt thereof.
[0258] As will be apparent to those skilled in the art, the order
of the steps in the foregoing reaction is not critical to the
practice of the process of the present invention. The foregoing
reaction steps may be carried out in any suitable order based upon
the knowledge of those skilled In the art. Further, if will be
apparent to those skilled in the art that certain reaction steps
may be most efficiently performed by Installing protecting groups
prior to the reaction, which are removed subsequently. The choice
of protecting groups as well as general techniques for their
installation and removal are within the skill of those in the
art.
[0259] More specifically, compounds of the invention can be
prepared by reacting a compound of formula (VII) with ammonia to
prepare a compound of formula (I).
##STR00016## [0260] wherein all variables are as defined above.
[0261] This reaction is typically performed in a sealed vessel with
an excess of ammonia. The reaction is typically heated to a
temperature of from about 50to about 120.degree. C., more
particularly, about 70.degree. C. Suitable solvents for this
reaction include but are not limited to methanol, ethanol,
isopropanol, tetrahydrofuran, and dioxane.
[0262] A compound of formula (I) wherein R.sup.3 is not H, may be
separated, using conventional separation techniques (e.g.,
supercritical fluid chromatography (SFC)) into its enantiomers, the
enantiomerically enriched compounds of formula (I-1) and (I-2).
##STR00017##
[0263] A compound of formula (VII) may be prepared by reacting a
compound of formula (V) with a compound of formula (VI) under
Mitsunobu reaction conditions.
##STR00018## [0264] wherein all variables are as defined above.
[0265] The reaction is carried out in an inert solvent under
standard Mitsunobu conditions. See, Hughes, D. L, Org. React.
42:335-656 (1892); and Mitsunobu, O., Synthesis 1-28 (1981).
Typically the compound of formula (V), the compound of formula
(VI), a tharylphosphine, and a dialkyl azodicarboxylate are reacted
together at room temperature. Examples of suitable
triarylphosphines include but are not limited to,
triphenylphospbine, tri-p-tolylphosphine, and trimesityiphosphine.
Examples of suitable dialkyl azodicarboxylates include but are not
limited to, diethyl azodicarboxylate, diisopropyl azodicarboxylate,
and di-tert-butyl azodicarboxylate. Examples of suitable inert
solvents for this reaction include but are not limited to,
tetrahydrofuran, dioxane, 1,2-dimethoxyethane, dichloromethane, and
toluene.
[0266] If desired, the compound of formula (VII) may be separated
using conventional separation techniques (e.g., SFC) into its
enantiomers, enantiomerically enriched compounds of formula (VII-1)
and (VII-2).
##STR00019##
[0267] As will be apparent to those skilled In the art, reaction of
an enantiomerically enriched compound of formula (VII-1) or (VII-2)
with ammonia will result in the corresponding enantiomerically
enriched compound of formula (I-1) or (I-2). respectively.
[0268] The compounds of formula (VI) may be prepared by reducing a
compound of formula (XI). The compounds of formula (XI) may be
prepared by reacting a compound of formula (IX) with a compound of
formula (X) under Mitsunobu reaction conditions.
##STR00020##
[0269] wherein:
[0270] Y.sup.1 is O;
[0271] R.sup.11 is H or R.sup.3; and
[0272] all variables are as defined above.
[0273] Suitable Mitsunobu reaction conditions and solvents are
described above. The Mitsunobu reaction yields a compound of
formula (XI).
[0274] Compounds of formula (XI), where R.sup.11 is H, may be
reacted with R.sup.3--Li (alkyl lithium) or R.sup.3--MgCl (alkyl
magnesium chloride) to prepare a compound of formula (VI). In one
embodiment, the compounds of formula (XI), where R.sup.11is H, may
be reacted with methyl lithium in the presence of titanium (VI)
chloride, or methyl magenesium chloride to prepare a compound of
formula (VI) where R.sup.3 is methyl. The reaction typically can be
carried out in an inert atmosphere. The suitable solvents may
Include ether and tetrahydrofuran. The reaction temperature may be
in the range of -78.degree. C. to room temperature.
[0275] Compounds of formula (XI) may also be reacted with reducing
agents such as borane, lithium hydride or sodium borohydrate to
prepare a compound of formula (VI). Suitable techniques for
conversion of an aldehyde or ketone to an alcohol are well known to
those skilled in the art. See, Larock, R. Comprehensive Organic
Transformation (2nd Edition), John Wiley & Sons, Inc. (1999)
1075-1077.
[0276] In one embodiment, the compound of formula (XI) is reacted
with borane/dimethylsulfide complex in tetrahydrofuran and
(R)-1-methyl-3,3-diphenyltetrahydro-3H-pyrrolo[1,2-c][1,3,2]oxazaborole
in a solvent such as toluene to prepare an enantiomerically
enriched compound of formula (VI) having the stereochemistry
depicted In formula (VI-1):
##STR00021## [0277] wherein all variables are as defined above.
[0278] As will be apparent to those skilled in the art, use of the
enantiomerically enriched compound of formula (VI-1) in the
reaction with the compound of formula (V) will yield an
enantiomerically enriched compound of formula (VII-1) which may be
reacted with ammonia to yield the enantiomerically enriched
compound of formula (I-1).
[0279] The compounds of formula (V) may be prepared by reacting a
compound of formula (IV) with a compound of formula (III).
##STR00022## [0280] wherein ail variables are as defined above.
[0281] Processes for the reaction of a compound of formula (IV)
with a compound of formula (III) are known to those skilled In the
art. See, PCT Int. Appl. WO 2004073612, Such reactions are
typically carried out In an inert solvent at room temperature.
Examples of suitable inert solvents for this reaction include but
are not limited to, chloroform, dichloromethane, tetrahydrofuran,
dioxane, and toluene and mixtures of any of the foregoing with
acetic acid (e.g., a mixture of chloroform and acetic acid). In one
embodiment, the inert solvent is selected from dichloromethane,
chloroform, tetrahydrofuran, diethyl ether, and toluene and a
mixture of any of the foregoing and acetic acid (e.g. a mixture of
chloroform and acetic acid).
[0282] The reaction may be carried out in the presence of one to
five equivalents of the base additive. The base additive is
believed to act as a scavenger for the hydrochloric acid generated
during the reaction. Examples of suitable base additives for this
reaction Include but are not limited to sodium bicarbonate,
triethylamine, sodium acetate, N-methylimidazole, pyridine,
N-methylbenzimidazole and potassium carbonate. In one embodiment,
the base additive is selected from sodium bicarbonate,
triethylamine, sodium acetate, N-methylimidazole, pyridine and
N-methylbenzimidazole. In one particular embodiment, the base
additive is sodium bicarbonate. In one particular embodiment, the
base additive is N-methylimidazole. Compounds of formula (IV) may
be prepared by a process depleted below:
##STR00023## [0283] wherein ail variables are as defined above.
[0284] This process comprises the steps of:
[0285] a) reducing a 2-nitroaniNne of formula (XII) to prepare a
substituted 1,2-diamine of formula (XIII); and
[0286] b) cyclizing the 1,2-diamine of formula (XIII) with a ring
forming reagent, such as trimethylorthoformate, to prepare
compounds of formula (IV).
[0287] The ring forming reaction may be carried out using
conventional techniques. See, White, A., et a., J. Med. Chem.
43:4084-4097 (2000); Jiang, J.-L., et al., Synthetic Comm.
28:4137-4142 (1998); Tanaka, A., et al., Chem. Pharm. Bull
42:560-569 (1994); Tian, W., et al., Synthesis 12:1283-1286 (1992);
Buckle, D. R., et al., J. Med. Chem., 30:2216-2221 (1987); and
Raban, M., et al., J. Org. Chem. 50:2205-2210 (1985). This reaction
may be carried out neat or in a suitable solvent. The reaction may
optionally be heated to a temperature of from about 50 to about
230.degree. C. The reaction is typically carried out with an excess
of trimethylorthoformate. An additional acid may be used. Examples
of suitable acids include but are not limited to, formic acid,
hydrochloric acid, hydrobromic acid, perchloric acid, sulfuric
acid, p-toluenesulfonic acid, methanesulfonic acid, and
trifluoromethanesulfonic acid. Examples of suitable solvents for
this reaction include but are not limited to water, methanol,
ethanol, isopropanol, tetrahydrofuran, dichloromethane, toluene,
N,N-dimethylformamide, dimethylsuifoxide, and acetonitrile. The
reduction of the 2-nitroaniline of formula (XII) may be carried out
using conventional techniques and reducing agents such as tin(II)
chloride. See, Rangarajan, M., et al., Bioorg. Med. Chem.
8:2591-2600 (2000); White, A. W., et al., J. Med. Chem. 43:
4084-4097 (2000); Silvestri, R., et al., Bioorg. Med. Chem.
8:2305-2309 (2000); Nagaraja, D., et al., Tetrahedron Lett.
40:7855-7856 (1999); Jung, F., et al., J. Med. Chem. 34:1110-1116
(1991); Srivastava, R. P., et al., Pharmazie 45:34-37 (1990);
Hankovszky, H. O., et al., Can. J. Chem. 67:1392-1400 (1989); Ladd,
D. L., et al., J. Org. Chem., 53:417-420 (1988); Mertens, A., et
al., J. Med. Chem. 30:1279-1287 (1987); and Sharma, K. S., et al.,
Synthesis 4:318-318 (1981). Examples of other suitable reducing
agents for this reaction include but are not limited to, palladium
with hydrogen, palladium with ammonium formate, platinum oxide with
hydrogen, nickel with hydrogen, iron with acetic acid, aluminum
with ammonium chloride, borane, sodium dithionite, and hydrazine.
The reaction may optionally be heated to between about 50 and about
120.degree. C. Suitable solvents for this reaction vary and include
but are not limited to, water, methanol, ethanol, ethyl acetate,
tetrahydrofuran, dioxane, and mixtures thereof.
[0288] Compounds of formula (lit) may be prepared by reacting a
compound of formula (II) with sulfuryl chloride.
##STR00024## [0289] wherein ail variables are as defined above.
[0290] Compounds of formula (II) are commercially available or can
be prepared using conventional techniques. Typically the reaction
is carried out at room temperature. Excess sulfuryl chloride may be
used if desired. Examples of suitable solvents Include but are not
limited to chloroform, dichloromethane, and toluene. See, Corral,
C.; Lissavetzky, J. Synthesis 847-850 (1984).
[0291] In another embodiment, a regioselective compound of formula
(V) may be prepared according to the process of Scheme 2:
##STR00025## ##STR00026##
[0292] wherein:
[0293] R.sup.10 Is selected from alkyl and suitable carboxylic acid
protecting groups; and all other variables are as defined
above.
[0294] Generally, the process for preparing the compounds of
formula (V) (all formulas and all variables having been defined
above) comprises the steps of:
[0295] a) reacting a compound of formula (XIV) with a protecting
group, such as benzyl bromide, to prepare a compound of formula
(XV);
[0296] b) reducing the compound of formula (XV) to prepare a
compound of formula (XVI);
[0297] c) reacting the compound of formula (XVl) with a
1,4-dibromo-2-nitrobenzene of formula (VIII) to prepare a compound
of formula (XVII-A);
[0298] d) reducing and cyclizing the compound of formula (XVII-A)
to prepare a compound of formula (XVIII-A);
[0299] e) reacting the compound of formula (XVIII-A) under
conventional cross-coupling reaction conditions to prepare a
compound of formula (XIX);
[0300] f) reacting the compound of formula (XIX) with acid to
prepare a compound of formula (V).
[0301] According to this process a compound of formula (V) is
prepared by reacting a compound of formula (XIX) with a suitable
acid, such as trifluoroacetic acid or hydrochloric acid.
##STR00027##
[0302] This reaction may be carried out in neat trifluoroacetic
acid or in an inert solvent such as dichloromethane at ambient
temperature.
[0303] The compound of formula (XIX) may be prepared by reacting a
compound of formula (XVIII-A) under conventional cross-coupling
reaction conditions.
##STR00028## [0304] wherein ail variables are as defined above.
[0305] In particular, a compound of formula (XIX) may be prepared
from a compound of formula (XVIII-A) using palladium-catalyzed
Suzuki, Stille, or Negishi cross-coupling techniques conventional
in the art of organic synthesis. For a review of the Suzuki
cross-coupling reaction, see: Miyaura, N.; Suzuki, A. Chemical
Reviews 1895, 95, 2457-2483. The Suzuki coupling may be carried out
using a suitable catalyst such as
dichloro[1,1'-bis(diphenylphosphino)ferrocene] palladium(II)
dlchloromethane adduct, a base such as aqueous sodium carbonate or
triethylamlne, and a suitable inert solvent such as
N,N-dimethylacetamide or tripropanol, optionally in the presence of
microwave irradiation, at temperatures from about 50.degree. C. to
about 150.degree. C. For a review of the Stille cross-coupling
reaction, see: Mitchell, T. N. Synthesis 1992, 803-815. The Stille
coupling may be carried out using
tetrakis(triphenylphoshine)-palladium (0) as the catalyst, in the
presence of promoters such as cesium fluoride and copper (I)
iodide, in a suitable inert solvent such as N,N-dimethylformamide
at a temperature of about 45.degree. C. For a review of the Negishi
cross-coupling reaction, see: Negishi, E.; Zingzhong, T. Z.; Qian,
M.; Hu, Q.; Huang, Z. Metal Catalyzed Cross-Coupling Reactions
(2.sup.nd Edition), 2004, 2, 815-889. The Negishi coupling may be
carried out using dichloro[1,1'-bis(diphenylphosphino)-ferrocene]
palladium(II) dlchloromethane adduct as the catalyst, in the
presence of a promoter such as copper (I) iodide, in a suitable
inert solvent such as N,N-dimethylacetamide at a temperature of
about 80.degree. C.
[0306] A compound of formula (XVIII-A) may be prepared by reducing
and cyclizing the compound of formula (XVII-A).
##STR00029## [0307] wherein ail variables are as described
above.
[0308] The step of reducing a compound of formula (XVII-A) may be
carried out using conventional reduction techniques suitable for
such compounds. Suitable reduction conditions will be apparent to
those skilled in the art of organic synthesis and may include, for
example, palladium on carbon under a hydrogen atmosphere, sulfided
platinum on carbon under a hydrogen atmosphere, or iron powder in
acetic acid. In one embodiment, the reduction may be effected using
conditions such as sulfided platinum on carbon under a hydrogen
atmosphere. The reaction may be carried out in an inert solvent at
either atmospheric or elevated pressure. Suitable Inert solvents
include but are not limited to ethanol, methanol, and ethyl
acetate.
[0309] Suitable cyclizing agents will be apparent to those skilled
in the art of organic synthesis and include, for example
triethylorthoformate or trimethylorthoformate, optionally in the
presence of an acid catalyst, for example p-toluenesuifonic acid or
pyridinium p-toluenesuifonate. In one embodiment, the cyclizlng
agent is triethylorthoformate and the catalyst is pyridinium
p-toluenesulfonate. Conveniently, the reaction of a compound of
formula (XVII-A) with the cyclization agent may be carried out
neat, at a temperature of from about 25.degree. C. to about
100.degree. C. In one embodiment the reaction is carried out at
about 25.degree. C.
[0310] In another embodiment, the process of preparing a compound
of formula (XVIII-A) may be conveniently carried out by performing
a one-pot reduction-cyclization procedure on a compound of formula
(XVII-A) using conditions such as sulfided platinum on carbon under
a hydrogen atmosphere in the presence of triethylorthoformate and
pyridinium p-toluenesulfonate. In this embodiment,
triethylorthoformate may be used as a solvent or a co-solvent with
another suitable inert solvent, such as ethyl acetate.
[0311] A compound of formula (XVII-A) may be prepared by reacting
(e.g., coupling) a compound of formula (XVI) with
1,4-dlbromo-2-nitrobenzene of formula (VIII).
##STR00030## [0312] wherein all variables are as defined above.
[0313] The step of coupling a compound of formula (XVI) with
1,4-dibromo-2-nitrobenzene of formula (VIII) to prepare a compound
of formula (XVII-A) may be carried out using coupling techniques
conventional in the art of organic synthesis. Examples of suitable
coupling reactions include but are not limited to
palladium-catalyzed cross-coupling conditions. Palladium catalyzed
cross-coupling conditions include but are not limited to reacting
the compound of formula (XVI) with 1,4-dibromo-2-nitrobenzene in
the presence of a palladium source, optionally a phosphine ligand,
and a base in a suitable inert solvent. Examples of suitable
palladium sources include but are not limited to
tris(dibenzylideneacetone)-dipalladium (0) or
acetato(2'-di-t-butylphosphino-1,1'-biphenyl-2-yl)palladium (II),
Examples of suitable phosphine ligands include but are not limited
to 9,9-dimethyl-4,5-bis(diphenylphosphino)-xanthene. Examples of
suitable bases include but are not limited to cesium carbonate,
sodium methoxide, and triethylamine. Examples of suitable inert
solvents include but are not limited to toluene or 1,4-dioxane. The
reaction may be carried out at a temperature of between about room
temperature and about 100.degree. C. In one embodiment, the
temperature is about 60.degree. C. For a review of
palladium-catalyzed cross-couplings of haloarenes and amines, see;
Yang, B. H.; Buchwald, S. L. Journal of Organometallic Chemistry
1999, 576, 125-148. See also: Yin, J.; Zhao, M. M.; Huffman, M. A.;
McNamara, J. M. Journal of Organic Chemistry 2002, 4,
3481-3484.
[0314] A compound of formula (XVI) may be prepared by reducing a
compound of formula (XV) using conventional reduction
techniques.
##STR00031## [0315] wherein all variables are as defined above.
[0316] Appropriate conditions for the reduction reaction will be
apparent to those skilled in the art and include, for example,
reducing agents, such as iron, in a suitable solvent, such as
acetic acid. The reaction may be carried out with elevated
temperatures, such as about 50.degree. C.
[0317] A compounds of formula (XV) may be prepared by reacting a
compound of formula (XIV) with benzyl bromide.
##STR00032## [0318] wherein all variables are as defined above.
[0319] This reaction may be carried out in an inert solvent,
conveniently at room temperature, in the presence of a suitable
base. The compound of formula (XIV) and benzyl bromide may be
present in equimolar amounts; however, a slight excess of benzyl
bromide may be employed if desired. Examples of suitable bases for
this reaction include but are not limited to, potassium carbonate,
sodium carbonate, cesium carbonate, sodium hydride, and potassium
hydride. Examples of suitable inert solvents for this reaction
include but are not limited to, N,N-dimethylformamide,
tetrahydrofuran, dioxane, and 1,2-dimethoxyethane.
[0320] As shown below, the order of the steps in the foregoing
reaction is not critical to the process and the steps may be
carried out in any suitable order as determined by those skilled in
the art. For example, in another embodiment of the present
invention, the compounds of formula (V) may be prepared by the
process out-lined in Scheme 3.
##STR00033##
[0321] wherein:
[0322] R.sup.10 is selected from alkyl and suitable carboxylic acid
protecting groups; and
[0323] all other variables are as defined above.
[0324] In particular, this process for preparing the compounds of
formula (V) (all formulas and all variables having been defined
above) comprises the steps of:
[0325] a) reacting a 4-bromo-2-nitroaniline of formula (XX) using a
conventional cross-coupling reaction to prepare a compound of
formula (XXI);
[0326] b) reacting the compound of formula (XXI) with iodine and
t-butyl nitrite to prepare a compound of formula (XXII);
[0327] c) reacting the compound of formula (XXII) with a compound
of formula (XVI) to prepare a compound of formula (XVII);
[0328] d) reducing and cyclizing the compound of formula (XVII) to
prepare a compound of formula (XIX); and
[0329] e) reacting the compound of formula (XIX) with acid to
prepare a compound of formula (V).
[0330] The reaction of the compound of formula (XIX) with acid to
prepare a compound of formula (V) is described above.
[0331] According to this process, a compound of formula (XIX) may
be prepared by reducing and cyclizing the compound of formula
(XVII) using conditions analogous to those described above for the
preparation of a compound of formula (XIX) from a compound of
formula (XVIII).
##STR00034## [0332] wherein all variables are as defined above.
[0333] A compound of formula (XVII) may be prepared by reacting a
compound of formula (XXII) with a compound of formula (XVI) using
conditions described above for the reaction of a compound of
formula (XVI) with 1,4-dibromo-2-nitrobenzene of formula
(VIII).
##STR00035## [0334] wherein all variables are as defined above.
[0335] A compound of formula (XXII) may be prepared by reacting a
compound of formula (XXI) with iodine and t-butyl nitrite.
##STR00036## [0336] wherein all variables are as defined above.
[0337] This reaction may be carried out using a Sartdmeyer-like
reaction known to those skilled in the art. For transformation of
aryi amines to aryl halides, see: Larock, R. Comprehensive Organic
Transformation (2nd Edition), John Wiley & Sons, Inc. (1999)
678-679, The compound of formula (XXII) may be prepared by reacting
a compound of formula (XXI) in an inert atmosphere, at a
temperature of 60.degree. C., with iodine and tett-butyl nitrite,
in a suitable solvent, such as acetonitriie.
[0338] Compounds of formula (XXI) may be prepared by reacting
4-bromo-2-nitroaniline of formula (XX) using conventional
cross-coupling reactions such as those described above.
##STR00037## [0339] wherein ail variables are as defined above.
[0340] Compounds of formula (XX) are commercially available or may
be prepared using conventional techniques.
[0341] In one particular embodiment, the compounds of the invention
may be conveniently prepared by the methods outlined in Scheme 4
below.
##STR00038##
[0342] wherein:
[0343] Y.sup.1 is O;
[0344] R.sup.10 is selected alkyl and suitable carboxyiic add
protecting groups;
[0345] and all other variables are as defined above.
[0346] Generally, the process for preparing compounds of the
invention (all formulas and all variables having been defined
above) comprises the steps of:
[0347] a) reacting regioisomer compounds of formula (V-A) and (V-B)
with a compound of formula (VI) to prepare regioisomer compounds of
formula (VII-A) and (VII-B); and
[0348] b) reacting the regioisomer compounds of formula (VII-A) and
(VII-B) under conventional cross-coupling reaction conditions to
prepare a compound of formula (VII).
[0349] A compound of formula (VII) prepared according to this
process may be reacted with ammonia to prepare a compound of
formula (I) as described above. A compound of formula (VIl) may
also be separated into its enantiomers as described above.
[0350] It will be apparent to those skilled in the art that certain
reaction steps may be most-efficiently performed by installing
protecting groups prior to the reaction, which are removed
subsequently. The choice of protecting groups as well as general
techniques for their installation and removal are within the skill
of those in the art.
[0351] Compounds of formula (VII-A) and (VII-B) may be prepared by
reacting the compound of formula (V-A) or the compound of formula
(V-B), respectively, with a compound of formula (VI) under
Mitsunobu reaction conditions, as described above. Br in the
compounds of formula (VII-A) and (VII-B) may be further converted
to other functional groups using chemistry transformation known to
those skilled in the art, for example, conventional cross-coupling
reactions to prepare a different compound of formula (VII).
[0352] More particularly, the compounds of formula (VII) may be
prepared from compounds of formula (VII-A and VII-B) using
palladium-catalyzed Suzuki, Stille, or Negishi cross-coupling
techniques (described above) which are conventional in the art of
organic synthesis.
[0353] As will be apparent to those skilled in the art. the order
of the steps in the foregoing reaction is not critical to the
practice of the process of the present invention. For example, the
compounds of formula (VII) may also be prepared by altering the
order of the steps such that the cross-coupling reaction is carried
out on the regioisomer compounds of formula (V-A) and (V-B) to
prepare a compound of formula (V) (as defined in Scheme 1 above)
followed by the reaction of a compound of formula (V) with a
compound of formula (VI) to prepare a compound of formula (VII).
Each of these reaction steps may be carried out using the
techniques described above.
[0354] As a further embodiment, the compounds of formula (VII-A)
and (VII-B) may first be reacted with ammonia to produce the
corresponding Br-substituted compounds of formula (I), followed by
the cross-coupling reaction to prepare a different compound of
formula (I) wherein the Br substituent is displaced by another
functional group defined by R.sup.1 and R.sup.2 above.
[0355] The compounds of formula (V-A) and (V-B) may be prepared by
reacting 5-bromobenzimidazole with a compound of formula (III).
##STR00039## [0356] wherein all variables are as defined above.
[0357] This reaction may be carried out using the same reaction
conditions described above for the preparation of a compound of
formula (V).
[0358] In another embodiment, the present invention provides
another process for preparing compounds of the invention, which is
out-lined in Scheme 5 below.
##STR00040##
[0359] wherein;
[0360] R.sup.10 is selected from alkyl and suitable carboxylic acid
protecting groups;
[0361] Y.sup.1 is O; and
[0362] all other variables are as defined above.
[0363] Generally, the process for preparing the compounds of the
invention (all formulas and all variables having been defined
above) comprises the steps of:
[0364] a) reacting the compound of formula (V) with a compound of
formula (XXV) to prepare a compound of formula (XXVI-A) and
removing the protecting group to prepare a compound of formula
(XXVI);
[0365] b) reacting the compound of formula (XXVI) with a compound
of formula (X) to prepare a compound of formula (VII);
[0366] c) reacting the compound of formula (VII) with ammonia to
prepare a compound of formula (I);
[0367] d) optionally separating the compound of formula (I) into
enantiomers;
[0368] e) optionally converting the compound of formula (l) to a
pharmaceutically acceptable salt thereof; and
[0369] f) optionally converting the compound of formula (I) or a
pharmaceutically acceptable salt thereof to a different compound of
formula (I) or a pharmaceutically acceptable salt thereof.
[0370] As will be apparent to those skilled in the art, the order
of the steps in the foregoing reaction is not critical to the
practice of the process of the present invention. The foregoing
reaction steps may be carried out in any suitable order based upon
the knowledge of those skilled in the art. Further, it will be
apparent to those skilled in the art that certain reaction steps
may be most efficiently performed by installing protecting groups
prior to the reaction, which are removed subsequently. The choice
of protecting groups as well as general techniques for their
installation and removal are within the skill of those in the
art.
[0371] The reaction of the compound of formula (VII) with ammonia
to prepare a compound of formula (I) is described above.
[0372] According to this method, a compound of formula (VII) is
prepared by reacting the compound of formula (XXVI) with a compound
of formula (X) using conventional Mitsunobu reaction conditions
such as those described above for preparation of the compound of
formula (VII) by reaction of the compound of formula (V) with a
compound of formula (VI).
##STR00041## [0373] wherein all variables are as defined above.
[0374] If desired, the enantiomers of the compound of formula (VII)
may be separated as described above to yield the enantiomerically
enriched compounds of formula (VII-1) and (VII-2), which may then
be used in the foregoing process to ultimately yield an
enantiomerically enriched compound of formula (I-1) or (I-2),
respectively.
[0375] Compounds of formula (X) are commercially avallable or may
be prepared using conventional techniques, A compound of formula
(XXVI) may be prepared by removing the siiyl protecting group from
the compound of formula (XXVI-A) using conventional techniques,
such as reaction with tetrabutylammonium fluoride. See, Kocienski,
P. J. Protecting Groups, Georg Thieme Veriag, Stuttgart, 1994; and
Greene, T. W., Wuts, P. G. M. Protecting Groups in Organic
Synthesis (2.sup.nd Edition), J. Wiley and Sons, 1991.
[0376] A compound of formula (XXVI-A) may be prepared by reacting a
compound of formula (V) with a compound of formula (XXV) using
conventional Mitsunobu reaction conditions such as those
described.
##STR00042## [0377] wherein all variables are as defined above.
[0378] If desired, the enantiomers of the compound of formula
(XXVI-A) may be separated as described above to yield the
enantiomerically enriched compounds of formula (XXVI-A1) and
(XXVI-A2),
##STR00043##
which may then be used in the foregoing process to ultimately yield
an enantiomerically enriched compound of formula (I-1) or (I-2),
respectively.
[0379] Processes for the preparation of compounds of formula (V)
are described above.
[0380] Compounds of formula (XXV) may be prepared according to the
following reaction scheme.
##STR00044## [0381] wherein all variables are as defined above.
[0382] The compounds of formula (XXVIII) are commercially avallable
or may be prepared using conventional techniques known to those
skilled in the art. The t-butyi-dimethylsilyl protecting group is
installed using conventional techniques to prepare the compound of
formula (XXIX). See, Kocienski, P. J. Protecting Groups, Georg
Thieme Verlag, Stuttgart, 1994; and Greene, T. W., Wuts, P. G. M.
Protecting Groups in Organic Synthesis (2.sup.nd Edition), J. Wiley
and Sons, 1991. The compound of formula (XXIX) is reacted with a
magnesium chloride of the formula R.sup.3--MgCl to prepare the
compound of formula (XXV). if desired, the enantiomers of the
compound of formula (XXV) may be separated using conventional
separation techniques (e.g., supercritical fluid chromatography
(SFC)) to yield the enantiomerically enriched compound of formula
(XXV-1)
##STR00045##
which may then be used in the foregoing process to ultimately yield
an enantiomerically enriched compound of formula (I-1).
[0383] In another embodiment, the present invention provides
another process for preparing compounds of the invention, which is
out-lined in Scheme 6 below.
##STR00046##
[0384] wherein:
[0385] R.sup.10 is selected from alkyl and suitable carboxylic acid
protecting groups;
[0386] Y.sup.1 is NH; and
[0387] all other variables are as defined above.
[0388] Generally, the process for preparing the compounds of the
invention (all formulas and all variables having been defined
above) comprises the steps of:
[0389] a) reacting the compound of formula (V) with a compound of
formula (XXX) to prepare a compound of formula (XXXI);
[0390] b) reacting the compound of formula (XXXI) with ammonia to
prepare a compound of formula (XXXII);
[0391] c) reducing the compound of formula (XXXII) to prepare a
compound of formula (XXXIII);
[0392] d) reacting the compound of formula (XXXIII) with a compound
of formula (XXXIV) to prepare a compound of formula (I);
[0393] e) optionally separating the compound of formula (I) Into
enantiomers;
[0394] f) optionally converting the compound of formula (I) to a
pharmaceuticaiiy acceptable salt thereof; and
[0395] g) optionally converting the compound of formula (I) or a
pharmaceuticaiiy acceptable salt thereof to a different compound of
formula (I) or a pharmaceuticaiiy acceptable salt thereof.
[0396] As will be apparent to those skilled in the art, the order
of the steps in the foregoing reaction is not critical to the
practice of the process of the present invention. The foregoing
reaction steps may be carried out in any suitable order based upon
the knowledge of those skilled in the art. Further, if will be
apparent to those skilled In the art that certain reaction steps
may be most efficiently performed by installing protecting groups
prior to the reaction, which are removed subsequently. The choice
of protecting groups as well as general techniques for their
installation and removal are within the skill of those in the
art.
[0397] More specifically, according to this method, a compound of
formula (I) wherein Y.sup.1 Is NH may be prepared by reacting the
compound of formula (XXXIII) with a compound of formula (XXXIV)
using conventional reductive amination reaction conditions. See,
Larock, R. C. Comprehensive Organic Transformation (2.sup.nd
Edition), Wiley-VCH, 1999.
##STR00047## [0398] wherein all variables are as defined above.
[0399] Compounds of formula (XXXIII) maybe prepared by reduction of
a compound of formula (XXXIII) using conventional nitro reaction
conditions such as those described above.
##STR00048## [0400] wherein all variables are as defined above.
[0401] If desired, the enantiomers of the compound of formula
(XXXIII) may be separated using conventional separation techniques
(e.g., SFC) to yield the enantiomerically enriched compounds of
formula (XXXIII-1) and (XXXIII-2)
##STR00049##
which may then be used in the foregoing process to ultimately yield
an enantiomerically enriched compound of formula (I-1) or (I-2),
respectively.
[0402] Compounds of formula (XXXII) may be prepared by reaction of
the compound of formula (XXXI) with ammonia using reaction
conditions such as those described above.
##STR00050## [0403] wherein all variables are as defined above.
[0404] If desired, the enantiomers of the compound of formula
(XXXII) may be separated using conventional separation techniques
(e.g., SFC) to yield the enantiomerically enriched compounds of
formula (XXXII-1) and (XXXII-2)
##STR00051##
which may then be used in the foregoing process to ultimately yield
an enantiomerically enriched compound of formula (I-1) or (I-2),
respectively,
[0405] Compounds of formula (XXXI) may be prepared by reacting a
compound of formula (V) with a compound of formula (XXX) using
conventional Mftsunobu reaction conditions such as those described
above.
##STR00052## [0406] wherein all variables are as defined above.
[0407] If desired, the enantiomers of the compound of formula
(XXXI) may be separated using conventional separation techniques
(e.g., SFC) to yield the enantiomerically enriched compounds of
formula (XXXI-1) and (XXXI-2)
##STR00053##
which may then be used in the foregoing process to ultimately yield
an enantiomerically enriched compound of formula (I-1) or (I-2),
respectively. Compounds of formula (XXX) may be prepared as
follows.
##STR00054## [0408] wherein all variables are as defined above.
[0409] The compounds of formula (XXXV) are commercially avallable
or may be prepared using conventional techniques known to those
skilled in the art. The compound of formula (XXXV) is reacted with
an alkyl lithium of the formula R.sup.3--Li in the presence of
titanium tetrachloride to prepare the compound of formula (XXX). If
desired, the enantiomers of the compound of formula (XXX) may be
separated using conventional separation techniques (e.g.,
supercritical fluid chromatography (SFC)) to yield the
enantiomerically enriched compound of formula (XXX-1)
##STR00055##
which may then be used in the foregoing process to ultimately yield
an enantiomerically enriched compound of formula (I-1).
[0410] A compound of formula (I) maybe converted into a different
compound of formula (I) using techniques known to those skilled in
the art.
[0411] In one embodiment, a compound of formula (I-1A) may be
converted to a compound of formula (I-1B) using standard
deprofection reaction conditions. A compound of formula (I-1B) may
be converted to a compound of formula (I-1C) using Michael addition
reactions known to those skilled in the art.
##STR00056## [0412] wherein all variables are as defined above.
[0413] The compound of formula (I-1A) may be converted to a
compound of formula (I-1B) using neat trifiuoroacetic acid (TFA) or
trlfiuoroaceticacid in a suitable solvent such as dicbJoromeihane.
The compound of formula (I-1B) may then be converted to a compound
of formula (I-1C) using methyl vinyl suifone in a suitable solvent
such as tetrahydrofuran.
[0414] In another embodiment, a compound of formula (I-1B) may be
converted to a compound of formula (I-1D) using reductive
alkylation condition.
##STR00057## [0415] wherein all variables are as defined above.
[0416] The compound of formula (I-1B) may be converted to a
compound of formula (I-1D) by reacting the compound of formula
(I-1B) with appropriate ketones or aldehydes such as formaldehyde,
and reducing agents such as sodium triacetoxyborohydride, in the
presence of a suitable acid such as acetic acid, and in a suitable
solvent such as dichloromethane and methanol.
[0417] In another embodiment, a compound of formula (I-1E) may be
converted to a compound of formula I-1F) using oxidation
conditions. A compound of formula (I-1F) may be converted to a
compound of formula (I-1G) using standard deprofection
conditions.
##STR00058## [0418] wherein all variables are as defined above.
[0419] A compound of formula (I-1E) may be converted to a compound
of formula (I-1F) using oxidizing agents such as
m-chloroperoxybenzoic acid (m-CPBA) in appropriate solvents such as
dlchloromethane or chloroform at room temperature. A compound of
formula (I-1F) may be converted to a compound of formula (I-1G)
using neat trifluoroacetic acid (TFA) or trifluoroacetic acid in a
suitable solvent such as dlchloromethane.
[0420] Based upon this disclosure and the examples contained herein
one skilled in the art can readily convert a compound of formula
(I) or (I-1) or a pharmaceutically acceptable salt thereof into
another compound of formula (I) or (I-1) or a pharmaceutically
acceptable salt thereof.
[0421] The following abbreviations as employed in the examples,
have the recited meanings. [0422] g gram(s) [0423] mg milligram(s)
[0424] mol mole(s) [0425] mmol mlilimole(s) [0426] N normal [0427]
L liter(s) [0428] ml milliliter(s) [0429] .mu.L microliter(s)
[0430] h hour(s) [0431] min minute(s) [0432] .degree. C. degrees
Centigrade [0433] HCl hydrochloric acid [0434] DCM dlchloromethane
[0435] CHCl.sub.3 chloroform [0436] Me methyl; --CH.sub.3 [0437]
MeOH methanol [0438] EtOH ethanol [0439] i-PrOH isopropanol [0440]
EtOAc ethyl acetate [0441] THF tetrahydrofuran [0442] TFA
trifluoroacetic acid [0443] DMA N.N-dimethylacetamide [0444] DMF
N,N-dimethylformamide [0445] NH.sub.4Cl ammonium chloride [0446]
MgSO.sub.4 magnesium sulfate [0447] NaOH sodium hydroxide [0448]
NaHCO.sub.3 sodium bicarbonate [0449] Na.sub.2CO.sub.3 sodium
carbonate [0450] K.sub.2CO.sub.3 potassium carbonate [0451]
Cs.sub.2CO.sub.3 cesium carbonate [0452] Na.sub.2SO.sub.4 sodium
sulfate [0453] N.sub.2 nitrogen [0454] H.sub.2 hydrogen [0455] rt
room temperature [0456] Cl.sub.2Pd(dppf)
dichloro[1,1'-bis(diphenylphosphino)ferrocene] palladlum(II) [0457]
XANTPHOS (4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene) is a
commercially avallable catalyst, from Aldrich [0458] SFC
supercritical fluid chromatography [0459] TLC thin layer
chromatography. [0460] ee enantiomeric excess
[0461] Reagents are commercially avallable or are prepared
according to procedures in the literature, in the following
structures, "Me" refers to the group --CH.sub.3.
[0462] All references to "ether" are to diethyl ether; brine refers
to a saturated aqueous solution of NaCl. Unless otherwise
indicated, all temperatures are expressed in .degree. C. (degrees
Centigrade). All reactions are conducted under an Inert atmosphere
at rt unless otherwise noted.
[0463] .sup.1H NMR spectra were recorded on a Varian VXR-300, a
Varian Unity-300, a Varian Unity-400 Instrument, or a General
Electric QE-300. Chemical shifts are expressed in parts per million
(ppm, .delta. units). Coupling constants are in units of hertz
(Hz). Splitting patterns describe apparent multiplicities and are
designated as s (singlet), d (doublet), t (triplet), q (quartet), m
(multiplel), br (broad).
[0464] Low-resolution mass spectra (MS) were recorded on a JOEL
JMS-AX505HA, JOEL SX-102, or a SGIEX-APIiii spectrometer; high
resolution MS were obtained using a JOEL SX-102A spectrometer. All
mass spectra were taken under electrospray ionization (ESI),
chemical ionization (CI), electron impact (EI) or by fast atom
bombardment (FAB) methods. Infrared (IR) spectra were obtained on a
Nieolet 510 FT-IR spectrometer using a 1-mm NaCl cell. All
reactions were monitored by thin-layer chromatography on 0.25 mm E.
Merck silica gel plates (60F-254), visualized with UV light, 5%
ethanolic phosphomoiybdic acid or p-anisaidehyde solution or mass
spectrometry (electrospray or AP). Flash column chromatography was
performed on silica gel (230-400 mesh, Merck) or using automated
silica gel chromatography (Isco, Inc. Sq 16.times. or 100 sg
Combiflash).
[0465] Reported HPLC retention times (RT) were obtained on a Waters
2795 instrument attached to a Waters 996 diode array defector
reading 210-500nm. The column used was a Synergi IVIax-RP
(50.times.2 mm) model #00B-4337-B0. Solvent gradient was 15%
MeOH:water to 100% MeOH (0.1% formic acid) over 6 min. Flow rate
was 0.8 mL/min. Injection volume was 3 .mu.L.
INTERMEDIATE 1
(1S)-1-(2-Chloro-3-nitrophenyl)ethanol
##STR00059##
[0467] To ether cooled to -78.degree. C. was added titanium (IV)
chloride (0.85 mL, 7.8 mmol) and a 1.6M solution of methyl lithium
in ether (4.9 ml, 7.8 mmol). After warming the mixture to
-40.degree. C., it was transferred via double-tipped needle to a
-78.degree. C. ether solution of 2-chloro-3-nitrobenzaldehyde (1.0
g, 5.6 mmol), which can be synthesized according to the procedure
in J. Med. Chem. 1088, 31, 936-944. The reaction was allowed to
slowly warm to rt and was quenched with the addition of MeOH and
water. The layers were separated, and the aqueous phase was
extracted with EtOAc. The combined organic phases were washed with
brine, dried over MgSO.sub.4 and concentrated to an oil. The crude
material was purified by flash column chromatography (10%
EtOAc:hexanes) to give 0.98 g of the racemic compound (84%). The
enantiomers were separated using packed column supercritical fluid
chromatography (SFC) on a 3.times.25 cm Dalcel.RTM. AD-H column
with a 90 g/min total flow (81 q/min CO.sub.2-90%) (9 g/min
MeOH-10%) to give the title compound as a yellow oil. .sup.1H NMR
(400 MHz, d.sub.6-DMSO) .delta. 7.86 (m, 1H), 7.58 (m, 1H), 5.62
(d, J=4.4 Hz, 1H), 5.06 (m, 1H), 1.30 (d, J=6.4 Hz, 3H).
INTERMEDIATE 2
Methyl
5-(5-chloro-1H-benzimidazol-1-yl)-3-{[(1R)-1-(2-chloro-3-hydroxyphe-
nyl)ethyl]oxy}-2-thiophenecarbpxylate
##STR00060##
[0468] Step A--Methyl
5-(5-chloro-1H-benzimidazol-1-yl)-3-{[(1,1-dimethylethyl)-(dimethyl)silyl-
]oxy}-2-thiophenecarboxylate
##STR00061##
[0470] To a mixture of chlorobenzimidazole (7.0 g, 48 mmol) and
methyl 2-chloro-3-oxo-2.3-dihydro-2-thiophenecarboxylate
(Synthesis, 1984, 10, 847-850) (9.8 g, 51 mmol) in 400 mL of
chloroform was added N-methylimidazole (5.5 mL, 69 mmol). After 16
h, tert-butylchlorodimethylsilane (6.9 g, 46 mmol) and
N-rnethylimidazole (3.7 mL, 48 mmol) was added. The reaction
mixture was diluted with water and the layers were separated. The
aqueous phase was extracted with DCM. The combined organic layers
were washed with water, dried over MgSO.sub.4 and concentrated onto
silica gel. The crude material was purified by flash column
chromatography (0-100% 25% EtOAc/hexanes) to give 5.8 g of the
desired product (30%). .sup.1H NMR (400 MHz, d.sub.6-DMSO) .delta.
8.79 (s, 1H), 7.88 (d, J=2.0 Hz, 1H), 7.81 (d, J=8.8 Hz, 1H), 7.44
(dd, J=8.8 and 2.0 Hz, 1H), 7.25 (s, 1H), 3.78 (s, 3H), 0.99 (s,
9H), 0.27 (s, 6H).
Step B--Methyl
5-(5-chloro-1H-benzimidazol-1-yl)-3-hydroxy-2-thiophene-carboxylate
##STR00062##
[0472] To a solution of methyl
5-(5-chloro-1H-benzimidazol-1-yl)-3-{[1,1-dimethylethyl)-(dimethyl]silyl}-
oxy)-2-thiophenecarboxylate (2.0 g, 4.7 mmol) in 40 mL of THF
cooled to 0.degree. C. was added a 1M solution of
tetrabutylammonium fluoride in THF. The reaction was diluted with
UeOH and concentrated onto silica gel. The crude material was
purified by flash column chromatography to give 1.4 g of the
desired product (97%). .sup.1H NMR (400 MHz, d.sub.6-DMSO) .delta.
10.87 (s, 1H), 8.73 (s, 1H), 7.88 (d, J=1.8 Hz, 1H), 7.79 (d, J=8.8
Hz, 1H), 7.42 (dd, J=8.8 and 1.6 Hz, 1H), 7.12 (s, 1H). 3.76 (s,
3H).
Step C--Methyl
5-(5-chloro-1H-benzimidazol-1-yl)-3-{[(1R)-1-(2-chloro-3-hydroxyphenyl)et-
hyl]oxy}-2-thiophenecarboxylate (Title Compound)
[0473] To a solution of methyl
5-(5-chloro-1H-benzimidazol-1-yl)-3-{[(1R)-1-(2-chloro-3-hydroxyphenyl)et-
hyl]oxy}-2-thiophenecarboxylate (330 mg, 1.1 mmol) and
(1S)-1-(2-chloro-3-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-phenyl)ethan-
ol (Intermediate 17, 370 mg, 1.3 mmol) in DCM was added
polymer-supported triphenyiphosphine (920 mg, 2.2 mmol) and
di-tert-butylazodicarboxylate (510 mg, 2.2 mmol). After 2 h, the
reaction was filtered and the resin was washed with alternating DCM
and MeOH. The filtrate was concentrated onto silica gei and
purified by flash column chromatography (0-100% 5% MeOH/DCM and
DCM). Fractions containing desired product were concentrated and
dissolved in 5 mL of THF. The solution was cooled to 0.degree. C.
and a 1M solution of tetrabutylammonium fluoride in THF (1.1 mL,
1.1 mmol) was added. After 30 min, the reaction was diluted with
MeOH and concentrated onto silica gel. The crude material was
purified by flash column chromatography (0-100% 10% MeOH/DCM+1%
NH.sub.4OH and DCM) to give 395 mg of the desired product (77%).
.sup.1H NMR (400 MHz, d.sub.6-DMSO) .delta. 10.27 (s, 1H), 8.70 (s,
1H), 7.86 (s, 1H), 7.59 (d, J=8.8 Hz, 1H), 7.39 (d, J=8.8 Hz, 1H),
7.32 (s, 1H), 7.17-7.09 (m, 2H), 8.89 (d, J=8.0 Hz, 1H), 5.91 (m,
1H), 3.79 (s, 3H), 1.58 (d, J=8.0 Hz, 3H).
INTERMEDIATE 3
Methyl
3-[(1R)-1-(2-chloro-3-hydroxyphenyl)ethoxy]-5-(6-cyano-1H-benzimida-
zol-1-yl)thiophene-2-carboxylate
##STR00063##
[0474] Step A -1H-benzimidazole-5-carbonitrile
##STR00064##
[0476] A stirred mixture of 3,4-diaminobenzonitrile (1.0 g, 7.5
mmol), catalytic formic acid (2 drops) and triethylorthoformate (15
mL, 90 mmol) was heated at 80.degree. C. for 1 h, then cooled to
rt, concentrated under vacuum and chromatographed on silica gel,
eluting with a gradient of 0.5-to-10% MeOH/DCM, with 1% ammonium
hydroxide, to give 803 mg (75%) of the title compound as a brown
solid. MS (ESI): 143 [M+H].sup.+.
Step B--Methyl
5-(5-cyano-1H-benzimidazol-1-yl)-3-hydroxy-2-thiophene-carboxylate
and methyl
5-(6-cyano-1H-benzimidazol-1-yl)-3-hydroxy-2-thiophenecarboxylate
##STR00065##
[0478] To a stirred mixture of 1H-benzimidazole-5-carbonitrile (1.9
g, 12 mmol) in DMF (28 ml) and CHCl.sub.3 (88 ml) was added
N-methylimidazole (3.0 mL, 38 mmol) followed by methyl
2-chloro-3-oxo-2,3-dihydro-2-thiophenecarboxylate (Synthesis, 1984,
10, 847-850), (2.7 g, 14 mmol). The reaction was then warmed to
35.degree. C. and stirred for 72 h. The reaction was cooled to rt
and diluted with EtOAc (800 mL) and aqueous 0.5N HCl (200 mL). The
aqueous layer was extracted with EtOAc (2.times.). The aqueous
layer was then treated with aqueous (saturated) NaHCO.sub.3 until
the pH was 7.0, then extracted again with EtOAc. The combined
organic layers were then washed with water (2.times.), brine, dried
over MgSO.sub.4, concentrated under vacuum and chromatographed on
silica gel (120 g), elutlng with a gradient of 30-to-90%
EtOAc/hexane to give 1.9 g (52%) of an approximate 1:1 regioisomer
mixture of the title compounds as a yellow solid. MS (ESI): 299
[M+H].sup.+.
Step C--Methyl 5-(6-cyano-1H-benzimidazol
-1-yl)-3-({(1R)-1-[2-(trifluoromethyl)phenyl]ethyl}oxy)-2-thiophenecarbox-
ylate
##STR00066##
[0480] A slurry of methyl
5-(5-cyano-1H-benzimidazol-1-yl)-3-hydroxy-2-thiophene-carboxylate
and methyl
5-(6-cyano-1H-benzimidazol-1-yl)-3-hydroxy-2-thiophenecarboxylate
(1.9 g, 6.4 mmol), (1S)-1-[2-(trifluoromethyl)phenyl]ethanol (1.9
g, 9.6 mmol) and polystyrene-triphenylphosphine (6.2 g, 13 mmol,
loading 2.12 mmol/g) in DCM (130 ml) was stirred at 30.degree. C.
for 10 min, then di-tert-butylazadicarboxylate (3.0 g, 13 mmol) was
added. The reaction was stirred at 30.degree. C. for 12 h, then
poured through filter paper, washing the resin solid with DCM and
MeOH. The filtrate was concentrated under vacuum and
chromatographed on silica gel (330 g), eiuting with a gradient of
10-to-50% EtOAc/hexane to give 782 mg (25%) of the title compound
as a light yellow solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6):
.delta. 8.86 (s, 1H), 8.08 (s, 1H), 8.01-7.94 (m, 2H), 7.80-7.71
(m, 4H), 7.54 (t, J=7.89 Hz, 1H), 7.44 (s, 1H), 8.01 (q, J=8.10 Hz,
1H), 3.84 (s, 3H), 1.88 (d, J=8.23 Hz, 3H); MS (ESI): 471
[M+H].sup.+.
Step D--Methyl
5-(6-cyano-1H-benzimidazol-1-yl)-3-hydroxythiophene-2-carboxylate
##STR00067##
[0482] A solution of methyl 5-(6-cyano-1H-benzimidazol
-1-yl)-3-{(1R)-1-[2-(tnfluoromethyl)phenyl]ethoxy}thiophene-2-carboxylate
(724 mg, 1.54 mmol) in 10 ml of TFA was heated at 70.degree. C. for
16 h, The reaction was concentrated and the residue was taken up in
MeOH. The solution was neutralized with 7N ammonia in MeOH. The
reaction was concentrated and the solid was triturated with ether.
The solid was rinsed with water and ether and dried to give 388 mg
of the desired product (84%),
Step E--Methyl
3-[(1R)-1-(3-{[tert-butyl(dimethyl)sliyl]oxy}-2-chlorophenyl)ethoxy]-5-(6-
-cyano-1H-benzimidazol-1-yl)thiophene-2-carboxylate
##STR00068##
[0484] To a slurry of methyl
5-(6-cyano-1H-benzimidazol-1-yl)-3-hydroxythiophene-2-carboxylate
(390 mg, 1.3 mmol) in 13 ml of DCM was added
(1S)-1-(2-chloro-3-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}phenyl)ethano-
l (460 mg, 1.6 mmol), triphenylphosphine (880 mg, 2.8 mmol) and
di-tert-butylazodicarboxylate (600 mg, 2.6 mmol). The reaction was
concentrated onto silica gel and purified by flash column
chromatography to give 440 mg of the desired product (60%). .sup.1H
NMR (400 MHz, d.sub.6-DMSO) .delta. 8.84 (s, 1H), 8.22 (s, 1H),
7.94 (d, J=7.6 Hz, 1H), 7.74 (d, J=8.4 Hz, 1H), 7.41 (s, 1H),
7.32-7.25 (m, 2H), 6.93 (d, J=7.6 Hz, 1H), 5.97 (m, 1H), 3.80 (s,
3H), 1.60 (d, J=6.4 Hz, 3H), 0.90 (s, 9H), 0.14 (s, 3H), 0.08 (s,
3H).
Step F--Methyl
3-[(1R)-1-(2-chloro-3-hydroxyphenyl)ethoxy]-5-(6-cyano-1H-benzimidazol-1--
yl)thiophene-2-carboxylate (Title Compound)
[0485] To a solution of methyl
3-[(1R)-1-(3-{[tert-butyl(dimethyl)silyl]oxy}-2-chlorophenyl)ethoxy]-5-(6-
-cyano-1H-benzimidazol-1-yl)thiophene-2-carboxylate (420 mg, 0.74
mmol) in THF cooled to 0.degree. C. was added a 1M solution of
fetfabutyfammonium fluoride in THF (0.8 ml, 0.81 mmol). MeOH was
added and the reaction was concentrated onto silica gel. The crude
material was purified by flash column chromatography to give 291 mg
of the title compound (87%). .sup.1H NMR (400 MHz, d.sub.6-DMSO)
.delta. 8.90 (s, 1H), 8.31 (s, 1H), 7.96 (d, J=8.4 Hz, 1H), 7.76
(dd, J=8.2 and 1.4 Hz, 1H), 7.20 (s, 1H), 3.78 (s, 3H).
INTERMEDIATE 4
Methyl
5-(5-bromo-1H-benzimidazol-1-yl)-3-{[tert-butyl(dimethyl)silyl]oxy}-
thiophene-2-carboxylate; and
INTERMEDIATE 5
Methyl
5-(6-bromo-1H-benzimidazol-1-yl)-3-{[tert-butyl(dimethyl)silyl]oxy}-
thiophene-2-carboxylate
##STR00069##
[0486] Step A--4-Bromobenzene-1,2-diamine
##STR00070##
[0488] A mixture of 4-hromo-2-nitroaniline (50 g, 230 mmol) and Tin
(II) chloride (174 g, 920 mmol) in 1.2 L of EtOH was heated at
80.degree. C. for 16 h. The reaction was cooled to rt and brought
to a basic pH with the addition of 5N and 1N NaOH, Once basic, 2 L
of EtOAc was added and the mixture stirred. The organic layer was
decanted off. This process was repeated until the EtOAc decant
provided very little material. The organic solution was washed with
brine, dried over MgSO.sub.4 and concentrated to give 48.9 g of
crude product. .sup.1H NMR (400 MHz, d.sub.6-DMSO) .delta. 6.60 (d,
J=2.4 Hz, 1H), 6.45 (dd, J=8.0 and 2.4 Hz, 1H), 6.39 (d, J=8.0 Hz,
1H), 4.83 (br s, 4H).
Step B <--5-Bromo-1H-benzimidazole
##STR00071##
[0490] A solution of crude, impure 4-bromobenzene-1,2-diamine (48.9
g, 230 mmol), trirnethylorthoformate (75 mL, 690 mmol), and 6 mL of
formic acid was heated at 80.degree. C. After 18 h, the reaction
was concentrated to give 46.2 g of a crude, impure orange residue.
.sup.1H NMR (400 MHz, d.sub.6-DMSO) .delta. 8.24 ($, 1H), 7.77 (d,
J=1.6 Hz, 1H), 7.53 (d, J=8.8 Hz, 1H), 7.30 (dd, J=8.8 and 1.8 Hz,
1H).
Step C--Methyl
5-(5-bromo-1H-henzimidazol-1-yl)-3-{[tert-butyl(dimethyl)silyl]oxy}thioph-
ene-2-carboxylate and methyl
5-(6-bromo-1H-benzimidazol-1-yl)-3-{[tert-butyl(dimethyl)silyl]oxy}thioph-
ene-2-carboxylate (Title Compounds)
[0491] To a solution of crude, impure 5-bromobenzimidazole (48.2 g)
and methyl 2-chloro-3-oxo-2,3-dihydrothiophene-2-carboxylate (42 g,
220 mmol) in 800 mL of CHCl.sub.3 was added N-methylimidazole (28
ml, 350 mmol). After 16 h, N-methylimidazole (17 mL, 220 mmol) and
tert-butylchlorodimethylsilane (36 g, 240 mmol) was added. When TLC
showed the reaction to be complete, the solution was diluted with
water. The layers were separated. The organic phase was washed with
water, dried over MgSO.sub.4 and concentrated onto celite. The
crude mixture was purified by flash column chromatography (0-25%
EtOAc:bexanes) in batches to separate the 2 regioisomers, giving
33.5 g of Intermediate 4 eluting first and 29.2 g of Intermediate 5
eluting second (58%). (Intermediate 4, 5-Br) .sup.1H NMR (400 MHz,
d.sub.6-DMSO) .delta. 8.77 (s, 1H), 8.01 (d, J=1.6 Hz, 1H), 7.78
(d, J=8.8 Hz, 1H), 7.58(dd, J=8.8 and 1.6 Hz, 1H), 7.25 (s, 1H),
3.78 (s, 3H), 0.99 (s, 9H), 0.27 (s, 6H). (Intermediate 5, 6-Br)
.sup.1H NMR (400 MHz, d.sub.6-DMSG) .delta. 8.71 (s, 1H), 7.88 (d,
J=1.6 Hz, 1H), 7.73 (d, J=8.8 Hz, 1H), 7.50 (dd, J=8.8 and 2.0 Hz,
1H), 7.26 (s, 1H), 3.77(s, 3H), 0.99 (s, 9H), 0.28 (s, 6H).
INTERMEDIATE 6
Methyl
5-(6-bromo-1H-benzimidazol-1-yl)-3-{[(1R)-1-(2-chloro-3-hydroxyphen-
yl)ethyl]oxy}-2-thiiophenecarboxylate
##STR00072##
[0492] Step A--Methyl
5-(6-bromo-1H-benzimidazol-1-yl)-3-hydroxy-2-thiophenecarboxylate
##STR00073##
[0494] To a solution of methyl
5-(6-bromo-1H-benzimidazol-1-yl)-3-{[tert-butyl(dimethyl)-silyl]oxy}thiop-
hene-2-carboxylate (Intermediate 5, 25 g, 54 mmol) in 540 mL THF
was added a 1M solution of tetrabutyl ammonium fluoride in THF (60
mL, 60 mmol). After 1.5 h, the reaction was diluted with saturated
aqueous NH.sub.4Cl (200 mL). After 15 min, the slurry was further
diluted with water (750 mL) and EtOAc (1L). The aqueous layer was
separated and brought to pH 3 by the addition of 1M HCl. The
aqueous solution was extracted several times with EtOAc. The
combined organic layers were washed with 0.1M HCl, dried over
MgSO.sub.4, and concentrated to give 19.4 g of the desired product
which was used without further purification (100%). .sup.1H NMR
(400 MHz, d.sub.6-DMSO) .delta. 8.62 (s, 1H), 7.90 (d, J=1.6 Hz,
1H), 7.72 (d, J=8.4 Hz, 1H), 7.47 (d, J=8.6 and 1.8 Hz, 1H), 6.83
(s, 1H), 3.66 (s, 3H).
Step B--Methyl
5-(6-bromo-1H-benzimidazol-1-yl)-3-{[(1R)-1-(2-chloro-3-{[(1,1-dimethylet-
hyl)(dJmethyl)silyl]oxy}phenyl)ethyI]oxy}-2-thsophenecarboxylate
##STR00074##
[0496] Methyl
5-(6-bromo-1H-benzimidazol-1-yl)-3-hydroxy-2-theophenecarboxylate
(250 mg, 0.70 mmol) and
(1S)-1-(2-chloro-3-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-phenyl)ethan-
ol (240 mg, 0.84 mmol) were coupled using a procedure analogous to
Intermediate 3, Step E to give 420 mg of the desired product with
impurity. .sup.1H NMR (400 MHz, d.sub.6-DMSO) .delta. 8.63 (s, 1H),
7.81 (s, J=1.6 Hz, 1H), 7.72 (s, J=8.4 Hz, 1H), 7.49 (dd, .J=8.8
and 2.0 Hz, 1H), 7.36 (s, 1H), 7.32-7.26 (m, 2H), 6.94 (dd, J=7.0
and 2.6 Hz, 1H), 5.97 (m, 1H), 3.81 (s, 3H), 1.61 (d, J=6.4 Hz,
3H), 0.92 (s, 9H), 0.15 (s, 3H), 0.10 (s,3H).
Step C--Methyl
5-(6-bromo-1H-benzimidazol-1-yl)-3-{[(1R)-1-(2-chloro-3-hydroxyphenyl)eth-
yl]oxy}-2-thiophenecarboxylate (Title Compound)
[0497] Methyl
5-(6-bromo-1H-benzimidazol-1-yl)-3-{[(1R)-1-(2-chloro-3-{[(1,1-dimethylet-
hyl)(dimethyl)silyl]oxy}phenyl)ethyl]oxy}-2-thiophenecarboxylate
(420 mg, 0.67 mmol) was deprotected using a procedure analogous to
Intermediate 3, Step F to give 343 mg of the desired product with
impurity. .sup.1H NMR (400 MHz, d.sub.6-DMSO) .delta. 10.22 (s,
1H), 8.63 (s, 1H), 7.76 (s, 1H), 7.71 (d, J=8.8 Hz, 1H), 7.48 (d,
J=8.8 Hz, 1H), 7.34 (s, 1H), 7.19-7.15 (m, 1H), 7.10 (d, J=7.6 Hz,
1H), 6.89 (d. J=7.6 Hz, 1H), 5.93 (m, 1H), 3.79 (s, 3H), 1.58 (d,
J=6.4 Hz, 3H).
INTERMEDIATE 7
Methyl
5-(5-brpmo-1H-benzimidazol-1-yl)-3-hydroxy-2-thiophenecarboxylate
##STR00075##
[0499] A solution of methyl
5-(5-bromo-1H-benzimidazol-1-yl)-3-[(phenylmethyl)oxy]-2-thiophenecarboxy-
late (15 g, 3.4 mmol) in 10 ml of TFA was heated to 50.degree. C.
After 6 h, the reaction was concentrated. The residue was dissolved
in MeOH and neutralized with 7N ammonia in MeOH. The slurry was
diluted with ether and filtered. The solid was washed with water
and air-dried to give 1.0 g of the title compound (85%).
[0500] In an alternative procedure, to a solution of methyl
5-(5-bromo-1H-benzimidazol-1-yl)-3-{[tert-bufyl(dimethyl)-silyl]oxy}thiop-
hene-2-carboxylate (12 g, 25 mmol) in 250 mL of THF cooied to
0.degree. C. was added a 1M solution of tetrabutylammonium fluoride
in THF (28 ml, 28 mmol). The reaction was quenched with water and
extracted with EtOAc. The combined organic layers were washed with
water, dried over MgSCU and concentrated onto silica gel. The crude
material was purified by flash column chromatography (0-5%
MeOH/DCM) to give the title compound.
[0501] .sup.1H NMR (400 MHz, d.sub.6-DMSO) .delta. 10.85 (s, 1H),
8.71 (s, 1H), 8.00 (s, 1H), 7.75 (d, J=8.8 Hz, 1H), 7.54 (d, J=8.4
Hz, 1H), 7.12 (s, 1H), 3.78 (s, 3H).
INTERMEDIATE 8
Methyl
5-(5-bromo-1H-benzimidazol-1-yl)-3-{[(1R)-1-(2-chloro-3-{[(1.1-dime-
thylethyl)(dimethyl)sllyl]oxy}phenyl)ethyl]oxy}-2-thiophenecarboxylate
##STR00076##
[0503] Methyl
5-(5-bromo-1H-benzimidazol-1-yl)-3-hydroxy-2-thiophenecarboxylate
(1.0 g, 2.9 mmol) and
(1S)-1-(2-chloro-3-{[(1,1-dimethylethyl)(dimethyl)silyl]-oxy}phenyl)ethan-
ol (1.0 g, 3.5 mmol) were coupled using a procedure analogous to
Intermediate 3, Step E to give 1.6 g of the title compound (89%).
.sup.1H NMR (400 MHz, d.sub.6-DMSO) .delta. 8.69 (s, 1H), 8.00 (s,
J=1.6 Hz, 1H), 7.59 (d, J=8.8 Hz, 1H), 7.50 (dd, J=8.8 and 1.6 Hz,
1H), 7.34-7.28 (m, 3H), 6.96 (dd, J=6.8 and 2.8 Hz, 1H), 5.93 (m,
1H), 3.81 (s, 3H), 1.60 (d, J=6.0 Hz, 3H), 0.94 (s, 9H), 0.17 (s,
3H), 0.13 (s, 3H).
