U.S. patent application number 15/684117 was filed with the patent office on 2017-12-28 for dihydropyrazoles.
The applicant listed for this patent is Merck Patent GmbH. Invention is credited to Lizbeth Celeste DESELM, Robert James FOGLESONG, Andreas GOUTOPOULOS, Thomas E. RICHARDSON, Henry YU.
Application Number | 20170368030 15/684117 |
Document ID | / |
Family ID | 46513842 |
Filed Date | 2017-12-28 |
United States Patent
Application |
20170368030 |
Kind Code |
A1 |
YU; Henry ; et al. |
December 28, 2017 |
Dihydropyrazoles
Abstract
Novel dihydropyrazole derivatives of formula (I) ##STR00001##
wherein L, R, R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7, X.sup.1,
X.sup.2, X.sup.3, X.sup.4, Y, m and n have the meaning according to
the claims, are positive allosteric modulators of the FSH receptor,
and can be employed, inter alia, for the treatment of fertility
disorders.
Inventors: |
YU; Henry; (Wellesley,
MA) ; RICHARDSON; Thomas E.; (Chapel Hill, NC)
; FOGLESONG; Robert James; (Durham, NC) ; DESELM;
Lizbeth Celeste; (Melrose, MA) ; GOUTOPOULOS;
Andreas; (Boston, MA) |
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Applicant: |
Name |
City |
State |
Country |
Type |
Merck Patent GmbH |
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Family ID: |
46513842 |
Appl. No.: |
15/684117 |
Filed: |
August 23, 2017 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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15342550 |
Nov 3, 2016 |
9775830 |
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15684117 |
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14300945 |
Jun 10, 2014 |
9517227 |
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15342550 |
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13533759 |
Jun 26, 2012 |
8791114 |
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14300945 |
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61503694 |
Jul 1, 2011 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 31/437 20130101;
C07D 231/06 20130101; A61P 15/08 20180101; C07D 405/06 20130101;
C07D 413/10 20130101; C07D 417/10 20130101; A61K 47/06 20130101;
C07D 409/06 20130101; A61P 5/06 20180101; C07D 405/04 20130101;
A61K 9/2018 20130101; C07D 403/10 20130101; C07D 403/06 20130101;
A61K 31/427 20130101; A61K 31/4155 20130101; C07D 403/04 20130101;
A61K 9/0019 20130101; C07D 401/10 20130101; A61K 9/06 20130101;
A61K 31/4709 20130101; C07D 471/04 20130101; C07D 413/06 20130101;
A61K 9/19 20130101; A61K 31/423 20130101; C07D 409/04 20130101;
A61K 31/5377 20130101; C07D 401/06 20130101; A61K 31/415 20130101;
A61K 9/0048 20130101; A61K 31/506 20130101; A61K 9/0078 20130101;
A61P 43/00 20180101; C07D 405/10 20130101; C07D 401/04 20130101;
A61K 9/0031 20130101; A61K 9/0014 20130101; A61K 45/06 20130101;
A61K 9/2059 20130101; A61K 9/48 20130101; C07D 405/14 20130101;
C07D 231/12 20130101 |
International
Class: |
A61K 31/415 20060101
A61K031/415; A61K 9/00 20060101 A61K009/00; C07D 413/10 20060101
C07D413/10; C07D 413/06 20060101 C07D413/06; C07D 409/06 20060101
C07D409/06; C07D 409/04 20060101 C07D409/04; C07D 405/14 20060101
C07D405/14; C07D 405/10 20060101 C07D405/10; C07D 405/06 20060101
C07D405/06; C07D 405/04 20060101 C07D405/04; C07D 403/10 20060101
C07D403/10; C07D 403/06 20060101 C07D403/06; C07D 403/04 20060101
C07D403/04; C07D 401/10 20060101 C07D401/10; C07D 401/06 20060101
C07D401/06; C07D 401/04 20060101 C07D401/04; C07D 231/12 20060101
C07D231/12; C07D 231/06 20060101 C07D231/06; A61K 47/06 20060101
A61K047/06; A61K 45/06 20060101 A61K045/06; A61K 31/5377 20060101
A61K031/5377; A61K 31/506 20060101 A61K031/506; A61K 31/4709
20060101 A61K031/4709; A61K 31/437 20060101 A61K031/437; A61K
31/427 20060101 A61K031/427; A61K 31/423 20060101 A61K031/423; A61K
31/4155 20060101 A61K031/4155; A61K 9/48 20060101 A61K009/48; A61K
9/20 20060101 A61K009/20; A61K 9/19 20060101 A61K009/19; A61K 9/06
20060101 A61K009/06; C07D 417/10 20060101 C07D417/10; C07D 471/04
20060101 C07D471/04 |
Claims
1-14. (canceled)
15. A compound selected from: ##STR00597## ##STR00598##
##STR00599## ##STR00600## ##STR00601## ##STR00602## ##STR00603##
##STR00604## ##STR00605## ##STR00606## ##STR00607## ##STR00608##
##STR00609## ##STR00610## ##STR00611## ##STR00612## ##STR00613##
##STR00614## ##STR00615## ##STR00616## ##STR00617## ##STR00618##
##STR00619## ##STR00620## ##STR00621## ##STR00622## ##STR00623##
##STR00624## ##STR00625## ##STR00626## ##STR00627## ##STR00628##
##STR00629## ##STR00630## ##STR00631## ##STR00632## ##STR00633##
##STR00634## ##STR00635## ##STR00636## ##STR00637## ##STR00638##
##STR00639##
Description
PRIORITY CLAIM
[0001] This application claims the benefit of U.S. Provisional
application Ser. No. 61/503,694 filed on Jul. 1, 2011, which is
hereby incorporated by reference.
FIELD OF THE INVENTION
[0002] The present invention relates to compounds of formula
(I)
##STR00002##
wherein L, R, R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7, X.sup.1,
X.sup.2, X.sup.3, X.sup.4, Y, m and n have the meaning according to
the claims, and/or physiologically acceptable salts thereof. The
compounds of formulas (I) can be used as positive allosteric
modulators of the follicle stimulating hormone receptor (FSHR).
Objects of the invention are also pharmaceutical compositions
comprising the compounds of formula (I), and the use of the
compounds of formula (I) for the treatment of fertility
disorders.
BACKGROUND
[0003] Gonadotropins serve important functions in a variety of
bodily functions including metabolism, temperature regulation and
the reproductive process. Gonadotropins act on specific gonadal
cell types to initiate ovarian and testicular differentiation and
steroidogenesis. The gonadotropin FSH (follicle stimulating
hormone) is released from the anterior pituitary under the
influence of gonadotropin-releasing hormone and estrogens, and from
the placenta during pregnancy. FSH is a heterodimeric glycoprotein
hormone that shares structural similarities with luteinizing
hormone (LH) and thyroid stimulating hormone (TSH), both of which
are also produced in the pituitary gland, and chorionic
gonadotropin (CG), which is produced in the placenta. In the
female, FSH plays a pivotal role in the stimulation of follicle
development and maturation and in addition, it is the major hormone
regulating secretion of estrogens, whereas LH induces ovulation. In
the male, FSH is responsible for the integrity of the seminiferous
tubules and acts on Sertoli cells to support gametogenesis.
[0004] The hormones are relatively large (28-38 kDa) and are
composed of a common .alpha.-subunit non-covalently bound to a
distinct .beta.-subunit that confers receptor binding specificity.
The cellular receptor for these hormones is expressed on testicular
Sertoli cells and ovarian granulosa cells. The FSH receptor is
known to be members of the G protein-coupled class of
membrane-bound receptors, which when activated stimulate an
increase in the activity of adenylyl cyclase. This results in an
increase in the level of the intracellular second messenger
adenosine 3', 5'-monophosphate (cAMP), which in turn causes
increased steroid synthesis and secretion. Hydropathicity plots of
the amino acid sequences of these receptors reveal three general
domains: a hydrophilic amino-terminal region, considered to be the
amino-terminal extracellular domain; seven hydrophobic segments of
membrane-spanning length, considered to be the transmembrane
domain; and a carboxy-terminal region that contains potential
phosphorylation sites (serine, threonine, and tyrosine residues),
considered to be the carboxy-terminal intracellular or cytoplasmic
domain. The glycoprotein hormone receptor family is distinguished
from other G protein-coupled receptors, such as the
.beta.-2-adrenergic, rhodopsin, and substance K receptors, by the
large size of the hydrophilic amino-terminal domain, which is
involved in hormone binding.
[0005] Annually in the U.S. there are 2.4 million couples
experiencing infertility that are potential candidates for
treatment. FSH, either extracted from urine or produced by
recombinant DNA technology, is a parenterally-administered protein
product used by specialists for ovulation induction and for
controlled ovarial hyperstimulation. Whereas ovulation induction is
directed at achieving a single follicle to ovulate, controlled
ovarial hyperstimulation is directed at harvesting multiple oocytes
for use in various in-vitro assisted reproductive technologies,
e.g. in-vitro fertilization (IVF). FSH is also used clinically to
treat male hypogonadism and male infertility, e.g. some types of
failure of spermatogenesis.
[0006] FSHR is a highly specific target in the ovarian follicle
growth process and is exclusively expressed in the ovary. However,
the use of FSH is limited by its high cost, lack of oral dosing,
and need of extensive monitoring by specialist physicians. Hence,
identification of a non-peptidic small molecule substitute for FSH
that could potentially be developed for oral administration is
desirable. Low molecular weight FSH mimetics with agonistic
properties are disclosed in the international applications WO
2002/09706 and WO 2010/136438 as well as the U.S. Pat. No.
6,653,338. There is still a need for low molecular weight hormone
mimetics that selectively activate FSHR.
SUMMARY OF THE INVENTION
[0007] The invention had the object of finding novel compounds
having valuable properties, in particular those which can be used
for the preparation of medicaments.
[0008] It has been surprisingly found that the compounds according
to the invention and salts thereof have very valuable
pharmacological properties while being well tolerated. In
particular, they act as FSHR agonists. The invention relates to
compounds of formula (I)
##STR00003##
wherein
[0009] R, L denote Ar.sup.1 or Het.sup.1; [0010] R.sup.1 denotes
Hal, A, --(CY.sub.2).sub.p--OY, --(CY.sub.2).sub.p--NY.sub.2, COOY,
CONY.sub.2, NHCOY, CN, SO.sub.2Y, -E-(CY.sub.2).sub.p--Ar.sup.2,
-E-(CY.sub.2).sub.p-Het.sup.1 or -E-(CY.sub.2).sub.p-Het.sup.3;
[0011] R.sup.2 denotes Hal, A, --(CY.sub.2).sub.p--OY,
--(CY.sub.2).sub.p--NY.sub.2, COOY, CONY.sub.2, --CONY-Cyc,
NO.sub.2, CN, SY, SOY, SO.sub.2Y, SO.sub.2NY.sub.2, NHSO.sub.2Y,
alkenyl or -E-(CY.sub.2).sub.p--Ar.sup.2; [0012] R.sup.3, R.sup.4,
R.sup.5, R.sup.6 denote independently from one another H, A or
Ar.sup.2; [0013] R.sup.7 denotes Y, OY or NY.sub.2; [0014] X.sup.1,
X.sup.2, X.sup.3, X.sup.4 denote independently from one another O,
NY or a single bond, with the proviso that m denotes 0 if X.sup.1
and X.sup.2 denote a single bond; [0015] E denotes --C.ident.C--,
SO.sub.2, --SO.sub.2--NY--, O, NY or a single bond; [0016] Y
denotes H or A; [0017] A denotes unbranched or branched alkyl
having 1-10 C atoms, [0018] in which 1-7 H atoms can be replaced by
Hal; [0019] Cyc denotes cycloalkyl having 3-7 C atoms, [0020] in
which 1-4 H atoms can be replaced independently from one another by
Hal or A; [0021] Ar.sup.1 denotes a saturated, unsaturated or
aromatic, mono- or bicyclic carbocycle having 3-10 C atoms, [0022]
which can be substituted by at least one substituent selected from
the group of R.sup.1, R.sup.2 and --C.ident.C--C(A).sub.2OH, or
which can be fused to Cyc, Het.sup.1 or Het.sup.3; [0023] Ar.sup.2
denotes an aromatic, mono- or bicyclic carbocycle having 6-10 C
atoms, which can be substituted by at least one substituent
selected from the group of Hal, A and --(CY.sub.2).sub.p--OY;
[0024] Het.sup.1 denotes an unsaturated or aromatic monocyclic
heterocycle having 3-7 C atoms and 1-4 N, O and/or S atoms, [0025]
which can be substituted by at least one substituent selected from
the group of Hal, A, --(CY.sub.2).sub.p--OY,
--(CY.sub.2).sub.p--NY.sub.2, --(CY.sub.2).sub.p--Ar.sup.2,
--(CY.sub.2).sub.p-Het.sup.2, Het.sup.3 and CN; [0026] Het.sup.2
denotes an aromatic monocyclic heterocycle having 5-7 C atoms and
1-3 N atoms, [0027] which can be substituted by at least one
substituent selected from the group of Hal, A and
--(CY.sub.2).sub.p--OY; [0028] Het.sup.3 denotes a saturated
monocyclic heterocycle having 3-7 C atoms and 1-4 N, O and/or S
atoms, [0029] which can be substituted by at least one substituent
selected from the group of Hal, A, --(CY.sub.2).sub.p--OY,
--(CY.sub.2).sub.p--NY.sub.2, COOY, COY, --CONY.sub.2, .dbd.O and
CN; [0030] Hal denotes F, Cl, Br or I; and [0031] m, n, p denote
independently from one another 0, 1, 2, 3 or 4; and/or
physiologically acceptable salts thereof.
[0032] For the sake of clarity, R and L denote both either Ar.sup.1
or Het.sup.1. R and L, respectively, can be bound on, substituted
at and/or fused via any (ring) atom unless stated otherwise. The
fusion of Cyc, Het.sup.1 or Het.sup.3 to the carbocycle in the
Ar.sup.1 definition refers to a condensed ring system, wherein
another ring system is constructed on the mono- or bicyclic
carbocycle with the result of a bi- or tricyclic carbocycle.
DETAILED DESCRIPTION OF THE INVENTION
[0033] In the meaning of the present invention, the compound is
defined to include pharmaceutically usable derivatives, solvates,
prodrugs, tautomers, enantiomers, racemates and stereoisomers
thereof, including mixtures thereof in all ratios.
[0034] The term "pharmaceutically usable derivatives" is taken to
mean, for example, the salts of the compounds according to the
invention and also so-called prodrug compounds. The term "solvates"
of the compounds is taken to mean adductions of inert solvent
molecules onto the compounds, which are formed owing to their
mutual attractive force. Solvates are, for example, mono- or
dihydrates or alkoxides. The invention also comprises solvates of
salts of the compounds according to the invention. The term
"prodrug" is taken to mean compounds according to the invention
which have been modified by means of, for example, alkyl or acyl
groups, sugars or oligopeptides and which are rapidly cleaved in
the organism to form the effective compounds according to the
invention. These also include biodegradable polymer derivatives of
the compounds according to the invention, as described, for
example, in Int. J. Pharm. 115, 61-67 (1995). It is likewise
possible for the compounds of the invention to be in the form of
any desired prodrugs such as, for example, esters, carbonates,
carbamates, ureas, amides or phosphates, in which cases the
actually biologically active form is released only through
metabolism. Any compound that can be converted in-vivo to provide
the bioactive agent (i.e. compounds of the invention) is a prodrug
within the scope and spirit of the invention. Various forms of
prodrugs are well known in the art and are described (e.g. Wermuth
C G et al., Chapter 31: 671-696, The Practice of Medicinal
Chemistry, Academic Press 1996; Bundgaard H, Design of Prodrugs,
Elsevier 1985; Bundgaard H, Chapter 5: 131-191, A Textbook of Drug
Design and Development, Harwood Academic Publishers 1991). Said
references are incorporated herein by reference. It is further
known that chemical substances are converted in the body into
metabolites which may where appropriate likewise elicit the desired
biological effect--in some circumstances even in more pronounced
form. Any biologically active compound that was converted in-vivo
by metabolism from any of the compounds of the invention is a
metabolite within the scope and spirit of the invention.
[0035] The compounds of the invention may be present in the form of
their double bond isomers as pure E or Z isomers, or in the form of
mixtures of these double bond isomers. Where possible, the
compounds of the invention may be in the form of the tautomers,
such as keto-enol tautomers. All stereoisomers of the compounds of
the invention are contemplated, either in a mixture or in pure or
substantially pure form. The compounds of the invention can have
asymmetric centers at any of the carbon atoms. Consequently, they
can exist in the form of their racemates, in the form of the pure
enantiomers and/or diastereomers or in the form of mixtures of
these enantiomers and/or diastereomers. The mixtures may have any
desired mixing ratio of the stereoisomers. Thus, for example, the
compounds of the invention which have one or more centers of
chirality and which occur as racemates or as diastereomer mixtures
can be fractionated by methods known per se into their optical pure
isomers, i.e. enantiomers or diastereomers. The separation of the
compounds of the invention can take place by column separation on
chiral or nonchiral phases or by recrystallization from an
optionally optically active solvent or with use of an optically
active acid or base or by derivatization with an optically active
reagent such as, for example, an optically active alcohol, and
subsequent elimination of the radical.
[0036] The invention also relates to the use of mixtures of the
compounds according to the invention, for example mixtures of two
diastereomers, for example in the ratio 1:1, 1:2, 1:3, 1:4, 1:5,
1:10, 1:100 or 1:1000. These are particularly preferably mixtures
of stereoisomeric compounds.
[0037] The nomenclature as used herein for defining compounds,
especially the compounds according to the invention, is in general
based on the rules of the IUPAC-organization for chemical compounds
and especially organic compounds. The terms indicated for
explanation of the above compounds of the invention always, unless
indicated otherwise in the description or in the claims, have the
following meanings:
[0038] The term "unsubstituted" means that the corresponding
radical, group or moiety has no substituents. The term
"substituted" means that the corresponding radical, group or moiety
has one or more substituents. Where a radical has a plurality of
substituents, and a selection of various substituents is specified,
the substituents are selected independently of one another and do
not need to be identical. Even though a radical has a plurality of
a specific-designated substituent (e.g. Y.sub.2) the expression of
such substituent may differ from each other (e.g. methyl and
ethyl). It shall be understood accordingly that a multiple
substitution by any radical of the invention (e.g. R.sup.2 in
sub-formula I-B) may involve identical or different radicals (e.g.
OA and/or Hal). Hence, if individual radicals occur a number of
times within a compound, the radicals adopt the meanings indicated,
independently of one another. In case of a multiple substitution,
the radical could be alternatively designated with R', R'', R'',
R''' etc.
[0039] The terms "alkyl" or "A" refer to acyclic saturated or
unsaturated hydrocarbon radicals, which may be branched or
straight-chain and preferably have 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10
carbon atoms, i.e. C.sub.1-C.sub.10-alkanyls. Examples of suitable
alkyl radicals are methyl, ethyl, n-propyl, isopropyl, 1,1-, 1,2-
or 2,2-dimethylpropyl, 1-ethylpropyl, 1-ethyl-1-methylpropyl,
1-ethyl-2-methylpropyl, 1,1,2- or 1,2,2-trimethylpropyl, n-butyl,
isobutyl, sec-butyl, tert-butyl, 1-, 2- or 3-methylbutyl, 1,1-,
1,2-, 1,3-, 2,2-, 2,3- or 3,3-dimethylbutyl, 1- or 2-ethylbutyl,
n-pentyl, iso-pentyl, neo-pentyl, tert-pentyl, 1-, 2-, 3- or
-methyl-pentyl, n-hexyl, 2-hexyl, isohexyl, n-heptyl, n-octyl,
n-nonyl, n-decyl, n-undecyl, n-dodecyl, n-tetradecyl, n-hexadecyl,
n-octadecyl, n-icosanyl, n-docosanyl.
[0040] In a preferred embodiment of the invention, "A" denotes
unbranched or branched alkyl having 1-10 C atoms, in which 1-7 H
atoms may be replaced by Hal. A more preferred "A" denotes
unbranched or branched alkyl having 1-5 C atoms, in which 1-3 atoms
may be replaced by F and/or Cl. Most preferred is C.sub.1-4-alkyl.
A C.sub.1-4-alkyl radical is for example a methyl, ethyl, propyl,
isopropyl, butyl, isobutyl, tert-butyl, sec-butyl, tert-butyl,
fluoromethyl, difluoromethyl, trifluoromethyl, pentafluoroethyl,
1,1,1-trifluoroethyl or bromomethyl, especially methyl, ethyl,
propyl or trifluoromethyl. It is a highly preferred embodiment of
the invention that "A" denotes methyl. It shall be understood that
the respective denotation of "A" is independently of one another in
any radical of the invention.
[0041] The terms "cycloalkyl" or "Cyc" for the purposes of this
invention refers to saturated and partially unsaturated
non-aromatic cyclic hydrocarbon groups/radicals, having 1 to 3
rings, that contain 3 to 20, preferably 3 to 12, more preferably 3
to 9 carbon atoms. The cycloalkyl radical may also be part of a bi-
or polycyclic system, where, for example, the cycloalkyl radical is
fused to an aryl, heteroaryl or heterocyclyl radical as defined
herein by any possible and desired ring member(s). The bonding to
the compounds of the general formula (I) can be effected via any
possible ring member of the cycloalkyl radical. Examples of
suitable cycloalkyl radicals are cyclopropyl, cyclobutyl,
cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclodecyl,
cyclohexenyl, cyclopentenyl and cyclooctadienyl.
[0042] In a preferred embodiment of the invention, "Cyc" denotes
cycloalkyl having 3-7 C atoms, in which 1-4 H atoms may be replaced
independently of one another by Hal and/or A. More preferred is
C.sub.3-C.sub.5-cycloalkyl, i.e. cyclopropyl, cyclobutyl or
cyclopentyl. Moreover, the definition of "A" shall also comprise
cycloalkyls and it is to be applied mutatis mutandis to "Cyc". It
shall be understood that the respective denotation of "Cyc" is
independently of one another in any radical of the invention.
[0043] The term "alkenyl" refers to unbranched or branched alkenyl
having 1, 2, 3, 4, 5 or 6 C atoms, i.e. C.sub.2-C.sub.6-alkenyls.
Alkenyls have at least one C--C double bond. Example of suitable
alkenyls are allyl, vinyl, propenyl, --CH.sub.2CH.dbd.CH.sub.2,
--CH.dbd.CH--CH.sub.3, --C(.dbd.CH.sub.2)--CH.sub.3), 1-, 2- or
3-butenyl, isobutenyl, 2-methyl-1- or 2-butenyl,
3-methyl-1-butenyl, 1,3-butadienyl, 2-methyl-1,3-butadienyl,
2,3-dimethyl-1,3-butadienyl, 1-, 2-, 3- or 4-pentenyl and
hexenyl.
[0044] The term "aryl" or "carboaryl" for the purposes of this
invention refers to a mono- or polycyclic aromatic hydrocarbon
systems having 3 to 14, preferably 4 to 10, more preferably 5 to 8
carbon atoms, which can be optionally substituted. The term "aryl"
also includes systems in which the aromatic cycle is part of a bi-
or polycyclic saturated, partially unsaturated and/or aromatic
system, such as where the aromatic cycle is fused to an "aryl",
"cycloalkyl", "heteroaryl" or "heterocyclyl" group as defined
herein via any desired and possible ring member of the aryl
radical. The bonding to the compounds of the general formula (I)
can be effected via any possible ring member of the aryl radical.
Examples of suitable "aryl" radicals are phenyl, biphenyl,
naphthyl, 1-naphthyl, 2-naphthyl and anthracenyl, but likewise
in-danyl, indenyl or 1,2,3,4-tetrahydronaphthyl. Preferred
"carboaryls" of the invention are optionally substituted phenyl,
naphthyl and biphenyl, more preferably optionally substituted
monocylic carboaryl having 5-8 C atoms, most preferably optionally
substituted phenyl, highly preferably optionally substituted phenyl
if defined in terms of R.sup.1 and/or R.sup.2 radical.
[0045] In another embodiment of the invention, a "carbocycle",
including, but not limited to, carboaryl, is defined as "Ar",
including "Ar.sup.1" and "Ar.sup.2". Examples of suitable "Ar"
radicals are phenyl, o-, m- or p-tolyl, o-, m- or p-ethylphenyl,
o-, m- or p-propylphenyl, o-, m- or p-isopropylphenyl, o-, m- or
p-tert.-butylphenyl, o-, m- or p-hydroxyphenyl, o-, m- or
p-methoxyphenyl, o-, m- or p-ethoxyphenyl, o-, m- or
p-fluorophenyl, o-, m- or p-bromophenyl, o-, m- or p-chlorophenyl,
o-, m- or p-sulfonamidophenyl, o-, m- or
p-(N-methyl-sulfonamido)phenyl, o-, m- or
p-(N,N-dimethyl-sulfonamido)phenyl, o-, m- or
p-(N-ethyl-N-methyl-sulfonamido)phenyl, o-, m- or
p-(N,N-diethyl-sulfonamido)-phenyl, particularly 2,3-, 2,4-, 2,5-,
2,6-, 3,4- or 3,5-difluorophenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or
3,5-dichlorophenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or
3,5-dibromophenyl, 2,3,4-, 2,3,5-, 2,3,6-, 2,4,6- or
3,4,5-trichlorophenyl, 2,4,6-trimethoxyphenyl,
2-hydroxy-3,5-dichlorophenyl, p-iodophenyl,
4-fluoro-3-chlorophenyl, 2-fluoro-4-bromophenyl,
2,5-difluoro-4-bromophenyl, 3-bromo-6-methoxyphenyl,
3-chloro-6-methoxyphenyl or 2,5-dimethyl-4-chlorophenyl.
[0046] "Ar.sup.1" preferably denotes a saturated, unsaturated or
aromatic, mono- or bicyclic carbocycle having 3-10 C atoms, which
can be substituted by at least one substituent selected from the
group of (R.sup.1).sub.q, (R.sup.2).sub.q, and
--C.ident.C--C(A).sub.2OH, or which can be fused to Cyc, Het.sup.1
or Het.sup.3. In a more preferred embodiment of the invention,
"Ar.sup.1" denotes a saturated, unsaturated or aromatic, mono- or
bicyclic carbocycle having 3-10 C atoms, which is substituted by at
least one substituent selected from the group of R.sup.1, R.sup.2
and --C.ident.C--C(A).sub.2OH, or which is fused to Cyc, Het.sup.1
or Het.sup.3. In another more preferred embodiment of the
invention, "Ar.sup.1" denotes an aromatic, monocyclic carbocycle
having 5-8 C atoms, which can be mono-, di- or trisubstituted by at
least one substituent selected from the group of R.sup.1 and
R.sup.2. It is most preferred that "Ar.sup.1" denotes an aromatic,
monocyclic carbocycle having 5-8 C atoms, which is mono-, di- or
trisubstituted by at least one substituent selected from the group
of R.sup.1 and R.sup.2. In a highly preferred embodiment of the
invention, "Ar.sup.1" denotes phenyl, which can be mono- or
disubstituted by R.sup.1 and R.sup.2. It shall be understood that
the respective denotation of "Ar.sup.1" is independently of one
another in any radical of the invention.
[0047] "Ar.sup.2" preferably denotes an aromatic, mono- or bicyclic
carbocycle having 6-10 C atoms, which can be substituted by at
least one substituent selected from the group of Hal, A and
--(CY.sub.2).sub.p--OY. In a more preferred embodiment of the
invention, "Ar.sup.2" denotes phenyl. It shall be understood that
the respective denotation of "Ar.sup.2" is independently of one
another in any radical of the invention.
[0048] The term "heteroaryl" for the purposes of this invention
refers to a 2-15, preferably 2-9, most preferably 5-, 6- or
7-membered mono- or polycyclic aromatic hydrocarbon radical which
comprises at least 1, where appropriate also 2, 3, 4 or 5
heteroatoms, preferably nitrogen, oxygen and/or sulfur, where the
heteroatoms are identical or different. The number of nitrogen
atoms is preferably 0, 1, 2, 3 or 4, and that of the oxygen and
sulfur atoms is independently 0 or 1. The term "heteroaryl" also
includes systems in which the aromatic cycle is part of a bi- or
polycyclic saturated, partially unsaturated and/or aromatic system,
such as where the aromatic cycle is fused to an "aryl",
"cycloalkyl", "heteroaryl" or "heterocyclyl" group as defined
herein via any desired and possible ring member of the heteroaryl
radical. The bonding to the compounds of the general formula (I)
can be effected via any possible ring member of the heteroaryl
radical. Examples of suitable "heteroaryl" are pyrrolyl, thienyl,
furyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, oxadiazolyl,
isoxazolyl, pyrazolyl, pyridinyl, pyrimidinyl, pyridazinyl,
pyrazinyl, indolyl, quinolinyl, isoquinolinyl, imidazolyl,
triazolyl, triazinyl, tetrazolyl, phthalazinyl, indazolyl,
indolizinyl, quinoxalinyl, quinazolinyl, pteridinyl, carbazolyl,
phenazinyl, phenoxazinyl, phenothiazinyl and acridinyl.
[0049] It is preferred that "heteroaryl" in the realms of
"Het.sup.1" represents an unsaturated or aromatic monocyclic
heterocycle having 3-7 C atoms and 1-4 N, O and/or S atoms, which
can be substituted by at least one substituent selected from the
group of Hal, A, --(CY.sub.2).sub.p--OY,
--(CY.sub.2).sub.p--NY.sub.2, --(CY.sub.2).sub.p--Ar.sup.2,
--(CY.sub.2).sub.p-Het.sup.2, Het.sup.3 and CN. In a more preferred
embodiment of the invention, "Het.sup.1" denotes an unsaturated or
aromatic monocyclic heterocycle having 3-6 C atoms and 1-3 N, O
and/or S atoms, which can be substituted by at least one
substituent selected from the group of Hal, A and OA. It is most
preferred that "Het.sup.1" denotes an unsaturated or aromatic
monocyclic heterocycle having 3-6 C atoms and 1-3 N, O and/or S
atoms, which is substituted by at least one substituent selected
from the group of Hal, A and OA. In another most preferred
embodiment of the invention, "Het.sup.1" denotes pyrrolyl, furyl,
thiophenyl, imidazolyl, pyrazyl, isoxazyl, thiazyl or pyridyl,
which can be mono- or disubstituted by at least one substituent
selected from the group of Hal, A and OA. It is particularly
preferred that "Het.sup.1" can be monosubstituted by A. It shall be
understood that the respective denotation of "Het.sup.1" is
independently of one another in any radical of the invention.
[0050] It is preferred that "heteroaryl" in the realms of
"Het.sup.2" represents an aromatic monocyclic heterocycle having
5-7 C atoms and 1-3 N atoms, which can be substituted by at least
one substituent selected from the group of Hal, A and
--(CY.sub.2).sub.p--OY. In a more preferred embodiment of the
invention, "Het.sup.2" denotes pyridyl.
[0051] The terms "heterocycle" or "heterocyclyl" for the purposes
of this invention refers to a mono- or polycyclic system of 3 to 20
ring atoms, preferably 3 to 14 ring atoms, more preferably 3 to 10
ring atoms, comprising carbon atoms and 1, 2, 3, 4 or 5
heteroatoms, which are identical or different, in particular
nitrogen, oxygen and/or sulfur. The cyclic system may be saturated
or mono- or poly-unsaturated. In the case of a cyclic system
consisting of at least two rings the rings may be fused or spiro or
otherwise connected. Such "heterocyclyl" radicals can be linked via
any ring member. The term "heterocyclyl" also includes systems in
which the heterocycle is part of a bi- or polycyclic saturated,
partially unsaturated and/or aromatic system, such as where the
heterocycle is fused to an "aryl", "cycloalkyl", "heteroaryl" or
"heterocyclyl" group as defined herein via any desired and possible
ring member of the heterocyclyl radical. The bonding to the
compounds of the general formula (I) can be effected via any
possible ring member of the heterocyclyl radical. Examples of
suitable "heterocyclyl" radicals are pyrrolidinyl,
thiapyrrolidinyl, piperidinyl, piperazinyl, oxapiperazinyl,
oxapiperidinyl, oxadiazolyl, tetrahydrofuryl, imidazolidinyl,
thiazolidinyl, tetrahydropyranyl, morpholinyl,
tetrahydrothiophenyl, dihydropyranyl.
[0052] In a preferred aspect of the invention, "Het.sup.3" denotes
a saturated monocyclic heterocycle having 3-7 C atoms and 1-4 N, O
and/or S atoms, which can be substituted by at least one
substituent selected from the group of Hal, A,
--(CY.sub.2).sub.p--OY, --(CY.sub.2).sub.p--NY.sub.2, COOY, COY,
--CONY.sub.2, .dbd.O and CN. In a more preferred embodiment of the
invention, "Het.sup.3" denotes a saturated monocyclic heterocycle
having 3-6 C atoms and 1-2 N and/or O atoms, which can be
substituted by at least one substituent selected from the group of
Hal, COA and .dbd.O. In a most preferred embodiment of the
invention, "Het.sup.3" denotes pyrrolidinyl, tetrahydrofuryl,
oxazolidinyl, dioxalanyl, piperazinyl, morpholinyl or dioxanyl,
which can be mono- or disubstituted by at least one substituent
selected from the group of Hal, COA and .dbd.O. It shall be
understood that the respective denotation of "Het.sup.3" is
independently of one another in any radical of the invention.
[0053] The term "alkyloxy", "alkoxy" or "OA" for the purposes of
this invention refers to an alkyl radical according to above
definition that is attached to an oxygen atom. The attachment to
the compounds of the general formula (I) is via the oxygen atom.
Examples are methoxy, ethoxy and n-propyloxy, propoxy and
isopropoxy. Preferred is "C.sub.1-C.sub.4-alkyloxy" having the
indicated number of carbon atoms.
[0054] The term "halogen", "halogen atom", "halogen substituent" or
"Hal" for the purposes of this invention refers to one or, where
appropriate, a plurality of fluorine (F, fluoro), bromine (Br,
bromo), chlorine (Cl, chloro) or iodine (I, iodo) atoms. The
designations "dihalogen", "trihalogen" and "perhalogen" refer
respectively to two, three and four substituents, where each
substituent can be selected independently from the group consisting
of fluorine, chlorine, bromine and iodine. "Halogen" preferably
means a fluorine, chlorine or bromine atom. Fluorine and chlorine
are more preferred, when the halogens are substituted on an alkyl
(haloalkyl) or alkoxy group (e.g. CF.sub.3 and CF.sub.3O). It shall
be understood that the respective denotation of "Hal" is
independently of one another in any radical of the invention.
[0055] It is a preferred embodiment of the present invention that
both R and L denote Ar.sup.1, which can be substituted as defined
above. In a more preferred embodiment of the invention, R denotes
Ar.sup.1, which can be substituted by R.sup.1. It is most preferred
that R denotes phenyl, which is monosubstituted in meta position by
R.sup.1. In another more preferred embodiment of the invention, L
denotes Ar.sup.1, which can be substituted by R.sup.2. It is most
preferred that L denotes phenyl, which is disubstituted in meta and
para position by R.sup.2.
[0056] It is a preferred embodiment of the R.sup.1 radical
according to the present invention to be Hal, A,
--(CY.sub.2).sub.p--OY, --(CY.sub.2).sub.p--NY.sub.2, COOY,
CONY.sub.2, NHCOY, CN, SO.sub.2Y, -E-(CY.sub.2).sub.p--Ar.sup.2,
-E-(CY.sub.2).sub.p-Het.sup.1 or -E-(CY.sub.2).sub.p-Het.sup.3,
more preferably Hal, A, --(CY.sub.2).sub.p--OY,
--(CY.sub.2).sub.p--NY.sub.2, CONY.sub.2, NHCOA, CN, SO.sub.2A,
-E-(CY.sub.2).sub.p--Ar.sup.2, Het.sup.1 or -E-Het.sup.3, most
preferably Hal, A, CN, -E-phenyl or Het.sup.3, highly preferably
Hal, CN or O-phenyl.
[0057] It is a preferred embodiment of the R.sup.2 radical
according to the present invention to be Hal, A,
--(CY.sub.2).sub.p--OY, --(CY.sub.2).sub.p--NY.sub.2, COOY,
CONY.sub.2, --CONY-Cyc, NO.sub.2, CN, SY, SOY, SO.sub.2Y,
SO.sub.2NY.sub.2, NHSO.sub.2Y, alkenyl or
-E-(CY.sub.2).sub.p--Ar.sup.2, more preferably Hal, A,
--(CY.sub.2).sub.p--OY, --(CY.sub.2).sub.p--NY.sub.2, CONY.sub.2,
--CONH-Cyc, NO.sub.2, CN, SA, SOA, SO.sub.2A, SO.sub.2NY.sub.2,
NHSO.sub.2A, alkenyl, -E-(CY.sub.2).sub.p--Ar.sup.2 or Het.sup.1,
most preferably Hal, A, OA, NH.sub.2, CN, SA, SO.sub.2A,
SO.sub.2NH.sub.2, O-phenyl or Het.sup.1, or in another most
preferred aspect Hal, A, --(CY.sub.2).sub.p--OY, CONY.sub.2, SA,
NHSO.sub.2A, -E-(CY.sub.2).sub.p--Ar.sup.2 or Het.sup.1, highly
preferably OA.
[0058] It is a preferred embodiment of the R.sup.3, R.sup.4,
R.sup.5, R.sup.6 radicals according to the present invention to be
independently from one another H, A or Ar.sup.2, more preferably
they denote independently from one another H or A, most preferably
R.sup.3, R.sup.4 denote H and R.sup.5, R.sup.6 denote A, or
R.sup.3, R.sup.4 denote A and R.sup.5, R.sup.6 denote H.
[0059] It is a preferred embodiment of the R.sup.7 radical
according to the present invention to be H, OA or NA.sub.2, more
preferably H or OA.
[0060] It is a preferred embodiment of the X.sup.1, X.sup.2,
X.sup.3, X.sup.4 radicals according to the present invention to be
independently from one another O, NY or a single bond with the
proviso that m denotes 0 if X.sup.1 and X.sup.2 denote a single
bond, more preferably they denote independently from one another O,
NH or a single bond with the proviso that m denotes 0 if X.sup.1
and X.sup.2 denote a single bond, preferably they denote a single
bond and m denotes 0.
[0061] It is a preferred embodiment of the E radical according to
the present invention to be --C.ident.C--, SO.sub.2,
--SO.sub.2--NY--, O, NY or a single bond, more preferably
--C.ident.C--, SO.sub.2, --SO.sub.2--NH--, O or a single bond, most
preferably O or a single bond.
[0062] In an aspect of the invention, Y denotes H or A.
[0063] It is a preferred embodiment of the m, n, p indices
according to the present invention to be independently from one
another 0, 1, 2, 3 or 4, more preferably they denote independently
from one another 0, 1, 2 or 3, most preferably they denote
independently from one another 0, 1 or 2, highly preferably they
denote independently from one another 0 or 1, particularly
preferably they denote independently from one another 0. It shall
be understood that the respective denotation of "p" is
independently of one another in any radical of the invention.
[0064] It is a preferred embodiment of the q index according to the
present invention to be 0, 1, 2, 3 or 4, more preferably 1, 2, 3 or
4, most preferably 1, 2 or 3, highly preferably 1 or 2.
[0065] Accordingly, the subject-matter of the invention relates to
compounds of formula (I), in which at least one of the
aforementioned radicals has any meaning, particularly realize any
preferred embodiment, as described above. Radicals, which are not
explicitly specified in the context of any embodiment of formula
(I), sub-formulae thereof or other radicals thereto, shall be
construed to represent any respective denotations according to
formula (I) as disclosed hereunder for solving the problem of the
invention. That means, the aforementioned radicals may adopt all
designated meanings as each described in the prior or following
course of the present specification, irrespective of the context to
be found, including, but not limited to, any preferred embodiments.
It shall be particularly understood that any embodiment of a
certain radical can be combined with any embodiment of one or more
other radicals.
[0066] In another preferred embodiment of the present invention,
dihydropyrazole derivatives of sub-formula (I-A) are provided
##STR00004##
wherein [0067] R.sup.1 denotes Hal, A, --(CY.sub.2).sub.p--OY,
--(CY.sub.2).sub.p--NY.sub.2, CONY.sub.2, NHCOA, CN, SO.sub.2A,
-E-(CY.sub.2).sub.p--Ar.sup.2, Het.sup.1 or -E-Het.sup.3; [0068]
R.sup.2 denotes Hal, A, --(CY.sub.2).sub.p--OY,
--(CY.sub.2).sub.p--NY.sub.2, CONY.sub.2, --CONH-Cyc, NO.sub.2, CN,
SA, SOA, SO.sub.2A, SO.sub.2NY.sub.2, NHSO.sub.2A, alkenyl,
-E-(CY.sub.2).sub.p--Ar.sup.2 or Het.sup.1; [0069] R.sup.3,
R.sup.4, R.sup.5, R.sup.6 denote independently from one another H
or A; [0070] R.sup.7 denotes H, OA or NA.sub.2; [0071] E denotes
--C.ident.C--, SO.sub.2, --SO.sub.2--NH--, O or a single bond;
[0072] Y denotes H or A; [0073] A denotes unbranched or branched
alkyl having 1-5 C atoms, in which 1-3 H atoms can be replaced by
Hal; [0074] Cyc denotes cycloalkyl having 3-5 C atoms; [0075]
Ar.sup.1 denotes an aromatic, monocyclic carbocycle having 5-8 C
atoms; [0076] Ar.sup.2 denotes phenyl; [0077] Het.sup.1 denotes an
unsaturated or aromatic monocyclic heterocycle having 3-6 C atoms
and 1-3 N, O and/or S atoms, which can be substituted by at least
one substituent selected from the group of Hal, A and OA; [0078]
Het.sup.3 denotes a saturated monocyclic heterocycle having 3-6 C
atoms and 1-2 N and/or O atoms, which can be substituted by at
least one substituent selected from the group of Hal, COA and
.dbd.O; [0079] Hal denotes F, Cl, Br or I; and [0080] m, p, q
denote independently from one another 0, 1, 2 or 3; and/or
physiologically acceptable salts thereof.
[0081] It is a preferred embodiment of the m index according to the
present invention to be 0 or 1. It is another preferred embodiment
of the q index according to the present invention to be 1, 2 or 3,
more preferably 1 or 2.
[0082] In a more preferred embodiment of the present invention,
dihydropyrazole derivatives of sub-formula (I-B) are provided
##STR00005##
wherein [0083] R.sup.1 denotes Hal, A, CN, -E-phenyl or Het.sup.3;
[0084] R.sup.2 denotes Hal, A, OA, NH.sub.2, CN, SA, SO.sub.2A,
SO.sub.2NH.sub.2, O-phenyl or Het.sup.1; [0085] R.sup.3, R.sup.4
denote H, and [0086] R.sup.5, R.sup.6 denote A, or vice versa;
[0087] E denotes O or a single bond; [0088] A denotes unbranched or
branched alkyl having 1-5 C atoms; [0089] Het.sup.1 denotes
pyrrolyl, furyl, thiophenyl, imidazolyl, pyrazyl, isoxazyl, thiazyl
or pyridyl, which can be mono- or disubstituted by at least one
substituent selected from the group of Hal, A and OA; [0090]
Het.sup.3 denotes pyrrolidinyl, tetrahydrofuryl, oxazolidinyl,
dioxalanyl, piperazinyl, morpholinyl or dioxanyl, which can be
mono- or disubstituted by at least one substituent selected from
the group of Hal, COA and =0; [0091] Hal denotes F, Cl or Br; and
[0092] m denotes 0 or 1; and/or physiologically acceptable salts
thereof.
[0093] Most preferred embodiments are those compounds of formulae
(I), (I-A) and (I-B) listed in Table 1.
TABLE-US-00001 TABLE 1 Compounds of formulae (I), (I-A), (I-B).
