U.S. patent application number 11/256477 was filed with the patent office on 2006-04-13 for benzofused heterozryl amide derivatives of thienopyridines useful as therapeutic agents, pharmaceutical compositions including the same, and methods for their use.
This patent application is currently assigned to AGOURON PHARMACEUTICALS, INC.. Invention is credited to Michael Collins, Stephan Cripps, Judith Deal, Mingying He, Robert Steven Kania, Jihong Lou, Cynthia Louise Palmer, William Henry III Romines, Ru Zhou.
Application Number | 20060079548 11/256477 |
Document ID | / |
Family ID | 29736588 |
Filed Date | 2006-04-13 |
United States Patent
Application |
20060079548 |
Kind Code |
A1 |
Collins; Michael ; et
al. |
April 13, 2006 |
Benzofused heterozryl amide derivatives of thienopyridines useful
as therapeutic agents, pharmaceutical compositions including the
same, and methods for their use
Abstract
The invention relates to compounds represented by the formula I
##STR1## and to prodrugs or metabolites thereof, or
pharmaceutically acceptable salts or solvates of said compounds,
said prodrugs, and said metabolites, wherein Z, Y, R.sup.11 and
R.sup.14, R.sup.15, R.sup.16, and R.sup.17 are as defined herein.
The invention also relates to pharmaceutical compositions
containing the compounds of formula I and to methods of treating
hyperproliferative disorders in a mammal by administering the
compounds of formula I.
Inventors: |
Collins; Michael; (San
Diego, CA) ; Cripps; Stephan; (San Diego, CA)
; Deal; Judith; (Wildomar, CA) ; Kania; Robert
Steven; (San Diego, CA) ; Lou; Jihong; (San
Diego, CA) ; He; Mingying; (San Diego, CA) ;
Palmer; Cynthia Louise; (La Mesa, CA) ; Romines;
William Henry III; (San Diego, CA) ; Zhou; Ru;
(Carlsbad, CA) |
Correspondence
Address: |
AGOURON PHARMACEUTICALS, INC.
10777 SCIENCE CENTER DRIVE
SAN DIEGO
CA
92121
US
|
Assignee: |
AGOURON PHARMACEUTICALS,
INC.
|
Family ID: |
29736588 |
Appl. No.: |
11/256477 |
Filed: |
October 21, 2005 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10796226 |
Mar 9, 2004 |
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11256477 |
Oct 21, 2005 |
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10460010 |
Jun 11, 2003 |
6869962 |
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10796226 |
Mar 9, 2004 |
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60389110 |
Jun 14, 2002 |
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Current U.S.
Class: |
514/301 ;
546/114 |
Current CPC
Class: |
A61P 11/00 20180101;
A61K 31/4743 20130101; A61P 15/08 20180101; A61P 17/00 20180101;
A61P 27/02 20180101; A61P 3/10 20180101; A61P 1/18 20180101; A61P
9/10 20180101; A61P 43/00 20180101; A61P 25/00 20180101; A61P 35/00
20180101; A61P 13/08 20180101; A61P 9/00 20180101; A61P 17/06
20180101; A61P 29/00 20180101; A61P 17/12 20180101; C07D 495/04
20130101 |
Class at
Publication: |
514/301 ;
546/114 |
International
Class: |
A61K 31/4743 20060101
A61K031/4743; C07D 498/02 20060101 C07D498/02 |
Claims
1. A pharmaceutical composition for the treatment of a
hyperproliferative disorder in a mammal comprising a
therapeutically effective amount of a compound represented by the
formula I: ##STR396## wherein: Y is --NH--, --O--, --S--, or
--CH.sub.2--; Z is --O-- or --N--; R.sup.14 is a C.sub.1-C.sub.6
alkyl, C.sub.1-C.sub.6 alkylamino, C.sub.1-C.sub.6 alkylhydroxy,
C.sub.3-C.sub.10 cycloalkyl, C.sub.1-C.sub.6 alkyl C.sub.3-C.sub.10
cycloalkyl or methylureido group; R.sup.15 and R.sup.17 are
independently H, halo, or a C.sub.1-C.sub.6 alkyl group
unsubstituted or substituted by one or more R.sup.5 groups;
R.sup.16 is H or a C.sub.1-C.sub.6 alkyl group when Z is N, and
R.sup.16 is absent when Z is --O--; R.sup.11 is H, C.sub.1-C.sub.6
alkyl, C.sub.3-C.sub.10 cycloalkyl, --C(O)NR.sup.12R.sup.13,
--C(O)(C.sub.6-C.sub.10 aryl), --(CH.sub.2).sub.t(C.sub.6-C.sub.10
aryl), --(CH.sub.2).sub.t(5 to 10 membered heterocyclic),
--(CH.sub.2).sub.tNR.sup.12R.sup.13, --SO.sub.2NR.sup.12R.sup.13 or
--CO.sub.2R.sup.12, wherein said C.sub.1-C.sub.6 alkyl,
--C(O)(C.sub.6-C.sub.10 aryl), --(CH.sub.2).sub.t(C.sub.6-C.sub.10
aryl), and --(CH.sub.2).sub.t(5 to 10 membered heterocyclic)
moieties of the said R.sup.11 groups are unsubstituted or
substituted by one or more R.sup.5 groups; each R.sup.5 is
independently selected from halo, cyano, nitro, trifluoromethoxy,
trifluoromethyl, azido, --C(O)R.sup.8, --C(O)OR.sup.8,
--OC(O)R.sup.8, --OC(O)OR.sup.8, --NR.sup.6C(O)R.sup.7,
--C(O)NR.sup.6R.sup.7, --NR.sup.6R.sup.7, --OR.sup.9,
--SO.sub.2NR.sup.6R.sup.7, C.sub.1-C.sub.6 alkyl, C.sub.6-C.sub.10
cycloalkyl, C.sub.1-C.sub.6 alkylamino,
--(CH.sub.2).sub.jO(CH.sub.2).sub.qNR.sup.6R.sup.7, --(C
H.sub.2).sub.tO(CH.sub.2).sub.qOR.sup.9,
--(CH.sub.2).sub.tOR.sup.9, --S(O).sub.j(C.sub.1-C.sub.6 alkyl),
--(CH.sub.2).sub.t(C.sub.8-C.sub.10 aryl), --(CH.sub.2).sub.t(5 to
10 membered heterocyclic), --C(O)(CH.sub.2).sub.t(C.sub.6-C.sub.10
aryl), --(CH.sub.2).sub.tO(CH.sub.2).sub.j(C.sub.6-C.sub.10 aryl),
--(CH.sub.2).sub.tO(CH.sub.2).sub.q(5 to 10 membered heterocyclic),
--C(O)(CH.sub.2).sub.t(5 to 10 membered heterocyclic),
--(CH.sub.2).sub.jNR.sup.7(CH.sub.2).sub.qNR.sup.6R.sup.7,
--(CH.sub.2).sub.jNR.sup.7CH.sub.2C(O)NR.sup.6R.sup.7,
(CH.sub.2).sub.jNR.sup.7(CH.sub.2).sub.qNR.sup.9C(O)R.sup.8,
(CH.sub.2).sub.jNR.sup.7(CH.sub.2).sub.tO(CH.sub.2).sub.qOR.sup.9,
--(CH.sub.2).sub.jNR.sup.7(CH.sub.2).sub.qS(O).sub.j(C.sub.1-C.sub.6
alkyl), --(CH.sub.2).sub.jNR.sup.7(CH.sub.2).sub.tR.sup.6,
--SO.sub.2(CH.sub.2).sub.t(C.sub.6-C.sub.10 aryl), and
--SO.sub.2(CH.sub.2).sub.t(5 to 10 membered heterocyclic), the
--(CH.sub.2).sub.q-- and --(CH.sub.2).sub.t-- moieties of the said
R.sup.5 groups optionally include a carbon-carbon double or triple
bond, and the alkyl, aryl and heterocyclic moieties of the said
R.sup.5 groups are unsubstituted or substituted with one or more
substituents independently selected from halo, cyano, nitro,
trifluoromethyl, azido, --OH, --C(O)R.sup.8, --C(O)OR.sup.8,
--OC(O)R.sup.8, --OC(O)OR.sup.8, --NR.sup.6C(O)R.sup.7,
--C(O)NR.sup.6R.sup.7, --(CH.sub.2).sub.tNR.sup.6R.sup.7,
C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.10 cycloalkyl,
--(CH.sub.2).sub.t(C.sub.6-C.sub.10 aryl), --(CH.sub.2).sub.t(5 to
10 membered heterocyclic),
--(CH.sub.2).sub.tO(CH.sub.2).sub.qOR.sup.9, and
--(CH.sub.2).sub.tOR.sup.9; each R.sup.6 and R.sup.7 is
independently selected from H, OH, C.sub.1-C.sub.6 alkyl,
C.sub.3-C.sub.10 cycloalkyl, --(CH.sub.2).sub.t(C.sub.6-C.sub.10
aryl), --(CH.sub.2).sub.t(5 to 10 membered heterocyclic),
--(CH.sub.2).sub.tO(CH.sub.2).sub.qOR.sup.9,
--(CH.sub.2).sub.tCN(CH.sub.2).sub.tOR.sup.9,
--(CH.sub.2).sub.tCN(CH.sub.2).sub.tR.sup.9 and
--(CH.sub.2).sub.tOR.sup.9, and the alkyl, aryl and heterocyclic
moieties of the said R.sup.6 and R.sup.7 groups are unsubstituted
or substituted with one or more substituents independently selected
from hydroxy, halo, cyano, nitro, trifluoromethyl, azido,
--C(O)R.sup.8, --C(O)OR.sup.8, --CO(O)R.sup.8, --OC(O)OR.sup.8,
--NR.sup.9C(O)R.sup.10, --C(O)NR.sup.9R.sup.10, --NR.sup.9R.sup.10,
C.sub.1-C.sub.6 alkyl, --(CH.sub.2).sub.t(C.sub.6-C.sub.10 aryl),
--(CH.sub.2).sub.t(5 to 10 membered heterocyclic),
--(CH.sub.2).sub.tO(CH.sub.2).sub.qOR.sup.9, and
--(CH.sub.2).sub.tOR.sup.9, where when R.sup.6 and R are both
attached to the same nitrogen, then R and R.sup.7 are not both
bonded to the nitrogen directly through an oxygen; each R.sup.8 is
independently selected from H, C.sub.1-C.sub.10 alkyl,
C.sub.3-C.sub.10 cycloalkyl, --(CH.sub.2).sub.t(C.sub.6-C.sub.10
aryl), and --(CH.sub.2).sub.t(5 to 10 membered heterocyclic); t is
an integer from 0 to 6; j is an integer from 0 to 2; q is an
integer from 2 to 6; each R.sup.9 and R.sup.10 is independently
selected from H, --OR.sup.6, C.sub.1-C.sub.6 alkyl, and
C.sub.3-C.sub.10 cycloalkyl; and each R.sup.12 and R.sup.13 is
independently selected from H, C.sub.1-C.sub.6 alkyl,
C.sub.3-C.sub.10 cycloalkyl, --(CH.sub.2).sub.t(C.sub.3-C.sub.10
cycloalkyl), --(CH.sub.2).sub.t(C.sub.6-C.sub.10 aryl),
--(CH.sub.2).sub.t(5 to 10 membered heterocyclic),
--(CH.sub.2).sub.tO(CH.sub.2).sub.qOR.sup.9, and
--(CH.sub.2).sub.tOR.sup.9, and the alkyl, aryl and heterocyclic
moieties of the said R.sup.12 and R.sup.13 groups are unsubstituted
or substituted with one or more substituents independently selected
from R.sup.5, or R.sup.12 and R.sup.13 are taken together with the
nitrogen to which they are attached to form a C.sub.5-C.sub.9
azabicyclic, aziridinyl, azetidinyl, pyrrolidinyl, piperidyl,
piperazinyl, morpholinyl, thiomorpholinyl, isoquinolinyl, or
dihydroisoquinolinyl ring, wherein said C.sub.5-C.sub.9
azabicyclic, aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl,
piperazinyl, morpholinyl, thiomorpholinyl, isoquinolinyl, or
dihydroisoquinolinyl rings are unsubstituted or substituted with
one or more R substituents, where R.sup.12 and R.sup.13 are not
both bonded to the nitrogen directly through an oxygen; or a
pharmaceutically acceptable salt or solvate thereof and a
pharmaceutically acceptable carrier.
2. The pharmaceutical composition of claim 1, wherein said
hyperproliferative disorder is cancer.
3. The pharmaceutical composition of claim 2, wherein said cancer
is brain, lung, kidney, renal, ovarian, ophthalmic, squamous cell,
bladder, gastric, pancreatic, breast, head, neck, oesophageal,
gynecological, prostate, colorectal or thyroid cancer.
4. The pharmaceutical composition of claim 1, wherein said
hyperproliferative disorder is noncancerous.
5. The pharmaceutical composition of claim 4, wherein said
hyperproliferative disorder is a benign hyperplasia of the skin or
prostate.
6. A pharmaceutical composition for the treatment of a
hyperproliferative disorder in a mammal comprising a
therapeutically effective amount of a compound, salt or solvate of
claim 1 in combination with an anti-tumor agent selected from the
group consisting of mitotic inhibitors, alkylating agents,
anti-metabolites, intercalating antibiotics, enzymes, topoisomerase
inhibitors, biological response modifiers, anti-hormones, and
anti-androgens, and a pharmaceutically acceptable carrier.
7. A pharmaceutical composition for the treatment of pancreatitis
or kidney disease in a mammal comprising a therapeutically
effective amount of a compound, salt or solvate of claim 1 and a
pharmaceutically acceptable carrier.
8. A pharmaceutical composition for the prevention of blastocyte
implantation in a mammal comprising a therapeutically effective
amount of a compound, salt or solvate of claim 1 and a
pharmaceutically acceptable carrier.
9. A pharmaceutical composition for treating a disease related to
vasculogenesis or angiogenesis in a mammal comprising a
therapeutically effective amount of a compound, salt or solvate of
claim 1 and a pharmaceutically acceptable carrier.
10. The pharmaceutical composition of claim 9 wherein said disease
is selected from the group consisting of tumor angiogenesis,
chronic inflammatory disease, atherosclerosis, skin diseases,
diabetes, diabetic retinopathy, retinopathy of prematurity,
age-related macular degeneration, hemangioma, glioma, melanoma,
Kaposi's sarcoma and ovarian, breast, lung, pancreatic, prostate,
colon and epidermoid cancer.
11. A pharmaceutical composition for treating a disease related to
vasculogenesis or angiogenesis in a mammal comprising a
therapeutically effective amount of a compound, salt or solvate of
claim 1, a therapeutically effective amount of a compound, salt or
solvate of an antihypertensive agent, and a pharmaceutically
acceptable carrier.
12. A method of treating a hyperproliferative disorder in a mammal
comprising administering to said mammal a therapeutically effective
amount of a compound, salt or solvate of claim 1.
13. The method of claim 12, wherein said hyperproliferative
disorder is cancer.
14. The method of claim 13 wherein said cancer is brain, lung,
ophthalmic, squamous cell, renal, kidney, ovarian, bladder,
gastric, pancreatic, breast, head, neck, oesophageal, prostate,
colorectal, gynecological or thyroid cancer.
15. The method of claim 12 wherein said hyperproliferative disorder
is noncancerous.
16. The method of claim 15 wherein said hyperproliferative disorder
is a benign hyperplasia of the skin or prostate.
17. A method for the treatment of a hyperproliferative disorder in
a mammal comprising administering to said mammal a therapeutically
effective amount of a compound, salt or solvate of claim 1 in
combination with an anti-tumor agent selected from the group
consisting of mitotic inhibitors, alkylating agents,
anti-metabolites, intercalating antibiotics, growth factor
inhibitors, cell cycle inhibitors, enzymes, topoisomerase
inhibitors, biological response modifiers, anti-hormones, and
anti-androgens.
18. A method of treating pancreatitis or kidney disease in a mammal
comprising administering to said mammal a therapeutically effective
amount of a compound, salt or solvate of claim 1.
19. A method of preventing blastocyte implantation in a mammal
comprising administering to said mammal a therapeutically effective
amount of a compound, salt or solvate of claim 1.
20. A method for treating a disease related to vasculogenesis or
angiogenesis in a mammal comprising administering to said mammal a
therapeutically effective amount of a compound, salt or solvate of
claim 1.
21. The method of claim 20 wherein said disease is selected from
the group consisting of tumor angiogenesis, chronic inflammatory
disease, atherosclerosis, skin diseases, diabetes, diabetic
retinopathy, retinopathy of prematurity, age-related macular
degeneration, hemangioma, glioma, melanoma, Kaposi's sarcoma and
ovarian, breast, lung, pancreatic, prostate, colon and epidermoid
cancer.
22. A method for treating a disease related to vasculogenesis or
angiogenesis in a mammal comprising administering to said mammal a
therapeutically effective amount of a compound, salt or solvate of
claim 1 in conjunction with a therapeutically effective amount of
an anti-hypertensive agent.
Description
[0001] The present patent application is a continuation of U.S.
application Ser. No. 10/796,226 filed on Mar. 9, 2004, which is a
divisional of U.S. application Ser. No. 10/460,010 filed on Jun.
11, 2003, which claims priority to U.S. Ser. No. 60/389,110, filed
Jun. 14, 2002, which is hereby incorporated by reference in its
entirety for all purposes.
FIELD OF THE INVENTION
[0002] This invention relates to novel thienopyridine and
thienopyridine derivatives that are useful in the treatment of
hyperproliferative diseases, such as cancers, in mammals. This
invention also relates to a method of using such compounds in the
treatment of hyperproliferative diseases in mammals, especially
humans, and to pharmaceutical compositions containing such
compounds.
BACKGROUND OF THE INVENTION
[0003] It is known that a cell may become cancerous by virtue of
the transformation of a portion of its DNA into an oncogene (i.e.,
a gene that upon activation leads to the formation of malignant
tumor cells). Many oncogenes encode proteins that are aberrant
tyrosine kinases capable of causing cell transformation.
Alternatively, the overexpression of a normal proto-oncogenic
tyrosine kinase may also result in proliferative disorders,
sometimes resulting in a malignant phenotype.
[0004] Receptor tyrosine kinases are large enzymes that span the
cell membrane and possess an extracellular binding domain for
growth factors such as epidermal growth factor, a transmembrane
domain, and an intracellular portion that functions as a kinase to
phosphorylate a specific tyrosine residue in proteins and hence to
influence cell proliferation. The foregoing tyrosine kinases may be
classified as growth factor receptor (e.g. EGFR, PDGFR, FGFR and
erbB2) or non-receptor (e.g. c-src and bcr-abl) kinases. It is
known that such kinases are often aberrantly expressed in common
human cancers such as breast cancer, gastrointestinal cancer such
as colon, rectal or stomach cancer, leukemia, and ovarian,
bronchial or pancreatic cancer. Aberrant erbB2 activity has been
implicated in breast, ovarian, non-small cell lung, pancreatic,
gastric and colon cancers. It has also been shown that epidermal
growth factor receptor (EGFR) is mutated or overexpressed in many
human cancers such as brain, lung, squamous cell, bladder, gastric,
breast, head and neck, oesophageal, gynecological and thyroid
cancers. Thus, it is believed that inhibitors of receptor tyrosine
kinases, such as the compounds of the present invention, are useful
as selective inhibitors of the growth of mammalian cancer
cells.
[0005] It has also been shown that EGFR inhibitors may be useful in
the treatment of pancreatitis and kidney disease (such as
proliferative glomerulonephritis and diabetes-induced renal
disease), and may reduce successful blastocyte implantation and
therefore may be useful as a contraceptive. See PCT international
application publication number WO 95/19970 (published Jul. 27,
1995), hereby incorporated by reference in its entirety.
[0006] It is known that polypeptide growth factors such as vascular
endothelial growth factor (VEGF) having a high affinity to the
human kinase insert-domain-containing receptor (KDR) or the murine
fetal liver kinase 1 (FLK-1) receptor have been associated with the
proliferation of endothelial cells and more particularly
vasculogenesis and angiogenesis. See PCT international application
publication number WO 95/21613 (published Aug. 17, 1995), hereby
incorporated by reference in its entirety. Agents, such as the
compounds of the present invention, that are capable of binding to
or modulating the KDR/FLK-1 receptor may be used to treat disorders
related to vasculogenesis or angiogenesis such as diabetes,
diabetic retinopathy, age related macular degeneration, hemangioma,
glioma, melanoma, Kaposi's sarcoma and ovarian, breast, lung,
pancreatic, prostate, colon and epidermoid cancer.
[0007] Compounds that are useful in the treatment of
hyperproliferative diseases are also disclosed in the following
patents and applications: PCT international patent application
publication number WO 00/38665 (published Jul. 6, 2001), PCT
international patent application publication number WO 97/49688
(published Dec. 31, 1997), PCT international patent application
publication number WO 98/23613 (published Jun. 4, 1998), U.S.
patent application No. 60/360,952 (filed Mar. 1, 2002), U.S. patent
application No. 60/299,879 (filed Jun. 21, 2001), U.S. patent
application Ser. No. 09/502,129 (filed Feb. 10, 2000), U.S. patent
application No. 60/209,686 (filed Jun. 6, 2000), U.S. patent
application No. 60/214,373 (filed Jun. 28, 2000), U.S. patent
application Ser. No. 08/953,078 (filed Oct. 17, 1997), U.S. Pat.
No. 6,071,935 issued Jun. 6, 2000, PCT international patent
application publication number WO 96/30347 (published Oct. 3,
1996), PCT international patent application publication number WO
96/40142 (published Dec. 19, 1996), PCT international patent
application publication number WO 97/13771 (published Apr. 17,
1997), and PCT international patent application publication number
WO 95/23141 (published Aug. 31, 1995). The foregoing patent and
applications are each incorporated herein by reference in their
entirety.
SUMMARY OF THE INVENTION
[0008] In one of the aspects, the present invention relates to a
compound represented by the formula I: ##STR2##
[0009] wherein: [0010] Y is --NH--, --O--, --S--, or --CH.sub.2--;
[0011] Z is --O--, --S--, or --N--; [0012] R.sup.14 is a
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkylamino, C.sub.1-C.sub.6
alkylhydroxy, C.sub.3-C.sub.10 cycloalkylamino, or methylureido
group; [0013] R.sup.15 and R.sup.17 are independently H, halo, or a
C.sub.1-C.sub.6 alkyl group unsubstituted or substituted by one or
more R.sup.5 groups; [0014] R.sup.16 is H or a C.sub.1-C.sub.6
alkyl group, preferably methyl, when Z is N, and R.sup.16 is absent
when Z is --O-- or --S--; [0015] R.sup.11 is H, C.sub.1-C.sub.6
alkyl, C.sub.3-C.sub.10 cycloalkyl, --C(O)NR.sup.12R.sup.13,
--C(O)(C.sub.6-C.sub.10 aryl), --(CH.sub.2).sub.t(C.sub.6-C.sub.10
aryl), --(CH.sub.2).sub.t(5 to 10 membered heterocyclic),
--(CH.sub.2).sub.tNR.sup.12R.sup.13, --SO.sub.2NR.sup.12R.sup.13 or
--CO.sub.2R.sup.12, wherein said C.sub.1-C.sub.6 alkyl,
--C(O)(C.sub.6-C.sub.10 aryl), --(CH.sub.2).sub.t(C.sub.6-C.sub.10
aryl), and --(CH.sub.2).sub.t(5 to 10 membered heterocyclic)
moieties of the said R.sup.11 groups are unsubstituted or
substituted by one or more R.sup.5 groups; [0016] each R.sup.5 is
independently selected from halo, cyano, nitro, trifluoromethoxy,
trifluoromethyl, azido, --C(O)R.sup.8, --C(O)OR.sup.8,
--OC(O)R.sup.8, --OC(O)OR.sup.8, --NR.sup.6C(O)R.sup.7,
--C(O)NR.sup.6R.sup.7, --NR.sup.6R.sup.7, --OR.sup.9,
--SO.sub.2NR.sup.6R.sup.7, C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.10
cycloalkyl, C.sub.1-C.sub.6 alkylamino,
--(CH.sub.2).sub.jO(CH.sub.2).sub.qNR.sup.6R.sup.7,
--(CH.sub.2).sub.tO(CH.sub.2).sub.qOR.sup.9,
--(CH.sub.2).sub.tOR.sup.9, --S(O).sub.j(C.sub.1-C.sub.6 alkyl),
--(CH.sub.2).sub.t(C.sub.6-C.sub.10 aryl), --(CH.sub.2).sub.t(5 to
10 membered heterocyclic), --C(O)(CH.sub.2).sub.t(C.sub.6-C.sub.10
aryl), --(CH.sub.2).sub.tO(CH.sub.2).sub.j(C.sub.6-C.sub.10 aryl),
--(CH.sub.2).sub.tO(CH.sub.2).sub.q(5 to 10 membered heterocyclic),
--C(O)(CH.sub.2).sub.t(5 to 10 membered heterocyclic),
--(CH.sub.2).sub.jNR.sup.7(CH.sub.2).sub.qNR.sup.6R.sup.7,
--(CH.sub.2).sub.jNR.sup.7CH.sub.2C(O)NR.sup.6R.sup.7,
--(CH.sub.2).sub.jNR.sup.7(CH.sub.2).sub.qNR.sup.9C(O)R.sup.8,
(CH.sub.2).sub.jNR(CH.sub.2).sub.tO(CH.sub.2).sub.qOR.sup.9,
--(CH.sub.2).sub.jNR.sup.7(CH.sub.2).sub.qS(O).sub.j(C.sub.1-C.sub.6
alkyl), --(CH.sub.2).sub.jNR.sup.7(CH.sub.2).sub.tR.sup.6,
--SO.sub.2(CH.sub.2).sub.t(C.sub.6-C.sub.10 aryl), and
--SO.sub.2(CH.sub.2).sub.t(5 to 10 membered heterocyclic), the
--(CH.sub.2).sub.q-- and --(CH.sub.2).sub.t-- moieties of the said
R.sup.5 groups optionally include a carbon-carbon double or triple
bond where t is an integer between 2 and 6, and the alkyl, aryl and
heterocyclic moieties of the said R.sup.5 groups are unsubstituted
or substituted with one or more substituents independently selected
from halo, cyano, nitro, trifluoromethyl, azido, --OH,
--C(O)R.sup.8, --C(O)OR.sup.8, --OC(O)R.sup.8, --OC(O)OR.sup.8,
--NR.sup.6C(O)R.sup.7, --C(O)NR.sup.6R.sup.7,
--(CH.sub.2).sub.tNR.sup.6R.sup.7, C.sub.1-C.sub.6 alkyl,
C.sub.3-C.sub.10 cycloalkyl, --(CH.sub.2).sub.t(C.sub.6-C.sub.10
aryl), --(CH.sub.2).sub.t(5 to 10 membered heterocyclic),
--(CH.sub.2).sub.tO(CH.sub.2).sub.qOR.sup.9, and
--(CH.sub.2).sub.tOR.sup.9; [0017] each R.sup.6 and R.sup.7 is
independently selected from H, OH, C.sub.1-C.sub.6 alkyl,
C.sub.3-C.sub.10 cycloalkyl, --(CH.sub.2).sub.t(C.sub.6-C.sub.10
aryl), --(CH.sub.2).sub.t(5 to 10 membered heterocyclic),
--(CH.sub.2).sub.tO(CH.sub.2).sub.qOR.sup.9,
--(CH.sub.2).sub.tCN(CH.sub.2).sub.tOR.sup.9,
--(CH.sub.2).sub.tCN(CH.sub.2).sub.tR.sup.9 and
--(CH.sub.2).sub.tOR.sup.9, and the alkyl, aryl and heterocyclic
moieties of the said R.sup.6 and R.sup.7 groups are unsubstituted
or substituted with one or more substituents independently selected
from hydroxy, halo, cyano, nitro, trifluoromethyl, azido,
--C(O)R.sup.8, --C(O)OR.sup.8, --CO(O)R.sup.8, --OC(O)OR.sup.8,
--NR.sup.9C(O)R.sup.10, --C(O)NR.sup.9R.sup.10, --NR.sup.9R.sup.10,
C.sub.1-C.sub.6 alkyl, --(CH.sub.2).sub.t(C.sub.6-C.sub.10 aryl),
--(CH.sub.2).sub.t(5 to 10 membered heterocyclic),
--(CH.sub.2).sub.tO(CH.sub.2).sub.qOR.sup.9, and
--(CH.sub.2).sub.tOR.sup.9, where when R.sup.6 and R.sup.7 are both
attached to the same nitrogen, then R.sup.6 and R.sup.7 are not
both bonded to the nitrogen directly through an oxygen; [0018] each
R.sup.8 is independently selected from H, C.sub.1-C.sub.10 alkyl,
C.sub.3-C.sub.10 cycloalkyl, --(CH.sub.2).sub.t(C.sub.6-C.sub.10
aryl), and --(CH.sub.2).sub.t(5 to 10 membered heterocyclic);
[0019] each R.sup.9 and R.sup.10 is independently selected from H,
--OR.sup.6, C.sub.1-C.sub.6 alkyl, and C.sub.3-C.sub.10 cycloalkyl;
[0020] wherein j is an integer from 0 to 2, t is an integer from 0
to 6, q is an integer from 2 to 6; and [0021] each R.sup.12 and
R.sup.13 is independently selected from H, C.sub.1-C.sub.6 alkyl,
C.sub.3-C.sub.10 cycloalkyl, --(CH.sub.2).sub.t(C.sub.3-C.sub.10
cycloalkyl), --(CH.sub.2).sub.t(C.sub.6-C.sub.10 aryl),
--(CH.sub.2).sub.t(5 to 10 membered heterocyclic),
--(CH.sub.2).sub.tO(CH.sub.2).sub.qOR.sup.9, and
--(CH.sub.2).sub.nOR.sup.9, and the alkyl, aryl and heterocyclic
moieties of the said R.sup.12 and R.sup.13 groups are unsubstituted
or substituted with one or more substituents independently selected
from R.sup.5, or R.sup.12 and R.sup.13 are taken together with the
nitrogen to which they are attached to form a C.sub.5-C.sub.9
azabicyclic, aziridinyl, azetidinyl, pyrrolidinyl, piperidyl,
piperazinyl, morpholinyl, thiomorpholinyl, isoquinolinyl, or
dihydroisoquinolinyl ring, wherein said C.sub.5-C.sub.9
azabicyclic, aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl,
piperazinyl, morpholinyl, thiomorpholinyl, isoquinolinyl, or
dihydroisoquinolinyl rings are unsubstituted or substituted with
one or more R.sup.5 substituents, where R.sup.12 and R.sup.13 are
not both bonded to the nitrogen directly through an oxygen; [0022]
or prodrugs thereof, or pharmaceutically acceptable salts or
solvates of said compounds and said prodrugs.
[0023] In one embodiment of the compound of formula I, R.sup.11 is
--(CH.sub.2).sub.t(5 to 10 membered heterocyclic),
--C(O)NR.sup.12R.sup.13, --SO.sub.2NR.sup.12R.sup.13 and
--CO.sub.2R.sup.12, wherein said R.sup.11 group
--(CH.sub.2).sub.t(5 to 10 membered heterocyclic) is unsubstituted
or substituted by one or more R.sup.5 groups and wherein each
R.sup.12 and R.sup.13 is independently selected from H,
C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.10 cycloalkyl,
--(CH.sub.2).sub.t(C.sub.3-C.sub.10 cycloalkyl),
--(CH.sub.2).sub.t(C.sub.6-C.sub.10 aryl), --(CH.sub.2).sub.t(5 to
10 membered heterocyclic),
--(CH.sub.2).sub.tO(CH.sub.2).sub.qOR.sup.9,
--(CH.sub.2).sub.tOR.sup.9, and the alkyl, aryl and heterocyclic
moieties of said R.sup.12 and R.sup.13 groups are unsubstituted or
substituted by one or more substituents independently selected from
R.sup.5, or R.sup.12 and R.sup.13 are taken together with the
nitrogen to which they are attached to form a C.sub.5-C.sub.9
azabicyclic, aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl,
piperazinyl, morpholinyl, thiomorpholinyl, isoquinolinyl, or
dihydroisoquinolinyl ring, wherein said C.sub.5-C.sub.9
azabicyclic, aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl,
piperazinyl, morpholinyl, thiomorpholinyl, isoquinolinyl, or
dihydroisoquinolinyl ring are unsubstituted or substituted by one
or more R.sup.5 substituents, where said R.sup.12 and R.sup.13 are
not both bonded to the nitrogen directly through an oxygen.
[0024] In another embodiment of the compound of formula I, R.sup.11
is --(CH.sub.2).sub.t(5 to 10 membered heterocyclic), and
--C(O)NR.sup.12R.sup.13.
[0025] In still another embodiment of the compound of formula I,
R.sup.11 is --C(O)NR.sup.12R.sup.13 wherein R.sup.12 and R.sup.13
are independently selected from H, C.sub.1-C.sub.6 alkyl,
C.sub.3-C.sub.10 cycloalkyl, --(CH.sub.2).sub.t(C.sub.3-C.sub.10
cycloalkyl), --(CH.sub.2).sub.t(C.sub.6-C.sub.10 aryl),
--(CH.sub.2).sub.t(5 to 10 membered heterocyclic),
--(CH.sub.2).sub.tO(CH.sub.2).sub.qOR.sup.9,
--(CH.sub.2).sub.tOR.sup.9, wherein t is an integer from 0 to 6, q
is an integer from 2 to 6, and the alkyl, aryl and heterocyclic
moieties of said R.sup.12 and R.sup.13 groups are unsubstituted or
substituted with one or more substituents independently selected
from R.sup.5, or R.sup.12 and R.sup.13 are taken together with the
nitrogen to which they are attached to form a C.sub.5-C.sub.9
azabicyclic, aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl,
piperazinyl, morpholinyl, thiomorpholinyl, isoquinolinyl, or
dihydroisoquinolinyl ring, wherein said C.sub.5-C.sub.9
azabicyclic, aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl,
piperazinyl, morpholinyl, thiomorpholinyl, isoquinolinyl, or
dihydroisoquinolinyl ring are unsubstituted or substituted with 1
to 5 R.sup.5 substituents, where R.sup.12 and R.sup.13 are not both
bonded to the nitrogen directly through an oxygen.
[0026] In another embodiment of the compound of formula I, R.sup.11
is --C(O)NR.sup.12R.sup.13, wherein R.sup.12 and R.sup.13 are taken
together with the nitrogen to which they are attached to form a
C.sub.5-C.sub.9 azabicyclic, aziridinyl, azetidinyl, pyrrolidinyl,
piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl,
isoquinolinyl, or dihydroisoquinolinyl ring, wherein said
C.sub.5-C.sub.9 azabicyclic, aziridinyl, azetidinyl, pyrrolidinyl,
piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl,
isoquinolinyl, or dihydroisoquinolinyl ring are unsubstituted or
substituted with 1 to 5 R.sup.5 substituents.
[0027] In still another embodiment of the compound of formula I,
R.sup.11 is --C(O)NR.sup.12R.sup.13, wherein R.sup.12 and R.sup.13
are taken together with the nitrogen to which they are attached to
form a pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl,
thiomorpholinyl, isoquinolinyl, or dihydroisoquinolinyl ring,
wherein said pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl,
thiomorpholinyl, isoquinolinyl, or dihydroisoquinolinyl ring are
unsubstituted or substituted with 1 to 5 R.sup.5 substituents.
[0028] In still another embodiment of the compound of formula I,
R.sup.11 is --C(O)NR.sup.12R.sup.13, wherein R.sup.12 and R.sup.13
are taken together with the nitrogen to which they are attached to
form a pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, or
thiomorpholinyl ring, wherein said pyrrolidinyl, piperidinyl,
piperazinyl, morpholinyl, or thiomorpholinyl rings are
unsubstituted or substituted with 1 to 5 R.sup.5 substituents.
[0029] In still another embodiment of the compound of formula I,
R.sup.11 is --C(O)NR.sup.12R.sup.13, wherein R.sup.12 and R.sup.13
are taken together with the nitrogen to which they are attached to
form a pyrrolidinyl or piperidinyl ring, wherein said pyrrolidinyl
or piperidinyl ring are unsubstituted or substituted with 1 to 5
R.sup.5 substituents.
[0030] In still another embodiment of the compound of formula I,
R.sup.11 is --C(O)NR.sup.12R.sup.13, wherein R.sup.12 and R.sup.13
are taken together with the nitrogen to which they are attached to
form a pyrrolidinyl ring, wherein said pyrrolidinyl is
unsubstituted or substituted with 1 to 5 R.sup.5 substituents.
[0031] In still another embodiment of the compound of formula I,
R.sup.11 is --C(O)NR.sup.12R.sup.13, wherein R.sup.12 and R.sup.13
are taken together with the nitrogen to which they are attached to
form a pyrrolidin-1-yl ring, wherein said pyrrolidin-1-yl is
unsubstituted or substituted by 1 to 5 R.sup.5 substituents.
[0032] In still another embodiment of the compound of formula I,
R.sup.11 is --(CH.sub.2).sub.t(5 to 10 membered heterocyclic)
group, wherein said --(CH.sub.2).sub.t(5 to 10 membered
heterocyclic) group is unsubstituted or substituted by 1 to 5
R.sup.5 groups.
[0033] In still another embodiment of the compound of formula I,
R.sup.11 is --(CH.sub.2).sub.t(5-8 membered heterocyclic) group,
said --(CH.sub.2).sub.t(5-8 membered heterocyclic) group is
unsubstituted or substituted by 1 to 5 R.sup.5 groups.
[0034] In still another embodiment of the compound of formula I,
R.sup.11 is --(CH.sub.2).sub.t(5 or 6 membered heterocyclic) group,
said --(CH.sub.2).sub.t(5 or 6 membered heterocyclic) group is
unsubstituted or substituted by 1 to 5 R.sup.5 groups.
[0035] In still another embodiment of the compound of formula I,
R.sup.11 is --(CH.sub.2).sub.t(5 membered heterocyclic) group, said
--(CH.sub.2).sub.t(5 membered heterocyclic) group is unsubstituted
or substituted by 1 to 5 R.sup.5 groups.
[0036] In still another embodiment the compound of formula I,
R.sup.11 is --(CH.sub.2).sub.tthiazolyl, wherein t is an integer
from 0 to 6, said --(CH.sub.2).sub.tthiazolyl is unsubstituted or
substituted by 1 to 5 R.sup.5 groups.
[0037] In still another embodiment, the compound of formula I,
R.sup.11 is a thiazolyl, said thiazolyl is unsubstituted or
substituted by 1 to 5 R.sup.5 groups.
[0038] In still another embodiment, the compound of formula I,
R.sup.11 is an imidazolyl, said imidazolyl is unsubstituted or
substituted by 1 to 5 R.sup.5 groups.
[0039] The present invention also relates to compounds represented
by formula II: ##STR3##
[0040] wherein: [0041] Z is --O--, --S--, or --N--; [0042] R.sup.14
is a C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkylamino,
C.sub.1-C.sub.6 alkylhydroxy, C.sub.3-C.sub.10 cycloalkylamino, or
methylureido group; [0043] R.sup.15 and R.sup.17 are independently
H, halo, or a C.sub.1-C.sub.6 alkyl group; [0044] R.sup.16 is H or
a C.sub.1-C.sub.6 alkyl group when Z is N; and R.sup.16 is absent
when Z is --O-- or --S--; and wherein R.sup.11 are as defined for
said compounds, prodrug, metabolite, salt or solvate of formula I
or prodrugs or metabolites thereof, pharmaceutically acceptable
salts or solvates of said compounds, said prodrugs, and said
metabolites.
[0045] In one embodiment, R.sup.16 is methyl.
[0046] In another embodiment, R.sup.14 is methyl.
[0047] The present invention further relates to compounds
represented by the formula III: ##STR4##
[0048] wherein: [0049] R.sup.14 is a C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.6 alkylamino, C.sub.1-C.sub.6 alkylhydroxy,
C.sub.3-C.sub.10 cycloalkylamino, or methylureido group; [0050]
R.sup.15 and R.sup.17 are independently H or a C.sub.1-C.sub.6
alkyl group; and [0051] R.sup.11 is a heterocyclic or a heteroaryl
group unsubstituted or substituted by one or more groups selected
from --C(O)OR.sup.8, C.sub.1-C.sub.6 alkyl, and
--(CH.sub.2).sub.tOR.sup.9, wherein t is an integer from 0 to 6;
[0052] each R.sup.8 is independently selected from H,
C.sub.1-C.sub.10 alkyl, C.sub.3-C.sub.10 cycloalkyl,
--(CH.sub.2).sub.t(C.sub.6-C.sub.10 aryl), and --(CH.sub.2).sub.t(5
to 10 membered heterocyclic), wherein t is an integer from 0 to 6;
[0053] each R.sup.9 is independently selected from H,
C.sub.1-C.sub.6 alkyl, and C.sub.3-C.sub.10 cycloalkyl; or [0054]
prodrugs thereof, pharmaceutically acceptable salts or solvates of
said compounds and said prodrugs.
[0055] In another embodiment, the present invention is a compound
represented by the formula IV: ##STR5##
[0056] wherein: [0057] R.sup.14 is a C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.6 alkylamino, C.sub.1-C.sub.6 alkylhydroxy,
C.sub.3-C.sub.10 cycloalkylamino, or methylureido group; [0058]
R.sup.15 and R.sup.17 are independently H or a C.sub.1-C.sub.6
alkyl group; and [0059] R.sup.11 is a heterocyclic or a heteroaryl
group unsubstituted or substituted by one or more groups selected
from --C(O)OR.sup.8, C.sub.1-C.sub.6 alkyl, and
--(CH.sub.2).sub.tOR.sup.9, wherein t is an integer from 0 to 6;
[0060] each R.sup.8 is independently selected from H,
C.sub.1-C.sub.10 alkyl, C.sub.3-C.sub.10 cycloalkyl,
--(CH.sub.2).sub.t(C.sub.6-C.sub.10 aryl), and --(CH.sub.2).sub.t(5
to 10 membered heterocyclic), wherein t is an integer from 0 to 6;
[0061] each R.sup.9 is independently selected from H,
C.sub.1-C.sub.6 alkyl, and C.sub.3-C.sub.10 cycloalkyl; [0062] or
prodrugs or metabolites thereof, pharmaceutically acceptable salts
or solvates of said compounds, said prodrugs, and said
metabolites.
[0063] The above compounds of formulas II, III, and IV may be used
to prepare the above compounds represented by formula I.
[0064] In another embodiment, the present invention comprises
compounds selected from the group consisting of: ##STR6## ##STR7##
##STR8## ##STR9## ##STR10## ##STR11## [0065] prodrugs or
metabolites thereof, or pharmaceutically acceptable salts or
solvates of said compounds, said prodrugs, and said
metabolites.
[0066] Patients that can be treated with the compounds of formula
I, and prodrugs thereof, pharmaceutically acceptable salts or
solvates of said compounds and said prodrugs, according to the
methods of this invention include, for example, patients that have
been diagnosed as having psoriasis, BPH, lung cancer, eye cancer,
bone cancer, pancreatic cancer, skin cancer, cancer of the head and
neck, cutaneous or intraocular melanoma, uterine cancer, ovarian
cancer, rectal cancer, cancer of the anal region, stomach cancer,
colon cancer, breast cancer, gynecologic tumors (e.g., uterine
sarcomas, carcinoma of the fallopian tubes, carcinoma of the
endometrium, carcinoma of the cervix, carcinoma of the vagina or
carcinoma of the vulva), Hodgkin's disease, cancer of the
esophagus, cancer of the small intestine, cancer of the endocrine
system (e.g., cancer of the thyroid, parathyroid or adrenal
glands), sarcomas of soft tissues, cancer of the urethra, cancer of
the penis, prostate cancer, chronic or acute leukemia, solid tumors
of childhood, lymphocytic lymphonas, cancer of the bladder, cancer
of the kidney or ureter (e.g., renal cell carcinoma, carcinoma of
the renal pelvis), or neoplasms of the central nervous system
(e.g., primary CNS lymphona, spinal axis tumors, brain stem gliomas
or pituitary adenomas).
[0067] This invention also relates to pharmaceutical compositions
containing and methods for treating abnormal cell growth through
administering prodrugs of compounds of the formula I. Compounds of
formula I having free amino, amido, hydroxy or carboxylic groups
that can be converted into prodrugs.
[0068] The invention also relates to a pharmaceutical composition
for the treatment of a hyperproliferative disorder in a mammal
which comprises a therapeutically effective amount of a compound of
formula I, or prodrugs thereof, pharmaceutically acceptable salts
or solvates of said compounds and said prodrugs, and a
pharmaceutically acceptable carrier. In one embodiment, said
pharmaceutical composition is for the treatment of cancer such as
brain, lung, ophthalmic, squamous cell, bladder, gastric,
pancreatic, breast, head, neck, renal, kidney, ovarian, prostate,
colorectal, oesophageal, gynecological or thyroid cancer. In
another embodiment, said pharmaceutical composition is for the
treatment of a non-cancerous hyperproliferative disorder such as
benign hyperplasia of the skin (e.g., psoriasis) or prostate (e.g.,
benign prostatic hypertropy (BPH)).
[0069] The invention also relates to a pharmaceutical composition
for the treatment of pancreatitis or kidney disease (including
proliferative glomerulonephritis and diabetes-induced renal
disease) in a mammal which comprises a therapeutically effective
amount of a compound of formula I, or prodrugs thereof,
pharmaceutically acceptable salts or solvates of said compounds and
said prodrugs, and a pharmaceutically acceptable carrier.
[0070] The invention also relates to a pharmaceutical composition
for the prevention of blastocyte implantation in a mammal which
comprises a therapeutically effective amount of a compound of
formula I, or prodrugs thereof, pharmaceutically acceptable salts
or solvates of said compounds and said prodrugs, and a
pharmaceutically acceptable carrier.
[0071] The invention also relates to a pharmaceutical composition
for treating a disease related to vasculogenesis or angiogenesis in
a mammal which comprises a therapeutically effective amount of a
compound of formula I, or prodrugs thereof, pharmaceutically
acceptable salts or solvates of said compounds and said prodrugs,
and a pharmaceutically acceptable carrier. In one embodiment, said
pharmaceutical composition is for treating a disease selected from
the group consisting of tumor angiogenesis, chronic inflammatory
disease such as rheumatoid arthritis, atherosclerosis, skin
diseases such as psoriasis, excema, and scleroderma, diabetes,
diabetic retinopathy, retinopathy of prematurity, age-related
macular degeneration, hemangioma, glioma, melanoma, Kaposi's
sarcoma and ovarian, breast, lung, pancreatic, prostate, colon and
epidermoid cancer.
[0072] The invention also relates to a method of treating a
hyperproliferative disorder in a mammal which comprises
administering to said mammal a therapeutically effective amount of
the compound of formula I, or prodrugs thereof, pharmaceutically
acceptable salts or solvates of said compounds and said prodrugs.
In one embodiment, said method relates to the treatment of cancer
such as brain, ophthalmic, squamous cell, bladder, gastric,
pancreatic, breast, head, neck, oesophageal, prostate, colorectal,
lung, renal, kidney, ovarian, gynecological or thyroid cancer. In
another embodiment, said method relates to the treatment of a
non-cancerous hyperproliferative disorder such as benign
hyperplasia of the skin (e.g., psoriasis) or prostate (e.g., benign
prostatic hypertropy (BPH)).
[0073] The invention also relates to a method for the treatment of
a hyperproliferative disorder in a mammal which comprises
administering to said mammal a therapeutically effective amount of
a compound of formula I, or prodrugs thereof, pharmaceutically
acceptable salts or solvates of said compounds and said prodrugs,
in combination with an anti-tumor agent selected from the group
consisting of mitotic inhibitors, alkylating agents,
anti-metabolites, intercalating antibiotics, growth factor
inhibitors, cell cycle inhibitors, enzymes, topoisomerase
inhibitors, biological response modifiers, anti-hormones, and
anti-androgens.
[0074] The treatment of a hyperproliferative disorder in a mammal
which comprises administering to said mammal a therapeutically
effective amount of a VEGF receptor tyrosine kinase inhibitor may
lead to a sustained increase in blood pressure. The compounds of
the present invention may be used in conjunction with an
anti-hypertensive, such as NORVASC or PROCARDIA XL, commercially
available from Pfizer, for use in the treatment of a
hyperproliferative disorder in a mammal.
[0075] This invention also relates to a pharmaceutical composition
for treating a disease related to vasculogenesis or angiogenesis in
a mammal comprising a therapeutically effective amount of a
compound, prodrug, metabolite, salt or solvate of claim 1, a
therapeutically effective amount of a compound, prodrug,
metabolite, salt or solvate of an antihypertensive agent, and a
pharmaceutically acceptable carrier.
[0076] This invention also relates to a pharmaceutical composition
for inhibiting abnormal cell growth in a mammal, including a human,
comprising an amount of a compound of the formula I as defined
above, or prodrug thereof, pharmaceutically acceptable salt or
solvate of said compound and said prodrug, that is effective in
inhibiting farnesyl protein transferase, and a pharmaceutically
acceptable carrier.
[0077] This invention also relates to a pharmaceutical composition
for inhibiting abnormal cell growth in a mammal which comprises an
amount of a compound of formula I, or prodrug thereof,
pharmaceutically acceptable salt or solvate of said compound and
said prodrug, in combination with an amount of a chemotherapeutic,
wherein the amounts of the compound, salt, solvate, or prodrug, and
of the chemotherapeutic are together effective in inhibiting
abnormal cell growth. Many chemotherapeutics are presently known in
the art. In one embodiment, the chemotherapeutic is selected from
the group consisting of mitotic inhibitors, alkylating agents,
anti-metabolites, intercalating antibiotics, growth factor
inhibitors, cell cycle inhibitors, enzymes, topoisomerase
inhibitors, biological response modifiers, anti-hormones, e.g.
anti-androgens.
[0078] This invention further relates to a method for inhibiting
abnormal cell growth in a mammal which method comprises
administering to the mammal an amount of a compound of formula I,
or prodrug thereof, pharmaceutically acceptable salt or solvate of
said compound and said prodrug, in combination with radiation
therapy, wherein the amount of the compound, salt, solvate or
prodrug is in combination with the radiation therapy effective in
inhibiting abnormal cell growth in the mammal. Techniques for
administering radiation therapy are known in the art, and these
techniques can be used in the combination therapy described herein.
The administration of the compound of the invention in this
combination therapy can be determined as described herein.
[0079] It is believed that the compounds of formula I can render
abnormal cells more sensitive to treatment with radiation for
purposes of killing and/or inhibiting the growth of such cells.
Accordingly, this invention further relates to a method for
sensitizing abnormal cells in a mammal to treatment with radiation
which comprises administering to the mammal an amount of a compound
of formula I or prodrug thereof, pharmaceutically acceptable salt
or solvate of said compound and said prodrug, which amount is
effective in sensitizing abnormal cells to treatment with
radiation. The amount of the compound, salt, solvate or prodrug in
this method can be determined according to the means for
ascertaining effective amounts of such compounds described
herein.
[0080] This invention also relates to a method of and to a
pharmaceutical composition for inhibiting abnormal cell growth in a
mammal which comprises an amount of a compound of formula I, or
prodrug thereof, pharmaceutically acceptable salt or solvate of
said compound and said prodrug, or an isotopically-labelled
derivative thereof, and an amount of one or more substances
selected from anti-angiogenesis agents, signal transduction
inhibitors, and antiproliferative agents.
[0081] Anti-angiogenesis agents, such as MMP-2
(matrix-metalloprotienase 2) inhibitors, MMP-9
(matrix-metalloprotienase 9) inhibitors, and COX-II (cyclooxygenase
II) inhibitors, can be used in conjunction with a compound of
formula 1 and pharmaceutical compositions described herein.
Examples of useful COX-II inhibitors include CELEBREX.TM.
(alecoxib), valdecoxib, and rofecoxib. Examples of useful matrix
metalloproteinase inhibitors are described in WO 96/33172
(published Oct. 24, 1996), WO 96/27583 (published Mar. 7, 1996),
European Patent Application No. 97304971.1 (filed Jul. 8, 1997),
European Patent Application No. 99308617.2 (filed Oct. 29, 1999),
WO 98/07697 (published Feb. 26, 1998), WO 98/03516 (published Jan.
29, 1998), WO 98/34918 (published Aug. 13, 1998), WO 98/34915
(published Aug. 13, 1998), WO 98/33768 (published Aug. 6, 1998), WO
98/30566 (published Jul. 16, 1998), European Patent Publication
606,046 (published Jul. 13, 1994), European Patent Publication
931,788 (published Jul. 28, 1999), WO 90/05719 (published May 31,
1990), WO 99/52910 (published Oct. 21, 1999), WO 99/52889
(published Oct. 21, 1999), WO 99/29667 (published Jun. 17, 1999),
PCT International Application No. PCT/IB98/01113 (filed Jul. 21,
1998), European Patent Application No. 99302232.1 (filed Mar. 25,
1999), Great Britain patent application number 9912961.1 (filed
Jun. 3, 1999), U.S. Provisional Application No. 60/148,464 (filed
Aug. 12, 1999), U.S. Pat. No. 5,863,949 (issued Jan. 26, 1999),
U.S. Pat. No. 5,861,510 (issued Jan. 19, 1999), and European Patent
Publication 780,386 (published Jun. 25, 1997), all of which are
incorporated herein in their entireties by reference. Preferred
MMP-2 and MMP-9 inhibitors are those that have little or no
activity inhibiting MMP-1. More preferred, are those that
selectively inhibit MMP-2 and/or MMP-9 relative to the other
matrix-metalloproteinases (i.e. MMP-1, MMP-3, MMP-4, MMP-5, MMP-6,
MMP-7, MMP-8, MMP-10, MMP-11, MMP-12, and MMP-13).
[0082] Some specific examples of MMP inhibitors useful in the
present invention are Prinomastat, RO 32-3555, RS 13-0830, and the
compounds recited in the following list:
3-[[4-(4-fluoro-phenoxy)-benzenesulfonyl]-(1-hydroxycarbamoyl-cyclopentyl-
)-amino]-propionic acid;
3-exo-3-[4-(4-fluoro-phenoxy)-benzenesulfonylamino]-8-oxa-bicyclo[3.2.1]o-
ctane-3-carboxylic acid hydroxyamide; (2R,3R)
1-[4-(2-chloro-4-fluoro-benzyloxy)-benzenesulfonyl]-3-hydroxy-3-methyl-pi-
peridine-2-carboxylic acid hydroxyamide;
4-[4-(4-fluoro-phenoxy)-benzenesulfonylamino]-tetrahydro-pyran-4-carboxyl-
ic acid hydroxyamide;
3-[[4-(4-fluoro-phenoxy)-benzenesulfonyl]-(1-hydroxycarbamoyl-cyclobutyl)-
-amino]-propionic acid;
4-[4-(4-chloro-phenoxy)-benzenesulfonylamino]-tetrahydro-pyran-4-carboxyl-
ic acid hydroxyamide; (R)
3-[4-(4-chloro-phenoxy)-benzenesulfonylamino]-tetrahydro-pyran-3-carboxyl-
ic acid hydroxyamide; (2R,3R)
1-[4-(4-fluoro-2-methyl-benzyloxy)-benzenesulfonyl]-3-hydroxy-3-methyl-pi-
peridine-2-carboxylic acid hydroxyamide;
3-[[4-(4-fluoro-phenoxy)-benzenesulfonyl]-(1-hydroxycarbamoyl-1-methyl-et-
hyl)-amino]-propionic acid;
3-[[4-(4-fluoro-phenoxy)-benzenesulfonyl]-(4-hydroxycarbamoyl-tetrahydro--
pyran-4-yl)-amino]-propionic acid;
3-exo-3-[4-(4-chloro-phenoxy)-benzenesulfonylamino]-8-oxa-bicyclo[3.2.1]o-
ctane-3-carboxylic acid hydroxyamide;
3-endo-3-[4-(4-fluoro-phenoxy)-benzenesulfonylamino]-8-oxa-bicyclo[3.2.1]-
octane-3-carboxylic acid hydroxyamide; and (R)
3-[4-(4-fluoro-phenoxy)-benzenesulfonylamino]-tetrahydro-furan-3-carboxyl-
ic acid hydroxyamide;
and pharmaceutically acceptable salts and solvates of said
compounds. Other anti-angiogenesis agents, including other COX-II
inhibitors and other MMP inhibitors, can also be used in the
present invention.
[0083] This invention further releates to a method for treating a
disease related to vasculogenesis or angiogenesis in a mammal
comprising administering to said mammal a therapeutically effective
amount of a compound, prodrug, metabolite, salt or solvate of claim
1 in conjunction with a therapeutically effective amount of an
anti-hypertensive agent.
[0084] A compound of formula I, can also be used with signal
transduction inhibitors, such as agents that can inhibit EGFR
(epidermal growth factor receptor) responses, such as EGFR
antibodies, EGF antibodies, and molecules that are EGFR inhibitors;
VEGF (vascular endothelial growth factor) inhibitors, such as VEGF
receptors and molecules that can inhibit VEGF; and erbB2 receptor
inhibitors, such as organic molecules or antibodies that bind to
the erbB2 receptor, for example, HERCEPTIN.TM. (Genentech, Inc. of
South San Francisco, Calif., USA).
[0085] EGFR inhibitors are described in, for example in WO 95/19970
(published Jul. 27, 1995), WO 98/14451 (published Apr. 9, 1998), WO
98/02434 (published Jan. 22, 1998), and U.S. Pat. No. 5,747,498
(issued May 5, 1998), and such substances can be used in the
present invention as described herein. EGFR-inhibiting agents
include, but are not limited to, the monoclonal antibodies C225 and
anti-EGFR 22Mab (ImClone Systems Incorporated of New York, N.Y.,
USA), the compounds ZD-1839 (AstraZeneca), BIBX-1382 (Boehringer
Ingelheim), MDX-447 (Medarex Inc. of Annandale, N.J., USA), and
OLX-103 (Merck & Co. of Whitehouse Station, N.J., USA),
VRCTC-310 (Ventech Research) and EGF fusion toxin (Seragen Inc. of
Hopkinton, Mass.). These and other EGFR-inhibiting agents can be
used in the present invention.
[0086] VEGF inhibitors, for example SU-5416 and SU-6668 (Sugen Inc.
of South San Francisco, Calif., USA), can also be combined with the
compound of the present invention. VEGF inhibitors are described
in, for example in WO 99/24440 (published May 20, 1999), PCT
International Application PCT/IB99/00797 (filed May 3, 1999), in WO
95/21613 (published Aug. 17, 1995), WO 99/61422 (published Dec. 2,
1999), U.S. Pat. No. 5,834,504 (issued Nov. 10, 1998), WO 98/50356
(published Nov. 12, 1998), U.S. Pat. No. 5,883,113 (issued Mar. 16,
1999), U.S. Pat. No. 5,886,020 (issued Mar. 23, 1999), U.S. Pat.
No. 5,792,783 (issued Aug. 11, 1998), WO 99/10349 (published Mar.
4, 1999), WO 97/32856 (published Sep. 12, 1997), WO 97/22596
(published Jun. 26, 1997), WO 98/54093 (published Dec. 3, 1998), WO
98/02438 (published Jan. 22, 1998), WO 99/16755 (published Apr. 8,
1999), and WO 98/02437 (published Jan. 22, 1998), all of which are
incorporated herein in their entireties by reference. Other
examples of some specific VEGF inhibitors useful in the present
invention are IM862 (Cytran Inc. of Kirkland, Wash., USA);
anti-VEGF monoclonal antibody of Genentech, Inc. of South San
Francisco, Calif.; and angiozyme, a synthetic ribozyme from
Ribozyme (Boulder, Colo.) and Chiron (Emeryville, Calif.). These
and other VEGF inhibitors can be used in the present invention as
described herein.
[0087] ErbB2 receptor inhibitors, such as GW-282974 (Glaxo Wellcome
plc), and the monoclonal antibodies AR-209 (Aronex Pharmaceuticals
Inc. of The Woodlands, Tex., USA) and 2B-1 (Chiron), can
furthermore be combined with the compound of the invention, for
example those indicated in WO 98/02434 (published Jan. 22, 1998),
WO 99/35146 (published Jul. 15, 1999), WO 99/35132 (published Jul.
15, 1999), WO 98/02437 (published Jan. 22, 1998), WO 97/13760
(published Apr. 17, 1997), WO 95/19970 (published Jul. 27, 1995),
U.S. Pat. No. 5,587,458 (issued Dec. 24, 1996), and U.S. Pat. No.
5,877,305 (issued Mar. 2, 1999), which are all hereby incorporated
herein in their entireties by reference. ErbB2 receptor inhibitors
useful in the present invention are also described in U.S.
Provisional Application No. 60/117,341, filed Jan. 27, 1999, and in
U.S. Provisional Application No. 60/117,346, filed Jan. 27, 1999,
both of which are incorporated in their entireties herein by
reference. The erbB2 receptor inhibitor compounds and substance
described in the aforementioned PCT applications, U.S. patents, and
U.S. provisional applications, as well as other compounds and
substances that inhibit the erbB2 receptor, can be used with the
compounds of the present invention.
[0088] The compounds of the invention can also be used with other
agents useful in treating abnormal cell growth or cancer,
including, but not limited to, agents capable of enhancing
antitumor immune responses, such as CTLA4 (cytotoxic lymphocyte
antigen 4) antibodies, and other agents capable of blocking CTLA4;
and anti-proliferative agents such as other farnesyl protein
transferase inhibitors, and the like. Specific CTLA4 antibodies
that can be used in the present invention include those described
in U.S. Provisional Application 60/113,647 (filed Dec. 23, 1998)
that is incorporated by reference in its entirety, however other
CTLA4 antibodies can be used in the present invention.
[0089] The subject invention also includes isotopically-labelled
compounds, which are identical to those recited in formula I, but
for the fact that one or more atoms are replaced by an atom having
an atomic mass or mass number different from the atomic mass or
mass number usually found in nature. Examples of isotopes that can
be incorporated into compounds of the invention include isotopes of
hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine and
chlorine, such as .sup.2H, .sup.3H, .sup.13C, .sup.14C, .sup.15N,
.sup.18O, .sup.17O, .sup.31P, .sup.32P, .sup.35S, .sup.18F, and
.sup.36Cl, respectively. Compounds of the present invention,
prodrugs thereof, and pharmaceutically acceptable salts of said
compounds or of said prodrugs which contain the aforementioned
isotopes and/or other isotopes of other atoms are within the scope
of this invention. Certain isotopically-labelled compounds of the
present invention, for example those into which radioactive
isotopes such as .sup.3H and .sup.14C are incorporated, are useful
in drug and/or substrate tissue distribution assays. Tritiated,
i.e., .sup.3H, and carbon-14, i.e., .sup.14C, isotopes are
particularly preferred for their ease of preparation and
detectability. Further, substitution with heavier isotopes such as
deuterium, i.e., .sup.2H, can afford certain therapeutic advantages
resulting from greater metabolic stability, for example increased
in vivo half-life or reduced dosage requirements and, hence, may be
preferred in some circumstances. Isotopically labelled compounds of
formula I, II, III, or IV of this invention and prodrugs thereof
can generally be prepared by carrying out the procedures disclosed
in the Schemes and/or in the Examples below, by substituting a
readily available isotopically labelled reagent for a
non-isotopically labelled reagent. The compounds of formula I and
their pharmaceutically acceptable salts and solvates can each
independently also be used in a palliative neo-adjuvant/adjuvant
therapy in alleviating the symptoms associated with the diseases
recited herein as well as the symptoms associated with abnormal
cell growth. Such therapy can be a monotherapy or can be in a
combination with chemotherapy and/or immunotherapy.
[0090] The terms "abnormal cell growth" and "hyperproliferative
disorder" are used interchangeably in this application.
[0091] "Abnormal cell growth", as used herein, refers to cell
growth that is independent of normal regulatory mechanisms (e.g.,
loss of contact inhibition), including the abnormal growth of
normal cells and the growth of abnormal cells. This includes, but
is not limited to, the abnormal growth of: (1) tumor cells
(tumors), both benign and malignant, expressing an activated Ras
oncogene; (2) tumor cells, both benign and malignant, in which the
Ras protein is activated as a result of oncogenic mutation in
another gene; (3) benign and malignant cells of other proliferative
diseases in which aberrant Ras activation occurs. Examples of such
benign proliferative diseases are psoriasis, benign prostatic
hypertrophy, human papilloma virus (HPV), and restinosis. "Abnormal
cell growth" also refers to and includes the abnormal growth of
cells, both benign and malignant, resulting from activity of the
enzyme farnesyl protein transferase.