INTERMEDIATE 9
Methyl
3-{[(1R)-1-(2-chloro-3-hydroxyphenyl)ethyl]ocy}-5-5-(6-methyl-3-pyr-
idinyl)-1H-benzimidazol-1-yl]-2-thiophenecarboxylate
##STR00077##
[0505] To a solution of methyl
5-(5-bromo-1H-benzimidazol-1-yl)-3-{[(1R)-1-(2-chloro-3-{[(1,1-dimethylet-
hyl)(dimethyl)silyl]oxy}phenyl)ethyl]oxy}-2-thiophenecarboxylate
(300 mg, 0.48 mmol) in 4.5 mL of DMA was added 2-picollne-5-boronic
acid hydrate (79 mg, 0.58 mmol), 1M Na.sub.2CO.sub.3 (1.44 ml, 1.44
mmol) and Cl.sub.2Pd(dppf) (41 mg, 0.05 mmol), and the reaction was
heated to 80.degree. C. The dark reaction was concentrated onto
silica gel and purified by flash column chromatography to give the
title compound, which was triturated into ether (147 mg, 59%).
.sup.1H NMR (400 MHz, d.sub.6-DMSO) .delta. 10.26 (s, 1H), 8.80 (s,
1H), 8.70 (s, 1H), 8.08 (s, 1H), 8.01 (dd, J=8.0 and 2.4 Hz, 1H),
7.68 (m, 2H), 7.34-7.32 (m, 2H), 7.20-7.11 (m, 2H), 6.91 (d, J=8.0
Hz, 1H), 5.93 (m, 1H), 3.70 (s, 3H), 2.49 (s, 3H), 1.60 (d, J=6.0
Hz, 3H).
INTERMEDIATE 10
Methyl
3-{[(1R)-1-(2-chloro-3-hydroxyphenyl)ethyl]oxy}-5-[5-(3-pyrldinyl)--
1H-benzimidazol-1-yl]-2-thiophenecarboxylate
##STR00078##
[0507] Methyl
5-(5-bromo-1H-benzimidazol-1-yl)-3-{[(1R)-1-(2-chloro-3-{[(1,1-dimethylet-
hyl)(dimethyl)silyl]oxy}phenyl)ethyl]oxy}-2-thiophenecarboxylate
(Intermediate 8, 500 mg, 0.80 mmol) and pyridine-3-boronic acid
(120 mg, 0.96 mmol) were coupled using a procedure analogous to
Intermediate 9 to give 213 mg of the title compound (53%). MS
m/z=508 (M+H).sup.+.
INTERMEDIATE 11A
Methyl
5-(1H-benzimidazol-1-yl)-3-{[(1R)-1-(2-chloro-3-hydroxyphenyl)ethyl-
]oxy}-2-thiophenecarboxylate
##STR00079##
[0509] Title compound (2.2 g) was prepared from methyl
5-(1H-benzimidazol-1-yl)-3-hydroxy-2-thiophenecarboxylate (J.
Heterocyclic Chem., 1987, 24, 1301-1303) (1.9 g, 7.0 mmol) and
(1S)-1-(2-chloro-3-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}phenyl)ethano-
l (Intermediate 17, 2.0 g, 7.0 mmol) using a procedure analogous to
Intermediate 2, Step C.
INTERMEDIATE 11B
Methyl
5-(1H-benzimidazol-1-yl)-3-[((1R)-1-{3-[(2-bromoethyl)oxy]-2-chlorp-
henyl}ethyl)oxy]-2-thiophenecarboxylate
##STR00080##
[0511] Methyl
5-(1H-benzimidazol-1-yl)-3-{[(1R)-1-(2-chloro-3-hydroxyphenyl)ethyl]oxy}--
2-thiophenecarboxylate (Intermediate 11A, 600 mg, 1.4 mmol) and
2-bromoethanof (120 .mu.L, 1.7 mmol) were coupled using a procedure
analogous to Example 4, Step A to give 529 mg of the title compound
(71%), .sup.1H NMR (400 MHz, d.sub.6-DMSO) .delta. 8.85 (s, 1H),
7.77 (d, J=7.2 Hz, 1H), 7.64 (d, J=8.0 Hz, 1H), 7.39-7.31 (m, 5H),
7.10 (dd, J=8.0 and 1.6 Hz, 1H), 5.98 (m, 1H), 4.40-4.37 (m, 2H),
3.81-3.79 (m. 5H), 1.81 (d, J=6.0 Hz, 3H).
INTERMEDIATE 12
Methyl
5-(5-chloro-1H-benzimidazol-1-yl)-3-({(1R)-1-[2-chloro--3-(4-piperi-
dinyloxy)phenyl]ethyl}exy)-2-thiophenecarboxylate
##STR00081##
[0513] 1,1-Dimethylethyl
4-({2-chloro-3-[(1R)-1-({5-(5-chloro-1H-benzimidazol-1-yl)-2-[(methyloxy)-
carbonyl]-3-thienyl}oxy)ethyl]phenyl}oxy)-1-piperidinecarboxylate
(Example 8, Step B, 690 mg, 1.07 mmol) was deprotected according to
the procedure analogous to Example 5, Step C to give the title
compound (576 mg, 99% yield). .sup.1H HMR (400 MHz, d.sub.6-DMSO)
.delta. 8.71 (s, 1H), 7.97 (br s, 1H), 7.86 (s, 1H), 7.67 (d, J=8.8
Hz, 1H), 7.41-7.32 (m, 4H), 7.18 (d, J=7.6 Hz, 1H), 5.95 (m, 1H),
4.89 (m. 1H), 3.80 (s, 3H), 3.17-3.12 (m, 2H), 3.01 (m, 2H), 2.00
(m, 2H), 1.78 (m, 2H), 1.59 (d, J=6.0 Hz, 3H).
INTERMEDIATE 13
Methyl
3-({(1R)-1-[2-chloro-3-(4-piperidinyloxy)phenyl]ethyl}oxy)-5-[5-(1--
methyl-1H-pyrazol-4-yl)-1H-benzimidazol-1-yl]-2-thiophenecarboxylate
##STR00082##
[0515] 1,1 -Dimethyleihyi
4-({2-chloro-3-[(1R)-1-({2-[(methyloxy)carbonyl]-5-[5-(1-rnethyl-1H-pyraz-
ol-4-yl)-1H-benzimidazol-1-yl]-3-thienyl}oxy)ethyl]phenyl}oxy)-1-piperidin-
ecarboxylate (Example 46, Step A, 1.0 g, 1.4 mmol) was deprotected
according to the procedure analogous to Example 5, Step C to give
850 mg of the title compound in quantitative yield. .sup.1H NMR
(400 MHz, d.sub.6-DMSO) .delta. 8.62 (s, 1H), 8.17 (s, 1H). 7.95
(s. 1H), 7.90 (s, 1H), 7.61-7.55 (m, 2H), 7.38-7.30 (m, 3H), 7.17
(d, J=8.0 Hz, 1H), 5.97 (m, 1H), 4.65 (m, 1H), 3.85 (s, 3H), 3.80
(s, 3H), 3.09 (m, 2H), 2.90 (m, 2H), 1.96 (m, 2H), 1.72 (m, 2H),
1.60 (d, J=6.4 Hz, 3H).
INTERMEDIATE 14
(1S)-1-(2-chloro-3-{[(1,1-dimethylethyl)(diphenyl)sylil]oxy}-4-ftuoropheny-
l)ethanol
##STR00083##
[0517] Step A--2-Chloro-3-{[(1,1
-dimethylethyl)(diphenyl)silyl]oxy}-4-fluorobenzaldehyde
##STR00084##
[0518] To a solution of 2-chloro-4-fluoro-3-(methyloxy)benzaldehyde
(which can be synthesized following the procedure found In PCT int.
Appi. WO 2004073612) (2.0 g, 11 mmol) in 80 mL of DCM was added a
1M solution of boron tribromide in DCM (42 mL, 4.0 mmol). After 16
h, the reaction was carefully quenched with the addition of ice
water and 1N HCl, and the mixture was stirred for 1 h. The layers
were separated and the aqueous phase was extracted with EtOAc. The
combined organic layers were extracted with 1N NaOH. These extracts
were acidified with cone. HCl. The aqueous phase was extracted with
DCM until TLC showed no more product. The organic extractions were
dried over MgSO.sub.4 and concentrated to an orange residue. The
orange residue was dissolved in 100 mL of DCM. Imidazole (1.4 g, 21
mmol) and ferf-hutyichlorodiphenylsilane (2.6 mL, 10 mmol) were
added, and the solution was stirred until the reaction was
complete. The solution was diluted with water and the two layers
were separated. The organic phase was washed with water and the
aqeous phase was back-extracted with DCM. The combined organic
solutions were dried over MgSO.sub.4 and concentrated onto silica
gel. The crude material was purified by flash column chromatography
(0-20% EtOAc: Hexanes) to give 2.2 g of the desired product (50%).
.sup.1H NMR (400 MHz, d.sub.6-DMSO) .delta. 10.24 (s, 1H),
7.65-7.63 (m, 4H), 7.48-7.39 (m, 7H), 7.22-7.18 (m, 1H), 1.07 (s,
9H).
Step
B--1-(2-Chloro-3-{[(1,1-dimethylethyl)(diphenyl)silyl]oxy}-4-fluoroph-
enyl)ethanol
##STR00085##
[0520] To a solution of
2-chloro-3-{[(1,1-dimethylethyl)(diphenyl)silyl]oxy}-4-fluorobenzaldehyde
(2.2 g, 5.3 mmol) in THF cooled to 0.degree. C. was added a 3M
solution of methyl magnesium chloride in THF (2.2 mL, 6.4 mmol).
When TLC showed the reaction to be complete, the reaction was
quenched with the addition of water. The aqueous solution was
extracted with DCM. The combined organic phases were washed with
water, dried over MgSO.sub.4 and concentrated onto silica gel. The
crude material was purified by flash column chromatography to give
1.8 g of the desired product (77%). .sup.1H NMR (400 MHz,
d.sub.6-DMSO) .delta. 7.65-7.59 (m, 4H), 7.45-7.36 (m, 8H),
7.14-7.11 (m, 1H), 7.02-6.97 (m, 1H), 5.35 (m, 1H), 4.96-4.93 (m,
1H), 1.24 (d, J=6.0 Hz, 3H), 1.05 (s, 9H).
Step
C--1-(2-Chloro-3-{[(1,1-dimethylethyl)(diphenyl)silyl]oxy}-4-fluoroph-
enyl)ethanone
##STR00086##
[0522] To a solution of
1-(2-chloro-3-{[(1,1-dimethylethyl)(diphenyl)silyl]oxy}-4-fluorophenyl)et-
hanol (1.8 g, 4.1 mmol) in DCM was added NaHCO.sub.3 (1.7 g, 20
mmol), water (0.07 ml, 4.1 mmol) and
[1,1,1-tris(acetyloxy)-1,1-dihydro-1,2-benziodoxol-3-(1H)-one (2.1
g, 4.9 mmol). When TLC showed the reaction to be complete, the
solution was quenched with the slow addition of 50 ml of saturated
aq. NaHCO.sub.3 solution and 50 ml of saturated aq.
Na.sub.3S.sub.2O.sub.3 solution, and the mixture was stirred
vigorously for 1.5 h. The layers were separated and the aqueous
phase was extracted with DCM. The combined organic phases were
washed with water, dried over MgSO.sub.4 and concentrated onto
silica gel. The crude material was purified by flash column
chromatography to give 1.70 g of the desired product (97%). .sup.1H
NMR (400 MHz, d.sub.6-DMSO) .delta. 7.63-7.61 (m, 4H), 7.47-7.37
(m, 6H), 7.26-7.23 (m, 1H), 7.13-7.08 (m, 1H), 2.52 (s, 3H), 1.04
(s, 9H).
Step
D--(1S)-1-(2-chloro-3-{[(1,1-dimethylethyl)(dlphenyl)silyl]oxy}-4-flu-
orophenyl)ethanol (Title Compound)
[0523]
1-(2-Chloro-3-{[(1,1-dimethylethyl)(diphenyl)silyl]oxy}-4-fluorophe-
nyl)ethanone (1.7 g, 4.0 mmol) was subjected to chiral reduction
using a procedure analogous to Intermediate 17, Step B to give the
title compound with an ee of 64%. The enantiomers were separated
using packed column SFC on a Diacel Chiralcel OJ-H column using a
mobile phase with 20% MeOH in carbon dioxide. The (S)-enantiomer
eluted first with a retention time of 3.6 min at a flow rate of 2
mL/min on the analytical instrument; the (R)-enantiomer elufed at
5.7 min. .sup.1H NMR (400 MHz, d.sub.6-DMSO) .delta. 7.65-7.59 (m,
4H), 7.45-7.36 (m, 6H), 7.14-7.11 (m, 1H), 7.02-6.97 (m, 1H), 5.35
(m, 1H), 4.96-4.93 (m, 1H), 1.24 (d, J=6.0 Hz, 3H), 1.05 (s,
9H).
INTERMEDIATE 15
1-(2-Chloro-3-{[(1,1-dimethylethyl)(diphenyl)silyl]oxy}-6-fluorophenyl)eth-
anol
##STR00087##
[0524] Step A--2-Chloro-3-{[(1,1
-dimethylethyl)(diphenyl)silyl]oxy}-6-fluorobenzaldehyde
##STR00088##
[0526] 2-Chloro-3-{[(1,1
-dimethylethyl)(diphenyl)silyl]oxy}-6-fluorobenzaldehyde was
prepared from 2-chloro-6-fluoro-3-methoxybenzaldehyde using a
procedure analogous to Intermediate 14, Step A. .sup.1H NMR (400
MHz, d.sub.6-DMSO) .delta. 10.29 (s, 1H), 7.88-7.85 (m, 4H),
7.52-7.43 (m, SH), 7.07-7.02 (m, 1H), 7.88-7.65 (m, 1H), 1.06 (s,
9H).
Step
B--1-(2-Chloro-3-{[(1,1-dimethylethyl)(diphenyl)silyl]oxy}-6-fluoroph-
enyl)ethanol (Title Compound)
[0527]
2-Chloro-3-{[(1,1-dimethylethyl)(diphenyl)silyl]oxy}-6-fluorobenzal-
dehyde was methylated using a procedure analogous to Intermediate
14, Step B to give 11.8 g of the title compound (75% over 3 steps).
.sup.1H NMR (400 MHz, d.sub.6-DMSO) .delta. 7.85-7.63 (m, 4H),
7.50-7.42 (m, 6H), 6.82-6.77 (m, 1H), 6.32-8.28 (m, 1H), 5.33 (d,
J=4.4 Hz, 1H), 5.28-5.22 (m, 1H), 1.41 (d, J=6.4 Hz, 3H), 1.04
(s,9H),
INTERMEDIATE 16
Methyl
3-hydroxy-5-[5-(1-methyl-1H-pyrazol-4-yl)-1-H-benzimidazol-1-yl]-2--
thiophenecarboxylate
##STR00089##
[0528] Step A--Methyl
5-[5-(1-methyl-1H-pyrazol-4-yl)-1H-benzimidazol-1-yl]-3-[(phenylmethyl)ox-
y]-2-thiophenecarboxylate
##STR00090##
[0530] To a solution of methyl
5-(5-bromo-1H-benzimidazol-1-yl)-3-[(phenylmethyl)oxy]-2-thiophenecarboxy-
late (Intermediate 28, 2.8 g, 6.3 mmol) in DMA (60 mL) and 1N
aqueous NasCQa (20 ml) was added
1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole
(1.6 g, 7.5 mmol), followed by Cl.sub.2Pd(dppf) (0.60 g, 0.75
mmol), and the reaction mixture was heated to 80.degree. C. for 1
h. The solution was filtered cooled to rt, diluted with EtOAc (250
mL) and washed with water (3.times.200 mL). The organic layer was
dried over MgSO.sub.4, filtered, and silica gel (10 g) was added.
The volafiies were evaporated under reduced pressure, and the
pre-adsorbed solids were loaded info a solid loading cartridge and
subjected to a gradient elution using DCM (100%) to
DCM:MeOH:ammonium hydroxide (90:10:1) using a RediSep silica gel
cartridge (40 g; ISCO). The appropriate fractions were combined and
concentrated under reduced pressure to give 1.6 g (3.6 mmol) of the
title compound. .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 8.03 (s,
1H), 7.90 (s, 1H), 7.79 (s, 1H), 7.64 (s, 1H), 7.54-7.32 (m, 7H),
6.88 (s, 1H), 5.32 (s, 2H), 3.96 (s, 3H), 3.90 (s, 3H).
Step B--Methyl
3-hydroxy-5-[5-(1-methyl-1H-pyrazol-4-yl)-1H-benzimidazol-1-yl]-2-thiophe-
necarboxylate (Title Compound)
[0531] To methyl 5-(5-(1-methyl-1H-pyrazol-4-yl)-1H-benzimidazol-1
-yl]-3-[(phenylmethyl)oxy]-2-thiophenecarboxylate (1.6 g, 3.6 mmol)
was added TFA (20 mL) and the mixture was stirred at rt for 18 h.
The solution was concentrated to give an oil and DCM (20 mL) was
added resulting in the precipitation of a solid. The acid was
neutralized by addition of 7N ammonia in MeOH and the solution
diluted with DCM and MeOH so that all the solid dissolved. Silica
gel (10 g) was added and the volatiies were evaporated under
reduced pressure, and the pre-adsorbed solids were loaded into a
solid loading cartridge and subjected to a gradient eiufion using
DCM (100%) to DCM:MeOH:ammonium hydroxide (90:10:1) using a RediSep
silica gel cartridge (40 g; ISCO). The appropriate fractions were
combined and concentrated under reduced pressure to give 1.3 g (3.6
mmol) of the title compound as a white solid. .sup.1H NMR (400 MHz,
DMSO-d.sub.6): .delta. 8.64 (s, 1H), 8.17 (s, 1H), 7.96 (d, J=1.1
Hz, 1H), 7.91 (d, J=0.7 Hz, 1H), 7.74 (d, J=8.4 Hz, 1H), 7.60 (dd,
J=8.4, 1.7 Hz, 1H), 7.11 (s, 1H), 3.84 (s, 3H), 3.76 (s, 3H).
ALTERNATIVE ROUTE TO INTERMEDIATE 16
Step A: Methyl
5-[5-(1-methyl-1H-pyrazol-4-yl)-1H-banzimidazol-yl]-3-[(phenylmethyl)oxy]-
-2-thiophenecarboxylate
Step A1--4-(1-Methyl-1H-pyrazol-4-yl)-2-nitroaniline
##STR00091##
[0533] 4-Bromo-2-nitroaniline (1.0 g, 4.6 mmol) and
1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole
(1.1 g, 5.1 mmol) were dissolved in 13 ml of DMA, placed under
nitrogen, and heated to 80.degree. C. A 2N aqueous solution of
Na.sub.2CO.sub.3 was added, followed by PdCl.sub.2(dppf)
dichloromethane adduct (0.076 g, 0.90 mmol). Reaction was stirred
at 80.degree. C. for 1 h and then cooled to rt, poured into 150 ml
of water and extracted with EtOAc (3.times.), Combined organics
were dried over anhydrous MgSO.sub.4, filtered, concentrated onto
silica gel, and purified by flash chromatography using 0-50%
EtOAc/hexanes. 4-(1 -Methyl-1H-pyrazol-4-yl)-2-nitroaniline was
isolated as a bright orange solid (1.0 g, 99%). MS (ESI): 219
[M+H].sup.+.
Step A2--4-(4-Iodo-3-nitrophenyl)-1-methyl-1H-pyrazole
##STR00092##
[0535] Iodine (3.5 g, 14 mmol), acetonitrile (40 ml), and
test-butyl nitrite (0.82 mL, 6.9 mmol) were combined under N.sub.2
in a 3-neck round bottom flask fitted with reflux condenser and an
addition funnel. The mixture was stirred at rt. To the addition
funnel was added a solution of
4-(1-methyl-1H-pyrazol-4-yl)-2-nitroaniline (1.0 g, 4.6 mmol)
dissolved in DCM (20 mL) and DMSO (2 mL). This solution was added
dropwise to flask at rt. The reaction was placed in a 60.degree. C.
oil bath and after 5-10 minutes bubbles began appearing. The
reaction was stirred for an additional 2 h at 60.degree. C. and
then the heat was turned off and the reaction stirred at rt
overnight. Aqueous sodium sulfite solution was added and the
mixture was extracted with EtOAc (3.times.). Combined organic
layers were dried over anhydrous MgSO.sub.4, filtered, concentrated
onto silica gel and purified by flash chromatography using 20-60%
EtOAc/hexanes. 1.43 g (95%) of
4-(4-iodo-3-nitrophenyl)-1-methyl-1H-pyrazole was isolated as a
yellow solid. MS (ESI): 330, 331 [M+H].sup.+.
Step A3--Methyl
5-{[4-(1-methyl-1H-pyrazol-4-yl)-2-nitrophenyl]amino}-3-[(phenylmethyl)ox-
y]-2-thiophenecarboxylate
##STR00093##
[0537] Methyl 5-amino-3-[(phenylmethyl)oxy]-2-thiophenecarboxylate
(1.0 g, 3.8 mmol) and 4-(4-iodo-3-nitrophenyl)-1-methyl-1H-pyrazole
(1.3 g, 3.8 mmol) were dissolved In anhydrous toluene (30 mL) and
degassed with N.sub.2 gas for 30 min. Cesium carbonate (6.2 g, 19
mmol) was added followed by XANTPHOS and trisdibenzyiideneacetone
palladium (II). The mixture was heated to 80.degree. C. for 2 h and
was then absorbed directly onto silica gel and flash
chromatographed using 0-50% EtOAc/CH.sub.2Cl.sub.2. 1.62 g (98%) of
methyl
5-{[4-(1-methyl-1H-pyrazol-4-yl)-2-nitrophenyl]amlno}-3-[(phenylmethyl)ox-
y]-2-thiophenecarboxylate was isolated as a dark red/purple solid.
MS (ESI): 485 [M+H].sup.+.
Step A4--Methyl
5-[5-(1-methyl-1H-pyrazol-4-yl)-1H-benzoimidazol-1-yl]-3-[(phenylmethyl)o-
xy]-2-thiophenecarboxylate (Title Compound)
[0538] Methyl
5-{[4-(1-methyl-1H-pyrazoi-4-yl)-2-nitrophenyl]amino}-3-[(phenylmethyl)ox-
y]-2-thiophenecarboxylate (1.0 g, 2.2 mmol) from a different batch
than that made in Step A3, was dissolved In MeOH (30 mL).
Trimethylorthoformate (6.0 mL, 54 mmol) was added followed by
formic acid (0.81 ml, 21.5 mmol). Zinc dust (0.70 g, 11 mmol) was
added and the reaction mixture was heated to 70.degree. C. for 2 h
and then cooled to rt. The reaction mixture was filtered through a
pad of celite which was then washed with 20% MeOH/DCM. The crude
reaction mixture was concentrated to remove the MeOH and the
remaining mixture was poured into half-saturated aqueous NaHCOs
solution and then extracted with a mixture of 4:1 DCM:i-PrOH. The
combined organics were dried over anhydrous MgSO.sub.4 and purified
by flash chromatography to give 850 mg (89%) of the title compound,
methyl
5-[5-(1-methyl-1H-pyrazol-4-yl)-1H-benzimidazol-1-yl]-3-[(phenylmethyl)ox-
y]-2-thiophenecarboxylate. MS (ESI): 445 [M+H].sup.+
ALTERNATIVE ROUTE TO INTERMEDIATE 16
Methyl
3-hydroxy-5-[5-(1-methyl-1H-pymzol-4-yl)-1H-benzimidazol-1-yl]-2-th-
iophenecarboxyJate
##STR00094##
[0540] Methyl
5-(5-bromo-1H-benzimidazol-1-yl)-3-{[(1,1-dimeihylethyl)(dimethyl)silyl]o-
xy}-2-thiophenecarboxylate (20 g, 43 mmol) and
1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaboroian-2-yl)-1H-pyrazole
(11 g, 53 mmol) were dissolved in DMF (285 mL) with stirring in a
flask equipped with an overhead stirrer, reflux condenser, and
thermometer. The solution was degassed for 15 min by bubbling
N.sub.2 through the stirring solution. PdCl.sub.2 (dppf) (0.53 g,
0.73 mmol) was added followed by 1.6 M K.sub.2CO.sub.3 (142 mL),
The reaction was heated to 80.degree. C. and stirred for 2 h. The
reaction was cooled to rt and transferred to 2L flask. The mixture
was acidified with acetic acid and then diluted with 1L of water.
The product was collected by filtration to give 14.3 g (94%) of the
title compound as a solid. MS (ESI): 355 [M+H]+.
INTERMEDIATE 17
(1S)-1-(2-chloro-3-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-phenyl)ethano-
l
##STR00095##
[0541] Step
A--1-(2-Chlcro-3-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}phenyl)ethanone
##STR00096##
[0543] To a solution of 1-(2-chloro-3-hydroxyphenyl)ethanone (8.4
g, 50 mmol) which can be synthesized according to the procedure in
Proceedings of the Indiana Academy of Science 1883, 92, 145-151 and
imidazole (3.8 g, 55 mmol) in DCM (100 ml) was added
chloro(fert-butyl)dimethylsilane (8.3 g, 55 mmol). The solution was
stirred for 1 h and silica (20 g) was added. The volatiles were
evaporated under reduced pressure, and the pre-adsorbed solids were
loaded into a solid loading cartridge and subjected to a gradient
efution using hexanes (100%) to hexanes:EtOAc (90:10) using a
RediSep silica gel cartridge (120 g; ISCO). The appropriate
fractions were combined and concentrated under reduced pressure to
give 7.1 g (25 mmol) of the title compound. .sup.1H NMR (400 MHz,
CDCl.sub.3): .delta.7.16 (dd, J=8.0, 7.7 Hz, 1H), 7.04 (dd, J=7.7,
1.5 Hz, 1.H), 6.96 (dd, 8.0, 1.5 Hz, 1H), 2.60 (s, 3H), 1.02 (s,
9H), 0.23 (s, 6H).
Step
B--(1S)-1-(2-chloro-3-{[(1,1-dimethylethyl)(dimethyl)silyI]oxy}phenyl-
)ethanol (Title Compound)
[0544] To a solution of borane, dimethylsulfide complex (1.8 mt, 30
mmol) in THF (10 rnL) was added a 1H-solution of
(R)-1-methyl-3,3-diphenyltetrahydro-3H-pyrrolo[1,2-c][1,3,2]oxazaborole
in toluene (0.25 ml, 0.25 mmol). To this mixture was slowly added
over 2 h a solution of
1-(2-chloro-3-{[(1,1-dimethylethyl)(dimethyl)sliyl]oxy}phenyl)ethanon
in THF (50 mL). The solution was stirred an additional 18 h then
MeOH was added dropwise to quench any excess borane. The volatiles
were evaporated under reduced pressure, and DCM was added (50 mL).
The resulting white solid was removed by filtration and the silica
was added to the filtrate. The volatiles were evaporated under
reduced pressure and the pre-adsorhed solids were loaded Into a
solid loading cartridge and subjected to a gradient eiution using
hexanes (100%) to hexanes:EtOAc (80:20) using a RediSep silica gel
cartridge (120 g; ISGO). The appropriate fractions were combined
and concentrated under reduced pressure to give 8.8 g (24 mmol) of
the title compound as a white solid. .sup.1H NMR (400 MHz,
CDCl.sub.3): .delta. 7.19-7.12 (m, 2H), 6.81-6.79 (m, 1H),
5.30-5.25 (m, 1H), 1.93 (d, J=3.6 Hz, 1H) 1.47 (d, J=6.4 Hz, 3H),
1.02 (s, 9H), 0.21 (s, 3H), 0.21 (s, 3H).
[0545] Alternatively, Intermediate 17 can be prepare by the
following method.
Step
A--2-chloro-3-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}benzaldehyde
##STR00097##
[0547] To a solution of 2-chloro-3-hydroxybenzaldehyde (30.0 g, 192
mmol) which was purchased from Stgma-Aidrich and imidazole (15.6 g,
230 mmol) in THF (200 ml) was added
chloro(tert-butyl)dimethylsiiane (30.0 g, 200 mmol). The solution
was stirred for overnight. The solution was poured into water and
extracted with ether (2.times.300 ml). The ether layers were dried
(MgSO.sub.4), filtered and the volatiles removed under reduced
pressure to give 51.0 g (188 mmol) of the title compound. .sup.1H
NMR (400 MHz, CDCl.sub.3): .delta. 10.49 (s, 1H), 7.54 (dd, J=7.7,
1.6 Hz, 1H), 7.24 (dd, J=8.0, 7.7 Hz, 1H), 7.13 (dd, J=8.0, 1.6 Hz,
1H), 1.05 (s, 9H), 0.25 (s, 6H).
Step
B--(1S)-1-(2-chloro-3-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}phenyl-
)ethanol (Title Compound)
[0548] To a solution of
2-chloro-3-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-benzaldehyde
(50.0 g, 184 mmol) in THF (500 mL) cooled to -78.degree. C. was
added a 3M solution of methylmagnesiumchioride in THF (67.0 mL 202
mmol). The solution was allowed to warm to rt and then water was
added to quenched the reaction. The solution was extracted with
ether, dried (MgSO.sub.4), filtered and the volatiles were
evaporated under reduced pressure to give 50.0 g of the racemic
title compound as a colorless oil. The enantiomers were separated
using SFC on a 3.times.25 cm OJ-H column with a 90 g/min total
flow, 92/8 CO2/MeOH, 103bar, 27.degree. C. The desired (S)
enantiomer eluted first under these separation conditions. Upon
standing, the enantiopure title compound solidified.
INTERMEDIATE 18
Methyl
3-([(1R)-1-{2-chloro-3-hydroxyphenyl)ethyl]oxy}-5-(5-(1-methyl-1H-p-
yrazol-4-yl)-1H-benzimidazol-1-yl]-2-thiophenecarboxylate
##STR00098##
[0549] Step A--Methyl
3-{[(1R)-1-(2-chloro-3-{[(1,1dimethylethyl)(dimethyl)silyl]oxy}phenyl)eth-
yl]oxy}-5-[5-(1-methyl-1H-pyrazol-4-yl)-1H-benzimidazol-1-yl]-2-thiophenec-
arboxylate
##STR00099##
[0551] To a slurry of methyl
3-hydroxy-5-[5-(1-methyl-1H-pyrazol-3-yl)-1H-henzimidazol-1-yl]-2-thiophe-
necarboxylate (Intermediate 16, 0.71 g, 2.0 mmol) and
(1S)-1-(2-chloro-3-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}phenyl)-ethan-
ol (Intermediate 17, 0.63 g, 2.2 mmol) in DCM (20 ml) was added
triphenylphosphine (1.1 g, 4.0 mmol) and di-tert-hutyl
azodicarboxylate (0.92 g, 4.0 mmol). The clear, yellow solution was
stirred 1 h then silica (5 g) was
[0552] > added. The volatiles were evaporated under reduced
pressure and the pre-adsorbed solids were loaded into a solid
loading cartridge and subjected to a gradient elution using DCM
(100%) to DCM:MeOH:ammonium hydroxide (90:10:1) using a RedlSep
silica gel cartridge (40 g; ISCO). The appropriate fractions were
combined and concentrated under reduced pressure to give 1.1 g (1.8
mmol) of the title compound as a white solid. 1H NMR (400 MHz,
CDCl.sub.3); .delta. 7.98 (s, 1H), 7.87 (s, 1H), 7.78 (s, 1H), 7.64
(s, 1H), 7.46-7.44 (m, 2H), 7.26-7.23 (m, 1H), 7.16 (dd, J=7.9, 7.8
Hz 1H), 6.85-6.83 (m, 1H), 5.82 (q, J=6.3 Hz, 1H), 3.96 (s, 3H),
3.91 (s, 3H), 1.72 (d, J=6.3 Hz, 3H), 1.01 (s, 9H), 0.21 (s, 3H),
0.19(s, 3H).
Step B--Methyl
3-{[(1R)-1-(2-chloro-3-hydroxyphenyl)ethyl]oxy}-5-[5-(1-methyl-1H-pyrazol-
-4-yl)-1H-benzimidazol-1-yl]-2-thiophenecarboxylate (Title
Compound)
[0553] To a solution of methyl
3-{[(1R)-1-(2-chloro-3-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}phenyl)et-
hyl]oxy}-5-[5-(1-methyl-1H-pyrazol-4-yl)-1H-benzimidazol-1-yl]-2-thiophene-
carboxylate (0.72 g, 1.2 mmol) in THF (5 mL) was added a solution
of 1N tetrabulylamrnonium fluoride in THF (1.4 mL, 1.4 mmol). After
10 min, silica (5 g) was added, the volatiles were evaporated under
reduced pressure and the pre-adsorbed solids were loaded into a
solid loading cartridge and subjected to a gradient elution using
DCM (100%) to DCM:MeOH:ammonium hydroxide (80:20:1) using a RediSep
silica gel cartridge (12 g; ISCO). The appropriate fractions were
combined and concentrated under reduced pressure to give 0.53 g
(1.0 mmol) of the title compound as a light yellow foam. 1H NMR
(400 MHz, CDCl.sub.3): .delta. 7.97 (s, 1H), 7.87 (s, 1H), 7.78 (s,
1H), 7.63 (s, 1H), 7.46-7.44 (m, 1H), 7.38 (d, J=7.8 Hz, 1H),
7.24-7.20 (m, 2H), 7.01-6.97 (m, 1H), 6.64 (s, 1H) 5.73 (q, J=6.4
Hz, 1H), 3.95 (s, 3H), 3.91 (s, 3H), 1.73 (d, J=6.4 Hz, 3H).
INTERMEDIATE 19
Methyl
5-[5,6-bis(methyloxy)-1H-benzimidazol-1-yl]-3-{[(1R)-1-(2-chloro-3--
hydroxyphenyl)ethyl]oxy}-2-thiophenecarboxylate
##STR00100##
[0554] Step A--Methyl
5-[5,6-bis(methiloxy)-1H-benzimidazol-1-yl]-3-{[(1R)-1-(2-chloro-3-{[(1,1-
-dimethylethyl)(dimethyl)silyl]oxy}phenyl)ethyl]oxy}-2-thiophenecarboxylat-
e
##STR00101##
[0556] Methyl
5-[5,6-bis(methyloxy)-1H-benzimidazol-1-yl]-3-hydrcxy-2-thiophenecarboxyl-
ate (which can be synthesized following the procedure found in PCT
Int. Appl. WO 2004073612) (3.3 g, 10 mmol) and
(1S)-1-(2-chloro-3-{[(
1,1-dimethylethyl)(dimethyl)silyl]oxy}phenyl)ethanol (Intermediate
17, 2.9 g, 10 mmol) were coupled using a procedure analogous to
Intermediate 18, Step A to give 4.8 g of the desired product (80%)
1H NMR (400 MHz, CDCl.sub.3): .delta. 7.85 (s, 1H), 7.27-7.14 (m,
3H), 6.92 (s, 1H), 6.82 (d, J=8.0 Hz, 1.6, 1H), 6.64 (s, 1H), 5.80
(q, J=6.4 Hz, 1H), 3.94 (s, 3H). 3.92 (s, 3H), 3.88 (s, 3H), 1.72
(d, J=6.4 Hz, 3H).
Step B--Methyl
5-[5,6-bis(methyloxy)-1H-benzimidazol-1-yl]-3-{[(1R)-1-(2-chloro-3-hydrox-
yphenyl)ethyl]oxy}-2-thiophenecarboxylate (Title Compound)
[0557] Methyl
5-[5,6-bls(methyloxy)-1H-benzimidazol-1-yl]-3-{[(1R)-1-(2-chloro-3-{[(1,1-
-dimethylethyl)(dimethyl)siiyl]oxy}phenyl)ethyl]oxy}-2-thiophenecarboxylat-
e (4.8 g, 8.0 mmol) was deprotected using a procedure analogous to
Intermediate 18, Step B to give 2.0 g (51%) of the title compound.
1H HMR (400 MHz, DMSO): .delta. 10.29 (s, 1H), 8.42 (s, 1H), 7.33
(s, 1H), 7.24 (s, 1H), 7.19 (dd, J=8.0, 7.8 Hz, 1H) 7.10 (dd,
J=7.8, 1.4 Hz, 1H), 7.06 (s, 1H), 6.90 (dd, J=8.0, 1.4, 1H), 5.97
(q, J=6.4 Hz, 1H), 3.82 (s, 3H), 3.81 (s, 3H), 3.80 (s, 3H), 1.61
(d, J=6.4 Hz, 3H).
lntermediate 20
Methyl
3-{[(1R)-1-(2-chloro-3-hydroxyphenyl)ethyl]oxy}-5-[5-(2-methyl-4-py-
ridinyl)-1H-benzimidazol-1-yl]-2-thiophenecarboxylate
##STR00102##
[0559] Methyl
5-(5-bromo-1H-benzimidazol-1-yl)-3-{[(1R)-1-(2-chloro-3-{[(1,1-dimethylet-
hyl)(dimethyl)silyl]oxy}phenyl)ethyl]oxy}-2-thiophenecarboxylate
(Intermediate 8, 400 mg, 0.64 mmol) and
(2-methyl-4-pyridinyl)boronic acid (105 mg, 0.77 mmol) were coupled
using a procedure analogous to Intermediate 9 to give the title
compound (126 mg, 38%). .sup.1H NMR (400 MHz, d.sub.6-DMSO) .delta.
8.54 (s, 1H), 8.09 (s, 1H), 7.62-7.22 (m, 8H), 7.03 (dd, J=6.9, 2.5
Hz, 1H), 6.69 (s, 1H) 5.77 (q, J=6.4 Hz, 1H), 3.93 (s, 3H), 2.64
(s, 3H), 1.77 (d, J=6.4 Hz, 3H).
INTERMEDIATE 21
Methyl
5-(6-cbloro-1H-benzimidazol-1-yl)-3-{[(1R)-1-(2-chloro-3-hydroxyphe-
nyl)ethyl]oxy}-2-thiophenecarboxylate
##STR00103##
[0560] Step A--Methyl
5-(6-chloro-1H-benzimidazol-1-yl)-3-{[(1,1-dimethylethyl)-(dimethyl)silyl-
]oxy}-2-thiophenecarboxylate
##STR00104##
[0562] To a mixture of chlorobenzimidazole (7.0 g, 46 mmol) and
methyl 2-chloro-3-oxo-2,3-dihydro-2-thiaphenecarboxylate (9.8 g, 51
mmol) in 400 mL of CHCl.sub.3was added N-methylimidazole (5.5 mL,
69 mmol). After 18 h, tert-butylchlorodimethylsilane (6.9 g, 46
mmol) and N-methylimidazole (3.7 mL, 46 mmol) was added. The
reaction mixture was diluted with water and the layers were
separated. The aqueous phase was extracted with DCM, The combined
organic layers were washed with water, dried over MgSO.sub.4 and
concentrated onto silica gel. The crude material was purified by
flash column chromatography (0-100% 25% EtOAc/hexanes) to give the
desired product. .sup.1H NMR (400 MHz, d.sub.6-DMSO) .delta. 8.74
(s, 1H), 7.80 (d, J=8.6 Hz, 1H), 7.78 (d, J=2.1 Hz, 1H), 7.40 (dd,
J=8.6 and 2.1 Hz, 1H), 7.28 (s, 1H), 3.77 (s, 3H), 1.00 (s, 9H),
0.27 (s, 6H).
Step B--Methyl
5-(6-chloro-1H-benzimidazol-1-yl)-3-hydroxy-2-thiophene-carboxylate
##STR00105##
[0564] Methyl
5-(6-chloro-1H-benzimidazol-1-yl)-3-{[(1,1-dimethylethyl)-(dimethyl)silyl-
]oxy}-2-thiophenecarboxylate (2.0 g, 4.7 mmol) was deprotected
using a procedure analogous to Intermediate 2, Step B to give 1.4 g
of the desired product (97%). .sup.1H NMR (400 MHz, d.sub.6-DMSO)
.delta. 8.65 (s, 1H), 7.77 (d, J=1.9 Hz, 1H), 7.77 (d, J=8.7 Hz,
1H), 7.36 (dd, J=8.7 and 1.9 Hz, 1H), 6.96 (s, 1H), 3.70 (s,
3H).
Step C--Methyl
5-(6-chloro-1H-benzimidazol-1-yl)-3-{[1R)-1-(2-chloro-3-hydroxyphenyl)eth-
yl]oxy}-2-thiophenecarboxylate (Title Compound)
[0565] Methyl
5-(6-chloro-1H-benzimidazol-yl)-3-{[(1R)-1-(2-chloro-3-hydroxyphenyl)ethy-
l]oxy}-2-thiophenecarboxylate (500 mg, 1.7 mmol) and
(1S)-1-(2-chloro-3-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}phenyl)ethano-
l (600 mg, 2.0 mmol) were coupled using a procedure analogous to
Intermediate 2, Step C to give 450 mg of the desired product (77%).
.sup.1H NMR (400 MHz, d.sub.6-DMSO) .delta. 10.24 (s, 1H), 8.65 (s,
1H), 7.77 (d, J=8.4 Hz, 1H), 7.63 (d, .J=1.6 Hz, 1H), 7.36 (dd,
J=8.6, 2.0 Hz, 1H), 7.34 (s, 1H), 7.17 (dd, J=8.0, 7.7 Hz 1H), 7.10
(dd, J=8.0, 1.6 Hz, 1H), 6.89 (dd, J=8.0, 1.6 Hz, 1H), 5.94 (q,
J=6.4 Hz, 1H), 3.79 (s, 3H), 1.58 (d, J=6.4 Hz, 3H).
INTERMEDIATE 22
1.1-Dimethylethyl
4-({2-chloro-3-[(1S)-1-hydroxyethyl]phenyl}oxy)-1-piperidinecarboxylate
##STR00106##
[0566] Step A--1,1-Dimethylethyl
4-[(3-acetyl-2-chlorophenyl)oxy]-1-piperidinecarboxylate
##STR00107##
[0568] To a solution of 2-chloro-3-hydroxyacetophenone (35 g, 205
mmol) in ether (500 mL) was added 4-hydroxy-N-Boc-piperdine (45 g,
225 mmol), triphenylphosphine (65 g, 246 mmol) and finally
di-tert-butylazodicarboxylate (57 g, 246 mmol) at such a rate that
the solvent barely refluxes (over .about.15 min). The reaction was
stirred for 2 h, filtered to remove the triphenylphosphine oxide
which precipitated during the reaction, then washed with 1N NaOH
(200 mL), water (200 mL) and brine (200 mL). The organics were
dried over MgSO.sub.4, filtered and concentrated onto silica (100
g) on a rotovap. The preabsorbed solids were split into two batches
and each purified on a 330 g ISCO column using a gradient of 100%
DCM for 60 min to 80:20 DCM:EtOAc over 30 min, hold at 80:20 for 30
min. The appropriate fractions were combined, and the solvent
removed to obtain 55 g of the title compound as a white solid
(76%). 1H NMR (400 MHz, DMSO): .delta. 7.37-7.33 (m, 2H), 7.17-7.13
(m, 1H), 4.74-4.67 (m, 1H), 3.97-3.90 (m, 2H), 3.32-3.23 (m, 2H),
2.53 (s, 3H), 1.91-1.82 (m, 2H), 1.63-1.53 (m, 2H), 1.39 (s,
9H).
Step B--1,1-Dimethylethyl
4-({2-chloro-3-[(1S)-1-hydroxyethyl]phenyl}oxy)-1-piperidinecarhoxylate
(Title Compound)
[0569] To a solution of borane-dimethylsuifide complex (7.2 ml, 72
mmol) in THF (100 ml) was added a 1M solution of
(R)-1-methyl-3,3-diphenyltetrahydro-3H-pyrrolo[1,2-c][1,3,2]oxazaborole
in toluene (1.0 mL, 1.0 mmol). To this mixture was slowly added
over 2 h a solution of 1,1-dimethylethyl
4-[(3-acetyi-2-chlorophenyl)oxy]-1-piperidinecarboxylate (36 g, 102
mmol) in THF (300 mL). The solution was stirred an additional 18 h
then MeOH was added dropwise to quench any excess borane. To the
solution was added silica (100 g) and the volatiles were evaporated
under reduced pressure. The preabsorbed solids were purified In
four batches on 120 g ISCO columns using a gradient of 100% hexanes
to 55:45 hexanes:EtOAc over 40 min. After combining the fractions
and removing the solvent, 26 g of the title compound was obtained
as a white solid (70%). Chirai analysis showed 92% ee (AD-H
column). The title compound could be further purified to >99% ee
using SFC on a 3.times.25 cm AD-H column with a 90 g/min total
flow, 90/10 CO2/MeOH, 103 bar, 27.degree. C. The desired (S)
enantiomer eiufed first under these separation conditions. 1H NMR
(400 MHz, DMSO): .delta. 7.34-7.22 (m, 2H), 7.13-7.09 (m, 1H), 5.33
(d, J=4.3 Hz, 1H), 5.10-5.01 (m, 1H), 4.71-4.62 (m, 1H), 3.66-3.54
(m, 2H), 3.37-3.26 (m, 2H), 1.96-1.82 (m, 2H), 1.70-1.53 (m, 2H),
1.44 (s, 9H), 1.32 (d, J=6.3 Hz, 3H).
INTERMEDIATE 23
Methyl
3-{[(1R)-1-(2-chloro-3-hydroxyphenyl)ethyl]oxy}-5-(6-[(methylsulfon-
yl)methyl]-1H-benzimidazol-1-yl]-2-thiophenecarboxylate
##STR00108##
[0570] Step A--Methyl
5-[6-(cbtoromethyl)-1H-benzimidazol-1-yl]-3-{[(1R)-1-(2-chlorophenyl)ethy-
l]oxy}-2-thiophenecarboxylate
##STR00109##
[0572] To a stirred solution of methyl methyl
3-{[(1R)-1-(2-chlorophenyl)ethyl]oxy}-5-[6-(hydroxymethyl)-1H-benzimidazo-
l-1-yl]-2-thiophenecarboxylate (Intermediate 32, 3.0 g, 6.8 mmol),
and triphenylphosphine (2.4 g, 9.1 mmol) in DCM (85 ml) was added
AAchlorosuccinimlde (1.2 g, 9.1 mmol). The reaction was then heated
to reflux and stirred for 20 min, then cooled to rt. The reaction
was diluted with DCM (400 mL) and half saturated aqueous brine
solution (150 ml). The aqueous layer was then extracted with
CH.sub.2Cl.sub.2. The combined organic layers were dried over
Na.sub.2SO.sub.4, concentrated under vacuum and purified by silica
gel chromatography (0 to 50% EtOAc:DCM) to give 2.86 g (90%) of the
title compound as a white solid. MS (ESI): 461 [M+H].sup.+.
Step B--Methyl
3-{[(1R)-1-(2-chlorophenyl)ethyl]oxy}-5-{6-[(methylsulfonyl)methyl]-1H-be-
nzimidazol-1-yl}-2-thiophenecarboxylate
##STR00110##
[0574] A mixture of methyl
5-[6-(chloromethyl)-1H-bensmidazol-1-yl]-3-{[(1R)-1-(2-chbrophenyl)ethyl]-
oxy}-2-thiophenecarboxylate (0.68 g, 1.5 mmol), methanesulfonic
acid sodium salt (0.19 g, 1.3 mmol) and EtOH (15.0 ml) was added to
a high-pressure glass reaction flask. The flask was sealed, then
heated to 85.degree. C. for approx. 16 h. The flask was cooled to
rt, opened, and the reaction mixture concentrated under vacuum,
then purified by silica gel chromatography (0 to 50% EtOAc:DCM) to
give 0.61 g (92%) of the title compound as a light yellow solid. MS
(ESI): 505 [M+H].sup.+.
Step C--Methyl
3-hydroxy-5-{6-[(methylsulfonyl)methyl]-1H-benzimidazol-1
-yl}-2-thiophenecarboxylate
##STR00111##
[0576] To methyl
3-{[(1R)-1-(2-chlorophenyl)ethyl]oxy}-5-{6-[(methylsulfonyl)methyl]-1H-be-
nzimidazol-1-yl}-2-thiophenecarboxylate (0.61 g, 1.2 mmol) in DCM
(5 mL) was added TFA (7 mL) and the mixture was stirred at
40.degree. C. for 2 h. The volatiies were evaporated under reduced
pressure and the residue was purified by flash column
chromatography (0 to 80% EtOAc:DCM) to give 0.35 g (80%) of the
title compound as a solid. MS (ESI): 367 [M+H].sup.+.
Step D--Methyl
3-{[(1R)-1-(2-chloro-3-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}phenyl)et-
hyl]oxy}-5-{6-[(methylsulfonyl)methyl]-1H-benzimidazol-1-yl}-2-thiopheneca-
rboxylate
##STR00112##
[0578] To a slurry of methyl
3-hydroxy-5-{6-[(methylsulfonyl)methyl]-1H-benzimidazol-1-yl}-2-thiophene-
carboxylate (0.29 g, 0.80 mmol) and
(1S)-1-(2-chloro-3-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}phenyl)ethano-
l (Intermdiate 17, 0.51 g, 1.9 mmol) in THF (10 mL) was added
4-(dsphenylphosphanyl)-N,N-dimethylaniline (0.72 g, 2.4 mmol) and
di-tert-butylazodicarboxylate (0.55 g, 2.4 mmol). The dear, yellow
solution was stirred for 24 h, and then silica gel (3 g) was added.
The volatiles were evaporated under reduced pressure 5 and the
residue was purified by flash column chromatography (0 to 50%
EtOAc:DCM) to give 0.24 g (47%) of the title compound as a white
solid. MS (ESI): 635 [M+H].sup.+.
Step E--Methyl
3-{[(1R)-1-(2-chloro-3-hydroxyphenyl)ethyl]oxy}-5-{6-[(methylsulfonyl)met-
hyl]-1H-benzimidazol-1-yl}-2-thiophenecarboxylate (Title
Compound)
[0579] To a solution of methyl
3-{[(1R)-1-(2-chloro-3-{[(1,1-dimethylethyl)(dimethyl)
silyl]oxy}phenyl)ethyl]oxy}-5-{6-[(methylsulfonyl)methyl]-1H-benzimidazol-
-1-yl}-2-thiophenecarboxylate (0.24 g, 0.38 mmol) In MeOH (10 mL)
was added a cesium fluoride (0.5 g, 3.3 mmol). The mixture was
heated to 60.degree. C. for 4 h and then cooled to room
temperature, The reaction was partitioned between EtOAc (200 mL)
and wafer (100 mL). The layers were separated, and the organics
were washed with water (1.times.50 mL), dried over MgSO.sub.4,
filtered and evaporated under reduced pressure to afford 0.16 g
(78%) of the title compound as a white solid. MS (ESI): 521
[M+H].sup.+.
INTERMEDIATE 24
4-Bromo-3-nitrophenyl trifiuoromethyl ether
##STR00113##
[0581] To a solution of 2-nitro-4-[(trifluoromethyl)oxy]aniline
(2.0 g, 9.0 mmol) in acetonitrlle (50 mL) was added
tert-butylnitrite (7.4 g, 72 mmol). The solution was stirred 2 min
and then Copper(II) bromide (40 g, 180 mmol) was added. The
solution stirred for 1 h at rt. The reaction was partitioned
between EtOAc (500 mL) and 1N HCl (aq) (100 mL). The layers were
separated, and the organics were washed with 1N HCl (aq)
(3.times.50 mL), dried over MgSO.sub.4, filtered, and the volatiies
were evaporated under reduced pressure, and the residue was
purified by flash column chromatography (0 to 20% EtOAc:hexanes) to
give 2.0 g (78%) of the title compound. .sup.1H NMR (400 MHz,
CDCl.sub.3): .delta. 7.78 (d, J=8.79 Hz, 1H), 7.76 (s, 1H), 7.32
(s, 1H, J=8.79 Hz).
INTERMEDIATE 25
Methyl
3-{[(1R)-1-(2-chloro-3-hydroxyphenyl)ethyl]oxy}-5-{5-[(trifluoromet-
hyl)oxy]-1H-benzimidazol-1-yl}-2-thiophenecarboxylate
##STR00114##
[0582] Step A--Methyl
3-{[(1R)-1-(2-chlorophenyl)ethyl]oxy}-5-({2-nitro-4-[(trlfluoromethyl)oxy-
]phenyl}amino)-2-thiophenecarboxylate
##STR00115##
[0584] 4-Bromo-3-nitrophenyl trifluoromethyl ether (2.0 g, 7.0
mmol) and methyl
5-amino-3-{[(1R)-1-(2-chlorophenyI)ethyl]oxy}-2-thiophenecarboxyla-
te (2.2 g, 7.0 mmol) were dissolved in 1,4-dioxane (80 mL) with
stirring in a flask equipped with a stir bar, reflux condenser, and
thermometer. The solution was degassed for 15 min by bubbling
N.sub.2 through the stirring solution.
9,9-Dimethyl-4,5-bis(diphenylphosphino)xanthene (0.18 g, 0.31
mmol), cesium carbonate (11 g, 35 mmol), and
tris(dibenzylideneacetone) dipaliadium(0) (0.13 g, 0.14 mmol) were
added. The reaction was heated to 60.degree. C. and stirred for 16
h. The reaction was cooled to rt and filtered through Celite. The
solid was washed with 20% MeOH in DCM. The volatiies were
evaporated under reduced pressure and the residue was purified by
flash column chromatography (0 to 50% EtOAc:DCM) to give 3.5 g
(97%) of the title compound as a solid. MS (ESI): 516 [M+H]+.
Step B--Methyl
3-hydroxy-5-{5-[(trifluoromethyl)oxy]-1H-benzimidazol-1-yl}-2-thiopheneca-
rboxylate
##STR00116##
[0586] Methyl
3-{[(1R)-1-(2-chlorophenyl)ethyl]oxy}-5-({2-nitro-4-[(trifluoromethyl)oxy-
]phenyl}amlno)-2-thiophenecarboxylate (3.5 g, 6.8 mmol) was
dissolved in EtOAc (100 mL) with stirring. Sulfided platinum (5%
weight on carbon, 1.32 g) was added, and the reaction was placed
under 50 atm of H.sub.2. After 36 h the reaction was filtered
through a Geiife pad washing with EtOAc. The filtrate was
concentrated to afford 3.3 g of methyl
5-({2-amino-4-(trifiuoromethyl)oxy]phenyl}amino)-3-{[(1R)-1-(2-chlorophen-
yl)ethyl]oxy}-2-thiophenecarhoxyiate which was immediately
dissolved in trimethyl orthoformate (50 mL) with stirring.
Pyridlnium p-toluenesulfonate (0.26 g, 1.0 mmol) was added in a
single portion. The reaction was stirred for 24 h. The voiatlies
were evaporated under reduced pressure and the residue was
dissolved in CHCl.sub.3 (30 mL) and TFA (30 mL). The mixture was
heated to 60.degree. C. for 2 h. The voiatlies were evaporated
under reduced pressure and the residue was quenched by the addition
of 7 N ammonia in MeOH (40 mL). The voiatlies were evaporated under
reduced pressure and the residue was partitioned between DCM (200
mL) and water (100 mL). The layers were separated, and the organlcs
were washed with water (3.times.50 mL), dried over
Na.sub.2SO.sub.4, filtered and evaporated under reduced pressure.
The resulting solid was taken up as a suspension in
ether/hexanes(1/9), filtered and washed with ether/hexanes(1/9) to
afford 1.5 g (62%) of the title compound as a solid. MS (ESI): 359
[M+H]+.
Step C--Methyl
3-{[(1R)-1-(2-chloro-3-hydroxyphenyl)ethyl]oxy}-5-{5-[(trifluoromethyl)ox-
y]-1H-benzimidazol-1-yl}-2-thiophenecarboxylate (Title
Compound)
[0587] To a slurry of methyl
3-hydroxy-5-{5-[(trifluoromethyl)oxy]-1H-benzimidazol-1-yl}-2-ihiopheneca-
rboxylate (0.71 g, 2.0 mmol) and
(1S)-1-(2-chloro-3-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}phenyl)ethano-
l (Intermediate 17, 0.63 g, 2.2 mmol) so DCM (20 mL) was added
triphenylphosphine (1.1 g, 4.0 mmol) and
di-tert-butylazodicarboxylate (0.92 g, 4.0 mmol). The clear, yellow
solution was stirred for 1 h, then silica gel (5 g) was added. The
volatiles were evaporated under reduced pressure and the residue
was purified by flash column chromatography (0 to 50% EtOAc:DCM) to
give 1.1 g (1.8 mmol) of the methyl
3-{[(1R)-1-(2-cbloro-3-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}phenyl)et-
hyl]oxy}-5-[5-(1-methyl-1H-pyrazol-4-yl)-1H-benzimidazol-1-yl]-2-thiophene-
carboxylate which was dissolved in THF (15 mL). 1 N
tetrabutylammonium fluoride in THF (1.8 mL, 1.8 mmol) was added.
After 10 min, silica (3 g) was added, the volatiles were evaporated
under reduced pressure and the residue was purified by flash column
chromatography (0 to 70% EtOAc:DCM) to afford 0.36 g (47%) of the
title compound as a solid. .sup.1H NMR (400 MHz, CD.sub.3OD):
.delta. 8.48 (s, 1H), 7.63 (s, 1H), 7.40 (d, J=8.97 Hz, 1H), 7.30
(d, J=8.79 Hz, 1H), 7.13 (m, 2H), 7.0 (s, 1H), 6.8 (d, J=7.51 Hz,
1H), 5.95 (q, J=6.17 Hz, 1H), 3.88 (s, 3H), 1.68(d, J=6.23 Hz,
3H).
INTERMEDIATE 26
Methyl
3-{[(1R)-1-(2-chloro-3-hydroxyphenyl)ethyl]oxy}-5-{6-[(trifluoromet-
hyl)oxy]-1H-benzimidazol-1-yl}-2-thiophenecarboxylate
##STR00117##
[0589] The title compound was prepared using procedures analogous
to Intermediate 25. MS (ESI): 513 [M+H].sup.+.
INTERMEDIATE 27
Methyl
3-{[(1R)-1-(2-chloro-3-hydroxyphenyl)ethyl]oxy}-5-(5,6-difluoro-1H--
benzimidazol-1-yl)-2-thiophenecarboxylate
##STR00118##
[0590] Step A--Methyl
5-(5,6-difluoro-1H-benzimidazol-1-yl)-3-hydroxy-2-thiophenecarboxylate
##STR00119##
[0592] To a mixture of 5,6-difiuoro-1H-benzimidazole (0.5 g, 3.2
mmol) and 2-chloro-3-oxo-2,3-dihydro-2-thiophenecarboxylate (0.72
g, 3.7 mmol) in 10 mL of CHCl.sub.3 was added N-methylimidazole
(0.4 g, 4.9 mmol) and NaHCO.sub.3 (0.82 g, 9.7 mmol). The mixture
was heated to 55.degree. C. for 24 h. Silica gel (2 g) was added
and the volatiies were evaporated under reduced pressure and the
residue was purified by flash column chromatography (0 to 50%
EtOAc:DCM) to afford 0.71 g of the titled compound. MS (ESI): 311
[M+H].sup.+.
Step B--Methyl
3-{[(1R)-1-(2-chloro-3-hydroxyphenyl)ethyl]oxy}-5-(5,6-difluoro-1H-benzim-
idazol-1-yl)-2-thiophenecarboxylate (Title Compound)
[0593] The title compound was prepared using a procedure analogous
to Intermediate 25, Step C. MS (ESI); 465 [M+H].sup.+.
INTERMEDIATE 28
Methyl
5-(5-bromo-1H-benzimidazol-1-yl)-3-[(phenylmethyl)oxy]-2-thiophenec-
arboxylate
##STR00120##
[0594] Step A--Methyl
5-nitro-3-[(phenylmethyl)oxy]-2-thiophenecarboxylate
##STR00121##
[0596] To a solution of methyl
3-hydroxy-5-nitro-2-thiophenecarboxylate, which can be prepared
according to the procedure in J. Chem. Research (M), 2001
1001-1004, (26.4 g, 130 mmol) in DMF (300 mL) was added
K.sub.2CO.sub.3 (20.0 g, 145 mmol), followed by benzyl bromide
(22.3 g, 130 mmol), and the reaction mixture was stirred at rt for
18 h. The solution was filtered to remove the solids, and the
filtrate was poured slowly into 1 N HCl (600 mL). A yellow solid
precipitated, and this solid was collected by vacuum filtration and
was washed with water (3.times.300 mL) providing 37.0 g (97%) of
the title compound. .sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta.
8.23 (s, IB), 7.48-7.28 (m, 5H), 5.37 (s, 2H), 3.79 (s, 3H).
Step B--Methyl
5-amino-3-[(phenylmethyl)oxy]-2-thiophenecarboxylate
##STR00122##
[0598] To a flask equipped with a temperature probe, an overhead
mechanical stirrer, a reflux condenser, and an addition funnel was
added iron powder (38.3 g, 650 mmol) and acetic acid (230 mL). The
iron/acetic acid slurry was
[0599] 5 stirred mechanically and heated to an internal temperature
of 50.degree. C. To the addition funnel was added a solution of
methyl 5-nitro-3-[(phenylmethyl)oxy]-2-thiophenecarboxylate (37.0
g, 126 mmol) in acetic acid (300 mL). The solution in the addition
funnel was then added dropwise to the iron/acetic acid slurry at a
rate such that the internal temperature was maintained at
<60.degree. C. (2.5 h total addition time). The reaction mixture
was cooled to rt, and the entire mixture was then filtered through
filter paper to remove insoluble material, rinsing with DCM (500
mL). The solution was concentrated to about 200 mL, rediluted with
EtOAc (500 mL) and then quenched by addition of 6 N NaOH (250 mL)
and saturated aqueous NaHCO.sub.3 (200 mL). The aqueous and organic
fractions were separated. The aqueous fraction was extracted with
EtOAc (2.times.400 mL). The organic fractions were combined, dried
over MgSO.sub.4, filtered, and concentrated to afford 27.0 g (82%)
of the title compound as a tan solid. .sup.1H NMR (400 MHz,
DMSO-d.sub.6): .delta. 7.42-7.26 (m, 5H), 6.78 (s, 2H), 5.76 (s,
1H), 5.10 (s, 2H), 3.56 (s, 3H); MS (ESI): 286 [M+H].sup.+.
Step C--Methyl
5-[(4-bromo-2-nitrophenyl)amIno]-3-[(phenylmethyl)oxy]-2-thiophenecarboxy-
late
##STR00123##
[0601] Methyl 5-amino-3-[(phenylmethyl)oxy]-2-thiophenecarboxylate
(3.2 g, 12 mmol) and 1,4-dibromo-2-nitrobenzene (3.9 g, 14 mmol)
were dissolved in 1,4-dioxane (100 mL). The solution was degassed
for 15 min by bubbling N.sub.2 through the stirring solution.
XANTPHOS (0.32 g, 0.55 mmol), cesium carbonate (20 g, 63 mmol), and
tris(dibenzylideneacetcne) dipalladium(0) (0.23 g, 0.25 mmol) were
added. The reaction was heated to 60.degree. C. and stirred for 16
h. The reaction was cooled to rt and filtered through Celite. The
solid was washed with 20% MeOH in DCM. Silica gei was added and the
volatiles were evaporated under reduced pressure and the residue
was purified by flash column chromatography (DCM to EtOAc) to give
3.9 g (70%) of the title compound as a solid. .sup.1H NMR (400 MHz,
CDCl.sub.3): .delta. 9.54 (s, 1H), 8.33 (s, 1H), 7.53-7.20 (m, 7H),
6.56 (s, 1H), 5.23 (s, 2H), 3.85 (s, 3H).
