Title of Invention

INDOZOLONE DERIVATIVES AS 11B-HSD 1 INHIBITORS

Abstract This invention is concerned with compounds of the formula (I) as well as pharmaceutically acceptable salts and esters thereof, wherein R1 to R7 have the significances given in the description and claims can be used in the form of pharmaceutical compositions.
Full Text The present invention is concerned with novel indazolone derivatives which are useful as 11b-HSDl inhibitors.
The invention is concerned particularly with compounds of formula (I)
(Formula Removed)
wherein:
R1 is hydrogen, C1-C7-alkyl, aryl, or aryl-C1-C7-alkyl;
R2 is aryl, aryl-C1-C7-alkyl, heteroaryl, heteroaryl-C1-C7-alkyl, cycloalkyl, cycloalkyl-
C1-C7-alkyl, fluoro-C1-C7-alkyl, or C1-C7-alkyl, which C1-C7-alkyl is optionally
substituted with 1 to 3 substituents selected from the group consisting of OH, CN,
halogen, C1-C7-alkoxy and C(O)NR8R9;
R3 is hydrogen, halogen, C1-C7-alkyl, fluoro-C1-C7-alkyl, C1-C7-alkoxy, or fluoro-C1-
C7-alkoxy;
R4 is hydrogen, halogen, C1-C7-alkyl, fluoro-C1-C7-alkyl, C1-C7-alkoxy, or fluoro-C1-
C7-alkoxy;
R5 is hydrogen, halogen, C1-C7-alkyl, fluoro-C1-C7-alkyl, C1-C7-alkoxy, or fluoro-C1-
C7-alkoxy;
R6 is hydrogen or C1-C7-alkyl;
R7 is aryl, heteroaryl, fluoro-C1-C7-alkyl, or C1-C7-alkyl, which C1-C7-alkyl is
optionally substituted with 1 to 3 substituents selected from the group consisting of OH,
CN, halogen, C1-C7-alkoxy and cycloalkyl;

