U.S. patent application number 15/477984 was filed with the patent office on 2017-07-20 for (1-azinone)-substituted pyridoindoles.
The applicant listed for this patent is Albany Molecular Research, Inc.. Invention is credited to James GRABOWSKI, Peter GUZZO, Mark HADDEN, Alan John HENDERSON, May Xiaowu JIANG, Matthew David SURMAN, Alexander USYATINSKY.
Application Number | 20170204095 15/477984 |
Document ID | / |
Family ID | 40429805 |
Filed Date | 2017-07-20 |
United States Patent
Application |
20170204095 |
Kind Code |
A1 |
GUZZO; Peter ; et
al. |
July 20, 2017 |
(1-AZINONE)-SUBSTITUTED PYRIDOINDOLES
Abstract
Substituted pyridoindoles for incorporation in pharmaceutical
compositions employed in the treatment of various diseases
correspond to formula (I) ##STR00001## wherein R.sup.1 is H or
optionally substituted alkyl; R.sup.2, R.sup.3, R.sup.4 are each
independently selected from H, --O-alkyl, --S-alkyl, alkyl, halo,
--CF.sub.3, and --CN; G is --CR.sup.12R.sup.13--NR.sup.5-- or
--NR.sup.5--CR.sup.12R.sup.13; R.sup.5 is H, optionally substituted
alkyl, optionally substituted heterocycle, --C(.dbd.O)--R.sup.6,
--C(.dbd.O)--O--R.sup.7, or --C(.dbd.O)--NR.sup.19R.sup.20; R.sup.6
and R.sup.7 are each optionally substituted alkyl or optionally
substituted heterocycle; R.sup.8, R.sup.9, R.sup.10, R.sup.11,
R.sup.12, R.sup.13, R.sup.19 and R.sup.20 are each independently
selected from H or optionally substituted alkyl; R.sup.14 and
R.sup.15 are each independently H or halogen; L is --CH.sub.2--O--,
--CH.sub.2CH.sub.2--, --CH.dbd.CH-- or a bond; and B is aryl or
heteroaryl or cycloalkyl; with the proviso that, when L is a direct
bond, B cannot be unsubstituted heteroaryl or heteroaryl
monosubstituted with fluorine.
Inventors: |
GUZZO; Peter; (Niskayuna,
NY) ; SURMAN; Matthew David; (Albany, NY) ;
HENDERSON; Alan John; (Albany, NY) ; JIANG; May
Xiaowu; (Guilderland, NY) ; HADDEN; Mark;
(Albany, NY) ; GRABOWSKI; James; (Castleton on
Hudson, NY) ; USYATINSKY; Alexander; (Troy,
NY) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Albany Molecular Research, Inc. |
Albany |
NY |
US |
|
|
Family ID: |
40429805 |
Appl. No.: |
15/477984 |
Filed: |
April 3, 2017 |
Related U.S. Patent Documents
|
|
|
|
|
|
Application
Number |
Filing Date |
Patent Number |
|
|
15045652 |
Feb 17, 2016 |
9650378 |
|
|
15477984 |
|
|
|
|
14223151 |
Mar 24, 2014 |
9296743 |
|
|
15045652 |
|
|
|
|
12351561 |
Jan 9, 2009 |
8716308 |
|
|
14223151 |
|
|
|
|
61020530 |
Jan 11, 2008 |
|
|
|
61048677 |
Apr 29, 2008 |
|
|
|
Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61P 25/22 20180101;
C07D 521/00 20130101; A61P 3/06 20180101; A61P 25/24 20180101; A61P
3/10 20180101; C07D 519/00 20130101; A61P 3/04 20180101; A61P 9/10
20180101; A61P 1/16 20180101; C07D 471/04 20130101; A61P 43/00
20180101; A61P 35/00 20180101 |
International
Class: |
C07D 471/04 20060101
C07D471/04; C07D 519/00 20060101 C07D519/00 |
Claims
1. A compound of formula I: ##STR00552## wherein R.sup.1 is H or
optionally substituted alkyl; R.sup.2, R.sup.3, R.sup.4 are each
independently selected from H, --O-alkyl, --S-alkyl, alkyl, halo,
--CF.sub.3, and --CN; G is --CR.sup.12R.sup.13--NR.sup.5-- or
--NR.sup.5--CR.sup.12R.sup.13; R.sup.5 is H, optionally substituted
alkyl, optionally substituted heterocycle, --C(.dbd.O)--R.sup.6,
--C(.dbd.O)--O--R.sup.7, or --C(.dbd.O)--NR.sup.19R.sup.20; R.sup.6
and R.sup.7 are each optionally substituted alkyl or optionally
substituted heterocycle; R.sup.8, R.sup.9, R.sup.10, R.sup.11,
R.sup.12, R.sup.13, R.sup.19 and R.sup.20 are each independently
selected from H or optionally substituted alkyl; R.sup.14 and
R.sup.15 are each independently H or halogen; Y is N; L is
--CH.sub.2--O--, --CH.sub.2CH.sub.2--, --CH.dbd.CH-- or a bond; and
B is aryl or heteroaryl or cycloalkyl; with the proviso that, when
L is a direct bond, B cannot be unsubstituted heteroaryl or
heteroaryl monosubstituted with fluorine.
2. A method of treating a disease or condition which is susceptible
to treatment with an MCH.sub.1 receptor modulator, comprising
administering to a patient in need thereof a therapeutically
effective amount of a compound according to claim 1.
Description
[0001] This application is a continuation of U.S. patent
application Ser. No. 15/045,652, filed Feb. 17, 2016, which is a
divisional of U.S. patent application Ser. No. 14/223,151, filed
Mar. 24, 2014, which is a divisional of U.S. patent application
Ser. No. 12/351,561, filed Jan. 9, 2009, which claims priority of
U.S. Provisional Patent Application Ser. No. 61/020,530, filed Jan.
11, 2008, and U.S. Provisional Patent Application Ser. No.
61/048,677, filed Apr. 29, 2008, which are hereby incorporated by
reference in their entirety.
FIELD OF THE INVENTION
[0002] The invention relates to human melanin-concentrating hormone
(MCH.sub.1) receptor-selective antagonists substituted
pyridoindoles that are useful for treating obesity, to
pharmaceutical compositions comprising these compounds, and to
methods for the treatment of obesity, anxiety, depression, and
psychiatric disorders in a mammal.
BACKGROUND OF THE INVENTION
[0003] Obesity and the multitude of co-morbidities associated with
obesity such as diabetes, dyslipidemia, coronary heart disease, and
certain cancers are a major concern for public health. The
currently available pharmaceutical therapies for the treatment of
obesity have limited efficacy and side effects that limit their
use. Thus, there is a significant medical need for better
pharmacotherapy for obesity.
[0004] Melanin-concentrating hormone (MCH) has been identified as
an orexigenic peptide that exerts an effect on food intake and body
weight regulation. MCH is a cyclic 19 amino acid neuropeptide
expressed in the zona incerta and lateral hypothalamus in response
to both energy restriction and leptin deficiency. MCH is known to
stimulate feeding when injected into the lateral ventricle of rats
and the mRNA for MCH is upregulated in the hypothalamus of
genetically obese mice (ob/ob) and in fasted control and ob/ob
animals. In addition, animals treated with MCH show increases in
glucose, insulin and leptin levels, mimicking human metabolic
syndrome (Gomori, A. Chronic infusion of MCH causes obesity in mice
Am. J. Physiol. Endocrinol. Metab. 284, E583, 2002). Mice lacking
MCH are hypophagic and lean with increased metabolic rate, whereas
animals over-expressing MCH gain excess weight on both standard and
high fat diets. MCH is thought to have effects on other nervous
system functions as well (Rocksz, L. L. Biological Examination of
Melanin Concentrating Hormone 1: Multi-tasking from the
hypothalamus Drug News Perspect 19(5), 273, 2006). An orphan
G-protein coupled receptor (GPCR) was recently identified as a
receptor for MCH. Disruption of the binding between MCH and the MCH
receptor, i.e. MCH antagonism, may thus be used to counteract the
effects of MCH (McBriar, M. D. Recent advances in the discovery of
melanin-concentrating hormone receptor antagonists Curr. Opin. Drug
Disc. & Dev. 9(4), 496, 2006).
SUMMARY OF THE INVENTION
[0005] In accordance the present invention, there is provided a
compound of formula (I)
##STR00002##
wherein R.sup.1 is H or optionally substituted alkyl; R.sup.2,
R.sup.3, R.sup.4 are each independently selected from H, --O-alkyl,
--S-alkyl, alkyl, halo, --CF.sub.3, and --CN; G is
--CR.sup.12R.sup.13--NR.sup.5-- or --NR.sup.5--CR.sup.12R.sup.13;
R.sup.5 is H, optionally substituted alkyl, optionally substituted
heterocycle, --C(.dbd.O)--R.sup.6, --C(.dbd.O)--O--R.sup.7, or
--C(.dbd.O)--NR.sup.19R.sup.20; R.sup.6 and R.sup.7 are each
optionally substituted alkyl or optionally substituted heterocycle;
R.sup.8, R.sup.9, R.sup.10, R.sup.11, R.sup.12, R.sup.13, R.sup.19
and R.sup.20 are each independently selected from H or optionally
substituted alkyl; R.sup.14 and R.sup.15 are each independently H
or halogen;
Y is CH or N;
[0006] L is --CH.sub.2--O--, --CH.sub.2CH.sub.2--, --CH.dbd.CH-- or
a bond; and B is aryl or heteroaryl or cycloalkyl; with the proviso
that, when L is a direct bond, B cannot be unsubstituted heteroaryl
or heteroaryl monosubstituted with fluorine.
DETAILED DESCRIPTION OF THE INVENTION
[0007] In accordance with the present invention, compounds
represented by formula (I) above may be substituted derivatives
either of tetrahydro-.beta.-carboline, where G is
--CR.sup.12R.sup.13--NR.sup.5--, or of tetrahydro-7-carboline,
where G is --NR.sup.5--CR.sup.12R.sup.13--. In some embodiments of
the invention, G is --CH.sub.2--NR.sup.5--; in other embodiments, G
is --NR.sup.5--CH.sub.2--.
[0008] In accordance with some embodiments of the invention,
R.sup.1 is H.
[0009] In accordance with other embodiments of the invention,
R.sup.1 is alkyl, for example, methyl or ethyl.
[0010] In accordance with some embodiments of the invention,
R.sup.5 is H. In other embodiments, R.sup.5 is optionally
substituted alkyl. In some embodiments, R.sup.5 is selected from
methyl, ethyl, 2-propyl, 2-hydroxyethyl, 2,2,2-trifluoroethyl,
3,3,3-trifluoropropyl, 2-oxo-2-(pyrrolidin-1-yl)ethyl,
2-(pyrrolidin-1-yl)ethyl and (S)-pyrrolidin-2-ylmethyl. In other
embodiments, R.sup.5 is optionally substituted heterocycle. In some
embodiments, R.sup.5 is selected from piperidin-4-yl and
1-methylpiperidin-4-yl. In other embodiments, R.sup.5 is
--C(.dbd.O)--R.sup.6. In other embodiments, R.sup.5 is
--C(.dbd.O)--O--R.sup.7.
[0011] In some embodiments, R.sup.6 and R.sup.7 are each optionally
substituted alkyl, for example, methyl, 2-propyl,
2-(pyrrolidin-1-yl)-ethyl, pyrrolidin-1-ylmethyl, and
dimethylaminomethyl. In some embodiments, R.sup.6 is optionally
substituted heterocycle, for example, pyrrolidin-3-yl,
(R)-pyrrolidin-2-yl, (S)-pyrrolidin-2-yl, 1-methylpyrrolidin-3-yl,
(R)-1-methylpyrrolidin-2-yl and (S)-1-methylpyrrolidin-2-yl.
[0012] In accordance with some embodiments of the invention, the
compound has the structure
##STR00003##
[0013] In accordance with other embodiments of the invention, the
compound has the structure
##STR00004##
[0014] In accordance with some embodiments of the invention, the L
is a bond. In accordance with other embodiments of the invention, L
is --CH.sub.2--O--. In accordance with some embodiments of the
invention, L is --CH.sub.2CH.sub.2--. In accordance with other
embodiments of the invention, L is --CH.dbd.CH--.
[0015] In accordance with some embodiments of the invention, B is
aryl, for example, phenyl. In accordance with other embodiments of
the invention, B is heteroaryl, for example, pyridinyl. In some
embodiments, B is pyridin-2-yl or pyridin-3-yl. In other
embodiments, B is pyridazinyl, for example, pyridazin-3-yl. In some
other embodiments, B is pyrimidinyl, for example, pyrimidin-5-yl or
pyrimidin-2-yl. In accordance with other embodiments of the
invention, B is cycloalkyl, for example, cyclohexyl.
[0016] In accordance with some embodiments of the invention,
R.sup.2, R.sup.3 and R.sup.4 are each H. In accordance with other
embodiments of the invention, two of R.sup.2, R.sup.3 and R.sup.4
are H, and the other of R.sup.2, R.sup.3 and R.sup.4 is selected
from trifluoromethyl, chloro, fluoro, methyl, methoxy and
methanethio.
[0017] In accordance with other embodiments of the invention, one
of R.sup.2, R.sup.3 and R.sup.4 is H, another of R.sup.2, R.sup.3
and R.sup.4 is Cl, and the third of R.sup.2, R.sup.3 and R.sup.4 is
F, Cl or methoxy. In accordance with other embodiments of the
invention, one of R.sup.2, R.sup.3 and R.sup.4 is H, another of
R.sup.2, R.sup.3 and R.sup.4 is F, and the third of R.sup.2,
R.sup.3 and R.sup.4 is methoxy. In accordance with other
embodiments of the invention, one of R.sup.2, R.sup.3 and R.sup.4
is H, another of R.sup.2, R.sup.3 and R.sup.4 is methoxy, and the
third of R.sup.2, R.sup.3 and R.sup.4 is methyl.
[0018] In accordance with some embodiments of the invention, B,
together with R.sup.2, R.sup.3 and R.sup.4, is selected from
phenyl, 4-trifluoromethylphenyl, 4-chlorophenyl,
2,4-dichlorophenyl, 4-fluorophenyl, 4-chloro-2-fluorophenyl,
2-fluoro-4-methoxyphenyl, pyridin-2-yl, 5-chloropyridin-2-yl,
5-(trifluoromethyl)pyridin-2-yl, 5-fluoropyridin-2-yl,
6-(trifluoromethyl)pyridazin-3-yl, 6-methylpyridazin-3-yl,
4-fluoro-2-methoxyphenyl, 6-(trifluoromethyl)pyridin-3-yl,
2-(trifluoromethyl)pyrimidin-5-yl,
5-(trifluoromethyl)pyrimidin-2-yl, 5-methylpyridin-2-yl,
6-methylpyridin-3-yl, cyclohexyl, 4-chloro-2-methoxyphenyl,
pyrimidin-2-yl, imidazo[1,2-a]pyridin-6-yl,
imidazo[1,2-a]pyridin-2-yl, 4-methoxyphenyl, 4-methanethiophenyl
and 4-methoxy-2-methylphenyl.
[0019] In accordance with some embodiments of the invention, at
least one of R.sup.8, R.sup.9, R.sup.10, R.sup.11, R.sup.12,
R.sup.13, R.sup.19 and R.sup.20 is H. In other embodiments, at
least one of R.sup.8, R.sup.9, R.sup.10, R.sup.11, R.sup.12,
R.sup.13, R.sup.19 and R.sup.20 is optionally substituted alkyl,
for example, methyl, ethyl, or hydroxymethyl.
[0020] In accordance with some embodiments of the invention, the
compound is selected from
##STR00005## ##STR00006## ##STR00007## ##STR00008## ##STR00009##
##STR00010## ##STR00011## ##STR00012## ##STR00013## ##STR00014##
##STR00015## ##STR00016## ##STR00017## ##STR00018## ##STR00019##
##STR00020## ##STR00021## ##STR00022## ##STR00023## ##STR00024##
##STR00025## ##STR00026## ##STR00027## ##STR00028## ##STR00029##
##STR00030## ##STR00031## ##STR00032## ##STR00033##
##STR00034##
[0021] In accordance with some embodiments of the invention, the
compound is a pharmaceutically acceptable salt thereof. In some
embodiments, the salt is an HCl salt.
[0022] There is also provided, in accordance with embodiments of
the invention, a pharmaceutical composition comprising a compound
as described herein, and a pharmaceutically acceptable carrier,
excipient or diluent therefore.
[0023] There is also provided, in accordance with embodiments of
the invention, a method of treating obesity, comprising
administering to a patient in need of obesity reduction an
obesity-reducing effective amount of a compound as described
herein.
[0024] There is also provided, in accordance with embodiments of
the invention, a method of treating anxiety, comprising
administering to a patient in need of such treatment a
therapeutically effective amount of a compound as described
herein.
[0025] There is also provided, in accordance with embodiments of
the invention, a method of treating depression, comprising
administering to a patient in need of such treatment a
therapeutically effective amount of a compound as described
herein.
[0026] There is also provided, in accordance with embodiments of
the invention, a method of treating non-alcoholic fatty liver
disease, comprising administering to a patient in need of such
treatment a therapeutically effective amount of a compound as
described herein.
[0027] There is also provided, in accordance with embodiments of
the invention, a method of treating a disease or condition which is
susceptible to treatment with an MCH.sub.1 receptor modulator,
comprising administering to a patient in need thereof a
therapeutically effective amount of a compound as described
herein.
Definitions
[0028] Throughout this specification the terms and substituents
retain their definitions.
[0029] Alkyl is intended to include linear, branched, or cyclic
hydrocarbon structures and combinations thereof. When not otherwise
restricted, the term refers to alkyl of 20 or fewer carbons. Lower
alkyl refers to alkyl groups of 1, 2, 3, 4, 5 and 6 carbon atoms.
Examples of lower alkyl groups include methyl, ethyl, propyl,
isopropyl, butyl, s- and t-butyl and the like. Cycloalkyl is a
subset of alkyl and includes cyclic hydrocarbon groups of 3, 4, 5,
6, 7, and 8 carbon atoms. Examples of cycloalkyl groups include
c-propyl, c-butyl, c-pentyl, norbornyl, adamantyl and the like.
[0030] C.sub.1 to C.sub.20 Hydrocarbon (e.g. C.sub.1, C.sub.2,
C.sub.3, C.sub.4, C.sub.5, C.sub.6, C.sub.7, C.sub.8, C.sub.9,
C.sub.10, C.sub.11, C.sub.12, C.sub.13, C.sub.14, C.sub.15,
C.sub.16, C.sub.17, C.sub.18, C.sub.19, C.sub.20) includes alkyl,
cycloalkyl, alkenyl, alkynyl, aryl and combinations thereof.
Examples include benzyl, phenethyl, cyclohexylmethyl, camphoryl and
naphthylethyl. The term "phenylene" refers to ortho, meta or para
residues of the formulae:
##STR00035##
[0031] Alkoxy or alkoxyl refers to groups of 1, 2, 3, 4, 5, 6, 7 or
8 carbon atoms of a straight, branched, cyclic configuration and
combinations thereof attached to the parent structure through an
oxygen. Examples include methoxy, ethoxy, propoxy, isopropoxy,
cyclopropyloxy, cyclohexyloxy and the like. Lower-alkoxy refers to
groups containing one to four carbons. For the purposes of the
present patent application alkoxy also includes methylenedioxy and
ethylenedioxy in which each oxygen atom is bonded to the atom,
chain or ring from which the methylenedioxy or ethylenedioxy group
is pendant so as to form a ring. Thus, for example, phenyl
substituted by alkoxy may be, for example,
##STR00036##
[0032] Oxaalkyl refers to alkyl residues in which one or more
carbons (and their associated hydrogens) have been replaced by
oxygen. Examples include methoxypropoxy, 3,6,9-trioxadecyl and the
like. The term oxaalkyl is intended as it is understood in the art
[see Naming and Indexing of Chemical Substances for Chemical
Abstracts, published by the American Chemical Society, 196, but
without the restriction of 127(a)], i.e. it refers to compounds in
which the oxygen is bonded via a single bond to its adjacent atoms
(forming ether bonds). Similarly, thiaalkyl and azaalkyl refer to
alkyl residues in which one or more carbons have been replaced by
sulfur or nitrogen, respectively. Examples include ethylaminoethyl
and methylthiopropyl.
[0033] Acyl refers to groups of 1, 2, 3, 4, 5, 6, 7 and 8 carbon
atoms of a straight, branched, cyclic configuration, saturated,
unsaturated and aromatic and combinations thereof, attached to the
parent structure through a carbonyl functionality. One or more
carbons in the acyl residue may be replaced by nitrogen, oxygen or
sulfur as long as the point of attachment to the parent remains at
the carbonyl. Examples include formyl, acetyl, propionyl,
isobutyryl, t-butoxycarbonyl, benzoyl, benzyloxycarbonyl and the
like. Lower-acyl refers to groups containing one to four
carbons.
[0034] Aryl and heteroaryl refer to aromatic or heteroaromatic
rings, respectively, as substituents. Heteroaryl contains one, two
or three heteroatoms selected from O, N, or S. Both refer to
monocyclic 5- or 6-membered aromatic or heteroaromatic rings,
bicyclic 9- or 10-membered aromatic or heteroaromatic rings and
tricyclic 13- or 14-membered aromatic or heteroaromatic rings.
Aromatic 6, 7, 8, 9, 10, 11, 12, 13 and 14-membered carbocyclic
rings include, e.g., benzene, naphthalene, indane, tetralin, and
fluorene and the 5, 6, 7, 8, 9 and 10-membered aromatic
heterocyclic rings include, e.g., imidazole, pyridine, indole,
thiophene, benzopyranone, thiazole, furan, benzimidazole,
quinoline, isoquinoline, quinoxaline, pyrimidine, pyrazine,
tetrazole and pyrazole.
[0035] Arylalkyl means an alkyl residue attached to an aryl ring.
Examples are benzyl, phenethyl and the like.
[0036] Substituted alkyl, aryl, cycloalkyl, heterocyclyl etc. refer
to alkyl, aryl, cycloalkyl, or heterocyclyl wherein up to three H
atoms in each residue are replaced with alkyl, halogen, haloalkyl,
hydroxy, loweralkoxy, carboxy, carboalkoxy (also referred to as
alkoxycarbonyl), carboxamido (also referred to as
alkylaminocarbonyl), cyano, carbonyl, nitro, amino, alkylamino,
dialkylamino, mercapto, alkylthio, sulfoxide, sulfone, acylamino,
amidino, phenyl, benzyl, heteroaryl, phenoxy, benzyloxy, or
heteroaryloxy.
[0037] The term "halogen" means fluorine, chlorine, bromine or
iodine.
[0038] The term "prodrug" refers to a compound that is made more
active in vivo. Commonly the conversion of prodrug to drug occurs
by enzymatic processes in the liver or blood of the mammal. Many of
the compounds of the invention may be chemically modified without
absorption into the systemic circulation, and in those cases,
activation in vivo may come about by chemical action (as in the
acid-catalyzed cleavage in the stomach) or through the intermediacy
of enzymes and microflora in the gastrointestinal GI tract.
[0039] In the characterization of some of the substituents, it is
recited that certain substituents may combine to form rings. Unless
stated otherwise, it is intended that such rings may exhibit
various degrees of unsaturation (from fully saturated to fully
unsaturated), may include heteroatoms and may be substituted with
lower alkyl or alkoxy.
[0040] It will be recognized that the compounds of this invention
can exist in radiolabeled form, i.e., the compounds may contain one
or more atoms containing an atomic mass or mass number different
from the atomic mass or mass number usually found in nature.
Radioisotopes of hydrogen, carbon, phosphorous, fluorine, iodine
and chlorine include .sup.3H, .sup.14C, .sup.35S, .sup.18F,
.sup.32P, .sup.33P, .sup.125I, and .sup.36Cl, respectively.
Compounds that contain those radioisotopes and/or other
radioisotopes of other atoms are within the scope of this
invention. Radiolabeled compounds described herein and prodrugs
thereof can generally be prepared by methods well known to those
skilled in the art. Conveniently, such radiolabeled compounds can
be prepared by carrying out the procedures disclosed in the
Examples and Schemes by substituting a readily available
radiolabeled reagent for a non-radiolabeled reagent.
[0041] The terms "methods of treating or preventing" mean
amelioration, prevention or relief from the symptoms and/or effects
associated with lipid disorders. The term "preventing" as used
herein refers to administering a medicament beforehand to forestall
or obtund an acute episode or, in the case of a chronic condition
to diminish the likelihood or seriousness of the condition. The
person of ordinary skill in the medical art (to which the present
method claims are directed) recognizes that the term "prevent" is
not an absolute term. In the medical art it is understood to refer
to the prophylactic administration of a drug to substantially
diminish the likelihood or seriousness of a condition, and this is
the sense intended in applicants' claims. As used herein, reference
to "treatment" of a patient is intended to include prophylaxis.
[0042] Throughout this application, various references are referred
to. Each of the patents, patent applications, patent publications,
and references mentioned herein is hereby incorporated by reference
in its entirety.
[0043] The term "mammal" is used in its dictionary sense. The term
"mammal" includes, for example, mice, hamsters, rats, cows, sheep,
pigs, goats, and horses, monkeys, dogs (e.g., Canis familiaris),
cats, rabbits, guinea pigs, and primates, including humans.
[0044] Compounds described herein may contain one or more
asymmetric centers and may thus give rise to enantiomers,
diastereomers, and other stereoisomeric forms. Each chiral center
may be defined, in terms of absolute stereochemistry, as (R)- or
(S)-. The present invention is meant to include all such possible
isomers, as well as mixtures thereof, including racemic and
optically pure forms. Optically active (R)- and (S)-, (-)- and
(+)-, or (D)- and (L)-isomers may be prepared using chiral synthons
or chiral reagents, or resolved using conventional techniques. When
the compounds described herein contain olefinic double bonds or
other centers of geometric asymmetry, and unless specified
otherwise, it is intended that the compounds include both E and Z
geometric isomers. The configuration of any carbon-carbon double
bond appearing herein is selected for convenience only and is not
intended to designate a particular configuration; thus a
carbon-carbon double bond depicted arbitrarily herein as E may be
Z, E, or a mixture of the two in any proportion. Likewise, all
tautomeric forms are also intended to be included.
[0045] As used herein, and as would be understood by the person of
skill in the art, the recitation of "a compound" is intended to
include salts, solvates and inclusion complexes of that compound as
well as any stereoisomeric form, or a mixture of any such forms of
that compound in any ratio. Thus, in accordance with some
embodiments of the invention, a compound as described herein,
including in the contexts of pharmaceutical compositions, methods
of treatment, and compounds per se, is provided as the salt form.
In accordance with some embodiments of the invention, the salt is a
hydrochloride salt.
[0046] The term "enantiomeric excess" is well known in the art and
is defined for a resolution of ab into a+b as
ee a = ( conc . of a - conc . of b conc . of a + conc . of b )
.times. 100 ##EQU00001##
[0047] The term "enantiomeric excess" is related to the older term
"optical purity" in that both are measures of the same phenomenon.
The value of ee will be a number from 0 to 100, zero being racemic
and 100 being pure, single enantiomer. A compound which in the past
might have been called 98% optically pure is now more precisely
described as 96% ee; in other words, a 90% ee reflects the presence
of 95% of one enantiomer and 5% of the other in the material in
question.
[0048] Terminology related to "protecting", "deprotecting" and
"protected" functionalities occurs throughout this application.
Such terminology is well understood by persons of skill in the art
and is used in the context of processes which involve sequential
treatment with a series of reagents. In that context, a protecting
group refers to a group which is used to mask a functionality
during a process step in which it would otherwise react, but in
which reaction is undesirable. The protecting group prevents
reaction at that step, but may be subsequently removed to expose
the original functionality. The removal or "deprotection" occurs
after the completion of the reaction or reactions in which the
functionality would interfere. Thus, when a sequence of reagents is
specified, as it is in the processes of the invention, the person
of ordinary skill can readily envision those groups that would be
suitable as "protecting groups". Suitable groups for that purpose
are discussed in standard textbooks in the field of chemistry, such
as Protective Groups in Organic Synthesis by T. W. Greene [John
Wiley & Sons, New York, 1991], which is incorporated herein by
reference. Particular attention is drawn to the chapters entitled
"Protection for the Hydroxyl Group, Including 1,2- and 1,3-Diols"
(pages 10-86).
[0049] The following abbreviations and terms have the indicated
meanings throughout: Ac=acetyl; Bu=butyl; c-=cyclo;
DIEA=N,N-diisopropylethyl amine; TEA=triethylamine; HOAc=acetic
acid; mesyl=methanesulfonyl; rt=room temperature; sat'd=saturated;
s-=secondary; t-=tertiary; TMS=trimethylsilyl;
tosyl=p-toluenesulfonyl; TFA=trifluoroacetic acid;
HATU=O-(7-azabenzotriazol-1-yl)-N,N,N'N'-tetramethyluronium
hexafluorophosphate. The abbreviations HPLC, THF, DCM and DMSO
represent high performance liquid chromatography, tetrahydrofuran,
dichloromethane and dimethylsulfoxide, respectively. The
abbreviations Me, Et, Ph, Tf, Ts, Boc and Ms represent methyl,
ethyl, phenyl, trifluoromethanesulfonyl, toluenesulfonyl,
butyloxycarbonyl and methanesulfonyl respectively. The term dppf
refers to 1,1'-Bis-(diphosphenylphosphino)ferrocene. A
comprehensive list of abbreviations utilized by organic chemists
(i.e. persons of ordinary skill in the art) appears in the first
issue of each volume of the Journal of Organic Chemistry. The list,
which is typically presented in a table entitled "Standard List of
Abbreviations" is incorporated herein by reference.
[0050] While it may be possible for the compounds of the invention
to be administered as the raw chemical, it is preferable to present
them as a pharmaceutical composition. In accordance with an
embodiment of the present invention there is provided a
pharmaceutical composition comprising a compound of formula I or a
pharmaceutically acceptable salt or solvate thereof, together with
one or more pharmaceutically carriers thereof and optionally one or
more other therapeutic ingredients. The carrier(s) must be
"acceptable" in the sense of being compatible with the other
ingredients of the formulation and not deleterious to the recipient
thereof. Furthermore, notwithstanding the statement above regarding
the term "compound" including salts thereof as well, so that
independent claims reciting "a compound" will be understood as
referring to salts thereof as well, if in an independent claim
reference is made to a compound or a pharmaceutically acceptable
salt thereof, it will be understood that claims which depend from
that independent claim which refer to such a compound also include
pharmaceutically acceptable salts of the compound, even if explicit
reference is not made to the salts in the dependent claim.
[0051] The formulations include those suitable for oral, parenteral
(including subcutaneous, intradermal, intramuscular, intravenous
and intraarticular), rectal and topical (including dermal, buccal,
sublingual and intraocular) administration. The most suitable route
may depend upon the condition and disorder of the recipient. The
formulations may conveniently be presented in unit dosage form and
may be prepared by any of the methods well known in the art of
pharmacy. Such methods include the step of bringing into
association a compound of formula I or a pharmaceutically
acceptable salt or solvate thereof ("active ingredient") with the
carrier, which constitutes one or more accessory ingredients. In
general, the formulations are prepared by uniformly and intimately
bringing into association the active ingredient with liquid
carriers or finely divided solid carriers or both and then, if
necessary, shaping the product into the desired formulation.
[0052] Formulations suitable for oral administration may be
presented as discrete units such as capsules, cachets or tablets
each containing a predetermined amount of the active ingredient; as
a powder or granules; as a solution or a suspension in an aqueous
liquid or a non-aqueous liquid; or as an oil-in-water liquid
emulsion or a water-in-oil liquid emulsion. The active ingredient
may also be presented as a bolus, electuary or paste.
[0053] A tablet may be made by compression or molding, optionally
with one or more accessory ingredients. Compressed tablets may be
prepared by compressing in a suitable machine the active ingredient
in a free-flowing form such as a powder or granules, optionally
mixed with a binder, lubricant, inert diluent, lubricating, 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. The tablets may optionally be coated
or scored and may be formulated so as to provide sustained, delayed
or controlled release of the active ingredient therein.
[0054] The pharmaceutical compositions may include a
"pharmaceutically acceptable inert carrier", and this expression is
intended to include one or more inert excipients, which include
starches, polyols, granulating agents, microcrystalline cellulose,
diluents, lubricants, binders, disintegrating agents, and the like.
If desired, tablet dosages of the disclosed compositions may be
coated by standard aqueous or nonaqueous techniques,
"Pharmaceutically acceptable carrier" also encompasses controlled
release means.
[0055] Pharmaceutical compositions may also optionally include
other therapeutic ingredients, anti-caking agents, preservatives,
sweetening agents, colorants, flavors, desiccants, plasticizers,
dyes, and the like. Any such optional ingredient must be compatible
with the compound of formula I to insure the stability of the
formulation. The composition may contain other additives as needed,
including for example lactose, glucose, fructose, galactose,
trehalose, sucrose, maltose, raffinose, maltitol, melezitose,
stachyose, lactitol, palatinite, starch, xylitol, mannitol,
myoinositol, and the like, and hydrates thereof, and amino acids,
for example alanine, glycine and betaine, and peptides and
proteins, for example albumen.
[0056] Examples of excipients for use as the pharmaceutically
acceptable carriers and the pharmaceutically acceptable inert
carriers and the aforementioned additional ingredients include, but
are not limited to binders, fillers, disintegrants, lubricants,
anti-microbial agents, and coating agents.
[0057] The dose range for adult humans is generally from 0.005 mg
to 10 g/day orally. Tablets or other forms of presentation provided
in discrete units may conveniently contain an amount of compound of
formula I which is effective at such dosage or as a multiple of the
same, for instance, units containing 5 mg to 500 mg, usually around
10 mg to 200 mg. The precise amount of compound administered to a
patient will be the responsibility of the attendant physician.
However, the dose employed will depend on a number of factors,
including the age and sex of the patient, the precise disorder
being treated, and its severity.
[0058] A dosage unit (e.g. an oral dosage unit) can include from,
for example, 1 to 30 mg, 1 to 40 mg, 1 to 100 mg, 1 to 300 mg, 1 to
500 mg, 2 to 500 mg, 3 to 100 mg, 5 to 20 mg, 5 to 100 mg (e.g. 1
mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 11 mg,
12 mg, 13 mg, 14 mg, 15 mg, 16 mg, 17 mg, 18 mg, 19 mg, 20 mg, 25
mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg,
75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 150 mg, 200 mg, 250 mg,
300 mg, 350 mg, 400 mg, 450 mg, 500 mg) of a compound described
herein.
[0059] For additional information about pharmaceutical compositions
and their formulation, see, for example, Remington: The Science and
Practice of Pharmacy, 20.sup.th Edition, 2000.
[0060] The agents can be administered, e.g., by intravenous
injection, intramuscular injection, subcutaneous injection,
intraperitoneal injection, topical, sublingual, intraarticular (in
the joints), intradermal, buccal, ophthalmic (including
intraocular), intranasaly (including using a cannula), or by other
routes. The agents can be administered orally, e.g., as a tablet or
cachet containing a predetermined amount of the active ingredient,
gel, pellet, paste, syrup, bolus, electuary, slurry, capsule,
powder, granules, as a solution or a suspension in an aqueous
liquid or a non-aqueous liquid, as an oil-in-water liquid emulsion
or a water-in-oil liquid emulsion, via a micellar formulation (see,
e.g. WO 97/11682) via a liposomal formulation (see, e.g., EP
736299, WO 99/59550 and WO 97/13500), via formulations described in
WO 03/094886 or in some other form. The agents can also be
administered transdermally (i.e. via reservoir-type or matrix-type
patches, microneedles, thermal poration, hypodermic needles,
iontophoresis, electroporation, ultrasound or other forms of
sonophoresis, jet injection, or a combination of any of the
preceding methods (Prausnitz et al. 2004, Nature Reviews Drug
Discovery 3:115)). The agents can be administered locally, for
example, at the site of injury to an injured blood vessel. The
agents can be coated on a stent. The agents can be administered
using high-velocity transdermal particle injection techniques using
the hydrogel particle formulation described in U.S. 20020061336.
Additional particle formulations are described in WO 00/45792, WO
00/53160, and WO 02/19989. An example of a transdermal formulation
containing plaster and the absorption promoter dimethylisosorbide
can be found in WO 89/04179. WO 96/11705 provides formulations
suitable for transdermal administration.
[0061] The agents can be administered in the form a suppository or
by other vaginal or rectal means. The agents can be administered in
a transmembrane formulation as described in WO 90/07923. The agents
can be administered non-invasively via the dehydrated particles
described in U.S. Pat. No. 6,485,706. The agent can be administered
in an enteric-coated drug formulation as described in WO 02/49621.
The agents can be administered intranasaly using the formulation
described in U.S. Pat. No. 5,179,079. Formulations suitable for
parenteral injection are described in WO 00/62759. The agents can
be administered using the casein formulation described in U.S.
20030206939 and WO 00/06108. The agents can be administered using
the particulate formulations described in U.S. 20020034536.
[0062] The agents, alone or in combination with other suitable
components, can be administered by pulmonary route utilizing
several techniques including but not limited to intratracheal
instillation (delivery of solution into the lungs by syringe),
intratracheal delivery of liposomes, insufflation (administration
of powder formulation by syringe or any other similar device into
the lungs) and aerosol inhalation. Aerosols (e.g., jet or
ultrasonic nebulizers, metered-dose inhalers (MDIs), and dry-Powder
inhalers (DPIs)) can also be used in intranasal applications.
Aerosol formulations are stable dispersions or suspensions of solid
material and liquid droplets in a gaseous medium and can be placed
into pressurized acceptable propellants, such as hydrofluoroalkanes
(HFAs, i.e. HFA-134a and HFA-227, or a mixture thereof),
dichlorodifluoromethane (or other chlorofluorocarbon propellants
such as a mixture of Propellants 11, 12, and/or 114), propane,
nitrogen, and the like. Pulmonary formulations may include
permeation enhancers such as fatty acids, and saccharides,
chelating agents, enzyme inhibitors (e.g., protease inhibitors),
adjuvants (e.g., glycocholate, surfactin, span 85, and nafamostat),
preservatives (e.g., benzalkonium chloride or chlorobutanol), and
ethanol (normally up to 5% but possibly up to 20%, by weight).
Ethanol is commonly included in aerosol compositions as it can
improve the function of the metering valve and in some cases also
improve the stability of the dispersion.
[0063] Pulmonary formulations may also include surfactants which
include but are not limited to bile salts and those described in
U.S. Pat. No. 6,524,557 and references therein. The surfactants
described in U.S. Pat. No. 6,524,557, e.g., a C.sub.8-C.sub.16
fatty acid salt, a bile salt, a phospholipid, or alkyl saccharide
are advantageous in that some of them also reportedly enhance
absorption of the compound in the formulation.
[0064] Also suitable in the invention are dry powder formulations
comprising a therapeutically effective amount of active compound
blended with an appropriate carrier and adapted for use in
connection with a dry-powder inhaler. Absorption enhancers that can
be added to dry powder formulations of the present invention
include those described in U.S. Pat. No. 6,632,456. WO 02/080884
describes new methods for the surface modification of powders.
Aerosol formulations may include U.S. Pat. No. 5,230,884, U.S. Pat.
No. 5,292,499, WO 017/8694, WO 01/78696, U.S. 2003019437, U. S.
20030165436, and WO 96/40089 (which includes vegetable oil).
Sustained release formulations suitable for inhalation are
described in U.S. 20010036481A1, 20030232019A1, and U.S.
20040018243A1 as well as in WO 01/13891, WO 02/067902, WO
03/072080, and WO 03/079885.
[0065] Pulmonary formulations containing microparticles are
described in WO 03/015750, U.S. 20030008013, and WO 00/00176.
Pulmonary formulations containing stable glassy state powder are
described in U.S. 20020141945 and U.S. Pat. No. 6,309,671. Other
aerosol formulations are described in EP 1338272A1 WO 90/09781,
U.S. Pat. No. 5,348,730, U.S. Pat. No. 6,436,367, WO 91/04011, and
U.S. Pat. No. 6,294,153 and U.S. Pat. No. 6,290,987 describes a
liposomal based formulation that can be administered via aerosol or
other means.
[0066] Powder formulations for inhalation are described in U.S.
20030053960 and WO 01/60341. The agents can be administered
intranasally as described in U.S. 20010038824.
[0067] Solutions of medicament in buffered saline and similar
vehicles are commonly employed to generate an aerosol in a
nebulizer. Simple nebulizers operate on Bernoulli's principle and
employ a stream of air or oxygen to generate the spray particles.
More complex nebulizers employ ultrasound to create the spray
particles. Both types are well known in the art and are described
in standard textbooks of pharmacy such as Sprowls' American
Pharmacy and Remington's The Science and Practice of Pharmacy.
[0068] Other devices for generating aerosols employ compressed
gases, usually hydrofluorocarbons and chlorofluorocarbons, which
are mixed with the medicament and any necessary excipients in a
pressurized container, these devices are likewise described in
standard textbooks such as Sprowls and Remington.
[0069] The agent can be incorporated into a liposome to improve
half-life. The agent can also be conjugated to polyethylene glycol
(PEG) chains. Methods for pegylation and additional formulations
containing PEG-conjugates (i.e. PEG-based hydrogels, PEG modified
liposomes) can be found in Harris and Chess, Nature Reviews Drug
Discovery 2:214-221 and the references therein. The agent can be
administered via a nanocochleate or cochleate delivery vehicle
(BioDelivery Sciences International). The agents can be delivered
transmucosally (i.e. across a mucosal surface such as the vagina,
eye or nose) using formulations such as that described in U.S. Pat.
No. 5,204,108. The agents can be formulated in microcapsules as
described in WO 88/01165. The agent can be administered
intra-orally using the formulations described in U.S. 20020055496,
WO 00/47203, and U.S. Pat. No. 6,495,120. The agent can be
delivered using nanoemulsion formulations described in WO
01/91728A2.
[0070] TABLE 1 lists compounds representative of embodiments of the
invention.
[0071] In general, the compounds of the present invention may be
prepared by the methods illustrated in the general reaction schemes
as, for example, described below, or by modifications thereof,
using readily available starting materials, reagents and
conventional synthesis procedures. In these reactions, it is also
possible to make use of variants that are in themselves known, but
are not mentioned here.
[0072] Processes for obtaining the compounds of the invention are
presented below. Other compounds of the invention may be prepared
in analogous fashion to those whose synthesis is exemplified
herein. The procedures below illustrate such methods. Furthermore,
although the syntheses depicted herein may result in the
preparation of enantiomers having a particular stereochemistry,
included within the scope of the present invention are compounds of
formula I in any stereoisomeric form, and preparation of compounds
of formula I in stereoisomeric forms other than those depicted
herein would be obvious to one of ordinary skill in the chemical
arts based on the procedures presented herein.
Synthetic Methods
##STR00037##
[0074] Compounds of formula 3 (wherein R.sup.14 is H or halogen;
R.sup.1 is H; R.sup.5 is a protecting group such as
tert-butoxycarbonyl or benzyloxycarbonyl; R.sup.8, R.sup.9,
R.sup.10, R.sup.11, R.sup.12 and R.sup.13 are each independently
selected from H or optionally substituted alkyl) can be prepared
from 3- or 4-bromo phenylhydrazine 1 (or a salt thereof) and
piperidinone 2 under heated acidic conditions. Optional
N5-alkylation or N5-protection of compound 3 can provide compounds
of formula 3 wherein R.sup.1 is alkyl or a protecting group such as
tert-butoxycarbonyl, benzyloxycarbonyl orp-toluenesulfonyl.
Optional removal of N2-protecting group R.sup.5 and reductive
amination, alkylation or acylation can provide compounds of formula
3 wherein R.sup.5 is alkyl or acyl.
##STR00038##
[0075] Compounds of formula 1 (wherein R.sup.14 is H or halogen)
can be treated with compounds of formula 4 (wherein R.sup.12 and
R.sup.13 are each independently selected from H or optionally
substituted alkyl and R.sup.16 is alkyl) and a Lewis acid such as
ZnCl.sub.2 under heated conditions to give compounds of formula 5.
Treatment of compounds of formula 5 with ethyl glyoxylate under
heated acidic conditions can provide compounds of formula 6 wherein
R.sup.10 and R.sup.11 are H. Alternatively, compounds of formula 5
can be treated with a ketone under heated acidic conditions to
provide compounds of formula 6 wherein R.sup.10 and R.sup.11 are
optionally substituted alkyl. Compounds of formula 5 also can be
treated with an acid chloride under basic conditions, followed by
heating with POCl.sub.3 and finally by treatment with a reducing
agent such as NaBH.sub.4 to provide compounds of formula 6 wherein
R.sup.10 is H and R.sup.11 is optionally substituted alkyl.
Protection of the N2-position on the tetrahydrocarboline ring can
provide compounds of formula 7 (wherein R.sup.5 is a protecting
group such as tert-butoxycarbonyl or benzyloxycarbonyl). Protection
of the N9-position on the tetrahydrocarboline ring can provide
compounds of formula 8 (wherein R.sup.1 is a protecting group such
as tert-butoxycarbonyl, benzyloxycarbonyl orp-toluenesulfonyl).
Alternatively, treatment of compound 7 with a base such as sodium
hydride and an alkylating agent can provide compounds of formula 8
wherein R.sup.1 is optionally substituted alkyl. Optional removal
of N2-protecting group R.sup.5 and reductive amination, alkylation
or acylation can provide compounds of formula 8 wherein R.sup.5 is
alkyl or acyl.
##STR00039##
[0076] Compounds of formula 12 (wherein B is aryl or heteroaryl;
R.sup.2, R.sup.3, R.sup.4 are each independently selected from H,
--O-alkyl, S-alkyl, alkyl, halo, --CF.sub.3, and --CN; and Y is CH)
can be prepared by treating compounds of formula 9 (wherein X.sup.1
is chlorine, bromine or iodine and Y is CH) with compounds of
formula 10 (wherein B is aryl or heteroaryl; R.sup.2, R.sup.3,
R.sup.4 are each independently selected from H, --O-alkyl, alkyl,
halo, --CF.sub.3, and --CN; Z.sup.1 is B(OH).sub.2,
B(OR.sup.17).sub.2, SnR.sup.17.sub.3 or the like and R.sup.17 is
alkyl), a catalyst such as palladium(0), and a base such as
potassium carbonate to give compounds of formula 11, wherein L is a
direct bond. Alternatively, in the case where Z.sup.1 is
--CH.sub.2OH and B is aryl, heteroaryl or cycloalkyl, compounds of
formula 10 can be treated with a base such as sodium hydride and
compounds of formula 9 under heated conditions to give compounds of
formula 11, wherein L is --CH.sub.2O--. In turn, compounds of
formula 11 can be treated with acetic anhydride under heated
conditions followed by methanol and water or methanol and sodium
hydroxide under ambient to heated conditions to provide compounds
of formula 12, wherein L is --CH.sub.2O-- or a direct bond.
##STR00040##
[0077] Alternatively, compounds of formula 12 (wherein B is aryl or
heteroaryl; R.sup.2, R.sup.3, R.sup.4 are each independently
selected from H, --O-alkyl, S-alkyl, alkyl, halo, --CF.sub.3, and
--CN; and Y is CH) can be prepared by treating compounds of formula
13 (wherein X is chlorine, bromine or iodine and Y is CH) with
compounds of formula 10 (wherein Z.sup.1 is
--CH.dbd.CH--B(OR.sup.17).sub.2, B(OR.sup.17).sub.2,
SnR.sup.17.sub.3 or the like and R.sup.17 is H or alkyl), a
catalyst such as palladium(0), and a base such as potassium
carbonate to give compounds of formula 14, wherein L is
--CH.dbd.CH-- or a direct bond, in accordance with Z.sup.1. In the
case where L is --CH.dbd.CH--, compounds of formula 14 can be
treated with palladium on carbon under an atmosphere of hydrogen to
give compounds of formula 14, wherein L is --CH.sub.2CH.sub.2--.
Alternatively, in the case where Z.sup.1 is --CH.sub.2OH, compounds
of formula 10 can be treated with compounds of formula 13, a
catalyst such as copper iodide, a ligand such as
3,4,7,8-tetramethylphenanthroline and a base such as cesium
carbonate under heated conditions to give compounds of formula 14,
wherein L is --CH.sub.2O--. In turn, when L is --CH.dbd.CH--,
--CH.sub.2CH.sub.2--, --CH.sub.2O-- or a direct bond, compounds of
formula 14 can be heated under acid conditions to provide compounds
of formula 12, wherein L is --CH.dbd.CH--, --CH.sub.2CH.sub.2--,
--CH.sub.2O-- or a direct bond, respectively.
##STR00041##
[0078] Alternatively, compounds of formula 12 (wherein B is aryl or
heteroaryl; R.sup.2, R.sup.3, R.sup.4 are each independently
selected from H, --O-alkyl, S-alkyl, alkyl, halo, --CF.sub.3, and
--CN; and Y is N) can be prepared from compounds of formula 15
(wherein Y is N and R.sup.18 is a protecting group such as
tetrahydropyran-2-yl). The hydroxyl group on compound 15 can be
converted to an appropriate activating group to give compounds of
formula 16. In the case where Z.sup.2 is triflate, compounds of
formula 15 can be treated with trifluoromethylsulfonic anhydride or
N-phenyl trifluoromethanesulfonamide and a base such as
triethylamine, pyridine or lithium bis(trimethylsilyl)amide under
cooled conditions to give compounds of formula 16. Treatment of
compounds of formula 16 with compounds of formula 10 (wherein B is
aryl or heteroaryl; R.sup.2, R.sup.3, R.sup.4 are each
independently selected from H, --O-alkyl, S-alkyl, alkyl, halo,
--CF.sub.3, and --CN; Z.sup.1=--CH.dbd.CH--B(OR.sup.17).sub.2,
B(OH).sub.2, B(OR.sup.17).sub.2, SnR.sup.17.sub.3 or the like, and
R.sup.17=alkyl), a catalyst such as palladium(0), and a base such
as potassium carbonate under heated conditions can provide
compounds of formula 17, wherein L is --CH.dbd.CH-- or a direct
bond. Removal of the protecting group R.sup.18 on compound 17 can
provide compounds of formula 12.
##STR00042##
[0079] Compounds of formula 18 (wherein B is aryl, heteroaryl or
cycloalkyl; R.sup.2, R.sup.3, R.sup.4 are each independently
selected from H, --O-alkyl, --S-alkyl, alkyl, halo, --CF.sub.3, and
--CN; L is --CH.sub.2--O--, --CH.dbd.CH--, --CH.sub.2CH.sub.2--, or
a bond; Y is CH or N; R.sup.14 is H or halogen; R.sup.5 is alkyl,
acyl or a protecting group such as tert-butoxycarbonyl or
benzyloxycarbonyl; R.sup.1 is alkyl or a protecting group such as
tert-butoxycarbonyl, benzyloxycarbonyl orp-toluenesulfonyl; and
R.sup.8, R.sup.9, R.sup.10, R.sup.11, R.sup.12 and R.sup.13 are
each independently selected from H or optionally substituted alkyl)
can be prepared by treating compounds of formula 3 (wherein R.sup.5
is alkyl, acyl or a protecting group such as tert-butoxycarbonyl or
benzyloxycarbonyl and R.sup.1 is alkyl or a protecting group such
as tert-butoxycarbonyl, benzyloxycarbonyl orp-toluenesulfonyl)
under heated conditions with a catalyst such as copper iodide, a
ligand such as trans-1,2-diaminocyclohexane or 8-hydroxyquinoline,
a base such as potassium carbonate, cesium carbonate or potassium
phosphate and compounds of formula 12 (wherein B is aryl,
heteroaryl or cycloalkyl; R.sup.2, R.sup.3, R.sup.4 are each
independently selected from H, --O-alkyl, --S-alkyl, alkyl, halo,
--CF.sub.3, and --CN; L is --CH.sub.2--O--, --CH.dbd.CH--,
--CH.sub.2CH.sub.2--, or a bond; and Y is CH or N). Removal of the
N2-protecting group R.sup.5 followed by reductive amination or
alkylation can provide compounds of formula 18, wherein R.sup.5 is
an optionally substituted alkyl group.
[0080] Alternatively, following deprotection, N2 can be acylated to
give compounds of formula 18 wherein R.sup.5 is
--C(.dbd.O)--R.sup.6 or --C(.dbd.O)--O--R.sup.7, and R.sup.6 and
R.sup.7 are each optionally substituted alkyl or optionally
substituted heterocycle. Additionally, in the case where R.sup.1 is
a protecting group, the protecting group can be removed to give
compounds of formula 18 wherein R.sup.1 is H.
[0081] Alternatively, following removal of the R.sup.1 protecting
group, N5 can be alkylated to give compounds of formula 18 wherein
R.sup.5 is an optionally substituted alkyl.
##STR00043##
[0082] Compounds of formula 19 (wherein B is aryl, heteroaryl or
cycloalkyl; R.sup.2, R.sup.3, R.sup.4 are each independently
selected from H, --O-alkyl, --S-alkyl, alkyl, halo, --CF.sub.3, and
--CN; L is --CH.sub.2--O--, --CH.dbd.CH--, --CH.sub.2CH.sub.2--, or
a bond; Y is CH or N; R.sup.14 is H or halogen; R.sup.5 is alkyl,
acyl or a protecting group such as tert-butoxycarbonyl or
benzyloxycarbonyl; R.sup.1 is alkyl or a protecting group such as
tert-butoxycarbonyl, benzyloxycarbonyl orp-toluenesulfonyl; and
R.sup.8, R.sup.9, R.sup.10, R.sup.11, R.sup.12 and R.sup.13 are
each independently selected from H or optionally substituted alkyl)
can be prepared by treating compounds of formula 3 (wherein R.sup.5
is alkyl, acyl or a protecting group such as tert-butoxycarbonyl or
benzyloxycarbonyl and R.sup.1 is alkyl or a protecting group such
as tert-butoxycarbonyl, benzyloxycarbonyl orp-toluenesulfonyl)
under heated conditions with a catalyst such as copper iodide, a
ligand such as trans-1,2-diaminocyclohexane or 8-hydroxyquinoline,
a base such as potassium carbonate, cesium carbonate or potassium
phosphate and compounds of formula 12 (wherein B is aryl,
heteroaryl or cycloalkyl; R.sup.2, R.sup.3, R.sup.4 are each
independently selected from H, --O-alkyl, --S-alkyl, alkyl, halo,
--CF.sub.3, and --CN; L is --CH.sub.2--O--, --CH.dbd.CH--,
--CH.sub.2CH.sub.2--, or a bond; and Y is CH or N). Removal of the
N2-protecting group R.sup.5 followed by reductive amination or
alkylation can provide compounds of formula 18, wherein R.sup.5 is
an optionally substituted alkyl group.
[0083] Alternatively, following deprotection, N2 can be acylated to
give compounds of formula 18 wherein R.sup.5 is
--C(.dbd.O)--R.sup.6 or --C(.dbd.O)--O--R.sup.7, and R.sup.6 and
R.sup.7 are each optionally substituted alkyl or optionally
substituted heterocycle. Additionally, in the case where R.sup.1 is
a protecting group, the protecting group can be removed to give
compounds of formula 18 wherein R.sup.1 is H.
[0084] Alternatively, following removal of the R.sup.1 protecting
group, N5 can be alkylated to give compounds of formula 18 wherein
R.sup.5 is an optionally substituted alkyl.
##STR00044##
[0085] Compounds of formula 20 (wherein Y is CH or N; R.sup.14 is H
or halogen; R.sup.5 is alkyl, acyl or a protecting group such as
tert-butoxycarbonyl or benzyloxycarbonyl; R.sup.1 is alkyl or a
protecting group such as tert-butoxycarbonyl, benzyloxycarbonyl
orp-toluenesulfonyl; and R.sup.8, R.sup.9, R.sup.10, R.sup.11,
R.sup.12 and R.sup.13 are each independently selected from H or
optionally substituted alkyl) can be treated with hydrogen and a
catalyst such as palladium on carbon to provide compounds of
formula 21. The hydroxyl group on compounds of formula 21 can be
converted to an appropriate activating group to give compounds of
formula 22. In the case where Z.sup.2 is triflate, compounds of
formula 21 can be treated with trifluoromethylsulfonic anhydride or
N-phenyl trifluoromethanesulfonamide and a base such as pyridine or
lithium bis(trimethylsilyl)amide under cooled conditions to give
compounds of formula 22. Treatment of compounds of formula 22 with
compounds of formula 10 (wherein B is aryl or heteroaryl; R.sup.2,
R.sup.3, R.sup.4 are each independently selected from H, --O-alkyl,
--S-alkyl, alkyl, halo, --CF.sub.3, and --CN;
Z.sup.1=--CH.dbd.CH--B(OR.sup.17).sub.2, B(OH).sub.2,
B(OR.sup.17).sub.2, SnR.sup.17.sub.3 or the like and
R.sup.17=alkyl), a catalyst such as palladium(0), and a base such
as potassium carbonate under heated conditions can provide
compounds of formula 18, wherein L is --CH.dbd.CH-- or a direct
bond. In the case where L is --CH.dbd.CH--, compounds of formula 18
can be treated with palladium on carbon under an atmosphere of
hydrogen to give compounds of formula 18, where L is
--CH.sub.2CH.sub.2--.
##STR00045##
[0086] Compounds of formula 23 (wherein Y is CH or N; R.sup.14 is H
or halogen; R.sup.5 is alkyl, acyl or a protecting group such as
tert-butoxycarbonyl or benzyloxycarbonyl; R.sup.1 is alkyl or a
protecting group such as tert-butoxycarbonyl, benzyloxycarbonyl
orp-toluenesulfonyl; and R.sup.8, R.sup.9, R.sup.10, R.sup.11,
R.sup.12 and R.sup.13 are each independently selected from H or
optionally substituted alkyl) can be treated with hydrogen and a
catalyst such as palladium on carbon to provide compounds of
formula 24. The hydroxyl group on compounds of formula 24 can be
converted to an appropriate activating group to give compounds of
formula 25. In the case where Z.sup.2 is triflate, compounds of
formula 24 can be treated with trifluoromethylsulfonic anhydride or
N-phenyl trifluoromethanesulfonamide and a base such as pyridine or
lithium bis(trimethylsilyl)amide under cooled conditions to give
compounds of formula 25.
[0087] Treatment of compounds of formula 25 with compounds of
formula 10 (wherein B is aryl or heteroaryl; R.sup.2, R.sup.3,
R.sup.4 are each independently selected from H, --O-alkyl,
--S-alkyl, alkyl, halo, --CF.sub.3, and --CN;
Z.sup.1=--CH.dbd.CH--B(OR.sup.17).sub.2, B(OH).sub.2,
B(OR.sup.17).sub.2, SnR.sup.17.sub.3 or the like and
R.sup.17=alkyl), a catalyst such as palladium(0), and a base such
as potassium carbonate under heated conditions can provide
compounds of formula 19, wherein L is --CH.dbd.CH-- or a direct
bond.
[0088] In the case where L is --CH.dbd.CH--, compounds of formula
18 can be treated with palladium on carbon under an atmosphere of
hydrogen to give compounds of formula 18, where L is
--CH.sub.2CH.sub.2--.
##STR00046##
[0089] Compounds of formula 26 (wherein B is aryl or heteroaryl;
R.sup.2, R.sup.3, R.sup.4 are each independently selected from H,
--O-alkyl, --S-alkyl, alkyl, halo, --CF.sub.3, and --CN; L is
--CH.sub.2--O--, --CH.dbd.CH--, --CH.sub.2CH.sub.2--, or a bond; G
is --CR.sup.12R.sup.13--NH-- or --NH--CR.sup.12R.sup.13--; R.sup.1
is alkyl; and R.sup.8, R.sup.9, R.sup.10, R.sup.11, R.sup.12 and
R.sup.13 are each independently selected from H or optionally
substituted alkyl) can be treated under halogenation conditions
such as 2-bromopropane under heated conditions to provide compounds
of formula 27 wherein R.sup.15 is a halogen such as bromine.
EXAMPLES
[0090] Unless otherwise noted, reagents and solvents were used as
received from commercial suppliers. Proton nuclear magnetic
resonance (NMR) spectra were obtained on Bruker spectrometers at
300, 400 or 500 MHz. Spectra are given in ppm (.delta.) and
coupling constants, J, are reported in Hertz. Tetramethylsilane
(TMS) was used as an internal standard. Mass spectra were collected
using either a Finnigan LCQ Duo LCMS ion trap electrospray
ionization (ESI) or a mass Varian 1200L single quadrapole mass
spectrometer (ESI). High performance liquid chromatograph (HPLC)
analyses were obtained using a Luna C18(2) column (250.times.4.6
mm, Phenomenex) or a Gemini C18 column (250.times.4.6 mm,
Phenomenex) with UV detection at 254 nm or 223 nm using a standard
solvent gradient program (Method A or Method B).
Method A:
TABLE-US-00001 [0091] Time Flow (min) (mL/min) % A % B 0.0 1.0 90.0
10.0 20 1.0 10.0 90.0 25 1.0 10.0 90.0 A = Water with 0.025%
Trifluoroacetic Acid B = Acetonitrile with 0.025% Trifluoroacetic
Acid
Method B:
TABLE-US-00002 [0092] Time Flow (min) (mL/min) % A % B 0.0 1.0 98.0
2.0 25 1.0 10.0 90.0 30 1.0 10.0 90.0 A = Water with 0.025%
Trifluoroacetic Acid B = Acetonitrile with 0.025% Trifluoroacetic
Acid
Example 1
Preparation of
4-(Benzyloxy)-1-(5-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-7-yl)p-
yridin-2(1H)-one hydrochloride
a) tert-Butyl
7-bromo-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate
##STR00047##
[0094] 3-Bromophenylhydrazine (40.0 g, 0.179 mol) and
N-Boc-4-oxo-piperidine (35.4 g, 0.179 mol) were dissolved in
ethanol (368 mL), and conc. HCl (72 mL) was added. The reaction
mixture was then heated to reflux for 18 h, concentrated and
basified using 10% NH.sub.4OH in methanol (10%, 100 mL). The
solvent was removed, and the residue was suspended in
CH.sub.2Cl.sub.2 (1.2 L). Boc.sub.2O (39.2 g, 0.179 mol) followed
by DMAP (195 mg, 1.6 mmol) and triethylamine (46.4 mL, 0.358 mol)
were then added, and the reaction progressed at room temperature
for 18 h. The mixture was washed with 0.5N HCl, and the organic
phase was removed, dried over Na.sub.2SO.sub.4, filtered and
concentrated to dryness. The resulting mixture of regioisomers was
purified by flash column chromatography (silica gel, hexanes/EtOAc,
100:0 to 80:20 to 50:50 then 25:75) to give the more polar title
compound (26.2 g, 42%) as a yellow solid: .sup.1H NMR (300 MHz,
CDCl.sub.3) .delta. 8.16 (br s, 1H), 7.42 (s, 1H), 7.28 (d, J=8.1
Hz, 1H, partially masked by solvent), 7.18 (d, J=8.1 Hz, 1H), 4.60
(s, 2H), 3.80 (t, J=5.5 Hz, 2H), 2.79 (t, J=5.6 Hz, 2H), 1.51 (s,
9H).
b) tert-Butyl
7-bromo-5-methyl-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate
##STR00048##
[0096] Sodium hydride (60% weight dispersion in mineral oil, 4.19
g, 0.105 mol) was added portionwise to a solution of tert-butyl
7-bromo-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate (23.6
g, 0.07 mol) in DMF (300 mL) at room temperature under N.sub.2.
After 1 h, methyl iodide (14.8 g, 6.47 mL, 0.105 mol) was added,
and the reaction was allowed to proceed for an additional 2 h. The
mixture was quenched with H.sub.2O, upon which a solid precipitated
out of solution. The suspension was therefore diluted to 2 L with
H.sub.2O and filtered. The solids were washed thoroughly with
water, then dissolved in CH.sub.2Cl.sub.2, dried over
Na.sub.2SO.sub.4, filtered and concentrated to dryness. This
provided the title compound (22.4 g, 91%) as a yellow solid:
.sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 7.41 (s, 1H), 7.30 (d,
J=8.3 Hz, 1H), 7.17 (d, J=8.4 Hz, 1H), 4.60 (s, 2H), 3.81 (br t,
2H), 3.58 (s, 3H), 2.77 (t, J=5.4 Hz, 2H), 1.50 (s, 9H).
c) tert-Butyl
7-(4-(benzyloxy)-2-oxopyridin-1(2H)-yl)-5-methyl-3,4-dihydro-1H-pyrido[4,-
3-b]indole-2(5H)-carboxylate
##STR00049##
[0098] tert-Butyl
7-bromo-5-methyl-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carbox-ylate
(7.0 g, 19 mmol), 4-benzyloxypyridone (3.85 g, 19.2 mmol),
K.sub.2CO.sub.3 (2.91 g, 21.1 mmol) and 8-hydroxyquinoline (418 mg,
2.88 mmol) were suspended in DMSO (50 mL) and the air removed under
vacuum for 15 min. The system was then flushed with N.sub.2. This
process was repeated and then copper iodide (547 mg, 2.88 mmol) was
added. The evacuation/N.sub.2 flushing process was repeated twice
more, and the reaction mixture was heated to 100-120.degree. C. for
18 h. The mixture was cooled, partitioned between EtOAc and sat.
NH.sub.4Cl and the organic phase removed, dried over
Na.sub.2SO.sub.4, filtered and concentrated to dryness.
Purification by flash column chromatography (silica gel,
CH.sub.2Cl.sub.2/MeOH, 100:0 to 98:2 to 95:5 to 92:8 then 90:10)
gave the title compound (4.71 g, 51%) as a yellow solid: .sup.1H
NMR (300 MHz, CDCl.sub.3) .delta. 7.50 (d, J=8.2 Hz, 1H), 7.43-7.35
(m, 5H), 7.32-7.29 (m, 2H), 7.01 (d, J=7.9 Hz, 1H), 6.10-6.03 (m,
2H), 5.06 (s, 2H), 4.64 (s, 2H), 3.89 (br t, 2H), 3.63 (s, 3H),
2.82 (br t, 2H), 1.50 (s, 9H).
d)
4-(Benzyloxy)-1-(5-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-7-yl-
)pyridin-2(1H)-one hydrochloride
##STR00050##
[0100] tert-Butyl
7-(4-(benzyloxy)-2-oxopyridin-1(2H)-yl)-5-methyl-3,4-dihydro-1H-pyrido[4,-
3-b]indole-2(5H)-carboxylate (12.0 g, 24.7 mmol) was dissolved in
MeOH (100 mL), and 2N HCl in Et.sub.2O (300 mL) was added. The
reaction was allowed to proceed for 18 h. The mixture was
concentrated, and the residue was partitioned between
CH.sub.2Cl.sub.2 and sat. Na.sub.2CO.sub.3 solution. The organic
phase was removed, and the aqueous phase was back extracted with
CH.sub.2Cl.sub.2. The combined organic extracts were dried over
Na.sub.2SO.sub.4, filtered and concentrated to dryness providing
the free base of the title compound (8.1 g, 85%) as a yellow solid.
A portion of the free base was converted to the HCl salt for
biological testing. Free base: .sup.1H NMR (500 MHz, CDCl.sub.3)
.delta. 7.47-7.34 (m, 6H), 7.32-7.28 (m, 2H), 6.98 (d, J=7.1 Hz,
1H), 6.07 (d, J=2.6 Hz, 1H), 6.04 (dd, J=7.5, 2.6 Hz, 1H), 5.05 (s,
2H), 4.15 (s, 2H), 3.61 (s, 3H), 3.34 (br s, 2H), 2.78 (br s, 2H).
HCl salt: melting point (mp) 296-302.degree. C.; .sup.1H NMR (500
MHz, CD.sub.3OD) .delta. 7.61-7.57 (2.times.d, 2H), 7.47-7.46 (m,
3H), 7.43-7.40 (m, 2H), 7.37-7.34 (m, 1H), 7.05 (dd, J=8.3, 1.7 Hz,
1H), 6.33 (dd, J=7.5, 2.7 Hz, 1H), 6.16 (d, J=2.6 Hz, 1H), 5.19 (s,
2H), 4.57 (s, 2H), 3.73 (s, 3H), 3.67 (t, J=6.2 Hz, 2H), 3.20 (t,
J=6.1 Hz, 2H); ESI MS m/z 386 [M+H].sup.+; HPLC (Method A) 95.7%
(AUC), t.sub.R=13.6 min.
Example 2
Preparation of
4-(Benzyloxy)-1-(2,5-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-7--
yl)pyridin-2(1H)-one hydrochloride
##STR00051##
[0102]
4-(Benzyloxy)-1-(5-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol--
7-yl)pyridin-2(1H)-one (8.1 g, 21.0 mmol) and 37% aqueous
formaldehyde (2.56 mL, 31.5 mmol) were dissolved in MeOH (200 mL)
and stirred at room temperature for 2 h. Sodium
triacetoxyborohydride (8.9 g, 42.0 mmol) was then added, and the
reaction was stirred at room temperature for an additional 1 h. The
mixture was concentrated, and the residue was partitioned between
CH.sub.2Cl.sub.2 and sat. Na.sub.2CO.sub.3 solution. The organic
phase was removed and the aqueous phase was back extracted with
CH.sub.2Cl.sub.2. The combined organics were dried over
Na.sub.2SO.sub.4, filtered and concentrated to dryness.
Purification by column chromatography (120 g ISCO column eluting
with methylene chloride and a methanol/ammonia mixture (10:1);
gradient 100% methylene chloride to 85% methylene chloride over 60
min) provided the free base of the title compound. This was
converted to the HCl salt using 2N HCl in Et.sub.2O providing the
title compound (5.57 g, 61%) as a yellow solid: mp 268-274.degree.
C.; .sup.1H NMR (500 MHz, CD.sub.3OD) .delta. 7.57 (dd, J=7.6, 1.7
Hz, 2H), 7.47-7.46 (m, 3H) 7.43-7.34 (m, 3H), 7.06 (dd, J=8.4, 1.9
Hz, 1H), 6.29 (dd, J=7.6, 2.7 Hz, 1H), 6.13 (d, J=2.6 Hz, 1H), 5.18
(s, 2H), 4.75 (d, J=14.3 Hz, 1H), 4.38 (d, J=14.2 Hz, 1H), 3.90 (m,
1H), 3.73 (s, 3H), 3.64-3.58 (m, 1H), 3.29-3.26 (m, 2H, partially
masked by solvent), 3.13 (s, 3H); ESI MS m/z 400 [M+H].sup.+; HPLC
(Method B) 97.4% (AUC), t.sub.R=14.7 min.
Example 3
Preparation of
4-(Benzyloxy)-1-(2-(2-hydroxyethyl)-5-methyl-2,3,4,5-tetrahydro-1H-pyrido-
[4,3-b]indol-7-yl)pyridin-2(1H)-one dihydrochloride
##STR00052##
[0104]
4-(Benzyloxy)-1-(5-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol--
7-yl)pyridin-2(1H)-one (75 mg, 0.16 mmol), 2-iodoethanol (17 .mu.L,
36 mg, 0.21 mmol) and triethylamine (105 .mu.L, 0.82 mmol) were
dissolved in MeCN (2 mL) and heated to reflux for 3 h. The mixture
was then concentrated and purified by flash column chromatography
(4 g ISCO column eluting with methylene chloride and a
methanol/ammonia mixture (10:1); gradient 100% methylene chloride
to 85% methylene chloride over 30 min) providing the free base.
This was converted to the HCl salt (2N HCl/Et.sub.2O) providing the
title compound (22 mg, 27%) as a yellow solid: mp 162-168.degree.
C.; .sup.1H NMR (500 MHz, CD.sub.3OD) .delta. 7.63 (dd, J=7.6, 2.0
Hz, 2H), 7.51-7.50 (m, 3H) 7.46-7.43 (m, 2H), 7.41-7.38 (m, 1H),
7.09 (dd, J=8.3, 1.7 Hz, 1H), 6.36 (dd, J=7.6, 2.7 Hz, 1H), 6.18
(d, J=2.7 Hz, 1H), 5.23 (s, 2H), 4.82 (d, 1H, partially masked by
solvent), 4.520 (d, J=14.3 Hz, 1H), 4.06-4.02 (m, 3H), 3.77 (s,
3H), 3.70-3.68 (m, 1H), 3.55-3.51 (m, 2H), 3.33-3.31 (m, 2H,
partially masked by solvent); ESI MS m/z 430 [M+H].sup.+; HPLC
(Method B) 95.1% (AUC), t.sub.R=12.4 min.
Example 4
Preparation of
4-(Benzyloxy)-1-(5-methyl-2-(2-(pyrrolidin-1-yl)acetyl)-2,3,4,5-tetrahydr-
o-1H-pyrido[4,3-b]indol-7-yl)pyridin-2(1H)-one dihydrochloride
a)
4-(Benzyloxy)-1-(2-(2-chloroacetyl)-5-methyl-2,3,4,5-tetrahydro-1H-pyri-
do[4,3-b]indol-7-yl)pyridin-2(1H)-one
##STR00053##
[0106]
4-(Benzyloxy)-1-(5-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol--
7-yl)pyridin-2(1H)-one (75 mg, 0.16 mmol) was dissolved in a
mixture of CH.sub.2Cl.sub.2 (1 mL) and sat. NaHCO.sub.3 solution (1
mL) and chloroacetyl chloride (28 mg, 0.25 mmol) was added. The
reaction mixture was vigorously stirred for 1 h then the phases
were separated. The aqueous phase was extracted with
CH.sub.2Cl.sub.2 and the combined organic extracts were dried over
Na.sub.2SO.sub.4, filtered and concentrated to dryness providing
the title compound (74 mg, 97%) as a beige solid which was a
mixture of rotamers: ESI MS m/z 462 [M+H].sup.+.
b)
4-(Benzyloxy)-1-(5-methyl-2-(2-(pyrrolidin-1-yl)acetyl)-2,3,4,5-tetrahy-
dro-1H-pyrido[4,3-b]indol-7-yl)pyridin-2(1H)-one
dihydrochloride
##STR00054##
[0108] 4-(Benzyloxy)-1-(2-(2-chloroacetyl)-5-methyl-2,
3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-7-yl)pyridin-2(1H)-one (70
mg, 0.15 mmol) was dissolved in MeCN (0.5 mL) and pyrrolidine (54
mg, 0.76 mmol) was added. The reaction mixture was refluxed for 2
h, concentrated and the residue purified by preparative HPLC. The
fractions were concentrated, and the residue was converted to the
free base by partitioning between CH.sub.2Cl.sub.2 and sat.
Na.sub.2CO.sub.3 solution. The organic phase was removed, and the
aqueous layer was extracted with CH.sub.2Cl.sub.2. The combined
organic extracts were dried over Na.sub.2SO.sub.4, filtered and
concentrated to dryness. Conversion to the HCl salt (2N
HCl/Et.sub.2O) provided the title compound (74 mg, 97%) as a beige
solid: .sup.1H NMR (500 MHz, CD.sub.3OD) .delta. 7.62 (dd, J=7.7,
1.9 Hz, 1H), 7.53 (d, J=8.0 Hz, 1H) 7.46-7.44 (m, 2H), 7.41-7.35
(m, 4H), 7.06 (dd, J=8.0, 1.7 Hz, 1H), 6.36 (d, J=7.6 Hz, 1H), 6.18
(s, 1H), 5.25 (s, 2H), 4.90 (m, 1H, masked by solvent), 4.82 (s,
1H), 4.53 (d, J=14.2 Hz, 2H), 4.09 (t, J=6.5 Hz, 1H), 3.91 (t,
J=6.4 Hz, 1H), 3.89-3.86 (m, 2H), 3.77 (s, 3H), 3.20-3.18 (m, 2H),
3.05-3.03 (m, 1H), 2.99-2.97 (m, 1H), 2.12-2.10 (m, 2H), 2.08-2.05
(m, 2H); ESI MS m/z 497 [M+H].sup.+; HPLC (Method B) 95.0% (AUC),
t.sub.R=13.1 min.
Example 5
Preparation of
4-(Benzyloxy)-1-(5-methyl-2-(2,2,2-trifluoroethyl)-2,3,4,5-tetrahydro-1H--
pyrido[4,3-b]indol-7-yl)pyridin-2(1H)-one dihydrochloride
##STR00055##
[0110]
4-(Benzyloxy)-1-(5-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol--
7-yl)pyridin-2(1H)-one (75 mg, 0.16 mmol) and triethylamine (105
.mu.L, 0.753 mmol) were dissolved in MeCN (2 mL) and
1,1,1-trifluoro-2-bromoethane (32 mg, 0.20 mmol) was added. The
reaction mixture was heated to reflux for 4 h, but no reaction
occurred. The mixture was concentrated, DMF (2 mL) and NaI (5 mg)
were added, and the reaction mixture was heated to reflux. Again,
no reaction occurred. 1,1,1-trifluoroethyl triflate (76 mg, 0.328
mmol) was then added, and the mixture was heated to reflux. After
1.5 h, the mixture was concentrated and purified by flash column
chromatography (4 g ISCO column eluting with methylene chloride and
a methanol/ammonia mixture (10:1); gradient 100% methylene chloride
to 85% methylene chloride over 30 min). Further purification by
preparative HPLC, followed by conversion to the HCl salt (2N
HCl/Et.sub.2O) provided the title compound (6 mg, 7%) as a white
solid: .sup.1H NMR (300 MHz, CD.sub.3OD) .delta. 7.48 (d, J=7.5 Hz,
1H), 7.40-7.24 (m, 7H), 6.87 (dd, J=8.3, 1.9 Hz, 1H), 6.19 (dd,
J=7.6, 2.7 Hz, 1H), 6.03 (d, J=2.7 Hz, 1H), 5.08 (s, 2H), 3.96 (s,
2H), 3.58 (s, 3H), 3.37 (q, J=9.7 Hz, 2H), 3.15-3.14 (m, 2H,
partially masked by solvent), 2.87 (t, J=5.5 Hz, 2H); ESI MS m/z
468 [M+H].sup.+; HPLC (Method B) 98.9% (AUC), t.sub.R=17.3 min.
Example 6
Preparation of
4-(Benzyloxy)-1-(5-methyl-2-(3,3,3-trifluoropropyl)-2,3,4,5-tetrahydro-1H-
-pyrido[4,3-b]indol-7-yl)pyridin-2(1H)-one dihydrochloride
##STR00056##
[0112]
4-(Benzyloxy)-1-(5-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol--
7-yl)pyridin-2(1H)-one (63 mg, 0.14 mmol) and K.sub.2CO.sub.3 (97
mg, 0.70 mmol) were suspended in DMF (1 mL) and
1,1,1-trifluoro-3-bromopropane (50 mg, 0.28 mmol) was added. The
reaction mixture was heated to 80.degree. C. for 18 h, cooled and
partitioned between ethyl acetate and water. The aqueous phase was
removed and the organic phase washed with 5% LiCl (5.times.), dried
over Na.sub.2SO.sub.4, filtered and concentrated to dryness.
Purification by flash column chromatography (4 g ISCO column
eluting with methylene chloride and a methanol/ammonia mixture
(10:1); gradient 100% methylene chloride to 85% methylene chloride
over 30 min) followed by conversion to the HCl salt (2N
HCl/Et.sub.2O) provided the title compound (12 mg, 16%) as a yellow
solid: .sup.1H NMR (500 MHz, CD.sub.3OD) .delta. 7.66 (d, J=8.3 Hz,
1H), 7.63 (d, J=7.6 Hz, 1H), 7.52-7.51 (m, 3H), 7.48-7.45 (m, 2H),
7.43 (d, J=7.2 Hz, 1H), 7.11 (dd, J=8.3, 1.7 Hz, 1H), 6.36 (dd,
J=7.6, 2.7 Hz, 1H), 6.19 (d, J=2.7 Hz, 1H), 5.24 (s, 2H), 4.96 (m,
6H, masked by solvent), 3.79-3.74 (m, 5H), 3.03-3.02 (m, 2H); ESI
MS m/z 482 [M+H].sup.+; HPLC (Method B) 95.6% (AUC), t.sub.R=14.3
min.
Example 7
Preparation of
1-(5-Methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-7-yl)-4-(4-(trifluor-
omethyl)benzyloxy)pyridin-2(1H)-one dihydrochloride
a) tert-Butyl
5-methyl-7-(2-oxo-4-(4-(trifluoromethyl)benzyloxy)pyridin-1(2H)-yl)-3,4-d-
ihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate
##STR00057##
[0114] The compound was prepared from tert-butyl
7-bromo-5-methyl-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate
(250 mg, 0.701 mmol) and
4-(4-(trifluoromethyl)benzyloxy)pyridin-2(1H)-one (142 mg, 0.526
mmol) according to the procedure in Example 1 (step c).
Purification by flash column chromatography (silica gel,
hexanes/EtOAc, 100:0 to 80:20 to 50:50 to 25:75 then 0:100)
provided the title compound (73 mg, 19%) as a solid, that contained
an impurity: ESI MS m/z 554 [M+H].sup.+.
b)
1-(5-Methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-7-yl)-4-(4-(triflu-
oromethyl)benzyloxy)pyridin-2(1H)-one dihydrochloride
##STR00058##
[0116] tert-Butyl
5-methyl-7-(2-oxo-4-(4-(trifluoromethyl)benzyloxy)pyridin-1(2H)-yl)-3,4-d-
ihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate (73 mg, 0.13 mmol)
was dissolved in MeOH (0.5 mL) and 2N HCl in Et.sub.2O (3 mL) was
added. The reaction was allowed to proceed for 3 h. The mixture was
concentrated and purified by preparative HPLC. Conversion to the
HCl salt (2N HCl/Et.sub.2O) provided the title compound (26 mg,
38%) as a yellow solid: mp 311-315.degree. C.; .sup.1H NMR (500
MHz, CD.sub.3OD) .delta. 7.77 (d, J=8.3 Hz, 2H), 7.71 (d, J=8.2 Hz,
2H), 7.65 (d, J=7.6 Hz, 1H), 7.62 (d, J=8.3 Hz, 1H), 7.50 (s, 1H),
7.09 (dd, J=8.3, 1.8 Hz, 1H), 6.38 (dd, J=7.6, 2.7 Hz, 1H), 6.17
(d, J=2.7 Hz, 1H), 5.33 (s, 2H), 4.51 (s, 2H), 3.77 (s, 3H), 3.71
(t, J=6.2 Hz, 2H), 3.24 (t, J=6.1 Hz, 2H); ESI MS m/z 454
[M+H].sup.+; HPLC (Method B) >99% (AUC), t.sub.R=14.2 min.
Example 8
Preparation of
4-(4-Chlorobenzyloxy)-1-(5-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indo-
l-7-yl)pyridin-2(1H)-one dihydrochloride
a) tert-Butyl
7-(4-(4-chlorobenzyloxy)-2-oxopyridin-1(2H)-yl)-5-methyl-3,4-dihydro-1H-p-
yrido[4,3-b]indole-2(5H)-carboxylate
##STR00059##
[0118] The compound was prepared from tert-butyl
7-bromo-5-methyl-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate
(200 mg, 0.548 mmol) and 4-(4-chlorobenzyloxy)pyridin-2(1H)-one
(129 mg, 0.548 mmol) according to the procedure in Example 1 (step
c). Purification by flash column chromatography (silica gel,
hexanes/EtOAc, 100:0 to 80:20 to 50:50 to 25:75 then 0:100)
provided the title compound (143 mg, 50%) as a yellow solid:
.sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 7.51 (d, J=8.0 Hz, 1H),
7.43-7.29 (m, 6H), 7.01 (d, J=7.9 Hz, 1H), 6.05-6.02 (m, 2H), 5.02
(s, 2H), 4.64 (br s, 2H), 3.84 (br s, 2H), 3.63 (s, 3H), 2.82 (br
s, 2H), 1.50 (s, 9H).
b)
4-(4-Chlorobenzyloxy)-1-(5-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]in-
dol-7-yl)pyridin-2(1H)-one dihydrochloride
##STR00060##
[0120]
tert-Butyl-7-(4-(4-chlorobenzyloxy)-2-oxopyridin-1(2H)-yl)-5-methyl-
-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate (143 mg,
0.275 mmol) was dissolved in MeOH (1 mL) and 2N HCl in Et.sub.2O (5
mL) was added. The reaction was allowed to proceed for 3 h. The
resulting precipitate was collected by filtration and washed with
Et.sub.2O to provide the title compound (95 mg, 71%) as a yellow
solid: mp 305-310.degree. C. dec; .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 9.54 (br s, 2H), 7.57 (m, 2H), 7.51 (s, 5H),
6.99 (d, J=7.8 Hz, 1H), 6.12 (dd, J=7.8, 2.7 Hz, 1H), 5.99 (d,
J=2.7 Hz, 1H), 5.16 (s, 2H), 4.33 (br s, 2H), 3.68 (s, 3H),
3.52-3.48 (m, 2H), 3.12-3.08 (m, 2H); ESI MS m/z 420 [M+H].sup.+;
HPLC (Method B) 97% (AUC), t.sub.R=13.99 min.