Assay A: Example 10; Assay B: Example 11. No. Name Assay A Assay B
1 ##STR00006## 16.70 .mu.M 0.878 .mu.M 2 ##STR00007## 41.50% 3
##STR00008## 40.30 .mu.M 0.656 .mu.M 4 ##STR00009## 6.00% 5
##STR00010## 6.00% 6 ##STR00011## 11.00% 7 ##STR00012## 8
##STR00013## 9 ##STR00014## 10 ##STR00015## 11 ##STR00016## 12
##STR00017## 13 ##STR00018## 14 ##STR00019## 15 ##STR00020## 16
##STR00021## 17 ##STR00022## 18 ##STR00023## 19 ##STR00024## 20
##STR00025## 21 ##STR00026## 22 ##STR00027## 23 ##STR00028## 24
##STR00029## 25 ##STR00030## 26 ##STR00031## 27 ##STR00032## 28
##STR00033## 29 ##STR00034## 30 ##STR00035## 31 ##STR00036## 32
##STR00037## 33 ##STR00038## 34 ##STR00039## 35 ##STR00040## 36
##STR00041## 40.50% 37 ##STR00042## 38 ##STR00043## 39 ##STR00044##
40 ##STR00045## 41 ##STR00046## 42 ##STR00047## 43 ##STR00048##
17.50% 44 ##STR00049## 45 ##STR00050## 4.00% 46 ##STR00051## 47
##STR00052## 48 ##STR00053## 4.24% 49 ##STR00054## 50 ##STR00055##
51 ##STR00056## 52 ##STR00057## 53 ##STR00058## 54 ##STR00059## 55
##STR00060## 56 ##STR00061## 57 ##STR00062## 58 ##STR00063## 59
##STR00064## 60 ##STR00065## 61 ##STR00066## 9.75 .mu.M 0.465 .mu.M
62 ##STR00067## 6.49 .mu.M 0.0981 .mu.M 63 ##STR00068## 25.90% 64
##STR00069## 11.00 .mu.M 0.348 .mu.M 65 ##STR00070## 21.00 .mu.M
5.090 .mu.M 66 ##STR00071## 15.40% 67 ##STR00072## 21.00 .mu.M
0.814 .mu.M 68 ##STR00073## 11.50% 69 ##STR00074## 33.50% 70
##STR00075## 39.00 .mu.M 0.110 .mu.M 71 ##STR00076## 14.70% 72
##STR00077## 40.00% 73 ##STR00078## 5.48% 74 ##STR00079## 34.00% 75
##STR00080## 5.70 .mu.M 76 ##STR00081## 24.00% 77 ##STR00082## 8.61
.mu.M 0.729 .mu.M 78 ##STR00083## 16.00% 79 ##STR00084## 35.00% 80
##STR00085## 28.00 .mu.M 1.190 .mu.M 81 ##STR00086## 8.12% 82
##STR00087## 83 ##STR00088## 33.00% 84 ##STR00089## 85 ##STR00090##
86 ##STR00091## 21.80% 87 ##STR00092## 88 ##STR00093## 89
##STR00094## 90 ##STR00095## 91 ##STR00096## 27.00% 92 ##STR00097##
22.00% 93 ##STR00098## 27.00 .mu.M 0.726 .mu.M 94 ##STR00099##
29.00% 95 ##STR00100## 4.00% 96 ##STR00101## 44.00% 97 ##STR00102##
29.00% 98 ##STR00103## 26.00% 99 ##STR00104## 22.00% 100
##STR00105## 5.00% 101 ##STR00106## 14.00% 102 ##STR00107## 15.00%
103 ##STR00108## 24.00% 104 ##STR00109## 20.00% 105 ##STR00110##
22.00% 106 ##STR00111## 1.00% 107 ##STR00112## 8.00% 108
##STR00113## 19.00% 109 ##STR00114## 2.00% 110 ##STR00115## 111
##STR00116## 2.00% 112 ##STR00117## 3.00% 113 ##STR00118## 114
##STR00119## 115 ##STR00120## 28.00% 116 ##STR00121## 1.00% 117
##STR00122## 4.00% 118 ##STR00123## 5.00% 119 ##STR00124## 21.00%
120 ##STR00125## 23.00% 121 ##STR00126## 16.00% 122
##STR00127##
123 ##STR00128## 124 ##STR00129## 125 ##STR00130## 25.00% 126
##STR00131## 127 ##STR00132## 128 ##STR00133## 28.00% 129
##STR00134## 35.00 .mu.M 0.363 .mu.M 130 ##STR00135## 131
##STR00136## 23.00 .mu.M 0.413 .mu.M 132 ##STR00137## 41.50 .mu.M
0.025 .mu.M 133 ##STR00138## 134 ##STR00139## 28.70% 135
##STR00140## 136 ##STR00141## 30.00 .mu.M 0.106 .mu.M 137
##STR00142## 36.50% 138 ##STR00143## 19.80% 139 ##STR00144## 16.00%
140 ##STR00145## 7.75% 141 ##STR00146## 23.50% 142 ##STR00147## 143
##STR00148## 4.47% 144 ##STR00149## 145 ##STR00150## 7.35% 146
##STR00151## 147 ##STR00152## 49.00% 148 ##STR00153## 2.88 .mu.M
3.400 .mu.M 149 ##STR00154## 0.382 .mu.M 150 ##STR00155## 34.90%
151 ##STR00156## 37.90% 152 ##STR00157## 26.90% 153 ##STR00158##
23.40% 154 ##STR00159## 6.93% 155 ##STR00160## 156 ##STR00161## 157
##STR00162## 158 ##STR00163## 159 ##STR00164## 160 ##STR00165## 161
##STR00166## 162 ##STR00167## 163 ##STR00168## 164 ##STR00169## 165
##STR00170## 166 ##STR00171## 167 ##STR00172## 168 ##STR00173## 169
##STR00174## 170 ##STR00175## 171 ##STR00176## 172 ##STR00177## 173
##STR00178## 174 ##STR00179## 175 ##STR00180## 176 ##STR00181## 3%
177 ##STR00182## 36.50% 178 ##STR00183## 3.61% 179 ##STR00184##
34.00 .mu.M 180 ##STR00185## 181 ##STR00186## 182 ##STR00187## 183
##STR00188## 184 ##STR00189## 185 ##STR00190## 4.50 .mu.M 186
##STR00191## 25.00% 187 ##STR00192## 20.00% 188 ##STR00193## 189
##STR00194## 28.00 .mu.M 190 ##STR00195## 12.00% 191 ##STR00196##
192 ##STR00197## 193 ##STR00198## 40.00% 194 ##STR00199## 195
##STR00200## 16.00% 196 ##STR00201## 46.00% 197 ##STR00202## 23.00%
198 ##STR00203## 199 ##STR00204## 34.30 .mu.M 200 ##STR00205## 201
##STR00206## 202 ##STR00207## 203 ##STR00208## 204 ##STR00209##
8.25 .mu.M 205 ##STR00210## 30.00 .mu.M 206 ##STR00211## 29.00% 207
##STR00212## 44.50 .mu.M 208 ##STR00213## 19.10% 209 ##STR00214##
210 ##STR00215## 7.39 .mu.M 211 ##STR00216## 8.39% 212 ##STR00217##
213 ##STR00218## 214 ##STR00219## 1.10 .mu.M 215 ##STR00220## 216
##STR00221## 217 ##STR00222## 218 ##STR00223## 219 ##STR00224##
22.40% 220 ##STR00225## 221 ##STR00226## 13.30% 222 ##STR00227##
223 ##STR00228## 31.20 .mu.M 224 ##STR00229## 225 ##STR00230##
15.30% 226 ##STR00231## 227 ##STR00232## 228 ##STR00233## 37.80%
0.134 .mu.M 229 ##STR00234## 35.90% 0.032 .mu.M 230 ##STR00235##
2.20 .mu.M 0.128 .mu.M 231 ##STR00236## 23.80 .mu.M 1.150 .mu.M 232
##STR00237## 38.70 .mu.M 0.572 .mu.M 233 ##STR00238## 27.80 .mu.M
0.216 .mu.M 234 ##STR00239## 22.40 .mu.M 0.699 .mu.M 235
##STR00240## 35.70 .mu.M 0.538 .mu.M 236 ##STR00241## 25.30 .mu.M
1.730 .mu.M 237 ##STR00242## 35.00 .mu.M 0.598 .mu.M 238
##STR00243## 5.00% 239 ##STR00244## 4.47% 240 ##STR00245## 11.50%
241 ##STR00246## 31.00 .mu.M 0.342 .mu.M 242 ##STR00247## 243
##STR00248## 244 ##STR00249## 245 ##STR00250## 246 ##STR00251##
25.00% 247 ##STR00252## 35.20 .mu.M 248 ##STR00253##
249 ##STR00254## 38.70% 250 ##STR00255## 251 ##STR00256## 27.10
.mu.M 252 ##STR00257## 253 ##STR00258## 254 ##STR00259## 255
##STR00260## 35.00 .mu.M 256 ##STR00261## 35.20% 257 ##STR00262##
33.20 .mu.M 258 ##STR00263## 40.90% 259 ##STR00264## 30.00 .mu.M
260 ##STR00265## 261 ##STR00266## 42.50% 262 ##STR00267## 16.10%
263 ##STR00268## 24.40% 264 ##STR00269## 37.80% 265 ##STR00270##
16.50% 266 ##STR00271## 267 ##STR00272## 268 ##STR00273## 269
##STR00274## 270 ##STR00275## 17.00% 271 ##STR00276## 43.00% 282
##STR00277## 27.00 .mu.M 273 ##STR00278## 35.00% 274 ##STR00279##
25.00 .mu.M 275 ##STR00280## 24.00 .mu.M 276 ##STR00281## 46.00%
277 ##STR00282## 2.00 .mu.M 278 ##STR00283## 279 ##STR00284##
20.00% 280 ##STR00285## 24.00% 281 ##STR00286## 282 ##STR00287##
283 ##STR00288## 26.00% 284 ##STR00289## 26.00% 285 ##STR00290##
35.00% 286 ##STR00291## 37.00% 287 ##STR00292## 11.00% 288
##STR00293## 10.00% 289 ##STR00294## 290 ##STR00295## 9.00% 5.40
.mu.M 291 ##STR00296## 38.00% 144.00% 292 ##STR00297## 29.00 .mu.M
186.00%
[0094] Highly preferred embodiments are the compounds selected from
the group of
##STR00298##
and/or physiologically acceptable salts thereof.
[0095] The dihydropyrazole derivatives according to formula (I) and
the starting materials for its preparation, respectively, are
produced by methods known per se, as described in the literature
(for example in standard works, such as Houben-Weyl, Methoden der
organischen Chemie [Methods of Organic Chemistry],
Georg-Thieme-Verlag, Stuttgart), i.e. under reaction conditions
that are known and suitable for said reactions.
[0096] Use can also be made of variants that are known per se, but
are not mentioned in greater detail herein. If desired, the
starting materials can also be formed in-situ by leaving them in
the un-isolated status in the crude reaction mixture, but
immediately converting them further into the compound according to
the invention. On the other hand, it is possible to carry out the
reaction stepwise.
[0097] The reactions are preferably performed under basic
conditions. Suitable bases are metal oxides, e.g. aluminum oxide,
alkaline metal hydroxide (potassium hydroxide, sodium hydroxide and
lithium hydroxide, inter alia), alkaline earth metal hydroxide
(barium hydroxide and calcium hydroxide, inter alia), alkaline
metal alcoholates (potassium ethanolate and sodium propanolate,
inter alia) and several organic bases (piperidine or
diethanolamine, inter alia).
[0098] The reaction is generally carried out in an inert solvent.
Suitable inert solvents are, for example, hydrocarbons, such as
hexane, petroleum ether, benzene, toluene or xylene; chlorinated
hydrocarbons, such as trichloroethylene, 1,2-dichloroethane, carbon
tetrachloride, chloroform or dichloromethane; alcohols, such as
methanol, ethanol, isopropanol, n-propanol, n-butanol or
tert-butanol; ethers, such as diethyl ether, diisopropyl ether,
tetrahydrofuran (THF) or dioxane; glycol ethers, such as ethylene
glycol monomethyl or monoethyl ether, ethylene glycol dimethyl
ether (diglyme); ketones, such as acetone or butanone; amides, such
as acetamide, dimethylacetamide or dimethylformamide (DMF);
nitriles, such as acetonitrile; sulfoxides, such as dimethyl
sulfoxide (DMSO); carbon disulfide; carboxylic acids, such as
formic acid or acetic acid; nitro compounds, such as nitromethane
or nitrobenzene; esters, such as ethyl acetate, or mixtures of the
said solvents. Particular preference is given to water, THF, tert.
butanol, tert. amylalcohol, NMP, triethylamine and/or dioxane.
[0099] Depending on the conditions used, the reaction time is
between a few minutes and 14 days, the reaction temperature is
between about -30.degree. C. and 140.degree. C., normally between
-10.degree. C. and 130.degree. C., preferably between 30.degree. C.
and 125.degree. C.
[0100] The present invention also relates to a process for
manufacturing compounds of formula (I) comprising the steps of:
[0101] (a) reacting a compound of formula (II)
##STR00299##
[0101] wherein [0102] L, R.sup.3, R.sup.4, R.sup.5, R.sup.6,
X.sup.3, X.sup.4, Y and n have the meaning as defined above or
below, with a compound of formula (III)
##STR00300##
[0102] wherein [0103] R.sup.8 denotes Hal or OH, and [0104] R,
R.sup.7, X.sup.1, X.sup.2, Y, Hal and m have the meaning as defined
above or below, to yield a compound of formula (I)
##STR00301##
[0104] wherein [0105] L, R, R.sup.3, R.sup.4, R.sup.5, R.sup.6,
R.sup.7, X.sup.1, X.sup.2, X.sup.3, X.sup.4, Y, m and n have the
meaning as defined above or below, and optionally [0106] (b)
converting a base or an acid of the compound of formula (I) into a
salt thereof.
[0107] The dihydropyrazole derivatives of formula (I) are
accessible via the route above. The starting materials, including
the compounds of formulae (II) and (III), are usually known to the
skilled artisan, or they can be easily prepared by known methods.
Accordingly, any compound of formulae (II) and (III) can be
purified, provided as intermediate product and used as starting
material for the preparation of compounds of formula (I).
[0108] The compounds of formula (I) can be modified, like
hydrogenated or metal-reduced, to remove the chlorine, or put into
a substitution reaction, and/or to be transformed with an acid or
base into a salt, preferably with a strong acid. Numerous papers
and methods are available and useful for the one skilled in the art
in respect for organic chemistry, chemical strategies and tactics,
synthetic routes, protection of intermediates, cleavage and
purification procedure, isolation and characterization. General
chemical modifications are known to the one skilled in the art.
Halogenation of aryls or hydroxy substitution by halogens of acids,
alcohols, phenols, and their tautomeric structures can be
preferably carried out by use of POCl.sub.3, or SOCl.sub.2,
PCl.sub.5, SO.sub.2Cl.sub.2. In some instances oxalyl chloride is
also useful. Temperatures can vary from 0.degree. C. to reflux
depending on the task to halogenate a pyridone structure or a
carboxylic acid or an sufonic acid. Time will also be adjusted from
minutes to several hours or even over night. Similarly, alkylation,
ether formation, ester formation, amide formation are known to the
one skilled in the art. Arylation with aryl boronic acids can be
performed in presence of a Pd catalyst, appropriate ligand and
base, preferably a carbonate, phosphate, borate salt of sodium,
potassium or cesium. Organic bases, like Et.sub.3N, DIPEA or the
more basic DBU can also be used. Solvents can vary too, from
toluene, dioxane, THF, diglyme, monoglyme, alcohols, DMF, DMA, NMP,
acetonitrile, in some cases even water, and others. Commonly used
catalysts like Pd (PPh.sub.3).sub.4, or Pd(OAc).sub.2, PdCl.sub.2
type precursors of PdO catalysts have advanced to more complex ones
with more efficient ligands. In C--C arylations instead of boronic
acids and esters (Stille coupling), aryl-trifluoroborate potassium
salts (Suzuki-Miyaura coupling), organo silanes (Hiyama coupling),
Grignard reagents (Kumada), zink organyles (Negishi coupling) and
tin organyles (Stille coupling) are useful. This experience can be
transferred to N- and O-arylations. Numerous papers and methods are
available and useful for the one skilled in the art in respect of
N-arylation and even of electron deficient anilines (Biscoe et al.
JACS 130: 6686 (2008)), and with aryl chlorides and anilines (Fors
et al. JACS 130: 13552 (2008) as well as for O-arylation by using
Cu catalysis and Pd catalysis.
[0109] In the final step of the processes above, a salt of the
compound according to formulae (I) to (III), preferably formula
(I), is optionally provided. The said compounds according to the
invention can be used in their final non-salt form. On the other
hand, the present invention also encompasses the use of these
compounds in the form of their pharmaceutically acceptable salts,
which can be derived from various organic and inorganic acids and
bases by procedures known in the art. Pharmaceutically acceptable
salt forms of the compounds according to the invention are for the
most part prepared by conventional methods. If the compound
according to the invention contains a carboxyl group, one of its
suitable salts can be formed by reacting the compound with a
suitable base to give the corresponding base-addition salt. Such
bases are, for example, alkali metal hydroxides, including
potassium hydroxide, sodium hydroxide and lithium hydroxide;
alkaline earth metal hydroxides, such as barium hydroxide and
calcium hydroxide; alkali metal alkoxides, for example potassium
ethoxide and sodium propoxide; and various organic bases, such as
piperidine, diethanolamine and N-methylglutamine. The aluminum
salts of the compounds according to the invention are likewise
included. In the case of certain compounds according to the
invention, acid-addition salts can be formed by treating these
compounds with pharmaceutically acceptable organic and inorganic
acids, for example hydrogen halides, such as hydrogen chloride,
hydrogen bromide or hydrogen iodide, other mineral acids and
corresponding salts thereof, such as sulfate, nitrate or phosphate
and the like, and alkyl- and monoarylsulfonates, such as
ethanesulfonate, toluenesulfonate and benzenesulfonate, and other
organic acids and corresponding salts thereof, such as acetate,
trifluoroacetate, tartrate, maleate, succinate, citrate, benzoate,
salicylate, ascorbate and the like. Accordingly, pharmaceutically
acceptable acid-addition salts of the compounds according to the
invention include the following: acetate, adipate, alginate,
arginate, aspartate, benzoate, benzenesulfonate (besylate),
bisulfate, bisulfite, bromide, butyrate, camphorate,
camphorsulfonate, caprylate, chloride, chlorobenzoate, citrate,
cyclopentanepropionate, digluconate, dihydrogenphosphate,
dinitrobenzoate, dodecylsulfate, ethanesulfonate, fumarate,
galacterate (from mucic acid), galacturonate, glucoheptanoate,
gluconate, glutamate, glycerophosphate, hemisuccinate, hemisulfate,
heptanoate, hexanoate, hippurate, hydrochloride, hydrobromide,
hydroiodide, 2-hydroxyethanesulfonate, iodide, isethionate,
isobutyrate, lactate, lactobionate, malate, maleate, malonate,
mandelate, metaphosphate, methanesulfonate, methylbenzoate,
monohydrogenphosphate, 2-naphthalenesulfonate, nicotinate, nitrate,
oxalate, oleate, palmoate, pectinate, persulfate, phenylacetate,
3-phenylpropionate, phosphate, phosphonate, phthalate, but this
does not represent a restriction.
[0110] With regard to that stated above, it can be seen that the
expressions "pharmaceutically acceptable salt" and "physiologically
acceptable salt", which are used interchangeable herein, in the
present connection are taken to mean an active ingredient which
comprises a compound according to the invention in the form of one
of its salts, in particular if this salt form imparts improved
pharmacokinetic properties on the active ingredient compared with
the free form of the active ingredient or any other salt form of
the active ingredient used earlier. The pharmaceutically acceptable
salt form of the active ingredient can also provide this active
ingredient for the first time with a desired pharmacokinetic
property which it did not have earlier and can even have a positive
influence on the pharmacodynamics of this active ingredient with
respect to its therapeutic efficacy in the body.
[0111] Object of the present invention is also the use of compounds
according to formula (I) and/or physiologically acceptable salts
thereof for modulating an FSH receptor, particularly in the
presence of FSH. The term "modulation" denotes any change in
FSHR-mediated signal transduction, which is based on the action of
the specific inventive compounds capable to interact with the FSHR
target in such a manner that makes recognition, binding and
activating possible. The compounds are characterized by such a high
affinity to FSHR, which ensures a reliable binding and preferably a
positive allosteric modulation of FSHR. More preferably, the
substances are mono-specific in order to guarantee an exclusive and
directed recognition with the single FSHR target. In the context of
the present invention, the term "recognition"--without being
limited thereto--relates to any type of interaction between the
specific compounds and the target, particularly covalent or
non-covalent binding or association, such as a covalent bond,
hydrophobic/hydrophilic interactions, van der Waals forces, ion
pairs, hydrogen bonds, ligand-receptor interactions, and the like.
Such association may also encompass the presence of other molecules
such as peptides, proteins or nucleotide sequences. The present
receptor/ligand-interaction is characterized by high affinity, high
selectivity and minimal or even lacking cross-reactivity to other
target molecules to exclude unhealthy and harmful impacts to the
treated subject.
[0112] A preferred object of the present invention relates to a
method for modulating an FSH receptor, preferably in a positive
allosteric manner, wherein a system capable of expressing the FSH
receptor, preferably expressing the FSH receptor, is contacted,
preferably in the presence of FSH, with at least one compound of
formula (I)
##STR00302##
wherein [0113] R, L denote independently from one another Ar.sup.1,
Het.sup.1, A or OY; [0114] R.sup.1 denotes Hal, A,
--(CY.sub.2).sub.p--OY, --(CY.sub.2).sub.p--NY.sub.2, COOY,
CONY.sub.2, NHCOY, CN, SO.sub.2Y, -E-(CY.sub.2).sub.p--Ar.sup.2,
-E-(CY.sub.2).sub.p-Het.sup.1 or -E-(CY.sub.2).sub.p-Het.sup.3;
[0115] R.sup.2 denotes Hal, A, --(CY.sub.2).sub.p--OY,
--(CY.sub.2).sub.p--NY.sub.2, COY, COOY, CONY.sub.2, --CONY-Cyc,
--O-Cyc, NO.sub.2, CN, SY, SOY, SO.sub.2Y, SO.sub.2NY.sub.2,
NHSO.sub.2Y, alkenyl or -E-(CY.sub.2).sub.p--Ar.sup.2; [0116]
R.sup.3, R.sup.4, R.sup.5, R.sup.6 denote independently from one
another H, A or Ar.sup.2; [0117] R.sup.7 denotes Y, OY or NY.sub.2;
[0118] X.sup.1, X.sup.2, X.sup.3, X.sup.4 denote independently from
one another O, NY or a single bond; [0119] E denotes --C.ident.C--,
SO.sub.2, --SO.sub.2--NY--, O, NY or a single bond; [0120] Y
denotes H or A; [0121] A denotes unbranched or branched alkyl
having 1-10 C atoms, [0122] in which 1-7 H atoms can be replaced by
Hal; [0123] Cyc denotes cycloalkyl having 3-7 C atoms, [0124] in
which 1-4 H atoms can be replaced independently from one another by
Hal or A; [0125] Ar.sup.1 denotes a saturated, unsaturated or
aromatic, mono- or bicyclic carbocycle having 3-10 C atoms, [0126]
which can be substituted by at least one substituent selected from
the group of R.sup.1, R.sup.2 and --C.ident.C--C(A).sub.2OH, and/or
which can be fused to Cyc, Het.sup.1 or Het.sup.3; [0127] Ar.sup.2
denotes an aromatic, mono- or bicyclic carbocycle having 6-10 C
atoms, which can be substituted by at least one substituent
selected from the group of Hal, A and --(CY.sub.2).sub.p--OY;
[0128] Het.sup.1 denotes an unsaturated or aromatic mono- or
bicyclic heterocycle having 3-8 C atoms and 1-4 N, O and/or S
atoms, which can be substituted by at least one substituent
selected from the group of Hal, A, --(CY.sub.2).sub.p--OY,
--(CY.sub.2).sub.p--NY.sub.2, --(CY.sub.2).sub.p--Ar.sup.2,
--CO--Ar.sup.2, SO.sub.2--Ar.sup.2, --(CY.sub.2).sub.p-Het.sup.2,
Het.sup.3 and CN; [0129] Het.sup.2 denotes an aromatic monocyclic
heterocycle having 5-7 C atoms and 1-3 N atoms, [0130] which can be
substituted by at least one substituent selected from the group of
Hal, A and --(CY.sub.2).sub.p--OY; [0131] Het.sup.3 denotes a
saturated monocyclic heterocycle having 3-7 C atoms and 1-4 N, O
and/or S atoms, [0132] which can be substituted by at least one
substituent selected from the group of Hal, A,
--(CY.sub.2).sub.p--OY, --(CY.sub.2).sub.p--NY.sub.2, COOY, COY,
--CONY.sub.2, .dbd.O and CN; [0133] Hal denotes F, Cl, Br or I; and
[0134] m, n, p denote independently from one another 0, 1, 2, 3 or
4; and/or physiologically acceptable salts thereof, under
conditions such that said FSH receptor is modulated, preferably in
a positive allosteric manner.
[0135] Although a cellular system is preferred in the scope of the
invention, an in-vitro translation system can be alternatively used
which is based on the protein synthesis without living cells. The
cellular system is defined to be any subject provided that the
subject comprises cells. Hence, the cellular system can be selected
from the group of single cells, cell cultures, tissues, organs and
animals. The prior teaching of the present specification concerning
the compounds of formula (I), including any preferred embodiment
thereof, is valid and applicable without restrictions to the
compounds according to formula (I) and their salts when used in the
method for modulating FSHR.
[0136] The compounds according to the invention preferably exhibit
an advantageous biological activity, which is easily demonstrated
in cell culture-based assays, for example assays as described
herein or in prior art (cf. e.g. WO 2002/09706, which is
incorporated herein by reference). In such assays, the compounds
according to the invention preferably exhibit and cause an
agonistic effect. It is preferred that the compounds of the
invention have an FSHR agonist activity, as expressed by an
EC.sub.50 standard, of less than 1000 nM, more preferably less than
500 nM. "EC.sub.50" is the effective concentration of a compound at
which 50% of the maximal response of that obtained with FSH would
be obtained.
[0137] As discussed herein, these signaling pathways are relevant
for various diseases, preferably fertility disorders. Accordingly,
the compounds according to the invention are useful in the
prophylaxis and/or treatment of diseases that are dependent on the
said signaling pathways by interaction with one or more of the said
signaling pathways. The present invention therefore relates to
compounds according to the invention as modulators, preferably
agonists, more preferably positive allosteric modulators, of the
signaling pathways described herein, preferably of the
FSHR-mediated signaling pathway. The compounds of the invention are
supposed to bind to the intracellular receptor domain without a
competitive interaction with FSH, but they act as an allosteric
enhancer of FSH on its receptor. The non-competitive interaction
refers to the nature of the agonist activity exhibited by the
compounds of the invention, wherein the compounds activate FSHR
without substantially reducing the magnitude of binding of FSH to
FSHR.
[0138] The method of the invention can be performed either in-vitro
or in-vivo. The susceptibility of a particular cell to treatment
with the compounds according to the invention can be particularly
determined by in-vitro tests, whether in the course of research or
clinical application. Typically, a culture of the cell is combined
with a compound according to the invention at various
concentrations for a period of time which is sufficient to allow
the active agents to modulate FSHR activity, usually between about
one hour and one week. In-vitro treatment can be carried out using
cultivated cells from a biopsy sample or cell line. In a preferred
aspect of the invention, a follicle cell is stimulated for
maturation. The viable cells remaining after the treatment are
counted and further processed.
[0139] The host or patient can belong to any mammalian species, for
example a primate species, particularly humans; rodents, including
mice, rats and hamsters; rabbits; horses, cows, dogs, cats, etc.
Animal models are of interest for experimental investigations,
providing a model for treatment of human disease.
[0140] For identification of a signal transduction pathway and for
detection of interactions between various signal transduction
pathways, various scientists have developed suitable models or
model systems, for example cell culture models and models of
transgenic animals. For the determination of certain stages in the
signal transduction cascade, interacting compounds can be utilized
in order to modulate the signal. The compounds according to the
invention can also be used as reagents for testing FSHR-dependent
signal transduction pathways in animals and/or cell culture models
or in the clinical diseases mentioned in this application.
[0141] The use according to the previous paragraphs of the
specification may be either performed in-vitro or in-vivo models.
The modulation can be monitored by the techniques described in the
course of the present specification. The in-vitro use is preferably
applied to samples of humans suffering from fertility disorders.
Testing of several specific compounds and/or derivatives thereof
makes the selection of that active ingredient possible that is best
suited for the treatment of the human subject. The in-vivo dose
rate of the chosen derivative is advantageously pre-adjusted to the
FSHR susceptibility and/or severity of disease of the respective
subject with regard to the in-vitro data. Therefore, the
therapeutic efficacy is remarkably enhanced. Moreover, the
subsequent teaching of the present specification concerning the use
of the compounds according to formula (I) and its derivatives for
the production of a medicament for the prophylactic or therapeutic
treatment and/or monitoring is considered as valid and applicable
without restrictions to the use of the compound for the modulation
of FSHR activity if expedient.
[0142] The invention furthermore relates to a medicament comprising
at least one compound according to the invention and/or
pharmaceutically usable derivatives, salts, solvates and
stereoisomers thereof, including mixtures thereof in all ratios.
Preferably, the invention relates to a medicament comprising at
least one compound according to the invention and/or
physiologically acceptable salts thereof.
[0143] A "medicament" in the meaning of the invention is any agent
in the field of medicine, which comprises one or more compounds of
formula (I) or preparations thereof (e.g. a pharmaceutical
composition or pharmaceutical formulation) and can be used in
prophylaxis, therapy, follow-up or aftercare of patients who suffer
from diseases, which are associated with FSHR activity, in such a
way that a pathogenic modification of their overall condition or of
the condition of particular regions of the organism could establish
at least temporarily.
[0144] Consequently, the invention also relates to a pharmaceutical
composition comprising as active ingredient an effective amount of
at least one compound according to formula (I) and/or
physiologically acceptable salts thereof together with
pharmaceutically tolerable adjuvants and/or excipients.
[0145] In the meaning of the invention, an "adjuvant" denotes every
substance that enables, intensifies or modifies a specific response
against the active ingredient of the invention if administered
simultaneously, contemporarily or sequentially. Known adjuvants for
injection solutions are, for example, aluminum compositions, such
as aluminum hydroxide or aluminum phosphate, saponins, such as
QS21, muramyldipeptide or muramyltripeptide, proteins, such as
gamma-interferon or TNF, M59, squalen or polyols.
[0146] Furthermore, the active ingredient may be administered alone
or in combination with other treatments. A synergistic effect may
be achieved by using more than one compound in the pharmaceutical
composition, i.e. the compound of formula (I) is combined with at
least another agent as active ingredient, which is either another
compound of formula (I) or a compound of different structural
scaffold. The active ingredients can be used either simultaneously
or sequentially.
[0147] The present compounds are suitable for combination with
known fertility-inducing agents. Preferably, the other active
pharmaceutical ingredient is selected from the group of FSH,
.alpha.-FSH (Gonal F), .beta.-FSH, LH, hMG and
2-(4-(2-chloro-1,2-diphenylethenyl)-phenoxy)-N,N-diethyl-ethanamine
citrate (Chlomifene citrate). Further ovulation adjuncts are known
to those of skill in the art (cf. e.g. WO 2002/09706, which is
incorporated herein by reference) and are useful with the compounds
of the present invention.
[0148] The invention also relates to a set (kit) consisting of
separate packs of an effective amount of a compound according to
the invention and/or pharmaceutically acceptable salts,
derivatives, solvates and stereoisomers thereof, including mixtures
thereof in all ratios, and an effective amount of a further
medicament active ingredient. The set comprises suitable
containers, such as boxes, individual bottles, bags or ampoules.
The set may, for example, comprise separate ampoules, each
containing an effective amount of a compound according to the
invention and/or pharmaceutically acceptable salts, derivatives,
solvates and stereoisomers thereof, including mixtures thereof in
all ratios, and an effective amount of a further medicament active
ingredient in dissolved or lyophilized form.
[0149] Pharmaceutical formulations can be adapted for
administration via any desired suitable method, for example by oral
(including buccal or sublingual), rectal, nasal, topical (including
buccal, sublingual or transdermal), vaginal or parenteral
(including subcutaneous, intramuscular, intravenous or intradermal)
methods. Such formulations can be prepared using all processes
known in the pharmaceutical art by, for example, combining the
active ingredient with the excipient(s) or adjuvant(s).
[0150] The pharmaceutical composition of the invention is produced
in a known way using common solid or liquid carriers, diluents
and/or additives and usual adjuvants for pharmaceutical engineering
and with an appropriate dosage. The amount of excipient material
that is combined with the active ingredient to produce a single
dosage form varies depending upon the host treated and the
particular mode of administration. Suitable excipients include
organic or inorganic substances that are suitable for the different
routes of administration, such as enteral (e.g. oral), parenteral
or topical application, and which do not react with compounds of
formula (I) or salts thereof. Examples of suitable excipients are
water, vegetable oils, benzyl alcohols, alkylene glycols,
polyethylene glycols, glycerol triacetate, gelatin, carbohydrates,
e.g. lactose or starch, magnesium stearate, talc and petroleum
jelly.
[0151] Pharmaceutical formulations adapted for oral administration
can be administered as separate units, such as, for example,
capsules or tablets; powders or granules; solutions or suspensions
in aqueous or non-aqueous liquids; edible foams or foam foods; or
oil-in-water liquid emulsions or water-in-oil liquid emulsions.
[0152] Pharmaceutical formulations adapted for parenteral
administration include aqueous and non-aqueous sterile injection
solutions comprising antioxidants, buffers, bacteriostatics and
solutes, by means of which the formulation is rendered isotonic
with the blood of the recipient to be treated; and aqueous and
non-aqueous sterile suspensions, which may comprise suspension
media and thickeners. The formulations can be administered in
single-dose or multi-dose containers, for example sealed ampoules
and vials, and stored in freeze-dried (lyophilized) state, so that
only the addition of the sterile carrier liquid, for example water
for injection purposes, immediately before use is necessary.
Injection solutions and suspensions prepared in accordance with the
recipe can be prepared from sterile powders, granules and
tablets.
[0153] It goes without saying that, in addition to the above
particularly mentioned constituents, the formulations may also
comprise other agents usual in the art with respect to the
particular type of formulation; thus, for example, formulations
which are suitable for oral administration may comprise
flavors.
[0154] In a preferred embodiment of the present invention, the
pharmaceutical composition is adapted for oral administration. The
preparations can be sterilized and/or can comprise auxiliaries,
such as carrier proteins (e.g. serum albumin), lubricants,
preservatives, stabilizers, fillers, chelating agents,
antioxidants, solvents, bonding agents, suspending agents, wetting
agents, emulsifiers, salts (for influencing the osmotic pressure),
buffer substances, colorants, flavorings and one or more further
active substances, for example one or more vitamins. Additives are
well known in the art, and they are used in a variety of
formulations.
[0155] The terms "effective amount" or "effective dose" or "dose"
are interchangeably used herein and denote an amount of the
pharmaceutical compound having a prophylactically or
therapeutically relevant effect on a disease or pathological
conditions, i.e. which causes in a tissue, system, animal or human
a biological or medical response which is sought or desired, for
example, by a researcher or physician. A "prophylactic effect"
reduces the likelihood of developing a disease or even prevents the
onset of a disease. A "therapeutically relevant effect" relieves to
some extent one or more symptoms of a disease or returns to
normality either partially or completely one or more physiological
or biochemical parameters associated with or causative of the
disease or pathological conditions. In addition, the expression
"therapeutically effective amount" denotes an amount which,
compared with a corresponding subject who has not received this
amount, has the following consequence: improved treatment, healing,
prevention or elimination of a disease, syndrome, condition,
complaint, disorder or side-effects or also the reduction in the
advance of a disease, complaint or disorder. The expression
"therapeutically effective amount" also encompasses the amounts
which are effective for increasing normal physiological
function.
[0156] The respective dose or dosage range for administering the
pharmaceutical composition according to the invention is
sufficiently high in order to achieve the desired prophylactic or
therapeutic effect of reducing symptoms of the aforementioned
diseases, cancer and/or fibrotic diseases. It will be understood
that the specific dose level, frequency and period of
administration to any particular human will depend upon a variety
of factors including the activity of the specific compound
employed, the age, body weight, general state of health, gender,
diet, time and route of administration, rate of excretion, drug
combination and the severity of the particular disease to which the
specific therapy is applied. Using well-known means and methods,
the exact dose can be determined by one of skill in the art as a
matter of routine experimentation. The prior teaching of the
present specification is valid and applicable without restrictions
to the pharmaceutical composition comprising the compounds of
formula (I) if expedient.
[0157] Pharmaceutical formulations can be administered in the form
of dosage units which comprise a predetermined amount of active
ingredient per dosage unit. The concentration of the
prophylactically or therapeutically active ingredient in the
formulation may vary from about 0.1 to 100 wt %. Preferably, the
compound of formula (I) or the pharmaceutically acceptable salts
thereof are administered in doses of approximately 0.5 to 1000 mg,
more preferably between 1 and 700 mg, most preferably 5 and 100 mg
per dose unit. Generally, such a dose range is appropriate for
total daily incorporation. In other terms, the daily dose is
preferably between approximately 0.02 and 100 mg/kg of body weight.
The specific dose for each patient depends, however, on a wide
variety of factors as already described in the present
specification (e.g. depending on the condition treated, the method
of administration and the age, weight and condition of the
patient). Preferred dosage unit formulations are those which
comprise a daily dose or part-dose, as indicated above, or a
corresponding fraction thereof of an active ingredient.
Furthermore, pharmaceutical formulations of this type can be
prepared using a process which is generally known in the
pharmaceutical art.
[0158] Although a therapeutically effective amount of a compound
according to the invention has to be ultimately determined by the
treating doctor or vet by considering a number of factors (e.g. the
age and weight of the animal, the precise condition that requires
treatment, severity of condition, the nature of the formulation and
the method of administration), an effective amount of a compound
according to the invention for the treatment of neoplastic growth,
for example colon or breast carcinoma, is generally in the range
from 0.1 to 100 mg/kg of body weight of the recipient (mammal) per
day and particularly typically in the range from 1 to 10 mg/kg of
body weight per day. Thus, the actual amount per day for an adult
mammal weighing 70 kg is usually between 70 and 700 mg, where this
amount can be administered as a single dose per day or usually in a
series of part-doses (such as, for example, two, three, four, five
or six) per day, so that the total daily dose is the same. An
effective amount of a salt or solvate or of a physiologically
functional derivative thereof can be determined as the fraction of
the effective amount of the compound according to the invention per
se. It can be assumed that similar doses are suitable for the
treatment of other conditions mentioned above.
[0159] The pharmaceutical composition of the invention can be
employed as medicament in human and veterinary medicine. According
to the invention, the compounds of formula (I) and/or
physiologically salts thereof are suited for the prophylactic or
therapeutic treatment and/or monitoring of diseases that are
caused, mediated and/or propagated by FSHR activity. It is
particularly preferred that the diseases are fertility disorders.
It shall be understood that the host of the compound is included in
the present scope of protection according to the present
invention.
[0160] Particular preference is given to the stimulation of
follicular development, ovulation induction, controlled ovarial
hyperstimulation, assisted reproductive technology, including
in-vitro fertilization, male hypogonadism and male infertility,
including some types of failure of spermatogenesis.
[0161] The invention also relates to the use of compounds according
to formula (I) and/or physiologically acceptable salts thereof for
the prophylactic or therapeutic treatment and/or monitoring of
diseases that are caused, mediated and/or propagated by FSHR
activity. Furthermore, the invention relates to the use of
compounds according to formula (I) and/or physiologically
acceptable salts thereof for the production of a medicament for the
prophylactic or therapeutic treatment and/or monitoring of diseases
that are caused, mediated and/or propagated by FSHR activity.
Compounds of formula (I) and/or a physiologically acceptable salt
thereof can furthermore be employed as intermediate for the
preparation of further medicament active ingredients. The
medicament is preferably prepared in a non-chemical manner, e.g. by
combining the active ingredient with at least one solid, fluid
and/or semi-fluid carrier or excipient, and optionally in
conjunction with a single or more other active substances in an
appropriate dosage form.
[0162] Another object of the present invention are compounds
according to formula (I) and/or physiologically acceptable salts
thereof for use in the prophylactic or therapeutic treatment and/or
monitoring of diseases that are caused, mediated and/or propagated
by FSHR activity. Another preferred object of the invention
concerns compounds of formula (I)
##STR00303##
wherein [0163] R, L denote independently from one another Ar.sup.1,
Het.sup.1, A or OY; [0164] R.sup.1 denotes Hal, A,
--(CY.sub.2).sub.p--OY, --(CY.sub.2).sub.p--NY.sub.2, COOY,
CONY.sub.2, NHCOY, CN, SO.sub.2Y, -E-(CY.sub.2).sub.p--Ar.sup.2,
-E-(CY.sub.2).sub.p-Het.sup.1 or -E-(CY.sub.2).sub.p-Het.sup.3;
[0165] R.sup.2 denotes Hal, A, --(CY.sub.2).sub.p--OY,
--(CY.sub.2).sub.p--NY.sub.2, COY, COOY, CONY.sub.2, --CONY-Cyc,
--O-Cyc, NO.sub.2, CN, SY, SOY, SO.sub.2Y, SO.sub.2NY.sub.2,
NHSO.sub.2Y, alkenyl or -E-(CY.sub.2).sub.p--Ar.sup.2; [0166]
R.sup.3, R.sup.4, R.sup.5, R.sup.6 denote independently from one
another H, A or Ar.sup.2; [0167] R.sup.7 denotes Y, OY or NY.sub.2;
[0168] X.sup.1, X.sup.2, X.sup.3, X.sup.4 denote independently from
one another O, NY or a single bond; [0169] E denotes --C.ident.C--,
SO.sub.2, --SO.sub.2--NY--, O, NY or a single bond; [0170] Y
denotes H or A; [0171] A denotes unbranched or branched alkyl
having 1-10 C atoms, [0172] in which 1-7 H atoms can be replaced by
Hal; [0173] Cyc denotes cycloalkyl having 3-7 C atoms, [0174] in
which 1-4 H atoms can be replaced independently from one another by
Hal or A; [0175] Ar.sup.1 denotes a saturated, unsaturated or
aromatic, mono- or bicyclic carbocycle having 3-10 C atoms, [0176]
which can be substituted by at least one substituent selected from
the group of R.sup.1, R.sup.2 and --C.ident.C--C(A).sub.2OH, and/or
which can be fused to Cyc, Het.sup.1 or Het.sup.3; [0177] Ar.sup.2
denotes an aromatic, mono- or bicyclic carbocycle having 6-10 C
atoms, which can be substituted by at least one substituent
selected from the group of Hal, A and --(CY.sub.2).sub.p--OY;
[0178] Het.sup.1 denotes an unsaturated or aromatic mono- or
bicyclic heterocycle having 3-8 C atoms and 1-4 N, O and/or S
atoms, [0179] which can be substituted by at least one substituent
selected from the group of Hal, A, --(CY.sub.2).sub.p--OY,
--(CY.sub.2).sub.p--NY.sub.2, --(CY.sub.2).sub.p--Ar.sup.2,
--CO--Ar.sup.2, SO.sub.2--Ar.sup.2, --(CY.sub.2).sub.p-Het.sup.2,
Het.sup.3 and CN; [0180] Het.sup.2 denotes an aromatic monocyclic
heterocycle having 5-7 C atoms and 1-3 N atoms, [0181] which can be
substituted by at least one substituent selected from the group of
Hal, A and --(CY.sub.2).sub.p--OY; [0182] Het.sup.3 denotes a
saturated monocyclic heterocycle having 3-7 C atoms and 1-4 N, O
and/or S atoms, [0183] which can be substituted by at least one
substituent selected from the group of Hal, A,
--(CY.sub.2).sub.p--OY, --(CY.sub.2).sub.p--NY.sub.2, COOY, COY,
--CONY.sub.2, .dbd.O and CN; [0184] Hal denotes F, Cl, Br or I; and
[0185] m, n, p denote independently from one another 0, 1, 2, 3 or
4; and/or physiologically acceptable salts thereof for use in the
prophylactic or therapeutic treatment and/or monitoring of
fertility disorders.
[0186] The prior teaching of the present specification concerning
the compounds of formula (I), including any preferred embodiment
thereof, is valid and applicable without restrictions to the
compounds according to formula (I) and their salts for use in the
prophylactic or therapeutic treatment and/or monitoring of
fertility disorders.
[0187] The compounds of formula (I) according to the invention can
be administered before or following an onset of disease once or
several times acting as therapy. The aforementioned compounds and
medical products of the inventive use are particularly used for the
therapeutic treatment. A therapeutically relevant effect relieves
to some extent one or more symptoms of a disorder, or returns to
normality, either partially or completely, one or more
physiological or biochemical parameters associated with or
causative of a disease or pathological condition. Monitoring is
considered as a kind of treatment provided that the compounds are
administered in distinct intervals, e.g. in order to booster the
response and eradicate the pathogens and/or symptoms of the disease
completely. Either the identical compound or different compounds
can be applied. The medicament can also be used to reducing the
likelihood of developing a disorder or even prevent the initiation
of disorders associated with FSHR activity in advance or to treat
the arising and continuing symptoms. The disorders as concerned by
the invention are preferably fertility disorders.
[0188] In the meaning of the invention, prophylactic treatment is
advisable if the subject possesses any preconditions for the
aforementioned physiological or pathological conditions, such as a
familial disposition, a genetic defect, or a previously passed
disease.
[0189] It is another object of the invention to provide a method
for treating diseases that are caused, mediated and/or propagated
by FSHR activity, wherein an effective amount of at least one
compound of formula (I) and/or physiologically acceptable salts
thereof is administered to a mammal in need of such treatment. It
is another preferred object of the invention to provide a method
for treating fertility disorders, wherein an effective amount of at
least one compound of formula (I) and/or physiologically acceptable
salts thereof is administered to a mammal in need of such
treatment. The preferred treatment is an oral administration. In
another preferred aspect, the method of treatment aims to achieve
ovulation induction and/or controlled ovarian hyperstimulation. In
still another preferred aspect, the method of treatment forms the
basis for a method for in-vitro fertilization comprising the steps
of: (a) treating a mammal according to the method of treatment as
described above, (b) collecting ova from said mammal, (c)
fertilizing said ova, and (d) implanting said fertilized ova into a
host mammal. The host mammal can be either the treated mammal (i.e.
the patient) or a surrogate. The prior teaching of the invention
and its embodiments is valid and applicable without restrictions to
the methods of treatment if expedient.
[0190] In the scope of the present invention, novel dihydropyrazole
compounds of formula (I) are provided for the first time. The low
molecular weight compounds of the invention are strong and
selective modulators of the FSH receptor. Their selectivity to the
FSH receptor is 10-fold over the LH receptor and even 100-fold over
the TSH receptor while the IC.sub.50 amounts to more than 10 .mu.M
on unrelated G protein-coupled receptors (GPCR) or non-GPCR
targets. The current invention comprises the use of present
dihydropyrazole derivatives in the regulation and/or modulation of
the FSHR signal cascade, which can be advantageously applied as
research tool, for diagnosis and/or in treatment of any disorder
arising from FSHR signaling.
[0191] For example, the compounds of the invention are useful
in-vitro as unique tools for understanding the biological role of
FSH, including the evaluation of the many factors thought to
influence, and be influenced by, the production of FSH and the
interaction of FSH with the FSHR (e. g. the mechanism of FSH signal
transduction/receptor activation). The present compounds are also
useful in the development of other compounds that interact with
FSHR since the present compounds provide important
structure-activity relationship (SAR) information that facilitate
that development. Compounds of the present invention that bind to
FSHR can be used as reagents for detecting FSHR on living cells,
fixed cells, in biological fluids, in tissue homogenates, in
purified, natural biological materials, etc. For example, by
labeling such compounds, one can identify cells having FSHR on
their surfaces. In addition, based on their ability to bind FSHR,
compounds of the present invention can be used in in-situ staining,
FACS (fluorescence-activated cell sorting), western blotting, ELISA
(enzyme-linked immunoadsorptive assay), etc., receptor
purification, or in purifying cells expressing FSHR on the cell
surface or inside permeabilized cells.
[0192] The compounds of the invention can also be utilized as
commercial research reagents for various medical research and
diagnostic uses. Such uses can include but are not limited to: use
as a calibration standard for quantifying the activities of
candidate FSH agonists in a variety of functional assays; use as
blocking reagents in random compound screening, i.e. in looking for
new families of FSH receptor ligands, the compounds can be used to
block recovery of the presently claimed FSH compounds; use in the
co-crystallization with FSHR receptor, i.e. the compounds of the
present invention will allow formation of crystals of the compound
bound to FSHR, enabling the determination of receptor/compound
structure by x-ray crystallography; other research and diagnostic
applications, wherein FSHR is preferably activated or such
activation is conveniently calibrated against a known quantity of
an FSH agonist, etc.; use in assays as probes for determining the
expression of FSHR on the surface of cells; and developing assays
for detecting compounds which bind to the same site as the FSHR
binding ligands.
[0193] The low molecular weight inhibitors can be applied either
themselves and/or in combination with physical measurements for
diagnostics of treatment effectiveness. Medicaments and
pharmaceutical compositions containing said compounds and the use
of said compounds to treat FSHR-mediated conditions is a promising,
novel approach for a broad spectrum of therapies causing a direct
and immediate improvement in the state of health, whether in man
and animal. The impact is of special benefit to efficiently combat
infertility, either alone or in combination with other
fertility-inducing treatments. In particular, the compounds of the
invention potentiate the native FSH effect for both ovulation
induction and assisted reproductive technology. The orally
bioavailable and active new chemical entities of the invention
improve convenience for patients and compliance for physicians. The
PK properties permit an administration twice daily.
[0194] The compounds of the invention have Log P lower than 4, a
solubility of more than 5 mg/ml in an acceptable vehicle
(preferably more than 10 mg/ml), and they are active in the primary
screen (0.1 nM CHO cells+FSHR; inactive in absence of FSHR),
secondary screen (preferably 10-100 nM), chimeric receptor
(TSHR/FSHR) screen (preferably 50-500 nM), granulosa cell aromatase
assay (preferably 1-10 nM) and ovulation induction assay
(preferably 0.5-50 mg/kg bid). Due to the surprisingly strong,
selective and positive allosteric modulation of FSHR, the compounds
of the invention can be advantageously administered at lower doses
compared to other less potent or selective agonists of prior art
while still achieving equivalent or even superior desired
biological effects. In addition, such a dose reduction
advantageously leads to less or even no medicinal adverse effects.
Neither hERG nor any toxic effects could be observed in-vitro or
in-vivo.
[0195] The compounds of formula (I), their salts, isomers,
tautomers, enantiomeric forms, diastereomers, racemates,
derivatives, prodrugs and/or metabolites are characterized by a
high specificity and stability, low manufacturing costs and
convenient handling. These features form the basis for a
reproducible action, wherein the lack of cross-reactivity is
included, and for a reliable and safe interaction with the target
structure.
[0196] All the references cited herein are incorporated by
reference in the disclosure of the invention hereby.
[0197] It is to be understood that this invention is not limited to
the particular compounds, pharmaceutical compositions, uses and
methods described herein, as such matter may, of course, vary. It
is also to be understood that the terminology used herein is for
the purpose of describing particular embodiments only and is not
intended to limit the scope of the present invention, which is only
defined by the appended claims. As used herein, including the
appended claims, singular forms of words such as "a," "an," and
"the" include their corresponding plural referents unless the
context clearly dictates otherwise. Thus, e.g., reference to "a
compound" includes a single or several different compounds, and
reference to "a method" includes reference to equivalent steps and
methods known to a person of ordinary skill in the art, and so
forth. Unless otherwise defined, all technical and scientific terms
used herein have the same meaning as commonly understood by a
person of ordinary skill in the art to which this invention
belongs.