R8 and R9, independently from each other, are selected from the group consisting of hydrogen and C1-C7-alkyl; and pharmaceutically acceptable salts thereof.
Glucocorticoids (Cortisol in humans, corticosterone in mice and rats) are an important class of adrenocorticosteroids that regulate many metabolic and homeostatic processes and form a key component of the response to stress. Glucocorticoids act via intracellular glucocorticoid receptors and, in some tissues, mineralocorticoid receptors; both being nuclear transcription factors. Glucocorticoid action on target tissues depends not only on circulating steroid concentrations and the cellular expression of receptors, but also on intracellular enzymes that critically determine to which extent glucocorticoids gain access to receptors in an active form. 1 lbeta-hydroxysteroid dehydrogenases (1 lbeta-HSD's) catalyze the interconversion of the principal active 11-hydroxy-glucocorticoid (Cortisol in men) and their inactive 11-keto metabolites (cortisone in men).
The enzyme 1 lbeta-hydroxysteroid dehydrogenase type 1 (1 lbeta-HSDl) inter-converts inactive into active glucocorticoids, thereby playing a major role in local modulation of cellular agonist concentration and thus activation of corticosteroid receptors in target tissues. In a recent study made by F. Hoffmann-La Roche differences in gene expression in lean and obese men were analyzed using gene array technology in order to identify specific changes in gene expression that might be associated with insulin resistance or altered metabolism. This study revealed that the mRNA for 1 lbeta-HSDl is approximately two-fold up regulated in adipose tissue in obese individuals. Moreover, overexpressing 1 lbeta-HSDl in adipocytes of mice led to visceral obesity and to a syndrome-X like phenotype (Masuzaki H. et al., Science. 2001 Dec 7; 294(5549):2166-70.). Taken together, these data very strongly support an important role of 1 lbeta-HSDl in the induction of obesity and the impairment of glucose homeostasis and lipid parameters. Thus, selective inhibition of this enzyme could lower blood glucose levels in Type 2 diabetic patients, normalize elevated lipid parameters and/or reduce weight in obese subjects.
The first pharmacological indication that 1 lbeta-HSDl inhibition in men might have beneficial effects were obtained by using carbenoxolone, an anti-ulcer drug
which inhibits both llbeta-HSDl and the related enzyme llbeta-HSD2. Treatment
with carbenoxolone led to an increase in insulin sensitivity indicating that that
inhibition of llbeta-HSDl may reduce cellular cortisol levels and therefore
minimizing some of its deleterious effects. (Walker et al. 1995; J. Clin. Endocrinol.
Metab. 80,31155-3159).
llbeta-HSDl is expressed in many tissues including liver, adipose tissue,
vascular smooth muscles, pancreas and brain. Its activity is dependent on NADP(H)
and it has a relatively low affmity for its substrate (compared to llbeta-HSD2). 11
beta-HSDl in tissue homogenates and when purified is bidirecţional, exhibiting both
llbeta-dehydrogenase and l Ibeta-reductase reactions, with greater stability of the
dehydrogenase activity (P.M. Stewart and Z.S. Krozowski, Vitam. Horm. 57 (1999),
pp. 249-324). However, when the enzyme activity is tested in intact cells, the l Ibetareductase
activity predominates, which regenerates active glucocorticoids from inert
11-keto forms. Such glucocorticoid regeneration will increase effective intracellular
glucocorticoid levels and thereby amplifying glucocorticoid activity. It is this elevated
cellular cortisol concentration that might lead to increased hepatic glucose production,
adipocyte differentiation and insulin resistance.
Inhibition of llbeta-HSDl should not only reduce the typical Syndrome-X /
Diabetes associated symptoms, but it should also be save and without major side
effect. Studies with the unspecific inhibitor carbenoxolone highlight the importance of
developing specific llbeta-HSDl inhibitors. The inhibition of the llbeta-HSD2
enzyme is badly tolerated and results in increased blood pressure. In contrast
inhibition of llbeta-HSDl should be well tolerated since llbeta-HSDl knockout
mice were found be healthy and to resist hyperglycemia provoked by obesity or stress
(Kotelevtsev Y. et al., Proc Natl Acad Sci U S A . 1997 Dec 23;94(26):14924-9).
Similar upon starvation these mice hâd attenuated activation of key hepatic enzymes
that are involved in gluconeogenesis. In addition, these mice hâd improved lipid and
lipoprotein profiles suggesting that inhibition of HSD1 might be highly efficacious
and safe. Recent reports indicate that llbeta-HSDl inhibitors might also be beneficial
to reduce high blood pressure (Masuzaki H. et al., J Clin Invest. 2003 July;l 12(1):83-
90; Rauz S. et al., QJM. 2003 July;96(7):481-90) to improve cognition (Sandeep TC.
et al., Proc Natl Acad Sci U S A . 2004 Apr. 27;101(17):6734-9) or to improve
Alzheimer associated deficits. Taken together llbeta-HSDl inhibition might be a
save and efficacious approach to treat symptoms of diabetes, obesity and other
diseases.
The compounds of formula I and their pharmaceutically acceptable salts and
esters are novei and have valuable pharmacological properties. In particular they are
llb-HSDl inhibitors and they display selectivity against the related llbeta-HSD2
enzyme. Therefore the compounds which are specific llbeta-HSDl inhibitors
represent an approach to e.g. lower blood glucose levels and normalize lipid
parameters in Type 2 diabetic patients by modulating the local concentratiqn of the
active glucocorticoid cortisol in target tissue (liver, adipose tissue).
The compounds of the present invention can be used in the prophylaxis and/or
treatment of metabolic disorders, obesity, dyslipidemiae, hypertension and/or diabetes,
particularly diabetes Type II. The compounds of this invention can further be used in
the prophylaxis and/or treatment of high ocular eye pressure, cognition, Alzheimer
and/or neurodegeneration.
Objects of the present invention are the compounds of formula I and their
aforementioned salts per se and their use as therapeutically active substances, a
process for the manufacture of the said compounds, intermediates, pharmaceutical
compositions, medicaments containing the said compounds, their pharmaceutically
acceptable salts, the use of the said compounds and salts for the prophylaxis and/or
therapy of illnesses, especially in the treatment or prophylaxis of metabolic disorders,
obesity, dyslipidemiae, hypertension and/or diabetes, particularly diabetes Type II, and
the use of the said compounds and salts for the production of medicaments for the
treatment or prophylaxis of metabolic disorders, obesity, dyslipidemiae, hypertension
and/or diabetes, particularly diabetes Type II.
The compounds of the present invention can further be combined with PPAR
(alpha, gamma, delta) agonists, DHEA (dehydroepiandrosterone), DPPIV inhibitors,
insulin and/or lipase inhibitors, particularly orlistat.
Unless otherwise indicated, the following defmitions are set forth to illustrate
and defme the meaning and scope of the various terms used to describe the invention
herein.
In this specification the term "lower" is used to mean a group consisting of one
to seven, preferably of one to four carbon atom(s).
The term "halogen" refers to fluorine, chlorine, bromine and iodine, with
fluorine, chlorine and bromine being preferred.
The term "alkyl", alone or in combination with other groups, refers to a
branched or straight-chain monovalent saturated aliphatic hydrocarbon radical of one
to twenty carbon atoms, preferably one to sixteen carbon atoms, more preferably one
to ten carbon atoms. Lower-alkyl groups as described below also are preferred alkyl
groups.
The term "lower-alkyl", alone or in combination with other groups, refers to a
branched or straight-chain monovalent alkyl radical of one to seven carbon atoms,
preferably one to four carbon atoms. This term is fiirther exemplified by such radicals
as methyl, ethyl, n-propyl, isopropyl, n-butyl, s-butyl, t-butyl and the like. Lower-alkyl
groups can optionally be substituted, e.g. by OH, CN, halogen, lower-alkoxy, or
aminocarbonyl. Unsubstituted lower-alkyl groups are preferred.
The term "fluoro-lower-alkyl" refers to lower-alkyl groups which are mono- or
multiply substituted with fluorine. Examples of fluoro-lower-alkyl groups are e.g.
CFH2, CF2H, CF3, CF3CH2, CF3(CH2)2, (CF3)2CH and CF2H-CF2
The term "cycloalkyl" refers to a monovalent carbocyclic radical of 3 to 10
carbon atoms, preferably 3 to 6 carbon atoms, such as cyclopropyl, cyclobutyl,
cyclopentyl, or cyclohexyl.
The term "alkoxy" refers to the group R'-O-, wherein R' is an alkyl. The term
"lower-alkoxy" refers to the group R'-O-, wherein R' is a lower-alkyl.
The term "fluoro-lower-alkoxy" refers to the group R"-O-, wherein R" is
fluoro-lower-alkyl. Examples of fluoro-lower-alkoxy groups are e.g. CFH2-0, CF2HO,
CF3-O, CF3CH2-O, CF3(CH2)2-O, (CF3)2CH-O, and CF2H-CF2-O.
The term "amino", alone or in combination, signifies a primary, secondary or
tertiary amino group bonded via the nitrogen atom, with the secondary amino group
carrying an alkyl or cycloalkyl substituent and the tertiary amino group carrying two
similar or different alkyl or cycloalkyl substituents or the two nitrogen substitutents
together forming a ring, such as, for example, -NHj, methylamino, ethylamino,
dimeţhylamino, diethylamino, methyl-ethylamino, pyrrolidin-1-yl or piperidino etc.,
preferably primary amino, dimeţhylamino and diethylamino and particularly
dimeţhylamino.
The term "alkylene" refers to a straight chain or branched divalent saturated
aliphatic hydrocarbon group of l to 20 carbon atoms, preferably l to 16 carbon atoms,
more preferably up to 10 carbon atoms. Lower-alkylene groups as described below
also are preferred alkylene groups. The term "lower-alkylene" refers to a straight chain
or branched divalent saturated aliphatic hydrocarbon group of l to 7, preferably l to 6
or 3 to 6 carbon atoms. Straight chain alkylene or lower-alkylene groups are preferred.
The term "aryl", alone or in combination, relates to the phenyl or naphthyl
group, preferably the phenyl group, which can optionally be substituted by l to 5 ,
preferably l to 3, substituents independently selected from the group consisting of
lower-alkyl, lower-alkoxy, halogen, hydroxy, CN, CFs, amino, aminocarbonyl,
carboxy, NOa, dioxo-lower-alkylene (forming e.g. a benzodioxyl group), loweralkylsufonyl,
aminosulfonyl, lower-alkylcarbonyl, lower-alkylcarbonyloxy, loweralkylcarbonyl-
NH, lower-alkoxycarbonyl, fluoro-lower-alkyl, fluoro-lower-alkoxy,
cycloalkyl, phenyloxy and methyl-oxadiazolyl. Preferred substituents are halogen,
lower-alkyl, fluoro-lower-alkyl and CN.
The term "heteroaryl" refers to an aromatic 5 to 6 membered monocyclic ring or
9 to 10 membered bicyclic ring which can comprise l, 2 or 3 atoms selected from
nitrogen, oxygen and/or sulphur, such as furyl, pyridinyl, pyridazinyl, oxo-pyridazinyl,
pyrimidinyl, 2-oxo-pyridinyl, 2-oxo-pyrimidinyl pyrazinyl, thienyl, isoxazolyl,
oxazolyl, oxadiazolyl, imidazolyl, pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl,
isothiazolyl, 1,2,3-thiadiazolyl, benzoimidazolyl, indolyl, indazolyl. A preferred
heteroaryl group is pyridinyl. A heteroaryl group may have a substitution pattern as
described earlier in connection with the term "aryl".
Compounds of formula (I) can form pharmaceutically acceptable acid addition
salts, Examples of such pharmaceutically acceptable salts are salts of compounds of
formula (I) with physiologically compatible mineral acids, such as hydrochloric acid,
sulphuric acid, sulphurous acid or phosphoric acid; or with organic acids, such as
methanesulphonic acid, p-toluenesulphonic acid, acetic acid, lactic acid,
trifluoroacetic acid, citric acid, fumărie acid, maleic acid, tartaric acid, succinic acid or
7
salicylic acid. The term "pharmaceutically acceptable salts" refers to such salts.
Compounds of formula (I) in which a COOH group is present can further form salts
with bases. Examples of such salts are alkaline, earth-alkaline and ammonium salts
such as e.g. Na-, K-, Ca- and Trimethylammoniumsalt. The term "pharmaceutically
acceptable salts" also refers to such salts. Salts obtained by the addition of an acid are
preferred.
The compounds of formula I can also be solvated, e.g. hydrated. The solvation
can be effected in the course of the manufacturing process or can take place e.g. as a
consequence of hygroscopic properties of an initially anhydrous compound of formula
I (hydration). The term pharmaceutically acceptable salts also includes physiologically
acceptable solvates.
In detail, the present invention relates to compounds of formula (I)
(Figure Remove)wherein
R1 is hydrogen, lower-alkyl, aryl, or aryl-lower-alkyl;
R2 is aryl, aryl-lower-alkyl, heteroaryl, heteroaryl-lower-alkyl, cycloalkyl,
cycloalkyl-lower-alkyl, fluoro-lower-alkyl, or lower-alkyl, which lower-alkyl is
optionally substituted with l to 3 substituents selected from the group consisting
of OH, CN, halogen, lower-alkoxy and C(O)NR8R9;
R3 is hydrogen, halogen, lower-alkyl, fluoro-lower-alkyl, lower-alkoxy, or fluorolower-
alkoxy;
R4 is hydrogen, halogen, lower-alkyl, fluoro-lower-alkyl, lower-alkoxy, or fluorolower-
alkoxy;
R5 is hydrogen, halogen, lower-alkyl, fluoro-lower-alkyl, lower-alkoxy, or fluorolower-
alkoxy;
R6 is hydrogen or lower-alkyl;
R7 is aryl, heteroaryl, fluoro-lower-alkyl, or lower-alkyl, which lower-alkyl is
optionally substituted with l to 3 substituents selected from the group consisting
of OH, CN, halogen, lower-alkoxy and cycloalkyl;
R8 and R9, independently from each other, are selected from the group consiting of
hydrogen and lower-alkyl;
and pharmaceutically acceptable salts thereof.
The compounds of formula I can have one or more asymmetric centers and can
be present in the form of optically pure enantiomers, mixtures of enantiomers such as,
for example, racemates, optically pure diastereioisomers, mixtures of diastereoisomers,
diastereoisomeric racemates or mixtures of diastereoisomeric racemates. The
invention embraces all of these forms. Preferred are the compounds of formula I.
Preferred compounds of formula (I) as described above are those wherein
R1 is hydrogen, lower-alkyl, aryl, or aryl-lower-alkyl;
R2 is aryl, aryl-lower-alkyl, heteroaryl, heteroaryl-lower-alkyl, cycloalkyl,
cycloalkyl-lower-alkyl, fluoro-lower-alkyl, or lower-alkyl, which lower-alkyl is
optionally substituted with l to 3 substituents selected from the group consisting
of OH, CN, halogen, lower-alkoxy and C(O)NR8R9;
R3 is hydrogen, halogen, lower-alkyl, fluoro-lower-alkyl, lower-alkoxy, or fluorolower-
alkoxy;
R4 is hydrogen, halogen, lower-alkyl, fluoro-lower-alkyl, lower-alkoxy, or fluorolower-
alkoxy;
R5 is hydrogen, halogen, lower-alkyl, fluoro-lower-alkyl, lower-alkoxy, or fluorolower-
alkoxy;
R6 is hydrogen or lower-alkyl;
R7 is aryl, heteroaryl, fluoro-lower-alkyl, or lower-alkyl, which lower-alkyl is
optionally substituted with l to 3 substituents selected from the group consisting
of OH, CN, halogen and lower-alkoxy;
R8 and R9, independently from each other, are selected from the group consiting of
hydrogen and lower-alkyl;
and pharmaceutically acceptable salts thereof.
A preferred embodiment of the present invention relates to compounds of
formula (I) as described above, wherein R1 is hydrogen or lower-alkyl, preferably
wherein R1 is hydrogen.
Another preferred object of the present invention are the compounds of formula
(I), wherein R2 is aryl-lower-alkyl, heteroaryl-lower-alkyl, cycloalkyl-lower-alkyl,
fluoro-lower-alkyl, or lower-alkyl, which lower-alkyl is optionally substituted with l
to 3 substituents selected from the group consisting of OH, CN, halogen, lower-alkoxy
and C(O)NR8R9, wherein R8 and R9 are as defined above. Preferably, R2 is aryl-loweralkyl
or heteroaryl-lower-alkyl, more preferably R2 is benzyl or pyridinylmethyl,
wherein benzyl can optionally be substituted with l or 2 halogen. Especially preferred
are those compounds wherein R2 is benzyl, 4-fluoro-benzyl, 4-chloro-benzyl, 3,4-
difluoro-benzyl, or pyridin-2-ylmethyl. Other preferred compounds are those, wherein
R2 is aryl, particularly phenyl.
Also preferred are the compounds of formula (I), wherein R3 is hydrogen.
Further preferred are those compounds according to formula (I), wherein R4 is
hydrogen or halogen, particularly wherein R4 is hydrogen, fluorine, or chlorine.
Another preferred aspect of the present invention are compounds of formula (I),
wherein R5 is hydrogen or halogen, particularly wherein R5 is hydrogen. Other
preferred compounds of formula (I) as defined above are those wherein R6 is
hydrogen.
In a further preferred embodiment of the present invention, R7 is lower-alkyl or
aryl. Particularly preferred are those compounds, wherein R7 is lower-alkyl, phenyl or
naphthyl, wherein phenyl can optionally be substituted with l to 3 substituents
independently selected from the group consisting of lower-alkyl, fluoro-lower-alkyl,
lower-alkoxy, fluoro-lower-alkoxy, dioxo-lower-alkylene, halogen, cyano, phenoxy
and 5-methyl-[l,3,4]-oxadiazol-2-yl. More preferably, R7 is phenyl substituted with l
to 2 substituents selected from the group consisting of lower-alkyl, fluoro-lower-alkyl,
halogen and cyano, particularly 3-chloro-2-methyl-phenyl, 2,3-dichloro-phenyl, 3-
chloro-4-fluoro-phenyl, 3-trifluoromethyl-4-fluoro-phenyl, 3-cyano-phenyl, 2,5-
difluoro-phenyl, 3-chloro-2-fluoro-phenyl, 5-chloro-2-fluoro-phenyl, or 2-chlorophenyl.
Other preferred compounds of formula (I) as described above are those,
wherein R7 is fluoro-lower-alkyl or lower-alkyl substituted with cyclopropyl,
especially those wherein R7 is cyclopropyl-methyl.
Examples of preferred compounds of formula (I) are those selected from the
group consisting of:
N-( l -Benzyl-3 -oxo-2,3 -dihydro-1 H-indazol-5 -yl)-3 -chloro-2-methylbenzenesulfonamide,
N-(l-Benzyl-3-oxo-2,3-dihydro-lH-indazol-5-yl)-3-chloro-4-fluorobenzenesu
Ifonam ide,
N-( l -Benzyl-3-oxo-2,3-dihydro-1 H-indazol-5-yl)-3-trifluoromethylbenzenesulfonamide,
N-(lBenzyl-3-oxo-2,3-dihydro-lH-indazol-5-yl)-2,4-dichloro-benzenesulfonamide,
Naphthalene-2-sulfonic acid (l-benzyl-3-oxo-2,3-dihydro-lH-indazol-5-yl)-amide,
N-(l-Benzyl-3-oxo-2,3-dihydro-lH-indazol-5-yl)-3-chloro-4-methylbenzenesulfonamide,
N-( l rBenzyl-3 -oxo-2,3-dihydro-1 H-indazol-5 -yl)-4-methoxy-benzenesulfonamide,
N-(l-Benzyl-3-oxo-2,3-dihydro-lH-indazol-5-yl)-2,4-dichloro-6-methylbenzenesulfonamide,
N-(l-Benzyl-3-oxo-2,3-dihydro-lH-indazol-5-yl)-2-trifluoromethylbenzenesulfonamide,
N-(l-Benzyl-3-oxo-2,3-dihydro-lH-indazol-5-yl)-2,4-difluoro-benzenesulfonamide,
N-(l-Benzyl-3-oxo-2,3-dihydro-lH-indazol-5-yl)-4-propyl-benzenesulfonamide,
2,3-Dihydro-benzo[l,4]dioxine-6-sulfonic acid (l-benzyl-3-oxo-2,3-dihydro-lHindazol-
5-yl)-amide,
N-(l-Benzyl-3-oxo-2,3-dihydro-lH-indazol-5-yl)-4-chloro-2,5-dimethylbenzenesulfonamide,
N-(l-Benzyl-3-oxo-2,3-dihydro-lH-indazol-5-yl)-4-chloro-3-trifluoromethylbenzenesulfonamide,
-(l-Benzyl-3-oxo-2,3-dihydro-lH-indazol-5-yl)-4-fluoro-3-trifluoromethylbenzenesulfonamide,
N-(l-Benzyl-3-oxo-2,3-dihydro-lH-indazol-5-yl)-2-chloro-5-trifluoromethylbenzenesulfonamide,
N-(l-Benzyl-3-oxo-2,3-dihydro-lH-indazol-5-yl)-3-phenoxy-benzenesulfonamide,
N-(l-Benzyl-3-oxo-2,3-dihydro-lH-indazol-5-yl)-3-(5-methyl-[l,3,4]oxadiazol-2-yl)-
benzenesulfonamide,
N-(l-Benzyl-3-oxo-2,3-dihydro-lH-indazol-5-yl)-3-chloro-benzenesulfonamide,
N-(l-Benzyl-3-oxo-2,3-dihydro-lH-indazol-5-yl)-3-methoxy-benzenesulfonamide,
N-(l-Benzyl-3-oxo-2,3-dihydro-lH-indazol-5-yl)-3-difluoromethoxybenzenesulfonamide,
N-(l-Benzyl-3-oxo-2,3-dihydro-lH-indazol-5-yl)-3,5-bis-trifluoromethylbenzenesulfonamide,
Propane-2-sulfonic acid (l-benzyl-3-oxo-2,3-dihydro-lH-indazol-5-yl)-amide,
N-(UBenzyl-3-oxo-2,3-dihydro-lH-indazol-5-yl)-3-chloro-2-N-dimethylbenzenesulfonamide,
N-(3-Oxo-l-propyl-2,3-dihydro-lH-indazol-5-yl)-3-trifluoromethylbenzenesulfonamide,
2,3-Dichloro-N-(3-oxo-l-propyl-2,3-dihydro-lH-indazol-5-yl)-benzenesulfonamide,
3-Chloro-4-fluoro-N-(3-oxo-l-propyl-2,3-dihydro-lH-indazol-5-yl)-
benzenesulfonamide,
3-Chloro-2-methyl-N-(3-oxo-l-phenethyl-2,3-dihydro-lH-indazol-5-yl)-
benzenesulfonamide,
3-Chloro-4-methyl-N-(3-oxo-l-phenethyl-2,3-dihydro-lH-indazol-5-yl)-
benzenesulfonamide,
4-Chloro-2,5-dimethyl-N-(3-oxo-1 -phenethyl-2,3-dihydro-1 H-indazol-5-yl)-
benzenesulfonamide,
N-(3-Oxo-l-phenethyl-2,3-dihydro-lH-indazol-5-yl)-3-trifluoromethylbenzenesulfonatnide,
N-( l LIsobutyl-3 -oxo-2,3-dihydro-1 H-indazol-5 -yl)-3 -trifluoromethylbenzenesulfonamide,
3-Chloro-N-( l -isobutyl-3-oxo-2,3-dihydro-1 H-indazol-5-yl)-4-methyl-
12
benzenesulfonamide,
3-Chloro-N-(l-isobutyl-3-oxo-2,3-dihydro-lH-indazol-5-yl)-2-methylbenzenesulfonamide,
3-Cyâno-(l-isobutyl-3-oxo-2,3-dihydro-indazol-5-yl)-benzenesulfonamide,
3-Difluoromethoxy-(l-isobutyl-3-oxo-2,3-dihydro-indazol-5-yl)-benzenesulfonamide,
4-Cyano-(l-isobutyl-3-oxo-2,3-dihydro-indazol-5-yl)-benzenesulfonamide,
4-Fluoro-N-(l-isobutyl-3-oxo-2,3-dihydro-lH-indazol-5-yl)-3-trifluoromethylbenzenesulfonamide,
3-Chloro-4-fluoro-N-(l-isobutyl-3-oxo-2,3-dihydro-lH-indazol-5-yl)-
benzenesulfonamide,
2,4-Dichloro-(l-isobutyl-3-oxo-2,3-dihydro-indazol-5-yl)-5-methylbenzenesulfonamide,
3-Chloro-N-(l-ethyl-3-oxo-2,3-dihydro-lH-indazol-5-yl)-2-methylbenzenesulfonamide,
3-Chloro-(l-cyclopropylmethyl-3-oxo-2,3-dihydro-indazol-5-yl)-2-methylbenzenesulfonamide,
3-Chloro-(l-cyclopropylmethyl-3-oxo-2,3-dihydro-indazol-5-yl)-4-fluorobenzenesulfonamide,
(l-Cyclopropylmethyl-3-oxo-2,3-dihydro-indazol-5-yl)-4-fluoro-3-trifluoromethylbenzenesulfonamide,
3-Chloro-(l-cyclopropylmethyl-3-oxo-2,3-dihydro-indazol-5-yl)-benzenesulfonamide,
2,4-Dichloro-(l-cyclopropylmethyl-3-oxo-2,3-dihydro-indazol-5-yl)-5-methylbenzenesulfonamide,
3-Chloro-[l-(2-methoxy-ethyl)-3-oxo-2,3-dihydro-indazol-5-yl]-2-methylbenzenesulfonamide,
4-Fluoro-[l-(2-methoxy-ethyl)-3-oxo-2,3-dihydro-indazol-5-yl]-3-trifluoromethylbenzenesulfonamide,
