U.S. patent number RE46,815 [Application Number 15/172,021] was granted by the patent office on 2018-05-01 for furanone derivative.
This patent grant is currently assigned to Carna Biosciences, Inc.. The grantee listed for this patent is Carna Biosciences, Inc.. Invention is credited to Tokiko Asami, Yoko Funakoshi, Takayuki Irie, Ayako Sawa, Masaaki Sawa, Chika Tanaka.
United States Patent |
RE46,815 |
Irie , et al. |
May 1, 2018 |
**Please see images for:
( Certificate of Correction ) ** |
Furanone derivative
Abstract
To provide a novel furanone derivative, and a medicine including
the same. The furanone derivative is represented by the formula
(I): ##STR00001## wherein A represents --COOR1 or a hydrogen atom;
R1 represents a hydrogen atom, an optionally substituted
hydrocarbon group, or an optionally substituted heterocycle; R2 and
R3 are the same or different and each independently represent a
hydrogen atom, an optionally substituted hydrocarbon group, an
optionally substituted phenyl group, an optionally substituted
heterocycle, an optionally substituted heterocyclic fused ring, or
an optionally substituted amino group; or alternatively, R2 and R3,
taken together with the nitrogen atom to which they are attached,
may form an optionally substituted heterocycle or an optionally
substituted heterocyclic fused ring; and R4 represents a hydrogen
atom or a halogen atom; with the proviso that when A represents
--COOR1, R2 and R3 are not optionally substituted amino groups at
the same time, and when A represents a hydrogen atom, R3 represents
a hydrogen atom.
Inventors: |
Irie; Takayuki (Kobe,
JP), Sawa; Ayako (Osaka, JP), Sawa;
Masaaki (Ibaraki, JP), Asami; Tokiko (Kobe,
JP), Funakoshi; Yoko (Tokyo, JP), Tanaka;
Chika (Tokyo, JP) |
Applicant: |
Name |
City |
State |
Country |
Type |
Carna Biosciences, Inc. |
Kobe |
N/A |
JP |
|
|
Assignee: |
Carna Biosciences, Inc.
(Kobe-Shi, JP)
|
Family
ID: |
46931496 |
Appl.
No.: |
15/172,021 |
Filed: |
June 2, 2016 |
PCT
Filed: |
March 30, 2012 |
PCT No.: |
PCT/JP2012/058636 |
371(c)(1),(2),(4) Date: |
September 27, 2013 |
PCT
Pub. No.: |
WO2012/113802 |
PCT
Pub. Date: |
October 04, 2012 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
Issue Date |
|
Reissue of: |
14008488 |
Mar 30, 2012 |
8742113 |
Jun 3, 2014 |
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Foreign Application Priority Data
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Mar 31, 2011 [JP] |
|
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2011-080185 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
C07D
519/00 (20130101); A61K 31/541 (20130101); A61K
31/506 (20130101); C07D 471/04 (20130101); A61K
31/444 (20130101); A61K 31/4709 (20130101); A61K
31/496 (20130101); A61K 31/506 (20130101); C07D
471/04 (20130101); A61K 31/4375 (20130101); A61K
31/541 (20130101); A61P 35/00 (20180101); A61K
31/4545 (20130101); A61K 31/5355 (20130101); A61K
31/437 (20130101); A61K 31/444 (20130101); C07D
519/00 (20130101); A61K 31/4375 (20130101); A61K
31/5355 (20130101); A61K 31/496 (20130101); A61K
31/4545 (20130101); A61K 31/437 (20130101); A61K
31/4709 (20130101); A61P 43/00 (20180101) |
Current International
Class: |
C07D
471/02 (20060101); A61K 31/4545 (20060101); A61K
31/4709 (20060101); C07D 519/00 (20060101); A61K
31/506 (20060101); A61K 31/5355 (20060101); A61K
31/541 (20060101); A61K 31/437 (20060101); A61K
31/496 (20060101); A61K 31/444 (20060101); C07D
498/02 (20060101); C07D 491/02 (20060101); C07D
515/02 (20060101); C07D 513/02 (20060101); C07D
471/04 (20060101); A61K 31/4375 (20060101) |
References Cited
[Referenced By]
U.S. Patent Documents
Foreign Patent Documents
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WO 2001/098299 |
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Dec 2001 |
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WO |
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WO-2004/007504 |
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Jan 2004 |
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WO |
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WO 2005/009370 |
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Feb 2005 |
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WO |
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WO 2005/013986 |
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Feb 2005 |
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WO |
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WO 2005/014572 |
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Feb 2005 |
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WO |
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WO 2006/037875 |
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Apr 2006 |
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WO |
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WO 2007/054508 |
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May 2007 |
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WO |
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2008/046982 |
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Apr 2008 |
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WO |
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WO 2008/046982 |
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Apr 2008 |
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WO |
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WO 2008/109443 |
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Sep 2008 |
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WO |
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WO 2009/155052 |
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Dec 2009 |
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WO |
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WO 2010/030727 |
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Mar 2010 |
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WO |
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WO 2011/008915 |
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Jan 2011 |
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WO |
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WO 2012/002568 |
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Jan 2012 |
|
WO |
|
Other References
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by examiner .
PCT International Search Report, International Application No.
PCT/JP2012/058636, Apr. 24, 2012. cited by applicant .
Masai, H., et al., "Cdc7 Kinase Complex: A Key Regulator in the
Initiation of DNA Replication," Journal of Cellular Physiology,
2002, pp. 287-296, vol. 190, No. 3. cited by applicant .
Kim, J.M., et al., "Cdc7 kinase mediates Claspin phosphorylation in
DNA replication checkpoint," Oncogene, 2008, pp. 3475-3482, vol.
27, No. 24. cited by applicant .
Bonte, D., et al., "Cdc7-Dbf4 Kinase Overexpression in Multiple
Cancers and Tumor Cell Lines is Correlated with p53 Inactiviation,"
Neoplasia, 2008, pp. 920-931, vol. 10, No. 9. cited by applicant
.
Rodriguez-Acebes, S., et al., "Targeting DNA Replication before it
Starts; Cdc7 as a Therapeutic Target in p53-Mutant Breast Cancers,"
The American Journal of Pathology, 2010, pp. 2034-2045, vol. 177,
No. 4. cited by applicant .
Montagnoli, A., et al., "Cdc7 Inhibition Reveals a p53-Dependent
Replication Checkpoint That Is Defective in Cancer Cells." Cancer
Research, 2004, pp. 7110-7116, vol. 64, No. 19. cited by applicant
.
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Organic Synthesis, 3rd Edition, 1999, pp. 377-380. cited by
applicant .
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Patent Application No. 2012233246, Apr. 4, 2016, 3 Pages. cited by
applicant .
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No. 12763979.7, Jul. 1, 2016, 4 Pages. cited by applicant .
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Synthesis and Antiallergic Activity of
Furo[2,3-b][1,8]naphthyridine-3,4(2H,9H)-diones and
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Pharm. Bull., 1988, vol. 36, No. 11, pp. 4403-4407. cited by
examiner .
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Response. 12. 4,5-Dihydro-4-oxo-2-(substituted
amino)-3-furancarboxylic Acids and Derivatives as Novel
Antiallergic Agents", J. Med. Chem., 1988, vol. 31, No. 10, pp.
1910-1918. cited by applicant .
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Esters Under Mild Conditions Catalyzed by Tetranuclear Zinc
Cluster", J. Org. Chem., 2008, vol. 73, No. 13, pp. 5147-5150.
cited by applicant .
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Dealkoxycarbonylation of Ethyl
2-Arylamino-4-oxo-4,5-dihydrofuran-3-carboxylates", Chem. Pharm.
Bull, 1990, vol. 38, No. 2, pp. 340-341. cited by
applicant.
|
Primary Examiner: Campell; Bruce
Attorney, Agent or Firm: Fenwick & West LLP
Claims
The invention claimed is:
1. A furanone derivative or a pharmaceutically acceptable salt
thereof, represented by .[.the formula (I): [Chemical Formula 1]
##STR00370## .]. .Iadd.the formula (I-Z) or the formula (I-E):
##STR00371## .Iaddend. wherein A represents --COOR1 or a hydrogen
atom; R1 represents a hydrogen atom, an optionally substituted
hydrocarbon group, or an optionally substituted heterocycle; R2 and
R3 are the same or different and each independently represent a
hydrogen atom, an optionally substituted hydrocarbon group, an
optionally substituted phenyl group, an optionally substituted
heterocycle, an optionally substituted heterocyclic fused ring, or
an optionally substituted amino group; or alternatively, R2 and R3,
taken together with the nitrogen atom to which they are attached,
form an optionally substituted heterocycle or an optionally
substituted heterocyclic fused ring; and R4 represents a hydrogen
atom or a halogen atom; with the proviso that when A represents
--COOR1, R2 and R3 are not optionally substituted amino groups at
the same time, and when A represents a hydrogen atom, R3 represents
a hydrogen atom.
2. The furanone derivative or a pharmaceutically acceptable salt
thereof according to claim 1, wherein A is --COOR1.
3. The furanone derivative or a pharmaceutically acceptable salt
thereof according to claim 1, wherein A is a hydrogen atom.
.Iadd.4. The furanone derivative or a pharmaceutically acceptable
salt thereof according to claim 1, wherein the furanone derivative
or a pharmaceutically acceptable salt thereof is represented by the
formula (II-Z) or formula (II-E): ##STR00372## ##STR00373## wherein
A represents --COOR1 or a hydrogen atom; R1 is selected from the
group consisting of a hydrogen atom, an optionally substituted 1 to
6 carbon hydrocarbon group, and an optionally substituted 3 to 8
membered heterocycle; R2 and R3, taken together with the nitrogen
atom to which they are attached, form an optionally substituted 3
to 8 membered heterocycle or an optionally substituted 3 to 8
membered heterocyclic fused ring; R4 represents a hydrogen atom or
a halogen atom; wherein any and all heterocyclic groups contain up
to four heteroatoms selected from the group consisting of nitrogen,
sulfur, and oxygen; with the proviso that when A represents
--COOR1, R2 and R3 are not optionally substituted amino groups at
the same time, and when A represents a hydrogen atom, R3 represents
a hydrogen atom. .Iaddend.
.Iadd.5. The furanone derivative or a pharmaceutically acceptable
salt thereof according to claim 1, wherein any and all heterocyclic
groups are optionally substituted 3 to 8 membered heterocycle
groups that contain up to two heteroatoms selected from the group
consisting of nitrogen, sulfur, and oxygen. .Iaddend.
.Iadd.6. The furanone derivative or a pharmaceutically acceptable
salt thereof according to claim 1, wherein any and all hydrocarbon
groups are 1 to 6 carbon hydrocarbon groups; and wherein any and
all heterocyclic groups are optionally substituted 3 to 8 membered
heterocycle groups that contain up to two heteroatoms selected from
the group consisting of nitrogen, sulfur, and oxygen. .Iaddend.
.Iadd.7. The furanone derivative or a pharmaceutically acceptable
salt thereof according to claim 4, wherein A and R4 are both a
hydrogen atom and R2 and R3 form a 3 to 8 membered heterocycle.
.Iaddend.
.Iadd.8. The furanone derivative or a pharmaceutically acceptable
salt thereof according to claim 4, wherein A is --COOR1 where R1 is
an optionally substituted 1 to 6 carbon hydrocarbon group, R4 is a
hydrogen atom and R2 and R3 form a 3 to 8 membered heterocycle
containing up to two heteroatoms selected from the group consisting
of nitrogen, sulfur, and oxygen. .Iaddend.
.Iadd.9. The furanone derivative or a pharmaceutically acceptable
salt thereof according to claim 1, wherein A is --COOR1 where R1 is
an optionally substituted 1 to 6 carbon hydrocarbon group, R4 is a
hydrogen atom and one of either of R2 and R3 is a hydrogen atom.
.Iaddend.
.Iadd.10. The furanone derivative or a pharmaceutically acceptable
salt thereof according to claim 1, wherein A is --COOR1 where R1 is
an optionally substituted 1 to 6 carbon hydrocarbon group, R4 is a
fluorine atom and one of either of R2 and R3 is a hydrogen atom.
.Iaddend.
.Iadd.11. The furanone derivative or a pharmaceutically acceptable
salt thereof according to claim 1, wherein A and R4 are both a
hydrogen atom, and one of either of R2 and R3 is a hydrogen atom.
.Iaddend.
.Iadd.12. The furanone derivative or a pharmaceutically acceptable
salt thereof according to claim 1, wherein A is --COOR1 where R1 is
an optionally substituted 1 to 6 carbon hydrocarbon group, R4 is a
hydrogen atom, one of either of R2 and R3 is a hydrogen atom and
one of either of R2 and R3 is an optionally substituted amino
group. .Iaddend.
.Iadd.13. The furanone derivative or a pharmaceutically acceptable
salt thereof according to claim 1, wherein A is --COOR1 where R1 is
an optionally substituted 1 to 6 carbon hydrocarbon group, R4 is a
hydrogen atom, one of either of R2 and R3 is an optionally
substituted 1 to 6 carbon hydrocarbon group and one of either of R2
and R3 is a 3 to 8 membered heterocycle containing up to two
heteroatoms selected from the group consisting of nitrogen, sulfur,
and oxygen. .Iaddend.
.Iadd.14. The furanone derivative or a pharmaceutically acceptable
salt thereof according to claim 1, wherein A is --COOR1 where R1 is
an optionally substituted 1 to 6 carbon hydrocarbon group, R4 is a
hydrogen atom, one of either of R2 and R3 is a hydrogen atom and
one of either of R2 and R3 is an optionally substituted 3 to 8
membered heterocyclic fused ring. .Iaddend.
.Iadd.15. The furanone derivative or a pharmaceutically acceptable
salt thereof according to claim 1, wherein A is --COOR1 where R1 is
a 3 to 8 membered heterocycle containing up to two heteroatoms
selected from the group consisting of nitrogen, sulfur, and oxygen,
R4 is a hydrogen atom and one of either of R2 and R3 is a hydrogen
atom. .Iaddend.
.Iadd.16. The furanone derivative or a pharmaceutically acceptable
salt thereof according to claim 1, wherein the furanone derivative
or pharmaceutically acceptable salt thereof is selected from the
group consisting of: ##STR00374## ##STR00375## .Iaddend.
.Iadd.17. The furanone derivative or a pharmaceutically acceptable
salt thereof according to claim 1, wherein the furanone derivative
or pharmaceutically acceptable salt thereof is selected from the
group consisting of: ##STR00376## .Iaddend.
.Iadd.18. The furanone derivative or a pharmaceutically acceptable
salt thereof according to claim 1, wherein the furanone derivative
or pharmaceutically acceptable salt thereof is selected from the
group consisting of: ##STR00377## ##STR00378## .Iaddend.
.Iadd.19. The furanone derivative or a pharmaceutically acceptable
salt thereof according to claim 1, wherein the pharmaceutically
acceptable salt is the hydrochloride or p-toluenesulfonate salt.
.Iaddend.
.Iadd.20. The furanone derivative or a pharmaceutically acceptable
salt thereof according to claim 16, wherein the pharmaceutically
acceptable salt is the hydrochloride or p-toluenesulfonate salt.
.Iaddend.
Description
.Iadd.The present application is a Reissue of application Ser. No.
14/008,488, filed Mar. 30, 2012, issued as U.S. Pat. No. 8,742,113
on Jun. 3, 2014. .Iaddend.
TECHNICAL FIELD
The present invention relates to a medicine, particularly a novel
furanone derivative having an inhibitory effect on Cdc7 or a
pharmaceutically acceptable salt thereof.
BACKGROUND ART
Cancer is a group of diseases caused by uncontrolled, unlimited
growth of cells within a living body. Since cancer cells usually
grow faster than normal cells, cancers would be capable of being
treated by controlling the replication of DNA during the cell
division, particularly during the division of chromosomes.
Actually, gemcitabine, which has the effect of inhibiting DNA
replication, is widely used in the treatment of non-small cell lung
cancer, pancreatic cancer, biliary tract cancer, bladder cancer,
breast cancer, ovarian cancer, or others.
Cdc7 is a serine-threonine protein kinase and is an enzyme which is
essential for the initiation of DNA replication in the cell cycle.
Specifically, Cdc7 forms a complex with cofactors such as Dbf4
(ASK), and phosphorylates its substrate, MCM (mini-chromosome
maintenance) proteins. It is supposed that this phosphorylation
results in assembly of Cdc45 and a DNA polymerase on the DNA to
form an MCM complex, thereby initiating the DNA replication (see
Non Patent Literature 1). Furthermore, it has been shown in a
recent study that Cdc7 plays an important role not only in the
replication of DNA, but also in DNA damaging pathways (see Non
Patent Literature 2).
Recently, Cdc7 has drawn attention as a target of anticancer
agents, and active researches on Cdc7 have been made. For example,
it was found that CDC7 is overexpressed not only in common
established cell lines derived from human tumors, but also in cells
taken from live tissues, such as breast cancer, colon cancer, and
lung cancer (see Non Patent Literature 3). Particularly, it was
shown, in more recent days, that CDC7 is overexpressed in
p53-mutated triple negative (ER-/PR-/Her2-) breast cancer cells
(see Non Patent Literature 4), and thus it has been expected that
Cdc7 will be a promising target molecule against a triple negative
type of breast cancer, which has been considered to be difficult to
treat. Actually, it was observed that in experiments for
suppressing the expression of Cdc7 using RNA interference
techniques, the arresting of the cell cycle was induced when the
expression of Cdc7 was inhibited. More importantly, the Cdc7
inhibition using RNA interference techniques suppressed the growth
of human tumor cells, such as HeLa and HCT116 cells, and exhibited
only limited effects on normal cells (normal human skin
fibroblasts) (see Non Patent Literature 5).
Therefore, selective inhibitors of Cdc7 can be expected to have an
effective therapeutic effect against various types of cancer.
Although various compounds having an inhibitory effect on Cdc7 have
been reported in the past, there are no reports in which novel
furanone derivatives of the present invention or pharmaceutically
acceptable salts thereof have an inhibitory effect on Cdc7.
CITATION LIST
Non Patent Literature
[Non Patent Literature 1] H. Masai et al., Journal of Cellular
Ohysiology, 190, 2002, 287-296
[Non Patent Literature 2] J M. Kim et al., Oncogene, 27, 2008,
3475-3482
[Non Patent Literature 3] D Bonte et al., Neoplasia, 10, 2008,
920-931
[Non Patent Literature 4] S. Rodriguez-Acebes et al., The American
Journal of Pathology, 177, 2010, 2034-2045
[Non Patent Literature 5] A. Montagnoli et al., Cancer Research,
64, 2004, 7110-7116
SUMMARY OF INVENTION
Technical Problem
An object of the present invention is to provide a medicine,
particularly a novel furanone derivative having an inhibitory
effect on Cdc7 or a pharmaceutically acceptable salt thereof.
Solution to Problem
The present invention is achieved by the following (1) to (3):
(1) A furanone derivative or a pharmaceutically acceptable salt
thereof, represented by the formula (I):
##STR00002## wherein A represents --COOR1 or a hydrogen atom; R1
represents a hydrogen atom, an optionally substituted hydrocarbon
group, or an optionally substituted heterocycle; R2 and R3 are the
same or different and each independently represent a hydrogen atom,
an optionally substituted hydrocarbon group, an optionally
substituted phenyl group, an optionally substituted heterocycle, an
optionally substituted heterocyclic fused ring, or an optionally
substituted amino group; or alternatively, R2 and R3, taken
together with the nitrogen atom to which they are attached, may
form an optionally substituted heterocycle or an optionally
substituted heterocyclic fused ring; and R4 represents a hydrogen
atom or a halogen atom; with the proviso that when A represents
--COOR1, R2 and R3 are not optionally substituted amino groups at
the same time, and when A represents a hydrogen atom, R3 represents
a hydrogen atom; (2) The furanone derivative or a pharmaceutically
acceptable salt thereof according to (1), wherein A is --COOR1; and
(3) The furanone derivative or a pharmaceutically acceptable salt
thereof according to (1), wherein A is a hydrogen atom.
Advantageous Effects of Invention
The present inventors have made various studies in order to solve
the above-mentioned problem, and found that novel furanone
derivatives represented by the formula (I) and pharmaceutically
acceptable salts thereof had excellent inhibitory effect on Cdc7,
resulting in completion of the present invention. The compounds
provided by the present invention are capable of controlling the
growth of cells. Therefore, the compounds of the present invention
having an inhibitory effect on Cdc7 will be useful as a medicine,
particularly an agent for the treatment of diseases derived from
abnormal growth of cells, such as cancers.
DESCRIPTION OF EMBODIMENTS
The present invention will be described in detail below.
A novel furanone derivative of the present invention is a compound
represented by the formula (I):
##STR00003## wherein A represents --COOR1 or a hydrogen atom; R1
represents a hydrogen atom, an optionally substituted hydrocarbon
group, or an optionally substituted heterocycle; R2 and R3 are the
same or different and each independently represent a hydrogen atom,
an optionally substituted hydrocarbon group, an optionally
substituted phenyl group, an optionally substituted heterocycle, an
optionally substituted heterocyclic fused ring, or an optionally
substituted amino group; or alternatively, R2 and R3, taken
together with the nitrogen atom to which they are attached, may
form an optionally substituted heterocycle or an optionally
substituted heterocyclic fused ring; and R4 represents a hydrogen
atom or a halogen atom; with the proviso that when A represents
--COOR1, R2 and R3 are not optionally substituted amino groups at
the same time, and when A represents a hydrogen atom, R3 represents
a hydrogen atom. In the formula (I), an optionally substituted
hydrocarbon group includes, for example, a) a linear or branched
alkyl group having 1 to 6 carbons (for example, methyl, ethyl,
isopropyl, tert-butyl, hexyl, etc.); b) a linear or branched
alkenyl group having 1 to 6 carbons (for example, vinyl, allyl,
isopropenyl, 2-butenyl, etc.); c) an alkynyl group having 2 to 6
carbons (for example, ethynyl, propargyl, 2-butynyl, etc.); d) a
cycloalkyl group having 3 to 8 carbons (for example, cyclopropyl,
cyclopentyl, cyclohexyl, cycloheptyl, etc.); e) a cycloalkenyl
group having 3 to 8 carbons (for example, cyclohexenyl,
cycloheptenyl, etc.); f) an aralkyl group, the aryl moiety of which
is an aryl having 6 to 14 carbons (for example, phenyl, naphthyl,
indenyl, etc.) and the alkylene moiety of which has the same
meaning as a group where one hydrogen atom has removed from the
above-mentioned alkyl group; and others.
The heterocyclic moiety of an optionally substituted heterocycle
includes an alicyclic heterocyclic group and an aromatic
heterocyclic group. An alicyclic heterocyclic group is, for
example, a 3- to 8-membered heterocyclic group containing at least
one heteroatom selected from a nitrogen atom, a sulfur atom, and an
oxygen atom. Specific examples of the alicyclic heterocyclic group
include pyrrolidinyl, piperidyl, piperazinyl, morpholinyl,
thiomorpholinyl, etc. An aromatic heterocyclic group is, for
example, a 5- or 6-membered monocyclic aromatic heterocyclic group
containing at least one heteroatom selected from a nitrogen atom, a
sulfur atom, and an oxygen atom. Specific examples of the aromatic
heterocyclic group include imidazolyl, pyrazolyl, thienyl,
thiazolyl, pyridyl, etc.
The heterocyclic fused ring moiety of an optionally substituted
heterocyclic fused ring is, for example, a fused heterocyclic group
which is bicyclic by fusing 3- to 8-membered rings and which
contains at least one heteroatom selected from a nitrogen atom, a
sulfur atom, and an oxygen atom. Specific examples of the fused
heterocyclic group include benzothiophenyl, benzimidazolyl,
indazolyl, benzoxazolyl, benzothiazolyl, indolyl, isoquinolyl,
phthalimide, etc.
An optionally substituted amino group is, for example, an amino
group having a linear, branched, or cyclic alkyl, aryl, or
heteroaryl group which is substituted or unsubstituted and
containing 1 to 6 carbons, for example, an amino group to which an
alkyl group, an alkylamino group, an aryl group, a heteroaryl
group, a heterocyclic group, a heterocyclic fused ring group, or
the like which is unsubstituted or substituted with one or more
substituents may be attached. The "one or more substituents" in
these groups attached to an amino group may be any one or more
substituents which are the same or different, unless otherwise
specified, and include, for example, a halogen atom, a substituted
or unsubstituted alkyl group, a substituted or unsubstituted
alkenyl group, a substituted or unsubstituted alkynyl group, a
substituted or unsubstituted alkoxy group, an amino group, a nitro
group, a cyano group, a hydroxy group, a substituted or
unsubstituted alkylamino group, a carbamoyl group, a carboxyl
group, a formyl group, an acetyl group, a benzoyl group, etc.
The "substituent(s)" in an optionally substituted hydrocarbon
group, an optionally substituted heterocycle, an optionally
substituted phenyl group, or an optionally substituted heterocyclic
fused ring is/are be one or more substituents of any type which are
allowed to be located at any chemically acceptable positions,
unless otherwise specified. When two or more substituents are
present, these substituents may be the same or different and
include, for example, a halogen atom, a substituted or
unsubstituted alkyl group, a substituted or unsubstituted alkoxy
group, a substituted or unsubstituted amino group, a nitro group, a
cyano group, a hydroxy group, a substituted or unsubstituted
alkylamino group, a carbamoyl group, a carboxyl group, a formyl
group, an acetyl group, a benzoyl group, etc.
The heterocyclic group in the case where R2 and R3, taken together
with the nitrogen atom to which they are attached, form an
optionally substituted heterocycle or an optionally substituted
heterocyclic fused ring is, for example, a 3- to 8-membered
heterocyclic group containing at least one heteroatom selected from
a nitrogen atom, a sulfur atom, and an oxygen atom, or a fused
alicyclic heterocyclic group which is bicyclic by fusing 3- to
8-membered rings and which contains at least one heteroatom
selected from a nitrogen atom, a sulfur atom, and an oxygen atom.
Specific examples of such heterocyclic groups include pyrrolidinyl,
piperidyl, morpholinyl, thiomorpholinyl, azepinyl, diazepinyl,
dihydroisoquinolyl, tetrahydroisoquinolyl, tetrahydroquinolyl,
isoindolinyl, indolinyl, tetrahydrobenzazepinyl, benzazepinyl,
benzodiazepinyl, benzoxyazepinyl, benzothiazepinyl, etc.
A halogen atom includes, for example, fluorine, chlorine, bromine,
and the like.
A compound (I) of the present invention may have isomers, for
example, depending on the type of its substituents. In the
specification, such a compound is sometimes described by the
chemical structure of only one of its isomeric forms. However, the
present invention includes all of the structurally possible isomers
of such a compound (geometrical isomers, optical isomers,
tautomers, etc.), and also include its individual isomers or
mixtures thereof.
Also, the present invention encompasses stereoisomers of a compound
of the present invention represented specifically by the formulae
(I-Z) and (I-E), and mixtures thereof.
##STR00004##
A pharmaceutically acceptable salt of a compound (I) of the present
invention includes a salt with an inorganic acid, such as
hydrochloric acid, sulfuric acid, carbonic acid, and phosphoric
acid, and a salt with an organic acid, such as formic acid, acetic
acid, fumaric acid, maleic acid, methanesulfonic acid, and
p-toluenesulfonic acid. Also included in the present invention are,
for example, a salt with an alkali metal, such as sodium and
potassium, a salt with an alkaline earth metal, such as magnesium
and calcium, a salt with an organic amine, such as a lower alkyl
amine and a lower alcohol amine, and a salt with a basic amino
acid, such as lysine, arginine, and ornithine, and in addition, an
ammonium salt.
Compounds (I) of the present invention and pharmaceutically
acceptable salts thereof can be produced, for example, by the
methods mentioned below. In the production methods mentioned below,
when a defined group is changed under conditions where the method
is performed, or when a defined group is not suitable for
performing the method, the production can be easily achieved by
applying methods usually used in organic synthetic chemistry, such
as procedures for protection and deprotection of functional groups
[T. W. Greene, Protective Groups in Organic Synthesis, 3rd Edition,
John Wiley & Sons, Inc., 1999]. In addition, the order of
reaction steps, for example, those for introducing a substituent or
substituents, may be changed as needed.
A compound (Ia) wherein A is --COOR1 can be produced, for example,
by scheme 1:
##STR00005## wherein R1, R2, R3 and R4 have the same meaning as
mentioned above.
A compound (Ia) of the present invention can be obtained by heating
and reacting a compound (III) and 1 to 5, preferably 1 to 1.5,
molar equivalents of a compound (IV) in a solvent under conditions
for a Knoevenagel condensation reaction, that is, in the presence
of a catalytic base such as piperidine. The solvent can be any
solvent which is inert in the reaction, and is not limited in
particular. For example, a lower alcohol, preferably ethanol, can
be used as the solvent. As the base, piperidine or proline, for
example, can be used in an amount of from a catalytic amount to an
equivalent amount relative to the compound (III). The reaction can
be carried out in the range of from room temperature to reflux
temperature and for a period of 3 hours to 2 weeks. Preferably, the
reaction can be carried out for 1 to 3 days under conditions of
reflux in ethanol, thereby to synthesize the compound. In addition,
this reaction can also be performed under other usual conditions
used in the Knoevenagel condensation reaction, for example, under
acidic conditions using hydrochloric acid, acetic acid, or the
like, to produce the compound.
The compound (IV) which can be used as one starting material in
scheme 1 is commercially available (for example, from
SIGMA-ALDRICH) or can be obtained by known methods (see, for
example, Rajesh H. Bahekar et al., Bioorganic & Medicinal
Chemistry, 15 (21), 6782-6795 (2007); and Seung-Jun Oh et al.,
Bioorganic & Medicinal Chemistry, 12 (21), 5505-5513
(2004)).
On the other hand, the compound (III) which can be used as the
other starting material in scheme 1 can be produced, for example,
by the procedures shown in scheme 2 or 3.
##STR00006## wherein R1, R2, and R3 have the same meaning as
mentioned above, and R1' represents a substituted or unsubstituted
lower alkyl group. Step 2-1
A compound (VII) can be obtained by converting a malonic diester
(V) to its enolate with a base, such as sodium hydride, in a
solvent, such as anhydrous tetrahydrofuran, followed by reaction
with chloroacetyl chloride (VI).
Step 2-2
The compound (III) can be obtained by reacting the compound (VII)
obtained in the previous step and an amine (VIII) in an amount of
from an equivalent amount to an excess amount, preferably in an
amount of 1.2 to 3 molar equivalents, in a solvent at room
temperature or at heated temperature.
The solvent can be any solvent which is inert in the reaction, and
is not limited in particular. For example, tetrahydrofuran,
dimethylformamide, ethanol, and the like can be used as the
solvent.
The reaction is dependent on the reactivity of the amine (VIII)
used, and generally is completed in a period of 1 hour to 1 day at
a temperature of from room temperature to the reflux temperature of
the solvent. When the reaction progresses at a significantly slow
rate, the desired product can be obtained by adding a base, such as
sodium hydride, sodium hydroxide, triethylamine, or the like, in an
amount of from an equivalent amount to an excess amount.
Further, the compound (III) can also be produced by mean of a
sequence of reactions without isolating the compound (VII), by
known methods (see, for example, Sheng-Chu Kuo et al., Chem. Pharm.
Bull., 36 (11), 4403-4407 (1988)) or their modified methods. That
is, the compound (III) can be obtained by adding the amine (VIII)
in an amount of from an equivalent amount to an excess amount,
preferably in an amount of 1.2 to 3 molar equivalents, to the
solution after the reaction in step 2-1, and performing the
reaction at room temperature or at heated temperature.
The malonic diester (V) and the amine (VIII) which can be used as
the starting materials in scheme 2 are commercially available or
can be obtained by known methods.
##STR00007## wherein R1 and R2 have the same meaning as mentioned
above.
Among the compounds (III), a compound (IIIa) wherein R3 is a
hydrogen atom can be produced by known methods (see, for example,
Robert A. Mack et al., J. Med. Chem., 31 (10), 1910-1918 (1988)) or
their modified methods. That is, the compound (IIIa) can be
obtained by cyclocondensation of a compound (IX) with 1 to 5,
preferably 1 to 1.5, molar equivalents of isocyanate (X) in a
solvent in the presence of a base, such as triethylamine.
The solvent can be any solvent which is inert in the reaction, and
is not limited in particular. For example, diethyl ether or ethyl
acetate, or mixed solvents thereof can be used as the solvent.
The reaction can be carried out in the range of from ice-cooled
temperature to reflux temperature and for a period of 30 minutes to
1 day. Preferably, the reaction can be carried out at room
temperature for 1 to 3 hours, thereby to synthesize the
compound.
The compound (IX) and isocyanate (X) that are the starting
materials in scheme 3 are commercially available or can be obtained
by known methods.
Further, a compound (Ia) of the present invention can also be
produced by a transesterification reaction of a compound (Ia'),
which is a lower alkyl ester compound, as shown in scheme 4:
##STR00008## wherein R1, R2, R3, and R4 have the same meaning as
mentioned above, and R1' represents a substituted or unsubstituted
lower alkyl group.
A compound (Ia) of the present invention can be produced by a
transesterification reaction of the compound (Ia') by known methods
(see, for example, Takanori Iwasaki et al., J. Org. Chem., 73 (13),
5147-5150 (2008)) or their modified methods. That is, the compound
(Ia) can be obtained by heating and reacting the compound (Ia') and
an excess amount, preferably more than 10 molar equivalents, of an
alcohol (XI) in a solvent in the presence of a tetranuclear zinc
cluster catalyst. The solvent can be any solvent which is inert in
the reaction, and is not limited in particular. For example,
dimethylacetamide, 1,4-dioxane, diisopropyl ether, or the like can
be used as the solvent. Alternatively, the alcohol (XI) may be used
as the solvent. As the tetranuclear zinc cluster catalyst,
catalysts which are commercially available (for example, under a
product name of ZnTAC24, from STREM CHEMICALS) or are produced by
the method described in the above-mentioned reference are used and
added in a catalytic amount, preferably in an amount of 1 to 10%
molar equivalents. Further, it is also possible that a tertiary
amine, such as dimethylaminopyridine or triethylamine, is added in
an amount of from a catalytic amount to 1 molar equivalent to
accelerate the reaction.
The reaction can be carried out in the range of from room
temperature to reflux temperature and for a period of 1 hour to 1
week. Preferably, the reaction can be carried out for 1 to 3 days
under reflux conditions, thereby to synthesize the compound.
Alternatively, the reaction may also be carried out using a
microwave reactor, for example, for a period of from several
minutes to several hours under temperature conditions of 60 to
150.degree. C., thereby to synthesize the compound.
This reaction can also be carried out under other usual conditions
used in the transesterification reaction, as shown in scheme 5, for
example, under acidic or basic conditions, or under conditions
using a catalyst, such as tetravalent titanium.
##STR00009## wherein R1', R2, R3, and R4 have the same meaning as
mentioned above.
A compound (Ib) of the present invention can be obtained by
hydrolysis of a compound (Ia'), which is a lower alkyl ester
compound, under reaction conditions used in usual organic synthetic
chemistry (using methods described in, for example, T. W. Greene,
Protective Groups in Organic Synthesis, 3rd Edition, John Wiley
& Sons, Inc., 1999, p. 377, or their modified methods). That
is, the compound (Ib) can be obtained by reacting the compound
(Ia') and a base or acid in an amount of from an equivalent amount
to an excess amount in a solvent at a temperature between 0.degree.
C. and the boiling point of the solvent used.
The solvent can be any solvent which is inert in the reaction, and
is not limited in particular. For example, 1,4-dioxane,
tetrahydrofuran, various alcohols, or the like can be used as the
solvent.
As the base or acid, use can be made of, for example, sodium
hydroxide, potassium hydroxide, or hydrochloric acid.
The reaction can be carried out at a temperature between 0.degree.
C. and the boiling point of the solvent used and for a period of 1
hour to 1 week. Preferably, the reaction can be carried out for 1
hour to 1 day under reflux conditions, thereby to synthesize the
compound.
Among the compounds (I) of the present invention, a compound (Ic)
wherein A and R3 are hydrogen atoms can be produced, for example,
as shown in scheme 6:
##STR00010## wherein R2 and R4 have the same meaning as mentioned
above, and R1'' represents a hydrogen atom or a substituted or
unsubstituted lower alkyl group.
A compound (Ic) of the present invention can be synthesized from a
compound (Ia''), which is a compound (Ia) wherein R1 is a
substituted or unsubstituted lower alkyl ester group and R3 is
hydrogen, using known methods (see, for example, Sheng-Chu Kuo et
al., Chem. Pharm. Bull., 38 (2), 340-341 (1990)) or their modified
methods.
The reaction can be carried out by heating a solution or suspension
of a compound (Ia'') in N,N-dimethylformamide or
N,N-dimethylacetamide at a temperature between 100.degree. C. and
the boiling point of the solvent used and for a period of 1 to 24
hours. Preferably, the reaction can be carried out for 1 to 12
hours under reflux conditions, thereby to synthesize the
compound.
This reaction can also be carried out by heating and stirring in
the presence of a base. For example, the reaction can be carried
out by heating to reflux in an alcohol solvent, such as ethanol, in
the presence of a highly-concentrated aqueous solution of potassium
hydroxide, thereby to synthesize compound.
Moreover, a compound (I) of the present invention which has a
desired functional group at a desired position can be obtained by
combining the above-mentioned methods as appropriate and carrying
out procedures usually used in organic synthetic chemistry (for
example, reactions for alkylation of amino groups, reactions for
oxidation of an alkylthio group to the corresponding sulfoxide or
sulfone group, reactions for converting an alkoxy group to a
hydroxy group or vice versa).
Compounds (I) of the present invention or pharmaceutically
acceptable salts thereof can be used as medicines, particularly
anti-tumor agents, in the form of conventional pharmaceutical
preparations for oral administration or for parenteral
administration, such as instillation.
Pharmaceutical preparations for oral administration include solid
formulations, such as tablets, granules, powders, and capsules, and
liquid formulations, such as syrups. These formulations can be
prepared by conventional methods. Solid formulations can be
prepared using conventional pharmaceutical carriers like lactose,
starches such as corn starch, crystalline cellulose such as
microcrystalline cellulose, hydroxypropylcellulose, calcium
carboxymethylcellulose, talc, magnesium stearate, and others.
Capsules can be prepared by encapsulating the granules or powders
thus prepared. Syrups can be prepared by dissolving or suspending a
compound (I) of the present invention or a pharmaceutically
acceptable salt thereof in an aqueous solution containing sucrose,
carboxymethylcellulose, or the like.
Pharmaceutical preparations for parenteral administration include
formulations for injection, such as instillation. Formulations for
injection can also be prepared by conventional methods, and may be
incorporated in tonicity adjusting agents (for example, mannitol,
sodium chloride, glucose, sorbitol, glycerol, xylitol, fructose,
maltose, mannose), stabilizing agents (for example, sodium sulfite,
albumin), antiseptics (for example, benzyl alcohol, methyl
p-hydroxybenzoate) as appropriate.
Compounds (I) of the present invention or pharmaceutically
acceptable salts thereof are effective for medicines, particularly
for the treatment of tumors. Tumors include solid tumors, such as
breast cancer, colon cancer, and lung cancer, and hematological
cancers, such as leukemia, lymphoma, and myeloma.
The amount of dosage of a compound (I) of the present invention or
a pharmaceutically acceptable salt thereof can be varied, according
to the severeness of the disease, the age and body weight of the
patient, its dosage form, and others, and usually is in the range
of 1 mg to 1,000 mg per day for adult humans, which can be
administered once, or twice or thrice by oral route or by
parenteral route.
EXAMPLES
The present invention will be more specifically described below by
way of Examples and Test Examples, which are not intended to limit
the present invention.
The identification of compounds was performed with hydrogen nuclear
magnetic resonance (.sup.1H-NMR) spectra and mass spectra (MS).
.sup.1H-NMR spectra were measured at 400 MHz, unless otherwise
specified. In the .sup.1H-NMR spectra, exchangeable hydrogens are
sometimes not clearly observed, depending on the compound being
measured and on the measurement conditions, and br denotes a broad
signal. HPLC preparative chromatography was carried out using a
commercial available ODS column, and fractions were collected using
a water/methanol system (containing formic acid) as an eluent in a
gradient mode, unless otherwise specified.
Example 1
Ethyl
5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-4-oxo-2-(phenylamino)-4-
,5-dihydrofuran-3-carboxylate
##STR00011##
To a solution of 7-azaindole-3-carboxaldehyde (0.10 g, 0.70 mmol)
and ethyl 4-oxo-2-(phenylamino)-4,5-dihydrofuran-3-carboxylate
(0.18 g, 0.70 mmol) in ethanol (3.0 mL), piperidine (0.083 mL, 0.84
mmol) was added at ambient temperature. The mixture was refluxed
for 12 h. Cooled to ambient temperature, the precipitate was
collected by filtration, washed with cold ethanol and isopropyl
ether then dried to afford the titled compound (0.13 g, y.
48%).
.sup.1H NMR (DMSO-d.sub.6) .delta. (ppm) 12.30 (br. s, 1H), 10.58
(s, 1H), 8.23 (dd, J=1.25, 4.52 Hz, 1H), 7.98 (d, J=7.28 Hz, 1H),
7.79 (d, J=2.76 Hz, 1H), 7.52-7.64 (m, 4H), 7.43-7.51 (m, 1H),
6.80-6.99 (m, 2H), 4.28 (q, J=7.03 Hz, 2H), 1.30 (t, J=7.03 Hz,
3H); LCMS (m/z): 376.0 [M+H].sup.+.
Example 2
Ethyl
5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-[(4-methoxyphenyl)ami-
no]-4-oxo-4,5-dihydrofuran-3-carboxylate
##STR00012## First Step
Under a nitrogen atmosphere, to a mixed solution of ethyl
4-chloroacetoacetate (0.82 mL, 6.0 mmol) and 4-methoxyphenyl
isocyanate 1.1 g, 7.2 mmol) in diethyl ether/ethyl acetate (10
mL/1.0 mL) that cooled with ice bath, triethylamine (0.96 mL, 6.9
mmol) was added dropwise. The reaction mixture was stirred at
ambient temperature for 1.5 h then the precipitate was collected by
filtration, washed with diethyl ether, 1M hydrochloric acid
solution, water and diethyl ether, and then dried to afford ethyl
2-[(4-methoxyphenyl)amino]-4-oxo-4,5-dihydrofuran-3-carboxylate as
solid (1.3 g, y. 78%).
.sup.1H NMR (CDCl.sub.3) .delta. (ppm) 10.11 (br. s, 1H), 7.24-7.33
(m, 2H), 6.90-6.96 (m, 2H), 4.65 (s, 2H), 4.38 (q, J=7.07 Hz, 2H),
3.83 (s, 3H), 1.40 (t, J=7.20 Hz, 3H); LCMS (m/z): 277.9
[M+H].sup.+.
Second Step
To a solution of ethyl
2-[(4-methoxyphenyl)amino]-4-oxo-4,5-dihydrofuran-3-carboxylate
(0.28 g, 1.0 mmol) and 7-azaindole-3-carboxaldehyde (0.15 g, 1.0
mmol) in ethanol (4.0 mL), piperidine (0.12 mL, 1.2 mmol) was added
at ambient temperature. The mixture was refluxed for 12 h. Cooled
to ambient temperature, the precipitate was collected by
filtration, washed with ethanol and diisopropyl ether then dried to
afford the titled compound (0.092 g, y. 22%).
.sup.1H NMR (DMSO-d.sub.6) .delta. (ppm) 12.31 (br. s, 1H), 10.47
(s, 1H), 8.24 (dd, J=1.51, 4.52 Hz, 1H), 7.94 (d, J=7.53 Hz, 1H),
7.77 (d, J=2.76 Hz, 1H), 7.50 (d, J=9.03 Hz, 2H), 7.09 (d, J=8.78
Hz, 2H), 6.81-6.92 (m, 2H), 4.26 (q, J=7.03 Hz, 2H), 3.87 (s, 3H),
1.29 (t, J=7.03 Hz, 3H); LCMS (m/z): 406.0 [M+H].sup.+.
Example 3
Ethyl
5-[(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-4-oxo-2-(pheny-
lamino)-4,5-dihydrofuran-3-carboxylate
##STR00013## First Step
To a mixed solution of 2-amino-5-chloropyridine (2.6 g, 0.020 mol)
in acetic acid/water (7.8 mL/1.8 mL) that cooled with ice bath,
conc.sulfuric acid (0.26 mL, 4.9 mmol) was added dropwise, and then
periodic acid (0.95 g, 4.2 mmol) and iodine (2.0 g, 8.0 mmol) were
added. The reaction mixture was stirred at 80.degree. C. for 6 h.
Cooled to ambient temperature, the reaction mixture was poured into
ice water, and neutralized by aqueous 5M sodium hydroxide solution.
After removal of the precipitate by filtration, the filtrate was
extracted with ethyl acetate. The organic layer was washed with
saturated sodium thiosulfate solution, aqueous 1M sodium hydroxide
solution and brine then dried over sodium sulfate and concentrated
to afford 2-amino-5-chloro-3-iodopyridine as solid (4.4 g, y.
85%).
.sup.1H NMR (CDCl.sub.3) .delta. (ppm) 7.96 (s, 1H), 7.82 (s, 1H),
4.93 (s, 2H); LCMS (m/z) 255.2 [M+H].sup.+.
Second Step
Under a nitrogen atmosphere, to a solution of
2-amino-5-chloro-3-iodopyridine (4.2 g, 0.017 mol), copper(I)
iodide (0.032 g, 0.17 mmol) and triethylamine (7.0 mL, 0.050 mol)
in anhydrous tetrahydrofuran (10 mL),
dichlorobis(triphenylphosphine)palladium(II) (0.12 g, 0.17 mmol)
and ethynyl trimethylsilane (3.0 mL, 0.021 mol) were added and the
mixture was stirred at ambient temperature for 2 h. The reaction
mixture was diluted with diethyl ether and removed the precipitate
by filtration with C elite. The filtrate was concentrated to afford
2-amino-5-chloro-3-[(trimethylsilyl)ethynyl]pyridine as solid (4.2
g).
.sup.1H NMR (CDCl.sub.3) .delta. (ppm) 7.94 (d, 1H, J=2.28 Hz),
7.49 (d, 1H, J=2.32 Hz), 5.02 (s, 2H), 0.18-0.25 (m, 9H); LCMS
(m/z): 225.5 [M+H].sup.+.
Third Step
Under a nitrogen atmosphere, to a solution of potassium
tert-butoxide (4.0 g, 0.036 mol) in 1-methyl-2-pyrrolidone (8.0 mL)
which stirred with heating at 80.degree. C., a solution of
2-amino-5-chloro-3-[(trimethylsilyl)ethynyl]pyridine (4.0 g, 0.018
mol) in 1-methyl-2-pyrrolidone (22 mL) was added dropwise and the
mixture was stirred for 1 h. Cooled to ambient temperature, the
reaction mixture was diluted with brine and stirred, then extracted
with diethyl ether for 3 times. The organic layer was washed with
brine, dried over sodium sulfate and concentrated to afford
5-chloro-7-azaindole as solid (2.3 g, y. 85%).
.sup.1H NMR (CDCl.sub.3) .delta. (ppm) 9.46 (s, 1H), 8.26 (s, 1H),
7.91 (d, 1H, J=1.12 Hz), 7.35 (s, 1H), 6.46 (s, 1H); LCMS (m/z):
153.2 [M+H].sup.+.
Fourth Step
To a solution of 5-chloro-7-azaindole (0.50 g, 3.3 mmol) in acetic
acid (5.0 mL), hexamethylenetetramine (0.69 g, 4.9 mmol) was added
at ambient temperature. The mixture was refluxed for 8 h. Cooled to
ambient temperature, the reaction mixture was diluted with water,
extracted with ethyl acetate for 2 times. The organic layer was
washed with water and brine, dried over sodium sulfate and
concentrated. The residue was purified by chromatography on silica
gel(hexane/ethyl acetate) to afford
5-chloro-7-azaindole-3-carboxaldehyde as solid (0.13 g, y.
22%).
.sup.1H NMR (CDCl.sub.3) .delta. (ppm) 10.01 (s, 1H), 9.77 (br. s,
1H), 8.61 (d, 1H, J=2.04 Hz), 8.37 (d, 1H, J=2.08 Hz), 7.99 (d, 1H,
J=2.64 Hz); LCMS (m/z): 181.2 [M+H].sup.+.
Fifth Step
To a solution of 5-chloro-7-azaindole-3-carboxaldehyde (0.019 g,
0.11 mmol) and ethyl
4-oxo-2-(phenylamino)-4,5-dihydrofuran-3-carboxylate (0.025 g, 0.10
mmol) in ethanol (1.0 mL), piperidine (0.012 mL, 0.12 mmol) was
added at ambient temperature. The mixture was refluxed for 2 days.
Cooled to ambient temperature, solvents were removed under reduced
pressure then the residue was purified by preparative HPLC to
afford the titled compound (0.0020 g, y. 4.6%).
.sup.1H NMR (DMSO-d.sub.6) .delta. (ppm) 12.52 (br. s, 1H), 10.58
(s, 1H), 8.42 (d, J=2.26 Hz, 1H), 8.26 (d, J=2.26 Hz, 1H), 7.71 (d,
J=2.51 Hz, 1H), 7.55-7.63 (m, 2H), 7.51 (t, J=7.78 Hz, 2H),
7.35-7.44 (m, 1H), 7.00 (s, 1H), 4.28 (q, J=7.03 Hz, 2H), 1.30 (t,
J=7.15 Hz, 3H); LCMS (m/z): 410.0 [M+H].sup.+.
Example 4
Ethyl
5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-4-oxo-2-piperidino-4,5--
dihydrofuran-3-carboxylate
##STR00014## First Step
Diethyl malonate (5.0 mL, 0.033 mol) was added dropwise to a
solution of sodium hydride (60% w/w in oil, 2.7 g, 0.066 mol) in
anhydrous tetrahydrofuran (50 mL) that cooled with ice bath. The
mixture was refluxed for 5 min. The reaction mixture was cooled
with ice bath, chloroacetyl chloride (2.8 mL, 0.035 mol) was added
dropwise to the reaction mixture and the mixture was stirred for 1
h then stirred at 45.degree. C. for 1 h. The reaction mixture was
cooled with ice bath again then piperidine (3.9 mL, 0.040 mol) was
added dropwise and stirred at ambient temperature for further 12 h.
The reaction mixture was diluted with aqueous saturated sodium
bicarbonate solution, and extracted with ethyl acetate for 2 times
then extracted with chloroform. The organic layer was washed with
brine, dried over sodium sulfate and concentrated. The residue was
purified by chromatography on silica gel(chloroform/methanol) to
afford ethyl 4-oxo-2-piperidino-4,5-dihydrofuran-3-carboxylate as
solid (3.5 g, y. 45%).
.sup.1H NMR (DMSO-d.sub.6) .delta. (ppm) 4.53 (s, 2H), 4.10 (q,
J=7.03 Hz, 2H), 3.48-3.60 (m, 4H), 1.56-1.67 (m, 6H), 1.20 (t,
J=7.03 Hz, 16H); LCMS (m/z): 240.0 [M+H].sup.+.
Second Step
To a solution of ethyl
4-oxo-2-piperidino-4,5-dihydrofuran-3-carboxylate (0.10 g, 0.42
mmol) and 7-azaindole-3-carboxaldehyde (0.061 g, 0.42 mmol) in
ethanol (2.0 mL), piperidine (0.041 mL, 0.42 mmol) was added at
ambient temperature. The mixture was refluxed for 24 h. Cooled to
ambient temperature, the precipitate was collected by filtration,
washed with ethanol and diisopropyl ether then dried to afford the
titled compound (0.045 g, y. 29%).
.sup.1H NMR (DMSO-d.sub.6) .delta. (ppm) 12.29 (br. s, 1H), 8.37
(dd, J=1.25, 8.03 Hz, 1H), 8.31 (dd, J=1.51, 4.52 Hz, 1H), 7.96 (d,
J=2.76 Hz, 1H), 7.19 (dd, J=4.64, 7.91 Hz, 1H), 6.84 (s, 1H), 4.16
(q, J=7.19 Hz, 2H), 3.70-3.80 (m, 4H), 1.65-1.78 (m, 6H), 1.24 (t,
J=7.03 Hz, 3H); LCMS (m/z): 368.0 [M+H].sup.+.
Example 5
Ethyl
5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-[(3-methoxyphenyl)ami-
no]-4-oxo-4,5-dihydrofuran-3-carboxylate
##STR00015##
To a solution of ethyl
2-[(3-methoxyphenyl)amino]-4-oxo-4,5-dihydrofuran-3-carboxylate
(0.28 g, 1.0 mmol) which similarly prepared according to the
procedure described in the Example 2, First step and
7-azaindole-3-carboxaldehyde (0.15 g, 1.2 mmol) in ethanol (4.0
mL), piperidine (0.12 mL, 1.2 mmol) was added at ambient
temperature. The mixture was refluxed for 2 days. Cooled to ambient
temperature, the precipitate was collected by filtration, washed
with ethanol and diisopropyl ether then dried to afford the titled
compound (0.17 g, y. 29%).
.sup.1H NMR (DMSO-d.sub.6) .delta. (ppm) 12.34 (br. s, 1H), 10.52
(s, 1H), 8.25 (dd, J=1.38, 4.64 Hz, 1H), 8.03 (d, J=7.03 Hz, 1H),
7.84 (d, J=2.76 Hz, 1H), 7.45 (t, J=8.03 Hz, 1H), 7.13-7.26 (m,
2H), 7.04 (dd, J=2.01, 8.28 Hz, 1H), 6.86-6.95 (m, 2H), 4.27 (q,
J=7.03 Hz, 2H), 3.77 (s, 3H), 1.30 (t, J=7.15 Hz, 3H); LCMS (m/z):
406.0 [M+H].sup.+.
Example 6
Ethyl
5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-4-oxo-2-(2-pyridinylami-
no)-4,5-dihydrofuran-3-carboxylate
##STR00016##
To a solution of ethyl
4-oxo-2-(2-pyridinylamino)-4,5-dihydrofuran-3-carboxylate (0.080 g,
0.32 mmol) which similarly prepared according to the procedure
described in the Example 4, First step and
7-azaindole-3-carboxaldehyde (0.047 g, 0.32 mmol) in ethanol (2.0
mL), piperidine (0.038 mL, 0.39 mmol) was added at ambient
temperature. The mixture was refluxed for 10 h. Cooled to ambient
temperature, the precipitate was removed by filtration and the
filtrate was purified by preparative HPLC to afford the titled
compound as solid (0.0030 g, y. 2.5%).
.sup.1H NMR (DMSO-d.sub.6) .delta. (ppm) 12.41 (br. s, 1H), 10.74
(br. s, 1H), 8.60 (d, J=3.26 Hz, 1H), 8.35 (d, J=7.78 Hz, 1H), 8.30
(dd, J=1.38, 4.64 Hz, 1H), 8.24 (br. s, 1H), 7.97 (dt, J=1.88, 7.84
Hz, 1H), 7.61 (d, J=8.03 Hz, 1H), 7.36-7.45 (m, 1H), 7.02-7.14 (m,
2H), 4.27 (q, J=7.03 Hz, 2H), 1.29 (t, J=7.03 Hz, 3H); LCMS (m/z):
377.0 [M+H].sup.+.
Example 7
Ethyl
5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-[(2-methoxyphenyl)ami-
no]-4-oxo-4,5-dihydrofuran-3-carboxylate
##STR00017##
To a solution of ethyl
2-[(2-methoxyphenyl)amino]-4-oxo-4,5-dihydrofuran-3-carboxylate
(0.28 g, 1.0 mmol) which similarly prepared according to the
procedure described in the Example 2, First step and
7-azaindole-3-carboxaldehyde (0.15 g, 1.2 mmol) in ethanol (4.0
mL), piperidine (0.12 mL, 1.2 mmol) was added at ambient
temperature. The mixture was refluxed for 2 days. Cooled to ambient
temperature, the precipitate was collected by filtration, washed
with ethanol and diisopropyl ether then dried to afford the titled
compound (0.30 g, y. 74%).
.sup.1H NMR (DMSO-d.sub.6) .delta. (ppm) 12.34 (br. s, 1H), 10.35
(s, 1H), 8.25 (dd, J=1.38, 4.64 Hz, 1H), 8.02 (d, J=7.03 Hz, 1H),
7.85 (d, J=2.76 Hz, 1H), 7.66 (dd, J=1.38, 7.91 Hz, 1H), 7.41-7.51
(m, 1H), 7.28 (d, J=7.53 Hz, 1H), 7.12 (t, J=7.65 Hz, 1H),
6.88-6.99 (m, 2H), 4.28 (q, J=7.03 Hz, 2H), 3.85 (s, 3H), 1.30 (t,
J=7.15 Hz, 3H); LCMS (m/z): 406.0 [M+H].sup.+.
Example 8
Ethyl
5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-[(4-chlorophenyl)amin-
o]-4-oxo-4,5-dihydrofuran-3-carboxylate
##STR00018##
To a solution of ethyl
2-[(4-chlorophenyl)amino]-4-oxo-4,5-dihydrofuran-3-carboxylate
(0.18 g, 0.61 mmol) which similarly prepared according to the
procedure described in the Example 2, First step and
7-azaindole-3-carboxaldehyde (0.088 g, 0.61 mmol) in ethanol (10
mL), piperidine (0.0044 mL, 0.044 mmol) was added at ambient
temperature. The mixture was refluxed for 6 days. Cooled to ambient
temperature, the precipitate was collected by filtration, washed
with ethanol and hexane then dried to afford the titled compound
(0.061 g, y. 23%).
.sup.1H NMR (DMSO-d.sub.6) .delta. (ppm) 12.33 (br. s, 1H), 10.61
(s, 1H), 8.26 (d, J=3.26 Hz, 1H), 7.96 (d, J=7.53 Hz, 1H), 7.82 (d,
J=2.76 Hz, 1H), 7.58-7.67 (m, 4H), 6.87-6.95 (m, 2H), 4.27 (q,
J=7.03 Hz, 2H), 1.29 (t, J=7.03 Hz, 3H); LCMS (m/z): 409.9
[M+H].sup.+.
Example 9
Ethyl
5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-[(3-chlorophenyl)amin-
o]-4-oxo-4,5-dihydrofuran-3-carboxylate
##STR00019##
To a solution of ethyl
2-[(3-chlorophenyl)amino]-4-oxo-4,5-dihydrofuran-3-carboxylate
(0.10 g, 0.36 mmol) which similarly prepared according to the
procedure described in the Example 2, First step and
7-azaindole-3-carboxaldehyde (0.051 g, 0.35 mmol) in ethanol (3.0
mL), piperidine (0.0035 mL, 0.035 mmol) was added at ambient
temperature. The mixture was refluxed for 6 days. Cooled to ambient
temperature, the precipitate was collected by filtration, washed
with ethanol then dried to afford the titled compound (0.061 g, y.
23%).
.sup.1H NMR (DMSO-d.sub.6) .delta. (ppm) 12.36 (br. s, 1H), 10.63
(s, 1H), 8.26 (dd, J=1.38, 4.64 Hz, 1H), 8.01 (d, J=7.28 Hz, 1H),
7.82 (d, J=2.76 Hz, 1H), 7.76 (s, 1H), 7.50-7.61 (m, 3H), 6.89-6.96
(m, 2H), 4.28 (q, J=7.03 Hz, 2H), 1.30 (t, J=7.03 Hz, 3H); LCMS
(m/z): 409.9 [M+H].sup.+.
Example 10
Ethyl
5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-(benzylamino)-4-oxo-4-
,5-dihydrofuran-3-carboxylate hydrochloride
##STR00020##
A solution of ethyl
2-(benzylamino)-4-oxo-4,5-dihydrofuran-3-carboxylate (0.026 g, 0.10
mmol) which similarly prepared according to the procedure described
in the Example 2, First step and 7-azaindole-3-carboxaldehyde
(0.015 g, 0.10 mmol) in 2M hydrochloric acid in ethanol (1.0 mL)
was refluxed for 4 h. Cooled to ambient temperature, the
precipitate was collected by filtration, washed with ethanol and
diisopropyl ether then dried to afford the titled compound (0.024
g, y. 56%).
.sup.1H NMR (DMSO-d.sub.6) .delta. (ppm) 12.25-12.56 (m, 1H), 9.54
(br. s, 1H), 8.25-8.42 (m, 2H), 7.86 (s, 1H), 7.35-7.48 (m, 4H),
7.24-7.33 (m, 1H), 7.08-7.18 (m, 1H), 6.87 (s, 1H), 4.86 (d, J=6.53
Hz, 2H), 4.23 (q, J=7.19 Hz, 2H), 1.27 (t, J=7.03 Hz, 3H); LCMS
(m/z): 390.0 [M+H].sup.+.
Example 11
5-[(1H-Pyrrolo[2,3-b]pyridin-3-yl)methylene]-4-oxo-2-piperidino-4,5-dihydr-
ofuran-3-carboxylic acid
##STR00021##
To a solution of the compound of Example 4 in dioxane (0.5 mL), 2M
sodium hydroxide solution (0.50 mL, 1.0 mmol) was added at ambient
temperature. The mixture was stirred at 110.degree. C. for 1.5 h.
Cooled to ambient temperature, the reaction mixture was neutralized
by 2M hydrochloric acid solution then the solvent was removed under
reduced pressure. The residue was purified by preparative HPLC to
afford the titled compound (0.0044 g, y. 45%).
.sup.1H NMR (DMSO-d.sub.6) .delta. (ppm) 12.24 (br. s, 1H), 8.39
(d, J=8.03 Hz, 1H), 8.30 (dd, J=1.38, 4.64 Hz, 1H), 7.92 (d, J=2.26
Hz, 1H), 7.19 (dd, J=4.77, 8.03 Hz, 1H), 6.73 (s, 1H), 3.35-3.62
(m, 4H), 1.45-1.69 (m, 6H); LCMS (m/z): 339.9 [M+H].sup.+.
Example 12
Ethyl
5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-(ethylamino)-4-oxo-4,-
5-dihydrofuran-3-carboxylate hydrochloride
##STR00022##
To a solution of ethyl
2-(ethylamino)-4-oxo-4,5-dihydrofuran-3-carboxylate (0.033 g, 0.17
mmol) which similarly prepared according to the procedure described
in the Example 2, First step and 7-azaindole-3-carboxaldehyde
(0.024 g, 0.17 mmol) in ethanol (1.5 mL), 2M hydrochloric acid in
ethanol (0.17 mL, 0.34 mmol) was added at ambient temperature. The
mixture was refluxed for 4 h. Cooled to ambient temperature, the
precipitate was collected by filtration, washed with ethanol and
diisopropyl ether then dried to afford the titled compound (0.026
g, y. 42%).
.sup.1H NMR (DMSO-d.sub.6) .delta. (ppm) 12.46 (br. s, 1H), 9.03
(t, J=6.02 Hz, 1H), 8.45-8.54 (m, 1H), 8.35 (dd, J=1.25, 4.77 Hz,
1H), 8.01 (d, J=1.25 Hz, 1H), 7.25 (dd, J=4.77, 8.03 Hz, 1H), 6.90
(s, 1H), 4.25-4.50 (m, 1H), 4.21 (q, J=7.19 Hz, 2H), 3.61-3.71 (m,
2H), 1.30 (t, J=7.15 Hz, 3H), 1.26 (t, J=7.03 Hz, 3H); LCMS (m/z):
328.0 [M+H].sup.+.
Example 13
Ethyl
5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-4-oxo-2-(phenethylamino-
)-4,5-dihydrofuran-3-carboxylate hydrochloride
##STR00023##
To a solution of ethyl
4-oxo-2-(phenethylamino)-4,5-dihydrofuran-3-carboxylate (0.041 g,
0.15 mmol) which similarly prepared according to the procedure
described in the Example 4, First step and
7-azaindole-3-carboxaldehyde (0.022 g, 0.15 mmol) in ethanol (1.0
mL), 2M hydrochloric acid in ethanol (0.16 mL, 0.32 mmol) was added
at ambient temperature. The mixture was refluxed for 3 h. Cooled to
ambient temperature, the precipitate was collected by filtration,
washed with ethanol and diisopropyl ether then dried to afford the
titled compound (0.023 g, y. 32%).
.sup.1H NMR (DMSO-d.sub.6) .delta. (ppm) 12.45 (br. s, 1H), 9.02
(t, J=6.15 Hz, 1H), 8.40 (d, J=6.78 Hz, 1H), 8.33 (dd, J=1.38, 4.64
Hz, 1H), 7.94 (d, J=2.26 Hz, 1H), 7.23-7.33 (m, 4H), 7.11-7.22 (m,
2H), 6.84 (s, 1H), 4.21 (q, J=7.19 Hz, 2H), 3.85 (q, J=6.94 Hz,
2H), 3.00 (t, J=7.28 Hz, 2H), 1.25 (t, J=7.03 Hz, 3H); LCMS (m/z):
404.0 [M+H].sup.+.