[0198] The techniques that are essential according to the invention
are described in detail in the specification. Other techniques
which are not described in detail correspond to known standard
methods that are well known to a person skilled in the art, or the
techniques are described in more detail in cited references, patent
applications or standard literature. Although methods and materials
similar or equivalent to those described herein can be used in the
practice or testing of the present invention, suitable examples are
described below. The following examples are provided by way of
illustration and not by way of limitation. Within the examples,
standard reagents and buffers that are free from contaminating
activities (whenever practical) are used. The example are
particularly to be construed such that they are not limited to the
explicitly demonstrated combinations of features, but the
exemplified features may be unrestrictedly combined again if the
technical problem of the invention is solved. Similarly, the
features of any claim can be combined with the features of one or
more other claims.
[0199] In the following examples, "conventional workup" means:
water was added if necessary, the pH was adjusted, if necessary, to
a value of between 2 and 10, depending on the constitution of the
end product, the mixture was extracted with ethyl acetate or
dichloromethane, the phases were separated, the organic phase was
dried over sodium sulfate and evaporated, and the product was
purified by chromatography on silica gel and/or by crystallization.
R.sub.f values were determined on silica gel. The eluent was ethyl
acetate/methanol 9:1.
[0200] Standard description of analytical equipment
[0201] NMR Spectra were acquired on a Varian .sup.UnityInova 400
MHz NMR spectrometer equipped with an Automation Triple Broadband
(ATB) probe. The ATB probe was simultaneously tuned to .sup.1H,
.sup.19F and .sup.13C. For typical .sup.1H NMR spectra, the pulse
angle was 45 degrees, 8 scans were summed and the spectral width
was 16 ppm (-2 ppm to 14 ppm). A total of 32768 complex points were
collected during the 5.1 second acquisition time, and the recycle
delay was set to 1 second. Spectra were collected at 25.degree. C.
.sup.1H NMR Spectra are typically processed with 0.2 Hz line
broadening and zero-filling to 131072 points prior to Fourier
transformation.
[0202] Method A (Rapid LC): A Shimadzu Shim-pack XR-ODS,
3.0.times.30 mm, 2.2 .mu.m, was used at a temperature of 50.degree.
C. and at a flow rate of 1.5 mL/min, 2 .mu.L injection, mobile
phase: (A) water with 0.1% formic acid and 1% acetonitrile, mobile
phase (B) methanol with 0.1% formic acid; retention time given in
minutes. Method details: (I) runs on a Binary Pump G1312B with
UV/Vis diode array detector G1315C and Agilent 6130 mass
spectrometer in positive and negative ion electrospray mode with
UV-detection at 220 and 254 nm with a gradient of 15-95% (B) in a
2.2 min linear gradient (II) hold for 0.8 min at 95% (B) (Ill)
decrease from 95-15% (B) in a 0.1 min linear gradient (IV) hold for
0.29 min at 15% (B).
[0203] Method B (Polar Stop-Gap): An Agilent Zorbax Bonus RP,
2.1.times.50 mm, 3.5 .mu.m, was used at a temperature of 50.degree.
C. and at a flow rate of 0.8 mL/min, 2 .mu.L injection, mobile
phase: (A) water with 0.1% formic acid and 1% acetonitrile, mobile
phase (B) methanol with 0.1% formic acid; retention time given in
minutes. Method details: (I) runs on a Binary Pump G1312B with
UV/Vis diode array detector G1315C and Agilent 6130 mass
spectrometer in positive and negative ion electrospray mode with
UV-detection at 220 and 254 nm with a gradient of 5-95% (B) in a
2.5 min linear gradient (II) hold for 0.5 min at 95% (B) (Ill)
decrease from 95-5% (B) in a 0.1 min linear gradient (IV) hold for
0.29 min at 5% (B).
[0204] Preparative HPLC--was performed using a system controlled by
Chromeleon software and consisting of two Varian PrepStar Model 218
Pumps, a Varian ProStar Model 320 UV/Vis detector, a SEDEX 55 ELSD
detector, and a Gilson 215 liquid handler. Typical HPLC--mobile
phases consist of water and methanol. The standard column is a
Varian Dynamax 21.4 mm diameter Microsorb Guard-8 C18 column.
Example 1: Synthetic Route Towards
[3-(3,4-dimethoxy-phenyl)-5,5-dimethyl-4,5-dihydro-pyrazol-1-yl]-phenyl-m-
ethanones
##STR00304##
[0206] It shall be understood that the phenyl moiety (radical R)
can be substituted in accordance with the Ar.sup.1 definition as
demonstrated below.
Step 1
##STR00305##
[0208] 1-(3,4-dimethoxy-phenyl)-3-methyl-but-2-en-1-one. A round
bottom flask equipped with a stir bar and nitrogen inlet was
charged with veratrole (2.5 mL, 20 mmol), 3,3-dimethyl acryloyl
chloride (2.2 mL, 20 mmol) and dry CH.sub.2Cl.sub.2, (100 mL). The
solution was cooled to 0.degree. C. and AlCl.sub.3 (2.6 g, 20 mmol)
was added portionwise. On completion of addition, the cooling bath
was removed and the reaction was allowed 3 h. TLC showed
consumption of SM. It was added to saturated NH.sub.4Cl (100 mL)
and stirred vigourously for 15 min. The phases were separated and
the CH.sub.2Cl.sub.2 phase was washed with saturated
Na.sub.2CO.sub.3 (100 mL), washed with brine, (100 mL), dried
(Na.sub.2SO.sub.4) and the solvent was evaporated under reduced
pressure. The material was used as is in the next step. Amount
obtained: 4.3 g, 19.5 mmol, 98% yield. LC-MS (ESI) m/e 221 (M+H).
.sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 2.02 (s, 3H) 2.20
(s, 3H) 3.96 (s, 6H) 6.73 (s, 1H) 6.89 (d, J=8.20 Hz, 1H) 7.53-7.60
(m, 2H).
Step 2
##STR00306##
[0210]
3-(3,4-Dimethoxy-phenyl)-5,5-dimethyl-4,5-dihydro-1H-pyrazole. A
100 mL round bottom flask equipped with a stir bar, Vigreux column
and nitrogen inlet was charged with
1-(3,4-dimethoxy-phenyl)-3-methyl-but-2-en-1-one (1.4 g, 10 mmol),
EtOH (40 mL) and hydrazine monohydrate (0.58 mL, 12 mmol). The
mixture was heated at 80.degree. C. for 2 h. LC-MS and TLC analysis
showed consumption of SM. The solvent was evaporated under reduced
pressure and trace hydrazine and EtOH was removed under high vacuum
for 30 min. The material was used as in the next step. Amount
obtained: 2.3 g, 10 mmol, 100% yield. LC-MS (ESI) m/e 235
(M+H).
Step 3
##STR00307##
[0212]
[3-(3,4-Dimethoxy-phenyl)-5,5-dimethyl-4,5-dihydro-pyrazol-1-yl]-(3-
-fluoro-phenyl)-methanone (129). A scintillation vial equipped with
a stir bar was charged with
3-(3,4-dimethoxy-phenyl)-5,5-dimethyl-4,5-dihydro-1H-pyrazole (469
mg, 2 mmol), Hunigs base (1 mL, 6 mmol) and dry CH.sub.2Cl.sub.2
(10 mL). To this mixture was added 3-fluorobenzoyl chloride (0.23
mL, 2 mmol) and the reaction was stirred at RT for 3 h. LC-MS
indicated consumption of SM. The mixture was diluted with
CH.sub.2Cl.sub.2 (50 mL) and added to water (50 mL). The phases
were separated and the CH.sub.2Cl.sub.2 phase was washed with
saturated Na.sub.2CO.sub.3 (50 mL), brine (50 mL), dried
(Na.sub.2SO.sub.4) and the solvent was evaporated under reduced
pressure. The material was purified using a 40 g silica cartridge
eluting with heptane-EtOAc, gradient 0 to 50% EtOAc. Amount
obtained: 350 mg, 1 mmol, 50% yield. LC-MS (ESI) m/e 357 (M+H).
.sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 1.79 (s, 6H) 3.17
(s, 2H) 3.88 (s, 3H) 3.93 (s, 3H) 6.87 (d, J=8.35 Hz, 1H) 7.10 (dd,
J=8.32, 1.83 Hz, 1H) 7.15 (td, J=8.33, 2.03 Hz, 1H) 7.28 (d, J=1.76
Hz, 1H) 7.38 (td, J=7.92, 5.88 Hz, 1H) 7.62-7.69 (m, 2H).
[0213] The following compounds were prepared with the same
procedure as
[3-(3,4-Dimethoxy-phenyl)-5,5-dimethyl-4,5-dihydro-pyrazol-1-yl]-(3-fluor-
o-phenyl)-methanone (129):
##STR00308##
[0214]
[1,3]Dioxol-5-yl-[3-(3,4-dimethoxy-phenyl)-5,5-dimethyl-4,5-dihydro-
-pyrazol-1-yl]-methanone (131). Amount obtained: 382 mg, 1 mmol,
50% yield. LC-MS (ESI) m/e 383 (M+H). .sup.1H NMR (400 MHz,
CHLOROFORM-d) .delta. ppm 1.77 (s, 6H) 3.14 (s, 2H) 3.90 (s, 3H)
3.93 (s, 3H) 6.02 (s, 2H) 6.86 (dd, J=14.91, 8.27 Hz, 2H) 7.12 (dd,
J=8.30, 1.85 Hz, 1H) 7.30 (d, J=1.76 Hz, 1H) 7.46 (d, J=1.46 Hz,
1H) 7.53 (dd, J=8.20, 1.56 Hz, 1H).
##STR00309##
[0215]
3-[3-(3,4-Dimethoxy-phenyl)-5,5-dimethyl-4,5-dihydro-pyrazole-1-car-
bonyl]-benzonitrile (132). Amount obtained: 471 mg, 1.2 mmol, 60%
yield. LC-MS (ESI) m/e 364 (M+H). .sup.1H NMR (400 MHz,
CHLOROFORM-d) .delta. ppm 1.80 (s, 6H) 3.19 (s, 2H) 3.91 (s, 3H)
3.93 (s, 3H) 6.88 (d, J=8.30 Hz, 1H) 7.09 (dd, J=8.27, 1.78 Hz, 1H)
7.27-7.28 (m, 1H) 7.54 (t, J=7.83 Hz, 1H) 7.73 (d, J=7.71 Hz, 1H)
8.12 (d, J=7.91 Hz, 1H) 8.30 (s, 1H).
##STR00310##
[0216]
3-(3,4-Dimethoxy-phenyl)-5,5-dimethyl-4,5-dihydro-pyrazole-1-carbox-
ylic acid 3-fluoro-benzylamide (133). Amount obtained: 33 mg, 0.09
mmol, 4% yield. LC-MS (ESI) m/e 386 (M+H). .sup.1H NMR (400 MHz,
CHLOROFORM-d) .delta. ppm 1.66 (s, 6H) 3.11 (s, 2H) 3.92 (s, 3H)
3.93 (s, 3H) 4.53 (d, J=6.25 Hz, 2H) 6.47 (t, J=5.93 Hz, 1H) 6.87
(d, J=8.35 Hz, 1H) 6.92-6.99 (m, 1H) 7.08 (dd, J=8.42, 1.59 Hz, 2H)
7.14 (d, J=7.61 Hz, 1H) 7.25-7.34 (m, 2H).
##STR00311##
[0217]
[3-(3,4-Dimethoxy-phenyl)-5,5-dimethyl-4,5-dihydro-pyrazol-1-yl]-(2-
-fluoro-phenyl)-methanone (228). Amount obtained: 17.4 mg, 0.05
mmol, 2% yield. LC-MS (ESI) 357 (M+H); .sup.1H NMR (400 MHz,
CHLOROFORM-d) .delta. ppm 1.78-1.82 (m, 6H) 3.19 (s, 2H) 3.81 (s,
3H) 3.90 (s, 3H) 6.83 (d, J=8.35 Hz, 1H) 7.02-7.11 (m, 2H)
7.14-7.22 (m, 2H) 7.36-7.44 (m, 1H) 7.52-7.57 (m, 1H).
##STR00312##
[0218]
[3-(3,4-Dimethoxy-phenyl)-5,5-dimethyl-4,5-dihydro-pyrazol-1-yl]-(3-
-phenoxy-phenyl)-methanone (229). Amount obtained: 196.8 mg, 0.46
mmol, 46% yield. LC-MS (ESI) 431 (M+H); .sup.1H NMR (400 MHz,
CHLOROFORM-d) .delta. ppm 1.78 (s, 6H) 3.14 (s, 2H) 3.83 (s, 3H)
3.92 (s, 3H) 6.85 (d, J=8.30 Hz, 1H) 7.01-7.16 (m, 5H) 7.27 (s, 1H)
7.31 (t, J=7.93 Hz, 2H) 7.39 (t, J=7.93 Hz, 1H) 7.59-7.68 (m,
2H).
##STR00313##
[0219]
[3-(3,4-Dimethoxy-phenyl)-5,5-dimethyl-4,5-dihydro-pyrazol-1-yl]-(4-
-phenoxy-phenyl)-methanone (230). Amount obtained: 151.7 mg, 0.35
mmol, 35% yield. LC-MS (ESI) 431 (M+H); .sup.1H NMR (400 MHz,
CHLOROFORM-d) .delta. ppm 1.79 (s, 6H) 3.16 (s, 2H) 3.89 (s, 3H)
3.93 (s, 3H) 6.87 (d, J=8.35 Hz, 1H) 7.01 (d, J=8.74 Hz, 2H) 7.07
(d, J=7.76 Hz, 2H) 7.10-7.19 (m, 2H) 7.29 (d, J=1.71 Hz, 1H) 7.37
(t, J=7.91 Hz, 2H) 7.93 (d, J=8.74 Hz, 2H).
##STR00314##
[0220]
[3-(3,4-Dimethoxy-phenyl)-5,5-dimethyl-4,5-dihydro-pyrazol-1-yl]-(3-
-trifluoromethoxy-phenyl)-methanone (231). Amount obtained: 151.7
mg, 0.36 mmol, 36% yield. LC-MS (ESI) 423 (M+H); .sup.1H NMR (400
MHz, CHLOROFORM-d) .delta. ppm 1.79 (s, 6H) 3.18 (s, 2H) 3.87 (s,
3H) 3.93 (s, 3H) 6.87 (d, J=8.35 Hz, 1H) 7.09 (dd, J=8.32, 1.88 Hz,
1H) 7.28 (d, J=1.81 Hz, 1H) 7.31 (d, J=8.05 Hz, 1H) 7.45 (t, J=8.08
Hz, 1H) 7.81-7.87 (m, 2H).
##STR00315##
[0221]
[3-(3,4-Dimethoxy-phenyl)-5,5-dimethyl-4,5-dihydro-pyrazol-1-yl]-m--
tolyl-methanone (232). Amount obtained: 295 mg, 0.84 mmol, 42%
yield. LC-MS (ESI) 353 (M+H); .sup.1H NMR (400 MHz, CHLOROFORM-d)
.delta. ppm 1.79 (s, 6H) 2.40 (s, 3H) 3.15 (s, 2H) 3.87 (s, 3H)
3.92 (s, 3H) 6.86 (d, J=8.35 Hz, 1H) 7.09 (dd, J=8.27, 1.88 Hz, 1H)
7.28-7.32 (m, 3H) 7.67 (d, J=7.08 Hz, 1H) 7.72 (s, 1H).
##STR00316##
[0222]
(3-Bromo-phenyl)-[3-(3,4-dimethoxy-phenyl)-5,5-dimethyl-4,5-dihydro-
-pyrazol-1-yl]-methanone (233). Amount obtained: 1.6 g, 3.76 mmol,
75% yield. LC-MS (ESI) 417 & 419 (M+H); .sup.1H NMR (400 MHz,
CHLOROFORM-d) .delta. ppm 1.79 (s, 6H) 3.17 (s, 2H) 3.92 (s, 3H)
3.93 (s, 3H) 6.87 (d, J=8.30 Hz, 1H) 7.06 (dd, J=8.30, 1.85 Hz, 1H)
7.30 (t, J=7.96 Hz, 1H) 7.34 (d, J=1.71 Hz, 1H) 7.58 (d, J=7.96 Hz,
1H) 7.82 (d, J=7.76 Hz, 1H) 8.14 (s, 1H).
##STR00317##
[0223]
[3-(3,4-Dimethoxy-phenyl)-5,5-dimethyl-4,5-dihydro-pyrazol-1-yl]-(4-
-ethyl-phenyl)-methanone (259). Amount obtained: 89.6 mg, 0.24
mmol, 12% yield. LC-MS (ESI) 367 (M+H); .sup.1H NMR (400 MHz,
CHLOROFORM-d) .delta. ppm 1.27 (t, J=7.61 Hz, 3H) 1.79 (s, 6H) 2.71
(q, J=7.60 Hz, 2H) 3.15 (s, 2H) 3.89 (s, 3H) 3.92 (s, 3H) 6.87 (d,
J=8.35 Hz, 1H) 7.12 (dd, J=8.30, 1.85 Hz, 1H) 7.23 (d, J=8.10 Hz,
2H) 7.29 (d, J=1.71 Hz, 1H) 7.84 (d, J=8.20 Hz, 2H).
##STR00318##
[0224]
[3-(3,4-Dimethoxy-phenyl)-5,5-dimethyl-4,5-dihydro-pyrazol-1-yl]-(3-
-trifluoromethyl-phenyl)-methanone (234). Amount obtained: 222 mg,
0.55 mmol, 27% yield. LC-MS (ESI) 407 (M+H); .sup.1H NMR (400 MHz,
CHLOROFORM-d) .delta. ppm 1.81 (s, 6H) 3.19 (s, 2H) 3.87 (s, 3H)
3.93 (s, 3H) 6.86 (d, J=8.30 Hz, 1H) 7.05 (dd, J=8.27, 1.88 Hz, 1H)
7.32 (d, J=1.81 Hz, 1H) 7.56 (t, J=7.81 Hz, 1H) 7.71 (d, J=7.76 Hz,
1H) 8.09 (d, J=7.81 Hz, 1H) 8.30 (s, 1H).
##STR00319##
[0225]
[3-(3,4-Dimethoxy-phenyl)-5,5-dimethyl-4,5-dihydro-pyrazol-1-yl]-p--
tolyl-methanone (235). Amount obtained: 119 mg, 0.34 mmol, 17%
yield. LC-MS (ESI) 353 (M+H); .sup.1H NMR (400 MHz, CHLOROFORM-d)
.delta. ppm 1.78 (s, 6H) 2.41 (s, 3H) 3.15 (s, 2H) 3.89 (s, 3H)
3.92 (s, 3H) 6.87 (d, J=8.35 Hz, 1H) 7.11 (dd, J=8.25, 1.22 Hz, 1H)
7.21 (d, J=7.96 Hz, 2H) 7.29 (s, 1H) 7.81 (d, J=8.00 Hz, 2H).
##STR00320##
[0226]
[3-(3,4-Dimethoxy-phenyl)-5,5-dimethyl-4,5-dihydro-pyrazol-1-yl]-(4-
-fluoro-3-trifluoromethyl-phenyl)-methanone (236). Amount obtained:
69.6 mg, 0.16 mmol, 16% yield. LC-MS (ESI) 425 (M+H); .sup.1H NMR
(400 MHz, CHLOROFORM-d) .delta. ppm 1.79 (s, 6H) 3.19 (s, 2H) 3.89
(s, 3H) 3.93 (s, 3H) 6.87 (d, J=8.35 Hz, 1H) 7.06 (dd, J=8.25, 1.90
Hz, 1H) 7.22-7.26 (m, 1H) 7.31 (d, J=1.76 Hz, 1H) 8.12-8.18 (m, 1H)
8.38 (dd, J=6.98, 1.61 Hz, 1H).
##STR00321##
[0227]
(3-Chloro-4-fluoro-phenyl)-[3-(3,4-dimethoxy-phenyl)-5,5-dimethyl-4-
,5-dihydro-pyrazol-1-yl]-methanone 237). Amount obtained: 83.3 mg,
0.21 mmol, 21% yield. LC-MS (ESI) 391 (M+H); .sup.1H NMR (400 MHz,
CHLOROFORM-d) .delta. ppm 1.78 (s, 6H) 3.17 (s, 2H) 3.91 (s, 3H)
3.93 (s, 3H) 6.88 (d, J=8.30 Hz, 1H) 7.08 (dd, J=8.27, 1.73 Hz, 1H)
7.18 (t, J=8.71 Hz, 1H) 7.32 (d, J=1.66 Hz, 1H) 7.83 (ddd, J=8.50,
4.77, 2.05 Hz, 1H) 8.12 (dd, J=7.30, 1.98 Hz, 1H).
##STR00322##
[0228]
(3,4-Difluoro-phenyl)-[3-(3,4-dimethoxy-phenyl)-5,5-dimethyl-4,5-di-
hydro-pyrazol-1-yl]-methanone (246). Amount obtained: 100 mg, 0.27
mmol, 27% yield. LC-MS (ESI) 375 (M+H); .sup.1H NMR (400 MHz,
CHLOROFORM-d) .delta. ppm 1.78 (s, 6H) 3.17 (s, 2H) 3.90 (s, 3H)
3.93 (s, 3H) 6.88 (d, J=8.35 Hz, 1H) 7.11 (dd, J=8.30, 1.90 Hz, 1H)
7.15-7.24 (m, 1H) 7.28 (br. s., 1H) 7.71 (ddd, J=6.43, 4.33, 2.22
Hz, 1H) 7.84 (ddd, J=11.53, 7.94, 2.00 Hz, 1H).
##STR00323##
[0229]
(4-Chloro-phenyl)-[3-(3,4-dimethoxy-phenyl)-5,5-dimethyl-4,5-dihydr-
o-pyrazol-1-yl]-methanone (247). Amount obtained: 139 mg, 0.37
mmol, 37% yield. LC-MS (ESI) 373 (M+H); .sup.1H NMR (400 MHz,
CHLOROFORM-d) .delta. ppm 1.78 (s, 6H) 3.16 (s, 2H) 3.89 (s, 3H)
3.93 (s, 3H) 6.87 (d, J=8.35 Hz, 1H) 7.11 (dd, J=8.32, 1.83 Hz, 1H)
7.25 (d, J=1.76 Hz, 1H) 7.38 (d, J=8.54 Hz, 2H) 7.84 (d, J=8.49 Hz,
2H).
##STR00324##
[0230]
[3-(3,4-Dimethoxy-phenyl)-5,5-dimethyl-4,5-dihydro-pyrazol-1-yl]-(3-
-fluoro-4-methyl-phenyl)-methanone (249). Amount obtained: 154 mg,
0.42 mmol, 42% yield. LC-MS (ESI) 371 (M+H); .sup.1H NMR (400 MHz,
CHLOROFORM-d) .delta. ppm 1.78 (s, 6H) 2.34 (d, J=1.12 Hz, 3H) 3.15
(s, 2H) 3.90 (s, 3H) 3.93 (s, 3H) 6.87 (d, J=8.35 Hz, 1H) 7.11 (dd,
J=8.30, 1.85 Hz, 1H) 7.22 (t, J=7.76 Hz, 1H) 7.31 (d, J=1.76 Hz,
1H) 7.60-7.68 (m, 2H).
##STR00325##
[0231]
4-[3-(3,4-Dimethoxy-phenyl)-5,5-dimethyl-4,5-dihydro-pyrazole-1-car-
bonyl]-benzonitrile (250). Amount obtained: 91 mg, 0.25 mmol, 25%
yield. LC-MS (ESI) 364 (M+H); .sup.1H NMR (400 MHz, CHLOROFORM-d)
.delta. ppm 1.79 (s, 6H) 3.19 (s, 2H) 3.87 (s, 3H) 3.93 (s, 3H)
6.87 (d, J=8.35 Hz, 1H) 7.10 (dd, J=8.30, 1.90 Hz, 1H) 7.19 (d,
J=1.85 Hz, 1H) 7.71 (d, J=8.35 Hz, 2H) 7.93 (d, J=8.35 Hz, 2H).
##STR00326##
[0232]
(3-Chloro-phenyl)-[3-(3,4-dimethoxy-phenyl)-5,5-dimethyl-4,5-dihydr-
o-pyrazol-1-yl]-methanone (251). Amount obtained: 129 mg, 0.34
mmol, 34% yield. LC-MS (ESI) 373 (M+H); .sup.1H NMR (400 MHz,
CHLOROFORM-d) .delta. ppm 1.79 (s, 6H) 3.17 (s, 2H) 3.90 (s, 3H)
3.93 (s, 3H) 6.87 (d, J=8.30 Hz, 1H) 7.07 (dd, J=8.30, 1.85 Hz, 1H)
7.33 (d, J=1.95 Hz, 1H) 7.36 (d, J=7.81 Hz, 1H) 7.40-7.46 (m, 1H)
7.77 (d, J=7.66 Hz, 1H) 7.97 (t, J=1.61 Hz, 1H).
##STR00327##
[0233]
1-[3-(3,4-Dimethoxy-phenyl)-5,5-dimethyl-4,5-dihydro-pyrazol-1-yl]--
2-(3-fluoro-phenyl)-ethanone (255). Amount obtained: 33 mg, 0.09
mmol, 9% yield. LC-MS (ESI) 371 (M+H); .sup.1H NMR (400 MHz,
CHLOROFORM-d) .delta. ppm 1.65 (s, 6H) 3.10 (s, 2H) 3.94 (s, 3H)
3.96 (s, 3H) 4.05 (s, 2H) 6.88 (d, J=8.35 Hz, 1H) 6.92 (td, J=8.61,
2.29 Hz, 1H) 7.06-7.12 (m, 2H) 7.14 (d, J=7.66 Hz, 1H) 7.23-7.31
(m, 1H) 7.36 (d, J=1.76 Hz, 1H).
##STR00328##
[0234]
(4-Bromo-phenyl)-[3-(3,4-dimethoxy-phenyl)-5,5-dimethyl-4,5-dihydro-
-pyrazol-1-yl]-methanone (257). Amount obtained: 136 mg, 0.32 mmol,
7% yield. LC-MS (ESI) 417 & 419 (M+H); .sup.1H NMR (400 MHz,
CHLOROFORM-d) .delta. ppm 1.78 (s, 6H) 3.16 (s, 2H) 3.89 (s, 3H)
3.93 (s, 3H) 6.87 (d, J=8.35 Hz, 1H) 7.11 (dd, J=8.30, 1.85 Hz, 1H)
7.24 (d, J=1.76 Hz, 1H) 7.54 (d, J=8.49 Hz, 2H) 7.77 (d, J=8.49 Hz,
2H).
##STR00329##
[0235]
(4-Chloro-3-fluoro-phenyl)-[3-(3,4-dimethoxy-phenyl)-5,5-dimethyl-4-
,5-dihydro-pyrazol-1-yl]-methanone. Amount obtained: 18 mg, 0.05
mmol, 16% yield. LC-MS (ESI) 391 (M+H); .sup.1H NMR (400 MHz,
CHLOROFORM-d) .delta. ppm 1.78 (s, 6H) 3.17 (s, 2H) 3.90 (s, 3H)
3.93 (s, 3H) 6.88 (d, J=8.35 Hz, 1H) 7.11 (dd, J=8.32, 1.88 Hz, 1H)
7.27 (s, 1H) 7.44 (t, J=7.86 Hz, 1H) 7.67 (dd, J=8.37, 1.00 Hz, 1H)
7.78 (dd, J=10.22, 1.83 Hz, 1H).
Example 2: Synthetic Route Towards
(5,5-Dimethyl-3-o-tolyl-4,5-dihydro-pyrazol-1-yl)-(3-fluoro-phenyl)-metha-
none
##STR00330##
[0236] Step 1
##STR00331##
[0238] 5,5-Dimethyl-pyrazolidin-3-one. A 100 mL round bottom flask
equipped with a stir bar, Vigreux column and nitrogen inlet was
charged with 3-methyl-but-2-enoic acid ethyl ester (1.4 mL, 10
mmol), EtOH (10 mL) and hydrazine monohydrate (0.58 mL, 12 mmol).
The mixture was heated at 80.degree. C. for 2 h. LC-MS and TLC
analysis showed consumption of SM. The solvent was evaporated under
reduced pressure and trace hydrazine and EtOH was removed under
high vacuum for 30 min. The material was used as in the next step.
Amount obtained: 1.1 g, 10 mmol, 100% yield. LC-MS (ESI) m/e 115
(M+H).
Step 2
##STR00332##
[0240] 5,5-Dimethyl-pyrazolidin-3-one. Hydrochloride. A
scintillation vial equipped with a stir bar was charged with
5,5-dimethyl-pyrazolidin-3-one (228 mg, 2.0 mmol) and 2.0 M HCl in
Et.sub.2O (2 mL) was added. A white PPT formed. This was filtered
and washed with further Et.sub.2O (20 mL). Amount obtained: 300 mg,
2.0 mmol, 100% yield.
Step 3
##STR00333##
[0242] 3-Chloro-5,5-dimethyl-4,5-dihydro-1H-pyrazole.
Hydrochloride. A round 50 mL round bottom flask equipped with stir
bar, Vigreux column and nitrogen inlet was charged with
5,5-dimethyl-pyrazolidin-3-one. Hydrochloride (300 mg, 2.0 mmol)
and POCl.sub.3 (4 mL). The mixture was heated at 90.degree. C. for
3 h. LC-MS showed consumption of SM. The POCl.sub.3 was evaporated
under reduced pressure and trace POCl.sub.3 was removed under high
vacuum for 30 min. Amount obtained: 336 mg, 2.0 mmol, 100% yield.
The material was used as in the next step.
Step 4
##STR00334##
[0244]
(3-Chloro-5,5-dimethyl-4,5-dihydro-pyrazol-1-yl)-(3-fluoro-phenyl)--
methanone. A 250 mL round bottom flask equipped with a stir bar and
nitrogen inlet was charged with dry CH.sub.2Cl.sub.2 (100 mL),
Hunigs base (7.8 mL, 45 mmol) DMAP (5 mg) and 3-fluorobenzoyl
chloride (1.8 mL. 15 mmol). The mixture was cooled to 0.degree. C.
To this mixture was added portionwise,
3-chloro-5,5-dimethyl-4,5-dihydro-1H-pyrazole. Hydrochloride (1.68
g, 10 mmol) and the reaction was allowed to warm to RT overnight.
LC-MS showed consumption of SM. The reaction was added to water
(100 mL), the phases were separated and the organic phase was
washed with NaHCO.sub.3 (100 mL), dried (Na.sub.2SO.sub.4) and the
solvent was evaporated under reduced pressure. The material was
purified by chromatography using a 40 g silica cartridge eluting
with heptane--EtOAc, gradient 0 to 20% EtOAc. Amount obtained: 0.9
g, 3.7 mmol, 37% yield. LC-MS (ESI) m/e 255 (M+H). .sup.1H NMR (400
MHz, CHLOROFORM-d) .delta. ppm 1.76 (s, 6H) 3.03 (s, 2H) 7.14 (td,
J=8.36, 1.98 Hz, 1H) 7.36 (td, J=7.96, 5.71 Hz, 1H) 7.43 (dd,
J=9.57, 2.25 Hz, 1H) 7.51 (d, J=7.76 Hz, 1H).
##STR00335##
[0245] (5, 5-Dimethyl-3-o-tolyl-4,
5-dihydro-pyrazol-1-yl)-(3-fluoro-phenyl)-methanone. A
scintillation vial equipped with a stir bar was charged with
3-chloro-5,5-dimethyl-4,5-dihydro-pyrazol-1-yl)-(3-fluoro-phenyl)-methano-
ne (64 mg, 0.25 mmol), 3,4-dimethoxy boronic acid (40 mg, 0.3
mmol), Cs.sub.2CO.sub.3 (162 mg, 0.5 mmol) and DMF (5 mL). This
mixture was degassed with nitrogen for 15 min and
Pd(PPh.sub.3).sub.4 (60 mg, 0.05 mmol) was added. The solution was
further degassed for another 15 min and then it was heated at
80.degree. C. for 2 h. LC-MS showed consumption of SM. The mixture
was added to water (50 mL), extracted with EtOAc (50 mL), the
organic phase washed with LiCl solution (50 mL), dried
(Na.sub.2SO.sub.4) and the solvent was evaporated under reduced
pressure. The material was purified by chromatography using a 12 g
silica cartridge eluting with heptane--EtOAc, gradient 0 to 30%
EtOAc. Amount obtained: 59 mg, 0.19 mmol, 76% yield. LC-MS (ESI)
m/e 311 (M+H). .sup.1H NMR (400 MHz, CHLOROFORM-d) 8 ppm 1.57 (s,
6H) 1.95 (s, 1H) 3.77 (s, 3H) 3.82 (s, 3H) 4.16 (dd, J=12.25, 4.98
Hz, 1H) 4.57 (t, J=11.91 Hz, 1H) 4.68 (dd, 1H) 6.68 (d, J=8.39 Hz,
1H) 6.98 (dd, J=8.35, 1.85 Hz, 1H) 7.13-7.22 (m, 4H) 7.36 (d,
J=8.20 Hz, 2H) 7.42 (td, J=8.07, 5.78 Hz, 1H) 7.81-7.87 (m,
2H).
Example 3: Synthetic route towards
[3-(3,4-dimethoxy-phenyl)-4,4-dimethyl-4,5-dihydro-pyrazol-1-yl]-(phenyl)-
-methanones
##STR00336##
[0247] It shall be understood that the phenyl moiety (radical R)
can be substituted in accordance with the Ar.sup.1 definition as
demonstrated below.
Step 1
##STR00337##
[0249] 3-Chloro-1-(3,4-dimethoxy-phenyl)-2,2-dimethyl-propan-1-one.
A 50 mL round bottom flask equipped with a stir bar was charged
with veratrole (1.3 mL, 10 mmol) and 3-chloropivaloyl chloride (1.4
g, 10 mmol). To this mixture was added polyphosphoric acid (20 g).
The mixture was heated at 70.degree. C. for 2 h. [The progress of
the reaction was followed by removing an aliquot for mini workup
and NMR analysis.] The material was added to a mixture of ice water
(100 mL)/EtOAc (100 mL) and stirred until the polyphosphoric acid
had dissolved. The phases were separated and the EtOAc phase was
washed with sat. NaHCO.sub.3 (100 mL), dried (Na.sub.2SO.sub.4) and
the solvent was evaporated under reduced pressure. The material was
used as is in the next step. Amount obtained: 2.4 g, 9.3 mmol, 93%
yield. LC-MS (ESI) m/e 257 (M+H). .sup.1H NMR (400 MHz,
CHLOROFORM-d) .delta. ppm 1.51 (s, 6H) 3.83 (s, 2H) 3.93 (s, 3H)
3.95 (s, 3H) 6.87 (d, J=8.44 Hz, 1H) 7.37 (d, J=1.95 Hz, 1H) 7.48
(dd, J=8.42, 1.98 Hz, 1H).
Step 2
##STR00338##
[0251]
3-(3,4-Dimethoxy-phenyl)-4,4-dimethyl-4,5-dihydro-1H-pyrazole. A
100 mL round bottom flask equipped with a stir bar, Vigreux column
and nitrogen inlet was charged with
3-chloro-1-(3,4-dimethoxy-phenyl)-2,2-dimethyl-propan-1-one (1.3 g,
5 mmol), EtOH (20 mL) and hydrazine monohydrate (0.3 mL, 6 mmol).
The mixture was heated at 80.degree. C. for 2 h. LC-MS and TLC
analysis showed consumption of SM. The solvent was evaporated under
reduced pressure and trace hydrazine and EtOH was removed under
high vacuum for 30 min. The material was used as in the next step.
Amount obtained: 1170 mg, 5 mmol, 100% yield. LC-MS (ESI) m/e 235
(M+H).
Step 3
##STR00339##
[0253]
[3-(3,4-Dimethoxy-phenyl)-4,4-dimethyl-4,5-dihydro-pyrazol-1-yl]-(3-
-fluoro-phenyl)-methanone (149). A scintillation vial equipped with
a stir bar was charged with
3-chloro-1-(3,4-dimethoxy-phenyl)-2,2-dimethyl-propan-1-one (469
mg, 2 mmol), Hunigs base (1 mL, 6 mmol) and dry CH.sub.2Cl.sub.2
(10 mL). To this mixture was added 3-fluorobenzoyl chloride (0.23
mL, 2 mmol) and the reaction was stirred at RT for 3 h. LC-MS
indicated consumption of SM. The mixture was diluted with
CH.sub.2Cl.sub.2 (50 mL) and added to water (50 mL). The phases
were separated and the CH.sub.2Cl.sub.2 phase was washed with
saturated Na.sub.2CO.sub.3, (50 mL), dried (Na.sub.2SO.sub.4) and
the solvent was evaporated under reduced pressure. The material was
purified using a 40 g silica cartridge eluting with heptane-EtOAc,
gradient 0 to 50% EtOAc. Amount obtained: 350 mg, 1 mmol, 50%
yield. LC-MS (ESI) m/e 357 (M+H). .sup.1H NMR (400 MHz,
CHLOROFORM-d) .delta. ppm 1.58 (s, 6H) 3.89 (s, 3H) 3.93 (s, 3H)
4.05 (s, 2H) 6.87 (d, J=8.39 Hz, 1H) 7.18 (td, J=8.31, 1.98 Hz, 1H)
7.30-7.43 (m, 3H) 7.80 (t, J=7.00 Hz, 2H).
[0254] The following compounds were prepared in a similar manner.
LC-MS and HPLC analysis were performed as follows: Method: A-0.1%
TFA in water, B-0.1% TFA in ACN: Flow--2 ml/min; Column: XBridge c8
(50.times.4.6 mm, 3.5 .mu.m); unless stated otherwise.
(3-Bromo-phenyl)-[3-(3, 4-dimethoxy-phenyl)-4, 4-dimethyl-4,
5-dihydro-pyrazol-1-yl]methanone
##STR00340##
[0256] White solid; 9.94% Yield
[0257] LC-MS: Mass found (M+, 419). Rt (min): 4.97; % Area: 95.97
(Max), 95.63 (220 nm).
[0258] HPLC--Rt (min): 4.94; % Area: 98.17 (Max), 97.86 (254
nm).
[0259] 400 MHz, DMSO-d6: .delta. 8.12 (s, 1H), 7.85-7.83 (m, 1H),
7.73-7.71 (m, 1H), 7.44 (t, J=8.00 Hz, 1H), 7.35-7.33 (m, 1H),
7.27-7.26 (m, 1H), 6.98 (d, J=8.00 Hz, 1H), 3.92 (s, 2H), 3.78 (s,
3H), 3.76 (s, 3H), 1.48 (s, 6H).
(3-Chloro-phenyl)-[3-(3, 4-dimethoxy-phenyl)-4, 4-dimethyl-4,
5-dihydro-pyrazol-1-yl]methanone
##STR00341##
[0261] White solid; 6.98% Yield
[0262] LC-MS: Mass found (M+, 373). Rt (min): 4.88; % Area: 96.54
(Max), 96.77 (254 nm).
[0263] HPLC--Rt (min): 4.87; % Area: 98.76 (Max), 99.01 (254
nm).
[0264] 400 MHz, DMSO-d6: .delta. 7.96 (s, 1H), 7.81-7.79 (m, 1H),
7.60-7.58 (m, 1H), 7.50 (t, J=8.00 Hz, 1H), 7.35-7.32 (m, 1H),
7.26-7.25 (m, 1H), 6.99 (d, J=12.00 Hz, 1H), 3.93 (s, 2H), 3.78 (s,
3H), 3.74 (s, 3H), 1.48 (s, 6H).
[3-(3, 4-Dimethoxy-phenyl)-4, 4-dimethyl-4,
5-dihydro-pyrazol-1-yl]-(3-methoxy-phenyl)-methanone
##STR00342##
[0266] White solid; 4.13% Yield
[0267] LC-MS: Mass found (M+, 369.3). Rt (min): 4.42; % Area: 95.08
(Max), 96.50 (254 nm).
[0268] HPLC--Rt (min): 4.39; % Area: 98.94 (Max), 98.15 (254
nm).
[0269] 400 MHz, DMSO-d6: .delta. 7.44-7.42 (m, 2H), 7.38-7.31 (m,
2H), 7.23 (d, J=4.00 Hz, 1H), 7.09-7.06 (m, 1H), 6.99 (d, J=8.00
Hz, 1H), 3.91 (s, 2H), 3.78 (s, 6H), 3.73 (s, 3H), 1.47 (s,
6H).
[3-(3, 4-Dimethoxy-phenyl)-4, 4-dimethyl-4,
5-dihydro-pyrazol-1-yl]-(3-ethoxy-phenyl)-methanone
##STR00343##
[0271] White solid; 5.47% Yield
[0272] LC-MS: Mass found (M+, 383.3). Rt (min): 4.71; % Area: 97.98
(Max), 98.48 (220 nm).
[0273] HPLC--Rt (min): 4.7; % Area: 98.82 (Max), 98.31 (254
nm).
[0274] 400 MHz, DMSO-d6: .delta. 7.42-7.40 (m, 2H), 7.37-7.31 (m,
2H), 7.24 (d, J=4.00 Hz, 1H), 7.07-7.04 (m, 1H), 6.98 (d, J=8.00
Hz, 1H), 4.07-4.02 (m, 2H), 3.91 (s, 2H), 3.78 (s, 3H), 3.73 (s,
3H), 1.47 (s, 6H), 1.31 (t, J=8.00 Hz, 3H).
[3-(3, 4-Dimethoxy-phenyl)-4, 4-dimethyl-4,
5-dihydro-pyrazol-1-yl]-(3-trifluoromethyl-phenyl)-methanone
##STR00344##
[0276] Brown solid; 5.02% Yield
[0277] LC-MS: Mass found (M+, 407.3). Rt (min): 5.12; % Area: 96.50
(Max), 97.34 (254 nm).
[0278] HPLC--Rt (min): 5.3; % Area: 98.42 (Max), 98.15 (254
nm).
[0279] 400 MHz, DMSO-d6: .delta. 8.29 (s, 1H), 8.15-8.13 (m, 1H),
7.91-7.89 (m, 1H), 7.72 (t, J=8.00 Hz, 1H), 7.36 (dd, J=8.00, 4.00
Hz, 1H), 7.25 (d, J=4.00 Hz, 1H), 6.98 (d, J=8.00 Hz, 1H), 3.96 (s,
2H), 3.78 (s, 3H), 3.71 (s, 3H), 1.50 (s, 6H).
[3-(3, 4-Dimethoxy-phenyl)-4, 4-dimethyl-4,
5-dihydro-pyrazol-1-yl]m-tolyl-methanone
##STR00345##
[0281] Brown gum; 15.29% Yield
[0282] LC-MS: Mass found (M+, 353.3). Rt (min): 4.66; % Area: 91.12
(Max), 92.42 (254 nm).
[0283] HPLC--Rt (min): 4.64; % Area: 94.23 (Max), 95.13 (254
nm).
[0284] 400 MHz, DMSO-d6: .delta. 7.71 (s, 1H), 7.64-7.62 (m, 1H),
7.35-7.31 (m, 3H), 7.25-7.24 (m, 1H), 6.98 (d, J=8.00 Hz, 1H), 3.91
(s, 2H), 3.78 (s, 3H), 3.73 (s, 3H), 2.35 (s, 3H), 1.47 (s,
6H).
3-[3-(3, 4-Dimethoxy-phenyl)-4, 4-dimethyl-4,
5-dihydro-pyrazole-1-carbonyl]benzonitrile
##STR00346##
[0286] Brown solid; 28.18% Yield
[0287] LC-MS: Mass found (M+, 364.3). Rt (min): 4.36; % Area: 96.95
(Max), 96.43 (254 nm).
[0288] HPLC--Rt (min): 4.34; % Area: 97.62 (Max), 95.87 (254
nm).
[0289] 400 MHz, DMSO-d6: .delta. 8.36 (s, 1H), 8.15-8.13 (m, 1H),
8.00-7.98 (m, 1H), 7.69 (t, J=8.00 Hz, 1H), 7.35-7.33 (m, 1H),
7.26-7.25 (m, 1H), 6.98 (d, J=8.00 Hz, 1H), 3.94 (s, 2H), 3.78 (s,
3H), 3.75 (s, 3H), 1.49 (s, 6H).
[3-(3, 4-Dimethoxy-phenyl)-4, 4-dimethyl-4,
5-dihydro-pyrazol-1-yl]-(3-trifluoromethoxy-phenyl)-methanone
##STR00347##
[0291] Brown solid; 7.82% Yield
[0292] LC-MS: Mass found (M+, 423.3). Rt (min): 5.24; % Area: 99.09
(Max), 98.87 (254 nm).
[0293] HPLC--Rt (min): 5.23; % Area: 99.18 (Max), 99.10 (254
nm).
[0294] 400 MHz, DMSO-d6: .delta. 7.90-7.88 (m, 2H), 7.61 (t, J=8.00
Hz, 1H), 7.55-7.53 (m, 1H), 7.35 (dd, J=12.00, 4.00 Hz, 1H),
7.24-7.23 (m, 1H), 6.98 (d, J=8.00 Hz, 1H), 3.94 (s, 2H), 3.78 (s,
3H), 3.72 (s, 3H), 1.49 (s, 6H).
[3-(3, 4-Dimethoxy-phenyl)-4, 4-dimethyl-4,
5-dihydro-pyrazol-1-yl]-(3-dimethylamino-phenyl)-methanone
##STR00348##
[0296] Yellow solid; 18.55% Yield
[0297] LC-MS: Mass found (M+, 382.3). Rt (min): 3.22; % Area: 91.47
(Max), 92.60 (254 nm).
[0298] HPLC--Rt (min): 3.18; % Area: 91.78 (Max), 91.41 (254
nm).
[0299] 400 MHz, DMSO-d6: .delta. 7.33 (dd, J=8.00, 4.00 Hz, 1H),
7.26-7.22 (m, 3H), 7.14-7.12 (m, 1H), 6.98 (d, J=8.00 Hz, 1H),
6.87-6.84 (m, 1H), 3.90 (s, 2H), 3.78 (s, 3H), 3.72 (s, 3H), 2.91
(s, 6H), 1.47 (s, 6H).
(3-Benzyloxy-phenyl)-[3-(3, 4-dimethoxy-phenyl)-4, 4-dimethyl-4,
5-dihydro-pyrazol-1-yl]-methanone
##STR00349##
[0301] Brown solid; 16.34% Yield
[0302] LC-MS: Mass found (M+, 445.3). Rt (min): 5.29; % Area: 96.04
(Max), 96.50 (254 nm).
[0303] HPLC--Rt (min): 5.49; % Area: 98.40 (Max), 97.32 (254
nm).
[0304] 400 MHz, DMSO-d6: .delta. 7.53-7.52 (m, 1H), 7.46-7.43 (m,
3H), 7.39-7.35 (m, 3H), 7.33-7.30 (m, 2H), 7.24 (s, 1H), 7.17 (dd,
J=8.00, 4.00 Hz, 1H), 6.98 (d, J=12.00 Hz, 1H), 5.13 (s, 2H), 3.91
(s, 2H), 3.78 (s, 3H), 3.67 (s, 3H), 1.47 (s, 6H).
[3-(3, 4-Dimethoxy-phenyl)-4, 4-dimethyl-4,
5-dihydro-pyrazol-1-yl]-(3-isopropoxy-phenyl)-methanone
##STR00350##
[0306] Brown solid; 22.40% Yield
[0307] LC-MS: Mass found (M+, 397.3). Rt (min): 4.45; % Area: 95.91
(Max), 96.11 (254 nm).
[0308] HPLC--Rt (min): 5.11; % Area: 97.30 (Max), 96.48 (254
nm).