[0092] The term "treating", as used herein, unless otherwise
indicated, means reversing, alleviating, inhibiting the progress
of, or preventing the disorder or condition to which such term
applies, or one or more symptoms of such disorder or condition. The
term "treatment", as used herein, refers to the act of treating, as
"treating" is defined immediately above.
[0093] The term "halo", as used herein, unless otherwise indicated,
means fluoro, chloro, bromo or iodo. Preferred halo groups are
fluoro, chloro and bromo.
[0094] The term "alkyl", as used herein, unless otherwise
indicated, means saturated monovalent hydrocarbon radicals having
straight, cyclic or branched moieties. Said "alkyl" group may
include an optional carbon-carbon double or triple bond where said
alkyl group comprises at least two carbon atoms. It is understood
that for cyclic moieties at least three carbon atoms are required
in said alkyl group.
[0095] The term "alkoxy", as used herein, unless otherwise
indicated, means O-alkyl groups wherein "alkyl" is as defined
above.
[0096] The term "aryl", as used herein, unless otherwise indicated,
means an organic radical derived from an aromatic hydrocarbon by
removal of one hydrogen, such as phenyl or naphthyl.
[0097] The term "hetero cyclic group", as used herein, includes
aromatic and non-aromatic heterocyclic groups. Unless otherwise
indicated, preferred heterocyclic groups include groups having from
3 to 13 ring atoms, more preferably from 5 to 10 ring atoms, and
still more preferably from 5 to 6 ring atoms. In addition,
preferred heterocyclic groups include groups containing one to four
heteroatoms each selected from O, S and N. The heterocyclic groups
include benzo-fused ring systems and ring systems substituted with
one or two oxo (.dbd.O) moieties such as pyrrolidin-2-one. An
example of a 5 membered heterocyclic group is thiazolyl, an example
of a 10 membered heterocyclic group is quinolinyl, and an example
of a 13 membered heterocyclic group is a carbazole group. Examples
of non-aromatic heterocyclic groups include pyrrolidinyl,
piperidino, morpholino, thiomorpholino and piperazinyl. Examples of
aromatic heterocyclic groups include pyridinyl, imidazolyl,
pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl,
thienyl, isoxazolyl and thiazolyl. Heterocyclic groups having a
fused benzene ring include benzimidazolyl, benzofuranyl, and
benzo[1,3]dioxolyl.
[0098] The phrase "pharmaceutically acceptable salt(s)", as used
herein, unless otherwise indicated, means salts of acidic or basic
groups which may be present in the compounds or prodrugs of formula
I. The compounds and prodrugs of formula I that are basic in nature
are capable of forming a wide variety of salts with various
inorganic and organic acids. The acids that may be used to prepare
pharmaceutically acceptable acid addition salts of such basic
compounds and prodrugs of formula I are those that form non-toxic
acid addition salts, i.e., salts containing pharmacologically
acceptable anions, such as the hydrochloride, hydrobromide,
hydroiodide, nitrate, sulfate, bisulfate, phosphate, acid
phosphate, isonicotinate, acetate, lactate, salicylate, citrate,
acid citrate, tartrate, pantothenate, bitartrate, ascorbate,
succinate, maleate, gentisinate, fumarate, gluconate, glucaronate,
saccharate, formate, benzoate, glutamate, methanesulfonate,
ethanesulfonate, benzenesulfonate, p-toluenesulfonate and pamoate
[i.e., 1,1'-methylene-bis-(2-hydroxy-3-naphthoate)] salts.
[0099] Those compounds and prodrugs of the formulas I that are
acidic in nature, are capable of forming base salts with various
pharmacologically acceptable cations. Examples of such salts
include the alkali metal or alkaline earth metal salts and
particularly, the sodium and potassium salts.
[0100] The compounds of the present invention may have asymmetric
carbon atoms. Such diasteromeric mixtures can be separated into
their individual diastereomers on the basis of their physical
chemical differences by methods known to those skilled in the art,
for example, by chromatography or fractional crystallization.
Enantiomers can be separated by converting the enantiomeric
mixtures into a diastereomeric mixture by reaction with an
appropriate optically active compound (e.g., alcohol), separating
the diastereomers and converting (e.g., hydrolyzing) the individual
diastereomers to the corresponding pure enantiomers. All such
isomers, including diastereomer mixtures and pure enantiomers are
considered as part of the invention.
[0101] The compounds of present invention may in certain instances
exist as tautomers. This invention relates to the use of all such
tautomers and mixtures thereof.
[0102] The term "prodrug", as used herein, unless otherwise
indicated, means compounds that are drug precursors, which
following administration, release the drug in vivo via some
chemical or physiological process (e.g., a prodrug on being brought
to the physiological pH is converted to the desired drug form).
[0103] Prodrugs include compounds wherein an amino acid residue, or
a polypeptide chain of two or more (e.g., two, three or four) amino
acid residues is covalently joined through an amide or ester bond
to a free amino, hydroxy or carboxylic acid group of compounds of
formula I. The amino acid residues include but are not limited to
the 20 naturally occurring amino acids commonly designated by three
letter symbols and also includes 4-hydroxyproline, hydroxylysine,
demosine, isodemosine, 3-methylhistidine, norvalin, beta-alanine,
gamma-aminobutyric acid, citrulline homocysteine, homoserine,
ornithine and methionine sulfone. Additional types of prodrugs are
also encompassed. For instance, free carboxyl groups can be
derivatized as amides or alkyl esters. Free hydroxy groups may be
derivatized using groups including but not limited to
hemisuccinates, phosphate esters, dimethylaminoacetates, and
phosphoryloxymethyloxycarbonyls, as outlined in Advanced Drug
Delivery Reviews, 1996, 19, 115. Carbamate prodrugs of hydroxy and
amino groups are also included, as are carbonate prodrugs,
sulfonate esters and sulfate esters of hydroxy groups.
Derivatization of hydroxy groups as (acyloxy)methyl and
(acyloxy)ethyl ethers wherein the acyl group may be an alkyl ester,
optionally substituted with groups including but not limited to
ether, amine and carboxylic acid functionalities, or where the acyl
group is an amino acid ester as described above, are also
encompassed. Prodrugs of this type are described in J. Med. Chem.
1996, 39, 10. Free amines can also be derivatized as amides,
sulfonamides or phosphonamides. All of these prodrug moieties may
incorporate groups including but not limited to ether, amine and
carboxylic acid functionalities.
[0104] It will be appreciated that any solvate (e.g. hydrate) form
of compounds of formula I and prodrugs thereof can be used for the
purpose of the present invention.
[0105] The terms "comprising" and "including" are used herein in
their open, non-limiting sense.
[0106] The term "alkyl" as used herein refers to straight- and
branched-chain alkyl groups having from one to twelve carbon atoms,
preferably from 1 to 6 carbons, and more preferably from 1 to 3
carbons. Exemplary alkyl groups include methyl (Me), ethyl,
n-propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl (tBu),
pentyl, isopentyl, tert-pentyl, hexyl, isohexyl, and the like.
[0107] The term "heteroalkyl" as used herein refers to straight-
and branched-chain alkyl groups containing one or more heteroatoms
selected from S, O, and N.
[0108] The term "alkenyl" refers to straight- and branched-chain
alkenyl groups having from two to twelve carbon atoms, preferably
from 2 to 6 carbons, and more preferably from 2 to 4 carbons.
Illustrative alkenyl groups include prop-2-enyl, but-2-enyl,
but-3-enyl, 2-methylprop-2-enyl, hex-2-enyl, and the like.
[0109] The term "alkynyl" refers to straight- and branched-chain
alkynyl groups having from two to twelve carbon atoms, preferably
from 2 to 6 carbons, and more preferably from 2 to 4 carbons.
Illustrative alkynyl groups include prop-2-ynyl, but-2-ynyl,
but-3-ynyl, 2-methylbut-2-ynyl, hex-2-ynyl, and the like.
[0110] The term "aryl" (Ar) refers to monocyclic and polycyclic
aromatic ring structures containing only carbon and hydrogen.
Preferred aryl groups have from 4 to 20 ring atoms, and more
preferably from 6 to 14 ring atoms. Illustrative examples of aryl
groups include the following moieties: ##STR12## and the like.
[0111] The term "heteroaryl" (heteroAr) refers to an aryl group
that includes one or more ring heteroatoms selected from nitrogen,
oxygen and sulfur. The polycyclic heteroaryl group may be fused or
non-fused. Illustrative examples of aryl groups include the
following moieties: ##STR13## and the like.
[0112] The term "cycloalkyl" refers to a monocyclic or polycyclic
radical which contain only carbon and hydrogen, and may be
saturated, partially unsaturated, or fully unsaturated. Preferred
cycloalkyl groups include groups having from three to twelve ring
atoms, more preferably from 5 to 10 ring atoms, and still more
preferably from 5 to 6 ring atoms. Illustrative examples of
cycloalkyl groups include the following moieties: ##STR14## and
compounds of the like.
[0113] A "heterocycloalkyl" group refers to a cycloalkyl group that
includes at least one heteroatom selected from nitrogen, oxygen and
sulfur. The radicals may be fused with an aryl or heteroaryl.
Illustrative examples of heterocycloalkyl groups include ##STR15##
and the like.
[0114] The term "heterocyclic" comprises both heterocycloalkyl and
heteroaryl groups.
[0115] The term "alkoxy" refers to the radical --O--R where R is an
alkyl as defined above. Examples of alkoxy groups include methoxy,
ethoxy, propoxy, and the like.
[0116] The term "halogen" represents chlorine, fluorine, bromine or
iodine. The term "halo" represents chloro, fluoro, bromo or
iodo.
[0117] The term "alcohol" refers to the radical --R--OH where R is
alkyl, alkenyl, alkynyl, Ar, heteroaryl, heterocycloalkyl, or
cycloalkyl as defined above. Examples of alcohols include methanol,
ethanol, propanol, phenol and the like.
[0118] The term "acyl" represents --C(O)R, --C(O)OR, --OC(O)R or
--OC(O)OR where R is alkyl, alkenyl, alkynyl, Ar, heteroaryl,
heterocycloalkyl, or cycloalkyl as defined as above.
[0119] The term "amide" refers to the radical --C(O)N(R')(R'')
where R' and R'' are each independently selected from hydrogen,
alkyl, alkenyl, alkynyl, --OH, alkoxy, cycloalkyl,
heterocycloalkyl, heteroaryl, aryl as defined above; or R' and R''
cyclize together with the nitrogen to form a heterocycloalkyl or
heteroaryl as defined above.
[0120] The term "substituted" as used herein means that the group
in question, e.g., alkyl group, etc., may bear one or more
substituents.
[0121] The alkyl, cycloalkyl, aryl, heterocycloalkyl and heteroaryl
groups and the substituents containing these groups, as defined
hereinabove, may be optionally substituted by at least one other
substituent. The term "optionally substituted" is intended to
expressly indicate that the specified group is unsubstituted or
substituted by one or more substituents as defined herein. Various
groups may be unsubstituted or substituted (i.e., they are
optionally substituted) as indicated.
[0122] If the substituents themselves are not compatible with the
synthetic methods of this invention, the substituent may be
protected with a suitable protecting group that is stable to the
reaction conditions used in these methods. The protecting group may
be removed at a suitable point in the reaction sequence of the
method to provide a desired intermediate or target compound.
Suitable protecting groups and the methods for protecting and
de-protecting different substituents using such suitable protecting
groups are well known to those skilled in the art; examples of
which may be found in T. Greene and P. Wuts, Protecting Groups in
Chemical Synthesis (3rd ed.), John Wiley & Sons, NY (1999),
which is incorporated herein by reference in its entirety. In some
instances, a substituent may be specifically selected to be
reactive under the reaction conditions used in the methods of this
invention. Under these circumstances, the reaction conditions
convert the selected substituent into another substituent that is
either useful in an intermediate compound in the methods of this
invention or is a desired substituent in a target compound.
[0123] Some of the inventive compounds may exist in various
stereoisomeric or tautomeric forms. The present invention
encompasses all such cell proliferation-inhibiting compounds,
including active compounds in the form of single pure enantiomers
(i.e., essentially free of other stereoisomers), racemates,
mixtures of enantiomers and/or diastereomers, and/or tautomers.
Preferably, the inventive compounds that are optically active are
used in optically pure form.
[0124] As generally understood by those skilled in the art, an
optically pure compound having one chiral center (i.e., one
asymmetric carbon atom) is one that consists essentially of one of
the two possible enantiomers (i.e., is enantiomerically pure), and
an optically pure compound having more than one chiral center is
one that is both diastereomerically pure and enantiomerically
pure.
[0125] Preferably, the compounds of the present invention are used
in a form that is at least 90% optically pure, that is, a form that
contains at least 90% of a single isomer (80% enantiomeric excess
("e.e.") or diastereomeric excess ("d.e.")), more preferably at
least 95% (90% e.e. or d.e.), even more preferably at least 97.5%
(95% e.e. or d.e.), and most preferably at least 99% (98% e.e. or
d.e.).
[0126] Additionally, the formulae are intended to cover solvated as
well as unsolvated forms of the identified structures. For example,
Formula I includes compounds of the indicated structure in both
hydrated and non-hydrated forms. Additional examples of solvates
include the structures in combination with isopropanol, ethanol,
methanol, DMSO, ethyl acetate, acetic acid, or ethanolamine.
[0127] In addition to compounds of Formula I, the invention
includes pharmaceutically acceptable prodrugs, pharmaceutically
active metabolites, and pharmaceutically acceptable salts of such
compounds and metabolites.
[0128] The term "pharmaceutically acceptable" means
pharmacologically acceptable and substantially non-toxic to the
subject being administered the agent.
[0129] "A pharmaceutically acceptable prodrug" is a compound that
may be converted under physiological conditions or by solvolysis to
the specified compound or to a pharmaceutically acceptable salt of
such compound. "A pharmaceutically active metabolite" is intended
to mean a pharmacologically active product produced through
metabolism in the body of a specified compound or salt thereof.
Prodrugs and active metabolites of a compound may be identified
using routine techniques known in the art. See, e.g., Bertolini et
al., J. Med. Chem., 40, 2011-2016 (1997); Shan et al., J. Pharm.
Sci., 86 (7), 765-767; Bagshawe, Drug Dev. Res., 34, 220-230
(1995); Bodor, Advances in Drug Res., 13, 224-331 (1984);
Bundgaard, Design of Prodrugs (Elsevier Press 1985); and Larsen,
Design and Application of Prodrugs, Drug Design and Development
(Krogsgaard-Larsen et al., eds., Harwood Academic Publishers,
1991).
[0130] "A pharmaceutically acceptable salt" is intended to mean a
salt that retains the biological effectiveness of the free acids
and bases of the specified compound and that is not biologically or
otherwise undesirable. A compound of the invention may possess a
sufficiently acidic, a sufficiently basic, or both functional
groups, and accordingly react with any of a number of inorganic or
organic bases, and inorganic and organic acids, to form a
pharmaceutically acceptable salt. Exemplary pharmaceutically
acceptable salts include those salts prepared by reaction of the
compounds of the present invention with a mineral or organic acid
or an inorganic base, such as salts including sulfates,
pyrosulfates, bisulfates, sulfites, bisulfites, phosphates,
monohydrogenphosphates, dihydrogenphosphates, metaphosphates,
pyrophosphates, chlorides, bromides, iodides, acetates,
propionates, decanoates, caprylates, acrylates, formates,
isobutyrates, caproates, heptanoates, propiolates, oxalates,
malonates, succinates, suberates, sebacates, fumarates, maleates,
butyne-1,4-dioates, hexyne-1,6-dioates, benzoates, chlorobenzoates,
methylbenzoates, dinitrobenzoates, hydroxybenzoates,
methoxybenzoates, phthalates, sulfonates, xylenesulfonates,
phenylacetates, phenylpropionates, phenylbutyrates, citrates,
lactates, .gamma.-hydroxybutyrates, glycolates, tartrates,
methane-sulfonates, propanesulfonates, naphthalene-1-sulfonates,
naphthalene-2-sulfonates, and mandelates.
[0131] If the inventive compound is a base, the desired
pharmaceutically acceptable salt may be prepared by any suitable
method available in the art, for example, treatment of the free
base with an inorganic acid, such as hydrochloric acid, hydrobromic
acid, sulfuric acid, sulfamic acid, nitric acid, phosphoric acid
and the like, or with an organic acid, such as acetic acid,
phenylacetic acid, propionic acid, stearic acid, lactic acid,
ascorbic acid, maleic acid, hydroxymaleic acid, isethionic acid,
succinic acid, mandelic acid, fumaric acid, malonic acid, pyruvic
acid, oxalic acid, glycolic acid, salicylic acid, a pyranosidyl
acid, such as glucuronic acid or galacturonic acid, an
alpha-hydroxy acid, such as citric acid or tartaric acid, an amino
acid, such as aspartic acid or glutamic acid, an aromatic acid,
such as benzoic acid, 2-acetoxybenzoic acid or cinnamic acid, a
sulfonic acid, such as p-toluenesulfonic acid, methanesulfonic acid
or ethanesulfonic acid, or the like.
[0132] If the inventive compound is an acid, the desired
pharmaceutically acceptable salt may be prepared by any suitable
method, for example, treatment of the free acid with an inorganic
or organic base, such as an amine (primary, secondary or tertiary),
an alkali metal hydroxide or alkaline earth metal hydroxide, or the
like. Illustrative examples of suitable salts include organic salts
derived from amino acids, such as glycine and arginine, ammonia,
carbonates, bicarbonates, primary, secondary, and tertiary amines,
and cyclic amines, such as benzylamines, pyrrolidines, piperidine,
morpholine and piperazine, and inorganic salts derived from sodium,
calcium, potassium, magnesium, manganese, iron, copper, zinc,
aluminum and lithium.
[0133] Pharmaceutical compositions according to the invention may,
alternatively or in addition to a compound of Formula I, comprise
as an active ingredient pharmaceutically acceptable prodrugs,
pharmaceutically active metabolites, and pharmaceutically
acceptable salts of such compounds and metabolites. Such compounds,
prodrugs, multimers, salts, and metabolites are sometimes referred
to herein collectively as "active agents" or "agents."
[0134] In the case of agents that are solids, it is understood by
those skilled in the art that the inventive compounds and salts may
exist in different crystal or polymorphic forms, all of which are
intended to be within the scope of the present invention and
specified formulas.
[0135] Therapeutically effective amounts of the active agents of
the invention may be used to treat diseases mediated by modulation
or regulation of protein kinases. An "effective amount" is intended
to mean that amount of an agent that significantly inhibits
proliferation and/or prevents de-differentiation of a eukaryotic
cell, e.g., a mammalian, insect, plant or fungal cell, and is
effective for the indicated utility, e.g., specific therapeutic
treatment.
[0136] The amount of a given agent that will correspond to such an
amount will vary depending upon factors such as the particular
compound, disease condition and its severity, the identity (e.g.,
weight) of the subject or host in need of treatment, but can
nevertheless be routinely determined in a manner known in the art
according to the particular circumstances surrounding the case,
including, e.g., the specific agent being administered, the route
of administration, the condition being treated, and the subject or
host being treated. "Treating" is intended to mean at least the
mitigation of a disease condition in a subject such as mammal
(e.g., human), that is affected, at least in part, by the activity
of one or more kinases, for example protein kinases such as
tyrosine kinases, and includes: preventing the disease condition
from occurring in a mammal, particularly when the mammal is found
to be predisposed to having the disease condition but has not yet
been diagnosed as having it; modulating and/or inhibiting the
disease condition; and/or alleviating the disease condition.
[0137] Agents that potently regulate, modulate, or inhibit cell
proliferation are preferred. For certain mechanisms, inhibition of
the protein kinase activity associated with CDK complexes, among
others, and those which inhibit angiogenesis and/or inflammation
are preferred. The present invention is further directed to methods
of modulating or inhibiting protein kinase activity, for example in
mammalian tissue, by administering an inventive agent. The activity
of agents as anti-proliferatives is easily measured by known
methods, for example by using whole cell cultures in an MTT assay.
The activity of the inventive agents as modulators of protein
kinase activity, such as the activity of kinases, may be measured
by any of the methods available to those skilled in the art,
including in vivo and/or in vitro assays. Examples of suitable
assays for activity measurements include those described in
International Publication No. WO 99/21845; Parast et al.,
Biochemistry, 37, 16788-16801 (1998); Connell-Crowley and Harpes,
Cell Cycle: Materials and Methods, (Michele Pagano, ed. Springer,
Berlin, Germany)(1995); International Publication No. WO 97/34876;
and International Publication No. WO 96/14843. These properties may
be assessed, for example, by using one or more of the biological
testing procedures set out in the examples below.
[0138] The active agents of the invention may be formulated into
pharmaceutical compositions as described below. Pharmaceutical
compositions of this invention comprise an effective modulating,
regulating, or inhibiting amount of a compound of Formula I or
Formula II and an inert, pharmaceutically acceptable carrier or
diluent. In one embodiment of the pharmaceutical compositions,
efficacious levels of the inventive agents are provided so as to
provide therapeutic benefits involving anti-proliferative ability.
By "efficacious levels" is meant levels in which proliferation is
inhibited, or controlled. These compositions are prepared in
unit-dosage form appropriate for the mode of administration, e.g.,
parenteral or oral administration.
[0139] An inventive agent can be administered in conventional
dosage form prepared by combining a therapeutically effective
amount of an agent (e.g., a compound of Formula I) as an active
ingredient with appropriate pharmaceutical carriers or diluents
according to conventional procedures. These procedures may involve
mixing, granulating and compressing or dissolving the ingredients
as appropriate to the desired preparation.
[0140] The pharmaceutical carrier employed may be either a solid or
liquid. Exemplary of solid carriers are lactose, sucrose, talc,
gelatin, agar, pectin, acacia, magnesium stearate, stearic acid and
the like. Exemplary of liquid carriers are syrup, peanut oil, olive
oil, water and the like. Similarly, the carrier or diluent may
include time-delay or time-release material known in the art, such
as glyceryl monostearate or glyceryl distearate alone or with a
wax, ethylcellulose, hydroxypropylmethylcellulose,
methylmethacrylate and the like.
[0141] A variety of pharmaceutical forms can be employed. Thus, if
a solid carrier is used, the preparation can be tableted, placed in
a hard gelatin capsule in powder or pellet form or in the form of a
troche or lozenge. The amount of solid carrier may vary, but
generally will be from about 25 mg to about 1 g. If a liquid
carrier is used, the preparation will be in the form of syrup,
emulsion, soft gelatin capsule, sterile injectable solution or
suspension in an ampoule or vial or non-aqueous liquid
suspension.
[0142] To obtain a stable water-soluble dose form, a
pharmaceutically acceptable salt of an inventive agent can be
dissolved in an aqueous solution of an organic or inorganic acid,
such as 0.3M solution of succinic acid or citric acid. If a soluble
salt form is not available, the agent may be dissolved in a
suitable cosolvent or combinations of cosolvents. Examples of
suitable cosolvents include, but are not limited to, alcohol,
propylene glycol, polyethylene glycol 300, polysorbate 80, glycerin
and the like in concentrations ranging from 0-60% of the total
volume. In an exemplary embodiment, a compound of Formula I is
dissolved in DMSO and diluted with water. The composition may also
be in the form of a solution of a salt form of the active
ingredient in an appropriate aqueous vehicle such as water or
isotonic saline or dextrose solution.
[0143] It will be appreciated that the actual dosages of the agents
used in the compositions of this invention will vary according to
the particular complex being used, the particular composition
formulated, the mode of administration and the particular site,
host and disease being treated. Optimal dosages for a given set of
conditions can be ascertained by those skilled in the art using
conventional dosage-determination tests in view of the experimental
data for an agent. For oral administration, an exemplary daily dose
generally employed is from about 0.001 to about 1000 mg/kg of body
weight, with courses of treatment repeated at appropriate
intervals. Administration of prodrugs is typically dosed at weight
levels that are chemically equivalent to the weight levels of the
fully active form.
[0144] The compositions of the invention may be manufactured in
manners generally known for preparing pharmaceutical compositions,
e.g., using conventional techniques such as mixing, dissolving,
granulating, dragee-making, levigating, emulsifying, encapsulating,
entrapping or lyophilizing. Pharmaceutical compositions may be
formulated in a conventional manner using one or more
physiologically acceptable carriers, which may be selected from
excipients and auxiliaries that facilitate processing of the active
compounds into preparations that can be used pharmaceutically.
[0145] Proper formulation is dependent upon the route of
administration chosen. For injection, the agents of the invention
may be formulated into aqueous solutions, preferably in
physiologically compatible buffers such as Hanks's solution,
Ringer's solution, or physiological saline buffer. For transmucosal
administration, penetrants appropriate to the barrier to be
permeated are used in the formulation. Such penetrants are
generally known in the art.
[0146] For oral administration, the compounds can be formulated
readily by combining the compounds with pharmaceutically acceptable
carriers known in the art. Such carriers enable the compounds of
the invention to be formulated as tablets, pills, dragees,
capsules, liquids, gels, syrups, slurries, suspensions and the
like, for oral ingestion by a patient to be treated. Pharmaceutical
preparations for oral use can be obtained using a solid excipient
in admixture with the active ingredient (agent), optionally
grinding the resulting mixture, and processing the mixture of
granules after adding suitable auxiliaries, if desired, to obtain
tablets or dragee cores. Suitable excipients include: fillers such
as sugars, including lactose, sucrose, mannitol, or sorbitol; and
cellulose preparations, for example, maize starch, wheat starch,
rice starch, potato starch, gelatin, gum, methyl cellulose,
hydroxypropylmethyl-cellulose, sodium carboxymethylcellulose, or
polyvinylpyrrolidone (PVP). If desired, disintegrating agents may
be added, such as crosslinked polyvinylpyrrolidone, agar, or
alginic acid or a salt thereof such as sodium alginate.
[0147] Dragee cores are provided with suitable coatings. For this
purpose, concentrated sugar solutions may be used, which may
optionally contain gum arabic, polyvinyl pyrrolidone, Carbopol gel,
polyethylene glycol, and/or titanium dioxide, lacquer solutions,
and suitable organic solvents or solvent mixtures. Dyestuffs or
pigments may be added to the tablets or dragee coatings for
identification or to characterize different combinations of
agents.
[0148] Pharmaceutical preparations that can be used orally include
push-fit capsules made of gelatin, as well as soft, sealed capsules
made of gelatin and a plasticizer, such as glycerol or sorbitol.
The push-fit capsules can contain the agents in admixture with
fillers such as lactose, binders such as starches, and/or
lubricants such as talc or magnesium stearate, and, optionally,
stabilizers. In soft capsules, the agents may be dissolved or
suspended in suitable liquids, such as fatty oils, liquid paraffin,
or liquid polyethylene glycols. In addition, stabilizers may be
added. All formulations for oral administration should be in
dosages suitable for such administration. For buccal
administration, the compositions take the form of tablets or
lozenges formulated in conventional manners.
[0149] For administration intranasally or by inhalation, the
compounds for use according to the present invention are
conveniently delivered in the form of an aerosol spray presentation
from pressurized packs or a nebuliser, with the use of a suitable
propellant, e.g., dichlorodifluoromethane, trichlorofluoromethane,
dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In
the case of a pressurized aerosol the dosage unit may be determined
by providing a valve to deliver a metered amount. Capsules and
cartridges of gelatin for use in an inhaler or insufflator and the
like may be formulated containing a powder mix of the compound and
a suitable powder base such as lactose or starch.
[0150] The compounds may be formulated for parenteral
administration by injection, e.g., by bolus injection or continuous
infusion. Formulations for injection may be presented in
unit-dosage form, e.g., in ampoules or in multi-dose containers,
with an added preservative. The compositions may take such forms as
suspensions, solutions or emulsions in oily or aqueous vehicles,
and may contain formulatory agents such as suspending, stabilizing
and/or dispersing agents.
[0151] Pharmaceutical formulations for parenteral administration
include aqueous solutions of the agents in water-soluble form.
Additionally, suspensions of the agents may be prepared as
appropriate oily injection suspensions. Suitable lipophilic
solvents or vehicles include fatty oils such as sesame oil, or
synthetic fatty acid esters, such as ethyl oleate or triglycerides,
or liposomes. Aqueous injection suspensions may contain substances
that increase the viscosity of the suspension, such as sodium
carboxymethyl cellulose, sorbitol, or dextran. Optionally, the
suspension may also contain suitable stabilizers or agents that
increase the solubility of the compounds to allow for the
preparation of highly concentrated solutions.
[0152] For administration to the eye, the agent is delivered in a
pharmaceutically acceptable ophthalmic vehicle such that the
compound is maintained in contact with the ocular surface for a
sufficient time period to allow the compound to penetrate the
corneal and internal regions of the eye, for example, the anterior
chamber, posterior chamber, vitreous body, aqueous humor, vitreous
humor, cornea, iris/ciliary, lens, choroid/retina and sclera. The
pharmaceutically acceptable ophthalmic vehicle may be an ointment,
vegetable oil, or an encapsulating material. A compound of the
invention may also be injected directly into the vitreous and
aqueous humor.
[0153] Alternatively, the agents may be in powder form for
constitution with a suitable vehicle, e.g., sterile pyrogen-free
water, before use. The compounds may also be formulated in rectal
compositions such as suppositories or retention enemas, e.g.,
containing conventional suppository bases such as cocoa butter or
other glycerides.
[0154] In addition to the formulations described above, the agents
may also be formulated as a depot preparation. Such long-acting
formulations may be administered by implantation (for example,
subcutaneously or intramuscularly) or by intramuscular injection.
Thus, for example, the compounds may be formulated with suitable
polymeric or hydrophobic materials (for example, as an emulsion in
an acceptable oil) or ion-exchange resins, or as sparingly soluble
derivatives, for example, as a sparingly soluble salt.
[0155] An exemplary pharmaceutical carrier for hydrophobic
compounds is a cosolvent system comprising benzyl alcohol, a
nonpolar surfactant, a water-miscible organic polymer, and an
aqueous phase. The cosolvent system may be a VPD co-solvent system.
VPD is a solution of 3% w/v benzyl alcohol, 8% w/v of the nonpolar
surfactant polysorbate 80, and 65% w/v polyethylene glycol 300,
made up to volume in absolute ethanol. The VPD co-solvent system
(VPD:5W) contains VPD diluted 1:1 with a 5% dextrose in water
solution. This co-solvent system dissolves hydrophobic compounds
well, and itself produces low toxicity upon systemic
administration. Naturally, the proportions of a co-solvent system
may be varied considerably without destroying its solubility and
toxicity characteristics. Furthermore, the identity of the
co-solvent components may be varied: for example, other
low-toxicity nonpolar surfactants may be used instead of
polysorbate 80; the fraction size of polyethylene glycol may be
varied; other biocompatible polymers may replace polyethylene
glycol, e.g. polyvinyl pyrrolidone; and other sugars or
polysaccharides may be substituted for dextrose.
[0156] Alternatively, other delivery systems for hydrophobic
pharmaceutical compounds may be employed. Liposomes and emulsions
are known examples of delivery vehicles or carriers for hydrophobic
drugs. Certain organic solvents such as dimethylsulfoxide also may
be employed, although usually at the cost of greater toxicity.
Additionally, the compounds may be delivered using a
sustained-release system, such as semi-permeable matrices of solid
hydrophobic polymers containing the therapeutic agent. Various
sustained-release materials have been established and are known by
those skilled in the art. Sustained-release capsules may, depending
on their chemical nature, release the compounds for a few weeks up
to over 100 days. Depending on the chemical nature and the
biological stability of the therapeutic reagent, additional
strategies for protein stabilization may be employed.
[0157] The pharmaceutical compositions also may comprise suitable
solid- or gel-phase carriers or excipients. Examples of such
carriers or excipients include calcium carbonate, calcium
phosphate, sugars, starches, cellulose derivatives, gelatin, and
polymers such as polyethylene glycols.
[0158] Some of the compounds of the invention may be provided as
salts with pharmaceutically compatible counter ions.
Pharmaceutically compatible salts may be formed with many acids,
including hydrochloric, sulfuric, acetic, lactic, tartaric, malic,
succinic, etc. Salts tend to be more soluble in aqueous or other
protonic solvents than are the corresponding free-base forms.
[0159] The agents of the invention may be useful in combination
with known anti-cancer treatments such as: DNA interactive agents
such as cisplatin or doxorubicin; topoisomerase II inhibitors such
as etoposide; topoisomerase I inhibitors such as CPT-11 or
topotecan; tubulin interacting agents such as paclitaxel, docetaxel
or the epothilones; hormonal agents such as tamoxifen; thymidilate
synthase inhibitors such as 5-fluorouracil; and anti-metalbolites
such as methotrexate. They may be administered together or
sequentially, and when administered sequentially, the agents may be
administered either prior to or after administration of the known
anticancer or cytotoxic agent.
[0160] The agents may be prepared using the reaction routes and
synthesis schemes as described below, employing the general
techniques known in the art using starting materials that are
readily available. The preparation of preferred compounds of the
present invention is described in detail in the following examples,
but the artisan will recognize that the chemical reactions
described may be readily adapted to prepare a number of other
anti-proliferatives or protein kinase inhibitors of the invention.
For example, the synthesis of non-exemplified compounds according
to the invention may be successfully performed by modifications
apparent to those skilled in the art, e.g., by appropriately
protecting interfering groups, by changing to other suitable
reagents known in the art, or by making routine modifications of
reaction conditions. Alternatively, other reactions disclosed
herein or generally known in the art will be recognized as having
applicability for preparing other compounds of the invention.
DETAILED DESCRIPTION OF THE INVENTION
EXAMPLES
[0161] In the examples described below, unless otherwise indicated,
all temperatures are set forth in degrees Celsius and all parts and
percentages are by weight. Reagents were purchased from commercial
suppliers such as Aldrich Chemical Company or Lancaster Synthesis
Ltd. and were used without further purification unless otherwise
indicated. Tetrahydrofuran (THF), N,N-dimethylformamide (DMF),
dichloromethane, toluene, and dioxane were purchased from Aldrich
in Sure seal bottles and used as received. All solvents were
purified using standard methods readily known to those skilled in
the art, unless otherwise indicated.
[0162] The reactions set forth below were done generally under a
positive pressure of argon or nitrogen or with a drying tube, at
ambient temperature (unless otherwise stated), in anhydrous
solvents, and the reaction flasks were fitted with rubber septa for
the introduction of substrates and reagents via syringe. Glassware
was oven dried and/or heat dried. Analytical thin layer
chromatography (TLC) was performed on glass-backed silica gel 60 F
254 plates Analtech (0.25 mm) and eluted with the appropriate
solvent ratios (v/v), and are denoted where appropriate. The
reactions were assayed by TLC and terminated as judged by the
consumption of starting material.
[0163] Visualization of the TLC plates was done with a
p-anisaldehyde spray reagent or phosphomolybdic acid reagent
(Aldrich Chemical 20 wt % in ethanol) and activated with heat.
Work-ups were typically done by doubling the reaction volume with
the reaction solvent or extraction solvent and then washing with
the indicated aqueous solutions using 25% by volume of the
extraction volume unless otherwise indicated. Product solutions
were dried over anhydrous Na.sub.2SO.sub.4 prior to filtration and
evaporation of the solvents under reduced pressure on a rotary
evaporator and noted as solvents removed in vacuo. Flash column
chromatography (Still et al., J. Org. Chem., 43, 2923 (1978)) was
done using Baker grade flash silica gel (47-61 .mu.m) and a silica
gel: crude material ratio of about 20:1 to 50:1 unless otherwise
stated. Hydrogenolysis was done at the pressure indicated in the
examples or at ambient pressure.
[0164] .sup.1H-NMR spectra were recorded on a Bruker instrument
operating at 300 MHz and .sup.13C-NMR spectra were recorded
operating at 75 MHz. NMR spectra were obtained as CDCl.sub.3
solutions (reported in ppm), using chloroform as the reference
standard (7.25 ppm and 77.00 ppm) or CD.sub.3OD (3.4 and 4.8 ppm
and 49.3 ppm), or internally tetramethylsilane (0.00 ppm) when
appropriate. Other NMR solvents were used as needed. When peak
multiplicities are reported, the following abbreviations are used:
s (singlet), d (doublet), t (triplet), m (multiplet), br
(broadened), dd (doublet of doublets), dt (doublet of triplets).
Coupling constants, when given, are reported in Hertz (Hz).
[0165] Infrared (IR) spectra were recorded on a Perkin-Elmer FT-IR
Spectrometer as neat oils, as KBr pellets, or as CDCl.sub.3
solutions, and when given are reported in wave numbers (cm.sup.-1).
The mass spectra were obtained using LSIMS or electrospray. All
melting points (mp) are uncorrected.
[0166] In one general synthetic process, compounds of Formula I are
prepared according to the following reaction scheme: ##STR16##
[0167] 6-Methoxy-2-methylbenzo[b]thiophene or the corresponding
benzofuran (compound 10), which are known in the literature, are
acylated with oxalyl chloride in the presence of aluminum
trichloride. Treatment of the resulting acid chloride with an
excess of the appropriate amine, e.g. methylamine, provides the
requisite amide derivative of formula 12. Demethylation with a
suitable reagent, such as boron tribromide, gives compounds of
formula 13. Compounds of formula 13 and 14 are combined by heating
them with base, preferably Cs.sub.2CO.sub.3, in a solvent such as
DMSO, DMF or acetonitrile to form compounds of formula 15.
Alternatively to using compounds of formula 14a, 14b and 14c,
compounds of formula 14 where R.sub.2 is a carboxylic acid may be
used in the coupling reaction that generates compounds of formula
15. Amide formation may then be the final step.
[0168] Indole analogs may be made in a similar fashion as described
above for benzofurans and benzothiophenes.
Example (1a)
6-methoxybenzo[b]thiophene
[0169] ##STR17##
[0170] A mixture of 3-methoxybenzenethiol (10 ml, 11.30 g, 80
mmole), K.sub.2CO.sub.3 (11.15 g, 80 mmole) and bromoacetaldehyde
diethyl acetal (12 ml, 15.72 g, 80 mmole) in acetone (100 ml) was
stirred at ambient temperature for 16 hours, then filtered. The
filtrate was subsequently concentrated, in vacuo. The residue
obtained was partitioned between H.sub.2O (150 ml) and Et.sub.2O
(150 ml). The layers were separated and the aqueous phase was
extracted with Et.sub.2O (150 ml). The combined organic extracts
were washed with 0.5 M KOH (aq), H.sub.2O and brine, then dried
over Na.sub.2SO.sub.4 and concentrated, in vacuo, to give 20.4 g of
an amber oil which was used directly in the subsequent cyclization
without any further purification.
[0171] Method A: A solution of this crude
1-(2,2-diethoxyethylsulfanyl)-3-methoxybenzene (6.41 g, 25 mmole)
in CH.sub.2Cl.sub.2 (50 ml) was added, dropwise, to a solution of
boron trifluoride etherate (3.4 ml, 3.81 g, 27 mmole) in
CH.sub.2Cl.sub.2 (500 ml). The resultant solution was stirred at
ambient temperature for an additional 30 minutes. Aqueous saturated
NaHCO.sub.3 (200 ml) was added and the two-phase mixture was
stirred for another hour. The layers were separated and the aqueous
phase was extracted with CH.sub.2Cl.sub.2 (150 ml). The combined
organic extracts were dried over Na.sub.2SO.sub.4 and concentrated,
in vacuo, to give 4.3 g of a red oil which was purified by silica
gel chromatography. Elution with hexane: Et.sub.2O (98:2) and
evaporation of the appropriate fractions gave 1.62 g (39%) of a
colourless oil.
[0172] Method B: A solution of the crude
1-(2,2-diethoxyethylsulfanyl)-3-methoxybenzene (8.27 g, 32.3 mmole)
in hexane (100 ml) was added, dropwise, to a solution of
methanesulfonic acid (1.05 ml, 1.55 g, 16.1 mmole) in hexane (1000
ml) containing 16.5 g of celite (2 wt. eq.). The resultant solution
was heated at reflux for one hour. After cooling to room
temperature, the reaction was quenched by addition of Et.sub.3N
(4.5 ml, 3.26 g, 32.3 mmole). The crude reaction mixture was
filtered and the filtrate was concentrated, in vacuo, to give a red
oil which was purified by silica gel chromatography. Elution with
hexane: Et.sub.2O (98:2) and evaporation of the appropriate
fractions gave 3.35 g (63%) of a colorless oil. .sup.1H NMR
(DMSO-d.sub.6) .delta. 7.74 (1H, d, J=8.7 Hz), 7.56 (1H, d, J=2.3
Hz), 7.52 (1H, d, J=5.3 Hz), 7.33 (1H, d, J=5.3 Hz), 6.99 (1H, dd,
J=2.3, 8.7 Hz), 3.81 (3H, s). Anal. Calcd. for C.sub.9H.sub.8OS: C,
65.82; H, 4.91; S, 19.53. Found: C, 66.01; H, 5.00; S, 19.40.
Example 1(b)
6-methoxy-2-methylbenzo[b]thiophene
[0173] ##STR18##
[0174] A 2.5 M solution of n-butyllithium in hexanes (20 ml, 50
mmole) was added under argon to a solution of
6-methoxybenzo[b]thiophene 1a (3.68 g, 22.4 mmole) in THF (150 ml)
at -750. After stirring at -750 for a further 30 minutes, the
cooling bath was exchanged and the reaction warmed to -10.degree.
C. prior to addition of CH.sub.3I (4.2 ml, 9.58 g, 67 mmole). The
resultant mixture was stirred at 0.degree. C. for an additional 30
minutes, then allowed to gradually warm to room temperature before
diluting with saturated NaHCO.sub.3 (150 ml). The layers were
separated and the aqueous phase was extracted with EtOAc
(2.times.100 ml). The combined organic extracts were dried over
Na.sub.2SO.sub.4 and concentrated, in vacuo, to give 4.2 g of an
amber oil which was purified by silica gel chromatography. Elution
with hexane: Et.sub.2O (98:2) and evaporation of the appropriate
fractions gave 3.63 g (91%) of a colourless oil. .sup.1H NMR
(DMSO-d.sub.6) .delta. 7.57 (1H, d, J=8.7 Hz), 7.43 (1H, d, J=2.4
Hz), 6.99 (1H, s), 6.92 (1H, dd, J=2.4, 8.7 Hz), 3.78 (3H, s), 2.50
(3H, s). Anal. Calcd. for C.sub.10H.sub.10OS: C, 67.38; H, 5.66; S,
17.99. Found: C, 67.42; H, 5.74; S, 17.87.
Example 1(c)
6-methoxy-2-methylbenzo[b]thiophene-3-carboxylic acid
methylamide
[0175] ##STR19##
[0176] A 2.0 M solution of oxalyl chloride in CH.sub.2Cl.sub.2 (10
ml, 20 mmole) was added to a slurry of AlCl.sub.3 (2.69 g, 20
mmole) in CH.sub.2Cl.sub.2 (20 ml) at 0.degree.. After stirring at
0.degree. for a further 30 minutes, a solution of
6-methoxy-2-methylbenzo[b]thiophene 1b (725 mg, 4.1 mmole) in
CH.sub.2Cl.sub.2 (40 ml) was added over a 10 minute interval. The
cooling bath was removed and the reaction was stirred at ambient
temperature for 3 hours prior to addition of crushed ice (50 ml).
The layers were separated and the aqueous phase was extracted with
CH.sub.2Cl.sub.2 (3.times.50 ml). The combined organic extracts
were dried over Na.sub.2SO.sub.4 and concentrated, in vacuo, to
give 950 mg of an amber resin which was employed without further
purification.
[0177] A solution of this crude
6-methoxy-2-methylbenzo[b]thiophene-3-carbonyl chloride in THF (50
ml) was combined with a 2.0 M solution of CH.sub.3NH.sub.2 in THF
(20 ml, 40 mmole). The resultant reaction mixture was stirred at
ambient temperature for 3 hours. The solvent was removed by
concentration, in vacuo, and the residue obtained was partitioned
between H.sub.2O (50 ml) and CH.sub.2Cl.sub.2 (50 ml). The layers
were separated and the aqueous phase was extracted with
CH.sub.2Cl.sub.2 (2.times.30 ml). The combined organic extracts
were dried over Na.sub.2SO.sub.4 and concentrated, in vacuo, to
give 0.8 g of an amber solid which was purified by silica gel
chromatography. Elution with CH.sub.2Cl.sub.2:EtOAc (80:20) and
evaporation of the appropriate fractions gave 693 mg (72%) of an
off-white solid. .sup.1H NMR (DMSO-d.sub.6) .delta. 8.15 (1H, q,
J=4.6 Hz), 7.62 (1H, d, J=8.9 Hz), 7.47 (1H, d, J=2.4 Hz), 6.97
(1H, dd, J=2.4, 8.9 Hz), 3.79 (3H, s), 2.80 (3H, d, J=4.6 Hz), 2.53
(3H, s). Anal. Calcd. for C.sub.12H.sub.13NO.sub.2S: C, 61.25; H,
5.57; N, 5.95; S, 13.63. Found: C, 60.97; H, 5.56; N, 5.85; S,
13.44.
Example 1(d)
6-hydroxy-2-methylbenzo[b]thiophene-3-carboxylic acid
methylamide
[0178] ##STR20##
[0179] A 1.0 M solution of BBr.sub.3 in CH.sub.2Cl.sub.2 (6 ml, 6
mmole) was added to a solution of
6-methoxy-2-methylbenzo[b]thiophene-3-carboxylic acid methylamide
1c (683 mg, 2.9 mmole) in CH.sub.2Cl.sub.2 (60 ml) at 0.degree..
The reaction was left stirring for 14 hours, gradually warming to
ambient temperature, then poured onto crushed ice (.about.70 g).
The layers were separated and the aqueous phase was extracted with
EtOAc (2.times.50 ml). The combined organic extracts were dried
over Na.sub.2SO.sub.4 and concentrated, in vacuo, to give 623 mg
(97%) of a beige solid which was employed without further
purification. .sup.1H NMR (DMSO-d.sub.6) .delta. 9.56 (1H, s), 8.11
(1H, q, J=4.4 Hz), 7.53 (1H, d, J=8.7 Hz), 7.18 (1H, d, J=2.3 Hz),
6.83 (1H, dd, J=2.3, 8.7 Hz), 2.79 (3H, d, J=4.4 Hz), 2.50 (3H,
s).
Example 1(e)
7-chloro-2-(1-methyl-1H-imidazol-2-yl)thieno[3,2-b]pyridine
[0180] ##STR21##
[0181] The title compound was prepared by the method described in
PCT application WO-99/24440, Example 149; incorporated herein by
reference.
Example 1
2-methyl-6-(2-[1-methyl-1H-imidazol-2-yl]thieno[3,2-b]pyridin-7-yloxy)benz-
o[b]thiophene-3-carboxylic acid methylamide
[0182] ##STR22##
[0183] A solution of
7-chloro-2-(1-methyl-1H-imidazol-2-yl)thieno[3,2-b]pyridine 1e (100
mg, 0.4 mmole) and 6-hydroxy-2-methylbenzo[b]thiophene-3-carboxylic
acid methylamide 1d (133 mg, 0.6 mmole) in DMSO (10 ml) was purged
with argon for minutes at ambient temperature prior to addition of
freshly crushed Cs.sub.2CO.sub.3 (651 mg, 2 mmole). The resultant
reaction mixture was heated at 100.degree. for 2 hours. After
cooling to room temperature, the crude reaction mixture was poured
into cold water (60 ml). The precipitate that formed was collected
by filtration and purified by silica gel chromatography. Elution
with CH.sub.2Cl.sub.2:CH.sub.3OH (95:5) and evaporation of the
appropriate fractions gave 69 mg (40%) of an off-white solid.
.sup.1H NMR (DMSO-d.sub.6): .delta. 8.52 (1H, d, J=5.4 Hz), 8.29
(1H, q, J=4.6 Hz), 7.95 (1H, d, J=2.3 Hz), 7.88 (1H, s), 7.85 (1H,
d, J=8.8 Hz), 7.40 (1H, d, J=0.8 Hz), 7.32 (1H, dd, J=2.3, 8.8 Hz),
7.02 (1H, d, J=0.8 Hz), 6.70 (1H, d, J=5.4 Hz), 3.98 (3H, s), 2.83
(3H, d, J=4.6 Hz), 2.60 (3H, s). Anal. Calcd. for
C.sub.22H.sub.18N.sub.4O.sub.2S.sub.2.0.3CH.sub.2Cl.sub.2.0.2CH.sub.3OH:
C, 57.94; H, 4.19; N, 12.01. Found: C, 57.67; H, 4.13; N,
12.04.
Example 2(a)
7-chloro-2-[(S)-2-(methoxymethyl)pyrrolidine-1-carbonyl]thieno[3,2-b]pyrid-
ine
[0184] ##STR23##
[0185] To a mixture of lithium
7-chlorothieno[3,2-b]pyridine-2-carboxylate (6.59 g, 30 mmole) in
DMF (100 ml) were added diisopropylethylamine, (6 ml, 4.45 g, 34.4
mmole), benzotriazol-1-yloxytris(pyrrolidino)phosphonium
hexafluorophosphate (16.16 g, 31 mmole) and
S-(+)-2-(methoxymethyl)pyrrolidine (3.73 g, 32.4 mmole). The
resultant reaction mixture was stirred at ambient temperaure for 16
hours. The crude reaction mixture was poured into water (600 ml)
and extracted with EtOAc (3.times.200 ml). The combined organic
extracts were washed with water (4.times.200 ml), dried over
Na.sub.2SO.sub.4 and concentrated, in vacuo, to give 8.8 g of an
amber oil, which was purified by silica gel chromatography. Elution
with Et.sub.2O:EtOAc (67:33) and evaporation of the appropriate
fractions gave 6.89 g (74%) of an orange syrup. .sup.1H NMR
(DMSO-d.sub.6): .delta. 8.62 (1H, d, J=5.0 Hz), 7.88 (1H, s), 7.35
(1H, d, J=5.0 Hz), 4.54-4.47 (1H, m), 3.93-3.75 (2H, m), 3.71-3.55
(2H, m), 3.37 (3H, s), 2.15-1.92 (4H, m). Anal. Calcd. for
C.sub.14H.sub.15N.sub.2O.sub.2SCl: C, 54.10; H, 4.87; N, 9.01; S,
10.32; Cl, 11.41. Found: C, 53.96;
Example 2
6-(2-[(S)-2-(methoxymethyl)pyrrolidine-1-carbonyl]thieno[3,2-b]pyridin-7-y-
loxy)-2-methylbenzo[b]thiophene-3-carboxylic acid methylamide
[0186] ##STR24##
[0187] This material was prepared by the reaction of
7-chloro-2-[(S)-2-(methoxymethyl)pyrrolidine-1-carbonyl]thieno[3,2-b]pyri-
dine 2a (153 mg, 0.5 mmole) with
6-hydroxy-2-methylbenzo[b]thiophene-3-carboxylic acid methylamide
1d (164 mg, 0.7 mmole) and Cs.sub.2CO.sub.3 (868 mg, 2.7 mmole) in
a manner as previously described for example 1 to give 178 mg (73%)
of a yellow solid. .sup.1H NMR (DMSO-d.sub.6): .delta. 8.57 (1H, d,
J=5.4 Hz), 8.29 (1H, q, J=4.5 Hz), 8.02 (1H, s), 7.95 (1H, d, J=2.2
Hz), 7.85 (1H, d, J=8.8 Hz), 7.32 (1H, dd, J=2.2, 8.8 Hz), 6.75
(1H, d, J=5.4 Hz), 4.37-4.23 (1H, m), 3.95-3.74 (2H, m), 3.60-3.48
(2H, m), 3.27 (3H, s), 2.83 (3H, d, J=4.5 Hz), 2.60 (3H, s),
2.08-1.81 (4H, m). Anal. Calcd. for
C.sub.25H.sub.25N.sub.3O.sub.4S.sub.2: C, 60.58; H, 5.08; N, 8.48;
S, 12.94. Found: C, 60.55; H, 5.33; N, 8.27; S, 12.68.
Example 3(a)
7-chloro-2-[(S)-2-(hydroxymethyl)pyrrolidine-1-carbonyl]thieno[3,2-b]pyrid-
ine
[0188] ##STR25##
[0189] This material was prepared by the coupling of lithium
7-chlorothieno[3,2-b]pyridine-2-carboxylate and
S-(+)-2-(hydroxymethyl)pyrrolidine in a manner as previously
described for example 2a to give 4.95 g (55%) of an off-white
solid. .sup.1H NMR (DMSO-d.sub.6): .delta. 8.72 (1H, d, J=5.1 Hz),
8.08 (1H, s), 7.68 (1H, d, J=5.1 Hz), 4.27-4.13 (1H, m), 3.94-3.73
(2H, m), 3.67-3.44 (2H, m), 2.09-1.79 (4H, m).
[0190] Anal. Calcd. for C.sub.13H.sub.13N.sub.2O.sub.2SCl: C,
52.61; H, 4.42; N, 9.44; S, 10.80; Cl, 11.95. Found: C, 52.61; H,
4.52; N, 9.62; S, 10.59; Cl, 11.96.
Example 3(b)
7-chloro-2-[(S)-2-([t-butyldimethylsilyloxy]methyl)pyrrolidine-1-carbonyl]-
thieno[3,2-b]pyridine
[0191] ##STR26##
[0192] To a stirred solution of
7-chloro-2-[(S)-2-(hydroxymethyl)pyrrolidine-1-carbonyl]thieno[3,2-b]pyri-
dine 3a (4.50 g, 15 mmole) were added t-butyldimethylchlorosilane
(3.18 g, 21 mmole) and triethylamine (3.4 ml, 2.47 g, 24 mmole).
The resultant reaction mixture was stirred at ambient temperaure
for 16 hours. The crude reaction mixture was poured into water (150
ml) and extracted with CH.sub.2Cl.sub.2 (150 ml). The combined
organic extracts were washed with brine (150 ml), dried over
Na.sub.2SO.sub.4 and concentrated, in vacuo, to give 7.8 g of an
orange syrup, which was purified by silica gel chromatography.
Elution with Et.sub.2O:hexane (67:33) and evaporation of the
appropriate fractions gave 5.73 g (92%) of an off-white solid.
.sup.1H NMR (DMSO-d.sub.6): .delta. 8.72 (1H, d, J=5.0 Hz), 8.07
(1H, s), 7.68 (1H, d, J=5.0 Hz), 4.30-4.15 (1H, m), 3.94-3.67 (4H,
m), 2.12-1.81 (4H, m), 0.85 (9H, s), 0.03 (3H, s), 0.00 (3H, s).
Anal. Calcd. for C.sub.19H.sub.27N.sub.2O.sub.2SClSi: C, 55.52; H,
6.62; N, 6.82; S, 7.80; Cl, 8.63. Found: C, 55.49; H, 6.46; N,
6.92; S, 7.80; Cl, 8.88.
Example 3
6-(2-[(S)-2-(hydroxymethyl)pyrrolidine-1-carbonyl]thieno[3,2-b]pyridin-7-y-
loxy)-2-methylbenzo[b]thiophene-3-carboxylic acid methylamide
[0193] ##STR27##
[0194] Example 3 was prepared by the reaction of
7-chloro-2-[(S)-2-([t-butyldimethylsilyloxy]methyl)-pyrrolidine-1-carbony-
l]thieno[3,2-b]pyridine 3b (812 mg, 2 mmole) with
6-hydroxy-2-methylbenzo[b]thiophene-3-carboxylic acid methylamide
1d (656 mg, 3 mmole) and Cs.sub.2CO.sub.3 (3.47 g, 11 mmole) in a
manner as previously described for example 1 to give 302 mg (32%)
of a yellow solid. .sup.1H NMR (DMSO-d.sub.6): .delta. 8.57 (1H, d,
J=5.3 Hz), 8.29 (1H, q, J=4.5 Hz), 8.01 (1H, s), 7.96 (1H, d, J=2.2
Hz), 7.85 (1H, d, J=8.8 Hz), 7.32 (1H, dd, J=2.2, 8.8 Hz), 6.75
(1H, d, J=5.3 Hz), 4.81 (1H, t, J=5.9 Hz), 4.24-4.12 (1H, m),
3.92-374 (2H, m), 3.63-3.44 (2H, m), 2.83 (3H, d, J=4.5 Hz), 2.60
(3H, s), 2.08-1.81 (4H, m).
[0195] Anal. Calcd. for
C.sub.24H.sub.23N.sub.3O.sub.4S.sub.2.0.4CH.sub.2Cl.sub.2: C,
56.84; H, 4.65; N, 8.15; S, 12.44. Found: C, 56.81; H, 4.78; N,
7.99; S, 12.49.
Example 4(a)
7-chloro-2-[(R)-3-hydroxypyrrolidine-1-carbonyl]thieno[3,2-b]pyridine
[0196] ##STR28##
[0197] This material was prepared by the coupling of lithium
7-chlorothieno[3,2-b]pyridine-2-carboxylate and
(R)-3-hydroxypyrrolidine in a manner as previously described for
example 2a to give 3.06 g (36%) of an off-white solid. .sup.1H NMR
(DMSO-d.sub.6): .delta. 8.73 (1H, d, J=5.1 Hz), 8.15, 8.09 (1H, s),
7.69 (1H, d, J=5.1 Hz), 5.10-5.06 (1H, m), 4.43-4.29 (1H, m),
4.05-3.89 (2H, m), 3.72-3.43 (2H, m), 2.08-1.79 (2H, m).
Example 4(b)
7-chloro-2-[(R)-3-methoxypyrrolidine-1-carbonyl]thieno[3,2-b]pyridine
[0198] ##STR29##
[0199] A solution of
7-chloro-2-[(R)-3-hydroxypyrrolidine-1-carbonyl]thieno[3,2-b]pyridine
4a (1.86 g, 6.6 mmole) in THF (150 ml) was cooled to -10.degree.
prior to addition of NaH (920 mg, 23 mmole as a 60% by wt. mineral
oil dispersion). The resultant mixture was stirred at 0.degree. for
40 minutes. Iodomethane (4 ml, 9.12 g, 64 mmole) was then added to
the reaction which was stirred for another 3 hours, gradually
warming to room temperature. The crude reaction mixture was
quenched with saturated NaHCO3 (150 ml), then extracted with EtOAc
(2.times.100 ml). The combined organic extracts were dried over
Na.sub.2SO.sub.4 and concentrated, in vacuo, to give 2.4 g of an
amber paste, which was purified by silica gel chromatography.
Elution with CH.sub.2Cl.sub.2:CH.sub.3OH (98:2) and evaporation of
the appropriate fractions gave 1.64 g (84%) of a yellow solid.
.sup.1H NMR (DMSO-d.sub.6): .delta. 8.73 (1H, d, J=5.1 Hz), 8.15
(1H, s), 7.69 (1H, d, J=5.1 Hz), 4.11-3.83 (3H, m), 3.69-3.47 (2H,
m), 3.27, 3.24 (3H, s), 2.18-1.93 (2H, m). Anal. Calcd. for
C.sub.13H.sub.23N.sub.2O.sub.2SCl: C, 52.61; H, 4.42; N, 9.44; S,
10.80; Cl, 11.95. Found: C, 52.76; H, 4.47; N, 9.38; S, 10.84; Cl,
12.01.
Example 4
6-(2-[(R)-3-methoxypyrrolidine-1-carbonyl]thieno[3,2-b]pyridin-7-yloxy)-2--
methylbenzo[b]thiophene-3-carboxylic acid methylamide
[0200] ##STR30##
[0201] This material was prepared by the reaction of
7-chloro-2-[(R)-3-methoxypyrrolidine-1-carbonyl]thieno[3,2-b]pyridine
4b (267 mg, 0.9 mmole) with
6-hydroxy-2-methylbenzo[b]thiophene-3-carboxylic acid methylamide
1d (299 mg, 1.4 mmole) and Cs.sub.2CO.sub.3 (1.47 g, 4.5 mmole) in
a manner as previously described for example 1 to give 356 mg (82%)
of a yellow solid. .sup.1H NMR (DMSO-d.sub.6): 8.58 (1H, d, J=5.4
Hz), 8.29 (1H, q, J=4.6 Hz), 8.06 (1H, s), 7.96 (1H, d, J=2.3 Hz),
7.85 (1H, d, J=8.7 Hz), 7.32 (1H, dd, J=2.3, 8.7 Hz), 6.75 (1H, d,
J=5.4 Hz), 4.11-3.82 (3H, m), 3.68-3.45 (2H, m), 3.27, 3.24 (3H,
s), 2.83 (3H, d, J=4.6 Hz), 2.60 (3H, s), 2.17-1.93 (2H, m). Anal.
Calcd. for C.sub.24H.sub.23N.sub.3O.sub.4S.sub.2.0.4H.sub.2O: C,
58.97; H, 4.91; N, 8.60; S, 13.12. Found: C, 58.98; H, 4.98; N,
8.40; S, 13.37.
Example 5(a)
3,4-cis-dihydroxy-pyrrolidine-1-carboxylic acid benzyl ester
[0202] ##STR31##
[0203] To a solution of benzyl 3-pyrroline-1-carboxylate (15 g,
90%, 66.4 mmole) in THF (100 ml) and water (25 ml) was added osmium
tetroxide (10 ml, 2.5 wt. % solution in 2-methyl-2-propanol, 0.8
mmole) and 4-methylmorpholine N-oxide (8.56 g, 73 mmole) as solid.
The mixture was stirred at room temperature overnight and
concentrated, in vacuo. The residue was re-dissolved in EtOAc (300
ml) and washed with aqueous Na.sub.2SO.sub.3 (1.5 g in 100 ml
water) solution, aqueous NaHCO.sub.3 solution and brine. The
combined aqueous layer was extracted once with EtOAc (100 ml). The
combined organic extracts were dried over Na.sub.2SO.sub.4 and
concentrated, in vacuo. The crude was further purified by flash
column chromatography eluting with 4-5% MeOH in CH.sub.2Cl.sub.2 to
give 15.26 g (97%) of a white solid. .sup.1H NMR (300 MHz,
CDCl.sub.3) .delta. 7.34 (5H, m), 5.11 (2H, bs), 4.26 (2H, m), 3.66
(2H, m), 3.41 (2H, m), 1.56 (2H, bs).
Example 5(b)
3,4-cis-dimethoxy-pyrrolidine-1-carboxylic acid benzyl ester
[0204] ##STR32##
[0205] To a stirred solution of
3,4-cis-dihydroxy-pyrrolidine-1-carboxylic acid benzyl ester 5a
(15.2 g, 64.3 mmole) in anhydrous THF (130 ml) was added
iodomethane (36 g, 257 mmole) at 0.degree.; sodium hydride (6.4 g,
60% in mineral oil, 160 mmole) was then added slowly as at
0.degree.. The mixture was allowed to warm to room temperature and
stirred at room temperature for 3 hours. Aqueous 1N HCl (30 ml) was
then added to the mixture which was concentrated, in vacuo, to
remove THF. The residue was re-dissolved in EtOAc (300 ml) and
washed with water and brine. The organic layer was dried over
Na.sub.2SO.sub.4, filtered, and concentrated, in vacuo. The crude
was further purified by flash column chromatography eluting with
5-25% EtOAc in CH.sub.2Cl.sub.2 to give 17 g (99%) of a yellow oil.
.sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 7.35 (5H, m), 5.12 (2H,
m), 3.87 (2H, m), 3.55 (2H, m), 3.42 (6H, bs), 1.58 (2H, s).
Example 5(c)
3,4-cis-Dimethoxy-pyrrolidine
[0206] ##STR33##
[0207] To a stirred solution of
3,4-cis-dimethoxy-pyrrolidine-1-carboxylic acid benzyl ester 5b
(16.95 g, 63.9 mmole) in MeOH (150 ml) was added 10% Pd on C (1.3
g). The mixture was stirred under H.sub.2 balloon at room
temperature for 3 hours and filtered through celite. The filtrate
was concentrated, in vacuo, re-dissolved in CH.sub.2Cl.sub.2 and
dried over Na.sub.2SO.sub.4. The solution was concentrated to give
8.3 g (99%) of a yellow oil. .sup.1H NMR (300 MHz, CDCl.sub.3)
.delta. 3.80 (2H, m), 3.47 (2H, bs), 3.41 (6H, s), 3.01 (2H,
bs).