Step D--Methyl
5-(5-bromo-1H-benzimidazol-1-yl)-3-[(phenylmethyl)oxy]-2-thiophenecarboxy-
late (Title Compound)
[0602] Methyl
5-[(4-bromo-2-nitrophenyl)amino]-3-[(phenylmethyl)oxy]-2-thiophenecarboxy-
late (3.9 g, 8.5 mmol) was dissolved in EtOAc (100 mL) with
stirring. Sulflded platinum (5% weight on carbon, 1.3 g) was added,
and the reaction was placed under 50 psi of H.sub.2. After 16 h,
additional sulfided platinum (5% weight on carbon, 1.3 g) was
added, and the reaction was placed under 50 psi of H.sub.2. After
an additional 24 h, the reaction was filtered through a Celite pad
washing with EtOAc. The filtrate was concentrated to afford 3.8 g
of methyl
5-({2-amino-4-[(trifluoromethyl)oxy]phenyl}amino)-3-{[(1R)-1-(2-chlorophe-
nyl)ethyl]oxy}-2-thiophenecarboxylate which was immediately
dissolved in trimethyl orthoformate (50 mL) with stirring. Formic
acid (1.0 mL, 26 mmol) was added and the reaction was stirred at
60.degree. C. for 24 h. The volatiles were evaporated under reduced
pressure and the residue was partitioned between DCM (200 mL) and
water (100 mL). The layers were separated, and the organics were
washed with water (3.times.50 mL), dried over MgSG.sub.4 and
filtered. Silica gel was added and the solvent evaporated under
reduced pressure, and the residue was purified by flash column
chromatography (Hexanes to EtOAc) to afford 3.3 g (87%) of the
title compound as a solid. .sup.1H NMR (400 MHz, CDCl.sub.3):
.delta. 8.05 (d, 1H), 8.01-7.99 (m, 1H), 7.49-7.35 (m, 6H), 7.26
(s, 1H), 6.88 (s, 1H), 5.33 (s, 2H), 3.91 (s, 3H); MS (ESI): 443
& 445 [M+1 & M+3].sup.+.
INTERMEDIATE 29
Methyl
5-amino-3-({(1R)-1-[2-(trifluoromethyl)phenyl]ethyl}oxy)-2-thiophen-
ecarboxylate
##STR00124##
[0603] Step A--Methyl
5-nitro-3-({(1R)-1-[2-(trifluoromethyl)phenyl]ethyl}oxy)-2-thiophenecarbo-
xylate
##STR00125##
[0605] A slurry of polymer-supported triphenylphosphine (62.4 g,
2.21 mmol/g, 138 mmol) in DCM (1.0 L) was stirred at rt for 10
minutes. The mixture was cooled to 0.degree. C. Methyl
3-iiydroxy-5-nitro-2-thiophenecarboxylate (20.0 g, 98.4 mmol),
which may be prepared in a manner analogous to the literature
procedure (Barker, J. M.; Huddleston, P. R.; Wood, M. L.; Burkiti,
S. A. Journal of Chemical Research (Miniprint) 2001, 1001-1022) was
added, followed by (1S)-1-[2-(trifluorcmethyl)phenyl]ethanol (26.2
g, 138 mmol) and di-tert-butyl azodicarboxylate (31.7 g, 138 mmol),
The reaction mixture was stirred at rt for 21.25 h and then was
filtered through a fritted funnel and concentrated. The residue was
treated with 4 N HCl in 1,4-dioxane (300 mL) and stirred at rt for
3 h. The mixture was then quenched by addition of 3 N NaOH (300 mL)
and saturated aqueous NaHCO.sub.3 (200 mL). The mixture was
extracted with DCM (3.times.250 mL). The combined organic fractions
were dried over MgSO.sub.4, filtered, and concentrated onto silica
gel. Purification by column chromatography (0 to 25% EtOAc:hexanes)
provided 36.1 g (98%) of the title compound as yellow oil. .sup.1H
NMR (300 MHz, CDCl.sub.3): .delta. 7.82 (d, 1H, J=7.8 Hz), 7.68 (d,
1H, J=7.8 Hz), 7.59 (t 1H, J=7.4 Hz), 7.46 (s, 1H), 7.42 (t, 1H,
J=7.6 Hz), 5.77 (q, 1H, J=6.1 Hz), 3.94 (s, 3H), 1.74 (d, 3H, J=6.1
Hz).
Step B--Methyl
5-amlno-3-({(1R)-1-[2-(trifluoromethyl)phenyl]ethyl}oxy)-2-thiophenecarbo-
xylate (Title Compound)
[0606] To a flask equipped with a temperature probe, an overhead
mechanical stirrer, a reflux condenser, and an addition funnel was
added Iron powder (26.8 g, 481 mmol) and acetic acid (130 mL). The
iron/acetic acid slurry was stirred mechanically and heated to an
internal temperature of 50.degree. C. To the addition funnel was
added a solution of methyl
5-nitro-3-({(1R)-1-[2-(trifiuoromethyl)phenyl]ethyl}oxy)-2-thio-
phenecarboxylate (36.1 g, 96.1 mmol) in acetic acid (160 mL). The
solution in the addition funnel was then added dropwlse to the
iron/acetic acid slurry at a rate such that the internal
temperature was maintained at <60.degree.C. (2.5 h total
addition time). The reaction mixture was cooled to room
temperature, diluted with DCM (500 mL), and then quenched by
addition of 6 N sodium hydroxide (750 mL) and saturated aqueous
NaHCO.sub.3 (200 mL), The entire mixture was then filtered through
a pad of Cetlte to remove insoluble material, rinsing the Celite
with additional DCM (250 mL). The aqueous and organic fractions
were separated. The aqueous fraction was extracted with EtOAc
(2.times.400 mL). The organic fractions were combined, dried over
MgSO.sub.4, filtered, and concentrated to afford 30.7 g (92%) of
the title compound as an orange solid. .sup.1H NMR (300 MHz,
CDCl.sub.3): .delta. 7.89 (d, 1H, J=7.7 Hz), 7.62 (d, 1H, J=7.7
Hz), 7.56 (t, 1H, J=7.7 Hz), 7.36 (t, 1H, J=7.7 Hz), 5.72 (s, 1H),
5.65 (q, 1H, J=6.3 Hz), 4.26 (br s, 2H), 3.80 (s, 3H), 1.66 (d, 3H,
J=6.3 Hz); MS (APCI): 368.00 [M+Na].sup.+.
INTERMEDIATE 30
Methyl
5-amino-3-{[(1R)-1-(2-chlorophenyl)ethyl]-oxy}-2-thiophenecarboxyla-
te
##STR00126##
[0607] Step A--Methyl
3-{[(1R)-1-(2-chlorophenyl)ethyl]oxy}-5-nitro-2-thiophenecarboxylate
##STR00127##
[0609] Methyl
3-{[(1R)-1-(2-chlorophenyl)ethyl]oxy}-5-nitro-2-thiophenecarboxylate
was prepared from methyl 3-hydroxy-5-nitro-2-thiophenecarboxylate
and (1S)-1-(2-chlorophenyl)ethanol by a procedure analogous to
Intermediate 29, Step A. .sup.1H NMR (400 MHz, DMSO-d.sub.6):
.delta. 7.96 (s, 1H), 7.65 (dd, 1H, J=1.7, 7.8 Hz), 7.47 (dd, 1H,
J=1.5, 7.7 Hz), 7.40 (dt, 1H, J=1.3, 7.5 Hz), 7.34 (dt, 1H, J=1.9,
7.5 Hz), 5.98 (q, 1H, J=6.0 Hz), 3.85 (s, 3H), 1.59 (d, 3H, J=6.2
Hz).
Step B--Methyl
5-amino-3-{[(1R)-1-(2-chlorophenyl)ethyl]oxy}-2-thiophenecarboxylate
(Title Compound)
[0610] Methyl
5-amlno-3-{[(1R)-1-(2-chlorophenyl)ethyl]oxy}-2-thiophenecarboxylate
was prepared from methyl
3-{[(1R)-1-(2-chlorophenyl)ethyl]oxy}-5-nitro-2-thiophenecarboxylate
by a procedure analogous to Intermediate 29, Step B. .sup.1H NMR
(400 MHz, DMSO-d.sub.6): .delta. 7.54 (dd, 1H, J=1.8, 7.9 Hz), 7.45
(dd, 1H, J=1.4, 7.7 Hz), 7.37 (dt, 1H, J=1.4, 7.7 Hz), 7.31 (dt,
1H, J=1.8, 7.6 Hz), 6.76 (br s, 2H), 5.57 (q, 1H, J=6.2 Hz), 5.49
(s, 1H), 3.63 (s, 3H), 1.51 (d, 3H, J=6.4 Hz); MS (ESI): 334.03
[M+Na].sup.+.
INTERMEDIATE 31
Methyl
5-[6-(hydroxymethyl)-1H-benzimidazol-1-yl]-3-({(1R)-1-[2-(trifluoro-
methyl)phenyl]ethyl}oxy)thiophene-2-carboxylate
##STR00128##
[0611] Step A--5-(Hydroxymethyl)-2-nitrophenol
##STR00129##
[0613] To a mixture of 3-hydroxy-4-nitrobenzoic acid (5.0 g, 27
mmol) in 1,2-dichloroethane (100 mL) was added trimethyl borate
(4.9 mL, 44 mmol), followed by boron trifluoride diethyl etherate
(5.5 mL. 44 mmol). Borane-pyridine complex (4.1 mL, 41 mmol) was
then slowly added drop wise. The reaction was stirred 4 h at rt,
then cooled to 0.degree. C. and quenched with MeOH (10 mL). The
mixture was concentrated under vacuum and the residue taken up in
toluene (200 mL), then extracted with aqueous 1 N NaOH (3.times.100
mL). The combined aqueous layers were adjusted to pH 1.0 by
addition of 12 N HCl, then extracted with EtOAc (3.times.250 mL).
The combined organic layers were washed with water, brine, dried
over MgSO.sub.4 and concentrated under vacuum to give 4.55 g (98%)
of the title compound as a light yellow solid. .sup.1H NMR (400
MHz, DMSO-d.sub.6): .delta. 10.87 (s, 1H), 7.85 (d, 1H, J=8.6 Hz),
7.08 (s, 1H), 6.88 (dd, 1H, J=1.19, 8.51 Hz), 5.43 (s, 1H), 3.33
(s, 2H).
Step B--3-Hydroxy-4-nitrobenzyl pivalate
##STR00130##
[0615] A mixture of 5-(hydroxymethyl)-2-nitrophenol (11.4 g, 67.2
mmol) and 3-(2,2-dimethylpropanoyl)-1,3-thiazoiidine-2-thione (15.0
g, 73.9 mmol), which may be prepared in a manner analogous to the
literature procedure (Yamada, S. Tetrahedron Letters 1992, 33,
2171-2174), was stirred in toluene (670 mL) at 100.degree. C. for
40 h, then cooled to rt. The reaction was concentrated under vacuum
to a volume of approximately 200 mL and the resulting slurry was
filtered through filter paper, washing the solid with cold toluene.
The filtrate was then concentrated under vacuum and purified by
silica gel chromatography eiuting with a gradient of 0-to-20%
EtOAc/hexanes to give 11.1 g (65%) of the title compound as a dear
yellow oil. .sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 11.05 (s,
1H), 7.87 (d, 1H, J=8.42 Hz), 7.06 (s, 1H), 6.90 (dd, 1H, J=1.46,
8.42 Hz), 5.09 (s, 2H), 1.18 (s, 9H).
Step C--4-Nitro-3-{[(trifiuoromethyl)suifonyl]oxy}benzyl
pivalate
##STR00131##
[0617] To a stirred, cooled (0.degree. C.) solution of
3-hydroxy-4-nitrobenzyl pivalate (11.1 g, 43.9 mmol) and
N-phenyltrifluoromethanesulfonimide (16.5 g, 46.2 mmol) in DCM (220
mL) was slowly added N,N-diisopropylethylamine (15.5 mL, 88.9
mmol). The reaction was stirred for 45 min at 0.degree. C., then 45
min at rt. The reaction was then concentrated under vacuum and
purified by silica gel chromatography eiuting with a gradient of
5-to-20% EtOAc/hexanes to give 16.9 g (99%) of the title compound
as an off white solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta.
8.36 (d, 1H, J=8.42 Hz), 7.75-7.69 (m, 2H), 5.27 (s, 2H), 1.19 (s,
9H).
Step D--Methyl
5-[(5-{[(2,2-dimethylpropanoyl)oxy]methyl}-2-nitrophenyl)amino]-3-({(1R)--
1-[2-(trifluoromethyl)phenyl]ethyl}oxy)thiophene-2-carboxylate
##STR00132##
[0619] A mixture of
4-nitro-3-([(trifluoromethyl)sulfonyl]oxy)benzyl pivalate (1.0 g,
2.6 mmol), methyl
5-amino-3-({(1R)-1-[2-(trifluoromethyl)phenyl]ethyl}-oxy)thiophene-2-carb-
oxylate (1.3 g, 3.9 mmol), tetrakis(triphenylphosphine)palladium
(0) (150 mg, 0.13 mmol), triphenylphosphine (68 mg, 0.26 mmol) and
K.sub.2CO.sub.3 (900 mg, 6.5 mmol) were stirred in toluene (5.2 mL)
at 100 .degree. C. for 2 h, then cooled to rt and filtered through
Celite, washing with EtOAc and DCM. The filtrate was concentrated
under vacuum and purified by silica gel chromatography eiuting with
a gradient of 5-to-25% EtOAc/hexane to give 1.26 g (84%) of the
title compound as a red oil .sup.1H NMR (400 MHz, DMSO-d.sub.6):
.delta. 9.75 (s, 1H), 8.09 (d, 1H, J=8.6 Hz), 7.89 (d, 1H, J=7.87
Hz), 7.69-7.78 (m, 2H), 7.52 (t, J=7.59 Hz), 7.34 (s, 1H), 7.01
(dd, 1H, J=1.46, 8.60 Hz), 6.62 (s, 1H), 5.70-5.75 (m, 1H), 5.07
(s, 2H), 3.74 (s, 3H), 1.58 (d, 3H, J=6.22 Hz), 1.13 (s, 9H).
Step E--Methyl
5-[(2-amino-5-{[(2,2-dimethylpropanoyl)oxy]methyl}phenyl)amino]-3-({(1R)--
1-[2-(trifluoromethyl)phenyl]ethyl}oxy)thiophene-2-carboxylate
##STR00133##
[0621] A mixture of methyl
5-[(5-{[(2,2-dimethylpropanoyl)oxy]methyl}-2-nitrophenyl)amino]-3-({(1R)--
1-[2-(trifluoromethyl)phenyl]ethyl}oxy)thiophene-2-carboxylate (2.4
g, from a different batch using procedure analogous to Intermediate
31, Step D 4.2 mmol) and platinum (sulfided, 5 wt % on carbon) (811
mg, 0.21 mmol) in EtOAc (30 ml) was added to a high-pressure
reaction flask. The reaction was purged with vacuum and N.sub.2
gas, then H.sub.2 gas was applied at 50 psi for 1 h. The reaction
mixture was filtered through Celite, washing with EtOAc. The
filtrate was concentrated under vacuum to give 2.3 g (99%) of the
title compound as a tan solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6):
.delta. 8.62 (s, 1H), 7.84 (d, 1H, J=7.87 Hz), 7.72 (dd, 2H,
J=7.60, 13.09 Hz), 7.50 (t, 1H, J=7.60 Hz), 7.01 (d, 1H, J=1.46
Hz), 6.88 (dd, 1H, J=1.74, 8.15 Hz), 6.68 (d, 1H, J=8.24 Hz), 5.83
(s, 1H), 5.59-5.65 (m, 1H), 4.97 (s, 2H), 4.85 (s, 2H), 3.64 (s,
3H), 1.55 (d, 3H, J=6.23 Hz), 1.11 (s, 9H); MS (ESI): 551
[M+H].sup.+.
Step F--Methyl
5-(6-{[(2,2-dimethylpropanoyl)oxy]methyl}-1H-benzimidazol-1-yl)-3-({(1R)--
1-[2-(trifiuoromethyl)phenyl]ethyl}oxy)thiophene-2-carboxylate
##STR00134##
[0623] To a mixture of methyl
5-[(2-amino-5-{[(2,2-dimethylpropanoyl)oxy]methyl}phenyl)amino]-3-({(1R)--
1-[2-(trifiuoromethyl)phenyl]ethyl}-oxy)thiophene-2-carboxylate
(2.3 g, 4.1 mmol) in triethylorthoformate (10 mL, 60 mmol) and DCM
(3 mL) was added pyridinium p-toluenesuifonate (100 mg, 0.40 mmol).
The reaction was stirred at 40.degree. C. for 1 h, then cooled to
rt. The entire reaction mixture was loaded onto silica gel and
purified by silica gel chromatography eiuting with a gradient of
0-to-50% EtOAc/hexanes to give 2.0 g (86%) of the title compound as
a light tan solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta.
8.65 (s, 1H), 7.99 (d, 1H, J=7.87 Hz), 7.75-7.80 (m, 2H), 7.72 (d,
1H, J=7.87 Hz), 7.63 (s, 1H), 7.53 (t, 1H, J=7.60 Hz), 7.40 (s,
1H), 7.35 (d, 1H, J=8.42 Hz), 5.96 (q, 1H, J=6.10 Hz), 5.21 (s,
2H), 3.83 (s, 3H), 1.65 (d, 3H, J=6.23 Hz), 1.16 (s, 9H); MS (ESI):
581 [M+H].sup.+.
Step G--Methyl
5-[6-(hydroxymethyl)-1H-benzimidazol-1-yl]-3-({(1R)-1-[2-(trifiuoromethyl-
)phenyl]ethyl}oxy)thiophene-2-carboxylate (Title Compound)
[0624] To a stirred solution of methyl
5-(6-{[(2,2-dimethylpropanoyl)oxy]methyl}-1H-benzimidazol-1-yl)-3-({(1R)--
1-[2-(trifluoromethyl)phenyl]ethyl}oxy)thiophene-2-carboxylate
(5.21 g, from a different batch using procedure analogous to
Intermediate 31, Step F, 9.30 mmol) in MeOH (24 mL) was added 0.5M
NaOH in MeOH (24.0 ml, 12.0 mmol). The reaction was stirred at rt
tor 72 h, then quenched with acetic acid (2 mL). The mixture was
diluted with DCM (350 mL) and half saturated aqueous brine solution
(150 mL), The aqueous layer was extracted with DCM (250 mL). The
combined organics were dried over MgSO.sub.4 and concentrated under
vacuum to give 4.40 g (99%) of the title compound as a light yellow
solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 8.58 (s, 1H),
7.99 (d, 1H, J=7.87 Hz), 7.69-7.81 (m, 3H), 7.51-7.58 (m, 2H), 7.38
(s, 1H), 7.30 (d, 1H, J=8.42), 5.96 (q, 1H, J=6.10 Hz), 5.30 (t,
1H, J=5.77 Hz) 4.82 (d, 2H, J=5.86 Hz), 3.83 (s, 3H), 1.65 (d, 3R
J=6.23 Hz); MS (ESI): 477 [M+H].sup.+.
INTERMEDIATE 32
Methyl
3-{[(1R)-1-(2-chlororphenyl)ethyl]oxy}-5[6-(hydroxymethyl)-1H-benzi-
midazol-1-yl]-2thiophenecarboxylate
##STR00135##
[0625] Step A--Methyl
3-{[(1R)-1-(2-chlorophenyl)ethyl]oxy}-5-[(5-{[(2,2-dimethylpropanoyl)oxy]-
methyl}-2-nitrophenyl)amino]-2-thiophenecarboxylate
##STR00136##
[0627] To a mixture of
(4-nitro-3-{[(trifiuoromethyl)sulfonyl]oxy}phenyl)methyl
2,2-dimethylpropanoate (1.0 g, 2.6 mmol), methyl
5-amino-3-{[(1R)-1-(2-chlorophenyl)ethyl]oxy}-2-thiophenecarboxylate
(Intermediate 30) (860 mg, 2.8 mmol),
tris(dibenzylideneacetone)dipalladium(0) (70 mg, 0.076 mmol), and
XANTPHOS (90 mg, 0.16 mmol) was added toluene (7.0 mL). Stirring
was begun, followed by the addition of Cs.sub.2CO.sub.3 (3.0 g, 9.1
mmol). The reaction was heated to 60.degree. C. and stirred for 30
min, then cooled to rt, diluted with EtOAc and filtered through
Celite, washing the solids with EtOAc and DCM. The filtrate was
concentrated under vacuum and chromatographed on silica gel (40 g),
eluting with a 5-to-15% gradient of acetone/hexane to give 920 mg
(65%) of the title compound as a red: solid. .sup.1H NMR (400 MHz,
DMSO-d.sub.6): .delta. 9.77 (s, 1H), 8.09 (d, 1H, J=8.61 Hz), 7.63
(dd, 1H, J=7.69 and 1.65 Hz), 7.46-7.30 (m, 4H), 7.01 (dd, 1H,
J=8.79 and 1.47 Hz), 6.67 (s, 1H), 5.76-5.70 (m, 1H), 5.09 (s, 2H),
3.73 (s, 3H), 1.56 (d, 3H, J=6.23 Hz), 1.14 (s, 9H); MS (ESI): 547
[M+H].sup.+.
Step B--Methyl
5-[(2-amino-5-{[(2,2-dimethylpropanoyl)oxy]methyl}-phenyl)amino]-3-{[(1R)-
-1-(2-chlorophenyl)ethyl]oxy}-2-thiophenecarboxylate
##STR00137##
[0629] To a high-pressure hydrogenation reaction flask was added
methyl
3-{[(1R)-1-(2-chlorophenyl)ethyl]oxy}-5-[(5-{[(2,2-dimethylpropanoyl)oxy]-
methyl}-2-nitrophenyl)amlno]-2-thiophenecarboxylate (6.5 g, from a
different batch using procedure analogous to Intermediate 32, Step
A, 12 mmol), 5% by weight platinum on carbon (suifided) (2.2 g,
0.56 mmol) and EtOAc (95 mL). The flask was purged with N.sub.2
(gas) vacuum (3.times.), then with H.sub.2 (gas) vacuum (3.times.).
Hydrogen gas was then applied at 50 psi for 3 h. The reaction
mixture was then filtered through Celite, washing the solids with
EtOAc and DCM. The filtrate was then concentrated under vacuum to
give 5.5 g (89%) of the title compound as a yellow solid. MS (ESI):
517 [M+H].sup.+.
Step C--Methyl
3-{[(1R)-1-(2-chlorophenyl)ethyl]oxy}-5-(6-{[(2,2-dimethylpropanoyl)oxy]m-
ethyl}-1H-benzimidazol-1-yl)-2-thiophenecarboxylate
##STR00138##
[0631] A stirred mixture of methyl
5-[(2-amino-5-{[(2,2-dimethylpropanoyl)oxy]methyl}phenyl)amino]-3-{[(1R)--
1-(2-chlorophenyl)ethyl]oxy}-2-thiophenecarboxylate (5.5 g, 11
mmol), pyridinium p-toiuene sulfonate (265 mg, 1.0 mmol) and
triethylorthoformate (15 mL) was heated to 40.degree. C. for 1 h,
then cooled to rt. The entire mixture was poured onto a silica gel
cartridge (25 g) and purified by silica gel chromatography (120 g),
eiuting with 100% hexanes for 10 min, then a 0-to-10% EtOAc/hexane
gradient to give 4.71 g (85%) of fee title compound as a yellow
solid. MS (ESI): 527 [M+H].sup.+.
Step D--Methyl
3-{[(1R)-1-(2-chlorophenyl)ethyl]oxy}-5-[6-(hydroxymethyl)-1H-benzimidazo-
l-1-yl]-2-thiophenecarboxylate (Title Compound)
[0632] The title compound was prepared from methyl
3-{[(1R)-1-(2-chlorophenyl)ethyl]oxy}-5-(6-{[(2,2-dimethylpropanoyl)oxy]m-
ethyl}-1H-benzimidazol-1-yl)-2-thiophenecarboxylate by a procedure
analogous to Intermediate 31, Step G. MS (ESI): 443
[M+H].sup.+.
INTERMEDIATE 33
1,1-Dimethylethyl
4-({3-[(1R)-1-({5-(5-bromo-1H-benzimidazol-1-yl)-2-[(methyloxy)carbonyl]--
3-thienyi}oxy)ethyl]-2-chlorophenyl}oxy)-1-piperidinecarboxylate
##STR00139##
[0634] The title compound was prepared from methyl
5-(5-brorno-1H-benzimidazol-1-yl)-3-hydroxy-2-thiophenecarboxylate
(0.64 g, 1.8 mmol) and 1,1-dimethylethyl
4-({2-chloro-3-[(1S)-1-hydroxyethyl]phenyl}oxy)-1-piperidinecarboxylate
(0.78 g, 2.2 mmol) using a procedure analogous to Intermediate 2,
Step C to give 1.22 g of the desired product. MS (ESI): 692.4
[M+H].sup.+.
INTERMEDIATE 34
1-{4-{[(1R)-1-(2-Chtorophenyl)ethyl]oxy}-5-[(methylpxy)carbonyl]-2-thienyl-
}-1H-benzimidazole-5-carboxylic acid
##STR00140##
[0635] Step A--2-Propen-1-yl 1H-benzimidazole-5-carhoxylate
##STR00141##
[0637] A flask was charged with 20.0 g (123 mmol) of
5-benzimidazole carboxyiie add, 7.80 ml (148 mmol) of sulfuric acid
and 400 mL of allyl alcohol. The reaction was stirred overnight at
90.degree. C. Most of the allyl alcohol was removed under vacuum,
5% i-PrOH/DCM was added and the mixture neutralized with saturated
NaHCO.sub.3 solution. The organics were separated, dried over
MgSO.sub.4 and concentrated. The crude product (16.8 g) was used
directly in the next step without further purification. MS (APCI);
203 [M+H].sup.+ .
Step B: 2-Propen-1-yl
1-{4-hydroxy-5-[(methyloxy)carbonyl]-2-thlenyi}-1H-benzimidazole-5-carbox-
ylate
##STR00142##
[0639] To a flask charged with 11.9 g (58.9 mmol) of 2-propen-1-yl
1H-benzimidazole-5-carboxylate, 11.4 g (58.9 mmol) of methyl
2-chloro-3-oxo-2,3-dihydro-2-thiophenecarboxylate and 14.9 g (177
mmol) of NaHCO.sub.3 was added 200 mL of CHCl.sub.3, followed by
7.1 mL (88.4 mmo) of N-methylimidazole. The reaction was stirred at
45.degree. C. for 8 h, cooled to rt and the slurry adsorbed onto
silica gel gel. This was chromatographed to give 8.5 g of the title
compound. MS (APCI); 359 [M+H].sup.+.
Step C: 2-Propen-1-yl
1-{4-{[(1R)-1-(2-chlorophenyl)ethyl]oxy}-5-[(methyloxy)carbonyl]-2-thseny-
l}-1H-benzimidazole-5-carboxylate
##STR00143##
[0641] To a solution of 8.41 g (23.5 mmol) of 2-propen-1-yl
1-{4-hydroxy-5-[(methyloxy)carbonyl]-2-thienyl}-1H-benzimidazole-5-carbox-
ylate and 4.40 g (28.2 mmol) of (1S)-1-(2-chlorophenyl)ethanol in
300 mL of DCM was added 24.0 g (47.0 mmol) of polymer-supported
triphenylphosphine followed by the portion wise addition of 10.8 g
(47.0 mmol) of di-t-butyl azodicarboxylate. The mixture was stirred
at rt for 2 h and filtered though a funnel. The filtrate was
concentrated, the residue dissolved in 200 mL of HCl (4.0 N in
dioxane) and stirred overnight. This solution was neutralized with
saturated NaHCO.sub.3 and the organics separated. The organics were
concentrated to give 10.4 g of the title compound. MS (APCI): 497
[M+H].sup.30 .
Step
D--1-{4-{[(1R)-1-(2-Chlorophenyl)ethyl]oxy}-5-[(methyloxy)carbonyl]-2-
-thienyl}-1H-benzimidazole-5-carboxyiic acid (Title Compound)
[0642] To a flask charged with 3.00 g (6.05 mmol) of 2-propen-1-yl
1-{4-{[(1R)-1-(2-chlorophenyl)ethyl]oxy}-5-[(methyloxy)carbonyl]-2-thieny-
l}-1H-benzimidazole-5-carboxylate, was added 50 mL of anhydrous
THF, 5.30 mL (60.5 mmol) of morpholine. and 698 mg (0.605 mmol) of
tefrakis triphenylphoshine. The reaction was stirred at rt for 1 h,
then the solvent removed. The mixture was diluted with EtOAc and
neutralized with 100 mL of 0.5 M HCl. The crude product was
ehromatographed via silica gel chromatography to give 2.20 g of the
title compound. MS (APCI): 457 [M+H].sup.+.
EXAMPLE 1
5-[5,6-Bis(methyloxy)-1H-benzimidazol-1-yl]-3-[((1R)-1-{2-chloro-3-[(4-pip-
erindinylmethyl)amino]pjenyl}ethyl)oxy]-2-thiophenecarboxamide
##STR00144##
[0643] Step A--Methyl
5-[5,6-bis(methyloxy)-1H-benzimidazol-1-yl]-3-{[(1R)-1-(2-chloro-3-nitrop-
henyl)ethyl]oxy}-2-thiophenecarboxylate
##STR00145##
[0645] To a solution of methyl
5-[5,6-bis(methyloxy)-1H-benzimidazol-1-yl]-3-hydroxy-2-thiophenecarboxyl-
ate (which can be synthesized following the procedure found in PCT
Int. Appl. WO 2004073812) (1.1 g, 3.4 mmol) and
(1S)-1-(2-chloro-3-nitrophenyl)ethanol (Intermediate 1, 820 mg, 4.1
mmol) in 30 mL of DCM was added polymer
supported-triphenySphosphine (3.0 g, 6.8 mmol) and di-tert-butyl
azodicarboxylate (1.6 g, 6.8 mmol). After 16 h, the reaction
mixture was filtered, and the resin was rinsed with alternating DCM
and MeOH. The filtrate was concentrated and purified by flash
column chromatography (10-20% EtOAc:hexanes) to give 1.4 g of the
desired product (80%). .sup.1H NMR (400 MHz, d.sub.6-DMSO) .delta.
8.42 (s, 1H), 8.03 (d, J=8.0 Hz, 1H), 7.98 (d, J=8.0 Hz, 1H), 7.68
(t, J=8.0 Hz, 1H), 7.50 (s, 1H), 7.30 (s, 1H), 7.14 (s, 1H), 6.06
(m, 1H), 3.81 (s, 3H), 3.79 (s, 6H), 1.64 (d, J=6.4 Hz, 3H).
Step
B--5-[5,6-Bis(methyloxy)-1H-benzimidazol-1-yl]-3-{[(1R)-1-(2-chloro-3-
-nitrophenyl)ethyl]oxy}-2-thiophenecarboxamide
##STR00146##
[0647] A mixture of methyl
5-[5,6-bis(methyloxy)-1H-benzimidazol-1-yl]-3--{[(1R)-1-(2-chloro-3-nstro-
phenyl)ethyl]oxy}-2-thiophenecarboxylate (1.4 g, 2.7 mmol) and 7 N
ammonia in MeOH in a sealed tube was heated at 80.degree. C. After
16 h, the reaction was cooled to rt. The precipitate was filtered,
rinsed with ether and dried to give 1.05 g of the desired product
(77%). .sup.1NMR (400 MHz, d.sub.6-DMSO) .delta. 8.32 (s, 1H),
7.99-7.96 (m. 2H); 7.80 (br s, 1H), 7.65 (t, J=8.0 Hz, 1H), 7.28
(s, 1H), 7.18 (s, 1H), 7.13 (br s, 1H), 7.06 (s, 1H), 6.06 (m, 1H),
3.78 (s, 3H), 3.76 (s, 3H), 1.72 9d, J=6.4 Hz, 3H).
Step
C--3-([(1R)-1-(3-amino-2-chlorophenyl)ethyl}oxy}-5-[5,6-bis(methyloxy-
)-1H-benzimidazol-1-yl]-2-thiophenecarboxamide
##STR00147##
[0649] To
5-[5,6-bis(methyloxy)-1H-benzimidazol-1-yl]-3-{[(1R)-1-(2-chloro-
-3-nitrophenyl)ethyl]oxy}-2-thiophenecarboxamide (1.0 g, 2.0 mmol)
and iron powder (0.56 g, 10 mmol) was added acetic acid (6.0 mL,
100 mmol). The dark mixture was heated at 50 .degree. C. After 30
rnin, EtOAc was added and 5N NaOH was added to neutralize the
mixture. The mixture was filtered through a pad of celite. The
organic layer was separated, dried over MgSO.sub.4 and concentrated
to give 0.47 g of the desired product (50%). .sup.1H NMR (400 MHz,
d.sub.6-DMSO) .delta. 8.32 (s, 1H), 7.78 (br s, 1H), 7.28 (s, 1H),
7.06-6.97 (m, 4H), 6.74-6.68 (m, 2H), 5.89 (m, 1H), 5.44 (s, 2H),
3.77 (s, 3H), 3.75 (s, 3H), 1.64 (d, J=6.4 Hz, 3H).
Step
D--5-[5,6-Bis(methyloxy)-1H-benzimidazol-1-yl]-3-[((1R)-1-{2-chloro-3-
-[(4-piperidinylmethyl)amino]phenyl}ethyl)oxy]-2-thiophenecarboxamide
(Title Compound)
[0650] To a solution of
3-{[(1R)-1-(3-amino-2-chlorophenyl)ethyl]oxy}-5-[5,6-bis(methyloxy)-1H-be-
nzimidazol-1-yl]-2-thiopheneoarboxamide (470 mg, 1.0 mmol) in 5 mL
of 1,2-dichloroethane was added 1,1-dimeihyiethyl
4-formyl-1-piperidinecarboxylate (320 mg, 1.5 mmol) and 2 drops of
acetic acid. After 40 min, sodium triacetoxyborohydride (420 mg,
2.0 mmol) was added. After 16 h, the reaction was diluted with DCM.
The organic solution was washed with sat'd aqueous NaHCO.sub.3 and
water, dried over MgSO.sub.4 and concentrated. The residue was
stirred in a 20% TFA and DCM solution. The reaction was
concentrated and redissolved in DCM. The organic solution was
washed with saturated NaHCO.sub.3 and water, dried over MgSO.sub.4
and concentrated. The crude material was purified by silica gel
chromatography (5-20% 10% NH.sub.3OH/MeOH and CH.sub.2Cl.sub.2) to
give 0.126 g of the title compound (22%). .sup.1H NMR (400 MHz,
d.sub.6-DMSO) .delta. 8.31 (s, 1H), 7.78 (br s, 1H), 7.28 (s, 1H),
7.13 (m, 1H), 7.07 (br s, 1H), 7.02-7.01 (m, 2H), 6.77 (m, 1H),
6.60 (m, 1H), 5.93 (m. 1H), 5.41 (m, 1H), 3.78 (s, 3H), 3.74 (s,
3H). 2.93 (m, 4H), 2.40 (m, 2H), 1.66-1.57 (m, 6H), 1.07-1.00 (m,
2H). HRMS calculated C.sub.28H.sub.32ClN.sub.5O.sub.4S [M+H].sup.+
570.1942, found 570.1946.
EXAMPLE 2
5-[5,6-Bis(methyloxy)-1H-benzimidazol-1-yl]-3-{[(1R)-1-(2-chlorp-3-{[(1-me-
thyl-4-piperidinyl)methyl]oxy}phenyl)ethyl]oxy}-2-thiophenecarboxamide
##STR00148##
[0652] To a solution of
5-[5,6-bis(methyloxy)-1H-benzimidazol-1-yl]-3-[((1R)-1-{2-chloro-3-[(4-pi-
peridinylmethyl)amino]phenyl}ethyl)oxy]-2-thtophenecarboxamide
(Exarapie 40, 86 mg, 0.015 mmol) in 2 mL of DCM and 1 mL of MeOH
was added formaldehyde (23 .mu.l, 0.30 mmol) and acetic acid (10
.mu.l, 0.18 mmol). After 10 min, sodium triacetoxyborohydride (49
mg, 0.23 mmol) was added and the reaction was stirred for 16 h. The
solution was diluted with DCM and washed with saturated NaHCO.sub.3
solution and water, dried over MgSO.sub.4 and concentrated to give
49 mg of the title compound (56%). .sup.1H NMR (400 MHz,
d.sub.6-DMSO) .delta. 8.31 (s, 1H), 7.78 (br s, 1H), 7.28 (s, 1H),
7.13 (t, J=7.8 Hz, 1H), 7.07 (br s, 1H), 7.01-7.00 (m, 2H), 6.76
(d, J=7.6 Hz, 1H), 6.60 (d, J=8.0 Hz, 1H), 5.92 (m, 1H), 5.39
(m,1H), 3.77 (s, 3H), 3.74 (s, 3H), 2.95 (m, 2H), 2.65 (m, 2H),
2.06 (s, 3H), 1.70-1.56 (m, 7H), 1.12-1.09 (m, 2H). HRMS calculated
C.sub.29H.sub.34ClN.sub.5O.sub.4S [M+H].sup.+ 584.2098, found
584.2093.
EXAMPLE 3
5-(5-Chloro-1H-benzimidazol-1-yl)-3-((1R)-1-{2-chloro-3-[1-methylpiperidin-
-4-yl)oxy]phenyl}ethoxy)thiophene-2-carboxamide
##STR00149##
[0654] To a slurry of methyl
5-(5-chloro-1H-benzimidazol-1-yl)-3-{[(1R)-1-(2-chloro-3-hydroxyphenyl)et-
hyl]oxy}-2-thiophenecarboxylate (Intermediate 2, Slap B, 195 mg,
0.42 mmol) in 5 mL of DCM was added 1-methylpiperidin-4-ol (59
.mu.l, 0.50 mmol), triphenytphosphine (220 mg, 0.84 mmol) and
di-tert-butylazodicarboxylate (160 mg, 0.84 mmol). After 2 h, the
reaction was concentrated onto silica gel and purified by flash
column chromatography. Fractions containing desired product were
concentrated and stirred in 6 mL of 7 N ammonia in MeOH in a sealed
tube heated at 80.degree. C. After 24 h, the reaction was allowed
to cool to rt. The precipitate was collected by filtration to give
35 mg of the title compound as a white solid (14% over both steps).
.sup.1H NMR (400 MHz, d.sub.6-DMSO) .delta. 8.63 (s, 1H), 7.86-7.83
(m, 2H), 7.52 (d, J=8.8 Hz, 1H), 7.37-7.30 (m, 2H), 7.20-7.11 (m,
4H), 5.97 (m, 1H), 4.46 (m, 1H), 2.31-2.12 (m, 5H), 2.60-2.48 (m
under DMSO peak, 2H), 1.85 (m, 2H), 1.70 -1.61 (m, 5H).
EXAMPLE 4
3-((1R)-1
-{2-chiore-3-[(1-methylpjperidin-4-yl)oxy]phenyl}-ethoxy)-5-(6-c-
yano-1H-benzimidazol-1-yl)thbphene-2-carboxamide
##STR00150##
[0655] Step A--Methyl
3-((1R)-1-(2-chloro-3-[(1-methylpiperidin-4-yl)oxy]phenyl}ethoxy)-5-(6-cy-
ano-1H-benzimidazol-1-yl)thiophene-2-carboxylate
##STR00151##
[0657] To a solution of methyl
3-[(1R)-1-(2-chloro-3-hydroxyphenyl)ethoxy]-5-(6-cyano-1H-benzimidazol-1--
yl)thiophene-2-carboxylate (Intermediate 3, 130 mg, 0.27 mmol) in 5
mL of DCM was added 1-methylpiperidin-4-ol (38 .mu.L, 0.32 mmol),
triphenylphosphine (140 mg, 0.54 mmol), and di-tert-butyl
azodicarhoxySate (120 mg, 0.54 mmol). Ater the reaction was
complete, the solution was concentrated onto silica gel and
purified by flash column chromatography (1-100% 10% MeOH/DCM and
DCM) to give 125 mg of the desired product (84%). .sup.1H NMR (400
MHz, d6-DMSO) .delta. 8.87 (s, 1H), 8.20 (s, 1H), 7.95 (d, J=8.0
Hz, 1H),7.75(d, J=8.4 Hz, 1H), 7.46 (s, 1H), 7.35-7.28 (m, 2H),
7.12 (d, J=6.8 Hz, 1H), 5.99 (m, 1H), 4.44 (m, 1H), 3.82 (s, 3H),
2.52 (m, 2H), 2.21-2.13 (m, 5H), 1.86 (m, 2H), 1.66-1.60 (m,
5H).
Step
B--3-((1R)-1-{2-Chloro-3-[(1-methylpiperidin-4-yl)oxy]phenyl}ethoxy)--
5-(6-cyano-1H-benzimidazol-1-yl)thiophene-2-carboxamide (Title
Compound)
[0658] A solution of methyl
3-((1R)-1-{2-chloro-3-[(1-methylpiperidin-4-yl)oxy]phenyl}ethoxy)-5-(6-cy-
ano-1H-benzimidazol-1-yl)thiophene-2-carboxylate (120 mg, 0.22
mmol) in 7 ml of a 7N ammonia in MeOH solution was heated in a
sealed tube at 80.degree. C. After 1-3 days, the reaction was
cooled to rt, concentrated onto silica gel, and purified by flash
column chromatography to give 85 mg of the title compound (72%).
.sup.1H NMR (400 MHz, d.sub.6-DMSO) .delta. 8.80 (s, 1H), 8.09 (s,
1H), 7.94 9d, J=8.4 Hz, 1H), 7.85 (s, 1H), 7.74 (dd, J=8.4 and 1.2
Hz, 1H), 7.32 (d, J=8.0 Hz, 1H), 7.23-7.19 (m, 2H), 7.14-7.12 (m,
2H), 6.01 (m, 1H), 4.44 (m, 1H), 2.52-2.78 (m under DMSO peak, 2H),
2.16-2.11 (m, 5H), 1.84 (m, 2H), 1.70 (d, J=6.4 Hz, 3H), 1.62 (m,
2H). HRMS calculated C.sub.27H.sub.27ClN.sub.5O.sub.3S [M+H].sup.+
536.1523, found 536.1519.
EXAMPLE 5
3-{(1R)-1-[2-chloro-3(piperidin-4-yloxy)phenyl]ethoxy}-5-(6-cyano-1H-benzi-
nidazol-1-yl)thiophene-2-carboxamide
##STR00152##
[0659] Step A--Tert-butyl
4-[2-chloro-3-((1R)-1-{[5-(6-cyano-1H-benzimidazol-1-yl)-2-(methoxycarbon-
yl)-3-thienyl]oxy}ethyl)phenoxy]piperidine-1-carboxylate
##STR00153##
[0661] To a solution of methyl
3-[(1R)-1-(2-chloro-3-hydroxyphenyl)ethoxy]-5-(6-cyano-1H-benzimidazol-1--
yl)thiophene-2-carboxylate (Intermediate 3, 160 mg, 0.36 mmol) in 5
mL of PCM was added tert-butyl 4-hydroxypiperidine-1-carboxylate
(87 mg, 0.43 mmol), triphenylphosphine (190 mg, 0.72 mmol), and
di-tert-butyl azodicarboxylate (170 mg, 0.72 mmol). The reaction
was concentrated onto silica gel and purified by flash column
chromatography to give the desired product plus impurity (264 mg).
.sup.1H NMR (400 MHz, d.sub.6-DMSO) .delta. 8.87 <s, 1H), 8.20
(s, 1H), 7.95 (d, J=8.4 Hz, 1H). 7.75 (dd, J=8.4 and 1.2 Hz, 1H),
7.48 (s, 1H), 7.37-7.30 (m, 2H), 7.16 (dd, J=7.6 and 1.6 Hz, 1H),
5.99 (m, 1H), 4.64 (m, 1H), 3.82 (s, 3H), 3.53 (m, 2H), 3.24 (m,
2H), 1.83 (m, 2H), 1.61 (d, J=6.0 Hz, 3H), 1.54 (m, 2H), 1.38 (s,
9H).
Step B--Tert-butyl
4-[3-((1R)-1-{[2-(aminocarbonyl)-5-(6-cyano-1H-benzimidazol
-1-yl)-3-thienyl]oxy}ethyl)-2-chlorophenoxy]piperidine-1-carboxylate
##STR00154##
[0663] A solution of tert-butyl
4-[2-chloro-3-((1R)-1-{[5-(6-cyano-1H-benzimidazol-1-yl)-2-(methoxycarbon-
yl)-3-thienyl]oxy}ethyl)phenoxy]piperidine-1-carboxylate (264 mg)
in 7 mL of a 7N ammonia in MeOH solution was heated at 80.degree.
C. After 1-3 days, the reaction was concentrated onto silica gel
and purified by flash column chromatography to give 136 mg of the
desired product (61% over steps A and B). .sup.1H NMR (400 MHz,
d.sub.6-DMSO) .delta. 8.80 (s, 1H), 8.08 (s, 1H), 7.94 (d, J=8.4
Hz, 1H), 7.85 (br s, 1H), 7.73 (dd, J=8.4 and 1.2 Hz, 1H), 7.34 (t,
J=8.0 Hz, 1H), 7.25-7.13 (m, 4H), 6.01 (m, 1H), 4.64 (m, 1H), 3.50
(m, 2H), 3.21 (m, 2H), 1.82 (m, 2H), 1.71 9d, J=6.4 Hz, 3H), 1.54
(m, 2H), 1.37 (s, 9H).
Step
C--3-{(1R)-1-[2-chloro-3-(plperidin-4-yloxy)phenyl]ethoxy}-5-(6-cyano-
-1H-benzimidazol-1-yl)thiophene-2-carboxamide (Title Compound)
[0664] A solution of tert-butyl
4-[3-((1R)-1-{[2-(aminocarbonyl)-5-(6-cyano-1H-benzimidazol-1-yl)-3-thien-
yl]oxy}ethyl)-2-chlorophenoxy]piperidin-1-carboxylate (136 mg, 0.22
mmol) was stirred in 5 mL of a 20% TFA/DCM solution. The reaction
was concentrated and the residue was taken up in DCM. The solution
was neutralized with 7N ammonia in MeOH. The solution was
concentrated onto silica gel and purified by flash column
chromatography to give 101 mg of the title compound (88%). .sup.1H
NMR (400 MHz, d.sub.6-DMSO) .delta. 8.79 (s, 1H), 8.45 (br s, 1H),
8.07 (s, 1H), 7.93 (d, J=8,4 Hz, 1H), 7.84 (br s, 1H), 7.73 (d,
J=8.4 Hz, 1H), 7.36 (t, J=8.0 Hz, 1H), 7.27-7.25 (m, 2H), 7.19 (d,
J=8.0 Hz, 1H), 7.12 (br s, 1H), 6.01 (m. 1H), 4.71 (m, 1H), 3.07
(m, 2H), 2.03 (m, 2H), 1.83 (m, 2H), 1.70 (d, J=6.4 Hz, 3H). HRMS
calculated C.sub.26H.sub.25ClN.sub.5O.sub.3S [M+H].sup.+ 522.1367
found 522.1371.
EXAMPLE 6
5-(6-Broroo-1H-benzimidazol-1-yl)-3-[((1R)-1-{2-chloro-3-[(1-methyl-4-pipe-
rldinyl)oxy]phenyl}ethyl)oxy]-2-thiophenecarboxamide
##STR00155##
[0665] Step A--Methyl
5-(6-bromo-1H-benzimidazol-1-yl)-3-[((1R)-1-{2-chloro-3-[(1-methyl-4-pipe-
ridinyl)oxy]phenyl}ethyl)oxy]-2-thiophenecarboxylate
##STR00156##
[0667] Methyl
5-(8-bromo-1H-benzimidazol-1-yl)-3-{[(1R)-1-(2-chloro-3-hydroxyphenyl)eth-
yl]oxy}-2-thiophenecarboxylate (Intermediate 6, 150 mg, 0.30 mmol)
and 1-methylpiperidin-4-ol (35 .mu.L, 0.30 mmol) were coupled using
a procedure analogous to Example 4, Step A to give 104 mg of the
desired product (57%). .sup.1H NMR (400 MHz, d.sub.6-DMSO) .delta.
8.69 (s, 1H), 7.83 (d, J=1.5 Hz, 1H), 7.78 (d, J=8.4 Hz, 1H), 7.54
(dd, J=8.7 and 1.8 Hz, 1H), 7.43 (s, 1H), 7.40-7.31 (m, 3H), 7.17
(m, 1H), 6.03 (m, 1H), 4.49 (m, 1H), 3.86 (s, 3H), 2.57-2.50 (m,
under DMSO peak, 2H), 2.17-2.15 (m, 5H), 1.89 (m, 2H), 1.71-1.64
(m, 5H).
Step B--5-(6-Bromo-1H-benzimidazol-1-yl)-3-[((1R)-1-(2-chloro-3-[(1
-methyl-4-piperidinyl)oxy]phenyl}ethyl)oxy]-2-thiophenecarboxamide
(Title Compound)
[0668] Methyl
5-(6-bromo-1H-benzimidazol-1-yl)-3-[((1R)-1-{2-chloro-3-[(1-methyl-4-pipe-
ridinyl)oxy]phenyl}ethyl)oxy}-2-thiophenecarboxylate (104 mg, 0.17
mmol) was subjected to an aminolysis reaction analogous to Example
4, Step B to give 61 mg of the title compound (61%). .sup.1H NMR
(400 MHz, d.sub.6-DMSO) .delta. 8.57 (s, 1H), 7.84 (br s, 1H), 7.71
(d, J=8.8 Hz, 1H), 7.68 (d, J=1.6 Hz, 1H), 7.48 (dd, J8.6 and 1.8
Hz, 1H), 7.32 (t, J=8.0 Hz, 1H), 7.20 (d, J=7.6 Hz, 1H), 7.16-7.12
(m, 3H), 5.99 (m, 1H), 4.44 (m, 1H), 2.52-2.48 (m under DMSO peak,
2H), 2.11 (m, 5H), 1.85 (m, 2H), 1.69 (d, J=6.4 Hz, 3H), 1.63 (m,
2H). HRMS calculated C.sub.26H.sub.27BrClN.sub.4O.sub.3S
[M+H].sup.+ 589.0676; found 589.0679.
EXAMPLE 7
5-(6-Bromo-1H-benzimidazol-1-yl)-3-({(1R)-1-[2-chloro-3-(4-piperidinyloxy)-
phenyl]ethyl}oxy)-2-thiophenecarboxamide
##STR00157##
[0669] Step A--1,1-Dimethylethyl
4-({3-[(1R)-1-({5-(6-bromo-1H-benzimidazol-1-yl)-2-[(methyloxy)carbonyl]--
3-thienyl}oxy)ethyl]-2-chlorophenyl}oxy)-1-piperidinecarboxylate
##STR00158##
[0671] Methyl
5-(6-bromo-1H-benzimidazol-1-yl)-3-{[(1R)-1-{2-chloro-3-hydroxyphenyl)eth-
yl]oxy}-2-thiophenecarboxylate (Intermediate 6, 193 mg, 0.38 mmol)
and tert-butyl 4-hydroxypiperidine-1-carboxylate (76 mg, 0.38 mmol)
were coupled using a procedure analogous to Example 5, Step A to
give 112 mg of the desired product (43%). .sup.1H NMR (400 MHz,
d.sub.6-DMSO) .delta. 8.65 (s, 1H), 7.78 (d, 1H, J=1.6 Hz), 7.73
9d, 1H, J=8.8 Hz), 7.49 (dd, 1H, J=8.6 and 1.8 Hz), 7.40 (s, 1H),
7.37-7.29 (m, 2H), 7.17 (dd, 1H, J=8.2 and 1.4 Hz), 5.98 (m, 1H),
4.65 (m, 1H), 3.81 (s, 3H), 3.53 (m, 2H), 3.28 (m, 2H), 1.83 (m,
2H), 1.60 (d, 3H, J=6.0 Hz), 1.55 (m, 2H), 1.38 (s, 9H).
Step B--1,1-Dimethylethyl
4-{[3-((1R)-1-{[2-(aminocarbonyl)-5-(6-bromo-1H-benzimidazol-1-yl)-3-thie-
nyl]oxy}ethyl)-2-chlorophenyl]oxy}-1-piperidinecarboxylate
##STR00159##
[0673] 1,1-Dimethylethyl
4-({3-[(1R)-1-({5-(6-bromo-1H-benzimidazol-1-yl)-2-[(methyloxy)carbonyl]--
3-thlenyl}oxy)ethyl]-2-chlorophenyl}oxy)-1-piperidinecarboxylate
(112 mg, 0.16 mmol) was subjected to an amlnoiysss procedure
analogous to Example 5, Step B to give 81 mg of the desired product
(75%). .sup.1H NMR (400 MHz, d.sub.6-DMSO) .delta. 8.56 (s, 1H),
7.82 (br s, 1H), 7.70 (d, J=8.8 Hz, 1H), 7.66 (s, 1H), 7.46 (d,
J=8.4 Hz, 1H), 7.33 (t, J=8.0 Hz, 1H), 7.22-7.15 (m, 3H), 7.10 (br
s, 1H), 5.98 (m, 1H), 4.64 (m, 1H), 3.51 (m, 2H), 3.22 (m, 2H),
1.81 (m, 2H), 1.68 (d, J=6.4 Hz, 3H), 1.56 (m, 2H), 1.36 (s,
9H).
Step
C--5-(6-Bromo-1H-benzimidazol-1-yl)-3-({(1R)-1-[2-chloro-3-(4-piperid-
inyloxy)phenyl]ethyl}oxy)-2-thiophenecarboxamide (Titie
Compound)
[0674] 1,1-Dimethylethyl
4-{[3-(1-{[2-(aminocarbonyl)-5-(6-bromo-1H-benzimidazol-1-yl)-3-thienyl]o-
xy}ethyl)-2-chlorophenyl]oxy}-1 -piperidinecarboxylate (81 mg, 0.12
mmol) was deprotected using a procedure analogous to Example 5,
Step C to give 58 mg of the title compound (84%). .sup.1H NMR (400
MHz, d.sub.6-DMSO) .delta. 8.55 (s, 1H), 7.82 (br s, 1H), 7.70 (d,
J=8.8 Hz, 1H), 7.66 (s, 1H), 7.46 (d, J=8.8 Hz, 1H), 7.31 (m, 1H),
7.20-7.11 (m, 4H), 5.97 (m, 1H), 4.48 (m, 1H), 2.90 (m, 2H), 2.54
(m, 2H), 1.83 (m, 2H), 1.68 (d, J=6.4 Hz, 3H), 1.48 (m, 2H). HRMS
calculated C.sub.25H.sub.25BrClN.sub.4O.sub.3S [M+H].sup.+
575.0519, found 575.0520.
EXAMPLE 8
5-(5-Chloro-1H-benzimidazol-1-yl)-3-({(1R)-1-[2-chloro-3-(4-piperidinyloxy-
)phenyl]ethyl}oxy)-2-thiophenecarboxamide
##STR00160##
[0675] Step A--1,1-Dimethylethyl
4-({2-chloro-3-[(1R)-1-({5-(5-chloro-1H-benzimidazol-1-yl)-2-[(methyloxy)-
carbonyl]-3-thienyi}oxy)ethyl]phenyi}oxy)-1-piperidinecarboxylate
##STR00161##
[0677] Methyl
5-(5-chloro-1H-benzimidazol-1-yl)-3-{[(1R)-1-(2-chloro-3-hydroxyphenyl)-e-
thyl]oxy}-2-thiophenecarboxylate (Intermediate 2, 213 mg, 0.46
mmol) and tert-butyl 4-hydroxypiperidine-1-carboxylate (110 mg,
0.55 mmol) were coupled using a procedure analogous to Example 5,
Step A to give 210 mg of the desired product (71%). .sup.1H NMR
(400 MHz, d.sub.6-DMSO) .delta. 8.72 (s, 1H), 7.87 (d, J=1.6 Hz,
1H), 7.65 (d, J=8.8 Hz, 1H), 7.41-7.29 (m, 4H), 7.18 (d, J=6.4 Hz,
1H), 5.95 (m,1H), 4.66 (m, 1H), 3.81 (s, 3H), 3.56-3.52 (m, 2H),
3.28-3.23 (m, 2H), 1.86-1.83 (m, 2H), 1.61-1.52 (m, 5H), 1.38 (s,
9H).
Step B--1,1-Dimethylethyl
4-{[3-((1R)-1-{[2-(aminocarbonyl)-5-(5-chloro-1H-benzimidazol-1-yl)-3-thi-
enyl]oxy}ethyl)-2-chloFophenyl]oxy}-1-piperidinecarboxylate
##STR00162##
[0679] 1,1-Dimethylethyl
4-({2-chloro-3-[(1R)-1-({5-(5-chloro-1H-benzimidazol-1-yl)-2-[(methyloxy)-
carbonyl]-3-thienyl}oxy)ethyl]phenyl}oxy)-1-piperidinecarboxylate
(210 mg, 0.32 mmol) was subjected to an aminolysis procedure
analogous to Example 5, Step B to give 114 mg of the desired
product (56%). .sup.1H NMR (400 MHz, d.sub.6-DMSO) .delta. 8.62 (s,
1H), 7.85 (d, J=2.0 Hz, 1H), 7.82 (br s, 1H), 7.52 (d, J=8.4 Hz,
1H), 7.37-7.32 (m, 2H), 7.23-7.16 (m, 3H), 7.10 (br s, 1H), 5.96
(m,1H), 4.68-4.64 (m, 1H), 3.56-3.52 (m, 2H), 3.28-3.20 (m, 2H),
1.85-1.83 (m, 2H), 1.70 (d, J=6.0 Hz, 3H), 1.58-1.52 (m,2H), 1.38
(s, 9H).
Step
C--5-(5-Chloro-1H-benzimidazol-1-yl)-3-({(1R)-1-[2-chloro-3-(4-piperi-
dinyloxy)phenyl]ethyl}oxy)-2-thiophenecarboxamide (Title
Compound)
[0680] 1,1-Dimethylethyl
4-{[3-((1R)-1-{[2-(aminocarbonyl)-5-(5-chloro-1H-benzimidazol-1-yl)-3-thi-
enyl]oxy}ethyl)-2-chlorophenyl}oxy}-1-psperidinecarboxylate (104
mg, 0.16 mmol) was deprotected using a procedure analogous to
Example 5, Step C to give 55 mg of the title compound (65%).
.sup.1H NMR (400 MHz, d.sub.6-DMSO) .delta. 8.62 (s, 1H), 7.85 (d,
J=2.0 Hz, 1H), 7.82 (br s, 1H), 7.51 (d, J=8.8 Hz, 1H), 7.37-7.30
(m, 2H). 7.21-7.15 (m, 3H), 7.10 (br s, 1H), 5.96 (m, 1H), 4.52 (m,
1H), 2.94 (m, 2H), 2.61 (m, 2H}, 1.88 (m, 2H), 1.69 (d, J=6.4 Hz,
3H), 1.52 (m, 2H). HRMS calculated
C.sub.25H.sub.25Cl.sub.2N.sub.4O.sub.3S [M+H] 531.1024; found
531.1028.
EXAMPLE 9
3-({(1R)-1-[2-chloro-3-(4-piperidinyloxy)phenyl]ethyl}oxy)-5-[5-(6-methyl--
3-pyridinyl)-1H-benzimidazol-1-yl]-2-thiophenecarboxamide
##STR00163##
[0681] Step A- 1,1-Dimethylethyl
4-({2-chJoro-3-[(1R)-1-({2-[(methyIoxy)carbonyl]-5-[5-(6-methyl-3-pyridin-
yl)-1H-benzimidazol-1-yl]-3-thianyl}oxy)ethyl]phenyl}oxy)-1-piperidinecarb-
oxylate
##STR00164##
[0683] Methyl
3-{[(1R)-1-{2-chloro-3-hydroxyphenyl)ethyl]oxy}-5-[5-(6-methyl-3-pyridiny-
l}-1H-benzimidazol-1-yl]-2-thiophenecarboxylate (Intermediate 9,
147 mg, 0.28 mmol) and 1,1-dirnethylethyl 4-hydroxy-1
-piperidinecarboxylate (68 mg, 0.34 mmol) were coupled using a
procedure analogous to Example 5, Stop A to give 151 mg of the
desired product (76%). .sup.1H NMR (400 MHz, d.sub.6-DMSO) .delta.
8.79 (s, 1H), 8.70 (s, 1H), 8.08 (s, 1H), 8.01 (d, J=8.0 Hz, 1H),
7.72-7.66 (m, 2H), 7.40 (s, 1H), 7.36-7.29 (m, 3H), 7.17 (d, J=7.6
Hz, 1H), 5.96 (m, 1H), 4.65 (m,1H), 3.80 (s, 3H), 3.52 (m, 2H),
3.22 (m, 2H), 2.49 (s, 3H), 1.83 (m, 2H), 1.61-1.54 {m, 5H), 1.35
(s, 9H).
Step B--1,1-Dimethylethyl
4-({3-[(1R)-1-({2-(aminocarbonyl)-5-[5-(6-methyl-3-pyridinyl)-1H-benzimid-
azol-1-yl]-3-thienyl}oxy)ethyl]-2-chlorophenyl}oxy)-1-psperidinecarboxylat-
e
##STR00165##
[0685] 1,1 -Dimethylethyl
4-({2-chloro-3-[(1R)-1-({2-[(methyloxy)carbonyl]-5-[5-(8-methyl-3-pyridin-
yl)-1H-benzimidazol-1yl]-3-thienyl}oxy)ethyl]phenyl}oxy)-1-piperidinecarbo-
xylate (150 mg, 0.21 mmol) was subjected to an aminolysis procedure
analogous to Exemple 5, Step B to give 81 mg of the desired product
(56%). .sup.1H NMR (400 MHz, d.sub.6-DMSO) .delta. 8.78 (s, 1H),
8.60 (s, 1H), 8.06 (s, 1H), 8.00 (d, J=8.0 Hz, 1H), 7.80 (br s,
1H), 7.64 (d, J=8.4 Hz, 1H), 7.58 (d, J=8.4 Hz, 1H), 7.36-7.23 (m,
2H), 7.21-7.16 (m, 3H), 7.09 (br s, 1H), 5.97 (M, 1H), 4.65 (M,
1H), 3.52 (m, 2H), 3.20 (m, 2H), 2.49 (s, 3H), 1.82 (m, 2H), 1.70
(d, J=6.0 Hz, 3H), 1.54 (m, 2H), 1.34 (s, 9H).
Step
C--3-({(1R)-1-[2-chloro-3-(4-piperidinyloxy}phenyl]ethyl}oxy)-5-[5-(6-
-rnethyl-3-pyridinyl)-1H-benzimidazol-1-yl]-2-thiophenecarboxamide
##STR00166##
[0687] 1,1 -Dimethylethyl
4-({3-[(1R)-1-({2-(aminocarhonyl)-5-[5-(6-methyl-3-pyridinyl)-1H-benzimid-
azol-1-yl]-3-thienyl}oxy)ethyl]-2-chlorophenyl}oxy)-1-piperidinecarboxytat-
e (81 mg, 0.12 mmol) was deprotected using a procedure analogous to
Example 5, Step C to give 61 mg of the title compound (86%).
.sup.1H NMR (400 MHz, d.sub.6-DMSO) .delta. 8.80 (d, J=2.0 Hz, 1H),
8.62 (s, 1H), 8.08 (d, J=1.2 Hz, 1H), 8.02 (dd, J=8.0 and 2.8 Hz,
1H), 7.82 (br s, 1H), 7.66 (dd, J=8.4 and 1.6 Hz, 1H), 7.57 (d,
J=8.8 Hz, 1H), 7.35-7.31 (m, 2H), 7.21-7.16 (m, 3H), 7.11 (br s,
1H), 5.99 (m, 1H), 4.52-4.47 (m, 1H), 2.92-2.84 (m, 2H), 2.58-2.46
(m under DMSO peak, 5H), 1.87-1.81 (m, 2H)f 1.71 (d, J=6.4 Hz, 3H),
1.50-1.43 (m, 2H). HRMS calculated [M+H].sup.+
C.sub.31H.sub.31ClN.sub.5O.sub.3S 588.1836; found 588.1837.