3-Chloro-4-fluoro-[l-(2-methoxy-ethyl)-3-oxo-2,3-dihydro-indazol-5-yl]-
benzenesulfonamide,
2,4-Dichloro-[l-(2-methoxy-ethyl)-3-oxo-2,3-dihydro-indazol-5-yl]-6-methylbenzenesulfonamide,
3-Chloro-2-methyl-N-[3-oxo-l-(2,2,2-trifluoro-ethyl)-2,3-dihydro-lH-indazol-5-yl]-
benzenesu Ifonam ide,
4-Fluoro-[3-oxo-l-(2,2,2-trifluoro-ethyl)-2,3-dihydro-indazol-5-yl]-3-trifluoromethylbenzenesulfonamide,
4-Fluoro-N-(3-oxo-l-pyridin-2-ylmethyl-2,3-dihydro-lH-indazol-5-yl)-3-
trifluoromethyl-benzenesulfonamide,
2,4-Dichloro-6-methyl-N-(3-oxo-l-pyridin-2-ylmethyl-2,3-dihydro-lH-indazol-5-yl)-
benzenesulfonamide,
3-Chloro-2-methyl-N-(3-oxo-l-pyridin-2-ylmethyl-2,3-dihydro-lH-indazol-5-yl)-
benzenesulfonamide,
4-Fluoro-N-[l-(2-hydroxy-2-methyl-propyl)-3-oxo-2,3-dihydro-lH-indazol-5-yl]-3-
trifluoromethyl-benzenesulfonamide,
N-(l-Benzyl-6-chloro-3-oxo-2,3-dihydro-lH-indazol-5-yl)-3-chloro-4-fluorobenzenesu
Ifonamide,
N-(l-Benzyl-6-chloro-3-oxo-2,3-dihydro-lH-indazol-5-yl)-4-fluoro-3-trifluoromethylbenzenesulfonamide,
N-(l-Benzyl-6-chloro-3-oxo-2,3-dihydro-lH-indazol-5-yl)-3-chloro-2-methylbenzenesulfonamide,
N-(l-Benzyl-6-chloro-3-oxo-2,3-dihydro-lH-indazol-5-yl)-2,3-dichlorobenzenesulfonamide,
N-(UBenzyl-6-chloro-3-oxo-2,3-dihydro-lH-indazol-5-yl)-3-cyanobenzenesulfonamide,
N-(l-Benzyl-6-chloro-3-oxo-2,3-dihydro-lH-indazol-5-yl)-3-chlorobenzenesulfonamide,
N-(UBenzyl-6-chloro-3-oxo-2,3-dihydro-lH-indazol-5-yl)-4-chloro-3-
trifluoromethyl-benzenesulfonamide,
N-(l-Benzyl-6-chloro-3-oxo-2,3-dihydro-lH-indazol-5-yl)-3-difluoromethoxybenzenesulfonamide,
N-( l rBenzyl-6-chloro-3-oxo-2,3-dihydro-1 H-indazol-5-yl)-2-trifluoromethylbenzenesulfonamide,
N-(l-Benzyl-6-chloro-3-oxo-2,3-dihydro-lH-indazol-5-yl)-3-trifluoromethoxybenzenesulfonamide,
N-(l-Benzyl-6-chloro-3-oxo-2,3-dihydro-lH-indazol-5-yl)-2,5-difluoro-
benzenesulfonamide,
N-(l-Benzyl-6-chloro-3-oxo-2,3-dihydro-lH-indazol-5-yl)-2,4-dichlorobenzenesulfonamide,
N-(l-Benzyl-6-chloro-3-oxo-2,3-dihydro-lH-indazol-5-yl)-3-chloro-2-fluorobenzenesulfonamide,
N-(l-Benzyl-6-chloro-3-oxo-2,3-dihydro-lH-indazol-5-yl)-3-trifluoromethylbenzenesulfonamide,
N-(l-Benzyl-6-chloro-3-oxo-2,3-dihydro-lH-indazol-5-yl)-5-chloro-2-fluorobenzenesulfonamide,
N-( l -Benzyl-6-chloro-3-oxo-2,3-dihydro-1 H-indazol-5-yl)-2-chlorobenzenesulfonamide,
(l-Benzyl-4-chloro-3-oxo-2,3-dihydro-indazol-5-yl)-3-chloro-2-methylbenzenesulfonamide,
N-(lBenzyl-6-fluoro-3-oxo-2,3-dihydro-lH-indazol-5-yl)-4-fluoro-3-trifluoromethylbenzenesu
Ifonam ide,
N-( l -Benzyl-6-fluoro-3-oxo-2,3-dihydro-1 H-indazol-5-yl)-2,3-dichlorobenzenesulfonamide,
N-( l -Benzyl-6-fluoro-3-oxo-2,3-dihydro-1 H-indazol-5-yl)-2,4-dichlorobenzenesu
Ifonamide,
N-(lfBenzyl-6-fluoro-3-oxo-2,3-dihydro-lH-indazol-5-yl)-3-chloro-2-fluorobenzenesu
Ifonamide,
N-(l"Benzyl-6-fluoro-3-oxo-2,3-dihydro-lH-indazol-5-yl)-5-chloro-2-fluorobenzenesulfonamide,
N-(l-Benzyl-6-fluoro-3-oxo-2,3-dihydro-lH-indazol-5-yl)-3-trifluoromethoxybenzenesulfonamide,
3-Chloro-N-[l-(4-fluoro-benzyl)-3-oxo-2,3-dihydro-lH-indazol-5-yl]-
benzenesu Ifonamide,
3-Difluoromethoxy-N-[l-(4-fluoro-benzyl)-3-oxo-2,3-dihydro-lH-indazol-5-yl]-
benzenesulfonamide,
4-Fluoro-N-[l-(4-fluoro-benzyl)-3-oxo-2,3-dihydro-lH-indazol-5-yl]-3-
trifluoromethyl-benzenesulfonamide,
2,3-Dihydro-benzo[l,4]dioxine-6-sulfonic acid [l-(4-fiuoro-benzyl)-3-oxo-2,3-
dihydro-1 H-indazol-5-yl]-amide,
2,4-Dichloro-N-[ l -(4-fluoro-benzyl)-3-oxo-2,3-dihydro-1 H-indazol-5-yl]-6-methylbenzenesulfonamide,
5-Chloro-2,4-difluoro-N-[l-(4-fluoro-benzyl)-3-oxo-2,3-dihydro-lH-indazol-5-yl]-
benzenesulfonam ide,
4-Chloro-2,5-difluoro-N-[l-(4-fluoro-benzyl)-3-oxo-2,3-dihydro-lH-indazol-5-yl]-
benzenesulfonam ide,
3-Chloro~[l-(4-fluoro-benzyl)-3-oxo-2,3-dihydro-indazol-5-yl]-2-methylbenzenesulfonamide,
3-Cyano-[l-(4-fluoro-benzyl)-3-oxo-2,3-dihydro-indazol-5-yl]-benzenesulfonamide,
Naphthalene-1-sulfonic acid [l-(4-fluoro-benzyl)-3-oxo-2,3-dihydro-lH-indazol-5-
yl]-amide,
3-Chloro-4-fluoro-N-[l-(4-fluoro-benzyl)-3-oxo-2,3-dihydro-lH-indazol-5-yl]-
benzenesulfonamide,
3-Chloro-[l-(3,4-difluoro-benzyl)-3-oxo-2,3-dihydro-indazol-5-yl]-2-methylbenzenesulfonamide,
3-Chloro-[l-(3,4-difluoro-benzyl)-3-oxo-2,3-dihydro-indazol-5-yl]-4-fluorobenzenesulfonamide,
[l-(3,4-Difluoro-benzyl)-3-oxo-2,3-dihydro-indazol-5-yl]-4-fluoro-3-trifluoromethylbenzenesulfonam
3-Chloro-[l-(3,4-difluoro-benzyl)-3-oxo-2,3-dihydro-indazol-5-yl]-
benzenesulfonamide,
[l-(3,4-Difluoro-benzyl)-3-oxo-2,3-dihydro-indazol-5-yl]-3-trifluoromethoxybenzenesulfonamide,
2,4-Dichloro-[l-(3,4-difluoro-benzyl)-3-oxo-2,3-dihydro-indazol-5-yl]-5-methylbenzenesulfonamide,
3,4-Dichloro-[l-(3,4-difluoro-benzyl)-3-oxo-2,3-dihydro-indazol-5-yl]-
benzenesulfonamide,
4,5-Dichloro-[l-(3,4-difluoro-benzyl)-3-oxo-2,3-dihydro-indazol-5-yl]-2-fluorobenzenesulfonamide,
2,4,5-Trichloro-[l-(3,4-difluoro-benzyl)-3-oxo-2,3-dihydro-indazol-5-yl]-
benzenesulfonam ide,
2,3-Dichloro-[l-(3,4-difluoro-benzyl)-3-oxo-2,3-dihydro-indazol-5-yl]-
benzenesulfonamide,
2,4-Dichloro-[l-(3,4-difluoro-benzyl)-3-oxo-2,3-dihydro-indazol-5-yl]-6-methylbenzenesulfonamide,
3-Chloro-N-[l-(2,4-difluoro-benzyl)-3-oxo-2,3-dihydro-lH-indazol-5-yl]-4-fluorobenzenesulfonamide,
N-[l-(2,4-Difluoro-benzyl)-3-oxo-2,3-dihydro-lH-indazol-5-yl]-4-fluoro-3-
trifluoromethyl-benzenesulfonamide,
3-Chloro-N-[l-(2,4-difluoro-benzyl)-3-oxo-2,3-dihydro-l H-indazol-5-yl]-2-methylbenzenesulfonamide,
N-[l-(4-Chloro-benzyl)-3-oxo-2,3-dihydro-lH-indazol-5-yl]-4-fluoro-3-
trifluoromethyl-benzenesulfonamide,
3-Chloro-N-[l-(4-chloro-benzyl)-3-oxo-2,3-dihydro-lH-indazol-5-yl]-2-methylbenzenesulfonamide,
2,3-Dichloro-N-[l-(4-chloro-benzyl)-3-oxo-2,3-dihydro-lH-indazol-5-yl]-
benzenesulfonamide,
Naphthalene-1-sulfonic acid [l-(4-chloro-benzyl)-3-oxo-2,3-dihydro-lH-indazol-5-
yl]-amide,
3-Chloro-N-[l-(2-chloro-4-fluoro-benzyl)-3-oxo-2,3-dihydro-lH-indazol-5-yl]-2-
methyl-benzenesulfonamide,
Naphthalene-1-sulfonic acid [l-(2-chloro-4-fluoro-benzyl)-3-oxo-2,3-dihydro-lHindazol-
5-yl]-amide,
2,3-Dichloro-N-[ l -(2-chloro-4-fluoro-benzyl)-3-oxo-2,3-dihydro-1 H-indazol-5-yl]-
benzenesulfonamide,
N-[l-(2-Chloro-4-fluoro-benzyl)-3-oxo-2,3-dihydro-lH-indazol-5-yl]-4-fluoro-3-
trifluoromethyl-benzenesulfonamide,
N-[lK2-Chloro-4-fluoro-benzyl)-3-oxo-2,3-dihydro-lH-indazol-5-yl]-3-
difluoromethoxy-benzenesulfonamide,
N-[l-(2-Chloro-4-fluoro-benzyl)-3-oxo-2,3-dihydro-lH-indazol-5-yl]-3-
trifluoromethoxy-benzenesulfonamide,
3-Chloro-N-[ l -(2-cyano-ethyl)-3-oxo-2,3-dihydro-1 H-indazol-5-yl]-2-methylbenzenesulfonamide,
N-[l-(2-Cyano-ethyl)-3-oxo-2,3-dihydro-lH-indazol-5-yl]-4-fluoro-3-trifluoromethylbenzenesulfonam
ide,
2,4-Dichloro-N-[l-(2-cyano-ethyl)-3-oxo-2,3-dihydro-lH-indazol-5-yl]-6-methylbenzenesulfonamide,
3-Chloro-N-[l-(2-cyano-ethyl)-3-oxo-2,3-dihydro-lH-indazol-5-yl]-4-fluorobenzenesulfonamide,
N-[6-Chloro-l-(2-chloro-benzyl)-3-oxo-2,3-dihydro-lH-indazol-5-yl]-4-fluoro-3-
trifluoromethyl-benzenesulfonamide,
5-Chloro-N-[6-chloro-l-(2-chloro-benzyl)-3-oxo-2,3-dihydro-lH-indazol-5-yl]-2-
fluoro-benzenesulfonamide,
2,3-Dichloro-N-[6-chloro-l-(2-chloro-benzyl)-3-oxo-2,3-dihydro-lH-indazol-5-yl]-
benzenesulfonam ide,
3-Chloro-N-(6-chloro-3-oxo-l-pyridin-2-ylmethyl-2,3-dihydro-lH-indazol-5-yl)-2-
methyl-benzenesulfonamide,
N-(6-Chloro-3-oxo-l-pyridin-2-ylmethyl-2,3-dihydro-lH-indazol-5-yl)-4-fluoro-3-
tri fluoromethyl-benzenesulfonamide,
2-[5-(3-Chloro-2-methyl-benzenesulfonylamino)-3-oxo-2,3-dihydro-indazol-l-yl]-
methyl-acetamide,
2,4-Dichloro-[l-(3,4-difluoro-benzyl)-2-methyl-3-oxo-2,3-dihydro-indazol-5-yl]-6-
methyl-benzenesulfonamide, and
3-Chloro-[l-(3,4-difluoro-benzyl)-2-methyl-3-oxo-2,3-dihydro-indazol-5-yl]-2-
methyl-benzenesulfonamide,
and pharmaceutically acceptable salts thereof.
Examples of particularly preferred compounds of formula (I) are those selected
front the group consisting of:
N-(l-Benzyl-6-chloro-3-oxo-2,3-dihydro-lH-indazol-5-yl)-3-chloro-2-methylbenzenesulfonamide,
N-(lrBenzyl-6-chloro-3-oxo-2,3-dihydro-lH-indazol-5-yl)-2,5-difluorobenzenesulfonamide,
N-(l-Benzyl-6-chloro-3-oxo-2,3-dihydro-lH-indazol-5-yl)-3-chloro-2-fluorobenzenesulfonamide,
N-(UBenzyl-6-chloro-3-oxo-2,3-dihydro-lH-indazol-5-yl)-2-chloro-
benzenesulfonamide,
N-(l-Benzyl-6-fluoro-3-oxo-2,3-dihydro-lH-indazol-5-yl)-3-chloro-2-fluorobenzenesulfonamide,
N-(l-Benzyl-6-fluoro-3-oxo-2,3-dihydro-lH-indazol-5-yl)-2,3-dichlorobenzenesulfonamide,
N-(l-Benzyl-6-fluoro-3-oxo-2,3-dihydro-lH-indazol-5-yl)-5-chloro-2-fluorobenzenesulfonamide,
N-(l-Benzyl-3-oxo-2,3-dihydro-lH-indazol-5-yl)-3-chloro-2-methylbenzenesulfonamide,
3 -Cyano-[ l -(4-fluoro-benzyl)-3 -oxo-2,3 -dihydro-indazol-5 -yl] -benzenesulfonam ide,
2,3-Dichloro-N-[l-(4-chloro-benzyl)-3-oxo-2,3-dihydro-lH-indazol-5-yl]-
benzenesulfonamide,
3-Chloro-N-[l-(4-chloro-benzyl)-3-oxo-2,3-dihydro-lH-indazol-5-yl]-2-methylbenzenesulfonamide,
4-Fluoro-N-[l-(4-fluoro-benzyl)-3-oxo-2,3-dihydro-lH-indazol-5-yl]-3-
trifluoromethyl-benzenesulfonamide,
3-Chloro-4-fluoro-N-[l-(4-fluoro-benzyl)-3-oxo-2,3-dihydro-lH-indazol-5-yl]-
benzenesulfonamide,
3-Chloro-[l-(3,4-difluoro-benzyl)-3-oxo-2,3-dihydro-indazol-5-yl]-2-methylbenzenesulfonamide,
N-[l-(4-Chloro-benzyl)-3-oxo-2,3-dihydro-lH-indazol-5-yl]-4-fluoro-3-
trifluoromethyl-benzenesulfonamide, and
3-Chloro-2-methyl-N-(3-oxo-1 -pyridin-2-ylmethyl-2,3-dihydro-1 H-indazol-5-yl)-
benzenesulfonamide,
and pharmaceutically acceptable salts thereof.
Other examples of preferred compounds of formula (I) are those selected from
the group consisting of:
2,3-Dichloro-N-(6-chloro-3-oxo-l-pyridin-2-ylmethyl-2,3-dihydro-lH-indazol-5-yl)-
benzenesulfonamide,
N-(l'Benzyl-6-fluoro-3-oxo-2,3-dihydro-lH-indazol-5-yl)-2,4-difluorobenzenesulfonamide,
2,4-Difluoro-N-(3-oxo-l-phenyl-2,3-dihydro-lH-indazol-5-yl)-benzenesulfonamide,
3-Chloro-2-fluoro-N-(3-oxo-l-phenyl-2,3-dihydro-lH-indazol-5-yl)-
benzenesulfonamide,
N-(l-Benzyl-6-fluoro-3-oxo-2,3-dihydro-lH-indazol-5-yl)-3-cyanobenzenesulfonamide,
Propiane-2-sulfonic acid (l -benzyl-6-fluoro-3-oxo-2,3-dihydro-1 H-indazol-5-yl)-
amide,
3-Cyano-N-(3-oxo-l-phenyl-2,3-dihydro-lH-indazol-5-yl)-benzenesulfonamide,
2,2,2-Trifluoro-ethanesulfonic acid (l-benzyl-6-fluoro-3-oxo-2,3-dihydro-lH-indazol-
5-yl)-amide,
Propane-2-sulfonic acid (l -benzyl-6-chloro-3-oxo-2,3-dihydro- lH-indazol-5-yl)-
amide,
Propane-2-sulfonic acid [6-chloro-l-(4-chloro-benzyl)-3-oxo-2,3-dihydro-lH-indazol-
5-yl]-amide,
N-(lBenzyl-6-fluoro-3-oxo-2,3-dihydro-lH-indazol-5-yl)-trifluoromethanesulfonamide,
Propane-2-sulfonic acid (l-isobutyl-3-oxo-2,3-dihydro-lH-indazol-5-yl)-amide,
Propane-2-sulfonic acid [l-(3,4-difluoro-benzyl)-3-oxo-2,3-dihydro-lH-indazol-5-yl]-
amide,
Propane-2-sulfonic acid [l-(2-methoxy-ethyl)-3-oxo-2,3-dihydro-lH-indazol-5-yl]-
amide, and
N-(l-Benzyl-3-oxo-2,3-dihydro-lH-indazol-5-yl)-C-cyclopropyl-methanesulfonamide
and pharmaceutically acceptable salts thereof.
Another example of a particularly preferred compound of formula (I) is:
N-(l-Benzyl-3-oxo-2,3-dihydro-lH-indazol-5-yl)-C-cyclopropyl-methanesulfonamide
and pharmaceutically acceptable salts thereof.
It will be appreciated that the compounds of the present invention may be
derivatised at funcţional groups to provide derivatives which are capable of
conversion back to the parent compound in vivo. Physiologically acceptable and
metabolically labile compounds, which are capable of producing the parent
compounds of general formula (I) in vivo are also within the scope of the present
invention.
A further aspect of the present invention is the process for the preparation of
compounds as defined above comprising the reaction of a compound of formula (II)
(Figure Remove)wherein R1 to R7 are as defined above.
Such a process can be carried out under conditions known to the person skilled
in the art, e.g. in the presence of a base such as trietylamine or (4-dimetylamino)-
pyridine (DMAP) in a solvent such THF, ethanol, methylene chloride DMF or
DMSO, or in pyridine as a solvent, with or without the addition of a base such as
trietylamine or DMAP, at room temperature or at elevated temperatures.
The invention further relates to compounds of formula (I) as described above,
when prepared by a process as defined above.
General description of the processes:
The preparation of compounds of formula I of the present invention may be
carried out in sequential or convergent synthetic routes. Syntheses of the invention are
shown in the following schemes. The skills required for carrying out the reaction and
purification of the resulting products are known to those persons skilled in the art. The
subsţituents and indices used in the following description of the processes have the
significance given above unless indicated to the contrary.
In general, compounds of type I are readily accessible by sulfonylation of
apprppriately substituted 5-amino-l,2-dihydro-indazol-3-one of formula Ila (R6=H)
with sulfonyl chlorides, under various conditions that are known to persons skilled in
art. Examples of such conditions are - as indicated in Scheme l below - e.g.
pyridine at elevated temperatures or THF under reflux conditions in the presence of a
base such as potassium carbonate, sodium carbonate, sodium hydride, triethyl amine
or the like. The sulfonyl chlorides are either commercially available or known in the
literature or available in analogy to known procedures to those persons skilled in the
(Figure Remove)Optionally, compounds of formula Ia with R6 = H obtained in this way can be further
substituted at the sulfonamide nitrogen by treatment with a base such as sodium
hydride, cesium carbonate, potassium carbonate or the like in a solvent such as DMF
or THF or similar followed by alkylation of the resulting anion with an alkyl halide
such as methyl iodide, ethyl bromide, benzyl bromide or the like in order to introduce
the desired R6 substituent. Optionally, R6 can be introduced via alkylation of
compound of formula Ila by procedures known to those persons skilled in the art.
Appropriately substituted 5-amino-l,2-dihydro-indazol-3-ones of formula Ila are
either known in the literature or can be made in analogy to literature procedures from
known starting materials according to scheme 2- e.g. by condensation of the
appropriately functionalized 2-fluorobenzoic acid of formula III with hydrazine
hydrâte in ethanol and cyclisation under acidic conditions, followed by alkylation with
R2-X to afford compounds of formula IVa (R6 = H), an opţional alkylation with R l-X
(under thermal or basic conditions in analogy to procedures described in Heterocycles
1997, 45, 129-36 or J. Med. Chem. 1991, 34, 1492-1503) to afford compounds of
formula IV, and hydrogenation of the nitro group. (Schindler et al., Arch. Pharm.
Pharm. Med. Chem., 1998, 357,13-21).
Alternatively, appropriately substituted 5-amino-l,2-dihydro-indazol-3-ones of
formula II are prepared according to the general Scheme 3 via a one-operation
condensation of the appropriately functionalized 2-fluorobenzoic acid of formula III
with an appropriately substituted hydrazine R1NHNH2 of formula V in the presence
of a coupling agent in DMF, followed by an opţional alkylation with Rl-X (under
therrnal or basic conditions in analogy to procedures described in Heterocydes 1997,
45, 129-36 or J. Med Chem. 1991, 34, 1492-1503) and a reduction of the nitro group.
5-Amino-l,2-dihydro-indazol-3-ones of formula II with R2 = aryl, heteroaryl can also
be prepared in analogy to Menon et al., Combin. Chem. and High-Throughput
Screen.2QQ3, 6, 471-480. The appropriately substituted starting materials of formula
III are either commercially available or are known in the literature or were prepared in
analogy to literature procedures from known starting materials. The corresponding
substituted hydrazines of formula V are either commercially available or are known in
the literature or synthesised in analogy to literature procedures (such as J. Org. Chem.
1984, 49, 336-42; J. Am. Chem. Soc. 1986, 108, 7981-4 or Bioorg. Med. Chem. 2004,
(Figure Remove)As described above, the compounds of formula (I) of the present invention can
be used as medicaments for the treatment and/or prevention of diseases which are
caused by disorders associated with the enzyme l Ibeta-hydroxysteroid dehydrogenase
l (llbHSDl). Examples of such diseases are metabolic disorders, obesity,
dyslipidemiae, hypertension and/or diabetes, particularly diabetes type II. The
compounds of this invention can further be used in the prophylaxis and/or treatment
of high ocular eye pressure, cognition, Alzheimer and/or neurodegeneration.
The invention therefore also relates to pharmaceutical compositions comprising
a compound as defined above and a pharmaceutically acceptable carrier and/or
adjuvant.
: Further, the invention relates to compounds as defined above for use as
therapeutic active substances, particularly as therapeutic active substances for the
treatment and/or prevention of diseases which are caused by disorders associated with
the enzyme l Ibeta-hydroxysteroid dehydrogenase l (llbHSDl), particlularly as
therapeutic active substances for the treatment and/or prevention of metabolic
disorders, obesity, dyslipidemiae, hypertension and/or diabetes, particularly diabetes
type II.
The invention further relates to a method for the treatment and/or prophylaxis of
diseases which are caused by disorders associated with the enzyme l Ibetahydroxysteroid
dehydrogenase l, particularly for the treatment and/or prophylaxis of
metabolic disorders, obesity, dyslipidemiae, hypertension and/or diabetes, particularly
diabetes type II, which method comprises administering an effective amount of a
compound as defined above.
In another embodiment, the present invention relates to the use of compounds as
defined above for the therapeutic and/or prophylactic treatment of diseases which are
caused by disorders associated with the enzyme l Ibeta-hydroxysteroid dehydrogenase
l, particularly for therapeutic and/or prophylactic treatment of metabolic disorders,
obesity, dyslipidemiae, hypertension and/or diabetes, particularly type II diabetes.
The invention further relates to the use of compounds as defmed above for the
preparation of medicaments for the treatment and prophylaxis of diseases which are
caused by disorders associated with the enzyme l Ibeta-hydroxysteroid dehydrogenase
l, particularly for the treatment and prophylaxis of metabolic disorders, obesity,
dyslipidemiae, hypertension and/or diabetes, particularly type II diabetes.
Prevention and/or treatment of type II diabetes is the preferred indication.
Assav Procedures
Tranşient expression and parţial Purification:
The cDNA encoding the human llbeta-HSDl protein was cloned into the expression
vector pcDNAS (Stratagene). This construct (for details see Alex Odermatt et al.; J
Biol Chem., 1999, Voi. 274, Issue 40, 28762-28770) was used to transiently express
the protein in HEK293 cells (ATCC number: CRL-1573, described in Graham, F.L.,
Smiley, J., Russell, W.C., Nairn, R.; (1977)) using lipofectamine. 48h after
transfection cells were washed twice with ice-cold PBS (Phsophate buffered Saline).
To l volume of cell suspension in PBS 2 volumes of ice-cold lysis buffer (50mM
Tris; pH7.5; ImM EDTA; lOOmM NaCl) were added. The cells were lysed by Potterhomogenization
(20 strokes). The resulting homogenate was sonicated wit a tip
sonicator (10% output; 2 x 30 sec.) and cleared by a low speed centrifugation (lOmin
x 9000g; 4°C). The microsomal fraction was collected by a high speed centrifugation
(60 min x 110'OOOg). The resulting pellet was resuspended in storage buffer (20mM
Tris pH 7.5; l mM EDTA; 10% Glycerol) and the centrifugation was repeated. The
resulting pellet containing the microsomal fraction was again taken up into storage
buffer and aliquots were kept frozen in liquid Nitrogen until use.
Generation of stable cell linesexpressing llbeta-HSDl:
The same construct used for transient expression of human llbeta-HSDl was also
used to establish cell lines stably expressing the protein. Briefly, (HEK293) cells were
transfected with l Ibeta-HSDl construct using the lipofectamine reagent (Gibco BRL)
according to the manufacturer's instruction. Two days after transfection, geneticin
selection (0.8 mg/ml) was initiated and several stable clones were isolated. Qne clone
was further used for pharmacological characterization.
Microsome Assay
Microsomes isolated from HEK293 cells transiently expressing human llbeta-HSDl
(for details see above) were incubated in assay buffer (100 mM NaCl; ImM EDTA;
ImM EGTA; ImM MgCl; 250 mM Sucrose; 20 mM Tris pH 7.4; Cortisone 50-
200nM and NADPH ImM) together with different concentrations of test substances.
After 60 min. of incubation at 37°C the assay was stopped by heating to 80°C (5 min.)
and by addition of the inhibitor Carbenoxolone (l uM). The amount of Cortisol
produced in this assay was determined using a commercially available, ELISA-based
Cortisol-detection kit (Distributed by Assay Design, Inc.). Inhibitors were
characterized by there IC50 values, e.g. the concentration at which the production of
cortisol was 50% reduced.
Cellular Assay
To measure the effect of inhibitors in intact cells HEK293 cells stably expressing
human llbeta-HSDl (see above) were cultivated in 96 well plates in DMEM. First
inhibitors and 60 min later Cortisone was added to the cells. After 60 min of
incubation at 37°C in a 5% CO2 atmosphere part of the medium was removed and the
conversion from Cortisone to Cortisol was measured using a commercially available
ELISA kit (Distributed by Assay Design, Inc.).
Results obtained in the microsome assay using representative compounds of the
invention as the test compounds are shown in the following table:
(Figure Remove)Compounds as described above have ICso values below 1000 nM; preferred
compounds have ICso values below 100 nM. More preferred compounds have
values below 10 nM. These results have been obtained by using the foregoing test.
The compounds of formula I and their pharmaceutically acceptable salts and