Example (5d)
7-chloro-2-[meso-3,4-dimethoxypyrrolidine-1-carbonyl]thieno[3,2-b]pyridine
[0208] ##STR34##
[0209] This material was prepared by the coupling of lithium
7-chlorothieno[3,2-b]pyridine-2-carboxylate and
3,4-cis-dimethoxypyrrolidine 5c in a manner as previously described
for example 2a to give a pale yellow syrup. .sup.1H NMR
(CD.sub.3OD): .delta. 8.70 (1H, d, J=5.1 Hz), 8.03 (1H, s), 7.61
(1H, d, J=5.1 Hz), 4.20-4.07 (2H, m), 3.97-3.75 (2H, m), 3.52 (3H,
s), 3.48 (3H, s), 3.35-3.29 (2H, m).
Example (5)
6-(2-[meso-3,4-dimethoxypyrrolidine-1-carbonyl]thieno[3,2-b]pyridin-7-ylox-
y)-2-methylbenzo[b]thiophene-3-carboxylic acid methylamide
[0210] ##STR35##
[0211] This material was prepared by the reaction of
7-chloro-2-[meso-3,4-dimethoxypyrrolidine-1-carbonyl]thieno[3,2-b]pyridin-
e 5d (164 mg, 0.5 mmole) with
6-hydroxy-2-methylbenzo[b]thiophene-3-carboxylic acid methylamide
1d (164 mg, 0.7 mmole) and Cs.sub.2CO.sub.3 (868 mg, 2.7 mmole) in
a manner as previously described for example 1 to give 123 mg (48%)
of an off-white solid. .sup.1H NMR (DMSO-d.sub.6): .delta. 8.59
(1H, d, J=5.4 Hz), 8.29 (1H, q, J=4.7 Hz), 8.07 (1H, s), 7.96 (1H,
d, J=2.3 Hz), 7.85 (1H, d, J=8.8 Hz), 7.32 (1H, dd, J=2.3, 8.8 Hz),
6.76 (1H, d, J=5.4 Hz), 4.12-3.98 (3H, m), 3.83 (1H, dd, J=3.6, 9.1
Hz), 3.66 (1H, dd, J=4.8, 12.9 Hz), 3.51 (1H, dd, J=4.2, 12.9 Hz),
3.36 (6H, s), 2.83 (3H, d, J=4.7 Hz), 2.60 (3H, s). Anal. Calcd.
for C.sub.25H.sub.25N.sub.3O.sub.5S.sub.2.0.6H.sub.2O: C, 57.47; H,
5.06; N, 8.04; S, 12.28. Found: C, 57.35; H, 5.02; N, 7.89; S,
12.37.
Example 6
6-(2-[(R)-3-hydroxypyrrolidine-1-carbonyl]thieno[3,2-b]pyridin-7-yloxy)-2--
methylbenzo[b]thiophene-3-carboxylic acid methylamide
[0212] ##STR36##
[0213] This material was prepared from
6-(2-[(R)-3-methoxypyrrolidine-1-carbonyl]thieno[3,2-b]pyridin-7-yloxy)-2-
-methylbenzo[b]thiophene-3-carboxylic acid methylamide 4 (172 mg,
0.4 mmole) by treatment with BBr.sub.3 in a manner as previously
described for example 1d to give 108 mg (65%) of an off-white
solid. .sup.1H NMR (DMSO-d.sub.6): .delta. 8.58 (1H, d, J=5.3 Hz),
8.29 (1H, q, J=4.4 Hz), 8.06 (1H, s), 7.96 (1H, d, J=1.2 Hz), 7.85
(1H, d, J=8.7 Hz), 7.33 (1H, dd, J=1.2, 8.7 Hz), 6.75 (1H, d, J=5.3
Hz), 4.44-4.27 (1H,m), 4.05-3.88 (1H, m), 3.71-3.42 (3H, m), 2.83
(3H, d, J=4.4 Hz), 2.60 (3H, s), 2.10-1.77 (2H, m). Anal. Calcd.
for C.sub.23H.sub.21N.sub.3O.sub.4S.sub.2.1.0 CH.sub.3OH: C, 57.70;
H, 5.04; N, 8.41; S, 12.84. Found: C, 57.41; H, 4.98; N, 8.42; S,
12.63.
Example 7
6-(2-[meso-3,4-dihydroxypyrrolidine-1-carbonyl]thieno[3,2-b]pyridin-7-ylox-
y)-2-methylbenzo[b]thiophene-3-carboxylic acid methylamide
[0214] ##STR37##
[0215] Example 7 was prepared from
6-(2-[meso-3,4-dimethoxypyrrolidine-1-carbonyl]thieno[3,2-b]pyridin-7-ylo-
xy)-2-methylbenzo[b]thiophene-3-carboxylic acid methylamide 5 (74
mg, 0.1 mmole) by treatment with BBr.sub.3 in a manner as
previously described for example 1d to give 51 mg (73%) of an
off-white solid. .sup.1H NMR (DMSO-d.sub.6): .delta. 8.58 (1H, d,
J=5.4 Hz), 8.29 (1H, q, J=4.6 Hz), 7.99 (1H, s), 7.96 (1H, d, J=2.3
Hz), 7.85 (1H, d, J=8.8 Hz), 7.32 (1H, dd, J=2.3, 8.8 Hz), 6.75
(1H, d, J=5.4 Hz), 5.1- (2H, d, J=5.3 Hz), 4.18-4.07 (2H, m), 4.02
(1H, dd, J=5.6, 10.2 Hz), 3.66 (1H, dd, J=4.9, 10.2 Hz), 3.62 (1H,
dd, J=5.1, 12.8 Hz), 3.40 (1H, dd, J=4.4, 12.8 Hz), 2.83 (3H, d,
J=4.7 Hz), 2.60 (3H, s). Anal. Calcd. for
C.sub.25H.sub.25N.sub.3O.sub.5S.sub.2.0.5NaBr.H.sub.2O: C, 49.95;
H, 4.19; N, 7.60; S, 11.60. Found: C, 49.93; H, 4.15; N, 7.44; S,
11.44.
Example 8a
6-hydroxy-2-methylbenzo[b]thiophene
[0216] ##STR38##
[0217] This material was prepared from
6-methoxy-2-methylbenzo[b]thiophene 1b (2.92 g, 16.4 mmole) by
treatment with BBr.sub.3 in a manner as previously described for
example 1d to give 2.51 g (93%) of a white solid. .sup.1H NMR
(DMSO-d.sub.6) .delta. 9.43 (1H, s), 7.47 (1H, d, J=8.5 Hz), 7.14
(1H, d, J=2.2 Hz), 6.92 (1H, s), 6.78 (1H, dd, J=2.2, 8.5 Hz), 2.46
(3H, s). Anal. Calcd. for C.sub.9H.sub.8OS: C, 65.82; H, 4.91; S,
19.53. Found: C, 65.96; H, 5.11; S, 19.69.
Example 8(b)
6-acetoxy-2-methyl benzo[b]thiophene
[0218] ##STR39##
[0219] Acetyl chloride (1.5 ml, 1.66 g, 21 mmole) and Et.sub.3N (3
ml, 2.18 g, 21.5 mmole) were added, sequentially, to a solution of
6-hydroxy-2-methylbenzo[b]thiophene 8a (2.51 g, 15 mmole) in THF
(120 ml) at 0.degree.. The reaction was left stirring for 14 hours,
gradually warming to ambient temperature, then diluted with EtOAc
(100 ml) and washed with H.sub.2O (100 ml) and brine (100 ml). The
combined aqueous layers were extracted with EtOAc (100 ml). The
combined organic extracts were subsequently dried over
Na.sub.2SO.sub.4 and concentrated, in vacuo, to give 3.9 g of a
yellow solid which was purified by silica gel chromatography.
Elution with hexane:Et.sub.2O (90:10) and evaporation of the
appropriate fractions gave 2.93 g (93%) of a white solid. .sup.1H
NMR (DMSO-d.sub.6) .delta. 7.70 (1H, d, J=8.6 Hz), 7.66 (1H, d,
J=2.2 Hz), 7.12 (1H, s), 7.07 (1H, dd, J=2.2, 8.6 Hz), 2.54 (3H,
s), 2.27 (3H, s). Anal. Calcd. for C.sub.11H.sub.10O.sub.2S: C,
64.05; H, 4.89; S, 15.55. Found: C, 63.84; H, 4.93; S, 15.57.
Example (8c)
6-hydroxy-2-methylbenzo[b]thiophene-3-carboxylic acid
cyclopropylamide
[0220] ##STR40##
[0221] This material was prepared from
6-acetoxy-2-methylbenzo[b]thiophene 8b (413 mg, 2 mmole) by
acylation with oxalyl chloride in the presence of AlCl.sub.3,
followed by treatment with cyclopropylamine in a manner as
previously described for example 1c to give 384 mg (78%) of a pale
yellow solid. .sup.1H NMR (DMSO-d.sub.6) .delta. 9.56 (1H, s), 8.29
(1H, d, J=4.3 Hz), 7.48 (1H, d, J=8.7 Hz), 7.17 (1H, d, J=2.2 Hz),
6.83 (1H, dd, J=2.2, 8.7 Hz), 2.92-2.81 (1H, m), 2.46 (3H, s),
0.74-0.66 (2H, m), 0.58-0.51 (2H, m). Anal. Calcd. for
C.sub.13H.sub.13NO.sub.2S.0.2H.sub.2O: C, 62.23; H, 5.38; N, 5.60.
Found: C, 62.22; H, 5.36; N, 5.60.
Example 8
6-(2-[(S)-2-(hydroxymethyl)pyrrolidine-1-carbonyl]thieno[3,2-b]pyridin-7-y-
loxy)-2-methylbenzo[b]thiophene-3-carboxylic acid
cyclopropylamide
[0222] ##STR41##
[0223] This material was prepared by the reaction of
7-chloro-2-[(S)-2-([t-butyldimethylsilyloxy]methyl)-pyrrolidine-1-carbony-
l]thieno[3,2-b]pyridine 3b (206 mg, 0.5 mmole) with
6-hydroxy-2-methylbenzo[b]thiophene-3-carboxylic acid
cyclopropylamide 8c (186 mg, 0.75 mmole) and Cs.sub.2CO.sub.3 (868
mg, 2.7 mmole) in a manner as previously described for example 1 to
give 132 mg (52%) of a yellow solid. .sup.1H NMR (DMSO-d.sub.6):
.delta. 8.58 (1H, d, J=5.4 Hz), 8.46 (1H, d, J=4.3 Hz), 8.00 (1H,
s), 7.95 (1H, d, J=2.3 Hz), 7.80 (1H, d, J=8.8 Hz), 7.32 (1H, dd,
J=2.3, 8.8 Hz), 6.75 (1H, d, J=5.4 Hz), 4.90-4.72 (1H, m),
4.24-4.11 (1H, m), 3.92-374 (2H, m), 3.64-3.43 (2H, m), 2.95-2.84
(1H, m), 2.57 (3H, s), 2.09-1.80 (4H, m) 0.77-0.67 (2H, m),
0.60-0.52 (2H, m). Anal. Calcd. for
C.sub.24H.sub.23N.sub.3O.sub.4S.sub.2.0.4CH.sub.2Cl.sub.2.0.4CH.sub.3OH:
C, 58.06; H, 4.98; N, 7.58. Found: C, 58.03; H, 4.98; N, 7.52.
Example 9(a)
1-benzhydrylazetidin-3-ol
[0224] ##STR42##
[0225] A mixture of (diphenylmethyl)amine (2.2 ml, 12.8 mmole),
2-chloromethyloxirane (2.0 ml, 25.6 mmole) in DMF (25 ml) were
heated at 95.degree. C. for 72 hours. The resultant yellow solution
was cooled to 0.degree. and treated with 0.5 M HCl (250 ml). The
aqueous layer was washed with methyl tert-butyl ether (3.times.150
ml), and the organic layers were discarded. The aqueous layer was
made basic with NaOH and the resultant milky white suspension was
extracted with methyl tert-butyl ether (3.times.150 ml). The
combined organic layers were washed with brine, dried over
MgSO.sub.4 and concentrated, in vacuo, to a clear oil (3.1 g). The
oil was triturated with cyclohexane and methyl tert-butyl ether and
provided a white solid (2.3 g, 74%): TLC (4% methanol-chloroform
with 0.1% ammonium hydroxide) R.sub.f 0.3; .sup.1H-NMR
(DMSO-d.sub.6, 400 MHz) .delta. 7.40-7.38 (4H, m), 7.27-7.23 (4H,
m), 7.17-7.13 (2H, m), 5.28 (1H, d, J=6.3 Hz), 4.34 (1H, s),
4.22-4.18 (1H,m), 3.36-3.34 (2H,m), 2.69-2.66 (2H,m).
Example 9(b)
3-hydroxyazetidine-1-carboxylic acid tert-butyl ester
[0226] ##STR43##
[0227] 1-Benzhydryl-azetidin-3-ol 9a (4.0 g, 16.7 mmole), EtOAc
(150 ml), di-tert-butyl dicarbonate (4.4 g, 20.1 mmole) and 20%
Pd(OH).sub.2 on carbon (0.8 g, 20 wt. %) were sequentially added to
a round bottom flask. The mixture was degassed and purged with
hydrogen. The hydrogenolysis was completed after 24 hours at one
atmosphere. The reaction mixture was filtered through celite and
concentrated, in vacuo, to a clear oil (7.0 g). The crude product
was dissolved in CH.sub.2Cl.sub.2 (10 ml) and purified over a
silica gel plug (35 g), which was eluted with CH.sub.2Cl.sub.2 (150
ml) followed by EtOAc (150 ml). The EtOAc fractions were
concentrated, in vacuo, to a clear oil (3.1 g, >100%): TLC (50%
ethyl acetate-cyclohexane) R.sub.f 0.4 (I.sub.2 stain); .sup.1H-NMR
(DMSO-d.sub.6, 300 MHz) .delta. 5.62 (1H, d, J=6.4 Hz), 4.39-4.32
(1H, m), 3.97 (2H, t, J=7.8 Hz), 3.57 (2H, t, J=4.4 Hz), 1.35 (9H,
s).
Example 9(c)
Azetidin-3-ol trifluoroacetic acid salt
[0228] ##STR44##
[0229] 3-Hydroxy-azetidine-1-carboxylic acid tert-butyl ester 9b
(0.73 g, 4.2 mmole) was dissolved in CH.sub.2Cl.sub.2 (2 ml) and
trifluoroacetic acid (2 ml). CAUTION: The deprotection generated a
rapid evolution of gas. The clear solution was stirred for 75
minutes and the solvent was removed, in vacuo, to a clear oil (1.4
g, >100%): .sup.1H-NMR (DMSO-d.sub.6, 400 MHz) .delta. 8.63 (2H,
br. s), 4.55-4.48 (1H, m), 4.09-4.02 (2H, m), 3.76-3.68 (2H,
m).
Example 9(d)
7-Chloro-2-[3-hydroxyazetidin-1-carbonyl]thieno[3,2-b]pyridine
[0230] ##STR45##
[0231] A mixture of the lithium salt of
7-chlorothieno[3,2-b]pyridine-2-carboxylic acid (0.92 g, 4.2
mmole), CH.sub.2Cl.sub.2 (40 ml) and thionyl chloride (0.92 ml,
12.6 mmole) was heated to reflux. The resultant white slurry gave
rise to an amber solution upon the addition of DMF (5 ml). After 60
minutes the reaction mixture was concentrated, in vacuo, to a white
slurry. The acid chloride was suspended in CH.sub.2Cl.sub.2 (40 ml)
and treated with a solution of azetidin-3-ol trifluoroacetic acid
salt 9c (0.78 g, 4.2 mmole) and Et.sub.3N (0.58 ml, 4.2 mmole) in
DMF (2 ml). After 60 minutes the CH.sub.2Cl.sub.2 layer was
removed, in vacuo, and the resultant beige residue was poured into
saturated NaHCO.sub.3 (100 ml). The aqueous layer was extracted
with EtOAc (3.times.100 mL). The combined organic layers were
washed with brine, dried over MgSO.sub.4 and concentrated, in
vacuo, to a beige slurry (1.7 g). The slurry was triturated with
methyl tert-butyl ether and provided a beige solid (0.23 g, 21%):
TLC (5% methanol-dichloromethane) R.sub.f 0.4; .sup.1H-NMR
(DMSO-d.sub.6, 400 MHz) .delta. 8.74 (1H, d, J=5.1 Hz), 7.99 (1H,
s), 7.70 (1H, d, J=4.8 Hz), 5.88 (1H,d, J=6.3 Hz), 4.80-4.78 (1H,
m), 4.60-4.56 (1H, m), 4.37-4.34 (2H, m), 3.86-3.84 (1H, m); ESIMS
m/z 269 (M+H).sup.+.
Example 9
6-(2-[3-Hydroxyazetidine-1-carbonyl]thieno[3,2-b]pyridin-7-yloxy)-2-methyl
benzo[b]thiophene-3-carboxylic acid methylamide
[0232] ##STR46##
[0233] A slurry of
7-chloro-2-[3-hydroxyazetidin-1-carbonyl]thieno[3,2-b]pyridine 9d
(120 mg, 0.45 mmole),
6-hydroxy-2-methylbenzo[b]thiophene-3-carboxylic acid methylamide
1d (100 mg, 0.45 mmole) and Cs.sub.2CO.sub.3 (0.73 g, 2.2 mmole) in
acetonitrile (15 ml) was heated to 70.degree.. After 30 hours both
starting materials remained, but the reaction was stopped. The
reaction mixture was poured into a solution of 50% saturated
NaHCO.sub.3 (150 ml). The aqueous layer was extracted with 10%
isopropanol-chloroform (3.times.150 ml). The combined organic
layers were dried with brine, magnesium sulfate, filtered and
concentrated, in vacuo, to a white solid (0.18 g). The crude
product was purified by silica gel radial chromatography and the
gradient mobile phase was 5-10% CH.sub.3OH--CH.sub.2Cl.sub.2 with
0.1% NH.sub.4OH. The product was triturated with ethyl
acetate-cyclohexane and isolated as a white solid (40 mg, 20%): TLC
(5% CH.sub.3OH--CH2Cl.sub.2) R.sub.f 0.2; .sup.1H-NMR
(DMSO-d.sub.6, 400 MHz) .delta. 8.58 (1H, d, J=5.3 Hz), 8.30-8.27
(1H, m), 7.96-7.84 (3H, m), 7.32 (1H, d, J=8.9 Hz), 6.75 (1H, d,
J=5.3 Hz), 5.88 (1H, d, J=6.6 Hz), 4.80-4.78 (1H, m), 4.58-4.55
(1H, m), 4.35-4.30 (2H, m), 3.87-3.82 (1H, m), 2.84 (3H, d, J=4.3
Hz), 2.60 (3H, s). ESIMS m/z 454 (M+H).sup.+. mp 237-239.degree. C.
Anal. Calcd for C.sub.22H.sub.19N.sub.3O.sub.4S.sub.2.0.9H.sub.2O:
C, 56.25; H, 4.46; N, 8.95; S, 13.65. Found: C, 56.36; H, 4.22; N,
9.00; S, 13.51.
Example 10(a)
1-Methyl-5-trimethylstannanyl-1H-pyrazole
[0234] ##STR47##
[0235] A solution of 1-methyl-1H-pyrazole (1.6 g, 20.0 mmole) in
Et.sub.2O was treated with n-butyllithium (12.5 ml, 1.6 M in
hexanes, 20.0 mmole) over a period of 10 minutes at room
temperature. The yellow slurry was stirred for a further 90
minutes. Subsequently, trimethyltin chloride (4.0 g, 20.0 mmole)
was added in one portion. The brown slurry was stirred for 30
minutes, filtered and the filtrate was concentrated, in vacuo, to a
black oil (5.0 g). The product was isolated by distillation at 1.5
Torr (67-72.degree. C.) as a clear oil (2.1 g, 42%): .sup.1H-NMR
(DMSO-d.sub.6, 400 MHz) .delta. 7.40 (1H, d, J=1.5 Hz), 6.27 (1H,
d, J=1.7 Hz), 3.84 (3H, s), 0.34 (9H, s). ESIMS m/z 243-247 ion
cluster (M+H).sup.+.
Example 10(b)
7-Chloro-2-(2-methyl-2H-pyrazol-3-yl)thieno[3,2-b]pyridine
[0236] ##STR48##
[0237] A mixture of 1-methyl-5-trimethylstannanyl-1H-pyrazole 10a
(2.1 g, 8.5 mmole), 7-chloro-2-iodo-thieno[3,2-b]pyridine (2.5 g,
8.5 mmole), tetrakis(triphenylphosphine)palladium(0) (0.5 g, 0.4
mmole, 5 mol %) in o-xylene (85 ml) was degassed, purged with
nitrogen and heated to 120.degree., which gave an orange solution.
After 14 hours the black reaction mixture was diluted with toluene
(100 ml) and extracted with 1.2 M HCl (3.times.60 ml). The combined
aqueous layers were washed with toluene (100 ml). The organic
layers were discarded and the aqueous layer was treated with NaOH
to pH 14. The resultant white solid was collected (1.1 g, 52%): TLC
(6% methanol-dichloromethane) R.sub.f 0.8; .sup.1H-NMR
(DMSO-d.sub.6, 400 MHz) .delta. 8.70 (1H, d, J=5.3 Hz), 8.00 (1H,
s), 7.63 (1H,d, J=5.3 Hz), 7.56 (1H, d, J=2.0 Hz), 6.79 (1H, d,
J=2.0 Hz), 4.09 (3H, s). ESIMS m/z 250 (M+H).sup.+.
Example 10
2-Methyl-6-(2-[2-methyl-2H-pyrazol-3-yl]thieno[3,2-b]pyridin-7-yloxy)benzo-
[b]thiophene-3-carboxylic acid methylamide
[0238] ##STR49##
[0239] Example 10 was prepared by the reaction of
7-Chloro-2-(2-methyl-2H-pyrazol-3-yl)thieno[3,2-b]pyridine 10b with
6-hydroxy-2-methylbenzo[b]thiophene-3-carboxylic acid methylamide
1d and Cs.sub.2CO.sub.3 in a manner as previously described for
example 1 to give 115 mg of a beige solid (60%): TLC (6%
methanol-dichloromethane) R.sub.f 0.6; .sup.1H-NMR (DMSO-d.sub.6,
400 MHz) .delta. 8.54 (1H, d, J=5.5 Hz), 8.28 (1H, q, J=4.5 Hz),
7.96 (1H, d, J=2.3 Hz), 7.92 (1H, s), 7.86 (1H, d, J=8.8 Hz), 7.54
(1H, d, J=2.0 Hz), 7.33 (1H, dd, J=2.3, 8.8 Hz), 6.72 (1H, d, J=2.0
Hz), 6.68 (1H, d, J=5.5 Hz), 4.08 (3H, s), 2.84 (1H, d, J=4.5 Hz),
2.60 (3H, s). ESIMS m/z 435 (M+H).sup.+. mp 210-212.degree. C.
Anal. Calcd for C.sub.22H.sub.18N.sub.4O.sub.2S.sub.2.1.3H.sub.2O:
C, 57.70; H, 4.53; N, 12.23; S, 14.00. Found: C, 57.75; H, 4.55; N,
12.21; S, 14.13.
Example 11(a)
Methyl 6-hydroxy-2-methylbenzo[b]thiophene-3-carboxylate
[0240] ##STR50##
[0241] This material was prepared from
6-acetoxy-2-methylbenzo[b]thiophene 8b (500 mg, 2.42 mmole) by
acylation with oxalyl chloride in the presence of AlCl.sub.3 as
previously described for example 1c. A solution of the crude
6-methoxy-2-methylbenzo[b]thiophene-3-carbonyl chloride in MeOH (24
ml) was cooled to 0.degree. C. prior to the addition of
K.sub.2CO.sub.3 (351 mg, 2.66 mmole). The reaction was warmed to
ambient temperature and stirred 3 hours. The solvent was removed,
in vacuo, and the resulting residue was diluted with
CH.sub.2Cl.sub.2 (75 ml) and H.sub.2O (25 ml). The organic layer
was separated and the aqueous layer was extracted with
CH.sub.2Cl.sub.2 (50 ml). The combined organics were washed with
brine (25 ml), dried (Na.sub.2SO.sub.4), filtered, and concentrated
in vacuo to afford the 468 mg (87%) of a pale brown solid. .sup.1H
NMR (300 MHz, DMSO-d.sub.6) .delta. 9.68 (1H, s), 8.06 (1H, d,
J=8.9 Hz), 7.23 (1H, d, J=2.3 Hz), 6.91 (1H, dd, J=2.3, 8.9
Hz).
Example 11(b)
Methyl
6-[(2-{[(3R)-3-methoxypyrrolidin-1-yl]carbonyl}thieno[3,2-b]pyridin-
-7-yl)oxy]-2-methyl benzo[b]thiophene-3-carboxylate
[0242] ##STR51##
[0243] Example 11(b) was prepared by the reaction of
7-chloro-2-[(R)-3-methoxypyrrolidine-1-carbonyl]thieno[3,2-b]pyridine
4b (417 mg, 1.40 mmole) with methyl
6-hydroxy-2-methylbenzo[b]thiophene-3-carboxylate 11a (417 mg, 2.11
mmole) and Cs.sub.2CO.sub.3 (2.29 g, 7.02 mmole) in a manner as
previously described for example 1 to give 290 mg (43%) of a yellow
solid. .sup.1H NMR (DMSO-d.sub.6): .delta.8.58 (1H, d, J=5.4 Hz),
8.39 (1H, d, J=9.0 Hz), 8.07 (1H, s), 8.02 (1H, d, J=2.3 Hz), 7.42
(1H, dd, J=2.3, 9.0 Hz), 6.79 (1H, d, J=5.4 Hz), 4.08-3.99 (3H, m),
3.87-3.86 (2H, m), 3.91 (3H, s), 3.64-3.59 (2H, m), 3.27, 3.24 (3H,
s), 2.82 (3H, s).
Example 11(c)
6-[(2-{[(3R)-3-methoxypyrrolidin-1-yl]carbonyl}thieno[3,2-b]pyridin-7-yl)o-
xy]-2-methylbenzo[b]thiophene-3-carboxylic acid
[0244] ##STR52##
[0245] To a solution of methyl
6-[(2-{[(3R)-3-methoxypyrrolidin-1-yl]carbonyl}thieno[3,2-b]pyridin-7-yl)-
oxy]-2-methylbenzo[b]thiophene-3-carboxylate 11b (258 mg, 0.535
mmole) in a mixture of THF/MeOH/H.sub.2O (3:2:1, 6 ml) was added
LiOH.H.sub.2O (224 mg, 5.35 mmole). The reaction was stirred 24
hours at ambient temperature. The mixture was diluted with H.sub.2O
(10 ml) and acidified to pH 1 with 1 M HCl. The precipitate was
collected by vacuum filtration, rinsed with MeOH, and dried at
50.degree. C. under vacuum to afford 116 mg (45%) of a pale brown
solid .sup.1H NMR (DMSO-d.sub.6) .delta. 8.58 (1H, d, J=5.4 Hz),
8.44 (1H, d, J=8.9 Hz), 8.07 (1H, s), 8.00 (1H, d, J=24 Hz), 7.39
(1H, dd, J=2.4, 8.9 Hz), 6.78 (1H, d, J=5.4 Hz), 4.10-3.81 (3H, m),
3.69-3.54 (4H, m), 3.27, 3.24 (3H, s), 2.81 (3H, s).
Example 11
6-[(2-{[(3R)-3-methoxypyrrolidin-1-yl]carbonyl}thieno[3,2-b]pyridin-7-yl)o-
xy]-2-methylbenzo[b]thiophene-3-carboxylic acid
cyclopropylamide
[0246] ##STR53##
[0247] Thionyl chloride (31 .mu.l, 0.427 mmole) was added to a
suspension of
6-[(2-{[(3R)-3-methoxypyrrolidin-1-yl]carbonyl}thieno[3,2-b]pyridin-7--
yl)oxy]-2-methylbenzo[b]thiophene-3-carboxylic acid 11c (40 mg,
0.085 mmole) in dichloroethane (1 ml). The reaction mixture was
heated to reflux for 90 minutes, cooled to room temperature, and
concentrated in vacuo. The yellow residue was dissolved in
CH.sub.2Cl.sub.2 (1 ml) and cyclopropylamine (30 .mu.l, 0.427
mmole) was added. The resulting mixture was stirred at ambient
temperature for 16 hours, diluted with CH.sub.2Cl.sub.2 (10 ml),
and washed with H.sub.2O (5 ml). The aqueous layer was extracted
with CH.sub.2Cl.sub.2 (2.times.5 ml) and the combined organics were
dried (Na.sub.2SO.sub.4), filtered, and concentrated in vacuo. The
crude mixture was purified by silica gel chromatography (5%
MeOH/EtOAc) to afford 20 mg (46%) of a pale yellow solid. .sup.1H
NMR (DMSO-d.sub.6, 300 MHz) .delta. 8.58 (1H, d, J=5.3 Hz), 8.46
(1H, d, J=4.5 Hz), 8.06 (1H, s) 7.96 (1H, d, J=2.3 Hz), 7.81 (1H,
J=8.7 Hz), 7.32 (1H, dd, J=2.3, 8.7 Hz), 6.75 (1H, d, J=5.3 Hz),
4.10-3.82 (4H, m), 3.61 (2H, m), 3.27, 3.24 (3H, s), 2.91 (1H, m),
2.72 (1H, m), 2.57 (3H, s), 0.76-0.70 (2H, m), 0.50-0.55 (2H, m).
Anal. Calcd. for C.sub.26H.sub.25N.sub.3O.sub.4S.sub.2: C, 61.52;
H, 4.96; N, 8.28; S, 12.63. Found: C, 59.30; H, 4.78; N, 7.95; S,
12.23.
Example 12(a)
6-methoxy-2-methylbenzofuran
[0248] ##STR54##
[0249] A pressure tube was charged with a stir bar
2-Iodo-5-methoxyphenol (500 mg, 2.0 mmol) (prepared according to
Heterocycles 45, (6), 1997, 1137), Cl.sub.2Pd(PPh.sub.3).sub.2 (70
mg, 0.1 mmol), CuI (19 mg, 0.1 mmol), 1,1,3,3-Tetramethylguanidine
(2.5 ml, 20.0 mmol) and DMF (10 ml), then cooled to -78.degree.
while propyne gas was condensed. The tube was sealed and allowed to
warm to room temperature. After 18 hours, the contents of the tube
were poured into sat NaCl solution and extracted with EtOAc
(2.times.). The combined organic layers were washed with brine
(3.times.), dried (MgSO.sub.4) and concentrated under reduced
pressure. The residue was flash chromatographed on silica gel
eluting 3:1 (hexanes/ethyl acetate) to give 239 mg (74%) of an
amber liquid. .sup.1H NMR (DMSO-d.sub.6) .delta. 7.31 (1H, d, J=8.3
Hz), 6.95 (1H, d, J=2.2 Hz), 6.80 (1H, dd, J=2.2, 8.3 Hz), 6.27
(1H, s), 3.85 (3H, s), 2.40 (3H, s). Anal. Calcd for
C.sub.10H.sub.10O.sub.2.0.05 hexanes: C, 74.30; H, 6.48. Found: C,
74.63; H, 6.48.
Example 12(b)
6-methoxy-2-methylbenzofuran-3-carboxylic acid methylamide
[0250] ##STR55##
[0251] This material was prepared from 6-methoxy-2methylbenzofuran
11a (500 mg, 3.1 mmole) by acylation with oxalyl chloride in the
presence of AlCl.sub.3, followed by treatment with methylamine in a
manner as previously described for example 1c to give 541 mg (80%)
of an off-white solid. .sup.1H NMR (CDCl.sub.3) .delta. (as a pair
of rotamers) 7.48, 7.41 (1H, d, J=8.6 Hz), 6.98, 6.55 (1H, s),
6.89, 6.71 (1H, dd, J=2.3, 8.6 Hz), 6.22, 5.83 (1H, bs), 3.84, 3.82
(3H, s), 3.03, 2.93 (3H, d, J=4.8 Hz), 2.69, 2.38 (3H, s). Anal.
Calcd for C.sub.12H.sub.13NO.sub.3: C, 65.74; H, 5.98; N, 6.39.
Found: C, 65.86; H, 5.96; N, 6.35.
Example (12c)
6-hydroxy-2-methylbenzofuran-3-carboxylic acid methylamide
[0252] ##STR56##
[0253] This material was prepared from
6-methoxy2methylbenzo[b]furan-3-carboxylic acid methylamide 11b
(516 mg, 2.35 mmol) by treatment with BBr.sub.3 in a manner as
previously described for example 1d to give 429 mg (89%) of an
off-white solid. .sup.1H NMR (DMSO-d.sub.8) .delta. 9.54 (1H, s),
7.80 (1H, d, J=4.5 Hz), 7.50 (1H, d, J=8.3 Hz), 6.88 (1H, s), 6.72
(1H, d, J=8.3 Hz), 2.79 (3H, d, J=4.5 Hz), 2.57 (3H, s). Anal.
Calcd for C.sub.11H.sub.11NO.sub.3.0.1EtOAc: C, 63.97; H, 5.56; N,
6.54. Found: C, 63.87; H, 5.68; N, 6.45.
Example 12
6-(2-[3-methoxypyrrolidine-1-carbonyl]thieno[3,2-b]pyridin-7-yloxy)-2-meth-
ylbenzofuran-3-carboxylic acid methylamide
[0254] ##STR57##
[0255] This material was prepared by the reaction of
7-chloro-2-[(R)-3-methoxypyrrolidine-1-carbonyl]thieno[3,2-b]pyridine
4b (144 mg, 0.5 mmole) with
6-hydroxy-2-methylbenzo[b]furan-3-carboxylic acid methylamide 11c
(120 mg, 0.6 mmole) and Cs.sub.2CO.sub.3 (794 mg, 2.4 mmole) in a
manner as previously described for example 1 to give 134 mg (59%)
of an off-white solid. .sup.1H NMR (DMSO-d.sub.6) .delta. 8.58 (1H,
d, J=5.3 Hz), 8.07 (1H, s), 7.97 (1H, d, J=4.5 Hz), 7.83 (1H, d,
J=8.6 Hz), 7.65 (1H, d, J=2.0 Hz), 7.24 (1H, dd, J=2.0, 8.6 Hz),
6.72 (1H, d, J=5.3 Hz), 4.25-3.75 (3H, m), 3.65-3.45 (2H, m), 3.27,
3.24 (3H, s), 2.82 (3H, d, J=4.3 Hz), 2.62 (3H, s), 2.15-1.95 (2H,
m). Anal. Calcd for C.sub.24H.sub.23N.sub.3O.sub.5S.0.5H.sub.2O: C,
60.74; H, 5.10; N, 8.86; S, 6.76. Found: C, 60.89; H, 5.16; N,
8.69; S, 6.58.
Example 13
2-methyl-6-[2-(1-methyl-1H-imidazol-2-yl)-thieno[3,2-b]pyridin-7-yloxy]-be-
nzofuran-3-carboxylic acid methylamide
[0256] ##STR58##
[0257] This material was prepared by the reaction of
7-chloro-2-(1-methyl-1H-imidazol-2-yl)thieno[3,2-b]pyridine 1e with
6-hydroxy-2-methylbenzo[b]furan-3-carboxylic acid methylamide 11c
and Cs.sub.2CO.sub.3 in a manner as previously described for
example 1 to give a 51% yield of a light yellow solid. .sup.1H NMR
(DMSO-d.sub.6) .delta. 8.50 (1H, d, J=5.6 Hz), 8.01 (1H, d, J=4.5
Hz), 7.88 (1H, s), 7.82 (1H, d, J=8.6 Hz), 7.64 (1H, s), 7.40 (1H,
s), 7.25 (1H, d, J=8.3 Hz), 7.03 (1H, s), 6.66 (1H, d, J=5.6 Hz),
3.97 (3H, s), 2.81 (3H, d, J=4.5 Hz), 2.64 (3H,s). Anal. Calcd for
C.sub.22H.sub.18N.sub.4O.sub.3S.0.25H.sub.2O: C, 62.47; H, 4.41; N,
13.25; S, 7.29. Found: C, 62.57; H, 4.37; N, 13.05; S, 7.29.
Example 14(a)
6-methoxy-2-ethylbenzofuran
[0258] ##STR59##
[0259] This material was prepared from 2-iodo-5-methoxyphenol (1 g,
4 mmole) and 1-butyne in a manner as previously described for
example 12a to give 570 mg (81%) of a brown oil. .sup.1H NMR
(CDCl.sub.3) .delta. 7.33 (1H, d, J=8.6 Hz), 6.97 (1H, d, J=2.2
Hz), 6.80 (1H, dd, J=2.2, 8.6 Hz), 6.26 (1H, s), 3.83 (3H, s), 3.04
(2H, q, J=7.3 Hz), 1.28 (3H, t, J=7.3 Hz).
Example 14(b)
methoxy-2-ethylbenzofuran-3-carboxylic acid methylamide
[0260] ##STR60##
[0261] Example 14(b) was prepared from 6-methoxy-2-ethylbenzofuran
14a (522 mg, 2.96 mmole) by acylation with oxalyl chloride in the
presence of AlCl.sub.3, followed by treatment with methylamine in a
manner as previously described in Example 1c to give 433 mg (63%)
of an off-white solid. .sup.1HNMR (DMSO-d.sub.6) .delta.7.83 (1H,
d, J=4.8 Hz), 7.56 (1H, d, J=8.8 Hz), 7.23 (1H, d, J=2.3 Hz), 6.83
(1H, dd, J=2.3, 8.8 Hz), 3.78 (3H, s), 3.05 (2H, q, J=7.2 Hz), 2.80
(3H, d, J=4.8 Hz), 1.26 (3H, t, J=7.2 Hz). Anal. Calcd for
C.sub.13H.sub.15NO.sub.3: C, 66.93; H, 6.48; N, 6.00. Found: C,
66.96; H, 6.46; N, 5.95.
Example (14c)
6-hydroxy-2-ethyl benzofuran-3-carboxylic acid methylamide
[0262] ##STR61##
[0263] Example 14(c) was prepared from
6-methoxy-2-ethylbenzo[b]furan-3-carboxylic acid methylamide 14b
(401 mg, 1.72 mmole) by treatment with BBr.sub.3 in a manner as
previously described for example 1d to give 318 mg (84%) of an
off-white solid. .sup.1H NMR (DMSO-d.sub.6) .delta. 9.53 (1H, s),
7.79 (1H, d, J=4.6 Hz), 7.45 (1H, d, J=8.6 Hz), 6.88 (1H, d, J=2.0
Hz), 6.74 (1H, dd, J=2.0, 8.6 Hz), 3.03 (2H, q, J=7.3 Hz), 2.77
(3H, d, J=4.6 Hz), 1.24 (3H, t, J=7.3 Hz). Anal. Calcd for
C.sub.12H.sub.13NO.sub.3: C, 65.74; H, 5.98; N, 6.39. Found: C,
65.61; H, 6.06; N, 6.32.
Example 14
6-(2-[3-methoxypyrrolidine-1-carbonyl]thieno[3,2-b]pyridin-7-yloxy)-2-ethy-
lbenzofuran-3-carboxylic acid methylamide
[0264] ##STR62##
[0265] Example 14 was prepared by the reaction of
7-chloro-2-[(R)-3-methoxypyrrolidine-1-carbonyl]thieno[3,2-b]pyridine
4b (135 mg, 0.46 mmole) with
6-hydroxy-2-ethylbenzo[b]furan-3-carboxylic acid methylamide 14c
(120 mg, 0.55 mmole) and Cs.sub.2CO.sub.3 (594 mg, 1.82 mmole) in a
manner as previously described for example 1 to give 75 mg (34%) of
an off-white solid. .sup.1H NMR (DMSO-d.sub.6) .delta. 8.57 (1H, d,
J=5.4 Hz), 8.07 (1H, s), 8.01 (1H, d, J=4.5 Hz), 7.83 (1H, d, J=8.6
Hz), 7.68 (1H, d, J=2.0 Hz), 7.26 (1H, dd, J=2.0, 8.6 Hz), 6.73
(1H, d, J=5.4 Hz), 4.11-3.82 (3H, m), 3.69-3.43 (2H, m), 3.27, 3.24
(3H, s), 3.05 (2H, q, J=7.5 Hz), 2.82 (3H, d, J=4.5 Hz), 2.18-1.94
(2H, m), 1.27 (3H, t, J=7.5 Hz). Anal. Calcd for
C.sub.25H.sub.25N.sub.3O.sub.5S.0.2CH.sub.2Cl.sub.2.0.25hexane: C,
61.90; H, 5.62; N, 8.11; S, 6.19. Found: C, 61.88; H, 5.64; N,
8.03; S, 6.11.
Example 15(a)
6-methoxy-2-(1-methylethyl)benzofuran
[0266] ##STR63##
[0267] Example 15(a) was prepared from 2-iodo-5-methoxyphenol (896
mg, 3.6 mmole) and 3-methyl-1-butyne in a manner as previously
described for example 12a to give 265 mg (38%) of an amber oil.
.sup.1H NMR (CDCl.sub.3) .delta. 7.33 (1H, d, J=8.6 Hz), 6.97 (1H,
d, J=2.2 Hz), 6.80 (1H, dd, J=2.2, 8.6 Hz), 6.26 (1H, s), 3.83 (3H,
s), 3.07-3.01 (1H, m), 1.31 (6H, d, J=7.1 Hz).
Example 15(b)
6-methoxy-2-(1-methylethyl)benzofuran-3-carboxylic acid
methylamide
[0268] ##STR64##
[0269] Example 15(b) was prepared from
6-methoxy-2-(1-methylethyl)benzofuran 15a (263 mg, 1.36 mmole) by
acylation with oxalyl chloride in the presence of AlCl.sub.3,
followed by treatment with methylamine in a manner as previously
described for example 1c to give 200 mg (60%) of an off-white
solid. .sup.1H NMR (DMSO-d.sub.6) .delta. 7.83 (1H, d, J=4.8 Hz),
7.56 (1H, d, J=8.8 Hz), 7.20 (1H, d, J=2.3 Hz), 6.89 (1H, dd,
J=2.3, 8.8 Hz), 3.78 (3H, s), 3.68-3.61 (1H, m), 2.78 (3H, d, J=4.8
Hz), 1.26 (6H, d, J=6.8 Hz).
Example 15(c)
6-hydroxy-2-(1-methylethyl)benzofuran-3-carboxylic acid
methylamide
[0270] ##STR65##
[0271] This material was prepared from 6-methoxy-2-(1-methylethyl)
benzo[b]furan-3-carboxylic acid methylamide 15b (173 mg, 0.84
mmole) by treatment with BBr.sub.3 in a manner as previously
described for example 1d to give 157 mg (80%) of a crisp foam.
.sup.1H NMR (DMSO-d.sub.6) .delta. 9.54 (1H, s), 7.76 (1H, d, J=4.6
Hz), 7.45 (1H, d, J=8.6 Hz), 6.88 (1H, d, J=2.0 Hz), 6.74 (1H, dd,
J=2.0, 8.6 Hz), 3.68-3.61 (1H, m), 2.75 (3H, d, J=4.6 Hz), 1.24
(6H, d, J=7.1 Hz).
Example 15
6-(2-[3-methoxypyrrolidine-1-carbonyl]thieno[3,2-b]pyridin-7-yloxy)-2-(1-m-
ethylethyl)benzofuran-3-carboxylic acid methylamide
[0272] ##STR66##
[0273] This material was prepared by the reaction of
7-chloro-2-[(R)-3-methoxypyrrolidine-1-carbonyl]thieno[3,2-b]pyridine
4b (122 mg, 0.41 mmole) with
6-hydroxy-2-(1-methylethyl)benzo[b]furan-3-carboxylic acid
methylamide 15c (125 mg, 0.53 mmole) and Cs.sub.2CO.sub.3 (200 mg,
0.61 mmole) in a manner as previously described for example 1 to
give 82 mg (40%) of a white solid. .sup.1H NMR (DMSO-d.sub.6)
.delta. 8.56 (1H, d, J=5.3 Hz), 8.06 (1H, s), 8.01 (1H, d, J=4.6
Hz), 7.79 (1H, d, J=8.6 Hz), 7.68 (1H, d, J=2.2 Hz), 7.25 (1H, dd,
J=2.2, 8.6 Hz), 6.73 (1H, d, J=5.3 Hz), 4.15-3.85 (3H, m),
3.70-3.45 (3H, m), 3.27, 3.24 (3H, s), 2.82 (3H, d, J=4.6 Hz),
2.15-1.95 (2H, m), 1.30 (6H, d, J=7.1 Hz). Anal. Calcd for
C.sub.26H.sub.27N.sub.3O.sub.5S.0.2H.sub.2O/0.2MTBE: C, 62.99; H,
5.84; N, 8.186; S, 6.23. Found: C, 62.92; H, 5.93; N, 7.97; S,
6.07.
Example 16(a)
6-methoxy-1H-indole-3-carboxylic acid
[0274] ##STR67##
[0275] The preparation of the title compound was adapted from work
previously published by Swain et al (J. Med. Chem. 1992, 35,
1019-1031). To a stirring solution of 6-methoxy-1H-indole (10 g, 68
mmole) in DMF (100 ml) at 0.degree. C. was added triflouroacetic
anhydride (21.4 ml, 150 mmole) dropwise. After the addition, the
mixture was heated at 165.degree. for 18 hours. The mixture was
removed from heat and added dropwise to ice water (1 L). The
resulting precipitate was collected by filtration, washed with
water then suspended in 20% aq. NaOH (200 ml). The suspension was
heated at 90.degree. until homogeneous (.about.2 hr). The dark
mixture was allowed to cool to RT and was washed with Et.sub.2O
(200 ml). The aqueous layer was washed with CH.sub.2Cl.sub.2. A
precipitate formed during the extraction which was collected by
filtration. The filtrate was divided into layers and the aqueous
layer acidified to pH 3 using 6N HCl resulting in the formation of
a precipitate. The previously collected solids were added to the
suspension and the mixture was stirred for 3 hours. The mixture was
acidified to pH 2 using 6N HCl and the solids collected by
filtration. The solids were washed with water and dried in air to
give 10.08 g (77%) of an off-white solid which was carried on
without further purification. .sup.1H NMR (DSMO-d.sub.6) .delta.
11.53 (1H, broad s), 7.88 (1H, d, J=8.7 Hz), 7.75 (1H, s), 6.91
(1H, d, J=2.0 Hz), 6.74 (1H, dd, J=2.0, 8.7 Hz), 3.75 (3H, s).
Example 16(b)
6-methoxy-1-methyl-1H-indole-3-carboxylic acid
[0276] ##STR68##
[0277] To a stirring solution of 6-methoxy-1H-indole-3-carboxylic
acid 16a (8.0 g, 41.2 mmole) in anhydrous DMF (100 ml) at 0.degree.
was added NaH (60% dispersion in oil, 4.12 g, 103 mmole) in a
single portion. After stirring at 0.degree. C. for 1.3 hour,
iodomethane (7.5 ml, 120 mmole) was added via syringe. The
resultant mixture was stirred for 18 hours, gradually warming to
room temperature, then poured into 0.2N NaOH (1 L) and extracted
with EtOAc (3.times.250 ml). The combined extracts were washed
sequentially with 1N NaOH (50 ml), water (3.times.50 ml), and brine
(50 ml) then dried over Na.sub.2SO.sub.4 and concentrated, in
vacuo. The resulting crude
6-methoxy-1-methyl-1H-indole-3-carboxylic acid methyl ester was
triturated with hexanes and collected by filtration. This material
was suspended in aqueous KOH (3.36 g, 60 mmol in 150 ml) and the
resulting suspension heated at reflux for 3.5 hours. The mixture
was then poured onto 200 g of ice and washed with CH.sub.2Cl.sub.2
(2.times.50 ml). The aqueous layer was acidified with 6N HCl to pH
2 resulting in a white precipitate which was collected by
filtration, washed with water and air dried to yield 7.25 g (86%)
of the title compound which was carried on without any further
purification. .sup.1H NMR (DMSO-d 6) .delta. 11.84 (1H, broad s),
7.88 (1H, s), 7.84 (1H, d, J=8.7 Hz), 7.02 (1H, d, J=2.2 Hz), 6.82
(1H, dd, J=2.2, 8.7 Hz), 3.81 (3H, s), 3.79 (3H, s). Anal. Calcd.
for C.sub.11H.sub.11NO.sub.3.0.2H.sub.2O: C, 63.27; H, 5.50; N,
6.71. Found: C, 63.36; H, 5.35; N, 6.63.
Example 16(c)
1,2-dimethyl-6-methoxy-1H-indole-3-carboxylic acid
[0278] ##STR69##
[0279] The preparation of the title compound was adapted from work
previously published by Buttery et al (J. Chem. Soc. Perkin Trans.
1993, 1425-1431). A solution of
6-methoxy-1-methyl-1H-indole-3-carboxylic acid 16b (5.2 g, 25.4
mmole) in anhydrous THF (100 ml) was added dropwise over 30 minutes
to a stirring solution of LDA [made from n-BuLi (69 mmole) and
diisopropylamine (60 mmole)] in anhydrous THF (50 ml) at
-78.degree. C. The resulting mixture was allowed to warm to
-10.degree. C. over 30 minutes, then cooled to -78.degree. C. prior
to addition of iodomethane (8 ml, 128.5 mmole) via syringe. The
resulting amber mixture was allowed to warm to 15.degree. C. over 3
hours, then was washed with 1N NaOH (100 ml). A precipitate formed
during the separation that was collected by filtration. The
filtrate was separated into layers. The organic layer was washed
again with 1N NaOH (50 ml). The solids were suspended in water and
the resulting suspension acidified to pH 3 using 0.5 N HCl. The
resulting thick suspension was sonicated and stirred for 15
minutes, then the solids were collected by filtration and washed
with water. The combined NaOH layers from above were acidified to
pH 4 using 6N HCl to yield another batch of solids which was
collected by filtration and washed with water. The first batch of
solids was suspended in hot CHCl.sub.3:MeOH (3:1) and the insoluble
material collected by filtration. This isolate was found to be
desired product. The filtrate was concentrated to dryness under
reduced pressure and the residue triturated twice with warm
CHCl.sub.3 to yield a second crop of product. The solids obtained
from acidification of the basic aqueous layer were triturated three
times with warm CHCl.sub.3 to yield a third crop of product. The
three crops were combined, triturated with MTBE and filtered to
give 3.13 g (56%) of a white solid. This material was of suitable
purity to be carried on without further purification. .sup.1H NMR
(DMSO-d.sub.6) .delta. 11.83 (1H, broad s), 7.81 (1H, d, J=8.6 Hz),
7.03 (1H,d, J=2.3 Hz), 6.76 (1H, dd, J=2.3, 8.6 Hz), 3.79 (3H, s),
3.67 (3H, s), 2.67 (3H, s). Anal. calcd for
C.sub.12H.sub.13NO.sub.3.0.2H.sub.2O: C, 64.68; H, 6.06; N, 6.29.
Found: C, 64.89; H, 5.91; N, 6.29.
Example 16(d)
6-methoxy-1,2-dimethyl-1H-indole-3-carboxylic acid methylamide
[0280] ##STR70##
[0281] To a stirring solution of the carboxylate 16c (700 mg, 3.2
mmole) in anhydrous CH.sub.2Cl.sub.2 (15 ml) at 0.degree. C. was
added a drop of DMF, followed by oxalyl chloride (0.55 ml, 6.4
mmole) via syringe. After stirring at 0.degree. C. for 15 minutes,
the ice bath was removed and the mixture was stirred at ambient
temperature for 55 minutes. The mixture was diluted with benzene
and concentrated to dryness under reduced pressure. The residue was
dissolved in CH.sub.2Cl.sub.2 (10 ml) and added via syringe to a 2
M solution of methylamine in THF (30 ml). After observing a slight
exotherm upon the start of the addition, the mixture was cooled to
0.degree. for the remainder of the addition. The reaction was
stirred for a further 16 hours, gradually warming to room
temperature, then partitioned between CH.sub.2Cl.sub.2 (100 ml) and
1N NaOH (100 ml). The organic layer was washed sequentially with 1N
NaOH (50 ml), brine (50 ml), then dried over Na.sub.2SO.sub.4 and
concentrated, in vacuo. The crude residue was triturated with MTBE
and filtered to give 590 mg (79%) of a white solid. .sup.1H NMR
(DMSO-d.sub.6) .delta. 7.60 (1H, d, J=8.6 Hz), 7.39-7.35 (1H, m),
7.00 (1H,d, J=2.3 Hz), 6.72 (1H, dd, J=2.3, 8.6 Hz), 3.79 (3H, s),
3.63 (3H, s), 2.76 (3H, d, J=4.6 Hz), 2.53 (3H, s).
[0282] Anal. Calcd. for C.sub.13H.sub.16N.sub.2O.sub.2: C, 67.22;
H, 6.54; N, 12.06. Found: C, 67.00; H, 6.95; N, 11.99.
Example 16(e)
6-hydroxy-1,2-dimethyl-1H-indole-3-carboxylic acid methylamide
[0283] ##STR71##
[0284] Example 16(e) was prepared from
6-methoxy-1,2-dimethyl-1H-indole-3-carboxylic acid methylamide 16d
(560 mg, 2.4 mmole) by treatment with BBr.sub.3 in a manner as
previously described for example 1d to obtain 380 mg (73%) of white
solid. .sup.1H NMR (DMSO-d 6) .delta. 9.05 (1H, s), 7.50 (1H, d,
J=8.59 Hz), 7.35-7.28 (1H, m), 6.73 (1H,d, J=1.77 Hz), 6.60 (1H,
dd, J=8.5, 2.27 Hz), 3.54 (3H, s), 2.75 (3H, d, J=4.55 Hz), 2.53
(3H, s). Anal. Calcd. for
C.sub.12H.sub.14N.sub.2O.sub.2.0.3H.sub.2O: C, 64.44; H, 6.58; N,
12.53. Found: C, 64.55; H, 6.49; N, 12.35.
Example 16
6-[2-(2-Hydroxymethyl-pyrrolidine-1-carbonyl)-thieno[3,2-b]pyridin-7-yloxy-
]-1,2-dimethyl-1H-indole-3-carboxylic acid methylamide
[0285] ##STR72##
[0286] This material was prepared by the reaction of
7-chloro-2-[(S)-2-([t-butyldimethylsilyloxy]methyl)-pyrrolidine-1-carbony-
l]thieno[3,2-b]pyridine 3b (76 mg, 0.3 mmole) with
6-hydroxy-1,2-dimethyl-1H-indole-3-carboxylic acid methylamide 16e
(100 mg, 0.46 mmole) and Cs.sub.2CO.sub.3 (488 mg, 1.5 mmole) in a
manner as previously described for example 1 to give 53 mg (43%) of
an off-white solid. .sup.1H NMR (DMSO-d.sub.6) .delta. 8.54 (1H, d,
J=5.46 Hz), 7.99 (1H, s), 7.83 (1H, d, J=8.67 Hz), 7.61-7.55 (1H,
m), 7.54 (1H, d, J=2.07 Hz), 7.03 (1H, dd, J=8.48, 2.07 Hz), 6.64
(1H, d, J=5.27 Hz), 5.10-4.80 (1H, 2m), 4.41-4.16 (1H, 2m),
3.91-3.77 (1H, m), 3.67 (3H, s), 3.64-3.47 (2H, m), 2.80 (3H, d,
J=4.52 Hz), 2.60 (3H, s), 2.04-1.81 (4H, m). Anal. Calcd for
C.sub.25H.sub.26N.sub.4O.sub.4S.0.4H.sub.2O.0.2EtOAc: C, 61.56; H,
5.69;
Example 17
1,2-dimethyl-6-(2-[1-methyl-1H-imidazol-2-yl]thieno[3,2-b]pyridin-7-yloxy)-
-1H-indole-3-carboxylic acid methylamide
[0287] ##STR73##
[0288] This material was prepared by the reaction of
7-chloro-2-(1-methyl-1H-imidazol-2-yl)thieno[3,2-b]pyridine 1e (76
mg, 0.3 mmole) with 6-hydroxy-1,2-dimethyl-1H-indole-3-carboxylic
acid methylamide 16e (100 mg, 0.46 mmole) and Cs.sub.2CO.sub.3 (488
mg, 1.5 mmole) in a manner as previously described for example 1 to
give 51 mg (39%) of product as an off-white solid. .sup.1H NMR
(DMSO-d.sub.6) .delta. 8.48 (1H, d, J=5.5 Hz), 7.88 (1H, s), 7.83
(1H, d, J=8.6 Hz), 7.61-7.55 (1H, m), 7.53 (1H, t, J=2.3 Hz),
7.41(1H, d, J=1.0 Hz), 7.0-6.99 (2H, m), 6.59 (1H, d, J=5.5 Hz),
3.98 (3H, s), 3.67 (3H, s), 2.80 (3H, d, J=4.6 Hz), 2.60 (3H, s).
Anal. Calcd for
C.sub.23H.sub.21N.sub.5O.sub.2S.0.3H.sub.2O.0.1EtOAc: C, 63.05; H,
5.07; N, 15.71; S: 7.19. Found: C, 63.06; H, 5.06; N, 15.56; S:
6.96.
Example 18
1,2-dimethyl-6-(2-[3-methoxy-pyrrolidine-1-carbonyl]thieno[3,2-b]pyridin-7-
-yloxy)-1H-indole-3-carboxylic acid methylamide
[0289] ##STR74##
[0290] This material was prepared by the reaction of
7-chloro-2-[(R)-3-methoxypyrrolidine-1-carbonyl]thieno[3,2-b]pyridine
4b (157 mg, 0.5 mmole) with
6-hydroxy-1,2-dimethyl-1H-indole-3-carboxylic acid methylamide 16e
(150 mg, 0.7 mmole) and Cs.sub.2CO.sub.3 (673 mg, 2.1 mmole) in a
manner as previously described for example 1 to give 51 mg (39%) of
a crisp foam. .sup.1H NMR (DMSO-d.sub.6) .delta. 8.54 (1H, dd,
J=5.5, 1.13 Hz), 8.05 (1H, s), 7.84 (1H, d, J=8.6 Hz), 7.61-7.55
(1H, m), 7.54 (1H, d, J=2.1 Hz), 7.03(1H, dd, J=2.1, 8.6 Hz), 6.64
(1H, d, J=5.5 Hz), 4.12-3.51 (5H, m), 3.67 (3H, s), 3.27, 3.24 (3H,
2s), 2.80 (3H, d, J=4.5 Hz), 2.60 (3H, s), 2.35-1.95 (2H, m). Anal.
Calcd for C.sub.25H.sub.26N.sub.4O.sub.4S.0.9H.sub.2O.0.2EtOAc: C,
60.47; H, 5.78; N, 10.93; S, 6.26. Found: C, 60.46; H, 5.56; N,
10.81; S, 6.34.
Example 19
1,2-dimethyl-6-(2-[3-hydroxy-pyrrolidine-1-carbonyl]thieno[3,2-b]pyridin-7-
-yloxy)-1H-indole-3-carboxylic acid methylamide
[0291] ##STR75##
[0292] This material was prepared from
1,2-dimethyl-6-(2-[3-methoxy-pyrrolidine-1-carbonyl]thieno[3,2-b]pyridin--
7-yloxy)-1H-indole-3-carboxylic acid methylamide 18 (128 mg, 0.27
mmole) by treatment with BBr.sub.3 in a manner as previously
described for example 1d to give 70 mg (56%) of a white solid.
.sup.1H NMR (DMSO-d.sub.6) .delta. 8.54 (1H, dd, J=5.3, 1.1 Hz),
8.05, 7.99 (1H, 2s), 7.83 (1H, d, J=8.6 Hz), 7.61-7.55 (1H, m),
7.54 (1H, d, J=2.2 Hz), 7.03 (1H, dd, J=2.2, 8.6 Hz), 6.64 (1H, dd,
J=5.3, 1.1 Hz), 5.10-5.05 (1H, m), 4.41-4.31 (1H, m), 4.00-3.90
(1H, m), 3.67 (3H, s), 3.66-3.42 (3H, m), 2.80 (3H, d, J=4.5 Hz),
2.60 (3H, s), 2.06-1.92 (2H, m). Anal. Calcd for
C.sub.24H.sub.24N.sub.4O.sub.4S.0.9H.sub.2O: C, 59.96; H, 5.41; N,
11.65; S, 6.67. Found: C, 59.87; H, 5.19; N, 11.51; S, 6.48.
Example 20(a)
6-Methoxy-1,2-dimethyl-1H-indol-3-carboxylic acid
cyclopropylamide
[0293] ##STR76##
[0294] This material was prepared from
1,2-dimethyl-6-methoxy1H-indole-3-carboxylic acid 16c (500 mg, 2.3
mmole), oxalyl chloride (0.4 ml, 4.6 mmole) and cyclopropylamine
(1.6 ml, 23 mmole) in a manner as previously described for example
16d to give 480 mg (82%) of a white solid. .sup.1H NMR
(DMSO-d.sub.6 .delta. 7.57 (1H, d, J=3.8 Hz), 7.50 (1H, d, J=8.8
Hz), 6.99 (1H, d, J=2.3 Hz), 6.71 (1H, dd, J=2.3, 8.8 Hz), 3.78
(3H, s), 3.63 (3H, s), 2.83-2.80 (1H, m), 2.51 (3H, s), 0.68-0.62
(2H, m), 0.57-0.53 (2H, m).
Example 20(b)
6-Hydroxy-1,2-dimethyl-1H-indol-3-carboxylic acid
cyclopropylamide
[0295] ##STR77##
[0296] This material was prepared from
6-methoxy-1,2-dimethyl-1H-indole-3-carboxylic acid cyclopropylamide
20a (655 mg, 2.5 mmole) by treatment with BBr.sub.3 in a manner as
previously described for example 1d to give 130 mg (21%) of a white
solid. .sup.1H NMR (DMSO-d 6) .delta. 9.06 (1H, s), 7.51 (1H, d,
J=4.0 Hz), 7.41 (1H, d, J=8.5 Hz), 6.73 (1H, d, J=1.8 Hz), 6.60
(1H, dd, J=1.8, 8.5 Hz), 3.56 (3H, s), 2.82 (1H, m), 2.50 (3H, s),
0.62 (2H, m), 0.52 (2H, m).
Example 20
1,2-Dimethyl-6-[2-(1-methyl-1H-imidazol-2-yl)-thieno[3,2-b]pyridin-7-yloxy-
]-1H-indole-3-carboxylic acid cyclopropylamide
[0297] ##STR78##
[0298] This material was prepared by the reaction of
7-chloro-2-(1-methyl-1H-imidazol-2-yl)thieno[3,2-b]pyridine 1e (79
mg, 0.3 mmole) with 1,2-dimethyl-6-hydroxy-1H-indole-3-carboxylic
acid cyclopropylamide 20b (93 mg, 0.4 mmole) and Cs.sub.2CO.sub.3
(517 mg, 1.6 mmole) in a manner as previously described for example
1 to give 84 mg (58%) of a white solid. .sup.1H NMR (DMSO-d.sub.6)
.delta. 8.47 (1H, d, J=4.9 Hz), 7.87 (1H, s), 7.78 (1H, d, J=3.7
Hz), 7.72 (1H, d, J=8.5 Hz), 7.52 (1H, s), 7.40 (1H, s), 7.02 (1H,
s), 7.01 (1H, d, J=8.9 Hz), 6.58 (1H, d, J=5.3 Hz), 3.98 (3H, s),
3.67 (3H, s), 2.85 (1H, m), 2.57 (3H, s), 0.68 (2H, m), 0.58 (2H,
m). Anal. Calcd for C.sub.25H.sub.23N.sub.5O.sub.2S.0.5MeOH: C,
64.67; H, 5.32; N, 14.79; S, 6.77. Found: C, 64.57; H, 5.24; N,
14.72; S, 6.81
Example 21(a)
6-methoxy-1-methyl-1H-indole-3-carboxylic acid methylamide
[0299] ##STR79##
[0300] This material was prepared from
6-methoxy-1-methyl-indole-3-carboxylic acid 16b (515 mg, 2.5
mmole), oxalyl chloride (0.9 ml, 12.6 mmole) and methylamine (7.5
mmole) in a manner as previously described for example 16d to give
457 mg of a pale brown solid (83%). .sup.1H NMR (CD.sub.3OD)
.delta. 7.83 (1H, d, J=8.7 Hz), 7.51 (1H, s), 6.81 (1H, d, J=2.3
Hz), 6.72 (1H, dd, J=2.3, 8.7 Hz), 3.75 (3H, s), 3.67 (3H, s), 2.80
(3H, s); ESIMS (MH.sup.+): 219.05.
