Note: Descriptions are shown in the official language in which they were submitted.
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AGENTS THAT DISRUPT CELLULAR REPLICATION AND THEIR USE IN INHIBITING
PATHOLOGICAL CONDITIONS
The present invention provides novel compounds that inhibit cell
proliferation, in
particular by disrupting normal chromatin segregation, and uses of these
compounds for treating,
ameliorating or preventing diseases, conditions or disorders benefiting from
the inhibition of
cellular replication, in particular hyperproliferative diseases.
BACKGROUND OF THE INVENTION
Estrogens are commonly recognized as pivotal in female reproductive physiology
(Nilsson et al.(2001), Physiol Rev 81: 1535-1565), however, they are also
involved in male
reproductive development and physiology (Lombardi et al., (2001), Mol. Cell
Endocrinol. 178:
51-55), in bone and lipid metabolism (Denger et al., (2001) Mol. Endocrinol.
15: 2064-2077;
(2001) Hum. Reprod. Update 7: 303-313) and in the maintenance of the
cardiovascular (Rosano
and Fini, (2001) Int. J. Fertil. Womens Med. 46: 248-256) and neuronal systems
(Green and
Simpkins (2000) Ann. N. Y. Acad. Sci. 924: 93-98). The physiological effects
of estrogens are
transduced through specific nuclear receptors, the estrogen receptors (ER(x
and ER(3), which are
dimeric, intranuclear, ligand dependent transcription factors. ERs recognize
defined palindromic
target sequences in the promoter of estrogen responsive target genes (Klinge
(2001) Nucleic
Acids Res. 29: 2905-2919). Upon binding ligand, ERa undergoes a major
conformational change
that generates surfaces that associate with intermediate transcription
factors, which, in turn,
activate transcription by recruiting polymerase II to the target promoter
(Brzozowski et al.,
(1997) Nature 389: 753-758; Reid et al., (2003) Mol. Cell 11: 695-707;
Metivier et al., (2003)
Cell 115: 751-763).
Estradiol (E2) has an obligate role in the development of the majority of
breast neoplasia.
E2 induces cellular proliferation in the endometrium and in breast, through
modulating the
expression and activity of key regulatory components of the cell cycle, in
particular cyclin
dependant kinases, cyclin D l, c-myc and pRb, (Cariou et al.,(2000) Proc.
Natl. Acad. Sci. U S A
97: 9042-9046; Carroll et al., (2000) J. Biol. Chem. 275: 38221-38229; Watts
et al., (1995) Mol.
Endocrinol. 9: 1804-1813). Epidemiological evidence is also consistent with E2
having a key
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2
role in the aetiology of breast neoplasia. Prolonged exposure to estrogens,
such as early
menarche (MacMahon et al., (1973 J. Natl. Cancer Inst. 50: 21-42), late
menopause
(Trichopoulos et al., (1972) J. Natl. Cancer Inst. 48: 605-613), nulliparity
and late age at first
pregnancy (Maciviahon et al., (1973 J Natl. Cancer Inst. 50: 21-42) are
associated with an
increased risk of developing breast cancer. Moreover, high levels of exogenous
estrogen are
directly associated with an increase in the frequency of breast cancer
incidence (London et al.,
(1992) JAMA 267: 941-944).
Cells expressing ERa are rare in normal breast and generally do not
concomitantly
express markers of cellular proliferation, such as Ki67. Dysregulation of the
inverse relationship
between proliferation and ERa expression is one of the earliest events that
occurs in the
progression of normal breast epithelia to neoplasia and is seen in
proliferative conditions such as
hyperplasia of the usual type (HUT), atypical ductal hyperplasia (ADH), ductal
carcinoma in situ
(DCIS) and lobular in situ neoplasia (LIN). There is strong epidemiological
evidence that these
hyperplastic situations are precursors of manifest breast cancer (Bodian et
al., (1993) Cancer 71:
3896-3907; (London et al., (1992) JAMA 267: 941-944). Concordant with the role
that ERa has
in the aetiology of breast cancer, tamoxifen and raloxifen, steroid mimetics
that block the
proliferative activity of the estrogen receptor in breast, are effective in
the treatment (Anon.