esters can be used as medicaments (e.g. in the form of pharmaceutical preparations).
The pharmaceutical preparations can be administered internally, such as orally (e.g. in
the form of tablets, coated tablets, drage"es, hard and soft gelatin capsules, solutions,
emulsions or suspensions), nasally (e.g. in the form of nasal sprays) or rectally (e.g. in
the form of suppositories). However, the administration can also be effected
parentally, such as intramuscularly or intravenously (e.g. in the form of injection
solutions).
The compounds of formula I and their pharmaceutically acceptable salts and
esters can be processed with pharmaceutically inert, inorganic or organic adjuvants for
the production of tablets, coated tablets, drage"es and hard gelatin capsules. Lactose,
corn starch or derivatives thereof, talc, stearic acid or its salts etc. can be used, for
example, as such adjuvants for tablets, drage"es and hard gelatin capsules.
Suitable adjuvants for soft gelatin capsules, are, for example, vegetable oils,
waxes, fats, semi-solid substances and liquid polyols, etc.
Suitable adjuvants for the production of solutions and syrups are, for example,
water, polyols, saccharose, invert sugar, glucose, etc.
Suitable adjuvants for injection solutions are, for example, water, alcohols,
polyols, glycerol, vegetable oils, etc.
Suitable adjuvants for suppositories are, for example, natural or hardened oils,
waxes, fats, semi-solid or liquid polyols, etc.
Moreover, the pharmaceutical preparations can contain preservatives,
solubilizers, viscosity-increasing substances, stabilizers, wetting agents, emulsifiers,
sweeteners, colorants, flavorants, salts for varying the osmotic pressure, buffers,
masking agents or antioxidants. They can also contain still other therapeutically
valuable substances.
In accordance with the invention the compounds of formula I and their
pharmaceutically acceptable salts can be used for the prophylaxis and treatment of
28
arthritis, cardiovascular diseases, diabetes, renal failure and particularly eating
disorders and obesity. The dosage can vary in wide limits and will, of course, be fitted
to the individual requirements in each particular case. In general, in the case of oral
administration a daily dosage of about 0.1 mg to 20 mg per kg body weight, preferably
about 0.5 mg to 4 mg per kg body weight (e.g. about 300 mg per person), divided into
preferably 1-3 individual doses, which can consist, for example, of the same amounts,
shou}d be appropriate. It will, however, be clear that the upper limit given above can
be exceeded when this is shown to be indicated.
The invention is illustrated hereinafter by examples, which have no limiting
character.
Examples
Example 1:
N-(l-Benzyl-3-oxo-2-dihydro-lH-indazol-5-yl)-3-chloro-2-methylbenzenesulfonamide
Step A] l-Benzyl-5-nitro-l,2-dihydro-indazol-3-one
To a solution of 2-fluoro-5-nitrobenzoic acid (0.5 g) in DMF (9 mL) was added TBTU
(1.04 g) followed by N-ethyldiisopropylamine (2.3 mL). After 10 minutes
benzylhydrazine.2HCl (0.63 g) was added. The reaction mixture was stirred at
ambient temperature for 22 hours and the reaction was poured onto aqueous IN HC1
solution and extracted with EtOAc. The organic layer was washed with brine, dried
over sodium sulfate, filtered and evaporated in vacuo. Purification via ISCO
combiflash chromatography afforded pure desired l-benzyl-5-nitro-l,2-dihydroindazol-
3-one (0.26 g) as a yellow solid. MS (ESr):268.3 ([M-H]").
Step B] 5-Amino-l-benzyl-l,2-dihydro-indazol-3-one
To a solution of l-benzyl-5-nitro-l,2-dihydro-indazol-3-one (0.44 g) in MeOH (50
mL) was added Pd/C(10%) catalyst (0.1 g) and the reaction mixture was stirred for
four hours at ambient temperature under a hydrogen atmosphere using a balloon. After
this ţime the reaction mixture was filtered through Celite®which was washed with
more EtOAc. The combined organic solution was evaporated in vacuo for afford the
desired 5-amino-l-benzyl-l,2-dihydro-indazol-3-one (0.39 g) which was taken into
the next reaction without further purification. MS (ESf): 240.1 ([M+H]+).
Step C] N-(l-Benzyl-3-oxo-2,3-dihydro-lH-indazol-5-yl)-3-chloro-2-methylbenzenesulfonam
ide
To a solution of 5-amino-l-benzyl-l,2-dihydro-indazol-3-one (0.04 g) in pyridine (l
mL) was added 3-chloro-2-methylbenzenesulfonylchoride (0.038 g) in one go. The
solution was stirred at 60°C for 24 hours. The pyridine was then removed in vacuo
and the residue was dissolved in EtOAc/water and separated. The aqueous phase was
extracted a further two times with EtOAc and the combined organic phases were
washed with brine and dried over sodium sulfate. The drying agent was removed by
flltration and the volatiles were removed in vacuo to afford a crude residue. The crude
material was purified via flash column chromatography eluting with
EtOAc/nHeptane/l%AcOH) to afford the desired N-(l-benzyl-3-oxo-2,3-dihydro-lHindazol-
5-yl)-3-chloro-2-methyl-benzenesulfonamide (0.015 g) as a pale yellow
Example 2:
N-(l-BenzyI-3-oxo-2 This; material was obtained in analogy to example l using 5-amino-l-benzyl-l,2-
dihydro-indazol-3-one and 3-chloro-4-fluoro-benzenesulfonyl chloride as an orange
solid. MS (ESF): 430.3 ([M-H]').
Example 3:
N-(l-Benzyl-3-oxo-2,3-dihydro-lH-indazol-5-yl)-3-trifluoromethylbenzenesulfonamide
This• material was obtained in analogy to example l using 5-amino-l-benzyl-l,2-
dihydro-indazol-3-one and 3-(trifluoromethyl)benzenesulfonyl chloride as a light
N-(l-Benzyl-3-oxo-2-dihydro-lH-indazol-5-yl)-2,4-dichlorobenzenesulfonamide
This material was obtained in analogy to example l using 5-amino-l-benzyl-l,2-
dihydro-indazol-3-one and 2,4-dichlorobenzenesulfonyl chloride as a light yellow
solid MS (ESP): 446.1 ([M-H]').
Example 5:
Naphthalene-2-sulfonic acid (l-benzyl-3-oxo-2,3-dihydro-lH-indazol-5-yl)-amide
This material was obtained in analogy to example l using 5-amino-l-benzyl-l,2-
dihydro-indazol-3-one and 1-naphthalenebenzenesulfonyl chloride as a light yellow
solid.
MS (ESF): 428.4 ([M-H]').
Example 6:
N-(l-Benzyl-3-oxo-2-dihydro-lH-indazol-5-yl)-3-chloro-4-methylbenzenesulfonamide
This material was obtained in analogy to example l using 5-amino-l-benzyl-l,2-
dihydro-indazol-3-one and 3-chloro-4-methylbenzenesulfonyl chloride as a light
yellow solid. MS (ESf): 428.4 ([M+Hf).
Example 7:
N-(l-Benzyl-3-oxo-2,3-dihydro-lH-indazol-5-yl)-4-methoxy-benzenesulfonamide
This material was obtained in analogy to example l using 5-amino-l-benzyl-l,2-
dihydro-indazol-3-one and 4-methoxybenzenesulfonyl chloride as a light yellow solid.
Example 8:
N-(l"Benzyl-3-oxo-2-dihydro-lH-indazol-5-yl)-2,4-dichloro-6-methylbenzenesulfonamide
This material was obtained in analogy to example l using 5-amino-l-benzyl-l,2-
dihydro-indazol-3-one and 2,4-dichloro-6-methylbenzenesulfonyl chloride as a brown
solid MS (ESF): 460.1 ([M-H]').
Example 9:
N-(l-Benzyl-3-oxo-2,3-dihydro-lH-indazol-5-yl)-2-trifluoromethylbenzenesulfonamide
This; material was obtained in analogy to example l using 5-amino-l-benzyl-l,2-
dihydro-indazol-3-one and 2-trifluoromethylbenzenesulfonyl chloride as a white solid.
Example 10:
N-(l-BenzyI-3-oxo-2,3-dihydro-lH-indazol-5-yl)-2,4-difluorobenzenesulfonamide
This material was obtained in analogy to example l using 5-amino-l-benzyl-l,2-
dihydro-indazol-3-one and 2,4-difluorobenzenesulfonyl chloride as a brown solid. MS
Example 11:
N-(l-Benzyl-3-oxo-2,3-dihydro-lH-indazol-5-yl)-4-propyl-benzenesulfonamide
This material was obtained in analogy to example l using 5-amino-l-benzyl-l,2-
dihydro-indazol-3-one and 4-propylbenzenesulfonyl chloride as a light yellow solid.
Example 12:
2,3-Dihydro-benzo[l,4]dioxine-6-sulfonic acid (l-benzyl-3-oxo-2,3-dihydro-lHindazol-
5-yl)-amide
This i material was obtained in analogy to example l using 5-amino-l-benzyl-l,2-
dihydro-indazol-3-one and 2,3-dihydro-l,4-benzodioxine-6-sulfonyl chloride as an
off-white solid. MS (ESf): 438.1 ([M+H]).
Example 13:
N-(l-Benzyl-3-oxo-2,3-dihydro-lH-indazol-5-yl)-4-chloro-2,5-dimethylbenzenesulfonamide
This material was obtained in analogy to example l using 5-amino-l-benzyl-l,2-
dihydro-indazol-3-one (0.040 g) and 4-chloro-2,5-dimethylsulfonylchloride as an offwhite
Example 14:
N-(l-Benzyl-3-oxo-2-dihydro-H-indazol-5-yl)-4-chloro-3-trifluoromethyIbenzenesulfonamide
This material was obtained in analogy to example l using 5-amino-l-benzyl-l,2-
dihydro-indazol-3-one and 3-trifluoromethyl-4-chlorobenzenesulfonylchloride as a
white solid. MS (ESI4): 482.3 ([M+H]+).
Example 15:
N-(l-Benzyl-3-oxo-2,3-dihydro-lH-indazoI-5-yl)-4-fluoro-3-trifluoromethyIbenzenesulfonamide
This material was obtained in analogy to example l using 5-amino-l-benzyl-l,2-
dihydro-indazol-3-one and 4-fluoro-3-trifluoromethylbenzenesulfonylchloride as a
light brown solid. MS (ESF): 464.4 ([M-H]').
Example 16:
N-(l-Benzyl-3-oxo-2,3-dihydro-lH-indazol-5-yl)-2-chloro-5-trifluoromethylbenzenesulfonamide
This material was obtained in analogy to example l using 5-amino-l-benzyl-l,2-
dihydro-indazol-3-one and 2-cloro-5-trifluoromethyl-benzenesulfonyl chloride as a
lightbrown solid. MS (ESI"): 480.3[M-H]').
Example 17:
N-(l-Benzyl-3-oxo-2,3-dihydro-lH-indazoI-5-yl)-3-phenoxy-benzenesulfonamide
This material was obtained in analogy to example l using 5-amino-l-benzyl-l,2-
dihydro-indazol-3-one and 3-penoxy-benzenesulfonyl chloride as a light brown solid.
MS (ESF): 470.3[M-H]').
Example 18:
N-(l-Benzyl-3-oxo-2,3-dihydro-lH-indazol-5-yl)-3-(5-methyl-[l,3,4]oxadiazol-2-
yl)-benzenesulfonamide
This material was obtained in analogy to example l using 5-amino-l-benzyl-l,2-
dihydro-indazol-3-one and 3-(5-methyl-l,3,4-oxadiazol-2-yl)benzenesulfonyl chloride
as a light brown solid. MS (ESF): 460.4[M-H]').
Example 19:
N-(l-Benzyl-3-oxo-2-dihydro-lH-indazol-5-yl)-3-chloro-benzenesulfonamide
This material was obtained in analogy to example l using 5-amino-l-benzyl-l,2-
dihydro-indazol-3-one and 3-chloro-benzenesulfonyl chloride as a light brown solid.
MS(ESr):412.1[M-H]').
Example 20:
N-(l-BenzyI-3-oxo-2-dihydro-lH-indazol-5-yl)-3-methoxy-benzenesulfonamide
This material was obtained in analogy to example l using 5-amino-l-benzyl-l,2-
dihydro-indazol-3-one and 3-methoxy-benzenesulfonyl chloride as a light brown
solid. MS (ESF): 408.0[M-H]-).
Example 21:
N-(l-Benzyl-3-oxo-23-dihydro-lH-indazol-5-yl)-3-difluoromethoxybenzenesulfonamide
This material was obtained in analogy to example l using 5-amino-l-benzyl-l,2-
dihydro-indazol-3-one and 3-(difluoromethoxy)-benzenesulfonyl chloride as a
colorless solid. MS (ESI'): 444.1[M-H]').
Example 22:
N-(lrBenzyl-3-oxo-2,3-dihydro-lH-indazol-5-yl)-3,5-bis-trifluoromethylbenzenesulfonamide
This l compound was obtained in analogy to example l using 5-amino-l-benzyl-l,2-
dihydro-indazol-3-one and 3,5-bistrifluoromethylbenzenesulfonyl chloride (step C) as
a white solid. MS (EST): 514.3 [M-H]').
Example 23:
Propane-2-sulfonic acid (l-benzyI-3-oxo-2,3-dihydro-lH-indazol-5-yl)-ainide
This compound was obtained in analogy to example l using 5-amino-l-benzyl-l,2-
dihydro-indazol-3-one and 3 propane-2-sulfonyl chloride (step C) as a white solid. MS
Example 24:
N-(lrBenzyl-3-oxo-2,3-dihydro-lH-indazol-5-yl)-3-chloro-2-N-diraethylbenzenesulfonamide
To a solution of NaH (0.005 g of a 60% dispersion in mineral oii) in DMF (2 mL) at
0°C was added N-(l-benzyl-3-oxo-2,3-dihydro-lH-indazol-5-yl)-3-chloro-2-methylbenzenesulfonamide
in DMF (l mL) dropwise. After 15 minutes Mei (0.017 g) was
added and the reaction mixture was allowed to warm to ambient temperature. The
reaction was quenched with water and diluted with EtOAc. The phases were separated
and the aqueous phase was extracted with more EtOAc. The combined organic phases
were washed with brine, dried over sodium sulfate, filtered and reduced in vacuo.
Flash column chromatography over silica (EtOAc/nheptane) afforded the desired N-
(l-benzyl-3-oxo-2,3-dihydro-lH-indazol-5-yl)-3-chloro-2-N-dimethylbenzenesulfonamide
as an off-white solid (13 mg). MS (ESI): 442.4[M+H]+).
Example 25:
N-(3-Oxo-l-propyl-2,3-dihydro-lH-indazol-5-yl)-3-trifluoromethylbenzenesulfonamide
Step A] l-Allyl-5-nitro-1,2-dihydro-indazol-3-one
5-Niţro-l,2-dihydro-indazol-3-one (prepared according to Org. Synth. 1949, 29, 54 or
Chem Ber. 1942, 75, 1104) (9.36 g) was suspended in 40 ml water and 57.5 ml IN
KOH. Allyl bromide (6.32 g) was added in one portion. The mixture was stirred at
75-80°C for 1.5 hours. Then NaOH (15%, 5 mL) and allyl bromide (l g) was added.
The reaction mixture was stirred for a further 30 min. The mixture was neutralized
with 3N HC1 at solid was then suspended in 10 ml ethyl acetate and stirred at ambient temperature for
3 hojurs, then filtered and dried to afford the desired l-allyl-5-nitro-l,2-dihydroindazol-
3-one (7.63 g) as a yellow solid.
Step B] 35
l-Allyl-5-nitroindazolone (1.42 g) and Pd/C (10%, 250 mg) were suspended in MeOH
(50 mL) and hydrogenated (hydrogen balloon) at RT for 4-5 h (or overnight.) After
filtration and removal of MeOH, the solid was dried in vacuo to afford the desired 5-
amino-l-propyl-l,2-dihydro-indazol-3-one (1.2 g) as a crude oii. This material was
used in the next reaction without any further purification.
Step C] N-(3-Oxo-1 -propyl-2,3-dihydro-1H-indazol-5-yl)-3-trifluoromethylbenzenesulfonamide
This material was obtained in analogy to example l using 5-amino-l-propyl-l,2-
dihydro-indazol-3-one and 2,3-dichlorobenzenesulfonyl chloride.
Example 26:
2,3-Dichloro-N-(3-oxo-l-propyl-2,3-dihydro-lH-indazol-5-yl)-
benzenesulfonamide
This;material was obtained in analogy to example 25 using 5-amino-l-propyl-l,2-
dihydro-indazol-3-one and 2,3-dichlorobenzenesulfonyl chloride.
Example 27:
3-Chloro-4-fluoro-N-(3-oxo-l-propyl-2,3-dihydro-lH-indazol-5-yI)-
benzenesulfonamide
This material was obtained in analogy to example 25 using 5-amino-l-propyl-l,2-
dihydro-indazol-3-one and 3-chloro-4-fluoro-benzenesulfonyl chloride.
Example 28:
3-CWoro-2-methyl-W-(3-oxo-l-phenethyl-2-dihydro-l/y-indazol-5-yl)-
benzenesulfonamide
This icompound was obtained in analogy to example l using phenethylhydrazine (step
A) and 3-chloro-2-methylbenzenesulfonyl chloride (step C) as a light yellow solid.
MS (ESf): 442.3[M+Hf).
Example 29:
3-Chloro-4-methyl-W-(3-oxo-l-phenethyl-2,3-dihydro-l//-indazol-5-yl)-
benzenesulfonamide
This compound was obtained in analogy to example l using phenethylhydrazine (step
A) and 3-chloro-4-methylbenzenesulfonyl chloride (step C) as a white solid. MS
(ESlt): 442.3[M+H]+).
Example 30:
4-Chloro-2,5-dimethyl-N-(3-oxo-l-phenethyl-2,3-dihydro-lH-indazol-5-yl)-
benzenesulfonamide
This compound was obtained in analogy to example l using phenethylhydrazine (step
A) and 4-chloro-2,5-dimethylbenzenesulfonyl chloride (step C) aş a white solid. MS
(ESlt): 456.4[M+H]+).
Example 31:
N-(3-Oxo-l-phenethyl-2,3-dihydro-lH-indazol-5-yl)-3-trifluoromethylbenzenesulfonamide
This compound was obtained in analogy to example l using phenethylhydrazine (step
A) and 3-trifluoromethylsulfonyl chloride (step C) as a red solid. MS (ESI4):
462.1[M+H]+).
Example 32:
N-(l-IsobutyW-oxo-2,3-dihydro-lH-indazol-5-yl)-3-trifluoromethylbenzenesulfonamide
StepiA] l-Isobutyl-5-nitro-l,2-dihydro-indazol-3-one
To a solution of 2-fluoro-5-nitrobenzoic acid (1.5 g) in DMF (50 mL) was added
EDCI.HC1 (1.71 g) followed by N-ethyldiisopropylamine (5.51 mL). After 10 minutes
isobutylhydrazine.p-toluenesulfonicacid salt (2.32 g) was added. The reaction mixture
was stirred at ambient temperature for 22 hours and the reaction was poured onto
aqueous IN HC1 solution and extracted with EtOAc. The organic layer was washed
withibrine, dried over sodium sulfate, filtered and evaporated .in vacuo. Purification
via ISCO combiflash chromatography afforded pure desired l-isobutyl-5-nitro-l,2-
dihydro-indazol-3-one (0.9 g) as ayellow solid. MS (ESr):234.1 ([M-H]').
Step B] 5-Amino-l-isobutyl-l,2-dihydro-indazol-3-one
To a solution of l-isobutyl-5-nitro-l,2-dihydro-indazol-3-one (0.9 g) in MeOH (50
mL) was added Pd/C(10%) catalyst (0.3 g) and the reaction mixture was stirred for l
hour at 40°C under a hydrogen atmosphere using a balloon. After this time the
reaction mixture was filtered through Celite®which was washed with more EtOAc.
The combined organic solution was evaporated in vacuo for afford the desired 5-
amino-l-isobutyl-l,2-dihydro-indazol-3-one (0.6 g) which was taken into the next
reaction without further purification. MS (ESI): 206.1 ([M+H]+).
Step C] N-(l-Isobutyl-3-oxo-2,3-dihydro-lH-indazol-5-yl)-3-trifluoromethylbenzenesulfonamide
To a solution of 5-amino-l-isobutyl-l,2-dihydro-indazol-3-one (0.04 g) in pyridine (l
mL) was added 3-trifluoromethylbenzenesulfbnylchoride (0.041 g) in one go. The
solution was stirred at 60°C for 24 hours. The pyridine was then removed in vacuo
and the residue was dissolved in EtOAc/water and separated. The aqueous phase was
extracted a further two times with EtOAc and the combined organic phases were
washed with brine and dried over sodium sulfate. The drying agent was removed by
flltration and the volatiles were removed in vacuo to afford a crude residue. The crude
material was purified via flash column chromatography eluting with
EtOAc/nHeptane/l%AcOH) to afford the desired N-(l-isobutyl-3-oxo-2,3-dihydrolH-
indazol-5-yl)-3-trifluoromethyl-benzenesulfonamide (0.015 g) as a pale yellow
powder. MS (ESf): 414.4[M+H]+).
Example33:
3-Chloro-N-(l-isobutyl-3-oxo-2-dihydro-lH-indazol-5-yl)-4-methylbenzenesulfonamide
This compound was obtained in analogy to example 32 using 5-amino-l-isobutyl-l,2-
dihydro-indazol-3-one and 3-chloro-4-methylbenzenesulfonyl chloride (step C) as a
white solid. MS (ESI4): 394.1 [M+H]).
Example 34:
3-ChIoro-N-(l-isobutyl-3-oxo-2,3-dihydro-lH-indazol-5-yI)-2-methylbenzenesulfonamide
38
This compound was obtained in analogy to example 32 using 5-amino-l-isobutyl-l,2-
dihydro-indazol-3-one and 3-chloro-2-methylbenzenesulfonyl chloride (step C) as a
white solid. MS (ESI): 394. l [M+H]).
Example 35:
3-Cyano-(l-isobutyl-3-oxo-2,3-dihydro-indazol-5-yl)-benzenesulfonamide
This compound was obtained in analogy to example 32 using 5-amino-l-isobutyl-l,2-
dihydro-indazol-3-one and 3-cyano-benzenesulfonyl chloride (step C) as an off-white
solid MS (ESI): 371.1[M+H]+).
Example 36:
3-Difluoromethoxy-(l-isobutyl-3-oxo-2,3-dihydro--indazol-5-yl)-
benzenesulfonamide
This compound was obtained in analogy to example 32 using 5-amino-l-isobutyl-l,2-
dihydro-indazol-3-one and 3-difluoromethoxy-benzenesulfonyl chloride (step C) as an
off-white solid. MS (ESf):
Example 37:
4-Cyano-(l-isobutyl-3-oxo-2,3-dihydro-indazol-5-yl)-benzenesulfonamide
This compound was obtained in analogy to example 32 using 5-amino-l-isobutyl-l,2-
dihydro-indazol-3-one and 4-cyano-benzenesulfonyl chloride (step C) as an off-white
solid MS (ESf): 371.1 [M+H]+).
Example 38:
4-Fluoro-N-(l-isobutyl-3-oxo-2,3-dihydro-lH-indazol-5-yl)-3-trifluoromethyIbenzenesulfonamide
This compound was obtained in analogy to example 32 using 5-amino-l-isobutyl-l,2-
dihydro-indazol-3-one and 4-fluoro-3-trifluoromethylbenzenesulfonyl chloride (step
C) as an off-white solid. MS (ESf): 432.4 [M+H]+).
Example 39:
39
3-Chloro-4-fluoro-W-(l-isobutyl-3-oxo-2,3-dihydro-l//-indazol-5-yl)-
benzenesulfonamide
This compound was obtained in analogy to example 32 using 5-amino-l-isobutyl-l,2-
dihydro-indazol-3-one and 3-chloro-4-fluorobenzenesulfonyl chloride (step C) as an
off-white solid. MS (ESI): 398.l [M+H]4).
Example 40:
2,4-Dichloro-(l-isobutyl-3-oxo-2,3-dihydro-indazol-5-yl)-5-methylbenzenesulfonamide
This compound was obtained in analogy to example 32 using 5-amino-l-isobutyl-l,2-
dihydro-indazol-3-one and 2,4-dimethyl-5-methylbenzenesulfonyl chloride (step C) as
an orange solid. MS (ESI+): 428.3 [M+H]+).
Example 41:
3-Chloro-N-(l-ethyl-3-oxo-2,3-dihydro-l#-indazol-5-yl)-2-methylbenzenesulfonamide
This compound was obtained in analogy to example l using ethylhydrazine.oxalate
salt (step A) and 3-chloro-2-methylbenzenesulfonyl chloride (step C) as light yellow
solid MS (ESf): 366.0 [M+H]).
Example 42:
3-Chloro-(l-cyclopropylmethyl-3-oxo-2,3-dihydro-indazol-5-yl)-2-methylbenzenesulfonamide
This compound was obtained in analogy to example 32 using cyclopropylmethylhydrazine
(step A) (prepared as described in J. Am. Chem. Soc. 1986, 108, 7981-4)
and 3-chloro-2-methylbenzenesulfonyl chloride (step C) as a light red solid. MS
(ESI;): 392.0 [M+H]+).
Example 43:
3-Chloro-(l-cyclopropylmethyl-3-oxo-2,3-dihydro-indazol-5-yl)-4-fluorobenzenesulfonamide
This compound was obtained in analogy to example 32 using cyclopropylmethylhydrazine
(step A) (prepared as described in J. Am. Chem. Soc. 1986, 108, 7981-4)
: 40
and 3-chloro-4-fluorobenzenesulfonyl chloride (step C) as a pink solid. MS (ESI+):
396.3 [M+H]+).
Example 44:
(l-Cyclopropylmethyl-3-oxo-2,3-dihydro-indazol-5-yl)-4-fluoro-3-
trifluoromethyl-benzenesulfonamide
This compound was obtained in analogy to example 32 using cyclopropylmethylhydrazine
(step A) (prepared as described in J. Am. Chem. Soc. 1986, 108, 7981-4)
and 4-fluoro-3-trifluoromethylbenzenesulfonyl chloride (step C) as a light red solid.
MS (ESf): 430.4 [M+H]).
Example 45:
3-Chloro-(l-cycIopropylmethyI-3-oxo-2,3-dihydro-indazoI-5-yl)-
benzenesulfonamide
This compound was obtained in analogy to example 32 using cyclopropylmethylhydrazine
(step A) (prepared as described in V. Am. Chem. Soc. 1986, 108, 7981-4)
and 3-chlorobenzenesulfonyl chloride (step C) as an orange solid. MS (ESI): 378.3
Example 46:
2,4-Dichloro-(l-cyclopropyImethyl-3-oxo-2y3-dihydro-indazol-5-yl)-5-methyIbenzenesulfonamide
This i compound was obtained in analogy to example 32 using cyclopropylmethylhydrazine
(step A) (prepared as described in J. Am. Chem. Soc. 1986, 1 08, 7981-4)
and 2,4-dichloro-5-methylbenzenesulfonyl chloride (step C) as an orange solid. MS
(ESlt):426.1 [M+H]+).
Example 47:
3-Chloro-[l-(2-methoxy-ethyl)-3-oxo-2,3-dihydro-indazol-5-yl]-2-methylbenzenesulfonamide
This compound was obtained in analogy to example 32 using (2-methoxy-ethyl)-
hydrâzine (step A) (prepared as described in J. Org. Chem. 1984, 49, 336-42) and 3-
41