Example 21(b)
6-hydroxy-1-methyl-1H-indole-3-carboxylic acid methylamide
[0301] ##STR80##
[0302] This material was prepared from
6-methoxy-1-methyl-1H-indole-3-carboxylic acid methylamide 21a (453
mg, 2.1 mmol) by treatment with BBr.sub.3 in a manner as previously
described for example 1d to give 219 mg (51%) of a pale orange
solid. .sup.1H NMR (CD.sub.3OD) .delta. 7.75 (1H, d, J=8.5 Hz),
7.47 (1H, s), 6.61-6.66 (2H, m), 3.62 (3H, s), 3.24 (1H, s), 2.79
(3H, s). ESIMS (MH.sup.+): 205.10.
Example 21
6-{2-[3-(R)-hydroxy-pyrrol
idine-1-carbonyl]thieno[3,2-b]pyridin-7-yloxy}-1-methyl-1H-indole-3-carbo-
xylic acid methylamide
[0303] ##STR81##
[0304] This material was prepared by the reaction of
7-chloro-2-[(R)-3-hydroxypyrrolidine-1-carbonyl]thieno[3,2-b]pyridine
4a (152 mg, 0.5 mmole) with
6-hydroxy-1-methyl-1H-indole-3-carboxylic acid methylamide 21b (110
mg, 0.5 mmole) and Cs.sub.2CO.sub.3 (176 mg, 0.5 mmole) in a manner
as previously described for example 1 to give 65 mg (27%) of a
white solid. .sup.1H NMR (CD.sub.3OD) .delta. 8.39 (1H, d, J=5.5
Hz), 8.12 (1H, d, J=8.7 Hz), 7.77 (1H, d, J=17.33 Hz), 7.72 (1H,
s), 7.32 (2H, m), 6.99 (dd, 1H, J.sub.1=6.59 Hz, J.sub.2=2.08 Hz),
6.60 (1H, d, J=5.5 Hz), 4.43 (m, 1H), 3.95 (1H, m), 3.73 (3H, s),
3.59-3.69 (3H, m), 2.83 (3H, s), 2.01 (2H, m). ESIMS (MH.sup.+):
451.10; Anal. Calcd. For
C.sub.23H.sub.22N4O.sub.4S.0.6CH.sub.3OH.0.2CH.sub.2Cl.sub.2: C,
57.91; H, 5.02; N, 11.35. Found: C, 57.68; H, 5.06; N, 11.43.
Example 22
6-[2-(3-methoxypyrrolidine-1-carbonyl)-thieno[3,2-b]pyridin-7-yloxy]-1-met-
hyl-1H-indole-3-carboxylic acid methylamide
[0305] ##STR82##
[0306] This material was prepared by the reaction of
7-chloro-2-[(R)-3-methoxypyrrolidine-1-carbonyl]thieno[3,2-b]pyridine
4b with 6-hydroxy-1-methyl-1H-indole-3-carboxylic acid methylamide
21 band Cs.sub.2CO.sub.3 in a manner as previously described for
example 1. .sup.1H NMR (300 MHz, CD.sub.3OD) .delta. 8.53 (1H, d,
J=5.5 Hz), 8.25 (1H, d, J=8.7 Hz), 7.96 (1H, d, J=6.2 Hz), 7.86
(1H, s), 7.46 (1H, d, J=1.9 Hz), 7.12 (1H, d, J=8.5 Hz), 6.74 (1H,
d, J=5.5 Hz), 4.19-4.11 (1H, m), 4.05-3.95 (2H, m), 3.38 (3H, s),
3.85-3.72 (2H, m), 3.40 (3H, d, J=13.9 Hz), 2.96 (3H, s), 2.30-2.09
(2H, m). LCMS (ESI+) [M+H]/z Calc'd 465, found 465. Anal.
(C.sub.24H.sub.24N.sub.4O.sub.4S.0.4CH.sub.2Cl.sub.2) C, H, N.
Example 23
1-Methyl-6-[2-(1-methyl-1H-imidazol-2-yl)-thieno[3,2-b]pyridin-7-yloxy]-1H-
-indole-3-carboxylic acid methylamide
[0307] ##STR83##
[0308] This material was prepared by the reaction of
7-chloro-2-(1-methyl-1H-imidazol-2-yl)thieno[3,2-b]pyridine 1e with
6-hydroxy-1-methyl-1H-indole-3-carboxylic acid methylamide 21 band
Cs.sub.2CO.sub.3 in a manner as previously described for example 1.
.sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 8.43 (1H, d, J=5.5 Hz),
8.05 (1H, d, J=8.7 Hz), 7.67 (1H, s), 7.61 (1H, s), 7.17 (1H, d,
J=2.1 Hz), 7.13 (1H, s), 7.08 (1H, dd, J=2.1, 8.7 Hz), 7.02 (1H,
s), 6.54 (1H, d, J=5.5 Hz), 3.95 (3H, s), 3.75 (3H, s), 3.01 (3H,
s). LCMS (ESI+) [M+H]/z Calc'd 418, found 418. Anal.
(C.sub.22H.sub.19N.sub.5O.sub.2S.0.25EtOAc) C, H, N.
Example 24(a)
6-Methoxy-2-methyl-1H-indol-3-carboxylic acid methylamide
[0309] ##STR84##
[0310] To a stirred solution of 6-methoxy-2-methyl-1H-indole (500
mg, 3.1 mmol) (prepared according to JACS 1988, 110, 2242) in 8 mL
anhydrous THF maintained at room temperature was added
methylmagnesium bromide (1.13 ml, 3.0 M solution in diethyl ether,
3.41 mmol). After stirring for 1 hour at room temperature, a
solution of 0.5M zinc chloride in THF (7.44 ml, 3.72 mmol) was
introduced and the mixture was stirred for 1 hour at room
temperature before addition of methyl isocyanate (424 mg, 7.44
mmol). The resulting mixture was stirred at ambient temperature
overnight, quenched with water, and extracted with EtOAc. The
combined organic layer was washed with brine, dried over
Na.sub.2SO.sub.4, filtered and concentrated. The residue was
purified by flash column chromatography eluting with 2-5% MeOH in
CH.sub.2Cl.sub.2 to give 200 mg product (30% yield). .sup.1H NMR
(300 MHz, CD.sub.3OD) .delta. 7.55 (1H, d, J=8.6 Hz), 6.78 (1H, d,
J=2.2 Hz), 6.70 (1H, dd, J=2.2, 8.6 Hz), 3.73 (3H, s), 2.90 (3H,
s), 2.52 (3H, s). LCMS (ESI+) [M+H]/z Calc'd 219, found 219.
Example 24(b)
6-Hydroxy-2-methyl-1H-indol-3-carboxylic acid methylamide
[0311] ##STR85##
[0312] This material was prepared from
6-methoxy-2-methyl-1H-indol-3-carboxylic acid methylamide 24a by
treatment with BBr.sub.3 in a manner as previously described for
example 1d. .sup.1H NMR (300 MHz, CD.sub.3OD) .delta. 7.52 (1H, d,
J=8.7 Hz), 6.72 (1H, d, J=2.3 Hz), 6.65 (1H, dd, J=2.3, 8.7 Hz),
2.93 (3H, s), 2.55 (3H, s). LCMS (ESI+) [M+H]/z Calc'd 205, found
205.
Example 24
6-[2-(3-Hydroxy-pyrrolidine-1-carbonyl)-thieno[3,2-b]pyridin-7-yloxy]-2-me-
thyl-1H-indole-3-carboxylic acid methylamide
[0313] ##STR86##
[0314] This material was prepared by the reaction of
7-chloro-2-[(R)-3-hydroxypyrrolidine-1-carbynyl]thieno[3,2,-b]pyridine
4a with 6-hydroxy-2-methyl-1H-indol-3-carboxylic acid methylamide
and Cs.sub.2CO.sub.3 in a manner as previously described for
Example 1. .sup.1H NMR (300 MHz, CD.sub.3OD) .delta. 8.48 (1H, d,
J=5.5 Hz), 7.91 (1H, d, J=17.3 Hz), 7.86 (1H, d, J=8.6 Hz), 7.21
(1H, s), 7.00 (1H, d, J=8.6 Hz), 6.69 (1H, d, J=5.5 Hz), 4.50 (1H,
m), 4.05-3.70 (4H, m), 2.97 (3H, s), 2.63 (3H, s), 2.40-1.90 (2H,
m). LCMS (ESI+) [M+H]/z Calc'd 451, found 451.
Example 25 (a)
2-(Azetidin-1-ylcarbonyl)-7-chlorothieno[3,2-b]pyridine
[0315] ##STR87##
[0316] This material was prepared from lithium
7-chlorothieno[3,2-b]pyridine-2-carboxylate (100 mg, 0.47 mmole) by
treatment with thionyl chloride followed by coupling with
azetidine, in a manner as previously described for example 9d to
afford 98 mg (83%) of a dark yellow solid. .sup.1H NMR
(DMSO-d.sub.6) .delta. 8.72 (1H, d, J=5.1 Hz), 7.96 (1H, s), 7.70
(1H, d, J=5.1 Hz), 4.62 (2H, t, J=7.4 Hz), 4.12 (2H, t, J=7.7 Hz),
2.34 (2H, tt, J=7.4, 7.7 Hz).
[0317] Anal. Calcd for C.sub.11H.sub.9N.sub.2OSCl: C, 52.28; H,
3.59; Cl, 14.03; N, 11.09; S, 12.69. Found: C, 52.39; H, 3.63; Cl,
14.29; N, 10.99; S, 12.74.
Example 25
6-[2-(Azetidine-1-carbonyl)-thieno[3,2-b]pyridin-7-yloxy]-1,2-dimethyl-3H--
indole-3-carboxylic acid methylamide
[0318] ##STR88##
[0319] This material was prepared by the reaction of
2-(azetidin-1-ylcarbonyl)-7-chlorothieno[3,2-b]pyridine 25a with
6-hydroxy-1,2-dimethyl-1H-indole-3-carbyxylic acid methylamide 16e
and Cs.sub.2CO.sub.3 in a manner as previously described for
example 1. .sup.1H NMR (300 MHz, CD.sub.3OD) .delta. 8.41 (1H, d,
J=5.5 Hz), 7.80 (1H, d, J=3.20 Hz), 7.74 (1H, d, J=11.68 Hz), 7.30
(1H, s), 6.94 (1H, d, J=8.66 Hz), 6.62 (1H, d, J=5.5 Hz), 4.64-4.59
(2H, m), 4.20-4.15 (2H, m), 3.63 (3H, s), 2.85 (3H, s), 2.57 (3H,
s), 2.44-2.36 (2H, m). LCMS (ESI+) [M+H]/z Calc'd 435, found
435.
[0320] Anal. (C.sub.23H.sub.22N.sub.4O.sub.3S.0.35CH.sub.2Cl.sub.2)
C, H, N.
Example 26
1,2-Dimethyl-6-(2-[4-(hydroxymethyl)thiazol-2-yl]thieno[3,2-b]pyridin-7-yl-
oxy)-1H-indole-3-carboxylic acid methylamide
[0321] ##STR89##
[0322] This material was prepared by the reaction of
[2-(7-chloro-thieno[3,2-b]pyridin-2-yl)-thiazol-4-yl]-methanol with
6-hydroxy-1,2-dimethyl-1H-indole-3-carboxylic acid methyl amide 16e
and Cs.sub.2CO.sub.3 in a manner as previously described for
example 1. .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 8.52 (1H, d,
J=5.5 Hz), 8.14 (1H, s), 7.83 (1H, d, J=8.6 Hz), 7.63 (1H, s), 7.58
(1H, d, J=4.7 Hz), 7.54 (1H, d, J=2.0 Hz), 7.04 (1H, dd, J=2.0, 8.6
Hz), 6.64 (1H, d, J=5.5 Hz), 4.60 (2H, s), 3.67 (3H, s), 2.80 (3H,
d, J=4.3 Hz), 2.61 (3H, s). LCMS (ESI+) [M+H]/z Calc'd 465, found
465. Anal. (C.sub.23H.sub.20N.sub.4O.sub.3S.sub.2.0.6CH.sub.3OH) C,
H, N.
Example 27(a)
(3R)-1-[(7-Chlorothieno[3,2-b]pyridin-2-yl)carbonyl]-N,N-dimethylpyrrolidi-
n-3-amine
[0323] ##STR90##
[0324] This material was prepared from lithium
7-chlorothieno[3,2-b]pyridine-2-carboxylate (0.214 g, 1.0 mmole) by
treatment with thionyl chloride followed by reaction of the
resultant acyl chloride with (3R)-N,N-dimethylpyrrolidin-3-amine
(0.114 g, 1.0 mmole) and Et.sub.3N (0.139 ml, 1.0 mmole), in a
manner as previously described for example 9d to give a brown solid
(0.134 g, 43%). .sup.1H NMR (300 MHz, CD.sub.3OD) .delta. 7.24 (1H,
d, J=5.1 Hz), 6.57 (1H, d, J=8.48 Hz), 6.15 (1H, d, J=5.1 Hz), 2.70
(1H, m), 2.51 (2H, m), 2.24 (1H, m), 2.04 (1H, m), 1.49 (1H, m),
0.93 (3H, s), 0.90 (3H, s), 0.52 (1H, m); ESIMS (MH.sup.+):
310.10.
Example 27
6-[(2-{[(3R)-3-(Dimethylamino)pyrrolidin-1-yl]carbonyl}thieno[3,2-b]pyridi-
n-7-yl)oxy]-N,1,2-trimethyl-1H-indole-3-carboxamide
[0325] ##STR91##
[0326] This material was prepared by the reaction
(3R)-1-[(7-chlorothieno[3,2-b]pyridin-2-yl)carbonyl]-N,N-dimethylpyrrolid-
in-3-amine 27a (0.136 g, 0.44 mmole) with
6-hydroxy-N,1,2-trimethyl-1H-indole-3-carboxamide 16e (0.064 g,
0.294 mmole) and Cs.sub.2CO.sub.3 (0.096 g, 0.29 mmole) in a manner
as previously described for example 1 to give a brown colored foam
(0.059 g, 17%). .sup.1H NMR (300 MHz, CD.sub.3OD) .delta. 8.40 (1H,
d, J=5.46 Hz), 7.84 (1H, d, J=6.59 Hz), 7.76 (1H, d, J=8.67 Hz),
7.29 (1H, d, J=2.07 Hz), 6.95 (1H, dd, J=8.57, 2.17 Hz), 6.62 (1H,
d, J=5.65 Hz), 4.06 (1H, m), 3.87 (2H, m), 3.63 (3H, s) 3.03 (2H,
m), 2.88 (3H, s), 2.57 (3H, s), 2.37 (3H, s), 2.32 (3H, s), 2.23
(1H, m), 1.95 (1H, m); HRMS (MH.sup.+): Calcd: 492.2085; Found:
492.2069.
Example 28(a)
(7Chloro-thieno[3,2-b]pyridin-2-yl)-pyrrolidin-1-yl-methanone
[0327] ##STR92##
[0328] This material was prepared from the coupling of
7-chlorothieno[3,2-b]pyridine-2-carboxylic acid and pyrrolidine in
a manner as previously described for example 9d. .sup.1H NMR (300
MHz, CD.sub.3OD) .delta. 8.60 (1H, d, J=5.1 Hz), 7.84 (1H, s), 7.32
(1H, d, J=5.1 Hz), 3.82 (2H, t, J=6.4 Hz), 3.70 (2H, t, J=6.6 Hz),
2.02 (4H, m). LCMS (ESI+) [M+H]/z Calc'd 267, found 267.
Example 28
1,2-Dimethyl-6-[2-(pyrrolidine-1-carbonyl)-thieno[3,2-b]pyridin-7-yloxy]-1-
H-indole-3-carboxylic acid methylamide
[0329] ##STR93##
[0330] This material was prepared from the reaction of
(7-chloro-thieno[3,2-b]pyridin-2-yl)-pyrrolidin-1-yl-methanone 28a
with 6-hydroxy-1,2-dimethyl-1H-indole-3-carboxylic acid methylamide
16e and Cs.sub.2CO.sub.3 in a manner as previously described for
example 1. .sup.1H NMR (300 MHz, CD.sub.3OD) .quadrature. 8.47 (1H,
d, J=5.3 Hz), 7.82 (1H, s), 7.74 (1H, d, J=8.4 Hz), 7.14 (1H, d,
J=1.7 Hz), 7.02 (1H, dd, J=1.7, 8.4 Hz), 6.55 (1H, d, J=5.3 Hz),
5.91 (1H, bs), 3.84 (2H, m), 3.70 (2H, m), 3.65 (3H, s), 3.05 (3H,
d, J=4.5 Hz), 2.72 (3H, s), 2.02 (4H, m). LCMS (ESI+) [M+H]/z
Calc'd 449, found 449.
[0331] Anal. (C.sub.24H.sub.24N.sub.4O.sub.3S.0.5CH.sub.3OH) C, H,
N.
Example 29(a)
7-Chloro-N-[2-(dimethylamino)ethyl]-N-methylthieno[3,2-b]pyridine-2-carbox-
amide
[0332] ##STR94##
[0333] This material was prepared from lithium
7-chlorothieno[3,2-b]pyridine-2-carboxylate (0.957 g, 4.48 mmole)
by treatment with thionyl chloride followed by reaction of the
resultant acyl chloride with N,N,N'-trimethylethane-1,2-diamine
(0.640 ml, 4.93 mmole) and Et.sub.3N (0.624 ml, 4.48 mmole), in a
manner as previously described for example 9d to give a brown solid
(0.167 g, 13%). .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.60 (1H,
d, J=5.1 Hz), 7.74 (1H, s), 7.32 (1H, d, J=5.1 Hz), 3.66 (2H, t,
J=6.4 Hz), 3.26 (3H, s), 2.57 (2H, t, J=6.4 Hz), 2.25 (6H, s);
ESIMS (MH.sup.+): 298.05.
Example 29
N-[2-(Dimethylamino)ethyl]-7-({1,2-dimethyl-3-[(methylamino)carbonyl]-1H-i-
ndol-6-yl}oxy)-N-methylthieno[3,2-b]pyridine-2-carboxamide
[0334] ##STR95##
[0335] This material was prepared by the reaction of
7-chloro-N-[2-(dimethylamino)ethyl]-N-methylthieno[3,2-b]pyridine-2-carbo-
xamide 29a (0.167 g, 0.56 mmole) with
6-hydroxy-N,1,2-trimethyl-1H-indole-3-carboxamide 16e (0.123 g,
0.56 mmole) and Cs.sub.2CO.sub.3 (0.182 g, 0.56 mmole) in a manner
as previously described for example 1 to give a yellow solid (0.040
g, 13%). .sup.1H NMR (400 MHz, CD.sub.3OD) .delta. 8.71 (1H, d,
J=6.8 Hz), 8.06 (1H, s), 7.83 (1H, d, J=8.6 Hz), 7.46 (1H, d, J=2.0
Hz), 7.09 (1H, d, J=6.8 Hz), 7.05 (1H, dd, J=2.0, 8.6 Hz), 3.90
(2H, t, J=5.8 Hz), 3.64 (3H, s), 3.42 (2H, t, J=5.8 Hz), 3.23 (6H,
s), 2.93 (3H, s), 2.88 (3H, s), 2.58 (3H, s). HRMS (MH.sup.+):
Calcd: 480.2090; Found: 480.2069.
Example 30
6-[2-(3-Hydroxy-azetidine-1-carbonyl)-thieno[3,2-b]pyridin-7-yloxy]-1,2-di-
methyl-1H-indole-3-carboxylic acid methylamide
[0336] ##STR96##
[0337] This material was prepared by the reaction of
(7-chloro-thieno[3,2-b]pyridin-2-yl)-(3-hydroxy-azetidin-1-yl)-methanone
9d with 6-hydroxy-1,2-dimethyl-1H-indole-3-carboxylic acid
methylamide 16e and Cs.sub.2CO.sub.3 in a manner as previously
described for example 1. .sup.1H NMR (300 MHz, CD.sub.3OD) .delta.
8.41 (1H, d, J=5.5 Hz), 7.78-7.74 (2H, m), 7.29 (1H, d, J=2.1 Hz),
6.95(1H, dd, J=2.1, 8.6 Hz), 6.62 (1H, d, J=5.5 Hz), 4.76-4.73 (2H,
m), 4.63 (1H, bs), 4.35-4.32 (2H, m), 3.97-3.94(1H, m), 3.62(3H,
s), 2.89(3H, s), 2.57 (3H, s). LCMS (ESI+) [M+H]/z Calc'd 451,
found 451.
[0338] Anal. (C.sub.23H.sub.22N.sub.4O.sub.4S.1.1CH.sub.2Cl.sub.2)
C, H, N.
Example 31(a)
7-Chloro-N-(2-hydroxyethyl)-N-methylthieno[3,2-b]pyridine-2-carboxamide
[0339] ##STR97##
[0340] This material was prepared from lithium
7-chlorothieno[3,2-b]pyridine-2-carboxylate (1.0 g, 4.68 mmole) by
treatment with thionyl chloride followed by reaction of the
resultant acyl chloride with 2-(methylamino)ethanol (0.414 ml, 5.15
mmole) and Et.sub.3N (0.718 ml, 5.15 mmole), in a manner as
previously described for example 9d to give a pale brown solid
(0.624 g, 49% yield). .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.
8.61 (1H, d, J=4.8 Hz), 7.80 (1H, s), 7.33 (1H, d, J=4.8 Hz), 3.92
(2H, m), 3.76 (2H, t, J=5.1 Hz), 3.37 (3H, s), 3.19 (1H, s); ESIMS
(MH.sup.+): 259.10.
Example 31(b)
N-(2-{[tert-Butyl(dimethyl)silyl]oxy}ethyl)-7-chloro-N-methylthieno[3,2-b]-
pyridine-2-carboxamide
[0341] ##STR98##
[0342] This material was prepared from
7-chloro-N-(2-hydroxyethyl)-N-methylthieno[3,2-b]pyridine-2-carboxamide
31a (1.27 g, 4.68 mmole), t-butyldimethylsilyl chloride (0.705 g,
4.68 mmole) and Et.sub.3N (0.718 ml, 4.68 mmole) in a manner as
previously described for 3b to give an orange oil (1.40 g, 78%).
.sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 8.61 (1H, d, J=5.1 Hz),
7.74 (1H, s), 7.32 (1H, d, J=5.1 Hz), 3.89 (2H, m), 3.71 (2H, m),
3.37 (3H, s), 0.89 (9H, m), 0.07 (6H, m); ESIMS (MH.sup.+):
385.10.
Example 31
N-({1,2-Dimethyl-3-[(methylamino)carbonyl]-1H-inden-6-yl}oxy)-N-(2-hydroxy-
ethyl)-N-methylthieno[3,2-b]pyridine-2-carboxamide
[0343] ##STR99##
[0344] This material was prepared by the reaction of
N-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-7-chloro-N-methylthieno[3,2-b-
]pyridine-2-carboxamide 31b (0.133 g, 0.35 mmole) with
6-hydroxy-N,1,2-trimethyl-1H-indole-3-carboxamide 16e (0.76 g, 0.35
mmole) and Cs.sub.2CO.sub.3 (0.114 g, 0.35 mmole) in a manner as
previously described for example 1 to give a mixture of
N-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-7-({1,2-dimethyl-3-[(methylam-
ino)carbonyl]-1H-indol-6-yl}oxy)-N-methylthieno[3,2-b]pyridine-2-carboxami-
de and
7-({1,2-dimethyl-3-[(methylamino)carbonyl]-1H-inden-6-yl}oxy)-N-(2--
hydroxyethyl)-N-methylthieno[3,2-b]pyridine-2-carboxamide, which
was dissolved in THF (10 ml) and treated with TBAF (0.7 ml) for 2
h. The reaction mixture was quenched with H.sub.2O and partitioned
between CH.sub.2Cl.sub.2 (50.times.2 ml) and H.sub.2O (50 ml). The
combined organic layers were dried over MgSO.sub.4 and
concentrated. The residue was purified by flash column
chromatography eluting with 5-8% CH.sub.3OH in CH.sub.2Cl.sub.2 to
give an off-white solid (0.064 g, 41% yield). .sup.1H NMR (400 MHz,
CD.sub.3OD) .delta. 8.38 (1H, d, J=5.4 Hz), 7.76 (2H, m), 7.29 (1H,
s), 6.95 (1H, dd, J=2.1, 8.7 Hz), 6.61 (1H, d, J=5.4 Hz), 3.72 (2H,
m), 3.62 (3H, s), 3.22 (3H, s), 3.12 (2H, m), 2.88 (3H, s), 2.57
(3H, s); HRMS (MH.sup.+): Calcd: 453.1606; Found: 453.1597.
Example 32(a)
7-Chloro-N-[3-(dimethylamino)propyl]-N-methylthieno[3,2-b]pyridine-2-carbo-
xamide
[0345] ##STR100##
[0346] This material was prepared from
7-chlorothieno[3,2-b]pyridine-2-carboxylic acid (1.0 g, 4.68
mmole), SOCl.sub.2 (10 ml), N,N,N'-trimethylpropane-1,3-diamine
(0.868 ml, 4.68 mmole) and Et.sub.3N (1.96 ml, 14.04 mmole) in a
manner as previously described for example 9d to give a white foam
(1.07 g, 77%). .sup.1H NMR (300 MHz, CD.sub.3OD) .delta. 8.56 (1H,
d, J=5.2 Hz), 7.76 (1H, s), 7.46 (1H, d, J=5.2 Hz), 3.51 (2H, m),
3.20 (3H, s), 2.33 (2H, m), 2.18 (6H, s), 1.79 (2H, m); ESIMS
(MH.sup.+): 312.05.
Example 32
N-[3-(Dimethylamino)propyl]-7-({1,2-dimethyl-3-[(methylamino)carbonyl]-1H--
indol-6-yl}oxy)-N-methylthieno[3,2-b]pyridine-2-carboxamide
[0347] ##STR101##
[0348] This material was prepared by the reaction of
7-chloro-N-[3-(dimethylamino)propyl]-N-methylthieno[3,2-b]pyridine-2-carb-
oxamide 32a (0.095 g, 0.32 mmole) with
6-hydroxy-N,1,2-trimethyl-1H-indole-3-carboxamide (0.070 g, 0.32
mmole) 16e and Cs.sub.2CO.sub.3 (0.104 g, 0.32 mmole) in a manner
as described previously for example 1 to give a white solid (0.098
g, 62%). .sup.1H NMR (300 MHz, CD.sub.3OD) .delta. 8.53 (1H, d,
J=5.3 Hz), 7.91 (2H, m), 7.38 (1H, s), 7.09 (1H, dd, J=2.1, 8.7
Hz), 6.81(1H, d, J=5.3 Hz), 3.73 (3H, s), 3.66 (2H, m), 3.28 (2H,
m), 3.01 (3H, s), 2.68 (9H, m), 2.06 (2H, m), 1.94(3H, s); HRMS
(MH.sup.+): Calcd: 494.2223; Found: 494.2226.
Example 33(a)
7-Chloro-N,N-dimethylthieno[3,2-b]pyridine-2-carboxamide
[0349] ##STR102##
[0350] This material was prepared from
7-chlorothieno[3,2-b]pyridine-2-carboxylic acid (0.57 g, 2.67
mmole), SOCl.sub.2 (5 ml), 2.0 M N,N-dimethylamine in THF (1.60 ml,
3.20 mmole) and Et.sub.3N (0.447 ml, 3.20 mmole) in a manner as
previously described for example 9d to give a brown solid (0.54 g,
84%). .sup.1H NMR (300 MHz, CDCl.sub.3) .delta..delta..delta. 1H,
d, J=5.0 Hz), 7.74 (1H, s), 7.35 (1H, d, J=5.0 Hz), 3.28 (3H, s),
3.22 (3H, s); ESIMS (MH.sup.+): 240.95.
Example 33
7-({1,2-Dimethyl-3-[(methylamino)carbonyl]-1H-indol-6-yl}oxy)-N,N-dimethyl-
thieno[3,2-b]pyridine-2-carboxamide
[0351] ##STR103##
[0352] This material was prepared by the reaction
7-chloro-N,N-dimethylthieno[3,2-b]pyridine-2-carboxamide 33a (0.077
g, 0.32 mmole) and
6-hydroxy-N,1,2-trimethyl-1H-indole-3-carboxamide 16e (0.070 g,
0.32 mmole) and Cs.sub.2CO.sub.3 (0.104 g, 0.32 mmole) in a manner
as previously described for example 1 to give a pale yellow solid
(0.098 g, 73%). .sup.1H NMR (300 MHz, CD.sub.3OD) .delta. 8.38 (1H,
d, J=5.5 Hz), 7.75 (1H, d, J=8.7 Hz), 7.66 (1H, s), 7.28 (1H, d,
J=2.1 Hz), 6.94 (1H, dd, J=2.1, 8.7 Hz), 6.60 (1H, d, J=5.5 Hz),
3.61 (3H, s), 3.21 (6H, m), 2.87 (3H, s), 2.56 (3H, s). ESIMS
(MH.sup.+): 423.05.
[0353] Anal. Calcd. For
C.sub.22H.sub.22N.sub.4O.sub.3S.sub.0.6H.sub.2O: C, 59.21; H, 5.28;
N, 12.44. Found: C, 59.20; H, 5.28; N, 12.44.
Example 34(a)
Benzyl
(3R)-3-[(tert-butoxycarbonyl)(methyl)amino]pyrrolidine-1-carboxylat-
e
[0354] ##STR104##
[0355] Boc.sub.2O (1.26 g, 5.78 mmole) and DMAP (6.4 mg, 0.053
mmole) was added to a solution of tert-butyl
methyl[(3R)-pyrrolidin-3-yl]carbamate (1.0 g, 5.26 mmole). The
reaction mixture was stirred at room temperature overnight and was
partitioned between CH.sub.2Cl.sub.2 (2.times.100 ml) and H.sub.2O
(100 ml). The combined organic layers were dried over MgSO.sub.4
and concentrated. The residue was purified by flash column
chromatography eluting with 1-2% CH.sub.3OH in CH.sub.2Cl.sub.2 to
give a pale yellow oil (1.51 g, 99%). .sup.1H NMR (300 MHz,
CDCl.sub.3) .delta. 7.30 (5H, m), 3.56 (2H, m), 2.82 (3H, s), 2.76
(2H, m), 2.53 (2H, m), 2.33 (1H, m), 2.09 (1H, m), 1.73 (1H, m),
1.42 (9H, m); ESIMS (MH.sup.+): 291.20.
Example 34(b)
tert-Butyl methyl [(3R)-pyrrolidin-3-yl]carbamate
[0356] ##STR105##
[0357] To a stirred solution of benzyl
(3R)-3-[(tert-butoxycarbonyl)(methyl)amino]pyrrolidine-1-carboxylate
34a (1.5 g, 5.17 mmole) in MeOH (10 ml) was added Pd(OH).sub.2 on
carbon (150 mg). The reaction mixture was under 1 atmosphere of
H.sub.2 overnight, filtered through celite and concentrated, in
vacuo. The residue obtained was used directly in the subsequent
reaction without any further purification, vide infra. .sup.1H NMR
(300 MHz, CD.sub.3OD) .delta. 4.47 (1H, m), 3.20 (1H, m), 2.91 (2H,
m), 2.76 (1H, m), 2.69 (3H, s), 1.89 (1H, m), 1.68 (1H, m), 1.35
(9H, s).
Example 34(c)
tert-Butyl
(3R)-1-[(7-chlorothieno[3,2-b]pyridin-2-yl)carbonyl]pyrrolidin--
3-yl(methyl)carbamate
[0358] ##STR106##
[0359] This material was prepared from
7-chlorothieno[3,2-b]pyridine-2-carboxylic acid (1.05 g, 4.94
mmole), SOCl.sub.2 (10 ml), tert-butyl
methyl[(3R)-pyrrolidin-3-yl]carbamate 34b (0.989 g, 4.94 mmole) and
Et.sub.3N (0.689 ml, 4.94 mmole) in a manner as previously
described for example 9d to give a brown oil (0.723 g, 0.30%).
.sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 8.62 (1H, d, J=5.1 Hz),
7.85 (1H, s), 7.35 (1H, d, J=5.1 Hz), 4.82 (1H, m), 3.93 (3H, m),
3.63 (1H, m), 2.82 (3H, s), 2.12 (2H, m), 1.47 (9H, s); ESIMS
(MH.sup.+): 396.05.
Example 34
tert-Butyl-(3R)-1-{[7-({1,2-dimethyl-3-[(methylamino)carbonyl]-1H-indol-6--
yl}oxy)thieno[3,2-b]pyridin-2-yl]carbonyl}pyrrolidin-3-yl(methyl)carbamate
[0360] ##STR107##
[0361] This material was prepared by the reaction of tert-butyl
(3R)-1-[(7-chlorothieno[3,2-b]pyridin-2-yl)carbonyl]pyrrolidin-3-yl(methy-
l)carbamate 34c (0.181 g, 0.46 mmole) with
6-hydroxy-N,1,2-trimethyl-1H-indole-3-carboxamide 16e (0.10 g, 0.46
mmole) and Cs.sub.2CO.sub.3 (0.149 g, 0.46 mmole) in a manner as
previously described for example 1 to give a yellow solid (0.105 g,
40%). .sup.1H NMR (300 MHz, CDCl.sub.3) .delta.8.48 (1H, d, J=5.4
Hz), 7.82 (1H, s), 7.75 (1H, d, J=8.7 Hz), 7.15 (1H, d, J=2.1 Hz),
7.02 (1H, dd, J=2.1, 8.7 Hz), 6.56 (1H, d, J=5.4 Hz), 5.91 (1H, d,
J=4.7 Hz), 4.82 (1H, m), 4.07 (2H, m), 3.87 (1H, m), 3.68 (1H, m),
3.65 (3H, s), 3.05 (3H, d, J=4.7 Hz), 2.84 (3H, s), 2.73 (3H, s),
2.17 (2H, m), 1.45 (9H, s); HRMS (MH.sup.+): Calcd: 578.2450;
Found: 578.2437.
Example 35
1,2-Dimethyl-6-[2-(3-methylamino-pyrrolidine-1-carbonyl)-thieno[3,2-b]pyri-
din-7-yloxy]-1H-indole-3-carboxylic acid methylamide
[0362] ##STR108##
[0363] 4N HCl in 1,4-dioxane (1.0 ml) was added to a solution of
tert-butyl
(3R)-1-{[7-({1,2-dimethyl-3-[(methylamino)carbonyl]-1H-indol-6-yl}oxy)thi-
eno[3,2-b]pyridin-2-yl]carbonyl}pyrrolidin-3-yl(methyl)carbamate 34
(0.090 g, 0.16 mmole) in 1,4-dioxane (5 ml). The reaction mixture
was stirred at room temperature for 3 hr., then concentrated, in
vacuo. The residue was purified by reverse phase chromatography
eluting with 10-60% CH.sub.3CN in H.sub.2O to give a white solid
(0.020 g, 26%). .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 8.54 (1H,
d, J=5.3 Hz), 8.01 (1H, s), 7.83 (1H, d, J=8.7 Hz), 7.53-7.57 (2H,
m), 7.03 (1H, dd, J=1.9, 8.7 Hz), 6.63 (1H, d, J=5.3 Hz), 3.88-3.99
(2H, m), 3.67 (3H, s), 3.61 (1H, m), 3.29 (3H, m), 2.80 (3H, d,
J=4.50 Hz), 2.61 (3H, s), 2.30 (3H, d, J=10.55 Hz), 1.78-1.83 (1H,
m); ESIMS (MH.sup.+): 478.10.
[0364] Anal. Calcd. For
C.sub.25H.sub.27N.sub.5O.sub.3S.1.2CH.sub.2Cl.sub.2: C, 54.30; H,
5.11; N, 12.09. Found: C, 53.95; H, 5.52; N, 11.96.
Example 36
6-[2-(3,4-Dimethoxy-pyrrolidine-1-carbonyl)-thieno[3,2-b]pyridin-7-yloxy]--
1,2-dimethyl-1H-indole-3-carboxylic acid methylamide (36)
[0365] ##STR109##
[0366] This material was prepared by the reaction of
7-chloro-2-{[(3R,4S)-3,4-dimethoxypyrrolidin-1-yl]carbonyl}thieno[3,2-b]p-
yridine 5d (0.152 g, 0.47 mmole) with
6-hydroxy-N,1,2-trimethyl-1H-indole-3-carboxamide 16e (0.102 g,
0.47 mmole) and Cs.sub.2CO.sub.3 (0.153 g, 0.47 mmole) in a manner
as previously described for example 1 to give an off-white solid
(0.093 g, 39%). .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 8.42 (1H,
d, J=5.3 Hz), 7.84 (1H, s), 7.77 (1H, dd, J=3.8, 8.7 Hz), 7.31 (1H,
d, J=2.30 Hz), 3.97 (1H, dd, J=2.3, 8.7 Hz), 6.63 (1H, d, J=5.3
Hz), 4.04 (4H, m), 3.68 (2H, m), 3.64 (3H, s), 3.42 (3H, s), 3.38
(3H, s), 2.90 (3H, s), 2.59 (3H, s); ESIMS (MH.sup.+): 409.15.
[0367] Anal. Calcd. For
C.sub.26H.sub.28N.sub.4O.sub.5S.0.2CH.sub.2Cl.sub.2.0.5EtOAc: C,
59.46; H, 5.73; N, 9.84. Found: C, 59.09; H, 5.95; N, 9.93.
Example 37
6-[2-(3,4-Dihydroxy-pyrrolidine-1-carbonyl)-thieno[3,2-b]pyridin-7-yloxy]--
1,2-dimethyl-1H-indole-3-carboxylic acid methylamide (37)
[0368] ##STR110##
[0369] This material was prepared by treating
6-[(2-{[(3R,4S)-3,4-dimethoxypyrrolidin-1-yl]carbonyl}thieno[3,2-b]pyridi-
n-7-yl)oxy]-1,2-dimethyl-1H-indole-3-carboxylic acid methylamide 36
(0.065 g, 0.13 mmole) with 1.0 M BBr.sub.3 in CH.sub.2Cl.sub.2
(0.070 ml, 0.77 mmole) in a manner as described previously for
example 1d to give a white solid (0.017 g, 33%). .sup.1H NMR (300
MHz, CD.sub.3OD) .delta. 8.38 (1H, d, J=5.5 Hz), 7.79 (2H, m), 7.28
(1H, d, J=2.1 Hz), 6.94 (1H, dd, J=2.1, 8.7 Hz), 6.60 (1H, d, J=5.5
Hz), 5.07-5.13 (2H, m), 4.41 (1H, m), 3.95 (2H, m), 3.70 (1H, m),
3.61 (3H, s), 2.55 (3H, m), 1.90 (3H, s); ESIMS (MH.sup.+):
481.10.
[0370] Anal. Calcd. For
C.sub.24H.sub.24N.sub.4O.sub.5S.0.2CH.sub.2Cl.sub.2.H.sub.2O: C,
56.38; H, 5.16; N, 10.87. Found: C, 56.36; H, 5.09; N, 10.60.
Example 38(a)
7-Chloro-2-pyridin-4-ylthieno[3,2-b]pyridine
[0371] ##STR111##
[0372] Tereakis(triphenylphosphine)palladium (54 mg, 0.05 mmole)
was added to a solution of 4-(tributylstannyl)pyridine (0.432 g,
1.17 mmole) and 7-chloro-2-iodothieno[3,2-b]pyridine (0.347 g, 1.17
mmole) in DMF (5 ml). The reaction mixture was stirred at reflux
for 3 h, cooled to room temperature. The mixture was filtered,
washed with CH.sub.2Cl.sub.2 and was partitioned between H.sub.2O
(50 ml) and CH.sub.2Cl.sub.2 (2.times.50 ml). The combined organic
layers were dried over MgSO.sub.4 and concentrated. The residue was
purified by flash column chromatography eluting with 30-60% EtOAc
in hexane to give pale yellow color solid (0.103 g, 36%); .sup.1H
NMR (300 MHz, CDCl.sub.3) .delta. 8.61 (1H, d, J=5.1 Hz), 7.95 (1H,
s), 7.66 (2H, m), 7.44 (2H, m), 7.31 (1H, d, J=5.1 Hz); ESIMS
(MH.sup.+): 481.10.
Example 38
1,2-Dimethyl-6-(2-pyridin-4-yl-thieno[3,2-b]pyridin-7-yloxy)-1H-indole-3-c-
arboxylic acid methylamide
[0373] ##STR112##
[0374] This material was prepared by the reaction
7-chloro-2-pyridin-4-ylthieno[3,2-b]pyridine 38a (0.103 g, 0.42
mmole) with 6-hydroxy-N,1,2-trimethyl-1H-indole-3-carboxamide 16e
(0.070 g, 0.32 mmole) and Cs.sub.2CO.sub.3 (0.104 g, 0.32 mmole) in
a manner as previously described for example 1 to give an off-white
solid (0.055 g, 31%). .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta.
8.70 (2H, m), 8.52 (1H, m), 8.37 (1H, m), 7.87 (3H, m), 7.56 (2H,
m), 7.05 (1H, d, J=8.3 Hz), 6.59 (1H, m), 3.68 (3H, s), 2.80 (3H,
s), 2.61 (3H, s); ESIMS (MH.sup.+): 429.05.
[0375] Anal. Calcd. For
C.sub.24H.sub.20N.sub.4O.sub.2S.0.5CH.sub.2Cl.sub.2.0.4EtOAc: C,
61.92; H, 4.82; N, 11.07. Found: C, 61.93; H, 4.97; N, 10.99.
Example 39(a)
7-Chloro-2-(trimethylstannyl)thieno[3,2-b]pyridine
[0376] ##STR113##
[0377] Tereakis(triphenylphosphine)palladium (238 mg, 0.2 mmole)
was added to a solution of hexamethyldistannane (1.68 g, 5.1 mmole)
and 7-chloro-2-iodothieno[3,2-b]pyridine (1.52 g, 5.1 mmole) in
1,4-dioxane (20 ml). The reaction mixture was stirred at
110.degree. C. for 3 hr. After cooling to room temperature, the
mixture was filtered, washed with CH.sub.2Cl.sub.2 and was
partitioned between H.sub.2O (100 ml) and CH.sub.2Cl.sub.2
(2.times.100 ml). The combined organic layers were dried over
MgSO.sub.4 and concentrated. The residue was purified by flash
column chromatography eluting with 10-15% EtOAc in hexane to give
an orange solid (1.09 g, 63%). .sup.1H NMR (300 MHz, CDCl.sub.3)
.delta. 8.16 (1H, d, J=5.1 Hz), 6.87 (1H, s), 6.82 (1H, d, J=5.1
Hz), 0.08 (9H, m); ESIMS (MH.sup.+): 333.95.
Example 39(b)
7-Chloro-2-pyrimidin-5-ylthieno[3,2-b]pyridine
[0378] ##STR114##
[0379] Tereakis(triphenylphosphine)palladium (17 mg) was added to a
solution of 5-bromopyrimidine (0.057 g, 0.36 mmole) and
7-chloro-2-(trimethylstannyl)thieno[3,2-b]pyridine 39a (0.119 g,
0.36 mmole) in toluene (10 ml). The reaction mixture was stirred at
90.degree. C. overnight. After cooling to room temperature, the
mixture was filtered, washed with CH.sub.2Cl.sub.2 and was
partitioned between H.sub.2O (20 ml) and CH.sub.2Cl.sub.2
(2.times.20 ml). The combined organic layers were dried over
MgSO.sub.4 and concentrated. The residue was purified by flash
column chromatography eluting with 0-1% MeOH in CH.sub.2Cl.sub.2 to
give white solid (0.045 g, 51%); .sup.1H NMR (300 MHz,
C.sub.6D.sub.6) .delta. 9.25 (1H, s), 9.10 (2H, s), 8.64 (1H, d,
J=5.1 Hz), 7.89 (1H, s), 7.34 (1H, d, J=5.1 Hz); ESIMS (MH.sup.+):
248.00.
Example 39
1,2-Dimethyl-6-(2-pyrimidin-5-yl-thieno[3,2-b]pyridin-7-yloxy)-1H-indole-3-
-carboxylic acid methylamide
[0380] ##STR115##
[0381] This material was prepared by the reaction of
7-chloro-2-pyrimidin-5-ylthieno[3,2-b]pyridine 39b (0.045 g, 0.18
mmole) with 6-hydroxy-N,1,2-trimethyl-1H-indole-3-carboxamide 16e
(0.040 g, 0.18 mmole) and Cs.sub.2CO.sub.3 (0.059 g, 0.18 mmole) in
a manner as previously described for example 1 to give an off-white
solid (0.018 g, 23%). .sup.1H NMR (300 MHz, CD.sub.3OD) .delta.
9.23 (3H, m), 8.63 (1H, d, J=6.2 Hz), 8.11 (1H, s), 7.82 (1H, d,
J=8.5 Hz), 7.43 (1H, s), 7.01 (2H, m), 3.63 (3H, s), 2.88 (3H, s),
2.55 (3H, s); ESIMS (MH.sup.+): 430.10.
[0382] Anal. Calcd. For
C.sub.24H.sub.20N.sub.4O.sub.2S.1.0CH.sub.2Cl.sub.2.1.5CH.sub.3OH:
C, 54.45; H, 4.84; N, 12.45. Found: C, 54.12; H, 4.89; N,
12.30.
Example 40(a)
2-[2-(7-Chlorothieno[3,2-b]pyridin-2-yl)-1,3-thiazol-4-yl]propan-2-ol
[0383] ##STR116##
[0384] The title compound was prepared by the method described in
PC10795A, section A, example 27.
Example 40
6-{2-[4-(1-Hydroxy-1-methyl-ethyl)-thiazol-2-yl]-thieno[3,2-b]pyridin-7-yl-
oxy}-1,2-dimethyl-1H-indole-3-carboxylic acid methylamide
[0385] ##STR117##
[0386] This material was prepared by the reaction of
2-[2-(7-chlorothieno[3,2-b]pyridin-2-yl)-1,3-thiazol-4-yl]propan-2-ol
40a (0.099 g, 0.32 mmole) with 6-hydroxy-N,
1,2-trimethyl-1H-indole-3-carboxamide 16e (0.071 g, 0.32 mmole) and
Cs.sub.2CO.sub.3 (0.106 g, 0.32 mmole) in a manner as previously
described for example 1 to give a yellow color solid (0.116 g,
73%). .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 8.50 (1H, d,
J=5.46 Hz), 8.12 (1H, s), 7.84 (1H, d, J=8.67 Hz), 7.58 (2H, m),
7.54 (1H, d, J=2.07 Hz), 7.04 (1H, dd, J=8.67, 2.26 Hz), 6.59 (1H,
d, J=5.46 Hz), 3.68 (3H, s), 2.80 (1H, d, J=4.71 Hz), 2.61 (3H, s),
2.53 (3H, s), 1.50 (6H, s).
[0387] Anal. Calcd. For
C.sub.25H.sub.24N.sub.4O.sub.3S.sub.2.0.45CH.sub.2Cl.sub.2.1.0CH.sub.3OH:
C, 55.64; H, 5.18; N, 9.95. Found: C, 56.37; H, 5.22; N, 9.89.
Example 41 (a)
7-Chloro-2-(1,3-thiazol-2-yl)thieno[3,2-b]pyridine
[0388] ##STR118##
[0389] This material was prepared by coupling of
7-chloro-2-(trimethylstannyl)thieno[3,2-b]pyridine 39a (0.140 g,
0.42 mmole) and 2-bromo-1,3-thiazole (0.038 ml, 0.42 mmole) with
tereakis(triphenylphosphine) palladium (0.019 g) in a manner as
previously described in example 39b to give a yellow solid (0.049
g, 46%). .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 8.59 (1H, d,
J=5.1 Hz), 7.93 (1H, s), 7.89 (1H, d, J=3.4 Hz), 7.45 (1H, d, J=3.4
Hz), 7.30 (1H, d, J=5.1 Hz).
Example 41
1,2-Dimethyl-6-(2-thiazol-2-yl-thieno[3,2-b]pyridin-7-yloxy)-1H-indole-3-c-
arboxylic acid methylamide
[0390] ##STR119##
[0391] This material was prepared by the reaction of
7-chloro-2-(1,3-thiazol-2-yl)thieno[3,2-b]pyridine 41a (0.049 g,
0.19 mmole) with 6-hydroxy-N,1,2-trimethyl-1H-indole-3-carboxamide
16e (0.043 g, 0.19 mmole) and Cs.sub.2CO.sub.3 (0.062 g, 0.19
mmole) in a manner as previously described for example 1 to give an
off-white solid (0.050 g, 60%). .sup.1H NMR (300 MHz, DMSO-d.sub.6)
.delta. 8.52 (1H, d, J=5.4 Hz), 8.18 (1H, s), 7.93 (2H, m), 7.84
(1H, d, J=8.9 Hz), 7.56 (2H, m), 7.05 (1H, m), 6.63 (1H, d, J=5.4
Hz), 3.68 (3H, s), 2.80 (3H, d, J=4.5 Hz), 2.61 (3H, s); ESIMS
(MH.sup.+): 430.10.
[0392] Anal. Calcd. For
C.sub.22H.sub.18N.sub.4O.sub.2S.sub.2.0.45CH.sub.2Cl.sub.2.1.0CH.sub.3OH:
C, 55.64; H, 5.18; N, 9.95. Found: C, 56.37; H, 5.22; N, 9.89.
Example 42(a)
7-Chloro-2-pyridin-2-ylthieno[3,2-b]pyridine
[0393] ##STR120##
[0394] This material was prepared by coupling
7-chloro-2-(trimethylstannyl)thieno[3,2-b]pyridine 39a (0.255 g,
0.77 mmole) with 2-bromopyridine (0.121 g, 0.77 mmole) using
tereakis(triphenylphosphine) palladium(0) (0.036 g) as catalyst in
a manner as previously described in example 39b to give a white
solid (0.058 g, 31%). .sup.1H NMR (300 MHz, CDCl.sub.3) .delta.
8.66 (1H, m), 8.57 (1H, d, J=5.1 Hz), 8.00 (1H, s), 7.83 (3H, m),
7.27 (1H, d, J=5.1 Hz); ESIMS (MH.sup.+): 246.95.
Example 42
1,2-Dimethyl-6-(2-pyridin-2-yl-thieno[3,2-b]pyridin-7-yloxy)-1H-indole-3-c-
arboxylic acid methylamide
[0395] ##STR121##
[0396] This material was prepared by the reaction of
7-chloro-2-pyridin-2-ylthieno[3,2-b]pyridine (0.100 g, 0.41 mmole)
42a with 6-hydroxy-N,1,2-trimethyl-1H-indole-3-carboxamide 16e
(0.089 g, 0.41 mmole) and Cs.sub.2CO.sub.3 (0.134 g, 0.41 mmole) in
a manner as previously described for example 1 to give an off-white
solid (0.048 g, 27%). .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta.
8.63 (1H, d, J=4.5 Hz), 8.49 (1H, d, J=5.5 Hz), 8.35 (1H, s), 8.28
(1H, d, J=7.72 Hz), 7.95 (1H, t, J=8.4 Hz), 7.84 (1H, d, J=8.6 Hz),
7.58 (1H, d, J=4.5 Hz), 7.54 (1H, d, J=1.9 Hz), 7.43 (1H, m), 7.04
(1H, dd, J=1.9, 8.6 Hz), 6.58 (1H, d, J=5.5 Hz), 3.68 (3H, s), 2.80
(3H, s), 2.62 (3H, s); ESIMS (MH.sup.+): 429.05.
[0397] Anal. Calcd. For
C.sub.24H.sub.20N.sub.4O.sub.2S.0.8H.sub.2O: C, 65.08; H, 4.92; N,
12.65. Found: C, 65.16; H, 4.93; N, 12.40.
Example 43(a)
2-(7-Chlorothieno[3,2-b]pyridin-2-yl)-1,3-thiazole-4-carboxylic
acid
[0398] ##STR122##
[0399] To a solution of methyl
2-(7-chlorothieno[3,2-b]pyridin-2-yl)-1,3-thiazole-4-carboxylate
(0.200 g, 0.62 mmole), prepared by the method described in
PC10795A, section A, example 26, in EtOAc (5 ml) was added 1N
aqueous NaOH solution (1.85 ml, 1.85 mmole). The reaction mixture
was stirred at 50.degree. C. for 1 h, cooled to room temperature,
diluted with H.sub.2O (10 ml) and acidified with 1N HCl to
pH.about.2. The resulting solution was extracted with 10% MeOH in
CH.sub.2Cl.sub.2 (5.times.10 ml), dried over MgSO.sub.4 and
concentrated and dried under vacuum to give yellow solid (0.181 g,
98%). .sup.1H NMR (300 MHz, DMSO-d.sub.6) .quadrature. 7.67 (1H, d,
J=5.09 Hz) 8.41 (1H, s) 8.65 (1H, s) 8.71 (1H, bs); ESIMS
(MH.sup.+): 309.95.
Example 43(b)
2-(7-Chlorothieno[3,2-b]pyridin-2-yl)-N-methyl-1,3-thiazole-4-carboxamide
[0400] ##STR123##
[0401] To a solution of
2-(7-chlorothieno[3,2-b]pyridin-2-yl)-1,3-thiazole-4-carboxylic
acid 43a (0.123 g, 0.41 mmole) in CH.sub.2Cl.sub.2 cooled at
0.degree. C. was added 2.0 M oxalyl chloride in CH.sub.2Cl.sub.2
(0.520 ml, 1.04 mmole) and DMF (2 drops). The reaction mixture was
stirred at room temperature for 1 h, concentrated and dried. The
residue was taken into CH.sub.2Cl.sub.2 (10 ml), and 2.0 M
methylamine in CH.sub.2Cl.sub.2 (0.250 ml, 0.492 mmole) was added.
The reaction mixture was stirred at room temperature for 1 h, and
then partitioned between H.sub.2O (100 ml) and CH.sub.2Cl.sub.2
(2.times.100 ml). The combined organic layers were dried over
MgSO.sub.4 and concentrated. The residue was purified by flash
column chromatography eluting with 2-8% CH.sub.3OH in
CH.sub.2Cl.sub.2 to give yellow solid (0.116 g, 91%). .sup.1H NMR
(300 MHz, CDCl.sub.3) .delta. 8.62 (1H, d, J=5.1 Hz), 8.19 (1H, s),
7.96 (1H, s), 7.33 (1H, d, J=5.1 Hz), 3.06 (3H, d, J=4.9 Hz); ESIMS
(MH.sup.+): 309.95.
Example 43
1,2-Dimethyl-6-[2-(4-methylcarbamoyl-thiazol-2-yl)-thieno[3,2-b]pyridin-7--
yloxy]-1H-indole-3-carboxylic acid methylamide
[0402] ##STR124##
[0403] This material was prepared by the reaction of
2-(7-chlorothieno[3,2-b]pyridin-2-yl)-N-methyl-1,3-thiazole-4-carboxamide
43b (0.125 g, 0.403 mmole) with
6-hydroxy-1,2-dimethyl-1H-indole-3-carboxylic acid methylamide 16e
(0.092 g, 0.403 mmole) and Cs.sub.2CO.sub.3 (0.137 g, 0.42 mmole)
in a manner as previously described for example 1 to give an
off-white solid (0.015 g, 9%). .sup.1H NMR (300 MHz, DMSO-d.sub.6)
.delta. 8.54 (1H, d, J=5.3 Hz), 8.43 (1H, d, J=4.7 Hz), 8.40 (1H,
s), 8.30 (1H, s), 7.84 (1H, d, J=8.7 Hz), 7.56 (2H, m), 7.05 (1H,
dd, J=2.1, 8.7 Hz), 6.63 (1H, d, J=5.3 Hz), 3.68 (3H, s), 2.81 (6H,
m), 2.61 (3H, s); ESIMS (MH.sup.+): 492.05.
[0404] Anal. Calcd. For
C.sub.24H.sub.21N.sub.4O.sub.3S.sub.2Cl.0.5CH.sub.2Cl.sub.2: C,
55.10; H, 4.15; N, 13.11. Found: C, 55.14; H, 4.42; N, 12.99.
Example 44(a)
tert-Butyl pyrrolidin-3-ylmethylcarbamate
[0405] ##STR125##
[0406] To a solution of tert-butyl
(1-benzylpyrrolidin-3-yl)methylcarbamate (3.0 g, 10.33 mmole) in
EtOAc (100 ml) was added Pd(OH).sub.2 on carbon (0.3 g). The
mixture was stirred under H.sub.2 balloon at room temperature for 3
h and filtered through Celite. The filtrate was concentrated to
give colorless oil (1.87 g, 90%).
Example 44(b)
tert-Butyl
{1-[(7-chlorothieno[3,2-b]pyridin-2-yl)carbonyl]pyrrolidin-3-yl-
}methylcarbamate
[0407] ##STR126##
[0408] This material was prepared from
7-chlorothieno[3,2-b]pyridine-2-carboxylic acid lithium salt (2.27
g, 10.33 mmole), SOCl.sub.2 (10 ml), tert-butyl
pyrrolidin-3-ylmethylcarbamate 44a (2.07 g, 10.33 mmole) and
Et.sub.3N (1.44 ml, 10.33 mmole) in a manner as previously
described for example 9d to give a yellow solid (2.44 g, 60%).
.sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 7.85 (1H, s), 7.34 (1H,
d, J=5.1 Hz), 4.73 (1H, s), 3.96 (1H, m), 3.85 (1H, m), 3.70 (1H,
m), 3.55 (1H, m), 3.42 (1H, m), 3.22 (2H, m), 2.54 (1H, m), 2.12
(1H, m), 0.1.43, 1.41 (9H, s); ESIMS (M.sup.+): 396.05.
Example 44
tert-Butyl(1-{[7-({1,2-dimethyl-3-[(methylamino)carbonyl]-1H-indol-6-yl}ox-
y)thieno[3,2-b]pyridin-2-yl]carbonyl}pyrrolidin-3-yl)methylcarbamate
[0409] ##STR127##
[0410] This material was prepared by the reaction of tert-butyl
{1-[(7-chlorothieno[3,2-b]pyridin-2-yl)carbonyl]pyrrolidin-3-yl}methylcar-
bamate 44b (0.206 g, 0.52 mmole) with
6-hydroxy-N,1,2-trimethyl-1H-indole-3-carboxamide 16e (0.113 g,
0.52 mmole) and Cs.sub.2CO.sub.3 (0.169 g, 0.52 mmole) in a manner
as previously described for example 1 to give an off-white solid
(0.168 g, 56%). .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 8.48 (1H,
d, J=5.3 Hz), 7.82 (1H, s), 7.75 (1H, d, J=8.7 Hz), 7.25 (1H, s),
7.15 (1H, d, J=2.0 Hz), 7.02 (1H, dd, J=2.0, 8.7 Hz), 6.56 (1H, d,
J=5.3 Hz), 5.89 (1H, s), 4.74 (1H, s), 3.97 (1H, m), 3.84 (1H, m),
3.65 (3H, s), 3.44 (1H, m), 3.20 (2H, m), 3.06 (3H, d, J=4.71 Hz),
2.72 (3H, s), 1.77 (1H, m), 1.44, 1.42 (9H, s), 0.84 (2H, m).
[0411] Anal. Calcd. For
C.sub.30H.sub.35N.sub.5O.sub.5S.1.0H.sub.2O.1.2EtOAc: C, 59.59; H,
6.70; N, 9.98. Found: C, 59.54; H, 6.44; N, 9.85.
Example 45
6-[2-(3-Aminomethyl-pyrrolidine-1-carbonyl)-thieno[3,2-b]pyridin-7-yloxy]--
1,2-dimethyl-1H-indole-3-carboxylic acid methylamide
[0412] ##STR128##
[0413] Trifluoroacetic acid (1 ml) was added to a stirred solution
of tert-butyl
(1-{[7-({1,2-dimethyl-3-[(methylamino)carbonyl]-1H-indol-6-yl}oxy)thieno[-
3,2-b]pyridin-2-yl]carbonyl}pyrrolidin-3-yl)methyl carbamate 44
(0.148 g, 0.26 mmole). The reaction mixture was stirred at room
temperature for 15 min and concentrated. The residue was triturated
with Et.sub.2O, filtrated to give a yellow solid (0.050 g, 40%).
.sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 8.56 (1H, d, J=5.5 Hz),
8.05 (1H, s), 7.84 (3H, m), 7.58 (1H, d, J=4.5 Hz), 7.54 (1H, d,
J=1.7 Hz), 7.02 (1H, d, J=8.8 Hz), 6.67 (1H, d, J=5.5 Hz), 4.08
(1H, m), 3.92 (1H, m), 3.78 (1H, m), 3.67 (3H, s), 3.54 (1H, m),
3.36 (1H, m), 2.96 (2H, m), 2.80 (3H, d, J=4.33 Hz), 2.61 (3H, s),
2.09 (1H, m), 1.78 (1H, m); ESIMS (MH.sup.+): 478.10.
[0414] Anal. Calcd. For
C.sub.25H.sub.27N.sub.5O.sub.3S-.1.0CF.sub.3CO.sub.2H.2.7CH.sub.2Cl.sub.2-
: C, 46.69; H, 4.41; N, 9.17. Found: C, 46.87; H, 4.27; N,
9.06.
Example 46(a)
N-({1-[(7-chlorothieno[3,2-b]pyridin-2-yl)carbonyl]pyrrolidin-3-yl}methyl)-
-N-methylamine
[0415] ##STR129##
[0416] NaH (0.033 g, 0.82 mmole) and CH.sub.3I (0.064 ml, 1.02
mmole) were added to a solution of tert-butyl
{1-[(7-chlorothieno[3,2-b]pyridin-2-yl)carbonyl]pyrrolidin-3-yl}methyl-ca-
rbamate 43 (0.271 g, 0.68 mmole) in THF at 0.degree. C. The
reaction mixture was stirred and warmed to room temperature
overnight and partitioned between H.sub.2O (50 ml) and EtOAc
(2.times.50 ml). The combined organic layers were dried over
MgSO.sub.4 and concentrated. The residue was purified by flash
column chromatography eluting with 0-2% CH.sub.3OH in
CH.sub.2Cl.sub.2 to give a yellow solid (0.283 g, 82%). .sup.1H NMR
(300 MHz, CDCl.sub.3) .delta. 8.62 (1H, d, J=5.1 Hz), 7.85 (1H, s),
7.34 (1H, d, J=5.1 Hz), 4.72 (1H, s), 3.99 (1H, m), 3.77 (2H, m),
3.50 (1H, m), 3.19 (2H, m), 2.88 (3H, d, J=12.06 Hz), 2.62 (1H, m),
2.14 (1H, m), 1.83 (1H, m); ESIMS (MH.sup.+): 310.10.
Example 46
1,2-Dimethyl-6-[2-(3-methylaminomethyl-pyrrolidine-1-carbonyl)-thieno[3,2--
b]pyridin-7-yloxy]-1H-indole-3-carboxylic acid methylamide
[0417] ##STR130##
[0418] This material was prepared by the reaction of
N-({1-[(7-chlorothieno[3,2-b]pyridin-2-yl)carbonyl]pyrrolidin-3-yl}methyl-
)-N-methylamine 46a (0.115 g, 0.41 mmole) with
6-hydroxy-N,1,2-trimethyl-1H-indole-3-carboxamide 16e (0.090 g,
0.41 mmole) and Cs.sub.2CO.sub.3 (0.147 g, 0.41 mmole) in a manner
as previously described for example 1 to give an off-white solid
(0.110 g, 54%). .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 8.54
(1H, s), 8.01 (1H, s), 7.83 (1H, m), 7.54 (2H, m), 7.02 (1H, s),
6.64 (1H, d, J=5.46 Hz), 3.93 (2H, m), 3.68 (3H, s), 3.54 (2H, m),
3.16 (2H, m), 2.99 (1H, m), 2.80 (3H, s), 2.79 (3H, s), 1.98 (2H,
m), 1.65 (1H, m); HRMS (MH.sup.+): Calcd: 492.2064; Found:
492.2048.