Example 14
Ethyl
5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-4-oxo-2-pyrrolidinyl-4,-
5-dihydrofuran-3-carboxylate hydrochloride
##STR00024##
To a solution of ethyl
4-oxo-2-pyrrolidinyl-4,5-dihydrofuran-3-carboxylate (0.034 g, 0.15
mmol) which similarly prepared according to the procedure described
in the Example 4, First step and 7-azaindole-3-carboxaldehyde
(0.022 g, 0.15 mmol) in ethanol (1.0 mL), 2M hydrochloric acid in
ethanol (0.16 mL, 0.32 mmol) was added at ambient temperature. The
mixture was refluxed for 3 h. Cooled to ambient temperature, the
precipitate was collected by filtration, washed with ethanol and
diisopropyl ether then dried to afford the titled compound (0.038
g, y. 61%).
.sup.1H NMR (DMSO-d.sub.6) .delta. (ppm) 12.38 (br. s, 1H), 8.46
(d, J=8.03 Hz, 1H), 8.33 (dd, J=1.38, 4.64 Hz, 1H), 7.95 (d, J=2.26
Hz, 1H), 7.23 (dd, J=4.77, 7.78 Hz, 1H), 6.84 (s, 1H), 4.16 (q,
J=7.03 Hz, 2H), 3.79-3.98 (m, 3H), 3.63-3.73 (m, 2H), 1.92-2.05 (m,
4H), 1.24 (t, J=7.03 Hz, 3H); LCMS (m/z): 354.0 [M+H].sup.+.
Example 15
Ethyl
5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-[(2-chlorophenyl)amin-
o]-4-oxo-4,5-dihydrofuran-3-carboxylate
##STR00025##
To a solution of ethyl
2[(2-chlorophenyl)amino]-4-oxo-4,5-dihydrofuran-3-carboxylate (0.14
g, 0.50 mmol) which similarly prepared according to the procedure
described in the Example 2, First step and
7-azaindole-3-carboxaldehyde (0.073 g, 0.50 mmol) in ethanol (2.0
mL), piperidine (0.054 mL, 0.55 mmol) was added at ambient
temperature. The mixture was refluxed for 12 h. Cooled to ambient
temperature, the precipitate was collected by filtration, washed
with ethanol and diisopropyl ether then dried to afford the titled
compound (0.099 g, y. 48%).
.sup.1H NMR (DMSO-d.sub.6) .delta. (ppm) 12.31 (br. s, 1H), 10.65
(s, 1H), 8.22 (dd, J=1.38, 4.64 Hz, 1H), 7.70-7.83 (m, 4H),
7.51-7.64 (m, 2H), 6.92 (s, 1H), 6.81 (dd, J=4.64, 7.91 Hz, 1H),
4.29 (q, J=7.11 Hz, 2H), 1.30 (t, J=7.03 Hz, 3H); LCMS (m/z): 409.8
[M+H].sup.+.
Example 16
Ethyl
5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-{[4-(dimethylamino)ph-
enyl]amino}-4-oxo-4,5-dihydrofuran-3-carboxylate hydrochloride
##STR00026##
To a solution of ethyl
2-{[4-(dimethylamino)phenyl]amino}-4-oxo-4,5-dihydrofuran-3-carboxylate
(0.073 g, 0.20 mmol) which similarly prepared according to the
procedure described in the Example 2, First step and
7-azaindole-3-carboxaldehyde (0.029 g, 0.20 mmol) in ethanol (1.5
mL), 2M hydrochloric acid in ethanol (0.33 mL, 0.66 mmol) was added
at ambient temperature. The mixture was refluxed for 1 h. Cooled to
ambient temperature, the precipitate was collected by filtration,
washed with ethanol and diisopropyl ether then dried to afford the
titled compound (0.034 g, y. 35%).
.sup.1H NMR (DMSO-d.sub.6) .delta. (ppm) 12.51 (br. s, 1H), 10.47
(br. s, 1H), 8.23-8.33 (m, 1H), 8.10 (d, J=7.78 Hz, 1H), 7.81 (s,
1H), 7.50 (d, J=8.03 Hz, 2H), 7.16 (br. s, 2H), 6.95 (dd, J=4.77,
7.78 Hz, 1H), 6.90 (s, 1H), 4.40-5.20 (m, 1H), 4.27 (q, J=7.03 Hz,
2H), 3.08 (s, 6H), 1.29 (t, J=7.15 Hz, 3H); LCMS (m/z): 419.0
[M+H].sup.+.
Example 17
Ethyl
5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-(diethylamino)-4-oxo--
4,5-dihydrofuran-3-carboxylate hydrochloride
##STR00027##
To a solution of ethyl
2-(diethylamino)-4-oxo-4,5-dihydrofuran-3-carboxylate (0.034 g,
0.15 mmol) which similarly prepared according to the procedure
described in the Example 4, First step and
7-azaindole-3-carboxaldehyde (0.022 g, 0.15 mmol) in ethanol (1.0
mL), 2M hydrochloric acid in ethanol (0.16 mL, 0.32 mmol) was added
at ambient temperature. The mixture was refluxed for 3 h. Cooled to
ambient temperature, the precipitate was collected by filtration,
washed with ethanol and diisopropyl ether then dried to afford the
titled compound (0.023 g, y. 38%).
.sup.1H NMR (DMSO-d.sub.6) .delta. (ppm) 12.36 (br. s, 1H), 8.41
(d, J=7.78 Hz, 1H), 8.33 (dd, J=1.25, 4.77 Hz, 1H), 7.93 (d, J=2.26
Hz, 1H), 7.22 (dd, J=4.77, 7.78 Hz, 1H), 6.84 (s, 1H), 4.18 (q,
J=7.11 Hz, 2H), 3.50-3.84 (m, 5H), 1.11-1.38 (m, 9H); LCMS (m/z):
356.0 [M+H].sup.+.
Example 18
Ethyl
5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-(cyclohexylamino)-4-o-
xo-4,5-dihydrofuran-3-carboxylate hydrochloride
##STR00028##
To a solution of ethyl
2-(cyclohexylamino)-4-oxo-4,5-dihydrofuran-3-carboxylate (0.019 g,
0.075 mmol) which similarly prepared according to the procedure
described in the Example 2, First step and
7-azaindole-3-carboxaldehyde (0.011 g, 0.075 mmol) in ethanol (1.0
mL), 2M hydrochloric acid in ethanol (0.079 mL, 0.16 mmol) was
added at ambient temperature. The mixture was refluxed for 4 h.
Cooled to ambient temperature, the precipitate was collected by
filtration, washed with ethanol and diisopropyl ether then dried to
afford the titled compound (0.0070 g, y. 22%).
.sup.1H NMR (DMSO-d.sub.6) .delta. (ppm) 12.40 (br. s, 1H), 8.53
(d, J=8.53 Hz, 1H), 8.46 (d, J=7.78 Hz, 1H), 8.34 (dd, J=1.26, 4.52
Hz, 1H), 7.99 (d, J=2.26 Hz, 1H), 7.22 (dd, J=4.64, 7.91 Hz, 1H),
6.90 (s, 1H), 4.21 (q, J=7.03 Hz, 2H), 3.91-4.09 (m, 1H), 1.98 (d,
J=9.79 Hz, 2H), 1.79 (d, J=13.05 Hz, 2H), 1.55-1.70 (m, 3H),
1.35-1.49 (m, 2H), 1.16-1.29 (m, 4H); LCMS (m/z): 382.4
[M+H].sup.+.
Example 19
Ethyl
5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-[(4-bromophenyl)amino-
]-4-oxo-4,5-dihydrofuran-3-carboxylate
##STR00029##
To a solution of ethyl
2-[(4-bromophenyl)amino]-4-oxo-4,5-dihydrofuran-3-carboxylate (0.15
g, 0.46 mmol) which similarly prepared according to the procedure
described in the Example 4, First step and
7-azaindole-3-carboxaldehyde (0.067 g, 0.46 mmol) in ethanol (5.0
mL), piperidine (0.85 mL, 0.92 mmol) was added at ambient
temperature. The mixture was refluxed for 24 h. Cooled to ambient
temperature, the precipitate was collected by filtration, washed
with ethanol then dried to afford the titled compound (0.075 g, y.
36%).
.sup.1H NMR (DMSO-d.sub.6) .delta. (ppm) 12.34 (br. s, 1H), 10.61
(br. s, 1H), 8.26 (d, J=3.42 Hz, 1H), 7.95 (d, J=7.34 Hz, 1H), 7.84
(br. s, 1H), 7.72 (d, J=8.31 Hz, 2H), 7.57 (d, J=8.31 Hz, 2H),
6.77-7.05 (m, 2H), 4.07-4.42 (m, 2H), 1.29 (t, J=6.85 Hz, 3H); LCMS
(m/z): 382.4 [M+H].sup.+.
Example 20
Ethyl
5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-4-oxo-2-(p-tolylamino)--
4,5-dihydrofuran-3-carboxylate
##STR00030##
The titled compound was similarly prepared according to the
procedure described in the Example 19.
.sup.1H NMR (DMSO-d.sub.6) .delta. (ppm) 12.30 (br. s, 1H), 10.51
(br. s, 1H), 8.24 (d, J=3.42 Hz, 1H), 7.97 (d, J=7.34 Hz, 1H), 7.80
(br. s, 1H), 7.46 (d, J=7.82 Hz, 2H), 7.34 (d, J=8.31 Hz, 2H),
6.74-7.02 (m, 2H), 4.14-4.37 (m, 2H), 2.44 (s, 3H), 1.29 (t, J=6.85
Hz, 3H); LCMS (m/z): 390.6 [M+H].sup.+.
Example 21
Ethyl
5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-[(4-fluorophenyl)amin-
o]-4-oxo-4,5-dihydrofuran-3-carboxylate
##STR00031##
The titled compound (solid) was similarly prepared according to the
procedure described in the Example 19.
.sup.1H NMR (DMSO-d.sub.6) .delta. (ppm) 12.28 (br. s, 1H), 10.57
(br. s, 1H), 8.24 (br. s, 1H), 7.95 (d, J=7.82 Hz, 1H), 7.75 (br.
s, 1H), 7.60-7.68 (m, 2H), 7.38 (t, J=8.31 Hz, 2H), 6.85-6.93 (m,
2H), 4.11-4.50 (m, 2H), 1.29 (t, J=6.85 Hz, 3H); LCMS (m/z): 394.2
[M+H].sup.+.
Example 22
5-[(1H-Pyrrolo[2,3-b]pyridin-3-yl)methylene]-4-oxo-2-(phenylamino)-4,5-dih-
ydrofuran-3-carboxylic acid
##STR00032##
To a solution of the compound (0.050 g, 0.13 mmol) of Example 1 in
ethanol (1.0 mL), 50% potassium hydroxide solution (0.5 mL, 0.13
mmol) was added at ambient temperature. The mixture was refluxed
for 1 h. Cooled to ambient temperature, the precipitate was
collected by filtration, washed with ethanol. The crude material
was dissolved in water (0.5 mL) and tetrahydrofuran (0.5 mL), then
2M hydrochloric acid (0.023 mL, 0.046 mmol) was added and the
mixture was stirred for 30 min. The precipitate was collected by
filtration, washed with water and diethyl ether then dried to
afford the titled compound (0.012 g, y. 26%).
.sup.1H NMR (DMSO-d.sub.6) .delta. (ppm) 12.11 (br. s, 2H), 8.21
(dd, J=1.25, 4.52 Hz, 1H), 8.06 (d, J=7.78 Hz, 1H), 7.73 (d, J=2.26
Hz, 1H), 7.38-7.49 (m, 2H), 7.32 (d, J=7.53 Hz, 2H), 7.19-7.27 (m,
1H), 6.91 (dd, J=4.64, 7.91 Hz, 1H), 6.66 (s, 1H); LCMS (m/z):
347.9 [M+H].sup.+.
Example 23
Ethyl
5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-[(2-hydroxyphenyl)ami-
no]-4-oxo-4,5-dihydrofuran-3-carboxylate
##STR00033##
To a solution of ethyl
2-[(2-hydroxyphenyl)amino]-4-oxo-4,5-dihydrofuran-3-carboxylate
(0.050 g, 0.19 mmol) which similarly prepared according to the
procedure described in the Example 4 and
7-azaindole-3-carboxaldehyde (0.023 g, 0.16 mmol) in ethanol (1.0
mL), piperidine (0.0010 mL, 0.010 mmol) was added at ambient
temperature. The mixture was refluxed for 2 days. The precipitate
was collected by filtration, washed with hot ethanol. The solid was
washed hexane then dried to afford the titled compound (0.008 g, y.
11%).
.sup.1H NMR (DMSO-d.sub.6) .delta. (ppm) 12.33 (br. s, 1H), 10.35
(s, 1H), 10.30 (s, 1H), 8.25 (dd, J=1.38, 4.64 Hz, 1H), 8.06 (d,
J=7.03 Hz, 1H), 7.87 (d, J=2.76 Hz, 1H), 7.58 (d, J=7.03 Hz, 1H),
7.24-7.33 (m, 1H), 7.07 (dd, J=1.00, 8.28 Hz, 1H), 6.90-7.01 (m,
3H), 4.28 (q, J=7.03 Hz, 2H), 1.30 (t, J=7.15 Hz, 3H); LCMS (m/z):
392.0 [M+H].sup.+.
Example 24
Ethyl
5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-[(2,4-dimethoxyphenyl-
)amino]-4-oxo-4,5-dihydrofuran-3-carboxylate
##STR00034##
To a solution of ethyl
2-[(2,4-dimethoxyphenyl)amino]-4-oxo-4,5-dihydrofuran-3-carboxylate
(0.35 g, 1.1 mmol) which similarly prepared according to the
procedure described in the Example 4, First step and
7-azaindole-3-carboxaldehyde (0.12 g, 1.1 mmol) in ethanol (10 mL),
piperidine (0.5 mL, 4.6 mmol) was added at ambient temperature. The
mixture was refluxed for 16 h. Cooled to ambient temperature, the
precipitate was collected by filtration, washed with ethanol then
dried to afford the titled compound (0.13 g, y. 26%).
.sup.1H NMR (DMSO-d.sub.6) .delta. (ppm) 12.31 (br. s, 1H), 10.14
(br. s, 1H), 8.24 (br. s, 1H), 7.94 (d, J=7.82 Hz, 1H), 7.80 (br.
s, 1H), 7.51 (d, J=8.80 Hz, 1H), 6.78-6.93 (m, 3H), 6.68 (d, J=8.31
Hz, 1H), 4.26 (d, J=6.85 Hz, 2H), 3.89 (s, 3H), 3.81 (s, 3H), 1.29
(t, J=6.60 Hz, 3H); LCMS (m/z): 436.2 [M+H].sup.+.
Example 25
Ethyl
5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-[(4-carbamoylphenyl)a-
mino]-4-oxo-4,5-dihydrofuran-3-carboxylate
##STR00035##
The titled compound (solid) was similarly prepared according to the
procedure described in the Example 24.
.sup.1H NMR (DMSO-d.sub.6) .delta. (ppm) 12.34 (br. s, 1H), 10.67
(br. s, 1H), 8.24 (br. s, 1H), 7.95-8.13 (m, 4H), 7.84 (br. s, 1H),
7.67 (d, J=7.34 Hz, 2H), 7.49 (br. s, 1H), 6.75-7.08 (m, 2H), 4.28
(d, J=6.85 Hz, 2H), 1.30 (t, J=6.36 Hz, 3H); LCMS (m/z): 419.0
[M+H].sup.+.
Example 26
Ethyl
5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-[(2,4-dimethylphenyl)-
amino]-4-oxo-4,5-dihydrofuran-3-carboxylate
##STR00036##
The titled compound (solid) was similarly prepared according to the
procedure described in the Example 24.
.sup.1H NMR (DMSO-d.sub.6) .delta. (ppm) 12.26 (br. s, 1H), 10.35
(br. s, 1H), 8.21 (d, J=3.91 Hz, 1H), 7.65-7.80 (m, 2H), 7.39 (d,
J=8.31 Hz, 1H), 7.27 (s, 1H), 7.20 (d, J=7.82 Hz, 1H), 6.84 (s,
1H), 6.73 (dd, J=4.40, 7.83 Hz, 1H), 4.27 (q, J=7.01 Hz, 2H), 2.44
(s, 3H), 2.23 (s, 3H), 1.30 (t, J=6.85 Hz, 3H); LCMS (m/z): 404.0
[M+H].sup.+.
Example 27
Ethyl
5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-4-oxo-2-(3-pyridinylami-
no)-4,5-dihydrofuran-3-carboxylate
##STR00037##
The titled compound (solid) was similarly prepared according to the
procedure described in the Example 24.
.sup.1H NMR (DMSO-d.sub.6) .delta. (ppm) 12.33 (br. s, 1H), 10.72
(br. s, 1H), 8.82 (br. s, 1H), 8.65 (br. s., 1H), 8.24 (br. s, 1H),
7.90-8.11 (m, 2H), 7.73 (br. s, 1H), 7.54-7.62 (m, 1H), 6.87-6.97
(m, 2H), 4.28 (d, J=6.85 Hz, 2H), 1.30 (t, J=6.36 Hz, 3H); LCMS
(m/z): 377.6 [M+H].sup.+.
Example 28
Ethyl
5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-[(3,4-dimethoxyphenyl-
)amino]-4-oxo-4,5-dihydrofuran-3-carboxylate
##STR00038##
The titled compound (solid) was similarly prepared according to the
procedure described in the Example 24.
.sup.1H NMR (DMSO-d.sub.6) .delta. (ppm) 12.33 (br. s, 1H), 10.44
(s, 1H), 8.24 (d, J=3.91 Hz, 1H), 7.96 (d, J=7.82 Hz, 1H), 7.82
(br. s, 1H), 7.24 (s, 1H), 7.06-7.14 (m, 2H), 6.78-6.94 (m, 2H),
4.27 (q, J=7.01 Hz, 2H), 3.87 (s, 3H), 3.71 (s, 3H), 1.29 (t,
J=7.09 Hz, 3H); LCMS (m/z): 436.5 [M+H].sup.+.
Example 29
Ethyl
5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-{[2-(2-hydroxyethoxy)-
phenyl]amino}-4-oxo-4,5-dihydrofuran-3-carboxylate
##STR00039## First Step
A solution of ethyl
2-[(2-hydroxyphenyl)amino]-4-oxo-4,5-dihydrofuran-3-carboxylate
(0.10 g, 0.38 mmol) which similarly prepared according to the
procedure described in the Example 4, First step, 2-chloroethanol
(0.038 mL, 0.57 mmol) and potassium carbonate (0.11 g, 0.80 mmol)
in N,N-dimethylformamide (2.0 mL) was stirred at 90.degree. C. for
2 days. Cooled to ambient temperature, ethyl acetate was added to
the reaction mixture, the organic layer was washed with aqueous 5%
citric acid solution, water and brine, dried over magnesium sulfate
and concentrated. To the residue, tert-butyl methyl ether was added
to precipitate the product. The precipitate was collected by
filtration, washed with hexane then dried to afford ethyl
2-{[2-(2-hydroxyethoxy)phenyl]amino}-4-oxo-4,5-dihydrofuran-3-carboxylate
as solid (0.041 g, y. 35%).
.sup.1H NMR (DMSO-d.sub.6) .delta. (ppm) 10.40 (s, 1H), 7.66 (d,
J=7.53 Hz, 1H), 7.16-7.25 (m, 2H), 6.97-7.05 (m, 1H), 4.82 (br. s,
1H), 4.75 (s, 2H), 4.24 (q, J=7.03 Hz, 2H), 4.15 (t, J=5.14 Hz,
2H), 3.72-3.80 (m, 2H), 1.26 (t, J=7.15 Hz, 3H); LCMS (m/z): 308.0
[M+H].sup.+.
Second Step
To a solution of ethyl
2-{[2-(2-hydroxyethoxy)phenyl]amino}-4-oxo-4,5-dihydrofuran-3-carboxylate
(0.021 g, 0.068 mmol) and 7-azaindole-3-carboxaldehyde (0.0087 g,
0.060 mmol) in ethanol (0.5 mL), 2M hydrochloric acid in ethanol
(0.030 mL, 0.059 mmol) was added at ambient temperature. The
mixture was refluxed for 4 h. Cooled to ambient temperature, the
precipitate was collected by filtration, washed with ethanol and
hexane then dried to afford the titled compound as solid (0.021 g,
y. 72%).
.sup.1H NMR (DMSO-d.sub.6) .delta. (ppm) 12.36 (br. s, 1H), 10.33
(s, 1H), 8.24-8.29 (m, 1H), 8.07 (d, J=6.78 Hz, 1H), 7.85 (s, 1H),
7.65-7.70 (m, 1H), 7.38-7.46 (m, 1H), 7.29 (d, J=7.78 Hz, 1H), 7.11
(t, J=7.65 Hz, 1H), 6.92-6.99 (m, 2H), 4.41 (br. s, 1H), 4.28 (q,
J=7.20 Hz, 2H), 4.10 (t, J=5.14 Hz, 2H), 3.65 (t, J=5.02 Hz, 2H),
1.30 (t, J=7.03 Hz, 3H); LCMS (m/z): 436 [M+H].sup.+.
Example 30
Ethyl
5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-{[2-(2-morpholinoetho-
xy)phenyl]amino}-4-oxo-4,5-dihydrofuran-3-carboxylate
##STR00040##
To a solution of ethyl
2-{[2-(2-morpholinoethoxy)phenyl]amino}-4-oxo-4,5-dihydrofuran-3-carboxyl-
ate (0.021 g, 0.054 mmol) which similarly prepared according to the
procedure described in the Example 29, First step and
7-azaindole-3-carboxaldehyde (0.0070 g, 0.048 mmol) in ethanol (0.5
mL), 2M hydrochloric acid in ethanol (0.024 mL, 0.048 mmol) was
added at ambient temperature. The mixture was refluxed for 4 h. The
reaction mixture was cooled with ice bath. Aqueous 2M sodium
hydroxide solution (0.024 mL, 0.048 mmol) was added dropwise to
neutralize and the mixture was stirred for 1 h. The precipitate was
collected by filtration then purified by preparative HPLC to afford
the titled compound as solid (0.0054 g, y. 21%).
.sup.1H NMR (DMSO-d.sub.6) .delta. (ppm) 12.31 (br. s, 1H), 10.35
(br. s, 1H), 8.24 (dd, J=1.25, 4.52 Hz, 1H), 7.94 (d, J=7.78 Hz,
1H), 7.83 (d, J=2.01 Hz, 1H), 7.62 (d, J=7.03 Hz, 1H), 7.42-7.50
(m, 1H), 7.28 (d, J=7.78 Hz, 1H), 7.12 (t, J=7.28 Hz, 1H), 6.92 (s,
1H), 6.88 (dd, J=4.64, 7.91 Hz, 1H), 4.27 (q, J=7.03 Hz, 2H), 4.14
(t, J=5.14 Hz, 2H), 3.36-3.42 (m, 4H), 2.59 (t, J=5.02 Hz, 2H),
2.25-2.35 (m, 4H), 1.30 (t, J=7.03 Hz, 3H); LCMS (m/z): 505.4
[M+H].sup.+.
Example 31
Ethyl
5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-[(2-fluorophenyl)amin-
o]-4-oxo-4,5-dihydrofuran-3-carboxylate
##STR00041##
To a solution of ethyl
2-[(2-fluorophenyl)amino]-4-oxo-4,5-dihydrofuran-3-carboxylate
(0.10 g, 0.38 mmol) which similarly prepared according to the
procedure described in the Example 4, First step and
7-azaindole-3-carboxaldehyde (0.050 g, 0.34 mmol) in ethanol (2.0
mL), piperidine (0.0034 mL, 0.034 mmol) was added at ambient
temperature. The mixture was refluxed for 36 h. The precipitate was
collected by filtration, washed with hot ethanol. The solid was
washed with hexane then dried to afford the titled compound as
solid (0.037 g, y. 27%).
.sup.1H NMR (DMSO-d.sub.6) .delta. (ppm) 12.31 (br. s, 1H), 10.55
(s, 1H), 8.22 (dd, J=1.38, 4.64 Hz, 1H), 7.84 (d, J=7.78 Hz, 1H),
7.67-7.77 (m, 2H), 7.55-7.63 (m, 1H), 7.45-7.53 (m, 1H), 7.37-7.44
(m, 1H), 6.92 (s, 1H), 6.83 (dd, J=4.64, 7.91 Hz, 1H), 4.28 (q,
J=7.03 Hz, 2H), 1.30 (t, J=7.03 Hz, 3H); LCMS (m/z): 393.9
[M+H].sup.+.
Example 32
Ethyl
5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-4-oxo-2-(o-tolylamino)--
4,5-dihydrofuran-3-carboxylate
##STR00042##
To a solution of ethyl
4-oxo-2-(o-tolylamino)-4,5-dihydrofuran-3-carboxylate (0.098 g,
0.38 mmol) which similarly prepared according to the procedure
described in the Example 4, First step and
7-azaindole-3-carboxaldehyde (0.050 g, 0.34 mmol) in ethanol (2.0
mL), piperidine (0.0034 mL, 0.034 mmol) was added at ambient
temperature. The mixture was refluxed for 32 h. The precipitate was
collected by filtration, washed with hot ethanol. The solid was
washed with hexane then dried to afford the titled compound as
solid (0.019 g, y. 27%).
.sup.1H NMR (DMSO-d.sub.6) .delta. (ppm) 12.26 (br. s, 1H), 10.43
(s, 1H), 8.18-8.22 (m, 1H), 7.69-7.75 (m, 2H), 7.54 (d, J=7.78 Hz,
1H), 7.45-7.49 (m, 2H), 7.37-7.44 (m, 1H), 6.85 (s, 1H), 6.78 (dd,
J=4.64, 7.91 Hz, 1H), 4.28 (q, J=7.19 Hz, 2H), 2.28 (s, 3H), 1.30
(t, J=7.03 Hz, 3H); LCMS (m/z): 390 [M+H].sup.+.
Example 33
Ethyl
5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-({2-([2-(dimethylamin-
o)ethoxy]phenyl}amino)-4-oxo-4,5-dihydrofuran-3-carboxylate
##STR00043##
To a solution of ethyl
2-({2-[2-(dimethylamino)ethoxy]phenyl}amino)-4-oxo-4,5-dihydrofuran-3-car-
boxylate (0.010 g, 0.031 mmol) which similarly prepared according
to the procedure described in the Example 29, First step and
7-azaindole-3-carboxaldehyde (0.0042 g, 0.029 mmol) in 2-propanol
(0.3 mL), piperidine (0.00028 mL, 0.0028 mmol) was added at ambient
temperature. The mixture was refluxed for 24 h. The precipitate was
collected by filtration, washed with hot ethanol. The solid was
washed with hexane then dried to afford the titled compound as
solid (0.0029 g, y. 22%).
.sup.1H NMR (DMSO-d.sub.6) .delta. (ppm) 12.24 (br. s, 1H), 8.23
(dd, J=1.26, 4.52 Hz, 1H), 7.98 (d, J=7.53 Hz, 1H), 7.79 (s, 1H),
7.58 (d, J=7.28 Hz, 1H), 7.36-7.45 (m, 1H), 7.28 (d, J=7.53 Hz,
1H), 7.13 (t, J=7.53 Hz, 1H), 6.89 (dd, J=4.64, 7.91 Hz, 1H), 6.83
(s, 1H), 4.26 (q, J=7.19 Hz, 2H), 4.15 (t, J=5.52 Hz, 2H),
2.55-2.65 (m, 2H), 2.19 (s, 6H), 1.29 (t, J=7.03 Hz, 3H); LCMS
(m/z): 463 [M+H].sup.+.
Example 34
Methyl
5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-4-oxo-2-piperidino-4,5-
-dihydrofuran-3-carboxylate
##STR00044##
To a solution of methyl
4-oxo-2-(phenylamino)-4,5-dihydrofuran-3-carboxylate (0.047 g, 0.20
mmol) which similarly prepared according to the procedure described
in the Example 2, First step using methyl 4-chloroacetoacetate and
phenyl isocyanate, and 7-azaindole-3-carboxaldehyde (0.029 g, 0.20
mmol) in methanol (1.0 mL), piperidine (0.022 mL, 0.22 mmol) was
added at ambient temperature. The mixture was refluxed for 5 days.
Cooled to ambient temperature, the precipitate was collected by
filtration, then purified by preparative HPLC, collected former
fraction to afford the titled compound as solid (0.0075 g, y.
11%).
.sup.1H NMR (DMSO-d.sub.6) .delta. (ppm) 12.30 (br. s, 1H),
8.35-8.43 (m, 1H), 8.31 (dd, J=1.38, 4.64 Hz, 1H), 7.97 (d, J=2.51
Hz, 1H), 7.19 (dd, J=4.64, 7.91 Hz, 1H), 6.87 (s, 1H), 3.70-3.82
(m, 4H), 3.68 (s, 3H), 1.64-1.80 (m, 6H); LCMS (m/z): 354.0
[M+H].sup.+
Example 35
Methyl
5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-4-oxo-2-(phenylamino)--
4,5-dihydrofuran-3-carboxylate
##STR00045##
To a solution of methyl
4-oxo-2-(phenylamino)-4,5-dihydrofuran-3-carboxylate (0.047 g, 0.20
mmol) which similarly prepared according to the procedure described
in the Example 2, First step using methyl 4-chloroacetoacetate and
phenyl isocyanate, and 7-azaindole-3-carboxaldehyde (0.029 g, 0.20
mmol) in 2-propanol (1.0 mL), piperidine (0.022 mL, 0.22 mmol) was
added at ambient temperature. The mixture was refluxed for 5 days.
Cooled to ambient temperature, the precipitate was collected by
filtration, washed with ethanol and diisopropyl ether then dried to
afford the titled compound as solid (0.031 g, y. 43%).
.sup.1H NMR (DMSO-d.sub.6) .delta. (ppm) 12.29 (br. s, 1H), 10.59
(s, 1H), 8.23 (dd, J=1.38, 4.64 Hz, 1H), 7.98 (d, J=7.53 Hz, 1H),
7.77 (d, J=2.51 Hz, 1H), 7.52-7.64 (m, 4H), 7.44-7.51 (m, 1H), 6.93
(s, 1H), 6.89 (dd, J=4.64, 7.91 Hz, 1H), 3.77 (s, 3H); LCMS (m/z):
361.9 [M+H].sup.+.
Example 36
Ethyl
5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-(4-methylpiperazinyl)-
-4-oxo-4,5-dihydrofuran-3-carboxylate hydrochloride
##STR00046##
To a solution of ethyl
2-(4-methylpiperazinyl)-4-oxo-4,5-dihydrofuran-3-carboxylate (0.038
g, 0.15 mmol) which similarly prepared according to the procedure
described in the Example 4, First step and
7-azaindole-3-carboxaldehyde (0.022 g, 0.15 mmol) in ethanol (1.0
mL), 2M hydrochloric acid in methanol (0.17 mL, 0.34 mmol) was
added at ambient temperature. The mixture was refluxed for 40 min.
Cooled to ambient temperature, the precipitate was collected by
filtration, washed with ethanol then dried to afford the titled
compound as solid (0.0069 g, y. 9%).
.sup.1H NMR (DMSO-d.sub.6) .delta. (ppm) 12.32-12.49 (m, 1H), 10.69
(br. s, 1H), 8.39 (d, J=8.03 Hz, 1H), 8.29-8.36 (m, 1H), 8.08 (d,
J=2.76 Hz, 1H), 7.22 (dd, J=4.64, 7.91 Hz, 1H), 6.95 (s, 1H), 4.19
(q, J=7.19 Hz, 2H), 3.57-3.75 (m, 4H), 3.33-3.40 (m, 4H), 2.87 (br.
s., 3H), 1.16-1.34 (m, 3H); LCMS (m/z): 383.0 [M+H].sup.+.
Example 37
Ethyl
5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-[(4-isopropylphenyl)a-
mino]-4-oxo-4,5-dihydrofuran-3-carboxylate
##STR00047##
To a solution of ethyl
2-[(4-isopropylphenyl)amino]-4-oxo-4,5-dihydrofuran-3-carboxylate
(0.26 g, 0.90 mmol) which similarly prepared according to the
procedure described in the Example 4, First step and
7-azaindole-3-carboxaldehyde (0.13 g, 0.90 mmol) in ethanol (6.0
mL), piperidine (0.045 mL, 0.45 mmol) was added at ambient
temperature. The mixture was refluxed for 16 h. Cooled to ambient
temperature, the precipitate was collected by filtration, washed
with ethanol then dried to afford the titled compound as solid
(0.13 g, y. 35%).
.sup.1H NMR (DMSO-d.sub.6) .delta. (ppm) 12.35 (br. s, 1H), 10.50
(br. s, 1H), 8.24 (d, J=3.42 Hz, 1H), 8.04 (d, J=7.82 Hz, 1H), 7.82
(br. s, 1H), 7.33-7.58 (m, 4H), 6.82-6.96 (m, 2H), 4.08-4.44 (m,
2H), 2.86-3.17 (m, 1H), 1.31 (s, 3H), 1.29 (s, 6H); LCMS (m/z):
418.0 [M+H].sup.+.
Example 38
Ethyl
5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-4-oxo-2-(5-pyrimidinyla-
mino)-4,5-dihydrofuran-3-carboxylate
##STR00048##
The titled compound (solid) was similarly prepared according to the
procedure described in the Example 37.
.sup.1H NMR (DMSO-d.sub.6) .delta. (ppm) 12.34 (br. s, 1H), 10.80
(br. s, 1H), 9.19 (s, 1H), 9.02-9.12 (m, 2H), 8.25 (d, J=4.40 Hz,
1H), 8.03 (d, J=7.82 Hz, 1H), 7.71 (br. s, 1H), 6.86-7.00 (m, 2H),
4.28 (q, J=6.85 Hz, 2H), 1.30 (t, J=6.00 Hz, 3H); LCMS (m/z): 378.2
[M+H].sup.+.
Example 39
Ethyl
5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-[(1,1'-biphenyl)-4-yl-
amino]-4-oxo-4,5-dihydrofuran-3-carboxylate
##STR00049##
The titled compound (solid) was similarly prepared according to the
procedure described in the Example 37.
.sup.1H NMR (DMSO-d.sub.6) .delta. (ppm) 12.34 (br. s, 1H), 10.63
(br. s, 1H), 8.20 (br. s, 1H), 8.09 (d, J=6.85 Hz, 1H), 7.75-7.93
(m, 5H), 7.62-7.74 (m, 2H), 7.50-7.58 (m, 2H), 7.39-7.48 (m, 1H),
6.94 (br. s, 1H), 6.83-6.91 (m, 1H), 4.29 (d, J=6.36 Hz, 2H), 1.31
(br. s, 3H); LCMS (m/z): 452.6 [M+H].sup.+.
Example 40
Ethyl
5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-[(4-nitrophenyl)amino-
]-4-oxo-4,5-dihydrofuran-3-carboxylate
##STR00050##
The titled compound (solid) was similarly prepared according to the
procedure described in the Example 37.
.sup.1H NMR (DMSO-d.sub.6) .delta. (ppm) 12.39 (br. s, 1H), 10.89
(br. s, 1H), 8.35 (d, J=8.80 Hz, 2H), 8.27 (d, J=3.91 Hz, 1H), 8.17
(d, J=7.82 Hz, 1H), 7.88 (d, J=8.80 Hz, 2H), 7.84 (d, J=2.45 Hz,
1H), 7.03 (s, 1H), 6.98 (dd, J=4.65, 8.07 Hz, 1H), 4.28 (q, J=7.17
Hz, 2H), 1.29 (t, J=7.09 Hz, 3H); LCMS (m/z): 421.4
[M+H].sup.+.
Example 41
Ethyl
5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-[(4-aminophenyl)amino-
]-4-oxo-4,5-dihydrofuran-3-carboxylate hydrochloride
##STR00051## First Step
To a solution of ethyl
2-({4-[(tert-butoxycarbonyl)amino]phenyl}amino)-4-oxo-4,5-dihydrofuran-3--
carboxylate (0.32 g, 0.88 mmol) which similarly prepared according
to the procedure described in the Example 4, First step and
7-azaindole-3-carboxaldehyde (0.13 g, 0.88 mmol) in ethanol (5.0
mL), piperidine (0.18 mL, 1.8 mmol) was added at ambient
temperature. The mixture was refluxed for 16 h. Cooled to ambient
temperature, the precipitate was collected by filtration, washed
with ethanol then dried to afford ethyl
5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-({4-[(tert-butoxycarbonyl)-
amino]phenyl}amino)-4-oxo-4,5-dihydrofuran-3-carboxylate as solid
(0.095 g, y. 21%).
.sup.1H NMR (DMSO-d.sub.6) .delta. 12.30 (br. s, 1H), 10.44 (br. s,
1H), 9.60 (s, 1H), 8.20 (d, J=3.76 Hz, 1H), 7.91 (d, J=7.72 Hz,
1H), 7.82 (s, 1H), 7.60 (d, J=8.40 Hz, 2H), 7.45 (d, J=8.56 Hz,
2H), 6.82-6.92 (m, 2H), 4.26 (q, J=6.86 Hz, 2H), 1.53 (s, 9H), 1.29
(t, J=6.90 Hz, 3H); LCMS (m/z): 491.4 [M+H].sup.+.
Second Step
A solution of ethyl
5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-{[4-(tert-butoxycarbonyl)a-
minophenyl]amino}-4-oxo-4,5-dihydrofuran-3-carboxylate (0.090 g,
0.18 mmol) in 4M hydrochloric acid in dioxane (3.0 mL) was stirred
at ambient temperature for 2 h. The solvent was removed under
reduced pressure, and diethyl ether was added to precipitate the
product. The precipitate was collected by filtration, washed with
diethyl ether then dried to afford the titled compound as solid
(0.066 g, y. 92%).
.sup.1H NMR (DMSO-d.sub.6) .delta. (ppm) 12.44 (br. s, 1H), 10.61
(br. s, 1H), 8.26 (d, J=3.91 Hz, 1H), 8.02 (d, J=7.82 Hz, 1H), 7.79
(s, 1H), 7.61 (d, J=8.31 Hz, 2H), 7.40 (d, J=7.34 Hz, 2H), 7.01
(dd, J=4.89, 7.83 Hz, 1H), 6.92 (s, 1H), 4.68 (br. s, 3H), 4.27 (q,
J=7.01 Hz, 2H), 1.29 (t, J=6.85 Hz, 3H); LCMS (m/z): 391.2
[M+H].sup.+.
Example 42
Ethyl
5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-[(4-morpholinophenyl)-
amino]-4-oxo-4,5-dihydrofuran-3-carboxylate
##STR00052##
The titled compound (solid) was similarly prepared according to the
procedure described in the Example 41, First step.
.sup.1H NMR (DMSO-d.sub.6) .delta. (ppm) 12.31 (br. s, 1H), 10.39
(br. s, 1H), 8.24 (br. s, 1H), 7.99 (d, J=7.34 Hz, 1H), 7.79 (br.
s, 1H), 7.42 (d, J=8.31 Hz, 2H), 7.07 (d, J=8.31 Hz, 2H), 6.81-6.96
(m, 2H), 4.26 (d, J=6.85 Hz, 2H), 3.28-3.40 (m, 4H), 3.15-3.28 (m,
4H), 1.29 (t, J=6.85 Hz, 3H); LCMS (m/z): 461.4 [M+H].sup.+.
Example 43
Ethyl
5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-4-oxo-2-(4-pyridinylami-
no)-4,5-dihydrofuran-3-carboxylate
##STR00053##
The titled compound (solid) was similarly prepared according to the
procedure described in the Example 41, First step.
.sup.1H NMR (DMSO-d.sub.6) .delta. (ppm) 12.30 (br. s, 1H), 11.18
(br. s, 1H), 8.59 (d, J=3.91 Hz, 2H), 8.28 (d, J=3.91 Hz, 1H), 8.19
(d, J=7.34 Hz, 1H), 7.88 (br. s, 1H), 7.55 (br. s, 2H), 7.02 (dd,
J=4.40, 7.83 Hz, 1H), 6.93 (br. s, 1H), 4.23 (d, J=6.85 Hz, 2H),
1.26 (t, J=6.85 Hz, 3H); LCMS (m/z): 377.6 [M+H].sup.+.
Example 44
Ethyl
5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-4-oxo-2-(6-quinolinylam-
ino)-4,5-dihydrofuran-3-carboxylate
##STR00054##
The titled compound (solid) was similarly prepared according to the
procedure described in the Example 41, First step.
.sup.1H NMR (DMSO-d.sub.6) .delta. (ppm) 12.29 (br. s, 1H), 10.82
(s, 1H), 9.01 (d, J=3.42 Hz, 1H), 8.39 (d, J=8.31 Hz, 1H), 8.23
(br. s, 1H), 8.17 (d, J=8.80 Hz, 1H), 8.11 (d, J=3.91 Hz, 1H), 8.00
(d, J=8.80 Hz, 1H), 7.88 (d, J=7.34 Hz, 1H), 7.83 (br. s, 1H), 7.62
(dd, J=4.16, 8.07 Hz, 1H), 6.94 (s, 1H), 6.26-6.51 (m, 1H), 4.30
(q, J=6.85 Hz, 2H), 1.32 (t, J=6.85 Hz, 3H); LCMS (m/z): 427.4
[M+H].sup.+.
Example 45
Ethyl
5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-[(4-fluorobenzyl)amin-
o]-4-oxo-4,5-dihydrofuran-3-carboxylate
##STR00055##
The titled compound (solid) was similarly prepared according to the
procedure described in the Example 41, First step.
.sup.1H NMR (DMSO-d.sub.6) .delta. (ppm) 12.31 (br. s, 1H), 9.51
(br. s, 1H), 8.22-8.37 (m, 2H), 7.86 (br. s, 1H), 7.47 (t, J=6.30
Hz, 2H), 7.22 (t, J=8.31 Hz, 2H), 7.05-7.15 (m, 1H), 6.87 (s, 1H),
4.84 (d, J=5.87 Hz, 2H), 4.23 (q, J=6.52 Hz, 2H), 1.27 (t, J=6.85
Hz, 3H); LCMS (m/z): 408.2 [M+H].sup.+.
Example 46
Ethyl
5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-[(2-fluorobenzyl)amin-
o]-4-oxo-4,5-dihydrofuran-3-carboxylate
##STR00056##
The titled compound (solid) was similarly prepared according to the
procedure described in the Example 41, First step.
.sup.1H NMR (DMSO-d.sub.6) .delta. (ppm) 12.35 (br. s, 1H), 9.44
(br. s, 1H), 8.15-8.42 (m, 2H), 7.86 (s, 1H), 7.45 (t, J=7.34 Hz,
1H), 7.33-7.40 (m, 1H), 7.18-7.32 (m, 2H), 7.07 (dd, J=5.14, 7.58
Hz, 1H), 6.87 (s, 1H), 4.91 (s, 2H), 4.23 (q, J=7.17 Hz, 2H), 1.27
(t, J=6.85 Hz, 3H); LCMS (m/z): 408.0 [M+H].sup.+.
Example 47
Ethyl
5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-[(4-fluorophenyl)-N-m-
ethylamino]-4-oxo-4,5-dihydrofuran-3-carboxylate hydrochloride
##STR00057## First Step
A solution of ethyl
2-[(4-fluorophenyl)amino]-4-oxo-4,5-dihydrofuran-3-carboxylate
(0.10 g, 0.38 mmol) which similarly prepared according to the
procedure described in the Example 4, First step, potassium
carbonate (0.063 g, 0.45 mmol) and methyliodide (0.026 mL, 0.42
mmol) in anhydrous N,N-dimethylformamide (2.0 mL) was stirred at
ambient temperature for 12 h. The reaction mixture was diluted with
water then extracted with ethyl acetate for 3 times. The organic
layer was dried over sodium sulfate and concentrated to afford
ethyl
2-[(4-fluorophenyl)-N-methylamino]-4-oxo-4,5-dihydrofuran-3-carboxylate
as solid (0.13 g).
.sup.1H NMR (DMSO-d.sub.6) .delta. (ppm) 7.38-7.47 (m, 2H),
7.21-7.32 (m, 2H), 4.65 (s, 2H), 3.60 (q, J=7.03 Hz, 2H), 3.43 (s,
3H), 0.96 (t, J=7.15 Hz, 3H); LCMS (m/z): 279.9 [M+H].sup.+.
Second Step
To a solution of ethyl
2-[(4-fluorophenyl)-N-methylamino]-4-oxo-4,5-dihydrofuran-3-carboxylate
(0.050 g, 0.18 mmol) and 7-azaindole-3-carboxaldehyde (0.026 g,
0.18 mmol) in ethanol (1.0 mL), 2M hydrochloric acid in ethanol
(0.19 mL, 0.38 mmol) was added at ambient temperature. The mixture
was refluxed for 2 h. Cooled to ambient temperature, the
precipitate was collected by filtration, washed with ethanol and
diisopropyl ether then dried to afford the titled compound as solid
(0.011 g, y. 13%).
.sup.1H NMR (DMSO-d.sub.6) .delta. (ppm) 12.38 (br. s, 1H), 8.28
(dd, J=1.25, 4.77 Hz, 1H), 8.12 (d, J=7.78 Hz, 1H), 7.81 (d, J=2.01
Hz, 1H), 7.53-7.62 (m, 2H), 7.31-7.38 (m, 2H), 7.05 (dd, J=4.77,
7.78 Hz, 1H), 6.90 (s, 1H), 3.80 (q, J=7.03 Hz, 2H), 3.63 (s, 3H),
1.01-1.10 (m, 3H); LCMS (m/z): 407.9 [M+H].sup.+.
Example 48
Ethyl
5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-[(2-methoxyethyl)amin-
o]-4-oxo-4,5-dihydrofuran-3-carboxylate
##STR00058##
To a solution of ethyl
2-[(2-methoxyethyl)amino]-4-oxo-4,5-dihydrofuran-3-carboxylate
(0.50 g, 2.2 mmol) which similarly prepared according to the
procedure described in the Example 4, First step and
7-azaindole-3-carboxaldehyde (0.32 g, 2.2 mmol) in ethanol (3.0
mL), piperidine (5 drops) was added at ambient temperature. The
mixture was refluxed for 16 h. Cooled to ambient temperature, the
precipitate was collected by filtration, washed with ethanol then
dried to afford the titled compound as solid.
.sup.1H NMR (DMSO-d.sub.6) .delta. (ppm) 12.34 (br. s, 1H), 8.89
(br. s, 1H), 8.43 (d, J=7.34 Hz, 1H), 8.31 (d, J=3.91 Hz, 1H), 8.03
(s, 1H), 7.19 (dd, J=4.40, 7.83 Hz, 1H), 6.90 (s, 1H), 4.21 (q,
J=7.17 Hz, 2H), 3.79 (d, J=4.40 Hz, 2H), 3.62 (t, J=5.14 Hz, 2H),
3.28 (s, 3H), 1.26 (t, J=7.09 Hz, 3H); LCMS (m/z): 358.4
[M+H].sup.+.
Example 49
Ethyl
5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-4-oxo-2-[(2-piperidinoe-
thyl)amino]-4,5-dihydrofuran-3-carboxylate
##STR00059##
The titled compound (solid) was similarly prepared according to the
procedure described in the Example 48.
.sup.1H NMR (DMSO-d.sub.6) .delta. (ppm) 12.35 (br. s, 1H), 8.83
(br. s, 1H), 8.38-8.47 (m, 1H), 8.31 (br. s, 1H), 8.02 (br. s, 1H),
7.20 (br. s, 1H), 6.88 (br. s, 1H), 4.12-4.28 (m, 2H), 3.67-3.80
(m, 2H), 2.25-2.70 (m, 6H), 1.32-1.53 (m, 6H), 1.18-1.32 (m, 3H);
LCMS (m/z): 411.5 [M+H].sup.+.
Example 50
Ethyl
5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-(benzyl-N-methylamino-
)-4-oxo-4,5-dihydrofuran-3-carboxylate
##STR00060##
The titled compound (solid) was similarly prepared according to the
procedure described in the Example 48.
.sup.1H NMR (DMSO-d.sub.6) .delta. (ppm) 12.28 (br. s, 1H),
8.24-8.39 (m, 2H), 7.88 (br. s, 1H), 7.29-7.47 (m, 5H), 7.10 (br.
s, 1H), 6.87 (s, 1H), 5.01 (s, 2H), 4.14 (d, J=6.85 Hz, 2H), 3.25
(br. s, 3H), 1.19 (t, J=6.36 Hz, 3H); LCMS (m/z): 404.6
[M+H].sup.+.
Example 51
Methyl
5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-[(4-fluorophenyl)ami-
no]-4-oxo-4,5-dihydrofuran-3-carboxylate
##STR00061##
To a solution of methyl
2-[(4-fluorophenyl)amino]-4-oxo-4,5-dihydrofuran-3-carboxylate
(0.25 g, 1.0 mmol) which similarly prepared according to the
procedure described in the Example 2, First step using methyl
4-chloroacetoacetate and 4-fluorophenyl isocyanate, and
7-azaindole-3-carboxaldehyde (0.15 g, 1.0 mmol) in 2-propanol (5.0
mL), L-proline (0.023 g, 0.20 mmol) was added at ambient
temperature. The mixture was refluxed for 2 days. Cooled to ambient
temperature, the precipitate was collected by filtration, washed
with ethanol and diisopropyl ether then dried to afford the titled
compound as solid (0.26 g, y. 68%).
.sup.1H NMR (DMSO-d.sub.6) .delta. (ppm) 12.28 (br. s, 1H), 10.58
(s, 1H), 8.25 (dd, J=1.38, 4.64 Hz, 1H), 7.96 (d, J=8.03 Hz, 1H),
7.74 (d, J=2.51 Hz, 1H), 7.59-7.69 (m, 2H), 7.36-7.43 (m, 2H), 6.92
(s, 1H), 6.89 (dd, J=4.77, 8.03 Hz, 1H), 3.76 (s, 3H); LCMS (m/z):
379.8 [M+H].sup.+.
Example 52
n-Butyl
5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-[(4-fluorophenyl)am-
ino]-4-oxo-4,5-dihydrofuran-3-carboxylate
##STR00062## First Step
Under a nitrogen atmosphere, a solution of methyl
2-[(4-fluorophenyl)amino]-4-oxo-4,5-dihydrofuran-3-carboxylate
(0.13 g, 0.50 mmol) which similarly prepared according to the
procedure described in the Example 2, First step using methyl
4-chloroacetoacetate and 4-fluorophenyl isocyanate, and zinc
cluster catalyst (Zn.sub.4(OCOCF.sub.3).sub.6O) (0.0062 g, 0.0065
mmol) in 1-butanol (2.0 mL) was stirred at 80.degree. C. for 3 days
then stirred at ambient temperature for further 3 days. The
precipitate was collected by filtration, washed with 2-propanol and
diisopropyl ether then dried to afford n-butyl
2-[(4-fluorophenyl)amino]-4-oxo-4,5-dihydrofuran-3-carboxylate as
solid (0.078 g, y. 53%).
.sup.1H NMR (DMSO-d.sub.6) .delta. (ppm) 10.25 (s, 1H), 7.45-7.55
(m, 2H), 7.21-7.31 (m, 2H), 4.65 (s, 2H), 4.17 (t, J=6.53 Hz, 2H),
1.57-1.67 (m, 2H), 1.33-1.45 (m, 2H), 0.92 (t, J=7.40 Hz, 3H); LCMS
(m/z): 293.8 [M+H].sup.+.
Second Step
To a solution of n-butyl
2-[(4-fluorophenyl)amino]-4-oxo-4,5-dihydrofuran-3-carboxylate
(0.035 g, 0.12 mmol) and 7-azaindole-3-carboxaldehyde (0.018 g,
0.12 mmol) in 2-propanol (1.0 mL), L-proline (0.0028 g, 0.024 mmol)
was added at ambient temperature. The mixture was refluxed for 2
days. Cooled to ambient temperature, the precipitate was collected
by filtration, washed with ethanol and diisopropyl ether then dried
to afford the titled compound as solid (0.019 g, y. 36%).
.sup.1H NMR (DMSO-d.sub.6) .delta. (ppm) 12.28 (br. s, 1H), 10.56
(s, 1H), 8.25 (dd, J=1.38, 4.64 Hz, 1H), 7.95 (d, J=7.78 Hz, 1H),
7.75 (d, J=2.76 Hz, 1H), 7.60-7.68 (m, 2H), 7.35-7.42 (m, 2H),
6.85-6.95 (m, 2H), 4.22 (t, J=6.65 Hz, 2H), 1.60-1.72 (m, 2H),
1.37-1.49 (m, 2H), 0.94 (t, J=7.40 Hz, 3H); LCMS (m/z): 421.9
[M+H].sup.+.
Example 53
Ethyl
5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-[(2,4-difluorophenyl)-
amino]-4-oxo-4,5-dihydrofuran-3-carboxylate
##STR00063##
To a solution of ethyl
2-[(2,4-difluorophenyl)amino]-4-oxo-4,5-dihydrofuran-3-carboxylate
(0.15 g, 0.54 mmol) which similarly prepared according to the
procedure described in the Example 2, First step and
7-azaindole-3-carboxaldehyde (0.074 g, 0.50 mmol) in 2-propanol
(2.5 mL), 2M hydrochloric acid in ethanol (0.25 mL, 0.50 mmol) was
added at ambient temperature then refluxed for 24 h. Cooled with
ice bath, aqueous 2M sodium hydroxide solution (0.024 mL, 0.048
mmol) was added dropwise to neutralize and the mixture was refluxed
for 1 h. The precipitate was collected by filtration, washed with
ethanol and hexane then dried to afford the titled compound as
solid (0.14 g, y. 69%).
.sup.1H NMR (DMSO-d.sub.6) .delta. (ppm) 12.27 (br. s, 1H), 10.51
(s, 1H), 8.24 (dd, J=1.38, 4.64 Hz, 1H), 7.84 (d, J=7.78 Hz, 1H),
7.66-7.77 (m, 2H), 7.50-7.59 (m, 1H), 7.29 (t, J=7.78 Hz, 1H),
6.80-6.89 (m, 2H), 4.26 (q, J=7.03 Hz, 2H), 1.29 (t, J=7.03 Hz,
3H); LCMS (m/z): 411.8 [M+H].sup.+.
Example 54
Ethyl
5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-[(3,4-difluorophenyl)-
amino]-4-oxo-4,5-dihydrofuran-3-carboxylate
##STR00064##
To a solution of ethyl
2-[(3,4-difluorophenyl)amino]-4-oxo-4,5-dihydrofuran-3-carboxylate
(0.084 g, 0.30 mmol) which similarly prepared according to the
procedure described in the Example 4, First step and
7-azaindole-3-carboxaldehyde (0.041 g, 0.28 mmol) in 2-propanol
(2.0 mL), 2M hydrochloric acid in ethanol (0.14 mL, 0.28 mmol) was
added at ambient temperature. The mixture was refluxed for 18 h.
Cooled with ice bath, aqueous 2M sodium hydroxide solution (0.13
mL, 0.26 mmol) was added dropwise to neutralize, ethanol (5.0 mL)
was added and the mixture was refluxed for 1.5 h. The precipitate
was collected by filtration, washed with hot ethanol. The solid was
washed with hexane then dried to afford the titled compound as
solid (0.051 g, y. 44%).
.sup.1H NMR (DMSO-d.sub.6) .delta. (ppm) 12.07 (br. s, 1H), 10.63
(br. s, 1H), 8.22 (dd, J=1.38, 4.64 Hz, 1H), 8.00 (d, J=7.78 Hz,
1H), 7.65 (s, 1H), 7.33-7.51 (m, 2H), 7.13 (br. s, 1H), 6.88 (dd,
J=4.64, 7.91 Hz, 1H), 6.56 (br. s, 1H), 4.16 (q, J=6.86 Hz, 2H),
1.24 (t, J=7.15 Hz, 3H); LCMS (m/z): 411.8 [M+H].sup.+.
Example 55
Ethyl
5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-4-oxo-2-{[4-(1-propoxy)-
phenyl]amino}-4,5-dihydrofuran-3-carboxylate
##STR00065##
To a solution of ethyl
4-oxo-2-{[4-(1-propoxy)phenyl]amino}-4,5-dihydrofuran-3-carboxylate
(0.15 g, 0.50 mmol) which similarly prepared according to the
procedure described in the Example 4, First step and
7-azaindole-3-carboxaldehyde (0.072 g, 0.50 mmol) in ethanol (6.0
mL), L-proline (0.0060 g, 0.05 mmol) was added at ambient
temperature. The mixture was refluxed for 16 h. Cooled to ambient
temperature, the precipitate was collected by filtration, washed
with ethanol then dried to afford the titled compound as solid
(0.060 g, y. 28%).
.sup.1H NMR (DMSO-d.sub.6) .delta. (ppm) 12.30 (br. s, 1H), 10.44
(br. s, 1H), 8.22 (br. s, 1H), 7.85-7.99 (m, 1H), 7.79 (br. s, 1H),
7.48 (d, J=6.85 Hz, 2H), 7.07 (d, J=7.34 Hz, 2H), 6.86 (br. s, 2H),
4.18-4.37 (m, 2H), 3.93-4.11 (m, 2H), 1.70-1.90 (m, 2H), 1.22-1.38
(m, 3H), 0.98-1.12 (m, 3H); LCMS (m/z): 433.9 [M+H].sup.+.
Example 56
Ethyl
5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-(isopropylamino)-4-ox-
o-4,5-dihydrofuran-3-carboxylate
##STR00066##
To a solution of ethyl
2-(isopropylamino)-4-oxo-4,5-dihydrofuran-3-carboxylate (0.50 g,
2.3 mmol) which similarly prepared according to the procedure
described in the Example 4, First step and
7-azaindole-3-carboxaldehyde (0.34 g, 2.3 mmol) in ethanol (15 mL),
L-proline (0.027 g, 0.23 mmol) was added at ambient temperature.
The mixture was refluxed for 16 h. Cooled to ambient temperature,
the precipitate was collected by filtration, washed with ethanol
then dried to afford the titled compound as solid (0.45 g, y.
56%).
.sup.1H NMR (DMSO-d.sub.6) .delta. (ppm) 12.32 (br. s, 1H), 8.56
(br. s, 1H), 8.41 (d, J=7.82 Hz, 1H), 8.32 (d, J=3.91 Hz, 1H), 7.99
(s, 1H), 7.20 (dd, J=4.40, 7.83 Hz, 1H), 6.90 (s, 1H), 4.39 (br. s,
1H), 4.21 (q, J=7.01 Hz, 2H), 1.38 (d, J=6.36 Hz, 6H), 1.26 (t,
J=6.85 Hz, 3H); LCMS (m/z): 342.3 [M+H].sup.+.
Example 57
Ethyl
5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-{[2-(dimethylamino)et-
hyl]amino}-4-oxo-4,5-dihydrofuran-3-carboxylate
##STR00067##
The titled compound (solid) was similarly prepared according to the
procedure described in the Example 56.
.sup.1H NMR (DMSO-d.sub.6) .delta. (ppm) 12.37 (br. s, 1H), 8.82
(br. s, 1H), 8.42 (d, J=7.82 Hz, 1H), 8.31 (d, J=3.91 Hz, 1H), 8.03
(s, 1H), 7.20 (dd, J=4.89, 7.83 Hz, 1H), 6.90 (s, 1H), 4.20 (q,
J=7.34 Hz, 2H), 3.68-3.80 (m, 2H), 2.38-2.65 (m, 2H), 2.23 (s, 6H),
1.26 (t, J=7.09 Hz, 3H); LCMS (m/z): 371.2 [M+H].sup.+.
Example 58
Ethyl
5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-[(3-fluorobenzyl)amin-
o]-4-oxo-4,5-dihydrofuran-3-carboxylate
##STR00068##
The titled compound (solid) was similarly prepared according to the
procedure described in the Example 56.
.sup.1H NMR (DMSO-d.sub.6) .delta. (ppm) 12.33 (br. s, 1H), 9.54
(br. s, 1H), 8.28 (d, J=5.87 Hz, 2H), 7.88 (s, 1H), 7.44 (q, J=7.34
Hz, 1H), 7.20-7.33 (m, 2H), 7.03-7.18 (m, 2H), 6.87 (s, 1H), 4.87
(br. s, 2H), 4.23 (q, J=6.85 Hz, 2H), 1.27 (t, J=6.85 Hz, 3H); LCMS
(m/z): 408.0 [M+H].sup.+.
Example 59
Ethyl
5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-(cycloheptylamino)-4--
oxo-4,5-dihydrofuran-3-carboxylate
##STR00069##
The titled compound (solid) was similarly prepared according to the
procedure described in the Example 56.
.sup.1H NMR (DMSO-d.sub.6) .delta. (ppm) 12.37 (br. s, 1H), 8.56
(d, J=8.16 Hz, 1H), 8.42 (d, J=7.82 Hz, 1H), 8.32 (d, J=3.91 Hz,
1H), 7.99 (s, 1H), 7.19 (dd, J=4.89, 7.82 Hz, 1H), 6.90 (s, 1H),
4.21 (q, J=6.85 Hz, 2H), 3.39-3.50 (m, 1H), 1.94-2.08 (m, 2H),
1.77-1.91 (m, 2H), 1.48-1.76 (m, 8H), 1.26 (t, J=7.09 Hz, 3H); LCMS
(m/z): 396.0 [M+H].sup.+.
Example 60
Ethyl
5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-4-oxo-2-[(2-thienylmeth-
yl)amino]-4,5-dihydrofuran-3-carboxylate
##STR00070##
The titled compound (solid) was similarly prepared according to the
procedure described in the Example 56.
.sup.1H NMR (DMSO-d.sub.6) .delta. (ppm) 12.36 (br. s, 1H), 9.55
(br. s, 1H), 8.37 (d, J=7.82 Hz, 1H), 8.30 (d, J=3.91 Hz, 1H), 8.03
(s, 1H), 7.45 (d, J=4.89 Hz, 1H), 7.09-7.22 (m, 2H), 7.00 (t,
J=3.96 Hz, 1H), 6.91 (s, 1H), 5.01 (br. s, 2H), 4.22 (q, J=7.01 Hz,
2H), 1.26 (t, J=6.85 Hz, 3H); LCMS (m/z): 395.8 [M+H].sup.+.
Example 61
Ethyl
5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-(cyclopropylamino)-4--
oxo-4,5-dihydrofuran-3-carboxylate
##STR00071##
The titled compound (solid) was similarly prepared according to the
procedure described in the Example 56.
.sup.1H NMR (DMSO-d.sub.6) .delta. (ppm) 12.33 (br. s, 1H), 8.86
(br. s, 1H), 8.57 (d, J=7.82 Hz, 1H), 8.31 (d, J=3.91 Hz, 1H), 8.06
(s, 1H), 7.21 (dd, J=4.89, 7.82 Hz, 1H), 6.92 (s, 1H), 4.19 (q,
J=7.01 Hz, 2H), 3.08-3.20 (m, 1H), 1.24 (t, J=6.85 Hz, 3H),
0.84-1.01 (m, 4H); LCMS (m/z): 340.0 [M+H].sup.+.
Example 62
Ethyl
5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-(3,5-dimethylpiperidi-
no)-4-oxo-4,5-dihydrofuran-3-carboxylate
##STR00072##
The titled compound (solid) was similarly prepared according to the
procedure described in the Example 56.
.sup.1H NMR (DMSO-d.sub.6) .delta. (ppm) 12.32 (br. s, 1H), 8.38
(d, J=7.82 Hz, 1H), 8.31 (d, J=3.91 Hz, 1H), 7.96 (s, 1H),
7.11-7.26 (m, 1H), 6.84 (s, 1H), 4.00-4.25 (m, 4H), 2.81 (t,
J=11.98 Hz, 2H), 1.74-1.93 (m, 3H), 1.24 (t, J=6.85 Hz, 3H),
0.82-1.02 (m, 7H); LCMS (m/z): 396.0 [M+H].sup.+.
Example 63
Ethyl
5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-azepinyl-4-oxo-4,5-di-
hydrofuran-3-carboxylate
##STR00073##
The titled compound (solid) was similarly prepared according to the
procedure described in the Example 56.