chloro-2-methylbenzenesulfonyl chloride (step C) as a white solid. MS (ESI): 396.3
Example 48:
4-Fluoro-[l-(2-methoxy-ethyl)-3-oxo-2-dihydro-indazol-5-yl]-3-trifluoroinethylbenzenesulfonamide
This compound was obtained in analogy to example 32 using (2-methoxy-ethyl)-
hydrazine (step A) (prepared as described in J. Org. Chem. 1984, 49, 336-42) and 4-
fluoro-3-trifluoromethylbenzenesulfonyl chloride (step C) as a white solid. MS (ESI):
434.3 [M+H]+).
Example 49:
3-Chloro-4-fluoro-[l-(2-methoxy-ethyl)-3-oxo-2,3-dihydro-indazol-5-yl]-
benzenesulfonamide
This compound was obtained in analogy to example 32 using (2-methoxy-ethyl)-
hydrâzine (step A) (prepared as described in J. Org. Chem. 1984, 49, 336-42) and 3-
chloro-4-fluorobenzenesulfonyl chloride (step C) as an off-white solid. MS (ESI+):
400.3 [M+HJ+).
Example 50:
2,4-DichIoro-[l-(2-methoxy-ethyl)-3-oxo-2r3-dihydro-indazol-5-yl]-6-methylbenzenesulfonamide
This compound was obtained in analogy to example 32 using (2-methoxy-ethyl)-
hydrâzine (step A) (prepared as described in J. Org. Chem. 1984, 49, 336-42) and 2,4-
dichlbro-6-methylbenzenesulfonyl chloride (step C) as a white solid. MS (ESI+):
430.3 [M+Hf).
Example 51:
3-ChIoro-2-methyl-A'-[3-oxo-l-(2,2-trifluoro-ethyl)-2,3-dihydro-l/r-indazol-5-
yl]-benzenesulfonamide
Thisicompound was obtained in analogy to example 32 using (2,2,2-trifluoro-ethyl)-
hydrazine (step A) and 3-chloro-2-methylbenzenesulfonyl chloride (step C) as a red
solii MS (ESf): 420.3 [M+H]+).
Example 52:
4-Fliioro-[3-oxo-l-(2,2,2-trifluoro-ethyl)-2,3-dihydro-indazol-5-yl]-3-
trifluoromethyl-benzenesulfonamide
This compound was obtained in analogy to example 32 using (2,2,2-trifluoro-ethyl)-
hydrazine (step A) and 4-fluoro-3-trifluoromethylbenzenesulfonyl chloride (step C) as
a brown solid. MS (ESf): 458.4 [M+H]+).
Example 53:
4-FIuoro-A3-oxo-l-pyridin-2-ylmethyI-2,3-dihydro-l/y-indazol-5-yl)-3-
trifluoromethyl-benzenesulfonamide
This; compound was obtained in analogy to example 32 using pyridin-2-ylmethylhydrazine
(step A) (prepared in analogy to examples described in J. Org. Chem. 1984,
49, 336-42) and 4-fluoro-3-trifluoromethylbenzenesulfonyl chloride (step C) as offwhite
solid. MS (ESf): 467.4 [M+H]+).
Example 54:
2,4-Dichloro-6-methyl-A43-oxo-l-pyridin-2-ylmethyl-2-dihydro-l//-indazol-5-
yl)-benzenesulfonamide
This; compound was obtained in analogy to example 32 using pyridin-2-ylmethylhydrazine
(step A) (prepared in analogy to examples described in J. Org. Chem. 1984,
49, 336-42) and 2,4-dichloro-6-methylbenzenesulfonyl chloride (step C) as off-white
solid MS (ESf): 463.3 [M+H]).
Example 55:
3-Chloro-2-methyl-V-(3-oxo-l-pyridin-2-ylmethyl-2-dihydro-ljy-indazdI-5-yl)-
benzenesulfonamide
This compound was obtained in analogy to example 32 using pyridin-2-ylmethylhydrazine
(step A) (prepared in analogy to examples described in J. Org. Chem. 1984,
49, 336-42) and 3-chloro-2-methylbenzenesulfonyl chloride (step C) as off-white
solid MS (ESf): 429.4 [M+H]+).
Example 56:
4-Fluoro-A'-[l-(2-hydroxy-2-methyl-propyl)-3-oxo-2,3-dihydro-lr-indazoI-5-yl]-
3-trifluoromethyl-benzenesulfonamide
This compound was obtained in analogy to example 32 using pyridin-2-ylmethylhydrazine
(step A) (prepared as described in Bioorg. Med. Chem. 2004, 12, 1357-
1366) and 4-fluoro-3-trifluoromethylbenzenesulfonyl chloride (step C) as off-white
solid, MS (ESI): 448.3 [M+Hf).
Example 57:
N-(l-Benzyl-6-chloro-3-oxo-2,3-dihydro-lH-indazol-5-yl)-3-chloro-4-fluorobenzenesulfonamide
This compound was obtained in analogy to example 32 using 4-chloro-2-fluoro-5-
nitro-benzoic acid, benzylhydrazine.2HCl (step A) and 3-chloro-4-
fluorobenzenesulfonyl chloride (step C) as a light brown solid. MS (ESI"): 464.1 [MExample
58:
N-(l-Benzyl-6-chloro-3-oxo-2,3-dihydro-lH-indazol-5-yl)-4-fluoro-3-
trifluoromethyl-benzenesulfonamide
This compound was obtained in analogy to example 32 using 4-chloro-2-fluoro-5-
nitro-benzoic acid, benzylhydrazine.2HCl (step A) and 4-fluoro-3-
trifluoromethylbenzenesulfonyl chloride (step C) as a light brown solid. MS (ESF):
498.0 [M-H]>
Example 59:
N-(lrBenzyl-6-chloro-3-oxo-2,3-dihydro-lH-indazol-5-yl)-3-chloro-2-methylbenzenesulfonamide
This compound was obtained in analogy to example 32 using 4-chloro-2-fluoro-5-
nitro-benzoic acid, benzylhydrazine.2HCl (step A) and 3-chloro-2-
methylbenzenesulfonyl chloride (step C) as a light brown solid. MS (ESI"): 460.0 [MExample
N-(l-Benzyl-6-chIoro-3-oxo-2,3-dihydro-lH-indazol-5-yl)-2,3-dichlorobenzenesulfonamide
This compound was obtained in analogy to example 32 using 4-chloro-2-fluoro-5-
nitrorbenzoic acid, benzylhydrazine.2HCl (step A) and 2,3-dichloro-benzenesulfonyl
chloride (step C) as a light brown solid. MS (ESI'): 480.1 [M-H]').
Example 61:
N-(l-Benzyl-6-chloro-3-oxo-2,3-dihydro-lH-indazol-5-yl)-3-cyanobenzenesulfonamide
This i compound was obtained in analogy to example 32 using 4-chloro-2-fluoro-5-
nitro-benzoic acid, benzylhydrazine.2HCl (step A) and 3-cyano-benzenesulfonyl
chloride (step C) as a light brown solid. MS (ESF): 437.0 [M-H]').
Example 62:
N-(lBenzyl-6-chloro-3-oxo-2,3-dihydro-lH-indazol-5-yl)-3-chlorobenzenesulfonamide
This compound was obtained in analogy to example 32 using 4-chloro-2-fluoro-5-
nitro-benzoic acid, benzylhydrazine.2HCl (step A) and 3-chloro-benzenesulfonyl
chloride (step C) as a white solid. MS (ESF): 446.l [M-H]').
Example 63:
N-(l"Benzyl-6-chloro-3-oxo-2,3-dihydro-lH-indazol-5-yl)-4-chloro-3-
trifluoromethyl-benzenesulfonamide
This compound was obtained in analogy to example 32 using 4-chloro-2-fluoro-5-
nitro-benzoic acid, benzylhydrazine.2HCl (step A) and 4-chloro-3-
trifluoromethylbenzenesulfonyl chloride (step C) as a white solid.
MS(ESr):514.3[M-HD.
Example 64:
N-(l--Benzyl-6-chloro-3-oxo-2,3-dihydro-lH-indazol-5-yl)-3-difluoromethoxybenzenesulfonamide
This compound was obtained in analogy to example 32 using 4-chloro-2-fluoro-5-
nitro-benzoic acid, benzylhydrazine.2HCl (step A) and 4-chloro-3-
trifluoromethylbenzenesulfonyl chloride (step C) as a white solid.
MS (ESF): 478.0 [M-H]').
Example65:
N-(l-Benzyl-6-chloro-3-oxo-2,3-dihydro-lH-indazol-5-yl)-2-trifluoromethyIbenzenesulfonamide
This compound was obtained in analogy to example 32 using 4-chloro-2-fluoro-5-
nitro-benzoic acid, benzylhydrazine.2HCl (step A) and 2-
trifluoromethylbenzenesulfonyl chloride (step C) as a white solid. MS (ESI"): 480.0
[M-H]-).
Example 66:
N-(l-Benzyl-6-chloro-3-oxo-2,3-dihydro-lH-indazol-5-yl)-3-trifluoromethoxybenzenesulfonamide
This compound was obtained in analogy to example 32 using 4-chloro-2-fluoro-5-
nitrol-benzoic acid, benzylhydrazine.2HCl (step A) and 3-
triflupromethoxybenzenesulfonyl chloride (step C) as a white solid. MS (ESF): 496.4
[M-H]').
Example 67:
N-(l-Benzyl-6-chloro-3-oxo-2,3-dihydro-lH-indazol-5-yl)-2,5-difluorobenzenesulfonamide
This compound was obtained in analogy to example 32 using 4-chloro-2-fluoro-5-
nitror-benzoic acid, benzylhydrazine.2HCl (step A) and 2,5-difluorobenzenesulfonyl
chloride (step C) as a light red solid. MS (ESF): 447.9 [M-H]').
Example 68:
N-(l-Benzyl-6-chIoro-3-oxo-2,3-dihydro-lH-indazol-5-yl)-2,4-dichlorobenzenesulfonamide
This compound was obtained in analogy to example 32 using 4-chloro-2-fluoro-5-
nitroţ-benzoic acid, benzylhydrazine.2HCl (step A) and 2,4-dichlorobenzenesulfonyl
chloride (step C) as a light brown solid. MS (ESI+): 482.4 [M+Hf).
Example 69:
N-(l-Benzyl-6-chloro-3-oxo-2,3-dihydro-lH-indazol-5-yl)-3-chloro-2-fluorobenzenesulfonamide
This \ compound was obtained in analogy to example 32 using 4-chloro-2-fluoro-5-
nitro-benzoic acid, benzylhydrazine.2HCl (step A) and 3-chloro-2-
fluorobenzenesulfonyl chloride (step C) as a yellow solid. MS (ESI"): 464.1 [M-H]").
Example 70:
N-(l-Benzyl-6-chloro-3-oxo-2,3-dihydro-lH-indazol-5-yl)-3-trifluoromethylbenzenesulfonamide
This compound was obtained in analogy to example 32 using 4-chloro-2-fluoro-5-
nitro-benzoic acid, benzylhydrazine.2HCl (step A) and 3-
trifluoromethylbenzenesulfonyl chloride (step C) as a light red solid. MS (ESF): 480.0
[M-H]-).
Example 71:
N-(lBenzyI-6-chloro-3-oxo-2,3-dihydro-lH-indazoI-5-yl)-5-chloro-2-fluorobenzenesulfonamide
This compound was obtained in analogy to example 32 using 4-chloro-2-fluoro-5-
nitro-benzoic acid, benzylhydrazine.2HCl (step A) and 3-chloro-6-
fluorobenzenesulfonyl chloride (step C) as a brown solid. MS (ESI'): 464.1 [M-H]").
Example 72:
N-(lBenzyl-6-chloro-3-oxo-2,3-dihydro-lH-indazol-5-yl)-2-chlorobenzenesulfonamide
This compound was obtained in analogy to example 32 using 4-chloro-2-fluoro-5-
nitro-benzoic acid, benzylhydrazine.2HCl (step A) and 2-chlorobenzenesulfonyl
chloride (step C) as a light brown solid. MS (ESI"): 446.1 [M-H]").
Example 73:
(l-Benzyl-4-chIoro-3-oxo-2,3-dihydro-indazol-5-yl)-3-chloro-2-methylbenzenesulfonamide
This compound was obtained in analogy to example 32 using 2-chloro-6-fluoro-3-
nitrorbenzoic acid, benzylhydrazine.2HCl (step A) and 3-chloro-4-
fluorpbenzenesulfonyl chloride (step C) as a light brown solid. MS (ESI"): 460.1 [MH]-).
Example 74:
N-(lBenzyl-6-fluoro-3-oxo-2,3-dihydro-lH-indazoI-5-yl)-4-fluoro-3-
trifluoromethyl-benzenesulfonamide
This compound was obtained in analogy to example 32 using 2,4-difluoro-5-nitrobenzoic
acid, benzylhydrazine.2HCl (step A) and 4-fluoro-3-
trifluoromethylbenzenesulfonyl chloride (step C) as a light brown solid. MS (ESF1):
484.5 [M+H]+).
Example 75:
N-(l-Benzyl-6-fluoroO-oxo-2,3-dihydro-lH-indazol-5-yl)-2,3-dichlorobenzenesulfonamide
This compound was obtained in analogy to example 32 using 2,4-difluoro-5-nitrobenzoic
acid, benzylhydrazine.2HCl (step A) and 2,3-dichlorobenzenesulfonyl
chloride (step C) as a light brown solid. MS (ESF): 464.1 [M-H]').
Example 76:
N-(l-BenzyI-6-fluoro-3-oxo-2,3-dihydro-lH-indazol-5-yl)-2,4-dichlorobenzenesulfonamide
This compound was obtained in analogy to example 32 using 2,4-difluoro-5-nitrobenzoic
acid, benzylhydrazine.2HCl (step A) and 2,4-dichlorobenzenesulfonyl
chloride (step C) as a light brown solid. MS (ESI'): 464. l [M-H]").
Example 77:
(l-Benzyl-â-fluoro-S-oxo-dihydro-lH-indazol-S-yO-S-chloro-fluorobenzenesulfonamide
This compound was obtained in analogy to example 32 using 2,4-difluoro-5-nitrobenzbic
acid, benzylhydrazine.2HCl (step A) and 3-chloro-2-fluorobenzenesulfonyl
chloride (step C) as a light brown solid. MS (ESI'): 447.9 [M-H]").
N-(lBenzyI-6-fluoro-3-oxo-2-dihydro-lH-indazoI-5-yl)-5-chloro-2-fluorobenzenesulfonamide
This compound was obtained in analogy to example 32 using 2,4-difluoro-5-nitrobenzoic
acid, benzylhydrazine.2HCl (step A) and 3-chloro-6-fluorobenzenesulfonyl
chloride (step C) as a light brown solid. MS (ESI'): 447.9[M-H]").
Example 79:
N-(l-Benzyl-6-fluoro-3-oxo-2-dihydro-lH-indazol-5-yl)-3-trifluoromethoxybenzenesulfonamide
This compound was obtained in analogy to example 32 using 2,4-difluoro-5-nitrobenzoic
acid, benzylhydrazine.2HCl (step A) and 3-trifluoromethoxybenzenesulfonyl
chloride (step C) as a light brown solid. MS (ESI): 482.4 [M+H]+).
Example 80:
3-CHloro-N-[l-(4-fluoro-benzyl)-3-oxo-2,3-dihydro-lH-indazoI-5-yl]-
benzenesulfonamide
Step A] l-(4-Fluoro-benzyl)-5-nitro-l,2-dihydro-indazol-3-one
5-Nitro-l,2-dihydro-indazol-3-one (prepared according to Org. Synth. 1949, 29, 54 or
Chem Ber. 1942, 75, 1104) (0.7 g) was suspended in l N NaOH (4.2 mL) and stirred
for 10 minutes at 75°C. 4-Fluorobenzylbromide (0.48 mL) was then added dropwise
over 2 hours. The reaction was stirred overnight and was quenched with 2 N HCI (aq.)
solution while cooling in an ice bath. The precipitate was collected by fîltration and
the crude solid was either purified by flash column chromatography or by trituration
with ether to give pure l-(4-fluoro-benzyl)-5-nitro-l,2-dihydro-indazol-3-one. MS
(ESI1): 286.1 [M-H]').
Step B] 5-Am ino-1 -(4-fluoro-benzyl)-1,2-dihydro-indazol-3 -one
To a solution of l-(4-fluoro-benzyl)-5-nitro-l,2-dihydro-indazol-3-one (0.81 g) in
MeOH (100 mL) was added Pd/C(10%) catalyst (0.1 g) and the reaction mixture was
stirred for three hours at 40°C under a hydrogen atmosphere using a balloon. After
this time the reaction mixture was filtered through Celite®which was washed with
more EtOAc. The combined organic solution was evaporated in vacuo for afford the
desired 5-amino-l-(4-fluoro-benzyl)-l,2-dihydro-indazol-3-one (0.617 g) which was
taken into the next reaction without further purification. MS (ESf): 258.3 ([M+H]+).
Step C] 3-Chloro-N-[l-(4-fluoro-benzyl)-3-oxo-2,3-dihydro-lH-indazol-5-yl]-
benzenesulfonamide
To a solution of 5-amino-l-(4-fluoro-benzyl)-l,2-dihydro-indazol-3-one (0.100 g) in
pyridine (l mL) was added 3-chlorobenzenesulfonylchoride (0.082 g) in one go. The
solution was stirred at 60°C for 24 hours. The pyridine was then removed in vacuo
and the residue was dissolved in EtOAc/water and separated. The aqueous phase was
extracted a further two times with EtOAc and the combined organic phases were
washed with brine and dried over sodium sulfate. The drying agent was removed by
filtration and the volatiles were removed in vacuo to afford a crude residue. The crude
material was purified via flash column chromatography eluting with
EtOAc/nHeptane/l%AcOH) to afford the desired 3-chloro-N-[l-(4-fluoro-benzyl)-3-
oxo-2,3-dihydro-lH-indazol-5-yl]-benzenesulfonamide (0.087 g) as a brown solid.
MS (ESI): 432.4 [M+H]).
Example 81:
3-Difluoromethoxy-N-[l-(4-fluoro-benzyl)-3-oxo-2,3-dihydro-lH-indazol-5-ylJbenzenesulfonamide
This compound was obtained in analogy to example 80 using 5-amino-l-(4-fluorobenzyl)-
l,2-dihydro-indazol-3-one and 3-difluoromethoxybenzenesulfonyl chloride
(step C) as a light brown solid. MS (ESI): 464.4 [M+Hf).
Example 82:
4-FlMoro-N-[l-(4-fluoro-benzyl)-3-oxo-2-dihydro-lH-indazol-5-yl]-3-
trifluoromethyl-benzenesulfonamide
This i compound was obtained in analogy to example 80 using 5-amino-l-(4-fluorobenzyl)-
1,2-dihydro-indazol-3-one and 4-fluoro-3-trifluoromethylbenzenesulfonyl
chloride (step C) as a light brown solid. MS (ESF): 482.3 [M-H]').
Example 83:
2,3-Dihydro-benzo[l,4]dioxine-6-sulfonic acid [l-(4-fluoro-benzyl)-3-oxo-2,3-
dihydro-lH-indazol-5-yl]-amide
50
This compound was obtained in analogy to example 80 using 5-amino-l-(4-fluorobenzyl)-
l,2-dihydro-indazol-3-one and 3-dihydro-l,4-benzodioxine-6-sulfonyl
chloride (step C) as a light brown solid. MS (ESF): 456.5 [M-H]').
Example 84:
2,4-Dich!oro-N-[l-(4-fluoro-benzyl)-3-oxo-2v3-dihydro-lH-indazol-5-yI]-6-
methyl-benzenesulfonamide
This compound was obtained in analogy to example 80 using 5-amino-l-(4-fluorobenzyl)-
l,2-dihydro-indazol-3-one and 2,4-dichloro-6-methylbenzenesulfonyl
chloride (step C) as a light brown solid. MS (ESf): 480.4 [M+H]+).
Example 85:
5-Chloro-2,4-difluoro-N-[l-(4-fluoro-benzyl)-3-oxo-2,3-dihydro-lH-indazol-5-yl]-
benzenesulfonamide
This compound was obtained in analogy to example 80 using 5-amino-l-(4-fluorobenzyl)-
l,2-dihydro-indazol-3-one and 3-chloro-4,6-difluorobenzenesulfonyl chloride
(step; C) as an off-white solid. MS (ESI): 468.4 [M+H]+).
Example 86:
4-ChIoro-2,5-difluoro-N-[l-(4-fluoro-benzyl)-3-oxo-2-dihydro-lH-indazol-5-yl]-
benzenesulfonamide
This compound was obtained in analogy to example 80 using 5-amino-l-(4-fluorobenzyl)-
l,2-dihydro-indazol-3-one and 4-chloro-2,5-difluorobenzenesulfonyl chloride
(step; C) as an off-white solid. MS (ESf): 468.4 [M+H]+).
Example 87:
3-CKloro—[l-(4-fluoro-benzyl)-3-oxo-2,3-dihydro-indazol-5-yl]-2-methylbenzenesulfonamide
This compound was obtained in analogy to example 80 using 5-amino-l-(4-fluorobenzyl)-
l,2-dihydrO-indazol-3-one and 3-chloro-2-methylbenzenesulfonyl chloride
(step; C) as an ofiwhite solid. MS (ESf): 446.0 [M+H]+).
Example 88:
l 51
3-Cyano-[l-(4-fluoro-benzyl)-3-oxo-2,3-dihydro-indazol-5-yl]-
benzenesulfonamide
This compound was obtained in analogy to example 80 using 5-amino-l-(4-fluorobenzyl)-
l,2-dihydro-indazol-3-one and 3-cyanobenzenesulfonyl chloride (step C) as
light brown solid. MS (ESI): 423.1 [M+H]4).
Example 89:
Naphthalene-l-sulfonic acid [l-(4-fluoro-benzyl)-3-oxo-2,3-dihydro-lH-indazol-
5-yl]-amide
This; compound was obtained in analogy to example 80 using 5-amino-l-(4-fluorobenzyl)-
l,2-dihydfo-indazol-3-one and 1-naphthalenesulfonyl chloride (step C) as
lightibrown solid. MS (ESI): 448.3 [M+H]+).
Example 90:
3-Chloro-4-fluoro-N-[l-(4-fluoro-benzyl)-3-oxo-2,3-dihydro-lH-indazoI-5-yl]-
benzenesulfonamide
This compound was obtained in analogy to example 80 using 5-amino-l-(4-fluorobenzyl)-
l,2-dihydro-indazol-3-one and 3-chloro-4-fluorobenzenesulfonyl chloride
(step; C) as light brown foam. MS (ESI): 449.9 [M+H]).
Example 91:
3-Chloro-[l-(3,4-difluoro-benzyl)-3-oxo-2,3-dihydro-indazol-5-yl]-2-methylbenzenesulfonamide
This compound was obtained in analogy to example 80 using 3,4-
difluorobenzylbromide (step A) and 3-chloro-2-methylbenzenesulfonyl chloride (step
C) as a white solid. MS (ESf): 464.3 [M+H].
Example 92:
3-Chloro-[l-(3,4-difluoro-benzyl)-3-oxo-2,3-dihydro-indazol-5-yl]-4-fluorobenzenesulfonamide
This compound was obtained in analogy to example 80 using 3,4-
difluorobenzylbromide (step A) and 3-chloro-4-fluorobenzenesulfonyl chloride (step
C) as a white solid. MS (ESf): 468.4 [M+H]).
Example 93:
[l-(3,4-Difluoro-benzyl)-3-oxo-2,3-dihydro-indazol-5-yl]-4-fluoro-3-
trifluoromethyl-benzenesulfonamide
This compound was obtained in analogy to example 80 using 3,4-
difluprobenzylbromide (step A) and 4-fluoro-3-trifluoromethylbenzenesulfonyl
chloride (step C) as a white solid. MS (ESI4): 502.1 [M+H]+).
Example 94:
3-Chloro-[l-(3,4-difluoro-benzyl)-3-oxo-2,3-dihydro-indazol-5-yl]-
benzenesulfonamide
This compound was obtained in analogy to example 80 using 3,4-
difluorobenzylbromide (step A) and 3-chlorobenzenesulfonyl chloride (step C) as an
organge solid. MS (ESf): 450.3 [M+H]).
Example 95:
[l-(3,4-Difluoro-benzyI)-3-oxo-2,3-dihydro-indazoI-5-yI]-3-trifluoromethoxybenzenesulfonamide
This compound was obtained in analogy to example 80 using 3,4-
difluQrobenzylbromide (step A) and 3-trifluoromethoxybenzenesulfonyl chloride (step
C) as a white solid. MS (ESI1): 500.3 [M+H]).
Example 96:
2,4-Dichloro-[l-(3,4-difluoro-benzyl)-3-oxo-2,3-dihydro-indazol-5-yl]-5-methylbenzenesulfonamide
This compound was obtained in analogy to example 80 using 3,4-
diflubrobenzylbromide (step A) and 2,4-dichloro-5-methylbenzenesulfonyl chloride
(step C) as a white solid. MS (ESI): 498.4 [M+H]+).
Example 97:
3,4-Dichloro-[l-(3,4-difluoro-benzyl)-3-oxo-2,3-dihydro-indazoI-5-yl]-
benzenesulfonamide
This compound was obtained in analogy to example 80 using 3,4-
difluorobenzylbromide (step A) and 3,4-dichloro-benzenesulfonyl chloride (step C) as
a white solid. MS (ESI4): 484.4 [M+H]+).
Example 98:
4,5-Dichloro-[l-(3,4-difluoro-benzyl)-3-oxo-2,3-dihydro-indazoI-5-yl]-2-fluorobenzenesulfonamide
This compound was obtained in analogy to example 80 using 3,4-
difluorobenzylbromide (step A) and 3,4-dichloro-6-fluorobenzenesulfonyl chloride
(step C) as a white solid. MS (ESf): 502.1 [M+H]+).
Example 99:
2,4,5-Trichloro-[l-(3,4-difluoro-benzyl)-3-oxo-23-dihydro-indazol-5-yl]-
benzenesulfonamide
This compound was obtained in analogy to example 80 using 3,4-
difluorobenzylbromide (step A) and 3,4,6-trichloro-benzenesulfonyl chloride (step C)
as a white solid. MS (ESI): 520.3 [M+H]+).
Example 100:
2,3-Dichloro-[l-(3,4-difluoro-benzyl)-3-oxo-2,3-dihydro-indazol-5-yl]-
benzenesulfonamide
This compound was obtained in analogy to example 80 using 3,4-
diflubrobenzylbromide (step A) and 2,3-dichlorobenzenesulfonyl chloride (step C) as
a white solid. MS (ESI): 484.4 [M+H]+).
Example 101:
2,4-DichIoro-[l-(3,4-difluoro-benzyl)-3-oxo-2,3-dihydro-indazol-5-yl]-6-methylbenzenesulfonamide
This compound was obtained in analogy to example 80 using 3,4-
difluorobenzylbromide (step A) and 2,4-dichloro-6-methylbenzenesulfonyl chloride
(step C) as a white solid. MS (ESf): 500.3 [M+H]+).
Example 102:
3-Chloro-N-[l-(2,4-difluoro-benzyl)-3-oxo-23-dihydro-lH-indazol-5-yl]-4-fluorobenzenesulfonamide
This compound was obtained in analogy to example 80 using 2,4-
difluorobenzylbromide (step A) and 3-chloro-4-fluorobenzenesulfonyl chloride (step
C) as a pink solid. MS (ESf): 468.4 [M+H]"1").
Example 103:
N-[l-(2,4-Difluoro-benzyl)-3-oxo-2,3-dihydro-lH-indazoI-5-yl]-4-fluoro-3-
trifluoromethyl-benzenesulfonamide
This compound was obtained in analogy to example 80 using 2,4-
difludrobenzylbromide (step A) and 4-fluoro-3-trifluoromethylbenzenesulfonyl
chloride (step C) as a white solid. MS (ESI): 502. l [M+H]+).
Example 104:
3-Chloro-N-[l-(2,4-difluoro-benzyl)-3-oxo-2,3-dihydro-l H-indazol-5-yl]-2-
methyl-benzenesulfonamide
This compound was obtained in analogy to example 80 using 2,4-
difluorobenzylbromide (step A) and 3-chloro-2-methylbenzenesulfonyl chloride (step
C) as a white solid. MS (ESf): 464.3 [M+H]).
Example 105:
N-[l-(4-Chloro-benzyl)-3-oxo-2,3-dihydro-lH-indazol-5-yl]-4-fluoro-3-
trifluoromethyl-benzenesulfonamide
Step A] l -(4-Chloro-benzyl)-5-nitro-1,2-dihydro-indazol-3-one
This compound was obtained in analogy to step A in example 77 using 5-nitro-l,2-
dihydro-indazol-3-one (prepared according to Org. Synth. 1949, 29, 54 or Chem Ber.
1942, 75, 1 104) and 4-chlorobenzylbromide to afford the desired l -(4-chloro-benzyl)-
5-nitro-l,2-dihydro-indazol-3-one as a brown solid. MS (ESI'): 302.3 [M-H]').
Step B] 5-Amino-l-(4-chloro-benzyl)-l,2-dihydro-indazol-3-one
To l-(4-chloro-benzyl)-5-nitro-l,2-dihydro-indazol-3-one (0.45 g) was added HC1
(37% aq.) solution (5 mL) followed by SnCl2.dihydrate (1.9 g). The mixture was
heated to 85 °C for one hour. The reaction was then neutralized with sodium
bicarbonate solution, filtered, and the filtrate extracted with EtOAc. The combined
organic phases were washed with brine, dried over sodium sulfate, filtered and
reduced in vacuo. Flash column chromatography of the residue over silica gel eluting
with methylene chloride/methanol afforded the desired 5-amino-l-(4-chloro-benzyl)-
l,2-dihydro-indazol-3-one (0.31 g) as a dark brown solid. MS (ESI): 274.4 [M+H]+).
Step C] N-[l-(4-Chloro-benzyl)-3-oxo-2,3-dihydro-lH-indazol-5-yl]-4-fluoro-3-