[0309] 400 MHz, DMSO-d6: .delta. 7.40-7.31 (m, 4H), 7.24 (d, J=4.00
Hz, 1H), 7.06-7.03 (m, 1H), 6.98 (d, J=8.00 Hz, 1H), 4.65-4.59 (m,
1H), 3.91 (s, 2H), 3.78 (s, 3H), 3.73 (s, 3H), 1.47 (s, 6H), 1.25
(d, J=8.00 Hz, 6H).
[3-(3,4-Dimethoxy-phenyl)-4,4-dimethyl-4,5-dihydro-pyrazol-1-yl]-(3-phenox-
y-phenyl)-methanone
##STR00351##
[0311] White solid; 23.35% Yield
[0312] LC-MS: Mass found (M+, 431.3). Rt (min): 5.29; % Area: 98.33
(Max), 98.71 (254 nm).
[0313] HPLC--Rt (min): 5.47; % Area: 98.66 (Max), 99.24 (254
nm).
[0314] 400 MHz, DMSO-d6: .delta. 7.65 (d, J=8.00 Hz, 1H), 7.51-7.47
(m, 2H), 7.39-7.35 (m, 2H), 7.28 (d, J=8.00 Hz, 1H), 7.21-7.12 (m,
3H), 7.03 (d, J=8.00 Hz, 2H), 6.97 (d, J=8.00 Hz, 1H), 3.90 (s,
2H), 3.79 (s, 3H), 3.69 (s, 3H), 1.46 (s, 6H).
Biphenyl-3-yl-[3-(3, 4-dimethoxy-phenyl)-4, 4-dimethyl-4,
5-dihydro-pyrazol-1-yl]methanone
##STR00352##
[0316] White solid; 10.46% Yield
[0317] LC-MS: Mass found (M+, 415.3). Rt (min): 5.23; % Area: 97.14
(Max), 98.20 (254 nm).
[0318] HPLC--Rt (min): 5.22; % Area: 98.53 (Max), 98.97 (254
nm).
[0319] 400 MHz, DMSO-d6: .delta. 8.20 (s, 1H), 7.83-7.79 (m, 2H),
7.69 (d, J=8.00 Hz, 2H), 7.56 (t, J=8.00 Hz, 1H), 7.48 (t, J=4.00
Hz, 2H), 7.41-7.33 (m, 2H), 7.20 (s, 1H), 6.97 (d, J=12.00 Hz, 1H),
3.96 (s, 2H), 3.77 (s, 3H), 3.50 (s, 3H), 1.50 (s, 6H).
(3-tert-Butyl-phenyl)-[3-(3,4-dimethoxy-phenyl)-4,4-dim
ethyl-4,5-dihydro-pyrazol-1-yl]-methanone
##STR00353##
[0321] White solid, 22.51% Yield
[0322] LC-MS: Mass found (M+, 395.3). Rt (min): 5.39; % Area: 96.81
(Max), 96.96 (220 nm).
[0323] HPLC--Rt (min): 5.57; % Area: 97.60 (Max), 97.74 (254
nm).
[0324] 400 MHz, DMSO-d6: .delta. 7.91 (s, 1H), 7.66-7.64 (m, 1H),
7.56-7.53 (m, 1H), 7.40-7.34 (m, 2H), 7.24 (d, J=4.00 Hz, 1H), 6.98
(d, J=8.00 Hz, 1H), 3.92 (s, 2H), 3.78 (s, 3H), 3.71 (s, 3H), 1.48
(s, 6H), 1.30 (s, 9H).
[3-(3, 4-Dimethoxy-phenyl)-4, 4-dimethyl-4,
5-dihydro-pyrazol-1-yl]-(3-methanesulfonyl-phenyl)-methanone
##STR00354##
[0326] White solid; 23.85% Yield
[0327] LC-MS: Mass found (M+, 417.3). Rt (min): 3.89; % Area: 96.94
(Max), 96.17 (220 nm).
[0328] HPLC--Rt (min): 4.07; % Area: 98.57 (Max), 97.36 (254
nm).
[0329] 400 MHz, DMSO-d6: .delta. 8.56 (s, 1H), 8.19-8.17 (m, 1H),
8.09-8.06 (m, 1H), 7.76 (t, J=8.00 Hz, 1H), 7.38 (dd, J=8.00, 4.00
Hz, 1H), 7.30 (d, J=4.00 Hz, 1H), 6.97 (d, J=8.00 Hz, 1H), 3.97 (s,
2H), 3.78 (s, 3H), 3.75 (s, 3H), 3.25 (s, 3H), 1.50 (s, 6H).
N-{3-[3-(3, 4-Dimethoxy-phenyl)-4, 4-dimethyl-4,
5-dihydro-pyrazole-1-carbonyl]-phenyl}-acetamide
##STR00355##
[0331] White solid; 6.40% Yield
[0332] LC-MS: Mass found (M+, 396.3). Rt (min): 3.62; % Area: 98.93
(Max), 99.25 (254 nm).
[0333] HPLC--Rt (min): 3.77; % Area: 99.61 (Max), 99.39 (254
nm).
[0334] 400 MHz, DMSO-d6: .delta. 10.07 (s, 1H), 8.19 (s, 1H),
7.69-7.67 (m, 1H), 7.51-7.49 (m, 1H), 7.38-7.33 (m, 2H), 7.30 (d,
J=4.00 Hz, 1H), 6.97 (d, J=8.00 Hz, 1H), 3.92 (s, 2H), 3.78 (s,
3H), 3.74 (s, 3H), 2.03 (s, 3H), 1.47 (s, 6H).
[3-(3,4-Dimethoxy-phenyl)-4,4-dimethyl-4,5-dihydro-pyrazol-1-yl]-(4-fluoro-
-phenyl)-methanone
##STR00356##
[0336] Brown solid; 48.79% Yield
[0337] LC-MS: Mass found (M+, 357.2). Rt (min): 4.63; % Area: 97.62
(Max), 95.61 (254 nm).
[0338] HPLC--Rt (min): 4.56; % Area: 96.57 (Max), 95.51 (254
nm).
[0339] 400 MHz, DMSO-d6: .delta. 7.97-7.94 (m, 2H), 7.34-7.27 (m,
3H), 7.23 (d, J=4.00 Hz, 1H), 6.98 (d, J=8.00 Hz, 1H), 3.91 (s,
2H), 3.78 (s, 3H), 3.74 (s, 3H), 1.47 (s, 6H).
(3,4-Difluoro-phenyl)-[3-(3,4-dimethoxy-phenyl)-4,4-dimethyl-4,5-dihydro-p-
yrazol-1-yl]-methanone
##STR00357##
[0341] White solid; 18.49% Yield
[0342] LC-MS: Mass found (M+, 375). Rt (min): 4.80; % Area: 99.11
(Max), 99.31 (254 nm).
[0343] HPLC--Rt (min): 4.82; % Area: 97.49 (Max), 98.77 (254
nm).
[0344] 400 MHz, DMSO-d6: .delta. 7.98-7.93 (m, 1H), 7.80-7.77 (m,
1H), 7.57-7.51 (m, 1H), 7.35 (dd, J=8.00, 4.00 Hz, 1H), 7.25 (d,
J=4.00 Hz, 1H), 7.00 (d, J=12.00 Hz, 1H), 3.92 (s, 2H), 3.78 (s,
3H), 3.74 (s, 3H), 1.48 (s, 6H).
[3-(3,4-Dimethoxy-phenyl)-4,4-dimethyl-4,5-dihydro-pyrazol-1-yl]-(3-fluoro-
-4-trifluoromethyl-phenyl)-methanone
##STR00358##
[0346] White solid; 20.15% Yield
[0347] LC-MS: Mass found (M+, 425). Rt (min): 5.35; % Area: 99.05
(Max), 99.46 (254 nm).
[0348] HPLC--Rt (min): 5.34; % Area: 98.71 (Max), 98.93 (254
nm).
[0349] 400 MHz, DMSO-d6: .delta. 7.84-7.79 (m, 2H), 7.35 (dd,
J=8.00, 4.00 Hz, 1H), 7.27-7.22 (m, 2H), 7.00 (d, J=8.00 Hz, 1H),
3.90 (s, 2H), 3.79 (s, 3H), 3.76 (s, 3H), 1.47 (s, 6H).
[3-(3,4-Dimethoxy-phenyl)-4,4-dimethyl-4,5-dihydro-pyrazol-1-yl]-(3-fluoro-
-4-methyl-phenyl)-methanone
##STR00359##
[0351] Brown solid; 5.82% Yield
[0352] LC-MS: Mass found (M+, 371.3). Rt (min): 4.87; % Area: 93.26
(Max), 94.56 (254 nm).
[0353] HPLC--Rt (min): 4.86; % Area: 95.35 (Max), 94.94 (254
nm).
[0354] 400 MHz, DMSO-d6: .delta. 7.68-7.65 (m, 2H), 7.39-7.32 (m,
2H), 7.25 (d, J=4.00 Hz, 1H), 6.99 (d, J=8.00 Hz, 1H), 3.91 (s,
2H), 3.78 (s, 3H), 3.75 (s, 3H), 2.29 (d, J=4.00 Hz, 3H), 1.47 (s,
6H).
[3-(3,4-Dimethoxy-phenyl)-4,5-dihydro-pyrazol-1-yl]-(3-fluoro-4-methoxy-ph-
enyl)-methanone
##STR00360##
[0356] White solid; 9.50% Yield
[0357] LC-MS: Mass found (M+, 387.3). Rt (min): 4.53; % Area: 98.58
(Max), 99.07 (254 nm).
[0358] HPLC--Rt (min): 4.54; % Area: 98.67 (Max), 99.14 (254
nm).
[0359] 400 MHz, DMSO-d6: .delta. 7.84-7.79 (m, 2H), 7.35 (dd,
J=8.00, 4.00 Hz, 1H), 7.27-7.22 (m, 2H), 7.00 (d, J=8.00 Hz, 1H),
3.90 (d, J=4.00 Hz, 5H), 3.79 (s, 3H), 3.76 (s, 3H), 1.47 (s,
6H).
(4-Bromo-3-fluoro-phenyl)-[3-(3,4-dimethoxy-phenyl)-4,4-dimethyl-4,5-dihyd-
ro-pyrazol-1-yl]-methanone
##STR00361##
[0361] White solid; 6.57% Yield
[0362] LC-MS: Mass found (M+, 437). Rt (min): 5.12; % Area: 97.72
(Max), 98.70 (254 nm).
[0363] HPLC--Rt (min): 5.11; % Area: 98.7 (Max), 98.93 (254
nm).
[0364] 400 MHz, DMSO-d6: .delta. 7.87-7.81 (m, 2H), 7.69-7.67 (m,
1H), 7.34 (dd, J=8.00, 4.00 Hz, 1H), 7.24 (d, J=4.00 Hz, 1H), 6.99
(d, J=8.00 Hz, 1H), 3.92 (s, 2H), 3.78 (s, 3H), 3.75 (s, 3H), 1.48
(s, 6H).
(2,3-Difluoro-phenyl)-[3-(3,4-dimethoxy-phenyl)-4,4-dimethyl-4,5-dihydro-p-
yrazol-1-yl]-methanone
##STR00362##
[0366] White solid; 13.77% Yield
[0367] LC-MS: Mass found (M+, 375). Rt (min): 4.55; % Area: 97.31
(Max), 97.42 (254 nm).
[0368] HPLC--Rt (min): 4.54; % Area: 98.87 (Max), 99.13 (254
nm).
[0369] 400 MHz, DMSO-d6: .delta. 7.59-7.52 (m, 1H), 7.38-7.35 (m,
1H), 7.31-7.28 (m, 1H), 7.25 (dd, J=8.00, 4.00 Hz, 1H), 7.10 (d,
J=4.00 Hz, 1H), 6.97 (d, J=12.00 Hz, 1H), 3.93 (s, 2H), 3.76 (s,
3H), 3.67 (s, 3H), 1.46 (s, 6H).
[3-(3,4-Dimethoxy-phenyl)-4,4-dimethyl-4,5-dihydro-pyrazol-1-yl]-(3-fluoro-
-2-methyl-phenyl)-methanone
##STR00363##
[0371] Brown Gum; 13.85% Yield
[0372] LC-MS: Mass found (M+, 371.3). Rt (min): 4.60; % Area: 92.64
(Max), 94.86 (254 nm).
[0373] HPLC--Rt (min): 4.61; % Area: 95.70 (Max), 96.29 (254
nm).
[0374] 400 MHz, DMSO-d6: .delta. 7.28-7.17 (m, 4H), 7.04 (d, J=4.00
Hz, 1H), 6.95 (d, J=8.00 Hz, 1H), 3.93 (s, 2H), 3.75 (s, 3H), 3.66
(s, 3H), 2.15 (d, J=4.00 Hz, 3H), 1.46 (s, 6H).
[3-(3,4-Dimethoxy-phenyl)-4,4-dimethyl-4,5-dihydro-pyrazol-1-yl]-(3-fluoro-
-2-trifluoromethyl-phenyl)-methanone
##STR00364##
[0376] Brown solid; 9.11% Yield
[0377] LC-MS: Mass found (M+, 425.3). Rt (min): 4.89; % Area: 91.76
(Max), 93.89 (254 nm).
[0378] HPLC--Rt (min): 4.89; % Area: 93.92 (Max), 94.22 (254
nm).
[0379] 400 MHz, DMSO-d6: .delta. 7.83-7.80 (m, 1H), 7.61-7.56 (m,
1H), 7.40-7.38 (m, 1H), 7.20 (dd, J=8.00, 4.00 Hz, 1H), 7.01 (d,
J=4.00 Hz, 1H), 6.95 (d, J=8.00 Hz, 1H), 3.88 (s, 2H), 3.75 (s,
3H), 3.63 (s, 3H), 1.45 (s, 6H).
[3-(3,4-Dimethoxy-phenyl)-4,4-dimethyl-4,5-dihydro-pyrazol-1-yl]-(3-fluoro-
-2-methoxy-phenyl)-methanone
##STR00365##
[0381] Yellow Gum; 24.56% Yield
[0382] LC-MS: Mass found (M+, 387.3). Rt (min): 4.40; % Area: 92.17
(Max), 92.25 (254 nm).
[0383] HPLC--Rt (min): 4.55; % Area: 93.05 (Max), 93.51 (254
nm).
[0384] 400 MHz, DMSO-d6: .delta. 7.37-7.31 (m, 1H), 7.23 (dd,
J=8.00, 4.00 Hz, 1H), 7.17-7.13 (m, 2H), 7.06 (s, 1H), 6.96 (d,
J=12.00 Hz, 1H), 3.91 (s, 2H), 3.80 (s, 3H), 3.76 (s, 3H), 3.66 (s,
3H), 1.46 (s, 6H).
(2-Bromo-3-fluoro-phenyl)-[3-(3,4-dimethoxy-phenyl)-4,4-dimethyl-4,5-dihyd-
ro-pyrazol-1-yl]-methanone
##STR00366##
[0386] White solid; 17.60% Yield
[0387] LC-MS: Mass found (M+, 435). Rt (min): 4.62; % Area: 98.72
(Max), 98.38 (220 nm).
[0388] HPLC--Rt (min): 4.78; % Area: 98.25 (Max), 98.99 (254
nm).
[0389] 400 MHz, DMSO-d6: .delta. 7.52-7.40 (m, 2H), 7.30 (dd,
J=6.00, 0.00 Hz, 1H), 7.20 (dd, J=8.00, 4.00 Hz, 1H), 7.04 (d,
J=4.00 Hz, 1H), 6.96 (d, J=12.00 Hz, 1H), 3.92 (s, 2H), 3.75 (s,
3H), 3.66 (s, 3H), 1.46 (s, 6H).
(2-Chloro-3-fluoro-phenyl)-[3-(3,4-dimethoxy-phenyl)-4,4-dimethyl-4,5-dihy-
dro-pyrazol-1-yl]-methanone
##STR00367##
[0391] White solid; 11.39% Yield
[0392] LC-MS: Mass found (M+, 391.3). Rt (min): 4.62; % Area: 93.71
(Max), 94.18 (220 nm).
[0393] HPLC--Rt (min): 4.77; % Area: 96.56 (Max), 96.01 (254
nm).
[0394] 400 MHz, DMSO-d6: .delta. 7.51-7.45 (m, 2H), 7.36-7.33 (m,
1H), 7.21 (dd, J=8.00, 4.00 Hz, 1H), 7.04 (d, J=4.00 Hz, 1H), 6.96
(d, J=12.00 Hz, 1H), 3.93 (s, 2H), 3.75 (s, 3H), 3.65 (s, 3H), (s,
6H).
[3-(3,4-Dimethoxy-phenyl)-4,4-dimethyl-4,5-dihydro-pyrazol-1-yl]-(2,3,4-tr-
ifluoro-phenyl)-methanone
##STR00368##
[0396] Brown solid; 8.66% Yield
[0397] LC-MS: Mass found (M+, 393.3). Rt (min): 4.77; % Area: 94.01
(Max), 93.90 (254 nm).
[0398] HPLC--Rt (min): 4.78; % Area: 95.89 (Max), 95.68 (254
nm).
[0399] 400 MHz, DMSO-d6: .delta. 7.46-7.40 (m, 2H), 7.27 (dd,
J=8.00, 4.00 Hz, 1H), 7.11 (d, J=4.00 Hz, 1H), 6.97 (d, J=8.00 Hz,
1H), 3.92 (s, 2H), 3.77 (s, 3H), 3.69 (s, 3H), 1.46 (s, 6H).
(2,3-Difluoro-4-methyl-phenyl)-[3-(3,4-dimethoxy-phenyl)-4,4-dimethyl-4,5--
dihydro-pyrazol-1-yl]-methanone
##STR00369##
[0401] White solid; 29.86% Yield
[0402] LC-MS: Mass found (M+, 389.3). Rt (min): 4.79; % Area: 97.73
(Max), 97.21 (254 nm).
[0403] HPLC--Rt (min): 4.95; % Area: 97.84 (Max), 97.61 (254
nm).
[0404] 400 MHz, DMSO-d6: .delta. 7.27-7.22 (m, 2H), 7.19-7.15 (m,
1H), 7.10 (d, J=4.00 Hz, 1H), 6.97 (d, J=8.00 Hz, 1H), 3.91 (s,
2H), 3.76 (s, 3H), 3.69 (s, 3H), 2.32 (d, J=4.00 Hz, 3H), 1.45 (s,
6H).
[3-(3,4-Dimethoxy-phenyl)-4,4-dimethyl-4,5-dihydro-pyrazol-1-yl]-(2,3,4,5--
tetrafluoro-phenyl)-methanone
##STR00370##
[0406] White solid; 3.94% Yield
[0407] LC-MS: Mass found (M+, 411.2). Rt (min): 5.04; % Area: 98.62
(Max), 98.04 (254 nm).
[0408] HPLC--Rt (min): 5.04; % Area: 98.61 (Max), 98.88 (254
nm).
[0409] 400 MHz, DMSO-d6: .delta. 7.70-7.66 (m, 1H), 7.28 (dd,
J=8.00, 4.00 Hz, 1H), 7.12 (d, J=4.00 Hz, 1H), 6.97 (d, J=8.00 Hz,
1H), 3.92 (s, 2H), 3.77 (s, 3H), 3.70 (s, 3H), 1.47 (s, 6H).
(6-Bromo-benzo[1,3]dioxol-5-yl)-[3-(3,4-dimethoxy-phenyl)-4,4-dimethyl-4,5-
-dihydro-pyrazol-1-yl]-methanone
##STR00371##
[0411] Off-white solid; 26.16% Yield
[0412] LC-MS: Mass found (M+, 463). Rt (min): 4.49; % Area: 95.76
(Max), 96.08 (254 nm).
[0413] HPLC--Rt (min): 4.50; % Area: 98.26 (Max), 97.72 (254
nm).
[0414] 400 MHz, DMSO-d6: .delta. 7.24-7.22 (m, 1H), 7.21-7.20 (m,
1H), 7.10 (d, J=4.00 Hz, 1H), 7.05 (s, 1H), 6.97 (d, J=12.00 Hz,
1H), 6.10 (s, 2H), 3.86 (s, 2H), 3.76 (s, 3H), 3.69 (s, 3H), 1.44
(s, 6H).
(2,2-Difluoro-benzo[1,3]dioxol-5-yl)-[3-(3,4-dimethoxy-phenyl)-4,4-dimethy-
l-4,5-dihydro-pyrazol-1-yl]-methanone
##STR00372##
[0416] Off-White solid; 17.98% Yield
[0417] LC-MS: Mass found (M+, 419). Rt (min): 5.17; % Area: 96.44
(Max), 97.53 (254 nm).
[0418] HPLC--Rt (min): 5.18; % Area: 97.36 (Max), 97.67 (254
nm).
[0419] 400 MHz, DMSO-d6: .delta. 7.90 (s, 1H), 7.79 (d, J=8.00 Hz,
1H), 7.51 (d, J=12.00 Hz, 1H), 7.34 (dd, J=8.00, 4.00 Hz, 1H),
7.24-7.23 (m, 1H), 7.00 (d, J=12.00 Hz, 1H), 3.92 (s, 2H), 3.79 (s,
3H), 3.75 (s, 3H), 1.48 (s, 6H).
(2,5-Dimethoxy-phenyl)-[3-(3,4-dimethoxy-phenyl)-4,4-dimethyl-4,5-dihydro--
pyrazol-1-yl]-methanone
##STR00373##
[0421] White solid; 11.23% Yield
[0422] LC-MS: Mass found (M+, 399.3). Rt (min): 4.14; % Area: 95.01
(Max), 96.10 (254 nm).
[0423] HPLC--Rt (min): 4.14; % Area: 95.86 (Max), 95.86 (254
nm).
[0424] 400 MHz, DMSO-d6: .delta. 7.20 (dd, J=12.00, 4.00 Hz, 1H),
7.05 (d, J=4.00 Hz, 1H), 7.02-6.99 (m, 1H), 6.97-6.96 (m, 1H),
6.95-6.94 (m, 1H), 6.87 (d, J=4.00 Hz, 1H), 3.86 (s, 2H), 3.76 (s,
3H), 3.71 (s, 3H), 3.68 (s, 3H), 3.67 (s, 3H), 1.44 (s, 6H).
[3-(3,4-Dimethoxy-phenyl)-4,4-dimethyl-4,5-dihydro-pyrazol-1-yl]-(3-hydrox-
y-4-methoxy-phenyl)-methanone
##STR00374##
[0426] White solid; 30.78% Yield
[0427] LC-MS: Mass found (M+, 385.3). Rt (min): 3.78; % Area: 97.28
(Max), 96.55 (254 nm).
[0428] HPLC--Rt (min): 3.75; % Area: 98.10 (Max), 98.01 (254
nm).
[0429] 400 MHz, DMSO-d6: .delta. 7.45 (s, 1H), 7.43 (d, J=4.00 Hz,
1H), 7.35 (dd, J=8.00, 4.00 Hz, 1H), 7.28 (d, J=4.00 Hz, 1H), 6.99
(d, J=8.00 Hz, 1H), 6.97 (d, J=4.00 Hz, 1H), 3.88 (s, 2H), 3.81 (s,
3H), 3.79 (s, 3H), 3.76 (s, 3H), 1.46 (s, 6H).
(2,3-Dihydro-benzofuran-5-yl)-[3-(3,4-dimethoxy-phenyl)-4,4-dimethyl-4,5-d-
ihydro-pyrazol-1-yl]-methanone
##STR00375##
[0431] Off-white solid; 44.35% Yield
[0432] LC-MS: Mass found (M+, 381.3). Rt (min): 4.34; % Area: 96.80
(Max), 97.33 (220 nm).
[0433] HPLC--Rt (min): 4.51; % Area: 96.93 (Max), 96.36 (254
nm).
[0434] 400 MHz, DMSO-d6: .delta. 7.86 (s, 1H), 7.75-7.82 (m, 1H),
7.33 (d, J=8.00 Hz, 1H), 7.27 (d, J=4.00 Hz, 1H), 6.99 (d, J=8.00
Hz, 1H), 6.81 (d, J=8.00 Hz, 1H), 4.60 (t, J=8.00 Hz, 2H), 3.89 (s,
2H), 3.79 (s, 3H), 3.76 (s, 3H), 3.12 (t, J=8.00 Hz, 2H), 1.47 (s,
6H).
[3-(3, 4-Dimethoxy-phenyl)-4, 4-dimethyl-4,
5-dihydro-pyrazol-1-yl]indan-5-yl-methanone
##STR00376##
[0436] Off-white solid; 16.78% Yield
[0437] LC-MS: Mass found (M+, 379.3). Rt (min): 5.00; % Area: 97.76
(Max), 97.82 (254 nm).
[0438] HPLC--Rt (min): 5.16; % Area: 98.08 (Max), 97.80 (254
nm).
[0439] 400 MHz, DMSO-d6: .delta. 7.76 (s, 1H), 7.64 (d, J=8.00 Hz,
1H), 7.33-7.24 (m, 3H), 6.97 (d, J=4.00 Hz, 1H), 3.90 (s, 2H), 3.78
(s, 3H), 3.75 (s, 3H), 2.91-2.87 (m, 4H), 2.05 (q, J=8.00 Hz, 2H),
1.47 (s, 6H).
5-[3-(3, 4-Dimethoxy-phenyl)-4, 4-dimethyl-4,
5-dihydro-pyrazole-1-carbonyl]-2-methyl-isoindole-1,3-dione
##STR00377##
[0441] Yellow solid; 11.18% Yield
[0442] LC-MS: Mass found (M+, 422.2). Rt (min): 4.22; % Area: 99.08
(Max), 98.59 (254 nm).
[0443] HPLC--Rt (min): 4.21; % Area: 99.27 (Max), 98.91 (254
nm).
[0444] 400 MHz, DMSO-d6: .delta. 8.34 (s, 1H), 8.23 (d, J=8.00 Hz,
1H), 7.95 (d, J=8.00 Hz, 1H), 7.34 (d, J=8.00 Hz, 1H), 7.26 (d,
J=4.00 Hz, 1H), 6.98 (d, J=8.00 Hz, 1H), 3.97 (s, 2H), 3.79 (s,
3H), 3.74 (s, 3H), 3.05 (s, 3H), 1.51 (s, 6H).
5-[3-(3, 4-Dimethoxy-phenyl)-4, 4-dimethyl-4,
5-dihydro-pyrazole-1-carbonyl]-1, 3-dihydro-indol-2-one
##STR00378##
[0446] Yellow solid; 14.71% Yield
[0447] LC-MS: Mass found (M+, 394.3). Rt (min): 2.94; % Area: 94.48
(Max), 95.26 (254 nm).
[0448] HPLC--Rt (min): 3.47; % Area: 95.98 (Max), 95.74 (254
nm).
[0449] 400 MHz, DMSO-d6: .delta. 10.62 (s, 1H), 7.82 (s, 1H), 7.81
(d, J=8.00 Hz, 1H), 7.34 (dd, J=8.00, 4.00 Hz, 1H), 7.26 (s, 1H),
6.98 (d, J=8.00 Hz, 1H), 6.87 (d, J=8.00 Hz, 1H), 3.90 (s, 2H),
3.79 (s, 3H), 3.76 (s, 3H), 3.52 (s, 2H), 1.47 (s, 6H).
5-[3-(3, 4-Dimethoxy-phenyl)-4, 4-dimethyl-4,
5-dihydro-pyrazole-1-carbonyl]-2-methyl-isoindole-1, 3-dione
##STR00379##
[0451] Yellow solid; 14.49% Yield
[0452] LC-MS: Mass found (M+, 379.3). Rt (min): 4.56; % Area: 93.42
(Max), 95.41 (254 nm).
[0453] HPLC--Rt (min): 4.56; % Area: 96.17 (Max), 96.21 (254
nm).
[0454] 400 MHz, DMSO-d6: .delta. 8.25 (s, 1H), 8.07 (d, J=4.00 Hz,
1H), 7.85 (d, J=8.00 Hz, 1H), 7.66 (d, J=8.00 Hz, 1H), 7.33 (d,
J=8.00 Hz, 1H), 7.25 (s, 1H), 7.07-7.06 (m, 1H), 6.98 (d, J=8.00
Hz, 1H), 3.95 (s, 2H), 3.78 (s, 3H), 3.73 (s, 3H), 1.49 (s,
6H).
[3-(3, 4-Dimethoxy-phenyl)-4, 4-dimethyl-4,
5-dihydro-pyrazol-1-yl]-quinolin-6-yl-methanone
##STR00380##
[0456] Yellow solid; 9.45% Yield
[0457] LC-MS: Mass found (M+, 390). Rt (min): 3.11; % Area: 98.54
(Max), 98.14 (254 nm).
[0458] HPLC--Rt (min): 3.08; % Area: 99.10 (Max), 98.28 (254
nm).
[0459] 400 MHz, DMSO-d6: .delta. 8.99-8.97 (m, 1H), 8.59 (s, 1H),
8.52 (d, J=8.00 Hz, 1H), 8.18 (d, J=12.00 Hz, 1H), 8.07 (d, J=8.00
Hz, 1H), 7.61-7.58 (m, 1H), 7.36 (dd, J=8.00, 4.00 Hz, 1H), 7.28
(s, 1H), 6.98 (d, J=8.00 Hz, 1H), 4.00 (s, 2H), 3.78 (s, 3H), 3.71
(s, 3H), 1.52 (s, 6H).
(2, 3-Dihydro-benzo [1, 4] dioxin-6-yl)-[3-(3,
4-dimethoxy-phenyl)-4, 4-dimethyl-4,
5-dihydro-pyrazol-1-yl]-methanone
##STR00381##
[0461] Brown solid; 11.58% Yield
[0462] LC-MS: Mass found (M+, 397.3). Rt (min): 4.31; % Area: 91.44
(Max), 93.57 (254 nm).
[0463] HPLC--Rt (min): 4.32; % Area: 91.86 (Max), 92.68 (254
nm).
[0464] 400 MHz, DMSO-d6: .delta. 7.49-7.45 (m, 2H), 7.34-7.31 (m,
1H), 7.26 (d, J=4.00 Hz, 1H), 7.00 (d, J=8.00 Hz, 1H), 6.91 (d,
J=8.00 Hz, 1H), 4.30-4.25 (m, 4H), 3.89 (s, 2H), 3.79 (s, 3H), 3.76
(s, 3H), 1.46 (s, 6H).
Example 4: Synthetic route towards
1-[3-(3,4-dimethoxy-phenyl)-4,5-dihydro-pyrazol-1-yl]-2-phenyl-ethanones
##STR00382##
[0466] It shall be understood that the phenyl moiety (radical R)
can be substituted in accordance with the Ar.sup.1 definition as
demonstrated below.
Step 1
##STR00383##
[0468] 1-(3,4-Dimethoxy-phenyl)-3-dimethylamino-propan-1-one. HCl.
A round bottom flask equipped with a stir bar, Vigreux column and
nitrogen inlet was charged with 1-(3,4-dimethoxy-phenyl)-ethanone
(18.0 g, 100 mmol), paraformaldehyde (6 g, 200 mmol),
dimethylamine.HCl (8.2 g, 100 mL) and EtOH, (50 mL). To this
mixture was added 20 drops of conc. HCl and the reaction was heated
at 80.degree. C. for 18 h. TLC still showed consumption of SM. It
was added to Et.sub.2O causing a ppt to form. This was filtered and
washed with Et.sub.2O. Amount HCl salt obtained: 3.98 g, 13 mmol,
88% yield. Material was used as is in the next step. LC-MS (ESI)
m/e 238 (M+H).
Step 2
##STR00384##
[0470] 3-(3,4-Dimethoxy-phenyl)-4,5-dihydro-1H-pyrazole. A 100 mL
round bottom flask equipped with a stir bar, Vigreux column and
nitrogen inlet was charged with
1-(3,4-dimethoxy-phenyl)-3-dimethylamino-propan-1-one.HCl, (1.4 g,
5 mmol) EtOH, (20 mL) and hydrazine monohydrate, (0.3 mL, 6 mmol).
The mixture was heated at 80.degree. C. for 2 h. LC-MS and TLC
analysis showed consumption of SM. The solvent was evaporated under
reduced pressure and trace hydrazine and EtOH was removed under
high vacuum for 30 min. The material was used as in the next step.
Amount obtained 1030 mg, 5 mmol, 100% yield. LC-MS (ESI) m/e 207
(M+H).
Step 3
##STR00385##
[0472]
1-[3-(3,4-Dimethoxy-phenyl)-4,5-dihydro-pyrazol-1-yl]-2-phenyl-etha-
none (29). A scintillation vial equipped with a stir bar was
charged with 3-(3,4-dimethoxy-phenyl)-4,5-dihydro-1H-pyrazole (412
mg, 2 mmol), Hunigs base (1 mL, 6 mmol) and dry CH.sub.2Cl.sub.2
(10 mL). To this mixture was added phenyl-acetyl chloride, (0.27
mL, 2 mmol) and the reaction was stirred at RT for 3 h. LC-MS
indicated consumption of SM. The mixture was diluted with
CH.sub.2Cl.sub.2 (50 mL) and added to water (50 mL). The phases
were separated and the CH.sub.2Cl.sub.2 phase was washed with
saturated Na.sub.2CO.sub.3, (50 mL), dried (Na.sub.2SO.sub.4) and
the solvent was evaporated under reduced pressure. The material was
purified using a 40 g silica cartridge eluting with heptane-EtOAc,
gradient 0 to 100% EtOAc. Amount obtained: 123 mg, 0.37 mmol, 19%
yield. LC-MS (ESI) m/e 325 (M+H). .sup.1H NMR (400 MHz,
CHLOROFORM-d) .delta. ppm 3.21 (t, J=10.03 Hz, 2H) 3.94 (s, 3H)
3.98 (s, 3H) 4.04 (t, J=10.03 Hz, 2H) 4.11 (s, 2H) 6.90 (d, J=8.35
Hz, 1H) 7.16 (dd, J=8.27, 1.88 Hz, 1H) 7.21-7.26 (m, 1H) 7.31 (t,
J=7.42 Hz, 2H) 7.40-7.44 (m, 3H).
##STR00386##
[0473]
1-[3-(3,4-Dimethoxy-phenyl)-4,5-dihydro-pyrazol-1-yl]-2-(3-fluoro-p-
henyl)-ethanone (241). Prepared following the same procedure as
1-[3-(3,4-Dimethoxy-phenyl)-4,5-dihydro-pyrazol-1-yl]-2-phenyl-ethanone
(29). Amount obtained: 50 mg, 0.15 mmol, 7% yield. LC-MS (ESI) m/e
343 (M+H). 1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 3.22 (t,
J=10.01 Hz, 2H) 3.95 (s, 3H) 3.98 (s, 3H) 4.05 (t, J=10.03 Hz, 2H)
4.10 (s, 2H) 6.90 (d, J=8.39 Hz, 1H) 6.93-6.96 (m, 1H) 7.13-7.21
(m, 2H) 7.24-7.30 (m, 2H) 7.41 (d, J=1.85 Hz, 1H).
##STR00387##
[0474]
2-(2,3-Difluoro-phenyl)-1-[3-(3,4-dimethoxy-phenyl)-4,5-dihydro-pyr-
azol-1-yl]-ethanone (261). Prepared following the same procedure as
1-[3-(3,4-Dimethoxy-phenyl)-4,5-dihydro-pyrazol-1-yl]-2-phenyl-ethanone
(29). Amount obtained: 23 mg, 0.06 mmol, 3% yield. LC-MS (ESI) m/e
361 (M+H). .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 3.22 (t,
J=9.98 Hz, 2H) 3.94 (s, 3H) 3.98 (s, 3H) 4.05 (t, J=9.98 Hz, 2H)
4.16 (s, 2H) 6.88 (d, J=8.30 Hz, 1H) 6.99-7.08 (m, 2H) 7.10-7.17
(m, 2H) 7.47 (d, J=1.81 Hz, 1H).
Example 5: Synthetic route towards
(3-Fluoro-phenyl)-(3-m-tolyl-4,5-dihydro-pyrazol-1-yl)-methanone
##STR00388##
##STR00389##
[0476]
[3-(3-Bromo-phenyl)-4,5-dihydro-pyrazol-1-yl]-(3-fluoro-phenyl)-met-
hanone. Prepared beginning with 1-(3-bromo-phenyl)-ethanone
following the same procedure as
1-[3-(3,4-Dimethoxy-phenyl)-4,5-dihydro-pyrazol-1-yl]-2-phenyl-ethanone
(29). LC-MS (ESI) m/e 347 & 349 (M+H). .sup.1H NMR
(CHLOROFORM-d) .delta.: 7.76-7.82 (m, 2H), 7.71 (d, J=9.7 Hz, 1H),
7.65 (d, J=7.8 Hz, 1H), 7.56 (d, J=8.0 Hz, 1H), 7.44 (td, J=8.0,
5.8 Hz, 1H), 7.30 (t, J=8.0 Hz, 1H), 7.22 (td, J=8.3, 2.1 Hz, 1H),
4.29 (t, 2H), 3.27 (t, 1H).
Step 1
##STR00390##
[0478]
3-[1-(3-Fluoro-benzoyl)-4,5-dihydro-1H-pyrazol-3-yl]-benzonitrile.
A scintillation vial equipped with a stir bar was charged with
[3-(3-bromo-phenyl)-4,5-dihydro-pyrazol-1-yl]-(3-fluoro-phenyl)-methanone
(347 mg, 1.0 mmol), Zn(CN).sub.2 (234 mg, 2.0 mmol), Zn dust (65
mg, 1.0 mmol) and DMA (10 mL). The mixture was degassed and then
Pd(t-Bu.sub.3P).sub.2 (51 mg, 0.1 mmol) was added. The mixture was
heated at 80.degree. C. for 4 h. LC-MS showed consumption of SM.
The material was filtered through a pad of Fluorosil and the
solvent was evaporated under reduced pressure. It was purified by
chromatography using a 12 g silica cartridge eluting with
heptane-EtOAc, gradient 30 to 100% EtOAc. Amount obtained: 225 mg,
0.76 mmol, 76% yield. LC-MS (ESI) m/e 294 (M+H). .sup.1H NMR
(CHLOROFORM-d) .delta.: 7.92-7.97 (m, 2H), 7.76 (d, J=7.8 Hz, 1H),
7.66-7.74 (m, 2H), 7.52-7.59 (m, 1H), 7.45 (td, J=8.0, 5.8 Hz, 1H),
7.20-7.30 (m, 1H), 4.32 (t, J=10.1 Hz, 2H), 3.26-3.34 (m, 2H).
Step 2
##STR00391##
[0480]
(3-Fluoro-phenyl)-(3-m-tolyl-4,5-dihydro-pyrazol-1-yl)-methanone
(179).
3-[1-(3-Fluoro-benzoyl)-4,5-dihydro-1H-pyrazol-3-yl]-benzonitrile
(88 mg, 0.30 mmol), dissolved in EtOH (10 mL) and EtOAc (10 mL) was
passed through the H-cube equipped with a 10% Pd/C cartridge.
Temperature 80.degree. C., 50 bar, flow rate, 1 mL/min. LC-MS
showed consumption of SM. The solvent was evaporated under pressure
and the material was purified by chromatography using a 12 g silica
cartridge eluting with heptane-EtOAc, gradient 0 to 50% EtOAc.
Amount obtained: 30 mg, 0.11 mmol, 35% yield. LC-MS (ESI) m/e 283
(M+H). .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 2.40 (s, 3H)
3.26-3.33 (m, 2H) 4.27 (t, J=9.96 Hz, 2H) 7.17-7.26 (m, 2H) 7.32
(t, J=7.81 Hz, 1H) 7.43 (td, J=7.98, 5.81 Hz, 1H) 7.49-7.54 (m, 2H)
7.73-7.84 (m, 2H).
##STR00392##
[0481]
(3-Fluoro-phenyl)-(3-o-tolyl-4,5-dihydro-pyrazol-1-yl)-methanone
(215). Prepared following the same procedure as
(3-Fluoro-phenyl)-(3-m-tolyl-4,5-dihydro-pyrazol-1-yl)-methanone
(29). Amount obtained: 33 mg, 0.12 mmol, 39% yield. LC-MS (ESI) m/e
283 (M+H). .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 2.53 (s,
3H) 3.36 (t, 2H) 4.22 (t, J=9.96 Hz, 2H) 7.18 (td, J=8.36, 2.03 Hz,
1H) 7.28-7.34 (m, 3H) 7.36-7.41 (m, 1H) 7.41-7.45 (m, 1H) 7.72 (d,
J=9.81 Hz, 1H) 7.77 (d, J=7.76 Hz, 1H).
Example 6: Synthetic route towards
(3-Fluoro-phenyl)-[3-(3-phenylethynyl-phenyl)-4,5-dihydro-pyrazol-1-yl]-m-
ethanone
##STR00393##
[0483]
(3-Fluoro-phenyl)-[3-(3-phenylethynyl-phenyl)-4,5-dihydro-pyrazol-1-
-yl]-methanone (183).
[3-(3-Bromo-phenyl)-4,5-dihydro-pyrazol-1-yl]-(3-fluoro-phenyl)-methanone
was prepared beginning with 1-(3-bromo-phenyl)-ethanone following
the same procedure as for
1-[3-(3,4-Dimethoxy-phenyl)-4,5-dihydro-pyrazol-1-yl]-2-phenyl-ethanone
(29). A scintillation vial equipped with a stir bar was charged
with the
[3-(3-bromo-phenyl)-4,5-dihydro-pyrazol-1-yl]-(3-fluoro-phenyl)-methanone
(138 mg, 0.40 mmol), phenyl acetylene (0.09 mL, 0.80 mmol) CuI (15
mg, 0.08 mmol), triethylamine (0.28 mL, 2.00 mmol) and acetonitrile
(4 mL). The mixture was degassed with nitrogen and
PdCl.sub.2(PPh.sub.3).sub.2 (56 mg, 0.08 mmol) was added. The
reaction was heated at 80.degree. C. under a nitrogen atmosphere
for 5 h. LC-MS showed consumption of SM. The solvent was evaporated
under reduced pressure. The material was dissolved in
CH.sub.2Cl.sub.2 (50 mL) and passed through a pad of Fluorosil. The
solvent was evaporated and the material was purified by
chromatography using a 12 g silica cartridge eluting with
heptane-EtOAc, gradient 0 to 50% EtOAc. Amount obtained: 13 mg,
0.04 mmol, 10% yield. LC-MS (ESI) m/e 369 (M+H). .sup.1H NMR (400
MHz, CHLOROFORM-d) .delta. ppm 3.31 (t, J=10.01 Hz, 2H) 4.29 (t,
J=10.01 Hz, 2H) 7.22 (td, J=8.32, 2.00 Hz, 1H) 7.36-7.48 (m, 5H)
7.54-7.62 (m, 3H) 7.70-7.77 (m, 2H) 7.79-7.83 (m, 2H).
##STR00394##
[0484]
(3-Fluoro-phenyl)-[3-(4-trifluoromethoxy-phenyl)-4,5-dihydro-pyrazo-
l-1-yl]-methanone (162). Prepared beginning with
1-(4-trifluoromethoxy-phenyl)-ethanone following the same procedure
as
1-[3-(3,4-Dimethoxy-phenyl)-4,5-dihydro-pyrazol-1-yl]-2-phenyl-ethanone
(29). Amount obtained: 103 mg, 0.29 mmol, 12% yield. LC-MS (ESI)
m/e 353 (M+H). .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 3.29
(t, 2H) 4.30 (t, 2H) 7.18-7.25 (m, 1H) 7.25-7.30 (m, 2H) 7.43 (td,
J=7.99, 5.78 Hz, 1H) 7.66-7.85 (m, 4H).
##STR00395##
[0485]
Benzo[1,3]dioxol-5-yl-[3-(4-trifluoromethoxy-phenyl)-4,5-dihydro-py-
razol-1-yl]-methanone (199). Prepared beginning with
1-(4-trifluoromethoxy-phenyl)-ethanone following the same procedure
as
1-[3-(3,4-Dimethoxy-phenyl)-4,5-dihydro-pyrazol-1-yl]-2-phenyl-ethanone
(29). Amount obtained 180 mg, 0.48 mmol, 19% yield. LC-MS (ESI) m/e
379 (M+H). .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 3.25 (t,
J=10.08 Hz, 2H) 4.27 (t, J=10.08 Hz, 2H) 6.05 (s, 2H) 6.88 (d,
J=8.20 Hz, 1H) 7.25-7.29 (m, 2H) 7.55 (d, J=1.46 Hz, 1H) 7.64 (dd,
J=8.17, 1.54 Hz, 1H) 7.75 (d, J=8.79 Hz, 2H).
##STR00396##
[0486]
(3-Fluoro-phenyl)-[3-(4-methylsulfanyl-phenyl)-4,5-dihydro-pyrazol--
1-yl]-methanone (204). Prepared beginning with
1-(4-methylsulfanyl-phenyl)-ethanone following the same procedure
as
1-[3-(3,4-Dimethoxy-phenyl)-4,5-dihydro-pyrazol-1-yl]-2-phenyl-ethanone
(29). Amount obtained: 178 mg, 0.57 mmol, 23% yield. LC-MS (ESI)
m/e 315 (M+H). .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 2.52
(s, 3H) 3.27 (t, J=9.96 Hz, 2H) 4.27 (t, J=9.96 Hz, 2H) 7.20 (td,
J=8.27, 2.34 Hz, 1H) 7.25 (s, 1H) 7.42 (td, J=7.97, 5.83 Hz, 2H)
7.62 (d, J=8.44 Hz, 2H) 7.75 (d, J=9.81 Hz, 1H) 7.80 (d, J=7.76 Hz,
1H).
##STR00397##
[0487]
Benzo[1,3]dioxol-5-yl-[3-(4-methylsulfanyl-phenyl)-4,5-dihydro-pyra-
zol-1-yl]-methanone (205). Prepared beginning with
1-(4-methylsulfanyl-phenyl)-ethanone following the same procedure
as
1-[3-(3,4-Dimethoxy-phenyl)-4,5-dihydro-pyrazol-1-yl]-2-phenyl-ethanone
(29). Amount obtained: 53 mg, 0.16 mmol, 6% yield. LC-MS (ESI) m/e
341 (M+H). .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 2.52 (s,
3H) 3.23 (t, J=10.01 Hz, 2H) 4.24 (t, J=10.01 Hz, 2H) 6.05 (s, 2H)
6.88 (d, J=8.20 Hz, 1H) 7.25 (s, 1H) 7.27 (s, 1H) 7.58 (d, J=1.27
Hz, 1H) 7.63 (d, J=8.44 Hz, 2H) 7.67 (dd, J=8.20, 1.37 Hz, 1H).
Example 7: Synthetic route towards 3-(3,4
dimethoxyphenyl)-4,5-dihydro-1H-pyrazole-1
[0488] carbonyl derivatives
##STR00398##
Step 1: Preparation of
1-(3,4-Dimethoxyphenyl-3-(dimethylamino)propan-1-one
##STR00399##
[0490] To a stirred solution of 3,4-Dimethoxy acetophenone (3 g,
0.0166 moles, 1 equiv.) in ethanol was added paraformaldehyde (0.5
g, 0.0166 moles, 1 equiv.), dimethylamine hydrochloride (4.2 g,
0.0499 moles, 3 equiv.) and the reaction mixture was refluxed at
80.degree. C. for 12 h. Consumption of starting materials was
confirmed by LC-MS analysis and TLC. Ethanol was evaporated under
reduced pressure; the crude solid residue was stirred with acetone
at 0.degree. C. for 1 h, filtered, washed with acetone, dried under
vacuum. After that the solid was suspended in water, basified with
10% sodium bicarbonate solution (pH .about.8), extracted by
dichloromethane (2.times.200 ml), washed with water followed by
satd. Brine solution. The organic layer was dried over sodium
sulfate and concentrated to get 2.9 g (73% yield) title compound as
green oily liquid. It was taken forward for the next step without
any further purification.
[0491] R.sub.f=0.15
[0492] Green oily liquid; 73% Yield
[0493] LC-MS: Mass found (M+, 238.2)
[0494] Method: A-: 0.1% HCOOH, B-: MeOH Flow--1 ml/min. Atlantis
dC18 (50.times.4.6 mm, 5 .mu.m). Rt (min): 0.946; % Area:
96.97.