Example 9
Preparation of
1-(5-Methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-7-yl)-4-phenethylpyr-
idin-2(1H)-one dihydrochloride
a) tert-Butyl
5-methyl-7-(2-oxo-4-phenethylpyridin-1(2H)-yl)-3,4-dihydro-1H-pyrido[4,3--
b]indole-2(5H)-carboxylate
##STR00061##
[0122] The compound was prepared from tert-butyl
7-bromo-5-methyl-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate
(200 mg, 0.548 mmol) and 4-phenethylpyridin-2(1H)-one (109 mg,
0.548 mmol) according to the procedure in Example 1 (step c).
Purification by flash column chromatography (silica gel,
hexanes/EtOAc, 100:0 to 80:20 to 50:50 to 25:75 then 0:100)
provided the title compound (126 mg, 48%) as a yellow solid:
.sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 7.52 (d, J=8.2 Hz, 1H),
7.34-7.30 (m, 4H), 7.24-7.20 (m, 3H, partially masked by solvent),
7.03 (d, J=7.8 Hz, 1H), 6.52 (s, 1H), 6.10 (dd, J=7.9, 1.7 Hz, 1H),
4.65 (br s, 2H), 3.84 (br s, 2H), 3.63 (s, 3H), 2.98-2.93 (m, 2H),
2.84-2.81 (m, 4H), 1.51 (s, 9H).
b)
1-(5-Methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-7-yl)-4-phenethylp-
yridin-2(1H)-one dihydrochloride
##STR00062##
[0124] tert-Butyl
5-methyl-7-(2-oxo-4-phenethylpyridin-1(2H)-yl)-3,4-dihydro-1H-pyrido[4,3--
b]indole-2(5H)-carboxylate (120 mg, 0.248 mmol) was dissolved in
MeOH (1.5 mL) and 2N HCl in Et.sub.2O (5 mL) was added. The
reaction was allowed to proceed for 3 h. The resulting precipitate
was collected by filtration and washed with Et.sub.2O to provide
the title compound (90 mg, 80%) as a yellow solid: mp
282-286.degree. C.; .sup.1H NMR (500 MHz, CD.sub.3OD) .delta. 7.70
(d, J=6.9 Hz, 1H), 7.62 (d, J=8.3 Hz, 1H), 7.52 (s, 1H), 7.33-7.26
(m, 4H), 7.22 (t, J=7.2 Hz, 1H), 7.09 (dd, J=8.3, 1.6 Hz, 1H),
6.59-6.56 (m, 2H), 4.50 (s, 2H), 3.76 (s, 3H), 3.70 (t, J=6.2 Hz,
2H), 3.24 (t, J=6.0 Hz, 2H), 3.04-3.01 (m, 2H), 2.98-2.95 (m, 2H);
ESI MS m/z 384 [M+H].sup.+; HPLC (Method B) >99% (AUC),
t.sub.R=13.3 min.
Example 10
Preparation of
1-(5-Methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-7-yl)-4-(4-(trifluor-
omethyl)phenyl)pyridin-2(1H)-one dihydrochloride
a) tert-Butyl
5-methyl-7-(2-oxo-4-(4-(trifluoromethyl)phenyl)pyridin-1(2H)-yl)-3,4-dihy-
dro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate
##STR00063##
[0126] The compound was prepared from tert-butyl
7-bromo-5-methyl-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate
(153 mg, 0.418 mmol) and
4-(4-(trifluoromethy)phenyl)pyridine-2(1H)-one (100 mg g, 0.418
mmol) according to the procedure in Example 1 (step c).
Purification by flash column chromatography (silica gel,
hexanes/EtOAc, 100:0 to 80:20 to 50:50 to 25:75 then 0:100)
provided the title compound (98 mg, 45%) as a yellow/green solid:
.sup.1H NMR (500 MHz, CDCl.sub.3) .delta. 7.75 (s, 4H), 7.57-7.53
(m, 2H), 7.37 (s, 1H), 7.09 (d, J=8.0 Hz, 1H), 6.92 (s, 1H), 6.50
(d, J=6.7 Hz, 1H), 4.67 (s, 2H), 3.86 (br s, 2H), 3.60 (s, 3H),
2.84 (br s, 2H), 1.51 (s, 9H).
b)
1-(5-Methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-7-yl)-4-(4-(triflu-
oromethyl)phenyl)pyridin-2(1H)-one dihydrochloride
##STR00064##
[0128] tert-Butyl
5-methyl-7-(2-oxo-4-(4-(trifluoromethyl)phenyl)pyridin-1(2H)-yl)-3,4-dihy-
dro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate (95 mg, 0.18 mmol) was
dissolved in MeOH (2 mL) and 2N HCl in Et.sub.2O (10 mL) was added.
The reaction was allowed to proceed for 3 h. The resulting
precipitate was collected by filtration and washed with Et.sub.2O
to provide the title compound (45 mg, 50%) as a pale yellow solid:
mp 318-323.degree. C.; .sup.1H NMR (500 MHz, CD.sub.3OD) .delta.
7.95 (d, J=8.2 Hz, 2H), 7.84 (d, J=8.2 Hz, 2H), 7.81 (d, J=7.1 Hz,
1H), 7.63 (d, J=8.3 Hz, 1H), 7.57 (s, 1H), 7.14 (dd, J=8.3, 1.3 Hz,
1H), 6.96 (d, J=1.6 Hz, 1H), 6.87 (dd, J=7.1, 1.7 Hz, 1H), 4.50 (s,
2H), 3.76 (s, 3H), 3.68 (t, J=6.1 Hz, 2H), 3.22 (t, J=6.1 Hz, 2H);
ESI MS m/z 424 [M+H].sup.+; HPLC (Method B) 97.6% (AUC),
t.sub.R=13.9 min.
Example 11
Preparation of
4-(4-Chlorophenyl)-1-(5-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-7-
-yl)pyridin-2(1H)-one dihydrochloride
a) 4-(4-Chlorophenyl)pyridine 1-oxide
[0129] Beilstein Registry Number 5510914
##STR00065##
[0130] 4-Chloropyridine-N-oxide (1.5 g, 12 mmol),
4-chlorophenylboronic acid (2.7 g, 17 mmol) and K.sub.2CO.sub.3
(4.78 g, 34.6 mmol) were suspended in DMSO (15 mL) and
[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II)
(PdCl.sub.2(dppf)) (225 mg, 0.276 mmol) was added. The reaction
mixture was placed under vacuum for 20 min and then flushed with
N.sub.2. This process was repeated, and the reaction mixture was
heated to 120.degree. C. for 3 h, cooled and partitioned between
ethyl acetate and brine. The aqueous phase was removed, and the
organic phase was washed with brine, dried over Na.sub.2SO.sub.4,
filtered and concentrated to dryness. Purification by flash column
chromatography (silica gel, hexanes/EtOAc, 100:0 to 80:20 to 50:50
then 25:75 followed by methylene chloride/MeOH 100:0 to 95:5 then
90:10) provided the title compound (1.05 g, 44%) as a grey solid:
.sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 8.26 (d, J=7.1 Hz, 2H),
7.58-7.43 (m, 6H).
b) 4-(4-Chlorophenyl)pyridin-2(1H)-one
##STR00066##
[0132] 4-(4-Chlorophenyl)pyridine 1-oxide (1.04 g, 5.07 mmol) and
acetic anhydride (25 mL) were heated to reflux for 24 h. The
mixture was then concentrated, and 1N NaOH (10 mL) in MeOH (10 mL)
was added. The reaction mixture was heated to reflux for 1 h, then
cooled, concentrated, and purified by flash column chromatography
(silica gel, methylene chloride/MeOH 100:0 to 98:2 to 95:5 then
90:10) providing the title compound (500 mg, 48%) as an off-white
solid: .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 11.64 (s, 1H),
7.73 (d, J=8.6 Hz, 2H), 7.54 (d, J=8.6 Hz, 2H), 7.46 (d, J=6.8 Hz,
1H), 6.60 (d, J=1.4 Hz, 1H), 6.50 (dd, J=6.9, 1.8 Hz, 1H).
c) tert-Butyl
7-(4-(4-chlorophenyl)-2-oxopyridin-1(2H)-yl)-5-methyl-3,4-dihydro-1H-pyri-
do[4,3-b]indole-2(5H)-carboxylate
##STR00067##
[0134] The compound was prepared from tert-Butyl
7-bromo-5-methyl-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate
(250 mg, 0.685 mmol) and 4-(4-chlorophenyl)pyridine-2(1H)-one (100
mg, 0.418 mmol) according to the procedure in Example 1 (step c).
Purification by flash column chromatography (silica gel,
hexanes/EtOAc, 100:0 to 80:20 to 50:50 to 25:75 then 0:100)
provided the title compound (59 mg, 18%) as a solid, that contained
an impurity: ESI MS m/z 490 [M+H].sup.+.
d)
4-(4-Chlorophenyl)-1-(5-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-
-7-yl)pyridin-2(1H)-one dihydrochloride
##STR00068##
[0136] tert-Butyl
7-(4-(4-chlorophenyl)-2-oxopyridin-1(2H)-yl)-5-methyl-3,4-dihydro-1H-pyri-
do[4,3-b]indole-2(5H)-carboxylate (59 mg, 0.12 mmol) was dissolved
in MeOH (0.5 mL) and 2N HCl in Et.sub.2O (3 mL) was added. The
reaction was allowed to proceed for 3 h. The mixture was
concentrated and purified by preparative HPLC. Conversion to the
HCl salt (2N HCl in Et.sub.2O) provided the title compound (22 mg,
40%) as a pale yellow solid: .sup.1H NMR (500 MHz, CD.sub.3OD)
.delta. 7.80-7.78 (m, 3H), 7.66 (d, J=8.5 Hz, 1H), 7.58-7.57 (m,
3H), 7.16 (dd, J=8.3, 1.7 Hz, 1H), 6.94 (d, J=1.8 Hz, 1H), 6.87
(dd, J=7.1, 1.9 Hz, 1H), 6.17 (d, J=2.7 Hz, 1H), 4.53 (s, 2H), 3.79
(s, 3H), 3.72 (t, J=5.9 Hz, 2H), 3.25 (t, J=5.9 Hz, 2H); ESI MS m/z
390 [M+H].sup.+; HPLC (Method B) 98.2% (AUC), t.sub.R=16.3 min.
Example 12
Preparation of
4-(2,4-Dichlorophenyl)-1-(5-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]ind-
ol-7-yl)pyridin-2(1H)-one dihydrochloride
a) tert-Butyl
7-(4-(2,4-dichlorophenyl)-2-oxopyridin-1(2H)-yl)-5-methyl-3,4-dihydro-1H--
pyrido[4,3-b]indole-2(5H)-carboxylate
##STR00069##
[0138] The compound was prepared from tert-butyl
7-bromo-5-methyl-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate
(200 mg, 0.548 mmol) and 4-(2,4-dichlorophenyl)pyridine-2(1H)-one
(132 mg, 0.548 mmol) according to the procedure in Example 1 (step
c). Purification by flash column chromatography (silica gel,
hexanes/EtOAc, 100:0 to 80:20 to 50:50 then 25:75) provided the
title compound (56 mg, 20%) as a yellow solid: .sup.1H NMR (500
MHz, CDCl.sub.3) .delta. 7.56-7.52 (m, 2H), 7.47 (d, J=7.0 Hz, 1H),
7.39-7.32 (m, 3H), 7.10 (br s, 1H), 6.69 (s, 1H), 6.35 (d, J=5.7
Hz, 1H), 4.66 (s, 2H), 3.85 (br s, 2H), 3.65 (s, 3H), 2.84 (br s,
2H), 1.51 (s, 9H).
b)
4-(2,4-Dichlorophenyl)-1-(5-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]i-
ndol-7-yl)pyridin-2(1H)-one dihydrochloride
##STR00070##
[0140] tert-Butyl
7-(4-(2,4-dichlorophenyl)-2-oxopyridin-1(2H)-yl)-5-methyl-3,4-dihydro-1H--
pyrido[4,3-b]indole-2(5H)-carboxylate (56 mg, 0.11 mmol) was
dissolved in MeOH (1 mL) and 2N HCl in Et.sub.2O (5 mL) was added.
The reaction was allowed to proceed for 3 h. The mixture was
concentrated and purified by preparative HPLC. Conversion to the
HCl salt (2N HCl in Et.sub.2O) provided the title compound (22 mg,
42%) as a yellow solid: mp 321-324.degree. C.; .sup.1H NMR (500
MHz, CD.sub.3OD) .delta. 7.80 (d, J=7.0 Hz, 1H), 7.70 (s, 1H), 7.68
(d, J=7.9 Hz, 1H), 7.62 (s, 1H), 7.54 (s, 2H), 7.13 (d, J=7.0 Hz,
1H), 6.73 (s, 1H), 6.61 (d, J=7.2 Hz, 1H), 4.54 (s, 2H), 3.80 (s,
3H), 3.72 (t, J=6.0 Hz, 2H), 3.26 (t, J=5.9 Hz, 2H); ESI MS m/z 424
[M+H].sup.+; HPLC (Method B) >99% (AUC), t.sub.R=14.1 min.
Example 13
Preparation of
4-(Benzyloxy)-1-(5-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-8-yl)p-
yridin-2(1H)-one hydrochloride
a) tert-Butyl
8-bromo-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate
##STR00071##
[0142] To a mixture of 4-bromophenylhydryzine hydrochloride (1.00
g, 4.47 mmol) and tert-butyl 4-oxopiperidine-1-carboxylate (0.89 g,
4.5 mmol) were added EtOH (10 mL) and conc. HCl (3 mL). The
reaction mixture was heated to 90.degree. C. and stirred at
90.degree. C. until the reaction was complete. Then the mixture was
concentrated and the residue was dissolved in CH.sub.2Cl.sub.2 (10
mL) and CH.sub.3OH (5 mL). To the above solution were added
Boc.sub.2O (1.46 g, 6.69 mmol), TEA (0.94 mL, 6.7 mmol) and DMAP
(55 mg, 0.45 mmol). The reaction mixture was stirred at room
temperature until it was complete. The mixture was concentrated and
the residue was dissolved in CH.sub.2Cl.sub.2, washed with H.sub.2O
and brine, dried with Na.sub.2SO.sub.4, filtered and concentrated.
Purification by flash column chromatography (silica gel,
hexanes/EtOAc, 1:1) gave the title compound (1.12 g, 72%) as a
yellow foam: .sup.1H NMR (500 MHz, CDCl.sub.3) .delta. 7.89 (br s,
1H), 7.57 (s, 1H), 7.17-7.24 (m, 2H), 4.58 (s, 2H), 3.81 (m, 2H),
2.83 (m, 2H), 1.5 (s, 9H); ESI MS m/z 351 [M+H].sup.+.
b) tert-Butyl
8-4-(benzyloxy)-2-oxopyridin-1(2H)-yl)-5-methyl-3,4-dihydro-1H-pyrido[4,3-
-b]indole-2-(5H)-carboxylate
##STR00072##
[0144] To a solution of tert-butyl
8-bromo-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate (0.53
g, 1.5 mmol) in DMF (6 mL) was added NaH (60% weight dispersion in
mineral oil, 91 mg, 2.3 mmol) and CH.sub.3I (0.14 mL, 2.3 mmol).
The reaction mixture was stirred at room temperature until the
reaction was complete. Then the reaction was quenched with H.sub.2O
and extracted with CH.sub.2Cl.sub.2. The organic layer was washed
with H.sub.2O and 5% LiCl, dried with Na.sub.2SO.sub.4, filtered
and concentrated to give tert-butyl
8-bromo-5-methyl-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate,
which was used directly without purification.
[0145] To a mixture of tert-butyl
8-bromo-5-methyl-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate
(0.48 g, 1.3 mmol), 4-(benzyloxy)pyridin-2(1H)-one (264 mg, 1.31
mmol), 8-hydroxyquinoline (29 mg, 0.20 mmol), K.sub.2CO.sub.3 (217
mg, 1.57 mmol) and CuI (38 mg, 0.20 mmol) was added DMSO (5 mL).
The reaction mixture was degassed and back-filled with N.sub.2. The
reaction mixture was heated to 130.degree. C. and stirred at
130.degree. C. overnight. After it was cooled, the mixture was
filtered through a layer of Celite. The filtrate was diluted with
CH.sub.2Cl.sub.2, washed with H.sub.2O and 5% LiCl, dried with
Na.sub.2SO.sub.4, filtered, and concentrated. Purification by flash
column chromatography (silica gel, 5% CH.sub.3OH in
CH.sub.2Cl.sub.2) gave the title compound (0.28 g, 44%) as a yellow
solid: .sup.1H NMR (500 MHz, CDCl.sub.3) .delta. 7.36-7.29 (m, 8H),
7.13 (d, J=8.0 Hz, 1H), 6.09 (d, J=2.0 Hz, 1H), 6.03 (dd, J=7.5,
2.0 Hz, 1H), 5.05 (s, 2H), 4.61 (s, 2H), 3.84 (m, 2H), 3.66 (s,
3H), 2.82 (m, 2H), 1.49 (s, 9H); ESI MS m/z 486 [M+H].sup.+.
c)
4-(Benzyloxy)-1-(5-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-8-yl-
)pyridin-2(1H)-one hydrochloride
##STR00073##
[0147] To a solution of tert-butyl
8-4-(benzyloxy)-2-oxopyridin-1(2H)-yl)-5-methyl-3,4-dihydro-1H-pyrido[4,3-
-b]indole-2-(5H)-carboxylate (180 mg, 0.37 mmol) in CH.sub.3OH (2
mL) was added 1N HCl in Et.sub.2O (2 mL). The reaction mixture was
stirred at room temperature until the reaction was complete. The
resulting solid was dried under vacuum to give the title compound
(142 mg, 91%) as a yellow solid: mp 280-285.degree. C. (decompose);
.sup.1H NMR (500 MHz, CD.sub.3OD) .delta. 7.59 (d, J=7.5 Hz, 1H),
7.54 (d, J=9.0 Hz, 1H), 7.48-7.40 (m, 5H), 7.38-7.36 (m, 1H), 7.17
(dd, J=8.5, 1.5 Hz, 1H), 6.33 (dd, J=7.5, 2.5 Hz, 1H), 6.16 (d,
J=2.5 Hz, 1H), 5.20 (s, 2H), 4.45 (s, 2H), 3.77 (s, 3H), 3.67 (t,
J=6.0 Hz, 2H), 3.21 (t, J=6.0 Hz, 2H); ESI MS m/z 386 [M+H].sup.+;
HPLC (Method B) 98.8% (AUC), t.sub.R=12.9 min.
Example 14
Preparation of
4-(Benzyloxy)-1-(2,5-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-8--
yl)pyridin-2(1H)-one hydrochloride
##STR00074##
[0149] To a solution of
4-(benzyloxy)-1-(5-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-8-yl)p-
yridin-2(1H)-one (100 mg, 0.26 mmol) in CH.sub.3OH (3 mL) was added
formaldehyde (30 .mu.L, 0.29 mmol) and NaBH(OAc).sub.3 (110 mg,
0.52 mmol). The reaction mixture was stirred at room temperature
until the reaction was complete. Then the mixture was concentrated
and the residue was dissolved in CH.sub.2Cl.sub.2. The organic
layer was washed with H.sub.2O and 5% LiCl, dried with
Na.sub.2SO.sub.4, filtered and concentrated. Purification by flash
column chromatography (silica gel, 10% CH.sub.3OH in
CH.sub.2Cl.sub.2) gave
4-(benzyloxy)-1-(2,5-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-8--
yl)pyridin-2(1H)-one (102 mg, 98%) as a yellow solid. The free base
was converted to the HCl salt to give the title compound (100 mg,
90%) as a yellow solid: mp 264-268.degree. C. (decompose); .sup.1H
NMR (500 MHz, DMSO-d.sub.6) .delta. 10.26 (s, 1H), 7.56-7.36 (m,
8H), 7.10 (dd, J=8.5, 1.5 Hz, 1H), 6.10 (dd, J=7.5, 3.0 Hz, 1H),
5.97 (d, J=3.0 Hz, 1H), 5.15 (s, 2H), 4.58 (m, 1H), 4.27 (m, 1H),
3.78 (m, 1H), 3.72 (s, 3H), 3.50 (m, 1H), 3.18 (m, 2H), 2.97 (s,
3H); ESI MS m/z 400 [M+H].sup.+; HPLC (Method B) >99% (AUC),
t.sub.R=12.9 min.
Example 15
Preparation of
2-(Pyrrolidin-1-yl)ethyl-7-4-(benzyloxy)-2-oxopyridin-1(2H)-5-methyl-3,4--
dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate hydrochloride
##STR00075##
[0151] To a solution of
4-benzyloxy-1-(5-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-7-yl)pyr-
idin-2(1H)-one hydrochloride (100 mg, 0.24 mmol) in DMSO (2 mL) was
added 1-(2-chloroethyl)pyrrolidine hydrochloride (53 mg, 0.29 mmol)
and Cs.sub.2CO.sub.3 (313 mg, 1.06 mmol). The reaction mixture was
stirred at room temperature under Ar until the reaction was
complete. The reaction was quenched with water and extracted with
CH.sub.2Cl.sub.2. The organic layer was washed with H.sub.2O and 5%
LiCl, dried with Na.sub.2SO.sub.4, filtered, and concentrated.
Purification by flash column chromatography (silica gel, 5%
CH.sub.3OH in CH.sub.2Cl.sub.2) gave
2-(pyrrolidin-1-yl)ethyl-7-4-(benzyloxy)-2-oxopyridin-1
(2H)-5-methyl-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate
(56 mg, 44%) as a yellow foam. The free base was converted to the
HCl salt to give the title compound (44 mg, 73%) as a yellow solid:
mp 95-97.degree. C.; .sup.1H NMR (500 MHz, CD.sub.3OD) .delta.
7.78-7.75 (m, 1H), 7.57-7.54 (m, 1H), 7.49-7.37 (m, 6H), 7.04-7.01
(m, 1H), 6.55-6.52 (m, 1H), 6.33-6.31 (m, 1H), 5.26 (s, 2H),
4.80-4.73 (m, 2H), 4.49-4.48 (m, 2H), 3.94-3.93 (m, 2H), 3.82-3.72
(m, 2H), 3.69 (s, 3H), 3.58-3.57 (m, 2H), 3.20-3.14 (m, 2H),
2.98-2.94 (m, 2H), 2.15-1.99 (m, 4H); ESI MS m/z 527 [M+H].sup.+;
HPLC (Method B) >99% (AUC), t.sub.R=13.8 min.
Example 16
Preparation of
4-(Benzyloxy)-1-(2-(2-(dimethylamino)acetyl)-5-methyl-2,3,4,5-tetrahydro--
1H-pyrido[4,3-b]indol-7-yl)pyridin-2(1H)-one hydrochloride
##STR00076##
[0153] To a solution of
4-benzyloxy-1-(5-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-7-yl)pyr-
idin-2(1H)-one (100 mg, 0.26 mmol) in CH.sub.2Cl.sub.2 (2 mL) was
added 2-chloroacetyl chloride (29 .mu.L, 0.36 mmol) and Et.sub.3N
(0.1 mL, 0.7 mmol). The reaction mixture was stirred at room
temperature until the reaction was complete. After the solvent was
removed, the residue was dissolved in DMF. To the DMF solution was
added (CH.sub.3).sub.2NH (64 .mu.L, 1.2 mmol) and K.sub.2CO.sub.3
(166 mg, 1.2 mmol). The reaction mixture was heated to 70.degree.
C. and stirred at 70.degree. C. until the reaction was complete.
After it was cooled, the reaction was quenched with water and
extracted with CH.sub.2Cl.sub.2. The organic layer was washed with
H.sub.2O and 5% LiCl, dried with Na.sub.2SO.sub.4, filtered, and
concentrated. Purification by flash column chromatography (silica
gel, 10% CH.sub.3OH in CH.sub.2Cl.sub.2) gave
4-(benzyloxy)-1-(2-(2-(dimethyl
amino)acetyl)-5-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-7-yl)pyri-
din-2(1H)-one (58 mg, 51%) as a yellow foam. The free base was
converted to the HCl salt to give the title compound (31 mg, 50%)
as a yellow solid and as a mixture of rotamers: mp 135-140.degree.
C.; .sup.1H NMR (500 MHz, CD.sub.3OD) .delta. 7.75-7.71 (m, 1H),
7.59-7.55 (m, 1H), 7.49-7.37 (m, 6H), 7.05-7.01 (m, 1H), 6.49-6.45
(m, 1H), 6.28-6.26 (m, 1H), 5.24 (s, 2H), 4.87 (br s, 1H), 4.69 (br
s, 1H), 4.44-4.41 (m, 2H), 4.11-4.07 (m, 1H), 3.85-3.82 (m, 1H),
3.70 (2.times.s, 3H), 3.06-2.92 (m, 2H), 2.97-2.94 (2.times.s, 6H);
ESI MS m/z 471 [M+H].sup.+; HPLC (Method B) 97.0% (AUC),
t.sub.R=13.2 min.
Example 17
Preparation of
4-(Benzyloxy)-1-(5-methyl-2-(2-oxo-2-(pyrrolidin-1-yl)ethyl)-2,3,4,5-tetr-
ahydro-1H-pyrido[4,3-b]indol-7-yl)pyridine-2(1H)-one
hydrochloride
##STR00077##
[0155] To a solution of
4-benzyloxy-1-(5-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-7-yl)pyr-
idin-2(1H)-one (100 mg, 0.26 mmol) in DMF (3 mL) was added
2-chloro-1-(pyrrolidin-1-yl)ethanone (77 mg, 0.52 mmol) and
K.sub.2CO.sub.3 (72 mg, 0.52 mmol). The reaction mixture was heated
to 70.degree. C. and stirred at 70.degree. C. until the reaction
was complete. After it was cooled, the reaction was quenched with
water and extracted with CH.sub.2Cl.sub.2. The organic layer was
washed with H.sub.2O and 5% LiCl, dried with Na.sub.2SO.sub.4,
filtered, and concentrated. Purification by flash column
chromatography (silica gel, 5% CH.sub.3OH in CH.sub.2Cl.sub.2) gave
4-(benzyloxy)-1-(5-methyl-2-(2-oxo-2-(pyrrolidin-1-yl)ethyl)-2,3,4,5-tetr-
ahydro-1H-pyrido[4,3-b]indol-7-yl)pyridine-2(1H)-one (35 mg, 27%)
as a yellow foam. The free base was converted to the HCl salt to
the give title compound (30 mg, 80%) as a yellow solid: mp
162-166.degree. C.; .sup.1H NMR (500 MHz, CD.sub.3OD) .delta. 7.60
(d, J=7.5 Hz, 1H), 7.56 (d, J=8.0 Hz, 1H), 7.49-7.35 (m, 6H), 7.06
(dd, J=8.5, 1.5 Hz, 1H), 6.33 (dd, J=7.5, 3.0 Hz, 1H), 6.16 (d,
J=3.0 Hz, 1H), 5.20 (s, 2H), 4.80 (d, J=14.5 Hz, 1H), 4.54 (d,
J=14.5 Hz, 1H), 4.36 (s, 2H), 4.00-3.98 (m, 1H), 3.75 (s, 3H),
3.68-3.65 (m, 1H), 3.54 (t, J=7.0 Hz, 2H), 3.49-3.45 (m, 2H),
3.35-3.33 (m, 2H), 2.05-1.92 (m, 4H); ESI MS m/z 497 [M+H].sup.+;
HPLC (Method B) 97.9% (AUC), t.sub.R=13.4 min.
Example 18
Preparation of
4-(Benzyloxy)-1-(5-methyl-2-(3-(pyrrolidin-1-yl)propanoyl)-2,3,4,5-tetrah-
ydro-1H-pyrido[4,3-b]indol-7-yl)pyridine-2(1H)-one
hydrochloride
##STR00078##
[0157] To a solution of
4-benzyloxy-1-(5-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-7-yl)pyr-
idin-2(1H)-one (100 mg, 0.26 mmol) in DMF (3 mL) was added
O-(7-azabenzotriazol-1-yl)-N,N,N'N'-tetramethyluronium
hexafluorophosphate (HATU) (148 mg, 0.389 mmol),
3-(pyrrolidin-1-yl)propanoic acid hydrochloride (56 mg, 0.31 mmol),
and Et.sub.3N (73 .mu.L, 0.52 mmol). The reaction mixture was
stirred at room temperature under Ar until the reaction was
complete. The reaction was quenched with water and extracted with
CH.sub.2Cl.sub.2. The organic layer was washed with H.sub.2O and 5%
LiCl, dried with Na.sub.2SO.sub.4, filtered and concentrated.
Purification by flash column chromatography (silica gel, 5%
CH.sub.3OH in CH.sub.2Cl.sub.2) gave
4-(benzyloxy)-1-(5-methyl-2-(3-(pyrrolidin-1-yl)propanoyl)-2,3,4,5-tetrah-
ydro-1H-pyrido[4,3-b]indol-7-yl)pyridine-2(1H)-one as a yellow
foam. The free base was converted to the HCl salt to give the title
compound (75 mg, 86%) as a yellow solid: mp 110-115.degree. C.;
.sup.1H NMR (500 MHz, CD.sub.3OD) .delta. 7.79-7.76 (m, 1H),
7.61-7.55 (m, 1H), 7.49-7.36 (m, 6H), 7.05-7.02 (m, 1H), 6.55-6.52
(m, 1H), 6.33-6.32 (m, 1H), 5.26 (s, 2H), 4.06 (t, J=5.5 Hz, 1H),
3.94 (t, J=5.5 Hz, 1H), 3.70-3.69 (m, 5H), 3.54-3.50 (m, 2H),
3.18-2.89 (m, 8H), 2.18-2.04 (m, 4H); ESI MS m/z 511 [M+H].sup.+;
HPLC (Method B) 97.7% (AUC), t.sub.R=13.6 min.
Example 19
Preparation of
4-(Benzyloxy)-1-(5-methyl-2-(pyrrolidine-3-carbonyl)-2,3,4,5-tetrahydro-1-
H-pyrido[4,3-b]indol-7-yl)pyridin-2(1H)-one hydrochloride
##STR00079##
[0159] Following the procedure of Example 18, but substituting
1-(tert-butoxycarbonyl)pyrrolidine-3-carboxylic acid for
3-(pyrrolidin-1-yl)propanoic acid hydrochloride, a yellow solid was
obtained in 78% yield (118 mg). The yellow solid was dissolved in
CH.sub.3OH (3 mL) and was treated with 1N HCl in Et.sub.2O (2 mL).
The resulting solid was isolated by filtration and dried under
vacuum to give the title compound (90 mg, 90%) as a green-yellow
powder: .sup.1H NMR (500 MHz, CD.sub.3OD) .delta. 7.75-7.72 (m,
1H), 7.63-7.55 (m, 1H), 7.49-7.36 (m, 6H), 7.05-7.02 (m, 1H),
6.51-6.46 (m, 1H), 6.29-6.27 (m, 1H), 5.25 (s, 2H), 4.79-4.76 (m,
2H), 4.14-3.97 (m, 2H), 3.87-3.82 (m, 1H), 3.71-3.69 (m, 4H),
3.60-3.50 (m, 1H), 3.45-3.36 (m, 3H), 3.04-3.03 (m, 1H), 2.94-2.92
(m, 1H), 2.52-2.36 (m, 1H), 2.18-2.00 (m, 1H); ESI MS m/z 483
[M+H].sup.+; HPLC (Method B) 98.1% (AUC), t.sub.R=13.2 min.
Example 20
Preparation of
(R)-4-(Benzyloxy)-1-(5-methyl-2-(pyrrolidine-2-carbonyl)-2,3,4,5-tetrahyd-
ro-1H-pyrido[4,3-b]indol-7-yl)pyridin-2(1H)-one hydrochloride
##STR00080##
[0161] Following the procedure of Example 19, but substituting
(R)-1-(tert-butoxycarbonyl)pyrrolidine-2-carboxylic acid for
1-(tert-butoxycarbonyl)pyrrolidine-3-carboxylic acid, the title
compound (67 mg, 50%) was obtained as a yellow solid and as a
mixture of rotamers: .sup.1H NMR (500 MHz, CD.sub.3OD) .delta.
7.82-7.79 (m, 1H), 7.66-7.56 (m, 1H), 7.49-7.36 (m, 6H), 7.07-7.03
(m, 1H), 6.59-6.56 (m, 1H), 6.36 (dd, J=5.0, 2.5 Hz, 1H), 5.28 (s,
2H), 4.82-4.81 (m, 2H), 4.14-4.05 (m, 1H), 3.97-3.95 (m, 1H),
3.71-3.69 (2.times.s, 3H), 3.58-3.34 (m, 3H), 3.07-2.94 (m, 2H),
2.70-2.57 (m, 1H), 2.17-1.85 (m, 3H); ESI MS m/z 483 [M+H].sup.+;
HPLC (Method B) >99% (AUC), t.sub.R=13.3 min.
Example 21
Preparation of
(S)-4-(Benzyloxy)-1-(5-methyl-2-(pyrrolidine-2-carbonyl)-2,3,4,5-tetrahyd-
ro-1H-pyrido[4,3-b]indol-7-yl)pyridin-2(1H)-one hydrochloride
##STR00081##
[0163] Following the procedure of Example 20, but substituting
(S)-1-(tert-butoxycarbonyl)pyrrolidine-2-carboxylic acid for
(R)-1-(tert-butoxycarbonyl)pyrrolidine-2-carboxylic acid, the title
compound (47 mg, 72%) was obtained as a yellow solid and as a
mixture of rotamers: .sup.1H NMR (500 MHz, CD.sub.3OD) .delta.
7.82-7.79 (m, 1H), 7.66-7.56 (m, 1H), 7.49-7.36 (m, 6H), 7.07-7.03
(m, 1H), 6.59-6.56 (m, 1H), 6.36 (dd, J=5.0, 2.5 Hz, 1H), 5.28 (s,
2H), 4.82-4.81 (m, 2H), 4.14-4.05 (m, 1H), 3.97-3.95 (m, 1H),
3.71-3.69 (2.times.s, 3H), 3.58-3.34 (m, 3H), 3.07-2.94 (m, 2H),
2.70-2.57 (m, 1H), 2.17-1.85 (m, 3H); ESI MS m/z 483 [M+H].sup.+;
HPLC (Method B) >99% (AUC), t.sub.R=13.3 min.
Example 22
Preparation of
4-(Benzyloxy)-1-(5-methyl-2-(1-methylpyrrolidine-3-carbonyl)-2,3,4,5-tetr-
ahydro-1H-pyrido[4,3-b]indol-7-yl)pyridin-2(1H)-one
hydrochloride
##STR00082##
[0165] To a solution of
4-(benzyloxy)-1-(5-methyl-2-(pyrrolidine-3-carbonyl)-2,3,4,5-tetrahydro-1-
H-pyrido[4,3-b]indol-7-yl)pyridin-2(1H)-one hydrochloride (105 mg,
0.197 mmol) in CH.sub.3OH (3 mL) was added Et.sub.3N (40 .mu.L,
0.29 mmol), formaldehyde (23 .mu.L, 0.29 mmol), and NaBH(OAc).sub.3
(86 mg, 0.41 mmol). The reaction mixture was stirred at room
temperature until the reaction was complete. Then the mixture was
concentrated and the residue was dissolved in CH.sub.2Cl.sub.2. The
organic layer was washed with H.sub.2O and 5% LiCl, dried with
Na.sub.2SO.sub.4, filtered and concentrated. Purification by flash
column chromatography (silica gel, 10% CH.sub.3OH in
CH.sub.2Cl.sub.2) gave
4-(benzyloxy)-1-(5-methyl-2-(1-methylpyrrolidine-3-carbonyl)-2,3,4,5-tetr-
ahydro-1H-pyrido[4,3-b]indol-7-yl)pyridin-2(1H)-one (60 mg, 60%) as
a yellow solid. The free base was converted to the HCl salt to give
the title compound (43 mg, 80%) as a yellow solid and as a mixture
of rotamers: mp 132-136.degree. C.; .sup.1H NMR (500 MHz,
CD.sub.3OD) .delta. 7.61-7.33 (m, 8H), 7.02-6.98 (m, 1H), 6.29-6.27
(m, 1H), 6.12-6.11 (m, 1H), 5.17 (s, 2H), 4.79-4.76 (m, 2H),
4.09-3.97 (m, 2H), 3.81-3.79 (m, 1H), 3.69-3.67 (m, 4H), 3.49-3.42
(m, 1H), 3.22-3.16 (m, 2H), 3.00 (m, 1H), 2.92-2.91 (m, 1H),
2.81-2.78 (2.times.s, 3H), 2.52-2.36 (m, 1H), 2.18-2.00 (m, 1H);
ESI MS m/z 497 [M+H].sup.+; HPLC (Method B) 98.7% (AUC),
t.sub.R=13.6 min.
Example 23
Preparation of
(R)-4-(Benzyloxy)-1-(5-methyl-2-(1-methylpyrrolidine-2-carbonyl)-2,3,4,5--
tetrahydro-1H-pyrido[4,3-b]indol-7-yl)pyridin-2(1H)-one
hydrochloride
##STR00083##
[0167] Following the procedure of Example 22, but substituting
(R)-4-(benzyloxy)-1-(5-methyl-2-(pyrrolidine-2-carbonyl)-2,3,4,5-tetrahyd-
ro-1H-pyrido[4,3-b]indol-7-yl)pyridin-2(1H)-one hydrochloride for
4-(benzyloxy)-1-(5-methyl-2-(pyrrolidine-3-carbonyl)-2,3,4,5-tetrahydro-1-
H-pyrido[4,3-b]indol-7-yl)pyridin-2(1H)-one hydrochloride, the
title compound (80 mg, 67%) was obtained as a yellow solid and as a
mixture of rotamers: mp 158-162.degree. C.; .sup.1H NMR (500 MHz,
CD.sub.3OD) .delta. 7.61-7.33 (m, 8H), 7.03-6.99 (m, 1H), 6.30 (dd,
J=7.5, 2.5 Hz, 1H), 6.13 (d, J=2.5 Hz, 1H), 5.18 (s, 2H), 4.80-4.70
(m, 2H), 4.12-4.09 (m, 1H), 3.92-3.90 (m, 1H), 3.78-3.72 (m, 1H),
3.69-3.68 (2s, 3H), 3.49-3.42 (m, 1H), 3.28-3.20 (m, 1H), 3.07-3.00
(m, 2H), 2.96-2.94 (2s, 3H), 2.79-2.65 (m, 1H), 2.21-2.09 (m, 1H),
2.09-1.86 (m, 2H); ESI MS m/z 497 [M+H].sup.+; HPLC (Method B)
>99% (AUC), t.sub.R=13.4 min.
Example 24
Preparation of
(S)-4-(Benzyloxy)-1-(5-methyl-2-(1-methylpyrrolidine-2-carbonyl)-2,3,4,5--
tetrahydro-1H-pyrido[4,3-b]indol-7-yl)pyridin-2(1H)-one
hydrochloride
##STR00084##
[0169] Following the procedure of Example 22, but substituting
(S)-4-(benzyloxy)-1-(5-methyl-2-(pyrrolidine-2-carbonyl)-2,3,4,5-tetrahyd-
ro-1H-pyrido[4,3-b]indol-7-yl)pyridin-2(1H)-one hydrochloride for
4-(benzyloxy)-1-(5-methyl-2-(pyrrolidine-3-carbonyl)-2,3,4,5-tetrahydro-1-
H-pyrido[4,3-b]indol-7-yl)pyridin-2(1H)-one hydrochloride, the
title compound (40 mg, 61%) was obtained as a yellow solid and as a
mixture of rotamers: mp 154-160.degree. C.; .sup.1H NMR (500 MHz,
CD.sub.3OD) .delta. 7.61-7.33 (m, 8H), 7.03-6.99 (m, 1H), 6.30 (dd,
J=7.5, 2.5 Hz, 1H), 6.13 (d, J=2.5 Hz, 1H), 5.18 (s, 2H), 4.80-4.70
(m, 2H), 4.12-4.09 (m, 1H), 3.92-3.90 (m, 1H), 3.78-3.72 (m, 1H),
3.69-3.68 (2s, 3H), 3.49-3.42 (m, 1H), 3.28-3.20 (m, 1H), 3.07-3.00
(m, 2H), 2.96-2.94 (2.times.s, 3H), 2.79-2.65 (m, 1H), 2.21-2.09
(m, 1H), 2.09-1.86 (m, 2H); ESI MS m/z 497 [M+H].sup.+; HPLC
(Method B) 98.9% (AUC), t.sub.R=13.3 min.
Example 25
Preparation of
1-(2,5-Dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-7-yl)-4-(4-fluor-
ophenyl)pyridine-2(1H)-one hydrochloride
a) tert-Butyl
5-methyl-7-(2-oxo-4-(trifluoromethylsulfonyloxy)pyridine-1
(2H)-yl)3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate
##STR00085##
[0171] To a solution of tert-butyl 7-(4-(benzyloxy)-2-oxopyridin-1
(2H)-yl)-5-methyl-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate
(0.98 g, 2.0 mmol) in CH.sub.3OH (30 mL) was added 5% Pd/C (0.3 g)
and ammonium formate (0.32 g, 5 mmol) under Ar atmosphere. The
reaction mixture was heated to 90.degree. C. and stirred at
90.degree. C. until the reaction was complete. After it was cooled,
the reaction mixture was filtered through a layer of Celite. The
solvent was concentrated to give tert-butyl
7-(4-hydroxy-2-oxopyridin-1
(2H)-yl)-5-methyl-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate,
which was used directly without purification.
[0172] To a solution of tert-butyl
7-(4-hydroxy-2-oxopyridin-1(2H)-yl)-5-methyl-3,4-dihydro-1H-pyrido[4,3-b]-
indole-2(5H)-carboxylate (800 mg, 2.02 mmol) in THF (10 mL) was
added LiN(SiMe.sub.3).sub.2(2.6 mL, 2.6 mmol) followed by
PhN(Tf).sub.2 (0.94 g, 2.6 mmol) under Ar atmosphere. The reaction
mixture was stirred at room temperature until the reaction was
complete. Then the mixture was concentrated and the residue was
purified by flash column chromatography (silica gel, hexanes/EtOAc,
1:1) to give the title compound (0.42 g, 40%) as a white solid:
.sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 7.57-7.53 (m, 2H), 7.30
(d, J=1.5 Hz, 1H), 7.02-6.99 (m, 1H), 6.60 (d, J=2.7 Hz, 1H), 6.27
(dd, J=7.8, 2.7 Hz, 1H), 4.65 (s, 2H), 3.85 (m, 2H), 3.65 (s, 3H),
2.84 (m, 2H), 1.51 (s, 9H); ESI MS m/z 528 [M+H].sup.+.
b)
1-(2,5-Dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-7-yl)-4-(4-flu-
orophenyl)pyridine-2(1H)-one hydrochloride
##STR00086##
[0174] To a solution of tert-butyl
5-methyl-7-(2-oxo-4-(trifluloromethylsulfonyloxy)
pyridine-1-(2H)-yl)3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate
(100 mg, 0.19 mmol) in DMSO (2 mL) was added 4-fluorophenylboronic
acid (66 mg, 0.48 mmol), K.sub.2CO.sub.3 (66 mg, 0.48 mmol), and
PdCl.sub.2(dppf) (14 mg, 0.019 mmol). The reaction mixture was
degassed, then back-filled with N.sub.2. The reaction mixture was
stirred at 80.degree. C. in a pre-heated oil bath for 2 hours.
After cooling, the reaction was quenched with water and extracted
with CH.sub.2Cl.sub.2. The organic layer was washed with H.sub.2O
and 5% LiCl, dried with Na.sub.2SO.sub.4, filtered and
concentrated. Purification by flash column chromatography (silica
gel, 5% CH.sub.3OH in CH.sub.2Cl.sub.2) gave a yellow solid (120
mg, >100%). The solid was dissolved in CH.sub.3OH (2 mL) and
treated with 1N HCl in Et.sub.2O (1.9 mL). The reaction mixture was
stirred at room temperature until the reaction was complete. After
the solvent was removed, the resulting solid was dissolved in
CH.sub.3OH (3 mL). Et.sub.3N (40 .mu.L), formaldehyde (22 .mu.L,
0.29 mmol), and NaBH(OAc).sub.3 were added sequentially. The
reaction mixture was stirred at room temperature until the reaction
was was complete. The solvent was removed and the residue was
dissolved in CH.sub.2Cl.sub.2. The organic layer was washed with
H.sub.2O and 5% LiCl, dried with Na.sub.2SO.sub.4, filtered and
concentrated. Purification by flash column chromatography (silica
gel, 5% CH.sub.3OH in CH.sub.2Cl.sub.2) gave
1-(2,5-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-7-yl)-4-(4-fluor-
ophenyl)pyridine-2(1H)-one (37 mg 50% yield over three steps) as a
yellow solid. The free base was converted to the HCl salt to give
the title compound (36.5 mg, 91%) as a yellow solid: mp
276-280.degree. C. (decompose); .sup.1H NMR (500 MHz, CD.sub.3OD)
.delta. 7.82-7.79 (m, 2H), 7.75 (d, J=7.0 Hz, 1H), 7.61 (d, J=8.5
Hz, 1H), 7.56 (d, J=1.5 Hz, 1H), 7.29-7.25 (m, 2H), 7.14 (dd,
J=8.5, 1.5 Hz, 1H), 6.88 (d, J=2.0 Hz, 1H), 6.82 (dd, J=7.0, 2.0
Hz, 1H), 4.77 (d, J=14.0 Hz, 1H), 4.41 (d, J=14.0 Hz, 1H),
3.93-3.90 (m, 1H), 3.76 (s, 3H), 3.66-3.60 (m, 1H), 3.27 (m, 2H),
3.15 (s, 3H); ESI MS m/z 388 [M+H].sup.+; HPLC (Method B) 98.1%
(AUC), t.sub.R=12.8 min.
Example 26
Preparation of
1-(2,5-Dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-7-yl)-4-(4-(trif-
luoromethylphenyl)pyridin-2(1H)-one hydrochloride
##STR00087##
[0176] Following the procedure of Example 25 (step b), but
substituting 4-trifluoromethylphenylboronic acid for
4-fluorophenylboronic acid, the title compound (47 mg, 53%) was
obtained as a yellow solid: mp 270-274.degree. C.; .sup.1H NMR (500
MHz, CD.sub.3OD) .delta. 7.95 (d, J=8.5 Hz, 2H), 7.84 (d, J=8.5 Hz,
2H), 7.80 (d, J=7.5 Hz, 1H), 7.62 (d, J=8.0 Hz, 1H), 7.57 (d, J=1.5
Hz, 1H), 7.15 (dd, J=8.5, 2.0 Hz, 1H), 6.96 (d, J=1.5 Hz, 1H), 6.87
(dd, J=7.5, 2.0 Hz, 1H), 4.78 (d, J=14.0 Hz, 1H), 4.41 (d, J=14.0
Hz, 1H), 3.93-3.90 (m, 1H), 3.77 (s, 3H), 3.66-3.60 (m, 1H), 3.27
(m, 2H), 3.15 (s, 3H); ESI MS m/z 438 [M+H].sup.+; HPLC (Method B)
>99% (AUC), t.sub.R=13.8 min.
Example 27
Preparation of
4-(4-Chlorophenyl)-1-(2,5-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]ind-
ol-7-yl)-pyridin-2(1H)-one hydrochloride
##STR00088##
[0178] Following the procedure of Example 25 (step b), but
substituting 4-chlorophenylboronic acid for 4-fluorophenylboronic
acid, the title compound (55 mg, 65%) was obtained as a yellow
solid: mp 276-280.degree. C.; .sup.1H NMR (500 MHz, CD.sub.3OD)
.delta. 7.77-7.75 (m, 3H), 7.62 (d, J=8.5 Hz, 1H), 7.57 (d, J=2.0
Hz, 1H), 7.56-7.54 (m, 2H), 7.15 (dd, J=8.5, 2.0 Hz, 1H), 6.91 (d,
J=2.0 Hz, 1H), 6.84 (dd, J=7.0, 2.0 Hz, 1H), 4.78 (d, J=14.0 Hz,
1H), 4.41 (d, J=14.0 Hz, 1H), 3.93-3.90 (m, 1H), 3.77 (s, 3H),
3.66-3.60 (m, 1H), 3.27 (m, 2H), 3.15 (s, 3H); ESI MS m/z 404
[M+H].sup.+; HPLC (Method B) 98% (AUC), t.sub.R=13.4 min.
Example 28
Preparation of
4-(4-Chloro-2-fluorophenyl)-1-(2,5-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[-
4,3-b]indol-7-yl)-pyridin-2(1H)-one hydrochloride
##STR00089##
[0180] Following the procedure of Example 25 (step b), but
substituting 4-chloro-2-fluorophenylboronic acid for
4-fluorophenylboronic acid, the title compound (20 mg, 32%) was
obtained as a yellow solid: mp 270-274.degree. C.; .sup.1H NMR (500
MHz, CD.sub.3OD) .delta. 7.76 (d, J=7.0 Hz, 1H), 7.66-7.57 (m, 2H),
7.57 (d, J=2.0 Hz, 1H), 7.42-7.39 (m, 2H), 7.15 (dd, J=8.5, 2.0 Hz,
1H), 6.84 (s, 1H), 6.73-6.71 (m, 1H), 4.77 (d, J=14.0 Hz, 1H), 4.41
(d, J=14.0 Hz, 1H), 3.93-3.90 (m, 1H), 3.76 (s, 3H), 3.64-3.61 (m,
1H), 3.27 (m, 2H), 3.15 (s, 3H); ESI MS m/z 422 [M+H].sup.+; HPLC
(Method B) >99% (AUC), t.sub.R=12.9 min.
Example 29
Preparation of
1-(2,5-Dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-7-yl)-4-(2-fluor-
o-4-methoxyphenyl)pyridin-2(1H)-one hydrochloride
##STR00090##
[0182] Following the procedure of Example 25 (step b), but
substituting 2-fluoro-4-methoxyphenylboronic acid for
4-fluorophenylboronic acid, the title compound (46 mg, 53%) was
obtained as a yellow solid: mp 280-282.degree. C.; .sup.1H NMR (500
MHz, CD.sub.3OD) .delta. 7.72 (d, J=7.0 Hz, 1H), 7.63-7.56 (m, 3H),
7.15 (dd, J=8.5, 1.5 Hz, 1H), 6.92 (dd, J=8.5, 2.5 Hz, 1H), 6.87
(dd, J=13.0, 2.0 Hz, 1H), 6.83 (s, 1H), 6.76 (d, J=7.0 Hz, 1H),
4.77 (d, J=14.0 Hz, 1H), 4.41 (d, J=14.0 Hz, 1H), 3.94-3.90 (m,
1H), 3.88 (s, 3H), 3.76 (s, 3H), 3.66-3.60 (m, 1H), 3.27 (m, 2H),
3.15 (s, 3H); ESI MS m/z 418 [M+H].sup.+; HPLC (Method B) >99%
(AUC), t.sub.R=12.9 min.
Example 30
Preparation of
4-(Benzyloxy)-1-(2,9-dimethyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-7--
yl)pyridin-2(1H)-one hydrochloride
a) 2-(6-Bromo-1H-indol-3-yl)ethanamine
[0183] Beilstein Registry Number 6056308
##STR00091##
[0184] 3-Bromophenylhydrazine hydrochloride (20.0 g, 85.8 mmol) was
reacted according to the procedure of Mascal et al. (Rinehart,
Kenneth L.; Kobayashi, Jun'ichi; Harbour, Gary C.; Gilmore, Jeremy;
Mascal, Mark; et al. J. Am. Chem. Soc. 1987, 109, 3378-3387) to
provide the title compound as a 1:1 mixture of the 6-bromo and
7-bromo-regioisomers (13.2 g, 65%), obtained as an orange solid:
ESI MS m/z 239 [M+H].sup.+.
b) 7-Bromo-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole
[0185] Beilstein Registry Number 5935540
##STR00092##
[0186] 2-(6-Bromo-1H-indol-3-yl)ethanamine (13.2 g, 55.2 mmol) was
reacted according to the procedure of Mascal et al. (Rinehart,
Kenneth L.; Kobayashi, Jun'ichi; Harbour, Gary C.; Gilmore, Jeremy;
Mascal, Mark; et al. J. Am. Chem. Soc. 1987, 109, 3378-3387) to
provide the title compound as a 1:1 mixture of the 7-bromo and
8-bromo-regioisomers (8.8 g, 63%), obtained as an orange solid: ESI
MS m/z 251 [M+H].sup.+.
c) tert-Butyl
7-bromo-3,4-dihydro-1H-pyrido[3,4-b]indole-2(9H)-carboxylate
##STR00093##
[0188] 7-Bromo-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (8.81 g,
35.1 mmol, present as a mixture with the 8-bromo regioisomer) was
suspended in CH.sub.2Cl.sub.2 (100 mL) and THF (10 mL). Boc
anhydride (7.83 g, 38.6 mmol) and a catalytic amount of
4-(dimethylamino)pyridine (DMAP) were added. After 24 h, the
mixture was concentrated. Purification by flash column
chromatography (silica gel, hexanes/ethyl acetate, 97:3 to 70:30)
separated the 7- and 8-regioisomers and gave the title compound
(3.37 g, 27%) as a white powder: .sup.1H NMR (500 MHz, CDCl.sub.3)
.delta. 7.94 (br s, 1H), 7.45 (d, J=1.6 Hz, 1H), 7.32 (d, J=8.3 Hz,
1H), 7.19 (dd, J=8.3, 1.3 Hz, 1H), 4.61 (br s, 2H), 3.75 (br s,
2H), 2.76 (br s, 2H), 1.50 (s, 9H).
d) tert-Butyl
7-bromo-9-methyl-3,4-dihydro-1H-pyrido[3,4-b]indole-2(9H)-carboxylate
##STR00094##
[0190] tert-Butyl
7-bromo-3,4-dihydro-1H-pyrido[3,4-b]indole-2(9H)-carboxylate (1.96
g, 5.58 mmol) was dissolved in DMF (20 mL), and sodium hydride (60%
weight dispersion in mineral oil, 330 mg, 8.37 mmol) was added.
After 30 minutes, methyl iodide (0.52 mL, 8.4 mmol) was added, and
the reaction stirred for a further 2 h. The mixture was diluted
with methylene chloride and washed with 5% lithium chloride
solution (5.times.), dried and concentrated. Purification by flash
column chromatography (silica gel, hexanes/ethyl acetate, 97:3 to
75:25) gave the title compound (1.75 g, 86%) as a white powder:
.sup.1H NMR (500 MHz, CD.sub.3OD) .delta. 7.41 (d, J=1.5 Hz, 1H),
7.32 (d, J=8.3 Hz, 1H), 7.18 (dd, J=8.4, 1.6 Hz, 1H), 4.60 (br s,
2H), 3.73 (br s, 2H), 3.59 (s, 3H), 2.76 (br s, 2H), 1.50 (s,
9H).
e) 7-Bromo-9-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole
##STR00095##
[0192]
tert-Butyl-7-bromo-9-methyl-3,4-dihydro-1H-pyrido[3,4-b]indole-2(9H-
)-carboxylate (1.75 g, 4.79 mmol) was dissolved in CH.sub.2Cl.sub.2
(10 mL) and trifluoroacetic acid (TFA) (10 mL) was added. After
stirring for 1 h, the mixture was diluted with methylene chloride
(50 mL), washed with saturated Na.sub.2CO.sub.3 solution, dried
over sodium sulfate and concentrated to provide the title compound
(1.24 g, 97%) as a yellow oil: .sup.1H NMR (300 MHz, CDCl.sub.3)
.delta. 7.41 (d, J=1.4 Hz, 1H), 7.32 (d, J=8.3 Hz, 1H), 7.17 (dd,
J=8.3, 1.4 Hz, 1H), 4.01 (s, 2H), 3.55 (s, 3H), 3.15 (t, J=6.0 Hz,
2H), 2.72 (t, J=5.7 Hz, 2H).
f)
7-Bromo-2,9-dimethyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole
##STR00096##
[0194] 7-Bromo-9-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole
(1.24 g, 4.68 mmol) was dissolved in a mixture of MeOH (20 mL) and
CH.sub.2Cl.sub.2 (5 mL) and formaldehyde (0.56 mL, 37% aqueous
solution) was added. After stirring for 1 h, NaBH(OAc).sub.3 (1.98
g, 9.34 mmol) was added and the mixture stirred for a further 10
minutes. The mixture was diluted with methylene chloride (50 mL),
washed with saturated Na.sub.2CO.sub.3 solution, concentrated and
purified by flash column chromatography (40 g ISCO column eluting
with methylene chloride and a methanol/ammonia mixture (10:1);
gradient 100% methylene chloride to 90% methylene chloride over 30
min at 40 mL/min) to provide the title compound (1.15 g, 88%) as a
white powder: .sup.1H NMR (500 MHz, CDCl.sub.3) .delta. 7.40 (d,
J=1.6 Hz, 1H), 7.32 (d, J=8.4 Hz, 1H), 7.16 (dd, J=8.3, 1.7 Hz,
1H), 3.61 (s, 2H), 3.55 (s, 3H), 2.86-2.76 (m, 4H), 2.56 (s,
3H).
g)
4-(Benzyloxy)-1-(2,9-dimethyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol--
7-yl)pyridin-2(1H)-one hydrochloride
##STR00097##
[0196] A stirred solution of
7-bromo-2,9-dimethyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (250
mg, 0.895 mmol) in DMSO (4 mL) under nitrogen was treated
sequentially with 4-(benzyloxy)pyridin-2(1H)-one (180 mg, 0.895
mmol), 8-hydroxyquinoline (20 mg, 0.14 mmol), CuI (196 mg, 1.04
mmol) and K.sub.2CO.sub.3 (142 mg, 1.04 mmol). The mixture was
placed under vacuum for 30 minutes and then flushed with nitrogen.
After stirring overnight at 130.degree. C., the mixture was allowed
to cool to room temperature, diluted with CH.sub.2Cl.sub.2, washed
with brine, dried over Na.sub.2SO.sub.4 and concentrated.
Purification by flash column chromatography (12 g ISCO column
eluting with methylene chloride and a methanol/ammonia mixture
(10:1); gradient 100% methylene chloride to 80% methylene chloride
over 30 min at 25 mL/min) provided the free-base. This was
dissolved in methylene chloride (2 mL) and treated with 2N HCl in
Et.sub.2O (1 equivalent) and the mixture was concentrated to
provide the title compound (131 mg, 33%) as a yellow solid: mp
270-274.degree. C.; .sup.1H NMR (500 MHz, CD.sub.3OD) .delta.
7.67-7.63 (m, 2H), 7.50-7.40 (m, 3H), 7.43-7.35 (m, 3H), 7.08 (dd,
J=8.3, 1.6 Hz, 1H), 6.40 (dd, J=7.5, 2.6 Hz, 1H), 6.21 (d, J=2.6
Hz, 1H), 5.22 (s, 2H), 4.81-4.80 (m, 1H), 4.58 (d, J=15.3 Hz, 1H),
3.88-3.84 (m, 1H), 3.72 (s, 3H), 3.55-3.49 (m, 1H), 3.21-3.16 (m,
5H); ESI MS m/z 400 [M+H].sup.+; HPLC (Method B) >98.9% (AUC),
t.sub.R=13.0 min.
Example 31
Preparation of
1-(2,9-Dimethyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-7-yl)-4-phenethy-
lpyridin-2(1H)-one hydrochloride
a) (E)-2-Methoxy-4-styrylpyridine
##STR00098##
[0198] 4-Bromo-2-methoxypyridine (1.85 g, 9.84 mmol),
(E)-phenylvinylboronic acid (4.3 g, 30 mmol), K.sub.2CO.sub.3 (4.0
g, 30 mmol) and PdCl.sub.2(dppf) (400 mg, 0.5 mmol) were stirred in
DMSO (15 mL) under vacuum for 30 min. The flask was flushed with
nitrogen and the mixture was heated to 90.degree. C. for 30 min.
Upon cooling, the mixture was diluted with methylene chloride and
washed with 5% lithium chloride solution (5.times.), dried,
concentrated, and the residue was purified by flash column
chromatography (silica gel, hexanes/ethyl acetate, 97:3 to 75:25)
to provide the title compound (1.93 g, 93%) as an orange oil:
.sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 8.12 (d, J=5.2 Hz, 1H),
7.51 (m, 2H), 7.40-7.22 (m, 4H), 7.02-6.94 (m, 2H), 6.78 (s, 1H),
3.95 (s, 3H).
b) 2-Methoxy-4-phenethylpyridine
##STR00099##
[0200] (E)-2-Methoxy-4-styrylpyridine (22.15 g, 104.8 mmol) was
dissolved in MeOH (400 mL) and degassed with a nitrogen stream for
10 minutes. Palladium on charcoal (10%, wet, 5 g) was added and the
reaction mixture was stirred under an atmosphere of hydrogen for 24
h. The reaction mixture was degassed again, and the catalyst was
removed by filtration. Concentration of the filtrate provided the
title compound (22 g, 98%) as a green oil: .sup.1H NMR (500 MHz,
CDCl.sub.3) .delta. 8.04 (d, J=5.3 Hz, 1H), 7.29-7.24 (m, 2H),
7.21-7.15 (m, 3H), 6.69-6.67 (m, 1H), 6.54 (s, 1H), 3.91 (s, 3H),
2.91-2.89 (m, 2H), 2.87-2.84 (m, 2H).
c) 4-Phenethylpyridin-2(1H)-one
##STR00100##
[0202] 2-Methoxy-4-phenethylpyridine (22.0 g, 102 mmol) was stirred
in concentrated hydrochloric acid (200 mL) at 120.degree. C. for 18
h and then concentrated. The residue was dissolved in MeOH (100 mL)
and made basic with aqueous 6N NaOH and re-concentrated until most
of the solvent had been removed. The solids were filtered off,
washed with water and dried under vacuum to provide the title
compound (21.3 g, 95%) as a beige solid: .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 11.31 (br s, 1H), 7.28-7.21 (m, 5H), 7.17 (t,
J=7.1 Hz, 1H), 6.10-6.08 (m, 2H), 2.85-2.82 (m, 2H), 2.70-2.67 (m,
2H).
d)
1-(2,9-Dimethyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-7-yl)-4-phenet-
hylpyridin-2(1H)-one hydrochloride
##STR00101##
[0204] 4-Phenethylpyridin-2(1H)-one (82 mg, 0.41 mmol) and
7-bromo-2,9-dimethyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (115
mg, 0.412 mmol) were reacted following the procedure for Example 30
(step g) to provide the title compound (54 mg, 30%) as a yellow
solid: mp 299-304.degree. C.; .sup.1H NMR (500 MHz, CD.sub.3OD)
.delta. 7.67-7.64 (m, 2H), 7.51 (d, J=1.8 Hz, 1H), 7.30-7.24 (m,
4H), 7.20-7.17 (m, 1H), 7.08 (dd, J=8.4, 1.9 Hz, 1H), 6.56 (dd,
J=6.9, 1.9 Hz, 1H), 6.53 (s, 1H), 4.85 (m, 1H), 4.49 (d, J=15.3 Hz,
1H), 3.89-3.84 (m, 1H), 3.72 (s, 3H), 3.55-3.50 (m, 1H), 3.21-3.19
(m, 2H), 3.16 (s, 3H), 3.02-2.99 (m, 2H), 2.96-2.93 (m, 2H); ESI MS
m/z 398 [M+H].sup.+; HPLC (Method B) 98.1% (AUC), t.sub.R=13.5
min.
Example 32
Preparation of
1-(2,9-Dimethyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-7-yl)-4-(4-(trif-
luoromethyl)benzyloxy)pyridin-2(1H)-one hydrochloride
a) 4-(4-(Trifluoromethyl)benzyloxy)pyridine 1-oxide
##STR00102##
[0206] 4-Trifluoromethylbenzylalcohol (4.2 g, 23 mmol) was
dissolved in DMF (20 mL) and NaH (60% weight dispersion in mineral
oil, 0.92 g, 23 mmol) was added. After stirring for 30 minutes,
4-chloropyridine-N-oxide (1.5 g, 11.5 mmol) was added and the
reaction mixture was heated for 1 h at 120.degree. C. Upon cooling
the mixture was diluted with methylene chloride and washed with 5%
lithium chloride solution (5.times.), dried and concentrated.
Purification by flash column chromatography (40 g ISCO column
eluting with methylene chloride and a methanol/ammonia mixture
(10:1); gradient 100% methylene chloride to 90% methylene chloride
over 30 min at 40 mL/min) provided the title compound (0.6 g, 19%)
as a yellow solid: .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 8.14
(d, J=7.8 Hz, 2H), 7.68 (d, J=8.1 Hz, 2H), 7.52 (d, J=8.1 Hz, 2H),
6.86 (d, J=7.8 Hz, 2H), 5.15 (s, 2H).
b) 4-(4-(Trifluoromethyl)benzyloxy)pyridin-2(1H)-one
##STR00103##
[0208] 4-(4-(Trifluoromethyl)benzyloxy)pyridine 1-oxide (600 mg,
2.22 mmol) was heated to 140.degree. C. in acetic anhydride (20 mL)
for 2 h. The mixture was concentrated and then heated at 80.degree.
C. for 1 h in a mixture of MeOH (10 mL) and aqueous 1N NaOH (10
mL). The resultant black solution was concentrated to a volume of
10 mL and extracted with CHCl.sub.3/EtOH (3:1). The organic layer
was removed and concentrated to provide the title compound (550 mg,
91%) as a tan solid: .sup.1H NMR (300 MHz, CD.sub.3OD) .delta.
7.70-7.60 (m, 4H), 7.41 (d, J=7.0 Hz, 1H), 6.17 (dd, J=7.0, 2.5 Hz,
1H), 5.96 (d, J=2.4 Hz, 1H), 5.18 (s, 2H).
c)
1-(2,9-Dimethyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-7-yl)-4-(4-(tr-
ifluoromethyl)benzyloxy)pyridin-2(1H)-one hydrochloride
##STR00104##
[0210] 4-(4-(Trifluoromethyl)benzyloxy)pyridin-2(1H)-one (100 mg,
0.37 mmol) and
7-bromo-2,9-dimethyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (103
mg, 0.47 mmol) were reacted following the procedure for Example 30
(step g) to provide the title compound (67 mg, 36%) as a
light-brown solid: mp 280-285.degree. C.; .sup.1H NMR (500 MHz,
CD.sub.3OD) .delta. 7.78-7.73 (m, 3H), 7.69-7.64 (m, 3H), 7.52 (d,
J=1.8 Hz, 1H), 7.18-7.08 (m, 1H), 6.55-6.52 (m, 1H), 6.28 (d, J=2.6
Hz, 1H), 5.35 (s, 2H), 4.82-4.80 (m, 1H), 4.50 (d, J=15.4 Hz, 1H),
3.89-3.85 (m, 1H), 3.73 (s, 3H), 3.55-3.50 (m, 1H), 3.22-3.16 (m,
5H); ESI MS m/z 468 [M+H].sup.+; HPLC (Method B) >99% (AUC),
t.sub.R=14.4 min.
Example 33
Preparation of
4-(4-Chlorobenzyloxy)-1-(2,9-dimethyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]-
indol-7-yl)pyridin-2(1H)-one hydrochloride
a) 4-(4-Chlorobenzyloxy)pyridine 1-oxide
[0211] Beilstein Registry Number 7707045
##STR00105##
[0212] 4-Chlorobenzylalcohol (5.0 g, 35 mmol) was dissolved in DMF
(25 mL) and NaH (60% weight dispersion in mineral oil, 0.92 g, 23
mmol) was added. After stirring for 30 minutes,
4-chloropyridine-N-oxide (2.27 g, 17.5 mmol) was added and the
reaction mixture was heated for 1 h at 120.degree. C. Upon cooling,
the mixture was diluted with methylene chloride and washed with 5%
lithium chloride solution (5.times.), dried and concentrated.
Purification by flash column chromatography (12 g ISCO column
eluting with methylene chloride and a methanol/ammonia mixture
(10:1); gradient 100% methylene chloride to 90% methylene chloride
over 30 min at 25 mL/min) provided the title compound (1.9 g, 47%)
as an orange solid: .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 8.11
(d, J=7.7 Hz, 2H), 7.40 (d, J=8.6 Hz, 2H), 7.34 (d, J=8.6 Hz, 2H),
6.86 (d, J=7.7 Hz, 2H), 5.06 (s, 2H).
b) 4-(4-Chlorobenzyloxy)pyridin-2(1H)-one
[0213] Beilstein Registry Number 7707762
##STR00106##
[0214] 4-(4-Chlorobenzyloxy)pyridine 1-oxide (1.95 g, 8.24 mmol)
was reacted according to the procedure of Example 32 (step b), and
the crude product was purified by flash column chromatography (40 g
ISCO column eluting with methylene chloride and a methanol/ammonia
mixture (10:1); gradient 100% methylene chloride to 90% methylene
chloride over 30 min at 40 mL/min) to provide the title compound
(1.0 g, 51%) as a yellow solid: .sup.1H NMR (500 MHz, CDCl.sub.3)
.delta. 12.70 (br s, 1H), 7.37 (d, J=8.5 Hz, 2H), 7.33 (d, J=8.5
Hz, 2H), 7.22 (d, J=7.3 Hz, 1H), 6.02 (dd, J=7.3, 2.5 Hz, 1H), 5.93
(d, J=2.5 Hz, 1H), 4.98 (s, 2H).
c)
4-(4-Chlorobenzyloxy)-1-(2,9-dimethyl-2,3,4,9-tetrahydro-1H-pyrido[3,4--
b]indol-7-yl)pyridin-2(1H)-one hydrochloride
##STR00107##
[0216] 4-(4-Chlorobenzyloxy)pyridin-2(1H)-one (82 mg, 0.34 mmol)
and 7-bromo-2,9-dimethyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole
(97 mg, 0.34 mmol) were reacted following the procedure for Example
30 (step g) to provide the title compound (28 mg, 17%) as a yellow
solid: mp 290-296.degree. C.; .sup.1H NMR (500 MHz, CD.sub.3OD)
.delta. 7.83 (d, J=7.6 Hz, 1H), 7.68 (d, J=8.3 Hz, 1H), 7.50-7.46
(m, 3H), 7.44-7.42 (m, 2H), 7.08 (dd, J=8.3, 1.8 Hz, 1H), 6.41 (dd,
J=7.6, 2.6 Hz, 1H), 6.21 (d, J=2.6 Hz, 1H), 5.21 (s, 2H), 4.86-4.84
(m, 1H), 4.49 (d, J=15.4 Hz, 1H), 3.88-3.84 (m, 1H), 3.72 (s, 3H),
3.55-3.50 (m, 1H), 3.21-3.16 (m, 5H); ESI MS m/z 434 [M+H].sup.+;
HPLC (Method B) 98.6% (AUC), t.sub.R=14.0 min.
Example 34
Preparation of
1-(2,9-Dimethyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-7-yl)-4-(pyridin-
-2-ylmethoxy)pyridin-2(1H)-one dihydrochloride
a) 4-(Pyridin-2-ylmethoxy)pyridine 1-oxide
##STR00108##
[0218] 2-Pyridylbenzylalcohol (1.67 g, 15.3 mmol) was dissolved in
1,4-dioxane (25 mL) and NaH (60% weight dispersion in mineral oil,
0.92 g, 23 mmol) was added. After stirring for 30 minutes,
4-chloropyridine-N-oxide (2.27 g, 17.5 mmol) was added and the
reaction mixture was heated for 1 h at 120.degree. C. Upon cooling,
the mixture was purified by flash column chromatography (40 g ISCO
column eluting with methylene chloride and a methanol/ammonia
mixture (10:1); gradient 100% methylene chloride to 90% methylene
chloride over 30 min at 40 mL/min) to provide the title compound
(600 mg, 38%) as a brown solid: .sup.1H NMR (500 MHz, CDCl.sub.3)
.delta. 8.62-8.61 (m, 1H), 8.13-8.10 (m, 2H), 7.74 (overlapping
ddd, J=7.8, 1.4 Hz, 1H), 7.44 (d, J=7.8 Hz, 1H), 7.30 (d, J=4.8 Hz,
1H), 6.92-6.89 (m, 2H), 5.23 (s, 2H).
b) 4-(Pyridin-2-ylmethoxy)pyridin-2(1H)-one
##STR00109##
[0220] 4-(Pyridin-2-ylmethoxy)pyridine 1-oxide (9.0 g, 45 mmol) was
heated to 140.degree. C. in acetic anhydride (100 mL) for 2 h. The
solution was concentrated and then heated at 80.degree. C. for 1 h
in a mixture of MeOH (50 mL) and H.sub.2O (50 mL). The resultant
black solution was concentrated and the residue was dissolved in
hot i-PrOH (40 ml). Et.sub.2O (250 mL) was added and the mixture
was placed in the freezer for 16 h. The solid was filtered off to
provide the title compound (1.9 g, 21%) as a brown solid: .sup.1H
NMR (300 MHz, DMSO-d.sub.6) .delta. 11.13 (br s, 1H), 8.58 (d,
J=4.7 Hz, 1H), 7.85 (overlapping ddd, J=7.9, 1.6 Hz, 1H), 7.49 (d,
J=7.9 Hz, 1H), 7.38-7.34 (m, 1H), 7.26 (d, J=7.3 Hz, 1H), 5.96 (dd,
J=7.3, 2.5 Hz, 1H), 5.76 (d, J=3.4 Hz, 1H), 5.12 (s, 2H).
c)
1-(2,9-Dimethyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-7-yl)-4-(pyrid-
in-2-ylmethoxy)pyridin-2(1H)-one dihydrochloride
##STR00110##
[0222] 4-(Pyridin-2-ylmethoxy)pyridin-2(1H)-one (109 mg, 0.539
mmol) and
7-bromo-2,9-dimethyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (97
mg, 0.34 mmol) were reacted following the procedure for Example 30
(step g) to provide the title compound (28 mg, 11%) as a yellow
solid: mp 160-175.degree. C.; .sup.1H NMR (500 MHz, CD.sub.3OD)
.delta. 8.90 (dd, J=5.8, 1.8 Hz, 1H), 8.65 (overlapping ddd, J=7.9,
1.6 Hz, 1H), 8.20 (d, J=8.0 Hz, 1H), 8.07 (overlapping dd, J=6.4
Hz, 1H), 7.70 (d, J=7.6 Hz, 1H), 7.65 (d, J=6.4 Hz, 1H), 7.49 (d,
J=1.7 Hz, 1H), 7.07 (dd, J=6.8, 1.8 Hz, 1H), 6.63 (dd, J=7.6, 2.7
Hz, 1H), 6.21 (d, J=2.7 Hz, 1H), 5.59 (s, 2H), 4.80 (m, 1H), 4.50
(d, J=15.3 Hz, 1H), 3.88-3.85 (m, 1H), 3.73 (s, 3H), 3.55-3.50 (m,
1H), 3.21-3.16 (m, 5H); ESI MS m/z 401 [M+H].sup.+; HPLC (Method B)
>99% (AUC), t.sub.R=9.3 min.
Example 35
Preparation of
4-((5-Chloropyridin-2-yl)methoxy)-1-(2,9-dimethyl-2,3,4,9-tetrahydro-1H-p-
yrido[3,4-b]indol-7-yl)pyridin-2(1H)-one dihydrochloride
a) 4-((5-Chloropyridin-2-yl)methoxy)pyridine 1-oxide
##STR00111##
[0224] 5-Chloro-2-pyridylbenzylalcohol (4.9 g, 34 mmol) and
4-chloropyridine-N-oxide (2.94 g, 22.7 mmol) were reacted according
to Example 34 (step a) to provide the title compound (2.2 g, 40%)
as a tan solid: .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 8.58 (d,
J=2.2 Hz, 1H), 8.13 (d, J=7.7 Hz, 2H), 7.74 (dd, J=8.4, 2.5 Hz,
1H), 7.43 (d, J=8.4 Hz, 1H), 6.90 (d, J=7.7 Hz, 2H), 5.20 (s,
2H).
##STR00112##
[0225] 5-Chloro-2-pyridylbenzylalcohol (4.9 g, 34 mmol) and
4-chloropyridine-N-oxide (2.94 g, 22.7 mmol) were reacted according
to Example 34 (step a) to provide the title compound (2.2 g, 40%)
as a tan solid: .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 8.58 (d,
J=2.2 Hz, 1H), 8.13 (d, J=7.7 Hz, 2H), 7.76-7.72 (dd, J=8.4, 2.5
Hz, 1H), 7.43 (d, J=8.4 Hz, 1H), 6.90 (d, J=7.7 Hz, 2H), 5.20 (s,
2H).
b) 4-((5-Chloropyridin-2-yl)methoxy)pyridin-2(1H)-one
##STR00113##
[0227] 4-((5-Chloropyridin-2-yl)methoxy)pyridine 1-oxide (2.2 g,
9.2 mmol) was reacted according to Example 34 (step b) to provide
the title compound (1.52 g, 69%) as a tan solid: .sup.1H NMR (500
MHz, CD.sub.3OD) .delta. 8.56 (d, J=2.3 Hz, 1H), 7.91-7.89 (dd,
J=8.4, 2.5 Hz, 1H), 7.56 (d, J=8.4 Hz, 1H), 7.34 (d, J=8.3 Hz, 1H),
6.21-6.19 (dd, J=7.2, 2.5 Hz, 1H), 5.97 (d, J=2.4 Hz, 1H), 5.18 (s,
2H).
c) tert-Butyl
7-(4-((5-chloropyridin-2-yl)methoxy)-2-oxopyridin-1(2H)-yl)-9-methyl-3,4--
dihydro-1H-pyrido[3,4-b]indole-2(9H)-carboxylate
##STR00114##
[0229] 4-((5-Chloropyridin-2-yl)methoxy)pyridin-2(1H)-one (259 mg,
1.09 mmol) and tert-butyl
7-bromo-9-methyl-3,4-dihydro-1H-pyrido[3,4-b]indole-2(9H)-carboxylate
(400 mg, 1.1 mmol) were reacted following the procedure of Example
30 (step g) to provide the title compound (145 mg, 25%) as a yellow
solid: ESI MS m/z 521 [M+H].sup.+.
d)
4-((5-Chloropyridin-2-yl)methoxy)-1-(9-methyl-2,3,4,9-tetrahydro-1H-pyr-
ido[3,4-b]indol-7-yl)pyridin-2(1H)-one dihydrochloride
##STR00115##
[0231] tert-Butyl
7-(4-((5-chloropyridin-2-yl)methoxy)-2-oxopyridin-1
(2H)-yl)-9-methyl-3,4-dihydro-1H-pyrido[3,4-b]indole-2(9H)-carboxylate
(145 mg, 0.278 mmol) was deprotected and converted to the
dihydrochloride salt according to the procedure of Example 30
(steps e and g) to provide the title compound (114 mg, 94%) as a
yellow solid: mp 275-280.degree. C.; .sup.1H NMR (500 MHz,
CD.sub.3OD) .delta. 8.61 (s, 1H), 7.77 (dd, J=8.3, 3.8 Hz, 1H),
7.64-7.62 (m, 3H), 7.47 (d, J=1.6 Hz, 1H), 7.03 (dd, J=8.4, 1.8 Hz,
1H), 6.37 (dd, J=7.6, 3.8 Hz, 1H), 6.15 (d, J=2.7 Hz, 1H), 5.28 (s,
2H), 4.54 (s, 2H), 3.71 (s, 3H), 3.60 (t, J=6.1 Hz, 2H), 3.12 (t,
J=6.0 Hz, 2H); ESI MS m/z 421 [M+H].sup.+; HPLC (Method B) 98.5%
(AUC), t.sub.R=12.1 min
Example 36
Preparation of
4-((5-Chloropyridin-2-yl)methoxy)-1-(2,9-dimethyl-2,3,4,9-tetrahydro-1H-p-
yrido[3,4-b]indol-7-yl)pyridin-2(1H)-one dihydrochloride
##STR00116##
[0233]
4-((5-Chloropyridin-2-yl)methoxy)-1-(9-methyl-2,3,4,9-tetrahydro-1H-
-pyrido[3,4-b]indol-7-yl)pyridin-2(1H)-one (80 mg, 0.19 mmol) was
dissolved a mixture of MeOH (3 mL) and CH.sub.2Cl.sub.2 (1 mL) and
formaldehyde (9.0 mg, 0.29 mmol, 37% aqueous solution) was added.
After stirring for 45 minutes, NaBH(OAc).sub.3 (80 mg, 0.38 mmol)
was added and the reaction mixture was stirred for a further 10
minutes. The mixture was diluted with CH.sub.2Cl.sub.2, washed with
saturated Na.sub.2CO.sub.3 solution and concentrated to provide the
free base. Conversion to the dihydrochloride salt using the
procedure of Example 30 (step g) provided the title compound (83
mg, 86%) as an orange solid: mp 202-210.degree. C.; .sup.1H NMR
(500 MHz, CD.sub.3OD) .delta. 8.68 (br s, 1H), 8.05 (dd, J=8.0, 2.4
Hz, 1H), 7.76 (d, J=8.4 Hz, 1H), 7.71 (d, J=8.4 Hz, 1H), 7.65 (d,
J=8.3 Hz, 1H), 7.51 (d, J=1.6 Hz, 1H), 7.09 (dd, J=8.3, 1.8 Hz,
1H), 6.53 (dd, J=7.6, 1.7 Hz, 1H), 6.28 (d, J=1.6 Hz, 1H), 5.36 (s,
2H), 4.85-4.80 (m, 1H), 4.49 (d, J=15.3 Hz, 1H), 3.89-3.84 (m, 1H),
3.72 (s, 3H), 3.53-3.47 (m, 1H), 3.22-3.19 (m, 2H), 3.16 (s, 3H);
ESI MS m/z 435 [M+H].sup.+; HPLC (Method B) 97.8% (AUC),
t.sub.R=12.2 min.
Example 37
Preparation of
4-(4-Chlorophenyl)-1-(2,9-dimethyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]ind-
ol-7-yl)pyridin-2(1H)-one hydrochloride
##STR00117##
[0235] 4-(4-Chlorophenyl)pyridin-2(1H)-one (80 mg, 0.33 mmol) and
7-bromo-2,9-dimethyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (49
mg, 0.33 mmol) were reacted following the procedure of Example 30
(step g) to provide the title compound (28 mg, 19%) as a
yellow-green solid: mp 316-323.degree. C.; .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 11.0 (br s, 1H), 7.83 (dd, J=6.8, 1.9 Hz,
2H), 7.76 (d, J=7.1 Hz, 1H), 7.62-7.57 (m, 4H), 7.07 (dd, J=8.3,
1.8 Hz, 1H), 6.81 (d, J=2.0 Hz, 1H), 6.69 (dd, J=7.2, 2.1 Hz, 1H),
4.79 (d, J=15.2 Hz, 1H), 4.44 (dd, J=15.2, 6.0 Hz, 1H), 3.74-3.68
(m, 4H), 3.48-3.38 (m, 1H), 3.10-2.99 (m, 5H); ESI MS m/z 404
[M+H].sup.+; HPLC (Method B) >99% (AUC), t.sub.R=13.5 min.
Example 38
Preparation of
4-(4-Chlorophenyl)-1-(9-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-7-
-yl)pyridin-2(1H)-one hydrochloride
a) tert-Butyl
7-(4-(4-chlorophenyl)-2-oxopyridin-1(2H)-yl)-9-methyl-3,4-dihydro-1H-pyri-
do[3,4-b]indole-2(9H)-carboxylate
##STR00118##
[0237] 4-(4-Chlorophenyl)pyridin-2(1H)-one (74 mg, 0.32 mmol) and
tert-butyl
7-bromo-9-methyl-3,4-dihydro-1H-pyrido[3,4-b]indole-2(9H)-carboxylate
(74 mg, 0.36 mmol) were coupled following the procedure of Example
30 (step g) to provide the title compound (85 mg, 54%) as a yellow
solid: .sup.1H NMR (300 MHz, CD.sub.3OD) .delta. 7.58-7.55 (m, 3H),
7.51-7.44 (m, 3H), 7.35 (s, 1H), 7.07 (dd, J=8.2, 1.6 Hz, 1H), 6.87
(d, J=1.8 Hz, 1H), 6.47 (dd, J=7.1, 1.8 Hz, 1H), 4.65 (br m, 2H),
3.75 (br m, 2H), 3.64 (s, 3H), 2.81 (br m, 2H), 1.52 (s, 9H).
b)
4-(4-Chlorophenyl)-1-(9-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-
-7-yl)pyridin-2(1H)-one hydrochloride
##STR00119##
[0239] tert-Butyl
7-(4-(4-chlorophenyl)-2-oxopyridin-1(2H)-yl)-9-methyl-3,4-dihydro-1H-pyri-
do[3,4-b]indole-2(9H)-carboxylate (85 mg, 0.17 mmol) was
deprotected and converted to the hydrochloride salt according to
the procedure of Example 30 (steps e and g) to provide the title
compound (38 mg, 52%) as a yellow solid: mp 310-315.degree. C.;
.sup.1H NMR (500 MHz, CD.sub.3OD) .delta. 7.78-7.75 (m, 3H), 7.67
(d, J=8.3 Hz, 1H), 7.55-7.53 (m, 3H), 7.13 (dd, J=8.3, 1.8 Hz, 1H),
6.91 (d, J=1.9 Hz, 1H), 6.84 (dd, J=7.1, 2.0 Hz, 1H), 4.56 (s, 2H),
3.74 (s, 3H), 3.61 (t, J=6.0 Hz, 2H), 3.14 (t, J=6.0 Hz, 2H); ESI
MS m/z 390 [M+H].sup.+; HPLC (Method B) >99% (AUC), t.sub.R=13.6
min.