trifluoromethyl-benzenesulfonamide
This compound was obtained in analogy to step C in example 77 using 4-fluoro-3-
trifluoromethylbenzenesulfonyl chloride (step C) as a white solid. MS (ESI+): 500.3
Example 106:
3-Chloro-N-[l-(4-chloro-benzyl)-3-oxo-2-dihydro-lH-indazoI-5-yl]-2-methylbenzenesulfonamide
This compound was obtained in analogy to example 105 using 5-amino-l-(4-chlorobenzyl)-
l,2-dihydro-indazol-3-one and 3-chloro-2-methylbenzenesulfonyl chloride
(step C) as a light brown solid. MS (ESf): 462.1 [M+H]+).
Example 107:
2,3-Dichloro-N-[l-(4-chloro-benzyl)-3-oxo-2,3-dihydro-lH-indazol-5-yl]-
benzenesulfonamide
This compound was obtained in analogy to example 105 using 5-amino-l-(4-chlorobenzyl)-
l,2-dihydro-indazol-3-one and 2,3-dichlorobenzenesulfonyl chloride (step C)
as a light brown solid. MS (ESf): 482.4 [M+H]+).
Example 108:
Naphthalene-1-sulfonic acid [l-(4-chloro-benzyl)-3-oxo-2,3-dihydro-lH-indazol-
5-yl]-amide
This compound was obtained in analogy to example 105 using 5-amino-l-(4-chlorobenzyl)-
l,2-dihydro-indazol-3-one and 1-naphthalenesulfonyl chloride (step C) as an
off-white solid. MS (ESI): 464.1 [M+H]).
Example 109:
3-ChIoro-N-[l-(2-chloro-4-fluoro-benzyl)-3-oxo-2,3-dihydro-lH-indazoI-5-yl]-2-
methyl-benzenesulfonamide
This compound was obtained in analogy to example 105 using 2-chloro-4-
fluorbbenzylbromide (step A) and 3-chloro-2-methylbenzenesulfonyl chloride (step C)
as a light brown solid. MS (ESf): 480.4 [M+H]+).
Example 110:
Naphthalene-1-sulfonic acid [l-(2-chloro-4-fluoro-benzyl)-3-oxo-2,3-dihydro-lHindazol-
5-yl]-amide
This compound was obtained in analogy to example 105 using 2-chloro-4-
fluorbbenzylbromide (step A) and 1-naphthalenesulfonyl chloride (step C) as a light
brown solid. MS (ESI): 482.4 [M+H]+).
Example 111:
2,3-Dichloro-N-[l-(2-chloro-4-fluoro-benzyl)-3-oxo-2,3-dihydro-lH-indazol-5-yI]-
benzenesulfonamide
This compound was obtained in analogy to example 105 using 2-chloro-4-
fluorobenzylbromide (step A) and 2,3-dichlorobenzenesulfonyl chloride (step C) as a
light brown solid. MS (ESI4): 500.1 [M+H]+).
Example 112:
N-[l-(2-Chloro-4-fluoro-benzyl)-3-oxo-2,3-dihydro-lH-indazol-5-yI]-4-fluoro-3-
trifluoromethyl-benzenesulfonamide
This compound was obtained in analogy to example 105 using 2-chloro-4-
fluorobenzylbromide (step A) and 4-fluoro-3-trifluoromethylbenzenesulfonyl chloride
(step C) as an off-white solid. MS (ESF): 516.2 [M-H]').
Example 113:
N-[l-(2-Chloro-4-fluoro-benzyI)-3-oxo-2,3-dihydro-lH-indazol-5-yI]-3-
difluoromethoxy-benzenesulfonamide
This compound was obtained in analogy to example 105 using 2-chloro-4-
fluorobenzylbromide (step A) and 3-difluoromethoxybenzenesulfonyl chloride (step
C) as a light brown solid. MS (ESF): 496.3 [M-HD.
Example 114:
N-[l-(2-Chloro-4-fluoro-benzyl)-3-oxo-2,3-dihydro-lH-indazol-5-yl]-3-
trifluoromethoxy-benzenesulfonamide
This i compound was obtained in analogy to example 105 using 2-chloro-4-
fluorobenzylbromide (step A) and 3-trifluoromethoxybenzenesulfonyl chloride (step
C) as an off-white solid. MS (ESI): 514.3 [M-H]').
Example 115:
3-Chloro-N-[l-(2-cyano-ethyl)-3-oxo-2r3-dihydro-lH-indazol-5-yl]-2-methylbenzenesulfonamide
Step A] 3-(5-Nitro-3-oxo-2,3-dihydro-indazol-l-yl)-propionitrile
5-Nitro-l,2-dihydro-indazol-3-one (prepared according to Org. Synth. 1949, 29, 54 or
Chem Ber. 1942, 75, 1104) (0.6 g) was suspended in water (8 mL) and 2N K2CO3
(aq.) (1.8 g) was added to the flask and the mixture was heated to 50°C for 10
minutes. Acrylonitrile (0.24 mL) was then added dropwise. The reaction was stirred
overnight and was quenched with 2 N HC1 (aq.) solution while cooling in an ice bath.
The aqueous phase was extracted with EtOAc and the combined phases were washed
with brine, dried over sodium sulfate, filtered and reduced in vacuo. Fash column
chromatography over silica gel (eluting with EtOAc, nheptane, 3% AcOH) afforded
pure desirede 3-(5-Nitro-3-oxo-2,3-dihydro-indazol-l-yl)-propionitrile as a white
solid, M
Step B] 3-(5-Amino-3-oxo-2,3-dihydro-indazol-l-yl)-propionitrile
To a solution of 3-(5-Nitro-3-oxo-2,3-dihydro-indazol-l-yl)-propionitrile (0.521 g) in
MeOH (50 mL) was added Pd/C(10%) catalyst (0.13 g) and the reaction mixture was
stirred for 20 hours at ambient temperature under a hydrogen atmosphere using a
balloon. After this time the reaction mixture was filtered through Celite®which was
washed with more EtOAc. The combined organic solution was evaporated in vacuo
for afford the desired 3-(5-amino-3-oxo-2,3-dihydro-indazol-l-yl)-propionitrile (0.45
g) which was taken into the next reaction without further purification. MS (ESI+):
203.4 ([M+H]).
Step C] 3-Chloro-N-[l-(2-cyano-ethyl)-3-oxo-2,3-dihydro-lH-indazol-5-yl]-2-
methyl-benzenesulfonamide
To a solution of 3-(5-amino-3-oxo-2,3-dihydro-indazol-l-yl)-propionitrile (0.08 g) in
pyridine (l mL) was added 3-chloro-2-methylbenzenesulfonylchoride (0.089 g) in one
go. The solution was stirred at 60°C for 24 hours. The pyridine was then removed in
vacuo and the residue was dissolved in EtOAc/water and separated. The aqueous
phase was extracted a further two times with EtOAc and the combined organic phases
were washed with brine and dried over sodium sulfate. The drying agent was removed
by filtration and the volatiles were removed in vacuo to afford a crude residue. The
crude material was purified via flash column chromatography eluting with
EtOAc/nHeptane/l%AcOH) to afford the desired 3-Chloro-N-[l-(2-cyano-ethyl)-3-
oxo-2,3-dihydro-lH-indazol-5-yl]-2-methyl-benzenesulfonamide (0.087 g) as a light
brown solid. MS (ESf): 391.0 [M+H]+).
Example 116:
N-[l-(2-Cyano-ethyl)-3-oxo-2,3-dihydro-lH-indazol-5-yl]-4-fluoro-3-
trifluoromethylbenzenesulfonamîde
This compound was obtained in analogy to example 115 using 3-(5-amino-3-oxo-2,3-
dihydro-indazol-1 -yl)-propionitrile and 4-fluoro-3-trifluoromethylbenzenesulfonyl
chloride (step C) as a white solid. MS (ESI): 429.5 [M+H]+).
Example 117:
2,4-Dichloro-N-[l-(2-cyano-ethyl)-3-oxo-2,3-dihydro-lH-indazol-5-yl]-6-methylbenzenesulfonamide
This compound was obtained in analogy to example 115 using 3-(5-amino-3-oxo-2,3-
dihydro-indazol-l-yl)-propionitrile and 2,4-dichloro-6-methylbenzenesulfonyl
chloride (step C) as a light red solid. MS (ESI): 425.3 [M+Hf).
Example 118:
3-Chloro-N-[l-(2-cyano-ethyl)-3-oxo-2-dihydro-lH-indazoI-5-yl]-4-fluorobenzenesulfonamide
This compound was obtained in analogy to example 115 using 3-(5-amino-3-oxo-2,3-
dihydro-indazol-l-yl)-propionitrile and 3-chloro-4-fluorobenzenesulfonyl chloride
(step C) as a light red solid. MS (ESf): 395.3 [M+H]+).
Example 119:
N-[6-Chloro-l-(2-chloro-benzyl)-3-oxo-2v3-dihydro-lH-indazol-5-yl]-4-fluoro-3-
trifluoromethyl-benzenesulfonamide
Step A] 6-Chloro-l-(2-chloro-benzyl)-5-nitro-l,2-dihydro-indazol-3-one
6-Chloro-5-nitro-l,2-dihydro-indazol-3-one (prepared in analogy to Org. Synth. 1949,
29, 54 or Chem Ber. 1942, 75, 1104 from 4-chloro-2-fluoro-5-nitro-benzoic acid over
two steps) (0.6 g) was suspended in water (5 mL) and 2N KCOs (aq.) (l g) was added
to the flask and the mixture was heated to 50°C for 10 minutes. 2-
Chlorobenzylbromide (0.40 g) was then added dropwise. The reaction was stirred
overnight and was neutralised with 2 N HC1 (aq.) while cooling in an ice bath. The
precipitate was collected by filtration and triturated with diethylether to afford pure
desired 6-chloro-l-(2-chloro-benzyl)-5-nitro-l,2-dihydro-indazol-3-one as a brown
solid MS (ESP: 336.3[M-H]").
Stepfl] 5-Amino-6-chloro-l-(2-chloro-benzyl)-l,2-dihydro-indazol-3-one
To ;6-chloro-l-(2-chloro-benzyl)-5-nitro-l,2-dihydro-indazol-3-one (0.49 g) was
added HC1 (37% aq.) solution (4 mL) followed by SnCl2.dihydrate (2.6 g). The
mixture was heated to 85°C for one hour. The reaction was then neutralized with
sodium bicarbonate solution, filtered, and the filtrate extracted with EtOAc. The
combined organic phases were washed with brine, dried over sodium sulfate, filtered
and reduced in vacuo. Flash column chromatography of the residue over silica gel
eluting with methylene chloride/methanol afforded the desired 5-amino-6-chloro-l-(2-
chloro-benzyl)-l,2-dihydro-indazol-3-one (0.33 g) as a yellow solid. MS (ESf): 308.3
Step C] N-[6-Chloro-l-(2-chloro-benzyl)-3-oxo-2,3-dihydro-lH-indazol-5-yl]-4-
fluorp-3-trifluoromethyl-benzenesulfonamide
To a solution of 5-amino-6-chloro-l-(2-chloro-benzyl)-l,2-dihydro-indazol-3-one
(0.070 g) in pyridine (l mL) was added f-fluoro-3-
trifluoromethylbenzenesulfonylchoride (0.072 g) in one go. The solution was stirred at
60°C for 24 hours. The pyridine was then removed in vacuo and the residue was
dissplved in EtOAc/water and separ ated. The aqueous phase was extracted a further
two times with EtOAc and the combined organic phases were washed with brine and
dried over sodium sulfate. The drying agent was removed by filtration and the
volatiles were removed in vacuo to afford a crude residue. The crude material was
purified via flash column chromatography eluting with EtOAc/nHeptane/l%AcOH) to
afford the desired N-[6-chloro-l-(2-chloro-benzyl)-3-oxo-2,3-dihydro-lH-indazol-5-
yl]-4i-fluoro-3-trifluoromethyl-benzenesulfonamide (0.024 g) as a light brown solid.
MS (ESf): 534.3 [M+H]+).
Example 120:
5-Chloro-N-[6-chloro-l-(2-chloro-benzyl)-3-oxo-2,3-dihydro-lH-indazol-5-yl]-2-
fluoro-benzenesulfonamide
This compound was obtained in analogy to example 119 using 5-amino-6-chloro-l-(2-
chloro-benzyl)- 1 ,2-dihydro-indazol-3-one and 3-chloro-6-fluorobenzenesulfbnyl
chloride (step C) as a light brown solid. MS (ESf): 500.3 [M+H]+).
Example 121:
2-Dichloro-N-[6-chloro-l-(2-chloro-benzyI)-3-oxo-2,3-dihydro-lH-indazoI-5-
yl]-benzenesulfonamide
This compound was obtained in analogy to example 119 using 5-amino-6-chloro-l-
(2-chloro-benzyl)-l,2-dihydro-indazol-3-one and 2,3-dichlorobenzenesulfonyl
chloride (step C) as a light brown solid. MS (ESI): 5 1 8.0 [M+H]+).
Example 122:
3-Chloro-N-(6-chloro-3-oxo-l-pyridin-2-ylmethyl-2-dihydro-lH-indazol-5-yl)-
2-methyl-benzenesulfonamide
This compound was obtained in analogy to example 119 using 2-chloromethylpyridine
(step A) and 3-chloro-2-methylbenzenesulfonyl chloride (step C) as an offwhite
solid. MS (ESO: 463.1 [M+H].
Example 123:
N-(6-Chloro-3-oxo-l-pyridin-2-ylmethyl-2,3-dihydro-lH-indazol-5-yl)-4-fluoro-
3-trifluoromethyl-benzenesulfonamide
This compound was obtained in analogy to example 119 using 2-chloromethylpyridine
(step A) and 4-fluoro-3-trifluoromethylbenzenesulfonyl chloride (step C) as a
white solid. MS (ESf): 501.4[M+H]+).
Example 124:
2-[5-(3-Chloro-2-methyI-benzenesulfonylamino)-3-oxo-2,3-dihydro-indazol-l-yI]-
methyl-acetamide
Part A] (5-Nitro-3-oxo-2,3-dihydro-indazol-l-yl)-acetic acid ethyl ester
This ;compound was obtained in analogy to example l (step A) using hydrazino-acetic
acid ethyl ester.HCl as an orange solid. MS (ESF): 264.1[M-H]~).
Part B] (5-Nitro-3-oxo-2,3-dihydro-indazol-l-yl)-acetic acid
To a| solution of (5-nitro-3-oxo-2,3-dihydro-indazol-l-yl)-acetic acid ethyl ester (0.24
g) in THF (9 mL), was added 2 N NaOH (aq.) (1.8 mL). The reaction mixture was
stirred at ambient temperature for 30 minutes. The reaction mixture was acidified with
2 N HC1 (aq.) and extracated with EtOAc. Evaporation of the organic phases afforded
the desired crude (5-nitro-3-oxo-2,3-dihydro-indazol-l-yl)-acetic acid (0.146 g) which
was taken into the next step without further purification.
Part C] N-Methyl-2-(5-nitro-3-oxo-2,3-dihydro-indazol-1 -yl)-acetamide
To a solution of crude (5-nitro-3-oxo-2,3-dihydro-indazol-l-yl)-acetic acid (0.14 g) in
DMF, was added TBTU (0.20 g), followed by N,N-ethyldiisopropylamine (0.40 mL)
and after 10 minutes methylamine (0.32 mL of a 2 M solution) was added. The
reaction was stirred overnight and was quenched with 2N HC1 (aq.) and extracted with
EtOAc. The combined organic layers were washed with brine, dried over sodium
sulfate, filtered and evaporated. Flash column chromatography of the residue over
silica gel afforded the desired N-methyl-2-(5-nitro-3-oxo-2,3-dihydro-indazol-l-yl)-
acetamide (0.040 g) as a yellow solid. MS (ESF): 249.1 ([M-H]').
Part D and E] 2-[5-(3-Chloro-2-methyl-benzenesulfonylamino)-3-oxo-2,3-
dihydro-indazol-1-yl]-methyl-acetamide
This compound was obtained in analogy to example l (step B and C) using 3-chloro-
2-methylbenzenesulfonyl chloride (step C) as an off-white solid. MS (ESI"1):
409.1[M+Hf).
Example 125:
2,4-DichIoro-[l-(3,4-difluoro-benzyI)-2-methyl-3-oxo-23-dihydro-indazol-5-yl]-6-
methyl-benzenesulfonamide
Part A] l -(3,4-Difluoro-benzyl)-2-methyl-5 -nitro-1,2-dihydro-indazol-3 -one
To a solution of l-(3,4-difluoro-benzyl)-5-nitro-l,2-dihydro-indazol-3-one (prepared
in analogy to example 80 using 3,4-difluorobenzylbromide (step A)) (0.2 g) in DMF
was added NaH (0.019 g) and the solution was stirred for l hour. lodomethane (0.14
g) was then added and the mixture was stirred overnight. The reaction mixture was
quenched with water and extracted with EtOAc. The combined organic layers were
washed with brine, dried over sodium sulfate, filtered and evaporated in vacuo to
afford a crude orange residue. Flash column chromatography of the crude residue over
silica gel afforded the desired l-(3,4-difluoro-benzyl)-2-methyl-5-nitro-l,2-dihydroindazol-
3-one (0.11 g) as a yellow solid. MS (ESI'): 318.1 ([M-H]').
Part B] 12,4-Dichloro-[l-(3,4-difluoro-benzyl)-2-methyl-3-oxo-2,3-dihydroindazol-
5-yl]-6-methyl-benzenesulfonamide
This; compound was obtained in analogy to example l (step B and C) using 2,4-
dichloro-6-methylbenzenesulfonyl chloride (step C) as a white solid. MS (ESI"1):
534.2 [M+Na]+).
Example 126:
3-Chloro-[l-(3,4-difluoro-benzyl)-2-methyl-3-oxo-2-dihydro-indazol-5-yl]-2-
methyl-benzenesulfonamide
This; compound was obtained in analogy to example 125 using 3-chloro-2-
methylbenzenesulfonyl chloride (step C) as a white solid. MS (ESI~): 478.3 [M-H]").
Example 127:
2,3-Dichloro-N-(6-chloro-3-oxo-l-pyridin-2-yImethyl-2,3-dihydro-lH-indazol-5-
yl)-benzenesulfonamide
This compound was obtained in analogy to example 119 using 2-chloromethylpyridine
(step A) and 2,3-dichlorobenzenesulfonyl chloride (step C) as a light brown
solid MS (ESI): 482.9[M+H]+).
Example 128:
N-(l-Benzyl-6-fluoro-3-oxo-2,3-dihydro-lH-indazol-5-yl)-2,4-difluorobenzenesulfonamide
This compound was obtained in analogy to example 32 using 2,4-difluoro-5-nitrobenzpic
acid, benzylhydrazine.2HCl (step A) and 2,4-difluorobenzenesulfonyl
chloride (step C) as a light brown solid. MS (ESI): 434. l [M+Hf).
Example 129:
N-(6Chloro-3-oxo-l-pyridin-2-ylmethyl-2,3-dihydro-lH-indazol-5-yl)-4-fluoro-
3-trifluoromethyl-benzenesulfonamide
This compound was obtained in analogy to example 32 (step B and C) using 5-nitrol-
phenyl-l,2-dihydro-indazol-3-one (prepared according to Combinatoriul Chemistry
and High Throughput Screening 2003, 6(5), 471-480) in step B and 2,4-
difluorobenzenesulfonyl chloride (step C) as a light brown solid. MS (ESI4):
402.3 [M+H]+).
Example 130:
N-(6ChIoro-3-oxo-l-pyridin-2-ylmethyl-2,3-dihydro-lH-indazol-5-yl)-4-fluoro-
3-trifIuoromethyl-benzenesuIfonamide
This compound was obtained in analogy to example 32 (step B and C) using 5-nitrol-
phenyl-l,2-dihydro-indazol-3-one (prepared according to Combinatoria! Chemistry
and High Throughput Screening 2003, 6(5), 471-480) in step B and and 3-chloro-
fluorbbenzenesulfonyl chloride (step C) as a light brown solid. MS (ESI1):
418.2[M+H]+).
Example 131:
N-(l-Benzyl-6-fluoro-3-oxo-2,3-dihydro-lH-indazoI-5-yI)-3-cyanobenzenesulfonamide
This compound was obtained in analogy to example 32 using 2,4-difluoro-5-nitrobenzoic
acid, benzylhydrazine.2HCl (step A) and 3-cyanobenzenesulfonyl chloride
(step; C) as a light brown solid. MS (ESI+'): 423.0[M+H]+).
Example 132:
Propane-2-sulfonic acid (l-beiizyI-6-fluoro-3-oxo-2,3-dihydro-lH-indazol-5-yl)-
amide
This compound was obtained in analogy to example 32 using 2,4-difluoro-5-nitrobenzoic
acid, benzylhydrazine.2HCl (step A) and 3 propane-2-sulfonyl chloride (step
C) as a light brown solid. MS (ESf): 364. l [M+H]+).
Example 133:
3-Cyano-N-(3-oxo-l-phenyl-2,3-dihydro-lH-indazol-5-yl)-benzenesulfonamide
This Icompound was obtained in analogy to example 32 (step B and C) using 5-nitrol-
phenyl-l,2-dihydro-indazol-3-one (prepared according to Combinatorial Chemisîry
and High Throughput Screening 2003, 6(5), 471-480) in step B and and 3-
cyanpbenzenesulfonyl chloride (step C) as a light brown solid. MS (ESI"1):
391.1[M+Hf).
Example 134:
2,2,2-Trifluoro-ethanesulfonic acid (l-benzyl-6-fluoro-3-oxo-2,3-dihydro-lHindazol-
5-yl)-amide
This; compound was obtained in analogy to example 32 using 2,4-difluoro-5-nitrobenzbic
acid, benzylhydrazine.2HCl (step A) 2,2,2-trifluoro-ethanesulfonyl chloride
(step; C) as a light brown solid. MS (ESf): 404.1[M+H]+).
Example 135:
Propane-2-suIfonic acid (l-benzyl-6-chloro-3-oxo-2,3-dihydro-lH-indazoI-5-yl)-
amide
This i compound was obtained in analogy to example 32 using 4-chloro-2-fluoro-5-
nitro-benzoic acid, benzylhydrazine.2HCl (step A) and 3 propane-2-sulfonyl chloride
(stepi C) as a light beige solid. MS (ESf): 380. l [M+H]+).
Example 136:
Propane-2-sulfonic acid [6-chloro-l-(4-chloro-benzyl)-3-oxo-2,3-dihydro-lHindazol-
5-yl]-amide
This compound was obtained in analogy to example 1 19 using 4-chlorobenzylbromide
and 5-amino-6-chloro-l-(2-chloro-benzyl)-l,2-dihydro-indazol-3-one (step A) and 3
propane-2-sulfonyl chloride (step C) as a light brown solid. MS (ESI1"): 414.3
Example 137:
N-(l-Benzyl-6-fluoro-3-oxo-2-dihydro-lH-indazol-5-yl)-trifluoromethanesulfonamide
This ; compound was obtained in analogy to example 32 using 2,4-difluoro-5-nitrobenzoic
acid, benzylhydrazine.2HCl (step A) and trifluoro-methanesulfonyl chloride
(step; C) as a light brown solid. MS (ESf): 390. l [M+Hf).
Example 138:
Propane-2-sulfonic acid (l-isobutyl-3-oxo-2,3-dihydro-lH-indazol-5-yl)-amide
This -compound was obtained in analogy to example 32 using 5-amino-l-isobutyl-l,2-
dihydro-indazol-3-one and 3 propane-2-sulfonyl chloride (step G) as a beige solid. MS
(ESrb:312.1[M+H]+).
Example 139:
Propane-2-sulfonic acid [l-(3,4-difluoro-benzyl)-3-oxo-2,3-dihydro-lH-indazol-5-
yl]-amide
This compound was obtained in analogy to example 80 using 3,4-
difluorobenzylbromide (step A) and 3 propane-2-sulfonyl chloride (step C) as a light
yellow solid. MS (ESI): 382.3 [M+H]).
Example 140:
Propane-2-sulfonic acid [l-(2-methoxy-ethyI)-3-oxo-2,3-dihydro-lH-indazol-5-
yl]-amide
This compound was obtained in analogy to example 32 using (2-methoxy-ethyl)-
hydrazine (step A) (prepared as described in J. Org. Chem. 1984, 49, 336-42) and 3
propâne-2-sulfonyl chloride (step C) as a light brown solid. MS (ESI): 314.0
[M+Hft.
Example 141:
N-(l-Benzyl-3-oxo-2,3-dihydro-lH-indazol-5-yl)-C-cyclopropylmethanesulfonamide
This i compound was obtained in analogy to example l using 5-amino-l-benzyl-l,2-
dihydro-indazol-3-one and cyclopropyl-methanesulfonyl chloride (step C) as a light
brown solid. MS (ESf): 358.4 ([M+Hf).
Example A
Film coated tablets containing the following ingredients can be manufactured in
a convenţional manner:
Ingredients
: Per tabiet
Kernel:
Compound of formula (I) 10.0 mg 200.0 mg
Microcrystalline cellulose 23.5 mg 43.5 mg
Lactose hydrous 60.0 mg 70.0 mg
PovidoneK30 12.5 mg 15.0 mg
Sodium starch glycolate 12.5 mg 17.0 mg
67
Magnesium stearate 1.5 mg 4.5 mg
(Kernel Weight) 120.0 mg 350.0 mg
Film Coat:
Hydroxypropyl methyl cellulose 3.5 mg 7.0 mg
Polyethylene glycol 6000 0.8 mg l .6 mg
Talc 1.3 mg 2.6 mg
Iron oxyde (yellow) 0.8 mg 1.6 mg
Titan dioxide 0.8 mg l .6 mg
The active ingredient is sieved and mixed with microcristalline cellulose and the
mixture is granulated with a solution of polyvinylpyrrolidon in water. The granulate is
mixed with sodium starch glycolate and magesiumstearate and compressed to yield
kernels of 120 or 350 mg respectively. The kernels are lacquered with an aqueous
solution / suspension of the above mentioned film coat.
Example B
Capsules containing the following ingredients can be manufactured in a
convenţional manner:
Ingredients Per capsule
Compound of formula (I) 25.0 mg
Lactose 150.0 mg
Maize starch 20.0 mg
Talc 5.0 mg
The eomponents are sieved and mixed and filled into capsules of size 2.
Example C
Injection solutions can have the following composition:
Compound of formula (I) 3.0 mg
Polyethylene Glycol 400 150.0 mg
Acetic Acid q.s. adpHS.O
Water for injection solutions ad l .0 ml
The active ingredient is dissolved in a mixture of Polyethylene Glycol 400 and
watef for injection (part). The pH is adjusted to 5.0 by Acetic Acid. The volume is
adjusted to 1.0 ml by addition of the residual amount of water. The solution is filtered,
filled into vials using an appropriate overage and sterilized.
69
Example D
Soft gelatin capsules containing the following ingredients can be manufactured
in a convenţional manner:
Capsule contents
Compound of formula (I) 5.0 mg
Yellow wax 8.0 mg
Hydrogenated Soya bean oii 8.0 mg
Partially hydrogenated plant oils 34.0 mg
Soya bean oii 110.0 mg
Weight of capsule contents 165.0 mg
Gelatin capsule
Gelatin 75.0 mg
Glycerol 85 % 32.0 mg
Karibn 83 8.0 mg (dry matter)
Titan dioxide 0.4 mg
Iron oxide yellow l. l mg
The active ingredient is dissolved in a warm melting of the other ingredients and
the mixture is filled into soft gelatin capsules of appropriate size. The filled soft
gelatin capsules are treated according to the usual procedures.
Example E
Sachets containing the following ingredients can be manufactured in a
convenţional manner:
Compound of formula (I) 50.0 mg
Lactose, fine powder 1015.0 mg
Microcristalline cellulose (AVICEL PH 102) 1400.0 mg
Sodium carboxymethyl cellulose 14.0 mg
Polyvinylpyrrolidon K 30 10.0 mg
Magnesiumstearate 10.0 mg
Flavoring additives 1.0 mg
The active ingredient is mixed with lactose, microcristalline cellulose and
sodium carboxymethyl cellulose and granulated with a mixture of polyvinylpyrrolidon
in water. The granulate is mixed with magnesiumstearate and the flavouring additives
and fii led into sachets.