EXAMPLE 10
3-[((1R)-1-{2-chloro-3-[(1-methyl-4-pjperidinyl)oxy]phenyl}ethyl)oxy]-5-[5-
-(6-methyl-3-pyridinyl)-1H-benzimidazol-1-yl]-2-thiophenecarboxamide
##STR00167##
[0689] Methyl
3-{[(1R)-1-(2-chloro-3-hydroxyphenyl)ethyl]oxy}-5-[5-(6-methyl-3-pyridiny-
l)-1H-benzimidazol-1-yl]-2-thlophenecarboxylate (Intermediate 9, 97
mg, 0.19 mmol) was coupled with 1-methyl-4-piperidinol and
subjected to aminolysis procedure analogous to Example 3 to give 74
mg of the title compound (65% over both steps). .sup.1H NMR (400
MHz, d.sub.6-DMSO) .delta. 8.79 (d, J=2.1 Hz, 1H), 8.61 (s, 1H),
8.08 (s, 1H), 8.01 (dd, J=8.0 and 2.4 Hz, 1H), 7.81 (br s, 1H),
7.66 (m, 1H), 7.57 (d, J=8.4 Hz, 1H), 7.35-7.31 (m, 2H), 7.21-7.14
(m, 3H), 7.10 (br s, 1H), 5.98 (m, 1H), 4.46 (m, 1H), 2.50 (s, 3H),
2.48-2.45 (m under DMSO peak, 2H), 2.18-2.08 (m, 5H), 1.83 (m, 2H),
1.70 (d, J=6.0 Hz, 3H), 1.63 (m, 2H). HRMS calculated [M+H].sup.+
C.sub.32H.sub.33ClN.sub.5O.sub.3S 602.1993; found 602.1993.
EXAMPLE 11
3-[((1R)-1-{2-chloro-3-[(1-methyl-4-piperidinyl)oxy]pheny}ethyl)oxy]-5-[5--
(3-pyridinyl)-1H-benzimidazol-1-yl]-2-thiopnenecarboxamide
##STR00168##
[0690] Step A--Methyl
3-[((1R)-1-{2-chloro-3-[(1-niethyl-4-piperidinyl)oxy]phenyl}ethyl)oxy]-5--
[5-(3-pyridinyl)-1H-benzimidazol-1-yl]-2-thiophenecarboxylate
##STR00169##
[0692] Methyl
3-{[(1R)-1-(2-chloro-3-hydroxyphenyl)ethyl]oxy}-5-[5-(3-pyridinyl)-1H-ben-
zimidazol-1-yl]-2-thiophenecarbaxylate (Intermediate 10, 94 mg,
0.19 mmol) and 1-methyl-4-piperidinol (27 .mu.l, 0.23 mmol) were
coupled using a procedure analogous to Escampte 4, Step A to give
97 mg of the desired product (84%). .sup.1H NMR (400 MHz,
d.sub.6-DMSO) .delta. 8.95 (d, J=2.4 Hz, 1H), 8.73 (s, 1H), 8.57
(dd, J=8.8 and 1.4 Hz, 1H), 8.15-8.13 (m, 2H), 7.73 (m, 2H), 7.49
(dd, J=8.0 and 4.8 Hz, 1H), 7.40 (s, 1H), 7.36-7.28 (m, 2H), 7.15
(d, J=6.8 Hz, 1H), 5.98 (m, 1H), 4.46 (m, 1H), 3.82 (s, 3H),
2.54-2.48 (m under DMSO peak, 2H), 2.17-2.11 (m, 2H), 2.10 (s, 3H),
1.84 (m, 2H), 1.67-1.61 (m, 5H).
Step
B--3-[((1R)-1-(2-chloro-3-[(1-methyl-4-piperidinyl)oxy]phenyl}ethyl}o-
xy]-5-[5-(3-pyridinyl)-1H-benzimidazol-1-yl]-2-thiophenecarboxamide
(Title Compound)
[0693] Methyl
3-[((1R)-1-{2-chloro-3-[(1-methyl-4-piperidinyl)oxy]phenyl}ethyl)oxy]-5-[-
5-(3-pyridinyl)-1H-benzimidazol-1-yl]-2-thiophenecarboxylate (90
mg, 0.15 mmol) was subjected to aminolysis procedure analogous to
Example 4, Step B to give 37 mg of the title compound (42%).
.sup.1H NMR (400 MHz, d.sub.6-DMSO) .delta. 8.93 (s, 1H), 8.62 (s,
1H), 8.55 (d, J=4.4 Hz, 1H), 8.13-8.11 (m, 2H), 7.81 (br s, 1H),
7.68 (d, J=8.4 Hz, 1H), 7.58 (d, J=8.4 Hz, 1H), 7.49-7.45 (m, 1H),
7.32 (t, J=8.0 Hz, 1H), 7.20-7.14 (m, 3H), 7.10 (br s, 1H), 5.97
(m, 1H), 4.45 (m, 1H), 2.51-2.47 (m under DMSO peak, 2H), 2.15-2.07
(m, 2H), 2.07 (s, 3H), 1.82 (m, 2H), 1.69 (d, J=6.0 Hz, 3H), 1.62
(m, 2H). HRMS calculated [M+H].sup.+
C.sub.31H.sub.31ClN.sub.5O.sub.3S 588.1836, found 588.1831.
EXAMPLE 12
3-({(1R)-1-[2-chloro-3-(4-piperidinyloxy)phenyl]ethyl}oxy)-5-[5-(pyridinyl-
)-1H-benzimidazol-yl]-2-thipphenecarboxamide
##STR00170##
[0694] Step
A--1,1-Dimethylethyl-4-({2-chloro-3-[(1R)-1-({2-[(methyloxy)carbonyl]-5-[-
5-(3-pyridinyl)-1H-benzimidazol-1-yl]-3-thienyl}oxy)ethyl]phenyl}oxy)-1-pi-
peridinecarboxylate
##STR00171##
[0696] Methyl
3-{[(1R)-1-(2-chloro-3-hydroxyphenyl)ethyl]oxy}-5-[5-(3-pyridinyl)-1H-ben-
zimidazol-1-yl]-2-thiophenecarboxylate (Intermediate 10, 108 mg,
0.21 mmol) and 1,1-dimethylethyl-4-hydroxy-1-piperidinecarboxylate
(50 mg, 0.25 mmol) were coupled using a procedure analogous to
Example 5, Step A to give 129 mg of the desired product (89%).
.sup.1H NMR (400 MHz, d.sub.6-DMSO) .delta. 8.95 (d, J=2.0 Hz, 1H),
8.74 (s, 1H), 8.56 (dd, J=4.8 and 1.6 Hz, 1H), 8.15-8.13 (m, 2H),
7.77-7.74 (m, 2H), 7.49 (dd, J=8.0 and 4.8 Hz, 1H), 7.44 (s, 1H),
7.38-7.31 (m, 2H), 7.20-7.18 (m, 1H), 5.98 (m, 1H), 4.66 (m. 1H),
3.82 (s, 3H), 3.53 (m, 2H), 2.25 (m, 2H), 1.85 (m, 2H), 1.62 (d,
J=6.4 Hz, 3H), 1.56 (m, 2H), 1.36 (s, 9H).
Step B--1,1-Dimethylethyl
4-({3-[(1R)-1-({2-(aminocarbonyl)-5-[5-(3-pyridinyl)-1H-benzimidazol-yl]--
3-thienyl}oxy)ethyl]-2-chlorophenyl}oxy)-1-piperidinecarboxylate
##STR00172##
[0698] 1,1-Dimethylethyl
4-({2-chloro-3-[(1R)-1-({2-[(methyloxy)carbonyl]-5-[5-(3-pyridinyl)-1H-be-
nzimidazol-1-yl]-3-thienyl}oxy)ethyl]pheny}oxy)-1-piperidinecarboxylate
(120 mg, 0.17 mmol) was subjected to aminolysis procedure analogous
to Example 5, Step B to give 70 mg of the desired product (61%).
.sup.1H NMR (400 MHz, d.sub.6-DMSO) .delta. 8.93 (s, 1H), 8.62 (s,
1H), 8.55 (d, J=4.4 Hz, 1H), 8.13-8.11 (m, 2H), 7.81 (br s, 1H),
7.69 (d, J=8.4 Hz, 1H), 7.61 (d, J=8.4 Hz, 1H), 7.48-7.45 (m, 1H),
7.34 (t, J=8.0 Hz, 1H), 7.23-7.17 (m, 3H), 7.09 (br s, 1H), 5.98
(m, 1H), 4.65 (m, 1H), 3.51 (m, 2H), 3.20 (m, 2H), 1.82 (m, 2H),
1.70 (d, J=6.0 Hz, 3H), 1.53 (m, 2H), 1.34 (s, 9H).
Step
C--3-({(1R)-1-[2-chloro-3-(4-piperidinyloxy)phenyl]ethyl}oxy)-5-[5-(3-
-pyridinyl)-1H-benzimidazol-yl]-2-thiophenecarboxamide (Title
Compound)
[0699] 1,1-Dimethylethyl
4-({3-[(1R)-1-({2-(aminocarbonyl)-5-[5-(3-pyridinyl)-1H-benzimidazol-1-yl-
]-3-thienyl}oxy)ethyl]-2-chlorophenyl}oxy)-1-piperidinecarboxylate
(65 mg, 0.10 mmol) was deprotected using a procedure analogous to
Example 5, Step C to give 20 mg of the title compound (36%).
.sup.1H NMR (400 MHz, d.sub.6-DMSO) .delta. 8.94 (s, 1H), 8.63 (s,
1H), 8.56 (d, J=4.4 Hz, 1H), 8.14-8.13 (m, 1H), 7.82 (br s, 1H),
7.89 (d, J=8.0 Hz, 1H), 7.59 (d, J=8.4 Hz, 1H), 7.48 (dd, J=7.6 and
4.8 Hz, 1H), 7.33 (t, J=8.0 Hz, 1H), 7.21-7.17 (m, 3H), 7.11 (br s,
1H), 5.99 (m, 1H), 4.50 (m, 1H), 2.90 (m. 2H), 2.48 (m, 2H), 1.85
(m, 2H), 1.71 (d, J=6.0 Hz, 3H), 1.47 (m, 2H). MS (ESI) m/z=574
[M+H]+.
EXAMPLE 13
5-(1H-benzimidazol-1-yl)-3-[((1R)-1-{2-chloro-3-[(1-methyl-4-piperidinyl)g-
xy]phenyl}ethyl)oxy]-2-thiophenecarboxamide
##STR00173##
[0700] Step A--Methyl
5-(1H-benzimidazol-1-yl)-3-[((1R)-1-{2-chloro-3-[(1-methyl-4-pipehdinyl)o-
xy]phenyl}ethyl)oxy]-2-thiophenecarboxylate
##STR00174##
[0702] Methyl
5-(1H-benzimidazol-1-yl)-3-{[(1R)-1-(2-chloro-3-hydroxyphenyl)ethyl]oxy}--
2-thiophenecarboxylate (Intermediate 11A, 125 mg, 0.29 mmol) and
1-methyl-4-piperidinol (41 .mu.l, 0.35 mmol) were coupled using a
procedure analogous to Example 4, Step A to give 84 mg of the
desired product (55%). MS m/z=526 [M+H].sup.+.
Step
B--5-(1H-benzimidazol-1-yl)-3-[((1R)-1-{2-chloro-3-[(1-methyl-4-piper-
idinyl)oxy]phenyl}ethyl)oxy]-2-thiophenecarboxamide (Title
Compound)
[0703] Methyl
5-(1H-benzimidazol-1-yl)-3-[((1R)-1-{2-chloro-3-[(1-methyl-4-piperidinyl)-
oxy]phenyl}ethyl)oxy]-2-thiophenecarboxylate (84 mg, 0.16 mmol) was
subjected to aminoSysis procedure analogous to Example 4, Step B to
give 58 mg of the title compound (71%). .sup.1H NMR (400 MHz,
d.sub.6-DMSO) .delta. 8.53 (s, 1h), 7.79-7.73 (m, 2H), 7.50-7.48
(m, 1H), 7.34-7.29 (m, 3H), 7.19-7.09 (m, 4H), 5.97 (m, 1H), 4.44
(m, 1H), 2.48-2.47 (m under DMSO peak, 2H), 2.14-2.11 (m, 5H), 1.86
(m, 2H), 1.69 (d, J=6.4 Hz, 3H), 1.70-1.59 (m, 2H). HRMS calculated
[M+H].sup.+ C.sub.26H.sub.28ClN.sub.4O.sub.3S 511.1571, found
511.1574.
EXAMPLE 14
5-(1H-Benzimidazol-1-yl)-3-({(1R)-1-[2-chloro-3-(4-piperidinyloxy)phenyl]e-
thyl}oxy)-2-thiophenecarboxamide
##STR00175##
[0704] Step A--1,1-Dimethylethyl
4-({3-[(1R)-1-({5-(1H-benzimidazol-1-yl)-2-[(methyloxy)carbonyl]-3-thieny-
l}oxy)ethyl]-2-chlorophenyl}oxy)-1-piperidinecarboxylate
##STR00176##
[0706] Methyl
5-(1H-benzimidazol-1-yl)-3-{[(1R)-1-(2-chloro-3-hydroxyphenyl)ethyl]oxy}--
2-thiophenecarboxylate (Intermediate 11A, 125 mg, 0.29 mmol) and
1,1-dimethylethyl 4-hydroxy-1-piperidinecarboxylate (70 mg, 0.35
mmol) were coupled using a procedure analogous to Exampls 5, Step A
to give 103 mg of the desired product (58%). .sup.1H NMR (400 MHz,
d.sub.6-DMSO) .delta. 8.63 (s, 1H), 7.77-7.75 (m, 1H), 7.63-7.61
(m, 1H), 7.37-7.28 (m, 5H), 7.16 (d, J=8.0 Hz, 1H), 5.95 (m, 1H),
4.64 (m, 1H), 3.80 (s, 3H), 3.53 (M, 2H), 3.28-3.21 (m, 2H), 1.59
(d, J=6.0 Hz, 3H), 1.60-1.52 (m, 2H), 1.37 (s, 9H).
Step
B--1,1-Dimethylethyl-4-{[3-((1R)-1-{[2-(aminocarbonyl)-5-(1H-benzimid-
azol-1-yl)-3-thienyl]oxy}ethyl)-2-chlorophenyl]oxy}-1-piperidinecarboxylat-
e
##STR00177##
[0708] 1,1-Dimethylethyl
4-({3-[(1R)-1-({5-(1H-benzimidazol-yl)-2-[(methyloxy)carbonyl]-3-thienyl}-
oxy)ethyl]-2-chlorophenyl}oxy}-1-piperidinecarboxylate (103 mg,
0.17 mmol) was subjected to aminolysis according to the procedure
analogous to Example 5, Step B to give 75 mg of the desired product
(74%). .sup.1H NMR (400 MHz, d.sub.6-DMSO) .delta. 8.55 (s, 1H),
7.80 (br s, 1H), 7.77-7.74 (m, 1H), 7.52-7.49 (m, 1H), 7.36-7.32
(m, 3H), 7.23-7.18 (m, 2H), 7.13 (s, 1H), 7.10 (br s, 1H), 5.98
(m,1H), 4.67-4.64 (m, 1H), 3.56-3.52 (m, 2H), 3.27-3.21 (m, 2H),
1.85 (m, 2H), 1.70 (d, J=6.4 Hz, 3H), 1.58-1.54 (m, 2H), 1.38 (s,
9H).
Step
C--5-(1H-benzimidazol-1-yl)-3-({(1R)-1-[2-chloro-3-(4-piperidinyloxy)-
phenyl]-ethyl}oxy)-2-thiophenecarboxamide (Title Compound)
[0709] 1,1-Dimethylethyl
4-{[3-((1R)-1-{[2-(aminocarbonyl)-5-(1H-benzimidazol-1-yl)-3-thienyl]oxy}-
ethyl)-2-chlorophenyl]oxy}-1 -piperidinecarboxylate (75 mg, 0.13
mmol) was deprotected using a procedure analogous to Example 5,
Step C to give 65 mg of the title compound (99%). .sup.1H NMR (400
MHz, d.sub.6-DMSO) .delta. 8.54 (s, 1H), 7.79 (br s, 1H), 7.75 (m,
1H), 7.50 (m, 1H), 7.36-7.30 (m, 3H), 7.23-7.17 (m, 2H), 7.12 (s,
1H), 7.09 (br s, 1H), 5.97 (m, 1H), 4.62 (m, 1H), 3.05 (m, 2H),
2.83 (m, 2H), 1.96 (m, 2H), 1.70-1.59 (m, 5H). HRMS calculated
[M+H].sup.+ C.sub.25H.sub.26ClN.sub.4O.sub.3S 497.1414, found
497.1421.
EXAMPLE 15
5-(1H-benzimidazol-1-yl)-3-{[(1R)-1-(2-chloro-3-{[2-(4-morpholinyl)ethyl]o-
xy}phenyl)ethyl]oxy}-2-thiophenecarboxamide
##STR00178##
[0710] Step A--Methyl
5-(1H-benzimidazol-1-yl)-3-{[(1R)-1-(2-chloro-3-{[2-(4-morpholinyl)-ethyl-
]oxy}phenyl)ethyl]oxy}-2-thiophenecarboxylate
##STR00179##
[0712] To a solution of methyl
5-(1H-benzimidazol-1-yl)-3-[((1R)-1-{3-[(2-bromoethyl)oxy]-2-chlorophenyl-
}ethyl)oxy]-2-thiophenecarboxylate (Intermediate 11B, 95 mg, 0.18
mmol) in 2 mL THF was added morpholine (63 .mu.L, 0.72 mmol) and
the reaction was heated to 60.degree. C. After 16 h, the reaction
was cooled to rt and diluted with DCM. The organic solution was
washed with water, dried over MgSO.sub.4 and concentrated onto
silica gel. The crude material was purified by flash column
chromatography to give 73 mg of the desired product (75%). .sup.1H
NMR (400 MHz, d.sub.6-DMSO) .delta. 8.63 (s, 1H), 7.76 (d, J=7.2
Hz, 1H), 7.59 (d, J=7.6 Hz, 1H), 7.37-7.31 (m, 4H), 7.26 (d, J=7.6
H, 1H), 7.09 (d, J=8.0 Hz, 1H), 5.96 (m, 1H), 4.14 (t, J=5.8 Hz,
2H), 3.80 (s, 3H), 3.52 (t, J=4.4 Hz, 4H), 2.69 (t, J=5.6 Hz, 2H),
2.47 (m under DMSO peak, 4H), 1.59 (d, J=6.4 Hz, 3H).
Step
B--5-(1H-benzimidazol-1-yl)-3-{[(1R)-1-(2-chloro-3-{[2-(4-morpholinyl-
)ethyl]-oxy}phenyl)ethyl]oxy}-2-thiophenecarboxamide (Title
Compound)
[0713] Methyl
5-(1H-benzimidazol-1-yl)-3-{[(1R)-1-(2-chloro-3-{[2-(4-morpholinyl)-ethyl-
]oxy}phenyl)ethyl]oxy}-2-thiophenecarboxylate (71 mg, 0.13 mmol)
was subjected to aminolysis procedure analogous to Exsmple 4, Step
B to give 57 mg of the title compound (83%). .sup.1H NMR (400 MHz,
d.sub.6-DMSO) .delta. 8.53 (s, 1H), 7.79-7.73 (m, 2H), 7.47 (d,
J=7.6 Hz, 1H), 7.35-7.31 (m, 3H), 7.19 (d, J=7.6 Hz, 1H), 7.12-7.09
(m, 3H), 5.97 (m, 1H), 4.14 (t, J=5.6 Hz, 2H), 3.51-3.49 (m, 4H),
2.69 (t, J=5.6 Hz, 2H), 2.47 (m under DMSO peak, 4H), 1.68 (d,
J=6.4 Hz, 3H). HRMS calculated [M+H].sup.+
C.sub.26H.sub.28ClN.sub.4O.sub.4S 527.1520, found 527.1527.
EXAMPLE 16
5-(1H-benzimidazol-1-yl)-3-{[(1R)-1-(2-chloro-3-{[2-(1-piperazinyl)ethyl]o-
xy}phenyl)ethyl]oxy}-2-thiophenecarboxamide
##STR00180##
[0714] Step A--Methyl
5-(1H-benzimidazol-1-yl)-3-{[(1R)-1-(2-chloro-3-{[2-(1-piperazinyl)ethyl]-
oxy}phenyl)ethyl]oxy}-2-thiophenecarboxylate
##STR00181##
[0716] Methyl
5-(1H-benzimidazol-yl)-3-[((1R)-1-{3-[(2-bromoethyl)oxy]-2-chlorophenyl}e-
thyl)oxy]-2-thiophenecarboxylate (Intermediate 11B, 125 mg, 0.23
mmol) and 1,1-dimethylethyt 1-piperazinecarboxylate (171 mg, 0.92
mmol) were coupled using a procedure analogous to Example 15, Step
A to give 89 mg of the desired product (61%). .sup.1H NMR (400 MHz,
d.sub.6-DMSO) .delta. 8.63 (s, 1H), 7.75 (d, J=7.2 Hz, 1H), 7.59
(d, J=7.2 Hz, 1H), 7.38-7.31 (m, 4H), 7.26 (d, J=7.2 Hz, 1H), 7.09
(d, J=8.0 Hz, 1H), 5.96 (m, 1H), 4.13 (t, J=5.6 Hz, 2H), 3.80 (s,
3H), 3.25 (m, 4H), 2.72 (t, J=5.6 Hz, 2H), 2.43 (m, 4H), 1.59 (d,
J=6.4 Hz, 3H), 1.35 (s, 9H).
Step B--1,1-Dimethylethyl
4-(2-{[3-((1R)-1-{[2-(aminocarbonyl)-5-(1H-benzimidazol-1-yl)-3-thienyl]o-
xy}ethyl)-2-chlorophenyl]oxy}ethyl)-1-piperazinecarboxylate
##STR00182##
[0718] Methyl
5-(1H-benzimidazol-1-yl)-3-{[(1R)-1-(2-chloro-3-{[2-(1-piperazinyl)ethyl]-
oxy}-phenyl)ethyl]oxy}-2-thiophenecarboxylate (84 mg, 0.13 mmol)
was subjected to aminolysis procedure analogous to Example 5, Step
B to give 53 mg of the desired product (65%). MS m/z=626
[M+H].sup.+.
Step
C--5-(1H-benzimidazol-1-yl)-3-{[(1R)-1-(2-chloro-3-{[2-{1-piperazinyl-
)ethyl]oxy}phenyl)ethyl]oxy}-2-thiophenecarboxamide (Title
Compound)
[0719] 1,1-Dimethylethyl
4-(2-{[3-((1R)-1-{[2-(aminocarbonyl)-5-(1H-benzimidazol-1-yl)-3-thienyl]o-
xy}ethyl}-2-chSorophenyl]oxy}ethyl)-1-piperazinecarboxylate (53 mg,
8.5 mmol) was deprotected using procedure analogous to Example 5,
Step C to give 44 mg of the title compound (99%). .sup.1H NMR (400
MHz, d.sub.6-DMSO) .delta. 8.55 (s, 1H), 7.80 (br s, 1H), 7.77-7.75
(m, 1H), 7.50-7.48 (m, 1H), 7.37-7.33 (m, 3H), 7.21 (d, J=7.6 Hz,
1H), 7.13-7.10 (m, 3H), 5.98 (m, 1H), 4.14 (t, J=5.6 Hz, 2H),
2.80-2.78 (m. 4H), 2.72 (t, J=5.6 Hz, 2H), 2.51 (m, 4H), 1.70 (d,
J=6.4 Hz, 3H). HRMS calculated [M+H].sup.+
C.sub.26H.sub.29ClN.sub.5O.sub.3S 526.1680, found 526.1677.
EXAMPLE 17
5-(1H-benzimidazol-1-yl)-3-{[(1R)-1-(2-chloro-3-{[2-(4-methyl-1-piperaziny-
l)ethyl]oxy}phenyl)ethyl]ocy}-2-thiophenecarboxanide
##STR00183##
[0720] Step A--Methyl
5-(1H-benzimidazol-1-yl)-3-{[(1R)-1-(2-chloro-3-{[2-(4-methyl-1-piperazin-
yl)ethyl]oxy}phenyj)ethyl]oxy}-2-thiophenecarboxylate
##STR00184##
[0722] Methyl
5-(1H-benzimidazol-1-yl)-3-[((1R)-1-{3-[(2-bromoethyl)oxy]-2-chlorophenyl-
}ethyl)oxy]-2-thiophenecarboxylate (Intermediate 11B, 125 mg, 0.23
mmol) and 1-methylpiperazine (102 .mu.L, 0.92 mmol) were coupled
using a procedure analogous to Example 15, Step A to give 82 mg of
the desired product (64%). .sup.1H NMR (400 MHz, d.sub.6-DMSO)
.delta. 8.63 (s, 1H), 7.76 (d, J=7.6 Hz, 1H), 7.59 (d, J=7.6 Hz,
1H), 7.39-7.31 (m, 4H), 7.25 (d, J=7.6 Hz, 1H), 7.09 (d, J=8.0 Hz,
1H), 5.95 (m, 1H), 4.11 (t, J=5.8 Hz, 2H), 3.80 (s, 3H), 2.68 (t,
J=5.6 Hz, 2H), 2.47 (m under DMSO peak, 4H), 2.24 (m, 4H), 2.08
(s,3H), 1.59 (d, J=6.4 Hz, 3H).
Step
B--5-(1H-benzimidazol-1-yl)-3-{[(1R)-1-(2-chloro-3-{[2-(4-methyl-1-pi-
perazinyi)ethyl]oxy}phenyl)ethyl]oxy}-2-thiophenecarboxamide (Title
Compound)
[0723] Methyl
5-(1H-benzimidazol-1-yl)-3-{[(1R)-1-(2-chloro-3-{[2-(4-methyl-1-piperazln-
yl)ethyl]oxy}phenyl)ethyl]oxy}-2-thiophenecarboxylate (80 mg, 0.14
mmol) was subjected to aminofysis procedure analogous to Example 5,
Step B to give 69 mg of the title compound (91%). .sup.1H NMR (400
MHz, d.sub.6-DMSO) .delta. 8.53 (s, 1H), 7.78-7.73 (m, 2H), 7.47
(d, J=7.6 Hz, 1H), 7.36-7.29 (m, 3H), 7.18 (d, J=8.0 Hz, 1H),
7.11-7.09 (m, 3H), 5.97 (m, 1H), 4.12 (t, J=5.6 Hz, 2H), 2.68 (t,
J=5.6 Hz, 2H), 2.47 (m under DMSO peak, 4H), 2.23 9M, 4H), 2.08 (s,
3H), 1.68 (d, J=6.0 Hz, 3H). HRMS calculated [M+H].sup.+
C.sub.27H.sub.31ClN.sub.5O.sub.3S 540.1836, found 540.1837.
EXAMPLE 18
3-[((1R)-1-{2-chloro-3-[(1-methyl-4-piperidinyl)oxy]phenyl}ethyl)oxy]-5-(5-
-{6-[(1-methyl-4-piperidinyl)amino]-3-pyridinyl}-1H-benzimidazol-1-yl)-2-t-
hiophenecarboxamide
##STR00185##
[0724] Step A--Methyl
3-{[(1R)-1-(2-chloro-3-hydroxyphenyl)ethyl]oxy}-5-[5-(6-fluoro-3-pyridiny-
l)-1H-benzimidazol-1-yl]-2-thiophenecarboxylate
##STR00186##
[0726] Methyl
5-(5-bromo-1H-benzimidazol-1-yl)-3-{[(1R)-1-(2-chloro-3-{[(1,1-dimethylet-
hyl)(dimethyl)silyl]oxy}phenyl)ethyl]oxy}-2-thiophenecarboxylate
(Intermediate 8, 930 mg, 1.5 mmol) and
(6-fluoro-3-pyridinyl)boronic acid (250 mg, 1.8 mmol) were coupled
using a procedure analogous to Intermediate 9 to give 781 mg of the
desired product (99%). .sup.1H NMR (400 MHz, d.sub.6-DMSO) .delta.
10.27 (s, 1H), 8.71 (s, 1H), 8.60 (s, 1H), 8.36-8.32 (m, 1H), 8.13
(s, 1H), 7.72-7.67 (m, 2H), 7.35 (s, 1H), 7.27 (dd, J=8.4 and 2.8
Hz, 1H), 7.20-7.11 (m, 2H), 6.90 (d, J=7.6 Hz, 1H), 5.94 (m, 1H),
3.80 (s, 3H), 1.59 (d, J=6.0 Hz, 3H).
Step B--Methyl
3-[((1R)-{2-chloro-3-[(1-niethyl-4-piperidinyl)oxy]phenyl}ethyl)oxy]-5-[5-
-(6-fluoro-3-pyridinyl)-1H-benzimidazol-1-yl}-2-thiophenecarboxylate
##STR00187##
[0728] Methyl
3-{[(1R)-1-(2-chloro-3-hydroxyphenyl)ethyl]oxy}-5-[5-(6-fluoro-3-pyridiny-
l)-1H-benzimidazol-1-yl]-2-thiophenecarboxylate (300 mg, 0.57 mmol)
and 1-methyl-4-piperidinol (80 .mu.L, 0.68 mmol) were coupled using
a procedure analogous to Example 4, Step A to give 274 mg of the
desired product (77%). .sup.1H NMR (400 MHz, d.sub.6-DMSO) .delta.
8.70 (s, 1H), 8.59 (s, 1H), 8.35-8.31 (m, 1H), 8.13 (s, 1H),
7.73-7.68 (m, 2H), 7.38 (s, 1H), 7.34-7.25 (m, 3H), 7.13 (d, J=7.6
Hz, 1H), 5.96 (m, 1H), 4.44 (m, 1H), 3.81 (s, 3H), 2.54-2.46 (m,
2H), 2.20-2.11 (m, 5H), 1.83 (m, 2H), 1.66-1.59 (m, 5H).
Step
C--3-[((1R)-1-{2-chloro-3-[(1-methyl-4-piperidinyl)oxy]phenyl}ethyl)o-
xy]-5-[5-(6-fluoro-3-pyridinyl)-1H-benzimidazol-1-yl]-2-thiophenecarboxami-
de
##STR00188##
[0730] Methyl
3-[((1R)-1-{2-chloro-3-[(1-methyl-4-plperidinyl)oxy]phenyl}ethyl)oxy]-5-[-
5-(6-fluoro-3-pyridinyl)-1H-benzimidazol-1-yl]-2-thiophenecarboxylate
(274 mg, 0.44 mmol) was subjected to aminolysis according to a
procedure analogous to Example 4, Step B to give 200 mg of the
desired product (75%). .sup.1H NMR (400 MHz, d.sub.6-DMSO) .delta.
8.63 (s, 1H), 8.60 (d, J=2.1 Hz, 1H), 8.37-8.32 (m, 1H), 8.13 (d,
J=1.6 Hz, 1H), 7.82 (br s, 1H), 7.69-7.67 (m, 1H), 7.60 (d, J=8.4
Hz, 1H), 7.35-7.27 (m, 2H), 7.21 (d, J=7.6 Hz, 1H), 7.17-7.14 (m,
2H), 7.11 (br s, 1H), 5.99 (m, 1H), 4.45 (m, 1H), 2.52-2.45 (m
under DMSO peak, 2H), 2.19-2.06 (m, 5H), 1.85-1.74 (m, 2H),
1.70-1.60 (m, 5H).
Step
D--3-[((1R)-1-{2-Chloro-3-[(1-methyl-4-piperidinyl)oxy]phenyl}ethyl)o-
xy]-5-(5-{6-[(1-methyl-4-piperidinyl)amino]-3-pyridinyl}-1H-benzimidazol-1-
-yl)-2-thiophenecarboxamide (Title Compound)
[0731]
3-[((1R)-1-{2-chloro-3-[(1-methyl-4-piperidinyl)oxy]prienyl}ethyl)o-
xy]-5-[5-(6-fluoro-3-pyridinyl)-1H-benzimidazol-1-yl]-2-thiophenecarboxami-
de (100 mg, 0.16 mmol) in 1 mL of 1-methyl-4-piperidinamine and 1
mL of i-PrOH was heated in the microwave at 180 .degree. C. in
cycles of 40 min each until there was more product than starting
material. The reaction was diluted with DCM and washed 3.times.
with water. The organic phase was dried over MgSO.sub.4 and
concentrated. The crude material was purified by reverse phase
liquid chromatography to give 16 mg of the title compound (14%).
.sup.1H NMR (400 MHz, d.sub.6-DMSO) .delta. 8.56 (s, 1H), 8.32 (s,
1H), 7.89 (s, 1H), 7.80 (s, 1H), 7.72-7.70 (m, 1H), 7.53-7.45 (m,
2H), 7.35-7.31 (m, 1H), 7.20-7.10 (m, 4H), 6.54-6.52 (m, 2H), 5.98
(m, 1H), 4.46 (m, 1H). 3.69 (m, 1H), 2.74-2.71 (m, 2H), 2.48 (m
under DMSO peak, 2H), 2.16-1.86 (m, 14H), 1.71-1.63 (m, 5H),
1.45-1.42 (m. 2H). MS (ESI) m/z=700.63 [M+H].sup.+.
EXAMPLE 19
5-(5-Chloro-1H-benzimidazol-1-yl)-3-[((1R)-1-{2-chloro-3-[(1-ethyl-4-piper-
idinyl)oxy]phenyl}ethyl)oxy]-2-thiophenecarboxamide
##STR00189##
[0732] Step A--Methyl
5-{5-chloro-1H-benzimidazol-1-yl)-3-[((1R)-1-{2-chloro-3-[(1-ethyl-4-pipe-
ridinyl)oxy]phenyl}ethyl)oxy]-2-thiophenecarboxylate
##STR00190##
[0734] To a solution of methyl
5-(5-chloro-1H-benzimidazol-1-yl)-3-({(1R)-1-[2-chloro-3-{4-piperidinylox-
y)phenyl]ethyl}oxy)-2-thiophenecarboxylate (Intermediate 12, 100
mg, 0.18 mmol) in 3 mL of acetonitrile was added Na.sub.2CO.sub.3
(23 mg, 0.22 mmol) and bromoethane (67 .mu.L, 0.90 mmol) and the
reaction was heated at 75 .degree. C. When the reaction was
complete, it was concentrated onto silica gel and purified by flash
column chromatography to give 85 mg of the desired producA (83%).
MS (ESI) m/z=574.23 [M+H].sup.+.
Step
B--5-(5-Chloro-1H-benzimidazol-1-yl)-3-[((1R)-1-{2-chloro-3-[(1-ethyl-
-4-piperidinyl)oxy]phenyl}ethyl)oxy]-2-thiophenecarboxamide (title
compound)
[0735] Methyl
5-(5-chloro-1H-benzimidazol-yl)-3-[((1R)-1-{2-chloro-3-[(1-ethyl-4-piperi-
dinyl)oxy]phenyl}ethyl)oxy]-2-thiophenecarboxylate (85 mg, 0.15
mmol) was subjected to aminolysis procedure analogous to Example 4,
Step B to give 68 mg of the title compound (81%). .sup.1H NMR (400
MHz, d.sub.6-DMSO) .delta. 8.61 (s, 1H), 7.83 (s, 1H), 7.81 (br s,
1H), 7.59 (d, J=8.8 Hz, 1H), 7.35-7.29 (m, 2H), 7.19-7.09 (m, 4H),
5.95 (m, 1H), 4.45 (m, 1H), 23.58-2.47 (m, 2H), 2.27-2.13 (m, 4H),
1.85 (m, 2H), 1.68 (d, J=6.4 Hz, 3H), 1.61 (m, 2H), 0.94 (t, J=7.0
Hz, 3H). HRMS calculated [M+H].sup.+
C.sub.27H.sub.29Cl.sub.2N.sub.4O.sub.3S 559.1337, found
559.1337.
EXAMPLE 20
5-(5-Chloro-1H-benzimidazol-1-yl)-3-{[(1R)-1-(2-chloro-3-{[1-(2-hydroxyeth-
yl)-4-piperidinyl]oxy}phenyl)ethyl]oxy}-2-thiophenecarboxamide
##STR00191##
[0736] Step A--Methyl
5-(5-chloro-1H-benzimidazol-1-yl)-3-{[(1R)-1-(2-chloro-3-{[1-(2-hydroxyet-
hyl)-4-piperidinyl]oxy}phenyl)ethyl]oxy}-2-thiophenecarboxylate
##STR00192##
[0738] Methyl
5-(5-chloro-1H-benzimidazol-1-yl)-3-({(1R)-1-[2-chloro-3-(4-piperidinylox-
y)phenyl]ethyl}oxy)-2-thiophenecarboxylate (Intermediate 12, 100
mg, 0.18 mmol) and 2-brornoethanol (16 .mu.L, 0.22 mmol) were
coupled using a procedure analogous to Example 19, Step A to give
the (82 mg, 77%) of the desired product. .sup.1H NMR (400 MHz,
d.sub.6-OMSO) .delta. 8.70 (s, 1H), 7.85 (m, 1H), 7.63 (d, J=8.8
Hz, 1H), 7.39-7.37 (m, 2H), 7.33-7.25 (M, 2H), 7.12 (d, J=7.6 Hz,
1H), 5.93 (m, 1H), 4.44 (m, 1H), 4.31 (M, 1H), 3.80 (s, 3H),
3.46-3.42 (m, 2H), 2.63 (m, 2H), 2.35-2.32 (m, 2H), 2.24 (m, 2H),
1.85 (m, 2H), 1.62-1.58 (m, 5H).
Step
B--5-(5-Chloro-1H-benzimidazol-1-yl)-3-{[(1R)-1-(2-chloro-3-{[1-(2-hy-
droxyethyl)-4-piperidinyl]oxy}phenyl)ethyl]oxy}-2-thiophenecarboxamide
(Title Compound)
[0739] Methyl
5-(5-ehioro-1H-benzimidazol-1-yl)-3-{[(1R)-1-(2-chloro-3-{[1-(2-hydroxyet-
hyl)-4-piperidinyl]oxy}phersyl)ethyl]oxy}-2-thioph8necarboxylate
(82 mg, 14 mmol) was subjected to amsnclysis procedure analogous to
Example 4, Step B to give 68 mg (85%) of the title compound.
.sup.1H NMR (400 MHz, d.sub.6-DMSO) .delta. 8.61 (s, 1H), 7.84-7.83
(m, 1H),7.81 (br s, 1H), 7.50 (d, J=8.8 Hz, 1H), 7.36-7.29 (m, 2H),
7.19-7.13 (m, 3H), 7.09 (br s, 1H), 5.95 (m, 1H), 4.44 (m, 2H),
4.32 (m, 1H), 3.44 (q, J=6.0 Hz, 2H), 2.61 (m, 2H), 2.35-2.32 (m,
2H), 2.23 (m, 2H), 1.85 (m, 2H), 1.68 (d, J=6.0 Hz, 3H), 1.61 (m,
2H). HRMS calculated [M+H].sup.+
C.sub.26H.sub.29Cl.sub.2N.sub.4O.sub.4S 575.1287, found
575.1297.
EXAMPLE 21
5-(5-Chloro-1H-benzimidazol-1-yl)-3-{[(1R)-1-(2-chloro-3-{[1-(2-fluoroethy-
l)-4-pipeildinyl]oxy}phenyl)ethyl]oxy}-2-thiophenecarboxamide
##STR00193##
[0740] Step A--Methyl
5-(5-chloro-1H-benzimidazol-1-yl)-3-{[(1R)-1-(2-chloro-3-{[1-(2-fluoroeth-
yl)-4-piperidinyl]oxy}phenyl)ethyl]oxy}-2-thiophenecarboxylate
##STR00194##
[0742] Methyl
5-{5-chloro-1H-benzimidazol-1-yl)-3-({(1R)-1-[2-chloro-3-(4-piperidinylox-
y)phenyl]ethyl}oxy)-2-thiophenecarboxylate (Intermediate 12, 100
mg, 0.16 mmol) and 1-bromo-2-fluoroethane were coupled using a
procedure analogous to Example 19, Step A to give 79 mg of the
desired product (74%). .sup.1H NMR (400 MHz, d.sub.6-DMSO) .delta.
8.70 (s, 1H), 7.85 (s, 1H), 7.63 (d, J=8.8 Hz, 1H), 7.39-7.37 (m,
2H), 7.33-7.25 (m, 2H), 7.13 (d, J=7.6 Hz, 1H), 5.94 (m, 1H),
4.55-4.52 (m, 1H), 4.47-4.40 (m, 2H), 3.80 (s, 3H), 3.26-2.59 (m,
3H), 2.55-2.52 (m, 1H), 2.30 (m, 2H), 1.87 (m, 2H), 1.65-1.58 (m,
5H).
Step
B--5-(5-Chloro-1H-benzimidazol-1-yl)-3-{[(1R)-1-(2-chloro-3-{[1-(2-fl-
uoroethyl)-4-pipeildinyl]oxy}phenyl)ethyl]oxy}-2-thiophenecarboxamide
(Title Compound)
[0743] Methyl
5-(5-chloro-1H-benzimidazol-1-yl)-3-{[(1R)-1-(2-chloro-3-{[1-(2-fluoroeth-
yl)-4-piperidinyl]oxy}phenyl)ethyl]oxy}-2-thiophenecarboxylate (79
mg, 0.13 mmol) was subjected to aminolysis procedure analogous to
Example 4, Step B to give 24 mg of the title compound (32%).
.sup.1H NMR (400 MHz, d.sub.6-DMSO) .delta. 8.38 (s, 1H), 7.71 (s,
1H), 7.32-7.28 (m, 3H), 7.15 (d. J=7.6 Hz, 1H), 7.09 (d, J=7.6 Hz,
1H), 6.92 (s, 1H), 6.06-6.02 (m, 1H), 4.62-4.60 (m, 1H), 4.53-4.48
(m, 2H), 2.81-2.26 (M, 4H), 2.50 (m, 1H), 2.43 (m, 1H), 2.40-1.92
(m, 2H), 1.88-1.80 (m, 2H), 1.76 (d, J=6.0 Hz, 3H). HRMS calculated
[M+H].sup.+ C.sub.27H.sub.28Cl.sub.2FN.sub.4O.sub.3S 577.1243,
found 577.1248.
EXAMPLE 22
3-{[(1R)-1-(3-{[1-(2-aminoethyl)-4-piperidinyl]oxy}-2-chlorophenyl)ethyl]o-
xy}-5-(5-chloro-1H-benzimidazol-1-yl)-2-thiophenecarboxamide
##STR00195##
[0745] Methyl
5-(5-chloro-1H-benzimidazol-1-yl)-3-{[(1R)-1-(2-chloro-3-{[1-(2-fluoroeth-
yl)-4-piperidinyl]oxy}phenyl)ethyl]oxy}-2-thiophenecarboxylate
(Example 21, 79 mg, 0.13 mmol) was subjected to aminolysis
procedure analogous to Example 4, Step B to give 43 mg of the title
compound (58%). .sup.1H NMR (400 MHz, d.sub.6-DMSO) .delta. 8.61
(s, 1H), 7.84-7.80 (m, 2H), 7.50 (d, J=8.8 Hz, 1H), 7.36-7.31 (m,
2H), 7.29-7.09 (m, 4H), 5.95 (m, 1H), 4.46 (m, 1H), 3.29 (s, 2H),
2.56 (m, 4H), 2.25-2.16 (m, 4H), 1.85 (m, 2H), 1.68 (d, J=6.4 Hz,
3H), 1.64-1.59 (m, 2H). HRMS calculated [M+H].sup.+
C.sub.27H.sub.30Cl.sub.2N.sub.5O.sub.3S 574.1446, found
574.1437.
EXAMPLE 23
5-(5-Chloro-1H-benzimidazol-1-yl)-3-({(1R)-1-[2-chloro-3-({1-[2-(methylsul-
fonyl)ethyl]-4-piperidinyl}oxy)phenyl]ethyl}oxy)-2-thiophenecarboxamide
##STR00196##
[0747] A solution of
5-{5-chloro-1H-benzimidazol-1-yl)-3-({(1R)-1-[2-chloro-3-(4-piperidinylox-
y)phenyl]ethyl}oxy}-2-thiophenecarboxamide (Intermediate 12, 112
mg, 0.21 mmol) and methyl vinyl sulfone (22 .mu.L, 0.25 mmol) in 2
mL THF were stirred until the starting material was consumed. The
reaction was concentrated onto silica gel and purified by flash
column chromatography to give 105 mg of the title compound (78%).
.sup.1H NMR (400 MHz, d.sub.6-DMSO) .delta. 8.61 (s, 1H), 7.83 (m,
1H), 7.80 (br s, 1H), 7.51 (d, J=8.8 Hz, 1H), 7.36-7.29 (m, 2H),
7.20-7.13 (m, 3H), 7.08 (br s, 1H), 5.95 (m, 1H), 4.48 (m, 1H),
3.25-3.21 (m, 2H), 2.99 (s, 3H), 2.67-2.64 (m, 4H), 2.29 (m, 2H),
1.85 (m, 2H), 1.68 (d, J=6.0 Hz, 3H), 1.62 (m, 2H). HRMS calculated
[M+H].sup.+ C.sub.28H.sub.31Cl.sub.2N.sub.4O.sub.5S.sub.2 637.1113,
found 637.1120.
EXAMPLE 24
5-(5-Chloro-1H-benzimidazol-1-yl)-3-{[(1R)-1-(2-chloro-3-{[1-(1-methylethy-
l)-4-piperidinyl]oxy}phenyl)ethyl]oxy}-2-thiophenecarboxamide
##STR00197##
[0748] Step A--Methyl
5-(5-chloro-1H-benzimidazol-1-yl)-3-{[(1R)-1-(2-chloro-3-{[1-(1-methyleth-
yl)-4-piperidinyl]oxy}phenyl)ethyl]oxy}-2-thiophenecarboxylate
##STR00198##
[0750] Methyl
5-(5-chloro-1H-benzimidazol-1-yl)-3-({(1R)-1-[2-chloro-3-(4-piperidinylox-
y)phenyl]ethyl}oxy)-2-thiophenecarboxylate (Intermidiate 12, 100
mg, 0.18 mmol) and 2-bromopropane were coupled using a procedure
analogous to Example 19, Step A to give 38 mg of the desired
product (36%). MS (ESI) m/z=588.25 [M+H].sup.+.
Step
B--5-(5-Chloro-1H-benzimidazol-1-yl)-3-{[(1R)-1-(2-chloro-3-{[1-(1-me-
thylethyl)-4-piperidinyl]oxy}phenyl)ethyl]oxy}-2-thiophenecarboxamide
(Title Compound)
[0751] Methyl
5-(5-chloro-1H-benzimidazol-1-yl)-3-{[(1R)-1-(2-chloro-3-{[1-(1-methyleth-
yl)-4-piperidinyl]oxy}phenyl)ethyl]oxy}-2-thiophenecarboxylate (38
mg, 0.06 mmol) was subjected to amlnoiysis procedure analogous to
Example 4S Step 3 to give 24 mg of the title compound (71%).
.sup.1H NMR (400 MHz, d.sub.6-DMSO) .delta. 8.40 (s, 1H), 7.72 (s,
1H), 7.34-7.30 (m, 3H), 7.17 (d, J=7.6 Hz, 1H), 7.11 (d, J=8.4 Hz,
1H), 6.93 (s, 1H), 6.08-6.03 (m, 1H), 4.55 (m, 1H), 2.87-2.83(m,
1H), 2.78-2.73 (m, 2H), 2.53 (m, 1H), 2.44 (m, 1H), 2.00-1.77 (m,
4H), 1.78 (d, J=6.4 Hz, 3H), 1.07 (d, J=6.4 Hz, 6H). HRMS
calculated [M+H].sup.+ C.sub.28H.sub.31Cl.sub.2N.sub.4S 573.1494,
found 573.1499.
EXAMPLE 25
3-{[(1R)-1-(2-chloro-3-{[2-(4-morpholinyl)ethyl]oxy}phenyl)ethyl]oxy}-5-[5-
-(1-methyl-1H-pyrazol-4-yl)-1H-benzimidazol-1-yl]-2-thiophenecarboxamide
##STR00199##
[0752] Step A--Methyl
3-[((1R)-1-{3-[(2-bromoethyl)oxy]-2-chlorophenyl]ethyl)oxy}-5-[5-(1-rneth-
yl-1H-pyrazol-4-yl)-1H-benzimidazol-1-yl]-2-thiophenecarboxylate
##STR00200##
[0754] Methyl
3-{[(1R)-1-(2-chloro-3-hydroxyphenyl)ethyl]oxy}-5-[5-(1-methyl-1H-pyrazol-
-4-yl)-1H-benzimidazol-1-yl]-2-thiophenecarboxylate (Intermediate
18, 200 mg, 0.39 mmol) and 2-bromoethanol (33 .mu.L, 0.47 mmol)
were coupled using a procedure analogous to Example 4, Step A to
give 191 mg of the desired product (80%). MS (ESI) m/z=615
[M+H].sup.+.
Step B--Methyl
3-{[(1R)-1-(2-chloro-3-{[2-(4-morpholinyl)ethyl]oxy}phenyl)ethyl]oxy}-5-[-
5-(1-methyl-1H-pyrazol-4-yl)-1H-benzimidazol-1-yl]-2-thiophenecarboxylate
##STR00201##
[0756] Methyl
3-[((1R)-1-{3-[(2-bromoethyl)oxy]-2-chlorophenyl}ethyl)oxy]-5-[5-(1-methy-
l-1H -pyrazal-4-yl)-1H-benzimidazol-1-yl]-2-thiophenecarboxylate
(191 mg, 0.31 mmol) and morpholine (105 .mu.L, 1.2 mmol} were
coupled using a procedure analogous to Example 15, Step A to give
96 mg of the desired product (50%). .sup.1H NMR (400 MHz,
d.sub.6-DMSO) .delta. 8.63 (s, 1H), 8.19 (s, 1H), 7.96 (s, 1H),
7.92 (s, 1H), 7.57 (s, 2H), 7.37-7.33 (m, 2H), 7.28-7.26 (m, 1H),
7.11 (d, J=8.0 Hz, 1H), 5.98 (m, 1H), 4.16 (t, J=5.8 Hz, 2H), 3.86
(d, 3H), 3.81 (s, 3H), 3.50 (t, J=4.6 Hz, 4H), 2.70 (t, J=5.8 Hz,
2H), 2.48-2.45 (m under DMSO peak, 2H), 1.61 (d, J=6.0 Hz, 3H).
Step
C--3-{[(1R)-1-(2-chloro-3-{[2-(4-morpholinyl)ethyl]oxy}phenyl)ethyl]o-
xy}-5-[5-(1-methyl-1H-pyrazol-4-yl)-1H-benzimidazol-1-yl]-2-thiophenecarbo-
xamide (Title Compound)
[0757] Methyl
3-{[(1R)-1-(2-chloro-3-{[2-(4-morpholinyl)ethyl]oxy}phenyl)ethyl]oxy}-5-[-
5-(1-methyl-1H-pyrazol-4-yl)-1H-benzimidazol-1-yl]-2-thiophenecarboxylate
(90 mg, 0.14 mmol) was subjected to aminofysis procedure analogous
to Example 4, Step B to give 91 mg of the title compound (99%).
.sup.1H NMR (400 MHz, d.sub.6-DMSO) .delta. 8.52 (s, 1H), 8.18 (s,
1H), 7.94 (s, 1H), 7.91 (s, 1H), 7.80 (br s, 1H), 7.54 (d, J=8.4
Hz, 1H), 7.45 (d, J=8.4 Hz, 1H), 7.35 (t, J=8.0 Hz, 1H), 7.21 (d,
J=7.6 Hz, 1H), 7.14-7.10 (m, 3H), 5.98 (m, 1H), 4.16 (m, 2H), 3.85
(s, 3H), 3.49 (t, J=4.6 Hz, 4H), 2.70 (t, J=5.8 Hz, 2H), 2.48-2.44
(m, 4H), 1.70 (d, J=6.4 Hz, 3H). HRMS calculated [M+H].sup.+
C.sub.30H.sub.32ClN.sub.6O.sub.4S 607.1894, found 607.1894.
EXAMPLE 26
5-(5-Chloro-1H-benzimidazol-yl)-3-{[(1R)-1-(2-chloro-3-{[2-(4-morpholinyl)-
ethyl]oxy}phenyl)ethyl]oxy}-2-thiophenecarboxamide
##STR00202##
[0758] Step A--Methyl
3-{((1R)-1-{3-[(2-bromoethyl)oxy]-2-chlorophenyl}ethyl)oxy]-5-(5-chloro-1-
H-benzimidazol-1-yl)-2-thiophenecarboxylate
##STR00203##
[0760] Methyl
5-(5-chloro-1H-benzimidazol-1-yl)-3-{[(1R)-1-(2-chloro-3-hydroxyphenyl)et-
hyl]oxy}-2-thiophenecarboxylate (Intermediate 2, 200 mg, 0.43 mmol)
and 2-bromo-ethanol (37 .mu.L, 0.52 mmol) were coupled using a 0
procedure analogous to Example 4, Step A to give 132 mg of the
desired product (54%). .sup.1H NMR (400 MHz, d.sub.6-DMSO) .delta.
8.72 (s, 1H), 7.87 (d, J=2.0 Hz, 1H), 7.66 (d, J=8.8 Hz, 1H),
7.43-7.30 (m, 4H), 7.12-7.10 (m, 1H), 6.00-5.95 (m, 1H), 4.40-4.37
(m, 2H), 3.83-3.79 (m, 5H), 1.60 (d, J=6.4 Hz, 3H).
Step B--Methyl
5-(5-chloro-1H-benzimidazol-1-yl)-3-{[(1R)-1-(2-chloro-3-{[2-(4-morpholin-
yl)ethyl]oxy}phenyl)ethyl]oxy}-2-thiophenecarboxylate
##STR00204##
[0762] Methyl
3-[((1R)-1-{3-[(2-bromoethyl)oxy]-2-chlorophenyl}etthyl)oxy]-5-(5-chloro--
1H-benzimidazol-1-yl}-2-thiophenecarboxytete (130 mg, 0.23 mmol)
and morphoilne (80 .mu.L, 0.92 mmol) were coupled using a procedure
analogoust to Example 15, Step A to give 93 mg of the desired
product (70%). .sup.1H NMR (400 MHz, d.sub.6-DMSO) .delta. 8.72 (s,
1H), 7.87 (m, 1H), 7.63 (d, J=8.8 Hz, 1H), 7.41-7.32 (m, 3H), 7.27
(d, J=7.2 Hz, 1H), 7.11 (d, J=8.4 Hz, 1H), 5.95 (m, 1H), 4.15 (t,
J=5.6 Hz, 2H), 3.81 (s, 3H), 3.52 (t, J=4.4 Hz, 4H), 2.70 (t, J=5.8
Hz, 2H), 2.49-2.48 (m under DMSO, 4H), 1.60 (d, J=6.4 Hz, 3H).
Step
C--5-(5-Chloro-1H-benzimidazol-yl)-3-{[(1R)-1-(2-chloro-3-{[2-(4-morp-
holinyl)ethyl]oxy}phenyl)ethyl]oxy}-2-thiophenecarboxamide (Title
Compound)
[0763] Methyl
5-(5-chloro-1H-benzimidazol-yl)-3-{[(1R)-1-(2-chloro-3-{[2-(4-morpholinyl-
)ethyl]oxy}phenyl)ethyl]oxy}-2-thiophenecarboxylate (90 mg, 0.16
mmol) was subjected to .aminoSysis according to procedure analogous
to Example 4, Step B to give 90 mg of the title compound (99%).
.sup.1H NMR (400 MHz, d.sub.6-DMSO) .delta. 8.62 (s, 1H), 7.85 (m,
1H), 7.82 (br s, 1H), 7.50 (d, J=8.4Hz, 1H), 7.38-7.32 (m, 2H),
7.20 (d, J=7.8 Hz, 1H), 7.13-7.11 (m, 3H), 5.97 (m, 1H), 4.15 (t,
J=5.6 Hz, 2H), 3.51 (t, J=4.6 Hz, 4H), 2.70 (f, J=5.6 Hz, 2H),
2.49-2.46 (m under DMSO peak, 4H), 1.69 (t, J=6.0 Hz, 3H). HRMS
calculated [M+H].sup.+ C.sub.26H.sub.27Cl.sub.2N.sub.4O.sub.4S
561.1130, found 561.1134.
EXAMPLE 27
5-(5-Chloro-1H-benzimidazol-1-yl)-3-{[(1R)-1-(2-chloro-3-{[(2R)-2-morpholi-
nylmethyl]oxy}phenyl)ethyl]oxy}-2-thiophenecarboxamide
##STR00205##
[0764] Step A--1,1-Dimethylethyl
2-[({2-chloro-3-[(1R)-1-({5-(5-chloro-1H-benzimidazol-1-yl)-2-[(methyloxy-
)carbonyl]-3-thienyl}oxy)ethyl]phenyl}oxy)methyl]-4-morpholinecarboxylate
##STR00206##
[0766] Methyl
5-(5-chloro-1H-benzimidazol-1-yl)-3-{[(1R)-1-(2-chloro-3-hydroxyphenyl)et-
hyl]oxy}-2-thiophenecarboxylate (Intermediate 2, 153 mg, 0.33 mmol)
and 1,1-dimethylethyl 2-(hydroxymethyl)-4-morphoilnecarboxylate (87
mg, 0.40 mmol) were coupled using a procedure analogous to Example
5, Step A to give 145 mg of the desired product (66%). .sup.1H NMR
(400 MHz, d.sub.6-DMSO) .delta. 8.70 (s, 1H), 7.85 (m, 1H), 7.61
(d, J=8.8 Hz, 1H), 7.42-7.27 (m, 4H), 7.10 (d, J=7.6 Hz, 1H), 5.95
(m, 1H), 4.13-3.94 (m, 3H), 3.84-3.80 (m, 4H), 3.70-3.67 (m, 2H),
3.45-3.39 (m, 1H), 2.85 (m, 2H), 1.59 (d, J=6.4 Hz, 3H), 1.36 (s,
9H).
Step B--1,1-Dimethylethyl
(2R)-2-({[3-((1R)-1-{[2-(aminocarbonyl)-5-(5-chloro-1H-benzimidazol-1-yl)-
-3-thienyl]oxy}ethyl)-2-chlorophenyl]oxy}methyl)-4-morpholinecarboxylate
##STR00207##
[0768] 1,1 -Dimethylethyl
2-[({2-chloro-3-[(1R)-1-({5-(5-chloro-1H-benzimidazol-1-yl)-2-[(methyloxy-
)carbonyl]-3-thienyl}oxy)ethyl]phenyl)oxy)methyl]-4-morphoiinecarboxylate
(145 mg, 0.22 mmol) was subjected to aminolysis according to the
procedure analogous to Example 5 Step B to give 108 mg of the
racemic product (76%). The diastereomers were separated using
packed column supercritical fluid chromatography (SFC) on a
Diacel.RTM. 3.times.25 Chiralcel OJ-H column using a mobile phase
with 30% MeOH in carbon dioxide, 5-(5-Chloro-1H
benzimidazol-yl)-3-{[(1R)-1-(2-chloro-3-{[(2S)-2-morpholimylmethyl]oxy}ph-
enyl)-ethyl]oxy}-2-thiophenecarboxamide efuted first with a
retention time of 9.64 min at a flow rate of 2 mL/min on the
analytical instrument. The titie compound eluted second with a
retention time of 12.40 min. .sup.1H NMR (400 MHz, d.sub.6-DMSO)
.delta. 8.61 (s, 1H), 7.83 (m, 1H), 7.81 (br s, 1H), 7.48 (d, J=8.8
Hz, 1H), 7.39-7.32 (m, 2H), 7.21 (d, J=7.6 Hz, 1H), 7.12-7.10 (m,
3H), 5.96 (m, 1H), 4.12-3.94 (m, 3H), 3.84-3.81 (m, 1H), 3.70-3.67
(m, 2H), 3.44-3.39 (m, 1H). 2.84 (m, 2H), 1.68 (d, J=6.0 Hz, 3H),
1.36 (s, 9H).
Step
C--5-(5-Chloro-1H-benzimidazol-1-yl)-3-{[(1R)-1-(2-chloro-3-{[(2R)-2--
morpholinylmethyl]oxy}phenyl)ethyl]oxy}-2-thiophenecarboxamide
(Title Compound)
[0769] 1,1-Dimethylethyl
(2R)-2-({[3-((1R)-1-{[2-(aminocarbonyl)-5-(5-chloro-1H-benzimidazol-1-yl)-
-3-thienyl]oxy}ethyl)-2-chlorophenyl]oxy}methyl)-4-morphoiinecarboxylate
(90 mg. 0.14 mmol) was deprotected using a procedure analogous to
Example 5, Step C to give 60 mg of the title compound (79%).
.sup.1H NMR (400 MHz, d.sub.6-DMSO) .delta. 8.62 (s, 1H), 7.84-7.82
(m, 2H), 7.49-7.31 (m, 3H), 7.20 (d, J=7.6 Hz, 1H), 7.13-7.09 (m,
3H), 5.96 (m, 1H), 4.03-3.95 (m, 2H), 3.73-3.64 (m, 2H), 3.46-3.40
(m, 1H), 2.87-2.84 (m, 1H), 2.65-2.51 (m, 3H), 1.69 (d, J=6.4 Hz,
3H). HRMS calculated [M+H].sup.+
C.sub.25H.sub.25Cl.sub.2N.sub.4O.sub.4S 547.0974, found
547.0968.
EXAMPLE 28
5-(5-Chloro-1H-benzimidazol-1-yl)-3-{[(1R)-1-(2-chloro-3-{[(2S)-2-morpholi-
nylmethyl]oxy}phenyl)ethyl]oxy}-2-thiophenecarboxamide
##STR00208##
[0771]
5-(5-Chloro-1H-benzimidazol-1-yl)-3-{[(1R)-1-(2-chloro-3-{[(2S)-2-m-
orpholinylmethyl]oxy}phenyl)ethyl]oxy}-2-thiophenecarboxamide
(Intermediate 2, 40 mg, 0.06 mmol) was deprotected using a
procedure analogous to Example 5, Step C to give 23 mg of the title
compound (82%). .sup.1H NMR (400 MHz, d.sub.6-DMSO) .delta. 8.61
(s, 1H), 7.83 (s, 1H), 7.80 (br s, 1H), 7.46-7.31 (m, 3H), 7.20 (d,
J=7.6 Hz, 1H), 7.11-7.08 (m, 3H), 5.96 (m, 1H), 4.05-3.95 (m, 2H),
3.78-3.75 (m, 2H), 3.50-3.44 (m, 1H), 2.95-2.91 (m, 1H), 2.74-2.66
(m, 2H), 2.60-2.54 (m, 1H), 1.68 (d, J=6.0 Hz, 3H). HRMS calculated
[M+H].sup.+ C.sub.25H.sub.25Cl.sub.2N.sub.4O.sub.4S 547.09681,
found 547.09655.
EXAMPLE 29
3-{[(1R)
-1-(2-Chloro-3-{[1-(2-fluoroethyl)-4-piperidinyl]oxy}phenyl)ethyl-
]oxy}-5-[5-(1-methyl-1H-pyrazol-4-yl)-1H-benzimidazol-1-yl]-2-thiophenecar-
boxamide
##STR00209##
[0772] Step A--Methyl
3-{[(1R)-1-(2-chloro-3-{[1-(2-fluoroethyl)-4-piperidinyl]oxy}phenyl)ethyl-
]oxy}-5-[5-(1-methyl-
1H-pyrazol-4-yl)-1H-benzimidazol-1-yl]-2-thiophenecarboxylate
##STR00210##
[0774] Methyl
3-({(1R)-1-[2-chloro-3-(4-piperidinyloxy)phenyl]oxy}-5-[5-(1-methyl-1H-py-
razol-4-yl)-1H-benzimidazol-1-yl]-2-thiophenecarboxylate
(Intermediate 13, 150 mg, 0.25 mmol) and 1-bromo-2-fluoroethane (37
mL, 0.50 mmol) were coupled using a procedure analogous to Example
19, Step A to give 78 mg of the desired product (49%). MS (ESI)
m/z=638.54 [M+H].sup.+.
