U.S. patent application number 10/851902 was filed with the patent office on 2007-10-18 for pyrrolopyridine-2-carboxylic acid amide inhibitors of glycogen phosphorylase.
Invention is credited to Stuart Edward Bradley, Thomas Martin Krulle, Peter John Murray, Martin James Procter, Robert John Rowley, Colin Peter Sambrook Smith, Gerard Hugh Thomas.
Application Number | 20070244090 10/851902 |
Document ID | / |
Family ID | 35375984 |
Filed Date | 2007-10-18 |
United States Patent
Application |
20070244090 |
Kind Code |
A9 |
Bradley; Stuart Edward ; et
al. |
October 18, 2007 |
PYRROLOPYRIDINE-2-CARBOXYLIC ACID AMIDE INHIBITORS OF GLYCOGEN
PHOSPHORYLASE
Abstract
Compounds represented by Formula (I): ##STR1## or
pharmaceutically acceptable salts thereof, are inhibitors of
glycogen phosphorylase and are useful in the prophylactic or
therapeutic treatment of diabetes, hyperglycemia,
hypercholesterolemia, hyperinsulinemia, hyperlipidemia,
hypertension, atherosclerosis or tissue ischemia e.g. myocardial
ischemia, and as cardioprotectants.
Inventors: |
Bradley; Stuart Edward;
(Oxford, GB) ; Krulle; Thomas Martin; (Oxford,
GB) ; Murray; Peter John; (Oxford, GB) ;
Procter; Martin James; (Oxford, GB) ; Rowley; Robert
John; (Oxford, GB) ; Sambrook Smith; Colin Peter;
(Oxford, GB) ; Thomas; Gerard Hugh; (Oxford,
GB) |
Correspondence
Address: |
OSI Pharmaceuticals, Inc.
41 Pinelawn Road
Melville
NY
11747
US
|
Prior
Publication: |
|
Document Identifier |
Publication Date |
|
US 20050261272 A1 |
November 24, 2005 |
|
|
Family ID: |
35375984 |
Appl. No.: |
10/851902 |
Filed: |
May 20, 2004 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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60551256 |
Mar 8, 2004 |
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60472375 |
May 21, 2003 |
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Current U.S.
Class: |
514/210.21 ;
514/218; 514/227.8; 514/234.2; 514/300; 544/125; 544/362; 544/60;
546/113 |
Current CPC
Class: |
A61P 3/10 20180101; C07D
471/04 20130101 |
Class at
Publication: |
514/210.21 ;
546/113; 544/362; 544/125; 544/060; 514/300; 514/234.2; 514/227.8;
514/218 |
International
Class: |
A61K 31/541 20060101
A61K031/541; A61K 31/551 20060101 A61K031/551; A61K 31/5377
20060101 A61K031/5377; A61K 31/496 20060101 A61K031/496; A61K
31/4745 20060101 A61K031/4745; C07D 471/02 20060101 C07D471/02 |
Claims
1. A compound of Formula (I): ##STR452## or a stereoisomer, or a
pharmaceutically acceptable salt thereof, wherein: one of X.sub.1,
X.sub.2, X.sub.3 and X.sub.4 must be N and the others must be C;
R.sup.1 and R.sup.1' are each independently, halogen, hydroxy,
cyano, C.sub.0-4alkyl, C.sub.1-4alkoxy, fluoromethyl,
difluoromethyl, trifluoromethyl, ethenyl, or ethynyl; R.sup.2 is
C.sub.0-4alkyl, COOR.sup.6, COR.sup.6,
C.sub.1-4alkoxyC.sub.1-4alkyl-, hydroxyC.sub.1-4alkyl-,
cycloalkylC.sub.0-4alkyl-, arylC.sub.0-4alkyl-,
hetarylC.sub.0-4alkyl-, wherein any of the aryl or hetaryl rings
are optionally substituted with 1-2 independent halogen, cyano,
C.sub.1-4alkyl, C.sub.1-4alkoxy,
--N(C.sub.0-4alkyl)(C.sub.0-4alkyl), --SO.sub.2C.sub.1-4alkyl,
--SO.sub.2N(C.sub.0-4alkyl)(C.sub.0-4alkyl), hydroxy, fluoromethyl,
difluoromethyl, or trifluoromethyl substituents; Y is
C.sub.0-2alkyl or --CH(OH)--; Z is CH.sub.2, --C(O)--, --O--,
>N(C.sub.0-4alkyl), >N(C.sub.3-6cycloalkyl), or absent; but
when Y is --CH(OH)--, Z or R.sup.3 must be bonded to Y through a
carbon-carbon bond; R.sup.3 is hydrogen, --COOC.sub.0-4alkyl,
C.sub.1-4alkoxy, C.sub.1-4alkyl, arylC.sub.1-4alkylthio-,
--C.sub.0-4alkylaryl, --C.sub.0-4alkyhetaryl,
--C.sub.0-4alkylcycloalkyl or --C.sub.0-4alkylheterocyclyl, wherein
any of the rings is optionally substituted with 1-3 independent
halogen, cyano, C.sub.1-4alkyl, fluoromethyl, difluoromethyl,
trifluoromethyl, --C.sub.0-4alkylNHC(O)O(C.sub.1-4alkyl),
--C.sub.0-4alkylNR.sup.7R.sup.8, --C(O)R.sup.9,
C.sub.1-4alkoxyC.sub.0-4alkyl-, --COOC.sub.0-4alkyl,
--C.sub.0-4alkylNHC(O)R.sup.9,
--C.sub.0-4alkylC(O)N(R.sup.10).sub.2,
--C.sub.1-4alkoxyC.sub.1-4alkoxy, hydroxyC.sub.0-4alkyl-,
--NHSO.sub.2R.sup.10, --SO.sub.2(C.sub.1-4alkyl),
--SO.sub.2NR.sup.11R.sup.12, 5- to 6-membered heterocyclyl,
phenylC.sub.0-2alkoxy, or phenylC.sub.0-2alkyl substituents,
wherein phenyl is optionally substituted with 1-2 independent
halogen, cyano, C.sub.1-4alkyl, C.sub.1-4alkoxy,
--N(C.sub.0-4alkyl)(C.sub.0-4alkyl), --SO.sub.2C.sub.1-4alkyl,
--SO.sub.2N(C.sub.0-4alkyl)(C.sub.0-4alkyl), hydroxy, fluoromethyl,
difluoromethyl or trifluoromethyl substituents, or two bonds on a
ring carbon of the heterocyclyl group optionally can form an oxo
(.dbd.O) substituent; or R.sup.3 is
--NR.sup.4(--C.sub.0-4alkylR.sup.5); R.sup.4 is C.sub.0-3alkyl,
--C.sub.2-3alkyl-NR.sup.7R.sup.8, C.sub.3-6cycloalkyl optionally
substituted by hydroxyC.sub.0-4alkyl- further optionally
substituted by hydroxy, C.sub.1-2alkoxyC.sub.2-4alkyl-, or
C.sub.1-2alkyl-S(O).sub.n--C.sub.2-3alkyl-; n is O, 1, or 2;
R.sup.5 is hydrogen, hydroxyC.sub.2-3alkyl-,
C.sub.1-2alkoxyC.sub.0-4alkyl-, or aryl, hetaryl, or heterocyclyl;
wherein a heterocyclic nitrogen-containing R.sup.5 ring optionally
is mono-substituted on the ring nitrogen with C.sub.1-4alkyl,
benzyl, benzoyl, C.sub.1-4alkyl-C(O)--, --SO.sub.2C.sub.1-4alkyl,
--SO.sub.2N(C.sub.0-4alkyl)(C.sub.0-4alkyl),
C.sub.1-4alkoxycarbonyl or aryl(C.sub.1-4alkoxy)carbonyl; and
wherein the R.sup.5 rings are optionally mono-substituted on a ring
carbon with halogen, cyano, C.sub.1-4alkyl-C(O)--,
C.sub.1-4alkyl-SO.sub.2--, C.sub.1-4alkyl, C.sub.1-4alkoxy,
hydroxy, --N(C.sub.0-4alkyl)(C.sub.0-4alkyl),
hydroxyC.sub.0-4alkyl-, or C.sub.0-4alkylcarbamoyl-, provided that
no quaternised nitrogen is included; or two bonds on a ring carbon
of the heterocyclyl group optionally can form an oxo (.dbd.O)
substituent; R.sup.6 is C.sub.1-4alkyl, aryl, or hetaryl; R.sup.7
and R.sup.8 are independently C.sub.0-4alkyl, C.sub.3-6cycloalkyl,
or CO(C.sub.1-4alkyl); R.sup.9 is C.sub.1-4alkyl, or
C.sub.3-6cycloalkyl; R.sup.10 is C.sub.0-4alkyl, or
C.sub.3-6cycloalkyl; R.sup.11 and R.sup.12 are independently
C.sub.0-4alkyl or together with the nitrogen to which they are
attached may form a 4- to 6-membered heterocycle; and wherein there
are no nitrogen-oxygen, nitrogen-nitrogen or nitrogen-halogen bonds
in linking the three components --Y-Z-R.sup.3 to each other.
2. A compound according to claim 1, or a stereoisomer, or a
pharmaceutically acceptable salt thereof, wherein X.sub.3 is N.
3. A compound according to claim 1, or a stereoisomer, or a
pharmaceutically acceptable salt thereof, wherein X.sub.1 is N.
4. A compound according to claim 1, or a stereoisomer, or a
pharmaceutically acceptable salt thereof, wherein X.sub.2 is N.
5. A compound according to claim 1, or a stereoisomer, or a
pharmaceutically acceptable salt thereof, wherein X.sub.4 is N.
6. A compound according to claim 1, or a stereoisomer, or a
pharmaceutically acceptable salt thereof, wherein R.sup.1 and
R.sup.1' are each independently, halogen, cyano or hydrogen.
7. A compound according to claim 6, or a stereoisomer, or a
pharmaceutically acceptable salt thereof, wherein one of R.sup.1
and R.sup.1' is hydrogen and the other is a 5-halo or 5-cyano
group.
8. A compound according to claim 1, or a stereoisomer, or a
pharmaceutically acceptable salt thereof, wherein Y is
C.sub.0-2alkyl.
9. A compound according to claim 1, wherein Z is --(O)--.
10. A compound according to claim 1, or a stereoisomer, or a
pharmaceutically acceptable salt thereof, wherein X.sub.3 is N; Y
is C.sub.0-2alkyl; and Z is --C(O)--.
11. A compound according to claim 8, or a stereoisomer, or a
pharmaceutically acceptable salt thereof, wherein Y is a direct
bond.
12. A compound according to claim 1, or a stereoisomer, or a
pharmaceutically acceptable salt thereof, wherein R.sup.2 is
C.sub.0-4alkyl or arylC.sub.0-4alkyl-, wherein the aryl ring is
optionally substituted with 1-2 independent halogen, cyano,
C.sub.1-4alkyl, C.sub.1-4alkoxy,
--N(C.sub.0-4alkyl)(C.sub.0-4alkyl), --SO.sub.2C.sub.1-4alkyl,
--SO.sub.2N(C.sub.0-4alkyl)(C.sub.0-4alkyl), hydroxy, fluoromethyl,
difluoromethyl, or trifluoromethyl substituents.
13. A compound according to claim 12, or a stereoisomer, or a
pharmaceutically acceptable salt thereof, wherein R.sup.2 is benzyl
optionally substituted with 1-2 halogen substituents.
14. A compound according to claim 1, or a stereoisomer, or a
pharmaceutically acceptable salt thereof, wherein R.sup.3 is
--C.sub.0-4alkylheterocyclyl optionally substituted with 1-3
independent halogen, cyano, C.sub.1-4alkyl, fluoromethyl,
difluoromethyl, trifluoromethyl,
--C.sub.0-4alkylNHC(O)O(C.sub.0-4alkyl),
--C.sub.0-4alkylNR.sup.7R.sup.8, --C(O)R.sup.9,
C.sub.1-4alkoxyC.sub.0-4alkyl-, --COOC.sub.4alkyl,
--C.sub.0-4alkylNHC(O)R.sup.9,
--C.sub.0-4alkylC(O)N(R.sup.10).sub.2,
--C.sub.0-4alkoxyC.sub.1-4alkoxy, hydroxyC.sub.0-4alkyl,
--NHSO.sub.2R.sup.10, --SO.sub.2(C.sub.1-4alkyl),
--SO.sub.2NR.sup.11R.sup.12, 5- to 6-membered heterocyclyl,
phenylC.sub.0-2alkoxy or phenylC.sub.0-2alkyl substituents, wherein
phenyl is optionally substituted with 1-2 independent halogen,
cyano, C.sub.1-4alkyl, C.sub.1-4alkoxy,
--N(C.sub.0-4alkyl)(C.sub.0-4alkyl), --SO.sub.2C.sub.1-4alkyl,
--SO.sub.2N(C.sub.0-4alkyl)(C.sub.0-4alkyl), hydroxy, fluoromethyl,
difluoromethyl, or trifluoromethyl substituents, or two bonds on a
ring carbon of the heterocyclyl group optionally can form an oxo
(.dbd.O) substituent; or R.sup.3 is
--NR.sup.4(--C.sub.0-4alkylR.sup.5).
15. A compound according to claim 14, wherein R.sup.3 is an
optionally substituted nitrogen containing heterocyclyl group,
linked to Z via a ring nitrogen atom; or R.sup.3 is
--NR.sup.4(--C.sub.0-4alkylR.sup.5).
16. A compound according to claim 15, wherein R.sup.3 is an
optionally substituted 4-8-membered nitrogen containing
heterocyclyl group.
17. A compound according to claim 16, or a stereoisomer, or a
pharmaceutically acceptable salt thereof, wherein R.sup.3 is
pyrrolidin-1-yl or piperidin-1-yl optionally substituted with
hydroxy.
18. A compound selected from the following: ##STR453## ##STR454##
##STR455## ##STR456## ##STR457## ##STR458## ##STR459## ##STR460##
##STR461## ##STR462## ##STR463## ##STR464## ##STR465## ##STR466##
##STR467## ##STR468## ##STR469## ##STR470## ##STR471## ##STR472##
##STR473## ##STR474## ##STR475## ##STR476## ##STR477## ##STR478##
##STR479## ##STR480## ##STR481## ##STR482## ##STR483## ##STR484##
##STR485## ##STR486## ##STR487## ##STR488## ##STR489## ##STR490##
##STR491## ##STR492## ##STR493## ##STR494## ##STR495## ##STR496##
##STR497## or a pharmaceutically acceptable salt thereof.
19. A compound selected from the following: ##STR498## or a
pharmaceutically acceptable salt thereof.
20. A compound selected from the following: ##STR499## ##STR500##
##STR501## ##STR502## ##STR503## or a pharmaceutically acceptable
salt thereof.
21. A compound selected from the following: ##STR504## or a
pharmaceutically acceptable salt thereof.
22. A composition comprising a compound according to claim 1, or a
stereoisomer, or a pharmaceutically acceptable salt thereof; and a
pharmaceutically acceptable carrier.
23. A method of prophylactic or therapeutic treatment of
hyperglycemia or diabetes comprising a step of administering an
effective amount of the compound according to claim 1, or a
stereoisomer, or a pharmaceutically acceptable salt thereof.
24. A method of prevention of diabetes in a human demonstrating
pre-diabetic hyperglycemia or impaired glucose tolerance comprising
a step of administering an effective prophylactic amount of the
compound according to claim 1, or a stereoisomer, or a
pharmaceutically acceptable salt thereof.
25. A method of prophylactic or therapeutic treatment of
hypercholesterolemia, hyperinsulinemia, hyperlipidemia,
atherosclerosis or myocardial ischemia comprising a step of
administering an effective amount of the compound according to
claim 1, or a stereoisomer, or a pharmaceutically acceptable salt
thereof.
26. A method of cardioprotection comprising a step of administering
to a subject in need thereof an effective amount of a compound of a
compound according to claim 1, or a stereoisomer or a
pharmaceutically acceptable salt thereof.
27. A process for the production of a compound of Formula (I)
according to claim 1, comprising: ##STR505## coupling a
pyrrolopyridine-2-carboxylic acid of Formula (II), or a protected
or activated derivative thereof, with an amine of Formula (III); or
##STR506## for compounds of Formula (I) wherein Z is C.dbd.O and
R.sup.3 is --NR.sup.4(--C.sub.0-4alkylR.sup.5), coupling a
carboxylic acid of Formula (I), or a protected or activated
derivative thereof, wherein Z is absent and R.sup.3 is --CO.sub.2H,
with an amine of Formula (IV); or ##STR507## for compounds of
Formula (III) wherein R.sup.2 is H, Y is C.sub.0 alkyl, Z is
--C(O)-- and R.sup.3 is --C.sub.0alkylaryl or --C.sub.0alkylhetaryl
coupling of a compound of Formula (XX) with a compound of Formula
(II) under standard coupling conditions to give a compound of
Formula (XIX), followed by removal of the ketal group in the
presence of acid; and ##STR508## for compounds of Formula (I)
wherein Z is C.dbd.O and R.sup.3 is C.sub.1-4alkoxy, coupling a
compound of Formula (II), or a protected or activated derivative
thereof, and a compound of Formula (XII); or e) for compounds of
Formula (I) wherein Z is absent and R.sup.3 is --CO.sub.2H, ester
hydrolysis of compounds of Formula (I) where Z is C.dbd.O and
R.sup.3 is a C.sub.1-4alkoxy group.
28. A compound of Formula (IIA): ##STR509## or a C.sub.1-4alkyl
ester or protected derivative thereof, wherein: one of X.sub.1,
X.sub.2, X.sub.3 and X.sub.4 must be N and the others must be C;
R.sup.1 and R.sup.1' are each independently, halogen, hydroxyl,
cyano, C.sub.0-4alkyl, C.sub.1-4alkoxy, fluoromethyl,
difluoromethyl, trifluoromethyl, ethenyl, or ethynyl or absent;
provided that when X.sub.1, X.sub.3 or X.sub.4 is N, then R.sup.1
and R.sup.1' are not both hydrogen.
29. A compound selected from:
5-Chloro-1H-pyrrolo[3,2-b]pyridine-2-carboxylic acid;
5-Bromo-1H-pyrrolo[3,2-b]pyridine-2-carboxylic acid;
5-Cyano-1H-pyrrolo[3,2-b]pyridine-2-carboxylic acid;
5-Methoxy-1H-pyrrolo[3,2-b]pyridine-2-carboxylic acid;
1H-Pyrrolo[3,2-c]pyridine-2-carboxylic acid;
6-Chloro-1H-pyrrolo[3,2-c]pyridine-2-carboxylic acid;
6-Cyano-1H-pyrrolo[3,2-c]pyridine-2-carboxylic acid;
5-Chloro-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid;
5-Bromo-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid;
5-Ethynyl-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid;
5-Cyano-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid;
5-Methyl-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid;
5-Chloro-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid;
6-Chloro-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid; and
6-Cyano-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid. or a
C.sub.1-4alkyl ester of any one thereof.
30. A compound of formula (XIX): ##STR510## wherein R.sup.1,
R.sup.1', X.sub.1, X.sub.2, X.sub.3, and X.sub.4 are as defined in
claim 1 and R.sup.3 is --C.sub.0alkylaryl or
--C.sub.0alkylhetaryl.
31. A compound consisting of
4(S)-(4-fluorobenzyl)oxazolidine-2,5-dione.
Description
BACKGROUND OF THE INVENTION
[0001] The present invention is directed to
pyrrolopyridine-2-carboxylic acid amides. In particular, the
present invention is directed to pyrrolopyridine-2-carboxylic acid
amides that are inhibitors of glycogen phosphorylase.
[0002] Insulin dependent Type I diabetes and non-insulin dependent
Type II diabetes continue to present treatment difficulties even
though clinically accepted regimens that include diet, exercise,
hypoglycemic agents, and insulin are available. Treatment is
patient dependent--therefore there is a continuing need for novel
hypoglycemic agents, particularly ones that may be better tolerated
with fewer adverse effects.
[0003] The liver and certain other organs produce glucose--thereby
raising the blood sugar level--by breaking down glycogen or by
synthesizing glucose from small molecule precursors. The breakdown
of glycogen is catalyzed by glycogen phosphorylase enzyme.
Accordingly, inhibiting glycogen phosphorylase ("GP") may lower the
elevated blood sugar level in diabetic patients.
[0004] Similarly, hypertension and its associated pathologies such
as, for example, atherosclerosis, lipidemia, hyperlipidemia and
hypercholesterolemia have been associated with elevated insulin
levels (hyperinsulinemia), which can lead to abnormal blood sugar
levels. Furthermore, myocardial ischemia can result. Such maladies
may be treated with hypoglycemic agents, including compounds that
inhibit glycogen phosphorylase. The cardioprotective effects of
glycogen phosphorylase inhibitors, for example following
reperfusion injury, has also been described (see, for example, Ross
et al., American Journal of Physiology. Heart and Circulatory
Physiology, March 2004, 286(3), H1177-84). Accordingly, it is
accepted that compounds that inhibit glycogen phosphorylase (see,
for example, U.S. Pat. No. 6,297,269) are useful in the treatment
of diabetes, hyperglycemia, hypercholesterolemia, hyperinsulinemia,
hyperlipidemia, atherosclerosis or myocardial ischemia.
Nevertheless, it would be desirable to obtain other novel compounds
that inhibit glycogen phosphorylase.
[0005] R. Kurukulasuriya, J. T. Link, et al., Current Medicinal
Chem., 10:99-121(2003) describes "Prospects for Pharmacologic
Inhibition of Hepatic Glucose Production." R. Kurukulasuriya, J. T.
Link, et al., Current Medicinal Chem., 10:123-153(2003) describes
"Potential Drug Targets and Progress Towards Pharmacologic
Inhibition of Hepatic Glucose Production."
[0006] U.S. Pat. No. 6,297,269 and European Patent Application No.
EP 0832066 describe substituted N-(indole-2-carbonyl)amides and
derivatives as glycogen phosphorylase inhibitors. U.S. Pat. Nos.
6,107,329 and 6,277,877 describe substituted
N-(indole-2-carbonyl)glycinamides and derivatives as glycogen
phosphorylase inhibitors. U.S. Pat. No. 6,399,601 describes
bicyclic pyrrolyl amides as glycogen phosphorylase inhibitors.
European Patent Application Nos. EP 0978276 and EP 1136071 describe
inhibitors of human glycogen phosphorylase and their use.
International Patent Publication No. WO 01/68055 describes glycogen
phosphorylase inhibitors. U.S. Pat. No. 5,952,322 describes a
method of reducing non-cardiac ischemial tissue damage using
glycogen phosphorylase inhibitors.
[0007] International Patent Publication No. WO 01/55146 describes
arylamidines. International Patent Publication No. WO 01/62775
describes antiarrhythmic peptides. International Patent Publication
No. WO 01/96346 describes tricyclic compounds. International Patent
Publication No. WO 02/16314 describes substituted polyamine
compounds. International Patent Publication No. WO 02/20475
describes serine protease activity inhibitors. International Patent
Publication No. WO 02/40469 describes bombesin receptor
antagonists. International Patent Publication No. WO 02/46159
describes guanidine and amidine derivatives. International Patent
Publication No. WO 00/69815 describes ureido-substituted cyclic
amine derivatives.
[0008] International Patent Publication No. WO 00/43384 describes
aromatic heterocyclic compounds. International Patent Publication
Nos. WO 02/26697 and WO 00/76970 describe aromatic derivatives.
International Patent Publication No. WO 01/32622 describes indoles.
European Patent Application No. EP 1101759 describes phenylazole
compounds. European Patent Application No. EP 1179341 describes
cyclic amino compounds. U.S. Pat. No. 6,037,325 describes
substituted heterocyclic compounds. U.S. Pat. No. 5,672,582
describes 4-substituted cyclohexylamine derivatives. European
Patent Application No. EP 1201239 describes cyclic amine CCR3
antagonists. International Patent Publication No. WO 98/25617
describes substituted aryl piperazines. U.S. Pat. No. 5,756,810
describes preparing 3-nitrobenzoate compounds.
[0009] U.S. Pat. No. 5,710,153 describes tetrazole compounds. U.S.
Pat. Nos. 6,174,887 and 6,420,561 describe amide compounds. S. P.
Hiremath et al., Acta Ciencia Indica, XVIII:397(1992) describes the
synthesis and biological activities of indolylthiosemicarbazides
and semicarbazides. International Patent Publication No. WO
96/36595 describes 3,4-disubstituted phenylsulfonamides. U.S. Pat.
No. 5,618,825 describes combinatorial sulfonamide libraries.
European Patent Application No. EP 0810221 describes
oxygen-containing heterocyclic derivatives. European Patent
Application No. EP 0345990 describes polypeptide compounds.
European Patent Application No. EP 0254545 describes diamine
compounds.
[0010] International Patent Publication No. WO 97/31016 describes
inhibitors of SH2-mediated processes. U.S. Pat. No. 6,034,067
describes serine protease inhibitors. International Patent
Publication No. WO 97/17985 and U.S. Pat. No. 6,107,309 describe
hemoregulatory compounds. U.S. Pat. No. 6,432,921 describes
thrombin inhibitors. U.K. Patent Application No. GB 2292149
describes peptide inhibitors of pro-interleukin-1.beta. converting
enzyme. U.S. Pat. No. 5,821,241 describes fibrinogen receptor
antagonists.
[0011] International Patent Publication No. WO 01/02424 describes
peptide boronic acid compounds. U.S. Pat. Nos. 6,001,811, 5,869,455
and 5,618,792 describe oxadiazole, thiadiazole and triazole
peptoids. U.S. Pat. Nos. 5,885,967, 6,090,787 and 6,124,277
describe thrombin inhibiting peptide derivatives. U.S. Pat. No.
6,455,529 describes adhesion receptor antagonists. U.S. Pat. No.
6,410,684 describes serine protease inhibitors.
[0012] International Patent Publication No. WO 01/94310 describes
bis-heterocyclic alkaloids. U.S. Patent Publication No.
20030004162A1, European Patent Application No. EP 0846464, and
International Publication No. WO 96/39384 describe glycogen
phosphorylase inhibitors. International Patent Publication No. WO
97/28798 describes pyrrolidine derivatives. U.S. Pat. No. 5,346,907
describes amino acid analogs.
SUMMARY OF THE INVENTION
[0013] Compounds represented by Formula (I): ##STR2## or
stereoisomers or pharmaceutically acceptable salts thereof, are
inhibitors of glycogen phosphorylase and are useful in the
prophylactic or therapeutic treatment of diabetes, hyperglycemia,
hypercholesterolemia, hyperinsulinemia, hyperlipidemia,
hypertension, atherosclerosis or tissue ischemia e.g. myocardial
ischemia, and as cardioprotectants.
DETAILED DESCRIPTION OF THE INVENTION
[0014] The present invention is directed to a compound of Formula
(I): ##STR3## or a stereoisomer, or a pharmaceutically acceptable
salt thereof, wherein:
[0015] one of X.sub.1, X.sub.2, X.sub.3 and X.sub.4 must be N and
the others must be C; [0016] R.sup.1 and R.sup.1' are each
independently, halogen, hydroxy, cyano, C.sub.0-4alkyl,
C.sub.1-4alkoxy, fluoromethyl, difluoromethyl, trifluoromethyl,
ethenyl, or ethynyl; [0017] R.sup.2 is C.sub.0-4alkyl, COOR.sup.6,
COR.sup.6, C.sub.1-4alkoxyC.sub.1-4alkyl-, hydroxyC.sub.1-4alkyl-,
cycloalkylC.sub.0-4alkyl-, arylC.sub.0-4alkyl-,
hetarylC.sub.0-4alkyl-, wherein any of the aryl or hetaryl rings
are optionally substituted with 1-2 independent halogen, cyano,
C.sub.1-4alkyl, C.sub.1-4alkoxy,
--N(C.sub.0-4alkyl)(C.sub.0-4alkyl), --SO.sub.2C.sub.1-4alkyl,
--SO.sub.2N(C.sub.0-4alkyl)(C.sub.0-4alkyl), hydroxy, fluoromethyl,
difluoromethyl, or trifluoromethyl substituents; [0018] Y is
C.sub.0-2alkyl or --CH(OH)--; [0019] Z is CH.sub.2, --C(O)--,
--O--, >N(C.sub.0-4alkyl), >N(C.sub.3-6cycloalkyl), or
absent; but when Y is --CH(OH)--, Z or R.sup.3 must be bonded to Y
through a carbon-carbon bond; [0020] R.sup.3 is hydrogen,
--COOC.sub.0-4alkyl, C.sub.1-4alkoxy, C.sub.1-4alkyl,
arylC.sub.1-4alkylthio-, --C.sub.0-4alkylaryl,
--C.sub.0-4alkylhetaryl, --C.sub.0-4alkylcycloalkyl or
--C.sub.0-4alkylheterocyclyl, wherein any of the rings is
optionally substituted with 1-3 independent halogen, cyano,
C.sub.1-4alkyl, fluoromethyl, difluoromethyl, trifluoromethyl,
--C.sub.0-4alkylNHC(O)O(C.sub.1-4alkyl),
--C.sub.0-4alkylNR.sup.7R.sup.8, --C(O)R.sup.9,
C.sub.1-4alkoxyC.sub.0-4alkyl-, --COOC.sub.0-4alkyl,
--C.sub.0-4alkylNHC(O)R.sup.9,
--C.sub.0-4alkylC(O)N(R.sup.10).sub.2,
--C.sub.1-4alkoxyC.sub.1-4alkoxy, hydroxyC.sub.0-4alkyl-,
--NHSO.sub.2R.sup.10, --SO.sub.2(C.sub.1-4alkyl),
--SO.sub.2NR.sup.11R.sup.12, 5- to 6-membered heterocyclyl,
phenylC.sub.0-2alkoxy, or phenylC.sub.0-2alkyl substituents,
wherein phenyl is optionally substituted with 1-2 independent
halogen, cyano, C.sub.1-4alkyl, C.sub.1-4alkoxy,
--N(C.sub.0-4alkyl)(C.sub.0-4alkyl), --SO.sub.2C.sub.1-4alkyl,
--SO.sub.2N(C.sub.0-4alkyl)(C.sub.0-4alkyl), hydroxy, fluoromethyl,
difluoromethyl or trifluoromethyl substituents, or two bonds on a
ring carbon of the heterocyclyl group optionally can form an oxo
(.dbd.O) substituent;
[0021] or R.sup.3 is --NR.sup.4(--C.sub.0-4alkylR.sup.5); [0022]
R.sup.4 is C.sub.0-3alkyl, --C.sub.2-3alkyl-NR.sup.7R.sup.8,
C.sub.3-6cycloalkyl optionally substituted by
hydroxyC.sub.0-4alkyl- further optionally substituted by hydroxy,
C.sub.1-2alkoxyC.sub.2-4alkyl-, or
C.sub.1-2alkyl-S(O).sub.n--C.sub.2-3alkyl-;
[0023] n is 0, 1, or 2; [0024] R.sup.5 is hydrogen,
hydroxyC.sub.2-3alkyl-, C.sub.1-2alkoxyC.sub.0-4alkyl-, or aryl,
hetaryl, or heterocyclyl;
[0025] wherein a heterocyclic nitrogen-containing R.sup.5 ring
optionally is mono-substituted on the ring nitrogen with
C.sub.1-4alkyl, benzyl, benzoyl, C.sub.1-4alkyl-C(O)--,
[0026] --SO.sub.2C.sub.1-4alkyl,
--SO.sub.2N(C.sub.0-4alkyl)(C.sub.0-4alkyl),
C.sub.1-4alkoxycarbonyl or aryl(C.sub.1-4alkoxy)carbonyl; and
wherein the R.sup.5 rings are optionally mono-substituted on a ring
carbon with halogen, cyano, C.sub.1-4alkyl-C(O)--,
C.sub.1-4alkyl-SO.sub.2--, C.sub.1-4alkyl, C.sub.1-4alkoxy,
hydroxy, --N(C.sub.0-4alkyl)(C.sub.0-4alkyl),
hydroxyC.sub.0-4alkyl-, or C.sub.0-4alkylcarbamoyl-, provided that
no quaternised nitrogen is included; or two bonds on a ring carbon
of the heterocyclyl group optionally can form an oxo (.dbd.O)
substituent;
[0027] R.sup.6 is C.sub.1-4alkyl, aryl, or hetaryl;
[0028] R.sup.7 and R.sup.8 are independently C.sub.0-4alkyl,
C.sub.3-6cycloalkyl, or CO(C.sub.1-4alkyl);
[0029] R.sup.9 is C.sub.1-4alkyl, or C.sub.3-6cycloalkyl;
[0030] R.sup.10 is C.sub.0-4alkyl, or C.sub.3-6cycloalkyl;
[0031] R.sup.11 and R.sup.12 are independently C.sub.0-4alkyl or
together with the nitrogen to which they are attached may form a 4-
to 6-membered heterocycle; and
[0032] wherein there are no nitrogen-oxygen, nitrogen-nitrogen or
nitrogen-halogen bonds in linking the three components
--Y-Z-R.sup.3 to each other.
[0033] The molecular weight of the compounds of Formula (I) is
preferably less than 800, more preferably less than 600.
[0034] In the first aspect, the present invention is directed to a
compound represented by Formula (I), or a stereoisomer, or a
pharmaceutically acceptable salt thereof, wherein X.sub.1 is N, and
the other variables are as defined above for Formula (I).
[0035] In an embodiment of the first aspect, the present invention
is directed to a compound represented by Formula (I), or a
stereoisomer, or a pharmaceutically acceptable salt thereof,
wherein X.sub.1 is N, Y is C.sub.0-2alkyl, and Z is --C(O)--, and
the other variables are as defined above for Formula (I).
[0036] In another embodiment of the first aspect, the present
invention is directed to a compound represented by Formula (I), or
a stereoisomer, or a pharmaceutically acceptable salt thereof,
wherein X.sub.1 is N, Y is C.sub.0-2alkyl, and Z is --O--, and the
other variables are as defined above for Formula (I).
[0037] In yet another embodiment of the first aspect, the present
invention is directed to a compound represented by Formula (I), or
a stereoisomer, or a pharmaceutically acceptable salt thereof,
wherein X.sub.1 is N, Y is C.sub.0-2alkyl, and Z is
>N(C.sub.0-4alkyl), and the other variables are as defined above
for Formula (I).
[0038] In a second aspect, the present invention is directed to a
compound represented by Formula (I), or a stereoisomer, or a
pharmaceutically acceptable salt thereof, wherein X.sub.2 is N, and
the other variables are as defined above for Formula (I).
[0039] In an embodiment of the second aspect, the present invention
is directed to a compound represented by Formula (I), or a
stereoisomer, or a pharmaceutically acceptable salt thereof,
wherein X.sub.2 is N, Y is C.sub.0-2alkyl, and Z is --C(O)--, and
the other variables are as defined above for Formula (I).
[0040] In a third aspect, the present invention is directed to a
compound represented by Formula (I), or a stereoisomer, or a
pharmaceutically acceptable salt thereof, wherein X.sub.3 is N, and
the other variables are as defined above for Formula (I).
[0041] In an embodiment of the third aspect, the present invention
is directed to a compound represented by Formula (I), or a
stereoisomer, or a pharmaceutically acceptable salt thereof,
wherein X.sub.3 is N, Y is C.sub.0-2alkyl, and Z is --C(O)--, and
the other variables are as defined above for Formula (I).
[0042] In another embodiment of the third aspect, the present
invention is directed to a compound represented by Formula (I), or
a stereoisomer, or a pharmaceutically acceptable salt thereof,
wherein X.sub.3 is N, Y is --CH(OH)--, and Z is --C(O)--, and the
other variables are as defined above for Formula (I).
[0043] In yet another embodiment of the third aspect, the present
invention is directed to a compound represented by Formula (I), or
a stereoisomer, or a pharmaceutically acceptable salt thereof,
wherein X.sub.3 is N, Y is C.sub.0-2alkyl, and Z is --O--, and the
other variables are as defined above for Formula (I).
[0044] In still another embodiment of the third aspect, the present
invention is directed to a compound represented by Formula (I), or
a stereoisomer, or a pharmaceutically acceptable salt thereof,
wherein X.sub.3 is N, Y is C.sub.0-2alkyl, and Z is absent, and the
other variables are as defined above for Formula (I).
[0045] In yet still another embodiment of the third aspect, the
present invention is directed to a compound represented by Formula
(I), or a stereoisomer, or a pharmaceutically acceptable salt
thereof, wherein X.sub.3 is N, Y is C.sub.0-2alkyl, and Z is
>N(C.sub.0-4alkyl), and the other variables are as defined above
for Formula (I).
[0046] In a fourth aspect, the present invention is directed to a
compound represented by Formula (I), or a stereoisomer, or a
pharmaceutically acceptable salt thereof, wherein X.sub.4 is N, and
the other variables are as defined above for Formula (I).
[0047] In an embodiment of the fourth aspect, the present invention
is directed to a compound represented by Formula (I), or a
stereoisomer, or a pharmaceutically acceptable salt thereof,
wherein X.sub.4 is N, Y is --CH(OH)--, and Z is --C(O)--, and the
other variables are as defined above for Formula (I).
[0048] When Y is a direct bond then Z is preferably other than
--O--, >N(C.sub.0-4alkyl) or >N(C.sub.3-6cycloalkyl).
[0049] Preferably X.sub.3 is N.
[0050] Preferably R.sup.1 and R.sup.1' are each independently,
halogen, cyano, hydrogen, methyl, methoxy, or ethynyl. More
preferably R.sup.1 and R.sup.1' are each independently, halogen,
cyano, or hydrogen.
[0051] Preferably at least one of R.sup.1 and R.sup.1' is hydrogen.
More preferably one of R.sup.1 and R.sup.1' is hydrogen.
[0052] A preferred group of compounds are those where X.sub.3 is N,
one of R.sup.1 and R.sup.1' is hydrogen and the other is a 5-halo
or 5-cyano group.
[0053] Preferably Y is C.sub.0-2alkyl, more preferably Y is a
direct bond.
[0054] Preferably Z is --C(O)--.
[0055] A preferred group of compounds are those wherein
[0056] X.sub.3 is N;
[0057] Y is C.sub.0-2alkyl; and
[0058] Z is --C(O)--.
[0059] Preferably R.sup.2 is C.sub.0-4alkyl or arylC.sub.0-4alkyl-,
wherein the aryl ring is optionally substituted with 1-2
independent halogen, cyano, C.sub.1-4alkyl, C.sub.1-4alkoxy,
--N(C.sub.0-4alkyl)(C.sub.0-4alkyl), --SO.sub.2C.sub.1-4alkyl,
--SO.sub.2N(C.sub.0-4alkyl)(C.sub.0-4alkyl), hydroxy, fluoromethyl,
difluoromethyl, or trifluoromethyl substituents. More preferably
R.sup.2 is benzyl optionally substituted with 1-2 halogen
substituents. A particular R.sup.2 substituent which may be
mentioned is -(S)-(4-fluorobenzyl).
[0060] Preferably R.sup.3 is --C.sub.0-4alkylheterocyclyl
optionally substituted with 1-3 independent halogen, cyano,
C.sub.1-4alkyl, fluoromethyl, difluoromethyl, trifluoromethyl,
--C.sub.0-4alkylNHC(O)O(C.sub.1-4alkyl),
--C.sub.0-4alkylNR.sup.7R.sup.8, --C(O)R.sup.9,
C.sub.1-4alkoxyC.sub.0-4alkyl-,
[0061] --COOC.sub.0-4alkyl, --C.sub.0-4alkylNHC(O)R.sup.9,
--C.sub.0-4alkylC(O)N(R.sup.10).sub.2,
--C.sub.1-4alkoxyC.sub.1-4alkoxy, hydroxyC.sub.0-4alkyl-,
--NHSO.sub.2R.sup.10, --SO.sub.2(C.sub.1-4alkyl),
--SO.sub.2NR.sup.11R.sup.12, 5- to 6-membered heterocyclyl,
phenylC.sub.0-2alkoxy, or phenylC.sub.0-2alkyl substituents,
wherein phenyl is optionally substituted with 1-2 independent
halogen, cyano, C.sub.1-4alkyl, C.sub.1-4alkoxy,
--N(C.sub.0-4alkyl)(C.sub.0-4alkyl), --SO.sub.2C.sub.1-4alkyl,
--SO.sub.2N(C.sub.0-4alkyl)(C.sub.0-4alkyl), hydroxy, fluoromethyl,
difluoromethyl, or trifluoromethyl substituents, or two bonds on a
ring carbon of the heterocyclyl group optionally can form an oxo
(.dbd.O) substituent; or R.sup.3 is
--NR.sup.4(--C.sub.0-4alkylR.sup.5).
[0062] More preferably R.sup.3 is a nitrogen containing
heterocyclyl group, especially a 4-8-membered nitrogen containing
heterocyclyl group, linked to Z via a ring nitrogen atom,
optionally substituted with 1-3 independent halogen, cyano,
C.sub.1-4alkyl, fluoromethyl, difluoromethyl, trifluoromethyl,
--C.sub.0-4alkylNHC(O)O(C.sub.1-4alkyl),
--C.sub.0-4alkylNR.sup.7R.sup.8, --C(O)R.sup.9,
C.sub.1-4alkoxyC.sub.0-4alkyl-, --COOC.sub.0-4alkyl,
--C.sub.0-4alkylNHC(O)R.sup.9,
--C.sub.0-4alkylC(O)N(R.sup.10).sub.2,
--C.sub.1-4alkoxyC.sub.1-4alkoxy, hydroxyC.sub.0-4alkyl-,
--NHSO.sub.2R.sup.10, --SO.sub.2(C.sub.1-4alkyl),
--SO.sub.2NR.sup.11R.sup.12, 5- to 6-membered heterocyclyl,
phenylC.sub.0-2alkoxy, or phenylC.sub.0-2alkyl substituents,
wherein phenyl is optionally substituted with 1-2 independent
halogen, cyano, C.sub.1-4alkyl, C.sub.1-4alkoxy,
--N(C.sub.0-4alkyl)(C.sub.0-4alkyl), --SO.sub.2C.sub.1-4alkyl,
--SO.sub.2N(C.sub.0-4alkyl)(C.sub.0-4alkyl), hydroxy, fluoromethyl,
difluoromethyl, or trifluoromethyl substituents, or two bonds on a
ring carbon of the heterocyclyl group optionally can form an oxo
(.dbd.O) substituent; or R.sup.3 is
--NR.sup.4(--C.sub.0-4alkylR.sup.5).
[0063] Examples of nitrogen containing heterocyclyl groups which
R.sup.3 may represent include azetidin-1-yl, pyrrolidin-1-yl,
piperidin-1-yl, 1,4-diazapan-1-yl, piperazin-1-yl, morpholin-4-yl,
thiomorpholin-4-yl, 1,1-dioxo-thiomorpholin-4-yl, or
thiazolidin-3-yl; which groups may be optionally substituted as
described above
[0064] Preferred substituent groups for R.sup.3 include
--C.sub.1-4alkoxy, hydroxy and oxo.