[0495] HPLC--Method: A-: 0.1% TFA in water, B-: 0.1% TFA in CAN:
Flow--1 ml/min. Column: Xbridge C8 (50.times.4.6 mm, 3.5 .mu.m). Rt
(min): 1.76; % Area: 95.21 (Max), 91.73 (254 nm).
[0496] .sup.1H NMR 400 MHz, DMSO-d6: .delta. 7.65 (dd, J=8.00, 4.00
Hz, 1H), 7.44 (d, J=4.00 Hz, 1H), 7.04 (d, J=8.00 Hz, 1H), 3.85 (s,
3H), 3.80 (s, 3H), 3.07 (t, J=8.00 Hz, 2H), 2.57 (t, J=8.00 Hz,
2H), 2.14 (s, 6H).
Step 2: Preparation of 3-(3,4
dimethoxyphenyl)-4,5-dihydro-1H-pyrazole
##STR00400##
[0497] To a stirred solution of
1-(3,4-dimethoxyphenyl-3-(dimethylamino)propan-1-one (2.9 g, 0.0122
moles, 1 equiv.) in absolute ethanol was added hydrazine hydrate
(99%-100%) (1.18 ml, 0.0244 moles, 2 equiv) drop wise. After that
the reaction mixture was refluxed for 4 h at 80.degree. C. under
inert atmosphere. Consumption of starting materials was confirmed
by LC-MS analysis and TLC. Ethanol and excess hydrazine hydrate was
evaporated under reduced pressure and to the crude product was
stirred with diethyl ether at RT for 30 mins, filtered washed with
ether and finally dried under vacuum to get 2.4 g (95% yield) of
the title product as yellow solid.
[0498] R.sub.f=0.2
[0499] White solid; 95% Yield
[0500] LC-MS: Mass found (M+, 207)
[0501] Method: A-: 0.1% TFA in water, B-: 0.1% TFA in ACN:
Flow--0.6 ml/min. Column: Xbridge C8 (50.times.4.6 mm, 3.5 .mu.m).
Rt (min): 1.49; % Area: 58.00.
[0502] .sup.1H NMR 400 MHz, DMSO-d6: .delta. 7.25 (d, J=4.00 Hz,
1H), 7.04 (d, J=8.00 Hz, 1H), 6.93 (d, J=8.00 Hz, 1H), 3.83-3.80
(m, 1H), 3.75 (s, 6H), 3.31 (t, J=8.00 Hz, 2H), 2.82 (t, J=8.00 Hz,
2H).
##STR00401##
[0503] In an 8 ml vial, a solution of
3-(3,4-Dimethoxy-phenyl)-4,5-dihydro-1H-pyrazole (100 mg, 0.48
mmol, 1 equiv) in 5 ml dichloromethane was mixed with respective
acid (4) (0.53 mmol, 1 equiv.) and triethylamine (147.3 mg, 1.4
mmol, 3 equiv). 1-propane phosphonic cyclic anhydride (60% in ethyl
acetate) (309.46 mg, 0.97 mmol, 3 equiv) was added to this reaction
mixture at 0.degree. C. After the addition, reaction mixture was
placed in the orbital shaker for about 12 h. Upon consumption of
SM, reaction mixture was concentrated in Genvac to remove the
solvent, dissolved in dichloromethane (4 ml) and washed with water
(4 ml), the organic layer was evaporated in Genvac. The residue was
passed through SPE-NH.sub.2 column (2 g, 6 ml) to get the pure
product. The solvents used for elution were pet
ether/dichloromethane/methanol.
[0504] The following compounds were prepared in a similar manner.
LC-MS and HPLC analysis were performed as follows: Method: A-0.1%
TFA in water, B-0.1% TFA in ACN: Flow--2 ml/min;
[0505] Column: XBridge c8 (50.times.4.6 mm, 3.5 .mu.m); unless
stated otherwise.
(3-Bromo-phenyl)-[3-(3,4-dimethoxy-phenyl)-4,5-dihydro-pyrazol-1-yl]-metha-
none
##STR00402##
[0507] White solid; 30.17% Yield
[0508] LC-MS: Mass found (M+, 389). Rt (min): 4.44; % Area: 99.16
(Max), 99.30 (254 nm).
[0509] HPLC--Flow--1.0 ml/min. Rt (min): 4.50; % Area: 99.68 (Max),
99.20 (254 nm).
[0510] .sup.1H NMR 400 MHz, CDCl.sub.3: .delta. 8.29 (s, 1H), 7.94
(d, J=8.00 Hz, 1H), 7.62 (td, J=2.00, 1.20 Hz, 1H), 7.40 (d, J=4.00
Hz, 1H), 7.33 (t, J=8.00 Hz, 1H), 7.14 (dd, J=8.40, 2.00 Hz, 1H),
6.89 (d, J=12.00 Hz, 1H), 4.26 (t, J=8.00 Hz, 2H), 3.93 (s, 6H),
3.28 (t, J=8.00 Hz, 2H).
(3-Chloro-phenyl)-[3-(3,4-dimethoxy-phenyl)-4,5-dihydro-pyrazol-1-yl]-meth-
anone
##STR00403##
[0512] White solid; 21.38% Yield
[0513] LC-MS: Mass found (M+, 345). Rt (min): 4.36; % Area: 99.73
(Max), 99.54 (254 nm).
[0514] HPLC--Flow--1.0 ml/min. Rt (min): 4.44; % Area: 98.76 (Max),
98.44 (254 nm).
[0515] .sup.1H NMR 400 MHz, DMSO-d6: .delta. 7.95 (s, 1H), 7.83 (d,
J=8.00 Hz, 1H), 7.61-7.58 (m, 1H), 7.51 (t, J=8.00 Hz, 1H),
7.25-7.04 (m, 2H), 7.03 (d, J=8.00 Hz, 1H), 4.09 (t, J=12.00 Hz,
2H), 3.79 (s, 3H), 3.76 (s, 3H), 3.33 (t, J=12.00 Hz, 2H).
[3-(3,4-Dimethoxy-phenyl)-4,5-dihydro-pyrazol-1-yl]-(3-methoxy-phenyl)-met-
hanone
##STR00404##
[0517] Yellow solid; 35.81% Yield
[0518] LC-MS: Mass found (M+, 341). Rt (min): 3.87; % Area: 96.42
(Max), 96.54 (254 nm).
[0519] HPLC--Flow--1.0 ml/min. Rt (min): 3.88; % Area: 96.96 (Max),
95.83 (254 nm).
[0520] .sup.1H NMR 400 MHz, CDCl.sub.3: .delta. 7.62-7.58 (m, 2H),
7.37-7.33 (m, 2H), 7.18 (d, J=8.00 Hz, 1H), 7.06-7.03 (m, 1H), 6.88
(d, J=8.00 Hz, 1H), 4.26 (t, J=12.00 Hz, 2H), 3.95 (s, 3H), 3.93
(s, 3H), 3.90 (s, 3H), 3.26 (t, J=12.00 Hz, 2H).
[3-(3,4-Dimethoxy-phenyl)-4,5-dihydro-pyrazol-1-yl]-(3-ethoxy-phenyl)-meth-
anone
##STR00405##
[0522] Yellow solid; 37.36% Yield
[0523] LC-MS: Mass found (M+, 355). Rt (min): 4.21; % Area: 95.38
(Max), 94.61 (254 nm).
[0524] HPLC--Flow--1.0 ml/min. Rt (min): 4.21; % Area: 95.51 (Max),
93.71 (254 nm).
[0525] .sup.1H NMR 400 MHz, CDCl.sub.3: .delta. 7.60-7.58 (m, 2H),
7.35-7.32 (m, 2H), 7.17 (dd, J=8.00, 4.00 Hz, 1H), 7.03 (td,
J=5.00, 1.20 Hz, 1H), 6.88 (d, J=8.00 Hz, 1H), 4.26 (t, J=8.00 Hz,
2H), 4.09 (q, J=8.00 Hz, 2H), 3.93 (s, 3H), 3.90 (s, 3H), 3.26 (t,
J=8.00 Hz, 2H), 1.42 (t, J=8.00 Hz, 3H).
[3-(3,4-Dimethoxy-phenyl)-4,5-dihydro-pyrazol-1-yl]-(3-trifluoromethyl-phe-
nyl)-methanone
##STR00406##
[0527] Yellow solid; 19.35% Yield
[0528] LC-MS: Mass found (M+, 379). Rt (min): 4.63; % Area: 99.37
(Max), 99.73 (254 nm).
[0529] HPLC--Rt (min): 4.64; % Area: 98.52 (Max), 98.24 (254
nm).
[0530] .sup.1H NMR 400 MHz, DMSO-d6: .delta. 8.31 (d, J=8.00 Hz,
1H), 8.15 (d, J=8.00 Hz, 1H), 7.90 (d, J=8.00 Hz, 1H), 7.73 (t,
J=8.00 Hz, 1H), 7.26-7.21 (m, 2H), 7.03 (d, J=8.00 Hz, 1H), 4.12
(t, J=12.00 Hz, 2H), 3.79 (s, 3H), 3.74 (s, 3H), 3.31 (t, J=12.00
Hz, 2H).
[3-(3,4-Dimethoxy-phenyl)-4,5-dihydro-pyrazol-1-yl]-m-tolyl-methanone
##STR00407##
[0532] Brown gum; 13.86% Yield
[0533] LC-MS: Mass found (M+, 325). Rt (min): 4.14; % Area: 97.97
(Max), 97.64 (254 nm).
[0534] HPLC--Rt (min): 4.14; % Area: 96.54 (Max), 95.92 (254
nm).
[0535] .sup.1H NMR 400 MHz, CDCl.sub.3: .delta. 7.83-7.79 (m, 2H),
7.35-7.29 (m, 3H), 7.16 (d, J=8.00 Hz, 1H), 6.88 (d, J=8.00 Hz,
1H), 4.26 (t, J=8.00 Hz, 2H), 3.95 (s, 3H), 3.90 (s, 3H), 3.26 (t,
J=8.00 Hz, 2H), 2.42 (s, 3H).
3-[3-(3,4-Dimethoxy-phenyl)-4,5-dihydro-pyrazole-1-carbonyl]-benzonitrile
##STR00408##
[0537] White solid; 82.23% Yield
[0538] LC-MS: Mass found (M+, 336). Rt (min): 3.84; % Area: 98.37
(Max), 98.63 (254 nm).
[0539] HPLC--Rt (min): 3.84; % Area: 97.96 (Max), 97.30 (254
nm).
[0540] .sup.1H NMR 400 MHz, CDCl.sub.3: .delta. 8.46 (s, 1H), 8.24
(d, J=8.00 Hz, 1H), 7.78 (dt, J=7.73, 1.20 Hz, 1H), 7.58 (t, J=8.00
Hz, 1H), 7.34 (d, J=2.00 Hz, 1H), 7.17 (dd, J=8.40, 2.00 Hz, 1H),
6.90 (d, J=8.00 Hz, 1H), 4.28 (t, J=8.00 Hz, 2H), 3.94 (s, 3H),
3.93 (s, 3H), 3.30 (t, J=12.00 Hz, 2H).
[3-(3,4-Dimethoxy-phenyl)-4,5-dihydro-pyrazol-1-yl]-(3-trifluoromethoxy-ph-
enyl)-methanone
##STR00409##
[0542] White solid; 20.97% Yield
[0543] LC-MS: Mass found (M+, 325). Rt (min): 4.74; % Area: 98.76
(Max), 98.56 (254 nm).
[0544] HPLC--Rt (min): 4.72; % Area: 97.48 (Max), 97.51 (254
nm).
[0545] .sup.1H NMR 400 MHz, CDCl.sub.3: .delta. 8.00 (s, 1H), 7.95
(d, J=8.00 Hz, 1H), 7.49 (t, J=8.00 Hz, 1H), 7.36-7.34 (m, 2H),
7.16 (dd, J=8.00, 4.00 Hz, 1H), 6.89 (d, J=8.00 Hz, 1H), 4.27 (t,
J=8.00 Hz, 2H), 3.93 (s, 3H), 3.90 (s, 3H), 3.29 (t, J=8.00 Hz,
2H).
[3-(3,4-Dimethoxy-phenyl)-4,5-dihydro-pyrazol-1-yl]-(3-dimethylamino-pheny-
l)-methanone
##STR00410##
[0547] Yellow solid; 11.15% Yield
[0548] LC-MS: Mass found (M+, 354). Rt (min): 2.65; % Area: 98.79
(Max), 99.07 (254 nm).
[0549] HPLC--Rt (min): 2.65; % Area: 96.98 (Max), 96.66 (254
nm).
[0550] .sup.1H NMR 400 MHz, DMSO-d6: .delta. 7.28-7.22 (m, 4H),
7.15 (d, J=4.00 Hz, 1H), 7.03 (d, J=12.00 Hz, 1H), 6.87 (dd,
J=8.00, 4.00 Hz, 1H), 4.07 (t, J=8.00 Hz, 2H), 3.79 (s, 3H), 3.75
(s, 3H), 3.27 (t, J=12.00 Hz, 2H), 2.92 (s, 6H).
(3-Benzyloxy-phenyl)-[3-(3,4-dimethoxy-phenyl)-4,5-dihydro-pyrazol-1-yl]-m-
ethanone
##STR00411##
[0552] White solid; 33.15% Yield
[0553] LC-MS: Mass found (M+, 417). Rt (min): 4.87; % Area: 94.89
(Max), 93.72 (254 nm).
[0554] HPLC--Rt (min): 4.88; % Area: 94.10 (Max), 91.01 (254
nm).
[0555] .sup.1H NMR 400 MHz, CDCl.sub.3: .delta. 7.80-7.70 (m, 1H),
7.64 (d, J=8.00 Hz, 1H), 7.45-7.32 (m, 7H), 7.17 (dd, J=8.00, 4.00
Hz, 1H), 7.12 (dd, J=4.60, 2.80 Hz, 1H), 6.88 (d, J=8.00 Hz, 1H),
5.12 (s, 2H), 4.26 (t, J=12.00 Hz, 2H), 3.95 (s, 3H), 3.99 (s, 3H),
3.26 (t, J=12.00 Hz, 2H).
[3-(3,4-Dimethoxy-phenyl)-4,5-dihydro-pyrazol-1-yl]-(3-isopropoxy-phenyl)--
methanone
##STR00412##
[0557] Yellow solid; 18.81% Yield
[0558] LC-MS: Mass found (M+, 369). Rt (min): 4.45; % Area: 97.00
(Max), 96.31 (254 nm).
[0559] HPLC--Rt (min): 4.48; % Area: 97.23 (Max), 95.98 (254
nm).
[0560] .sup.1H NMR 400 MHz, CDCl.sub.3: .delta. 7.56 (d, J=8.00 Hz,
2H), 7.35-7.27 (m, 2H), 7.02 (dt, J=8.13, 0.80 Hz, 1H), 6.88 (d,
J=8.00 Hz, 1H), 4.62-4.59 (m, 1H), 4.26 (t, J=8.00 Hz, 2H), 3.93
(s, 3H), 3.89 (s, 3H), 3.26 (t, J=8.00 Hz, 2H), 1.36 (s, 3H), 1.35
(s, 3H).
[3-(3,4-Dimethoxy-phenyl)-4,5-dihydro-pyrazol-1-yl]-(3-phenoxy-phenyl)-met-
hanone
##STR00413##
[0562] Brown gum; 35.41% Yield
[0563] LC-MS: Mass found (M+, 403). Rt (min): 4.80; % Area: 97.93
(Max), 96.41 (254 nm).
[0564] HPLC--Rt (min): 4.85; % Area: 97.21 (Max), 95.15 (254
nm).
[0565] .sup.1H NMR 400 MHz, CDCl.sub.3: .delta. 7.77-7.73 (m, 2H),
7.42 (t, J=8.00 Hz, 1H), 7.34-7.30 (m, 3H), 7.17-7.03 (m, 5H), 6.87
(d, J=8.00 Hz, 1H), 4.24 (t, J=8.00 Hz, 2H), 3.93 (s, 3H), 3.83 (s,
3H), 3.25 (t, J=8.00 Hz, 2H).
[0566]
Biphenyl-3-yl-[3-(3,4-dimethoxy-phenyl)-4,5-dihydro-pyrazol-1-yl]-m-
ethanone
##STR00414##
[0567] White solid; 35.56% Yield
[0568] LC-MS: Mass found (M+, 387). Rt (min): 4.79; % Area: 99.10
(Max), 99.47 (254 nm).
[0569] HPLC--Rt (min): 4.85; % Area: 97.41 (Max), 98.79 (254
nm).
[0570] .sup.1H NMR 400 MHz, CDCl.sub.3: .delta. 8.32 (s, 1H), 7.98
(d, J=8.00 Hz, 1H), 7.74-7.71 (m, 1H), 7.65 (d, J=8.00 Hz, 2H),
7.53 (t, J=4.00 Hz, 1H), 7.46-7.42 (m, 2H), 7.38-7.34 (m, 2H), 7.14
(dd, J=8.00, 4.00 Hz, 1H), 6.87 (d, J=8.00 Hz, 1H), 4.30 (t, J=8.00
Hz, 2H), 3.92 (s, 3H), 3.73 (s, 3H), 3.28 (t, J=12.00 Hz, 2H).
[3-(3,4-Dimethoxy-phenyl)-4,5-dihydro-pyrazol-1-yl]-[3-(2-methyl-thiazol-4-
-yl)-phenyl]-methanone
##STR00415##
[0572] White solid; 22.83% Yield
[0573] LC-MS: Mass found (M+, 408). Rt (min): 4.05; % Area: 98.13
(Max), 98.83 (254 nm).
[0574] HPLC--Rt (min): 4.05; % Area: 98.86 (Max), 99.07 (254
nm).
[0575] .sup.1H NMR 400 MHz, CDCl.sub.3: .delta. 8.51 (s, 1H), 8.11
(d, J=8.00 Hz, 1H), 7.96 (d, J=8.00 Hz, 1H), 7.52 (t, J=4.00 Hz,
1H), 7.40-7.36 (m, 1H), 7.27-7.26 (m, 1H), 7.16 (d, J=8.00 Hz, 1H),
6.87 (d, J=8.00 Hz, 1H), 4.28 (t, J=12.00 Hz, 2H), 3.92 (s, 3H),
3.80 (s, 3H), 3.28 (t, J=12.00 Hz, 2H), 2.83 (s, 3H).
(3-tert-Butyl-phenyl)-[3-(3,4-dimethoxy-phenyl)-4,5-dihydro-pyrazol-1-yl]--
methanone
##STR00416##
[0577] Yellow solid, 12.55% Yield
[0578] LC-MS: Mass found (M+, 367). Rt (min): 4.91; % Area: 94.01
(Max), 92.83 (254 nm).
[0579] HPLC--Rt (min): 4.95; % Area: 97.22 (Max), 95.98 (254
nm).
[0580] .sup.1H NMR 400 MHz, CDCl.sub.3: .delta. 8.08 (s, 1H), 7.80
(d, J=8.00 Hz, 1H), 7.51 (dd, J=5.00, 2.00 Hz, 1H), 7.38 (dd,
J=10.00, 8.00 Hz, 2H), 7.15 (dd, J=11.00, 2.00 Hz, 1H), 6.88 (d,
J=12.00 Hz, 1H), 4.27 (t, J=12.00 Hz, 2H), 3.93 (s, 3H), 3.87 (s,
3H), 3.27 (t, J=8.00 Hz, 2H), 1.38 (s, 9H).
[3-(3,4-Dimethoxy-phenyl)-4,5-dihydro-pyrazol-1-yl]-(3-ethyl-phenyl)-metha-
none
##STR00417##
[0582] Yellow solid; 42.48% Yield
[0583] LC-MS: Mass found (M+, 339). Rt (min): 4.45; % Area: 92.47
(Max), 91.15 (220 nm).
[0584] HPLC--Rt (min): 4.46; % Area: 92.59 (Max), 91.02 (254
nm).
[0585] .sup.1H NMR 400 MHz, CDCl.sub.3: .delta. 7.86 (s, 1H), 7.81
(d, J=8.00 Hz, 1H), 7.38-7.31 (m, 3H), 7.16 (dd, J=8.00, 4.00 Hz,
1H), 6.88 (d, J=8.00 Hz, 1H), 4.26 (t, J=12.00 Hz, 2H), 3.93 (s,
3H), 3.89 (s, 3H), 3.26 (t, J=12.00 Hz, 2H), 2.72 (q, J=8.00 Hz,
2H), 1.29 (t, J=8.00 Hz, 3H).
[3-(3,4-Dimethoxy-phenyl)-4,5-dihydro-pyrazol-1-yl]-(3-methanesulfonyl-phe-
nyl)-methanone
##STR00418##
[0587] Yellow solid; 40.62% Yield
[0588] LC-MS: Mass found (M+, 389). Rt (min): 3.36; % Area: 98.64
(Max), 98.30 (254 nm).
[0589] HPLC--Rt (min): 3.35; % Area: 99.08 (Max), 98.77 (254
nm).
[0590] .sup.1H NMR 400 MHz, CDCl.sub.3: .delta. 8.86 (s, 1H), 8.30
(d, J=8.00 Hz, 1H), 8.07 (dt, J=8.13, 1.20 Hz, 1H), 7.68 (t, J=8.00
Hz, 1H), 7.45 (d, J=1.60 Hz, 1H), 7.14 (dd, J=8.40, 2.00 Hz, 1H),
6.88 (d, J=8.00 Hz, 1H), 4.29 (t, J=8.00 Hz, 2H), 3.95 (s, 3H),
3.93 (s, 3H), 3.31 (t, J=8.00 Hz, 2H), 3.08 (s, 3H).
[3-(3,4-Dimethoxy-phenyl)-4,5-dihydro-pyrazol-1-yl]-(3-hydroxy-phenyl)-met-
hanone
##STR00419##
[0592] Yellow solid; 20.35% Yield
[0593] LC-MS: Mass found (M+, 327). Rt (min): 3.23; % Area: 97.80
(Max), 97.47 (254 nm).
[0594] HPLC--Rt (min): 3.24; % Area: 97.68 (Max), 96.88 (254
nm).
[0595] .sup.1H NMR 400 MHz, CDCl.sub.3: .delta. 7.59 (s, 2H),
7.33-7.27 (m, 3H), 7.19 (d, J=8.00 Hz, 1H), 7.00-6.97 (m, 1H),
6.89-6.86 (m, 1H), 4.25 (t, J=12.00 Hz, 2H), 3.93 (s, 3H), 3.90 (s,
3H), 3.26 (t, J=12.00 Hz, 2H).
(3-Difluoromethoxy-phenyl)-[3-(3,4-dimethoxy-phenyl)-4,5-dihydro-pyrazol-1-
-yl]-methanone
##STR00420##
[0597] Yellow solid; 7.18% Yield
[0598] LC-MS: Mass found (M+, 377). Rt (min): 4.28; % Area: 94.48
(Max), 93.62 (254 nm).
[0599] HPLC--Rt (min): 4.30; % Area: 97.41 (Max), 97.37 (254
nm).
[0600] .sup.1H NMR 400 MHz, CDCl.sub.3: .delta. 7.90-7.86 (m, 2H),
7.45 (t, J=8.00 Hz, 1H), 7.36 (d, J=2.00 Hz, 1H), 7.25 (d, J=4.00
Hz, 1H), 7.17 (dd, J=8.00, 4.00 Hz, 1H), 6.88 (d, J=8.00 Hz, 1H),
6.76-6.39 (m, 1H), 4.26 (t, J=12.00 Hz, 2H), 3.93 (s, 3H), 3.90 (s,
3H), 3.28 (t, J=12.00 Hz, 2H).
N-{3-[3-(3,4-Dimethoxy-phenyl)-4,5-dihydro-pyrazole-1-carbonyl]-phenyl}-ac-
etamide
##STR00421##
[0602] White solid; 20.93% Yield
[0603] LC-MS: Mass found (M+, 368). Rt (min): 3.13; % Area: 96.09
(Max), 96.43 (254 nm).
[0604] HPLC--Rt (min): 3.09; % Area: 98.62 (Max), 98.33 (254
nm).
[0605] .sup.1H NMR 400 MHz, CDCl.sub.3: .delta. 8.12 (s, 1H), 7.76
(d, J=8.00 Hz, 1H), 7.71 (d, J=8.00 Hz, 1H), 7.42-7.37 (m, 2H),
7.33 (s, 1H), 7.17 (d, J=8.00 Hz, 1H), 6.88 (d, J=12.00 Hz, 1H),
4.25 (t, J=8.00 Hz, 2H), 3.93 (s, 3H), 3.92 (s, 3H), 3.26 (t,
J=12.00 Hz, 2H), 2.19 (s, 3H).
[3-(3,4-Dimethoxy-phenyl)-4,5-dihydro-pyrazol-1-yl]-(4-fluoro-phenyl)-meth-
anone
##STR00422##
[0607] White solid; 59.29% Yield
[0608] LC-MS: Mass found (M+, 329). Rt (min): 4.06; % Area: 98.85
(Max), 98.98 (254 nm).
[0609] HPLC--Rt (min): 4.05; % Area: 98.89 (Max), 98.62 (254
nm).
[0610] .sup.1H NMR 400 MHz, CDCl.sub.3: .delta. 8.07-8.04 (m, 2H),
7.31 (d, J=1.60 Hz, 1H), 7.19 (dd, J=8.00, 4.00 Hz, 1H), 7.14-7.10
(m, 2H), 6.89 (d, J=8.00 Hz, 1H), 4.26 (t, J=8.00 Hz, 2H), 3.93 (s,
3H), 3.91 (s, 3H), 3.27 (t, J=8.00 Hz, 2H).
(3,4-Difluoro-phenyl)-[3-(3,4-dimethoxy-phenyl)-4,5-dihydro-pyrazol-1-yl]--
methanone
##STR00423##
[0612] White solid; 53.59% Yield
[0613] LC-MS: Mass found (M+, 347). Rt (min): 4.29; % Area: 99.49
(Max), 99.34 (254 nm).
[0614] HPLC--Rt (min): 4.32; % Area: 99.39 (Max), 98.67 (254
nm).
[0615] .sup.1H NMR 400 MHz, CDCl.sub.3: .delta. 8.02-7.97 (m, 1H),
7.86-7.83 (m, 1H), 7.33 (d, J=4.00 Hz, 1H), 7.24-7.21 (m, 1H), 7.19
(dd, J=8.00, 4.00 Hz, 1H), 6.90 (d, J=8.00 Hz, 1H), 4.25 (t,
J=12.00 Hz, 2H), 3.94 (s, 3H), 3.92 (s, 3H), 3.28 (t, J=4.00 Hz,
2H).
[3-(3,4-Dimethoxy-phenyl)-4,5-dihydro-pyrazol-1-yl]-(3-fluoro-4-trifluorom-
ethyl-phenyl)-methanone
##STR00424##
[0617] White solid; 21.65% Yield
[0618] LC-MS: Mass found (M+, 397). Rt (min): 4.86; % Area: 97.60
(Max), 97.07 (254 nm).
[0619] HPLC--Rt (min): 4.97; % Area: 97.92 (Max), 97.38 (254
nm).
[0620] .sup.1H NMR 400 MHz, CDCl.sub.3: .delta. 7.90 (t, J=12.00
Hz, 2H), 7.69 (t, J=4.00 Hz, 1H), 7.30 (d, J=4.00 Hz, 1H), 7.20
(dd, J=8.00, 4.00 Hz, 1H), 6.90 (d, J=8.00 Hz, 1H), 4.27 (t, J=8.00
Hz, 2H), 3.94 (s, 3H), 3.92 (s, 3H), 3.31 (t, J=8.00 Hz, 2H).
[3-(3,4-Dimethoxy-phenyl)-4,5-dihydro-pyrazol-1-yl]-(3-fluoro-4-methyl-phe-
nyl)-methanone
##STR00425##
[0622] Yellow solid; 31.63% Yield
[0623] LC-MS: Mass found (M+, 343). Rt (min): 4.36; % Area: 96.11
(Max), 97.09 (254 nm).
[0624] HPLC--Rt (min): 4.37; % Area: 98.71 (Max), 98.42 (254
nm).
[0625] .sup.1H NMR 400 MHz, CDCl.sub.3: .delta. 7.76 (dd, J=16.00,
8.00 Hz, 2H), 7.36 (d, J=1.60 Hz, 1H), 7.27-7.17 (m, 2H), 6.89 (d,
J=8.00 Hz, 1H), 4.25 (t, J=12.00 Hz, 2H), 3.93 (s, 3H), 3.92 (s,
3H), 3.26 (t, J=12.00 Hz, 2H), 2.35 (s, 3H).
(4-Chloro-3-fluoro-phenyl)-[3-(3,4-dimethoxy-phenyl)-4,5-dihydro-pyrazol-1-
-yl]-methanone
##STR00426##
[0627] Brown solid; 33.64% Yield
[0628] LC-MS: Mass found (M+, 343). Rt (min): 4.36; % Area: 98.34
(Max), 98.75 (254 nm).
[0629] HPLC--Rt (min): 4.37; % Area: 99.08 (Max), 98.92 (254
nm).
[0630] .sup.1H NMR 400 MHz, CDCl.sub.3: .delta. 7.93 (dd, J=9.20,
4.00 Hz, 1H), 7.80 (d, J=8.00 Hz, 1H), 7.47 (t, J=8.00 Hz, 1H),
7.33 (d, J=1.60 Hz, 1H), 7.19 (dd, J=8.00, 4.00 Hz, 1H), 6.90 (d,
J=12.00 Hz, 1H), 4.25 (t, J=12.00 Hz, 2H), 3.94 (s, 3H), 3.92 (s,
3H), 3.28 (t, J=8.00 Hz, 2H).
[3-(3,4-Dimethoxy-phenyl)-4,5-dihydro-pyrazol-1-yl]-(3-fluoro-4-methoxy-ph-
enyl)-methanone
##STR00427##
[0632] Yellow solid; 50.99% Yield
[0633] LC-MS: Mass found (M+, 359). Rt (min): 4.04; % Area: 98.61
(Max), 99.28 (254 nm).
[0634] HPLC--Rt (min): 4.03; % Area: 98.30 (Max), 97.91 (254
nm).
[0635] .sup.1H NMR 400 MHz, CDCl.sub.3: .delta. 7.98 (dd, J=12.80,
1.60 Hz, 1H), 7.89 (d, J=8.00 Hz, 1H), 7.37 (d, J=2.00 Hz, 1H),
7.19 (dd, J=8.20, 2.00 Hz, 1H), 7.01 (t, J=8.00 Hz, 1H), 6.89 (d,
J=8.00 Hz, 1H), 4.25 (t, J=12.00 Hz, 2H), 3.96 (s, 3H), 3.94 (s,
3H), 3.93 (s, 3H), 3.25 (t, J=12.00 Hz, 2H).
(4-Bromo-3-fluoro-phenyl)-[3-(3,4-dimethoxy-phenyl)-4,5-dihydro-pyrazol-1--
yl]-methanone
##STR00428##
[0637] Yellow solid; 25.12% Yield
[0638] LC-MS: Mass found (M+, 409). Rt (min): 4.62; % Area: 95.45
(Max), 96.43 (254 nm).
[0639] HPLC--Rt (min): 4.63; % Area: 95.39 (Max), 95.86 (254
nm).
[0640] .sup.1H NMR 400 MHz, CDCl.sub.3: .delta. 7.90 (dd, J=9.60,
1.60 Hz, 1H), 7.73 (d, J=8.00 Hz, 1H), 7.63 (t, J=8.00 Hz, 1H),
7.32 (d, J=2.00 Hz, 1H), 7.19 (dd, J=8.20, 2.00 Hz, 1H), 6.89 (d,
J=8.00 Hz, 1H), 4.25 (t, J=8.00 Hz, 2H), 3.94 (s, 3H), 3.92 (s,
3H), 3.28 (t, J=12.00 Hz, 2H).
(2,3-Difluoro-phenyl)-[3-(3,4-dimethoxy-phenyl)-4,5-dihydro-pyrazol-1-yl]--
methanone
##STR00429##
[0642] Yellow solid; 14.83% Yield
[0643] LC-MS: Mass found (M+, 347). Rt (min): 3.99; % Area: 98.85
(Max), 99.26 (254 nm).
[0644] HPLC--Rt (min): 4.07; % Area: 98.85 (Max), 98.67 (254
nm).
[0645] .sup.1H NMR 400 MHz, CDCl.sub.3: .delta. 7.36-7.33 (m, 1H),
7.28-7.27 (m, 1H), 7.22 (d, J=2.00 Hz, 1H), 7.18-7.12 (m, 2H), 6.85
(d, J=8.00 Hz, 1H), 4.25 (t, J=4.00 Hz, 2H), 3.91 (s, 3H), 3.85 (s,
3H), 3.32 (t, J=12.00 Hz, 2H).
[3-(3,4-Dimethoxy-phenyl)-4,5-dihydro-pyrazol-1-yl]-(3-fluoro-2-methyl-phe-
nyl)-methanone
##STR00430##
[0647] Yellow solid; 28.49% Yield
[0648] LC-MS: Mass found (M+, 343). Rt (min): 4.05; % Area: 98.93
(Max), 99.15 (254 nm).
[0649] HPLC--Rt (min): 4.13; % Area: 98.99 (Max), 99.12 (254
nm).
[0650] .sup.1H NMR 400 MHz, CDCl.sub.3: .delta. 7.22-7.20 (m, 2H),
7.16 (d, J=4.00 Hz, 1H), 7.13-7.07 (m, 2H), 6.84 (d, J=8.00 Hz,
1H), 4.26 (t, J=8.00 Hz, 2H), 3.90 (s, 3H), 3.83 (s, 3H), 3.30 (t,
J=12.00 Hz, 2H), 2.27 (s, 3H).
[3-(3,4-Dimethoxy-phenyl)-4,5-dihydro-pyrazol-1-yl]-(3-fluoro-2-trifluorom-
ethyl-phenyl)-methanone
##STR00431##
[0652] Brown solid; 24.46% Yield
[0653] LC-MS: Mass found (M+, 397). Rt (min): 4.39; % Area: 93.14
(Max), 92.71 (254 nm).
[0654] HPLC--Rt (min): 4.44; % Area: 93.80 (Max), 91.92 (254
nm).
[0655] .sup.1H NMR 400 MHz, CDCl.sub.3: .delta. 7.61-7.60 (m, 1H),
7.30-7.28 (m, 2H), 7.16 (d, J=4.00 Hz, 1H), 7.08 (dd, J=8.00, 4.00
Hz, 1H), 6.83 (d, J=8.00 Hz, 1H), 4.21 (t, J=8.00 Hz, 2H), 3.90 (s,
3H), 3.82 (s, 3H), 3.31 (t, J=12.00 Hz, 2H).
(2-Chloro-3-fluoro-phenyl)-[3-(3,4-dimethoxy-phenyl)-4,5-dihydro-pyrazol-1-
-yl]-methanone
##STR00432##
[0657] White solid; 33.69% Yield
[0658] LC-MS: Mass found (M+, 363). Rt (min): 4.09; % Area: 96.66
(Max), 95.86 (254 nm).
[0659] HPLC--Rt (min): 4.12; % Area: 97.87 (Max), 97.52 (254
nm).
[0660] .sup.1H NMR 400 MHz, CDCl.sub.3: .delta. 7.34-7.28 (m, 2H),
7.24-7.19 (m, 1H), 7.16 (d, J=4.00 Hz, 1H), 7.12 (dd, J=8.00, 4.00
Hz, 1H), 6.84 (d, J=8.00 Hz, 1H), 4.26 (t, J=8.00 Hz, 2H), 3.90 (s,
3H), 3.83 (s, 3H), 3.32 (t, J=12.00 Hz, 2H).
[3-(3,4-Dimethoxy-phenyl)-4,5-dihydro-pyrazol-1-yl]-(2,3,4-trifluoro-pheny-
l)-methanone
##STR00433##
[0662] White solid; 58.13% Yield
[0663] LC-MS: Mass found (M+, 365). Rt (min): 4.27; % Area: 99.31
(Max), 99.04 (254 nm).
[0664] HPLC--Rt (min): 4.30; % Area: 99.02 (Max), 98.68 (254
nm).
[0665] .sup.1H NMR 400 MHz, CDCl.sub.3: .delta. 7.38-7.30 (m, 1H),
7.22 (d, J=4.00 Hz, 1H), 7.14 (dd, J=8.00, 4.00 Hz, 1H), 7.08-7.01
(m, 1H), 6.86 (d, J=8.00 Hz, 1H), 4.23 (t, J=12.00 Hz, 2H), 3.92
(s, 3H), 3.87 (s, 3H), 3.32 (t, J=12.00 Hz, 2H).
(2,3-Difluoro-4-methyl-phenyl)-[3-(3,4-dimethoxy-phenyl)-4,5-dihydro-pyraz-
ol-1-yl]-methanone
##STR00434##
[0667] White solid; 33.53% Yield
[0668] LC-MS: Mass found (M+, 361). Rt (min): 4.29; % Area: 97.01
(Max), 96.49 (220 nm).
[0669] HPLC--Rt (min): 4.35; % Area: 98.83 (Max), 98.99 (254
nm).
[0670] .sup.1H NMR 400 MHz, CDCl.sub.3: .delta. 7.26-7.24 (m, 2H),
7.24 (d, J=2.00 Hz, 1H), 7.14 (dd, J=8.40, 2.00 Hz, 1H), 7.00 (t,
J=8.00 Hz, 1H), 4.24 (t, J=8.00 Hz, 2H), 3.91 (s, 3H), 3.87 (s,
3H), 3.31 (t, J=8.00 Hz, 2H), 2.37 (s, 3H).
(2,3-Difluoro-4-methoxy-phenyl)-[3-(3,4-dimethoxy-phenyl)-4,5-dihydro-pyra-
zol-1-yl]-methanone
##STR00435##
[0672] Yellow solid; 5.26% Yield
[0673] LC-MS: Mass found (M+, 377). Rt (min): 4.02; % Area: 97.62
(Max), 97.66 (254 nm).
[0674] HPLC--Rt (min): 4.05; % Area: 97.43 (Max), 97.79 (254
nm).
[0675] .sup.1H NMR 400 MHz, CDCl.sub.3: .delta. 7.37-7.33 (m, 1H),
7.26 (d, J=1.60 Hz, 1H), 7.14 (dd, J=8.00, 4.00 Hz, 1H), 6.86 (d,
J=8.00 Hz, 1H), 6.83-6.79 (m, 1H), 4.23 (t, J=8.00 Hz, 2H), 3.96
(s, 3H), 3.91 (s, 3H), 3.87 (s, 3H), 3.30 (t, J=12.00 Hz, 2H).
[3-(3,4-Dimethoxy-phenyl)-4,5-dihydro-pyrazol-1-yl]-(2,3,4,5-tetrafluoro-p-
henyl)-methanone
##STR00436##
[0677] White solid; 21.79% Yield
[0678] LC-MS: Mass found (M+, 383). Rt (min): 4.52; % Area: 97.94
(Max), 97.96 (254 nm).
[0679] HPLC--Rt (min): 4.63; % Area: 97.82 (Max), 97.91 (254
nm).
[0680] .sup.1H NMR 400 MHz, DMSO-d6: .delta. 7.64-7.59 (m, 1H),
7.21 (d, J=8.00 Hz, 1H), 7.14 (d, J=1.60 Hz, 1H), 7.01 (d, J=12.00
Hz, 1H), 4.09 (t, J=8.00 Hz, 2H), 3.78 (s, 3H), 3.72 (s, 3H), 3.38
(t, J=8.00 Hz, 2H).
(7-Chloro-benzo[1,3]dioxol-5-yl)-[3-(3,4-dimethoxy-phenyl)-4,5-dihydro-pyr-
azol-1-yl]-methanone
##STR00437##
[0682] Brown solid; 5.47% Yield
[0683] LC-MS: Mass found (M+, 389). Rt (min): 4.33; % Area: 98.31
(Max), 98.28 (220 nm).
[0684] HPLC--Rt (min): 4.34; % Area: 97.52 (Max), 98.07 (254
nm).
[0685] .sup.1H NMR 400 MHz, CDCl.sub.3: .delta. 7.82 (s, 1H), 7.51
(d, J=8.00 Hz, 1H), 7.40 (d, J=4.00 Hz, 1H), 7.17 (dd, J=8.40, 2.00
Hz, 1H), 6.89 (d, J=8.00 Hz, 1H), 6.12 (s, 2H), 4.24 (t, J=8.00 Hz,
2H), 3.94 (s, 3H), 3.92 (s, 3H), 3.25 (t, J=12.00 Hz, 2H).
(6-Bromo-benzo[1,3]dioxol-5-yl)-[3-(3,4-dimethoxy-phenyl)-4,5-dihydro-pyra-
zol-1-yl]-methanone
##STR00438##
[0687] Brown solid; 23.85% Yield
[0688] LC-MS: Mass found (M+, 433). Rt (min): 3.95; % Area: 98.38
(Max), 98.32 (254 nm).
[0689] HPLC--Rt (min): 3.94; % Area: 97.76 (Max), 98.98 (254
nm).
[0690] .sup.1H NMR 400 MHz, CDCl.sub.3: .delta. 7.22 (d, J=4.00 Hz,
1H), 7.15 (dd, J=8.00, 4.00 Hz, 1H), 7.04 (s, 1H), 6.93 (s, 1H),
6.85 (d, J=8.00 Hz, 1H), 6.03 (s, 2H), 4.22 (t, J=12.00 Hz, 2H),
3.91 (s, 3H), 3.87 (s, 3H), 3.29 (t, J=12.00 Hz, 2H).
[3-(3,4-Dimethoxy-phenyl)-4,5-dihydro-pyrazol-1-yl]-(6-nitro-benzo[1,3]dio-
xol-5-yl)-methanone
##STR00439##
[0692] Brown solid; 6.97% Yield
[0693] LC-MS: Mass found (M+, 400). Rt (min): 3.75; % Area: 94.53
(Max), 92.65 (254 nm).
[0694] HPLC--Rt (min): 3.78; % Area: 93.42 (Max), 91.57 (254
nm).
[0695] .sup.1H NMR 400 MHz, CDCl.sub.3: .delta. 7.56 (s, 1H), 7.12
(d, J=2.00 Hz, 1H), 7.05-7.01 (m, 2H), 6.82 (d, J=8.00 Hz, 1H),
6.18 (s, 2H), 4.20 (t, J=12.00 Hz, 2H), 3.94 (s, 3H), 3.89 (s, 3H),
3.27 (t, J=8.00 Hz, 2H).
(2,2-Difluoro-benzo[1,3]dioxol-5-yl)-[3-(3,4-dimethoxy-phenyl)-4,5-dihydro-
-pyrazol-1-yl]-methanone
##STR00440##
[0697] Yellow solid; 9.62% Yield
[0698] LC-MS: Mass found (M+, 391). Rt (min): 4.69; % Area: 93.95
(Max), 93.64 (220 nm).
[0699] HPLC--Rt (min): 4.72; % Area: 97.44 (Max), 97.76 (254
nm).
[0700] .sup.1H NMR 400 MHz, CDCl.sub.3: .delta. 7.86 (d, J=8.00 Hz,
2H), 7.31 (d, J=4.00 Hz, 1H), 7.20 (d, J=8.00 Hz, 1H), 7.13 (d,
J=8.00 Hz, 1H), 6.90 (d, J=8.00 Hz, 1H), 4.26 (t, J=8.00 Hz, 2H),
3.94 (s, 3H), 3.92 (s, 3H), 3.28 (t, J=8.00 Hz, 2H).
(2,3-Dimethoxy-phenyl)-[3-(3,4-dimethoxy-phenyl)-4,5-dihydro-pyrazol-1-yl]-
-methanone
##STR00441##
[0702] Brown solid; 5.68% Yield
[0703] LC-MS: Mass found (M+, 371). Rt (min): 3.62; % Area: 95.22
(Max), 95.61 (254 nm).
[0704] HPLC--Rt (min): 3.62; % Area: 95.26 (Max), 95.30 (254
nm).
[0705] .sup.1H NMR 400 MHz, CDCl.sub.3: .delta. 7.17-7.07 (m, 3H),
6.99 (d, J=8.00 Hz, 2H), 6.82 (d, J=8.00 Hz, 1H), 4.26 (t, J=8.00
Hz, 2H), 3.90 (s, 9H), 3.76 (s, 3H), 3.28 (t, J=12.00 Hz, 2H).
(2,5-Dimethoxy-phenyl)-[3-(3,4-dimethoxy-phenyl)-4,5-dihydro-pyrazol-1-yl]-
-methanone
##STR00442##
[0707] Yellow gum; 10.02% Yield
[0708] LC-MS: Mass found (M+, 371). Rt (min): 3.59; % Area: 96.83
(Max), 96.46 (254 nm).
[0709] HPLC--Rt (min): 3.61; % Area: 96.33 (Max), 96.54 (254
nm).
[0710] .sup.1H NMR 400 MHz, CDCl.sub.3: .delta. 7.20 (d, J=1.60 Hz,
1H), 7.11 (dd, J=8.20, 2.00 Hz, 1H), 7.01 (d, J=2.40 Hz, 1H),
6.96-6.88 (m, 2H), 6.84 (d, J=8.00 Hz, 1H), 4.25 (t, J=8.00 Hz,
2H), 3.93 (s, 3H), 3.90 (s, 3H), 3.79 (s, 3H), 3.78 (s, 3H), 3.27
(t, J=12.00 Hz, 2H).
[3-(3,4-Dimethoxy-phenyl)-4,5-dihydro-pyrazol-1-yl]-(4-hydroxy-3-methoxy-p-
henyl)-methanone
##STR00443##
[0712] Brown solid; 9.02% Yield
[0713] LC-MS: Mass found (M+, 357). Rt (min): 3.22; % Area: 90.88
(Max), 90.37 (254 nm).
[0714] HPLC--Rt (min): 3.19; % Area: 91.29 (Max), 90.03 (254
nm).
[0715] .sup.1H NMR 400 MHz, CDCl.sub.3: .delta. 7.74 (d, J=8.00 Hz,
1H), 7.68 (d, J=2.00 Hz, 1H), 7.36 (d, J=4.00 Hz, 1H), 7.19 (dd,
J=8.00, 4.00 Hz, 1H), 6.97 (d, J=12.00 Hz, 1H), 6.89 (d, J=8.00 Hz,
1H), 5.89 (s, 1H), 4.26 (t, J=8.00 Hz, 2H), 3.94 (s, 3H), 3.92 (s,
3H), 3.91 (s, 3H), 3.25 (t, J=8.00 Hz, 2H).
[3-(3,4-Dimethoxy-phenyl)-4,5-dihydro-pyrazol-1-yl]-(3-hydroxy-4-methoxy-p-
henyl)-methanone
##STR00444##
[0717] White solid; 37.84% Yield
[0718] LC-MS: Mass found (M+, 357). Rt (min): 3.23; % Area: 97.05
(Max), 97.01 (254 nm).
[0719] HPLC--Rt (min): 3.19; % Area: 97.08 (Max), 97.03 (254
nm).
[0720] .sup.1H NMR 400 MHz, CDCl.sub.3: .delta. 7.75 (s, 1H), 7.65
(d, J=-4.00 Hz, 1H), 7.38 (s, 1H), 7.19 (dd, J=-4.00, -8.00 Hz,
1H), 6.90 (t, J=-8.00 Hz, 2H), 4.25 (t, J=-8.00 Hz, 2H), 3.96 (s,
3H), 3.93 (s, 6H), 3.24 (t, J=-12.00 Hz, 2H).
(2,3-Dihydro-benzofuran-5-yl)-[3-(3,4-dimethoxy-phenyl)-4,5-dihydro-pyrazo-
l-1-yl]-methanone
##STR00445##
[0722] Brown solid; 44.59% Yield
[0723] LC-MS: Mass found (M+, 353). Rt (min): 3.85; % Area: 97.90
(Max), 98.57 (254 nm).