Example 39
Preparation of
1-(9-Methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-7-yl)-4-(4-(trifluor-
omethyl)phenyl)pyridin-2(1H)-one hydrochloride hydrochloride
a) 4-(4-(Trifluoromethyl)phenyl)pyridine 1-oxide
##STR00120##
[0241] 4-Chloropyridine-N-oxide (3.0 g, 23 mmol),
4-trifluoromethylphenylboronic acid (6.57 g, 34.6 mmol),
K.sub.2CO.sub.3 (4.8 g, 35 mmol) and PdCl.sub.2(dppf) (470 mg, 0.57
mmol) were stirred in DMSO (40 mL) under vacuum for 30 min. The
flask was flushed with nitrogen and the mixture was heated to
80.degree. C. for 10 min. Upon cooling, the mixture was diluted
with methylene chloride and washed with 5% lithium chloride
solution (5.times.), dried, concentrated and the residue was
purified by flash column chromatography (40 g ISCO column eluting
with methylene chloride and a methanol/ammonia mixture (10:1);
gradient 100% methylene chloride to 80% methylene chloride over 30
min at 40 mL/min) to provide the title compound (1.90 g, 34%) as a
tan solid: ESI MS m/z 240 [M+H].sup.+.
b) 4-(4-(Trifluoromethyl)phenyl)pyridin-2(1H)-one
##STR00121##
[0243] 4-(4-(Trifluoromethyl)phenyl)pyridine-1-oxide (1.9 g, 7.9
mmol) was reacted according to the procedure of Example 32 (step b)
to provide the title compound (1.26 g, 66%) as a brown solid:
.sup.1H NMR (300 MHz, CD.sub.3OD) .delta. 7.80-7.74 (br m, 5H),
6.85-6.66 (br m, 2H).
c) tert-Butyl
9-methyl-7-(2-oxo-4-(4-(trifluoromethyl)phenyl)pyridin-1(2H)-yl)-3,4-dihy-
dro-1H-pyrido[3,4-b]indole-2(9H)-carboxylate
##STR00122##
[0245] 4-(4-(Trifluoromethyl)phenyl)pyridin-2(1H)-one (86 mg, 0.36
mmol) and tert-butyl
7-bromo-9-methyl-3,4-dihydro-1H-pyrido[3,4-b]indole-2(9H)-carboxylate
(120 mg, 0.32 mmol) were reacted following the procedure of Example
30 (step g) to provide the title compound (97 mg, 58%) as a yellow
solid: .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 7.74 (s, 4H),
7.58-7.52 (m, 2H), 7.36 (s, 1H), 7.08 (dd, J=8.2, 1.8 Hz, 1H), 6.92
(d, J=1.9 Hz, 1H), 6.50 (dd, J=7.2, 2.0 Hz, 1H), 4.65 (br m, 2H),
3.76 (br m, 2H), 3.65 (s, 3H), 2.81 (br m, 2H), 1.52 (s, 9H).
d)
1-(9-Methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-7-yl)-4-(4-(triflu-
oromethyl)phenyl)pyridin-2(1H)-one hydrochloride
##STR00123##
[0247] tert-Butyl
9-methyl-7-(2-oxo-4-(4-(trifluoromethyl)phenyl)pyridin-1(2H)-yl)-3,4-dihy-
dro-1H-pyrido[3,4-b]indole-2(9H)-carboxylate (97 mg, 0.19 mmol) was
deprotected and converted to the hydrochloride salt according to
the procedure of Example 30 (steps e and g) to provide the title
compound (53 mg, 62%) as a yellow solid: mp 316-321.degree. C.;
.sup.1H NMR (300 MHz, CD.sub.3OD) .delta. 7.97 (d, J=8.1 Hz, 2H),
7.87-7.80 (m, 3H), 7.68 (d, J=8.2 Hz, 1H), 7.57 (d, J=1.5 Hz, 1H),
7.14 (dd, J=8.3, 1.8 Hz, 1H), 6.96 (d, J=1.8 Hz, 1H), 6.87 (dd,
J=7.2, 1.8 Hz, 1H), 4.56 (s, 2H), 3.74 (s, 3H), 3.61 (t, J=6.0 Hz,
2H), 3.14 (t, J=6.0 Hz, 2H); ESI MS m/z 424 [M+H].sup.+; HPLC
(Method B) 96.3% (AUC), t.sub.R=14.0 min.
Example 40
Preparation of
1-(2,9-Dimethyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-7-yl)-4-(4-(trif-
luoromethyl)phenyl)pyridin-2(1H)-one hydrochloride
##STR00124##
[0249] 4-(4-(Trifluoromethyl)phenyl)pyridin-2(1H)-one (100 mg, 0.42
mmol) and
7-bromo-2,9-dimethyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (117
mg, 0.419 mmol) were reacted following the procedure of Example 30
(step g) to provide the title compound (70 mg, 35%) as a
yellow-brown solid: mp 294-299.degree. C.; .sup.1H NMR (500 MHz,
CD.sub.3OD) .delta. 7.96 (d, J=8.2 Hz, 2H), 7.85-7.83 (m, 3H), 7.68
(d, J=8.3 Hz, 1H), 7.58 (d, J=1.6 Hz, 1H), 7.16 (dd, J=8.3, 1.7 Hz,
1H), 6.98 (d, J=1.8 Hz, 1H), 6.90 (dd, J=7.1, 1.9 Hz, 1H),
4.87-4.86 (m, 1H), 4.51 (d, J=15.3 Hz, 1H), 3.90-3.86 (m, 1H), 3.74
(s, 3H), 3.57-3.51 (m, 1H), 3.23-3.20 (m, 2H), 3.17 (s, 3H); ESI MS
m/z 438 [M+H].sup.+; HPLC (Method B) 95.6% (AUC), t.sub.R=14.1
min.
Example 41
Preparation of
4-(2,4-Dichlorophenyl)-1-(2,9-dimethyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b-
]indol-7-yl)pyridin-2(1H)-one hydrochloride
a) 4-(2,4-Dichlorophenyl)pyridine 1-oxide
##STR00125##
[0251] 4-Chloropyridine-N-oxide (1.5 g, 12 mmol),
2,4-dichlorophenylboronic acid (5.4 g, 29 mmol) were reacted
according to the procedure of Example 39 (step a) to provide the
title compound (1.40 g, 50%) as a grey solid: .sup.1H NMR (500 MHz,
CD.sub.3OD) .delta. 8.26 (d, J=6.9 Hz, 2H), 7.53 (d, J=2.0 Hz, 1H),
7.37-7.35 (m, 3H), 7.29 (d, J=8.3 Hz, 1H).
b) 4-(2,4-Dichlorophenyl)pyridin-2(1H)-one
##STR00126##
[0253] 4-(2,4-Dichlorophenyl)pyridine 1-oxide (1.4 g, 5.8 mmol) was
reacted according to the procedure of Example 32 (step b) to
provide the title compound (0.95 g, 67%) as a brown solid: .sup.1H
NMR (300 MHz, DMSO-d.sub.6) .delta. 11.75 (br m, 1H), 7.75 (s, 1H),
7.51-7.46 (m, 3H), 6.31-6.22 (m, 2H).
c)
4-(2,4-Dichlorophenyl)-1-(2,9-dimethyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-
-b]indol-7-yl)pyridin-2(1H)-one hydrochloride
##STR00127##
[0255] 4-(2,4-Dichlorophenyl)pyridin-2(1H)-one (103 mg, 0.429 mmol)
and 7-bromo-2,9-dimethyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole
(120 mg, 0.43 mmol) were reacted following the procedure of Example
30 (step g) to provide the title compound (44 mg, 21%) as a yellow
solid: mp 308-313.degree. C.; .sup.1H NMR (500 MHz, CD.sub.3OD)
.delta. 7.77 (d, J=7.0 Hz, 1H), 7.68 (d, J=8.4 Hz, 1H), 7.65
(overlapping dd, J=1.1 Hz, 1H), 7.58 (d, J=1.7 Hz, 1H), 7.49 (s,
2H), 7.16 (dd, J=8.3, 1.8 Hz, 1H), 6.70 (d, J=1.5 Hz, 1H), 6.62
(dd, J=7.0, 1.9 Hz, 1H), 4.86 (m, 1H), 4.50 (d, J=15.3 Hz, 1H),
3.89-3.85 (m, 1H), 3.74 (s, 3H), 3.56-3.55 (m, 1H), 3.23-3.20 (m,
2H), 3.16 (s, 3H); ESI MS m/z 438 [M+H].sup.+; HPLC (Method B)
98.5% (AUC), t.sub.R=14.3 min.
Example 42
Preparation of
4-(Benzyloxy)-1-(9-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-7-yl)p-
yridin-2(1H)-one hydrochloride
a) tert-Butyl 7-(4-(benzyloxy)-2-oxopyridin-1
(2H)-yl)-9-methyl-3,4-dihydro-1H-pyrido[3,4-b]indole-2(9H)-carboxylate
##STR00128##
[0257] 4-(Benzyloxy)pyridin-2(1H)-one (580 mg, 0.28 mmol) and
tert-butyl
7-bromo-9-methyl-3,4-dihydro-1H-pyrido[3,4-b]indole-2(9H)-carboxylate
(850 mg, 0.23 mmol) were reacted following the procedure of Example
30 (step g) to provide the title compound (700 mg, 62%) as a green
solid: .sup.1H NMR (500 MHz, CDCl.sub.3) .delta. 7.52 (d, J=8.2 Hz,
1H), 7.44-7.39 (m, 4H), 7.38-7.35 (m, 1H), 7.31-7.28 (m, 2H), 7.01
(dd, J=8.3, 1.8 Hz, 1H), 6.09 (d, J=2.6 Hz, 1H), 6.04 (dd, J=7.6,
2.6 Hz, 1H), 5.05 (s, 2H), 4.64 (br m, 2H), 3.74 (br m, 2H), 3.62
(s, 3H), 2.79 (br m, 2H), 1.47 (s, 9H).
b)
4-(Benzyloxy)-1-(9-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-7-yl-
)pyridin-2(1H)-one hydrochloride
##STR00129##
[0259] tert-Butyl 7-(4-(benzyloxy)-2-oxopyridin-1
(2H)-yl)-9-methyl-3,4-dihydro-1H-pyrido[3,4-b]indole-2(9H)-carboxylate
(700 mg, 1.44 mmol) was deprotected and converted to the
hydrochloride salt according to the procedure of Example 30 (steps
e and g) to provide the title compound (530 mg, 83%) as a yellow
solid: mp 251-257.degree. C.; .sup.1H NMR (500 MHz, DMSO-d.sub.6)
.delta. 9.71 (br s, 2H), 7.56 (d, J=7.6 Hz, 1H), 7.54 (d, J=8.3 Hz,
1H), 7.50-7.47 (m, 3H), 7.44-7.41 (m, 2H), 7.38-7.37 (m, 1H), 6.99
(dd, J=8.3, 1.8 Hz, 1H), 6.11 (dd, J=7.6, 2.8 Hz, 1H), 5.97 (d,
J=2.6 Hz, 1H), 5.15 (s, 2H), 4.45 (s, 2H), 3.81 (s, 3H), 3.42-3.41
(m, 2H), 2.98-2.97 (m, 2H); ESI MS m/z 386 [M+H].sup.+; HPLC
(Method B) >99% (AUC), t.sub.R=12.9 min.
Example 43
Preparation of
4-(Benzyloxy)-1-(2-(2-hydroxyethyl)-9-methyl-2,3,4,9-tetrahydro-1H-pyrido-
[3,4-b]indol-7-yl)pyridin-2(1H)-one hydrochloride
##STR00130##
[0261]
4-(Benzyloxy)-1-(9-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol--
7-yl)pyridin-2(1H)-one (70 mg, 0.18 mmol), 2-iodoethanol (156 mg,
0.907 mmol) and K.sub.2CO.sub.3 (250 mg, 1.8 mmol) were combined in
DMF (3 mL) and heated to 80.degree. C. for 1 h. Upon cooling, the
product was purified by preparative HPLC and then flash column
chromatography (12 g ISCO column eluting with methylene chloride
and a methanol/ammonia mixture (10:1); gradient 100% methylene
chloride to 90% methylene chloride over 30 min at 25 mL/min) to
provide the free-base. This was converted to the hydrochloride salt
as of Example 30 (step g) to provide the title compound (14.8 mg,
18%) as a yellow solid: .sup.1H NMR (500 MHz, CD.sub.3OD) .delta.
7.63 (d, J=8.4 Hz, 1H), 7.61 (d, J=7.5 Hz, 1H), 7.47-7.46 (m, 3H),
7.42-7.39 (m, 2H), 7.36 (d, J=7.1 Hz, 1H), 7.06 (dd, J=8.3, 1.8 Hz,
1H), 6.33 (dd, J=7.6, 2.6 Hz, 1H), 6.15 (d, J=2.6 Hz, 1H), 5.19 (s,
2H), 4.81-4.79 (m, 1H), 4.59 (d, J=15.3 Hz, 1H), 4.01 (t, J=5.1 Hz,
2H), 3.97-3.94 (m, 1H), 3.73 (s, 3H), 3.58-3.50 (m, 3H), 3.21-3.16
(m, 2H); ESI MS m/z 430 [M+H].sup.+; HPLC (Method B) 97.2% (AUC),
t.sub.R=12.8 min.
Example 44
Preparation of
4-(Benzyloxy)-1-(9-methyl-2-(2-(pyrrolidin-1-yl)acetyl)-2,3,4,9-tetrahydr-
o-1H-pyrido[3,4-b]indol-7-yl)pyridin-2(1H)-one hydrochloride
a)
4-(Benzyloxy)-1-(2-(2-chloroacetyl)-9-methyl-2,3,4,9-tetrahydro-1H-pyri-
do[3,4-b]indol-7-yl)pyridin-2(1H)-one
##STR00131##
[0263]
4-(Benzyloxy)-1-(2-(2-hydroxyethyl)-9-methyl-2,3,4,9-tetrahydro-1H--
pyrido[3,4-b]indol-7-yl)pyridin-2(1H)-one hydrochloride (100 mg,
0.23 mmol) was stirred in a mixture of CH.sub.2Cl.sub.2 (2 mL) and
saturated NaHCO.sub.3 solution (2 mL) and chloroacetyl chloride (32
mg, 0.28 mmol) was added. After 1.5 h, the organic layer was
removed and concentrated to provide the title compound (120 mg,
100%) as a yellow oil: ESI MS m/z 462 [M+H].sup.+.
b)
4-(Benzyloxy)-1-(9-methyl-2-(2-(pyrrolidin-1-yl)acetyl)-2,3,4,9-tetrahy-
dro-1H-pyrido[3,4-b]indol-7-yl)pyridin-2(1H)-one hydrochloride
##STR00132##
[0265] 4-(Benzyloxy)-1-(2-(2-chloroacetyl)-9-methyl-2,
3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-7-yl)pyridin-2(1H)-one (120
mg. 0.23 mmol), pyrrolidine (85 mg, 1.2 mmol) and K.sub.2CO.sub.3
(331 mg, 2.39 mmol) were combined in DMF (3 mL) and heated to
80.degree. C. for 1 h. Upon cooling, the mixture was diluted with
methylene chloride and washed with 5% lithium chloride solution
(5.times.), dried over Na.sub.2SO.sub.4 and concentrated. The
residue was converted to the hydrochloride salt as of Example 30
(step g) to provide the title compound (110 mg, 60%) as a yellow
solid: mp 190-200.degree. C.; .sup.1H NMR (500 MHz, CD.sub.3OD)
.delta. 7.86 (d, J=7.5 Hz, 1H), 7.62 (dd, J=8.2, 2.7 Hz, 1H),
7.51-7.50 (m, 3H), 7.46-7.43 (m, 2H), 7.41-7.40 (m, 1H), 7.08-7.06
(m, 1H), 6.63 (dd, J=7.8, 2.6 Hz, 1H), 6.40 (d, J=1.4 Hz, 1H), 5.31
(s, 2H), 4.93 (s, 1.3H), 4.77 (s, 0.7H), 4.56-4.55 (m, 2H),
4.04-4.02 (m, 0.6H), 3.81-3.78 (m, 3.4H), 3.76 (s, 3H), 3.24-3.19
(m, 2H), 2.79-2.97 (m, 1.3H), 2.92-2.85 (m, 0.7H), 2.22-2.19 (m,
2H), 2.11-2.19 (m, 2H); ESI MS m/z 497 [M+H].sup.+; HPLC (Method B)
>99% (AUC), t.sub.R=13.7 min.
Example 45
Preparation of
(S)-4-(Benzyloxy)-1-(9-methyl-2-(pyrrolidine-2-carbonyl)-2,3,4,9-tetrahyd-
ro-1H-pyrido[3,4-b]indol-7-yl)pyridin-2(1H)-one hydrochloride
a) (S)-tert-Butyl 2-(7-(4-(benzyloxy)-2-oxopyridin-1
(2H)-yl)-9-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-2-carbonyl)py-
rrolidine-1-carboxylate
##STR00133##
[0267]
4-(Benzyloxy)-1-(9-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol--
7-yl)pyridin-2(1H)-one hydrochloride (50 mg, 0.12 mmol) was stirred
in DMF (1 mL) and saturated Boc-L-proline (30 mg, 0.14 mmol), HATU
(68 mg, 0.18 mmol) and Et.sub.3N (36 mg, 0.36 mmol) were added.
After 16 h, the mixture was diluted with methylene chloride and
washed with 5% lithium chloride solution (5.times.), dried over
Na.sub.2SO.sub.4 and concentrated. The residue was purified by
flash column chromatography (12 g ISCO column eluting with
methylene chloride and a methanol/ammonia mixture (10:1); gradient
100% methylene chloride to 90% methylene chloride over 30 min at 25
mL/min) to provide the title compound (55 mg, 78%) as a colorless
oil: ESI MS m/z 583 [M+H].sup.+.
b)
(S)-4-(Benzyloxy)-1-(9-methyl-2-(pyrrolidine-2-carbonyl)-2,3,4,9-tetrah-
ydro-1H-pyrido[3,4-b]indol-7-yl)pyridin-2(1H)-one hydrochloride
##STR00134##
[0269] (S)-tert-Butyl 2-(7-(4-(benzyloxy)-2-oxopyridin-1
(2H)-yl)-9-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-2-carbonyl)py-
rrolidine-1-carboxylate (55 mg, 0.094 mmol) was stirred in a
mixture of MeOH (2 mL) and 2N HCl in Et.sub.2O (8 mL) for 5 h. The
reaction mixture was concentrated to provide the title compound (42
mg, 85%) as a yellow-green solid: mp 220-226.degree. C.; .sup.1H
NMR (500 MHz, CD.sub.3OD) .delta. 7.79 (dd, J=7.5, 1.4 Hz, 1H),
7.47 (d, J=8.3 Hz, 1H), 7.49-7.46 (m, 3H), 7.44-7.46 (m, 2H),
7.39-7.36 (m, 1H), 7.04 (dd, J=8.3, 1.6 Hz, 1H), 6.57-6.55 (m, 1H),
6.34 (d, J=2.5 Hz, 1H), 5.27 (s, 2H), 4.96-4.87 (m, 2H), 3.90-8.86
(m, 2H), 3.77 (s, 3H), 3.48-3.34 (m, 3H), 3.00-2.86 (m, 2H),
2.67-2.61 (m, 1H), 2.17-2.02 (m, 3H); ESI MS m/z 483 [M+H].sup.+;
HPLC (Method B) 95.5% (AUC), t.sub.R=13.5 min.
Example 46
Preparation of
4-(Benzyloxy)-1-(9-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-6-yl)p-
yridin-2(1H)-one hydrochloride
a) 2-(5-Bromo-1H-indol-3-yl)ethanamine
[0270] Beilstein Registry Number 143491
##STR00135##
[0271] 4-Bromophenylhydrazine hydrochloride (20.0 g, 85.8 mmol) was
reacted according to the procedure of Mascal et al. (Rinehart,
Kenneth L.; Kobayashi, Jun'ichi; Harbour, Gary C.; Gilmore, Jeremy;
Mascal, Mark; et al. J. Am. Chem. Soc. 1987, 109, 3378-3387) to
provide the title compound (5.2 g, 25%) as an orange solid: ESI MS
m/z 239 [M+H].sup.+.
b) 6-Bromo-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole
[0272] Beilstein Registry Number 911238
##STR00136##
[0273] 2-(5-Bromo-1H-indol-3-yl)ethanamine (5.2 g, 22 mmol) was
reacted according to the procedure of Mascal et al. (Rinehart,
Kenneth L.; Kobayashi, Jun'ichi; Harbour, Gary C.; Gilmore, Jeremy;
Mascal, Mark; et al. J. Am. Chem. Soc. 1987, 109, 3378-3387) to
provide the title compound (2.6 g, 48%) as an orange solid: ESI MS
m/z 251 [M+H].sup.+.
c) tert-Butyl
6-bromo-3,4-dihydro-1H-pyrido[3,4-b]indole-2(9H)-carboxylate
##STR00137##
[0275] 6-Bromo-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (2.6 g, 10
mmol) was suspended in CH.sub.2Cl.sub.2 (50 mL) and THF (7.5 mL)
and Boc.sub.2O (2.3 g, 11 mmol) was added. After 2.5 h, the mixture
was concentrated. Purification by flash column chromatography
(silica gel, hexanes/ethyl acetate, 97:3 to 70:30) gave the title
compound (1.15 g, 30%) as an orange powder: .sup.1H NMR (300 MHz,
CDCl.sub.3) .delta. 7.59 (s, 1H), 7.23 (d, J=8.5 Hz, 1H), 7.18 (d,
J=8.5 Hz, 1H), 4.68-4.59 (br m, 2H), 3.80-3.70 (br m, 2H),
2.78-2.71 (br m, 2H), 1.50 (s, 9H).
d) tert-Butyl
6-bromo-9-methyl-3,4-dihydro-1H-pyrido[3,4-b]indole-2(9H)-carboxylate
##STR00138##
[0277] tert-Butyl
6-bromo-3,4-dihydro-1H-pyrido[3,4-b]indole-2(9H)-carboxylate (1.15
g, 3.26 mmol) was dissolved in DMF (20 mL) and sodium hydride (60%
weight dispersion in mineral oil, 196 mg, 4.89 mmol) was added.
After 1 h, methyl iodide (0.30 mL, 4.9 mmol) was added and the
reaction mixture was stirred for a further 30 min. The mixture was
diluted with methylene chloride and washed with 5% lithium chloride
solution (5.times.), dried over Na.sub.2SO.sub.4 and concentrated.
Purification by flash column chromatography (silica gel,
hexanes/ethyl acetate, 97:3 to 75:25) gave the title compound (740
mg, 36%) as a yellow solid: .sup.1H NMR (500 MHz, CDCl.sub.3)
.delta. 7.58 (s, 1H), 7.24 (d overlapped by solvent, J=8.5, 1H),
7.14 (d, J=8.5, 1H), 4.67-4.53 (br m, 2H), 3.79-3.67 (br m, 2H),
3.60 (s, 3H), 2.78-2.66 (br m, 2H), 1.51 (s, 9H).
e) tert-Butyl 6-(4-(benzyloxy)-2-oxopyridin-1
(2H)-yl)-9-methyl-3,4-dihydro-1H-pyrido[3,4-b]indole-2(9H)-carboxylate
##STR00139##
[0279] A solution of
tert-Butyl-6-bromo-9-methyl-3,4-dihydro-1H-pyrido[3,4-b]indole-2(9H)-carb-
oxylate (750 mg, 2.03 mmol) in DMSO (10 mL) was stirred under
nitrogen and treated sequentially with
4-(benzyloxy)pyridin-2(1H)-one (448 mg, 2.23 mmol),
8-hydroxyquinoline (44 mg, 0.305 mmol), CuI (58 mg, 0.305 mmol) and
K.sub.2CO.sub.3 (308 mg, 2.23 mmol). After stirring overnight at
130.degree. C., the mixture was allowed to cool to room temperature
and a mixture of MeOH and NH.sub.4OH (10:1, 10 mL) was added. After
stirring for 15 min, the mixture was diluted with CH.sub.2Cl.sub.2,
washed with brine, dried over Na.sub.2SO.sub.4, filtered and
concentrated to dryness. Purification by flash column
chromatography (40 g ISCO column eluting with a 1:1
ethylacetate/hexanes and a methanol/ammonia mixture (10:1);
gradient 100% 1:1 ethylacetate/hexanes to 90% 1:1
ethylacetate/hexanes/10% methanol/ammonia mixture (10:1) over 30
min at 25 mL/min) provided the title compound (340 mg, 33%) as a
yellow solid; .sup.1H NMR (500 MHz, CDCl.sub.3) .delta. 7.50-7.36
(m, 8H), 7.13 (d, J=7.8, Hz, 1H), 6.09 (d, J=2.6 Hz, 1H), 6.03 (dd,
J=7.5, 2.7 Hz, 1H), 5.05 (s, 2H), 4.65 (br s, 2H), 3.73 (br s, 2H),
3.66 (s, 3H), 2.77 (br s, 2H), 1.51 (s, 9H).
f)
4-(Benzyloxy)-1-(9-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-6-yl-
)pyridin-2(1H)-one hydrochloride
##STR00140##
[0281] tert-Butyl 6-(4-(benzyloxy)-2-oxopyridin-1
(2H)-yl)-9-methyl-3,4-dihydro-1H-pyrido[3,4-b]indole-2(9H)-carboxylate
(0.340 g, 0.70 mmol) was dissolved in MeOH (5 mL) and 2N HCl in
ether (15 mL) was added. After stirring for 1 h, the liquid was
decanted off and the resultant solid was filtered and washed with
ether (3.times.). This provided the title compound (267 mg, 98%) as
a light yellow solid: mp 290-300.degree. C.; .sup.1H NMR (500 MHz,
CD.sub.3OD) .delta. 7.66 (d, J=7.5 Hz, 1H), 7.57-7.52 (m, 2H), 7.46
(d, J=7.7 Hz, 2H), 7.41 (overlapping dd, J=7.3 Hz, 2H), 7.36 (d,
J=7.5 Hz, 1H), 7.19 (dd, J=8.6, 2.0 Hz, 1H), 6.42 (dd, J=7.5, 2.7
Hz, 1H), 6.22 (d, J=2.6 Hz, 1H), 5.22 (s, 2H), 4.55 (s, 2H), 3.75
(s, 3H), 3.58 (t, J=6.0 Hz, 2H), 3.10 (t, J=6.0 Hz, 2H); ESI MS m/z
386 [M+H].sup.+; HPLC (Method B) 98.8% (AUC), t.sub.R=12.8 min.
Example 47
Preparation of
4-(Benzyloxy)-1-(2,9-dimethyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-7--
yl)pyridin-2(1H)-one hydrochloride
##STR00141##
[0283]
4-(Benzyloxy)-1-(9-methyl-2,3,4,9-tetrahydro-1H-pydido[3,4-b]indol--
6-yl)pyridine-2(1H)-one hydrochloride (126 mg, 0.325 mmol) was
dissolved in MeOH (2 mL) and CH.sub.2Cl.sub.2 (0.5 mL) and
formaldehyde (0.036 mL, 37% aqueous solution) was added. After
stirring for 1 h, NaBH(OAc).sub.3 (138 mg, 0.651 mmol) was added
and the mixture was stirred for a further 40 min. The mixture was
diluted with methylene chloride (50 mL), washed with saturated
Na.sub.2CO.sub.3 solution, concentrated and purified by flash
column chromatography (12 g ISCO column eluting with methylene
chloride and a methanol/ammonia mixture (10:1); gradient 100%
methylene chloride to 85% methylene chloride over 30 min at 40
mL/min), and further purified by preparative HPLC to provide the
title compound (55.5 mg, 43%) as a white powder: mp 260-270.degree.
C.; .sup.1H NMR (500 MHz, CD.sub.3OD) .delta. 7.56-7.53 (m, 2H),
7.51 (d, J=1.8, 1H), 7.46 (d, J=7.3 Hz, 2H), 7.41 (overlapping dd,
J=7.4 Hz, 2H), 7.36 (d, J=7.2 Hz, 1H), 7.19 (dd, J=8.6, 2.0 Hz,
1H), 6.27 (dd, J=7.6, 2.7 Hz, 1H), 6.11 (d, J=2.6 Hz, 1H), 5.18 (s,
2H), 4.64 (br s, 2H), 3.75 (s, 3H), 3.67 (br s, 2H), 3.18-3.13 (m,
5H); ESI MS m/z 400 [M+H].sup.+; HPLC (Method B) >99% (AUC),
t.sub.R=12.9 min.
Example 48
Preparation of
1-(5-Methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-7-yl)-4-(5-(trifluor-
omethyl)pyridin-2-yl)pyridin-2(1H)-one dihydrochloride
a) 2'-Methoxy-5-(trifluoromethyl)-2,4'-bipyridine
##STR00142##
[0285] 2-Bromo-5-trifluoromethylpyridine (410 mg, 2.13 mmol) and
2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine
(500 mg, 1.81 mmol) were reacted according to Example 31 (step a)
to provide the title compound (337 mg, 62%) as a white solid:
.sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 8.96 (s, 1H), 8.31 (d,
J=5.4 Hz, 1H), 8.04 (dd, J=8.3, 2.1 Hz, 1H), 7.87 (d, J=8.3 Hz,
1H), 7.51 (dd, J=5.4, 1.4 Hz, 1H), 7.36 (s, 1H), 3.52 (s, 3H).
b) 4-(5-(Trifluoromethyl)pyridin-2-yl)pyridin-2(1H)-one
##STR00143##
[0287] 2'-Methoxy-5-(trifluoromethyl)-2,4'-bipyridine (337 mg, 1.32
mmol) was reacted reacted according to Example 31 (step c) to
provide the title compound (289 mg, 89%) as a white solid: .sup.1H
NMR (300 MHz, DMSO-d.sub.6) .delta. 11.08 (s, 1H) 9.10 (s, 1H),
8.35 (dd, J=8.4, 2.1 Hz, 1H), 8.25 (d, J=8.3 Hz, 1H), 7.53 (d,
J=6.8, 1H), 7.09 (d, J=1.3 Hz, 1H), 6.90 (dd, J=6.8, 1.6 Hz,
1H).
c) tert-Butyl
5-methyl-7-(2-oxo-4-(5-(trifluoromethyl)pyridin-2-yl)pyridin-1(2H)-yl)-3,-
4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate
##STR00144##
[0289] 4-(5-(Trifluoromethyl)pyridin-2-yl)pyridin-2(1H)-one (100
mg, 0.41 mmol) and tert-butyl
7-bromo-5-methyl-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate
(152 mg, 0.416 mmol) were reacted following the procedure of
Example 30 (step g) to provide the title compound (83 mg, 38%) as a
green solid: .sup.1H NMR (500 MHz, CDCl.sub.3) .delta. 9.00 (s,
1H), 8.06 (dd, J=8.3, 2.1 Hz, 1H), 7.91 (d, J=8.3 Hz, 1H), 7.58 (d,
J=7.2 Hz, 1H), 7.55 (d, J=8.2 Hz, 1H), 7.37 (d, J=1.6 Hz, 1H), 7.25
(d, J=1.6 Hz, 1H), 7.08 (d, J=7.5 Hz, 1H), 7.03 (dd, J=7.1, 1.8 Hz,
1H), 4.66 (s, 2H), 3.85 (br m, 2H), 3.66 (s, 3H), 2.84 (br m, 2H),
1.51 (s, 9H).
d)
1-(5-Methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-7-yl)-4-(5-(triflu-
oromethyl)pyridin-2-yl)pyridin-2(1H)-one dihydrochloride
##STR00145##
[0291] tert-Butyl
5-methyl-7-(2-oxo-4-(5-(trifluoromethyl)pyridin-2-yl)pyridin-1(2H)-yl)-3,-
4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate (83 mg, 0.16
mmol) was deprotected and converted to the dihydrochloride salt
according to the procedure of Example 30 (steps e and g) to provide
the title compound (51 mg, 78%) as a yellow solid: mp
320-330.degree. C.; .sup.1H NMR (500 MHz, CD.sub.3OD) .delta. 9.06
(s, 1H), 8.28 (dd, J=8.4, 2.1 Hz, 1H), 8.23 (d, J=8.2 Hz, 1H), 7.87
(d, J=7.1 Hz, 1H), 7.64 (d, J=8.3 Hz, 1H), 7.58 (d, J=1.6 Hz, 1H),
7.43 (d, J=1.6 Hz, 1H), 7.29 (dd, J=Hz, 1H), 7.17 (dd, J=8.3, 1.8
Hz, 1H), 4.50 (s, 2H), 3.76 (s, 3H), 3.69 (t, J=6.0 Hz, 2H), 3.22
(t, J=Hz, 2H); ESI MS m/z 425 [M+H].sup.+; HPLC (Method B) >99%
(AUC), t.sub.R=12.5 min.
Example 49
Preparation of
4-((5-Fluoropyridin-2-yl)methoxy)-1-(9-methyl-2,3,4,9-tetrahydro-1H-pyrid-
o[3,4-b]indol-7-yl)pyridin-2(1H)-one dihydrochloride
a) 4-((5-Fluoropyridin-2-yl)methoxy)pyridine 1-oxide
##STR00146##
[0293] 5-Fluoro-2-pyridylbenzylalcohol (3.00 g, 23.6 mmol) and
4-chloropyridine-N-oxide (2.03 g, 15.7 mmol) were reacted according
to Example 34 (step a) to provide the title compound (1.76 g, 50%)
as a tan solid: .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 8.48 (s,
1H), 8.12 (d, J=7.7 Hz, 2H), 7.48-7.46 (m, 2H), 6.90 (d, J=7.7 Hz,
2H), 5.20 (s, 2H).
b) 4-((5-Fluoroyridin-2-yl)methoxy)pyridin-2(1H)-one
##STR00147##
[0295] 4-((5-Fluoropyridin-2-yl)methoxy)pyridine 1-oxide (1.76 g,
7.99 mmol) was reacted according to Example 34 (step b) to provide
the title compound (1.29 g, 73%) as a yellow solid: .sup.1H NMR
(500 MHz, DMSO-d.sub.6) .delta. 11.12 (s, 1H), 8.59 (d, J=2.9 Hz,
1H), 7.79 (dt, J=8.7, 2.9 Hz, 1H), 7.60 (dd, J=8.7, 4.5 Hz, 1H),
7.26 (d, J=7.3 Hz, 1H), 5.95 (dd, J=7.4, 2.6 Hz, 1H), 5.78 (d,
J=2.5 Hz, 1H), 5.12 (s, 2H).
c) tert-Butyl
7-(4-((5-fluoropyridin-2-yl)methoxy)-2-oxopyridin-1(2H)-yl)-5-methyl-3,4--
dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate
##STR00148##
[0297] 4-((5-Fluoropyridin-2-yl)methoxy)pyridin-2(1H)-one (275 mg,
1.25 mmol) and tert-butyl
7-bromo-5-methyl-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate
(456 mg, 1.25 mmol) were reacted following the procedure of Example
30 (step g) to provide the title compound (420 mg, 66%) as a yellow
solid: .sup.1H NMR (500 MHz, CDCl.sub.3) .delta. 8.15 (d, J=2.1 Hz,
1H), 7.50 (m, 3H), 7.36 (d, J=7.8 Hz, 1H), 7.31 (d, J=1.6 Hz, 1H),
7.01 (d, J=8.9 Hz, 1H), 6.11-6.08 (m, 2H), 5.18 (s, 2H), 4.65 (s,
2H), 3.87 (t, J=5.3 Hz, 2H), 3.65 (s, 3H), 2.84 (t, J=4.2 Hz, 2H),
1.60 (s, 9H).
d)
4-((5-Fluoropyridin-2-yl)methoxy)-1-(5-methyl-2,3,4,5-tetrahydro-1H-pyr-
ido[4,3-b]indol-7-yl)pyridin-2(1H)-one dihydrochloride
##STR00149##
[0299] tert-Butyl
7-(4-((5-fluoropyridin-2-yl)methoxy)-2-oxopyridin-1(2H)-yl)-5-methyl-3,4--
dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate (415 mg, 0.823
mmol) was deprotected and converted to the dihydrochloride
according to procedure of Example 30 (steps e and g) to provide the
title compound (328 mg, 84%) as a white solid: mp 174-180.degree.
C.; .sup.1H NMR (500 MHz, CD.sub.3OD) .delta. 8.70 (s, 1H), 8.00
(dt, J=8.4, 2.8 Hz, 1H), 7.91-7.88 (m, 2H), 7.63 (d, J=8.4 Hz, 1H),
7.55 (s, 1H), 7.11 (dd, J=8.3, 1.7 Hz, 1H), 6.69 (dd, J=7.5, 2.7
Hz, 1H), 6.45 (d, J=2.6 Hz, 1H), 5.46 (s, 2H), 4.49 (s, 2H), 3.75
(s, 3H), 3.68 (t, J=6.1 Hz, 2H), 3.22 (t, J=6.1 Hz, 2H); ESI MS m/z
405 [M+H].sup.+; HPLC (Method B) 95.5% (AUC), t.sub.R=10.9 min.
Example 50
Preparation of
1-(5-Methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-7-yl)-4-(6-(trifluor-
omethyl)pyridazin-3-yl)pyridin-2(1H)-one hydrochloride
a) 3-(2-Methoxypyridin-4-yl)-6-(trifluoromethyl)pyridazine
##STR00150##
[0301] 3-Chloro-6-(trifluoromethyl)pyridazine (137 mg, 0.751 mmol)
and
2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine
(176 mg, 0.749 mmol) were reacted according to Example 31 (step a)
to provide the title compound (115 mg, 60%) as a white solid:
.sup.1H NMR (500 MHz, CDCl.sub.3) .delta. 8.39 (d, J=5.8 Hz, 1H),
8.05 (d, J=8.8 Hz, 1H), 7.94 (d, J=8.8 Hz, 1H), 7.62 (dd, J=5.4,
1.5 Hz, 1H), 7.45 (s, 1H), 4.03 (s, 3H).
b) 4-(6-(Trifluoromethyl)pyridazin-3-yl)pyridin-2(1H)-one
##STR00151##
[0303] 3-(2-Methoxypyridin-4-yl)-6-(trifluoromethyl)pyridazine (115
mg, 0.451 mmol) was reacted according to Example 31 (step c) to
provide the title compound (120 mg, quant) as a white solid:
.sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 11.87 (s, 1H), 8.61 (d,
J=8.9 Hz, 1H), 8.42 (d, J=8.9 Hz, 1H), 7.62 (d, J=6.8 Hz, 1H), 7.19
(s, 1H), 7.01 (dd, J=6.8, 1.6 Hz, 1H).
c) tert-Butyl
5-methyl-7-(2-oxo-4-(6-(trifluoromethyl)pyridazin-3-yl)pyridin-1(2H)-yl)--
3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate
##STR00152##
[0305] 4-(6-(Trifluoromethyl)pyridazin-3-yl)pyridin-2(1H)-one (60
mg, 0.25 mmol) and tert-butyl
7-bromo-5-methyl-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate
(90 mg, 0.25 mmol) were reacted following the procedure of Example
30 (step g) to provide the title compound (60 mg, 46%) as a yellow
solid: .sup.1H NMR (500 MHz, CDCl.sub.3) .delta. 8.10 (d, J=8.8 Hz,
1H), 7.79 (d, J=8.8 Hz, 1H), 7.66 (d, J=7.0 Hz, 1H), 7.56 (d, J=8.2
Hz, 1H), 7.38 (d, J=1.3 Hz, 1H), 7.26-7.24 (m, 2H), 7.10 (d, J=7.8
Hz, 1H), 4.66 (s, 2H), 3.66 (t, J=3.3 Hz, 2H), 3.86 (s, 3H), 2.84
(t, J=3.3 Hz, 2H), 1.51 (s, 9H).
d)
1-(5-Methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-7-yl)-4-(6-(triflu-
oromethyl)pyridazin-3-yl)pyridin-2(1H)-one hydrochloride
##STR00153##
[0307] tert-Butyl
5-methyl-7-(2-oxo-4-(6-(trifluoromethyl)pyridazin-3-yl)pyridin-1(2H)-yl)--
3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate (60 mg, 0.11
mmol) was deprotected and converted to the hydrochloride salt
according to the procedure of Example 30 (steps e and g) to provide
the title compound (44 mg, 88%) as a yellow solid: mp
315-320.degree. C.; .sup.1H NMR (500 MHz, CD.sub.3OD) .delta. 8.54
(d, J=8.8 Hz, 1H), 8.28 (d, J=8.9 Hz, 1H), 7.91 (d, J=7.0 Hz, 1H),
7.64 (d, J=8.4 Hz, 1H), 7.60 (d, J=1.5 Hz, 1H), 7.44 (d, J=1.5 Hz,
1H), 7.35 (dd, J=7.2, 1.9 Hz, 1H), 7.16 (dd, J=8.3, 1.8 Hz, 1H),
4.50 (s, 2H), 3.77 (s, 3H), 3.69 (t, J=6.1 Hz, 2H), 3.22 (t, J=6.0
Hz, 2H); ESI MS m/z 426 [M+H].sup.+; HPLC (Method B) 95.9% (AUC),
t.sub.R=11.7 min.
Example 51
Preparation of
4-((5-Chloropyridin-2-yl)methoxy)-1-(5-methyl-2,3,4,5-tetrahydro-1H-pyrid-
o[4,3-b]indol-7-yl)pyridin-2(1H)-one dihydrochloride
a) tert-Butyl
7-(4-((5-chloropyridin-2-yl)methoxy)-2-oxopyridin-1(2H)-yl)-5-methyl-3,4--
dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate
##STR00154##
[0309] 4-((5-Chloropyridin-2-yl)methoxy)pyridin-2(1H)-one (127 mg,
0.537 mmol) and tert-butyl
7-bromo-5-methyl-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate
(200 mg, 1.1 mmol) were reacted following the procedure of Example
30 (step g) to provide the title compound (113 mg, 40%) as a white
solid: .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 8.59 (d, J=2.4 Hz,
1H), 7.73 (dd, J=8.4, 2.4 Hz, 1H), 7.51 (d, J=8.3 Hz, 1H), 7.45 (d,
J=8.3 Hz, 1H), 7.33 (d, J=7.5 Hz, 1H), 7.29 (d, J=1.5 Hz, 1H), 7.01
(d, J=7.9 Hz, 1H), 6.09 (dd, J=7.5, 2.7 Hz, 1H), 6.05 (d, J=2.5 Hz,
1H), 5.17 (s, 2H), 4.64 (s, 2H), 3.84 (t, J=5.4 Hz, 2H), 3.63 (s,
3H), 2.82 (t, J=5.4 Hz, 2H), 1.50 (s, 9H).
b)
4-((5-Chloropyridin-2-yl)methoxy)-1-(5-methyl-2,3,4,5-tetrahydro-1H-pyr-
ido[4,3-b]indol-7-yl)pyridin-2(1H)-one dihydrochloride
##STR00155##
[0311] tert-Butyl
7-(4-((5-chloropyridin-2-yl)methoxy)-2-oxopyridin-1(2H)-yl)-5-methyl-3,4--
dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate (108 mg, 0.207
mmol) was deprotected and converted to the dihydrochloride salt
according to the procedure of Example 30 (steps e and g) to provide
the title compound (99 mg, 97%) as a white solid: mp
290-320.degree. C. dec; .sup.1H NMR (300 MHz, CD.sub.3OD) .delta.
8.61 (d, J=2.1 Hz, 1H), 7.95 (dd, J=8.4, 2.4 Hz, 1H), 7.62 (d,
J=7.6 Hz, 2H), 7.58 (d, J=8.4 Hz, 1H), 7.47 (d, J=1.6 Hz, 1H), 7.05
(dd, J=8.3, 1.8 Hz, 1H), 6.36 (dd, J=7.6, 2.2 Hz, 1H), 6.13 (d,
J=2.6 Hz, 1H), 5.28 (s, 2H), 4.48 (s, 2H), 3.73 (s, 3H), 3.67 (t,
J=6.2 Hz, 2H), 3.02 (t, J=6.2 Hz, 2H); ESI MS m/z 421 [M+H].sup.+;
HPLC (Method B) 98.2% (AUC), t.sub.R=12.0 min.
Example 52
Preparation of
4-((5-Chloropyridin-2-yl)methoxy)-1-(2,5-dimethyl-2,3,4,5-tetrahydro-1H-p-
yrido[4,3-b]indol-7-yl)pyridin-2(1H)-one dihydrochloride
##STR00156##
[0313]
4-((5-Chloropyridin-2-yl)methoxy)-1-(5-methyl-2,3,4,5-tetrahydro-1H-
-pyrido[4,3-b]indol-7-yl)pyridin-2(1H)-one (50 mg, 0.12 mmol) was
reacted according to the procedure of Example 47 to provide the
free-base. Conversion to the dihydrochloride salt using the
procedure of Example 30 (step g) provided the title compound (39
mg, 64%) as a white solid: mp 278-282.degree. C.; 1H NMR (300 MHz,
CD.sub.3OD) .delta. 8.60 (d, J=2.0 Hz, 1H), 7.96-7.92 (m, 1H), 7.61
(d, J=7.7 Hz, 2H), 7.57 (d, J=8.3 Hz, 1H), 7.47 (d, J=1.4 Hz, 1H),
7.06 (dd, J=8.4, 1.7 Hz, 1H), 6.34 (dd, J=7.6, 2.6 Hz, 1H), 6.12
(d, J=2.6 Hz, 1H), 5.27 (s, 2H), 4.75 (d, J=14.2 Hz, 1H), 4.38 (d,
J=14.1 Hz, 1H), 3.95-3.85 (m, 1H), 3.73 (s, 3H), 3.63 (m, 1H), 3.31
(m overlapping with solvent, 2H), 3.13 (s, 3H); ESI MS m/z 435
[M+H].sup.+; HPLC (Method B) 98.9% (AUC), t.sub.R=12.1 min.
Example 53
Preparation of
1-(5-Methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-7-yl)-4-(pyridin-2-y-
lmethoxy)pyridin-2(1H)-one dihydrochloride
a) tert-Butyl
5-methyl-7-(2-oxo-4-(pyridin-2-ylmethoxy)pyridin-1(2H)-yl)-3,4-dihydro-1H-
-pyrido[4,3-b]indole-2(5H)-carboxylate
##STR00157##
[0315] 4-(Pyridin-2-ylmethoxy)pyridin-2(1H)-one (110 mg, 0.54 mmol)
and tert-butyl
7-bromo-5-methyl-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate
(200 mg, 0.54 mmol) were reacted following the procedure of Example
30 (step g) to provide the title compound (113 mg, 43%) as a yellow
oil: .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 8.63 (ddd, J=4.9,
1.6, 0.9 Hz, 1H), 7.75 (overlapping ddd, J=7.6, 1.8 Hz, 1H), 7.49
(t, J=7.3 Hz, 2H), 7.33 (d, J=7.5 Hz, 1H), 7.29 (d, J=1.4 Hz, 1H),
7.26 (m overlapping with solvent, 1H), 7.01 (d, J=7.9 Hz, 1H),
6.12-6.07 (m, 2H), 5.19 (s, 2H), 4.64 (s, 2H), 3.84 (t, J=5.4 Hz,
2H), 3.62 (s, 3H), 2.82 (t, J=5.4 Hz, 2H), 1.52 (s, 9H).
b)
1-(5-Methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-7-yl)-4-(pyridin-2-
-ylmethoxy)pyridin-2(1H)-one dihydrochloride
##STR00158##
[0317] tert-Butyl
5-methyl-7-(2-oxo-4-(pyridin-2-ylmethoxy)pyridin-1(2H)-yl)-3,4-dihydro-1H-
-pyrido[4,3-b]indole-2(5H)-carboxylate (113 mg, 0.23 mmol) was
deprotected and converted to the dihydrochloride salt according to
the procedure of Example 30 (steps e and g) to provide the title
compound (81 mg, 77%) as a white solid: mp 206-211.degree. C.;
.sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 8.88 (d, J=5.2 Hz, 1H),
8.59 (dd, J=7.9, 1.5 Hz, 1H), 8.15 (d, J=8.0 Hz, 1H), 8.01
(overlapping dd, J=6.6 Hz, 1H), 7.69 (d, J=7.6 Hz, 1H), 7.60 (d,
J=8.4 Hz, 1H), 7.48 (d, J=1.6 Hz, 1H), 7.06 (dd, J=8.4, 1.8 Hz,
1H), 6.44 (dd, J=7.6, 2.7 Hz, 1H), 6.21 (d, J=2.7 Hz, 1H), 5.57 (s,
2H), 4.48 (s, 2H), 3.74 (s, 3H), 3.68 (t, J=6.2 Hz, 2H), 3.21 (t,
J=6.2 Hz, 2H); ESI MS m/z 387 [M+H].sup.+; HPLC (Method B) 98%
(AUC), t.sub.R=9.3 min.
Example 54
Preparation of
1-(2,5-Dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-7-yl)-4-(pyridin-
-2-ylmethoxy)pyridin-2(1H)-one dihydrochloride
##STR00159##
[0319]
1-(5-Methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-7-yl)-4-(pyrid-
in-2-ylmethoxy)pyridin-2(1H)-one (45 mg, 0.116 mmol) was reacted
according to the procedure of Example 47 to provide the free-base.
Conversion to the dihydrochloride salt using the procedure of
Example 30 (step g) provided the title compound (54 mg, 98%) as a
white solid: mp 260-265.degree. C.; .sup.1H NMR (500 MHz,
CD.sub.3OD) .delta. 8.87 (d, J=5.7 Hz, 1H), 8.58 (overlapping dd,
J=8.2 Hz, 1H), 8.14 (d, J=7.9 Hz, 1H), 8.00 (overlapping dd, J=6.6
Hz, 1H), 7.69 (d, J=7.6 Hz, 1H), 7.59 (d, J=8.3 Hz, 1H), 7.49 (s,
1H), 7.07 (dd, J=8.3, 1.7 Hz, 1H), 6.44 (dd, J=7.5, 2.6 Hz, 1H),
6.20 (d, J=2.0 Hz, 1H), 5.56 (s, 2H), 4.76 (d, J=14.2 Hz, 1H), 4.40
(d, J=14.2 Hz, 1H), 3.91 (m, 1H), 3.74 (s, 3H), 3.61 (m, 1H),
3.29-3.17 (m overlapping with solvent, 2H), 3.13 (s, 3H); ESI MS
m/z 401 [M+H].sup.+; HPLC (Method B) >99% (AUC), t.sub.R=9.2
min.
Example 55
Preparation of
1-(9-Methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-7-yl)-4-(pyridin-2-y-
lmethoxy)pyridin-2(1H)-one dihydrochloride
a) tert-Butyl
9-methyl-7-(2-oxo-4-(pyridin-2-ylmethoxy)pyridin-1(2H)-yl)-3,4-dihydro-1H-
-pyrido[3,4-b]indole-2(9H)-carboxylate
##STR00160##
[0321] 4-(Pyridin-2-ylmethoxy)pyridin-2(1H)-one (138 mg, 0.682
mmol) and tert-butyl
7-bromo-9-methyl-3,4-dihydro-1H-pyrido[3,4-b]indole-2(9H)-carboxylate
(250 mg, 0.68 mmol) were reacted following the procedure of Example
30 (step g) to provide the title compound (170 mg, 51%) as a white
foam: .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 8.63 (d, J=4.1 Hz,
1H), 7.76 (overlapping ddd, J=7.7, 1.7 Hz, 1H), 7.53 (d, J=8.3 Hz,
1H), 7.48 (d, J=7.8 Hz, 1H), 7.33 (d, J=7.4 Hz, 1H), 7.29-7.26 (m
overlapping with solvent, 2H), 7.01 (dd, J=8.2, 1.8 Hz, 1H),
6.12-6.07 (m, 2H), 5.19 (s, 2H), 4.63 (s, 2H), 3.74 (br s, 2H),
3.62 (s, 3H), 2.79 (s, 2H), 1.51 (s, 9H).
b)
1-(9-Methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-7-yl)-4-(pyridin-2-
-ylmethoxy)pyridin-2(1H)-one dihydrochloride
##STR00161##
[0323] tert-Butyl
9-methyl-7-(2-oxo-4-(pyridin-2-ylmethoxy)pyridin-1(2H)-yl)-3,4-dihydro-1H-
-pyrido[3,4-b]indole-2(9H)-carboxylate (167 mg, 0.34 mmol) was
deprotected and converted to the dihydrochloride salt according to
the procedure of Example 30 (steps e and g) to provide the title
compound (124 mg, 79%) as a yellow solid: mp 226-231.degree. C.;
.sup.1H NMR (500 MHz, CD.sub.3OD) .delta. 8.89 (d, J=5.4 Hz, 1H),
8.61 (overlapping ddd, J=8.0, 1.6 Hz, 1H), 8.16 (d, J=8.0 Hz, 1H),
8.02 (overlapping dd, J=6.6 Hz, 1H), 7.70 (d, J=7.6 Hz, 1H), 7.63
(d, J=8.4 Hz, 1H), 7.47 (d, J=1.6 Hz, 1H), 7.06 (dd, J=8.4, 1.8 Hz,
1H), 6.44 (dd, J=7.6, 2.7 Hz, 1H), 6.21 (d, J=2.6 Hz, 1H), 5.57 (s,
2H), 4.56 (s, 2H), 3.73 (s, 3H), 3.60 (t, J=6.0, 2H), 3.13 (t,
J=6.0, 2H); ESI MS m/z 387 [M+H].sup.+; HPLC (Method B) 98.6%
(AUC), t.sub.R=9.2 min.
Example 56
Preparation of
1-(9-Methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-7-yl)-4-phenethylpyr-
idin-2(1H)-one dihydrochloride
a) tert-Butyl
9-methyl-7-(2-oxo-4-phenethylpyridin-1(2H)-yl)-3,4-dihydro-1H-pyrido[3,4--
b]indole-2(9H)-carboxylate
##STR00162##
[0325] 4-Phenethylpyridin-2(1H)-one (817 mg, 4.10 mmol) and
tert-butyl
7-bromo-9-methyl-3,4-dihydro-1H-pyrido[3,4-b]indole-2(9H)-carboxylate
(1.5 g, 4.1 mmol) were reacted following the procedure of Example
30 (step g) to provide the title compound (1.2 g, 60%) as a yellow
solid: .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 7.53 (d, J=8.1 Hz,
1H), 7.34-7.29 (m, 4H), 7.26-7.20 (m, 3H), 7.03 (dd, J=8.2, 1.5 Hz,
1H), 6.50 (s, 1H), 6.09 (dd, J=6.9, 1.6 Hz, 1H), 4.63 (br s, 2H),
3.74 (br s, 2H), 3.63 (s, 3H), 2.98-2.91 (m, 2H), 2.84-2.79 (m,
4H), 1.51 (s, 9H).
b)
1-(9-Methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-7-yl)-4-phenethylp-
yridin-2(1H)-one dihydrochloride
##STR00163##
[0327] tert-Butyl
9-methyl-7-(2-oxo-4-phenethylpyridin-1(2H)-yl)-3,4-dihydro-1H-pyrido[3,4--
b]indole-2(9H)-carboxylate (1.2 g, 2.4 mmol) was deprotected and
converted to the dihydrochloride salt according to the procedure of
Example 30 (steps e and g) to provide the title compound (550 mg,
51%) as a yellow solid: mp 280-295.degree. C.; .sup.1H NMR (300
MHz, DMSO-d.sub.6) .delta. 9.67 (s, 2H), 7.59-7.52 (m, 3H),
7.35-7.27 (m, 4H), 7.24-7.17 (m, 1H), 7.01 (dd, J=7.4, 2.0 Hz, 1H),
6.38-6.27 (m, 2H), 4.45 (s, 2H), 3.67 (s, 3H), 3.42 (t, J=6.4 Hz,
2H), 2.97-2.89 (m, 4H), 2.81-2.76 (m, 2H); ESI MS m/z 384
[M+H].sup.+; HPLC (Method B) >99% (AUC), t.sub.R=13.3 min.
Example 57
Preparation of
4-(5-Chloropyridin-2-yl)-1-(5-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]i-
ndol-7-yl)pyridin-2(1H)-one dihydrochloride
a) tert-Butyl
7-(4-(5-chloropyridin-2-yl)-2-oxopyridin-1(2H)-yl)-5-methyl-3,4-dihydro-1-
H-pyrido[4,3-b]indole-2(5H)-carboxylate
##STR00164##
[0329] 4-(5-Chloropyridin-2-yl)pyridin-2(1H)-one (111 mg, 0.537
mmol) and tert-butyl
7-bromo-5-methyl-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate
(200 mg, 0.54 mmol) were reacted following the procedure of Example
30 (step g) to provide the title compound (80 mg, 30%) as a green
solid: .sup.1H NMR (500 MHz, CDCl.sub.3) .delta. 8.69 (d, J=2.2 Hz,
1H), 7.79 (dd, J=8.5, 2.4 Hz, 1H), 7.74 (d, J=8.5 Hz, 1H), 7.53 (d,
J=7.2 Hz, 2H), 7.36 (d, J=1.5 Hz, 1H), 7.17 (d, J=1.5 Hz, 1H), 7.07
(d, J=7.4 Hz, 1H), 6.98 (dd, J=7.1, 1.8 Hz, 1H), 4.65 (br s, 2H),
3.85 (br s, 2H), 3.65 (s, 3H), 2.83 (br s, 2H), 1.50 (s, 9H).
b)
4-(5-Chloropyridin-2-yl)-1-(5-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b-
]indol-7-yl)pyridin-2(1H)-one dihydrochloride
##STR00165##
[0331] tert-Butyl 7-(4-(5-chloropyridin-2-yl)-2-oxopyridin-1
(2H)-yl)-5-methyl-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate
(80 mg, 0.16 mmol) was deprotected and converted to the
dihydrochloride salt according to the procedure of Example 30
(steps e and g) to provide the title compound (40 mg, 54%) as a
white solid: .sup.1H NMR (500 MHz, CD.sub.3OD) .delta. 8.74 (d,
J=2.4 Hz, 1H), 8.06 (d, J=8.5 Hz, 1H), 8.02 (dd, J=8.7, 2.4 Hz,
1H), 7.86 (d, J=7.2 Hz, 1H), 7.64 (d, J=8.3 Hz, 1H), 7.58 (d, J=1.9
Hz, 1H), 7.37 (d, J=1.5 Hz, 1H), 7.27 (dd, J=8.5, 1.8 Hz, 1H), 7.15
(dd, J=8.4, 1.8 Hz, 1H), 4.50 (s, 2H), 3.75 (s, 3H), 3.68 (t, J=6.5
Hz, 2H), 3.22 (t, J=6.5 Hz, 2H); ESI MS m/z 391 [M+H].sup.+; HPLC
(Method B) >99% (AUC), t.sub.R=12.2 min.
Example 59
Preparation of
1-(2,5-Dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-7-yl)-4-((5-fluo-
ropyridin-2-yl)methoxy)pyridin-2(1H)-one dihydrochloride
##STR00166##
[0333] 4-((5-Fluoropyridin-2-yl)methoxy)-1-(5-methyl-2,
3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-7-yl)pyridin-2(1H)-one (75
mg, 0.19 mmol) was reacted according to the procedure of Example 47
to provide the free-base. Conversion to the dihydrochloride salt
using the procedure of Example 30 (step g) provided the title
compound (71 mg, 78%) as a white solid: mp 215-230.degree. C.;
.sup.1H NMR (500 MHz, CD.sub.3OD) .delta. 8.65 (d, J=2.6 Hz, 1H),
7.91 (overlapping ddd, J=9.6, 2.1 Hz, 1H), 7.83-7.20 (m, 2H), 7.61
(d, J=8.4 Hz, 1H), 7.53 (d, J=1.8 Hz, 1H), 7.09 (dd, J=8.4, 1.8 Hz,
1H), 6.59 (dd, J=7.5, 2.6 Hz, 1H), 6.36 (d, J=2.6 Hz, 1H), 5.41 (s,
2H), 4.76 (d, J=14.2 Hz, 1H), 4.39 (d, J=14.2 Hz, 1H), 3.94-3.82
(m, 2H), 3.74 (s, 3H), 3.65-3.58 (m, 2H), 3.13 (s, 3H); ESI MS m/z
419 [M+H].sup.+; HPLC (Method B) 95.8% (AUC), t.sub.R=11.0 min.
Example 60
Preparation of
4-(5-Chloropyridin-2-yl)-1-(2,5-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-
-b]indol-7-yl)pyridin-2(1H)-one dihydrochloride
##STR00167##
[0335]
4-(5-Chloropyridin-2-yl)-1-(5-methyl-2,3,4,5-tetrahydro-1H-pyrido[4-
,3-b]indol-7-yl)pyridin-2(1H)-one (57 mg, 0.14 mmol) was reacted
according to the procedure of Example 47 to provide the free-base.
Conversion to the dihydrochloride salt using the procedure of
Example 30 (step g) provided the title compound (54.5 mg, 81%) as a
yellow solid: .sup.1H NMR (500 MHz, CD.sub.3OD) .delta. 8.72 (d,
J=1.7 Hz, 1H), 8.03 (d, J=7.9 Hz, 1H), 7.99 (dd, J=8.2, 2.2 Hz,
1H), 7.79 (d, J=7.1 Hz, 1H), 7.61 (d, J=8.3 Hz, 1H), 7.56 (d, J=1.3
Hz, 1H), 7.34 (d, J=1.5 Hz, 1H), 7.19 (dd, J=7.2, 1.8 Hz, 1H), 7.14
(dd, J=8.3, 1.8 Hz, 1H), 4.80-4.72 (br m, 1H), 4.46-4.34 (m, 1H),
3.96-3.86 (m, 1H), 3.75 (s, 3H), 3.65-3.55 (br m, 1H), 3.28 (s,
2H), 3.14 (s, 3H); ESI MS m/z 405 [M+H].sup.+; HPLC (Method B)
>99% (AUC), t.sub.R=12.0 min.
Example 61
Preparation of
4-(Benzyloxy)-1-(5-methyl-2-(2-(pyrrolidin-1-yl)ethyl)-2,3,4,5-tetrahydro-
-1H-pyrido[4,3-b]indol-7-yl)pyridin-2(1H)-one dihydrochloride
##STR00168##
[0337]
4-(Benzyloxy)-1-(5-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol--
7-yl)pyridin-2(1H)-one (180 mg, 0.46 mmol),
1-(2-chloroethyl)pyrrolidine hydrochloride (95 mg, 0.56 mmol),
(i-Pr).sub.2EtN (0.25 mL, 1.4 mmol) were combined in ethanol (2 mL)
and heated at 60.degree. C. for 2 h. Purification by preparative
HPLC and conversion to the dihydrochloride salt using the procedure
of Example 30 (step g) provided the title compound as a white
solid: mp 285-289.degree. C.; .sup.1H NMR (300 MHz, D.sub.2O)
.delta. 7.50 (d, J=8.3 Hz, 1H), 7.46 (d, J=7.7 Hz, 1H), 7.42-7.31
(m, 6H), 6.96 (dd, J=8.3, 1.6 Hz, 1H), 6.27 (dd, J=7.7, 2.6 Hz,
1H), 6.10 (d, J=2.6 Hz, 1H), 5.90 (s, 2H), 4.59 (br s, 2H),
3.81-3.59 (m, 8H), 3.55 (s, 3H), 3.20 (t, J=5.7 Hz, 2H), 3.18-3.05
(br m, 2H), 2.15-1.90 (m, 4H); ESI MS m/z 483 [M+H].sup.+; HPLC
(Method B) 98.8% (AUC), t.sub.R=11.3 min.
Example 62
Preparation of
1-(2,5-Dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-7-yl)-4-(5-(trif-
luoromethyl)pyridin-2-yl)pyridin-2(1H)-one dihydrochloride
##STR00169##
[0339]
1-(5-Methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-7-yl)-4-(5-(tr-
ifluoromethyl)pyridin-2-yl)pyridin-2(1H)-one (68 mg, 0.16 mmol) was
reacted according to the procedure of Example 47 to provide the
free-base. Conversion to the dihydrochloride salt using the
procedure of Example 30 (step g) provided the title compound (39.6
mg, 48%) as a brown solid: mp 274-280.degree. C.; .sup.1H NMR (500
MHz, CD.sub.3OD) .delta. 9.04 (s, 1H), 8.28 (dd, J=8.7, 1.9 Hz,
1H), 8.21 (d, J=2.1 Hz, 1H), 7.83 (d, J=7.1 Hz, 1H), 7.62 (d, J=8.3
Hz, 1H), 7.58 (d, J=1.3 Hz, 1H), 7.39 (d, J=1.6 Hz, 1H), 7.24 (dd,
J=7.1, 1.9 Hz, 1H), 7.15 (dd, J=8.3, 1.7 Hz, 1H), 4.80-4.71 (br m,
1H), 4.44-4.35 (br m, 1H), 3.96-3.86 (br m, 1H), 3.75 (s, 3H),
3.67-3.57 (br m, 1H), 3.28 (s, 2H), 3.14 (s, 3H); ESI MS m/z 439
[M+H].sup.+; HPLC (Method B) 96.4% (AUC), t.sub.R=12.6 min.
Example 63
Preparation of
1-(5-Methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-7-yl)-4-(6-methylpyr-
idazin-3-yl)pyridin-2(1H)-one dihydrochloride
a) 3-(2-Methoxypyridin-4-yl)-6-methylpyridazine
##STR00170##
[0341] 3-Chloro-6-methylpyridazine (343 mg, 2.67 mmol) and
2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine
(470 mg, 2.0 mmol) were reacted according to Example 31 (step a) to
provide the title compound (183 mg, 45%) as a cream solid: .sup.1H
NMR (500 MHz, CDCl.sub.3) .delta. 8.31 (d, J=5.3 Hz, 1H), 7.62 (d,
J=8.7 Hz, 1H), 7.59 (dd, J=5.3, 1.5 Hz, 1H), 7.43 (d, J=8.6 Hz,
1H), 7.38 (s, 1H), 4.00 (s, 3H), 2.79 (s, 3H).
b) 4-(6-Methylpyridazin-3-yl)pyridin-2(1H)-one
##STR00171##
[0343] 3-(2-Methoxypyridin-4-yl)-6-methylpyridazine (183 mg, 0.909
mmol) was reacted according to Example 31 (step c) to provide the
title compound (133 mg, 75%) as a white solid: .sup.1H NMR (300
MHz, CD.sub.3OD) .delta. 8.12 (d, J=8.8 Hz, 1H), 7.73 (d, J=8.8 Hz,
1H), 7.59 (d, J=6.6 Hz, 1H), 7.17-7.14 (m, 2H), 2.75 (s, 3H).
c) tert-Butyl
5-methyl-7-(4-(6-methylpyridazin-3-yl)-2-oxopyridin-1(2H)-yl)-3,4-dihydro-
-1H-pyrido[4,3-b]indole-2(5H)-carboxylate
##STR00172##
[0345] 3-(2-Methoxypyridin-4-yl)-6-methylpyridazine (133 mg, 0.710
mmol) and tert-butyl
7-bromo-5-methyl-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate
(259 mg, 0.71 mmol) were reacted following the procedure of Example
30 (step g) to provide the title compound (200 mg, 59%) as a yellow
solid: .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 7.83 (d, J=8.7 Hz,
1H), 7.60 (d, J=7.2 Hz, 1H), 7.56 (d, J=8.3 Hz, 1H), 7.48 (d, J=8.8
Hz, 1H), 7.39 (d, J=1.6 Hz, 1H), 7.29 (overlapping ddd, J=7.3, 1.8
Hz, 1H), 7.17 (d, J=1.8 Hz, 1H), 7.11 (d, J=7.6 Hz, 1H), 4.67 (br
s, 2H), 3.91-3.83 (br m, 2H), 3.67 (s, 3H), 2.89-2.83 (br m, 2H),
2.53 (s, 3H), 1.52 (s, 9H).
d)
1-(5-Methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-7-yl)-4-(6-methylp-
yridazin-3-yl)pyridin-2(1H)-one dihydrochloride
##STR00173##
[0347] tert-Butyl
5-methyl-7-(4-(6-methylpyridazin-3-yl)-2-oxopyridin-1(2H)-yl)-3,4-dihydro-
-1H-pyrido[4,3-b]indole-2(5H)-carboxylate (200 mg, 0.42 mmol) was
deprotected and converted to the dihydrochloride salt according to
the procedure of Example 30 (steps e and g) to provide the title
compound (57 mg, 33%) as an orange solid: mp 310-315.degree. C.;
.sup.1H NMR (500 MHz, CD.sub.3OD) .delta. 8.47 (d, J=8.8 Hz, 1H),
8.03 (d, J=8.8 Hz, 1H), 7.89 (d, J=7.4 Hz, 1H), 7.64 (d, J=8.4 Hz,
1H), 7.58 (d, J=1.6 Hz, 1H), 7.35 (d, J=1.6 Hz, 1H), 7.25 (dd,
J=7.1, 1.9 Hz, 1H), 7.15 (dd, J=8.3, 1.9 Hz, 1H), 4.49 (s, 2H),
3.75 (s, 3H), 3.68 (t, J=6.2 Hz, 2H), 3.24 (t, J=6.2 Hz, 2H), 2.85
(s, 3H); ESI MS m/z 372 [M+H].sup.+; HPLC (Method B) 98% (AUC),
t.sub.R=9.3 min.
Example 64
Preparation of
1-(2,5-Dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-7-yl)-4-(6-methy-
lpyridazin-3-yl)pyridin-2(1H)-one dihydrochloride
##STR00174##
[0349]
1-(5-Methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-7-yl)-4-(6-met-
hylpyridazin-3-yl)pyridin-2(1H)-one (77 mg, 0.21 mmol) was reacted
according to the procedure of Example 47 to provide the free-base.
Conversion to the dihydrochloride salt using the procedure of
Example 30 (step g) provided the title compound (60 mg, 74%) as a
yellow solid: mp 285-288.degree. C.; .sup.1H NMR (300 MHz,
DMSO-d.sub.6) .delta. 10.9 (s, 1H), 8.32 (d, J=8.8 Hz, 1H), 7.85
(d, J=7.2 Hz, 1H), 7.79 (d, J=8.8 Hz, 1H), 7.64 (d, J=1.5 Hz, 1H),
7.56 (d, J=8.3 Hz, 1H), 7.25 (d, J=1.7 Hz, 1H), 7.14-7.11 (m, 2H),
4.65 (d, J=12.1 Hz, 1H), 4.31 (dd, J=14.2, 7.5 Hz, 1H), 3.81-3.74
(m, 1H), 3.71 (s, 3H), 3.55-3.45 (m, 1H), 3.26-3.15 (m, 2H), 2.98
(s, 3H), 2.72 (s, 3H); ESI MS m/z 386 [M+H].sup.+; HPLC (Method B)
>99% (AUC), t.sub.R=9.4 min.
Example 65
Preparation of
4-(4-Fluoro-2-methoxyphenyl)-1-(5-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-
-b]indol-7-yl)pyridin-2(1H)-one hydrochloride
a) 4-(4-Fluoro-2-methoxyphenyl)pyridine 1-oxide
##STR00175##
[0351] 4-Chloropyridine-N-oxide (305 mg, 2.35 mmol),
4-fluoro-2-methoxyphenylboronic acid (1.0 g, 8.8 mmol) were reacted
according to the procedure of Example 39 (step a) to provide the
title compound (450 mg, 87%) as a purple solid: .sup.1H NMR (300
MHz, CDCl.sub.3) .delta. 8.21 (d, J=7.2 Hz, 2H), 7.45 (d, J=7.2 Hz,
2H), 7.31 (d, J=6.5 Hz, 1H), 6.80-6.71 (m, 2H), 3.85 (s, 3H).
b) 4-(4-Fluoro-2-methoxyphenyl)pyridin-2(1H)-one
##STR00176##
[0353] 4-(4-Fluoro-2-methoxyphenyl)pyridine 1-oxide (450 mg, 2.05
mmol) was reacted according to the procedure of Example 32 (step b)
to provide the title compound (291 mg, 66%) as a brown solid:
.sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 11.4 (br s, 1H),
7.39-7.31 (m, 2H), 7.03 (d, J=10.2 Hz, 1H), 6.85 (overlapping dd,
J=7.4 Hz, 1H), 6.35 (s, 1H), 6.27 (d, J=6.1 Hz, 1H), 3.80 (s,
3H).
c) tert-Butyl
7-(4-(4-fluoro-2-methoxyphenyl)-2-oxopyridin-1(2H)-yl)-5-methyl-3,4-dihyd-
ro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate
##STR00177##
[0355] 4-(4-Fluoro-2-methoxyphenyl)pyridin-2(1H)-one (100 mg, 0.45
mmol) and tert-butyl
7-bromo-5-methyl-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate
(166 mg, 0.454 mmol) were reacted following the procedure of
Example 30 (step g) to provide the title compound (106 mg, 46%) as
a yellow oil: .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 7.53 (d,
J=8.2 Hz, 1H), 7.41 (d, J=7.1 Hz, 1H), 7.39-7.32 (m, 2H), 7.08 (d,
J=8.0 Hz, 1H), 6.80-6.70 (m, 3H), 6.46 (dd, J=7.1, 1.9 Hz, 1H),
4.66 (br s, 2H), 3.87 (s, 3H), 3.86-3.78 (m, 2H), 3.64 (s, 3H),
2.83 (t, J=6.1 Hz, 2H), 1.50 (s, 9H).
d)
4-(4-Fluoro-2-methoxyphenyl)-1-(5-methyl-2,3,4,5-tetrahydro-1H-pyrido[4-
,3-b]indol-7-yl)pyridin-2(1H)-one hydrochloride
##STR00178##
[0357] tert-Butyl
7-(4-(4-fluoro-2-methoxyphenyl)-2-oxopyridin-1(2H)-yl)-5-methyl-3,4-dihyd-
ro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate (106 mg, 0.211 mmol)
was deprotected according to the procedure of Example 30 (step e)
to provide the free base (74 mg, 88%). The free-base (37 mg, 0.092
mmol) was converted to the hydrochloride salt according to the
procedure of Example 30 (steps g) to provide the title compound (35
mg, 89%) as a yellow solid: mp 296-300.degree. C.; .sup.1H NMR (300
MHz, DMSO-d.sub.6) .delta. 9.56 (br s, 2H), 7.64 (d, J=7.1 Hz, 1H),
7.62-7.55 (m, 2H), 7.47 (dd, J=8.4, 6.9 Hz, 1H), 7.12-7.06 (m, 2H),
6.90 (overlapping ddd, J=8.4, 2.4 Hz, 1H), 6.55 (d, J=1.6 Hz, 1H),
6.47 (dd, J=7.1, 1.8 Hz, 1H), 4.37-4.30 (br m, 2H), 3.81 (s, 3H),
3.69 (s, 3H), 3.56-3.45 (br m, 2H), 3.10 (t, J=5.5 Hz, 2H); ESI MS
m/z 404 [M+H].sup.+; HPLC (Method B) >99% (AUC), t.sub.R=12.5
min.
Example 66
Preparation of
1-(2,5-Dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-7-yl)-4-(4-fluor-
o-2-methoxyphenyl)pyridin-2(1H)-one hydrochloride
##STR00179##
[0359]
4-(4-Fluoro-2-methoxyphenyl)-1-(5-methyl-2,3,4,5-tetrahydro-1H-pyri-
do[4,3-b]indol-7-yl)pyridin-2(1H)-one (37 mg, 0.092 mmol) was
reacted according to the procedure of Example 47 to provide the
free-base. Conversion to the dihydrochloride salt using the
procedure of Example 30 (step g) provided the title compound (21
mg, 52%) as a yellow solid: mp 294-298.degree. C.; .sup.1H NMR (300
MHz, DMSO-d.sub.6) .delta. 10.83 (br s, 1H), 7.65 (d, J=7.1 Hz,
1H), 7.61 (d, J=1.4 Hz, 1H), 7.54 (d, J=8.3 Hz, 1H), 7.46 (dd,
J=8.4, 6.9 Hz, 1H), 7.12-7.10 (m, 1H), 7.08 (d, J=1.4 Hz, 1H), 6.91
(overlapping ddd, J=8.4, 2.4 Hz, 1H), 6.55 (d, J=1.6 Hz, 1H), 6.48
(dd, J=7.1, 1.6 Hz, 1H), 4.62 (d, J=12.2 Hz, 1H), 4.30 (dd, J=14.2,
7.5 Hz, 1H), 3.86 (s, 3H), 3.80-3.76 (m, 1H), 3.75 (s, 3H),
3.52-3.42 (m, 1H), 3.24-3.15 (m, 2H), 2.79 (d, J=4.6 Hz, 3H); ESI
MS m/z 418 [M+H].sup.+; HPLC (Method B) >99% (AUC), t.sub.R=12.6
min.
Example 67
Preparation of
4-(Benzyloxy)-1-(5-methyl-2-(piperidin-4-yl)-2,3,4,5-tetrahydro-1H-pyrido-
[4,3-b]indol-7-yl)pyridin-2(1H)-one dihydrochloride
a) tert-Butyl 4-(7-(4-(benzyloxy)-2-oxopyridin-1
(2H)-yl)-5-methyl-3,4-dihydro-1H-pyrido[4,3-b]indol-2(5H)-yl)piperidine-1-
-carboxylate
##STR00180##
[0361]
4-(Benzyloxy)-1-(5-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol--
7-yl)pyridin-2(1H)-one (100 mg, 0.26 mmol) and tert-butyl
4-oxopiperidine-1-carboxylate (27 mg, 0.26 mmol) were stirred in
methylene chloride (1 mL) and AcOH (0.1 mL), and picoline borane
complex (27 mg, 0.26 mmol) was added. After stirring for 16 h, the
mixture was diluted with methylene chloride, washed with sodium
carbonate solution and concentrated. The obtained residue was
purified by flash column chromatography (silica gel, (1:1
EtOAc/hexanes)/(10:1 methanol/ammonia), 10:0 to 9:1) to provide the
title compound (90 mg, 61%) as a white solid: .sup.1H NMR (300 MHz,
CDCl.sub.3) .delta. 7.45-7.36 (m, 5H), 7.32-7.30 (m, 1H), 7.32-7.27
(m, 2H), 6.99 (dd, J=8.2, 1.6 Hz, 1H), 6.05-6.01 (m, 2H), 5.05 (s,
2H), 4.20 (s, 2H), 3.85 (s, 2H), 3.60 (s, 3H), 3.04-2.93 (m, 2H),
2.88-2.66 (m, 5H), 1.98-1.87 (m, 2H), 1.60-1.54 (m, 2H), 1.47 (s,
9H).
b)
4-(Benzyloxy)-1-(5-methyl-2-(piperidin-4-yl)-2,3,4,5-tetrahydro-1H-pyri-
do[4,3-b]indol-7-yl)pyridin-2(1H)-one dihydrochloride
##STR00181##
[0363] tert-Butyl 4-(7-(4-(benzyloxy)-2-oxopyridin-1
(2H)-yl)-5-methyl-3,4-dihydro-1H-pyrido[4,3-b]indol-2(5H)-yl)piperidine-1-
-carboxylate (90 mg, 0.16 mmol) was deprotected and converted to
the dihydrochloride salt according to the procedure of Example 30
(steps e and g) to provide the title compound (85 mg, 100%) as an
orange solid: .sup.1H NMR (500 MHz, D.sub.2O) .delta. 7.56-7.53 (m,
2H), 7.48-7.40 (m, 6H), 7.02 (dd, J=8.4, 1.4 Hz, 1H), 6.33 (dd,
J=7.5, 2.4 Hz, 1H), 6.17 (d, J=2.4 Hz, 1H), 5.16 (s, 2H), 4.63 (br
s, 2H), 4.09-3.79 (br m, 2H), 3.69-3.53 (m, 6H), 3.26-3.23 (m, 2H),
3.14 (t, J=12.8 Hz, 2H), 2.49 (d, J=1.3 Hz, 2H), 2.16-2.04 (m, 2H);
ESI MS m/z 469 [M+H].sup.+; HPLC (Method B) 98.1% (AUC),
t.sub.R=11.4 min.
Example 68
Preparation of
4-(Benzyloxy)-1-(5-methyl-2-(1-methylpiperidin-4-yl)-2,3,4,5-tetrahydro-1-
H-pyrido[4,3-b]indol-7-yl)pyridin-2(1H)-one dihydrochloride
##STR00182##
[0365]
4-(Benzyloxy)-1-(5-methyl-2-(piperidin-4-yl)-2,3,4,5-tetrahydro-1H--
pyrido[4,3-b]indol-7-yl)pyridin-2(1H)-one (50 mg, 0.11 mmol) was
methylated according to the procedure of Example 47 to provide the
title compound (30 mg, 51%) as a white solid: .sup.1H NMR (500 MHz,
D.sub.2O) .delta. 7.56-7.52 (m, 2H), 7.48-7.38 (m, 6H), 7.02 (dd,
J=8.3, 1.6 Hz, 1H), 6.33 (dd, J=7.5, 2.6 Hz, 1H), 6.16 (d, J=2.5
Hz, 1H), 5.16 (s, 2H), 4.63 (s, 2H), 3.85-3.83 (m, 2H), 3.74-3.71
(m, 2H), 3.62 (s, 3H), 3.26-3.14 (m, 5H), 2.89 (s, 3H), 2.55-2.50
(m, 2H), 2.19-2.12 (m, 2H); ESI MS m/z 483 [M+H].sup.+; HPLC
(Method B) >99% (AUC), t.sub.R=11.4 min.
Example 69
Preparation of
1-(5-Methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-7-yl)-4-(6-(trifluor-
omethyl)pyridin-3-yl)pyridin-2(1H)-one dihydrochloride
a) 2'-Methoxy-6-(trifluoromethyl)-3,4'-bipyridine
##STR00183##
[0367]
2-Methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine
(1.24 g, 0.53 mmol) and 5-bromo-2-(trifluoromethyl)pyridine (2.4 g,
11 mmol) were reacted according to the procedure of Example 31
(step a) to provide the title compound (1.1 g, 81%) as a white
solid: ESI MS m/z 255 [M+H].
b) 4-(6-(Trifluoromethyl)pyridin-3-yl)pyridin-2(1H)-one
##STR00184##
[0369] 2'-Methoxy-6-(trifluoromethyl)-3,4'-bipyridine (1.1 g, 4.3
mmol) was reacted according to the procedure of Example 31 (step c)
to provide the title compound (522 mg, 50%) as a white solid:
.sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 11.8 (br s, 1H), 9.10
(s, 1H), 8.40 (dd, J=8.1, 1.2 Hz, 1H), 8.00 (d, J=8.2 Hz, 1H), 7.56
(d, J=6.7 Hz, 1H), 6.81 (s, 1H), 6.63 (dd, J=6.7, 1.3 Hz, 1H).
c) tert-Butyl
5-methyl-7-(2-oxo-4-(6-(trifluoromethyl)pyridin-3-yl)pyridin-1(2H)-yl)-3,-
4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate
##STR00185##
[0371] 4-(6-(Trifluoromethyl)pyridin-3-yl)pyridin-2(1H)-one (131
mg, 0.54 mmol) and tert-butyl
7-bromo-5-methyl-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate
(200 mg, 0.54 mmol) were reacted following the procedure of Example
30 (step g) to provide the title compound (167 mg, 59%) as a green
solid: .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 8.99 (d, J=2.0 Hz,
1H), 8.10 (dd, J=8.1, 1.8 Hz, 1H), 7.84 (d, J=8.2 Hz, 1H),
7.60-7.54 (m, 2H), 7.32 (d, J=1.9 Hz, 1H), 7.07 (d, J=8.0 Hz, 1H),
6.93 (d, J=1.8 Hz, 1H), 6.49 (dd, J=7.1, 2.0 Hz, 1H), 4.66 (s, 2H),
3.85 (br m, 2H), 3.65 (s, 3H), 2.84 (s, 2H), 1.50 (s, 9H).
d)
1-(5-Methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-7-yl)-4-(6-(triflu-
oromethyl)pyridin-3-yl)pyridin-2(1H)-one dihydrochloride
##STR00186##
[0373] tert-Butyl
5-methyl-7-(2-oxo-4-(6-(trifluoromethyl)pyridin-3-yl)pyridin-1(2H)-yl)-3,-
4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate (165 mg, 0.315
mmol) was deprotected and converted to the dihydrochloride salt
according to the procedure of Example 30 (steps e and g) to provide
the title compound (40 mg, 26%) as a yellow solid: .sup.1H NMR (300
MHz, CD.sub.3OD) .delta. 9.10 (d, J=2.0 Hz, 1H), 8.41 (dd, J=8.2,
1.7 Hz, 1H), 7.98 (d, J=8.2 Hz, 1H), 7.85 (d, J=7.2 Hz, 1H), 7.61
(d, J=8.2 Hz, 1H), 7.57 (d, J=1.6 Hz, 1H), 7.14 (dd, J=8.3, 1.9 Hz,
1H), 7.02 (d, J=1.6 Hz, 1H), 6.89 (dd, J=7.1, 2.0 Hz, 1H), 4.49 (s,
2H), 3.76 (s, 3H), 3.68 (t, J=6.2 Hz, 2H), 3.22 (t, J=6.2 Hz, 2H);
ESI MS m/z 425 [M+H].sup.+; HPLC (Method B) >99% (AUC),
t.sub.R=12.3 min.