[0065] Even more preferably R.sup.3 is pyrrolidin-1-yl or
piperidin-1-yl optionally substituted with hydroxyl, e.g.
4-hydroxypiperidin-1-yl and 3-(S)-hydroxypyrrolidin-1-yl.
[0066] Specific compounds of the invention which may be mentioned
are those included in the examples, in particular
5-chloro-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid
[1-(S)-(4-fluorobenzyl)-2-(4-hydroxypiperidin-1-yl)-2-oxoethyl]amide
and 5-chloro-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid
[1-(S)-(4-fluorobenzyl)-2-(3-(S)-hydroxypyrrolidin-1-yl)-2-oxoethyl]amide-
.
[0067] A particular group of compounds which may be mentioned are
those represented by Formula (IA): ##STR4## or a stereoisomer, or a
pharmaceutically acceptable salt thereof, wherein:
[0068] one of X.sub.1, X.sub.2, X.sub.3 and X.sub.4 must be N and
the others must be C; [0069] R.sup.1 and R.sup.1' are each
independently, halogen, hydroxy, cyano, C.sub.0-4alkyl,
C.sub.1-4alkoxy, fluoromethyl, difluoromethyl, trifluoromethyl,
ethenyl, or ethynyl; [0070] R.sup.2 is C.sub.0-4alkyl,
arylC.sub.0-4alkyl-, hetarylC.sub.0-4alkyl-, wherein any of the
aryl or hetaryl rings are optionally substituted with 1-2
independent halogen, cyano, C.sub.1-4alkyl, C.sub.1-4alkoxy,
--N(C.sub.0-4alkyl)(C.sub.0-4alkyl), --SO.sub.2C.sub.1-4alkyl,
--SO.sub.2N(CO.sub.0-4alkyl)(C.sub.0-4alkyl), hydroxy,
fluoromethyl, difluoromethyl, or trifluoromethyl substituents;
[0071] Y is C.sub.0-2alkyl or --CH(OH)--; [0072] Z is CH.sub.2,
--C(O)--, --O--, >N(C.sub.0-4alkyl), >N(C.sub.3-6cycloalkyl),
or absent; but when Y is --CH(OH)--, Z or R.sup.3 must be bonded to
Y through a carbon-carbon bond; [0073] R.sup.3 is hydrogen,
--COOC.sub.0-4alkyl, C.sub.1-4alkoxy, arylC.sub.1-4alkylthio-,
--C.sub.0-4alkylaryl, --C.sub.0-4alkylhetaryl, or
--C.sub.0-4alkylheterocyclyl, wherein any of the rings is
optionally substituted with 1-3 independent halogen, cyano,
C.sub.1-4alkyl, fluoromethyl, difluoromethyl, trifluoromethyl,
--C.sub.0-4alkylN(C.sub.0-4alkyl)(C.sub.0-4alkyl),
--C(O)(C.sub.0-4alkyl), C.sub.1-4alkoxyC.sub.0-4alkyl-,
--COOC.sub.0-4alkyl, C.sub.0-4alkylcarbamoyl-,
--C.sub.1-4alkoxymethoxy, hydroxyC.sub.0-4alkyl-,
--SO.sub.2(C.sub.1-4alkyl), or phenylC.sub.0-2alkyl substituents,
or two bonds on a ring carbon of the heterocyclyl group optionally
can form an oxo (.dbd.O) substituent;
[0074] or R.sup.3 is --NR.sup.4(--C.sub.0-4alkylR.sup.5); [0075]
R.sup.4 is C.sub.0-3alkyl,
--C.sub.2-3alkyl-N(C.sub.1-3alkyl)(C.sub.1-3alkyl),
C.sub.3-6cycloalkyl, hydroxyC.sub.2-3alkyl-,
C.sub.1-2alkoxyC.sub.2-4alkyl-, or
C.sub.1-2alkyl-S(O).sub.n--C.sub.2-3alkyl-;
[0076] n is 0, 1, or 2; [0077] R.sup.5 is hydrogen,
hydroxyC.sub.2-3alkyl-, C.sub.1-2alkoxyC.sub.2-4alkyl, or an aryl,
hetaryl, or heterocyclyl;
[0078] wherein a heterocyclic nitrogen-containing R.sup.5 ring
optionally is mono-substituted on the ring nitrogen with
C.sub.1-4alkyl, benzyl, benzoyl, C.sub.1-4alkyl-C(O)--,
[0079] --SO.sub.2C.sub.1-4alkyl,
--SO.sub.2N(C.sub.0-4alkyl)(C.sub.0-4alkyl),
C.sub.1-4alkoxycarbonyl or aryl(C.sub.1-4alkoxy)carbonyl; and
wherein the R.sup.5 rings are optionally mono-substituted on a ring
carbon with halogen, cyano, C.sub.1-4alkyl-C(O)--,
C.sub.1-4alkyl-SO.sub.2--, C.sub.1-4alkyl, C.sub.1-4alkoxy,
--N(C.sub.0-4alkyl)(C.sub.0-4alkyl), hydroxyC.sub.0-4alkyl-, or
C.sub.0-4alkylcarbamoyl-, provided that no quaternised nitrogen is
included; and
[0080] wherein there are no nitrogen-oxygen, nitrogen-nitrogen or
nitrogen-halogen bonds in linking the three components
--Y-Z-R.sup.3 to each other.
[0081] While the preferred groups for each variable have generally
been listed above separately for each variable, preferred compounds
of this invention include those in which several or each variable
in Formula (I) is selected from the preferred, more preferred, most
preferred, especially or particularly listed groups for each
variable. Therefore, this invention is intended to include all
combinations of preferred, more preferred, most preferred,
especially and particularly listed groups.
[0082] As used herein, unless stated otherwise, "alkyl" as well as
other groups having the prefix "alk" such as, for example, alkoxy,
alkanyl, alkenyl, alkynyl, and the like, means carbon chains which
may be linear or branched or combinations thereof. Examples of
alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, sec-
and tert-butyl, pentyl, hexyl, heptyl and the like. "Alkenyl",
"alkynyl" and other like terms include carbon chains having at
least one unsaturated carbon-carbon bond.
[0083] As used herein, for example, "C.sub.0-4alkyl" is used to
mean an alkyl having 0-4 carbons--that is, 0, 1, 2, 3, or 4 carbons
in a straight or branched configuration. An alkyl having no carbon
is hydrogen when the alkyl is a terminal group. An alkyl having no
carbon is a direct bond when the alkyl is a bridging (connecting)
group.
[0084] The terms "cycloalkyl" and "carbocyclic ring" mean
carbocycles containing no heteroatoms, and include mono-, bi-, and
tricyclic saturated carbocycles, as well as fused and bridged
systems. Such fused ring systems can include one ring that is
partially or fully unsaturated, such as a benzene ring, to form
fused ring systems, such as benzofused carbocycles. Cycloalkyl
includes such fused ring systems as spirofused ring systems.
Examples of cycloalkyl and carbocyclic rings include
C.sub.3-10cycloalkyl groups, particularly C.sub.3-8cycloalkyl
groups, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,
and decahydronaphthalene, adamantane, indanyl,
1,2,3,4-tetrahydronaphthalene and the like.
[0085] The term "halogen" includes fluorine, chlorine, bromine, and
iodine atoms.
[0086] The term "carbamoyl" unless specifically described otherwise
means --C(O)--NH-- or --NH--C(O)--.
[0087] The term "aryl" is well known to chemists. The preferred
aryl groups are phenyl and naphthyl, more preferably phenyl.
[0088] The term "hetaryl" is well known to chemists. The term
includes 5- or 6-membered heteroaryl rings containing 1-4
heteroatoms chosen from oxygen, sulfur, and nitrogen in which
oxygen and sulfur are not next to each other. Examples of such
heteroaryl rings are furyl, thienyl, pyrrolyl, pyrazolyl,
imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl,
triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyridyl,
pyridazinyl, pyrimidinyl, pyrazinyl, and triazinyl. The term
"hetaryl" includes hetaryl rings with fused carbocyclic ring
systems that are partially or fully unsaturated, such as a benzene
ring, to form a benzofused hetaryl. For example, benzimidazole,
benzoxazole, benzothiazole, benzofuran, quinoline, isoquinoline,
quinoxaline, and the like.
[0089] Unless otherwise stated, the terms "heterocyclic ring",
"heterocyclyl" and "heterocycle" are equivalent, and include
4-10-membered, e.g. 4-8-membered, saturated or partially saturated
rings containing one or two heteroatoms chosen from oxygen, sulfur,
and nitrogen. The sulfur and oxygen heteroatoms are not directly
attached to one another. Any nitrogen heteroatoms in the ring may
optionally be substituted with C.sub.1-4alkyl. Examples of
heterocyclic rings include azetidine, oxetane, tetrahydrofuran,
tetrahydropyran, oxepane, oxocane, thietane, thiazolidine,
oxazolidine, oxazetidine, pyrazolidine, isoxazolidine,
isothiazolidine, tetrahydrothiophene, tetrahydrothiopyran,
thiepane, thiocane, azetidine, pyrrolidine, piperidine,
N-methylpiperidine, azepane, 1,4-diazapane, azocane, [1,3]dioxane,
oxazolidine, piperazine, homopiperazine, morpholine,
thiomorpholine, 1,2,3,6-tetrahydropyridine and the like. Other
examples of heterocyclic rings include the oxidized forms of the
sulfur-containing rings. Thus, tetrahydrothiophene-1,1-oxide,
tetrahydrothiophene-1,1-dioxide, thiomorpholine-1-oxide,
thiomorpholine-1,1-dioxide, tetrahydrothiopyran-1-oxide,
tetrahydrothiopyran-1,1-dioxide, thiazolidine-1-oxide, and
thiazolidine-1,1-dioxide are also considered to be heterocyclic
rings. The term "heterocyclic" also includes fused ring systems and
can include a carbocyclic ring that is partially or fully
unsaturated, such as a benzene ring, to form benzofused
heterocycles. For example, 3,4-dihydro-1,4-benzodioxine,
tetrahydroquinoline, tetrahydroisoquinoline and the like.
[0090] Compounds described herein may contain one or more
asymmetric centers and may thus give rise to diastereomers and
optical isomers. The present invention includes all such possible
diastereomers as well as their racemic mixtures, their
substantially pure resolved enantiomers, all possible geometric
isomers, and pharmaceutically acceptable salts thereof. The above
Formula (I) is shown without a definitive stereochemistry at
certain positions. The present invention includes all stereoisomers
of Formula (I) and pharmaceutically acceptable salts thereof.
Further, mixtures of stereoisomers as well as isolated specific
stereoisomers are also included. During the course of the synthetic
procedures used to prepare such compounds, or in using racemization
or epimerization procedures known to those skilled in the art, the
products of such procedures can be a mixture of stereoisomers.
[0091] When a tautomer of the compound of Formula (I) exists, the
present invention includes any possible tautomers and
pharmaceutically acceptable salts thereof, and mixtures thereof,
except where specifically drawn or stated otherwise.
[0092] When the compound of Formula (I) and pharmaceutically
acceptable salts thereof exist in the form of solvates or
polymorphic forms, the present invention includes any possible
solvates and polymorphic forms. A type of a solvent that forms the
solvate is not particularly limited so long as the solvent is
pharmacologically acceptable. For example, water, ethanol,
propanol, acetone or the like can be used.
[0093] The invention also encompasses a pharmaceutical composition
that is comprised of a compound of Formula (I), or a
pharmaceutically acceptable salt thereof, in combination with a
pharmaceutically acceptable carrier.
[0094] Preferably the composition is comprised of a
pharmaceutically acceptable carrier and a non-toxic therapeutically
effective amount of a compound of Formula (I), or a
pharmaceutically acceptable salt thereof.
[0095] Moreover, within this preferred embodiment, the invention
encompasses a pharmaceutical composition for the treatment of
disease by inhibiting glycogen phosphorylase, resulting in the
prophylactic or therapeutic treatment of diabetes, hyperglycemia,
hypercholesterolemia, hyperinsulinemia, hyperlipidemia,
hypertension, atherosclerosis or tissue ischemia e.g. myocardial
ischemia comprising a pharmaceutically acceptable carrier and a
non-toxic therapeutically effective amount of compound of Formula
(I), or a pharmaceutically acceptable salt thereof.
[0096] The term "pharmaceutically acceptable salts" refers to salts
prepared from pharmaceutically acceptable non-toxic bases or acids.
When the compound of the present invention is acidic, its
corresponding salt can be conveniently prepared from
pharmaceutically acceptable non-toxic bases, including inorganic
bases and organic bases. Salts derived from such inorganic bases
include aluminum, ammonium, calcium, copper (ic and ous), ferric,
ferrous, lithium, magnesium, potassium, sodium, zinc and the like
salts. Particularly preferred are the ammonium, calcium, magnesium,
potassium and sodium salts. Salts derived from pharmaceutically
acceptable organic non-toxic bases include salts of primary,
secondary, and tertiary amines, as well as cyclic amines and
substituted amines such as naturally occurring and synthesized
substituted amines. Other pharmaceutically acceptable organic
non-toxic bases from which salts can be formed include arginine,
betaine, caffeine, choline, N'N'-dibenzylethylenediamine,
diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol,
ethanolamine, ethylenediamine, N-ethylmorpholine,
N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine,
isopropylamine, lysine, methylglucamine, morpholine, piperazine,
piperidine, polyamine resins, procaine, purines, theobromine,
triethylamine, trimethylamine, tripropylamine, tromethamine and the
like.
[0097] When the compound of the present invention is basic, its
corresponding salt can be conveniently prepared from
pharmaceutically acceptable non-toxic acids, including inorganic
and organic acids. Such acids include, for example, acetic,
benzenesulfonic, benzoic, camphorsulfonic, citric, ethanesulfonic,
fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic,
lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric,
pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric,
p-toluenesulfonic acid and the like. Particularly preferred are
citric, hydrobromic, hydrochloric, maleic, phosphoric, sulfuric and
tartaric acids.
[0098] Since the compounds of Formula (I) are intended for
pharmaceutical use they are preferably provided in substantially
pure form, for example at least 60% pure, more suitably at least
75% pure especially at least 98% pure (% are on a weight for weight
basis).
[0099] The pharmaceutical compositions of the present invention
comprise a compound represented by Formula (I), or a
pharmaceutically acceptable salt thereof, as an active ingredient,
a pharmaceutically acceptable carrier and optionally other
therapeutic ingredients or adjuvants. The compositions include
those suitable for oral, rectal, topical, and parenteral (including
subcutaneous, intramuscular, and intravenous) administration,
although the most suitable route in any given case will depend on
the particular host, and nature and severity of the conditions for
which the active ingredient is being administered. The compositions
are preferably suitable for oral administration The pharmaceutical
compositions may be conveniently presented in unit dosage form and
prepared by any of the methods well known in the art of
pharmacy.
[0100] In practice, the compounds of Formula (I), or
pharmaceutically acceptable salts thereof, can be combined as the
active ingredient in intimate admixture with a pharmaceutical
carrier according to conventional pharmaceutical compounding
techniques. The carrier may take a wide variety of forms depending
on the form of preparation desired for administration, e.g. oral or
parenteral (including intravenous). Thus, the pharmaceutical
compositions of the present invention can be presented as discrete
units suitable for oral administration such as capsules, sachets or
tablets each containing a predetermined amount of the active
ingredient. Further, the compositions can be presented as a powder,
as granules, as a solution, as a suspension in an aqueous liquid,
as a non-aqueous liquid, as an oil-in-water emulsion, or as a
water-in-oil liquid emulsion. In addition to the common dosage
forms set out above, the compounds of Formula (I), or
pharmaceutically acceptable salts thereof, may also be administered
by controlled release means and/or delivery devices. The
compositions may be prepared by any of the methods of pharmacy. In
general, such methods include a step of bringing into association
the active ingredient with the carrier that constitutes one or more
necessary ingredients. In general, the compositions are prepared by
uniformly and intimately admixing the active ingredient with liquid
carriers or finely divided solid carriers or both. The product can
then be conveniently shaped into the desired presentation.
[0101] Thus, the pharmaceutical compositions of this invention may
include a pharmaceutically acceptable carrier and a compound of
Formula (I) or a pharmaceutically acceptable salt thereof. The
compounds of Formula (I), or pharmaceutically acceptable salts
thereof, can also be included in pharmaceutical compositions in
combination with one or more other therapeutically active
compounds.
[0102] The pharmaceutical carrier employed can be, for example, a
solid, liquid, or gas. Examples of solid carriers include lactose,
terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium
stearate, and stearic acid. Examples of liquid carriers are sugar
syrup, peanut oil, olive oil, and water. Examples of gaseous
carriers include carbon dioxide and nitrogen.
[0103] In preparing the compositions for oral dosage form, any
convenient pharmaceutical media may be employed. For example,
water, glycols, oils, alcohols, flavoring agents, preservatives,
coloring agents, and the like may be used to form oral liquid
preparations such as suspensions, elixirs and solutions; while
carriers such as starches, sugars, microcrystalline cellulose,
diluents, granulating agents, lubricants, binders, disintegrating
agents, and the like may be used to form oral solid preparations
such as powders, capsules and tablets. Because of their ease of
administration, tablets and capsules are the preferred oral dosage
units whereby solid pharmaceutical carriers are employed.
Optionally, tablets may be coated by standard aqueous or nonaqueous
techniques.
[0104] A tablet containing the composition of this invention may be
prepared by compression or molding, optionally with one or more
accessory ingredients or adjuvants. Compressed tablets may be
prepared by compressing, in a suitable machine, the active
ingredient in a free-flowing form such as powder or granules,
optionally mixed with a binder, lubricant, inert diluent, surface
active or dispersing agent. Molded tablets may be made by molding
in a suitable machine, a mixture of the powdered compound moistened
with an inert liquid diluent. Each tablet preferably contains from
about 0.05 mg to about 5 g of the active ingredient and each sachet
or capsule preferably contains from about 0.05 mg to about 5 g of
the active ingredient.
[0105] For example, a formulation intended for oral administration
to humans may contain from about 0.5 mg to about 5 g of active
agent, compounded with an appropriate and convenient amount of
carrier material, which may vary from about 5 to about 95% of the
total composition. Unit dosage forms will generally contain from
about 1 mg to about 2 g of the active ingredient, typically 25 mg,
50 mg, 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 800 mg, or
1000 mg.
[0106] Pharmaceutical compositions of the present invention
suitable for parenteral administration may be prepared as solutions
or suspensions of the active compounds in water. A suitable
surfactant can be included such as, for example,
hydroxypropylcellulose. Dispersions can also be prepared in
glycerol, liquid polyethylene glycols, and mixtures thereof in
oils. Further, a preservative can be included to prevent the
detrimental growth of microorganisms.
[0107] Pharmaceutical compositions of the present invention
suitable for injectable use include sterile aqueous solutions or
dispersions. Furthermore, the compositions can be in the form of
sterile powders for the extemporaneous preparation of such sterile
injectable solutions or dispersions. In all cases, the final
injectable form must be sterile and must be effectively fluid for
easy syringability. The pharmaceutical compositions must be stable
under the conditions of manufacture and storage; thus, preferably
should be preserved against the contaminating action of
microorganisms such as bacteria and fungi. The carrier can be a
solvent or dispersion medium containing, for example, water,
ethanol, polyol (e.g. glycerol, propylene glycol and liquid
polyethylene glycol), vegetable oils, and suitable mixtures
thereof.
[0108] Pharmaceutical compositions of the present invention can be
in a forn suitable for topical use such as, for example, an
aerosol, cream, ointment, lotion, dusting powder, or the like.
Further, the compositions can be in a form suitable for use in
transdermal devices. These formulations may be prepared, utilizing
a compound of Formula (I), or a pharmaceutically acceptable salt
thereof, via conventional processing methods. As an example, a
cream or ointment is prepared by admixing hydrophilic material and
water, together with about 5 wt % to about 10 wt % of the compound,
to produce a cream or ointment having a desired consistency.
[0109] Pharmaceutical compositions of this invention can be in a
form suitable for rectal administration wherein the carrier is a
solid. It is preferable that the mixture forms unit dose
suppositories. Suitable carriers include cocoa butter and other
materials commonly used in the art. The suppositories may be
conveniently formed by first admixing the composition with the
softened or melted carrier(s) followed by chilling and shaping in
molds.
[0110] In addition to the aforementioned carrier ingredients, the
pharmaceutical formulations described above may include, as
appropriate, one or more additional carrier ingredients such as
diluents, buffers, flavoring agents, binders, surface-active
agents, thickeners, lubricants, preservatives (including
anti-oxidants) and the like. Furthermore, other adjuvants can be
included to render the formulation isotonic with the blood of the
intended recipient. Compositions containing a compound of Formula
(I), or a pharmaceutically acceptable salt thereof, may also be
prepared in powder or liquid concentrate form.
[0111] Generally, dosage levels on the order of 0.01 mg/kg to about
150 mg/kg of body weight per day are useful in the treatment of the
above-indicated conditions, or alternatively about 0.5 mg to about
7 g per patient per day. For example, diabetes and hyperglycemia
may be effectively treated by the administration of from about 0.01
to 50 mg of the compound per kilogram of body weight per day, or
alternatively about 0.5 mg to about 3.5 g per patient per day.
Similarly, hypercholesterolemia, hyperinsulinemia, hyperlipidemia,
hypertension, atherosclerosis or tissue ischemia e.g. myocardial
ischemia may be effectively treated by the administration of from
about 0.01 to 50 mg of the compound per kilogram of body weight per
day, or alternatively about 0.5 mg to about 3.5 g per patient per
day.
[0112] It is understood, however, that the specific dose level for
any particular patient will depend upon a variety of factors
including the age, body weight, general health, sex, diet, time of
administration, route of administration, rate of excretion, drug
combination and the severity of the particular disease undergoing
therapy.
[0113] The compounds of Formula (I) and pharmaceutically acceptable
salts thereof, may be used in the treatment of diseases or
conditions in which glycogen phosphorylase plays a role.
[0114] Thus the invention also provides a method for the treatment
of a disease or condition in which glycogen phosphorylase plays a
role comprising a step of administering to a subject in need
thereof an effective amount of a compound of Formula (I), or a
pharmaceutically acceptable salt thereof.
[0115] Diseases or conditions in which glycogen phosphorylase plays
a role include diabetes (including Type I and Type II, impaired
glucose tolerance, insulin resistance and diabetic complications
such as neuropathy, nephropathy, retinopathy and cataracts),
hyperglycemia, hypercholesterolemia, hyperinsulinemia,
hyperlipidemia, hypertension, atherosclerosis, tissue ischemia e.g.
myocardial ischemia.
[0116] The invention also provides a method for the treatment of
hyperglycemia or diabetes comprising a step of administering to a
subject in need thereof an effective amount of a compound of
Formula (I), or a pharmaceutically acceptable salt thereof.
[0117] The invention also provides a method for the prevention of
diabetes in a human demonstrating pre-diabetic hyperglycemia or
impaired glucose tolerance comprising a step of administering to a
subject in need thereof an effective prophylactic amount of a
compound of Formula (I), or a pharmaceutically acceptable salt
thereof.
[0118] The invention also provides a method for the treatment of
hypercholesterolemia, hyperinsulinemia, hyperlipidemia,
hypertension, atherosclerosis or tissue ischemia comprising a step
of administering to a patient in need thereof an effective amount
of a compound of Formula (I), or a pharmaceutically acceptable salt
thereof.
[0119] The invention also provides a method of cardioprotection
e.g. following reperfusion injury, comprising a step of
administering to a subject in need thereof an effective amount of a
compound of Formula (I), or a pharmaceutically acceptable salt
thereof.
[0120] The invention also provides the use of a compound of Formula
(I), or a pharmaceutically acceptable salt thereof, in the
treatment of a condition as defined above.
[0121] The invention also provides the use of a compound of Formula
(I), or a pharmaceutically acceptable salt thereof, in the
manufacture of a medicament for the treatment of a condition as
defined above.
[0122] In the methods of the invention the term "treatment"
includes both therapeutic and prophylactic treatment.
[0123] The compounds of Formula (I), or pharmaceutically acceptable
salts thereof, may be administered alone or in combination with one
or more other therapeutically active compounds. The other
therapeutically active compounds may be for the treatment of the
same disease or condition as the compounds of Formula (I) or a
different disease or condition. The therapeutically active
compounds may be administered simultaneously, sequentially or
separately.
[0124] The compounds of Formula (I) may be administered with other
active compounds for the treatment of diabetes, for example insulin
and insulin analogs, sulfonyl ureas and analogs, biguanides,
.alpha.2 agonists, fatty acid oxidation inhibitors,
.alpha.-glucosidase inhibitors, .beta.-agonists, phosphodiesterase
inhibitors, lipid lowering agents, antiobesity agents, amylin
antagonists, lipoxygenase inhibitors, somostatin analogs,
glucokinase activators, glucagon antagonists, insulin signalling
agonists, PTP1B inhibitors, gluconeogenesis inhibitors,
antilypolitic agents, GSK inhibitors, galanin receptor agonists,
anorectic agents, CCK receptor agonists, leptin, CRF antagonists or
CRF binding proteins.
[0125] The compounds of Formula (I) may also be administered in
combination with thyromimetic compounds, aldose reductase
inhibitors, glucocorticoid receptor antagonists, NHE-1 inhibitors
or sorbitol dehydrogenase inhibitors.
[0126] The compounds of Formula (I) may exhibit advantageous
properties compared to known glycogen phosphorylase inhibitors, for
example, the compounds may exhibit improved solubility thus
improving absorption properties and bioavailability. Furthermore
the compounds of Formula (I) may exhibit further advantageous
properties such as reduced inhibition of cytochrome P450 enzymes,
meaning that they are less likely to cause adverse drug-drug
interactions than known glycogen phosphorylase inhibitors.
[0127] All publications, including, but not limited to, patents and
patent application cited in this specification, are herein
incorporated by reference as if each individual publication were
specifically and individually indicated to be incorporated by
reference herein as fully set forth.
[0128] In accordance with this invention, the compounds of Formula
(I) can be prepared as outlined in Scheme 1 below wherein R.sup.1,
R.sup.1', R.sup.2, R.sup.3, X.sub.1, X.sub.2, X.sub.3, X.sub.4, Y
and Z are as defined above for Formula (I): ##STR5##
[0129] According to Scheme 1, the compounds of Formula (I) may be
prepared by coupling the appropriate pyrrolopyridine-2-carboxylic
acid of Formula (II), or a protected or activated derivative
thereof, with the appropriate amine of Formula (III). Compounds of
Formula (II) can be obtained by the syntheses described in Schemes
3 and 5 below. Compounds of Formula (III) are generally
commercially available or can be obtained by the syntheses
described in Schemes 8 and 9 below.
[0130] Typically, the compound of Formula (II), or a protected or
activated derivative thereof, is combined with a compound of
Formula (III) in the presence of a suitable coupling agent.
Examples of suitable coupling reagents are
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide
hydrochloride/hydroxybenzotriazole (EDCI/HOBt),
1,1-carbonyldiimidazole (CDI),
dicyclohexylcarbodiimide/hydroxybenzotriazole (DCC/HOBt),
O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium
tetrafluoroborate (R. Knorr et al., Tetrahedron Lett., 1989, 30,
1927-1930) and polymer supported
carbodiimide-1-hydroxybenzotriazole (for representative procedures,
see for example, Argonaut Technical Note 501 available from
Argonaut Technologies, Inc., Foster City, Calif.). The couplings
are performed in an inert solvent, preferably an aprotic solvent at
a temperature of about 0.degree. C. to about 45.degree. C. for
about 1 to 72 h in the presence of a tertiary amine base such as
diisopropylethylamine (DIPEA) or triethylamine. Exemplary solvents
include acetonitrile, chloroform, dichloromethane,
N,N-dimethylformamide (DMF) or mixtures thereof. Use of these
coupling agents and appropriate selection of solvents and
temperatures are known to those skilled in the art or can be
readily determined from the literature. These and other exemplary
conditions useful for coupling carboxylic acids are described in
Houben-Weyl, Vol XV, part II, E. Wunsch, Ed., G. Thieme Verlag,
1974, Stuttgart, and M. Bodansky, Principles of Peptide Synthesis,
Springer-Verlag, Berlin, 1984 and The Peptides, Analysis, Synthesis
and Biology (Ed., E. Gross and J. Meienhofer), Vols 1-5, Academic
Press NY 1979-1983. ##STR6##
[0131] In a second process, the compounds of Formula (I) (wherein Z
is C.dbd.O and R.sup.3 is --NR.sup.4(--C.sub.0-4alkylR.sup.5)) may
be prepared according to Scheme 2 by coupling the appropriate
carboxylic acid of Formula (I), or a protected or activated
derivative thereof, (wherein Z is absent and R.sup.3 is
--CO.sub.2H) with the appropriate amine of Formula (IV). Examples
of suitable coupling agents and conditions are as described above.
Compounds of Formula (IV) are commercially available or are readily
prepared by known techniques.
[0132] Compounds of Formula (II) can be prepared as illustrated in
Scheme 3. ##STR7##
[0133] Compounds of Formula (VI) may be prepared by condensation of
ortho methyl nitro compounds of Formula (V) with an oxalate ester
in a solvent such as diethyl ether in the presence of a base such
as potassium ethoxide or DBU. Compounds of Formula (VII) are
prepared from compounds of Formula (VI) under reducing conditions,
such as iron powder and ammonium chloride, or by hydrogenation in
ethanol using palladium catalysis. Compounds of Formula (VII)
undergo ester hydrolysis using aqueous alkali to give
pyrrolopyridine-2-carboxylic acids of Formula (II). Further
information on the conversion of compounds of Formula (V) to
compounds of Formula (II) are described in the literature
(Kerrnack, et al., J. Chem, Soc., 1921, 119, 1602; Cannon et al.,
J. Med. Chem., 1981, 24, 238; Julian et al., in Heterocyclic
Compounds, Vol 3 (Wiley, New York, N.Y., 1962, R. C. Elderfield,
Ed.) p 18.
[0134] Alternatively, the compound of Formula (VII) wherein X.sub.2
is nitrogen can be prepared as illustrated in Scheme 4.
##STR8##
[0135] Deprotonation of compounds of Formula (VIII) with an
organolithium such as n-butyllithium in a suitable solvent such as
THF, followed by quenching with methyl iodide gives compounds of
Formula (IX). Such compounds can undergo further deprotonation with
tert-butyllithium, in a suitable solvent such as THF, followed by
quenching with diethyl oxalate and subsequent heating of the
intermediate under reflux in hydrochloric acid, to give compounds
of Formula (VII).
[0136] Compounds of Formula (II) may also be prepared according to
Scheme 5 by Heck coupling of an ortho-iodo aminopyridine (XIV)
followed by cyclisation at a temperature of between 100 to
150.degree. C. in the presence of catalyst such as palladium
acetate and a base such as DABCO in a solvent such as DMF (See Chen
et al, J. Org. Chem. 1997, 62, 2676). The ortho-iodo aminopyridines
(XIV) can be made by direct iodination of the appropriate
aminopyridine (XIII) using iodine in the presence of silver sulfate
in a solvent such as ethanol at ambient temperature (see Sy, W.,
Synth. Commun., 1992, 22, 3215). ##STR9##
[0137] Alternatively compounds of Formula (XIV) may be prepared
according to Scheme 6 by deprotection of N-pivaloyl compounds (XV)
by heating under refluk using hydrochloric acid. The N-pivaloyl
compounds (XV) are in turn made by deprotonation of compounds of
Formula (XVI) with an organolithium such as tert-butyllithium in a
suitable solvent such as THF, followed by quenching with iodine at
a low temperature. Compounds of formula (XVI) may be made by
protection of commercially available aminopyridines (XIII) with
trimethylacetyl chloride and a base such as triethylamine in a
solvent such as dichloromethane. ##STR10##
[0138] Alternatively compounds of Formula (XIV) may be prepared
according to Scheme 7 by deprotection of N-BOC protected compounds
(XVII) using an acid such as trifluoroacetic acid in a solvent such
as dichloromethane at ambient temperature. The N-BOC compounds
(XVII) are in turn made by deprotonation of compounds of Formula
(XVIII) with an organolithium such as n-butyllithium in the
presence of N,N,N',N'-tetramethylethylenediamine (TMEDA) in a
suitable solvent such as ether at temperatures around -70.degree.
C. followed by the addition of iodine at temperatures around
-10.degree. C. The N-BOC aminopyridines (XVIII) are routinely made
from the commercially available aminopyridines (XIII) using
di-tert-butyldicarbonate by heating in a solvent such as
1,4-dioxane. ##STR11##
[0139] Protected or activated derivatives of the compounds of
Formula (II) may be prepared by methods known to those skilled in
the art.
[0140] Compounds of Formula (III) can be prepared as illustrated in
Scheme 8.
[0141] Compounds of Formula (X) are generally commercially
available or are readily prepared by known techniques. PG
represents a protecting group such as, for example,
tert-butyloxycarbonyl (Boc). Compounds of Formula (XI) are made
from carboxylic acids of Formula (X) using standard coupling
conditions as described above for Scheme 1.
[0142] Compounds of Formula (III) can be prepared as illustrated in
Scheme 8. ##STR12##
[0143] Compounds of Formula (III) may be prepared from compounds of
Formula (XI) by removal of the protecting group, where PG=Boc,
under acidic conditions using for example trifluoroacetic acid in
dichloromethane at temperatures of around 25.degree. C.
[0144] Compounds of Formula (III) wherein R.sup.2 is H, Y is
C.sub.0 alkyl, Z is --C(O)-- and R.sup.3 is --C.sub.0alkylaryl or
--C.sub.0alkylhetaryl can be prepared according to Scheme 9.
##STR13##
[0145] Compounds of Formula (XXIII) are reacted with potassium
phthalimide in a solvent such as DMF to give compounds of Formula
(XXII) which can then be reacted with ethylene glycol in the
presence of a catalytic amount of acid such as p-toluene sulfonic
acid in a solvent such as toluene whilst removing water to give
compounds of Formula (XXI). The phthalimide protecting group can
then be removed using hydrazine hydrate by heating as a neat
solution or by heating in a solvent such as ethanol to give
compounds of Formula (XX). These amines are then coupled with
compounds of Formula (II) under standard coupling conditions as
described in Scheme 1, and then the ketal group is removed in the
presence of acid such as hydrochloric acid in a solvent such as
acetone at reflux temperature to give the compounds of Formula (I).
##STR14##
[0146] Compounds of Formula (I) (wherein Z is C.dbd.O and R.sup.3
is C.sub.1-4alkoxy) may be prepared as illustrated in Scheme 10 by
combination of compounds of Formula (II) and compounds of Formula
(XII) under standard coupling conditions as described for Scheme 1.
Compounds of Formula (XII) are generally commercially available or
are readily prepared by known techniques
[0147] Compounds of Formula (I) (wherein Z is absent and R.sup.3 is
--CO.sub.2H) may be prepared by ester hydrolysis of compounds of
Formula (I) (where Z is C.dbd.O and R.sup.3 is a C.sub.1-4alkoxy
group) using aqueous alkali typically at a temperature of around
25.degree. C. for 30 min to 20 h.
[0148] The compounds of Formula (I) may be prepared singly or as
compound libraries comprising at least 2, for example 5 to 1,000
compounds and more preferably 10 to 100 compounds of Formula (I).
Compound libraries may be prepared by a combinatorial "split and
mix" approach or by multiple parallel synthesis using either
solution or solid phase chemistry, using procedures known to those
skilled in the art.
[0149] During the synthesis of the compounds of Formula (I), labile
functional groups in the intermediate compounds, e.g. hydroxy,
carboxy and amino groups, may be protected. The compounds of
Formula (II) may be protected in the 1-position e.g. with an
arylmethyl, acyl, alkoxycarbonyl, sulfonyl or silyl group. The
protecting groups may be removed at any stage in the synthesis of
the compounds of Formula (I) or may be present on the final
compound of Formula (I). A comprehensive discussion of the ways in
which various labile functional groups may be protected and methods
for cleaving the resulting protected derivatives is given in for
example, Protective Groups in Organic Chemistry, T. W. Greene and
P. G. M. Wuts, (1991) Wiley-Interscience, New York, 2.sup.nd
edition.
[0150] Any novel intermediates as defined above are also included
within the scope of the invention.
[0151] The invention also provides a compound of Formula (IIA):
##STR15##
[0152] or a C.sub.1-4alkyl ester or protected derivative thereof,
wherein:
[0153] one of X.sub.1, X.sub.2, X.sub.3 and X.sub.4 must be N and
the others must be C; [0154] R.sup.1 and R.sup.1' are each
independently, halogen, hydroxyl, cyano, C.sub.0-4alkyl,
C.sub.1-4alkoxy, fluoromethyl, difluoromethyl, trifluoromethyl,
ethenyl, or ethynyl or absent;
[0155] provided that when X.sub.1, X.sub.3 or X.sub.4 is N, then
R.sup.1 and R.sup.1' are not both hydrogen.
[0156] Preferred compounds of formula (IIA) include those where
X.sub.3 is N.
[0157] Preferably one of R.sup.1 and R.sup.1' is hydrogen and the
other is halo or cyano, in particular, when X.sub.1, X.sub.3 or
X.sub.4 is N, 5-halo e.g. 5-chloro, or 5-cyano.
[0158] Specific compounds of Formula (IIA) include: [0159]
5-Chloro-1H-pyrrolo[3,2-b]pyridine-2-carboxylic acid; [0160]
5-Bromo-1H-pyrrolo[3,2-b]pyridine-2-carboxylic acid; [0161]
5-Cyano-1H-pyrrolo[3,2-b]pyridine-2-carboxylic acid; [0162]
5-Methoxy-1H-pyrrolo[3,2-b]pyridine-2-carboxylic acid; [0163]
1H-Pyrrolo[3,2-c]pyridine-2-carboxylic acid; [0164]
6-Chloro-1H-pyrrolo[3,2-c]pyridine-2-carboxylic acid; [0165]
6-Cyano-1H-pyrrolo[3,2-c]pyridine-2-carboxylic acid; [0166]
5-Chloro-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid; [0167]
5-Bromo-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid; [0168]
5-Ethynyl-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid; [0169]
5-Cyano-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid; [0170]
5-Methyl-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid; [0171]
5-Chloro-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid; [0172]
6-Chloro-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid; and [0173]
6-Cyano-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid.
[0174] The invention also provides a compound of formula (XIX):
##STR16##
[0175] wherein R.sup.1, R.sup.1', X.sub.1, X.sub.2, X.sub.3, and
X.sub.4 are as defined above for Formula (I) and R.sup.3 is
--C.sub.0alkylaryl or --C.sub.0alkylhetaryl.
[0176] The invention also provides the novel compound
4(S)-(4-fluorobenzyl)oxazolidine-2,5-dione, which may be prepared
as described in the Experimental section below.
EXPERIMENTAL
Materials & Methods
[0177] Column chromatography was carried out on SiO.sub.2 (40-63
mesh). LCMS data were obtained using a Waters Symmetry 3.5.mu.
C.sub.18 column (2.1.times.30.0 mm, flow rate=0.8 mL/min) eluting
with a (5% MeCN in H.sub.2O)-MeCN solution containing 0.1%
HCO.sub.2H over 6 min and UV detection at 220 nm. Gradient
information: 0.0-1.2 min: 100% (5% MeCN in H.sub.2O); 1.2-3.8 min:
ramp up to 10% (5% MeCN in H.sub.2O)--90% MeCN; 3.8-4.4 min: hold
at 10% (5% MeCN in H.sub.2O)--90% MeCN; 4.4-5.5 min: ramp up to
100% MeCN; 5.5-6.0 min: return to 100% (5% MeCN in H.sub.2O). The
mass spectra were obtained employing an electrospray ionisation
source in the positive (ES.sup.+) ion mode. NMR spectra were
acquired at 27.degree. C. on a Varian Mercury 400 spectrometer
operating at 400 MHz or on a Bruker AMX2 500 spectrometer operating
at 500 MHz. Mass directed purification was performed on a Micromass
Platform LC with cone voltage 30 v, employing an electrospray
ionisation source in the positive (ES.sup.+) ion mode, Waters 996
Photodiode Array Detector (210-390 nm), Xterra Prep MS, C.sub.18,
5.mu. 19.times.50 mm columns, and a mobile Phase of MeCN+0.1%
Formic Acid/H.sub.2O+5% MeCN+0. 1% Formic Acid
[0178] Abbreviations and acronyms: BOC: tert-butyloxycarbonyl;
DABCO: bicyclo(2,2,2)-1,4-diazaoctane; DBU:
1,8-Diazabicyclo[5.4.0]undec-7-ene; DCM: Dichloromethane; DIPEA:
N,N-Diisopropylethylamine; DMAP: 4-(N,N-dimethylamino)pyridine;
DMF: N,N-Dimethylformamide; DMSO: Dimethylsulfoxide; DMTMM:
4-(4,6-dimethoxy[ 1.3.5]triazin-2-yl)-4-methylmorpholinium chloride
hydrate; EDCI: 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide
hydrochloride; GP: Glycogen Phosphorylase; HATU:
O-(7-Azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium
hexafluorophosphate; HOBt: 1-Hydroxybenzotriazole; MDP: Mass
directed purification; MgSO.sub.4: Magnesium sulfate; PS: Polymer
supported; rt: room temperature; RT: Retention time; THF:
Tetrahydrofuran, TBTU: O-(benzotriazol-1-yl)
N,N,N',N'-tetramethyluronium tetrafluoroborate Preparation 1:
6-Methyl-5-nitropyridin-2-ylamine ##STR17##
[0179] The title compound was prepared according to the method of
Parker and Shive (J. Am. Chem. Soc., 1947, 69, 63) as a brown
powder. .delta..sub.H (d.sub.6 DMSO): 2.6 (3H, s), 6.37 (1H, d,
9.13 Hz), 7.31 (2H, s), 8.08 (1H, d, 9.13 Hz); m/z
(ES.sup.+)=154.06 [M+H].sup.+; RT=0.57 min. Preparation 2:
6-Methyl-5-nitro-1H-pyridin-2-one ##STR18##
[0180] The title compound was prepared according to the method of
Baumgarten and Su (J. Am. Chem. Soc, 1952, 74, 3828) as a brown
powder. .delta..sub.H (d.sub.6 DMSO): 2.62 (3H, s), 6.28 (1H, d,
9.94 Hz), 8.10 (1H, d, 9.94 Hz).
[0181] Preparation 3: 2-Chloro-6-methyl-5-nitropyridine
##STR19##
[0182] A suspension of 6-methyl-5-nitro-1H-pyridin-2-one
(Preparation 2, 3.53 g, 22.9 mmol) in phosphorous oxychloride (20
mL) was heated to 115.degree. C. (oil bath temperature) for 3 h
then allowed to cool to rt. The phosphorous oxychloride was removed
in vacuo and the residue poured into iced water (100 mL). The
mixture was quenched by addition of saturated sodium bicarbonate
solution, then the aqueous mixture was extracted with ethyl acetate
(3.times.100 mL). The combined organics were washed with brine,
dried (MgSO.sub.4), filtered and concentrated in vacuo to furnish
the title compound as a brown solid. .delta..sub.H (CDCl.sub.3):
2.86 (3H, s), 7.36 (1H, d, 8.59 Hz), 8.27 (1H, d, 8.32 Hz).