Step B--3-{[(1R)
-1-(2-Chloro-3-{[1-(2-fluoroethyl)-4-piperidinyl]oxy}phenyl)ethyl]oxy}-5--
[5-(1-methyl-1H-pyrazol-4-yl)-1H-benzimidazol-1-yl]-2-thiophenecarboxamide
(Title Compound)
[0775] Methyl
3-{((1R)-1-(2-chloro-3-{[1-(2-fluoroethyl)-4-piperidinyl]oxy}pheny)ethyl]-
oxy}-5-[5-(1-methyl-1H-pyrazol-4-yl)-1H-benzimidazol-1-yl]-2-thiophenecarb-
oxylate (78 mg, 0.12 mmol) was subjected to aminolysis using a
procedure analogous to Example 4, Step B to give 50 mg of the title
compound (67%). .sup.1H NMR (400 MHz, d.sub.6-DMSO) .delta. 8.51
(s, 1H), 8.15 (s, 1H), 7.93 (s, 1H), 7.89 (s, 1H), 7.78 (br s, 1H),
7.53 (d, J=8.8 Hz, 1H), 7.45 (d, J=8.8 Hz, 1H), 7.32 (t, J=8.0 Hz,
1H), 7.20-7.14 (m, 2H), 7.09 (m, 2H), 5.97 (m, 1H), 4.51-4.47 {m,
2H), 4.40-4.37 (m. 1H), 3.84 (s, 3H), 2.63-2.56 (m, 3H), 2.51-2.46
(m, 1H), 2.31-2.24 (m, 2H), 1.86 (m, 2H), 1.70-1.62 (m, 5H). HRMS
calculated [M+H].sup.+ C.sub.31H.sub.33CIFN.sub.6O.sub.3S
623.20019, found 623.20020.
EXAMPLE 30
3-{[](1R)-1-(2-chloro-3-{[1-(3,3,3-trifluoropropyl)-4-piperidinyl]oxy}phen-
yl)ethyl]oxy}-5-[5-(1-methyl-1H-pyrazol-4-yl)-1H-benzimidazol-1-yl]-2-thio-
penecarboxamide
##STR00211##
[0776] Step A--Methyl
3-{[(1R)-1-{2-chloro-3-{[1-(3,3,3-trifluoropropyl)-4-piperidinyl]oxy}phen-
yl)ethyl]oxy}-5-[5-(1-methyl-1H-pyrazol-4-yl)-1H-benzimidazol-1-yl]-2-thio-
phenecarboxylate
##STR00212##
[0778] Methyl
3-({(1R)-1-[2-chloro-3-(4-piperidinyloxy)phenyl]ethyl}oxy)-5-[5-(1-methyl-
-1H-pyrazol-4-yl)-1H-benzimidazol-1-yl]-2-thiophenecarboxylate
(Intermediate 13, 150 mg, 0.25 mmol) and
3-bromo-1,1,1-trsfluoropropane (53 .mu.l, 0.50 mmol) were coupled
using a procedure analogous to Example 19, Step A to give 107 mg of
the desired product (62%). .sup.1H NMR (400 MHz, d6-DMSO) .delta.
8.62 (s, 1H), 8.17 (s, 1H), 7.95 (s, 1H), 7.90 (s, 1H), 7.58 (m,
2H), 7.35-7.27 (m, 3H), 7.14 (d, J=7.6 Hz, 1H), 5.96 (m, 1H), 4.48
(m, 1H), 3.85 (s, 3H), 3.81 (s, 3H), 2.65-2.58 (m, 2H), 2.48-2.38
(m under DMSO peak, 4H), 2.31-2.23 (m, 2H), 1.87 (m, 2H), 1.66-1.60
(m, 5H).
Step
B--3-{[](1R)-1-(2-chloro-3-{[1-(3,3,3-trifluoropropyl)-4-piperidinyl]-
oxy}phenyl)ethyl]oxy}-5-[5-(1-methyl-1H-pyrazol-4-yl)-1H-benzimidazol-1-yl-
]-2-thiopenecarboxamide (Title Compound)
[0779] Methyl
3-{[(1R)1-(2-chloro-3-{[1-(3,3,3-tnfluoropropyl)-4-plperldsnyl]oxy}phenyl-
)ethyl]oxy}-5-[5-(1-methyl-1H-pyrazol-4-yl)-1H-benzimidazol-1-yl]-2-thioph-
enecarboxylate (103 mg, 0.15 mmol) was subjected to aminolysis
using a procedure analogous to Example 4, Step B to give 74 mg of
the title compound (73%). .sup.1H NMR (400 MHz, d.sub.6-DMSO)
.delta. 8.51 (s, 1H), 8.15 (s, 1H), 7.92 (s, 1H), 7.89 (s, 1H),
7.79 (br s, 1H), 7.53 (d, J=8.4 Hz, 1H), 7.45 (d, J=8.4 Hz, 1H),
7.32 (t, J=8.2 Hz, 1H), 7.20-7.14 (m, 2H), 7.09 (m, 2H), 5.99-5.94
(m, 1H), 4.47 (m, 1H), 3.84 (s, 3H), 2.61-2.55 (m, 2H), 2.47-2.35
(rn under DMSO peak, 4H), 2.28-2.17 (m, 2H), 1.85-1.72 (m, 2H),
1.70-1.59 (m, 5H). HRMS calculated [M+H].sup.+
C.sub.32H.sub.33ClF3N.sub.6O.sub.3S 873.19700, found 673.19712.
EXAMPLE 31
3-({(1R)-1-[2-Chloro-3-({1-(2-(methylsulfonyl)ethyl]-4-piperldinyl}oxy)phe-
nyl]ethyl}oxy)-5-[5-(1-methyl-1H-pyrazol-4-yl)-1H-benzimidazol-1-yl]-2-thi-
ophenecarboxamide
##STR00213##
[0781]
3-({(1R)-1-[2-chloro-3-(4-piperidinyloxy)phenyl]ethyl}oxy)-5-[5-(1--
methyl-1H-pyrazol-4-yl)-1H-benzimidazol-1-yl]-2-thiophenecarboxamide
(Intermediate 13, 144 mg, 0.25 mmol) and methyl vinyl suifone (26
.mu.L, 0.30 mmol) were coupled using a procedure analogous to
Example 23 to give 74 mg of the title compound (43%). .sup.1H NMR
(400 MHz, d.sub.6-DMSO) .delta. 8.51 (s, 1H), 8.16 (s, 1H), 7.93
(s, 1H), 7.89 (s, 1H), 7.79 (br s, 1H), 7.53 (d, J=8.8 Hz, 1H),
7.45 (d, J=8.4 Hz, 1H), 7.32 (t, J=8.0 Hz, 1H), 7.20-7 14 (m, 2H),
7.09 (m, 2H), 5.99-5.94 (m, 1H), 4.48 (m, 1H). 3.84 (s, 3H). 3.20
(t, J=6.6 Hz, 2H). 2.97 (s, 3H), 2.65-2.59 (m, 4H), 2.29-2.21 (M,
2H), 1.86-1.72 (m, 2H), 1.69 (d, J=6.4 Hz, 3H), 1.64-1.60 (m, 2H).
HRMS calculated [M+H].sup.+ C.sub.32H.sub.36ClN.sub.6O.sub.5S.sub.2
683,18716, found 683.18702.
EXAMPLE 32
5-(5-Chloro-1H-benzimidazol-1-yl)-3-[((1R)-1-{2-chloro-4-fluoro-3-[(1-meth-
yl-4-piperidinyl)oxy]phenyl}ethyl)oxy]-2-thiophenecarboxamide
##STR00214##
[0782] Step A--Methyl
5-(5-chloro-1H-benzimidazol-1-yl)-3-{[(1R)-1-(2-chloro-4-fluoro-3-hydroxy-
phenyl)ethyl]oxy}-2-thiophenecarboxylate
##STR00215##
[0784] Methyl
5-(5-chloro-1H-benzimidazol-1-yl)-3-hydroxy-2-thiophene-carboxylate
(Intermediate 2, Step B, 153 mg, 0.50 mmol) and
(1S)-1-(2-chloro-3-{[(1,1-dimethylethyl)(diphenyl)silyl]oxy}-4-fluorophen-
yl)ethanol (Intermediate 14, 257 mg, 0.60 mmol) were coupled using
a procedure analogous to Intermediate 2, Step C to give 200 mg of
the desired product (83%). .sup.1H NMR (400 MHz, d.sub.6-DMSO)
.delta. 10.47 (s, 1H), 8.72 (s, 1H), 7.87 (d, J=2.0 Hz, 1H), 7.67
(d, J=8.8 Hz, 1H), 7.43-7.40 (m, 2H), 7.27-7.23 (m, 1H), 7.18-7.14
(m, 1H), 5.91-5.86 (m, 1H), 3.80 (s, 3H), 1.59-1.58 (m, 3H).
Step B--Methyl
5-(5-chloro-1H-benzimidazol-1-yl)-3-[((1R)-1-{2-chloro-4-fluoro-3-[(1-met-
hyl-4-piperidinyl)oxy]phenyl}ethyl)oxy]-2-thiophenecarboxylate
##STR00216##
[0786] Methyl
5-(5-chloro-1H-benzimidazol-1-yl)-3-{[(1R)-1-{2-chloro-4-fSuoro-3-hydroxy-
phenyl)ethyl]oxy}-2-thiophenecarboxylate (110 mg, 0.23 mmol) and
1-methyl-4-piperidinol (32 .mu.L, 0.27 mmol) were coupled using a
procedure analogous to Example 4, Step A to give 68 mg of the
desired product (51%). 1H HUR (400 MHz, d.sub.6-DMSO) .delta. 8.72
(s, 1H), 7.87 (m, 1H), 7.73 (d, J=8.8 Hz, 1H), 7.50-7.35 (m, 4H),
5.91 (m, 1H), 4.12 (m, 1H), 3.81 (s, 3H), 2.65-2.58 (m, 2H), 2.13
(s, 3H), 2.04 (m, 2H), 1.83-1.79 (m, 2H), 1.72-1.66 (m, 2H), 1.60
(d, J=6.4 Hz, 3H).
Step
C--5-(5-Chloro-1H-benzimidazol-1-yl)-3-[((1R)-1-{2-chloro-4-fluoro-3--
[(1-methyl-4-piperidinyl)oxy]phenyl}ethyl)oxy]-2-thiophenecarboxamide
(Title Compound)
[0787] Methyl
5-(5-chloro-1H-benzimidazol-1-yl)-3-[((1R)-1-(2-chloro-4-fluoro-3-[(1-met-
hyl-4-piperidinyl)oxy]phenyl}ethyl)oxy]-2-thiophenecarboxylate (65
mg, 0.11 mmol) was subjected to aminolysis according to the
procedure analogous to Example 4, Step B to give 45 mg of the title
compound (69%). .sup.1H NMR (400 MHz, d.sub.6-DMSO) .delta. 8.60
(s, 1H), 7.84 (s, 1H), 7.79 (br s, 1H), 7.60 (d, J=8.8 Hz, 1H),
7.43-7.32 (m, 3H), 7.14 (s, 1H), 7.08 (br s, 1H), 5.91 (m, 1H),
4.09 (m, 1H), 2.57 (m, 1H), 2.08 (s, 3H), 1.93-1.60 (m, 10H).
EXAMPLE 33
3-({(1R)-1-[2-Chloro-4-fluoro-3-(4-piperidinyloxy)phenyl]ethyl 56
oxy)-5-[5-(1-methyl-1H-pyrazol-4-yl)-1H-benzimidazol-1-yl]-2-thiophenecar-
boxamide
##STR00217##
[0788] Step A--Methyl
3-{[(1R)-1-(2-chloro-4-fluoro-3-hydroxyphenyl)ethyl]oxy}-5-[5-(1-methyl-1-
H-pyrazol-4-yl)-1H-benzimidazol-1-yl]-2-thiophenecarboxylate
##STR00218##
[0790] Methyl
3-hydroxy-5-[5-(1-methyl-1H-pyrazol-4-yl)-1H-benzimidazol-1-yl]-2-thiophe-
necarboxylate (Intermediate 16, 710 mg, 2.0 mmol) and
(1S)-1-(2-chloro-3-{[(1,1-dimethylethyl)(diphenyl)silyl]oxy}-4-fluorophen-
yl)ethanol (Intermediate 14, 1.03 g, 2.4 mmol) were coupled and
deprotected using a procedure analogous to Intermediate 2, Step C
to give 802 mg of the desired product (76% over 2 steps). .sup.1H
NMR (400 MHz, d.sub.6-DMSO) .delta. 10.48 (s, 1H), 8.63 (s, 1H),
8.19 (s, 1H), 7.96 (s, 1H), 7.92 (s, 1H), 7.65-7.58 (m, 2H), 7.39
(s, 1H), 7.28-7.23 (m, 1H), 7.18-7.15 (m, 1H), 5.93-5.89 (m, 1H),
3.86 (s, 3H), 3.81 (s, 3H), 1.59 (d, J=6.4 Hz, 3H).
Step B--1,1-Dimethylethyl
4-({2-chloro-6-fluoro-3-[(1R)-1-({2-](methyloxy)carbonyl]-5-[5-(1-methyl--
1H-pyrazol-4-yl)-1H
-benzimidazol-1-yl]-3-thienyl}oxy)ethyl]phenyl}oxy)-1-piperidinecarboxyla-
te
##STR00219##
[0792] Methyl
3-{[(1R)-1-{2-chloro-4-fluoro-3-hydroxyphenyl)ethyl]oxy}-5-[5-(1-methyl-1-
H-pyrazol-4-yl)-1H-benzimidazol-1-yl]-2-thiophenecarboxylate (490
mg, 0.93 mmol) and 1,1-dimethylethyl
4-hydroxy-1-piperidinecarboxylate (221 mg, 1.1 mmol) were coupled
using a procedure analogous to Example 5, Step A to give the
desired product. MS (ESI) m/z=710.56 [M+H].sup.+.
Step C--Methyl
3-({(1R)-1-[2-chloro-4-fluoro-3-(4-piperidinyloxy)phenyl]ethyl}oxy)-5-[5--
(1-methyl-1H-pyrazol-4-yl)-1H-benzimidazol-1-yl]-2-thiophenecarboxylate
##STR00220##
[0794] 1,1-Dimethylethyl
4-({2-chloro-6-fluoro-3-[(1R)-1-({2-[(methytoxy)carbonyl]-5-[5-(1-methyl--
1H-pyrazol-4-yl)-1H-benzimidazol-1-yl]-3-thienyl}oxy)ethyl]phenyl}oxy)-1-p-
iperidinecarboxylate (crude from above) was deprotected using a
procedure analogous to Example 5, Step C to give 298 mg of the
desired product (53% over 2 steps). .sup.1H NMR (400 MHz,
d.sub.6-DMSO) .delta. 8.63 (s, 1H), 8.19 (s, 1H), 7.96 (s, 1H),
7.92 (s, 1H), 7.68 (d, J=8.2 Hz, 1H), 7.61-7.58 (m, 1H), 7.50-7.47
(m, 1H), 7.43-7.35 (m, 2H), 5.93 (m, 1H), 4.19-4.15 (m, 1H), 3.86
(s, 3H), 3.81 (s, 3H), 2.95-2.87 (m, 2H), 2.43-2.38 (m, 2H),
1.86-1.79 (m, 2H), 4.61 (d, J=6.4 Hz, 3H), 1.56-1.51 (m, 2H).
Step
D--3-({(1R)-1-[2-Chloro-4-fluoro-3-(4-piperidinyloxy)phenyl]ethyl
56
oxy)-5-[5-(1-methyl-1H-pyrazol-4-yl)-1H-benzimidazol-1-yl]-2-thiophenecar-
boxamide (Title Compound)
[0795] Methyl
3-({(1R)-1-[2-chloro-4-fluoro-3-(4-piperidinyloxy)phenyl]ethyl}oxy)-5-[5--
(1-methyl-1H-pyrazol-4-yl)-1H-benzimidazol-1-yl]-2-thiophenecarboxylate
(195 mg, 0.32 mmol) was subjected to aminolysis according to a
procedure analogous to Example 5, Step B to give 126 mg of the
title compound (66%). .sup.1H NMR (400 MHz, d.sub.6-DMSO) .delta.
8.52 (s, 1H), 8.18 (s, 1H), 7.95 (s, 1H), 7.91 (s, 1H), 7.78 (br s,
1H), 7.56 (m, 2H), 7.45-7.34 (m, 2H), 7.15 (s, 1H), 7.08 (br s,
1H), 5.94 (m, 1H), 4.17-4.12 (m, 1H), 3.85 (s, 3H), 2.93-2.80 (m,
2H), 2.39-2.29 (m, 2H), 2.12 (br s, 1H), 1.83-1.74 (m, 2H), 1.70
(d, J=6.0 Hz, 3H), 1.55-1.43 (m, 2H). HRMS calculated [M+H].sup.+
C.sub.29H.sub.29ClFN.sub.6O.sub.3S 595.16889, found 595,16893.
EXAMPLE 34
3-[((1R)-1-{2-Chloro-4-fluoro-3-[(1-methyl-4-piperidinyl)oxy]phenyl}ethyl)-
oxy]-5-[5-(1-methyl-1H-pyrazol-4-yl)-1H-benzimidazol-1-yl]-2-thiophenecarb-
oxamide trifluoroacetate
##STR00221##
[0796] Step A--Methyl
3-[((1R)-1-{2-chloro-4-fluoro-3-[(1-methyl-4-piperidinyl)oxy]phenyl}ethyl-
)oxy]-5-[5-(1-methyl-1H-pyrazol-4-yl)-1H-benzimidazol-1-yl]-2-thiophenecar-
boxylate
##STR00222##
[0798] Methyl
3-{[(1R)-1-(2-chloro-4-fluoro-3-hydroxyphenyl)ethyl]oxy}-5-[5-(1-methyl-1-
H-pyrazol-4-yl)-1H-benzimidazol-1-yl]-2-thiophenecarboxylate
(Example 33, Step A, 125 mg, 0.24 mmol) and 1-methyl-4-piperidinol
(34 .mu.l, 0.29 mmol) were coupled using a procedure analogous to
Example 4, Step A to give 95 mg of the desired product (63%).
.sup.1H NMR (400 MHz, d.sub.6-DMSO) .delta. 8.63 (s, 1H), 8.19 (s,
1H), 7.96 (s, 1H), 7.92 (s, 1H), 7.67 (d, J=8.8 Hz, 1H), 7.59 (m,
1H), 7.49-7.46 (m, 1H), 7.40-7.35 (m, 2H), 5.93 (m, 1H), 4.11 (m,
1H), 3.86 (s, 3H), 3.81 (s, 3H), 2.58-2.50 (m, 2H), 2.07 (s, 3H),
1.95 (m, 2H), 1.80 (m, 2H), 1.69 <m, 2H), 1.61 (d, J=6.0 Hz,
3H).
Step
B--3-[((1R)-1-{2-Chloro-4-fluoro-3-[(1-methyl-4-piperidinyl)oxy]pheny-
l}ethyl)oxy]-5-[5-(1-methyl-1H-pyrazol-4-yl)-1H-benzimidazol-1-yl]-2-thiop-
henecarboxamide trifluoroacetate (Title Compound)
[0799] Methyl
3-[((1R)-1-{2-chloro-4-fluoro-3-[(1-methyl-4-piperidinyl)oxy]phenyl}ethyl-
)oxy]-5-[5-(1-methyl-1H-pyrazol-4-yl)-1H-benzimidazol-1-yl]-2-thiophenecar-
boxylate (95 mg, 0.15 mmol) was subjected to amlnolysis according
to a procedure analogous to Example 4, Step B. The crude material
was purified by reverse-phase liquid chromatography to give 40 mg
of the title compound (44%). .sup.1H NMR (400 MHz, d4-CD.sub.3OD)
.delta. 8.42 (s, 1H), 8.01 (s, 1H), 7.88 (s, 1H), 7.85 (s, 1H),
7.62-7.53 (m, 2H), 7.45-7.41 (m, 1H), 7.31-7.26 (m, 1H), 7.03-7.01
(m, 1H), 6.02 (m, 1H), 7.37 (m, 1H), 3.93 (s, 3H), 3.52-3.33 (m,
2H), 3.01-2.80 (m, 5H), 2.30-2.19 (m, 2H), 2.01-1.94 (m, 2H), 1.79
(m, 3H). HRMS calculated [M+H].sup.+
C.sub.30C.sub.31ClFN.sub.6O.sub.3S 609.18454, found 609.18425.
EXAMPLE 35
3-{[(1R)-1-(2-Chloro-4-fluoro-3-{[1-(2-fluoroethyl)-4-piperidinyl]oxy}phen-
yl)ethyl]oxy}-5-[5-(1-methyl-1H-pyrazol-4-yl)-1H-benzimidazol-1-yl]-2-thio-
phenecarboxamide
##STR00223##
[0800] Step A--Methyl
3-{[(1R)-1-(2-chloro-4-fluoro-3-{[1-(2-fluoroethyl)-4-piperidinyl]oxy}phe-
nyl)ethyl]oxy}-5-[5-(1-methyl-1H-pyrazol-4-yl)-1H-benzimidazol-1-yl]-2-thi-
ophenecarboxylate
##STR00224##
[0802] Methyl
3-({(1R)-1-(2-chloro-4-fluoro-3-(4-piperidinyloxy)phenyl]ethyl}oxy)-5-[5--
(1-methyl-1H
-pyrazol-4-yl)-1H-benzimidazol-1-yl]-2-thiophenecarboxylate
(Example 33, Step A, 90 mg, 0.15 mmol) and 1-bromo-2-fluoroethane
(22 .mu.L, 0.30 mmol) were coupled using a procedure analogous to
Example 19, Step A to give 92 mg of the desired product (94%).
.sup.1H NMR (400 MHz, d.sub.6-DMSO) .delta. 8.63 (s, 1H), 8.18 (s,
1H), 7.96 (s, 1H), 7.92 (s, 1H), 7.68 (d, J=8.4 Hz, 1H), 7.60 (m,
1H), 7.50-7.46 (m, 1H), 7.41-7.35 (m, 2H), 5.93 (m,1H), 4.50 (t,
J=5.0 Hz, 1H), 4.38 (t, J=5.0 Hz, 1H), 3.86 (s, 3H), 3.81 (s, 3H),
2.74-2.65 (m, 2H), 2.56 (t, J=5.0 Hz, 1H), 2.48 (m under DMSO peak,
1H), 2.13 (m, 2H), 2.11 (m, 2H), 1.82 (m, 2H), 1.67 (m, 2H), 1.61
(d, .J=6.0 Hz, 3H).
Step B--
3-{[(1R)-1-(2-Chloro-4-fluoro-3-{[1-(2-fluoroethyl)-4-piperidinyl]oxy}phen-
yl)ethyl]oxy}-5-[5-(1-methyl-1H-pyrazol-4-yl)-1H-benzimidazol-1-yl]-2-thio-
phenecarboxamide (Title Compound)
[0803] Methyl
3-{[(1R)-1-(2-chloro-4-fluoro-3-{[1-(2-fluoroethyI)-4-piperidinyl]oxy}phe-
nyl)ethyl]oxy}-5-[5-(1-methyl-1H-pyrazol
-4-yl)-1H-benzimidazol-1-yl]-2-thiophenecarboxylate (89 mg, 0.14
mmol) was subjected to aminolysis according to a procedure
analogous to Example 4, Step B to give 46 mg of the title compound
(55%). .sup.1H NMR (400 MHz, d.sub.6-DMSO) .delta. 8.52 (s, 1H),
8.18 (s, 1H), 7.95 (s, 1H), 7.91 (s, 1H), 7.80 (br s, 1H), 7.56 (m,
2H), 7.45-7.35 (m, 2H), 7.13 (s, 1H), 7.09 (br s, 1H), 5.97-5.92
(m, 1H), 4.47 (t, J=4.8 Hz, 1H), 4.35 (t, J=5.0 Hz, 1H), 4.14-4.12
(m, 1H), 3.85 (s, 3H), 2.71-2.68 (m, 1H), 2.61-2.58 (m, 1H), 2.51
(t, J=4.8 Hz, 1H), 2.44 ft, J=5.0 Hz, 1H), 2.13-2.02 (m, 2H),
1.82-1.61 (m, 7H). HRMS calculated [M+H].sup.+
C.sub.31H.sub.32ClF.sub.2N.sub.6O.sub.3S 641.19077, found
641.19054.
EXAMPLE 36
3-({(1R)-1-[2-ChJoro-4-fluoro-3-({1-[2-(methylsulfonyl)ethyl]-4-piperidiny-
l}oxy)phenyl]ethyl}oxy)-5-[5-(1-methyl-1H-pyrazol-4-yl)-1H-benzimidazel-1--
yl]-2-thiophenecarboxamide
##STR00225##
[0805]
3-({(1R)-1-[2-chloro-4-fluoro-3-(4-piperidinyloxy)phenyl]ethyl}oxy)-
-5-[5-(1-methyl-1H-pyrazol-4-yl)-1H-benzimidazol-1-yl]-2-thiophenecarboxam-
ide (Example 33, Step A, 80 mg, 0.13 mmol) and methyl vinyl suifone
(13 .mu.L, 0.15 mmol) were coupled using a procedure analogous to
Example 23 to give 72 mg of the title compound (79%). .sup.1H NMR
(400 MHz, d.sub.6-DMSO) .delta. 8.52 (s, 1H), 8.17 (s, 1H), 7.95
(s, 1H), 7.91 (s, 1H), 7.79 (br s, 1H), 7.56 (m, 2H), 7.45-7.35 (m,
2H), 7.13 (s, 1H), 7.08 (br s, 1H), 5.94 (m, 1H), 4.13 (m, 1H),
3.85 (s, 3H), 3.17 (t, J=6.2 Hz, 2H), 2.97 (ss 3H), 2.69-2.58 (m,
4H), 2.07 (m, 2H), 1.81-1.66 (m, 7H). HRMS calculated [M+H].sup.+
C.sub.32H.sub.35ClFN.sub.6O.sub.5S.sub.2 701.17774, found
701.17740.
EXAMPLE 37
3-({(1R)-1-8
2-Chloro-3-(4-piperidinyloxy)phenyl]ethyl}oxy)-5-[5-(1-oxido-4-pyridinyl)-
-1H-benzimidazol-1-yl]-2-thiophenecarboxamide
##STR00226##
[0806] Step A--1,1-Dimethylethyl
4-({2-Chloro-[(1R)-1-({2-[(methyloxy)carbonyl]-5-[5-(4-pyridinyl)-1H-benz-
imidazol-1-yl]-3-thienyl}oxy)ethyl]phenyl}oxy)-1-piperidinecarboxylate
##STR00227##
[0808] The title compound was prepared from 1,1-dimethylethyl
4-({3-[(1R)-1-({5-(5-bromo-1H-benzimidazol-1-yl)-2-[(methyloxy)carbonyl]--
3-thienyl}oxy)ethyl]-2-chlorophenyl}oxy)-1-piperidinecarboxylate
(400 mg, 0.58 mmol) and pyridine-4-boronic acid (92 mg, 0.75 mmol)
using a procedure analogous to Intermediate 9 to give 135 mg of the
desired product. MS (ESI): 689.6 [M+H].sup.+.
Step B--1,1-Dimethylethyl
4-({3-[(1R)-1-({2-(aminocarbonyI)-5-[5-(4-pyridinyl)-1H-benzimidazol-1-yl-
]-3-thieoyl}oxy)ethyl]-2-chlorophenyl}oxy)-1-piperidinecarboxylate
##STR00228##
[0810] The title compound was prepared froml, 1-dimethylethyl
4-({2-chJoro-3-[(1R)-1-({2-[(methytoxy)carbonyl]-5-[5-(4-pyridinyl)-1H-be-
nzimidazoS-1-yl]-3-thienyl}oxy)ethyl]phenyl}oxy)-1-piperidinecarboxylate
(135 mg, 0.196 mmol) using a procedure analogous to Example 5S Step
3 to give 109 mg of the desired product. MS (AP); 674.3
[M+H].sup.+.
Step C--1,1-Dimethylethyl
4-({3-(1R)-1-({2-(aminocarbonyl)-5-[5-(1-oxido-4-pyridinyl)-1H
-benzimidazol-1-yl]-3-thienyl}oxy)ethyl]-2-chlorophenyl}oxy)-1-piperidmec-
arboxylate
##STR00229##
[0812] 1,1 -Dtmethylethyl
4-({3-[(1R)-1-({2-(aminocarbonyl)-5-[5-(4-pyridinyl)-1H-benzimidazol-1-yl-
]-3-thienyl}oxy)ethyl]-2-chlorophenyl}oxy)-1-piperidinecarboxylate
(0.109 g, 0.16 mmol) and 50% m-chloroperoxybenzoic acid (0.44 g,
1.3 mmol) were combined in DCM (8 mL) at 0.degree. C. The reaction
mixture was stirred overnight, warming to rt, after which time the
reaction was quenched with aqueous saturated NaHCO.sub.3 and
extracted three times with DCM. The organics were combined, dried
over MgSO.sub.4, filtered and concentrated. The resulting yellow
oil was used directly in the next step without purification. MS
(ESI): 692.4 [M+H].sup.+.
Step D--3-({(1R)-1-8
2-Chloro-3-(4-piperidinyloxy)phenyl]ethyl}oxy)-5-[5-(1-oxido-4-pyridinyl)-
-1H-benzimidazol-1-yl]-2-thiophenecarboxamide (Title Compound)
[0813] The title compound was prepared from 1,1-dimethylethyl
4-({3-[(1R)-1-({2-(aminocarbonyl)-5-[5-(1-axido-4-pyridinyl)-1H-benzimida-
zol-1-yl]-3-thienyl}oxy)ethyl]-2-chlorophenyl}oxy)-1-piperidinecarboxylate
(crude material from Example 37, Step C) using a procedure
analogous to Example 5, Step C to give 0.012 g of the desired
product. .sup.1H NMR (400 MHz, CD.sub.3OD): .delta. 8.44 (s, 1H),
8.36 (d, J=6.8 Hz, 2H), 8.11 (s, 1H), 7.90 (d, J=6.8 Hz, 2H), 7.75
(d, J=8.2 Hz, 1H), 7.61 (d, J=8.6 Hz, 1H), 7.35 (t, J=8.0 Hz, 1H),
7.23 (d, J=7.5 Hz, 1H), 7.16 (d, J=8.1 Hz, 1H), 7.02 (s, 1H), 6.06
(q, J=6.4 Hz, 1H), 4.79 (m, 1H), 3.41-3.31 (m, 2H), 3.25-3.13 (m,
2H), 2.18-1.97 (m, 4H), 1.78 (d, J=6.2 Hz, 3H); MS (ESI): 590,3
[M+H].sup.+.
EXAMPLE 38
3-[((1R)-1-{2-Chloro-6-fluoro-3-[(1-methyl-4-piperidinyl)oxy]phenyl}ethyl)-
oxy]-5-[5-(1-methyl-1H-pyrazol-4-yl)-1H-baenzimidazol-1-yl]-2-thiophenecar-
boxamide
##STR00230##
[0814] Step A--Methyl
3-{[1-(2-chloro-3-{[(1,1-dimethylethyl)(diphenyl)silyl]oxy}-6-fluoropheny-
l)ethyl]oxy}-5-[5-(1-methyl-1H-pyrazol-4-yl)-1H-benzimidazol-1-yl]-2-thiop-
henecarboxylate
##STR00231##
[0816] Methyl 3-hydroxy-5-[5-(1-methyl-1H
-pyrazol-4-yl)-1H-benzimidazol-1-yl]-2-thiophenecarboxylate
(Intermediate 18, 450 mg, 1.3 rnrhoi) and 1-(2-chloro-3-{[(1,1
-dimethylethyl)(diphenyl)silyl]oxy}-6-fluorophenyl)ethanol
(Intermediate 15, 686 mg, 1.6 mmol) were coupled using a procedure
analogous to intermedials 3, Step B to give the desired product,
which was not separated from the triphenylphosphine oxide.
Step B--Methyl
3-{[1-(2-chloro-6-fluoro-3-hydroxyphenyl)ethyl]oxy}-5-[5-(1-methyl-1H-pyr-
azol-4-yl)-1H-benzimidazol-1-yl]-2-thiophenecarboxylate
##STR00232##
[0818] Methyl
3-{[1-(2-chloro-3-{[(1,1-dimethylethyl)(diphenyl)silyl]oxy}-6-fluoropheny-
l)ethyl]oxy}-5-[5-(1-methyl-1H-pyrazol-4-yl)-1H-benzimidazol-1-yl]-2-thiop-
henecarboxylate was deprotected using a procedure analogous to
Intermediate 3, Step F to give 288 mg of the desired product.
.sup.1H NMR (400 MHz, d.sub.6-DMSO) .delta. 10.29 (s, 1H), 8.60 (s,
1H), 8.19 (s, 1H), 7.97 (s, 1H), 7.93 (s, 1H), 7.60 (dd, J=8.4 and
1.2 Hz, 1H), 7.51 (d, J=8.8 Hz, 1H), 7.20 (s, 1H), 7.10-7.05 (m,
1H), 6.97-6.93 (m, 1H), 6.10-6.05 (m, 1H), 3.86 (s, 3H), 3.76 (s,
3H), 1.75 (d, J=6.4 Hz, 3H).
Step C--Methyl
3-[(1-{2-chloro-6-fluoro-3-[(1-methyl-4-piperidinyl)oxy]phenyl}ethyl)oxy]-
-5-[5-(1-methyl-1H-pyrazol-4-yl)-1H-benzimidazol-1-yl]-2-thiophenecarboxyl-
ate
##STR00233##
[0820] Methyl
3-{[1-(2-chloro-6-fluoro-3-hydroxyphenyl)ethyl]oxy}-5-[5-{1-methyl-1H-pyr-
azol-4-yl)-1H-benzimidazol-1-yl]-2-thiophenecarboxylate (288 mg,
0.55 mmol) and 1-methyl-4-piperidinol (76 mg, 0.66 mmol) were
coupled using a procedure analogous to Example 4, Step A to give
297 mg of the desired product (87%). .sup.1H NMR (400 MHz,
d.sub.6-DMSO) .delta. 8.59 (s, 1H), 8.19 (s, 1H), 7.97 (s, 1H),
7.92 (s, 1H), 7.60-7.52 (m, 2H), 7.22-7.17 (m, 3H), 6.12-6.07 (m,
1H), 4.38 (m, 1H), 3.86 (s, 3H), 3.76 (s, 3H), 2.48-2.43 (m under
DMSO peak, 2H, 2.13-2.08 (m, 5H), 1.81-1.75 (m, 5H), 1.63-1.56 (m,
2H).
Step
D--3-[((1R)-1-{2-Chloro-6-fluoro-3-[(1-methyl-4-piperidinyl)oxy]pheny-
l}ethyl)oxy]-5-[5-(1-methyl-1H-pyrazol-4-yl)-1H-baenzimidazol-1-yl]-2-thio-
phenecarboxamide (Title Compound)
[0821] Methyl
3-[(1-{2-chloro-6-fluoro-3-[(1-methyl-4-piperidinyl)oxy]phenyl}ethyl)oxy]-
-5-[5-(1-methyl-1H-pyrazol-4-yl)-1H-benzimidazol-1-yl]-2-thiophenecarboxyl-
ate (297 mg, 0.48 mmol) was subjected to aminolysis using a
procedure analogous to Example 4, Step B to give 268 mg of the
racemic compound (92%). NMR (400 MHz, d.sub.6-DMSO) .delta. 8.54
(s, 1H), 8.17 (s, 1H), 7.95 (s, 1H), 7.90 (s, 1H), 7.83 (bs, 1H),
7.59-7.55 (m, 2H), 7.31 (s, 1H), 7.24-7.22 (m, 2H), 6.97 (bs, 1H),
6.19-6.14 (m, 1H), 4.41-4.37 (m, 1H), 3.84 (s, 3H), 2.47-2.41 (m
under DMSO peak, 2H), 2.12-2.02 (m, 5H), 1.81-1.77 (m, 5H),
1.63-1.56 (m, 2H). MS (ESI): 609 [M+H].sup.+.
EXAMPLE 39
1,1-Dimethylethyl
4-[({3-[(1R)-1-({2-{aminocarbonyl)-5-[5,6-bis(methyloxy)-1H-benzimidazol--
1-yl]-3-thienyl}oxy)ethyl]-2-chlorophenyl}oxy)methyl]-1-piperidinecarboxyl-
ate
##STR00234##
[0822] Step A--1,1-Dimethylethyl
4-[({3-[(1R)-1-({5-[5,6-bis(methyloxy)-1H-benzimidazol-1-yl]-2-[(methylox-
y)carbonyl]-3-thienyl}oxy)ethyl]-2-chlorophenyl}oxy)methyl]-1-piperidineca-
rboxylate
##STR00235##
[0824] Methyl
5-[5,6-bis(methyloxy)-1H-benzimidazol-1-yl]-3-{[(1R)-1-(2-chloro-3-hydrox-
yphenyl)ethyl]oxy}-2-thiophenecarboxylate (Intermediate 19, 150 mg,
0.31 mmol) and 1,1-dimethylethyl
4-(hydroxymethyl)-1-piparidinecarboxylate (73 mg, 0.47 mmol) were
coupled using a procedure analogous to Example 5, Step A to give
170 mg of the desired product (80%). .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 7.86 (s, 1H), 7.28-7.22 (m, 3H), 6.93 (s, 1H),
6.82 (dd, J=6.0, 4.01 Hz, 1H), 6.65 (s, 1H) 5.83 (q, J=6.4 Hz, 1H),
4.23-4.12 (m, 2H), 3.94 (s, 3H), 3.92 (s, 3H), 3.88 (s, 3H),
3.87-3.78 (m, 2H), 2.82-2.69 (m, 2H), 2.06-1.97 (m, 1H) 1.92-1.79
(m, 2H), 1.71 (d, J=6.4 Hz, 3H), 1.47 (s, 9H), 1.36-1.24 (m, 2H).
MS (ESI): 686 [M+H].sup.+.
Step B--1,1-Dimethylethyl
4-[({3-[(1R)-1-({2-{aminocarbonyl)-5-[5,6-bis(methyloxy)-1H-benzimidazol--
1-yl]-3-thienyl}oxy)ethyl]-2-chlorophenyl}oxy)methyl]-1-piperidinecarboxyl-
ate (Title Compound)
[0825] 1,1-Dimethylethyl
4-[({3-(1R)-1-({5-[5,6-bis(methyloxy)-1H-benzimidazol
-yl]-2-[(methyloxy)carbonyl]-3-thienyl}oxy)ethyl]-2-chlorophenyl}oxy)meth-
yl]-1-piperidinecarboxylate (206 mg, 0.30 mmol) was subjected to
aminoiysis using a procedure analogous to Example 4, Step B to give
200 mg of the title compound, .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta. 7.81 (s, 1H), 7.25-7.19 (m, 3H) 7.02 (dd, J=7.8, 1.1 Hz,
1H), 6.90 (s, 1H), 6.82 (dd, J=8.4, 1.1 Hz, 1H), 6.74 (bs, 1H),
6.54 (s, 1H) 5.84 (q, J=6.4 Hz, 1H), 4.25-4.05 (m, 2H), 3.90 (s,
3H), 3.82 (S, 3H), 3.82-3.75 (m, 2H), 2.76-2.69 (m, 2H), 2.06-1.92
(m, 1H) 1.87-1.77 (m, 2H), 1.71 (d, J=6.4 Hz, 3H), 1.43 (s, 9H),
1.32-1.20 (m, 2H). MS (ESI): 671 [M+H].sup.+.
EXAMPLE 40
5-[5.6-Bis(methyloxy)-1H-benzimidazol-1-yl]-3-[((1R)-1-{2-chloro-3-[(4-pip-
eridinylmethyl)oxy]phenyl}ethyl)oxy]-2-thiophenecarboxamode
##STR00236##
[0827] 1,1-Dimethylethyl
4-[({3-[(1R)-1-({2-(aminocarbonyl)-5-[5,6-bis(methyloxy)-1H-benzimidazol--
1-yl]-3-thienyl}oxy)ethyl]-2-chlorophenyl}oxy)mwthyl]-1-piperidinecarboxyl-
ate (Example 39, 180 mg, 0.27 mmol) was deprotected using a
procedure analogous to Example 5. Step C to give 120 mg of the
title compound. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.20-7.80
(m, 2H), 7.85 (s, 1H), 7.34-7.22 (m, 2H) 7.14-6.99 (m, 2H), 6.96
(s, 1H), 6.86 (d, J=7.3 Hz, 1H), 6.58 (s, 1H). 5.87 (q, J=6.4 Hz,
1H), 3.99-3.83 (m, 2H), 3.93 (s, 3H), 3.87 (s, 3H), 3.52 (d, J=12.2
Hz, 2H), 2.97 (dd, J=12.2, 10.8 Hz, 2H), 2.25-2.01 (m, 3H)
1.82-1.69 (m, 2H), 1.75 (d, J=6.4 Hz, 3H). MS (ESI): 571
[M+H].sup.+.
EXAMPLE 41
5-[5,6-Bis(methyloxy)-1H-benzimidazol-1-yl]-3-{[(1R)-1-(2-chloro-3-{[(1-me-
thyl-4-piperidinyl)methyl]oxy}phenyl)ethyl]oxy}-2-thiophenecarboxamide
##STR00237##
[0829]
5-[5,6-bis(methyloxy)-1H-benzimidazol-1-yl]-3-[((1R)-1-{2-chloro-3--
[(4-piperidinylmethyl)oxy]phenyl}ethyl)oxy]-2-thiophenecarboxamide
(Example 40, 70 mg, 0.12 mmol) was reductively methylated using a
procedure analogous to Example 48 to give 50 mg of the title
compound (71%). .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.84 (s,
1H), 7.29-7.21 (m, 3H) 7.05 (d, J=7.4 Hz, 1H), 6.95 (s, 1H), 6.86
(d, J=7.4 Hz, 1H), 6.58 (s, 1H), 6.33 (bs, 1H), 5.89 (q, J=6.4 Hz,
1H), 3.94 (s, 3H), 3.91-3.79 (m, 2H), 3.87 (s, 3H), 2.92 (d, J=11.3
Hz, 2H), 2.30 {s, 3H), 2.10-1.80 (m, 5H) 1.75 (d, J=6.4 Hz, 3H),
1.54-1.40 (m, 2H). MS (ESI): 585 [M+H]+.
EXAMPLE 42
5-[5,6-Bis(methyloxy)-1H-benzimidazol-1-yl]-3-{[(1B)-1-(2-chJoro-3-{[2-(4--
methyl-1-piperazinyl)ethyl]oxy}phenyl)ethyl]oxy}-2-thiophenecarboxamide
##STR00238##
[0830] Step A--Methyl
5-[5,6-bis(methyloxy)-1H-benzimidazol-1-yl)-3-[((1R)-1-{3-[(2-bromoethyl)-
oxy]-2-chlorophenyl}ethyl)oxy]-2-thiophenecarboxylate
##STR00239##
[0832] Methyl
5-[5,6-bis(methyloxy)-1H-benzimidazol-1-yl]-3-{[(1R)-1-(2-chloro-3-hydrox-
yphenyl)ethyl]oxy}-2-thiophenecarboxylate (Intermediate 19, 980 mg,
2.0 mmol) and 2-bromoethanol (350 .mu.L, 5.0 mmol) were coupled
using a procedure analogous to Example 4, Step A to give 520 mg of
the desired product (44%). .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta. 7.86 (s, 1H), 7.32-7.22 (m, 3H), 6.95 (s, 1H), 6.86 (dd,
J=8.0, 2.4 Hz, 1H), 6.65 (s, 1H), 5.84 (q, J=6.4 Hz, 1H), 4.33 (t,
J=6.4, 2H) 3.95 (s, 3H), 3.92 (s, 3H), 3.90 is, 3H), 3.68 (t, J=6.4
Hz, 2H), 1.73 (d, J=6.4 Hz, 3H).
Step B--Methyl
5-[5,6-bis(methyloxy)-1H-benzimidazol-yl]-3-{[(1R)-1-(2-chloro-3-{[2-(4-m-
ethyl-1-piperazinyl)ethyl]oxy}phenyl)ethyl]oxy}-2-thiophenecarboxylate
##STR00240##
[0834] Methyl
5-[5,6-bis(methyloxy)-1H-benzimidazol-1-yl]-3-[((1R)-1-{3-[(2-bromoethyl)-
oxy]-2-chlorophenyl}ethyl)oxy]-2-throphenecarboxylate (100 rug,
0.17 mmol) and 1-methylpiperazine (52 .mu.L, 0.51 mmol) were
coupled using a procedure analogous to Example 15, Step A to give
54 mg of the desired product (53%). MS (ESI): 615 [M+H].sup.+.
Step
C--5-[5,6-Bis(methyloxy)-1H-benzimidazol-1-yl]-3-{[(1B)-1-(2-chJoro-3-
-{[2-(4-methyl-1-piperazinyl)ethyl]oxy}phenyl)ethyl]oxy}-2-thiophenecarbox-
amide (Title Compound)
[0835] Methyl
5-(5,6-bis(methyloxy)-1H-benzimidazol-1-yl]-3-{[(1R)-1-(2-chloro-3-{[2-(4-
-methyl-1-piperazinyl)ethyl]oxy}phenyl)ethyl]oxy}-2-miophenecarboxylate
(54 mg, was subjected to aminolysis using a procedure analogous to
Example 4, Step B to give 50 mg of the title compound. .sup.1H NMR
(400 MHz, CDCl.sub.3) .delta. 7.84 (s, 1H), 7.29-7.23 (m, 3H), 7.07
(d, J=7.4 Hz, 1H), 6.96 (s, 1H), 6.89 (d, J=7.4 Hz, 1H), 6.58 (s,
1H), 6.57 (bs, 1H), 5.89 (q, J=6.4 Hz, 1H), 4.15 (dd, J=6.8, 5.8,
2H) 3.94 (s, 3H), 3.88 (s, 3H), 2.90 (ddd, J=7.8, 5.8, 2.0 Hz, 2H),
2.76-2.36 (m, 8H), 2.29 (s, 3H), 1.75 (d, J=6.4 Hz, 3H). MS (ESI):
600 [M+H].sup.+.
EXAMPLE 43
1,1-Dimethylethyl
4-[({3-[(1R)-1-({2-(aminocarbonyl)-5-[5-(1-methyl-1H-pyrazol-4-yl)-1H-ben-
zimidazol-1-yl]-3-thienyl}oxy)ethyl]-2-chlorophenyl}oxy)methyl]-1-piperidi-
necarboxylate
##STR00241##
[0836] Step A--1,1-Dimethylethyl
4-[({2-chloro-3-[(1R)-1-({2-[(methyloxy)carbonyl]-5-[5-(1-methyl-1H
-pyrazol-4-yl)-1H-benzimidazol-1-yl]-3-thienyl}oxy)ethyl]phenyl}oxy)methy-
l]-1-piperidinecarboxylate
##STR00242##
[0838] Methyl
3-hydroxy-5-[5-(1-methyl-1H-pyrazol-4-yl)-1H-benzimidazol-1-yl]-2-thiophe-
necarboxylate (Intermediate 16, 250 mg, 0.50 mmol) and
1,1-dimethylethyl 4-(hydroxymethyl)-1-piperidinecarboxylate (129
mg, 0.60 mmol) were coupled using a procedure analogous to Example
5, Step A to give the desired product (275 mg, 78 %). MS (ESI); 706
[M+H].sup.+.
Step B--1,1-Dimethylethyl
4-[({3-[(1R)-1-({2-(aminocarbonyl)-5-[5-(1-methyl-1H-pyrazol-4-yl)-1H-ben-
zimidazol-1-yl]-3-thienyl}oxy)ethyl]-2-chlorophenyl}oxy)methyl]-1-piperidi-
necarboxylate (Title Compound)
[0839] 1,1 -Dimethylethyl
4-[({2-chloro-3-[(1R)-1-({2-[(methyloxy)carbonyl]-5-[5-(1-methyl-1H-pyraz-
ol-4-yl)-1H-benzimidazol-1-yl]-3-thienyl}oxy)ethyl]phenyl}oxy)methyl]-1-pi-
peridinecarboxylate) (275 mg, 0.39 mmol) was subjected to
aminoiysis using a procedure analogous to Example 4, Step B to give
200 mg of the title compound (74%). .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 7.95 (s, 1H), 7.88 (s, 1H), 7.79 (s, 1H), 7.65
(s, 1H) 7.50-7.42 (m. 2H), 7.26 (dd, J=7.9. 8.1 Hz, 1H), 7.22 (bs,
1H), 7.05 (dd, J=7.9, 1.3 Hz, 1H), 6.87 (dd, J=8.1, 1.3 Hz, 1H),
6.60 (s, 1H), 6.13 (bs, 1H), 5.90 (q, J=6.4 Hz, 1H), 4.25-4.05 (m,
2H) 3.96 (s, 3H), 3.91-3.80 (m, 2H), 2.83-2.68 (m, 2H), 2.09-1.98
(m, 1H), 1.91-1.79 (m, 2H), 1.75 (d, J=6.4 Hz, 3H), 1.45 (s, 9H),
1.37-1.23 (m, 2H). MS (ESI): 692 [M+H].sup.+.
EXAMPLE 44
3-[((1R)-1-{2-Chloro-3-[(4-piperidinylmethyl)oxy]phenyl}ethyl)oxy]-5-[5-(1-
-methyl-1H-pyrazol
-4-yl)-1H-benzimidazol-1-yl]-2-thiophenecarboxamide
trifluoroacetate
##STR00243##
[0841] 1,1 -Dimethylethyl
4-[({3-[(1R)-1-({2-(aminocarbonyl)-5-[5-(1-methyl-1H-pyrazol-4-yl)-1H-ben-
zimidazol-1-yl]-3-thlenyl}oxy)ethyl]-2-chlorophenyl}oxy)methyl]-1-piperidi-
necarboxylate (Example 43, 180 mg, 0.26 mmol) was deprotected using
a procedure analogous to Example 5, Step C to give 155 mg of trie
title compound. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.97-8.87
(m, 1H), 8.77 (s, 1H), 8.66-8.53 (m, 1H), 8.00 (s, 1H), 7.90 (s,
1H), 7.78 (s, 1H), 7.65-7.58 (m, 2H), 7.44 (bs, 1H), 7.32-7.24 (m,
3H), 7.06 (d, J=6.9 Hz, 1H), 6.89 (d, J=8.6 Hz, 1H), 6.87 (s, 1H),
5.94 (q, J=6.4 Hz, 1H), 4.02 (s, 3H), 3.97-3.91 (m, 2H), 3.06-2.94
(m, 2H), 2.21-2.04 (m, 3H), 1.87-1.73 (m, 2H), 1.79 (d, J=6.4 Hz,
3H), 1.27-1.19 (m, 2H).
EXAMPLE 45
3-{[(1R)-1-(2-Chloro--3-{[(1-methyl-4-piperidinyl)methyl]oxy}phenyl)ethyl]-
oxy}-5-[5-(1-methyl-1H-pyrazol-4-yl)-1H-benzimidazol-1-yl]-2-thiopnenecarb-
oxamide
##STR00244##
[0843]
3-[((1R)-1-{2-chloro-3-[(4-piperidinylmethyl)oxy]phenyl}ethyl)oxy]--
5-[5-(1-methyl-1H-pyrazol-4-yl)-1H-benzimidazol-1-yl]-2-thiophenecarboxami-
de trifluoroacetate (Example 44, 124 mg, 0.18 mmol) was reductively
methylated using a procedure analogous to Example 48 to give 65 mg
of the title compound, .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.
7.97 (s, 1H), 7.88 (s, 1H), 7.79 (s, 1H), 7.65 (s, 1H), 7.49-7.42
(m, 2H), 7.28-7.22 (m, 2H), 7.06 (d, J=7.9 Hz, 1H), 6.88 (d, J=8.3
Hz, 1H), 6.63 (bs, 1H), 6.63 (s, 1H), 5.91 (q, J=6.4 Hz, 1H), 3.97
(s, 3H), 3.92-3.81 (m, 2H), 2.90 (d, J=11.6, 2H), 2.29 (s, 3H),
2.02-1.82 (m, 5H), 1.76 (d, J=6.4 Hz, 3H), 1.53-1.42 (m, 2H). MS
{ESI}: 605 [M+H].sup.+.
EXAMPLE 46
1,1-Dimethylethyl
4-({3-[(1R)-1-({2-(aminocarbonyl)-5-[5-(1-methyl-1H-pyrazol-4-yl)-1H-benz-
imidazol-1-yl]-3-thienyl}oxy)ethyl]-2-chlorophenyl}oxy)-1-piperidinecarbex-
ylate
##STR00245##
[0844] Step A--1,1-Dimethylethyl
4-({2-chloro-3-[(1R)-1-({2-[(methyloxy)carbonyl]-5-[5-(1-methyl-1H-pyrazo-
l-4-yl)
-1H-benzimidazol-1-yl]-3-thienyl}oxy)ethyl]phenyl}oxy)-1-piperidin-
ecarboxylate
##STR00246##
[0846] Methyl
3-{[(1R)-1-(2-chloro-3-hydroxyphenyl)ethyl]oxy}-5-[5-(1-methyl-1H-pyrazol-
-4-yl)-1H-benzimidazol-1-yl]-2-thiophenecarboxylate (Intermediate
18, 650 mg, 1.3 mmol) and terfhutyl
4-hydroxypiperidine-1-carboxylate (402 mg, 2.0 mmol) were coupled
using a procedure analogous to Example 5, Step A to give 680 mg of
the desired product (75%). MS (ESI): 605 [M+H].sup.+.
Step B--1,1-Dimethylethyl
4-({3-[(1R)-1-({2-(aminocarbonyl)-5-[5-(1-methyl-1H-pyrazol-4-yl)-1H-benz-
imidazol-1-yl]-3-thienyl}oxy)ethyl]-2-chlorophenyl}oxy)-1-piperidinecarbex-
ylate (Title Compound)
[0847] 1,1 -Dimethylethyl
4-({2-chloro-3-[(1R)-1-({2-[(methyloxy)carbonyl]-5-[5-(1-methyl-1H-pyrazo-
l-4-yl)-1H-benzimidazol-1-yl]-3-thienyi}oxy)ethyl]phenyl}oxy)-1-piperidine-
carboxylate) (680 mg, 0.98 mmol) was subjected to aminolysis using
a procedure analogous to Example 4, Step B to give 500 mg of the
title compound (75%). .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.
7.97 (s, 1H), 7.89 (s, 1H), 7.79 (s, 1H), 7.67 (s, 1H) 7.49-7.43
(m, 2H), 7.30-7.21 (m, 1H), 7.08 (dd, J=7.8, 1.1 Hz, 1H), 6.93 (dd,
J=8.4, 1.1 Hz, 1H), 6.63 (s, 1H), 6.59 (bs, 1H), 5.91 (q, J=6.4 Hz,
1H), 4.61-4.54 (m, 1H) 3.97 (s, 3H), 3.71-3.59 Cm, 2H), 3.52-3.42
(m, 2H), 1.97-1.80 (m, 4H), 1.77 (d, J=6.4 Hz, 3H), 1.46 (s, 9H).
MS (ESI): 677 [M+H].sup.+.
EXAMPLE 47
3-({(1R)-1-[2-Chloro-3-(4-piperidinyloxy)phenyl]ethyl}oxy)-5-[5-(1-methyl--
1H-pyrazol-4-yl)-1H-benzimidazol-1-yl]-2-thiophenecarboxamide
##STR00247##
[0849] 1,1-Dimethylethyl
4-({3-[(1R)-1-({2-(aminocarbonyl)-5-[5-(1-methyl-1H-pyrazol-4-yl)-1H-benz-
imidazol-1-yl]-3-thienyl}oxy)ethyl]-2-chlorophenyl}oxy)-1-piperidinecarbox-
ylate (Example 46, 500 mg, 0.74 mmol) was deprotected using a
procedure analogous to Example 5, Stsp C to give 290 mg of the
title compound (68%). .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.
7.96 (s, 1H), 7.88 (s, 1H), 7.79 (s, 1H), 7.65 (s, 1H) 7.48-7.44
(m, 2H), 7.29-7.23 Cm, 1H), 7.21 (bs, 1H) 7.06 (d, J=6.6 Hz, 1H),
6.93 (d, J=8.4 Hz, 1H), 6.62 (s, 1H), 5.92 (q, J=6.4 Hz, 1H), 5.73
(bs, 1H), 4.52-4.44 (m, 1H) 3.97 (s, 3H), 3.22-3.12 (m, 2H),
2.81-2.71 (m, 2H), 2.06-1.96 (m, 2H), 1.85-1.75 (m, 2H), 1.77 (d,
J=6.4 Hz, 3H).
EXAMPLE 48
3-[((1R)-1-{2-Chloro-3-[(1-methyl-4-piperidinyl)oxy]phenyl}ethyl)oxy]-5-[5-
-(1-methyl-1H-pyrazol-4-yl)-1H-benzimidazol-1-yl]-2-thiophenecarboxamide
##STR00248##
[0851] To a solution of
3-({(1R)-1-[2-chloro-3-(4-piperidinyloxy)phenyl]ethyl}oxy)-5-[5-(1-methyl-
-1H-pyrazol-4-yl)-1H-benzimidazol-1-yl]-2-thiophenecarboxamide
(Example 47, 230 mg, 0.40 mmol) in DCM (4 mL) and MeOH (2 mL) was
added formaldehyde (0.033 mL, 1.2 mmol) and acetic acid (0.046 mL,
0.80 mmol) followed by sodium triacetoxy borohydride (0.17 g, 0.80
mmol). The solution was stirred for 1 h. The solution was diluted
with DCM (20 mL) and washed with sat'd NaHCO.sub.3 solution (10
mL). The organic layers were dried (MgSO.sub.4), filtered and the
solvent removed on a rotovap. The residue was dissolved in DCM and
loaded onto a 4 g ISCO chromatography column and eluted with a
gradient of 100:0 to 30:70 DCM : (80:20:2 DCM:MeOH:ammonium
hydroxide) over 20 min. The appropriate fractions were combined and
the solvent removed to provide 0.20 g of the titie compound as a
white solid (85 %). .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.97
(s, 1H), 7.88 (s, 1H), 7.79 (s, 1H), 7.65 (s, 1H), 7.45 (d, J=1.1
Hz, 2H), 7.30-7.22 (m, 2H), 7.06 (d, J=7.9 Hz, 1H), 6.93 (d, J=8.4
Hz, 1H), 6.74 (bs, 1H), 6.64 (s, 1H), 5.91 (q, J=6.4 Hz, 1H),
4.45-4.38 (m, 1H), 3.97 (s, 3H), 2.71-2.61 (m, 2H), 2.47-2.27 (m,
2H), 2.29 (s, 3H), 2.05-1.87 (m, 4H), 1.77 (d, J=6.4 Hz, 3H). MS
(ESI): 591 [M+H]+.
EXAMPLE 49
3-({(1R)-1-[2-Chloro-3-(4-piperidinyloxy)phenyl]ethyl}oxy)-5-[5-(2-methyl--
4-pyridinyl)-1H-benzimidazol-1-yl]-2-thiophenecarboxamide
##STR00249##
[0852] Step A--1,1-Dimethylethyl
4-({2-chloro-3-[(1R)-1-({2-[(methyloxy)carbonyl]-5-[5-(2-methyl-4-pyridln-
yl)-1H-benzimidazol-1-yl]-3-thienyl}oxy)ethyl]phenyl}oxy)-1-piperidinecarb-
oxylate
##STR00250##
[0854] Methyl
3-{[(1R)-1-(2-chloro-3-hydroxyphenyl)ethyl]oxy}-5-[5-(2-methyl-4-pyridiny-
l)-1H-benzimidazol-yl]-2-thiophenecarboxylate (Intermediate 20, 126
mg, 0.24 mmol) and tert-butyl 4-hydroxypiperidine-1-earboxylate (97
mg, 0.48 mmol) were coupled using a procedure analogous to Example
5, Slap A to give the desired product (120 mg, 71%) MS (ESI): 703
[M+H].sup.+.
Step B--1,1-Dirnethylethyl
4-({3-[(1R)-1-({2-(aminocarbonyl)-5-[5-(2-methyl-4-pyridinyl)-1H-benzimid-
azol-1-yl]-3-thienyl}oxy)ethyl]-2-chlorophenyl}oxy)-1-piperidinecarboxylat-
e
##STR00251##
[0856] 1,1-Dimethylethyl
4-({2-chloro-3-[(1R)-1-({2-[(methyloxy)carbonyl]-5-[5-(2-methyl-4-pyridin-
yl)-1H-benzimidazol-1-yl]-3-thienyl}oxy)ethyl]phenyl}oxy)-1-piperidinecarb-
oxylate (120 mg, 0.17 mmol) was subjected to amlnoiysis using a
procedure analogous to Example 4, Step B to give 100 mg of the
titie compound (85%). .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.
8.57 (d, J=5.1 Hz, 1H), 8.08 (s, 1H), 8.04 (s, 1H), 7.63-7.56 (m,
2H) 7.43 (s, 1H), 7.37 (d, J=5.1 Hz, 1H), 7.28 (dd, J=8.2, 7.8 Hz,
1H) 7.24 (bs, 1H), 7.08 (d, J=7.8 Hz, 1H), 6.94 (d, J=8.2 Hz, 1H),
6.67 (s, 1H), 6.47 (bs, 1H), 5.93 (q, J=6.4 Hz, 1H), 4.62-4.53 (m,
1H), 3.71-3.58 (m, 2H), 3.52-3.40 (m, 2H), 2.65 (s, 3H), 1.97-1.80
(m, 4H), 1.78 (d, J=6.4 Hz, 3H), 1.46 (s, 9H). MS (ESI): 688
[M+H].sup.+.
Step
C--3-({(1R)-1-[2-Chloro-3-(4-piperidinyloxy)phenyl]ethyl}oxy)-5-[5-(2-
-methyl-4-pyridinyl)-1H-benzimidazol-1-yl]-2-thiophenecarboxamide
(Title Compound)
[0857] 1,1-Dimethylethyl
4-({3-[(1R)-1-({2-(aminocarbonyl)-5-[5-(2-methyl-4-pyridinyl)-1H-benzimid-
azol-1-yl]-3-thienyl}oxy)ethyl]-2-chlorophenyl}oxy)-1-piperidinecarboxylat-
e (100 mg, 0.14 mmol) was deprotected using a procedure analogous
to Example 5, Step C to give 50 mg of the title compound (59%).
.sup.1H NMR (400 MHz, DMSO) .delta. 8.63 (s, 1H), 8.47 (d, J=5.1,
1H), 8.19 (d, J=1.5 Hz, 1H), 7.82 (bs, 1H) 7.74 (dd, J=8.7, 1.5 Hz,
1H), 7.65 (s, 1H), 7.56 (d, J=8.3 Hz, 1H) 7.32 (dd, J=8.2, 7.7 Hz,
1H), 7.20-7.07 (ms 3H), 5.97 (q, J=6.4 Hz, 1H), 4.53-4.44 (m, 1H)
3.29 (s, 3H), 2.93-2.81 (m, 2H), 2.55-2.44 (m, 2H), 1.90-1.78 (m,
2H), 1.70 (d, J=6.4 Hz, 3H), 1.50-1.40 (m, 2H). MS (ESI): 587
[M+H].sup.+.