Example 70
Preparation of
1-(2,5-Dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-7-yl)-4-(6-(trif-
luoromethyl)pyridin-3-yl)pyridin-2(1H)-one
##STR00187##
[0375]
1-(5-Methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-7-yl)-4-(6-(tr-
ifluoromethyl)pyridin-3-yl)pyridin-2(1H)-one (77 mg, 0.18 mmol) was
reacted according to the procedure of Example 47 and converted to
the dihydrochloride to provide the title compound (27 mg, 29%) as a
yellow solid: mp 295-300.degree. C.; .sup.1H NMR (500 MHz,
CD.sub.3OD) .delta. 9.09 (d, J=1.7 Hz, 1H), 8.42 (dd, J=8.1, 2.0
Hz, 1H), 7.97 (d, J=8.2 Hz, 1H), 7.85 (d, J=7.1 Hz, 1H), 7.62 (d,
J=8.3 Hz, 1H), 7.58 (d, J=1.5 Hz, 1H), 7.15 (dd, J=8.3, 1.8 Hz,
1H), 7.02 (d, J=1.8 Hz, 1H), 6.89 (dd, J=7.1, 2.0 Hz, 1H),
4.79-4.37 (br m, 2H), 3.90-3.60 (br m, 5H), 3.30 (br m, 2H), 3.14
(s, 3H); ESI MS m/z 439 [M+H].sup.+; HPLC (Method B) >99% (AUC),
t.sub.R=12.4 min.
Example 71
Preparation of
1-(2,3,4,5-Tetrahydro-1H-pyrido[4,3-b]indol-7-yl)-4-(5-(trifluoromethyl)p-
yridin-2-yl)pyridin-2(1H)-one dihydrochloride
a) tert-Butyl
7-bromo-5-tosyl-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate
##STR00188##
[0377] tert-Butyl
7-bromo-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate (1.07
g, 3.04 mmol) was reacted according to the procedure of Example 87
(step a) to provide the title compound (1.39 g, 91%) as a white
solid: .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 8.35 (s, 1H), 7.66
(d, J=6.6 Hz, 2H), 7.35 (d, J=8.2 Hz, 1H), 7.28-7.21 (m, 2H), 7.18
(d, J=8.1 Hz, 1H), 4.47 (s, 2H), 3.77-3.65 (br m, 2H), 3.11-3.03
(br m, 2H), 2.36 (s, 3H), 1.48 (s, 9H).
b) tert-Butyl
7-(2-oxo-4-(5-(trifluoromethyl)pyridin-2-yl)pyridin-1(2H)-yl)-5-tosyl-3,4-
-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate
##STR00189##
[0379] 4-(5-(Trifluoromethyl)pyridin-2-yl)pyridin-2(1H)-one (131
mg, 0.545 mmol) and tert-butyl
7-bromo-5-tosyl-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate
(255 mg, 0.505 mmol) were reacted following the procedure of
Example 30 (step g) to provide the title compound (125 mg, 34%) as
a yellow oil: .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 9.01 (s,
1H), 8.29 (d, J=1.6 Hz, 1H), 8.08 (dd, J=8.3, 1.9 Hz, 1H), 7.92 (d,
J=8.3 Hz, 1H), 7.74 (d, J=8.3 Hz, 1H), 7.57 (d, J=7.2 Hz, 1H), 7.46
(d, J=8.2 Hz, 1H), 7.33 (dd, J=8.2, 1.6 Hz, 1H), 7.29-7.23 (m, 4H),
7.09 (dd, J=7.2, 1.8 Hz, 1H), 4.52 (s, 2H), 3.80-3.73 (br m, 2H),
3.18-3.09 (br m, 2H), 2.35 (s, 3H), 1.50 (s, 9H).
b)
1-(5-Tosyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-7-yl)-4-(5-(trifluo-
romethyl)pyridin-2-yl)pyridin-2(1H)-one trifluoroacetic acid
salt
##STR00190##
[0381] tert-Butyl 7-(2-oxo-4-(5-(trifluoromethyl)pyridin-2-yl)pyri
din-1(2H)-yl)-5-tosyl-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylat-
e (165 mg, 0.248 mmol) was stirred in TFA (3 mL) and methylene
chloride (1 mL) for 3 h. Concentration of the solution under
reduced pressure provided the title compound (164 mg, 100%) as a
yellow oil; ESI MS m/z 565 [M+H].sup.+.
c)
1-(2,3,4,5-Tetrahydro-1H-pyrido[4,3-b]indol-7-yl)-4-(5-(trifluoromethyl-
)pyridin-2-yl)pyridin-2(1H)-one dihydrochloride
##STR00191##
[0383]
1-(5-Tosyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-7-yl)-4-(5-(tri-
fluoromethyl)pyridin-2-yl)pyridin-2(1H)-one trifluoroacetic acid
salt (163 mg, 0.248 mmol) was deprotected and converted to the
dihydrochloride salt according to the procedure of Example 106
(step b) to provide the title compound (30 mg, 25%) as an orange
solid: mp 308-313.degree. C.; .sup.1H NMR (500 MHz, CD.sub.3OD)
.delta. 9.04 (s, 1H), 8.28 (dd, J=8.3, 2.2 Hz, 1H), 8.22 (d, J=8.2
Hz, 1H), 7.81 (d, J=7.0 Hz, 1H), 7.62 (d, J=8.3 Hz, 1H), 7.46 (d,
J=1.8 Hz, 1H), 7.38 (d, J=1.8 Hz, 1H), 7.24 (dd, J=7.1, 2.0 Hz,
1H), 7.11 (dd, J=8.3, 2.0 Hz, 1H), 4.49 (s, 2H), 3.65 (t, J=6.2 Hz,
2H), 3.21 (t, J=6.2 Hz, 2H); ESI MS m/z 411 [M+H].sup.+; HPLC
(Method B) 97.6% (AUC), t.sub.R=12.4 min.
Example 72
Preparation of
1-(2,3,4,5-Tetrahydro-1H-pyrido[4,3-b]indol-7-yl)-4-(6-(trifluoromethyl)p-
yridazin-3-yl)pyridin-2(1H)-one hydrochloride
a) tert-Butyl
7-bromo-5-(triisopropylsilyl)-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-ca-
rboxylate
##STR00192##
[0385] tert-Butyl
7-bromo-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate (300
mg, 0.85 mmol) was dissolved in DMF (3 mL), and NaH (60% weight
dispersion in mineral oil, 40 mg, 1.02 mmol) and TIPSCl (164 mg,
1.02 mmol) were added. After stirring for 1 h, the mixture was
poured into water and extracted with EtOAc. Concentration of the
organic extracts and purification of the residue by flash column
chromatography (silica gel, EtOAc/hexanes) provided the title
compound (262 mg, 61%) as a clear oil: .sup.1H NMR (300 MHz,
CDCl.sub.3) .delta. 7.70 (s, 1H), 7.25 (d, J=8.2 Hz, 1H), 7.19 (dd,
J=8.2, 1.4 Hz, 1H), 4.59 (s, 2H), 3.76-3.71 (br m, 2H), 2.96-2.90
(br m, 2H), 1.81-1.71 (m, 3H), 1.51 (s, 9H), 1.15 (d, J=7.5 Hz,
18H).
b) tert-Butyl
7-(2-oxo-4-(6-(trifluoromethyl)pyridazin-3-yl)pyridin-1(2H)-yl)-3,4-dihyd-
ro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate
##STR00193##
[0387] tert-Butyl
7-bromo-5-(triisopropylsilyl)-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-ca-
rboxylate (260 mg, 0.51 mmol) and
4-(6-(trifluoromethyl)pyridazin-3-yl)pyridin-2(1H)-one (123 mg,
0.510 mmol) were reacted according to the procedure of Example 30
(step g) to provide the title compound (80 mg, 30%) as a yellow
solid: ESI MS m/z 512 [M+H].sup.+.
c)
1-(2,3,4,5-Tetrahydro-1H-pyrido[4,3-b]indol-7-yl)-4-(6-(trifluoromethyl-
)pyridazin-3-yl)pyridin-2(1H)-one hydrochloride
##STR00194##
[0389] tert-Butyl
7-(2-oxo-4-(6-(trifluoromethyl)pyridazin-3-yl)pyridin-1(2H)-yl)-3,4-dihyd-
ro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate (80 mg, 0.15 mmol) was
deprotected and converted to the hydrochloride salt according to
the procedure of Example 30 (steps e and g) to provide the title
compound (30 mg, 44%) as an orange solid: mp 314-318.degree. C.;
.sup.1H NMR (300 MHz, CD.sub.3OD) .delta. 8.52 (d, J=8.9 Hz, 1H),
8.28 (d, J=8.9 Hz, 1H), 7.89 (d, J=7.2 Hz, 1H), 7.62 (d, J=8.3 Hz,
1H), 7.48 (d, J=1.5 Hz, 1H), 7.43 (d, J=1.5 Hz, 1H), 7.33 (dd,
J=7.2, 2.0 Hz, 1H), 7.14 (dd, J=7.4, 2.0 Hz, 1H), 4.49 (s, 2H),
3.65 (t, J=6.2 Hz, 2H), 3.21 (t, J=6.2 Hz, 2H); ESI MS m/z 412
[M+H].sup.+; HPLC (Method B) 96.0% (AUC), t.sub.R=11.6 min.
Example 73
Preparation of
1-(5-Methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-7-yl)-4-(2-(trifluor-
omethyl)pyrimidin-5-yl)pyridin-2(1H)-one hydrochloride
a) 5-(2-Methoxypyridin-4-yl)-2-(trifluoromethyl)pyrimidine
##STR00195##
[0391]
2-Methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine
(2.0 g, 8.5 mmol) and 5-chloro-2-(trifluoromethyl)pyrimidine (2.3
g, 13 mmol) were reacted according to the procedure of Example 31
(step a) to provide the title compound (1.0 g, 46%) as a white
solid: .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 9.10 (s, 2H), 8.35
(d, J=5.5 Hz, 1H), 7.11 (dd, J=5.5, 1.6 Hz, 1H), 6.98 (d, J=1.6 Hz,
1H), 4.02 (s, 3H).
b) 4-(2-(Trifluoromethyl)pyrimidin-5-yl)pyridin-2(1H)-one
##STR00196##
[0393] 5-(2-Methoxypyridin-4-yl)-2-(trifluoromethyl)pyrimidine (900
mg, 3.5 mmol) was reacted according to the procedure of Example 31
(step c) to provide the title compound (470 mg, 56%) as an orange
solid: .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 11.6 (br s, 1H),
9.41 (s, 2H), 7.61 (d, J=6.8 Hz, 1H), 6.91 (s, 1H), 6.68 (dd,
J=6.8, 1.6 Hz, 1H).
c) tert-Butyl
5-methyl-7-(2-oxo-4-(2-(trifluoromethyl)pyrimidin-5-yl)pyridin-1(2H)-yl)--
3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate
##STR00197##
[0395] 4-(2-(Trifluoromethyl)pyrimidin-5-yl)pyridin-2(1H)-one (100
mg, 0.42 mmol) and tert-butyl
7-bromo-5-methyl-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate
(116 mg, 0.32 mmol) were reacted following the procedure of Example
30 (step g) to provide the title compound (41 mg, 24%) as a yellow
oil: ESI MS m/z 526 [M+H].sup.+.
d)
1-(5-Methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-7-yl)-4-(2-(triflu-
oromethyl)pyrimidin-5-yl)pyridin-2(1H)-one hydrochloride
##STR00198##
[0397] tert-Butyl
5-methyl-7-(2-oxo-4-(2-(trifluoromethyl)pyrimidin-5-yl)pyridin-1
(2H)-yl)-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate (41
mg, 0.078 mmol) was deprotected and converted to the hydrochloride
salt according to the procedure of Example 30 (steps e and g) to
provide the title compound (29 mg, 80%) as a yellow solid: .sup.1H
NMR (500 MHz, DMSO-d.sub.6) .delta. 9.51 (s, 2H), 9.37 (br s, 2H),
7.90 (d, J=7.2 Hz, 1H), 7.62-7.60 (m, 2H), 7.13 (d, J=1.9 Hz, 1H),
7.10 (dd, J=8.3, 1.7 Hz, 1H), 6.88 (dd, J=7.1, 2.0 Hz, 1H),
4.38-4.34 (br m, 2H), 3.70 (s, 3H), 3.56-3.50 (br m, 2H), 3.11 (t,
J=5.8 Hz, 2H); ESI MS m/z 426 [M+H].sup.+; HPLC (Method B) >100%
(AUC), t.sub.R=12.2 min.
Example 74
Preparation of
1-(5-Methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-7-yl)-4-(5-(trifluor-
omethyl)pyrimidin-2-yl)pyridin-2(1H)-one hydrochloride
a) 2-(2-Methoxypyridin-4-yl)-5-(trifluoromethyl)pyrimidine
##STR00199##
[0399]
2-Methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine
(1.66 g, 7.06 mmol) and 2-chloro-5-(trifluoromethyl)pyrimidine (1.3
g, 7.1 mmol) were reacted according to the procedure of Example 31
(step a) to provide the title compound (307 mg, 16%) as a white
solid: .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 9.08 (s, 2H), 8.34
(d, J=5.3 Hz, 1H), 7.89 (dd, J=5.3, 1.4 Hz, 1H), 7.81 (s, 1H), 4.01
(s, 3H).
b) 4-(5-(Trifluoromethyl)pyrimidin-2-yl)pyridin-2(1H)-one
##STR00200##
[0401] 2-(2-Methoxypyridin-4-yl)-5-(trifluoromethyl)pyrimidine (400
mg, 1.56 mmol) was reacted according to the procedure of Example 31
(step c) to provide the title compound (200 mg, 63%) as a white
solid: .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 11.9 (br s, 1H),
9.43 (s, 2H), 7.58 (d, J=6.8 Hz, 1H), 7.34 (s, 1H), 7.06 (dd,
J=6.8, 1.7 Hz, 1H).
c) tert-Butyl
5-methyl-7-(2-oxo-4-(5-(trifluoromethyl)pyrimidin-2-yl)pyridin-1(2H)-yl)--
3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate
##STR00201##
[0403] 4-(5-(Trifluoromethyl)pyrimidin-2-yl)pyridin-2(1H)-one (100
mg, 0.34 mmol) and tert-butyl
7-bromo-5-methyl-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate
(124 mg, 0.339 mmol) were reacted following the procedure of
Example 30 (step g) to provide the title compound (70 mg, 39%) as a
yellow solid: .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 9.11 (s,
2H), 7.86 (s, 1H), 7.59-7.53 (m, 2H), 7.38 (s, 1H), 7.28-7.26 (m,
1H), 7.08 (d, J=8.4 Hz, 1H), 4.89-4.63 (br m, 2H), 3.90-3.80 (br m,
2H), 3.65 (s, 3H), 2.88-2.79 (br m, 2H), 1.50 (s, 9H).
d)
1-(5-Methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-7-yl)-4-(5-(triflu-
oromethyl)pyrimidin-2-yl)pyridin-2(1H)-one hydrochloride
##STR00202##
[0405] tert-Butyl
5-methyl-7-(2-oxo-4-(5-(trifluoromethyl)pyrimidin-2-yl)pyridin-1(2H)-yl)--
3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate (70 mg, 0.13
mmol) was deprotected and converted to the hydrochloride salt
according to the procedure of Example 30 (steps e and g) to provide
the title compound (51 mg, 87%) as a yellow solid: mp
301-309.degree. C.; .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta.
9.48 (s, 2H), 9.37 (br s, 2H), 7.89 (d, J=7.2 Hz, 1H), 7.65 (d,
J=1.6 Hz, 1H), 7.61 (d, J=8.3 Hz, 1H), 7.50 (d, J=1.6 Hz, 1H), 7.21
(dd, J=7.6, 1.9 Hz, 1H), 7.12 (dd, J=8.3, 1.8 Hz, 1H), 4.41-4.31
(br m, 2H), 3.71 (s, 3H), 3.51-3.48 (br m, 2H), 3.10 (t, J=5.6 Hz,
2H); ESI MS m/z 426 [M+H].sup.+; HPLC (Method B) 97.9% (AUC),
t.sub.R=12.6 min.
Example 75
Preparation of
1-(5-Methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-7-yl)-4-((6-(trifluo-
romethyl)pyridin-3-yl)methoxy)pyridin-2(1H)-one hydrochloride
a)
2-Methoxy-4-((6-(trifluoromethyl)pyridin-3-yl)methoxy)pyridine
##STR00203##
[0407] 4-BromoBromo-2-methoxypyridine (3.06 g, 16.2 mmol),
(6-(trifluoromethyl)pyridin-3-yl)methanol (2.74 g, 15.5 mmol),
3,4,7,8-tetramethylphenanthroline (0.36 g, 0.15 mmol), CuI (0.14 g,
0.74 mmol) and Cs.sub.2CO.sub.3 (7.57 g, 23.2 mmol) were combined
in toluene (15 mL) and heated to reflux under a nitrogen atmosphere
for 16 h. Upon cooling the mixture was purified by flash column
chromagraphy (silica gel, hexanes/EtOAc, 1:0 to 1:1) to provide the
title compound (3.19 g, 72%) as a red oil: .sup.1H NMR (300 MHz,
CDCl.sub.3) .delta. 8.78 (s, 1H), 8.02 (d, J=5.9 Hz, 1H), 7.95 (d,
J=8.1 Hz, 1H), 7.32 (d, J=8.0 Hz, 1H), 6.55 (dd, J=5.9, 2.2 Hz,
1H), 6.26 (d, J=2.2 Hz, 1H), 5.16 (s, 2H), 3.93 (s, 3H).
b)
4-((6-(Trifluoromethyl)pyridin-3-yl)methoxy)pyridin-2(1H)-one
##STR00204##
[0409]
2-Methoxy-4-((6-(trifluoromethyl)pyridin-3-yl)methoxy)pyridine
(3.19 g, 11.2 mmol) was reacted according to the procedure of
Example 31 (step c) to provide the title compound (2.04 g, 67%) as
a white solid: .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 11.2 (br
s, 1H), 8.84 (s, 1H), 8.14 (d, J=8.5 Hz, 1H), 7.96 (d, J=8.0 Hz,
1H), 7.28 (d, J=7.3 Hz, 1H), 5.95 (dd, J=7.3, 2.5 Hz, 1H), 5.82 (d,
J=2.4 Hz, 1H), 5.25 (s, 2H).
c) tert-Butyl
5-methyl-7-(2-oxo-4-((6-(trifluoromethyl)pyridin-3-yl)methoxy)pyridin-1(2-
H)-yl)-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate
##STR00205##
[0411]
4-((6-(Trifluoromethyl)pyridin-3-yl)methoxy)pyridin-2(1H)-one (177
mg, 0.655 mmol) and tert-butyl
7-bromo-5-methyl-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate
(200 mg, 0.54 mmol) were reacted following the procedure of Example
30 (step g) to provide the title compound (120 mg, 40%) as a yellow
oil: .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 8.80 (s, 1H), 7.95
(d, J=8.1 Hz, 1H), 7.76 (d, J=8.0 Hz, 1H), 7.51 (d, J=7.9 Hz, 1H),
7.35 (d, J=8.0 Hz, 1H), 7.28 (m, 1H), 7.01 (d, J=8.1 Hz, 1H),
6.06-6.04 (m, 2H), 5.16 (s, 2H), 4.65-4.60 (br m, 2H), 3.89-3.79
(br m, 2H), 3.63 (s, 3H), 2.87-2.78 (br m, 2H), 1.50 (s, 9H).
d)
1-(5-Methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-7-yl)-4-((6-(trifl-
uoromethyl)pyridin-3-yl)methoxy)pyridin-2(1H)-one
dihydrochloride
##STR00206##
[0413] tert-Butyl
5-methyl-7-(2-oxo-4-((6-(trifluoromethyl)pyridin-3-yl)methoxy)pyridin-1(2-
H)-yl)-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate (120
mg, 0.21 mmol) was deprotected and converted to the dihydrochloride
salt according to the procedure of Example 30 (steps e and g) to
provide the title compound (90 mg, 81%) as a white solid: mp
286-291.degree. C.; .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta.
9.54 (br s, 2H), 8.89 (s, 1H), 8.19 (dd, J=7.9, 1.4 Hz, 1H), 8.00
(d, J=8.0 Hz, 1H), 7.60 (d, J=7.6 Hz, 1H), 7.55 (d, J=8.3 Hz, 1H),
7.50 (d, J=1.7 Hz, 1H), 6.98 (dd, J=8.3, 1.8 Hz, 1H), 6.15 (dd,
J=7.5, 2.7 Hz, 1H), 6.02 (d, J=2.7 Hz, 1H), 5.35 (s, 2H), 4.35-4.30
(br m, 2H), 3.67 (s, 3H), 3.53-3.47 (br m, 2H), 3.09 (t, J=5.8 Hz,
2H); ESI MS m/z 455 [M+H].sup.+; HPLC (Method B) >99% (AUC),
t.sub.R=12.7 min.
Example 76
Preparation of
1-(5-Methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-7-yl)-4-((5-(trifluo-
romethyl)pyridin-2-yl)methoxy)pyridin-2(1H)-one
a) tert-Butyl
5-methyl-7-(2-oxo-4-((5-(trifluoromethyl)pyridin-2-yl)methoxy)pyridin-1(2-
H)-yl)-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate
##STR00207##
[0415] 2-(Bromomethyl)-5-(trifluoromethyl)pyridine (140 mg, 0.58
mmol), tert-butyl 7-(4-hydroxy-2-oxopyridin-1
(2H)-yl)-5-methyl-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate
(230 mg, 0.58 mmol) and K.sub.2CO.sub.3 (160 mg, 1.16 mmol) were
stirred in acetonitrile/DMF (3 mL/0.5 mL) for 72 h. The mixture was
diluted with methylene chloride, washed with water and concentrated
to provide the title compound (96 mg, 29%) as a yellow solid:
.sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 8.88 (s, 1H), 8.00 (dd,
J=8.2, 2.0 Hz, 1H), 7.63 (d, J=8.2 Hz, 1H), 7.51 (d, J=8.2 Hz, 1H),
7.36 (d, J=7.6 Hz, 1H), 7.28-7.26 (m, 1H), 7.00 (d, J=7.7 Hz, 1H),
6.12 (dd, J=7.6, 2.7 Hz, 1H), 6.04 (d, J=2.7 Hz, 1H), 5.26 (s, 2H),
4.63-4.58 (br m, 2H), 3.87-3.76 (br m, 2H), 3.63 (s, 3H), 2.86-2.76
(br m, 2H), 1.50 (s, 9H).
b)
1-(5-Methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-7-yl)-4-((5-(trifl-
uoromethyl)pyridin-2-yl)methoxy)pyridin-2(1H)-one
dihydrochloride
##STR00208##
[0417] tert-Butyl
5-methyl-7-(2-oxo-4-((5-(trifluoromethyl)pyridin-2-yl)methoxy)pyridin-1(2-
H)-yl)-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate (90 mg,
0.16 mmol) was deprotected and converted to the dihydrochloride
salt according to the procedure of Example 30 (steps e and g) to
provide the title compound (76 mg, 90%) as a white solid: mp
296-300.degree. C.; .sup.1H NMR (300 MHz, CD.sub.3OD) .delta. 8.93
(s, 1H), 8.23 (dd, J=8.2, 2.1 Hz, 1H), 7.82 (d, J=8.2 Hz, 1H), 7.70
(d, J=7.5 Hz, 1H), 7.59 (d, J=8.3 Hz, 1H), 7.49 (d, J=1.7 Hz, 1H),
7.06 (dd, J=8.3, 1.8 Hz, 1H), 6.47 (dd, J=7.5, 2.7 Hz, 1H), 6.20
(d, J=2.6 Hz, 1H), 5.42 (s, 2H), 4.48 (s, 2H), 3.73 (s, 3H), 3.67
(t, J=6.1 Hz, 2H), 3.20 (t, J=6.1 Hz, 2H); ESI MS m/z 455
[M+H].sup.+; HPLC (Method B) 97.6% (AUC), t.sub.R=12.6 min.
Example 77
Preparation of
5-(Benzyloxy)-2-(5-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-7-yl)p-
yridazin-3(2H)-one hydrochloride
a) 5-(Benzyloxy)pyridazin-3 (2H)-one
[0418] CAS Registry Number 1008517-73-4
##STR00209##
[0419] This compound was prepared in accordance with the procedure
of Stenkamp et al., WO 2008/022979.
b) tert-Butyl
7-(4-(benzyloxy)-6-oxopyridazin-1(6H)-yl)-5-methyl-3,4-dihydro-1H-pyrido[-
4,3-b]indole-2(5H)-carboxylate
##STR00210##
[0421] 5-(Benzyloxy)pyridazin-3(2H)-one (100 mg, 0.5 mmol) and
tert-butyl
7-bromo-5-methyl-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate
(180 mg, 0.5 mmol) were reacted following the procedure of Example
30 (step g) to provide the title compound (106 mg, 43%) as a solid:
ESI MS m/z 487 [M+H].sup.+.
c)
5-(Benzyloxy)-2-(5-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-7-yl-
)pyridazin-3(2H)-one hydrochloride
##STR00211##
[0423] tert-Butyl 7-(4-(benzyloxy)-6-oxopyridazin-1
(6H)-yl)-5-methyl-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate
(100 mg, 0.2 mmol) was deprotected and converted to the
hydrochloride salt according to the procedure of Example 30 (steps
e and g) to provide the title compound (30 mg, 35%) as a white
solid: mp 261-265.degree. C.; .sup.1H NMR (500 MHz, DMSO-d.sub.6)
.delta. 9.23 (s, 2H), 7.96 (d, J=2.8 Hz, 1H), 7.59 (d, J=1.6 Hz,
1H), 7.54 (d, J=8.4 Hz, 1H), 7.51-7.48 (m, 2H), 7.46-7.42 (m, 2H),
7.40 (d, J=7.5 Hz, 1H), 7.13 (dd, J=8.4, 1.7 Hz, 1H), 6.51 (d,
J=2.8 Hz, 1H), 5.22 (s, 2H), 4.34 (s, 2H), 3.69 (s, 3H), 3.52 (t,
J=5.8 Hz, 2H), 3.09 (t, J=5.8 Hz, 2H); ESI MS m/z 387 [M+H].sup.+;
HPLC (Method B) 97.7% (AUC), t.sub.R=12.8 min.
Example 78
Preparation of
2-(5-Methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-7-yl)-5-(4-(trifluor-
omethyl)phenyl)pyridazin-3(2H)-one hydrochloride
a) 5-Hydroxy-2-(tetrahydro-2H-pyran-2-yl)pyridazin-3 (2H)-one
[0424] CAS Registry Number 1008517-74-5
##STR00212##
[0425] This compound was prepared in accordance with the procedure
of Stenkamp et al., WO 2008/022979.
b) 6-Oxo-1-(tetrahydro-2H-pyran-2-yl)-1,6-dihydropyridazin-4-yl
trifluoromethanesulfonate
##STR00213##
[0427] 5-Hydroxy-2-(tetrahydro-2H-pyran-2-yl)pyridazin-3(2H)-one
(2.4 g, 13 mmol) dissolved in methylene chloride (75 mL) and cooled
to 0.degree. C. Triethylamine (3.5 mL, 25 mmol) and Tf.sub.2O (2.3
mL, 14 mmol) were added and the mixture stirred for a further 2.5
h. Saturated NaHCO.sub.3 solution was added and the organic phase
removed, dried over Na.sub.2SO.sub.4 and concentrated. Purification
by flash column chromaotgraphy (silica gel, EtOAc/hexanes) provided
the title compound (2.47 g, 60%) as a yellow oil: .sup.1H NMR (500
MHz, CDCl.sub.3) .delta. 7.85 (d, J=2.8 Hz, 1H), 6.86 (d, J=2.7 Hz,
1H), 6.01 (dd, J=10.2, 2.2 Hz, 1H), 4.15-4.12 (m, 1H), 3.75 (dt,
J=11.6, 2.5 Hz, 1H), 2.18-2.02 (m, 2H), 1.78-1.66 (m, 3H),
1.62-1.55 (m, 1H).
c)
2-(Tetrahydro-2H-pyran-2-yl)-5-(4-(trifluoromethyl)phenyl)pyridazin-3
(2H)-one
##STR00214##
[0429] 6-Oxo-1-(tetrahydro-2H-pyran-2-yl)-1,6-dihydropyridazin-4-yl
trifluoromethanesulfonate (2.47 g, 7.5 mmol) and
4-trifluoromethylphenylboronic acid (2.56 g, 15 mmol) were reacted
according to the procedure of Example 31 (step a) to provide the
title compound (500 mg, 20%) as a white solid: ESI MS m/z 325
[M+H].sup.+.
d) 5-(4-(Trifluoromethyl)phenyl)pyridazin-3 (2H)-one
##STR00215##
[0431]
2-(Tetrahydro-2H-pyran-2-yl)-5-(4-(trifluoromethyl)phenyl)pyridazin-
-3(2H)-one (500 mg, 1.54 mmol) was reacted according to the
procedure of Example 31 (step c) to provide the title compound (100
mg, 27%) as a solid: ESI MS m/z 241 [M+H].sup.+.
e) tert-Butyl
5-methyl-7-(6-oxo-4-(4-(trifluoromethyl)phenyl)pyridazin-1(6H)-yl)-3,4-di-
hydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate
##STR00216##
[0433] 5-(4-(Trifluoromethyl)phenyl)pyridazin-3 (2H)-one (100 mg,
0.41 mmol) and tert-butyl
7-bromo-5-methyl-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate
(151 mg, 0.41 mmol) were reacted following the procedure of Example
30 (step g) to provide the title compound (65 mg, 30%) as a yellow
solid: .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 8.20 (s, 1H), 7.81
(d, J=8.4 Hz, 2H), 7.76 (d, J=8.4 Hz, 2H), 7.59 (d, J=1.6 Hz, 1H),
7.54 (d, J=8.4 Hz, 1H), 7.31 (d, J=6.9 Hz, 1H), 7.26-7.24 (m, 1H),
4.62 (s, 2H), 3.89-3.80 (br m, 2H), 3.66 (s, 3H), 2.84 (br m, 2H),
1.51 (s, 9H).
f)
2-(5-Methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-7-yl)-5-(4-(triflu-
oromethyl)phenyl)pyridazin-3 (2H)-one hydrochloride
##STR00217##
[0435] tert-Butyl
5-methyl-7-(6-oxo-4-(4-(trifluoromethyl)phenyl)pyridazin-1(6H)-yl)-3,4-di-
hydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate (65 mg, 0.12 mmol)
was deprotected and converted to the hydrochloride salt according
to the procedure of Example 30 (steps e and g) to provide the title
compound (47 mg, 80%) as an orange solid: mp 315-320.degree. C.;
.sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 9.37 (s, 2H), 8.56 (d,
J=2.2 Hz, 1H), 8.13 (d, J=Hz, 2H), 7.93 (d, J=8.2 Hz, 2H), 7.72 (d,
J=1.6 Hz, 1H), 7.61 (d, J=8.4 Hz, 1H), 7.48 (d, J=2.2 Hz, 1H), 7.25
(dd, J=8.4, 1.8 Hz, 1H), 4.36 (s, 2H), 3.70 (s, 3H), 3.58-3.48 (br
m, 2H), 3.11 (t, J=5.7 Hz, 2H); ESI MS m/z 425 [M+H].sup.+; HPLC
(Method A) 96.6% (AUC), t.sub.R=15.7 min.
Example 79
Preparation of
4-(5-Chloropyridin-2-yl)-1-(9-methyl-2,3,4,5-tetrahydro-1H-pyrido[3,4-b]i-
ndol-7-yl)pyridin-2(1H)-one hydrochloride
a) tert-Butyl
7-(4-(5-chloropyridin-2-yl)-2-oxopyridin-1(2H)-yl)-9-methyl-3,4-dihydro-1-
H-pyrido[3,4-b]indole-2(9H)-carboxylate
##STR00218##
[0437] tert-Butyl
7-bromo-9-methyl-3,4-dihydro-1H-pyrido[3,4-b]indole-2(9H)-carboxylate
(200 mg, 0.549 mmol) and 4-(5-chloropyridin-2-yl)pyridin-2(1H)-one
(87 mg, 0.42 mmol) were reacted following the procedure of Example
30 (step g) to provide the title compound (97 mg, 47%) as a yellow
solid: .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 8.69 (d, J=2.0 Hz,
1H), 7.80 (dd, J=8.5, 2.3 Hz, 1H), 7.75 (d, J=8.4 Hz, 1H), 7.55
(overlapping dd, J=7.4 Hz, 2H), 7.36 (s, 1H), 7.18 (d, J=1.7 Hz,
1H), 7.08 (dd, J=8.3, 1.6 Hz, 1H), 7.00 (dd, J=7.1, 1.8 Hz, 1H),
4.65 (s, 2H), 3.76 (br m, 2H), 3.65 (s, 3H), 2.82 (br m, 2H), 1.52
(s, 9H).
b)
4-(5-Chloropyridin-2-yl)-1-(9-methyl-2,3,4,5-tetrahydro-1H-pyrido[3,4-b-
]indol-7-yl)pyridin-2(1H)-one hydrochloride
##STR00219##
[0439] tert-Butyl 7-(4-(5-chloropyridin-2-yl)-2-oxopyridin-1
(2H)-yl)-5-methyl-3,4-dihydro-1H-pyrido[3,4-b]indole-2(5H)-carboxylate
(97 mg, 0.20 mmol) was deprotected and converted to the
hydrochloride salt according to the procedure of Example 30 (steps
e and g) to provide the title compound as a orange solid (68 mg,
88%): mp 310-320.degree. C.; .sup.1H NMR (500 MHz, CD.sub.3OD)
.delta. 8.73 (dd, J=2.4, 0.6 Hz, 1H), 8.03 (dd, J=8.5, 0.5 Hz, 1H),
8.00 (dd, J=8.5, 2.4 Hz, 1H), 7.80 (d, J=7.1 Hz, 1H), 7.67 (d,
J=8.3 Hz, 1H), 7.56 (d, J=1.7 Hz, 1H), 7.31 (d, J=1.7 Hz, 1H), 7.19
(dd, J=7.1, 2.0 Hz, 1H), 7.14 (dd, J=8.4, 1.8 Hz, 1H), 4.56 (s,
2H), 3.74 (s, 3H), 3.61 (t, J=6.1 Hz, 2H), 3.14 (t, J=6.1 Hz, 2H);
ESI MS m/z 391 [M+H].sup.+; HPLC (Method A) >99% (AUC),
t.sub.R=11.9 min.
Example 80
Preparation of
1-(2,9-Dimethyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-7-yl)-4-(5-chlor-
opyridin-2-yl)pyridin-2(1H)-one hydrochloride
##STR00220##
[0441]
4-(5-Chloropyridin-2-yl)-1-(5-methyl-2,3,4,5-tetrahydro-1H-pyrido[3-
,4-b]indol-7-yl)pyridin-2(1H)-one (104 mg, 0.266 mmol) was reacted
following the procedure of Example 47 to provide the title compound
(75 mg, 70%) as a yellow solid: mp 283-295.degree. C.; .sup.1H NMR
(500 MHz, CD.sub.3OD) .delta. 8.73 (d, J=2.3 Hz, 1H), 8.03 (d,
J=8.5 Hz, 1H) 7.99 (dd, J=8.5, 2.3 Hz, 1H), 7.79 (d, J=7.2 Hz, 1H),
7.67 (d, J=8.3 Hz, 1H), 7.57 (s, 1H), 7.31 (d, J=1.6 Hz, 1H), 7.19
(dd, J=7.1, 1.8 Hz, 1H), 7.15 (dd, J=8.3, 1.7 Hz, 1H), 4.65 (br s,
2H), 3.74 (m, 5H), 3.21 (t, J=5.7 Hz, 2H), 3.17 (s, 3H); ESI MS m/z
405 [M+H].sup.+; HPLC (Method B) 98.7% (AUC), t.sub.R=12.1 min.
Example 81
Preparation of
4-(5-(Trifluoromethyl)pyridin-2-yl)-1-(9-methyl-2,3,4,5-tetrahydro-1H-pyr-
ido[3,4-b]indol-7-yl)pyridin-2(1H)-one hydrochloride
a) tert-Butyl
9-methyl-7-(2-oxo-4-(5-(trifluoromethyl)pyridin-2-yl)pyridin-1(2H)-yl)-3,-
4-dihydro-1H-pyrido[3,4-b]indole-2(9H)-carboxylate
##STR00221##
[0443] tert-Butyl
7-bromo-9-methyl-3,4-dihydro-1H-pyrido[3,4-b]indole-2(9H)-carboxylate
(100 mg, 0.417 mmol) and
4-(5-(trifluoromethyl)pyridin-2-yl)pyridin-2(1H)-one (197 mg, 0.542
mmol), were reacted following the procedure of Example 30 (step g)
to provide the title compound (168 mg, 66%) as a yellow solid:
.sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 9.00 (s, 1H), 8.07 (dd,
J=8.3, 1.9 Hz, 1H), 7.90 (d, J=8.3 Hz, 1H), 7.58 (overlapping dd,
J=7.1 Hz, 2H), 7.37 (s, 1H), 7.26 (d, 1H under solvent), 7.08 (dd,
J=8.3, 1.7 Hz, 1H), 7.03 (dd, J=7.1, 1.9 Hz, 1H), 4.66 (s, 2H),
3.76 (br m, 2H), 3.65 (s, 3H), 2.82 (br m, 2H), 1.52 (s, 9H).
b)
4-(5-(Trifluoromethyl)pyridin-2-yl)-1-(9-methyl-2,3,4,5-tetrahydro-1H-p-
yrido[3,4-b]indol-7-yl)pyridin-2(1H)-one hydrochloride
##STR00222##
[0445] tert-Butyl
9-methyl-7-(2-oxo-4-(5-(trifluoromethyl)pyridin-2-yl)pyridin-1
(2H)-yl)-3,4-dihydro-1H-pyrido[3,4-b]indole-2(9H)-carboxylate (168
mg, 0.321 mmol) was deprotected and converted to the hydrochloride
salt according to the procedure of Example 30 (steps e and g) to
provide the title compound as an orange solid (73 mg, 54%): mp
305-315.degree. C.; .sup.1H NMR (500 MHz, CD.sub.3OD) .delta. 9.05
(s, 1H), 8.28 (dd, J=8.3, 2.2 Hz, 1H), 8.22 (d, J=8.3, Hz, 1H),
7.84 (d, J=7.1 Hz, 1H), 7.67 (d, J=8.4 Hz, 1H), 7.58 (d, J=1.8 Hz,
1H), 7.40 (d, J=1.8 Hz, 1H), 7.25 (dd, J=7.2, 2.0 Hz, 1H), 7.15
(dd, J=8.4, 1.8 Hz, 1H), 4.57 (s, 2H), 3.74 (s, 3H), 3.62 (t, J=6.1
Hz, 2H), 3.15 (t, J=5.9 Hz, 2H); ESI MS m/z 425 [M+H].sup.+; HPLC
(Method A) 96.4% (AUC), t.sub.R=12.6 min.
Example 82
Preparation of
1-(2,9-Dimethyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-7-yl)-4-(5-(trif-
luoromethyl) pyridin-2-yl)pyridin-2(1H)-one hydrochloride
##STR00223##
[0447]
4-(5-(Trifluoromethyl)pyridin-2-yl)-1-(9-methyl-2,3,4,5-tetrahydro--
1H-pyrido[3,4-b]indol-7-yl)pyridin-2(1H)-one (125 mg, 0.294 mmol)
was reacted following the procedure of Example 47 to provide the
title compound (97.9 g, 78%) as a yellow solid: mp 280-290.degree.
C.; .sup.1H NMR (500 MHz, CD.sub.3OD) .delta. 9.05 (s, 1H), 8.28
(dd, J=8.3, 2.1 Hz, 1H) 8.22 (d, J=8.4, Hz, 1H), 7.84 (d, J=7.1 Hz,
1H), 7.68 (d, J=8.3 Hz, 1H), 7.59 (d, J=1.6, 1H), 7.40 (d, J=1.7
Hz, 1H), 7.25 (dd, J=7.2, 1.9 Hz, 1H), 7.16 (dd, J=8.3, 1.8 Hz,
1H), 4.87 (s, 1H), 4.51 (s, 1H), 3.87 (s, 1H), 3.75 (br s, 3H),
3.55 (br s, 1H), 3.21-3.17 (m, 5H); ESI MS m/z 439 [M+H].sup.+;
HPLC (Method B) 98.3% (AUC), t.sub.R=12.8 min.
Example 84
Preparation of
4-((5-Fluoropyridin-2-yl)methoxy)-1-(9-methyl-2,3,4,9-tetrahydro-1H-pyrid-
o[3,4-b]indol-7-yl)pyridin-2(1H)-one hydrochloride
a) tert-Butyl
7-(4-((5-fluoropyridin-2-yl)methoxy)-2-oxopyridin-1(2H)-yl)-9-methyl-3,4--
dihydro-1H-pyrido[3,4-b]indole-2(9H)-carboxylate
##STR00224##
[0449] tert-Butyl
7-bromo-9-methyl-3,4-dihydro-1H-pyrido[3,4-b]indole-2(9H)-carboxylate
(306 mg, 0.840 mmol) and 4-(4-fluorobenzyloxy)pyridin-2(1H)-one
(142 mg, 0.640 mmol) were reacted following the procedure of
Example 30 (step g) to provide the title compound (157 mg, 49%) as
a yellow/green solid: .sup.1H NMR (300 MHz, CDCl.sub.3) .delta.
8.49 (d, J=2.0 Hz, 1H), 7.54-7.46 (m, 3H), 7.34-7.28 (m, 2H), 7.01
(dd, J=8.2, 1.8 Hz, 1H), 6.10 (d, J=2.7 Hz, 1H), 6.07 (s, 1H), 5.17
(s, 2H), 4.63 (br m, 2H), 3.74 (br m, 2H), 3.62 (s, 3H), 2.80 (br
m, 2H), 1.51 (s, 9H).
b)
4-((5-Fluoropyridin-2-yl)methoxy)-1-(9-methyl-2,3,4,9-tetrahydro-1H-pyr-
ido[3,4-b]indol-7-yl)pyridin-2(1H)-one hydrochloride
##STR00225##
[0451] tert-Butyl
7-(4-((5-fluoropyridin-2-yl)methoxy)-2-oxopyridin-1(2H)-yl)-9-methyl-3,4--
dihydro-1H-pyrido[3,4-b]indole-2(9H)-carboxylate (157 mg, 0.312
mmol) was deprotected and converted to the hydrochloride salt
according to the procedure of Example 30 (steps e and g) to provide
the title compound as a yellow solid (72.7 mg, 54%): mp
285-295.degree. C.; .sup.1H NMR (500 MHz, CD.sub.3OD) .delta. 8.51
(s, 1H), 7.72-7.59 (m, 4H), 7.46 (d, J=1.0 Hz, 1H), 7.05 (dd,
J=8.3, 1.5 Hz, 1H), 6.32 (dd, J=7.6, 2.6 Hz, 1H), 7.05 (d, J=2.6
Hz, 1H), 5.26 (s, 2H), 4.54 (s, 2H), 3.71 (s, 3H), 3.60 (t, J=6.0
Hz, 2H), 3.12 (t, J=5.8 Hz, 2H); ESI MS m/z 405 [M+H].sup.+; HPLC
(Method B) 98.3% (AUC), t.sub.R=12.0 min.
Example 85
Preparation of
1-(2,9-Dimethyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-7-yl)-4-((5-fluo-
ropyridin-2-yl)methoxy)pyridin-2(1H)-one hydrochloride
##STR00226##
[0453]
4-((5-Fluoropyridin-2-yl)methoxy)-1-(9-methyl-2,3,4,9-tetrahydro-1H-
-pyrido[3,4-b]indol-7-yl)pyridin-2(1H)-one (76 mg, 0.19 mmol) was
reacted following the procedure of Example 47 to provide the title
compound (61 mg, 79%) as a yellow solid: mp 287-300.degree. C.;
.sup.1H NMR (500 MHz, CD.sub.3OD) .delta. 8.51 (d, J=2.6 Hz, 1H),
7.72-7.59 (m, 4H), 7.47 (s, 1H), 7.06 (dd, J=8.3, 1.7 Hz, 1H), 6.32
(dd, J=7.6, 2.6 Hz, 1H), 6.13 (d, J=2.6 Hz, 1H), 5.26 (s, 2H), 4.68
(m, 2H), 3.71 (m, 5H), 3.18 (t, J=5.9 Hz, 2H), 3.15 (s, 3H); ESI MS
m/z 419 [M+H].sup.+; HPLC (Method B) 98.4% (AUC), t.sub.R=11.1
min.
Example 86
Preparation of
1-(9-Methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-7-yl)-4-(6-(trifluor-
omethyl)pyridin-3-yl)pyridin-2(1H)-one hydrochloride
a) tert-Butyl
9-methyl-7-(2-oxo-4-(6-(trifluoromethyl)pyridin-3-yl)pyridin-1(2H)-yl)-3,-
4-dihydro-1H-pyrido[3,4-b]indole-2(9H)-carboxylate
##STR00227##
[0455] 4-(6-(Trifluoromethyl)pyridin-3-yl)pyridin-2(1H)-one (145
mg, 0.604 mmol) and tert-butyl
7-bromo-9-methyl-3,4-dihydro-1H-pyrido[3,4-b]indole-2(9H)-carboxylate
(200 mg, 0.549 mmol) were coupled following the procedure of
Example 30 (step g) to provide the title compound (129 mg, 45%) as
a yellow/green solid: .sup.1H NMR (500 MHz, CDCl.sub.3) .delta.
9.00 (s, 1H), 8.10 (dd, J=8.1, 2.0 Hz, 1H), 7.82 (d, J=8.2 Hz, 1H),
7.60-7.57 (m, 2H), 7.36 (s, 1H), 7.08 (dd, J=8.3, 1.8 Hz, 1H), 6.93
(d, J=1.8 Hz, 1H), 6.49 (dd, J=7.1, 2.0 Hz, 1H), 4.66 (br m, 2H),
3.76 (br m, 2H), 3.66 (s, 3H), 2.82 (br m, 2H), 1.52 (s, 9H).
b)
1-(9-Methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-7-yl)-4-(6-(triflu-
oromethyl)pyridin-3-yl)pyridin-2(1H)-one hydrochloride
##STR00228##
[0457] tert-Butyl
9-methyl-7-(2-oxo-4-(6-(trifluoromethyl)pyridin-3-yl)pyridin-1
(2H)-yl)-3,4-dihydro-1H-pyrido[3,4-b]indole-2(9H)-carboxylate (129
mg, 0.25 mmol) was deprotected and converted to the hydrochloride
salt according to the procedure of Example 30 (steps e and g) to
provide the title compound (67 mg, 58%) as a yellow/brown solid: mp
315-320.degree. C.; .sup.1H NMR (500 MHz, CD.sub.3OD) .delta. 9.10
(d, J=1.9 Hz, 1H), 8.41 (dd, J=8.2, 2.2 Hz, 1H), 7.97 (d, J=8.3 Hz,
1H), 7.85 (d, J=7.0 Hz, 1H), 7.68 (d, J=8.3 Hz, 1H), 7.57 (d, J=1.7
Hz, 1H), 7.15 (dd, J=8.3, 1.8 Hz, 1H), 7.03 (d, J=1.8 Hz, 1H), 6.89
(dd, J=7.1, 2.0 Hz, 1H), 4.57 (br m, 2H), 3.75 (s, 3H), 3.62 (br m,
2H), 3.15 (br m, 2H); ESI MS m/z 425 [M+H].sup.+; HPLC (Method B)
97.4% (AUC), t.sub.R=12.3 min.
Example 87
Preparation of
1-(2,3,4,9-Tetrahydro-1H-pyrido[3,4-b]indol-7-yl)-4-(5-(trifluoromethyl)p-
yridin-2-yl)pyridin-2(1H)-one hydrochloride
a) tert-Butyl
7-bromo-9-tosyl-3,4-dihydro-1H-pyrido[3,4-b]indole-2(9H)-carboxylate
##STR00229##
[0459] 6N NaOH solution (6 mL), (Bu.sub.4N).sub.2SO.sub.4 (50% wt.
solution in H.sub.2O, 0.20 mL), and TsCl (646 mg, 3.39 mmol) were
added to a suspension of tert-butyl
7-bromo-3,4-dihydro-1H-pyrido[3,4-b]indole-2(9H)-carboxylate (991
mg, 2.82 mmol) in toluene (20 mL) and the resulting suspension was
stirred at 25.degree. C. for 1.5 h. H.sub.2O and EtOAc were added
to the suspension and the phases were separated. The organic phase
was washed with H.sub.2O, dried over Na.sub.2SO.sub.4 and
concentrated under reduced pressure to afford the title compound
(1.285 g, 90%) as a white foam: .sup.1H NMR (300 MHz, CDCl.sub.3)
.delta. 8.32 (d, J=1.5 Hz, 1H), 7.78-7.66 (m, 2H), 7.36 (dd, J=8.4,
1.5 Hz, 1H), 7.25-7.21 (m, 2H), 7.21-7.13 (m, 1H), 4.92-4.81 (m,
2H), 3.74-3.63 (m, 2H), 2.70-2.61 (m, 2H), 2.37 (s, 3H), 1.50 (s,
9H).
b) tert-Butyl
7-(2-oxo-4-(5-(trifluoromethyl)pyridin-2-yl)pyridin-1(2H)-yl)-9-tosyl-3,4-
-dihydro-1H-pyrido[3,4-b]indole-2(9H)-carboxylate
##STR00230##
[0461] 4-(5-(Trifluoromethyl)pyridin-2-yl)pyridin-2(1H)-one (200
mg, 0.830 mmol) and tert-butyl
7-bromo-9-tosyl-3,4-dihydro-1H-pyrido[3,4-b]indole-2(9H)-carboxylate
(419 mg, 0.830 mmol) were coupled following the procedure of
Example 30 (step g) to provide the title compound (222 mg, 40%) as
a yellow solid: .sup.1H NMR (500 MHz, CDCl.sub.3) .delta. 9.02 (s,
1H), 8.26 (s, 1H), 8.08 (d, J=7.6 Hz, 1H), 7.80 (br s, 2H), 7.57
(d, J=7.2 Hz, 1H), 7.47 (d, J=7.2 Hz, 1H), 7.47 (d, J=8.0 Hz, 1H),
7.32 (d, J=7.9 Hz, 1H), 7.27 (3H, under solvent peak), 7.07 (d,
J=6.8 Hz, 1H), 4.91 (br m, 2H), 3.71 (br m, 2H), 2.71 (br m, 2H),
2.36 (s, 3H), 1.52 (s, 9H).
c)
1-(9-Tosyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-7-yl)-4-(5-(trifluo-
romethyl)pyridin-2-yl)pyridin-2(1H)-one
##STR00231##
[0463] tert-Butyl
7-(2-oxo-4-(5-(trifluoromethyl)pyridin-2-yl)pyridin-1(2H)-yl)-9-tosyl-3,4-
-dihydro-1H-pyrido[3,4-b]indole-2(9H)-carboxylate (222 mg, 0.334
mmol) was deprotected according to the procedure of Example 30
(step e) to provide the title compound (131 mg, 58%) as a yellow
solid: .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 9.02 (s, 1H), 8.25
(d, J=1.6 Hz, 1H), 8.08 (dd, J=8.3, 1.9 Hz, 1H), 7.93 (d, J=8.3 Hz,
1H), 7.75 (d, J=8.4 Hz, 2H), 7.58 (d, J=7.2 Hz, 1H), 7.48 (d, J=8.3
Hz, 1H), 7.32 (dd, J=8.3, 1.8 Hz, 1H), 7.28-7.24 (3H, under solvent
peak), 7.08 (dd, J=7.2, 2.0 Hz, 1H), 4.30 (br s, 2H), 3.13 (t,
J=5.6 Hz, 2H), 3.61 (br m, 2H), 2.36 (s, 3H).
d)
1-(2,3,4,9-Tetrahydro-1H-pyrido[3,4-b]indol-7-yl)-4-(5-(trifluoromethyl-
)pyridin-2-yl)pyridin-2(1H)-one dihydrochloride
##STR00232##
[0465]
1-(9-Tosyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-7-yl)-4-(5-(tri-
fluoromethyl)pyridin-2-yl)pyri din-2(1H)-one (130 mg, 0.23 mmol)
was deprotected according to the procedure of Example 106 (step b)
to provide the title compound (39.5 mg, 36%) as a yellow solid: mp
320-330.degree. C.; .sup.1H NMR (500 MHz, CD.sub.3OD) .delta. 9.05
(s, 1H), 8.28 (dd, J=8.4, 2.1 Hz, 1H), 8.22 (d, J=8.4 Hz, 1H), 7.82
(d, J=7.2 Hz, 1H), 7.66 (d, J=8.4 Hz, 1H), 7.48 (d, J=7.1 Hz, 1H),
7.39 (d, J=1.7 Hz, 1H), 7.24 (dd, J=7.2, 1.9 Hz, 1H), 7.13 (dd,
J=8.4, 1.8 Hz, 1H), 4.50 (s, 2H), 3.63 (t, J=6.1 Hz, 2H), 3.14 (t,
J=6.1 Hz, 2H); ESI MS m/z 411 [M+H].sup.+; HPLC (Method B) 98.4%
(AUC), t.sub.R=12.6 min.
Example 88
Preparation of
5-(Benzyloxy)-2-(9-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-7-yl)p-
yridazin-3(2H)-one hydrochloride
a) tert-Butyl
7-(4-(benzyloxy)-6-oxopyridazin-1(6H)-yl)-9-methyl-3,4-dihydro-1H-pyrido[-
3,4-b]indole-2(9H)-carboxylate
##STR00233##
[0467] 5-(Benzyloxy)pyridazin-3(2H)-one (197 mg, 0.974 mmol) and
tert-butyl
7-bromo-9-methyl-3,4-dihydro-1H-pyrido[3,4-b]indole-2(9H)-carboxylate
(353 mg, 0.966 mmol) were coupled following the procedure of
Example 30 (step g) to provide the title compound (130 mg, 28%) as
a yellow/green solid: .sup.1H NMR (300 MHz, CDCl.sub.3) .delta.
7.77 (d, J=2.7 Hz, 1H), 7.52 (d, J=8.2 Hz, 1H), 7.45-7.40 (m, 7H),
7.21 (dd, J=8.4, 1.5 Hz, 1H), 5.08 (s, 2H), 4.64 (br m, 2H), 3.75
(br m, 2H), 3.63 (s, 3H), 2.80 (br m, 2H), 1.52 (s, 9H).
b)
5-(Benzyloxy)-2-(9-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-7-yl-
)pyridazin-3(2H)-one hydrochloride
##STR00234##
[0469] tert-Butyl 7-(4-(benzyloxy)-6-oxopyridazin-1
(6H)-yl)-9-methyl-3,4-dihydro-1H-pyrido[3,4-b]indole-2(9H)-carboxylate
(130 mg, 0.27 mmol) was deprotected and converted to the
hydrochloride salt according to the procedure of Example 30 (steps
e and g) to provide the title compound (55.7, 48%) as a yellow
solid: mp 235-245.degree. C.; .sup.1H NMR (500 MHz, CD.sub.3OD)
.delta. 7.93 (d, J=2.7 Hz, 1H), 7.59 (d, J=8.4 Hz, 1H), 7.56 (d,
J=1.5 Hz, 1H), 7.50-7.48 (m, 2H), 7.43 (overlapping dd, J=7.8 Hz,
2H), 7.39 (d, J=1.7 Hz, 1H), 7.18 (dd, J=8.4, 1.7 Hz, 1H), 6.48 (d,
J=2.7 Hz, 1H), 5.22 (s, 2H), 4.54 (s, 2H), 3.71 (s, 3H), 3.59 (t,
J=5.6 Hz, 2H), 3.12 (t, J=5.9 Hz, 2H); ESI MS m/z 387 [M+H].sup.+;
HPLC (Method B) >99% (AUC), t.sub.R=11.7 min.
Example 89
Preparation of
1-(9-Methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-7-yl)-4-((6-(trifluo-
romethyl)pyridin-3-yl)methoxy)pyridin-2(1H)-one hydrochloride
a) tert-Butyl
9-methyl-7-(2-oxo-4-((6-(trifluoromethyl)pyridin-3-yl)methoxy)pyridin-1(2-
H)-yl)-3,4-dihydro-1H-pyrido[3,4-b]indole-2(9H)-carboxylate
##STR00235##
[0471]
4-((6-(Trifluoromethyl)pyridin-3-yl)methoxy)pyridin-2(1H)-one (100
mg, 0.37 mmol) and tert-butyl
7-bromo-9-methyl-3,4-dihydro-1H-pyrido[3,4-b]indole-2(9H)-carboxylate
(135 mg, 0.370 mmol) were coupled following the procedure of
Example 30 (step g) to provide the title compound (44 mg, 21%) as a
yellow/brown solid: .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 8.81
(s, 1H), 7.96 (d, J=8.6 Hz, 1H), 7.75 (d, J=8.0 Hz, 1H), 7.54 (d,
J=8.3 Hz, 1H), 7.37-7.34 (m, 1H), 7.27 (1H, under solvent peak),
7.02 (dd, J=8.3, 1.7 Hz, 1H), 6.07-6.04 (m, 2H), 5.16 (s, 2H), 4.64
(br m, 2H), 3.75 (br m, 2H), 3.63 (s, 3H), 2.80 (br m, 2H), 1.52
(s, 9H).
b)
1-(9-Methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-7-yl)-4-((6-(trifl-
uoromethyl)pyridin-3-yl)methoxy)pyridin-2(1H)-one hydrochloride
##STR00236##
[0473] tert-Butyl
9-methyl-7-(2-oxo-4-((6-(trifluoromethyl)pyridin-3-yl)methoxy)pyridin-1(2-
H)-yl)-3,4-dihydro-1H-pyrido[3,4-b]indole-2(9H)-carboxylate (44 mg,
0.079 mmol) was deprotected and converted to the hydrochloride salt
according to the procedure of Example 30 (steps e and g) to provide
the title compound (28 mg, 65%) as a yellow solid: mp
285-295.degree. C.; .sup.1H NMR (500 MHz, CD.sub.3OD) .delta. 8.75
(s, 1H), 8.08 (d, J=7.9 Hz, 1H), 7.79 (d, J=8.1 Hz, 1H), 7.53 (dd,
J=7.9, 2.0 Hz, 2H), 7.38 (d, J=1.7 Hz, 1H), 6.97 (dd, J=8.4, 1.8
Hz, 1H), 6.25 (dd, J=7.6, 2.7 Hz, 1H), 6.08 (d, J=2.6 Hz, 1H), 5.26
(s, 2H), 4.46 (s, 2H), 3.63 (s, 3H), 3.51 (t, J=6.1 Hz, 2H), 3.03
(t, J=6.1 Hz, 2H); ESI MS m/z 455 [M+H].sup.+; HPLC (Method B)
>99% (AUC), t.sub.R=12.8 min.
Example 90
Preparation of
1-(9-Methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-7-yl)-4-(5-methylpyr-
idin-2-yl)pyridin-2(1H)-one dihydrochloride
a) 2'-Methoxy-5-methyl-2,4'-bipyridine
##STR00237##
[0475] 2-Bromo-5-methylpyridine (2.93 g, 17.0 mmol) and
2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine
(3.34 g, 14.2 mmol) were reacted according to Example 31 (step a)
to provide the title compound (1.2 g, 42%) as a brown solid: ESI MS
m/z 201 [M+H].sup.+.
b) 4-(5-Methylpyridin-2-yl)pyridin-2(1H)-one
##STR00238##
[0477] 2'-Methoxy-5-methyl-2,4'-bipyridine (1.2 g, 6.0 mmol) was
reacted according to Example 31 (step c) to provide the title
compound (301 mg, 27%) as a white solid: .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 11.58 (s, 1H) 8.53 (s, 1H), 7.88 (overlapping
dd, J=8.2 Hz, 1H), 7.71 (d, J=6.0 Hz, 1H), 7.43 (d, J=7.7, 1H),
6.95 (d, J=1.5 Hz, 1H), 6.84 (dd, J=6.9, 1.7 Hz, 1H), 2.34 (s,
3H).
c) tert-Butyl
9-methyl-7-(4-(5-methylpyridin-2-yl)-2-oxopyridin-1(2H)-yl)-3,4-dihydro-1-
H-pyrido[3,4-b]indole-2(9H)-carboxylate
##STR00239##
[0479] 4-(5-methylpyridin-2-yl)pyridin-2(1H)-one (150 mg, 0.81
mmol) and tert-butyl
7-bromo-9-methyl-3,4-dihydro-1H-pyrido[3,4-b]indole-2(9H)-carboxylate
(294 mg, 0.805 mmol) were reacted following the procedure of
Example 30 (step g) to provide the title compound (138 mg, 36%) as
a yellow/green solid: .sup.1H NMR (500 MHz, CDCl.sub.3) .delta.
8.56 (s, 1H), 7.71 (d, J=8.2 Hz, 1H), 7.63-7.61 (m, 1H), 7.56 (d,
J=8.3 Hz, 1H), 7.52 (d, J=7.2 Hz, 1H), 7.37 (s, 1H), 7.17 (d, J=1.6
Hz, 1H), 7.09 (dd, J=8.3, 1.7 Hz, 1H), 7.04 (dd, J=7.2, 1.9 Hz,
1H), 4.65 (br m, 2H), 3.76 (br m, 2H), 3.65 (s, 3H), 2.82 (br m,
2H), 2.42 (s, 3H), 1.51 (s, 9H).
d)
1-(9-Methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-7-yl)-4-(5-methylp-
yridin-2-yl)pyridin-2(1H)-one dihydrochloride
##STR00240##
[0481] tert-Butyl
9-methyl-7-(4-(5-methylpyridin-2-yl)-2-oxopyridin-1(2H)-yl)-3,4-dihydro-1-
H-pyrido[3,4-b]indole-2(9H)-carboxylate (138 mg, 0.27 mmol) was
deprotected and converted to the dihydrochloride salt according to
the procedure of Example 30 (steps e and g) to provide the title
compound (18 mg, 15%) as a yellow solid: mp 303-310.degree. C.;
.sup.1H NMR (500 MHz, CD.sub.3OD) .delta. 8.59 (s, 1H), 7.95 (d,
J=8.1 Hz, 1H), 7.87 (d, J=6.5 Hz, 1H), 7.80 (d, J=7.0 Hz, 1H), 7.67
(d, J=8.4 Hz, 1H), 7.56 (d, J=1.4 Hz, 1H), 7.24 (d, J=1.6 Hz, 1H),
7.15-7.12 (m, 2H), 4.57 (s, 2H), 3.74 (s, 3H), 3.61 (t, J=6.0 Hz,
2H), 3.14 (t, J=6.1 Hz, 2H), 2.46 (s, 3H); ESI MS m/z 371
[M+H].sup.+; HPLC (Method B) >99% (AUC), t.sub.R=11.0 min.
Example 91
Preparation of
1-(5-Methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-7-yl)-4-(5-methylpyr-
idin-2-yl)pyridin-2(1H)-one dihydrochloride
a) tert-Butyl
5-methyl-7-(4-(5-methylpyridin-2-yl)-2-oxopyridin-1(2H)-yl)-3,4-dihydro-1-
H-pyrido[4,3-b]indole-2(5H)-carboxylate
##STR00241##
[0483] 4-(5-Methylpyridin-2-yl)pyridin-2(1H)-one (150 mg, 0.81
mmol) and tert-butyl
7-bromo-5-methyl-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate
(294 mg, 0.805 mmol) were reacted following the procedure of
Example 30 (step g) to provide the title compound (245 mg, 64%) as
a yellow/green solid: .sup.1H NMR (300 MHz, CDCl.sub.3) .delta.
8.57 (d, J=2.0 Hz, 1H), 7.71 (d, J=8.0 Hz, 1H), 7.64-7.60 (m, 1H),
7.55-7.51 (m, 2H), 7.37 (d, J=1.6 Hz, 1H), 7.17 (d, J=1.6 Hz, 1H),
7.10-7.03 (m, 2H), 4.66 (br m, 2H), 3.85 (br m, 2H), 3.65 (s, 3H),
2.84 (br m, 2H), 2.42 (s, 3H), 1.51 (s, 9H).
b)
1-(5-Methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-7-yl)-4-(5-methylp-
yridin-2-yl)pyridin-2(1H)-one dihydrochloride
##STR00242##
[0485] tert-Butyl
5-methyl-7-(4-(5-methylpyridin-2-yl)-2-oxopyridin-1(2H)-yl)-3,4-dihydro-1-
H-pyrido[4,3-b]indole-2(5H)-carboxylate (245 mg, 0.520 mmol) was
deprotected and converted to the dihydrochloride salt according to
the procedure of Example 30 (steps e and g) to provide the title
compound (57 mg, 30%) as a yellow solid: mp 295-305.degree. C.;
.sup.1H NMR (500 MHz, CD.sub.3OD) .delta. 8.76 (d, J=1.8 Hz, 1H),
8.34 (d, J=6.9 Hz, 1H), 8.24 (d, J=8.2 Hz, 1H), 7.94 (d, J=7.2 Hz,
1H), 7.67 (d, J=8.3 Hz, 1H), 7.61 (d, J=1.7 Hz, 1H), 7.23 (d, J=1.8
Hz, 1H), 7.17 (dd, J=8.3, 1.8 Hz, 1H), 7.04 (dd, J=7.1, 2.1 Hz,
1H), 4.53 (s, 2H), 3.79 (s, 3H), 3.71 (t, J=6.2 Hz, 2H), 3.25 (t,
J=6.2 Hz, 2H), 2.61 (s, 3H); ESI MS m/z 371 [M+H].sup.+; HPLC
(Method B) 97.3% (AUC), t.sub.R=10.9 min.
Example 92
Preparation of
1-(5-Methyl-2,3,4,9-tetrahydro-1H-pyrido[4,3-b]indol-7-yl)-4-(6-methylpyr-
idin-3-yl)pyridin-2(1H)-one dihydrochloride
a) 2'-Methoxy-6-methyl-3,4'-bipyridine
##STR00243##
[0487]
2-Methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine
(3.5 g, 16 mmol) and 4-bromo-2-methoxypyridine (2.0 g, 11 mmol)
were reacted according to Example 31 (step a) to provide the title
compound (2.1 g, 98%) as a brown solid: .sup.1H NMR (300 MHz,
CDCl.sub.3) .delta. 8.75 (d, J=2.1 Hz, 1H), 8.23 (d, J=5.4 Hz, 1H),
7.78 (dd, J=8.0, 2.4 Hz, 1H), 7.24 (d, J=8.1, 1H), 7.08 (dd, J=5.4,
1.5 Hz, 1H), 6.84 (d, J=1.0, 1H), 3.98 (s, 3H), 2.61 (s, 3H).
b) 4-(6-Methylpyridin-3-yl)pyridin-2(1H)-one
##STR00244##
[0489] 2'-Methoxy-6-methyl-3,4'-bipyridine (2.1 g, 10.4 mmol) was
reacted according to Example 31 (step c) to provide the title
compound (1.36 mg, 68%) as a white solid: .sup.1H NMR (300 MHz,
DMSO-d.sub.6) .delta. 11.65 (s, 1H) 8.78 (d, J=2.1 Hz, 1H), 8.01
(dd, J=8.1, 2.5 Hz, 1H), 7.47 (d, J=6.9 Hz, 1H), 7.36 (d, J=8.1,
1H), 6.66 (d, J=1.4 Hz, 1H), 6.55 (dd, J=6.9, 1.8 Hz, 1H), 2.51 (s,
3H).
c) tert-Butyl
5-methyl-7-(4-(6-methylpyridin-3-yl)-2-oxopyridin-1(2H)-yl)-3,4-dihydro-1-
H-pyrido[4,3-b]indole-2(5H)-carboxylate
##STR00245##
[0491] 4-(6-Methylpyridin-3-yl)pyridin-2(1H)-one (150 mg, 0.81
mmol) and tert-butyl
7-bromo-5-methyl-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate
(294 mg, 0.805 mmol) were reacted following the procedure of
Example 30 (step g) to provide the title compound (220 mg, 58%) as
a yellow/green solid: .sup.1H NMR (500 MHz, CDCl.sub.3) .delta.
8.79 (d, J=8.2 Hz, 1H), 7.83 (dd, J=8.1, 2.4 Hz, 1H), 7.56-7.51 (m,
2H), 7.37 (d, J=1.4 Hz, 1H), 7.30 (1H, partially under solvent),
7.08 (d, J=8.7 Hz, 1H), 6.90 (d, J=1.6 Hz, 1H), 6.50 (dd, J=7.1,
1.9 Hz, 1H), 4.66 (br s, 2H), 3.85 (br m, 2H), 3.65 (s, 3H), 2.84
(br m, 2H), 2.64 (s, 3H), 1.51 (s, 9H).
d)
1-(5-Methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-7-yl)-4-(6-methylp-
yridin-3-yl)pyridin-2(1H)-one dihydrochloride
##STR00246##
[0493] tert-Butyl
5-methyl-7-(4-(6-methylpyridin-3-yl)-2-oxopyridin-1(2H)-yl)-3,4-dihydro-1-
H-pyrido[4,3-b]indole-2(5H)-carboxylate (220 mg, 0.47 mmol) was
deprotected and converted to the dihydrochloride salt according to
the procedure of Example 30 (steps e and g) to provide the title
compound (50.2 mg, 29%) as a yellow solid: mp 295-305.degree. C.;
.sup.1H NMR (500 MHz, CD.sub.3OD) .delta. 8.80 (d, J=2.2 Hz, 1H),
8.12 (dd, J=8.1, 2.5 Hz, 1H), 7.79 (d, J=7.0 Hz, 1H), 7.59 (d,
J=8.3 Hz, 1H), 7.52 (d, J=1.7 Hz, 1H), 7.47 (d, J=8.2 Hz, 1H), 7.10
(dd, J=8.3, 1.9 Hz, 1H), 6.93 (d, J=1.8 Hz, 1H), 6.85 (dd, J=7.1,
2.0 Hz, 1H), 4.34 (s, 2H), 3.73 (s, 3H), 3.52 (t, J=6.1 Hz, 2H),
3.10 (t, J=6.1 Hz, 2H), 2.62 (s, 3H); ESI MS m/z 371 [M+H].sup.+;
HPLC (Method B) >99% (AUC), t.sub.R=8.7 min.
Example 93
Preparation of
1-(9-Methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-7-yl)-4-(6-methylpyr-
idin-3-yl)pyridin-2(1H)-one dihydrochloride
a) tert-Butyl
9-methyl-7-(4-(6-methylpyridin-3-yl)-2-oxopyridin-1(2H)-yl)-3,4-dihydro-1-
H-pyrido[3,4-b]indole-2(9H)-carboxylate
##STR00247##
[0495] 4-(6-Methylpyridin-3-yl)pyridin-2(1H)-one (150 mg, 0.81
mmol) and tert-butyl
7-bromo-9-methyl-3,4-dihydro-1H-pyrido[3,4-b]indole-2(9H)-carboxylate
(294 mg, 0.805 mmol) were reacted following the procedure of
Example 30 (step g) to provide the title compound (208 mg, 55%) as
a yellow/green solid: .sup.1H NMR (300 MHz, CDCl.sub.3) .delta.
8.79 (d, J=8.2 Hz, 1H), 7.83 (dd, J=8.0, 2.3 Hz, 1H), 7.58-7.51 (m,
2H), 7.36 (s, 1H), 7.30 (1H, partially under solvent), 7.08 (dd,
J=8.3, 1.8 Hz, 1H), 6.90 (d, J=1.7 Hz, 1H), 6.50 (dd, J=7.1, 2.0
Hz, 1H), 4.65 (br s, 2H), 3.76 (br m, 2H), 3.65 (s, 3H), 2.82 (br
m, 2H), 2.64 (s, 3H), 1.52 (s, 9H).
b)
1-(9-Methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-7-yl)-4-(6-methylp-
yridin-3-yl)pyridin-2(1H)-one dihydrochloride
##STR00248##
[0497] tert-Butyl
9-methyl-7-(4-(6-methylpyridin-3-yl)-2-oxopyridin-1(2H)-yl)-3,4-dihydro-1-
H-pyrido[3,4-b]indole-2(9H)-carboxylate (208 mg, 0.442 mmol) was
deprotected and converted to the dihydrochloride salt according to
the procedure of Example 30 (steps e and g) to provide the title
compound (40.6 mg, 23%) as a yellow solid: mp 305-313.degree. C.;
.sup.1H NMR (500 MHz, CD.sub.3OD) .delta. 8.80 (d, J=8.1 Hz, 1H),
8.11 (dd, J=8.2, 2.5 Hz, 1H), 7.79 (d, J=7.0 Hz, 1H), 7.64 (d,
J=8.3 Hz, 1H), 7.52 (d, J=1.7 Hz, 1H), 7.47 (d, J=8.2 Hz, 1H), 7.11
(dd, J=8.3, 1.8 Hz, 1H), 6.93 (d, J=1.9 Hz, 1H), 6.85 (dd, J=7.1,
2.0 Hz, 1H), 4.40 (s, 2H), 3.71 (s, 3H), 3.46 (t, J=5.9 Hz, 2H),
3.04 (t, J=5.9 Hz, 2H), 2.62 (s, 3H); ESI MS m/z 371 [M+H].sup.+;
HPLC (Method B) >99% (AUC), t.sub.R=8.9 min.
Example 94
Preparation of
4-(Benzyloxy)-1-(1,9-dimethyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-7--
yl)pyridin-2(1H)-one hydrochloride
a) tert-Butyl
7-bromo-1,9-dimethyl-3,4-dihydro-1H-pyrido[4,3-b]indole-2(9H)-carboxylate
##STR00249##
[0499] To a solution of 2-(6-bromo-1H-indol-3-yl)ethanamine (1.9 g,
8.0 mmol) in THF (30 mL) at 0.degree. C. was added saturated
aqueous NaHCO.sub.3 (30 mL) and acetyl chloride (0.56 mL, 7.95
mmol). The reaction was warmed up to room temperature and stirred
at room temperature until complete. The solution was concentrated,
and the residue was dissolved in CH.sub.2Cl.sub.2, washed with
H.sub.2O and brine and dried with Na.sub.2SO.sub.4. The organic
solution was filtered and concentrated to give a pale yellow foam.
The foam was suspended in benzene (70 mL) and treated with
POCl.sub.3 (3.52 mL, 38.4 mmol). The reaction was heated and
stirred at 85.degree. C. for one hour. After the solution was
concentrated, the residue was purified by flash column
chromatography (silica gel, 10% CH.sub.3OH in CH.sub.2Cl.sub.2) to
give a brown solid (1.83 g 91%). The solid was suspended in EtOH
(20 mL) and CHCl.sub.3 (20 mL) and cooled to 0.degree. C.
NaBH.sub.4 (0.26 g, 6.95 mmol) was added, and the reaction was
stirred from 0.degree. C. to room temperature for one hour. The
reaction was quenched with H.sub.2O, extracted with
CH.sub.2Cl.sub.2, washed with H.sub.2O and brine and dried over
Na.sub.2SO.sub.4. The organic solution was filtered and
concentrated to give a yellow foam (1.44 g, 78%). The foam was
dissolved in i-PrOH (15 mL) and H.sub.2O (10 mL) and treated with
Boc.sub.2O (1.36 g, 6.24 mmol) and K.sub.2CO.sub.3 (0.86 g, 6.2
mmol). The reaction was stirred at room temperature for one hour
and then concentrated under reduced pressure. The resulting residue
was dissolved in CH.sub.2Cl.sub.2, washed with H.sub.2O and brine
and dried over Na.sub.2SO.sub.4. After filtration and
concentration, the residue was purified by flash column
chromatography (silica gel, hexanes/EtOAc, 4:1) to give a yellow
foam (0.92 g, 46%). The foam was dissolved in DMF (6 mL) and cooled
to 0.degree. C. The solution was treated with NaH (60% weight
dispersion in mineral oil, 108 mg, 2.68 mmol) followed by CH.sub.3I
(0.17 mL, 0.69 mmol). The reaction was stirred at 0.degree. C.
until complete. The reaction was quenched with H.sub.2O, extracted
with CH.sub.2Cl.sub.2, washed with H.sub.2O and brine and dried
over Na.sub.2SO.sub.4. The organic solution was filtered and
concentrated, and the residue was purified by flash column
chromatography (silica gel, hexanes/EtOAc, 4:1) to give the title
compound as a white foam (0.82 g, 89%). .sup.1H NMR (300 MHz,
CDCl.sub.3) .delta. 7.42 (s, 1H), 7.31 (d, J=8.0 Hz, 1H), 7.18 (d,
J=8.0 Hz, 1H), 5.43-5.20 (m, 1H), 4.48-4.26 (m, 1H), 3.62 (s, 3H),
3.24-3.13 (m, 1H), 2.78-2.66 (m, 2H), 1.49 (s, 9H), 1.47 (d, J=6.5
Hz, 3H); MS (ESI) m/z 380 [M+H].sup.+.
b)
4-(Benzyloxy)-1-(1,9-dimethyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol--
7-yl)pyridin-2(1H)-one hydrochloride
##STR00250##
[0501] To a mixture of tert-butyl
7-bromo-1,9-dimethyl-3,4-dihydro-1H-pyrido[4,3-b]indole-2(9H)-carboxylate
(0.57 g, 1.6 mmol), 4-(benzyloxy)pyridin-2(1H)-one (0.32 g, 1.6
mmol), 8-hydroxyquilinine (46 mg, 0.32 mmol), K.sub.2CO.sub.3 (0.26
g, 1.9 mmol) and CuI (0.15 g, 0.79 mmol) was added DMSO (4 mL). The
reaction mixture was degassed and back-filled with N.sub.2. The
reaction was stirred at 130.degree. C. overnight. The mixture was
cooled and filtered through a layer of Celite. The filtrate was
diluted with CH.sub.2Cl.sub.2, washed with H.sub.2O and 5% aqueous
LiCl and dried over Na.sub.2SO.sub.4. The organic solution was
filtered and concentrated. The residue was purified by flash column
chromatography (silica gel, 5% CH.sub.3OH in CH.sub.2Cl.sub.2) to
give a yellow solid (0.5 g, 64%). The solid was dissolved in
CH.sub.3OH (8 mL) and treated with 1N HCl in Et.sub.2O (5 mL). The
reaction was stirred at room temperature until complete. The
solvent was removed under reduced pressure and the resulting solid
was dried under vacuum to give the title compound (0.44 g, 100%) as
a yellow powder: .sup.1H NMR (500 MHz, CD.sub.3OD) .delta. 7.79 (d,
J=7.0 Hz, 1H), 7.66 (d, J=8.0 Hz, 1H), 7.53 (s, 1H), 7.48-7.36 (m,
5H), 7.10 (d, J=8.5 Hz, 1H), 6.55 (d, J=6.5 Hz, 1H), 6.33 (s, 1H),
5.27 (s, 2H), 4.98 (q, J=6.5 Hz, 1H), 3.76 (s, 3H), 3.67-3.59 (m,
2H), 3.13-3.08 (m, 2H), 1.76 (d, J=7.0 Hz, 3H); ESI MS m/z 400
[M+H].sup.+; HPLC (Method A) >99% (AUC), t.sub.R=12.9 min.
Example 95
Preparation of
4-(Benzyloxy)-1-(1,2,9-trimethyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-
-7-yl)pyridin-2(1H)-one hydrochloride
##STR00251##
[0503] To a solution of
4-(benzyloxy)-1-(1,9-dimethyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-7--
yl)pyridin-2(1H)-one hydrochloride (205 mg, 0.470 mmol) in
CH.sub.3OH (8 mL) was added formaldehyde (53 .mu.L, 0.71 mmol) and
NaBH(OAc).sub.3 (200 mg, 0.94 mmol). The reaction was stirred at
room temperature until complete and then concentrated under reduced
pressure. The residue was dissolved in CH.sub.2Cl.sub.2 and washed
with H.sub.2O and 5% aqueous LiCl and dried over Na.sub.2SO.sub.4.
The organic solution was filtered and concentrated. The residue was
purified by flash column chromatography (silica gel, 10% CH.sub.3OH
in CH.sub.2Cl.sub.2) to give
4-(benzyloxy)-1-(1,2,9-trimethyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-
-7-yl)pyridin-2(1H)-one as a white solid (0.15 g, 77%). The free
base was converted to the HCl salt to give the title compound (147
mg, 90%) as an off-white powder: .sup.1H NMR (500 MHz, CD.sub.3OD)
.delta. 7.58-7.55 (m, 2H), 7.47-7.34 (m, 6H), 6.99 (d, J=8.5, 1.0
Hz, 1H), 6.28 (dd, J=7.5, 2.5 Hz, 1H), 6.11 (d, J=2.5 Hz, 1H), 5.18
(s, 2H), 4.27 (q, J=6.5 Hz, 1H), 3.69 (s, 3H), 3.36-3.33 (m, 1H),
3.10-2.96 (m, 2H), 2.84-2.80 (m, 1H), 2.65 (s, 3H), 1.51 (d, J=6.5
Hz, 3H); ESI MS m/z 414 [M+H].sup.+; HPLC (Method A) >99% (AUC),
t.sub.R=13.0 min.
Example 96
Preparation of
4-(Benzyloxy)-1-(5-(ethoxymethyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indo-
l-7-yl)pyridin-2(1H)-one hydrochloride
a) tert-Butyl
7-(4-(benzyloxy)-2-oxopyridin-1(2H)-yl)-5-(ethoxymethyl)-3,4-dihydro-1H-p-
yrido[4,3-b]indole-2(5H)-carboxylate
##STR00252##
[0505] To a solution of tert-butyl
7-bromo-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate (0.66
g, 1.9 mmol) in DMF (8 mL) was added NaH (60% weight dispersion in
mineral oil, 113 mg, 2.82 mmol) followed by SEMCl (0.50 mL, 2.8
mmol). The reaction was stirred at room temperature until complete.
The reaction was quenched with H.sub.2O, and the aqueous mixture
was extracted with CH.sub.2Cl.sub.2. The organic phase was washed
with H.sub.2O and brine and dried over Na.sub.2SO.sub.4. After
filtration and concentration, the residue was dried under vacuum to
give tert-butyl
7-bromo-5-((2-(trimethylsilyl)ethoxy)methyl)-3,4-dihydro-1H-pyrido[4,3-b]-
indole-2(5H)-carboxylate, which and used directly in the next step.
To a mixture of tert-butyl
7-bromo-5-((2-(trimethylsilyl)ethoxy)methyl)-3,4-dihydro-1H-pyrido[4,3-b]-
indole-2(5H)-carboxylate (0.75 g, 1.6 mmol), 4-benzyloxypyridone
(0.31 g, 1.6 mmol), 8-hydroxyquilinine (34 mg, 0.23 mmol),
K.sub.2CO.sub.3 (0.26 g, 1.9 mmol) and CuI (45 mg, 0.23 mmol) was
added DMSO (6 mL). The reaction mixture was degassed and
back-filled with N.sub.2. The reaction was stirred at 130.degree.
C. overnight. The mixture was cooled and filtered through a layer
of Celite. The filtrate was diluted with CH.sub.2Cl.sub.2, washed
with H.sub.2O and 5% aqueous LiCl and dried over Na.sub.2SO.sub.4.
The organic solution was filtered and concentrated, and the residue
was purified by flash column chromatography (silica gel, 5%
CH.sub.3OH in CH.sub.2Cl.sub.2) to give the title compound as a
yellow oil (0.12 g, 13%): .sup.1H NMR (500 MHz, CDCl.sub.3) .delta.