.sup.1H NMR (DMSO-d.sub.6) .delta. (ppm) 12.29 (br. s, 1H), 8.38
(d, J=7.78 Hz, 1H), 8.31 (dd, J=1.51, 4.77 Hz, 1H), 7.93 (d, J=2.26
Hz, 1H), 7.19 (dd, J=4.64, 7.91 Hz, 1H), 6.84 (s, 1H), 4.17 (q,
J=7.19 Hz, 2H), 3.73-3.84 (m, 4H), 1.75-1.93 (m, 4H), 1.51-1.64 (m,
4H), 1.24 (t, J=7.03 Hz, 3H); LCMS (m/z): 382.0 [M+H].sup.+.
Example 64
Ethyl
5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-[(cyclopropylmethyl)a-
mino]-4-oxo-4,5-dihydrofuran-3-carboxylate
##STR00074##
The titled compound (solid) was similarly prepared according to the
procedure described in the Example 56.
.sup.1H NMR (DMSO-d.sub.6) .delta. (ppm) 12.33 (br. s, 1H), 9.06
(br. s, 1H), 8.41 (d, J=7.82 Hz, 1H), 8.31 (d, J=3.91 Hz, 1H), 8.00
(br. s, 1H), 7.19 (dd, J=4.65, 7.58 Hz, 1H), 6.89 (s, 1H), 4.22 (q,
J=7.01 Hz, 2H), 3.52 (t, J=6.36 Hz, 2H), 1.15-1.35 (m, 4H), 0.52
(d, J=6.85 Hz, 2H), 0.36 (d, J=4.40 Hz, 2H); LCMS (m/z): 354.2
[M+H].sup.+.
Example 65
Ethyl
5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-[(1-methyl-4-piperidi-
nyl)amino]-4-oxo-4,5-dihydrofuran-3-carboxylate
##STR00075##
The titled compound (solid) was similarly prepared according to the
procedure described in the Example 56.
.sup.1H NMR (DMSO-d.sub.6) .delta. (ppm) 12.36 (br. s, 1H), 8.58
(br. s, 1H), 8.42 (d, J=7.83 Hz, 1H), 8.33 (d, J=3.42 Hz, 1H), 7.98
(s, 1H), 7.19 (dd, J=4.65, 7.58 Hz, 1H), 6.90 (s, 1H), 4.21 (q,
J=6.85 Hz, 2H), 3.90-4.07 (m, 1H), 2.79 (d, J=10.27 Hz, 2H), 2.21
(s, 3H), 2.08 (t, J=10.27 Hz, 2H), 1.80-1.99 (m, 4H), 1.26 (t,
J=6.85 Hz, 3H); LCMS (m/z): 397.2 [M+H].sup.+.
Example 66
Ethyl
5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-(4-acetylpiperazinyl)-
-4-oxo-4,5-dihydrofuran-3-carboxylate
##STR00076##
The titled compound (solid) was similarly prepared according to the
procedure described in the Example 56.
.sup.1H NMR (DMSO-d.sub.6) .delta. (ppm) 12.37 (br. s, 1H), 8.38
(d, J=7.34 Hz, 1H), 8.32 (d, J=3.42 Hz, 1H), 8.01 (s, 1H), 7.21
(dd, J=4.89, 7.82 Hz, 1H), 6.89 (s, 1H), 4.18 (q, J=7.34 Hz, 2H),
3.77-3.95 (m, 4H), 3.62-3.77 (m, 4H), 2.07 (s, 3H), 1.25 (t, J=6.85
Hz, 3H); LCMS (m/z): 411.4 [M+H].sup.+.
Example 67
Ethyl
5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-[(3-pyrazolyl)amino]--
4-oxo-4,5-dihydrofuran-3-carboxylate
##STR00077##
To a solution of ethyl
2-[(3-pyrazolyl)amino]-4-oxo-4,5-dihydrofuran-3-carboxylate (0.30
g, 1.3 mmol) which similarly prepared according to the procedure
described in the Example 4, First step, and
7-azaindole-3-carboxaldehyde (0.19 g, 1.3 mmol) in ethanol (6.0
mL), L-proline (0.015 g, 0.13 mmol) was added at ambient
temperature. The mixture was refluxed for 16 h. Cooled to ambient
temperature, the precipitate was collected by filtration, washed
with ethanol then dried to afford the titled compound as solid
(0.20 g, y. 35%).
.sup.1H NMR (DMSO-d.sub.6) .delta. (ppm) 13.07 (br. s, 1H), 12.34
(br. s, 1H), 10.46 (br. s, 1H), 8.27 (d, J=3.91 Hz, 1H), 8.14 (d,
J=7.82 Hz, 1H), 7.91-8.20 (m, 2H), 7.08 (dd, J=4.65, 7.58 Hz, 1H),
6.94 (s, 1H), 6.47 (br. s, 1H), 4.26 (q, J=6.85 Hz, 2H), 1.29 (t,
J=7.09 Hz, 3H); LCMS (m/z): 366.0 [M+H].sup.+.
Example 68
Ethyl
5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-[(6-indazolyl)amino]--
4-oxo-4,5-dihydrofuran-3-carboxylate
##STR00078##
The titled compound (solid) was similarly prepared according to the
procedure described in the Example 67.
.sup.1H NMR (DMSO-d.sub.6) .delta. (ppm) 13.22 (br. s, 1H), 12.24
(br. s, 1H), 10.66 (br. s, 1H), 8.22 (br. s, 1H), 8.12 (br. s, 1H),
7.91 (d, J=8.31 Hz, 1H), 7.71-7.86 (m, 3H), 7.33 (d, J=7.83 Hz,
1H), 6.89 (s, 1H), 6.33 (br. s, 1H), 4.29 (d, J=6.85 Hz, 2H), 1.31
(t, J=6.60 Hz, 3H); LCMS (m/z): 416.4 [M+H].sup.+.
Example 69
Ethyl
5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-[4-(hydroxymethyl)pip-
eridino]-4-oxo-4,5-dihydrofuran-3-carboxylate
##STR00079##
The titled compound (solid) was similarly prepared according to the
procedure described in the Example 67.
.sup.1H NMR (DMSO-d.sub.6) .delta. (ppm) 12.30 (br. s, 1H), 8.37
(d, J=7.82 Hz, 1H), 8.31 (d, J=3.91 Hz, 1H), 7.97 (br. s, 1H), 7.19
(dd, J=4.40, 7.82 Hz, 1H), 6.84 (s, 1H), 4.57 (t, J=4.89 Hz, 1H),
4.08-4.32 (m, 4H), 3.22-3.40 (m, 4H), 1.70-1.95 (m, 3H), 1.37 (q,
J=11.09 Hz, 2H), 1.24 (t, J=6.85 Hz, 3H); LCMS (m/z): 398.0
[M+H].sup.+.
Example 70
2-Methoxyethyl
5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-[(4-fluorophenyl)amino]-4--
oxo-4,5-dihydrofuran-3-carboxylate
##STR00080## First Step
A solution of methyl
2-[(4-fluorophenyl)amino]-4-oxo-4,5-dihydrofuran-3-carboxylate
(0.063 g, 0.25 mmol) which similarly prepared according to the
procedure described in the Example 2, First step using methyl
4-chloroacetoacetate and 4-fluorophenyl isocyanate,
2-methoxyethanol (0.2 mL, 2.5 mmol) and zinc cluster catalyst
(Zn.sub.4(OCOCF.sub.3).sub.6O) (0.0048 g, 0.0050 mmol) in anhydrous
dioxane (1.0 mL) was stirred with the microwave synthesizer
(Biotage Initiator.TM.) at 120.degree. C. for 1 h. Cooled to
ambient temperature, the reaction mixture was concentrated under
reduced pressure. The residue was purified by chromatography on
silica gel(chloroform/ethyl acetate) to afford 2-methoxyethyl
2-[(4-fluorophenyl)amino]-4-oxo-4,5-dihydrofuran-3-carboxylate as
solid (0.024 g, y. 33%).
.sup.1H NMR (DMSO-d.sub.6) .delta. (ppm) 10.22 (s, 1H), 7.43-7.56
(m, 2H), 7.27 (t, J=8.78 Hz, 2H), 4.66 (s, 2H), 4.22-4.37 (m, 2H),
3.52-3.66 (m, 2H), 3.30 (s, 3H); LCMS (m/z): 295.8 [M+H].sup.+
Second Step
To a solution of 2-methoxyethyl
2-[(4-fluorophenyl)amino]-4-oxo-4,5-dihydrofuran-3-carboxylate
(0.023 g, 0.078 mmol) and 7-azaindole-3-carboxaldehyde (0.011 g,
0.078 mmol) in 2-propanol (1.0 mL), L-proline (0.0018 g, 0.016
mmol) was added at ambient temperature. The mixture was refluxed
for 2 days. Cooled to ambient temperature, the precipitate was
collected by filtration. The solid was purified by preparative HPLC
to afford the titled compound as solid (0.046 g, y. 14%).
.sup.1H NMR (DMSO-d.sub.6) .delta. (ppm) 12.22 (br. s, 1H), 10.65
(br. s, 1H), 8.24 (dd, J=1.25, 4.52 Hz, 1H), 7.96 (d, J=7.53 Hz,
1H), 7.72 (d, J=2.26 Hz, 1H), 7.52-7.63 (m, 2H), 7.35 (t, J=8.78
Hz, 2H), 6.89 (dd, J=4.77, 8.03 Hz, 1H), 6.82 (br. s, 1H), 4.32 (t,
J=4.77 Hz, 2H), 3.54-3.72 (m, 2H), 3.33 (s, 3H); LCMS (m/z): 423.8
[M+H].sup.+.
Example 71
2-(Dimethylamino)ethyl
5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-[(4-fluorophenyl)amino]-4--
oxo-4,5-dihydrofuran-3-carboxylate formate
##STR00081##
Under a nitrogen atmosphere, a solution of methyl
5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-[(4-fluorophenyl)amino]-4--
oxo-4,5-dihydrofuran-3-carboxylate (0.038 g, 0.10 mmol) which
afforded in the Example 51, 2-(dimethylamino)ethanol (0.10 mL, 1.0
mmol) and zinc cluster catalyst (Zn.sub.4(OCOCF.sub.3).sub.6O)
(0.0019 g, 0.0020 mmol) in N,N-dimethylacetamide (0.9 mL) was
stirred with the microwave synthesizer (Biotage Initiator.TM.) at
130.degree. C. for 1 h. Cooled to ambient temperature, the reaction
mixture was purified by preparative HPLC to afford the titled
compound as solid (0.016 g, y. 36%).
.sup.1H NMR (DMSO-d.sub.6) .delta. (ppm) 12.15 (br. s, 1H), 8.23
(dd, J=1.38, 4.64 Hz, 1H), 8.14 (s, 1H), 7.97 (d, J=7.53 Hz, 1H),
7.68 (d, J=2.01 Hz, 1H), 7.45 (dd, J=5.14, 8.41 Hz, 2H), 7.27-7.36
(m, 2H), 6.89 (dd, J=4.64, 7.91 Hz, 1H), 6.72 (s, 1H), 4.30 (t,
J=5.77 Hz, 2H), 2.80 (t, J=5.77 Hz, 2H), 2.41 (s, 6H); LCMS (m/z):
436.9 [M+H].sup.+.
Example 72
2-Hydroxyethyl
5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-[(4-fluorophenyl)amino]-4--
oxo-4,5-dihydrofuran-3-carboxylate
##STR00082##
Under a nitrogen atmosphere, a solution of the compound (0.038 g,
0.10 mmol) of Example 51, ethylene glycol (0.50 mL, 9.0 mmol) and
zinc cluster catalyst (Zn.sub.4(OCOCF.sub.3).sub.6O) (0.0019 g,
0.0020 mmol) in N,N-dimethylacetamide (0.5 mL) was stirred with the
microwave synthesizer (Biotage Initiator.TM.) at 150.degree. C. for
1 h. Cooled to ambient temperature, the precipitate was removed by
filtration. The filtrate was purified by preparative HPLC to afford
the titled compound as solid (0.0040 g, y. 10%).
.sup.1H NMR (DMSO-d.sub.6) .delta. (ppm) 12.24 (br. s, 1H), 10.52
(br. s, 1H), 8.21-8.28 (m, 1H), 7.96 (d, J=7.78 Hz, 1H), 7.74 (d,
J=2.40 Hz, 1H), 7.58 (br. s, 2H), 7.36 (t, J=8.66 Hz, 2H),
6.80-6.94 (m, 2H), 4.90 (br. s, 1H), 4.22 (t, J=5.27 Hz, 2H), 3.67
(t, J=5.27 Hz, 2H); LCMS (m/z): 409.8 [M+H].sup.+.
Example 73
2-Morpholinoethyl
5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-[(4-fluorophenyl)amino]-4--
oxo-4,5-dihydrofuran-3-carboxylate formate
##STR00083##
Under a nitrogen atmosphere, a solution of the compound (0.038 g,
0.10 mmol) of Example 51, N-(2-hydroxyethyl)morpholine (0.20 mL,
1.6 mmol) and zinc cluster catalyst (Zn.sub.4(OCOCF.sub.3).sub.6O)
(0.0019 g, 0.0020 mmol) in N,N-dimethylacetamide (0.8 mL) was
stirred with the microwave synthesizer (Biotage Initiator.TM.) at
150.degree. C. for 40 min. Cooled to ambient temperature, the
precipitate was removed by filtration. The filtrate was purified by
preparative HPLC to afford the titled compound as solid (0.0075 g,
y. 15%).
.sup.1H NMR (DMSO-d.sub.6) .delta. (ppm) 12.25 (br. s, 1H), 8.24
(d, J=4.02 Hz, 1H), 8.15 (s, 1H), 7.95 (d, J=7.78 Hz, 1H), 7.72 (s,
1H), 7.60 (br. s, 2H), 7.33-7.43 (m, 2H), 6.84-6.93 (m, 2H), 4.31
(t, J=5.77 Hz, 2H), 3.47-3.58 (m, 4H), 2.78 (s, 2H), 2.62-2.70 (m,
2H), 2.35-2.42 (m, 2H); LCMS (m/z): 478.9 [M+H].sup.+.
Example 74
Ethyl
5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-{[4-(2-hydroxyethoxy)-
-2-methylphenyl]amino}-4-oxo-4,5-dihydrofuran-3-carboxylate
##STR00084## First Step
A solution of 4-nitro-m-cresol (1.4 g, 9.4 mmol), 2-bromoethanol
(1.0 mL, 0.014 mol) and potassium carbonate (3.3 g, 0.024 mol) in
N,N-dimethylformamide (10 mL) was stirred with heating at
70.degree. C. for 12 h. Cooled to ambient temperature, the reaction
mixture was poured into ice water and extracted with ethyl acetate.
The organic layer was washed with water and brine, dried over
sodium sulfate, filtered and concentrated. The residue was purified
by chromatography on silica gel(hexane/ethyl acetate) to afford
2-(3-methyl-4-nitrophenoxy)ethanol as solid (1.3 g, y. 70%).
.sup.1H NMR (DMSO-d.sub.6) .delta. (ppm) 8.04 (d, J=9.08 Hz, 1H),
7.03 (br. s, 1H), 6.98 (dd, J=2.44, 9.04 Hz, 1H), 4.92 (t, J=5.42
Hz, 1H), 4.11 (t, J=4.80 Hz, 2H), 3.73 (q, J=4.99 Hz, 2H), 2.55 (s,
3H); LCMS (m/z): 198.3 [M+H].sup.+.
Second Step
Under a nitrogen atmosphere, 2-(3-methyl-4-nitrophenoxy)ethanol
(1.0 g, 5.3 mmol) was dissolved in methanol/tetrahydrofuran (30
mL/30 mL) and 10% palladium on carbon (0.37 g) was added at ambient
temperature. The reaction mixture was agitated under a hydrogen
atmosphere for 4 h. Palladium on carbon was removed by filtration
with Celite and the solvent was removed under reduced pressure to
afford 4-(2-hydroxyethoxy)-2-methylaniline as solid (0.80 g, y.
90%).
.sup.1H NMR DMSO-d.sub.6) .delta. (ppm) 6.57 (br. s, 1H), 6.52 (br.
s, 2H), 4.74 (t, J=5.56 Hz, 1H), 4.34 (br. s, 2H), 3.82 (t, J=5.16
Hz, 2H), 3.63 (q, J=5.30 Hz, 2H), 2.02 (s, 3H); LCMS (m/z): 168.0
[M+H].sup.+.
Third Step
Diethyl malonate (8.0 mL, 0.052 mol) was added dropwise to a
solution of sodium hydride (60% w/w in oil, 4.2 g, 0.11 mol) in
anhydrous tetrahydrofuran (130 mL) that cooled with ice bath. The
mixture was refluxed for 7 min. The reaction mixture was cooled
with ice bath, chloroacetyl chloride (4.2 mL, 0.052 mol) was added
dropwise to the reaction mixture and stirred for 1 h then stirred
at 45.degree. C. for 1 h. Cooled to ambient temperature, the
reaction mixture was diluted with water, and extracted with
chloroform for 4 times. The organic layer was dried over magnesium
sulfate and concentrated. The residue was purified by
chromatography on silica gel (chloroform/methanol) to afford ethyl
2-ethoxy-4-oxo-4,5-dihydrofuran-3-carboxylate as solid (5.0 g, y.
48%).
.sup.1H NMR (CDCl.sub.3) .delta. (ppm) 4.58-4.70 (m, 4H), 4.30 (q,
J=7.03 Hz, 2H), 1.53 (t, J=7.03 Hz, 3H), 1.33 (t, J=7.15 Hz,
3H)
Fourth Step
A solution of 4-(2-hydroxyethoxy)-2-methylaniline (0.69 g, 4.1
mmol) and ethyl 2-ethoxy-4-oxo-4,5-dihydrofuran-3-carboxylate (0.83
g, 4.2 mmol) in ethanol (8.3 mL) was stirred at ambient temperature
for 16 h. The solvent was removed under reduced pressure, and
ethanol was added to precipitate the product. The precipitate was
collected by filtration then dried to afford ethyl
2-{[4-(2-hydroxyethoxy)-2-methylphenyl]amino}-4-oxo-4,5-dihydrofuran-3-ca-
rboxylate as solid (0.55 g, y. 42%).
.sup.1H NMR (DMSO-d.sub.6) .delta. (ppm) 9.99 (br. s, 1H), 7.24 (d,
J=7.84 Hz, 1H), 6.89 (br. s, 1H), 6.80 (d, J=8.40 Hz, 1H),
4.83-4.91 (m, 1H), 4.56 (br. s, 2H), 4.20 (q, J=6.95 Hz, 2H), 3.97
(t, J=4.88 Hz, 2H), 3.65-3.74 (m, 2H), 2.20 (s, 3H), 1.24 (t,
J=7.04 Hz, 3H); LCMS (m/z): 322.2 [M+H].sup.+.
Fifth Step
To a solution of 7-azaindole-3-carboxaldehyde (0.16 g, 1.1 mmol)
and ethyl
2-{[4-(2-hydroxyethoxy)-2-methylphenyl]amino}-4-oxo-4,5-dihydrofura-
n-3-carboxylate (0.36 g, 1.1 mmol) in ethanol (11 mL), L-proline
(0.022 g, 0.19 mmol) was added at ambient temperature. The mixture
was refluxed for 2 days. Cooled to ambient temperature, the
precipitate was collected by filtration, washed with diethyl ether
then dried to afford the titled compound as solid (0.24 g, y.
48%).
.sup.1H NMR (DMSO-d.sub.6) .delta. (ppm) 12.27 (br. s, 1H), 10.29
(br. s, 1H), 8.19 (d, J=3.91 Hz, 1H), 7.75 (br. s, 1H), 7.68 (d,
J=7.83 Hz, 1H), 7.41 (d, J=8.31 Hz, 1H), 7.03 (br. s, 1H), 6.94 (d,
J=8.31 Hz, 1H), 6.72-6.86 (m, 2H), 4.97 (t, J=5.38 Hz, 1H), 4.26
(q, J=6.85 Hz, 2H), 4.09 (t, J=4.65 Hz, 2H), 3.80 (dd, J=5.14, 9.98
Hz, 2H), 2.23 (s, 3H), 1.29 (t, J=7.09 Hz, 3H); LCMS (m/z): 450.2
[M+H].sup.+.
Example 75
Ethyl
5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-(benzo[d]thiazol-6-yl-
amino)-4-oxo-4,5-dihydrofuran-3-carboxylate
##STR00085##
To a solution of ethyl
2-(benzo[d]thiazol-6-ylamino)-4-oxo-4,5-dihydrofuran-3-carboxylate
(0.070 g, 0.23 mmol) which similarly prepared according to the
procedure described in the Example 4, First step and
7-azaindole-3-carboxaldehyde (0.034 g, 0.23 mmol) in ethanol (6.0
mL), L-proline (0.0030 g, 0.023 mmol) was added at ambient
temperature. The mixture was refluxed for 16 h. Cooled to ambient
temperature, the precipitate was collected by filtration, washed
with ethanol then dried to afford the titled compound as solid
(0.045 g, y. 45%).
.sup.1H NMR (DMSO-d.sub.6) .delta. (ppm) 12.25 (br. s, 1H), 10.77
(br. s, 1H), 9.52 (s, 1H), 8.40 (s, 1H), 8.23 (d, J=8.80 Hz, 1H),
8.12 (d, J=3.42 Hz, 1H), 7.69-7.85 (m, 3H), 6.89 (s, 1H), 6.36 (t,
J=5.94 Hz, 1H), 4.16-4.47 (m, 2H), 1.31 (t, J=6.85 Hz, 3H); LCMS
(m/z): 433.2 [M+H].sup.+.
Example 76
Ethyl
5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-[4-(2-hydroxyethyl)pi-
perazinyl]-4-oxo-4,5-dihydrofuran-3-carboxylate
##STR00086##
To a solution of ethyl
2-[4-(2-hydroxyethyl)piperazinyl]-4-oxo-4,5-dihydrofuran-3-carboxylate
(0.35 g, 1.2 mmol) which similarly prepared according to the
procedure described in the Example 74, Fourth step and
7-azaindole-3-carboxaldehyde (0.18 g, 1.2 mmol) in ethanol (6.0
mL), piperidine (0.12 mL, 1.4 mmol) was added at ambient
temperature. The mixture was refluxed for 16 h. Cooled to ambient
temperature, the precipitate was collected by filtration, washed
with ethanol then dried to afford the titled compound as solid
(0.050 g, y. 10%).
.sup.1H NMR (DMSO-d.sub.6) .delta. (ppm) 12.34 (br. s, 1H), 8.37
(d, J=7.82 Hz, 1H), 8.31 (d, J=3.91 Hz, 1H), 7.99 (s, 1H), 7.20
(dd, J=4.89, 7.82 Hz, 1H), 6.87 (s, 1H), 4.50 (br. s, 1H), 4.16 (q,
J=7.34 Hz, 2H), 3.71-3.88 (m, 4H), 3.55 (t, J=5.87 Hz, 2H),
2.57-2.72 (m, 4H), 2.40-2.58 (m, 2H), 1.24 (t, J=7.09 Hz, 3H); LCMS
(m/z): 413.2 [M+H].sup.+.
Example 77
Ethyl
5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-(4-hydroxypiperidino)-
-4-oxo-4,5-dihydrofuran-3-carboxylate
##STR00087##
The titled compound (solid) was similarly prepared according to the
procedure described in the Example 76.
.sup.1H NMR (DMSO-d.sub.6) .delta. (ppm) 12.30 (br. s, 1H), 8.37
(d, J=7.82 Hz, 1H), 8.31 (d, J=3.42 Hz, 1H), 7.98 (s, 1H), 7.19
(dd, J=4.40, 7.83 Hz, 1H), 6.85 (s, 1H), 4.92 (d, J=3.91 Hz, 1H),
4.17 (q, J=6.85 Hz, 2H), 3.92-4.02 (m, 2H), 3.80-3.90 (m, 1H), 3.58
(t, J=9.29 Hz, 2H), 1.94 (d, J=3.42 Hz, 2H), 1.52-1.69 (m, 2H),
1.24 (t, J=6.85 Hz, 3H); LCMS (m/z): 384.2 [M+H].sup.+.
Example 78
Ethyl
5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-(4-methylpiperidino)--
4-oxo-4,5-dihydrofuran-3-carboxylate
##STR00088##
The titled compound (solid) was similarly prepared according to the
procedure described in the Example 76.
.sup.1H NMR (DMSO-d.sub.6) .delta. (ppm) 12.30 (br. s, 1H), 8.37
(d, J=7.34 Hz, 1H), 8.31 (d, J=3.91 Hz, 1H), 7.97 (s, 1H), 7.19
(dd, J=4.40, 7.82 Hz, 1H), 6.84 (s, 1H), 4.08-4.29 (m, 4H),
3.22-3.40 (m, 2H), 1.68-1.92 (m, 3H), 1.28-1.42 (m, 2H), 1.24 (t,
J=6.85 Hz, 3H), 0.96 (d, J=5.87 Hz, 3H); LCMS (m/z): 382.2
[M+H].sup.+.
Example 79
Ethyl
5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-morpholino-4-oxo-4,5--
dihydrofuran-3-carboxylate
##STR00089##
The titled compound (solid) was similarly prepared according to the
procedure described in the Example 76.
.sup.1H NMR (DMSO-d.sub.6) .delta. (ppm) 12.34 (br. s, 1H), 8.37
(d, J=7.82 Hz, 1H), 8.31 (d, J=3.42 Hz, 1H), 8.00 (s, 1H), 7.20
(dd, J=4.40, 7.82 Hz, 1H), 6.89 (s, 1H), 4.16 (q, J=7.17 Hz, 2H),
3.73-3.89 (m, 8H), 1.24 (t, J=7.09 Hz, 3H); LCMS (m/z): 370.4
[M+H].sup.+.
Example 80
Ethyl
5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-{[2-fluoro-4-(2-metho-
xyethoxy)phenyl]amino}-4-oxo-4,5-dihydrofuran-3-carboxylate
##STR00090##
To a solution of ethyl
2-{[2-fluoro-4-(2-methoxyethoxy)phenyl]amino}-4-oxo-4,5-dihydrofuran-3-ca-
rboxylate (0.011 g, 0.032 mmol) which similarly prepared according
to the procedure described in the Example 29, First step and
7-azaindole-3-carboxaldehyde (0.0045 g, 0.031 mmol) in ethanol (0.2
mL), 2M hydrochloric acid in ethanol (0.016 mL, 0.032 mmol) was
added at ambient temperature. The mixture was refluxed for 4 h.
Cooled with ice bath, 2M sodium hydroxide solution (0.015 mL, 0.029
mmol) was added dropwise to neutralize, and ethanol (1.5 mL) was
added. The mixture was refluxed for further 30 min. The precipitate
was collected by filtration, washed with hot ethanol. The solid was
washed with hexane then dried to afford the titled compound as
solid (0.0051 g, y. 32%).
.sup.1H NMR (DMSO-d.sub.6) .delta. (ppm) 12.34 (br. s, 1H), 10.38
(s, 1H), 8.21 (dd, J=1.38, 4.64 Hz, 1H), 7.81 (d, J=7.53 Hz, 1H),
7.75 (d, J=2.51 Hz, 1H), 7.58 (t, J=9.03 Hz, 1H), 7.13 (dd, J=2.51,
12.05 Hz, 1H), 6.98 (dd, J=2.26, 8.78 Hz, 1H), 6.89 (s, 1H), 6.82
(dd, J=4.64, 7.91 Hz, 1H), 4.20-4.31 (m, 4H), 3.71-3.77 (m, 2H),
3.37 (br. s, 3H), 1.29 (t, J=7.03 Hz, 3H); LCMS (m/z): 467.9
[M+H].sup.+.
Example 81
Ethyl
5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-{[2-fluoro-4-(2-hydro-
xyethoxy)phenyl]amino}-4-oxo-4,5-dihydrofuran-3-carboxylate
##STR00091##
To a solution of ethyl
2-{[2-fluoro-4-(2-hydroxyethoxy)phenyl]amino}-4-oxo-4,5-dihydrofuran-3-ca-
rboxylate (0.017 g, 0.052 mmol) which similarly prepared according
to the procedure described in the Example 29, First step and
7-azaindole-3-carboxaldehyde (0.0075 g, 0.051 mmol) in ethanol (0.2
mL), 2M hydrochloric acid in ethanol (0.052 mL, 0.10 mmol) was
added at ambient temperature. The mixture was refluxed for 8.5 h.
Cooled with ice bath, 2M sodium hydroxide solution (0.047 mL, 0.094
mmol) was added dropwise to neutralize, and ethanol (0.5 mL) was
added and refluxed for further 16 min. The precipitate was
collected by filtration, washed with hot ethanol. The solid was
washed with hexane then dried to afford the titled compound as
solid (0.014 g, y. 59%).
.sup.1H NMR (DMSO-d.sub.6) .delta. (ppm) 12.14 (br. s, 1H), 10.38
(s, 1H), 8.21 (dd, J=1.20, 4.80 Hz, 1H), 7.87 (d, J=7.20 Hz, 1H),
7.65 (br. s, 1H), 7.38 (br. s, 1H), 6.95-7.07 (m, 1H), 6.85-6.95
(m, 1H), 6.83 (dd, J=4.80, 8.00 Hz, 1H), 6.64 (br. s, 1H), 4.96 (t,
J=5.40 Hz, 1H), 4.15-4.25 (m, 2H), 4.09 (t, J=4.80 Hz, 2H), 3.78
(q, J=5.07 Hz, 2H), 1.26 (t, J=7.00 Hz, 3H); LCMS (m/z): 453.8
[M+H].sup.+.
Example 82
Ethyl
5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-{[2-(2-methoxyethoxy)-
-4-methylphenyl]amino}-4-oxo-4,5-dihydrofuran-3-carboxylate
##STR00092##
To a solution of ethyl
2-{[2-(2-methoxyethoxy)-4-methylphenyl]amino}-4-oxo-4,5-dihydrofuran-3-ca-
rboxylate (0.015 g, 0.045 mmol) which similarly prepared according
to the procedure described in the Example 29, First step and
7-azaindole-3-carboxaldehyde (0.0067 g, 0.046 mmol) in ethanol (0.2
mL), 2M hydrochloric acid in ethanol (0.023 mL, 0.045 mmol) was
added at ambient temperature. The mixture was refluxed for 4 h.
Cooled to ambient temperature, the solvent was removed under
reduced pressure. The residue was purified by preparative HPLC to
afford the titled compound as solid (0.0090 g, y. 43%).
.sup.1H NMR (DMSO-d.sub.6) .delta. (ppm) 12.29 (br. s, 1H), 10.30
(br. s, 1H), 8.25 (dd, J=1.38, 4.64 Hz, 1H), 8.00 (d, J=7.03 Hz,
1H), 7.83 (s, 1H), 7.49 (d, J=7.78 Hz, 1H), 7.10 (s, 1H), 6.84-6.95
(m, 3H), 4.26 (q, J=7.03 Hz, 2H), 4.09-4.17 (m, 2H), 3.53-3.60 (m,
2H), 3.17 (s, 3H), 2.43 (s, 3H), 1.29 (t, J=7.03 Hz, 3H); LCMS
(m/z): 463.9 [M+H].sup.+.
Example 83
Ethyl
5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-({2-[2-(dimethylamino-
)ethoxy]-4-methylphenyl}amino)-4-oxo-4,5-dihydrofuran-3-carboxylate
##STR00093##
To a stirred solution of ethyl
2-({2-[2-(dimethylamino)ethoxy]-4-methylphenyl}amino)-4-oxo-4,5-dihydrofu-
ran-3-carboxylate (0.011 g, 0.030 mmol) which similarly prepared
according to the procedure described in the Example 29, First step
and 7-azaindole-3-carboxaldehyde (0.0044 g, 0.030 mmol) in ethanol
(0.2 mL), 2M hydrochloric acid in ethanol (0.045 mL, 0.091 mmol)
was added at ambient temperature. The mixture was refluxed for 9 h.
Cooled with ice bath, 2M sodium hydroxide solution (0.041 mL, 0.082
mmol) was added dropwise to neutralize, and ethanol (0.5 mL) was
added. The mixture was refluxed for further 16 min. The precipitate
was collected by filtration, washed with hot ethanol. The solid was
washed with hexane then dried to afford the titled compound as
solid (0.00079 g, y. 5%).
.sup.1H NMR (DMSO-d.sub.6) .delta. (ppm) 12.27 (br. s, 1H), 8.24
(d, J=4.52 Hz, 1H), 8.16 (s, 1H), 7.96 (d, J=8.03 Hz, 1H),
7.79-7.82 (m, 1H), 7.46 (d, J=7.53 Hz, 1H), 7.09-7.12 (m, 1H), 6.93
(d, J=7.53 Hz, 1H), 6.81-6.89 (m, 2H), 4.25 (q, J=6.94 Hz, 2H),
4.10 (t, J=4.64 Hz, 2H), 2.52-2.58 (m, 2H), 2.43 (s, 3H), 2.13 (s,
6H), 1.29 (t, J=7.03 Hz, 3H); LCMS (m/z): 477.0 [M+H].sup.+.
Example 84
Isopropyl
5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-[(4-fluorophenyl)-
amino]-4-oxo-4,5-dihydrofuran-3-carboxylate
##STR00094##
Under a nitrogen atmosphere, a solution of the compound (0.039 g,
0.10 mmol) of Example 21, 4-dimethylaniline (0.0024 g, 0.020 mmol)
and zinc cluster catalyst (Zn.sub.4(OCOCF.sub.3).sub.6O) (0.0012 g,
0.0013 mmol) in 2-propanol (1.0 mL) and N,N-dimethylacetamide (1.0
mL) was stirred with the microwave synthesizer (Biotage
Initiator.TM.) at 150.degree. C. for 1.5 h. Cooled to ambient
temperature, the precipitate was removed by filtration. The
filtrate was purified by preparative HPLC to afford the titled
compound as solid (0.011 g, y. 27%).
.sup.1H NMR (DMSO-d.sub.6) .delta. (ppm) 12.29 (br. s, 1H), 10.54
(s, 1H), 8.25 (dd, J=1.51, 4.77 Hz, 1H), 7.94 (d, J=7.03 Hz, 1H),
7.76 (d, J=2.76 Hz, 1H), 7.56-7.70 (m, 2H), 7.28-7.44 (m, 2H),
6.80-6.98 (m, 2H), 5.08-5.17 (m, 1H), 1.31 (d, J=6.27 Hz, 6H); LCMS
(m/z): 408.0 [M+H].sup.+.
Example 85
Cyclopropylmethyl
5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-[(4-fluorophenyl)amino]-4--
oxo-4,5-dihydrofuran-3-carboxylate
##STR00095##
Under a nitrogen atmosphere, a solution of the compound (0.038 g,
0.10 mmol) of Example 51, cyclopropyl carbinol (0.10 mL, 1.3 mmol)
and zinc cluster catalyst (Zn.sub.4(OCOCF.sub.3).sub.6O) (0.0019 g,
0.0020 mmol) in N,N-dimethylacetamide (0.9 mL) was stirred with the
microwave synthesizer (Biotage Initiator.TM.) at 150.degree. C. for
30 min. Cooled to ambient temperature, the precipitate was removed
by filtration. The filtrate was purified by preparative HPLC to
afford the titled compound as solid (0.0080 g, y. 19%).
.sup.1H NMR (DMSO-d.sub.6) .delta. (ppm) 12.29 (br. s, 1H), 10.57
(s, 1H), 8.25 (d, J=3.51 Hz, 1H), 7.95 (d, J=7.78 Hz, 1H), 7.75 (d,
J=2.51 Hz, 1H), 7.60-7.69 (m, 2H), 7.34-7.43 (m, 2H), 6.85-6.95 (m,
2H), 4.08 (d, J=7.03 Hz, 2H), 1.16-1.31 (m, 1H), 0.55 (dd, J=1.51,
8.03 Hz, 2H), 0.36 (d, J=5.02 Hz, 2H); LCMS (m/z): 419.8
[M+H].sup.+.
Example 86
Methyl
5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-[(2,4-difluorophenyl-
)amino]-4-oxo-4,5-dihydrofuran-3-carboxylate
##STR00096##
To a solution of methyl
2-[(2,4-difluorophenyl)amino]-4-oxo-4,5-dihydrofuran-3-carboxylate
(0.27 g, 1.0 mmol) which similarly prepared according to the
procedure described in the Example 2, First step using methyl
4-chloroacetoacetate and 2,4-difluorophenyl isocyanate, and
7-azaindole-3-carboxaldehyde (0.15 g, 1.0 mmol) in 2-propanol (5.0
mL), L-proline (0.023 g, 0.20 mmol) was added at ambient
temperature. The mixture was refluxed for 12 h. Cooled to ambient
temperature, the precipitate was collected by filtration, washed
with ethanol and diisopropyl ether then dried to afford the titled
compound as solid (0.30 g, y. 75%).
.sup.1H NMR (DMSO-d.sub.6) .delta. (ppm) 12.32 (br. s, 1H), 10.53
(s, 1H), 8.24 (dd, J=1.38, 4.64 Hz, 1H), 7.74-7.87 (m, 2H), 7.70
(d, J=2.51 Hz, 1H), 7.54-7.63 (m, 1H), 7.27-7.37 (m, 1H), 6.94 (s,
1H), 6.84 (dd, J=4.77, 8.03 Hz, 1H), 3.77 (s, 3H); LCMS (m/z):
397.9 [M+H].sup.+.
Example 87
Ethyl
5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-[bis(2-methoxyethyl)a-
mino]-4-oxo-4,5-dihydrofuran-3-carboxylate
##STR00097##
To a solution of ethyl
2-[bis(2-methoxyethyl)amino]-4-oxo-4,5-dihydrofuran-3-carboxylate
(0.30 g, 1.0 mmol) which similarly prepared according to the
procedure described in the Example 4, First step and
7-azaindole-3-carboxaldehyde (0.15 g, 1.0 mmol) in ethanol (5.0
mL), L-proline (0.023 g, 0.20 mmol) was added at ambient
temperature. The mixture was refluxed for 2 days. Cooled to ambient
temperature, the precipitate was collected by filtration, washed
with ethanol then dried to afford the titled compound as solid
(0.048 g, y. 11%).
.sup.1H NMR (DMSO-d.sub.6) .delta. (ppm) 12.36 (br. s, 1H), 8.38
(d, J=7.82 Hz, 1H), 8.31 (d, J=4.89 Hz, 1H), 7.98 (s, 1H), 7.19
(dd, J=4.65, 8.07 Hz, 1H), 6.85 (s, 1H), 4.16 (q, J=6.85 Hz, 2H),
3.97 (t, J=5.14 Hz, 4H), 3.57-3.67 (m, 4H), 3.25 (s, 6H), 1.24 (t,
J=7.09 Hz, 3H); LCMS (m/z): 416.2 [M+H].sup.+.
Example 88
Ethyl
5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-{[4-(hydroxymethyl)ph-
enyl]amino}-4-oxo-4,5-dihydrofuran-3-carboxylate
##STR00098##
The titled compound (solid) was similarly prepared according to the
procedure described in the Example 87.
.sup.1H NMR (DMSO-d.sub.6) .delta. (ppm) 12.27 (br. s, 1H), 10.66
(br. s, 1H), 8.22 (d, J=3.42 Hz, 1H), 7.97 (d, J=7.34 Hz, 1H), 7.79
(br. s, 1H), 7.42-7.55 (m, 4H), 6.86-6.94 (m, 1H), 6.84 (br. s,
1H), 5.34 (br. s, 1H), 4.62 (d, J=4.40 Hz, 2H), 4.26 (d, J=6.85 Hz,
2H), 1.29 (t, J=6.85 Hz, 3H); LCMS (m/z): 406.4 [M+H].sup.+.
Example 89
3-Hydroxypropyl
5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-[(4-fluorophenyl)amino]-4--
oxo-4,5-dihydrofuran-3-carboxylate
##STR00099##
A solution of the compound of Example 51 and zinc cluster catalyst
(Zn.sub.4(OCOCF.sub.3).sub.6O) (0.0019 g, 0.0020 mmol) in
1,3-propanediol (0.5 mL) and N,N-dimethylacetamide (0.5 mL) was
stirred at 120.degree. C. for 2 h then at 100.degree. C. for 12 h.
Cooled to ambient temperature, the reaction mixture was diluted
with water, and the precipitate was collected by filtration. Ethyl
acetate was added to the filtrate, and the precipitate was
collected by filtration. Those precipitates were combined then
purified by preparative HPLC to afford the titled compound as solid
(0.0067 g, y. 16%).
.sup.1H NMR (DMSO-d.sub.6) .delta. (ppm) 12.22 (br. s, 1H), 10.72
(br. s, 1H), 8.24 (dd, J=1.38, 4.64 Hz, 1H), 7.97 (d, J=7.03 Hz,
1H), 7.72 (d, J=2.51 Hz, 1H), 7.50-7.60 (m, 2H), 7.35 (t, J=8.78
Hz, 2H), 6.89 (dd, J=4.52, 8.03 Hz, 1H), 6.81 (br. s, 1H), 4.77
(br. s, 1H), 4.25 (t, J=6.27 Hz, 2H), 3.59 (t, J=5.77 Hz, 2H),
1.79-1.87 (m, 2H); LCMS (m/z): 423.8 [M+H].sup.+.
Example 90
Isopropyl
5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-[(2,4-difluorophe-
nyl)amino]-4-oxo-4,5-dihydrofuran-3-carboxylate
##STR00100##
A solution of the compound (0.040 g, 0.10 mmol) of Example 86 and
zinc cluster catalyst (Zn.sub.4(OCOCF.sub.3).sub.6O) (0.0012 g,
0.0013 mmol) in 2-propanol (0.5 mL) was stirred at 95.degree. C.
for 4 days. Cooled to ambient temperature, the reaction mixture was
purified by preparative HPLC to afford the titled compound as solid
(0.0061 g, y. 13%).
.sup.1H NMR (DMSO-d.sub.6) .delta. (ppm) 12.32 (br. s, 1H), 10.47
(s, 1H), 8.24 (dd, J=1.51, 4.52 Hz, 1H), 7.67-7.88 (m, 3H),
7.54-7.63 (m, 1H), 7.26-7.38 (m, 1H), 6.88 (s, 1H), 6.83 (dd,
J=4.64, 7.91 Hz, 1H), 5.10-5.18 (m, 1H), 1.31 (d, J=6.27 Hz, 6H);
LCMS (m/z): 426.2 [M+H].sup.+.
Example 91
2-(Dimethylamino)ethyl
5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-[(2,4-difluorophenyl)amino-
]-4-oxo-4,5-dihydrofuran-3-carboxylate
##STR00101##
A solution of the compound (0.040 g, 0.10 mmol) of Example 86,
2-dimethylaminoethanol (0.10 mL, 1.0 mmol) and zinc cluster
catalyst (Zn.sub.4(OCOCF.sub.3).sub.6O) (0.0019 g, 0.0020 mmol) in
N,N-dimethylacetamide (0.9 mL) was stirred at 100.degree. C. for 24
h. Cooled to ambient temperature, the precipitate was removed by
filtration. The filtrate was purified by preparative HPLC to afford
the titled compound as solid (0.010 g, y. 22%).
.sup.1H NMR (DMSO-d.sub.6) .delta. (ppm) 11.97 (br. s, 1H), 8.19
(dd, J=1.51, 4.52 Hz, 1H), 8.14 (s, 1H), 7.93 (d, J=7.78 Hz, 1H),
7.52 (br. s, 1H), 7.16-7.36 (m, 2H), 7.03-7.13 (m, 1H), 6.83 (dd,
J=4.89, 7.91 Hz, 1H), 6.42 (s, 1H), 4.35 (t, J=5.27 Hz, 2H), 3.22
(t, J=5.27 Hz, 2H), 2.67-2.87 (m, 6H); LCMS (m/z): 455.2
[M+H].sup.+.
Example 92
5-[(1H-Pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-[(2,4-difluorophenyl)amino]-
-4-oxo-4,5-dihydrofuran-3-carboxylic acid
##STR00102##
To a solution of the compound (0.20 g, 0.45 mmol) of Example 53 in
ethanol (2.0 mL), aqueous 50% w/v potassium hydroxide solution (0.5
mL) was added at ambient temperature. The mixture was stirred at
95.degree. C. for 3 h. Cooled to ambient temperature, diluted with
water and conc. hydrochloric acid was added dropwise to neutralize.
The precipitate was collected by filtration, washed with ethanol
and diisopropyl ether then dried to afford the titled compound as
solid (0.19 g, y. 98%).
.sup.1H NMR (DMSO-d.sub.6) .delta. (ppm) 12.36 (br. s, 1H), 8.25
(dd, J=1.51, 4.52 Hz, 1H), 7.86 (d, J=7.03 Hz, 1H), 7.69-7.82 (m,
2H), 7.57 (ddd, J=2.76, 8.97, 10.35 Hz, 1H), 7.25-7.37 (m, 1H),
7.01 (s, 1H), 6.85 (dd, J=4.77, 8.03 Hz, 1H); LCMS (m/z): 381.9
[M-H].sup.-
Example 93
Ethyl
5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-{[2-(2-hydroxyethoxy)-
-4-methylphenyl]amino}-4-oxo-4,5-dihydrofuran-3-carboxylate
##STR00103##
To a solution of ethyl
5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-[(2,4-difluorophenyl)amino-
]-4-oxo-4,5-dihydrofuran-3-carboxylate (0.017 g, 0.052 mmol) which
similarly prepared according to the procedure described in the
Example 29, First step and 7-azaindole-3-carboxaldehyde (0.0075 g,
0.051 mmol) in ethanol (0.2 mL), 2M hydrochloric acid in ethanol
(0.052 mL, 0.10 mmol) was added at ambient temperature. The mixture
was refluxed for 8.5 h. Cooled with ice bath, 2M sodium hydroxide
solution (0.047 mL, 0.094 mmol) was added dropwise to neutralize
then the solvent was removed under reduced pressure. The residue
was purified by preparative HPLC to afford the titled compound as
solid (0.0066 g, y. 28%).
.sup.1H NMR (DMSO-d.sub.6) .delta. (ppm) 12.30 (br. s, 1H), 10.22
(br. s, 1H), 8.25 (d, J=3.51 Hz, 1H), 8.03 (d, J=7.78 Hz, 1H), 7.83
(br. s, 1H), 7.43-7.56 (m, 1H), 7.10 (s, 1H), 6.85-6.95 (m, 3H),
4.79 (br. s, 1H), 4.26 (q, J=7.19 Hz, 2H), 4.06 (t, J=5.14 Hz, 2H),
3.62 (t, J=5.20 Hz, 2H), 2.42 (s, 3H), 1.29 (t, J=7.15 Hz, 3H);
LCMS (m/z): 449.5 [M+H].sup.+.
Example 94
Methyl
5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-(cyclopropylamino)-4-
-oxo-4,5-dihydrofuran-3-carboxylate
##STR00104##
To a solution of methyl
2-(cyclopropylamino)-4-oxo-4,5-dihydrofuran-3-carboxylate (0.50 g,
2.5 mmol) which similarly prepared according to the procedure
described in the Example 4, First step using dimethyl malonate,
chloroacetyl chloride and cyclopropylamine, and
7-azaindole-3-carboxaldehyde (0.37 g, 2.5 mmol) in ethanol (6.0
mL), L-proline (0.029 g, 0.25 mmol) was added at ambient
temperature. The mixture was refluxed for 16 h. Cooled to ambient
temperature, the precipitate was collected by filtration, washed
with methanol then dried to afford the titled compound as solid
(0.012 g, y. 30%).
.sup.1H NMR (DMSO-d.sub.6) .delta. (ppm) 12.33 (br. s, 1H), 8.88
(br. s, 1H), 8.57 (d, J=7.82 Hz, 1H), 8.31 (d, J=3.91 Hz, 1H), 8.06
(s, 1H), 7.20 (dd, J=4.89, 7.82 Hz, 1H), 6.94 (s, 1H), 3.69 (s,
3H), 3.08-3.20 (m, 1H), 0.84-1.00 (m, 4H); LCMS (m/z): 326.0
[M+H].sup.+.
Example 95
Ethyl
5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-[(2-hydroxy-4-methylp-
henyl)amino]-4-oxo-4,5-dihydrofuran-3-carboxylate
##STR00105##
To a solution of ethyl
2-[(2-hydroxy-4-methylphenyl)amino]-4-oxo-4,5-dihydrofuran-3-carboxylate
(0.10 g, 0.36 mmol) which similarly prepared according to the
procedure described in the Example 74, Fourth step and
7-azaindole-3-carboxaldehyde (0.061 g, 0.42 mmol) in ethanol (2.5
mL), 2M hydrochloric acid in ethanol (0.56 mL, 1.1 mmol) was added
at ambient temperature. The mixture was refluxed for 19 h. Cooled
with ice bath, 2M sodium hydroxide solution (0.49 mL, 0.97 mmol)
was added dropwise to neutralize, and ethanol (8.0 mL) was added
and the mixture was refluxed for 30 min. The precipitate was
collected by filtration, washed with hot ethanol. The solid was
washed with hexane then dried to afford the titled compound as
solid (0.027 g, y. 18%).
.sup.1H NMR (DMSO-d.sub.6) .delta. (ppm) 12.32 (br. s, 1H), 10.21
(s, 1H), 10.19 (s, 1H), 8.22-8.30 (m, 1H), 8.04 (d, J=7.53 Hz, 1H),
7.87 (d, J=2.26 Hz, 1H), 7.44 (d, J=8.03 Hz, 1H), 6.84-6.94 (m,
3H), 6.77 (d, J=8.03 Hz, 1H), 4.27 (q, J=7.03 Hz, 2H), 2.35 (s,
3H), 1.30 (t, J=7.03 Hz, 3H); LCMS (m/z): 405.9 [M+H].sup.+.
Example 96
Ethyl
5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-[(4-hydroxy-2-methylp-
henyl)amino]-4-oxo-4,5-dihydrofuran-3-carboxylate
##STR00106##
To a solution of ethyl
2-[(4-hydroxy-2-methylphenyl)amino]-4-oxo-4,5-dihydrofuran-3-carboxylate
(0.10 g, 0.37 mmol) which similarly prepared according to the
procedure described in the Example 74, Fourth step and
7-azaindole-3-carboxaldehyde (0.063 g, 0.43 mmol) in ethanol (2.5
mL), 2M hydrochloric acid in ethanol (0.46 mL, 0.92 mmol) was added
at ambient temperature. The mixture was refluxed for 2.5 days.
Cooled with ice bath, 2M sodium hydroxide solution (0.46 mL, 0.92
mmol) was added dropwise to neutralize, and ethanol (11 mL) was
added and the mixture was refluxed for further 40 min. The
precipitate was collected by filtration, washed with hot ethanol.
The solid was washed with hexane then dried to afford the titled
compound as solid (0.10 g, y. 70%).
.sup.1H NMR (DMSO-d.sub.6) .delta. (ppm) 12.27 (br. s, 1H), 10.20
(s, 1H), 9.76 (s, 1H), 8.20 (dd, J=1.25, 4.52 Hz, 1H), 7.81 (d,
J=2.51 Hz, 1H), 7.64 (d, J=7.53 Hz, 1H), 7.28 (d, J=8.28 Hz, 1H),
6.72-6.87 (m, 4H), 4.26 (q, J=7.03 Hz, 2H), 2.16 (s, 3H), 1.29 (t,
J=7.03 Hz, 3H); LCMS (m/z): 405.8 [M+H].sup.+.
Example 97
Ethyl
5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-[(4-fluoro-2-methylph-
enyl)amino]-4-oxo-4,5-dihydrofuran-3-carboxylate
##STR00107##
To a solution of ethyl
2-[(4-fluoro-2-methylphenyl)amino]-4-oxo-4,5-dihydrofuran-3-carboxylate
(0.30 g, 1.1 mmol) which similarly prepared according to the
procedure described in the Example 4, First step and
7-azaindole-3-carboxaldehyde (0.16 g, 1.1 mmol) in ethanol (7.0
mL), L-proline (0.013 g, 0.10 mmol) was added at ambient
temperature. The mixture was refluxed for 3 days. Cooled to ambient
temperature, the precipitate was collected by filtration, washed
with methanol then dried to afford the titled compound as solid
(0.25 g, y. 58%).
.sup.1H NMR (DMSO-d.sub.6) .delta. (ppm) 12.28 (br. s, 1H), 10.40
(s, 1H), 8.22 (d, J=3.91 Hz, 1H), 7.66-7.76 (m, 2H), 7.59 (dd,
J=5.62, 8.56 Hz, 1H), 7.36 (dd, J=2.45, 9.78 Hz, 1H), 7.18-7.28 (m,
1H), 6.85 (s, 1H), 6.78 (dd, J=4.89, 7.83 Hz, 1H), 4.27 (q, J=7.01
Hz, 2H), 2.27 (s, 3H), 1.30 (t, J=7.09 Hz, 3H); LCMS (m/z): 408.4
[M+H].sup.+.
Example 98
Methyl
5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-[(2-methoxyethyl)ami-
no]-4-oxo-4,5-dihydrofuran-3-carboxylate
##STR00108##
The titled compound (solid) was similarly prepared according to the
procedure described in the Example 97.
.sup.1H NMR (DMSO-d.sub.6) .delta. (ppm) 12.36 (br. s, 1H), 8.94
(br. s, 1H), 8.44 (d, J=7.83 Hz, 1H), 8.31 (d, J=4.40 Hz, 1H), 8.03
(s, 1H), 7.19 (dd, J=4.40, 7.82 Hz, 1H), 6.92 (s, 1H), 3.76-3.84
(m, 2H), 3.71 (s, 3H), 3.62 (t, J=5.14 Hz, 2H), 3.31 (br. s, 3H);
LCMS (m/z): 344.2 [M+H].sup.+.
Example 99
Ethyl
5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-{[4-(2-methoxyethoxy)-
-2-methylphenyl]amino}-4-oxo-4,5-dihydrofuran-3-carboxylate
##STR00109## First Step
To a solution of ethyl
2-[(4-hydroxy-2-methylphenyl)amino]-4-oxo-4,5-dihydrofuran-3-carboxylate
(0.10 g, 0.36 mmol) which similarly prepared according to the
procedure described in the Example 74, Fourth step,
2-methoxyethanol (0.051 mL, 0.65 mmol) and triphenylphosphine (0.19
g, 0.72 mmol) in dichloromethane (2.0 mL) that cooled with ice
bath, 2.2M diethyl azodicarboxylate (40% in toluene, 0.33 mL, 0.73
mmol) was added dropwise then the mixture was stirred at ambient
temperature for 24 h. The reaction mixture was diluted with water,
and extracted with chloroform. The organic layer was washed with 1M
sodium hydroxide solution and brine, dried over magnesium sulfate
and concentrated to afford ethyl
2-{[4-(2-methoxyethoxy)-2-methylphenyl]amino}-4-oxo-4,5-dihydrofuran-3-ca-
rboxylate as oil (0.30 g, crude material).
Second Step
To a solution of ethyl
2-{[4-(2-methoxyethoxy)-2-methylphenyl]amino}-4-oxo-4,5-dihydrofuran-3-ca-
rboxylate (0.12 g, 0.36 mmol, crude material) which afforded in the
previous step and 7-azaindole-3-carboxaldehyde (0.043 g, 0.30 mmol)
in ethanol (4.0 mL), 2M hydrochloric acid in ethanol (0.30 mL, 0.60
mmol) was added at ambient temperature. The mixture was refluxed
for 24 h. Cooled with ice bath, 2M sodium hydroxide solution (0.30
mL, 0.60 mmol) was added dropwise to neutralize, and the solvent
was removed under reduced pressure. The residue was suspended in
chloroform, then the precipitate was collected by filtration,
washed with water, ethanol and hexane then dried to afford the
titled compound as solid (0.028 g, y. 12%).
.sup.1H NMR (DMSO-d.sub.6) .delta. (ppm) 11.78 (br. s, 1H), 8.13
(d, J=3.51 Hz, 1H), 7.89 (d, J=7.53 Hz, 1H), 7.47 (s, 1H),
6.77-6.90 (m, 3H), 6.72 (d, J=8.28 Hz, 1H), 6.12 (s, 1H), 4.05-4.14
(m, 2H), 3.66-3.74 (m, 2H), 3.36 (s, 3H), 3.28-3.35 (m, 2H), 2.08
(s, 3H), 1.22 (t, J=7.03 Hz, 3H); LCMS (m/z): 464.0
[M+H].sup.+.
Example 100
Ethyl
5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-{[2-methyl-4-(2-morph-
olinoethoxy)phenyl]amino}-4-oxo-4,5-dihydrofuran-3-carboxylate
##STR00110##
To a stirred solution of ethyl
2-({2-methyl-4-[2-(N-morpholino)ethoxy]phenyl}amino)-4-oxo-4,5-dihydrofur-
an-3-carboxylate (0.14 g, 0.36 mmol) which similarly prepared
according to the procedure described in the Example 99, First step
and 7-azaindole-3-carboxaldehyde (0.038 g, 0.26 mmol) in ethanol
(4.0 mL), 2M hydrochloric acid in ethanol (0.60 mL, 1.2 mmol) was
added at ambient temperature. The mixture was refluxed for 2 days.
Cooled with ice bath, 2M sodium hydroxide solution (0.57 mL, 1.1
mmol) was added dropwise to neutralize and refluxed for further 10
min. Then the solvent was removed under reduced pressure. The
precipitate was collected by filtration, washed with water and
ethyl acetate then dried to afford the titled compound as solid
(0.010 g, y. 5%).
.sup.1H NMR (DMSO-d.sub.6) .delta. (ppm) 12.28 (br. s, 1H), 10.29
(s, 1H), 8.19 (dd, J=1.26, 4.52 Hz, 1H), 7.77 (s, 1H), 7.67 (d,
J=7.78 Hz, 1H), 7.42 (d, J=8.53 Hz, 1H), 7.05 (br. s, 1H), 6.95 (d,
J=8.28 Hz, 1H), 6.83 (s, 1H), 6.74 (dd, J=4.77, 7.78 Hz, 1H), 4.27
(q, J=7.03 Hz, 2H), 4.15-4.23 (m, 2H), 3.58-3.68 (m, 4H), 2.74-2.82
(m, 2H), 2.50-2.60 (m, 4H), 2.23 (s, 3H), 1.30 (t, J=7.03 Hz, 3H);
LCMS (m/z): 519.0 [M+H].sup.+.
Example 101
Methyl
5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-[(2-fluorobenzyl)ami-
no]-4-oxo-4,5-dihydrofuran-3-carboxylate
##STR00111##
To a solution of methyl
2-[(2-fluorobenzyl)amino]-4-oxo-4,5-dihydrofuran-3-carboxylate
(0.35 g, 1.5 mmol) which similarly prepared according to the
procedure described in the Example 4, First step using dimethyl
malonate, chloroacetyl chloride and 2-fluorobenzylamine, and
7-azaindole-3-carboxaldehyde (0.22 g, 1.5 mmol) in ethanol (10 mL),
L-proline (0.018 g, 0.15 mmol) was added at ambient temperature.
The mixture was refluxed for 3 days. Cooled to ambient temperature,
the precipitate was collected by filtration, washed with methanol
then dried to afford the titled compound as solid (0.13 g, y.
24%).
.sup.1H NMR (DMSO-d.sub.6) .delta. (ppm) 12.36 (br. s, 1H), 9.49
(br. s, 1H), 8.28 (br. s, 2H), 7.86 (br. s, 1H), 7.16-7.53 (m, 4H),
7.07 (br. s, 1H), 6.90 (br. s, 1H), 4.91 (br. s, 2H), 3.73 (br. s,
3H); LCMS (m/z): 394.4 [M+H].sup.+.
Example 102
Ethyl
5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-(3,4-dihydroisoquinol-
in-2(1H)-yl)-4-oxo-4,5-dihydrofuran-3-carboxylate
##STR00112##
To a solution of ethyl
2-(3,4-dihydroisoquinolin-2(1H-)yl)-4-oxo-4,5-dihydrofuran-3-carboxylate
(0.15 g, 0.60 mmol) which similarly prepared according to the
procedure described in the Example 4, First step and
7-azaindole-3-carboxaldehyde (0.091 g, 0.60 mmol) in ethanol (5.0
mL), L-proline (0.0070 g, 0.060 mmol) was added at ambient
temperature. The mixture was refluxed for 3 days. Cooled to ambient
temperature, the precipitate was collected by filtration, washed
with methanol then dried to afford the titled compound as solid
(0.037 g, y. 14%).
.sup.1H NMR (DMSO-d.sub.6) .delta. (ppm) 12.36 (br. s, 1H), 8.42
(d, J=7.82 Hz, 1H), 8.33 (d, J=3.91 Hz, 1H), 8.07 (s, 1H),
7.17-7.37 (m, 5H), 6.90 (s, 1H), 4.98 (br. s, 2H), 4.21 (q, J=6.85
Hz, 2H), 3.97 (br. s, 2H), 3.09 (t, J=5.62 Hz, 2H), 1.27 (t, J=7.09
Hz, 3H); LCMS (m/z): 416.2 [M+H].sup.+.
Example 103
Ethyl
5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-(cyclopentylamino)-4--
oxo-4,5-dihydrofuran-3-carboxylate
##STR00113##
The titled compound (solid) was similarly prepared according to the
procedure described in the Example 102.
.sup.1H NMR (DMSO-d.sub.6) .delta. (ppm) 12.32 (br. s, 1H), 8.53
(br. s, 1H), 8.42 (d, J=7.82 Hz, 1H), 8.32 (d, J=4.40 Hz, 1H), 8.01
(s, 1H), 7.20 (dd, J=4.40, 7.83 Hz, 1H), 6.90 (s, 1H), 4.50 (br. s,
1H), 4.21 (q, J=6.85 Hz, 2H), 2.02-2.15 (m, 2H), 1.57-1.71 (m, 6H),
1.26 (t, J=7.09 Hz, 3H); LCMS (m/z): 368.0 [M+H].sup.+.
Example 104
Methyl
5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-[(cyclopropylmethyl)-
amino]-4-oxo-4,5-dihydrofuran-3-carboxylate
##STR00114##
To a solution of methyl
2-[(cyclopropylmethyl)amino]-4-oxo-4,5-dihydrofuran-3-carboxylate
(0.30 g, 1.4 mmol) which similarly prepared according to the
procedure described in the Example 4, First step using dimethyl
malonate, chloroacetyl chloride and cyclopropylmethylamine, and
7-azaindole-3-carboxaldehyde (0.21 g, 1.4 mmol) in ethanol (10 mL),
L-proline (0.016 g, 0.14 mmol) was added at ambient temperature.
The mixture was refluxed for 3 days. Cooled to ambient temperature,
the precipitate was collected by filtration, washed with methanol
then dried to afford the titled compound as solid (0.065 g, y.
14%).
.sup.1H NMR (DMSO-d.sub.6) .delta. (ppm) 12.33 (br. s, 1H), 9.08
(br. s, 1H), 8.42 (d, J=7.82 Hz, 1H), 8.31 (d, J=3.42 Hz, 1H), 8.00
(s, 1H), 7.19 (dd, J=4.40, 7.34 Hz, 1H), 6.92 (s, 1H), 3.72 (s,
3H), 3.52 (d, J=6.36 Hz, 2H), 1.23 (br. s, 1H), 0.52 (d, J=7.34 Hz,
2H), 0.37 (d, J=3.91 Hz, 2H); LCMS (m/z): 340.4 [M+H].sup.+.
Example 105
Ethyl
5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-isoindolinyl-4-oxo-4,-
5-dihydrofuran-3-carboxylate
##STR00115##
To a solution of ethyl
2-isoindolinyl-4-oxo-4,5-dihydrofuran-3-carboxylate (0.20 g, 0.70
mmol) which similarly prepared according to the procedure described
in the Example 4, First step and 7-azaindole-3-carboxaldehyde (0.11
g, 0.70 mmol) in ethanol (10 mL), L-proline (0.0080 g, 0.070 mmol)
was added at ambient temperature. The mixture was refluxed for 3
days. Cooled to ambient temperature, the precipitate was collected
by filtration, washed with methanol then dried to afford the titled
compound as solid (0.080 g, y. 27%).
.sup.1H NMR (DMSO-d.sub.6) .delta. (ppm) 12.39 (br. s, 1H), 8.44
(d, J=7.34 Hz, 1H), 8.33 (d, J=3.91 Hz, 1H), 8.08 (s, 1H),
7.43-7.53 (m, 2H), 7.33-7.43 (m, 2H), 7.23 (dd, J=4.89, 7.82 Hz,
1H), 6.91 (s, 1H), 5.37 (br. s, 2H), 5.17 (br. s, 2H), 4.23 (q,
J=7.34 Hz, 2H), 1.29 (t, J=7.09 Hz, 3H); LCMS (m/z): 402.0
[M+H].sup.+.