Preparation 4: 3-(2-Chloro-5-nitropyridin-6-yl)-2-oxopropionic acid
ethyl ester ##STR20##
[0183] To a solution of potassium ethoxide (134 mg, 1.59 mmol) in
diethyl ether (5 mL) and ethanol (1 mL) was added diethyl oxalate
(218 .mu.L, 1.59 mmol) in one portion and the resulting solution
was stirred for 30 min at rt. 2-Chloro-6-methyl-5-nitropyridine
(Preparation 3, 250 mg, 1.45 mmol) was added as a suspension in
diethyl ether (2 mL, anhydrous) and stirring was continued for 17 h
at rt. The mixture was filtered on a sinter, washing with cold
diethyl ether. The collected precipitate was dissolved in glacial
acetic acid then evaporated to dryness in vacuo to give the title
compound as a brown powder. .delta..sub.H (CDCl.sub.3): 1.40 (3H,
t, 7.27 Hz), 4.38 (2H, q, 7.25 Hz), 7.33 (1H, d, 8.59 Hz), 7.37
(1H, s), 8.40 (1H, d, 8.86 Hz). Preparation 5:
5-Chloro-1H-pyrrolo[3,2-b]pyridine-2-carboxylic acid ethyl ester
##STR21##
[0184] To a solution of
3-(2-chloro-5-nitropyridin-6-yl)-2-oxopropionic acid ethyl ester
(Preparation 4, 1.53 g, 5.6 mmol) in THF (65 mL) and ethanol (30
mL) was added saturated aqueous ammonium chloride solution (30 mL)
and the suspension was vigorously stirred at rt. Iron powder (1.95
g, 34.8 mmol) was added portionwise and the mixture was heated
under reflux for 2 h then allowed to cool prior to filtration
through a celite plug, and washed through with warm THF. The
mixture was concentrated under reduced pressure to give an aqueous
suspension, which was filtered through a sinter, washing with
water. The wet solid was washed with methanol and dried. The
residue was adsorbed onto silica gel and purified via flash
chromatography eluting with ethyl acetate/hexane (1:19) to give the
title compound as a white solid. .delta..sub.H (CD.sub.3OD): 1.42
(3H, t, 7.03 Hz), 4.42 (2H, q, 7.32 Hz), 7.15 (1H, s), 7.30 (1H, d,
8.79 Hz), 7.89 (1H, d, 8.35 Hz); m/z (ES.sup.+)=225.03 [M+H]+;
RT=3.32 min. Preparation 6:
5-Chloro-1H-pyrrolo[3,2-b]pyridine-2-carboxylic acid ##STR22##
[0185] To a stirred solution of
5-chloro-1H-pyrrolo[3,2-b]pyridine-2-carboxylic acid ethyl ester
(Preparation 5, 151 mg, 0.67 mmol) in ethanol (10 mL) was added
sodium hydroxide (0.35 mL, 2M) and the stirred solution was heated
at 70.degree. C. for 2 h. The reaction mixture was then allowed to
cool to rt and left to stand for 16 h. The pH was adjusted to 4 by
addition of glacial acetic acid, the solvents removed in vacuo to
give a white solid, which was suspended in dichloromethane and
filtered through a sinter, washing with additional dichloromethane.
The filter cake was washed with ethyl acetate (3.times.30 mL) and
dried to give the title compound as a white solid. .delta..sub.H
(CD.sub.3OD): 6.97 (1H, s), 7.17 (1H, d, 8.35 Hz), 7.83 (1H, d,
8.35 Hz); m/z (ES.sup.+)=197 [M+H].sup.+; RT=2.82 min. Preparation
7: N-tert-Butyloxycarbonyl-(S)-phenylalanine dimethylamide
##STR23##
[0186] A solution of dimethylamine hydrochloride (1.45 g, 17.8
mmol) in DMF (46 mL) was cooled to -10.degree. C. and triethylamine
(2.7 mL, 19.4 mmol) was added. N-Boc-L-phenylalanine (4.59 g, 17.3
mmol, Aldrich) and HOBt (3.49 g, 26 mmol) were then added and the
reaction stirred for 5 min before addition of EDCI (3.33 g, 17.4
mmol). The reaction mixture was left to stir for 16 h then diluted
with ethyl acetate (400 mL), washed sequentially with aqueous
sodium hydroxide solution (2M, 2.times.100 mL), hydrochloric acid
(2N, 2.times.100 mL), brine (250 mL) and then dried (MgSO.sub.4).
Evaporation in vacuo gave the title compound as a pale yellow oil.
.delta..sub.H (CDCl.sub.3): 1.41 (9H, s), 2.61, 2.85 (6H, 2s),
2.91-2.99 (2H, m), 4.83 (H1, m), 5.40 (1H, br d), 7.18-7.29 (5H,
m). Preparation 8: 2-(S)-Amino-N,N-dimethyl-3-phenylpropionamide
hydrochloride ##STR24##
[0187] To a solution of N-tert-butyloxycarbonyl-(S)-phenylalanine
dimethylamide (Preparation 7, 24.8 g, 84 mmol) in methanol (50 mL)
was added a solution of hydrochloric acid (4N, in dioxane, 40 mL)
and the mixture stirred at rt for 3 h. The resulting solution was
concentrated in vacuo then dissolved in water (300 mL). The aqueous
solution was washed with ethyl acetate (3.times.100 mL) and
concentrated again. Successive recrystallisations with methanol
(200 mL) and a mixture of methanol and toluene (1:1, 200 mL) gave
the title compound as colourless crystals. .delta..sub.H (D.sub.2O)
2.75, 2.90 (6H, 2.times.s), 3.18 (2H, m), 4.72 (1H, t), 7.28-7.45
(5H, m). Preparation 9: Pyridin-4-ylcarbamic acid tert-butyl ester
##STR25##
[0188] Pyridin-4-ylcarbamic acid tert-butyl ester was prepared
according to the method of Spivey et al., (J. Org. Chem., 1999, 64,
9430) to give the title compound as a white crystalline solid.
.delta..sub.H (CDCl.sub.3): 1.52 (9H, s), 7.08 (1H, br s), 7.32
(2H, d), 8.43 (2H, d). Preparation 10:
(3-Methylpyridin-4-yl)carbamic acid tert-butyl ester ##STR26##
[0189] (3-Methylpyridin-4-yl)carbamic acid tert-butyl ester was
prepared according to the method of Hands et al., (Synthesis, 1996,
7, 877) to give the title compound as a pale yellow solid.
.delta..sub.H (CDCl.sub.3): 1.55 (9H, s), 2.22 (3H, s), 6.52 (1H,
s), 7.97 (1H, d), 8.27 (1H, s), 8.36 (1H, d). Preparation 11:
1H-Pyrrolo[3,2-c]pyridine-2-carboxylic acid ethyl ester
##STR27##
[0190] A solution of (3-methylpyridin-4-yl)carbamic acid tert-butyl
ester (Preparation 10, 1.0 g, 4.8 mmol) in anhydrous THF (10 mL)
was cooled to -40.degree. C. and tert-butyl lithium (5.9 mL, 10.1
mmol) added dropwise. The temperature was maintained at -40.degree.
C. for 1 h and then a solution of diethyl oxalate (0.72 mL, 5.3
mmol) in THF (20 mL) was added to the mixture. The reaction was
warmed to 0.degree. C., maintained at this temperature for 2 h,
warmed to rt and stirred for 16 h. Hydrochloric acid (2N, 40 mL)
was added and the reaction heated under reflux for 90 min,
concentrated in vacuo and adjusted to pH 8 with saturated aqueous
sodium hydrogen carbonate solution. The mixture was extracted with
ethyl acetate (3.times.100 mL) and the organic solution dried
(MgSO.sub.4) and concentrated in vacuo to give the title compound.
.delta..sub.H (d.sub.6 DMSO): 1.33 (3H, t), 4.35 (2H, q), 7.27 (1H,
s), 7.38 (1H, d), 8.25 (1H, d), 8.95 (1H, s); m/z (ES.sup.+)=191
[M+H].sup.+. Preparation 12: 1H-Pyrrolo[3,2-c]pyridine-2-carboxylic
acid ##STR28##
[0191] Aqueous sodium hydroxide solution (2.4 mL, 2M, 4.8 mmol) was
added to a solution of 1H-pyrrolo[3,2-c]pyridine-2-carboxylic acid
ethyl ester (Preparation 11, 0.76 g, 4.0 mmol) in ethanol (40 mL)
and the mixture heated under reflux for 2 h before being cooled and
concentrated in vacuo. The residue was dissolved in a minimum
amount of water, glacial acetic acid (1 mL) was added and the
solution cooled in a refrigerator for 3 days. The resultant
precipitate was collected by filtration washed with ether and dried
in vacuo to give the title compound as a cream coloured solid.
.delta..sub.H (D.sub.2O): 7.05 (1H, s), 7.63 (1H, d), 8.08 (1H, d),
8.94 (1H, s). Preparation 13:
3-(3-Nitropyridin-4-yl)-2-oxopropionic acid ethyl ester
##STR29##
[0192] To a solution of potassium ethoxide (3.1 g, 36.2 mmol) in
diethyl ether (70 mL) and ethanol (10 mL) under an argon atmosphere
was added diethyl oxalate (4.9 mL, 36.2 mmol) and the reaction
stirred at rt for 30 min. A solution of 4-methyl-3-nitropyridine
(5.0 g, 36.2 mmol) in diethyl ether (20 mL) was added resulting in
the immediate formation of a dark red precipitate. The reaction
mixture was stirred at rt for 72 h, then cooled to 0.degree. C. and
filtered. The solid was dissolved in water (500 mL) acidified to pH
4 with acetic acid and the precipitate collected and dried to give
the title compound as a red solid. .delta..sub.H (d.sub.6 DMSO):
1.27 (3H, t), 4.25 (2H, q), 6.74 (1H, s), 8.34 (1H, d), 8.43 (1H,
d), 8.98 (1H, s); m/z (ES.sup.+)=239 [M+H].sup.+. Preparation 14:
1H-Pyrrolo[2,3-c]pyridine-2-carboxylic acid ethyl ester
##STR30##
[0193] To a solution of 3-(3-nitropyridin-4-yl)-2-oxopropionic acid
ethyl ester (Preparation 13, 500 mg, 2.1 mmol) in ethanol (20 mL)
and THF (10 mL) was added saturated ammonium chloride solution (10
mL) and iron powder (700 mg, 12.6 mmol). The reaction was heated
under reflux for 1 h, then filtered through celite and washed
through with hot ethyl acetate (3.times.30 mL). The combined
organic fractions were washed with brine (2 mL), dried (MgSO.sub.4)
and concentrated in vacuo to give the title compound as a brown
solid. .delta..sub.H (CD.sub.3OD): 1.44 (3H, t), 4.43 (2H, q), 7.21
(1H, s), 7.69 (1H, d), 8.12 (1H, d), 8.80 (1H, s). Preparation 15:
1H-Pyrrolo[2,3-c]pyridine-2-carboxylic acid ##STR31##
[0194] To a solution of 1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid
ethyl ester (Preparation 14, 310 mg, 1.6 mmol) in ethanol (20 mL)
was added 2N sodium hydroxide solution (1 mL, 2.0 mmol) and the
reaction mixture heated under reflux for 1.5 h then concentrated in
vacuo. The residue was dissolved in water (10 mL) and acidified
with acetic acid giving an immediate brown precipitate. The solid
was filtered and dried to give the title compound as a beige solid.
.delta..sub.H (D.sub.2O): 7.11 (1H, s), 7.99 (1H, d), 8.05 (1H, d),
8.85 (1H, s); m/z (ES.sup.+)=163 [M+H].sup.+. Preparation 16:
3-(2-Chloro-5-nitropyridin-4-yl)-2-oxopropionic acid ethyl ester
##STR32##
[0195] Route A: To a solution of potassium ethoxide (1.46 g, 17.4
mmol) in diethyl ether (80 mL) and ethanol (10 mL) under an argon
atmosphere was added diethyl oxalate (2.4 mL, 17.4 mmol) and the
mixture stirred at rt for 0.5 h. A solution of
2-chloro-4-methyl-5-nitropyridine (3.0 g, 17.4 mmol) in diethyl
ether (20 mL) was added resulting in the formation of a dark green
precipitate. The reaction was stirred at rt for 15 h, cooled to
0.degree. C., filtered and washed with cold diethyl ether to give a
dark green solid. The solid was dissolved in water (200 mL) and
acidified to pH 4 with acetic acid to give an orange precipitate.
The solid was collected by filtration and dried to give the title
compound. m/z (ES.sup.+)=273 [M+H].sup.+.
[0196] Route B: To a solution of 2-chloro-4-methyl-5-nitropyridine
(1.0 g, 5.8 mmol) in diethyl oxalate (4.23 g, 29 mmol) under an
argon atmosphere was added 1,8-diazabicyclo[5.4.0]undec-7-ene (0.95
mL, 6.4 mol). The mixture was stirred at rt for 1.5 h then diluted
with t-butyl methyl ether (40 mL), water (3 mL) and acetic acid (1
ml). The organic layer was separated, washed with water, dried
(MgSO.sub.4) and evaporated to dryness. The resultant damp red
solid residue was finally dried under high vacuum at 40-50.degree.
C. to give the title compound. Preparation 17:
5-Chloro-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid ethyl ester
##STR33##
[0197] 3-(2-Chloro-5-nitropyridin-4-yl)-2-oxopropionic acid ethyl
ester (Preparation 16, 3.0 g, 11.0 mmol) was dissolved in ethanol
(100 mL) and THF (50 mL). Iron powder (3.7 g, 66.0 mmol) and
saturated ammonium chloride solution (50 mL) were added and the
mixture heated under reflux for 2 h. The mixture was cooled,
filtered through celite and washed several times with ethyl
acetate. The organic layers were combined, washed with brine (100
mL), dried (MgSO.sub.4) and concentrated in vacuo to give the title
compound as a brown solid. .delta..sub.H (CD.sub.3OD): 1.42 (3H,
t), 4.44 (2H, q), 7.15 (1H, s), 7.70 (1H, s), 8.59 (1H, s); m/z
(ES.sup.+)=225 [M+H].sup.+. Preparation 18:
5-Chloro-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid ##STR34##
[0198] Route A: To a solution of
5-chloro-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid ethyl ester
(Preparation 17, 1.78 g, 7.9 mmol) in ethanol (70 mL) was added
sodium hydroxide solution (5.2 mL, 2M, 10.3 mmol) and the mixture
heated under reflux for 2 h. The solvent was removed in vacuo and
the solid dissolved in water (150 mL) and acidified to pH 4 with
acetic acid to give the title compound as a brown solid that was
isolated by filtration. .delta..sub.H (CD.sub.3OD): 7.13 (1H, s),
7.68 (1H, s), 8.58 (1H, s); m/z (ES.sup.+)=197 [M+H].sup.+.
[0199] Route B: A mixture of 6-chloro-4-iodopyridin-3-ylamine
(Preparation 106, 0.33 g, 1.30 mmol), pyruvic acid (0.27 mL, 3.89
mmol), DABCO (0.44 g, 3.89 mmol) and palladium acetate (0.015 g,
0.07 mmol) in dry DMF was stirred vigorously and degassed with
argon for 15 min. The reaction mixture was heated to 107.degree. C.
for 5 h. The reaction mixture was allowed to cool to rt and stirred
for 16 h. The volatiles were removed under reduced pressure and the
residue partitioned between ethyl acetate (100 mL) and water (50
mL). The layers were separated and the aqueous extracted with ethyl
acetate (2.times.50 mL). The combined organics were extracted with
aqueous NaOH (2M, 3.times.70 mL). The combined aqueous extracts
were acidified to pH 4 by careful addition of glacial acetic acid,
then extracted with ethyl acetate (3.times.60 mL). The combined
organics were washed with brine (50 mL), dried (MgSO.sub.4),
filtered and concentrated in vacuo to give the title compound as a
brown solid. RT=2.72 min, m/z (ES.sup.+)=197 [M+H].sup.+
Preparation 19:
[1-(S)-(4-Fluorobenzyl)-2-(4-hydroxypiperidin-1-yl)-2-oxoethyl]carbamic
acid tert-butyl ester ##STR35##
[0200] To a stirred solution of Boc-3-(4-fluorophenyl)-(S)-alanine
(10.0 g, 35.3 mmol), 4-hydroxypiperidine hydrochloride (5.1 g, 37.1
mmol) and HOBt (7.2 g, 52.9 mmol) in DMF (100 mL), was added DIPEA
(12.3 mL, 70.6 mmol) and after 5 min, EDCI (7.4 g, 38.8 mmol) and
the reaction stirred at rt for 16 h. The solvent was removed in
vacuo and the residue partitioned between water (150 mL) and ethyl
acetate (2.times.150 mL). The combined organic fractions were
washed with sodium hydroxide solution (2M, 50 mL), hydrochloric
acid (2N, 50 mL), dried (MgSO.sub.4) and concentrated in vacuo. The
product was chromatographed on silica gel eluting with ethyl
acetate to give the title compound as a white solid. m/z
(ES.sup.+)=367 [M+H].sup.+; RT=3.28 min. Preparation 20:
2-(S)-Amino-3-(4-fluorophenyl)-1-(4-hydroxypiperidin-1-yl)propan-1-one
hydrochloride ##STR36##
[0201] Route A: To a solution of [1
(S)-(4-fluorobenzyl)-2-(4-hydroxypiperidin-1-yl)-2-oxoethyl]carbamic
acid tert-butyl ester (Preparation 19, 11.6 g, 31.7 mmol) in
methanol (40 mL) was added hydrochloric acid in dioxane (24 mL, 4N,
95.0 mmol) and the reaction mixture stirred at rt for 6 h. The
solvent was removed in vacuo and the residue was dissolved in water
(100 mL) and extracted into ethyl acetate (2.times.50 mL). The
aqueous phase was evaporated to dryness to give the title compound
as a white solid. .delta..sub.H (D.sub.2O): 0.52-0.63 (0.5H, m),
1.12-1.23 (0.5H, m), 1.26-1.38 (1H, m), 1.42-1.50 (0.5H, m),
1.59-1.69 (0.5H, m), 1.72-1.82 (1H, m), 2.61-2.71 (0.5H, m),
2.91-3.15 (4H, m), 3.33-3.47 (1H, m), 3.69-3.78 (1H, m), 3.88-3.96
(1H, m), 4.60-4.72 (1H, m), 7.02-7.11 (2H, m), 7.14-7.26 (2H,
m).
[0202] Route B: To a solution of 4-hydroxypiperidine (40 mg, 0.4
mmol) in anhydrous THF (3 mL) under an argon atmosphere was added a
solution of 4(S)-(4-fluorobenzyl)oxazolidine-2,5-dione (Preparation
117, 100 mg, 0.48 mmol) in THF (2 mL) dropwise over 15 min. The
resulting mixture was stirred for 40 h at rt before removal of the
solvent in vacuo. The crude material was purified by column
chromatography (SiO.sub.2, 9:1 dichloromethane/methanol) to afford
an oil. The free amine was dissolved in methanol (2 mL) and a
solution of 4M HCl in dioxane (0.3 mL) was added and stirring was
continued for 15 min. The solvent was removed in vacuo and the
material partitioned between ethyl acetate (5 mL) and water (5 mL).
The aqueous layer was concentrated in vacuo to give the title
compound. .delta..sub.H (CD.sub.3OD): 7.36-7.29 (2H, m), 7.17-7.10
(2H, m), 4.70 (1H, t), 4.09-4.00 (0.5H, m), 3.91-3.74 (1.5H, m),
3.64-3.56 (0.5H, m), 3.43-3.31 (1H, m), 3.26-3.07 (3H, m),
2.89-2.80 (0.5H, m), 1.87-1.69 (1.5H, m), 1.56-1.36 (2H, m),
1.09-0.99 (0.5H, m). Preparation 21:
(3S,2R)-3-Amino-2-hydroxy-4-phenylbutyric acid methyl ester
##STR37##
[0203] (3S,2R)-3-Amino-2-hydroxy-4-phenylbutyric acid methyl ester
was synthesized according to the method of A. Fassler et al.,
(Tetrahedron Lett., 1998, 39, 4925) in three steps from
commercially available N-(tert-butyloxycarbonyl)-L-phenylalaninal.
R.sub.f 0.29 (dichloromethane/methanol: 9/1); .delta..sub.H
(CDCl.sub.3): 2.04 (3H, m), 2.73 (1H, dd), 2.92 (1H, dd), 3.36 (1H,
ddd), 3.79 (3H, s), 4.08 (1H, d), 7.22-7.33 (5H, m). Preparation
21A: (3S,2S)-3-Amino-2-hydroxy-4-phenylbutyric acid methyl ester
##STR38##
[0204] (3S,2S)-3-Amino-2-hydroxy-4-phenylbutyric acid methyl ester
was obtained as a side product in Preparation 21. R.sub.f 0.19
(dichloromethane/methanol: 9/1); .delta..sub.H (CDCl.sub.3): 2.10
(2H, br s), 2.61 (1H, dd), 2.84 (1H, dd), 3.38 (1H, m), 3.78 (3H,
s), 4.14(1H, br s). Preparation 22:
Cis-3,4-Dihydroxypyrrolidine-1-carboxylic acid benzyl ester
##STR39##
[0205] A solution of benzyl-2,5-dihydro-1H-pyrrole-1-carboxylate
(10.0 g, 49.3 mmol) in THF (200 mL) was treated with osmium
tetroxide solution (2.5% in tert-butanol, 5 mL) and
N-methylmorpholine (6.90 g, 59.0 mmol) and the reaction mixture
stirred at rt under argon for 72 h. Aqueous sodium thiosulfate
solution (10%, 200 mL) was added and the mixture stirred for a
further 1 h and then concentrated in vacuo. The resulting aqueous
layer was extracted with ethyl acetate (3.times.200 mL) and the
combined organic layers washed with aqueous sodium thiosulfate
solution (10%, 300 mL) and hydrochloric acid (1N, 300 mL). The
organic fraction was dried (MgSO.sub.4) and concentrated in vacuo
to give the title compound as an off-white solid. .delta..sub.H
(CDCl.sub.3): 2.67 (2H, br s), 3.38-3.45 (2H, m), 3.63-3.67 (2H,
m), 4.22-4.26 (2H, m), 5.12 (2H, s), 7.30-7.38 (5H, m); m/z
(ES.sup.+)=238 [M+H].sup.+. Preparation 23:
Cis-3,4-Dihydroxypyrrolidine ##STR40##
[0206] Palladium-on-carbon (144 mg, 10 wt %) was added to a
solution of cis-3,4-dihydroxypyrrolidine-1-carboxylic acid benzyl
ester (Preparation 22, 403 mg, 1.70 mmol) in ethanol (20 mL) and
cyclohexene (2 mL) and the mixture stirred and heated under reflux
for 6 h. After filtration through celite and repeated washing of
the catalyst with methanol (CARE!), the filtrate and washings were
combined and concentrated in vacuo to give the title compound as a
colourless oil. .delta..sub.H (d.sub.4 MeOH): 2.81 (2H, dd), 3.03
(2H, m), 4.07 (2H, m). Preparation 24:
2-Bromo-4-methyl-5-nitropyridine ##STR41##
[0207] To a suspension of 2-hydroxy-4-methyl-5-nitropyridine (1 g,
6.5 mmol) in dichloroethane (10 mL) was added a solution of
phosphorus oxybromide (2.8 g, 9.7 mmol) in dichloroethane (10 mL).
The reaction mixture was heated under reflux for 4 h, then cooled
to rt and quenched with water (4 mL). The layers were separated and
the aqueous layer extracted into dichloromethane (2.times.3 mL).
The combined organics were dried (MgSO.sub.4), concentrated in
vacuo and chromatographed on silica gel eluting with
dichloromethane to give the title compound as a pale yellow solid.
.delta..sub.H (CDCl.sub.3): 2.63 (3H, s), 7.52 (1H, s), 8.96 (1H,
s). Preparation 25: 3-(2-Bromo-5-nitropyridin-4-yl)-2-oxopropionic
acid ethyl ester ##STR42##
[0208] To a solution of potassium ethoxide (2.05 g, 24.3 mmol) in
diethyl ether (70 mL) and ethanol (10 mL) under an argon atmosphere
was added diethyl oxalate (3.3 mL, 24.3 mmol) and the reaction
stirred at rt for 15 min. A solution of
2-bromo-4-methyl-5-nitropyridine (Preparation 24, 4.8 g, 22.1 mmol)
in diethyl ether (20 mL) was added to the reaction mixture giving
an immediate black precipitate. The reaction was allowed to stir at
rt for 6 h, then cooled to 0.degree. C. and filtered to give a
black solid. The solid was dissolved in water (250 mL) and
acidified to pH 4 with acetic acid resulting in formation of a red
precipitate. The solid was collected and dried to give the title
compound as a red solid. .delta..sub.H (d.sub.6 DMSO): 1.16 (3H,
t), 4.01 (2H, q), 6.55 (1H, s), 7.92 (1H, s), 8.96 (1H, s).
Preparation 26: 5-Bromo-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid
ethyl ester ##STR43##
[0209] Route A: To a solution of
3-(-bromo-5-nitropyridin-4-yl)-2-oxopropionic acid ethyl ester
(Preparation 25, 3.38 g, 10.7 mmol) in THF (50 mL) and ethanol (100
mL) was added saturated ammonium chloride solution (50 mL) and iron
powder (3.57 g, 64.0 mmol) and the reaction heated under reflux for
2 h. The reaction mixture was filtered through celite and washed
several times with ethyl acetate. The solvent was removed in vacuo
and the remainder partitioned between saturated sodium hydrogen
carbonate solution (100 mL) and ethyl acetate (3.times.150 mL). The
combined organic fractions were dried (MgSO.sub.4) and concentrated
in vacuo to give the title compound as a brown solid. .delta..sub.H
(CD.sub.3OD): 1.42 (3H, t), 4.43 (2H, q), 7.14 (1H, s), 7.85 (1H,
s), 8.58 (1H, s); m/z (ES.sup.+)=269 [M+H].sup.+.
[0210] Route B: To a solution of 2-bromo-4-methyl-5-nitropyridine
(Preparation 24, 5.7 g, 26.3 mmol) in diethyl oxalate (17.9 mL)
under argon was added 1,8-diazabicyclo[5,4,0]undec-7-ene (4.5 mL,
30.2 mmol) to give a dark red precipitate. Reaction mixture was
stirred at rt for 4.5 h and concentrated in vacuo. Acetic acid (140
mL) was added to the residue under argon and heated to 60.degree.
C. Iron (2.94 g, 52.6 mmol) was added in small portions over a
period of 1 h. he reaction mixture was heated at 80.degree. C. for
4 h. The reaction mixture was cooled to rt and poured into water
(300 mL) which gave a beige precipitate. The precipitate was
isolated and washed with water. The solid obtained was dissolved in
ethyl acetate (700 ml) and filtered. The filtrate was concentrated
in vacuo to give the title compound. m/z (ES+)=269 [M+H].sup.+;
RT=3.39 min. Preparation 27:
5-Bromo-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid ##STR44##
[0211] Sodium hydroxide solution (1.1 mL, 2M, 2.23 mmol) was added
to a solution of 5-bromo-1H-pyrrolo[2,3-c]pyridine-2-carboxylic
acid ethyl ester (Preparation 26, 500 mg, 1.86 mmol) in ethanol (20
mL), and the reaction mixture heated under reflux for 1.5 h and
then concentrated in vacuo. The residue was dissolved in water (15
mL) and acidified with acetic acid resulting in formation of a
brown precipitate. The solid was collected by filtration and dried
to give the title compound as a brown solid. .delta..sub.H (d.sub.6
DMSO): 7.08 (1H, s), 7.97 (1H, s), 8.60 (1H, s); m/z (ES.sup.+)=241
[M+H].sup.+. Preparation 28: 1H-Pyrrolo[2,3-b]pyridine-2-carboxylic
acid ##STR45##
[0212] The title compound was prepared according to the method of
Romero and Mitchell (WO 91/09849). Preparation 29:
2-Methyl-3-nitropyridine ##STR46##
[0213] A mixture of 2-chloro-3-nitropyridine (1.00 g, 6.30 mmol),
potassium carbonate (2.62 g, 18.90 mmol),
tetrakis(triphenylphosphine)palladium (0.73 g, 0.63 mmol) and
trimethyl boroxine (0.88 mL, 6.30 mmol) in 1,4-dioxane (2 mL) and
water (8 mL) was heated to 110.degree. C. (oil bath temperature)
for 6 h and then stirred for 16 h at rt. The mixture was then
filtered through a celite pad, washing through with THF. The
filtrate was adsorbed onto silica gel in vacuo and purified via
flash column chromatography eluting with ethyl acetate/hexanes
(3:7) to give the title compound as a yellow solid. .delta..sub.H
(CDCl.sub.3): 2.86 (3H, s), 7.34 (1H, dd), 8.26 (1H, dd), 8.71 (1H,
dd). Preparation 30: 3-(3-Nitropyridin-2-yl)-2-oxopropionic acid
ethyl ester ##STR47##
[0214] To a solution of potassium ethoxide (2.44 g, 27.7 mmol) in
diethyl ether (90 mL) and ethanol (8 mL) was added diethyl oxalate
(3.79 mL, 27.7 mmol) resulting in a yellow suspension. The reaction
mixture was stirred for 5 min prior to the addition of
2-methyl-3-nitropyridine (Preparation 29, 3.40 g, 24.6 mmol) in one
portion. The resulting red suspension was stirred at rt, under
argon, for 20 h. The mixture was filtered, washed thoroughly with
diethyl ether and dried. The red solid was dissolved in water and
the mixture adjusted to pH 4 by addition of glacial acetic acid.
The resulting precipitate was collected by filtration, dissolved in
dichloromethane, washed with brine, dried (MgSO.sub.4), and then
filtered and concentrated in vacuo to give the title compound as an
orange solid. .delta..sub.H (CDCl.sub.3): 1.40 (3H, t), 4.39 (2H,
q), 7.34 (1H, s), 7.36 (1H, dd), 8.43 (1H, dd), 8.66 (1H, dd).
Preparation 31: 1H-Pyrrolo[3,2-b]pyridine-2-carboxylic acid ethyl
ester ##STR48##
[0215] To a suspension of 3-(3-nitropyridin-2-yl)-2-oxopropionic
acid ethyl ester (Preparation 30, 1.00 g, 4.20 mmol) in ethanol (30
mL, absolute) was added palladium (10% on activated carbon, 447 mg,
0.42 mmol) and the reaction mixture placed under an atmosphere of
hydrogen at a pressure of 20-30psi for 12 h with vigorous stirring.
The reaction mixture was filtered through celite, washing with
ethyl acetate and the filtrate concentrated in vacuo to ca. 20 mL.
Water (150 mL) was added and the mixture cooled to between
0.degree. C. and 5.degree. C. The precipitate that formed was
collected by filtration and dried to give the title compound as a
beige solid. .delta..sub.H (CDCl.sub.3): 1.44 (3H, t), 4.45 (2H,
q), 7.25 (1H, dd), 7.39 (1H, s), 7.75 (1H, dd), 8.57 (1H, dd), 8.98
(1H, s). Preparation 32: 1H-Pyrrolo[3,2-b]pyridine-2-carboxylic
acid ##STR49##
[0216] A suspension of 1H-pyrrolo[3,2-b]pyridine-2-carboxylic acid
ethyl ester (Preparation 31, 0.34 g, 1.77 mmol) in aqueous sodium
hydroxide solution (2M, 10 mL) was heated under reflux for 3 h and
the resulting solution was allowed to cool to rt. The pH was
adjusted to 4 by addition of glacial acetic acid. Excess acetic
acid was removed in vacuo and the resulting suspension cooled to
0.degree. C. and then left standing at rt for 16 h. The resulting
beige precipitate was collected by filtration and dried to give the
title compound as a beige solid. .delta..sub.H (d.sub.6 DMSO): 7.12
(1H, s), 7.23 (1H, dd), 7.79 (1H, d), 8.42 (1H, dd). Preparation
33: 6-Methoxy-2-methyl-3-nitropyridine ##STR50##
[0217] To a stirred suspension of
2-chloro-6-methoxy-3-nitropyridine (2.44 g, 12.9 mmol) in 10% v/v
aqueous dioxane (25 mL) was added tetrakis(triphenyl phosphine)
palladium (1.50 g, 1.3 mmol) and the mixture stirred for 15 min
prior to the addition of trimethylboroxine (1.81 mL, 12.9 mmol) and
potassium carbonate (5.36 g, 38.8 mmol). The reaction mixture was
heated under reflux for 6 h then allowed to cool to rt over 16 h.
Ethyl acetate (100 mL) was added and the mixture stirred vigorously
for 1 h. The mixture was filtered through celite, washing through
with ethyl acetate. The aqueous phase was separated and extracted
with ethyl acetate (3.times.30 mL) and the combined organics were
washed with brine (50 mL), dried (MgSO.sub.4), filtered and
adsorbed onto silica gel. Purification via flash column
chromatography (SiO.sub.2, ethyl acetate/isohexane, 1:20) gave the
title compound as a pale yellow solid. .delta..sub.H (CDCl.sub.3):
2.81 (3H, s), 4.01 (3H, s), 6.65 (1H, d), 8.26 (1H, d). Preparation
34: 3-(6-Methoxy-3-nitropyridin-2-yl)-2-oxopropionic acid ethyl
ester ##STR51##
[0218] To a stirred suspension of potassium ethoxide (0.55 g, 6.55
mmol) in diethyl ether (20 mL, anhydrous) and ethanol (4 mL) was
added diethyl oxalate (894 .mu.L, 6.55 mmol) and the reaction
mixture was stirred for 30 min prior to the addition of
6-methoxy-2-methyl-3-nitropyridine (Preparation 33, 1.0 g, 5.95
mmol) in diethyl ether (8 mL). The resulting red suspension was
stirred at rt, under argon, for 20 h. The mixture was filtered, the
solid washed thoroughly with diethyl ether then dried. The red
solid was then taken up in hot water and the solution cooled to
0.degree. C. The precipitate was filtered, washed with cold water,
and dried to give the title compound as a beige solid.
.delta..sub.H (CDCl.sub.3): 1.40 (3H, t), 4.07 (3H, s), 4.39 (2H,
q), 6.74 (1H, d), 7.57 (1H, s), 8.40 (1H, d), 13.82 (1H, s).
Preparation 35: 5-Methoxy-1H-pyrrolo[3,2-b]pyridine-2-carboxylic
acid ethyl ester ##STR52##
[0219] To a suspension of
3-(6-methoxy-3-nitropyridin-2-yl)-2-oxopropionic acid ethyl ester
(Preparation 34, 276 mg, 1.03 mmol) in THF (12 mL) and ethanol (5
mL) was added saturated aqueous ammonium chloride solution (5 mL)
and iron powder (346 mg, 6.18 mmol) in one portion. The reaction
mixture was heated under reflux for 1 h then filtered whilst still
hot through a celite plug, washing with hot ethyl acetate. The
filtrate was cooled and washed with brine (20 mL), dried
(MgSO.sub.4), filtered and adsorbed onto silica gel in vacuo.
Purification via flash column chromatography (SiO.sub.2, ethyl
acetate/hexanes, 1:9) gave the title compound as a beige solid.
.delta..sub.H (CDCl.sub.3): 1.40 (3H, t), 3.99 (3H, s), 4.41 (2H,
q), 6.74 (1H, d), 7.20 (1H, m), 7.62 (1H, d), 9.27 (1H, s).
Preparation 36: 5-Methoxy-1H-pyrrolo[3,2-b]pyridine-2-carboxylic
acid ##STR53##
[0220] To a solution of
5-methoxy-1H-pyrrolo[3,2-b]pyridine-2-carboxylic acid ethyl ester
(Preparation 35, 128 mg, 0.58 mmol) in ethanol (10 mL, absolute)
was added aqueous sodium hydroxide (0.35 mL, 2M) and the mixture
heated to 70.degree. C. for 3 h then cooled to rt. The solution was
adjusted to pH 4 by addition of glacial acetic acid and the
solvents removed under reduced pressure. Ethyl acetate (20 mL) was
added to the resulting oil and the mixture sonicated until a fine
suspension formed. The mother liquor was decanted and the remaining
solid was washed with ethyl acetate and dried in vacuo to give the
title compound as a pale orange powder. .delta..sub.H (CD.sub.3OD):
3.92 (3H, s), 6.63 (1H, d), 6.94 (1H, s), 7.72 (1H, d). Preparation
37: 2-[2-(4-Methoxyphenyl)-2-oxoethyl]isoindole-1,3-dione
##STR54##
[0221] To a solution of 4-methoxyphenacyl bromide (5.78 g, 25.23
mmol) in DMF (20 mL) was added potassium phthalimide (5.00 g, 26.99
mmol) and the reaction stirred at rt for 18 h. The reaction mixture
was partitioned between dichloromethane (200 mL) and water (100
mL). The layers were separated and the aqueous layer extracted with
dichloromethane (3.times.50 mL). The combined organics were washed
with sodium hydroxide (2M, 50 mL), water (50 mL) and brine (50 mL)
and dried (MgSO.sub.4). Filtration, then concentration in vacuo
gave an off white solid. Trituration with diethyl ether followed by
collection by filtration gave the title compound as a white solid.
.delta..sub.H (CDCl.sub.3): 3.86 (3H, s), 5.15 (2H, s), 7.09 (2H,
d), 7.81-8.01 (4H, m), 8.05 (2H, d).
[0222] The following compounds were synthesised according to
Preparation 37 from potassium phthalimide and the appropriate
.alpha.-bromoketone. TABLE-US-00001 ##STR55## Preparation R NMR 38
##STR56## .delta.H (d.sub.6 DMSO): 5.25 (2H, d), 7.60-7.75 (1H, m),
7.85-8.06 (5H, m), 8.10-8.24 (1H, m) 39 ##STR57## .delta.H (g.sub.6
DMSO): 5.24 (2H, s), 7.66 (2H, d), 7.83-8.02 (4H, m), 8.10 (2H, d)
40 ##STR58## .delta.H (d.sub.6 DMSO): 5.24 (2H, s), 7.36-7.52 (2H,
m), 7.84-8.02 (4H, m), 8.11-8.25 (2H, m)
Preparation 41:
2-[2-(4-Methoxyphenyl)-[1,3]dioxolan-2-ylmethyl]isoindole-1,3-dione
##STR59##
[0223] 2-[2-(4-Methoxyphenyl)-2-oxoethyl]isoindole-1,3-dione
(Preparation 37, 6.35 g, 21.5 mmol) was suspended in toluene (50
mL) and ethylene glycol (12 mL) added. p-Toluenesulfonic acid (300
mg, 1.58 mmol) was added and the resulting mixture heated under
reflux for 40 h, removing water with a Dean-Stark trap. The
reaction mixture was allowed to cool to rt then partitioned between
ethyl acetate (200 mL) and saturated aqueous sodium bicarbonate
solution (100 mL). The organic layer was washed with brine (50 mL),
dried (MgSO.sub.4), filtered and concentrated under reduced
pressure, to give the title compound as an off-white solid.
.delta..sub.H (d.sub.6 DMSO): 3.66 (2H, t), 3.72 (3H, s), 3.87 (4H,
m), 6.88 (2H, d), 7.32 (2H, d), 7.83 (4H, m).
[0224] The following compounds were synthesised according to
Preparation 41 from ethylene glycol and the appropriate ketone.
TABLE-US-00002 ##STR60## Preparation R NMR 42 ##STR61## .delta.H
(d.sub.6 DMSO): 3.69-3.81 (2H, m), 3.85-4.04 (4H, m), 7.15-7.30
(1H, m), 7.32-7.49 (2H, m), 7.74-7.96 (4H, m) 43 ##STR62## .delta.H
(d.sub.6 DMSO): 3.62-3.78 (2H, m), 3.84-3.99 (4H, m), 7.32-7.49
(4H, m), 7.74-7.94 (4H, m) 44 ##STR63## .delta.H (d.sub.6 DMSO):
3.64-3.80 (2H, m), 3.85-4.03 (4H, m), 7.08-7.24 (2H, m), 7.35-7.52
(2H, m), 7.75-7.93 (4H, m)
Preparation 45: [2-(4-Methoxyphenyl)-[1,3]dioxolan-2-yl]methylamine
##STR64##
[0225]
2-[2-(4-Methoxyphenyl)-[1,3]dioxolan-2-ylmethyl]isoindole-1,3-dion-
e (Preparation 41, 2.0 g, 5.90 mmol) and hydrazine hydrate (5 mL)
were combined. The stirred reaction mixture was heated under reflux
for 48 h then allowed to cool to rt. Aqueous sodium hydroxide (2M,
10-15 mL) and water (20 mL) were added and the mixture stirred
until a solution was formed. Diethyl ether (20 mL) was added and
the biphasic mixture stirred vigorously for 16 h. The layers were
separated and the aqueous layer was extracted with diethyl ether
(3.times.20 mL), then the combined organic extracts were washed
with brine (20 mL). The ethereal solution was passed through a
filter paper then evaporated to dryness in vacuo to give the title
compound as a yellow oil, which solidified on standing.
.delta..sub.H (CDCl.sub.3): 1.42 (2H, br s), 3.06 (2H, s), 3.97
(3H, s), 4.00 (2H, t), 4.21 (2H, t), 7.04 (2H, d), 7.53 (2H,
d).