7.60 (d, J=8.5 Hz, 1H), 7.44-7.37 (m, 6H), 7.31 (d, J=7.5 Hz, 1H),
7.09 (m, 1H), 6.12 (s, 1H), 6.07 (d, J=6.5 Hz, 1H), 5.40 (s, 2H),
5.07 (s, 2H), 4.65 (m, 2H), 3.86 (m, 2H), 3.51 (t, J=8.0 Hz, 2H),
2.73 (m, 2H), 1.53 (s, 9H), 0.89 (t, J=8.0 Hz, 2H), -0.04 (s, 9H);
ESI MS m/z 602 [M+H].sup.+.
b)
4-(Benzyloxy)-1-(5-(ethoxymethyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]in-
dol-7-yl)pyridin-2(1H)-one hydrochloride
##STR00253##
[0507] To a solution of tert-butyl
7-(4-(benzyloxy)-2-oxopyridin-1(2H)-yl)-5-(ethoxymethyl)-3,4-dihydro-1H-p-
yrido[4,3-b]indole-2(5H)-carboxylate (120 mg, 0.20 mmol) in EtOH (2
mL) was added 1N HCl in Et.sub.2O (1 mL). The reaction was stirred
at 60.degree. C. until complete. The solvent was concentrated and
the residue was purified by preparative HPLC (Phenomenex Luna C18
(2), 250.times.50 mm, 15 micron, H.sub.2O with 0.05% TFA and
CH.sub.3CN with 0.05% TFA) to give
4-(benzyloxy)-1-(5-(ethoxymethyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indo-
l-7-yl)pyridin-2(1H)-one as a white solid (54 mg, 73%). The free
base was converted to the HCl salt to give the title compound (35
mg, 65%) as a white powder: mp 148-149.degree. C.; .sup.1H NMR (500
MHz, DMSO-d.sub.6) .delta. 9.12 (s, 2H), 7.66 (d, J=2.0 Hz, 1H),
7.59-7.56 (m, 2H), 7.49-7.37 (m, 5H), 7.08-7.05 (m, 1H), 6.14-6.12
(m, 1H), 5.99 (d, J=2.5 Hz, 1H), 5.57 (s, 2H), 5.17 (s, 2H), 4.38
(m, 2H), 3.55 (m, 2H), 3.45-3.40 (m, 2H), 3.13 (m, 2H), 1.08-1.05
(m, 3H); ESI MS m/z 430 [M+H].sup.+; HPLC (Method A) >99% (AUC),
t.sub.R=12.8 min.
Example 97
Preparation of
1-(5-Methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-7-yl)-4-phenylpyridi-
n-2(1H)-one hydrochloride
a) tert-Butyl
5-methyl-7-(2-oxo-4-(trifluoromethylsulfonyloxy)pyridine-1(2H)-yl)3,4-dih-
ydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate
##STR00254##
[0509] To a solution of tert-butyl
7-(4-(benzyloxy)-2-oxopyridin-1(2H)-yl)-5-methyl-3,4-dihydro-1H-pyrido[4,-
3-b]indole-2(5H)-carboxylate (0.98 g, 2.0 mmol) in CH.sub.3OH (30
mL) was added 5% Pd/C (0.3 g) and ammonium formate (0.32 g, 5.1
mmol) under an atmosphere of argon. The reaction was stirred at
90.degree. C. until complete. The reaction mixture was cooled and
filtered through a layer of Celite. The solvent was removed under
reduced pressure to give tert-butyl
7-(4-hydroxy-2-oxopyridin-1(2H)-yl)-5-methyl-3,4-dihydro-1H-pyrido[4,3-b]-
indole-2(5H)-carboxylate, which was used directly in the next step.
To a solution of tert-butyl
7-(4-hydroxy-2-oxopyridin-1(2H)-yl)-5-methyl-3,4-dihydro-1H-pyrido[4,3-b]-
indole-2(5H)-carboxylate (800 mg, 2.02 mmol) in THF (10 mL) was
added LiN(SiMe.sub.3).sub.2(1.0M in THF, 2.6 mL, 2.6 mmol) followed
by PhN(Tf).sub.2 (0.94 g, 2.6 mmol) under an atmosphere of argon.
The reaction was stirred at room temperature until complete. The
solvent was removed under reduced pressure, and the residue was
purified by flash column chromatography (silica gel, hexanes/EtOAc,
1:1) to give the title compound (0.42 g, 40% yield) as a white
solid: .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 7.57-7.53 (m, 2H),
7.30 (d, J=1.5 Hz, 1H), 7.02-6.99 (m, 1H), 6.60 (d, J=2.7 Hz, 1H),
6.27 (dd, J=7.8, 2.7 Hz, 1H), 4.65 (s, 2H), 3.85 (m, 2H), 3.65 (s,
3H), 2.84 (m, 2H), 1.51 (s, 9H); ESI MS m/z 528 [M+H].sup.+.
b)
1-(5-Methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-7-yl)-4-phenylpyri-
din-2(1H)-one hydrochloride
##STR00255##
[0511] Following the procedure of Example 25 (step b), but
substituting phenylboronic acid for 4-fluorophenylboronic acid and
eliminating the methylation step, the title compound (37 mg, 46%)
was obtained as a yellow solid: mp 275-280.degree. C. (decompose);
.sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 9.26 (s, 2H), 7.79 (dd,
J=8.0, 1.5 Hz, 2H), 7.75 (d, J=7.5 Hz, 1H), 7.62 (d, J=1.5 Hz, 1H),
7.59 (d, J=8.5 Hz, 1H), 7.55-7.50 (m, 3H), 7.10 (dd, J=8.5, 2.0 Hz,
1H), 6.78 (d, J=1.5 Hz, 1H), 6.70 (dd, J=7.0, 2.0 Hz, 1H), 4.37 (m,
2H), 3.71 (s, 3H), 3.54-3.53 (m, 2H), 3.10 (t, J=6.0 Hz, 2H); ESI
MS m/z 356 [M+H].sup.+; HPLC (Method A) >99% (AUC), t.sub.R=12.3
min.
Example 98
Preparation of
1-(2,5-Dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-7-yl)-4-phenylpy-
ridin-2(1H)-one hydrochloride
##STR00256##
[0513] Following the procedure of Example 25 (step b), but
substituting phenylboronic acid for 4-fluorophenylboronic acid, the
title compound (56 mg, 83%) was obtained as an off-white solid: mp
290-295.degree. C. (decompose); .sup.1H NMR (500 MHz, DMSO-d.sub.6)
.delta. 10.46 (s, 1H), 7.80-7.74 (m, 3H), 7.63 (s, 1H), 7.56-7.52
(m, 4H), 7.11 (d, J=8.0 Hz, 1H), 6.78 (s, 1H), 6.70 (d, J=7.0 Hz,
1H), 4.68-4.65 (m, 1H), 4.34-4.30 (m, 1H), 3.82-3.79 (m, 1H), 3.71
(s, 3H), 3.53-3.51 (m, 1H), 3.20 (m, 2H), 3.00 (d, J=4.0 Hz, 3H);
ESI MS m/z 370 [M+H].sup.+; HPLC (Method A) 98% (AUC), t.sub.R=12.5
min.
Example 99
Preparation of
4-(2-Fluoro-4-methoxyphenyl)-1-(5-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-
-b]indol-7-yl)pyridin-2(1H)-one hydrochloride
##STR00257##
[0515] Following the procedure of Example 25 (step b), but
substituting 2-fluoro-4-methoxyphenylboronic acid for
4-fluorophenylboronic acid and eliminating the methylation step,
the title compound (34 mg, 19%) was obtained as a green powder: mp
270-274.degree. C.; .sup.1H NMR (500 MHz, CD.sub.3OD) .delta. 7.72
(d, J=7.0 Hz, 1H), 7.63-7.56 (m, 3H), 7.14 (dd, J=8.5, 1.5 Hz, 1H),
6.92 (dd, J=8.5, 2.5 Hz, 1H), 6.87 (dd, J=13.0, 2.5 Hz, 1H), 6.84
(s, 1H), 6.77-6.75 (m, 1H), 4.50 (s, 2H), 3.88 (s, 3H), 3.76 (s,
3H), 3.68 (t, J=6.0 Hz, 2H), 3.22 (t, J=6.0 Hz, 2H); ESI MS m/z 404
[M+H].sup.+; HPLC (Method A) >99% (AUC), t.sub.R=12.3 min
Example 100
Preparation of
1-(2-Acetyl-5-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-7-yl)-4-(be-
nzyloxy)pyridin-2(1H)-one
##STR00258##
[0517] To a solution of
4-(benzyloxy)-1-(5-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-7-yl)p-
yridin-2(1H)-one (0.2 g, 0.5 mmol) in CH.sub.2Cl.sub.2 (6 mL) was
added triethylamine (0.20 mL, 1.4 mmol) followed by acetyl chloride
(50 .mu.L, 0.71 mmol). The reaction was stirred at room temperature
until complete. After the solvent was removed under reduced
pressure, the residue was purified by flash column chromatography
(silica gel, 5% CH.sub.3OH in CH.sub.2Cl.sub.2) to give the title
compound (72.2 mg, 36%) as a yellow solid and as a mixture of
rotamers: mp 225-230.degree. C.; .sup.1H NMR (500 MHz, CDCl.sub.3)
.delta. 7.53-7.36 (m, 6H), 7.32-7.30 (m, 2H), 7.06-7.00 (m, 1H),
6.09 (d, J=3.0 Hz, 1H), 6.07-6.04 (m, 1H), 5.06 (s, 2H), 4.82 (s,
1H), 4.67 (s, 1H), 4.03 (t, J=5.5 Hz, 1H), 3.84 (t, J=5.5 Hz, 1H),
3.64 (s, 3H), 2.90 (t, J=5.5 Hz, 1H), 2.84 (t, J=5.5 Hz, 1H), 2.24,
2.22 (2.times.s, 3H); ESI MS m/z 428 [M+H].sup.+; HPLC (Method A)
95.7% (AUC), t.sub.R=16.8 min.
Example 101
Preparation of
1-(2-Acetyl-5-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-7-yl)-4-((5-
-fluoropyridin-2-yl)methoxy)pyridin-2(1H)-one
##STR00259##
[0519] Following the procedure of Example 100, but substituting
4-((5-fluoropyridin-2-yl)methoxy)-1-(5-methyl-2,3,4,5-tetrahydro-1H-pyrid-
o[4,3-b]indol-7-yl)-pyridin-2(1H)-one for
4-(benzyloxy)-1-(5-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-7-yl)p-
yridin-2(1H)-one, the title compound (71 mg, 61%) was obtained as a
yellow solid and as a mixture of rotamers: mp 220-224.degree. C.;
.sup.1H NMR (500 MHz, CDCl.sub.3) .delta. 8.50 (d, J=1.5 Hz, 1H),
7.54-7.46 (m, 3H), 7.35 (d, J=7.5 Hz, 1H), 7.32 (d, J=2.0 Hz, 1H),
7.03 (ddd, J=20, 8.0, 1.5 Hz, 1H), 6.15-6.08 (m, 2H), 5.18 (s, 2H),
4.83, 4.70 (2.times.s, 2H), 4.04 (t, J=5.5 Hz, 1H), 3.85 (t, J=5.5
Hz, 1H), 3.65, 3.64 (2.times.s, 3H), 2.91 (t, J=5.5 Hz, 1H), 2.85
(t, J=5.5 Hz, 1H), 2.23, 2.25 (2.times.s, 3H); ESI MS m/z 447
[M+H].sup.+; HPLC (Method A) 96.4% (AUC), t.sub.R=14.5 min.
Example 102
Preparation of
4-(Cyclohexylmethoxy)-1-(9-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indo-
l-7-yl)pyridin-2(1H)-one hydrochloride
a) 4-(Cyclohexylmethoxy)pyridin-2(1H)-one
##STR00260##
[0521] To a solution of cyclohexylmethanol (1.1 mL, 9.3 mmol) in
DMF (8 mL) was added NaH (60% weight dispersion in mineral oil,
0.37 g, 9.3 mmol) in one portion. After the bubbles disappeared,
4-chloropyridine N-oxide (1.0 g, 7.7 mmol) was added. The reaction
was stirred at room temperature under Ar until complete. The
reaction was quenched with water and the aqueous mixture was
extracted with CH.sub.2Cl.sub.2. The combined organic extracts were
washed with H.sub.2O and 5% aqueous LiCl and dried over
Na.sub.2SO.sub.4. After filtration and concentration, the residue
was purified by flash column chromatography (silica gel, 10%
CH.sub.3OH in CH.sub.2Cl.sub.2) to give a yellow solid. The yellow
solid was suspended in Ac.sub.2O (5 mL) and heated at 140.degree.
C. for 4 h. The reaction mixture was cooled, diluted with
CH.sub.3OH/H.sub.2O (10 mL, 1:1) and stirred at room temperature
for 1 h. The mixture was concentrated, and the residue was purified
by flash column chromatography (silica gel, 10% CH.sub.3OH in
CH.sub.2Cl.sub.2) to give the title compound (0.92 g, 58%) as a
brown solid: .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 11.03 (s,
1H), 7.21 (d, J=7.2 Hz, 1H), 5.83 (dd, J=7.2, 2.4 Hz, 1H), 5.64 (d,
J=2.4 Hz, 1H), 3.72 (d, J=6.0 Hz, 2H), 1.84-1.68 (m, 6H), 1.30-1.01
(m, 5H).
##STR00261##
[0522] Following the procedure of Example 1 (steps c and d), but
substituting 4-(cyclohexylmethoxy)pyridin-2(1H)-one for
4-benzyloxypyridone, the title compound (56 mg, 81%) was obtained
as a yellow solid: mp 256-260.degree. C.; .sup.1H NMR (500 MHz,
CD.sub.3OD) .delta. 7.67-7.65 (m, 2H), 7.50 (s, 1H), 7.09 (d, J=8.5
Hz, 1H), 6.35 (d, J=6.0 Hz, 1H), 6.10 (s, 1H), 4.58 (s, 2H), 3.92
(d, J=5.5 Hz, 2H), 3.75 (s, 3H), 3.63 (t, J=6.0 Hz, 2H), 3.15 (d,
J=6.0 Hz, 2H), 1.92-1.74 (m, 6H), 1.39-1.19 (m, 5H); ESI MS m/z 392
[M+H].sup.+; HPLC (Method A) 97.8% (AUC), t.sub.R=14.4 min.
Example 103
Preparation of
4-(Cyclohexylmethoxy)-1-(5-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indo-
l-7-yl)pyridin-2(1H)-one hydrochloride
##STR00262##
[0524] Following the procedure of Example 102, but substituting
substituting tert-butyl
7-bromo-5-methyl-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate
for tert-butyl
7-bromo-9-methyl-3,4-dihydro-1H-pyrido[4,3-b]indole-2(9H)-carboxylate,
the title compound (197 mg, 100%) was obtained as a pale green
solid: mp 245-250.degree. C. (decompose); .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 9.21 (s, 2H), 7.55 (d, J=8.5 Hz, 1H), 7.52
(d, J=7.5 Hz, 1H), 7.50 (s, 1H), 6.99 (dd, J=8.5, 1.5 Hz, 1H), 6.04
(dd, J=7.5, 2.5 Hz, 1H), 5.85 (d, J=2.5 Hz, 1H), 4.35 (s, 2H), 3.82
(d, J=6.0 Hz, 2H), 3.68 (s, 3H), 3.54-3.53 (m, 2H), 3.09 (t, J=5.5
Hz, 2H), 1.80-1.65 (m, 6H), 1.30-1.01 (m, 5H); ESI MS m/z 392
[M+H].sup.+; HPLC (Method A) >99% (AUC), t.sub.R=14.3 min.
Example 104
Preparation of
4-(Cyclohexylmethoxy)-1-(2,5-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]-
indol-7-yl)pyridin-2(1H)-one hydrochloride
##STR00263##
[0526] To a solution of
4-(cyclohexylmethoxy)-1-(5-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indo-
l-7-yl)pyridin-2(1H)-one hydrochloride (110 mg, 0.26 mmol) in
CH.sub.3OH (5 mL) was added triethylamine (90 .mu.L, 2.5 mmol),
formaldehyde (30 .mu.L, 0.39 mmol) and NaBH(OAc).sub.3 (110 mg,
0.52 mmol). The reaction was stirred at room temperature until
complete. The solvent was removed under reduced pressure, and the
residue was dissolved in CH.sub.2Cl.sub.2. The organic solution was
washed with H.sub.2O and 5% aqueous LiCl and dried over
Na.sub.2SO.sub.4. After filtration and concentration, the residue
was purified by flash column chromatography (silica gel, 10%
CH.sub.3OH in CH.sub.2Cl.sub.2) to give 4-(cyclohexylmethoxy)-1-(2,
5-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-7-yl)pyridin-2(1H)-on-
e as a white solid (73 mg, 69%). The free base was converted to the
HCl salt to give the title compound (84 mg, 100%) as a white
powder: mp 270-272.degree. C.; .sup.1H NMR (500 MHz, DMSO-d.sub.6)
.delta. 10.53 (s, 1H), 7.53 (d, J=7.5 Hz, 1H), 7.51 (d, J=8.0 Hz,
1H), 7.50 (d, J=1.5 Hz, 1H), 7.00 (dd, J=8.5, 1.5 Hz, 1H), 6.04
(dd, J=7.5, 2.5 Hz, 1H), 5.85 (d, J=3.0 Hz, 1H), 4.64 (d, J=13 Hz,
1H), 4.30 (dd, J=14, 7.5 Hz, 1H), 3.82 (d, J=6.0 Hz, 2H), 3.80-3.78
(m, 1H), 3.69 (s, 3H), 3.51-3.47 (m, 1H), 3.18 (t, J=5.5 Hz, 2H),
2.98 (d, J=4.5 Hz, 3H), 1.80-1.65 (m, 6H), 1.30-1.01 (m, 5H); ESI
MS m/z 406 [M+H].sup.+; HPLC (Method A) >99% (AUC), t.sub.R=14.4
min.
Example 105
Preparation of
4-(Benzyloxy)-1-(1-(hydroxymethyl)-9-methyl-2,3,4,9-tetrahydro-1H-pyrido[-
3,4-b]indol-7-yl)pyridin-2(1H)-one hydrochloride
a) 7-Bromo-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-1-carboxylic
acid
##STR00264##
[0528] Glyoxylic acid monohydrate (3.69 g, 40.1 mmol) was added to
a solution of a 2:1 mixture of 2-(6-bromo-1H-indol-3-yl)ethanamine
and 2-(4-bromo-1H-indol-3-yl)ethanamine (7.38 g, 30.9 mmol) in 0.4N
HCl (50 mL), and the resulting solution was stirred at 25.degree.
C. for 30 min. The solution was adjusted to pH 3.5 with 6N NaOH
solution, and the resulting tan suspension was stirred at
25.degree. C. for 22 h. The suspension was adjusted to pH 5 with 6N
NaOH solution, and the resulting suspension was filtered. The
filtered solid was dried under reduced pressure to afford 3.85 g
(42%) of a 2:1 mixture of the title compound and an undesired
regioisomer as a tan solid: .sup.1H NMR (300 MHz, DMSO-d.sub.6)
.delta. 10.90 (s, 1H), 9.00 (br s, 1H), 7.63 (s, 1H), 7.33 (d,
J=8.4 Hz, 1H), 7.12-7.04 (m, 1H), 4.66 (s, 1H), 3.50-2.70 (m, 4H).
Undesired regioisomer: .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta.
11.09 (s, 1H), 9.00 (br s, 1H), 7.47 (d, J=8.0 Hz, 1H), 7.12-7.04
(m, 1H), 6.91 (overlapping dd, J=8.0 Hz, 1H), 4.66 (s, 1H),
3.50-2.70 (m, 4H).
b)
7-Bromo-1-((tert-butyldimethylsilyloxy)methyl)-2,3,4,9-tetrahydro-1H-py-
rido[3,4-b]indole
##STR00265##
[0530] A 1.0M solution of LiAlH.sub.4 in THF (26 mL, 26.1 mmol) was
added to a solution of a 2:1 mixture of
7-bromo-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-1-carboxylic acid
and the undesired regioisomer (3.85 g, 13.1 mmol) in THF (50 mL)
under N.sub.2, and the resulting solution was heated at reflux for
1 h. The solution was cooled to 0.degree. C. and H.sub.2O, 6N NaOH
in H.sub.2O and H.sub.2O were added carefully in succession. The
resulting suspension was filtered through celite. The filtrate was
dried over Na.sub.2SO.sub.4 and concentrated under reduced
pressure. Flash chromatography (silica gel, (1:1
EtOAc/hexanes)/(9:0.9:0.1 CH.sub.2Cl.sub.2/MeOH/NH.sub.4OH), 100:0
to 0:100) afforded 2.48 g of a tan foam. Et.sub.3N (6.2 mL, 44.3
mmol) was added to a suspension of TBSCl (6.68 g, 44.3 mmol) and
the above tan foam in CH.sub.2Cl.sub.2 (50 mL) under N.sub.2, and
the resulting suspension was stirred at 25.degree. C. overnight.
H.sub.2O was added to the suspension, and the phases were
separated. The organic phase was dried over Na.sub.2SO.sub.4 and
concentrated under reduced pressure. Flash chromatography (silica
gel, (1:1 EtOAc/hexanes)/(9:0.9:0.1 Et.sub.2O/MeOH/NH.sub.4OH),
100:0 to 75:25) yielded the title compound (1.186 g, 32%) as a
clear oil: .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 8.50 (s, 1H),
7.45 (d, J=1.7 Hz, 1H), 7.35 (d, J=8.4 Hz, 1H), 7.18 (dd, J=8.4,
1.7 Hz, 1H), 4.19-4.10 (m, 1H), 3.92 (dd, J=9.2, 5.0 Hz, 1H), 3.69
(dd, J=9.2, 9.2 Hz, 1H), 3.32 (ddd, J=12.6, 4.2, 4.2 Hz, 1H),
3.11-3.01 (m, 1H), 2.75-2.62 (m, 2H), 0.97 (s, 9H), 0.13 (s,
6H).
c) tert-Butyl
7-bromo-1-((tert-butyldimethylsilyloxy)methyl)-9-methyl-3,4-dihydro-1H-py-
rido[3,4-b]indole-2(9H)-carboxylate
##STR00266##
[0532] Boc.sub.2O (752 mg, 3.45 mmol) was added to a suspension of
7-Bromo-1-((tert-butyldimethyl-silyloxy)methyl)-2,3,4,9-tetrahydro-1H-pyr-
ido[3,4-b]indole (1.239 g, 3.14 mmol) and K.sub.2CO.sub.3 (476 mg,
3.45 mmol) in a 1:1 mixture of H.sub.2O/i-PrOH (80 mL), and the
resulting suspension was stirred at 25.degree. C. for 2 h. The
suspension was filtered, and the solid was concentrated under
reduced pressure. MeI (0.19 mL, 3.1 mmol) was added to a suspension
of the above solid and Cs.sub.2CO.sub.3 (1.34 g, 4.12 mmol) in DMSO
(20 mL) under N.sub.2, and the resulting suspension was stirred at
25.degree. C. for 4 h. H.sub.2O was added to the suspension, and
the resulting suspension was filtered. The solid was dried under
reduced pressure to afford the title compound (728 mg, 46%) as a
white solid: .sup.1H NMR (500 MHz, CDCl.sub.3) .delta. 7.44 (br s,
1H), 7.37-7.28 (m, 1H), 7.23-7.15 (m, 1H), 5.49-5.43 (m, 0.6H),
5.37-5.32 (m, 0.4H), 4.56-4.48 (m, 0.4H), 4.35-4.24 (m, 0.6H),
3.98-3.84 (m, 2H), 3.68 (s, 3H), 3.43-3.35 (m, 0.6H), 3.30-3.21 (m,
0.4H), 2.90-2.75 (m, 1H), 2.72-2.63 (m, 1H), 1.50 (s, 9H),
0.90-0.82 (m, 9H), 0.14-0.02 (m, 6H).
d)
4-(Benzyloxy)-1-(1-(hydroxymethyl)-9-methyl-2,3,4,9-tetrahydro-1H-pyrid-
o[3,4-b]indol-7-yl)pyridin-2(1H)-one
##STR00267##
[0534] A suspension of tert-butyl
7-bromo-1-((tert-butyldimethylsilyloxy)methyl)-9-methyl-3,4-dihydro-1H-py-
rido[3,4-b]indole-2(9H)-carboxylate (727 mg, 1.47 mmol),
4-(benzyl-oxy)pyridin-2(1H)-one (591 mg, 2.94 mmol), CuI (110 mg,
0.576 mmol), 8-hydroxyquinoline (84 mg, 0.58 mmol) and
Cs.sub.2CO.sub.3 (720 mg, 2.21 mmol) in DMSO (10 mL) was degassed
under reduced pressure for 45 min. The suspension was put under Ar
and heated at 135.degree. C. with stirring for 14 h. The suspension
was cooled, 1:1 MeOH/NH.sub.4OH (40 mL) was added, and the
resulting suspension was stirred for 30 min. CH.sub.2Cl.sub.2 was
added and the phases were separated. The aqueous phase was
extracted with CH.sub.2Cl.sub.2, and the combined organic extracts
were washed with brine, dried over Na.sub.2SO.sub.4 and
concentrated under reduced pressure. Flash chromatography (silica
gel, (1:1 EtOAc/hexanes)/(9:0.9:0.1 Et.sub.2O/MeOH/NH.sub.4OH)
100:0 to 0:100) afforded the amine as a yellow amorphous solid. A
1.0M solution of TBAF in THF (0.57 mL, 0.57 mmol) was added to a
solution of the above yellow semi-solid in THF (10 mL) under
N.sub.2, and the resulting solution was stirred at 25.degree. C.
for 1.5 h. H.sub.2O and CH.sub.2Cl.sub.2 were added to the solution
and the phases were separated. The aqueous phase was extracted with
CH.sub.2Cl.sub.2, and the combined organic phases were dried over
Na.sub.2SO.sub.4 and concentrated under reduced pressure. Flash
chromatography (silica gel, (1:1 EtOAc/hexanes)/(9:0.9:0.1
Et.sub.2O/MeOH/NH.sub.4OH) 100:0 to 0:100) yielded a yellow
amorphous solid. TFA (2 mL) was added to a solution of the above
amorphous solid in CH.sub.2Cl.sub.2 (10 mL) under N.sub.2, and the
resulting solution was stirred at 25.degree. C. for 1 h. The
solution was concentrated under reduced pressure. The resulting
residue was diluted with CH.sub.2Cl.sub.2 and neutralized with a
saturated aqueous NaHCO.sub.3 solution. The phases were separated.
The organic phase was dried over Na.sub.2SO.sub.4 and concentrated
under reduced pressure. Flash chromatography (silica gel, (1:1
EtOAc/hexanes)/(9:0.9:0.1 CH.sub.2Cl.sub.2/MeOH/NH.sub.4OH) 100:0
to 0:100) yielded the title compound (56 mg, 9%) as a viscous oil:
.sup.1H NMR (500 MHz, CDCl.sub.3) .delta. 7.56 (d, J=8.0 Hz, 1H),
7.46-7.37 (m, 5H), 7.32 (d, J=7.5 Hz, 1H), 7.30 (d, J=1.5 Hz, 1H),
7.03 (dd, J=8.0, 1.5 Hz, 1H), 6.11 (d, J=2.5 Hz, 1H), 6.06 (dd,
J=7.5, 2.5 Hz, 1H), 5.08 (s, 2H), 4.14 (dd, J=10.0, 4.5 Hz, 1H),
3.80 (dd, J=10.0, 4.5 Hz, 1H), 3.69-3.62 (m, 4H), 3.23 (ddd,
J=14.0, 4.5, 4.5 Hz, 1H), 3.12-3.05 (m, 1H), 2.78-2.73 (m, 2H); ESI
MS m/z 416 [M+H].sup.+.
e)
4-(Benzyloxy)-1-(1-(hydroxymethyl)-9-methyl-2,3,4,9-tetrahydro-1H-pyrid-
o[3,4-b]indol-7-yl)pyridin-2(1H)-one hydrochloride
##STR00268##
[0536] A 1.0M solution of HCl in Et.sub.2O (0.13 mL, 0.13 mmol) was
added to a solution of
4-(benzyloxy)-1-(1-(hydroxymethyl)-9-methyl-2,3,4,9-tetrahydro-1H-pyrido[-
3,4-b]indol-7-yl)pyridin-2(1H)-one (55 mg, 0.13 mmol) in
CH.sub.2Cl.sub.2 (10 mL) under N.sub.2 and stirred at 25.degree. C.
for 1 h. The solution was concentrated to afford the title compound
(32 mg, 54%) as an off-white powder: mp 168-170.degree. C.; .sup.1H
NMR (500 MHz, DMSO-d.sub.6) .delta. 9.48 (br s, 1H), 9.10 (br s,
1H), 7.56 (overlapping dd, J=8.5 Hz, 2H), 7.52 (s, 1H), 7.49-7.41
(m, 4H), 7.40-7.36 (m, 1H), 7.01 (dd, J=7.0, 1.5 Hz, 1H), 6.12 (dd,
J=7.5, 1.5 Hz, 1H), 5.98 (d, J=1.5 Hz, 1H), 5.72 (t, J=3.3 Hz, 1H),
5.16 (s, 2H), 4.89-4.82 (m, 1H), 4.07-4.01 (m, 1H), 3.80-3.71 (m,
1H), 3.72 (s, 3H), 3.61-3.50 (m, 1H), 3.49-3.43 (m, 1H), 3.02-2.94
(m, 2H); ESI MS m/z 416 [M+H].sup.+.
Example 106
Preparation of
4-(Benzyloxy)-1-(2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-7-yl)pyridin-2(-
1H)-one hydrochloride
a) tert-Butyl
7-(4-(benzyloxy)-2-oxopyridin-1(2H)-yl)-9-tosyl-3,4-dihydro-1H-pyrido[3,4-
-b]indole-2(9H)-carboxylate
##STR00269##
[0538] A suspension of 4-(benzyloxy)pyridin-2(1H)-one (426 mg, 2.12
mmol), tert-butyl
7-bromo-9-tosyl-3,4-dihydro-1H-pyrido[3,4-b]indole-2(9H)-carboxylate
(1.28 g, 2.54 mmol), CuI (484 mg, 2.54 mmol), 8-hydroxyquinoline
(369 mg, 2.54 mmol) and Cs.sub.2CO.sub.3 (760 mg, 2.33 mmol) in
DMSO (10 mL) was degassed under reduced pressure for 45 min. The
suspension was put under Ar and heated at 135.degree. C. with
stirring for 1.5 h. The suspension was cooled, 4:1
CH.sub.2Cl.sub.2/(9:1 MeOH/NH.sub.4OH) (50 mL) was added and the
resulting suspension was stirred at 25.degree. C. for 10 min. The
suspension was passed through a plug of silica gel and the filtrate
was washed with brine. The solution was dried over Na.sub.2SO.sub.4
and concentrated under reduced pressure to afford an amorphous
solid. Flash chromatography (silica gel, (1:1
EtOAc/hexanes)/(9:0.9:0.1 CH.sub.2Cl.sub.2/MeOH/NH.sub.4OH) 100:0
to 0:100) yielded the title compound (715 mg, 54%) as an off-white
solid: .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 8.18 (br s, 1H),
7.82-7.73 (m, 2H), 7.48-7.35 (m, 6H), 7.33-7.23 (m, 4H), 6.12-5.97
(m, 2H) 5.07 (s, 2H), 4.90 (br s, 2H), 3.72-3.64 (m, 2H), 2.73-2.63
(m, 2H), 2.34 (s, 3H), 1.51 (s, 9H).
b)
4-(Benzyloxy)-1-(2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-7-yl)pyridin--
2(1H)-one hydrochloride
##STR00270##
[0540] TFA (2 mL) was added to a solution of tert-butyl
7-(4-(benzyloxy)-2-oxopyridin-1(2H)-yl)-9-tosyl-3,4-dihydro-1H-pyrido[3,4-
-b]indole-2(9H)-carboxylate (678 mg, 1.09 mmol) in CH.sub.2Cl.sub.2
(10 mL) under N.sub.2, and the resulting solution was stirred at
25.degree. C. for 1 h. Saturated NaHCO.sub.3 solution and EtOAc
were added, and the phases were separated. The aqueous phase was
extracted with CH.sub.2Cl.sub.2, and the combined organic phases
were dried over Na.sub.2SO.sub.4. The organic solution was
concentrated under reduced pressure to afford 510 mg of an
off-white solid. NaOH (469 mg, 11.7 mmol) was added to a solution
of the off-white solid (123 mg) in CH.sub.2Cl.sub.2/MeOH (10 mL)
that had been degassed with N.sub.2. The resulting solution was
heated at 40.degree. C. with stirring for 5 h under N.sub.2. The
solution was allowed to cool, saturated NH.sub.4Cl solution and
CH.sub.2Cl.sub.2 were added, and the phases were separated. The
organic phase was washed with saturated NaHCO.sub.3 solution, dried
over Na.sub.2SO.sub.4 and concentrated under reduced pressure to
yield an off-white solid. Flash chromatography (silica gel, (1:1
EtOAc/hexanes)/(9:0.9:0.1 CH.sub.2Cl.sub.2/MeOH/NH.sub.4OH) 100:0
to 0:100) afforded a white solid. 1M HCl in Et.sub.2O (0.28 ml,
0.28 mmol) was added to a solution of the white solid in
CH.sub.2Cl.sub.2 (10 mL) under N.sub.2, and the resulting solution
was stirred at 25.degree. C. for 30 min. The resulting suspension
was filtered. The solid was washed with CH.sub.2Cl.sub.2 and dried
under reduced pressure to afford the title compound (26 mg, 24%) as
a white solid: mp 246-248.degree. C.; .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 11.22 (s, 1H), 9.29 (br s, 2H), 7.54 (dd,
J=12.0, 8.0 Hz, 2H), 7.50-7.41 (m, 4H), 7.40-7.33 (m, 2H), 6.96
(dd, J=8.0, 1.5 Hz, 1H), 6.09 (dd, J=7.5, 2.5 Hz, 1H), 5.97 (d,
J=2.5 Hz, 1H), 5.15 (s, 2H), 4.38 (s, 2H), 3.50-3.42 (m, 2H)
3.00-2.92 (m, 2H); ESI MS m/z 372 [M+H].sup.+.
Example 107
Preparation of
4-(Benzyloxy)-1-(2-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-7-yl)p-
yridin-2(1H)-one hydrochloride
a)
4-(Benzyloxy)-1-(2-methyl-9-tosyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]in-
dol-7-yl)pyridin-2(1H)-one
##STR00271##
[0542] TFA (2 mL) was added to a solution of tert-butyl
7-(4-(benzyloxy)-2-oxopyridin-1(2H)-yl)-9-tosyl-3,4-dihydro-1H-pyrido[3,4-
-b]indole-2(9H)-carboxylate (678 mg, 1.09 mmol) in CH.sub.2Cl.sub.2
(10 mL) under N.sub.2 and the resulting solution was stirred at
25.degree. C. for 1 h. Saturated NaHCO.sub.3 solution and EtOAc
were added to the solution and the phases were separated. The
aqueous phase was extracted with CH.sub.2Cl.sub.2 and the combined
organic phases were dried over Na.sub.2SO.sub.4. The organic
solution was concentrated under reduced pressure to afford 510 mg
of an off-white solid. Formaldehyde (37% in H.sub.2O, 0.04 mL, 0.49
mmol) was added to a solution of the off-white solid (170 mg) in
1:1 MeOH/CH.sub.2Cl.sub.2 (10 mL) and the resulting solution was
stirred at 25.degree. C. for 45 min. NaBH(OAc).sub.3 (137 mg, 0.648
mmol) was added to the solution and the resulting suspension was
stirred at 25.degree. C. for 30 min. The suspension was
concentrated under reduced pressure and the resulting residue was
diluted with CH.sub.2Cl.sub.2 and saturated NaHCO.sub.3 solution.
The phases were separated. The organic phase was dried over
Na.sub.2SO.sub.4 and concentrated under reduced pressure to yield
the title compound (174 mg, 89%) as a viscous oil: .sup.1H NMR (300
MHz, CDCl.sub.3) .delta. 8.14 (d, J=1.5 Hz, 1H), 7.72 (d, J=8.4 Hz,
2H), 7.47-7.35 (m, 6H), 7.33-7.28 (m, 1H), 7.26-7.21 (m, 3H),
6.12-6.05 (m, 2H), 5.07 (s, 2H), 3.92 (br s, 2H), 2.79-2.70 (m,
4H), 2.56 (s, 3H), 2.33 (s, 3H).
b)
4-(Benzyloxy)-1-(2-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-7-yl-
)pyridin-2(1H)-one hydrochloride
##STR00272##
[0544] NaOH (644 mg, 16.1 mmol) was added to a solution of the
4-(benzyloxy)-1-(2-methyl-9-tosyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indo-
l-7-yl)pyridin-2(1H)-one (174 mg, 0.322 mmol) in
CH.sub.2Cl.sub.2/MeOH (10 mL) that had been degassed with N.sub.2.
The resulting solution was heated at reflux with stirring for 2 h
under N.sub.2. The solution was allowed to cool, saturated
NH.sub.4Cl solution and CH.sub.2Cl.sub.2 were added, and the phases
were separated. The organic phase was washed with saturated
NaHCO.sub.3 solution, dried over Na.sub.2SO.sub.4 and concentrated
under reduced pressure to yield a white solid. 1M HCl in Et.sub.2O
(0.38 ml, 0.38 mmol) was added to a solution of the white solid in
9:1 CH.sub.2Cl.sub.2/MeOH (10 mL) under N.sub.2, and the resulting
solution was stirred at 25.degree. C. for 30 min. The solution was
concentrated, and the residue was diluted with a small amount of
CH.sub.2Cl.sub.2/CH.sub.3CN. The resulting suspension was filtered,
and the solid was dried under reduced pressure to yield the title
compound (46 mg, 34%) as a white solid: mp 168-170.degree. C.;
.sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 11.30 (s, 1H),
10.50-10.41 (m, 1H), 7.58-7.52 (m, 2H), 7.49-7.40 (m, 4H),
7.39-7.35 (m, 2H), 6.96 (br d, J=8.0 Hz, 1H), 6.09 (br d, J=7.5 Hz,
1H), 5.97 (br s, 1H), 5.15 (s, 2H), 4.60 (br d, J=15.0 Hz, 1H),
4.41 (dd, J=15.0, 7.5 Hz, 1H), 3.78-3.71 (m, 1H), 3.45-3.38 (m,
1H), 3.09-2.98 (m, 5H); ESI MS m/z 386 [M+H].sup.+.
Example 108
Preparation of
1-(2,3,4,9-Tetrahydro-1H-pyrido[3,4-b]indol-7-yl)-4-(4-(trifluoro-methyl)-
phenyl)pyridin-2(1H)-one hydrochloride
a) tert-Butyl 7-(2-oxo-4-(4-(trifluoromethyl)phenyl)pyridin-1
(2H)-yl)-9-tosyl-3,4-dihydro-1H-pyrido[3,4-b]indole-2(9H)-carboxylate
##STR00273##
[0546] A suspension of
4-(4-(trifluoromethyl)phenyl)pyridin-2(1H)-one (121 mg, 0.504
mmol), tert-butyl
7-bromo-9-tosyl-3,4-dihydro-1H-pyrido[3,4-b]indole-2(9H)-carboxylate
(305 mg, 0.605 mmol), CuI (115 mg, 0.605 mmol), 8-hydroxyquinoline
(88 mg, 0.605 mmol) and Cs.sub.2CO.sub.3 (181 mg, 0.605 mmol) in
DMSO (5 mL) was degassed under reduced pressure for 45 min. The
suspension was put under Ar and heated at 135.degree. C. with
stirring for 2.5 h. The suspension was cooled, 4:1
CH.sub.2Cl.sub.2/(9:1 MeOH/NH.sub.4OH) (25 mL) was added and the
resulting suspension was stirred at 25.degree. C. for 10 min. The
suspension was passed through a plug of silica gel and the filtrate
was washed with brine. The solution was dried over Na.sub.2SO.sub.4
and concentrated under reduced pressure to afford an amorphous
solid. Flash chromatography (silica gel, (1:1
EtOAc/hexanes)/(9:0.9:0.1 CH.sub.2Cl.sub.2/MeOH/NH.sub.4OH) 100:0
to 0:100) gave the title compound (170 mg, 51%) as a pink foam:
.sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 8.26 (br s, 1H),
7.83-7.74 (m, 6H), 7.53 (d, J=7.2 Hz, 1H), 7.51-7.45 (m, 1H),
7.35-7.23 (m, 3H), 6.93 (d, J=1.8 Hz, 1H), 6.54 (dd, J=7.2, 1.8 Hz,
1H), 4.91 (br s, 2H), 3.75-3.65 (m, 2H), 2.73-2.68 (m, 2H), 2.36
(s, 3H), 1.52 (s, 9H).
b)
1-(2,3,4,9-Tetrahydro-1H-pyrido[3,4-b]indol-7-yl)-4-(4-(trifluoromethyl-
)phenyl)pyridin-2(1H)-one hydrochloride
##STR00274##
[0548] TFA (1 mL) was added to a solution of tert-butyl
7-(2-oxo-4-(4-(trifluoro-methyl)phenyl)pyridin-1(2H)-yl)-9-tosyl-3,4-dihy-
dro-1H-pyrido[3,4-b]indole-2(9H)-carboxylate (170 mg, 0.256 mmol)
in CH.sub.2Cl.sub.2 (5 mL) under N.sub.2, and the resulting
solution was stirred at 25.degree. C. for 30 min. Saturated
NaHCO.sub.3 solution and CH.sub.2Cl.sub.2 were added to the
solution, and the phases were separated. The organic phase was
dried over Na.sub.2SO.sub.4 and concentrated under reduced pressure
to afford 145 mg of a pink solid. NaOH (227 mg, 5.67 mmol) was
added to a solution of the pink solid (64 mg) in
CH.sub.2Cl.sub.2/MeOH (10 mL) that had been degassed with N.sub.2.
The resulting solution was heated at reflux with stirring for 7 h
under N.sub.2. The solution was allowed to cool, saturated
NH.sub.4Cl solution and CH.sub.2Cl.sub.2 were added, and the phases
were separated. The organic phase was washed with saturated
NaHCO.sub.3 solution, dried over Na.sub.2SO.sub.4 and concentrated
under reduced pressure to yield a yellow powder. Flash
chromatography (silica gel, (1:1 EtOAc/hexanes)/(9:0.9:0.1
CH.sub.2Cl.sub.2/MeOH/NH.sub.4OH) 100:0 to 0:100) afforded a yellow
solid. 1M HCl in Et.sub.2O (0.07 ml, 0.06 mmol) was added to a
solution of the yellow solid in 9:1 CH.sub.2Cl.sub.2/MeOH (10 mL)
under N.sub.2 and the resulting solution was stirred at 25.degree.
C. for 30 min. The solution was concentrated under reduced pressure
to yield the title compound (27 mg, 54%) as a yellow solid: .sup.1H
NMR (500 MHz, DMSO-d.sub.6) .delta. 11.28 (s, 1H), 9.21 (br s, 2H),
8.01 (d J=8.3 Hz, 2H), 7.88 (d, J=8.3 Hz, 2H), 7.80 (d, J=7.0 Hz,
1H), 7.58 (d, J=8.0 Hz, 1H), 7.49 (d, J=1.5 Hz, 1H), 7.07 (dd,
J=8.0, 1.5 Hz, 1H), 6.87 (d, J=2.0 Hz, 1H), 6.72 (dd, J=7.0, 2.0
Hz, 1H), 4.40 (s, 2H), 3.52-3.48 (m, 2H), 2.99 (t, J=6.0 Hz, 2H);
ESI MS m/z 410 [M+H].sup.+.
Example 109
Preparation of
1-(2-Methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-7-yl)-4-(4-(trifluor-
o-methyl)phenyl)pyridin-2(1H)-one hydrochloride
a)
1-(2-Methyl-9-tosyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-7-yl)-4-(4-
-(trifluoromethyl)phenyl)pyridin-2(1H)-one
##STR00275##
[0550] TFA (1 mL) was added to a solution of tert-butyl
7-(2-oxo-4-(4-(trifluoro-methyl)phenyl)pyridin-1(2H)-yl)-9-tosyl-3,4-dihy-
dro-1H-pyrido[3,4-b]indole-2(9H)-carboxylate (170 mg, 0.256 mmol)
in CH.sub.2Cl.sub.2 (5 mL) under N.sub.2, and the resulting
solution was stirred at 25.degree. C. for 30 min. Saturated
NaHCO.sub.3 solution and CH.sub.2Cl.sub.2 were added to the
solution, and the phases were separated. The organic phase was
dried over Na.sub.2SO.sub.4 and concentrated under reduced pressure
to afford 145 mg of a pink solid. Formaldehyde (37% in H.sub.2O,
0.02 mL, 0.2 mmol) was added to a solution of the pink solid (80
mg) in 1:1 MeOH/CH.sub.2Cl.sub.2 (4 mL) and the resulting solution
was stirred at 25.degree. C. for 45 min. NaBH(OAc).sub.3 (60 mg,
0.28 mmol) was added to the solution and the resulting suspension
was stirred at 25.degree. C. for 30 min. The suspension was
concentrated under reduced pressure. The residue was diluted with
CH.sub.2Cl.sub.2 and saturated NaHCO.sub.3 solution. The phases
were separated. The organic phase was dried over Na.sub.2SO.sub.4
and concentrated under reduced pressure to yield the title compound
(61 mg, 74%) as a pink foam: .sup.1H NMR (300 MHz, CDCl.sub.3)
.delta. 8.23 (d, J=1.8 Hz, 1H), 7.79-7.71 (m, 6H), 7.53 (d, J=7.2
Hz, 1H), 7.47 (d, J=8.4 Hz, 1H), 7.32 (dd, J=8.4, 1.8 Hz, 1H),
7.27-7.22 (m, 2H), 6.93 (d, J=1.8 Hz, 1H), 6.53 (dd, J=7.2, 1.8 Hz,
1H), 3.93 (br s, 2H), 2.80-2.60 (m, 4H), 2.57 (s, 3H), 2.34 (s,
3H).
b)
1-(2-Methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-7-yl)-4-(4-(triflu-
oro-methyl)phenyl)pyridin-2(1H)-one hydrochloride
##STR00276##
[0552] NaOH (211 mg, 5.28 mmol) was added to a solution of
1-(2-methyl-9-tosyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-7-yl)-4-(4-(-
trifluoromethyl)phenyl)pyri din-2(1H)-one (61 mg, 0.11 mmol) in
CH.sub.2Cl.sub.2/MeOH (10 mL) that had been degassed with N.sub.2.
The resulting solution was heated at reflux with stirring for 7 h
under N.sub.2. The solution was allowed to cool, saturated
NH.sub.4Cl solution and CH.sub.2Cl.sub.2 were added, and the phases
were separated. The organic phase was washed with saturated
NaHCO.sub.3 solution, dried over Na.sub.2SO.sub.4 and concentrated
under reduced pressure to yield a yellow solid. Flash
chromatography (silica gel, (1:1 EtOAc/hexanes)/(9:0.9:0.1
CH.sub.2Cl.sub.2/MeOH/NH.sub.4OH) 100:0 to 0:100) afforded a yellow
solid. 1M HCl in Et.sub.2O (0.06 ml, 0.06 mmol) was added to a
solution of the yellow solid in 9:1 CH.sub.2Cl.sub.2/MeOH (10 mL)
under N.sub.2 and the resulting solution was stirred at 25.degree.
C. for 30 min. The solution was concentrated under reduced pressure
to yield the title compound (28 mg, 58%) as a yellow solid: mp
200-204.degree. C.; .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta.
11.36 (s, 1H), 10.35 (br s, 1H), 8.02 (d, J=8.3 Hz, 2H), 7.88 (d,
J=8.3 Hz, 2H), 7.80 (d, J=7.0 Hz, 1H), 7.59 (d, J=8.0 Hz, 1H), 7.49
(br s, 1H), 7.07 (dd, J=8.0, 1.5 Hz, 1H), 6.87 (d, J=1.5 Hz, 1H),
6.72 (d, J=7.0, 1.5 Hz, 1H), 4.62 (br d, J=16.0 Hz, 1H), 4.49-4.40
(m, 1H), 3.81-3.73 (m, 1H), 3.49-3.39 (m, 1H), 3.12-3.00 (m, 5H);
ESI MS m/z 424 [M+H].sup.+.
Example 110
Preparation of
4-(Benzyloxy)-1-(1,1,9-trimethyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-
-7-yl)pyridin-2(1H)-one hydrochloride
a)
7-Bromo-1,1-dimethyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole
##STR00277##
[0554] Concentrated HCl (10 mL) was added to a suspension of a 2:1
mixture of 2-(6-bromo-1H-indol-3-yl)ethanamine and
2-(4-bromo-1H-indol-3-yl)ethanamine (9.90 g, 41.4 mmol) and
Na.sub.2SO.sub.4 (30 g) in 1:1 acetone/n-butanol (100 mL). The
resulting suspension was heated at 60.degree. C. with stirring for
4 d. The suspension was cooled and concentrated under reduced
pressure. The residue was diluted with EtOAc, and the suspension
was filtered. The filtrate was washed with saturate NaHCO.sub.3
solution, dried over Na.sub.2SO.sub.4 and concentrated under
reduced pressure. Flash chromatography (silica gel, (1:1
EtOAc/hexanes)/(9:0.9:0.1 CH.sub.2Cl.sub.2/MeOH/NH.sub.4OH) 100:0
to 0:100) yielded the title compound (1.68 g, 15%) as a red foam:
.sup.1H NMR (500 MHz, CDCl.sub.3) .delta. 7.66 (br s, 1H), 7.45 (d,
J=1.5 Hz, 1H), 7.32 (d, J=8.5 Hz, 1H), 7.19 (dd, J=8.5, 1.5 Hz,
1H), 3.20 (t, J=5.5 Hz, 2H), 2.68 (t, J=5.5 Hz, 2H), 1.47 (s,
6H).
b) tert-Butyl
7-bromo-1,1,9-trimethyl-3,4-dihydro-1H-pyrido[3,4-b]indole-2(9H)-carboxyl-
ate
##STR00278##
[0556] Boc.sub.2O (7.88 g, 36.1 mmol) was added to a suspension of
7-bromo-1,1-dimethyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole
(1.68 g, 6.02 mmol) and K.sub.2CO.sub.3 (1.66 g, 12.0 mmol) in 1:1
H.sub.2O/i-PrOH (80 mL), and the resulting suspension was stirred
at 25.degree. C. for 2 h. The suspension was filtered. The solid
was washed with H.sub.2O and dried under reduced pressure to afford
1.285 g of a white solid. NaH (60% dispersion in oil, 152 mg, 3.80
mmol) was added to a solution of the white solid (720 mg) in DMF
(10 mL) under N.sub.2 and the resulting suspension was stirred at
25.degree. C. for 30 min. MeI (0.18 mL, 2.9 mmol) was added to the
suspension, and the resulting suspension was stirred at 25.degree.
C. for 30 min. The suspension was cooled to 0.degree. C., and
H.sub.2O was added slowly. Hexanes was added and the phases were
separated. The organic phase was dried over Na.sub.2SO.sub.4 and
concentrated under reduced pressure. Flash chromatography (silica
gel, hexanes/(1:1 EtOAc/hexanes) 100:0 to 60:40) yielded the title
compound (471 mg, 36%) as a white solid: .sup.1H NMR (300 MHz,
CDCl.sub.3) .delta. 7.43 (d, J=1.5 Hz, 1H), 7.33 (d, J=8.4 Hz, 1H),
7.20 (dd, J=8.4, 1.5 Hz, 1H), 3.79-3.72 (m, 5H), 2.73 (t, J=5.4 Hz,
2H), 1.88 (s, 6H), 1.53 (s, 9H).
c) tert-Butyl
7-(4-(benzyloxy)-2-oxopyridin-1(2H)-yl)-1,1,9-trimethyl-3,4-dihydro-1H-py-
rido[3,4-b]indole-2(9H)-carboxylate
##STR00279##
[0558] A suspension of 4-(benzyloxy)pyridin-2(1H)-one (107 mg,
0.532 mmol), tert-butyl
7-bromo-1,1,9-trimethyl-3,4-dihydro-1H-pyrido[3,4-b]indole-2(9H)-carboxyl-
ate (251 mg, 0.639 mmol), CuI (122 mg, 0.639 mmol),
8-hydroxyquinoline (93 mg, 0.639 mmol) and Cs.sub.2CO.sub.3 (190
mg, 0.585 mmol) in DMSO (10 mL) was degassed under reduced pressure
for 45 min. The suspension was put under Ar and heated at
135.degree. C. with stirring overnight. The suspension was cooled,
40:9:1 CH.sub.2Cl.sub.2/MeOH/NH.sub.4OH was added and the resulting
suspension was stirred at 25.degree. C. for 30 min. The suspension
was passed through a plug of silica gel, and the filtrate was
washed with brine. The solution was dried over Na.sub.2SO.sub.4 and
concentrated under reduced pressure to afford an amorphous solid.
Flash chromatography (silica gel, (1:1 EtOAc/hexanes)/(9:0.9:0.1
CH.sub.2Cl.sub.2/MeOH/NH.sub.4OH) 100:0 to 1:1) yielded the title
compound (74 mg, 27%) as a white powder: .sup.1H NMR (300 MHz,
CDCl.sub.3) .delta. 7.54 (d, J=8.1 Hz, 1H), 7.46-7.35 (m, 4H),
7.33-7.25 (m, 3H), 7.12 (dd, J=8.1, 2.1 Hz, 1H), 6.09 (d, J=2.6 Hz,
1H), 6.04 (dd, J=7.5, 2.6 Hz, 1H), 5.06 (s, 2H), 3.80 (s, 3H), 3.77
(t, J=4.8 Hz, 2H), 2.77 (t, J=4.8 Hz, 2H), 1.89 (s, 6H), 1.54 (s,
9H).
d)
4-(Benzyloxy)-1-(1,1,9-trimethyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]ind-
ol-7-yl)pyridin-2(1H)-one hydrochloride
##STR00280##
[0560] TFA (1 mL) was added to a solution of tert-butyl
7-(4-(benzyloxy)-2-oxopyridin-1(2H)-yl)-1,1,9-trimethyl-3,4-dihydro-1H-py-
rido[3,4-b]indole-2(9H)-carboxylate (72 mg, 0.14 mmol) in
CH.sub.2Cl.sub.2 (10 mL) under N.sub.2, and the resulting solution
was stirred at 25.degree. C. for 30 min. Saturated NaHCO.sub.3
solution and CH.sub.2Cl.sub.2 were added to the solution and the
phases were separated. The organic phase was dried over
Na.sub.2SO.sub.4 and concentrated under reduced pressure.
Purification by semi-preparative HPLC (Phenomenex Luna C18 (2),
250.0.times.21.20 mm, 10 micron, H.sub.2O with 0.05% TFA and
CH.sub.3CN with 0.05% TFA) afforded 14 mg of clear crystals. 1M HCl
in Et.sub.2O (0.04 ml, 0.04 mmol) was added to a solution of the
clear crystals in CH.sub.2Cl.sub.2 (10 mL) under N.sub.2 and the
resulting solution was stirred at 25.degree. C. for 30 min. The
solution was concentrated under reduced pressure to yield the title
compound (15 mg, 24%) as an off-white powder: mp 296-298; .sup.1H
NMR (500 MHz, DMSO-d.sub.6) .delta. 9.59 (s, 2H), 7.58-7.51 (m,
3H), 7.49-7.41 (m, 4H), 7.40-7.35 (m, 1H), 7.01 (dd, J=8.5, 1.5 Hz,
1H), 6.10 (dd, J=7.5, 2.8 Hz, 1H), 5.97 (d, J=2.8 Hz, 1H), 5.16 (s,
2H), 3.80 (s, 3H), 3.52-3.48 (m, 2H), 2.99 (t, J=6.0 Hz, 2H), 1.81
(s, 6H); ESI MS m/z 414 [M+H].sup.+.
Example 111
Preparation of
(S)-4-(Benzyloxy)-1-(9-methyl-2-(pyrrolidin-2-ylmethyl)-2,3,4,9-tetrahydr-
o-1H-pyrido[3,4-b]indol-7-yl)pyridin-2(1H)-one dihydrochloride
a) (S)-tert-Butyl 2-(bromomethyl)pyrrolidine-1-carboxylate
[0561] Beilstein Registry Number 6325435
##STR00281##
[0562] This compound was prepared in accordance with the procedure
of Kawara et al., Tetrahedron Lett., 1994, 35, 8805-8808.
b)
(S)-4-(Benzyloxy)-1-(9-methyl-2-(pyrrolidin-2-ylmethyl)-2,3,4,9-tetrahy-
dro-1H-pyrido[3,4-b]indol-7-yl)pyridin-2(1H)-one
dihydrochloride
##STR00282##
[0564] A suspension of
4-(benzyloxy)-1-(9-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-7-yl)p-
yridin-2(1H)-one (250 mg, 0.646 mmol), (S)-tert-butyl
2-(bromomethyl)pyrrolidine-1-carboxylate (342 mg, 1.29 mmol) and
Cs.sub.2CO.sub.3 (841 mg, 2.58 mmol) in DMSO (10 mL) under N.sub.2
was stirred at 25.degree. C. for 16 h. The suspension was heated at
60.degree. C. for 1 d. The suspension was cooled, and H.sub.2O was
added. The suspension was filtered. The solid was washed with
H.sub.2O and dried under reduced pressure. Flash chromatograph
(silica gel, hexanes/(9:0.9:0.1 Et.sub.2O/MeOH/NH.sub.4OH), 100:0
to 0:100) afforded 18 mg of a yellow solid. TFA (1 mL) was added to
a solution of the yellow solid in CH.sub.2Cl.sub.2 (5 mL) under
N.sub.2 and the resulting solution was stirred at 25.degree. C. for
3.5 h. Saturated NaHCO.sub.3 solution and CH.sub.2Cl.sub.2 were
added and the phases were separated. The organic phase was dried
over Na.sub.2SO.sub.4 and concentrated under reduced pressure.
Flash chromatograph (silica gel,(1:1 EtOAc/hexanes)/(9:0.9:0.1
Et.sub.2O/MeOH/NH.sub.4OH), 100:0 to 0:100) yielded 10 mg of a
yellow solid. 1M HCl in Et.sub.2O (0.04 ml, 0.04 mmol) was added to
a solution of the yellow solid in CH.sub.2Cl.sub.2 (10 mL) under
N.sub.2, and the resulting solution was stirred at 25.degree. C.
for 30 min. The solution was concentrated under reduced pressure to
yield the title compound (10 mg, 3%) as an off-white powder: mp
160-162.degree. C.; .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta.
9.25 (br s, 1H), 7.56 (d, J=7.5 Hz, 1H), 7.54-7.40 (m, 6H),
7.39-7.34 (m, 1H), 7.04-6.93 (m, 1H), 6.11 (dd, J=7.5, 2.5 Hz, 1H),
5.97 (d, J=2.5 Hz, 1H), 5.16 (s, 2H), 3.98-3.45 (m, 11H), 3.39 (s,
1H), 3.30-3.21 (m, 2H), 2.25-2.10 (m, 1H), 2.05-1.74 (m, 2H),
1.73-1.60 (m, 1H); ESI MS m/z 469 [M+H].sup.+.
Example 112
Preparation of
4-(4-Chloro-2-methoxyphenyl)-1-(5-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-
-b]indol-7-yl)pyridin-2(1H)-one hydrochloride
a) 4-(4-Chloro-2-methoxyphenyl)pyridine 1-oxide
##STR00283##
[0566] 4-Chloropyridine-N-oxide (500 mg, 3.85 mmol),
2-methoxy-4-chlorophenylboronic acid (862 mg, 4.63 mmol) and
K.sub.2CO.sub.3 (1.59 g, 11.55 mmol) were suspended in DMSO (5 mL)
and PdCl.sub.2(dppf) (314 mg, 0.385 mmol) was added. The reaction
mixture was placed under vacuum for 20 min and flushed with
N.sub.2. This process was repeated, and the reaction mixture was
heated at 120.degree. C. for 3 h. The reaction mixture was cooled
to 25.degree. C. and partitioned between methylene chloride and 5%
lithium chloride. The aqueous phase was removed, and the organic
phase was washed with brine, dried over Na.sub.2SO.sub.4, filtered
and concentrated to dryness under reduced pressure. Flash
chromatography (ISCO 40 g column, methylene chloride/MeOH 100:0 to
90:10) provided the title compound (673 mg, 74%) as a tan solid:
.sup.1H NMR (300 MHz, CD.sub.3OD) .delta. 8.21 (dd, J=5.4, 1.8 Hz,
2H), 7.47 (dd, J=5.6, 1.6 Hz, 2H), 7.26 (d, J=8.2 Hz, 1H), 7.06
(dd, J=8.3, 2.4 Hz, 1H), 7.00 (d, J=1.7 Hz, 1H), 3.87 (s, 3H); ESI
MS m/z 235 [M+H].sup.+.
b) 4-(4-Chloro-2-methoxyphenyl)pyridin-2(1H)-one
##STR00284##
[0568] 4-(4-Chloro-2-methoxyphenyl)pyridine 1-oxide (673 mg, 2.86
mmol) and acetic anhydride (10 mL) were heated at reflux for 3 h.
The mixture was concentrated under reduced pressure, and a 1:1
solution of H.sub.2O/MeOH (20 mL) was added. The reaction mixture
was heated to reflux for 1 h, cooled to 25.degree. C. and
concentrated under reduced pressure. The resulting residue was
dissolved in hot 2-propanol (3 mL), triturated with Et.sub.2O,
sonicated for 30 min then placed in the freezer. The solid was
filtered off providing the title compound (550 mg, 91%) as a tan
solid: .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 11.54 (s, 1H),
7.35-7.33 (m, 2H), 7.01 (s, 1H), 7.08 (d, J=6.6 Hz, 1H), 6.36 (s,
1H), 6.28 (s, 1H), 3.82 (s, 3H); ESI MS m/z 235 [M+H].sup.+.
c) tert-Butyl
7-(4-(4-chloro-2-methoxyphenyl)-2-oxopyridin-1(2H)-yl)-5-methyl-3,4-dihyd-
ro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate
##STR00285##
[0570] A suspension of
4-(4-chloro-2-methoxyphenyl)pyridin-2(1H)-one (126 mg, 0.534 mmol),
tert-butyl
7-bromo-5-methyl-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate
(234 mg, 0.641 mmol), CuI (122 mg, 0.641 mmol), 8-hydroxyquinoline
(93 mg, 0.64 mmol) and Cs.sub.2CO.sub.3 (191 mg, 0.587 mmol) in
DMSO (5 mL) was degassed under reduced pressure for 45 min. The
suspension was put under Ar and heated at 135.degree. C. with
stirring overnight. The suspension was cooled, 40:9:1
CH.sub.2Cl.sub.2/MeOH/NH.sub.4OH was added, and the resulting
suspension was stirred at 25.degree. C. for 10 min. The suspension
was passed through a plug of silica gel, and the filtrate was
washed with brine. The solution was dried over Na.sub.2SO.sub.4 and
concentrate under reduced pressure. Flash chromatography (silica
gel, (1:1 EtOAc/hexanes)/(9:0.9:0.1
CH.sub.2Cl.sub.2/MeOH/NH.sub.4OH) 100:0 to 0:100) gave the title
compound (123 mg, 44%) as a yellow solid: .sup.1H NMR (300 MHz,
CDCl.sub.3) .delta. 7.54 (d, J=8.1 Hz, 1H), 7.42-7.35 (m, 2H), 7.31
(d, J=8.1 Hz, 1H), 7.12-7.02 (m, 2H), 6.99 (d, J=1.8 Hz, 1H), 6.81
(d, J=1.8 Hz, 1H), 6.44 (dd, J=7.2, 1.8 Hz, 1H), 4.65 (br s, 2H),
3.88 (s, 3H), 3.90-3.81 (m, 2H), 3.65 (s, 3H), 2.87-2.79 (m, 2H),
1.51 (s, 9H).
d)
4-(4-Chloro-2-methoxyphenyl)-1-(5-methyl-2,3,4,5-tetrahydro-1H-pyrido[4-
,3-b]indol-7-yl)pyridin-2(1H)-one hydrochloride
##STR00286##
[0572] TFA (2 mL) was added to a solution of tert-butyl
7-(4-(4-chloro-2-methoxyphenyl)-2-oxopyridin-1(2H)-yl)-5-methyl-3,4-dihyd-
ro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate (124 mg, 0.238 mmol) in
CH.sub.2Cl.sub.2 (10 mL) under N.sub.2, and the resulting solution
was stirred at 25.degree. C. for 1 h. Saturated NaHCO.sub.3
solution and CH.sub.2Cl.sub.2 were added to the solution, and the
phases were separated. The organic phase was dried over
Na.sub.2SO.sub.4 and concentrated under reduced pressure. Flash
chromatography (silica gel, (1:1 EtOAc/hexanes)/(9:0.9:0.1
CH.sub.2Cl.sub.2/MeOH/NH.sub.4OH) 100:0 to 0:100) yielded 70 mg of
an off-white solid. 1M HCl in Et.sub.2O (0.03 ml, 0.03 mmol) was
added to a solution of the off-white solid (10 mg) in
CH.sub.2Cl.sub.2 (10 mL) under N.sub.2 and the resulting solution
was stirred at 25.degree. C. for 30 min. The solution was
concentrated under reduced pressure to yield the title compound (9
mg, 26%) as an off-white powder: mp 290-292.degree. C.; .sup.1H NMR
(500 MHz, DMSO-d.sub.6) .delta. 9.17 (br s, 2H), 7.65 (d, J=7.0 Hz,
1H), 7.62 (d, J=1.8 Hz, 1H), 7.59 (d, J=8.5 Hz, 1H), 7.44 (d, J=8.0
Hz, 1H), 7.26 (d, J=1.8 Hz, 1H), 7.14 (dd, J=8.0, 1.8 Hz, 1H), 7.09
(dd, J=8.5, 1.8 Hz, 1H), 6.57 (d, J=2.0 Hz, 1H), 6.47 (dd, J=7.0,
2.0 Hz, 1H), 4.37 (br s, 2H), 3.87 (s, 3H), 3.70 (s, 3H), 3.57-3.52
(m, 2H), 3.10 (t, J=6.0 Hz, 2H); ESI MS m/z 420 [M+H].sup.+.
Example 113
Preparation of
4-(4-Chloro-2-methoxyphenyl)-1-(2,5-dimethyl-2,3,4,5-tetrahydro-1H-pyrido-
[4,3-b]indol-7-yl)pyridin-2(1H)-one hydrochloride
a)
4-(4-Chloro-2-methoxyphenyl)-1-(2,5-dimethyl-2,3,4,5-tetrahydro-1H-pyri-
do[4,3-b]indol-7-yl)pyridin-2(1H)-one hydrochloride
##STR00287##
[0574] TFA (2 mL) was added to a solution of tert-butyl
7-(4-(4-chloro-2-methoxyphenyl)-2-oxopyridin-1(2H)-yl)-5-methyl-3,4-dihyd-
ro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate (124 mg, 0.238 mmol) in
CH.sub.2Cl.sub.2 (10 mL) under N.sub.2, and the resulting solution
was stirred at 25.degree. C. for 1 h. Saturated NaHCO.sub.3
solution and CH.sub.2Cl.sub.2 were added to the solution, and the
phases were separated. The organic phase was dried over
Na.sub.2SO.sub.4 and concentrated under reduced pressure. Flash
chromatography (silica gel, (1:1 EtOAc/hexanes)/(9:0.9:0.1
CH.sub.2Cl.sub.2/MeOH/NH.sub.4OH), 100:0 to 0:100) yielded 70 mg of
an off-white solid. Formaldehyde (37% in H.sub.2O, 0.02 mL, 0.2
mmol) was added to a solution of the off-white solid (43 mg) in 1:1
MeOH/CH.sub.2Cl.sub.2 (5 mL) and the resulting solution was stirred
at 25.degree. C. for 45 min. NaBH(OAc).sub.3 (43 mg, 0.20 mmol) was
added to the solution, and the resulting suspension was stirred at
25.degree. C. for 30 min. The suspension was concentrated under
reduced pressure, and the resulting residue was diluted with
CH.sub.2Cl.sub.2 and saturated NaHCO.sub.3 solution. The phases
were separated. The organic phase was dried over Na.sub.2SO.sub.4
and concentrated under reduced pressure. Purification by
semi-preparative HPLC (Phenomenex Luna C18 (2), 250.0.times.21.20
mm, 10 micron, H.sub.2O with 0.05% TFA and CH.sub.3CN with 0.05%
TFA) afforded 13 mg of an off-white solid. 1M HCl in Et.sub.2O
(0.03 ml, 0.03 mmol) was added to a solution of the off-white solid
in CH.sub.2Cl.sub.2 (10 mL) under N.sub.2 and the resulting
solution was stirred at 25.degree. C. for 30 min. The solution was
concentrated under reduced pressure to yield the title compound (14
mg, 17%) as an off-white powder: mp 270-272.degree. C.; .sup.1H NMR
(500 MHz, DMSO-d.sub.6) .delta. 10.15 (br s, 1H), 7.66 (d, J=7.0
Hz, 1H), 7.63 (d, J=1.5 Hz, 1H), 7.55 (d, J=8.0 Hz, 1H), 7.44 (d,
J=8.5 Hz, 1H), 7.26 (d, J=1.8 Hz, 1H), 7.14 (dd, J=8.5, 1.5 Hz,
1H), 7.11 (dd, J=8.0, 1.8 Hz, 1H), 6.57 (d, J=2.0 Hz, 1H), 6.47
(dd, J=7.0, 2.0 Hz, 1H), 4.67 (d, J=13.5 Hz, 1H), 4.33 (dd, J=14.3,
6.0 Hz, 1H), 3.87 (s, 3H), 3.86-3.79 (m, 1H), 3.71 (s, 3H),
3.55-3.47 (m, 1H), 3.24-3.15 (m, 2H), 3.01 (s, 3H); ESI MS m/z 434
[M+H].sup.+.
Example 114
Preparation of
1-(5-Methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-7-yl)-4-(pyrimidin-2-
-ylmethoxy)pyridin-2(1H)-one dihydrochloride
a) 4-(Pyrimidin-2-ylmethoxy)pyridine 1-oxide
##STR00288##
[0576] Following the procedure of Example 137 (step a), but
substituting pyrimidin-2ylmethanol (3.0 g, 27 mmol) for
imidazo[1,2-a]pyridine-2-ylmethanol, the title compound (0.95 g,
17%) was prepared as an orange solid: .sup.1H NMR (300 MHz,
CD.sub.3OD) .delta. 8.81 (d, J=5.1 Hz, 2H), 8.23-8.21 (m, 2H), 7.45
(t, J=4.8 Hz, 1H), 7.24-7.21 (m, 2H), 5.46 (s, 2H).
b) 4-(Pyrimidin-2-ylmethoxy)pyridin 2(1H)-one
##STR00289##
[0578] Following the procedure of Example 137 (step b), but
substituting 4-(pyrimidin-2-ylmethoxy)pyridine 1-oxide (0.95 g, 4.6
mmol) for 4-(imidazo[1,2-a]pyridin-2-ylmethoxy)pyridine 1-oxide,
the title compound (0.55 g, 58%) was prepared as a dark brown
solid: .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 11.09 (br s,
1H), 8.84 (d, J=4.5 Hz, 2H), 7.48 (t, J=5.0 Hz, 1H), 7.25-7.23 (m,
1H), 5.92 (dd, J=7.0, 2.5 Hz, 1H), 5.66 (d, J=8.0, 2.5 Hz, 1H),
5.23 (s, 2H).
c) tert-Butyl
5-methyl-7-(2-oxo-4-(pyrimidin-2-ylmethoxy)pyridin-1(2H)-yl)-3,4-dihydro--
1H-pyrido[4,3-b]indole-2(5H)-carboxylate
##STR00290##
[0580] A suspension of 4-(pyrimidin-2-ylmethoxy)pyridin-2(1H)-one
(242 mg, 1.19 mmol), tert-butyl
7-bromo-5-methyl-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate
(522 mg, 1.43 mmol), CuI (272 mg, 1.43 mmol), 8-hydroxyquinoline
(35 mg, 0.24 mmol) and Cs.sub.2CO.sub.3 (426 mg, 1.31 mmol) in DMSO
(10 mL) was degassed under reduced pressure for 45 min. The
suspension was put under Ar and heated at 135.degree. C. with
stirring overnight. The suspension was cooled, 40:9:1
CH.sub.2Cl.sub.2/MeOH/NH.sub.4OH (50 mL) was added, and the
resulting suspension was stirred at 25.degree. C. for 1 h. The
suspension was passed through a plug of silica gel, and the
filtrate was washed with brine. The solution was dried over
Na.sub.2SO.sub.4 and concentrated under reduced pressure. Flash
chromatography (silica gel, (1:1 EtOAc/hexanes)/(4:0.9:0.1
CH.sub.2Cl.sub.2/MeOH/NH.sub.4OH), 100:0 to 0:100) yielded the
title compound (256 mg, 44%) as a yellow solid: .sup.1H NMR (500
MHz, CDCl.sub.3) .delta. 8.81 (d, J=4.5 Hz, 1H), 7.50 (d, J=8.0 Hz,
1H), 7.32 (d, J=7.5 Hz, 1H), 7.31-7.27 (m, 3H), 7.01 (br d, J=8.0
Hz, 1H), 6.17 (dd, J=7.5, 2.8 Hz, 1H), 6.00 (d, J=2.8 Hz, 1H), 5.32
(s, 2H), 4.64 (br s, 2H), 3.88-3.79 (m, 2H), 3.62 (s, 3H),
2.84-2.78 (m, 2H), 1.50 (s, 9H).
d)
1-(5-Methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-7-yl)-4-(pyrimidin-
-2-ylmethoxy)pyridin-2(1H)-one dihydrochloride
##STR00291##
[0582] TFA (2 mL) was added to a solution of tert-butyl
5-methyl-7-(2-oxo-4-(pyrimidin-2-ylmethoxy)pyridin-1(2H)-yl)-3,4-dihydro--
1H-pyrido[4,3-b]indole-2(5H)-carboxylate (256 mg, 0.525 mmol) in
CH.sub.2Cl.sub.2 (10 mL) under N.sub.2, and the resulting solution
was stirred at 25.degree. C. for 1 h. Saturated NaHCO.sub.3
solution and CH.sub.2Cl.sub.2 were added to the solution, and the
phases were separated. The organic phase was dried over
Na.sub.2SO.sub.4 and concentrated under reduced pressure. Flash
chromatography (silica gel, (1:1 EtOAc/hexanes)/(4:0.9:0.1
CH.sub.2Cl.sub.2/MeOH/NH.sub.4OH), 100:0 to 0:100) yielded 35 mg of
a yellow foam. 1M HCl in Et.sub.2O (0.08 ml, 0.08 mmol) was added
to a solution of the yellow foam (16 mg) in CH.sub.2Cl.sub.2 (10
mL) under N.sub.2, and the resulting solution was stirred at
25.degree. C. for 30 min. The solution was concentrated under
reduced pressure to yield the title compound (16 mg, 14%) as an
off-white powder: mp 234-236.degree. C.; .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 9.10 (br s, 2H), 8.88 (d, J=5.0 Hz, 2H),
7.58-7.52 (m, 4H), 6.99 (dd, J=8.0, 1.8 Hz, 1H), 6.14 (dd, J=7.5,
2.5 Hz, 1H), 5.86 (d, J=2.5 Hz, 1H), 5.33 (s, 2H), 4.36 (br s, 2H),
3.68 (s, 3H), 3.57-3.52 (m, 2H), 3.11-3.05 (m, 2H); ESI MS m/z 388
[M+H].sup.+.
Example 115
Preparation of
4-(Imidazo[1,2-a]pyridin-6-ylmethoxy)-1-(5-methyl-2,3,4,5-tetrahydro-1H-p-
yrido[4,3-b]indol-7-yl)pyridin-2(1H)-one dihydrochloride
a) tert-Butyl
7-(4-(imidazo[1,2-a]pyridin-6-ylmethoxy)-2-oxopyridin-1(2H)-yl)-5-methyl--
3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate
##STR00292##
[0584] A suspension of
4-(imidazo[1,2-a]pyridin-6-ylmethoxy)pyridin-2(1H)-one (270 mg,
1.12 mmol), tert-butyl
7-bromo-5-methyl-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate
(493 mg, 1.35 mmol), CuI (257 mg, 1.35 mmol), 8-hydroxyquinoline
(98 mg, 0.67 mmol) and Cs.sub.2CO.sub.3 (401 mg, 1.23 mmol) in DMSO
(10 mL) was degassed under reduced pressure for 45 min. The
suspension was put under Ar and heated at 135.degree. C. with
stirring for 4.5 h. The suspension was cooled, 40:9:1
CH.sub.2Cl.sub.2/MeOH/NH.sub.4OH (50 mL) was added, and the
resulting suspension was stirred at 25.degree. C. for 30 min. The
suspension was passed through a plug of silica gel, and the
filtrate was washed with brine. The solution was dried over
Na.sub.2SO.sub.4 and concentrate under reduced pressure. Flash
chromatography (silica gel, (1:1 EtOAc/hexanes)/(4:0.9:0.1
CH.sub.2Cl.sub.2/MeOH/NH.sub.4OH), 100:0 to 0:100) yielded the
title compound (167 mg, 28%) as a yellow solid: .sup.1H NMR (300
MHz, CDCl.sub.3) .delta. 8.34-8.25 (m, 1H), 7.79-7.61 (m, 3H),
7.58-7.50 (m, 1H), 7.40-7.25 (m, 3H), 7.07-6.69 (m, 1H), 6.17-6.10
(m, 1H), 6.09-6.02 (m, 1H), 5.11 (s, 2H), 4.65 (br s, 2H),
3.92-3.80 (m, 2H), 3.65 (s, 3H), 2.89-2.80 (m, 2H), 1.52 (s, 9H);
ESI MS m/z 526 [M+H].sup.+.
b)
4-(Imidazo[1,2-a]pyridin-6-ylmethoxy)-1-(5-methyl-2,3,4,5-tetrahydro-1H-
-pyrido[4,3-b]indol-7-yl)pyridin-2(1H)-one dihydrochloride
##STR00293##
[0586] TFA (2 mL) was added to a solution of tert-butyl
7-(4-(imidazo[1,2-a]pyridin-6-ylmethoxy)-2-oxopyridin-1(2H)-yl)-5-methyl--
3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate (167 mg, 0.317
mmol) in CH.sub.2Cl.sub.2 (10 mL) under N.sub.2, and the resulting
solution was stirred at 25.degree. C. for 1 h. Saturated
NaHCO.sub.3 solution and CH.sub.2Cl.sub.2 were added to the
solution, and the phases were separated. The organic phase was
dried over Na.sub.2SO.sub.4 and concentrated under reduced
pressure. Flash chromatography (silica gel, (1:1
EtOAc/hexanes)/(4:0.9:0.1 CH.sub.2Cl.sub.2/MeOH/NH.sub.4OH), 100:0
to 0:100) yielded 51 mg of a yellow solid. Purification by
semi-preparative HPLC (Phenomenex Luna C18 (2), 250.0.times.21.20
mm, 10 micron, H.sub.2O with 0.05% TFA and CH.sub.3CN with 0.05%
TFA) afforded 7 mg of a white solid. 1M HCl in Et.sub.2O (0.03 ml,
0.03 mmol) was added to a solution of the white solid (7 mg) in
CH.sub.2Cl.sub.2 (10 mL) under N.sub.2, and the resulting solution
was stirred at 25.degree. C. for 30 min. The solution was
concentrated under reduced pressure to yield the title compound (8
mg, 5%) as a white powder: .sup.1H NMR (500 MHz, DMSO-d.sub.6)
.delta. 9.28 (br s, 2H), 9.06 (s, 1H), 8.38 (s, 1H), 8.19 (s, 1H),
8.05-7.94 (m, 2H), 7.62 (d, J=7.5 Hz, 1H), 7.56 (d, J=8.0 Hz, 1H),
7.50 (d, J=1.5 Hz, 1H), 6.99 (dd, J=8.0, 1.5 Hz, 1H), 6.13 (dd,
J=7.5, 2.5 Hz, 1H), 6.09 (d, J=2.5 Hz, 1H), 5.33 (s, 2H), 4.35 (br
s, 2H), 3.69 (s, 3H), 3.56-3.50 (m, 2H), 3.12-3.05 (m, 2H); ESI MS
m/z 426 [M+H].sup.+.
Example 116
Preparation of
4-(Imidazo[1,2-a]pyridin-2-ylmethoxy)-1-(5-methyl-2,3,4,5-tetrahydro-1H-p-
yrido[4,3-b]indol-7-yl)pyridin-2(1H)-one dihydrochloride
a) tert-Butyl
7-(4-(imidazo[1,2-a]pyridin-2-ylmethoxy)-2-oxopyridin-1(2H)-yl)-5-methyl--
3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate
##STR00294##
[0588] A suspension of
4-(imidazo[1,2-a]pyridin-2-ylmethoxy)pyridin-2(1H)-one (231 mg,
0.960 mmol), tert-butyl
7-bromo-5-methyl-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate
(421 mg, 1.15 mmol), CuI (219 mg, 1.15 mmol), 8-hydroxyquinoline
(84 mg, 0.576 mmol) and Cs.sub.2CO.sub.3 (345 mg, 1.06 mmol) in
DMSO (10 mL) was degassed under reduced pressure for 45 min. The
suspension was put under Ar and heated at 135.degree. C. with
stirring overnight. The suspension was cooled, 40:9:1
CH.sub.2Cl.sub.2/MeOH/NH.sub.4OH (50 mL) was added, and the
resulting suspension was stirred at 25.degree. C. for 30 min. The
suspension was passed through a plug of silica gel, and the
filtrate was washed with brine and 10% CuSO.sub.4 solution. The
solution was dried over Na.sub.2SO.sub.4 and concentrated under
reduced pressure. Flash chromatography (silica gel, (1:1
EtOAc/hexanes)/(4:0.9:0.1 CH.sub.2Cl.sub.2/MeOH/NH.sub.4OH), 100:0
to 0:100) gave the title compound (132 mg, 26%) as a yellow solid:
.sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 8.12 (d, J=6.9 Hz, 1H),
7.70 (br s, 1H), 7.62 (d, J=8.7 Hz, 1H), 7.50 (d, J=8.4 Hz, 1H),
7.33-7.18 (m, 3H), 7.02 (d, J=7.5 Hz, 1H), 6.82 (dd, J=6.9, 6.9 Hz,
1H), 6.17 (d, J=2.1 Hz, 1H), 6.08 (dd, J=7.5, 2.1 Hz, 1H), 5.25 (s,
2H), 3.84 (br s, 2H), 3.63 (s, 3H), 2.84-2.79 (m, 2H), 1.72-1.60
(m, 2H), 1.50 (s, 9H).
b)
4-(Imidazo[1,2-a]pyridin-2-ylmethoxy)-1-(5-methyl-2,3,4,5-tetrahydro-1H-
-pyrido[4,3-b]indol-7-yl)pyridin-2(1H)-one dihydrochloride
##STR00295##
[0590] TFA (1 mL) was added to a solution of tert-butyl
7-(4-(imidazo[1,2-a]pyridin-2-ylmethoxy)-2-oxopyridin-1(2H)-yl)-5-methyl--
3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate (132 mg, 0.251
mmol) in CH.sub.2Cl.sub.2 (10 mL) under N.sub.2, and the resulting
solution was stirred at 25.degree. C. for 1 h. Saturated
NaHCO.sub.3 solution and CH.sub.2Cl.sub.2 were added to the
solution, and the phases were separated. The aqueous phase was
extracted with EtOAc. The combined organic phases were dried over
Na.sub.2SO.sub.4 and concentrated under reduced pressure. Flash
chromatography (silica gel, (1:1 EtOAc/hexanes)/(4:0.9:0.1
CH.sub.2Cl.sub.2/MeOH/NH.sub.4OH), 100:0 to 0:100) yielded 42 mg of
an off-white solid. 1M HCl in Et.sub.2O (0.07 ml, 0.07 mmol) was
added to a solution of the off-white solid (15 mg) in
CH.sub.2Cl.sub.2 (10 mL) under N.sub.2, and the resulting solution
was stirred at 25.degree. C. for 30 min. The solution was
concentrated under reduced pressure to yield the title compound (15
mg, 34%) as a white powder: .sup.1H NMR (500 MHz, DMSO-d.sub.6)
.delta. 9.30 (br s, 2H), 8.84 (s, 1H), 8.37 (s, 1H), 7.89-7.70 (m,
2H), 7.64-7.53 (m, 2H), 7.50 (s, 1H), 7.37-7.29 (m, 1H), 7.03-6.97
(m, 1H), 6.20-6.09 (m, 2H), 5.41 (s, 2H), 4.35 (br s, 2H), 3.69 (s,
3H), 3.58-3.50 (m, 2H), 3.13-3.07 (m, 2H); ESI MS m/z 426
[M+H].sup.+.