Example 106
Ethyl
5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-4-oxo-2-[(1-phenylethyl-
)amino]-4,5-dihydrofuran-3-carboxylate
##STR00116##
To a solution of ethyl
4-oxo-2-[(1-phenylethyl)amino]-4,5-dihydrofuran-3-carboxylate (0.40
g, 1.5 mmol) which similarly prepared according to the procedure
described in the Example 4, First step and
7-azaindole-3-carboxaldehyde (0.21 g, 1.5 mmol) in ethanol (20 mL),
L-proline (0.017 g, 0.15 mmol) was added at ambient temperature.
The mixture was refluxed for 3 days. Cooled to ambient temperature,
the precipitate was collected by filtration, washed with methanol
then dried to afford the titled compound as solid (0.20 g, y.
34%).
.sup.1H NMR (DMSO-d.sub.6) .delta. (ppm) 12.35 (br. s, 1H), 8.97
(br. s, 1H), 8.25-8.34 (m, 2H), 7.82 (br. s, 1H), 7.49-7.57 (m,
2H), 7.38-7.45 (m, 2H), 7.24-7.33 (m, 1H), 7.12-7.19 (m, 1H), 6.86
(s, 1H), 5.41 (br. s, 1H), 4.24 (q, J=6.68 Hz, 2H), 1.70 (d, J=6.36
Hz, 3H), 1.27 (t, J=6.85 Hz, 3H); LCMS (m/z): 403.8
[M+H].sup.+.
Example 107
Ethyl
5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-[3-(2,6-dimethylpyrid-
inyl)amino]-4-oxo-4,5-dihydrofuran-3-carboxylate
##STR00117##
The titled compound (solid) was similarly prepared according to the
procedure described in the Example 106.
.sup.1H NMR (DMSO-d.sub.6) .delta. (ppm) 12.27 (br. s, 1H), 10.47
(s, 1H), 8.21 (d, J=3.91 Hz, 1H), 7.81 (d, J=7.82 Hz, 1H),
7.64-7.76 (m, 2H), 7.27 (d, J=7.83 Hz, 1H), 6.84 (s, 1H), 6.74 (dd,
J=4.65, 7.58 Hz, 1H), 4.26 (q, J=7.17 Hz, 2H), 2.57 (s, 3H), 2.41
(s, 3H), 1.29 (t, J=7.09 Hz, 3H); LCMS (m/z): 405.0
[M+H].sup.+.
Example 108
Ethyl
5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-[N-methyl-N-(2-thieny-
lmethyl)amino]-4-oxo-4,5-dihydrofuran-3-carboxylate
##STR00118##
The titled compound (solid) was similarly prepared according to the
procedure described in the Example 106.
.sup.1H NMR (DMSO-d.sub.6) .delta. (ppm) 12.33 (br. s, 1H), 8.37
(d, J=7.82 Hz, 1H), 8.30 (d, J=3.91 Hz, 1H), 8.03 (s, 1H), 7.53 (d,
J=4.89 Hz, 1H), 7.14-7.23 (m, 2H), 7.01-7.07 (m, 1H), 6.91 (s, 1H),
5.20 (s, 2H), 4.18 (q, J=7.34 Hz, 2H), 3.26 (br. s, 3H), 1.23 (t,
J=7.09 Hz, 3H); LCMS (m/z): 409.8 [M+H].sup.+.
Example 109
Ethyl
5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-4-oxo-2-thiomorpholino--
4,5-dihydrofuran-3-carboxylate
##STR00119##
The titled compound (solid) was similarly prepared according to the
procedure described in the Example 106.
.sup.1H NMR (DMSO-d.sub.6) .delta. (ppm) 12.33 (br. s, 1H),
8.27-8.45 (m, 2H), 7.94-8.04 (m, 1H), 7.20 (dd, J=4.65, 7.58 Hz,
1H), 6.88 (s, 1H), 4.17 (q, J=6.85 Hz, 2H), 4.02 (br. s, 4H), 2.89
(br. s, 4H), 1.25 (t, J=7.09 Hz, 3H); LCMS (m/z): 386.2
[M+H].sup.+.
Example 110
Ethyl
5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-(3-hydroxypiperidino)-
-4-oxo-4,5-dihydrofuran-3-carboxylate
##STR00120##
The titled compound (solid) was similarly prepared according to the
procedure described in the Example 106.
.sup.1H NMR (DMSO-d.sub.6) .delta. (ppm) 12.32 (br. s, 1H), 8.39
(d, J=7.82 Hz, 1H), 8.31 (d, J=3.91 Hz, 1H), 7.93-8.00 (m, 1H),
7.20 (dd, J=4.40, 7.83 Hz, 1H), 6.85 (s, 1H), 5.11 (br. s, 1H),
4.17 (q, J=6.85 Hz, 2H), 3.85-3.94 (m, 1H), 3.72-3.84 (m, 2H),
3.54-3.65 (m, 1H), 3.41-3.53 (m, 1H), 1.83-2.02 (m, 2H), 1.51-1.69
(m, 2H), 1.25 (t, J=7.09 Hz, 3H); LCMS (m/z): 384.0
[M+H].sup.+.
Example 111
Ethyl
5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-({4-[2-(dimethylamino-
)ethoxy]-2-methylphenyl}amino)-4-oxo-4,5-dihydrofuran-3-carboxylate
formate
##STR00121##
To a solution of ethyl
2-({4-[2-(dimethylamino)ethoxy]-2-methylphenyl}amino)-4-oxo-4,5-dihydrofu-
ran-3-carboxylate (0.070 g, 0.20 mmol) which similarly prepared
according to the procedure described in the Example 74, Fourth step
and 7-azaindole-3-carboxaldehyde (0.029 g, 0.20 mmol) in ethanol
(2.0 mL), piperidine (0.020 mL, 0.20 mmol) was added at ambient
temperature. The mixture was refluxed for 5 days. Cooled to ambient
temperature, the precipitate was collected by filtration then
purified by preparative HPLC to afford the titled compound as solid
(0.016 g, y. 16%).
.sup.1H NMR (DMSO-d.sub.6) .delta. (ppm) 12.28 (br. s, 1H), 10.53
(br. s, 1H), 8.18 (dd, J=1.63, 4.64 Hz, 1H), 8.16 (s, 1H), 7.76 (s,
1H), 7.67 (d, J=7.28 Hz, 1H), 7.41 (d, J=8.78 Hz, 1H), 7.04 (d,
J=3.01 Hz, 1H), 6.94 (dd, J=2.89, 8.66 Hz, 1H), 6.82 (s, 1H), 6.75
(dd, J=4.77, 8.03 Hz, 1H), 4.26 (q, J=7.03 Hz, 2H), 4.16 (t, J=5.77
Hz, 2H), 2.74 (t, J=5.65 Hz, 2H), 2.30 (s, 6H), 2.28 (s, 3H), 1.29
(t, J=7.03 Hz, 3H); LCMS (m/z): 477.1 [M+H].sup.+.
Example 112
Ethyl
5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-4-oxo-2-[(2-phenyl-2-pr-
opinyl)amino]-4,5-dihydrofuran-3-carboxylate
##STR00122##
To a solution of ethyl
4-oxo-2-[(2-phenyl-2-propinyl)amino]-4,5-dihydrofuran-3-carboxylate
(0.40 g, 1.4 mmol) which similarly prepared according to the
procedure described in the Example 4, First step and
7-azaindole-3-carboxaldehyde (0.20 g, 1.4 mmol) in ethanol (10 mL),
L-proline (0.016 g, 0.14 mmol) was added at ambient temperature.
The mixture was refluxed for 3 days. Cooled to ambient temperature,
the precipitate was collected by filtration, washed with methanol
then dried to afford the titled compound as solid (0.15 g, y.
26%).
.sup.1H NMR (DMSO-d.sub.6) .delta. (ppm) 12.22 (br. s, 1H), 8.92
(br. s, 1H), 8.25 (d, J=3.42 Hz, 1H), 8.10 (d, J=7.82 Hz, 1H), 7.58
(d, J=7.34 Hz, 2H), 7.44-7.53 (m, 2H), 7.23-7.33 (m, 1H), 7.06 (dd,
J=4.65, 7.09 Hz, 1H), 6.90 (br. s, 1H), 6.78 (br. s, 1H), 4.27 (q,
J=6.52 Hz, 2H), 1.85 (br. s, 6H), 1.29 (t, J=6.85 Hz, 3H); LCMS
(m/z): 418.0 [M+H].sup.+.
Example 113
Ethyl
5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-(2-adamantylamino)-4--
oxo-4,5-dihydrofuran-3-carboxylate
##STR00123##
The titled compound (solid) was similarly prepared according to the
procedure described in the Example 112.
.sup.1H NMR (DMSO-d.sub.6) .delta. (ppm) 12.37 (br. s, 1H), 8.71
(d, J=6.85 Hz, 1H), 8.42 (d, J=7.82 Hz, 1H), 8.32 (d, J=3.91 Hz,
1H), 7.99 (s, 1H), 7.20 (dd, J=4.89, 7.83 Hz, 1H), 6.92 (s, 1H),
4.30-4.40 (m, 1H), 4.24 (q, J=7.01 Hz, 2H), 2.10-2.19 (m, 2H),
1.81-1.99 (m, 8H), 1.67-1.80 (m, 4H), 1.27 (t, J=7.09 Hz, 3H); LCMS
(m/z): 433.8 [M+H].sup.+.
Example 114
Ethyl
5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-[3-(6-methylpyridinyl-
)amino]-4-oxo-4,5-dihydrofuran-3-carboxylate
##STR00124##
The titled compound (solid) was similarly prepared according to the
procedure described in the Example 112.
.sup.1H NMR (DMSO-d.sub.6) .delta. (ppm) 12.23 (br. s, 1H),
8.41-8.61 (m, 2H), 8.25 (d, J=4.40 Hz, 1H), 8.02 (br. s, 1H), 7.79
(d, J=1.96 Hz, 1H), 7.50 (br. s, 1H), 6.89-7.00 (m, 1H), 6.78-6.89
(m, 1H), 4.08-4.28 (m, 2H), 2.27 (s, 3H), 1.18-1.30 (m, 3H); LCMS
(m/z): 391.4 [M+H].sup.+.
Example 115
Ethyl
5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-[4-(3-methylpyridinyl-
)amino]-4-oxo-4,5-dihydrofuran-3-carboxylate
##STR00125##
The titled compound (solid) was similarly prepared according to the
procedure described in the Example 112.
.sup.1H NMR (DMSO-d.sub.6) .delta. (ppm) 12.23 (br. s, 1H),
8.41-8.61 (m, 2H), 8.25 (d, J=4.40 Hz, 1H), 8.02 (br. s, 1H), 7.79
(d, J=1.96 Hz, 1H), 7.50 (br. s, 1H), 6.89-7.00 (m, 1H), 6.83 (br.
s, 1H), 4.19 (br. s, 2H), 2.27 (s, 3H), 1.24 (br. s, 3H); LCMS
(m/z): 391.4 [M+H].sup.+.
Example 116
Ethyl
5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-[(trans-4-hydroxycycl-
ohexyl)amino]-4-oxo-4,5-dihydrofuran-3-carboxylate
##STR00126##
To a solution of ethyl
2-[(trans-4-hydroxycyclohexyl)amino]-4-oxo-4,5-dihydrofuran-3-carboxylate
(0.30 g, 1.1 mmol) which similarly prepared according to the
procedure described in the Example 4, First step and
7-azaindole-3-carboxaldehyde (0.16 g, 1.1 mmol) in ethanol (20 mL),
L-proline (0.013 g, 0.11 mmol) was added at ambient temperature.
The mixture was refluxed for 2 days. Cooled to ambient temperature,
the precipitate was collected by filtration, washed with methanol
then dried to afford the titled compound as solid (0.14 g, y.
40%).
.sup.1H NMR (DMSO-d.sub.6) .delta. (ppm) 12.36 (br. s, 1H),
8.39-8.54 (m, 2H), 8.33 (d, J=4.40 Hz, 1H), 7.99 (s, 1H), 7.20 (dd,
J=4.89, 7.83 Hz, 1H), 6.89 (s, 1H), 4.69 (d, J=3.91 Hz, 1H), 4.20
(q, J=7.34 Hz, 2H), 3.97 (br. s, 1H), 3.41-3.53 (m, 1H), 1.86-2.03
(m, 4H), 1.61-1.76 (m, 2H), 1.29-1.42 (m, 2H), 1.25 (t, J=7.09 Hz,
3H); LCMS (m/z): 398.1 [M+H].sup.+.
Example 117
Ethyl
5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-[4-(2-fluoropyridinyl-
)amino]-4-oxo-4,5-dihydrofuran-3-carboxylate
##STR00127##
The titled compound (solid) was similarly prepared according to the
procedure described in the Example 116.
.sup.1H NMR (DMSO-d.sub.6) .delta. (ppm) 12.44 (br. s, 1H), 10.86
(br. s, 1H), 8.30 (d, J=5.38 Hz, 2H), 8.21 (d, J=7.82 Hz, 1H), 7.94
(d, J=1.96 Hz, 1H), 7.63 (d, J=5.38 Hz, 1H), 7.44 (s, 1H),
7.00-7.09 (m, 2H), 4.29 (q, J=7.01 Hz, 2H), 1.30 (t, J=7.09 Hz,
3H); LCMS (m/z): 395.0 [M+H].sup.+.
Example 118
Ethyl
5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-[(5-indazolyl)amino]--
4-oxo-4,5-dihydrofuran-3-carboxylate
##STR00128##
The titled compound (solid) was similarly prepared according to the
procedure described in the Example 116.
.sup.1H NMR (DMSO-d.sub.6) .delta. (ppm) 13.36 (s, 1H), 12.25 (br.
s, 1H), 10.62 (br. s, 1H), 8.17 (s, 1H), 8.09 (d, J=3.91 Hz, 1H),
7.99 (s, 1H), 7.78 (d, J=1.96 Hz, 1H), 7.63-7.72 (m, 2H), 7.52 (d,
J=7.82 Hz, 1H), 6.85 (s, 1H), 6.12-6.27 (m, 1H), 4.28 (q, J=7.01
Hz, 2H), 1.30 (t, J=6.85 Hz, 3H); LCMS (m/z): 416.2
[M+H].sup.+.
Example 119
Ethyl
5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-[(5-benzimidazolyl)am-
ino]-4-oxo-4,5-dihydrofuran-3-carboxylate
##STR00129##
To a solution of ethyl
2-[(5-benzimidazolyl)amino]-4-oxo-4,5-dihydrofuran-3-carboxylate
(0.30 g, 1.0 mmol) which similarly prepared according to the
procedure described in the Example 74, Fourth step and
7-azaindole-3-carboxaldehyde (0.15 g, 1.0 mmol) in ethanol (5.0
mL), piperidine (0.20 mL, 3.1 mmol) was added at ambient
temperature. The mixture was refluxed for 24 h. Cooled to ambient
temperature, the precipitate was collected by filtration, washed
with methanol then dried to afford the titled compound as solid
(0.015 g, y. 4%).
.sup.1H NMR (DMSO-d.sub.6) .delta. (ppm) 12.28 (br. s, 1H), 10.82
(s, 1H), 9.55 (s, 1H), 8.16 (d, J=3.91 Hz, 1H), 8.08 (s, 1H), 7.98
(d, J=8.80 Hz, 1H), 7.87 (d, J=7.34 Hz, 1H), 7.59-7.89 (m, 1H),
7.74 (s, 1H), 6.93 (s, 1H), 6.53 (dd, J=4.89, 7.34 Hz, 1H), 4.30
(q, J=7.34 Hz, 2H), 1.31 (t, J=7.09 Hz, 3H); LCMS (m/z): 416.2
[M+H].sup.+.
Example 120
Ethyl
5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-indolinyl-4-oxo-4,5-d-
ihydrofuran-3-carboxylate
##STR00130## First Step
To a solution of potassium tert-butoxide (0.56 g, 5.0 mmol) in
tetrahydrofuran (5.0 mL) that cooled with ice bath, a solution of
indoline (0.36 g, 3.0 mmol) in tetrahydrofuran (5.0 mL) was added
dropwise. The mixture was stirred at ambient temperature for 30
min. Then the reaction mixture was cooled with ice bath, a solution
of ethyl 2-ethoxy-4-oxo-4,5-dihydrofuran-3-carboxylate (0.50 g, 2.5
mmol) which afforded in the Example 74, Third step dissolved in
tetrahydrofuran (5.0 mL) was added dropwise. The mixture was
stirred at ambient temperature for further 16 h. The reaction
mixture was poured into ice water, extracted with ethyl acetate for
3 times. The combined organic layer was dried over sodium sulfate
and concentrated. The residue was purified by chromatography on
silica gel. Eluted with hexane/ethyl acetate to afford
2-indolinyl-4-oxo-4,5-dihydrofuran-3-carboxylate as solid (0.095 g,
y. 8%).
.sup.1H NMR (DMSO-d.sub.6) .delta. (ppm) 7.49 (d, J=8.00 Hz, 1H),
7.35 (d, J=7.60 Hz, 1H), 7.24 (t, J=7.46 Hz, 1H), 7.13 (t, J=7.46
Hz, 1H), 4.73 (s, 2H), 4.05-4.20 (m, 4H), 3.20 (t, J=8.12 Hz, 2H),
1.21 (t, J=7.08 Hz, 3H); LCMS (m/z): 274.0 [M+H].sup.+.
Second Step
To a solution of 2-indolinyl-4-oxo-4,5-dihydrofuran-3-carboxylate
(0.090 g, 0.32 mmol) and 7-azaindole-3-carboxaldehyde (0.048 g,
0.32 mmol) in ethanol (5.0 mL), L-proline (0.0040 g, 0.030 mmol)
was added at ambient temperature. The mixture was refluxed for 2
days. Cooled to ambient temperature, the precipitate was collected
by filtration, washed with ethanol then dried to afford the titled
compound as solid (0.076 g, y. 58%).
.sup.1H NMR (DMSO-d.sub.6) .delta. (ppm) 12.40 (br. s, 1H), 8.36
(d, J=6.85 Hz, 1H), 8.31 (d, J=3.91 Hz, 1H), 8.01 (s, 1H),
7.56-7.63 (m, 1H), 7.44 (d, J=7.34 Hz, 1H), 7.33 (t, J=7.58 Hz,
1H), 7.21-7.27 (m, 1H), 7.12 (dd, J=4.89, 7.83 Hz, 1H), 7.00 (s,
1H), 4.26 (t, J=7.82 Hz, 2H), 4.19 (q, J=7.17 Hz, 2H), 3.24-3.28
(m, 2H), 1.22 (t, J=7.09 Hz, 3H); LCMS (m/z): 402.0
[M+H].sup.+.
Example 121
Ethyl
5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-(1,1-dioxidothiomorph-
olino)-4-oxo-4,5-dihydrofuran-3-carboxylate
##STR00131##
To a solution of ethyl
2-(1,1-dioxidothiomorpholino)-4-oxo-4,5-dihydrofuran-3-carboxylate
(0.027 g, 0.092 mmol) which similarly prepared according to the
procedure described in the Example 74, Fourth step and
7-azaindole-3-carboxaldehyde (0.014 g, 0.092 mmol) in ethanol (0.5
mL), piperidine (0.00092 mL, 0.0093 mmol) was added at ambient
temperature. The mixture was refluxed for 2 days. The precipitate
was collected by filtration, washed with hot ethanol. The solid was
washed with hexane then dried to afford the titled compound as
solid (0.037 g, y. 47%).
.sup.1H NMR (DMSO-d.sub.6) .delta. (ppm) 12.40 (br. s, 1H), 8.38
(d, J=8.03 Hz, 1H), 8.32 (dd, J=1.51, 4.77 Hz, 1H), 8.03 (d, J=2.51
Hz, 1H), 7.22 (dd, J=4.64, 7.91 Hz, 1H), 6.94 (s, 1H), 4.12-4.25
(m, 6H), 3.47-3.55 (m, 4H), 1.25 (t, J=7.03 Hz, 3H); LCMS (m/z):
418.0 [M+H].sup.+.
Example 122
Ethyl
5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-[3-(hydroxymethyl)pip-
eridino]-4-oxo-4,5-dihydrofuran-3-carboxylate
##STR00132##
To a solution of ethyl
2-[(3-hydroxymethyl)piperidino]-4-oxo-4,5-dihydrofuran-3-carboxylate
(0.30 g, 1.0 mmol) which similarly prepared according to the
procedure described in the Example 74, Fourth step and
7-azaindole-3-carboxaldehyde (0.16 g, 1.0 mmol) in ethanol (5.0
mL), L-proline (0.0040 g, 0.030 mmol) was added at ambient
temperature. The mixture was refluxed for 2 days. Cooled to ambient
temperature, the precipitate was collected by filtration, washed
with ethanol then dried to afford the titled compound as solid
(0.045 g, y. 10%).
.sup.1H NMR (DMSO-d.sub.6) .delta. (ppm) 12.33 (br. s, 1H), 8.38
(d, J=7.82 Hz, 1H), 8.31 (d, J=4.40 Hz, 1H), 7.98 (s, 1H), 7.19
(dd, J=4.89, 7.82 Hz, 1H), 6.84 (s, 1H), 4.72 (br. s, 1H),
4.12-4.24 (m, 2H), 3.24-3.50 (m, 4H), 3.17 (t, J=11.74 Hz, 2H),
1.74-1.91 (m, 2H), 1.60-1.72 (m, 2H), 1.29-1.41 (m, 1H), 1.24 (t,
J=6.85 Hz, 3H); LCMS (m/z): 398.2 [M+H].sup.+.
Example 123
2-(Dimethylamino)ethyl
5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-azepinyl-4-oxo-4,5-dihydro-
furan-3-carboxylate formate
##STR00133##
A solution of the compound (0.052 g, 0.14 mmol) of Example 63,
2-dimethylaminoethanol (0.14 mL, 1.4 mmol), zinc cluster catalyst
(Zn.sub.4(OCOCF.sub.3).sub.6O) (0.0019 g, 0.0020 mmol) and
4-dimethylaminopyridine (0.0049 g, 0.040 mmol) in
N,N-dimethylacetamide (1.0 mL) was stirred with the microwave
synthesizer (Biotage Initiator.TM.) at 150.degree. C. for 1 h. The
reaction mixture was purified by preparative HPLC to afford the
titled compound as solid (0.018 g, y. 24%).
.sup.1H NMR (DMSO-d.sub.6) .delta. (ppm) 12.31 (br. s, 1H), 8.39
(dd, J=1.25, 7.78 Hz, 1H), 8.31 (dd, J=1.38, 4.64 Hz, 1H), 8.16 (s,
1H), 7.94 (d, J=1.76 Hz, 1H), 7.20 (dd, J=4.77, 7.78 Hz, 1H), 6.86
(s, 1H), 4.22 (t, J=5.77 Hz, 2H), 3.72-3.92 (m, 4H), 2.54-2.60 (m,
2H), 2.24 (s, 6H), 1.78-1.90 (m, 4H), 1.52-1.63 (m, 4H); LCMS
(m/z): 425.1 [M+H].sup.+.
Example 124
Ethyl
5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-{[2-(3-methylthienyl)-
methyl]amino}-4-oxo-4,5-dihydrofuran-3-carboxylate
##STR00134##
To a solution of ethyl
2-{[2-(3-methylthienyl)methyl]amino}-4-oxo-4,5-dihydrofuran-3-carboxylate
(0.38 g, 1.4 mmol) which similarly prepared according to the
procedure described in the Example 74, Fourth step and
7-azaindole-3-carboxaldehyde (0.20 g, 1.4 mmol) in ethanol (4.0
mL), piperidine (0.014 mL, 0.14 mmol) was added at ambient
temperature. The mixture was refluxed for 5 days. The precipitate
was collected by filtration, washed with hot ethanol. The solid was
washed with hexane then dried to afford the titled compound as
solid (0.12 g, y. 21%).
.sup.1H NMR (DMSO-d.sub.6) .delta. (ppm) 12.38 (br. s, 1H), 9.47
(t, J=6.27 Hz, 1H), 8.35 (d, J=8.03 Hz, 1H), 8.30 (dd, J=1.38, 4.64
Hz, 1H), 7.97 (d, J=2.26 Hz, 1H), 7.32 (d, J=5.02 Hz, 1H), 7.15
(dd, J=4.64, 7.91 Hz, 1H), 6.92 (s, 1H), 6.88 (d, J=5.02 Hz, 1H),
4.95 (d, J=6.27 Hz, 2H), 4.22 (q, J=7.03 Hz, 2H), 2.28 (s, 3H),
1.26 (t, J=7.03 Hz, 3H); LCMS (m/z): 410.0 [M+H].sup.+.
Example 125
Ethyl
5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-({4-[(2-hydroxyethyl)-
-N-methylamino]-2-methylphenyl}amino)-4-oxo-4,5-dihydrofuran-3-carboxylate
##STR00135## First Step
A solution of 5-fluoro-2-nitrotoluene (1.5 g, 9.6 mmol),
N-methylethanolamine (0.90 mL, 0.012 mol) and triethylamine (1.6
mL, 0.012 mol) in N-methyl-2-pyrrolidone (15 mL) was stirred at
60.degree. C. for 12 h. Cooled to ambient temperature, the reaction
mixture was poured into ice water, extracted with ethyl acetate.
The organic layer was washed with water and brine, dried over
sodium sulfate and concentrated to afford
2-[(3-methyl-4-nitrophenyl)-N-methylamino]ethanol as solid (2.0 g,
y. 98%).
.sup.1H NMR (DMSO-d.sub.6) .delta. (ppm) 7.99 (d, J=9.32 Hz, 1H),
6.58-6.71 (m, 2H), 4.78 (t, J=5.22 Hz, 1H), 3.46-3.63 (m, 4H), 3.06
(s, 3H), 2.56 (s, 3H); LCMS (m/z): 211.2 [M+H].sup.+.
Second Step
2-[(3-Methyl-4-nitrophenyl)-N-methylamino]ethanol (0.70 g, 3.3
mmol) was dissolved in ethanol (10 mL) and 10% palladium on carbon
(0.050 g) was added at ambient temperature. The reaction mixture
was agitated under a hydrogen atmosphere at ambient temperature for
4 h. Palladium on carbon was removed by filtration with Celite and
the solvent was removed under reduced pressure to afford
2-[(4-amino-3-methylphenyl)-N-methylamino]ethanol as solid (0.58 g,
y. 97%).
.sup.1H NMR (DMSO-d.sub.6) .delta. (ppm) 6.49 (d, J=8.44 Hz, 1H),
6.43 (d, J=2.60 Hz, 1H), 6.38 (q, J=6.13 Hz, 1H), 4.50 (t, J=5.38
Hz, 1H), 4.12 (br. s, 2H), 3.48 (dd, J=6.38, 12.00 Hz, 2H), 3.16
(t, J=6.58 Hz, 2H), 2.73 (s, 3H), 2.02 (s, 3H); LCMS (m/z): 181.1
[M+H].sup.+.
Third Step
A solution of ethyl 2-ethoxy-4-oxo-4,5-dihydrofuran-3-carboxylate
(0.70 g, 3.5 mmol) which afforded in the Example 74, Third step and
2-[(4-amino-3-methylphenyl)-N-methylamino]ethanol (0.60 g, 3.5
mmol) in ethanol (8.3 mL) was stirred at ambient temperature for 16
h. The solvent was removed under reduced pressure, and ethanol was
added to precipitate the product. The precipitate was collected by
filtration, washed with ethanol then dried to afford
2-({4-[(2-hydroxyethyl)-N-methylamino]-2-methylphenyl}amino)-4-oxo-4,5-di-
hydrofuran-3-carboxylate as solid (0.60 g, y. 60%).
.sup.1H NMR (DMSO-d.sub.6) .delta. (ppm) 9.86 (br. s, 1H), 7.12 (d,
J=8.76 Hz, 1H), 6.60 (d, J=2.60 Hz, 1H), 5.54 (dd, J=2.74, 8.80 Hz,
1H), 4.65 (br. s, 1H), 4.57 (s, 2H), 4.20 (q, J=7.06 Hz, 2H), 3.53
(t, J=6.14 Hz, 2H), 3.38 (t, J=6.22 Hz, 2H), 2.92 (s, 3H), 2.17 (s,
3H); LCMS (m/z): 335.0 [M+H].sup.+.
Fourth Step
To a solution of
2-({4-[(2-hydroxyethyl)-N-methylamino]-2-methylphenyl}amino)-4-oxo-4,5-di-
hydrofuran-3-carboxylate (0.20 g, 0.60 mmol) and
7-azaindole-3-carboxaldehyde (0.097 g, 0.60 mmol) in ethanol (11
mL), piperidine (0.10 mL, 1.0 mmol) was added at ambient
temperature. The mixture was refluxed for 2 days. Cooled to ambient
temperature, the precipitate was collected by filtration, washed
with diethyl ether then dried to afford the titled compound as
solid (0.055 g, y. 19%).
.sup.1H NMR DMSO-d.sub.6) .delta. (ppm) 12.22 (br. s, 1H), 10.12
(br. s, 1H), 8.15 (d, J=4.40 Hz, 1H), 7.77 (br. s, 1H), 7.68 (d,
J=7.82 Hz, 1H), 7.22 (d, J=8.80 Hz, 1H), 6.77 (s, 1H), 6.67-6.73
(m, 2H), 6.63 (d, J=8.31 Hz, 1H), 4.69 (t, J=5.14 Hz, 1H), 4.23 (q,
J=6.85 Hz, 2H), 3.55-3.63 (m, 2H), 3.43-3.50 (m, 2H), 3.01 (s, 3H),
2.15 (s, 3H), 1.26 (t, J=6.85 Hz, 3H); LCMS (m/z): 463.2
[M+H].sup.+.
Example 126
Ethyl
5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-({4-[(2-hydroxyethyl)-
amino]-2-methylphenyl}amino)-4-oxo-4,5-dihydrofuran-3-carboxylate
##STR00136##
The titled compound (solid) was similarly prepared according to the
procedure described in the Example 125.
.sup.1H NMR (DMSO-d.sub.6) .delta. (ppm) 12.25 (br. s, 1H), 10.11
(s 1H), 8.18 (d, J=4.40 Hz, 1H), 7.81-7.87 (m, 1H), 7.70 (d, J=7.83
Hz, 1H), 7.16 (d, J=8.31 Hz, 1H), 6.75-6.87 (m, 2H), 6.53-6.67 (m,
2H), 5.85 (t, J=5.38 Hz, 1H), 4.75 (t, J=5.38 Hz, 1H), 4.26 (q,
J=6.85 Hz, 2H), 3.63 (q, J=5.87 Hz, 2H), 3.20 (q, J=5.71 Hz, 2H),
2.13 (s, 3H), 1.29 (t, J=7.09 Hz, 3H); LCMS (m/z): 449.2
[M+H].sup.+.
Example 127
Ethyl
5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-{[4-(2,3-dihydroxypro-
poxy)-2-methylphenyl]amino}-4-oxo-4,5-dihydrofuran-3-carboxylate
##STR00137##
To a stirred solution of ethyl
2-{[4-(2,3-dihydroxypropoxy)-2-methylphenyl]amino}-4-oxo-4,5-dihydrofuran-
-3-carboxylate (0.17 g, 0.50 mmol) which similarly prepared
according to the procedure described in the Example 74, First step
to Fourth step and 7-azaindole-3-carboxaldehyde (0.070 g, 0.50
mmol) in ethanol (5.0 mL), piperidine (0.10 mL, 1.0 mmol) was added
at ambient temperature. The mixture was refluxed for 2 days. Cooled
to ambient temperature, the precipitate was collected by
filtration, washed with diethyl ether then dried to afford the
titled compound as solid (0.054 g, y. 23%).
.sup.1H NMR (DMSO-d.sub.6) .delta. (ppm) 12.28 (br. s, 1H), 10.30
(br. s, 1H), 8.18 (d, J=2.93 Hz, 1H), 7.78 (br. s, 1H), 7.64 (d,
J=7.34 Hz, 1H), 7.41 (d, J=8.31 Hz, 1H), 7.03 (br. s, 1H), 6.94 (d,
J=7.34 Hz, 1H), 6.82 (s, 1H), 6.70-6.79 (m, 1H), 5.06 (d, J=4.40
Hz, 1H), 4.76 (t, J=5.04 Hz, 1H), 4.20-4.32 (m, 2H), 4.05-4.15 (m,
1H), 3.93-4.02 (m, 1H), 3.83-3.92 (m, 1H), 3.47-3.57 (m, 2H), 2.22
(br. s, 3H), 1.29 (t, J=6.60 Hz, 3H); LCMS (m/z): 480.2
[M+H].sup.+.
Example 128
Ethyl
5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-({2-methyl-4-[2-(meth-
ylthio)ethoxy]phenyl}amino)-4-oxo-4,5-dihydrofuran-3-carboxylate
##STR00138##
The titled compound (solid) was similarly prepared according to the
procedure described in the Example 127.
.sup.1H NMR (DMSO-d.sub.6) .delta. (ppm) 12.28 (br. s, 1H), 10.30
(br. s, 1H), 8.19 (d, J=4.40 Hz, 1H), 7.77 (s, 1H), 7.65 (d, J=7.82
Hz, 1H), 7.42 (d, J=8.80 Hz, 1H), 7.05 (br. s, 1H), 6.95 (dd,
J=2.69, 8.56 Hz, 1H), 6.82 (br. s, 1H), 6.76 (dd, J=4.40, 7.83 Hz,
1H), 4.21-4.32 (m, 4H), 2.94 (t, J=6.36 Hz, 2H), 2.23 (s, 3H), 2.22
(s, 3H), 1.29 (t, J=7.09 Hz, 3H); LCMS (m/z): 480.2
[M+H].sup.+.
Example 129
Ethyl
5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-({4-[(dimethylamino)m-
ethyl]-2-methylphenyl}amino)-4-oxo-4,5-dihydrofuran-3-carboxylate
##STR00139## First Step
A solution of 3-methyl-4-nitrobenzyl bromide (1.0 g, 4.3 mmol),
anhydrous dimethylamine (0.34 mL, 5.1 mmol) and potassium carbonate
(1.5 g, 0.011 mol) in N,N-dimethylformamide (4.5 mL) was stirred at
70.degree. C. for 12 h. Cooled to ambient temperature, the reaction
mixture was poured into ice water, extracted with ethyl acetate.
The organic layer was washed with water and brine, dried over
sodium sulfate and concentrated to afford
N,N-dimethyl-1-(3-methyl-4-nitrophenyl)methanamine as oil (0.80 g,
y. 95%).
.sup.1H NMR (DMSO-d.sub.6) .delta. (ppm) 7.65 (d, J=8.32 Hz, 1H),
7.41 (s, 1H), 7.36 (d, J=8.36 Hz, 1H), 3.44 (s, 2H), 2.52 (s, 3H),
2.15 (s, 6H); LCMS (m/z): 195.4 [M+H].sup.+.
Second Step
N,N-Dimethyl-1-(3-methyl-4-nitrophenyl)methanamine (0.80 g, 4.1
mmol) was dissolved in ethanol (5.0 mL) and 10% palladium on carbon
(0.18 g) was added at ambient temperature. The reaction mixture was
agitated under a hydrogen atmosphere at ambient temperature for 4
h. Palladium on carbon was removed by filtration with Celite and
the solvent was removed under reduced pressure to afford
4-[(dimethylamino)methyl]-2-methylaniline (0.65 g, y. 96%).
.sup.1H NMR (DMSO-d.sub.6) .delta. (ppm) 6.81 (s, 1H), 6.77 (d,
J=7.92 Hz, 1H), 6.52 (d, J=7.96 Hz, 1H), 4.68 (s, 2H), 3.16 (s,
2H), 2.07 (s, 6H), 2.02 (s, 3H).
Third Step
A solution of ethyl 2-ethoxy-4-oxo-4,5-dihydrofuran-3-carboxylate
(0.47 g, 2.3 mmol) which afforded in the Example 74, Third step and
4-[(dimethylamino)methyl]-2-methylaniline (0.35 g, 2.1 mmol) in
ethanol (10 mL) was stirred at ambient temperature for 16 h. The
solvent was removed under reduced pressure, and ethanol was added
to precipitate the product. The precipitate was collected by
filtration to afford ethyl
2-({4-[(dimethylamino)methyl]-2-methylphenyl}amino)-4-oxo-4,5-dihydrofura-
n-3-carboxylate (0.26 g, crude material) as solid.
.sup.1H NMR (DMSO-d.sub.6) .delta. (ppm) 10.18 (br. s, 1H), 7.48
(d, J=6.96 Hz, 1H), 7.25-7.40 (m, 2H), 4.65 (s, 2H), 4.23 (q,
J=7.04 Hz, 2H), 2.40-2.60 (m, 9H), 1.26 (t, J=7.04 Hz, 3H); LCMS
(m/z): 319.2 [M+H].sup.+.
Fourth Step
To a solution of ethyl
2-({4-[(dimethylamino)methyl]-2-methylphenyl}amino)-4-oxo-4,5-dihydrofura-
n-3-carboxylate (0.26 g, 0.82 mmol) and
7-azaindole-3-carboxaldehyde (0.12 g, 0.82 mmol) in ethanol (5.0
mL), piperidine (0.16 mL, 1.6 mmol) was added at ambient
temperature. The mixture was refluxed for 2 days. Cooled to ambient
temperature, the precipitate was collected by filtration, washed
with diethyl ether then dried to afford the titled compound as
solid (0.015 g, y. 4%).
.sup.1H NMR (DMSO-d.sub.6) .delta. (ppm) 12.26 (br. s, 1H), 8.20
(d, J=3.91 Hz, 1H), 8.15 (s, 1H), 7.82 (d, J=7.34 Hz, 1H), 7.72 (s,
1H), 7.47 (d, J=7.83 Hz, 1H), 7.37 (s, 1H), 7.30 (d, J=8.31 Hz,
1H), 6.83 (s, 1H), 6.79 (dd, J=4.89, 7.82 Hz, 1H), 4.26 (q, J=7.17
Hz, 2H), 3.54 (s, 2H), 2.22-2.29 (m, 9H), 1.29 (t, J=6.85 Hz, 3H);
LCMS (m/z): 447.4 [M+H].sup.+
Example 130
Ethyl
5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-4-oxo-2-{[(1R,2S)-2-phe-
nylcyclopropyl]amino}-4,5-dihydrofuran-3-carboxylate
##STR00140##
To a solution of ethyl
4-oxo-2-{[(1R,2S)-2-phenylcyclopropyl]amino}-4,5-dihydrofuran-3-carboxyla-
te (0.090 g, 0.31 mmol) which similarly prepared according to the
procedure described in the Example 74, Fourth step and
7-azaindole-3-carboxaldehyde (0.045 g, 0.30 mmol) in ethanol (5.0
mL), L-proline (0.0035 g, 0.031 mmol) was added at ambient
temperature. The mixture was refluxed for 2 days. Cooled to ambient
temperature, the solvent was removed under reduced pressure then
the residue was purified by preparative HPLC to afford the titled
compound as solid (0.018 g, y. 14%).
.sup.1H NMR (DMSO-d.sub.6) .delta. (ppm) 12.11 (br. s, 1H), 9.10
(br. s, 1H), 8.41 (d, J=7.34 Hz, 1H), 8.26 (d, J=3.91 Hz, 1H), 7.81
(s, 1H), 7.28-7.36 (m, 2H), 7.19-7.27 (m, 3H), 7.03 (dd, J=4.40,
7.82 Hz, 1H), 6.88 (s, 1H), 4.21 (q, J=6.85 Hz, 2H), 3.40-3.48 (m,
1H), 2.88-3.10 (m, 1H), 1.63-1.72 (m, 1H), 1.35-1.43 (m, 1H), 1.26
(t, J=7.08 Hz, 3H); LCMS (m/z): 415.8 [M+H].sup.+.
Example 131
Ethyl
5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-({4-[2-(2-hydroxyetho-
xy)ethoxy]-2-methylphenyl}amino)-4-oxo-4,5-dihydrofuran-3-carboxylate
##STR00141##
To a solution of ethyl
2-({4-[2-(2-hydroxyethoxy)ethoxy]-2-methylphenyl}amino)-4-oxo-4,5-dihydro-
furan-3-carboxylate (0.15 g, 0.50 mmol) which similarly prepared
according to the procedure described in the Example 74, First step
to Fourth step and 7-azaindole-3-carboxaldehyde (0.070 g, 0.50
mmol) in ethanol (10 mL), L-proline (0.010 g, 0.087 mmol) was added
at ambient temperature. The mixture was refluxed for 2 days. Cooled
to ambient temperature, the precipitate was collected by
filtration, washed with diethyl ether then dried to afford the
titled compound (0.031 g, y. 15%) as solid.
.sup.1H NMR (DMSO-d.sub.6) .delta. (ppm) 12.28 (br. s, 1H), 10.29
(br. s, 1H), 8.20 (d, J=3.91 Hz, 1H), 7.75 (br. s, 1H), 7.68 (d,
J=7.82 Hz, 1H), 7.42 (d, J=8.80 Hz, 1H), 7.05 (br. s, 1H), 6.95
(dd, J=2.40, 8.60 Hz, 1H), 6.83 (s, 1H), 6.77 (dd, J=4.40, 7.83 Hz,
1H), 4.64-4.70 (m, 1H), 4.26 (q, J=6.85 Hz, 2H), 4.17-4.23 (m, 2H),
3.79-3.87 (m, 2H), 3.52-3.62 (m, 4H), 2.23 (s, 3H), 1.29 (t, J=6.85
Hz, 3H); LCMS (m/z): 494.0 [M+H].sup.+.
Example 132
Ethyl
5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-{[4-(3-hydroxypropoxy-
)-2-methylphenyl]amino}-4-oxo-4,5-dihydrofuran-3-carboxylate
##STR00142##
The titled compound (solid) was similarly prepared according to the
procedure described in the Example 131.
.sup.1H NMR (DMSO-d.sub.6) .delta. (ppm) 12.25 (br. s, 1H), 8.19
(d, J=4.40 Hz, 1H), 7.74 (s, 1H), 7.67 (d, J=7.82 Hz, 1H), 7.36 (d,
J=8.80 Hz, 1H), 7.00 (d, J=2.4 Hz, 1H), 6.91 (d, J=8.31 Hz, 1H),
6.71-6.79 (m, 2H), 4.59-4.65 (m, 1H), 4.25 (q, J=6.85 Hz, 2H), 4.14
(t, J=6.11 Hz, 2H), 3.60-3.67 (m, J=5.38 Hz, 2H), 2.21 (s, 3H),
1.94 (t, J=6.11 Hz, 2H), 1.28 (t, J=7.06 Hz, 3H); LCMS (m/z): 464.2
[M+H].sup.+.
Example 133
Ethyl
2-({4-[2-(1H-pyrrol-1-yl)ethoxy]-2-methylphenyl}amino)-5-[(1H-pyrrol-
o[2,3-b]pyridin-3-yl)methylene]-4-oxo-4,5-dihydrofuran-3-carboxylate
##STR00143##
The titled compound (solid) was similarly prepared according to the
procedure described in the Example 131.
.sup.1H NMR (DMSO-d.sub.6) .delta. (ppm) 12.04 (br. s, 1H), 8.08
(d, J=3.91 Hz, 1H), 7.60-7.76 (m, 2H), 7.16 (br. s, 1H), 6.88-6.94
(m, 3H), 6.84 (d, J=7.82 Hz, 1H), 6.60-6.68 (m, 1H), 6.48-6.57 (m,
1H), 6.02-6.07 (m, 2H), 4.22-4.37 (m, 4H), 4.13-4.22 (m, 2H), 2.14
(s, 3H), 1.25 (t, J=6.85 Hz, 3H); LCMS (m/z): 499.2
[M+H].sup.+.
Example 134
Ethyl
5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-{[2-methyl-4-(1-pyrro-
lidinylmethyl)phenyl]amino}-4-oxo-4,5-dihydrofuran-3-carboxylate
##STR00144##
To a solution of
2-{[2-methyl-4-(1-pyrrolidinylmethyl)phenyl]amino}-4-oxo-4,5-dihydrofuran-
-3-carboxylate (0.25 g, 0.70 mmol) which similarly prepared
according to the procedure described in the Example 129, First step
to Third step and 7-azaindole-3-carboxaldehyde (0.10 g, 0.70 mmol)
in ethanol (10 mL), piperidine (0.014 mL, 0.14 mmol) was added at
ambient temperature. The mixture was refluxed for 2 days. Cooled to
ambient temperature then the reaction mixture was purified by
preparative HPLC to afford the titled compound as solid (0.035 g,
y. 10%).
.sup.1H NMR (DMSO-d.sub.6) .delta. (ppm) 12.27 (br. s, 1H), 8.20
(d, J=3.91 Hz, 1H), 8.14 (s, 1H), 7.72-7.82 (m, 2H), 7.48 (d,
J=7.83 Hz, 1H), 7.41 (s, 1H), 7.34 (d, J=7.34 Hz, 1H), 6.76-6.86
(m, 2H), 4.26 (q, J=6.85 Hz, 2H), 3.81 (br. s, 2H), 2.57-2.69 (m,
4H), 2.27 (s, 3H), 1.70-1.85 (m, 4H), 1.29 (t, J=6.85 Hz, 3H); LCMS
(m/z): 473.2 [M+H].sup.+.
Example 135
Ethyl
5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-({2-methyl-4-[(4-meth-
ylpiperazinyl)methyl]phenyl}amino)-4-oxo-4,5-dihydrofuran-3-carboxylate
##STR00145##
The titled compound (solid) was similarly prepared according to the
procedure described in the Example 134.
.sup.1H NMR (DMSO-d.sub.6) .delta. (ppm) 12.43 (br. s, 1H), 8.18
(br. s, 1H), 8.01 (br. s, 1H), 7.41 (br. s, 1H), 6.99-7.17 (m, 3H),
6.87 (br. s, 2H), 6.40 (d, J=12.72 Hz, 1H), 4.26 (br. s, 2H), 3.57
(br. s, 2H), 2.42 (br. s, 8H), 2.28 (br. s, 3H), 2.08 (br. s, 3H),
1.12-1.39 (m, 3H); LCMS (m/z): 502.4 [M+H].sup.+.
Example 136
Ethyl
5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-{[2-methyl-4-(morphol-
inomethyl)phenyl]amino}-4-oxo-4,5-dihydrofuran-3-carboxylate
##STR00146##
The titled compound (solid) was similarly prepared according to the
procedure described in the Example 134.
.sup.1H NMR (DMSO-d.sub.6) .delta. (ppm) 12.29 (br. s, 1H), 10.38
(br. s, 1H), 8.21 (d, J=4.40 Hz, 1H), 7.72-7.83 (m, 2H), 7.46-7.54
(m, 1H), 7.28-7.44 (m, 2H), 6.86 (s, 1H), 6.75-6.81 (m, 1H), 4.27
(q, J=7.17 Hz, 2H), 3.51-3.74 (m, 6H), 2.35-2.59 (m, 4H), 2.27 (s,
3H), 1.30 (t, J=7.09 Hz, 3H); LCMS (m/z): 489.2 [M+H].sup.+.
Example 137
Ethyl
5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-[(4-{[2-(dimethylamin-
o)ethyl]amino}-2-methylphenyl)amino]-4-oxo-4,5-dihydrofuran-3-carboxylate
formate
##STR00147##
To a solution of ethyl
2-[(4-{[2-(dimethylamino)ethyl]amino}-2-methylphenyl)amino]-4-oxo-4,5-dih-
ydrofuran-3-carboxylate (0.27 g, 0.70 mmol) which similarly
prepared according to the procedure described in the Example 125,
First step to Third step and 7-azaindole-3-carboxaldehyde (0.11 g,
0.70 mmol) in ethanol (5.0 mL), piperidine (0.10 mL, 1.0 mmol) was
added at ambient temperature. The mixture was refluxed for 16 h.
Cooled to ambient temperature, the solvent was removed under
reduced pressure then the residue was purified by preparative HPLC
to afford the titled compound as solid (0.015 g, y. 8%).
.sup.1H NMR (DMSO-d.sub.6) .delta. (ppm) 12.29 (br. s, 1H), 10.12
(br. s, 1H), 8.11-8.23 (m, 2H), 7.86 (s, 1H), 7.67 (d, J=7.82 Hz,
1H), 7.17 (d, J=8.31 Hz, 1H), 6.75-6.83 (m, 2H), 6.51-6.69 (m, 2H),
5.79 (br. s, 1H), 4.25 (q, J=6.85 Hz, 2H), 3.16-3.28 (m, 2H), 2.58
(t, J=6.11 Hz, 2H), 2.29 (s, 6H), 2.13 (s, 3H), 1.29 (t, J=6.85 Hz,
3H); LCMS (m/z): 476.0 [M+H].sup.+.
Example 138
2-Methoxyethyl
5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-azepinyl-4-oxo-4,5-dihydro-
furan-3-carboxylate
##STR00148## First Step
A solution of ethyl malonyl chloride (0.10 mL, 0.78 mmol) and
2-methoxyethanol (0.061 mL, 0.78 mmol) in dichloromethane (1.5 mL)
was cooled with ice bath. To this solution, triethylamine (0.13 mL,
0.94 mmol) was added and stirred at ambient temperature for 1.5 h.
The reaction mixture was diluted with water, extracted with
dichloromethane. The organic layer was washed with brine, dried
over magnesium sulfate and concentrated. The residue was purified
by chromatography on silica gel(hexane/ethyl acetate) to afford
ethyl 2-methoxyethyl malonate (0.10 g, y. 69%) as oil.
.sup.1H NMR (CDCl.sub.3) .delta. (ppm) 4.28-4.34 (m, 2H), 4.21 (q,
J=7.11 Hz, 2H), 3.59-3.64 (m, 2H), 3.42 (s, 2H), 3.39 (s, 3H), 1.29
(t, J=7.15 Hz, 3H)
Second Step
A solution of ethyl 2-methoxyethyl malonate (0.10 g, 0.53 mmol) in
anhydrous tetrahydrofuran (1.5 mL) was added dropwise to a solution
of sodium hydride (60% w/w in oil, 0.043 g, 1.1 mmol) in anhydrous
tetrahydrofuran (2.0 mL) that cooled with ice bath. The mixture was
refluxed for 5 min. The reaction mixture was cooled with ice bath,
chloroacetyl chloride (0.042 mL, 0.53 mmol) was added dropwise to
the reaction mixture and the mixture was stirred for 1 h then
stirred with heating at 45.degree. C. for 1 h. The reaction mixture
was cooled to ambient temperature then hexamethyleneimine (0.071
mL, 0.63 mmol) was added dropwise and the mixture was stirred at
ambient temperature for further 1 h. The reaction mixture was
diluted with water, and extracted with chloroform. The organic
layer was dried over magnesium sulfate and concentrated. The
residue was purified by chromatography on silica gel, eluted with
chloroform/methanol to afford 2-methoxyethyl
2-azepinyl-4-oxo-4,5-dihydrofuran-3-carboxylate as oil (0.065 g, y.
43%).
.sup.1H NMR (CDCl.sub.3) .delta. (ppm) 4.51 (s, 2H), 4.35-4.39 (m,
2H), 3.56-3.75 (m, 6H), 3.40 (s, 3H), 1.80 (br. s, 4H), 1.61 (br.
s, 4H); LCMS (m/z): 284.1 [M+H].sup.+.
Third Step
To a solution of 2-methoxyethyl
2-azepinyl-4-oxo-4,5-dihydrofuran-3-carboxylate (0.065 g, 0.23
mmol) and 7-azaindole-3-carboxaldehyde (0.033 g, 0.23 mmol) in
ethanol (0.5 mL), hexamethyleneimine (0.026 mL, 0.023 mmol) was
added at ambient temperature. The mixture was refluxed for 3 days.
Cooled to ambient temperature, the precipitate was collected by
filtration, washed with ethanol and hexane then dried to afford the
titled compound as solid (0.019 g, y. 20%).
.sup.1H NMR (DMSO-d.sub.6) .delta. (ppm) 12.31 (br. s, 1H), 8.39
(dd, J=1.38, 7.91 Hz, 1H), 8.31 (dd, J=1.38, 4.64 Hz, 1H), 7.94 (s,
1H), 7.20 (dd, J=4.64, 7.91 Hz, 1H), 6.85 (s, 1H), 4.21-4.28 (m,
2H), 3.70-3.90 (m, 4H), 3.54-3.62 (m, 2H), 3.29 (s, 3H), 1.78-1.91
(m, 4H), 1.51-1.63 (m, 4H); LCMS (m/z): 412.1 [M+H].sup.+.
Example 139
Isopropyl
5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-azepinyl-4-oxo-4,-
5-dihydrofuran-3-carboxylate
##STR00149##
To a stirred solution of isopropyl
2-azepinyl-4-oxo-4,5-dihydrofuran-3-carboxylate (0.033 g, 0.12
mmol) which similarly prepared according to the procedure described
in the Example 4, First step and 7-azaindole-3-carboxaldehyde
(0.019 g, 0.13 mmol) in 2-propanol (1.0 mL), hexamethyleneimine
(0.0014 mL, 0.012 mmol) was added at ambient temperature. The
mixture was refluxed for 12 days. Cooled to ambient temperature,
the reaction mixture was purified by preparative HPLC to afford the
titled compound as solid (0.024 g, y. 49%).
.sup.1H NMR (DMSO-d.sub.6) .delta. (ppm) 12.30 (br. s, 1H), 8.37
(dd, J=1.38, 7.91 Hz, 1H), 8.31 (dd, J=1.38, 4.64 Hz, 1H), 7.93 (s,
1H), 7.20 (dd, J=4.77, 7.78 Hz, 1H), 6.81 (s, 1H), 4.94-5.05 (m,
1H), 3.70-3.90 (m, 4H), 1.75-1.91 (m, 4H), 1.52-1.62 (m, 4H), 1.25
(d, J=6.27 Hz, 6H); LCMS (m/z): 396.1 [M+H].sup.+.
Example 140
Ethyl
5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-{[2-methyl-4-(2-pyrid-
inylmethoxy)phenyl]amino}-4-oxo-4,5-dihydrofuran-3-carboxylate
##STR00150##
The titled compound was similarly prepared as solid according to
the procedure described in the Example 1, using ethyl
2-{[2-methyl-4-(2-pyridinylmethoxy)phenyl]amino}-4-oxo-4,5-dihydrofuran-3-
-carboxylate which similarly prepared according to the procedure
described in the Example 74, First step to Fourth step and
7-azaindole-3-carboxaldehyde as starting materials.
.sup.1H NMR (DMSO-d.sub.6) .delta. (ppm) 12.29 (br. s, 1H), 10.30
(br. s, 1H), 8.63 (d, J=3.91 Hz, 1H), 8.17 (d, J=3.91 Hz, 1H), 7.89
(t, J=7.09 Hz, 1H), 7.67-7.79 (m, 2H), 7.62 (d, J=7.34 Hz, 1H),
7.34-7.49 (m, 2H), 7.16 (br. s, 1H), 7.04 (d, J=8.31 Hz, 1H), 6.83
(s, 1H), 6.70-6.77 (m, 1H), 5.29 (s, 2H), 4.26 (q, J=6.85 Hz, 2H),
2.23 (s, 3H), 1.29 (t, J=7.09 Hz, 3H); LCMS (m/z): 497.0
[M+H].sup.+.
Example 141
Ethyl
5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-{[2-methyl-4-(3-pyrid-
inylmethoxy)phenyl]amino}-4-oxo-4,5-dihydrofuran-3-carboxylate
##STR00151##
To a solution of ethyl
2-{[2-methyl-4-(3-pyridinylmethoxy)phenyl]amino}-4-oxo-4,5-dihydrofuran-3-
-carboxylate (0.080 g, 0.20 mmol) which similarly prepared
according to the procedure described in the Example 74, First step
to Fourth step and 7-azaindole-3-carboxaldehyde (0.032 g, 0.20
mmol) in ethanol (5.0 mL), L-proline (0.0050 g, 0.043 mmol) was
added at ambient temperature. The mixture was refluxed for 2 days.
Cooled to ambient temperature, the reaction mixture was purified by
preparative HPLC to afford the titled compound as solid (0.010 g,
y. 9%).
.sup.1H NMR (DMSO-d.sub.6) .delta. (ppm) 12.25 (br. s, 1H), 10.25
(br. s, 1H), 8.76 (s, 1H), 8.59 (d, J=3.42 Hz, 1H), 8.18 (d, J=4.40
Hz, 1H), 7.96 (d, J=7.83 Hz, 1H), 7.69-7.79 (m, 2H), 7.45-7.53 (m,
1H), 7.41 (d, J=8.80 Hz, 1H), 7.14 (br. s, 1H), 7.04 (d, J=8.31 Hz,
1H), 6.79 (br. s, 1H), 6.68-6.76 (m, 1H), 5.27 (s, 2H), 4.20-4.30
(m, 2H), 2.23 (s, 3H), 1.29 (t, J=7.09 Hz, 3H); LCMS (m/z): 497.4
[M+H].sup.+.
Example 142
Ethyl
5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-(morpholinoamino)-4-o-
xo-4,5-dihydrofuran-3-carboxylate
##STR00152##
A solution of ethyl 2-ethoxy-4-oxo-4,5-dihydrofuran-3-carboxylate
(0.10 g, 0.50 mmol) which afforded in the Example 74, Third step
and 4-aminomorpholine (0.046 mL, 0.48 mmol) in ethanol (2.0 mL) was
stirred at ambient temperature for 15 h. To this reaction mixture,
7-azaindole-3-carboxaldehyde (0.061 g, 0.42 mmol) and piperidine
(0.0048 mL, 0.048 mmol) were added. The mixture was refluxed for 3
days. The precipitate was collected by filtration, washed with hot
ethanol. The solid was washed with hexane then dried to afford the
titled compound (0.045 g, y. 24%) as solid.
.sup.1H NMR (DMSO-d.sub.6) .delta. (ppm) 12.34 (br. s, 1H), 10.07
(s, 1H), 8.93 (d, J=7.78 Hz, 1H), 8.33 (d, J=3.51 Hz, 1H), 8.12
(br. s, 1H), 7.20-7.26 (m, 1H), 6.88 (s, 1H), 4.21 (q, J=6.78 Hz,
2H), 3.74-3.88 (m, 4H), 3.02-3.14 (br. s, 4H), 1.26 (t, J=6.90 Hz,
3H); LCMS (m/z): 385.1 [M+H].sup.+.
Example 143
Ethyl
5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-{[2-methyl-4-(4-pyrid-
inylmethoxy)phenyl]amino}-4-oxo-4,5-dihydrofuran-3-carboxylate
##STR00153##
The titled compound (solid) was similarly prepared according to the
procedure described in the Example 141.
.sup.1H NMR (DMSO-d.sub.6) .delta. (ppm) 12.28 (br. s, 1H), 10.30
(br. s, 1H), 8.62 (d, J=4.40 Hz, 2H), 8.17 (d, J=4.40 Hz, 1H),
7.67-7.79 (m, 2H), 7.52 (d, J=4.89 Hz, 2H), 7.45 (d, J=8.31 Hz,
1H), 7.15 (br. s, 1H), 7.03 (d, J=8.31 Hz, 1H), 6.83 (s, 1H),
6.68-6.75 (m, 1H), 5.31 (s, 2H), 4.26 (q, J=7.17 Hz, 2H), 2.23 (s,
3H), 1.29 (t, J=6.85 Hz, 3H); LCMS (m/z): 496.8 [M+H].sup.+.
Example 144
Ethyl
5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-({4-[2-(diethylamino)-
ethoxy]-2-methylphenyl}amino)-4-oxo-4,5-dihydrofuran-3-carboxylate
Acetate
##STR00154##
The crude material, which similarly prepared according to the
procedure described in the Example 141, was purified by preparative
HPLC (aqueous ammonium acetate/acetonitrile) to afford the titled
compound (solid).
.sup.1H NMR (DMSO-d.sub.6) .delta. (ppm) 12.17 (br. s, 1H), 8.16
(d, J=3.91 Hz, 1H), 7.75 (s, 1H), 7.68 (d, J=7.34 Hz, 1H), 7.34 (d,
J=8.31 Hz, 1H), 7.00 (br. s, 1H), 6.91 (d, J=8.80 Hz, 1H),
6.70-6.79 (m, 2H), 4.19-4.30 (m, 2H), 4.10 (t, J=5.87 Hz, 2H), 2.86
(t, J=5.87 Hz, 2H), 2.61 (q, J=6.85 Hz, 4H), 2.20 (s, 3H), 1.90 (s,
3H), 1.28 (t, J=6.85 Hz, 3H), 1.02 (t, J=7.09 Hz, 6H); LCMS (m/z):
505.6 [M+H].sup.+.
Example 145
Ethyl
5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-({2-methyl-4-[2-(4-me-
thylpiperazinyl)ethoxy]phenyl}amino)-4-oxo-4,5-dihydrofuran-3-carboxylate
acetate
##STR00155## First Step
A solution of 4-nitro-m-cresol (2.0 g, 0.013 mol),
1-bromo-2-chloroethane (1.7 mL, 0.020 mol) and potassium carbonate
(4.7 g, 0.034 mol) in N,N-dimethylformamide (21 mL) was stirred at
70.degree. C. for 18 h. Cooled to ambient temperature, the reaction
mixture was poured into ice water, extracted with ethyl acetate.
The organic layer was washed with water and brine, dried over
sodium sulfate and concentrated. The residue was purified by
chromatography on silica gel(hexane/ethyl acetate) to afford
4-(2-chloroethoxy)-2-methyl-1-nitrobenzene as solid (2.1 g, y.
73%).
.sup.1H NMR (DMSO-d.sub.6) .delta. (ppm) 8.05 (d, J=9.12 Hz, 1H),
7.08 (d, J=2.48 Hz, 1H), 7.01 (dd, J=2.72, 9.08 Hz, 1H), 4.38 (t,
J=5.04 Hz, 2H), 3.98 (t, J=5.08 Hz, 2H), 2.55 (s, 3H); LCMS (m/z):
216.2 [M+H].sup.+.
Second Step
A solution of 4-(2-chloroethoxy)-2-methyl-1-nitrobenzene (2.1 g,
9.7 mmol), N-methylpiperazine (1.5 g, 15 mmol) and potassium
carbonate (3.4 g, 0.025 mol) in N,N-dimethylformamide (15 mL) was
stirred with heating at 70.degree. C. for 18 h. Cooled to ambient
temperature, the reaction mixture was poured into ice water,
extracted with ethyl acetate. The organic layer was washed with
water and brine, dried over sodium sulfate and concentrated. The
residue was purified by chromatography on silica
gel(dichloromethane/methanol) to afford
1-methyl-4-[2-(3-methyl-4-nitrophenoxy)ethyl]piperazine as solid
(1.8 g, y. 64%).
.sup.1H NMR (DMSO-d.sub.6) .delta. (ppm) 8.03 (d, J=9.12 Hz, 1H),
7.05 (d, J=2.68 Hz, 1H), 6.98 (dd, J=2.76, 9.08 Hz, 1H), 4.18 (t,
J=5.78 Hz, 2H), 2.69 (t, J=5.74 Hz, 2H), 2.54 (s, 3H), 2.39-2.52
(m, 4H), 2.22-2.37 (m, 4H), 2.14 (s, 3H); LCMS (m/z): 280.2
[M+H].sup.+.
Third Step
1-Methyl-4-[2-(3-methyl-4-nitrophenoxy)ethyl]piperazine (0.69 g,
2.5 mmol) was dissolved in ethanol (10 mL) and 10% wt palladium on
carbon (0.055 g) was added at ambient temperature. The reaction
mixture was agitated under a hydrogen atmosphere at ambient
temperature for 4 h. Palladium on carbon was removed by filtration
with Celite and the solvent was removed under reduced pressure to
afford 2-methyl-4-[2-(4-methylpiperazinyl)ethoxy]aniline as oil
(0.60 g, y. 97%).
.sup.1H NMR (DMSO-d.sub.6) .delta. (ppm) 6.57 (br. s, 1H), 6.51
(br. s, 2H), 4.35 (br. s, 2H), 3.90 (t, J=5.90 Hz, 2H), 3.17 (br.
s, 3H), 2.60 (t, J=5.88 Hz, 2H), 2.38-2.54 (m, 4H), 2.30 (br. s,
4H), 2.14 (s, 3H); LCMS (m/z): 250.4 [M+H].sup.+.
Fourth Step
A solution of ethyl 2-ethoxy-4-oxo-4,5-dihydrofuran-3-carboxylate
(0.32 g, 1.6 mmol) which afforded in the Example 74, Third step and
2-methyl-4-[2-(4-methylpiperazinyl)ethoxy]aniline (0.40 g, 1.6
mmol) in ethanol (5.0 mL) was stirred at 60.degree. C. for 30 min.
The solvent was removed under reduced pressure, then the residue
was purified by chromatography on silica
gel(dichloromethane/methanol) to afford
2-({2-methyl-4-[2-(4-methylpiperazinyl)ethoxy]phenyl}amino)-4-oxo-4,5-dih-
ydrofuran-3-carboxylate as solid (0.30 g, y. 46%).