[0226] The following compounds were synthesised according to
Preparation 45 from hydrazine hydrate and the corresponding
phthalimide. TABLE-US-00003 ##STR65## Preparation R NMR 46
##STR66## .delta.H (CDCl.sub.3): 1.31 (2H, br s), 2.87 (2H, s),
3.79-3.87 (2H, m), 3.99-4.08 (2H, m), 7.00-7.20 (2H, m), 7.23-7.29
(1H, m) 47 ##STR67## .delta.H (CDCl.sub.3): 1.23 (2H, br s), 2.89
(2H, s), 3.75-3.87 (2H, m), 3.99-4.10 (2H, m), 7.29-7.33 (2H, m),
7.36-7.40 (2H, m) 48 ##STR68## .delta.H (d.sub.6 DMSO): 2.72 (2H,
s), 3.25 (2H, br s), 3.67-3.78 (2H, m), 3.93-4.06 (2H, m),
7.11-7.18 (2H, m), 7.37-7.44 (2H, m)
Preparation 49: 5-Chloro-1H-pyrrolo[2,3-c]pyridine-2-carboxylic
acid [2-(4-methoxyphenyl)-[1,3]-dioxolan-2-ylmethyl]amide
##STR69##
[0227] To a solution of
[2-(4-methoxyphenyl)-[1,3]-dioxolan-2-yl]methylamine (Preparation
45, 0.117 g, 0.56 mmol) in dichloromethane (5 mL) was added DIPEA
(213 .mu.L, 1.22 mmol),
5-chloro-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid (Preparation
18, 0.100 g, 0.51 mmol) and HOBT (0.076 g, 0.56 mmol). The
resulting solution was stirred for 2 min then EDCI (0.117 g, 0.61
mmol) was added and stirring was continued for 18 h at rt. The
reaction mixture was partitioned between dichloromethane (30 mL)
and water (20 mL) and the layers separated. The aqueous phase was
extracted with dichloromethane (3.times.20 mL) then the combined
organics were washed with brine (20 mL), dried (MgSO.sub.4),
filtered and concentrated in vacuo. Recrystallisation from
methanol/dichloromethane gave the title compound as an orange
solid. .delta..sub.H (CDCl.sub.3): 3.81 (3H, s), 3.84-3.91 (4H, m),
4.05 (2H, m), 6.56 (1H, t), 6.76 (1H,s), 6.89 (2H, d), 7.44 (2H,
d), 7.57 (1H, s), 8.68 (1H, s), 9.94 (1H, br s).
[0228] The following compounds were synthesised according to
Preparation 49 from 5-chloro-1H-pyrrolo[2,3-c]pyridine-2-carboxylic
acid (Preparation 18) and the appropriate amine. TABLE-US-00004
##STR70## Prep- aration R m/z 50 ##STR71## m/z (ES.sup.+) = 394 [M
+ H].sup.+; RT = 3.49 min 51 ##STR72## m/z (ES.sup.+) = 392 [M +
H].sup.+; RT = 1.48 min 52 ##STR73## m/z (ES.sup.+) = 376 [M +
H].sup.+; RT = 3.26 min
Preparation 53: (S)-2-Amino-N,N-dimethyl-3-pyridin-3-ylpropionamide
hydrochloride ##STR74##
[0229] To a solution of
(S)-2-tert-butoxycarbonylamino-3-pyridin-3-ylpropionic acid (500
mg, 1.88 mmol) in DMF (10 mL) was added dimethylamine hydrochloride
(153 mg, 1.88 mmol), DIPEA (1.2 mL, 6.57 mmol) and TBTU (602 mg,
1.88 mol). The reaction mixture was stirred at rt for 16 h. The
solvent was removed in vacuo and the residue dissolved in methanol
(20 mL). To this was added 4M hydrochloric acid in dioxane (20 mL)
and the reaction was stirred for 16 h at rt. The solvent was
removed in vacuo and the residue was partitioned between water (100
mL) and ethyl acetate (2.times.100 mL). The aqueous layer was
evaporated to dryness and the residue recrystallised from
ethanol/ethoxyethanol (9:1), to give the title compound as a white
solid. .delta..sub.H (CD.sub.3OD): 2.99 (3H, s), 3.06 (3H, s),
3.35-3.42 (1H, m), 3.45-3.53 (1H, m), 4.87-4.94 (1H, m), 8.04-8.10
(1H, m), 8.48-8.53 (1H, m), 8.84-8.90 (2H, m). Preparation 54:
(S)-2-Amino-3-pyridin-3-yl-1-pyrrolidin-1-ylpropan-1-one
hydrochloride ##STR75##
[0230] To a solution of pyrrolidine (157 .mu.L, 1.88 mmol) in DMF
(10 mL) was added DIPEA (817 .mu.L, 4.69 mmol),
(S)-2-tert-butoxycarbonylamino-3-pyridin-3-ylpropionic acid (500
mg, 1.88 mmol) and TBTU (663 mg, 2.06 mmol). The reaction was
stirred at rt for 72 h. The solvent was removed in vacuo and the
residue was dissolved in methanol (15 mL). To this was added 4M
hydrochloric acid in dioxane (20 mL) and the reaction was stirred
at rt for 16 h. The solvent was removed in vacuo and the residue
was partitioned between water (100 mL) and ethyl acetate
(2.times.100 mL). The aqueous layer was evaporated to dryness, to
give the title compound as a green oil. .delta..sub.H (CD.sub.3OD):
1.86-2.05 (4H, m), 3.20-3.28 (2H, m), 3.39-3.58 (2H, m), 3.68-3.78
(2H, m), 4.63-4.71 (1H, m), 8.11-8.17 (1H, m), 8.56-8.64 (1H, m),
8.85-8.93 (2H, m). Preparation 55:
(S)-2-Amino-N,N-dimethylamino-3-pyridin-2-ylpropionamide
hydrochloride ##STR76##
[0231] To a stirred solution of dimethylamine hydrochloride (153 g,
187 mmol) in DMF (8 mL) was added DIPEA (2 mL, 6.55 mmol),
(S)-2-tert-butoxycarbonylamino-3-pyridin-2-ylpropionic acid (0.50
g, 1.87 mmol, Acros) and TBTU (0.60 g, 1.87 mmol). The reaction
mixture was stirred at rt for 16 h. The solvent was removed in
vacuo and the residue was dissolved in methanol (15 mL). To this
was added 4M hydrochloric acid in dioxane (20 mL) and the reaction
stiffed at rt for 16 h. The solvent was removed in vacuo and the
residue partitioned between water (100 mL) and ethyl acetate
(2.times.100 mL). The aqueous layer was evaporated to dryness to
give a solid, which was recrystallised from ethanol to give the
title compound as a pale brown solid. mr/z (ES.sup.+)=194.
Preparation 56: 5-Chloro-3-iodopyridin-2-ylamine ##STR77##
[0232] Silver sulfate (3.40 g, 10.9mmol) and
2-amino-5-chloropyridine (1 g, 7.8 mmol) was added to a solution of
iodine (2.76 g, 10.9 mmol) in ethanol (50 ml) and the reaction
mixture stiffed at rt for 72 h. The mixture was filtered, washed
with methanol and the filtrate concentrated in vacuo. The residue
was partitioned between saturated Na.sub.2S.sub.2O.sub.3 solution
(50 ml) and DCM (2.times.50 ml). The combined organics were dried
(MgSO.sub.4), concentrated in vacuo and purified by chromatography
on silica gel eluting with DCM to give the title compound as a
beige solid. .delta..sub.H (CDCl.sub.3): 4.95 (2H, br s), 7.84 (1H,
d), 7.98 (1H, d). Preparation 57:
5-Chloro-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid ##STR78##
[0233] Pyruvic acid (0.43 ml, 6.24 mmol) was added to a solution of
5-chloro-3-iodopyridin-2-ylamine (Preparation 56, 500 mg, 2.08
mmol), palladium acetate (23 mg, 0.10 mmol) and DABCO (700 mg, 6.24
mmol) in anhydrous DMF (20 ml). The reaction mixture was degassed
with argon for 20 min, then heated to 110.degree. C. for 16 h. The
solvent was removed in vacuo and the residue suspended in water (10
ml) and acetic acid (5 ml) and then filtered. The solid was
dissolved in EtOAc (50 ml), extracted into 2N NaOH solution (50 ml)
and the organic layer discarded. The aqueous solution was acidified
with concentrated HCl and extracted into EtOAc (2.times.40 ml). The
combined organics were dried (MgSO.sub.4) and concentrated in vacuo
to give the title compound as a beige solid. .delta..sub.H
(CD.sub.3OD): 7.14 (1H, s), 8.14 (1H, d), 8.35 (1H, d). Preparation
58:
5-Trimethylsilylacetylene-1H-pyrrolo[2,3-c]pyridine-2-carboxylic
acid ethyl ester ##STR79##
[0234] PdCl.sub.2(PPh.sub.3).sub.2 (0.026 g, 0.037 mmol) and Cu(|)I
(0.007 g, 0.037 mmol) were added sequentially to
5-bromo-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid ethyl ester
(Preparation 26, 0.100 g, 0.370 mmol) under an argon atmosphere.
1,4-Dioxane (7 mL, anhydrous) followed by diisopropylamine (0.063
mL, 0.45 mmol) were added and the stirred mixture was purged with
argon for 5 min. Trimethylsilylacetylene (0.064 mL, 0.45 mmol) was
added dropwise and the resulting mixture stirred at rt for 24 h.
The reaction mixture was partitioned between water (50 mL) and
ethyl acetate (100 mL) and the layers separated. The aqueous phase
was extracted with ethyl acetate (3.times.30 mL). The combined
organics were washed with brine (50 mL), dried (MgSO.sub.4),
filtered and concentrated in vacuo. The residue was dissolved in
the minimum amount of dichloromethane and loaded onto a silica
column. Purification via flash column chromatography (SiO.sub.2,
dichloromethane then 25% ethyl acetate/isohexane) gave a pale
yellow solid. .delta..sub.H (CDCl.sub.3): 0.28 (9H, s), 1.43 (3H,
t), 4.45 (2H, q), 7.18 (1H, s), 7.83 (1H, s), 8.86 (1H, s), 9.21
(1H, br s). Preparation 59:
5-Ethynyl-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid ethyl ester
##STR80##
[0235] To a stirred solution of the ester (Preparation 58, 0.123 g)
was added tetra-n-butylammonium fluoride (1.0M in THF, 5% wt
H.sub.2O, 0.47 mL, 0.47 mmol) and the solution immediately turned
dark pink in colour. After 5 min the reaction was partitioned
between ethyl acetate (60 mL) and water (40 mL). The layers were
separated and the aqueous layer extracted with ethyl acetate
(2.times.20 mL). Glacial acetic acid was added to the combined
organics until the colour changed from pink to yellow. The solution
was washed with water (20 mL), brine (20 mL) then dried
(MgSO.sub.4), filtered and concentrated in vacuo. The residue was
dissolved in methanol and adsorbed onto silica gel. Purification
via flash column chromatography (SiO.sub.2, ethyl
acetate:isohexane, 1:1, v/v) gave the title compound as a pale
yellow powder. .delta..sub.H (CDCl.sub.3): 1.44 (3H, t), 3.08 (1H,
s), 4.46 (2H, q), 7.20 (1H, s), 7.85 (1H, s), 8.89 (1H, s), 9.33
(1H, s). Preparation 60:
5-Ethynyl-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid ##STR81##
[0236] To a suspension of ester (Preparation 59, 0.065 g, 0.30
mmol) in ethanol (6 mL) was added sodium hydroxide (2M aqueous, 1.5
mL, 3.0 mmol) and the reaction mixture stirred at 50.degree. C. for
3 h. The mixture was allowed to cool to rt and glacial acetic acid
added, causing precipitation of a white solid. This was collected
by filtration, washed with water (20 mL) and then diethyl ether (20
mL). The solid was air dried to give the title compound as a white
powder. m/z (ES.sup.+)=187 [M+H].sup.+; RT=1.85 min. Preparation
61: 5-Cyano-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid ethyl ester
##STR82##
[0237] To a solution of
5-bromo-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid ethyl ester
(Preparation 26, 0.160 g, 0.590 mmol) in DMF (anhydrous, 5 mL) was
added zinc (II) cyanide (0.041 g, 0.35 mmol) then
tetrakis-triphenylphosphine palladium (0). The reaction mixture was
degassed by bubbling argon through it for 10 min. The reaction
mixture was heated to reflux temperature for 4.5 h then allowed to
cool to rt. Water (30 mL) was added and the mixture extracted with
ethyl acetate (2.times.50 mL). The combined organics were washed
with brine (30 mL), dried (MgSO.sub.4), filtered and concentrated
in vacuo. The residue was dissolved in ethyl acetate then adsorbed
onto silica gel. Purification via flash column chromatography
(SiO.sub.2, ethyl acetate:isohexane, 1:3, v/v) gave the title
compound as a white solid. .delta..sub.H (CDCl.sub.3): 1.45 (3H,
t), 4.49 (2H, quartet), 7.31 (1H, s), 8.09 (1H, s), 8.97 (1H, s),
9.60 (1H, br s); m/z (ES.sup.+)=216 [M+H].sup.+; RT=3.03 min.
Preparation 62: 5-Cyano-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid
##STR83##
[0238] To a stirred suspension of ester (Preparation 61, 0.266 g,
1.24 mmol) in ethanol (6 mL) and water (0.6 mL) was added sodium
hydroxide (0.108 g, 2.72 mmol). The reaction mixture was heated to
50.degree. C. for 24 h then allowed to cool to rt. The reaction
mixture was diluted with diethyl ether (30 mL), collected by
filtration and washed with diethyl ether. The solid was washed with
aqueous acetic acid (2.times.50 mL), then diethyl ether. The solid
was air-dried to give the title compound as a white solid.
.delta..sub.H (d.sub.6 DMSO): 7.22 (1H, s), 8.37 (1H, s), 8.88 (1H,
s), 12.88 (1H, s). Preparation 63: 2,4-Dimethyl-5-nitropyridine
##STR84##
[0239] To a stirred suspension of 2-chloro-4-methyl-5-nitropyridine
(9.419 g, 54.6 mmol) in dioxane (110 mL) was added
tetrakis(triphenyl phosphine) palladium (6.330 g, 5.46 mmol) and
the mixture stirred for 15 min prior to the addition of trimethyl
boroxine (7.68 mL, 54.6 mmol) and potassium carbonate (22.64 g,
164.0 mmol). The reaction mixture was heated under reflux for 6 h
then allowed to cool to rt over 16 h. Ethyl acetate (200 mL) was
added and the mixture stirred vigorously for 1 h. The mixture was
filtered through celite, washing through with ethyl acetate/THF
(1:1, v/v). Brine (100 mL) was added and attempted separation of
layers resulted in a thick emulsion. After removal of all
volatiles, ethyl acetate (300 mL) was added and the mixture
filtered, giving rise to a biphasic mixture. The layers were
separated and the aqueous phase was extracted with ethyl acetate
(3.times.100 mL). The combined organics were washed with brine (100
mL), dried (MgSO.sub.4), filtered and concentrated in vacuo. The
resulting oil was dissolved in dichloromethane then purified via
flash column chromatography (SiO.sub.2, ethyl acetate/isohexane,
3:7, v/v) to give the title compound as an orange oil.
.delta..sub.H (CDCl.sub.3): 2.59 (3H, s), 2.60 (3H, s), 7.12 (1H,
s), 9.07 (1H, s). Preparation 64:
3-(2-Methyl-5-nitropyridin-4-yl)-2-oxopropionic acid ethyl ester
##STR85##
[0240] To a solution of potassium ethoxide (0.262 g, 2.96 mmol) in
diethyl ether (10 mL) and ethanol (1 mL) was added diethyl oxalate
(0.404 mL, 2.96 mmol) in one portion and the resulting solution
stirred for 10 min at rt. 2,4-Dimethyl-5-nitropyridine (Preparation
63, 0.400 g, 2.63 mmol) was added as a suspension in diethyl ether
(1 mL)/ethanol (1.5 mL) and stirring continued for 16 h at rt. The
mixture was filtered, washing with cold diethyl ether. The
collected precipitate was dissolved in water and the pH adjusted to
4 by the addition of glacial acetic acid. The resulting precipitate
was collected by filtration and air dried. The solid was
partitioned between ethyl acetate (150 mL) and water (50 mL) and
the layers separated. The aqueous layer was extracted with ethyl
acetate (3.times.20 mL) and the combined organics washed with brine
(50 mL), dried (MgSO.sub.4), filtered and concentrated under
reduced pressure to give the title compound as a red solid which
required no further purification. .delta..sub.H (CDCl.sub.3): 1.40
(3H, t), 4.40 (2H, q), 4.52 (2H, s), 7.11 (1H, s), 9.25 (1H, s).
Preparation 65: 5-Methyl-1H-pyrrolo[2,3-c]pyridine-2-carboxylic
acid ethyl ester ##STR86##
[0241] To a solution of the pyruvate (Preparation 64, 0.749 g, 2.97
mmol) in THF (30 mL) and ethanol (15 mL) was added saturated
aqueous ammonium chloride solution (15 mL) and the suspension
vigorously stirred at rt. Iron powder (1.38 g, 24.64 mmol) was
added portionwise and the mixture heated under reflux for 2 h then
allowed to cool prior to filtration through a celite plug, and
washed through with warm methanol. The mixture was concentrated
under reduced pressure, the residue partitioned between ethyl
acetate (250 mL) and water (250 mL) and the layers separated. The
aqueous phase was extracted with ethyl acetate (3.times.50 mL) then
the combined organics were washed with brine (100 mL), dried
(MgSO.sub.4), filtered and concentrated in vacuo. The residue was
adsorbed onto silica gel and purified via flash chromatography
(SiO.sub.2, ethyl acetate) to give the title compound as a pale
orange solid. .delta..sub.H (CDCl.sub.3): 1.42 (3H, t), 2.63 (3H,
s), 4.43 (2H, q), 7.10 (1H, s), 7.40 (1H, s), 8.81 (1H, s), 9.08
(1H, br s). Preparation 66:
5-Methyl-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid ##STR87##
[0242] To a stirred solution of ester (Preparation 65, 117 mg,
0.574 mmol) in ethanol (10 mL) was added aqueous sodium hydroxide
(2M, 0.43 mL, 0.861 mmol). The resulting solution heated to
55.degree. C. for 4 h then allowed to cool to room temperature and
stirred for 17 h. Excess glacial acetic acid was added then all
volatiles were removed under reduced pressure. The residue was
triturated with water and the resulting solid collected by
filtration, washed with water then air dried. The title compound
was isolated as a pale yellow solid. m/z (ES.sup.+)=177
[M+H].sup.+; RT=1.60 min. Preparation 67:
4-Methoxypiperidine-1-carboxylic acid tert-butyl ester
##STR88##
[0243] To a vigourosly stirred solution of
4-hydroxypiperidine-1-carboxylic acid tert-butyl ester (2.07 g,
10.3 mmol) in DMF (25 mL) was added a 60% sodium hydride dispersion
in mineral oil (500 mg, 12.5 mmol). After stirring for 20 min,
methyl iodide (0.9 mL, 14.5 mmol) was added and the resulting
mixture stirred for 48 h before being added to a mixture of water
and brine (250 mL, 1:1). Extraction with ethyl acetate (4.times.50
mL), washing of the combined extracts with brine (100 mL) and
drying (MgSO.sub.4) gave, after concentration, a residue which was
purified via flash chromatography (silica gel, ethyl
acetate/hexane, 1:1) to give the title compound as a colourless
oil. .delta..sub.H (CDCl.sub.3): 1.50 (9H, s), 1.52, 1.88 (4H, 2m)
3.12 (2H, ddd), 3.18 (1H, m), 3.19 (3H, s), 3.77 (2H, m);
R.sub.f0.33 (ethyl acetate/hexane: 1/1). Preparation 68:
4-Methoxypiperidine hydrochloride ##STR89##
[0244] To a solution of 4-methoxypiperidine-1-carboxylic acid
tert-butyl ester (Preparation 67, 1.58 g, 7.34 mmol) in methanol
(20 mL) was added hydrochloric acid in 1,4-dioxane (4M, 10 mL) and
the mixture stirred for 3 h at rt. Concentration in vacuo gave an
oil which was redissolved in water (100 mL). The aqueous layer was
washed with ethyl acetate (2.times.30 mL) and concentrated to give
the title compound as colourless solid. .delta..sub.H (D.sub.2O):
1.80, 2.14 (4H, 2m), 3.13 (2H, m), 3.38 (2H, m), 3.40 (3H, s), 3.68
(m, 1H). Preparation 69: (R)-3-Methoxypyrrolidine-1-carboxylic acid
tert-butyl ester ##STR90##
[0245] (R)-3-Hydroxypyrrolidine-1-carboxylic acid tert-butyl ester
(Sigma-Aldrich) (1.04 g, 5.55 mmol) was methylated and purified in
a similar way to Preparation 67 using 60% sodium hydride dispersion
(267 mg, 6.68 mmol) and methyl iodide (0.5 mL, 8.06 mmol) in DMF
(15 ml). .delta..sub.H (CDCl.sub.3): 1.50 (9H, s),1.94-2.02 (2H,
m), 3.37 (3H, s), 3.38-3.58 (4H, m), 3.95 (11H, m); R.sub.f0.47
(ethyl acetate/hexane: 1/1). Preparation 70:
(R)-3-Methoxypyrrolidine hydrochloride ##STR91##
[0246] (R)-3-Methoxypyrrolidine-1-carboxylic acid tert-butyl ester
(840 mg, 4.17 mmol) was deprotected and purified in a similar way
to Preparation 68 using methanol (10 mL) and hydrochloric acid in
1,4-dioxane (4 M, 5.0 mL). .delta..sub.H (D.sub.2O): 2.12 (2H, m),
3.10-3.56 (8H, m), 4.20 (1H, m). Preparation 71:
(S)-3-Methoxypyrrolidine-1-carboxylic acid tert-butyl ester
##STR92##
[0247] (S)-3-Hydroxypyrrolidine-1-carboxylic acid tert-butyl ester
(Omega Chemical Company) (950 mg, 5.55 mmol) was methylated and
purified in a similar way to Preparation 67 using 60% sodium
hydride dispersion (260 mg, 6.50 mmol) and methyl iodide (0.5 mL,
8.06 mmol) in DMF (15 ml). .sup.1H NMR and R.sub.f were identical
to the (R)-enantiomer. Preparation 72: (S)-3-Methoxypyrrolidine
hydrochloride ##STR93##
[0248] (S)-3-Methoxypyrrolidine-1-carboxylic acid tert-butyl ester
(720 mg, 3.58 mmol) was deprotected and purified in a similar way
to Preparation 68 using methanol (10 mL) and hydrochloric acid in
1,4-dioxane (4 M, 5.0 mL). .sup.1-H NMR and R.sub.f were identical
to (R)-enantiomer. Preparation 73:
4-(2-Nitrobenzenesulfonylamino)piperidine-1-carboxylic acid
tert-butyl ester ##STR94##
[0249] To a solution of 4-aminopiperidine-1-carboxylic acid
tert-butyl ester (400 mg, 200 mmol) in anhydrous dichloromethane
(14 mL) under argon was added triethylamine (340 .mu.L, 2.4 mmol)
and the solution cooled in an ice bath. 2-Nitrophenylsulfonyl
chloride (443 mg, 2.0 mmol) was added and the reaction allowed to
stir at rt for 16 h. The crude solution was washed with water
(2.times.30 mL) before removing the solvent in vacuo. The crude
material was purified by chromatography using ethyl
acetate/petroleum ether (30-60%) as the eluent to give the title
compound as an off-white powder. .delta..sub.H (d.sub.6 DMSO): 8.43
(2H, m), 8.17 (1H, s), 8.09 (2H, m), 3.80-3.69 (2H, m), 3.31-3.23
(1H, m), 2.86-2.69 (2H, m), 1.63-1.51 (2H, m), 1.39 (9H, s),
1.29-1.17 (2H, m). Preparation 74:
4-[Methyl-(2-nitrobenzenesulfonyl)amino]piperidine-1-carboxylic
acid tert-butyl ester ##STR95##
[0250] To a solution of
4-(2-nitrobenzenesulfonylamino)piperidine-1-carboxylic acid
tert-butyl ester (Preparation 73) (400 mg, 1.04 mmol) in DMF (10
mL) was added caesium carbonate (507 mg, 1.56 mmol) and the mixture
stirred at rt for 40 min. Iodomethane (323 .mu.L, 5.19 mmol) was
added and the mixture stirred for 16 h. Solvent was removed in
vacuo and the crude residue partitioned between ethyl acetate (20
mL) and water (20 mL). The organic layer was separated and washed
with 1M HCl (2.times.20 mL), water (20 mL), then brine (2.times.20
mL) before being dried (MgSO.sub.4). The solvent was removed in
vacuo to give the title compound as a yellow powder. .delta..sub.H
(d.sub.6 DMSO): 8.43 (2H, m), 8.01 (2H, m), 4.00-3.89 (3H, m),
2.83-2.67 (5H, m), 1.54-1.43 (2H, m), 1.39 (9H, s), 1.34-1.24 (2H,
m). Preparation 75: N-Methyl-2-nitro-N-piperidin-4-yl
benzenesulfonamide ##STR96##
[0251] Prepared according to EXAMPLE 182 from
4-[methyl(2-nitrobenzenesulfonyl)amino]piperidine-1-carboxylic acid
tert-butyl ester (Preparation 74). .delta..sub.H (d.sub.6-DMSO):
8.44 (2H, m), 8.13 (2H, m), 4.20-7.07 (1H, m), 3.29-3.17 (2H, m),
3.03-2.90 (2H, m), 2.77 (3H, s), 2.00-1.84 (2H, m), 1.51-1.43 (2H,
m). Preparation 76: 5-Chloro-1H-pyrrolo[2,3-c]pyridine-2-carboxylic
acid
(1-(S)-(4-fluorobenzyl)-2-{4-[methyl(2-nitrobenzenesulfonyl)amino]piperid-
in-1-yl} -2-oxoethyl)amide ##STR97##
[0252] Prepared according to EXAMPLE 231 from
2-(S)-[(5-chloro-1H-pyrrolo[2,3-c]pyridine-2-carbonyl)amino]-3-(4-fluorop-
henyl)-propionic acid (EXAMPLE 230) and
N-methyl-2-nitro-N-piperidin-4-yl-benzenesulfonamide hydrochloride
(Preparation 75). m/z (ES.sup.+)=643.36 [M+H].sup.+. Preparation
77: Thiomorpholine 1,1-dioxide ##STR98##
[0253] To a solution of thiomorpholine (1.0 g, 9.69 mmol) in acetic
acid (11.5 mL) cooled to 0.degree. C. (ice bath) was added aqueous
hydrogen peroxide solution (30% w/v, 4 mL) and the reaction heated
to 100.degree. C. for 16 h. The mixture was cooled and solvent
removed in vacuo before trituration of the residue with methanol
gave a white precipitate. The solid was filtered and washed with
methanol to give the title compound as an off-white powder. m/z
(ES.sup.+)=136.06 [M+H].sup.+. Preparation 78:
Piperidine-4-carboxylic acid methyl ester hydrochloride
##STR99##
[0254] To a cooled solution of anhydrous methanol (100 mL) was
added acetyl chloride (7.1 mL, 0.1 mol) and the solution stirred
for 75 min. Piperidine-4-carboxylic acid (150 mg, 1.16 mmol) was
dissolved in the prepared solution (10 mL) and the reaction stirred
for 16 h. The solvent was removed in vacuo to give the title
compound as its hydrochloride salt. m/z (ES.sup.+)=144.12
[M+H].sup.+. Preparation 79:
2-(S)-Carbamoyl-piperidine-1-carboxylic acid tert-butyl ester
##STR100##
[0255] To a solution of N-Boc-1-pipecolinic acid (200 mg, 0.87
mmol) in DMF (3.5 mL) was added TBTU (336 mg, 1.05 mmol), ammonium
chloride (93 mg, 1.74 mmol) then DIPEA (182 .mu.L, 1.05 mmol) and
the reaction stirred for 16 h. The mixture was partitioned between
ethyl acetate (2.times.30 mL) and water (30 mL), and the organics
combined before being washed with 1M sodium hydroxide (3.times.30
mL) and brine (3.times.30 mL). The organic solution was dried
(MgSO.sub.4) and solvent removed in vacuo to give the title
compound as a white solid. .delta..sub.H (d.sub.6 DMSO): 7.23 (1H,
s), 6.97 (1H, s), 4.56-4.39 (1H, br m), 3.43-3.74 (1H, d),
3.14-2.90 (1H, br m), 2.09-2.00 (1H, d), 1.63-1.47 (3H, m),
1.30-1.17 (2H, m). Preparation 80: (S)-Piperidine-2-carboxylic acid
amide hydrochloride ##STR101##
[0256] Piperidine-2-carboxylic acid amide was prepared according to
the method of Johnson et.al., (J. Med. Chem., 1986, 29, 2100-2104)
to give the title compound as an off-white solid. .delta..sub.H
(CD.sub.3OD): 3.87-3.75 (1H, m), 3.43-3.34 (1H, m), 3.09-2.96 (1H,
br m), 2.31-2.16 (1H, m), 1.97-1.81 (2H, br m), 1.77-1.57 (3H, br
m). Preparation 81: 4-(2-Methoxyethoxy)piperidine-1-carboxylic acid
tert-butyl ester ##STR102##
[0257] To a solution of tert-butyl-4-hydroxy-1-piperidine
carboxylate (300 mg, 1.49 mmol) in DMF (2 mL) was added
1-bromo-2-methoxyethane (168 .mu.L, 1.79 mmol) followed by
potassium iodide (25 mg, 0.15 mmol) and sodium hydride (83.5 mg,
2.09 mmol) and the reaction stirred at rt for 16 h. Solvent was
removed in vacuo and crude residue was partitioned between ethyl
acetate (10 mL) and water (10 mL). The organic layer was washed
with 1M HCl (10 mL), 1M NaOH (10 mL) then brine (2.times.10 mL)
before being dried (MgSO.sub.4) and removing the solvent in vacuo.
Purification by chromatography using dichloromethane/methanol
(97:3) as the eluent gave the title compound as a yellow oil.
.delta..sub.H (CDCl.sub.3): 3.89-3.77 (2H, m), 3.66 (2H, m), 2.57
(2H, m), 3.54-3.46 (1H, m), 3.43 (3H, s), 3.11-3.03 (2H, m),
1.93-1.83 (2H, m), 1.60-1.46 (11H, m). Preparation 82:
4-(2-Methoxyethoxy)piperidine hydrochloride ##STR103##
[0258] To a solution of 4-(2-methoxyethoxy)-piperidine-1-carboxylic
acid tert-butyl ester (Preparation 81, 114 mg, 0.44 mmol) in
methanol (3 mL) was added 4M HCl in dioxane (550 .mu.L, 2.20 mmol)
and the reaction stirred at rt for 16 h. Solvent was removed in
vacuo and the crude residue dissolved in water (10 mL). The aqueous
solution was extracted with ethyl acetate (2.times.10 mL) then
concentrated in vacuo. Purification by trituration in ethyl acetate
gave the title compound as the hydrochloride salt. .delta..sub.H
(CD.sub.3OD): 3.74-3.67 (1H, m), 3.64 (2H, m), 3.56 (2H, m),
3.40-2.39 (7H, m), 2.11-1.96 (2H, m), 1.93-1.83 (2H, m).
Preparation 83:
[1-(R)-(4-Fluorobenzyl)-2-(4-hydroxypiperidin-1-yl)-2-oxoethyl]
carbamic acid tert-butyl ester ##STR104##
[0259] The title compound was prepared according to EXAMPLE 231 but
using Boc-3-(4-fluorophenyl)-(R)-alanine and 4-hydroxypiperidine.
m/z (ES.sup.+)=367.34 [M+H].sup.+. Preparation 84:
2-(R)-Amino-3-(4-fluorophenyl)-1-(4-hydroxypiperidin-1-yl)propan-1-one
hydrochloride ##STR105##
[0260] The title compound was prepared according to Preparation 20
from
[1-(R)-(4-fluorobenzyl)-2-(4-hydroxypiperidin-1-yl)-2-oxoethyl]
carbamic acid tert-butyl ester (Preparation 83). m/z
(ES.sup.+)=267.20 [M+H].sup.+. Preparation 85:
4-(N-Benzyl-N-methylamino)piperidine-1-carboxylic acid tert-butyl
ester ##STR106##
[0261] To a solution of N-benzylmethylamine (648 .mu.L, 5.02 mmol)
and 1-tert-butoxycarbonyl-4-piperidone (500 mg, 2.51 mmol) in THF
(8 mL) was added sodium triacetoxyborohydride (798 mg, 3.76 mmol)
followed by acetic acid (144 .mu.L, 2.51 mmol) and the reaction
stirred at rt for 40 h. Solvent was removed in vacuo and the
residue partitioned between ethyl acetate (15 mL) and water (15
mL). The organic layer was washed with sodium bicarbonate solution
(2.times.15 mL) then brine (2.times.20 mL), dried (MgSO.sub.4) and
the solvent removed in vacuo. The crude material was purified by
chromatography using ethyl acetate/petroleum ether (2:1) as the
eluent to give the title compound as yellow oil. m/z
(ES.sup.+)=305.32 [M+H].sup.+. Preparation 86:
4-Methylaminopiperidine-1-carboxylic acid tert-butyl ester
##STR107##
[0262] The title compound was prepared according to Preparation 23
from 4-(benzylmethylamino)piperidine-1-carboxylic acid tert-butyl
ester (Preparation 85). .delta..sub.H (CD.sub.3OD): 4.13-4.03 (2H,
m), 2.90-2.76 (2H, br m), 2.63-2.53 (1H, m), 2.40 (3H, s),
2.97-1.87 (2H, m), 1.49 (9H, s), 1.27-1.16 (2H, m). Preparation 87:
Benzylmethyl(tetrahydropyran-4-yl)amine ##STR108##
[0263] The title compound was prepared according to Preparation 85
from N-benzylmethylamine and tetrahydro-4H-pyran-4-one.
Purification of the crude material by chromatography using
dichloromethane/methanol (98:2) as the eluent gave the title
compound as a yellow oil. .delta..sub.H (CD.sub.3OD): 7.50-7.40
(5H, m), 4.08 (2H, m), 4.06-(2H, s), 3.49-3.40 (2H, ddd), 3.23-3.14
(1H, m), 2.51 (3H, s), 2.03-1.97 (2H, m), 1.89-1.76 (2H, m).
Preparation 88: Methyl(tetrahydropyran-4-yl)amine hydrochloride
##STR109##
[0264] The title compound was prepared according to Preparation 23
from benzylmethyl(tetrahydropyran-4-yl)amine (Preparation 87).
Crude material was dissolved in methanol and a solution of 1M HCl
in ether was added dropwise to form a precipitate. The product was
filtered and washed with ether to give the title compound as the
hydrochloride salt as a white crystalline solid. .delta..sub.H
(CD.sub.3OD): 4.11-4.00 (2H, m), 3.53-3.43 (2H, m), 3.37-3.27 (11H,
m), 2.74 (3H, s), 2.11-2.03 (2H, m), 1.74-1.60 (2H, m). Preparation
89: 1-Benzylpiperidin-4-yl-dimethylamine ##STR110##
[0265] To a solution of 4-amino-1-benzylpiperidine (536 .mu.L, 2.63
mmol) in formic acid (8.5 mL) at 0.degree. C. was added
formaldehyde solution (37%, 5.5 mL) and the mixture heated to
reflux for 6 h. Solvent was removed in vacuo and the crude residue
partitioned between ethyl acetate (20 mL) and water (20 mL). The
aqueous layer was separated and taken to pH12 with 2M NaOH solution
before being extracted with ethyl acetate (2.times.20 mL). The
organic portion was washed with brine (30 mL) and dried
(MgSO.sub.4) before removing the solvent in vacuo to give the title
compound as a yellow oil. m/z (ES.sup.+)=219.25 [M+H].sup.+.
Preparation 90: Dimethylpiperidin4-yl amine ##STR111##
[0266] The title compound was prepared according to Preparation 23
from 1-benzylpiperidin-4-yl-dimethylamine (Preparation 89).
.delta..sub.H (CD.sub.3OD): 3.17-3.09 (2H, m), 2.66-2.54 (2H, m),
2.30 (6H, s), 2.26 (1H, m), 1.94-1.86 (2H, m), 1.49-1.29 (2H, m).
Preparation 91: 4-Methanesulfonylamino-piperidine-1-carboxylic acid
tert-butyl ester ##STR112##
[0267] To a solution of 4-amino-1-Boc-piperidine (300 mg, 1.50
mmol) in dichloromethane (2.0 mL) was added a solution of
methanesulfonyl chloride (348 .mu.L, 4.49 mmol) in dichloromethane
(1 mL) followed by a solution of pyridine (485 .mu.L, 5.99 mmol) in
dichloromethane (1 mL), and the reaction stirred at rt for 16 h.
Water (10 mL) was added, the mixture separated and the organic
layer washed with 1M HCl (10 mL), sodium bicarbonate solution (10
mL) then brine (2.times.10 mL). The solution was dried (MgSO.sub.4)
and solvent removed in vacuo. The crude material was purified by
chromatography using dichloromethane/methanol (95:5) as the eluent
to give the title compound as an off-white powder. .delta..sub.H
(CD.sub.3OD): 4.46-4.40 (1H, m), 4.09-3.97 (2H, m), 3.53-3.40 (1H,
m), 3.0 (3H, s), 2.93-2.81 (2H, m), 2.01-1.93 (2H, m), 1.50-1.37
(2H, m). Preparation 92: N-Piperidin-4-yl methanesulfonamide
##STR113##
[0268] The title compound was prepared from
4-methanesulfonylaminopiperidine-1-carboxylic acid tert-butyl ester
(Preparation 91) according to Preparation 82 as an off-white
powder. .delta..sub.H (CD.sub.3OD): 3.67-3.57 (1H, m), 3.47-3.40
(2H, m), 3.19-3.10 (2H, m), 3.03 (3H, s), 2.26-2.17 (2H, m),
1.87-1.76 (2H, m). Preparation 93: 2-(S)-Amino-3-pyridin-4-yl
propionic acid methyl ester hydrochloride ##STR114##
[0269] The title compound was prepared according to Preparation 78,
using Boc-3-(4-pyridyl)-L-alanine as the starting acid.
.delta..sub.H (CD.sub.3OD): 8.90 (2H, br s), 8.16 (2H, br s),
4.73-4.60 (1H, m), 3.84 (3H, s), 3.73-3.50 (2H, m). Preparation 94:
1,4-Dioxa-7-aza-spiro [4.5] decane ##STR115##
[0270] To a solution of 1-Boc-3-piperidone (700 mg, 3.51 mmol) in
toluene (20 mL) was added ethylene glycol (588 .mu.L, 10.54 mmol)
followed by p-toluene sulfonic acid hydrate (1.0 g, 5.27 mmol) and
the reaction heated to reflux using Dean-Stark apparatus for 7 h.
To the mixture was added NaHCO.sub.3 solution, and the organic
layer was removed. The aqueous phase was evaporated to dryness and
the resulting residue dissolved in THF. Filtration through celite
and removal of the solvent in vacuo gave the desired product as
light brown oil. .delta..sub.H (CD.sub.3OD): 3.99 (2H, s),
3.73-3.57 (2H, m), 3.63 (4H, m), 2.77 (1H, m), 2.73 (1H, m), 1.76
(2H, m). Preparation 95:
2-Phenyl-1-(S)-(2-phenyl-[1,3]dioxolan-2-yl)ethylamine
##STR116##
[0271] To a solution of commercially available
2-(S)-(N-tert-butyloxycarbonyl)-amino-1,3-diphenyl-1-propanone (250
mg, 0.768 mmol) in toluene (100 mL) was added ethylene glycol (1.0
mL, 17.9 mmol) and p-toluenesulfonic acid monohydrate (262 mg, 1.38
mmol). The resulting mixture was heated under reflux for 48 h,
removing water with a Dean-Stark trap. After cooling to ambient
temperature the mixture was diluted with ethyl acetate (200 mL) and
successively washed with diluted sodium hydroxide solution (1M,
2.times.50 mL) and brine (50 mL). The solution was dried
(MgSO.sub.4) and concentrated to an oil that was purified by flash
chromatography on silica gel (eluent: ethyl acetate) to give the
title compound as colourless oil. .delta..sub.H (CDCl.sub.3): 2.07
(2H, br s), 2.37 (1H, dd), 2.92 (1H, dd), 3.36 (1H, m), 3.85-4.35
(4H, 3m), 7.14-7.59 (10H, m); m/z (ES.sup.+)=270.20 [M+H].sup.+;
RT=2.63 min. Preparation 96:
5-Chloro-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid
[2-phenyl-1-(S)-(2-phenyl-[1,3]dioxolan-2-yl)ethyl]amide
##STR117##
[0272] To a solution of
5-chloro-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid (Preparation
18, 88 mg, 0.403 mmol) and 2-phenyl-1-(S)-(2-phenyl-[
1,3]dioxolan-2-yl)ethylamine (Preparation 95, 104 mg, 0.386 mmol)
in DMF (5 mL) was added HOBt (65 mg, 0.424 mmol), DIPEA (0.155 mL,
0.890 mmol) and EDCI (90 mg, 0.469 mmol). After stirring at rt for
12 h the mixture was added to diluted brine (100 mL, water/brine:
1/1). Extraction with ethyl acetate (4.times.25 mL), washing of the
combined extracts with diluted hydrochloric acid (1M, 30 mL),
diluted aqueous sodium hydroxide solution (1M, 30 ml) and brine (5
mL) followed by drying (MgSO.sub.4) gave after concentration a
residue which was purified by flash chromatography on silica gel
(eluent: hexane/ethyl acetate: 50/50). The title compound was
obtained as a colourless oil. .delta..sub.H (CDCl.sub.3): 2.73 (1H,
dd), 3.10 (1H, dd), 3.84-4.22 (4H, 4m), 5.01 (1H, ddd), 6.37 (1H,
d), 6.72 (1H, s), 7.05-7.62 (1.1H, 3m), 8.64 (1H, s), 10.48 (1H,
s); m/z (ES.sup.+)=448.24 [M+H].sup.+; RT=3.64 min. Preparation 97:
2-(2-Oxo-2-pyridin-3-yl-ethyl)isoindole-1,3-dione ##STR118##
[0273] A solution of bromomethylpyridin-3-yl ketone (4.55 g, 16.2
mmol) and potassium phthalimide (6.0 g, 32.4 mmol) in DMF (50 mL)
was stirred for 3 days at rt before the added to diluted brine (500
ml, 1:1). The solution was made acidic (pH 2) with diluted
hydrochloric acid (1M) before washed with ethyl acetate
(2.times.100 ml). The aqueous layer was then made alkaline (pH 12)
again with sodium hydroxide solution (2 M) and extracted with DCM
(4.times.200 ml). The extracts were combined and dried (MgSO.sub.4)
before concentrated in vacuo. Recrystallisation from methanol
(2.times.) allows to remove crystalline phthalimide and to enrich
the title compound in the mother liquer. The crude product was used
in Preparation 98 without further purification. .delta..sub.H
(d.sub.6 DMSO): 5.33 (2H, s), 7.64 (1H, dd), 7.92, 7.97 (4H, 2m),
8.43 (1H, m), 8.88 (1H, m), 9.28 (1H, s); m/z (ES.sup.+)=308.13
[M+MeCN +H].sup.+; RT=2.39 min. Preparation 98:
2-Amino-1-pyridin-3-ylethanol ##STR119##
[0274] To a solution of crude
2-(2-oxo-2-pyridin-3-ylethyl)isoindole-1,3-dione (Preparation 97,
5.0 g, .about.19.0 mmol) in aqueous isopropanol (210 ml,
water/IPA:1/6) was added sodium borohydride (10.2 g, 270 mmol) in 2
portions. The mixture was stirred at rt for 12 h before being
carefully acidified (pH 2) with dilute hydrochloric acid (1M).