Example 117
Preparation of
1-(2,5-Dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-7-yl)-4-(imidazo-
[1,2-a]pyridin-2-ylmethoxy)pyridin-2(1H)-one dihydrochloride
a)
1-(2,5-Dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-7-yl)-4-(imida-
zo[1,2-a]pyridin-2-ylmethoxy)pyridin-2(1H)-one dihydrochloride
##STR00296##
[0592] TFA (1 mL) was added to a solution of tert-butyl
7-(4-(imidazo[1,2-a]pyridin-2-ylmethoxy)-2-oxopyridin-1(2H)-yl)-5-methyl--
3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate (132 mg, 0.251
mmol) in CH.sub.2Cl.sub.2 (10 mL) under N.sub.2, and the resulting
solution was stirred at 25.degree. C. for 1 h. Saturated
NaHCO.sub.3 solution and CH.sub.2Cl.sub.2 were added to the
solution, and the phases were separated. The aqueous phase was
extracted with EtOAc. The combined organic phases were dried over
Na.sub.2SO.sub.4 and concentrated under reduced pressure. Flash
chromatography (silica gel, (1:1 EtOAc/hexanes)/(4:0.9:0.1
CH.sub.2Cl.sub.2/MeOH/NH.sub.4OH), 100:0 to 0:100) yielded 42 mg of
an off-white solid. Formaldehyde (37% in H.sub.2O, 0.01 mL, 0.12
mmol) was added to a solution of the off-white solid (27 mg) in 1:1
MeOH/CH.sub.2Cl.sub.2 (5 mL), and the resulting solution was
stirred at 25.degree. C. for 45 min. NaBH(OAc).sub.3 (27 mg, 0.13
mmol) was added to the solution, and the resulting suspension was
stirred at 25.degree. C. for 30 min. The suspension was
concentrated under reduced pressure, and the residue was diluted
with CH.sub.2Cl.sub.2 and saturated NaHCO.sub.3 solution. The
phases were separated. The organic phase was dried over
Na.sub.2SO.sub.4 and concentrated under reduced pressure to afford
25 mg of a viscous oil. 1M HCl in Et.sub.2O (0.11 ml, 0.11 mmol)
was added to a solution of the off-white solid in CH.sub.2Cl.sub.2
(10 mL) under N.sub.2, and the resulting solution was stirred at
25.degree. C. for 30 min. The solution was concentrated under
reduced pressure to yield the title compound (25 mg, 30%) as an
off-white powder: .sup.1H NMR (500 MHz, DMSO-d.sub.6) 10.79 (br s,
1H), 8.87 (d, J=6.5 Hz, 1H), 8.41 (s, 1H), 7.90-7.78 (m, 2H), 7.61
(d, J=7.5 Hz, 1H), 7.53-7.49 (m, 2H), 7.42-7.35 (m, 1H), 7.00 (dd,
J=8.5, 1.5 Hz, 1H), 6.15 (d, J=2.5 Hz, 1H), 6.12 (dd, J=7.5, 2.5
Hz, 1H), 5.43 (s, 2H), 4.62 (d, J=14.0 Hz, 1H), 4.29 (dd, J=14.0,
7.5 Hz, 1H), 3.80-3.75 (m, 1H), 3.69 (s, 3H), 3.55-3.46 (m, 1H),
3.23-3.16 (m, 2H), 2.97 (s, 3H); ESI MS m/z 440 [M+H].sup.+.
Example 118
Preparation of
1-(2-Acetyl-9-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-7-yl)-4-(be-
nzyloxy)pyridin-2(1H)-one
##STR00297##
[0594] AcCl (0.023 mL, 0.32 mmol) was added to a solution of
4-(benzyloxy)-1-(9-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-7-yl)p-
yridin-2(1H)-one dihydrochloride (100 mg, 0.216 mmol), DMAP (5 mg,
0.04 mmol) and Et.sub.3N (0.09 mL, 0.6 mmol) in CH.sub.2Cl.sub.2
(20 mL) under N.sub.2, and the resulting solution was stirred at
25.degree. C. for 4 h. H.sub.2O was added to the solution, and the
phases were separated. The organic phase was washed with saturated
NH.sub.4Cl solution, dried over Na.sub.2SO.sub.4 and concentrated
under reduced pressure. Flash chromatography (silica gel, (1:1
EtOAc/hexanes)/(9:0.9:0.1 CH.sub.2Cl.sub.2/MeOH/NH.sub.4OH), 100:0
to 0:100) afforded the title compound (61 mg, 66%) as a mixture of
rotomers as a white powder: mp 80-82.degree. C.; .sup.1H NMR (500
MHz, DMSO-d.sub.6) .delta. 7.56 (d, J=7.5 Hz, 1H), 7.52-7.35 (m,
7H), 6.94 (dd, J=8.0, 1.5 Hz, 1H), 6.12-6.08 (m, 1H), 5.97 (d,
J=3.0 Hz, 1H), 5.15 (s, 2H), 4.77-4.72 (m, 2H), 3.82-3.72 (m, 2H),
3.69-3.65 (m, 3H), 3.82-2.78 (m, 1.3H), 2.71-2.68 (m, 0.7H), 2.16
(s, 3H); ESI MS m/z 428 [M+H].sup.+.
Example 119
Preparation of
1-(2-Acetyl-5-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-7-yl)-4-(5--
(trifluoromethyl)pyridin-2-yl)pyridin-2(1H)-one
##STR00298##
[0596] AcCl (0.03 mL, 0.4 mmol) was added to a solution of
1-(5-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-7-yl)-4-(5-(trifluor-
omethyl)pyridin-2-yl)pyridin-2(1H)-one (125 mg, 0.294 mmol), DMAP
(7 mg, 0.06 mmol) and Et.sub.3N (0.08 mL, 0.6 mmol) in
CH.sub.2Cl.sub.2 (10 mL) under N.sub.2, and the resulting solution
was stirred at 25.degree. C. for 17 h. H.sub.2O was added to the
solution, and the phases were separated. The organic phase was
washed with saturated NH.sub.4Cl solution, dried over
Na.sub.2SO.sub.4 and concentrated under reduced pressure. Flash
chromatography (silica gel, (1:1 EtOAc/hexanes)/(9:0.9:0.1
CH.sub.2Cl.sub.2/MeOH/NH.sub.4OH), 100:0 to 0:100) afforded the
title compound (116 mg, 84%) as a mixture of rotomers as a white
powder: mp 232-236.degree. C.; .sup.1H NMR (500 MHz, DMSO-d.sub.6)
.delta. 9.15 (s, 1H), 8.38 (d, J=8.3 Hz, 1H), 8.35 (d, J=8.3 Hz,
1H), 7.84 (d, J=7.5 Hz, 1H), 7.59-7.54 (m, 2H), 7.28 (d, J=1.5 Hz,
1H), 7.08-7.03 (m, 2H), 4.70 (s, 0.8H), 4.68 (s, 1.2H), 3.88 (t,
J=5.5 Hz, 0.8H), 3.83 (t, J=5.5 Hz, 1.2H), 3.67 (s, 3H), 2.97-2.91
(m, 1.2H), 2.86-2.81 (m, 0.8H), 2.15 (s, 1.8H), 2.13 (s, 1.2H); ESI
MS m/z 467 [M+H].sup.+.
Example 120
Preparation of
1-(2-Ethyl-5-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-7-yl)-4-(5-(-
trifluoromethyl)pyridin-2-yl)pyridin-2(1H)-one dihydrochloride
##STR00299##
[0598] 2-Picoline borane (63 mg, 0.59 mmol) was added to a
suspension of
1-(5-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-7-yl)-4-(5-(trifluor-
omethyl)pyridin-2-yl)pyridin-2(1H)-one dihydrochloride (98 mg, 0.20
mmol) and acetylaldhyde (0.03 mL, 1 mmol) in 9:1
CH.sub.2Cl.sub.2/AcOH (10 mL) under N.sub.2, and the resulting
solution was stirred under N.sub.2 for 4 h. Acetylaldhyde (0.03 mL,
1 mmol) was added to the solution under N.sub.2 and the resulting
solution was stirred at 25.degree. C. for 15 min. The solution was
neutralized with saturated NaHCO.sub.3 solution, and the phases
were separated. The organic phase was dried over Na.sub.2SO.sub.4
and concentrated under reduced pressure. Flash chromatography
(silica gel, (1:1 EtOAc/hexanes)/(9:0.9:0.1
CH.sub.2Cl.sub.2/MeOH/NH.sub.4OH), 100:0 to 0:100) afforded 67 mg
of a yellow powder. 2N HCl in Et.sub.2O (0.15 mL, 0.330 mmol) was
added to a solution of the yellow powder in 1:1
MeOH/CH.sub.2Cl.sub.2 (10 mL) under N.sub.2, and the resulting
solution was stirred at 25.degree. C. for 15 min. Et.sub.2O was
added to the solution, and the resulting suspension was filtered
under N.sub.2 to afford the title compound (78 mg, 75%) as a yellow
powder: mp 300-302.degree. C.; .sup.1H NMR (500 MHz, DMSO-d.sub.6)
.delta. 10.16 (br s, 1H), 9.15 (s, 1H), 8.42-8.35 (m, 2H), 7.85 (d,
J=7.0 Hz, 1H), 7.65 (d, J=1.5 Hz, 1H), 7.61 (d, J=8.5 Hz, 1H), 7.30
(d, J=2.0 Hz, 1H), 7.13 (dd, J=8.5, 1.5 Hz, 1H), 7.08 (dd, J=7.5,
2.0 Hz, 1H), 4.70 (d, J=12.5 Hz, 1H), 4.32 (dd, J=14.5, 8.0 Hz,
1H), 3.91-3.83 (m, 1H), 3.72 (s, 3H), 3.52-3.43 (m, 1H), 3.41-3.30
(m, 2H), 3.24-3.16 (m, 2H), 1.38 (t, J=7.3 Hz, 3H); ESI MS m/z 453
[M+H].sup.+.
Example 121
Preparation of
1-(2-Isopropyl-5-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-7-yl)-4--
(5-(trifluoromethyl)pyridin-2-yl)pyridin-2(1H)-one
dihydrochloride
##STR00300##
[0600] 2-Picoline borane (87 mg, 0.81 mmol) was added to a
suspension of
1-(5-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-7-yl)-4-(5-(trifluor-
omethyl)pyridin-2-yl)pyridin-2(1H)-one dihydrochloride (134 mg,
0.27 mmol) and acetone (0.10 mL, 1.4 mmol) in 9:1
CH.sub.2Cl.sub.2/AcOH (10 mL) under N.sub.2, and the resulting
solution was stirred for 24 h. Acetone (1 mL) was added to the
solution and the resulting solution was stirred at 25.degree. C.
for 24 h. Acetone (1 mL) and 2-picoline borane (87 mg, 0.81 mmol)
were added to the solution, and the resulting solution was stirred
at reflux for 24 h. The solution was cooled, H.sub.2O was added,
and the reaction mixture was neutralized with saturated NaHCO.sub.3
solution. The phases were separated, and the organic phase was
dried over Na.sub.2SO.sub.4 and concentrated under reduced
pressure. Flash chromatography (silica gel, (1:1
EtOAc/hexanes)/(9:0.9:0.1 CH.sub.2Cl.sub.2/MeOH/NH.sub.4OH), 100:0
to 0:100) afforded 88 mg of a yellow powder. 2N HCl in Et.sub.2O
(0.15 mL, 0.330 mmol) was added to a solution of the yellow powder
in 1:1 MeOH/CH.sub.2Cl.sub.2 (10 mL) under N.sub.2, and the
resulting solution was stirred at 25.degree. C. for 30 min.
Et.sub.2O was added to the solution, and the resulting solid was
collected by filtration under N.sub.2. The solid was washed with
Et.sub.2O to afford the title compound (25 mg, 17%) as a yellow
powder: .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 9.80 (br s,
1H), 9.15 (d, J=2.0 Hz, 1H), 8.42-8.35 (m, 2H), 7.85 (d, J=7.5 Hz,
1H), 7.66 (d, J=1.5 Hz, 1H), 7.62 (d, J=8.5 Hz, 1H), 7.30 (d, J=2.0
Hz, 1H), 7.14 (dd, J=8.5, 1.5 Hz, 1H), 7.08 (dd, J=7.5, 2.0 Hz,
1H), 4.58 (d, J=13.0 Hz, 1H), 4.48-4.40 (m, 1H), 3.90-3.82 (m, 1H),
3.78-3.70 (m, 4H), 3.51-3.42 (m, 1H), 3.38-3.15 (m, 2H), 1.45-1.36
(m, 6H); ESI MS m/z 467 [M+H].sup.+.
Example 122
Preparation of
4-(4-Methoxyphenyl)-1-(9-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol--
7-yl)pyridin-2(1H)-one hydrochloride
a) 4-(4-Methoxyphenyl)pyridin-2(1H)-one
##STR00301##
[0602] A suspension of 4-bromo-2-methoxypyridine (1.22 g, 6.49
mmol), 4-methoxyphenyl boronic acid (1.97 g, 13.0 mmol),
PdCl.sub.2(dppf) (530 mg, 0.649 mmol) and K.sub.2CO.sub.3 (1.79 g,
13.0 mmol) in DMSO (10 mL) was degassed under reduced pressure for
45 min. The suspension was put under Ar and stirred at 95.degree.
C. for 2 h. The suspension was cooled, H.sub.2O was added, and the
suspension was filtered to afford a light colored solid. Flash
chromatography (silica gel, hexanes/(1:1 EtOAc/hexanes), 100:0 to
0:100) afforded 1.10 g of a white powder. The white powder was
diluted with concentrated HCl solution (50 mL) and stirred at
reflux for 12 h. The reaction was cooled and concentrated under
reduced pressure. Flash chromatography (silica gel, (1:1
EtOAc/hexanes)/(9:0.9:0.1 CH.sub.2Cl.sub.2/MeOH/NH.sub.4OH), 100:0
to 0:100) afforded the title compound (313 mg, 24%) as a white
powder: .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 11.47 (s, 1H),
7.65 (d, J=8.7 Hz, 2H), 7.38 (d, J=6.8 Hz, 1H), 7.01 (d, J=8.7 Hz,
2H), 6.51 (br s, 1H), 6.47 (d, J=6.8 Hz, 1H), 3.79 (s, 3H).
b) tert-Butyl
7-(4-(4-methoxyphenyl)-2-oxopyridin-1(2H)-yl)-9-methyl-3,4-dihydro-1H-pyr-
ido[3,4-b]indole-2(9H)-carboxylate
##STR00302##
[0604] A suspension of 4-(4-methoxyphenyl)pyridin-2(1H)-one (103
mg, 0.510 mmol), tert-butyl
7-bromo-9-methyl-3,4-dihydro-1H-pyrido[3,4-b]indole-2(9H)-carboxylate
(223 mg, 0.612 mmol), CuI (116 mg, 0.612 mmol), 8-hydroxyquinoline
(15 mg, 0.10 mmol) and Cs.sub.2CO.sub.3 (183 mg, 0.561 mmol) in
DMSO (10 mL) was degassed under reduced pressure for 45 min. The
suspension was put under Ar and stirred at 135.degree. C.
overnight. The suspension was cooled, 9:0.9:0.1
CH.sub.2Cl.sub.2/MeOH/NH.sub.4OH was added, and the resulting
suspension was stirred at 25.degree. C. for 30 min. The suspension
was passed through a plug of silica gel, and the filtrate was
washed with brine. The resulting solution was dried over
Na.sub.2SO.sub.4 and concentrated under reduced pressure. Flash
chromatography (silica gel, (1:1 EtOAc/hexanes)/(9:0.9:0.1
CH.sub.2Cl.sub.2/MeOH/NH.sub.4OH), 100:0 to 0:100) afforded the
title compound (98 mg, 40%) as a yellow powder: .sup.1H NMR (300
MHz, CDCl.sub.3) .delta. 7.64-7.53 (m, 3H), 7.46 (d, J=7.2 Hz, 1H),
7.36 (br s, 1H), 7.08 (dd, J=8.1, 1.5 Hz, 1H), 7.01 (d, J=8.7 Hz,
2H), 6.87 (d, J=1.8 Hz, 1H), 6.51 (dd, J=7.2, 1.8 Hz, 1H),
4.68-4.60 (m, 2H), 3.88 (s, 3H), 3.82-3.73 (m, 2H), 3.65 (s, 3H),
2.85-2.78 (m, 2H), 1.52 (s, 9H).
c)
4-(4-Methoxyphenyl)-1-(9-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indo-
l-7-yl)pyridin-2(1H)-one hydrochloride
##STR00303##
[0606] TFA (1 ml) was added to a solution of tert-butyl
7-(4-(4-methoxyphenyl)-2-oxopyridin-1
(2H)-yl)-9-methyl-3,4-dihydro-1H-pyrido[3,4-b]indole-2(9H)-carboxylate
(98 mg, 0.20 mmol) in CH.sub.2Cl.sub.2 (10 mL) under N.sub.2 and
the resulting solution was stirred for 2.5 h at 25.degree. C.
Saturated NaHCO.sub.3 solution was added, and the phases were
separated. The organic phase was dried over Na.sub.2SO.sub.4 and
concentrated under reduced pressure. Flash chromatography (silica
gel, (1:1 EtOAc/hexanes)/(9:0.9:0.1
CH.sub.2Cl.sub.2/MeOH/NH.sub.4OH), 100:0 to 0:100) afforded 49 mg
of a white powder. 1N HCl in Et.sub.2O (0.07 mL, 0.07 mmol) was
added to a solution of the white powder in CH.sub.2Cl.sub.2 (10 mL)
under N.sub.2, and the resulting solution was stirred at 25.degree.
C. for 1 h. The solution was concentrated under reduced pressure to
yield the title compound (47 mg, 55%) as a yellow powder: mp
306-308.degree. C.; .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta.
9.43 (br s, 2H), 7.76 (d, J=9.0 Hz, 2H), 7.70 (d, J=7.0 Hz, 1H),
7.61-7.58 (m, 2H), 7.11-7.05 (m, 3H), 6.73 (d, J=2.0 Hz, 1H), 6.68
(dd, J=7.0, 2.0 Hz, 1H), 4.51-4.45 (m, 2H), 3.83 (s, 3H), 3.70 (s,
3H), 3.48-3.42 (m, 2H), 2.99 (t, J=6.0 Hz, 2H); ESI MS m/z 386
[M+H].sup.+.
Example 123
Preparation of
1-(5-Methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-7-yl)-4-(4-(methylth-
io)phenyl)pyridin-2(1H)-one hydrochloride
a) 4-(4-(Methylthio)phenyl)pyridin-2(1H)-one
##STR00304##
[0608] A suspension of 4-bromo-2-methoxypyridine (1.225 g, 6.511
mmol), 4-methylthiophenyl boronic acid (2.188 g, 13.02 mmol),
PdCl.sub.2(dppf) (531 mg, 0.651 mmol) and K.sub.2CO.sub.3 (1.797 g,
13.02 mmol) in DMSO (10 mL) was degassed under reduced pressure for
25 min. The suspension was put under N.sub.2 and stirred at
95.degree. C. for 16 h. The suspension was cooled, H.sub.2O was
added, and the suspension was filtered to afford a light colored
solid. Flash chromatography (silica gel, hexanes/(1:1
EtOAc/hexanes), 100:0 to 0:100) afforded 1.10 g of a white powder.
The white powder was diluted with concentrated HCl solution (50 mL)
and stirred at reflux for 24 h. The reaction was cooled and
concentrated under reduced pressure. The residue was neutralized
with saturated NaHCO.sub.3 solution, and the solid was collected by
filtration. The solid was washed with H.sub.2O to afford the title
compound (1.103 g, 71%) as a tan solid: .sup.1H NMR (300 MHz,
DMSO-d.sub.6) .delta. 7.65 (d, J=8.4 Hz, 2H), 7.43 (d, J=6.9 Hz,
1H), 7.34 (d, J=8.4 Hz, 2H), 6.57 (d, J=1.7 Hz, 1H), 6.50 (dd,
J=6.9, 1.7 Hz, 1H), 3.34 (s, 3H).
b)
1-(5-Methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-7-yl)-4-(4-(methyl-
thio)phenyl)pyridine-2(1H)-one hydrochloride
##STR00305##
[0610] A suspension of 4-(4-(methylthio)phenyl)pyridine-2(1H)-one
(134 mg, 0.615 mmol), tert-butyl
7-bromo-5-methyl-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate
(247 mg, 0.676 mmol), CuI (140 mg, 0.738 mmol), 8-hydroxyquinoline
(18 mg, 0.12 mmol) and Cs.sub.2CO.sub.3 (220 mg, 0.676 mmol) in
DMSO (10 mL) was degassed under reduced pressure for 45 min. The
suspension was put under N.sub.2 and stirred at 135.degree. C.
overnight. The suspension was cooled, 9:0.9:0.1
CH.sub.2Cl.sub.2/MeOH/NH.sub.4OH was added, and the resulting
suspension was stirred at 25.degree. C. for 30 min. The suspension
was passed through a plug of silica gel, and the filtrate was
washed with brine. The resulting solution was dried over
Na.sub.2SO.sub.4 and concentrated under reduced pressure. Flash
chromatography (silica gel, (1:1 EtOAc/hexanes)/(9:0.9:0.1
CH.sub.2Cl.sub.2/MeOH/NH.sub.4OH), 100:0 to 0:100) afforded 179 mg
of a yellow powder. 2N HCl in Et.sub.2O (300 mL) was added to a
solution of the yellow powder in 1:1 CH.sub.2Cl.sub.2/MeOH (8 mL)
under N.sub.2, and the resulting suspension was stirred at
25.degree. C. for 17 h. The suspension was filtered and the solid
was washed with CH.sub.2Cl.sub.2 and 99:1 CH.sub.2Cl.sub.2/MeOH to
afford the title compound (41 mg, 15%) as an off-white solid: mp
306-310.degree. C.; .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta.
9.27 (br s, 2H), 7.77-7.71 (m, 3H), 7.61-7.58 (m, 2H), 7.39 (d,
J=8.5 Hz, 2H), 7.09 (dd, J=8.5, 2.0 Hz, 1H), 6.78 (d, J=2.0 Hz,
1H), 6.69 (dd, J=7.5, 2.0 Hz, 1H), 4.36 (br s, 2H), 3.70 (s, 3H),
3.56-3.51 (m, 2H), 3.10 (t, J=5.5 Hz, 2H), 2.54 (s, 3H); ESI MS m/z
402 [M+H].sup.+.
Example 124
Preparation of
1-(9-Methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-7-yl)-4-(4-(methylth-
io)phenyl)pyridine-2(1H)-one hydrochloride
a) tert-Butyl
9-methyl-7-(4-(4-(methylthio)phenyl)-2-oxopyridin-1(2H)-yl)-3,4-dihydro-1-
H-pyrido[3,4-b]indole-2(9H)-carboxylate
##STR00306##
[0612] A suspension of 4-(4-(methylthio)phenyl)pyridine-2(1H)-one
(110 mg, 0.505 mmol), tert-butyl
7-bromo-9-methyl-3,4-dihydro-1H-pyrido[3,4-b]indole-2(9H)-carboxylate
(203 mg, 0.555 mmol), CuI (115 mg, 0.606 mmol), 8-hydroxyquinoline
(15 mg, 0.10 mmol) and Cs.sub.2CO.sub.3 (181 mg, 0.555 mmol) in
DMSO (10 mL) was degassed under reduced pressure for 45 min. The
suspension was put under N.sub.2 and stirred at 135.degree. C.
overnight. The suspension was cooled, 9:0.9:0.1
CH.sub.2Cl.sub.2/MeOH/NH.sub.4OH was added, and the resulting
suspension was stirred at 25.degree. C. for 30 min. The suspension
was passed through a plug of silica gel, and the filtrate was
washed with brine. The resulting solution was dried over
Na.sub.2SO.sub.4 and concentrated under reduced pressure. Flash
chromatography (silica gel, (1:1 EtOAc/hexanes)/(9:0.9:0.1
CH.sub.2Cl.sub.2/MeOH/NH.sub.4OH), 100:0 to 0:100) afforded the
title compound (97 mg, 38%) as an off-white powder: .sup.1H NMR
(500 MHz, CDCl.sub.3) .delta. 7.61-7.54 (m, 3H), 7.48 (d, J=7.5 Hz,
1H), 7.38-7.32 (m, 3H), 7.08 (dd, J=8.5, 2.0 Hz, 1H), 6.89 (d,
J=2.0 Hz, 1H), 6.50 (dd, J=7.5, 2.0 Hz, 1H), 4.70-4.61 (m, 2H),
3.81-3.73 (m, 2H), 3.65 (s, 3H), 2.84-2.78 (m, 2H), 2.54 (s, 3H),
1.52 (s, 9H).
b)
1-(9-Methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-7-yl)-4-(4-(methyl-
thio)phenyl)pyridine-2(1H)-one hydrochloride
##STR00307##
[0614] TFA (1 ml) was added to a solution of tert-butyl
9-methyl-7-(4-(4-(methylthio)phenyl)-2-oxopyridin-1(2H)-yl)-3,4-dihydro-1-
H-pyrido[3,4-b]indole-2(9H)-carboxylate (97 mg, 0.19 mmol) in
CH.sub.2Cl.sub.2 (10 mL) under N.sub.2, and the resulting solution
was stirred for 1.5 h at 25.degree. C. Saturated NaHCO.sub.3
solution was added to the reaction mixture, and the resulting
suspension was filtered. Flash chromatography (silica gel, (1:1
EtOAc/hexanes)/(9:0.9:0.1 CH.sub.2Cl.sub.2/MeOH/NH.sub.4OH), 100:0
to 0:100) afforded 35 mg of a yellow powder. 2N HCl in Et.sub.2O
(0.09 mL, 0.09 mmol) was added to a solution of the yellow solid in
CH.sub.2Cl.sub.2 (10 mL) under N.sub.2, and the resulting solution
was stirred at 25.degree. C. for 15 min. Et.sub.2O was added to the
solution, and the resulting suspension was filtered under N.sub.2.
The solid was washed with Et.sub.2O to afford the title compound
(37 mg, 17%) as a yellow powder: mp 300-304.degree. C.; .sup.1H NMR
(500 MHz, DMSO-d.sub.6) .delta. 9.32 (br s, 2H), 7.75 (d, J=8.5 Hz,
2H), 7.73 (d, J=7.3 Hz, 1H), 7.62-7.58 (m, 2H), 7.38 (d, J=8.5 Hz,
2H), 7.10 (dd, J=8.5, 2.0 Hz, 1H), 6.78 (d, J=2.0 Hz, 1H), 6.69
(dd, J=7.3, 2.0 Hz, 1H), 4.49 (br s, 2H), 3.70 (s, 3H), 3.60-3.32
(m, 2H), 2.99 (t, J=5.5 Hz, 2H), 2.54 (s, 3H); ESI MS m/z 402
[M+H].sup.+.
Example 125
Preparation of
4-(Benzyloxy)-1-(3,3,9-trimethyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-
-7-yl)pyridine-2(1H)-one hydrochloride
a) 4-(1,3-Dioxolan-2-yl)-2-methylbutan-2-amine
[0615] Beilstein Registry Number 9387059
##STR00308##
[0616] This compound was prepared in accordance with the procedure
of Hinderaker, et al., Protien Sci. 2003, 12, 1188-1194.
b) tert-Butyl
7-bromo-3,3-dimethyl-3,4-dihydro-1H-pyrido[3,4-b]indole-2(9H)-carboxylate
##STR00309##
[0618] A mixture of 4-(1,3-dioxolan-2-yl)-2-methylbutan-2-amine
(3.28 g, 20.4 mmol), 3-bromophenylhydrazine hydrochloride (4.34 g,
19.4 mmol) and ZnCl.sub.2 (2.90 g, 21.3 mmol) was stirred at
180.degree. C. for 2.5 h. The mixture was cooled to 120.degree. C.,
MeOH was added, and the resulting suspension was concentrated on
silica gel. Flash chromatography (silica gel, (1:1
EtOAc/hexanes)/(9:0.9:0.1 CH.sub.2Cl.sub.2/MeOH/NH.sub.4OH), 100:0
to 0:100) afforded 4.20 g of a red amorphous solid. Glyoxylic acid
(1.87 g, 20.4 mmol) was added to a suspension of the red amorphous
solid in 4:2:1 H.sub.2O/MeOH/(concentrated HCl solution) (70 mL),
and the resulting solution was stirred at 25.degree. C. for 30 min.
The solution was adjusted to pH 3.5 with 6N NaOH in H.sub.2O, and
the resulting solution was stirred at 25.degree. C. overnight. The
solution was adjusted to pH 5 with saturated NaHCO.sub.3 solution
and the suspension was filtered. The solid was diluted with 2N HCl
in H.sub.2O, and the resulting suspension was stirred at reflux for
2.5 h. The solution was concentrated under reduced pressure and
neutralized with saturated NaHCO.sub.3 solution. The resulting
suspension was filtered, and the solid was dissolved in
CH.sub.2Cl.sub.2. The resulting solution was dried over
Na.sub.2SO.sub.4 and concentrated under reduced pressure. Flash
chromatography (silica gel, (1:1 EtOAc/hexanes)/(9:0.9:0.1
CH.sub.2Cl.sub.2/MeOH/NH.sub.4OH), 100:0 to 0:100) afforded 577 mg
of a white solid. Boc.sub.2O (2.71 g, 12.4 mmol) was added to a
suspension of the white solid and K.sub.2CO.sub.3 (571 mg, 4.14
mmol) in 1:1 H.sub.2O/i-PrOH (40 mL), and the resulting suspension
was stirred at 25 C for 5.5 h. The suspension was concentrated
under reduced pressure, and the residue was diluted with water. The
solid was collected by filtration, and flash chromatography (silica
gel, hexanes/(1:1 EtOAc/hexanes), 100:0 to 0:100) afforded the
title compound (200 mg, 3%) as a white solid: .sup.1H NMR (300 MHz,
CDCl.sub.3) .delta. 7.83 (br s, 1H), 7.47 (br s, 1H), 7.31 (br d,
J=8.7 Hz, 1H), 7.20 (br d, J=8.7 Hz, 1H), 4.62 (br s, 2H), 2.77 (br
s, 2H), 1.53 (s, 6H), 1.48 (s, 9H).
c) tert-Butyl
7-bromo-3,3,9-trimethyl-3,4-dihydro-1H-pyrido[3,4-b]indole-2(9H)-carboxyl-
ate
##STR00310##
[0620] NaH (60% dispersion in oil, 42 mg, 1.1 mmol) was added to a
solution of tert-butyl
7-bromo-3,3-dimethyl-3,4-dihydro-1H-pyrido[3,4-b]indole-2(9H)-carboxylate
(200 mg, 0.528 mmol) in DMF (10 mL) under N.sub.2, and the
resulting suspension was stirred at 25.degree. C. for 30 min. MeI
(0.05 mL, 0.8 mmol) was added to the suspension, and the resulting
suspension was stirred at 25.degree. C. for 1 h. H.sub.2O was
added, and the resulting solid was collected by filtration. Flash
chromatography (silica gel, hexanes/(1:1 EtOAc/hexanes), 100:0 to
0:100) afforded the title compound (145 mg, 70%) as a white solid:
.sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 7.43 (d, J=1.5 Hz, 1H),
7.30 (d, J=8.3 Hz, 1H), 7.18 (dd, J=8.3, 1.5 Hz, 1H), 4.62 (s, 2H),
3.61 (s, 3H), 2.77 (s, 2H), 1.52 (s, 6H), 1.49 (s, 9H).
d)
4-(Benzyloxy)-1-(3,3,9-trimethyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]ind-
ol-7-yl)pyridine-2(1H)-one hydrochloride
##STR00311##
[0622] A suspension of 4-(benzyloxy)pyridine-2(1H)-one (67 mg, 0.34
mmol), tert-butyl
7-bromo-3,3,9-trimethyl-3,4-dihydro-1H-pyrido[3,4-b]indole-2(9H)-carboxyl-
ate (145 mg, 0.369 mmol), CuI (76 mg, 0.40 mmol),
8-hydroxyquinoline (10 mg, 0.07 mmol) and Cs.sub.2CO.sub.3 (120 mg,
0.369 mmol) in DMSO (10 mL) was degassed under reduced pressure for
45 min. The suspension was put under Ar and stirred at 135.degree.
C. overnight. The suspension was cooled, 9:0.9:0.1
CH.sub.2Cl.sub.2/MeOH/NH.sub.4OH (10 mL) was added, and the
resulting suspension was stirred at 25.degree. C. for 30 min. The
suspension was passed through a plug of silica gel, and the
filtrate was washed with brine. The resulting solution was dried
over Na.sub.2SO.sub.4 and concentrated under reduced pressure.
Flash chromatography (silica gel, (1:1 EtOAc/hexanes)/(9:0.9:0.1
CH.sub.2Cl.sub.2/MeOH/NH.sub.4OH), 100:0 to 0:100) afforded 28 mg
of a white solid. TFA (1 ml) was added to a solution of the white
solid in CH.sub.2Cl.sub.2 (10 mL) under N.sub.2, and the resulting
solution was stirred for 1 h at 25.degree. C. Saturated NaHCO.sub.3
solution was added to the solution, and the phases were separated.
The aqueous phase was extracted with CH.sub.2Cl.sub.2, and the
combined organic extracts were dried over Na.sub.2SO.sub.4. The
resulting solution was concentrated under reduced pressure. Flash
chromatography (silica gel, (1:1 EtOAc/hexanes)/(9:0.9:0.1
CH.sub.2Cl.sub.2/MeOH/NH.sub.4OH), 100:0 to 0:100) afforded 14 mg
of a white powder. 2N HCl in Et.sub.2O (0.01 mL, 0.02 mmol) was
added to a solution of the white solid in CH.sub.2Cl.sub.2 (10 mL)
under N.sub.2, and the resulting solution was stirred at 25.degree.
C. for 30 min. The solution was concentrated under reduced pressure
to afford the title compound (5.2 mg, 3%) as a white powder: mp
184-186.degree. C.; .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta.
9.34 (br s, 2H), 7.57 (d, J=7.5 Hz, 1H), 7.53-7.50 (m, 2H),
7.49-7.41 (m, 4H), 7.40-7.35 (m, 1H), 6.99 (dd, J=8.0, 2.0 Hz, 1H),
6.11 (dd, J=8.0, 2.5 Hz, 1H), 5.98 (d, J=2.5 Hz, 1H), 5.16 (s, 2H),
4.50 (br s, 2H), 3.70 (s, 3H), 2.89 (s, 2H), 1.42 (s, 6H); ESI MS
m/z 414 [M+H].sup.+.
Example 126
Preparation of
4-(4-Methoxy-2-methylphenyl)-1-(9-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-
-b]indol-7-yl)pyridin-2(1H)-one hydrochloride
a) 4-(4-Methoxy-2-methylphenyl)pyridin-2(1H)-one
##STR00312##
[0624] A suspension of 4-bromo-2-methoxypyridine (341 mg, 1.82
mmol), 4-methyloxy-2-methylphenyl boronic acid (452 mg, 2.72 mmol),
Pd(PPh.sub.3).sub.2Cl.sub.2 (133 mg, 0.182 mmol) and
K.sub.2CO.sub.3 (503 mg, 3.64 mmol) in DMSO (10 mL) was degassed
under reduced pressure for 1 h. The suspension was put under Ar and
stirred at 90.degree. C. for 2 h. The suspension was cooled,
H.sub.2O was added, and the suspension was filtered to afford a
light colored solid. Flash chromatography (silica gel, hexanes/(1:1
EtOAc/hexanes), 100:0 to 0:100) afforded 235 mg of a white powder.
The white powder was diluted with concentrated HCl solution (20 mL)
and stirred at reflux for 24 h. The reaction was cooled and
concentrated under reduced pressure. The residue was neutralized
with saturated NaHCO.sub.3 solution, and the solid was collected by
filtration. Flash chromatography (silica gel, (1:1
EtOAc/hexanes)/(9:0.9:0.1 CH.sub.2Cl.sub.2/MeOH/NH.sub.4OH), 100:0
to 0:100) afforded the title compound (62 mg, 16%) as a white
powder: .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 11.54 (br s,
1H), 7.35 (d, J=6.9 Hz, 1H), 7.13 (d, J=8.4 Hz, 1H), 6.87-6.76 (m,
2H), 6.15-6.09 (m, 2H), 3.75 (s, 3H), 1.97 (s, 3H).
b)
4-(4-Methoxy-2-methylphenyl)-1-(9-methyl-2,3,4,9-tetrahydro-1H-pyrido[3-
,4-b]indol-7-yl)pyridin-2(1H)-one hydrochloride
##STR00313##
[0626] A suspension of
4-(4-methoxy-2-methylphenyl)pyridin-2(1H)-one (62 mg, 0.29 mmol),
tert-butyl
7-bromo-3,3,9-trimethyl-3,4-dihydro-1H-pyrido[3,4-b]indole-2(9H)-carboxyl-
ate (126 mg, 0.344 mmol), CuI (66 mg, 0.34 mmol),
8-hydroxyquinoline (8 mg, 0.06 mmol) and Cs.sub.2CO.sub.3 (103 mg,
0.316 mmol) in DMSO (10 mL) was degassed under reduced pressure for
45 min. The suspension was put under Ar and stirred at 135.degree.
C. overnight. The suspension was cooled, 9:0.9:0.1
CH.sub.2Cl.sub.2/MeOH/NH.sub.4OH (10 mL) was added, and the
resulting suspension was stirred at 25.degree. C. for 1 h. The
suspension was passed through a plug of silica gel, and the
filtrate was washed with brine. The resulting solution was dried
over Na.sub.2SO.sub.4 and concentrated under reduced pressure.
Flash chromatography (silica gel, (1:1 EtOAc/hexanes)/(9:0.9:0.1
CH.sub.2Cl.sub.2/MeOH/NH.sub.4OH), 100:0 to 0:100) afforded 52 mg
of a yellow amorphous solid. TFA (1 ml) was added to a solution of
the yellow amorphous solid in CH.sub.2Cl.sub.2 (10 mL) under
N.sub.2 and the resulting solution was stirred for 1 h at
25.degree. C. Saturated NaHCO.sub.3 solution was added to the
solution, and the phases were separated. The aqueous phase was
extracted with CH.sub.2Cl.sub.2, and the combined organic extracts
were dried over Na.sub.2SO.sub.4. The resulting solution was
concentrated under reduced pressure. Flash chromatography (silica
gel, (1:1 EtOAc/hexanes)/(9:0.9:0.1
CH.sub.2Cl.sub.2/MeOH/NH.sub.4OH), 100:0 to 0:100) afforded 19 mg
of a viscous oil. 1N HCl in Et.sub.2O (0.05 mL, 0.05 mmol) was
added to a solution of the viscous oil in CH.sub.2Cl.sub.2 (10 mL)
under N.sub.2, and the resulting solution was stirred at 25.degree.
C. for 30 min. The solution was concentrated under reduced pressure
to afford the title compound (16 mg, 13%) as a white powder: mp
308-310.degree. C.; .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta.
9.44 (br s, 2H), 7.67 (d, J=7.0 Hz, 1H), 7.63 (d, J=1.5 Hz, 1H),
7.60 (d, J=8.0 Hz, 1H), 7.25 (d, J=8.5 Hz, 1H), 7.11 (dd, J=8.5,
1.5 Hz, 1H), 6.92 (d, J=2.5 Hz, 1H), 6.88 (dd, J=8.5, 2.5 Hz, 1H),
6.37 (s, 1H), 6.34 (dd, J=7.5, 1.5 Hz, 1H), 4.89 (br s, 2H), 3.79
(s, 3H), 3.70 (s, 3H), 3.49-3.43 (m, 2H), 2.99 (t, J=6.0 Hz, 2H),
2.36 (s, 3H); ESI MS m/z 400 [M+H].sup.+.
Example 127
Preparation of
4-(Benzyloxy)-1-(9-methyl-2-(2-(pyrrolidin-1-yl)ethyl)-2,3,4,9,-tetrahydr-
o-1H-pyrido[3,4-b]indol-7-yl)pyridine-2(1H)-one hydrochloride
a)
4-(Benzyloxy)-1-(9-methyl-2-(2-(pyrrolidin-1-yl)ethyl)-2,3,4,9,-tetrahy-
dro-1H-pyrido[3,4-b]indol-7-yl)pyridine-2(1H)-one
##STR00314##
[0628] 1-(2-Chloroethyl)pyrrolidine hydrochloride (50 mg, 0.29
mmol) was added to a solution of
4-(benzyloxy)-1-(9-methyl-2,3,4,9,-tetrahydro-1H-pyrido[3,4-b]indol-7-yl)-
pyridine-2(1H)-one (0.10 g, 0.27 mmol) and diisoproylethyl amine
(0.14 mL) in EtOH (4 mL), and the resulting solution was heated at
65.degree. C. for 2 h. The reaction mixture was concentrated to
dryness under reduced pressure. Purification by flash column
chromatography (40 g ISCO column, CH.sub.2Cl.sub.2/(80:18:2
CH.sub.2Cl.sub.2/MeOH/NH.sub.4OH), 100:0 hold 5 column volumes
increased to to 0:100 over 20 column volumes) followed by
preparative TLC (Analtech, 20.times.20 cm, 1000 microns, uV 254,
80:18:2 CH.sub.2Cl.sub.2/MeOH/NH.sub.4OH) followed by preparative
HPLC (Phenomenex Luna C18 (2), 250.0.times.21.2 mm, 10 micron,
H.sub.2O with 0.05% TFA and CH.sub.3CN with 0.05% TFA) and
filtration through SCX-2 column gave the title compound (10 mg, 7%)
as a yellow solid: .sup.1H NMR (500 MHz, CD.sub.3OD) .delta. 7.54
(d, J=7.5 Hz, 1H), 7.51 (d, J=8.5 Hz, 1H), 7.46-7.33 (m, 6H), 6.96
(dd, J=8.0, 1.5 Hz, 1H), 6.26 (dd, J=7.5, 2.5, Hz, 1H), 6.11 (d,
J=3.0 Hz, 1H), 5.16 (s, 2H), 3.82 (s, 2H), 3.64 (s, 3H), 3.01-2.99
(m, 2H), 2.94-2.85 (m, 10H), 1.91-1.90 (m, 4H); HPLC (Method A)
95.1% (AUC), t.sub.R=13.8 min.
b)
4-(Benzyloxy)-1-(9-methyl-2-(2-(pyrrolidin-1-yl)ethyl)-2,3,4,9,-tetrahy-
dro-1H-pyrido[3,4-b]indol-7-yl)pyridine-2(1H)-one hydrochloride
##STR00315##
[0630] 2N HCl in Et.sub.2O (20 .mu.L, 0.04 mmol) was added to a
solution of
4-(benzyloxy)-1-(9-methyl-2-(2-(pyrrolidin-1-yl)ethyl)-2,
3,4,9,-tetrahydro-1H-pyrido[3,4-b]indol-7-yl)pyridine-2(1H)-one (10
mg, 0.020 mmol) in CH.sub.2Cl.sub.2 (3 mL) and the reaction was
stirred at ambient temperature for 1 h under N.sub.2. The reaction
was concentrated to dryness under reduced pressure to provide the
title compound (10 mg, quantitative) as a yellow solid: .sup.1H NMR
(500 MHz, CD.sub.3OD) .delta. 7.62-7.57 (m, 2H), 7.47-7.34 (m, 6H),
7.03 (dd, J=8.5, 1.5 Hz, 1H), 6.29 (dd, J=7.5, 2.5 Hz, 1H), 6.12
(d, J=2.5 Hz, 1H), 5.18 (s, 2H), 4.55-4.43 (m, 2H), 3.72 (s, 3H),
3.38-3.14 (m, 12H), 2.14 (m, 4H); ESI MS m/z 483 [M+H].sup.+; HPLC
(Method A) 92.8% (AUC), t.sub.R=13.6 min.
Example 128
Preparation of
4-(4-Chloro-2-methoxyphenyl)-1-(9-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-
-b]indol-7-yl)pyridin-2(1H)-one hydrochloride
a) tert-Butyl-7-(4-(4-chloro-2-methoxyphenyl)-2-oxopyridin-1
(2H)-yl)-9-methyl-3,4-dihydro-1H-pyrido[3,4-b]indole-2(9H)-carboxylate
##STR00316##
[0632]
tert-Butyl-7-bromo-9-methyl-3,4-dihydro-1H-pyrido[3,4-b]indole-2(9H-
)-carboxylate (0.19 g, 0.81 mmol),
4-(4-chloro-2-methoxyphenyl)pyridin-2(1H)-one (0.30 g, 0.81 mmol),
Cs.sub.2CO.sub.3 (0.29 g, 0.89 mmol) were diluted with DMSO (3.3
mL), and argon was bubbled through the suspension for 10 min.
8-Hydroxyquinoline (59 mg, 0.41 mmol) and copper iodide (0.18 g,
0.97 mmol) were added, and the resulting suspension was placed
under vacuum for 15 min. The system was flushed with argon, and the
degassing/argon flushing process was repeated a total of three
times. The reaction mixture was heated at 130.degree. C. for 18 h
and stirred under argon. The suspension was cooled. A solution of
20% NH.sub.4OH in MeOH (40 mL) was added, and the resulting mixture
was stirred for 1 h. The mixture was diluted with CH.sub.2Cl.sub.2
and filtered through celite. The filtrate was washed with brine
(2.times.50 mL), dried over Na.sub.2SO.sub.4, and concentrated
under reduced pressure. Flash chromatography (40 g ISCO (1:1
hexanes/EtOAc)/(80:18:2 CH.sub.2Cl.sub.2/MeOH/NH.sub.4OH), 100:0
for 3 column volumes then increase to 50:50 over 10 column volumes
and hold for 10 column volumes) gave the title compound (0.23 g,
54%) as an olive-green film: .sup.1H NMR (500 MHz, DMSO-d.sub.6)
.delta. 7.65 (d, J=7.0 Hz, 1H), 7.54 (d, J=2.0 Hz, 1H), 7.50 (d,
J=8.0 Hz, 1H), 7.44 (d, J=8.0 Hz, 1H), 7.25 (d, J=1.5 Hz, 1H), 7.13
(dd, J=8.0, 1.5 Hz, 1H), 7.02 (dd, J=8.0, 1.5 Hz, 1H), 6.55 (d,
J=2.0 Hz, 1H), 6.54 (dd, J=7.0, 1.5 Hz, 1H), 4.64 (s, 2H), 3.87 (s,
3H), 3.68-3.66 (m, 5H), 2.74-2.72 (m, 2H), 1.46 (s, 9H).
b)
4-(4-Chloro-2-methoxyphenyl)-1-(9-methyl-2,3,4,9-tetrahydro-1H-pyrido[3-
,4-b]indol-7-yl)pyridin-2(1H)-one hydrochloride
##STR00317##
[0634] Trifluoroacetic acid (1.0 mL) was added to a solution of
tert-butyl-7-(4-(4-chloro-2-methoxyphenyl)-2-oxopyridin-1(2H)-yl)-9-methy-
l-3,4-dihydro-1H-pyrido[3,4-b]indole-2(9H)-carboxylate (0.23 g,
0.44 mmol) in CH.sub.2Cl.sub.2 (2 mL) under argon and stirred for 1
h. The mixture was concentrated under reduced pressure, and the
residue was partitioned between CH.sub.2Cl.sub.2 and saturated
NaHCO.sub.3 solution. The organic phase was removed, and the
aqueous phase was extracted with CH.sub.2Cl.sub.2 (10.times.25 mL).
The combined organic extracts were washed with brine (25 mL), dried
over Na.sub.2SO.sub.4, and concentrated under reduced pressure.
Flash column chromatography (12 g ISCO CH.sub.2Cl.sub.2/(80:18:2
CH.sub.2Cl.sub.2/MeOH/NH.sub.4OH), 100:0 for 2 column volumes to
0:100 over 20 column volumes and hold for 10 column volumes)
provided the free base of the title compound. The free base was
converted to the HCl salt using 2N HCl in Et.sub.2O as of Example
129 (step b), providing the title compound (0.13 g, 33%) as a
yellow solid: mp 294-300.degree. C.; .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 9.43 (br s, 2H), 7.65 (d, J=7.0 Hz, 1H), 7.61
(d, J=1.5 Hz, 1H), 7.59 (d, J=8.0 Hz, 1H), 7.44 (d, J=8.5 Hz, 1H),
7.26 (d, J=2.0 Hz, 1H), 7.13 (dd, J=8.5, 2.0 Hz, 1H), 7.09 (dd,
J=8.0, 2.0 Hz, 1H), 6.56 (d, J=2.0 Hz, 1H), 6.47 (dd, J=7.0, 1.5
Hz, 1H), 4.49-4.47 (m, 2H), 3.87 (m, 3H), 3.69 (s, 3H), 3.47-3.43
(m, 2H), 3.00-2.97 (m, 2H); ESI MS m/z 420 [M+H].sup.+; HPLC
(Method A) 96.7% (AUC), t.sub.R=15.5 min.
Example 129
Preparation of
4-(4-Chloro-2-methoxyphenyl)-1-(2,9-dimethyl-2,3,4,9-tetrahydro-1H-pyrido-
[3,4-b]indol-7-yl)pyridin-2(1H)-one hydrochloride
a)
4-(4-Chloro-2-methoxyphenyl)-1-(2,9-dimethyl-2,3,4,9-tetrahydro-1H-pyri-
do[3,4-b]indol-7-yl)pyridin-2(1H)-one
##STR00318##
[0636]
4-(4-Chloro-2-methoxyphenyl)-1-(9-methyl-2,3,4,9-tetrahydro-1H-pyri-
do[3,4-b]indol-7-yl)pyridin-2(1H)-one (83 mg, 0.20 mmol) and 37%
aqueous formaldehyde (24 .mu.L, 0.30 mmol) were dissolved in 1:1
MeOH/CH.sub.2Cl.sub.2 (1.4 mL) and stirred at room temperature for
45 min. Sodium triacetoxyborohydride (84 mg, 0.40 mmol) was added,
and the reaction was stirred at ambient temperature for 30 min. The
reaction mixture was neutralized with saturated NaHCO.sub.3
solution and extracted with CH.sub.2Cl.sub.2 (3.times.25 mL). The
combined organics were washed with brine (25 mL), dried over
Na.sub.2SO.sub.4, filtered and concentrated to dryness under
reduced pressure. Purification by flash column chromatography (12 g
ISCO (1:1 hexanes/EtOAc)/(80:18:2
CH.sub.2Cl.sub.2/MeOH/NH.sub.4OH), 95:5 to 10:90 over 20 column
volumes, hold for 10 column volumes) provided the title compound
(77 mg, 89%) as a yellow film: .sup.1H NMR (500 MHz, CDCl.sub.3)
.delta. 7.55 (d, J=8.0 Hz, 1H), 7.41 (d, J=7.0 Hz, 1H), 7.35-7.34
(m, 1H), 7.31 (d, J=8.0 Hz, 1H), 7.07-7.03 (m, 2H), 7.00-6.99 (m,
1H), 6.81-6.80 (m, 1H), 6.43-6.42 (m, 1H), 3.87 (s, 3H), 3.66-3.65
(m, 2H), 3.48 (s, 3H), 2.87-2.86 (m, 2H), 2.81-2.80 (m, 2H), 2.58
(s, 3H).
b)
4-(4-Chloro-2-methoxyphenyl)-1-(2,9-dimethyl-2,3,4,9-tetrahydro-1H-pyri-
do[3,4-b]indol-7-yl)pyridin-2(1H)-one hydrochloride
##STR00319##
[0638] 2N HCl in Et.sub.2O (0.17 mL, 0.34 mmol) was added to a
solution of 4-(4-chloro-2-methoxyphenyl)-1-(2,9-dimethyl-2,3,4,
9-tetrahydro-1H-pyrido[3,4-b]indol-7-yl)pyridin-2(1H)-one (74 mg,
0.17 mmol) in CH.sub.2Cl.sub.2 (2 mL) and the reaction was stirred
at ambient temperature for 1.5 h under N.sub.2. The solids were
collected by filtration, washed with Et.sub.2O and dried under
reduced pressure to yield the title compound (54 mg, 68%) as a
yellow powder: mp 272-280.degree. C.; .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 10.82 (br s, 1H), 7.65 (d, J=7.0 Hz, 1H),
7.62 (d, J=1.5 Hz, 1H), 7.60 (d, J=8.5 Hz, 1H), 7.44 (d, J=8.5 Hz,
1H), 7.26 (d, J=1.5 Hz, 1H), 7.14-7.09 (m, 2H), 6.56 (d, J=1.5 Hz,
1H), 6.47 (dd, J=7.0, 1.5 Hz, 1H), 4.79-4.76 (m, 1H), 4.53-4.42 (m,
1H), 3.87 (s, 3H), 3.72-3.68 (m, 4H), 3.42-3.40 (m, 1H), 3.08-3.06
(m, 2H), 3.00 (s, 3H); ESI MS m/z 434 [M+H].sup.+; HPLC (Method A)
96.5% (AUC), t.sub.R=15.3 min.
Example 130
Preparation of
(S)-4-(Benzyloxy)-1-(5-methyl-2-pyrrolidin-2-ylmethyl)-2,3,4,5-tetrahydro-
-1H-pyrido[4,3-b]indol-7yl)pyridine-2(1H)-one hydrochloride
a) (S)-tert-Butyl
2-((7-(4-(benzyloxy)-2-oxopyridin-1(2H)-yl)-5-methyl-3,4-dihydro-1H-pyrid-
o[4,3-b]indol-2(5H)-yl)methyl)pyrrolidine-1-carboxylate
##STR00320##
[0640] A solution of
(S)-tert-butyl-2-(bromomethyl)pyrrolidine-1-carboxylate (0.45 g,
1.7 mmol) in DMSO (1.5 mL) was added to a solution of
4-(benzyloxy)-1-(9-methyl-2,3,4,9,-tetrahydro-1H-pyrido[3,4-b]indol-7-yl)-
pyridine-2(1H)-one (0.33 g, 0.85 mmol), and Cs.sub.2CO.sub.3 (1.10
g, 3.4 mmol) in DMSO (2.8 mL), and the resulting solution was
heated at 60.degree. C. for 18 h. The reaction mixture was diluted
with H.sub.2O and extracted with CH.sub.2Cl.sub.2 (3.times.25 mL).
The combined organic extracts were washed with brine (2.times.25
mL), dried over Na.sub.2SO.sub.4 and concentrated to dryness under
reduced pressure. Purification by flash column chromatography (40 g
ISCO column, CH.sub.2Cl.sub.2/(80:18:2
CH.sub.2Cl.sub.2/MeOH/NH.sub.4OH), 100:0 hold 5 column volumes,
increased to 0:100:0 over 20 column volumes) provided a clear film.
The film was diluted with EtOAc and washed with brine (4.times.10
mL), dried over Na.sub.2SO.sub.4, filtered and concentrated under
reduced pressure to provide the title compound (19 mg, 3%) as a
clear film: ESI MS m/z 569 [M+H].sup.+.
b)
(S)-4-(Benzyloxy)-1-(5-methyl-2-pyrrolidin-2-ylmethyl)-2,3,4,5-tetrahyd-
ro-1H-pyrido[4,3-b]indol-7yl)pyridine-2(1H)-one
##STR00321##
[0642] Trifluoroacetic acid (1.0 mL) was added to a solution
of(S)-tert-butyl
2-((7-(4-(benzyloxy)-2-oxopyridin-1(2H)-yl)-5-methyl-3,4-dihydro-1H-pyrid-
o[4,3-b]indol-2(5H)-yl)methyl)pyrrolidine-1-carboxylate (19 mg,
0.033 mmol) in 2:1 CDCl.sub.3/MeOH (1.5 mL) under argon and stirred
for 30 min. The mixture was concentrated to dryness under reduced
pressure. Flash column chromatography (4 g ISCO
CH.sub.2Cl.sub.2/(80:18:2 CH.sub.2Cl.sub.2/MeOH/NH.sub.4OH), 95:5
for 20 column volumes to 0:100 over 40 column volumes and hold for
100 column volumes) yielded the title compound (10 mg, 65%) as a
clear film: ESI MS m/z 469 [M+H].sup.+
c)
(S)-4-(Benzyloxy)-1-(5-methyl-2-pyrrolidin-2-ylmethyl)-2,3,4,5-tetrahyd-
ro-1H-pyrido[4,3-b]indol-7yl)pyridine-2(1H)-one hydrochloride
##STR00322##
[0644] 2N HCl in Et.sub.2O (0.12 .mu.L, 0.024 mmol) was added to a
solution of
(S)-4-(benzyloxy)-1-(5-methyl-2-pyrrolidin-2-ylmethyl)-2,3,4,5-tetrahydro-
-1H-pyrido[4,3-b]indol-7yl)pyridine-2(1H)-one) (10 mg, 0.021 mmol)
in CH.sub.2Cl.sub.2 (0.6 mL), and the solution was stirred at
ambient temperature for 1.5 h under N.sub.2. The reaction mixture
was concentrated under reduced pressure to provide the title
compound (6.0 mg, 56%) as a white solid: .sup.1H NMR (500 MHz,
CD.sub.3OD) .delta. 7.59-7.56 (m, 2H), 7.47-7.45 (m, 3H), 7.42-7.39
(m, 2H), 7.37-7.34 (m, 1H), 7.06 (dd, J=8.5, 2.0 Hz, 1H), 6.29 (dd,
J=7.5, 2.5 Hz, 1H), 6.12 (d, J=3.0 Hz, 1H), 5.18 (s, 2H), 4.70-4.49
(br m, 2H), 4.28-4.26 (m, 1H), 3.75-3.73 (m, 7H), 3.46-3.43 (m,
2H), 3.34-3.33 (m, 2H), 2.46-2.43 (m, 1H), 2.21-2.08 (m, 2H),
1.91-1.86 (m, 1H); ESI MS m/z 469 [M+H].sup.+; HPLC (Method A)
93.8% (AUC), t.sub.R=13.5 min.
Example 131
Preparation of
4-(4-Methoxyphenyl)-1-(5-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol--
7-yl)pyridin-2(1H)-one hydrochloride
c) tert-Butyl
7-(4-(4-methoxyphenyl)-2-oxopyridin-1(2H)-yl)-5-methyl-3,4-dihydro-1H-pyr-
ido[4,3-b]indole-2(5H)-carboxylate
##STR00323##
[0646]
tert-Butyl-7-bromo-5-methyl-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H-
)-carboxylate (0.19 g, 0.54 mmol),
4-(4-methoxyphenyl)pyridin-2(1H)-one (90 mg, 0.45 mmol) and
Cs.sub.2CO.sub.3 (0.16 g, 0.49 mmol) were suspended in DMSO (2.0
mL) and degassed under vacuum for 15 min. The system was then
flushed with Ar and 8-hydroxyquinoline (19 mg, 0.13 mmol) and
copper iodide (0.10 g, 0.54 mmol) were added. The degassing/Ar
flushing process was repeated twice more, and the reaction mixture
was heated at 133.degree. C. for 18 h under N.sub.2. The suspension
was cooled, diluted with 20% NH.sub.4OH/MeOH (25 mL) and stirred at
ambient temperature for 30 min. The suspension was further diluted
with CH.sub.2Cl.sub.2 (100 mL). The solution was filtered through
silica gel and concentrated under reduced pressure. The concentrate
was diluted with CH.sub.2Cl.sub.2 and washed with brine (3.times.25
mL). The organic phase was dried over Na.sub.2SO.sub.4, filtered
and concentrated to dryness. Flash column chromatography (12 g ISCO
column, (1:1 hexanes/EtOAc)/(80:18:2
CH.sub.2Cl.sub.2/MeOH/NH.sub.4OH), 100:0 for 10 column volumes,
increased to 50:50 over 20 column volumes and then hold for 5
column volumes) gave the title compound (75 mg, 34%) as a yellow
solid: .sup.1H NMR (500 MHz, CDCl.sub.3) .delta. 7.60 (d, J=9.0 Hz,
2H), 7.53 (d, J=8.0 Hz, 1H), 7.46 (d, J=7.5 Hz, 1H), 7.37 (d, J=1.5
Hz, 1H), 7.08 (d, J=7.5 Hz, 1H), 7.00 (d, J=9.0 Hz, 2H), 6.86 (d,
J=2.0 Hz, 1H), 6.50 (dd, J=7.0, 2.0 Hz, 1H), 4.66-4.64 (m, 2H),
3.87 (s, 3H), 3.85-3.84 (m, 2H), 3.64 (s, 3H), 2.84-2.83 (m, 2H),
1.50 (s, 9H).
b)
4-(4-Methoxyphenyl)-1-(5-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indo-
l-7-yl)pyridin-2(1H)-one
##STR00324##
[0648] Trifluoroacetic acid (1.0 mL) was added to a solution of
tert-butyl
7-(4-(4-methoxyphenyl)-2-oxopyridin-1(2H)-yl)-5-methyl-3,4-dihydro-1H-pyr-
ido[4,3-b]indole-2(5H)-carboxylate (74 mg, 0.15 mmol) in
CH.sub.2Cl.sub.2 (1 mL) under N.sub.2 and stirred for 2 h at
ambient temperature. The mixture was concentrated, and the residue
was partitioned between CH.sub.2Cl.sub.2 and saturated NaHCO.sub.3
solution. The organic phase was removed, and the aqueous phase was
extracted with CH.sub.2Cl.sub.2 (4.times.25 mL). The combined
organic extracts were washed with brine (25 mL), dried over
Na.sub.2SO.sub.4 and concentrated under reduced pressure. Flash
column chromatography (12 g ISCO CH.sub.2Cl.sub.2/(80:18:2
CH.sub.2Cl.sub.2/MeOH/NH.sub.4OH), 100:0 for 5 column volumes to
0:100 over 20 column volumes and hold for 5 column volumes) yielded
the title compound (46 mg, 78%) as a yellow solid: .sup.1H NMR (500
MHz, CDCl.sub.3) .delta. 7.60 (d, J=9.0 Hz, 2H), 7.50-7.46 (m, 2H),
7.36 (d, J=2.0 Hz, 1H), 7.05 (dd, J=8.5, 2.0 Hz, 1H), 7.00 (d,
J=8.5 Hz, 2H), 6.86 (d, J=1.5 Hz, 1H), 6.49 (dd, J=7.0, 2.0 Hz,
1H), 4.08 (s, 2H), 3.87 (s, 3H), 3.63 (s, 3H), 3.27 (t, J=6.0 Hz,
2H), 2.77 (t, J=5.5 Hz, 2H).
c)
4-(4-Methoxyphenyl)-1-(5-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indo-
l-7-yl)pyridin-2(1H)-one hydrochloride
##STR00325##
[0650] 2N HCl in Et.sub.2O (0.12 mL, 0.24 mmol) was added to a
solution of
4-(4-methoxyphenyl)-1-(5-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol--
7-yl)pyridin-2(1H)-one (45 mg, 0.12 mmol) in CH.sub.2Cl.sub.2 (2.0
mL), and the solution was stirred at ambient temperature for 2.5 h
under N.sub.2. The reaction mixture was concentrated, partially
diluted with H.sub.2O and lyophilized to provide the title compound
(46 mg, 95%) as a yellow powder: .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 9.26 (br s, 2H), 7.76 (d, J=9.0 Hz, 2H), 7.70
(d, J=7.0 Hz, 1H), 7.60-7.57 (m, 2H), 7.09-7.06 (m, 3H), 6.73 (d,
J=2.0 Hz, 1H), 6.68 (dd, J=7.5, 2.0 Hz, 1H), 4.37-4.35 (m, 2H),
3.83 (s, 3H), 3.70 (s, 3H), 3.54-3.53 (m, 2H), 3.10 (t, J=6.0 Hz,
2H); ESI MS m/z 386 [M+H].sup.+.
Example 132
Preparation of
4-(4-Methoxy-2-methylphenyl)-1-(5-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-
-b]indol-7-yl)pyridin-2(1H)-one hydrochloride
a) tert-Butyl
7-(4-(4-methoxy-2-methylphenyl)-2-oxopyridin-1(2H)-yl)-5-methyl-3,4-dihyd-
ro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate
##STR00326##
[0652]
tert-Butyl-7-bromo-5-methyl-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H-
)-carboxylate (0.35 g, 0.96 mmol),
4-(4-methoxy-2-methylphenyl)pyridin-2(1H)-one (0.21 g, 0.96 mmol)
and Cs.sub.2CO.sub.3 (0.35 g, 1.1 mmol) were suspended in DMSO (5.6
mL), and the resulting suspension was degassed under vacuum for 15
min. The system was then flushed with Ar, and 8-hydroxyquinoline
(42 mg, 0.29 mmol) and copper iodide (0.22 g, 1.2 mmol) were added.
The evacuation/Ar flushing process was repeated twice more, and the
reaction mixture was heated at 130.degree. C. for 18 h under
N.sub.2. The suspension was cooled, diluted with 20%
NH.sub.4OH/MeOH (10 mL) and stirred at ambient temperature for 30
min. The reaction was further diluted with CH.sub.2Cl.sub.2 (100
mL). The solution was filtered through silica gel and concentrated.
The concentrate was diluted with CH.sub.2Cl.sub.2 and washed with
brine (4.times.20 mL). The organic phase was dried over
Na.sub.2SO.sub.4 and concentrated to dryness under reduced
pressure. Flash column chromatography (12 g ISCO column, (1:1
hexanes/EtOAc)/(80:18:2 CH.sub.2Cl.sub.2/MeOH/NH.sub.4OH), 100:0
for 5 column volumes, increased to 50:50 over 20 column volumes and
then hold for 5 column volumes, increase to 0:100 over 10 column
volumes and hold for 5 column volumes) gave the title compound
(0.25 g, 52%) as a yellow film: .sup.1H NMR (500 MHz, CDCl.sub.3)
.delta. 7.54 (d, J=8.0 Hz, 1H), 7.42 (d, J=6.5 Hz, 1H), 7.39 (d,
J=1.5 Hz, 1H), 7.22 (d, J=8.0 Hz, 1H), 7.10 (d, J=7.0 Hz, 1H),
6.82-6.80 (m, 2H), 6.60 (d, J=1.5 Hz, 1H), 6.24 (dd, J=6.5, 1.5 Hz,
1H), 4.67-4.65 (m, 2H), 3.86-3.83 (m, 5H), 3.65 (s, 3H), 2.93 (m,
3H), 2.82-2.84 (m, 2H), 1.50 (s, 9H).
b)
4-(4-Methoxy-2-methylphenyl)-1-(5-methyl-2,3,4,5-tetrahydro-1H-pyrido[4-
,3-b]indol-7-yl)pyridin-2(1H)-one
##STR00327##
[0654] Trifluoroacetic acid (1.0 mL) was added to a solution of
tert-butyl 7-(4-(4-methoxy-2-methylphenyl)-2-oxopyridin-1
(2H)-yl)-5-methyl-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate
(0.25 g, 0.50 mmol) in CH.sub.2Cl.sub.2 (2.0 mL) under N.sub.2 and
stirred for 1 h. The reaction mixture was made basic with saturated
NaHCO.sub.3 solution and the resolution solution was extracted with
CH.sub.2Cl.sub.2 (3.times.25 mL). The combined organic extracts
were dried over Na.sub.2SO.sub.4 and concentrated under reduced
pressure. Flash column chromatography (12 g ISCO
CH.sub.2Cl.sub.2/(80:18:2 CH.sub.2Cl.sub.2/MeOH/NH.sub.4OH), 100:0
for 5 column volumes to 0:100 over 20 column volumes and hold for
40 column volumes) yielded the title compound (0.16 g, 80%) as an
off-white film: .sup.1H NMR (500 MHz, CDCl.sub.3) .delta. 7.50 (d,
J=8.0 Hz, 1H), 7.42 (d, J=7.0 Hz, 1H), 7.38 (m, 1H), 7.22 (d, J=8.0
Hz, 1H), 7.07 (dd, J=8.5, 2.0 Hz, 1H), 6.82-6.80 (m, 2H), 6.60 (d,
J=1.5 Hz, 1H), 6.23 (dd, J=7.0, 1.5 Hz, 1H), 4.09 (s, 2H), 3.84 (s,
3H), 3.64 (s, 3H), 2.77 (t, J=5.5 Hz, 2H), 2.27 (t, J=6.0 Hz, 2H),
2.39 (s, 3H).
c)
4-(4-Methoxy-2-methylphenyl)-1-(5-methyl-2,3,4,5-tetrahydro-1H-pyrido[4-
,3-b]indol-7-yl)pyridin-2(1H)-one hydrochloride
##STR00328##
[0656] 2N HCl in Et.sub.2O (0.40 mL, 0.80 mmol) was added to a
solution of
4-(4-methoxy-2-methylphenyl)-1-(5-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-
-b]indol-7-yl)pyridin-2(1H)-one (0.16 g, 0.40 mmol) in
CH.sub.2Cl.sub.2 (1.5 mL), and the solution was stirred at ambient
temperature for 1 h under N.sub.2. The solids were collected by
filtration, washed with Et.sub.2O and dried to yield the title
compound (0.15 g, 85%) as an off-white powder: .sup.1H NMR (500
MHz, DMSO-d.sub.6) .delta. 9.39 (br s, 2H), 7.67 (d, J=7.0 Hz, 1H),
7.59 (d, J=8.0 Hz, 1H), 7.27 (d, J=2.0 Hz, 1H), 7.25 (d, J=8.5 Hz,
1H), 7.10 (dd, J=8.5, 2.0 Hz, 1H), 6.92 (d, J=2.5 Hz, 1H), 6.88
(dd, J=8.0, 2.5 Hz, 1H), 6.37 (d, J=2.0 Hz, 1H), 6.34 (dd, J=7.0,
2.0 Hz, 1H), 4.36-4.34 (m, 2H), 3.79 (s, 3H), 3.71 (s, 3H),
3.53-3.52 (m, 2H), 3.10 (t, J=6.0 Hz, 2H), 2.35 (s, 3H); ESI MS m/z
400 [M+H].sup.+; HPLC (Method A) 95.8% (AUC), t.sub.R=14.5 min.
Example 133
Preparation of
(4-Benzyloxy)-1-(9-(difluoromethyl)-2,3,4,9-tetrahydro-1H-pyrido[4,3-b]in-
dol-7-yl)pyridin-2(1H)-one hydrochloride
a) tert-Butyl
7-bromo-9-(difluoromethyl)-3,4-dihydro-1H-pyrido[4,3-b]indole-2(9H)-carbo-
xylate
##STR00329##
[0658] Sodium hydride (60% in mineral oil, 0.347 g, 8.71 mmol) was
added to a solution of tert-butyl
7-bromo-3,4-dihydro-1H-pyrido[3,4-b]indole-2(9H)-carboxylate (2.04
g, 5.81 mmol) in DMF (20 mL) at room temperature under N.sub.2 and
stirred for 30 minutes. Difluoroiodomethane (.about.1.5 mL), which
had been condensed with a cold finger into a separate flask, was
added via syringe. The reaction was sealed with a rubber septum and
stirred overnight at ambient temperature. The mixture was quenched
with H.sub.2O. EtOAc was added and the mixture was stirred for 40
minutes. The mixture was extracted with EtOAc (3.times.40 mL), and
the combined organic extracts were washed with brine (2.times.20
mL), dried over Na.sub.2SO.sub.4 and concentrated under reduced
pressure. Flash chromatography (40+M Biotage column, hexanes/(4:1
hexanes/EtOAc), 100:0 to 0:100) provided the title compound (0.93
g, 40%) as a white solid: .sup.1H NMR (300 MHz, CDCl.sub.3) .delta.
7.62 (s, 1H), 7.17 (t, J=56.0 Hz, 1H), 7.33 (m, 2H), 4.71 (s, 2H),
3.75 (m, 2H), 2.74 (s, 2H), 1.50 (s, 9H).
b) tert-Butyl
7-(4-benzyloxy)-2-oxopyridin-1(2H)-yl)-9-(difluoromethyl)-3,4-dihydro-1H--
pyrido[4,3-b]indole-2(9H)-carboxylate
##STR00330##
[0660] tert-Butyl
7-bromo-9-(difluoromethyl)-3,4-dihydro-1H-pyrido[4,3-b]indole-2(9H)-carbo-
xylate (0.936 g, 2.33 mmol), 4-benzyloxypyridone (0.469 g, 2.33
mmol), Cs.sub.2CO.sub.3 (0.834 g, 2.57 mmol) and H.sub.2O (1 drop)
were diluted with DMSO (10.4 mL) and argon was bubbled through the
suspension for 10 minutes. 8-Hydroxyquinoline (0.101 g, 0.699 mmol)
and copper iodide (133 mg, 0.699 mmol) were added, and the
resulting suspension was placed under vacuum for 15 min. The system
was flushed with argon. The degassing/argon flushing process was
repeated a total of three times. The reaction mixture was heated to
130.degree. C. for 18 h and stirred under argon. The suspension was
cooled. A solution of 20% NH.sub.4OH in MeOH (40 mL) was added, and
the resulting mixture was stirred for 1 h. The mixture was diluted
with CH.sub.2Cl.sub.2 and filtered through celite. The filtrate was
washed with brine (3.times.25 mL), dried over Na.sub.2SO.sub.4 and
concentrated under reduced pressure. Flash chromatography (40+M
Biotage column, (20% EtOAc in hexanes)/(50% EtOAc in
hexanes)/(80:18:2 CH.sub.2Cl.sub.2/MeOH/NH.sub.4OH), 100:0:0 to
0:100:0 over 1.2 L then 0:100:0 to 0:0:100 over 1.2 L) gave the
title compound (0.41 g, 33%) as a yellow foam: .sup.1H NMR (500
MHz, DMSO-d.sub.6) .delta. 8.10 (t, J=58.0 Hz, 1H), 7.74 (d, J=1.4
Hz, 1H), 7.60 (d, J=3.2 Hz, 1H), 7.58 (d, J=3.9 Hz, 1H), 7.47-7.35
(m, 5H), 7.16 (dd, J=8.3, 1.7 Hz, 1H), 6.12 (dd, J=7.6, 2.6 Hz,
1H), 5.99 (d, J=2.7 Hz, 1H), 5.15 (s, 2H), 4.72 (m, 2H), 4.03 (s,
2H), 3.70 (m, 2H), 1.44 (s, 9H).
c)
(4-Benzyloxy)-1-(9-(difluoromethyl)-2,3,4,9-tetrahydro-1H-pyrido[4,3-b]-
indol-7-yl)pyridin-2(1H)-one hydrochloride
##STR00331##
[0662] 2N HCl in Et.sub.2O (15.0 mL) was added to a solution of
tert-butyl
7-(4-benzyloxy)-2-oxopyridin-1(2H)-yl)-9-(difluoromethyl)-3,4-dihydro-1H--
pyrido[4,3-b]indole-2(9H)-carboxylate (0.39 g, 0.75 mmol) in 1:1
MeOH/CH.sub.2Cl.sub.2 (5 mL). The reaction was stirred at ambient
temperature for 2 h under N.sub.2. The reaction was diluted with
Et.sub.2O, and the resulting solids were collected by filtration to
yield the title compound (0.31 g, 92%) as a yellow solid: mp
220-230.degree. C.; .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta.
9.60 (br s, 2H), 8.11 (t, J=58.0 Hz, 1H), 7.78 (d, J=1.5 Hz, 1H),
7.68 (d, J=8.0 Hz, 1H), 7.60 (d, J=7.5 Hz, 1H), 7.48-7.36 (m, 5H),
7.22 (dd, J=8.5, 1.5 Hz, 1H), 6.14 (dd, J=7.5, 2.5 Hz, 1H), 5.99
(d, J=2.5 Hz, 1H), 5.16 (s, 2H), 4.52 (m, 2H), 3.49-3.48 (m, 2H),
2.99 (m, 2H); ESI MS m/z 422 [M+H].sup.+; HPLC (Method A) 96.5%
(AUC), t.sub.R=14.4 min
Example 134
Preparation of
(4-Benzyloxy)-1-(9-(difluoromethyl)-2-methyl-2,3,4,9-tetrahydro-1H-pyrido-
[3,4-b]indol-7-yl)pyridin-2(1H)-one hydrochloride
a)
(4-Benzyloxy)-1-(9-(difluoromethyl)-2-methyl-2,3,4,9-tetrahydro-1H-pyri-
do[3,4-b]indol-7-yl)pyridin-2(1H)-one
##STR00332##
[0664]
(4-Benzyloxy)-1-(9-(difluoromethyl)-2,3,4,9-tetrahydro-1H-pyrido[4,-
3-b]indol-7-yl)pyridin-2(1H)-one (83 mg, 20 mmol) and 37% aqueous
formaldehyde (22 .mu.L, 0.30 mmol) were dissolved in 1:1
CH.sub.2Cl.sub.2/MeOH (1.0 mL) and stirred at ambient temperature
for 45 min. Sodium triacetoxyborohydride (83 mg, 0.39 mmol) was
added, and the resulting suspension was stirred at ambient
temperature for 15 min. The suspension was concentrated, and the
residue was diluted with saturated NaHCO.sub.3 solution. The
aqueous solution was extracted with CH.sub.2Cl.sub.2. The combined
organic extracts were dried over Na.sub.2SO.sub.4 and concentrated
under reduced pressure. Flash chromatography (10 g Biotage SNAP
column, CH.sub.2Cl.sub.2/(80:18:2
CH.sub.2Cl.sub.2/MeOH/NH.sub.4OH), 100:0 to 0:100) gave the title
compound (57 mg, 67%) as a clear oil. ESI MS m/z 436 [M+H].sup.+;
HPLC (Method A) 98.9% (AUC), t.sub.R=14.3 min.
b)
(4-Benzyloxy)-1-(9-(difluoromethyl)-2-methyl-2,3,4,9-tetrahydro-1H-pyri-
do[3,4-b]indol-7-yl)pyridin-2(1H)-one hydrochloride
##STR00333##
[0666] A solution of
(4-benzyloxy)-1-(9-(difluoromethyl)-2-methyl-2,3,4,9-tetrahydro-1H-pyrido-
[3,4-b]indol-7-yl)pyridin-2(1H)-one (58 mg, 0.13 mmol) in
CH.sub.2Cl.sub.2 (1.0 mL) was treated with anhydrous 1.0M HCl in
diethyl ether (0.13 mL, 0.13 mmol). The reaction was stirred at
ambient temperature for 1 h, and the solids were collected and
dried to yield the title compound (53 mg, 86%) as a yellow solid:
mp 250-256.degree. C.; .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta.
10.89 (br s, 1H), 8.15 (t, J=58.0 Hz, 1H), 7.82 (d, J=1.5 Hz, 1H),
7.69 (d, J=8.3 Hz, 1H), 7.60 (d, J=7.6 Hz, 1H), 7.47-7.36 (m, 5H),
7.23 (dd, J=8.4, 1.5 Hz, 1H), 6.14 (dd, J=7.6, 2.7 Hz, 1H), 6.00
(d, J=2.7 Hz, 1H), 5.16 (s, 2H), 4.77 (m, 1H), 4.55 (m, 1H),
3.76-3.75 (m, 1H), 3.45-3.40 (m, 1H), 3.07-3.02 (m, 5H); ESI MS m/z
436 [M+H].sup.+; HPLC (Method A) 98.9% (AUC), t.sub.R=14.4 min.
Example 135
Preparation of
4-(2-Fluoro-4-methoxyphenyl)-1-(9-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-
-b]indol-7-yl)pyridin-2(1H)-one hydrochloride
a) 4-(2-Fluoro-4-methoxyphenyl)-2-methoxypyridine
##STR00334##
[0668] 4-Bromo-2-methoxypyridine (1.39 g, 7.42 mmol),
2-fluoro-4methoxyphenylboronic acid (2.40 g, 14.1 mmol),
K.sub.2CO.sub.3 (2.05 g, 14.8 mmol) and bis(triphenylphosphine)
palladium(II)chloride (Pd(PPh.sub.3).sub.2Cl.sub.2) (52 mg, 0.74
mmol) were stirred in DMSO (8.5 mL) under vacuum for 20 min. The
flask was flushed with argon and the mixture was heated to
90.degree. C. for 3 h. Upon cooling, the mixture was diluted with
brine, and the aqueous solution was extracted with CH.sub.2Cl.sub.2
(3.times.50 mL). The combined organic extracts were washed with
water (3.times.20 mL), dried over Na.sub.2SO.sub.4 and concentrated
under reduced pressure. Flash chromatography (40+M Biotage column,
CH.sub.2Cl.sub.2/(80:18:2 CH.sub.2Cl.sub.2/MeOH/NH.sub.4OH), 100:0
to 80:20) provided the title compound (0.98 g, 57%) as a yellow
oil: .sup.1H NMR (500 MHz, CDCl.sub.3) .delta. 8.20 (d, J=5.4 Hz,
1H), 7.42-7.38 (m, 1H), 7.07 (d, J=5.4 Hz, 1H), 6.93 (s, 1H), 6.80
(dd, J=8.6, 2.5 Hz, 1H), 6.74 (dd, J=12.6, 2.5 Hz, 1H), 3.99 (s,
3H), 3.85 (s, 3H).
b) 4-(2-Fluoro-4-methoxyphenyl)pyridin-2(1H)-one
##STR00335##
[0670] 4-(2-Fluoro-4-methoxyphenyl)-2-methoxypyridine (1.34 g, 5.72
mmol) was stirred in concentrated hydrochloric acid (25.5 mL) at
reflux for 18 h. The reaction was cooled to 0.degree. C. and
neutralized with solid NaOH. The resulting solids were collected by
filtration and dried under vacuum to yield the title compound (1.09
g, 87%) as a light brown solid: .sup.1H NMR (300 MHz, DMSO-d.sub.6)
.delta. 7.52-7.38 (m, 2H), 6.97-6.85 (m, 2H), 6.42-6.33 (m, 2H),
3.80 (s, 3H); ESI MS m/z 220 [M+H].sup.+.
c)
tert-Butyl-7(4(2-fluoro-4-methoxyphenyl)-2-oxopyridin-2(1H)-yl)-9-methy-
l-3,4-dihydro-1H-pyrido[3,4-b]indole-2(9H)-carboxylate
##STR00336##
[0672] Following the procedure of Example 133 (step b), but
substituting 4-(2-fluoro-4-methoxyphenyl)pyridin-2(1H)-one (359 mg,
1.64 mmol) for 4-benzyloxypyridone, the title compound (288 mg,
41%) was prepared as a yellow foam: .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 7.71 (d, J=7.1 Hz, 1H), 7.61 (m, 1H), 7.55
(d, J=1.6 Hz, 1H), 7.51 (d, J=8.3 Hz, 1H), 7.04-6.99 (m, 2H), 6.94
(dd, J=6.9, 2.5 Hz, 1H), 6.61 (s, 1H), 6.51-6.50 (m, 1H), 4.64 (s,
2H), 3.84 (s, 3H), 3.69-3.67 (m, 5H), 2.74-2.72 (m, 2H), 1.45 (s,
9H).
d)
4-(2-Fluoro-4-methoxyphenyl)-1-(9-methyl-2,3,4,9-tetrahydro-1H-pyrido[3-
,4-b]indol-7-yl)pyridin-2(1H)-one
##STR00337##
[0674] Trifluoroacetic acid (1.0 mL) was added to a solution of
tert-butyl-7(4(2-fluoro-4-methoxyphenyl)-2-oxopyridin-2(1H)-yl)-9-methyl--
3,4-dihydro-1H-pyrido[3,4-b]indole-2(9H)-carboxylate (0.28 g, 0.56
mmol) in CH.sub.2Cl.sub.2 (5 mL) under argon and stirred for 1 h.
The mixture was concentrated, and the residue was partitioned
between CH.sub.2Cl.sub.2 and saturated NaHCO.sub.3 solution. The
organic phase was removed, and the aqueous phase was extracted with
CH.sub.2Cl.sub.2. The combined organic extracts were dried over
Na.sub.2SO.sub.4 and concentrated under reduced pressure.