EXAMPLE 50
3-[((1R)-1-{2-Chloro-3-[(1-methyl-4-piperidinyl)oxy]phenyl}ethyl)oxy]-5-[5-
-(2-methyl-4-pyridinyl)-1H-benzimidazol-1-yl]-2-thiophenecarboxamide
##STR00252##
[0859]
3-({(1R)-1-[2-chloro-3-(4-piperidinyloxy)phenyl]ethyl}oxy)-5-[5-(2--
methyl-4-pyridsnyl)-1H-benzimidazol-1-yl]-2-thiophenecarboxamide
(Example 49, 30 mg, 0.050 mmol) was reductively methylated using a
procedure analogous to Example 48 to give 20 mg of the title
compound (65%). .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.56 (d,
J=5.2 Hz, 1H), 8.08 (d, J=1.4 Hz, 1H), 8.04 (s, 1H), 7.61 (dd,
J=8.6, 1.7 Hz, 1H), 7.54 (d, J=8.6 Hz, 1H) 7.43 (s, 1H), 7.37 (dd,
J=5.2, 1.8 Hz, 1H), 7.29-7.22 (m, 2H), 7.08 (dd, J=7.9, 1.4 Hz,
1H), 6.94 (dd, J=8.5, 1.2 Hz, 1H), 6.68 (s, 1H), 6.56 (bs, 1H),
5.93 (q, J=6.4 Hz, 1H), 4.46-4.38 (m, 1H), 2.71-2.61 (m, 2H), 2.65
(s, 3H), 2.39-2.26 (m, 2H), 2.29 (s, 3H), 2.06-1.87 (m, 4H), 1.78
(d, J=6.4 Hz, 3H). MS (ESI): 602 [M+H].sup.+.
EXAMPLE 51
5-(5-Bromo-1H-benzimidazol-1-yl)-3-[((1R)-1-{2-chloro-3-[(1-methyl-4-piper-
ldinyl)oxy]phenyl}ethyl)oxy]-2-thiophenecarboxamide
##STR00253##
[0860] Step A--Methyl
5-(5-bromo-1H-benzimidazol-1-yl)-3-{[(1R)-1-(2-chloro-3-hydroxyphenyl)eth-
yl]oxy}-2-thiophenecarboxylate
##STR00254##
[0862] Methyl
5-(5-bromo-1H-benzimidazol-1-yl)-3-{[(1R)-1-(2-chloro-3-{[(1,1-dimethylet-
hyl)(dimethyl)silyl]oxy}phenyl)ethyl]oxy}-2-thiophenecarboxylate
(Intermediate 8, 9.0 g, 14 mmol) was deprotected using a procedure
analogous to Intermediate 18, Step B to give 6.2 g of the desired
product (85%). .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.96 (s,
1H), 7.44 (d, J=8.8 Hz, 1H), 7.24-7.18 (m, 4H), 6.99 (dd, J=7.1,
2.5 Hz, 1H), 6.62 (s, 1H), 5.72 (q, J=6.4, 1H), 3.90 (s, 3H), 1.73
(d, J=6.4 Hz, 3H).
Step B--Methyl
5-(5-bromo-1H-benzimidazol-1-yl)-3-[((1R)-1-{2-chloro-3-[(1-methyl-4-pipe-
ridinyl)oxy]phenyl}ethyl)oxy}-2-thiophenecarboxylate
##STR00255##
[0864] Methyl
5-(5-bromo-1H-benzimidazol-1-yl)-3-{[(1R)-1-(2-chbro-3-hydroxyphenyl)ethy-
l]oxy}-2-thiophenecarboxylate (6.2 g, 12 mmol) and
1-methylpiperidin-4-ol (2.1 g, 18 mmol) were coupled using a
procedure analogous to Example 4, Step A to give 8.4 g of the
desired product (85%). .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.
7.96 (s, 1H), 7.42 (d, J=8.7 Hz, 1H), 7.31-7.18 (m, 4H), 6.88 (dd,
J=5.3, 4.2 Hz, 1H), 6.66 (s, 1H), 5.82 (q, J=6.4, 1H), 4.43-4.34
(m, 1H), 3.90 (s, 3H), 2.71-2.60 (m, 2H), 2.39-2.25 (m, 2H), 2.30
(s, 3H), 2.04-1.85 (m, 4H), 1.72 (d, J=6.4 Hz, 3H).
Step
C--5-(5-Bromo-1H-benzimidazol-1-yl)-3-[((1R)-1-{2-chloro-3-[(1-methyl-
-4-piperldinyl)oxy]phenyl}ethyl)oxy]-2-thiophenecarboxamide (Title
Compound)
[0865] Methyl
5-(5-bromo-1H-benzimidazol-1-yl)-3-[((1R)-1-{2-chloro-3-[(1-methyl-4-pipe-
ridinyl)oxy]phenyl}ethyl)oxy]-2-thiophenecarboxylate (6.0 g, 9.9
mmol) was subjected to an amlnoiysis reaction analogous to Example
4, Step B to give 3.9 g of the title compound (66%). .sup.1H NMR
(400 MHz, CDCl.sub.3) .delta. 7.96 (d, J=7.5 Hz, 1H), 7.43 (d,
J=8.8 Hz, 1H), 7.31-7.22 (m, 3H), 7.20 (bs, 1H), 7.04 (d, J=7.9 Hz,
1H), 6.93 (d, J=8.1 Hz, 1H), 6.60 (s, 1H), 5.89 (q, J=6.4Hz, 1H),
5.73 (bs, 1H), 4.46-4.38 Cm, 1H), 2.71-2.61 (m, 2H), 2.38-2.27 (m,
2H), 2.32 (s, 3H), 2.05-1.87 (m, 4H), 1.77 (d, J=6.4 Hz, 3H). MS
(ESI): 589 & 591 [M+H].sup.+.
EXAMPLE 52
5-(6-Chloro-1H-benzimidazol-1-yl)-3-({(1R)-1-{2-chloro-3-(4-piperidinyloxy-
)phenyl]ethyl}oxy)-2-thiophenecarboxamide
##STR00256##
[0866] Step A--1,1-Dimethylethyl
4-({2-chloro-3-[(1R)-1-({5-(6-chloro-1H-benzimidazol-1-yl)-2-[(methyloxy)-
carbonyl]-3-thienyl}oxy)ethyl]phenyl}oxy)-1-piperidinecarboxylate
##STR00257##
[0868] Methyl
5-(6-chloro-1H-benzimidazol-1-yl)-3-{[(1R)-1-(2-chloro-3-hydroxyphenyl)et-
hyl]oxy}-2-thiophenecarboxylate (Intermediate 21, 430 mg, 0.93
mmol) and tert-butyl 4-hydroxypiperidine-1-carboxylate (280 mg, 1.4
mmol) were coupled using a procedure analogous to Example 5, Step A
to give the desired product (420 mg, 70%). MS (ESI): 646
[M+H].sup.+.
Step B--1,1-Dimethylethyl
4-{[3-{(1R)-1-{[2-(aminocarbonyl)-5-(6-chloro-1H-benzimidazol-1-yl)-3-thi-
enyl]oxy}ethyl)-2-cbiorophenyl]oxy}-1-piperidinecarboxylate
##STR00258##
[0870] 1,1-Dimethylethyl
4-({2-chloro-3-[(1R)-1-({5-(6-chloro-1H-benzimidazol-1-yl)-2-[(methyloxy)-
carbonyl]-3-thienyl}oxy)ethyl]phenyl}oxy)-1-piperidinecarboxylate
(420 mg, 0.65 mmol) was subjected to amlnoiysis using a procedure
analogous to Example 4, Step B to give 300 mg of the title compound
(72%). .sup.1H NMR (400 MHz, DMSO) .delta. 8.57 (s, 1H), 8.56 (s,
1H), 7.81 (bs, 1H), 7.75 (d, J=8.6 Hz, 1H), 7.53 (d, J=2.0 Hz, 1H),
7.34 (dd, J=8.6, 2.0 Hz, 1H), 7.32 (d, J=7.5 Hz, 1H), 7.23-7.14 (m,
3H), 7.10 (bs, 1H), 5.98 (q, J=6.4 Hz, 1H), 4.68-4.60 (m, 1H),
3.57-3.45 (m, 2H), 3.30-3.13 (m, 2H), 1.87-1.75 (m, 2H), 1.68 (d,
J=6.4 Hz, 3H), 1.59-1.46 (m, 2H). MS (ESI): 631 [M+H].sup.+.
Step
C--5-(6-Chloro-1H-benzimidazol-1-yl)-3-({(1R)-1-{2-chloro-3-(4-piperi-
dinyloxy)phenyl]ethyl}oxy)-2-thiophenecarboxamide (Title
Compound)
[0871] 1,1-Dimethylethyl
4-({3-[(1R)-1-({2-(amimocarbonyl)-5-[5-(2-methyl-4-pyrldinyl)-1H-benzimid-
azol-1-yl]-3-thienyl}oxy)ethyl]-2-chlorophenyl}oxy)-1-piperidinecarboxylat-
e was deprotected using a procedure analogous to Example 5, Step G
to give 150 mg of the title compound (59%). .sup.1H HMR (400 MHz,
DMSO) .delta. 8.59 (s, 1H), 7.85 (bs, 1H), 7.77 (d, J=8.8 Hz, 1H),
7.55 (d, J=2.0 Hz, 1H), 7.36 (dd, J=8.6, 2.0 Hz, 1H), 7.33 (d,
J=8.0 Hz, 1H), 7.23-7.15 (m, 3H), 7.13 (bs, 1H), 6.00 (q, J=6.4 Hz,
1H). 4.57-4.40 (m, 1H), 3.01-2.91 (m, 2H), 2.71-2.61 (m, 2H),
1.94-1.83 (m, 2H), 1.70 (d, J=6.4 Hz, 3H), 1.61-1.50 (m, 2H). MS
(ESI): 531 [M+H].sup.+.
EXAMPLE 53
5-(6-Chloro-1H-benzimidazol-1-yl)-3-[(1R)-1-{2-chloro-3-[(1-methyl-4-piper-
idinyl)oxy]phenyl}ethyl)oxy]-2-thiophenecarboxamide
##STR00259##
[0873]
5-(6-Chloro-1H-benzimidazol-1-yl)-3-({(1R)-1-[2-chloro-3-(4-piperid-
inyloxy)phenyl]ethyl}oxy)-2-thiophenecarboxamide (Example 52, 100
mg, 0.19 mmol) was reductively methylated using a procedure
analogous to Example 48 to give 55 mg of the title compound.
.sup.1H MMR (400 MHz, DMSO) .delta. 8.59 (s, 1H), 7.85 (bs, 1H),
7.77 (d, J=8.6 Hz, 1H), 7.55 (d, J=2.0 Hz, 1H), 7.36 (dd, J=8.6,
2.0 Hz, 1H), 7.31 (d, J=8.0 Hz, 1H), 7.23-7.10 (m, 4H), 6.00 (q,
J=6.4 Hz, 1H), 4.48-4.41 (m, 1H), 2.58-2.43 (m, 2H), 2.21-2.06 (m,
2H), 2.11 (s, 3H), 1.92-1.78 (m, 2H), 1.70 (d, J=6.4 Hz, 3H),
1.68-1.57 (m, 2H). MS (ESI): 545 [M+H].sup.+.
EXAMPLE 54
3-({(1R)-1-[2-Chloro-3-(4-piperidinyloxy)phenyl]ethyl}oxy)-5-{6-[(methylsu-
lfonyl)methyl]-1H-benzimidazol-1-yl}-2-thiophenecarboxamide
##STR00260##
[0875] To a slurry of methyl
3-{[(1R)-1-(2-chloro-3-hydroxyphenyl)ethyl]oxy}-5-{6-[(methylsulfonyl)met-
hyl]-1H-benzimidazol-1-yl}-2-thiophenecarboxylate (Intermediate 23,
0.050 g, 0.095 mmol) and 1,1-dirnethyIethyl
4-hydroxy-1-piperidinecarboxylate (0.058 g. 0.29 mmol) in THF (10
mL) was added 4-(diphenylphosphanyl)-N,N-dimethylaniline (0.088 g,
0.28 mmol) and di-tert-butylazodicarboxylate (0.066 g, 0.28 mmol).
The clear, yellow solution was stirred for 24 h, and then silica
gel (1 g) was added. The volatiles were evaporated under reduced
pressure and the residue was purified by flash column
chromatography (0 to 50% EtOAc:CH.sub.2Cl.sub.2) to give
1,1-dimethyleihyl
4-[(2-chloro-3-{(1R)-1-[2-[(methyloxy)carbonyl]-5-{6--[(methylsulfonyl)me-
thyl]-1H-benzimidazol-1-yl}-3-thienyl)oxy]ethyl}phenyl)oxy]-1-piperidineca-
rboxylate 0.06 g (0.085 mmol) which was then was added to a
solution of 7 N ammonia in MeOH (10 mL). The mixture was heated in
a sealed tube to 80.degree. C. for 40 h and then cooled to rt and
the volatiles were evaporated under reduced pressure. The residue
was then dissolved in DCM (5 rnL) and TFA (1 mL, 5.9 mmol) was
added. After 1 h the volatiles were evaporated under reduced
pressure and the residue was dissolved in 10 mL of DCM and 1 g of
MP-Carbonate resin was added to remove excess TFA. After 30 min the
resin was removed by filtration and the volatiles were evaporated
under reduced pressure to afford 0.04 g (70%) of the title compound
as a light yellow solid. .sup.1H NMR (400 MHz, CD.sub.3OD): .delta.
8.40 (s, 1H), 7.74 (d, J=8.42 Hz, 1H), 7.54 (s, 1H), 7.45 (d,
J=8.42 Hz, 1H), 7.30 (t, J=7.97 Hz, 1H), 7.16 (d, J=7.87 Hz, 1H),
7.09 (d, J=7.87 Hz, 1H), 6.99 (s, 1H), 6.05 (q, J=6.29 Hz, 1H) 4.56
(m, 3H), 2.85 (s, 3H), 1.94 (br m, 2H), 1.86 (br m, 4H), 1.76 (d,
J=6.23 Hz, 3H), 170 (br m, 2H); MS (ESI): 589 [M+H].sup.+.
EXAMPLE 55
3-[((1R)-1-{2-chloro-3-[(1-methyl-4-piperidinyl)oxy]phenyl}ethyl)oxy]-5,6--
{6-[(methylsulfonyl)methyl]-1H-benzimidazol-1-yl}-2-thiophenecarboxamide
##STR00261##
[0877] To a solution of
3-({(1R)-1-[2-chloro-3-(4-piperidinyloxy)phenyl]ethyl}oxy)-5-{6-[(methyls-
ulfonyi)methyl]-1H-benzimidazol-1-yl}-2-thiophenecarboxamide
(Example 54, 0.03 g, 0.05 mmol) in DCM/MeOH (3:2) (5 mL) was added
formaldehyde (0.037 g, 1.23 mmol), followed by sodium triacetoxy
borohydride (0.025 g, 0.122 mmol) and the mixture stirred at rt for
30 min. Silica (1 g) was added, the volatiles were evaporated under
reduced pressure and the residue was purified by flash column
chromatography (0 to 100% 80/20/1 DCM/MeOH/ammonlum hydroxide: DCM)
to afford 0.026 g (86%) of the title compound as a light yellow
solid. .sup.1H NMR (400 MHz, CD.sub.3OD): .delta. 8.42 (s, 1H),
7.77 (d, J=8.23 Hz, 1H), 7.56 (s, 1H), 7.47 (d, J=8.42 Hz, 1H),
7.32 (t, J=7.96 Hz, 1H), 7.17 (d, J=7.87 Hz, 1H), 7.11 (d, J=8.23
Hz, 1H), 7.01 (s, 1H), 6.07 (q, J=6.34 Hz, 1H) 4.55 (m, 3H), 2.85
(s, 3H), 2.66 (br m, 2H), 2.35 (br m, 2H), 2.27 (s, 3H), 1.96 (br
m, 2H), 1.86 (br m, 2H) 1.78 (d, J=6.22 Hz, 3H); MS (ESI): 603
[M+H].sup.+.
EXAMPLE 56
3-[((1R)-1-{2-chloro-3-[(4-piperidinylmethyl)oxy]phenyl}ethyl)oxy]-5-{6-[(-
methylsulfonyl)methyl]-1H-benzimidazol-1-yl}-2-thiophenecarboxamide
##STR00262##
[0879] The title compound was prepared by a procedure analogous to
Example 54 using methyl
3-{[(1R)-1-(2-chloro-3-hydroxyphenyl)ethyl]oxy}-5-{6-[(methylsulfonyl)met-
hyl]-1H-benzimidazol-1-yl)-2-thiophenecarboxylate (Intermediate 23,
0.1 g, 0.2 mmol) and 1,1-dimethylethyl
4-(hydroxymethyl)-1-pipehdinecarboxylate (0.124 g, 0.57 mmol) to
afford 0.05 g (43%) of the title compound. .sup.1H NMR (400 MHz,
CD.sub.3OD): .delta. 8.39 (s, 1H), 7.73 (d, J=8.24 Hz, 1H), 7.51
(s, 1H), 7.43 (d, J=8.43 Hz, 1H), 7.30 (t, J=7.97 Hz, 1H), 7.14 (d,
J=7.87 Hz, 1H), 7.01 (m, 2H), 6.05 (q, J=6.35 Hz, 1H), 4.47 (q,
J=13.92 Hz, 2H,), 3.99 (m, 1H), 3.85 Cm, 1H), 3.15 (d, J=12.82 Hz,
2H), 2.81 (s, 3H), 2.73 (t, J=11.99 Hz, 2H), 2.05 (br s, 1H,), 1.91
(q, J=13.28 Hz, 2H), 1.75 (d, 3H), 1.41 (m, 2H); MS (ESI): 603
[M+H].sup.+.
EXAMPLE 57
3-({(1R)-1-[2-Chloro-3-({[(2S)-1-methyl-2-pyrrolidinyl]metliyl}oxy)phenyl]-
ethyl}oxy)-5-{6-[(methylsulfonyl)methyl]-1H-benzimidazol-1-yl}-2-thiophene-
carboxamide
##STR00263##
[0881] To methyl
3-{[(1R)-1-(2-chloro-3-hydroxyphenyl)ethyl]oxy}-5-{6-[(methylsulfonyl)met-
hyl]-1H-benzimidazol-1-yl}-2-thiophenecarboxylate (Intermediate 23,
0.050 g, 0.095 mmol) in dimemylformamide (5 mL) was added
1,1-dimethylethyl
(2S)-2-({[(4-methylplienyl)sulfonyl]oxy}methyl)-1-pyrrolidinecarhoxylate
(which may be prepared using literature reference: Tetrahedron
Lett, 1991, 47, 7179-7184) (0.053 g, 0.14 mmol), and
Cs.sub.2CO.sub.3 (0.046 g, 0.14 mmol). The mixture was heated in a
sealed tube to 60.degree. C. for 24 h and then cooled to rt. The
DMF was evaporated under reduced pressure and the residue was
purified by flash column chromatography (0 to 50% EtOAc:DCM) to
afford 0.050 g (0.071 mmol) of 1,1-dimethylethyl
(2S)-2-{[(2-chloro-3-{(1R)-1-[(2-[(methyloxy)carbobyl]-5-{6-[(methylsulfo-
nyl)methyl]-1H-benzimidazol-1-yl}-3-thienyl)oxy]ethyl}phenyl)oxy]methyl}-1-
-pyrrolidinecarboxylate which was then dissolved in DCM (5 mL) and
TFA (1.0 mL, 5.9 mmol) was added. After 1 h the volatiles were
evaporated under reduced pressure and the residue was dissolved in
10 mL of DCM and 1 g of MP-Carbonate resin was added to remove
excess TFA. After 30 min the resin was removed by filtration and
the volatiles were evaporated under reduced pressure to afford
0.040 g (0.068 mmol) of methyl
3-{[(1R)-1-(2-chloro-3-{[(2S)-2-pyrroiidinylmethyl]oxy}phenyl)ethyl]oxy}--
5-{6-[(methylsuifonyl)methyl]-1H-benzimidazol-1-yl}-2-thiophenecarboxylate
which was then dissolved in DCM/MeOH (3:2) (5 mL). Formaldehyde was
added (0.037 g, 1.23 mmol), followed by sodium triacetoxy
borohydride (0.025 g, 0.122 mmol) and the mixture stirred at rt for
30 min. The volatiles were evaporated under reduced pressure and
the residue was dissolved in 7 N ammonia In MeOH (10 mL). The
mixture was heated in a sealed tube to 80.degree. C. for 40 h and
then cooled to rt. Silica (1 g) was added, the volatiles were
evaporated under reduced pressure and the residue was purified by
flash column chromatography (0 to 100% 80/20/1 DCM/MeOH/ammonium
hydroxide: DCM) to give 0.024 g (0.04 mmol) of the title compound
as a yellow solid. .sup.1H NMR (400 MHz, DMSO): .delta. 8.60 (s,
1H), 7.84 (s, 1H), 7.78 (d, J=8.23 Hz, 1H), 7.73 (s, 1H), 7.36 (m,
2H), 7.20 (t, J=3.93 Hz, 2H), 7.10 (m, 2H), 5.95 (q, J=6.22 Hz,
1H), 4.61 (m, 2H), 4.00-3.85 (m, 2H), 2.87 (br s, 4H), 2.58 (m,
1H), 2.34 (s, 3H), 2.15 (m, 1H), 1.92 (m, 1H), 1.71 (d, 3H)
1.67-1.52 (m, 3H); MS (ESI): 603 [M+H].sup.+.
EXAMPLE 53
3-({(1R)-1-[2-chloro-3-({[(2S)-1-methyl-2-pyrrolidinyl]methyl}oxy)phenyl]e-
thyl}oxy)-5-{6-[(methylsulfonyl)methyl]-1H-benzimidazol-1-yl}-2-thiophenec-
arboxanide
##STR00264##
[0883] The title compound was prepared using a procedure analogous
to Example 57 from methyl
3-{[(1R)-1-(2-chloro-3-hydroxyphenyl)ethyl]oxy}-5-{6-[(methylsulfonyl)met-
hyl]-1H-benztmidazol-1-yl}-2-thiophenecarboxylate (Intermediate 23,
0.050 g, 0.095 mmol) and 1,1-dimethytethyl
(2R)-2-({[(4-methylphenyl)sulfonyl]oxy}methyl)-1-pyrrolidinecarboxylate
(which may be prepared using procedures similarly described for the
(S)-enantiomer in Tetrahedron Lett, 1991, 47, 7179-7184) (0.053 g,
0.14 mmol). .sup.1H NMR (400 MHz, CD.sub.3OD): .delta. 8.42 (s,
1H), 7.76 (d, J=8.23 Hz, 1H), 7.61 (s, 1H), 7.55 (s, 1H), 7.46 (d,
J=8.42 Hz, 1H), 7.34 (t, J=8.05 Hz, 1H), 7.18 (d, J=7.87 Hz, 1H)
7.07 (d, J=7.32 Hz, 1H), 7.00 (s, 1H), 6.08 (q, J=6.40 Hz, 1H),
4.53 (m, J=14.00 Hz, 2H), 4.17 (dd, J=3.84, 9.70 Hz, 1H,), 3.97 (m,
1H), 3.07 (m, 1H), 2.83 (m, 4H), 2.37 (m, 1H), 2.09 (m, 1H), 1.8
(m, 5H) 1.8 (s, 1H); MS (ESI): 603[M+H].sup.+.
EXAMPLEs 59
3-({(1R)-1-[2-chloro-3-(4-piperidineloxy)phenyl]ethyl}oxy)-5-[5-(methylsul-
fonyl)-1H-benzimidazol-1-yl]-2-thiophenecarboxamide; and
EXAMPLE 60
3-({(1R)-1-[2-chloro-3-(4-piperidineloxy)phenyl]ethyl}oxy)-5-[6-(methylsul-
fonyl)-1H-benzimidazol-1-yl]-2-thiophenecarboxamide
##STR00265##
[0884] Step A--5-(Methylthio)-2-nitroaniline
##STR00266##
[0886] 5-Chloro-2-nitroaniline (15 g, 87.2 mmol) was dissolved in
250 mL of DMF with stirring. Sodium thiomethoxsde (9.8 g, 140 mmol)
was added and the reaction stirred at 65.degree. C. for 20 h. The
reaction was cooled to rt and diluted with EtOAc. then washed with
water (5.times.), brine (1.times.), dried over MgSO.sub.4,
filtered, and concentrated in vacuo. The residue was purified by
flash chromatography to afford 12.9 g (81%) of
5-(methylthio)-2-nitroaniline as a red-orange solid. .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. 7.85 (d, J=8.97 Hz, 1H), 7.45 (br
s, 2 H), 6.78 (d, J=1.83 Hz, 1H), 6.47 (dd, J=1.83 and 9.16 Hz,
1H), 2.47 (s, 3 H).
Step B--4-(Methylthio)benzene-1,2-diamine
##STR00267##
[0888] 5-(Methylthio)-2-nitroaniline (12.9 g, 70.1 mmol) was
dissolved In 475 mL of EiOH with stirring. Tin (II) Chloride (74.0
g, 392 mmol) was added and the reaction was reftuxed for 20 h. The
reaction was cooled to rt and concentrated in vacuo to a volume of
150 mL. The pH of the solution was adjusted to approximately 10
using concentrated aqueous 3N NaOH. EtOAc (1.5 L) was added and the
reaction was filtered through Celite, washing with water and EtOAc.
The aqueous layer was separated, then extracted with EtOAc
(2.times.). The combined organic layers were washed with brine,
dried over MgSO.sub.4, filtered, and concentrated in vacuo to give
10.7 g (99%) of the crude 4-(methylthio)benzene-1,2-diamtne as a
dark oil. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 6.52 (m, 1H).
6.44 (m, 1H), 6.37 (m, 1H), 4.49 (br s, 4 H), 2.29 (s, 3H).
Step C--8-(Methylthio)-1H-benzimidazole
##STR00268##
[0890] 4-(Methylthio)benzene-1,2-diamine (10.7 g, 69.2 mmol) was
dissolved in 230 mL of aqueous 4N HCl with stirring. Formic acid
(7.85 mL, 208 mmol) was added and the reaction was reftuxed for 1
h. The reaction was cooled to rt then concentrated in vacuo to a
dark solid. The dark solid was dissolved In 500 mL of MeOH with
stirring, NaHCO.sub.3 (51.0 g, 607 mmol) was added and the reaction
was stirred for 1 h. The reaction was then filtered, and the
filtrate concentrated in vacuo to a solid. The solid was stirred in
400 mL of EtOAc and heated to reflux, then filtered. The filtrate
was concentrated in vacuo to a solid. The solid dissolved in 400 mL
of DCM with stirring, then dried over MgSO.sub.4, and filtered. The
filtrate was concentrated in vacuo to give 11.3 g (99%) of the
crude 6-(methylthio)-1H-benzimidazole as a dark oil. .sup.1H NMR
(400 MHz, CD.sub.3OD) .delta. 8.12 (s, 1H), 7.52 (m, 2 H), 7.24 (m,
1H), 2.50 (s, 3H). MS m/z 165 (M+1).
Step D--Methyl
3-hydroxy-5-[5-(nethylthio)-1H-benzimidazol-1-yl]thiophene-2-carboxylate
and Methyl
3-hydroxy-5-[6-(methylthio)-1H-benzimidazol-1-yl]thiophene-2-carbaxyiate
##STR00269##
[0892] Methyl 2-chloro-3-oxo-2,3-dihydro-2-thiophenecarboxylate
(1.69 g, 8.80 mmol) was added to a stirred solution of
6-(methylthio)-1H-benzimidazole (2.71 g, 17.6 mmol) in 35 mL of
CHCl.sub.3, and the mixture was allowed to stir at 45.degree. C.
for 24 h. The reaction was diluted with CHCl.sub.3 (700 mL) and
water (250 mL). The aqueous layer was extracted with CHCl.sub.3
(2.times.150 mL). The combined organic layers were dried over
MgSO.sub.4. filtered, and concentrated in vacuo. Purification by
flash chromatography afforded 1.84 g (65%) of a regioisomeric
mixture of Methyl
3-hydroxy-5-[5-(methylthio)-1H-benzimidazol-1-yl]thiophene-2-carboxylate
and Methyl
3-hydroxy-5-[6-(methylthio)-1H-benzimidazol-1-yl]thiophene-2-carboxylate.
MS (ESI): 321 [M+H].sup.+.
Step E--Methyl
5-[5-(methylthio)-1H-benzimidazol-1-yl]-3-[(phenylmethyl)oxy]-2-thiophene-
carboxylate and Methyl
5-[6-(methylthio)-1H-benzimidazol-1-yl]-3-[(phenylmethyl)oxy]-2-thiophene-
carboxylate
##STR00270##
[0894] To a solution of a regioisomeric mixture of methyl
3-hydroxy-5-[5-(methylthio)-1H-benzimidazol-1-yl]thiophene-2-carboxylate
and methyl
3-hydroxy-5-[6-(methylthio)-1H-benzimidazol-1-yl]thiophene-2-carboxylate
which was prepared using a procedure analogous to Example 59, Step
D (8.81 g, 27.5 mmol) in 150 mL of DMF was added K.sub.2CO.sub.3
(11.4 g, 82.5 mmol) and benzyl bromide (3.90 mL, 33.0 mmol). The
reaction stirred for 16 h and was then poured into water and
extracted with EtOAc (3.times.). Combined organics were dried over
anhydrous MgSO.sub.4, filtered, concentrated onto silica gel and
purified by flash chromatography to give 8.75 g (78%) of a mixture
of 5 and 6-regioisomers which was carried on to the next step
without further purification. MS (ESI): 411 [M+H].sup.+.
Step F--Methyl
5-[5-{methylsulfonyl)-1H-benzimidazol-1-yl]-3-[(phenylmethyl)oxy]-2-thiop-
henecarboxylate and Methyl
5-[6-(methylsulfonyl)-1H-benzimidazol-1-yl]-3-[(phenylmethyl)oxy]-2-thiop-
henecarboxylate
##STR00271##
[0896] To a solution of a regioisomeric mixture of methyl
5-[5-(methylthso)-1H-benzimidazol-1-yl]-3-[(phenylmethyl)oxy]-2-thiophene-
carboxylate and methyl
5-[6-(methylihio)-1H-benzimidazol-1-yl]-3-[(phenylmethyl)oxy]-2-thiophene-
carboxylate (8.75 g, 21.3 mmol) in 200 mL of DCM was added
3-chloroperoxybenzoic acid (70%) (11.6 g, 46.9 mmol). The reaction
stirred for 16 h and was then poured into saturated aqueous
NaHCO.sub.3 solution and extracted with DCM (1.times.) and EtOAc
(2.times.). Combined organics were dried over anhydrous MgSO.sub.4,
filtered, concentrated onto silica gel and purified by flash
chromatography to give 9.0 g (95%) of a mixture of 5 and
6-regsoisomers which was carried on to the next step without
further purification. MS (ESI): 443 [M+H].sup.+.
Step G--Methyl
3-hydroxy-5-[5--(methylsulfonyl)-1H-benzimidazol-1-yl]-2-thiophenecarboxy-
late and Methyl
3-hydroxy-5-[6-(methylsuifonyl)-1H-benzimidazol-1-yl]-2-thiophenecarboxyl-
ate
##STR00272##
[0898] A regioisomeric mixture of methyl
5-[5-(methylsulfonyl)-1H-benzimidazol-1-yl]-3-[(phenylmethyl)oxy]-2-thiop-
henecarboxylate and methyl
5-[8-(methylsulfonyl)-1H-benzimidazol-1-yl]-3-[(phenylmethyl)oxy]-2-thiop-
henecarboxylate (9.00 g, 21.3 mmol) was dissolved in 50 mL of neat
TFA. The reaction stirred for 16 h and was then heated to
50.degree. C. for 2 h at which time most of the TFA was removed in
vacuo. The remaining mixture was quenched with saturated aqueous
NaHCO.sub.3 solution and extracted with EtOAc (3.times.). Combined
organics were dried over anhydrous MgSO.sub.4, filtered and
concentrated. The crude product was triturated with ether filtered
and air dried to give 4.5 g (60%) of a mixture of 5 and
6-regioisomers which was carried on to the next step without
further purification. MS (ESi): 353 {M+H].sup.+.
Step H--Methyl
3-{[(1R)-1-(2-chloro-3-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}phenyl)et-
hyl]oxy}-5-[5-(methylsulforryl)-1H-benzinidazol-1-yl]-2-thiophenecarboxyla-
te; and Methyl
3-{[(1R)-1-(2-chloro-3-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}phenyl)
ethyl]oxy}-5-[6-(methylsulfonyl)-1H-benzimidazol-1-yl]-2-thiophenecarboxy-
late
##STR00273##
[0900] Title compounds were prepared from a regioisomeric mixture
of methyl
3-hydroxy-5-[5-(methylsulfonyl)-1H-benzimidazol-1-yl]-2-thiophenee-
arhoxylate and methyl
3-hyriroxy-5-[6-(methylsulfonyl)-1H-benzimidazol-1-yl]-2-thiophenecarboxy-
late (783 mg) using a procedure analogous to Intermediate 3, Step E
to give 800 mg (58%) of a mixture of 5 and 6-regiolsomers which was
carried on to the next step without further purification. MS (ESI):
622 [M+H].sup.+.
Step I--Methyl
3-{[(1R)-1-(2-chloro-3-hydroxyphenyl)ethyl]oxy}-5-[6-(methylsulfonyl)-1H--
benzimidazol-1-yl]-2-thiophenecarboxylate; and Methyl
3-{[(1R)-1-(2-chloro-3-hydroxyphenyl)ethyl]oxy}-5-[5-(methylsulfonyl)-1H--
benzimidazol-1-yl]-2-thiophenecarboxylate
##STR00274##
[0902] Title compounds were prepared from a regioisomeric mixture
of methyl
3-{[(1R)-1-(2-chloro-3-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}ph-
enyl)ethyl]oxy}-5-[5-(methylsulfonyl)-1H-benzimidazol-1-yl]-2-thiophenecar-
boxylate and methyl
3-{[(1R)-1-(2-chloro-3-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}phenyl)et-
hyl]oxy}-5-[6-(methylsulfonyl)-1H-benzimidazol-1-yl]-2-thiophenecarboxylat-
e (800 mg) using a procedure analogous to Intermediate 3, Step F to
give 650 mg (100%) of a mixture of 5 and 6-regioisomers which was
carried on to the next step without further purification. MS (ESI):
507 [M+H].sup.+.
Step J--1,1-Dimethylethyl
4-({2-chloro-3-[(1R)-1-({2-[(methyloxy)carbonyl]-5-[5-(methylsulfonyl)-1H-
-benzimidazol-1-yl]-3-thienyl}oxy)ethyl]phenyl}oxy)-1-piperidinecarboxylat-
e; and 1,1-Dimethylethyl
4-({2-chloro-3-[(1R)-1-({2-[(methyloxy)carbonyl]-5-[8-(methylsulfonyl)-1H-
-benzimidazol-1-yl]-3-thlenyl}oxy)ethyl]phenyl}oxy)-1-piperidinecarboxylat-
e
##STR00275##
[0904] Title compounds were prepared from a regioisomeric mixture
of methyl
3-{[(1R)-1-(2-chloro-3-hydroxyphenyl)ethyl]oxy}-5-[6-(methylsulfon-
yl)-1H-benzimidazol-yl]-2-thiophenecarboxylate and methyl
3-{[(1R)-1-(2-chloro-3-hydroxyphenyl)ethyl]oxy}-5-[5-(methylsulfonyl)-1H--
benzimidazol-1-yl]-2-thiophenecarboxylate (650 mg) using a
procedure analogous to Example 5, Step A to give 800 mg (90%) of a
mixture of 5 and 6-regioisomers which was carried on to the next
step without further purification. MS (ESI): 691 [M+H].sup.+.
Step K--1,1-Dimethylethyl
4-({3-[(1R)-1-({2-(aminocarbonyl)-5-[5-(methylsulfonyl)-1H-benzimidazol-1-
-yl]-3-thienyl}oxy)ethyl]-2-chlorophenyl}oxy)-1-piperidinecarboxylate;
and 1,1-Dimethylethyl
4-({3-[(1R)-1-({2-(aminocarbonyl)-5-[6-(methylsulfonyl)-1H-benzimidazol-1-
-yl]-3-thienyl}oxy)ethy]-2-chlorophenyl}oxy)-1-piperidinecarboxylate
##STR00276##
[0906] Title compounds were prepared from a regioisomeric mixture
of 1,1-dimethylethyl
4-({2-chloro-3-[(1R)-1-({2-[(methyloxy)carbonyl]-5-[5-(methylsulfonyl)-1H-
-benzimidazol-1-yl]-3-thienyl}oxy)ethyl]phenyl}oxy)-1-piperidinecarboxylat-
e and 1,1-dimethylethyl
4-({2-chloro-3-[(1R)-1-({2-[(methyloxy)carbonyl]-5-[6-(methylsulfonyl)-1H-
-benzimidazol-1-yl]-3-thienyl}oxy)ethyl]phenyl}oxy)-1-piperidinecarboxylat-
e (800 mg) using a procedure analogous to Example 5, Step B to give
750 mg (96%) of a mixture of 5 and 8-regloisomers which was carried
on to the next step without further purification. US (ESI): 676
[M+H].sup.+.
Step
L--3-({(1R)-1-[2-chloro-3-(4-piperidineloxy)phenyl]ethyl}oxy)-5-[5-(m-
ethylsulfonyl)-1H-benzimidazol-1-yl]-2-thiophenecarboxamide; and
3-({(1R)-1-[2-chloro-3-(4-piperidineloxy)phenyl]ethyl}oxy)-5-[6-(methylsu-
lfonyl)-1H-benzimidazol-1-yl]-2-thiophenecarboxamide (Title
Compounds)
[0907] Title compounds were prepared from a regioisomeric mixture
of 1,1-dimethylethyl
4-({3-[(1R)-1-({2-(aminocarbonyl)-5-[5-(methylsulfonyl)-1H-benzimidazol-1-
-yl]-3-thienyi}oxy)ethyl]-2-chlorophenyl}oxy)-1-piperidinecarboxylate
and 1,1-dimethylethyl
4-({3-[(1R)-1-({2-(aminocarbonyl)-5-[6-(methylsulfonyl)-1H-benzimidazol-1-
-yl]-3-thienyl}oxy)ethyl]-2-cblorophenyl}oxy)-1-piperidinecarboxylate
(750 mg) using a procedure analogous to Example 5, Step C and then
the regioisomers were separated using packed column supercritical
fluid chromatography (SFC) on a Diacel.RTM. 3.times.25 Chiralcel
OJ-H column at 103 bar, 27.degree. C. using a mobile phase of 75%
Carbon Dioxide/25% (89.5% MeOH/10% CHCl.sub.3/0.5% Diethylamine).
The 6-regioisomer title compound,
3-({(1R)-1-[2-chloro-3-(4-piperidinyloxy)phenyl]ethyl}oxy)-5-[6-
-(methylsulfonyl)-1H-benzimidazol-1-yl]-2-thiophenecarboxamide (246
mg) eiuted first with a retention time of 5.32 min at a flow rate
of 2 mL/min on the analytical instrument .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 8.81 (s, 1H), 8.11 (s, 1H), 7.98 (d, J=8.5
Hz, 1H), 7.85 (dd. J=8.6, 1.6 Hz, 2H), 7.34-7.29 (m, 2 H), 7.22 (d,
J=7.7 Hz, 1H), 7.15 (d, J=8.2 Hz, 1H), 7.11 (s, 1H), 5.94 (q, J=6.2
Hz, 1H), 4.57 (m, 1H), 3.23 (s, 3H), 3.00 (m, 2H), 2.78 (rn. 2 H),
1.93 (m, 2H), 1.68 (d, J=6.3 Hz, 3H), 1.65 (m, 2H). MS (ESI): 576
[M+H].sup.+. The 5-regioisomer title compound,
3-({(1R)-1-[2-chloro-3-(4-piperidinyloxy)phenyl]ethyl}oxy)-5-[5-(methylsu-
lfonyl)-1H-benzimidazol-1-yl]-2-thiophenecarboxamide (134 mg)
eiuted second with a retention time of 8.89 min at a flow rate of 2
mL/min. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 8.78 (s, 1H),
8.29 (s, 1H), 7.87-7.82 (m, 2H), 7.68 (d, J=8.6 Hz, 1H), 7.38-7.31
(m, 1H), 7.25-7.18 (m, 3H), 7.11 (s, 1H), 5.95 (q, J=6.3 Hz, 1H),
4.73 (m, 1H), 3.23 (s, 3H), 3.13 (m, 2H), 3.03 (m, 2H), 2.06 (m,
2H), 1.84 (m, 2H), 1.68 (d, J=6.5 Hz, 3H). MS (ESS): 576
[M+H].sup.+.
EXAMPLE 61
3-({(1R)-1-[2-cbloro-3-(4-piperidinyloxy)phenyl]ethyl}oxy)-5-{5-[(trifluor-
omethyl)oxy]-1H-benzimidazol-1-yl}-2-thiophenecarboxamide
##STR00277##
[0909] To a slurry of methyl
3-{[(1R)-1-(2-chloro-3-hydroxyphenyl)ethyl]oxy}-5-{5-[(trifluoromethyl)ox-
y]-1H-benzsmldazol-1-yl}-2-thiophenecarboxylate (Intermediate 25,
0.18 g, 0.35 mmol) and 1,1-dirnethylethyl
4-hydroxy-1-piperidinecarboxylate (0.21 g, 1.0 mmol) in DCM (10 mL)
was added triphenylphosphine (0.18 g, 0.70 mmol) and
di-te/fbutylazodicarboxylate (0.16 g, 0.70 mmol). The dear, yellow
solution was stirred for 1 h, and then silica gel (3 g) was added.
The volatiles were evaporated under reduced pressure and the
residue was purified by flash column chromatography (0 to 50%
EtOAc:CH.sub.2Cl.sub.2) to give 0.20 g (0.29 mmol) of
1,1-dimethylethyl
4-[(2-chloro-3-{(1R)-1-[(2-[(methytoxy)carbonyl]-5-{5-[(trifluoromethyl)o-
xy]-1H-benzimidazol-1-yl}-3-thienyl)oxy]ethyl}phenyl)oxy]-1-piperidinecarb-
oxylate which was then dissolved in 5 mL of DCM and TFA (1 mL, 5.9
mmol) was added. After 1 h the volatiles were evaporated under
reduced pressure and the residue was dissolved in a solution of 7 N
ammonia in MeOH (10 mL). The mixture was heated in a sealed tube to
80.degree. C for 40 h and then cooled to rt. Silica (1 g) was
added, the volatiles were evaporated under reduced pressure and the
residue was purified by flash column chromatography (0 to 100%
80/20/1 DCM/MeOH/ammonium hydroxide; DCM) to afford 0.14 g (69%) of
the title compound as a light yellow solid. .sup.1H NMR (400 MHz,
CD.sub.3OD): .delta. 8.45 (s, 1H), 7.63 (s, 1H), 7.42 (d, J=8.79
Hz,1H), 7.30 (m, 2H), 7.15 (d, J=7.87 Hz, 1H), 7.10 (d. J=7.87 Hz,
1H), 6.97 (s, 1H), 6.05 (q, J=6.29 Hz, 1H), 4.56 (m, 3H), 3.06 (m,
2H), 2.69 (m, 2H), 1.95 (m, 2H), 1.77 (d, J=6.23 Hz, 3H), 1.71 (br
m, 2H); MS (ESI): 581 [M+H].sup.+.
EXAMPLE 62
3-[((1R)-1-{2-chloro-3-[(1-methyl-4-piperidinyl)oxy]phenyl}ethyl)oxy]-5-{5-
-[(trifluoromethyl)oxy]-1H-benzimidazol-1-yl}-2-thiophenecarboxamide
##STR00278##
[0911] To a slurry of methyl
3-{[(1R)-1-(2-cbioro-3-hydroxyphenyl)ethyl]oxy}-5-{5-[(trifluoromethyl)ox-
y]-1H-benzimidazol-1-yl}-2-thiophenecarboxylate (Intermediate 25,
0.18 g, 0.35 mmol) and 1-methyl-4-piperidinof (0.12 g, 1.1 mmol) in
DCM (10 mL) was added triphenylphosphine (0.18 g, 0.70 mmol) and
di-tert-butyl azodicarboxylate (0.16 g, 0.70 mmol). The clear,
yellow solution was stirred for 1 h, and then silica gel (3 g) was
added. The volatiles were evaporated under reduced pressure and the
residue was purified by flash column chromatography (0 to 100%
80/20/1 DCM/MeOH/ammonium hydroxide: DCM) to give 0.20 g (0.34
mmol) of methyl
3-[((1R)-1-(2-chloro-3-[(1-methyl-4-piperidinyl)oxy]phenyl}ethyl)oxy]-5-{-
5-[(trifluoromethyl)oxy]-1H-benzimidazol-1-yl}-2-thiophenecarboxylate
which was then dissolved in a solution of 7 N ammonia in MeOH (10
mL). The mixture was heated in a sealed tube to 80.degree. C. for
40 h and then cooled to rt. Silica (1 g) was added, the volatiles
were evaporated under reduced pressure and the residue was purified
by flash column chromatography (0 to 100% 80/20/1 DCM/MeOH/ammonium
hydroxide: DCM) to afford 0.18 g (86%) of the title compound as a
light yellow solid. .sup.1H NMR (400 MHz, CD.sub.3OD): .delta. 8.45
(s, 1H), 7.63 (s, 1H), 7.45 (d, J=8.79 Hz, 1H), 7.31 (m, 2H), 7.17
(d, J=7.51 Hz, 1H), 7.10 (d, J=8.24 Hz, 1H), 6.97 (s, 1H), 6.05 (q,
J=6.29 Hz, 1H), 4.56 (m, 3H), 2.72 (br m, 2H), 2.47 (br m, 2H),
2.33 (s, 3H), 1.95 (br m, 4H), 1.77 (d, J=6.41 Hz, 3H): MS (ESI):
595 [M+H].sup.+.
EXAMPLE 63
3-({(1R)-1-[2-chloro-3-(4-piperidinyloxy)phenyl]ethyl}oxy)-5-{6-[(trifluor-
omethyl)oxy]-1H-benzimidazol-1-yl}-2-thiophenecarboxamide
##STR00279##
[0913] The title compound was prepared from methyl
3-{[(1R)-1-(2-chloro-3-hydroxyphenyl)ethyl]oxy}-5-{6-[(trifluoromethyl)ox-
y]-1H-benzimidazol-1-yl}-2-thiophenecarboxylate (Intermediate 26,
0.350 g, 0.682 mmol) and 1,1-dimethylethyl
4-hydroxy-1-piperidinecarboxylate (0.314 g, 1.36 mmol) using a
procedure analogous to Example 61 to give 0.119 g (30%) of the
desired product. .sup.1H NMR (400 MHz, CD.sub.3OD): .delta. 8.43
(s, 1H), 7.78 (d, J=8.61 Hz, 1H), 7.30 (m, 3H), 7.15 (d, J=7.51 Hz,
1H), 7.07 (d, J=7.87 Hz, 1H), 6.94 (s, 1H), 6.04 (q, J=6.29 Hz,
1H), 4.54 (m, 3H), 3.03 (m, 2H), 2.67 (m, 2H), 1.94 (m, 2H), 1.76
(d, J=6.23 Hz, 3H), 1.69 (br m, 2H); MS (ESI): 581 [M+H].sup.+.
EXAMPLE 64
3-[((1R)-1-{2-chloro-3-[(1-methyl-4-piperidinyl)oxy]phenyl}ethyl)oxy]-5-{6-
-[(trifluoromethyl)oxy]-1H-benzimidazol-1-yl}-2-thlpphenecarboxanide
##STR00280##
[0915] The title compound was prepared from methyl
3-{[(1R)-1-(2-chloro-3-hydroxyphenyl)ethyl]oxy}-5-{6-[(tnfluoromethyl)oxy-
]-1H-benzimidazol-1-yl}-2-thiophenecarboxylate (Intermediate 26,
0.350 g, 0.682 mmol) and 1-methyl-4-plperidinol (0.314 g, 1.36
mmol) using a procedure analogous to Example 62 to give 0.119 g
(29%) of the desired product. .sup.1H NMR (400 MHz, CD.sub.3OD):
.delta. 8.44 (s, 1H), 7.80 (d, J=8.61 Hz, 1H), 7.31 (m, 3H), 7.16
(d, J=7.69 Hz, 1H), 7.07 (d, J=8.24 Hz, 1H), 6.95 (s, 1H), 6.04 (q,
J=6.17 Hz, 1H), 4.52 (m, 3H), 2.66 (br m, 2H), 2.39 (br m, 2H),
2.27 (s, 3H), 1.89 (br m, 4H), 1.77 (d, J=6.23 Hz, 3H): MS (ESI):
595 [M+H].sup.+.
EXAMPLE.65
3-({(1R)-1-[2-chloro-3-(4-piperidinyloxy)phenyl]ethyl}oxy)-5-(5,6-difluoro-
-1H-benziniidazol-1-yl)-2-thiophenecarboxamide
##STR00281##
[0917] The title compound was prepared from methyl
3-{[(1R)-1-(2-chloro-3-hydroxyphenyl)ethyl]oxy}-5-(5,6-difluoro-1H-benzim-
idazol-1-yl)-2-thiophenecarboxylate (Intermediate 27, 0.20 g, 0.43
mmol) and 1,1-dimethylethyl 4-hydroxy-1-piperidinecarboxylate (0.26
g, 1.3 mmol) using a procedure analogous to Example 61 to give 0.1
g (43%) of the desired product. .sup.1H NMR (400 MHz,
DMSO-d.sub.6): .delta. 8.59 (s, 1H), 7.85 (m, 2H), 7.59 (m, 1H),
7.30 (t, J=7.97 Hz, 1H), 7.14 (m, 4H), 5.99 (q. J=6.17 Hz, 1H),
4.44 (m, 1H), 2.87 (m, 2H), 2.50 (m, 2H), 1.82 (m, 2H), 1.68 (d,
J=6.04 Hz, 3H), 1.44 (br m, 2H); MS (ESI): 533 [M+H].sup.+.
EXAMPLE 66
3-[((1R)-1-{2-chloro-3-[(1-methyl-4-piperidinyl)oxy]phenyl}ethyl)-oxy]-5-(-
5,6-difluoro-1H-benzimidazol-1-yl)-2-thiophenecarboxamide
##STR00282##
[0919] The title compound was prepared from methyl
3-{[(1R)-1-(2-chloro-3-hydroxyphenyl)ethyl]oxy}-5-(5,6-difluoro-1H-benzim-
idazol-1-yl)-2-thiophenecarboxylate (Intermediate 27, 0.20 g, 0.43
mmol) and 1-methyl-4-piperidinol (0.15 g, 1.3 mmol) using a
procedure analogous to Example 62 to give 0.165 g (70%) of the
desired product. .sup.1H NMR (400 MHz, CD.sub.3OD): .delta. 8.40
(s, 1H), 7.63 (m, 1H), 7.32 <t, J=7.96 Hz, 3H), 7.25 (m, 1H),
7.16 (d, J=7.50 Hz, 1H), 7.10 (d, J=8.05 Hz, 1H), 6.93 (s, 1H),
6.07 (q, J=6.34 Hz, 1H), 4.52 (br m, 1H), 2.65 (br m, 2H), 2.38 (br
m, 2H), 2.27 (s, 3H), 1.91 (br m, 4H), 1.77 (d, J=6.40 Hz, 3H): MS
(ESI): 547 [M+H].sup.+.
EXAMPLE 67
5-(5-Chloro-6-fluoro-1H-benzimidazol-1-yl)-3-({(1R)-1-2-chloro-3-(4-piperi-
dinyloxy)phenyl]ethyl}oxy)-2-thiophenecarboxamide
##STR00283##
[0920] Step A--1-Bromo-4-chloro-5-fluoro-2-nitrobenzene
##STR00284##
[0922] To a solution of 4-bromo-1-chloro-2-fluorobenzene (8.4 g, 40
mmol) and ammonium nitrate in DCM (335 mL) at 0.degree. C. was
added TFA anhydride (41.3 mL) via addition funnel over 15 min. The
reaction mixture was stirred at 0.degree. C. for 15 min and then at
rt for 2 h. The reaction was quenched with 560 mL saturated
MaHCO.sub.3 solution and the layers separated. The aqueous layer
was extracted with DCM and then EtOAc. The combined organic layer
was dried over Na.sub.2SO.sub.4, filtered and silica gel was added.
The volatiles were evaporated under reduced pressure, and the
residue was purified by flash column chromatography (0 to 15%
EtOAc: hexane) to give 3.7 g (36%) of the titie compound. .sup.1H
NMR (400 MHz, DMSO-d.sub.6): .delta. 8.46 (d, J=6.9 Hz, 1H), 8.18
(d, J=8.8 Hz, 1H).
Step B--Methyl
5-(5-chloro-6-fluoro-1H-benzimidazol-1-yl)-3-{[(1R)-1-(2-chlorophenyl)eth-
yl]oxy}-2-thiophenecarboxylate
##STR00285##
[0924] To a solution of 1-bromo-4-chloro-5-fluoro-2-nitrobenzene
(6.0 g, from a different batch prepared analogous to Example 67,
Step A, 23.0 mmol) and methyl
5-amino-3-{[(1R)-1-(2-chlorophenyl)ethyl]oxy}-2-thiophenecarboxyIate
(Intermediate 30, 11.0 g, 35.0 mmol) in toluene (70 mL) was added
tris(dibenzylideneacetone) dipalladium (0) chloroform complex (595
mg, 0.58 mmol), 9,9-dimethyl-4,5-bis(diphenylphosphino)xantphos
(665 mg, 1.20 mmol) and Cs.sub.2CO.sub.3 (22.5 g, 69.0 mmol)) with
vigorous stirring. The reaction flask was sealed and carefully
evacuated and refilled with N.sub.2 three times and the reaction
mixture was stirred at 60.degree. C. for 15 h. The reaction mixture
was filtered through a pad of silica gel washing with copious
amounts of 20% EtOAc in hexanes. The volatiles were evaporated
under reduced pressure to give methyl
5-[(4-chloro-5-fluoro-2-nitrophenyl)amlno]-3-{[(1R)-1-{2-chlorophenyl)eth-
yl]oxy}-2-thiopheneearboxylate 7.24 g (64%). This intermediate was
dissolved in acetic acid (25 mL) and added via an addition funnel
to a solution of iron power (4.0 g, 75 mmol) and acetic acid (20
mL) at 55.degree. C. with vigorous stirring. The reaction mixture
was then cooled to rt, diluted with EtOAc and filtered through
celite and the resulting filtrate was neutralized with 6N MaOH
solution and saturated NaHCO.sub.3 solution. The layers were
separated and the aqueous layer was extracted three times with
EtOAc. The combined organic layer was dried over Na.sub.2SO.sub.4
and the volatiles were evaporated under reduced pressure to give
methyl
5-[(2-amlnc-4-chloro-5-fluorophenyl)amino]-3-{[(1R)-1-(2-chiofophenyl)eth-
yl]oxy}-2-thiophenecarboxylate. To this material was added
trimethylorthoformate (150 mL) and formic acid (10 mL) and the
resulting reaction mixture was stirred at 40.degree. C. for 1 h.
Silica gel was added and the volatiles were evaporated under
reduced pressure and the residue was purified by flash
chromatography (0 to 15% EtOAc: hexane) to afford 4.7 g (67%) of
the title compound. .sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta.
8.70 (s, 1H), 8.03 (d, J=6.8 Hz, 1H), 7.58-7.83 (m, 2H), 7.38-7.50
(m, 2H), 7.44 (s, 1H), 7.25 -7.37 (m, 1H), 5.99 (q, J=8.2 Hz, 1H),
3.82 (s, 3H), 1.62 (d, J=6.2 Hz, 3H), MS (ESI): 467
[M+H].sup.+.
Step C--Methyl
5-(5-chloro-6-fluoro-1H-benzimidazol-1-yl)-3-hydroxy-2-thiophenecarboxyla-
te
##STR00286##
[0926] To a solution of methyl
5-(5-chloro-6-fluoro-1H-benzimidazol-1-yl)-3-{[(1R)-1-(2-chlorophenyl)eth-
yl]oxy}-2-thiophenecarboxylate (2.5 g, 5.4 mmol) in dichloroethane
(10 mL) was added TFA (10 mL) and the reaction mixture was stirred
at 60.degree. C. for 1 h. The reaction mixture was cooled to rt,
diluted with EtOAc and neutralized with saturated NaHCO.sub.3
solution. The layers were separated and the aqueous layer extracted
two times with EtOAc. The combined organic layer was dried over
Na.sub.2SO.sub.4 and the volatiles were evaporated under reduced
pressure. The residue was washed with 10% EtOAc.hexane and filtered
to afford 1.5 g (84%) of the title compound. .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 11.13 (s, 1H), 8.72 (s, 1H), 8.03 (d, J=6.8
Hz, 1H), 7.80 (d, J=9.1 Hz, 1H), 7.20 (s, 1H), 3.77 (s, 3H), MS
(ESI): 326 [M+H].sup.+.
Step D--Methyl
5-(5-chloro-6-fluoro-1H-benzimidazol-1-yl)-3-({(1R)-1-[2-chloro-3-(4-pipe-
ridinyloxy)phenyl]ethyl}oxy)-2-thiophenecarboxylate
##STR00287##
[0928] To a solution of methyl
5-(5-chloro-6-fluoro-1H-benzimidazol-1-yl)-3-hydroxy-2-thiophenecarboxyla-
te (0.25 g, 0.77 mmol) and 1,1-dimethylethyl
4-({2-chloro-3-[(1S)-1-hydroxyethyl]phenyl}oxy)-1-piperidinecarboxylate
(0.33 g, 0.93 mmol) in CH.sub.2Cl.sub.2 (8 mL) was added
polymer-supported triphenylphosphine (0.45 g, 1.5 mmol) and
di-tert-butylazodicarboxylate (0.36 g, 1.4 mmol) and the reaction
mixture stirred at rt overnight. The reaction mixture was filtered
with DCM washings and the volatiles evaporated under reduced
pressure. The residue was dissolved in DCM (1 mL) and TFA (1 mL)
was added. After 1 h, silica was added and the volatiles evaporated
under reduced pressure and the residue was purified by flash
chromatography (0 to 100% 89/10/1 DCM/MeOH/ammonium hydroxide:DCM)
to afford 0.27 g, (62%) of the title compound. MS (ESI): 564
[M+H].sup.+.
Step
E--5-(5-Chloro-6-fluoro-1H-benzimidazol-1-yl)-3-({(1R)-1-[2-chloro-3--
(4-piperidinyloxy)phenyl]ethyl}oxy)-2-thiophenecarboxamide (Title
Compound)
[0929] To methyl
5-(5-chloro-8-fluoro-1H-benzimidazol-1-yl)-3-({(1R)-1-[2-chloro-3-(4-pipe-
ridinyloxy)phenyl]ethyl}oxy)-2-thiophenecarboxylate (0.26 g, 0.46
mmol) was added a solution of 7 N ammonia in MeOH (10 mL). The
mixture was heated In a sealed tube to 70.degree. C. for 40 h and
then cooled to rt. Silica was added and the volatiles evaporated
under reduced pressure and the residue was purified by flash
chromatography (0 to 100% 89/10/1 DCM/MeOH/ammonium hydroxide:DCM)
to afford 0.20 g (80%) of the title compound. .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 8.64 (s, 1H), 8.47 (br. s, 1H), 8.05 (d,
J=6.6 Hz, 1H), 7.85 (s, 1H), 7.61 (d, J=9.3 Hz, 1H), 7.37 (t, J=8.0
Hz, 1H), 7.07-7.31 (m, 4H), 6.03 (q, J=6.6 Hz, 1H), 4.64-4.88 (m,
1H), 3.14-3.26 (m, 2H), 3.00-3.14 (m, 2H), 1.99-2.18 (m, 2H),
1.78-1.92 (m, 2H), 1.72 (d, J=6.2 Hz, 3H). MS (ESI): 549
[M+H].sup.+.
EXAMPLE 68
5-(5-Chloro-6-fluoro-1H-benzimidazol-1-yl)-3-[((1R)-1-{2-chloro-3-[(1-meth-
yl-4-piperidinyl)oxy]phenyl}ethyl)oxy]-2-thiophenecarboxamide
##STR00288##
[0930] Step A--Methyl
5-(5-chloro-6-fluoro-1H-benzimidazol-1-yl)-3-{[(1R)-1-(2-chloro-3-hydroxy-
phenyl)ethyl]oxy}-2-thiophenecarboxylate
##STR00289##
[0932] To a solution of methyl
5-(5-chloro-6-fluoro-1H-benzimidazol-1-yl)-3-hydroxy-2-thiophenecarboxyla-
te (Example 67, Step C, 0.33 g, 1.0 mmol) and
(1S)-1-(2-chloro-3-{[(1,1
-dimethylethyl)(dimethyl)silyl]-oxy}phenyl)ethanol (Intermediate
17, 0.34 g, 1.2 mmol) in DCM (10 mL) was added polymer-supported
triphenylphosphine (0.91 g, 2.0 mmol),
dl-tert-butylazodicarboxylate (0.46 g, 4.0 mmol). The reaction
mixture was stirred overnight. The reaction was filtered with DCM
washings arid the volatiles evaporated under reduced pressure. The
residues was dissolved in THF (10 mL) and a solution of 1 N
tetrabutylammonlum fluoride in THF (1 mL, 1 mmol) was added. After
10 min, silica was added, the volatiles were evaporated under
reduced pressure and the residue was purified by flash column
chromatography (0 to 100% 84/15/1 DCM/MeOH/ammonium hydroxide:DCM)
to give 0.34 g (71%) of the title compound. MS (ESI): 481
[M+H].sup.+.
Step
B--5-(5-Chloro-6-fluoro-1H-benzimidazol-1-yl)-3-[((1R)-1-{2-chloro-3--
[(1-methyl-4-piperidinyl)oxy]phenyl}ethyl)oxy]-2-thiophenecarboxanide
##STR00290##
[0934] To a solution of methyl
5-(5-chloro-6-fluoro-1H-benzimidazol-1-yl)-3-{[(1R)-1-(2-chloro-3-hydroxy-
phenyl)ethyl]oxy}-2-thiophenecarboxylate (0.30 g, 0.62 mmol) and
1-methyl-4-piperidinol (0.11 g, 0.95 mmol) in DCM was added
polymer-supported triphenylphosphine (0.56 g, 1.2 mmol),
di-tert-butylazodicarboxylate (0.29 g, 1.2 mmol). The reaction
mixture was stirred overnight. The reaction mixture was filtered
with DCM washings and the volatiles evaporated under reduced
pressure. To the residue was added a solution of 7 N ammonia in
MeOH (10 mL). The mixture was heated in a sealed tube to 70.degree.
C. for 48 h and then cooled to rt. Silica was added and the
volatiles evaporated under reduced pressure and the residue was
purified by flash chromatography ((0 to 100% 89/10/1
DCM/MeOH/ammonium hydroxide:DCM) to afford 0.12 g (34%) of the
title compound. .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 8.64
(s, 1H), 8.05 (d, J=6.7 Hz, 1H), 7.85 (s, 1H), 7.60 (d, J=9.3 Hz,
1H), 7.33 (t, J=7.9 Hz, 1H), 7.05-7.26 (m, 4H), 6.02 (q, J=6.4 Hz,
1H), 4.45 (s, 1H), 2.54 (s, 2H), 2.02-2.26 (m, 5H), 1.88 (s, 1H),
1.56-1.74 (m, 4H), 1.31-1.46 (m, 2H). MS (ESI): 563
[M+H].sup.+.