Example 47(a)
Methyl
N-[(7-chlorothieno[3,2-b]pyridin-2-yl)carbonyl]-L-serinate
[0419] ##STR131##
[0420] This material was prepared from lithium
7-chlorothieno[3,2-b]pyridine-2-carboxylic acid (2.69 g, 12.25
mmole), SOCl.sub.2 (10 ml), L-serine methyl ester hydrochloride
(2.86 g, 18.4 mmole) and Et.sub.3N (5.12 ml, 37.7 mmole) in a
manner as previously described for example 9d to give a white solid
(2.09 g, 54%). .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 8.61 (1H,
d, J=5.1 Hz), 8.02 (1H, s), 7.35 (1H, d, J=5.1 Hz), 4.89 (1H, m),
4.15 (2H, m), 3.84 (3H, m).
Example 47(b)
2-[2-(7-Chlorothieno[3,2-b]pyridin-2-yl)-4,5-dihydro-1,3-oxazol-4-yl]propa-
n-2-ol
[0421] ##STR132##
[0422] Burgess reagent (0.606 g, 2.54 mmole) was added to a stirred
solution of methyl
N-[(7-chlorothieno[3,2-b]pyridin-2-yl)carbonyl]-L-serinate 47a
(0.728 g, 2.31 mmole) in THF (10 ml). The reaction mixture was
stirred at reflux for 2 h, quenched with MeOH (1 ml) and was
partitioned between saturated H.sub.2O (30 ml) and EtOAc
(2.times.30 ml). The combined organic layers were dried over
MgSO.sub.4 and concentrated. The residue was purified by flash
column chromatography eluting with 20-60% EtOAc in hexane to a
white solid (0.314 g, 46%). .sup.1H NMR (300 MHz, CDCl.sub.3)
.delta. 8.66 (1H, d, J=5.1 Hz), 8.08 (1H, s), 7.37 (1H, d, J=5.1
Hz), 5.03 (1H, m), 4.81 (1H, t, J=8.4 Hz), 4.70 (1H, m), 3.85 (3H,
s); ESIMS (MH.sup.+): 296.95.
Example 47(c)
Methyl
2-(7-chlorothieno[3,2-b]pyridin-2-yl)-1,3-oxazole-4-carboxylate
[0423] ##STR133##
[0424] MnO.sub.2 (0.628 mg) was added to a solution of
2-[2-(7-chlorothieno[3,2-b]pyridin-2-yl)-4,5-dihydro-1,3-oxazol-4-yl]prop-
an-2-ol 47b (0.314 g, 1.06 mmole) in benzene (15 ml). The reaction
mixture was heated to reflux for 2 hr., then filtered through
celite. The filtrate was concentrated and the residue was purified
by flash column chromatography eluting with 10-60% EtOAc in hexane
to give a white solid (0.220 g, 71%). .sup.1H NMR (300 MHz,
CDCl.sub.3) .delta. 8.65 (1H, d, J=5.0 Hz), 8.35 (1H, s), 8.20 (1H,
s), 7.36 (1H, d, J=5.0 Hz), 3.97 (3H, s); ESIMS (MH.sup.+):
294.95.
Example 47(d)
2-[2-(7-chlorothieno[3,2-b]pyridin-2-yl)-1,3-oxazol-4-yl]propan-2-ol
[0425] ##STR134##
[0426] MeMgBr (0.483 ml, 1.45 mmole) was added to a solution of
methyl
2-(7-chlorothieno[3,2-b]pyridin-2-yl)-1,3-oxazole-4-carboxylate 47c
(0.171 g, 0.58 mmole) in THF (10 ml) at 0.degree. C. The reaction
mixture was stirred at 0.degree. C. for 1 h, quenched with
saturated NH.sub.4Cl (1 ml) and partitioned between saturated
NaHCO.sub.3 (20 ml) and EtOAc (2.times.20 ml). The combined organic
layers were dried over MgSO.sub.4 and concentrated. The residue was
purified by flash column chromatography eluting with 0-2%
CH.sub.3OH in 1:1 EtOAc and CH.sub.2Cl.sub.2 to give a off-white
solid (0.070 g, 41%). .sup.1H NMR (300 MHz, CDCl.sub.3) .delta.
8.65 (1H, d, J=5.0 Hz), 8.35 (1H, s), 8.20 (1H, s), 7.36 (1H, d,
J=5.0 Hz), 3.97 (6H, s); ESIMS (MH.sup.+): 294.95.
Example 47
6-{2-[4-(1-Hydroxy-1-methyl-ethyl)-oxazol-2-yl]-thieno[3,2-b]pyridin-7-ylo-
xy}-1,2-dimethyl-1H-indole-3-carboxylic acid methylamide (47)
[0427] ##STR135##
[0428] This material was prepared by the reaction of
2-[2-(7-chlorothieno[3,2-b]pyridin-2-yl)-1,3-oxazol-4-yl]propan-2-ol
47d (0.068 g, 0.23 mmole) with
6-hydroxy-N,1,2-trimethyl-1H-indole-3-carboxamide 16e (0.051 g,
0.23 mmole) and Cs.sub.2CO.sub.3 (0.081 g, 0.23 mmole) in a manner
as previously described for example 1 to give a yellow solid (0.046
g, 42%). .sup.1H NMR (300 MHz, CD.sub.3OD) .delta. 8.39 (1H, d,
J=5.3 Hz), 7.94 (1H, d, J=1.0 Hz), 7.79 (1H, s), 7.77 (1H, s), 7.32
(1H, s), 6.98 (1H, d, J=8.6 Hz), 6.62 (1H, d, J=5.3 Hz), 3.63 (3H,
s), 2.90 (3H, s), 2.58 (3H, s), 1.51 (6H, s); ESIMS (MH.sup.+):
477.10.
[0429] Anal. Calcd. For
C.sub.25H.sub.25N.sub.4O.sub.4S.0.25CH.sub.2Cl.sub.2: C, 60.80; H,
5.15; N, 11.26. Found: C, 60.84; H, 5.21; N, 10.98.
Example 48(a)
7-Chloro-2-(5-methoxypyridin-2-yl)thieno[3,2-b]pyridine
[0430] ##STR136##
[0431] This material was prepared by coupling
7-chloro-2-(trimethylstannyl)thieno[3,2-b]pyridine 39a (0.214 g,
0.64 mmole) with 2-iodo-5-methoxypyridine (0.152 g, 0.64 mmole)
using tereakis (triphenylphosphine)palladium(0) (30 mg) as catalyst
in a manner as previously described for example 39b to give a
yellow solid (0.060 g, 34%). .sup.1H NMR (300 MHz, CDCl.sub.3)
.delta. 8.55 (1H, d, J=5.1 Hz), 8.43 (1H, s), 8.28 (1H, dd, J=1.3,
4.6 Hz), 7.34 (1H, m), 7.28 (1H, m), 7.24 (1H, d, J=5.8 Hz), 4.04
(3H, s).
Example 48
6-[2-(5-Methoxy-pyridin-2-yl)-thieno[3,2-b]pyridin-7-yloxy]-1,2-dimethyl-1-
H-indole-3-carboxylic acid methylamide
[0432] ##STR137##
[0433] This material was prepared by the reaction
7-chloro-2-(5-methoxypyridin-2-yl)thieno[3,2-b]pyridine 48a (0.058
g, 0.21 mmole) with
6-hydroxy-N,1,2-trimethyl-1H-indole-3-carboxamide 16e (0.046 g,
0.21 mmole) and Cs.sub.2CO.sub.3 (0.068 g, 0.21 mmole) in a manner
as previously described for example 1 to give a pale yellow solid
(0.014 g, 15%). .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 8.42 (2H,
m), 8.26 (1H, dd, J=1.1, 4.6 Hz), 7.73 (1H, d, J=8.6 Hz), 7.34 (1H,
m), 7.27 (1H, d, J=4.6 Hz), 7.15 (1H, d, J=2.0 Hz), 7.05 (1H, dd,
J=2.0, 8.6 Hz), 6.49 (1H, d, J=5.31 Hz), 5.91 (1H, bs), 4.03 (3H,
s), 3.64 (3H, s), 3.06 (3H, d, J=4.8 Hz), 2.72 (3H, s); ESIMS
(MH.sup.+): 459.03.
[0434] Anal. Calcd. For
C.sub.25H.sub.22N.sub.4O.sub.3S.0.7CH.sub.3OH: C, 64.18; H, 5.20;
N, 11.65. Found: C, 64.28; H, 5.27; N, 11.47.
Example 49(a)
7-Chloro-2-(6-methoxypyridin-2-yl)thieno[3,2-b]pyridine
[0435] ##STR138##
[0436] This material was prepared by coupling
7-chloro-2-(trimethylstannyl)thieno[3,2-b]pyridine 39a (0.478 g,
1.44 mmole) with 2-bromo-6-methoxypyridine (0.177 ml, 1.44 mmole)
using tereakis (triphenylphosphine)palladium(0) (67 mg) as catalyst
in a manner as previously described for example 39b to give a pale
yellow solid (0.249 g, 63%). .sup.1H NMR (300 MHz, CDCl.sub.3)
.delta. 8.56 (1H, d, J=5.1 Hz), 7.98 (1H, s), 7.66 (3H, m), 6.75
(1H, d, J=8.3 Hz), 4.05 (3H, s); ESIMS (MH.sup.+): 276.95.
Example 49
6-[2-(6-Methoxy-pyridin-2-yl)-thieno[3,2-b]pyridin-7-yloxy]-1,2-dimethyl-1-
H-indole-3-carboxylic acid methylamide
[0437] ##STR139##
[0438] This material was prepared by the reaction of
7-chloro-2-(6-methoxypyridin-2-yl)thieno[3,2-b]pyridine 49a (0.093
g, 0.34 mmole) with
6-hydroxy-N,1,2-trimethyl-1H-indole-3-carboxamide 16e (0.074 g,
0.34 mmole) and Cs.sub.2CO.sub.3 (0111 g, 0.34 mmole) in a manner
as previously described for example 1 to give a white solid (0.029
g, 19%). .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 8.43 (1H, d,
J=5.46 Hz), 7.99 (1H, s), 7.76 (1H, d, J=8.7 Hz), 7.65 (1H, m),
7.45 (1H, d, J=7.4 Hz), 7.18 (1H, d, J=2.0 Hz), 7.07 (1H, dd,
J=2.0, 8.7 Hz), 6.73 (1H, d, J=8.1 Hz), 6.47 (1H, m), 5.87 (1H, s),
4.03 (3H, s), 3.66 (3H, s), 3.07 (3H, d, J=4.9 Hz), 2.74 (3H, s);
ESIMS (MH.sup.+): 459.20.
[0439] Anal. Calcd. For
C.sub.25H.sub.22N.sub.4O.sub.3S.0.85H.sub.2O: C, 63.37; H, 5.04; N,
11.82. Found: C, 63.48; H, 4.98; N, 11.43.
Example 50(a)
7-Chloro-2-pyrimidin-2-ylthieno[3,2-b]pyridine
[0440] ##STR140##
[0441] This material was prepared by coupling
7-chloro-2-(trimethylstannyl)thieno[3,2-b]pyridine 39a (0.218 g,
0.66 mmole) with 2-bromopyrimidine (0.104 g, 0.66 mmole) using
tereakis(triphenylphosphine) palladium(0) (31 mg) as catalyst in a
manner as previously described for example 39b to give a white
solid (0.066 g, 40%). .sup.1H NMR (300 MHz, CDCl.sub.3) .delta.
8.76 (2H, d, J=4.90 Hz), 8.57 (1H, d, J=5.1 Hz), 8.41 (1H, s), 7.26
(1H, d, J=5.1 Hz), 7.20 (1H, m); ESIMS (MH.sup.+): 248.00.
Example 50
1,2-Dimethyl-6-(2-pyrimidin-2-yl-thieno[3,2-b]pyridin-7-yloxy)-1H-indole-3-
-carboxylic acid methylamide
[0442] ##STR141##
[0443] This material was prepared by the reaction of
7-chloro-2-pyrimidin-2-ylthieno[3,2-b]pyridine 50a (0.066 g, 0.23
mmole) with 6-hydroxy-N,1,2-trimethyl-1H-indole-3-carboxamide 16e
(0.050 g, 0.23 mmole) and Cs.sub.2CO.sub.3 (0.075 g, 0.23 mmole) in
a manner as previously described for example 1 to give a white
solid (0.041 g, 41%). .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta.
8.90 (2H, d, J=4.9 Hz), 8.50 (1H, d, J=5.3 Hz), 8.29 (1H, s), 7.81
(1H, d, J=8.5 Hz), 7.50 (3H, m), 7.01 (1H, dd, J=2.2, 8.5 Hz), 6.60
(1H, d, J=5.3 Hz), 3.64 (3H, s), 2.76 (3H, d, J=4.5 Hz), 2.57 (3H,
s); ESIMS (MH.sup.+): 430.10.
[0444] Anal. Calcd. For
C.sub.23H.sub.19N.sub.5O.sub.2S.0.75CH.sub.3OH: C, 62.90; H, 4.89;
N, 15.44. Found: C, 62.92; H, 4.61; N, 15.39.
Example 51(a)
1-(7-Chlorothieno[3,2-b]pyridin-2-yl)propan-1-one
[0445] ##STR142##
[0446] 2.5 M nBuLi in hexane (0.619 ml, 1.55 mmole) was added to a
solution of 7-chlorothieno[3,2-b]pyridine (0.250 g, 1.47 mmole) in
THF (5 ml) at -78.degree. C. The reaction mixture was stirred at
-78.degree. C. for 30 min, and then propanoyl chloride (0.162 ml,
1.76 mmole) was added. The reaction mixture stirred at -78.degree.
C. and slowly warmed to 0.degree. C. and quenched with H.sub.2O (10
ml), extracted with EtOAc (2.times.10 ml). The organic layer was
dried over MgSO.sub.4 and concentrated. The residue was purified by
flash column chromatography eluting with 10-70% EtOAc in hexane to
a off-white solid (0.084 g, 25%). .sup.1H NMR (300 MHz, CDCl.sub.3)
.delta. 8.66 (1H, d, J=4.9 Hz), 8.12 (1H, s), 7.38 (1H, d, J=4.9
Hz), 3.09 (2H, q, J=7.3 Hz), 1.29 (3H, t, J=7.3 Hz); ESIMS
(MH.sup.+): 225.95.
Example 51
1,2-Dimethyl-6-(2-propionyl-thieno[3,2-b]pyridin-7-yloxy)-1H-indole-3-carb-
oxylic acid methylamide
[0447] ##STR143##
[0448] This material was prepared by the reaction of
1-(7-chlorothieno[3,2-b]pyridin-2-yl)propan-1-one 51a (0.062 g,
0.28 mmole) with 6-hydroxy-N,1,2-trimethyl-1H-indole-3-carboxamide
16e (0.061 g, 0.28 mmole) and Cs.sub.2CO.sub.3 (0.091 g, 0.28
mmole) in a manner as previously described for example 1 to give an
off-white solid (0.035 g, 31%). .sup.1H NMR (300 MHz, CDCl.sub.3)
.delta. 8.51 (1H, d, J=5.5 Hz), 8.11 (1H, s), 7.76 (1H, d, J=8.6
Hz), 7.15 (1H, d, J=2.1 Hz), 7.02 (1H, dd, J=2.1, 8.6 Hz), 6.58
(1H, d, J=5.5 Hz), 5.87 (1H, d, J=4.3 Hz), 3.66 (3H, s), 3.10 (2H,
m), 3.06 (3H, d, J=4.9 Hz), 2.73 (3H, s), 1.31 (3H, t, J=7.3 Hz);
ESIMS (MH.sup.+): 408.05.
[0449] Anal. Calcd. For
C.sub.22H.sub.21N.sub.3O.sub.3S.0.15CH.sub.2Cl.sub.2: C, 63.31; H,
5.11; N, 10.00. Found: C, 63.42; H, 5.03; N, 9.83.
Example 52(a)
6-(7-Chlorothieno[3,2-b]pyridin-2-yl)pyridine-2-carbaldehyde
[0450] ##STR144##
[0451] This material was prepared by coupling
7-chloro-2-(trimethylstannyl)thieno[3,2-b]pyridine 39a (0.707 g,
2.17 mmole) with 6-bromopyridine-2-carbaldehyde (0.396 g, 2.17
mmole) using tereakis (triphenylphosphine) palladium(0) (100 mg) as
catalyst in a manner as previously described for example 39b to
give a white solid (0.161 g, 27%). .sup.1H NMR (300 MHz,
CDCl.sub.3) .delta. 10.15 (1H, s), 8.61 (1H, d, J=5.1 Hz),
7.93-8.09 (4H, m) 7.31 (1H, d, J=5.1 Hz); ESIMS (MH.sup.+):
275.00.
Example 52(b)
N-{[6-(7-Chlorothieno[3,2-b]pyridin-2-yl)pyridin-2-yl]methyl}-N,N-dimethyl-
amine
[0452] ##STR145##
[0453] To a solution of
6-(7-chlorothieno[3,2-b]pyridin-2-yl)pyridine-2-carbaldehyde 52a
(0.127 g, 0.46 mmole) in THF (20 ml) was added 2.0 M dimethylamine
in THF (1.5 ml, 2.3 mmole), NaCNBH.sub.3 (0.063 g, 0.92 mmole) and
NaOAc (0.076 g, 0.92 mmole). The reaction mixture was stirred at
room temperature overnight and concentrated. The residue was
purified by flash column chromatography eluting with 2-10%
CH.sub.3OH in CHCl.sub.3 to give a yellow solid (0.086 g, 61%).
.sup.1H NMR (300 MHz, CD.sub.3OD) .delta. 8.50 (1H, d, J=5.3 Hz),
8.11 (1H, s), 8.03 (1H, d, J=7.9 Hz), 7.90 (1H, t, J=7.9 Hz), 7.41
(2H, m), 4.16 (2H, s), 2.71 (6H, s).
Example 52
6-[2-(6-Dimethylaminomethyl-pyridin-2-yl)-thieno[3,2-b]pyridin-7-yloxy]-1,-
2-dimethyl-1H-indole-3-carboxylic acid methylamide
[0454] ##STR146##
[0455] This material was prepared by the reaction of
N-{[6-(7-chlorothieno[3,2-b]pyridin-2-yl)pyridin-2-yl]methyl}-N,N-dimethy-
lamine 52b (0.080 0.26 mmole) with
6-hydroxy-N,1,2-trimethyl-1H-indole-3-carboxamide 16e (0.058 g,
0.26 mmole) and Cs.sub.2CO.sub.3 (0.085 g, 0.26 mmole) in a manner
as previously described for example 1 to give a white solid (0.016
g, 13%). .sup.1H NMR (300 MHz, CD.sub.3OD) .delta.8.27 (1H, d,
J=5.5 Hz), 7.91 (1H, s), 7.77 (3H, m), 7.31 (1H, d, J=7.0 Hz), 7.24
(1H, d, J=2.0 Hz), 6.93 (1H, dd, J=2.0, 8.6 Hz), 6.49 (1H, d, J=5.5
Hz), 3.57 (5H, m), 2.88 (3H, s), 2.54 (3H, s), 2.26 (6H, s).
[0456] Anal. Calcd. For
C.sub.27H.sub.27N.sub.5O.sub.2S.1.5CH.sub.2Cl.sub.2: C, 55.84; H,
4.93; N, 11.43. Found: C, 55.75; H, 5.15; N, 11.01.
Example 53
6-[2-((R)-3-Hydroxy-pyrrol
idine-1-carbonyl)-thieno[3,2-b]pyridin-7-yloxy]-1,2-dimethyl-1H-indole-3--
carboxylic acid cyclopropylamide
[0457] ##STR147##
[0458] This material was prepared by the reaction of
(7-chloro-thieno[3,2-b]pyridin-2-yl)-((R)-3-hydroxy-pyrrolidin-1-yl)-meth-
anone 4a with 6-hydroxy-1,2-dimethyl-1H-indole-3-carboxylic acid
cyclopropylamide 20b and Cs.sub.2CO.sub.3 in a manner as previously
described for example 1. .sup.1H NMR (300 MHz, CD.sub.3OD)
.delta.8.50 (1H, d, J=5.5 Hz), 7.93 (1H, d, J=17.33 Hz), 7.80 (1H,
d, J=8.6 Hz), 7.39 (1H, d, J=2.1 Hz), 7.05 (1H, dd, J=2.1, 8.6 Hz),
6.71 (1H, d, J=5.5 Hz), 4.54 (1H, bs), 4.11-4.00 (2H, m),
3.85-3.72(6H, m), 2.93-2.86(1H, m), 2.66 (3H, s), 2.19-2.07 (2H,
m), 0.90-0.84 (2H, m), 0.76-0.68 (2H, m). LCMS (ESI+) [M+H]/z
Calc'd 491, found 491.
[0459] Anal. (C.sub.26H.sub.26N.sub.4O.sub.4S.0.2CH.sub.2Cl.sub.2)
C, H, N.
Example 54
N-Cyclopropyl-6-[(2-{[(2S)-2-(hydroxymethyl)pyrrolidin-1-yl]carbonyl}thien-
o[3,2-b]pyridin-7-yl)oxy]-1,2-dimethyl-1H-indole-3-carboxamide
[0460] ##STR148##
[0461] This material was prepared by the reaction of
{(2S)-1-[(7-chlorothieno[3,2-b]pyridin-2-yl)carbonyl]pyrrolidin-2-yl}meth-
anol 3b (0.107 g, 0.345 mmole) with
N-cyclopropyl-6-hydroxy-1,2-dimethyl-1H-indole-3-carboxamide 20b
(0.055 g, 0.23 mmole) and Cs.sub.2CO.sub.3 (0.073 g, 0.23 mmole) in
a manner as previously described for example 1 to give brown solid
(0.059 g, 51%). .sup.1H NMR (300 MHz, CD.sub.3OD) .delta. 8.37 (1H,
d, J=5.6 Hz), 7.81 (1H, s), 7.67 (1H, d, J=8.6 Hz), 7.27 (1H, d,
J=2.1 Hz), 6.92 (1H, dd, J=2.1, 8.6 Hz), 6.59 (1H, d, J=5.6 Hz),
4.25 (1H, m), 3.82 (3H, m), 3.61 (3H, s), 2.76 (1H, m), 2.54 (3H,
s), 2.00 (4H, m), 1.84 (1H, m), 1.14 (2H, m), 0.77 (2H, m). ESIMS
(MH.sup.+): 505.15.
[0462] Anal. Calcd. for
C.sub.27H.sub.28N.sub.4O.sub.4S.0.45CH.sub.2Cl.sub.2: C, 60.74; H,
5.37; N, 10.32. Found: C, 60.40; H, 5.56; N, 10.06.
Example 55(a)
N-(Cyclopropylmethyl)-6-methoxy-1,2-dimethyl-1H-indole-3-carboxamide
[0463] ##STR149##
[0464] This material was prepared from
6-methoxy-1,2-dimethyl-1H-indole-3-carboxylic acid 16c (0.80, 3.65
mmole) with SOCl.sub.2 (0.799 ml, 10.95 mmole) and
cyclopropylmethylamine (0.38 ml, 4.38 mmole) in a manner as
previously described for example 9d to give a pale yellow solid
(0.382 g, 38%). .sup.1H NMR (300 MHz, CD.sub.3OD) .delta. 7.50 (1H,
d, J=8.7 Hz), 6.81 (1H, d, J=2.2 Hz), 6.69 (1H, dd, J=2.2, 8.7 Hz),
3.74 (3H, s), 3.56 (3H, s), 3.20 (2H, m), 2.50 (3H, m), 1.07 (1H,
m), 0.44 (2H, m), 0.21 (2H, m); ESIMS (MH.sup.+): 273.10.
Example 55(b)
N-(Cyclopropylmethyl)-6-hydroxy-1,2-dimethyl-1H-indole-3-carboxamide
[0465] ##STR150##
[0466] This material was prepared by reaction of
N-(cyclopropylmethyl)-6-methoxy-1,2-dimethyl-1H-indole-3-carboxamide
55a (0.38 g, 1.4 mmole) with 1.0 M BBr.sub.3 in CH.sub.2Cl.sub.2
(4.19 ml, 4.19 mmole) in a manner as previously described for
example 1d to give a pale yellow solid (0.278 g, 77%). .sup.1H NMR
(400 MHz, CD.sub.3OD) .delta. 7.55 (1H, d, J=8.5 Hz), 6.77 (1H, s),
6.71 (1H, d, J=8.5 Hz), 3.63 (3H, s), 3.28 (2H, m), 2.61 (3H, s),
1.18 (1H, m), 0.56 (2H, m); ESIMS (MH.sup.+): 259.10.
Example 55
N-(Cyclopropylmethyl)-1,2-dimethyl-6-{[2-(1-methyl-1H-imidazol-2-yl)thieno-
[3,2-b]pyridin-7-yl]oxy}-1H-indole-3-carboxamide
[0467] ##STR151##
[0468] This material was prepared by the reaction of
7-chloro-2-(1-methyl-1H-imidazol-2-yl)thieno[3,2-b]pyridine 1e
(0.76 g, 0.32 mmole) with
6-hydroxy-N,1,2-trimethyl-1H-indole-3-carboxamide 55b (0.074 g,
0.32 mmole) and Cs.sub.2CO.sub.3 (0.098 g, 0.30 mmole) in a manner
as previously described for example 1 to give a pale yellow solid
(0.060 g, 40%). .sup.1H NMR (400 MHz, CD.sub.3OD) .delta. 8.33 (1H,
d, J=5.6 Hz), 7.75 (1H, d, J=8.6 Hz), 7.67 (1H, s), 7.28 (1H, d,
J=2.2 Hz), 7.21 (1H, d, J=1.1 Hz), 6.99 (1H, d, J=1.1 Hz), 6.95
(1H, dd, J=2.2, 8.6 Hz), 6.57 (1H, d, J=5.6 Hz), 3.92 (3H, s), 3.61
(3H, s), 2.55 (3H, s), 1.06 (1H, m), 0.46 (2H, m), 0.23 (2H, m).
ESIMS (MH.sup.+): 472.10.
[0469] Anal. Calcd. For
C.sub.26H.sub.25N.sub.5O.sub.2S.0.5CH.sub.3OH: C, 65.27; H, 5.58;
N, 14.36. Found: C, 65.52; H, 5.58; N, 14.12.
Example 56
N-(Cyclopropylmethyl)-6-[(2-{[(3R)-3-hydroxypyrrolidin-1-yl]carbonyl}thien-
o[3,2-b]pyridin-7-yl)oxy]-1,2-dimethyl-1H-indole-3-carboxamide
[0470] ##STR152##
[0471] This material was prepared by the reaction of
(3R)-1-[(7-chlorothieno[3,2-b]pyridin-2-yl) carbonyl]
pyrrolidin-3-ol 4a (0.083 g, 0.29 mmole) with
6-hydroxy-N,1,2-trimethyl-1H-indole-3-carboxamide 55b (0.075 g,
0.29 mmole) and Cs.sub.2CO.sub.3 (0.094 g, 0.29 mmole) in a manner
as previously described for example 1 to give a pale yellow solid
(0.050 g, 34%). .sup.1H NMR (300 MHz, CD.sub.3OD) .delta. 8.50 (1H,
d, J=5.3 Hz), 7.83 (1H, s), 7.73 (1H, d, J=8.7 Hz), 7.50 (1H, d,
J=4.7 Hz), 7.42 (1H, d, J=2.1 Hz), 6.99 (1H, d, J=2.1, 8.7 Hz),
4.53 (1H, m), 3.96 (2H, m), 3.65 (2H, m), 3.61 (3H, s), 3.10 (4H,
m), 2.35 (3H, s),1.09 (1H, m), 0.88 (2H, m), 0.45 (2H, m); ESIMS
(MH.sup.+): 505.20.
[0472] Anal. Calcd. For
C.sub.27H.sub.28N.sub.4O.sub.4S.0.25CH.sub.2Cl.sub.2: C, 62.24; H,
5.46; N, 10.66. Found: C, 62.10; H, 5.74; N, 10.33.
Example 57
6-{2-[4-(1-Hydroxy-1-methyl-ethyl)-thiazol-2-yl]-thieno[3,2-b]pyridin-7-yl-
oxy}-1,2-dimethyl-1H-indole-3-carboxylic acid
cyclopropylmethyl-amide
[0473] ##STR153##
[0474] This material was prepared by the reaction of
2-[2-(7-chlorothieno[3,2-b]pyridin-2-yl)-1,3-thiazol-4-yl]propan-2-ol
40a (0.102 g, 0.33 mmole) with
N-(cyclopropylmethyl)-6-hydroxy-1,2-dimethyl-1H-indole-3-carboxamide
55b (0.085 g, 0.33 mmole) and Cs.sub.2CO.sub.3 (0.108 g, 0.33
mmole) in a manner as previously described for example 1. .sup.1H
NMR (300 MHz, DMSO-d.sub.6) .delta. 8.50 (1H, d, J=5.5 Hz), 8.12
(1H, s), 7.83 (1H, d, J=8.6 Hz), 7.73 (1H, t, J=5.8 Hz), 7.58 (1H,
s), 7.54 (1H, d, J=2.1 Hz), 7.05 (1H, dd, J=2.1, 8.6 Hz), 6.59 (1H,
d, J=5.5 Hz), 3.68 (3H, s), 3.17 (2H, t, J=6.1 Hz), 2.61 (3H, s),
1.50 (6H, s), 1.08 (2H, m), 0.43 (2H, m), 0.25 (2H, m); ESIMS
(MH.sup.+): 533.15.
[0475] Anal. Calcd. For
C.sub.28H.sub.28N.sub.4O.sub.3S.sub.2.0.25H.sub.2O: C, 62.60; H,
5.35; N, 10.43. Found: C, 62.65; H, 5.37; N, 10.20.
Example 58(a)
6-Methoxy-1,2-dimethyl-1H-indol-3-carboxylic acid propylamide
[0476] ##STR154##
[0477] This material was prepared from
1,2-dimethyl-6-methoxy-1H-indole-3-carboxylic acid 16c, thionyl
chloride and propylamine in a manner as previously described for
example 9d. .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 7.55 (1H, d,
J=8.6 Hz), 6.84 (1H, dd, J=2.2, 8.6 Hz), 6.78 (1H, d, J=2.2 Hz),
5.87 (1H, bs), 3.87 (3H, s), 3.63 (3H, s), 3.45 (2H, m), 2.69 (3H,
s), 1.67 (2H, m), 1.02 (3H, t, J=7.4 Hz). LCMS (ESI+) [M+H]/z
Calc'd 261, found 261.
Example 58(b)
6-Hydroxy-1,2-dimethyl-1H-indol-3-carboxylic acid propylamide
[0478] ##STR155##
[0479] This material was prepared from
6-methoxy-1,2-dimethyl-1H-indol-3-carboxylic acid propylamide 58a
by treatment with BBr.sub.3 in a manner as previously described for
example 1d. .sup.1H NMR (300 MHz, CD.sub.3OD) .delta. 7.50 (1H, d,
J=8.7 Hz), 6.74 (1H, d, J=1.9 Hz), 6.68 (1H, dd, J=1.9, 8.7 Hz),
3.61 (3H, s), 3.32 (2H, m), 2.58 (3H, s), 1.66 (2H, m), 1.01 (3H,
t, J=7.4 Hz). LCMS (ESI+) [M+H]/z Calc'd 247, found 247.
Example 58
6-(2-[2-(S)Hydroxymethyl-pyrrolidine-1-carbonyl]thieno[3,2-b]pyridin-7-ylo-
xy)-1,2-dimethyl-1H-indole-3-carboxylic acid propylamide
[0480] ##STR156##
[0481] This material was prepared by the reaction of
(7-chloro-thieno[3,2-b]pyridin-2-yl)-(3-hydroxymethyl-pyrrolidin-1-yl)-me-
thanone 3a (0.127 g, 0.43 mmole) with
6-hydroxy-1,2-dimethyl-1H-indole-3-carboxylic acid propylamide 58b
(0.070 g, 0.285 mmole) and Cs.sub.2CO.sub.3 (0.099 g, 0.35 mmole)
in a manner as previously described for example 1 to give 30 mg
(14% yield) of pale yellow solid. .sup.1H NMR (CD.sub.3OD) .delta.
8.33 (1H, d, J=5.1 Hz), 7.69-7.75 (2H, m), 7.24 (1H, s), 6.9 (1H,
d, J=8.1 Hz), 6.56 (1H, d, J=5.1 Hz), 4.22 (1H, m), 3.64-3.78 (4H,
m), 3.56 (3H, s), 3.20-3.31 (2H, m), 2.52 (3H, s), 1.90-1.98 (4H,
m), 1.62-1.55 (2H, m), 0.95-0.90 (3H, m). ESIMS (MH.sup.+):
507.20.
[0482] Anal. Calcd. For
C.sub.27H.sub.30N.sub.4O.sub.4S.1.0CH.sub.3OH: C, 62.43; H, 6.36;
N, 10.40. Found: C, 62.44; H, 6.13; N, 10.13.
Example 59
6-[2-(3-Hydroxy-pyrrolidine-1-carbonyl)-thieno[3,2-b]pyridin-7-yloxy]-1,2--
dimethyl-3H-indole-3-carboxylic acid propylamide
[0483] ##STR157##
[0484] This material was prepared by the reaction of
7-chloro-2-[(R)-3-hydroxypyrrolidine-1-carbynyl]thieno[3,2,-b]pyridine
4a with 6-hydroxy-1,2-dimethyl-1H-indol-3-carboxylic acid
propylamide 58b and Cs.sub.2CO.sub.3 in a manner as previously
described for example 1. .sup.1H NMR (300 MHz, CD.sub.3OD) .delta.
8.50 (1H, d, J=5.6 Hz), 7.96 (1H, d, J=17.3 Hz), 7.86 (1H, d, J=8.7
Hz), 7.40 (1H, s), 7.06 (1H, d, J=10.7 Hz), 6.72 (1H, d, J=5.6 Hz),
4.61-4.53 (1H, m), 4.15-4.00 (2H, m), 3.91-3.73 (3H, m), 3.73 (3H,
s), 3.53-3.40 (2H, m), 2.67 (3H, s), 2.28-2.07 (2H, m), 1.78-1.69
(2H, m), 1.18-1.04 (3H, m). LCMS (ESI+) [M+H]/z Calc'd 493, found
493. Anal. (C.sub.26H.sub.28N.sub.4O.sub.4S.0.3CH.sub.2Cl.sub.2) C,
H, N.
Example 60
1,2-Dimethyl-6-(2-thiazol-2-yl-thieno[3,2-b]pyridin-7-yloxy)-1H-indole-3-c-
arboxylic acid propylamide
[0485] ##STR158##
[0486] This material was prepared by the reaction of
7-chloro-2-(1,3-thiazol-2-yl)thieno[3,2-b]pyridine 41a (0.078 g,
0.314 mmole) with
6-hydroxy-1,2-dimethyl-N-propyl-1H-indole-3-carboxamide 58b (0.076
g, 0.31 mmole) and Cs.sub.2CO.sub.3 (0.101 g, 0.31 mmole) in a
manner as previously described for example 1 to give a yellow solid
(0.035 g, 24%). .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 8.46 (1H,
d, J=5.3 Hz), 7.92 (1H, s), 7.88 (1H, d, J=3.2 Hz), 7.74 (1H, d,
J=8.7 Hz), 7.42 (1H, d, J=3.2 Hz), 7.17 (1H, d, J=1.7 Hz), 7.05
(1H, dd, J=1.7, 8.7 Hz), 6.55 (1H, d, J=5.3 Hz), 5.90 (1H, m), 3.66
(3H, s), 3.47 (2H, m), 2.73 (3H, s), 1.69 (2H, m), 1.03 (3H, t,
J=7.4 Hz); ESIMS (MH.sup.+): 463.10.
[0487] Anal. Calcd. For
C.sub.24H.sub.22N.sub.4O.sub.2S.sub.2.0.05CH.sub.2Cl.sub.2: C,
61.87; H, 4.77; N, 12.00. Found: C, 61.90; H, 4.77; N, 11.90.
Example 61
1,2-Dimethyl-6-[2-(1-methyl-1H-imidazol-2-yl)-thieno[3,2-b]pyridin-7-yloxy-
]-1H-indole-3-carboxylic acid propylamide
[0488] ##STR159##
[0489] This material was prepared from
7-chloro-2-(1-methyl-1H-imidazol-2-yl)thieno[3,2-b]pyridine 1e with
6-hydroxy-1,2-dimethyl-1H-indole-3-carboxylic acid propylamide 58b
and Cs.sub.2CO.sub.3 in a manner as previously described for
example 1. .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 8.42 (1H, d,
J=5.5 Hz), 7.82 (1H, d, J=8.7 Hz), 7.76 (1H, s), 7.37 (1H, d, J=1.8
Hz), 7.30 (1H, s), 7.08 (1H, s), 7.03 (1H, dd, J=1.8, 8.7 Hz), 6.65
(1H, d, J=5.5 Hz), 4.01 (3H, s), 3.70 (3H, s), 3.39 (2H, m), 2.64
(3H, s), 1.70 (2H, m), 1.03 (3H, m). LCMS (ESI+) [M+H]/z Calc'd
460, found 460.
[0490] Anal. (C.sub.25H.sub.25N.sub.5O.sub.2S.sub.1.0CH.sub.3OH) C,
H, N.
Example 62(a)
6-Methoxy-1,2-dimethyl-1H-indole-3-carboxylic acid butylamide
[0491] ##STR160##
[0492] This material was prepared from the reaction of
6-methoxy-1,2-dimethyl-1H-indole-3-carboxylic acid (1.12 g, 5.11
mmole) 16c with oxalyl chloride (0.682 ml, 13.6 mmole) and
butan-1-amine (1.51 ml, 15.33 mmole) in a manner as previously
described for example 16d to give a yellow solid (0.990 g, 71%).
.sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 8.01 (1H, d, J=8.6 Hz),
7.31 (1H, dd, J=2.3, 8.6 Hz), 7.25 (1H, d, J=2.3 Hz), 6.32 (1H, s),
4.34 (3H, s), 4.09 (3H, s), 3.95 (2H, m), 3.16 (3H, s), 2.10 (2H,
m), 1.92 (2H, m), 1.44 (3H, t, J=7.4 Hz); ESIMS (MH.sup.+):
275.15.
Example 62(b)
6-Hydroxy-1,2-dimethyl-1H-indole-3-carboxylic acid butylamide
[0493] ##STR161##
[0494] This material was prepared by the reaction of
6-methoxy-1,2-dimethyl-1H-indole-3-carboxylic acid butylamide 62a
(0.78 g, 2.84 mmole) with 1.0 M BBr.sub.3 in CH.sub.2Cl.sub.2 (8.53
ml, 8.53 mmole) in a manner as previously described for example 1d
to give an off-white solid (0.623 g, 96%). .sup.1H NMR (300 MHz,
CD.sub.3OD) .delta. 7.40 (1H, d, J=8.5 Hz), 6.64 (1H, d, J=2.1 Hz),
6.59 (1H, dd, J=2.1, 8.5 Hz), 3.50 (3H, s), 3.29 (2H, m), 2.48 (3H,
s), 1.54 (2H, m), 1.36 (2H, m), 0.90 (3H, t, J=7.3 Hz); ESIMS
(MH.sup.+): 261.15.
Example 62
1,2-Dimethyl-6-(2-thiazol-2-yl-thieno[3,2-b]pyridin-7-yloxy)-1H-indole-3-c-
arboxylic acid butylamide
[0495] ##STR162##
[0496] This material was prepared by the reaction of
7-chloro-2-(1,3-thiazol-2-yl)thieno[3,2-b]pyridine 41a (0.085 g,
0.33 mmole) with 6-Hydroxy-1,2-dimethyl-1H-indole-3-carboxylic acid
butylamide 62b (0.087 g, 0.33 mmole) and Cs.sub.2CO.sub.3 (0.108 g,
0.33 mmole) in a manner as previously described for example 1 to
give a yellow solid (0.090 g, 57%). .sup.1H NMR (300 MHz,
CD.sub.3OD) .delta. 8.32 (1H, d, J=5.5 Hz), 7.83 (1H, s), 7.78 (1H,
d, J=3.2 Hz), 7.72 (1H, d, J=8.7 Hz), 7.63 (1H, d, J=3.2 Hz), 7.28
(1H, d, J=2.0 Hz), 6.94 (1H, dd, J=2.0, 8.7 Hz), 6.56 (1H, d, J=5.5
Hz), 3.59 (3H, s), 3.34 (2H, m), 2.54 (3H, s), 1.57 (2H, m), 1.38
(2H, m), 0.90 (3H, t, J=7.4 Hz); ESIMS (MH.sup.+): 477.05.
[0497] Anal. Calcd. For
C.sub.25H.sub.24N.sub.4O.sub.2S.sub.2.0.7H.sub.2O: C, 61.37; H,
5.23; N, 11.45. Found: C, 61.34; H, 5.22; N, 11.11.
Example 63(a)
6-Methoxy-1,2-dimethyl-1H-indole-3-carboxylic acid
(3-hydroxy-propyl)-amide
[0498] ##STR163##
[0499] This material was prepared by the reaction of
1,2-dimethyl-6-methoxy-1H-indole-3-carboxylic acid 16c with
3-hydroxy-propyl amine and oxalyl chloride in a manner as
previously described for 16d. .sup.1H NMR (300 MHz, CD.sub.3OD)
.delta. 7.52 (1H, d, J=8.6 Hz), 6.73 (1H, d, J=2.1 Hz), 6.68 (1H,
dd, J=2.1, 8.6 Hz), 3.69 (2H, t, J=6.1 Hz), 3.79 (3H, s), 3.63 (3H,
s), 3.51 (2H, m), 2.57 (3H, s), 1.85 (2H, m). LCMS (ESI+) [M+H]/z
Calc'd 291, found 291.
Example 63(b)
6-Hydroxy-1,2-dimethyl-1H-indole-3-carboxylic acid
(3-hydroxy-propyl)-amide
[0500] ##STR164##
[0501] This material was prepared from
6-methoxy-1,2-dimethyl-1H-indole-3-carboxylic acid
(3-methoxy-propyl)-amide 63a by treatment with BBr.sub.3 in a
manner as previously described for example 1d. .sup.1H NMR (300
MHz, CD.sub.3OD) .delta. 7.52 (1H, d, J=8.6 Hz), 6.73 (1H, d, J=2.1
Hz), 6.68 (1H, dd, J=2.1, 8.6 Hz), 3.69 (2H, t, J=6.1 Hz), 3.57
(3H, s), 3.51 (2H, m), 2.57 (3H, s), 1.85 (2H, m). LCMS (ESI+)
[M+H]/z Calc'd 263, found 263.
Example 63
6-[2-(Azetidine-1-carbonyl)-thieno[3,2-b]pyridin-7-yloxy]-1,2-dimethyl-1H--
indole-3-carboxylic acid (3-hydroxy-propyl)-amide
[0502] ##STR165##
[0503] This material was prepared by the reaction of
2-(azetidin-1-ylcarbonyl)-7-chlorothieno[3,2-b]pyridine 25a with
6-hydroxy-1,2-dimethyl-1H-indole-3-carboxylic acid
(3-hydroxy-propyl)-amide 63b and Cs.sub.2CO.sub.3 in a manner as
previously described for example 1. .sup.1H NMR (300 MHz,
CD.sub.3OD) .delta. 8.50 (1H, d, J=5.5 Hz), 7.89 (1H, d, J=8.7 Hz),
7.82 (1H, s), 7.40 (1H, s), 7.06 (1H, d, J=6.6 Hz), 6.72 (1H, d,
J=5.5 Hz), 4.74-4.65 (2H, m), 4.31-3.68 (5H, m), 3.60-3.55(2H, m),
2.68 (3H, s), 2.54-2.46 (2H, m), 1.95-1.87 (2H, m). LCMS (ESI+)
[M+H]/z Calc'd 478, found 478.
[0504] Anal. (C.sub.25H.sub.26N.sub.4O.sub.3S.0.9CH.sub.2Cl.sub.2)
C, H, N.
Example 64
6-[2-((R)-3-Hydroxy-pyrrolidine-1-carbonyl)-thieno[3,2-b]pyridin-7-yloxy]--
1,2-dimethyl-1H-indole-3-carboxylic acid
(3-hydroxy-propyl)-amide
[0505] ##STR166##
[0506] This material was prepared by the reaction of
(7-chloro-thieno[3,2-b]pyridin-2-yl)-((R)-3-hydroxy-pyrrolidin-1-yl)-meth-
anone 4a with 6-hydroxy-1,2-dimethyl-1H-indole-3-carboxylic acid
(3-hydroxy-propyl)-amide 63b and Cs.sub.2CO.sub.3 in a manner as
previously described for example 1. .sup.1H NMR (300 MHz,
CD.sub.3OD) .delta. 8.38 (1H, d, J=5.5 Hz), 7.84-7.74 (2H,m), 7.28
(1H, d, J=2.1 Hz), 6.94 (1H, dd, J=2.1, 8.6 Hz), 6.60 (1H, d, J=5.5
Hz), 4.45-4.42 (1H, m), 3.93-3.91 (2H, m), 3.71-3.60 (8H, m), 3.45
(2H, m), 2.56 (3H, s), 2.02-1.98 (2H, m), 1.72-1.68 (2H, m). LCMS
(ESI+) [M+H]/z Calc'd 509, found 509. Anal.
(C.sub.26H.sub.28N.sub.4O.sub.5S.0.6CH.sub.2Cl.sub.2) C, H, N.
Example 65
1,2-Dimethyl-6-[2-(pyrrolidine-1-carbonyl)-thieno[3,2-b]pyridin-7-yloxy]-1-
H-indole-3-carboxylic acid (3-hydroxy-propyl)-amide
[0507] ##STR167##
[0508] This material was prepared from the reaction of
(7-chloro-thieno[3,2-b]pyridin-2-yl)-pyrrolidin-1-yl-methanone with
6-hydroxy-1,2-dimethyl-1H-indole-3-carboxylic acid
(3-hydroxy-propyl)-amide 63b and Cs.sub.2CO.sub.3 in a manner as
previously described for example 1. .sup.1H NMR (300 MHz,
CD.sub.3OD) .delta. 8.44 (1H, d, J=5.5 Hz), 7.85 (1H, s), 7.83 (1H,
d, J=10.0 Hz), 7.35 (1H, d, J=1.9 Hz), 7.01 (1H, dd, J=1.9, 8.5
Hz), 6.66 (1H, d, J=5.5 Hz), 3.88 (2H, m), 3.67 (7H, m), 3.54 (2H,
m), 2.63 (3H, s), 1.83-2.10 (6H, m). LCMS (ESI+) [M+H]/z Calc'd
493, found 493.
[0509] Anal. (C.sub.26H.sub.28N.sub.4O.sub.4S.0.5CH.sub.3OH) C, H,
N.
Example 66(a)
6-Methoxy-1,2-dimethyl-1H-indole-3-carboxylic acid
isopropylamide
[0510] ##STR168##
[0511] This material was prepared from
1,2-dimethyl-6-methoxy-1H-indole-3-carboxylic acid 16c, oxalyl
chloride and isopropylamine in a manner as previously described for
example 16d. .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 7.53 (1H, d,
J=8.7 Hz), 6.85 (1H, dd, J=2.3, 8.7 Hz), 6.77 (1H, d, J=2.3 Hz),
4.35 (1H, m), 3.87 (3H, s), 3.63 (3H, s), 2.69 (3H, s), 1.30 (3H,
s), 1.27 (3H, s). LCMS (ESI+) [M+H]/z Calc'd 261, found 261.
Example 66(b)
6-Hydroxy-1,2-dimethyl-1H-indole-3-carboxylic acid
isopropylamide
[0512] ##STR169##
[0513] This material was prepared from
6-methoxy-1,2-dimethyl-1H-indol-3-carboxylic acid isopyropylamide
66a by treatment with BBr.sub.3 in a manner as previously described
for example 1d. .sup.1H NMR (300 MHz, CD.sub.3OD) .delta. 7.47 (1H,
d, J=8.5 Hz), 6.74 (1H, d, J=2.1 Hz), 6.67 (1H, dd, J=2.1, 8.5 Hz),
4.22 (1H, m), 3.61 (3H, s), 2.56 (3H, s), 1.28 (3H, s), 1.26 (3H,
s). LCMS (ESI+) [M+H]/z Calc'd 247, found 247.
Example 66
1,2-Dimethyl-6-(2-thiazol-2-yl-thieno[3,2-b]pyridin-7-yloxy)-1H-indole-3-c-
arboxylic acid isopropylamide
[0514] ##STR170##
[0515] This material was prepared by the reaction
7-chloro-2-(1,3-thiazol-2-yl)thieno[3,2-b]pyridine 41a (0.084 g,
0.33 mmole) with
6-hydroxy-N-isopropyl-1,2-dimethyl-1H-indole-3-carboxamide 66b
(0.082 g, 0.33 mmole) and Cs.sub.2CO.sub.3 (0.116 g, 0.33 mmole) to
give a off-white solid (0.058 g, 38%). .sup.1H NMR (300 MHz,
CDCl.sub.3) .delta. 8.46 (1H, d, J=5.4 Hz), 7.93 (1H, s), 7.88 (1H,
d, J=3.2 Hz), 7.73 (1H, d, J=8.6 Hz), 7.42 (1H, d, J=3.2 Hz), 7.17
(1H, d, J=2.1 Hz), 7.07 (1H, dd, J=2.1, 8.6 Hz), 6.54 (1H, d, J=5.4
Hz), 5.71 (1H, d, J=7.7 Hz), 4.36 (1H, m), 3.66 (3H, s), 2.72 (3H,
s), 1.31 (6H, d, J=6.6 Hz); ESIMS (MH.sup.+): 463.10.
[0516] Anal. Calcd. For
C.sub.24H.sub.22N.sub.4O.sub.2S.sub.2.0.3H.sub.2O: C, 61.59; H,
4.87; N, 11.97. Found: C, 61.48; H, 4.67; N, 11.86.
Example 67(a)
6-Methoxy-1,2-dimethyl-1H-indole-3-carboxylic acid
isobutyl-amide
[0517] ##STR171##
[0518] This material was prepared from
1,2-dimethyl-6-methoxy-1H-indole-3-carboxylic acid 16c, oxalyl
chloride and isobutylamine in a manner as previously described for
example 16d. .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 7.56 (1H, d,
J=8.6 Hz), 6.85 (1H, dd, J=2.2, 8.6 Hz), 6.78 (1H, d, J=2.2 Hz),
3.87 (3H, s), 3.63 (3H, s), 3.32 (2H, m), 2.69 (3H, s), 1.93 (1H,
m), 1.02 (3H, s), 1.00 (3H, s). LCMS (ESI+) [M+H]/z Calc'd 275,
found 275.
Example 67(b)
6-Hydroxy-1,2-dimethyl-1H-indole-3-carboxylic acid
isobutyl-amide
[0519] ##STR172##
[0520] This material was prepared from
6-methoxy-1,2-dimethyl-1H-indol-3-carboxylic acid isobutyl-amide
67a by treatment with BBr.sub.3 in a manner as previously described
for example 1d. .sup.1H NMR (300 MHz, CD.sub.3OD) .delta. 7.52 (1H,
d, J=8.5 Hz), 6.74 (1H, d, J=2.3 Hz), 6.68 (1H, dd, J=2.3, 8.5 Hz),
3.61 (3H, s), 3.22 (2H, m), 2.58 (3H, s), 1.95 (1H, m), 1.02 (3H,
s), 1.00 (3H, s). LCMS (ESI+) [M+H]/z Calc'd 261, found 261.
Example 67
1,2-Dimethyl-6-(2-thiazol-2-yl-thieno[3,2-b]pyridin-7-yloxy)-1H-indole-3-c-
arboxylic acid isobutyl-amide
[0521] ##STR173##
[0522] This material was prepared by the reaction tert-butyl
7-chloro-2-(1,3-thiazol-2-yl)thieno[3,2-b]pyridine 41a (0.086 g,
0.34 mmole) with
6-hydroxy-N-isobutyl-1,2-dimethyl-1H-indole-3-carboxamide 67b
(0.087 g, 0.34 mmole) and Cs.sub.2CO.sub.3 (0.120 g, 0.34 mmole) to
give a pale yellow solid (0.065 g, 40%). .sup.1H NMR (300 MHz,
CDCl.sub.3) .delta. 8.46 (1H, d, J=5.5 Hz), 7.93 (1H, s), 7.88 (1H,
d, J=3.2 Hz), 7.75 (1H, d, J=8.6 Hz), 7.42 (1H, d, J=3.2 Hz), 7.18
(1H, d, J=2.1 Hz), 7.06 (1H, dd, J=2.1, 8.6 Hz), 6.55 (1H, d, J=5.5
Hz), 5.95 (1H, s), 3.66 (3H, s), 3.35 (1H, t, J=6.4 Hz), 2.73 (3H,
s), 1.95 (1H, m), 1.03 (6H, d, J=6.8 Hz); ESIMS (MH.sup.+):
477.05.
[0523] Anal. Calcd. For
C.sub.25H.sub.24N.sub.4O.sub.2S.sub.2.0.4H.sub.2O: C, 62.06; H,
5.17; N, 11.58. Found: C, 61.97; H, 5.00; N, 11.47.
Example 68(a)
6-Methoxy-1,2-dimethyl-N-(3-morpholin-4-ylpropyl)-1H-indole-3-carboxamide
[0524] ##STR174##
[0525] This material was prepared from
6-methoxy-1,2-dimethyl-1H-indole-3-carboxylic acid 16c (0.483 g,
2.20 mmole) with 2.0 M oxalyl chloride in CH.sub.2Cl.sub.2 (2.2 ml,
4.4 mmole) and 3-morpholin-4-ylpropylamine in a manner as
previously described for example 16d to give a white solid (0.445
g, 59%). .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 7.60 (1H, d,
J=8.6 Hz), 6.82 (1H, dd, J=2.3, 8.6 Hz), 6.77 (1H, d, J=2.3 Hz),
6.71 (1H, s), 3.87 (3H, s), 3.62 (3H, s), 3.57 (6H, m), 2.69 (3H,
s), 2.50 (2H, t, J=6.6 Hz), 2.43 (4H, m), 1.81 (2H, m); ESIMS
(MH.sup.+): 346.20.
Example 68(b)
6-Hydroxy-1,2-dimethyl-N-(3-morpholin-4-ylpropyl)-1H-indole-3-carboxamide
[0526] ##STR175##
[0527] This material was prepared from
6-methoxy-1,2-dimethyl-N-(3-morpholin-4-ylpropyl)-1H-indole-3-carboxamide
68a (0.445 g, 1.29 mmole) by treatment with 1.0 M BBr.sub.3 in
CH.sub.2Cl.sub.2 (3.86 ml, 3.86 mmole) in a manner as described
previously for example 1d to give a white solid (0.445 g, 59%).
.sup.1H NMR (300 MHz, CD.sub.3OD) .delta. 7.49 (1H, d, J=8.6 Hz),
6.71 (1H, s), 6.64 (1H, dd, J=2.2, 8.6 Hz), 3.87 (4H, m), 3.56 (3H,
s), 3.47 (2H, t, J=6.4 Hz), 3.10-3.24 (6H, m), 2.55 (3H, s), 2.00
(2H, m); ESIMS (MH.sup.+): 332.15.
Example 68
1,2-Dimethyl-6-(2-propionyl-thieno[3,2-b]pyridin-7-yloxy)-1H-indole-3-carb-
oxylic acid (3-morpholin-4-yl-propyl)-amide
[0528] ##STR176##
[0529] This material was prepared by the reaction of
1-(7-Chlorothieno[3,2-b]pyridin-2-yl)propan-1-one 51a (0.074 g,
0.33 mmole) with
6-hydroxy-1,2-dimethyl-N-(3-morpholin-4-ylpropyl)-1H-indole-3-carboxamide
68b (0.110 g, 0.33 mmole) and Cs.sub.2CO.sub.3 (0.108 g, 0.33
mmole) in a manner as previously described for example 1 to give a
white solid (0.019 g, 11%). .sup.1H NMR (300 MHz, DMSO-d.sub.6)
.delta. 8.58 (1H, d, J=5.5 Hz), 8.47 (1H, s), 7.82 (1H, d, J=8.5
Hz), 7.69 (1H, t, J=5.6 Hz), 7.55 (1H, d, J=2.1 Hz), 7.04 (1H, dd,
J=2.1, 8.5 Hz), 6.67 (1H, d, J=5.5 Hz), 3.67 (3H, s), 3.54 (4H, m),
3.20 (2H, q, J=7.2 Hz), 2.60 (3H, s), 2.36 (8H, m), 1.71 (2H, m),
1.13 (3H, t, J=7.2 Hz); ESIMS (MH.sup.+): 521.15.
[0530] Anal. Calcd. For
C.sub.28H.sub.32N.sub.4O.sub.4S.1.5H.sub.2O: C, 61.40; H, 6.44; N,
10.23. Found: C, 61.40; H, 6.13; N, 10.09.
Example 69(a)
6-Methoxy-1,2-dimethyl-1H-indole-3-carboxylic acid
pyridin-2-ylamide
[0531] ##STR177##
[0532] This material was prepared from
1,2-dimethyl-6-methoxy-1H-indole-3-carboxylic acid 16c, oxalyl
chloride and propylamine in a manner as previously described for
example 16d. .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 8.34-8.37
(2H, m), 8.30 (1H, d, J=5.0 Hz), 7.78 (1H, d, J=8.7 Hz), 7.71 (1H,
d, J=8.9 Hz), 7.03 (1H, m), 6.92 (1H, dd, J=2.3, 8.9 Hz), 6.82 (1H,
d, J=2.3 Hz), 3.89 (3H, s), 3.68 (3H, s), 2.76 (3H, s). LCMS (ESI+)
[M+H]/z Calc'd 296, found 296.
Example 69(b)
6-Hydroxy-1,2-dimethyl-1H-indole-3-carboxylic acid
pyridin-2-ylamide
[0533] ##STR178##
[0534] This material was prepared from
6-methoxy-1,2-dimethyl-1H-indol-3-carboxylic acid pyridin-2-ylamide
69a by treatment with BBr.sub.3 in a manner as previously described
for example 1d. .sup.1H NMR (300 MHz, CD.sub.3OD) .delta. 8.29 (1H,
m), 8.24 (1H, d, J=8.3 Hz), 7.82 (1H, m), 7.64 (1H, d, J=8.7 Hz),
7.12 (1H, m), 6.82 (1H, d, J=2.2 Hz), 6.76 (1H, dd, J=2.2, 8.7 Hz),
3.66 (3H, s), 2.69 (3H, s). LCMS (ESI+) [M+H]/z Calc'd 282, found
282.
Example 69
1,2-Dimethyl-6-[2-(1-methyl-1H-imidazol-2-yl)-thieno[3,2-b]pyridin-7-yloxy-
]-1H-indole-3-carboxylic acid pyridin-2-ylamide
[0535] ##STR179##
[0536] This material was prepared by the reaction of
7-chloro-2-(1-methyl-1H-imidazol-2-yl)thieno[3,2-b]pyridine 1e with
6-hydroxy-1,2-dimethyl-1H-indole-3-carboxylic acid
pyridin-2-ylamide 69b and Cs.sub.2CO.sub.3 in a manner as
previously described for example 1. .sup.1H NMR (300 MHz,
DMSO-d.sub.6) .delta. 8.43 (1H, d, J=5.5 Hz), 8.33 (1H, s), 8.20
(1H, d, J=3.8 Hz), 7.75-7.95 (3H, m), 7.61 (1H, s), 7.40 (1H, s),
7.11 (2H, m), 7.03 (1H, s), 6.60 (1H, d, J=5.5 Hz), 4.05 (3H, s),
3.73 (3H, s), 2.68 (3H, s). LCMS (ESI+) [M+H]/z Calc'd 495, found
495.
[0537] Anal. (C.sub.27H.sub.22N.sub.6O.sub.2S.1.0H.sub.2O) C, H,
N.
Example 70
1,2-Dimethyl-6-(2-thiazol-2-yl-thieno[3,2-b]pyridin-7-yloxy)-1H-indole-3-c-
arboxylic acid pyridin-2-ylamide
[0538] ##STR180##
[0539] This material was prepared by the reaction of
7-chloro-2-(1,3-thiazol-2-yl)thieno[3,2-b]pyridine 41a (0.117 g,
0.46 mmole) with
6-hydroxy-1,2-dimethyl-N-pyridin-2-yl-1H-indole-3-carboxamide 69b
(0.130 g, 0.46 mmole) and Cs.sub.2CO.sub.3 (0.150 g, 0.46 mmole) in
a manner as previously described for example 1 to give a yellow
solid (0.051 g, 22%). .sup.1H NMR (300 MHz, CDCl.sub.3) .delta.
8.48 (1H, d, J=5.5 Hz), 8.38 (1H, s), 8.35 (1H, s), 8.30 (1H, d,
J=3.77 Hz), 7.95 (2H, s), 7.88 (1H, d, J=3.2 Hz), 7.75 (1H, m),
7.42 (1H, d, J=3.39 Hz), 7.22 (1H, d, J=1.9 Hz), 7.12 (1H, dd,
J=1.9, 8.6 Hz), 7.04 (1H, dd, J=5.1, 6.6 Hz), 6.56 (1H, d, J=5.5
Hz), 3.70 (3H, m), 2.80 (3H, m); ESIMS (MH.sup.+): 498.05.
[0540] Anal. Calcd. For
C.sub.26H.sub.19N.sub.5O.sub.2S.sub.2.0.1H.sub.2O: C, 62.53; H,
3.88; N, 14.02. Found: C, 62.44; H, 3.96; N, 13.83.
Example 71(a)
2,2,2-Trifluoro-1-(6-methoxy-2-methyl-1H-indol-3-yl)-ethanone
[0541] ##STR181##
[0542] To a solution of 6-methoxy-2-methyl-1H-indole (1 g, 6.2
mmole) (prepared according to JACS 1998, 110, 2242) in 25 ml of THF
was added TFAA (1.56 g, 7.44 mmole) with ice bath cooling. The
mixture was warmed to room temperature and stirred for two hours
and concentrated in vacuo. The residue was further purified by
column chromatography (eluting with CH2Cl2) to give 1.34 g product
as pale yellow solid (82% yield). .sup.1H NMR (300 MHz, CDCl.sub.3)
.delta. 7.90 (1H, d, J=8.9 Hz), 6.87 (1H, dd, J=2.2, 8.9 Hz), 6.80
(1H, d, J=2.2 Hz), 3.82 (3H, s), 2.69 (3H, s).
Example 71(b)
1-(1-Ethyl-6-methoxy-2-methyl-1H-indol-3-yl)-2,2,2-trifluoro-ethanone
[0543] ##STR182##
[0544] To a solution of
2,2,2-trifluoro-1-(6-methoxy-2-methyl-1H-indol-3-yl)-ethanone 71a
(1.3 g, 5.05 mmole) in 20 ml anhydrous THF was added ethyl iodide
(2.36 g, 15.15 mmole) and sodium hydride (404 mg, 60% in mineral
oil, 10.1 mmole) with ice bath cooling. The mixture was warmed
slowly to room temperature and stirred for an additional four
hours. The reaction was quenched with water and extracted with
EtOAc. The combined organic layer was dried over Na.sub.2SO.sub.4,
filtered and concentrated under rot vap. The residue was purified
by column chromatography (eluting with 20-30% EtOAc in hexanes) to
give a brown oil (580 mg, 40% yield). .sup.1H NMR (300 MHz,
CDCl.sub.3) .delta. 7.91 (1H, d, J=8.9 Hz), 6.93 (1H, dd, J=2.3,
8.9 Hz), 6.82 (1H, d, J=2.3 Hz), 4.18 (2H, m), 3.88 (3H, s), 2.76
(3H, s), 1.40 (3H, m).
Example 71(c)
1-Ethyl-6-methoxy-2-methyl-1H-indole-3-carboxylic acid
[0545] ##STR183##
[0546] To a solution of
1-(1-ethyl-6-methoxy-2-methyl-1H-indol-3-yl)-2,2,2-trifluoro-ethanone
71b (580 mg, 2.03 mmole) in 10 ml ethanol was added a solution of
KOH (1.1 g, 20 mmole) in 10 ml water. The mixture was heated to
reflux for 1 hour and cooled to room temperature. Concentrated HCl
was added to adjust pH to 1. The mixture was extracted with EtOAc
and the combined organic layer was dried over Na.sub.2SO.sub.4,
filtered and concentrated in vacuo. The residue was further
purified by column chromatography (eluting with 1-2% MeOH in
CH.sub.2Cl.sub.2) to give 350 mg product as brown solid (74%
yield). .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.07 (1H, d,
J=8.7 Hz), 6.90 (1H, dd, J=2.2, 8.7 Hz), 6.80 (1H, d, J=2.2 Hz),
4.14 (2H, q, J=7.2 Hz), 3.88 (3H, s), 2.77 (3H, s), 1.37 (3H, t,
J=7.2 Hz).