[0724] HPLC--Rt (min): 3.84; % Area: 97.54 (Max), 98.84 (254
nm).
[0725] .sup.1H NMR 400 MHz, CDCl.sub.3: .delta. 7.93-7.90 (m, 2H),
7.36 (d, J=2.00 Hz, 1H), 7.18 (dd, J=8.00, 4.00 Hz, 1H), 6.89 (d,
J=8.00 Hz, 1H), 6.82 (d, J=8.00 Hz, 1H), 4.65 (t, J=8.00 Hz, 2H),
4.25 (t, J=8.00 Hz, 2H), 3.93 (s, 3H), 3.91 (s, 3H), 3.25 (q,
J=8.00 Hz, 4H).
[3-(3,4-Dimethoxy-phenyl)-4,5-dihydro-pyrazol-1-yl]-indan-5-yl-methanone
##STR00446##
[0727] Brown solid; 12.12% Yield
[0728] LC-MS: Mass found (M+, 351). Rt (min): 4.54; % Area: 97.17
(Max), 98.23 (254 nm).
[0729] HPLC--Rt (min): 4.52; % Area: 98.03 (Max), 98.59 (254
nm).
[0730] .sup.1H NMR 400 MHz, CDCl.sub.3: .delta. 7.88 (s, 1H), 7.80
(d, J=8.00 Hz, 1H), 7.36 (s, 1H), 7.29 (s, 1H), 7.17 (dd, J=8.00,
4.00 Hz, 1H), 6.88 (d, J=8.00 Hz, 1H), 4.26 (t, J=8.00 Hz, 2H),
3.93 (s, 3H), 3.91 (s, 3H), 3.25 (t, J=8.00 Hz, 2H), 2.96 (t,
J=8.00 Hz, 4H), 2.16-2.10 (m, 2H).
5-[3-(3,4-Dimethoxy-phenyl)-4,5-dihydro-pyrazole-1-carbonyl]-2-methyl-isoi-
ndole-1,3-dione
##STR00447##
[0732] Yellow solid; 4.29% Yield
[0733] LC-MS: Mass found (M+, 394). Rt (min): 3.68; % Area: 96.28
(Max), 95.65 (220 nm).
[0734] HPLC--Rt (min): 3.68; % Area: 98.12 (Max), 98.84 (254
nm).
[0735] .sup.1H NMR 400 MHz, CDCl.sub.3: .delta. 8.58 (s, 1H), 8.33
(d, J=8.00 Hz, 1H), 7.92 (d, J=8.00 Hz, 1H), 7.34 (s, 1H), 7.16 (d,
J=8.00 Hz, 1H), 6.89 (d, J=12.00 Hz, 1H), 4.29 (t, J=12.00 Hz, 2H),
3.93 (s, 3H), 3.91 (s, 3H), 3.32 (t, J=8.00 Hz, 2H), 3.22 (s,
3H).
6-[3-(3,4-Dimethoxy-phenyl)-4,5-dihydro-pyrazole-1-carbonyl]-1,3-dihydro-i-
ndol-2-one
##STR00448##
[0737] Brown solid; 6.72% Yield
[0738] LC-MS: Mass found (M+, 366). Rt (min): 2.95; % Area: 98.45
(Max), 98.53 (254 nm).
[0739] HPLC--Rt (min): 3.00; % Area: 98.86 (Max), 99.05 (254
nm).
[0740] .sup.1H NMR 400 MHz, CDCl.sub.3: .delta. 7.80-7.60 (m, 1H),
7.52-7.31 (m, 2H), 7.29-7.27 (m, 2H), 7.25-7.00 (m, 1H), 6.89 (d,
J=8.00 Hz, 1H), 4.26 (t, J=8.00 Hz, 2H), 3.93 (s, 3H), 3.90 (s,
3H), 3.60 (s, 2H), 3.28 (t, J=8.00 Hz, 2H).
1-{5-[3-(3,4-Dimethoxy-phenyl)-4,5-dihydro-pyrazole-1-carbonyl]-2,3-dihydr-
o-indol-1-yl}-ethanone
##STR00449##
[0742] Yellow solid; 13.73% Yield
[0743] LC-MS: Mass found (M+, 394). Rt (min): 3.44; % Area: 90.94
(Max), 92.33 (254 nm).
[0744] HPLC--Rt (min): 3.37; % Area: 90.93 (Max), 90.20 (254
nm).
[0745] .sup.1H NMR 400 MHz, CDCl.sub.3: .delta. 8.24 (d, J=8.00 Hz,
1H), 7.98 (d, J=8.00 Hz, 1H), 7.86 (s, 1H), 7.34 (s, 1H), 7.17 (d,
J=8.00 Hz, 1H), 6.88 (d, J=8.00 Hz, 1H), 4.25 (t, J=8.00 Hz, 2H),
4.13 (t, J=8.00 Hz, 2H), 3.95 (s, 3H), 3.93 (s, 3H), 3.25 (q,
J=8.00 Hz, 4H), 2.27 (s, 3H).
5-[3-(3,4-Dimethoxy-phenyl)-4,5-dihydro-pyrazole-1-carbonyl]-1,3-dihydro-i-
ndol-2-one
##STR00450##
[0747] Yellow solid; 9.14% Yield
[0748] LC-MS: Mass found (M+, 366). Rt (min): 2.94; % Area: 90.16
(Max), 90.02 (254 nm).
[0749] HPLC--Rt (min): 2.93; % Area: 92.14 (Max), 90.70 (254
nm).
[0750] .sup.1H NMR 400 MHz, CDCl.sub.3: .delta. 7.99 (d, J=8.00 Hz,
1H), 7.97 (s, 1H), 7.54 (d, J=4.00 Hz, 1H), 7.32 (d, J=4.00 Hz,
1H), 7.19 (d, J=8.00 Hz, 1H), 6.90 (t, J=8.00 Hz, 2H), 4.26 (t,
J=8.00 Hz, 2H), 3.93 (s, 3H), 3.91 (s, 3H), 3.59 (s, 2H), 3.26 (t,
J=12.00 Hz, 2H).
5-[3-(3,4-Dimethoxy-phenyl)-4,5-dihydro-pyrazole-1-carbonyl]-3H-benzooxazo-
l-2-one
##STR00451##
[0752] Yellow solid; 8.25% Yield
[0753] LC-MS: Mass found (M+, 368). Rt (min): 3.25; % Area: 98.89
(Max), 98.63 (254 nm).
[0754] HPLC--Rt (min): 3.27; % Area: 98.75 (Max), 98.64 (254
nm).
[0755] .sup.1H NMR 400 MHz, CDCl.sub.3: .delta. 7.99 (s, 1H), 7.90
(d, J=8.00 Hz, 1H), 7.75 (s, 1H), 7.29-7.19 (m, 3H), 6.90 (d,
J=8.00 Hz, 1H), 4.27 (t, J=12.00 Hz, 2H), 3.94 (s, 3H), 3.90 (s,
3H), 3.29 (t, J=8.00 Hz, 2H).
6-[3-(3,4-Dimethoxy-phenyl)-4,5-dihydro-pyrazole-1-carbonyl]-2,3-dihydro-i-
soindol-1-one
##STR00452##
[0757] Yellow solid; 4.85% Yield
[0758] LC-MS: Mass found (M+, 366). Rt (min): 2.82; % Area: 93.91
(Max), 94.20 (220 nm).
[0759] HPLC--Rt (min): 2.82; % Area: 96.33 (Max), 96.44 (254
nm).
[0760] .sup.1H NMR 400 MHz, CDCl.sub.3: .delta. 8.71 (s, 1H),
8.25-8.22 (m, 1H), 7.56 (d, J=8.00 Hz, 1H), 7.42 (d, J=4.00 Hz,
1H), 7.1 5 (d, J=8.00 Hz, 1H), 6.87 (d, J=8.00 Hz, 1H), 6.18 (s,
1H), 4.53 (s, 2H), 4.30 (t, J=8.00 Hz, 2H), 3.94 (s, 3H), 3.93 (s,
3H), 3.29 (t, J=12.00 Hz, 2H).
[0761]
Benzofuran-5-yl-[3-(3,4-dimethoxy-phenyl)-4,5-dihydro-pyrazol-1-yl]-
-methanone
##STR00453##
[0762] Brown solid; 13.89% Yield
[0763] LC-MS: Mass found (M+, 351). Rt (min): 4.07; % Area: 97.88
(Max), 98.80 (254 nm).
[0764] HPLC--Rt (min): 4.06; % Area: 97.93 (Max), 98.39 (254
nm).
[0765] .sup.1H NMR 400 MHz, CDCl.sub.3: .delta. 8.32 (s, 1H), 8.00
(d, J=8.00 Hz, 1H), 7.69 (d, J=4.00 Hz, 1H), 7.54 (d, J=8.00 Hz,
1H), 7.33 (s, 1H), 7.19 (dd, J=8.00, 4.00 Hz, 1H), 6.88 (d, J=8.00
Hz, 1H), 6.85 (dd, J=2.00, 0.80 Hz, 1H), 4.29 (t, J=12.00 Hz, 2H),
3.93 (s, 3H), 3.88 (s, 3H), 3.28 (t, J=12.00 Hz, 2H).
[3-(3,4-Dimethoxy-phenyl)-4,5-dihydro-pyrazol-1-yl]-quinolin-6-yl-methanon-
e
##STR00454##
[0767] Yellow solid; 14.32% Yield
[0768] LC-MS: Mass found (M+, 362). Rt (min): 2.56; % Area: 98.56
(Max), 99.01 (254 nm).
[0769] HPLC--Rt (min): 2.61; % Area: 99.09 (Max), 99.08 (254
nm).
[0770] .sup.1H NMR 400 MHz, CDCl.sub.3: .delta. 9.02 (d, J=3.20 Hz,
1H), 8.56 (s, 1H), 8.40-8.36 (m, 2H), 8.30-8.28 (m, 1H), 7.58-7.52
(m, 1H), 7.31 (d, J=4.00 Hz, 1H), 7.20 (dd, J=8.20, 1.60 Hz, 1H),
6.89 (d, J=8.00 Hz, 1H), 4.33 (t, J=8.00 Hz, 2H), 3.95 (s, 3H),
3.86 (s, 3H), 3.33 (t, J=8.00 Hz, 2H).
(2,3-Dihydro-benzo[1,4]dioxin-6-yl)-[3-(3,4-dimethoxy-phenyl)-4,5-dihydro--
pyrazol-1-yl]-methanone
##STR00455##
[0772] Yellow solid; 25.87% Yield
[0773] LC-MS: Mass found (M+, 369). Rt (min): 3.79; % Area: 98.91
(Max), 99.13 (254 nm).
[0774] HPLC--Rt (min): 3.86; % Area: 99.02 (Max), 99.47 (254
nm).
[0775] .sup.1H NMR 400 MHz, CDCl.sub.3: .delta. 7.69 (s, 1H), 7.62
(d, J=8.00 Hz, 1H), 7.37 (s, 1H), 7.19 (dd, J=10.80, 1.60 Hz, 1H),
6.90 (dd, J=8.00, 4.00 Hz, 2H), 4.33-4.28 (m, 4H), 4.24 (t, J=8.00
Hz, 2H), 3.93 (s, 3H), 3.92 (s, 3H), 3.23 (t, J=12.00 Hz, 2H).
Example 8: Synthetic route towards
(3-Benzylamino-4,5-dihydro-pyrazol-1-yl)-(3-fluoro-phenyl)-methanones,
[3-(Benzyl-methyl-amino)-4,5-dihydro-pyrazol-1-yl]-(3-fluoro-phenyl)-meth-
anones and
(3-Benzyloxy-4,5-dihydro-pyrazol-1-yl)-(3-fluoro-phenyl)-methan-
ones
##STR00456##
[0777] It shall be understood that the phenyl moiety (radical L)
can be substituted in accordance with the Ar.sup.1 definition as
demonstrated below.
Step 1: Preparation of pyrazolidin-3-one
##STR00457##
[0778] To a solution of hydrazine hydrate (6.67 ml, 0.14 mmol, 1
equiv.) in 75 ml of absolute ethanol was added drop-wise, ethyl
acrylate (13.53 ml, 0.125 mmol, 1.12 equiv.) in 50 ml of absolute
ethanol. The resulting solution was stirred for 1 h at ambient
temperature and then at reflux for 4 h. The reaction mixture was
concentrated in vacuum to get viscous oil. The crude product
obtained was purified by silica gel column using (60-120) mesh to
afford the titled product as pale yellow oil (7 gm, 50% yield).
[0779] Yellow oily liquid; 46.13% Yield 400 MHz, CDCl.sub.3:
.delta. 7.06 (s, 1H), 5.50 (s, 1H), 3.52 (t, J=8.00 Hz, 2H), 2.50
(t, J=8.00 Hz, 2H). STEP 2: Preparation of
1-(3-fluorobenzoyl)pyrazolidin-3-one
##STR00458##
[0780] To a solution of pyrazolidin-3-one (6.9 gm, 0.080 mmol, 1
equiv.) in dry dichloromethane (70 ml), 3-fluorobenzoic acid (12.3
gm, 0.088 mmol, 1.1 equiv.), triethylamine (24.3 gm, 0.240 mmol, 3
equiv.) and 1-propane phosphonic acid cyclic anhydride (60% by
weight in ethyl acetate) (51 gm, 0.16 mmol, 2 equiv.) were added in
cooling condition and stirred for overnight at room temperature.
The reaction mixture was concentrated and the residue was poured in
water (500 ml), extracted with dichloromethane (100 ml.times.2) and
concentrated. The crude product was purified by silica gel column
using (60-120) mesh to get the pure product as yellow oil (5.4 gm,
32% yield).
[0781] Yellow oil; 32% Yield
[0782] LC-MS: Mass found (M+, 209)
[0783] Method: A-0.1% HCOOH, B--MeOH--1 ml/min. Atlantis dC18
(50.times.4.6 mm, 5 .mu.m). Rt (min): 1.64; % Area: 98.34.
[0784] 400 MHz, CDCl.sub.3: .delta. 9.20 (s, 1H), 7.47-7.38 (m,
2H), 7.34-7.31 (m, 1H), 7.27-7.21 (m, 1H), 4.17 (t, J=8.00 Hz, 2H),
2.81 (t, J=4.00 Hz, 2H).
Step 3: Synthesis of
3-chloro-1-(3-fluorobenzoyl)-4,5-dihydro-1H-pyrazole
##STR00459##
[0785] Phosphorus oxychloride (54 ml for 5.4 gm of SM, 10 volume)
was added drop wise directly to 1-(3-fluorobenzoyl)
pyrazolidin-3-one (5.4 gm, 0.0238 mmol, 1 equiv.) at 0.degree. C.
and then refluxed at 85.degree. C. for an hour. The reaction
mixture was cooled to RT, concentrated and basified with solid
NaCO.sub.3 (pH: 8-9), extracted with dichloromethane (100
ml.times.2) and concentrated. The crude product was purified by
silica gel column using (60-120) mesh to get the pure product as
off green solid (4.8, 88.9% yield).
[0786] Off green solid; 88.9% Yield
[0787] LC-MS: Mass found (M+, 227) Method: A-0.1% TFA in water,
B-0.1% TFA in ACN: Flow--0.6 ml/min. Column: Xbridge C8
(50.times.4.6 mm, 3.5 .mu.m). Rt (min): 3.57; % Area: 97.92 (Max),
97.52 (254 nm).
[0788] 400 MHz, CDCl.sub.3: .delta. 7.65 (d, J=1.60 Hz, 1H),
7.59-7.55 (m, 1H), 7.42-7.37 (m, 1H), 7.21-7.16 (m, 1H), 4.26 (t,
J=4.00 Hz, 2H), 3.19 (t, J=4.00 Hz, 2H).
[0789] Compounds of the invention can be subsequently prepared
according to the general method:
##STR00460##
[0790] SC02 (1 eq) and amine (3 eq) were taken in a 8 ml vial and
heated at 150.degree. C. for 12 hours. The reaction mixture was
taken in saturated bicarbonate (5 ml) and extracted with
dichloromethane (5 ml.times.2) and concentrated in Genevac
overnight. The crude product was purified by column chromatography
(230-400 mesh) to get the pure target product.
[0791] The following compounds were prepared in a similar manner.
LC-MS and HPLC analysis were performed as follows: Method: A-0.1%
TFA in water, B-0.1% TFA in ACN: Flow--2 ml/min;
[0792] Column: XBridge c8 (50.times.4.6 mm, 3.5 .mu.m); unless
stated otherwise.
(3-Benzylamino-4,5-dihydro-pyrazol-1-yl)-(3-fluoro-phenyl)-methanone
##STR00461##
[0794] Yellow solid; 11.51% Yield
[0795] LC-MS: Mass found (M+, 298.3). Rt (min): 3.91; % Area: 92.20
(Max), 92.90 (254 nm).
[0796] HPLC--Flow--1.0 ml/min. Rt (min): 3.96; % Area: 93.79 (Max),
92.74 (254 nm).
[0797] 400 MHz, CDCl.sub.3: .delta. 7.71-7.69 (m, 2H), 7.39-7.27
(m, 6H), 7.25-7.09 (m, 1H), 4.38 (s, 2H), 4.15 (t, J=8.00 Hz, 2H),
2.89 (t, J=12.00 Hz, 2H).
[3-(4-Fluoro-benzylamino)-4,5-dihydro-pyrazol-1-yl]-(3-fluoro-phenyl)-meth-
anone
##STR00462##
[0799] Brown solid; 40.36% Yield
[0800] LC-MS: Mass found (M+, 316). Rt (min): 3.99; % Area: 97.94
(Max), 97.97 (254 nm).
[0801] HPLC--Flow--1.0 ml/min. Rt (min): 4.03; % Area: 96.51 (Max),
97.27 (254 nm).
[0802] 400 MHz, CDCl.sub.3: .delta. 7.71-7.69 (m, 2H), 7.35-7.26
(m, 3H), 7.15-7.11 (m, 1H), 7.05 (t, J=4.00 Hz, 2H), 4.35 (s, 1H),
4.34 (s, 2H), 4.16 (t, J=4.00 Hz, 2H), 2.89 (t, J=12.00 Hz,
2H).
[3-(2,4-Difluoro-benzylamino)-4,5-dihydro-pyrazol-1-yl]-(3-fluoro-phenyl)--
methanone
##STR00463##
[0804] Orange solid; 59.43% Yield
[0805] LC-MS: Mass found (M+, 334). Rt (min): 4.14; % Area: 96.06
(Max), 97.06 (254 nm).
[0806] HPLC--Flow--1.0 ml/min. Rt (min): 4.14; % Area: 98.13 (Max),
98.46 (254 nm).
[0807] 400 MHz, DMSO-d6: .delta. 7.61 (d, J=8.00 Hz, 1H), 7.56-7.53
(m, 1H), 7.43-7.32 (m, 3H), 7.28-7.17 (m, 2H), 7.05-7.01 (m, 1H),
4.22 (d, J=8.00 Hz, 2H), 3.90 (t, J=8.00 Hz, 2H), 2.84 (t, J=12.00
Hz, 2H).
[3-(3,4-Difluoro-benzylamino)-4,5-dihydro-pyrazol-1-yl]-(3-fluoro-phenyl)--
methanone
##STR00464##
[0809] Yellow solid; 53.07% Yield
[0810] LC-MS: Mass found (M+, 334). Rt (min): 4.11; % Area: 90.56
(Max), 91.60 (254 nm).
[0811] HPLC--Flow--1.0 ml/min. Rt (min): 4.18; % Area: 93.32 (Max),
92.10 (254 nm).
[0812] 400 MHz, CDCl.sub.3: .delta. 7.67-7.61 (m, 2H), 7.33 (dd,
J=16.00, 8.00 Hz, 1H), 7.17-7.10 (m, 3H), 7.04 (s, 1H), 4.47 (s,
1H), 4.31 (d, J=8.00 Hz, 2H), 4.15 (t, J=8.00 Hz, 2H), 2.89 (t,
J=8.00 Hz, 2H).
{3-[(4-Fluoro-benzyl)-methyl-amino]-4,5-dihydro-pyrazol-1-yl}-(3-fluoro-ph-
enyl)-methanone
##STR00465##
[0814] Yellow gum; 16.14% Yield
[0815] LC-MS: Mass found (M+, 330.3). Rt (min): 4.36; % Area: 91.22
(Max), 95.34 (254 nm).
[0816] HPLC--Flow--1.0 ml/min. Rt (min): 4.38; % Area: 93.82 (Max),
95.05 (254 nm).
[0817] 400 MHz, CDCl.sub.3: .delta. 7.79-7.74 (m, 2H), 7.35-7.30
(m, 1H), 7.21-7.17 (m, 2H), 7.12-7.01 (m, 3H), 4.37 (s, 2H), 4.19
(t, J=8.00 Hz, 2H), 2.96 (t, J=12.00 Hz, 2H), 2.91 (s, 3H).
(3-Fluoro-phenyl)-{3-[(3-methoxy-benzyl)-methyl-amino]-4,5-dihydro-pyrazol-
-1-yl}-methanone
##STR00466##
[0819] Yellow gum; 8.46% Yield
[0820] LC-MS: Mass found (M+, 342.3). Rt (min): 4.26; % Area: 95.68
(Max), 96.68 (254 nm).
[0821] HPLC--Flow--1.0 ml/min. Rt (min): 4.27; % Area: 93.14 (Max),
95.01 (254 nm).
[0822] 400 MHz, CDCl.sub.3: .delta. 7.81 (t, J=8.00 Hz, 2H),
7.36-7.26 (m, 2H), 7.12-7.07 (m, 1H), 6.85-6.76 (m, 3H), 4.40 (s,
2H), 4.21 (t, J=8.00 Hz, 2H), 3.78 (s, 3H), 2.98 (t, J=8.00 Hz,
2H), 2.94 (s, 3H).
{3-[(3-Fluoro-benzyl)-methyl-amino]-4,5-dihydro-pyrazol-1-yl}-(3-fluoro-ph-
enyl)-methanone
##STR00467##
[0824] Yellow gum; 11.97% Yield
[0825] LC-MS: Mass found (M+, 330.3). Rt (min): 4.34; % Area: 91.12
(Max), 94.21 (254 nm).
[0826] HPLC--Flow--1.0 ml/min. Rt (min): 4.37; % Area: 91.70 (Max),
94.99 (254 nm).
[0827] 400 MHz, CDCl.sub.3: .delta. 7.79-7.74 (m, 2H), 7.35-7.27
(m, 2H), 7.13-7.08 (m, 1H), 7.01-6.92 (m, 3H), 4.42 (s, 2H), 4.21
(t, J=8.00 Hz, 2H), 3.02 (t, J=8.00 Hz, 2H), 2.96 (s, 3H).
Example 9: General Method for the Preparation of the Following
Compounds
##STR00468##
[0829] It shall be understood that Ar includes Ar.sup.1 and
Ar.sup.2.
[0830] Taking the example of 4-methoxyphenylboronic acid, the
Suzuki reaction is performed as follows:
##STR00469##
[0831] To a degassed solution of
(3-Chloro-4,5-dihydro-pyrazol-1-yl)-(3-fluoro-phenyl)-methanone
(0.19 g, 0.0008 moles, 1 equiv) in dry 1,2-DME-water, 5 mL, (4:1)
was added 4-Methoxyphenylboronic acid (0.17 g, 0.0112 moles, 1.4
equiv), anhydrous sodium carbonate (0.17 g, 0.0016 moles, 2 equiv)
and Tetrakis-(triphenylphosphine)-palladium(0) (0.092 g, 0.00008
moles, 0.1 equiv). The reaction mixture was heated at 110.degree.
C. for 0.5 h and er nitrogen atmosphere in microwave conditions or
6-8 h in thermal conditions. Consumption of starting material was
confirmed by TLC and LC-MS. 1,2-DME was distilled under reduced
pressure, the crude residue was dissolved in dichloromethane (25
mL), washed with water, saturated brine, dried over anhydrous
sodium sulfate. The crude product was purified by column
chromatography to get the pure compound
(3-Fluorophenyl)-[3-(4-methoxyphenyl)-4,5-dihydropyrazol-1-yl]-methanone
in 0.100 g. P.S.: (a) In case of Carboxy boronic acid, LiCl (3 eq)
was added to the reaction mixture as an additive. (b) In Case of
Cyano boronic acid, K.sub.3PO.sub.4 (2 eq) was used as base.
[0832] The following compounds were prepared in a similar manner.
LC-MS and HPLC analysis were performed as follows: Method: A-0.1%
TFA in water, B-0.1% TFA in ACN: Flow--2 ml/min; Column: XBridge c8
(50.times.4.6 mm, 3.5 .mu.m); unless stated otherwise.
(3-Fluoro-phenyl)-(3-phenyl-4,
5-dihydro-pyrazol-1-yl)-methanone
##STR00470##
[0834] Off white solid; 46.81% Yield
[0835] LC-MS: Mass found (M+, 269.0). Rt (min): 4.47; % Area: 99.47
(Max), 99.55 (220 nm).
[0836] HPLC--Rt (min): 4.55; % Area: 98.88 (Max), 99.70 (254
nm).
[0837] 400 MHz, CDCl.sub.3: .delta. 7.76-7.70 (m, 4H), 7.45-7.40
(m, 4H), 7.23-7.18 (m, 1H), 4.28 (t, J=8.00 Hz, 2H), 3.30 (t,
J=12.00 Hz, 2H).
(3-Fluoro-phenyl)-(3-p-tolyl-4,5-dihydro-pyrazol-1-yl)-methanone
##STR00471##
[0839] Off white solid; 30.31% Yield
[0840] LC-MS: Mass found (M+, 283.0). Rt (min): 4.80; % Area: 97.87
(Max), 97.31 (254 nm).
[0841] HPLC--Rt (min): 4.87; % Area: 99.21 (Max), 99.0 (254
nm).
[0842] 400 MHz, CDCl.sub.3: .delta. 7.82-7.80 (m, 1H), 7.77-7.75
(m, 1H), 7.61-7.59 (m, 2H), 7.45-7.40 (m, 1H), 7.24-7.18 (m, 3H),
4.26 (t, J=9.76 Hz, 2H), 3.28 (t, J=10.12 Hz, 2H), 2.40 (s,
3H).
(3-Biphenyl-4-yl-4,5-dihydro-pyrazol-1-yl)-(3-fluoro-phenyl)-methanone
##STR00472##
[0844] Yellow solid; 52.83% Yield
[0845] LC-MS: Mass found (M+, 345.3). Rt (min): 5.35; % Area: 98.25
(Max), 94.69 (254 nm).
[0846] HPLC--Rt (min): 5.43; % Area: 98.34 (Max), 95.50 (254
nm).
[0847] 400 MHz, CDCl.sub.3: .delta. 7.82-7.76 (m, 4H), 7.68-7.62
(m, 4H), 7.50-7.40 (m, 4H), 7.38-7.21 (m, 1H), 4.30 (t, J=9.60 Hz,
2H), 3.37-3.32 (m, 2H).
(3-Fluoro-phenyl)-[3-(4-phenoxy-phenyl)-4,5-dihydro-pyrazol-1-yl]-methanon-
e
##STR00473##
[0849] White solid; 69.10% Yield
[0850] LC-MS: Mass found (M+, 361). Flow--0.6 ml/min. Rt (min):
5.40; % Area: 95.59 (Max), 94.88 (220 nm).
[0851] HPLC--Rt (min): 3.45; % Area: 97.77 (Max), 97.44 (220
nm).
[0852] 400 MHz, CDCl.sub.3: .delta. 7.80 (d, J=8.00 Hz, 1H),
7.75-7.73 (m, 1H), 7.69-7.66 (m, 2H), 7.44-7.37 (m, 3H), 7.22-7.16
(m, 2H), 7.07-7.00 (m, 4H), 4.27 (t, J=8.00 Hz, 2H), 3.28 (t,
J=12.00 Hz, 2H).
4-[1-(3-Fluoro-benzoyl)-4,5-dihydro-1H-pyrazol-3-yl]-benzoic
acid
##STR00474##
[0854] Off white solid; 100% Yield
[0855] LC-MS: Mass found (M+, 313). Flow--0.6 ml/min. Rt (min):
3.65; % Area: 98.41 (Max), 97.27 (220 nm).
[0856] HPLC--Rt (min): 3.60; % Area: 97.42 (Max), 94.73 (254
nm).
[0857] 400 MHz, DMSO-d6: .delta. 13.00 (brs, 1H), (8.00 (d, J=8.00
Hz, 2H), 7.79 (d, J=12.00 Hz, 2H), 7.70 (d, J=8.00 Hz, 1H),
7.64-7.60 (m, 1H), 7.57-7.52 (m, 1H), 7.42-7.37 (m, 1H), 4.14 (t,
J=12.00 Hz, 2H), 3.36-3.34 (m, 2H).
(3-Fluoro-phenyl)-[3-(4-trifluoromethyl-phenyl)-4,5-dihydro-pyrazol-1-yl]--
methanone
##STR00475##
[0859] Off white solid; 38.73% Yield
[0860] LC-MS: Mass found (M+, 337.0). Flow--0.6 ml/min. Rt (min):
5.22; % Area: 98.50 (Max), 97.31 (254 nm).
[0861] HPLC--Rt (min): 5.28; % Area: 98.50 (Max), 99.20 (254
nm).
[0862] 400 MHz, CDCl.sub.3: .delta. 7.80-7.73 (m, 3H), 7.71-7.67
(m, 3H), 7.47-7.42 (m, 1H), 7.25-7.20 (m, 1H), 4.32 (t, J=9.76 Hz,
2H), 3.32 (t, J=10.36 Hz, 2H).
(3-Fluoro-phenyl)-[3-(4-vinyl-phenyl)-4,5-dihydro-pyrazol-1-yl]-methanone
##STR00476##
[0864] Off white solid; 2.06% Yield
[0865] LC-MS: Mass found (M+, 295.0). Rt (min): 4.90; % Area: 97.52
(Max), 95.52 (220 nm).
[0866] HPLC--Rt (min): 5.02; % Area: 96.52 (Max), 96.25 (220
nm).
[0867] 400 MHz, CDCl.sub.3: .delta. 7.80-7.77 (m, 1H), 7.74-7.68
(m, 1H), 7.66-7.47 (m, 2H), 7.46-7.41 (m, 3H), 7.24-7.19 (m, 1H),
6.78-6.71 (m, 1H), 5.84 (d, J=16.96 Hz, 1H), 5.35 (d, J=11.28 Hz,
1H), 4.28 (t, J=9.72 Hz, 2H), 3.30 (t, J=10.36 Hz, 2H).
(3-Fluoro-phenyl)-[3-(4-hydroxymethyl-phenyl)-4,5-dihydro-pyrazol-1-yl]-me-
thanone
##STR00477##
[0869] White Solid; 58.71% Yield
[0870] LC-MS: Mass found (M+, 299.0). Rt (min): 3.36; % Area: 98.53
(Max), 96.80 (220 nm).
[0871] HPLC--Rt (min): 3.45; % Area: 99.82 (Max), 99.46 (254
nm).
[0872] 400 MHz, CDCl.sub.3: .delta. 7.82-7.76 (m, 1H), 7.74-7.33
(m, 1H), 7.70-7.68 (m, 2H), 7.46-7.40 (m, 3H), 7.23-7.18 (m, 1H),
4.75 (s, 2H), 4.24 (t, J=9.64 Hz, 2H), 3.30-3.25 (m, 2H).
[3-(4-Ethyl-phenyl)-4,5-dihydro-pyrazol-1-yl]-(3-fluoro-phenyl)-methanone
##STR00478##
[0874] Green solid; 31.13% Yield
[0875] LC-MS: Mass found (M+, 297.2). Rt (min): 5.13; % Area: 99.3
(Max), 99.21 (254 nm).
[0876] HPLC--Rt (min): 5.21; % Area: 99.42 (Max), 98.15 (254
nm).
[0877] 400 MHz, CDCl.sub.3: .delta. 7.82-7.80 (m, 1H), 7.77-7.74
(m, 1H), 7.64-7.62 (m, 2H), 7.45-7.39 (m, 1H), 7.24-7.22 (m, 2H),
7.21-7.17 (m, 1H), 4.26 (t, J=8.00 Hz, 2H), 3.31-3.26 (m, 2H),
2.72-2.66 (m, 2H), 1.26 (t, J=4.00 Hz, 3H).
[3-(4-tert-Butyl-phenyl)-4,5-dihydro-pyrazol-1-yl]-(3-fluoro-phenyl)-metha-
none
##STR00479##
[0879] White solid; 68.24% Yield
[0880] LC-MS: Mass found (M+, 325.3). Flow--0.6 ml/min. Rt (min):
5.64; % Area: 91.91 (Max), 90.29 (220 nm).
[0881] HPLC--Rt (min): 5.67; % Area: 99.16 (Max), 99.52 (254
nm).
[0882] 400 MHz, CDCl.sub.3: .delta. 7.82 (d, J=8.00 Hz, 1H), 7.77
(d, J=12.00 Hz, 1H), 7.66 (d, J=12.00 Hz, 2H), 7.46-7.40 (m, 3H),
7.23-7.18 (m, 1H), 4.27 (t, J=8.00 Hz, 2H), 3.29 (t, J=12.00 Hz,
2H), 1.35 (s, 9H).
(3-Fluoro-phenyl)-[3-(4-isopropyl-phenyl)-4,5-dihydro-pyrazol-1-yl]-methan-
one
##STR00480##
[0884] White solid; 32.35% Yield
[0885] LC-MS: Mass found (M+, 311.3). Rt (min): 5.39; % Area: 98.99
(Max), 99.09 (254 nm).
[0886] HPLC--Rt (min): 5.49; % Area: 99.35 (Max), 98.07 (254
nm).
[0887] 400 MHz, CDCl.sub.3: .delta. 7.82-7.80 (m, 1H), 7.77-7.74
(m, 1H), 7.65-7.63 (m, 2H), 7.44-7.39 (m, 1H), 7.28-7.27 (m, 2H),
7.22-7.17 (m, 1H), 4.26 (t, J=9.60 Hz, 2H), 3.30 (t, J=3.60 Hz,
2H), 2.98-2.91 (m, 1H), 1.28 (s, 3H), 1.27 (d, J=8 Hz, 3H).
(3-Fluoro-phenyl)-[3-(4-hydroxy-phenyl)-4,5-dihydro-pyrazol-1-yl]-methanon-
e
##STR00481##
[0889] White solid; 76.73% Yield
[0890] LC-MS: Mass found (M+, 285.2). Flow--0.6 ml/min. Rt (min):
4.26; % Area: 92.32 (Max), 98.21 (254 nm).
[0891] HPLC--Rt (min): 4.29; % Area: 95.02 (Max), 97.61 (254
nm).
[0892] 400 MHz, CDCl.sub.3: .delta. 7.57 (d, J=8.00 Hz, 1H),
7.50-7.47 (m, 1H), 7.41-7.37 (m, 2H), 7.36-7.29 (m, 3H), 7.25-7.22
(m, 1H), 7.17-7.13 (m, 1H), 4.25 (t, J=8.00 Hz, 2H), 3.21 (t,
J=8.00 Hz, 2H).
(3-Fluoro-phenyl)-[3-(4-trifluoromethoxy-phenyl)-4,5-dihydro-pyrazol-1-yl]-
-methanone
##STR00482##
[0894] White solid; 48.11% Yield
[0895] LC-MS: Mass found (M+, 353.0). Rt (min): 5.28; % Area: 98.08
(Max), 98.31 (254 nm).
[0896] HPLC--Rt (min): 5.34; % Area: 98.97 (Max), 98.90 (254
nm).
[0897] 400 MHz, CDCl.sub.3: .delta. 7.75-7.71 (m, 4H), 7.46-7.44
(m, 1H), 7.43-7.41 (m, 1H), 7.24-7.19 (m, 2H), 4.32-4.27 (m, 2H),
3.32-3.27 (m, 2H).
1-{4-[1-(3-Fluoro-benzoyl)-4,5-dihydro-1H-pyrazol-3-yl]-phenyl}-ethanone
##STR00483##
[0899] Off white solid; 53.87% Yield
[0900] LC-MS: Mass found (M+, 311.3). Flow--0.6 ml/min. Rt (min):
4.10; % Area: 98.68 (Max), 97.93 (254 nm).
[0901] HPLC--Rt (min): 4.13; % Area: 99.20 (Max), 98.38 (254
nm).
[0902] 400 MHz, CDCl.sub.3: .delta. 8.01 (d, J=8.00 Hz, 2H),
7.81-7.72 (m, 4H), 7.47-7.42 (m, 1H), 7.23-7.21 (m, 1H), 4.32 (t,
J=8.00 Hz, 2H), 3.33 (t, J=12.00 Hz, 2H), 2.64 (s, 3H).
[3-(4-Dimethylaminomethyl-phenyl)-4,5-dihydro-pyrazol-1-yl]-(3-fluoro-phen-
yl)-methanone
##STR00484##
[0904] White solid; 77.26% Yield
[0905] LC-MS: Mass found (M+, 326.3). Flow--0.6 ml/min. Rt (min):
2.75; % Area: 97.95 (Max), 97.13 (254 nm).
[0906] HPLC--Rt (min): 2.71; % Area: 98.51 (Max), 97.78 (254
nm).
[0907] 400 MHz, CDCl.sub.3: .delta. 7.81 (d, J=8.00 Hz, 1H),
7.76-7.74 (m, 1H), 7.67 (d, J=8.00 Hz, 2H), 7.45-7.40 (m, 1H), 7.37
(d, J=8.00 Hz, 2H), 7.23-7.18 (m, 1H), 4.27 (t, J=12.00 Hz, 2H),
3.47 (s, 2H), 3.30 (t, J=8.00 Hz, 2H), 2.26 (s, 6H).
(3-Fluoro-phenyl)-[3-(4-methanesulfonyl-phenyl)-4,5-dihydro-pyrazol-1-yl]--
methanone
##STR00485##
[0909] Off white solid; 1.93% Yield
[0910] LC-MS: Mass found (M+, 347.0). Rt (min): 3.60; % Area: 97.31
(Max), 96.0 (220 nm).
[0911] HPLC--Rt (min): 3.73; % Area: 98.07 (Max), 96.61 (254
nm).
[0912] 400 MHz, CDCl.sub.3: .delta. 8.01-7.99 (m, 2H), 7.89-7.87
(m, 2H), 7.78-7.76 (m, 1H), 7.72-7.69 (m, 1H), 7.48-7.42 (m, 1H),
7.28-7.23 (m, 1H), 4.34 (t, J=9.80 Hz, 2H), 3.36-3.31 (m, 2H), 3.08
(s, 3H).
4-[1-(3-Fluoro-benzoyl)-4,
5-dihydro-1H-pyrazol-3-yl]-N,N-dimethyl-benzamide
##STR00486##
[0914] White Solid; 92.16% Yield
[0915] LC-MS: Mass found (M+, 340.0). Rt (min): 3.44; % Area: 97.35
(Max), 98.22 (254 nm).
[0916] HPLC--Rt (min): 3.56; % Area: 97.53 (Max), 97.70 (254
nm).
[0917] 400 MHz, CDCl.sub.3: .delta. 7.75-7.73 (m, 1H), 7.73-7.72
(m, 3H), 7.50-7.47 (m, 2H), 7.46-7.41 (m, 1H), 7.24-7.19 (m, 1H),
4.32-4.27 (m, 2H), 3.34-3.29 (m, 2H), 3.06 (brs, 6H).
[3-(4-tert-Butoxy-phenyl)-4,5-dihydro-pyrazol-1-yl]-(3-fluoro-phenyl)-meth-
anone
##STR00487##
[0919] Off white Solid; 71.83% Yield
[0920] LC-MS: Mass found (M+, 341.0). Rt (min): 5.21; % Area: 95.26
(Max), 95.0 (254 nm).
[0921] HPLC--Rt (min): 5.31; % Area: 95.36 (Max), 95.12 (254
nm).
[0922] 400 MHz, CDCl.sub.3: .delta. 7.80 (d, J=8.00 Hz, 1H),
7.76-7.73 (m, 1H), 7.64-7.61 (m, 2H), 7.44-7.39 (m, 1H), 7.22-7.17
(m, 1H), 7.05-7.01 (m, 2H), 4.25 (t, J=12.00 Hz, 2H), 3.27 (t,
J=12.00 Hz, 2H), 1.39 (s, 9H).
4-[1-(3-Fluoro-benzoyl)-4,5-dihydro-1H-pyrazol-3-yl]-N,N-dimethyl-benzenes-
ulfonamide
##STR00488##
[0924] White solid; 1.93% Yield
[0925] LC-MS: Mass found (M+, 376.0). Rt (min): 4.21; % Area: 99.06
(Max), 98.96 (220 nm).
[0926] HPLC--Rt (min): 4.32; % Area: 99.11 (Max), 98.07 (254
nm).
[0927] 400 MHz, CDCl.sub.3: .delta. 7.87-7.84 (m, 4H), 7.83-7.77
(m, 1H), 7.73-7.72 (m, 1H), 7.48-7.42 (m, 1H), 7.28-7.23 (m, 1H),
4.33 (t, J=9.76 Hz, 2H), 3.33 (t, J=10.56 Hz, 2H), 2.74 (s,
6H).
3-[1-(3-Fluoro-benzoyl)-4,5-dihydro-1H-pyrazol-3-yl]-benzoic
acid
##STR00489##
[0929] Grey solid; 100% Yield
[0930] LC-MS: Mass found (M+, 313.3). Flow--0.6 ml/min. Rt (min):
3.68; % Area: 96.31 (Max), 97.70 (254 nm).
[0931] HPLC--Rt (min): 3.66; % Area: 96.38 (Max), 97.14 (254
nm).
[0932] 400 MHz, DMSO-d6: .delta. 13.25 (brs, 1H), 8.18 (brs, 1H),
8.01 (d, J=8.00 Hz, 1H), 7.92 (d, J=8.00 Hz, 1H), 7.69 (d, J=8.00
Hz, 1H), 7.64-7.52 (m, 3H), 7.42-7.37 (m, 1H), 4.14 (t, J=8.00 Hz,
2H), 3.41-3.32 (m, 2H).
(3-Fluoro-phenyl)-(3-m-tolyl-4,5-dihydro-pyrazol-1-yl)-methanone
##STR00490##
[0934] Off white solid; 57.44% Yield
[0935] LC-MS: Mass found (M+, 283.0). Rt (min): 4.77; % Area: 96.24
(Max), 97.25 (254 nm).
[0936] HPLC--Rt (min): 4.88; % Area: 96.34 (Max), 96.52 (254
nm).
[0937] 400 MHz, CDCl.sub.3: .delta. 7.81 (d, J=8.00 Hz, 1H),
7.76-7.74 (m, 1H), 7.52-7.50 (m, 2H), 7.46-7.42 (m, 1H), 7.33-7.29
(m, 1H), 7.24-7.18 (m, 2H), 4.26 (t, J=12.00 Hz, 2H), 3.29 (t,
J=8.00 Hz, 2H), 2.40 (s, 3H).
(3-Fluoro-phenyl)-[3-(3-trifluoromethyl-phenyl)-4,5-dihydro-pyrazol-1-yl]--
methanone
##STR00491##
[0939] Yellow solid; 59.97% Yield
[0940] LC-MS: Mass found (M+, 337.0). Rt (min): 5.12; % Area: 98.56
(Max), 98.32 (254 nm).
[0941] HPLC--Rt (min): 5.22; % Area: 99.58 (Max), 99.09 (254
nm).
[0942] 400 MHz, CDCl.sub.3: .delta. 7.93 (d, J=8.00 Hz, 1H), 7.88
(brs, 1H), 7.78 (d, J=8.00 Hz, 1H), 7.72-7.68 (m, 2H), 7.58-7.54
(m, 1H), 7.47-7.41 (m, 1H), 7.25-7.20 (m, 1H), 4.32 (t, J=8.00 Hz,
2H), 3.33 (t, J=8.00 Hz, 2H).
[3-(3-Amino-phenyl)-4,5-dihydro-pyrazol-1-yl]-(3-fluoro-phenyl)-methanone
##STR00492##
[0944] Off white solid; 42.93% Yield
[0945] LC-MS: Mass found (M+, 284). Rt (min): 2.61; % Area: 96.86
(Max), 93.73 (254 nm).
[0946] HPLC--Rt (min): 2.60; % Area: 96.52 (Max), 93.72 (254
nm).
[0947] 400 MHz, CDCl.sub.3: .delta. 7.79 (d, J=8.00 Hz, 1H),
7.75-7.72 (m, 1H), 7.45-7.40 (m, 1H), 7.23-7.18 (m, 2H), 7.07-7.01
(m, 2H), 6.78-6.75 (m, 1H), 4.25 (t, J=12.00 Hz, 2H), 3.78 (brs,
2H), 3.26 (t, J=12.00 Hz, 2H).
N-{3-[1-(3-Fluoro-benzoyl)-4,5-dihydro-1H-pyrazol-3-yl]-phenyl}-acetamide
##STR00493##
[0949] White solid; 15.45% Yield
[0950] LC-MS: Mass found (M+, 326.3). Rt (min): 3.51; % Area: 98.63
(Max), 99.22 (254 nm).
[0951] HPLC--Rt (min): 3.50; % Area: 98.69 (Max), 99.55 (254
nm).
[0952] 400 MHz, CDCl.sub.3: .delta. 7.79 (d, J=8.00 Hz, 1H),
7.74-7.71 (m, 1H), 7.66 (d, J=8.00 Hz, 1H), 7.47-7.36 (m, 3H),
7.24-7.21 (m, 2H), 4.28 (t, J=8.00 Hz, 2H), 3.30 (t, J=12.00 Hz,
2H), 2.21 (s, 3H).
(3-Fluoro-phenyl)-[3-(3-fluoro-phenyl)-4,5-dihydro-pyrazol-1-yl]-methanone
##STR00494##
[0954] White solid; 60.45% Yield
[0955] LC-MS: Mass found (M+, 326.3). Rt (min): 4.61; % Area: 99.22
(Max), 98.49 (254 nm).
[0956] HPLC--Rt (min): 4.63; % Area: 99.50 (Max), 98.40 (254
nm).
[0957] 400 MHz, CDCl.sub.3: .delta. 7.79 (d, J=4.00 Hz, 1H),
7.73-7.70 (m, 1H), 7.48-7.38 (m, 4H), 7.24-7.19 (m, 1H), 7.17-7.12
(m, 1H), 4.29 (t, J=12.00 Hz, 2H), 3.31-3.26 (m, 2H).
[3-(3-Ethoxy-phenyl)-4,5-dihydro-pyrazol-1-yl]-(3-fluoro-phenyl)-methanone
##STR00495##
[0959] Yellow solid; 41.55% Yield
[0960] LC-MS: Mass found (M+, 313.0). Rt (min): 4.83; % Area: 97.72
(Max), 98.24 (254 nm).
[0961] HPLC--Rt (min): 4.91; % Area: 98.07 (Max), 98.95 (254
nm).
[0962] 400 MHz, CDCl.sub.3: .delta. 7.94-7.74 (m, 2H), 7.45-7.39
(m, 2H), 7.35-7.31 (m, 1H), 7.28-7.24 (m, 1H), 7.22-7.19 (m, 1H),
6.98-6.95 (m, 1H), 4.26 (t, J=12.00 Hz, 2H), 4.09-4.04 (m, 2H),
3.28 (t, J=8.00 Hz, 2H), 1.44 (t, J=8.00 Hz, 3H).
(3-Fluoro-phenyl)-[3-(3-hydroxy-phenyl)-4,5-dihydro-pyrazol-1-yl]-methanon-
e
##STR00496##
[0964] White Solid; 11.26% Yield
[0965] LC-MS: Mass found (M+, 285.3). Rt (min): 3.70; % Area: 93.85
(Max), 95.49 (254 nm).
[0966] HPLC--Rt (min): 3.72; % Area: 97.02 (Max), 96.72 (254
nm).