After removal of the solvent the residue was taken up in
destillated water (100 mL) and passed down a column filled with
ion-exchange resin (Amberlite IR 120, H.sup.+-form, 300 g, eluent:
500 mL water then 1L of 2 M aqueous ammonia solution).
Concentration of the alkaline fractions gave the title compound as
a yellow oil. .delta..sub.H (d.sub.6 DMSO): 2.74, 2.85 (2H, 2m),
4.66 (11H, m), 5.15 (3H, br s), 7.36 (1H, dd), 7.75 (1H, m), 8.46
(1H, m), 8.56 (1H, m); m/z (ES.sup.+)=139.11 [M+H].sup.+; RT=0.21
min. Preparation 99:
2-(S)-Amino-3-(tert-butyldimethylsilanyloxy)-1-(S)-phenylpropan-1-ol
##STR120##
[0275] To a solution of (1S,2S)-2-amino-1-phenyl-1,3-propanediol
(2.07 g, 12.4 mmol) in DMF (10 mL) was added imidazole (1.0 g, 14.7
mmol) and tert-butyldimethylsilyl chloride (2.30 g, 15.3 mmol).
After stirring at rt for 12 h the mixture was added to diluted
brine (150 mL, water/brine:1/1). Extraction with ethyl acetate
(4.times.30 mL), washing of the combined extracts with brine (30
mL) and drying (MgSO.sub.4) gave after concentration a residue
which was purified by flash chromatography on silica gel (eluent:
ethyl acetate). The title compound was obtained as colourless oil.
.delta..sub.H (CDCl.sub.3): 0.24, 0.26 (6H, 2s), 1.12 (9H, s),
2.50-2.78 (3H, br s), 3.16 (1H, ddd), 3.78 (1H, dd), 3.85 (1H, dd),
4.84 (1H, d), 7.49-7.55 (5H, m); m/z (ES.sup.+)=282.32 [M+H].sup.+;
RT=2.87 min. Preparation 100:
5-Chloro-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid
[1-(S)-(tert-butyldimethylsilanyloxymethyl)-2-(S)-hydroxy-2-phenylethyl]a-
mide ##STR121##
[0276] To a solution of
5-chloro-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid (Preparation
18, 520 mg, 2.65 mmol) and
2-amino-3-(tert-butyldimethylsilanyloxy)-1-phenylpropan-1-ol
(Preparation 99, 780 mg, 2.77 mmol) in DMF (15 mL) was added HOBt
(411 mg, 2.68 mmol), DIPEA (0.96 mL, 5.51 mmol) and EDCI (589 mg,
3.07 mmol). After stirring at rt for 12 h the mixture was added to
diluted brine (150 mL, water/brine:1/1). Extraction with ethyl
acetate (4.times.50 mL), washing of the combined extracts with
diluted hydrochloric acid (1M, 50 ml), diluted aqueous sodium
hydroxide solution (1M, 50 ml) and brine (50 mL) followed by drying
(MgSO.sub.4) gave after concentration a residue which was purified
by flash chromatography on silica gel (eluent: hexane/ethyl
acetate:50/50). The title compound was obtained as colourless oil.
.delta..sub.H (CD.sub.3OD): 0.00, 0.01 (6H, 2s), 0.84 (9H, s), 3.60
(1H, dd), 3.84 (1H, dd), 4.33 (1H, ddd), 4.98 (1H, d), 7.05 (1H,
s), 7.12-7.37 (5H, 3m), 7.60 (1H, s), 8.49 (11H, s); m/z
(ES.sup.+)=460.36 [M+H].sup.+; RT=4.16 min. Preparation 101:
5-Chloro-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid
[1-(S)-(tert-butyldimethylsilanyloxymethyl)-2-oxo-2-phenylethyl]amide
##STR122##
[0277] To a solution of
5-chloro-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid
[1-(S)-(tert-butyldimethylsilanyloxymethyl)-2-(S)-hydroxy-2-phenylet-
hyl]amide (Preparation 100, 304 mg, 0.661 mmol) in dry DCM (10 mL)
was added Dess-Martin periodinane (342 mg, 0.806 mmol). After
stirring for 3 h at room temperature alkaline sodium thiosulfate
solution was added (5.4 g Na.sub.2SO.sub.3 dissolved in 20 mL
saturated NaHCO.sub.3 solution) and the emulsion vigorously stirred
for an additional 30 min. Ethyl acetate (150 ml) was added and the
aqueous layer removed. The organic layer was washed with brine (50
ml), dried (MgSO.sub.4) and concentrated to a residue which was
purified by flash chromatography on silica gel (eluent:
hexane/ethyl acetate:50/50) to give the title compound as
colourless solid. m/z (ES.sup.+)=458.34 [M+H].sup.+; RT=4.32 min.
Preparation 102:
[1-(S)-(4-Fluorobenzyl)-2-(3-(S)-hydroxypyrrolidin-1-yl)-2-oxoethyl]carba-
mic acid tert-butyl ester ##STR123##
[0278] To a stirred solution of (S)-N-Boc-4-fluorophenylalanine
(5.08 g, 17.9 mmol) and (S)-3-hydroxypyrrolidine (1.05 mL, 19.7
mmol) in anhydrous DMF (200 mL), was added DIPEA (6.87 mL, 39.5
mmol) and HOBt.H.sub.2O (3.02 g, 19.7 mmol). The reaction mixture
was stirred for 10 min at room temperature then EDCI (4.13 g, 21.5
mmol) was added and the resulting mixture stirred for 20 h at rt.
The volatiles were removed in vacuo then the residue partitioned
between water (200 mL) and ethyl acetate (200 mL). The layers were
separated and the aqueous layer extracted with ethyl acetate
(3.times.50 mL). The combined organics were washed with aqueous
sodium hydroxide solution (2M, 3.times.50 mL), brine (100 mL),
dried (MgSO.sub.4), filtered and concentrated in vacuo. The oily
residue was purified via flash chromatography (SiO.sub.2,
methanol/dichloromethane, 1:19, v/v) to give the title compound as
a colourless oil which became a white solid on standing. m/z
(ES.sup.+)=353 [M+H].sup.+; RT=3.17 min. Preparation 103:
2-(S)-Amino-3-(4-fluorophenyl)-1-(3-(S)-hydroxypyrrolidin-1-yl)propan-1-o-
ne hydrochloride ##STR124##
[0279] To a solution of ester (Preparation 102, 5.25 g, 14.9 mmol)
in methanol (anhydrous, 30 mL) was added 4M HCl in dioxane (7.64
mL, 30.6 mmol) and the resulting solution stirred for 18 h at rt
then the solvents removed in vacuo. The residue was partitioned
between ethyl acetate (150 mL) and water (100 mL). The layers were
separated and the organic layer extracted with water (2.times.50
mL). The combined aqueous extracts were washed once with ethyl
acetate (30 mL), then the combined organic extracts were evaporated
to dryness under reduced pressure to give the title compound as a
white foam. .delta..sub.H (CD.sub.3OD): 1.47-1.62 (0.5H, m),
1.67-1.80 (1H, m), 1.83-1.96 (0.5H, m), 2.72-2.87 (1H, m),
2.96-3.12 (2H, m), 3.19-3.29 (1H, m), 3.30-3.62 (2H, m), 4.14-4.39
(2H, m), 6.91-7.08 (2H, m), 7.22 (2H, dd). Preparation 104:
(6-Chloropyridin-3-yl)carbamic acid tert-butyl ester ##STR125##
[0280] The title compound was prepared according to the method
described by Dinnell et al(US 2002/0022624 A1). .delta..sub.H
(CDCl.sub.3): 1.52(9H, s), 6.52(1H, s), 7.26 (1H, d), 7.97 (1H, d),
8.23 (1H, d). Preparation 105:
(6-Chloro-4-iodopyridin-3-yl)carbamic acid tert-butyl ester
##STR126##
[0281] The title compound was prepared according to the method
described by Dinnell et al (US 2002/0022624 A1) from the compound
of Preparation 104. .delta..sub.H (CDCl.sub.3): 1.54 (9H, s), 6.62
(1H, s), 7.72 (1H, s), 8.93 (1H, s). Preparation 106:
6-Chloro4-iodopyridin-3-ylamine ##STR127##
[0282] The title compound was prepared according to the method
described by Dinnell et al (US 2002/0022624 A1) from the compound
of Preparation 105. .delta..sub.H (CDCl.sub.3): 4.12 (2H, br s),
7.60 (1H, s), 7.79 (1H, s). Preparation 107:
N-(6-Chloropyridin-2-yl)-2,2-dimethyl propionamide. ##STR128##
[0283] To a solution of 2-amino-6-chloropyridine (3.0 g, 23.3 mmol)
in dichloromethane (45 mL) under argon was added triethylamine
(4.10 mL, 29.2 mmol) and the reaction cooled to 0.degree. C. (ice
bath). A solution of trimethylacetyl chloride (3.16 mL, 25.7 mmol)
in dichloromethane (10 mL) was added dropwise over 20 min before
stirring for 30 min at 0.degree. C. The reaction was brought up to
rt and stirred for a further 5 h, then water (30 mL) was added. The
organics were separated and washed with Na.sub.2CO.sub.3 solution
(2.times.50 mL), dried,(MgSO.sub.4) and solvent removed in vacuo.
Purification by column chromatography (SiO.sub.2, CH.sub.2Cl.sub.2)
gave the title compound. m/z (ES.sup.+)=213.04 [M+H].sup.+.
Preparation 108: N-(6-Chloro-3-iodopyridin-2-yl)-2,2-dimethyl
propionamide. ##STR129##
[0284] To a dry solution of N-(6-chloropyridin-2-yl)-2,2-dimethyl
propionamide (Preparation 107, 8.0 g, 37.6 mmol) in THF (120 mL),
cooled to -78.degree. C., was added dropwise, a solution of
tert-butyllithium in pentane (1.7M, 48.7 mL, 82.8 mmol) over 40
min. The reaction was stirred at --78.degree. C. for 3 h before
adding a solution of iodine (11.46 g, 45.1 mmol) in THF (40 mL)
dropwise. The mixture was brought up to rt and stirred for 16 h. 2M
HCl (3 mL) was added to the reaction, and after 20 min the solvent
was removed in vacuo. Crude material was partitioned between ethyl
acetate (200 mL) and water (150 mL). Organics were separated and
washed with 10% sodium thiosulfate solution (4.times.100 mL) then
NaHCO.sub.3 solution (2.times.100 mL), dried (MgSO.sub.4) and the
solvent removed in vacuo. The residue was purified by column
chromatography (SiO.sub.2, CH.sub.2Cl.sub.2) to give the title
compound. m/z (ES.sup.+)=338.93 [M+H].sup.+. Preparation 109:
6-Chloro-3-iodopyridin-2-ylamine. ##STR130##
[0285] A suspension of N-(6-chloro-3-iodopyridin-2-yl)-2,2-dimethyl
propionamide (Preparation 108, 5.0 g, 14.8 mmol) in 1M HCl was
heated to reflux for 4.5 h. The reaction was cooled to rt and then
extracted with diethyl ether (2.times.50 mL). The organics were
washed with Na.sub.2CO.sub.3 solution (2.times.50 mL) before being
dried (MgSO.sub.4) and the solvent removed in vacuo. Purification
by column chromatography (SiO.sub.2, CH.sub.2Cl.sub.2) afforded the
title compound. .delta..sub.H (CDCl.sub.3): 7.76 (1H, d), 6.46 (1H,
d), 5.43-5.20 (2H, br s). Preparation 110:
6-Chloro-1H-pyrrolo[2,3b]pyridine-2-carboxylic acid. ##STR131##
[0286] To a dry solution of 6-chloro-3-iodo-pyridin-2-ylamine
(Preparation 109, 2.80 g, 11.0 mmol) in DMF (8 mL) under argon was
added pyruvic acid (2.29 mL, 33.0 mmol), DABCO (3.70 g, 33.0 mmol)
then palladium(II)acetate (124 mg, 0.55 mmol) and the mixture
purged with argon for 20 min. The reaction was heated to
105.degree. C. (bath temp.) for 3 h before being allowed to cool to
rt. Solvent was removed in vacuo then crude material partitioned
between ethyl acetate (100 mL) and water (75 mL). The organic layer
was separated and washed with water (2.times.75 mL) before being
extracted into 2M NaOH (2.times.75 mL). The aqueous layer was
acidified to pH 3 with 2M HCl and extracted into ethyl acetate
(2.times.100 mL). Organic layers were combined, dried (MgSO.sub.4)
and concentrated in vacuo. The residue was suspended in water and
the filtrate removed to give the title compound. m/z
(ES.sup.+)=196.91 [M+H].sup.+, RT=3.07 min. Preparation 111:
[1-(S)-(4-Fluorobenzyl)-2-oxo-2-(5-oxo-[1,4]diazepam-1-yl)ethyl]carbamic
acid tert-butyl ester ##STR132##
[0287] DIPEA (2.08 mL, 11.95 mmol), BOC-L-phenylalanine (1.128 g,
3.98 mmol) and HOBt (592 mg, 4.38 mmol) was added to a solution of
[1,4]-diazepan-5-one (500 mg, 4.38 mmol) in DMF (10 mL) and the
mixture stirred for 5 min. EDCI (992 mg, 5.18 mmol) was added and
the reaction stirred for 16 h before removing the solvent in vacuo.
Purification by column chromatography (SiO.sub.2, 9:1
CH.sub.2Cl.sub.2/MeOH) gave the title compound. m/z
(ES.sup.+)=380.00 [M+H].sup.+. Preparation 112:
1-(S)-[2-Amino-3-(4-fluorophenyl)propionyl][1,4]diazepan-5-one
##STR133##
[0288] To a solution of
[1-(S)-(4-fluorobenzyl)-2-oxo-2-(5-oxo-[1,4]diazepam-1-yl)ethyl]carbamic
acid tert-butyl ester (Preparation 111, 1.23 g, 3.24 mmol) in
methanol (15 mL) was added a solution of 4M HCl in dioxane (6.48
mL, 25.9 mmol) and the reaction stirred for 3.5 h. Solvent was
removed in vacuo then crude material taken into water (20 mL). The
aqueous layer was extracted with ethyl acetate (15 mL) then water
removed in vacuo to afford the title compound as its hydrochloride
salt. m/z (ES.sup.+)=279.95 [M+H].sup.+. Preparation 113:
2-(S)-tert-Butoxycarbonylamino-3-(4-fluorophenyl)propionic acid
tert-butyl ester ##STR134##
[0289] To a stirred solution of (S)-N-Boc-4-fluorophenylalanine
(2.83 g, 10.0 mmol), DMAP (0.12 g, 1.0 mmol) in DCM (20 mL) and
2-methyl-2-propanol (1.05 mL, 11.0 mmol), was added DCC (2.27 g,
11.0 mmol). The reaction mixture was stirred at rt for 16 h. The
reaction mixture was filtered and washed several times with DCM.
The filtrate was concentrated in vacuo and chromatographed on
silica gel eluting with ethyl acetate:isohexane (1:4) to give the
title compound. .delta..sub.H (CDCl.sub.3): 1.39 (9H, s), 1.41 (9H,
s), 3.01 (2H, m), 4.41 (1H, m), 4.98 (1H, m), 6.95 (2H, m), 7.12
(2H, m). Preparation 114: 2-(S)-Amino-3-(4-fluorophenyl)propionic
acid tert-butyl ester hydrochloride ##STR135##
[0290] A stirred solution of ethyl acetate (10 mL) and methanol
(0.60 mL, 14.7 mmol) was cooled to 0.degree. C. under an argon
atmosphere. Acetyl chloride (1.05 mL, 14.7 mmol) was added
dropwise, and the solution warmed to rt and stirred for 30 min.
2-(S)-tert-butoxycarbonylamino-3-(4-fluorophenyl)propionic acid
tert-butyl ester (Preparation 113, 1 g, 2.95 mmol) was added, and
the reaction mixture stirred at rt for 4 h. The reaction mixture
was filtered, washed several times with diethyl ether and dried
under vacuum to give the title compound. .delta..sub.H (DMSO): 1.30
(9H, s), 3.01 (1H, dd), 3.20 (11H, dd), 4.08 (1H, m), 7.15 (2H, m),
7.32 (2H, m), 8.64 (3H, br s). Preparation 115:
2-Chloro-5-iodopyridin-4-ylamine ##STR136##
[0291] Silver sulfate (7.1 g, 22.8 mmol) and
4-amino-2-chloropyridine (4.06 g, 31.6 mmol) were added to a
solution of iodine (5.65 g, 22.3 mmol) in ethanol (100 mL) and the
reaction mixture stirred at rt for 72 h. The bright yellow
suspension was filtered, washed with methanol and the filtrate
concentrated in vacuo. The residue was partitioned between
saturated Na.sub.2CO.sub.3 solution (200 mL) and ethyl acetate (200
ml). After separation the organic layer was washed with
Na.sub.2S.sub.2O.sub.3 solution (50 mL, 25%) and brine (50 mL),
dried (MgSO.sub.4), concentrated in vacuo and purified by
chromatography on silica gel eluting with iso-hexane/ethyl acetate
(3:1 to 2.5:1) to give the title compound. .delta..sub.H
(CDCl.sub.3): 4.81 (2H, br s), 6.63 (1H, s), 8.38 (1H, s); m/z
(ES.sup.+)=254.86 [M+H].sup.+; RT=2.51 min. Preparation 116:
6-Chloro-1H-pyrrolo[3,2-c]pyridine-2-carboxylic acid ##STR137##
[0292] Pyruvic acid (0.86 mL, 12.4 mmol) was added to a solution of
2-chloro-5-iodo-pyridin-4-ylamine (Preparation 115, 1.05 mg, 4.13
mmol), palladium acetate (56 mg, 0.25 mmol) and DABCO (1.39 g, 12.4
mmol) in anhydrous DMF (30 ml). The reaction mixture was degassed
with argon for 20 min, then heated to 145.degree. C. for 2 h. The
solvent was removed in vacuo and the residue taken up in water (200
mL). The suspension was made alkaline (pH 9-10) with dilute NaOH
solution (1M) and filtered through Celite. After washing of the
filtrate with ethyl acetate (50 mL) and ether (50 mL) the pH was
adjusted to 3 with dilute HCl solution (1M). Extraction with ethyl
acetate (5.times.50 mL), drying of the combined extracts
(MgSO.sub.4) and concentration gave the title compound.
.delta..sub.H (d.sub.6 DMSO): 7.24 (1H, s), 7.42 (1H, s), 8.80 (1H,
s); m/z (ES.sup.-)=195.02 [M-H].sup.-; RT=2.36 min. Preparation
117: 4(S)-(4-Fluorobenzyl)oxazolidine-2,5-dione ##STR138##
[0293] To a solution of
2(S)-tert-butoxycarbonylamino-3-(4-fluorophenyl)propionic acid (1.5
g, 5.29 mmol) in ethyl acetate (100 mL) under an argon atmosphere
was added triphosgene (628 mg, 2.12 mmol). To the solution was
added triethylamine (0.8 mL 5.76 mmol,) over 1 min, and the
reaction stirred for 72 h at rt. The reaction mixture was filtered,
and the filtrate concentrated in vacuo to yield an oily residue.
The crude material was crystallised from cold dichloromethane and
petroleum ether to give the title compound. .delta..sub.H
(CD.sub.3OD): 7.20 (2H, m), 7.10 (2H, m), 5.86 (1H, s, (NH)), 4.58
(1H, s), 3.33-3.23 (2H, m), 3.11-3.00 (1H, m).
EXAMPLE 1
5-Chloro-1H-pyrrolo[3,2-b]pyridine-2-carboxylic acid
(1-dimethylcarbamoyl-2-(S)-phenylethyl)amide
[0294] ##STR139##
[0295] To a solution of
5-chloro-1H-pyrrolo[3,2-b]pyridine-2-carboxylic acid (Preparation
6, 36 mg, 0.18 mmol) in DMF (4 mL, anhydrous), was added
2-(S)-amino-N,N-dimethyl-3-phenylpropionamide hydrochloride
(Preparation 8, 46 mg, 0.20 mmol), DIPEA (105 .mu.L, 6.05 mmol) and
HOBt (25 mg, 0.18 mmol) sequentially. The solution was stirred for
5 min prior to the addition of EDCI (42 mg, 0.22 mmol) in one
portion. The resulting solution was stirred for 16 h at rt. The
reaction mixture was partitioned between ethyl acetate (50 mL) and
brine (20 mL). The layers were separated and the aqueous phase
extracted with ethyl acetate (3.times.20 mL), then the combined
organics were washed with water (3.times.10 mL) and brine (10 mL).
The organic phase was dried (MgSO.sub.4), filtered and concentrated
in vacuo. Purification via flash column chromatography eluting with
methanol/dichloromethane (1:19) gave an orange oil which was
triturated with diethyl ether/hexane to give the title compound as
an orange solid. .delta..sub.H (CDCl.sub.3): 2.71 (3H, s), 2.93
(3H, s), 3.05-3.21 (2H, m), 5.28-5.39 (1H, m), 7.00 (1H, s),
7.17-7.36 (6H, m), 7.69 (1H, d, 9.23 Hz), 9.27 (1H, s); m/z
(ES.sup.+)=371.15 [M+H].sup.+; RT=3.28 min.
EXAMPLE 2
1H-pyrrolo [3,2-c]pyridine-2-carboxylic acid
(1-dimethylcarbamoyl-2(S)-phenylethyl)amide
[0296] ##STR140##
[0297] To a solution of 1H-pyrrolo[3,2-c]pyridine-2-carboxylic acid
(Preparation 12, 100 mg, 0.62 mmol) in DMF (15 mL) was added
2-(S)-amino-N,N-dimethyl-3-phenylpropionamide hydrochloride
(Preparation 8, 141 mg, 0.62 mmol), HOBt (83 mg, 0.62 mmol) and
DIPEA (0.21 mL, 1.23 mmol). After 30 min, EDCI (154 mg, 0.80 mmol)
was added and the mixture was stirred at rt for 72 h. The solvent
was removed in vacuo and the solid partitioned between water (50
mL) and ethyl acetate (3.times.50 mL). The combined organic layer
was dried (MgSO.sub.4), concentrated in vacuo and purified by
chromatography on silica gel using methanol/dichloromethane (6:94)
as eluant to give the title compound as a beige solid.
.delta..sub.H (CD.sub.3OD): 3.06-3.19 (2H, m), 4.83 (6H, s), 5.27
(1H, t), 7.20-7.32 (5H, m), 7.34 (1H, s), 7.45 (1H, d), 8.20 (1H,
d), 8.87 (1H, s); m/z (ES.sup.+)=337 [M+H].sup.+.
EXAMPLE 3
1H-Pyrrolo[2,3-c]pyridine-2-carboxylic acid
(1-dimethylcarbamoyl-2(S)-phenylethyl)amide
[0298] ##STR141##
[0299] To a solution of 1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid
(Preparation 15, 100 mg, 0.62 mmol) in DMF (15 mL), was added
2-(S)-amino-N,N-dimethyl-3-phenylpropionamide hydrochloride
(Preparation 8, 141 mg, 0.62 mmol), HOBt (83 mg, 0.62 mmol) and
DIPEA (0.21 mL, 1.23 mmol). The reaction was stirred at rt for 0.5
h, followed by addition of EDCI (154 mg, 0.80 mmol). The mixture
was stirred at rt for 72 h then partitioned between water (50 mL)
and ethyl acetate (3.times.50 mL). The combined organic fractions
were dried (MgSO.sub.4), concentrated in vacuo and chromatographed
on silica gel eluting with methanol/dichloromethane (1:19) to give
the title compound as a yellow solid. .delta..sub.H (CD.sub.3OD):
2.88 (6H, s), 3.07-3.20 (2H, m), 5.28 (1H, t), 7.20 (1H, s),
7.22-7.31 (5H, m), 7.65 (1H, d), 8.10 (1H, d), 8.76 (1H, s); m/z
(ES.sup.+)=337 [M+H].sup.+.
EXAMPLE 4
5-Chloro-1H-pyrrolo[2,3-c]pydridine-2-carboxylic acid
(1-dimethylcarbamoyl-2(S)-phenylethyl)amide
[0300] ##STR142##
[0301] To a solution of
5-chloro-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid (Preparation
18, 100 mg, 0.51 mmol) in DMF (15 mL) was added
2-(S)-amino-N,N-dimethyl-3-phenylpropionamide hydrochloride
(Preparation 8, 116 mg, 0.51 mmol), HOBt (69 mg, 0.51 mmol) and
DIPEA (0.18 mL, 1.02 mmol). After 15 min, EDCI (127 mg, 0.66 mmol)
was added and the mixture stirred at rt for 15 h. The solvent was
removed in vacuo and the solid partitioned between water (50 mL)
and ethyl acetate (3.times.50 mL). The combined organic phases were
dried (MgSO.sub.4), concentrated in vacuo and purified by
chromatography on silica gel eluting with methanol/dichloromethane
(1:19) to give the title compound as a beige solid. .delta..sub.H
(CD.sub.3OD): 2.89 (6H, s), 3.05-3.19 (2H, m), 5.27 (1H, t), 7.16
(1H, s), 7.20-7.32 (5H, m), 7.67 (1H, s), 8.56 (1H, s); m/z
(ES.sup.+)=371 [M+H].sup.+.
EXAMPLE 5
5-Chloro-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid
[1-(S)-(4-fluorobenzyl)-2-(4-hydroxypiperidin-1-yl)-2-oxoethyl]amide
[0302] ##STR143##
[0303] Route A: To a solution of
2-(S)-[(5-chloro-1H-pyrrolo[2,3-c]pyridine-2-carbonyl)amino]-3-(4-fluorop-
henyl)propionic acid (EXAMPLE 228, 1.4 g, 3.87 mmol) in DMF (35 mL)
was added HATU (1.77 g, 4.64 mmol) and the reaction stirred for 10
min. 4-Hydroxypiperidine (0.43 g, 4.26 mmol) was added, followed by
DIPEA (0.8 mL, 4.64 mmol,) and the reaction stirred at rt for 16 h.
Solvent was removed in vacuo and the crude material partitioned
between ethyl acetate (50 mL) and water (50 mL). The organics were
washed with sodium bicarbonate (2.times.30 mL) and brine
(2.times.30 mL), dried (MgSO.sub.4) and the solvent removed in
vacuo. Purification by column chromatography (SiO.sub.2, 96:4
dichloromethane/methanol) gave the title compound. m/z
(ES.sup.+)=445.15 [M+H].sup.+; RT=3.24 min.
[0304] Route B: The title compound was prepared as outlined in
EXAMPLE 1 from 5-chloro-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid
(Preparation 18) and
2-(S)-amino-3-(4-fluorophenyl)-1-(4-hydroxypiperidin-1-yl)propan--
1-one hydrochloride (Preparation 20). The product was purified by
chromatography on silica gel eluting with methanol/dichloromethane
(1:19) to give the title compound as a pale yellow solid.
.delta..sub.H (CD.sub.3OD): 1.08-1.19 (0.5H, m), 1.29-1.51 (1.5H,
m), 1.54-1.62 (0.5H, m), 1.73-1.84 (1.5H, m), 3.06-3.36 (4H, m),
3.67-3.95 (2.5H, m), 4.03-4.10 (0.5H, m), 5.32 (1H, t), 6.97-7.04
(2H, m), 7.14 (1H, s), 7.26-7.33 (2H, m), 7.66 (1H, s), 8.55 (1H,
s); m/z (ES.sup.+)=445 [M+H].sup.+; RT=3.27 min.
EXAMPLE 6
5-Chloro-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid
[1-(S)-benzyl-3-(cis-3,4-dihydroxypyrrolidin-1-yl)-2(R)-hydroxy-3-oxoprop-
yl]amide
[0305] ##STR144##
[0306] To a solution of
(S)-3-[(5-chloro-1H-pyrrolo[2,3-c]pyridine-2-carbonyl)amino]-2-(R)-hydrox-
y-4-phenylbutyric acid (EXAMPLE 44, 50 mg, 0.13 mmol),
cis-3,4-dihydroxypyrrolidine (Preparation 23, 15 mg, 0.15 mmol) and
HOBt (27 mg, 0.20 mmol) in DMF (5 mL), was added DIPEA (47 .mu.L,
0.27 mmol). After stirring for 5 min, EDCI (28 mg, 0.15 mmol) was
added and the reaction stirred at rt for 72 h. The solvent was
removed in vacuo and the residue partitioned between water (30 mL)
and ethyl acetate (3.times.30 mL). The combined organic fractions
were dried (MgSO.sub.4), concentrated in vacuo and the residue
purified by chromatography on silica gel eluting with
methanol/dichloromethane (1:9) to give the title compound as a
white solid. m/z (ES.sup.+)=459 [M+H].sup.+. RT=3.07 min.
EXAMPLE 7
5-Bromo-1H-pyarrolo[2,3-c]pyridine-2-carboxylic acid
(1-dimethylcarbamoyl-2-(S)-phenylethyl)amide
[0307] ##STR145##
[0308] To a solution of
5-bromo-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid (Preparation
27, 50 mg, 0.21 mmol) in DMF (5 mL), was added
2-(S)-amino-N,N-dimethyl-3-phenylpropionamide hydrochloride
(Preparation 8, 52 mg, 0.23 mmol), HOBt (31 mg,0.23 mmol) and DIPEA
(72 .mu.L, 0.41 mmol). After 5 min, EDCI (44 mg, 0.23 mmol) was
added and the reaction was stirred at rt for 16 h. The solvent was
removed in vacuo and the residue partitioned between water (30 mL)
and ethyl acetate (3.times.30 mL). The combined organic fractions
were dried (MgSO.sub.4), concentrated in vacuo and the residue
purified by chromatography on silica gel eluting with
methanol/dichloromethane (3:97) to give the title compound as an
off-white solid. .delta..sub.H (CD.sub.3OD): 2.88 (6H, s),
3.06-3.18 (2H, m), 5.27 (1H, t), 7.13 (1H, s), 7.19-7.29 (5H, m),
7.80 (1H, s), 8.53 (1H, s); m/z (ES.sup.+)=415 [M+H].sup.+.
EXAMPLE 8
1H-Pyrrolo[2,3-b]pyridine-2-carboxylic acid
(1-dimethylcarbamoyl-2-(S)-phenylethyl)amide
[0309] ##STR146##
[0310] Triethylamine (82 .mu.L, 0.59 mmol) was added to
2-(S)-amino-N,N-dimethyl-3-phenylpropionamide hydrochloride
(Preparation 8, 117 mg,0.51 mmol) in DCM (5 mL) at rt under
nitrogen. The mixture was cooled to 0.degree. C. and
1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid (Preparation 28, 75 mg,
0.51 mmol) was added followed by HOBt (102 mg, 0.765 mmol) and then
EDCI (98 mg, 0.51 mmol). The reaction mixture was then left to warm
to rt, stirred for 4 days and then diluted with ethyl acetate (25
mL), washed with aqueous sodium hydroxide solution (2M, 2.times.25
mL), aqueous hydrochloric acid (2N, 2.times.25 mL) and dried
(MgSO.sub.4). The organic solution was concentrated in vacuo to
give a beige foam which was purified by column chromatography
eluting with methanol/dichloromethane (2:98) to give the title
compound as a white solid. .delta..sub.H (CDCl.sub.3): 2.74 (3H,
s), 2.95 (3H, s), 3.17 (2H, m), 5.41 (1H, dd), 6.90 (1H, s),
7.08-7.48 (7H, m), 7.98 (1H, d), 8.55 (1H, d); m/z (ES.sup.+)=337.2
[M+H]+, RT=1.38 min.
EXAMPLE 9
5-Chloro-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid
(2-phenoxyethyl)amide
[0311] ##STR147##
[0312] The title compound was prepared as outlined in EXAMPLE 1
from 5-chloro-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid
(Preparation 18) and 2-phenoxyethylamine. The product was purified
by chromatography on silica gel eluting with
methanol/dichloromethane (1:19) to give the title compound as a
yellow solid. .delta..sub.H (CD.sub.3OD): 3.79 (2H, t), 4.17 (2H,
t), 6.88-6.97 (3H, m), 7.08 (1H, s), 7.16 (2H, t), 7.67 (1H, s),
8.58 (1H, s); m/z (ES.sup.+)=316 [M+H].sup.+.
EXAMPLE 10
5-Chloro-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid
(2-morpholin4-ylethyl)amide
[0313] ##STR148##
[0314] The title compound was prepared as outlined in EXAMPLE 1
from 5-chloro-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid
(Preparation 18) and 2-morpholin-4-ylethylamine. The product was
purified by chromatography on silica gel eluting with
methanol/dichloromethane (1:19) to give the title compound as a
yellow solid. .delta..sub.H (CD.sub.3OD): 2.54-2.60 (4H, m), 2.64
(2H, t), 3.58 (2H, t), 3.69-3.73 (4H, m), 7.05 (1H, s), 7.66 (1H,
s), 8.58 (1H, s); m/z (ES.sup.+)=309 [M+H].sup.+.
EXAMPLE 11
5-Chloro-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid
[2-(4-methoxyphenoxy)ethyl]amide
[0315] ##STR149##
[0316] The title compound was prepared as outlined in EXAMPLE 1
from 5-chloro-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid
(Preparation 18) and 2-(4-methoxyphenoxy)ethylamine. The product
was purified by chromatography on silica gel eluting with
methanol/dichloromethane (3:97) to give the title compound as a
yellow solid. .delta..sub.H (CD.sub.3OD): 3.71 (3H, s), 3.77 (2H,
t), 4.12 (2H, t), 6.81-6.91 (4H, m), 7.09 (1H, s), 7.67 (1H, s),
8.58 (1H, s); m/z (ES.sup.+)=346 [M+H].sup.+.
EXAMPLE 12
5-Chloro-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid
(2-thiophen-2-ylethyl)amide
[0317] ##STR150##
[0318] The title compound was prepared as outlined in EXAMPLE 1
from 5-chloro-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid
(Preparation 18) and 2-thiophen-2-ylethylamine. The product was
purified by chromatography on silica gel eluting with
methanol/dichloromethane (3:97) to give the title compound as a
yellow solid. .delta..sub.H (CD.sub.3OD): 3.16 (2H, t), 3.65 (2H,
t), 6.89-6.94 (2H, m), 7.03 (1H, s), 7.20 (1H, d), 7.66 (1H, s),
8.57 (1H, s); m/z (ES.sup.+)=306 [M+H].sup.+.
EXAMPLE 13
5-Chloro-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid
[2-(2-methoxyphenyl)ethyl]amide
[0319] ##STR151##
[0320] The title compound was prepared as outlined in EXAMPLE 1
from 5-chloro-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid
(Preparation 18) and 2-(2-methoxyphenyl)ethylamine. The product was
purified by chromatography on silica gel eluting with
methanol/dichloromethane (3:97) to give the title compound as a
yellow solid. .delta..sub.H (CD.sub.3OD): 2.94 (2H, t), 3.59 (2H,
t), 3.78 (3H, s), 6.84 (1H, t), 6.89 (1H, d), 6.97 (1H, s),
7.12-7.18 (2H, m), 7.60 (1H, s), 8.55 (1H, s); m/z (ES.sup.+)=330
[M+H].sup.+.
EXAMPLE 14
5-Chloro-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid
(2-oxo-2-phenylethyl)amide
[0321] ##STR152##
[0322] The title compound was prepared as outlined in EXAMPLE 1
from 5-chloro-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid
(Preparation 18) and 2-oxo-2-phenylethylamine. The product was
purified by mass directed purification to give the title compound
as an orange solid. m/z (ES.sup.+)=314 [M+H].sup.+; RT=3.30
min.
EXAMPLE 15
5-Chloro-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid
(1H-benzoimidazol-2-ylmethyl)amide
[0323] ##STR153##
[0324] The title compound was prepared as outlined in EXAMPLE 1
from 5-chloro-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid
(Preparation 18) and 2-oxo-2-phenylethylamine. The product was
purified by mass directed purification to give the title compound
as a yellow solid. m/z (ES.sup.+)=326 [M+H].sup.+; RT=2.66 min.
EXAMPLE 16
5-Chloro-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid
phenethylamide
[0325] ##STR154##
[0326] The title compound was prepared as outlined in EXAMPLE 1
from 5-chloro-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid
(Preparation 18) and phenethylamine. The product was purified by
mass directed purification to give the title compound as an orange
solid. .delta..sub.H (CD.sub.3OD): 2.94 (2H, t), 3.63 (2H, t), 7.00
(1H, s), 7.15-7.30 (5H, m), 7.64 (1H, s), 8.57 (1H, s); m/z
(ES.sup.+)=300 [M+H].sup.+.
EXAMPLE 17
5-Chloro-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid
[2-(4-fluorophenyl)ethyl]amide
[0327] ##STR155##
[0328] The title compound was prepared as outlined in EXAMPLE 1
from 5-chloro-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid
(Preparation 18) and 4-fluorophenethylamine. The product was
purified by mass directed purification to give the title compound
as an orange solid. .delta..sub.H (CD.sub.3OD): 2.93 (2H, t), 3.60
(2H, t), 6.97-7.04 (3H, m), 7.24-7.30 (2H, m), 7.65 (1H, s), 8.56
(1H, s); m/z (ES.sup.+)=318 [M+H].sup.+.
EXAMPLE 18
5-Chloro-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid
[2-(2-chloro-6-fluorobenzalsulfanyl)ethyl]amide
[0329] ##STR156##
[0330] The title compound was prepared as outlined in EXAMPLE 1
from 5-chloro-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid
(Preparation 18) and 2-(2-chloro-6-fluorobenzylsulfanyl)ethylamine.
The product was purified by mass directed purification to give the
title compound as a yellow solid. .delta..sub.H (CD.sub.3OD): 2.82
(2H, t), 3.64 (2H, t), 3.95 (2H, s), 7.04-7.09 (2H, m), 7.20-7.25
(2H, m), 7.67 (1H, s), 8.58 (1H, s); m/z (ES.sup.+)=398
[M+H].sup.+.
EXAMPLE 19
5-Chloro-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid
(2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)amide
[0331] ##STR157##
[0332] The title compound was prepared as outlined in EXAMPLE 1
from 5-chloro-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid
(Preparation 18) and 2,3-dihydrobenzo[1,4]dioxin-2-ylmethylamine.
The product was purified by mass directed purification to give the
title compound as a yellow solid. .delta..sub.H (CD.sub.3OD):
3.69-3.73 (2H, m), 3.97-4.03 (1H, m), 4.32-4.42 (2H, m), 6.77-6.88
(4H, m), 7.10 (1H, s), 7.67 (1H, s), 8.58 (1H, s); m/z
(ES.sup.+)=344 [M+H].sup.+.
EXAMPLE 20
5-Chloro-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid
[2-(naphthalen-1-ylamino)ethyl]amide
[0333] ##STR158##
[0334] The title compound was prepared as outlined in EXAMPLE 1
from 5-chloro-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid
(Preparation 18) and 2-(naphthalen-1-ylamino)ethylamine. The
product was purified by mass directed purification to give the
title compound as a brown solid. .delta..sub.H (CD.sub.3OD): 3.55
(2H, t), 3.80 (2H, t), 6.68 (1H, d), 7.04 (1H, s), 7.14 (1H, d),
7.28 (1H, t), 7.36-7.42 (2H, m), 7.65 (1H, s), 7.70-7.74 (1H, m),
7.98-8.02 (1H, m), 8.58 (1H, s); m/z (ES.sup.+)=365
[M+H].sup.+.
EXAMPLE 21
1H-Pyrrolo[2,3-c]pyridine-2-carboxylic acid
(2-phenylaminoethyl)amide
[0335] ##STR159##
[0336] The title compound was prepared as outlined in EXAMPLE 1
from 1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid (Preparation 15)
and 2-phenylaminoethylamine to give the title compound as a pale
yellow solid. .delta..sub.H (CD.sub.3OD): 3.37 (2H, t), 3.63 (2H,
t), 6.61 (1H, t), 6.69 (2H, d), 7.08-7.13 (2H, m), 7.64 (1H, d),
8.10 (1H, d), 8.78 (1H, s); m/z (ES.sup.+)=281 [M+H].sup.+.
EXAMPLE 22
1H-Pyrrolo[2,3-c]pyridine-2-carboxylic acid
(2-phenoxyethyl)amide
[0337] ##STR160##
[0338] The title compound was prepared as outlined in EXAMPLE 1
from 1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid (Preparation 15)
and 2-phenoxyethylamine to give the title compound as a pale yellow
solid. .delta..sub.H (CD.sub.3OD): 3.81 (2H, t), 4.18 (2H, t),
6.89-6.97 (3H, m), 7.14 (1H, s), 7.26 (2H, t), 7.65 (1H, d), 8.10
(1H, d), 8.78 (1H, s); m/z (ES.sup.+)=282 [M+H].sup.+.
EXAMPLE 23
5-Methoxy-1H-pyrrolo[3,2-b]pyridine-2-carboxylic acid
(1-dimethylcarbamoyl-2-(S)-phenylethyl)amide
[0339] ##STR161##
[0340] To a solution of
5-methoxy-1H-pyrrolo[3,2-b]pyridine-2-carboxylic acid (Preparation
36, 50 mg, 0.26 mmol) in DMF (3 mL), was added DIPEA (100 .mu.L,
0.57 mmol), HOBt (35 mg, 0.26 mmol) and EDCI (60 mg, 0.31 mmol)
sequentially. The reaction mixture was stirred for 5 min prior to
the addition of 2-(S)-amino-N,N-dimethyl-3-phenylpropionamide
hydrochloride (Preparation 8, 65 mg, 0.29 mmol) in one portion. The
reaction mixture was stirred for 21 h at rt then water (15 mL) and
dichloromethane (30 mL) were added. The mixture was stirred
vigorously for 10 min and the layers separated. The aqueous phase
was extracted with dichloromethane (3.times.15 mL) and the combined
organics washed with brine (30 mL), dried (MgSO.sub.4), filtered
and concentrated in vacuo. Purification via flash column
chromatography (SiO.sub.2, ethyl acetate/isohexane, 1:1) gave a
yellow oil. Trituration with water followed by filtration and
drying gave the title compound as a white solid. .delta..sub.H
(CD.sub.3OD): 2.88 (6H, 2.times.s), 3.12 (2H, m), 3.94 (3H, s),
5.26 (1H, dd), 6.71 (1H, d), 7.13 (1H, s), 7.25 (5H, m), 7.74 (1H,
d); m/z (ES.sup.+)=367 [M+H].sup.+; RT=3.20 min.