Preparative HPLC (Phenomenex Luna C18 (2), 250.0.times.50.0 mm, 10
micron, H.sub.2O with 0.05% TFA and CH.sub.3CN with 0.05% TFA)
provided the title compound (87 mg, 39%) as a yellow solid: .sup.1H
NMR (500 MHz, DMSO-d.sub.6) .delta. 7.71 (d, J=7.1 Hz, 1H), 7.61
(m, 1H), 7.49-7.46 (m, 2H), 7.02-6.99 (m, 2H), 6.93 (dd, J=8.7, 2.1
Hz, 1H), 6.60 (s, 1H), 6.50 (d, J=7.1 Hz, 1H), 3.96 (m, 2H), 3.84
(s, 3H), 3.61 (s, 3H), 3.01-2.99 (m, 2H), 2.66 (m, 2H); ESI MS m/z
404 [M+H].sup.+.
e)
4-(2-Fluoro-4-methoxyphenyl)-1-(9-methyl-2,3,4,9-tetrahydro-1H-pyrido[3-
,4-b]indol-7-yl)pyridin-2(1H)-one hydrochloride
##STR00338##
[0676] A solution of
4-(2-fluoro-4-methoxyphenyl)-1-(9-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-
-b]indol-7-yl)pyridin-2(1H)-one (80 mg, 0.20 mmol) in
CH.sub.2Cl.sub.2 (2.6 mL) was treated with anhydrous 1.0M HCl in
diethyl ether (0.22 mL, 0.22 mmol). The reaction was stirred at
ambient temperature for 1 h, and then the solids were collected by
filtration and dried to yield the title compound (68 mg, 77%) as a
yellow solid: mp 290-292.degree. C.; .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 9.54 (s, 2H), 7.71 (d, J=7.2 Hz, 1H),
7.62-7.58 (m, 3H), 7.10 (dd, J=8.3, 1.8 Hz, 1H), 7.01 (dd, J=13.2,
2.4 Hz, 1H), 6.94 (dd, J=8.6, 2.3 Hz, 1H), 6.62 (s, 1H), 6.53-6.52
(m, 1H), 4.48 (s, 2H), 3.95 (s, 3H), 3.69 (s, 3H), 3.45-3.44 (m,
2H), 3.00-2.97 (m, 2H); ESI MS m/z 404 [M+H].sup.+; HPLC (Method A)
>99% (AUC), t.sub.R=14.6 min.
Example 136
Preparation of
1-(2,9-Dimethyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-7-yl)-4-(2-fluor-
o-4-methoxyphenyl)pyridin-2(1H)-one hydrochloride
a)
1-(2,9-Dimethyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-7-yl)-4-(2-flu-
oro-4-methoxyphenyl)pyridin-2(1H)-one
##STR00339##
[0678] Following the procedure of Example 134 (step a), but
substituting
4-(2-fluoro-4-methoxyphenyl)-1-(9-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-
-b]indol-7-yl)pyridin-2(1H)-one (57 mg, 0.14 mmol) for
(4-benzyloxy)-1-(9-(difluoromethyl)-2,3,4,9-tetrahydro-1H-pyrido[4,3-b]in-
dol-7-yl)pyridin-2(1H)-one, the title compound (35 mg, 59%) was
provided as an off-white solid: .sup.1H NMR (500 MHz, DMSO-d.sub.6)
.delta. 7.71 (d, J=7.0 Hz, 1H), 7.61 (m, 1H), 7.51 (d, J=1.8 Hz,
1H), 7.48 (d, J=8.3 Hz, 1H), 7.02-6.99 (m, 2H), 6.94 (dd, J=8.6,
2.4 Hz, 1H), 6.60 (s, 1H), 6.53-6.52 (m, 1H), 3.84 (s, 3H), 3.62
(m, 5H), 2.74-2.70 (m, 4H), 2.46 (s, 3H).
b)
1-(2,9-Dimethyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-7-yl)-4-(2-flu-
oro-4-ethoxyphenyl)pyridin-2(1H)-one hydrochloride
##STR00340##
[0680] Following the procedure of Example 134 (step b), but
substituting
1-(2,9-dimethyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-7-yl)-4-(2-fluor-
o-4-methoxyphenyl)pyridin-2(1H)-one (35 mg, 0.84 mmol) for
(4-benzyloxy)-1-(9-(difluoromethyl)-2-methyl-2,3,4,9-tetrahydro-1H-pyrido-
[3,4-b]indol-7-yl)pyridin-2(1H)-one, the title compound (33 mg,
87%) was provided as a yellow solid: mp 290-294.degree. C.; .sup.1H
NMR (500 MHz, DMSO-d.sub.6) .delta. 10.71 (s, 1H), 7.71 (d, J=7.2
Hz, 1H), 7.63-7.59 (m, 3H), 7.11 (dd, J=8.3, 1.6 Hz, 1H), 7.01 (dd,
J=13.2, 2.4 Hz, 1H), 6.94 (dd, J=8.7, 2.4 Hz, 1H), 6.62 (s, 1H),
6.53-6.52 (m, 1H), 4.80-4.77 (m, 1H), 4.45-4.43 (m, 1H), 3.84 (s,
3H), 3.73 (br s, 1H), 3.68 (s, 3H), 3.42-3.34 (m, 1H), 3.07-3.06
(m, 2H), 3.00 (s, 3H); ESI MS m/z 418 [M+H].sup.+; HPLC (Method A)
97.0% (AUC), t.sub.R=14.0 min.
Example 137
Preparation of
4-(Imidazo[1,2-a]pyridin-2-ylmethoxy)-1-(9-methyl-2,3,4,9-tetrahydro-1H-p-
yrido[3,4-b]indol-7-yl)pyridin-2(1H)-one hydrochloride
a) 4-(Imidazo[1,2-a]pyridin-2-ylmethoxy)pyridine 1-oxide
##STR00341##
[0682] Imidazo[1,2-a]pyridine-2-ylmethanol (3.01 g, 20.3 mmol) was
partially dissolved in 5:1 dioxane/DMF (30 mL) and the resulting
slurry was added slowly to a stirring suspension of NaH (60% in
mineral oil, 0.812 g, 16.9 mmol) in dioxane (29 mL). The resulting
mixture was heated to 60.degree. C. for 15 min.
4-Chloropyridine-N-oxide (1.5 g, 11.5 mmol) was added and the
reaction mixture was heated for 1 h at 110.degree. C. Upon cooling,
the mixture was diluted with methylene chloride and a 20%
NH.sub.4OH in MeOH solution. The resulting suspension was filtered
through a silica gel plug using CH.sub.2Cl.sub.2 (200 mL) and 20%
4:1 MeOH/NH.sub.4OH in CH.sub.2Cl.sub.2 (500 mL). The filtrate was
collected and concentrated under reduced pressure. Flash
chromatography (120 g ISCO column, CH.sub.2Cl.sub.2/(80:18:2
CH.sub.2Cl.sub.2/MeOH/NH.sub.4OH), 100:0 to 0:100 over 60 min)
provided the title compound (1.5 g, 30%) as an orange-brown solid:
.sup.1H NMR (300 MHz, CD.sub.3OD) .delta. 8.42 (m, 1H), 8.24-8.22
(m, 2H), 7.97 (d, J=0.5 Hz, 1H), 7.54 (dd, J=9.1, 0.7 Hz, 1H)
7.37-7.32 (m, 1H), 7.27-7.25 (m, 2H), 6.94 (m, 1H), 5.37 (s,
2H).
b) 4-(Imidazo[1,2-a]pyridin-2-ylmethoxy)pyridine-2(1H)-one
##STR00342##
[0684] 4-(Imidazo[1,2-a]pyridin-2-ylmethoxy)pyridine 1-oxide (1.50
g, 6.25 mmol) was heated at 140.degree. C. in acetic anhydride (18
mL) for 2 h. The mixture was concentrated and heated at 80.degree.
C. for 2 h in 1:1 MeOH/H.sub.2O (50 mL). The resulting black
solution was concentrated. The material was then partially
dissolved in iPrOH (20 mL). Et.sub.2O (70 mL) was added, and the
mixture was allowed to sit at ambient temperature for 1 h. The
resulting solids were collected by filtration and washed with
Et.sub.2O to yield the title compound (951 mg, 63%) as a dark brown
solid: .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 11.08 (br s,
1H), 8.54 (m, 1H), 8.01 (s, 1H), 7.53 (d, J=9.0 Hz, 1H), 7.26-7.23
(m, 2H), 6.90 (m, 1H), 5.89-5.87 (m, 2H), 5.14 (s, 2H).
c)
tert-Butyl-7-(4-(imidazo[1,2-a]pyridin-2-ylmethoxy)-2-oxopyridin-1(2H)--
yl)-9-methyl-3,4-dihydro-1H-pyrido[3,4-b]indole-2(9H)-carboxylate
##STR00343##
[0686]
tert-Butyl-7-bromo-9-methyl-3,4-dihydro-1H-pyrido[3,4-b]indole-2(9H-
)-carboxylate (0.328 g, 0.898 mmol),
4-(imidazo[1,2-a]pyridin-2-ylmethoxy)pyridine-2(1H)-one (0.240 g,
0.998 mmol) and Cs.sub.2CO.sub.3 (0.358 g, 1.09 mmol) were
suspended in DMSO (4.0 mL), and argon was bubbled through the
system for 10 minutes. 8-Hydroxyquinoline (43.4 mg, 0.299 mmol) and
copper iodide (228 mg, 1.20 mmol) were added, and resulting
suspension was placed under vacuum for 15 min. The system was
flushed with argon. The evacuation/argon flushing process was
repeated a total of three times. The reaction mixture was heated at
130.degree. C. for 18 h under argon. The mixture was cooled, and a
solution of 20% NH.sub.4OH in MeOH (40 mL) was added. The resulting
mixture was stirred for 1 h. The mixture was diluted with
CH.sub.2Cl.sub.2 and filtered through a silica gel plug. The
filtrate was collected and concentrated. The residue was diluted
with CH.sub.2Cl.sub.2, washed with brine (3.times.25 mL), dried
over Na.sub.2SO.sub.4 and concentrated under reduced pressure.
Purification by flash column chromatography (80 g ISCO column, (1:1
hexanes/EtOAc)/(80:18:2 CH.sub.2Cl.sub.2/MeOH/NH.sub.4OH), 80:20 to
0:100:0 over 10 column volumes and then hold for 8 column volumes)
gave the title compound (0.190 g, 40%) as a yellow foam: .sup.1H
NMR (500 MHz, DMSO-d.sub.6) .delta. 8.12 (d, J=6.8 Hz, 1H), 7.69
(s, 1H), 7.61 (d, J=9.1 Hz, 1H), 7.52 (d, J=8.3 Hz, 1H), 7.31-7.29
(m, 2H), 7.22-7.19 (m, 1H), 7.02 (dd, J=8.3, 1.7 Hz, 1H), 6.83-6.80
(m, 1H), 6.17 (d, J=2.7 Hz, 1H), 6.07 (dd, J=7.6, 2.7 Hz, 1H), 5.25
(s, 2H), 4.64 (m, 2H), 3.75 (m, 2H), 3.63 (s, 3H), 2.80 (m, 2H),
1.52 (s, 9H), ESI MS m/z 526 [M+H].sup.+
d)
4-(Imidazo[1,2-a]pyridin-2-ylmethoxy)-1-(9-methyl-2,3,4,9-tetrahydro-1H-
-pyrido[3,4-b]indol-7-yl)pyridin-2(1H)-one
##STR00344##
[0688] Following the procedure of Example 135 (step d), but
substituting
tert-butyl-7-(4-(imidazo[1,2-a]pyridin-2-ylmethoxy)-2-oxopyridin-1(2H)-yl-
)-9-methyl-3,4-dihydro-1H-pyrido[3,4-b]indole-2(9H)-carboxylate
(190 mg, 362 mmol) for
tert-butyl-7(4(2-fluoro-4-methoxyphenyl)-2-oxopyridin-2(1H)-yl)-9-methyl--
3,4-dihydro-1H-pyrido[3,4-b]indole-2(9H)-carboxylate, the title
compound (0.105 g, 68%) was prepared as a yellow film: .sup.1H NMR
(500 MHz, CD.sub.3OD) .delta. 8.45-8.43 (m, 1H), 7.98 (s, 1H),
7.59-7.54 (m, 3H), 7.41 (d, J=1.8 Hz, 1H), 7.37-7.33 (m, 1H), 7.02
(dd, J=8.3, 1.8 Hz, 1H), 6.96-6.94 (m, 1H), 6.29 (dd, J=7.6, 2.7
Hz, 1H), 6.21 (d, J=2.7 Hz, 1H), 5.31 (s, 2H), 3.96 (s, 2H), 3.68
(s, 3H), 3.42 (t, J=6.0 Hz, 2H), 3.00 (t, J=6.0 Hz, 2H); ESI MS m/z
426 [M+H].sup.+.
e)
4-(Imidazo[1,2-a]pyridin-2-ylmethoxy)-1-(9-methyl-2,3,4,9-tetrahydro-1H-
-pyrido[3,4-b]indol-7-yl)pyridin-2(1H)-one-hydrochloride
##STR00345##
[0690] Following the procedure of Example 134 (step b), but
substituting
4-(imidazo[1,2-a]pyridin-2-ylmethoxy)-1-(9-methyl-2,3,4,9-tetrahydro-1H-p-
yrido[3,4-b]indol-7-yl)pyridin-2(1H)-one (102 mg, 0.240 mmol) for
(4-benzyloxy)-1-(9-(difluoromethyl)-2-methyl-2,3,4,9-tetrahydro-1H-pyrido-
[3,4-b]indol-7-yl)pyridin-2(1H)-one, the title compound (95 mg,
86%) was prepared as a yellow solid: .sup.1H NMR (500 MHz,
CD.sub.3OD) .delta. 8.81 (d, J=7.0, 1.0 Hz, 1H), 8.38 (s, 1H),
8.02-7.99 (m, 1H), 7.92 (d, J=9.5 Hz, 1H), 7.66-7.62 (m, 2H),
7.52-7.49 (m, 1H), 7.46 (s, 1H), 7.05 (d, J=7.0 Hz, 1H), 6.33 (dd,
J=7.5, 3.0 Hz, 1H), 6.23 (d, J=3.0 Hz, 1H), 5.50 (s, 2H), 4.55 (s,
2H), 3.72 (s, 3H), 3.60 (t, J=6.0 Hz, 2H), 3.14-3.12 (m, 2H); ESI
MS m/z 426 [M+H].sup.+; HPLC (Method A) 98.5% (AUC), t.sub.R=9.2
min.
Example 138
Preparation of
1-(2,9-Dimethyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-7-yl)-4-(imidazo-
[1,2-a]pyridin-2-ylmethoxy)pyridin-2(1H)-one hydrochloride
a)
1-(2,9-Dimethyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-7-yl)-4-(imida-
zo[1,2-a]pyridin-2-ylmethoxy)pyridin-2(1H)-one
##STR00346##
[0692] Following the procedure of Example 134 (step a), but
substituting
4-(imidazo[1,2-a]pyridin-2-ylmethoxy)-1-(9-methyl-2,3,4,9-tetrahydro-1H-p-
yrido[3,4-b]indol-7-yl)pyridin-2(1H)-one (57 mg, 0.14 mmol) for
(4-benzyloxy)-1-(9-(difluoromethyl)-2,3,4,9-tetrahydro-1H-pyrido[4,3-b]in-
dol-7-yl)pyridin-2(1H)-one, the title compound (25 mg, 62%) was
prepared as a yellow solid: .sup.1H NMR (500 MHz, DMSO-d.sub.6)
.delta. 7.54 (d, J=7.5 Hz, 1H), 7.47-7.36 (m, 7H), 6.95 (dd, J=8.5,
1.5 Hz, 1H), 6.10 (dd, J=7.5, 2.5 Hz, 1H), 5.96 (d, J=3.0 Hz, 1H),
5.15 (s, 2H), 3.64 (m, 4H), 3.18-3.16 (m, 1H), 3.05-3.02 (m, 1H),
2.90-2.84 (m, 4H), 2.42-2.39 (m, 1H), 2.00-1.92 (m, 1H).
b)
1-(2,9-Dimethyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-7-yl)-4-(imida-
zo[1,2-a]pyridin-2-ylmethoxy)pyridin-2(1H)-one hydrochloride
##STR00347##
[0694] Following the procedure of Example 134 (step b), but
substituting
1-(2,9-dimethyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-7-yl)-4-(imidazo-
[1,2-a]pyridin-2-ylmethoxy)pyridin-2(1H)-one (25 mg, 0.056 mmol)
for
(4-benzyloxy)-1-(9-(difluoromethyl)-2-methyl-2,3,4,9-tetrahydro-1H-pyrido-
[3,4-b]indol-7-yl)pyridin-2(1H)-one, the title compound (27 mg,
98%) was prepared as a yellow solid: .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 10.91 (br s, 1H), 8.86 (d, J=6.0 Hz, 1H),
8.39 (s, 1H), 7.87-7.79 (m, 2H), 7.61 (d, J=7.5 Hz, 1H), 7.57 (d,
J=8.0 Hz, 1H), 7.51 (s, 1H), 7.37-7.35 (m, 1H), 7.01 (dd, J=8.5,
1.0 Hz, 1H), 6.15-6.11 (m, 2H), 5.42 (s, 2H), 4.77 (d, J=15.0 Hz,
1H), 4.43 (dd, J=14.0, 6.0 Hz, 1H), 3.80-3.77 (m, 1H), 3.66 (s,
3H), 3.41-3.39 (m, 1H), 3.08-3.04 (m, 2H), 2.99 (s, 3H); ESI MS m/z
440 [M+H].sup.+; HPLC (Method A) 97.1% (AUC), t.sub.R=9.8 min.
Example 139
Preparation of
1-(2,9-Dimethyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-7-yl)-4-(4-(trif-
luoromethyl)benzyloxy)pyridin-2(1H)-one hydrochloride
a) 4-(Imidazo[1,2-a]pyridin-6-ylmethoxy)pyridine 1-oxide
##STR00348##
[0696] Following the procedure of Example 137 (step a), but
substituting imidazo[1,2-a]pyridine-6-ylmethanol (2.91 g, 19.6
mmol) for imidazo[1,2-a]pyridine-2-ylmethanol, the title compound
(1.69 g, 42%) was prepared as an orange solid: .sup.1H NMR (300
MHz, DMSO-d.sub.6) .delta. 8.70 (s, 1H), 8.13-8.10 (m, 2H), 7.97
(s, 1H), 7.60-7.59 (m, 2H), 7.30 (dd, J=9.3, 1.7 Hz, 1H), 7.14-7.11
(m, 2H), 5.18 (s, 2H).
b) 4-(Imidazo[1,2-a]pyridin-6-ylmethoxy)pyridine-2(1H)-one
##STR00349##
[0698] 4-(Imidazo[1,2-a]pyridin-6-ylmethoxy)pyridine 1-oxide (1.69
g, 7.04 mmol) was heated at 140.degree. C. in acetic anhydride (20
mL) for 4 h. The mixture was concentrated and heated at 80.degree.
C. for 3 h in a mixture of 1:1 MeOH/H.sub.2O (50 mL). The resulting
solution was concentrated. The residue was partially dissolved in
iPrOH (75 mL). Et.sub.2O (200 mL) was added, and the mixture was
allowed to sit at ambient temperature for 1 h. The resulting solids
were collected by filtration, washed with Et.sub.2O and dried under
reduced pressure. The solids were again subjected to iPrOH and
Et.sub.2O, and the solids were removed by filtration. The filtrate
was concentrated to afford the title compound (0.47 g, 28%) as a
dark brown solid: .sup.1H NMR (300 MHz, CD.sub.3OD) .delta. 8.60
(d, J=0.7 Hz, 1H), 7.87 (d, J=0.6 Hz, 1H), 7.59 (d, J=1.4 Hz, 1H),
7.57 (s, 1H), 7.40-7.27 (m, 2H), 6.18 (dd, J=7.3, 2.5 Hz, 1H), 6.05
(d, J=2.5 Hz, 1H), 5.13 (s, 2H).
c)
tert-Butyl-7-(4-(imidazo[1,2-a]pyridin-6-ylmethoxy)-2-oxopyridin-1
(2H)-yl)-9-methyl-3,4-dihydro-1H-pyrido[3,4-b]indole-2(9H)-carboxylate
##STR00350##
[0700] Following the procedure of Example 133 (step b), but
substituting
4-(imidazo[1,2-a]pyridin-6-ylmethoxy)pyridine-2(1H)-one (218 mg,
0.901 mmol) for 4-benzyloxypyridone, the title compound (112 mg,
26%) was prepared as a yellow solid: .sup.1H NMR (500 MHz,
CDCl.sub.3) .delta. 8.25 (s, 1H), 7.68-7.65 (m, 2H), 7.64-7.61 (m,
1H), 7.53-7.52 (m, 1H), 7.33 (d, J=7.6 Hz, 1H), 7.28-7.26 (m, 1H),
7.22 (dd, J=9.3, 1.5 Hz, 1H), 7.01 (dd, J=8.2, 1.8 Hz, 1H), 6.11
(d, J=2.7 Hz, 1H), 6.03 (dd, J=7.5, 2.7 Hz, 1H), 5.06-5.04 (m, 2H),
4.70-4.57 (m, 2H), 3.75 (m, 2H), 3.62 (s, 3H), 2.79 (m, 2H), 1.51
(s, 9H).
d)
4-(Imidazo[1,2-a]pyridin-6-ylmethoxy)-1-(9-methyl-2,3,4,9-tetrahydro-1H-
-pyrido[3,4-b]indol-7-yl)pyridin-2(1H)-one hydrochloride
##STR00351##
[0702] Following the procedure of Example 135 (step d), but
substituting
tert-butyl-7-(4-(imidazo[1,2-a]pyridin-6-ylmethoxy)-2-oxopyridin-1
(2H)-yl)-9-methyl-3,4-dihydro-1H-pyrido[3,4-b]indole-2(9H)-carboxylate
(112 mg, 0.213 mmol) for
tert-butyl-7(4(2-fluoro-4-methoxyphenyl)-2-oxopyridin-2(1H)-yl)-9-methyl--
3,4-dihydro-1H-pyrido[3,4-b]indole-2(9H)-carboxylate, the crude
title compound was prepared. Preparative HPLC (Phenomenex Luna C18
(2), 250.0.times.21.2 mm, 10 micron, H.sub.2O with 0.05% TFA and
CH.sub.3CN with 0.05% TFA) yielded the title compound (12 mg, 13%)
as an off-white film: .sup.1H NMR (500 MHz, CDCl.sub.3) .delta.
8.24 (s, 1H), 7.67-7.65 (m, 2H), 7.59 (s, 1H), 7.53 (d, J=8.3 Hz,
1H), 7.34 (d, J=7.6 Hz, 1H), 7.26 (m, 1H overlapping with solvent),
7.22 (dd, J=9.3, 1.6 Hz, 1H), 7.00 (dd, J=8.3, 1.8 Hz, 1H), 6.11
(d, J=2.7 Hz, 1H), 6.03 (dd, J=7.6, 2.7 Hz, 1H), 5.04 (s, 2H), 4.04
(s, 2H), 3.57 (s, 3H), 3.17 (t, J=5.6 Hz, 2H), 2.76 (t, J=5.6 Hz,
2H).
e)
4-(Imidazo[1,2-a]pyridin-6-ylmethoxy)-1-(9-methyl-2,3,4,9-tetrahydro-1H-
-pyrido[3,4-b]indol-7-yl)pyridin-2(1H)-one hydrochloride
##STR00352##
[0704] Following the procedure of Example 134 (step b), but
substituting
4-(imidazo[1,2-a]pyridin-6-ylmethoxy)-1-(9-methyl-2,3,4,9-tetrahydro-1H-p-
yrido[3,4-b]indol-7-yl)pyridin-2(1H)-one (12 mg, 0.028 mmol) for
(4-benzyloxy)-1-(9-(difluoromethyl)-2-methyl-2,3,4,9-tetrahydro-1H-pyrido-
[3,4-b]indol-7-yl)pyridin-2(1H)-one, the title compound (14 mg,
100%) was prepared as a light yellow solid: .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 9.55 (br s, 2H), 9.01 (s, 1H), 8.33 (s, 1H),
8.11 (s, 1H), 7.97 (d, J=9.2 Hz, 1H), 7.89 (d, J=9.2 Hz, 1H), 7.61
(d, J=7.6 Hz, 1H), 7.56 (d, J=8.4 Hz, 1H), 7.50 (d, J=1.6 Hz, 1H),
7.00 (dd, J=8.4, 1.7 Hz, 1H), 6.13 (dd, J=7.6, 2.7 Hz, 1H), 6.08
(d, J=2.7 Hz, 1H), 5.31 (s, 2H), 4.46 (m, 2H), 3.67 (s, 3H), 3.44
(m, 2H), 2.97 (t, J=5.7 Hz, 2H); ESI MS m/z 426 [M+H].sup.+; HPLC
(Method A) >99% (AUC), t.sub.R=9.7 min.
Example 140
Preparation of
4-(Benzyloxy)-1-(8-fluoro-2,5-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b-
]indol-7-yl)pyridin-2(1H)-one hydrochloride
a) (3-Bromo-4-fluorophenyl)hydrazine hydrochloride
##STR00353##
[0706] A solution of sodium nitrite (4.2 g, 60 mmol) was added
drop-wise to a mixture of 3-bromo-4-fluoroaniline (11.2 g, 58.9
mmol) and concentrated HCl (30 mL, 0.36M) at 0.degree. C. over 30
min. The resulting clear solution was stirred for 45 min, and a
solution of SnCl.sub.2.2H.sub.2O (27 g, 120 mmol) in concentrated
HCl (30 mL) was added drop-wise at 0.degree. C. over 1.5 h. The
mixture was stirred for 18 h at room temperature. The resulting
precipitate was collected by filtration and crystallized from
ethanol to provide the title compound (6.2 g, 42%) as a yellow
powder: .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 10.24 (s, 3H),
8.42 (s, 1H), 7.36-7.30 (m, 2H), 7.03-6.98 (m, 1H).
b)
7-Bromo-8-fluoro-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate
##STR00354##
[0708] A mixture of (3-bromo-4-fluorophenyl)hydrazine hydrochloride
(3.0 g, 12 mmol), tert-butyl 4-oxopiperidine-1-carboxylate (2.48 g,
12.5 mmol) and concentrated HCl (6.0 mL, 72 mmol) in ethanol (40
mL) was stirred for 18 h at reflux. The solvent was removed under
reduced pressure, the residue was suspended in dichloromethane (50
mL), and di-tert-butyl dicarbonate (3.3 g, 15 mmol) and
triethylamine (2.1 mL, 30 mmol) were added. The mixture was stirred
for 18 h at ambient temperature. The resulting clear solution was
concentrated, and the residue was purified by flash chromatography
(silica gel, hexanes/ethyl acetate, 1:0 to 1:1) to afford the title
compound (0.9 g, 20%) as a yellow solid: .sup.1H NMR (500 MHz,
CDCl.sub.3) .delta. 7.94 (br s, 1H), 7.45 (d, J=5.5 Hz, 1H), 7.14
(br s, 1H), 4.56 (br s 2H), 3.81 (br m 2H), 2.81 (br m 2H), 1.57
(s, 9H); ESI MS m/z 369 [M+H].sup.+.
c) tert-Butyl
7-bromo-8-fluoro-5-methyl-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carbox-
ylate
##STR00355##
[0710] Sodium hydride (60% weight dispersion in mineral oil, 150
mg, 3.66 mmol) was added to a solution of tert-butyl
7-bromo-8-fluoro-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate
(0.9 g, 2.44 mmol) in 20 ml of DMF, and the mixture was stirred for
40 min at ambient temperature. Iodomethane (0.25 mL, 3.66 mmol) was
added, and the resulting suspension was stirred for 2 h. The
resulting mixture was concentrated under reduced pressure to
.about.1/3 of initial volume and treated with water (20 mL). The
resulting precipitate was collected by filtration, sequentially
washed with water and diethyl ether and dried under vacuum to
afford the title compound (0.75 g, 83%) as a yellow solid: .sup.1H
NMR (300 MHz, CDCl.sub.3) .delta. 7.42 (d, J=5.4 Hz, 1H), 7.17 (d,
J=9.3 Hz, 1H), 4.45 (br s, 2H), 3.81 (br m, 2H), 3.60 (s, 3H), 2.78
(br m, 2H), 1.52 (s, 9H); ESI MS m/z 383 [M+H].sup.+.
d)
4-(Benzyloxy)-1-(8-fluoro-5-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]i-
ndol-7-yl)pyridin-2(1H)-one
##STR00356##
[0712] tert-Butyl
7-bromo-8-fluoro-5-methyl-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carbox-
ylate (720 mg, 1.88 mmol), 4-benzyloxypyridone (380 mg, 1.9 mmol)
and Cs.sub.2CO.sub.3 (680 mg, 2.1 mmol) were suspended in DMSO (8.0
mL) and the resulting suspension was degassed for 15 min. The
system was flushed with Ar. Then 8-hydroxyquinoline (87 mg, 0.60
mmol) and copper iodide (114 mg, 0.599 mmol) were added. The
degassing/Ar flushing process was repeated twice more, and the
reaction mixture was heated at 133.degree. C. for 18 h under argon.
The reaction mixture was cooled, diluted with 15% solution of
concentrated ammonium hydroxide in methanol (25 mL) and stirred at
ambient temperature for 30 min. The reaction was further diluted
with dichloromethane (75 mL). The solution was filtered through
silica gel and concentrated under reduced pressure. The residue was
diluted with CH.sub.2Cl.sub.2 and washed with H.sub.2O (25 mL) and
brine (3.times.50 mL). The combined organics were dried over
Na.sub.2SO.sub.4 and concentrated to dryness. The crude material
was purified by flash chromatography (silica gel, (1:1
hexanes/EtOAc)/(10:1:0.1 dichloromethane/methanol/concentrated
ammonium hydroxide), 1:0 to 0:1) to afford crude tert-butyl
7-(4-(benzyloxy)-2-oxopyridin-1(2H)-yl)-8-fluoro-5-methyl-3,4-dihydro-1H--
pyrido[4,3-b]indole-2(5H)-carboxylate (280 mg) as a yellow oil.
This oil was dissolved in dichloromethane (3 mL) and TFA (1 mL) was
added. The reaction mixture was stirred at ambient temperature for
1 h, concentrated and dried under vacuum overnight to provide the
title compound (200 mg), which was used in the next step without
further purification: ESI MS m/z 404 [M+H].sup.+.
e)
4-(Benzyloxy)-1-(8-fluoro-2,5-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-
-b]indol-7-yl)pyridin-2(1H)-one hydrochloride
##STR00357##
[0714] To a solution of
4-(benzyloxy)-1-(8-fluoro-5-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]ind-
ol-7-yl)pyridin-2(1H)-one (100 mg, 0.26 mmol) in
dichloromethane/acetic acid (1% acetic acid, 10 mL) were
sequentially added formaldehyde (37% aqueous solution, 22 .mu.L,
0.74 mmol) and NaBH(OAc).sub.3 (316 mg, 1.49 mmol). The reaction
mixture was stirred at room temperature for 2.5 h. The mixture was
concentrated under reduced pressure, and the residue was dissolved
in CH.sub.2Cl.sub.2. The organic layer was washed with H.sub.2O and
5% aqueous LiCl, dried over Na.sub.2SO.sub.4, filtered and
concentrated. Purification by flash chromatography (silica gel,
CH.sub.2Cl.sub.2/(10:1:0.1 CH.sub.2Cl.sub.2/MeOH/NH.sub.4OH), 0:1
to 1:1) gave
4-(benzyloxy)-1-(8-fluoro-2,5-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[-
4,3-b]indol-7-yl)pyridin-2(1H)-one (78 mg, 38%) as a yellow solid.
The free base was converted to the HCl salt using 1.25M HCl in
methanol providing the title compound (75 mg, 95%) as a off-white
solid: .sup.1H NMR (300 MHz, CD.sub.3OD) .delta. 7.53-7.33 (m, 7H),
7.27 (d, J=10.5 Hz, 1H), 7.28 (dd, J=7.8, 2.4 Hz, 1H), 6.10 (d,
J=2.7 Hz, 1H), 5.17 (s, 2H), 3.79 (br s, 2H), 3.67 (s, 3H),
3.03-3.00 (m, 4H), 2.64 (s, 3H); ESI MS m/z 418 [M+H].sup.+; HPLC
(Method A) 95.7% (AUC), t.sub.R=14.5 min.
Example 141
Preparation of
4-(Benzyloxy)-1-(6-fluoro-9-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]ind-
ol-7-yl)pyridin-2(1H)-one hydrochloride
a) 2-(6-Bromo-5-fluoro-1H-indol-3-yl)ethanamine
##STR00358##
[0716] 4,4-Diethoxybutan-1-amine (4.72 g, 29.3 mmol) was added to
(3-bromo-4-fluorophenyl)hydrazine hydrochloride (6.4 g, 27 mmol).
The resulting mixture in an open round bottom flask was placed into
a preheated oil bath at 180.degree. C. The mixture was stirred at
180.degree. C. for 2.5 h and then cooled to 120.degree. C. Methanol
(300 mL) was added, and the mixture was stirred at ambient
temperature for 18 h. The resulting suspension was filtered through
a silica gel plug, and the silica gel was then washed with methanol
(5.times.300 mL). The combined methanol fractions were concentrated
under vacuum to provide the crude title compound (8.1 g) as a
yellow solid, which was used in the next step without further
purification: ESI MS m/z 257 [M+H].sup.+.
b) tert-Butyl
7-bromo-6-fluoro-3,4-dihydro-1H-pyrido[3,4-b]indole-2(9H)-carboxylate
##STR00359##
[0718] Glyoxylic acid (8.6 g, 95 mmol) was added to a solution of
2-(6-bromo-5-fluoro-1H-indol-3-yl)ethanamine (8.1 g 31 mmol) in 2N
HCl (150 ml), and the pH of the resulting solution was adjusted to
pH 3.5 with 6N NaOH solution. The reaction mixture was stirred at
ambient temperature for 18 h. The solution was adjusted to pH 5.5
with 6N NaOH solution. The resulting precipitate was collected by
filtration and dried under vacuum to afford a yellow solid. The
yellow solid was suspended in 2N HCl (100 mL), and the resulting
mixture was stirred at reflux for 4.5 h. The reaction mixture was
cooled to ambient temperature and was adjusted to pH 10 by addition
of 2N sodium hydroxide solution. The resulting precipitate was
collected by filtration and dried under vacuum to afford a crude
mixture of
7-bromo-6-fluoro-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole and
6-bromo-7-fluoro-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (2.0 g,
23%) as a yellow solid. The mixture (1.9 g, 7.1 mmol) was suspended
in dichloromethane (100 mL) and di-tert-butyl carbonate (1.85 g,
8.7 mmol) was added, followed by addition of DMAP (100 mg, 0.82
mmol). The reaction mixture was stirred at ambient temperature for
18 h and concentrated under vacuum. The residue was purified twice
by column chromatography (silica gel, hexanes/ethyl acetate, 0:1 to
1:1) to afford the title compound (300 mg, 12%) as a pale yellow
solid: .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 7.46 (d, J=5.7 Hz,
1H), 7.18 (d, J=9.0 Hz, 1H), 4.61 (s, 2H), 3.75 (br m, 2H), 2.73
(br m, 2H), 1.56 (s, 9H); ESI MS m/z 369 [M+H].sup.+.
c) tert-Butyl
7-bromo-6-fluoro-9-methyl-3,4-dihydro-1H-pyrido[3,4-b]indole-2(9H)-carbox-
ylate
##STR00360##
[0720] Sodium hydride (60% weight dispersion in mineral oil, 25 mg,
0.60 mmol) was added to a solution of tert-butyl
7-bromo-6-fluoro-3,4-dihydro-1H-pyrido[3,4-b]indole-2(9H)-carboxylate
(150 mg, 0.40 mmol) in DMF (10 mL) at room temperature under
N.sub.2 and stirred for 1 h at ambient temperature. Methyl iodide
(230 mg, 0.16 mL, 0.60 mmol) was added, and the reaction mixture
was stirred for 1 h. The resulting mixture was concentrated under
reduced pressure to approximately 1/3 of initial volume and treated
with water (20 mL). The resulting precipitate was collected by
filtration, washed with water and diethyl ether and dried under
vacuum to afford the title compound (140 mg, 91%) as a yellow
powder: ESI MS m/z 383 [M+H].sup.+.
d)
4-(Benzyloxy)-1-(6-fluoro-9-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]i-
ndol-7-yl)pyridin-2(1H)-one hydrochloride
##STR00361##
[0722] tert-Butyl
7-bromo-6-fluoro-9-methyl-3,4-dihydro-1H-pyrido[3,4-b]indole-2(9H)-carbox-
ylate (160 mg, 0.40 mmol), 4-benzyloxypyridone (80 mg, 0.33 mmol)
and Cs.sub.2CO.sub.3 (390 mg, 0.38 mmol) were suspended in DMSO
(8.0 mL) and degassed under vacuum for 15 min. The system was then
flushed with Ar, and 8-hydroxyquinoline (30 mg, 0.18 mmol) and
copper iodide (80 mg, 0.40 mmol) were added. The degassing/Ar
flushing process was repeated twice, and the reaction mixture was
heated at 133.degree. C. for 18 h under argon. The mixture was
cooled, diluted with 15% solution of concentrated ammonium
hydroxide in methanol (25 mL) and stirred at ambient temperature
for 30 min. The reaction was further diluted with CH.sub.2Cl.sub.2
(75 mL) and filtered through silica gel and concentrated. The
concentrate was diluted with CH.sub.2Cl.sub.2 and washed with
H.sub.2O (25 mL) and brine (3.times.50 mL). The combined organics
were dried over Na.sub.2SO.sub.4, filtered and concentrated under
reduced pressure to dryness. The crude material was purified by
flash chromatography (silica gel, (1:1 hexanes/EtOAc)/(10:1:0.1
dichloromethane/methanol/concentrated ammonium hydroxide), 1:0 to
0:1) to afford 75 mg of crude material containing the desired
product. The crude mixture was dissolved in a mixture of
dichloromethane and methanol (1:1, 5 mL), treated with TFA (2 mL)
and stirred at ambient temperature for 30 min. The solvent was
removed under reduced pressure, and the residue was neutralized by
ion-exchange chromatography (SCX-2 column, 5 g). Purification by
preparatory TLC (silica gel, 10:1:0.1
dichloromethane/methanol/concentrated ammonium hydroxide) provided
the free base of the title compound (12 mg, 10%) as a white foam:
ESI MS m/z 404 [M+H].sup.+. The free base was dissolved in methanol
(25 mL) and treated with a solution of HCl (1.25M in methanol, 0.1
mL, 0.13 mmol). The reaction mixture was sonicated for 5 min at
ambient temperature. The mixture was concentrated, and the
resulting residue was lyophilized from water (5 mL) to afford the
title compound (14 mg, 8%) as a white powder: .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 9.56 (br s, 2H), 7.61 (d, J=6.0 Hz, 1H), 7.54
(d, J=7.5 Hz, 1H), 7.50-7.37 (m, 6H), 6.14-6.12 (m, 1H), 5.99 (s,
1H), 5.16 (s, 2H), 4.46 (br s, 2H), 3.67 (s, 3H), 3.43 (br m, 2H),
2.94 (m, 2H); ESI MS m/z 404 [M+H].sup.+; HPLC (Method A) 95.7%
(AUC), t.sub.R=14.8 min
Example 142
Preparation of
4-(Benzyloxy)-1-(2-ethyl-9-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indo-
l-7-yl)pyridin-2(1H)-one hydrochloride
##STR00362##
[0724] To a solution of
4-(benzyloxy)-1-(9-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-7-yl)p-
yridin-2(1H)-one hydrochloride (120 mg, 0.28 mmol) in
dichloromethane/acetic acid (1% acetic acid, 10 mL) were
sequentially added acetaldehyde (0.50 mL, 13 mmol) and
NaBH(OAc).sub.3 (1.0 g, 4.7 mmol). The reaction mixture was stirred
at ambient temperature for 1 h. The mixture was concentrated, and
the residue was purified by flash chromatography (silica gel silica
gel, (1:1 hexanes/EtOAc)/(10:1:0.1
dichloromethane/methanol/concentrated ammonium hydroxide), 1:0 to
0:1) to provide
4-(benzyloxy)-1-(2-ethyl-9-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,-
4-b]indol-7-yl)pyridin-2(1H)-one (120 mg, 72%) as a white solid.
The free base was converted to the HCl salt using 1.25M HCl in
methanol, providing the title compound (120 mg, 95%) as an
off-white solid: .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 7.57
(d, J=7.5 Hz, 1H), 7.54-7.34 (m, 7H), 6.97 (d, J=8.0 Hz, 1H), 6.10
(dd, J=7.5, 2.0 Hz, 1H), 5.97 (s, 1H), 5.16 (s, 2H), 3.67 (s, 3H),
3.45-3.18 (4H, overlapping with solvent peak), 3.26 (br m, 2H),
2.96 (m, 2H), 1.33 (br m, 3H); ESI MS m/z 414 [M+H].sup.+; HPLC
(Method A) 95.7% (AUC), t.sub.R=14.6 min.
Example 143
Preparation of
4-(Benzyloxy)-1-(2-isopropyl-9-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]-
indol-7-yl)pyridin-2(1H)-one hydrochloride
##STR00363##
[0726] 2-Bromopropane (1.5 mL, 16 mmol) was added to a mixture of
4-(benzyloxy)-1-(9-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-7-yl)p-
yridin-2(1H)-one hydrochloride (138 mg, 0.327 mmol) and
Cs.sub.2CO.sub.3 (1.2 g, 3.7 mmol) in acetonitrile (25 mL). The
mixture was stirred at 55.degree. C. for 72 h. The resulting
mixture was cooled, and the precipitate was filtered off. The
mother liquor was concentrated under vacuum. The residue was
purified by preparatory TLC (silica gel, 10:1:0.1
dichloromethane/methanol/concentrated ammonium hydroxide) to afford
4-(benzyloxy)-1-(2-isopropyl-9-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]-
indol-7-yl)pyridin-2(1H)-one. The free base was converted to the
HCl salt using 1.25M HCl in methanol to provide the title compound
(26 mg, 19%) as a off white solid: .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 10.50 (s, 1H), 7.56 (d, J=4.5 Hz, 2H),
7.52-7.38 (m, 6H), 7.01 (dd, J=4.5, 1.0 Hz, 1H), 6.11 (dd, J=4.5,
1.0 Hz, 1H), 5.97 (s, 1H), 5.16 (s, 2H), 4.60-4.53 (m, 2H),
3.78-3.70 (m, 2H), 3.70 (s, 3H), 3.40-3.28 (m, 1H), 3.18-2.98 (m,
2H), 1.44-1.39 (m, 6H); ESI MS m/z 428 [M+H].sup.+; HPLC (Method A)
95.7% (AUC), t.sub.R=15.1 min.
Example 144
Preparation of Isopropyl
7-(4-(benzyloxy)-2-oxopyridin-1(2H)-yl)-9-methyl-3,4-dihydro-1H-pyrido[3,-
4-b]indole-2(9H)-carboxylate
##STR00364##
[0728] Following the procedure of Example 143, the title compound
(12 mg, 8%) was obtained as a second product as an off-white powder
after lyophilization from acetonitrile/water: .sup.1H NMR (500 MHz,
CDCl.sub.3) .delta. 7.48 (d, J=8.5 Hz, 1H), 7.50-7.32 (m, 7H), 6.99
(d, J=8.5 Hz, 1H), 6.90 (s, 1H), 6.34 (d, J=6.5 Hz, 1H), 5.17 (s,
2H), 5.05-5.00 (m, 1H), 4.72-4.58 (m, 2H), 3.79 (br m, 2H), 3.76
(s, 3H), 2.82 (m, 2H), 1.42-1.32 (m, 6H); ESI MS m/z 472
[M+H].sup.+; HPLC (Method A) 95.7% (AUC), t.sub.R=19.9 min.
Example 145
Preparation of
4-(Benzyloxy)-3-bromo-1-(9-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indo-
l-7-yl)pyridine-2(1H)-one hydrochloride
##STR00365##
[0730] 2-Bromopropane (0.25 mL, 2.7 mmol) was added to a solution
of
4-(benzyloxy)-1-(9-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-7-yl)p-
yridin-2(1H)-one in DMSO (5 mL). The reaction mixture was stirred
at 55.degree. C. for 3 d. The mixture was diluted with a saturated
solution of sodium bicarbonate and extracted with dichloromethane
(3.times.50 mL). The combined organics were washed with water and
brine, dried over sodium sulfate and concentrated under reduced
pressure. Purification by preparatory TLC (silica gel, 10:1:0.1
dichloromethane/methanol/concentrated ammonium hydroxide) provided
the free base of the title compound. The free base was converted to
the HCl salt using 2.5M HCl in methanol to afford, after
lyophilization from acetonitrile/water, the title compound (15 mg,
14%) as a yellow solid: .sup.1H NMR (300 MHz, CD.sub.3OD) .delta.
7.71 (d, J=7.8 Hz, 1H), 7.63 (d, J=8.4, Hz, 1H), 7.53-7.30 (m, 6H),
7.05 (dd, J=7.8, 1.2 Hz, 1H), 6.60 (d, J=7.6 Hz, 1H), 5.40 (s, 2H),
4.54 (s, 2H), 3.71 (s, 3H), 3.62-3.55 (m, 2H), 3.22-3.02 (m, 2H);
ESI MS m/z 465 [M+H].sup.+; HPLC (Method A) 95.7% (AUC),
t.sub.R=15.3 min.
Example 146
Preparation of
4-(Benzyloxy)-1-(2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-7-yl)pyridin-2(-
1H)-one dihydrochloride
a) Di-tert-butyl
7-bromo-3,4-dihydro-1H-pyrido[4,3-b]indole-2,5-dicarboxylate
##STR00366##
[0732] To a solution of tert-butyl
7-bromo-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate (1.00
g, 2.85 mmol), Boc.sub.2O (683 mg, 3.13 mol) and triethylamine
(0.73 mL, 5.7 mmol) in methylene chloride (30 mL) at room
temperature was added DMAP (50 mg, 0.41 mmol), and the reaction
progressed for 18 h. The mixture was washed with 0.5N HCl, and the
organic phase was removed, dried over Na.sub.2SO.sub.4, filtered
and concentrated to dryness. The crude title product (1.25 g, 98%)
was recovered as an orange solid: .sup.1H NMR (500 MHz, CDCl.sub.3)
.delta. 8.37 (br s, 1H), 7.34 (dd, J=8.2, 1.6 Hz, 1H), 7.24 (d,
J=8.25 Hz, 1H), 4.54 (br s, 2H), 3.73 (m, 2H), 3.07 (t, J=5.6 Hz,
2H), 1.66 (s, 9H), 1.50 (s, 9H).
b) tert-Butyl
7-(4-(benzyloxy)-2-oxopyridin-1(2H)-yl)-3,4-dihydro-1H-pyrido[4,3-b]indol-
e-2(5H)-carboxylate
##STR00367##
[0734] Prepared from di-tert-butyl
7-bromo-3,4-dihydro-1H-pyrido[4,3-b]indole-2,5-dicarboxylate (1.24
g, 2.72 mmol) and 4-benzyloxypyridone (547 mg, 2.72 mmol) according
to the procedure of Example 1 (step c). Purification by flash
column chromatography (silica gel, hexanes/ethyl acetate, 100:0 to
80:20 to 50:50 to 25:75 then 0:100) gave the title compound (155
mg, 10%) as a yellow solid: .sup.1H NMR (500 MHz, CDCl.sub.3)
.delta. 9.40 (br s, 1H), 7.44-7.38 (m, 5H), 7.30 (d, J=7.5 Hz, 1H),
7.22 (d, J=8.2 Hz, 1H), 7.16 (s, 1H), 6.82 (dd, J=8.2, 1.4 Hz, 1H),
6.12-6.09 (m, 2H), 5.09 (s, 2H), 4.46 (br s, 2H), 3.70 (br m, 2H),
2.54 (br m, 2H), 1.50 (s, 9H).
c)
4-(Benzyloxy)-1-(2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-7-yl)pyridin--
2(1H)-one dihydrochloride
##STR00368##
[0736] Prepared from tert-butyl
7-(4-(benzyloxy)-2-oxopyridin-1(2H)-yl)-3,4-dihydro-1H-pyrido[4,3-b]indol-
e-2(5H)-carboxylate (150 mg, 0.32 mmol) according to the procedure
of Example 1 (step d). Purification by flash column chromatography
(4 g ISCO column eluting with methylene chloride and a
methanol/ammonia mixture (10:1); gradient 100% methylene chloride
to 85% methylene chloride over 30 min) provided the free-base as a
yellow solid. This was converted to the bis-HCl salt (2N
HCl/Et.sub.2O in CH.sub.2Cl.sub.2) providing the title compound (36
mg, 26%) as a yellow solid: mp 240.degree. C. dec.; .sup.1H NMR
(500 MHz, CD.sub.3OD) .delta. 7.65 (d, J=7.5 Hz, 1H), 7.57 (d,
J=8.2 Hz, 1H), 7.47 (d, J=7.2 Hz, 2H), 7.42-7.36 (m, 4H), 7.03 (d,
J=8.5 Hz, 1H), 6.39 (dd, J=7.6, 2.5 Hz, 1H), 6.21 (d, J=2.5 Hz,
1H), 5.21 (s, 2H), 4.47 (s, 2H), 3.64 (t, J=6.0 Hz, 2H), 3.20 (t,
J=6.1 Hz, 2H); ESI MS m/z 372 [M+H].sup.+; HPLC (Method A) 95.0%
(AUC), t.sub.R=12.2 min.
Example 147
Preparation of
4-(Benzyloxy)-1-(5-ethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-7-yl)py-
ridin-2(1H)-one dihydrochloride
a) tert-Butyl
7-bromo-5-ethyl-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate
##STR00369##
[0738] Prepared from tert-butyl
7-bromo-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate (500
mg, 1.43 mmol) according to the procedure of Example 1 (step b).
This provided the title compound (520 mg, 96%) as a yellow/orange
solid: .sup.1H NMR (500 MHz, CDCl.sub.3) .delta. 7.36 (s, 1H), 7.23
(d, J=8.3 Hz, 1H), 7.10 (d, J=8.2 Hz, 1H), 4.54 (s, 2H), 3.96 (q,
J=7.2 Hz, 2H), 3.76 (br m, 2H), 2.71 (br m, 2H), 1.43 (s, 9H), 1.25
(t, J=7.2 Hz, 3H).
b) tert-Butyl
7-(4-(benzyloxy)-2-oxopyridin-1(2H)-yl)-5-ethyl-3,4-dihydro-1H-pyrido[4,3-
-b]indole-2(5H)-carboxylate
##STR00370##
[0740] Prepared from tert-butyl
7-bromo-5-ethyl-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate
(500 mg, 1.32 mmol) and 4-benzyloxypyridone (265 mg, 1.32 mmol),
according to the procedure of Example 1 (step c). Purification by
flash column chromatography (silica gel, hexanes/EtOAc, 100:0 to
80:20 to 50:50 to 25:75 then 0:100) gave the title compound (317
mg, 48%) as a yellow solid: .sup.1H NMR (300 MHz, CDCl.sub.3)
.delta. 7.53 (d, J=8.2 Hz, 1H), 7.44-7.37 (m, 5H), 7.32-7.29 (m,
2H), 7.04 (d, J=8.0 Hz, 1H), 6.10-6.03 (m, 2H), 5.08 (s, 2H), 4.66
(br s, 2H), 4.10 (q, J=7.1 Hz, 2H), 3.86 (br m, 2H), 2.84 (br m,
2H), 1.53 (s, 9H), 1.25 (t, J=7.1 Hz, 3H).
c)
4-(Benzyloxy)-1-(5-ethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-7-yl)-
pyridin-2(1H)-one dihydrochloride
##STR00371##
[0742] Prepared from tert-butyl
7-(4-(benzyloxy)-2-oxopyridin-1(2H)-yl)-5-ethyl-3,4-dihydro-1H-pyrido[4,3-
-b]indole-2(5H)-carboxylate (315 mg, 0.631 mmol) according to the
procedure of Example 1 (step d) providing the title compound (207
mg, 74%) as a yellow solid: mp 176-181.degree. C.; .sup.1H NMR (300
MHz, CD.sub.3OD) .delta. 7.83 (d, J=7.5 Hz, 1H), 7.62-7.57 (m, 2H),
7.45-7.40 (m, 5H), 7.09 (dd, J=8.4, 1.6 Hz, 1H), 6.59 (dd, J=7.5,
2.3 Hz, 1H), 6.36 (d, J=2.3 Hz, 1H), 5.28 (s, 2H), 4.49 (s, 2H),
4.23 (q, J=7.2 Hz, 2H), 3.68 (t, J=6.1 Hz, 2H), 3.22 (t, J=5.9 Hz,
2H), 1.35 (t, J=7.1 Hz, 3H); ESI MS m/z 400 [M+H].sup.+; HPLC
(Method A) >99% (AUC), t.sub.R=13.2 min.
[0743] In accordance with further embodiments of the invention,
there are provided the following compounds, which may be
synthesized by analogy by the methods shown and described
above:
TABLE-US-00003 Name Structure
1-(2-Isobutyryl-5-methyl-2,3,4,5-tetrahydro-1H-
pyrido[4,3-b]indol-7-yl)-4-(5-(trifluoromethyl)pyridin-
2-yl)pyridin-2(1H)-one ##STR00372##
1-(5-Methyl-2-propionyl-2,3,4,5-tetrahydro-1H-
pyrido[4,3-b]indol-7-yl)-4-(5-(trifluoromethyl)pyridin-
2-yl)pyridin-2(1H)-one ##STR00373##
4-(Benzyloxy)-1-(4,4,5-trimethyl-2,3,4,5-tetrahydro-
1H-pyrido[4,3-b]indol-7-yl)pyridin-2(1H)-one ##STR00374##
N,N,5-Trimethyl-7-(2-oxo-4-(5-
(trifluoromethyl)pyridin-2-yl)pyridin-1(2H)-yl)-3,4-
dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxamide ##STR00375##
4-((5-Fluoropyridin-2-yl)methoxy)-1-(2-isobutyryl-5-
methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-7-
yl)pyridin-2(1H)-one ##STR00376##
1-(2-Ethyl-5-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-
b]indol-7-yl)-4-((5-fluoropyridin-2- yl)methoxy)pyridin-2(1H)-one
##STR00377## 1-(2-(3-Hydroxy-2,2-dimethylpropanoyl)-5-methyl-
2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-7-yl)-4-(5-
(trifluoromethyl)pyridin-2-yl)pyridin-2(1H)-one ##STR00378##
1-(2-(3-Hydroxy-3-methylbutanoyl)-5-methyl-2,3,4,5-
tetrahydro-1H-pyrido[4,3-b]indol-7-yl)-4-(5-
(trifluoromethyl)pyridin-2-yl)pyridin-2(1H)-one ##STR00379##
1-(2-(2-Hydroxyacetyl)-5-methyl-2,3,4,5-tetrahydro-
1H-pyrido[4,3-b]indol-7-yl)-4-(5-
(trifluoromethyl)pyridin-2-yl)pyridin-2(1H)-one ##STR00380##
4-(Benzyloxy)-1-(2-isopropyl-9-methyl-2,3,4,9-
tetrahydro-1H-pyrido[3,4-b]indol-7-yl)pyridin-2(1H)- one
##STR00381## Isopropyl 7-(4-(benzyloxy)-2-oxopyridin-1(2H)-yl)-9-
methyl-3,4-dihydro-1H-pyrido[3,4-b]indole-2(9H)- carboxylate
##STR00382## 1-(5-Methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-
7-yl)-4-(5-(trifluoromethyl)pyrazin-2-yl)pyridin- 2(1H)-one
##STR00383## 1-(9-Methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-
7-yl)-4-(5-(trifluoromethyl)pyrazin-2-yl)pyridin- 2(1H)-one
##STR00384## 2-(5-Methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-
7-yl)-5-(5-(trifluoromethyl)pyridin-2-yl)pyridazin- 3(2H)-one
##STR00385## 2-(9-Methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-
7-yl)-5-(5-(trifluoromethyl)pyridin-2-yl)pyridazin- 3(2H)-one
##STR00386## 2-(5-Methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-
7-yl)-5-(6-(trifluoromethyl)pyridazin-3-yl)pyridazin- 3(2H)-one
##STR00387## 2-(9-Methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-
7-yl)-5-(6-(trifluoromethyl)pyridazin-3-yl)pyridazin- 3(2H)-one
##STR00388## 2-(5-Methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-
7-yl)-5-(4-(trifluoromethyl)phenyl)pyridazin-3(2H)- one
##STR00389## 2-(9-Methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-
7-yl)-5-(4-(trifluoromethyl)phenyl)pyridazin-3(2H)- one
##STR00390## 4-(Benzyloxy)-1-(2-isobutyl-5-methyl-2,3,4,5-
tetrahydro-1H-pyrido[4,3-b]indol-7-yl)pyridin-2(1H)- one
##STR00391## 4-(Benzyloxy)-1-(2-isobutyl-9-methyl-2,3,4,9-
tetrahydro-1H-pyrido[3,4-b]indol-7-yl)pyridin-2(1H)- one
##STR00392## 4-(Benzyloxy)-1-(2-(cyclopropylmethyl)-5-methyl-
2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-7-yl)pyridin- 2(1H)-one
##STR00393## 4-(Benzyloxy)-1-(2-(cyclopropylmethyl)-9-methyl-
2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-7-yl)pyridin- 2(1H)-one
##STR00394## 4-(5-Methoxypyridin-2-yl)-1-(5-methyl-2,3,4,5-
tetrahydro-1H-pyrido[4,3-b]indol-7-yl)pyridin-2(1H)- one
##STR00395## 4-(5-Methoxypyridin-2-yl)-1-(9-methyl-2,3,4,9-
tetrahydro-1H-pyrido[3,4-b]indol-7-yl)pyridin-2(1H)- one
##STR00396## 4-(Benzyloxy)-1-(4,4,9-trimethyl-2,3,4,9-tetrahydro-
1H-pyrido[3,4-b]indol-7-yl)pyridin-2(1H)-one ##STR00397##
4-(Benzyloxy)-1-(1,1,5-trimethyl-2,3,4,5-tetrahydro-
1H-pyrido[4,3-b]indol-7-yl)pyridin-2(1H)-one ##STR00398##
4-(Benzyloxy)-1-(1,1,3,3,5-pentamethyl-2,3,4,5-
tetrahydro-1H-pyrido[4,3-b]indol-7-yl)pyridin-2(1H)- one
##STR00399## 4-(Benzyloxy)-1-(3,3,5-trimethyl-2,3,4,5-tetrahydro-
1H-pyrido[4,3-b]indol-7-yl)pyridin-2(1H)-one ##STR00400##
1-(5-Methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-
7-yl)-4-(4-(methylsulfonyl)phenyl)pyridin-2(1H)-one ##STR00401##
1-(9-Methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-
7-yl)-4-(4-(methylsulfonyl)phenyl)pyridin-2(1H)-one ##STR00402##
1-(5-Methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-
7-yl)-4-(4-(methylsulfinyl)phenyl)pyridin-2(1H)-one ##STR00403##
1-(9-Methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-
7-yl)-4-(4-(methylsulfinyl)phenyl)pyridin-2(1H)-one ##STR00404##
1-(5-Methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-
7-yl)-4-(5-(methylthio)pyridin-2-yl)pyridin-2(1H)-one ##STR00405##
1-(9-Methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-
7-yl)-4-(5-(methylthio)pyridin-2-yl)pyridin-2(1H)-one
##STR00406##
Binding Assay I for Human Melanin-Concentrating Hormone (MCH.sub.1)
Receptor
[0744] Evaluation of the affinity of compounds for the human
MCH.sub.1 receptor was accomplished in transfected Chinese Hamster
Ovary (CHO) cells determined in a radioligand binding assay, as
described in MacDonald et al., "Molecular characterization of the
melanin-concentrating hormone/receptor complex: identification of
critical residues involved in binding and activation", Mol
Pharmacol., 58:217 (2000). Cell membrane homogenates (5 g protein)
were incubated for 60 min at 22.degree. C. with 0.1 nM
[.sup.125I][Phe.sup.13,Tyr.sup.19]-MCH in the absence or presence
of the test compound in a buffer containing 25 mM Hepes/Tris (pH
7.4), 5 mM MgCl.sub.2, 1 mM CaCl.sub.2 and 0.5% bovine serum
albumin (BSA). Nonspecific binding was determined in the presence
of 0.1M MCH. Following incubation, the samples were filtered
rapidly under vacuum through glass fiber filters (GF/B, Packard)
and rinsed several times with an ice-cold buffer containing 25 mM
Hepes/Tris (pH 7.4), 500 mM NaCl, 5 mM MgCl.sub.2, 1 mM CaCl.sub.2
and 0.1% BSA using a 96-sample cell harvester (Unifilter, Packard).
The filters were dried, then counted for radioactivity in a
scintillation counter (Topcount, Packard) using a scintillation
cocktail (Microscint 0, Packard).
[0745] The results are expressed as a percent inhibition of the
control radioligand specific binding. The IC.sub.50 value
(concentration causing a half-maximal inhibition of control
specific binding) and Hill coefficient (n.sub.H) were determined by
non-linear regression analysis of the competition curve using Hill
equation curve fitting. The inhibition constant (K.sub.i) was
calculated from the Cheng Prusoff equation:
(K.sub.i=IC.sub.50/(1+(L/K.sub.D)), where L=concentration of
radioligand in the assay, and K.sub.D=affinity of the radioligand
for the receptor).
Binding Assay II for Human Melanin-Concentrating Hormone (MCH1)
Receptor
[0746] Evaluation of the affinity of compounds for the human
MCH.sub.1 receptor was accomplished using
4-(3,4,5-tritritiumbenzyloxy)-1-(1-(2-(pyrrolidin-1-yl)ethyl)-1H-indazol--
5-yl)pyridin-2(1H)-one and membranes prepared from stable CHO-K1
cells expressing the human MCH.sub.1 receptor obtained from
Euroscreen (Batch 1138). Cell membrane homogenates (8.92 g protein)
were incubated for 60 min at 25.degree. C. with 1.4 nM of the
[.sup.3H]-labeled compound in the absence or presence of the test
compound in 50 mM Tris-HCl buffer, pH 7.4. Nonspecific binding was
determined in the presence of 50 .mu.M
1-(5-(4-cyanophenyl)bicyclo[3.1.0]hexan-2-yl)-3-(4-fluoro-3-(trifluoromet-
hyl)phenyl)-1-(3-(4-methylpiperazin-1-yl)propyl)urea. Following
incubation, the samples were filtered rapidly under vacuum through
Skatron 11731 filters, pre-soaked in 0.5% polyethylenimine, and
washed with ice-cold 50 mM Tris-HCl buffer, pH 7.4, (wash setting
9,9,0) using a Skatron cell harvester. The filters were counted for
radioactivity in a liquid scintillation counter (Tri-Carb 2100TR,
Packard) using a scintillation cocktail (Ultima Gold MV, Perkin
Elmer).
[0747] The results are expressed as a percent inhibition of the
control radioligand specific binding. The IC.sub.50 value
(concentration causing a half-maximal inhibition of control
specific binding) and Hill coefficient (n.sub.H) were determined by
non-linear regression analysis of the competition curve using Hill
equation curve fitting. The inhibition constant (K.sub.i) was
calculated from the Cheng Prusoff equation:
(K.sub.i=IC.sub.50/(1+(L/K.sub.D)), where L=concentration of
radioligand in the assay, and K.sub.D=affinity of the radioligand
for the receptor.
[0748] By methods as described above, the compounds listed in TABLE
1 were synthesized and tested for biological activity. All of the
compounds in TABLE 1 exhibited K.sub.i of less than or equal to 3.5
.mu.M in MCH.sub.1 binding assays I or II.
TABLE-US-00004 TABLE 1 Ex. Mass No. Structure Spec .sup.1H NMR Data
1 ##STR00407## 386 .sup.1H NMR (500 MHz, CD.sub.3OD) .delta.
7.61-7.57 (2 .times. d, 2H), 7.47-7.46 (m, 3H), 7.43-7.40 (m, 2H),
7.37- 7.34 (m, 1H), 7.05 (dd, J = 8.3, 1.7 Hz, 1H), 6.33 (dd, J =
7.5, 2.7 Hz, 1H), 6.16 (d, J = 2.6 Hz, 1H), 5.19 (s, 2H), 4.57 (s,
2H), 3.73 (s, 3H), 3.67 (t, J = 6.2 Hz, 2H), 3.20 (t, J = 6.1 Hz,
2H) 2 ##STR00408## 400 .sup.1H NMR (500 MHz, CD.sub.3OD) .delta.
7.57 (dd, J = 7.6, 1.7 Hz, 2H), 7.47-7.46 (m, 3H) 7.43-7.34 (m,
3H), 7.06 (dd, J = 8.4, 1.9 Hz, 1H), 6.29 (dd, J = 7.6, 2.7 Hz,
1H), 6.13 (d, J = 2.6 Hz, 1H), 5.18 (s, 2H), 4.75 (d, J = 14.3 Hz,
1H), 4.38 (d, J = 14.2 Hz, 1H), 3.90 (m, 1H), 3.73 (s, 3H),
3.64-3.58 (m, 1H), 3.29-3.26 (m, 2H, partially masked by solvent),
3.13 (s, 3H) 3 ##STR00409## 430 .sup.1H NMR (500 MHz, CD.sub.3OD)
.delta. 7.63 (dd, J = 7.6, 2.0 Hz, 2H), 7.51-7.50 (m, 3H) 7.46-7.43
(m, 2H), 7.41-7.38 (m, 1H), 7.09 (dd, J = 8.3, 1.7 Hz, 1H), 6.36
(dd, J = 7.6, 2.7 Hz, 1H), 6.18 (d, J = 2.7 Hz, 1H), 5.23 (s, 2H),
4.82 (d, 1H, partially masked by solvent), 4.520 (d, J = 14.3 Hz,
1H), 4.06-4.02 (m, 3H), 3.77 (s, 3H), 3.70-3.68 (m, 1H), 3.55-3.51
(m, 2H), 3.33-3.31 (m, 2H, partially masked by solvent) 4
##STR00410## 497 .sup.1H NMR (500 MHz, CD.sub.3OD) .delta. 7.62
(dd, J = 7.7, 1.9 Hz, 1H), 7.53 (d, J = 8.0 Hz, 1H) 7.46-7.44 (m,
2H), 7.41-7.35 (m, 4H), 7.06 (dd, J = 8.0, 1.7 Hz, 1H), 6.36 (d, J
= 7.6 Hz, 1H), 6.18 (s, 1H), 5.25 (s, 2H), 4.90 (m, 1H, masked by
solvent), 4.82 (s, 1H), 4.53 (d, J = 14.2 Hz, 2H), 4.09 (t, J = 6.5
Hz, 1H), 3.91 (t, J = 6.4 Hz, 1H), 3.89-3.86 (m, 2H), 3.77 (s, 3H),
3.20-3.18 (m, 2H), 3.05- 3.03 (m, 1H), 2.99-2.97 (m, 1H), 2.12-2.10
(m, 2H), 2.08-2.05 (m, 2H) 5 ##STR00411## 468 .sup.1H NMR (300 MHz,
CD.sub.3OD) .delta. 7.48 (d, J = 7.5 Hz, 1H), 7.40-7.24 (m, 7H),
6.87 (dd, J = 8.3, 1.9 Hz, 1H), 6.19 (dd, J = 7.6, 2.7 Hz, 1H),
6.03 (d, J = 2.7 Hz, 1H), 5.08 (s, 2H), 3.96 (s, 2H), 3.58 (s, 3H),
3.37 (q, J = 9.7 Hz, 2H), 3.15-3.14 (m, 2H, partially masked by
solvent), 2.87 (t, J = 5.5 Hz, 2H) 6 ##STR00412## 482 .sup.1H NMR
(500 MHz, CD.sub.3OD) .delta. 7.66 (d, J = 8.3 Hz, 1H), 7.63 (d, J
= 7.6 Hz, 1H), 7.52-7.51 (m, 3H), 7.48-7.45 (m, 2H), 7.43 (d, J =
7.2 Hz, 1H), 7.11 (dd, J = 8.3, 1.7 Hz, 1H), 6.36 (dd, J = 7.6, 2.7
Hz, 1H), 6.19 (d, J = 2.7 Hz, 1H), 5.24 (s, 2H), 4.96 (m, 6H,
masked by solvent), 3.79-3.74 (m, 5H), 3.03-3.02 (m, 2H) 7
##STR00413## 454 .sup.1H NMR (500 MHz, CD.sub.3OD) .delta. 7.77 (d,
J = 8.3 Hz, 2H), 7.71 (d, J = 8.2 Hz, 2H), 7.65 (d, J = 7.6 Hz,
1H), 7.62 (d, J = 8.3 Hz, 1H), 7.50 (s, 1H), 7.09 (dd, J = 8.3, 1.8
Hz, 1H), 6.38 (dd, J = 7.6, 2.7 Hz, 1H), 6.17 (d, J = 2.7 Hz, 1H),
5.33 (s, 2H), 4.51 (s, 2H), 3.77 (s, 3H), 3.71 (t, J = 6.2 Hz, 2H),
3.24 (t, J = 6.1 Hz, 2H) 8 ##STR00414## 420 .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 9.54 (br s, 2H), 7.57 (m, 2H), 7.51 (s, 5H),
6.99 (d, J = 7.8 Hz, 1H), 6.12 (dd, J = 7.8, 2.7 Hz, 1H), 5.99 (d,
J = 2.7 Hz, 1H), 5.16 (s, 2H), 4.33 (br s, 2H), 3.68 (s, 3H),
3.52-3.48 (m, 2H), 3.12-3.08 (m, 2H) 9 ##STR00415## 384 .sup.1H NMR
(500 MHz, CD.sub.3OD) .delta. 7.70 (d, J = 6.9 Hz, 1H), 7.62 (d, J
= 8.3 Hz, 1H), 7.52 (s, 1H), 7.33-7.26 (m, 4H), 7.22 (t, J = 7.2
Hz, 1H), 7.09 (dd, J = 8.3, 1.6 Hz, 1H), 6.59-6.56 (m, 2H), 4.50
(s, 2H), 3.76 (s, 3H), 3.70 (t, J = 6.2 Hz, 2H), 3.24 (t, J = 6.0
Hz, 2H), 3.04-3.01 (m, 2H), 2.98-2.95 (m, 2H) 10 ##STR00416## 424
.sup.1H NMR (500 MHz, CD.sub.3OD) .delta. 7.95 (d, J = 8.2 Hz, 2H),
7.84 (d, J = 8.2 Hz, 2H), 7.81 (d, J = 7.1 Hz, 1H), 7.63 (d, J =
8.3 Hz, 1H), 7.57 (s, 1H), 7.14 (dd, J = 8.3, 1.3 Hz, 1H), 6.96 (d,
J = 1.6 Hz, 1H), 6.87 (dd, J = 7.1, 1.7 Hz, 1H), 4.50 (s, 2H), 3.76
(s, 3H), 3.68 (t, J = 6.1 Hz, 2H), 3.22 (t, J = 6.1 Hz, 2H) 11
##STR00417## 390 .sup.1H NMR (500 MHz, CD.sub.3OD) .delta.
7.80-7.78 (m, 3H), 7.66 (d, J = 8.5 Hz, 1H), 7.58-7.57 (m, 3H),
7.16 (dd, J = 8.3, 1.7 Hz, 1H), 6.94 (d, J = 1.8 Hz, 1H), 6.87 (dd,
J = 7.1, 1.9 Hz, 1H), 6.17 (d, J = 2.7 Hz, 1H), 4.53 (s, 2H), 3.79
(s, 3H), 3.72 (t, J = 5.9 Hz, 2H), 3.25 (t, J = 5.9 Hz, 2H) 12
##STR00418## 424 .sup.1H NMR (500 MHz, CD.sub.3OD) .delta. 7.80 (d,
J = 7.0 Hz, 1H), 7.70 (s, 1H), 7.68 (d, J = 7.9 Hz, 1H), 7.62 (s,
1H), 7.54 (s, 2H), 7.13 (d, J = 7.0 Hz, 1H), 6.73 (s, 1H), 6.61 (d,
J = 7.2 Hz, 1H), 4.54 (s, 2H), 3.80 (s, 3H), 3.72 (t, J = 6.0 Hz,
2H), 3.26 (t, J = 5.9 Hz, 2H) 13 ##STR00419## 386 .sup.1H NMR (500
MHz, CD.sub.3OD) .delta. 7.59 (d, J = 7.5 Hz, 1H), 7.54 (d, J = 9.0
Hz, 1H), 7.48-7.40 (m, 5H), 7.38-7.36 (m, 1H), 7.17 (dd, J = 8.5,
1.5 Hz, 1H), 6.33 (dd, J = 7.5, 2.5 Hz, 1H), 6.16 )d, J = 2.5 Hz,
1H), 5.20 (s, 2H), 4.45 (s, 2H), 3.77 (s, 3H), 3.67 (t, J = 6.0 Hz,
2H), 3.21 (t, J = 6.0 Hz, 2H) 14 ##STR00420## 400 .sup.1H NMR (500
MHz, DMSO-d.sub.6) .delta. 10.26 (s, 1H), 7.56-7.36 (m, 8H), 7.10
(dd, J = 8.5, 1.5 Hz, 1H), 6.10 (dd, J = 7.5, 3.0 Hz, 1H), 5.97 (d,
J = 3.0 Hz, 1H), 5.15 (s, 2H), 4.58 (m, 1H), 4.27 (m, 1H), 3.78 (m,
1H), 3.72 (s, 3H), 3.50 (m, 1H), 3.18 (m, 2H), 2.97 (s, 3H) 15
##STR00421## 527 .sup.1H NMR (500 MHz, CD.sub.3OD) .delta.
7.78-7.75 (m, 1H), 7.57-7.54 (m, 1H), 7.49-7.37 (m, 6H), 7.04- 7.01
(m, 1H), 6.55-6.52 (m, 1H), 6.33-6.31 (m, 1H), 5.26 (s, 2H),
4.80-4.73 (m, 2H), 4.49-4.48 (m, 2H), 3.94-3.93 (m, 2H), 3.82-3.72
(m, 2H), 3.69 (s, 3H), 3.58-3.57 (m, 2H), 3.20-3.14 (m, 2H),
2.98-2.94 (m, 2H), 2.15-1.99 (m, 4H) 16 ##STR00422## 471 .sup.1H
NMR (500 MHz, CD.sub.3OD) .delta. 7.75-7.71 (m, 1H), 7.59-7.55 (m,
1H), 7.49-7.37 (m, 6H), 7.05- 7.01 (m, 1H), 6.49-6.45 (m, 1H),
6.28-6.26 (m, 1H), 5.24 (s, 2H), 4.87 (br s, 1H), 4.69 (br s, 1H),
4.44-4.41 (m, 2H), 4.11-4.07 (m, 1H), 3.85-3.82 (m, 1H), 3.70 (2
.times. s, 3H), 3.06-2.92 (m, 2H), 2.97-2.94 (2 .times. s, 6H) 17
##STR00423## 497 .sup.1H NMR (500 MHz, CD.sub.3OD) .delta. 7.60 (d,
J = 7.5 Hz, 1H), 7.56 (d, J = 8.0 Hz, 1H), 7.49-7.35 (m, 6H), 7.06
(dd, J = 8.5, 1.5 Hz, 1H), 6.33 (dd, J = 7.5, 3.0 Hz, 1H), 6.16 (d,
J = 3.0 Hz, 1H), 5.20 (s, 2H), 4.80 (d, J = 14.5 Hz, 1H), 4.54 (d,
J = 14.5 Hz, 1H), 4.36 (s, 2H), 4.00-3.98 (m, 1H), 3.75 (s, 3H),
3.68-3.65 (m, 1H), 3.54 (t, J = 7.0 Hz, 2H), 3.49-3.45 (m, 2H),
3.35-3.33 (m, 2H), 2.05-1.92 (m, 4H) 18 ##STR00424## 511 .sup.1H
NMR (500 MHz, CD.sub.3OD) .delta. 7.79-7.76 (m, 1H), 7.61-7.55 (m,
1H), 7.49-7.36 (m, 6H), 7.05- 7.02 (m, 1H), 6.55-6.52 (m, 1H),
6.33-6.32 (m, 1H), 5.26 (s, 2H), 4.06 (t, J = 5.5 Hz, 1H), 3.94 (t,
J = 5.5 Hz, 1H), 3.70-3.69 (m, 5H), 3.54-3.50 (m, 2H), 3.18-2.89
(m, 8H), 2.18-2.04 (m, 4H) 19 ##STR00425## 483 .sup.1H NMR (500
MHz, CD.sub.3OD) .delta. 7.75-7.72 (m, 1H), 7.63-7.55 (m, 1H),
7.49-7.36 (m, 6H), 7.05- 7.02 (m, 1H), 6.51-6.46 (m, 1H), 6.29-6.27
(m, 1H), 5.25 (s, 2H), 4.79-4.76 (m, 2H), 4.14-3.97 (m, 2H),
3.87-3.82 (m, 1H), 3.71-3.69 (m, 4H), 3.60-3.50 (m, 1H), 3.45-3.36
(m, 3H), 3.04-3.03 (m, 1H), 2.94-2.92 (m, 1H), 2.52-2.36 (m, 1H),
2.18-2.00 (m, 1H) 20 ##STR00426## 483 .sup.1H NMR (500 MHz,
CD.sub.3OD) .delta. 7.82-7.79 (m, 1H), 7.66-7.56 (m, 1H), 7.49-7.36
(m, 6H), 7.07- 7.03 (m, 1H), 6.59-6.56 (m, 1H), 6.36 (dd, J = 5.0,
2.5 Hz, 1H), 5.28 (s, 2H), 4.82-4.81 (m, 2H), 4.14-4.05 (m, 1H),
3.97-3.95 (m, 1H), 3.71-3.69 (2 .times. s, 3H), 3.58-3.34 (m, 3H),
3.07-2.94 (m, 2H), 2.70-2.57 (m, 1H), 2.17-1.85 (m, 3H) 21
##STR00427## 483 .sup.1H NMR (500 MHz, CD.sub.3OD) .delta.
7.82-7.79 (m, 1H), 7.66-7.56 (m, 1H), 7.49-7.36 (m, 6H), 7.07- 7.03
(m, 1H), 6.59-6.56 (m, 1H), 6.36 (dd, J = 5.0, 2.5 Hz, 1H), 5.28
(s, 2H), 4.82-4.81 (m, 2H), 4.14-4.05 (m, 1H), 3.97-3.95 (m, 1H),
3.71-3.69 (2 .times. s, 3H), 3.58-3.34 (m, 3H), 3.07-2.94 (m, 2H),
2.70-2.57 (m, 1H), 2.17-1.85 (m, 3H) 22 ##STR00428## 497 .sup.1H
NMR (500 MHz, CD.sub.3OD) .delta. 7.61-7.33 (m, 8H), 7.02-6.98 (m,
1H), 6.29-6.27 (m, 1H), 6.12- 6.11 (m, 1H), 5.17 (s, 2H), 4.79-4.76
(m, 2H), 4.09-3.97 (m, 2H), 3.81-3.79 (m, 1H), 3.69-3.67 (m, 4H),
3.49-3.42 (m, 1H), 3.22-3.16 (m, 2H), 3.00 (m, 1H), 2.92-2.91 (m,
1H), 2.81-2.78 (2 .times. s, 3H), 2.52-2.36 (m, 1H), 2.18-2.00 (m,
1H) 23 ##STR00429## 497 .sup.1H NMR (500 MHz, CD.sub.3OD) .delta.
7.61-7.33 (m, 8H), 7.03-6.99 (m, 1H), 6.30 (dd, J = 7.5, 2.5 Hz,
1H), 6.13 (d, J = 2.5 Hz, 1H), 5.18 (s, 2H), 4.80- 4.70 (m, 2H),
4.12-4.09 (m, 1H), 3.92-3.90 (m, 1H), 3.78-3.72 (m, 1H), 3.69-3.68
(2 s, 3H), 3.49-3.42 (m, 1H), 3.28-3.20 (m, 1H), 3.07-3.00 (m, 2H),
2.96-2.94 (2 s, 3H), 2.79-2.65 (m, 1H), 2.21-2.09 (m, 1H),
2.09-1.86 (m, 2H) 24 ##STR00430## 497 .sup.1H NMR (500 MHz,
CD.sub.3OD) .delta. 7.61-7.33 (m, 8H), 7.03-6.99 (m, 1H), 6.30 (dd,
J = 7.5, 2.5 Hz, 1H), 6.13 (d, J = 2.5 Hz, 1H), 5.18 (s, 2H), 4.80-
4.70 (m, 2H), 4.12-4.09 (m, 1H), 3.92-3.90 (m, 1H), 3.78-3.72 (m,
1H), 3.69-3.68 (2 s, 3H), 3.49-3.42 (m, 1H), 3.28-3.20 (m, 1H),
3.07-3.00 (m, 2H), 2.96-2.94 (2 .times. s, 3H), 2.79-2.65 (m, 1H),
2.21-2.09 (m, 1H), 2.09-1.86 (m, 2H) 25 ##STR00431## 388 .sup.1H
NMR (500 MHz, CD.sub.3OD) .delta. 7.82-7.79 (m, 2H), 7.75 (d, J =
7.0 Hz, 1H), 7.61 (d, J = 8.5 Hz, 1H), 7.56 (d, J = 1.5 Hz, 1H),
7.29-7.25 (m, 2H), 7.14 (dd, J = 8.5, 1.5 Hz, 1H), 6.88 (d, J = 2.0
Hz, 1H), 6.82 (dd, J = 7.0, 2.0 Hz, 1H), 4.77 (d, J = 14.0 Hz, 1H),
4.41 (d, J = 14.0 Hz, 1H), 3.93- 3.90 (m, 1H), 3.76 (s, 3H),
3.66-3.60 (m, 1H), 3.27 (m, 2H), 3.15 (s, 3H) 26 ##STR00432## 438
.sup.1H NMR (500 MHz, CD.sub.3OD) .delta. 7.95 (d, J = 8.5 Hz, 2H),
7.84 (d, J = 8.5 Hz, 2H), 7.80 (d, J = 7.5 Hz, 1H), 7.62 (d, J =
8.0 Hz, 1H), 7.57 (d, J = 1.5 Hz, 1H), 7.15 (dd, J = 8.5, 2.0 Hz,
1H), 6.96 (d, J = 1.5 Hz, 1H), 6.87 (dd, = 7.5, 2.0 Hz, 1H), 4.78
(d, J = 14.0 Hz, 1H), 4.41 (d, J = 14.0 Hz, 1H), 3.93-3.90 (m, 1H),
3.77 (s, 3H), 3.66-3.60 (m, 1H), 3.27 (m, 2H), 3.15 (s, 3H) 27
##STR00433## 404 .sup.1H NMR (500 MHz, CD.sub.3OD) .delta.