EXAMPLE 69
5-(6-Chtoro-5-ftuoro-1H-benzimidazol-1-yl)-3-({(1R)-1-[2-chloro-3-(4-piper-
idinyloxy)phenyl]ethyl}oxy)-2-thiophenecarboxamide
##STR00291##
[0935] Step A--1-Bromo-5-chloro-4-fluoro-2-nitrobenzene
##STR00292##
[0937] A solution of 5-chlcro-4-fluoro-2-nitroaniline (3.62 g, 19.0
mmol) in aeetonitrlie (60 mL) was slowly added via an addition
funnel to a mixture or copper (II) bromide (6.37 g,. 28.5 mmol),
tert-butyl nitriie (4.33 g, 42.0 mmol) in acetonitriie (40 mL) at
60.degree. C. The reaction mixture was stirred for 10 min, cooled
to rt and poured into a solution of 2 N HCl (400 mL). EtOAc was
added and the layers separated. The aqueous layer was extracted
three times with EtOAc. The combine organic layer was washed with
brine and dried over Na.sub.2SO.sub.4. The volatiles were
evaporated under reduced pressure and the residue dissolved in 5%
EtOAc:hexane and passed through a pad of silica with copious hexane
washings to afford 4.53 g (94%) of the title compound. .sup.1H NMR
(300 MHz, DMSO-d.sub.6) .delta. 8.3 (m, 2 H).
Step B--Methyl
5-[(5-chloro-4-fluoro-2-nitrophenyl)amino]-3-[(phenylmethyl)oxy]-2-thioph-
enecarboxylate
##STR00293##
[0939] To a solution of bromo-5-chloro-4-fluoro-2-nitrobenzene and
methyl 5-amino-3-[(phenylmethyl)oxy]-2-thiophenecarboxylate (1.0 g,
4.0 mmol) in toluene (11 mL) was added
tris(dibenzylideneacetone)dipalladium (0) chloroform complex (100
mg, 0.10 mmol), XANTPHOS (110 mg, 0.20 mmol) and Cs.sub.2CO.sub.3
(3.8 g, 12 mmol)). The reaction flask was sealed and carefully
evacuated and refilled with N.sub.2 three times and the reaction
mixture was stirred at 60.degree. C. overnight. Silica gel was
added and the volatiles evaporated under reduced pressure, the
residue was purified by flash chromatography (0 to 50%
EtOAc:hexane) to give 1.2 g (68%) of the titie compound. .sup.1H
NMR (300 MHz, DMSO-dp.sub.6) .delta. 9.73 (s, 1H) 8.19 (d, J=9.3
Hz, 1H) 7.57 (d, J=6.6 Hz, 1H) 7.26-7.49 (m, 5H) 6.94 (s, 1H) 5.23
(s, 2H) 3.71 (s, 3H). MS (ESI): 436 [M+H].sup.+.
Step C--Methyl
5-(6-chloro-5-ffuoro-1H-benzimidazol-1-yl)-3-[(phenylmethyl)oxy]-2-thioph-
enecarboxylate
##STR00294##
[0941] To a solution of methyl
5-[(5-chloro-4-fluoro-2-nitrophenyl)amino]-3-[(phenylmethyl)oxy]-2-thioph-
enecarboxylate (1.0 g, 2.3 mmol) in acetic acid (7 mL) at
55.degree. C. was added iron power (0.64, 12 mmol) and the reaction
mixture stirred 1 h. The reaction mixture was cooled to rt, diluted
with EtOAc and filtered and the resulting filtrate was neutralized
with saturated NaHCO.sub.3 and separated. The aqueous layer was
extracted two times with EtOAc. The combined organic layer was
dried over Na.sub.2SO.sub.4 and the volatiles were evaporated under
reduced pressure. To this material was added trimethylorthoformate
(50 mL) and formic acid (1 mL) and the resulting reaction mixture
was stirred at rt overnight. Silica was added and the volatiles
were evaporated under reduced pressure and the residue was purified
by flash chromatography (0 to 60% EtOAc: hexane) to afford 0.82 g
(82%) of the titie compound. .sup.1H NMR (300 MHz, DMSO-d.sub.6)
.delta. 8.75 (s, 1H) 7.93 (d, J=6.5 Hz, 1H), 7.87 (d, J=9.7 Hz,
1H), 7.66 (s, 1H), 7.47-7.53 (m, 2H), 7.30-7.46 (m, 3H), 5.38 (s,
2H), 3.77 (s, 3H). MS (ESI): 416 [M+H].sup.+.
Step D--Methyl
5-(6-chloro-5-fluoro-1H-benzimidazol-1-yl)-3-hydroxy-2-thiophenecarboxyla-
te
##STR00295##
[0943] To a solution of methyl
5-(6-chloro-5-fluoro-1H-benzimidazol-1-yl)-3-[(phenylmethyl)oxy]-2-thioph-
enecarboxylate (0.80 g, 1.9 mmol) In 95% EtOH (12 mL) was added 10%
palladium on carbon (0.16 g, 1.5 mmol) and stirred under H.sub.2
balloon for 48 h. The reaction mixture was filtered through a pad
of silica with copious EtOAc washings to give 0.34 g (54%) of the
title compound. MS (ESI): 326 [M+H].sup.+.
Step E--Methyl
5-(6-chloro-5-fluoro-1H-benzimidazol-1-yl)-3-{[(1R)-1-{2-chloro-3-hydroxy-
phenyl)ethyl]oxy}-2-thiophenecarboxylate
##STR00296##
[0945] To a solution of methyl
5-(6-chloro-5-fluoro-1H-benzimidazol-1-yl)-3-hydroxy-2-thiophenecarhoxyia-
te (0.33 g, 1.0 mmol) and
(1S)-1-(2-chloro-3-{[(1,1-dimethylethyl)(dimethyl)sliyl]-oxy}phenyl)ethan-
ol (0.34 g, 1.2 mmol) in DCM (10 mL) was added polymer-supported
triphenylphosphine (0.91 g, 2.0 mmol),
di-tert-butylazodicarboxylate (0.46 g, 4.0 mmol). The reaction
mixture was stirred overnight. The reaction was filtered with DCM
washings and the volatiles were evaporated under reduced pressure.
The residue was dissolved in THF (10 mL) and a solution of 1 N
tetrabufylammonium fluoride in THF (1 mL, 1 mmol) was added. After
10 min, silica was added, the volatiles were evaporated under
reduced pressure and the residue was purified by flash column
chromatography (0 to 100% EfOAc:hexane) to give 0.30 g (60%) of the
title compound. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 10.25
(s, 1H), 8.72 (s, 1H), 7.87 (d, J=9.5 Hz, 1H), 7.79 (d, J=6.6 Hz,
1H), 7.36 (s, 1H), 7.06-7.25 (m, 2H), 6.91 (d. J=7.7 Hz, 1H), 5.96
(q, J=6.1 Hz, 1H), 3.82 (s, 3H). 1.60 (d, J=6.2 Hz, 3H). MS (ESI):
481 [M+H].sup.+.
Step F--Methyl
5-(6-chloro-5-fluoro-1H-benzimidazol-1-yl)-3-({(1R)-1-[2-chloro-3-(4-pipe-
ridinyloxy)phenyl]ethyl}oxy)-2-thiophenecarboxylate
##STR00297##
[0947] To a solution of methyl
5-(6-chloro-5-fluoro-1H-benzimidazol-1-yl)-3-{[(1R)-1-(2-chloro-3-hydroxy-
phenyl)ethyl]oxy}-2-thiophenecarboxylate (0.16 g, 0.33 mmol) and
1,1-dimethylethyl 4-hydroxy-1-piperidinecarboxylate (0.13 g, 0.66
mmol) in DCM (4 mL) was added polymer-supported triphenylphosphine
(0.30 g, 0.66 mmol), di-tert-butylazodicarboxylate (0.15 g, 0.66
mmol). The reaction mixture was stirred for 8 h. The reaction
mixture was filtered with DCM washings and the volatiles were
evaporated under reduced pressure. The residue was dissolved in THF
(3 mL) and a solution of 1 N tetrabiityiammonium fluoride in THF (1
mL, 1 mmol) was added. After 10 min, silica was added, the
volatiles were evaporated under reduced pressure and the residue
was purified by flash column chromatography (0 to 100% 89/10/1
DCM/MeOH/ammonium hydroxide:DCM) to give 0.18 g (97%) of the title
compound. MS (ESI): 564 [M+H].sup.+.
Step
G--5-(6-Chtoro-5-ftuoro-1H-benzimidazol-1-yl)-3-({(1R)-1-[2-chloro-3--
(4-piperidinyloxy)phenyl]ethyl}oxy)-2-thiophenecarboxamide (Title
Compound)
[0948] To methyl 5-(6-chloro-5-fluoro-1
H-benzimidazol-1-yl)-3-({(1R)-1-[2-chloro-3-(4-piperidinyloxy)phenyl]ethy-
l}oxy)-2-thiophenecarboxylate (0.18 g, 0.32 mmol) was added a
solution of 7 N ammonia in MeOH (10 mL). The mixture was heated in
a sealed tube to 70.degree. C. for 48 h and then cooled to rt.
Silica was added and the volatiles evaporated under reduced
pressure and the residue was purified by flash chromatography ((0
to 100% 89/10/1 DCM/MeOH/ammontum hydroxtde:DCM) to afford 0.13
(76%) of the title compound. .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta. 8.67 (s, 1H), 8.52 (s, 1H). 7.77-7.99 (m, 1H), 7.72 (d,
J=6.4 Hz, 1H), 7.39 (t, J=8.0 Hz, 1H). 7.14 (s, 1H), 7.03-7.35 (m,
4H), 6.03 (q, J=6.6 Hz, 1H), 4.64-4.88 (m, 1H), 3.14-3.26 (m, 2H),
3.00-3.14 (m, 2H), 1.99-2.18 (m, 2H), 1.78-1.92 (m, 2H), 1.72 (d,
J=6.2 Hz, 3H). MS (ESI): 549 [M+H].sup.+.
EXAMPLE 70
5-(6-Chloro-5-fluoro-1H-benzimidazol-1-yl)-3-[((1R)-1-{2-chloro-3-[(1-meth-
yl-4-piperidinyl)oxy]phenyl}ethyl)oxy]-2-thiophenecarboxamide
##STR00298##
[0950] To a solution of methyl
5-(6-chloro-5-fluoro-1H-benzimidazol-1-yl)-3-{[(1R)-1-(2-chloro-3-hydroxy-
phenyl)ethyl]oxy}-2-thiophenecarboxylate (Example 69, Step E, 0.10
g, 0.21 mmol) and 1-methyl-4-piperidinol (0.05 g, 0.42 mmol) in DCM
(2 mL) was added polymer-supported triphenylphosphine (0.19 g, 0.42
mmol), di-tert-butylazodicarboxylate (0.10 g, 0.42 mmol). The
reaction mixture was stirred for 8 h. The reaction was filtered
with DCM washings and the volatiles were evaporated under reduced
pressure. To the residue was added a solution of 7 N ammonia in
MeOH (8 mL). The mixture was heated in a sealed tube to 70.degree.
C. for 48 h and then cooled to rt. Silica; was added and the
volatiles evaporated under reduced pressure and the residue was
purified by flash chromatography ((0 to 100% 89/10/1
DCM/MeOH/ammonium hydroxide:DCM) to afford 0.72 g (61%) of the
title compound. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 8.65
(s, 1H), 7.86 (d, J=9.7 Hz, 1H), 7.84 (s, 1H), 7.72 (d, J=6.4 Hz,
1H), 7.33 (t, J=8.0 Hz, 1H), 7.20 (d, J=7.5 Hz, 1H), 7.17 (s, 1H),
7.15 (d, J=8.2 Hz, 1H), 7.13 (s, 1H), 6.00 (q, J=6.0 Hz, 1H), 4.45
(s. 1H), 2.51-2.62 (m,2H), 2.15-2.25 (m, 2H), 2.13 (s, 3H),
1.78-1.93 (m, 2H). 1.70 (d, J=6.4 Hz, 3H), 1.56-1.67 (m, 2H). MS
(ESI): 564 [M+H].sup.+.
EXAMPLE 71
3-({(1R)-1-[2-Chloro-3-(4-piperidinyloxy)phenyl]ethyl}oxy)-5-(5,6-dichloro-
-1H-benzJmidazol-1-yl)-2-thiophenecarboxamide
##STR00299##
[0951] Step A--5,6-Dicnloro-1H-benzimidazole
##STR00300##
[0953] To 4,5-dichloro-1,2-benzenediamine (15 g, 85 mmol) was added
trimethylorthoforrnate (850 mL) and formic acid (0.32 mL) and the
reaction mixture heated to 70.degree. C. overnight. Silica was
added and the volatiles evaporated under reduced pressure and the
residue was purified by flash column chromatography (0 to 15%
MeOH:DCM) to give 12 g (76%) of the title compound. .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. 12.73 <s, 1H), 8.34 (s, 1H),
7.87 (s,2H). MS (ESI): 187 [M+H].sup.+.
Step B--Methyl
5-(5,6-dichloro-1H-benzimidazol-1-yl)-3-hydroxy-2-thiophenecarboxylate
##STR00301##
[0955] To a solution of 5,6-dichloro-1H-benzimidazole (1.26 g, 6.72
mmol) and methyl 2-chloro-3-oxo-23-dihydro-2-thiophenecarboxylate
(1.49 g, 7.73 mmol) in DCM (34 mL) was added NaHCO.sub.3 (1.70 g,
20.2 mmol) and N-methylimidazole (0.830 g, 10.1 mmol) and heated at
40.degree. C. overnight. The reaction mixture was cooled to rt and
DCM and water were added. The layers were separated and the aqueous
layer was extracted with DCM. The combined organic layers were
dried over Na.sub.2SO.sub.4 and filtered. Silica was added to the
filtrate and the volatiles were evaporated under reduced pressure
and the residue was purified by flash column chromatography (0 to
100% EtOAc:hexane) to afford 1.5 g (65%) of the title compound.
.sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 10.88 (s, 1H), 8.76 (s,
1H), 8.10 (s, 1H), 7.99 (s, 1H), 7.17 (s, 1H), 3.79 (s, 3H). MS
(ESI): 343 (M+H].sup.+.
Step C--Methyl
3-({(1R)-1-[2-chloro-3-(4-piperidinyloxy)phenyl]ethyl}oxy)-5-(5,6-dichlor-
o-1-benzimidazol-yl)-2-thiophenecarboxylate
##STR00302##
[0957] To a solution of methyl
5-(5,6-dichloro-1H-benzimidazol-1-yl)-3-hydroxy-2-thiophenecarboxylate
(0.34 g, 1.0 mmol) and 1,1-dimethyl ethyl
4-({2-chloro-3-[(1S)-1-hydroxyethyl]phenyl}oxy)-1-plperidinecarboxylate
(0.43 g, 1.2 mmol) in DCM (4 mL) was added polymer-supported
triphenylphosphine (0.36 g, 0.80 mmol) and
di-tert-butylazodicarboxylate (0.18 g, 0.80 mmol) and the reaction
mixture stirred at rt overnight. The reaction mixture was filtered
with DCM washings and the volatiles removed. The residue was
dissolved in DCM (10 mL) and TFA (5 mL) was added. After 1 h,
silica was added and the volatiles evaporated under reduced
pressure and the residue was purified by flash chromatography (0 to
100% 89/10/1 DCM/MeOH/ammonium hydroxide:DCM) to afford 0.40 g
(68%) of the title compound. MS (ESI): 580 (M+H].sup.+.
Step
D--3-({(1R)-1-[2-Chloro-3-(4-piperidinyloxy)phenyl]ethyl}oxy)-5-(5,6--
dichloro-1H-benzJmidazol-1-yl)-2-thiophenecarboxamide (Title
Compound)
[0958] To methyl
3-({(1R)-1-[2-chloro-3-(4-piperidinyloxy)phenyl]ethyl}oxy)-5-(5,6-dichlor-
o-1H-benzimidazol-1-yl)-2-thiophenecarboxylate (0.38 g, 0.65 mmol)
was added a solution of 7 N ammonia in MeOH (10 mL). The mixture
was heated in a sealed tube to 70.degree. C. for 48 h and then
cooled to rt. Silica was added and the volatiles evaporated under
reduced pressure and the residue was purified by flash
chromatography ((0 to 100% 89/10/1 DCM/MeOH/ammonium hydroxlde:DCM
to afford 0.13 g (36%) of the title compound. .sup.1H HMR (400 MHz,
DMSO-d.sub.6) .delta. 8.67 (s, 1H), 8.09 (s, 1H), 7.87 (s, 1H),
7.76 (s, 1H), 7.33 (t, J=8.0 Hz, 1H), 7.12-7.24 (m, 4H), 6.00 (q,
J=6.1 Hz, 1H), 4.57-4.37 (m, 1H), 3.25 (s, 1H), 2.79-3.02 (m, 2H),
2.35-2.65 (m, 2H), 1.76-1.96 (m, 2H), 1.71 (d, J=6.2 Hz, 3H),
1.39-1.57 (m, 2H). MS (ESI): 565 (M+H].sup.+.
EXAMPLE 72
3-[((1R)-1-{2-chloro-3-[(1-methyl-4-piperidinyl)oxy]phenyl}ethyl)oxy]-5-(5-
,6-dichloro-1H-benzimidazol-1-yl)-2-thiophenecarboxamide
##STR00303##
[0959] Step A--Methyl
3-{[(1R)-1-(2-chloro-3-hydroxyphenyl)ethyl]oxy}-5-(5,8-dichloro-1H-benzim-
idazol-1-yl)-2-thiophenecarboxylate
##STR00304##
[0961] Methyl 5-(5,6-dichloro-1H-benzimidazol
-yl)-3-hydroxy-2-thiophenecarboxylate (Example 71, Step B, 0.32 g,
0.93 mmol) and
(1S)-1-(2-chloro-3-{[(1,1-dimethylethyl)(dimethyl)silyl]-oxy}ph-
enyl)ethanol (Intermediate 17, 0.32 g, 1.1 mmol) in DCM (9 mL) was
added polymer-supported triphenylphosphine (0.82 g,1.9 mmol),
di-tert-butylazodicarboxylate (0.43 g, 1.9 mmol). The reaction
mixture was stirred overnight. Filtered, washed with DCM and
concentrated under reduced pressure. The residuce was dissolved in
THF (9 mL) and a solution of 1 N tetrabutylammonium fluoride in THF
(1 mL, 1.0 mmol) was added. After 10 min, sica was added, the
volatiles were evaporated under reduced pressure and the residue
was purified by flash column chromatography (0 to 100%
EtOAc:hexane) to give 0.17 g (37%) of the title compound. MS (ESI):
497 (M+H].sup.+
Step
B--3-[((1R)-1-{2-chloro-3-[(1-methyl-4-piperidinyl)oxy]phenyl}ethyl)o-
xy]-5-(5,6-dichloro-1H-benzimidazol-1-yl)-2-thiophenecarboxamide
(Title Compound)
[0962] To a solution of methyl
3-{[(1R)-1-(2-chloro-3-hydroxyphenyl)ethyl]oxy}-5-(5,6-dichloro-1H-benzim-
idazol-1-yl)-thiophenecarboxylate (0.12 g, 0.24 mmol) and
1-methyl-4-piperidinol (0.042 g, 0.36 mmol) in DCM (3 mL) was added
polymer-supported triphenylphosphine (0.22 g, 0.48 mmol),
di-tert-butylazodicarboxylate (0.11 g, 0.48 mmol). The reaction
mixture was stirred overnight. The reaction mixture was then
filtered, washed with DCM and concentrated under reduced pressure.
To the residue was added a solution of 7 N ammonia in MeOH (10 mL).
The mixture was heated in a sealed tube to 75.degree. C. for 48 h
and then cooled to rt Silica was added and the volatiles evaporated
under reduced pressure and the residue was purified by flash
chromatography (0 to 100% 89/10/1 DCM/MeOH/ammonlum hydroxide:DCM)
to afford 0.70 g (50%) of the title compound, .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 8.66 (s, 1H), 8.08 (s, 1H), 7.85 (s, 1H),
7.77 (s, 1H), 7.32 (t, J=8.1 Hz, 1H), 7.20 (d, J=7.7 Hz, 1H), 7.17
(s, 1H), 7.15 (d, J=8.4 Hz, 1H), 7.12 (s, 1H), 6.00 (q, J=6.0 Hz,
1H), 4.33-4.55 (m, 1H), 2.50-2.63 (m, 2H), 2.12-2.25 (m, 2H), 2.11
(s, 3H), 1.84 (s, 2H), 1.70 (d, J=6.4 Hz, 3H), 1.62 (s, 2H). MS
(ESI): 579 [M+H].sup.+.
EXAMPLE 73
(+/-)-5-[5-(1-Methyl-1H-pyrazol-4-yl)-1H-benzimidazol-1-yl]-3-({1-[3-(4-pi-
peridinyloxy)phenyl]ethyl}oxy)-2-thiophenecarboxamide
##STR00305##
[0963] Step A--(3-Hydroxyphenyl)methyl 2,2-dimethylpropanoate
##STR00306##
[0965] 3-Hydroxybenzyl alcohol (3.00 g, 24.2 mmol) and
3-(2,2-dimethylpropanoyl)-1,3-thiazolidine-2-thione (Yamada. S. J.
Org. Cnem 1992, 57, 1591) (5.41 g, 26.6 mmol) were dissolved in 80
mL of toluene and heated to reflux for 18 h. The reaction was
cooled to rt and concentrated onto silica gel. Purification by
flash chromatography afforded 2.71 g (54%) of the titie compound.
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 9.42 (s, 1H), 7.12 (m,
1H), 6.73-6.63 (m, 3H), 4.97 (s, 2H), 1.14(s, 9H).
Step B--1,1-Dimethylethyl
4-[(3-{[(2,2-dimethylpropanoyl)oxy]-methyl}phenyl)oxy]-1-piperidinecarbox-
ylate
##STR00307##
[0967] (3-Hydroxyphenyl)methyl 2,2-dimethylpropanoate (2.71 g, 13.0
mmol), triphenylphosphine (10.2 g, 39.0 mmol), and t-butyl 4
hydroxy-1-piperidinecarboxylate (5.23 g, 26.0 mmol) were dissolved
in 80 mL of DCM with stirring and cooled to 0.degree. C.
Diisopropyl azodicarboxylate (3.9 mL, 20 mmol) was added dropwise
via syringe over 5 min. The reaction was warmed to rt and stirred
for 18 h. The solution was concentrated onto silica gel.
Purification by flash chromatography afforded 3.68 g (72%) of the
titie compound. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 7.25
(m, 1H), 6.93-6.83 (m, 3H), 5.01 (s, 2H), 4.51 (m, 1H), 3.67-3.57
(m, 2H), 3.20-3.06 (m, 2H), 1.91-1.81 (m, 2H), 1.54-1.42 (m, 2H),
1.37 (s, 9H), 1.14 (s, 9H).
Step C--1,1-Dmethylethyl
4-{[3-(hydroxymemyl)phenyl]oxy}-1-piperidinecarboxylate
##STR00308##
[0969] 1,1-Dimethylethyl
4-[(3-{[(2,2-dsmethylpropanoyl)oxy]methyl}phenyl)oxy]-1-piperidinecarboxy-
late (3.68 gs 9.40 mmol) was dissolved in 50 mL of dioxane with
stirring. Aqueous lithium hydroxide solution (50 mL, 1N, 50 mmol)
was added and the solution was stirred for 1.5 h. The reaction was
placed in a 50.degree. C. oil bath and heated at that temperature
for 2 h. The reaction was cooled to rt and poured into water and
EtOAc. The layers were separated, and the organic layer was washed
with brine. The combined aqueous layers were washed with EtOAc. The
combined organic layers were dried over MgSO.sub.4, filtered, and
concentrated in vacuo to provide 3.14 g (>90% pure, >90%) of
the title compound. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.
7.18 (m, 1H), 6.93-6.75 (m, 3H), 5.12 (t, J=5.8 Hz, 1H), 4.50 (m,
1H), 4.42 (d, J=5.8 Hz, 2H), 3.66-3.56 (m, 2H), 3.22-3.08 (m, 2H),
1.91-1.80 (m, 2H), 1.54-1.41 (m, 2H), 1.37 (s, 9H).
Step D--1,1-Dimethylethyl
4-[(3-formylphenyl)oxy]-1-piperidinecarboxylate
##STR00309##
[0971] 1,1-Dimethylethyl
4-{[3-(hydroxymethyl)phenyl]oxy}-1-piperidinecarboxylate (0.590 g,
1.82 mmol) was dissolved in 20 mL of DCM with stirring. Manganese
dioxide (1.67 g, 19.2 mmol) was added in a single portion. The
mixture was stirred for 4 h and filtered through a celite pad,
washing with DCM. The filtrate was concentrated. Purification by
flash chromatography afforded 0.320 g (55%) of the tie compound.
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 9.95 (s, 1H), 7.54-7.42
(m, 3H), 7.33-7.27 (m, 1H), 4.66 (m, 1H), 3.69-3.60 (m, 2H),
3.24-3.12 (m, 2H), 1.96-1.85 (m, 2H), 1.59-1.46 (rn. 2H), 1.39 (s,
9H).
Step E--(+/-)-1,1-Dtmethylethyl
4-{[3-(1-hydroxyethyl)phenyl]oxy}-1-piperidinecarboxylate
##STR00310##
[0973] Methyl magnesium chloride (0.53 mL, 3M in THF, 1.6 mmol) was
added to 6 mL of ether, and the solution was cooled to -15.degree.
C. with stirring. 1,1-Dimethylethyl
4-[(3-formylphenyl)oxy]-1-piperidinecarboxylate (0.319 g, 1.05
mmol) dissolved in 8 mL of ether was added slowly dropwise via
syringe. After 15 min, an additional amount of methyl magnesium
chloride (0.25 mL, 3M in THF, 0.75 mmol) was added. The reaction
was stirred for 15 min more and quenched by the addition of aqueous
saturated ammonium chloride. The mixture was poured into wafer and
EtOAc, and the layers were separated. The aqueous layer was washed
with EtOAc. The combined organic layers were dried over MgSO.sub.4,
filtered, and concentrated. Purification by flash chromatography
gave 0.286 g (85%) of the title compound, .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 7.17 (dd, J=7.8, 7.8 Hz, 1H), 6.90-6.83 (m,
2H), 6.77 (dd, J=8.1, 2.6 Hz, 1H), 5.07 (d, J=4.4 Hz, 1H), 4.63 (m,
1H), 4.50 (m, 1H), 3.66-3.57 (m, 2H), 3.21-3.09 (m, 2H), 1.90-1.81
(m, 2H), 1.54-1.42 (m, 2H), 1.37 (s, 9H), 1.26 (d, J=6.4 Hz,
3H).
Step F--(+/-)-1,1-Dimethylethyl
4-({3-[1-({2-[(methyloxy)carbonyl]-5-[5-(1-methyl-1H-pyrazol-4-yl)-1H-ben-
zimidazol-1-yl]-3-thienyl}oxy)ethyl]phenyl}oxy)-1-piperidinecarboxylate
##STR00311##
[0975] Methyl
3-hydroxy-5-[5-(1-methyl-1H-pyrazol-4-yl)-1H-benzimidazol-1-yl]-2-thiophe-
necarboxylate (0.300 g, 0.847 mmol), (+/-)-1,1-dimethylethyl
4-{[3-(1-hydroxyethyl)phenyl]oxy}-1-piperidinecarboxylate (0.285
mmol), and triphenylphosphine (0.667 g, 2.54 mmol) were dissolved
in 25 mL of DCM with stirring. Biisopropyi azodicarboxylate was
added slowly dropwise via syringe. The reaction was stirred
overnight, and the mixture was adsorbed onto silica gel.
Purification by flash chromatography afforded 0.467 g (84%) of the
title compound. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 8.68
(s, 1H), 8.17 (s, 1H), 7.94 (s, 1H), 7.90 (s, 1H), 7.56 (s, 2H),
7.48 (s, 1H), 7.26 (dd, J=8.1, 7.9 Hz, 1H), 7.08 (m, 1H), 7.01 (d,
J=7.9 Hz, 1H), 6.87 (dd, J=8.1, 2.2 Hz, 1H), 5.69 (q, J=6.0 Hz,
1H), 4.50 (m, 1H), 3.84 (s, 3H), 3.78 (s, 3H), 3.65-3.56 (m, 2H),
3.18-3.05 (m, 2H), 1.91-1.78 (m, 2H), 1.58 (d, J=6.2 Hz, 3H),
1.53-1.40 (m, 2H), 1.35 (s, 9H).
Step G--(+/-)-1,1-Dimethylethyl
4-({3-[1-({2-(aminocarbonyl)-5-[5-(1-methyl-1H-pyrazol-4-yl)-1H-benzimida-
zol-1-yl]-3-thlenyl}oxy)ethyl]phenyl}oxy)-1-piperidinecarboxylate
##STR00312##
[0977] (+/-)-1,1-Dimethylethyl
4-({3-[1-({2-[(methyloxy)carbonyl]-5-[5-(1-methyl-1H-pyrazol-4-yl)-1H-ben-
zimidazol-1-yl]-3-thienyl}axy)ethyl]phenyl}oxy)-1-piperidinecarboxylate
(0.466 g, 0.708 mmol) was placed in a pressure vessel. Ammonia
solution (20 mL, 7.0N in MeOH, 140 mmol) was added and the vessel
was sealed and placed in an 80.degree. C. oil bath. The reaction
was stirred at this temperature for 2.5 days and cooled to rt. The
mixture was adsorbed onto silica gel. Purification by flash
chromatography gave 0.379 g (83%) of the title compound. .sup.1H
NMR (400 MHz, DMSO-d.sub.6) .delta. 8.52 (s, 1H), 8.17 (s, 1H),
7.93 (m, 1H), 7.90 (s, 1H), 7.77 (br s, 1H), 7.57-7.48 (m, 2H),
7.43 (s, 1H), 7.27 (dd, J=8.1, 7.9 Hz, 1H), 7.15-7.08 (m, 2H), 7.06
(d, J=7.9 Hz, 1H), 6.88 (dd, J=8.1, 2.2 Hz, 1H), 5.69 (q, J=6.2 Hz,
1H), 4.51 (m, 1H), 3.84 (s, 3H), 3.67-3.57 (m, 2H), 3.15-3.03 (m,
2H), 1.92-1.77 (m, 2H), 1.67 (d, J=6.2 Hz, 3H), 1.64-1.35 (m, 2H),
1.35 (s, 9H).
Step
H--(+/-)-5-[5-(1-Methyl-1H-pyrazol-4-yl)-1H-benzimidazol-1-yl]-3-({1--
[3-(4-piperidinyloxy)phenyl]ethyl}oxy)-2-thiophenecarboxamide
(Title Compound)
[0978] (+/-)-1,1-Dimethylethyl
4-({3-[1-({2-(aminocarbcnyl)-5-[5-(1-methyl-1H-pyrazol-4-yl)-1H-benzimida-
zol-1-yl]-3-thienyl}oxy)ethyl]phenyl}oxy)-1-piperidinecarboxylate
(0.378 g, 0.588 mmol) was dissolved in 12 mL of DCM with stirring
and cooled to 0.degree. C. TFA (3.0 mL, 39 mmol) was added, and the
reaction was stirred for 1.5 h. The reaction was pipeted onto 80 mL
of aqueous 2N NaOH solution, rinsing with DCM. The mixture was
extracted three times with 4:1 DCM/i-PrOH. The combined organic
layers were dried over MgSO.sub.4, filtered, and concentrated in
vacuo. Purification by flash chromatography afforded 0.218 g (68%)
of the title compound. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.
8.51 (s, 1H), 8.17 (s, 1H), 7.93 (m, 1H), 7.90 (s, 1H), 7.75 (br s,
1H), 7.55 (dd, J=8.4, 1.4 Hz, 1H), 7.49 (d, J=8.4 Hz, 1H), 7.42 (s,
1H), 7.26 (dd, J=8.1, 7.9 Hz, 1H), 7.11-7.06 (m, 2H), 7.04 (d,
J=7.9 Hz, 1H), 6.84 (dd, J=8.1, 2.2 Hz, 1H), 5.69 (q, J=6.4 Hz,
1H), 4.34 (m, 1H), 3.84 (s, 3H), 2.90-2.81 (m, 2H), 2.53-2.43 (m,
2H), 1.88-1.76 (m, 2H), 1.67 (d, J=6.4 Hz, 3H), 1.42-1.26 (m, 2H).
MS (APCI): 543 [M+H].sup.+.
EXAMPLE 74
(+/-)-3-[(1-{3-[(1-methyl-4-piperidinyl)oxy]phenyl}ethyl)oxy]-5-[5-(1-meth-
yl-1H-pyrazol-4-yl)-1H
-benzimidazol-1-yl]-2-thiophenecarboxamide
##STR00313##
[0980]
(+/-)-5-[5-(1-Methyl-1H-pyrazol-4-yl)-1H-benzimidazol-1-yl]-3-({1-[-
3-(4-piperidinyloxy)phenyl]ethyl}oxy)-2-thiophenecarboxamide (0.108
g, 0.199 mmol) was dissolved in 9 mL of DCM and 4.5 mL of MeOH with
stirring. Acetic acid solution (0.24 mL, 1.0M in DCM, 0.24 mmol)
and formaldehyde solution (0.030 mL, 37% in water, 0.40 mmol) were
added. Sodium trlacetoxyborohydride (0.0633 g, 0.299 mmol) was
added in a single portion. The reaction was stirred for 1.5 h and
poured into 1N aqueous NaOH solution. The mixture was extracted
three times with 4:1 DCM/i-PrOH. The combined organic layers were
dried over MgSO.sub.4, filtered, and concentrated in vacuo. The
solid was triturated with 1:1 ether/hexanes, filtered, and washed
with hexanes. The solid was dried and collected to afford 0.099 g
(90%) of the title compound. .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta. 8.51 (s, 1H), 8.17 (s, 1H), 7.93 (m, 1H), 7.90 (s, 1H),
7.75 (br s, 1H), 7.55 (dd, J=8.6, 1.5 Hz, 1H), 7.49 (d, J=8.6 Hz,
1H), 7.42 (s, 1H), 7.26 (dd, J=7.9, 7.9 Hz, 1H), 7.12-7.07 (m, 2H),
7.05 (d, J=7.9 Hz, 1H), 6.85 (dd, J=7.9, 2.2 Hz, 1H), 5.69 (q,
J=6.4 Hz, 1H), 4.30 (m, 1H), 3.84 (s, 3H), 2.57-2.43 (m, 2H), 2.09
(s, 3H), 2.10-2.00 (m, 2H), 1.88-1.78 (m, 2H), 1.67 (d, J=8.4 Hz,
3H), 1.60-1.47 (m, 2H). MS (ESI): 557 [M+H].sup.+.
EXAMPLE 75
(+/-)-3-({1-[2-Fluoro-3-(4-piperidinyloxy)phenyl]ethyl}oxy)-5-[5-(1-methyl-
-1H-pyrazol-4-yl)-1H-benzimidazol-1-yl]-2-thiophenecarboxamide
##STR00314##
[0981] Step A--2-Fluoro-3-(hydroxymethyl)phenol
##STR00315##
[0983] Reduction of 2-fluoro-3-hydroxybenzaldehyde (Kirk, K. L.,
et. al. J. Med. Chem. 1986, 29, 1982) with sodium borohydride would
provide the title compound.
Step
B--3-({[(1,1-Dimethylethyl)(diphenyl)silyl]oxy}methyl)-2-fluorophenol
##STR00316##
[0985] 2-Fluoro-3-(hydroxymethyl)phenol (2.87 g, 20.2 mmol) was
dissolved in 100 mL of DCM and 10 mL of N,N-DMF with stirring and
cooled to 0.degree. C. Triethylamine (6.20 mL, 44.5 mmol) and
4-(dimethylamino)pyridine (5.43 g, 44.4 mmol) were added and the
mixture was stirred for 10 min. Tert-butylchlorodiphenylsilane
(5.25 mL, 20.2 mmol) was added and the solution was allowed to
reach rt slowly. The mixture was stirred for 4 h and poured into 1N
HCl solution. The layers were separated, and the aqueous layer was
washed with EtOAc. The combined organic layers were dried over
MgSO.sub.4, filtered, and concentrated in vacuo. Purification by
flash chromatography afforded 5.31 g (69%) of the title compound.
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 9.74 (s, 1H), 7.63-7.58
(m, 4H), 7.46-7.37 (m, 8H), 7.00-6.81 (m, 3H), 4.73 (s, 2H), 0.99
(s, 9H).
Step C--1,1-Dimethylethyl
4-{[3-({[(1,1-dimethylethyl)(diphenyl)silyl]-oxy}methyl)-2-fluorophenyl]o-
xy}-1-piperidinecarboxylate
##STR00317##
[0987] Title compound was prepared from
3-({[(1,1-Dimethylethyl)(diphenyl}silyl]-oxy}methyl)-2-fluorophenol
(5.31 g, 14.0 mmol) using a procedure analogous to Example 73, Step
B (6.34 g, 80%). .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta.
7.70-7.63 (m, 4H), 7.55-7.43 (m, 8H), 7.25-7.11 (m, 3H), 4.81 (s,
2H), 4.56 (m, 1H), 3.73-3.62 (m, 2H), 3.26-3.13 (m, 2H), 1.97-1.86
(m, 2H), 1.63-1.48 (m, 2H), 1.43 (s, 9H), 1.05 (s, 9H).
Step D--1,1-Dimethylethyl
4-{[2-fluoro-3-(hydroxymethyl)phenyl]oxy}-1-piperidinecarboxylate
##STR00318##
[0989] 1,1 -Dimethylethyl
4-{[3-({[(1,1-dimethyl.ethyl)(diphenyl)silyl]-oxy}methyl)-2-fluorophenyl]-
oxy}-1-piperidinecarboxylate (6.34 g, 11.2 mmol) was dissolved in
80 mL of THF with stirring. Tetrabutylammonium fluoride (13.4 mL,
1M in THF, 13.4 mmol) was added via syringe. The reaction was
stirred for 2 h and poured into 0.5 M sodium hydrogensulfate
solution and EtOAc. The layers were separated and the organic layer
was washed with brine. The combined organic layers were washed with
EtOAc. The combined organic layers were dried over MgSO.sub.4,
filtered, and concentrated in vacuo. Purification by flash
chromatography afforded 3.42 g (94%) of the title compound. .sup.1H
NMR (400 MHz, DMSO-d.sub.6 .delta. 7.13-6.96 (m, 3H), 5.19 (t,
J=5.7 Hz, 1H), 4.49 (m, 1H), 4.49 (d, J=5.7 Hz, 2H), 3.66-3.56 (m,
2H), 3.20-3.08 (m, 2H), 1.90-1.80 (m, 2H), 1.56-1.44 (m, 2H), 1.37
(s, 9H).
Step E--1,1-Dimethylethyl
4-[(2-fluoro-3-formylphenyl)oxy]-1-piperidinecarboxylate
##STR00319##
[0991] Oxalyl chloride (2.06 mL, 2M in DCM, 4.12 mmol) was added to
10 mL of DCM and cooled to -78.degree. C. Dimethyl sulfoxide (0.59
mL, 8.31 mmol) was added slowly dropwise via syringe. The reaction
was stirred for 5 min. 1,1-Dimethylethyl
4-{[2-fluoro-3-(hydroxymethyl)phenyl]oxy}-1-piperidinecarboxylate
(0.895 g, 2.75 mmol) was dissolved in 10 mL of DCM and added slowly
via syringe, The reaction was stirred for 30 min. Triethylamine
(1.92 mL, 13.8 mmol) was added dropwise via syringe, and the cold
bath was taken away. The reaction was allowed to reach rt slowly.
The mixture was poured Into half-saturated NaHCO.sub.3 solution and
1:1EtOAc/ether. The layers were separated, and the organic layer
was washed with brine. The combined aqueous layers were extracted
with EtOAc, The combined organic layers were dried over MgSO.sub.4,
filtered, and concentrated in vacuo. Purification by flash
chromatography gave 0.827 g (93%) of the title compound. .sup.1H
NMR (400 MHz, DMSO-d.sub.6 .delta. 10.18 (s, 1H), 7.57 (m, 1H),
7.36 (m, 1H), 7.26 (m, 1H), 4.61 (m, 1H), 3.67-3.57 (m, 2H),
3.21-3.10 (m, 2H), 1.94-1.84 (m, 2H), 1.59-1.48 (m, 2H), 1.37 (s,
9H).
Step F--(+/-)-1,1-Dimethylethyl
4-{[2-fluoro-3-(1-hydroxyethyl)phenyl]-oxy}-1-piperidinecarboxylate
##STR00320##
[0993] Title compound was prepared from 1,1-dimethylethyl
4-[{2-fluoro-3-formylphenyl)oxy]-1-piperidinecarboxylate (0.826 g,
2.55 mmol) using a procedure analogous to Example 73, Step E (0.820
g, 95%). .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 7.09-7.01 (m,
3H), 5.22 (d, J=4.4 Hz, 1H), 4.93 (m, 1H), 4.48 (m, 1H), 3.66-3.56
(m, 2H), 3.21-3.07 (m, 2H), 1.91-1.81 (m, 2H), 1.56-1.44 (m, 2H),
1.37 (s, 9H), 1.28 (d, J=6.4 Hz, 3H).
Step G--(+/-)-1,1-Dimethylethyl
4-({2-ftuoro-3-[1-({2-[(methyloxy)carbonyl]-5-[5-(1-methyl-1H-pyrazol-4-y-
l)-1H-benzimidazol-1-yl]-3-thienyl}oxy)ethyl]phenyl}oxy)-1-piperidinecarbo-
xylate
##STR00321##
[0995] Reaction of (+/-)-1,1-dimethylethyl
4-{[2-fluoro-3-(1-hydroxyethyl)phenyl]-oxy}-1-piperidinecarboxylate
(0.819 g, 2.41 mmol) and methyl
3-hydroxy-5-[5-(1-methyl-1H-pyrazol-4-yl)-1H-benzimidazol-1-yl]-2-thiophe-
necarboxylate (0.750 g, 2.12 mmol) using a procedure analogous to
that described In Example 73, Step F afforded 1.36 g (95%) of the
title compound. .sup.1H NMR (400 MHz, OMSO-d.sub.6) .delta. 8.64
(s, 1H), 8.19 (s, 1H), 7.96 (s, 1H), 7.92 (s, 1H), 7.66 (d, J=8.4
Hz, 1H), 7.59 (dd, J=8.6, 1.5 Hz, 1H), 7.53 (s, 1H), 7.22-7.13 (m,
3H), 5.94 (q, J=6.4 Hz, 1H), 4.64 (m, 1H), 3.86 (s, 3H), 3.80 (s,
3H), 3.67-3.56 (m, 2H), 3.20-3.07 (m, 2H), 1.94-1.79 (m, 2H), 1.63
(d, J=6.4 Hz, 3H), 1.57-1.44 (m, 2H), 1.37 (s, 9H).
Step H--(+/-)-1,1-Dimethylemyl
4-({3-[1-({2-(aminocarbonyl)-5-[5-(1-methyl-1H-pyrazol-4-yl)-1H-
benzimidazol-1-yl]-3-thienyl}oxy)ethyl]-2-fluorophenyl}oxy)-1-piperidinec-
arboxylate
##STR00322##
[0997] Reaction of (+/-)-1,1-Dimethylethyl
4-({2-fluoro-3-[1-({2-[(methyloxy)carbonyl]-5-[5-(1-methyl-1H-pyrazol-4-y-
l)-1H-benzimidazol-1-yl]-3-thienyl}oxy)ethyl]phenyl}oxy)-1-piperidinecarbo-
xylate (1.36 g, 2.01 mmol) using a procedure analogous to that
described in Example 73, Step G afforded 0.904 g (68%) of the title
compound. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 8.54 (s, 1H),
8.17 (s, 1H), 7.94 (s, 1H), 7.90 (s, 1H), 7.78 (br s, 1H),
7.58-7.54 (m, 2H), 7.42 (s, 1H), 7.25-7.10 (m, 3H), 7.02 (br s,
1H), 5.92 (q, J=6.4 Hz, 1H), 4.52 (m, 1H), 3.84 (s. 3H), 3.66-3.54
(m, 2H), 3.18-3.04 (m, 2H), 1.92-1.79 (m, 2H), 1.71 (d, J=6.4 Hz,
3H), 1.56-1.43 (m. 2H), 1.35 (s, 9H).
Step
I--(+/-)-3-({1-[2-Fluoro-3-(4-piperidinyloxy)phenyl]ethyl}oxy)-5-[5-(-
1-methyl-1H-pyrazol-4-yl)-1H-benzimidazol-1-yl]-2-thiophenecarboxamide
(Title Compound)
[0998] Reaction of (+/-)-1,1-dimethylethyl
4-({3-[1-({2-(aminocarbonyl)-5-[5-(1-methyl-1H-pyrazol-4-yl)-1H-benzimida-
zol-1-yl]-3-thienyl}oxy)ethyl]-2-fluorophenyl}oxy)-1-piperidinecarboxylate
(0.903 g, 1.37 mmol) using a procedure analogous to that described
in Example 73, Step H afforded 0.656 g (85%) of the title compound.
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 8.56 (s, 1H), 8.19 (s,
1H), 7.96 (s, 1H), 7.92 (s, 1H), 7.80 (br s, 1H), 7.68 (s, 2H).
7.43 (s, 1H), 7.21-7.10 (m, 3H). 7.04 (br s, 1H), 5.93 (q, J=6.2
Hz, 1H), 4.37 (m, 1H), 3.86 (s, 3H), 2.95-2.82 (m, 2H), 2.55-2.43
(m, 2H), 1.92-1.80 (m, 2H), 1.72 (d, J=6.2 Hz, 3H), 1.50-1.35 (m,
2H). MS (ESI): 561 [M+H].sup.+.
EXAMPLE 76
(+/-)-3-[(1-{2-Fluoro-3-[(1-methyl-4-piperidinyl)oxy]phenyl}ethyl)oxy]-5-[-
5-(1-methyl-1H-pyrazol-4-yl)-1H-benzimidazol-1-yl]-2-thiophenecarboxamide
##STR00323##
[1000] Reaction of
(+/-)-3-({1-[2-fluoro-3-(4-piperidinyloxy)phenyl]ethyl}oxy)-5-[5-(1-methy-
l-1H -pyrazol-4-yl)-1H-benzimidazol-1-yl]-2-thiophenecarboxamide
(Example 75, 0.362 g, 0.646 mmol) using a procedure analogous to
that described In Example 74 afforded 0.311 g (84%) of the title
compound. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 8.53 (s, 1H),
8.16 (s, 1H), 7.93 (s, 1H), 7.90 (s, 1H), 7.77 (s. 1H), 7.56 (s,
2H), 7.40 (s, 1H), 7.19-7.09 (m, 3H), 7.02 (br s, 1H), 5.91 (q,
J=6.2 Hz, 1H), 4.32 (m, 1H), 3.84 (s, 3H), 2.57-2.42 (m, 2H),
2.12-1.98 (m, 2H), 2.08 (s, 3H), 1.90-1.77 (m, 2H), 1.70 (d, J=6.2
Hz, 3H), 1.65-1.51 (m, 2H). MS (ESI): 575 [M+H].sup.+.
EXAMPLE 77
(+/-)-5-[5-(1-Methyl-1H
-pvrazol-4-yl)-1H-benzimidazol-1-yl]-3-({1-[2-(4-piperidinylpxy)-4-pyrimi-
dinyl]ethyl}oxy)-2-thiophenecarboxamide
##STR00324##
[1001] Step
A--4-[Bis(methyloxy)methyl]-2-(methylsulfonyl)pyrimidine
##STR00325##
[1003] 4-[Bis(methyloxy)methyl]-2-(methylthio)pyrimidine (U.S. Pat.
No. 6,218,537, 2001) (9.24 g, 46.1 rnmol) was dissolved in 150 mL
of DCM and cooled to 0.degree. C. with stirring.
3-Chloroperoxybenzoic acid (23.87 g, 70%, 96.8 mmol) was added in a
single portion. The reaction was allowed to reach rt slowly. The
reaction was stirred 2 h and quenched by the addition of 150 mL of
10% sodium sulfite solution. The mixture was poured into a
separatory funnel and the layers were separated. The organic layer
was washed with 150 mL of 10% Na.sub.2CO.sub.3 solution (2.times.)
and brine (1.times.). The organic layer was dried over MgSO.sub.4,
filtered, and concentrated in vacuo. Purification by flash
chromatography afforded 10.25 g (96%) of the title compound.
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.96 (d, J=4.9 Hz, 1H),
7.78 (d, J=4.9 Hz, 1H), 5.34 (s, 1H), 3.46 (s, 6H), 3.38 (s,
3H).
Step B--2-Propen-1-yl 4-hydroxy-1-piperidinecarboxylate
##STR00326##
[1005] 4-Hydroxypiperidine (5.00 g, 49.4 mmol) was dissolved in 150
mL of DCM with stirring. Triethylamine (10.3 mL, 73.9 mmol) was
added, and the solution was cooled to 0.degree. C. Allyl
chloroformate (8.30 mL, 59.4 mmol) was added dropwise via addition
funnel over 20 min. The reaction was stirred for an additional 30
min and poured into 1N HCl solution. The layers were separated, and
the aqueous layer was washed with EtOAc. The combined organic
layers were dried over MgSO.sub.4, filtered, and concentrated in
vacuo. Purification by flash chromatography gave 7.81 g (85%) of
the titie compound. .sup.1H NMR (400 MHz, DMSO-d.sub.6 .delta. 5.90
(m, 1H), 5.28-5.13 (m, 2H), 4.72 (d, J=4.0 Hz, 1H), 4.51-4.46 (m,
2H), 3.73-3.64 (m, 2H), 3.62 (m, 1H), 3.15-2.94 (m, 2H), 1.72-1.63
Cm, 2H), 1.30-1.19 (m, 2H).
Step C--2-Propen-1-yl
4-({4-[bis(methyloxy)methyl]-2-pyrimidinyl}oxy)-1-piperidinecarboxylate
##STR00327##
[1007] Sodium hydride (1.69 g, 60% dispersion in mineral oil, 42.3
mmol) was washed with hexanes (2.times.), and 40 mL of dry THF was
added, 2-Propen-1-yl 4-hydroxy-1-piperidinecarboxylate (7.81 g,
42.2 mmol) was dissolved in 20 mL of THF and added dropwise via
addition funnel, The addition funnel was rinsed with 10 mL of THF.
The mixture was stirred for 45 min,
4-[Bis(methyloxy)methyl]-2-(methylsulfonyl)pyrimidine (6.53 g, 28.1
mmol) was dissolved in 20 mL of THF and added via addition funnel.
The addition funnel was rinsed with 10 mL of THF. The reaction was
stirred for 3 h and quenched by the addition of water. The mixture
was poured into water and EtOAc, and the layers were separated. The
organic layer was washed with brine, and the combined aqueous
layers were extracted with EtOAc. The combined organic layers were
dried over MgSO.sub.4, filtered, and concentrated in vacuo.
Purification by flash chromatography provided 8.39 g (89%) of the
title compound. .sup.1H NMR (400 MHz, DMSO-d.sub.6 .delta. 8.63 (d,
J=4.9 Hz, 1H), 7.15 (d, J=4.9 Hz, 1H), 5.93 (m, 1H), 5.30-5.15 (m,
2H), 5.16 (s, 1H), 5.14 (m, 1H), 4.54-4.50 (m, 2H), 3.75-3.65 (m,
2H), 3.39-3.21 (m, 2H), 3.31 (s, 6H), 2.03-1.92 (m,2H), 1.69-1.57
(m, 2H).
Step D--2-Propen-1-yl
4-{[4-(hydroxymethyl)-2-pyrimidinyl]oxy}-1-piperidinecarboxylate
##STR00328##
[1009] 2-Propen-1-yl
4-({4-[bis(methyloxy)methyl]-2-pyrimidinyl}oxy)-1-piperidinecarboxylate
(8.39 g, 24.9 mmol) was dissolved in 100 mL of THF with stirring.
100 mL of 2N HCl was added. The mixture was sirred for 4 h and then
placed in a 50.degree. C. oil bath. The reaction was stirred at
that temperature for 8 h and cooled to rt. The reaction was stirred
an additional 12 h at rt. The mixture was cooled to 0.degree. C.,
and quenched by portionwise addition of solid NaHCO.sub.3 until the
pH was basic. The mixture was poured into water and EtOAc, and the
layers were separated. The organic layer was washed with brine, and
the combined aqueous layers were extracted with EtOAc. The combined
organic layers were dried over MgSO.sub.4, filtered, and
concentrated in vacuo. The residue was dissolved in 60 mL of THF
and 60 mL of EtOH with stirring. Sodium borohydride (1.88 g, 49.7
mmol) was added in a single portion. The reaction was stirred for 1
h and quenched with 2N NaOH solution. The mixture was poured into
wafer and EtOAc, and the layers were separated. The organic layer
was washed with brine, and the combined aqueous layers were
extracted with EtOAc. The combined organic layers were dried over
MgSO.sub.4, filtered, and concentrated in vacuo. Purification by
flash chromatography afforded 2.63 g (36%) of the title compound.
.sup.1H NMR (400 MHz, DMSO-d.sub.6 .delta. 8.54 (d, J=4.9 Hz, 1H),
7.15 (d, J=4.9 Hz, 1H), 5.92 (m, 1H), 5.58 (t, J=6.0 Hz, 1H),
5.31-5.14 (m, 2H), 5.12 (m, 1H), 4.55-4.49 (m, 2H), 4.44 (d, J=6.0
Hz, 2H), 3.76-3.64 (m, 2H), 3.38-3.19 (m, 2H), 2.01-1.90 (m, 2H),
1.66-1.53 (m, 2H).
Step E--1,1-Dimethylethyl
4-{[4-(hydroxymethyl)-2-pyrimidinyl]oxy}-1-plperidinecarboxylate
##STR00329##
[1011] 2-Propen-1-yl
4-{[4-(hydroxymethyl)-2-pyrimidinyl]oxy}-1-piperidinecarboxylate
(0.768 g, 2.62 mmol) and dl-fe/fbutyl-dicarbonafe (1.43 g, 6.55
mmol) were dissolved tn 20 mL of DCM with stirring. The solution
was degassed with N.sub.2 for 10 min. Tributyltin hydride (1.06 mL,
3.94 mmol) was added via syringe.
Tetrakis(triphenylphosphlne)palladium (0) (0.151 g, 0.131 mmol) was
added in a single portion. The reaction was stirred for 2 h and
adsorbed onto silica gel. Purification by flash chromatography gave
0.573 g (71%) of the title compound. .sup.1H NMR (400 MHz,
DMSO-d.sub.6 .delta. 8.52 (d, J=5.0 Hz, 1H), 7.14 (d, J=5.0 Hz,
1H), 5.56 (t, J=5.9 Hz, 1H), 5.09 (m, 1H), 4.42 (d, J=5.9 Hz, 2H),
3.67-3.58 (m, 2H), 3.23-3.08 (m, 2H), 1.97-1.85 (m, 2H), 1.60-1.47
(m, 2H), 1.37 (s, 9H).
Step F--1,1-Dimethylethyl
4-[(4-formyl-2-pyrimidinyl)oxy]-1-pipersdinecarboxylate
##STR00330##
[1013] Reaction of 1,1-dimethylethyl
4-{[4-(hydroxymethyl)-2-pyrimidinyl]oxy}-1-piperidinecarboxylate
(0.572 g, 1.85 mmol) using a procedure analogous to that described
in Example 75, Step E afforded 0.545 g (96%) of the title compound.
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 9.80 (s, 1H), 8.88 (d,
J=5.0 Hz, 1H), 7.47 (d, J=5.0 Hz, 1H), 5.20 (m, 1H), 3.70-3.60 (m,
2H), 3.27-3.10 (m, 2H), 2.02-1.88 (m, 2H), 1.67-1.52 (m, 2H), 1.38
(s, 9H).
Step G--(+/-)-1,1-Dimethylethyl
4-{[4-(1-hydroxyethyl)-2-pyrimidinyl]oxy}-1-piperidinecarboxylate
##STR00331##
[1015] Reaction of 1,1-dimethylethyl
4-[(4-formyl-2-pyrimidinyl)oxy]-1-piperidinecarboxylate (0.544 g,
1.77 mmol) using a procedure analogous to that described in Example
73, Step E afforded 0.391 g (68%) of the title compound. .sup.1H
NMR (400 MHz, DMSO-d.sub.6) .delta. 8.61 (d, J=5.1 Hz, 1H), 7.16
(d, J=5.1 Hz, 1H), 5.51 (d, J=4.8 Hz, 1H), 5.08 (m, 1H), 4.53 (m,
1H), 3.70-3.60 (m, 2H), 3.21-3.09 (m, 2H), 1.97-1.87 (m, 2H),
1.60-1.48 (m, 2H), 1.37 (s, 9H), 1.31 (d, J=6.8 Hz, 3H).
Step H--(+/-)-1,1-Dimethylethyl
4-({4-[1-({2-[(methyloxy)carbonyl]-5-[5-(1-methyl-1H-pyrazol-4-yl)-1H-ben-
zimidazol
-yl]-3-thienyl}oxy)ethyl]-2-pyrimidinyl}oxy)-1-piperidinecarboxy-
late
##STR00332##
[1017] Reaction of (+/-)-1,1-dimethylethyl
4-{[4-(1-hydroxyethyl)-2-pyrimidinyl]oxy}-1-piperidinecarhoxytate
(0.390 g, 1.21 mmol) and methyl
3-hydroxy-5-[5-(1-methyl-1H-pyrazol-4-yl)-1H-benztmidazol-1-yl]-2-thiophe-
necarboxylate (0.390 g, 1.10 mmol) using a procedure analogous to
that described in Example 73, Step F afforded 0.654 g (90%) of the
title compound, .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.
8.67-8.64 (m, 2H), 8.19 (s, 1H), 7.97 (d, J=1.6 Hz, 1H), 7.92 (s,
1H), 7.74 (d, J=8.4 Hz, 1H), 7.62-7.58 (m, 2H), 7.37 (d, J=5.1 Hz,
1H), 5.65 (q, J=6.5 Hz, 1H), 5.10 (m, 1H), 3.86 (s, 3H). 3.82 (s,
3H), 3.71-3.61 (m, 2H), 3.20-3.08 (m, 2H), 1.99-1.86 (m, 2H), 1.65
(d, J=6.5 Hz, 3H), 1.62-1.50 (m, 2H), 1.38 (s, 9H).
Step I--1,1-Dimethylethyl
4-({4-[1-({2-(aminocarbonyl)-5-[5-(1-methyl-1H-pyrazol-4-yl)-1H-benzimida-
zol-1-yl]-3-thienyi}oxy)ethyl]-2-pyrimidinyl}oxy)-1-piperidinecarboxylate
##STR00333##
[1019] Reaction of (+/-)-1,1-dimethylethyl
4-({4-[1-({2-[(methyloxy)carbonyl]-5-[5-{1-methyl-1H-pyrazol-4-yl)-1H-ben-
zimidazol-1-yl]-3-thienyl}oxy)ethyl]-2-pyrimidinyl}oxy)-1-piperidinecarbox-
ylate (0.653 g g, 0.990 mmol) using a procedure analogous to that
described in Example 73, Step G afforded 0.610 g (96%) of the title
compound. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 8.61 (d,
J=5.0 Hz, 1H), 8.54 (s, 1H), 8.17 (s, 1H), 7.93 (m, 1H). 7.90 (s,
1H), 7.84 (br s, 1H), 7.62 (d, J=8.4 Hz, 1H), 7.56 (dd, J=8.4, 1.4
Hz, 1H), 7.45 (s, 1H), 7.23 (d, J=5.0 Hz, 1H), 7.20 (br s, 1H),
5.71 (q, J=6.4 Hz, 1H), 5.07 (m, 1H), 3.84 (s, 3H), 3.68-3.58 (m,
2H), 3.19-3.05 (m, 2H), 1.97-1.81 (m, 2H), 1.67 (d, J=6.4 Hz, 3H).
1.61-1.44 (m, 2H), 1.36 (s, 9H).
Step J--(+/-)-5-[5-(1-Methyl-1H
-pvrazol-4-yl)-1H-benzimidazol-1-yl]-3-({1-[2-(4-piperidinylpxy)-4-pyrimi-
dinyl]ethyl}oxy)-2-thiophenecarboxamide (Title Compound)
[1020] Reaction of (+/-)-1,1-dimethylethyl
4-({4-[1-({2-(aminocarbonyl)-5-[5-(1-methyl-1H-pyrazol-4-yl)-1H-benzimida-
zoI-1-yl]-3-thienyr}oxy)ethyl]-
2-pyrimldinyl}oxy)-1-piperidinecarboxylate (0.609 g, 0.945 mmol)
using a procedure analogous to that described in Example 73, Step H
afforded 0.455 g (88%) of the titie compound. .sup.1H NMR (400 MHz,
DMSO-d6) .delta. 8.61 (d, J=5.1 Hz, 1H), 8.55 (s, 1H), 8.19 (s,
1H), 7.95 (d, J=1.3 Hz, 1H), 7.92 (d, J=0.6 Hz, 1H), 7.84 (br s,
1H), 7.64 (d, J=8.5 Hz, 1H), 7.58 (dd, J=8.5 Hz, 1.3 Hz, 1H), 7.46
(s, 1H), 7.23 (d, J=5.1 Hz, 1H), 7.18 (br s, 1H), 5.71 (q, J=6.4
Hz, 1H), 4.97 (m, 1H), 3.86 (s, 3H), 2.97-2.89 (m, 2H), 2.62-2.52
(m, 2H), 1.98-1.83 (m, 2H), 1.70 (d, J=6.4 Hz, 3H), 1.58-1.41 (m,
2H). MS (ESI): 545 [M+H].sup.+.
EXAMPLE 78
(+/-)-3-[(1-{2-[(1-methyl-4-piperidinyl)oxy]-4-pyrimidinyl}ethyl)oxy]-5-[5-
-(1-methyl-1H-pyrazol-4-yl)-1H-benzimidazol-1-yl]-2-thiophenecarboxamide
##STR00334##
[1022] Reaction of
(+/-)-5-[5-(1-methyl-1H-pyrazoI-4-yl)-1H-benzimidazol-1-yl]-3-({1-[2-(4-p-
iperidinyloxy)-4-pyrimidinyl]ethyl}oxy)-2-thiophenecarboxamide
(Example 77, 0.236 g, 0.433 mmol) using a procedure analogous to
that described in Example 74 afforded 0.231 g (95%) of the titie
compound. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 8.63 (d,
J=4.9 Hz, 1H), 8.56 (s, 1H), 8.19 (s, 1H), 7.96 (d, J=1.4 Hz, 1H),
7.92 (s, 1H), 7.84 (br s, 1H), 7.65 (d, J=8.6 Hz, 1H), 7.59 (dd,
J=8.6, 1.4 Hz, 1H), 7.46 (s, 1H), 7.24 (d, J=4.9 Hz, 1H), 7.17 (br
s, 1H), 5.71 (q, J=6.4 Hz, 1H), 4.90 (m, 1H), 3.86 (s, 3H),
2.66-2.51 (m, 2H), 2.21-2.06 (m, 2H), 2.15 (s, 3H), 1.99-1.84 (m,
2H), 1.74-1.58 (m, 2H), 1.70 (d, J=6.4 Hz, 3H). MS (ESI): 559
[M+H].sup.+.
EXAMPLE 79
(+/-)-5-[5-(1-Methyl-1H-pyrazol-4-yl)-1H-benzimidazol-1-yl]-3-({1-[2-(4-pi-
peridinyloxy)-4-pyridinyl]ethyl}oxy)-2-thiophenecarboxamide
##STR00335##
[1023] Step
A--2-FIuoro-4-({[tris(1-methylethyl)silyl]oxy}methyl)pyridine
##STR00336##
[1025] (2-Fluoro-4-pyridinyl)methanol (Pesti, J. A., et. al. J.