EXAMPLE 24
1H-Pyrrolo[3,2-b]pyridine-2-carboxylic acid
(1-dimethylcarbamoyl-2-(S)-phenylethylamide
[0341] ##STR162##
[0342] Prepared as outlined in EXAMPLE 1 from
1H-pyrrolo[3,2-b]pyridine-2-carboxylic acid (Preparation 32) and
2-(S)-amino-N,N-dimethyl-3-phenyl-propionamide hydrochloride
(Preparation 8, 78 mg, 0.34 mmol). The title compound was isolated
as a white solid. .delta..sub.H (d.sub.6 DMSO): 2.82 (3H, s), 2.98
(3H, s), 3.03 (2H, m), 5.12 (1H, m), 7.16 (2H, m), 7.24 (2H, m),
7.32 (2H, m), 7.40 (1H, d), 7.74 (1H, d), 8.37 (1H, dd), 8.93 (1H,
d); m/z (ES.sup.+)=337 [M+H].sup.+; RT=3.10 min.
EXAMPLE 25
1H-Pyrrolo[3,2-b]pyridine-2-carboxylic acid
(2-phenoxyethyl)amide
[0343] ##STR163##
[0344] To a solution of 1H-pyrrolo[3,2-b]pyridine-2-carboxylic acid
(Preparation 32, 50 mg, 0.31 mmol) in DMF (5 mL), was added
2-phenoxyethylamine (44 .mu.L, 0.34 mmol), DIPEA (118 .mu.L, 0.68
mmol) and HOBt (42 mg, 0.31 mmol) sequentially. The reaction
mixture was stirred for 5 min prior to the addition of EDCI (42 mg,
0.22 mmol) in one portion. The resulting mixture was stirred for 20
h at rt and partitioned between ethyl acetate (50 mL) and water (20
mL). The layers were separated and the aqueous phase extracted with
ethyl acetate (2.times.30 mL). The combined organic fractions were
washed with brine (20 mL), dried (MgSO.sub.4), filtered and
concentrated in vacuo to give an oil. Trituration with diethyl
ether/isohexane and collection by filtration gave, after
air-drying, the title compound as a cream coloured solid.
.delta..sub.H (d.sub.6 DMSO): 3.48 (2H, m), 4.14 (2H, t), 6.94 (3H,
m), 7.17 (1H, dd), 7.28 (3H, m), 7.77 (1H, d), 8.37 (1H, dd), 8.86
(1H, t); m/z (ES.sup.+)=282 [M+H].sup.+; RT=2.60 min.
EXAMPLE 26
1H-Pyrrolo[3,2-b]pyridine-2-carboxylic acid
(2-phenylaminoethyl)amide
[0345] ##STR164##
[0346] The title compound was prepared as outlined in EXAMPLE 25
except N-phenylethylenediamine (44 .mu.L, 0.34 mmol) was used in
place of 2-phenoxyethylamine. The title compound was isolated as a
cream solid. .delta..sub.H (d.sub.6 DMSO): 3.23 (2H, m), 3.37 (2H,
m), 5.70 (1H, t), 6.52 (1H, t), 6.63 (2H, dd), 7.07 (2H, dd), 7.17
(1H, dd), 7.22 (1H, s), 7.77 (1H, d), 8.37 (1H, dd), 8.73 (1H, t);
m/z (ES.sup.+)=281 [M+H].sup.+; RT=2.36 min.
EXAMPLE 27
5-Chloro-1H-pyrrolo[3,2-b]pyridine-2-carboxylic acid
(2-phenoxyethyl)amide
[0347] ##STR165##
[0348] The title compound was prepared as outlined in EXAMPLE 1
from 5-chloro-1H-pyrrolo[3,2-b]pyridine-2-carboxylic acid
(Preparation 6) and 2-phenoxyethylamine. On completion of the
reaction, the mixture was partitioned between water and
dichloromethane on a hydrophobic frit, washing with
dichloromethane. The organic filtrate was concentrated in vacuo
then triturated with dichloromethane/methanol/ethyl acetate to give
the title compound as a white solid. .delta..sub.H (d.sub.6 DMSO):
3.68 (2H, m), 4.13 (2H, m), 6.94 (3H, m), 7.25 (4H, m), 7.83 (1H,
d), 8.95 (1H, t), 12.09 (1H, s). m/z (ES.sup.+)=316 [M+H].sup.+;
RT=3.45 min.
EXAMPLE 28
5-Chloro-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid
[2-(4-benzylpiperazin-1-yl)ethyl]amide
[0349] ##STR166##
[0350] The title compound was prepared as outlined in EXAMPLE 1
from 5-chloro-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid
(Preparation 18) and 4-benzylpiperazin-1ylethylamine. The product
was purified by mass directed purification to give the title
compound as an orange solid. m/z (ES.sup.+)=398 [M+H].sup.+;
RT=2.75 min.
EXAMPLE 29
5-Chloro-1H-pyrrolo [2,3-c]pyridine-2-carboxylic acid
(2-benzylaminoethyl)amide
[0351] ##STR167##
[0352] The title compound was prepared as outlined in EXAMPLE 1
from 5-chloro-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid
(Preparation 18) and 2-benzylaminoethylamine. The product was
purified by mass directed purification to give the title compound
as an off-white solid. m/z (ES.sup.+)=329 [M+H].sup.+; RT=2.75
min.
EXAMPLE 30
5-Chloro-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid
phenylcarbamoylmethylamide
[0353] ##STR168##
[0354] To a solution of
[(5-chloro-1H-pyrrolo[2,3-c]pyridine-2-carbonyl)amino] acetic acid
(EXAMPLE 40, 30 mg, 0.12 mmol) in DMF (2 mL) was added aniline (12
.mu.L, 0.13 mmol), HOBt (16 mg, 0.12 mmol) and DIPEA (41 .mu.L,
0.24 mmol). After 5 min, EDCI (29 mg, 0.15 mmol) was added, and the
reaction stirred at rt for 16 h. The solvent was removed in vacuo
and the solid partitioned between water (20 mL) and ethyl acetate
(3.times.20 mL). The combined organic fractions were dried
(MgSO.sub.4), concentrated in vacuo and the residue purified by
chromatography on silica gel eluting with methanol/dichloromethane
(1:19) to give the title compound as a yellow solid. m/z
(ES.sup.+)=329 [M+H].sup.+; RT=3.17 min.
EXAMPLE 31
5-Chloro-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid
[(tetrahydropyran-4-ylcarbomoyl)methyl]amide
[0355] ##STR169##
[0356] The title compound was prepared according to the procedure
of EXAMPLE 30 except 4-aminotetrahydropyran was used in place of
aniline. After 16 h the reaction mixture was poured into water and
left for a further 16 h. The solid was filtered and dried to give
the title compound as a white crystalline solid. m/z (ES.sup.+)=337
[M+H].sup.+; RT=2.72 min.
EXAMPLE 32
5-Chloro-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid
{[(thiophen-2-ylmethyl)carbamoyl]methyl}amide
[0357] ##STR170##
[0358] The title compound was prepared according to EXAMPLE 30
except 2-aminomethylthiophene was used in place of aniline. After
stirring for 16 h the reaction mixture was poured into water and
the precipitate was filtered and dried to give the title compound
as a white solid. m/z (ES.sup.+)=349 [M+H].sup.+; RT=3.07 min.
EXAMPLE 33
5-Chloro-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid
[(4-methoxyphenylcarbamoyl)methyl]amide
[0359] ##STR171##
[0360] The title compound was prepared according to EXAMPLE 30
except p-anisidine was used in place of aniline. After stirring for
16 h, the reaction mixture was poured into water and the
precipitate was filtered and dried to give the title compound as a
beige solid. m/z (ES.sup.+)=359 [M+H].sup.+; RT=3.22 min.
EXAMPLE 34
5-Chloro-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid
(1-(S)-benzyl-2-oxo-2-pyrrolidin-1-ylethyl)amide
[0361] ##STR172##
[0362] To a solution of
2-(S)-[(5-chloro-1H-pyrrolo[2,3-c]pyridine-2-carbonyl)amino]-3-phenylprop-
ionic acid (EXAMPLE 42, 50 mg, 0.15 mmol) in DMF (3 mL) was added
pyrrolidine (13 .mu.L, 0.16 mmol), HOBt (20 mg, 0.15 mmol) and
DIPEA (51 .mu.L, 0.29 mmol). After 5 min, EDCI (36 mg, 0.19 mmol)
was added and the reaction was stirred at rt for 16 h. The solvent
was removed in vacuo and the solid was triturated with water,
filtered and dried to give the title compound as a beige solid. m/z
(ES.sup.+)=397 [M+H].sup.+; RT=3.38 min.
EXAMPLE 35
5-Chloro-1H-pyrrolo[2,3-cl]pyridine-2-carboxylic acid
[1-(S)-benzal-2-(3-(S)-hydroxypyrrolidin-1-yl-2-oxoethyl]amide
[0363] ##STR173##
[0364] To a solution of
2-(S)-[(5-chloro-1H-pyrrolo[2,3-c]pyridine-2-carbonyl)amino]-3-phenylprop-
ionic acid (EXAMPLE 42, 50 mg, 0.15 mmol) in DMF (3 mL) was added
3-(S)-hydroxypyrrolidine (13.9 mg, 0.16 mmol), HOBt (20 mg, 0.15
mmol) and DIPEA (51 .mu.L, 0.29 mmol). After 5 min, EDCI (36 mg,
0.19 mmol) was added and the reaction stirred at rt for 16 h. The
solvent was removed in vacuo and the residue partitioned between
water (20 mL) and ethyl acetate (3.times.20 mL), dried (MgSO.sub.4)
and concentrated in vacuo. Purification via chromatography on
silica gel eluting with methanol/dichloromethane (4:96) gave the
title compound as a white solid. m/z (ES.sup.+)=413 [M+H].sup.+;
RT=3.20 min.
EXAMPLE 36
5-Chloro-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid
[1-(S)-benzyl-2-(3,4-dihydroxypyrrolidin-1-yl)-2-oxo-ethyl]amide
[0365] ##STR174##
[0366] The title compound was prepared according to EXAMPLE 35
except cis-3,4-dihydroxypyrrolidine was used in place of
3-(S)-hydroxypyrrolidine. Purification via chromatography on silica
gel eluting with a gradient of methanol/dichloromethane (4:96 to
1:9) gave the title compound as a white solid. m/z (ES.sup.+)=429
[M+H].sup.+; RT=3.12 min.
EXAMPLE 37
5-Chloro-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid
(1-(S)-benzal-2-oxo-2-thiomorpholin-4-ylethyl)amide
[0367] ##STR175##
[0368] The title compound was prepared according to the procedure
used for EXAMPLE 35 except thiomorpholine was used in place of
3-(S)-hydroxypyrrolidine. Purification via chromatography on silica
gel eluting with methanol/dichloromethane (3:97) gave the title
compound as a white solid. m/z (ES.sup.+)=429 [M+H].sup.+; RT=3.54
min.
EXAMPLE 38
5-Chloro-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid
[2-phenyl-1-(S)-(tetrahydropyran-4-ylcarbamoyl)ethyl]amide
[0369] ##STR176##
[0370] The title compound was prepared according to EXAMPLE 35
except 4-aminotetrahydropyran was used in place of
3-(S)-hydroxypyrrolidine. The product was recrystallised from
methanol/dichloromethane (3:97) to give the title compound as a
white solid. m/z (ES.sup.+)=427 [M+H].sup.+; RT=3.23 min.
EXAMPLE 39
[(5-Chloro-1H-pyrrolo[2,3-c]pyridine-2-carbonyl aminolacetic acid
ethyl ester
[0371] ##STR177##
[0372] To a solution of
5-chloro-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid (Preparation
18, 800 mg, 4.1 mmol) in DMF (40 mL) was added glycine ethyl ester
hydrochloride (625 mg, 4.5 mmol), HOBt (0.55 g, 4.1 mmol) and DIPEA
(2.13 mL, 12.2 mmol). After 5 min, EDCI (1.01 g, 5.3 mmol) was
added and the reaction stirred at rt for 16 h. The solvent was
removed in vacuo and the solid partitioned between water (100 mL)
and ethyl acetate (3.times.80 mL). The combined organic fractions
were dried (MgSO.sub.4), concentrated in vacuo and purified by
chromatography on silica gel eluting with methanol/dichloromethane
(4:96) to give the title compound as a yellow solid. .delta..sub.H
(CD.sub.3OD): 1.28 (3H, t), 4.14 (2H, s), 4.23 (2H, q), 7.10 (1H,
s), 7.68 (1H, s), 8.59 (1H, s); m/z (ES.sup.+)=282 [M+H].sup.+.
EXAMPLE 40
[(5-Chloro-1H-pyrrolo[2,3-c]pyridine-2-carbonyl)amino]acetic
acid
[0373] ##STR178##
[0374] To a solution of
[(5-chloro-1H-pyrrolo[2,3-c]pyridine-2-carbonyl)amino] acetic acid
ethyl ester (EXAMPLE 39, 500 mg, 1.8 mmol) in THF (30 mL) was added
sodium hydroxide solution (1.8 mL, 2M, 3.6 mmol) and the reaction
stirred at rt for 4 h. The solvent was removed in vacuo and the
solid partitioned between hydrochloric acid (1M, 100 mL) and ethyl
acetate (2.times.100 mL). The aqueous layer was concentrated in
vacuo and the solid residue suspended in water (10 mL), filtered
and dried to give the title compound as an off-white solid.
.delta..sub.H (d.sub.6 DMSO): 3.97 (2H, d), 7.18 (1H, s), 7.76 (1H,
s), 8.57 (1H, s), 9.17 (1H, t), 12.32 (1H, s); m/z (ES.sup.+)=254
[M+H].sup.+.
EXAMPLE 41
2-(S)-[(5-Chloro-1H-pyrrolo[2,3-c]pyridine-2-carbonyl)amino]-3-phenylpropi-
onic acid ethyl ester
[0375] ##STR179##
[0376] To a solution of
5-chloro-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid (Preparation
18, 2.00 g, 10.2 mmol) in DMF (50 mL) was added L-phenylalanine
ethyl ester hydrochloride (2.45 g, 10.7 mmol), HOBt (1.37 g, 10.2
mmol) and DIPEA (5.3 mL, 30.5 mmol). After 5 min, EDCI (2.54 g,
13.2 mmol) was added and the reaction mixture stirred at rt for 16
h. The solvent was removed in vacuo and the solid dissolved in
ethyl acetate (150 mL) and washed with water (200 mL). The organic
phase was dried (MgSO.sub.4), concentrated in vacuo and purified by
chromatography on silica gel eluting with methanol/dichloromethane
(3:97) to give the title compound as a pale yellow solid.
.delta..sub.H (CD.sub.3OD): 1.21 (3H, t), 3.13 (1H, dd), 3.28 (1H,
dd), 4.17 (2H, q), 4.86 (1H, m), 7.09 (1H, s), 7.16-7.26 (5H, m),
7.65 (1H, s), 8.55 (1H, s); m/z (ES.sup.+)=372 [M+H].sup.+.
EXAMPLE 42
2-(S)-[(5-Chloro-1H-pyrrolo[2,3-c]pyridine-2-carbonyl)aminol-3-phenylpropi-
onic acid
[0377] ##STR180##
[0378] Sodium hydroxide solution (2.5 mL,2M, 5.1 mmol) was added to
a solution of
2-(S)-[(5-chloro-1H-pyrrolo[2,3-c]pyridine-2-carbonyl)amino]-3-phenylprop-
ionic acid ethyl ester (EXAMPLE 41, 940 mg, 2.5 mmol) in THF (30
mL) and the reaction mixture was stirred at rt for 16 h. The
solvent was removed in vacuo and the solid partitioned between
hydrochloric acid (2M, 40 mL) and ethyl acetate (3.times.40 mL).
The combined organic fractions were dried (MgSO.sub.4) and
concentrated in vacuo to give the title compound as a yellow solid.
m/z (ES.sup.+)=344 [M+H].sup.+; RT=3.29 min.
EXAMPLE 43
(S)-3-r(5-Chloro-1H-pyrrolo[2,3-c]pyridine-2-carbonyl)aminol-(R)-2-hydroxy-
-4-phenylbutyric acid methyl ester
[0379] ##STR181##
[0380] To a solution of
5-chloro-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid (Preparation
18, 165 mg, 0.84 mmol) and
(3S,2R)-3-amino-2-hydroxy-4-phenylbutyric acid methyl ester
(Preparation 21, 175 mg, 0.84 mmol) in DMF (10 mL)was added HOBt
(125 mg, 0.92 mmol), DIPEA (0.29 mL, 1.68 mmol) and EDCI (177 mg,
0.92 mmol) and the reaction stirred at rt for 72 h. The reaction
solvent was removed in vacuo, and the residue partitioned between
water (40 mL) and ethyl acetate (3.times.40 mL). The combined
organic fractions were dried (MgSO.sub.4), concentrated in vacuo
and the residue purified by chromatography on silica gel eluting
with methanol/dichloromethane (3:97) to give the title compound as
a yellow solid. .delta..sub.H (CD.sub.3OD): 2.97-3.12 (2H, m), 3.67
(1H, s), 4.25 (1H, d), 4.70-4.75 (1H, m), 7.08 (1H, s), 7.15-7.21
(1H, m), 7.25-7.34 (4H, m), 7.65 (1H, s), 8.55 (1H, s); m/z
(ES.sup.+)=388 [M+H].sup.+.
EXAMPLE 44
(S)-3-[(5-Chloro-1H-pyrrolo[2,3-c]pyridine-2-carbonyl)aminol-(R)-2-hydroxy-
-4-phenylbutyric acid
[0381] ##STR182##
[0382] Sodium hydroxide solution (0.24 mL, 2M, 0.48 mmol) was added
to a solution of
(S)-3-[(5-chloro-1H-pyrrolo[2,3-c]pyridine-2-carbonyl)amino]-(R)-2-hydrox-
y-4-phenylbutyric acid methyl ester (EXAMPLE 43, 170 mg, 0.44 mmol)
in methanol (5 mL) and the reaction stirred at rt for 24 h. The
solvent was removed in vacuo and the residue partitioned between
hydrochloric acid (1N, 30 mL) and ethyl acetate (3.times.3 mL). The
combined organic fractions were dried (MgSO.sub.4) and concentrated
in vacuo to give the title compound as a yellow solid.
.delta..sub.H (DMSO): 2.71 (1H, dd), 2.91 (1H, dd), 3.56 (1H, d),
4.38-4.46 (1H, m), 4.77 (1H, s), 6.76 (1H, s), 7.11-7.16 (1H, m),
7.19-7.27 (4H, m), 7.45 (1H, s), 8.44-8.52 (2H, m); m/z
(ES.sup.+)=374 [M+H].sup.+.
EXAMPLE 45
5-Chloro-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid
[2-(4-methoxyphenyl)-2-oxoethyl]amide
[0383] ##STR183##
[0384] Aqueous hydrochloric acid (2.1 mL, 2M) was added to a
solution of 5-chloro-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid
[2-(4-methoxyphenyl)[1,3]dioxolan-2-ylmethyl]amide (Preparation 49,
160 mg, 0.41 mmol) in acetone (20 mL). The mixture was heated under
reflux for 90 min then allowed to cool to rt. The suspension was
filtered then washed with acetone and air dried, to give the title
compound as a pale yellow solid. .delta..sub.H (d.sub.6 DMSO): 3.86
(3H, s), 4.79 (2H, d), 7.08 (2H, d), 7.23 (1H, s), 7.77 (1H, s),
8.03 (2H, d), 8.58 (1H, s), 9.14 (1H, t), 12.31 (1H, br s). m/z
(ES.sup.+)=344 [M+H].sup.+; RT=3.34 min.
[0385] The following compounds were synthesised according to the
method of EXAMPLE 45 using the appropriate ketal and aqueous
hydrochloric acid. TABLE-US-00005 ##STR184## Ex- ample R m/z 46
##STR185## m/z (ES.sup.+) = 350 [M + H].sup.+; RT = 3.20 min 47
##STR186## m/z (ES.sup.+) = 348 [M + H].sup.+; RT = 3.32 min 48
##STR187## m/z (ES.sup.+) = 332 [M + H].sup.+; RT = 3.25 min
EXAMPLE 49
5-Chloro-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid
[2-(4-fluorophenyl)-2-hydroxyethyl]amide
[0386] ##STR188##
[0387] To a stirred suspension of
5-chloro-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid
[2-(4-fluorophenyl)-2-oxoethyl]amide EXAMPLE 48 (0.05 g, 151 mmol)
in ethanol (5 mL, absolute) was added polymer-supported borohydride
(2.5 mmol/g, 0.09 g, 226 mmol) and the mixture sonicated with
gentle warming until the ketone had dissolved. The reaction mixture
was stirred for 2 days at rt then filtered, washing with methanol.
The filtrate was evaporated to dryness in vacuo to give a
colourless oil. Purification via flash column chromatography
(SiO.sub.2, ethyl acetate:isohexane, 1:1, v/v) gave the title
compound as a white solid. m/z (ES.sup.+)=334 [M+H].sup.+; RT=2.93
min.
EXAMPLE 50
5-Chloro-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid
(1-dimethylcarbamoyl-2-(S)-pyridin-3-yl-ethyl)amide
[0388] ##STR189##
[0389] To a solution of
(S)-2-amino-N,N-dimethyl-3-pyridin-3-ylpropionamide hydrochloride
(Preparation 53, 170 mg, 0.74 mmol) in DMF (5 mL) was added DIPEA
(0.45 mL, 2.58 mmol),
5-chloro-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid (Preparation
18, 145 mg, 0.74 mmol) and TBTU (262 mg, 0.82 mmol). The reaction
mixture was stirred at rt for 16 h. The solvent was removed in
vacuo and the remainder was purified by preparative HPLC, to give
the title compound as an off-white solid. .delta..sub.H
(CD.sub.3OD): 2.95 (3H, s), 3.08 (3H, s), 3.11-3.18 (1H, m),
3.22-3.28 (1H, m), 5.31-5.37 (1H, m), 7.12 (1H, s), 7.34-7.38 (1H,
m), 7.65 (1H, s), 7.79-7.84 (1H, m), 8.37-8.41 (1H, m), 8.45-8.51
(1H, m), 8.54 (1H, s); m/z (ES.sup.+)=372 [M+H].sup.+.
EXAMPLE 51
5-Chloro-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid
(2-oxo-1-(S)-pyridin-3-ylmethyl-2-pyrrolidin-1-yl-ethylamide
[0390] ##STR190##
[0391] To a solution of
(S)-2-amino-3-pyridin-3-yl-1-pyrrolidin-1-ylpropan-1-one
hydrochloride (Preparation 54, 239 mg, 0.94 mmol) in DMF (5 mL) was
added DIPEA (0.60 mL, 3.28 mmol),
5-chloro-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid (Preparation
18, 184 mg, 0.94 mmol) and TBTU (330 mg, 1.03 mmol). The reaction
mixture was stirred at rt for 16 h. The solvent was removed in
vacuo and the residue partitioned between ethyl acetate (100 mL)
and sodium hydroxide solution (2.times.100 mL, 1N). The organic
phase was dried (MgSO.sub.4) and evaporated to dryness give the
title compound as a brown solid. .delta..sub.H (CD.sub.3OD):
1.74-1.94 (4H, m), 3.12-3.39 (4H, m), 3.41-3.48 (1H, m), 3.69-3.75
(1H, m), 5.07-5.12 (1H, m), 7.16 (1H, s), 7.34-7.39 (1H, m), 7.67
(1H, s), 7.79-7.83 (1H, m), 8.37-8.42 (1H, m), 8.45-8.51 (1H, m),
8.56 (1H, s); m/z (ES.sup.+)=398 [M+H].sup.+.
EXAMPLE 52
5-Chloro-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid
(1-dimethylcarbamoyl-2-(S)-pyridin-2-yl-ethyl)amide
[0392] ##STR191##
[0393] To a solution of
2-(S)-amino-N,N-dimethylamino-3-pyridin-2-yl-propionamide
hydrochloride (Preparation 53, 0.15 g, 0.66 mmol) in DMF (5 mL) was
added DIPEA (0.4 mL, 2.31 mmol), TBTU (0.212 g, 0.66 mmol) and
5-chloro-1H-indole-2-carboxylic acid (Preparation 18, 0.130 g, 0.66
mmol). The reaction mixture was stirred at rt for 16 h then
concentrated under reduced pressure. The residue was dissolved in
ethyl acetate (200 mL) and washed with sodium hydroxide solution
(100 mL, 1N). The organic extract was dried and concentrated in
vacuo. Purification by preparative hplc gave the title compound as
a white solid. m/z (ES.sup.+)=372 [M+H].sup.+; RT=2.47 min.
EXAMPLE 53
5-Chloro-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid
[1-(S)-(4-fluorobenzal)-2-(3-(S)-hydroxypyrrolidin-1-yl)-2-oxoethyl]amide
[0394] ##STR192##
[0395] To a solution of carboxylic acid (Preparation 18, 2.66 g,
13.6 mmol) in DMF (anhydrous, 120 mL) was added amine.HCl
(Preparation 103, 4.30 g, 14.9 mmol), DIPEA (7.79 mL, 44.7 mmol)
and HOBt.H.sub.2O (2.280 g, 14.9 mmol). The resulting solution was
stirred at rt for 10 min prior to the addition of EDCI (3.12 g,
16.3 mmol) and the reaction mixture stirred for 17 h at rt. The
volatiles were removed in vacuo then the residue was partitioned
between ethyl acetate (200 mL) and water (200 mL). The aqueous
phase was extracted with ethyl acetate (3.times.50 mL) then the
combined organics washed with sodium hydroxide solution (2M,
3.times.50 mL), hydrochloric acid (2M, 2.times.50 mL), brine (100
mL), dried (MgSO.sub.4), filtered and concentrated in vacuo. The
isolated solid was dissolved in methanol/dichloromethane (15:185,
v/v) then purified via flash chromatography (SiO.sub.2, dissolved
in methanol/dichloromethane, 15:185, v/v) to give the title
compound as a pale yellow powder. .delta..sub.H (CD.sub.3OD):
1.72-2.02 (2H, m), 3.01-3.13 (1H, m), 3.13-3.26 (2H, m), 3.35-3.52
(1.5H, m), 3.55-3.65 (0.5H, m), 3.71-3.81 (0.5H, m), 3.84 (0.5H,
dd), 4.23-4.33 (0.5H, m), 4.37-4.45 (0.5H, m), 4.99 (0.5H, t), 5.07
(0.5H, t), 6.90-7.07 (2H, m), 7.13 (1H, d), 7.31 (2H, dd), 7.66
(1H, s), 8.54 (1H, d); m/z (ES.sup.+)=431 [M+H].sup.+; RT=3.17
min.
EXAMPLE 54
5-Chloro-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid
[2-(S)-(4-fluorophenyl)-1-isopropylcarbamoylethyl]amide
[0396] ##STR193##
[0397] To a solution of
2-(S)-[(5-chloro-1H-pyrrolo[2,3-c]pyridine-2-carbonyl)-amino]-3-(4-fluoro-
phenyl)propionic acid (30 mg, 0.08 mmol) in DMF (3 mL) was added
DIPEA (17.3 .mu.L, 0.10 mmol) and HATU (37.8 mg, 0.10 mmol). After
15 min, isopropylamine (7.1 .mu.L, 0.08 mmol) was added. The
reaction mixture was stirred at rt for 24 h then concentrated under
reduced pressure (genevac). Purification by mass directed
purification gave the title compound as a yellow solid. m/z
(ES.sup.+)=403 [M+H].sup.+; RT=3.39 min.
EXAMPLES 55-98
[0398] ##STR194##
[0399] The following compounds were prepared according to the
method of EXAMPLE 54 from
2-(S)-[(5-chloro-1H-pyrrolo[2,3-c]pyridine-2-carbonyl)amino]-3-(4-fluorop-
henyl)propionic acid and the appropriate amine. TABLE-US-00006
Example NR.sup.1R.sup.2 m/z RT (min) 55 ##STR195## 375 3.11 56
##STR196## 389 3.24 57 ##STR197## 415 3.36 58 ##STR198## 429 3.51
59 ##STR199## 443/445 3.11 60 ##STR200## 457/459 3.22 61 ##STR201##
471/473 3.29 62 ##STR202## 445 3.20 63 ##STR203## 441 3.44 64
##STR204## 401 3.19 65 ##STR205## 415 3.31 66 ##STR206## 429 3.51
67 ##STR207## 445 3.24 68 ##STR208## 445 3.14 69 ##STR209## 459
3.39 70 ##STR210## 431 3.07 71 ##STR211## 472 3.04 72 ##STR212##
431 3.17 73 ##STR213## 444 2.69 74 ##STR214## 405 3.06 75
##STR215## 419 3.19 76 ##STR216## 435 3.36 77 ##STR217## 432 2.77
78 ##STR218## 449 2.99 79 ##STR219## 389 3.24 80 ##STR220## 417
3.37 81 ##STR221## 474 2.67 82 ##STR222## 444 3.04 83 ##STR223##
452 2.65 84 ##STR224## 437 357 85 ##STR225## 443 3.52 86 ##STR226##
477 3.31 87 ##STR227## 475 3.11 88 ##STR228## 447 2.99 89
##STR229## 443 3.51 90 ##STR230## 433 3.32 91 ##STR231## 445 3.19
92 ##STR232## 447 3.37 93 ##STR233## 446 2.64 94 ##STR234## 419
3.04 95 ##STR235## 474 2.64 96 ##STR236## 498 2.70 97 ##STR237##
445 3.14 98 ##STR238## 443 3.20
EXAMPLE 99
5-Chloro-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid
[1-cyclopropylcarbamoyl-2-(S)-(4-fluorophenyl)ethyl]amide
[0400] ##STR239##
[0401] To a solution of
2-(S)-[(5-chloro-1H-pyrrolo[2,3-c]pyridine-2-carbonyl)-amino]-3-(4-fluoro-
phenyl)propionic acid (100 mg, 0.28 mmol) in DMF (5 ml) was added
cyclopropylamine (19.2 .mu.l, 0.28 mmol), HOBt (37 mg, 0.28 mmol)
and DIPEA (96 .mu.l, 0.55 mmol). After 5 min, EDCI (69 mg, 0.36
mmol) was added and the reaction mixture stirred at rt for 16 h.
The solvent was removed in vacuo and the residue triturated with
water and chromatographed on silica gel eluting with
methanol:dichloromethane (1:24) to give the title compound as an
off-white solid. m/z (ES.sup.+)=401 [M+H].sup.+; RT=3.22 min.
EXAMPLES 100-106
[0402] ##STR240##
[0403] The following compounds were prepared according to the
method of EXAMPLE 99 from 2-(S)-[(5-chloro-1H-pyrrolo
[2,3-c]pyridine-2-carbonyl)amino]3-(4-fluorophenyl)propionic acid
and the appropriate amine. All compounds were purified by
chromatography on silica gel eluting with the described solvent
system. TABLE-US-00007 RT Example NR.sup.1R.sup.2 Eluent m/z (min)
100 ##STR241## MeOH:DCM 1:19 433 3.06 101 ##STR242## MeOH:DCM 3:97
433 3.20 102 ##STR243## MeOH:DCM 6:94 435 2.95 103 ##STR244##
MeOH:DCM 3:97 486 3.15 104 ##STR245## NH.sub.4OH:MeOH:DCM 1:9:90
500 2.82 105 ##STR246## MeOH:DCM 1:19 550 3.24 106 ##STR247##
MeOH:DCM 1:19 520 3.36
EXAMPLE 107
5-Chloro-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid
[1-(S)-(4-fluorobenzyl)-2-(3-hydroxyazetidin-1-yl)-2-oxoethyl]amide
[0404] ##STR248##
[0405]
2-(S)-[(5-Chloro-1H-pyrrolo[2,3-c]pyridine-2-carbonyl)amino]-3-(4--
fluorophenyl)propionic acid (100 mg, 0.28 mmol), 3-hydroxyazetidine
hydrochloride (Heterocycles, 2002, 56(1-2), 433-442; 30 mg, 0.28
mmol) and HOBt (37 mg, 0.28 mmol) were dissolved in DMF (5 ml) and
DIPEA (0.14 ml, 0.83 mmol). After 5 min, EDCI (69 mg, 0.36 mmol)
was added and the reaction mixture stirred at rt for 16 h. The
solvent was removed in vacuo and the residue triturated with water.
Purification by chromatography on silica gel eluting with
methanol:dichloromethane (1:49 to 3:97) gave the title compound as
a yellow solid. .delta..sub.H (CD.sub.3OD): 3.08-3.21 (2H, m),
3.58-3.63 (0.5H, m), 3.84-3.91 (0.5H, m), 4.03-4.09 (0.5H, m),
4.25-4.32 (0.5H, m), 4.38-4.94 (4H, m), 7.03-7.12 (2H, m),
7.15-7.19 (1H, m), 7.30-7.38 (2H, m), 7.68 (1H, s), 8.59 (1H, s);
RT=3.32 min.
EXAMPLE 108
5-Chloro-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid
[1-(S)-benzyl-2-(3-hydroxazetidin-1-yl)-2-oxoethyl]amide
[0406] ##STR249##
[0407]
2-(S)-[(5-Chloro-1H-pyrrolo[2,3-c]pyridine-2-carbonyl)amino]-3-phe-
nylpropionic acid (100 mg, 0.29 mmol), 3-hydroxyazetidine
hydrochloride (32 mg, 0.29 mmol) and HOBt (39 mg, 0.29 mmol) were
dissolved in DMF (5 ml) and DIPEA (0.15 ml, 0.87 mmol). After 5
min, EDCI (72 mg, 0.38 mmol) was added and the reaction mixture
stirred at rt for 16 h. The solvent was removed in vacuo and the
residue triturated with water. Purification by chromatography on
silica gel eluting with methanol:dichloromethane (1:49 to 3:97)
gave the title compound as an off-white solid. .delta..sub.H
(CD.sub.3OD): 3.12-3.20 (2H, m), 3.45-3.51 (0.5H, m), 3.83-3.90
(0.5H, m), 4.00-4.13 (1H, m), 4.35-4.52 (2H, m), 4.57-4.94 (2H, m),
7.18-7.22 (1H, m), 7.27-7.40 (5H, m), 7.68 (1H, s), 8.59 (1H, s);
RT=3.27 min.
EXAMPLE 109
5-Chloro-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid
[2-(3-hydroxyazetidin-1-yl)-2-oxoethyl]amide
[0408] ##STR250##
[0409] [(5-Chloro-1H-pyrrolo[2,3-c]pyridine-2-carbonyl)amino]acetic
acid (30 mg, 0.12 mmol), 3-hydroxyazetidine hydrochloride (13 mg,
0.12 mmol) and HOBt (16 mg, 0.12 mmol) were dissolved in DMF (3 ml)
and DIPEA (43 .mu.l, 0.25 mmol). After 5 min, EDCI (30 mg, 0.15
mmol) was added and the reaction mixture stirred at rt for 16 h.
The solvent was removed in vacuo and the residue partitioned
between water (20 ml) and DCM (3.times.20 ml). The combined
organics were dried (MgSO.sub.4), concentrated in vacuo and the
residue purified by chromatography on silica gel eluting with
methanol:dichloromethane (1:24) to give the title compound as a
white solid. .delta..sub.H (CD.sub.3OD): 4.06-4.15 (3H, m),
4.40-4.46 (1H, m), 4.55-4.63 (1H, m), 4.77-4.94 (2H, m), 7.14 (1H,
s), 7.71 (1H, s), 8.62 (1H, s); RT=2.82 min.
EXAMPLES 110-111
[0410] ##STR251##
[0411] The following compounds were prepared according to the
method of EXAMPLE 109 from
[(5-chloro-1H-pyrrolo[2,3-c]pyridine-2-carbonyl)amino]acetic acid
and the appropriate amine. All compounds were purified by
chromatography on silica gel eluting with the described solvent
system. TABLE-US-00008 RT Example NR.sup.1R.sup.2 Eluent m/z (min)
110 ##STR252## MeOH:DCM 6:94 to 8:92 337 2.61 111 ##STR253##
MeOH:DCM 1:24 323 2.65
EXAMPLE 112
2-[(5-Chloro-1H-pyrrolo[2,3-c]pyridine-2-carbonyl)amino]-3-oxo-3-phenylpro-
pionic acid ethyl ester
[0412] ##STR254##
[0413] 5-Chloro-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid (100
mg, 0.51 mmol) and
4-(4,6-dimethoxy[1.3.5]triazin-2-yl)-4-methylmorpholinium chloride
(DMTMM) (183 mg, 0.66 mmol) were dissolved in THF (20 ml). After 5
min, 2-amino-3-oxo-3-phenylpropionic acid ethyl ester hydrochloride
(Tetrahedron Lett., 1993, 34(2), 211-214; 124 mg, 0.51 mmol) and
4-methylmorpholine (56 .mu.l, 0.51 mmol) were added and the
reaction mixture stirred at rt for 72 h. The solvent was removed in
vacuo and the residue partitioned between water (40 ml) and EtOAc
(3.times.30 ml). The combined organics were dried (MgSO.sub.4),
concentrated in vacuo and purified by chromatography on silica gel
eluting with methanol:dichloromethane (1:19). This material was
further triturated with methanol:diethyl ether (1:19) to give the
title compound as a pale yellow solid. m/z (ES.sup.+)=386
[M+H].sup.+; RT=3.56 min.
EXAMPLE 113
5-Chloro-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid
[2-(S)-(4-fluorophenyl)-1-(methoxymethylcarbomoyl)ethyl]amide
[0414] ##STR255##
[0415]
2-(S)-[(5-Chloro-1H-pyrrolo[2,3-c]pyridine-2-carbonyl)amino]-3-(4--
fluorophenyl)propionic acid (80 mg, 0.22 mmol) and
N,O-dimethylhydroxylamine hydrochloride (24 mg, 0.24 mmol) were
dissolved in ethanol (10 ml) and 4-methylmorpholine (27 .mu.l, 0.24
mmol). To this was added DMTMM (67 mg, 0.24 mmol) and the reaction
mixture was stirred at rt for 16 h. Further
N,O-dimethylhydroxylamine hydrochloride (12 mg, 0.12 mmol),
4-methylmorpholine (14 .mu.l, 0.12 mmol) and DMTMM (34 mg, 0.12
mmol) were added and the reaction mixture was stirred at rt for 96
h. The solvent was removed in vacuo and the residue partitioned
between water (40 ml) and EtOAc (2.times.40 ml). The combined
organics were dried (MgSO.sub.4), concentrated in vacuo and
purified by chromatography on silica gel eluting with
methanol:dichloromethane (1:19) to give the title compound as a
white solid. m/z (ES.sup.+)=405 [M+H].sup.+; RT=3.36 min.
EXAMPLE 114
5-Chloro-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid
[1-(S)-(4-fluorobenzyl)-2-(4-hydroxypiperidin-1-yl)-2-oxoethyl]amide
[0416] ##STR256##
[0417] 5-Chloro-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid
(Preparation 57, 50 mg, 0.25 mmol),
2-(S)-amino-3-(4-fluorophenyl)-1-(4-hydroxypiperidin-1-yl)propan-1-one
hydrochloride (85 mg, 0.25 mmol) and DMTMM (85 mg, 0.31 mmol) were
dissolved in ethanol (5 ml) and 4-methylmorpholine (31 .mu.l, 0.28
mmol). The reaction mixture was stirred at rt for 16 h. The solvent
was removed in vacuo and the residue partitioned between water (30
ml) and EtOAc (3.times.25 ml). The combined organics were dried
(MgSO.sub.4), concentrated in vacuo and purified by chromatography
on silica gel eluting with methanol:dichloromethane (1:19) to give
the title compound as a beige solid. m/z (ES.sup.+)=445
[M+H].sup.+; RT=3.31 min.
EXAMPLE 115
5-Chloro-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid
(1-dimethylcarbamoyl-2-(S)-phenylethyl)amide
[0418] ##STR257##
[0419] 5-Chloro-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid
(Preparation 57, 55 mg, 0.28 mmol),
2-(S)-amino-N,N-dimethyl-3-phenylpropionamide hydrochloride (70 mg,
0.31 mmol) and DMTMM (93 mg, 0.34 mmol) were dissolved in ethanol
(5 ml) and 4-methylmorpholine (34 .mu.l, 0.31 mmol). The reaction
mixture was stirred at rt for 24 h. The solvent was removed in
vacuo and the residue partitioned between water (40 ml) and EtOAc
(2.times.40 ml). The combined organics were washed with 2N NaOH
solution (40 ml), brine (40 ml), dried (MgSO.sub.4), concentrated
in vacuo and purified by chromatography on silica gel eluting with
methanol:dichloromethane (3:97) to give the title compound as a
yellow solid. m/z (ES.sup.+)=371 [M+H].sup.+; RT=3.49 min.
EXAMPLE 116
5-Ethynyl-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid
(1-(S)-dimethylcarbamoyl-2-phenylethyl)amide
[0420] ##STR258##
[0421] To a solution of
2-(S)-amino-N,N-dimethyl-3-phenylpropionamide hydrochloride
(Preparation 8, 0.0135 g, 0.059 mmol) in DMF (anhydrous, 3 mL) was
added DIPEA (0.031 mL, 0.177 mmol) then carboxylic acid
(Preparation 60, 0.010 g, 0.054 mmol). To the stirred solution was
added HOBt.H.sub.2O (0.008 g, 0.059 mmol) then, after 10 min, EDCI
(0.012 g, 0.065 mmol). The reaction mixture was stirred for 18 h
then all volatiles were removed in vacuo. The residue was
partitioned between ethyl acetate (30 mL) and water (20 mL). The
layers were separated and the aqueous layer extracted with ethyl
acetate (3.times.20 mL). The combined organics were washed with
brine (30 mL), dried (MgSO.sub.4), filtered and concentrated in
vacuo. The residue was dissolved in methanol then adsorbed onto
silica gel. Purification via flash column chromatography
(SiO.sub.2, CH.sub.2Cl.sub.2:MeOH, 19:1, v/v) gave the title
compound as an off-white solid. .delta..sub.H (CD.sub.3OD): 2.88
(3H, s), 2.89 (3H, s), 3.00-3.23 (2H, m), 3.50 (1H, s), 5.27 (1H,
t), 7.10-7.37 (6H, m), 7.86 (1H, s), 8.70 (1H, s). m/z
(ES.sup.+)=361 [M+H].sup.+; RT=2.65 min.