We Claim:
1. Compounds of formula (I)
(Formula Removed)
wherein
R1 is hydrogen, C1-C7-alkyl, aryl, or aryl-C1-C7-alkyl;
R2 is aryl, aryl-C1-C7-alkyl, heteroaryl, heteroaryl-C1-C7-alkyl, cycloalkyl, cycloalkyl-
C1-C7-alkyl, fluoro-C1-C7-alkyl, or C1-C7-alkyl, which C1-C7-alkyl is optionally
substituted with 1 to 3 substituents selected from the group consisting of OH, CN,
halogen, C1-C7-alkoxy and C(O)NR8R9;
R3 is hydrogen, halogen, C1-C7-alkyl, fluoro-C1-C7-alkyl, C1-C7-alkoxy, or fluoro-C1-
C7-alkoxy;
R4 is hydrogen, halogen, C1-C7-alkyl, fluoro-C1-C7-alkyl, C1-C7-alkoxy, or fiuoro-C1-
C7-alkoxy;
R5 is hydrogen, halogen, C1-C7-alkyl, fluoro-C1-C7-alkyl, C1-C7-alkoxy, or fluoro-C1-
C7-alkoxy;
R6 is hydrogen or C1-C7-alkyl;
R7 is aryl, heteroaryl, fluoro-C1-C7-alkyl, or C1-C7-alkyl, which C1-C7-alkyl is
optionally substituted with 1 to 3 substituents selected from the group consisting of OH,
CN, halogen, C1-C7-alkoxy and cycloalkyl;
R8 and R9 , independently from each other, are selected from the group consisting of hydrogen and C1-C7-alkyl;
and pharmaceutically acceptable salts thereof.
2. The compounds as claimed in claim 1, wherein
R1 is hydrogen, C1-C7-alkyl, aryl, or aryl-C1-C7-alkyl;
R2 is aryl, aryl-C1-C7-alkyl, heteroaryl, heteroaryl-C1-C7-alkyl, cycloalkyl, cycloalkyl-
C1-C7-alkyl, fluoro-C1-C7-alkyl, or C1-C7-alkyl, which C1-C7-alkyl is optionally
substituted with 1 to 3 substituents selected from the group consisting of OH, CN,
halogen, C1-C7-alkoxy and C(O)NR8R9;
R3 is hydrogen, halogen, C1-C7-alkyl, fluoro-C1-C7-alkyl, C1-C7-alkoxy, or fluoro-C1-
C7-alkoxy;
R4 is hydrogen, halogen, C1-C7-alkyl, fluoro-C1-C7-alkyl, C1-C7-alkoxy, or fluoro-C1-
C7-alkoxy;
R5 is hydrogen, halogen, C1-C7-alkyl, fiuoro-C1-C7-alkyl, C1-C7-alkoxy, or fluoro-C1-
C7-alkoxy;
R6 is hydrogen or C1-C7-alkyl;
R7 is aryl, heteroaryl, fluoro-C1-C7-alkyl, or C1-C7-alkyl, which C1-C7-alkyl is
optionally substituted with 1 to 3 substituents selected from the group consisting of OH,
CN, halogen and C1-C7-alkoxy;
R8 and R9, independently from each other, are selected from the group consisting of
hydrogen and C1-C7-alkyl;
and pharmaceutically acceptable salts thereof.
3. The compounds as claimed in any of claims 1 to 2, wherein R1 is hydrogen or C1-C7-alkyl.
4. The compounds as claimed in any of claims 1 to 3, wherein R1 is hydrogen.
5. The compounds as claimed in any of claims 1 to 4, wherein R2 is aryl-C1-C7-alkyl, heteroaryl-C1-C7-alkyl, cycloalkyl-C1-C7-alkyl, fluoro-C1-C7-alkyl, or C1-C7-alkyl, which C1-C7-alkyl is optionally substituted with 1 to 3 substituents selected from the group consisting of OH, CN, halogen, C1-C7-alkoxy and C(O)NR8R9, wherein R8 and R9 are as defined in claim 1.
6. The compounds as claimed in any of claims 1 to 5, wherein R2 is aryl-C1-C7-alkyl or heteroaryl-C1-C7-alkyl.
7. The compounds as claimed in any of claims 1 to 6, wherein R2 is benzyl or pyridinylmethyl, wherein benzyl can optionally be substituted with 1 or 2 halogen.
8. The compounds as claimed in any of claims 1 to 7, wherein R2 is benzyl, 4-fluoro-benzyl, 4-chloro-benzyl, 3,4-difiuoro-benzyl, or pyridin-2-ylmethyl.
9. The compounds as claimed in any of claims 1 to 4, wherein R2 is aryl.
10. The compounds as claimed in any of claims 1 to 9, wherein R3 is hydrogen.
11. The compounds as claimed in any of claims 1 to 10, wherein R4 is hydrogen or halogen.
12. The compounds as claimed in any of claims 1 to 11, wherein R4 is hydrogen, fluorine, or chlorine.
13. The compounds as claimed in any of claims 1 to 12, wherein R5 is hydrogen or halogen.
14. The compounds as claimed in any of claims 1 to 13, wherein R5 is hydrogen.
15. The compounds as claimed in any of claims 1 to 14, wherein R6 is hydrogen.
16. The compounds as claimed in any of claims 1 to 15, wherein R7 is C1-C7-alkyl or aryl.
17. The compounds as claimed in any of claims 1 to 16, wherein R7 is C1-C7-alkyl, phenyl or naphthyl, wherein phenyl can optionally be substituted with 1 to 3 substituents independently selected from the group consisting of C1-C7-alkyl, fluoro-C1-C7-alkyl, C1-C7-alkoxy, fluoro-C1-C7-alkoxy, dioxo-C1-C7-alkylene, halogen, cyano, phenoxy and 5-methyl-[l,3,4]-oxadiazol-2-yl.
18. The compounds as claimed in any one of claims 1 to 17, wherein R7 is phenyl substituted with 1 to 2 substituents selected from the group consisting of C1-C7-alkyl, fluoro-C1-C7-alkyl, halogen and cyano.
19. The compounds as claimed in claim 18, wherein R7 is 3-chloro-2-methyl-phenyl, 2,3-dichloro-phenyl, 3-chloro-4-fluoro-phenyl, 3-trifluoromethyl-4-fluoro-phenyl, 3-cyano-phenyl, 2,5-difluoro-phenyl, 3-chloro-2-fluoro-phenyl, 5-chloro-2-fluoro-phenyl, or 2-chloro-phenyl.
20. The compounds as claimed in any of claims 1 to 15, wherein R7 is fluoro-C1-C7-alkyl or C1-C7-alkyl substituted with cyclopropyl.
21. The compounds as claimed in claim 20, wherein R7 is cyclopropyl-methyl.
22. The compounds as claimed in any of claims 1 to 21 selected from the group consisting of:
N-(l-Benzyl-3-oxo-2,3-dihydro-lH-indazol-5-yl)-3-chloro-2-methyl-
benzenesulfonamide,
N-(l-Benzyl-3-oxo-2,3-dihydro-lH-indazol-5-yl)-3-chloro-4-fluoro-benzenesulfonamide,
N-(l-Benzyl-3-oxo-2,3-dihydro-lH-indazol-5-yl)-3-trifluoromethyl-benzenesulfonamide,
N-(l-Benzyl-3-oxo-2,3-dihydro-lH-indazol-5-yl)-2,4-dichloro-benzenesulfonamide,
Naphthalene-2-sulfonicacid(l-benzyl-3-oxo-2,3-dihydro-lH-indazol-5-yl)-amide,
N-(l-Benzyl-3-oxo-2,3-dihydro-lH-indazol-5-yl)-3-chloro-4-methyl-benzenesulfonamide,
N-(l-Benzyl-3-oxo-2,3-dihydro-1H-indazol-5-yl)-4-methoxy-benzenesulfonamide,
N-(l-Benzyl-3-oxo-2,3-dihydro-lH-indazol-5-yl)-2,4-dichloro-6-methyl-benzenesulfonamide,
N-(l-Benzyl-3-oxo-2,3-dihydro-lH-indazol-5-yl)-2-trifluoromethyl-benzenesulfonamide,
N-(l-Benzyl-3-oxo-2,3-dihydro-lH-indazol-5-yl)-2,4-difluoro-benzenesulfonamide,
N-(l-Benzyl-3-oxo-2,3-dihydro-lH-indazol-5-yl)-4-propyl-benzenesulfonamide,
2,3-Dihydro-benzo[l,4]dioxine-6-sulfonic acid(l-benzyl-3-oxo-2,3-dihydro-lH-indazol-5-yl)-amide,
N-(l-Benzyl-3-oxo-2,3-dihydro-lH-indazol-5-yl)-4-chloro-2,5-dimethyl-benzenesulfonamide,
N-(l-Benzyl-3-oxo-2,3-dihydro-lH-indazol-5-yl)-4-chloro-3-trifluoromethyl-benzenesulfonamide,
N-(1-Benzyl-3 -oxo-2,3 -dihydro-1H-indazol-5-yl)-4-fluoro-3 -trifluoromethyl-benzenesulfonamide,
N-(l-Benzyl-3-oxo-2,3-dihydro-lH-indazol-5-yl)-2-chloro-5-trifluoromethyl-benzenesulfonamide,
N-(l-Benzyl-3-oxo-2,3-dihydro-lH-indazol-5-yl)-3-phenoxy-benzenesulfonamide,
N-(l -Benzyl-3-oxo-2,3-dihydro-1H-indazol-5-yl)-3-(5-methyl-[ 1,3,4]oxadiazol-2-yl)-benzenesulfonamide,
N-(l-Benzyl-3-oxo-2,3-dihydro-lH-indazol-5-yl)-3-chloro-benzenesulfonamide,
N-(l-Benzyl-3-oxo-2,3-dihydro-lH-indazol-5-yl)-3-methoxy-benzenesulfonamide,
N-(l-Benzyl-3-oxo-2,3-dihydro-lH-indazol-5-yl)-3-difluoromethoxy-benzenesulfonamide,
N-(l-Benzyl-3-oxo-2,3-dihydro-lH-indazol-5-yl)-3,5-bis-trifluoromethyl-benzenesulfonamide,
Propane-2-sulfonic acid (1 -benzyl-3-oxo-2,3-dihydro-lH-indazol-5-yl)-amide,
N-(l-Benzyl-3-oxo-2,3-dihydro-lH-indazol-5-yl)-3-chloro-2-N-dimethyl-benzenesulfonamide,
N-(3-Oxo-l-propyl-2,3-dihydro-lH-indazol-5-yl)-3-trifluoromethyl-benzenesulfonamide,
2,3-Dichloro-N-(3-oxo-l-propyl-2,3-dihydro-lH-indazol-5-yl)-benzenesulfonamide,
3-Chloro-4-fluoro-N-(3-oxo-l-propyl-2,3-dihydro-lH-indazol-5-yl)-benzenesulfonamide,
3-Chloro-2-methyl-N-(3-oxo-l-phenethyl-2,3-dihydro-lH-indazol-5-yl)-benzenesulfonamide,
3-Chloro-4-methyl-N-(3-oxo-l-phenethyl-2,3-dihydro-lH-indazol-5-yl)-benzenesulfonamide,
4-Chloro-2,5-dimethyl-N-(3-oxo-l-phenethyl-2,3-dihydro-lH-indazol-5-yl)-benzenesulfonamide,
N-(3 -Oxo-1 -phenethyl-2,3 -dihydro-1H-indazol-5-yl)-3 -trifluoromethyl-benzenesulfonamide,
N-(l -Isobutyl-3-oxo-2,3-dihydro-1 H-indazol-5-yl)-3-trifluoromethyl-benzenesxilfonamide,
3 -Chloro-N-( 1 -isobutyl-3 -oxo-2,3 -dihydro-1 H-indazol-5-yl)-4-methyl-benzenesulfonamide,
3-Chloro-N-(l-isobutyl-3-oxo-2,3-dihydro-lH-indazol-5-yl)-2-methyl-benzenesulfonamide,
3-Cyano-(l-isobutyl-3-oxo-2,3-dihydro-indazol-5-yl)-benzenesulfonamide,
3-Difluoromethoxy-(l-isobutyl-3-oxo-2,3-dihydro-indazol-5-yl)-benzenesulfonamide,
4-Cyano-(l-isobutyl-3-oxo-2,3-dihydro-indazol-5-yl)-benzenesulfonamide,
4-Fluoro-N-(l-isobutyl-3-oxo-2,3-dihydro-lH-indazol-5-yl)-3-trifluoromethyl-benzenesulfonamide,
3-Chloro-4-fluoro-N-(l-isobutyl-3-oxo-2,3-dihydro-lH-indazol-5-yl)-benzenesulfonamide,
2,4-Dichloro-(l-isobutyl-3-oxo-2,3-dihydro-indazol-5-yl)-5-methyl-benzenesulfonamide,
3-Chloro-N-(l-ethyl-3-oxo-2,3-dihydro-lH-indazol-5-yl)-2-methyl-benzenesulfonamide,
3-Chloro-(l-cyclopropylmethyl-3-oxo-2,3-dihydro-indazol-5-yl)-2-methyl-benzenesulfonamide,
3-Chloro-(l-cyclopropylmethyl-3-oxo-2,3-dihydro-indazol-5-yl)-4-fluoro-benzenesulfonamide,
(l-Cyclopropylmethyl-3-oxo-2,3-dihydro-indazol-5-yl)-4-fluoro-3-trifluoromethyl-benzenesulfonamide,
3-Chloro-(l-cyclopropylmethyl-3-oxo-2,3-dihydro-indazol-5-yl)-benzenesulfonamide,
2,4-Dichloro-(l-cyclopropylmethyl-3-oxo-2,3-dihydro-indazol-5-yl)-5-methyl-benzenesulfonamide,
3-Chloro-[l-(2-methoxy-ethyl)-3-oxo-2,3-dihydro-indazol-5-yl]-2-methyl-benzenesulfonamide,
4-Fluoro-[l-(2-methoxy-ethyl)-3-oxo-2,3-dihydro-indazol-5-yl]-3-trifluoromethyl-benzenesulfonamide,
3-Chloro-4-fluoro-[l-(2-methoxy-ethyl)-3-oxo-2,3-dihydro-indazol-5-yl]-benzenesulfonamide,
2,4-Dichloro-[l-(2-methoxy-ethyl)-3-oxo-2,3-dihydro-indazol-5-yl]-6-methyl-benzenesulfonamide,
3-Chloro-2-methyl-N-[3-oxo-l-(2,2,2-trifluoro-ethyl)-2,3-dihydro-lH-indazol-5-yl]-benzenesulfonamide,
4-Fluoro-[3-oxo-l-(2,2,2-trifluoro-ethyl)-2,3-dihydro-indazol-5-yl]-3-trifluoromethyl-
benzenesulfonamide,
4-Fluoro-N-(3 -oxo-1 -pyridin-2-ylmethyl-2,3 -dihydro-1 H-indazol-5-yl)-3 -trifluoromethyl-benzenesulfonamide,
2,4-Dichloro-6-methyl-N-(3-oxo-l-pyridin-2-ylmethyl-2,3-dihydro-lH-indazol-5-yl)-benzenesulfonamide,
3-Chloro-2-methyl-N-(3-oxo-l-pyridin-2-ylmethyl-2,3-dihydro-lH-indazol-5-yl)-benzenesulfonamide,
4-Fluoro-N-[l-(2-hydroxy-2-methyl-propyl)-3-oxo-2,3-dihydro-lH-indazol-5-yl]-3-trifluoromethyl-benzenesulfonamide,
N-( 1 -Benzyl-6-chloro-3-oxo-2,3-dihydro-1 H-indazol-5-yl)-3-chloro-4-fluoro-benzenesulfonamide,
N-(l-Benzyl-6-chloro-3-oxo-2,3-dihydro-lH-indazol-5-yl)-4-fluoro-3-trifluoromethyl-benzenesulfonamide,
N-(l-Benzyl-6-chloro-3-oxo-2,3-dihydro-lH-indazol-5-yl)-3-chloro-2-methyl-benzenesulfonamide,
N-(l-Benzyl-6-chloro-3-oxo-2,3-dihydro-lH-indazol-5-yl)-2,3-dichloro-benzenesulfonamide,
N-(l-Benzyl-6-chloro-3-oxo-2,3-dihydro-lH-indazol-5-yl)-3-cyano-benzenesulfonamide,
N-(l-Benzyl-6-chloro-3-oxo-2,3-dihydro-lH-indazol-5-yl)-3-chloro-benzenesulfonamide,
N-(l-Benzyl-6-chloro-3-oxo-2,3-dihydro-lH-indazol-5-yl)-4-chloro-3-trifluoromethyl-benzenesulfonamide,
N-( 1 -Benzyl-6-chloro-3 -oxo-2,3 -dihydro-1 H-indazol-5-yl)-3 -difluoromethoxy-benzenesulfonamide,
N-(l-Benzyl-6-chloro-3-oxo-2,3-dihydro-lH-indazol-5-yl)-2-trifluoromethyl-benzenesulfonamide,
N-(l-Benzyl-6-chloro-3-oxo-2,3-dihydro-lH-indazol-5-yl)-3-trifluoromethoxy-benzenesulfonamide,
N-(l-Benzyl-6-chloro-3-oxo-2,3-dihydro-lH-indazol-5-yl)-2,5-difluoro-
benzenesulfonamide,
N-(l-Benzyl-6-chloro-3-oxo-2,3-dihydro-lH-indazol-5-yl)-2,4-dichloro-benzenesulfonamide,
N-(l-Benzyl-6-chloro-3-oxo-2,3-dihydro-lH-indazol-5-yl)-3-chloro-2-fluoro-benzenesulfonamide,
N-( 1 -Benzyl-6-chloro-3 -oxo-2,3 -dihydro-1 H-indazol-5 -yl)-3 -trifluoromethyl-benzenesulfonamide,
N-(l-Benzyl-6-chloro-3-oxo-2,3-dihydro-lH-indazol-5-yl)-5-chloro-2-fluoro-benzenesulfonamide,
N-(l-Benzyl-6-chloro-3-oxo-2,3-dihydro-lH-indazol-5-yl)-2-chloro-benzenesulfonamide,
(l-Benzyl-4-chloro-3-oxo-2,3-dihydro-indazol-5-yl)-3-chloro-2-methyl-benzenesulfonamide,
N-(l-Benzyl-6-fluoro-3-oxo-2,3-dihydro-lH-indazol-5-yl)-4-fluoro-3-trifluoromethyl-benzenesulfonamide,
N-(l-Benzyl-6-fluoro-3-oxo-2,3-dihydro-lH-indazol-5-yl)-2,3-dichloro-benzenesulfonamide,
N-(l-Benzyl-6-fluoro-3-oxo-2,3-dihydro-lH-indazol-5-yl)-2,4-dichloro-benzenesulfonamide,
N-(l -Benzyl-6-fluoro-3-oxo-2,3-dihydro-1 H-indazol-5-yl)-3-chloro-2-fluoro-benzenesulfonamide,
N-( 1 -Benzyl-6-fluoro-3 -oxo-2,3 -dihydro-1 H-indazol-5-yl)-5-chloro-2-fluoro-benzenesulfonamide,
N-(l -Benzyl-6-fluoro-3-oxo-2,3-dihydro-1 H-indazol-5-yl)-3-trifluoromethoxy-benzenesulfonamide,
3-Chloro-N-[ 1 -(4-fluoro-benzyl)-3-oxo-2,3-dihydro-l H-indazol-5-yl]-benzenesulfonamide,
3-Difluoromethoxy-N-[l-(4-fluoro-benzyl)-3-oxo-2,3-dihydro-lH-indazol-5-yl]-benzenesulfonamide,
4-Fluoro-N-[ 1 -(4-fluoro-benzyl)-3-oxo-2,3-dihydro-1 H-indazol-5-yl]-3-trifluoromethyl-
benzenesulfonamide,
2,3-Dihydro-benzo[l,4]dioxine-6-sulfonicacid [l-(4-fluoro-benzyl)-3-oxo-2,3-dihydro-1 H-indazol-5-yl]-amide,
2,4-Dichloro-N-[l-(4-fluoro-benzyl)-3-oxo-2,3-dihydro-lH-indazol-5-yl]-6-methyl-benzenesulfonamide,
5-Chloro-2,4-difluoro-N-[l-(4-fluoro-benzyl)-3-oxo-2,3-dihydro-lH-indazol-5-yl]-benzenesulfonamide,
4-Chloro-2,5-difluoro-N-[ 1 -(4-fluoro-benzyl)-3-oxo-2,3-dihydro-1 H-indazol-5-yl]-benzenesulfonamide,
3-Chloro-N-[l-(4-fluoro-benzyl)-3-oxo-2,3-dihydro-indazol-5-yl]-2-methyl-benzenesulfonamide,
3-Cyano-[l-(4-fluoro-benzyl)-3-oxo-2,3-dihydro-indazol-5-yl]-benzenesulfonamide,
Naphthalene-1 -sulfonic acid [ 1 -(4-fluoro-benzyl)-3-oxo-2,3-dihydro-l H-indazol-5-yl]-amide,
3-Chloro-4-fluoro-N-[l-(4-fluoro-benzyl)-3-oxo-2,3-dihydro-lH-indazol-5-yl]-benzenesulfonamide,
3-Chloro-[l-(3,4-difluoro-benzyl)-3-oxo-2,3-dihydro-indazol-5-yl]-2-methyl-benzenesulfonamide,
3-Chloro-[l-(3,4-difluoro-benzyl)-3-oxo-2,3-dihydro-indazol-5-yl]-4-fluoro-benzenesulfonamide,
[l-(3,4-Difluoro-benzyl)-3-oxo-2,3-dihydro-indazol-5-yl]-4-fluoro-3-trifluoromethyl-benzenesulfonamide,
3-Chloro-[l-(3,4-difiuoro-benzyl)-3-oxo-2,3-dihydro-indazol-5-yl]-benzenesulfonamide,
[l-(3,4-Difluoro-benzyl)-3-oxo-2,3-dihydro-indazol-5-yl]-3-trifluoromethoxy-benzenesulfonamide,
2,4-Dichloro-[l-(3,4-difluoro-benzyl)-3-oxo-2,3-dihydro-indazol-5-yl]-5-methyl-benzenesulfonamide,
3,4-Dichloro-[ 1 -(3,4-difluoro-benzyl)-3 -oxo-2,3 -dihydro-indazol-5-yl] -benzenesulfonamide,
4,5-Dichloro-[l-(3,4-difluoro-benzyl)-3-oxo-2,3-dihydro-indazol-5-yl]-2-fluoro-benzenesulfonamide,
2,4,5-Trichloro-[ 1 -(3,4-difiuoro-benzyl)-3-oxo-2,3-dihydro-indazol-5-yl]-benzenesulfonamide,
2,3-Dichloro-[l-(3,4-difluoro-benzyl)-3-oxo-2,3-dihydro-indazol-5-yl]-benzenesulfonamide,
2,4-Dichloro-[l-(3,4-difiuoro-benzyl)-3-oxo-2,3-dihydro-indazol-5-yl]-6-methyl-benzenesulfonamide,
3-Chloro-N-[l-(2,4-difluoro-benzyl)-3-oxo-2,3-dihydro-lH-indazol-5-yl]-4-fluoro-benzenesulfonamide,
N- [ 1 -(2,4-Difluoro-benzyl)-3 -oxo-2,3 -dihydro-1 H-indazol-5 -yl]-4-fluoro-3 -trifluoromethyl-benzenesulfonamide,
3-Chloro-N-[l-(2,4-difluoro-benzyl)-3-oxo-2,3-dihydro-lH-indazol-5-yl]-2-methyl-benzenesulfonamide,
N-[l-(4-Chloro-benzyl)-3-oxo-2,3-dihydro-lH-indazol-5-yl]-4-fluoro-3-trifluoromethyl-benzenesulfonamide,
3-Chloro-N-[l-(4-chloro-benzyl)-3-oxo-2,3-dihydro-lH-indazol-5-yl]-2-methyl-benzenesulfonamide,
2,3-Dichloro-N-[l-(4-chloro-benzyl)-3-oxo-2,3-dihydro-lH-indazol-5-yl]-benzenesulfonamide,
Naphthalene-1 -sulfonic acid [ 1 -(4-chloro-benzyl)-3-oxo-2,3-dihydro-lH-indazol-5-yl]-amide,
3-Chloro-N-[l-(2-chloro-4-fluoro-benzyl)-3-oxo-2,3-dihydro-lH-indazol-5-yl]-2-methyl-benzenesulfonamide,
Naphthalene-1 -sulfonic acid [ 1 -(2-chloro-4-fluoro-benzyl)-3 -oxo-2,3 -dihydro-1H-indazol-5-yl]-amide,
2,3-Dichloro-N-[l-(2-chloro-4-fluoro-benzyl)-3-oxo-2,3-dihydro-lH-indazol-5-yl]-benzenesulfonamide,
N-[l-(2-Chloro-4-fluoro-benzyl)-3-oxo-2,3-dihydro-lH-indazol-5-yl]-4-fluoro-3-trifiuoromethyl-benzenesulfonamide,
N-[ 1 -(2-Chloro-4-fluoro-benzyl)-3-oxo-2,3-dihydro-1 H-indazol-5-yl]-3-difluoromethoxy-benzenesulfonamide,
N-[l-(2-Chloro-4-fluoro-benzyl)-3-oxo-2,3-dihydro-lH-indazol-5-yl]-3-trifluoromethoxy-benzenesulfonamide,
3-Chloro-N-[ 1 -(2-cyano-ethyl)-3-oxo-2,3-dihydro-1 H-indazol-5-yl]-2-methyl-benzenesulfonamide,
N-[l-(2-Cyano-ethyl)-3-oxo-2,3-dihydro-lH-indazol-5-yl]-4-fluoro-3-trifluoromethyl-benzenesulfonamide,
2,4-Dichloro-N-[ 1 -(2-cyano-ethyl)-3-oxo-2,3-dihydro-1 H-indazol-5-yl]-6-methyl-benzenesulfonamide,
3-Chloro-N-[l-(2-cyano-ethyl)-3-oxo-2,3-dihydro-lH-indazol-5-yl]-4-fluoro-benzenesulfonamide,
N-[6-Chloro-l-(2-chloro-benzyl)-3-oxo-2,3-dihydro-lH-indazol-5-yl]-4-fluoro-3-trifluoromethyl-benzenesulfonamide,
5-Chloro-N-[6-chloro-l-(2-chloro-benzyl)-3-oxo-2,3-dihydro-lH-indazol-5-yl]-2-fluoro-benzenesulfonamide,
2,3-Dichloro-N-[6-chloro-l-(2-chloro-benzyl)-3-oxo-2,3-dihydro-lH-indazol-5-yl]-benzenesulfonamide,
3-Chloro-N-(6-chloro-3-oxo-l-pyridin-2-ylmethyl-2,3-dihydro-lH-indazol-5-yl)-2-methyl-benzenesulfonamide,
N-(6-Chloro-3-oxo-l-pyridin-2-ylmethyl-2,3-dihydro-lH-indazol-5-yl)-4-fluoro-3-trifluoromethyl-benzenesulfonamide,
2-[5-(3-Chloro-2-methyl-benzenesulfonylamino)-3-oxo-2,3-dihydro-indazol-l-yl]-methyl-acetamide,
2,4-Dichloro-[l-(3,4-difluoro-benzyl)-2-methyl-3-oxo-2,3-dihydro-indazol-5-yl]-6-methyl-benzenesulfonamide, and
3-Chloro-[l-(3,4-difluoro-benzyl)-2-methyl-3-oxo-2,3-dihydro-indazol-5-yl]-2-methyl-benzenesulfonamide,
and pharmaceutically acceptable salts thereof.
23. The compounds as claimed in any one of claims 1 to 22 selected from the group
consisting of:
N-( 1 -Benzyl-6-chloro-3-oxo-2,3-dihydro-1 H-indazol-5-yl)-3-chloro-2-methyl-
benzenesulfonamide,
N-( 1-Benzyl-6-chloro-3-oxo-2,3-dihydro-1 H-indazol-5-yl)-2,5-difluoro-
benzenesulfonamide,
N-(l-Benzyl-6-chloro-3-oxo-2,3-dihydro-lH-indazol-5-yl)-3-chloro-2-fluoro-
benzenesulfonamide,
N-( 1 -Benzyl-6-chloro-3 -oxo-2,3-dihydro-1 H-indazol-5-yl)-2-chloro-
benzenesulfonamide,
N-(l-Benzyl-6-fluoro-3-oxo-2,3-dihydro-lH-indazol-5-yl)-3-chloro-2-fluoro-
benzenesulfonamide,
N-(l-Benzyl-6-fluoro-3-oxo-2,3-dihydro-lH-indazol-5-yl)-2,3-dichloro-
benzenesulfonamide,
N-(l-Benzyl-6-fiuoro-3-oxo-2,3-dihydro-lH-indazol-5-yl)-5-chloro-2-fluoro-
benzenesulfonamide,
N-( 1 -Benzyl-3 -oxo-2,3 -dihydro-1 H-indazol-5 -yl)-3 -chloro-2-methyl-
benzenesulfonamide,
3-Cyano-[l-(4-fluoro-benzyl)-3-oxo-2,3-dihydro-indazol-5-yl]-benzenesulfonamide,
2,3-Dichloro-N-[l-(4-chloro-benzyl)-3-oxo-2,3-dihydro-lH-indazol-5-yl]-
benzenesulfonamide,
3-Chloro-N-[ 1 -(4-chloro-benzyl)-3-oxo-2,3-dihydro-1 H-indazol-5-yl]-2-methyl-
benzenesulfonamide,
4-Fluoro-N-[ 1 -(4-fluoro-benzyl)-3 -oxo-2,3 -dihydro-1 H-indazol-5-yl] -3 -trifluoromethyl-
benzenesulfonamide,
3-Chloro-4-fluoro-N-[l-(4-fluoro-benzyl)-3-oxo-2,3-dihydro-lH-indazol-5-yl]-
benzenesulfonamide,
3-Chloro-[l-(3,4-difluoro-benzyl)-3-oxo-2,3-dihydro-indazol-5-yl]-2-methyl-
benzenesulfonamide,
N-[l-(4-Chloro-benzyl)-3-oxo-2,3-dihydro-lH-indazol-5-yl]-4-fluoro-3-trifiuoroniethyl-
benzenesulfonamide, and
3 -Chloro-2-methyl-N-(3 -oxo-1 -pyridin-2-ylmethyl-2,3 -dihydro-1 H-indazol-5-yl)-
benzenesulfonamide,
and pharmaceutically acceptable salts thereof.
24. The compounds as claimed in any one of claims 1 to 21 selected from the group
consisting of:
2,3-Dichloro-N-(6-chloro-3 -oxo-1 -pyridin-2-ylmethyl-2,3 -dihydro-1 H-indazol-5-yl)-
benzenesulfonamide,
N-( 1 -Benzyl-6-fluoro-3 -oxo-2,3 -dihydro-1 H-indazol-5-yl)-2,4-difiuoro-
benzenesulfonamide,
2,4-Difluoro-N-(3-oxo-l-phenyl-2,3-dihydro-lH-indazol-5-yl)-benzenesulfonamide,
3 -Chloro-2-fluoro-N-(3 -oxo-1 -phenyl-2,3 -dihydro-1 H-indazol-5-yl)-
benzenesulfonamide,
N-(l-Benzyl-6-fluoro-3-oxo-2,3-dihydro-lH-indazol-5-yl)-3-cyano-benzenesulfonamide,
Propane-2-sulfonic acid (1 -benzyl-6-fluoro-3-oxo-2,3-dihydro-1 H-indazol-5-yl)-amide,
3-Cyano-N-(3-oxo-l-phenyl-2,3-dihydro-lH-indazol-5-yl)-benzenesulfonamide,
2,2,2-Trifluoro-ethanesulfonic acid (1 -benzyl-6-fiuoro-3 -oxo-2,3 -dihydro-1 H-indazol-5-
yl)-amide,
Propane-2-sulfonic acid (1 -benzyl-6-chloro-3-oxo-2,3-dihydro-1 H-indazol-5-yl)-amide,
Propane-2-sulfonic acid [6-chloro-1 -(4-chloro-benzyl)-3-oxo-2,3-dihydro-1 H-indazol-5-
yl]-amide,
N-(l-Benzyl-6-fluoro-3-oxo-2,3-dihydro-lH-indazol-5-yl)-trifluoro-
methanesulfonamide,
Propane-2-sulfonic acid (1 -isobutyl-3 -oxo-2,3 -dihydro-1 H-indazol-5-yl)-amide,
Propane-2-sulfonic acid [ 1 -(3,4-difluoro-benzyl)-3 -oxo-2,3 -dihydro-1 H-indazol-5-yl] -
amide,
Propane-2-sulfonic acid [ 1 -(2-methoxy-ethyl)-3-oxo-2,3-dihydro-1 H-indazol-5-yl]-
amide, and
N-(l-Benzyl-3-oxo-2,3-dihydro-lH-indazol-5-yl)-C-cyclopropyl-methanesulfonamide
and pharmaceutically acceptable salts thereof.
25. The compound as claimed in any one of claims 1 to 21 which is:
N-(l-Benzyl-3-oxo-2,3-dihydro-lH-indazol-5-yl)-C-cyclopropyl-methanesulfonamide
and pharmaceutically acceptable salts thereof.
26. A process for the preparation of compounds as claimed in any of claims 1 to 25
comprising the reaction of a compound of formula (II)
(Formula Removed)
with a compound of formula (III)
(Formula Removed)
wherein R1 to R7 are as defined in any of claims 1 to 25.
27. The compounds as claimed in any of claims 1 to 25 for use as therapeutic active substances for the preparation of medicaments for the treatment and/or prophylaxis of diseases which are caused by disorders associated with the enzyme 1 lbeta-hydroxysteroid dehydrogenase 1, such as metabolic disorders, obesity, dyslipidemiae, hypertension and/or diabetes.