Example 71(d)
1-Ethyl-6-methoxy-2-methyl-1H-indole-3-carboxylic acid
methylamide
[0547] ##STR184##
[0548] This material was prepared from the reaction of
1-ethyl-6-methoxy-2-methyl-1H-indole-3-carboxylic acid 71c (350 mg,
1.5 mmole), oxalyl chloride (1.1 ml, 2.0M solution) and methylamine
(1.5 ml, 2.0M solution) in a manner as previously described for
example 16d to give 350 mg product as beige solid (95% yield).
.sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 7.56 (1H, d, J=8.7 Hz),
6.84 (1H, dd, J=2.3, 8.7 Hz), 6.80 (1H, d, J=2.3 Hz), 5.84 (1H,
bs), 4.10 (2H, q, J=7.2 Hz), 3.87 (3H, s), 3.03 (3H, d, J=4.9 Hz),
2.70 (3H, s), 1.33 (3H, t, J=7.2 Hz).
Example 71(e)
1-Ethyl-6-hydroxy-2-methyl-1H-indole-3-carboxylic acid
methylamide
[0549] ##STR185##
[0550] This material was prepared from
1-ethyl-6-methoxy-2-methyl-1H-indole-3-carboxylic acid methylamide
71d (350 mg, 1.42 mmole) by treatment with BBr.sub.3 in a manner as
previously described for example 1d to give 280 mg product as white
solid (85% yield). .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.48
(1H, d, J=8.3 Hz), 6.73-6.77 (2H, m), 6.01 (1H, bs), 4.04 (2H, q,
J=7.2 Hz, 3.03 (3H, d, J=4.9 Hz), 2.66 (3H, s), 1.31 (3H, t, J=7.2
Hz).
Example 71
6-[2-(Azetidine-1-carbonyl)-thieno[3,2-b]pyridin-7-yloxy]-1-ethyl-2-methyl-
-1H-indole-3-carboxylic acid methylamide
[0551] ##STR186##
[0552] This material was prepared by the reaction of
2-(azetidin-1-ylcarbonyl)-7-chlorothieno[3,2-b]pyridine 25a with
1-ethyl-6-hydroxy-2-methyl-1H-indole-3-carboxylic acid methylamide
71e and Cs.sub.2CO.sub.3 in a manner as previously described for
example 1. .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 8.47 (1H, d,
J=5.5 Hz), 7.75 (2H, m), 7.16 (1H, d, J=1.7 Hz), 7.01 (1H, dd,
J=1.7, 8.4 Hz), 6.56 (1H, d, J=5.5 Hz), 5.91 (1H, bs), 4.59 (2H,
m), 4.28 (2H, m), 4.11 (2H, m), 3.05 (3H, d, J=4.0 Hz), 2.72 (3H,
s), 2.45 (2H, m), 1.33 (3H, m). LCMS (ESI+) [M+H]/z Calc'd 449,
found 449.
[0553] Anal. (C.sub.24H.sub.24N.sub.4O.sub.3S.0.5H.sub.2O.0.25MeOH)
C, H, N.
Example 72
1-Ethyl-2-methyl-6-[2-(1-methyl-1H-imidazol-2-yl)-thieno[3,2-b]pyridin-7-y-
loxy]-1H-indole-3-carboxylic acid methylamide
[0554] ##STR187##
[0555] This material was prepared by the reaction of
7-chloro-2-(1-methyl-1H-imidazol-2-yl)thieno[3,2-b]pyridine 1e with
1-ethyl-6-hydroxy-2-methyl-1H-indole-3-carboxylic acid methylamide
71e and Cs.sub.2CO.sub.3 in a manner as previously described for
example 1. .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 8.44 (1H, d,
J=5.4 Hz), 7.74 (1H, d, J=8.7 Hz), 7.68 (1H, s), 7.18 (1H, d, J=1.9
Hz), 7.14 (1H, s), 7.05 (1H, d, J=1.9 Hz), 7.02 (1H, s), 6.54 (1H,
d, J=5.4 Hz), 5.92 (1H, bs), 4.11 (2H, m), 3.96 (3H, s), 3.05 (3H,
d, J=4.7 Hz), 2.72 (3H, s), 1.33 (3H, m). LCMS (ESI+) [M+H]/z
Calc'd 446, found 446.
[0556] Anal. (C.sub.24H.sub.23N.sub.5O.sub.2S.0.5H.sub.2O.0.5MeOH)
C, H, N.
Example 73(a)
[2-(2-Hydroxy-butyl)-5-methoxy-phenyl]-carbamic acid t-butyl
ester
[0557] ##STR188##
[0558] To a solution of (5-methoxy-2-methyl-phenyl)-carbamic acid
t-butyl ester (6.95 g, 29.3 mmole) in 100 ml THF cooled at
-45.degree. C. was added sec-BuLi (45 ml, 58.5 mmole) slowly to
keep temperatue lower than -45.degree. C. The reaction mixture was
stirred and warmed to -20.degree. C., then cooled to -45.degree. C.
and propionaldehyde (2.67 ml, 36.63 mmole) was added. The reaction
mixture was stirred and warmed to room temperature for 1 h,
quenched with 1N HCl and extracted with EtOAc, dried over
MgSO.sub.4 and concentrated. The residue was purified by flash
column chromatography (10-15% EtOAc in hexane) to give colorless
oil (3.40 g, 39%). .sup.1H NMR (CDCl.sub.3) .delta. 7.96 (1H, s),
7.44 (1H, s), 6.96-7.00 (1H, m), 6.55 (1H, m), 3.80 (3H, s),
2.60-2.76 (2H, m), 1.93-1.95 (2H, m), 1.50 (9H, s), 0.93-1.01 (4H,
m). ESIMS (MNa.sup.+): 318.20.
Example 73(b)
[5-Methoxy-2-(2-oxo-butyl)-phenyl]-carbamic acid t-butyl ester
[0559] ##STR189##
[0560] To a solution of Dess-Martin reagent (2.82 g, 6.68 mmole) in
80 ml THF cooled at 0.degree. C. was added
[2-(2-hydroxy-butyl)-5-methoxy-phenyl]-carbamic acid t-butyl ester
73a (1.64 g, 5.57 mmole) in 20 ml THF. The reaction mixture was
stirred and warmed to room temperature for 2 h, quenched with half
saturated NaHCO.sub.3, extracted with EtOAc. The organic layer was
dried over MgSO.sub.4 and concentrated. The residue was purified by
flash column chromatography (10-15% EtOAc in hexane) to give
colorless oil (1.36 g, 84%). .sup.1H NMR (CDCl.sub.3) .delta. 7.67
(1H, bs), 7.48 (1H, s), 6.99-7.03 (1H, m), 6.56-6.60 (1H, m), 3.79
(3H, s), 3.59 (2H, s), 2.53-2.61 (2H, q, J=7.2 Hz), 1.51 (9H, s),
1.02 (3H, t, J=7.2 Hz). ESIMS (MNa.sup.+): 316.10.
Example 73(c)
2-Ethyl-6-methoxy-1H-indole
[0561] ##STR190##
[0562] To a solution of [5-methoxy-2-(2-oxo-butyl)-phenyl]-carbamic
acid t-butyl ester 73b (1.36 g, 4.65 mmole) in 10 ml THF was added
4 ml TFA. The reaction mixture was stirred at room temperature for
5 h, quenched with 50 ml H.sub.2O and extracted with EtOAc. The
organic layer was dried over MgSO.sub.4 and concentrated. The
residue was purified by flash column chromatography (10-15% EtOAc
in hexane) to give pale yellow solid (1.36 g, 73%). .sup.1H NMR
(CDCl.sub.3) .delta. 7.75 (1H, bs), 7.49 (1H, d, J=8.6 Hz), 6.81
(1H, s), 6.73 (1H, d, J=8.6 Hz), 3.83 (3H, s), 2.75 (2H, q, J=7.5
Hz), 1.32 (3H, t, J=7.5 Hz). ESIMS (MH.sup.+): 272.10.
Example 73(d)
1-(2-Ethyl-6-methoxy-1-methyl-1H-indol-3-yl)-2,2,2-trifluoro-ethanone
[0563] ##STR191##
[0564] To a solution of 2-ethyl-6-methoxy-1H-indole 73c (1.79 g,
10.2 mmole) in 50 ml THF at 0.degree. C. was added TFAA (1.58 ml,
11.22 mmole). The reaction mixture was stirred at 0.degree. C. for
1 h, then concentrated and dried under vacuum, which was used
without purification. ESIMS (MH.sup.+): 272.10. The above residue
was dissolved in 25 ml THF and cooled to 0.degree. C., MeI (1.59
ml, 25.5 ml) and NaH (60%, 0.816 g, 20.4 mmole) was added. The
reaction was stirred at room temperature for 1 h, quenched with
H.sub.2O and extracted with EtOAc. The organic layer was dried over
MgSO.sub.4, and concentrated. The residue was purified by flash
column chromatography (25% EtOAc in hexane) to give yellow color
solid (2.42 g, 73%). .sup.1H NMR (CDCl.sub.3) .delta. 7.88 (1H, d,
J=8.9 Hz), 6.94 (1H, dd, J=2.4, 8.9 Hz), 6.81 (1H, s), 3.88 (3H,
s), 3.72 (3H, s), 3.20 (2H, q, J=7.5 Hz), 1.27 (3H, t, J=7.5 Hz).
ESIMS (MH.sup.+): 286.10
Example 73(e)
2-Ethyl-6-methoxy-1-methyl-1H-indole-3-carboxylic acid
[0565] ##STR192##
[0566] KOH (1.9 g, 33.49 mmole) in 20 ml H.sub.2O was added to a
solution of
1-(2-ethyl-6-methoxy-1-methyl-1H-indol-3-yl)-2,2,2-trifluoro-ethanone
73d (2.42 g, 8.47 mmole) in 20 ml EtOH. The reaction mixture was
heated to reflux for 8 h and concentrated. The residue was
dissolved in H.sub.2O, acidified with 1N HCl to pH .about.1 and
filtrated. The solid was purified by flash column chromatography
(2-5% CH.sub.3OH in CH.sub.2Cl.sub.2) to give yellow color solid
(1.3 g, 72%). .sup.1H NMR (CDCl.sub.3) .delta. 11.88 (1H, bs), 7.82
(1H, d, J=8.7 Hz), 7.04 (1H, s), 6.77 (1H, d, J=8.7 Hz), 3.80 (3H,
s), 3.70 (3H, s), 3.51 (2H, q, J=7.4 Hz), 1.15 (3H, t, J=7.4 Hz).
ESIMS (MH.sup.+): 234.05.
Example 73(f)
2-Ethyl-6-methoxy-1-methyl-1H-indole-3-carboxylic acid
methylamide
[0567] ##STR193##
[0568] Thionyl chloride (0.383 ml, 4.45 mmole) was added to a
solution of 2-ethyl-6-methoxy-1-methyl-1H-indole-3-carboxylic acid
73e (0.347 g, 1.48 mmole). The reaction mixture was heated to
reflux for 30 min and concentrated. The residue was dissolved in 5
ml CH.sub.2Cl.sub.2 and added methylamine (2.0 M in THF, 2.22 ml,
4.44 mmole). The reaction mixture was stirred at room temperature
for 1 hr, then concentrated. The residue was purified by flash
column chromatography (2-5% CH.sub.3OH in CH.sub.2Cl.sub.2) to give
yellow color solid (0.267 g, 73%). .sup.1H NMR (CDCl.sub.3) .delta.
7.47 (1H, d, J=8.7 Hz), 6.80 (1H, s), 6.69 (1H, d, J=8.7 Hz), 3.47
(3H, s), 3.58 (3H, s), 3.00 (2H, q, J=7.4 Hz), 2.83 (3H, s), 1.14
(3H, t, J=7.4 Hz). ESIMS (MH.sup.+): 247.10.
Example 73(g)
2-Ethyl-6-hydroxy-1-methyl-1H-indole-3-carboxylic acid
methylamide
[0569] ##STR194##
[0570] To a solution of
2-ethyl-6-methoxy-1-methyl-1H-indole-3-carboxylic acid methylamide
73f (0.267 g, 1.08 mmole) in 15 ml CH.sub.2Cl.sub.2 at 0.degree. C.
was added BBr.sub.3 (1.0 M in CH.sub.2Cl.sub.2, 3.25 ml, 3.25
mmole). The reaction mixture was stirred at room temperature for 2
h, quenched with saturated NH.sub.4OH to make pH.about.10. The
mixture was diluted with H.sub.2O and extracted with 10% CH.sub.3OH
in CH.sub.2Cl.sub.2. The organic layer was dried over MgSO.sub.4
and concentrated. The residue purified by flash column
chromatography (3-5% CH.sub.3OH in CH.sub.2Cl.sub.2) to give pale
yellow color solid (0.170 g, 68%). .sup.1H NMR (CDCl.sub.3) .delta.
7.40 (1H, d, J=8.5 Hz), 6.65 (1H, s), 6.59 (1H, d, J=8.5 Hz), 3.53
(3H, s), 3.28 (2H, q, J=7.5 Hz), 2.82 (3H, s), 1.13 (3H, t, J=7.5
Hz). ESIMS (MH.sup.+): 233.15.
Example 73
2-Ethyl-6-[2-(3-hydroxy-pyrrolidine-1-carbonyl)-thieno[3,2-b]pyridin-7-ylo-
xy]-1-methyl-1H-indole-3-carboxylic acid methylamide
[0571] ##STR195##
[0572] The material was prepared by the reaction of
(7-chloro-thieno[3,2-b]pyridin-2-yl)-(3-hydroxy-pyrrolidin-1-yl)-methanon-
e 4a (0.146 g, 0.517 mmole) with
2-ethyl-6-hydroxy-1-methyl-1H-indole-3-carboxylic acid methylamide
73 g (0.080 g, 0.344 mmole) and Cs.sub.2CO.sub.3 (0.112 g, 0.344
mmole) in a manner as previously described for example 1 to give 30
mg (18% yield) of pale yellow solid. .sup.1H NMR (CD.sub.3OD)
.delta. 8.34 (1H, d, J=5.5 Hz), 7.69-7.70 (2H, m), 7.26 (1H, s),
6.91 (1H, d, J=6.8 Hz), 6.65 (1H, d, J=5.5 Hz), 4.39 (1H, m), 3.90
(2H, m), 3.67-3.61 (5H, m), 2.99 (2H, m), 2.86 (3H, m), 2.00 (2H,
m), 1.14-1.19 (3H, m). ESIMS (MH.sup.+): 479.10.
[0573] Anal. Calcd. For
C.sub.25H.sub.26N.sub.4O.sub.4S.0.55CH.sub.2Cl.sub.2: C, 58.42; H,
5.20; N, 10.67. Found: C, 58.47; H, 5.43; N, 11.31.
Example 74
2-Ethyl-1-methyl-6-[2-(1-methyl-1H-imidazol-2-yl)-thieno[3,2-b]pyridin-7-y-
loxy]-1H-indole-3-carboxylic acid methylamide
[0574] ##STR196##
[0575] This material was prepared by the reaction
7-chloro-2-(1-methyl-1H-imidazol-2-yl)thieno[3,2-b]pyridine 1e
(0.084 g, 0.34 mmole) with
2-ethyl-6-hydroxy-N,1-dimethyl-1H-indole-3-carboxamide 73 g (0.078
g, 0.33 mmole) and Cs.sub.2CO.sub.3 (0.111 g, 0.34 mmole) in a
manner as previously described for example 1 to give an off-white
solid (0.058 g, 40%). .sup.1H NMR (300 MHz, CD.sub.3OD .delta. 8.27
(1H, d, J=5.4 Hz), 7.68 (1H, d, J=8.6 Hz), 7.59 (1H, s), 7.24 (1H,
d, J=1.9 Hz), 7.17 (1H, s), 6.96 (1H, s), 6.90 (1H, dd, J=1.9, 8.6
Hz), 6.50 (1H, d, J=5.4 Hz), 3.87 (3H, s), 3.58 (3H, s), 3.01 (2H,
m), 2.85 (3H, s), 1.14 (3H, m). HRMS (MH.sup.+): Calcd: 446.1655;
Found: 446.1651.
Example 75(a)
6-Methoxy-1-methyl-1H-indole-3-carboxylic acid methylamide
[0576] ##STR197##
[0577] This material was prepared from
6-methoxy-1-methyl-1H-indole-3-carboxylic acid 16b (2.39 g, 10.9
mmole), oxalyl chloride and methylamine in a manner as previously
described for example 16d to give a brown solid (1.08 g, 45%).
.sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 7.97 (1H, d, J=8.7 Hz),
7.76 (2H, m), 6.99 (1H, d, J=2.3 Hz), 6.77 (1H, dd, J=2.3, 8.7 Hz),
3.80 (3H, s), 3.76 (3H, s), 2.74 (3H, s); ESIMS (MH.sup.+):
219.05.
Example 75(b)
2-Chloro-6-methoxy-1-methyl-1H-indole-3-carboxylic acid
methylamide
[0578] ##STR198##
[0579] N-Chlorosuccinimide (0.150 g, 1.12 mmole) was added to a
solution of 6-methoxy-N,1-dimethyl-1H-indole-3-carboxamide 75a
(0.243 g, 1.11 mmole) in CCl.sub.4 (10 ml) and DMF (3 ml). The
reaction mixture was heated to 60.degree. C. for 3 h and
concentrated. The residue was purified by reverse phase
chromatography eluting with 0-1% CH.sub.3OH in 1:1 EtOAc and
CH.sub.2Cl.sub.2 to give a brown colored oil (0.243 g, 87% yield);
.sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 7.61 (1H, d, J=8.6 Hz),
6.38 (1H, d, J=8.6 Hz), 6.19 (1H, s), 3.35 (3H, s), 2.96 (3H, s),
2.52 (3H, s); ESIMS (MH.sup.+): 253.05.
Example 75(c)
2-Chloro-6-hydroxy-1-methyl-1H-indole-3-carboxylic acid
methylamide
[0580] ##STR199##
[0581] This material was prepared by reaction of
2-chloro-6-methoxy-N,1-dimethyl-1H-indole-3-carboxamide 75b (0.38
g, 1.4 mmole) with 1.0 M BBr.sub.3 in CH.sub.2Cl.sub.2 (4.19 ml,
4.19 mmole) in a manner as previously described for example 1d to
give an off-white solid (0.195 g, 85%). .sup.1NMR (300 MHz,
CD.sub.3OD) .delta. 7.61 (1H, d, J=8.3 Hz), 6.65 (1H, s), 6.62 (1H,
d, J=2.1 Hz), 3.56 (3H, s) 2.85 (3H, s); ESIMS (MH.sup.+):
239.00.
Example 75
2-Chloro-6-{2-[4-(1-hydroxy-1-methyl-ethyl)-thiazol-2-yl]-thieno[3,2-b]pyr-
idin-7-yloxy}-1-methyl-1H-indole-3-carboxylic acid methylamide
[0582] ##STR200##
[0583] This material was prepared by the reaction of
2-[2-(7-chlorothieno[3,2-b]pyridin-2-yl)-1,3-thiazol-4-yl]propan-2-ol
40a (0.102 g, 0.33 mmole) with
2-chloro-6-hydroxy-N,1-dimethyl-1H-indole-3-carboxamide 75c (0.085
g, 0.33 mmole) and Cs.sub.2CO.sub.3 (0.108 g, 0.33 mmole) in a
manner as previously described for example 1 to give an off-white
solid (0.039 g, 21%). .sup.1H NMR (300 MHz, CDCl.sub.3) .delta.
8.40 (1H, d, J=5.5 Hz), 8.31 (1H, d, J=8.3 Hz), 7.82 (1H, m), 7.20
(1H, s), 7.14 (1H, s), 7.07 (2H, m), 6.47 (1H, d, J=5.5 Hz), 6.34
(1H, m), 3.69 (3H, s), 3.01 (3H, d, J=4.7 Hz), 1.60 (6H, s).
[0584] Anal. Calcd. For
C.sub.24H.sub.21N.sub.4O.sub.3S.sub.2Cl.0.6H.sub.2O.1.0CH.sub.3OH:
C, 54.71; H, 4.53; N, 10.36. Found: C, 54.56; H, 4.45; N,
10.17.
Example 76(a)
2-Iodo-5-methoxy-phenylamine
[0585] ##STR201##
[0586] To a solution of 4-iodo-3-nitroanisole (5 g, 17.9 mmole) in
100 ml methanol was added FeCl.sub.3 (50 mg, 0.3 mmole) and
activated carbon (40 mg). The mixture was heated to reflux and
hydrazine hydrate (1.75 g, 35 mmole) was added dropwise. The
mixture was refluxed for an additional 8 hours and cooled to room
temperature, filtered through Celite. The filtrate was concentrated
and purified by column chromatography (eluting with 10% EtOAc in
hexanes) to give 4.05 g product as pale yellow oil (91% yield).
.sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 7.47 (1H, d, J=8.7 Hz),
6.31 (1H, d, J=2.8 Hz), 6.13 (1H, dd, J=2.8, 8.7 Hz), 3.73 (3H,
s).
Example 76(b)
2,2,2-Trifluoro-N-(2-iodo-5-methoxy-phenyl)-acetamide
[0587] ##STR202##
[0588] To a solution of 2-iodo-5-methoxy-phenylamine 76a (4.05 g,
16.3 mmole) in 10 ml anhydrous CH.sub.2Cl.sub.2 was added TFAA (4.1
g, 19.5 mmole). The mixture was stirred at 36.degree. C. overnight,
TLC indicated some starting material remained. Additional TFAA (4.1
g, 19.5 mmole) was added and stirred at 38.degree. C. for another
24 hours. The mixture was concentrated under rot vap and purified
by column chromatography (eluting with 5-10% EtOAc in hexanes) to
give 4.6 g product (81% yield). .sup.1H NMR (300 MHz, CDCl.sub.3)
.delta. 7.92 (1H, d, J=2.8 Hz), 7.66 (1H, d, J=8.9 Hz), 6.59 (1H,
dd, J=2.8, 8.9 Hz), 3.82 (3H, s).
Example 76(c)
4,4,4-Trifluoro-3-(2-iodo-5-methoxy-phenylamino)-but-2-enoic acid
ethyl ester
[0589] ##STR203##
[0590] A solution of
2,2,2-trifluoro-N-(2-iodo-5-methoxy-phenyl)-acetamide 76b (4.6 g,
13.3 mmole) and methyl (triphenylphosphoranylidene)acetate (8.7 g,
25 mmole) in 50 ml toluene was brought to reflux for 5 hours and
cooled to room temperature. The solution was concentrated, in vacuo
and purified by column chromatography (eluting with 2-6% EtOAc in
hexanes) to give 4.8 g product (87% yield). .sup.1H NMR (300 MHz,
CDCl.sub.3) .delta. 9.57 (1H, s), 7.68 (1H, d, J=8.8 Hz), 6.83 (1H,
d, J=2.8 Hz), 6.57 (1H, dd, J=2.8, 8.8 Hz), 5.43 (1H, s), 4.23 (2H,
m), 3.76 (3H, s), 1.55 (3H, s), 1.31 (3H, m).
Example 76(d)
6-Methoxy-2-trifluoromethyl-1H-indole-3-carboxylic acid ethyl
ester
[0591] ##STR204##
[0592] A mixture of
4,4,4-trifluoro-3-(2-iodo-5-methoxy-phenylamino)-but-2-enoic acid
ethyl ester 76c (0.5 g, 1.2 mmole), Pd(OAc).sub.2 (22.4 mg, 0.1
mmole), PPh.sub.3 (52.5 mg, 0.2 mmole) and NaHCO.sub.3 (505 mg, 6
mmole) in 5 ml DMF was heated at 120.degree. C. under argon for 24
hours and cooled to room temperature. The mixture was poured into
EtOAc/water and washed with brine. The organic layer was dried over
Na.sub.2SO.sub.4 and concentrated under rot vap. The residue was
purified by column chromatography to give 217 mg product (63%
yield). .sup.1H NMR (300 MHz, CD.sub.3OD) .delta. 8.00 (1H, d,
J=9.0 Hz), 6.96 (1H, d, J=2.0 Hz), 6.90 (1H, dd, J=2.0, 9.0 Hz),
4.37 (2H, m), 3.84 (3H, s), 1.40 (3H, m).
Example 76(e)
6-Methoxy-1-methyl-2-trifluoromethyl-1H-indole-3-carboxylic acid
ethyl ester
[0593] ##STR205##
[0594] This material was prepared from
6-methoxy-2-trifluoromethyl-1H-indole-3-carboxylic acid ethyl ester
76d (1.64 g, 5.7 mmole) by treatment with NaH (274 mg, 60% in
mineral oil, 6.84 mmole) and methyl iodide (1.21 g, 8.55 mmole) and
NaH in a manner as previously described for example 16b to give 1.5
g product (87% yield). .sup.1H NMR (300 MHz, CDCl.sub.3) .delta.
7.96 (1H, dd, J=3.7, 8.8 Hz), 6.94 (1H, dd, J=2.3, 9.1 Hz), 6.77
(1H, d, J=2.1 Hz), 4.40 (2H, m), 3.89 (3H, s), 3.86 (3H, s), 1.41
(3H, m).
Example 76(f)
6-Methoxy-1-methyl-2-trifluoromethyl-1H-indole-3-carboxylic
acid
[0595] ##STR206##
[0596] To a solution of
6-methoxy-1-methyl-2-trifluoromethyl-1H-indole-3-carboxylic acid
ethyl ester 76e (1.5 g, 4.98 mmole) in 10 ml THF and 5 ml MeOH was
added a solution of KOH (2.8 g, 50 mmole) in 5 ml water with ice
bath cooling. The mixture was warmed to room temperature and
stirred overnight. Concentrated aqueous HCl solution was added to
adjust the pH to 1. The mixture was extracted with EtOAc and the
combined organic layer was dried over Na.sub.2SO.sub.4, filtered
and concentrated. The residue was further purified by column
chromatography (eluting with 1-5% MeOH in CH.sub.2Cl.sub.2) to give
880 mg product (65% yield). .sup.1H NMR (300 MHz, CD.sub.3OD)
.delta. 7.90 (1H, d, J=9.0 Hz), 7.01 (1H, d, J=2.1 Hz), 6.91 (1H,
dd, J=2.1, 9.0 Hz), 3.90 (3H, s), 3.88 (3H, s).
Example 76(g)
6-Methoxy-1-methyl-2-trifluoromethyl-1H-indole-3-carboxylic acid
methylamide
[0597] ##STR207##
[0598] This material was prepared from
6-methoxy-1-methyl-2-trifluoromethyl-1H-indole-3-carboxylic acid
76f (880 mg, 3.22 mmole), oxalyl chloride (3 ml, 2.0M solution) and
methylamine (5 ml, 2.0M solution) in a manner as previously
described for example 16d to give 900 mg product as white solid
(98% yield). .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 7.62 (1H, d,
J=8.9 Hz), 6.88 (1H, dd, J=2.1, 8.9 Hz), 6.73 (1H, d, J=2.1 Hz),
5.80 (1H, bs), 3.88 (3H, s), 3.79 (3H, s), 3.04 (3H, d, J=4.9
Hz).
Example 76(h)
6-Hydroxy-1-methyl-2-trifluoromethyl-1H-indole-3-carboxylic acid
methylamide
[0599] ##STR208##
[0600] This material was prepared from
6-hydroxy-1-methyl-2-trifluoromethyl-1H-indole-3-carboxylic acid
methylamide 76 g (900 mg, 3.14 mmole) by treatment with BBr.sub.3
in a manner as previously described for example 1d to give 780 mg
product as white solid (89% yield). .sup.1H NMR (300 MHz,
CD.sub.3OD) .delta. 7.44 (1H, d, J=8.7 Hz), 6.76-6.81 (2H, m), 3.77
(1H, s), 2.93 (3H, s).
Example 76
1-Methyl-6-[2-(1-methyl-1H-imidazol-2-yl)-thieno[3,2-b]pyridin-7-yloxy]-2--
trifluoromethyl-1H-indole-3-carboxylic acid methylamide
[0601] ##STR209##
[0602] The material was prepared by the reaction of
7-chloro-2-(1-methyl-1H-imidazol-2-yl)thieno[3,2,-b]pyridine 1e
with 6-hydroxy-1-methyl-2-trifluoromethyl-1H-indole-3-carboxylic
acid methylamide 76h and Cs.sub.2CO.sub.3 in a manner as previously
described for example 1. .sup.1H NMR (300 MHz, DMSO-d.sub.6)
.delta. 8.51 (1H, d, J=5.5 Hz), 7.89 (1H, s), 7.78 (1H, s), 7.72
(1H, d, J=8.6 Hz), 7.41 (1H, s), 7.18 (1H, d, J=9.8 Hz), 7.03 (1H,
s), 6.66 (1H, d, J=5.4 Hz), 3.99 (3H, s), 3.86 (3H, s), 2.81 (3H,
s). LCMS (ESI+) [M+H]/z Calc'd 486, found 486.
[0603] Anal. (C.sub.23H.sub.18F.sub.3N.sub.5O.sub.2S.1.3H.sub.2O)
C, H, N.
Example 77
6-[2-(Azetidine-1-carbonyl)-thieno[3,2-b]pyridin-7-yloxy]-2-methyl-benzofu-
ran-3-carboxylic acid methylamide
[0604] ##STR210##
[0605] This material was prepared by the reaction
2-(azetidin-1-ylcarbonyl)-7-chlorothieno[3,2-b]pyridine 25a (100
mg, 0.40 mmole) with 6-hydroxy-2-methylbenzofuran-3-carboxylic acid
methylamide (100 mg, 0.49 mmole) and Cs.sub.2CO.sub.3 (257 mg, 0.79
mmole) in a manner as previously described for example 1 to give
124 mg (74%) of a tan solid. .sup.1H NMR (DMSO-d.sub.6) .delta.
8.56 (1H, d, J=5.6 Hz), 7.99 (1H, d, J=4.6 Hz), 7.89 (1H, s), 7.83
(1H, d, J=8.6 Hz), 7.66 (1H, d, J=2.0 Hz), 7.24 (1H, dd, J=8.6, 2.3
Hz), 6.70 (1H, d, J=5.3 Hz), 4.61 (2H, t, J=7.6 Hz), 4.10 (2H, t,
J=7.3 Hz), 2.81 (3H, d, J=4.6 Hz), 2.63 (3H, s), 2.35 (2H, p, J=7.7
Hz).
[0606] Anal. Calcd for C.sub.22H.sub.19N.sub.3O.sub.4S.0.5H.sub.2O:
C, 62.03; H, 4.61; N, 9.86; S, 7.53. Found: C, 62.31; H, 4.65; N,
9.60; S, 7.34.
Example 78(a)
1-Benzhydryl-3-methoxy-azetidine
[0607] ##STR211##
[0608] To an ice cold solution of 1-benzhydrylazetidin-3-ol 9a (1.0
g, 4.2 mmole) in DMF (10 ml) was added 60% dispersion NaH in
mineral oil (0.25 g, 6.3 mmole). After 30 min at 0.degree. C., 5 ml
more DMF was added along with methyl iodide (0.39 ml, 6.3 mmole).
The ice bath was removed, and the reaction was stirred at room
temperature (rt). After 1.5 hr, the reaction was poured into brine
and extracted with Et.sub.2O (2.times.). The combined organic
layers were washed with brine, dried (MgSO.sub.4) and concentrated
under reduced pressure. The residue was flash chromatographed on
silica gel eluting Hexanes/EtOAc (1:1) to give 919 mg (92%) of a
colorless oil which crystallized on standing. .sup.1H NMR
(DMSO-d.sub.6) .delta. 7.42 (4H, d, J=7.3 Hz), 7.27 (4H, t, J=7.3
Hz), 7.13 (2H, t, J=7.3 Hz), 4.39 (1H, s), 3.95 (1H, p, J=5.8 Hz),
3.35 (2H, t, J=6.3 Hz), 3.11 (3H, s), 2.75 (2H, t, J=5.6 Hz).
Example 78(b)
(7-Chloro-thieno[3,2-b]pyridin-2-yl)-(3-methoxy-azetidin-1-yl)-methanone
[0609] ##STR212##
[0610] A 100 ml round bottom flask was charged with
1-benzhydryl-3-methoxy-azetidine 78a (447 mg, 1.77 mmole), 10% Pd/C
(300 mg), trifluoroacetic acid (0.15 ml, 1.94 mmole) and EtOH (30
ml) and placed under 1 atm H.sub.2 and vigorously stirred at rt.
After 2 hr, the catalyst was removed and washed with MeOH. The
filtrate was concentrated under reduced pressure to give the crude
azetidine which was dissolved in CH.sub.2Cl.sub.2. To this solution
were added triethylamine (0.6 ml, 4.41 mmole) and
7-chloro-thieno[3,2-b]pyridine-2-carbonyl chloride, prepared as
previously described in example 25a. After stirring at ambient
temperature overnight, the reaction mixture was diluted with more
CH.sub.2Cl.sub.2, then washed sequentially with 0.5N HCl, satd.
NaHCO.sub.3 (aq), and brine. The organic layer was dried
(MgSO.sub.4) and concentrated to near dryness under reduced
pressure, then triturated with hexanes to give 278 mg (56%) of the
desired product as a light yellow solid. .sup.1H NMR (DMSO-d.sub.8)
.delta. 8.73(1H, d, J=5.1 Hz), 8.00 (1H, s), 7.70 (1H, d, J=5.1
Hz), 4.77 (1H, m), 4.49 (1H, m), 4.31 (2H, m), 3.90 (1H, m), 3.24
(3H, s). APCI m/z 283/285 (M+H).sup.+.
Example 78
Methoxy-azetidine-1-carbonyl)-thieno[3,2-b]pyridin-7-yloxy]-2-methyl-benzo-
furan-3-carboxylic acid methylamide
[0611] ##STR213##
[0612] This material was prepared by the reaction of
(7-Chloro-thieno[3,2-b]pyridin-2-yl)-(3-methoxy-azetidin-1-yl)-methanone
78b (241 mg, 0.85 mmole) with
6-hydroxy-2-methylbenzo[b]furan-3-carboxylic acid methylamide 12c
(210 mg, 1.02 mmole) and Cs.sub.2CO.sub.3 (833 mg, 2.56 mmole) in a
manner as previously described in example 1 to give 298 mg (77%) of
a yellow solid. .sup.1H NMR (DMSO-d.sub.6) .delta. 8.57 (1H, d,
J=5.3 Hz), 7.99 (1H, d, J=4.7 Hz), 7.94 (1H, s), 7.82 (1H, d, J=8.5
Hz), 7.66 (1H, d, J=2.3 Hz), 7.24 (1H, dd, J=8.5, 2.3 Hz), 6.72
(1H, d, J=5.5 Hz), 4.76 (1H, m), 4.47 (1H, m), 4.30 (2H, m), 3.90
(1H, m), 3.25 (3H, s), 2.82 (3H, d, J=4.5 Hz), 2.63 (3H, s).
[0613] Anal. Calcd for C.sub.23H.sub.21N.sub.3O.sub.5S.0.4H.sub.2O:
C, 60.22; H, 4.79; N, 9.16; S, 6.99. Found: C, 60.33; H, 4.78; N,
9.13; S, 6.79.
Example 79
6-(2-[(S)-2-(methoxymethyl)pyrrolidine-1-carbonyl]thieno[3,2-b]pyridin-7-y-
loxy)-2-methyl-benzofuran-3-carboxylic acid methyl amide
[0614] ##STR214##
[0615] This material was prepared by the reaction of
7-chloro-2-[(R)-2-methoxymethylpyrrolidine-1-carbonyl]thieno[3,2-b]pyridi-
ne 2a with 6-Hydroxy-2-methyl-benzofuran-3-carboxylic acid methyl
amide 12c and Cs.sub.2CO.sub.3 in a manner as previously described
for example 1. .sup.1H NMR (DMSO-d.sub.6) .delta. 8.57 (1H, d,
J=5.3 Hz), 8.02 (1H, s), 7.98 (1H, m), 7.83 (1H, d, J=8.6 Hz), 7.66
(1H, d, J=2.0 Hz), 7.25 (1H, dd, J=8.6, 2.0 Hz), 6.72 (1H, d, J=5.3
Hz), 4.31 (1H,m), 3.94-3.80 (2H, m), 3.60-3.39 (2H, m), 3.28 (3H,
s), 2.82 (3H, d, J=4.6 Hz), 2.63 (3H, s), 2.06-1.85 (4H,m).
[0616] Anal. Calcd for
C.sub.25H.sub.25N.sub.3O.sub.5S.0.6H.sub.2O.0.2Hexanes: C, 61.99;
H, 5.76; N, 8.28; S, 6.32. Found: C, 61.94; H, 5.74; N, 8.12; S,
6.32.
Example 80
6-(2-[(S)-2-(hydroxymethyl)pyrrolidine-1-carbonyl]thieno[3,2-b]pyridin-7-y-
loxy)-2-methyl-benzofuran-3-carboxylic acid methylamide
[0617] ##STR215##
[0618] This material was prepared from
2-methyl-6-[2-(2-methoxymethyl-pyrrolidine-1-carbonyl)-thieno[3,2-b]pyrid-
in-7-yloxy]-benzofuran-3-carboxylic acid methylamide 79 by
treatment with BBr.sub.3 in a manner as previously described for
example 1d. .sup.1H NMR (DMSO-d.sub.6) .delta. 8.56 (1H, d, J=5.1
Hz), 8.00-7.98 (2H, m), 7.83 (1H, d, J=8.6 Hz), 7.66 (1H, d, J=2.0
Hz), 7.25 (1H, dd, J=8.6, 2.0 Hz), 6.73 (1H, d, J=5.1 Hz), 4.81
(1H, m), 4.18 (1H, m), 3.91-3.32 (4H, m), 2.81 (3H, d, J=4.5 Hz),
2.63 (3H, s), 2.05-1.83 (4H, m).
[0619] Anal. Calcd for
C.sub.24H.sub.23N.sub.3O.sub.5S.2H.sub.2O.0.2EtOAc: C, 57.37; H,
5.55; N, 8.09; S, 6.18. Found: C, 57.15; H, 5.24; N, 7.71; S,
6.01.
Example 81
6-[2-(4-Hydroxymethyl-thiazol-2-yl)-thieno[3,2-b]pyridin-7-yloxy]-2-methyl-
-benzofuran-3-carboxylic acid methylamide
[0620] ##STR216##
[0621] This material was prepared by the reaction of
[2-(7-Chloro-thieno[3,2-b]pyridin-2-yl)-thiazol-4-yl]-methanol with
6-hydroxy-2-methyl-benzofuran-3-carboxylic acid methyl amide 12c
and Cs.sub.2CO.sub.3 in a manner as previously described for
example 1. .sup.1H NMR (DMSO-d.sub.6) .delta. 8.55 (1H, d, J=5.6
Hz), 8.16 (1H, s), 7.98 (1H, m), 7.84 (1H, d, J=8.6 Hz), 7.67 (1H,
d, J=2.0 Hz), 7.63 (1H, s), 7.26 (1H, dd, J=8.6, 2.0 Hz), 6.73 (1H,
d, J=5.6 Hz), 5.43 (1H, m), 4.61 (2H,s), 2.82 (3H, d, J=4.6 Hz),
2.64 (3H, s).
[0622] Anal. Calcd for
C.sub.22H.sub.17N.sub.3O.sub.4S.sub.2.0.6H.sub.2O: C, 57.15; H,
3.97; N, 9.09; S, 13.87. Found: C, 57.13; H, 4.07; N, 8.95; S,
13.87.
Example 82(a)
6-Methoxy-2-methyl-benzofuran-3-carboxylic acid isopropyl amide
[0623] ##STR217##
[0624] This material was prepared from 6-methoxy-2-methylbenzofuran
12a (500 mg, 3.1 mmole) by acylation with oxalyl chloride in the
presence of AlCl.sub.3, followed by treatment with isopropylamine
in a manner as previously described for example 1c to give 540 mg
(71%) of an off-white solid. .sup.1H NMR (DMSO-d.sub.6) .delta.
7.80 (1H, d, J=7.8 Hz), 7.50 (1H, d, J=8.6 Hz), 7.14 (1H, d, J=2.2
Hz), 6.89 (1H, dd, J=8.6, 2.2 Hz), 4.09 (1H, m), 3.76 (3H, s), 2.56
(3H, s), 1.16 (6H, d, J=6.6 Hz).
[0625] Anal. Calcd for C.sub.14H.sub.17NO.sub.3: C, 67.99; H, 6.93;
N, 5.66. Found: C, 67.86; H, 6.87; N, 5.60.
Example 82(b)
6-Hydroxy-2-methyl-benzofuran-3-carboxylic acid isopropyl amide
[0626] ##STR218##
[0627] This material was prepared from
6-methoxy-2-methylbenzofuran-3-carboxylic acid isopropylamide 82a
(507 mg, 2.05 mmole) by treatment with BBr.sub.3 in a manner as
previously described for example 1d to give 425 mg (89%) of lt. tan
solid. .sup.1H NMR (DMSO-d.sub.6) .delta. 9.54 (1H, s), 7.71 (1H,
d, J=8.1 Hz), 7.38 (1H, d, J=8.6 Hz), 6.87 (1H, s), 6.70 (1H, d,
J=8.6 Hz), 4.07 (1H, m), 2.51 (3H, s), 1.17 (6H, d, J=6.8 Hz).
[0628] Anal. Calcd for C.sub.13H.sub.15NO.sub.3.0.1MeOH: C, 66.54;
H, 6.56; N, 5.92. Found: C, 66.38; H, 6.48; N, 5.93.
Example 82
6-(2-[(S)-2-(methoxymethyl)pyrrolidine-1-carbonyl]thieno[3,2-b]pyridin-7-y-
loxy)-2-methyl-benzofuran-3-carboxylic acid isopropylamide
[0629] ##STR219##
[0630] This material was prepared by the reaction of
7-chloro-2-[(S)-2-(methoxymethyl)pyrrolidine-1-carbonyl]thieno[3,2-b]pyri-
dine 2a (133 mg, 0.43 mmole)
6-hydroxy-2-methyl-benzofuran-3-carboxylic acid isopropy amide 82b
(120 mg, 0.51 mmole) and Cs.sub.2CO.sub.3 (279 mg, 0.86 mmole) in a
manner as previously described to give 150 mg (69%) of an off-white
brittle foam. .sup.1H NMR (DMSO-d.sub.6): .delta. 8.56 (1H, d,
J=5.3 Hz), 8.03 (1H, s), 7.96 (1H, d, J=8.1 Hz), 7.75 (1H, d, J=8.3
Hz), 7.65 (1H, d, J=2.3 Hz), 7.24 (1H, dd, J=8.6, 2.3 Hz), 6.72
(1H, d, J=5.3 Hz), 4.30 (1H, m), 4.12 (1H, m), 3.85 (2H, m), 3.56
(1H, m), 3.42 (1H, m), 3.25 (3H, s), 2.59 (3H, s), 2.08-1.81 (4H,
m), 1.20 (6H, d, J=6.6 Hz). Anal. Calcd for
C.sub.27H.sub.29N.sub.3O.sub.5S.0.3EtOAc: C, 63.42; H, 5.93; N,
7.87; S, 6.00. Found: C, 63.20; H, 5.90; N, 7.85; S, 6.03.
Example 83
2-Methyl-6-[2-(1-methyl-1H-imidazol-2-yl)-thieno[3,2-b]pyridin-7-yloxy]-be-
nzofuran-3-carboxylic acid isopropyl amide
[0631] ##STR220##
[0632] This material was prepared by the reaction of
7-chloro-2-(1-methyl-1H-imidazol-2-yl)thieno[3,2-b]pyridine 1e (89
mg, 0.36 mmole) with 6-hydroxy-2-methylbenzo[b]furan-3-carboxylic
acid isopropylamide 82a (100 mg, 0.43 mmole) and Cs.sub.2CO.sub.3
(233 mg, 0.72 mmole) in a manner as previously described for
example 1 to give a 37% yield of a light yellow solid. .sup.1H NMR
(DMSO-d.sub.6) .delta. 8.51 (1H, d, J=5.3 Hz), 7.97 (1H, d, J=7.8
Hz), 7.88 (1H, s), 7.74 (1H, d, J=8.6 Hz), 7.65 (1H, d, J=2.3 Hz),
7.40 (1H, s), 7.24 (1H, dd, J=8.3, 2.0 Hz), 7.01 (1H, s), 6.65 (1H,
d, J=5.6 Hz), 4.12 (1H, m), 3.98 (3H, s), 2.60 (3H, s), 1.20 (6H,d,
J=6.6 Hz).
[0633] Anal. Calcd for C.sub.24H.sub.22N.sub.4O.sub.3S.0.9EtOAc: C,
63.04; H, 5.60; N, 10.66; S, 6.10. Found: C, 62.85; H, 5.52; N,
10.76; S, 6.24.
Example 84(a)
6-Methoxy-2-methyl-benzofuran-3-carboxylic acid isobutyl-amide
[0634] ##STR221##
[0635] This material was prepared from 6-methoxy-2-methylbenzofuran
12a (500 mg, 3.1 mmole) by acylation with oxalyl chloride in the
presence of AlCl.sub.3, followed by treatment with isobutylamine in
a manner as previously described for example 1c to give 585 mg
(73%) of an off-white solid. .sup.1H NMR (DMSO-d.sub.6) .delta.
7.95 (1H, t, J=5.8 Hz), 7.56 (1H, d, J=8.6 Hz), 7.15(1H, d, J=2.3
Hz), 6.91 (1H, dd, J=8.6, 2.3 Hz), 3.76 (3H, s), 3.07 (2H, m), 2.57
(3H, s), 1.83 (1H, m), 0.88 (6H, d, J=6.8 Hz).
[0636] Anal. Calcd for C.sub.15H.sub.19NO.sub.3: C, 68.94; H, 7.33;
N, 5.36. Found: C, 68.75; H, 7.27; N, 5.38.
Example 84(b)
6-Hydroxy-2-methyl-benzofuran-3-carboxylic acid isobutyl amide
[0637] ##STR222##
[0638] This material was prepared from
6-methoxy-2-methyl-benzofuran-3-carboxylic acid isobutyl amide 84a
by treatment with BBr.sub.3 in a manner as previously described for
example 1d. .sup.1H NMR (DMSO-d.sub.6) .delta. 9.53 (1H, s), 7.90
(1H, t, J=6.1 Hz), 7.44 (1H, d, J=8.3 Hz), 6.86 (1H, s), 6.74 (1H,
dd, J=8.6, 1.8 Hz), 3.07 (2H, t, J=6.1 Hz), 2.52 (3H, s), 1.81 (1H,
m) 0.90 (6H, d, J=6.8 Hz).
Example 84
2-Methyl-6-[2-(1-methyl-1H-imidazol-2-yl)-thieno[3,2-b]pyridin-7-yloxy]-be-
nzofuran-3-carboxylic acid isobutyl amide
[0639] ##STR223##
[0640] This material was prepared by the reaction of
7-chloro-2-(1-methyl-1H-imidazol-2-yl)thieno[3,2-b]pyridine 1e with
6-hydroxy-2-methyl-benzofuran-3-carboxylic acid isobutyl amide 84b
and Cs.sub.2CO.sub.3 in a manner as previously described for
example 1. .sup.1H NMR (CD.sub.3CN) .delta. 8.48 (1H, d, J=5.6 Hz),
7.81 (1H, d, J=8.3 Hz), 7.74 (1H, s), 7.43 (1H, d, J=2.0 Hz), 7.21
(1H, dd, J=8.6, 2.3 Hz), 7.17 (1H, s), 7.04 (1H, s), 6.70 (1H, m),
6.67 (1H, d, J=5.6 Hz), 3.97 (3H, s), 3.23 (2H, t, J=6.6 Hz), 2.66
(3H, s), 1.78 (1H,m), 0.98 (6H, d, J=6.6 Hz).
[0641] Anal. Calcd for C.sub.25H.sub.24N.sub.4O.sub.3S.0.3H.sub.2O:
C, 64.44; H, 5.32; N, 12.02; S, 6.88. Found: C, 64.40; H, 5.38; N,
11.76; S, 6.72.
Example 85
6-[2-(2-Methoxymethyl-pyrrol
idine-1-carbonyl)-thieno[3,2-b]pyridin-7-yloxy]-2-methyl-benzofuran-3-car-
boxylic acid isobutyl amide
[0642] ##STR224##
[0643] This material was prepared by the reaction of
7-chloro-2-[(R)-2-methoxymethylpyrrolidine-1-carbonyl]thieno[3,2-b]pyridi-
ne 2a with 6-hydroxy-2-methyl-benzofuran-3-carboxylic acid isobutyl
amide 84b and Cs.sub.2CO.sub.3 in a manner as previously described
for example 1. .sup.1H NMR (CD.sub.3CN) .delta. 8.53 (1H,d, J=5.3
Hz), 7.87 (1H, s), 7.82 (1H, d, J=8.5 Hz), 7.41 (1H, d, J=1.9 Hz),
7.20 (1H, dd, J=8.5, 1.9 Hz), 6.70 (1H, d, J=5.5 Hz), 4.38 (1H, m),
3.85 (2H, m), 3.65-3.41 (2H, m), 3.32 (3H, s), 3.23 (2H, t, J=6.4
Hz), 2.65 (3H, s), 2.15-1.94 (4H,m, partially obscured by
CD.sub.3CN), 1.73 (1H, m).
[0644] Anal. Calcd for C.sub.28H.sub.31N.sub.3O.sub.5S.0.2H.sub.2O:
C, 64.03; H, 6.03; N, 8.00; S, 6.10. Found: C, 64.02; H, 6.11; N,
7.79; S, 5.89.
Example 86
2-Methyl-6-[2-(2-hydroxymethyl-pyrrolidine-1-carbonyl)-thieno[3,2-b]pyridi-
n-7-yloxy]-benzofuran-3-carboxylic acid isobutyl amide
[0645] ##STR225##
[0646] This material was prepared from
2-methyl-6-[2-(2-methoxymethyl-pyrrolidine-1-carbonyl)-thieno[3,2-b]pyrid-
in-7-yloxy]-benzofuran-3-carboxylic acid isobutyl amide 85 by
treatment with BBr.sub.3 in a manner as previously described for
example 1 d. .sup.1H NMR (CD.sub.3CN) .delta. 8.52 (1H, d, J=5.5
Hz), 7.89 (1H, s), 7.81 (1H, d, J=8.5 Hz), 7.42 (1H, d, J=2.1 Hz),
7.20 (1H, dd, J=8.5, 2.1 Hz), 6.78 (1H, m), 6.71 (1H, d, J=5.3 Hz),
4.29 (1H, m), 3.94-3.63 (4H, m), 3.22 (2H, t, J=6.4 Hz), 2.65 (3H,
s), 2.22-1.95 (4H, m), 0.98 (6H, d, J=6.8 Hz).
[0647] Anal. Calcd for C.sub.27H.sub.29N.sub.3O.sub.5S: C, 63.89;
H, 5.76; N, 8.28; S, 6.32. Found: C, 63.56; H, 5.95; N, 8.01; S,
6.07.
Example 87
6-[2-(3-Methoxy-pyrrolidine-1-carbonyl)-thieno[3,2-b]pyridin-7-yloxy]-2-me-
thyl-benzofuran-3-carboxylic acid isobutyl amide
[0648] ##STR226##
[0649] This material was prepared by the reaction of
7-chloro-2-[(R)-3-methoxypyrrolidine-1-carbonyl]thieno[3,2-b]pyridine
4b with 6-hydroxy-2-methyl-benzofuran-3-carboxylic acid isobutyl
amide 83b and Cs.sub.2CO.sub.3 in a manner as previously described
for example 1. .sup.1H NMR (CD.sub.3CN) .delta. 8.53 (1H,d, J=5.5
Hz), 7.88 (1H, d, J=3.0 Hz), 7.82 (1H, d, J=8.5 Hz), 7.41 (1H, d,
J=2.3 Hz), 7.20 (1H, dd, J=8.5, 2.3 Hz), 6.70 (2H, d, J=5.5 Hz),
4.10-3.83 (3H, m), 3.73-3.58 (2H, m), 3.33, 3.29 (3H, 2s), 3.23
(2H, t, J=6.8 Hz), 2.65 (3H, s), 2.10-1.95 (2H,m), 0.98 (6H, d,
J=6.6 Hz).
[0650] Anal. Calcd for C.sub.27H.sub.29N3.sub.2O.sub.5S: C, 63.89;
H, 5.76; N, 8.28; S, 6.32. Found: C, 63.83; H, 5.95; N, 8.08; S,
6.10.
Example 88
2-Methyl-6-[2-(3-hydroxy-pyrrolidine-1-carbonyl)-thieno[3,2-b]pyridin-7-yl-
oxy]-benzofuran-3-carboxylic acid isobutyl amide
[0651] ##STR227##
[0652] This material was prepared from
2-methyl-6-[2-(3-methoxy-pyrrolidine-1-carbonyl)-thieno[3,2-b]pyridin-7-y-
loxy]-benzofuran-3-carboxylic acid isobutyl amide 87 by treatment
with BBr.sub.3 in a manner as previously described for 1d. .sup.1H
NMR (CD.sub.3CN/DMSO-d.sub.6) .delta. 8.55 (1H, d, J=5.6 Hz), 7.94,
7.88 (1H, 2s), 7.81 (1H, d, J=8.5 Hz), 7.46 (1H, d, J=2.1 Hz), 7.38
(1H, m), 7.20 (1H, dd, J=8.5, 2.1 Hz), 6.76 (1H, d, J=5.7 Hz), 4.39
(1H, m), 3.94 (1H, m), 3.74-3.51 (3H, m), 3.18 (2H, t, J=6.5 Hz),
2.63 (3H, s), 2.07-1.86 (2H, m, partially obscured by CD.sub.3CN),
0.96 (6H, d, J=6.6 Hz).
[0653] Anal. Calcd for
C.sub.26H.sub.27N.sub.3O.sub.5S.0.5CH.sub.2Cl.sub.2: C, 59.37; H,
5.27; N, 7.84; S, 5.96. Found: C, 59.42; H, 5.44; N, 7.86; S,
5.99.
Example 89(a)
6-Hydroxy-2-methylbenzofuran
[0654] ##STR228##
[0655] This material was prepared from 6-methoxy-2-methylbenzofuran
(1.00 g, 6.17 mmole) by treatment with BBr.sub.3 in a manner as
previously described for 1d to give a colorless oil (690 mg, 75%)
which solidified on standing.
[0656] .sup.1H NMR (DMSO-d.sub.6) .delta. 9.32 (1H, s), 7.23 (1H,
d, J=8.3 Hz), 6.80 (1H, s), 6.64 (1H, d, J=8.3 Hz), 6.37 (1H, s),
2.35 (3H, s).
[0657] Anal. Calcd for C.sub.9H.sub.8O.sub.2: C, 72.96; H, 5.44.
Found: C, 72.72; H, 5.43.
Example 89(b)
6-Acetoxy-2-methylbenzofuran
[0658] ##STR229##
[0659] This material was prepared from 6-hydroxy-2-methylbenzofuran
(654 mg, 4.41 mmole) by treatment with acetyl chloride (0.41 ml,
5.74 mmole) and triethylamine (0.74 ml, 5.30 mmole) in a manner as
previously described for 8b to give the desired product as an oil
(850 mg, .about.quant). .sup.1H NMR (CDCl.sub.3) .delta. 7.41 (1H,
d, J=8.3 Hz), 7.13 (1H, s), 6.88 (1H, dd, J=8.3, 1.9 Hz), 6.32 (1H,
s), 2.42 (3H, s), 2.30 (3H, s).
[0660] Anal. Calcd for C.sub.11H.sub.10O.sub.3: C, 69.46; H, 5.30.
Found: C, 69.02; H, 5.44.
Example 89(c)
Methyl 6-Hydroxy-2-methylbenzofuran-3-carboxylate
[0661] ##STR230##
[0662] This material was prepared from 6-acetoxy-2-methylbenzofuran
89b (0.81 g, 4.3 mmole) by acylation with oxalyl chloride in the
presence of AlCl.sub.3, followed by treatment with methanol and
K.sub.2CO.sub.3 in a manner as previously described for example 11a
to give a beige solid (607 mg, 69%). .sup.1H NMR (DMSO-d.sub.6)
.delta. 9.64 (1H, s), 7.62 (1H, d, J=8.5 Hz), 6.93 (1H, d, J=1.9
Hz), 6.78 (1H, dd, J=8.5, 2.0 Hz), 3.79 (3H, s), 2.66 (3H, s).
[0663] Anal. Calcd for C.sub.11H.sub.10O.sub.4: C, 64.07; H, 4.89.
Found: C, 64.06; H, 4.89.
Example 89(d)
Methyl
6-[2-(3-methoxypyrrolidine-1-carbonyl)-thieno[3,2-b]pyridin-7-yloxy-
]-2-methyl-benzofuran-3-carboxylate
[0664] ##STR231##
[0665] This material was prepared by the reaction of
7-chloro-2-[(R)-3-methoxypyrrolidine-1-carbonyl]thieno[3,2-b]pyridine
4b (707 mg, 2.38 mmole) with methyl
6-hydroxy-2-methyl-benzofuran-3-carboxylate 89c (565 mg, 2.74
mmole) and Cs.sub.2CO.sub.3 (3.10 g, 9.53 mmole) in a manner as
previously described for example to give 650 mg (58%) of an
off-white solid. .sup.1H NMR (DMSO-d.sub.6) .delta. 8.57 (1H,d,
J=5.3 Hz), 8.07 (1H, s), 7.96 (1H, d, J=8.6 Hz), 7.75 (1H, d, J=2.0
Hz), 7.31 (1H, dd, J=8.6, 2.0 Hz), 6.74 (1H, d, J=5.6 Hz),
4.10-3.85 (3H, m), 3.90 (3H, s), 3.65-3.45 (2H, m), 3.25 (3H, d,
J=12.6 Hz), 2.77 (3H, s), 2.15-1.95 (2H,m).
[0666] Anal. Calcd for C.sub.24H.sub.22N.sub.2O.sub.6S.0.2H.sub.2O:
C, 61.31; H, 4.80; N, 5.96; S, 6.82. Found: C, 61.21; H, 4.99; N,
5.90; S, 6.68.
Example 89(e)
6-[2-(3-Methoxypyrrolidine-1-carbonyl)-thieno[3,2-b]pyridin-7-yloxy]-2-met-
hyl-benzofuran-3-carboxylic acid
[0667] ##STR232##
[0668] To a stirred solution of methyl
6-[2-(3-methoxypyrrolidine-1-carbonyl)-thieno[3,2-b]pyridin-7-yloxy]-2-me-
thyl-benzofuran-3-carboxylate 89d (540 mg, 1.16 mmole) in
THF/MeOH/MeOH (6 ml, 1:1:1) was added lithium hydroxide monohydrate
(54 mg, 1.29 mmole). When the ester disappeared by thin layer
chromatography (tic), the organic solvents removed under reduced
pressure, and the aqueous residue was neutralized with 2N HCl. The
white solid which precipitated was collected by filtration and
dried under vacuum to give the desired acid (411 mg, 83%). .sup.1H
NMR (DMSO-d.sub.6).delta. 13.02 (1H, bs), 8.57 (1H,d, J=5.3 Hz),
8.05 (1H, s), 7.94 (1H, d, J=8.5 Hz), 7.68 (1H, s), 7.25 (1H, d,
J=8.5 Hz), 6.75 (1H, d, J=5.5 Hz), 4.10-3.85 (3H, m), 3.65-3.45
(2H, m), 3.25 (3H, d, J=9.4 Hz), 2.74 (3H, s), 2.15-1.95
(2H,m).
Example 89
6-[2-(3-Methoxypyrrolidine-1-carbonyl)-thieno[3,2-b]pyridin-7-yloxy]-2-met-
hyl-benzofuran-3-carboxylic acid cyclopropylamide
[0669] ##STR233##
[0670] This material was prepared from
6-[2-(3-methoxypyrrolidine-1-carbonyl)-thieno[3,2-b]pyridin-7-yloxy]-2-me-
thyl-benzofuran-3-carboxylic acid 89e (37 mg, 0.08 mmole) by
treatment with oxalyl chloride (15 .mu.l, 0.17 mmole) and
cyclopropylamine (56 .mu.l, 0.81 mmole) in a manner as previously
described for example 16d to give a white solid (13 mg, 33%).
.sup.1H NMR (DMSO-d.sub.6) .delta. 8.57 (1H, d, J=5.1 Hz), 8.19
(1H,s), 8.06 (1H, bs), 7.74 (1H, d, J=6.1 Hz), 7.65 (1H, s), 7.24
(1H, d, J=6.1 Hz), 6.71 (1H, d, J=1.8 Hz), 4.10-3.80 (3H, m),
3.70-3.35 (2H, m), 3.25 (3H, d, J=13.1 Hz), 2.86 (1H, m), 2.59 (3H,
s), 2.25-1.95 (2H, m), 0.71 (2H, m), 0.60 (2H, m).
[0671] Anal. Calcd for C.sub.26H.sub.25N.sub.3O.sub.5S.0.1Hexanes:
C, 63.87; H, 5.32; N, 8.40; S, 6.41. Found: C, 63.61; H, 5.51; N,
8.31; S, 6.23.
Example 90
6-[2-(3-Methoxy-pyrrolidine-1-carbonyl)-thieno[3,2-b]pyridin-7-yloxy]-2-me-
thyl-benzofuran-3-carboxylic acid
(2-morpholin-4-yl-ethyl)-amide
[0672] ##STR234##
[0673] This material was prepared from
6-[2-(3-methoxypyrrolidine-1-carbonyl)-thieno[3,2-b]pyridin-7-yloxy]-2-me-
thyl-benzofuran-3-carboxylic acid 89e by treatment with oxalyl
chloride and 2-(morpholin-4-yl)ethylamine in a manner as previously
described for example 16d. .sup.1H NMR (DMSO-d.sub.6) .delta. 8.57
(1H, d, J=5.1 Hz), 8.06 (1H,s), 7.97 (1H, bs), 7.83 (1H, d, J=8.6
Hz), 7.66 (1H, s), 7.27 (1H, d, J=8.3 Hz), 6.71 (1H, d, J=5.3 Hz),
4.20-3.95 (4H, m), 3.70-3.35 (10H, m), 3.25 (3H, d, J=12.6 Hz),
2.64 (3H, s), 2.41 (3H, s), 2.06 (2H, m).
[0674] Anal. Calcd for C.sub.29H.sub.32N.sub.4O.sub.6S.0.7H.sub.2O:
C, 60.34; H, 5.83; N, 9.71; S, 5.55. Found: C, 60.67; H, 5.92; N,
9.71; S, 5.39.
Example 91
6-[2-(3-Methoxy-pyrrolidine-1-carbonyl)-thieno[3,2-b]pyridin-7-yloxy]-2-me-
thyl-benzofuran-3-carboxylic acid cyclopropylmethyl-amide
[0675] ##STR235##
[0676] This material was prepared from
6-[2-(3-methoxypyrrolidine-1-carbonyl)-thieno[3,2-b]pyridin-7-yloxy]-2-me-
thyl-benzofuran-3-carboxylic acid 89e by treatment with oxalyl
chloride and (aminomethyl)cyclopropane in a manner as previously
described for example 16d. .sup.1H NMR (DMSO-d.sub.6) .delta. 8.55
(1H, d, J=5.1 Hz), 8.20 (1H,s), 8.05 (1H, s), 7.80 (1H, d, J=8.6
Hz), 7.64 (1H, s), 7.22 (1H, d, J=8.3 Hz), 6.69 (1H, d, J=5.3 Hz),
4.10-3.80 (3H, m), 3.70-3.50 (2H, m), 3.26 (3H, d, J=12.6 Hz), 3.15
(2H, m), 2.63 (3H, s), 2.20-1.95 (2H, m), 1.08 (1H,m), 0.45 (2H, d,
J=7.1 Hz), 0.25 (2H, d, J=4.3 Hz).
[0677] Anal. Calcd for
C.sub.27H.sub.27N.sub.3O.sub.5S.0.2Hexanes.0.6H.sub.2O: C, 63.47;
H, 5.86; N, 8.87; S, 6.01. Found: C, 63.54; H, 5.88; N, 7.74; S,
5.91.