EXAMPLE 117
5-Cyano-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid
(1-(S)-dimethylcarbamoyl-2-phenylethyl)amide
[0422] ##STR259##
[0423] To a solution of
2-(S)-amino-N,N-dimethyl-3-phenylpropionamide hydrochloride
(Preparation 8, 0.023 g, 0.100 mmol) in DMF (anhydrous, 4 mL) was
added DIPEA (0.052 mL, 0.300 mmol) then carboxylic acid
(Preparation 62, 0.017 g, 0.091 mmol). To the stirred solution was
added HOBt.H.sub.2O (0.0135 g, 0.100 mmol) then, after 10 min, EDCI
(0.021 g, 0.109 mmol). The reaction mixture was stirred for 18 h
then all volatiles were removed in vacuo. The residue was
partitioned between ethyl acetate (30 mL) and water (20 mL). The
layers were separated and the aqueous layer extracted with ethyl
acetate (3.times.20 mL). The combined organics were washed with
brine (30 mL), dried (MgSO.sub.4), filtered and concentrated in
vacuo. The residue was dissolved in ethyl acetate then adsorbed
onto silica gel. Purification via flash column chromatography
(SiO.sub.2, ethyl acetate:isohexane, 1:1, v/v) gave the title
compound as a pale brown solid. .delta..sub.H (CDCl.sub.3): 2.77
(3H, s), 2.96 (3H, s), 3.08-8.20 (2H, m), 5.23-5.41 (1H, m), 6.99
(1H, s), 7.14-7.36 (5H, m), 7.65 (1H, d), 8.01 (1H, s), 8.87 (1H,
s), 10.01 (1H, s); m/z (ES.sup.+)=362 [M+H].sup.+; RT=3.11 min.
EXAMPLE 118
5-Cyano-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid
[1-(S)-(4-fluorobenzyl)-2-(4-hydroxypiperidin-1-yl)-2-oxoethyl]amide
[0424] ##STR260##
[0425] To a solution of
2-(S)-amino-3-(4-fluorophenyl)-1-(4-hydroxypiperidin-1-yl)propan-1-one
hydrochloride (Preparation 20, 0.036 g, 0.118 mmol) in DMF
(anhydrous, 5 mL) was added DIPEA (0.061 mL, 0.353 mmol) then
carboxylic acid (Preparation 62, 0.020 g, 0.107 mmol). To the
stirred solution was added HOBt.H.sub.2O (0.016 g, 0.107 mmol)
then, after 10 min, EDCI (0.025 g, 0.128 mmol). The reaction
mixture was stirred for 18 h then all volatiles were removed in
vacuo. The residue was partitioned between CH.sub.2Cl.sub.2 (30 mL)
and water (20 mL). The layers were separated then the aqueous was
extracted with CH.sub.2Cl.sub.2 (2.times.30 mL). The combined
organics were washed with brine (50 mL), dried (MgSO.sub.4),
filtered and concentrated in vacuo. The residue was dissolved in
methanol then adsorbed onto silica gel. Purification via flash
column chromatography (SiO.sub.2, methanol:dichloromethane, 7:93,
v/v) gave the title compound as a white solid. .delta..sub.H
(d.sub.6 DMSO): 1.05-1.32 (2H, m), 1.49-1.72 (2H, m), 2.86-3.42
(4H, m), 3.53-3.87 (2.5H, m), 3.93-4.05 (0.5H, m), 4.69 (1H, d),
5.07-5.21 (1H, m), 6.97-7.12 (2H, m), 7.26-7.39 (2H, m), 7.47 (1H,
s), 8.41 (1H, s), 8.81 (1H, s), 9.01-9.41 (1H, m), 12.64 (1H, s);
m/z (ES.sup.+)=436 [M+H].sup.+; RT=1.51 min.
EXAMPLE 119
5-Methyl-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid
(1-dimethylcarbamoyl-2-(S)-phenylethyl)amide
[0426] ##STR261##
[0427] To a solution of
2-(S)-amino-N,N-dimethyl-3-phenylpropionamide hydrochloride
(Preparation 8, 0.0286 g, 0.125 mmol) in DMF (anhydrous, 5 mL) was
added DIPEA (0.071 mL, 0.409 mmol) then carboxylic acid
(Preparation 66, 0.020 g, 0.114 mmol). To the stirred solution was
added HOBt.H.sub.2O (0.017 g, 0.125 mmol) then, after 10 min, EDCI
(0.026 g, 0.136 mmol). The reaction mixture was stirred for 16 h at
room temperature then all volatiles were removed in vacuo. The
residue was partitioned between CH.sub.2Cl.sub.2 (50 mL) and water
(50 mL). The layers were separated then the aqueous layer extracted
with CH.sub.2Cl.sub.2 (3.times.20 mL). The combined organics were
washed with brine (30 mL), dried (MgSO.sub.4), filtered and
concentrated in vacuo. The residue was dissolved in
CH.sub.2Cl.sub.2 then purified via flash column chromatography
(SiO.sub.2, CH.sub.2Cl.sub.2 then methanol:CH.sub.2Cl.sub.2, 1:19,
v/v) to give the title compound as a pale yellow solid.
.delta..sub.H (CDCl.sub.3): 2.63 (3H, s), 2.77 (3H, s), 2.97 (3H,
s), 3.11-3.25 (2H, m), 5.34-5.44 (1H, m), 6.85 (1H, s), 7.20-7.33
(6H, m), 7.34 (1H, s), 7.83 (1H, d), 8.78 (1H, s); m/z
(ES.sup.+)=351 [M+H].sup.+; RT=2.36 min.
EXAMPLE 120
5-Chloro-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid
[1-(S)-(4-fluorobenzyl)-2-(4-methoxypiperidin-1-yl)-2-oxoethyl]amide
[0428] ##STR262##
[0429] To a solution of
2-(S)-[(5-chloro-1H-pyrrolo[2,3-c]pyridine-2-carbonyl)amino]-3-phenylprop-
ionic acid (EXAMPLE 42, 150 mg, 0.42 mmol) and 4-methoxypiperidine
hydrochloride (Preparation 68, 86 mg, 0.57 mmol) in DMF (5 mL) was
added HOBt (66 mg, 0.43 mmol), DIPEA (0.23 mL, 1.34 mmol) and EDCI
(102 mg, 0.53 mmol). After stirring at rt for 12 h the mixture was
added to diluted brine (100 mL, water/brine: 1/1). Extraction with
ethyl acetate (4.times.25 mL), washing of the combined extracts
with brine (50 mL) and drying (MgSO.sub.4) gave, after
concentration, a residue which was purified by recrystallisation
from methanol to give the title compound as a colourless solid. m/z
(ES.sup.+)=459.38 [M+H].sup.+; RT=3.40 min.
EXAMPLE 121
5-Chloro-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid
[1-(S)-(4-fluorobenzyl)-2-(3-(R)-methoxypyrrolidin-1-yl)-2-oxoethyl]amide
[0430] ##STR263##
[0431] To a solution of
2-(S)-[(5-chloro-1H-pyrrolo[2,3-c]pyridine-2-carbonyl)amino]-3-phenylprop-
ionic acid (EXAMPLE 42, 104 mg, 0.29 mmol) and
(R)-3-methoxypyrrolidine hydrochloride (Preparation 70, 40 mg, 0.29
mmol) in DMF (5 mL) was added HOBt (44 mg, 0.29 mmol), DIPEA (0.15
mL, 0.88 mmol) and EDCI (66 mg, 0.344 mmol). After stirring at rt
for 12 h the mixture was added to diluted brine (100 mL,
water/brine: 1/1). Extraction with ethyl acetate (4.times.25 mL),
washing of the combined extracts with brine (50 mL) and drying
(MgSO.sub.4) gave, after concentration, a residue which was
recrystallised from acetonitrile to give the title compound as a
colourless solid. m/z (ES.sup.+)=445.31 [M+H].sup.+; RT=3.36
min.
EXAMPLE 122
5-Chloro-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid
[(1-(S)-(4-fluorobenzyl)-2-(3-(S)-methoxypyrrolidin-1-yl)-2-oxoethyl]amid-
e
[0432] ##STR264##
[0433] To a solution of
2-(S)-[(5-chloro-1H-pyrrolo[2,3-c]pyridine-2-carbonyl)amino]-3-phenylprop-
ionic acid (EXAMPLE 42, 53 mg, 0.15 mmol) and
(S)-3-methoxypyrrolidine hydrochloride (Preparation 72, 20 mg, 0.15
mmol) in DMF (5 mL) was added HOBt (25 mg, 0.16 mmol), DIPEA (76
.mu.L, 0.44 mmol) and EDCI (34 mg, 0.18 mmol). After stirring at rt
for 12 h the mixture was added to diluted brine (100 mL,
water/brine: 1/1). Extraction with ethyl acetate (4.times.25 mL),
washing of the combined extracts with brine (50 mL) and drying
(MgSO.sub.4) gave, after concentration, a residue which was
purified via flash chromatography (silica gel,
dichloromethane/methanol, 95:5) to give the title compound as a
colourless solid. m/z (ES.sup.+)=445.34 [M+H].sup.+; RT=3.34
min.
EXAMPLE 123
3-(S)-[(5-Chloro-1H-pyrrolo[2,3-c]pyridine-2-carbonyl)amino]-2-(S)-hydroxy-
-4-phenylbutyric acid methyl ester
[0434] ##STR265##
[0435] 5-Chloro-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid
(Preparation 18, 170 mg, 0.86 mmol) and
(3S,2S)-3-amino-2-hydroxy-4-phenylbutyric acid methyl ester
(Preparation 21A, 174 mg, 0.83 mmol) were coupled under similar
conditions to EXAMPLE 43 using HOBt (142 mg, 0.93 mmol), EDCI (200
mg, 1.04 mmol), DIPEA (0.32 ml, 1.87 mmol) in DMF (10 ml). The
crude product was purified by chromatography on silica gel eluting
with hexane/ethyl acetate (25:75) to give the title compound as a
colourless oil. .delta..sub.H (CDCl.sub.3): 3.04 (4H, 2dd), 3.74
(3H, s), 4.36 (1H, br s), 4.63 (1H, m), 4.98 (1H, ddd), 6.66 (1H,
s), 6.96 (1H, d), 7.18-7.35 (5H, m), 7.48 (1H, s), 8.63 (1H,
s).
EXAMPLE 124
3-(S)-[(5-Chloro-1H-pyrrolo[2,3-c]pyridine-2-carbonyl)amino]-2-(S)-hydroxy-
-4-phenylbutyric acid
[0436] ##STR266##
[0437]
3-(S)-[(5-Chloro-1H-pyrrolo[2,3-c]pyridine-2-carbonyl)amino]-2-(S)-
-hydroxy-4-phenylbutyric acid methyl ester (152 mg, 0.39 mmol) was
hydrolysed in a similar way to EXAMPLE 44 using sodium hydroxide
solution (0.44 ml, 1N, 0.44 mmol) in methanol (10 mL).
.delta..sub.H (d.sub.6 DMSO): 2.83, 2.95 (2H, 2dd), 4.19 (1H, d),
4.52 (1H, m), 5.75 (1H, br s), 7.10-7.33 (6H, 2m), 7.68 (1H, s),
8.54 (1H, s), 8.72 (1H, d).
EXAMPLE 125
5-Chloro-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid
(1-(S)-benzyl-2-dimethylcarbamoyl-2-(S)-hydroxyethyl)amide
[0438] ##STR267##
[0439] Dimethylamine hydrochloride (7 mg, 0.085 mmol) was added to
a solution of
3-(S)-[(5-chloro-1H-pyrrolo[2,3-c]pyridine-2-carbonyl)amino]-2-(S)-hydrox-
y-4-phenylbutyric acid (EXAMPLE 124, 30 mg, 0.080 mmol), HOBt (14
mg, 0.091 mmol), DIPEA (31 .mu.L, 0.18 mmol) and EDCI (18 mg, 0.094
mmol) in DMF (3 mL). After the addition of DIPEA (14 ml, 0.080
mmol) the mixture was stirred for 12 h before adding to diluted
brine (100 mL, water/brine: 1/1). Extraction with ethyl acetate
(4.times.25 mL), washing of the combined extracts with brine (50
mL) and drying (MgSO.sub.4) gave, after concentration, a residue
which was purified by preparative LCMS to give the title compound
as a colourless solid. m/z (ES.sup.+)=401.28 [M+H].sup.+; RT=3.06
min.
EXAMPLE 126
5-Chloro-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid
(1-(S)-benzyl-2-(S)-hydroxy-3-oxo-3-pyrrolidin-1-ylpropyl)amide
[0440] ##STR268##
[0441] Pyrrolidine (7 .mu.g, 0.084 mmol) was added to a solution of
3-(S)-[(5-chloro-1H-pyrrolo[2,3-c]pyridine-2-carbonyl)amino]-2-(S)-hydrox-
y-4-phenylbutyric acid (EXAMPLE 124, 30 mg, 0.080 mmol), HOBt (14
mg, 0.091 mmol), DIPEA (31 .mu.L, 0.18 mmol) and EDCI (18 mg, 0.094
mmol) in DMF (3 mL). After stirring for 12 h the mixture was added
to diluted brine (100 mL, water/brine: 1/1). Extraction with ethyl
acetate (4.times.25 mL), washing of the combined extracts with
brine (50 mL) and drying (MgSO.sub.4), gave, after concentration, a
residue which was purified by preparative LCMS to give the title
compound as a colourless solid. m/z (ES.sup.+)=427.31 [M+H].sup.+;
RT=3.27 min.
EXAMPLE 127
5-Chloro-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid
[1-(S)-benzyl-3-(3,4-dihydroxypyrrolidin-1-yl)-2-(S)-hydroxy-3-oxopropyl]-
amide
[0442] ##STR269##
[0443] cis-3,4-Dihydroxypyrrolidine (Preparation 23, 9 mg, 0.087
mmol) was added to a solution of
3-(S)-[(5-chloro-1H-pyrrolo[2,3-c]pyridine-2-carbonyl)amino]-2-(S)-hydrox-
y-4-phenylbutyric acid (EXAMPLE 124, 30 mg, 0.080 mmol), HOBt (14
mg, 0.091 mmol), DIPEA (31 .mu.L, 0.18 mmol) and EDCI (18 mg, 0.094
mmol) in DMF (3 mL). After stirring for 12 h the mixture was added
to diluted brine (100 mL, water/brine: 1/1). Extraction with ethyl
acetate (4.times.25 mL), washing of the combined extracts with
brine (50 mL) and drying (MgSO.sub.4) gave, after concentration, a
residue which was purified by preparative LCMS to give the title
compound as a colourless solid. m/z (ES.sup.+)=459.29 [M+H].sup.+;
RT=2.87 min.
EXAMPLE 128
5-Chloro-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid
(1-(S)-benzyl-2-(R)-hydroxy-2-propylcarbamoylethyl)amide
[0444] ##STR270##
[0445] n-Propylamine (16 .mu.L, 0.19 mmol) was added to a solution
of
3-(S)-[(5-chloro-1H-pyrrolo[2,3-c]pyridine-2-carbonyl)amino]-2-(R)-hydrox-
y-4-phenylbutyric acid (EXAMPLE 44, 40 mg, 0.11 mmol), HOBt (16.4
mg, 0.11 mmol), DIPEA (41 .mu.L, 0.24 mmol) and EDCI (25 mg, 0.13
mmol) in DMF (3 mL). After stirring for 72 h at room temperature
the solvent was removed in vacuo and the remaining residue was
purified by preparative LCMS to give the title compound as
colourless solid. m/z (ES.sup.+)=415.34 [M+H].sup.+; RT=3.10
min.
EXAMPLES 129-147
[0446] The following compounds were prepared according to the
method of EXAMPLE 128 from
3-(S)-[(5-chloro-1H-pyrrolo[2,3-c]pyridine-2-carbonyl)-amino]-2-(R)-hydro-
xy-4-phenylbutyric acid and the appropriate amine. TABLE-US-00009
Example Structure RT (min) m/z 129 ##STR271## 2.87 373.26 130
##STR272## 2.89 417.31 131 ##STR273## 3.09 417.32 132 ##STR274##
3.23 401.29 133 ##STR275## 3.03 413.33 134 ##STR276## 3.20 427.34
135 ##STR277## 3.22 441.37 136 ##STR278## 3.19 413.32 137
##STR279## 3.65 449.34 138 ##STR280## 3.09 427.30 139 ##STR281##
3.12 443.33 140 ##STR282## 2.87 443.33 141 ##STR283## 3.41 441.32
142 ##STR284## 2.91 457.30 143 ##STR285## 3.21 471.40 144
##STR286## 2.63 456.39 145 ##STR287## 2.57 442.37 146 ##STR288##
3.06 443.35 147 ##STR289## 3.16 484.37
EXAMPLES 148-174
[0447] The following compounds were prepared according to the
procedure outlined below from
5-chloro-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid (Preparation
18) and the appropriate amine.
[0448] To a solution of
5-chloro-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid (0.12 mmol,
1.5 eq) in 1:1.2 DMF/DCM (2 ml), HOBT (0.16 mmol, 2 eq) was added,
followed by PS-carbodiimide (0.16 mmol, 2 eq). The reaction mixture
was shaken for 15 min and a solution of amine (0.08 mmol, 1 eq) in
DCM (0.5 ml) was added. The reaction mixture was shaken overnight.
HOBT and unreacted starting material acid were scavenged with
MP-Trisamine (0.36 mmol, 4.5 eq). MP-Trisamine was added to the
reaction mixture and the mixture shaken for 5 h. The resin was
filtered and washed with a solution of 1:1 DMF/DCM (2.times.4 ml).
The filtrate was concentrated to give the product amide.
TABLE-US-00010 Example Structure RT (min) m/z (ES.sup.+) 148
##STR290## 2.47 456.2 [M + H].sup.+ 149 ##STR291## 3.51 411.3 [M +
H].sup.+ 150 ##STR292## 2.57 426.3 [M + H].sup.+ 151 ##STR293##
2.53 456.3 [M + H].sup.+ 152 ##STR294## 3.26 454.4 [M + H].sup.+
153 ##STR295## 2.94 401.3 [M + H].sup.+ 154 ##STR296## 3.11 441.2
[M + H].sup.+ 155 ##STR297## 2.97 454.4 [M + H].sup.+ 156
##STR298## 2.9 454.4 [M + H].sup.+ 157 ##STR299## 3.04 441.4 [M +
H].sup.+ 158 ##STR300## 2.99 427.3 [M + H].sup.+ 159 ##STR301##
3.42 409.3 [M + H].sup.+ 160 ##STR302## 3.7 411.3 [M + H].sup.+ 161
##STR303## 3.17 413.3 [M + H].sup.+ 162 ##STR304## 3.15 461.3 [M +
H].sup.+ 163 ##STR305## 3.12 427.3 [M + H].sup.+ 164 ##STR306##
3.34 415.3 [M + H].sup.+ 165 ##STR307## 3.45 441.3 [M + H].sup.+
166 ##STR308## 3.06 427.4 [M + H].sup.+ 167 ##STR309## 3.14 383.3
[M + H].sup.+ 168 ##STR310## 3.17 454.3 [M + H].sup.+ 169
##STR311## 2.94 426.3 [M + H].sup.+ 170 ##STR312## 3.37 429.4 [M +
H].sup.+ 171 ##STR313## 3.57 397.3 [M + H].sup.+ 172 ##STR314##
3.39 314.2 [M + H].sup.+ 173 ##STR315## 3.7 334.2 [M + H].sup.+ 174
##STR316## 3.24 369.3 [M + H].sup.+
EXAMPLE 175
5-Chloro-1H-pyrrolo]2,3-c]pyridine-2-carboxylic acid
[2-(4-benzyloxypiperidin-1-yl)-1-(S)-(4-fluorobenzyl)-2-oxoethyl]amide
[0449] ##STR317##
[0450] To 5-chloro-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid
[1-(S)-(4-fluorobenzyl)-2-(4-hydroxypiperidin-1-yl)-2-oxoethyl]amide
(EXAMPLE 5, 50 mg, 0.11 mmol) in anhydrous DMF (3 mL) under argon
was added benzylbromide (16 .mu.l, 0.13 mmol) followed by sodium
hydride (6.3 mg, 0.16 mmol) and the reaction stirred for 16 h.
Solvent was removed in vacuo and the residue partitioned between
ethyl acetate (2.times.20 mL) and water (20 mL). The organic
fractions were washed with 1M HCl (20 mL), NaHCO.sub.3 (2.times.20
mL) then brine (2.times.20 mL), dried (MgSO.sub.4) and the solvent
removed in vacuo. Crude material was purified by chromatography on
silica gel with dichloromethane/methanol (9:1) as the eluent to
give the title compound as an off-white powder. m/z
(ES.sup.+)=535.33 [M+H].sup.+; RT=3.44 min.
EXAMPLE 176
1-[2-(S)-[5-Chloro-1H-pyrrolo[2,3-c]pyridine-2-carbonyl)amino]-3-(4-fluoro-
phenyl)propionyl]piperidine-4-carboxylic acid
[0451] ##STR318##
[0452] To a solution of
1-[2-(S)-[5-chloro-1H-pyrrolo[2,3-c]pyridine-2-carbonyl)amino]-3-(4-fluor-
ophenyl)propionyl]piperidine-4-carboxylic acid methyl ester
(EXAMPLE 239, 48 mg, 0.1 mmol) in THF (2.0 mL) was added 1M sodium
hydroxide solution (0.11 mL, 0.11 mmol) and the reaction stirred at
rt for 3 h. Solvent was removed in vacuo and the crude material
partitioned between diethyl ether (20 mL) and water (2.times.20
mL). The aqueous layers were combined and acidified to pH2 with 2M
HCl, and organics were extracted into ethyl acetate (2.times.20
mL). Organic layers were combined and washed with brine (2.times.15
mL), dried (MgSO.sub.4) and solvent removed in vacuo. The crude
material was crystallised from ethyl acetate/petroleum ether to
give the title compound as a white powder. m/z (ES.sup.+)=473.30
[M+H].sup.+; RT=3.20 min.
EXAMPLES 177 AND 178 WERE PREPARED IN A SIMILAR WAY TO EXAMPLE
176
[0453] TABLE-US-00011 EXAMPLE Amine m/z RT (min) 177 ##STR319##
473.29 3.26 178 ##STR320## 473.3 3.33
EXAMPLE 179
Acetic acid
1-[2-(S)-[5-chloro-1H-pyrrolo[2,3-c]pyridine-2-carbonyl)amino]-3-(4-fluor-
ophenyl)propionyl]piperidin4-yl ester
[0454] ##STR321##
[0455] The title compound was prepared from
5-chloro-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid
[1-(S)-(4-fluorobenzyl)-2-(4-hydroxypiperidin 1-yl)-2-oxoethyl]
amide (EXAMPLE 5). To a solution of the starting amide (50 mg, 0.14
mmol) in anhydrous pyridine (2 mL) under argon was added acetic
anhydride (1 mL) and the reaction stirred at rt over 4 h. Solvent
was removed in vacuo and the crude material dissolved in ethyl
acetate (30 mL). Organics were washed with 1M HCl (2.times.15 mL),
water (15 mL) then brine (2.times.15 mL), dried (MgSO.sub.4) and
solvent removed in vacuo. The residue was purified by
chromatography with dichloromethane/methanol (99:1) as the eluent
to give the title compound as a white powder. m/z (ES.sup.+)=487.26
[M+H].sup.+; RT=3.38 min.
EXAMPLE 180
5-Chloro-1H-pyrrolo[2,3-cpydridine-2-carboxylic acid
[2-(4-aminopiperidin-1-yl-1-(S)-(4-fluorobenzl)-2-oxoethyl]amide
[0456] ##STR322##
[0457] To a suspension of
{1-[2-(S)-[(5-chloro-1H-pyrrolo[2,3-c]pyridine-2-carbonyl)amino]-3-(4-flu-
orophenyl)propionyl]piperidin-4-yl}carbamic acid tert-butyl ester
(EXAMPLE 230, 500 mg, 0.92 mmol) in methanol (12 mL) was added a
solution of 4M HCl in dioxane (0.69 mL, 2.76 mmol) and the reaction
stirred for 48 h. The resulting precipitate was filtered and washed
with ethyl acetate to give the title compound as the hydrochloride
salt as a pale yellow powder. m/z (ES.sup.+)=444.16 [M+H].sup.+;
RT=2.65 min. The product was dissolved in saturated sodium
bicarbonate solution. Solvent was removed in vacuo and the crude
material dissolved in THF (30 mL). The solution was filtered
through celite and solvent removed in vacuo to give the title
compound as a yellow powder. m/z (ES.sup.+)=444.32 [M+H].sup.+;
RT=2.59 min.
EXAMPLES 181-189 WERE PREPARED ACCORDING TO EXAMPLE 180 FROM THE
APPROPRIATE BOC-PROTECTED AMINE
[0458] TABLE-US-00012 EXAMPLE Structure m/z RT (min) 181 ##STR323##
458.3 2.66 182 ##STR324## 430.35 2.66 183 ##STR325## 430.39 2.62
184 ##STR326## 430.34 2.73 185 ##STR327## 430.38 2.69 186
##STR328## 444.37 2.65 187 ##STR329## 444.41 2.59 188 ##STR330##
444.37 2.84 189 ##STR331## 444.4 2.78
EXAMPLE 190
5-Chloro-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid
[2-(4-diacetylaminopiperidin-1-yl)-1-(S)-(4-fluorobenzyl)-2-oxoethyl]amid-
e
[0459] ##STR332##
[0460] Prepared from
5-chloro-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid
[2-(4-aminopiperidin-1-yl)-1-(S)-(4-fluorobenzyl)-2-oxoethyl]amide
(EXAMPLE 180). The compound was synthesised according to EXAMPLE
179 and purified by preparative HPLC to give the title compound as
a white powder. m/z (ES.sup.+)=486.28
[M-CH.sub.3CO.sub.2H+NH.sub.4].sup.+; RT=3.18 min.
EXAMPLE 191
5-Chloro-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid
[1-(S)-(4-fluorobenzyl)-2-(4-methylaminopiperidin-1-yl)-2-oxoethyl]amide
[0461] ##STR333##
[0462] To a solution of
5-chloro-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid
(1-(S)-(4-fluorobenzyl)-2-{4-[methyl-(2-nitrobenzenesulfonyl)amino]p-
iperidin-1-yl}-2-oxoethyl)amide (Preparation 76, 82 mg, 0.13 mmol)
in acetonitrile (6 mL) was added phenylthiol (145 .mu.L, 1.4 mmol)
followed by potassium carbonate (230 mg, 1.66 mmol) and the
reaction heated to 50.degree. C. for 24 h. To the mixture was added
diethyl ether (10 mL) and 1M HCl (15 mL) and stirred for 5 min. The
organic layer was separated and washed with 1M HCl (15 mL) before
combining the aqueous layers. The solution was basified to pH9 with
solid potassium carbonate and extracted with ethyl acetate
(2.times.20 mL). Organic layers were combined, washed with brine
(2.times.20 mL) and dried (MgSO.sub.4). Removal of the solvent in
vacuo provided the desired product as an off-white powder. m/z
(ES.sup.+)=458.40 [M+H].sup.+; RT=2.67 min. A small portion of the
product (10 mg) was dissolved in methanol (2 mL) and 1M HCl added
to bring the solution to pH 1-2. After stirring for 20 min the
solvent was removed in vacuo to give the title compound as the
hydrochloride salt as a yellow powder. m/z (ES.sup.+)=458.38
[M+H].sup.+; RT=2.64 min.
EXAMPLE 192
5-Chloro-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid
[1-(S)-(4-fluorobenzyl)-2-(4-methylaminomethylpiperidin-1-yl)-2-oxoethyl]-
amide
[0463] ##STR334##
[0464] Prepared according to EXAMPLE 191 from
5-chloro-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid
[1-(S)-(4-fluorobenzyl)-2-(4-{[methyl-(2-nitrobenzenesulfonyl)amino]methy-
l}piperidin-1-yl)-2-oxoethyl]amide (synthesised according to
Preparations 73-76 from the 4-aminomethylpiperidine-1-carboxylic
acid tert-butyl ester starting material). m/z (ES.sup.+) free
base=472.33 [M+H].sup.+; RT=2.80 min. m/z (ES.sup.+) HCl
salt=430.43 [M+H].sup.+; RT=2.72 min.
EXAMPLE 193
5-Chloro-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid
[1-(S)-benzyl-2-(3-(R)-hydroxypyrrolidin-1-yl)-2-oxoethyl]amide
[0465] ##STR335##
[0466] Prepared according to EXAMPLE 35, using
3-(R)-hydroxypyrrolidine in place of 3-(S)-hydroxypyrrolidine.
Purification via chromatography using dichloromethane/methanol
(95:5) as the eluent gave the title compound as an off-white
powder. m/z (ES.sup.+)=413.22 [M+H].sup.+; RT=3.13 min.
EXAMPLE 194
5Chloro-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid
[1-(S)-(4-fluorobenzyl)-2-oxo-2-(4-trifluoromethylpiperidin-1-yl)ethyl]am-
ide
[0467] ##STR336##
[0468] To 4-trifluoromethyl piperidine (17 mg, 0.11 mmol) was added
a solution of
2-(S)-[(5-chloro-1H-pyrrolo[2,3-c]pyridine-2-carbonyl)amino]-3-(4-fluorop-
henyl)propionic acid (EXAMPLE 228, 40 mg, 0.11 mmol) in DMF (400
.mu.L) followed by a solution of HATU (50 mg, 0.13 mmol) in DMF
(400 .mu.L) and finally a solution of DIPEA (23 .mu.L, 0.13 mmol)
in DMF (200 .mu.L). The resulting mixture was stirred at rt for 96
h then solvent was removed in vacuo. The crude material was
purified by crystallisation from THF/petroleum ether to give the
title compound as a yellow powder. (ES.sup.+)=497.23 [M+H].sup.+;
RT=3.50 min.
EXAMPLES 195-225 WERE PREPARED IN THE SAME WAY AS EXAMPLE 194
[0469] TABLE-US-00013 EXAMPLE Amine Purification m/z RT (min) 195
##STR337## Crystallisation (THF/PE) 501.26 3.43 196 ##STR338## MDP
459.3 3.13 197 ##STR339## MDP 512.37 2.77 198 ##STR340## MDP 471.3
3.24 199 ##STR341## MDP 447.27 3.37 200 ##STR342## MDP 472.3 3.03
201 ##STR343## MDP 473.32 3.09 202 ##STR344## MDP 472.29 3.08 203
##STR345## MDP 528.38 3.3 204 ##STR346## MDP 472.3 3.09 205
##STR347## MDP 501.32 3.55 206 ##STR348## MDP 487.3 3.57 207
##STR349## MDP 488.34 2.75 208 ##STR350## MDP 488.4 2.59 209
##STR351## MDP 502.38 2.77 210 ##STR352## MDP 527.37 2.47 211
##STR353## MDP 486.29 3.09 212 ##STR354## MDP 460.4 2.65 213
##STR355## MDP 458.36 3.18 214 ##STR356## MDP 530.45 3.52 215
##STR357## MDP 530.45 3.46 216 ##STR358## MDP 498.4 3.23 217
##STR359## MDP 544.48 3.61 218 ##STR360## MDP 458.35 3 219
##STR361## MDP 544.46 3.61 220 ##STR362## Chromatography (DCM/MeoH
98:2) 473.33 3.48 221 ##STR363## Chromatography (DCM/MeoH 98:2)
502.38 3.43 222 ##STR364## Trituration (EtOAc) 530.39 3.65 223
##STR365## Trituration (EtOAc) 458.32 2.8 224 ##STR366## Prep HPLC
488.35 2.63 225 ##STR367## Crystallisation (MeOH) 501.4 2.62
EXAMPLE 226
5Chloro-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid
[1-(S)-(4-fluorobenzyl)-2-oxo-2-piperazin-1-ylethyl]amide
[0470] ##STR368##
[0471] Prepared according to EXAMPLE 180 from
4-[2-(S)-[5-chloro-1H-pyrrolo[2,3-c]pyridine-2-carbonyl)amino]-3-(4-fluor-
ophenyl)propionyl]piperazine-1-carboxylic acid tert-butyl ester
(prepared according to EXAMPLE 222). Purification gave the title
compound as a yellow powder. m/z (ES.sup.+)=430.34 [M+H].sup.+;
RT=2.56 min.
EXAMPLE 227
2-(S)-[(5-Chloro-1H-pyrrolo[2,3-c]pyridine-2-carbonyl)amino]-3-(4-fluoroph-
enyl)propionic acid ethyl ester
[0472] ##STR369##
[0473] Prepared according to EXAMPLE 41 using
p-fluoro-L-phenylalanine ethyl ester hydrochloride instead of
L-phenylalanine ethyl ester hydrochloride. Chromatography gave the
title compound as a yellow powder. m/z (ES.sup.+)=390.27
[M+H].sup.+; RT=3.71 min.
EXAMPLE 228
2-(S)-[(5-Chloro-1H
-pyrrolo[2,3-c]pyridine-2-carbonyl)amino]-3-(4-fluorophenyl)propionic
acid
[0474] ##STR370##
[0475] The title compound was prepared according to EXAMPLE 42
using
2-(S)-[(5-chloro-1H-pyrrolo[2,3-c]pyridine-2-carbonyl)amino]-3-(4-fluorop-
henyl)propionic acid ethyl ester (EXAMPLE 227). Solvent was removed
in vacuo and the residue taken into water. The aqueous layer was
extracted with ethyl acetate (3.times.) then acidified with 2M HCl
solution to pH 2. The precipitate was filtered and washed
thoroughly with water to give the title compound as a
cream-coloured powder. (ES.sup.+)=362.24 [M+H].sup.+; RT=3.21
min.
EXAMPLE 229
5-Chloro-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid
[2-(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)-1-(S)-(4-fluorobenzyl)-2-oxoethyl]-
amide
[0476] ##STR371##
[0477] To a solution of
2-(S)-[(5-chloro-1H-pyrrolo[2,3-c]pyridine-2-carbonyl)amino]-3-(4-fluorop-
henyl)propionic acid (EXAMPLE 228, 40 mg, 0.11 mmol) in DMF (4 mL)
was added HATU (50 mg, 0.13 mmol) and the reaction stirred for 10
min. 4-Piperidone ethylene ketal (19 mg, 0.13 mmol) was added,
followed by DIPEA (23 .mu.L, 0.13 mmol) and the reaction stirred at
rt for 16 h. Solvent was removed in vacuo and the crude material
partitioned between ethyl acetate (15 mL) and water (15 mL). The
organic layer was washed with 1M HCl solution (15 mL), sodium
bicarbonate solution (2.times.20 mL) then brine (2.times.20 mL),
dried (MgSO.sub.4) and the solvent removed in vacuo. Purification
by chromatography using dichloromethane/methanol (9:1) as the
eluent gave the title compound as a pale yellow powder.
(ES.sup.+)=487.30 [M+H].sup.+; RT=3.28 min.
EXAMPLES 230-237 WERE PREPARED IN A SIMILAR WAY TO EXAMPLE 229
[0478] TABLE-US-00014 EXAMPLE Amine Purification m/z RT (min) 230
##STR372## Chromatography (DCM/MeOH 9:1) 544.45 5.39 231 ##STR373##
Chromatography (DCM/MeOH 9:1) 558.22 3.67 232 ##STR374##
Chromatography (DCM/MeOH 9:1) 514.28 2.67 233 ##STR375##
Chromatography (DCM/MeOH 9:1) 488.38 2.69 234 ##STR376##
Chromatography (DCM/MeOH 9:1) 445.28 3.17 235 ##STR377##
Chromatography (EtOAc/PE 3:1) 427.35 3.5 236 ##STR378## prep. HPLC
459.4 3.2 237 ##STR379## Chromatography (EtOAc) 413.2 3.31
EXAMPLE 238
5-Chloro-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid
[2-(1,1-dioxo-1,6-thiomorpholin-4-yl)-1-(S)-(4-fluorobenzyl)-2-oxoethyl]a-
mide
[0479] ##STR380##
[0480] Prepared according to EXAMPLE 229 from
2-(S)-[(5-chloro-1H-pyrrolo[2,3-c]pyridine-2-carbonyl)amino]-3-(4-fluorop-
henyl)propionic acid (EXAMPLE 228) and thiomorpholine-1,1-dioxide
(Preparation 77). Purification by trituration with methanol gave
the title compound as a pale yellow powder. (ES.sup.+)=479.24
[M+H].sup.+; RT=3.17 min.
EXAMPLE 239
1-[2-(S)-[(5-Chloro-1H-pyrrolo[2,3-c]pyridine-2-carbonyl)amino]-3-(4-fluor-
ophenyl)propionly]piperidine-4-carboxylic acid methyl ester
[0481] ##STR381##
[0482] Prepared according to EXAMPLE 229 from
2-(S)-[(5-chloro-1H-pyrrolo[2,3-c]pyridine-2-carbonyl)amino]-3-(4-fluorop-
henyl)propionic acid (EXAMPLE 228) and piperidine-4-carboxylic acid
methyl ester hydrochloride (Preparation 78). Purification by
chromatography using ethyl acetate/petroleum ether (70:30) as the
eluent gave the title compound as a pale yellow powder. m/z
(ES.sup.+)=487.32 [M+H].sup.+; RT=3.44 min.
EXAMPLE 240 WAS PREPARED IN A SIMILAR WAY TO EXAMPLE 239
[0483] ##STR382##
[0484] m/z (ES.sup.+)=487.35 [M+H].sup.+; RT=3.88 min.
EXAMPLE 241
5-Chloro-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid
[1-(S)-benzyl-2-(4-hydroxypiperidin-1-yl)-2-oxoethyl]amide
[0485] ##STR383##
[0486] The title compound was prepared according to EXAMPLE 229
using
2-(S)-[(5-chloro-1H-pyrrolo[2,3-c]pyridine-2-carbonyl)amino]-3-phenylprop-
ionic acid (EXAMPLE 42) and 4-hydroxypiperidine. Purification by
chromatography using dichloromethane/methanol (9:1) as the eluent
gave the title compound as an orange powder. m/z (ES.sup.+)=427.35
[M+H].sup.+; RT=2.99 min.
EXAMPLE 242
5-Chloro-1H-pyrrolo[2.3-c]pyridine-2-carboxylic acid
[2-(2-carbamoylpiperidin-1-yl)-1-(S)-(4-fluorobenzyl)-2-oxoethyl]amide
[0487] ##STR384##
[0488] To a solution of piperidine-2-carboxylic acid amide
hydrochloride (Preparation 80, 24 mg, 0.17 mmol) in DMF (3 mL) was
added
2-(S)-[(5-chloro-1H-pyrrolo[2,3-c]pyridine-2-carbonyl)amino]-3-(4-fluorop-
henyl)propionic acid (EXAMPLE 230, 52 mg, 0.14 mmol), followed by
HATU (65.6 mg, 0.17 mmol) and DIPEA (63 .mu.L, 0.36 mmol), and the
reaction stirred at rt for 16 h. Solvent was removed in vacuo,
purification via preparative HPLC gave the title compound as an
off-white powder. m/z (ES.sup.+)=472.31 [M+H].sup.+; RT=3.19
min.
EXAMPLE 243
5-Chloro-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid
{1-(S)-(4-fluorobenzl)-2-[4-(2-methoxyethoxy)piperidin-1-yl]-2-oxoethyl}a-
mide
[0489] ##STR385##
[0490] The title compound was prepared according to EXAMPLE 229
from
2-(S)-[(5-chloro-1H-pyrrolo[2,3-c]pyridine-2-carbonyl)amino]-3-(4-fluorop-
henyl)propionic acid (EXAMPLE 228) and
4-(2-methoxyethoxy)piperidine hydrochloride (Preparation 82).
Purification by chromatography using dichloromethane/methanol
(95:5) as the eluent gave the title compound as an off-white
powder. m/z (ES.sup.+)=503.26 [M+H].sup.+; RT=3.31 min.
EXAMPLE 244
5-Chloro-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid
{1-(S)-(4-fluorobenzyl)-2-[4-(3-methoxypropoxy)piperidin-1-yl]-2-oxoethyl-
}amide
[0491] ##STR386##
[0492] The title compound was prepared according to EXAMPLE 229
using 4-(3-methoxypropoxy)piperidine hydrochloride, synthesised
from the appropriate starting materials (Preparations 81 and 82).
Purification by chromatography using dichloromethane/methanol (9:1)
as the eluent gave the title compound as an off-white powder. m/z
(ES.sup.+)=517.36 [M+H].sup.+; RT=3.41 min.
EXAMPLE 245
5-Chloro-1H-pyrrolo[2.3-c]pyridine-2-carboxylic acid
[2-(4-acetylaminopiperidin-1-yl)-1-(S)-(4-fluorobenzyl)-2-oxoethyl]amide
[0493] ##STR387##
[0494] To a solution of acetic acid (7.5 .mu.L, 0.13 mmol) in DMF
(5 mL) was added EDCI (33 mg, 0.17 mmol), HOBt (19.5 mg, 0.14
mmol), 5-chloro-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid
[2-(4-aminopiperidin-1-yl)-1-(S)-(4-fluorobenzyl)-2-oxoethyl]amide
(EXAMPLE 180, 70 mg, 0.16 mmol) and DIPEA (57 .mu.L, 0.33 mmol),
and the reaction stirred at rt for 16 h. Solvent was removed in
vacuo then crude material partitioned between ethyl acetate (15 mL)
and water (15 mL). The organic layer was washed with NaHCO.sub.3
(2.times.20 mL) and brine (2.times.30 mL), dried (MgSO.sub.4) and
the solvent removed in vacuo. Purification by chromatography using
dichloromethane/methanol (95:5) as the eluent gave the title
compound as an off-white powder. m/z (ES.sup.+)=486.27 [M+H].sup.+;
RT=3.16 min.
EXAMPLE 246
5-Chloro-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid
[2-[4-(acetylaminomethylpiperidin-1-yl]-1-(S)-(4-fluorobenzyl)-2-oxoethyl-
]amide
[0495] ##STR388##
[0496] The title compound was prepared from
5-chloro-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid
[2-(4-aminomethylpiperidin-1-yl)-1-(S)-(4-fluorobenzyl)-2-oxyethyl]amide
(EXAMPLE 229 then 180 from the appropriate
piperidin-4-ylmethylcarbamic acid tert-butyl ester). Purification
by preparative HPLC gave the title compound as a white powder. m/z
(ES.sup.+)=500.38 [M+H].sup.+; RT=3.14 min.
EXAMPLE 247
5-Chloro-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid
[1-(R)-(4-fluorobenzyl)-2-(4-hydroxypiperidin-1-yl)-2-oxoethyl]amide
[0497] ##STR389##
[0498] The title compound was prepared according to EXAMPLE 1 from
5-chloro-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid (Preparation
18) and 2-(R)-amino-3-(4-fluorophenyl)-1-(4-hydroxypiperidin-1-yl)
propan-1-one hydrochloride (Preparation 84). Purification by
chromatography using dichloromethane/methanol (92:8) as the eluent
gave the title compound as a pale yellow powder. m/z
(ES.sup.+)=445.34 [M+H].sup.+; RT=3.10 min.