.sup.1H NMR (DMSO-d.sub.6) .delta. (ppm) 9.99 (br. s, 1H), 7.26 (d,
J=8.56 Hz, 1H), 6.91 (d, J=2.28 Hz, 1H), 6.78-6.86 (m, 1H), 4.58
(s, 2H), 4.21 (q, J=7.04 Hz, 2H), 4.03-4.12 (m, 2H), 3.31 (s, 3H),
2.27-2.80 (m, 10H), 2.20 (s, 3H), 1.25 (t, J=7.04 Hz, 3H); LCMS
(m/z): 404.2 [M+H].sup.+.
Fifth Step
To a solution of
2-({2-methyl-4-[2-(4-methylpiperazinyl)ethoxy]phenyl}amino)-4-oxo-4,5-dih-
ydrofuran-3-carboxylate (0.22 g, 0.55 mmol) and
7-azaindole-3-carboxaldehyde (0.080 g, 0.55 mmol) in ethanol (14
mL), L-proline (0.014 g, 0.12 mmol) was added at ambient
temperature. The mixture was refluxed for 2 days. The solvent was
removed under reduced pressure, and then the residue was purified
by preparative HPLC (aqueous ammonium acetate/acetonitrile) to
afford the titled compound as solid. (0.032 g, y. 11%).
.sup.1H NMR (DMSO-d.sub.6) .delta. (ppm) 12.16 (br. s, 1H), 8.17
(d, J=4.40 Hz, 1H), 7.64-7.79 (m, 2H), 7.31 (d, J=8.31 Hz, 1H),
7.00 (br. s, 1H), 6.90 (d, J=8.31 Hz, 1H), 6.65-6.80 (m, 2H),
4.10-4.30 (m, 4H), 2.76 (t, J=5.62 Hz, 2H), 2.25-2.65 (m, 9H),
2.19-2.21 (m, 5H), 1.86 (s, 3H), 1.28 (t, J=6.85 Hz, 3H); LCMS
(m/z): 532.3 [M+H].sup.+.
Example 146
Ethyl
5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-{[4-(2-hydroxy-2-meth-
ylpropoxy)-2-methylphenyl]amino}-4-oxo-4,5-dihydrofuran-3-carboxylate
##STR00156##
The titled compound (solid) was similarly prepared according to the
procedure described in the Example 141.
.sup.1H (DMSO-d.sub.6) .delta. (ppm) 12.28 (br. s, 1H), 10.30 (br.
s, 1H), 8.16 (d, J=3.91 Hz, 1H), 7.80 (s, 1H), 7.60 (d, J=7.82 Hz,
1H), 7.40 (d, J=8.31 Hz, 1H), 7.03 (br. s, 1H), 6.94 (d, J=8.31 Hz,
1H), 6.81 (s, 1H), 6.73 (dd, J=4.40, 7.82 Hz, 1H), 4.72 (s, 1H),
4.27 (q, J=7.17 Hz, 2H), 3.81 (s, 2H), 2.22 (s, 3H), 1.25-1.33 (m,
9H); LCMS (m/z): 478.2 [M+H].sup.+.
Example 147
Ethyl
5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-[(2-methyl-4-{[2-(pyr-
rolidino)ethyl]amino}phenyl)amino]-4-oxo-4,5-dihydrofuran-3-carboxylate
acetate
##STR00157##
To a solution of
2-[(2-methyl-4-{[2-(pyrrolidino)ethyl]amino}phenyl)amino]-4-oxo-4,5-dihyd-
rofuran-3-carboxylate (0.32 g, 0.85 mmol) which similarly prepared
according to the procedure described in the Example 125, First step
to Third step and 7-azaindole-3-carboxaldehyde (0.13 g, 0.85 mmol)
in ethanol (5.0 mL), piperidine (0.10 mL, 1.0 mmol) was added at
ambient temperature. The mixture was refluxed for 24 h. Cooled to
ambient temperature, the reaction mixture was purified by
preparative HPLC (aqueous ammonium acetate/acetonitrile) to afford
the titled compound as solid (0.010 g, y. 3%).
.sup.1H NMR (DMSO-d.sub.6) .delta. (ppm) 12.05 (br. s, 1H),
8.11-8.20 (m, 1H), 7.71-7.84 (m, 2H), 7.01-7.10 (m, 1H), 6.77-6.85
(m, 1H), 6.49-6.68 (m, 3H), 5.57 (br. s, 1H), 4.15-4.25 (m, 2H),
3.21 (br. s, 2H), 2.63-2.73 (m, 2H), 2.52-2.61 (m, 4H), 2.10 (s,
3H), 1.85 (s, 3H), 1.65-1.78 (m, 4H), 1.27 (t, J=6.85 Hz, 3H); LCMS
(m/z): 502.4 [M+H].sup.+.
Example 148
Isopropyl
5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-[N-methyl-N-(2-th-
ienylmethyl)amino]-4-oxo-4,5-dihydrofuran-3-carboxylate
##STR00158##
A solution of isopropyl
2-isopropoxy-4-oxo-4,5-dihydrofuran-3-carboxylate (0.10 g, 0.44
mmol) which similarly prepared according to the procedure described
in the Example 74, Third step using diisopropyl malonate and
chloroacetyl chloride, N-methyl-N-(2-thienylmethyl)amine (0.061 mg,
0.048 mmol) and triethylamine (0.18 mL, 1.3 mmol) in 2-propanol
(2.0 mL) was stirred for 7 days then refluxed for further 24 h. To
this reaction mixture, 7-azaindole-3-carboxaldehyde (0.065 g, 0.44
mmol) was added then the mixture was refluxed for 24 h. Cooled to
ambient temperature, the reaction mixture was purified by
preparative HPLC to afford the titled compound as solid (0.0038 g,
y. 2%).
.sup.1H NMR (DMSO-d.sub.6) .delta. (ppm) 12.33 (br. s, 1H), 8.35
(d, J=8.03 Hz, 1H), 8.28-8.32 (m, 1H), 8.02 (s, 1H), 7.53 (dd,
J=1.13, 5.14 Hz, 1H), 7.14-7.22 (m, 2H), 7.04 (dd, J=3.51, 5.02 Hz,
1H), 6.88 (s, 1H), 5.19 (s, 2H), 4.97-5.05 (m, 1H), 3.26 (s, 3H),
1.24 (d, J=6.27 Hz, 6H); LCMS (m/z): 424.1 [M+H].sup.+.
Example 149
Isopropyl
5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-(cyclohexylamino)-
-4-oxo-4,5-dihydrofuran-3-carboxylate
##STR00159##
A solution of isopropyl
2-isopropoxy-4-oxo-4,5-dihydrofuran-3-carboxylate (0.10 g, 0.44
mmol) which similarly prepared according to the procedure described
in the Example 74, Third step using diisopropyl malonate and
chloroacetyl chloride, and cyclohexylamine (0.055 mL, 0.48 mmol) in
2-propanol (2.0 mL) was stirred at ambient temperature for 14 h. To
this reaction mixture, 7-azaindole-3-carboxaldehyde (0.065 g, 0.44
mmol) and piperidine (0.0044 mL, 0.044 mmol) were added then the
mixture was refluxed for further 8 days. Cooled to ambient
temperature, the reaction mixture was purified by preparative HPLC
to afford the titled compound as solid (0.0079 g, y. 4%).
.sup.1H NMR (DMSO-d.sub.6) .delta. (ppm) 12.35 (br. s, 1H), 8.51
(d, J=8.28 Hz, 1H), 8.41 (d, J=7.78 Hz, 1H), 8.32 (dd, J=1.38, 4.64
Hz, 1H), 7.99 (d, J=2.51 Hz, 1H), 7.20 (dd, J=4.64, 7.91 Hz, 1H),
6.86 (s, 1H), 5.00-5.12 (m, 1H), 3.96-4.05 (m, 1H), 1.93-2.04 (m,
2H), 1.72-1.84 (m, 2H), 1.54-1.69 (m, 3H), 1.35-1.49 (m, 2H),
1.18-1.31 (m, 7H); LCMS (m/z): 396.2 [M+H].sup.+.
Example 150
Isopropyl
5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-[(cyclohexylmethy-
l)amino]-4-oxo-4,5-dihydrofuran-3-carboxylate
##STR00160##
A solution of isopropyl
2-isopropoxy-4-oxo-4,5-dihydrofuran-3-carboxylate (0.10 g, 0.44
mmol) which similarly prepared according to the procedure described
in the Example 74, Third step using diisopropyl malonate and
chloroacetyl chloride, and aminomethylcyclohexane (0.063 mL, 0.48
mmol) in 2-propanol (2.0 mL) was stirred at ambient temperature for
14 h. To this reaction mixture, 7-azaindole-3-carboxaldehyde (0.065
g, 0.44 mmol) and piperidine (0.0044 mL, 0.044 mmol) were added
then the mixture was refluxed for further 8 days. Cooled to ambient
temperature, the reaction mixture was purified by preparative HPLC
to afford the titled compound as solid (0.036 g, y. 19%).
.sup.1H NMR (DMSO-d.sub.6) .delta. (ppm) 12.35 (br. s, 1H),
8.90-8.98 (m, 1H), 8.41 (d, J=6.78 Hz, 1H), 8.32 (dd, J=1.38, 4.64
Hz, 1H), 7.99 (s, 1H), 7.19 (dd, J=4.77, 8.03 Hz, 1H), 6.84 (s,
1H), 5.00-5.13 (m, 1H), 3.45-3.53 (m, 2H), 1.56-1.81 (m, 5H), 1.27
(d, J=6.27 Hz, 6H), 1.08-1.24 (m, 4H), 0.94-1.07 (m, 2H); LCMS
(m/z): 410.2 [M+H].sup.+.
Example 151
Isopropyl
5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-[(trans-4-hydroxy-
cyclohexyl)amino]-4-oxo-4,5-dihydrofuran-3-carboxylate
##STR00161##
A solution of isopropyl
2-[(trans-4-hydroxycyclohexyl)amino]-4-oxo-4,5-dihydrofuran-3-carboxylate
(0.10 g, 0.44 mmol) which similarly prepared according to the
procedure described in the Example 74, Third step using diisopropyl
malonate and chloroacetyl chloride, and
trans-4-aminomethylcyclohexanol (0.056 mg, 0.49 mmol) in 2-propanol
(1.0 mL) was stirred at ambient temperature for 20 h. To this
reaction mixture, 7-azaindole-3-carboxaldehyde (0.065 g, 0.44 mmol)
and L-proline (0.0050 g, 0.044 mmol) were added then the mixture
was refluxed for further 1.5 days. The precipitate was collected by
filtration, washed with hot ethanol. The solid was washed with
hexane then dried to afford isopropyl
5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-[(trans-4-hydroxycyclohexy-
l)amino]-4-oxo-4,5-dihydrofuran-3-carboxylate as solid (0.0076 g,
y. 4%).
.sup.1H NMR (DMSO-d.sub.6) .delta. (ppm) 12.36 (br. s, 1H), 8.46
(d, J=8.28 Hz, 1H), 8.42 (d, J=7.53 Hz, 1H), 8.33 (dd, J=1.38, 4.64
Hz, 1H), 7.99 (d, J=2.51 Hz, 1H), 7.20 (dd, J=4.64, 7.91 Hz, 1H),
6.85 (s, 1H), 5.01-5.09 (m, 1H), 4.69 (d, J=4.27 Hz, 1H), 3.93-3.99
(m, 1H), 3.43-3.51 (m, 1H), 1.86-2.03 (m, 4H), 1.60-1.73 (m, 2H),
1.29-1.42 (m, 2H), 1.26 (d, J=6.27 Hz, 6H); LCMS (m/z): 412.1
[M+H].sup.+.
Example 152
Cyclopropylmethyl
5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-({4-[2-(dimethylamino)etho-
xy]-2-methylphenyl}amino)-4-oxo-4,5-dihydrofuran-3-carboxylate
formate
##STR00162##
A solution of ethyl
5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-({4-[2-(dimethylamino)etho-
xy]-2-methylphenyl}amino)-4-oxo-4,5-dihydrofuran-3-carboxylate
(0.033 g, 0.070 mmol) which similarly prepared according to the
procedure described in the Example 111, cyclopropyl carbinol (0.10
mL, 1.3 mmol) and zinc cluster catalyst
(Zn.sub.4(OCOCF.sub.3).sub.6O) (0.0033 g, 0.0035 mmol) in
N,N-dimethylacetamide (0.9 mL) was stirred with the microwave
synthesizer (Biotage Initiator.TM.) at 150.degree. C. for 30 min.
Cooled to ambient temperature, the precipitate was removed by
filtration. The filtrate was purified by preparative HPLC to afford
the titled compound as solid (0.0029 g, y. 8%).
.sup.1H NMR (DMSO-d.sub.6) .delta. (ppm) 12.25 (br. s, 1H),
8.04-8.29 (m, 2H), 7.75 (s, 1H), 7.68 (d, J=7.78 Hz, 1H), 7.38 (d,
J=8.28 Hz, 1H), 7.03 (d, J=2.51 Hz, 1H), 6.93 (d, J=8.78 Hz, 1H),
6.70-6.83 (m, 2H), 6.55 (br. s, 1H), 4.15 (t, J=5.65 Hz, 2H), 4.06
(d, J=6.78 Hz, 2H), 2.70 (t, J=5.80 Hz, 2H), 2.28 (s, 6H), 2.22 (s,
3H), 1.15-1.32 (m, 1H), 0.49-0.62 (m, 2H), 0.32-0.39 (m, 2H); LCMS
(m/z): 503.2 [M+H].sup.+.
Example 153
Cyclopropylmethyl
5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-{[4-(2-hydroxyethoxy)-2-me-
thylphenyl]amino}-4-oxo-4,5-dihydrofuran-3-carboxylate
##STR00163##
A solution of the compound (0.032 g, 0.070 mmol) of Example 74,
cyclopropyl carbinol (0.10 mL, 1.3 mmol) and zinc cluster catalyst
(Zn.sub.4(OCOCF.sub.3).sub.6O) (0.0033 g, 0.0035 mmol) in
N,N-dimethylacetamide (0.9 mL) was stirred with the microwave
synthesizer (Biotage Initiator.TM.) at 150.degree. C. for 30 min.
Cooled to ambient temperature, the precipitate was removed by
filtration. The filtrate was purified by preparative HPLC to afford
the titled compound as solid (0.0040 g, y. 11%).
.sup.1H NMR (DMSO-d.sub.6) .delta. (ppm) 12.23 (br. s, 1H), 10.36
(br. s, 1H), 8.19 (d, J=3.51 Hz, 1H), 7.65-7.80 (m, 2H), 7.38 (d,
J=8.53 Hz, 1H), 7.01 (d, J=2.26 Hz, 1H), 6.92 (dd, J=2.51, 8.53 Hz,
1H), 6.72-6.84 (m, 2H), 4.95 (t, J=5.40 Hz, 1H), 4.01-4.12 (m, 4H),
3.79 (q, J=5.02 Hz, 2H), 2.22 (s, 3H), 1.14-1.26 (m, 1H), 0.51-0.58
(m, 2H), 0.31-0.39 (m, 2H); LCMS (m/z): 476.1 [M+H].sup.+.
Example 154
Isopropyl
5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-({4-[2-(dimethyla-
mino)ethoxy]-2-methylphenyl}amino)-4-oxo-4,5-dihydrofuran-3-carboxylate
formate
##STR00164##
A solution of ethyl
5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-({4-[2-(dimethylamino)etho-
xy]-2-methylphenyl}amino)-4-oxo-4,5-dihydrofuran-3-carboxylate
(0.033 g, 0.070 mmol) which similarly prepared according to the
procedure described in the Example 111, and zinc cluster catalyst
(Zn.sub.4(OCOCF.sub.3).sub.6O) (0.0033 g, 0.0035 mmol) in
2-propanol (0.5 mL) and N,N-dimethylacetamide (0.5 mL) was stirred
with the microwave synthesizer (Biotage Initiator.TM.) at
150.degree. C. for 30 min. Cooled to ambient temperature, the
precipitate was removed by filtration. The filtrate was purified by
preparative HPLC to afford the titled compound as solid (0.0046 g,
y. 11%).
.sup.1H NMR (DMSO-d.sub.6) .delta. (ppm) 12.28 (br. s, 1H), 10.20
(br. s, 1H), 8.18 (dd, J=1.60, 4.40 Hz, 1H), 8.14 (s, 1H), 7.78 (s,
1H), 7.67 (d, J=8.03 Hz, 1H), 7.42 (d, J=8.53 Hz, 1H), 7.04 (d,
J=2.51 Hz, 1H), 6.94 (dd, J=2.76, 8.78 Hz, 1H), 6.72-6.81 (m, 2H),
5.10-5.17 (m, 1H), 4.16 (t, J=5.65 Hz, 2H), 2.75 (t, J=5.52 Hz,
2H), 2.31 (s, 6H), 2.23 (s, 3H), 1.31 (d, J=6.27 Hz, 6H); LCMS
(m/z): 491.2 [M+H].sup.+.
Example 155
n-Butyl
5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-({4-[2-(dimethylami-
no)ethoxy]-2-methylphenyl}amino)-4-oxo-4,5-dihydrofuran-3carboxylate
formate
##STR00165##
A solution of ethyl
5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-({4-[2-(dimethylamino)etho-
xy]-2-methylphenyl}amino)-4-oxo-4,5-dihydrofuran-3-carboxylate
(0.033 g, 0.070 mmol) which similarly prepared according to the
procedure described in the Example 111, and zinc cluster catalyst
(Zn.sub.4(OCOCF.sub.3).sub.6O) (0.0033 g, 0.0035 mmol) in n-butanol
(0.5 mL) and N,N-dimethylacetamide (0.5 mL) was stirred with the
microwave synthesizer (Biotage Initiator.TM.) at 150.degree. C. for
30 min. Cooled to ambient temperature, the precipitate was removed
by filtration. The filtrate was purified by preparative HPLC to
afford the titled compound as solid (0.011 g, y. 31%).
.sup.1H NMR (DMSO-d.sub.6) .delta. (ppm) 12.28 (br. s, 1H), 10.32
(br. s, 1H), 8.18 (dd, J=1.38, 4.64 Hz, 1H), 8.15 (s, 1H), 7.76 (s,
1H), 7.67 (d, J=7.78 Hz, 1H), 7.41 (d, J=8.78 Hz, 1H), 7.04 (d,
J=2.51 Hz, 1H), 6.94 (dd, J=2.76, 8.78 Hz, 1H), 6.81 (s, 1H), 6.75
(dd, J=4.77, 8.03 Hz, 1H), 4.22 (t, J=6.78 Hz, 2H), 4.16 (t, J=5.65
Hz, 2H), 2.74 (t, J=5.65 Hz, 2H), 2.30 (s, 6H), 2.22 (s, 3H),
1.60-1.72 (m, 2H), 1.34-1.51 (m, 2H), 0.94 (t, J=7.40 Hz, 3H); LCMS
(m/z): 505.2 [M+H].sup.+.
Example 156
n-Butyl
5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-{[4-(2-hydroxyethox-
y)-2-methylphenyl]amino}-4-oxo-4,5-dihydrofuran-3-carboxylate
##STR00166##
A solution of the compound (0.032 g, 0.070 mmol) of Example 74, and
zinc cluster catalyst (Zn.sub.4(OCOCF.sub.3).sub.6O) (0.0033 g,
0.0035 mmol) in n-butanol (0.5 mL) and N,N-dimethylacetamide (0.5
mL) was stirred with the microwave synthesizer (Biotage
Initiator.TM.) at 150.degree. C. for 30 min. Cooled to ambient
temperature, the precipitate was removed by filtration. The
filtrate was purified by preparative HPLC to afford the titled
compound as solid (0.015 g, y. 44%).
.sup.1H NMR (DMSO-d.sub.6) .delta. (ppm) 12.27 (br. s, 1H), 10.27
(s, 1H), 8.19 (dd, J=1.13, 4.64 Hz, 1H), 7.74 (d, J=2.26 Hz, 1H),
7.69 (d, J=7.78 Hz, 1H), 7.42 (d, J=8.78 Hz, 1H), 7.03 (d, J=2.76
Hz, 1H), 6.94 (dd, J=2.64, 8.66 Hz, 1H), 6.74-6.85 (m, 2H),
4.88-5.05 (m, 1H), 4.22 (t, J=6.65 Hz, 2H), 4.09 (t, J=4.89 Hz,
2H), 3.75-3.85 (m, 2H), 2.23 (s, 3H), 1.59-1.73 (m, 2H), 1.36-1.49
(m, 2H), 0.94 (t, J=7.40 Hz, 3H); LCMS (m/z): 478.2
[M+H].sup.+.
Example 157
Isopropyl
5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-{[4-(2-hydroxyeth-
oxy)-2-methylphenyl]amino}-4-oxo-4,5-dihydrofuran-3-carboxylate
##STR00167##
A solution of the compound (0.032 g, 0.070 mmol) of Example 74, and
zinc cluster catalyst (Zn.sub.4(OCOCF.sub.3).sub.6O) (0.0033 g,
0.0035 mmol) in 2-propanol (0.5 mL) and N,N-dimethylacetamide (0.5
mL) was stirred with the microwave synthesizer (Biotage
Initiator.TM.) at 150.degree. C. for 30 min. Cooled to ambient
temperature, the precipitate was removed by filtration. The
filtrate was purified by preparative HPLC to afford the titled
compound as solid (0.010 g, y. 28%).
.sup.1H NMR (DMSO-d.sub.6) .delta. (ppm) 12.27 (br. s, 1H), 10.22
(s, 1H), 8.19 (dd, J=1.26, 4.77 Hz, 1H), 7.76 (d, J=2.51 Hz, 1H),
7.69 (d, J=7.78 Hz, 1H), 7.42 (d, J=8.53 Hz, 1H), 7.03 (d, J=2.51
Hz, 1H), 6.94 (dd, J=2.76, 8.78 Hz, 1H), 6.73-6.84 (m, 2H),
5.08-5.18 (m, 1H), 4.95 (t, J=5.40 Hz, 1H), 4.09 (t, J=4.89 Hz,
2H), 3.80 (q, J=5.27 Hz, 2H), 2.23 (s, 3H), 1.31 (d, J=6.27 Hz,
6H); LCMS (m/z): 464.1 [M+H].sup.+.
Example 158
Isopropyl
5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-(cyclopropylamino-
)-4-oxo-4,5-dihydrofuran-3-carboxylate
##STR00168##
A solution of isopropyl
2-isopropoxy-4-oxo-4,5-dihydrofuran-3-carboxylate (0.10 g, 0.44
mmol) which similarly prepared according to the procedure described
in the Example 74, Third step using diisopropyl malonate and
chloroacetyl chloride, and cyclopropylamine (0.034 mL, 0.48 mmol)
in 2-propanol (2.0 mL) was stirred at ambient temperature for 14 h.
To this reaction mixture, 7-azaindole-3-carboxaldehyde (0.065 g,
0.44 mmol) and piperidine (0.0044 mL, 0.044 mmol) were added then
the mixture was refluxed for further 12 days. Cooled to ambient
temperature, the reaction mixture was purified by preparative HPLC
to afford the titled compound as solid (0.0020 g, y. 1%).
.sup.1H NMR (DMSO-d.sub.6) .delta. (ppm) 12.33 (br. s, 1H), 8.81
(br. s, 1H), 8.56 (d, J=7.28 Hz, 1H), 8.31 (d, J=3.51 Hz, 1H), 8.06
(d, J=2.26 Hz, 1H), 7.21 (dd, J=4.64, 7.91 Hz, 1H), 6.88 (s, 1H),
4.99-5.10 (m, 1H), 3.09-3.18 (m, 1H), 1.26 (d, J=6.27 Hz, 6H),
0.89-0.97 (m, 4H); LCMS (m/z): 354.1 [M+H].sup.+.
Example 159
Ethyl
5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-[(cyclohexylmethyl)am-
ino]-4-oxo-4,5-dihydrofuran-3-carboxylate
##STR00169##
A solution of ethyl 2-ethoxy-4-oxo-4,5-dihydrofuran-3-carboxylate
(0.10 g, 0.51 mmol) which afforded in the Example 74, Third step
and aminomethylcyclohexane (0.072 mL, 0.55 mmol) in ethanol (2.0
mL) was stirred at ambient temperature for 1.5 h. To this reaction
mixture, 7-azaindole-3-carboxaldehyde (0.073 g, 0.50 mmol) and
L-proline (0.012 mg, 0.10 mmol) were added then the mixture was
refluxed for further 5 days. The precipitate was collected by
filtration, washed with hot ethanol. The solid was washed with
hexane then dried to afford the titled compound as solid (0.024 g,
y. 12%).
.sup.1H NMR (DMSO-d.sub.6) .delta. (ppm) 12.35 (br. s, 1H), 8.98
(t, J=6.27 Hz, 1H), 8.42 (d, J=7.78 Hz, 1H), 8.32 (dd, J=1.38, 4.64
Hz, 1H), 7.99 (d, J=2.51 Hz, 1H), 7.19 (dd, J=4.64, 7.91 Hz, 1H),
6.88 (s, 1H), 4.21 (q, J=7.03 Hz, 2H), 3.48 (t, J=6.40 Hz, 2H),
1.65-1.81 (m, 5H), 1.62 (d, J=9.29 Hz, 1H), 1.09-1.30 (m, 6H),
0.95-1.06 (m, 2H); LCMS (m/z): 396.2 [M+H].sup.+.
Example 160
2-Hydroxyethyl
5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-[N-methyl-N-(2-thienylmeth-
yl)amino]-4-oxo-4,5-dihydrofuran-3-carboxylate
##STR00170##
A solution of the compound (0.050 g, 0.12 mmol) of Example 108,
ethylene glycol (0.20 mL, 3.6 mmol), 4-dimethylaminopyridine
(0.0030 g, 0.024 mmol) and zinc cluster catalyst
(Zn.sub.4(OCOCF.sub.3).sub.6O) (0.0058 g, 0.0061 mmol) in
N,N-dimethylacetamide (0.5 mL) was stirred with the microwave
synthesizer (Biotage Initiator.TM.) at 150.degree. C. for 30 min.
Cooled to ambient temperature, the precipitate was removed by
filtration. The filtrate was purified by preparative HPLC to afford
the titled compound as solid (0.0061 g, y. 10%).
.sup.1H NMR (DMSO-d.sub.6) .delta. (ppm) 12.34 (br. s, 1H), 11.7
(br. s, 1H), 8.35-8.44 (m, 1H), 8.30 (dd, J=1.38, 4.64 Hz, 1H),
8.04 (s, 1H), 7.53 (dd, J=1.13, 5.14 Hz, 1H), 7.21 (d, J=3.01 Hz,
1H), 7.17 (dd, J=4.64, 7.91 Hz, 1H), 7.04 (dd, J=3.51, 5.02 Hz,
1H), 6.94 (s, 1H), 5.20 (s, 2H), 4.17 (t, J=5.14 Hz, 2H), 3.62 (q,
J=5.52 Hz, 2H), 3.23-3.37 (m, 3H); LCMS (m/z): 426.1
[M+H].sup.+.
Example 161
Ethyl
5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-{[2-methyl-4-(2-pyrim-
idinylmethoxy)phenyl]amino}-4-oxo-4,5-dihydrofuran-3-carboxylate
##STR00171## First Step
A solution of 4-nitro-m-cresol (0.25 g, 1.6 mmol),
2-(chloromethyl)pyrimidine hydrochloride (0.40 g, 2.4 mmol) and
potassium carbonate (0.50 g, 4.0 mmol) in N,N-dimethylformamide
(6.0 mL) was stirred at 70.degree. C. for 18 h. Cooled to ambient
temperature, the reaction mixture was poured into ice water,
extracted with ethyl acetate. The organic layer was washed with
water and brine, dried over sodium sulfate, filtered and
concentrated to afford
2-[(3-methyl-4-nitrophenoxy)methyl]pyrimidine as crude material
(0.32 g, y. 81%) as solid.
.sup.1H NMR (DMSO-d.sub.6) .delta. (ppm) 8.84 (d, J=4.92 Hz, 2H),
8.03 (d, J=9.08 Hz, 1H), 7.48 (t, J=4.90 Hz, 1H), 7.10 (d, J=2.68
Hz, 1H), 7.00 (dd, J=2.80, 9.12 Hz, 1H), 5.43 (s, 2H), 2.53 (s,
3H); LCMS (m/z): 246.4 [M+H].sup.+.
Second Step
To a solution of 2-[(3-methyl-4-nitrophenoxy)methyl]pyrimidine
(0.18 g, 0.7 mmol) in ethanol (4.0 mL) and water (1.0 mL), iron
(0.40 g, 7.2 mmol) and ammonium chloride (0.020 g, 0.37 mmol) were
added. The mixture was refluxed for 1.5 h. Cooled to ambient
temperature, the reaction mixture was filtered over Celite to
remove unneeded materials and the filtrate was concentrated to
afford 2-methyl-4-(2-pyrimidinylmethoxy)aniline (0.15 g, crude
material) as solid.
.sup.1H NMR (DMSO-d.sub.6) .delta. (ppm) 8.82 (d, J=4.88 Hz, 2H),
7.45 (t, J=4.90 Hz, 1H), 6.62 (d, J=2.64 Hz, 1H), 6.55 (dd, J=2.74,
8.60 Hz, 1H), 6.50 (d, J=8.52 Hz, 1H), 5.08 (s, 2H), 4.40 (br. s,
2H), 2.01 (s, 3H); LCMS (m/z): 216.0 [M+H].sup.+.
Third Step
A solution of ethyl 2-ethoxy-4-oxo-4,5-dihydrofuran-3-carboxylate
(0.14 g, 0.60 mmol) which afforded in the Example 74, Third step
and 2-methyl-4-(2-pyrimidinylmethoxy)aniline (0.13 g, 0.6 mmol) in
ethanol (5.0 mL) was stirred at 60.degree. C. for 30 h. The solvent
was removed under reduced pressure, then the residue was purified
by chromatography on silica gel(hexane/ethyl acetate) to afford
ethyl
2-{[2-methyl-4-(2-pyrimidinylmethoxy)phenyl]amino}-4-oxo-4,5-dihydrofuran-
-3-carboxylate as solid (0.035 g, y. 15%).
.sup.1H NMR (DMSO-d.sub.6) .delta. (ppm) 9.98 (br. s, 1H), 8.84 (d,
J=4.88 Hz, 2H), 7.47 (t, J=4.90 Hz, 1H), 7.25 (d, J=8.76 Hz, 1H),
6.96 (d, J=2.72 Hz, 1H), 6.84 (dd, J=2.82, 8.70 Hz, 1H), 5.28 (s,
2H), 4.57 (s, 2H), 4.21 (q, J=7.07 Hz, 2H), 2.19 (s, 3H), 1.24 (t,
J=7.04 Hz, 3H); LCMS (m/z): 370.0 [M+H].sup.+.
Fourth Step
To a solution of ethyl
2-{[2-methyl-4-(2-pyrimidinylmethoxy)phenyl]amino}-4-oxo-4,5-dihydrofuran-
-3-carboxylate (0.035 g, 0.10 mmol) and
7-azaindole-3-carboxaldehyde (0.014 g, 0.10 mmol) in ethanol (5.0
mL), piperidine (0.050 mL, 0.50 mmol) was added at ambient
temperature then the mixture was refluxed for 3 days. Cooled to
ambient temperature, the solvent was removed under reduced
pressure. The residue was suspended in ethanol, then the
precipitate was collected by filtration, washed with ethanol then
dried to afford the titled compound as solid (9.0 mg, y. 19%).
.sup.1H NMR (DMSO-d.sub.6) .delta. (ppm) 12.28 (br. s, 1H), 10.27
(br. s, 1H), 8.88 (d, J=4.40 Hz, 2H), 8.19 (d, J=3.42 Hz, 1H), 7.77
(br. s, 1H), 7.68 (d, J=7.34 Hz, 1H), 7.50 (t, J=4.60 Hz, 1H), 7.42
(d, J=8.80 Hz, 1H), 7.10 (br. s, 1H), 6.98 (d, J=8.31 Hz, 1H),
6.74-6.86 (m, 2H), 5.39 (s, 2H), 4.19-4.32 (m, J=6.80 Hz, 2H), 2.22
(br. s, 3H), 1.18-1.47 (m, 3H); LCMS (m/z): 498.4 [M+H].sup.+.
Example 162
Ethyl
5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-({2-methyl-4-[2-(1-py-
rrolidinyl)ethoxy]phenyl}amino)-4-oxo-4,5-dihydrofuran-3-carboxylate
acetate
##STR00172##
The mixture, which similarly prepared according to the procedure
described in the Example 161, was purified by preparative HPLC
(aqueous ammonium acetate/acetonitrile were used as eluents) to
afford the titled compound (solid).
.sup.1H NMR (DMSO-d.sub.6) .delta. (ppm) 12.25 (br. s, 1H), 8.16
(d, J=3.91 Hz, 1H), 7.74 (s, 1H), 7.68 (d, J=7.82 Hz, 1H), 7.35 (d,
J=7.82 Hz, 1H), 7.02 (br. s, 1H), 6.86-6.96 (m, 2H), 6.70-6.80 (m,
1H), 4.20-4.35 (m, 2H), 4.16 (t, J=5.62 Hz, 2H), 2.87 (t, J=5.62
Hz, 2H), 2.50-2.72 (m, 4H), 2.21 (s, 3H), 1.90 (s, 3H), 1.68-1.78
(m, 4H), 1.28 (t, J=7.09 Hz, 3H); LCMS (m/z): 503.2
[M+H].sup.+.
Example 163
Ethyl
5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-({2-methyl-4-[2-(meth-
ylsulfonyl)ethoxy]phenyl}amino)-4-oxo-4,5-dihydrofuran-3-carboxylate
##STR00173##
To a mixed solution of the compound (0.070 g, 0.14 mmol) of Example
128 and saturated sodium bicarbonate solution (0.80 mL) in methanol
(0.4 mL) and dichloromethane (1.6 mL) that cooled with ice bath,
3-chloroperoxybenzoic acid (0.050 g, 0.28 mmol) was added at
0.degree. C. The mixture was stirred for 1 h. The reaction mixture
was extracted with dichloromethane, and the organic layer was
washed with saturated sodium bicarbonate solution, dried over
sodium sulfate and concentrated. The residue was purified by
preparative HPLC to afford the titled compound as solid (0.010 g,
y. 13%).
.sup.1H NMR (DMSO-d.sub.6) .delta. (ppm) 12.18 (br. s, 1H), 10.4
(br. s, 1H), 8.19 (d, J=4.40 Hz, 1H), 7.74 (br. s, 1H), 7.64 (d,
J=7.34 Hz, 1H), 7.36 (d, J=8.31 Hz, 1H), 7.06 (br. s, 1H), 6.97 (d,
J=8.31 Hz, 1H), 6.66-6.80 (m, 2H), 4.44 (t, J=5.38 Hz, 2H),
4.18-4.30 (m, J=6.80 Hz, 2H), 3.66-3.76 (m, 2H), 3.15 (s, 3H), 2.21
(s, 3H), 1.28 (t, J=7.09 Hz, 3H); LCMS (m/z): 512.2
[M+H].sup.+.
Example 164
Ethyl
5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-(7,8-dihydro-1,6-naph-
thyridin-6(5H)-yl)-4-oxo-4,5-dihydrofuran-3-carboxylate formate
##STR00174##
To a solution of 5,6,7,8-tetrahydro-1,6-naphthyridine
dihydrochloride (0.049 g, 0.24 mmol) in ethanol (1.0 mL), 4M sodium
hydroxide solution (0.13 mL, 0.52 mmol) was added at ambient
temperature and the mixture was stirred for 5 min. To this reaction
mixture, ethyl 2-ethoxy-4-oxo-4,5-dihydrofuran-3-carboxylate (0.049
g, 0.24 mmol), which afforded in the Example 74, Third step was
added and stirred for 1 h. The solvent was removed under reduced
pressure, then chloroform and water were added to the residue and
two phases were separated. The organic layer was washed with brine,
dried over magnesium sulfate and concentrated. To this residue,
7-azaindole-3-carboxaldehyde (0.027 g, 0.18 mmol),
5,6,7,8-tetrahydro-1,6-naphthyridine (0.0063 g, 0.047 mmol) and
ethanol (1.0 mL) were added and the mixture was refluxed for
further 14 days. The reaction mixture was filtered and washed with
hot ethanol. The solid was purified by preparative HPLC to afford
the titled compound as solid (0.0058 g, y. 5%).
.sup.1H NMR (DMSO-d.sub.6) .delta. (ppm) 12.38 (br. s, 1H), 8.46
(d, J=3.51 Hz, 1H), 8.42 (d, J=7.78 Hz, 1H), 8.33 (dd, J=1.13, 4.64
Hz, 1H), 8.10 (s, 1H), 7.71 (d, J=7.78 Hz, 1H), 7.31 (dd, J=4.77,
7.78 Hz, 1H), 7.22 (dd, J=4.64, 7.91 Hz, 1H), 6.91 (s, 1H),
5.01-5.07 (m, 2H), 4.22 (q, J=7.03 Hz, 2H), 4.07-4.13 (m, 2H), 3.19
(t, J=5.90 Hz, 2H), 1.27 (t, J=7.03 Hz, 3H); LCMS (m/z): 417.1
[M+H].sup.+.
Example 165
Ethyl
5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-(5,6-dihydro-1,7-naph-
thyridin-7(8H)-yl)-4-oxo-4,5-dihydrofuran-3-carboxylate formate
##STR00175##
To a solution of 5,6,7,8-tetrahydro-1,7-naphthyridine
dihydrochloride (0.050 g, 0.24 mmol) in ethanol (1.3 mL), 4M sodium
hydroxide solution (0.13 mL, 0.52 mmol) was added at ambient
temperature and the mixture was stirred for 5 min. To this reaction
mixture, ethyl 2-ethoxy-4-oxo-4,5-dihydrofuran-3-carboxylate (0.049
g, 0.24 mmol), which afforded in the Example 74, Third step was
added and stirred for 1 h. The solvent was removed under reduced
pressure, then chloroform and water were added to the residue and
two phases were separated. The organic layer was washed with brine,
dried over magnesium sulfate and concentrated. To this residue,
7-azaindole-3-carboxaldehyde (0.023 g, 0.15 mmol),
5,6,7,8-tetrahydro-1,7-naphthyridine dihydrochloride (0.0056 g,
0.042 mmol) and ethanol (1.0 mL) were added and refluxed for
further 14 days. Cooled to ambient temperature, the reaction
mixture was purified by preparative HPLC to afford the titled
compound as solid (0.0033 g, y. 3%).
.sup.1H NMR (DMSO-d.sub.6) .delta. (ppm) 12.39 (br. s, 1H),
8.39-8.49 (m, 2H), 8.33 (d, J=4.52 Hz, 1H), 8.05 (d, J=2.26 Hz,
1H), 7.70 (d, J=7.03 Hz, 1H), 7.31 (dd, J=4.77, 7.78 Hz, 1H), 7.21
(dd, J=4.77, 7.78 Hz, 1H), 6.92 (s, 1H), 5.00 (br. s, 2H), 4.22 (q,
J=7.03 Hz, 2H), 4.02-4.10 (m, 2H), 3.12 (t, J=5.52 Hz, 2H), 1.27
(t, J=7.03 Hz, 3H); LCMS (m/z): 417.1 [M+H].sup.+.
Example 166
2-[(tert-Butoxycarbonyl)oxy]ethyl
5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-azepinyl-4-oxo-4,5-dihydro-
furan-3-carboxylate
##STR00176## First Step
To a solution of triethylamine (0.65 mL, 4.7 mmol) in ethylene
glycol (1.8 mL, 0.031 mol) that cooled with ice bath, ethyl malonyl
chloride (0.40 mL, 3.1 mmol) was added dropwise and the mixture was
stirred for 2.5 h. The reaction was terminated by addition of
aqueous 10% citric acid solution, the reaction mixture was
extracted with chloroform. The organic layer was dried over
magnesium sulfate, filtered and concentrated. The residue was
purified by chromatography on silica gel(chloroform/methanol) to
afford ethyl (2-hydroxyethyl)malonate as oil (0.37 g, y. 66%).
.sup.1H NMR (CDCl.sub.3) .delta. (ppm) 4.28-4.35 (m, 2H), 4.22 (q,
J=7.19 Hz, 2H), 3.80-3.88 (m, 2H), 3.43 (s, 2H), 2.18 (br. s, 1H),
1.29 (t, J=7.15 Hz, 3H)
Second Step
To a solution of ethyl 2-hydroxyethyl malonate (0.36 mg, 2.1 mmol)
and di-tert-butyl dicarbonate (0.57 mL, 2.5 mmol) in
tetrahydrofuran (2.0 mL) that cooled with ice bath, triethylamine
(0.43 mL, 3.1 mmol) was added dropwise and 4-dimethylaminopyridine
(0.019 mg, 0.16 mmol) was added then the mixture was stirred at
ambient temperature for 2 weeks. The reaction mixture was diluted
with water, and extracted with ethyl acetate. The organic layer was
washed with brine, dried over magnesium sulfate and concentrated.
The residue was purified by chromatography on silica
gel(hexane/ethyl acetate) to afford
2-[(tert-butoxycarbonyl)oxy]ethyl ethyl malonate as oil (0.37 g, y.
43%).
.sup.1H NMR (CDCl.sub.3) .delta. (ppm) 4.33-4.39 (m, 2H), 4.26-4.31
(m, 2H), 4.21 (q, J=7.03 Hz, 2H), 3.41 (s, 2H), 1.49 (s, 9H), 1.28
(t, J=7.15 Hz, 3H)
Third Step
A solution of 2-[(tert-butoxycarbonyl)oxy]ethyl ethyl malonate
(0.36 g, 1.3 mmol) in anhydrous tetrahydrofuran (1.0 mL) was added
dropwise to a solution of sodium hydride (60% w/w in oil, 0.10 g,
2.6 mmol) in anhydrous tetrahydrofuran (4.0 mL) that cooled with
ice bath. The mixture was refluxed for 14 min. The reaction mixture
was cooled with ice bath, chloroacetyl chloride (0.11 mL, 1.3 mmol)
was added dropwise to the reaction mixture and the mixture was
stirred for 1 h then stirred at 45.degree. C. for further 1 h. The
reaction mixture was diluted with water, extracted with chloroform
for 2 times. The organic layer was dried over magnesium sulfate and
concentrated. The residue was purified by chromatography on silica
gel(ethyl acetate/methanol) then concentrated. To this residue (ca.
0.11 g) in ethanol (3.0 mL), hexamethyleneimine (0.046 mL, 0.41
mmol) was added dropwise and the mixture was stirred at ambient
temperature for 30 min. Then to the reaction mixture,
7-azaindole-3-carboxaldehyde (0.043 g, 0.30 mmol) was added at
ambient temperature then the mixture was refluxed for further 4
days. Cooled to ambient temperature, the reaction mixture was
purified by preparative HPLC to afford the titled compound as solid
(0.020 g, y. 3%).
.sup.1H NMR (DMSO-d.sub.6) .delta. (ppm) 12.31 (br. s, 1H), 8.39
(d, J=8.03 Hz, 1H), 8.31 (dd, J=1.38, 4.64 Hz, 1H), 7.95 (d, J=2.51
Hz, 1H), 7.20 (dd, J=4.64, 7.91 Hz, 1H), 6.85 (s, 1H), 4.30-4.36
(m, 2H), 4.21-4.27 (m, 2H), 3.70-3.90 (m, 4H), 1.80-1.90 (m, 4H),
1.53-1.62 (m, 4H), 1.42 (s, 9H); LCMS (m/z): 498.2 [M+H].sup.+.
Example 167
2-Methoxyethyl
5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-[N-methyl-N-(2-thienylmeth-
yl)amino]-4-oxo-4,5-dihydrofuran-3-carboxylate
##STR00177##
A solution of the compound (0.050 g, 0.12 mmol) of Example 108,
2-methoxyethanol (0.20 mL, 2.6 mmol), 4-dimethylaminopyridine
(0.0030 g, 0.024 mmol) and zinc cluster catalyst
(Zn.sub.4(OCOCF.sub.3).sub.6O) (0.0058 g, 0.0061 mmol) in
N,N-dimethylacetamide (0.5 mL) was stirred with the microwave
synthesizer (Biotage Initiator.TM.) at 150.degree. C. for 3.5 h.
Cooled to ambient temperature, the reaction mixture was purified by
preparative HPLC to afford the titled compound as solid (0.0029 g,
y. 5%).
.sup.1H NMR (DMSO-d.sub.6) .delta. (ppm) 12.34 (br. s, 1H), 8.38
(d, J=8.03 Hz, 1H), 8.30 (dd, J=1.38, 4.64 Hz, 1H), 8.03 (d, J=2.26
Hz, 1H), 7.53 (dd, J=1.00, 5.02 Hz, 1H), 7.13-7.22 (m, 2H), 7.04
(dd, J=3.51, 5.02 Hz, 1H), 6.93 (s, 1H), 5.20 (s, 2H), 4.23-4.28
(m, 2H), 3.55-3.60 (m, 2H), 3.22-3.32 (m, 6H); LCMS (m/z): 440.1
[M+H].sup.+.
Example 168
n-Butyl
5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-[N-methyl-N-(2-thie-
nylmethyl)amino]-4-oxo-4,5-dihydrofuran-3-carboxylate
##STR00178##
A solution of the compound (0.050 g, 0.12 mmol) of Example 108,
1-butanol (0.50 mL, 5.5 mmol), 4-dimethylaminopyridine (0.0030 g,
0.024 mmol) and zinc cluster catalyst
(Zn.sub.4(OCOCF.sub.3).sub.6O) (0.0058 g, 0.0061 mmol) in
N,N-dimethylacetamide (0.5 mL) was stirred with the microwave
synthesizer (Biotage Initiator.TM.) at 150.degree. C. for 1.5 h.
Cooled to ambient temperature, the reaction mixture was purified by
preparative HPLC to afford the titled compound as solid (0.0044 g,
y. 6%).
.sup.1H NMR (DMSO-d.sub.6) .delta. (ppm) 12.33 (br. s, 1H), 8.37
(d, J=7.78 Hz, 1H), 8.30 (dd, J=1.25, 4.52 Hz, 1H), 8.01-8.04 (m,
1H), 7.53 (dd, J=1.25, 5.02 Hz, 1H), 7.14-7.22 (m, 2H), 7.04 (dd,
J=3.51, 5.02 Hz, 1H), 6.91 (s, 1H), 5.21 (s, 2H), 4.13 (t, J=6.53
Hz, 2H), 3.24-3.31 (m, 3H), 1.55-1.65 (m, 2H), 1.36-1.47 (m, 2H),
0.90 (t, J=7.40 Hz, 3H); LCMS (m/z): 438.1 [M+H].sup.+.
Example 169
2-Hydroxyethyl
5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-azepinyl-4-oxo-4,5-dihydro-
furan-3-carboxylate hydrochloride
##STR00179##
To a mixed solution of the compound (0.018 g, 0.037 mmol) of
Example 166 in dioxane (0.2 mL) and chloroform (1.0 mL) that cooled
with ice bath, 4M hydrochloric acid in dioxane (0.25 mL, 1.0 mmol)
was added dropwise. The mixture was stirred at ambient temperature
for 24 h. The precipitate was collected by filtration, washed with
chloroform and hexane then dried to afford the titled compound as
solid (6.3 mg, y. 37%).
.sup.1H NMR (DMSO-d.sub.6) .delta. (ppm) 12.39 (br. s, 1H), 8.44
(d, J=7.78 Hz, 1H), 8.33 (dd, J=1.38, 4.64 Hz, 1H), 7.96 (s, 1H),
7.23 (dd, J=4.77, 8.03 Hz, 1H), 6.89 (s, 1H), 4.16 (t, J=5.27 Hz,
2H), 3.67-3.95 (m, 6H), 3.62 (t, J=5.14 Hz, 2H), 1.75-1.93 (m, 4H),
1.50-1.65 (m, 4H); LCMS (m/z): 398.1 [M+H].sup.+.
Example 170
2-(Dimethylamino)ethyl
5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-[N-methyl-N-(2-thienylmeth-
yl)amino]-4-oxo-4,5-dihydrofuran-3-carboxylate
##STR00180##
A solution of the compound (0.10 g, 0.25 mmol) of Example 108,
2-(dimethylamino)ethanol (0.40 mL, 4.0 mmol),
4-dimethylaminopyridine (0.0060 g, 0.049 mmol) and zinc cluster
catalyst (Zn.sub.4(OCOCF.sub.3).sub.6O) (0.012 g, 0.012 mmol) in
N,N-dimethylacetamide (0.5 mL) was stirred with the microwave
synthesizer (Biotage Initiator.TM.) at 150.degree. C. for 30 min.
Cooled to ambient temperature, the reaction mixture was purified by
preparative HPLC to afford the titled compound as solid (0.0023 g,
y. 2%).
.sup.1H NMR (DMSO-d.sub.6) .delta. (ppm) 12.33 (br. s, 1H), 8.38
(d, J=8.03 Hz, 1H), 8.28-8.32 (m, 1H), 8.03 (s, 1H), 7.53 (dd,
J=1.00, 5.02 Hz, 1H), 7.14-7.22 (m, 2H), 7.04 (dd, J=3.51, 5.02 Hz,
1H), 6.92 (s, 1H), 5.20 (s, 2H), 4.21 (t, J=5.90 Hz, 2H), 3.51 (s,
3H), 3.25-3.29 (m, 2H), 2.18 (s, 6H); LCMS (m/z): 453.1
[M+H].sup.+.
Example 171
Ethyl
5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-({2-methyl-4-[2-(2-py-
ridinyl)ethoxy]phenyl}amino)-4-oxo-4,5-dihydrofuran-3-carboxylate
##STR00181## First Step
To a solution of 4-nitro-m-cresol (3.0 g, 0.020 mmol) and
triphenylphosphine (7.7 g, 0.029 mmol) in tetrahydrofuran (50 mL)
cooled with ice bath, diisopropyl azodicarboxylate (5.8 mL, 0.030
mmol) was added dropwise. The mixture was stirred at ambient
temperature for 30 min. The reaction mixture was cooled with ice
bath, and a solution of 2-pyridineethanol (2.6 mL, 0.024 mmol) in
tetrahydrofuran (5.0 mL) was added dropwise to the reaction mixture
then the mixture was stirred at ambient temperature for further 16
h. The solvent was removed under reduced pressure, then the residue
was purified by chromatography on silica gel(hexane/ethyl acetate)
to afford 2-methyl-4-[2-(2-pyridinyl)ethoxy]-1-nitrobenzene as
solid (2.0 g, y. 40%).
.sup.1H NMR (DMSO-d.sub.6) .delta. (ppm) 8.43-8.59 (m, 1H), 8.03
(d, J=9.08 Hz, 1H), 7.73 (t, J=7.62 Hz, 1H), 7.37 (d, J=7.80 Hz,
1H), 7.25 (t, J=6.12 Hz, 1H), 7.03 (s, 1H), 6.98 (d, J=9.20 Hz,
1H), 4.49 (t, J=6.46 Hz, 2H), 3.22 (t, J=6.54 Hz, 2H), 2.53 (s,
3H); LCMS (m/z): 259.0 [M+H].sup.+.
Second Step
Under a nitrogen atmosphere,
2-methyl-4-[2-(2-pyridinyl)ethoxy]-1-nitrobenzene (2.0 g, 7.7 mmol)
was dissolved in tetrahydrofuran (40 mL) and 10% palladium on
carbon (0.20 g) was added at ambient temperature. The reaction
mixture was agitated under a hydrogen atmosphere at ambient
temperature for 4 h. Palladium on carbon was removed by filtration
with Celite and the solvent was removed under reduced pressure to
afford 2-methyl-4-[2-(2-pyridinyl)ethoxy]aniline as solid (1.4 g,
y. 80%).
.sup.1H NMR (DMSO-d.sub.6) .delta. (ppm) 8.49 (d, J=4.36 Hz, 1H),
7.71 (t, J=7.64 Hz, 1H), 7.33 (d, J=7.76 Hz, 1H), 7.22 (t, J=6.10
Hz, 1H), 6.45-6.58 (m, 3H), 4.35 (br. s, 2H), 4.18 (t, J=6.66 Hz,
2H), 3.10 (t, J=6.62 Hz, 2H), 2.00 (s, 3H); LCMS (m/z): 229.4
[M+H].sup.+.
Third Step
A solution of ethyl 2-ethoxy-4-oxo-4,5-dihydrofuran-3-carboxylate
(0.35 g, 1.8 mmol) which afforded in the Example 74, Third step and
2-methyl-4-[2-(2-pyridinyl)ethoxy]aniline (0.40 g, 1.8 mmol) in
ethanol (5.0 mL) was stirred at ambient temperature for 1.5 days.
The solvent was removed under reduced pressure, then the residue
was purified by preparative HPLC to afford ethyl
2-({2-methyl-4-[2-(2-pyridinyl)ethoxy]phenyl}amino)-4-oxo-4,5-dihydrofura-
n-3-carboxylate as solid (0.15 g, y. 22%).
.sup.1H NMR (DMSO-d.sub.6) .delta. (ppm) 9.98 (br. s, 1H), 8.51 (d,
J=4.52 Hz, 1H), 7.70-7.78 (m, 1H), 7.37 (d, J=7.92 Hz, 1H),
7.22-7.28 (m, 2H), 6.87-6.92 (m, 1H), 6.77-6.84 (m, 1H), 4.57 (s,
2H), 4.36 (t, J=6.62 Hz, 2H), 4.21 (q, J=7.06 Hz, 2H), 3.13-3.25
(m, 2H), 2.19 (s, 3H), 1.21 (s, 3H); LCMS (m/z): 383.2
[M+H].sup.+.
Fourth Step
To a stirred solution of ethyl
2-({2-methyl-4-[2-(2-pyridinyl)ethoxy]phenyl}amino)-4-oxo-4,5-dihydrofura-
n-3-carboxylate (0.15 g, 0.39 mmol) and
7-azaindole-3-carboxaldehyde (0.057 g, 0.39 mmol) in ethanol (5.0
mL), L-proline (5.0 mg, 0.043 mmol) was added at ambient
temperature. The mixture was refluxed for 3 days. The solvent was
removed under reduced pressure and the residue was purified by
preparative HPLC to afford the titled compound as solid (0.015 g,
y. 8%).
.sup.1H NMR (DMSO-d.sub.6) .delta. (ppm) 8.57 (d, J=3.91 Hz, 1H),
8.11 (d, J=3.91 Hz, 1H), 7.78 (t, J=7.58 Hz, 1H), 7.65-7.73 (m,
2H), 7.44 (d, J=7.82 Hz, 1H), 7.24-7.33 (m, 2H), 6.97 (br. s, 1H),
6.88 (d, J=8.31 Hz, 1H), 6.63-6.72 (m, 2H), 4.45 (t, J=6.36 Hz,
2H), 4.21 (d, J=6.85 Hz, 2H), 3.23-3.27 (m, 2H), 2.17 (s, 3H), 1.27
(t, J=6.85 Hz, 3H); LCMS (m/z): 511.2 [M+H].sup.+.
Example 172
2-Hydroxyethyl
5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-[(2-chlorophenyl)amino]-4--
oxo-4,5-dihydrofuran-3-carboxylate
##STR00182##
A solution of the compound (0.10 g, 0.24 mmol) of Example 15,
ethylene glycol (0.14 mL, 2.5 mmol) and zinc cluster catalyst
(Zn.sub.4(OCOCF.sub.3).sub.6O) (0.012 g, 0.012 mmol) in
N,N-dimethylacetamide (2.0 mL) was stirred with the microwave
synthesizer (Biotage Initiator.TM.) at 130.degree. C. for 1 h.
Cooled to ambient temperature, the reaction mixture was purified by
preparative HPLC to afford the titled compound as solid (0.030 g,
y. 29%).
.sup.1H NMR (DMSO-d.sub.6) .delta. (ppm) 12.11 (br. s, 1H), 8.18
(d, J=4.24 Hz, 1H), 7.82 (d, J=7.34 Hz, 1H), 7.59-7.66 (m, 2H),
7.29-7.55 (m, 3H), 6.79 (dd, J=4.65, 7.58 Hz, 1H), 6.62 (br. s,
1H), 4.12-4.22 (m, 2H), 3.65 (t, J=4.89 Hz, 2H); LCMS (m/z): 426
[M+H].sup.+.
Example 173
2-Methoxyethyl
5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-[(2-chlorophenyl)amino]-4--
oxo-4,5-dihydrofuran-3-carboxylate
##STR00183##
The titled compound (solid) was similarly prepared according to the
procedure described in the Example 172.
.sup.1H NMR (DMSO-d.sub.6) .delta. (ppm) 12.12 (br. s, 1H), 8.18
(d, J=4.04 Hz, 1H), 7.82 (d, J=7.34 Hz, 1H), 7.58-7.67 (m, 2H),
7.32-7.54 (m, 3H), 6.79 (dd, J=4.65, 7.58 Hz, 1H), 6.63 (br. s,
1H), 4.22-4.32 (m, 2H), 3.56-3.66 (m, 2H), 3.30 (s, 3H); LCMS
(m/z): 440.2 [M+H].sup.+.
Example 174
3-Hydroxypropyl
5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-[(2-chlorophenyl)amino]-4--
oxo-4,5-dihydrofuran-3-carboxylate
##STR00184##
The titled compound (solid) was similarly prepared according to the
procedure described in the Example 172.
.sup.1H NMR (DMSO-d.sub.6) .delta. (ppm) 12.23 (br. s, 1H), 10.70
(br. s, 1H), 8.20 (d, J=3.42 Hz, 1H), 7.62-7.85 (m, 4H), 7.43-7.58
(m, 2H), 6.73-6.83 (m, 2H), 4.72 (br. s, 1H), 4.20-4.30 (m, 2H),
3.58 (t, J=5.38 Hz, 2H), 1.75-1.89 (m, 2H); LCMS (m/z): 440.2
[M+H].sup.+.
Example 175
(1R,2S)-2-Hydroxycyclopentyl
5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-[(4-fluorophenyl)amino]-4--
oxo-4,5-dihydrofuran-3-carboxylate
##STR00185##
A solution of the compound (0.10 g, 0.25 mmol) of Example 21,
(1R,2S)-1,2-cyclopentanediol (0.26 g, 2.5 mmol) and zinc cluster
catalyst (Zn.sub.4(OCOCF.sub.3).sub.6O) (0.012 g, 0.012 mmol) in
N,N-dimethylacetamide (1.5 mL) was stirred with the microwave
synthesizer (Biotage Initiator.TM.) at 130.degree. C. for 2 h.
Cooled to ambient temperature, the precipitate was removed by
filtration. The filtrate was purified by preparative HPLC to afford
the titled compound as solid (0.025 g, y. 20%).
.sup.1H NMR (DMSO-d.sub.6) .delta. (ppm) 12.26 (br. s, 1H), 10.60
(br. s, 1H), 8.26 (d, J=4.40 Hz, 1H), 8.05 (d, J=7.82 Hz, 1H), 7.77
(br. s, 1H), 7.52-7.61 (m, 2H), 7.36 (t, J=8.31 Hz, 2H), 6.94 (dd,
J=4.65, 7.58 Hz, 1H), 6.87 (br. s, 1H), 5.37 (br. s, 1H), 4.88-4.98
(m, 1H), 4.09-4.18 (m, 1H), 1.94-2.06 (m, 1H), 1.70-1.90 (m, 3H),
1.43-1.69 (m, 2H); LCMS (m/z): 450.2 [M+H].sup.+.
Example 176
4-Hydroxycyclohexyl
5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-[(4-fluorophenyl)amino]-4--
oxo-4,5-dihydrofuran-3-carboxylate
##STR00186##
The titled compound (solid) was similarly prepared according to the
procedure described in the Example 175.
.sup.1H NMR (DMSO-d.sub.6) .delta. (ppm) 12.26 (br. s, 1H), 10.65
(br. s, 1H), 8.25 (d, J=2.93 Hz, 1H), 7.95 (d, J=7.34 Hz, 1H), 7.75
(br. s, 1H), 7.55-7.65 (br. s, 2H), 7.36 (t, J=8.07 Hz, 2H),
6.87-6.94 (m, 1H), 6.82 (br. s, 1H), 4.94 (br. s, 1H), 4.53 (br. s,
1H), 3.56-3.68 (m, 1H), 1.79-1.95 (m, 2H), 1.46-1.77 (m, 6H); LCMS
(m/z): 463.8 [M+H].sup.+.
Example 177
3-Hydroxy-2,2-dimethylpropyl
5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-[(4-fluorophenyl)amino]-4--
oxo-4,5-dihydrofuran-3-carboxylate
##STR00187##
A solution of the compound (0.10 g, 0.25 mmol) of Example 21,
2,2-dimethyl-1,3-propanediol (0.40 g, 3.8 mmol) and zinc cluster
catalyst (Zn.sub.4(OCOCF.sub.3).sub.6O) (0.018 g, 0.019 mmol) in
N,N-dimethylacetamide (1.5 mL) was stirred with the microwave
synthesizer (Biotage Initiator.TM.) at 130.degree. C. for 24 h.
Cooled to ambient temperature, the precipitate was removed by
filtration. The filtrate was purified by preparative HPLC to afford
the titled compound as solid (0.020 g, y. 17%).
.sup.1H NMR (DMSO-d.sub.6) .delta. (ppm) 12.27 (br. s, 1H), 10.68
(br. s, 1H), 8.25 (d, J=3.91 Hz, 1H), 7.97 (d, J=7.82 Hz, 1H), 7.74
(br. s, 1H), 7.57-7.65 (m, 2H), 7.37 (t, J=8.31 Hz, 2H), 6.83-6.97
(m, 2H), 4.88 (br. s, 1H), 3.93-4.02 (m, 2H), 3.26-3.36 (m, 2H),
0.93 (s, 6H); LCMS (m/z): 452.4 [M+H].sup.+.
Example 178
2-(1-Pyrrolidinyl)ethyl
5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-[(4-fluorophenyl)amino]-4--
oxo-4,5-dihydrofuran-3-carboxylate formate
##STR00188##
The titled compound (solid) was similarly prepared according to the
procedure described in the Example 177.
.sup.1H NMR (DMSO-d.sub.6) .delta. (ppm) 12.11 (br. s, 1H), 8.21
(d, J=4.12 Hz, 1H), 8.17 (s, 1H), 7.96 (d, J=7.83 Hz, 1H), 7.65 (s,
1H), 7.34-7.43 (m, 2H), 7.24-7.33 (m, 2H), 6.87 (dd, J=4.89, 7.34
Hz, 1H), 6.65 (s, 1H), 4.25-4.38 (m, 2H), 3.03-3.12 (m, 2H),
2.87-3.00 (m, 4H), 1.65-1.80 (m, 4H); LCMS (m/z): 463.2
[M+H].sup.+.
Example 179
Ethyl
5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-[(4-methyl-1-piperazi-
nyl)amino]-4-oxo-4,5-dihydrofuran-3-carboxylate
##STR00189##
To a solution of ethyl
2-[(4-methyl-1-piperazinyl)amino]-4-oxo-4,5-dihydrofuran-3-carboxylate
(0.080 g, 0.30 mmol) which similarly prepared according to the
procedure described in the Example 74, Fourth step and
7-azaindole-3-carboxaldehyde (0.040 g, 0.30 mmol) in ethanol (2.0
mL), L-proline (0.020 g, 0.17 mmol) was added at ambient
temperature. The mixture was refluxed for 1.5 days. Cooled to
ambient temperature, the precipitate was collected by filtration,
washed with ethanol and hexane then dried to afford the titled
compound as solid (0.017 g, y. 14%).
.sup.1H NMR (DMSO-d.sub.6) .delta. (ppm) 12.36 (br. s, 1H), 9.95
(br. s, 1H), 8.96 (d, J=7.34 Hz, 1H), 8.35 (d, J=3.42 Hz, 1H), 8.11
(br. s, 1H), 7.23 (dd, J=4.65, 7.58 Hz, 1H), 6.85 (br. s, 1H), 4.21
(q, J=7.30 Hz, 2H), 3.06 (br. s, 3H), 2.43-2.70 (m, 6H), 2.24-2.35
(m, 2H), 1.26 (t, J=6.85 Hz, 3H); LCMS (m/z): 398.2
[M+H].sup.+.
Example 180
1-Methyl-4-piperidinyl
5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-[(4-fluorophenyl)amino]-4--
oxo-4,5-dihydrofuran-3-carboxylate formate
##STR00190##
A solution of the compound (0.10 g, 0.25 mmol) (of Example 21,
4-hydroxy-1-methylpiperidine (0.44 g, 3.8 mmol) and zinc cluster
catalyst (Zn.sub.4(OCOCF.sub.3).sub.6O) (0.018 g, 0.019 mmol) in
N,N-dimethylacetamide (1.0 mL) was stirred at 180.degree. C. for 16
h then at 130.degree. C. for further 16 h. Cooled to ambient
temperature, the precipitate was removed by filtration. The
filtrate was purified by preparative HPLC to afford the titled
compound as solid (0.016 g, y. 13%).