Org. Chem. 2000, 65, 7718) (2.59 g, 20.4 mmol) was dissolved in 100
mL of DCM with stirring. Imidazole (3.06 g, 44.9 mmol) was added in
a single portion. Triisopropylsilyl chloride (4.80 mL, 22.4 mmol)
was added via syringe. The reaction was stirred for 2 h, and
imidazole (1.00 g, 14.7 mmol) and triisopropylsilyl chloride (0.50
mL, 2.3 mmol) were added. The reaction was stirred an additional 1
h and poured Into water. The layers were separated, and the aqueous
layer was washed with EtOAc, The DCM layer was washed with brine,
and the combined aqueous layers were extracted with EtOAc. The
combined organic layers were dried over MgSO.sub.4, filtered, and
concentrated in vacua Purification by flash chromatography afforded
6.07 g (>90 % pure) of the title compound. .sup.1H NMR (400 MHz,
DMSO-d.sub.6 .delta. 8.17 (d, 75.1 Hz, 1H), 7.28 (m, 1H), 7.03 (s,
1H), 4.87 (s, 2H), 1.20-1.06 (m, 3H), 1.02 (d, J=7.1 Hz, 18H).
Step B--1,1-Dimethylethyl
4-{[4-({[tris(1-methylethyl)silyl]oxy}methyl)-2-pyridinyl]oxy}-1-piperidi-
necarboxylate
##STR00337##
[1027] Sodium hydride (1.63 g, 60% dispersion in mineral oil, 40.8
mmol) was washed with hexanes (2.times.), and 60 mL of dry THF was
added, t-Butyl 4-hydroxy-1-piperidinecarboxylate (8.21 g, 40.8
mmol) was dissolved in 30 mL of THF and added dropwise via addition
funnel. The addition funnel was rinsed with 10 mL of THF. The
mixture was stirred for 45 min.
2-Fluoro-4-({[tris(1-methylethyl)silyl]oxy}methyl)pyridine (5.78 g,
20.4 mmol) was dissolved in 15 mL of THF and added via addition
funnel. The addition funnel was rinsed with 5 mL of THF. The
reaction was stirred for 24 h and quenched by the addition of
water. The mixture was poured into water and EtOAc, and the layers
were separated. The organic layer was washed with brine, and the
combined aqueous layers were extracted with EtOAc. The combined
organic layers were dried over MgSO.sub.4, filtered, and
concentrated in vacuo, Purification by flash chromatography
provided 8.16 g (86%, over 2 steps) of the title compound. .sup.1H
NMR (400 MHz, DMSO-d.sub.6 .delta. 8.07 (d, J=5.3 Hz, 1H), 6.90 (d,
J=5.3 Hz, 1H), 6.69 (s, 1H), 5.13 (m, 1H), 4.76 (s, 2H), 3.74-3.64
(m, 2H), 3.18-3.04 (m, 2H), 1.97-1.87 (m, 2H), 1.57-1.45 (m, 2H),
1.38 (s, 9H), 1.19-1.08 (m, 3H), 1.03 (d, J=6.8 Hz, 18 H).
Step C--1,1-Dimethylethyl
4-{[4-(hydroxymethyl)-2-pyridinyl]oxy}-1-piperidinecarboxylate
##STR00338##
[1029] 1,1-Dimethylethyl
4-{[4-({[tris(1-methylethyl)silyl]oxy}methyl)-2-pyridinyl]oxy}-1-piperidi-
necarboxylate (8.16 g, 17.6 mmol) was dissolved in 60 ml of THF
with stirring. Tetrabutyammonium fluoride (23.0 ml, 1M in THF, 23.0
mmol) was added via syringe. The reaction was stirred for 2 h and
poured into water and EtOAc. The layers were separated, and the
organic layer was washed with brine. The combined aqueous layers
were extracted with EtOAc. The combined organic layers were dried
over MgSO.sub.4, filtered, and concentrated in vacuo. Purification
by flash chromatography gave 5.20 g (96%) of the title compound.
.sup.1H NMR (400 MHz, DMSO-d.sub.6 .delta. 8.04 (d, J=5.3 Hz, 1H),
6.87 (m, 1H), 6.68 <s, 1H), 5.33 (t, J=5.9 Hz, 1H), 5.14 (m,
1H), 4.46 (d, J=5.9 Hz, 2H), 3.71-3.62 (m, 2H), 3.21-3.09 (m, 2H),
1.95-1.86 (m, 2H), 1.57-1.46 (m, 2H), 1.39 (s, 9H).
Step D--1,1-Dimethylethyl
4-[(4-formyl-2-pyridinyl)oxy]-1-piperidinecarboxylate
##STR00339##
[1031] Reaction of 1,1-dimethylethyl
4-{[4-(hydroxymethyl)-2-pyridtnyl]oxy}-1-piperidinecarboxylate
(0.700 g, 2.27 mmol) using a procedure analogous to that described
In Example 75, Step E afforded 0.712 g (>90% pure) of the title
compound. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 10.00 (s,
1H), 8.88 (d, J=5.1 Hz, 1H), 7.34 (dd, J=5.1, 1.3 Hz, 1H), 7.25 (m,
1H), 5.21 (m, 1H), 3.72-3.64 (m, 2H), 3.25-3.11 (m, 2H), 1.99-1.90
(m, 2H), 1.63-1.51 (m, 2H), 1.39 (s, 9H).
Step E--(+/-)-1,1-Dimethylethyl
4-{[4-(1-hydroxyethyl)-2-pyridinyl]oxy}-1-piperidinecarboxylate
##STR00340##
[1033] Reaction of 1,1-dimethylethyl
4-[(4-formyl-2-pyridinyl)oxy]-1-piperidinecarboxylate (0.695 g,
2.27 mmol) using a procedure analogous to that described in Example
73, Step E afforded 0.708 g (97%, over 2 steps) of the title
compound. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 8.01 (d,
J=5.3 Hz, 1H), 6.89 (m, 1H), 6.68 (m, 1H), 5.28 (d, J=4.6 Hz, 1H),
5.12 (m, 1H), 4.62 (m, 1H), 3.69-3.60 (m, 2H), 3.20-3.05 (m, 2H),
1.94-1.84 (m, 2H), 1.55-1.44 (m, 2H), 1.37 (s, 9H), 1.26 (d, J=6.4
Hz, 3H).
Step F--(+/-)-1,1-Dimethylethyl
4-({4-[1-({2-[(methyloxy)carbonyl]-5-[5-(1-methyl-1H-pyrazol-4-yl)-1H-ben-
zimidazol-1-yl]-3-thienyl}oxy)ethyl]-2-pyridinyl}oxy)-1-piperidinecarboxyl-
ate
##STR00341##
[1035] Reaction of (+/-)-1,1-dimethylethyl
4-{[4-(1-hydroxyethyl)-2-pyridinyl]oxy}-1-piperidinecarboxylate
(0.705 g, 2.19 mmol) and methyl
3-hydroxy-5-[5-(1-methyl-1H-pyrazoi-4-yl)-1H-benzimidazol-1-yl]-2-thiophe-
necarboxylate (Intermediate 16, 0.517 g, 1.46 mmol) using a
procedure analogous to that described In Example 73, Step F
afforded 0.759 g (79%) of the title compound. .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 8.62 (s, 1H), 8.19 (s, 1H), 8.15 (d, J=5.5
Hz, 1H), 7.96 (d, J=1.5 Hz, 1H), 7.92 (s, 1H), 7.67 (d, J=8.5 Hz,
1H), 7.59 (dd, J=8.5, 1.6 Hz, 1H), 7.53 (s, 1H), 7.06 (dd, J=5.3,
1.5 Hz, 1H), 6.89 (s, 1H), 5.73 (q, J=6.4 Hz, 1H), 5.14 (m, 1H),
3.86 (s, 3H), 3.81 (s, 3H), 3.72-3.63 (m, 2H), 3.20-3.06 (m, 2H),
1.96-1.86 (m, 2H), 1.59 (d, J=6.4 Hz, 3H), 1.56-1.45 (m, 2H), 1.38
(s, 9H).
Step G--(+/-)-1,1-Dimethylethyl
4-({4-[1-({2-(amlnocarbonyl)-5-[5-(1-methyl-1H-pyrazol-4-yl)-1H-benzimida-
zol-1-yl]-3-thienyl}oxy)ethyl]-2-pyodinyl}oxy)-1-piperidinecarboxylate
##STR00342##
[1037] Reaction of (+/-)-1,1-dimethylethyl
4-({4-[1-({2-[(methyloxy)carbonyl]-5-[5-(1-methyl-1H-pyrazol-4-yl)-1H-ben-
zimidazol-1-yl]-3-thienyl}oxy)ethyl]-2-pyridinyl}oxy)-1-piperidinecarboxyl-
ate (0.758 g, 1.15 mmol) using a procedure analogous to that
described in Example 73, Step G afforded 0.696 g (94%) of the title
compound. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 8.52 (s, 1H),
8.16 (s, 1H), 8.14 (d, J=5.3 Hz, 1H), 7.93 (s, 1H), 7.90 (d, J=0.7
Hz, 1H), 7.77 (br s, 1H), 7.554 (s, 1H), 7.552 (s, 1H), 7.41 (s,
1H), 7.10 (br s, 1H), 7.09 (dd, J=5.3. 1.3 Hz, 1H), 6.92 (s, 1H),
5.69 (q, J=6.4 Hz, 1H), 5.12 (m, 1H), 3.84 (s, 3H), 3.71-3.62 (m,
2H), 3.15-3.02 (m, 2H), 1.96-1.85 (m, 2H), 1.66 (d, J=6.4 Hz, 3H),
1.55-1.43 (m, 2H), 1.36 (s, 9H).
Step
H--(+/-)-5-[5-(1-Methyl-1H-pyrazol-4-yl)-1H-benzimidazol-1-yl]-3-({1--
[2-(4-piperidinyloxy)-4-pyridinyl]ethyl}oxy)-2-thiophenecarboxamide
(Title Compound)
[1038] Reaction of (+/-)-1,1-dimethylethyl
4-({4-[1-({2-(aminocarbonyl)-5-[5-(1-methyl-1H-pyrazol-4-yl)-1H-benzimida-
zol-1-yl]-3-thienyl}oxy)ethyl]-2-pyridinyl}oxy)-1-piperidinecarboxylate
(0.695 g, 1.08 mmol) using a procedure analogous to that described
in Example 73, Step H afforded 0.542 g (92%) of the title compound.
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 8.54 (s, 1H), 8.18 (s,
1H), 8.14 (d, J=5.1 Hz, 1H), 7.95 (s, 1H), 7.91 (s, J=1H), 7.80 (br
s, 1H), 7.57 (s, 2H), 7.43 (s, 1H), 7.12 (br s, 1H), 7.08 (dd,
J=5.4, 1.4 Hz, 1H), 6.91 (s, 1H), 5.70 (q, J=6.4 Hz, 1H), 5.00 (m,
1H), 3.85 (s, 3H), 2.96-2.88 (m, 2H), 2.60-2.50 (m, 2H), 1.96-1.86
(m, 2H), 1.67 (d, J=6.4 Hz, 3H), 1.52-1.38 (m, 2H). MS (ESI): 544
[M+H].sup.+.
EXAMPLE 80
3-[(1-{2-[(1-Methyl-4-piperidgnyl)oxy)-4-pyridinyl}ethyl)oxy]-5-[5-(1-meth-
yl-1H-pyrazol-4-yl)-1H-benzimidazol-1-yl]-2-thiophenecarboxamide
##STR00343##
[1040] Reaction of
(+/-)-5-[5-(1-methyl-1H-pyrazol-4-yl)-1H-benzimidazol-1-yl]-3-({1-[2-(4-p-
iperidinyloxy)-4-pyridinyl]ethyl}oxy)-2-thiophenecarboxamide
(Example 79, 0.322 g, 0.592 mmol) using a procedure analogous to
that described in Example 74 afforded 0.313 g (95%) of the title
compound. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 8.53 (s, 1H),
8.18 (s, 1H), 8.15 (d, J=5.2 Hz, 1H), 7.95 (m, 1H), 7.91 <m,
1H), 7.79 (br s, 1H), 7.569 (s, 1H), 7.567 (s, 1H), 7.43 (s. 1H),
7.12 (br s, 1H), 7.08 (dd, J=5.2, 1.3 Hz, 1H), 6.92 (s, 1H), 5.70
(q, J=6.4 Hz, 1H), 4.93 (m, 1H), 3.85 (s, 3H), 2.64-2.53 (m, 2H),
2.13 (s, 3H), 2.15-2.03 (m, 2H), 1.97-1.87 (m, 2H), 1.67 (d, J=6.4
Hz, 3H), 1.67-1.55 (m, 2H). MS (ESI): 558 [M+H].sup.+.
EXAMPLE 81
(+/-)-5-[5-(1-Methyl-1H-pyrazol-4-yl)-1H-benzimidazol-1-yl]-3-({1-[6-(4-pi-
peridinyloxy)-2-pyridinyl]ethyl}oxy)-2-thiophenecarboxamide
##STR00344##
[1041] Step
A--6-Fluoro-N-methyl-M-(methyloxy)-2-pyridinecarboxamide
##STR00345##
[1043] 2-Fluoropyridine-6-carboxylic acid (1.00 g, 7.09 mmol) was
dissolved in 50 mL of DCM with stirring. DMF (3 drops) was added.
Gxalyi chloride (4.3 mL, 2M in DCM, 8.6 mmol) was added dropwise
via syringe. The reaction was stirred for 1 h and cooled to
0.degree. C. N,O-Dimethylhydroxylamine hydrochloride (0.761 g, 7.80
mmol) was added in a single portion. Pyridine (1.26 mL, 15.6 mmol)
was added via syringe, and the reaction was allowed to warm to room
temperature. The reaction was stirred for 16 h and poured into
half-saturated NaHCO.sub.3 solution and DCM. The layers were
separated, and the aqueous layer was washed with EtOAc, The
combined organic layers were dried over MgSO.sub.4, filtered, and
concentrated in vacuo. Purification by flash chromatography
provided 1.10 g (84%) of the title compound. .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 8.11 (m, 1H), 7.56 (m, 1H), 7.32 (dd, J=8.2,
2.4 Hz, 1H), 3.65 (s, 3H), 3.25 (s, 3H).
Step B--1-(6-Fluoro-2-pyridinyl)ethanone
##STR00346##
[1045] 6-Fluoro-N-methyl-N-(methyloxy)-2-pyridinecarboxamide (1.10
g, 5.97 mmol) was dissolved in 40 mL of THF with stirring and
cooled to 0.degree. C. Methyl magnesium chloride (8.0 mL, 3.0M in
THF, 24 mmol) was added via syringe. The reaction was stirred for
30 min and quenched by the addition of saturated ammonium chloride
solution. The mixture was poured into water and ether. The layers
were separated, and the organic layer was washed with brine. The
combined aqueous layers were washed with ether. The combined
organic layers were dried over MgSO.sub.4, filtered, and
concentrated in vacuo to afford 0.746 g (90%) of the title
compound. .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 8.24 (m, 1H),
7.94 (ddd, J=7.4, 2.5, 0.7 Hz, IB), 7.54 (odd, J=8.2, 2.7, 0.7 Hz,
1H),2.62 is, 3H).
Step C--(+/-)-1-(6-Fluoro-2-pyridinyl)ethanol
##STR00347##
[1047] 1-(6-Fluoro-2-pyridinyl)sthanone (0.745 g, 5.35 mmol) was
dissolved in 40 mL of THF with stirring and cooled to -78.degree.
C. Diisobutylaluminum hydride (16.0 mL, 1.0M in cyclohexane, 16.0
mmol) was added dropwise via addition funnel over 10 min. The
addition funnel was rinsed with 10 mL of THF. The reaction was
stirred for 45 min and quenched by the dropwise addition of 10 mL
of i-PrOH. 60 mL of saturated sodium/potassium tartrate solution
was added, and the mixture was stirred at rt for 1.5 h. The mixture
was poured into water and EtOAc, and the layers were separated. The
organic layer was washed with brine, and the combined aqueous
layers were extracted with EtOAc. The combined organic layers were
dried over MgSO.sub.4, filtered, and concentrated in vacuo to
afford 0.708 g (94%) of the title compound. .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 7.95 (m, 1H), 7.42 (ddd, J=7.5, 2.7, 0.6 Hz,
1H), 6.98 (dd, J=8.1, 2.5 Hz, 1H), 5.47 (d, J=4.9 Hz, 1H), 4.62 (m,
1H), 1.32 (d, J=6.6 Hz, 3H).
Step
D--(+/-)-2-(1-{[(1,1-Dimethytethyl)(dimethyl)silyl]oxy}ethyl)-6-fluor-
opyridine
##STR00348##
[1049] (+/-)-1-(6-FIuoro-2-pyridinyl)ethanol (0.707 g, 5.01 mmol)
was dissolved in 50 mL of DCM with stirring, imidazole (0.750 g,
11.0 mmol) and terf butyfdimethylsilyl chloride (0.831 g, 5.51
mmol) were added. The reaction was stirred for 16 h and poured into
water. The layers were separated, and the aqueous layer was washed
with 1:1 EtOAc/hexanes. The combined organic layers were dried over
MgSO.sub.4, filtered, and concentrated in vacuoto provide 1.10 g
(86%) of the title compound, .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta. 7.97 (m, 1H), 7.37 (m, 1H), 7.00 (m, 1H), 4.79 (q, J=6.4
Hz, 1H), 1.34 (d, 6.4 Hz, 3H), 0.85 (s, 9H), 0.04 (s, 3H), 0.03 (s,
3H).
Step E--(+/-)-1,1-Dimethylethyl
4-{[6-(1-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}ethyl)-2-pyridinyl]oxy}-
-1-piperidinecarboxylate
##STR00349##
[1051] Sodium hydride (0.310 g, 60% dispersion in mineral oil, 7.75
mmol) was washed with hexanes (2.times.), and 15 mL of dry THF was
added. t-Butyl 4-hydroxy-1-piperidinecarboxylate (1.56 g, 7.75
mmol) was dissolved in 10 mL of THF and added dropwise via syringe,
The mixture was stirred for 30 min. (+/-)-2-(1-{[(1,1
-Dimethylethyl)(dimethyl)silyl]oxy}ethyl)-6-fluoropyridine (1.10 g,
4.31 mmol) was dissolved in 10 mL of THF and added via syringe.
After 2 h, the reaction was heated to 50.degree. C. using an oil
bath. The reaction was stirred for 2 days more at this temperature
and quenched by the addition of saturated ammonium chloride
solution. The mixture was poured into saturated ammonium chloride
solution and EtOAc, and the layers were separated. The organic
layer was washed with brine, and the combined aqueous layers were
extracted with 1:1 EtOAc/hexanes. The combined organic layers were
dried over magnesium sulfate, filtered, and concentrated in vacuo.
Purification by flash chromatography provided 1.16 g (62%) of the
title compound. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 7.67
(dd, J=8.2, 7.3 Hz, 1H), 7.00 (d, J=7.3 Hz, 1H), 6.61 (d, J=8.2 Hz,
1H), 5.11 (m, 1H), 4.74 (q, J=6.2 Hz, 1H), 3.69-3.59 (m, 2H),
3.23-3.10 (m, 2H), 1.98-1.85 (m, 2H), 1.59-1.45 (m, 2H), 1.38 (s,
9H), 1.36 (d, J=6.2 Hz, 3H), 0.87 (s, 9H), 0.05 (s, 3H), -0.01 (s,
3H).
Step F--(+/-)-1,1-Dimethylethyl
4-{[6-(1-hydroxyethyl)-2-pyridinyl]oxy}-1-piperidinicarboxylate
##STR00350##
[1053] (+/-)-1,1-Dirnethylethyl
4-{[6-(1-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}ethyl)-2-pyridinyl]oxy}-
-1-piperidineearboxylate (1.16 g, 2.66 mmol) was dissolved in 25 mL
of THF with stirring, Tetrabutyammonium fluoride (3.20 mL, 1M in
THF, 3.20 mmol) was added via syringe. The reaction was stirred for
1 h and poured Into saturated ammonium chloride solution and EtOAc.
The layers were separated, and the organic layer was washed with
brine. The combined aqueous layers were extracted with EtC3Ac, The
combined organic layers were dried over MgSC.sub.4, filtered, and
concentrated in vacuo. Purification by flash chromatography gave
0.810 g (94%) of the title compound. .sup.1H MMR (300 MHz,
DMSO-d.sub.6) .delta. 7.69 (dd, J=8.1, 7.3 Hz, 1H), 7.08 (d, J=7.3
Hz, 1H), 6.64 (d, J=8.1 Hz, 1H), 5.28 (d, J=4.9 Hz, 1H), 5.18 (m,
1H), 4.62 (m, 1H), 3.75-3.63 (m, 2H), 3.29-3.15 (m, 2H), 2.03-1.91
(m, 2H), 1.66-1.50 (m, 2H), 1.44 (s, 9H), 1.87 (d, J=6.5 Hz,
3H).
Step G--{(+/-)-1,1-Dimethylethyl
4-({6-[1-({2-[(methyloxy)carbonyl]-5-[5-(1-methyl-1H-pyrazol-4-yl)-1H-ben-
zimidazol-1-yl]-3-thienyl}oxy)ethyl]-2-pyrldinyl}oxy)-1-piperidinecarboxyl-
ate
##STR00351##
[1055] Reaction of (+/-)-1,1-dimethylethyl
4-{[6-(1-hydroxyethyl)-2-pyridlnyl]oxy}-1-pip&ridinecarboxylate
(0.808 g, 2.51 mmol) and methyl 3-hydroxy-5-[5-(1-methyl-1H
-pyrazol-4-yl)-1H-benzimidazol-1-yl]-2-thiophenecarboxylate
(Intermediate 16, 0.593 g, 1.67 mmol) using a procedure analogous
to that described in Example 73, Step F afforded 0.615 g (56%) of
the title compound. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.
8.63 (s, 1H), 8.17 (s, 1H), 7.95 (m, 1H), 7.90 (ss 1H), 7.73 (dd,
J=8.3, 7.4 Hz, 1H), 7.67-7.49 (m. 3H), 7.19 (d, J=7.4 Hz, 1H), 6.70
(d, J=8.3 Hz, 1H), 5.63 (q, J=6.4 Hz, 1H), 5.09 (m, 1H), 3.84 (s,
3H), 3.78 (s, 3H), 3.66-3.55 (m, 2H), 3.13-3.02 (m. 2H), 1.93-1.81
(m, 2H), 1.64 (d, J=6.4 Hz, 3H), 1.55-1.42 (m, 2H), 1.35 (s,
9H).
Step H--(+/-)-1,1-Dimethylethyl
4-({6-[1-({2-(aminocarbonyl)-5-[5-(1-methyl-1H-pyrazol-4-yl)-1H-benzimida-
zol-1-yl]-3-thienyl}oxy)ethyl]-2-pyridinyl}oxy)-1-piperidinecarboxylate
##STR00352##
[1057] Reaction of (+/-)-1,1-dimethylethyl
4-({6-[1-({2-[(methyloxy)carbonyl]-5-[5-(1-methyl-1H-pyrazol-4-yl)-1H-ben-
zimidazol-1-yl]-3-thienyl}oxy)ethyl]-2-pyridinyl}oxy)-1-piperidinecarboxyl-
ate (0.614 g, 0.932 mmol) using a procedure analogous to that
described in Example 73, Step G afforded 0.509 g (85%) of the title
compound. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 8.54 (s, 1H),
8.17 (s, 1H), 7.94 (s, 1H), 7.90 (s, 1H), 7.86 (br s, 1H), 7.71
(dd, J=8.2, 7.1 Hz, 1H), 7.57 (s, 2H), 7.49 (s, 1H), 7.15 (br s,
1H), 7.10 (d, J=7.1 Hz, 1H), 6.71 (d, J=8.2 Hz, 1H), 5.72 (q, J=6.4
Hz, 1H), 5.08 (m, 1H), 3.84 (s, 3H), 3.67-3.55 (m, 2H), 3.17-3.02
(m, 2H), 1.95-1.76 (m. 2H), 1.67 (d, J=6.4 Hz, 3H), 1.56-1.37 (m,
2H), 1.36 (s, 9H).
Step
I--(+/-)-5-[5-(1-Methyl-1H-pyrazol-4-yl)-1H-benzimidazol-1-yl]-3-({1--
[6-(4-piperidinyloxy)-2-pyridinyl]ethyl}oxy)-2-thiophenecarboxamide
(Title Compound)
[1058] Reaction of (+/-)-1,1-dimethylethyl
4-({6-[1-({2-(aminocarbonyl)-5-[5-{1-methyl-1H-pyrazol-4-yl)-1H-benzimida-
zol-1-yl]-3-thienyl}oxy)ethyl]-2-pyridinyl}oxy)-1-piperidinecarboxylate
(0.508 g, 0.789 mmol) using a procedure analogous to that described
in Example 73, Step H afforded 0.422 g (98%) of the title compound.
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 8.54 (s, 1H), 8.19 (s,
1H), 7.95 (m, 1H), 7.92 (m, 1H), 7.84 (br s, 1H), 7.71 (del J=8.1,
7.3 Hz, 1H), 7.59-7.57 (m, 2H), 7.48 (s, 1H), 7.13 (br s,
1H),7.10(d, J=7.3 Hz, 1H), 6.70 (d, J=8.1 Hz, 1H), 5.71 (q, J=6.4
Hz, 1H). 4.98 (m, 1H), 3.86 (s, 3H), 2.96-2.84 (m, 2H), 2.67-2.49
(m, 2H), 1.94-1.79 (m, 2H), 1.69 (d, J=6.4 Hz, 3H), 1.52-1.34 (m,
2H). MS (ESI): 544 [M+H].sup.+.
EXAMPLE 82
(+/-)-3-[(1-{6-[(.sup.1
-Methyl-4-piperidinyl)oxy]-2-pyridinyl}ethyl)oxy]-5-[5-(1-methyl-1H-pyraz-
ol-4-yl)-1H-benzimidazol-1-yl]-2-thiophenecarboxamide
##STR00353##
[1060] Reaction of
(+/-)-5-[5-(1-methyl-1H-pyrazol-4-yl)-1H-benzimidazol-1-yl]-3-({1-[6-(4-p-
iperidinyloxy)-2-pyridinyl]ethyl}oxy)-2-thiophenecarboxamide
(Example 81, 0.222 g, 0.408 mmol) using a procedure analogous to
that described in Example 74 afforded 0.170 g (75%) of the title
compound. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 8.55 (s, 1H),
8.19 (s, 1H), 7.95 (m, 1H), 7.92 (m, 1H), 7.82 (br s, 1H), 7.71
(dd, J=8.2, 7.1 Hz, 1H), 7.61-7.58 (m, 2H), 7.49 (s, 1H), 7.11 (br
s, 1H), 7.11 (d, J=7.1 Hz, 1H), 6.70 (d, J=8.2 Hz, 1H), 5.71 (q,
J=6.4 Hz, 1H), 4.89 (m, 1H), 3.85 (s, 3H), 2.58-2.40 (m, 2H),
2.12-1.94 (m, 2H), 2.08 (s, 3H), 1.91-1.79 (m, 2H), 1.69 (d, J=6.4
Hz, 3H), 1.63-1.48 (m, 2H). MS (ESI): 558 [M+H].sup.+.
EXAMPLE 83
5-[5-(1-Msthyl-1H-pyrazol-4-yl)-1H-benzimidazol-1-yl]-3-({[3-(4-piperazimy-
loxy)phenyl]methyl}oxy)-2-thiophenecarboxamide
##STR00354##
[1061] Step A--1,1-Dimethylethyl
4-({3-[({2-[(methyloxy)carbonyl]-5-[5-(1-methyl-1H-pyrazol-4-yl)-1H-benzi-
midazol-1-yl]-3-thienyl}oxy)methyl]phenyl}oxy)-1-piperidinecarboxylate
##STR00355##
[1063] Reaction of 1,1-dimethylethyl
4-{[3-(hydroxymethyl)phenyl]oxy}-1-piperidinecarboxylate (0.386 g,
1.26 mmol) and methyl
3-hydrcxy-5-[5-(1-methyl-1H-pyrazol-4-yl)-1H-benzimidazol-1-yl]-2-thiophe-
necarboxylate (Intermediate 16, 0.300 g, 0.847 mmol) using a
procedure analogous to that described in Example 73, Step F
afforded 0.501 g (92%) of the title compound. .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 8.67 (s, 1H), 8.20 (s, 1H), 7.98 (d, J=1.4
Hz, 1H), 7.93 (d, J=0.6 Hz, 1H), 7.75 (d, J=8.4 Hz, 1H), 7.64 (s,
1H), 7.61 (dd, J=8.6, 1.7 Hz, 1H), 7.32 (dd, J=8.1, 7.9 Hz,
1H),7.12 (m, 1H), 7.04 (d, J=7.9 Hz, 1H), 6.94 (m, 1H), 5.35 (s,
2H), 4.55 (m, 1H), 3.86 (s, 3H), 3.77 (s, 3H), 3.69-3.60 (m, 2H),
3.21-3.09 (m, 2H), 1.95-1.85 (m, 2H), 1.56-1.44 (m, 2H), 1.38 (s,
9H).
Step B--1,1 -Dimethylethyl
4-({3-[({2-(aminocarbonyl)-5-[5-(1-methyl-1H-pyrazol-4-yl)-1H-benzimidazo-
l-1-yl]-3-thienyl}oxy)methyl]phenyl}oxy)-1-piperidinecarboxylate
##STR00356##
[1065] Reaction of 1-dimethylethyl
4-({3-[({2-[(methyloxy)carbonyl]-5-[5-(1-methyl-1H-pyrazol-4-yl)-1H-benzi-
midazol-1-yl]-3-thienyl}oxy)methyl]phenyl}oxy)-1-piperidinecarboxylate
(0.500 g, 0.777 mmol) using a procedure analogous to that described
in Example 73, Step G afforded 0.417 g (85%) of the title compound.
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 8.59 (s, 1H). 8.19 (s,
1H), 7.96 (m, 1H), 7.92 (s, 1H), 7.73 (br s, 1H), 7.68 (d, J=8.4
Hz, 1H), 7.61 (s, 1H), 7.60 (m, 1H), 7.31 (dd, J=8.1, 7.8 Hz, 1H),
7.17 (m, 1H), 7.11-7.03 (m, 2H), 6.94 (m, 1H), 5.36 (s, 2H), 4.53
(m, 1H), 3.86 (s, 3H), 3.77 (s, 3H), 3.69-3.59 (m, 2H), 3.18-3.07
(m, 2H), 1.92-1.82 (m, 2H), 1.55-1.42 (m, 2H), 1.37 (s, 9H).
Step
C--5-[5-(1-Msthyl-1H-pyrazol-4-yl)-1H-benzimidazol-1-yl]-3-({[3-(4-pi-
perazimyloxy)phenyl]methyl}oxy)-2-thiophenecarboxamide (Title
Compound)
[1066] Reaction of 1,1-dimethylethyl
4-({3-[({2-(aminocarbonyl)-5-[5-(1-methyl-1H-pyrazol-4-yl)-1H-benzimidazo-
l-1-yl]-3-thienyl}oxy)methyl]phenyl}oxy)-1-piperidinecarboxylate
(0.416 g, 0.662 mmol) using a procedure analogous to that described
in Example 73, Step H afforded 0.263 g (75%) of the title compound.
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 8.57 (s, 1H), 8.18 (s,
1H), 7.95 (s, 1H), 7.91 (s, 1H), 7.70 (br s, 1H), 7.66 (d, J=8.2
Hz, 1H), 7.61-7.56 (m, 2H), 7.28 (dd, J=8.1, 7.7 Hz, 1H), 7.11 (s,
1H), 7.07-7.01 (m, 2H), 6.89 (m, 1H), 5.35 (s, 2H), 4.34 (m, 1H),
3.84 (s, 3H), 2.91-2.83 (m, 2H), 2.54-2.43 (m, 2H), 1.89-1.80 (m,
2H), 1.43-1.31 (m, 2H). MS (ESI): 529 [M+H].sup.+.
EXAMPLE 84
3-[({3-[(1-Methyl-4-piperidinyl)oxy]phenyl}methyl)oxy]-5-5-(1-methyl-1H-py-
razol-4-yl)-1H-benzimidazol-1-yl]-2-thiophenecarboxamide
##STR00357##
[1068] Reaction of
5-[5-(1-methyl-1H-pyrazol-4-yl)-1H-benzimidazol-1-yl]-3-({[3-(4-piperidin-
yloxy)phenyl]methyl}oxy)-2-thiophenecarboxamide (Example 83, 0.175
g, 0.330 mmol) using a procedure analogous to that described in
Example 74 afforded 0.132 g (74%) of the title compound. 1H MMR
(400 MHz, DMSO-d.sub.6) .delta. 8.57 (s, 1H), 8.18 (s, 1H), 7.95
(s, 1H), 7.91 (s, 1H), 7.69 (br s, 1H), 7.67 (d, J=8.4 Hz, 1H),
7.61-7.56 (ms 2H), 7.28 (dd, J=8.2, 7.9 Hz, 1H), 7.12 (s, 1H),
7.08-7.01 (m, 2H), 6.90 (m, 1H), 5.35 (s, 2H), 4.31 (m, 1H), 3.85
(s, 3H), 2.57-2.44 (m, 2H), 2.10 (s, 3H), 2.10-2.02 (m, 2H),
1.90-1.81 (m, 2H), 1.61-1.50 (m, 2H). MS (ESI): 543
[M+H].sup.+.
EXAMPLE 85
5-[5-(1-Methyl-1H-pyrazol-4-yl)-1H-henzimidazol-1-yl]-3-({1-[4-(4-piperidi-
nyloxy)-2-pyridinyl]ethyl}oxy)-2-thiophenecarboxamide
##STR00358##
[1069] Step A: 1,1-Dimethylethyl
4-[(2-chloro-4-pyrldinyl)oxy]-1-piperidinecarboxylate
##STR00359##
[1071] 1,1-Dimethylethyl 4-hydroxy-1-piperidinecarboxylate (5.50 g,
27.4 mmol) was dissolved in 100.0 mL of THF and cooled to 0.degree.
C. Next, sodium hydride (1.19 g, 29.7 mmol, 60% dispersed in
mineral oil) was added portion wise and the mixture stirred at rt
for 1 h. The mixture was cooled to 0.degree. C. again and
2-chloro-4-fluoropyridine (3.00 g, 22.8 mmol) was added dropwise as
a THF solution. The reaction was allowed to stir at rt, and after 6
h TLC indicated that all of the 2-chloro-4-fluoropyridine had
reacted. The mixture was again cooled to 0.degree. C. and quenched
with water. EtOAc was added and the organics separated. The
organics were washed with brine and dried over anhydrous
MgSO.sub.4, The crude was purified via silica gel chromatography to
give 6.14 g (86% yield) of a colorless oil. .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 8.16 (d, J=5.9 Hz, 1H), 7.12 (d, J=2.2 Hz,
1H), 6.99 (d, J=5.9 Hz, 1H), 4.62-4.87 (m, 1H), 3.51-3.69 (m, 2H),
2.96-3.22 (m, 2H), 1.78-1.93 (m, 2H), 1.41-1.57 (m, 2H), 1.36 (s, 9
H).
Step B: 1,1-Dimethylethyl
4-[(2-acetyl-4-pyridinyl)oxy]-1-piperidinecarboxylate
##STR00360##
[1073] 1,1-Dimethylethyl
4-[(2-chloro-4-pyridinyl)oxy]-1-piperidinecarboxylate (3.00 g, 9.59
mmol) was dissolved in 100 mL of acetonitrsie. Next,
tefraethylammonium-chloride (4.77, 28.7 mmol),
dichlorobis(triphenylphosphine) palladium (II) (336 mg, 0.479
mmol), and tributyl(1-ethoxyvinyl)tin (3.96 g, 10.6 mmol) was
added. The reaction was stirred at rt for 72 h. Water and EtOAc was
added and the organics separated. The organics were concentrated to
give the vinyl ether as a dark solid. This was re-dissolved in 50.0
mL of acetone, before addition of a speck of p-toluenesulfonic
acid. The reaction was stirred for 4 h before TLC indicated
complete consumption of the vinyl ether. The solvent was removed
and the crude adsorbed onto silica gel and chromatographed to give
1.9 g (62% yield) of a white solid. .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 8.48 (d, J=5.7 Hz, 1H), 7.54 (d, J=2.6 Hz, 1H),
6.96 (dd, J=5.7, 2.6 Hz, 1H), 4.49-4.78 (m, 1H), 3.58-3.77 (m, 2H),
3.21-3.47 (m, 2H), 2.71 (s, 3H), 1.86-2.05 (m, 2H),1.66-1.82 (m,
2H), 1.46 (s, 9H).
Step C: 1,1-Dimethylethyl
4-{[2-(1-hydroxyethyl)-4-pyridinyl]oxy}-1-piperidine
carboxylate
##STR00361##
[1075] 1,1-Dimethylethyl
4-{(2-acetyl-4-pyndinyl)oxy]-1-piperidinecarboxylate (1.62 g, 5.06
mmol) was dissolved in 50.0 mL of anhydrous DCM and the solution
cooled to -78.degree. C. Diisobutylaluminumhydride (15.2 ml, 15.2
mmol, 1.0M solution in hexanes) was added dropwise over 15 min and
the reaction continued to be stirred at -78.degree. C. for 1.5 h.
The reaction was quenched with 50 mL of saturated sodium potassium
tartrate solution, warmed to rt and stirred overnight. The organics
were separated, washed with brine and dried over MgSO.sub.4. The
crude was purified via silica gel chromatography to give 0.962 g
(59% yield) of the title compound, .sup.1H NMR (300 MHz,
Chloroform-d) .delta. 8.40 (d, J=5.8 Hz, 1H), 6.83 (d, J=2.4 Hz,
1H), 6.77 (dd, J=5.8, 2.4 Hz, 1H), 4.82-4.97 (m, J=6.5, 6.5 Hz,
1H), 4.51-4.74 (m, 1H), 3.62-3.83 (m, 2H), 3.29-3.53 (m, 2H),
1.90-2.08 (m, 2H), 1.66-1.90 (m, 2H), 1.55 (d, J=6.5 Hz, 3H), 1.52
(s, 9H).
Step D: 1,1-Dimethylethyl
4-({2-[1-({2-[(methyloxy)carbonyl]-5-[5-(1-methyl-1H-pyrazol-4-yl)-1H-ben-
zimidazol-1-yl]-3-thienyl}oxy)ethyl]-4-pyridinyl}oxy)-1-piperidinecarboxyl-
ate
##STR00362##
[1077] The title compound was prepared from methyl
3-hydroxy-5-[5-(1-methyl-1H-pyrazol-4-yl)-1H-
benzirrtidazol-1-yl]-2-thiophenecarboxylate (teerrrediate 16, 500
mg, 1.41 mmol) and 1,1-dimethylethyl
4-{[2-(1-hydroxyethyl)-4-pyridinyl]oxy}-1-piperidinecarboxylate
(544 mg, 1.69 mmol) using a procedure analogous to Example 73, Step
F to give 870 mg of the desired product. MS (ESI): 659
[M+H].sup.+.
Step E: 1,1-Dimethylethyl
4-({2-[1-({2-(aminocarbonyl)-5-[5-(1-methyl-1H-pyrazol-4-yl)-1H-benzimida-
zol-1-yl]-3-thienyl}oxy)ethyl]-4-pyridinyl}oxy)-1-piperidinecarboxylate
##STR00363##
[1079] The title compound was prepared from 1,1-dimethylethyl
4-({2-[1-({2-[(methyloxy)carbonyl]-5-[5-(1-methyl-1H-pyrazol-4-yl)-1H-ben-
zimidazol-1-yl]-3-thienyl}oxy)ethyl]-4-pyridinyl}oxy)-1-piperidinecarboxyl-
ate (870 mg, 1.32 mmol) using a procedure analogous to Example 73,
Step G to give 765 mg of the desired product. MS (ESI): 644
[M+H].sup.+.
Step F:
5-[5-(1-Methyl-1H-pyrazol-4-yl)-1H-henzimidazol-1-yl]-3-({1-[4-(4--
piperidinyloxy)-2-pyridinyl]ethyl}oxy)-2-thiophenecarboxamide
(Title Compound)
[1080] The title compound was prepared from 1,1-dimethylethyl
4-({2-[1-({2-(aminocarbonyl)-5-[5-(1-methyl-1H-pyrazol-4-yl)-1H-benzimida-
zol-1-yl]-3-thienyl}oxy)ethyl]-4-pyridinyl}oxy)-1-piperidinecarboxylate
(765 mg) using a procedure analogous to Example 73, Step H to give
542 mg of the desired product .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta. 8.54 (s, 1H), 8.34 (d, J=5.9 Hz, 1H), 8.17 (s, 1H), 7.94
(s, 1H), 7.90 (s, 1H), 7.74 (br s, 1H), 7.56-7.60 (m, 2H), 7.46 (s.
1H), 7.38 (br s, 1H), 7.07-7.16 <m, 1H), 6.90 (dd, J=5.8, 2.5
Hz, 1H), 5.69 (q, J=6.3 Hz, 1H), 4.38-4.59 (m, 1H), 3.73-3.91 (m,
3H), 2.75-2.95 (m, 2H), 2.48-2.58 (m, 3H), 1.75-1.94 (m, 2H), 1.67
(d, J=6.4 Hz, 3H), 1.29-1.48 (m, 2H). MS: 544 [M+H].sup.+.
EXAMPLE 86
3-[(1-{4-[(1-Methyl-4-piperidinyl)oxy]-2-pyridinyl}ethyl)oxy]-6-5-(1-methy-
l-1H-pyrazef-4-yl)-1H-benzimidazol-1-yl]-2-thiophenecarboxamide
##STR00364##
[1082] The title compound was prepared from 5-[5-(1-methyl-
1H-pyrazol-4-yl)-1H-benzimidazol-1-yl]-3-({1-[4-(4-plperidinyloxy)-2-pyri-
dinyl]ethyl}oxy)-2-thiophene carboxamide (Example 85, 212 mg) using
a procedure analogous to Example 74 to give 187 mg of the desired
product. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 8.56 (s, 1H),
8.36 (d, J=5.7 Hz, 1H), 8.19 (s, 1H), 7.88-7.98 (m, 2H), 7.75 (br
s, 1H), 7.58-7.62 (m, 2H), 7.47 (s, 1H), 7.39 (br s, 1H), 7.13 (d,
J=2.4 Hz, 1H), 6.92 (dd, J=5.8, 2.5 Hz, 1H), 5.70 (q, J=6.4 Hz,
1H), 4.42-4.57 (m, 1H), 3.86 (s, 3H), 2.51-2.68 (m, 2H), 2.05-2.26
(m, 5H), 1.80-1.96 (m, 2H), 1.69 (d, J=6.4 Hz, 3H), 1.45-1.65 (m,
2H). MS (APCI): 558 [M+H].sup.+.
EXAMPLE 87
3-({(1R)-1-[2-Chloro-3-(4-piperidinyloxy)phenyl]ethyl}oxy)-5-[5-(5-methyl--
1,3,4-oxadiazol-2-yl)-1H-benziroidazol-1-yl]-2-thiophenecarboxamide
##STR00365##
[1083] Step A: Methyl
5-{5-[(2-acetylhydrazino)carbonyl]-1H-benzimidazol-1-yl}-3-{[(1R)-1-(2-ch-
lorophenyl)ethyl]oxy}-2-thiophenecarboxylate
##STR00366##
[1085] A 20.0 mL flask was charged with 150 mg (0.329 mmol) of
1-{4-{[(1R)-1-(2-chlorophenyl)ethyl]oxy}-5-[(methyloxy)carbonyl]-2-thieny-
l}-1H-benzimidazole-5-carboxylic acid (Intermediate 34, 0.120 mL,
0.658 mmol) of diisopropyl ethylamine, 24.4 mg (0.329 mmol) of
acethydrazide and 2.00 ml of DMF. Next, 125 mg (0.329 mmol) of
O-(7-Aza benzotriazole-1-yl)-N,N,N',N' tetramethyluranium
hexafluoro phosphate was added and the reaction mixture stirred at
rt for 30 min. 10 mL of water and 30 mL of DCM was added and the
organic layer separated. The organic layer was adsorbed onto silica
gel and chromatographed to give 154 mg (91% yield) of a tan solid.
MS (APCl): 513 [M+H].sup.+.
Step B: Methyl
3-{[(1R)-1-(2-chlorophenyl)ethyl]oxy}-5-[5-(5-methyl-1,3,4-oxadiazol-2-yl-
)-1H -benzimidazol-1-yl]-2-thiophenecarboxylate
##STR00367##
[1087] A 5.0 ml microwave vial was charged with 1.00 ml of THF, 286
mg (1.20 mmol) of methoxycarbonylsulfamoyl)triethylammonium
hydroxide inner salt, and 154 mg (0.301 mmol) of methyl
5-{5-[(2-acetylhydrazino)carbonyl]-1H-benzimidazol-1-yl}-3-{[(1R)-1-(2-ch-
larophenyl)ethyl]oxy}-2-thiophene carboxylate. The reaction was
heated in the microwave at 150.degree. C. for 10 min. The crude was
adsorbed onto silica gel and chromatographed to give 139 mg of a
tan solid as the title compound, MS (APCl): 495 [M+H].sup.+.
Step C: Methyl
3-hydroxy-5-[5-(5-methyl-1,3,4-oxadiazol-2-yl)-1H-benzimidazol-1-yl]-2-th-
iophenecarboxylate
##STR00368##
[1089] The titie compound was prepared from methyl
3-{[(1R)-1-(2-chlorophenyl)
ethyl]oxy}-5-[5-(5-methyl-1,3,4-oxadiazol-2-yl)-1H-benzimidazol-1-yl]-2-t-
hiophenecarboxylate (139 mg) using a procedure analogous to
Intermediate 3, Step D to give 82.0 mg of the desired product. MS
(ESI): 357 [M+H].sup.+.
Step D: Methyl
3-{[(1R)-1-(2-chloro-3-{[(1,1-dimethylethyI)(dimethyl)silyl]oxy}phenyl)et-
hyl]oxy}-5-[5-(5-methyl-1,3,4-oxadiazol-2-yl)-1H-benzimidazol
-yl]-2-thiocarboxylate
##STR00369##
[1091] The title compound was prepared from methyl
3-hydroxy-5-[5-(5-methyl-1,3,4-oxadiazol-2-yl)-1H-benzimidazol-1-yl]-2-th-
iophenecarboxylate (65.0 mg, 0.183 mmol) using a procedure
analogous to Intermediate 3, Step E to give 105 mg of the desired
product. MS (ESI): 625 [M+H].sup.+.
Step E: Methyl
3-{[(1R)-1-(2-chloro-3-hydroxyphenyl)ethyl]oxy}-5-[5-(5-methyl-1,3,4-oxad-
iazol-2-yl)-1H-benziroidazol-1-yl]-2-thiophenecarboxylate
##STR00370##
[1093] The titie compound was prepared from methyl
3-{[(1R)-1-(2-chloro-3-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}phenyl)et-
hyl]oxy}-5-[5-(5-methyl-1,3,4-oxadiazol-2-yl)-1H-benzimidazol-1-yl]-2-thio-
phenecarboxylate (82.0 mg, 0.312 mmol) using a procedure analogous
to intermediate 3, Step F to give 55.9 mg of the desired product.
MS (ESI): 511 [M+H].sup.+.
Step F: 1,1-Dimethylethyl
4-({2-chloro-3-[(1R)-1-({5-[5-(5-methyl-1,3,4-oxadiazol-2-yl)-1H-benzimid-
azol-1-yl]-2-[(methyloxy)carbonyl]-thlenyl}oxy)ethyl]phenyl}oxy)-1-piperid-
inecarboxylate
##STR00371##
[1095] The title compound was prepared from methyl
3-{[(1R)-1-(2-chloro-3-hydroxyphenyl)ethyl]oxy}-5-[5-(5-methyl-1,3,4-oxad-
iazol-2-yl)-1H-benzimidazol-1-yl]-2-thiophenecarboxylate (58.2 mg,
0.114 mmol) using a procedure analogous to Example 5, Step A to
give 72.0 mg of the desired product MS (ESI): 694 [M+H].sup.+.
Step G: 1,1-Dimethylethyl
4-({3-[(1R)-1-({2-(aminocarhonyl)-5-[5-(5-methyl-1,3,4-oxadiazoi-2-yl)-1H-
-benzimidazol-1-yl]-3-thienyl}oxy)ethyl]-2-chlorophenyl}oxy)-1-piperidinec-
arboxytate
##STR00372##
[1097] The title compound was prepared from 1,1-dimethylethyl
4-({2-chloro-3-[(1R)-1-({5-[5-(5-methyl-1,3,4-oxadiazol-2-yl)-1H-benzimid-
azol-1-yl]-2-[(methyloxy)carbonyl]-3-thienyl}oxy)ethyl]phenyl}oxy)-1-piper-
idinecarboxylate (70 mg, 0.101 mmol) using a procedure analogous to
Example 5, Step .delta. to give 62.0 mg of the desired product. MS
(ESI): 679 [M+H].sup.+.
Step H:
3-({(1R)-1-[2-chloro-3-(4-piperidinyloxy)phenyl]ethyI}oxy)-5-[5-(5-
-methyl-1,3,4-oxadiazol-2-yl)-1H-benzimidazol-1-yl]-2-thiophenecarboxamide
(Title Compound)
[1098] The title compound was prepared from 1,1-dimethylethyl
4-({3-[(1R)-1-({2-(aminocarbonyl)-5-[5-(5-methyl-1,3,4-oxadiazol-2-yl)-1H-
-benzimidazol
-yl]-3-thienyl}oxy)ethyl]-2-chlorophenyl}oxy)-1-piperidinecarboxylate
[240 mg (62.0 mg from previous step plus 178 mg from a different
batch using a procedure analogous to Example 87, Step G), 0.353
mmol] using a procedure analogous to Example 5, Step C) to give 187
mg of the title compound. .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta. ppm 8.73 (s, 1H), 8.30 (s, 1H), 7.97 (dd, J=8.6, 1.5 Hz,
1H), 7.86 (br s, 1H), 7.64 (d, J=8.6 Hz, 1H), 7.35 (t, J=8.1 Hz,
1H), 7.16-7.25 (m, 3H), 7.13 (br s, 1H), 5.99 (q, J=8.0 Hz, 1H),
4.44-4.62 (m, 1H), 2.84-3.00 (m, 2H), 2.60 (s, 3H), 2.51-2.59 (m,
3H), 1.82-1.97 (m, 2H), 1.72 <d, J=6.2 Hz, 3H), 1.41-1.59 (m,
2H). MS (ESS): 579 [M+H].sup.+.
EXAMPLE 88
3-[((1R)-1-{2-chloro-3-[(1-methyl-4-piperidinyl)oxy]phenyl}ethyl)-oxy]-5-[-
5-(5-methyl-1,3,4-oxadiazol-2-yl)-1H-benzimidazol-1-yl]-2-thiophenecarboxa-
mide
##STR00373##
[1100] The title compound was prepared from
3-({(1R)-1-[2-chloro-3-(4-pipericiinyloxy)phenyl]ethyl}oxy)-5-[5-(5-methy-
l-1,3,4-oxadiazol-2-yl)-1H-benzimidazol-yl]-2-thiophenecarboxamsde
(Example 87, 60.0 mg, 0.104 mmol) using a procedure analogous to
Example 74 to give 61.0 mg of the desired product .sup.1H NMR (400
MHz, DMSO-d.sub.6) .delta. ppm 8.70 (s, 1H), 8.27 (s, 1H), 7.93 (d,
J=7.3 Hz, 1H), 7.83 (br s, 1H), 7.61 (d, 8.6 Hz, 1H), 7.32 (t,
J=8.0 Hz, 1H), 7.13-7.21 (m, 3H), 7.11 (br s, 1H), 5.96 (q, J=8.0
Hz, 1H), 4.35-4.53 (m, 1H), 2.57 (s. 3H), 2.49-2.55 (m, 2H),
2.12-2.22 (m, 2H), 2.11 (s, 3H), 1.79-1.94 (m, 2H), 1.69 (d, J=6.2
Hz, 3H), 1.57 -1.67 (m, 2H). MS (ESI): 593 [M+H].sup.+.
BIOLOGICAL EXAMPLES
I. Assay for Inhibition of PLK1
[1101] A. Preparation of 6.times. N-Terminal His-tagged PLK Kinase
Domain
[1102] 6.times. N-terminal His-tagged PLK kinase domain (amino
acids 21-346 preceded by MKKGHHHHHHD) SEQ ID: No. 1. was prepared
from bacuiovirus infected I. ni cells under poiyhedrtn promoter
control. All procedures were performed at 4.degree. C. Ceils were
lysed In 50 mM HEPES, 200 mM NaCl, 50 mM imidazole, 5% glycerol; pH
7.5. The homogenate was centrifuged at 14K rpm in a SLA-1500 rotor
for 1 hr and the supernatant filtered through a 1.2 micron filter.
The supernatant was loaded onto a Nickel chelating Sepharose
(Amersham Pharmacia) column and washed with lysis buffer. Protein
was eluted using 20%, 30% and 100% buffer B steps where buffer B
was 50 mM HEPES, 200 mM NaCl, 300 mM imidazole, 5% glycerol; pH
7.5. Fractions containing PLK were determined by SDS-PAGE.
Fractions containing PLK were diluted five-fold with 50 mM HEPES, 1
mM DTT, 5% glycerol; pH 7.5, then loaded on an SP Sepharose
(Amersham Pharmacia) column. After washing the column with 50 mM
HEPES, 1 mM DTT, 5% glycerol; pH 7.5, PLK was step eluted with 50
mM HEPES, 1 mM DTT, 500 mM NaCl; 5% glycerol; pH 7.5. PLK was
concentrated using a 10 kDa molecular weight cutoff membrane and
then loaded onto a Superdex 200 gel filtration (Amersham Pharmacia)
column equilibrated in 25 mM HEPES, 1 mM DTT, 500 mM NaCl, 5%
glycerol; pH 7.5. Fractions containing PLK were determined by
SDS-PAGE. PLK was pooled, aliguoted and stored at -80.degree. C.
Samples were quality controlled using mass spectrometry, N-terminal
sequencing and amino acid analysis.
[1103] B. Enzyme Activity +/- Inhibitors Was Determined as
Follows:
[1104] All measurements were obtained under conditions where signal
production increased linearly with time and enzyme. Test compounds
were added to white 384-weli assay plates (0.1 .mu.L for 10 .mu.L
and some 20 .mu.L assays, 1 .mu.L for some 20 .mu.L assays) at
variable known concentrations in 100% DMSO. DMSO (1-5% final, as
appropriate) and EDTA (65 mM in reaction) were used as controls.
Reaction Mix was prepared as follows at 22.degree. C.: [1105] 25 mM
HEPES, pH 7.2 [1106] 15 mM MgCl.sub.2 [1107] 1 pM ATP [1108] 0.05
.mu.Ci/weli .sup.33P-.gamma. ATP (10 Ci/mMol) [1109] 1 .mu.M
substrate peptide (Biotin-Ahx-SFNDTLDFD) SEQ ID:No. 2. [1110] 0.15
mg/mL 8SA [1111] 1 mM DTT [1112] 2 nM PLK1 kinase domain (added
last)
[1113] Reaction Mix (10 or 20 .mu.L) was quickly added to each well
immediately following addition of enzyme via automated liquid
handlers and incubated 1-1.5 h at 22.degree. C. The 20 .mu.L
enzymatic reactions were stopped with 50 .mu.L of stop mix (50 mM
EDTA, 4.0 mg/mL Streptavidin SPA beads in Standard Dulbecco's PBS
(without Mg.sup.2+ and Ca.sup.2+), 50 .mu.M ATP) per well. The 10
.mu.L reactions were stopped with 10 .mu.L of stop mix (50 mM EDTA,
3.0 mg/mL Streptavidin-coupled SPA imaging Beads ("LeadSeeker") in
Standard Dulbecco's PBS (without Mg.sup.2+ and Ca.sup.2+), 50 .mu.M
ATP) per well. Plates were sealed with clear plastic seals, spun at
500.times. g for 1 min or settled overnight, and counted in Packard
TopCount for 30 seconds/well (regular SPA) or imaged using a
Viewlux imager (LeadSeeker SPA). Signal above background (EDTA
controls) was converted to percent Inhibition relative to that
obtained in control (DMSO-only) wells.
[1114] C. Besults
[1115] The data obtained is reported in Table 1 below, in Table 1,
+=plC.sub.50<6; ++=plC.sub.506-7; +++=plC.sub.50>7.
II. Inhibition of Cell Proliferation by PLK1 Inhibitors.
[1116] Exponentially growing cell lines of different tumor origins,
cultured in appropriate media containing 10% fet al bovine serum at
37.degree. C. In a 5% CO.sub.2incubator were plated in 96 or
384-weIl plates. Twenty four hours post-plating, cells were treated
with different concentrations of test compounds ranging from 20
.mu.M to 0.04 nM. Several wells were Set untreated as a control.
Seventy two hours post-treatment, cell numbers were determined
using different techniques; 100 .mu.l per well of methylene blue
(Sigma M9140) (0.5% in 50:50 Ethanol:water), or 10-100 .mu.l per
well of CeliTiter-Gio (Promega #G7573), deperiding on well size.
For methylene blue staining, stain was incubated at room
temperature for 30 minutes before plates were rinsed and dye
solubllized in 1% N-lauroyl sarcoslne, sodium salt, (Sigma L5125,
In PBS). Plates were read on a micropiate reader, measuring the OD
at 620 nm. For CeliTiter-Glo, plates were incubated at room
temperature for 15 minutes and the chemiiuminescent signal was read
on the Victor V or Envison 2100 reader.
[1117] Percent inhibition of cell growth was expressed as percent
proliferation relative to 100% proliferation (control).
Concentration of test compound that inhibited 50% of cell growth
(IC.sub.50) was determined by 4 parameter fit of data using XLfit,
(value of no cell control was substracted from all samples for
background). The data are shown in Tabte 1 and Table 2 below and
represent a compilation of several different experiments each
performed using the general parameters outlined above, although
minor variations may have been employed in some instances. In Table
1 and Table 2, +=IC.sub.50>1 .mu.M; ++=IC.sub.50 0.5-1 .mu.M:
+++=IC.sub.50<0.5 .mu.M.
TABLE-US-00001 TABLE 1 HCT116 Example PLK1 pIC.sub.50 IC.sub.50 1
+++ ++ 2 +++ +++ 3 +++ +++ 4 +++ +++ 5 +++ +++ 6 +++ +++ 7 +++ +++
8 +++ +++ 9 +++ +++ 10 +++ +++ 11 +++ +++ 12 +++ +++ 13 +++ +++ 14
+++ +++ 15 +++ +++ 16 +++ +++ 17 +++ +++ 18 +++ +++ 19 +++ +++ 20
+++ +++ 21 +++ +++ 22 +++ +++ 23 +++ +++ 24 +++ +++ 25 +++ +++ 26
+++ +++ 27 +++ +++ 28 +++ +++ 29 +++ +++ 30 +++ +++ 31 +++ +++ 32
+++ +++ 33 +++ +++ 34 +++ +++ 35 +++ +++ 36 +++ +++ 37 +++ + 38 +++
+++ 39 +++ ++ 40 +++ +++ 41 +++ +++ 42 +++ +++ 43 ++ + 44 +++ +++
45 +++ +++ 46 +++ +++ 47 +++ +++ 48 +++ +++ 49 +++ +++ 50 +++ +++
51 +++ +++ 52 +++ +++ 53 +++ +++ 54 +++ + 55 +++ + 56 +++ + 57 +++
+ 58 +++ + 59 +++ + 60 +++ + 61 +++ +++ 62 +++ +++ 63 +++ +++ 64
+++ +++ 65 +++ +++ 66 +++ +++ 67 +++ +++ 68 +++ +++ 69 +++ +++ 70
+++ +++ 71 +++ +++ 72 +++ +++ 73 +++ + 74 +++ +++ 75 +++ +++ 76 +++
+++ 77 ++ + 78 ++ + 79 +++ + 80 +++ + 81 +++ + 82 +++ + 83 +++ + 84
+++ ++ 85 +++ + 85 +++ + 87 +++ +++ 88 +++ +++
TABLE-US-00002 TABLE 2 Exam- Exam- Exam- Exam- Cell Line Tissue ple
3 ple 31 ple 45 ple 47 A549-L IC.sub.50 lung +++ +++ COLO205 Colon
+++ +++ +++ +++ IC.sub.50 HT29 IC.sub.50 Colon +++ +++ +++ +++ MX-1
IC.sub.50 Breast +++ +++ +++ +++ SKOV-3 IC.sub.50 Ovarian +++ +++
+++ +++ LNCaP IC.sub.50 Prostate ++ P388 IC.sub.50 Mouse +++ +++
+++ leukemia H1299 IC.sub.50 Lung +++ Hela IC.sub.50 Endometrial
+++ HN5 IC.sub.50 Head and +++ neck MCF7 IC.sub.50 Breast +++ MV522
IC.sub.50 Lung MDA-MB-468 Breast +++ IC.sub.50 PANC-1 IC.sub.50
pancreatic MiaPaca IC.sub.50 Pancreatic ASPC3 IC.sub.50 Pancreatic
BXPC3 IC.sub.50 Pancreatic RPMI 8226 leukemia +++ IC.sub.50 Saos-2
bone U87-MG brain BT474 breast BT549 breast HCC1937 breast HCC1954
breast SK-BR-3 breast T-47D breast HCT-15 colon LoVo colon HT-1080
connective tissue HN5 head/neck A 704 kidney A498 kidney SW156
kidney Hep3B liver Calu1 lung NCI-H358 lung NCI-H727 lung A2780
ovary Capan-2 pancreas Panc 02.03 pancreas BC-1 peripheral blood
BC-2 peripheral blood BDCM peripheral blood CA46 peripheral blood
CEM/C1 peripheral blood CRO-AP2 peripheral blood EB-3 peripheral
blood A431 skin SKMEL28 skin SKMEL3 skin SKMEL5 skin MALME-3M skin,
derived from lung NCI-N87 stomach T24 urinary bladder Exam- Example
Example Cell Line Tissue ple 48 49 66 A549-L IC.sub.50 lung +++
COLO205 Colon +++ +++ +++ IC.sub.50 HT29 IC.sub.50 Colon +++ +++
+++ MX-1 IC.sub.50 Breast +++ +++ +++ SKOV-3 IC.sub.50 Ovarian +++
+++ +++ LNCaP IC.sub.50 Prostate +++ P388 IC.sub.50 Mouse +++ +++
leukemia H1299 IC.sub.50 Lung +++ Hela IC.sub.50 Endometrial +++
HN5 IC.sub.50 Head and +++ neck MCF7 IC.sub.50 Breast +++ MV522
IC.sub.50 Lung +++ MDA-MB-468 Breast +++ IC.sub.50 PANC-1 IC.sub.50
pancreatic +++ MiaPaca IC.sub.50 Pancreatic +++ ASPC3 IC.sub.50
Pancreatic +++ BXPC3 IC.sub.50 Pancreatic +++ RPMI 8226 leukemia
+++ IC.sub.50 Saos-2 bone +++ U87-MG brain +++ BT474 breast + BT549
breast +++ HCC1937 breast + HCC1954 breast +++ SK-BR-3 breast +++
T-47D breast + HCT-15 colon +++ LoVo colon +++ HT-1080 connective
+++ tissue HN5 head/neck +++ A 704 kidney +++ A498 kidney +++ SW156
kidney + Hep3B liver +++ Calu1 lung +++ NCI-H358 lung +++ NCI-H727
lung + A2780 ovary +++ Capan-2 pancreas + Panc 02.03 pancreas +++
BC-1 peripheral +++ blood BC-2 peripheral + blood BDCM peripheral
+++ blood CA46 peripheral +++ blood CEM/C1 peripheral +++ blood
CRO-AP2 peripheral +++ blood EB-3 peripheral +++ blood A431 skin
+++ SKMEL28 skin + SKMEL3 skin +++ SKMEL5 skin +++ MALME-3M skin, +
derived from lung NCI-N87 stomach +++ T24 urinary +++ bladder
Sequence CWU 1
1
2111PRTbaculovirus infected T.ni cells 1Met Lys Lys Gly His His His
His His His Asp1 5 1029PRTArtificial Sequenceoptimized PLK peptide
substrate 2Ser Phe Asn Asp Thr Leu Asp Phe Asp1 5
* * * * *