EXAMPLE 248
4-{[2-(S)-[(5-Chloro-1H-pyrrolo[2,3-c]pyridine-2-carbonyl)amino]-3-(4-fluo-
rophenyl)propionyl]methylamino}piperidine-1-carboxylic acid
tert-butyl ester
[0499] ##STR390##
[0500] The title compound was prepared according to EXAMPLE 229
from
2-(S)-[(5-chloro-1H-pyrrolo[2,3-c]pyridine-2-carbonyl)amino]-3-(4-fluorop-
henyl)-propionic acid (EXAMPLE 228) and
4-methylaminopiperidine-1-carboxylic acid tert-butyl ester
(Preparation 86). Purification by chromatography using
dichloromethane/methanol (95:5) as the eluent gave the title
compound as a pale yellow powder. m/z (ES.sup.+)=558.48
[M+H].sup.+; RT=3.82 min.
EXAMPLE 249
5-Chloro-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid
[2-(S)-(4-fluorophenyl)-1-(methylpiperidin-4-yl
carbamoyl)ethyl]amide
[0501] ##STR391##
[0502] The title compound was prepared according to Preparation 82,
from
4-{[2-(S)-[(5-chloro-1H-pyrrolo[2,3-c]pyridine-2-carbonyl)amino]-3-(4-flu-
orophenyl)propionyl]methylamino}piperidine-1-carboxylic acid
tert-butyl ester (EXAMPLE 248), to give the title compound as the
hydrochloride salt as a yellow crystalline solid. m/z
(ES.sup.+)=458.30 [M+H].sup.+; RT=2.86 min. The product was
dissolved in saturated sodium bicarbonate solution and extracted
into ethyl acetate. Organic solvent was removed in vacuo to give
the title compound as the free base as a yellow powder. m/z
(ES.sup.+)=458.33 [M+H].sup.+; RT=2.82 min.
EXAMPLE 250
5-Chloro-1H-pyrrolo2,3-c]pyridine-2-carboxylic acid
{2-(S)-(4-fluorophenyl)-1-[methyl(tetrahydropyran-4-yl)carbamoyl]ethyl}am-
ide
[0503] ##STR392##
[0504] The title compound was prepared according to EXAMPLE 229
from
2-(S)-[(5-chloro-1H-pyrrolo[2,3-c]pyridine-2-carbonyl)amino]-3-(4-fluorop-
henyl)propionic acid (EXAMPLE 228) and methyl(tetrahydropyran-4-yl)
amine hydrochloride (Preparation 88). m/z (ES.sup.+)=459.27
[M+H].sup.+; RT=3.41 min.
EXAMPLE 251
5-Chloro-1H-pyrrolo2,3-c]pyridine-2-carboxylic acid
[2-(4-dimethylaminopiperidin-1-yl)-1-(S)-(4-fluorobenzyl)-2-oxoethyl]amid-
e
[0505] ##STR393##
[0506] The title compound was prepared according to EXAMPLE 35 from
2-(S)-[(5-chloro-1H-pyrrolo[2,3-c]pyridine-2-carbonyl)amino]-3-(4-fluorop-
henyl)propionic acid (EXAMPLE 228) and dimethylpiperidin-4-yl amine
(Preparation 90). Purification by preparative HPLC gave the title
compound as a yellow crystalline solid. m/z (ES.sup.+)=472.34
[M+H].sup.+; RT=2.64 min.
EXAMPLE 252
5-Chloro-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid
[1-(S)-(4-fluorobenzyl)-2-(4-methanesulfonylaminopiperidin-1-yl)-2-oxoeth-
yl]amide
[0507] ##STR394##
[0508] The title compound was prepared according to EXAMPLE 229
from
2-(S)-[(5-chloro-1H-pyrrolo[2,3-c]pyridine-2-carbonyl)amino]-3-(4-fluorop-
henyl)propionic acid (EXAMPLE 228) and N-piperidin-4-yl
methanesulfonamide hydrochloride (Preparation 92). Purification
gave the title compound as an off-white powder. m/z
(ES.sup.+)=522.30 [M+H].sup.+; RT=3.29 min.
EXAMPLE 253
2-(S)-[(5-Chloro-1H-pyrrolo[2,3-c]pyridine-2-carbonyl)-amino]-3-pyridin-4y-
l-propionic acid methyl ester
[0509] ##STR395##
[0510] To a solution of
5-chloro-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid (Preparation
18, 185 mg, 0.94 mmol) in DMF (7 mL) was added
2-(S)-amino-3-pyridin-4-yl propionic acid methyl ester
hydrochloride (Preparation 93, 204 mg, 0.94 mmol) followed by TBTU
(333 mg, 1.04 mmol) and DIPEA (740 .mu.L, 4.24 mmol), and the
reaction stirred at rt for 16 h. Solvent was removed in vacuo and
the residue partitioned between ethyl acetate (30 mL) and water (30
mL). The organic layer was washed with water (2.times.30 mL),
NaHCO.sub.3 solution (3.times.40 mL) then brine (3.times.50 mL),
dried (MgSO.sub.4) and the solvent removed in vacuo. Purification
by chromatography (SiO.sub.2, EtOAc) gave the title compound as a
pink powder. m/z (ES.sup.+)=359.11 [M+H].sup.+; RT=2.42 min.
EXAMPLE 254
5-Chloro-1H-pyrrolo2,3-c]pyridine-2-carboxylic acid
(1-dimethylcarbamoyl-2-(S)-pyridin-4-yl-ethyl)amide
[0511] ##STR396##
[0512] The title compound was prepared according to EXAMPLE 253
from
2-(S)-[(5-chloro-1H-pyrrolo[2,3-c]pyridine-2-carbonyl)amino]-3-pyridin-4--
yl-propionic acid (EXAMPLE 259) and dimethylamine hydrochloride.
Purification by preparative HPLC gave the title compound as an
off-white powder. m/z (ES.sup.+)=372.13 [M+H].sup.+; RT=2.31
min.
EXAMPLE 255 WAS PREPARED IN A SIMILAR WAY TO EXAMPLE 254
[0513] ##STR397##
[0514] m/z (ES.sup.+)=398.15 [M+H].sup.+; RT=2.53 min.
EXAMPLE 256
5-Chloro-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid
[2-(1,4-dioxa-7-aza-spiro[4.5]dec-7-yl)-1-(S)-(4-fluorobenzyl)-2-oxoethyl-
]amide
[0515] ##STR398##
[0516] To a suspension of
2-(S)-[(5-chloro-1H-pyrrolo[2,3-c]pyridine-2-carbonyl)amino]-3-(4-fluorop-
henyl)propionic acid (EXAMPLE 228, 80 mg, 0.22 mmol) in ethanol (6
mL) was added DMTMM (78 mg, 0.27 mmol) and the reaction stirred for
5 min. To the mixture was added 1,4-dioxa-7-aza-spiro[4.5]decane
(Preparation 94, 35 mg, 0.24 mmol) and stirring continued for 16 h.
Solvent was removed in vacuo and the crude material partitioned
between ethyl acetate and water. The organic layer was washed with
NaHCO.sub.3 solution (2.times.20 mL) then brine (2.times.20 mL),
dried (MgSO.sub.4) and the solvent removed in vacuo. Purification
by chromatography using dichloromethane/methanol (95:5) as the
eluent gave the title compound as a pale yellow powder. m/z
(ES.sup.+)=487.21 [M+H].sup.+; RT=3.50 min.
EXAMPLE 257
5-Chloro-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid [2-(3R,4R)
dihydroxypyrrolidin-1-yl)-1-(S)-(4-fluorobenzyl)-2-oxoethyl]amide
[0517] ##STR399##
[0518] The title compound was prepared according to EXAMPLE 229
using (3R,4R)-dihydroxypyrrolidine (prepared according to
Preparation 23 from the commercially available benzyl derivative).
Additional crystallisation from methanol gave the title compound as
colourless crystals. m/z (ES.sup.+)=447.33 [M+H].sup.+; RT=2.99
min.
EXAMPLE 258
5-Chloro-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid
[2-(3-(S)-4-(S)
dihydroxypyrrolidin-1-yl)-1-(S)-(4-fluorobenzyl)-2-oxoethyl]amide
[0519] ##STR400##
[0520] The title compound was prepared according to EXAMPLE 229
using 3-(S)-4-(S)-dihydroxypyrrolidine (prepared according to
Preparation 23). Additional crystallisation from methanol gave the
title compound as colourless crystals. m/z (ES.sup.+)=447.33
[M+H].sup.+; RT=3.07 min.
EXAMPLE 259
2-(S)-[(5-Chloro-1H-pyrrolo[2,3-c]pyridine-2-carbonyl)amino]-3-pyridin-4-y-
l-propionic acid
[0521] ##STR401##
[0522] The title compound was prepared according to EXAMPLE 42 from
2-(S)-[(5-chloro-1H-pyrrolo[2,3-c]pyridine-2-carbonyl)amino]-3-pyridin-4--
yl-propionic acid methyl ester (EXAMPLE 253). m/z (ES.sup.+)=345.09
[M+H].sup.+.
EXAMPLE 260
5-Chloro-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid
(1-(S)-benzyl-2-oxo-2-phenylethyl)amide
[0523] ##STR402##
[0524] To a solution of
5-chloro-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid
[2-phenyl-1-(S)-(2-phenyl-[1,3]dioxolan-2-yl)ethyl]amide
(Preparation 96, 47 mg, 0.105 mmol) in acetone (20 mL) was added
aqueous hydrochloric acid (1 mL, 1M). After stirring under reflux
for 3 days the solvent was removed in vacuo. The residue was
distributed between ethyl acetate (100 mL) and saturated sodium
carbonate solution (50 mL). After separation the organic layer was
washed with brine (50 ml), dried (MgSO.sub.4) and concentrated to a
residue which was purified by flash chromatography on silica gel
(eluent: hexane/ethyl acetate: 50/50) to give the title compound as
colourless solid. m/z (ES.sup.+)=404.21 [M+H].sup.+; RT=3.58
min.
EXAMPLE 261
5-Chloro-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid
(2-hydroxy-2-pyridin-3-yl-ethyl)amide
[0525] ##STR403##
[0526] To a solution of
5-chloro-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid (Preparation
18, 296 mg, 1.51 mmol) and 2-amino-1-pyridin-3-ylethanol
(Preparation 98, 214 mg, 1.55 mmol) in DMF (10 mL) was added HOBt
(225 mg, 1.47 mmol), DIPEA (0.55 mL, 3.16 mmol) and EDCI (340 mg,
1.77 mmol). After stirring at rt for 12 h the solvent was removed
in vacuo and the residue then taken up in THF (150 mL) and washed
with diluted sodium hydroxide solution (1M, 50 mL) and brine
(2.times.50 mL). The solution was dried (MgSO.sub.4) and
concentrated to an oil that was further purified by flash
chromatography on silica gel (eluent: DCM/methanol: 90/10+0.5%
triethylamine) to give the title compound as off-white solid.
.delta..sub.H (d.sub.6 DMSO): 3.53 (2H, m), 4.85 (1H, m), 5.75 (1H,
d), 7.15 (1H, s), 7.37 (1H, dd), 7.75 (2H, m), 8.47 (1H, m), 8.57
(1H, s), 8.89 (1H, appt), 12.24 (1H, s); m/z (ES.sup.+)=317.17
[M+H].sup.+; RT=2.71 min.
EXAMPLE 262
5-Chloro-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid
(2-(S)-hydroxy-1-(S)-methoxymethyl-2-phenylethyl)amide
[0527] ##STR404##
[0528] To a solution of
5-chloro-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid (Preparation
18, 223 mg, 1.13 mmol) and commercially available
(1S,2S)-(+)-2-amino-3-methoxy-1-phenyl-1-propanol (200 mg, 1.10
mmol) in DMF (5 mL) was added HOBt (173 mg, 1.13 mmol), DIPEA (0.42
mL, 2.41 mmol) and EDCI (260 mg, 1.36 mmol). After stirring at rt
for 12 h the mixture was added to diluted brine (100 mL,
water/brine: 1/1). Extraction with ethyl acetate (4.times.25 mL),
washing of the combined extracts with diluted hydrochloric acid
(1M, 30 ml), diluted aqueous sodium hydroxide solution (1M, 30 ml)
and brine (30 mL) followed by drying over magnesium sulphate gave
after concentration a residue which was purified by flash
chromatography on silica gel (eluent: ethyl acetate). The title
compound was obtained as colourless solid. .delta..sub.H
(CD.sub.3OD): 3.37 (3H, s), 3.34 (1H, dd), 3.66 (1H, dd), 4.53 (1H,
ddd), 5.03 (1H, d), 7.15 (1H, s), 7.25-7.45 (5H, 3m), 7.68 (1H, s),
8.58 (1H, s); m/z (ES.sup.+)=360.22 [M+H].sup.+; RT=3.12 min.
EXAMPLE 263
5-Chloro-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid
(1-(S)-hydroxymethyl-2-oxo-2-phenylethyl)amide
[0529] ##STR405##
[0530] To a solution of
5-chloro-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid [1-(S)
-(tert-butyldimethylsilanyloxymethyl)-2-oxo-2-phenylethyl]amide
(Preparation 101, 220 mg, 0.48 mmol) in THF (10 mL) was added
acetic acid (60 .mu.L) and tetrabutylammonium fluoride solution (1
ml, 1M in THF) at rt. After stirring for 3 h the reaction mixture
was distributed between ethyl acetate (100 mL) and water (30 mL).
The organic layer was separated, then washed with brine (50 ml),
dried (MgSO.sub.4) and concentrated to a solid residue.
Recrystallisation from THF gave the title compound. m/z
(ES.sup.+)=344.21 [M+H].sup.+; RT=3.02 min.
EXAMPLE 264
5-Chloro-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid
(1-(S)-methoxymethyl-2-oxo-2-phenylethyl)amide
[0531] ##STR406##
[0532] 5-Chloro-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid
(2-(S)-hydroxy-1-(S)-methoxymethyl-2-phenylethyl)amide (EXAMPLE
262, 101 mg, 0.281 mmol) was oxidised and isolated in a similar way
to Preparation 101 using Dess-Martin periodinane (240 mg, 0.566
mmol) in DCM (10 mL). The title compound was obtained by
recrystallisation of the crude product from methanol. m/z
(ES.sup.+)=358.24 [M+H].sup.+; RT=3.18 min.
EXAMPLE 265
5-Chloro-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid
(2-oxo-2-pyridin-3-ylethyl)amide
[0533] ##STR407##
[0534] To a solution of racemic
5-chloro-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid
(2-hydroxy-2-pyridin-3-ylethyl)amide (EXAMPLE 261, 80 mg, 0.253
mmol) in dry THF (20 mL) was added Dess-Martin periodinane (307 mg,
0.724 mmol). After stirring for 4 h at rt alkaline sodium
thiosulfate solution was added (5.4 g Na.sub.2SO.sub.3 dissolved in
20 mL saturated NaHCO.sub.3 solution) and the emulsion was
vigorously stirred for additional 30 min before further diluted
with water (.about.150 mL). Extraction with THF (4.times.50 mL),
washing of the combined extracts with saturated sodium hydrogen
carbonate (50 mL) and brine (50 mL) gave a solution which was
concentrated after drying (MgSO.sub.4). Purification of the residue
by flash chromatography on silica gel (eluent: DCM/methanol: 90/10)
gave the title compound as off-white solid. m/z (ES.sup.+)=315.19
[M+H].sup.+; RT=2.65 min.
EXAMPLE 266
6-Chloro-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid
(1-dimethylcarbamoyl-2-(S)-phenethyl)amide
[0535] ##STR408##
[0536] DIPEA (155 .mu.L, 0.89 mmol), HOBt (43 mg, 0.28 mmol) and
6-chloro-1H-pyrrolo[2,3b]pyridine-2-carboxylic acid (Preparation
110, 50 mg, 0.25 mmol) was added to a stirred solution of
2-(S)-amino-N,N-dimethyl-3-phenyl propionamide hydrochloride
(Preparation 8, 61 mg, 0.27 mmol) in DMF (4 mL). After 5 min EDCI
(63 mg, 0.33 mmol) was added and the reaction stirred for 22 h.
Purification by column chromatography (SiO.sub.2, 95:5
CH.sub.2Cl.sub.2/MeOH) afforded the title compound. m/z
(ES.sup.+)=370.93 [M+H].sup.+; RT=3.62 min.
EXAMPLE 267
6-Chloro-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid
[1-(S)-(4-fluorobenzyl)-2-(3-(S)-hydroxypyrrolidin-1-yl)-2-oxoethyl]amide
[0537] ##STR409##
[0538] The title compound was prepared according to EXAMPLE 266 but
using
2-(S)-amino-3-(4-fluorophenyl)-1-(3-(S)-hydroxypyrrolidin-1-yl)-propan-1--
one hydrochloride (Preparation 103) instead of
2-(S)-amino-N,N-dimethyl-3-phenyl propionamide hydrochloride. m/z
(ES.sup.+)=430.94 [M+H].sup.+; RT=4.31 min.
EXAMPLE 268
6-Chloro-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid
[1-(S)-(4-fluorobenzyl)-2-(4-hydroxypiperidin-1-yl)-2-oxoethyl]amide
[0539] ##STR410##
[0540] The title compound was prepared according to EXAMPLE 266 but
using
2-(S)-amino-3-(4-fluorophenyl)-1-(4-hydroxypiperidin-1-yl)-propan-1-one
hydrochloride (Preparation 20) instead of
2-(S)-amino-N,N-dimethyl-3-phenyl propionamide hydrochloride.
Purification by column chromatography (SiO.sub.2, 9:1
CH.sub.2Cl.sub.2/MeOH) gave the title compound. m/z
(ES.sup.+)=444.91 [M+H].sup.+; RT=3.55 min.
EXAMPLE 269
6-Chloro-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid
[1-(S)-(4-fluorobenzyl)-2-oxo-2-(5-oxo-[1,4]diazepam-1-yl)ethyl]amide
[0541] ##STR411##
[0542] The title compound was prepared according to EXAMPLE 266 but
using
1-[2-(S)-amino-3-(4-fluorophenyl)propionyl]-[1,4]diazepan-5-one
hydrochloride (Preparation 112) instead of
2-(S)-amino-N,N-dimethyl-3-phenyl propionamide hydrochloride.
Purification by column chromatography (SiO.sub.2, 94:6
CH.sub.2Cl.sub.2/MeOH) gave the title compound. m/z
(ES.sup.+)=457.91 [M+H].sup.+; RT=3.74 min.
EXAMPLE 270
6-Chloro-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid (2-oxo-2
phenethyl)amide
[0543] ##STR412##
[0544] To a solution of
6-chloro-1H-pyrrolo[2,3b]pyridine-2-carboxylic acid (Preparation
110, 60 mg, 0.31 mmol) in ethanol (5 mL) was added
2-aminoacetophenone hydrochloride (58 mg, 0.34 mmol),
N-methylmorpholine (74 .mu.L, 0.67 mmol) and DMTMM (198 mg, 0.67
mmol) and the reaction stirred at rt for 16 h. Solvent was removed
in vacuo and the resulting residue partitioned between ethyl
acetate (20 mL) and water (20 mL). Organics were washed with 1M HCl
(20 mL), water (20 mL), NaHCO.sub.3 solution (2.times.20 mL) then
brine (20 mL) before being dried (MgSO.sub.4) and solvent
concentrated in vacuo. Purification by column chromatography
(SiO.sub.2, 2:1 Pet. Ether/EtOAc then 97:3 CH.sub.2Cl.sub.2/MeOH)
gave the title compound.
EXAMPLE 271
2-(S)-[(6-Chloro-1H-pyrrolo[2,3-b]pyridine-2-carbonyl)amino]-3-(4-fluoroph-
enyl) propionic acid ethyl ester
[0545] ##STR413##
[0546] To a solution of
6-chloro-1H-pyrrolo[2,3b]pyridine-2-carboxylic acid (Preparation
110, 450 mg, 2.29 mmol) in DMF (20 mL) was added 4-fluoro
phenylalanine ethyl ester hydrochloride (624 mg, 2.52 mmol), DIPEA
(1.40 mL, 8.01 mmol) and HOBt. (386 mg, 2.52 mmol) and the reaction
stirred. After 5 min EDCI (570 mg, 2.98 mmol) was added and
stirring continued for 16 hr. Solvent was removed in vacuo then
crude material partitioned between ethyl acetate (75 mL) and water
(50 mL). Organics were washed with NaHCO.sub.3 solution (3.times.50
mL) then brine (2.times.50 mL), dried (MgSO.sub.4) and THE solvent
removed in vacuo to give the title compound. m/z (ES.sup.+)=389.90
[M+H].sup.+; RT 3.79 min.
EXAMPLE 272
2-(S)-[(6-Chloro-1H-pyrrolo[2,3-b]pyridine-2-carbonyl)aminol-3-(4-fluoroph-
enyl)propionic acid
[0547] ##STR414##
[0548] To a solution of
2-[(6-chloro-1H-pyrrolo[2,3-b]pyridine-2-carbonyl)amino]-3-(4-fluoropheny-
l)propionic acid ethyl ester (EXAMPLE 271, 780 mg, 2.0 mmol) in
methanol (15 mL) was added 2M NaOH (2 mL, 4.0 mmol) and the
reaction was stirred for 16 hr. Solvent was removed in vacuo and
crude residue dissolved in water (20 mL). The aqueous phase was
washed with ethyl acetate (2.times.20 mL), then acidified to Ph 3
with 2M HCl. The organics were extracted into ethyl acetate
(2.times.30 mL), and then dried (MgSO.sub.4) before concentrating
the solvent in vacuo to provide the title compound. m/z
(ES.sup.+)=361.88 [M+H].sup.+.
EXAMPLE 273
6-Chloro-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid
[1-(S)-(4-fluorobenzyl)-2-oxo-2-pyrrolidin-1-yl-ethyl]amide
[0549] ##STR415##
[0550] To pyrrolidine (11.5 mg, 0.14 mmol) was added a solution of
DIPEA (60 .mu.L, 0.35 mmol) in DMF (500 .mu.L) followed by
2-(S)-[(6-chloro-1H-pyrrolo[2,3-b]pyridine-2-carbonyl)amino]-3-(4-fluorop-
henyl) propionic acid (EXAMPLE 272, 50 mg, 0.14 mmol) in DMF (500
.mu.L) and HOBt (23 mg, 0.15 mmol) in DMF (500 .mu.L) and the
mixture stirred. After 5 min EDCI (34.5 mg, 0.18 mmol) in DMF (500
.mu.L) was added and the reaction stirred for 16 hr. Solvent was
removed in vacuo then crude material purified by mass-directed
purification to give the title compound. m/z (ES.sup.+)=414.93
[m+H].sup.+; RT=3.77 min.
EXAMPLES 274-276 WERE PREPARED IN THE SAME WAY
[0551] TABLE-US-00015 Example Structure m/z RT (min) 274 ##STR416##
430.92 3.46 275 ##STR417## 471.92 3.51 276 ##STR418## 432.92
3.79
EXAMPLES 277-280 WERE PREPARED IN THE SAME WAY, BUT PURIFICATION
WAS BY TRITURATION FROM METHANOL
[0552] TABLE-US-00016 Example Structure m/z RT (min) 277 ##STR419##
428.95 5.06 278 ##STR420## 430.93 3.65 279 ##STR421## 446.9 3.9 280
##STR422## 443.92 3.05
EXAMPLE 281
2-(S)-[(5-Chloro-1H-pyrrolo[2,3-b]pyridine-2-carbonyl)amino]-3-(4-fluoroph-
enyl)-propionic acid tert-butyl ester
[0553] ##STR423##
[0554] To a solution of
5-chloro-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid (Preparation
57, 500 mg, 2.54 mmol) in DMF (20 mL) was added
2-(S)-amino-3-(4-fluorophenyl)propionic acid tert-butyl ester
hydrochloride (Preparation 114, 701 mg, 2.54 mmol), HOBt (344 mg,
2.54 mmol) and DIPEA (1.4 mL, 7.88 mmol). After 5 min, EDCI (634
mg, 3.31 mmol) was added and the reaction mixture stirred at rt for
72 h. The solvent was removed in vacuo and the solid partitioned
between water (50 mL) and ethyl acetate (3.times.40 mL). The
combined organic phase was washed with brine (20 mL), dried
(MgSO.sub.4), concentrated in vacuo and purified by chromatography
on silica gel eluting with methanol:dichloromethane (1:99) to give
the title compound. .delta..sub.H (CD.sub.3OD): 1.42 (9H, s), 3.09
(1H, dd), 3.22 (1H, dd), 4.76 (1H, m), 6.98 (2H, m), 7.07 (11H, s),
7.27 (2H, m), 8.06 (1H, d), 8.28 (1H, d); m/z (ES.sup.+)=418
[M+H].sup.+.
EXAMPLE 282
2-(S)-[(5-Chloro-1H-pyrrolo[2,3-b]pyridine-2-carbonyl)amino]-3-(4-fluoroph-
enyl)-propionic acid
[0555] ##STR424##
[0556] Trifluoroacetic acid (1.9 mL, 24.3 mmol) was added to a
suspension of
2-(S)-[(5-chloro-1H-pyrrolo[2,3-b]pyridine-2-carbonyl)amino]-3-(4-fluo-
rophenyl)-propionic acid tert-butyl ester (EXAMPLE 281, 507 mg,
1.21 mmol) in DCM (25 mL) and the reaction mixture was stirred at
rt for 16 h. Further trifluoroacetic acid (2 mL) was added and the
reaction was stirred at rt for 48 h. The solvent was removed in
vacuo and the solid partitioned between 1N hydrochloric acid (50
mL) and ethyl acetate (3.times.30 mL). The combined organic
fractions were washed with brine (20 mL), dried (MgSO.sub.4) and
concentrated in vacuo to give the title compound. .delta..sub.H
(CD.sub.3OD): 3.11 (1H, dd), 3.33 (1H, dd), 4.88 (1H, m), 6.97 (2H,
m), 7.06 (1H, s), 7.28 (2H, m), 8.08 (1H, d), 8.29 (1H, d); m/z
(ES.sup.+)=362 [M+H].sup.+; RT=3.67 min.
EXAMPLE 283
5-Chloro-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid
[1-(S)-(4-fluoro-benzyl)-2-(3-hydroxy-pyrrolidin-1-yl)-2-oxo-ethyl]-amide
[0557] ##STR425##
[0558] To a solution of
5-chloro-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid (Preparation
57, 34 mg, 0.17 mmol) in DMF (5 mL) was added
2-(S)-amino-3-(4-fluorophenyl)-1-(3-(S)-hydroxypyrrolidin-1-yl)propan-1-o-
ne hydrochloride (Preparation 103, 50 mg, 0.17 mmol), HOBt (23 mg,
0.17 mmol) and DIPEA (94 .mu.L, 0.54 mmol). After 5 min, EDCI (43
mg, 0.23 mmol) was added and the reaction stirred at rt for 16 h.
The solvent was removed in vacuo and the residue partitioned
between water (25 mL) and ethyl acetate (3.times.20 mL). The
combined organic layer was washed with 2N sodium hydroxide solution
(2.times.10 mL), brine (10 mL), dried (MgSO.sub.4) and concentrated
in vacuo. Purification via chromatography on silica gel eluting
with methanol:dichloromethane (7:93) gave the title compound. m/z
(ES.sup.+)=431 [M +H].sup.+; RT=3.49 min.
EXAMPLE 284
5-Chloro-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid
(2-oxo-2-phenylethyl)amide
[0559] ##STR426##
[0560] 5-Chloro-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid
(Preparation 57, 50 mg, 0.25 mmol), 2-aminoacetophenone
hydrochloride (48 mg, 0.28 mmol) and DMTMM (85 mg, 0.31 mmol) were
dissolved in THF (5 mL) and 4-methylmorpholine (31 .mu.L, 0.28
mmol). The reaction mixture was stirred at rt for 16 h. The solvent
was removed in vacuo and the residue partitioned between water (20
mL) and EtOAc (3.times.20 mL). The combined organics were dried
(MgSO.sub.4), concentrated in vacuo and purified by chromatography
on silica gel eluting with methanol:dichloromethane (1:19) to give
the title compound. m/z (ES.sup.+)=314 [M+H].sup.+; RT=3.47
min.
EXAMPLE 285
5-Chloro-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid
[2-(S)-(4-fluorophenyl)-1-(methoxymethylcarbamoyl)ethyl]amide
[0561] ##STR427##
[0562]
2-(S)-[(5-Chloro-1H-pyrrolo[2,3-b]pyridine-2-carbonyl)amino]-3-(4--
fluorophenyl)propionic acid (EXAMPLE 282, 300 mg, 0.08 mmol) and
N,O-dimethylhydroxylamine hydrochloride (8 mg, 0.08 mmol) were
dissolved in THF (5 mL) and 4-methylmorpholine (9 .mu.L, 0.08
mmol). To this was added DMTMM (28 mg, 0.10 mmol) and the reaction
mixture was stirred at rt for 16 h. The solvent was removed in
vacuo and the residue partitioned between water (30 mL) and EtOAc
(3.times.30 mL). The combined organics were washed with 2N sodium
hydroxide solution (2.times.20 ml), brine (20 ml), dried
(MgSO.sub.4) and concentrated in vacuo. The crude residue was
purified by chromatography on silica gel eluting with
methanol:dichloromethane (1:24) to give the title compound. m/z
(ES.sup.+)=405 [M+H].sup.+; RT=3.69 min.
EXAMPLE 286
5-Chloro-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid
[1-(S)-(4-fluorobenzyl)-2-(3-hydroxy-pyrrolidin-1-yl-2-oxo-ethyl]-amide
[0563] ##STR428##
[0564] To a solution of
2-(S)-[(5-chloro-1H-pyrrolo[2,3-b]pyridine-2-carbonyl)amino]-3-(4-fluorop-
henyl)propionic acid (EXAMPLE 286, 30 mg, 0.08 mmol) in DMF (3 mL)
was added (R)-(+)-3-hydroxypyrrolidine (7.2 mg, 0.08 mmol), HOBt
(11.2 mg, 0.08 mmol) and DIPEA (30.3 .mu.L, 0.17 mmol). After 5
min, EDCI (20.7 mg, 0.11 mmol) was added and the reaction was
stirred at rt for 16 h. The solvent was removed in vacuo and the
residue partitioned between water (20 mL) and ethyl acetate
(3.times.20 mL). The combined organic fractions were washed with 2N
sodium hydroxide solution (20 mL), brine (20 mL), dried
(MgSO.sub.4) and concentrated in vacuo. The crude product was
triturated from methanol to give the title compound. m/z
(ES.sup.+)=431 [M+H]+; RT=3.44 min.
EXAMPLES 287-294
[0565] ##STR429##
[0566] The following compounds were prepared according to the
method of EXAMPLE 286 from
2-(S)-[(5-chloro-1H-pyrrolo[2,3-c]pyridine-2-carbonyl)amino]-3-(4-fluorop-
henyl)propionic acid (EXAMPLE 282) and the appropriate amine, with
the exception that all compounds were purified by mass directed
purification. TABLE-US-00017 Example NR.sup.1R.sup.2 m/z RT (min)
287 ##STR430## 431 3.47 288 ##STR431## 444 2.89 289 ##STR432## 405
3.20 290 ##STR433## 474 2.92 291 ##STR434## 472 3.37 292 ##STR435##
445 3.61 293 ##STR436## 433 3.51 294 ##STR437## 433 3.34
EXAMPLE 295
6-Chloro-1H-pyrrolo[3,2-c]pyridine-2-carboxylic acid
(1-dimethylcarbamoyl-2-(S)-phenylethyl)amide
[0567] ##STR438##
[0568] To a solution of
6-chloro-1H-pyrrolo[3,2-c]pyridine-2-carboxylic acid (Preparation
116, 47 mg, 0.24 mmol) in DMF (5 mL, anhydrous) was added
2-(S)-amino-N,N-dimethyl-3-phenylpropionamide hydrochloride
(Preparation 8, 56 mg, 0.25 mmol), DIPEA (131 .mu.L, 0.75 mmol) and
HOBt (40 mg, 0.26 mmol) sequentially. The solution was stirred for
5 min prior to the addition of EDCI (55 mg, 0.29 mmol) in one
portion. The resulting solution was stirred for 12 h at rt. The
reaction mixture was partitioned between ethyl acetate (50 mL) and
water/brine (150 mL, 1:1). The layers were separated and the
aqueous phase extracted with ethyl acetate (3.times.50 mL), then
the combined organics were washed with dilute HCl solution (1M, 50
mL), dilute NaOH solution (1M, 50 mL) and brine (50 mL). The
organic phase was dried (MgSO.sub.4), filtered and concentrated in
vacuo. Purification via flash column chromatography eluting with
toluene/acetone (3:1) gave the title compound. .delta..sub.H
(CDCl.sub.3): 2.88, 3.05 (6H, 2s), 3.18, 3.28 (2H, 2 dd), 5.41 (2H,
m), 7.02 (1H, s), 7.28-7.34 (6H, m), 8.17 (1H, d), 8.68 (1H, s),
10.58 (1H, br s); m/z (ES.sup.+)=371.13 [M+H].sup.+; RT=3.28
min.
EXAMPLE 296
6-Chloro-1H-pyrrolo [3,2-c]pyridine-2-carboxylic acid
[1-(S)-(4-fluorobenzyl)-2-(4-hydroxypiperidin-1-yl-2-oxoethyl]amide
[0569] ##STR439##
[0570] The title compound was prepared as outlined in EXAMPLE 295
from 6-chloro-1H-pyrrolo[3,2-c]pyridine-2-carboxylic acid
(Preparation 116) and
2-(S)-amino-3-(4-fluorophenyl)-1-(4-hydroxypiperidin-1-yl)propan-1-on-
e hydrochloride (Preparation 20). The product was purified by
chromatography on silica gel eluting with methanol/dichloromethane
(1:19) to give the title compound. .delta..sub.H (CD.sub.3OD):
1.16-1.88 (4H, 3m), 3.04-3.19 (4H, m), 3.69-4.16 (3H, 2m), 5.31
(1H, m), 7.00 (2H, m), 7.29 (3H, m), 7.42 (1H, s), 8.67 (11H, s);
m/z (ES.sup.+)=444.89 [M+H].sup.+; RT=3.27 min.
EXAMPLE 297
6-Chloro-1H-pyrrolo [3.2-c]pyridine-2-carboxylic acid
[1-(S)-(4-fluorobenzyl)-2-(3-(S)-hydroxypyrrolidin-1-yl)-2-oxoethyl]amide
[0571] ##STR440##
[0572] The title compound was prepared as outlined in EXAMPLE 295
from 6-chloro-1H-pyrrolo[3,2-c]pyridine-2-carboxylic acid
(Preparation 116) and
2-(S)-amino-3-(4-fluorophenyl)-1-(3-(S)-hydroxypyrrolidin-1-yl)propan-
-1-one hydrochloride (Preparation 103). The crude product was
recrystallised from ethyl acetate to give the title compound.
.delta..sub.H (CD.sub.3OD): 1.77-1.98 (2H, m), 3.08-3.88 (6H, 6m),
4.30, 4.42 (1H, 2m), 5.07, 5.09 (1H, 2m), 7.00 (2H, m), 7.30 (3H,
m), 7.43 (1H, m), 8.67 (1H, s); m/z (ES.sup.+)=430.90 [M+H].sup.+;
RT=3.29 min.
EXAMPLE 298
5-Cyano-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid
(2-oxo-2-phenylethyl)amide
[0573] ##STR441##
[0574] To a solution of
5-cyano-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid (Preparation
62, 0.035 g, 0.19 mmol) in THF (15 mL) under argon was added
2-aminoacetophenone hydrochloride (0.036 g, 0.21 mmol),
N-methylmorpholine (25 .mu.M, 0.23 mmol) and DMTMM (0.072 g, 0.27
mmol). The reaction mixture was stirred at rt for 16 h. The
reaction mixture was concentrated to dryness in vacuo. The residue
was partitioned between ethyl acetate (100 mL) and water (50 mL).
The organic phase was separated and the aqueous phase was further
extracted with ethyl acetate (100 mL). The combined organic extract
was washed with 1N NaOH (40 mL), saturated sodium chloride (40 mL),
dried (MgSO.sub.4), filtered and concentrated in vacuo. Crude
material was purified by chromatography in hexane/ethyl acetate
(1:2) and recrystallised from methanol to give the title compound.
m/z (ES.sup.+)=304 [M+H].sup.+; RT=4.37.
EXAMPLE 299
2-[(5-Cyano-1H-pyrrolo[2,3-c]pyridine-2-carbonyl)amino]-3
(S)-(4-fluorophenyl)propionic acid ethyl ester
[0575] ##STR442##
[0576] To a solution of 2-amino-3-(S)-(4-fluorophenyl)propionic
acid ethyl ester hydrochloride (0.530 g, 2.14 mmol) in DMF (15 mL)
was added DIPEA (1.3 mL, 7.49 mmol), HOBt (0.290 g, 2.14 mmol),
5-cyano-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid (Preparation
62, 0.400 g, 2.14 mmol) and EDCI (0.492 g, 2.57 mmol).
[0577] The reaction mixture was stirred at rt for 16 h. Reaction
mixture was concentrated in vacuo and the residue was partitioned
between water (150 mL) and ethyl acetate (200 mL). Organic phase
was separated and the aqueous phase was further extracted with
ethyl acetate (200 mL). The combined organic extracts were washed
with saturated NaHCO.sub.3 (75 mL), saturated sodium chloride (100
mL), dried (MgSO.sub.4), filtered and concentrated in vacuo to give
the title compound. m/z (ES.sup.+)=381 [M+H].sup.+; RT=4.79
min.
EXAMPLE 300
2-[(5-Cyano-1H-pyrrolo[2,3-c]pyridine-2-carbonyl)aminol-3-(S)-(4-fluorophe-
nyl)propionic acid
[0578] ##STR443##
[0579] To a solution
of2-[(5-cyano-1H-pyrrolo[2,3-c]pyridine-2-carbonyl)amino]-3-(S)-(4-fluoro-
phenyl)propionic acid ethyl ester (EXAMPLE 299, 0.800 g, 2.1 mmol)
in methanol/water (2:1) was added 1N NaOH (4.2 mL, 4.2 mmol) and
stirred at rt for 16 h. Reaction mixture was concentrated in vacuo
to remove methanol. Water (150 mL) was added to the residue and
washed with ethyl acetate (2.times.75 ml). The aqueous phase was
cooled in an ice bath and acidified to pH 4 using 2N HCl. The
precipitate formed was isolated and washed with water and ether to
give the title compound. m/z (ES.sup.+)=353 [M+H].sup.+; RT=3.27
min.
EXAMPLE 301
5-Cyano-1H-pyrrolo[2.3-c]pyridine-2-carboxylic acid
[1-dimethylcarbamoyl-2-(S)-(4-fluorophenyl)ethyl]amide
[0580] ##STR444##
[0581] To a solution of N-dimethylamine hydrochloride (0.006 g,
0.07 mmol) in DMF (6 mL) was added DIPEA (37 .mu.L, 0.21 mmol),
HOBt (0.009 g, 0.07 mmol),
2-[(5-cyano-1H-pyrrolo[2,3-c]pyridine-2-carbonyl)amino]-3-(5)-(4-fluoroph-
enyl)propionic acid (EXAMPLE 300, 0.025 g, 0.07 mmol) and EDCI
(0.016 g, 0.084 mmol). The reaction mixture was stirred at rt for
16 h then concentrated in vacuo and the residue was partitioned
between water (50 mL) and ethyl acetate (100 mL). The organic phase
was separated and the aqueous phase was further extracted with
ethyl acetate (100 mL). The combined organic extracts were washed
with saturated NaHCO.sub.3 (50 mL), saturated sodium chloride (75
mL), dried (MgSO.sub.4), filtered and concentrated in vacuo to give
the title compound. m/z (ES+)=380; RT=3.45.
EXAMPLES 302-307
[0582] ##STR445##
[0583] The following compounds were prepared according to the
method of EXAMPLE 301 from
2-[(5-cyano-1H-pyrrolo[2,3-c]pyridine-2-carbonyl)amino]-3-(S)-(4-fluoroph-
enyl)propionic acid (EXAMPLE 300) and the appropriate amine.
TABLE-US-00018 Example Amine m/z RT (min) 302 ##STR446## 422 3.36
303 ##STR447## 422 3.32 304 ##STR448## 420 3.92 305 ##STR449## 422
3.44 306 ##STR450## 420 3.72 307 ##STR451## 449 3.26
In Vitro GP Activity Materials
[0584] .alpha.-D-Glucose-1-phosphate (disodium salt), Glycogen,
D-Glucose, Malachite Green Hydrochloride, Ammonium Molybdate
tetrahydrate, BSA, HEPES and rabbit muscle phosphorylase a (P1261)
were purchased from Sigma. All other reagents were analytical
grade.
Method
Glycogen Phosphorylase Assay in vitro:
[0585] An assay for glycogen phosphorylase activity in the reverse
direction was developed based on the method described by Engers et
al., Can. J. Biochem., 1970, 48, 746-754]. Rabbit muscle glycogen
phosphorylase a (Sigma) was reconstituted at a stock concentration
of 100 .mu.g/mL in 25 mM Tris/HCl. The pH was measured in a 96-well
plate in a final volume of 100 .mu.L containing 50 mM Hepes pH 7.2,
7.5 mM glucose 0.5 mM glucose-1-phosphate and 1 mg/mL glycogen.
After incubation at 3020 C. for 30 min, the inorganic phosphate
released from glucose-1-phosphate was measured by the addition of
150 .mu.L of malachite green/molybdate solution prepared as
follows: 5 mL of 4.2% ammonium molybdate in 4N HCl, 15 mL of 0.045%
malachite green, 50 .mu.L of Tween 20. Following a 30 min
incubation at rt, the absorbance was measured at 620 nm. For
IC.sub.50 determination, 10 .mu.L of a serial dilution of compound
(100 .mu.M to 0.004 .mu.M) in DMSO was added to each reaction in
duplicate with the equivalent concentration of DMSO added to the
control uninhibited reaction. Dose response curves were then
obtained by plotting % inhibition versus log.sub.10 compound
concentration. IC.sub.50 is defined as the concentration of
compound achieving 50% inhibition under the assay conditions
described.
[0586] The EXAMPLES have an IC.sub.50 of <1 mM. For example,
EXAMPLES 1-20, 22, 27, and 30-48 demonstrated efficacy by measuring
values of IC.sub.50 in the range of 62.8-0.07 .mu.M. Examples 21,
23-26, 28, and 29 yielded IC.sub.50 100 .mu.M or higher. It is
advantageous that the measured IC.sub.50 be lower than 100 .mu.M.
It is still more advantageous for the IC.sub.50 to be lower than 50
.mu.M. It is even more advantageous for the IC.sub.50 to be lower
than 5 .mu.M. It is yet more advantageous for the IC.sub.50 to be
lower than 0.5 .mu.M.
* * * * *