[0967] 400 MHz, DMSO-d6: .delta. 7.69 (d, J=8.00 Hz, 1H), 7.63-7.61
(m, 1H), 7.56-7.51 (m, 1H), 7.41-7.36 (m, 1H), 7.26 (t, J=8.00 Hz,
1H), 7.11-7.10 (m, 2H), 6.86-6.84 (m, 1H), 4.09 (t, J=12.00 Hz,
2H), 3.32-3.26 (m, 2H).
(3-Fluoro-phenyl)-[3-(3-isopropyl-phenyl)-4,5-dihydro-pyrazol-1-yl]-methan-
one
##STR00497##
[0969] Yellow gum; 7.50% Yield
[0970] LC-MS: Mass found (M+, 311.3). Rt (min): 5.39; % Area: 98.67
(Max), 97.0 (254 nm).
[0971] HPLC--Rt (min): 5.49; % Area: 98.55 (Max), 96.42 (254
nm).
[0972] 400 MHz, CDCl.sub.3: .delta. 7.89-7.86 (m, 1H), 7.82-7.79
(m, 1H), 7.54-7.52 (m, 2H), 7.43-7.42 (m, 1H), 7.35-7.30 (m, 2H),
7.26-7.20 (m, 1H), 4.27 (t, J=8.00 Hz, 2H), 3.30 (t, J=12.00 Hz,
2H), 2.97-2.93 (m, 1H), 1.28 (s, 3H), 1.26 (s, 3H).
(3-Fluoro-phenyl)-[3-(3-hydroxymethyl-phenyl)-4,5-dihydro-pyrazol-1-yl]-me-
thanone
##STR00498##
[0974] White Solid; 43.46% Yield
[0975] LC-MS: Mass found (M+, 299.3). Rt (min): 3.51; % Area: 97.69
(Max), 95.92 (254 nm).
[0976] HPLC--Rt (min): 3.52; % Area: 97.98 (Max), 95.78 (254
nm).
[0977] 400 MHz, CDCl.sub.3: .delta. 7.80 (d, J=8.00 Hz, 1H),
7.75-7.72 (m, 1H), 7.69-7.65 (m, 2H), 7.46-7.41 (m, 3H), 7.24-7.18
(m, 1H), 4.76 (d, J=4.00 Hz, 2H), 4.28 (t, J=8.00 Hz, 2H), 3.31 (t,
J=12.00 Hz, 2H), 1.80 (t, J=8.00 Hz, 1H).
(3-Biphenyl-3-yl-4,5-dihydro-pyrazol-1-yl)-(3-fluoro-phenyl)-methanone
##STR00499##
[0979] White Solid; 71.85% Yield
[0980] LC-MS: Mass found (M+, 345.3). Rt (min): 5.40; % Area: 98.51
(Max), 99.15 (254 nm).
[0981] HPLC--Rt (min): 5.42; % Area: 99.52 (Max), 98.95 (254
nm).
[0982] 400 MHz, CDCl.sub.3: .delta. 7.88 (brs, 1H), 7.82 (d, J=8.00
Hz, 1H), 7.78-7.71 (m, 2H), 7.68-7.65 (m, 1H), 7.62-7.60 (m, 2H),
7.52-7.38 (m, 5H), 7.24-7.19 (m, 1H), 4.31 (t, J=8.00 Hz, 2H), 3.36
(t, J=12.00 Hz, 2H).
3-[1-(3-Fluoro-benzoyl)-4,5-dihydro-1H-pyrazol-3-yl]-benzonitrile
##STR00500##
[0984] White Solid; 100% Yield
[0985] LC-MS: Mass found (M+, 294.0). Rt (min): 4.22; % Area: 97.71
(Max), 98.24 (254 nm).
[0986] HPLC--Rt (min): 4.25; % Area: 98.09 (Max), 98.66 (254
nm).
[0987] 400 MHz, CDCl.sub.3: .delta. 7.95-7.93 (m, 2H), 7.77-7.66
(m, 3H), 7.58-7.53 (m, 1H), 7.49-7.43 (m, 1H), 7.24-7.21 (m, 1H),
4.33 (t, J=8.00 Hz, 2H), 3.31 (t, J=8.00 Hz, 2H).
[3-(3-Dimethylamino-phenyl)-4,5-dihydro-pyrazol-1-yl]-(3-fluoro-phenyl)-me-
thanone
##STR00501##
[0989] Off white solid; 8.80% Yield
[0990] LC-MS: Mass found (M+, 312.3). Rt (min): 3.0; % Area: 98.03
(Max), 96.58 (254 nm).
[0991] HPLC--Rt (min): 3.01; % Area: 98.58 (Max), 97.49 (254
nm).
[0992] 400 MHz, CDCl.sub.3: .delta. 7.83-7.78 (m, 2H), 7.43-7.38
(m, 1H), 7.30-7.27 (m, 1H), 7.21-7.16 (m, 1H), 7.08 (brs, 1H),
7.04-7.02 (m, 1H), 6.83-6.80 (m, 1H), 4.26 (t, J=-8.00 Hz, 2H),
3.32-3.27 (m, 2H), 2.98 (s, 6H).
(3-Fluoro-phenyl)-[3-(3-methylsulfanyl-phenyl)-4,5-dihydro-pyrazol-1-yl]-m-
ethanone
##STR00502##
[0994] Off White Solid; 73.81% Yield
[0995] LC-MS: Mass found (M+, 315.3). Rt (min): 4.89; % Area: 95.38
(Max), 94.13 (254 nm).
[0996] HPLC--Rt (min): 4.90; % Area: 96.80 (Max), 95.64 (254
nm).
[0997] 400 MHz, CDCl.sub.3: .delta. 7.80 (d, J=8.00 Hz, 1H),
7.77-7.74 (m, 1H), 7.58 (brs, 1H), 7.48-7.42 (m, 2H), 7.37-7.30 (m,
2H), 7.24-7.21 (m, 1H), 4.28 (t, J=12.00 Hz, 2H), 3.29 (t, J=8.00
Hz, 2H), 2.52 (s, 3H).
(3-Fluoro-phenyl)-[3-(3-trifluoromethoxy-phenyl)-4,5-dihydro-pyrazol-1-yl]-
-methanone
##STR00503##
[0999] White solid; 48.57% Yield
[1000] LC-MS: Mass found (M+, 353.0). Rt (min): 5.26; % Area: 99.73
(Max), 99.55 (254 nm).
[1001] HPLC--Rt (min): 5.34; % Area: 99.59 (Max), 98.97 (254
nm).
[1002] 400 MHz, CDCl.sub.3: .delta. 7.78 (d, J=8.00 Hz, 1H), 7.71
(d, J=8.00 Hz, 1H), 7.63 (d, J=8.00 Hz, 1H), 7.53 (brs, 1H),
7.48-7.41 (m, 2H), 7.30-7.28 (m, 1H), 7.24-7.19 (m, 1H), 4.30 (t,
J=8.00 Hz, 2H), 3.29 (t, J=12.00 Hz, 2H).
N-{3-[1-(3-Fluoro-benzoyl)-4,5-dihydro-1H-pyrazol-3-yl]-phenyl}-methanesul-
fonamide
##STR00504##
[1004] Off white Solid; 67.48% Yield
[1005] LC-MS: Mass found (M+, 362.0). Rt (min): 3.62; % Area: 99.17
(Max), 98.40 (254 nm).
[1006] HPLC--Rt (min): 3.77; % Area: 99.44 (Max), 99.11 (254
nm).
[1007] 400 MHz, CDCl.sub.3: .delta. 7.78 (d, J=8.00 Hz, 1H), 7.72
(d, J=8.00 Hz, 1H), 7.54-7.53 (m, 1H), 7.51-7.48 (m, 1H), 7.45-7.41
(m, 2H), 7.34-7.32 (m, 1H), 7.24-7.19 (m, 1H), 6.56 (brs, 1H), 4.29
(t, J=8.00 Hz, 2H), 3.29 (t, J=12.00 Hz, 2H), 3.04 (s, 3H).
3-[1-(3-Fluoro-benzoyl)-4,5-dihydro-1H-pyrazol-3-yl]-N-methyl-benzamide
##STR00505##
[1009] White solid; 46.40% Yield
[1010] LC-MS: Mass found (M+, 326.0). Rt (min): 3.31; % Area: 98.77
(Max), 99.10 (254 nm).
[1011] HPLC--Rt (min): 3.40; % Area: 98.47 (Max), 99.25 (254
nm).
[1012] 400 MHz, CDCl.sub.3: .delta. 8.05 (brs, 1H), 7.90-7.88 (m,
1H), 7.79-7.77 (m, 2H), 7.72 (d, J=12.00 Hz, 1H), 7.51-7.41 (m,
2H), 7.24-7.19 (m, 1H), 6.19 (brs, 1H), 4.29 (t, J=12.00 Hz, 2H),
3.33 (t, J=12.00 Hz, 2H), 3.05 (d, J=4.00 Hz, 3H).
N-Cyclopentyl-3-[1-(3-fluoro-benzoyl)-4,5-dihydro-1H-pyrazol-3-yl]-benzami-
de
##STR00506##
[1014] Off white solid; 4.15% Yield
[1015] LC-MS: Mass found (M+, 380.0). Rt (min): 4.32; % Area: 93.75
(Max), 94.50 (254 nm).
[1016] HPLC--Rt (min): 4.44; % Area: 93.94 (Max), 94.41 (254
nm).
[1017] 400 MHz, CDCl.sub.3: .delta. 8.05 (brs, 1H), 7.88-7.86 (m,
1H), 7.80-7.75 (m, 3H), 7.50-7.40 (m, 2H), 7.24-7.19 (m, 1H),
4.45-4.39 (m, 1H), 4.30 (t, J=8.00 Hz, 2H), 3.36-3.31 (m, 2H),
2.15-2.08 (m, 2H), 1.77-1.68 (m, 4H), 1.56-1.49 (m, 2H).
(3-Fluoro-phenyl)-[3-(3-pyrazol-1-yl-phenyl)-4,5-dihydro-pyrazol-1-yl]-met-
hanone
##STR00507##
[1019] Off White Solid; 80.01% Yield
[1020] LC-MS: Mass found (M+, 335.0). Rt (min): 4.33; % Area: 98.42
(Max), 98.52 (254 nm).
[1021] HPLC--Rt (min): 4.35; % Area: 98.50 (Max), 98.49 (254
nm).
[1022] 400 MHz, CDCl.sub.3: .delta. 8.01 (brs, 1H), 7.97 (d, J=4.00
Hz, 1H), 7.81-7.66 (m, 5H), 7.53-7.47 (m, 1H), 7.46-7.42 (m, 1H),
7.25-7.20 (m, 1H), 6.52-6.51 (m, 1H), 4.31 (t, J=12.00 Hz, 2H),
3.36 (t, J=12.00 Hz, 2H).
[3-(3-Fluoro-4-methoxy-phenyl)-4,5-dihydro-pyrazol-1-yl]-(3-fluoro-phenyl)-
-methanone
##STR00508##
[1024] Off White Solid; 18.58% Yield
[1025] LC-MS: Mass found (M+, 317.3). Rt (min): 4.49; % Area: 99.44
(Max), 99.09 (254 nm).
[1026] HPLC--Rt (min): 4.50; % Area: 99.48 (Max), 99.51 (254
nm).
[1027] 400 MHz, CDCl.sub.3: .delta. 7.72-7.70 (m, 2H), 7.53-7.40
(m, 3H), 7.23-7.18 (m, 1H), 7.00-6.96 (m, 1H), 4.26 (t, J=12.00 Hz,
2H), 3.94 (s, 3H), 3.27-3.22 (m, 2H).
(3-Fluoro-phenyl)-[3-(4-methoxy-3-methyl-phenyl)-4,5-dihydro-pyrazol-1-yl]-
-methanone
##STR00509##
[1029] Grey solid; 44.61% Yield
[1030] LC-MS: Mass found (M+, 313.0). Rt (min): 4.18; % Area: 99.32
(Max), 99.31 (254 nm).
[1031] HPLC--Rt (min): 4.98; % Area: 97.95 (Max), 99.85 (254
nm).
[1032] 400 MHz, CDCl.sub.3: .delta. 7.81 (d, J=8.00 Hz, 1H), 7.76
(d, J=8.00 Hz, 1H), 7.52-7.50 (m, 2H), 7.45-7.40 (m, 1H), 7.22-7.17
(m, 1H), 6.85 (d, J=8.00 Hz, 1H), 4.24 (t, J=12.00 Hz, 2H), 3.88
(s, 3H), 3.26 (t, J=12.00 Hz, 2H), 2.24 (s, 3H).
[3-(3-Nitro-4-methoxy-phenyl)-4,5-dihydro-pyrazol-1-yl]-(3-fluoro-phenyl)--
methanone
##STR00510##
[1034] Yellow solid; 12.69% Yield
[1035] LC-MS: Mass found (M+, 344.0). Rt (min): 4.45; % Area: 93.51
(Max), 91.34 (254 nm).
[1036] HPLC--Rt (min): 4.40; % Area: 94.94 (Max), 94.32 (220
nm).
[1037] 400 MHz, CDCl.sub.3: .delta. 7.94 (s, 1H), 7.76 (d, J=8.00
Hz, 1H), 7.69 (d, J=8.00 Hz, 1H), 7.53-7.41 (m, 1H), 7.72-7.14 (m,
3H), 4.30 (t, J=12.00 Hz, 2H), 4.02 (s, 3H), 3.29 (t, J=8.00 Hz,
2H).
[3-(3-Cyclopentyloxy-4-methoxy-phenyl)-4,5-dihydro-pyrazol-1-yl]-(3-fluoro-
-phenyl)-methanone
##STR00511##
[1039] White Solid; 36.55% Yield
[1040] LC-MS: Mass found (M+, 383.0). Rt (min): 5.14; % Area: 97.77
(Max), 98.83 (254 nm).
[1041] HPLC--Rt (min): 5.13; % Area: 98.99 (Max), 98.49 (254
nm).
[1042] 400 MHz, CDCl.sub.3: .delta. 7.83 (d, J=8.00 Hz, 2H),
7.44-7.38 (m, 2H), 7.22-7.17 (m, 1H), 7.15-7.13 (m, 1H), 6.87 (d,
J=8.00 Hz, 1H), 4.80-4.76 (m, 1H), 4.26 (t, J=12.00 Hz, 2H), 3.90
(s, 3H), 3.27 (t, J=8.00 Hz, 2H), 2.02-1.83 (m, 6H), 1.66-1.65 (m,
2H).
[3-(3-Chloro-4-methoxy-phenyl)-4,5-dihydro-pyrazol-1-yl]-(3-fluoro-phenyl)-
-methanone
##STR00512##
[1044] Off white solid; 12.22% Yield
[1045] LC-MS: Mass found (M+, 333.0). Rt (min): 4.74; % Area: 97.19
(Max), 95.73 (254 nm).
[1046] HPLC--Rt (min): 4.74; % Area: 96.09 (Max), 95.64 (254
nm).
[1047] 400 MHz, CDCl.sub.3: .delta. 7.79 (d, J=4.00 Hz, 1H),
7.73-7.71 (m, 2H), 7.60-7.57 (m, 1H), 7.46-7.41 (m, 1H), 7.24-7.19
(m, 1H), 6.98-6.96 (m, 1H), 4.27 (t, J=8.00 Hz, 2H), 3.92 (s, 3H),
3.25 (t, J=12.00 Hz, 2H).
[3-(3-Amino-4-methoxy-phenyl)-4,5-dihydro-pyrazol-1-yl]-(3-fluoro-phenyl)--
methanone
##STR00513##
[1049] White solid; 24.94% Yield
[1050] LC-MS: Mass found (M+, 314.0). Rt (min): 2.72; % Area: 96.03
(Max), 93.93 (220 nm).
[1051] HPLC--Rt (min): 2.70; % Area: 96.75 (Max), 94.64 (254
nm).
[1052] 400 MHz, CDCl.sub.3: .delta. 7.80 (d, J=8.00 Hz, 1H), 7.75
(d, J=8.00 Hz, 1H), 7.45-7.39 (m, 1H), 7.22-7.17 (m, 1H), 7.15-7.12
(m, 1H), 7.03-7.01 (m, 1H), 6.80 (d, J=12.00 Hz, 1H), 4.23 (t,
J=12.00 Hz, 2H), 3.90 (s, 5H), 3.24 (t, J=12.00 Hz, 2H).
5-[1-(3-Fluoro-benzoyl)-4,5-dihydro-1H-pyrazol-3-yl]-2-methoxy-benzoic
acid
##STR00514##
[1054] White solid; 100% Yield
[1055] LC-MS: Mass found (M+, 343.3). Rt (min): 3.39; % Area: 92.46
(Max), 92.31 (254 nm).
[1056] HPLC--Rt (min): 3.40; % Area: 94.26 (Max), 93.30 (220
nm).
[1057] 400 MHz, DMSO-d6: .delta. 12.87 (brs, 1H), 7.91 (d, J=4.00
Hz, 1H), 7.83-7.80 (m, 1H), 7.69 (d, J=8.00 Hz, 1H), 7.64-7.61 (m,
1H), 7.56-7.50 (m, 1H), 7.40-7.35 (m, 1H), 7.23 (d, J=12.00 Hz,
1H), 4.10 (t, J=12.00 Hz, 2H), 3.86 (s, 3H), 3.32 (m, 2H).
(3-Fluoro-phenyl)-[3-(4-methoxy-3-trifluoromethyl-phenyl)-4,5-dihydro-pyra-
zol-1-yl]-methanone
##STR00515##
[1059] Grey solid; 91.22% Yield
[1060] LC-MS: Mass found (M+, 367.0). Rt (min): 5.06; % Area: 98.62
(Max), 98.09 (254 nm).
[1061] HPLC--Rt (min): 5.07; % Area: 98.87 (Max), 98.88 (254
nm).
[1062] 400 MHz, CDCl.sub.3: .delta. 7.91-7.90 (m, 1H), 7.88 (brs,
1H), 7.79 (d, J=8.00 Hz, 1H), 7.73 (d, J=12.00 Hz, 1H), 7.46-7.40
(m, 1H), 7.24-7.19 (m, 1H), 7.06 (d, J=8.00 Hz, 1H), 4.29 (t,
J=8.00 Hz, 2H), 3.97 (s, 3H), 3.29 (t, J=8.00 Hz, 2H).
(3-Fluoro-phenyl)-{3-[4-methoxy-3-(morpholine-4-sulfonyl)-phenyl]-4,5-dihy-
dro-pyrazol-1-yl}-methanone
##STR00516##
[1064] Grey solid; 13.95% Yield
[1065] LC-MS: Mass found (M+, 448.0). Rt (min): 3.87; % Area: 99.57
(Max), 99.73 (220 nm).
[1066] HPLC--Rt (min): 3.93; % Area: 96.23 (Max), 98.86 (254
nm).
[1067] 400 MHz, CDCl.sub.3: .delta. 8.08-8.07 (m, 1H), 8.02-7.99
(m, 1H), 7.78 (d, J=8.00 Hz, 1H), 7.75-7.70 (m, 1H), 7.46-7.41 (m,
1H), 7.23-7.18 (m, 1H), 6.99-6.97 (m, 1H), 4.29 (t, J=8.00 Hz, 2H),
4.00-3.99 (m, 4H), 3.76-3.73 (m, 4H), 3.32-3.26 (m, 5H).
N,N-Diethyl-5-[1-(3-fluoro-benzoyl)-4,5-dihydro-1H-pyrazol-3-yl]-2-methoxy-
-benzenesulfonamide
##STR00517##
[1069] White solid; 22.14% Yield
[1070] LC-MS: Mass found (M+, 434.0). Rt (min): 4.54; % Area: 98.98
(Max), 98.55 (254 nm).
[1071] HPLC--Rt (min): 4.60; % Area: 98.91 (Max), 98.61 (254
nm).
[1072] 400 MHz, CDCl.sub.3: .delta. 8.12 (d, J=4.00 Hz, 1H),
7.98-7.96 (m, 1H), 7.79 (d, J=8.00 Hz, 1H), 7.72 (d, J=8.00 Hz,
1H), 7.46-7.40 (m, 1H), 7.23-7.18 (m, 1H), 7.05 (d, J=12.00 Hz,
1H), 4.28 (t, J=12.00 Hz, 2H), 3.99 (s, 3H), 3.39-3.28 (m, 6H),
1.15-1.11 (m, 6H).
5-[1-(3-Fluoro-benzoyl) 4,
5-dihydro-1-H-pyrazole-3-yl]-2-methoxy-N-phenyl-benzenesulfonamide
##STR00518##
[1074] Off white solid; 5.89% Yield
[1075] LC-MS: Mass found (M+, 468.0). Rt (min): 4.46; % Area: 98.14
(Max), 98.48 (254 nm).
[1076] HPLC--Rt (min): 4.57; % Area: 98.34 (Max), 98.23 (220
nm).
[1077] 400 MHz, CDCl.sub.3: .delta. 8.07-0.00 (m, 1H), 8.02-8.01
(m, 1H), 8.00-7.99 (m, 1H), 7.81-7.79 (m, 1H), 7.47-7.42 (m, 1H),
7.28-7.21 (m, 4H), 7.21-7.12 (m, 2H), 7.00-6.98 (m, 1H), 5.15-5.12
(m, 1H), 4.33-4.28 (m, 2H), 4.14-4.13 (m, 2H), 3.89 (s, 3H),
3.33-3.29 (m, 2H).
[3-(3-Ethoxy-4-methoxy-phenyl)-4,5-dihydro-pyrazol-1-yl]-(3-fluoro-phenyl)-
-methanone
##STR00519##
[1079] Off white solid; 47.07% Yield
[1080] LC-MS: Mass found (M+, 343.0). Rt (min): 4.34; % Area: 91.93
(Max), 93.17 (254 nm).
[1081] HPLC--Rt (min): 4.42; % Area: 92.49 (Max), 94.39 (254
nm).
[1082] 400 MHz, CDCl.sub.3: .delta. 7.82-7.78 (m, 2H), 7.54-7.42
(m, 1H), 7.41-7.39 (m, 1H), 7.20-7.16 (m, 2H), 6.90-6.88 (m, 1H),
4.26 (t, J=9.60 Hz, 2H), 4.16-4.11 (m, 2H), 3.92 (s, 3H), 3.27 (t,
J=10.00 Hz, 2H), 1.49 (t, J=-6.40 Hz, 3H).
[3-(3-Benzyloxy-4-methoxy-phenyl)-4,5-dihydro-pyrazol-1-yl]-(3-fluoro-phen-
yl)-methanone
##STR00520##
[1084] Brown solid; 6.01% Yield
[1085] LC-MS: Mass found (M+, 405.0). Rt (min): 5.03; % Area: 95.97
(Max), 95.98 (220 nm).
[1086] HPLC--Rt (min): 5.09; % Area: 95.49 (Max), 93.96 (254
nm).
[1087] 400 MHz, CDCl.sub.3: .delta. 7.76-7.74 (m, 2H), 7.45-7.40
(m, 3H), 7.36-7.31 (m, 4H), 7.31-7.27 (m, 1H), 7.23-7.21 (m, 1H),
7.18-6.89 (m, 1H), 5.31-5.19 (m, 2H), 4.23 (t, J=9.60 Hz, 2H), 3.94
(s, 3H), 3.21 (t, J=10.00 Hz, 2H).
(3-Fluoro-phenyl)-[3-(3-isopropoxy-4-methoxy-phenyl)-4,5-dihydro-pyrazol-1-
-yl]-methanone
##STR00521##
[1089] Off white solid; 2.47% Yield
[1090] LC-MS: Mass found (M+, 357.3). Rt (min): 4.66; % Area: 98.26
(Max), 98.37 (254 nm).
[1091] HPLC--Rt (min): 4.72; % Area: 90.49 (Max), 91.41 (254
nm).
[1092] 400 MHz, CDCl.sub.3: .delta. 7.82-7.78 (m, 2H), 7.44-7.40
(m, 1H), 7.38-7.36 (m, 1H), 7.20-7.18 (m, 2H), 6.90-6.88 (m, 1H),
4.59-4.53 (m, 1H), 4.28-4.23 (m, 2H), 3.90 (s, 3H), 3.28-3.23 (m,
2H), 1.40-1.38 (m, 6H).
(3-Fluoro-phenyl)-[3-(3-hydroxy-4-methoxy-phenyl)-4,5-dihydro-pyrazol-1-yl-
]-methanone
##STR00522##
[1094] Yellow solid; 100% Yield
[1095] LC-MS: Mass found (M+, 315). Rt (min): 3.68; % Area: 94.03
(Max), 97.23 (254 nm).
[1096] HPLC--Rt (min): 3.63; % Area: 95.31 (Max), 97.24 (254
nm).
[1097] 400 MHz, DMSO-d6: .delta. 9.32 (brs, 1H), 7.69 (d, J=8.00
Hz, 1H), 7.63-7.61 (m, 1H), 7.56-7.50 (m, 1H), 7.40-7.35 (m, 1H),
7.16-7.15 (m, 1H), 7.10-7.07 (m, 1H), 6.98 (d, J=12.00 Hz, 1H),
4.07 (t, J=8.00 Hz, 2H), 3.79 (s, 3H), 3.26 (t, J=8.00 Hz, 2H).
(3-Fluoro-phenyl)-(3-o-tolyl-4,5-dihydro-pyrazol-1-yl)-methanone
##STR00523##
[1099] Off white solid; 28.90% Yield
[1100] LC-MS: Mass found (M+, 283.0). Rt (min): 4.80; % Area: 99.36
(Max), 99.56 (254 nm).
[1101] HPLC--Rt (min): 4.83; % Area: 99.10 (Max), 99.04 (254
nm).
[1102] 400 MHz, CDCl.sub.3: .delta. 7.78-7.70 (m, 2H), 7.45-7.37
(m, 2H), 7.32-7.29 (m, 2H), 7.28-7.27 (m, 1H), 7.20-7.16 (m, 1H),
4.22 (t, J=8.00 Hz, 2H), 3.37 (t, J=8.00 Hz, 2H), 2.52 (s, 3H).
(3-Biphenyl-2-yl-4,5-dihydro-pyrazol-1-yl)-(3-fluoro-phenyl)-methanone
##STR00524##
[1104] Off white solid; 43.67% Yield
[1105] LC-MS: Mass found (M+, 345.3). Rt (min): 5.26; % Area: 97.11
(Max), 97.01 (254 nm).
[1106] HPLC--Rt (min): 5.27; % Area: 97.08 (Max), 97.44 (254
nm).
[1107] 400 MHz, CDCl.sub.3: .delta. 7.53-7.50 (m, 1H), 7.48-7.40
(m, 8H), 7.39-7.31 (m, 3H), 7.14-7.13 (m, 1H), 4.03 (t, J=8.00 Hz,
2H), 2.67 (t, J=8.00 Hz, 2H).
(3-Fluoro-phenyl)-[3-(2-methoxy-phenyl)-4,5-dihydro-pyrazol-1-yl]-methanon-
e
##STR00525##
[1109] Off white solid; 40.13% Yield
[1110] LC-MS: Mass found (M+, 299.0). Rt (min): 4.52; % Area: 98.52
(Max), 99.25 (254 nm).
[1111] HPLC--Rt (min): 4.58; % Area: 99.29 (Max), 99.59 (254
nm).
[1112] 400 MHz, CDCl.sub.3: .delta. 7.83 (d, J=8.00 Hz, 2H),
7.74-7.72 (m, 1H), 7.43-7.38 (m, 2H), 7.21-7.16 (m, 1H), 7.01-6.97
(m, 2H), 4.21 (t, J=12.00 Hz, 2H), 3.91 (s, 3H), 3.43 (t, J=8.00
Hz, 2H).
(3-Fluoro-phenyl)-[3-(2-trifluoromethyl-phenyl)-4,5-dihydro-pyrazol-1-yl]--
methanone
##STR00526##
[1114] White solid; 66.60% Yield
[1115] LC-MS: Mass found (M+, 337.3). Rt (min): 4.85; % Area: 99.10
(Max), 99.46 (254 nm).
[1116] HPLC--Rt (min): 4.87; % Area: 97.36 (Max), 98.45 (254
nm).
[1117] 400 MHz, CDCl.sub.3: .delta. 7.78 (d, J=8.00 Hz, 1H), 7.73
(d, J=8.00 Hz, 1H), 7.68-7.64 (m, 1H), 7.62-7.60 (m, 1H), 7.57-7.53
(m, 2H), 7.40-7.34 (m, 1H), 7.18-7.13 (m, 1H), 4.30 (t, J=8.00 Hz,
2H), 3.31 (t, J=8.00 Hz, 2H).
(3-Fluoro-phenyl)-[3-(2-hydroxy-phenyl)-4,5-dihydro-pyrazol-1-yl]-methanon-
e
##STR00527##
[1119] Off white solid; 8.03% Yield
[1120] LC-MS: Mass found (M-, 283). Method: A-10 mM
NH.sub.4HCO.sub.3, B: ACN; Flow Rate: 1.0 ml/min. Rt (min): 5.68; %
Area: 93.65 (Max), 93.47 (220 nm).
[1121] HPLC--Rt (min): 4.36; % Area: 95.36 (Max), 96.10 (254
nm).
[1122] 400 MHz, DMSO-d6: .delta. 10.04 (brs, 1H), 7.60-7.48 (m,
4H), 7.41-7.31 (m, 2H), 6.95-6.90 (m, 2H), 4.07 (t, J=12.00 Hz,
2H), 3.46 (t, J=8.00 Hz, 2H).
[3-(2-Amino-phenyl)-4,5-dihydro-pyrazol-1-yl]-(3-fluoro-phenyl)-methanone
##STR00528##
[1124] Brown solid; 4.30% Yield
[1125] LC-MS: Mass found (M+, 284.2). Rt (min): 3.96; % Area: 98.39
(Max), 100.0 (254 nm).
[1126] HPLC--Rt (min): 3.90; % Area: 97.96 (Max), 98.62 (254
nm).
[1127] 400 MHz, DMSO-d6: .delta. 7.52-7.50 (m, 3H), 7.48-7.34 (m,
1H), 7.28-7.25 (m, 1H), 7.13-7.09 (m, 1H), 6.70-6.68 (m, 1H),
6.60-6.56 (m, 1H), 4.48 (m, 2H), 4.00 (t, J=8.00 Hz, 2H), 3.42-3.31
(m, 2H).
(3-Fluoro-phenyl)-[3-(2-methylsulfanyl-phenyl)-4,5-dihydro-pyrazol-1-yl]-m-
ethanone
##STR00529##
[1129] White Solid; 66.36% Yield
[1130] LC-MS: Mass found (M+, 315). Rt (min): 4.69; % Area: 98.74
(Max), 99.16 (254 nm).
[1131] HPLC--Rt (min): 4.61; % Area: 98.13 (Max), 99.03 (254
nm).
[1132] 400 MHz, CDCl.sub.3: .delta. 7.98-7.95 (m, 1H), 7.90-7.88
(m, 1H), 7.46-7.37 (m, 3H), 7.31-7.29 (m, 1H), 7.22-7.19 (m, 2H),
4.25 (t, J=8.00 Hz, 2H), 3.39 (t, J=8.00 Hz, 2H), 2.48 (s, 3H).
[3-(2-Dimethylamino-phenyl)-4,5-dihydro-pyrazol-1-yl]-(3-fluoro-phenyl)-me-
thanone
##STR00530##
[1134] Red gum; 22.62% Yield
[1135] LC-MS: Mass found (M+, 312.3). Rt (min): 2.24; % Area: 98.61
(Max), 95.58 (254 nm).
[1136] HPLC--Rt (min): 2.32; % Area: 99.74 (Max), 96.54 (254
nm).
[1137] 400 MHz, CDCl.sub.3: .delta. 7.83-7.78 (m, 2H), 7.55-7.52
(m, 1H), 7.43-7.35 (m, 2H), 7.20-7.15 (m, 1H), 7.12-7.10 (m, 1H),
7.05-7.03 (m, 1H), 4.23 (t, J=8.00 Hz, 2H), 3.42 (t, J=12.00 Hz,
2H), 2.73 (s, 6H).
2-[1-(3-Fluoro-benzoyl)-4,5-dihydro-1H-pyrazol-3-yl]-benzonitrile
##STR00531##
[1139] Off white solid; 20.21% Yield
[1140] LC-MS: Mass found (M+, 294.0). Rt (min): 3.96; % Area: 94.87
(Max), 96.73 (254 nm).
[1141] HPLC--Rt (min): 4.00; % Area: 94.56 (Max), 96.71 (254
nm).
[1142] 400 MHz, CDCl.sub.3: .delta. 7.91 (d, J=8.00 Hz, 1H),
7.80-7.78 (m, 2H), 7.72 (d, J=8.00 Hz, 1H), 7.67-7.64 (m, 1H),
7.54-7.51 (m, 1H), 7.47-7.41 (m, 1H), 7.24-7.19 (m, 1H), 4.34 (t,
J=12.00 Hz, 2H), 3.46 (t, J=12.00 Hz, 2H).
N-{2-[1-(3-Fluoro-benzoyl)-4,5-dihydro-1H-pyrazol-3-yl]-phenyl}-methanesul-
fonamide
##STR00532##
[1144] White Solid; 4.75% Yield
[1145] LC-MS: Mass found (M+, 362). Rt (min): 3.87; % Area: 97.67
(Max), 98.43 (254 nm).
[1146] HPLC--Rt (min): 3.94; % Area: 99.54 (Max), 99.61 (254
nm).
[1147] 400 MHz, CDCl.sub.3: .delta. 7.73 (d, J=8.00 Hz, 1H),
7.62-7.60 (m, 1H), 7.55-7.42 (m, 4H), 7.25-7.24 (m, 1H), 7.19-7.14
(m, 1H), 4.24 (t, J=12.00 Hz, 2H), 3.45 (t, J=12.00 Hz, 2H), 2.97
(s, 3H).
2-[1-(3-Fluoro-benzoyl)-4,5-dihydro-1H-pyrazol-3-yl]-N,N-dimethyl-benzamid-
e
##STR00533##
[1149] Off white solid; 52.29% Yield
[1150] LC-MS: Mass found (M+, 340.0). Rt (min): 3.33; % Area: 99.53
(Max), 99.21 (254 nm).
[1151] HPLC--Rt (min): 3.39; % Area: 99.31 (Max), 99.28 (254
nm).
[1152] 400 MHz, CDCl.sub.3: .delta. 7.66-7.63 (m, 1H), 7.56-7.52
(m, 2H), 7.46-7.40 (m, 3H), 7.27-7.24 (m, 1H), 7.21-7.18 (m, 1H),
4.22 (t, J=12.00 Hz, 2H), 3.31 (t, J=12.00 Hz, 2H), 2.69 (s, 3H),
2.57 (s, 3H).
[3-(4-Chloro-3-methoxy-phenyl)-4,5-dihydro-pyrazol-1-yl]-(3-fluoro-phenyl)-
-methanone
##STR00534##
[1154] White solid; 50.44% Yield
[1155] LC-MS: Mass found (M+, 333.0). Rt (min): 4.96; % Area: 96.37
(Max), 96.96 (254 nm).
[1156] HPLC--Rt (min): 4.92; % Area: 97.08 (Max), 96.70 (254
nm).
[1157] 400 MHz, CDCl.sub.3: .delta. 7.80-7.74 (m, 2H), 7.45-7.40
(m, 2H), 7.33-0.00 (m, 1H), 7.24-7.21 (m, 1H), 7.17-7.14 (m, 1H),
4.29 (t, J=12.00 Hz, 2H), 3.93 (s, 3H), 3.29 (t, J=8.00 Hz,
2H).
4-[1-(3-Fluoro-benzoyl)-4,5-dihydro-1H-pyrazol-3-yl]-2-methoxy-benzoic
acid
##STR00535##
[1159] Grey solid; 100% Yield
[1160] LC-MS: Mass found (M+, 343.0). Rt (min): 3.50; % Area: 91.12
(Max), 90.07 (254 nm).
[1161] HPLC--Rt (min): 3.53; % Area: 92.15 (Max), 90.03 (254
nm).
[1162] 400 MHz, DMSO-d6: .delta. 12.81 (brs, 1H), 7.75-7.64 (m,
3H), 7.57-7.52 (m, 1H), 7.42-7.37 (m, 1H), 7.33-7.31 (m, 2H), 4.15
(t, J=8.00 Hz, 2H), 3.84 (s, 3H), 3.40-3.32 (m, 2H).
[3-(4-Fluoro-3-methoxy-phenyl)-4,5-dihydro-pyrazol-1-yl]-(3-fluoro-phenyl)-
-methanone
##STR00536##
[1164] White solid; 100% Yield
[1165] LC-MS: Mass found (M+, 317.0). Rt (min): 4.56; % Area: 91.74
(Max), 97.03 (254 nm).
[1166] HPLC--Rt (min): 4.61; % Area: 94.59 (Max), 98.11 (254
nm).
[1167] 400 MHz, CDCl.sub.3: .delta. 7.80-7.74 (m, 2H), 7.45-7.38
(m, 2H), 7.23-7.12 (m, 3H), 4.29 (t, J=8.00 Hz, 2H), 3.94-3.92 (m,
3H), 3.28 (t, J=12.00 Hz, 2H).
(3-Fluoro-phenyl)-[3-(3-methoxy-4-methyl-phenyl)-4,5-dihydro-pyrazol-1-yl]-
-methanone
##STR00537##
[1169] White solid; 9.55% Yield
[1170] LC-MS: Mass found (M+, 313.0). Rt (min): 4.93; % Area: 96.69
(Max), 97.70 (254 nm).
[1171] HPLC--Rt (min): 4.99; % Area: 96.88 (Max), 97.19 (254
nm).
[1172] 400 MHz, CDCl.sub.3: .delta. 7.81 (t, J=8.00 Hz, 2H),
7.45-7.39 (m, 1H), 7.24-7.19 (m, 3H), 7.18-7.17 (m, 2H), 4.27 (t,
J=8.00 Hz, 2H), 3.86 (s, 3H), 3.29 (t, J=12.00 Hz, 2H), 2.26 (s,
3H).
[3-(4-Benzyloxy-3-methoxy-phenyl)-4,5-dihydro-pyrazol-1-yl]-(3-fluoro-phen-
yl)-methanone
##STR00538##
[1174] White solid; 10.72% Yield
[1175] LC-MS: Mass found (M+, 405.0). Rt (min): 5.18; % Area: 98.51
(Max), 97.41 (220 nm).
[1176] HPLC--Rt (min): 5.19; % Area: 97.35 (Max), 99.08 (254
nm).
[1177] 400 MHz, CDCl.sub.3: .delta. 7.79 (t, J=8.00 Hz, 2H),
7.45-7.31 (m, 7H), 7.22-7.18 (m, 1H), 7.13-7.10 (m, 1H), 6.89 (d,
J=8.00 Hz, 1H), 5.22 (s, 2H), 4.25 (t, J=12.00 Hz, 2H), 3.92 (s,
3H), 3.26 (t, J=8.00 Hz, 2H).
4-[1-(3-Fluoro-benzoyl)-4,5-dihydro-1H-pyrazol-3-yl]-2-methoxy-benzonitril-
e
##STR00539##
[1179] Off white solid; 71.84% Yield
[1180] LC-MS: Mass found (M+, 324.0). Rt (min): 4.41; % Area: 99.68
(Max), 99.45 (254 nm).
[1181] HPLC--Rt (min): 4.49; % Area: 99.48 (Max), 99.19 (254
nm).
[1182] 400 MHz, CDCl.sub.3: .delta. 7.62-7.60 (m, 2H), 7.46-7.44
(m, 1H), 7.42-7.40 (m, 1H), 7.32-7.26 (m, 1H), 7.24-7.20 (m, 2H),
4.32 (t, J=12.00 Hz, 2H), 3.96 (s, 3H), 3.30 (t, J=8.00 Hz,
2H).
[3-(2,4-Dimethoxy-phenyl)-4,5-dihydro-pyrazol-1-yl]-(3-fluoro-phenyl)-meth-
anone
##STR00540##
[1184] Grey solid; 72.76% Yield
[1185] LC-MS: Mass found (M+, 329.0). Rt (min): 4.47; % Area: 97.16
(Max), 98.36 (254 nm).
[1186] HPLC--Rt (min): 4.54; % Area: 96.70 (Max), 98.61 (254
nm).
[1187] 400 MHz, CDCl.sub.3: .delta. 7.87-7.83 (m, 2H), 7.68 (d,
J=12.00 Hz, 1H), 7.43-7.37 (m, 1H), 7.20-7.15 (m, 1H), 6.54 (dd,
J=8.00, 4.00 Hz, 1H), 6.50 (d, J=4.00 Hz, 1H), 4.18 (t, J=12.00 Hz,
2H), 3.88 (s, 3H), 3.86 (s, 3H), 3.38 (t, J=12.00 Hz, 2H).
(3-Fluoro-phenyl)-[3-(4-methoxy-2-methyl-phenyl)-4,5-dihydro-pyrazol-1-yl]-
-methanone
##STR00541##
[1189] White Solid; 44.94% Yield
[1190] LC-MS: Mass found (M+, 313.3). Rt (min): 4.71; % Area: 99.43
(Max), 99.14 (254 nm).
[1191] HPLC--Rt (min): 4.74; % Area: 98.94 (Max), 98.51 (220
nm).
[1192] 400 MHz, CDCl.sub.3: .delta. 7.78-7.71 (m, 2H), 7.42-7.36
(m, 2H), 7.19-7.14 (m, 1H), 6.80-6.78 (m, 1H), 4.19 (t, J=8.00 Hz,
2H), 3.84 (s, 3H), 3.33 (t, J=12.00 Hz, 2H), 2.51 (s, 3H).
(3-Fluoro-phenyl)-[3-(4-methoxy-2-trifluoromethyl-phenyl)-4,5-dihydro-pyra-
zol-1-yl]-methanone
##STR00542##
[1194] Yellow gum; 43.71% Yield
[1195] LC-MS: Mass found (M+, 367.0). Rt (min): 4.90; % Area: 95.75
(Max), 97.14 (254 nm).
[1196] HPLC--Rt (min): 4.97; % Area: 92.76 (Max), 96.42 (254
nm).
[1197] 400 MHz, CDCl.sub.3: .delta. 7.74 (d, J=8.00 Hz, 1H),
7.69-7.66 (m, 1H), 7.50 (d, J=8.00 Hz, 1H), 7.40-7.34 (m, 1H),
7.28-7.27 (m, 1H), 7.18-7.14 (m, 1H), 7.10-7.07 (m, 1H), 4.27 (t,
J=8.00 Hz, 2H), 3.89 (s, 3H), 3.27 (t, J=12.00 Hz, 2H).
[3-(2-Chloro-4-methoxy-phenyl)-4,5-dihydro-pyrazol-1-yl]-(3-fluoro-phenyl)-
-methanone
##STR00543##
[1199] White Solid; 8.75% Yield
[1200] LC-MS: Mass found (M+, 333). Rt (min): 4.80; % Area: 96.09
(Max), 93.73 (254 nm).
[1201] HPLC--Rt (min): 4.79; % Area: 96.35 (Max), 94.47 (254
nm).
[1202] 400 MHz, CDCl.sub.3: .delta. 7.82-7.75 (m, 2H), 7.62 (d,
J=12.00 Hz, 1H), 7.43-7.37 (m, 1H), 7.21-7.15 (m, 1H), 6.98 (d,
J=4.00 Hz, 1H), 6.87-6.84 (m, 1H), 4.25 (t, J=8.00 Hz, 2H), 3.85
(s, 3H), 3.45 (t, J=12.00 Hz, 2H).
[3-(2-Fluoro-4-methoxy-phenyl)-4,5-dihydro-pyrazol-1-yl]-(3-fluoro-phenyl)-
-methanone
##STR00544##
[1204] White Solid; 72.23% Yield
[1205] LC-MS: Mass found (M+, 317.3). Rt (min): 4.70; % Area: 96.67
(Max), 95.03 (220 nm).
[1206] HPLC--Rt (min): 4.62; % Area: 98.12 (Max), 97.77 (254
nm).
[1207] 400 MHz, CDCl.sub.3: .delta. 7.81-7.74 (m, 3H), 7.44-7.39
(m, 1H), 7.22-7.17 (m, 1H), 6.75 (dd, J=8.00 Hz, 4.00, Hz, 1H),
6.67-6.63 (m, 1H), 4.23 (t, J=12.00 Hz, 2H), 3.85 (s, 3H),
3.40-3.34 (m, 2H).
(3-Fluoro-phenyl)-[3-(4-methoxy-2-trifluoromethoxy-phenyl)-4,5-dihydro-pyr-
azol-1-yl]-methanone
##STR00545##
[1209] White solid; 29.40% Yield
[1210] LC-MS: Mass found (M+, 383.3). Rt (min): 5.16; % Area: 98.97
(Max), 98.63 (254 nm).
[1211] HPLC--Rt (min): 5.16; % Area: 99.47 (Max), 99.84 (254
nm).
[1212] 400 MHz, CDCl.sub.3: .delta. 7.79-7.69 (m, 2H), 7.72-7.69
(m, 1H), 7.43-7.38 (m, 1H), 7.21-7.16 (m, 1H), 6.89-6.84 (m, 2H),
4.24 (t, J=8.00 Hz, 2H), 3.87 (s, 3H), 3.35 (t, J=8.00 Hz, 2H).
(3-Fluoro-phenyl)-[3-(2-hydroxymethyl-4-methoxy-phenyl)-4,5-dihydro-pyrazo-
l-1-yl]-methanone
##STR00546##
[1214] Off white solid; 43.16% Yield
[1215] LC-MS: Mass found (M+, 329.0). Rt (min): 3.48; % Area: 99.68
(Max), 99.46 (254 nm).
[1216] HPLC--Rt (min): 3.60; % Area: 99.78 (Max), 99.67 (254
nm).
[1217] 400 MHz, CDCl.sub.3: .delta. 7.52-7.47 (m, 1H), 7.46-7.40
(m, 3H), 7.22-7.20 (m, 1H), 7.19-7.17 (m, 1H), 6.96-6.88 (m, 1H),
4.51 (s, 2H), 4.23 (t, J=8.00 Hz, 2H), 3.86 (s, 3H), 3.41 (t,
J=8.00 Hz, 2H).
[3-(2-Fluoro-3-methoxy-phenyl)-4,5-dihydro-pyrazol-1-yl]-(3-fluoro-phenyl)-
-methanone
##STR00547##
[1219] Off white solid; 33.35% Yield
[1220] LC-MS: Mass found (M+, 317.0). Rt (min): 4.41; % Area: 99.73
(Max), 99.92 (254 nm).
[1221] HPLC--Rt (min): 4.54; % Area: 99.51 (Max), 99.65 (254
nm).
[1222] 400 MHz, CDCl.sub.3: .delta. 7.79-7.72 (m, 1H), 7.44-7.42
(m, 1H), 7.40-7.36 (m, 2H), 7.22-7.19 (m, 1H), 7.17-7.10 (m, 1H),
7.10-7.00 (m, 1H), 4.26 (t, J=8.00 Hz, 2H), 3.92 (s, 3H), 3.44-3.38
(m, 2H).
[3-(2,3-Dimethoxy-phenyl)-4,5-dihydro-pyrazol-1-yl]-(3-fluoro-phenyl)-meth-
anone
##STR00548##
[1224] Off white solid; 59.74% Yield
[1225] LC-MS: Mass found (M+, 329.0). Rt (min): 4.45; % Area: 97.93
(Max), 98.83 (254 nm).
[1226] HPLC--Rt (min): 4.46; % Area: 97.56 (Max), 98.13 (254
nm).
[1227] 400 MHz, CDCl.sub.3: .delta. 7.80 (d, J=8.00 Hz, 1H),
7.76-7.73 (m, 1H), 7.43-7.38 (m, 1H), 7.34-7.32 (m, 1H), 7.21-7.15
(m, 1H), 7.08 (t, J=8.00 Hz, 1H), 6.99 (dd, J=8.00, 4.00 Hz, 1H),
4.23 (t, J=12.00 Hz, 2H), 3.90 (s, 3H), 3.85 (s, 3H), 3.43 (t,
J=8.00 Hz, 2H).