Example 92
6-[2-(3-Methoxy-pyrrolidine-1-carbonyl)-thieno[3,2-b]pyridin-7-yloxy]-2-me-
thyl-benzofuran-3-carboxylic acid propyl amide
[0678] ##STR236##
[0679] This material was prepared from
6-[2-(3-methoxypyrrolidine-1-carbonyl)-thieno[3,2-b]pyridin-7-yloxy]-2-me-
thyl-benzofuran-3-carboxylic acid 89e by treatment with oxalyl
chloride and 1-aminopropane in a manner as previously described for
example 16d. .sup.1H NMR (DMSO-d.sub.6) .delta. 8.57 (1H, dd,
J=5.6, 1.3 Hz), 8.09 (1H, m), 8.06 (1H,s), 7.79 (1H, d, J=8.6 Hz),
7.66 (1H, d, J=2.0 Hz), 7.26 (1H, dd, J=8.6, 2.0 Hz), 6.72 (1H, d,
J=5.6 Hz), 4.08-3.82 (3H, m), 3.70-3.44 (2H, m), 3.27-3.22 (5H, m),
2.62 (3H, s), 2.15-1.92 (2H, m), 1.56-1.54 (2H, m), 0.92 (3H, t,
J=7.3 Hz).
[0680] Anal. Calcd for
C.sub.26H.sub.27N.sub.3O.sub.5S.0.7H.sub.2O.0.3MTBE: C, 62.01; H,
6.06; N, 7.89; S, 6.02. Found: C, 61.82; H, 6.07; N, 7.87; S,
5.97.
Example 93
6-[2-(3-Methoxy-pyrrolidine-1-carbonyl)-thieno[3,2-b]pyridin-7-yloxy]-2-me-
thyl-benzofuran-3-carboxylic acid 2-hydroxyethyl amide
[0681] ##STR237##
[0682] This material was prepared from
6-[2-(3-methoxypyrrolidine-1-carbonyl)-thieno[3,2-b]pyridin-7-yloxy]-2-me-
thyl-benzofuran-3-carboxylic acid 89e by treatment with oxalyl
chloride and 2-aminoethanol in a manner as previously described for
example 16d. .sup.1H NMR (DMSO-d.sub.6) .delta. 8.57 (1H, d, J=5.6
Hz), 8.06 (1H,s), 8.00 (1H, t, J=5.3 Hz), 7.82 (1H, d, J=8.6 Hz),
7.66 (1H, d, J=2.3 Hz), 7.26 (1H, dd, J=8.3, 2.3 Hz), 6.72 (1H, d,
J=5.3 Hz), 4.76(1H, m), 4.10-3.82 (3H, m), 3.67-3.59 (2H, m), 3.55
(2H, t, J=6.1 Hz), 3.37 (2H, t, J=6.1 Hz), 3.27, 3.24 (3H, 2s),
2.63 (3H, s), 2.06 (2H, m).
Example 94
2-Ethyl-6-[2-(1-methyl-1H-imidazol-2-yl)-thieno[3,2-b]pyridin-7-yloxy]-ben-
zofuran-3-carboxylic acid methylamide
[0683] ##STR238##
[0684] This material was prepared by the reaction of
7-chloro-2-(1-methyl-1H-imidazol-2-yl)thieno[3,2-b]pyridine 1e (114
mg, 0.46 mmole) with 6-hydroxy-2-ethylbenzofuran-3-carboxylic acid
methylamide 14c (120 mg, 0.55 mmole) and Cs.sub.2CO.sub.3 (594 mg,
1.82 mmole) in a manner as previously described for example 1 to
give 60 mg (30%) of a tan solid. .sup.1H NMR (DMSO-d.sub.6) .delta.
8.49 (1H, d, J=5.6 Hz), 8.00 (1H, d, J=4.6 Hz), 7.89 (1H, s), 7.82
(1H, d, J=8.6 Hz), 7.67 (1H, s), 7.41 (1H, s), 7.26 (1H, d, J=8.6
Hz), 7.03 (1H, s), 6.68 (1H, d, J=5.6 Hz), 3.99 (3H, s), 3.04 (2H,
q, J=7.6 Hz), 2.81 (3H, d, J=4.6 Hz), 1.28 (3H, t, J=7.3 Hz).
[0685] Anal. Calcd for
C.sub.23H.sub.20N.sub.4O.sub.3S.0.1Hexanes.0.3H.sub.2O: C, 63.48;
H, 4.97; N, 12.55; S, 7.18. Found: C, 63.40; H, 5.07; N, 12.28; S,
7.15.
Example 95
2-Ethyl-6-[2-(3-hydroxy-pyrrol
idine-1-carbonyl)-thieno[3,2-b]pyridin-7-yloxy]-benzofuran-3-carboxylic
acid methylamide
[0686] ##STR239##
[0687] This material was prepared from
2-ethyl-6-[2-(3-methoxypyrrolidine-1-carbonyl)-thieno[3,2-b]pyridin-7-ylo-
xy]benzofuran-3-carboxylic acid methylamide 14 by treatment with
BBr.sub.3 in a manner as previously described for 1d. .sup.1H NMR
(DMSO-d.sub.6) .delta. 8.56 (1H, d, J=5.3 Hz), 8.07 (1H, s), 8.00
(1H, d, J=4.1 Hz), 7.82 (1H, d, J=8.6 Hz), 7.68 (1H, d, J=2.0 Hz),
7.25 (1H, dd, J=8.6, 2.0 Hz), 6.73 (1H, d, J=5.3 Hz), 5.07 (1H, t,
J=3.5 Hz), 4.35 (1H, m), 3.97 (1H, m), 3.86-3.46 (3H, m), 3.03 (2H,
q, J=7.6 Hz), 2.80 (3H, d, J=4.5 Hz), 2.10-1.80 (2H, m), 1.27 (3H,
t, J=7.6 Hz).
[0688] Anal. Calcd for C.sub.24H.sub.23N.sub.3O.sub.5S.0.5H.sub.2O:
C, 60.74; H, 5.10; N, 8.86; S, 6.76. Found: C, 60.79; H, 5.24; N,
8.61; S, 6.69.
Example 96
2-ethyl-6-(2-[(S)-2-(methoxymethyl)pyrrolidine-1-carbonyl]thieno[3,2-b]pyr-
idin-7-yloxy)-benzofuran-3-carboxylic acid methyl amide
[0689] ##STR240##
[0690] This material was prepared by the reaction of
7-chloro-2-[(R)-2-methoxymethylpyrrolidine-1-carbonyl]thieno[3,2-b]pyridi-
ne 2a with 6-hydroxy-2-ethylbenzofuran-3-carboxylic acid methyl
amide 14c and Cs.sub.2CO.sub.3 in a manner as previously described.
.sup.1H NMR (DMSO-d.sub.6) .delta. 8.57 (1H,d, J=5.5 Hz), 8.03 (1H,
s), 8.01 (1H, m), 7.83 (1H, d, J=8.6 Hz), 7.67 (1H, d, J=2.1 Hz),
7.25 (1H, dd, J=8.7, 2.1 Hz), 6.73 (1H, d, J=5.5 Hz), 4.31 (1H, m),
3.92-3.77 (2H, m), 3.58-3.45 (2H, m), 3.27 (3H, s), 3.04 (2H, q,
J=7.5 Hz), 2.82 (3H, d, J=4.5 Hz), 2.06-1.85 (4H,m), 1.26 (3H, t,
J=7.5 Hz).
[0691] Anal. Calcd for C.sub.26H.sub.27N.sub.3O.sub.5S.0.5H.sub.2O
0.2MTBE C, 62.34; H, 5.89; N, 8.08; S, 6.16. Found: C, 62.38; H,
5.86; N, 7.97; S, 6.15.
Example 97
2-ethyl-6-(2-[(S)-2-(hydroxymethyl)pyrrolidine-1-carbonyl]thieno[3,2-b]pyr-
idin-7-yloxy)-benzofuran-3-carboxylic acid methylamide
[0692] ##STR241##
[0693] This material was prepared from
2-ethyl-6-[2-(2-methoxymethyl-pyrrolidine-1-carbonyl)-thieno[3,2-b]pyridi-
n-7-yloxy]-benzofuran-3-carboxylic acid methylamide 95 by treatment
with BBr.sub.3 in a manner as previously described for 1d. .sup.1H
NMR (DMSO-d.sub.6) .delta. 8.56 (1H, d, J=5.3 Hz), 8.01 (2H, m),
7.82 (1H, d, J=8.6 Hz), 7.68 (1H, s), 7.25 (1H, dd, J=8.3, 2.0 Hz),
6.73 (1H, d, J=5.1 Hz), 4.82 (1H, m), 4.20 (1H, m), 3.92-3.47 (4H,
m), 3.04 (2H, q, J=7.6 Hz), 2.81 (3H, d, J=4.5 Hz), 2.08-1.83 (4H,
m), 1.26 (3H, t, J=7.6 Hz).
[0694] Anal. Calcd for C.sub.25H.sub.25N.sub.3O.sub.5S.1H.sub.2O:
C, 60.35; H, 5.47; N, 8.45; S, 6.44. Found: C, 60.59; H, 5.47; N,
8.28; S, 6.20.
Example 98
6-[2-(Azetidine-1-carbonyl)-thieno[3,2-b]pyridin-7-yloxy]-2-ethyl-benzofur-
an-3-carboxylic acid methylamide
[0695] ##STR242##
[0696] This material was prepared by the reaction of
2-(azetidin-1-ylcarbonyl)-7-chlorothieno[3,2-b]pyridine 25a with
6-hydroxy-2-ethylbenzofuran-3-carboxylic acid methyl amide 14c and
Cs.sub.2CO.sub.3 in a manner as previously described for example 1.
.sup.1H NMR (DMSO-d.sub.6) .delta. 8.56 (1H, d, J=5.6 Hz), 7.99
(1H, m), 7.89 (1H, s), 7.82 (1H, d, J=8.6 Hz), 7.67 (1H, d, J=2.0
Hz), 7.25 (1H, dd, J=8.6, 2.3 Hz), 6.72 (1H, d, J=5.3 Hz), 4.62
(2H, t, J=7.8 Hz), 4.11 (2H, t, J=7.8 Hz), 3.04 (2H, q, J=7.6 Hz),
2.81 (3H, d, J=4.6 Hz), 2.35 (2H, p, J=7.7 Hz), 1.26 (3H, t, J=7.6
Hz).
[0697] Anal. Calcd for C.sub.23H.sub.2,
N.sub.3O.sub.4S.0.3H.sub.2O: C, 62.65; H, 4.94; N, 9.53; S, 7.27.
Found: C, 62.66; H, 4.84; N, 9.47; S, 7.52.
Example 99
6-[Thieno(3,2-b)pyridin-7-yloxy]-2-methyl-benzofuran-3-carboxylic
acid methyl amide
[0698] ##STR243##
[0699] This material was prepared by the reaction of
7-chloro-thieno[3,2-b]pyridine with
6-hydroxy-2-methylbenzofuran-3-carboxylic acid methyl amide 12c and
Cs.sub.2CO.sub.3 in a manner as previously described for example 1.
.sup.1H NMR (CD.sub.3CN) 68.48 (1H,d, J=5.3 Hz), 7.91 (1H, d, J=5.6
Hz), 7.84 (1H, d, J=8.6 Hz), 7.53 (1H, d, J=5.6 Hz), 7.41 (1H, d,
J=2.0 Hz), 7.20 (1H, dd, J=8.6, 2.0 Hz), 6.62 (1H, d, J=5.3 Hz),
6.60 (1H, bm), 2.91 (3H, d, J=4.6 Hz) 2.66 (3H, s).
Example 100(a)
Methyl
2-Methyl-6-[thieno[3,2-b]pyridin-7-yloxy]benzofuran-3-carboxylate
[0700] ##STR244##
[0701] This material was prepared by the reaction of
7-chloro-thieno[3,2-b]pyridine with methyl
6-hydroxy-2-methylbenzofuran-3-carboxylate 89c and Cs.sub.2CO.sub.3
in a manner as previously described. .sup.1H NMR (CDCl.sub.3)
.delta.8.48 (1H,d, J=5.3 Hz), 7.99 (1H, d, J=8.3 Hz), 7.74 (1H, d,
J=5.6 Hz), 7.56 (1H, d, J=5.3 Hz), 7.29 (1H, d, J=2.0 Hz), 7.16
(1H, dd, J=8.6, 2.3 Hz), 6.53 (1H, d, J=5.3 Hz), 3.96 (3H, s), 2.79
(3H, s).
Example 100
2-Methyl-6-[thieno[3,2-b]pyridin-7-yloxy]benzofuran-3-carboxylic
acid
[0702] ##STR245##
[0703] This material was prepared from methyl
2-methyl-6-[thieno[3,2-b]pyridin-7-yloxy]benzofuran-3-carboxylate
100a in a manner as previously described for example 89e. .sup.1H
NMR (DMSO-d.sub.6) .delta. 12.95 (1H, bs), 8.50 (1H, d, J=5.3 Hz),
8.15 (1H, d, J=5.5 Hz), 7.97 (1H, d, J=8.3 Hz), 7.69 (1H, d, J=2.1
Hz), 7.59 (1H, d, J=5.5 Hz), 7.26 (1H, dd, J=8.5, 2.1 Hz), 6.64
(1H, d, J=5.5 Hz), 2.74 (3H, s).
Example 101
2-Methyl-6-[thieno[3,2-b]pyridin-7-yloxy]benzofuran-3-carbonyl
chloride
[0704] ##STR246##
[0705] To a stirred suspension of
2-methyl-6-[thieno[3,2-b]pyridin-7-yloxy]benzofuran-3-carboxylic
acid 100 (800 mg, 2.33 mmole) in CHCl.sub.3 (20 ml) was added
thionyl chloride (850 .mu.l, 11.6 mmole) and a catalytic amount of
DMF. The reaction was allowed to stir at 50.degree. C. for 3 hr
before the volatiles were removed under reduced pressure. The crude
residue was triturated with MTBE to give the acid chloride as a
pale yellow solid. .sup.1H NMR (DMSO-d.sub.6) .delta. 8.81 (1H, d,
J=6.6 Hz), 8.57 (1H, d, J=5.6 Hz), 8.03 (1H, d, J=8.6 Hz), 7.86
(1H, d, J=2.0 Hz), 7.82 (1H, d, J=5.6 Hz), 7.39 (1H, dd, J=8.6, 2.0
Hz), 7.06 (1H, d, J=6.3 Hz), 2.76 (3H, s).
Example 102
2-Methyl-6-(thieno[3,2-b]pyridin-7-yloxy)benzofuran-3-carboxylic
acid (6-morpholin-4-yl-pyridin-3-yl)amide
[0706] ##STR247##
[0707] A solution of
2-methyl-6-[thieno[3,2-b]pyridin-7-yloxy]benzofuran-3-carboxylic
acid 100 (70 mg, 0.215 mmole), 6-Morpholin-4-yl-pyridin-3-ylamine
(77 mg, 0.43 mmole), HATU (163 mg, 0.43 mmole), and
diisopropylethylamine (75 .mu.l, 0.43 mmole) were stirred in DMF (2
ml) at ambient temperature for 17 hr. The mixture was then added
dropwise to a solution of cold aqueous NaHCO.sub.3 resulting in a
precipitate which was collected by filtration. This material was
purified on silica gel using a gradient of 0 to 5% methanol in a
1:1 mixture of ethyl acetate and dichloromethane as eluent to give
77 mg (74%) of a lavander solid. .sup.1H NMR (CD.sub.3CN) .delta.
8.50 (1H, d, J=5.3 Hz), 8.37 (1H, d, J=2.5 Hz), 8.29 (1H, s),
7.92-7.88 (3H, m), 7.54 (1H, d, J=5.3 Hz), 7.45 (1H, d, J=2.0 Hz),
7.23 (1H, dd, J=8.6, 2.0 Hz), 6.78 (1H, d, J=9.1 Hz), 6.64 (1H, d,
J=5.3 Hz), 3.76 (4H, t, J=4.9 Hz), 3.44 (4H, t, J=4.9 Hz), 2.72
(3H, s).
[0708] Anal. Calcd for C.sub.26H.sub.22N.sub.4O.sub.4S: C, 64.18;
H, 4.56; N, 11.52; S, 6.59. Found: C, 64.42; H, 4.77; N, 11.32; S,
6.50.
Example 103
2-Methyl-6-[thieno[3,2-b]pyridin-7-yloxy]benzofuran-3-carboxylic
acid (2-morpholin-4-yl-ethyl)-amide
[0709] ##STR248##
[0710] This material was prepared from
2-methyl-6-[thieno[3,2-b]pyridin-7-yloxy]benzofuran-3-carboxylic
acid 100 and 2-(morpholin-4-yl)ethylamine in a similar manner as
that described for example 102. .sup.1H NMR (CD.sub.3CN)
.delta.8.50 (1H, d, J=5.3 Hz), 7.92 (1H, d, J=5.6 Hz), 7.89 (1H, d,
J=8.6 Hz), 7.54 (1H, d, J=5.6 Hz), 7.42 (1H, d, J=2.3 Hz), 7.23
(1H, dd, J=8.6, 2.3 Hz), 6.83 (1H, bm), 6.63 (1H, d, J=5.6 Hz),
3.65 (4H, t, J=4.6 Hz), 3.51 (2H, q, J=6.1 Hz), 2.69 (3H, s), 2.59
(2H, t, J=6.1 Hz), 2.50 (4H, bm).
[0711] Anal. Calcd for
C.sub.23H.sub.23N.sub.3O.sub.4S.1.4H.sub.2O.0.05CH.sub.2Cl.sub.2:
C, 59.28; H, 5.59; N, 9.00; S, 6.87. Found: C, 59.18; H, 5.23; N,
8.99; S, 6.74.
Example 104
2-Methyl-6-(thieno[3,2-b]pyridin-7-yloxy)-benzofuran-3-carboxylic
acid [2-(6-fluoro-1H-indol-3-yl)-ethyl]-amide
[0712] ##STR249##
[0713] This material was prepared from
2-methyl-6-[thieno[3,2-b]pyridin-7-yloxy]benzofuran-3-carboxylic
acid 100 and 2-(6-fluoro-1H-indol-3-yl)ethylamine in a similar
manner as that described for example 102. .sup.1H NMR (CD.sub.3CN)
.delta. 8.48 (1H, d, J=5.6 Hz), 7.91 (1H, d, J=5.6 Hz), 7.63-7.59
(2H, m), 7.54 (1H, d, J=5.6 Hz), 7.38 (1H, d, J=2.3 Hz), 7.17 (1H,
d, J=2.3 Hz), 7.14 (1H, t, J=2.3 Hz), 7.11 (1H, d, J=2.3 Hz), 6.85
(1H, m), 6.65 (1H, bm), 6.61 (1H, d, J=5.6 Hz), 3.69 (2H, q, J=7.1
Hz), 3.06 (2H, t, J=7.1 Hz), 2.57 (3H, s).
[0714] Anal. Calcd for
C.sub.27H.sub.20N.sub.3O.sub.3SF.0.7H.sub.2O: C, 65.10; H, 4.33; N,
8.44; S, 6.44. Found: C, 65.04; H, 4.42; N, 8.34; S, 6.40.
Example 105
2-Methyl-6-[Thieno(3,2-b)pyridin-7-yloxy]benzofuran-3-carboxylic
acid butyl amide
[0715] ##STR250##
[0716] This material was prepared from
2-methyl-6-[thieno[3,2-b]pyridin-7-yloxy]benzofuran-3-carboxylic
acid 100 and butylamine in a similar manner as that described for
example 102. .sup.1H NMR (CD.sub.3CN) .delta. 8.48 (1H,d, J=5.3
Hz), 7.91 (1H, d, J=5.6 Hz), 7.81 (1H, d, J=8.6 Hz), 7.53 (1H, d,
J=5.6 Hz), 7.41 (1H, d, J=2.3 Hz), 7.20 (1H, dd, J=8.6, 2.3 Hz),
6.62 (1H, d, J=5.3 Hz), 6.62 (1H, bm), 3.40 (2H, q, J=6.9 Hz), 2.65
(3H, s), 1.60 (2H, m), 1.42 (2H, m), 0.97 (3H, t, J=7.3 Hz).
Example 106
2-Methyl-6-(thieno[3,2-b]pyridin-7-yloxy)-benzofuran-3-carboxylic
acid (5-phenyl-[1,3,4]thiadiazol-2-yl)-amide
[0717] ##STR251##
[0718] This material was prepared from
2-methyl-6-[thieno[3,2-b]pyridin-7-yloxy]benzofuran-3-carboxylic
acid 100 and 5-phenyl-[1,3,4]thiadiazol-2-ylamine in a similar
manner as that described for example 102. .sup.1H NMR
(CD.sub.3CN/CD.sub.3OD) .delta.8.45 (1H, d, J=5.6 Hz), 8.00-7.95
(4H, m), 7.52-7.50 (4H, m), 7.48 (1H, d, J=2.3 Hz), 7.25 (1H, dd,
J=8.6, 2.3 Hz), 6.66 (1H, d, J=5.3 Hz), 2.76 (3H, s).
Example 107
2-Methyl-6-[Thieno(3,2-b)pyridin-7-yloxy]benzofuran-3-carboxylic
acid 2-[(4-pyridyl)-methyl]amide
[0719] ##STR252##
[0720] This material was prepared from
2-methyl-6-[thieno[3,2-b]pyridin-7-yloxy]benzofuran-3-carboxylic
acid 100 and 4-(aminomethyl)pyridine in a similar manner as that
described for example 102. .sup.1H NMR (DMSO-d.sub.6) .delta. 8.68
(1H, t, J=5.6 Hz), 8.53 (2H, d, J=5.3 Hz), 8.50 (1H, d, J=5.3 Hz),
8.15 (1H, d, J=5.3 Hz), 7.88 (1H, d, J=8.3 Hz), 7.68 (1H, d, J=2.0
Hz), 7.60 (1H, d, J=5.6 Hz), 7.36 (2H, d, J=5.6 Hz), 7.27 (1H, dd,
J=8.6, 2.3 Hz), 6.62 (1H, d, J 1 5=5.3 Hz), 4.53 (2H, d, J=6.1 Hz),
2.67 (3H, s).
[0721] Anal. Calcd for C.sub.23H.sub.17N.sub.3O.sub.3S.0.4H.sub.2O:
C, 65.36; H, 4.25; N, 9.94; S, 7.59. Found: C, 65.33; H, 4.21; N,
9.92; S, 7.49.
Example 108
2-Methyl-6-(thieno[3,2-b]pyridin-7-yloxy)-benzofuran-3-carboxylic
acid [2-(4-sulfamoyl-phenyl)-ethyl]-amide
[0722] ##STR253##
[0723] A suspension of
2-methyl-6-[thieno[3,2-b]pyridin-7-yloxy]benzofuran-3-carbonyl
chloride 101 (100 mg, 0.29 mmol) in DMF (1 ml) was added dropwise
to a solution of 2-(4-sulfamoyl-phenyl)-ethyl]-amine (116 mg, 0.58
mmol), triethylamine (80 .mu.l, 0.58 mmol), and
dimethylaminopyridine (5 mg) in DMF (2 ml) at 50C. The resulting
yellow solution was stirred at 50 C for 2 hr then added to an ice
cold aqueous sodium bicarbonate solution. The resulting ppt was
collected by filtration, washed with water and air dried. The
filtrate was extracted with twice ethyl acetate. The extracts were
washed with 1N NaOH, then combined with the earlier solid and dried
over MgSO.sub.4, and concentrated to dryness. The residue was
triturated with MTBE then with EtOAc to obtain 49 mg (33%) of an
off-white solid. .sup.1H NMR (CD.sub.3CN) .delta. 8.48 (1H, d,
J=5.3 Hz), 7.91 (1H, d, J=5.6 Hz), 7.81 (1H, d, J=8.3 Hz), 7.64
(1H, d, J=8.6 Hz), 7.54 (1H, d, J=5.3 Hz), 7.48 (1H, d, J=8.3 Hz),
7.39 (1H, d, J=2.0 Hz), 7.16 (1H, dd, J=8.6, 2.0 Hz), 6.68 (1H,
bm), 6.62 (1H, d, J=5.6 Hz), 5.62 (2H, bs), 3.69 (2H, q, J=6.8 Hz),
3.04 (2H, t, J=6.8 Hz), 2.57 (3H, s).
[0724] Anal. Calcd for
C.sub.25H.sub.21N.sub.3O.sub.5S.sub.2.0.9H.sub.2O.0.4EtOAc: C,
57.15; H, 4.69; N, 7.52; S, 11.47. Found: C, 57.15; H, 4.42; N,
7.60; S, 11.55.
Example 109
2-Methyl-6-(thieno[3,2-b]pyridin-7-yloxy)-benzofuran-3-carboxylic
acid (2-isopropoxy-ethyl)-amide
[0725] ##STR254##
[0726] This material was prepared from
2-methyl-6-[thieno[3,2-b]pyridin-7-yloxy]benzofuran-3-carbonyl
chloride 101 and 2-(isopropoxy)ethylamine in a similar manner as
that described for example 108. .sup.1H NMR (CD.sub.3CN) .delta.
8.49 (1H, d, J=5.6 Hz), 7.91 (1H, d, J=5.6 Hz), 7.82 (1H, d, J=8.6
Hz), 7.54 (1H, d, J=5.6 Hz), 7.41 (1H, d, J=2.3 Hz), 7.20 (1H, dd,
J=8.6, 2.3 Hz), 6.67 (1H, bm), 6.63 (1H, d, J=5.3 Hz), 3.8-3.51
(5H, m), 2.66 (3H, s), 1.15 (6H, d, J=6.1 Hz). Anal. Calcd for
C.sub.22H.sub.22N.sub.2O.sub.4S: C, 64.37; H, 5.40; N, 6.82; S,
7.81. Found: C, 64.35; H, 5.51; N, 6.76; S, 7.74.
Example 110
2-Methyl-6-(thieno[3,2-b]pyridin-7-yloxy)-benzofuran-3-carboxylic
acid [2-(1-methyl-pyrrolidin-2-yl)-ethyl]-amide
[0727] ##STR255##
[0728] This material was prepared from
2-methyl-6-[thieno[3,2-b]pyridin-7-yloxy]benzofuran-3-carbonyl
chloride 101 and 2-(1-methylpyrrolidin-2-yl)ethylamine in a similar
manner as that described for example 108. .sup.1H NMR (CD.sub.3CN)
.delta. 8.49 (1H, d, J=5.6 Hz), 7.91 (1H, d, J=5.3 Hz), 7.85 (1H,
d, J=8.3 Hz), 7.61 (1H, bm), 7.53 (1H, d, J=5.6 Hz), 7.40 (1H, d,
J=2.0 Hz), 7.20 (1H, dd, J=8.6, 2.3 Hz), 6.63 (1H, d, J=5.6 Hz),
3.61-3.53 (1H, m), 3.45-3.40 (1H, m), 3.05-3.00 (1H, m), 2.67 (3H,
s), 2.42-2.36 (1H, m), 2.29 (3H, s), 2.18 (1H, q, J=8.8 Hz),
2.05-1.95 (1H, m, partially obscured by CD.sub.3CN), 1.87-1.66 (5H,
m).
[0729] Anal. Calcd for C.sub.24H.sub.25N.sub.3O.sub.3S.0.5H.sub.2O:
C, 64.84; H, 5.90; N, 9.45; S, 7.21. Found: C, 64.73; H, 5.94; N,
9.41; S, 6.98.
Example 111
2-Methyl-6-(thieno[3,2-b]pyridin-7-yloxy)-benzofuran-3-carboxylic
acid (5-methyl-1H-pyrazol-3-yl)-amide
[0730] ##STR256##
[0731] This material was prepared from
2-methyl-6-[thieno[3,2-b]pyridin-7-yloxy]benzofuran-3-carbonyl
chloride 101 and (5-methyl-1H-pyrazol-3-yl)amine in a similar
manner as that described for example 108. .sup.1H NMR
(DMSO-d.sub.6) .delta. 12.09 (1H, bs), 10.45 (1H, s), 8.50 (1H, d,
J=5.6 Hz), 8.14 (1H, d, J=5.6 Hz), 7.77 (1H, d, J=8.6 Hz), 7.65
(1H, d, J=2.3 Hz), 7.59 (1H, d, J=5.3 Hz), 7.24 (1H, dd, J=8.3, 2.0
Hz), 6.64 (1H, d, J=5.6 Hz), 6.39 (1H, bs), 2.64 (3H, s), 2.23 (3H,
s).
Example 112
2-Methyl-6-(thieno[3,2-b]pyridin-7-yloxy)benzofuran-3-carboxylic
acid (3-morpholin-4-ylpropyl)-amide
[0732] ##STR257##
[0733] This material was prepared from
2-methyl-6-[thieno[3,2-b]pyridin-7-yloxy]benzofuran-3-carbonyl
chloride 101 and 3-(morpholin-4-yl)propylamine in a similar manner
as that described for example 108. .sup.1H NMR (DMSO-d.sub.6)
.delta. 8.50 (1H, d, J=5.6 Hz), 8.14 (1H, d, J=5.6 Hz), 8.07 (1H,
bm), 7.80 (1H, d, J=8.6 Hz), 7.64 (1H, d, J=2.0 Hz), 7.59 (1H, d,
J=5.6 Hz), 7.24 (1H, dd, J=8.3, 2.0 Hz), 6.61 (1H, d, J=5.6 Hz),
3.56 (4H, bm), 3.35-3.27 (4H, m), 2.63 (3H, s), 2.36 (4H, bm), 1.73
(2H, bm).
Example 113
2-Methyl-6-(thieno[3,2-b]pyridin-7-yloxy)-benzofuran-3-carboxylic
acid (1H-indol-5-yl)-amide
[0734] ##STR258##
[0735] This material was prepared from
2-methyl-6-[thieno[3,2-b]pyridin-7-yloxy]benzofuran-3-carbonyl
chloride 101 and 5-aminoindole in a similar manner as that
described for example 108. .sup.1H NMR (DMSO-d.sub.6) .delta. 11.04
(1H, s), 9.96 (1H, s), 8.52 (1H, d, J=5.6 Hz), 8.15 (1H, d, J=5.3
Hz), 7.97 (1H, s), 7.83 (1H, d, J=8.3 Hz), 7.69 (1H, d, J=2.3 Hz),
7.60 (1H, d, J=5.6 Hz), 7.36 (2H, s), 7.33 (1H, t, J=2.8 Hz), 7.27
(1H, dd, J=8.6, 2.3 Hz), 6.64 (1H, d, J=5.3 Hz), 6.41 (1H, t, J=2.5
Hz), 2.69 (3H, s).
Example 114(a)
2-(Hydroxymethyl)-7-chlorothieno[3,2-b]pyridine
[0736] ##STR259##
[0737] 7-Chloro-thieno[3,2-b]pyridine-2-carboxylic acid lithium
salt (2.0 g, 9.1 mmole) was dissolved in a solution of DMF (10 mL)
and chloroform (50 mL). The carboxylate was treated with thionyl
chloride (2.0 mL, 27.3 mmole) and refluxed for one hour. The
resultant acid chloride was cooled to room temperature and added
dropwise to a solution of sodium borohydride (0.7 g, 18.2 mmole) in
DMF (10 mL) at 0.degree. C. The temperature was allowed to reach
room temperature over 2 hours and the reaction was quenched with
concentrated HCl. The reaction mixture was neutralized with NaOH
and the workup was performed with MTBE, brine and MgSO.sub.4. The
crude product was triturated with MTBE, which provided the title
compound as a beige solid (0.7 g, 40%): .sup.1H-NMR (DMSO-d.sub.6,
400 MHz) .delta. 8.58 (1H, d, J=5.1 Hz), 7.51 (1H, d, J=5.1 Hz),
7.47 (1H, s), 5.94 (1H, t, J=5.8 Hz), 4.84-4.82 (2H, m); MS m/z 200
(M+H).sup.+.
Example 114(b)
7-Chloro-2-[2-(pyrrolidin-1-yl]ethoxymethyl)thieno[3,2-b]pyridine
[0738] ##STR260##
[0739] A mixture of 2-(hydroxymethyl)-7-chlorothieno[3,2-b]pyridine
114a (0.35 g, 1.8 mmole), 1-(2-chloro-ethyl)-pyrrolidine
hydrochloride (31 g, 18 mmole), benzyltriethylammonium bromide (0.2
g, 0.7 mmole) and 19 M sodium hydroxide (10 mL) in toluene was
refluxed for three hours. The reaction mixture was buffered with
50% saturated sodium bicarbonate and the workup was performed with
ethyl acetate, brine and magnesium sulfate. The crude product was
purified over silica gel (100 g) using 2-7% methanol-chloroform
with 0.1% ammonium hydroxide, which provided the title compound as
an amber oil (0.38 g, 62%): .sup.1H-NMR (DMSO-d.sub.6, 400 MHz)
.delta. 8.62 (1H, d, J=5.0 Hz), 7.58 (1H, s), 7.54 (1H, d, J=5.1
Hz), 4.86 (2H, s), 3.62 (2H, t, J=6.0 Hz), 2.64 (2H, t, J=5.8 Hz),
2.49-2.47 (4H, m), 1.67-1.63 (4H, m); MS m/z 297 (M+H).sup.+.
Example 114
2-Methyl-6-(2-[2-(pyrrolidin-1-yl)ethoxymethyl]thieno[3,2-b]pyridin-7-ylox-
y)benzo[b]thiophene-3-carboxylic acid methylamide
[0740] ##STR261##
[0741] This material was prepared from
7-chloro-2-(2-pyrrolidin-1-yl-ethoxymethyl)-thieno[3,2-b]pyridine
114b (150 mg, 0.51 mmole),
6-hydroxy-2-methyl-benzo[b]thiophene-3-carboxylic acid methylamide
1d (123 mg, 0.56 mmole) and cesium carbonate (497 mg, 01.53 mmole)
in a similar manner as described for example 1 to give a beige
solid (0.1 g, 41%): .sup.1H-NMR (DMSO-d.sub.6, 400 MHz) .delta.
8.48 (1H, d, J=5.3 Hz), 8.28 (1H, q, J=4.5 Hz), 7.92 (1H, d, J=2.3
Hz), 7.84 (1H, d, J=8.9 Hz), 7.51 (1H, s), 7.30 (1H, dd, J=2.3, 8.9
Hz), 6.63 (1H, d, J=5.6 Hz), 4.82 (2H, s), 3.60 (2H, t, J=6.0 Hz),
2.82 (3H, d, J=4.5 Hz), 2.64-2.60 (5H, m), 2.47 (4H, bs), 1.66-1.63
(4H, m); MS m/z 482 (M+H).sup.+;
[0742] Anal. Calcd for
C.sub.25H.sub.27N.sub.3O.sub.3S.sub.2.0.3H.sub.2O: C, 61.65; H,
5.71; N, 8.63; S, 13.17. Found: C, 61.55; H, 5.71; N, 8.47; S,
12.97.
Example 115(a)
7-Chloro-2-(pyrrolidin-1-ylmethyl)thieno[3,2-b]pyridine
[0743] ##STR262##
[0744] A solution of
2-(hydroxymethyl)-7-chlorothieno[3,2-b]pyridine 114a (100 mg, 0.5
mmole) in dichloroethane was treated with triethylamine (0.08 mL,
0.55 mmole) and mesyl chloride (0.04 mL, 0.55 mmole). The clear
solution was stirred for 30 minutes and treated with pyrrolidine
(0.12 mL, 1.5 mmole). After one hour, the reaction mixture was
poured into 5% sodium bicarbonate and the workup was performed with
dichloromethane, brine and magnesium sulfate. The crude product
(167 mg greenish oil) was purified over silica gel (1 mm plate)
using 2% methanol-chloroform with 0.1% ammonium hydroxide, which
provided the title compound as a clear oil (71 mg, 56%):
.sup.1H-NMR (DMSO-d.sub.6, 400 MHz) .delta. 8.58 (1H, d, J=5.1 Hz),
7.51-7.49 (2H, m), 3.96 (2H, s), 2.56 (4H, bs), 1.75-1.72 (4H, m);
MS m/z 253 (M+H).sup.+.
Example 115
2-Methyl-6-(2-[pyrrolidin-1-ylmethyl]thieno[3,2-b]pyridin-7-yloxy)benzo[b]-
thiophene-3-carboxylic acid methylamide
[0745] ##STR263##
[0746] This material was prepared from
7-Chloro-2-(pyrrolidin-1-ylmethyl)thieno[3,2-b]pyridine 115a,
6-hydroxy-2-methyl-benzo[b]thiophene-3-carboxylic acid methylamide
1 d and cesium carbonate in a similar manner as described in
example 1. .sup.1H-NMR (DMSO-d.sub.6, 400 MHz) .delta. 8.44 (1H, d,
J=5.3 Hz), 8.27 (1H, q, J=4.6 Hz), 7.91 (1H, d, J=2.3 Hz), 7.83
(1H, d, J=8.6 Hz), 7.43 (1H, s), 7.28 (1H, dd, J=2.3, 8.6 Hz), 6.60
(1H, d, J=5.6 Hz), 3.93 (2H, s), 2.82 (3H, d, J=4.8 Hz), 2.60 (3H,
s), 2.54 (4H, bs), 1.72 (4H, s); MS m/z 438 (M+H).sup.+;
[0747] Anal. Calcd for C.sub.23H.sub.23N.sub.3O.sub.2S.sub.2: C,
63.13; H, 5.30; N, 9.60; S, 14.66. Found: C, 62.75; H, 5.38; N,
9.35; S, 14.39.
Example 116
6-(2-[Dimethylaminomethyl]thieno[3,2-b]pyridin-7-yloxy)-2-methylbenzo[b]th-
iophene-3-carboxylic acid methylamide
[0748] ##STR264##
[0749] This material was prepared from
7-chloro-2-(dimethylaminomethyl)thieno[3,2-b]pyridine,
6-hydroxy-2-methyl-benzo[b]thiophene-3-carboxylic acid methylamide
1d and cesium carbonate in a similar manner as described for
example 1. .sup.1H-NMR (DMSO-d.sub.6, 400 MHz) .delta. 8.45 (1H, d,
J=5.3 Hz), 8.27 (1H, q, J=4.5 Hz), 7.92 (1H, d, J=2.3 Hz), 7.83
(1H, d, J=8.8 Hz), 7.44 (1H, s), 7.28 (1H, dd, J=2.3, 8.9 Hz), 6.62
(1H, d, J=5.3 Hz), 3.75 (2H, bs), 2.82 (3H, d, J=4.5 Hz), 2.60 (3H,
s), 2.24 (6H, s); MS m/z 412 (M+H).sup.+;
[0750] Anal. Calcd for
C.sub.21H.sub.21N.sub.3O.sub.2S.sub.2.0.3H.sub.2O: C, 60.49; H,
5.22; N, 10.08; S, 15.38. Found: C, 60.47; H, 5.01; N, 9.76; S,
15.09.
Example 117(a)
Methyl
2-methyl-6-{[2-(1-methyl-1H-imidazol-2-yl)thieno[3,2-b]pyridin-7-yl-
]oxy}benzo[b]thiophene-3-carboxylate
[0751] ##STR265##
[0752] This material was prepared from the reaction of methyl
6-hydroxy-2-methylbenzo[b]thiophene-3-carboxylate 11a (200 mg, 0.90
mmole) with
7-chloro-2-(1-methyl-1H-imidazol-2-yl)thieno[3,2-b]pyridine 1e (188
mg, 0.75 mmole) and Cs.sub.2CO.sub.3 (1.22 g, 3.75 mmole) in a
manner as previously described for example 1 to give a yellow solid
(200 mg, 51%). .sup.1H NMR (DMSO-d.sub.6, 300 MHz) .delta. 8.52
(1H, d, J=5.46 Hz), 8.38 (1H, d, J=9.04 Hz), 8.02 (1H, d, J=2.26
Hz), 7.89 (1H, s), 7.40 (2H, s), 7.02 (1H, s), 6.73 (1H, d, J=5.46
Hz), 3.98 (3H, s), 3.91 (3H, s), 2.82 (3H, s).
Example 117(b)
2-Methyl-6-{[2-(1-methyl-1H-imidazol-2-yl)thieno[3,2-b]pyridin-7-yl]oxy}be-
nzo[b]thiophene-3-carboxylic acid
[0753] ##STR266##
[0754] This material was prepared by the reaction of methyl
2-methyl-6-{[2-(1-methyl-1H-imidazol-2-yl)thieno[3,2-b]pyridin-7-yl]oxy}b-
enzo[b]thiophene-3-carboxylate 117a (200 mg, 0.46 mmole) with
LiOH.H.sub.2O (192 mg, 4.6 mmole) in a manner as previously
described for example 1c to give a yellow solid (165 mg, 85%).
.sup.1H NMR (DMSO-d.sub.6, 300 MHz): .delta. 8.57 (1H, d, J=5.46
Hz), 8.45 (1H, d, J=8.85 Hz), 8.00 (2H, s), 7.53 (1H, s), 7.40 (1H,
dd, J=2.35, 8.95 Hz), 7.22 (1H, s), 6.79 (1H, d, J=5.46 Hz), 4.00
(3H, s), 2.82 (3H, s).
Example 117
2-Methyl-6-{[2-(1-methyl-1H-imidazol-2-yl)thieno[3,2-b]pyridin-7-yl]oxy}be-
nzo[b]thiophene-3-carboxylic acid cyclopropylamide
[0755] ##STR267##
[0756] To a solution of
2-methyl-6-{[2-(1-methyl-1H-imidazol-2-yl)thieno[3,2-b]pyridin-7-yl]oxy}b-
enzo[b]thiophene-3-carboxylic acid 117b (75 mg, 0.18 mmole) in DMF
(1.5 mL) at 0.degree. C. were added N,N-diisopropylethylamine (68
.mu.L, 0.39 mmole) and HBTU (100 mg, 0.27 mmole). The reaction
mixture was stirred 30 min at 0.degree. C. then warmed to room
temperature and stirred 18 hr. The mixture was poured onto H.sub.2O
(25 mL) and the precipitate was collected by vacuum filtration. The
filter paper was extracted with a mixture of CH.sub.2Cl.sub.2 (10
mL) and MeOH (10 mL). The solution was concentrated and the crude
mixture was purified by silica gel chromatography (5% MeOH/EtOAc)
to afford a pale yellow solid (58 mg, 71%). .sup.1H NMR
(DMSO-d.sub.6, 300 MHz) .delta. 8.52 (1H, d, J=5.46 Hz), 8.46 (1H,
d, J=4.33 Hz), 7.95 (1H, d, J=2.26 Hz), 7.88 (1H, s), 7.80 (1H, d,
J=8.67 Hz), 7.40 (1H, s), 7.32 (1H, dd, J=2.26, 8.85 Hz), 7.02 (1H,
s), 6.70 (1H, d, J=5.46 Hz), 3.98 (3H, s), 2.90 (1H, m), 2.57 (3H,
s); 0.73 (2H, m), 0.57 (2H, m).
[0757] Anal. Calcd. for C.sub.24H.sub.20N.sub.4O.sub.2S.sub.2: C,
62.59; H, 4.38; N, 12.17; S, 13.92. Found: C, 62.04; H, 4.22; N,
11.91; S, 13.49.
Example 118
2-Methyl-6-{[2-(1-methyl-1H-imidazol-2-yl)thieno[3,2-b]pyridin-7-yl]oxy}be-
nzo[b]thiophene-3-carboxylic acid 3-hydroxypropylamide
[0758] ##STR268##
[0759] This material was prepared by the reaction of
2-methyl-6-{[2-(1-methyl-1H-imidazol-2-yl)thieno[3,2-b]pyridin-7-yl]oxy}b-
enzo[b]thiophene-3-carboxylic acid 117b (85 mg, 0.20 mmole) with
3-amino-1-propanol (46 .mu.L, 0.44 mmole),
N,N-diisopropylethylamine (77 .mu.L, 0.30 mmole), and HBTU (115 mg,
0.303 mmole) in a manner as previously described for example 117.
The crude material was purified by silica gel chromatography
(10:30:60% MeOH/CH.sub.2Cl.sub.2/EtOAc) to give a yellow solid (57
mg, 59%). .sup.1H NMR (DMSO-d.sub.6, 300 MHz) .delta. 8.52 (1H, d,
J=5.27 Hz), 8.37 (1H, t, J=5.56 Hz), 7.95 (1H, d, J=2.26 Hz), 7.88
(1H, s), 7.82 (1H, d, J=8.85 Hz), 7.40 (1H, s), 7.33 (1H, dd,
J=2.35, 8.76 Hz), 7.02 (1H, d, J=0.94 Hz), 6.70 (1H, d, J=5.46 Hz),
4.51 (1H, t, J=5.09 Hz), 3.98 (3H, s), 3.50 (2H, q, J=6.22 Hz),
3.35 (2H, m), 2.60 (3H, s), 1.71 (2H, m).
[0760] Anal. Calcd. for C.sub.24H.sub.22N.sub.4O.sub.3S.sub.2: C,
60.23; H, 4.63; N, 11.71; S, 13.40. Found: C, 59.01; H, 4.70; N,
11.13; S, 12.89.
Example 119
2-Methyl-6-{[2-(1-methyl-1H-imidazol-2-yl)thieno[3,2-b]pyridin-7-yl]oxy}be-
nzo[b]thiophene-3-carboxylic acid (cyclopropylmethyl)amide
[0761] ##STR269##
[0762] This material was prepared from the reaction of
2-methyl-6-{[2-(1-methyl-1H-imidazol-2-yl)thieno[3,2-b]pyridin-7-yl]oxy}b-
enzo[b]thiophene-3-carboxylic acid 117b (70 mg, 0.166 mmole),
(aminomethyl)cyclopropane (43 .mu.L, 0.50 mmole) and
diisopropylethylamine (58 .mu.L, 0.33 mmole), and HBTU (94 mg, 0.25
mmole) in a manner similar to that previously described for example
117 to afford a pale yellow solid (64 mg, 53%). .sup.1H NMR
(DMSO-d.sub.6, 300 MHz) .delta. 8.61 (1H, d, J=5.46 Hz), 8.49 (1H,
t, J=5.65 Hz), 8.07 (1H, s), 7.99 (1H, d, J=2.26 Hz), 7.85 (1H, d,
J=8.67 Hz), 7.63 (1H, s), 7.37 (1H, s), 7.36 (1H, dd, J=2.4, 8.67
Hz), 6.81 (1H, d, J=5.65 Hz), 4.01 (3H, s), 3.20 (2H, t, J=6.31
Hz), 2.62 (3H, s), 1.08 (1H, m), 0.47 (2H, m), 0.27 (2H, m).
[0763] Anal. Calcd. for
C.sub.25H.sub.22N.sub.4O.sub.2S.sub.2.2(CF.sub.2 CO.sub.2H): C,
49.57; H, 3.44; N, 7.97; S, 9.13. Found: C, 48.25; H, 3.48; N,
7.64; S, 8.77.
Example 120
6-[(2-{[(2S)-2-(Methoxymethyl)pyrrolidin-1-yl]carbonyl}thieno[3,2-b]pyridi-
n-7-yl)oxy]-2-methylbenzo[b]thiophene-3-carboxylic acid
cyclopropylamide
[0764] ##STR270##
[0765] This material was prepared by the reaction of
7-chloro-2-{[(2S)-2-(methoxymethyl)pyrrolidin-1-yl]carbonyl}thieno[3,2-b]-
pyridine 2a (124 mg, 0.40 mmole) with
6-hydroxy-2-methylbenzo[b]thiophene-3-carboxylic acid
cyclopropylamide 8c (119 mg, 0.48 mmole) and Cs.sub.2CO.sub.3 (391
mg, 1.2 mmole) in a manner as previously described for example 1 to
give a yellow solid (146 mg, 70%). .sup.1H NMR (DMSO-d.sub.6, 300
MHz) 68.58 (1H, d, J=5.27 Hz), 8.46 (1H, d, J=4.33 Hz), 8.03 (1H,
s), 7.96 (1H, d, J=2.26 Hz), 7.80 (1H, d, J=8.67 Hz), 7.32 (1H, dd,
J=2.17, 8.76 Hz), 6.75 (1H, d, J=5.27 Hz), 4.30 (1H, m), 3.84 (2H,
m), 3.53 (1H, m) 3.42 (1H, m), 3.27 (3H, s), 2.89 (1H, m), 2.57
(3H, s), 2.09-1.81 (4H, m) 0.72 (2H, m), 0.59 (2H, m).
[0766] Anal. Calcd. for C.sub.27H.sub.27N.sub.3O.sub.4S.sub.2: C,
62.17; H, 5.22; N, 8.06; S, 12.19. Found: C, 60.94; H, 5.34; N,
7.71; S, 11.71.
Example 121
6-[(2-{[(3R)-3-Hydroxypyrrolidin-1-yl]carbonyl}thieno[3,2-b]pyridin-7-yl)o-
xy]-2-methyl benzo[b]thiophene-3-carboxylic acid
cyclopropylamide
[0767] ##STR271##
[0768] This material was prepared by the reaction of
7-chloro-2-[(R)-3-hydroxypyrrolidine-1-carbonyl]thieno[3,2-b]pyridine
4a (113 mg, 0.40 mmole) with
6-hydroxy-2-methylbenzo[b]thiophene-3-carboxylic acid
cyclopropylamide 8c (119 mg, 0.48 mmole) and Cs.sub.2CO.sub.3 (391
mg, 1.2 mmole) in a manner as previously described for example 1 to
give a yellow solid (130 mg, 66%). .sup.1H NMR (DMSO-d.sub.6, 300
MHz) .delta. 8.58 (1H, d, J=5.46 Hz), 8.46 (1H, d, J=4.33 Hz),
8.06, 8.00 (1H, s), 7.96 (1H, d, J=2.26 Hz), 7.80 (1H, d, J=8.85
Hz), 7.33 (1H, dd, J=2.35, 8.76 Hz), 6.75 (1H, d, J=5.27 Hz), 5.07
(1H, m), 4.38, 4.33 (1H, br s), 4.02-3.92 (2H, m), 3.67-3.44 (2H,
m), 2.93-2.87 (1H, m), 2.57 (3H, s), 2.08-1.79 (2H, m), 0.76-0.70
(2H, m), 0.60-0.55 (2H, m).
[0769] Anal. Calcd. for C.sub.25H.sub.23N.sub.3O.sub.4S: C, 60.83;
H, 4.70; N, 8.51; S, 12.99. Found: C, 57.46; H, 4.80; N, 7.81; S,
13.85.
Example 122(a)
Methyl
6-[(2-{[(2S)-2-(methoxymethyl)pyrrolidin-1-yl]carbonyl}thieno[3,2-b-
]pyridin-7-yl)oxy]-2-methyl benzo[b]thiophene-3-carboxylate
[0770] ##STR272##
[0771] This material was prepared from the reaction of methyl
6-hydroxy-2-methylbenzo[b]thiophene-3-carboxylate 11a (85.8 mg,
0.386 mmole) with
7-chloro-2-{[(2S)-2-(methoxymethyl)pyrrolidin-1-yl]carbonyl}thieno[3,2-b]-
pyridine 2a (100 mg, 0.322 mmole) and Cs.sub.2CO.sub.3 (524 mg,
1.61 mmole) in a manner similar to that previously described for
example 1 to give a brown solid (64 mg, 40%). .sup.1H NMR
(DMSO-d.sub.6, 300 MHz) 68.70 (1H, d, J=4.90 Hz), 8.51 (1H, d,
J=9.04 Hz), 8.15 (1H, s), 8.14 (1H, s), 7.54 (1H, dd, J=2.17, 8.95
Hz), 6.91 (1H, d, J=5.46 Hz), 4.47-4.38 (1H, m), 4.07-3.90 (2H, m),
4.03 (3H, s), 3.72-3.50 (2H, m), 3.42, 3.39 (3H, s), 2.94 (3H, s),
2.21-1.93 (4H, m).
Example 122(b)
6-[(2-{[(2S)-2-(Methoxymethyl)pyrrolidin-1-yl]carbonyl}thieno[3,2-b]pyridi-
n-7-yl)oxy]-2-methylbenzo[b]thiophene-3-carboxylic acid
[0772] ##STR273##
[0773] This material was prepared by the hydrolysis of methyl
6-[(2-{[(2S)-2-(methoxymethyl)pyrrolidin-1-yl]carbonyl}thieno[3,2-b]pyrid-
in-7-yl)oxy]-2-methylbenzo[b]thiophene-3-carboxylate 122a (63 mg,
0.13 mmole) with LiOH.H.sub.2O (54 mg, 13 mmole) in a manner as
previously described for example 11c to give a white solid (46 mg,
75%). .sup.1H NMR (DMSO-d.sub.6, 300 MHz) 68.58 (1H, d, J=5.46 Hz),
8.44 (1H, d, J=8.85 Hz), 8.03 (1H, s), 8.00 (1H, d, J=2.26 Hz),
7.38 (1H, dd, J=2.45, 9.04 Hz), 6.78 (1H, d, J=5.84 Hz), 4.35-4.25
(1H, m), 3.93-3.76 (2H, m), 3.59-3.50 (2H, m), 3.27, 3.15 (3H, s),
2.81 (3H, s), 2.11-1.83 (4H, m).
Example 122
6-[(2-{[(2S)-2-(Methoxymethyl)pyrrolidin-1-yl]carbonyl}thieno[3,2-b]pyridi-
n-7-yl)oxy]-2-methylbenzo[b]thiophene-3-carboxylic acid
3-hydroxypropylamide
[0774] ##STR274##
[0775] This material was prepared by the reaction of
6-[(2-{[(2S)-2-(methoxymethyl)-pyrrolidin-1-yl]carbonyl}thieno[3,2-b]pyri-
din-7-yl)oxy]-2-methylbenzo[b]thiophene-3-carboxylic acid 121b (45
mg, 0.093 mmole) with 3-amino-1-propanol (21 .mu.L, 0.28 mmole),
HBTU (53 mg, 0.14 mmole), and diisopropylethylamine (36 .mu.L, 0.21
mmole) in a manner as previously described for example 117 to give
a yellow solid (44 mg, 88%). .sup.1NMR (DMSO-d.sub.6, 300 MHz)
.delta. 8.58 (1H, d, J=5.27 Hz), 8.36 (1H, t, J=5.46 Hz), 8.03 (1H,
s), 7.96 (1H, d, J=2.26 Hz), 7.82 (1H, d, J=8.85 Hz), 7.33 (1H, dd,
J=1.70, 8.67 Hz), 6.75 (1H, d, J=5.27 Hz), 4.51 (1H, t, J=5.18 Hz),
4.30 (1H, m), 3.85 (2H, m), 3.37 (2H, m), 3.27 (3H, s), 2.60 (3H,
s), 2.09-1.83 (4H, m), 1.71 (2H, m).
[0776] Anal. Calcd. for C.sub.27H.sub.29N.sub.3O.sub.5S.sub.2: C,
60.09; H, 5.42; N, 7.79; S, 11.88. Found: C, 57.22; H, 5.72; N,
7.22; S, 11.16.
Example 123(a)
Methyl
6-[(2-{[(3R)-3-methoxypyrrolidin-1-yl]carbonyl}thieno[3,2-b]pyridin-
-7-yl)oxy]-2-methyl benzo[b]thiophene-3-carboxylate
[0777] ##STR275##
[0778] This material was prepared from the reaction of
6-hydroxy-2-methylbenzo[b]thiophene-3-carboxylate 11a (267 mg, 1.20
mmole) with
7-chloro-2-{[(3R)-3-methoxypyrrolidin-1-yl]carbonyl}thieno[3,2-b]pyridine
4b (297 mg, 1.00 mmole) and Cs.sub.2CO.sub.3 (977 mg, 3.00 mmole)
in a manner similar to that previously described for example 1 to
give a brown solid (480 mg, 100%). .sup.1H NMR (DMSO-d.sub.6, 300
MHz) .delta. 8.58 (1H, d, J=5.46 Hz), 8.39 (1H, d, J=8.85 Hz), 8.07
(1H, s), 8.02 (1H, d, J=2.26 Hz), 7.42 (1H, dd, J=2.35, 8.95 Hz),
6.79 (1H, d, J=5.46 Hz), 4.12-3.80 (3H, m), 3.91 (3H, s), 3.68-3.46
(2H, m), 3.27, 3.24 (3H, s), 2.82 (3H, s), 2.17-1.92 (2H, m).
Example 123(b)
6-[(2-{[(3R)-3-Methoxypyrrolidin-1-yl]carbonyl}thieno[3,2-b]pyridin-7-yl)o-
xy]-2-methyl benzo[b]thiophene-3-carboxylic acid
[0779] ##STR276##
[0780] This material was prepared by the reaction of methyl
6-[(2-{[(3R)-3-methoxypyrrolidin-1-yl]carbonyl}thieno[3,2-b]pyridin-7-yl)-
oxy]-2-methylbenzo[b]thiophene-3-carboxylate 122a (483 mg, 1.00
mmole) with LiOH.H.sub.2O (420 mg, 10.0 mmole) in a manner
analogous to that described for example 11c. The crude material was
flushed through a silica gel plug with 10% MeOH/CH.sub.2Cl.sub.2
and the resulting mixture of products was used in subsequent
reaction without further purification.
Example 123
6-[(2-{[(3R)-3-Methoxypyrrolidin-1-yl]carbonyl}thieno[3,2-b]pyridin-7-yl)o-
xy]-2-methyl benzo[b]thiophene-3-carboxylic acid
2-hydroxyethylamide
[0781] ##STR277##
[0782] This material was prepared from the reaction of
6-[(2-{[(3R)-3-methoxypyrrolidin-1-yl]carbonyl}thieno[3,2-b]pyridin-7-yl)-
oxy]-2-methylbenzo[b]thiophene-3-carboxylic acid 123b (130 mg,
0.278 mmole) with ethanolamine (84 .mu.L, 1.39 mmole),
N,N-diisopropylethylamine (0.15 mL, 0.83 mmole), and HBTU (263 mg,
0.694 mmole) in a manner similar to that previously described for
example 117 to give a yellow solid (40 mg, 28%). .sup.1H NMR
(DMSO-d.sub.6, 300 MHz) .delta. 8.58 (1H, d, J=5.27 Hz), 8.33 (1H,
t, J=5.56 Hz), 8.06 (1H, s), 7.96 (1H, d, J=2.26 Hz), 7.86 (1H, d,
J=8.85 Hz), 7.32 (1H, dd, J=2.26, 8.85 Hz), 6.75 (1H, d, J=5.46
Hz), 4.76 (1H, br s), 4.13-3.81 (3H, m), 3.67-3.50 (4H, m),
3.43-3.32 (2H, m), 3.27, 3.24 (3H, s), 2.61 (3H, s), 2.18-1.94 (2H,
m).
[0783] Anal. Calcd. for C.sub.25H.sub.25N.sub.3O.sub.5S.sub.2: C,
58.69; H, 4.93; N, 8.21; S, 12.54. Found: C, 56.56; H, 5.01; N,
7.62; S, 11.67.
Example 124
6-[(2-{[(3R)-3-Methoxypyrrolidin-1-yl]carbonyl}thieno[3,2-b]pyridin-7-yl)o-
xy]-2-methyl benzo[b]thiophene-3-carboxylic acid
3-hydroxypropylamide
[0784] ##STR278##
[0785] This material was prepared from the reaction of
6-[(2-{[(3R)-3-methoxypyrrolidin-1-yl]carbonyl}thieno[3,2-b]pyridin-7-yl)-
oxy]-2-methylbenzo[b]thiophene-3-carboxylic acid 123b (130 mg,
0.278 mmole) with 3-amino-1-propanol (106 .mu.L, 1.39 mmole),
N,N-diisopropylethylamine (0.15 mL, 0.83 mmole), and HBTU (263 mg,
0.694 mmole) in a manner similar to that previously described for
example 117 to give a yellow solid (34 mg, 23%). .sup.1H NMR
(DMSO-d.sub.6, 300 MHz) .delta. 8.58 (1H, d, J=5.27 Hz), 8.36 (1H,
t, J=5.65 Hz), 8.06 (1H, s), 7.96 (1H, d, J=2.07 Hz), 7.83 (1H, d,
J=8.85 Hz), 7.33 (1H, dd, J=2.07, 8.85 Hz), 6.75 (1H, d, J=5.27
Hz), 4.51 (1H, t, J=5.18 Hz), 4.13-3.82 (3H, m), 3.62 (2H, m), 3.50
(2H, m), 3.39-3.30 (2H, m), 3.27, 3.24 (3H, s), 2.60 (3H, s),
2.18-1.93 (2H, m), 1.71 (2H, quintet, J=6.6 Hz).
[0786] Anal. Calcd. for C.sub.26H.sub.27N.sub.3O.sub.5S.sub.2.HCl:
C, 55.56; H, 5.02; N, 7.48; S, 11.41. Found: C, 53.38; H, 4.96; N,
7.09; S, 10.83.
Example 125
6-[(2-{[(3R)-3-Methoxypyrrolidin-1-yl]carbonyl}thieno[3,2-b]pyridin-7-yl)o-
xy]-2-methyl benzo[b]thiophene-3-carboxylic acid
(cyclopropylmethyl)amide
[0787] ##STR279##
[0788] This material was prepared by the reaction of
6-[(2-{[(3R)-3-methoxypyrrolidin-1-yl]carbonyl}thieno[3,2-b]pyridin-7-yl)-
oxy]-2-methylbenzo[b]thiophene-3-carboxylic acid 123b (130 mg,
0.278 mmole) with (aminomethyl)cyclopropane (120 .mu.L, 1.39
mmole), diisopropylethylamine (0.15 mL, 0.83 mmole), and HBTU (263
mg, 0.694 mmole) in a manner similar to that previously described
for example 117 to afford a pale yellow solid (42 mg, 24%). .sup.1H
NMR (DMSO-d.sub.6, 300 MHz) .delta. 8.61 (1H, d, J=5.56 Hz), 8.49
(1H, t, J=5.56 Hz), 8.06 (1H, s), 7.97 (1H, s), 7.84 (1H, d, J=8.59
Hz), 7.34 (1H, dd, J=2.27, 8.84 Hz), 6.79 (1H, d, J=5.56 Hz),
4.11-3.80 (3H, m), 3.70-3.46 (2H, m), 3.27, 3.24 (3H, s), 3.20 (2H,
t, J=6.19 Hz), 2.62 (3H, s) 2.18-1.91 (2H, m), 1.08 (1H, m), 0.47
(2H, m), 0.26 (2H, m).
[0789] Anal. Calcd. for
C.sub.27H.sub.27N.sub.3O.sub.4S.sub.2.2(CF.sub.2CO.sub.2H): C,
49.66; H, 3.90; N, 5.60; S, 8.55. Found: C, 49.29; H, 4.03; N,
5.64; S, 8.59.
Example 126(a)
6-[(2-{[(3R)-3-Hydroxypyrrolidin-1-yl]carbonyl}thieno[3,2-b]pyridin-7-yl)o-
xy]-2-methyl benzo[b]thiophene-3-carboxylic acid
[0790] ##STR280##
[0791] This material was prepared from the reaction of methyl
6-hydroxy-2-methylbenzo[b]thiophene-3-carboxylate 11a (283 mg, 1.00
mmole) with
7-chloro-2-[(R)-3-hydroxypyrrolidine-1-carbonyl]thieno[3,2-b]pyridine
4a and Cs.sub.2CO.sub.3 (977 mg, 3.00 mmole) in a manner as
previously described for example 1. The crude product was then
reacted with LiOH.H.sub.2O (227 mg, 5.4 mmole) in a manner similar
to that described for example 1c to give a yellow solid (202 mg,
45%). .sup.1H NMR (DMSO-d.sub.6, 300 MHz) .delta. 8.58 (1H, d,
J=5.31 Hz), 8.44 (1H, d, J=8.84 Hz), 8.14, 8.07 (1H, s), 8.00 (1H,
s), 7.39 (1H, dd, J=2.40, 8.97 Hz), 6.78 (1H, d, J=5.56 Hz), 4.38,
4.33 (1H, br s), 4.01-3.91 (1H, m), 3.68-3.56 (2H, m), 3.49-3.22
(2H, m), 2.81 (3H, s), 2.07-1.79 (2H, m).