7.77-7.75 (m, 3H), 7.62 (d, J = 8.5 Hz, 1H), 7.57 (d, J = 2.0 Hz,
1H), 7.56-7.54 (m, 2H), 7.15 (dd, J = 8.5, 2.0 Hz, 1H), 6.91 (d, J
= 2.0 Hz, 1H), 6.84 (dd, J = 7.0, 2.0 Hz, 1H), 4.78 (d, J = 14.0
Hz, 1H), 4.41 (d, J = 14.0 Hz, 1H), 3.93-3.90 (m, 1H), 3.77 (s,
3H), 3.66-3.60 (m, 1H), 3.27 (m, 2H), 3.15 (s, 3H) 28 ##STR00434##
422 .sup.1H NMR (500 MHz, CD.sub.3OD) .delta. 7.76 (d, J = 7.0 Hz,
1H), 7.66-7.57 (m, 2H), 7.57 (d, J = 2.0 Hz, 1H), 7.42-7.39 (m,
2H), 7.15 (dd, J = 8.5, 2.0 Hz, 1H), 6.84 (s, 1H), 6.73-6.71 (m,
1H), 4.77 (d, J = 14.0 Hz, 1H), 4.41 (d, J = 14.0 Hz, 1H), 3.93-
3.90 (m, 1H), 3.76(s, 3H), 3.64-3.61 (m, 1H), 3.27 (m, 2H), 3.15
(s, 3H) 29 ##STR00435## 418 .sup.1H NMR (500 MHz, CD.sub.3OD)
.delta. 7.72 (d, J = 7.0 Hz, 1H), 7.63-7.56 (m, 3H), 7.15 (dd, J =
8.5, 1.5 Hz, 1H), 6.92 (dd, J = 8.5, 2.5 Hz, 1H), 6.87 (dd, J =
13.0, 2.0 Hz, 1H), 6.83 (s, 1H), 6.76 (d, J = 7.0 Hz, 1H), 4.77 (d,
J = 14.0 Hz, 1H), 4.41 (d, J = 14.0 Hz, 1H), 3.94-3.90 (m, 1H),
3.88 (s, 3H), 3.76 (s, 3H), 3.66-3.60 (m, 1H), 3.27 (m, 2H), 3.15
(s, 3H) 30 ##STR00436## 400 .sup.1H NMR (500 MHz, CD.sub.3OD)
.delta. 7.67-7.63 (m, 2H), 7.50-7.40 (m, 3H), 7.43-7.35 (m, 3H),
7.08 (dd, J = 8.3, 1.6 Hz, 1H), 6.40 (dd, J = 7.5, 2.6 Hz, 1H),
6.21 (d, J = 2.6 Hz, 1H), 5.22 (s, 2H), 4.81-4.80 (m, 1H), 4.58 (d,
J = 15.3 Hz, 1H), 3.88-3.84 (m, 1H), 3.72 (s, 3H), 3.55-3.49 (m,
1H), 3.21-3.16 (m, 5H) 31 ##STR00437## 398 .sup.1H NMR (500 MHz,
CD.sub.3OD) .delta. 7.67-7.64 (m, 2H), 7.51 (d, J = 1.8 Hz, 1H),
7.30-7.24 (m, 4H), 7.20-7.17(m, 1H), 7.08 (dd, J = 8.4, 1.9 Hz,
1H), 6.56 (dd, J = 6.9, 1.9 Hz, 1H), 6.53 (s, 1H), 4.85 (m, 1H),
4.49 (d, J = 15.3 Hz, 1H), 3.89-3.84 (m, 1H), 3.72 (s, 3H),
3.55-3.50 (m, 1H), 3.21-3.19 (m, 2H), 3.16 (s, 3H), 3.02-2.99 (m,
2H), 2.96- 2.93 (m, 2H) 32 ##STR00438## 468 .sup.1H NMR (500 MHz,
CD.sub.3OD) .delta. 7.78-7.73 (m, 3H), 7.69-7.64 (m, 3H), 7.52 (d,
J = 1.8 Hz, 1H), 7.18-7.08 (m, 1H), 6.55-6.52 (m, 1H), 6.28 (d, J =
2.6 Hz, 1H), 5.35 (s, 2H), 4.82-4.80 (m, 1H), 4.50 (d, J = 15.4 Hz,
1H), 3.89-3.85 (m, 1H), 3.73 (s, 3H), 3.55-3.50 (m, 1H), 3.22-3.16
(m, 5H) 33 ##STR00439## 434 .sup.1H NMR (500 MHz, CD.sub.3OD)
.delta. 7.83 (d, J = 7.6 Hz, 1H), 7.68 (d, J = 8.3 Hz, 1H),
7.50-7.46 (m, 3H), 7.44-7.42 (m, 2H), 7.08 (dd, J = 8.3, 1.8 Hz,
1H), 6.41 (dd, J = 7.6, 2.6 Hz, 1H), 6.21 (d, J = 2.6 Hz, 1H), 5.21
(s, 2H), 4.86-4.84 (m, 1H), 4.49 (d, J = 15.4 Hz, 1H), 3.88-3.84
(m, 1H), 3.72 (s, 3H), 3.55-3.50 (m, 1H), 3.21-3.16 (m, 5H) 34
##STR00440## 401 .sup.1H NMR (500 MHz, CD.sub.3OD) .delta. 8.90
(dd, J = 5.8, 1.8 Hz, 1H), 8.65 (overlapping ddd, J = 7.9, 1.6 Hz,
1H), 8.20 (d, J = 8.0 Hz, 1H), 8.07 (overlapping dd, J = 6.4 Hz,
1H), 7.70 (d, J = 7.6 Hz, 1H), 7.65 (d, J = 6.4 Hz, 1H), 7.49 (d, J
= 1.7 Hz, 1H), 7.07 (dd, J = 6.8, 1.8 Hz, 1H), 6.63 (dd, J = 7.6,
2.7 Hz, 1H), 6.21 (d, J = 2.7 Hz, 1H), 5.59 (s, 2H), 4.80 (m, 1H),
4.50 (d, J = 15.3 Hz, 1H), 3.88-3.85 (m, 1H), 3.73 (s, 3H),
3.55-3.50 (m, 1H), 3.21-3.16 (m, 5H) 35 ##STR00441## 421 .sup.1H
NMR (500 MHz, CD.sub.3OD) .delta. 8.61 (s, 1H), 7.77 (dd, J = 8.3,
3.8 Hz, 1H), 7.64-7.62 (m, 3H), 7.47 (d, J = 1.6 Hz, 1H), 7.03 (dd,
J = 8.4, 1.8 Hz, 1H), 6.37 (dd, J = 7.6, 3.8 Hz, 1H), 6.15 (d, J =
2.7 Hz, 1H), 5.28 (s, 2H), 4.54 (s, 2H), 3.71 (s, 3H), 3.60 (t, J =
6.1 Hz, 2H), 3.12 (t, J = 6.0 Hz, 2H) 36 ##STR00442## 435 .sup.1H
NMR (500 MHz, CD.sub.3OD) .delta. 8.68 (br s, 1H), 8.05 (dd, J =
8.0, 2.4 Hz, 1H), 7.76 (d, J = 8.4 Hz, 1H), 7.71 (d, J = 8.4 Hz,
1H), 7.65 (d, J = 8.3 Hz, 1H), 7.51 (d, J = 1.6 Hz, 1H), 7.09 (dd,
J = 8.3, 1.8 Hz, 1H), 6.53 (dd, J = 7.6, 1.7 Hz, 1H), 6.28 (d, J =
1.6 Hz, 1H), 5.36 (s, 2H), 4.85-4.80 (m, 1H), 4.49 (d, J = 15.3 Hz,
1H), 3.89-3.84 (m, 1H), 3.72 (s, 3H), 3.53-3.47 (m, 1H), 3.22-3.19
(m, 2H), 3.16 (s, 3H) 37 ##STR00443## 404 .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 11.0 (br s, 1H), 7.83 (dd, J = 6.8, 1.9 Hz,
2H), 7.76 (d, J = 7.1 Hz, 1H), 7.62-7.57 (m, 4H), 7.07 (dd, J =
8.3, 1.8 Hz, 1H), 6.81 (d, J = 2.0 Hz, 1H), 6.69 (dd, J = 7.2, 2.1
Hz, 1H), 4.79 (d, J = 15.2 Hz, 1H), 4.44 (dd,
J = 15.2, 6.0 Hz, 1H), 3.74-3.68 (m, 4H), 3.48- 3.38 (m, 1H),
3.10-2.99 (m, 5H) 38 ##STR00444## 390 .sup.1H NMR (500 MHz,
CD.sub.3OD) .delta. 7.78-7.75 (m, 3H), 7.67 (d, J = 8.3 Hz, 1H),
7.55-7.53 (m, 3H), 7.13 (dd, J = 8.3, 1.8 Hz, 1H), 6.91 (d, J = 1.9
Hz, 1H), 6.84 (dd, J = 7.1, 2.0 Hz, 1H), 4.56 (s, 2H), 3.74 (s,
3H), 3.61 (t, J = 6.0 Hz, 2H), 3.14 (t, J = 6.0 Hz, 2H) 39
##STR00445## 424 .sup.1H NMR (300 MHz, CD.sub.3OD) .delta. 7.97 (d,
J = 8.1 Hz, 2H), 7.87-7.80 (m, 3H), 7.68 (d, J = 8.2 Hz, 1H), 7.57
(d, J = 1.5 Hz, 1H), 7.14 (dd, J = 8.3, 1.8 Hz, 1H), 6.96 (d, J =
1.8 Hz, 1H), 6.87 (dd, J = 7.2, 1.8 Hz, 1H), 4.56 (s, 2H), 3.74 (s,
3H), 3.61 (t, J = 6.0 Hz, 2H), 3.14 (t, J = 6.0 Hz, 2H) 40
##STR00446## 438 .sup.1H NMR (500 MHz, CD.sub.3OD) .delta. 7.96 (d,
J = 8.2 Hz, 2H), 7.85-7.83 (m, 3H), 7.68 (d, J = 8.3 Hz, 1H), 7.58
(d, J = 1.6 Hz, 1H), 7.16 (dd, J = 8.3, 1.7 Hz, 1H), 6.98 (d, J =
1.8 Hz, 1H), 6.90 (dd, J = 7.1, 1.9 Hz, 1H), 4.87-4.86 (m, 1H),
4.51 (d, J = 15.3 Hz, 1H), 3.90-3.86 (m, 1H), 3.74 (s, 3H),
3.57-3.51 (m, 1H), 3.23-3.20 (m, 2H), 3.17 (s, 3H) 41 ##STR00447##
438 .sup.1H NMR (500 MHz, CD.sub.3OD) .delta. 7.77 (d, J = 7.0 Hz,
1H), 7.68 (d, J = 8.4 Hz, 1H), 7.65 (overlapping dd, J = 1.1 Hz,
1H), 7.58 (d, J = 1.7 Hz, 1H), 7.49 (s, 2H), 7.16 (dd, J = 8.3, 1.8
Hz, 1H), 6.70 (d, J = 1.5 Hz, 1H), 6.62 (dd, J = 7.0, 1.9 Hz, 1H),
4.86 (m, 1H), 4.50 (d, J = 15.3 Hz, 1H), 3.89-3.85 (m, 1H), 3.74
(s, 3H), 3.56-3.55 (m, 1H), 3.23-3.20 (m, 2H), 3.16 (s, 3H) 42
##STR00448## 386 .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 9.71
(br s, 2H), 7.56 (d, J = 7.6 Hz, 1H), 7.54 (d, J = 8.3 Hz, 1H),
7.50-7.47 (m, 3H), 7.44-7.41 (m, 2H), 7.38-7.37 (m, 1H), 6.99 (dd,
J = 8.3, 1.8 Hz, 1H), 6.11 (dd, J = 7.6, 2.8 Hz, 1H), 5.97 (d, J =
2.6 Hz, 1H), 5.15 (s, 2H), 4.45 (s, 2H), 3.81 (s, 3H), 3.42-3.41
(m, 2H), 2.98-2.97 (m, 2H) 43 ##STR00449## 430 .sup.1H NMR (500
MHz, CD.sub.3OD) .delta. 7.63 (d, J = 8.4 Hz, 1H), 7.61 (d, J = 7.5
Hz, 1H), 7.47-7.46 (m, 3H), 7.42-7.39 (m, 2H), 7.36 (d, J = 7.1 Hz,
1H), 7.06 (dd, J = 8.3, 1.8 Hz, 1H), 6.33 (dd, J = 7.6, 2.6 Hz,
1H), 6.15 (d, J = 2.6 Hz, 1H), 5.19 (s, 2H), 4.81-4.79 (m, 1H),
4.59 (d, J = 15.3 Hz, 1H), 4.01 (t, J = 5.1 Hz, 2H), 3.97-3.94 (m,
1H), 3.73 (s, 3H), 3.58-3.50 (m, 3H), 3.21-3.16 (m, 2H) 44
##STR00450## 497 .sup.1H NMR (500 MHz, CD.sub.3OD) .delta. 7.86 (d,
J = 7.5 Hz, 1H), 7.62 (dd, J = 8.2, 2.7 Hz, 1H), 7.51-7.50 (m, 3H),
7.46-7.43 (m, 2H), 7.41-7.40 (m, 1H), 7.08-7.06 (m, 1H), 6.63 (dd,
J = 7.8, 2.6 Hz, 1H), 6.40 (d, J = 1.4 Hz, 1H), 5.31 (s, 2H), 4.93
(s, 1.3H), 4.77 (s, 0.7H), 4.56-4.55 (m, 2H), 4.04- 4.02 (m, 0.6H),
3.81-3.78 (m, 3.4H), 3.76 (s, 3H), 3.24-3.19 (m, 2H), 2.79-2.97 (m,
1.3H), 2.92- 2.85 (m, 0.7H), 2.22-2.19 (m, 2H), 2.11-2.19 (m, 2H)
45 ##STR00451## 483 .sup.1H NMR (500 MHz, CD.sub.3OD) .delta. 7.79
(dd, J = 7.5, 1.4 Hz, 1H), 7.47 (d, J = 8.3 Hz, 1H), 7.49-7.46 (m,
3H), 7.44-7.46 (m, 2H), 7.39-7.36 (m, 1H), 7.04 (dd, J = 8.3, 1.6
Hz, 1H), 6.57-6.55 (m, 1H), 6.34 (d, J = 2.5 Hz, 1H), 5.27 (s, 2H),
4.96-4.87 (m, 2H), 3.90-8.86 (m, 2H), 3.77 (s, 3H), 3.48- 3.34 (m,
3H), 3.00-2.86 (m, 2H), 2.67-2.61 (m, 1H), 2.17-2.02 (m, 3H) 46
##STR00452## 386 .sup.1H NMR (500 MHz, CD.sub.3OD) .delta. 7.66 (d,
J = 7.5 Hz, 1H), 7.57-7.52 (m, 2H), 7.46 (d, J = 7.7 Hz, 2H), 7.41
(overlapping dd, J = 7.3 Hz, 2H), 7.36 (d, J = 7.5 Hz, 1H), 7.19
(dd, J = 8.6, 2.0 Hz, 1H), 6.42 (dd, J = 7.5, 2.7 Hz, 1H), 6.22 (d,
J = 2.6 Hz, 1H), 5.22 (s, 2H), 4.55 (s, 2H), 3.75 (s, 3H), 3.58 (t,
J = 6.0 Hz, 2H), 3.10 (t, J = 6.0 Hz, 2H) 47 ##STR00453## 400
.sup.1H NMR (500 MHz, CD.sub.3OD) .delta. 7.56-7.53 (m, 2H), 7.51
(d, J = 1.8, 1H), 7.46 (d, J = 7.3 Hz, 2H), 7.41 (overlapping dd, J
= 7.4 Hz, 2H), 7.36 (d, J = 7.2 Hz, 1H), 7.19 (dd, J = 8.6, 2.0 Hz,
1H), 6.27 (dd, J = 7.6, 2.7 Hz, 1H), 6.11 (d, J = 2.6 Hz, 1H), 5.18
(s, 2H), 4.64 (br s, 2H), 3.75 (s, 3H), 3.67 (br s, 2H), 3.18-3.13
(m, 5H) 48 ##STR00454## 425 .sup.1H NMR (500 MHz, CD.sub.3OD)
.delta. 9.06 (s, 1H), 8.28 (dd, J = 8.4, 2.1 Hz, 1H), 8.23 (d, J =
8.2 Hz, 1H), 7.87 (d, J = 7.1 Hz, 1H), 7.64 (d, J = 8.3 Hz, 1H),
7.58 (d, J = 1.6 Hz, 1H), 7.43 (d, J = 1.6 Hz, 1H), 7.29 (dd, J =
Hz, 1H), 7.17 (dd, J = 8.3, 1.8 Hz, 1H), 4.50 (s, 2H), 3.76 (s,
3H), 3.69 (t, J = 6.0 Hz, 2H), 3.22 (t, J = Hz, 2H) 49 ##STR00455##
405 .sup.1H NMR (500 MHz, CD.sub.3OD) .delta. 8.70 (s, 1H), 8.00
(dt, J = 8.4, 2.8 Hz, 1H), 7.91-7.88 (m, 2H), 7.63 (d, J = 8.4 Hz,
1H), 7.55 (s, 1H), 7.11 (dd, J = 8.3, 1.7 Hz, 1H), 6.69 (dd, J =
7.5, 2.7 Hz, 1H), 6.45 (d, J = 2.6 Hz, 1H), 5.46 (s, 2H), 4.49 (s,
2H), 3.75 (s, 3H), 3.68 (t, J = 6.1 Hz, 2H), 3.22 (t, J = 6.1 Hz,
2H) 50 ##STR00456## 426 .sup.1H NMR (500 MHz, CD.sub.3OD) .delta.
8.54 (d, J = 8.8 Hz, 1H), 8.28 (d, J = 8.9 Hz, 1H), 7.91 (d, J =
7.0 Hz, 1H), 7.64 (d, J = 8.4 Hz, 1H), 7.60 (d, J = 1.5 Hz, 1H),
7.44 (d, J = 1.5 Hz, 1H), 7.35 (dd, J = 7.2, 1.9 Hz, 1H), 7.16 (dd,
J = 8.3, 1.8 Hz, 1H), 4.50 (s, 2H), 3.77 (s, 3H), 3.69 (t, J = 6.1
Hz, 2H), 3.22 (t, J = 6.0 Hz, 2H) 51 ##STR00457## 421 .sup.1H NMR
(300 MHz, CD.sub.3OD) .delta. 8.61 (d, J = 2.1 Hz, 1H), 7.95 (dd, J
= 8.4, 2.4 Hz, 1H), 7.62 (d, J = 7.6 Hz, 2H), 7.58 (d, J = 8.4 Hz,
1H), 7.47 (d, J = 1.6 Hz, 1H), 7.05 (dd, J = 8.3, 1.8 Hz, 1H), 6.36
(dd, J = 7.6, 2.2 Hz, 1H), 6.13 (d, J = 2.6 Hz, 1H), 5.28 (s, 2H),
4.48 (s, 2H), 3.73 (s, 3H), 3.67 (t, J = 6.2 Hz, 2H), 3.02 (t, J =
6.2 Hz, 2H) 52 ##STR00458## 435 .sup.1H NMR (300 MHz, CD.sub.3OD)
.delta. 8.60 (d, J = 2.0 Hz, 1H), 7.96-7.92 (m, 1H), 7.61 (d, J =
7.7 Hz, 2H), 7.57 (d, J = 8.3 Hz, 1H), 7.47 (d, J = 1.4 Hz, 1H),
7.06 (dd, J = 8.4, 1.7 Hz, 1H), 6.34 (dd, J = 7.6, 2.6 Hz, 1H),
6.12 (d, J = 2.6 Hz, 1H), 5.27 (s, 2H), 4.75 (d, J = 14.2 Hz, 1H),
4.38 (d, J = 14.1 Hz, 1H), 3.95-3.85 (m, 1H), 3.73 (s, 3H), 3.63
(m, 1H), 3.31 (m overlapping with solvent, 2H), 3.13 (s, 3H) 53
##STR00459## 387 .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 8.88 (d,
J = 5.2 Hz, 1H), 8.59 (dd, J = 7.9, 1.5 Hz, 1H), 8.15 (d, J = 8.0
Hz, 1H), 8.01 (overlapping dd, J = 6.6 Hz, 1H), 7.69 (d, J = 7.6
Hz, 1H), 7.60 (d, J = 8.4 Hz, 1H), 7.48 (d, J = 1.6 Hz, 1H), 7.06
(dd, J = 8.4, 1.8 Hz, 1H), 6.44 (dd, J = 7.6, 2.7 Hz, 1H), 6.21 (d,
J = 2.7 Hz, 1H), 5.57 (s, 2H), 4.48 (s, 2H), 3.74 (s, 3H), 3.68 (t,
J = 6.2 Hz, 2H), 3.21 (t, J = 6.2 Hz, 2H) 54 ##STR00460## 401
.sup.1H NMR (500 MHz, CD.sub.3OD) .delta. 8.87 (d, J = 5.7 Hz, 1H),
8.58 (overlapping dd, J = 8.2 Hz, 1H), 8.14 (d, J = 7.9 Hz, 1H),
8.00 (overlapping dd, J = 6.6 Hz, 1H), 7.69 (d, J = 7.6 Hz, 1H),
7.59 (d, J = 8.3 Hz, 1H), 7.49 (s, 1H), 7.07 (dd, J = 8.3, 1.7 Hz,
1H), 6.44 (dd, J = 7.5, 2.6 Hz, 1H), 6.20 (d, J = 2.0 Hz, 1H), 5.56
(s, 2H), 4.76 (d, J = 14.2 Hz, 1H), 4.40 (d, J = 14.2 Hz, 1H), 3.91
(m, 1H), 3.74 (s, 3H), 3.61 (m, 1H), 3.29-3.17 (m overlapping with
solvent, 2H), 3.13 (s, 3H) 55 ##STR00461## 387 .sup.1H NMR (500
MHz, CD.sub.3OD) .delta. 8.89 (d, J = 5.4 Hz, 1H), 8.61
(overlapping ddd, J = 8.0, 1.6 Hz, 1H), 8.16 (d, J = 8.0 Hz, 1H),
8.02 (overlapping dd, J = 6.6 Hz, 1H), 7.70 (d, J = 7.6 Hz, 1H),
7.63 (d, J = 8.4 Hz, 1H), 7.47 (d, J = 1.6 Hz, 1H), 7.06 (dd, J =
8.4, 1.8 Hz, 1H), 6.44 (dd, J = 7.6, 2.7 Hz, 1H), 6.21 (d, J = 2.6
Hz, 1H), 5.57 (s, 2H), 4.56 (s, 2H), 3.73 (s, 3H), 3.60 (t, J =
6.0, 2H), 3.13 (t, J = 6.0, 2H) 56 ##STR00462## 384 .sup.1H NMR
(300 MHz, DMSO-d.sub.6) .delta. 9.67 (s, 2H), 7.59-7.52 (m, 3H),
7.35-7.27 (m, 4H), 7.24-7.17 (m, 1H), 7.01 (dd, J = 7.4, 2.0 Hz,
1H), 6.38-6.27 (m, 2H), 4.45 (s, 2H), 3.67 (s, 3H), 3.42 (t, J =
6.4 Hz, 2H), 2.97-2.89 (m, 4H), 2.81-2.76 (m, 2H) 57 ##STR00463##
391 .sup.1H NMR (500 MHz, CD.sub.3OD) .delta. 8.74 (d, J = 2.4 Hz,
1H), 8.06 (d, J = 8.5 Hz, 1H), 8.02 (dd, J = 8.7, 2.4 Hz, 1H), 7.86
(d, J = 7.2 Hz, 1H), 7.64 (d, J = 8.3 Hz, 1H), 7.58 (d, J = 1.9 Hz,
1H), 7.37 (d, J = 1.5 Hz, 1H), 7.27 (dd, J = 8.5, 1.8 Hz, 1H), 7.15
(dd, J = 8.4, 1.8 Hz, 1H), 4.50 (s, 2H), 3.75 (s, 3H), 3.68 (t, J =
6.5 Hz, 2H), 3.22 (t, J = 6.5 Hz, 2H) 59 ##STR00464## 419 .sup.1H
NMR (500 MHz, CD.sub.3OD) .delta. 8.65 (d, J = 2.6 Hz, 1H), 7.91
(overlapping ddd, J = 9.6, 2.1 Hz, 1H), 7.83-7.20 (m, 2H), 7.61 (d,
J = 8.4 Hz, 1H), 7.53 (d, J = 1.8 Hz, 1H), 7.09 (dd, J = 8.4, 1.8
Hz, 1H), 6.59 (dd, J = 7.5, 2.6 Hz, 1H), 6.36 (d, J = 2.6 Hz, 1H),
5.41 (s, 2H), 4.76 (d, J = 14.2 Hz, 1H), 4.39 (d, J = 14.2 Hz, 1H),
3.94-3.82 (m, 2H), 3.74 (s, 3H), 3.65-3.58 (m, 2H), 3.13 (s, 3H) 60
##STR00465## 405 .sup.1H NMR (500 MHz, CD.sub.3OD) .delta. 8.72 (d,
J = 1.7 Hz, 1H), 8.03 (d, J = 7.9 Hz, 1H), 7.99 (dd, J = 8.2, 2.2
Hz, 1H), 7.79 (d, J = 7.1 Hz, 1H), 7.61 (d, J = 8.3 Hz, 1H), 7.56
(d, J = 1.3 Hz, 1H), 7.34 (d, J = 1.5 Hz, 1H), 7.19 (dd, J = 7.2,
1.8 Hz, 1H), 7.14 (dd, J = 8.3, 1.8 Hz, 1H), 4.80-4.72 (br m, 1H),
4.46-4.34 (m, 1H), 3.96-3.86 (m, 1H), 3.75 (s, 3H), 3.65-3.55 (br
m, 1H), 3.28 (s, 2H), 3.14 (s, 3H) 61 ##STR00466## 483 .sup.1H NMR
(300 MHz, D.sub.2O) .delta. 7.50 (d, J = 8.3 Hz, 1H), 7.46 (d, J =
7.7 Hz, 1H), 7.42-7.31 (m, 6H), 6.96 (dd, J = 8.3, 1.6 Hz, 1H),
6.27 (dd, J = 7.7, 2.6 Hz, 1H), 6.10 (d, J = 2.6 Hz, 1H), 5.90 (s,
2H), 4.59 (br s, 2H), 3.81-3.59 (m, 8H), 3.55 (s, 3H), 3.20 (t, J =
5.7 Hz, 2H), 3.18-3.05 (br m, 2H), 2.15-1.90 (m, 4H) 62
##STR00467## 439 .sup.1H NMR (500 MHz, CD.sub.3OD) .delta. 9.04 (s,
1H), 8.28 (dd, J = 8.7, 1.9 Hz, 1H), 8.21 (d, J = 2.1 Hz, 1H), 7.83
(d, J = 7.1 Hz, 1H), 7.62 (d, J = 8.3 Hz, 1H), 7.58 (d, J = 1.3 Hz,
1H), 7.39 (d, J = 1.6 Hz, 1H), 7.24 (dd, J = 7.1, 1.9 Hz, 1H), 7.15
(dd, J = 8.3, 1.7 Hz, 1H), 4.80-4.71 (br m, 1H), 4.44-4.35 (br m,
1H), 3.96-3.86 (br m, 1H), 3.75 (s, 3H), 3.67- 3.57 (br m, 1H),
3.28 (s, 2H), 3.14 (s, 3H) 63 ##STR00468## 372 .sup.1H NMR (500
MHz, CD.sub.3OD) .delta. 8.47 (d, J = 8.8 Hz, 1H), 8.03 (d, J = 8.8
Hz, 1H), 7.89 (d, J = 7.4 Hz, 1H), 7.64 (d, J = 8.4 Hz, 1H), 7.58
(d, J = 1.6 Hz, 1H), 7.35 (d, J = 1.6 Hz, 1H), 7.25 (dd, J = 7.1,
1.9 Hz, 1H), 7.15 (dd, J = 8.3, 1.9 Hz, 1H), 4.49 (s, 2H), 3.75 (s,
3H), 3.68 (t, J = 6.2 Hz, 2H), 3.24 (t, J = 6.2 Hz, 2H), 2.85 (s,
3H) 64 ##STR00469## 386 .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta.
10.9 (s, 1H), 8.32 (d, J = 8.8 Hz, 1H), 7.85 (d, J = 7.2 Hz, 1H),
7.79 (d, J = 8.8 Hz, 1H), 7.64 (d, J = 1.5 Hz, 1H), 7.56 (d, J =
8.3 Hz, 1H), 7.25 (d, J = 1.7 Hz, 1H), 7.14-7.11 (m, 2H), 4.65 (d,
J = 12.1 Hz, 1H), 4.31 (dd, J = 14.2, 7.5 Hz, 1H), 3.81-3.74 (m,
1H), 3.71 (s, 3H), 3.55-3.45 (m, 1H), 3.26-3.15 (m, 2H), 2.98 (s,
3H), 2.72 (s, 3H) 65 ##STR00470## 404 .sup.1H NMR (300 MHz,
DMSO-d.sub.6) .delta. 9.56 (br s, 2H), 7.64 (d, J = 7.1 Hz, 1H),
7.62-7.55 (m, 2H), 7.47 (dd, J = 8.4, 6.9 Hz, 1H), 7.12-7.06 (m,
2H), 6.90 (overlapping ddd, J = 8.4, 2.4 Hz, 1H), 6.55 (d, J = 1.6
Hz, 1H), 6.47 (dd, J = 7.1, 1.8 Hz, 1H), 4.37-4.30 (br m, 2H), 3.81
(s, 3H), 3.69 (s, 3H), 3.56-3.45 (br m, 2H), 3.10 (t, J = 5.5 Hz,
2H) 66 ##STR00471## 418 .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta.
10.83 (br s, 1H), 7.65 (d, J = 7.1 Hz, 1H), 7.61 (d, J = 1.4 Hz,
1H), 7.54 (d, J = 8.3 Hz, 1H), 7.46 (dd, J = 8.4, 6.9 Hz, 1H),
7.12-7.10 (m, 1H), 7.08 (d, J = 1.4 Hz, 1H), 6.91 (overlapping ddd,
J = 8.4, 2.4 Hz, 1H), 6.55 (d, J = 1.6 Hz, 1H), 6.48 (dd, J = 7.1,
1.6 Hz, 1H), 4.62 (d, J = 12.2 Hz, 1H), 4.30 (dd, J = 14.2, 7.5 Hz,
1H), 3.86 (s, 3H), 3.80-3.76 (m, 1H), 3.75 (s, 3H), 3.52-3.42 (m,
1H), 3.24-3.15 (m, 2H), 2.79 (d, J = 4.6 Hz, 3H) 67 ##STR00472##
469 .sup.1H NMR (500 MHz, D.sub.2O) .delta. 7.56-7.53 (m, 2H),
7.48-7.40 (m, 6H), 7.02 (dd, J = 8.4, 1.4 Hz, 1H), 6.33 (dd, J =
7.5, 2.4 Hz, 1H), 6.17 (d, J = 2.4 Hz, 1H), 5.16 (s, 2H), 4.63 (br
s, 2H), 4.09-3.79 (br m, 2H), 3.69-3.53 (m, 6H), 3.26-3.23 (m, 2H),
3.14 (t, J 12.8 Hz, 2H), 2.49 (d, J = 1.3 Hz, 2H), 2.16-2.04 (m,
2H) 68 ##STR00473## 483 .sup.1H NMR (500 MHz, D.sub.2O) .delta.
7.56-7.52 (m, 2H), 7.48-7.38 (m, 6H), 7.02 (dd, J = 8.3, 1.6 Hz,
1H), 6.33 (dd, J = 7.5, 2.6 Hz, 1H), 6.16 (d, J = 2.5 Hz, 1H), 5.16
(s, 2H), 4.63 (s, 2H), 3.85-3.83 (m, 2H), 3.74-3.71 (m, 2H), 3.62
(s, 3H), 3.26-3.14 (m, 5H), 2.89 (s, 3H), 2.55-2.50 (m, 2H), 2.19-
2.12 (m, 2H) 69 ##STR00474## 425 .sup.1H NMR (300 MHz, CD.sub.3OD)
.delta. 9.10 (d, J = 2.0 Hz, 1H), 8.41 (dd, J = 8.2, 1.7 Hz, 1H),
7.98 (d, J = 8.2 Hz, 1H), 7.85 (d, J = 7.2 Hz, 1H), 7.61 (d, J =
8.2 Hz, 1H), 7.57 (d, J = 1.6 Hz, 1H), 7.14 (dd, J = 8.3, 1.9 Hz,
1H), 7.02 (d, J = 1.6 Hz, 1H), 6.89 (dd, J = 7.1, 2.0 Hz, 1H), 4.49
(s, 2H), 3.76 (s, 3H), 3.68 (t, J = 6.2 Hz, 2H), 3.22 (t, J = 6.2
Hz, 2H) 70 ##STR00475## 439 .sup.1H NMR (500 MHz, CD.sub.3OD)
.delta. 9.09 (d, J = 1.7 Hz, 1H), 8.42 (dd, J = 8.1, 2.0 Hz, 1H),
7.97 (d, J = 8.2 Hz, 1H), 7.85 (d, J = 7.1 Hz, 1H), 7.62 (d, J =
8.3 Hz, 1H), 7.58 (d, J = 1.5 Hz, 1H), 7.15 (dd, J = 8.3, 1.8 Hz,
1H), 7.02 (d, J = 1.8 Hz, 1H), 6.89 (dd, J = 7.1, 2.0 Hz, 1H),
4.79-4.37 (br m, 2H), 3.90-3.60 (br m, 5H), 3.30 (br m, 2H), 3.14
(s, 3H) 71 ##STR00476## 411 .sup.1H NMR (500 MHz, CD.sub.3OD)
.delta. 9.04 (s, 1H), 8.28 (dd, J = 8.3, 2.2 Hz, 1H), 8.22 (d, J =
8.2 Hz, 1H), 7.81 (d, J = 7.0 Hz, 1H), 7.62 (d, J = 8.3 Hz, 1H),
7.46 (d, J = 1.8 Hz, 1H), 7.38 (d, J = 1.8 Hz, 1H), 7.24 (dd, J =
7.1, 2.0 Hz, 1H), 7.11 (dd, J = 8.3, 2.0 Hz, 1H), 4.49 (s, 2H),
3.65 (t, J = 6.2 Hz, 2H), 3.21 (t, J = 6.2 Hz, 2H) 72 ##STR00477##
412 .sup.1H NMR (300 MHz, CD.sub.3OD) .delta. 8.52 (d, J = 8.9 Hz,
1H), 8.28 (d, J = 8.9 Hz, 1H), 7.89 (d, J = 7.2 Hz, 1H), 7.62 (d, J
= 8.3 Hz, 1H), 7.48 (d, J = 1.5 Hz, 1H), 7.43 (d, J = 1.5 Hz, 1H),
7.33 (dd, J = 7.2, 2.0 Hz, 1H), 7.14 (dd, J = 7.4, 2.0 Hz, 1H),
4.49 (s, 2H), 3.65 (t, J = 6.2 Hz, 2H), 3.21 (t, J = 6.2 Hz, 2H) 73
##STR00478## 426 .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 9.51
(s, 2H), 9.37 (br s, 2H), 7.90 (d, J = 7.2 Hz, 1H), 7.62- 7.60 (m,
2H), 7.13 (d, J = 1.9 Hz, 1H), 7.10 (dd, J = 8.3, 1.7 Hz, 1H), 6.88
(dd, J = 7.1, 2.0 Hz, 1H), 4.38-4.34 (br m, 2H), 3.70 (s, 3H),
3.56-3.50 (br m, 2H), 3.11 (t, J = 5.8 Hz, 2H) 74 ##STR00479## 426
.sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 9.48 (s, 2H), 9.37 (br
s, 2H), 7.89 (d, J = 7.2 Hz, 1H), 7.65 (d, J = 1.6 Hz, 1H), 7.61
(d, J = 8.3 Hz, 1H), 7.50 (d, J = 1.6 Hz, 1H), 7.21 (dd, J = 7.6,
1.9 Hz, 1H), 7.12 (dd, J = 8.3, 1.8 Hz, 1H), 4.41-4.31 (br m, 2H),
3.71 (s, 3H), 3.51-3.48 (br m, 2H), 3.10 (t, J = 5.6 Hz, 2H) 75
##STR00480## 455 .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 9.54
(br
s, 2H), 8.89 (s, 1H), 8.19 (dd, J = 7.9, 1.4 Hz, 1H), 8.00 (d, J =
8.0 Hz, 1H), 7.60 (d, J = 7.6 Hz, 1H), 7.55 (d, J = 8.3 Hz, 1H),
7.50 (d, J = 1.7 Hz, 1H), 6.98 (dd, J = 8.3, 1.8 Hz, 1H), 6.15 (dd,
J = 7.5, 2.7 Hz, 1H), 6.02 (d, J = 2.7 Hz, 1H), 5.35 (s, 2H),
4.35-4.30 (br m, 2H), 3.67 (s, 3H), 3.53-3.47 (br m, 2H), 3.09 (t,
J = 5.8 Hz, 2H) 76 ##STR00481## 455 .sup.1H NMR (300 MHz,
CD.sub.3OD) .delta. 8.93 (s, 1H), 8.23 (dd, J = 8.2, 2.1 Hz, 1H),
7.82 (d, J = 8.2 Hz, 1H), 7.70 (d, J = 7.5 Hz, 1H), 7.59 (d, J =
8.3 Hz, 1H), 7.49 (d, J = 1.7 Hz, 1H), 7.06 (dd, J = 8.3, 1.8 Hz,
1H), 6.47 (dd, J = 7.5, 2.7 Hz, 1H), 6.20 (d, J = 2.6 Hz, 1H), 5.42
(s, 2H), 4.48 (s, 2H), 3.73 (s, 3H), 3.67 (t, J = 6.1 Hz, 2H), 3.20
(t, J = 6.1 Hz, 2H) 77 ##STR00482## 387 .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 9.23 (s, 2H), 7.96 (d, J = 2.8 Hz, 1H), 7.59
(d, J = 1.6 Hz, 1H), 7.54 (d, J = 8.4 Hz, 1H), 7.51-7.48 (m, 2H),
7.46-7.42 (m, 2H), 7.40 (d, J = 7.5 Hz, 1H), 7.13 (dd, J = 8.4, 1.7
Hz, 1H), 6.51 (d, J = 2.8 Hz, 1H), 5.22 (s, 2H), 4.34 (s, 2H), 3.69
(s, 3H), 3.52 (t, J = 5.8 Hz, 2H), 3.09 (t, J = 5.8 Hz, 2H) 78
##STR00483## 425 .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 9.37
(s, 2H), 8.56 (d, J = 2.2 Hz, 1H), 8.13 (d, J = Hz, 2H), 7.93 (d, J
= 8.2 Hz, 2H), 7.72 (d, J = 1.6 Hz, 1H), 7.61 (d, J = 8.4 Hz, 1H),
7.48 (d, J = 2.2 Hz, 1H), 7.25 (dd, J = 8.4, 1.8 Hz, 1H), 4.36 (s,
2H), 3.70 (s, 3H), 3.58-3.48 (br m, 2H), 3.11 (t, J = 5.7 Hz, 2H)
79 ##STR00484## 391 .sup.1H NMR (500 MHz, CD.sub.3OD) .delta. 8.73
(dd, J = 2.4, 0.6 Hz, 1H), 8.03 (dd, J = 8.5, 0.5 Hz, 1H), 8.00
(dd, J = 8.5, 2.4 Hz, 1H), 7.80 (d, J = 7.1 Hz, 1H), 7.67 (d, J =
8.3 Hz, 1H), 7.56 (d, J = 1.7 Hz, 1H), 7.31 (d, J = 1.7 Hz, 1H),
7.19 (dd, J = 7.1, 2.0 Hz, 1H), 7.14 (dd, J = 8.4, 1.8 Hz, 1H),
4.56 (s, 2H), 3.74 (s, 3H), 3.61 (t, J = 6.1 Hz, 2H), 3.14 (t, J =
6.1 Hz, 2H) 80 ##STR00485## 405 .sup.1H NMR (500 MHz, CD.sub.3OD)
.delta. 8.73 (d, J = 2.3 Hz, 1H), 8.03 (d, J = 8.5 Hz, 1H) 7.99
(dd, J = 8.5, 2.3 Hz, 1H), 7.79 (d, J = 7.2 Hz, 1H), 7.67 (d, J =
8.3 Hz, 1H), 7.57 (s, 1H), 7.31 (d, J = 1.6 Hz, 1H), 7.19 (dd, J =
7.1, 1.8 Hz, 1H), 7.15 (dd, J = 8.3, 1.7 Hz, 1H), 4.65 (br s, 2H),
3.74 (m, 5H), 3.21 (t, J = 5.7 Hz, 2H), 3.17 (s, 3H) 81
##STR00486## 425 .sup.1H NMR (500 MHz, CD.sub.3OD) .delta. 9.05 (s,
1H), 8.28 (dd, J = 8.3, 2.2 Hz, 1H), 8.22 (d, J = 8.3, Hz, 1H),
7.84 (d, J = 7.1 Hz, 1H), 7.67 (d, J = 8.4 Hz, 1H), 7.58 (d, J =
1.8 Hz, 1H), 7.40 (d, J = 1.8 Hz, 1H), 7.25 (dd, J = 7.2, 2.0 Hz,
1H), 7.15 (dd, J = 8.4, 1.8 Hz, 1H), 4.57 (s, 2H), 3.74 (s, 3H),
3.62 (t, J = 6.1 Hz, 2H), 3.15 (t, J = 5.9 Hz, 2H) 82 ##STR00487##
439 .sup.1H NMR (500 MHz, CD.sub.3OD) .delta. 9.05 (s, 1H), 8.28
(dd, J = 8.3, 2.1 Hz, 1H) 8.22 (d, J = 8.4, Hz, 1H), 7.84 (d, J =
7.1 Hz, 1H), 7.68 (d, J = 8.3 Hz, 1H), 7.59 (d, J = 1.6, 1H), 7.40
(d, J = 1.7 Hz, 1H), 7.25 (dd, J = 7.2, 1.9 Hz, 1H), 7.16 (dd, J =
8.3, 1.8 Hz, 1H), 4.87 (s, 1H), 4.51 (s, 1H), 3.87 (s, 1H), 3.75
(br s, 3H), 3.55 (br s, 1H), 3.21-3.17 (m, 5H) 84 ##STR00488## 405
.sup.1H NMR (500 MHz, CD.sub.3OD) .delta. 8.51 (s, 1H), 7.72-7.59
(m, 4H), 7.46 (d, J = 1.0 Hz, 1H), 7.05 (dd, J = 8.3, 1.5 Hz, 1H),
6.32 (dd, J = 7.6, 2.6 Hz, 1H), 7.05 (d, J = 2.6 Hz, 1H), 5.26 (s,
2H), 4.54 (s, 2H), 3.71 (s, 3H), 3.60 (t, J = 6.0 Hz, 2H), 3.12 (t,
J = 5.8 Hz, 2H) 85 ##STR00489## 419 .sup.1H NMR (500 MHz,
CD.sub.3OD) .delta. 8.51 (d, J = 2.6 Hz, 1H), 7.72-7.59 (m, 4H),
7.47 (s, 1H), 7.06 (dd, J = 8.3, 1.7 Hz, 1H), 6.32 (dd, J = 7.6,
2.6 Hz, 1H), 6.13 (d, J = 2.6 Hz, 1H), 5.26 (s, 2H), 4.68 (m, 2H),
3.71 (m, 5H), 3.18 (t, J = 5.9 Hz, 2H), 3.15 (s, 3H) 86
##STR00490## 425 .sup.1H NMR (500 MHz, CD.sub.3OD) .delta. 9.10 (d,
J = 1.9 Hz, 1H), 8.41 (dd, J = 8.2, 2.2 Hz, 1H), 7.97 (d, J = 8.3
Hz, 1H), 7.85 (d, J = 7.0 Hz, 1H), 7.68 (d, J = 8.3 Hz, 1H), 7.57
(d, J = 1.7 Hz, 1H), 7.15 (dd, J = 8.3, 1.8 Hz, 1H), 7.03 (d, J =
1.8 Hz, 1H), 6.89 (dd, J = 7.1, 2.0 Hz, 1H), 4.57 (br m, 2H), 3.75
(s, 3H), 3.62 (br m, 2H), 3.15 (br m, 2H) 87 ##STR00491## 411
.sup.1H NMR (500 MHz, CD.sub.3OD) .delta. 9.05 (s, 1H), 8.28 (dd, J
= 8.4, 2.1 Hz, 1H), 8.22 (d, J = 8.4 Hz, 1H), 7.82 (d, J = 7.2 Hz,
1H), 7.66 (d, J = 8.4 Hz, 1H), 7.48 (d, J = 7.1 Hz, 1H), 7.39 (d, J
= 1.7 Hz, 1H), 7.24 (dd, J = 7.2, 1.9 Hz, 1H), 7.13 (dd, J = 8.4,
1.8 Hz, 1H), 4.50 (s, 2H), 3.63 (t, J = 6.1 Hz, 2H), 3.14 (t, J =
6.1 Hz, 2H) 88 ##STR00492## 387 .sup.1H NMR (500 MHz, CD.sub.3OD)
.delta. 7.93 (d, J = 2.7 Hz, 1H), 7.59 (d, J = 8.4 Hz, 1H), 7.56
(d, J = 1.5 Hz, 1H), 7.50-7.48 (m, 2H), 7.43 (overlapping dd, J =
7.8 Hz, 2H), 7.39 (d, J = 1.7 Hz, 1H), 7.18 (dd, J = 8.4, 1.7 Hz,
1H), 6.48 (d, J = 2.7 Hz, 1H), 5.22 (s, 2H), 4.54 (s, 2H), 3.71 (s,
3H), 3.59 (t, J = 5.6 Hz, 2H), 3.12 (t, J = 5.9 Hz, 2H) 89
##STR00493## 455 .sup.1H NMR (500 MHz, CD.sub.3OD) .delta. 8.75 (s,
1H), 8.08 (d, J = 7.9 Hz, 1H), 7.79 (d, J = 8.1 Hz, 1H), 7.53 (dd,
J = 7.9, 2.0 Hz, 2H), 7.38 (d, J = 1.7 Hz, 1H), 6.97 (dd, J = 8.4,
1.8 Hz, 1H), 6.25 (dd, J = 7.6, 2.7 Hz, 1H), 6.08 (d, J = 2.6 Hz,
1H), 5.26 (s, 2H), 4.46 (s, 2H), 3.63 (s, 3H), 3.51 (t, J = 6.1 Hz,
2H), 3.03 (t, J = 6.1 Hz, 2H) 90 ##STR00494## 371 .sup.1H NMR (500
MHz, CD.sub.3OD) 8.59 (s, 1H), 7.95 (d, J = 8.1 Hz, 1H), 7.87 (d, J
= 6.5 Hz, 1H), 7.80 (d, J = 7.0 Hz, 1H), 7.67 (d, J = 8.4 Hz, 1H),
7.56 (d, J = 1.4 Hz, 1H), 7.24 (d, J = 1.6 Hz, 1H), 7.15-7.12 (m,
2H), 4.57 (s, 2H), 3.74 (s, 3H), 3.61 (t, J = 6.0 Hz, 2H), 3.14 (t,
J = 6.1 Hz, 2H), 2.46 (s, 3H) 91 ##STR00495## 371 .sup.1H NMR (500
MHz, CD.sub.3OD) .delta. 8.76 (d, J = 1.8 Hz, 1H), 8.34 (d, J = 6.9
Hz, 1H), 8.24 (d, J = 8.2 Hz, 1H), 7.94 (d, J = 7.2 Hz, 1H), 7.67
(d, J = 8.3 Hz, 1H), 7.61 (d, J = 1.7 Hz, 1H), 7.23 (d, J = 1.8 Hz,
1H), 7.17 (dd, J = 8.3, 1.8 Hz, 1H), 7.04 (dd, J = 7.1, 2.1 Hz,
1H), 4.53 (s, 2H), 3.79 (s, 3H), 3.71 (t, J = 6.2 Hz, 2H), 3.25 (t,
J = 6.2 Hz, 2H), 2.61 (s, 3H) 92 ##STR00496## 371 .sup.1H NMR (500
MHz, CD.sub.3OD) .delta. 8.80 (d, J = 2.2 Hz, 1H), 8.12 (dd, J =
8.1, 2.5 Hz, 1H), 7.79 (d, J = 7.0 Hz, 1H), 7.59 (d, J = 8.3 Hz,
1H), 7.52 (d, J = 1.7 Hz, 1H), 7.47 (d, J = 8.2 Hz, 1H), 7.10 (dd,
J = 8.3, 1.9 Hz, 1H), 6.93 (d, J = 1.8 Hz, 1H), 6.85 (dd, J = 7.1,
2.0 Hz, 1H), 4.34 (s, 2H), 3.73 (s, 3H), 3.52 (t, J = 6.1 Hz, 2H),
3.10 (t, J = 6.1 Hz, 2H), 2.62 (s, 3H) 93 ##STR00497## 371 .sup.1H
NMR (500 MHz, CD.sub.3OD) .delta. 8.80 (d, J = 8.1 Hz, 1H), 8.11
(dd, J = 8.2, 2.5 Hz, 1H), 7.79 (d, J = 7.0 Hz, 1H), 7.64 (d, J =
8.3 Hz, 1H), 7.52 (d, J = 1.7 Hz, 1H), 7.47 (d, J = 8.2 Hz, 1H),
7.11 (dd, J = 8.3, 1.8 Hz, 1H), 6.93 (d, J = 1.9 Hz, 1H), 6.85 (dd,
J = 7.1, 2.0 Hz, 1H), 4.40 (s, 2H), 3.71 (s, 3H), 3.46 (t, J = 5.9
Hz, 2H), 3.04 (t, J = 5.9 Hz, 2H), 2.62 (s, 3H) 94 ##STR00498## 400
.sup.1H NMR (500 MHz, CD.sub.3OD) .delta. 7.79 (d, J = 7.0 Hz, 1H),
7.66 (d, J = 8.0 Hz, 1H), 7.53 (s, 1H), 7.48-7.36 (m, 5H), 7.10 (d,
J = 8.5 Hz, 1H), 6.55 (d, J = 6.5 Hz, 1H), 6.33 (s, 1H), 5.27 (s,
2H), 4.98 (q, J = 6.5 Hz, 1H), 3.76 (s, 3H), 3.67-3.59 (m, 2H),
3.13-3.08 (m, 2H), 1.76 (d, J = 7.0 Hz, 3H) 95 ##STR00499## 414
.sup.1H NMR (500 MHz, CD.sub.3OD) .delta. 7.58-7.55 (m, 2H),
7.47-7.34 (m, 6H), 6.99 (d, J = 8.5, 1.0 Hz, 1H), 6.28 (dd, J =
7.5, 2.5 Hz, 1H), 6.11 (d, J = 2.5 Hz, 1H), 5.18 (s, 2H), 4.27 (q,
J = 6.5 Hz, 1H), 3.69 (s, 3H), 3.36-3.33 (m, 1H), 3.10-2.96 (m,
2H), 2.84-2.80 (m, 1H), 2.65 (s, 3H), 1.51 (d, J = 6.5 Hz, 3H) 96
##STR00500## 430 .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 9.12
(s, 2H), 7.66 (d, J = 2.0 Hz, 1H), 7.59-7.56 (m, 2H), 7.49-7.37 (m,
5H), 7.08-7.05 (m, 1H), 6.14-6.12 (m, 1H), 5.99 (d, J = 2.5 Hz,
1H), 5.57 (s, 2H), 5.17 (s, 2H), 4.38 (m, 2H), 3.55 (m, 2H), 3.45-
3.40 (m, 2H), 3.13 (m, 2H), 1.08-1.05 (m, 3H) 97 ##STR00501## 356
.sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 9.26 (s, 2H), 7.79 (dd,
J = 8.0, 1.5 Hz, 2H), 7.75 (d, J = 7.5 Hz, 1H), 7.62 (d, J = 1.5
Hz, 1H), 7.59 (d, J = 8.5 Hz, 1H), 7.55-7.50 (m, 3H), 7.10 (dd, J =
8.5, 2.0 Hz, 1H), 6.78 (d, J = 1.5 Hz, 1H), 6.70 (dd, J = 7.0, 2.0
Hz, 1H), 4.37 (m, 2H), 3.71 (s, 3H), 3.54- 3.53 (m, 2H), 3.10 (t, J
= 6.0 Hz, 2H) 98 ##STR00502## 370 .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 10.46 (s, 1H), 7.80-7.74 (m, 3H), 7.63 (s,
1H), 7.56-7.52 (m, 4H), 7.11 (d, J = 8.0 Hz, 1H), 6.78 (s, 1H),
6.70 (d, J = 7.0 Hz, 1H), 4.68-4.65 (m, 1H), 4.34- 4.30 (m, 1H),
3.82-3.79 (m, 1H), 3.71 (s, 3H), 3.53-3.51 (m, 1H), 3.20 (m, 2H),
3.00 (d, J = 4.0 Hz, 3H) 99 ##STR00503## 404 .sup.1H NMR (500 MHz,
CD.sub.3OD) .delta. 7.72 (d, J = 7.0 Hz, 1H), 7.63-7.56 (m, 3H),
7.14 (dd, J = 8.5, 1.5 Hz, 1H), 6.92 (dd, J = 8.5, 2.5 Hz, 1H),
6.87 (dd, J = 13.0, 2.5 Hz, 1H), 6.84 (s, 1H), 6.77-6.75 (m, 1H),
4.50 (s, 2H), 3.88 (s, 3H), 3.76 (s, 3H), 3.68 (t, J = 6.0 Hz, 2H),
3.22 (t, J = 6.0 Hz, 2H) 100 ##STR00504## 428 .sup.1H NMR (500 MHz,
CDCl.sub.3) .delta. 7.53-7.36 (m, 6H), 7.32-7.30 (m, 2H), 7.06-7.00
(m, 1H), 6.09 (d, J = 3.0 Hz, 1H), 6.07-6.04 (m, 1H), 5.06 (s, 2H),
4.82 (s, 1H), 4.67 (s, 1H), 4.03 (t, J = 5.5 Hz, 1H), 3.84 (t, J =
5.5 Hz, 1H), 3.64 (s, 3H), 2.90 (t, J = 5.5 Hz, 1H), 2.84 (t, J =
5.5 Hz, 1H), 2.24, 2.22 (2 .times. s, 3H) 101 ##STR00505## 447
.sup.1H NMR (500 MHz, CDCl.sub.3) .delta. 8.50 (d, J = 1.5 Hz, 1H),
7.54-7.46 (m, 3H), 7.35 (d, J = 7.5 Hz, 1H), 7.32 (d, J = 2.0 Hz,
1H), 7.03 (ddd, J = 20, 8.0, 1.5 Hz, 1H), 6.15-6.08 (m, 2H), 5.18
(s, 2H), 4.83, 4.70 (2 .times. s, 2H), 4.04 (t, J = 5.5 Hz, 1H),
3.85 (t, J = 5.5 Hz, 1H), 3.65, 3.64 (2 .times. s, 3H), 2.91 (t, J
= 5.5 Hz, 1H), 2.85 (t, J = 5.5 Hz, 1H), 2.23, 2.25 (2 .times. s,
3H) 102 ##STR00506## 392 .sup.1H NMR (500 MHz, CD.sub.3OD) .delta.
7.67-7.65 (m, 2H), 7.50 (s, 1H), 7.09 (d, J = 8.5 Hz, 1H), 6.35 (d,
J = 6.0 Hz, 1H), 6.10 (s, 1H), 4.58 (s, 2H), 3.92 (d, J = 5.5 Hz,
2H), 3.75 (s, 3H), 3.63 (t, J = 6.0 Hz, 2H), 3.15 (d, J = 6.0 Hz,
2H), 1.92-1.74 (m, 6H), 1.39-1.19 (m, 5H) 103 ##STR00507## 392
.sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 9.21 (s, 2H), 7.55 (d,
J = 8.5 Hz, 1H), 7.52 (d, J = 7.5 Hz, 1H), 7.50 (s, 1H), 6.99 (dd,
J = 8.5, 1.5 Hz, 1H), 6.04 (dd, J = 7.5, 2.5 Hz, 1H), 5.85 (d, J =
2.5 Hz, 1H), 4.35 (s, 2H), 3.82 (d, J = 6.0 Hz, 2H), 3.68 (s, 3H),
3.54-3.53 (m, 2H), 3.09 (t, J = 5.5 Hz, 2H), 1.80-1.65 (m, 6H),
1.30-1.01 (m, 5H) 104 ##STR00508## 406 .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 10.53 (s, 1H), 7.53 (d, J = 7.5 Hz, 1H), 7.51
(d, J = 8.0 Hz, 1H), 7.50 (d, J = 1.5 Hz, 1H), 7.00 (dd, J = 8.5,
1.5 Hz, 1H), 6.04 (dd, J = 7.5, 2.5 Hz, 1H), 5.85 (d, J = 3.0 Hz,
1H), 4.64 (d, J = 13 Hz, 1H), 4.30 (dd, J = 14, 7.5 Hz, 1H), 3.82
(d, J = 6.0 Hz, 2H), 3.80- 3.78 (m, 1H), 3.69 (s, 3H), 3.51-3.47
(m, 1H), 3.18 (t, J = 5.5 Hz, 2H), 2.98 (d, J = 4.5 Hz, 3H),
1.80-1.65 (m, 6H), 1.30-1.01 (m, 5H) 105 ##STR00509## 416 .sup.1H
NMR (500 MHz, DMSO-d.sub.6) .delta. 9.48 (br s, 1H), 9.10 (br s,
1H), 7.56 (overlapping dd, J = 8.5 Hz, 2H), 7.52 (s, 1H), 7.49-7.41
(m, 4H), 7.40-7.36 (m, 1H), 7.01 (dd, J = 7.0, 1.5 Hz, 1H), 6.12
(dd, J = 7.5, 1.5 Hz, 1H), 5.98 (d, J = 1.5 Hz, 1H), 5.72 (t, J =
3.3 Hz, 1H), 5.16 (s, 2H), 4.89-4.82 (m, 1H), 4.07-4.01 (m, 1H),
3.80-3.71 (m, 1H), 3.72 (s, 3H), 3.61-3.50 (m, 1H), 3.49-3.43 (m,
1H), 3.02-2.94 (m, 2H) 106 ##STR00510## 372 .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 11.22 (s, 1H), 9.29 (br s, 2H), 7.54 (dd, J =
12.0, 8.0 Hz, 2H), 7.50-7.41 (m, 4H), 7.40-7.33 (m, 2H), 6.96 (dd,
J = 8.0, 1.5 Hz, 1H), 6.09 (dd, J = 7.5, 2.5 Hz, 1H), 5.97 (d, J =
2.5 Hz, 1H), 5.15 (s, 2H), 4.38 (s, 2H), 3.50-3.42 (m, 2H)
3.00-2.92 (m, 2H) 107 ##STR00511## 386 .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 11.30 (s, 1H), 10.50-10.41 (m, 1H), 7.58-7.52
(m, 2H), 7.49- 7.40 (m, 4H), 7.39-7.35 (m, 2H), 6.96 (br d, J = 8.0
Hz, 1H), 6.09 (br d, J = 7.5 Hz, 1H), 5.97 (br s, 1H), 5.15 (s,
2H), 4.60 (br d, J = 15.0 Hz, 1H), 4.41 (dd, J = 15.0, 7.5 Hz, 1H),
3.78-3.71 (m, 1H), 3.45-3.38 (m, 1H), 3.09-2.98 (m, 5H) 108
##STR00512## 410 .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 11.28
(s, 1H), 9.21 (br s, 2H), 8.01 (d J = 8.3 Hz, 2H), 7.88 (d, J = 8.3
Hz, 2H), 7.80 (d, J = 7.0 Hz, 1H), 7.58 (d, J = 8.0 Hz, 1H), 7.49
(d, J = 1.5 Hz, 1H), 7.07 (dd, J = 8.0, 1.5 Hz, 1H), 6.87 (d, J =
2.0 Hz, 1H), 6.72 (dd, J = 7.0, 2.0 Hz, 1H), 4.40 (s, 2H), 3.52-
3.48 (m, 2H), 2.99 (t, J = 6.0 Hz, 2H) 109 ##STR00513## 424 .sup.1H
NMR (500 MHz, DMSO-d.sub.6) .delta. 11.36 (s, 1H), 10.35 (br s,
1H), 8.02 (d, J = 8.3 Hz, 2H), 7.88 (d, J = 8.3 Hz, 2H), 7.80 (d, J
= 7.0 Hz, 1H), 7.59 (d, J = 8.0 Hz, 1H), 7.49 (br s, 1H), 7.07 (dd,
J = 8.0, 1.5 Hz, 1H), 6.87 (d, J = 1.5 Hz, 1H), 6.72 (d, J = 7.0,
1.5 Hz, 1H), 4.62 (br d, J = 16.0 Hz, 1H), 4.49-4.40 (m, 1H),
3.81-3.73 (m, 1H), 3.49-3.39 (m, 1H), 3.12-3.00 (m, 5H) 110
##STR00514## 414 .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 9.59
(s, 2H), 7.58-7.51 (m, 3H), 7.49-7.41 (m, 4H), 7.40-7.35 (m, 1H),
7.01 (dd, J = 8.5, 1.5 Hz, 1H), 6.10 (dd, J = 7.5, 2.8 Hz, 1H),
5.97 (d, J = 2.8 Hz, 1H), 5.16 (s, 2H), 3.80 (s, 3H), 3.52-3.48 (m,
2H), 2.99 (t, J = 6.0 Hz, 2H), 1.81 (s, 6H) 111 ##STR00515## 469
.sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 9.25 (br s, 1H), 7.56
(d, J = 7.5 Hz, 1H), 7.54-7.40 (m, 6H), 7.39-7.34 (m, 1H),
7.04-6.93 (m, 1H), 6.11 (dd, J = 7.5, 2.5 Hz, 1H), 5.97 (d, J = 2.5
Hz, 1H), 5.16 (s, 2H), 3.98-3.45 (m, 11H), 3.39 (s, 1H), 3.30- 3.21
(m, 2H), 2.25-2.10 (m, 1H), 2.05-1.74 (m, 2H), 1.73-1.60 (m, 1H)
112 ##STR00516## 420 .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta.
9.17 (br s, 2H), 7.65 (d, J = 7.0 Hz, 1H), 7.62 (d, J = 1.8 Hz,
1H), 7.59 (d, J = 8.5 Hz, 1H), 7.44 (d, J = 8.0 Hz, 1H), 7.26 (d, J
= 1.8 Hz, 1H), 7.14 (dd, J = 8.0, 1.8 Hz, 1H), 7.09 (dd, J = 8.5,
1.8 Hz, 1H), 6.57 (d, J = 2.0 Hz, 1H), 6.47 (dd, J = 7.0, 2.0 Hz,
1H), 4.37 (br s, 2H), 3.87 (s, 3H), 3.70 (s, 3H), 3.57-3.52 (m,
2H), 3.10 (t, J = 6.0 Hz, 2H) 113 ##STR00517## 434 .sup.1H NMR (500
MHz, DMSO-d.sub.6) .delta. 10.15 (br s, 1H), 7.66 (d, J = 7.0 Hz,
1H), 7.63 (d, J = 1.5 Hz, 1H), 7.55 (d, J = 8.0 Hz, 1H), 7.44 (d, J
= 8.5 Hz, 1H), 7.26 (d, J = 1.8 Hz, 1H), 7.14 (dd, J = 8.5, 1.5 Hz,
1H), 7.11 (dd, J = 8.0, 1.8 Hz, 1H), 6.57 (d, J = 2.0 Hz, 1H), 6.47
(dd, J = 7.0, 2.0 Hz, 1H), 4.67 (d, J = 13.5 Hz, 1H),
4.33 (dd, J = 14.3, 6.0 Hz, 1H), 3.87 (s, 3H), 3.86-3.79 (m, 1H),
3.71 (s, 3H), 3.55-3.47 (m, 1H), 3.24-3.15 (m, 2H), 3.01 (s, 3H)
114 ##STR00518## 388 .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta.
9.10 (br s, 2H), 8.88 (d, J = 5.0 Hz, 2H), 7.58-7.52 (m, 4H), 6.99
(dd, J = 8.0, 1.8 Hz, 1H), 6.14 (dd, J = 7.5, 2.5 Hz, 1H), 5.86 (d,
J = 2.5 Hz, 1H), 5.33 (s, 2H), 4.36 (br s, 2H), 3.68 (s, 3H),
3.57-3.52 (m, 2H), 3.11-3.05 (m, 2H) 115 ##STR00519## 426 .sup.1H
NMR (500 MHz, DMSO-d.sub.6) .delta. 9.28 (br s, 2H), 9.06 (s, 1H),
8.38 (s, 1H), 8.19 (s, 1H), 8.05-7.94 (m, 2H), 7.62 (d, J = 7.5 Hz,
1H), 7.56 (d, J = 8.0 Hz, 1H), 7.50 (d, J = 1.5 Hz, 1H), 6.99 (dd,
J = 8.0, 1.5 Hz, 1H), 6.13 (dd, J = 7.5, 2.5 Hz, 1H), 6.09 (d, J =
2.5 Hz, 1H), 5.33 (s, 2H), 4.35 (br s, 2H), 3.69 (s, 3H), 3.56-3.50
(m, 2H), 3.12-3.05 (m, 2H) 116 ##STR00520## 426 .sup.1H NMR (500
MHz, DMSO-d.sub.6) .delta. 9.30 (br s, 2H), 8.84 (s, 1H), 8.37 (s,
1H), 7.89-7.70 (m, 2H), 7.64-7.53 (m, 2H), 7.50 (s, 1H), 7.37-7.29
(m, 1H), 7.03-6.97 (m, 1H), 6.20-6.09 (m, 2H), 5.41 (s, 2H), 4.35
(br s, 2H), 3.69 (s, 3H), 3.58-3.50 (m, 2H), 3.13-3.07 (m, 2H) 117
##STR00521## 440 .sup.1H NMR (500 MHz, DMSO-d.sub.6) 10.79 (br s,
1H), 8.87 (d, J = 6.5 Hz, 1H), 8.41 (s, 1H), 7.90-7.78 (m, 2H),
7.61 (d, J = 7.5 Hz, 1H), 7.53-7.49 (m, 2H), 7.42-7.35 (m, 1H),
7.00 (dd, J = 8.5, 1.5 Hz, 1H), 6.15 (d, J = 2.5 Hz, 1H), 6.12 (dd,
J = 7.5, 2.5 Hz, 1H), 5.43 (s, 2H), 4.62 (d, J = 14.0 Hz, 1H), 4.29
(dd, J = 14.0, 7.5 Hz, 1H), 3.80-3.75 (m, 1H), 3.69 (s, 3H),
3.55-3.46 (m, 1H), 3.23- 3.16 (m, 2H), 2.97 (s, 3H) 118
##STR00522## 428 .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 7.56
(d, J = 7.5 Hz, 1H), 7.52-7.35 (m, 7H), 6.94 (dd, J = 8.0, 1.5 Hz,
1H), 6.12-6.08 (m, 1H), 5.97 (d, J = 3.0 Hz, 1H), 5.15 (s, 2H),
4.77-4.72 (m, 2H), 3.82-3.72 (m, 2H), 3.69-3.65 (m, 3H), 3.82-2.78
(m, 1.3H), 2.71-2.68 (m, 0.7H), 2.16 (s, 3H) 119 ##STR00523## 467
.sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 9.15 (s, 1H), 8.38 (d,
J = 8.3 Hz, 1H), 8.35 (d, J = 8.3 Hz, 1H), 7.84 (d, J = 7.5 Hz,
1H), 7.59-7.54 (m, 2H), 7.28 (d, J = 1.5 Hz, 1H), 7.08-7.03 (m,
2H), 4.70 (s, 0.8H), 4.68 (s, 1.2H), 3.88 (t, J = 5.5 Hz, 0.8H),
3.83 (t, J = 5.5 Hz, 1.2 H), 3.67 (s, 3H), 2.97-2.91 (m, 1.2H),
2.86-2.81 (m, 0.8H), 2.15 (s, 1.8H), 2.13 (s, 1.2H) 120
##STR00524## 453 .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 10.16
(br s, 1H), 9.15 (s, 1H), 8.42-8.35 (m, 2H), 7.85 (d, J = 7.0 Hz,
1H), 7.65 (d, J = 1.5 Hz, 1H), 7.61 (d, J = 8.5 Hz, 1H), 7.30 (d, J
= 2.0 Hz, 1H), 7.13 (dd, J = 8.5, 1.5 Hz, 1H), 7.08 (dd, J = 7.5,
2.0 Hz, 1H), 4.70 (d, J = 12.5 Hz, 1H), 4.32 (dd, J = 14.5, 8.0 Hz,
1H), 3.91-3.83 (m, 1H), 3.72 (s, 3H), 3.52- 3.43 (m, 1H), 3.41-3.30
(m, 2H), 3.24-3.16 (m, 2H), 1.38 (t, J = 7.3 Hz, 3H) 121
##STR00525## 467 .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 9.80
(br s, 1H), 9.15 (d, J = 2.0 Hz, 1H), 8.42-8.35 (m, 2H), 7.85 (d, J
= 7.5 Hz, 1H), 7.66 (d, J = 1.5 Hz, 1H), 7.62 (d, J = 8.5 Hz, 1H),
7.30 (d, J = 2.0 Hz, 1H), 7.14 (dd, J = 8.5, 1.5 Hz, 1H), 7.08 (dd,
J = 7.5, 2.0 Hz, 1H), 4.58 (d, J = 13.0 Hz, 1H), 4.48-4.40 (m, 1H),
3.90-3.82 (m, 1H), 3.78-3.70 (m, 4H), 3.51- 3.42 (m, 1H), 3.38-3.15
(m, 2H), 1.45-1.36 (m, 6H) 122 ##STR00526## 386 .sup.1H NMR (500
MHz, DMSO-d.sub.6) .delta. 9.43 (br s, 2H), 7.76 (d, J = 9.0 Hz,
2H), 7.70 (d, J = 7.0 Hz, 1H), 7.61-7.58 (m, 2H), 7.11-7.05 (m,
3H), 6.73 (d, J = 2.0 Hz, 1H), 6.68 (dd, J = 7.0, 2.0 Hz, 1H),
4.51-4.45 (m, 2H), 3.83 (s, 3H), 3.70 (s, 3H), 3.48-3.42 (m, 2H),
2.99 (t, J = 6.0 Hz, 2H) 123 ##STR00527## 402 .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 9.27 (br s, 2H), 7.77-7.71 (m, 3H), 7.61-7.58
(m, 2H), 7.39 (d, J = 8.5 Hz, 2H), 7.09 (dd, J = 8.5, 2.0 Hz, 1H),
6.78 (d, J = 2.0 Hz, 1H), 6.69 (dd, J = 7.5, 2.0 Hz, 1H), 4.36 (br
s, 2H), 3.70 (s, 3H), 3.56-3.51 (m, 2H), 3.10 (t, J = 5.5 Hz, 2H),
2.54 (s, 3H) 124 ##STR00528## 402 .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 9.32 (br s, 2H), 7.75 (d, J = 8.5 Hz, 2H),
7.73 (d, J = 7.3 Hz, 1H), 7.62-7.58 (m, 2H), 7.38 (d, J = 8.5 Hz,
2H), 7.10 (dd, J = 8.5, 2.0 Hz, 1H), 6.78 (d, J = 2.0 Hz, 1H), 6.69
(dd, J = 7.3, 2.0 Hz, 1H), 4.49 (br s, 2H), 3.70 (s, 3H), 3.60-3.32
(m, 2H), 2.99 (t, J = 5.5 Hz, 2H), 2.54 (s, 3H) 125 ##STR00529##
414 .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 9.34 (br s, 2H),
7.57 (d, J = 7.5 Hz, 1H), 7.53-7.50 (m, 2H), 7.49-7.41 (m, 4H),
7.40-7.35 (m, 1H), 6.99 (dd, J = 8.0, 2.0 Hz, 1H), 6.11 (dd, J =
8.0, 2.5 Hz, 1H), 5.98 (d, J = 2.5 Hz, 1H), 5.16 (s, 2H), 4.50 (br
s, 2H), 3.70 (s, 3H), 2.89 (s, 2H), 1.42 (s, 6H) 126 ##STR00530##
400 .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 9.44 (br s, 2H),
7.67 (d, J = 7.0 Hz, 1H), 7.63 (d, J = 1.5 Hz, 1H), 7.60 (d, J =
8.0 Hz, 1H), 7.25 (d, J = 8.5 Hz, 1H), 7.11 (dd, J = 8.5, 1.5 Hz,
1H), 6.92 (d, J = 2.5 Hz, 1H), 6.88 (dd, J = 8.5, 2.5 Hz, 1H), 6.37
(s, 1H), 6.34 (dd, J = 7.5, 1.5 Hz, 1H), 4.89 (br s, 2H), 3.79 (s,
3H), 3.70 (s, 3H), 3.49-3.43 (m, 2H), 2.99 (t, J = 6.0 Hz, 2H),
2.36 (s, 3H) 127 ##STR00531## 483 .sup.1H NMR (500 MHz, CD.sub.3OD)
.delta. 7.62-7.57 (m, 2H), 7.47-7.34 (m, 6H), 7.03 (dd, J = 8.5,
1.5 Hz, 1H), 6.29 (dd, J = 7.5, 2.5 Hz, 1H), 6.12 (d, J = 2.5 Hz,
1H), 5.18 (s, 2H), 4.55-4.43 (m, 2H), 3.72 (s, 3H), 3.38-3.14 (m,
12H), 2.14 (m, 4H) 128 ##STR00532## 420 .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 9.43 (br s, 2H), 7.65 (d, J = 7.0 Hz, 1H),
7.61 (d, J = 1.5 Hz, 1H), 7.59 (d, J = 8.0 Hz, 1H), 7.44 (d, J =
8.5 Hz, 1H), 7.26 (d, J = 2.0 Hz, 1H), 7.13 (dd, J = 8.5, 2.0 Hz,
1H), 7.09 (dd, J = 8.0, 2.0 Hz, 1H), 6.56 (d, J = 2.0 Hz, 1H), 6.47
(dd, J = 7.0, 1.5 Hz, 1H), 4.49- 4.47 (m, 2H), 3.87 (m, 3H), 3.69
(s, 3H), 3.47- 3.43 (m, 2H), 3.00-2.97 (m, 2H) 129 ##STR00533## 434
.sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 10.82 (br s, 1H), 7.65
(d, J = 7.0 Hz, 1H), 7.62 (d, J = 1.5 Hz, 1H), 7.60 (d, J = 8.5 Hz,
1H), 7.44 (d, J = 8.5 Hz, 1H), 7.26 (d, J = 1.5 Hz, 1H), 7.14-7.09
(m, 2H), 6.56 (d, J = 1.5 Hz, 1H), 6.47 (dd, J = 7.0, 1.5 Hz, 1H),
4.79-4.76 (m, 1H), 4.53-4.42 (m, 1H), 3.87 (s, 3H), 3.72-3.68 (m,
4H), 3.42-3.40 (m, 1H), 3.08-3.06 (m, 2H), 3.00 (s, 3H) 130
##STR00534## 469 .sup.1H NMR (500 MHz, CD.sub.3OD) .delta.
7.59-7.56 (m, 2H), 7.47-7.45 (m, 3H), 7.42-7.39 (m, 2H), 7.37- 7.34
(m, 1H), 7.06 (dd, J = 8.5, 2.0 Hz, 1H), 6.29 (dd, J = 7.5, 2.5 Hz,
1H), 6.12 (d, J = 3.0 Hz, 1H), 5.18 (s, 2H), 4.70-4.49 (br m, 2H),
4.28-4.26 (m, 1H), 3.75-3.73 (m, 7H), 3.46-3.43 (m, 2H), 3.34- 3.33
(m, 2H), 2.46-2.43 (m, 1H), 2.21-2.08 (m, 2H), 1.91-1.86 (m, 1H)
131 ##STR00535## 386 .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta.
9.26 (br s, 2H), 7.76 (d, J = 9.0 Hz, 2H), 7.70 (d, J = 7.0 Hz,
1H), 7.60-7.57 (m, 2H), 7.09-7.06 (m, 3H), 6.73 (d, J = 2.0 Hz,
1H), 6.68 (dd, J = 7.5, 2.0 Hz, 1H), 4.37-4.35 (m, 2H), 3.83 (s,
3H), 3.70 (s, 3H), 3.54-3.53 (m, 2H), 3.10 (t, J = 6.0 Hz, 2H) 132
##STR00536## 400 .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 9.39
(br s, 2H), 7.67 (d, J = 7.0 Hz, 1H), 7.59 (d, J = 8.0 Hz, 1H),
7.27 (d, J = 2.0 Hz, 1H), 7.25 (d, J = 8.5 Hz, 1H), 7.10 (dd, J =
8.5, 2.0 Hz, 1H), 6.92 (d, J = 2.5 Hz, 1H), 6.88 (dd, J = 8.0, 2.5
Hz, 1H), 6.37 (d, J = 2.0 Hz, 1H), 6.34 (dd, J = 7.0, 2.0 Hz, 1H),
4.36- 4.34 (m, 2H), 3.79 (s, 3H), 3.71 (s, 3H), 3.53- 3.52 (m, 2H),
3.10 (t, J = 6.0 Hz, 2H), 2.35 (s, 3H) 133 ##STR00537## 422 .sup.1H
NMR (500 MHz, DMSO-d.sub.6) .delta. 9.60 (br s, 2H), 8.11 (t, J =
58.0 Hz, 1H), 7.78 (d, J = 1.5 Hz, 1H), 7.68 (d, J = 8.0 Hz, 1H),
7.60 (d, J = 7.5 Hz, 1H), 7.48-7.36 (m, 5H), 7.22 (dd, J = 8.5, 1.5
Hz, 1H), 6.14 (dd, J = 7.5, 2.5 Hz, 1H), 5.99 (d, J = 2.5 Hz, 1H),
5.16 (s, 2H), 4.52 (m, 2H), 3.49-3.48 (m, 2H), 2.99 (m, 2H) 134
##STR00538## 436 .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 10.89
(br s, 1H), 8.15 (t, J = 58.0 Hz, 1H), 7.82 (d, J = 1.5 Hz, 1H),
7.69 (d, J = 8.3 Hz, 1H), 7.60 (d, J = 7.6 Hz, 1H), 7.47-7.36 (m,
5H), 7.23 (dd, J = 8.4, 1.5 Hz, 1H), 6.14 (dd, J = 7.6, 2.7 Hz,
1H), 6.00 (d, J = 2.7 Hz, 1H), 5.16 (s, 2H), 4.77 (m, 1H), 4.55 (m,
1H), 3.76-3.75 (m, 1H), 3.45-3.40 (m, 1H), 3.07- 3.02 (m, 5H) 135
##STR00539## 404 .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 9.54
(s, 2H), 7.71 (d, J = 7.2 Hz, 1H), 7.62-7.58 (m, 3H), 7.10 (dd, J =
8.3, 1.8 Hz, 1H), 7.01 (dd, J = 13.2, 2.4 Hz, 1H), 6.94 (dd, J =
8.6, 2.3 Hz, 1H), 6.62 (s, 1H), 6.53-6.52 (m, 1H), 4.48 (s, 2H),
3.95 (s, 3H), 3.69 (s, 3H), 3.45-3.44 (m, 2H), 3.00-2.97 (m, 2H)
136 ##STR00540## 418 .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta.
10.71 (s, 1H), 7.71 (d, J = 7.2 Hz, 1H), 7.63-7.59 (m, 3H), 7.11
(dd, J = 8.3, 1.6 Hz, 1H), 7.01 (dd, J = 13.2, 2.4 Hz, 1H), 6.94
(dd, J = 8.7, 2.4 Hz, 1H), 6.62 (s, 1H), 6.53-6.52 (m, 1H),
4.80-4.77 (m, 1H), 4.45- 4.43 (m, 1H), 3.84 (s, 3H), 3.73 (br s,
1H), 3.68 (s, 3H), 3.42-3.34 (m, 1H), 3.07-3.06 (m, 2H), 3.00 (s,
3H) 137 ##STR00541## 426 .sup.1H NMR (500 MHz, CD.sub.3OD) .delta.
8.81 (d, J = 7.0, 1.0 Hz, 1H), 8.38 (s, 1H), 8.02-7.99 (m, 1H),
7.92 (d, J = 9.5 Hz, 1H), 7.66-7.62 (m, 2H), 7.52-7.49 (m, 1H),
7.46 (s, 1H), 7.05 (d, J = 7.0 Hz, 1H), 6.33 (dd, J = 7.5, 3.0 Hz,
1H), 6.23 (d, J = 3.0 Hz, 1H), 5.50 (s, 2H), 4.55 (s, 2H), 3.72 (s,
3H), 3.60 (t, J = 6.0 Hz, 2H), 3.14-3.12 (m, 2H) 138 ##STR00542##
440 .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 10.91 (br s, 1H),
8.86 (d, J = 6.0 Hz, 1H), 8.39 (s, 1H), 7.87- 7.79 (m, 2H), 7.61
(d, J = 7.5 Hz, 1H), 7.57 (d, J = 8.0 Hz, 1H), 7.51 (s, 1H),
7.37-7.35 (m, 1H), 7.01 (dd, J = 8.5, 1.0 Hz, 1H), 6.15-6.11 (m,
2H), 5.42 (s, 2H), 4.77 (d, J = 15.0 Hz, 1H), 4.43 (dd, J = 14.0,
6.0 Hz, 1H), 3.80-3.77 (m, 1H), 3.66 (s, 3H), 3.41-3.39 (m, 1H),
3.08-3.04 (m, 2H), 2.99 (s, 3H) 139 ##STR00543## 426 .sup.1H NMR
(500 MHz, DMSO-d.sub.6) .delta. 9.55 (br s, 2H), 9.01 (s, 1H), 8.33
(s, 1H), 8.11 (s, 1H), 7.97 (d, J = 9.2 Hz, 1H), 7.89 (d, J = 9.2
Hz, 1H), 7.61 (d, J = 7.6 Hz, 1H), 7.56 (d, J = 8.4 Hz, 1H), 7.50
(d, J = 1.6 Hz, 1H), 7.00 (dd, J = 8.4, 1.7 Hz, 1H), 6.13 (dd, J =
7.6, 2.7 Hz, 1H), 6.08 (d, J = 2.7 Hz, 1H), 5.31 (s, 2H), 4.46 (m,
2H), 3.67 (s, 3H), 3.44 (m, 2H), 2.97 (t, J = 5.7 Hz, 2H) 140
##STR00544## 418 .sup.1H NMR (300 MHz, CD.sub.3OD) .delta.
7.53-7.33 (m, 7H), 7.27 (d, J = 10.5 Hz, 1H), 7.28 (dd, J = 7.8,
2.4 Hz, 1H), 6.10 (d, J = 2.7 Hz, 1H), 5.17 (s, 2H), 3.79 (br s,
2H), 3.67 (s, 3H), 3.03-3.00 (m, 4H), 2.64 (s, 3H) 141 ##STR00545##
404 .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 9.56 (br s, 2H),
7.61 (d, J = 6.0 Hz, 1H), 7.54 (d, J = 7.5 Hz, 1H), 7.50-7.37 (m,
6H), 6.14-6.12 (m, 1H), 5.99 (s, 1H), 5.16 (s, 2H), 4.46 (br s,
2H), 3.67 (s, 3H), 3.43 (br m, 2H), 2.94 (m, 2H) 142 ##STR00546##
414 .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 7.57 (d, J = 7.5
Hz, 1H), 7.54-7.34 (m, 7H), 6.97 (d, J = 8.0 Hz, 1H), 6.10 (dd, J =
7.5, 2.0 Hz, 1H), 5.97 (s, 1H), 5.16 (s, 2H), 3.67 (s, 3H),
3.45-3.18 (4H, overlapping with solvent peak), 3.26 (br m, 2H),
2.96 (m, 2H), 1.33 (br m, 3H) 143 ##STR00547## 428 .sup.1H NMR (500
MHz, DMSO-d.sub.6) .delta. 10.50 (s, 1H), 7.56 (d, J = 4.5 Hz, 2H),
7.52-7.38 (m, 6H), 7.01 (dd, J = 4.5, 1.0 Hz, 1H), 6.11 (dd, J =
4.5, 1.0 Hz, 1H), 5.97 (s, 1H), 5.16 (s, 2H), 4.60-4.53 (m, 2H),
3.78-3.70 (m, 2H), 3.70 (s, 3H), 3.40-3.28 (m, 1H), 3.18-2.98 (m,
2H), 1.44-1.39 (m, 6H) 144 ##STR00548## 472 .sup.1H NMR (500 MHz,
CDCl.sub.3) .delta. 7.48 (d, J = 8.5 Hz, 1H), 7.50-7.32 (m, 7H),
6.99 (d, J = 8.5 Hz, 1H), 6.90 (s, 1H), 6.34 (d, J = 6.5 Hz, 1H),
5.17 (s, 2H), 5.05-5.00 (m, 1H), 4.72-4.58 (m, 2H), 3.79 (br m,
2H), 3.76 (s, 3H), 2.82 (m, 2H), 1.42- 1.32 (m, 6H) 145
##STR00549## 465 .sup.1H NMR (300 MHz, CD.sub.3OD) .delta. 7.71 (d,
J = 7.8 Hz, 1H), 7.63 (d, J = 8.4, Hz, 1H), 7.53-7.30 (m, 6H), 7.05
(dd, J = 7.8, 1.2 Hz, 1H), 6.60 (d, J = 7.6 Hz, 1H), 5.40 (s, 2H),
4.54 (s, 2H), 3.71 (s, 3H), 3.62-3.55 (m, 2H), 3.22-3.02 (m, 2H)
146 ##STR00550## 372 .sup.1H NMR (500 MHz, CD.sub.3OD) .delta. 7.65
(d, J = 7.5 Hz, 1H), 7.57 (d, J = 8.2 Hz, 1H), 7.47 (d, J = 7.2 Hz,
2H), 7.42-7.36 (m, 4H), 7.03 (d, J = 8.5 Hz, 1H), 6.39 (dd, J =
7.6, 2.5 Hz, 1H), 6.21 (d, J = 2.5 Hz, 1H), 5.21 (s, 2H), 4.47 (s,
2H), 3.64 (t, J = 6.0 Hz, 2H), 3.20 (t, J = 6.1 Hz, 2H) 147
##STR00551## 400 .sup.1H NMR (300 MHz, CD.sub.3OD) .delta. 7.83 (d,
J = 7.5 Hz, 1H), 7.62-7.57 (m, 2H), 7.45-7.40 (m, 5H), 7.09 (dd, J
= 8.4, 1.6 Hz, 1H), 6.59 (dd, J = 7.5, 2.3 Hz, 1H), 6.36 (d, J =
2.3 Hz, 1H), 5.28 (s, 2H), 4.49 (s, 2H), 4.23 (q, J = 7.2 Hz, 2H),
3.68 (t, J = 6.1 Hz, 2H), 3.22 (t, J = 5.9 Hz, 2H), 1.35 (t, J =
7.1 Hz, 3H)
[0749] As compounds that bind strongly to MCH.sub.1, compounds of
formula I are expected to be effective in reducing obesity.
[0750] The present invention is not limited to the compounds found
in the above examples, and many other compounds falling within the
scope of the invention may also be prepared using the procedures
set forth in the above synthetic schemes. The preparation of
additional compounds of formula (I) using these methods will be
apparent to one of ordinary skill in the chemical arts.
[0751] The invention has been described in detail with particular
reference to some embodiments thereof, but it will be understood by
those skilled in the art that variations and modifications can be
effected within the spirit and scope of the invention.
* * * * *