(3-Fluoro-phenyl)-[3-(2-hydroxy-3-methoxy-phenyl)-4,5-dihydro-pyrazol-1-yl-
]-methanone
##STR00549##
[1229] Off white solid; 21.92% Yield
[1230] LC-MS: Mass found (M+, 315.0). Rt (min): 3.95; % Area: 97.35
(Max), 97.55 (254 nm).
[1231] HPLC--Rt (min): 4.04; % Area: 98.52 (Max), 98.60 (220
nm).
[1232] 400 MHz, CDCl.sub.3: .delta. 7.58-7.56 (m, 1H), 7.49-7.42
(m, 2H), 7.21-7.16 (m, 1H), 7.01-6.95 (m, 1H), 6.94-6.89 (m, 2H),
4.24 (t, J=8.00 Hz, 2H), 3.91 (s, 3H), 3.44 (t, J=12.00 Hz,
2H).
(3-Fluoro-phenyl)-[3-(2,3,4-trimethoxy-phenyl)-4,5-dihydro-pyrazol-1-yl]-m-
ethanone
##STR00550##
[1234] White solid; 49.44% Yield
[1235] LC-MS: Mass found (M+, 359.0). Rt (min): 4.38; % Area: 95.44
(Max), 97.08 (254 nm).
[1236] HPLC--Rt (min): 4.40; % Area: 95.40 (Max), 96.51 (254
nm).
[1237] 400 MHz, CDCl.sub.3: .delta. 7.81-7.75 (m, 2H), 7.46-7.37
(m, 2H), 7.20-7.15 (m, 2H), 4.21 (t, J=8.00 Hz, 2H), 3.91 (s, 6H),
3.88 (s, 3H), 3.38 (t, J=12.00 Hz, 2H).
(3-Fluoro-phenyl)-[3-(1H-indol-5-yl)-4,5-dihydro-pyrazol-1-yl]-methanone
##STR00551##
[1239] Off white solid; 12.44% Yield
[1240] LC-MS: Mass found (M+, 308.3). Rt (min): 4.09; % Area: 98.67
(Max), 99.43 (254 nm).
[1241] HPLC--Rt (min): 4.10; % Area: 98.73 (Max), 99.13 (254
nm).
[1242] 400 MHz, CDCl.sub.3: .delta. 8.32 (brs, 1H), 7.91 (brs, 1H),
7.87-7.80 (m, 2H), 7.72 (d, J=8.00 Hz, 1H), 7.53-7.42 (m, 2H), 7.27
(s, 1H), 7.23-7.19 (m, 1H), 6.63 (brs, 1H), 4.29 (t, J=8.00 Hz,
2H), 3.39 (t, J=8.00 Hz, 2H).
[3-(2,3-Dihydro-benzofuran-5-yl)-4,5-dihydro-pyrazol-1-yl]-(3-fluoro-pheny-
l)-methanone
##STR00552##
[1244] White solid; 40.77% Yield
[1245] LC-MS: Mass found (M+, 311.0). Rt (min): 4.33; % Area: 98.26
(Max), 97.53 (254 nm).
[1246] HPLC--Rt (min): 4.44; % Area: 98.34 (Max), 97.57 (254
nm).
[1247] 400 MHz, CDCl.sub.3: .delta. 7.60-7.73 (m, 1H), 7.45-7.45
(m, 1H), 7.44-7.43 (m, 1H), 7.42-7.39 (m, 2H), 7.22-7.16 (m, 1H),
6.81 (d, J=8.40 Hz, 1H), 4.64 (t, J=8.00 Hz, 2H), 4.24 (t, J=8.00
Hz, 2H), 3.28-3.23 (m, 4H).
(3-Fluoro-phenyl)-[3-(1H-indol-6-yl)-4,5-dihydro-pyrazol-1-yl]-methanone
##STR00553##
[1249] Off white solid; 58.08% Yield
[1250] LC-MS: Mass found (M+, 308.0). Rt (min): 4.35; % Area: 94.89
(Max), 98.41 (254 nm).
[1251] HPLC--Rt (min): 4.45; % Area: 96.20 (Max), 99.28 (254
nm).
[1252] 400 MHz, CDCl.sub.3: .delta. 8.35 (brs, 1H), 7.83-7.82 (m,
3H), 7.79-7.76 (m, 1H), 7.68-7.65 (m, 1H), 7.54-7.51 (m, 1H),
7.47-7.41 (m, 1H), 7.27-7.21 (m, 1H), 6.61-6.69 (m, 1H), 4.31-4.26
(m, 2H), 3.39-3.34 (m, 2H).
(3-Fluoro-phenyl)-[3-(1-methyl-1H-indol-5-yl)-4,5-dihydro-pyrazol-1-yl]-me-
thanone
##STR00554##
[1254] White solid; 35.36% Yield
[1255] LC-MS: Mass found (M+, 322.0). Rt (min): 4.53; % Area: 98.26
(Max), 98.89 (254 nm).
[1256] HPLC--Rt (min): 4.70; % Area: 97.78 (Max), 98.34 (254
nm).
[1257] 400 MHz, CDCl.sub.3: .delta. 7.88-7.78 (m, 4H), 7.47-7.45
(m, 1H), 7.43-7.41 (m, 1H), 7.35-7.33 (m, 1H), 7.23-7.19 (m, 1H),
7.11-7.10 (m, 1H), 4.32-4.25 (m, 2H), 3.83-3.79 (m, 3H), 3.44-3.36
(m, 2H).
[3-(1-Benzenesulfonyl-1H-indol-6-yl)-4,5-dihydro-pyrazol-1-yl]-(3-fluoro-p-
henyl)-methanone
##STR00555##
[1259] White solid; 1.91% Yield
[1260] LC-MS: Mass found (M+, 448.0). Rt (min): 5.15; % Area: 96.93
(Max), 98.12 (254 nm).
[1261] HPLC--Rt (min): 5.16; % Area: 97.39 (Max), 98.18 (254
nm).
[1262] 400 MHz, CDCl.sub.3: .delta. 8.26 (s, 1H), 7.89-7.82 (m,
4H), 7.68-7.65 (m, 2H), 7.57-7.55 (m, 2H), 7.48-7.44 (m, 3H),
7.24-7.21 (m, 1H), 6.71 (d, J=4.00 Hz, 1H), 4.32 (t, J=8.00 Hz,
2H), 3.39 (t, J=8.00 Hz, 2H).
(3-Benzofuran-5-yl-4,5-dihydro-pyrazol-1-yl)-(3-fluoro-phenyl)-methanone
##STR00556##
[1264] Off white solid; 95.49% Yield
[1265] LC-MS: Mass found (M+, 309.0). Rt (min): 4.76; % Area: 99.04
(Max), 97.95 (254 nm).
[1266] HPLC--Rt (min): 4.76; % Area: 98.86 (Max), 99.18 (254
nm).
[1267] 400 MHz, CDCl.sub.3: .delta. 7.82-7.80 (m, 1H), 7.76-7.73
(m, 2H), 7.68-7.55 (m, 1H), 7.53-7.47 (m, 1H), 7.46-7.45 (m, 1H),
7.44-7.42 (m, 1H), 7.24-7.19 (m, 1H), 6.83-6.80 (m, 1H), 4.32-4.27
(m, 2H), 3.37 (t, J=10.40 Hz, 2H).
(3-Benzo[b]thiophen-5-yl-4,5-dihydro-pyrazol-1-yl)-(3-fluoro-phenyl)-metha-
none
##STR00557##
[1269] Off white solid; 79.55% Yield
[1270] LC-MS: Mass found (M+, 325.0). Rt (min): 4.92; % Area: 91.98
(Max), 94.40 (254 nm).
[1271] HPLC--Rt (min): 4.92; % Area: 91.38 (Max), 93.89 (254
nm).
[1272] 400 MHz, CDCl.sub.3: .delta. 7.82-7.81 (m, 1H), 7.75-7.73
(m, 2H), 7.65-7.56 (m, 1H), 7.53-7.47 (m, 1H), 7.46-7.43 (m, 1H),
7.44-7.40 (m, 1H), 7.24-7.19 (d, J=8 Hz, 1H), 6.83 (d, J=8 Hz, 1H),
4.32-4.27 (m, 2H), 3.35 (t, J=10.40 Hz, 2H).
(3-Fluoro-phenyl)-[3-(1-methyl-1H-indazol-6-yl)-4,5-dihydro-pyrazol-1-yl]--
methanone
##STR00558##
[1274] Off white solid; 25.17% Yield
[1275] LC-MS: Mass found (M+, 323.0). Rt (min): 4.04; % Area: 94.55
(Max), 91.93 (254 nm).
[1276] HPLC--Rt (min): 4.12; % Area: 96.92 (Max), 96.75 (254
nm).
[1277] 400 MHz, CDCl.sub.3: .delta. 8.00 (s, 1H), 7.84-7.76 (m,
1H), 7.74-7.73 (m, 2H), 7.63-7.60 (m, 2H), 7.48-7.42 (m, 1H),
7.27-7.20 (m, 1H), 4.33 (t, J=8.00 Hz, 2H), 4.13 (s, 3H), 3.43-3.38
(m, 2H).
(3-Fluoro-phenyl)-[3-(3-methyl-3H-benzoimidazol-5-yl)-4,5-dihydro-pyrazol--
1-yl]-methanone
##STR00559##
[1279] White solid; 37.75% Yield
[1280] LC-MS: Mass found (M+, 323.0). Rt (min): 3.26; % Area: 94.53
(Max), 96.10 (220 nm).
[1281] HPLC--Rt (min): 2.67; % Area: 98.44 (Max), 97.92 (254
nm).
[1282] 400 MHz, CDCl.sub.3: .delta. 10.23-10.21 (s, 1H), 8.08-8.05
(m, 1H), 7.95-7.93 (m, 1H), 7.89-7.88 (m, 1H), 7.77-7.76 (m, 1H),
7.71-7.69 (m, 1H), 7.52-7.45 (m, 1H), 7.27-7.22 (m, 1H), 4.36 (t,
J=12.00 Hz, 2H), 4.27 (s, 3H), 3.40 (t, J=12.00 Hz, 2H).
(3-Fluoro-phenyl)-[3-(2-methyl-benzooxazol-6-yl)-4,5-dihydro-pyrazol-1-yl]-
-methanone
##STR00560##
[1284] Brown solid; 70.60% Yield
[1285] LC-MS: Mass found (M+, 324.0). Rt (min): 3.94; % Area: 98.34
(Max), 97.96 (220 nm).
[1286] HPLC--Rt (min): 3.93; % Area: 99.03 (Max), 97.94 (254
nm).
[1287] 400 MHz, CDCl.sub.3: .delta. 7.83-7.80 (m, 2H), 7.76-7.74
(m, 1H), 7.68 (d, J=4.00 Hz, 2H), 7.47-7.42 (m, 1H), 7.25-7.20 (m,
1H), 4.31 (t, J=12.00 Hz, 2H), 3.36 (t, J=8.00 Hz, 2H), 2.68 (s,
3H).
(3-Fluoro-phenyl)-(3-indan-5-yl-4,5-dihydro-pyrazol-1-yl)-methanone
##STR00561##
[1289] Light brown solid; 19.19% Yield
[1290] LC-MS: Mass found (M+, 309.2). Rt (min): 5.19; % Area: 96.85
(Max), 98.04 (254 nm).
[1291] HPLC--Rt (min): 5.21; % Area: 96.41 (Max), 98.34 (254
nm).
[1292] 400 MHz, CDCl.sub.3: .delta. 7.81 (d, J=8.00 Hz, 1H),
7.77-7.74 (m, 1H), 7.49-7.40 (m, 2H), 7.26-7.25 (m, 2H), 7.23-7.18
(m, 1H), 4.26 (t, J=8.00 Hz, 2H), 3.29 (t, J=8.00 Hz, 2H),
2.96-2.93 (m, 4H), 2.15-2.08 (m, 2H).
6-[1-(3-Fluoro-benzoyl)-4,5-dihydro-1H-pyrazol-3-yl]-2,3-dihydro-isoindol--
1-one
##STR00562##
[1294] White solid; 38.84% Yield
[1295] LC-MS: Mass found (M+, 324.0). Rt (min): 3.11; % Area: 97.97
(Max), 98.73 (254 nm).
[1296] HPLC--Rt (min): 3.11; % Area: 99.20 (Max), 99.38 (254
nm).
[1297] 400 MHz, CDCl.sub.3: .delta. 8.09-8.06 (m, 2H), 7.79 (d,
J=8.00 Hz, 1H), 7.73-7.71 (m, 1H), 7.54 (d, J=8.00 Hz, 1H),
7.48-7.42 (m, 1H), 7.24-7.20 (m, 1H), 4.53 (s, 2H), 4.34-4.29 (m,
2H), 3.38-3.33 (m, 2H).
(3-Fluoro-phenyl)-(3-naphthalen-2-yl-4,5-dihydro-pyrazol-1-yl)-methanone
##STR00563##
[1299] White solid; 76.65% Yield
[1300] LC-MS: Mass found (M+, 319.0). Rt (min): 5.05; % Area: 98.80
(Max), 99.47 (254 nm).
[1301] HPLC--Rt (min): 5.10; % Area: 99.48 (Max), 99.72 (254
nm).
[1302] 400 MHz, CDCl.sub.3: .delta. 7.98-7.96 (m, 2H), 7.91-7.84
(m, 4H), 7.81-7.79 (m, 1H), 7.58-7.53 (m, 2H), 7.49-7.43 (m, 1H),
7.26-7.21 (m, 1H), 4.34 (t, J=8.00 Hz, 2H), 3.46-3.41 (m, 2H).
[3-(2,3-Dihydro-benzo[1,4]dioxin-6-yl)-4,5-dihydro-pyrazol-1-yl]-(3-fluoro-
-phenyl)-methanone
##STR00564##
[1304] White solid; 80.13% Yield
[1305] LC-MS: Mass found (M+, 327.0). Rt (min): 4.34; % Area: 95.92
(Max), 98.10 (254 nm).
[1306] HPLC--Rt (min): 4.42; % Area: 95.32 (Max), 97.92 (254
nm).
[1307] 400 MHz, CDCl.sub.3: .delta. 7.80-7.78 (m, 1H), 7.73-7.71
(m, 1H), 7.42-7.38 (m, 1H), 7.26-7.16 (m, 3H), 6.95-6.88 (m, 1H),
4.31-4.26 (m, 4H), 4.23-4.21 (m, 2H), 3.23 (t, J=8.00 Hz, 2H).
(3-Fluoro-phenyl)-(3-quinolin-6-yl-4,5-dihydro-pyrazol-1-yl)-methanone
##STR00565##
[1309] White solid; 14.02% Yield
[1310] LC-MS: Mass found (M+, 320.0). Rt (min): 2.75; % Area: 94.85
(Max), 96.42 (254 nm).
[1311] HPLC--Rt (min): 2.77; % Area: 96.57 (Max), 98.30 (254
nm).
[1312] 400 MHz, CDCl.sub.3: .delta. 9.02-9.00 (m, 1H), 8.68-8.66
(m, 2H), 8.40-8.37 (m, 1H), 8.14 (s, 1H), 7.82-7.79 (m, 2H),
7.73-7.71 (m, 1H), 7.75-7.45 (m, 1H), 7.28-7.23 (m, 1H), 4.39 (t,
J=8.00 Hz, 2H), 3.44 (t, J=12.00 Hz, 2H).
(3-Chroman-6-yl-4,5-dihydro-pyrazol-1-yl)-(3-fluoro-phenyl)-methanone
##STR00566##
[1314] White solid; 18.10% Yield
[1315] LC-MS: Mass found (M+, 325.3). Rt (min): 4.68; % Area: 96.60
(Max), 94.10 (220 nm).
[1316] HPLC--Rt (min): 2.41; % Area: 99.93 (Max), 99.28 (254
nm).
[1317] 400 MHz, CDCl.sub.3: .delta. 7.81 (d, J=4.00 Hz, 1H),
7.76-7.74 (m, 1H), 7.47-7.38 (m, 3H), 7.22-7.17 (m, 1H), 6.82 (d,
J=8.00 Hz, 1H), 4.26-4.21 (m, 4H), 3.27-3.22 (m, 2H), 2.82 (t,
J=8.00 Hz, 2H), 2.07-2.01 (m, 2H).
(3-Fluoro-phenyl)-(3-pyridin-4-yl-4,5-dihydro-pyrazol-1-yl)-methanone
##STR00567##
[1319] White solid; 12.99% Yield
[1320] LC-MS: Mass found (M+, 270.0). Rt (min): 2.23; % Area: 98.21
(Max), 96.25 (220 nm).
[1321] HPLC--Rt (min): 2.27; % Area: 98.52 (Max), 95.92 (254
nm).
[1322] 400 MHz, CDCl.sub.3: .delta. 8.71-8.69 (m, 2H), 7.77 (d,
J=8.00 Hz, 1H), 7.72-7.69 (m, 1H), 7.55-7.54 (m, 2H), 7.47-7.42 (m,
1H), 7.24-7.21 (m, 1H), 4.33 (t, J=8.00 Hz, 2H), 3.30 (t, J=12.00
Hz, 2H).
[3-(5-Fluoro-2-methoxy-pyridin-4-yl)-4,5-dihydro-pyrazol-1-yl]-(3-fluoro-p-
henyl)-methanone
##STR00568##
[1324] Light brown solid; 20.33% Yield
[1325] LC-MS: Mass found (M+, 318.0). Rt (min): 4.36; % Area: 97.91
(Max), 95.52 (220 nm).
[1326] HPLC--Rt (min): 4.36; % Area: 97.83 (Max), 96.12 (254
nm).
[1327] 400 MHz, CDCl.sub.3: .delta. 8.10 (d, J=4.00 Hz, 1H),
7.79-7.76 (m, 1H), 7.72-7.68 (m, 1H), 7.46-7.40 (m, 1H), 7.24-7.19
(m, 1H), 7.06 (d, J=4.00 Hz, 1H), 4.29 (t, J=8.00 Hz, 2H), 3.93 (s,
3H), 3.40-3.34 (m, 2H).
[3-(3-Chloro-2-methoxy-pyridin-4-yl)-4,5-dihydro-pyrazol-1-yl]-(3-fluoro-p-
henyl)-methanone
##STR00569##
[1329] Off white solid; 43.85% Yield
[1330] LC-MS: Mass found (M+, 334.0). Rt (min): 4.56; % Area: 97.24
(Max), 97.32 (220 nm).
[1331] HPLC--Rt (min): 4.62; % Area: 98.91 (Max), 98.79 (254
nm).
[1332] 400 MHz, CDCl.sub.3: .delta. 8.06 (d, J=8.00 Hz, 1H),
7.78-7.76 (m, 1H), 7.73-7.69 (m, 1H), 7.44-7.39 (m, 1H), 7.23-7.17
(m, 2H), 4.30 (t, J=8.00 Hz, 2H), 4.06 (s, 3H), 3.51 (t, J=12.00
Hz, 2H).
(3-Fluoro-phenyl)-[3-(3-methoxy-pyridin-4-yl)-4,5-dihydro-pyrazol-1-yl]-me-
thanone
##STR00570##
[1334] White Solid; 38.60% Yield
[1335] LC-MS: Mass found (M+, 300). Rt (min): 2.49; % Area: 99.66
(Max), 99.21 (254 nm).
[1336] HPLC--Rt (min): 2.55; % Area: 98.14 (Max), 98.58 (254
nm).
[1337] 400 MHz, CDCl.sub.3: .delta. 8.42 (s, 1H), 8.30 (d, J=4.00
Hz, 1H), 7.80-7.76 (m, 2H), 7.59 (d, J=4.00 Hz, 2H), 7.45-7.41 (m,
1H), 7.24-7.19 (m, 1H), 4.25 (t, J=12.00 Hz, 2H), 4.02 (s, 3H),
3.43 (t, J=8.00 Hz, 2H).
(3-Fluoro-phenyl)-[3-(2-methoxy-pyridin-4-yl)-4,5-dihydro-pyrazol-1-yl]-me-
thanone
##STR00571##
[1339] Off white solid; 8.49% Yield
[1340] LC-MS: Mass found (M+, 300.3). Rt (min): 3.87; % Area: 94.48
(Max), 90.84 (220 nm).
[1341] HPLC--Rt (min): 3.74; % Area: 96.03 (Max), 93.16 (254
nm).
[1342] 400 MHz, CDCl.sub.3: .delta. 8.26-8.24 (m, 1H), 7.76-7.74
(m, 1H), 7.69-7.66 (m, 1H), 7.47-7.41 (m, 1H), 7.31-7.27 (m, 1H),
7.23-7.21 (m, 1H), 6.99 (s, 1H), 4.32 (t, J=12.00 Hz, 2H),
4.14-4.10 (m, 3H), 3.27 (t, J=8.00 Hz, 2H).
(3-Fluoro-phenyl)-[3-(6-methoxy-pyridin-3-yl)-4,5-dihydro-pyrazol-1-yl]-me-
thanone
##STR00572##
[1344] White solid; 61.49% Yield
[1345] LC-MS: Mass found (M+, 300.0). Rt (min): 3.95; % Area: 98.57
(Max), 96.66 (220 nm).
[1346] HPLC--Rt (min): 3.94; % Area: 98.84 (Max), 98.34 (254
nm).
[1347] 400 MHz, CDCl.sub.3: .delta. 8.40-8.39 (m, 1H), 8.01-7.99
(m, 1H), 7.79-7.71 (m, 2H), 7.45-7.39 (m, 1H), 7.23-7.18 (m, 1H),
6.80 (d, J=8.00 Hz, 1H), 4.28 (t, J=8.00 Hz, 2H), 3.99 (s, 3H),
3.28 (t, J=12.00 Hz, 2H).
(3-Fluoro-phenyl)-[3-(2-methoxy-pyridin-3-yl)-4,5-dihydro-pyrazol-1-yl]-me-
thanone
##STR00573##
[1349] White solid; 4.35% Yield
[1350] LC-MS: Mass found (M+, 300.3). Rt (min): 4.14; % Area: 96.89
(Max), 98.37 (220 nm).
[1351] HPLC--Rt (min): 4.05; % Area: 99.08 (Max), 99.25 (254
nm).
[1352] 400 MHz, CDCl.sub.3: .delta. 8.24-8.22 (m, 1H), 8.04-8.02
(m, 1H), 7.81-7.78 (m, 2H), 7.44-7.39 (m, 1H), 7.22-7.17 (m, 1H),
6.97-6.94 (m, 1H), 4.23 (t, J=12.00 Hz, 2H), 4.04 (s, 3H), 3.43 (t,
J=12.00 Hz, 2H).
(3-Fluoro-phenyl)-[3-(5-methoxy-pyridin-3-yl)-4,5-dihydro-pyrazol-1-yl]-me-
thanone
##STR00574##
[1354] Off white solid; 66.64% Yield
[1355] LC-MS: Mass found (M+, 300.0). Rt (min): 2.81; % Area: 97.26
(Max), 99.15 (254 nm).
[1356] HPLC--Rt (min): 2.81; % Area: 99.26 (Max), 99.24 (254
nm).
[1357] 400 MHz, CDCl.sub.3: .delta. 8.61-8.54 (m, 1H), 8.45-8.37
(m, 1H), 7.95-7.91 (m, 1H), 7.71-7.65 (m, 1H), 7.64-7.61 (m, 1H),
7.48-7.42 (m, 1H), 7.27-7.22 (m, 1H), 4.37 (t, J=8.00 Hz, 2H), 4.00
(s, 3H), 3.33 (t, J=12.00 Hz, 2H).
[3-(5-Fluoro-6-methoxy-pyridin-3-yl)-4,5-dihydro-pyrazol-1-yl]-(3-fluoro-p-
henyl)-methanone
##STR00575##
[1359] White solid; 7.91% Yield
[1360] LC-MS: Mass found (M+, 318.0). Rt (min): 4.24; % Area: 95.74
(Max), 90.08 (220 nm).
[1361] HPLC--Rt (min): 4.44; % Area: 97.55 (Max), 95.14 (254
nm).
[1362] 400 MHz, CDCl.sub.3: .delta. 8.13 (d, J=4.00 Hz, 1H),
7.76-7.73 (m, 2H), 7.69-7.66 (m, 1H), 7.45-7.40 (m, 1H), 7.23-7.19
(m, 1H), 4.29 (t, J=8.00 Hz, 2H), 4.08 (s, 3H), 3.27 (t, J=12.00
Hz, 2H).
[3-(5-Chloro-2-methoxy-pyridin-3-yl)-4,5-dihydro-pyrazol-1-yl]-(3-fluoro-p-
henyl)-methanone
##STR00576##
[1364] White solid; 31.93% Yield
[1365] LC-MS: Mass found (M+, 334.0). Rt (min): 4.87; % Area: 92.17
(Max), 93.85 (254 nm).
[1366] HPLC--Rt (min): 4.88; % Area: 92.21 (Max), 93.13 (254
nm).
[1367] 400 MHz, CDCl.sub.3: .delta. 8.16-8.15 (m, 1H), 7.97 (d,
J=4.00 Hz, 1H), 7.76 (t, J=8.00 Hz, 2H), 7.46-7.41 (m, 1H),
7.24-7.19 (m, 1H), 4.24 (t, J=8.00 Hz, 2H), 4.02 (s, 3H), 3.41 (t,
J=8.00 Hz, 2H).
[3-(5-Chloro-6-methoxy-pyridin-3-yl)-4,5-dihydro-pyrazol-1-yl]-(3-fluoro-p-
henyl)-methanone
##STR00577##
[1369] Off white solid; 4.62% Yield
[1370] LC-MS: Mass found (M+, 334.0). Rt (min): 4.81; % Area: 92.84
(Max), 93.84 (254 nm).
[1371] HPLC--Rt (min): 4.93; % Area: 94.76 (Max), 94.37 (254
nm).
[1372] 400 MHz, CDCl.sub.3: .delta. 8.16-8.15 (m, 1H), 7.97 (d,
J=4.00 Hz, 1H), 7.75 (t, J=8.00 Hz, 2H), 7.45-7.40 (m, 1H),
7.23-7.18 (m, 1H), 4.23 (t, J=12.00 Hz, 2H), 4.01 (s, 3H), 3.40 (t,
J=12.00 Hz, 2H).
(3-Fluoro-phenyl)-[3-(6-methoxy-2-methyl-pyridin-3-yl)-4,5-dihydro-pyrazol-
-1-yl]-methanone
##STR00578##
[1374] White solid; 13.88% Yield
[1375] LC-MS: Mass found (M+, 314.0). Rt (min): 3.78; % Area: 97.78
(Max), 98.61 (254 nm).
[1376] HPLC--Rt (min): 3.75; % Area: 97.99 (Max), 98.66 (254
nm).
[1377] 400 MHz, CDCl.sub.3: .delta. 7.77 (d, J=8.00 Hz, 1H),
7.73-7.70 (m, 1H), 7.61 (d, J=8.00 Hz, 1H), 7.43-7.37 (m, 1H),
7.21-7.16 (m, 1H), 6.64 (d, J=8.00 Hz, 1H), 4.22 (t, J=8.00 Hz,
2H), 3.97 (s, 3H), 3.30 (t, J=8.00 Hz, 2H), 2.67 (s, 3H).
[3-(6-Dimethylamino-pyridin-3-yl)-4,5-dihydro-pyrazol-1-yl]-(3-fluoro-phen-
yl)-methanone
##STR00579##
[1379] White solid; 60.38% Yield
[1380] LC-MS: Mass found (M+, 313.0). Rt (min): 2.50; % Area: 99.51
(Max), 99.73 (254 nm).
[1381] HPLC--Rt (min): 2.55; % Area: 99.37 (Max), 99.47 (254
nm).
[1382] 400 MHz, CDCl.sub.3: .delta. 8.40-8.39 (m, 1H), 7.87-7.74
(m, 3H), 7.43-7.38 (m, 1H), 7.21-7.16 (m, 1H), 6.55 (d, J=12.00 Hz,
1H), 4.23 (t, J=12.00 Hz, 2H), 3.24 (t, J=12.00 Hz, 2H), 3.16 (s,
6H).
(3-Fluoro-phenyl)-[3-(1H-pyrrolo[2,3-b]pyridin-5-yl)-4,5-dihydro-pyrazol-1-
-yl]-methanone
##STR00580##
[1384] Off white solid; 65.27% Yield
[1385] LC-MS: Mass found (M+, 309.0). Rt (min): 3.11; % Area: 96.77
(Max), 96.14 (254 nm).
[1386] HPLC--Rt (min): 3.10; % Area: 98.69 (Max), 99.09 (254
nm).
[1387] 400 MHz, CDCl.sub.3: .delta. 8.71-0.00 (m, 1H), 8.27 (s,
1H), 7.85-7.83 (m, 1H), 7.79-7.76 (m, 1H), 7.48-7.42 (m, 1H),
7.39-7.38 (m, 1H), 7.24-7.20 (m, 1H), 6.60-6.59 (m, 1H), 4.32 (t,
J=8.00 Hz, 2H), 3.40 (t, J=8.00 Hz, 2H).
[3-(6-Amino-pyridin-3-yl)-4,5-dihydro-pyrazol-1-yl]-(3-fluoro-phenyl)-meth-
anone
##STR00581##
[1389] Off white solid; 11.10% Yield
[1390] LC-MS: Mass found (M+, 285.0). Rt (min): 2.35; % Area: 99.45
(Max), 98.80 (254 nm).
[1391] HPLC--Rt (min): 2.33; % Area: 98.97 (Max), 98.92 (254
nm).
[1392] 400 MHz, DMSO-d6: .delta. 8.19-8.18 (m, 1H), 7.72-7.66 (m,
2H), 7.63-7.61 (m, 1H), 7.54-7.49 (m, 1H), 7.39-7.33 (m, 1H), 6.55
(s, 2H), 6.48 (d, J=8.00 Hz, 1H), 4.05 (t, J=8.00 Hz, 2H), 3.25 (t,
J=8.00 Hz, 2H).
(3-Fluoro-phenyl)-(3-pyrimidin-5-yl-4,5-dihydro-pyrazol-1-yl)-methanone
##STR00582##
[1394] White Solid; 11.71% Yield
[1395] LC-MS: Mass found (M+, 271). Rt (min): 2.80; % Area: 95.20
(Max), 96.55 (254 nm).
[1396] HPLC--Rt (min): 2.81; % Area: 96.24 (Max), 94.46 (254
nm).
[1397] 400 MHz, CDCl.sub.3: .delta. 9.26 (s, 1H), 9.04 (s, 2H),
7.76 (d, J=8.00 Hz, 1H), 7.70-7.66 (m, 1H), 7.47-7.42 (m, 1H),
7.28-7.22 (m, 1H), 4.35 (t, J=8.00 Hz, 2H), 3.33 (t, J=12.00 Hz,
2H).
(3-Fluoro-phenyl)-[3-(2-methoxy-pyrimidin-5-yl)-4,5-dihydro-pyrazol-1-yl]--
methanone
##STR00583##
[1399] White solid; 40.79% Yield
[1400] LC-MS: Mass found (M+, 301.2). Rt (min): 2.80; % Area: 98.80
(Max), 98.32 (254 nm).
[1401] HPLC--Rt (min): 3.34; % Area: 99.20 (Max), 98.82 (254
nm).
[1402] 400 MHz, CDCl.sub.3: .delta. 8.83 (s, 2H), 7.76 (d, J=8.00
Hz, 1H), 7.70-7.67 (m, 1H), 7.45-7.40 (m, 1H), 7.24-7.19 (m, 1H),
4.30 (t, J=12.00 Hz, 2H), 4.08 (s, 3H), 3.28 (t, J=12.00 Hz,
2H).
(3-Fluoro-phenyl)-[3-(2-methyl-pyrimidin-5-yl)-4,5-dihydro-pyrazol-1-yl]-m-
ethanone
##STR00584##
[1404] White Solid; 14.21% Yield
[1405] LC-MS: Mass found (M+, 285.0). Rt (min): 4.19; % Area: 99.30
(Max), 98.66 (254 nm).
[1406] HPLC--Rt (min): 4.33; % Area: 98.83 (Max), 97.31 (254
nm).
[1407] 400 MHz, CDCl.sub.3: .delta. 8.92 (s, 2H), 7.76 (d, J=8.00
Hz, 1H), 7.71-7.67 (m, 1H), 7.46-7.40 (m, 1H), 7.25-7.20 (m, 1H),
4.32 (t, J=12.00 Hz, 2H), 3.31 (t, J=8.00 Hz, 2H), 2.80 (s,
3H).
[3-(2-Amino-pyrimidin-5-yl)-4,5-dihydro-pyrazol-1-yl]-(3-fluoro-phenyl)-me-
thanone
##STR00585##
[1409] Yellow solid; 14.88% Yield
[1410] LC-MS: Mass found (M+, 286.2). Rt (min): 2.48; % Area: 99.76
(Max), 97.20 (254 nm).
[1411] HPLC--Rt (min): 2.43; % Area: 98.82 (Max), 96.54 (254
nm).
[1412] 400 MHz, CDCl.sub.3: .delta. 8.61 (s, 2H), 7.76 (d, J=8.00
Hz, 1H), 7.69 (d, J=8.00 Hz, 1H), 7.44-7.39 (m, 1H), 7.23-7.18 (m,
1H), 5.34-5.30 (m, 2H), 4.26 (t, J=12.00 Hz, 2H), 3.23 (t, J=12.00
Hz, 2H).
[3-(2-Dimethylamino-pyrimidin-5-yl)-4,5-dihydro-pyrazol-1-yl]-(3-fluoro-ph-
enyl)-methanone
##STR00586##
[1414] White Solid; 7.79% Yield
[1415] LC-MS: Mass found (M+, 314.3). Rt (min): 3.49; % Area: 99.52
(Max), 98.83 (254 nm).
[1416] HPLC--Rt (min): 4.62; % Area: 99.60 (Max), 97.57 (254
nm).
[1417] 400 MHz, CDCl.sub.3: .delta. 8.63 (s, 2H), 7.79 (d, J=8.00
Hz, 1H), 7.73 (d, J=12.00 Hz, 1H), 7.42-7.37 (m, 1H), 7.22-7.17 (m,
1H), 4.24 (t, J=12.00 Hz, 2H), 3.26 (s, 6H), 3.22 (t, J=8.00 Hz,
2H).
(3-Fluoro-phenyl)-(3-thiophen-3-yl-4,5-dihydro-pyrazol-1-yl)-methanone
##STR00587##
[1419] Brown solid; 14.46% Yield
[1420] LC-MS: Mass found (M+, 275.0). Rt (min): 4.27; % Area: 98.69
(Max), 99.55 (254 nm).
[1421] HPLC--Rt (min): 4.27; % Area: 97.97 (Max), 98.53 (254
nm).
[1422] 400 MHz, DMSO-d6: .delta. 7.98-7.97 (m, 1H), 7.71 (d, J=8.00
Hz, 1H), 7.65-7.61 (m, 2H), 7.55-7.49 (m, 1H), 7.40-7.35 (m, 2H),
4.08 (t, J=8.00 Hz, 2H), 3.32-3.27 (m, 2H).
(3-Benzofuran-2-yl-4,5-dihydro-pyrazol-1-yl)-(3-fluoro-phenyl)-methanone
##STR00588##
[1424] White solid; 29.06% Yield
[1425] LC-MS: Mass found (M+, 309.0). Rt (min): 4.70; % Area: 98.71
(Max), 98.00 (220 nm).
[1426] HPLC--Rt (min): 4.72; % Area: 98.56 (Max), 98.68 (220
nm).
[1427] 400 MHz, CDCl.sub.3: .delta. 7.83 (d, J=4.00 Hz, 1H),
7.77-7.74 (m, 1H), 7.63 (d, J=8.00 Hz, 1H), 7.56 (d, J=8.00 Hz,
1H), 7.48-7.37 (m, 2H), 7.31-7.29 (m, 1H), 7.25-7.21 (m, 1H),
7.17-7.10 (m, 1H), 4.31 (t, J=12.00 Hz, 2H), 3.36 (t, J=12.00 Hz,
2H).
(3-Fluoro-phenyl)-[3-(5-phenyl-thiophen-2-yl)-4,5-dihydro-pyrazol-1-yl]-me-
thanone
##STR00589##
[1429] Yellow solid; 48.86% Yield
[1430] LC-MS: Mass found (M+, 351.0). Rt (min): 5.24; % Area: 98.94
(Max), 98.59 (254 nm).
[1431] HPLC--Rt (min): 5.26; % Area: 99.31 (Max), 97.80 (254
nm).
[1432] 400 MHz, CDCl.sub.3: .delta. 7.83 (d, J=4.00 Hz, 1H), 7.76
(d, J=8.00 Hz, 1H), 7.65-7.63 (m, 2H), 7.47-7.39 (m, 3H), 7.36-7.32
(m, 1H), 7.30-7.29 (m, 1H), 7.27-7.26 (m, 1H), 7.24-7.19 (m, 1H),
4.29 (t, J=12.00 Hz, 2H), 3.31 (t, J=12.00 Hz, 2H).
(4,5-Dihydro-1'H-[3,3']bipyrazolyl-1-yl)-(3-fluoro-phenyl)-methanone
##STR00590##
[1434] White Solid; 69.02% Yield
[1435] LC-MS: Mass found (M+, 259.0). Rt (min): 3.30; % Area: 94.11
(Max), 96.78 (254 nm).
[1436] HPLC--Rt (min): 3.36; % Area: 96.98 (Max), 97.91 (254
nm).
[1437] 400 MHz, CDCl.sub.3: .delta. 8.12 (d, J=4.00 Hz, 1H),
7.73-7.71 (m, 2H), 7.69-7.64 (m, 1H), 7.44-7.39 (m, 1H), 7.23-7.18
(m, 1H), 6.49-6.47 (m, 1H), 4.36 (t, J=12.00 Hz, 2H), 3.59 (t,
J=8.00 Hz, 2H).
[3-(3,5-Dimethyl-isoxazol-4-yl)-4,5-dihydro-pyrazol-1-yl]-(3-fluoro-phenyl-
)-methanone
##STR00591##
[1439] Off white solid; 26.69% Yield
[1440] LC-MS: Mass found (M+, 288.0). Rt (min): 3.82; % Area: 98.67
(Max), 99.34 (254 nm).
[1441] HPLC--Rt (min): 3.85; % Area: 99.67 (Max), 99.65 (254
nm).
[1442] 400 MHz, CDCl.sub.3: .delta. 7.72-7.70 (m, 1H), 7.68-7.64
(m, 1H), 7.43-7.37 (m, 1H), 7.21-7.16 (m, 1H), 4.22 (t, J=12.00 Hz,
2H), 3.26 (t, J=12.00 Hz, 2H), 2.58 (s, 3H), 2.37 (s, 3H).
(1'-Benzyl-4,5-dihydro-1'H-[3,4]'bipyrazolyl-1-yl)-(3-fluoro-phenyl)-metha-
none
##STR00592##
[1444] Off white solid; 35.08% Yield
[1445] LC-MS: Mass found (M+, 349.0). Rt (min): 4.20; % Area: 98.60
(Max), 98.61 (254 nm).
[1446] HPLC--Rt (min): 4.31; % Area: 99.31 (Max), 98.84 (254
nm).
[1447] 400 MHz, CDCl.sub.3: .delta. 8.85-8.81 (m, 1H), 8.80-8.72
(m, 1H), 8.71-8.65 (m, 2H), 7.42-7.33 (m, 4H), 7.27-7.23 (m, 2H),
7.20-7.14 (m, 1H), 5.33 (s, 2H), 4.18 (t, J=8.00 Hz, 2H), 3.14 (t,
J=12.00 Hz, 2H).
(3-Fluoro-phenyl)-[3-(5-methoxy-benzofuran-2-yl)-4,5-dihydro-pyrazol-1-yl]-
-methanone
##STR00593##
[1449] Off white solid; 36.53% Yield
[1450] LC-MS: Mass found (M+, 339.0). Rt (min): 4.64; % Area: 97.45
(Max), 96.85 (254 nm).
[1451] HPLC--Rt (min): 4.66; % Area: 97.47 (Max), 96.13 (254
nm).
[1452] 400 MHz, CDCl.sub.3: .delta. 7.82 (d, J=8.00 Hz, 1H),
7.76-7.73 (m, 1H), 7.47-7.42 (m, 2H), 7.25-7.20 (m, 1H), 7.07-7.04
(m, 2H), 7.00 (dd, J=8.00, 4.00 Hz, 1H), 4.30 (t, J=8.00 Hz, 2H),
3.86 (s, 3H), 3.34 (t, J=12.00 Hz, 2H).
(4,5-Dihydro-2'H-[3,3']bipyrazolyl-1-yl)-(3-fluoro-phenyl)-methanone
##STR00594##
[1454] Off white solid; 85.33% Yield
[1455] LC-MS: Mass found (M+, 259.0). Rt (min): 3.31; % Area: 97.42
(Max), 96.70 (254 nm).
[1456] HPLC--Rt (min): 3.36; % Area: 97.17 (Max), 95.99 (254
nm).
[1457] 400 MHz, CDCl.sub.3: .delta. 8.12-8.11 (m, 1H), 7.73-7.71
(m, 2H), 7.65 (d, J=8.00 Hz, 1H), 7.45-7.39 (m, 1H), 7.23-7.18 (m,
1H), 4.36 (t, J=12.00 Hz, 2H), 3.59 (t, J=8.00 Hz, 2H).
(4,5-Dihydro-1'H-[3,4']bipyrazolyl-1-yl)-(3-fluoro-phenyl)-methanone
##STR00595##
[1459] White solid; 18.88% Yield
[1460] LC-MS: Mass found (M+, 259). Rt (min): 3.35; % Area: 96.38
(Max), 92.65 (220 nm).
[1461] HPLC--Rt (min): 3.34; % Area: 99.36 (Max), 99.07 (254
nm).
[1462] 400 MHz, CDCl.sub.3: .delta. 8.12-8.11 (m, 1H), 7.73-7.71
(m, 2H), 7.65 (d, J=8.00 Hz, 1H), 7.45-7.39 (m, 1H), 7.23-7.18 (m,
1H), 6.49-6.47 (m, 1H), 4.36 (t, J=12.00 Hz, 2H), 3.59 (t, J=8.00
Hz, 2H).
(3-Fluoro-phenyl)-(1'-pyridin-4-ylmethyl-4,5-dihydro-1'H-[3,4']bipyrazolyl-
-1-yl)-methanone
##STR00596##
[1464] Off white solid; 23.01% Yield
[1465] LC-MS: Mass found (M+, 350.0). Rt (min): 2.33; % Area: 98.97
(Max), 99.03 (254 nm).
[1466] HPLC--Rt (min): 2.46; % Area: 98.16 (Max), 98.27 (254
nm).
[1467] 400 MHz, CDCl.sub.3: .delta. 8.54 (brs, 2H), 7.79-7.76 (m,
2H), 7.69-7.67 (m, 1H), 7.63-7.61 (m, 1H), 7.36-7.27 (m, 1H),
7.13-7.08 (m, 1H), 7.03-7.02 (m, 2H), 5.31 (s, 2H), 4.13 (t, J=8.00
Hz, 2H), 3.14-3.04 (m, 2H).
Example 10: EC.sub.50 of cyclic AMP production in CHO FSHR
cells+EC.sub.20 FSH (Assay A)
[1468] 2500 Cho-FSHR-LUC-1-1-43 cells were plated per well in 5
.mu.l of phenol red free DMEM/F12+1% FBS. Cells were plated in 384
well, solid white low volume plates (Greiner 784075) by Multidrop.
Cells were assayed by adding 100 .mu.l of 2.times.EC.sub.20
FSH/IBMX in DMEM/F12+0.1% BSA) by Multidrop to 2 .mu.l of test
compound stamped in 384 well plates (compounds are diluted 1:50).
The final FSH concentration was 0.265 pM, and the final IBMX
concentration was 200 .mu.M. The compound plate map was as follows:
Column 1: 2 .mu.l of DMSO; Column 2: 2 .mu.l of DMSO; Columns 3-12
and 13-24: 2 .mu.l of test compound, diluted 1:4 in 100% DMSO, or 2
.mu.l of FSH, diluted 1:4 in DMEM/F12+0.1% BSA. The starting
concentration for FSH was 50 nM (final concentration was 0.5 nM).
Furthermore, Column 23 contained 2 .mu.l of EC.sub.100 FSH
reference (100.times.) (diluted in DMEM/F12+0.1% BSA) at a final
concentration of 0.5 nM, and Column 24 contained 2 .mu.l of 1 mM
AS707664/2 reference compound 2. 5 .mu.l of compound+EC.sub.20 FSH
mixture were transferred to cell plates (1:2 dilution into 5 .mu.l
of cell media). The plates were incubated at 37.degree. C. for 1 h.
10 .mu.l of mixed HTRF (CisBio #62AM4PEC) reagents were added per
well and incubated at room temperature for 1 h. The plates were
read on Envision using the cAMP HTRF--low volume 384 well protocol.
The readout was the calculated fluorescence ratio (665 nm/620 nm).
Results are given in Table 1.
Example 11: Rat granulosa EC.sub.50 FSH (Assay B)
[1469] The assay was performed pursuant to the teaching of Yanofsky
et al. (2006) Allosteric activation of the follicle-stimulating
hormone (FSH) receptor by selective, nonpeptide agonists. JBC
281(19): 13226-13233, which is incorporated by reference in the
disclosure of the invention. Results are given in Table 1.
Example 12: Pharmaceutical Preparations
[1470] (A) Injection vials: A solution of 100 g of an active
ingredient according to the invention and 5 g of disodium hydrogen
phosphate in 3 l of bidistilled water was adjusted to pH 6.5 using
2 N hydrochloric acid, sterile filtered, transferred into injection
vials, lyophilized under sterile conditions and sealed under
sterile conditions. Each injection vial contained 5 mg of active
ingredient.
[1471] (B) Suppositories: A mixture of 20 g of an active ingredient
according to the invention was melted with 100 g of soy lecithin
and 1400 g of cocoa butter, poured into moulds and allowed to cool.
Each suppository contained 20 mg of active ingredient.
[1472] (C) Solution: A solution was prepared from 1 g of an active
ingredient according to the invention, 9.38 g of
NaH.sub.2PO.sub.4.2H.sub.2O, 28.48 g of
Na.sub.2HPO.sub.4.12H.sub.2O and 0.1 g of benzalkonium chloride in
940 ml of bidistilled water. The pH was adjusted to 6.8, and the
solution was made up to 1 l and sterilized by irradiation. This
solution could be used in the form of eye drops.
[1473] (D) Ointment: 500 mg of an active ingredient according to
the invention were mixed with 99.5 g of Vaseline under aseptic
conditions.
[1474] (E) Tablets: A mixture of 1 kg of an active ingredient
according to the invention, 4 kg of lactose, 1.2 kg of potato
starch, 0.2 kg of talc and 0.1 kg of magnesium stearate was pressed
to give tablets in a conventional manner in such a way that each
tablet contained 10 mg of active ingredient.
[1475] (F) Coated tablets: Tablets were pressed analogously to
Example E and subsequently coated in a conventional manner with a
coating of sucrose, potato starch, talc, tragacanth and dye.
[1476] (G) Capsules: 2 kg of an active ingredient according to the
invention were introduced into hard gelatin capsules in a
conventional manner in such a way that each capsule contained 20 mg
of the active ingredient.
[1477] (H) Ampoules: A solution of 1 kg of an active ingredient
according to the invention in 60 l of bidistilled water was sterile
filtered, transferred into ampoules, lyophilized under sterile
conditions and sealed under sterile conditions. Each ampoule
contained 10 mg of active ingredient.
[1478] (I) Inhalation spray: 14 g of an active ingredient according
to the invention were dissolved in 10 l of isotonic NaCl solution,
and the solution was transferred into commercially available spray
containers with a pump mechanism. The solution could be sprayed
into the mouth or nose. One spray shot (about 0.1 ml) corresponded
to a dose of about 0.14 mg.
* * * * *