Documents:

2319-DELNP-2007-Abstract-(06-03-2012).pdf

2319-delnp-2007-abstract.pdf

2319-delnp-2007-assignment.pdf

2319-DELNP-2007-Claims-(06-03-2012).pdf

2319-delnp-2007-claims.pdf

2319-DELNP-2007-Correspondence Others-(06-03-2012).pdf

2319-delnp-2007-correspondence-others-1.pdf

2319-delnp-2007-correspondence-others.pdf

2319-DELNP-2007-Description (Complete)-(06-03-2012).pdf

2319-delnp-2007-description (complete).pdf

2319-delnp-2007-form-1.pdf

2319-delnp-2007-form-18.pdf

2319-delnp-2007-form-2.pdf

2319-DELNP-2007-Form-3-(06-03-2012).pdf

2319-delnp-2007-form-3.pdf

2319-delnp-2007-form-5.pdf

2319-delnp-2007-gpa.pdf

2319-delnp-2007-pct-210.pdf

2319-delnp-2007-pct-304.pdf

2319-delnp-2007-pct-409.pdf

abstract.jpg


Patent Number 252371
Indian Patent Application Number 2319/DELNP/2007
PG Journal Number 19/2012
Publication Date 11-May-2012
Grant Date 10-May-2012
Date of Filing 26-Mar-2007
Name of Patentee H.HOFFMANN-LA ROCHE AG
Applicant Address GRENZACHERSTRASSE 124, CH-4070 BASEL (CH)
Inventors:
# Inventor's Name Inventor's Address
1 CAI, JIANPING 99 PARK STREET, WEST CALDWELL, NJ 07006, USA
2 KUHN, BERND SONNMATTWEG 42, CH-4410 LIESTAL, SWITZERLAND
3 NEIDHART, WERNER 9, RUE DU STEINER, F-68220 HAGENTHAL LE BAS, FRANCE
4 GOODNOW, ROBERT, ALAN, JR 799 LONG HILL ROAD, MORRIS COUNTY, GILLETTE, NJ 07933, USA
5 HUNZIKER, DANIEL BUERKLISTRASSE 14, CH-4313 MOEHLIN, SWITZERLAND
6 MAYWEG, ALEXANDER MARTINSGASSE 8, CH-4051 BASEL, SWITZERLAND
7 AMREIN, KURT LETTENWEG 8, CH-4452 ITINGEN, SWITZERLAND
PCT International Classification Number C07D 231/56
PCT International Application Number PCT/EP2005/010175
PCT International Filing date 2005-09-21
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 04104753.1 2004-09-29 EUROPEAN UNION