.sup.1H NMR (DMSO-d.sub.6) .delta. (ppm) 12.15 (br. s, 1H), 8.23
(d, J=3.91 Hz, 1H), 8.18 (s, 1H), 7.96 (d, J=7.82 Hz, 1H), 7.69 (s,
1H), 7.42-7.49 (m, 2H), 7.25-7.36 (m, 2H), 6.89 (dd, J=4.89, 7.83
Hz, 1H), 6.68 (s, 1H), 4.83-4.93 (m, 1H), 2.77-2.87 (m, 2H),
2.35-2.45 (m, 2H), 2.30 (s, 3H), 1.85-1.95 (m, 2H), 1.68-1.80 (m,
2H); LCMS (m/z): 463.2 [M+H].sup.+.
Example 181
Isobutyl
5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-[(4-fluorophenyl)a-
mino]-4-oxo-4,5-dihydrofuran-3-carboxylate formate
##STR00191##
The titled compound (solid) was similarly prepared according to the
procedure described in the Example 180.
.sup.1H NMR (DMSO-d.sub.6) .delta. (ppm) 12.17 (br. s, 1H), 8.23
(d, J=3.91 Hz, 1H), 8.19 (s, 1H), 7.96 (d, J=7.82 Hz, 1H), 7.70 (s,
1H), 7.43-7.54 (m, 2H), 7.31 (t, J=8.07 Hz, 2H), 6.84-6.96 (m, 1H),
6.72 (br. s, 1H), 3.96 (d, J=5.87 Hz, 2H), 1.90-2.05 (m, 1H), 0.97
(d, J=6.36 Hz, 6H); LCMS (m/z): 422.2 [M+H].sup.+.
Example 182
2-(Dimethylamino)ethyl
5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-[(2-chlorophenyl)amino]-4--
oxo-4,5-dihydrofuran-3-carboxylate acetate
##STR00192##
A solution of the compound (0.10 g, 0.24 mmol) of Example 15,
2-(dimethylamino)ethanol (0.40 mL, 4.0 mmol),
4-dimethylaminopyridine (0.010 g, 0.082 mmol) and zinc cluster
catalyst (Zn.sub.4(OCOCF.sub.3).sub.6O) (0.018 g, 0.019 mmol) in
N,N-dimethylacetamide (2.0 mL) was stirred at 130.degree. C. for 24
h. Cooled to ambient temperature, the precipitate was removed by
filtration. The filtrate was purified by preparative HPLC (aqueous
ammonium acetate/acetonitrile as eluents) to afford the titled
compound as solid (0.012 g, y. 11%).
.sup.1H NMR (DMSO-d.sub.6) .delta. (ppm) 11.92 (br. s, 1H), 8.15
(d, J=3.91 Hz, 1H), 7.86 (d, J=7.82 Hz, 1H), 7.48-7.55 (m, 2H),
7.30-7.37 (m, 1H), 7.15-7.23 (m, 2H), 6.73-6.79 (m, 1H), 6.39 (s,
1H), 4.30-4.39 (m, 2H), 3.12-3.22 (m, 2H), 2.73 (br. s, 6H), 1.91
(s, 3H); LCMS (m/z): 453.0 [M+H].sup.+.
Example 183
3-Hydroxycyclohexyl
5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-[(4-fluorophenyl)amino]-4--
oxo-4,5-dihydrofuran-3-carboxylate
##STR00193##
A solution of the compound (0.10 g, 0.25 mmol) of Example 21,
1,3-cyclohexanediol (0.44 g, 3.8 mmol) and zinc cluster catalyst
(Zn.sub.4(OCOCF.sub.3).sub.6O) (0.018 g, 0.019 mmol) in
N,N-dimethylacetamide (1.0 mL) was stirred at 130.degree. C. for
1.5 days. Cooled to ambient temperature, the precipitate was
removed by filtration. The filtrate was purified by preparative
HPLC to afford the titled compound as solid (0.010 g, y. 13%).
.sup.1H NMR (DMSO-d.sub.6) .delta. (ppm) 12.25 (br. s, 1H), 8.24
(d, J=3.91 Hz, 1H), 7.92-8.00 (m, 1H), 7.74 (br. s, 1H), 7.55-7.65
(m, 2H), 7.31-7.42 (m, 2H), 6.90 (dd, J=4.89, 7.82 Hz, 1H),
6.78-6.86 (m, 1H), 5.19-5.28 (m, 1H), 4.92-5.02 (m, 1H), 4.55 (d,
J=3.42 Hz, 1H), 1.15-2.08 (m, 8H); LCMS (m/z): 463.8
[M+H].sup.+.
Example 184
(1-Methyl-2-piperidinyl)methyl
5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-[(4-fluorophenyl)amino]-4--
oxo-4,5-dihydrofuran-3-carboxylate formate
##STR00194##
The titled compound (solid) was similarly prepared according to the
procedure described in the Example 183.
.sup.1H NMR (DMSO-d.sub.6) .delta. (ppm) 12.11 (br. s, 1H), 8.22
(d, J=4.40 Hz, 1H), 8.16 (s, 1H), 7.98 (d, J=7.82 Hz, 1H), 7.66 (s,
1H), 7.34-7.42 (m, 2H), 7.25-7.33 (m, 2H), 6.88 (dd, J=4.65, 7.58
Hz, 1H), 6.65 (s, 1H), 4.23-4.35 (m, 2H), 2.90-3.00 (m, 1H),
2.62-2.72 (m, 1H), 2.46-2.56 (m, 4H), 1.18-1.83 (m, 6H); LCMS
(m/z): 477.4 [M+H].sup.+.
Example 185
2-(4-Methyl-1-piperazinyl)ethyl
5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-[(4-fluorophenyl)amino]-4--
oxo-4,5-dihydrofuran-3-carboxylate formate
##STR00195##
The titled compound (solid) was similarly prepared according to the
procedure described in the Example 183.
.sup.1H NMR (DMSO-d.sub.6) .delta. (ppm) 12.14 (br. s, 1H),
8.16-8.25 (m, 2H), 7.95 (d, J=6.85 Hz, 1H), 7.67 (br. s, 1H),
7.38-7.48 (m, 2H), 7.25-7.36 (m, 2H), 6.84-6.91 (m, 1H), 6.68 (br.
s, 1H), 4.20-4.34 (m, 2H), 2.22-2.71 (m, 10H), 2.13 (br. s, 3H);
LCMS (m/z): 492.4 [M+H].sup.+.
Example 186
2-(N,N-Dimethylamino)-2-methylpropyl
5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-[(4-fluorophenyl)amino]-4--
oxo-4,5-dihydrofuran-3-carboxylate formate
##STR00196##
The titled compound (solid) was similarly prepared according to the
procedure described in the Example 183.
.sup.1H NMR (DMSO-d.sub.6) .delta. (ppm) 12.01 (br. s, 1H),
8.15-8.29 (m, 2H), 7.98 (d, J=7.34 Hz, 1H), 7.60 (br. s, 1H),
7.05-7.33 (m, 4H), 6.83-6.93 (m, 1H), 6.47 (s, 1H), 4.20 (br. s,
2H), 2.55 (br. s, 6H), 1.22 (br. s, 6H); LCMS (m/z): 465.0
[M+H].sup.+.
Example 187
(1-Methyl-4-piperidinyl)methyl
5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-[(4-fluorophenyl)amino]-4--
oxo-4,5-dihydrofuran-3-carboxylate formate
##STR00197##
The titled compound (solid) was similarly prepared according to the
procedure described in the Example 183.
.sup.1H NMR (DMSO-d.sub.6) .delta. (ppm) 12.09 (br. s, 1H),
8.18-8.24 (m, 2H), 7.96 (d, J=7.82 Hz, 1H), 7.66 (s, 1H), 7.33-7.43
(m, 2H), 7.22-7.32 (m, 2H), 6.89 (dd, J=4.89, 7.83 Hz, 2H), 6.59
(s, 1H), 4.01 (d, J=6.36 Hz, 2H), 2.88-2.96 (m, 2H), 2.29 (s, 3H),
2.03-2.15 (m, 2H), 1.62-1.82 (m, 3H), 1.26-1.41 (m, 2H); LCMS
(m/z): 477.3 [M+H].sup.+.
Example 188
Ethyl
5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-(4-morpholinopiperidi-
n-1-yl)-4-oxo-4,5-dihydrofuran-3-carboxylate
##STR00198##
To a stirred solution of ethyl
2-(4-morpholinopiperidin-1-yl)-4-oxo-4,5-dihydrofuran-3-carboxylate
(0.10 g, 0.31 mmol) which similarly prepared according to the
procedure described in the Example 74, Fourth step and
7-azaindole-3-carboxaldehyde (0.045 g, 0.31 mmol) in ethanol (10
mL), piperidine (0.020 mL, 0.20 mmol) was added at ambient
temperature. The mixture was refluxed for 16 h. Cooled to ambient
temperature, the precipitate was collected by filtration, washed
with ethanol and hexane then dried to afford the titled compound
(0.018 g, y. 13%) as solid.
.sup.1H NMR (DMSO-d.sub.6) .delta. (ppm) 12.31 (br. s, 1H), 8.37
(d, J=7.34 Hz, 1H), 8.31 (d, J=3.42 Hz, 1H), 7.97 (br. s, 1H),
7.16-7.23 (m, 1H), 6.85 (s, 1H), 4.11-4.30 (m, 4H), 3.52-3.64 (m,
4H), 3.23-3.43 (m, 7H), 1.90-2.02 (m, 2H), 1.54-1.76 (m, 2H), 1.24
(t, J=6.60 Hz, 3H); LCMS (m/z): 453.2 [M+H].sup.+.
Example 189
Ethyl
5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-(3-carbamoylpiperidin-
o)-4-oxo-4,5-dihydrofuran-3-carboxylate
##STR00199##
To a solution of ethyl
2-(3-carbamoylpiperidino)-4-oxo-4,5-dihydrofuran-3-carboxylate
(0.15 g, 0.53 mmol) which similarly prepared according to the
procedure described in the Example 74, Fourth step and
7-azaindole-3-carboxaldehyde (0.078 g, 0.53 mmol) in ethanol (10
mL), piperidine (0.020 mL, 0.20 mmol) was added at ambient
temperature. The mixture was refluxed for 16 h. Cooled to ambient
temperature, the precipitate was collected by filtration, washed
with ethanol and hexane then dried to afford the titled compound as
solid (0.018 g, y. 9%).
.sup.1H NMR (DMSO-d.sub.6) .delta. (ppm) 12.34 (br. s, 1H), 8.38
(d, J=7.52 Hz, 1H), 8.31 (d, J=3.72 Hz, 1H), 7.97 (br. s, 1H), 7.44
(br. s, 1H), 7.13-7.23 (m, 1H), 6.99 (br. s, 1H), 6.85 (s, 1H),
4.10-4.22 (m, 4H), 3.25-3.46 (m, 2H), 2.54-2.64 (m, 1H), 1.96-2.06
(m, 1H), 1.82-1.92 (m, 1H), 1.60-1.74 (m, 2H), 1.24 (t, J=6.85 Hz,
3H); LCMS (m/z): 411.4 [M+H].sup.+.
Example 190
Ethyl
5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-4-oxo-2-(3-oxopiperazin-
o)-4,5-dihydrofuran-3-carboxylate
##STR00200##
The titled compound (solid) was similarly prepared according to the
procedure described in the Example 189.
.sup.1H NMR (DMSO-d.sub.6) .delta. (ppm) 12.38 (br. s, 1H),
8.29-8.44 (m, 2H), 8.01 (br. s, 1H), 7.15-7.25 (m, 1H), 6.92 (br.
s, 1H), 4.30-4.40 (m, 2H), 4.11-4.23 (m, 2H), 3.92-4.04 (m, 2H),
3.41-3.49 (m, 2H), 1.18-1.31 (m, 3H); LCMS (m/z): 383.0
[M+H].sup.+.
Example 191
Ethyl
5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-(4-acetyl-1,4-diazepa-
nyl)-4-oxo-4,5-dihydrofuran-3-carboxylate
##STR00201##
The titled compound (solid) was similarly prepared according to the
procedure described in the Example 189.
.sup.1H NMR (DMSO-d.sub.6) .delta. (ppm) 12.36 (br. s, 1H), 8.41
(d, J=7.68 Hz, 1H), 8.35 (d, J=4.36 Hz, 1H), 7.99 (br. s, 1H),
7.17-7.29 (m, 1H), 6.89 (d, J=3.91 Hz, 1H), 4.15-4.27 (m, 2H),
3.92-4.10 (m, 3H), 3.73-3.90 (m, 3H), 3.51-3.64 (m, 2H), 1.83-2.08
(m, 5H), 1.28 (t, J=6.60 Hz, 3H); LCMS (m/z): 425.3
[M+H].sup.+.
Example 192
Ethyl
5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-(4-methyl-1,4-diazepa-
nyl)-4-oxo-4,5-dihydrofuran-3-carboxylate acetate
##STR00202##
The titled compound (solid) was similarly prepared according to the
procedure described in the Example 189. Further, preparative HPLC
(aqueous ammonium acetate/acetonitrile) was used as purification
procedure.
.sup.1H NMR (DMSO-d.sub.6) .delta. (ppm) 12.48 (br. s, 1H), 8.36
(d, J=7.82 Hz, 1H), 8.30 (d, J=4.40 Hz, 1H), 7.96 (s, 1H), 7.18
(dd, J=4.89, 7.82 Hz, 1H), 6.85 (s, 1H), 4.16 (q, J=7.34 Hz, 2H),
3.70-3.92 (m, 4H), 2.72-2.82 (m, 2H), 2.53-2.63 (m, 2H), 2.28 (s,
3H), 1.92-2.02 (m, 2H), 1.62 (s, 3H), 1.24 (t, J=7.09 Hz, 3H); LCMS
(m/z): 397.2 [M+H].sup.+.
Example 193
Ethyl
5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-(2-methyl-2-phenylhyd-
razinyl)-4-oxo-4,5-dihydrofuran-3-carboxylate
##STR00203##
To a solution of ethyl
2-(2-methyl-2-phenylhydrazinyl)-4-oxo-4,5-dihydrofuran-3-carboxylate
(0.10 g, 0.36 mmol) which similarly prepared according to the
procedure described in the Example 74, Fourth step and
7-azaindole-3-carboxaldehyde (0.053 g, 0.36 mmol) in ethanol (10
mL), L-proline (0.020 g, 0.17 mmol) was added at ambient
temperature. The mixture was refluxed for 2 days. Cooled to ambient
temperature, the precipitate was collected by filtration, washed
with ethanol and hexane then dried to afford the titled compound as
solid (0.015 g, y. 10%).
.sup.1H NMR (DMSO-d.sub.6) .delta. (ppm) 12.28 (br. s, 1H), 10.79
(s, 1H), 8.48 (d, J=8.31 Hz, 1H), 8.22 (d, J=3.91 Hz, 1H), 7.90
(br. s, 1H), 7.32 (t, J=7.82 Hz, 2H), 6.83-7.05 (m, 5H), 4.25 (q,
J=6.85 Hz, 2H), 3.34 (s, 3H), 1.29 (t, J=6.85 Hz, 3H); LCMS (m/z):
405.2 [M+H].sup.+.
Example 194
Ethyl
5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-[4-(diethylamino)pipe-
ridino]-4-oxo-4,5-dihydrofuran-3-carboxylate
##STR00204## First Step
Under a nitrogen atmosphere, to a solution of tert-butyl
4-oxopiperidine-1-carboxylate (5.0 g, 0.025 mol) and diethylamine
(9.1 mL, 0.090 mol) in methanol (40 mL), 10% palladium on carbon
(0.50 g) was added at ambient temperature. The reaction mixture was
agitated under a hydrogen atmosphere at ambient temperature for 16
h. Palladium on carbon was removed by filtration with Celite and
the solvent was removed under reduced pressure, then the residue
was purified by chromatography on silica
gel(dichloromethane/methanol) to afford tert-butyl
4-(diethylamino)piperidine-1-carboxylate as solid (6.1 g, y.
95%).
.sup.1H NMR (CDCl.sub.3) .delta. (ppm) 4.12 (br. s, 2H), 3.76-3.89
(m, 1H), 2.45-2.72 (m, 6H), 1.30-1.53 (m, 13H), 0.90-1.10 (m,
6H)
Second Step
Cooled with ice bath, 4M hydrochloric acid in dioxane (25 mL) was
added to tert-butyl 4-(N,N-diethylamino)piperidine-1-carboxylate
(6.1 g, 0.024 mol) and the mixture was stirred at ambient
temperature for 2 h. The solvent was removed under reduced
pressure, and the residue was suspended in diethyl ether, then the
precipitate was collected by filtration, washed with diethyl ether
and then dried to afford 4-(diethylamino)piperidine dihydrochloride
as solid (3.9 g, y. 99%).
Third Step
To a solution of 4-(diethylamino)piperidine dihydrochloride (3.0 g,
0.019 mmol) in water (20 mL), 2M sodium hydroxide solution (5.0 mL)
was added at ambient temperature. The mixture was stirred for 30
min. The solvent was removed under reduced pressure, and methanol
(10 mL) was added to the crude material, then the residue was
removed by filtration. The filtrate was concentrated and dried to
afford 4-(diethylamino)piperidine (1.7 g, y. 77%) as solid.
.sup.1H NMR (DMSO-d.sub.6) .delta. (ppm) 3.20-3.29 (m, 2H),
3.09-3.14 (m, 1H), 2.77-2.93 (m, 3H), 2.52-2.62 (m, 4H), 1.64-1.90
(m, 4H), 1.00 (t, J=7.04 Hz, 6H)
Fourth Step
A solution of 4-(diethylamino)piperidine (0.50 g, 3.2 mmol), ethyl
2-ethoxy-4-oxo-4,5-dihydrofuran-3-carboxylate (0.76 g, 3.8 mmol)
which afforded in the Example 74, Third step and triethylamine
(0.60 mL, 4.3 mmol) in tetrahydrofuran (10 mL) was stirred at
ambient temperature for 24 h. The solvent was removed under reduced
pressure, then the crude material was purified by chromatography on
silica gel (dichloromethane/methanol) to afford ethyl
2-[4-(diethylamino)piperidino]-4-oxo-4,5-dihydrofuran-3-carboxylate
as oil (0.29 g, y. 30%).
.sup.1H NMR (DMSO-d.sub.6) .delta. (ppm) 4.53 (s, 2H), 4.03-4.15
(m, 4H), 3.05-3.19 (m, 2H), 2.82 (br. s, 1H), 2.42-2.58 (m, 4H),
1.73-1.86 (m, 2H), 1.40-1.59 (m, 2H), 1.20 (t, J=7.08 Hz, 3H),
0.91-1.02 (m, 6H); LCMS (m/z): 311.0 [M+H].sup.+
Fifth Step
To a solution of ethyl
2-[4-(diethylamino)piperidino]-4-oxo-4,5-dihydrofuran-3-carboxylate
(0.10 g, 0.30 mmol) and 7-azaindole-3-carboxaldehyde (0.047 g, 0.30
mmol) in ethanol (5.0 mL), L-proline (0.0040 mg, 0.035 mmol) was
added at ambient temperature. The mixture was refluxed for 16 h.
Cooled to ambient temperature, the precipitate was collected by
filtration, washed with ethanol and hexane then dried to afford the
titled compound as solid (0.035 g, y. 25%).
.sup.1H NMR (DMSO-d.sub.6) .delta. (ppm) 12.30 (br. s, 1H), 8.37
(d, J=7.82 Hz, 1H), 8.31 (d, J=3.91 Hz, 1H), 7.97 (s, 1H), 7.19
(dd, J=4.89, 7.82 Hz, 1H), 6.84 (s, 1H), 4.11-4.33 (m, 4H),
3.27-3.37 (m, 2H), 2.82-2.92 (m, 1H), 2.41-2.60 (m, 4H), 1.82-1.92
(m, 2H), 1.56-1.71 (m, 2H), 1.24 (t, J=6.85 Hz, 3H), 0.98 (t,
J=7.09 Hz, 6H); LCMS (m/z): 439.4 [M+H].sup.+.
Example 195
Ethyl
5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-4-oxo-2-(N-piperidinoam-
ino)-4,5-dihydrofuran-3-carboxylate
##STR00205##
To a solution of ethyl
4-oxo-2-(N-piperidinoamino)-4,5-dihydrofuran-3-carboxylate (0.25 g,
0.98 mmol) which similarly prepared according to the procedure
described in the Example 74, Fourth step and
7-azaindole-3-carboxaldehyde (0.14 g, 0.98 mmol) in ethanol (10
mL), L-proline (0.011 mg, 0.096 mmol) was added at ambient
temperature. The mixture was refluxed for 2 days. Cooled to ambient
temperature, the precipitate was collected by filtration, washed
with ethanol and diethyl ether then dried to afford the titled
compound as solid (0.015 g, y. 4%).
.sup.1H NMR (DMSO-d.sub.6) .delta. (ppm) 12.34 (br. s, 1H), 9.86
(br. s, 1H), 9.00 (d, J=7.82 Hz, 1H), 8.33 (d, J=3.91 Hz, 1H), 8.10
(d, J=2.45 Hz, 1H), 7.18 (dd, J=4.65, 8.07 Hz, 1H), 6.85 (s, 1H),
4.20 (q, J=6.85 Hz, 2H), 2.95-3.05 (m, 4H), 1.69-1.79 (m, 4H),
1.42-1.53 (m, 2H), 1.26 (t, J=6.85 Hz, 3H); LCMS (m/z): 383.2
[M+H].sup.+.
Example 196
Ethyl
5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-(2,2-dimethylhydrazin-
yl)-4-oxo-4,5-dihydrofuran-3-carboxylate
##STR00206##
The titled compound (solid) was similarly prepared according to the
procedure described in the Example 195.
.sup.1H NMR (DMSO-d.sub.6) .delta. (ppm) 11.85 (br. s, 1H), 8.52
(d, J=7.82 Hz, 1H), 8.23 (d, J=3.91 Hz, 1H), 7.83 (s, 1H), 7.10
(dd, J=4.89, 7.82 Hz, 1H), 6.14 (s, 1H), 4.02 (q, J=6.85 Hz, 2H),
1.70 (s, 6H), 1.18 (t, J=7.09 Hz, 3H); LCMS (m/z): 342.8
[M+H].sup.+.
Example 197
Ethyl
5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-{[2-(dimethylamino)et-
hyl]-N-methylamino}-4-oxo-4,5-dihydrofuran-3-carboxylate
formate
##STR00207##
To a solution of ethyl
2-{[2-(dimethylamino)ethyl]-N-methylamino}-4-oxo-4,5-dihydrofuran-3-carbo-
xylate (0.20 g, 0.78 mmol) which similarly prepared according to
the procedure described in the Example 74, Fourth step and
7-azaindole-3-carboxaldehyde (0.11 g, 0.78 mmol) in ethanol (6.0
mL), L-proline (0.0093 mg, 0.078 mmol) was added at ambient
temperature. The mixture was refluxed for 20 h. Cooled to ambient
temperature, the reaction mixture was purified by preparative HPLC
to afford the titled compound as solid (0.035 g, y. 12%).
.sup.1H NMR (DMSO-d.sub.6) .delta. (ppm) 12.35 (br. s, 1H), 8.38
(d, J=7.83 Hz, 1H), 8.27-8.34 (m, 1H), 8.18 (s, 1H), 7.98 (s, 1H),
7.16-7.22 (m, 1H), 6.85 (s, 1H), 4.17 (q, J=6.85 Hz, 2H), 3.83 (t,
J=6.60 Hz, 2H), 3.29 (br. s, 3H), 2.54-2.61 (m, 2H), 2.19 (s, 6H),
1.21-1.28 (m, 3H); LCMS (m/z): 385.0 [M+H].sup.+.
Example 198
Ethyl
5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-(1,4-oxoazepan-4-yl)--
4-oxo-4,5-dihydrofuran-3-carboxylate acetate
##STR00208##
The titled compound (solid) was similarly prepared according to the
procedure described in the Example 197. Further, preparative HPLC
(aqueous ammonium acetate/acetonitrile) was used as purification
procedure.
.sup.1H NMR (DMSO-d.sub.6) .delta. (ppm) 8.35 (d, J=7.82 Hz, 1H),
8.30 (d, J=4.40 Hz, 1H), 7.97 (s, 1H), 7.18 (dd, J=4.89, 7.82 Hz,
1H), 6.87 (s, 1H), 4.17 (q, J=7.17 Hz, 2H), 3.80-4.01 (m, 6H), 3.74
(t, J=5.14 Hz, 2H), 1.95-2.07 (m, 2H), 1.63 (s, 3H), 1.24 (t,
J=7.09 Hz, 3H); LCMS (m/z): 383.8 [M+H].sup.+.
Example 199
Ethyl
5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-[(cis-4-hydroxycycloh-
exyl)amino]-4-oxo-4,5-dihydrofuran-3-carboxylate
##STR00209## First Step
Cooled with ice bath, to a mixed solution of cyclohexanone oxime
(4.0 g, 0.035 mol) in dichloromethane (40 mL) and ethanol (5.0 mL),
tert-butyl hypochlorite (4.7 mL, 0.038 mol) was added dropwise and
the reaction mixture was cooled to -20.degree. C. then stirred for
30 min. To this reaction mixture, 1,3-cyclohexadiene (5.0 mL, 0.052
mol) was added dropwise and the reaction mixture was allowed to
warm to 0.degree. C. then stirred for 4 days. The reaction mixture
was concentrated under reduced pressure to half the solvents, and
then diethyl ether (80 mL) was added at ambient temperature then
the mixture was stirred for further 1 day. To this reaction
mixture, ethanol (10 mL) was added and the mixture was stirred for
further 4 h, then the precipitate was collected by filtration. The
solid was washed with mixed solution of diethyl ether/ethanol
(10/1), diethyl ether and hexane then dried to afford
2-oxa-3-azabicyclo[2.2.2]-5-octene hydrochloride as solid (4.2 g,
y. 82%).
.sup.1H NMR (CDCl.sub.3) .delta. (ppm) 12.43 (br. s, 1H), 11.29
(br. s, 1H), 6.81-6.88 (m, 1H), 6.64-6.71 (m, 1H), 4.87-4.93 (m,
1H), 4.58-4.65 (m, 1H), 2.54-2.66 (m, 1H), 2.31-2.47 (m, 1H),
1.45-1.59 (m, 2H)
Second Step
Under a nitrogen atmosphere, to a mixed solution of
2-oxa-3-azabicyclo[2.2.2]-5-octene hydrochloride (0.20 g, 1.4 mol)
in ethanol (2.0 mL) and methanol (1.0 mL), platinum oxide (0.12 g,
0.53 mmol) was added at ambient temperature. The reaction mixture
was agitated under a hydrogen atmosphere at ambient temperature for
6.5 h. Platinum oxide was removed by filtration with Celite, cooled
this filtrate with ice bath, and 2M hydrochloric acid in ethanol
(1.6 mL, 3.2 mmol) was added then the mixture was stirred for 10
min. The solvent was removed under reduced pressure, then
2-propanol (2.0 mL) and ethanol (0.20 mL) were added to the residue
then the mixture was refluxed for 40 min and filtered. The filtrate
was refluxed for further 10 min, stirred at ambient temperature for
14 h, then cooled with ice bath and stirred for further 30 min. The
precipitate was collected by filtration, washed with ice-cold
2-propylalcohol and hexane then dried to afford
cis-4-aminocyclohexanol hydrochloride as solid (0.056 g, y.
27%).
.sup.1H NMR (DMSO-d.sub.6) .delta. (ppm) 7.92 (br. s, 3H), 4.47
(br. s, 1H), 3.70-3.82 (m, 1H), 2.89-3.04 (m, 1H), 1.57-1.76 (m,
6H), 1.37-1.51 (m, 2H)
Third Step
To a solution of cis-4-aminocyclohexanol hydrochloride (0.051 g,
0.34 mmol) and ethyl 2-ethoxy-4-oxo-4,5-dihydrofuran-3-carboxylate
(0.073 g, 0.37 mmol) which afforded in the Example 74, Third step
in ethanol (0.8 mL), triethylamine (0.052 mL, 0.37 mmol) was added.
The mixture was stirred at ambient temperature for 1 h. To this
reaction mixture, 7-azaindole-3-carboxaldehyde (0.044 g, 0.30 mmol)
and piperidine (0.0067 mL, 0.067 mmol) was added at ambient
temperature then the mixture was refluxed for 4 days. Ethanol (2.0
mL) was added then the mixture was refluxed for further 1 h, the
precipitate was collected by filtration, washed with hot ethanol.
The solid was washed with hexane then dried to afford the titled
compound as solid (0.013 g, y. 11%).
.sup.1H NMR (DMSO-d.sub.6) .delta. (ppm) 12.33 (br. s, 1H), 8.50
(d, J=8.03 Hz, 1H), 8.42 (d, J=7.78 Hz, 1H), 8.32 (dd, J=1.38, 4.64
Hz, 1H), 8.02 (d, J=2.51 Hz, 1H), 7.20 (dd, J=4.64, 7.91 Hz, 1H),
6.90 (s, 1H), 4.55 (d, J=3.26 Hz, 1H), 4.22 (q, J=7.03 Hz, 2H),
4.03-4.14 (m, 1H), 3.74-3.82 (m, 1H), 1.90-2.02 (m, 2H), 1.72-1.81
(m, 2H), 1.61-1.69 (m, 4H), 1.26 (t, J=7.15 Hz, 3H); LCMS (m/z):
396.1 [M+H].sup.+.
Example 200
Ethyl
5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-[4-(dimethylamino)pip-
eridino]-4-oxo-4,5-dihydrofuran-3-carboxylate
##STR00210##
The titled compound (solid) was similarly prepared according to the
procedure described in the Example 194.
.sup.1H NMR (DMSO-d.sub.6) .delta. (ppm) 12.37 (br. s, 1H), 8.39
(d, J=7.00 Hz, 1H), 8.33 (d, J=5.16 Hz, 1H), 8.01 (s, 1H), 7.21
(dd, J=5.12, 7.72 Hz, 1H), 6.89 (s, 1H), 4.35-4.45 (m, 2H),
4.13-4.23 (m, 2H), 3.88-3.98 (m, 1H), 3.61-3.71 (m, 1H), 3.51-3.61
(m, 1H), 2.50 (s, 6H), 2.18-2.28 (m, 1H), 1.95-2.05 (m, 1H),
1.80-1.95 (m, 1H), 1.25 (t, J=6.96 Hz, 3H); LCMS (m/z): 411.2
[M+H].sup.+.
Example 201
Ethyl
5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-({2-[(2-methoxyethoxy-
)methoxy]ethyl}-N-methylamino)-4-oxo-4,5-dihydrofuran-3-carboxylate
##STR00211## First Step
To a solution of ethyl
2-[(2-hydroxyethyl)-N-methylamino]-4-oxo-4,5-dihydrofuran-3-carboxylate
(0.5 g, 2.18 mmol) which similarly prepared according to the
procedure described in the Example 74, Fourth step in
dichloromethane (6.0 mL) that cooled with ice bath,
diisopropylethylamine (0.75 mL, 4.36 mmol) then
2-methoxyethoxymethyl chloride (0.5 mL, 4.36 mmol) were added. The
reaction mixture was allowed to warm to ambient temperature and
stirred for 16 h. The reaction mixture was diluted with water,
extracted with ethyl acetate for 3 times. The organic layer was
dried over sodium sulfate and concentrated. The residue was
purified by chromatography on silica gel(hexane/ethyl acetate) to
afford ethyl
2-({2-[(2-methoxyethoxy)methoxy]ethyl}-N-methylamino)-4-oxo-4,5-dihydrofu-
ran-3-carboxylate as oil (0.31 g, y. 46%).
.sup.1H NMR (DMSO-d.sub.6) .delta. (ppm) 4.62 (s, 2H), 4.54 (s,
2H), 4.10 (q, J=7.04 Hz, 2H), 3.63-3.80 (m, 4H), 3.52-3.62 (m, 2H),
3.38-3.48 (m, 2H), 3.24 (s, 3H), 3.12 (s, 3H), 1.20 (t, J=7.04 Hz,
3H); LCMS (m/z): 230.0 [M+H].sup.+
Second Step
To a solution of ethyl
2-({2-[(2-methoxyethoxy)methoxy]ethyl}-N-methylamino)-4-oxo-4,5-dihydrofu-
ran-3-carboxylate (0.146 g, 0.46 mmol) and
7-azaindole-3-carboxaldehyde (0.067 g, 0.46 mmol) in ethanol (6.0
mL), L-proline (0.005 g, 0.046 mmol) was added at ambient
temperature. The mixture was refluxed for 16 h. Cooled to ambient
temperature, the reaction mixture was purified by chromatography on
silica gel(hexane/ethyl acetate) to afford the titled compound as
solid (0.035 g, y. 17%).
.sup.1H NMR (DMSO-d.sub.6) .delta. (ppm) 12.33 (br. s, 1H), 8.39
(d, J=7.34 Hz, 1H), 8.31 (d, J=4.40 Hz, 1H), 7.98 (s, 1H), 7.19
(dd, J=4.65, 7.58 Hz, 1H), 6.85 (s, 1H), 4.64 (s, 2H), 4.16 (q,
J=7.17 Hz, 2H), 3.93-4.00 (m, 2H), 3.75-3.83 (m, 2H), 3.51-3.59 (m,
2H), 3.36-3.42 (m, 2H), 3.25-3.37 (m, 3H), 3.17 (s, 3H), 1.24 (t,
J=7.09 Hz, 3H); LCMS (m/z): 446.2 [M+H].sup.+
Example 202
Ethyl
5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-[(2-hydroxyethyl)-N-m-
ethylamino]-4-oxo-4,5-dihydrofuran-3-carboxylate
##STR00212##
Cooled with ice bath, 4M hydrochloric acid in dioxane (4.0 mL) was
added to ethyl
5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-({2-[(2-methoxyet-
hoxy)methoxy]ethyl}-N-methylamino)-4-oxo-4,5-dihydrofuran-3-carboxylate
(0.020 mg, 0.046 mmol) which afforded in the Example 201. The
mixture was stirred at ambient temperature for 3 h. The solvent was
removed under reduced pressure, and the precipitate was suspended
in diethyl ether, then collected by filtration. The solid was
washed with diethyl ether then dried to afford the titled compound
as solid (0.012 g, y. 75%).
.sup.1H NMR (DMSO-d.sub.6) .delta. (ppm) 12.35 (br. s, 1H), 8.42
(d, J=7.82 Hz, 1H), 8.32 (d, J=3.91 Hz, 1H), 7.99 (s, 1H), 7.21
(dd, J=4.89, 7.82 Hz, 1H), 6.84 (s, 1H), 4.16 (q, J=6.85 Hz, 2H),
3.80-3.86 (m, 2H), 3.65-3.78 (m, 2H), 3.31 (br. s., 3H), 1.24 (t,
J=7.09 Hz, 4H); LCMS (m/z): 358.2 [M+H].sup.+
Example 203
Ethyl
5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-{4-[(2-hydroxyethyl)--
N-methylamino]piperidino}-4-oxo-4,5-dihydrofuran-3-carboxylate
##STR00213##
The titled compound (solid) was similarly prepared according to the
procedure described in the Example 194.
.sup.1H NMR (DMSO-d.sub.6) .delta. (ppm) 12.30 (br. s, 1H), 8.37
(d, J=7.82 Hz, 1H), 8.31 (d, J=4.40 Hz, 1H), 7.97 (s, 1H), 7.20
(dd, J=4.65, 7.58 Hz, 1H), 6.85 (s, 1H), 4.22-4.38 (m, 4H), 4.17
(q, J=6.85 Hz, 2H), 3.45 (q, J=5.87 Hz, 2H), 3.25-3.40 (m, 2H),
2.69-2.81 (m, 1H), 2.23 (s, 3H), 1.85-1.95 (m, 2H), 1.58-1.72 (m,
2H), 1.25 (t, J=6.85 Hz, 3H); LCMS (m/z): 441.2 [M+H].sup.+.
Example 204
2-[(1H-Pyrrolo[2,3-b]pyridin-3-yl)methylene]-5-(phenylamino)furan-3(2H)-on-
e
##STR00214##
A solution of the compound (0.050 g, 0.13 mmol) of Example 1 in
N,N-dimethylformamide (1.0 mL) was refluxed for 6 h. Cooled to
ambient temperature, the reaction mixture was purified by
preparative HPLC to afford the titled compound as solid (0.010 g,
y. 25%).
.sup.1H NMR (DMSO-d.sub.6) .delta. (ppm) 12.36 (br. s, 1H), 10.74
(s, 1H), 8.42 (d, J=7.53 Hz, 1H), 8.31 (dd, J=1.25, 4.52 Hz, 1H),
8.10 (d, J=2.26 Hz, 1H), 7.41-7.49 (m, 2H), 7.34 (d, J=7.53 Hz,
2H), 7.13-7.25 (m, 2H), 6.81 (s, 1H), 5.25 (s, 1H); LCMS (m/z):
304.0 [M+H].sup.+.
Example 205
2-[(1H-Pyrrolo[2,3-b]pyridin-3-yl)methylene]-5-[(4-methoxyphenyl)amino]fur-
an-3(2H)-one
##STR00215##
To a solution of the compound (0.31 g, 0.76 mmol) of Example 2 in
ethanol (6.0 mL), 18M potassium hydroxide solution (0.41 mL, 7.4
mmol) was added at ambient temperature. The mixture was refluxed
for 24 h. Cooled to ambient temperature, the precipitate was
removed by filtration. The filtrate was purified by preparative
HPLC to afford the titled compound as solid (0.031 g, y. 12%).
.sup.1H NMR (DMSO-d.sub.6) .delta. (ppm) 12.31 (br. s, 1H), 10.56
(s, 1H), 8.39 (d, J=7.53 Hz, 1H), 8.30 (dd, J=1.51, 4.52 Hz, 1H),
8.05 (s, 1H), 7.25-7.32 (m, 2H), 7.14 (dd, J=4.64, 7.91 Hz, 1H),
6.99-7.04 (m, 2H), 6.76 (s, 1H), 5.05 (s, 1H), 3.79 (s, 3H); LCMS
(m/z): 334.0 [M+H].sup.+.
Example 206
2-[(1H-Pyrrolo[2,3-b]pyridin-3-yl)methylene]-5-[(4-chlorophenyl)amino]fura-
n-3(2H)-one
##STR00216##
A solution of the compound (0.050 g, 0.12 mmol) of Example 8 in
N,N-dimethylformamide (1.0 mL) was refluxed for 6 h. Cooled to
ambient temperature, the reaction mixture was purified by
preparative HPLC to afford the titled compound as solid (0.0072 g,
y. 17%).
.sup.1H NMR (DMSO-d.sub.6) .delta. (ppm) 12.36 (br. s, 1H), 10.87
(br. s, 1H), 8.41 (d, J=7.28 Hz, 1H), 8.31 (dd, J=1.38, 4.64 Hz,
1H), 8.08 (d, J=2.26 Hz, 1H), 7.48 (d, J=8.78 Hz, 2H), 7.36 (d,
J=8.78 Hz, 2H), 7.17 (dd, J=4.64, 7.91 Hz, 1H), 6.82 (s, 1H), 5.27
(s, 1H); LCMS (m/z): 337.9 [M+H].sup.+.
Example 207
2-[(1H-Pyrrolo[2,3-b]pyridin-3-yl)methylene]-5-[(3-chlorophenyl)amino]fura-
n-3(2H)-one
##STR00217##
A solution of the compound (0.040 g, 0.098 mmol) of Example 9 in
N,N-dimethylformamide (1.0 mL) was refluxed for 6 h. Cooled to
ambient temperature, the reaction mixture was purified by
preparative HPLC to afford the titled compound as solid (0.0075 g,
y. 23%).
.sup.1H NMR (DMSO-d.sub.6) .delta. (ppm) 12.40 (br. s, 1H), 10.85
(s, 1H), 8.41 (d, J=7.28 Hz, 1H), 8.32 (dd, J=1.38, 4.64 Hz, 1H),
8.09 (d, J=2.76 Hz, 1H), 7.42-7.51 (m, 1H), 7.36-7.41 (m, 1H), 7.32
(d, J=8.03 Hz, 1H), 7.26 (dd, J=1.00, 8.03 Hz, 1H), 7.17 (dd,
J=4.64, 7.91 Hz, 1H), 6.85 (s, 1H), 5.31 (s, 1H); LCMS (m/z): 337.9
[M+H].sup.+.
Example 208
2-[(1H-Pyrrolo[2,3-b]pyridin-3-yl)methylene]-5-[(2-chlorophenyl)amino]fura-
n-3(2H)-one
##STR00218##
A solution of the compound (0.050 g, 0.12 mmol) of Example 15 in
N,N-dimethylformamide (1.0 mL) was stirred at 150.degree. C. for 6
h. Cooled to ambient temperature, the reaction mixture was purified
by preparative HPLC to afford the titled compound as solid (0.0050
g, y. 11%).
.sup.1H NMR (DMSO-d.sub.6) .delta. (ppm) 12.29 (br. s, 1H), 10.63
(br. s, 1H), 8.21-8.32 (m, 2H), 8.01 (br. s, 1H), 7.63 (d, J=8.03
Hz, 1H), 7.57 (d, J=7.28 Hz, 1H), 7.45 (t, J=7.40 Hz, 1H),
7.32-7.39 (m, 1H), 7.06 (dd, J=4.77, 7.53 Hz, 1H), 6.75 (s, 1H),
4.89 (br. s, 1H); LCMS (m/z): 337.9 [M+H].sup.+.
Example 209
2-[(1H-Pyrrolo[2,3-b]pyridin-3-yl)methylene]-5-[(2,4-dimethoxyphenyl)amino-
]furan-3(2H)-one
##STR00219##
A solution of the compound (0.10 g, 0.23 mmol) of Example 24 in
N,N-dimethylformamide (3.0 mL) was refluxed for 7 h. Cooled to
ambient temperature, the reaction mixture was purified by
preparative HPLC to afford the titled compound as solid (0.015 g,
y. 18%).
.sup.1H NMR (DMSO-d.sub.6) .delta. (ppm) 12.27 (br. s, 1H), 10.11
(br. s, 1H), 8.25-8.36 (br. s, 2H), 8.03 (br. s, 1H), 7.30 (d,
J=8.31 Hz, 1H), 7.08 (br. s, 1H), 6.72 (d, J=17.12 Hz, 2H), 6.60
(d, J=8.31 Hz, 1H), 4.74 (br. s, 1H), 3.75-3.92 (m, 6H); LCMS
(m/z): 364.2 [M+H].sup.+.
Example 210
2-[(1H-Pyrrolo[2,3-b]pyridin-3-yl)methylene]-5-[(4-isopropylphenyl)amino]f-
uran-3(2H)-one
##STR00220##
A solution of the compound (0.12 g, 0.29 mmol) of Example 37 in
N,N-dimethylformamide (3.0 mL) was refluxed for 6 h. Cooled to
ambient temperature, the reaction mixture was purified by
preparative HPLC to afford
2-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-5-[(4-isopropylphenyl-
)amino]furan-3(2H)-one as solid (0.0050 g, y. 5%).
.sup.1H NMR (DMSO-d.sub.6) .delta. (ppm) 12.34 (br. s, 1H), 10.68
(br. s, 1H), 8.41 (d, J=7.82 Hz, 1H), 8.30 (d, J=3.91 Hz, 1H), 8.09
(br. s, 1H), 7.21-7.37 (m, 4H), 7.15 (d, J=4.40 Hz, 1H), 6.77 (s,
1H), 5.18 (br. s, 1H), 2.84-3.00 (m, 1H), 1.22 (d, J=6.85 Hz, 6H);
LCMS (m/z): 346.2 [M+H].sup.+.
Example 211
2-[(1H-Pyrrolo[2,3-b]pyridin-3-yl)methylene]-5-(3-pyridinylamino)furan-3(2-
H)-one
##STR00221##
The titled compound (solid) was similarly prepared according to the
procedure described in the Example 210, using the compound of
Example 27.
.sup.1H NMR (DMSO-d.sub.6) .delta. (ppm) 12.35 (br. s, 1H), 10.95
(br. s, 1H), 8.58 (br. s, 1H), 8.35-8.43 (m, 2H), 8.27-8.33 (m,
1H), 8.06 (br. s, 1H), 7.76 (d, J=6.85 Hz, 1H), 7.38-7.53 (m, 1H),
7.09-7.24 (m, 1H), 6.81 (br. s, 1H), 5.27 (br. s, 1H); LCMS (m/z):
305.2 [M+H].sup.+.
Example 212
2-[(1H-Pyrrolo[2,3-b]pyridin-3-yl)methylene]-5-[(4-carbamoylphenyl)amino]f-
uran-3(2H)-one
##STR00222##
The titled compound (solid) was similarly prepared according to the
procedure described in the Example 210, using the compound of
Example 25.
.sup.1H NMR (DMSO-d.sub.6) .delta. (ppm) 12.37 (br. s, 1H), 8.42
(d, J=7.34 Hz, 1H), 8.32 (br. s, 1H), 8.12 (br. s, 1H), 7.85-8.04
(m, 4H), 7.28-7.44 (m, 3H), 7.14-7.21 (m, 1H), 6.83 (br. s, 1H),
5.38 (br. s, 1H); LCMS (m/z): 347.2 [M+H].sup.+.
Example 213
2-[(1H-Pyrrolo[2,3-b]pyridin-3-yl)methylene]-5-[(2,4-dimethylphenyl)amino]-
furan-3(2H)-one
##STR00223##
The titled compound (solid) was similarly prepared according to the
procedure described in the Example 210, using the compound of
Example 26.
.sup.1H NMR (DMSO-d.sub.6) .delta. (ppm) 12.22 (br. s, 1H), 10.21
(br. s, 1H), 8.11-8.34 (m, 2H), 7.94 (br. s, 1H), 7.25 (d, J=7.92
Hz, 1H), 7.17 (br. s, 1H), 6.99-7.14 (m, 2H), 6.74 (s, 1H), 4.78
(br. s, 1H), 2.31 (s, 3H), 2.22 (s, 3H); LCMS (m/z): 332.2
[M+H].sup.+.
Example 214
2-[(1H-Pyrrolo[2,3-b]pyridin-3-yl)methylene]-5-(p-tolylamino)furan-3(2H)-o-
ne
##STR00224##
The titled compound (solid) was similarly prepared according to the
procedure described in the Example 210, using the compound of
Example 20.
.sup.1H NMR (DMSO-d.sub.6) .delta. (ppm) 12.32 (br. s, 1H), 8.40
(d, J=7.34 Hz, 1H), 8.30 (br. s, 1H), 8.06 (br. s, 1H), 7.10-7.36
(m, 5H), 6.74 (br. s, 1H), 5.12 (br. s, 1H), 2.32 (s, 3H); LCMS
(m/z): 318.4 [M+H].sup.+.
Example 215
2-[(1H-Pyrrolo[2,3-b]pyridin-3-yl)methylene]-5-[(4-bromophenyl)amino]furan-
-3(2H)-one
##STR00225##
The titled compound (solid) was similarly prepared according to the
procedure described in the Example 210, using the compound of
Example 19.
.sup.1H NMR (DMSO-d.sub.6) .delta. (ppm) 12.31 (br. s, 1H), 8.39
(d, J=7.76 Hz, 1H), 8.23-8.35 (m, 1H), 8.05 (s, 1H), 7.58 (d,
J=8.31 Hz, 2H), 7.27 (d, J=8.31 Hz, 2H), 7.18 (dd, J=4.65, 7.58 Hz,
1H), 6.80 (s, 1H), 5.20 (br. s, 1H); LCMS (m/z): 382.5
[M+H].sup.+.
Example 216
2-[(1H-Pyrrolo[2,3-b]pyridin-3-yl)methylene]-5-[(3,4-dimethoxyphenyl)amino-
]furan-3(2H)-one
##STR00226##
A solution of the compound (0.043 g, 0.099 mmol) of Example 28 in
N,N-dimethylformamide (1.2 mL) was refluxed for 6 h. Cooled to
ambient temperature, the reaction mixture was purified by
preparative HPLC to afford the titled compound (0.0050 g, y.
12%).
.sup.1H NMR (DMSO-d.sub.6) .delta. (ppm) 12.35 (br. s, 1H), 10.56
(br. s, 1H), 8.40 (d, J=7.34 Hz, 1H), 8.30 (d, J=3.91 Hz, 1H), 8.06
(br. s, 1H), 7.08-7.22 (m, 1H), 7.01 (d, J=8.31 Hz, 1H), 6.92 (br.
s, 1H), 6.87 (d, J=8.31 Hz, 1H), 6.77 (s, 1H), 5.12 (s, 1H), 3.78
(s, 6H); LCMS (m/z): 364.0 [M+H].sup.+.
Example 217
2-[(1H-Pyrrolo[2,3-b]pyridin-3-yl)methylene]-5-[(4-fluorophenyl)amino]fura-
n-3(2H)-one
##STR00227##
The titled compound (solid) was similarly prepared according to the
procedure described in the Example 216, using the compound of
Example 21.
.sup.1H NMR (DMSO-d.sub.6) .delta. (ppm) 12.34 (br. s, 1H), 10.72
(br. s, 1H), 8.40 (d, J=7.34 Hz, 1H), 8.31 (d, J=3.91 Hz, 1H), 8.06
(br. s, 1H), 7.33-7.46 (m, 2H), 7.22-7.33 (m, 2H), 7.16 (dd,
J=4.65, 7.58 Hz, 1H), 6.80 (s, 1H), 5.18 (s, 1H); LCMS (m/z): 322.0
[M+H].sup.+.
Example 218
2-[(1H-Pyrrolo[2,3-b]pyridin-3-yl)methylene]-5-[(1,1'-biphenyl)-4-ylamino]-
furan-3(2H)-one
##STR00228##
The titled compound (solid) was similarly prepared according to the
procedure described in the Example 216, using the compound of
Example 39.
.sup.1H NMR (DMSO-d.sub.6) .delta. (ppm) 12.29 (br. s, 1H),
8.24-8.49 (m, 3H), 8.07 (br. s, 1H), 7.70 (br. s, 3H), 7.48 (br. s,
2H), 7.38 (br. s, 3H), 7.15 (br. s, 1H), 6.72 (br. s, 1H), 5.19
(br. s, 1H); LCMS (m/z): 380.2 [M+H].sup.+.
Example 219
2-[(1H-Pyrrolo[2,3-b]pyridin-3-yl)methylene]-5-{[2-(2-hydroxyethoxy)phenyl-
]amino}furan-3(2H)-one
##STR00229##
A solution of the compound (0.015 g, 0.034 mmol) of Example 29 in
N,N-dimethylformamide (0.50 mL) was refluxed for 4 h. Cooled to
ambient temperature, the reaction mixture was purified by
preparative HPLC to afford the titled compound as solid (0.0013 g,
y. 11%).
.sup.1H NMR (DMSO-d.sub.6) .delta. (ppm) 12.24 (br. s, 1H), 8.44
(br. s, 1H), 8.24-8.35 (m, 2H), 8.03 (br. s, 1H), 7.32-7.41 (m,
1H), 6.96-7.25 (m, 4H), 6.67 (br. s, 1H), 4.90 (br. s, 1H),
4.01-4.12 (m, 2H), 3.67-3.80 (m, 2H); LCMS (m/z): 363.9
[M+H].sup.+.
Example 220
2-[(1H-Pyrrolo[2,3-b]pyridin-3-yl)methylene]-5-(6-quinolinylamino)furan-3(-
2H)-one
##STR00230##
A solution of the compound (0.075 g, 0.18 mmol) of Example 44 in
N,N-dimethylformamide (4.0 mL) was refluxed for 6 h. Cooled to
ambient temperature, the reaction mixture was purified by
preparative HPLC to afford the titled compound as solid (0.0080 g,
y. 13%).
.sup.1H NMR (DMSO-d.sub.6) .delta. (ppm) 12.41 (br. s, 1H), 11.07
(br. s, 1H), 8.81-8.87 (m, 1H), 8.42 (t, J=8.56 Hz, 2H), 8.31 (d,
J=3.91 Hz, 1H), 8.15 (br. s, 1H), 8.07 (d, J=8.80 Hz, 1H), 7.88
(br. s, 1H), 7.73 (d, J=8.80 Hz, 1H), 7.55 (dd, J=3.91, 7.82 Hz,
1H), 7.15 (d, J=4.40 Hz, 1H), 6.85 (br. s, 1H), 5.56 (br. s, 1H);
LCMS (m/z): 355.2 [M+H].sup.+.
Example 221
2-[(1H-Pyrrolo[2,3-b]pyridin-3-yl)methylene]-5-[(2-methoxyphenyl)amino]fur-
an-3(2H)-one
##STR00231##
A solution of the compound (0.099 g, 0.24 mmol) of Example 7 in
N,N-dimethylformamide (2.0 mL) was refluxed for 9 h. Cooled to
ambient temperature, the reaction mixture was diluted with
2-butanol and washed with 4M sodium hydroxide solution. The organic
layer was concentrated then purified by chromatography on silica
gel(chloroform/methanol) to afford the titled compound as solid
(0.0097 g, y. 12%).
.sup.1H NMR (DMSO-d.sub.6) .delta. (ppm) 12.31 (br. s, 1H), 10.29
(s, 1H), 8.33 (d, J=7.78 Hz, 1H), 8.27-8.30 (m, 1H), 8.12 (s, 1H),
7.42 (d, J=7.78 Hz, 1H), 7.26-7.33 (m, 1H), 7.18 (d, J=7.28 Hz,
1H), 7.10 (dd, J=4.77, 8.03 Hz, 1H), 7.04 (t, J=7.65 Hz, 1H), 6.75
(s, 1H), 4.90-4.94 (m, 1H), 3.88 (s, 3H); LCMS (m/z): 333.9
[M+H].sup.+.
Example 222
2-[(1H-Pyrrolo[2,3-b]pyridin-3-yl)methylene]-5-[(2,4-difluorophenyl)amino]-
furan-3(2H)-one
##STR00232##
A solution of the compound (0.099 g, 0.24 mmol) of Example 53 in
N,N-dimethylformamide (1.0 mL) was refluxed for 4 h. Cooled to
ambient temperature, the reaction mixture was purified by
preparative HPLC to afford the titled compound as solid (0.0030 g,
y. 4%).
.sup.1H NMR (DMSO-d.sub.6) .delta. (ppm) 12.31 (br. s, 1H), 10.60
(br. s, 1H), 8.26-8.36 (m, 2H), 8.01 (br. s, 1H), 7.55-7.65 (m,
1H), 7.44-7.54 (m, 1H), 7.16-7.25 (m, 1H), 7.06-7.14 (m, 1H), 6.79
(br. s, 1H), 4.95 (br. s, 1H); LCMS (m/z): 339.8 [M+H].sup.+.
Example 223
2-[(1H-Pyrrolo[2,3-b]pyridin-3-yl)methylene]-5-[(4-morpholinophenyl)amino]-
furan-3(2H)-one
##STR00233##
A solution of the compound (0.080 g, 0.17 mmol) of Example 42 in
N,N-dimethylacetamide (3.0 mL) was stirred at 160.degree. C. for 4
h. Cooled to ambient temperature, the reaction mixture was diluted
with water and the precipitate was collected by filtration. The
solid was washed with water, tetrahydrofuran and diethyl ether then
dried to afford the titled compound as solid (0.015 g, y. 22%).
.sup.1H NMR (DMSO-d.sub.6) .delta. (ppm) 12.32 (br. s, 1H), 10.53
(br. s, 1H), 8.41 (d, J=8.12 Hz, 1H), 8.31 (d, J=4.28 Hz, 1H), 8.05
(br. s, 1H), 7.23 (d, J=8.31 Hz, 2H), 7.12-7.18 (m, 1H), 7.02 (d,
J=8.31 Hz, 2H), 6.75 (s, 1H), 5.05 (s, 1H), 3.70-3.83 (m, 4H),
3.05-3.18 (m, 4H); LCMS (m/z): 389.4 [M+H].sup.+.
Example 224
2-[(1H-Pyrrolo[2,3-b]pyridin-3-yl)methylene]-5-[(4-fluorobenzyl)amino]fura-
n-3(2H)-one
##STR00234##
A solution of the compound (0.10 g, 0.31 mmol) of Example 45 in
N,N-dimethylacetamide (3.0 mL) was refluxed for 7 h. Cooled to
ambient temperature, the reaction mixture was diluted with water
and the precipitate was collected by filtration. The solid was
washed with water and diethyl ether then dried to afford the titled
compound as solid (0.0070 g, y. 9%).
.sup.1H NMR (DMSO-d.sub.6) .delta. (ppm) 12.23 (br. s, 1H), 9.08
(s, 1H), 8.40 (br. s, 1H), 8.21-8.32 (m, 2H), 7.96 (br. s, 1H),
7.34-7.50 (m, 1H), 7.05-7.32 (m, 3H), 6.67 (s, 1H), 4.91 (s, 1H),
4.35-4.60 (m, 2H); LCMS (m/z): 336.0 [M+H].sup.+.
Example 225
2-[(1H-Pyrrolo[2,3-b]pyridin-3-yl)methylene]-5-[(2-thienylmethyl)amino]fur-
an-3(2H)-one
##STR00235##
A solution of the compound (0.10 g, 0.26 mmol) of Example 60 in
N,N-dimethylformamide (0.80 mL) was refluxed for 16 h. Cooled to
ambient temperature, the reaction mixture was diluted with
chloroform and the precipitate was collected by filtration. The
solid was washed with chloroform/methanol (10/1) and hexane then
dried to afford the titled compound as solid (0.019 g, y. 22%).
.sup.1H NMR (DMSO-d.sub.6) .delta. (ppm) 12.25 (br. s, 1H), 9.20
(t, J=6.02 Hz, 1H), 8.41 (d, J=7.53 Hz, 1H), 8.29 (dd, J=1.26, 4.52
Hz, 1H), 7.99 (d, J=2.01 Hz, 1H), 7.49 (dd, J=1.00, 5.02 Hz, 1H),
7.12-7.20 (m, 2H), 7.02 (dd, J=3.51, 5.02 Hz, 1H), 6.67 (s, 1H),
4.96 (br. s, 1H), 4.69 (br. s, 2H); LCMS (m/z): 324.0
[M+H].sup.+.
Example 226
2-[(1H-Pyrrolo[2,3-b]pyridin-3-yl)methylene]-5-(cycloheptylamino)furan-3(2-
H)-one
##STR00236##
A solution of the compound (0.040 g, 0.10 mmol) of Example 59 in
N,N-dimethylformamide (2.0 mL) was refluxed for 8 h. Cooled to
ambient temperature, the reaction mixture was purified by
preparative HPLC to afford the titled compound as solid (0.0040 g,
y. 12%).
.sup.1H NMR (DMSO-d.sub.6) .delta. (ppm) 12.26 (br. s, 1H), 8.64
(d, J=7.82 Hz, 1H), 8.39 (d, J=7.34 Hz, 1H), 8.29 (d, J=3.91 Hz,
1H), 8.00 (br. s, 1H), 7.17 (dd, J=4.89, 7.82 Hz, 1H), 6.61 (s,
1H), 4.78 (br. s, 1H), 2.83-3.11 (m, 1H), 1.85-2.02 (m, 2H),
1.40-1.78 (m, 10H); LCMS (m/z): 324.2 [M+H].sup.+.
Example 227
2-[(1H-Pyrrolo[2,3-b]pyridin-3-yl)methylene]-5-(isopropylamino)furan-3(2H)-
-one
##STR00237##
A solution of the compound (0.15 g, 0.43 mmol) of Example 56 in
N,N-dimethylacetamide (1.5 mL) was refluxed for 12 h. Cooled to
ambient temperature, the reaction mixture was diluted with water
and the precipitate was collected by filtration. The solid was
washed with diethyl ether then dried to afford the titled compound
as solid (0.015 g, y. 12%).
.sup.1H NMR (DMSO-d.sub.6) .delta. (ppm) 12.24 (br. s, 1H), 8.58
(d, J=7.82 Hz, 1H), 8.38 (d, J=7.83 Hz, 1H), 8.27 (d, J=4.40 Hz,
1H), 7.97 (br. s, 1H), 7.15 (dd, J=4.89, 7.82 Hz, 1H), 6.60 (s,
1H), 4.79 (br. s, 1H), 3.53-3.69 (m, 1H), 1.22 (d, J=6.36 Hz, 6H);
LCMS (m/z): 270.2 [M+H].sup.+.
Example 228
2-[(1H-Pyrrolo[2,3-b]pyridin-3-yl)methylene]-5-[(3-pyrazolyl)amino]furan-3-
(2H)-one
##STR00238##
The titled compound (solid) was similarly prepared according to the
procedure described in the Example 227, using the compound of
Example 67.
.sup.1H NMR (DMSO-d.sub.6) .delta. (ppm) 12.52 (br. s, 2H), 11.67
(br. s, 1H), 8.45 (d, J=6.85 Hz, 1H), 8.16 (d, J=3.42 Hz, 1H), 7.72
(br. s, 2H), 7.56 (br. s, 1H), 7.13-7.25 (m, 1H), 6.98-7.09 (m,
1H), 4.69 (s, 1H); LCMS (m/z): 294.2 [M+H].sup.+.
Example 229
2-[(1H-Pyrrolo[2,3-b]pyridin-3-yl)methylene]-5-[(3-fluorobenzyl)amino]fura-
n-3(2H)-one
##STR00239##
A solution of the compound (0.050 g, 0.12 mmol) of the Example 58
in N,N-dimethyacetamide (1.5 mL) was refluxed for 12 h. Cooled to
ambient temperature, the reaction mixture was diluted with water
and the precipitate was collected by filtration. The solid was
purified by preparative HPLC to afford the titled compound as solid
(0.012 g, y. 30%).
.sup.1H NMR (DMSO-d.sub.6) .delta. (ppm) 12.26 (br. s, 1H),
9.13-9.23 (m, 1H), 8.41 (br. s, 1H), 8.29 (d, J=3.91 Hz, 1H), 7.98
(br. s, 1H), 7.38-7.53 (m, 1H), 7.20-7.32 (m, 2H), 7.16 (d, J=6.36
Hz, 2H), 6.66 (s, 1H), 4.91 (br. s, 1H), 4.41-4.60 (m, 2H); LCMS
(m/z): 336.0 [M+H].sup.+.
Example 230
2-[(1H-Pyrrolo[2,3-b]pyridin-3-yl)methylene]-5-(cyclopropylamino)furan-3(2-
H)-one
##STR00240##
To a solution of the compound (0.25 g, 0.76 mmol) of Example 94 in
ethanol (7.0 mL), 50% potassium hydroxide solution (4.0 mL, 0.071
mol) was added at ambient temperature. The mixture was refluxed for
2 h. Cooled to ambient temperature, the solvent was removed under
reduced pressure. The residue was diluted with water, 1M
hydrochloric acid was added to adjust pH to acidic, and then the
solvent was removed under reduced pressure. The residue was
purified by preparative HPLC to afford the titled compound as solid
(0.0090 g, y. 4%).
.sup.1H NMR (DMSO-d.sub.6) .delta. (ppm) 12.26 (br. s, 1H), 8.88
(br. s, 1H), 8.44 (d, J=6.85 Hz, 1H), 8.22-8.34 (m, 1H), 7.97 (br.
s, 1H), 7.12-7.20 (m, 1H), 6.66 (br. s, 1H), 4.87 (br. s, 1H),
2.62-2.80 (m, 1H), 0.72-0.88 (m, 2H), 0.55-0.72 (m, 2H); LCMS
(m/z): 268.0 [M+H].sup.+.
Example 231
2-[(1H-Pyrrolo[2,3-b]pyridin-3-yl)methylene]-5-[(2-methoxyethyl)amino]fura-
n-3(2H)-one
##STR00241##
To a solution of the compound (0.070 g, 0.20 mmol) of Example 98 in
ethanol (2.0 mL), 50% potassium hydroxide solution (1.0 mL, 0.018
mol) was added at ambient temperature. The mixture was refluxed for
1 h. Cooled to ambient temperature, 1M hydrochloric acid was added
to adjust pH to acidic, and then the solvent was removed under
reduced pressure. To this residue, ethanol (2.0 mL) and water (2.0
mL) were added then refluxed for 1 h. Cooled to ambient
temperature, the solvent was removed under reduced pressure, and
the residue was purified by preparative HPLC to afford the titled
compound as solid (0.0060 g, y. 12%).