Example 126
6-[(2-{[(3R)-3-Hydroxypyrrolidin-1-yl]carbonyl}thieno[3,2-b]pyridin-7-yl)o-
xy]-2-methylbenzo[b]thiophene-3-carboxylic acid
(cyclopropylmethyl)amide
[0792] ##STR281##
[0793] This material was prepared from the reaction of
6-[(2-{[(3R)-3-hydroxypyrrolidin-1-yl]carbonyl}thieno[3,2-b]pyridin-7-yl)-
oxy]-2-methylbenzo[b]thiophene-3-carboxylic acid 126a (65 mg, 0.14
mmole) with (aminomethyl)cyclopropane (37 .mu.L, 0.43 mmole),
diisopropylethylamine (50 .mu.L, 0.29 mmole), and HBTU (81 mg, 0.22
mmole) in a similar manner previously described for example 117 to
give a pale yellow solid (47 mg, 46%). .sup.1H NMR (DMSO-d.sub.6,
300 MHz) .delta. 8.60 (1H, d, J=5.56 Hz), 8.49 (1H, t, J=5.68 Hz),
8.07, 8.01 (1H, s), 7.97 (1H, d, J=2.27 Hz), 7.84 (1H, d, J=8.59
Hz), 7.34 (1H, dd, J=2.27, 8.84 Hz), 6.78 (1H, d, J=5.31 Hz), 4.38,
4.33 (0.5H, br s), 4.01-3.93 (3H, m), 3.67-3.47 (2H, m), 3.20 (2H,
t, J=6.19 Hz), 2.62 (3H, s), 2.07-1.81 (2H, m), 1.08 (1H, m), 0.46
(2H, m), 0.26 (2H, m).
[0794] Anal. Calcd. for
C.sub.26H.sub.25N.sub.3O.sub.4S.sub.2.2(CF.sub.2CO.sub.2H): C,
49.72; H, 3.77; N, 5.86; S, 8.95. Found: C, 49.52; H, 3.71; N,
5.83; S, 8.92.
Example 127
6-{[2-(Azetidin-1-ylcarbonyl)thieno[3,2-b]pyridin-7-yl]oxy}2-methylbenzo[b-
]thiophene-3-carboxylic acid cyclopropylamide
[0795] ##STR282##
[0796] This material was prepared by reacting
2-(azetidin-1-ylcarbonyl)-7-chlorothieno[3,2-b]pyridine 25a (90 mg,
0.36 mmole) with 6-hydroxy-2-methylbenzo[b]thiophene-3-carboxylic
acid cyclopropyl amide 8c (106 mg, 0.43 mmole) and Cs.sub.2CO.sub.3
(349 mg, 1.07 mmole) in a manner analogous to that described for
example 1 to give a yellow solid (106 mg, 47%). .sup.1H NMR
(DMSO-d.sub.6, 300 MHz), .delta. 8.58 (1H, d, J=5.27), 8.45 (1H, d,
J=3.77 Hz), 7.95 (1H, d, J=2.07 Hz), 7.89 (1H, s), 7.80 (1H, d,
J=8.67 Hz), 7.32 (1H, dd, J=2.17, 8.95 Hz), 6.75 (1H, d, J=5.46
Hz), 4.62 (2H, t, J=7.35 Hz), 4.10 (2H, t, J=7.72 Hz), 2.90 (1H,
m), 2.57 (3H, s), 2.34 (2H, m), 0.73 (2H, m), 0.58 (2H, m).
[0797] Anal. Calcd. for C.sub.24H.sub.21N.sub.3O.sub.3S.sub.2.1.5
(CF.sub.3CO.sub.2H): C, 51.10; H, 3.57; N, 6.62; S, 10.11. Found:
C, 51.40; H, 3.95; N, 6.85; S, 10.29.
Example 128
[0798]
(6-({2-[4-(hydroxymethyl)-1,3-thiazol-2-yl]thieno[3,2-b]pyridin-7--
yl}oxy)-2-methyl benzo[b]thiophene-3-carboxylic acid methyylamide
##STR283##
[0799] This material was prepared by reacting
7-chloro-2-[4-(hydroxymethyl)-1,3-thiazol-2-yl]thieno[3,2-b]pyridine
(113 mg, 0.4 mmole) with
6-hydroxy-2-methylbenzo[b]thiophene-3-carboxylic acid methylamide
1d (111 mg, 0.5 mmole) and Cs.sub.2CO.sub.3 (6511 mg, 2 mmole) in a
manner similar to that previously described for example 1 to give a
yellow solid (99 mg, 53%). .sup.1H NMR (DMSO-d.sub.6, 300 MHz)
88.56 (1H, d, J=5.4 Hz), 8.29 (1H, q, J=4.5 Hz), 8.17 (1H, s), 7.96
(1H, d, J=2.2 Hz), 7.85 (1H, d, J=8.7 Hz), 7.63 (1H, s), 7.33 (1H,
dd, J=2.2, 8.7 Hz), 6.75 (1H, d, J=5.4 Hz), 5.45 (1H, bs), 4.60
(2H, s), 2.83 (3H, d, J=4.5 Hz), 2.60 (3H, s).
[0800] Anal. Calcd. for
C.sub.22H.sub.17N.sub.3O.sub.3S.sub.3.0.3CH.sub.3OH.0.2EtOAc: C,
56.07; H, 4.03; N, 8.49; S, 19.44. Found: C, 56.05; H, 4.08; N,
8.43; S, 19.47.
Example 129
(6-({2-[4-(Hydroxymethyl)-1,3-thiazol-2-yl]thieno[3,2-b]pyridin-7-yl}oxy)--
2-methylbenzo[b]thiophene-3-carboxylic acid cyclopropylamide
[0801] ##STR284##
[0802] This material was prepared by reacting
[2-(7-chlorothieno[3,2-b]pyridin-2-yl)-1,3-thiazol-4-yl]methanol
(124 mg, 0.5 mmole) with
6-hydroxy-2-methylbenzo[b]thiophene-3-carboxylic acid
cyclopropylamide 8c (113 mg, 0.4 mmole) and Cs.sub.2CO.sub.3 (391
mg, 1.2 mmole) in a manner similar to that previously described for
example 1 to give a yellow solid (86 mg, 44%). .sup.1H NMR
(DMSO-d.sub.6, 300 MHz) .delta. 8.56 (1H, d, J=5.4 Hz), 8.46 (1H,
d, J=4.3 Hz), 8.17 (1H, s), 7.96 (1H, d, J=2.2 Hz), 7.81 (1H, d,
J=8.8 Hz), 7.63 (1H, s), 7.34 (1H, dd, J=2.2, 8.8 Hz), 6.75 (1H, d,
J=5.4 Hz), 4.60 (2H, d, J=4.9 Hz), 2.96-2.85 (1H, m), 2.57 (3H, s),
0.78-0.67 (2H, m), 0.62-0.53 (2H, m).
[0803] Anal. Calcd. for
C.sub.24H.sub.19N.sub.3O.sub.3S.sub.3.1.2H.sub.2O: C, 55.94; H,
4.19; N, 8.16; S, 18.67. Found: C, 55.85; H, 4.19; N, 7.95; S,
19.01.
Example 130(a)
6-Hydroxy-2-methyl-1-benzo[b]thiophene-3-carboxylic acid
(cyclopropylmethyl)amide
[0804] ##STR285##
[0805] This material was prepared by the reaction of crude
3-(chlorocarbonyl)-2-methyl-1-benzothien-6-yl acetate (650 mg, 2.42
mmole (theoretical)) with (aminomethyl)cyclopropane (1.2 mL, 13.8
mmole) and N,N-diisopropylethylamine (0.5 mL, 2.9 mmole) in a
manner similar to that previously described for example 8c. The
crude product was purified by silica gel chromatography (25-50%
EtOAc/hexanes) to afford a yellow glass (457 mg, 72%). .sup.1H NMR
.delta. 9.56 (1H, s), 8.31 (1H, t, J=5.56 Hz), 7.52 (1H, d, J=8.67
Hz), 7.18 (1H, d, J=2.07 Hz), 6.84 (1H, dd, J=2.26, 8.67 Hz), 3.16
(2H, m), 2.51 (3H, s), 1.05 (1H, m), 0.44 (2H, m), 0.24 (2H,
m).
Example 130
(6-({2-[4-(Hydroxymethyl)-1,3-thiazol-2-yl]thieno[3,2-b]pyridin-7-yl}oxy)--
2-methyl benzo[b]thiophene-3-carboxylic acid
(cyclopropylmethyl)amide
[0806] ##STR286##
[0807] This material was prepared by reacting
[2-(7-chlorothieno[3,2-b]pyridin-2-yl)-1,3-thiazol-4-yl]methanol
(85 mg, 0.30 mmole) with
6-hydroxy-2-methylbenzo[b]thiophene-3-carboxylic acid
(cyclopropylmethyl)amide 130a (94 mg, 0.36 mmole) and
Cs.sub.2CO.sub.3 (195 mg, 0.60 mmole) in a manner similar to that
previously described for example 1 to give a yellow solid (57 mg,
25%). .sup.1H NMR (DMSO-d.sub.6, 300 MHz) .delta. 8.56 (1H, d,
J=5.46 Hz), 8.49 (1H, t, J=5.75 Hz), 8.17 (1H, s), 7.98 (1H, d,
J=2.26 Hz), 7.84 (1H, d, J=8.67 Hz), 7.65 (1H, s), 7.36 (1H, dd,
J=2.35, 8.76 Hz), 6.80 (1H, d, J=5.46 Hz), 4.60 (2H, s), 3.20 (2H,
t, J=6.22 Hz), 2.62 (3H, s), 1.07 (1H, m), 0.47 (2H, m), 0.26 (2H,
m).
[0808] Anal. Calcd. for
C.sub.25H.sub.21N.sub.3O.sub.3S.sub.3.2(CF.sub.3CO.sub.2H): C,
47.34; H, 3.15; N, 5.71; S, 13.08. Found: C, 46.72; H, 3.15; N,
5.71; S, 12.92.
Example 131
6-{([2-(Azetidin-1-ylcarbonyl)thieno[3,2-b]pyridin-7-yl]oxy}-2-methylbenzo-
[b]thiophene-3-carboxylic acid (cyclopropylmethyl)amide
[0809] ##STR287##
[0810] This material was prepared by reacting
2-(azetidin-1-ylcarbonyl)-7-chlorothieno[3,2-b]pyridine 25a (88 mg,
0.35 mmole) with
6-hydroxy-2-methyl-1-benzo[b]thiophene-3-carboxylic acid
(cyclopropylmethyl)amide 130a (110 mg, 0.42 mmole) and
Cs.sub.2CO.sub.3 (228 mg, 0.70 mmole) in a manner similar to that
previously described for example 1 to give a yellow solid (90 mg,
54%). .sup.1H NMR (DMSO-d.sub.6, 300 MHz) .delta. 8.58 (1H, d,
J=5.46 Hz), 8.49 (1H, t, J=5.46 Hz), 7.96 (1H, d, J=2.26 Hz), 7.89
(1H, s), 7.83 (1H, d, J=8.85 Hz), 7.33 (1H, dd, J=2.35, 8.76 Hz),
6.75 (1H, d, J=5.46 Hz), 4.62 (2H, t, J=7.72 Hz), 4.10 (2H, t,
J=7.82 Hz), 3.20 (2H, t, J=6.31 Hz), 2.62 (3H, s), 2.35 (2H, m),
1.07 (1H, m), 0.46 (2H, m), 0.26 (2H, m).
[0811] Anal. Calcd. for C.sub.25H.sub.23N.sub.3O.sub.3S.sub.2: C,
62.87; H, 4.85; N, 8.80; S, 13.43. Found: C, 62.58; H, 4.90; N,
8.66; S, 13.33.
Example 132
6-[(2-{[(2S)-2-(Methoxymethyl)pyrrolidin-1-yl]carbonyl}thieno[3,2-b]pyridi-
n-7-yl)oxy]-2-methylbenzo[b]thiophene-3-carboxylic acid
(cyclopropylmethyl)amide
[0812] ##STR288##
[0813] This material was prepared from
7-chloro-2-{[(3R)-3-methoxypyrrolidin-1-yl]carbonyl}thieno[3,2-b]pyridine
2a (93 mg, 0.30 mmole),
6-hydroxy-2-methylbenzo[b]thiophene-3-carboxylic acid
(cyclopropylmethyl)amide 130a (94 mg, 0.36 mmole) and
Cs.sub.2CO.sub.3 (195 mg, 0.60 mmole) in a manner similar to that
previously described for example 1 to give a yellow solid (33 mg,
18%). .sup.1H NMR (DMSO-d.sub.6, 300 MHz) .delta. 8.64 (1H, d,
J=5.46 Hz), 8.51 (1H, t, J=5.65 Hz), 8.05 (1H, s), 7.99 (1H, d,
J=2.26 Hz), 7.85 (1H, d, J=8.85 Hz), 7.36 (1H, dd, J=2.26, 8.85
Hz), 6.83 (1H, d, J=5.46 Hz), 4.30 (1H, m), 3.85 (2H, m), 3.53 (1H,
m), 3.42 (1H, m), 3.27 (3H, s), 3.20 (2H, m), 2.63 (3H, s), 1.97
(2H, m), 1.90 (2H, m), 1.07 (1H, m), 0.46 (2H, m), 0.26 (2H,
m).
[0814] Anal. Calcd. for
C.sub.28H.sub.29N.sub.3O.sub.4S.sub.2.1.5(HCl): C, 56.96; H, 5.21;
N, 7.12; S, 10.86. Found: C, 56.05; H, 5.44; N, 709; S, 10.68.
Example 133(a)
2-Methyl-6-(thieno[3,2-b]pyridin-7-yloxy)benzo[b]thiophene-3-carboxylic
acid
[0815] ##STR289##
[0816] This material was prepared by reacting
7-chlorothieno[3,2-b]pyridine (170 mg, 1.0 mmole) with methyl
6-hydroxy-2-methylbenzo[b]thiophene-3-carboxylate 11a (267 mg, 1.2
mmole) and Cs.sub.2CO.sub.3 (488 mg, 1.5 mmole) in a manner similar
to that previously described for example 1. Silica gel
chromatography (10% MeOH/CHCl.sub.2) provided the title compound as
a brown viscous oil (93 mg, 27%) of. .sup.1H NMR (DMSO-d.sub.6, 300
MHz) .delta. 8.47 (1H, d, J=5.27 Hz), 8.41 (1H, d, J=8.85 Hz), 8.11
(1H, d, J=5.46 Hz), 7.93 (1H, d, J=2.07 Hz), 7.55 (1H, d, J=7.55
Hz), 7.32 (1H, dd, J=2.26, 8.85 Hz), 6.64 (1H, d, J=5.27 Hz), 2.77
(3H, s).
Example 133
2-Methyl
6-(thieno[3,2-b]pyridin-7-yloxy)benzo[b]thiophene-3-carboxylic acid
(2-morpholin-4-yl)ethylamide
[0817] ##STR290##
[0818] This material was prepared from the reaction of
2-methyl-6-(thieno[3,2-b]pyridin-7-yloxy)benzo[b]thiophene-3-carboxylic
acid 133a (93 mg, 0.27 mmole) with 4-(2-aminoethyl)morpholine (0.12
mL, 0.82 mmole), diisopropylethylamine (0.10 mL, 0.55 mmole), and
HBTU (155 mg, 0.41 mmole) in a manner similar to that previously
described for example 117 to give a white crystalline solid (35 mg,
28%). .sup.1H NMR (DMSO-d.sub.6, 300 MHz) .delta. 8.51 (1H, d,
J=5.27 Hz), 8.28 (1H, t, J=5.37 Hz), 8.15 (1H, d, J=5.46 Hz), 7.94
(1H, dd, J=2.26 Hz), 7.94 (1H, d, J=8.48 Hz), 7.59 (1H, d, J=5.46
Hz), 7.33 (1H, dd, J=2.26, 8.85 Hz), 6.64 (1H, d, J=5.27 Hz), 3.58
(4H, t, J=4.33 Hz), 3.43 (2H, q, J=6.09 Hz), 3.32 (2H, m), 2.63
(3H, s), 2.52-2.39 (4H, m).
[0819] Anal. Calcd. for C.sub.23H.sub.23N.sub.3O.sub.3S.sub.2: C,
60.90; H, 5.11; N, 9.26; S, 14.4. Found: C, 61.12; H, 5.16; N,
9.16; S, 14.02.
Example 134(a)
2-Ethyl 6-hydroxybenzo[b]thiophene
[0820] ##STR291##
[0821] This material was prepared from 6-methoxybenzo[b]thiophene
1a (2.63 g, 16 mmole) by treatment with n-BuLi and ethyl iodide
(7.80 g, 50 mmole) in a manner as previously described for example
1b to give a white solid (2.78 g, 90%). .sup.1H NMR (DMSO-d.sub.6)
.delta. 7.58 (1H, d, J=8.7 Hz), 7.44 (1H, d, J=2.3 Hz), 7.02 (1H,
s), 6.92 (1H, dd, J=2.3, 8.7 Hz), 2.84 (2H, q, J=7.5 Hz), 1.27 (3H,
t, J=7.5 Hz).
[0822] Anal. Calcd. for C.sub.11H.sub.12OS: C, 68.71; H, 6.29; S,
16.68. Found: C, 68.50; H, 6.21; S, 16.93.
Example 134(b)
2-Ethyl-6-hydroxybenzo[b]thiophene
[0823] ##STR292##
[0824] This material was prepared from
2-ethyl-6-methoxybenzo[b]thiophene 134a (2.30 g, 12 mmole) by
treatment with BBr.sub.3 in a manner as previously described for
example 1d to give a white solid (1.75 g, 82%). .sup.1H NMR
(DMSO-d.sub.6) .delta. 9.43 (1H, s), 7.48 (1H, d, J=8.5 Hz), 7.16
(1H, d, J=2.2 Hz), 6.95 (1H, s), 6.78 (1H, dd, J=2.2, 8.5 Hz), 2.81
(2H, q, J=7.5 Hz), 1.26 (3H, t, J=7.5 Hz).
Example 134(c)
6-Acetoxy-2-ethylbenzo[b]thiophene
[0825] ##STR293##
[0826] This material was prepared by treatment of
2-ethyl-6-hydroxybenzo[b]thiophene 134b (1.60 g, 9 mmole) with
acetyl chloride (1 ml, 1.10 g, 14 mmole) and Et.sub.3N (2 ml, 1.45
g, 14 mmole) in a manner as previously described for example 8b to
give a white solid (2.93 g, 93%). .sup.1H NMR (DMSO-d.sub.6)
.delta. 7.72 (1H, d, J=8.5 Hz), 7.68 (1H, d, J=2.2 Hz), 7.15 (1H,
s), 7.08 (1H, dd, J=2.2, 8.5 Hz), 2.89 (2H, q, J=7.5 Hz), 2.28 (3H,
s), 1.29 (3H, t, J=7.5 Hz).
[0827] Anal. Calcd. for C.sub.12H.sub.12O.sub.2S: C, 65.43; H,
5.49; S, 14.56. Found: C, 65.64; H, 5.61; S, 14.49.
Example 134(d)
2-Ethyl-6-hydroxybenzo[b]thiophene-3-carboxylic acid
methylamide
[0828] This material was prepared from
6-acetoxy-2-ethylbenzo[b]thiophene 134c (1.77 g, ##STR294## 8
mmole) by acylation with oxalyl chloride in the presence of
AlCl.sub.3, followed by treatment with methylamine in a manner as
previously described for example 1d to give a pale yellow solid
(1.55 g, 82%). .sup.1H NMR (DMSO-d.sub.6) .delta. 9.57 (1H, s),
8.15 (1H, q, J=4.5 Hz), 7.48 (1H, d, J=8.6 Hz), 7.19 (1H, d, J=2.3
Hz), 6.84 (1H, dd, J=2.3, 8.6 Hz), 2.90 (2H, q, J=7.5 Hz), 2.78
(3H, d, J=4.5 Hz), 1.22 (3H, t, J=7.5 Hz).
[0829] Anal. Calcd for C.sub.12H.sub.13NO.sub.2S: C, 61.25; H,
5.57; N, 5.95; S, 13.63. Found: C, 61.11; H, 5.68; N, 5.88; S,
13.41.
Example 134
2-Ethyl
6-{[2-(1-methyl-1H-imidazol-2-yl)thieno[3,2-b]pyridin-7-yl]oxy}ben-
zo[b]thiophene-3-carboxylic acid methylamide
[0830] ##STR295##
[0831] This material was prepared by reacting
7-chloro-2-(1-methyl-1H-imidazol-2-yl)thieno[3,2-b]pyridine 1e (87
mg, 0.35 mmole) with
2-ethyl-6-hydroxybenzo[b]thiophene-3-carboxylic acid methylamide
134d (99 mg, 0.42 mmole) and Cs.sub.2CO.sub.3 (342 mg, 1.05 mmole)
in a manner analogous to that described for example 1 to give a
yellow solid (89 mg, 37%). .sup.1H NMR (DMSO-d.sub.6, 300 MHz),
.delta. 8.52 (1H, d, J=5.56 Hz), 8.33 (1H, m), 7.98 (1H, d, J=2.27
Hz), 7.89 (1H, s), 7.81 (1H, d, J=8.59 Hz), 7.40 (1H, s), 7.33 (1H,
dd, J=2.27, 8.84 Hz), 7.02 (1H, s), 6.97 (1H, d, J=5.31 Hz), 3.98
(3H, s), 3.00 (2H, q, J=7.58 Hz), 2.83 (3H, d, J=4.80 Hz), 1.28
(3H, t, J=7.58 Hz).
[0832] Anal. Calcd. for
C.sub.23H.sub.20N.sub.4O.sub.2S.sub.2.2(CF.sub.2CO.sub.2H): C,
47.93; H, 3.28; N, 8.28; S, 9.48. Found: C, 47.63; H, 3.24; N,
8.14; S, 9.29.
Example 135
2-Ethyl-6-[(2-{[(3R)-3-methoxypyrrolidin-1-yl]carbonyl}thieno[3,2-b]pyridi-
n-7-yl)oxy]benzo[b]thiophene-3-carboxylic acid methylamide
[0833] ##STR296##
[0834] This material was prepared by reacting
7-chloro-2-{[(3R)-3-methoxypyrrolidin-1-yl]carbonyl}thieno[3,2-b]pyridine
4b (74 mg, 0.25 mmole) with
2-ethyl-6-hydroxybenzo[b]thiophene-3-carboxylic acid methylamide
134d (71 mg, 0.30 mmole) and Cs.sub.2CO.sub.3 (244 mg, 0.75 mmole)
in a manner analogous to that described for example 1 to give a
yellow solid (34 mg, 19%). .sup.1H NMR (DMSO-d.sub.6, 300 MHz),
.delta. 8.59 (1H, d, J=5.31 Hz), 8.33 (1H, q, J=4.46 Hz), 8.06 (1H,
s), 7.99 (1H, d, J=2.27 Hz), 7.81 (1H, d, J=8.84 Hz), 7.34 (1H, dd,
J=2.27, 8.84 Hz), 6.76 (1H, d, J=5.56 Hz), 4.08-3.83 (3H, m),
3.67-3.48 (2H, m), 3.27, 3.24 (3H, s), 3.00 (2H, t, J=7.49 Hz),
2.83 (3H, d, J=4.55 Hz), 2.16-1.95 (2H, m), 1.28 (3H, t, J=7.58
Hz).
[0835] Anal. Calcd. for
C.sub.25H.sub.25N.sub.3O.sub.4S.sub.2.1.25(CH.sub.3CO.sub.2H): C,
51.76; H, 4.15; N, 6.58; S, 10.05. Found: C, 51.24; H, 4.23; N,
6.55; S, 10.05.
Example 136
2-Ethyl-6-[(2-{[(3R)-3-hydroxypyrrolidin-1-yl]carbonyl}thieno[3,2-b]pyridi-
n-7-yl)oxy]benzo[b]thiophene-3-carboxylic acid methylamide
[0836] ##STR297##
[0837] This material was prepared by reacting
7-chloro-2-{[(3R)-3-hydroxypyrrolidin-1-yl]carbonyl}thieno[3,2-b]pyridine
4a (71 mg, 0.25 mmole) with
2-ethyl-6-hydroxybenzo[b]thiophene-3-carboxylic acid methylamide
134d (71 mg, 0.30 mmole) and Cs.sub.2CO.sub.3 (244 mg, 0.75 mmole)
in a manner analogous to that described for example 1 to give a
light brown solid (76 mg, 63%). .sup.1H NMR (DMSO-d.sub.6, 300
MHz), .delta. 8.58 (1H, d, J=5.56 Hz), 8.32 (1H, q, J=4.38 Hz),
8.07, 8.00 (1H, s), 7.98 (1H, d, J=2.27 Hz), 7.80 (1H, d, J=8.84
Hz), 7.33 (1H, dd, J=2.27, 8.59 Hz), 6.75 (1H, d, J=5.31 Hz), 4.38,
4.33 (1H, br s), 4.01-3.93 (2H, m), 3.67-3.45 (3H, m), 3.00 (2H, t,
J=7.49 Hz), 2.83 (3H, d, J=4.55 Hz), 2.06-1.80 (2H, m), 1.28 (3H,
t, J=7.58 Hz).
[0838] Anal. Calcd. for C.sub.24H.sub.23N.sub.3O.sub.4S.sub.2: C,
59.86; H, 4.81; N, 8.73; S, 13.32. Found: C, 58.63; H, 4.78; N,
8.46; S, 13.33.
Example 137
2-Ethyl-6-[(2-{[(2S)-2-(methoxymethyl)pyrrolidin-1-yl]carbonyl}thieno[3,2--
b]pyridin-7-yl)oxy]benzo[b]thiophene-3-carboxylic acid
methylamide
[0839] ##STR298##
[0840] This material was prepared by reacting
7-chloro-2-{[(3R)-3-methoxypyrrolidin-1-yl]carbonyl}thieno[3,2-b]pyridine
2a (155 mg, 0.5 mmole) with
2-ethyl-6-hydroxybenzo[b]thiophene-3-carboxylic acid methylamide
134d (141 mg, 0.60 mmole) and Cs.sub.2CO.sub.3 (488 mg, 1.5 mmole)
in a manner analogous to that described for example 1 to give a
yellow solid (25 mg, 10%). .sup.1H NMR (DMSO-d.sub.6, 300 MHz),
.delta. 8.59 (1H, d, J=5.56 Hz), 8.33 (1H, d, J=4.55 Hz), 8.03 (1H,
s), 7.99 (1H, d, J=2.02 Hz), 7.81 (1H, d, J=8.59 Hz), 7.33 (1H, dd,
J=2.27, 8.84 Hz), 6.77 (1H, d, J=5.56 Hz), 4.31 (1H, br s),
3.90-3.81 (2H, m), 3.37-3.15 (2H, m), 3.37 (3H, s), 3.00 (2H, q,
J=7.41 Hz), 2.83 (3H, d, J=4.55 Hz), 2.09-1.84 (4H, m), 1.28 (3H,
t, J=7.58 Hz).
[0841] Anal. Calcd. for
C.sub.26H.sub.27N.sub.3O.sub.4S.sub.2.1.75(HCl): C, 54.46; H, 5.05;
N, 7.33; S, 11.18. Found: C, 54.50; H, 5.19; N, 7.30; S, 11.22.
Example 138
6-{[2-(Azetidin-1-ylcarbonyl)thieno[3,2-b]pyridin-7-yl]oxy}-2-ethylbenzo[b-
]thiophene-3-carboxylic acid methylamide
[0842] ##STR299##
[0843] This material was prepared by reacting
2-(azetidin-1-ylcarbonyl)-7-chlorothieno[3,2-b]pyridine 25a (97 mg,
0.40 mmole) with 2-ethyl-6-hydroxybenzo[b]thiophene-3-carboxylic
acid methylamide 134d (113 mg, 0.48 mmole) and Cs.sub.2CO.sub.3
(391 mg, 1.2 mmole) in a manner similar to that previously
described for example 1 to give a yellow solid (120 mg, 52%).
.sup.1H NMR (DMSO-d.sub.6, 300 MHz) .delta. 8.59 (1H, d, J=5.67
Hz), 8.31 (1H, m), 7.98 (1H, d, J=2.27 Hz), 7.89 (1H, s), 7.81 (1H,
d, J=8.69 Hz), 7.33 (1H, dd, J=1.51, 8.69 Hz), 6.76 (1H, d, J=5.29
Hz), 4.62 (2H, t, J=7.37 Hz), 4.11 (2H, t, J=7.37 Hz), 3.00 (2H, q,
J=7.55 Hz), 2.83 (3H, d, J=4.53 Hz), 2.35 (2H, m), 1.28 (3H, t,
J=7.55 Hz).
[0844] Anal. Calcd. for
C.sub.24H.sub.21N.sub.3O.sub.3S.sub.2.CF.sub.3CO.sub.2H: C, 53.09;
H, 3.92; N, 7.43; S, 11.34. Found: C, 52.58; H, 3.80; N, 7.26; S,
11.12.
Example 139(a)
7-Chloro-2-methylthieno[3,2-b]pyridine
[0845] ##STR300##
[0846] This material was prepared from
7-chlorothieno[3,2-b]pyridine (1.69 g, 10 mmole) by treatment with
n-BuLi and iodomethane (2 ml, 4.56 g, 32 mmole) in a manner as
previously described for example 1b to give a pale yellow,
low-melting solid (1.48 g, 81%). .sup.1H NMR (DMSO-d.sub.6):
.delta. 8.56 (1H, d, J=5.1 Hz), 7.48 (1H, d, J=5.1 Hz), 7.38 (1H,
s), 2.65 (3H, s).
[0847] Anal. Calcd. for C.sub.8H.sub.6NSCl: C, 52.32; H, 3.29; N,
7.63; S, 17.46; Cl, 19.30. Found: C, 52.13; H, 3.36; N, 7.86; S,
17.44; Cl, 19.20.
Example 139(b)
Methyl
2-methyl-6-(2-methylthieno[3,2-b]pyridin-7-yloxy)-benzo[b]thiophene-
-3-carboxylate
[0848] ##STR301##
[0849] This material was prepared by the reaction of
7-chloro-2-methylthieno[3,2-b]pyridine 139a (1.29 g, 7 mmole) with
methyl 6-hydroxy-2-methylbenzo[b]thiophene-3-carboxylate 11a (2.18
g, 9.8 mmole) and Cs.sub.2CO.sub.3 (6.51 g, 20 mmole) in a manner
as previously described for example 1 to give a yellow solid (1.91
g, 74%). .sup.1H NMR (CDCl.sub.3) .delta. 8.43 (1H,d, J=5.4 Hz),
8.37 (1H, d, J=9.0 Hz), 7.97 (1H, d, J=2.2 Hz), 7.37 (1H, dd,
J=2.2, 9.0 Hz), 7.30 (1H, s), 6.63 (1H, d, J=5.4 Hz), 3.91 (3H, s),
2.81 (3H, s), 2.61 (3H, s).
[0850] Anal. Calcd for
C.sub.19H.sub.15N.sub.3O.sub.2S.0.1CH.sub.2Cl.sub.2: C, 60.70; H,
4.05; N, 3.71; S, 16.97. Found: C, 60.71; H, 4.17; N, 3.60; S,
17.11.
Example 139(c)
2-Methyl-6-(2-methylthieno[3,2-b]pyridin-7-yloxy)benzo[b]thiophene-3-carbo-
xylic acid
[0851] ##STR302##
[0852] This material was prepared from methyl
2-methyl-6-(2-methylthieno[3,2-b]pyridin-7-yloxy)benzo[b]thiophene-3-carb-
oxylate 139b (1.80 g, 4.8 mmole) in a manner as previously
described for example 11c to give a yellow solid (1.41 g, 82%).
.sup.1H NMR (DMSO-d.sub.6) .delta. 13.08 (1H, bs), 8.45 (1H, d,
J=5.5 Hz), 8.43 (1H, d, J=8.8 Hz), 7.96 (1H, d, J=2.4 Hz), 7.35
(1H, dd, J=2.4, 8.8 Hz), 7.32 (1H, s), 6.66 (1H, d, J=5.5 Hz), 2.81
(3H, s), 2.62 (3H, s).
[0853] Anal. Calcd for C.sub.18H.sub.13NO.sub.3S.sub.2.0.5H.sub.2O:
C, 59.32; H, 3.87; N, 3.84; S, 17.60. Found: C, 59.31; H, 3.74; N,
3.79; S, 17.49.
Example 139(d)
2-Methyl-6-(2-methylthieno[3,2-b]pyridin-7-yloxy)benzo[b]thiophene-3-carbo-
nyl chloride
[0854] ##STR303##
[0855] This material was prepared from
2-methyl-6(2-methylthieno[3,2-b]pyridin-7-yloxy)benzo[b]thiophene-3-carbo-
xylic acid 139c (1.34 g, 3.8 mmole) by treatment with thionyl
chloride (1 ml, 1.63 g, 13.7 mmole) in a manner as previously
described for example 11 to give an orange solid (1.37 g, 97%).
.sup.1H NMR (DMSO-d.sub.6): .delta. 8.74 (1H, d, J=6.6 Hz), 8.50
(1H, d, J=9.0 Hz), 8.12 (1H, d, J=2.4 Hz), 7.60 (1H, s), 7.48 (1H,
dd, J=2.4, 9.0 Hz), 7.05 (1H, d, J=6.6 Hz), 2.83 (3H, s), 2.75 (3H,
s).
[0856] Anal. Calcd for C.sub.18H.sub.12NOS.sub.2Cl.0.9HCl: C,
50.69; H, 3.57; N, 3.28; S, 15.04; Cl, 15.79. Found: C, 50.64; H,
3.56; N, 3.22; S, 14.98; Cl, 15.65.
Example 139
2-Methyl-6-(2-methylthieno[3,2-b]pyridin-7-yloxy)benzo[b]thiophene-3-carbo-
xylic acid (2-morpholin-4-yl-ethyl)-amide
[0857] ##STR304##
[0858] This material was prepared from
2-methyl-6-(2-methylthieno[3,2-b]pyridin-7-yloxy)benzo[b]thiophene-3-carb-
onyl chloride 139d (112 mg, 0.3 mmole) and
2-(morpholin-4-yl)ethylamine (157 mg, 1.2 mmole) in a similar
manner as that described for example 108 to give a yellow solid
(105 mg, 75%). .sup.1H NMR (DMSO-d.sub.6) .delta. 8.44 (1H, d,
J=5.5 Hz), 8.29 (1H, t, J=4.8 Hz), 7.94 (1H, d, J=8.7 Hz), 7.92
(1H, d, J=2.3 Hz), 7.31 (1H, s), 7.30 (1H, dd, J=2.3, 8.7 Hz), 6.60
(1H, d, J=5.5 Hz), 3.60 (4H, t, J=4.2 Hz), 3.45 (2H, dt, J=4.8, 6.2
Hz), 2.64 (3H, s), 2.62 (3H, s), 2.55-2.41 (6H, m).
[0859] Anal. Calcd for C.sub.24H.sub.25N.sub.3O.sub.3S.sub.2: C,
61.64; H, 5.39; N, 8.99; S, 13.71. Found: C, 61.34; H, 5.49; N,
8.90; S, 13.68.
Example 140
2-Methyl-6-(2-methylthieno[3,2-b]pyridin-7-yloxy)benzo[b]thiophene-3-carbo-
xylic acid (3-morpholin-4-ylpropyl)-amide
[0860] ##STR305##
[0861] This material was prepared from
2-methyl-6-(2-methylthieno[3,2-b]pyridin-7-yloxy)benzo[b]thiophene-3-carb-
onyl chloride 139d (112 mg, 0.3 mmole) and
3-(morpholin-4-yl)propylamine (175 mg, 1.2 mmole) in a similar
manner as that described for example 108 to give a yellow solid (64
mg, 44%). .sup.1H NMR (DMSO-d.sub.6) .delta. 8.43 (1H, d, J=5.5
Hz), 8.38 (1H, t, J=5.3 Hz), 7.91 (1H, d, J=2.3 Hz), 7.81 (1H, d,
J=8.6 Hz), 7.30 (1H, s), 7.28 (1H, dd, J=2.3, 8.6 Hz), 6.59 (1H, d,
J=5.5 Hz), 3.56 (4H, t, J=4.3 Hz), 3.33 (2H, dt, J=5.3, 6.8 Hz),
2.61 (3H, s), 2.60 (3H, s), 2.42-2.31 (6H, m), 1.72 (2H, tt, J=6.8,
7.0 Hz).
[0862] Anal. Calcd for
C.sub.25H.sub.27N.sub.3O.sub.3S.sub.2.0.1CH.sub.2Cl.sub.2: C,
61.51; H, 5.59; N, 8.57; S, 13.08. Found: C, 61.53; H, 5.55; N,
8.25; S, 13.08.
[0863] The exemplary compounds described above may be tested for
their activity using the tests described below.
Biological Testing; Enzyme Assays
[0864] The stimulation of cell proliferation by growth factors such
as VEFG, FGF, and others is dependent upon their induction of
autophosphorylation of each of their respective receptor's tyrosine
kinases. Therefore, the ability of a protein kinase inhibitor to
block cellular proliferation induced by these growth factors is
directly correlated with its ability to block receptor
autophosphorylation. To measure the protein kinase inhibition
activity of the compounds, the following constructs were
devised.
VEGF-R2 Construct for Assay:
[0865] This construct determines the ability of a test compound to
inhibit tyrosine kinase activity. A construct (VEGF-R2.DELTA.50) of
the cytosolic domain of human vascular endothelial growth factor
receptor 2 (VEGF-R2) lacking the 50 central residues of the 68
residues of the kinase insert domain was expressed in a
baculovirus/insect cell system. Of the 1356 residues of full-length
VEGF-R2, VEGF-R2.DELTA.50 contains residues 806-939 and 990-1171,
and also one point mutation (E990V) within the kinase insert domain
relative to wild-type VEGF-R2. Autophosphorylation of the purified
construct was performed by incubation of the enzyme at a
concentration of 4 .mu.M in the presence of 3 mM ATP and 40 mM
MgCl.sub.2 in 100 mM HEPES, pH 7.5, containing 5% glycerol and 5 mM
DTT, at 4.degree. C. for 2 h. After autophosphorylation, this
construct has been shown to possess catalytic activity essentially
equivalent to the wild-type autophosphorylated kinase domain
construct. See Parast et al., Biochemistry, 37, 16788-16801
(1998).
FGF-R1 Construct for Assay:
[0866] The intracellular kinase domain of human FGF-R1 was
expressed using the baculovirus vector expression system starting
from the endogenous methionine residue 456 to glutamate 766,
according to the residue numbering system of Mohammadi et al., Mol.
Cell. Biol., 16, 977-989 (1996). In addition, the construct also
has the following 3 amino acid substitutions: L457V, C488A, and
C584S.
VEGF-R2 Assay
Coupled Spectrophotometric (FLVK-P) Assay
[0867] The production of ADP from ATP that accompanies phosphoryl
transfer was coupled to oxidation of NADH using phosphoenolpyruvate
(PEP) and a system having pyruvate kinase (PK) and lactic
dehydrogenase (LDH). The oxidation of NADH was monitored by
following the decrease of absorbance at 340 nm (e.sub.340=6.22
cm.sup.-1 mM.sup.-1) using a Beckman DU 650 spectrophotometer.
Assay conditions for phosphorylated VEGF-R2.DELTA.50 (indicated as
FLVK-P in the tables below) were the following: 1 mM PEP; 250 .mu.M
NADH; 50 units of LDH/mL; 20 units of PK/mL; 5 mM DTT; 5.1 mM
poly(E.sub.4Y.sub.1); 1 mM ATP; and 25 mM MgCl.sub.2 in 200 mM
HEPES, pH 7.5. Assay conditions for unphosphorylated
VEGF-R2.DELTA.50 (indicated as FLVK in the tables) were the
following: 1 mM PEP; 250 .mu.M NADH; 50 units of LDH/mL; 20 units
of PK/mL; 5 mM DTT; 20 mM poly(E.sub.4Y.sub.1); 3 mM ATP; and 60 mM
MgCl.sub.2 and 2 mM MnCl.sub.2 in 200 mM HEPES, pH 7.5. Assays were
initiated with 5 to 40 nM of enzyme. K.sub.i values were determined
by measuring enzyme activity in the presence of varying
concentrations of test compounds. The percent inhibition at 50 nm
(% inhibition @ 50 nm) was determined by linear least-squares
regression analysis of absorpbance as a function of time. The
binding inhibitions were fitted to equation as described by
Morrison. The data were analyzed using Enzyme Kinetic and
Kaleidagraph software.
FGF-R Assay
[0868] The spectrophotometric assay was carried out as described
above for VEGF-R2, except for the following changes in
concentration: FGF-R=50 nM, ATP=2 mM, and poly(E4Y1)=15 mM.
HUVEC+VEGF Proliferation Assay
[0869] This assay determines the ability of a test compound to
inhibit the growth factor-stimulated proliferation of human
umbilical vein endothelial cells ("HUVEC"). HUVEC cells (passage
3-4, Clonetics, Corp.) were thawed into EGM2 culture medium
(Clonetics Corp) in T75 flasks. Fresh EGM2 medium was added to the
flasks 24 hours later. Four or five days later, cells were exposed
to another culture medium (F12K medium supplemented with 10% fetal
bovine serum (FBS), 60 .mu.g/mL endothelial cell growth supplement
(ECGS), and 0.1 mg/mL heparin). Exponentially-growing HUVEC cells
were used in experiments thereafter. Ten to twelve thousand HUVEC
cells were plated in 96-well dishes in 100 .mu.l of rich, culture
medium (described above). The cells were allowed to attach for 24
hours in this medium. The medium was then removed by aspiration and
105 .mu.l of starvation media (F12K+1% FBS) was added to each well.
After 24 hours, 15 .mu.l of test agent dissolved in 1% DMSO in
starvation medium or this vehicle alone was added into each
treatment well; the final DMSO concentration was 0.1%. One hour
later, 30 .mu.l of VEGF (30 ng/mL) in starvation media was added to
all wells except those containing untreated controls; the final
VEGF concentration was 6 ng/mL. Cellular proliferation was
quantified 72 hours later by MTT dye reduction, at which time cells
were exposed for 4 hours MTT (Promega Corp.). Dye reduction was
stopped by addition of a stop solution (Promega Corp.) and
absorbance at 595 nm was determined on a 96-well spectrophotometer
plate reader.
Mouse PK Assay
[0870] The pharmacokinetics (e.g., absorption and elimination) of
drugs in mice were analyzed using the following experiment. Test
compounds were formulated as a suspension in a 30:70 (PEG 400:
acidified H.sub.2O) vehicle. This solution was administered orally
(p.o.) and intraperitoneally (i.p.) at 50 mg/kg to two distinct
groups (n=4) of B6 female mice. Blood samples were collected via an
orbital bleed at time points: 0 hour (pre-dose), 0.5 hr, 1.0 hr,
2.0 hr, and 4.0 hr post dose. Plasma was obtained from each sample
by centrifugation at 2500 rpm for 5 min. Test compound was
extracted from the plasma by an organic protein precipitation
method. For each time bleed, 50 .mu.L of plasma was combined with
1.0 mL of acetonitrile, vortexed for 2 min. and then spun at 4000
rpm for 15 min. to precipitate the protein and extract out the test
compound. Next, the acetonitrile supernatant (the extract
containing test compound) was poured into new test tubes and
evaporated on a hot plate (25.degree. C.) under a steam of N.sub.2
gas. To each tube containing the dried test compound extract, 125
.mu.L of mobile phase (60:40, 0.025 M NH.sub.4H.sub.2PO.sub.4+2.5
mL/L TEA:acetonitrile) was added. The test compound was resuspended
in the mobile phase by vortexing and more protein was removed by
centrifugation at 4000 rpm for 5 min. Each sample was poured into
an HPLC vial for test compound analysis on an Hewlett Packard 1100
series HPLC with UV detection. From each sample, 95 .mu.L was
injected onto a Phenomenex-Prodigy reverse phase C-18,
150.times.3.2 mm column and eluted with a 45-50% acetonitrile
gradient run over 10 min. Test-compound plasma concentrations
(.mu.g/mL) were determined by a comparison to standard curve (peak
area vs. conc. .mu.g/mL) using known concentrations of test
compound extracted from plasma samples in the manner described
above. Along with the standards and unknowns, three groups (n=4) of
quality controls (0.25 .mu.g/mL, 1.5 .mu.g/mL, and 7.5 .mu.g/mL)
were run to insure the consistency of the analysis. The standard
curve had an R.sub.2>0.99 and the quality controls were all
within 10% of their expected values. The quantitated test samples
were plotted for visual display using Kalidagraph software and
their pharmacokinetic parameters were determined using WIN NONLIN
software.
Human Liver Microsome (HLM) Assay
[0871] Compound metabolism in human liver microsomes was measured
by LC-MS analytical assay procedures as follows. First, human liver
microsomes (HLM) were thawed and diluted to 5 mg/mL with cold 100
mM potassium phosphate (KPO.sub.4) buffer. Appropriate amounts of
KPO.sub.4 buffer, NADPH-regenerating solution (containing B-NADP,
glucose-6-phosphate, glucose-6-phosphate dehydrogenase, and
MgCl.sub.2), and HLM were preincubated in 13.times.100 mm glass
tubes at 37.degree. C. for 10 min. (3 tubes per test
compound--triplicate). Test compound (5 .mu.M final) was added to
each tube to initiate reaction and was mixed by gentle vortexing,
followed by incubation at 37.degree. C. At t=0, and 2 h, a 250-uL
sample was removed from each incubation tube to separate
12.times.75 mm glass tubes containing 1 mL ice-cold acetonitrile
with 0.05 .mu.M reserpine. Samples were centrifuged at 4000 rpm for
20 min. to precipitate proteins and salt (Beckman Allegra 6KR, S/N
ALK98D06, #634). Supernatant was transferred to new 12.times.75 mm
glass tubes and evaporated by Speed-Vac centrifugal vacuum
evaporator. Samples were reconstituted in 200 .mu.L 0.1% formic
acid/acetonitrile (90/10) and vortexed vigorously to dissolve. The
samples were then transferred to separate polypropylene
microcentrifuge tubes and centrifuged at 14000.times. g for 10 min.
(Fisher Micro 14, S/N M0017580). For each replicate (#1-3) at each
timepoint (0 and 2 h), an aliquot sample of each test compound was
combined into a single HPLC vial insert (6 total samples) for LC-MS
analysis, which is described below.
[0872] The combined compound samples were injected into the LC-MS
system, composed of a Hewlett-Packard HP1100 diode array HPLC and a
Micromass Quattro II triple quadruple mass spectrometer operating
in positive electrospray SIR mode (programmed to scan specifically
for the molecular ion of each test compound). Each test compound
peak was integrated at each timepoint. For each compound, peak area
at each timepoint (n=3) was averaged, and this mean peak area at 2
h was divided by the average peak area at time 0 hour to obtain the
percent test compound remaining at 2 h.
KDR (VEGFR2) Phosphorylation in PAE-KDR Cells Assay
[0873] This assay determines the ability of a test compound to
inhibit the autophosphorylation of KDR in porcine aorta endothelial
(PAE)-KDR cells. PAE cells that overexpress human KDR were used in
this assay. The cells were cultured in Ham's F12 media supplemented
with 10% fetal bovine serum (FBS) and 400 ug/mL G418. Thirty
thousands cells were seeded into each well of a 96-well plate in 75
.mu.L of growth media and allowed to attach for 6 hours at
37.degree. C. Cells were then exposed to the starvation media
(Ham's F12 media supplemented with 0.1% FBS) for 16 hours. After
the starvation period was over, 10 .mu.L of test agent in 5% DMSO
in starvation media were added to the test wells and 10 .mu.L of
the vehicle (5% DMSO in starvation media) were added into the
control wells. The final DMSO concentration in each well was 0.5%.
Plates were incubated at 37.degree. C. for 1 hour and the cells
were then stimulated with 500 ng/ml VEGF (commercially available
from R & D System) in the presence of 2 mM Na.sub.3VO.sub.4 for
8 minutes. The cells were washed once with 1 mm Na.sub.3VO.sub.4 in
HBSS and lysed by adding 50 .mu.L per well of lysis buffer. One
hundred .mu.L of dilution buffer were then added to each well and
the diluted cell lysate was transferred to a 96-well goat
ant-rabbit coated plate (commercially available from Pierce) which
was pre-coated with Rabbit anti Human Anti-flk-1 C-20 antibody
(commercially available from Santa Cruz). The plates were incubated
at room temperature for 2 hours and washed seven times with 1%
Tween 20 in PBS. HRP-PY20 (commercially available from Santa Cruz)
was diluted and added to the plate for a 30-minute incubation.
Plates were then washed again and TMB peroxidase substrate
(commercially available from Kirkegaard & Perry) was added for
a 10-minute incubation. One hundred .mu.L of 0.09 N H.sub.2SO.sub.4
was added to each well of the 96-well plates to stop the reaction.
Phosphorylation status was assessed by spectrophotometer reading at
450 nm. IC.sub.50 values were calculated by curve fitting using a
four-parameter analysis.
PAE-PDGFR.beta. Phosphorylation in PAE-PDGFRB Cells Assay
[0874] This assay determines the ability of a test compound to
inhibit the autophosphorylation of PDGFR.beta. in porcine aorta
endothelial (PAE)-PDGFR.beta. cells. PAE cells that overexpress
human PDGFR.beta. were used in this assay. The cells were cultured
in Ham's F12 media supplemented with 10% fetal bovine serum (FBS)
and 400 ug/ml G418. Twenty thousands cells were seeded in each well
of a 96-well plate in 50 .mu.L of growth media and allowed to
attach for 6 hours at 37.degree. C. Cells were then exposed to the
starvation media (Ham's F12 media supplemented with 0.1% FBS) for
16 hours. After the starvation period was over, 10 .mu.L of test
agent in 5% DMSO in starvation media were added to the test wells
and 10 .mu.L of the vehicle (5% DMSO in starvation media) were
added into the control wells. The final DMSO concentration in each
well was 0.5%. Plates were incubated at 37.degree. C. for 1 hour
and the cells were then stimulated with 1 .mu.g/mL PDGF-BB (R &
D System) in the presence of 2 mM Na.sub.3VO.sub.4 for 8 minutes.
The cells were washed once with 1 mm Na.sub.3VO.sub.4 in HBSS and
lysed by adding 50 .mu.L per well of lysis buffer. One hundred
.mu.L of dilution buffer were then added to each well and the
diluted cell lysate was transferred to a 96-well goat ant-rabbit
coated plate (Pierce), which was pre-coated with Rabbit anti Human
PDGFR.beta. antibody (Santa Cruz). The plates were incubated at
room temperature for 2 hours and washed seven times with 1% Tween
20 in PBS. HRP-PY20 (Santa Cruz) was diluted and added to the plate
for a 30-minute incubation. Plates were then washed again and TMB
peroxidase substrate (Kirkegaard & Perry) was added for a
10-minute incubation. One hundred .mu.L of 0.09 N H.sub.2SO.sub.4
was added into each well of the 96-well plate to stop the reaction.
Phosphorylation status was assessed by spectrophotometer reading at
450 nm. IC.sub.50 values were calculated by curve fitting using a
four-parameter analysis.
[0875] The results of the testing of the compounds using various
assays are summarized in Tables 1 and 2 below, where a notation of
"% @" indicates the percent inhibition at the stated
concentration.
[0876] All of the amines listed in Table 3 were reacted with
Example 101, denoted as R.sub.101 in Table 3 having the following
structure: ##STR306## The library plates for Table 3 were prepared
in the following general manner:
[0877] General Procedure for Amide Bond Formation:
[0878] 0.13 M solution of each amine in Table 3 in a 1:1 mixture of
anhydrous pyridine and DMF were prepared and placed into the
appropriate wells of a 1 mL deepwell plate. 0.10 M solution of
Example 101, denoted as R.sub.101 in Table 3, in a DMF solution was
prepared and added to each well. The reactions were agitated at
50.degree. C. for 4 h. The volatiles were removed using the
Speedvac.TM. apparatus, and the crude mixtures were reconstituted
in DMSO to afford solutions with a final theoretical concentration
of 0.01M. TABLE-US-00001 TABLE 1 PAE PAE KDR PDGFR bFGF FLVK HUVEC
+ VEGF autophos autophos Huvec (% inh @ FLVK Ki IC50 (nM) IC50 (nM)
IC50 (nM) IC50 (nM) Compound 50 nM) (nM) AVG AVG AVG Avg. 1 92%
1.02 0.68 0.31 164 122 2 75% 4.14 2.3 1.8 912 3333 3 59% 0.811
0.442 0.9 756 942 4 88% 2.58 0.404 0.47 284 NT 5 73% 1.91 1.55 NT
1000 235 6 94% 0.721 1.2 NT 255 145 7 95% 1.04 1.21 1.95 1000 2474
8 94% 0.403 1.37 NT 1000 504 9 83% 1.57 13 NT 313 135 10 74% 2.31
10 NT 451 99 11 93% 0.492 0.56 NT 103.5 40 12 100% 0.314 0.26 0.14
14.4 20 13 97% 0.322 0.082 0.21 41 27 14 81% 1.46 9.4 NT NT 287 15
13% 48.3 NT NT NT NT 16 46% 8.14 10 NT NT 1000 17 77% 2.77 1.2 0.47
20 847 18 78% 2.373 0.64 0.62 32 1000 19 75% 2.63 2.7 1.7 172 10000
20 99% 0.082 0.19 0.217 43 1902 21 43% 13.11 NT NT NT NT 22 38%
25.8 NT NT NT NT 23 19% 78 NT NT NT NT 24 69% 4.2 32 NT NT 10000 25
70% 4.08 0.45 NT 12 7460 26 83% 3.66 0.74 NT 13 2233 27 13% 96 NT
NT 205 NT 28 78% 2.8 0.272 NT 15 462 29 6% 88.77 NT NT NT NT 30 63%
6 33.6 NT 74 10000 31 25% 30.2 NT NT NT NT 32 22% 39.4 NT NT 29.2
NT 33 61% 11.5 10 NT 63 10000 34 45% 11.4 NT NT 31.3 NT 35 23%
35.166 NT NT 70 NT 36 41% 11.513 NT NT NT NT 37 66% 4.3 10 NT 1000
NT 38 60% 6.12 27 NT 12.3 10000 39 12% 47 8.7 NT 61 NT 40 77% 2.95
1.12 NT 24.2 7798 41 71% 3.3 3.7 NT 22.1 1224 42 76% 2.8 4.34 NT
8.9 NT 43 67% 3.21 10 NT 1000 NT 44 87% 1.2 1.78 NT 21.26 6036 45
64% 4.65 10 NT 26.9 NT 46 68% 6.49 3.13 NT NT NT 47 41% 19.7 NT NT
NT NT 48 91% NT 0.94 NT 21 239 49 67% 16 7 NT NT NT 50 36% 36.5 NT
NT NT NT 51 34% 27.7 82 NT NT NT 52 41% 24.9 NT NT NT NT 53 93%
1.07 1.8 NT 229 7233 54 89% 1.71 1.8 NT 133 10000 55 62% 4.86 5.8
NT 31 NT 56 60% 3.8 22 NT 109 10000 57 63% 9.8 NT 87 NT 58 55% 7.59
3.65 NT 124 7830 59 81% 1.378 0.045 NT 115 1164 60 81% 2.17 1.34 NT
38.3 1703 61 89% NT 0.605 0.4 17.8 3995 62 91% 0.57 2.15 0.24 18.7
619 63 67% 9.33 10 NT 84 10000 64 64% 11.8 10 NT 1000 10000 65 65%
7.97 10 NT 59 10000 66 75% 5.2 5.8 NT 90.7 NT 67 58% 12.51 NT NT NT
NT 68 37% NT NT NT NT NT 69 95% 0.3 0.57 NT 6.52 4314 70 95% 0.43
0.537 NT 47.1 3975 71 5% NT NT NT NT NT 72 2% NT NT NT NT NT 73 48%
10.286 NT NT NT NT 74 43% 12.721 NT NT 312.5 NT 75 84% 2.62 1.4 NT
16.6 10000 76 36% 6.26 NT NT NT NT 77 99% 0.2 0.2 NT 7.4 8 78 93%
0.221 0.507 NT 14.8 30 79 90% 0.276 0.223 NT 15.5 130 80 95% 0.438
0.239 NT 31 60 81 100% 0.2 0.09 NT 7 25.96 82 89% 0.884 2.28 NT
53.1 2058 83 98% 0.2 0.77 NT 28.8 142 84 94% 0.58 0.322 NT 12.4 429
85 83% 1.71 3.92 NT 27.3 6987 86 81% 1.44 3.07 NT 17.9 87 96% 0.615
1.25 NT 17.8 6044 88 94% 0.574 0.46 NT 15.1 363 89 95% 0.419 NT NT
250 5.2 90 93% 0.739 2.14 NT 33 745 91 94% 0.356 0.168 NT 16.5 250
92 100% 0.2 0.18 NT 4.4 13 93 84% 2.72 NT NT 44 NT 94 81% 1.453 0.7
NT 112 251 95 89% 0.848 10 NT 235 96 96 51% 9.61 NT NT NT NT 97 70%
4.84 10 NT 293 223 98 86% 0.38 9.4 NT 126.6 NT 99 66% 4.68 NT NT
562.6 NT 100 0% NT NT NT NT NT 102 96% 0.91 0.186 NT 49 1718 103
52% 7 NT NT 203.4 NT 104 100% NT 8.4 NT 163.9 227 105 61% 8.37 NT
NT 127 NT 106 98% NT 10 NT 1000 638 107 17% 36.69 NT NT NT NT 108
61% NT NT NT NT NT 109 82% NT NT NT NT NT 110 21% NT NT NT NT NT
111 96% NT NT NT NT NT 112 91% NT NT NT NT NT 113 99% NT NT NT NT
NT 114 16% 118.85 NT NT 1000 NT 115 4% NT NT NT 1000 NT 116 4% NT
NT NT NT NT 117 87% 0.2 0.07 NT 189 86 118 84% 1.2 0.9 NT 1000 736
119 95% 0.375 1.46 NT 90.6 1827 120 93% 0.6 0.491 NT 405 489 121
94% 0.2 0.24 NT 220 100 122 58% 5.14 NT NT 351 NT 123 74% 2.63 10
NT 229 NT 124 82% 2.19 1.6 NT 376 8243 125 95% 0.219 2 NT 179 969
126 96% 0.5896 10 NT 336 5656 127 100% 0.2 1 NT 102 41 128 91% 0.57
0.13 NT 148 100 129 88% 0.2 0.219 NT 168 100 130 95% 0.39 0.49 NT
335 100 131 96% 0.2 1.89 NT 97 260 132 80% 1.78 5.8 NT 467 NT 133
40% 5.9 NT NT 467.9 NT 134 94% 1.44 0.656 NT 176.9 1070 135 87%
1.5411 1.02 NT 212 559 136 88% 1.1704 10 NT 609 NT 137 64% 5.1 2.1
NT 213 294 138 85% 0.78 9.9 NT 110 NT 139 40% NT NT NT NT NT 140
90% NT NT NT NT NT
[0879] TABLE-US-00002 TABLE 2 mouse % remain % remain PK AUC, mouse
mouse (HLM- (HLM po ng- C.sub.max, po C.sub.min, po UDPGA, NADPH,
Compound h/mL** (ng/mL) (ng/mL) 0.5 h) 0.5 h) 1 182608 124745 2793
NT NT 2 NT NT NT NT NT 3 2450 956 66 NT NT 4 7674 2340 200 NT NT 5
12254 6743 256 NT NT 6 586 355 20 NT NT 7 NT NT NT NT NT 8 2348 666
105 NT NT 9 NT NT NT NT NT 10 NT NT NT NT NT 11 NT NT NT NT NT 12
11970 5423 270 NT NT 13 63000 24760 1700 NT NT 14 NT NT NT NT NT 15
NT NT NT NT NT 16 NT NT NT NT NT 17 71580 28817 2334 NT NT 18 8724
4120 342 NT NT 19 120 51 4 NT NT
[0880] TABLE-US-00003 TABLE 3 PAE PDGFR FLVK (% @ 100 autophos IC50
Amine % TIC nM) FGF (%@100 nM) (nM) ##STR307## 56.552 52 NT 49
##STR308## 53.7991 103 2 53 ##STR309## 0 26 NT NT ##STR310##
51.8111 79 20 50 ##STR311## 5.4277 20 NT NT ##STR312## 88.1771 75
35 >100 ##STR313## 0 16 NT NT ##STR314## 55.2161 17 NT NT
##STR315## 65.4679 68 0 >100 ##STR316## 95.752 36 NT NT
##STR317## 97.7442 24 NT NT ##STR318## 65.2303 20 NT NT ##STR319##
48.6673 22 NT NT ##STR320## 45.8972 24 NT NT ##STR321## 12.783 90
20 >100 ##STR322## 55.6 14 NT NT ##STR323## 0 20 NT NT
##STR324## 0 27 NT NT ##STR325## 0 26 NT NT ##STR326## 0 14 NT NT
##STR327## 5.35845 62 7 >100 ##STR328## 0 14 NT NT ##STR329## 0
16 NT NT ##STR330## 0 30 NT NT ##STR331## 19.2675 100 4 46
##STR332## 58.6779 16 NT NT ##STR333## 29.8321 87 0 57 ##STR334##
10.8303 29 NT NT ##STR335## 77.1177 16 NT NT ##STR336## 0 20 NT NT
##STR337## 0 13 NT NT ##STR338## 55.2355 14 NT NT ##STR339## 0 14
NT NT ##STR340## 49.6134 25 NT NT ##STR341## 43.8419 25 NT NT
##STR342## 11.5047 21 NT NT ##STR343## ##STR344## 75.9693 96 0
.about.100 ##STR345## 0 10 NT NT ##STR346## 28.1067 13 NT NT
##STR347## 28.1967 97 0 >100 ##STR348## 24.8781 28 NT NT
##STR349## 0 10 NT NT ##STR350## 22.1224 8 NT NT ##STR351## 1.78077
7 NT NT ##STR352## 0 18 NT NT ##STR353## 0 22 NT NT ##STR354##
28.8916 87 13 .about.100 ##STR355## 50.8697 12 NT NT ##STR356##
1.10495 13 NT NT ##STR357## 36.7228 100 4 >100 ##STR358## 0 4 NT
NT ##STR359## 0 15 NT NT ##STR360## 24.5486 36 NT NT ##STR361##
22.7289 17 NT NT ##STR362## 55.7071 94 0 61 ##STR363## 25.3022 51
NT >100 ##STR364## 74.3164 91 NT >100 ##STR365## 0 23 8 NT
##STR366## 4.01991 13 NT NT ##STR367## 43.6451 85 7 >100
##STR368## 15.565 96 0 >100 ##STR369## 0 5 NT NT ##STR370##
58.6541 101 0 57 ##STR371## 20.5224 100 56 >100 ##STR372##
29.3082 22 NT NT ##STR373## 3.03715 56 3 >100 ##STR374## 54.7208
24 NT NT ##STR375## 0 27 NT NT ##STR376## 0 24 NT NT ##STR377##
27.931 94 0 >100 ##STR378## 16.4145 92 1 >100 ##STR379## 0 10
NT NT ##STR380## 49.5375 10 NT NT ##STR381## 41.0058 25 NT NT
##STR382## 0 13 NT NT ##STR383## 45.0518 85 3 >100 ##STR384##
38.7067 12 NT NT ##STR385## 33.1065 85 0 .about.100 ##STR386##
1.9193 35 NT NT ##STR387## 0 61 0 >100 ##STR388## 0 19 NT NT
##STR389## 0 17 NT NT ##STR390## 0 15 NT NT ##STR391## 15.0813 101
1 >100 ##STR392## 19.6253 19 NT NT ##STR393## 64.8885 16 NT NT
##STR394## 20.3244 9 NT NT ##STR395## 24.2001 46 NT NT
[0881] The exemplary compounds described above may be formulated
into pharmaceutical compositions according to the following general
examples.
Example 1
Parenteral Composition
[0882] To prepare a parenteral pharmaceutical composition suitable
for administration by injection, 100 mg of a water-soluble salt of
a compound of Formula I is dissolved in DMSO and then mixed with 10
mL of 0.9% sterile saline. The mixture is incorporated into a
dosage unit form suitable for administration by injection.
Example 2
Oral Composition
[0883] To prepare a pharmaceutical composition for oral delivery,
100 mg of a compound of Formula I is mixed with 750 mg of lactose.
The mixture is incorporated into an oral dosage unit for, such as a
hard gelatin capsule, which is suitable for oral
administration.
[0884] It is to be understood that the foregoing description is
exemplary and explanatory in nature, and is intended to illustrate
the invention and its preferred embodiments. Through routine
experimentation, the artisan will recognize apparent modifications
and variations that may be made without departing from the spirit
of the invention. Thus, the invention is intended to be defined not
by the above description, but by the following claims and their
equivalents.
* * * * *