.sup.1H NMR (DMSO-d.sub.6) .delta. (ppm) 12.24 (br. s, 1H),
8.65-8.90 (m, 1H), 8.41 (d, J=6.85 Hz, 1H), 8.29 (br. s, 1H), 8.01
(br. s, 1H), 7.08-7.32 (m, 1H), 6.53-6.70 (m, 1H), 4.72-4.97 (m,
1H), 3.30-3.55 (m, 4H), 3.26 (br. s, 3H); LCMS (m/z): 286.2
[M+H].sup.+.
Example 232
2-[(1H-Pyrrolo[2,3-b]pyridin-3-yl)methylene]-5-[(1-methyl-4-piperidinyl)am-
ino]furan-3(2H)-one
##STR00242##
The titled compound (solid) was similarly prepared according to the
procedure described in the Example 231, using the compound of
Example 65.
.sup.1H NMR (DMSO-d.sub.6) .delta. (ppm) 12.25 (br. s, 1H), 8.61
(d, J=7.34 Hz, 1H), 8.39 (d, J=7.82 Hz, 1H), 8.23-8.34 (m, 1H),
8.17 (br. s, 1H), 7.99 (br. s, 1H), 7.06-7.24 (m, 1H), 6.62 (s,
1H), 4.77-4.99 (m, 1H), 2.73-2.85 (m, 2H), 2.22 (s, 3H), 2.00-2.14
(m, 2H), 1.82-1.97 (m, 2H), 1.49-1.67 (m, 2H); LCMS (m/z): 325.4
[M+H].sup.+.
Example 233
2-[(1H-Pyrrolo[2,3-b]pyridin-3-yl)methylene]-5-[(4-fluoro-2-methylphenyl)a-
mino]furan-3(2H)-one
##STR00243##
To a solution of the compound (0.15 g, 0.37 mmol) of Example 97 in
ethanol (4.0 mL), 50% potassium hydroxide solution (2.0 mL, 0.036
mol) was added at ambient temperature. The mixture was refluxed for
2 h. Cooled to ambient temperature, the solvent was removed under
reduced pressure. Water was added to this residue, the mixture was
washed with ethyl acetate then 1M hydrochloric acid was added to
adjust pH to acidic. The precipitate was collected by filtration,
washed with water, diethyl ether, ethyl acetate and hexane then
dried to afford the titled compound as solid (0.12 g, y. 93%).
.sup.1H NMR (DMSO-d.sub.6) .delta. (ppm) 12.28 (br. s, 1H), 10.24
(s, 1H), 8.19-8.32 (m, 2H), 7.97 (br. s, 1H), 7.43 (dd, J=5.62,
8.56 Hz, 1H), 7.26 (d, J=7.34 Hz, 1H), 7.11-7.19 (m, 1H), 7.04-7.10
(m, 1H), 6.74 (s, 1H), 4.72 (s, 1H), 2.31 (s, 3H); LCMS (m/z):
335.8 [M+H].sup.+.
Example 234
2-[(1H-Pyrrolo[2,3-b]pyridin-3-yl)methylene]-5-[(2,6-dimethyl-3-pyridinyl)-
amino]furan-3(2H)-one
##STR00244##
To a solution of the compound (0.090 g, 0.20 mmol) of Example 107
in ethanol (4.0 mL), 50% potassium hydroxide solution (2.0 mL,
0.036 mol) was added at ambient temperature. The mixture was
refluxed for 2 h. Cooled to ambient temperature, the solvent was
removed under reduced pressure. Water was added to this residue,
the mixture was washed with ethyl acetate then 1M hydrochloric acid
was added to adjust pH to acidic. The precipitate was collected by
filtration, washed with water and diethyl ether then dried to
afford the titled compound (0.037 g, y. 50%) as solid.
.sup.1H NMR (DMSO-d.sub.6) .delta. (ppm) 12.26 (br. s, 1H), 10.33
(br. s, 1H), 8.28 (d, J=4.40 Hz, 2H), 7.96 (br. s, 1H), 7.64 (d,
J=8.31 Hz, 1H), 7.17 (d, J=7.82 Hz, 1H), 7.02-7.12 (m, 1H), 6.70
(br. s, 1H), 4.73 (br. s, 1H), 2.48 (br. s, 3H), 2.44 (br. s, 3H);
LCMS (m/z): 333.3 [M+H].sup.+.
Example 235
2-[(1H-Pyrrolo[2,3-b]pyridin-3-yl)methylene]-5-[(2-fluorobenzyl)amino]fura-
n-3(2H)-one
##STR00245##
To a solution of the compound (0.10 g, 0.25 mmol) of Example 101 in
ethanol (4.0 mL), 50% potassium hydroxide solution (2.0 mL, 0.036
mol) was added at ambient temperature. The mixture was refluxed for
2 h. Cooled to ambient temperature, the solvent was removed under
reduced pressure. Water was added to this residue, the mixture was
washed with ethyl acetate then 1M hydrochloric acid was added to
adjust pH to acidic, and then extracted with ethyl acetate. The
organic layer was dried over sodium sulfate and concentrate then
purified by chromatography on silica gel(dichloromethane/methanol)
to afford the titled compound as solid (0.012 g, y. 14%).
.sup.1H NMR (DMSO-d.sub.6) .delta. (ppm) 12.24 (br. s, 1H),
9.08-9.17 (m, 1H), 8.34-8.46 (m, 1H), 8.22-8.33 (m, 1H), 7.98 (br.
s, 1H), 7.45-7.55 (m, 1H), 7.34-7.43 (m, 1H), 7.20-7.31 (m, 2H),
7.10-7.19 (m, 1H), 6.65 (s, 1H), 4.83-4.97 (m, 1H), 4.40-4.64 (m,
2H); LCMS (m/z): 335.8 [M+H].sup.+.
Example 236
2-[(1H-Pyrrolo[2,3-b]pyridin-3-yl)methylene]-5-[(2-phenyl-2-propanyl)amino-
]furan-3(2H)-one
##STR00246##
To a solution of the compound (0.060 g, 0.14 mmol) of Example 112
in ethanol (2.0 mL), 50% potassium hydroxide solution (1.0 mL,
0.018 mol) was added at ambient temperature. The mixture was
refluxed for 2 h. Cooled to ambient temperature, the solvent was
removed under reduced pressure. Water was added to this residue,
the mixture was washed with ethyl acetate then 1M hydrochloric acid
was added to adjust pH to acidic. The precipitate was collected by
filtration, washed with water and diethyl ether then dried to
afford the titled compound as solid (0.010 g, y. 20%).
.sup.1H NMR (DMSO-d.sub.6) .delta. (ppm) 12.26 (br. s, 1H), 9.05
(br. s, 1H), 8.24-8.38 (m, 2H), 8.0 (br, 1H), 7.36-7.50 (m, 4H),
7.25-7.32 (m, 1H), 7.12-7.18 (m, 1H), 6.57 (s, 1H), 4.06 (br. s,
1H), 1.70 (s, 6H); LCMS (m/z): 346.2 [M+H].sup.+.
Example 237
2-[(1H-Pyrrolo[2,3-b]pyridin-3-yl)methylene]-5-(2-adamantylamino)furan-3(2-
H)-one
##STR00247##
The titled compound (solid) was similarly prepared according to the
procedure described in the Example 236, using the compound of
Example 113.
.sup.1H NMR (DMSO-d.sub.6) .delta. (ppm) 12.29 (br. s, 1H), 8.55
(br. s, 1H), 8.37 (d, J=7.82 Hz, 1H), 8.30 (d, J=4.40 Hz, 1H), 8.14
(br. s, 1H), 7.17 (dd, J=4.89, 7.83 Hz, 1H), 6.64 (s, 1H), 4.83 (s,
1H), 3.25-3.40 (m, 1H), 1.96-2.11 (m, 4H), 1.80-1.92 (m, 4H),
1.69-1.77 (m, 2H), 1.55-1.63 (m, 2H), 1.09 (t, J=7.00 Hz, 2H); LCMS
(m/z): 362.4 [M+H].sup.+.
Example 238
2-[(1H-Pyrrolo[2,3-b]pyridin-3-yl)methylene]-5-(cyclopentylamino)furan-3(2-
H)-one
##STR00248##
To a solution of the compound (0.10 g, 0.27 mmol) of Example 103 in
ethanol (4.0 mL), 50% potassium hydroxide solution (2.0 mL, 0.036
mol) was added at ambient temperature. The mixture was refluxed for
2 h. Cooled to ambient temperature, the solvent was removed under
reduced pressure. Water was added to this residue, the mixture was
washed with ethyl acetate then 1M hydrochloric acid was added to
adjust pH to acidic, and then the solvent was removed under reduced
pressure. The residue was purified by preparative HPLC to afford
the titled compound as solid (0.0015 g, y. 5%).
.sup.1H NMR (DMSO-d.sub.6) .delta. (ppm) 12.25 (br. s, 1H),
8.58-8.70 (m, 1H), 8.39 (d, J=7.83 Hz, 1H), 8.22-8.32 (m, 1H), 7.99
(br. s, 1H), 7.17 (dd, J=4.65, 7.58 Hz, 1H), 6.62 (s, 1H), 6.55 (s,
1H), 4.75-4.96 (m, 1H), 1.90-2.03 (m, 2H), 1.65-1.77 (m, 2H),
1.50-1.65 (m, 4H); LCMS (m/z): 296.2 [M+H].sup.+.
Example 239
2-[(1H-Pyrrolo[2,3-b]pyridin-3-yl)methylene]-5-[(5-indazolyl)amino]furan-3-
(2H)-one
##STR00249##
To a solution of the compound (0.14 g, 0.33 mmol) of Example 118 in
ethanol (4.0 mL), 50% potassium hydroxide solution (2.2 mL, 0.039
mol) was added at ambient temperature. The mixture was refluxed for
2 h. Cooled to ambient temperature, 1M hydrochloric acid was added
to adjust pH to acidic, and the solvent was removed under reduced
pressure. The residue was purified by preparative HPLC to afford
the titled compound as solid (0.010 g, y. 9%).
.sup.1H NMR (DMSO-d.sub.6) .delta. (ppm) 13.16 (br. s, 1H), 12.30
(br. s, 1H), 8.42 (br. s, 1H), 8.37 (d, J=7.76 Hz, 1H), 8.28 (d,
J=3.91 Hz, 1H), 8.09 (br. s, 1H), 8.05 (br. s, 1H), 7.71 (s, 1H),
7.61 (d, J=8.80 Hz, 1H), 7.35 (d, J=8.80 Hz, 1H), 7.04-7.11 (m,
1H), 6.73 (s, 1H), 5.10 (s, 1H); LCMS (m/z): 344.2 [M+H].sup.+.
Example 240
2-[(1H-Pyrrolo[2,3-b]pyridin-3-yl)methylene]-5-[(5-benzimidazolyl)amino]fu-
ran-3(2H)-one
##STR00250##
To a solution of the compound (0.055 g, 0.13 mmol) of Example 119
in ethanol (6.0 mL), 50% potassium hydroxide solution (3.0 mL,
0.053 mol) was added at ambient temperature. The mixture was
refluxed for 1.5 h. Cooled to ambient temperature, 1M hydrochloric
acid was added to adjust pH to acidic, and the solvent was removed
under reduced pressure. The residue was purified by preparative
HPLC to afford the titled compound (0.0090 g, y. 20%) as solid.
.sup.1H NMR (DMSO-d.sub.6) .delta. (ppm) 12.28 (br. s, 1H), 12.10
(br. s, 1H), 8.34 (br. s, 1H), 8.22-8.29 (m, 1H), 8.10-8.20 (m,
1H), 7.95 (br. s, 1H), 7.50-7.62 (m, 1H), 7.25-7.38 (m, 1H),
6.98-7.15 (m, 2H), 6.34-6.67 (m, 2H), 4.84 (s, 1H); LCMS (m/z):
344.0 [M+H].sup.+.
Example 241
2-[(1H-Pyrrolo[2,3-b]pyridin-3-yl)methylene]-5-[(1-phenylethyl)amino]furan-
-3(2H)-one
##STR00251##
The titled compound (solid) was similarly prepared according to the
procedure described in the Example 240, using the compound of
Example 106.
.sup.1H NMR (DMSO-d.sub.6) .delta. (ppm) 12.29 (br. s, 1H), 9.15
(d, J=7.83 Hz, 1H), 8.23-8.43 (m, 2H), 7.80 (br. s, 1H), 7.11-7.49
(m, 6H), 6.62 (s, 1H), 5.00-5.10 (m, 1H), 4.60-4.80 (m, 1H),
1.36-1.60 (m, 3H); LCMS (m/z): 332.2 [M+H].sup.+.
Example 242
2-[(1H-Pyrrolo[2,3-b]pyridin-3-yl)methylene]-5-{[(3-methyl-2-thienyl)methy-
l]amino}furan-3(2H)-one
##STR00252##
A solution of the compound (0.050 g, 0.12 mmol) of Example 124 in
N,N-dimethylformamide (1.0 mL) was refluxed for 16 h. Cooled to
ambient temperature, the reaction mixture was purified by
preparative HPLC to afford the titled compound as solid (0.012 g,
y. 28%).
.sup.1H NMR (DMSO-d.sub.6) .delta. (ppm) 12.25 (br. s, 1H), 9.09
(t, J=5.77 Hz, 1H), 8.40 (d, J=7.78 Hz, 1H), 8.29 (dd, J=1.38, 4.64
Hz, 1H), 7.99 (d, J=2.26 Hz, 1H), 7.38 (d, J=5.02 Hz, 1H), 7.15
(dd, J=4.77, 8.03 Hz, 1H), 6.90 (d, J=5.02 Hz, 1H), 6.66 (s, 1H),
4.92 (br. s, 1H), 4.59 (br. s, 2H), 2.25 (s, 3H); LCMS (m/z): 338.1
[M+H].sup.+.
Example 243
2-[(1H-Pyrrolo[2,3-b]pyridin-3-yl)methylene]-5-[(trans-4-hydroxycyclohexyl-
)amino]furan-3(2H)-one
##STR00253##
The titled compound (solid) was similarly prepared according to the
procedure described in the Example 240, using the compound of
Example 116.
.sup.1H NMR (DMSO-d.sub.6) .delta. (ppm) 12.23 (br. s, 1H),
8.51-8.60 (m, 1H), 8.34-8.43 (m, 1H), 8.24-8.32 (m, 1H), 7.92-8.10
(m., 1H), 7.16 (dd, J=4.64, 7.91 Hz, 1H), 6.61 (s, 1H), 4.85 (br.
s, 1H), 4.40-4.72 (m, 2H), 1.69-2.07 (m, 4H), 1.02-1.54 (m, 4H);
LCMS (m/z): 326.1 [M+H].sup.+.
Example 244
Ethyl
5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-(7-methoxy-3,4-dihydr-
oisoquinolin-2(1H)-yl)-4-oxo-4,5-dihydrofuran-3-carboxylate
##STR00254## First Step
To a suspension of 7-methoxy-1,2,3,4-tetrahydroisoquinoline
hydrochloride (2.10 g, 10.5 mmol) in tetrahydrofuran, triethylamine
(3.48 mL, 25.0 mmol) was added at ambient temperature and the
mixture was stirred for 30 min. To this reaction mixture, ethyl
2-ethoxy-4-oxo-4,5-dihydrofuran-3-carboxylate (2.00 g, 10.0 mmol),
which afforded in the Example 74, Third step was added and the
mixture was stirred for 5 days. Water was added to the reaction
mixture, and the mixture was extracted with ethyl acetate. The
organic layer was washed with brine, dried over sodium sulfate and
concentrated. The residue was purified by chromatography on silica
gel(chloroform/methanol) to afford ethyl
2-[7-methoxy-3,4-dihydroisoquinolin-2(1H)-yl]-4-oxo-4,5-dihydrofura-
n-3-carboxylate as oil (2.85 g, y. 89%).
.sup.1H NMR (CDCl.sub.3) .delta. (ppm) 7.09 (d, J=8.4 Hz, 1H), 6.80
(dd, J=8.4, 2.6 Hz, 1H), 6.64 (d, J=2.4 Hz, 1H), 4.78 (s, 2H), 4.54
(s, 2H), 4.33 (q, J=7.1 Hz, 2H), 3.89 (t, J=5.9 Hz, 2H), 3.79 (d,
J=2.9 Hz, 3H), 2.86-3.04 (m, 2H), 1.38 (t, J=7.1 Hz, 3H); LCMS
(m/z): 318.2 [M+H].sup.+.
Second Step
To a solution of ethyl
2-[7-methoxy-3,4-dihydroisoquinolin-2(1H)-yl]-4-oxo-4,5-dihydrofuran-3-ca-
rboxylate (2.58 g, 8.98 mmol) and 7-azaindole-3-carboxaldehyde
(1.31 g, 8.98 mmol) in ethanol (12 mL), L-proline was added at
ambient temperature. The mixture was refluxed for 24 h. The
precipitate was collected by filtration, washed with ethanol and
diisopropyl ether then dried to afford the titled compound as solid
(1.20 g, y. 30%).
.sup.1H NMR (DMSO-d.sub.6) .delta. (ppm) 12.37 (s, 1H), 8.41 (dd,
J=7.9, 1.5 Hz, 1H), 8.33 (dd, J=4.7, 1.5 Hz, 1H), 8.08 (s, 1H),
7.26-7.13 (m, 2H), 6.90 (s, 2H), 6.85 (dd, J=8.3, 2.6 Hz, 1H), 4.95
(br. s, 2H), 4.21 (q, J=7.1 Hz, 2H), 3.85-4.05 (m, 2H), 3.76 (s,
3H), 3.00 (t, J=5.8 Hz, 2H), 1.26 (t, J=7.1 Hz, 3H); LCMS (m/z):
446.2 [M+H].sup.+.
Example 245
Isopropyl
5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-(morpholinoamino)-
-4-oxo-4,5-dihydrofuran-3-carboxylate
##STR00255## First Step
To a solution of isopropyl
2-isopropoxy-4-oxo-4,5-dihydrofuran-3-carboxylate (12.2 g, 53.6
mmol), which similarly prepared according to the procedure
described in the Example 74, Third step using diisopropyl malonate
and chloroacetyl chloride, in ethanol (45 mL), 4-aminomorpholine
(5.7 mL, 59.2 mmol) was added at ambient temperature. The mixture
was stirred for 18 h. The solvent was removed under reduced
pressure, and the crude product was suspended in methyl tert-butyl
ether, then the precipitate was collected by filtration, washed
with methyl tert-butyl ether and hexane then dried to afford
isopropyl 2-(morpholinoamino)-4-oxo-4,5-dihydrofuran-3-carboxylate
as solid (11.2 g, y. 75%).
.sup.1H NMR (DMSO-d.sub.6) .delta. (ppm) 9.60 (s, 1H), 4.95-5.05
(m, 1H), 4.57 (s, 2H), 3.60-3.68 (m, 4H), 2.87-2.95 (m, 4H), 1.22
(d, J=6.40 Hz, 6H); LCMS (m/z): 271.0 [M+H].sup.+
Second Step
To a stirred solution of isopropyl
2-(morpholinoamino)-4-oxo-4,5-dihydrofuran-3-carboxylate (5.00 g,
18.5 mmol) and 7-azaindole-3-carboxaldehyde (2.49 g, 17.1 mmol) in
ethanol (25 mL), L-proline (0.24 g, 2.04 mmol) was added at ambient
temperature. The mixture was refluxed for 3 days. The precipitate
was collected by filtration, washed with hot ethanol then hexane,
and then dried to afford the titled compound as solid (4.22 g, y.
62%).
.sup.1H NMR (DMSO-d.sub.6) .delta. (ppm) 12.34 (br. s, 1H), 10.07
(s, 1H), 8.94 (d, J=7.78 Hz, 1H), 8.33 (dd, J=1.38, 4.64 Hz, 1H),
8.12 (d, J=2.76 Hz, 1H), 7.22 (dd, J=4.52, 8.03 Hz, 1H), 6.84 (s,
1H), 4.99-5.12 (m, 1H), 3.75-3.86 (m, 4H), 3.03-3.13 (m, 4H), 1.27
(d, J=6.27 Hz, 6H); LCMS (m/z): 399.1 [M+H].sup.+.
Example 246
Ethyl
5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-4-oxo-2-{[4-(2,2,2-trif-
luoroethyl)piperazinyl]amino}-4,5-dihydrofuran-3-carboxylate
##STR00256## First Step
To a solution of 1-(2,2,2-trifluoroethyl)piperazine (4.88 g, 29.0
mmol) in water (4.9 mL) that cooled with ice bath, a solution of
sodium nitrite (4.04 g, 58.6 mmol) in water (20 mL) and acetic acid
(5.0 mL, 87.0 mmol) were added dropwise slowly, then the mixture
was stirred for 1 h. The reaction mixture was all owed to warm to
ambient temperature, stirred for further 2 h. The reaction mixture
was adjusted to pH9 using sodium carbonate, diluted with ethyl
acetate and washed with water and brine. The organic layer was
dried over magnesium sulfate and concentrated to afford
1-nitrso-4-(2,2,2-trifluoroethyl)piperazine as oil (5.57 g, y.
97%).
.sup.1H NMR (DMSO-d.sub.6) .delta. (ppm) 4.18-4.22 (m, 2H),
3.72-3.76 (m, 2H), 3.32 (q, J=10.13 Hz, 2H), 2.84-2.89 (m, 2H),
2.59-2.64 (m, 2H).
Second Step
To a suspension of lithium aluminum hydride (2.22 g, 58.5 mmol) in
tetrahydrofuran (100 mL) that cooled with ice bath, a solution of
1-nitroso-4-(2,2,2-trifluoroethyl)piperazine (5.43 g, 27.5 mmol) in
tetrahydrofuran (10 mL) was added dropwise and the reaction mixture
was allowed to warm to ambient temperature, then stirred for 5
days. The reaction mixture was cooled with ice bath, ethyl acetate
was added until cease bubbling up, and water (2.1 mL) was added
then the mixture was stirred for 20 min. To this mixture, 15% w/v
sodium hydroxide solution (2.1 mL) and water (6.3 mL) were added,
then the suspension mixture was allowed to warm to ambient
temperature and then the mixture was stirred vigorously for 1 h.
Magnesium sulfate was added to the mixture and stirred for a while,
then the suspension was filtered. The filtrate was concentrated to
afford 4-(2,2,2-trifluoroethyl)piperazine-1-amine as oil (4.72 g,
y. 94%).
.sup.1H NMR (DMSO-d.sub.6) .delta. (ppm) 3.12 (br. s, 1H), 2.98 (q,
J=9.6 Hz, 2H), 2.60-2.80 (m, 8H).
Third Step
To a solution of 4-(2,2,2-trifluoroethyl)piperazine-1-amine (4.72
g, 25.8 mmol) in ethanol (43 mL), ethyl
2-ethoxy-4-oxo-4,5-dihydrofuran-3-carboxylate (4.70 g, 23.5 mmol)
which similarly prepared according to the procedure described in
the Example 74, Third step was added at ambient temperature. The
mixture was stirred for 2 h. The precipitate was collected by
filtration, washed with diethyl ether and hexane then dried to
afford ethyl
4-oxo-2-{[4-(2,2,2-trifluoroethyl)piperazinyl]amino}-4,5-dihydrofuran-3-c-
arboxylate as solid (5.64 g, y. 71%).
.sup.1H NMR (DMSO-d.sub.6) .delta. (ppm) 8.94 (s, 1H), 4.61 (s,
2H), 4.32 (q, J=7.07 Hz, 2H), 3.03 (q, J=9.47 Hz, 2H), 2.95-2.99
(m, 4H), 2.85-2.90 (m, 4H), 1.37 (t, J=7.20 Hz, 3H); LCMS (m/z):
338.1 [M+H].sup.+.
Fourth Step
To a solution of ethyl
4-oxo-2-{[4-(2,2,2-trifluoroethyl)piperazinyl]amino}-4,5-dihydrofuran-3-c-
arboxylate (3.01 g, 8.93 mmol) and 7-azaindole-3-carboxaldehyde
(1.25 g, 8.55 mmol) in ethanol (25 mL), L-proline (99 mg, 0.86
mmol) was added at ambient temperature then the mixture was
refluxed for 2 days. The precipitate was collected by filtration,
washed with hot ethanol then hexane, and then dried to afford the
titled compound a solid (2.64 g, y. 66%).
.sup.1H NMR (DMSO-d.sub.6) .delta. (ppm) 12.32 (s, 1H), 10.09 (s,
1H), 8.95 (d, J=7.6 Hz, 1H), 8.33 (d, J=4.1 Hz, 1H), 8.09 (s, 1H),
7.30-7.16 (m, 1H), 6.80 (s, 1H), 4.19 (q, J=7.1 Hz, 2H), 3.31-3.41
(m, 2H), 3.06 (s, 4H), 2.88 (s, 4H), 1.25 (t, J=7.0 Hz, 3H); LCMS
(m/z): 466.0 [M+H].sup.+.
Each of the Example compounds shown in the following [Table 1-1] to
[Table 1-10] were prepared according to the procedure described in
the above Examples or modified procedure well known in the art of
organic chemistry if needed, using appropriate starting materials
(those materials which are commercially available, or which are
derivatized by known methods or their modified methods from
commercial compounds). The physicochemical data of each compound
were shown in the following [Table 2-1] to [Table 2-6].
TABLE-US-00001 TABLE 1-1 Example Chemical Formula Chemical Name 247
##STR00257## Ethyl 5-[(1H-pyrrolo[2,3-b]pyridin-
3-yl)methylene]-2-(1,4-diazepan-1- yl)-4-oxo-4,5-dihydrofuran-3-
carboxylate 248 ##STR00258## Ethyl 5-[(1H-pyrrolo[2,3-b]pyridin-
3-yl)methylene]-2-(4,5- dihydrothieno[2,3-c]pyridin-6(7H)-yl)-
4-oxo-4,5-dihydrofuran-3-carboxylate 249 ##STR00259## Ethyl
5-[(1H-pyrrolo[2,3-b]pyridin- 3-yl)methylene]-2-(4,5-dihydro-1H-
benzo[c]azepin-2(3H)-yl)-4-oxo- 4,5-dihydrofuran-3-carboxylate 250
##STR00260## Ethyl 5-[(1H-pyrrolo[2,3-b]pyridin-
3-yl)methylene]-2-(2,3-dihydrobenzo-
[f][1,4]oxazepin-4(5H)-yl)-4-oxo- 4,5-dihydrofuran-3-carboxylate
251 ##STR00261## Carbamoylmethyl 5-[(1H-pyrrolo
[2,3-b]pyridin-3-yl)methylene]-2- [(4-fluorophenyl)amino]-4-oxo-
4,5-dihydrofuran-3-carboxylate 252 ##STR00262## Ethyl
5-[(1H-pyrrolo[2,3-b]pyridin- 3-yl)methylene]-2-[(1-hydroxypropan-
2-yl)amino]-4-oxo-4,5-dihydrofuran- 3-carboxylate 253 ##STR00263##
Ethyl 5-[(1H-pyrrolo[2,3-b]pyridin-
3-yl)methylene]-2-[(2,2-dimethyl- 1,3-dioxolan-4-yl)methylamino]-4-
oxo-4,5-dihydrofuran-3-carboxylate 254 ##STR00264## Ethyl
5-[(1H-pyrrolo[2,3-b]pyridin- 3-yl)methylene]-2-[(2-hydroxypropyl)
amino]-4-oxo-4,5-dihydrofuran-3- carboxylate 255 ##STR00265## Ethyl
5-[(1H-pyrrolo[2,3-b]pyridin- 3-yl)methylene]-4-oxo-2-(prop-2-yn-
1-ylamino)-4,5-dihydrofuran-3- carboxylate 256 ##STR00266## Ethyl
5-[(1H-pyrrolo[2,3-b]pyridin- 3-yl)methylene]-2-(2-
benzoylhydrazinyl)-4-oxo-4,5- dihydrofuran-3-carboxylate 257
##STR00267## Ethyl 5-[(1H-pyrrolo[2,3-b]pyridin-
3-yl)methylene]-2-(2,3-dihydrobenzo
[f][1,4]thiazepin-4(5H)-yl)-4-oxo- 4,5-dihydrofuran-3-carboxylate
258 ##STR00268## Ethyl 5-[(1H-pyrrolo[2,3-b]pyridin-
3-yl)methylene]-2-(2,3-dihydro-1H-
benzo[e][1,4]diazepin-4(5H)-yl)-4-
oxo-4,5-dihydrofuran-3-carboxylate
TABLE-US-00002 TABLE 1-2 259 ##STR00269## Ethyl
5-[(1H-pyrrolo[2,3-b]pyridin- 3-yl)methylene]-2-(5-methoxy-3,4-
dihydroisoquinolin-2(1H)-yl)-4-oxo- 4,5-dihydrofuran-3-carboxylate
260 ##STR00270## Ethyl 5-[(1H-pyrrolo[2,3-b]pyridin-
3-yl)methylene]-2-[(2S,6R)-2,6- dimethylmorpholino]-4-oxo-4,5-
dihydrofuran-3-carboxylate 261 ##STR00271## Ethyl
5-[(1H-pyrrolo[2,3-b]pyridin- 3-yl)methylene]-4-oxo-2-
[(tetrahydro-2H-pyran-4-yl)amino]- 4,5-dihydrofuran-3-carboxylate
262 ##STR00272## Ethyl 5-[(1H-pyrrolo[2,3-b]pyridin-
3-yl)methylene]-4-oxo-2-(pyrrolidin- 1-ylamino)-4,5-dihydrofuran-3-
carboxylate 263 ##STR00273## Ethyl 5-[(1H-pyrrolo[2,3-b]pyridin-
3-yl)methylene]-2-(azepan-1- 4-oxo-4,5-dihydrofuran-3- carboxylate
264 ##STR00274## Ethyl 5-[(1H-pyrrolo[2,3-b]pyridin-
3-yl)methylene]-2-({4-[(4- isopropylpiperazinyl)methyl]-2-
methylphenyl}amino)-4-oxo-4,5- dihydrofuran-3-carboxylate 265
##STR00275## Ethyl 5-[(1H-pyrrolo[2,3-b]pyridin-
3-yl)methylene]-2-({4- [(cyclopentylamino)methyl]-2-
methylphenyl}amino-4-oxo-4,5- dihydrofuran-3-carboxylate 266
##STR00276## Ethyl 5-[(1H-pyrrolo[2,3-b]pyridin-
3-yl)methylene]-2-({4- [(isopropylamino)methyl]-2-
methylphenyl}amino)-4-oxo-4,5- dihydrofuran-3-carboxylate 267
##STR00277## Ethyl 5-[(1H-pyrrolo[2,3-b]pyridin-
3-yl)methylene]-2-{[4-(4- hydroxypiperidinomethyl)-2-
methylphenyl]amino}-4-oxo-4,5- dihydrofuran-3-carboxylate 268
##STR00278## Ethyl 5-[(1H-pyrrolo[2,3-b]pyridin-
3-yl)methylene]-2-(cyanomethylamino)-
4-oxo-4,5-dihydrofuran-3-carboxylate 269 ##STR00279## Ethyl
5-[(1H-pyrrolo[2,3-b]pyridin- 3-yl)methylene]-2-[(1,3-
dihydroxypropan-2-yl)amino]-4- oxo-4,5-dihydrofuran-3-carboxylate
270 ##STR00280## Ethyl 5-[(1H-pyrrolo[2,3-b]pyridin-
3-yl)methylene]-2-[(2,3-dihydroxypropyl)
amino]-4-oxo-4,5-dihydrofuran- 3-carboxylate
TABLE-US-00003 TABLE 1-3 271 ##STR00281## Ethyl
5-[(1H-pyrrolo[2,3-b]pyridin- 3-yl)methylene]-2-(4-{[2-
(dimethylamino)ethyl](N-methyl) amino}piperidino)-4-oxo-4,5-
dihydrofuran-3-carboxylate 272 ##STR00282## Ethyl
5-[(1H-pyrrolo[2,3-b]pyridin- 3-yl)methylene]-2-(2-{[(2-
methoxyethoxy)methoxy]methyl} piperidino)-4-oxo-4,5-dihydrofuran-
3-carboxylate 273 ##STR00283## Ethyl 5-[(1H-pyrrolo[2,3-b]pyridin-
3-yl)methylene]-2-(6-methoxy-3,4-
dihydroisoquinolin-2(1H)-yl)-4-oxo- 4,5-dihydrofuran-3-carboxylate
274 ##STR00284## Ethyl 5-[(1H-pyrrolo[2,3-b]pyridin-
3-yl)methylene]-2-({2-methyl-4- [(methylamino)methyl]phenyl}
amino)-4-oxo-4,5-dihydrofuran-3- carboxylate 275 ##STR00285## Ethyl
5-[(1H-pyrrolo[2,3-b]pyridin- 3-yl)methylene]-2-(3-
methylpiperidino)-4-oxo-4,5- dihydrofuran-3-car boxylate 276
##STR00286## Ethyl 5-[(1H-pyrrolo[2,3-b]pyridin-
3-yl)methylene]-2-(2,6- dimethylmorpholino)-4-oxo-4,5-
dihydrofuran-3-carboxylate 277 ##STR00287## Ethyl
5-[(1H-pyrrolo[2,3-b]pyridin- 3-yl)methylene]-2-{[4-(2-
hydroxyethyl)piperazinyl]amino}-4-
oxo-4,5-dihydrofuran-3-carboxylate 278 ##STR00288## Ethyl
5-[(1H-pyrrolo[2,3-b]pyridin- 3-yl)methylene]-2-[(3R,5S)-3,5-
dimethylpiperidino]-4-oxo-4,5- dihydrofuran-3-carboxylate 279
##STR00289## Ethyl 5-[(1H-pyrrolo[2,3-b]pyridin-
3-yl)methylene]-2-[(4H-1,2,4- triazol-4-yl)amino]-4-oxo-4,5-
dihydrofuran-3-carboxylate 280 ##STR00290## Ethyl
5-[(1H-pyrrolo[2,3-b]pyridin- 3-yl)methylene]-2-[8-methoxy-3,4-
dihydroisoquinolin-2(1H)-yl]-4-oxo-
4,5-dihydrofuran-3-carboxylate
TABLE-US-00004 TABLE1-4 281 ##STR00291## Ethyl
5-[(1H-pyrrolo[2,3-b]pyridin- 3-yl)methylene]-2-(2,6-
dimethylpiperidinoamino)-4-oxo-4,5- dihydrofuran-3-carboxylate 282
##STR00292## Ethyl 5-[(1H-pyrrolo[2,3-b]pyridin-
3-yl)methylene]-2-[(3S,5S)-3,5- dimethylpiperidino]-4-oxo-4,5-
dihydrofuran-3-carboxylate 283 ##STR00293## Ethyl
5-[(1H-pyrrolo[2,3-b]pyridin- 3-yl)methylene]-2-(3,3-
dimethylpiperidino)-4-oxo-4,5- dihydrofuran-3-carboxylate 284
##STR00294## Ethyl 5-[(1H-pyrrolo[2,3-b]pyridin-
3-yl)methylene]-2-[2-(hydroxymethyl) piperidino]-4-oxo-4,5-
dihydrofuran-3-carboxylate 285 ##STR00295## Ethyl
5-[(1H-pyrrolo[2,3-b]pyridin- 3-yl)methylene]-2-{[2-methyl-4-(2-
morpholinoethyl)phenyl]aminol-4- oxo-4,5-dihydrofuran-3-carboxylate
286 ##STR00296## Ethyl 5-[(1H-pyrrolo[2,3-b]pyridin-
3-yl)methylene]-2-{[4-(2- hydroxyethyl)-2-methylphenyl]amino}-
4-oxo-4,5-dihydrofuran-3-carboxylate 287 ##STR00297## Ethyl
5-[(1H-pyrrolo[2,3-b]pyridin- 3-yl)methylene]-2-({2-methy1-4-
[3-(pyrrolidinyl)prop-1-yn-1-yl]
phenyl}amino)-4-oxo-4,5-dihydrofuran- 3-carboxylate acetate 288
##STR00298## Ethyl 5-[(1H-pyrrolo[2,3-b]pyridin-
3-yl)methylene]-2-{[2-methyl-4- (3-morpholinoprop-1-yn-1-yl)phenyl]
amino}-4-oxo-4,5-dihydrofuran-3- carboxylate formate 289
##STR00299## Ethyl 5-[(1H-pyrrolo[2,3-b]pyridin-
3-yl)methylene]-2-({4-[3-(4- hydroxypiperidino)prop-1-yn-1-yl]-
2-methylphenyl}amino)-4-oxo-4,5- dihydrofuran-3-carboxylate 290
##STR00300## Ethyl 5-[(1H-pyrrolo[2,3-b]pyridin-
3-yl)methylene]-2-({2-methyl-4-
[2-(4-methylpiperazinyl)ethyl]phenyl}
amino)-4-oxo-4,5-dihydrofuran-3- carboxylate 291 ##STR00301## Ethyl
5-[(1H-pyrrolo[2,3-b]pyridin- 3-yl)methylene]-2-[ethyl(N-methyl)
amino]-4-oxo-4,5-dihydrofuran-3- carboxylate
TABLE-US-00005 TABLE 1-5 292 ##STR00302## Ethyl
5-[(1H-pyrrolo[2,3-b]pyridin- 3-yl)methylene]-2-[isopropyl(N-
methyl)amino]-4-oxo-4,5- dihydrofuran-3-carboxylate 293
##STR00303## Ethyl 5-[(1H-pyrrolo[2,3-b]pyridin-
3-yl)methylene]-2-(3- hydroxypiperidinoamino)-4-oxo-
4,5-dihydrofuran-3-carboxylate 294 ##STR00304## Isopropyl
5-[(1H-pyrrolo[2,3-b] pyridin-3-yl)methylene]-2-(4-
methylpiperidino)-4-oxo-4,5- dihydrofuran-3-carboxylate 295
##STR00305## Isopropyl 5-[(1H-pyrrolo[2,3-b]
pyridin-3-yl)methylene]-2-(3,4- dihydroisoquinolin-2(1H)-yl)-4-
oxo-4,5-dihydrofuran-3- carboxylate 296 ##STR00306## Isopropyl
5-[(1H-pyrrolo[2,3-b] pyridin-3-yl)methylene]-2-(2,2-
dimethylhydrazinyl)-4-oxo-4,5- dihydrofuran-3-carboxylate 297
##STR00307## Isopropyl 5-[(1H-pyrrolo[2,3-b]pyridin-
3-yl)methylene]-2-({4-[(2- hydroxyethyl)amino]-2-methylphenyl}
amino)-4-oxo-4,5-dihydrofuran- 3-carboxylate 298 ##STR00308## Ethyl
5-[(1H-pyrrolo[2,3-b]pyridin- 3-yl)methylene]-2-({2-methyl-4-
[3-(4-methylpiperazinyl)prop-1-yn-1- yl]phenyl}amino)-4-oxo-4,5-
dihydrofuran-3-carboxylate 299 ##STR00309## Ethyl
5-[(1H-pyrrolo[2,3-b]pyridin- 3-yl)methylene]-2-({2-methyl-4-
[2-(pyrrolidinyl)ethyl]phenyl}amino)-
4-oxo-4,5-dihydrofuran-3-carboxylate 300 ##STR00310## Ethyl
5-[(1H-pyrrolo[2,3-b]pyridin- 3-yl)methylene]-2-[cyclohexyl(N-
methyl)amino]-4-oxo-4,5- dihydrofuran-3-carboxylate 301
##STR00311## Ethyl 5-[(1H-pyrrolo[2,3-b]pyridin-
3-yl)methylene]-2-(2-cyclohexyl-2- methylhydraziny1)-4-oxo-4,5-
dihydrofuran-3-carboxylate 302 ##STR00312## Ethyl
5-[(1H-pyrrolo[2,3-b]pyridin- 3-yl)methylene]-2-[(4-
acetylpiperazinyl)amino]-4-oxo-4,5- dihydrofuran-3-carboxylate
TABLE-US-00006 TABLE 1-6 303 ##STR00313## Isopropyl
5-[(1H-pyrrolo[2,3-b] pyridin-3-yl)methylene]-2-({2-methyl-
4-[2-(pyrrolidinyl)ethoxy]phenyl {amino)-4-oxo-4,5-dihydrofuran-
3-carboxylate 304 ##STR00314## Ethyl 5-[(1H-pyrrolo[2,3-b]pyridin-
3-yl)methylene]-2-(2-ethyl-2- methylhydrazinyl)-4-oxo-4,5-
dihydrofuran-3-carboxylate 305 ##STR00315## Ethyl
5-[(1H-pyrrolo[2,3-b]pyridin- 3-yl)methylene]-2-(2,2-
diethylhydraziny1)-4-oxo-4,5- dihydrofuran-3-carboxylate 306
##STR00316## Ethyl 5-[(1H-pyrrolo[2,3-b]pyridin-
3-yl)methylene]-2-(4- hydroxypiperidinoamino)-4-oxo-
4,5-dihydrofuran-3-carboxylate 307 ##STR00317## Isopropyl
5-[(1H-pyrrolo[2,3-b] pyridin-3-yl)methylene]-2-{[2-methyl-
4-(2-morpholinoethoxy)phenyl] aminol-4-oxo-4,5-dihydrofuran-
3-carboxylate 308 ##STR00318## Isopropyl 5-[(1H-pyrrolo[2,3-b]
pyridin-3-yl)methylene]-2-({2-methyl-
4-[2-(4-methylpiperazinyl)ethoxy] phenyl}amino)-4-oxo-4,5-
dihydrofuran-3-carboxylate 309 ##STR00319## 2-Methoxyethyl
5-[(1H-pyrrolo[2,3-b] pyridin-3-yl)methylene]-2-
(cyclohexylamino)-4-oxo-4,5- dihydrofuran-3-carboxylate 310
##STR00320## 2-Methoxyethyl 5-[(1H-pyrrolo[2,3-b]
pyridin-3-yl)methylene]-2-(2,2- dimethylhydrazinyl)-4-oxo-4,5-
dihydrofuran-3-carboxylate 311 ##STR00321## Ethyl
5-[(1H-pyrrolo[2,3-b]pyridin- 3-yl)methylene]-2-{[4-(3-hydroxyprop-
1-yn-1-yl)-2-methylphenyl]amino}-
4-oxo-4,5-dihydrofuran-3-carboxylate 312 ##STR00322## Ethyl
5-[(1H-pyrrolo[2,3-b]pyridin- 3-yl)methylene]-2-({4-[3-
(dimethylamino)prop-1-yn-1-yl]- 2-methylphenyl}amino)-4-oxo-4,5-
dihydrofuran-3-carboxylate 313 ##STR00323## Ethyl
5-[(1H-pyrrolo[2,3-b]pyridin- 3-yl)methylene]-2-({4-[2-
(dimethylamino)ethyl]-2-methylphenyl}
amino)-4-oxo-4,5-dihydrofuran-3- carboxylate
TABLE-US-00007 TABLE 1-7 314 ##STR00324## Ethyl
5-[(1H-pyrrolo[2,3-b]pyridin- 3-yl)methylene]-2-({4-[2-(4-
hydroxypiperidino)ethyl]-2- methylphenyl}amino)-4-oxo-
4,5-dihydrofuran-3-carboxylate 315 ##STR00325## Ethyl
5-[(1H-pyrrolo[2,3-b]pyridin- 3-yl)methylene]-2-(2-isopropyl-2-
methylhydrazinyl)-4-oxo-4,5- dihydrofuran-3-carboxylate 316
##STR00326## Ethyl 5-[(1H-pyrrolo[2,3-b]pyridin-
3-yl)methylene]-4-oxo-2-[(3- oxopiperazinyl)amino]-4,5-
dihydrofuran-3-carboxylate 317 ##STR00327## 2-Methoxyethyl
5-[(1H-pyrrolo[2,3-b] pyridin-3-yl)methylene]-2-(3,4-
dihydroisoquinolin-2 (1H)-yl)-4-oxo- 4,5-dihydrofuran-3-carboxylate
318 ##STR00328## 2-Methoxyethyl 5-[(1H-pyrrolo[2,3-b]
pyridin-3-yl)methylene]-2-({4- [(2-hydroxyethyl)amino]-2-
methylphenyl}amino)-4-oxo-4,5- dihydrofuran-3-carboxylate 319
##STR00329## Ethyl 5-[(1H-pyrrolo[2,3-b]pyridin-
3-yl)methylene]-4-oxo-2-[4-(2,2,2- trifluoroethyl)piperazinyl]-4,5-
dihydrofuran-3-carboxylate 320 ##STR00330## Isopropyl
5-[(1H-pyrrolo[2,3-b] pyridin-3-yl)methylene]-2-({4-
[(dimethylamino)methyl]-2- methylphenyl}amino)-4-oxo-
4,5-dihydrofuran-3- carboxylate acetate 321 ##STR00331##
2-Methoxyethyl 5-[(1H-pyrrolo[2,3-b] pyridin-3-yl)methylene]-2-(4-
methylpiperidino)-4-oxo-4,5- dihydrofuran-3-carboxylate 322
##STR00332## 2-Methoxyethyl 5-[(1H-pyrrolo[2,3-b]
pyridin-3-yl)methylene]-2-{[2- methyl-4-(2-morpholinoethoxy)phenyl]
amino}-4-oxo-4,5-dihydrofuran-3- carboxylate 323 ##STR00333##
2-Methoxyethyl 5-[(1H-pyrrolo[2,3-b] pyridin-3-yl)methylene]-2-({2-
methy1-4-[2-(4-methylpiperazinyl) ethoxy]phenyl}amino)-4-oxo-4,5-
dihydrofuran-3-carboxylate acetate 324 ##STR00334## 2-Methoxyethyl
5-[(1H-pyrrolo[2,3-b] pyridin-3-yl)methylene]-2-({4-
[(dimethylamino)methyl]-2- methylphenyl}amino)-4-oxo-4,5-
dihydrofuran-3-carboxylate 325 ##STR00335## 3-Hydroxypropyl
5-[(1H-pyrrolo[2,3-b] pyridin-3-yl)methylene]-2-
(cyclohexylamino)-4-oxo-4,5- dihydrofuran-3-carboxylate
TABLE-US-00008 TABLE 1-8 326 ##STR00336## 2-(Dimethylamino)ethyl
5-[(1H- pyrrolo[2,3-b]pyridin-3-yl)methylene]-
2-(cyclohexylamino)-4-oxo-4,5- dihydrofuran-3-carboxylate 327
##STR00337## 2-(Dimethylamino)ethyl 5-[(1H-
pyrrolo[2,3-b]pyridin-3-yl)methylene]-
2-(4-methylpiperidino)-4-oxo-4,5- dihydrofuran-3-carboxylate 328
##STR00338## 3-Hydroxypropyl 5-[(1H-pyrrolo[2,3-b]
pyridin-3-yl)methylene]-2-azepinyl-
4-oxo-4,5-dihydrofuran-3-carboxylate 329 ##STR00339##
3-Hydroxypropyl 5-[(1H-pyrrolo[2,3-b] pyridin-3-yl)methylene]-2-(4-
methylpiperidino)-4-oxo-4,5- dihydrofuran-3-carboxylate 330
##STR00340## 2-Methoxyethyl 5-[(1H-pyrrolo[2,3-b]
pyridin-3-yl)methylene]-2-({2- methyl-4-[2-(pyrrolidinyl)ethoxy]
phenyl}amino)-4-oxo-4,5-dihydrofuran- 3-carboxylate acetate 331
##STR00341## 3-Hydroxypropyl 5-[(1H-pyrrolo[2,3-b]
pyridin-3-yl)methylene]-2-(3,4- dihydroisoquinolin-2(1H)-yl)-4-oxo-
4,5-dihydrofuran-3-carboxylate 332 ##STR00342## 3-Hydroxypropyl
5-[(1H-pyrrolo[2,3-b] pyridin-3-yl)methylene]-2-
(morpholinoamino)-4-oxo-4,5- dihydrofuran-3-carboxylate 333
##STR00343## 3-Hydroxypropyl 5-[(1H-pyrrolo[2,3-b]
pyridin-3-yl)methylene]-2-(2,2- dimethylhydrazinyl)-4-oxo-4,5-
dihydrofuran-3-carboxylate 334 ##STR00344## 2-Methoxyethyl
5-[(1H-pyrrolo[2,3-b] pyridin-3-yl)methylene]-2-
(morpholinoamino)-4-oxo-4,5- dihydrofuran-3-carboxylate 335
##STR00345## Ethyl 5-[(1H-pyrrolo[2,3-b]pyridin-
3-yl)methylene]-2-(4,5-dihydrofuro [2, 3-c]
pyridin-6(7H)-yl)-4-oxo-4,5- dihydrofuran-3-carboxylate 336
##STR00346## 3-Hydroxypropyl 5-[(1H-pyrrolo[2,3-b]
pyridin-3-yl)methylene]-2-({4- [(2-hydroxyethyl)amino]-2-
methylphenyl}amino)-4-oxo-4,5- dihydrofuran-3-carboxylate 337
##STR00347## 3-Hydroxypropyl 5-[(1H-pyrrolo[2,3-b]
pyridin-3-yl)methylene]-2-({4- [(dimethylamino)methyl]-2-
methylphenyl}amino)-4-oxo-4,5- dihydrofuran-3-carboxylate
hydrochloride 338 ##STR00348## 2-(Dimethylamino)ethyl
5-[(1H-pyrrolo [2,3-b]pyridin-3-yl)methylene]-
2-(2,2-dimethylhydrazinyl)-4-oxo- 4,5-dihydrofuran-3-carboxylate
acetate
TABLE-US-00009 TABLE 1-9 339 ##STR00349## 2-(Dimethylamino)ethyl
5-[(1H- pyrrolo[2,3-b]pyridin-3-yl)methylene]-
2-(morpholinoamino)-4-oxo-4,5- dihydrofuran-3-carboxylate acetate
340 ##STR00350## 2-(Dimethylamino)ethyl 5-[(1H-pyrrolo
[2,3-b]pyridin-3-yl)methylene]- 2-({4-[(2-hydroxyethyl) amino]-2-
methylphenyl}amino)-4-oxo-4,5- dihydrofuran-3-carboxylate acetate
341 ##STR00351## Ethyl 5-[(1H-pyrrolo[2,3-b]pyridin-
3-yl)methylene]-2-{[4-(cyanomethyl)-
2-methylphenyl]amino}-4-oxo-4,5- dihydrofuran-3-carboxylate 342
##STR00352## 2-(Dimethylamino)ethyl 5-[(1H-pyrrolo
[2,3-b]pyridin-3-yl)methylene]- 2-({4-[(dimethylamino)methyl]-2-
methylphenyl}amino)-4-oxo-4,5- dihydrofuran-3-carboxylate diformate
343 ##STR00353## Isopropyl 5-[(1H-pyrrolo[2,3-b]pyridin-
3-yl)methylene]-2-{[4-(2-hydroxyethoxy)- 2-methylphenyl]amino}-4-
oxo-4,5-dihydrofuran-3-carboxylate 344 ##STR00354## Propyl
5-[(1H-pyrrolo[2,3-b]pyridin- 3-yl)methylene]-2-(morpholinoamino)-
4-oxo-4,5-dihydrofuran-3-carboxylate 345 ##STR00355## Isobutyl
5-[(1H-pyrrolo[2,3-b]pyridin- 3-yl)methylene]-2-(morpholinoamino)-
4-oxo-4,5-dihydrofuran-3-carboxylate 346 ##STR00356##
2-Hydroxyethyl 5-[(1H-pyrrolo[2,3-b] pyridin-3-yl)methylene]-2-
(morpholinoamino)-4-oxo-4,5- dihydrofuran-3-carboxylate 347
##STR00357## Cyclopropylmethyl 5-[(1H-pyrrolo
[2,3-b]pyridin-3-yl)methylene]-2- (morpholinoamino)-4-oxo-4,5-
dihydrofuran-3-carboxylate 348 ##STR00358## Cyclopentyl
5-[(1H-pyrrolo[2,3-b] pyridin-3-yl)methylene]-2-
(morpholinoamino)-4-oxo-4,5- dihydrofuran-3-carboxylate 349
##STR00359## (S)-sec-Butyl 5-[(1H-pyrrolo[2,3-b]
pyridin-3-yl)methylene]-2- (morpholinoamino)-4-oxo-4,5-
dihydrofuran-3-carboxylate 350 ##STR00360## (R)-sec-Butyl
5-[(1H-pyrrolo[2,3-b] pyridin-3-yl)methylene]-2-
(morpholinoamino)-4-oxo-4,5- dihydrofuran-3-carboxylate 351
##STR00361## Isopropyl 5-[(1H-pyrrolo[2,3-b]pyridin-
3-yl)methylene]-4-oxo-2-{[4- (2,2,2-trifluoroethyl)piperazinyl]
amino}-4,5-dihydrofuran-3-carboxylate
TABLE-US-00010 TABLE 1-10 352 ##STR00362## Isopropyl
5-[(1H-pyrrolo[2,3-b]pyridin- 3-yl)methylene]-4-oxo-2-[(tetrahydro-
2H-pyran-4-yl)amino]-4,5-dihydrofuran- 3-carboxylate 353
##STR00363## Isopropyl 5-[(1H-pyrrolo[2,3-b]pyridin-
3-yl)methylene]-4-oxo-2-[(1,1- dioxidothiomorpholino)amino]-4,5-
dihydrofuran-3-carboxylate 354 ##STR00364## Isopropyl
5-[(1H-pyrrolo[2,3-b]pyridin- 3-yl)methylene]-2-(7-methoxy-
3,4-dihydroisoquinolin-2(1H)-yl)-4-
oxo-4,5-dihydrofuran-3-carboxylate 355 ##STR00365## Isopropyl
5-[(1H-pyrrolo[2,3-b]pyridin- 3-yl)methylene]-2-(7-methyl-?
3,4-dihydroisoquinolin-2 (1H)-yl)-4-
oxo-4,5-dihydrofuran-3-carboxylate acetate 356 ##STR00366##
Isopropyl 5-[(1H-pyrrolo[2,3-b]pyrlidin-
3-yl)methylene]-2-(7-chloro- 3,4-dihydroisoquinolin-2(1H)-yl)-4-
oxo-4,5-dihydrofuran-3-carboxylate acetate 357 ##STR00367##
Isopropyl 5-[(1H-pyrrolo[2,3-b]pyridin-
3-yl)methylene]-2-(7-fluoro- 3,4-dihydroisoquinolin-2(1H)-yl)-4-
oxo-4,5-dihydrofuran-3-carboxylate 358 ##STR00368## Isopropyl
5-[(1H-pyrrolo[2,3-b]pyridin- 3-yl)methylene]-2-(5-methoxy-
3,4-dihydroisoquinolin-2(1H)-yl)-4-
oxo-4,5-dihydrofuran-3-carboxylate 359 ##STR00369## Isopropyl
5-[(1H-pyrrolo[2,3-b]pyridin- 3-yl)methylene]-2-(6-methoxy-
3,4-dihydroisoquinolin-2(1H)-yl)-4-
oxo-4,5-dihydrofuran-3-carboxylate
TABLE-US-00011 TABLE 2-1 LCMS m/z Example .sup.1H-NMR .delta. (ppm)
[M + H].sup.+ 247 (DMSO-d6): 12.17-12.43 (m, 1H), 8.18-8.41 (m,
3H), 7.94 (br. s, 1H), 7.12- 383.2 7.23 (m, 1H), 6.85 (br. s, 1H),
4.10-4.23 (m, 2H), 3.65-3.93 (m, 2H), 2.93- 3.13 (m, 2H), 2.77-2.93
(m, 2H), 1.80-1.98 (m, 2H), 1.10-1.35 (m, 5H). 248 (DMSO-d6): 12.37
(s, 1H), 8.40 (d, J = 7.6 Hz, 1H), 8.33 (d, J = 3.7 Hz, 1H), 422.0
8.09 (s, 1H), 7.47 (d, J = 4.9 Hz, 1H), 7.21 (dd, J = 7.7, 4.7 Hz,
1H), 6.87- 6.98 (m, 2H), 5.07 (s, 2H), 4.21 (q, J = 6.9 Hz, 2H),
3.98-4.08 (m, 2H), 2.92- 3.03 (m, 2H), 1.26 (t, J = 7.0 Hz, 3H).
249 (DMSO-d6): 12.37 (s, 1H), 8.28-8.39 (m, 2H), 8.02 (br. s, 1H),
7.10-7.29 430.0 (m, 5H), 6.81 (s, 1H), 5.13 (s, 2H), 4.18-4.30 (m,
2H), 4.00-4.18 (m, 2H), 2.99-3.12 (m, 2H), 1.92-2.07 (m, 2H), 1.28
(t, J = 6.6 Hz, 3H). 250 (DMSO-d6): 12.42 (s, 1H), 8.27-8.38 (m,
2H), 7.97 (s, 1H), 7.30-7.43 (m, 1H), 432.3 7.15-7.27 (m, 2H)
7.03-7.13 (m, 1H), 6.96 (d, J = 7.7 Hz, 1H), 6.85 (s, 1H), 5.18 (s,
2H), 4.40-4.50 (m, 2H), 4.14-4.26 (m, 2H), 4.00-4.14 (m, 2H), 1.26
(t, J = 6.6 Hz, 3H). 251 (DMSO-d6): 12.14 (s, 1H), 10.70-12.05 (m,
1H), 8.23 (d, J = 4.0 Hz, 1H), 8.00 423.2 (d, J = 7.8 Hz, 1H), 7.69
(s, 1H), 7.20-7.50 (m, 5H), 6.91 (dd, J = 7.7, 4.7 Hz, 1H), 4.51
(s, 2H). 252 (DMSO-d6): 12.33 (br. s, 1H), 8.57 (d, J = 6.02 Hz,
1H), 8.42 (dd, J = 1.38, 358.0 7.91 Hz, 1H), 8.31 (dd, J = 1.25,
4.52 Hz, 1H), 8.01 (s, 1H), 7.20 (dd, J = 4.77, 8.03 Hz, 1H), 6.90
(s, 1H), 5.20 (t, J = 5.27 Hz, 1H), 4.16-4.34 (m, 3H), 3.52-3.68
(m, 2H), 1.32 (d, J = 6.53 Hz, 3H), 1.26 (t, J = 7.15 Hz, 3H). 253
(DMSO-d6): 12.38 (br. s, 1H), 8.93 (br. s, 1H), 8.43 (dd, J = 1.38,
7.91 Hz, 414.0 1H), 8.31 (dd, J = 1.38, 4.64 Hz, 1H), 8.06 (s, 1H),
7.19 (dd, J = 4.64, 7.91 Hz, 1H), 6.90 (s, 1H), 4.37-4.46 (m, 1H),
4.22 (q, J = 7.03 Hz, 2H), 4.06 (dd, J = 6.53, 8.78 Hz, 1H)
3.68-3.89 (m, 3H), 1.32 (s, 3H), 1.23-1.29 (m, 6H). 254 (DMSO-d6):
12.35 (br. s, 1H), 8.84 (br. s, 1H), 8.46 (dd, J = 1.38, 7.91 Hz,
358.0 1H), 8.31 (dd, J = 1.38, 4.64 Hz, 1H), 8.04 (s, 1H), 7.19
(dd, J = 4.77, 8.03 Hz, 1H), 6.89 (s, 1H), 5.17 (d, J = 4.52 Hz,
1H), 4.21 (q, J = 7.03 Hz, 2H), 3.8 9-4.00 (m, 1H) 3.57-3.67 (m,
1H), 3.45-3.56 (m, 1H), 1.26 (t, J = 7.15 Hz, 3H), 1.16 (d, J =
6.27 Hz, 3H). 255 (DMSO-d6): 12.41 (br. s, 1H), 9.29 (br. s, 1H),
8.49 (d, J = 7.78 Hz, 1H), 8.32 338.0 (dd, J = 1.13, 4.64 Hz, 1H),
8.12 (s, 1H), 7.19 (dd, J = 4.64, 7.91 Hz, 1H), 6.96 (s, 1H), 4.43
(d, J = 1.51 Hz, 2H), 4.22 (q, J = 7.03 Hz, 2H), 3.42 (t, J = 2.26
Hz, 1H), 1.26 (t, J = 7.15 Hz, 3H). 256 (DMSO-d6): 12.35 (s, 1H),
11.34 (s, 1H), 10.67 (s, 1H), 8.33 (d, J = 7.3 Hz, 419.2 1H), 8.10
(d, J = 4.4 Hz, 1H), 7.94-8.05 (m, 3H), 7.68-7.76 (m, 1H), 7.58-
7.68 (m, 2H), 6.93 (s, 1H), 6.29-6.36 (m, 1H), 4.26 (q, J = 7.0 Hz,
2H), 1.29 (t, J = 7.0 Hz, 3H). 257 (DMSO-d6): 12.20-12.50 (m, 1H),
8.26-8.40 (m, 2H), 7.89 (s, 1H), 7.15-7.59 448.2 (m, 5H), 6.84 (s,
1H), 5.03-5.30 (m, 2H), 4.12-4.31 (m, 4H), 3.10-3.50 (m, 2H),
1.22-1 .32 (m, 3H). 258 (DMSO-d6): 12.10-12.60 (m, 1H), 8.25-8.40
(m, 2H), 7.93 (s, 1H), 7.12-7.24 431.2 (m, 2H), 6.96-7.05 (m, 1H),
6.82 (s, 1H), 6.66-6.78 (m, 2H), 5.85 (s, 1H), 5.05 (s, 2H),
4.15-4.30 (m, 2H), 3.75-4.00 (m, 2H), 3.40-3.55 (m, 2H), 1.26 (t, J
= 7.0 Hz, 3H). 259 (DMSO-d6): 12.33 (br. s, 1H), 8.40 (d, J = 7.8
Hz, 1H), 8.32 (d, J = 4.3 Hz, 446.2 1H), 8.07 (s, 1H), 7.17-7.29
(m, 2H), 6.80-6.95 (m 3H), 4.96 (s, 2H), 4.21 (q, J = 7.0 Hz, 2H),
3.90-4.07 (m, 2H), 3.81 (s, 3H), 2.88-3.00 (m, 2H), 1.26 (t, J =
7.1 Hz, 3H). 260 (DMSO-d6): 12.32 (s, 1H), 8.37 (d, J = 7.9 Hz,
1H), 8.28-8.34 (m, 1H), 8.01 398.2 (s, 1H), 7.19 (dd, J = 8.0, 4.5
Hz, 1H), 6.88 (s, 1H), 4.08-4.24 (m, 4H), 3.73- 3.87 (m, 2H),
2.95-3.06 (m, 2H), 1.24 (t, J = 7.0 Hz, 3H), 1.18 (d, J = 6.0 Hz,
6H). 261 (DMSO-d6): 12.35 (s, 1H), 8.66 (br. s, 1H), 8.41 (d, J =
7.9 Hz, 1H), 8.32 (d, 384.2 J = 3.5 Hz, 1H), 8.01 (s, 1H), 7.21
(dd, J = 7.9, 4.7 Hz, 1H), 6.90 (s, 1H), 4.18-4.30 (m, 3H),
3.89-4.00 (m, 2H), 3.40-3.53 (m, 2H), 1.82-1.96 (m, 4H), 1.25 (q, J
= 7.1 Hz, 3H). 262 (DMSO-d6): 12.31 (s, 1H), 9.87 (s, 1H), 8.93 (d,
J = 7.8 Hz, 1H), 8.30 (d, J = 369.2 3.6 Hz, 1H), 8.06 (d, J = 2.2
Hz, 1H), 7.14 (dd, J = 8.0, 4.6 Hz, 1H), 6.85 (s, 1H), 4.20 (q, J =
7.0 Hz, 2H), 3.04-3.17 (m, 4H), 1.85-1.98 (m, 4H), 1.26 (t, J = 7.1
Hz, 3H). 263 (DMSO-d6): 12.39 (s, 1H), 10.05 (s, 1H), 8.85 (d, J =
7.8 Hz, 1H), 8.33 (d, J = 397.2 3.8 Hz, 1H), 8.12 (s, 1H), 7.17
(dd, J = 7.8, 4.6 Hz, 1H), 6.87 (s, 1H), 4.20 (q, J = 7.0 Hz, 2H),
3.08-3.20 (m, 4H), 1.63-1.84 (m, 8H), 1.26 (t, J = 7.0 Hz, 3H). 264
(DMSO-d6): 12.26 (s, 1H), 8.16-8.24 (m, 2H), 7.85 (d, J = 7.9 Hz,
1H), 7.62 530.4 (s, 1H), 7.38 (d, J = 7.5 Hz, 1H), 7.31 (s, 1H),
7.25 (d, J = 7.6 Hz, 1H), 6.82 (dd, J = 7.8, 4.7 Hz, 1H), 6.75 (s,
1H), 4.20-4.30 (m, 2H), 3.57 (s, 2H), 3.10-3.60 (m, 8H), 2.68-2.77
(m, 1H), 2.24 (s, 3H), 1.29 (t, J = 7.1 Hz, 3H), 0.99 (d, J = 6.5
Hz, 6H). 265 (DMSO-d6): 8.21 (s, 1H), 8.17 (d, J = 3.4 Hz, 1H),
7.83 (d, J = 7.7 Hz, 1H), 487.2 7.62 (s, 1H), 7.40 (s, 1H), 7.33
(s, 2H), 6.81 (dd, J = 8.0, 4.7 Hz, 1H), 6.63 (s, 1H), 4.15-4.30
(m, 3H), 3.95 (s, 2H), 2.43-2.56 (m, 2H), 2.22 (s, 3H), 1.81-1.94
(m, 2H), 1.63-1.75 (m, 2H), 1.43-1.60 (m, 4H), 1.22-1.33 (m, 3H).
266 (DMSO-d6): 8.16 (d, J = 3.8 Hz, 1H), 7.83 (d, J = 7.6 Hz, 1H),
7.60 (s, 1H), 461.2 7.18-7.39 (m, 3H), 6.87 (s, 1H), 6.75-6.84 (m,
1H), 6.54 (s, 1H), 4.10-4.25 (m, 2H), 3.93 (s, 2H), 2.95-3.10 (m,
1H), 2.15-2.20 (m, 3H), 1.20-1.30 (m, 3H), 1.10-1.20 (m, 6H).
TABLE-US-00012 TABLE 2-2 267 (DMSO-d6): 12.26 (s, 1H), 10.32 (br.
s, 1H), 8.20 (d, J = 3.5 Hz, 1H), 7.71- 503.2 7.82 (m, 2H), 7.46
(d, J = 8.2 Hz, 1H), 7.35 (s, 1H), 7.29 (d, J = 8.5 Hz, 1H), 6.83
(s, 1H), 6.73-6.81 (m, 1H), 4.53-4.61 (m, 1H), 4.20-4.32 (m, 2H),
3.42-3.62 (m, 3H), 2.68-2.80 (m, 2H), 2.26 (s, 3H), 2.03-2.20 (m,
2H), 1.67-1.80 (m, 2H), 1.36-1.51 (m, 2H), 1.29 (t, J = 7.0 Hz,
3H). 268 (DMSO-d6): 12.49 (br. s, 1H), 9.38 (br. s, 1H), 8.44 (d, J
= 7.53 Hz, 1H), 8.33 339.0 (dd, J = 1.25, 4.52 Hz, 1H), 8.17 (d, J
= 2.51 Hz, 1H), 7.21 (dd, J = 4.77, 8.03 Hz, 1H), 7.02 (s, 1H),
4.79 (s, 2H), 4.23 (q, J = 7.19 Hz, 2H), 1.26 (t, J = 7.03 Hz, 3H).
269 (DMSO-d6): 12.35 (br. s, 1H), 8.60 (d, J = 8.78 Hz, 1H), 8.45
(dd, J = 1.26, 373.9 8.03 Hz, 1H), 8.31 (dd, J = 1.25, 4.52 Hz,
1H), 8.04 (s, 1H), 7.19 (dd, J = 4.77, 8.03 Hz, 1H), 6.90 (s, 1H),
5.18 (t, J = 5.14 Hz, 2H), 4.11-4.27 (m, 3H), 3.67 (t, J = 5.40 Hz,
4H), 1.26 (t, J = 7.15 Hz, 3H). 270 (DMSO-d6): 12.40 (br. s, 1H),
8.84 (t, J = 5.90 Hz, 1H), 8.49 (d, J = 8.03 Hz, 374.0 1H), 8.32
(dd, J = 1.38, 4.64 Hz, 1H), 8.06 (d, J = 2.51 Hz, 1H), 7.21 (dd, J
= 4.77, 8.03 Hz, 1H), 6.90 (s, 1H), 4.21 (q, J = 7.03 Hz, 2H),
3.73-3.83 (m, 2H), 3.33-3.66 (m, 5H), 1.26 (t, J = 7.03 Hz, 3H).
271 (DMSO-d6): 12.10-12.20 (m, 1H), 8.20-8.42 (m, 2H), 7.98 (s,
1H), 7.19 (dd, 468.3 J = 7.9, 4.6 Hz, 1H), 6.85 (s, 1H), 4.10-4.40
(m, 4H), 3.85-4.05 (m, 2H), 3.25-3.40 (m, 4H), 2.35-3.45 (m, 3H),
2.65-2.80 (m, 1H), 2.15-2.25 (m, 6H), 1.80-1.95 (m, 2H), 1.53-1.72
(m, 2H), 1.20-1.28 (m, 3H). 272 (DMSO-d6): 12.30 (s, 1H), 8.37 (d,
J = 7.9 Hz, 1H), 8.31 (d, J = 4.2 Hz, 1H), 486.2 7.98 (s, 1H), 7.19
(dd, J = 7.8, 4.6 Hz, 1H), 6.84 (s, 1H), 4.58-4.73 (m, 3H), 4.16
(q, J = 7.0 Hz, 2H), 3.93-4.01 (m, 2H), 3.68-3.77 (m, 1H), 3.40-
3.56 (m, 3H), 3.31-3.39 (m, 2H), 3.16 (s, 3H), 1.74-1.90 (m, 3H),
1.58- 1.72 (m, 3H), 1.24 (t, J = 7.1 Hz, 3H). 273 (DMSO-d6): 12.35
(s, 1H), 8.41 (d, J = 6.8 Hz, 1H), 8.32 (d, J = 3.4 Hz, 1H), 446.0
8.06 (s, 1H), 7.22 (dd, J = 7.9, 4.6 Hz, 2H), 6.83-6.93 (m, 3H),
4.90 (s, 2H), 4.20 (q, J = 7.0 Hz, 2H), 3.84-4.00 (m, 2H), 3.76 (s,
3H), 3.01-3.09 (m, 2H), 1.26 (t, J = 7.1 Hz, 3H). 274 (DMSO-d6):
12.24 (s, 1H), 8.26-8.48 (m, 2H), 7.95 (s, 1H), 7.10-7.17 (m, 1H),
433.2 6.84-6.94 (m, 3H), 6.59 (d, J = 8.0 Hz, 1H), 4.90 (s, 2H),
4.77 (s, 2H), 4.15 (q, J = 7.1 Hz, 2H), 3.16 (s, 3H), 2.01 (s, 3H),
1.25-1.19 (m, 3H). 275 (DMSO-d6): 12.31 (s, 1H), 8.37 (d, J = 8.0
Hz, 1H), 8.31 (d, J = 3.6 Hz, 1H), 382.2 7.96 (s, 1H), 7.19 (dd, J
= 7.9, 4.6 Hz, 1H), 6.84 (s, 1H), 4.00-4.25 (m, 4H), 3.22-3.32 (m,
1H), 3.05-2.95 (m, 1H), 1.75-1.91 (m, 3H), 1.60-1.74 (m, 1H),
1.17-1.33 (m, 4H), 0.95 (d, J = 6.2 Hz, 3H). 276 (DMSO-d6): 12.32
(s, 1H), 8.37 (d, J = 7.9 Hz, 1H), 8.31 (d, J = 4.6 Hz, 1H), 398.2
8.01 (s, 1H), 7.19 (dd, J = 7.9, 4.7 Hz, 1H), 6.88 (s, 1H),
4.12-4.22 (m, 4H), 3.76-3.86 (m, 2H), 2.96-3.06 (m, 2H), 1.24 (t, J
= 7.1 Hz, 3H), 1.18 (d, J = 6.2 Hz, 6H). 277 (DMSO-d6): 12.37 (s,
1H), 9.96 (s, 1H), 8.99 (d, J = 7.8 Hz, 1H), 8.34 (d, 428.4 J = 3.3
Hz, 1H), 8.11 (d, J = 2.5 Hz, 1H), 7.23 (dd, J = 8.0, 4.7 Hz, 1H),
6.85 (s, 1H), 4.49 (t, J = 5.2 Hz, 1H), 4.21 (q, J = 7.1 Hz, 2H),
3.56 (q, J = 6.0 Hz, 2H), 2.98-3.12 (m, 4H), 2.57-2.77 (m, 4H),
2.45-2.55 (m, 2H), 1.26 (t, J = 7.1 Hz, 3H). 278 (DMSO-d6): 12.21
(br. s, 1H), 8.28-8.42 (m, 2H), 7.96 (s, 1H), 7.18 (dd, J = 396.2
7.9, 4.7 Hz, 1H), 6.84 (s, 1H), 4.06-4.23 (m, 4H), 2.72-2.88 (m,
2H), 1.75- 1.92 (m, 3H), 1.24 (t, J = 7.0 Hz, 3H), 0.86-1.00 (m,
7H). 279 (DMSO-d6): 12.27 (s, 1H), 9.22 (br. s, 1H), 6.4-8.6 (m,
7H), 4.15-4.25 (m, 367.2 2H), 1.18-1.30 (m, 3H). 280 (DMSO-d6):
12.10-12.65 (m, 1H), 8.25-8.53 (m, 2H), 8.01 (s, 1H), 7.14-7.29
446.0 (m, 2H), 6.80-6.95 (m, 3H), 4.68-4.93 (m, 2H), 4.15-4.27 (m,
2H), 3.93- 4.05 (m, 2H), 3.80-3.92 (m, 3H), 2.98-3.10 (m, 2H),
1.23-1.32 (m, 3H). 281 (DMSO-d6): 12.34 (s, 1H), 9.51 (br. s, 1H),
9.17 (d, J = 7.3 Hz, 1H), 8.33 (d, 411.2 J = 3.3 Hz, 1H), 8.12 (s,
1H), 7.18 (dd, J = 8.0, 4.6 Hz, 1H), 6.82 (s, 1H), 4.22 (q, J = 7.0
Hz, 2H), 2.95-3.10 (m, 2H), 1.70-1.85 (m, 3H), 1.37-1.53 (m, 3H),
1.27 (t, J = 7.1 Hz, 3H), 0.98 (d, J = 6.0 Hz, 6H). 282 (DMSO-d6):
12.25 (br. s, 1H), 8.34-8.39 (m, 1H), 8.32 (d, J = 4.6 Hz, 1H),
7.97 396.2 (s, 1H), 7.19 (dd, J = 7.9, 4.6 Hz, 1H), 6.84 (s, 1H),
4.10-4.27 (m, 2H), 3.73 (dd, J = 13.1, 3.5 Hz, 2H), 3.43-3.59 (m,
2H), 2.06-2.20 (m, 2H), 1.54 (t, J = 5.7 Hz, 2H), 1.25 (t, J = 6.7
Hz, 3H), 0.95 (d, J = 7.3 Hz, 6H). 283 (DMSO-d6): 12.30 (s, 1H),
8.37 (d, J = 7.9 Hz, 1H), 8.32 (d, J = 4.7 Hz, 1H), 396.2 7.97 (s,
1H), 7.19 (dd, J = 7.8, 4.7 Hz, 1H), 6.84 (s, 1H), 4.18 (q, J = 7.1
Hz, 2H), 3.62-3.71 (m, 2H), 3.54 (s, 2H), 1.71-1.82 (m, 2H),
1.45-1.56 (m, 2H), 1.25 (t, J = 7.1 Hz, 3H), 0.97 (s, 6H). 284
(DMSO-d6): 12.30 (s, 1H), 8.38 (d, J = 8.2 Hz, 1H), 8.31 (d, J =
4.2 Hz, 1H), 398.0 8.00 (s, 1H), 7.19 (dd, J = 8.0, 4.6 Hz, 1H),
6.83 (s, 1H), 4.97-5.10 (m, 1H), 4.42-4.56 (m, 1H), 4.10-4.23 (m,
2H), 3.80-3.95 (m, 2H), 3.57-3.72 (m, 2H), 1.70-1.90 (m, 3H),
1.55-1.70 (m, 3H), 1.24 (t, J = 7.0 Hz, 3H). 285 (DMSO-d6): 12.28
(br. s, 1H), 10.34 (br. s, 1H), 8.20 (dd, J = 1.38, 4.64 Hz, 503.3
1H), 7.73-7.79 (m, 2H), 7.42 (d, J = 7.78 Hz, 1H), 7.31 (s, 1H),
7.25 (d, J = 8.03 Hz, 1H), 6.84 (s, 1H), 6.76 (dd, J = 4.64, 7.91
Hz, 1H), 4.27 (q, J = 7.03 Hz, 2H), 3.61 (t, J = 4.52 Hz, 4H),
3.28-3.34 (m, 4H), 2.82-2.90 (m, 2H), 2.58-2.64 (m, 2H), 2.24 (s,
3H), 1.30 (t, J = 7.03 Hz, 3H). 286 (DMSO-d6): 12.25 (s, 1H), 10.37
(s, 1H), 8.20 (d, J = 3.7 Hz, 1H), 7.78 (d, J = 434.0 7.8 Hz, 1H),
7.72 (s, 1H), 7.42 (d, J = 8.0 Hz, 1H), 7.30 (s, 1H), 7.23 (d, J =
7.7 Hz, 1H), 6.85 (s, 1H), 6.80 (dd, J = 7.8, 4.7 Hz, 1H), 4.77 (t,
J = 5.1 Hz, 1H), 4.27 (q, J = 6.9 Hz, 2H), 3.72 (q, J = 6.7 Hz,
2H), 2.85 (t, J = 6.9 Hz, 2H), 2.24 (s, 3H), 1.30 (t, J = 7.0 Hz,
3H).
TABLE-US-00013 TABLE 2-3 287 (DMSO-d6): 12.11 (br. s, 1H), 8.15 (d,
J = 3.8 Hz, 1H), 7.68-7.78 (m, 2H), 7.43 497.2 (s, 1H), 7.26-7.38
(m, 2H), 6.80 (dd, J = 7.7, 4.8 Hz, 1H), 6.60 (s, 1H), 4.15- 4.25
(m, 2H), 3.66 (s, 2H), 2.60-2.70 (m, 4H), 2.19 (s, 3H), 1.91 (s,
3H), 1.70- 1.82 (m, 4H), 1.27 (t, J = 7.0 Hz, 3H). 288 (DMSO-d6):
11.80-12.15 (m, 1H), 8.22-8.37 (m, 2H), 8.12-8.18 (m, 1H), 7.74-
513.0 7.83 (m, 1H), 7.54-7.72 (m, 1H), 7.33 (s, 1H), 7.26 (d, J =
8.9 Hz, 1H), 6.9- 7.05 (m, 1H), 6.77-6.84 (m, 1H), 6.27-6.39 (m,
1H), 4.04-4.23 (m, 2H), 3.60- 3.70 (m, 4H), 3.56 (s, 2H), 2.53-2.62
(m, 4H), 2.10 (s, 3H), 1.20-1.30 (m, 3H). 289 (DMSO-d6): 8.05-8.15
(m, 1H), 7.82 (d, J = 7.4 Hz, 1H), 7.52 (s, 1H), 7.27 (s, 1H),
527.0 7.20 (d, J = 7.8 Hz, 1H), 6.91 (d, J = 7.9 Hz, 1H), 6.75-6.84
(m, 1H), 6.18 (s, 1H), 4.02-4.13 (m, 2H), 3.30-3.70 (m, 3H),
2.75-2.85 (m, 2H), 2.36-2.26 (m, 2H), 2.07 (s, 3H), 1.72-1.82 (m,
2H), 1.40-1.50 (m, 2H), 1.15-1.30 (m, 3H). 290 (DMSO-d6): 12.27
(br. s, 1H), 8.20 (dd, J = 1.25, 4.77 Hz, 1H), 7.72-7.80 (m, 2H),
516.3 7.40 (d, J = 8.03 Hz, 1H), 7.30 (s, 1H), 7.23 (d, J = 7.78
Hz, 1H), 6.82 (s, 1H), 6.76 (dd, J = 4.64, 7.91 Hz, 1H), 4.26 (q, J
= 7.03 Hz, 2H), 3.25-3.50 (m, 4H), 2.79-2.89 (m, 2H), 2.56-2.66 (m,
2H), 2.31-3.47 (m, 4H), 2.23 (s, 3H), 2.20 (s, 3H), 1.29 (t, J =
7.15 Hz, 3H). 291 (DMSO-d6): 12.31 (s, 1H), 8.39 (d, J = 6.9 Hz,
1H), 8.31 (d, J = 4.6 Hz, 1H), 7.95 342.2 (s, 1H), 7.20 (dd, J =
7.9, 4.7 Hz, 1H), 6.84 (s, 1H), 4.17 (q, J = 7.1 Hz, 2H), 3.73 (q,
J = 7.0 Hz, 2H), 3.26 (s, 3H), 1.20-1.33 (m, 6H). 292 (DMSO-d6):
8.38 (d, J = 7.9 Hz, 1H), 8.31 (d, J = 3.3 Hz, 1H), 7.95 (s, 1H),
7.19 356.0 (dd, J = 7.9, 4.7 Hz, 1H), 6.84 (s, 1H), 4.50-4.62 (m,
1H), 4.17 (d, J = 7.1 Hz, 2H), 3.09 (s, 3H), 1.36-1.20 (m, 9H). 293
(DMSO-d6): 12.31 (br. s, 1H), 10.01 (br. s, 1H), 8.92 (d, J = 7.8
Hz, 1H), 8.31 399.2 (d, J = 3.7 Hz, 1H), 8.08 (s, 1H), 7.18 (dd, J
= 7.9, 4.7 Hz, 1H), 6.83 (s, 1H), 4.97 (br. s, 1H), 4.20 (q, J =
7.0 Hz, 2H), 3.72-3.83 (m, 1H), 3.12-3.20 (m, 1H), 2.97-3.06 (m,
1H), 2.71-2.91 (m, 2H), 1.80-1.93 (m, 2H), 1.56-1.68 (m, 1H),
1.18-1.31 (m, 4H). 294 (DMSO-d6): 12.29 (s, 1H), 8.29-8.38 (m, 2H),
7.96 (s, 1H), 7.19 (dd, J = 7.9, 396.4 4.7 Hz, 1H), 6.82 (s, 1H),
4.95-5.10 (m, 1H), 4.15-4.25 (m, 2H), 3,24-3.34 (m, 2H), 1.68-1.88
(m, 3H), 1.25-1.40 (m, 2H), 1.25 (d, J = 6.2 Hz, 6H), 0.97 (d, J =
6.3 Hz, 3H). 295 (DMSO-d6): 12.35 (s, 1H), 8.40 (d, J = 6.6 Hz,
1H), 8.33 (d, J = 4.6 Hz, 1H), 8.07 430.2 (s, 1H), 7.24-7.32 (m,
4H), 7.22 (dd, J = 7.9, 4.7 Hz, 1H), 6.87 (s, 1H), 5.00- 5.12 (m,
1H), 4.97 (s, 2H), 3.90-4.02 (m, 2H), 3.03-3.13 (m, 2H), 1.27 (t, J
= 8.9 Hz, 6H). 296 (DMSO-d6): 12.31 (s, 1H), 9.86 (s, 1H), 8.84 (d,
J = 7.8 Hz, 1H), 8.30 (d, J = 3.3 357.2 Hz, 1H), 8.05 (d, J = 2.5
Hz, 1H), 7.20 (dd, J = 8.0, 4.6 Hz, 1H), 6.83 (s, 1H), 4.99-5.10
(m, 1H), 2.77 (s, 6H), 1.27 (d, J = 6.3 Hz, 6H). 297 (DMSO-d6):
12.26 (s, 1H), 10.07 (s, 1H), 8.17 (s, 1H), 7.85 (s, 1H), 7.69 (d,
J = 462.8 7.4 Hz, 1H), 7.17 (d, J = 8.3 Hz, 1H), 6.72-6.88 (m, 2H),
6.52-6.67 (m, 2H), 5.80-5.92 (m, 1H), 5.07-5.18 (m, 1H), 4.71-4.81
(m, 1H), 3.58-3.69 (m, 2H), 3.15-3.25 (m, 2H), 2.13 (s, 3H), 1.30
(d, J = 5.9 Hz, 6H). 298 (MeOD): 8.15-8.24 (m, 1H), 7.86 (d, J =
7.5 Hz, 1H), 7.65 (br. s, 1H), 7.40-7.55 526.4 (m, 3H), 6.90-7.03
(m, 2H), 6.61 (s, 1H), 4.34-4.43 (m, 2H), 3.66 (s, 2H), 2.70-2.98
(m, 8H), 2.49 (s, 3H), 2.32 (s, 3H), 1.35-1.42 (m, 3H). 299
(DMSO-d6): 12.31 (s, 1H), 10.42 (br. s, 1H), 8.23 (dd, J = 4.6, 1.4
Hz, 1H), 7.79 487.0 (d, J = 7.3 Hz, H), 7.72 (d, J = 2.7 Hz, 1H),
7.51 (d, J = 8.0 Hz, 1H), 7.37 (s, 1H), 7.30 (d, J = 7.9 Hz, 1H),
6.87 (s, 1H), 6.78 (dd, J = 7.9, 4.8 Hz, 1H), 4.27 (q, J = 7.1 Hz,
H), 3.35-3.70 (m, 4H), 3.03-3.15 (m, 4H), 2.27 (s, 3H), 1.85- 2.10
(s, 4H), 1.30 (t, J = 7.1 Hz, 3H). 300 (DMSO-d6): 12.30 (br. s,
1H), 8.39 (d, J = 7.6 Hz, 1H), 8.31 (d, J = 4.4 Hz, 1H), 396.0 7.93
(s, 1H), 7.19 (dd, J = 7.9, 4.7 Hz, 1H), 6.85 (s, 1H), 4.16 (q, J =
7.1 Hz, 3H), 3.11 (s, 3H), 1.79-1.92 (m, 4H), 1.60-1.75 (m, 3H),
1.28-1.44 (m, 2H), 1.11-1.28 (m, 4H). 301 (DMSO-d6): 12.30 (br. s,
1H), 9.62 (br. s, 1H), 8.91 (d, J = 8.0 Hz, 1H), 8.31 (d, 411.0 J =
3.8 Hz, 1H), 8.07 (s, 1H), 7.16 (dd, J = 8.0, 4.6 Hz, 1H), 6.84 (s,
1H), 4.21 (q, J = 7.0 Hz, 2H), 2.78-2.88 (m, 1H), 2.77 (s, 3H),
1.88-2.00 (m, 2H), 1.68- 1.80 (m, 2H), 1.48-1.59 (m, 1H), 1.16-1.31
(m, 7H), 1.00-1.12 (m, 1H). 302 (DMSO-d6): 12.31 (s, 1H), 10.07 (s,
1H), 8.94 (d, J = 7.5 Hz, 1H), 8.32 (d, J = 426.0 3.4 Hz, 1H), 8.12
(s, 1H), 7.21 (dd, J = 8.0, 4.7 Hz, 1H), 6.88 (s, 1H), 4.21 (q, J =
7.1 Hz, 2H), 3.57-3.76 (m, 4H), 2.97-3.12 (m, 4H), 2.08 (s, 3H),
1.26 (t, J = 7.1 Hz, 3H). 303 (DMSO-d6): 12.30 (br. s, 1H),
8.15-8.21 (m, 2H), 7.77 (s, 1H), 7.68 (d, J = 7.8 517.4 Hz, 1H),
7.42 (d, J = 8.7 Hz, 1H), 7.04 (s, 1H), 6.94 (d, J = 8.7 Hz, 1H),
6.73- 6.81 (m, 2H), 5.08-5.19 (m, 1H), 4.19 (t, J = 5.6 Hz, 2H),
2.94 (t, J = 5.6 Hz, 2H), 2.62-2.71 (m, 4H), 2.23 (s, 3H),
1.70-1.80 (m, 4H), 1.31 (d, J = 6.2 Hz, 6H). 304 (DMSO-d6): 12.25
(br. s, 1H), 9.80 (br. s, 1H), 8.85 (d, J = 7.4 Hz, 1H), 8.29 (d,
357.2 J = 3.6 Hz, 1H), 8.04 (s, 1H), 7.17 (dd, J = 8.0, 4.7 Hz,
1H), 6.78 (br. s, 1H), 4.19 (q, J = 6.9 Hz, 2H), 2.88-3.00 (m, 2H),
2.74 (s, 3H), 1.25 (t, J = 7.1 Hz, 3H), 1.05 (t, J = 7.1 Hz, 3H).
305 (DMSO-d6): 12.31 (br. s, 1H), 9.49 (br. s, 1H), 8.96 (d, J =
7.8 Hz, 1H), 8.31 (d, 371.2 J = 3.3 Hz, 1H), 8.08 (s, 1H), 7.18
(dd, J = 8.0, 4.6 Hz, 1H), 6.86 (s, 1H), 4.22 (q, J = 7.1 Hz, 2H),
3.00 (q, J = 7.0 Hz, 4H), 1.27 (t, J = 7.1 Hz, 3H), 1.04 (t, J =
7.1 Hz, 6H).
TABLE-US-00014 TABLE 2-4 306 (DMSO-d6): 12.09 (br. s, 1H), 8.98 (d,
J = 7.6 Hz, 1H), 8.32 (d, J = 3.4 Hz, 1H), 399.2 8.05 (s, 1H), 7.21
(dd, J = 8.0, 4.7 Hz, 1H), 6.73 (s, 1H), 4.80 (s, 1H), 4.17 (q, J =
7.0 Hz, 2H), 3.54-3.69 (m, 1H), 3.04-3.15 (m, 2H), 2.82-2.95 (m,
2H), 1.83-1.94 (m, 2H), 1.63-1.77 (m, 2H), 1.24 (t, J = 7.0 Hz,
3H). 307 (DMSO-d6): 12.29 (s, 1H), 10.23 (s, 1H), 8.18 (d, J = 3.4
Hz, 1H), 7.78 (d, J = 533.4 2.5 Hz, 1H), 7.66 (d, J = 7.9 Hz, 1H),
7.42 (d, J = 8.6 Hz, 1H), 7.05 (d, J = 2.4 Hz, 1H), 6.94 (dd, J =
8.6, 2.7 Hz, 1H), 6.79 (s, 1H), 6.74 (dd, J = 7.9, 4.7 Hz, 1H),
5.09-5.18 (m, 1H), 4.19 (t, J = 5.6 Hz, 2H), 3.58-3.67 (m, 4H),
2.78 (t, J = 5.6 Hz, 2H), 2.49-2.57 (m, 4H), 2.23 (s, 3H), 1.31 (d,
J = 6.3 Hz, 6H). 308 (DMSO-d6): 12.20 (br. s, 1H), 10.26 (br. s,
1H), 8.18 (d, J = 3.9 Hz, 1H), 7.66- 546.6 7.77 (m, 2H), 7.26-7.39
(m, 1H), 7.00 (s, 1H), 6.86-6.93 (m, 1H), 6.61-6.78 (s, 2H),
5.06-5.17 (m, 1H), 4.11-4.18 (m, 2H), 2.76 (t, J = 5.5 Hz, 2H),
2.30- 2.50 (m, 8H), 2.20 (s, 3H), 2.17 (s, 3H), 1.29 (d, J = 6.2
Hz, 6H). 309 (DMSO-d6): 12.30 (br. s, 1H), 8.42 (d, J = 8.0 Hz,
1H), 8.32 (d, J = 3.3 Hz, 1H), 412.2 7.98 (s, 1H), 7.20 (dd, J =
8.0, 4.7 Hz, 1H), 6.89 (s, 1H), 4.23-4.35 (m, 2H), 3.96-4.07 (m,
1H), 3.54-3.64 (m, 2H), 3.30 (s, 3H), 1.94-2.03 (m, 2H), 1.73- 1.84
(m, 2H), 1.51-1.69 (m, 3H), 1.35-1.49 (m, 2H), 1.15-1.28 (m, 1H).
310 (DMSO-d6): 12.32 (s, 1H), 9.84 (s, 1H), 8.83 (d, J = 8.2 Hz,
1H), 8.30 (d, J = 3.4 373.4 Hz, 1H), 8.05 (s, 1H), 7.20 (dd, J =
8.0, 4.5 Hz, 1H), 6.88 (s, 1H), 4.25-4.32 (m, 2H), 3.57-3.63 (m,
2H), 3.30 (s, 3H), 2.78 (s, 6H). 311 (DMSO-d6): 12.31 (s, 1H),
10.43 (s, 1H), 8.23 (d, J = 3.8 Hz, 1H), 7.73-7.81 (m, 444.4 2H),
7.58 (d, J = 8.1 Hz, 1H), 7.53 (s, 1H), 7.44 (d, J = 7.9 Hz, 1H),
6.88 (s, 1H), 6.83 (dd, J = 7.9, 4.7 Hz, 1H), 5.42 (t, J = 5.9 Hz,
1H), 4.38 (d, J = 5.9 Hz, 2H), 4.27 (q, J = 7.0 Hz, 2H), 2.27 (s,
3H), 1.30 (t, J = 7.0 Hz, 3H). 312 (DMSO-d6): 12.27 (s, 1H), 10.41
(s, 1H), 8.16 (d, J = 3.4 Hz, 1H), 7.79 (d, J = 1.9 471.1 Hz, 1H),
7.64 (d, J = 7.5 Hz, 1H), 7.48-755 (m, 2H), 7.42 (d, J = 7.9 Hz,
1H), 6.82 (s, 1H), 6.79 (dd, J = 7.9, 4.6 Hz, 1H), 4.24 (q, J = 7.0
Hz, 2H), 3.53 (s, 2H), 2.30 (s, 6H), 2.23 (s, 3H), 1.27 (t, J = 7.0
Hz, 3H). 313 (DMSO-d6): 12.28 (s, 1H), 10.17 (br. s, 1H), 8.21 (d,
J = 3.3 Hz, 1H), 7.71-7.80 461.1 (m, 2H), 7.44 (d, J = 8.1 Hz, 1H),
7.32 (s, 1H), 7.25 (d, J = 8.0 Hz, 1H), 6.84 (s, 1H), 6.75-6.81 (m,
1H), 4.23-4.32 (m, 2H), 2.85-2.95 (m, 2H), 2.75-2.85 (m, 2H), 2.42
(s, 6H), 2.24 (s, 3H), 1.30 (t, J = 7.1 Hz, 3H). 314 (DMSO-d6):
12.28 (s, 1H), 10.27 (br. s, 1H), 8.21 (d, J = 4.6 Hz, 1H),
7.72-7.78 517.1 (m, 2H), 7.42 (d, J = 8.0 Hz, 1H), 7.30 (s, 1H),
7.24 (d, J = 8.3 Hz, 1H), 6.84 (s, 1H), 6.76 (dd, J = 7.9, 4.6 Hz,
1H), 4.58-4.72 (m, 1H), 4.22-4.32 (m, 2H), 3.44-3.60 (m, 1H),
2.80-3.00 (m, 4H), 2.40-2.60 (m, 4H), 2.24 (s, 3H), 1.72- 1.85 (m,
2H), 1.38-1.53 (m, 2H), 1.29 (t, J = 7.1 Hz, 3H). 315 (DMSO-d6):
12.26 (br. s, 1H), 9.72 (br. s, 1H), 8.91 (d, J = 7.6 Hz, 1H), 8.30
(d, 371.0 J = 3.7 Hz, 1H), 8.05 (s, 1H), 7.16 (dd, J = 7.8, 4.6 Hz,
1H), 6.77 (br. s, 1H), 4.13-4.24 (m, 2H), 3.08-3.20 (m, 1H), 2.72
(s, 3H), 1.25 (t, J = 7.1 Hz, 3H), 1.10 (d, J = 6.3 Hz, 6H). 316
(DMSO-d6): 12.33 (br. s, 1H), 10.25 (br. s, 1H), 8.87-8.99 (m, 1H),
8.30 (d, J = 398.0 3.4 Hz, 1H), 8.01-8.18 (m, 2H), 7.07 (dd, J =
8.0, 4.6 Hz, 1H), 6.85 (br. s, 1H), 4.15-4.26 (m, 2H), 3.60-3.72
(m, 2H), 3.20-3.30 (m, 4H), 1.26 (t, J = 7.0 Hz, 3H). 317
(DMSO-d6): 12.36 (s, 1H), 8.42 (d, J = 7.3 Hz, 1H), 8.33 (d, J =
3.4 Hz, 1H), 8.07 446.1 (s, 1H), 7.24-7.32 (m, 4H), 7.22 (dd, J =
7.9, 4.7 Hz, 1H), 6.91 (s, 1H), 4.98 (br. s, 2H), 4.25-4.33 (m,
2H), 3.89-4.03 (m, 2H), 3.56-3.64 (m, 2H), 3.30 (s, 3H), 3.08 (t, J
= 5.7 Hz, 2H). 318 (DMSO-d6): 12.26 (s, 1H), 10.09 (s, 1H), 8.18
(d, J = 3.3 Hz, 1H), 7.83 (s, 1H), 479.1 7.70 (d, J = 7.7 Hz, 1H),
7.16 (d, J = 8.5 Hz, 1H), 6.75-6.86 (m, 2H), 6.61 (s, 1H), 6.57 (d,
J = 8.5 Hz, 1H), 5.81-5.89 (m, 1H), 4.76 (t, J = 5.4 Hz, 1H), 4.28-
4.36 (m, 2H), 3.58-3.67 (m, 4H), 3.32 (s, 1H), 3.20 (q, J = 5.9 Hz,
2H), 2.13 (s, 3H). 319 (DMSO-d6): 12.24 (br. s, 1H), 8.36 (d, J =
8.0 Hz, 1H), 8.31 (d, J = 4.5 Hz, 1H), 451.2 8.00 (s, 1H), 7.20
(dd, J = 7.9, 4.6 Hz, 1H), 6.88 (s, 1H), 4.16 (q, J = 7.1 Hz, 2H),
3.76-3.86 (s, 4H), 3.26-3.32 (m, 2H), 2.82-2.90 (m, 4H), 1.25 (q, J
= 7.0 Hz, 3H). 320 (DMSO-d6): 12.22 (br. s, 1H), 8.19 (s, 1H), 7.83
(d, J = 7.7 Hz, 1H), 7.72 (s, 461.4 1H), 7.21-7.47 (m, 3H),
6.70-6.85 (m, 2H), 5.06-5.18 (m, 1H), 3.49 (s, 2H), 2.25 (s, 3H),
2.22 (s, 6H), 1.91 (s, 3H), 1.30 (d, J = 5.8 Hz, 6H). 321
(DMSO-d6): 8.27-8.35 (m, 2H), 7.95 (s, 1H), 7.24-7.18 (m, 1H), 6.84
(s, 1H), 412.1 4.21-4.27 (m, 2H), 3.54-3.62 (m, 4H), 3.23-3.32 (m,
5H), 1.70-1.85 (m, 3H), 1.23-1.37 (m, 2H), 0.94 (d, J = 6.2 Hz,
3H). 322 (DMSO-d6): 12.27 (s, 1H), 10.24 (s, 1H), 8.16-8.23 (m,
1H), 7.76 (s, 1H), 7.68 548.8 (d, J = 7.9 Hz, 1H), 7.42 (d, J = 8.6
Hz, 1H), 7.05 (s, 1H), 6.95 (d, J = 8.1 Hz, 1H), 6.83 (s, 1H),
6.71-6.79 (m, 1H), 4.30-4.38 (m, 2H), 4.15-4.23 (m, 2H), 3.56-3.69
(m, 6H), 3.33 (s, 3H), 2.74-2.82 (m, 2H), 2.48-2.58 (m, 4H), 2.23
(s, 3H). 323 (DMSO-d6): 11.18 (br. s, 1H), 8.18 (d, J = 3.4 Hz,
1H), 7.66-7.75 (m, 2H), 7.32 562.2 (d, J = 8.6 Hz, 1H), 7.00 (s,
1H), 6.91 (d, J = 8.6 Hz, 1H), 6.70-6.78 (m, 2H), 4.27-4.35 (m,
2H), 4.16 (t, J = 5.7 Hz, 2H), 3.60-3.66 (m, 2H), 3.33 (s, 3H),
2.76 (t, J = 5.6 Hz, 2H), 2.48-2.58 (s, 4H), 2.31-2.42 (m, 4H),
2.20 (s, 3H), 2.17 (s, 3H), 1.90 (s, 3H).
TABLE-US-00015 TABLE 2-5 324 (MeOD): 8.16-8.23 (m, 1H), 7.97 (d, J
= 7.7 Hz, 1H), 7.30-7.60 (m, 4H), 6.90- 477.0 6.71 (m, 2H), 6.60
(s, 1H), 4.42-4.53 (m, 2H), 3.65-3.80 (m, 4H), 3.41 (s, 3H), 2.41
(s, 6H), 2.35 (s, 3H). 325 (DMSO-d6): 12.39 (s, 1H), 8.59 (d, J =
8.4 Hz, 1H), 8.44 (d, J = 7.8 Hz, 1H), 8.34 412.2 (d, J = 4.6 Hz,
1H), 7.98 (d, J = 2.4 Hz, 1H), 7.22 (dd, J = 7.9, 4.7 Hz, 1H), 6.89
(s, 1H), 4.21 (t, J = 6.3 Hz, 2H), 3.94-4.06 (m, 1H), 3.56 (t, J =
5.9 Hz, 3H), 1.93-2.03 (m, 2H), 1.74-1.84 (m, 4H), 1.53-1.70 (m,
3H), 1.34-1.48 (m, 2H), 1.15-1.28 (m, 1H). 326 (DMSO-d6): 12.35 (s,
1H), 8.50 (br. s, 1H), 8.41 (d, J = 7.0 Hz, 1H), 8.30-8.35 425.2
(m, 1H), 7.98 (s, 1H), 7.20 (dd, J = 7.9, 4.7 Hz, 1H), 6.89 (s,
1H), 4.22 (t, J = 5.8 Hz, 2H), 3.94-4.06 (m, 1H), 2.51-2.58 (m,
2H), 2.23 (s, 6H), 1.96-2.05 (m, 2H), 1.75-1.86 (m, 2H), 1.62-1.72
(m, 1H), 1.34-1.59 (m, 4H), 1.16-1.29 (m, 1H). 327 (DMSO-d6): 12.30
(s, 1H), 8.37 (d, J = 7.8 Hz, 1H), 8.31 (d, J = 4.2 Hz, 1H), 7.96
425.2 (s, 1H), 7.19 (dd, J = 7.9, 4.4 Hz, 1H), 6.85 (s, 1H), 4.21
(t, J = 5.7 Hz, 2H), 2.40-2.60 (m, 6H), 2.22 (s, 6H), 1.73-1.87 (m,
2H), 1.15-1.42 (m, 3H), 0.97 (d, J = 6.1 Hz, 3H). 328 (DMSO-d6):
8.37 (d, J = 7.8 Hz, 1H), 8.31 (d, J = 3.6 Hz, 1H), 7.93 (s, 1H),
7.20- 412.2 7.27 (m, 1H), 6.85 (s, 1H), 4.17 (t, J = 6.2 Hz, 2H),
3.70-3.90 (m, 4H), 3.50- 3.56 (m, 2H), 1.70-1.88 (m, 6H), 1.50-1.60
(m, 4H). 329 (DMSO-d6): 12.42 (s, 1H), 8.43 (d, J = 7.9 Hz, 1H),
8.34 (d, J = 4.2 Hz, 1H), 7.98 412.2 (s, 1H), 7.24 (dd, J = 7.9,
4.8 Hz, 1H), 6.88 (s, 1H), 4.35-4.13 (m, 5H), 3.56 (t, J = 6.0 Hz,
2H), 3.25-3.37 (m, 2H), 1.70-1.88 (m, 5H), 1.26-1.40 (m, 2H), 0.96
(d, J = 6.2 Hz, 3H). 330 (DMSO-d6): 8.12-8.17 (m, 1H), 7.72-7.79
(m, 1H), 7.65 (s, 1H), 7.14-7.22 (m, 533.6 1H), 6.94 (s, 1H),
6.82-6.88 (m, 1H), 6.73-6.80 (m, 1H), 6.55 (s, 1H), 4.21- 4.30 (m,
2H), 4.09-4.16 (m, 2H), 3.55-3.66 (m, 2H), 3.32 (s, 3H), 2.85 (t, J
= 5.7 Hz, 2H), 2.54-2.61 (m, 4H), 2.16 (s, 3H), 1.90 (s, 3H),
1.68-1.76 (m, 4H). 331 (DMSO-d6): 12.47 (s, 1H), 8.47 (d, J = 7.9
Hz, 1H), 8.36 (br. s, 1H), 8.09 (s, 446.0 1H), 7.16-7.32 (m, 6H),
6.93 (s, 1H), 5.00 (br. s, 2H), 4.22 (t, J = 6.4 Hz, 2H), 3.80-4.10
(m, 2H), 3.57 (t, J = 6.0 Hz, 2H), 3.08 (t, J = 5.6 Hz, 2H),
1.75-1.85 (m, 2H). 332 (DMSO-d6): 12.39 (s, 1H), 10.14 (s, 1H),
8.95 (d, J = 8.0 Hz, 1H), 8.34 (d, J = 415.1 4.5 Hz, 1H), 8.12 (d,
J = 2.6 Hz, 1H), 7.24 (dd, J = 8.0, 4.7 Hz, 1H), 6.88 (s, 1H), 4.21
(t, J = 6.3 Hz, 2H), 3.76-3.86 (m, 4H), 3.53-3.61 (m, 3H),
3.02-3.12 (m, 4H), 1.87-1.74 (m, 2H). 333 (DMSO-d6): 12.38 (s, 1H),
9.95 (br. s, 1H), 8.87 (d, J = 7.7 Hz, 1H), 8.32 (d, J = 373.2 3.4
Hz, 1H), 8.03-8.09 (m, 1H), 7.23 (dd, J = 8.0, 4.7 Hz, 1H), 6.88
(s, 1H), 4.21 (t, J = 6.3 Hz, 2H), 3.57 (t, J = 5.8 Hz, 2H), 3.39
(s, 1H), 2.77 (s, 6H), 1.75- 1.85 (m, 2H). 334 (DMSO-d6): 12.31
(br. s, 1H), 8.91 (d, J = 7.53 Hz, 1H), 8.33 (d, J = 3.51 Hz, 415.2
1H), 8.09 (br. s, 1H), 7.22 (dd, J = 4.64, 7.91 Hz, 1H), 6.83 (br.
s, 1H), 4.27 (t, J = 4.64 Hz, 2H), 3.77-3.85 (m, 4H), 3.56-3.62 (m,
2H), 3.30 (s, 3H), 3.00- 3.10 (m, 4H). 335 (DMSO-d6): 12.37 (br. s,
1H), 8.40 (dd, J = 1.26, 8.03 Hz, 1H), 8.33 (dd, J = 1.38, 406.2
4.64 Hz, 1H), 8.06 (s, 1H), 7.63 (d, J = 1.51 Hz, 1H), 7.21 (dd, J
= 4.64, 7.91 Hz, 1H), 6.92 (s, 1H), 6.47 (d, J = 1.76 Hz, 1H), 4.90
(br. s, 2H), 4.21 (q, J = 7.19 Hz, 2H), 3.95-4.05 (m, 2H),
2.74-2.83 (m, 2H), 1.26 (t, J = 7.03 Hz, 3H). 336 (DMSO-d6): 12.27
(s, 1H), 10.19 (s, 1H), 8.18 (d, J = 3.5 Hz, 1H), 7.80-7.86 (m,
479.2 1H), 7.68 (d, J = 7.8 Hz, 1H), 7.16 (d, J = 8.4 Hz, 1H),
6.76-6.84 (m, 2H), 6.62 (s, 1H), 6.58 (d, J = 8.5 Hz, 1H), 4.26 (t,
J = 6.3 Hz, 2H), 3.54-3.66 (m, 4H), 3.20 (t, J = 6.2 Hz, 3H), 2.13
(s, 3H), 1.78-1.87 (m, 2H). 337 (DMSO-d6): 12.36 (s, 1H), 10.61
(br. s, 1H), 10.54 (s, 1H), 8.24 (d, J = 3.8 Hz, 477.4 1H), 7.97
(d, J = 8.6 Hz, 1H), 7.55-7.70 (m, 4H), 6.89-6.95 (m, 2H), 4.38 (d,
J = 4.8 Hz, 2H), 4.29 (t, J = 6.3 Hz, 2H), 3.62-3.55 (m, 2H), 3.39
(s, 1H), 2.76 (d, J = 4.6 Hz, 6H), 2.32 (s, 3H), 1.80-1.89 (m, 2H).
338 (DMSO-d6): 12.23 (s, 1H), 8.78 (d, J = 7.5 Hz, 1H), 8.29 (d, J
= 4.1 Hz, 1H), 8.01 386.4 (s, 1H), 7.19 (dd, J = 7.9, 4.7 Hz, 1H),
6.77 (s, 1H), 4.20 (t, J = 5.8 Hz, 2H), 2.73 (s, 6H), 2.53-2.58 (m,
2H), 2.24 (s, 6H), 1.90 (s, 3H). 339 (DMSO-d6): 8.71 (d, J = 7.1
Hz, 1H), 8.27 (d, J = 4.6 Hz, 1H), 7.89 (s, 1H), 7.15 428.4 (dd, J
= 7.8, 4.6 Hz, 1H), 6.37 (s, 1H), 4.10 (t, J = 5.9 Hz, 3H),
3.76-3.82 (m, 4H), 2.81-2.88 (m, 4H), 2.45-2.55 (m, 2H), 2.24 (s,
6H), 1.88 (s, 3H). 340 (DMSO-d6): 12.23 (br. s, 1H), 8.17 (d, J =
3.7 Hz, 1H), 7.80 (s, 1H), 7.67-7.74 492.4 (m, 1H), 7.08-7.17 (m,
1H), 6.78-6.84 (m, 1H), 6.70-6.78 (m, 1H), 6.60 (s, 1H), 6.53-6.58
(m, 1H), 5.81 (br. s, 1H), 4.71-4.79 (m, 1H), 4.21-4.30 (m, 2H),
3.59-3.67 (m, 2H), 3.15-3.25 (m, 2H), 2.55-2.60 (m, 2H), 2.21 (s,
6H), 2.12 (s, 3H), 1.90 (s, 3H). 341 (DMSO-d6): 12.28 (br. s, 1H),
10.45 (s, 1H), 8.18 (dd, J = 1.38, 4.64 Hz, 1H), 7.70- 429.1 7.76
(m, 2H), 7.55 (d, J = 8.03 Hz, 1H), 7.43 (s, 1H), 7.36 (d, J = 7.78
Hz, 1H), 6.85 (s, 1H), 6.77 (dd, J = 4.64, 7.91 Hz, 1H), 4.27 (q, J
= 7.03 Hz, 2H), 4.17 (s, 2H), 2.28 (s, 3H), 1.30 (t, J = 7.15 Hz,
3H) 342 (DMSO-d6): 12.19 (br. s., 1H), 9.17 (s, 1H), 8.12-8.24 (m,
3H), 7.82 (d, J = 8.03 490.2 Hz, 1H), 7.66 (s, 1H), 7.21-7.40 (m,
3H), 6.78 (dd, J = 4.64, 7.91 Hz, 1H), 6.72 (s, 1H), 4.29 (t, J =
5.77 Hz, 2H), 3.52 (s, 2H), 2.65-2.73 (m, 2H), 2.30 (s, 6H), 2.23
(s, 9H). 343 (DMSO-d6): 12.39 (br. s, 1H), 9.93 (br. s, 1H), 8.28
(dd, J = 1.26, 4.52 Hz, 1H), 463.9 7.86 (s, 1H), 7.33 (d, J = 8.53
Hz, 2H), 7.10-7.19 (m, 2H), 7.00 (dd, J = 2.76, 8.53 Hz, 1H), 5.49
(br. s, 1H), 5.04-5.17 (m, 1H), 4.99 (t, J = 5.40 Hz, 1H), 4.12 (t,
J = 4.89 Hz, 2H), 3.81 (q, J = 4.94 Hz, 2H), 2.23 (s, 3H), 1.28 (d,
J = 6.27 Hz, 6H)
TABLE-US-00016 TABLE 2-6 344 (DMSO-d6): 12.33 (s, 1H), 10.07 (s,
1H), 8.93 (d, J = 7.8 Hz, 1H), 8.33 (d, J = 399.0 3.6 Hz, 1H), 8.11
(s, 1H), 7.22 (dd, J = 8.0, 4.6 Hz, 1H), 6.86 (s, 1H), 4.11 (t, J =
6.7 Hz, 2H), 3.76-3.86 (s, 4H), 3.02-3.13 (s, 4H), 1.60-1.72 (m,
2H), 0.94 (t, J = 7.4 Hz, 3H). 345 (DMSO-d6): 12.34 (s, 1H), 10.07
(s, 1H), 8.92 (d, J = 7.5 Hz, 1H), 8.33 (d, J = 413.4 3.3 Hz, 1H),
8.11 (d, J = 2.5 Hz, 1H), 7.22 (dd, J = 8.0, 4.7 Hz, 1H), 6.86 (s,
1H), 3.94 (d, J = 6.6 Hz, 2H), 3.75-3.87 (m, 4H), 3.00-3.15 (m,
4H), 1.88-2.02 (m, 1H), 0.95 (d, J = 6.7 Hz, 6H). 346 (DMSO-d6):
12.02 (br. s, 1H), 8.89 (d, J = 7.7 Hz, 1H), 8.32 (d, J = 3.4 Hz,
1H), 401.4 8.07 (s, 1H), 7.21 (dd, J = 8.0, 4.7 Hz, 1H), 6.77 (s,
1H), 4.15 (t, J = 5.4 Hz, 2H), 3.73-3.87 (m, 4H), 3.63 (t, J = 5.4
Hz, 2H), 3.17 (s, 1H), 2.95-3.07 (m, 4H). 347 (DMSO-d6): 12.35 (s,
1H), 10.09 (s, 1H), 8.94 (d, J = 7.9 Hz, 1H), 8.33 (d, J = 411.3
3.5 Hz, 1H), 8.12 (d, J = 2.4 Hz, 1H), 7.22 (dd, J = 8.0, 4.7 Hz,
1H), 6.87 (s, 1H), 4.02 (d, J = 7.1 Hz, 2H), 3.72-3.90 (m, 4H),
3.00-3.16 (m, 4H), 1.12-1.23 (m, 1H), 0.48-0.58 (m, 2H), 0.26-0.37
(m, 2H). 348 (DMSO-d6): 12.34 (s, 1H), 10.08 (s, 1H), 8.93 (d, J =
7.7 Hz, 1H), 8.33 (d, J = 425.4 4.5 Hz, 1H), 8.12 (d, J = 2.6 Hz,
1H), 7.22 (dd, J = 8.0, 4.7 Hz, 1H), 6.82 (s, 1H), 5.15-5.22 (m,
1H), 3.75-3.87 (m, 4H), 3.02-3.13 (m, 4H), 1.83-1.96 (m, 2H),
1.63-1.78 (m, 4H), 1.50-1.62 (m, 2H). 349 (DMSO-d6): 12.24 (br. s,
1H), 10.20 (br. s, 1H), 8.88 (d, J = 7.9 Hz, 1H), 8.32 413.6 (d, J
= 3.5 Hz, 1H), 8.07 (s, 1H), 7.21 (dd, J = 8.0, 4.7 Hz, 1H), 6.72
(s, 1H), 4.94-4.79 (m, 1H), 3.74-3.88 (m, 4H), 2.90-3.14 (m, 4H),
1.48-1.70 (m, 2H), 1.23 (d, J = 6.2 Hz, 3H), 0.91 (t, J = 7.4 Hz,
3H). 350 (DMSO-d6): 12.48-12.19 (m, 1H), 10.04 (br. s, 1H), 8.93
(s, 1H), 8.33 (d, J = 413.4 3.7 Hz, 1H), 8.10 (s, 1H), 7.22 (dd, J
= 7.9, 4.7 Hz, 1H), 6.81 (s, 1H), 4.80-4.96 (m, 1H), 3.74-3.87 (m,
4H), 3.01-3.14 (m, 4H), 1.50-1.68 (m, 2H), 1.24 (d, J = 6.2 Hz,
3H), 0.91 (t, J = 7.3 Hz, 3H). 351 (DMSO-d6): 12.34 (br. s, 1H),
9.86 (br. s, 1H), 8.97 (d, J = 7.8 Hz, 1H), 8.33 (d, 480.2 J = 3.4
Hz, 1H), 8.11 (s, 1H), 7.25 (dd, J = 8.0, 4.7 Hz, 1H), 6.80 (s,
1H), 5.00- 5.09 (m, 1H), 3.30-3.40 (m, 2H), 3.01-3.13 (m, 4H),
2.81-2.94 (m, 4H), 1.27 (d, J = 6.3 Hz, 6H). 352 (DMSO-d6): 12.35
(br. s, 1H), 8.62 (br. s, 1H), 8.40 (dd, J = 8.0, 1.3 Hz, 1H),
398.0 8.32 (d, J = 4.6 Hz, 1H), 8.01 (s, 1H), 7.21 (dd, J = 7.9,
4.7 Hz, 1H), 6.86 (s, 1H), 4.99-5.13 (m, 1H), 4.18-4.31 (m, 1H),
3.87-3.99 (m, 2H), 3.39-3.54 (m, 2H), 1.80-1.97 (m, 4H), 1.27 (d, J
= 6.3 Hz, 6H). 353 (DMSO-d6): 12.36 (s, 1H), 10.43 (br. s, 1H),
8.88 (d, J = 6.5 Hz, 1H), 8.35 (d, 447.2 J = 3.5 Hz, 1H), 8.14 (s,
1H), 7.17 (dd, J = 8.0, 4.7 Hz, 1H), 6.86 (s, 1H), 4.99- 5.11 (m,
1H), 3.47-3.62 (m, 4H), 3.35-3.42 (m, 4H), 1.27 (d, J = 6.2 Hz,
6H). 354 (DMSO-d6): 12.36 (br. s, 1H), 8.39 (d, J = 7.9 Hz, 1H),
8.33 (d, J = 4.7 Hz, 1H), 460.2 8.07 (s, 1H), 7.16-7.26 (m, 2H),
6.80-6.92 (m, 3H), 5.01-5.12 (m, 1H), 4.94 (br. s, 2H), 3.83-4.02
(m, 2H), 3.76 (s, 3H), 3.00 (t, J = 5.7 Hz, 2H), 1.27 (d, J = 6.2
Hz, 6H). 355 (DMSO-d6): 13.04 (br. s, 1H), 8.40 (dd, J = 7.9, 1.4
Hz, 1H), 8.33 (dd, J = 4.6, 444.2 1.3 Hz, 1H), 8.07 (s, 1H), 7.22
(dd, J = 7.9, 4.7 Hz, 1H), 7.16 (d, J = 7.7 Hz, 1H), 7.08 (d, J =
7.1 Hz, 2H), 6.87 (s, 1H), 5.00-5.12 (m, 1H), 4.93 (br. s, 2H),
3.88-3.98 (m, 2H), 3.03 (t, J = 5.5 Hz, 2H), 2.30 (s, 3H), 1.89 (s,
3H), 1.28 (d, J = 6.2 Hz, 6H). 356 (DMSO-d6): 11.33 (br. s, 1H),
8.39 (dd, J = 7.9, 1.4 Hz, 1H), 8.33 (dd, J = 4.6, 464.2 1.3 Hz,
1H), 8.09 (s, 1H), 7.42 (s, 1H), 7.32 (s, 2H), 7.22 (dd, J = 7.9,
4.7 Hz, 1H), 6.88 (s, 1H), 4.94-5.11 (m, 3H), 3.87-4.00 (m, 2H),
3.07 (t, J = 5.7 Hz, 2H), 1.89 (s, 3H), 1.27 (t, J = 6.0 Hz, 6H).
357 (MeOD): 9.17 (s, 1H), 8.16-8.34 (m, 3H), 7.19-7.27 (m, 3H),
6.94-7.04 (m, 448.0 2H), 5.14-5.28 (m, 1H), 4.93 (br. s, 2H), 3.99
(t, J = 5.8 Hz, 2H), 3.05 (t, J = 5.5 Hz, 2H), 1.37 (d, J = 6.3 Hz,
6H). 358 (DMSO-d6): 12.36 (s, 1H), 8.39 (d, J = 7.9 Hz, 1H), 8.33
(d, J = 4.6 Hz, 1H), 8.06 460.2 (s, 1H), 7.18-7.28 (m, 2H),
6.81-6.94 (m, 3H), 5.00-5.11 (m, 1H), 4.96 (s, 2H), 3.91-4.06 (m,
2H), 3.81 (s, 3H), 2.94 (t, J = 5.7 Hz, 2H), 1.28 (d, J = 6.2 Hz,
6H). 359 (DMSO-d6): 12.34 (br. s, 1H), 8.39 (dd, J = 7.9, 1.1 Hz,
1H), 8.33 (dd, J = 4.6, 460.4 1.1 Hz, 1H), 8.06 (s, 1H), 7.17-7.25
(m, 2H), 6.82-6.90 (m, 3H), 5.00-5.10 (m, 1H), 4.89 (br. s, 2H),
3.84-4.00 (m, 2H), 3.76 (s, 3H), 3.05 (t, J = 5.7 Hz, 2H), 1.27 (d,
J = 6.2 Hz, 6H).
Biological activities of several compounds of the present invention
were measured according to the methods mentioned blow.
[Preparation and Storage of Solutions of Test Compounds]
A test compound was dissolved or suspended in DMSO so as to be at
10 mM or 1 mM, thereby making a stock solution, which was stored at
-20.degree. C. in the dark before being tested.
Test Example 1
[Inhibitory Effect on Cdc7 Protein Kinase]
Measurement of kinase activity was carried out using an MSA assay
kit (QuickScout Screening Assist.TM. Kit, Carna Biosciences,
Inc.).
Assay buffer (20 mM HEPES, 0.01% Triton X-100.TM., 2 mM
dithiothreitol, pH 7.5) was used to prepare a substrate mixture
solution comprising 4 .mu.M of a kinase-reaction substrate
(FITC-labeled MCM2 peptide), 40 mM MgCl.sub.2, and 20 .mu.M
ATP.
The enzyme supplied in the kit (human Cdc7/human ASK complex
protein) was diluted in the assay buffer so as to be at 7 nM,
thereby preparing an enzyme solution.
The stock solution of each test compound was diluted in DMSO to
prepare diluted DMSO solutions of 10 concentrations (0.00003 mM,
0.0001 mM, 0.0003 mM, 0.001 mM, 0.003 mM, 0.01 mM, 0.03 mM, 0.1 mM,
0.3 mM, 1 mM), each of which was further diluted 25 times in the
assay buffer to make a drug solution (a solution containing 4%
DMSO).
The kinase reaction was performed in wells of a polypropylene
384-well plate in which 5 .mu.l of each of the drug solutions or of
a solvent (assay buffer containing 4% DMSO), 5 .mu.l of the
substrate mixture solution, and 10 .mu.l of the enzyme solution
were mixed. The assay buffer, instead of the enzyme solution, was
added to blank wells. After the reaction at room temperature for 5
hours, 60 .mu.l of the termination buffer supplied in the kit was
added to each well to stop the reaction. The percent inhibition of
each reaction was determined using a LabChip EZ Reader II system
(manufactured by Caliper Life Sciences), according to the protocol
provided with the assay kit. In this case, the peak heights of the
separated substrate and the phosphorylated substrate were
represented as S and P, respectively, and the percent inhibition
(%) by a tested compound was calculated according to the following
formula: Percent inhibition(%)=(1-(C-A)/(B-A)).times.100 wherein A
denotes P/(P+S) for a blank well, B denotes P/(P+S) for a solvent
well, and C denotes P/(P+S) for a compound-added well.
The IC.sub.50 value of a tested compound was calculated by
regression analysis of the percent inhibition values versus the
(logarithmic) concentrations of the tested compound.
The IC.sub.50 values of several compounds of the present invention
against Cdc7 were all less than 1 .mu.M, as shown in Table 4
below.
Test Example 2
[Inhibitory Effect on Phosphorylation Using Cells]
Cultured Cells
COLO205 cells derived from human colon adenocarcinoma (RCB2127,
RIKEN BRC) were cultured in 10 cm dishes using RPMI-1640 medium
(SIGMA, R8758) supplemented with 10% FCS (Equitech-bio) and 5%
penicillin/streptomycin (GIBCO, 15140). After the cells were
cultured to a confluence of 70 to 90%, the medium was removed, and
the cells were treated with trypsin (2 mL, TrypLE Express, GIBCO,
12604-021) and then harvested using a new medium.
Addition of Drugs to Cultured Cells
COLO205 cells were seeded in 6-well plates (FALCON, 35046) to
2.5.times.10.sup.5 cells (1 ml) per well and cultured overnight in
a 5% CO.sub.2 incubator. A drug solution, which was prepared by
adding 1.5 .mu.l of a 0.1-mM stock solution in DMSO of a test
compound to 500 .mu.l of medium, was added to each well (to a final
drug concentration of 0.1 .mu.M), and then cultured for another 24
hours.
Determination of Inhibitory Effect on MCM2 Phosphorylation
Cells were cultured for 24 hours in the presence of a test
compound, harvested using a similar way as described above, washed
with PBS, and then pelletized and stored at -80.degree. C. The
frozen cells were thawed, subsequently suspended immediately in
2.times.SDS-PAGE electrophoresis buffer (1.times.10.sup.5 cells per
10 .mu.l), and heated at 95.degree. C. for 10 minutes, leading to
the dissolution and denaturation of the proteins. The resulting
sample solutions were subjected to SDS-PAGE using a 5-20% gradient
acrylamide gel (e-PAGEL (5-20%), ATTO, E-T520L). After the
electrophoresis was completed, the gel was immersed in tris-glycine
buffer supplemented with 20% methanol, and the proteins in the gel
were transferred onto a PVDF membrane (MILLIPORE, Immobilon-P,
IPVH00010) using a semi-dry transfer apparatus (TRNS-BLOT SD
SEMI-DRY TRANSFER CELL, BIO RAD).
The transferred PVDF membrane was blocked with 5% skim milk (Difco
Skim Milk, BD, 232100), and then subjected to reaction with an
anti-MCM2 goat antibody (N-19, Santa Cruz, sc-9839) or
anti-phosphorylated MCM2 rabbit antibody (S53) (Bethyl, A300-756A)
as a primary antibody and additionally with an anti-.alpha. tubulin
mouse antibody (Clone DM 1A, SIGMA, 9026) as an internal control.
Each band was detected by chemiluminescence using an HRP-labeled
anti-goat IgG donkey antibody (Santa Cruz, sc2020), anti-rabbit IgG
sheep antibody (Roche, 12015218001), or anti-mouse IgG donkey
antibody (Jackson ImmunoResearch, 715-035-151) as a secondary
antibody. The combinations of and the diluted concentrations of the
primary and secondary antibodies were as indicated below.
TABLE-US-00017 TABLE 3 Primary antibody Secondary antibody (diluted
concentration) (diluted concentration) 1 Anti-MCM2 goat antibody
Anti-goat IgG donkey (1/500) antibody (1/10000) 2
Anti-phosphorylated MCM2 Anti-rabbit IgG sheep rabbit antibody
(S53) antibody (1/5000) (1/500) 3 Anti-.alpha.-tubulin mouse
Anti-mouse IgG donkey antibody (1/1000) antibody (1/100000)
The bands which were detected were normalized using the amount of
endogenous .alpha.-tubulin as a reference, and the percent
phosphorylation of MCM2 was calculated for each of the tested
compounds. Their inhibitory effects on MCM2 phosphorylation were
indicated by a triple asterisk (***) in the case where the percent
phosphorylation of MCM2 was less than 20%, by a dual asterisk (**)
in the case where the percent phosphorylation of MCM2 was not less
than 20% and less than 50%, and by a single asterisk (*) in the
case where the percent phosphorylation of MCM2 was not less than
50% and less than 70%.
It was found from this testing that as shown in Table-4, the tested
compounds of the present invention inhibited the phosphorylation of
MCM2 at a concentration of 0.1 .mu.M.
TABLE-US-00018 TABLE 4 Test Example 2 Test Example 1 Inhibitory
effect on Example Cdc7 IC.sub.50 value (.mu.M) MCM2 phosphorylation
15 0.002 ** 22 0.010 * 63 0.006 *** 68 0.004 *** 78 0.011 *** 81
0.005 *** 89 0.003 *** 91 0.004 *** 102 0.004 *** 126 0.003 *** 129
0.009 *** 142 0.003 ** 157 0.003 ** 173 0.003 *** 226 0.004 *** 233
0.002 ** 239 0.001 ** 242 0.001 *** 244 0.004 *** 245 0.008 *** 246
0.008 ***
INDUSTRIAL APPLICABILITY
The compounds provided by the present invention are capable of
controlling the growth of cells through their inhibitory effects on
Cdc7. Therefore, the compounds of the present invention which have
an inhibitory effect on Cdc7 will be useful as a medicine,
especially an agent for the treatment of diseases derived from
abnormal growth of cells, such as cancers.
* * * * *