(1998) Lancet 351: 1451-1467) and in the prevention (Anon. (2002) Lancet 360:
817-824) of
breast cancer. Tamoxifen in particular has limitations in therapy, with
resistance to treatment
being a frequent outcome (Kurebayashi, J. (2003) Breast Cancer 10: 112-119)
and moreover,
tamoxifen induces uterine proliferation (Shang and Brown (2002) Science 295:
2465-2468).
Consequently, a need remains for alternative approaches that achieve profound
anti-estrogenic
effects that are mechanistically different from analogues of E2 or inhibitors
of aromatase.
While characterising the class of compounds presented herein, which act as
inhibitors of
estrogen signaling, it was found that they are potent inhibitors of the normal
process of cellular
replication. These compounds induce arrests in the G2/M phase of the cell
cycle and provoke
abnormal chromatin structures in treated cells, characterized as aster and
micronuclei. Moreover,
they induce abnormal aster-like structures of tubulin. These compounds induce
clearance of ERa
protein from ERa positive cells. The compounds of the present invention
represent a novel class
of inhibitors that also act to abrogate estrogen signaling within cells and
which can be used for
the treatment, prevention or amelioration of hyperproliferative diseases, in
particular those where
estrogen receptor signaling contributes to the disease.
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3
SUMMARY OF THE INVENTION
The present invention provides compounds capable of disrupting chromosome
segregation, which are suitable in particular in antagonizing estrogen
receptor signalling. Data
presented herein establishes that compounds of formula (I) and formulas
(LXVII) and in
particular of formulas (VII) to (LXVI) and (LXXI) to (LXXIII) can inhibit
estrogen signalling in
a cell based assay format and that these compounds induce a profound arrest in
the G2/M phase
of the cell cycle.
In a first aspect the present invention relates to a compound of formula (I)
X
R1 , N)~ NR3
I I
R2 R4
(I)
wherein
X is O or S;
R' is aryl, heteroaryl, aralkyl, cycloalkyl, or heteroaralkyl, optionally
substituted;
R 2 is H, alkyl, cycloalkyl, or aryl, optionally substituted;
R3 is aryl, heteroaryl, aralkyl, heteroaralkyl, or linear or branched alkyl,
optionally substituted
and/or interrupted one or more times by 0, N or S; and
R4 is H, alkyl, alkenyl, or alkynyl, optionally substituted;
or R3 and R4 together form a heterocycloalkyl ring or an alicyclic system,
optionally substituted
and pharmaceutically acceptable salts thereof.
In a further aspect the present invention relates to compounds according to
formula
(LXVII)
Xzz~S
,N4
R21 R22
(LXVII)
wherein
RZ1 is aralkyl or heteroaralkyl, optionally substituted
R22 is aryl or heteroaryl, optionally substituted; and
X isOorS
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and pharmaceutically acceptable salts thereof.
In a preferred embodiment the compound of the present invention has a
structure
according to formula (LXXI), (LXXII) or (LXXIII)
o
_ ~ - r
s \ / _
-O
(LXXI) (LXXII)
o
s
o
-o
(LXXIII)
In a further aspect the present invention is directed at pharmaceutical
composition
comprising an effective amount of at least one compound of the present
invention and a
pharmaceutically acceptable carrier or excipient.
In a further aspect the present invention is directed at the use of a compound
of the
invention for the production of a medicament for treating, ameliorating or
preventing diseases,
conditions and/or disorders which benefit from a reduced cellular replication.
DETAILED DESCRIPTION
Definitions
Before the present invention is described in detail below, it is to be
understood that this
invention is not limited to the particular methodology, protocols and reagents
described herein as
these may vary. It is also to be understood that the terminology used herein
is for the purpose of
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describing particular embodiments only, and is not intended to limit the scope
of the present
invention which will be limited only by the appended claims. Unless defined
otherwise, all
technical and scientific terms used herein have the same meanings as commonly
understood by
one of ordinary skill in the art.
5 Preferably, the terms used herein are defined as described in "A
multilingual glossary of
biotechnological terms: (IUPAC Recommendations)", Leuenberger, H.G.W, Nagel,
B. and Klbl,
H. eds. (1995), Helvetica Chimica Acta, CH-4010 Basel, Switzerland).
Throughout this specification and the claims which follow, unless the context
requires
otherwise, the word "comprise", and variations such as "comprises" and
"comprising", will be
understood to imply the inclusion of a stated integer or step or group of
integers or steps but not
the exclusion of any other integer or step or group of integers or steps.
Several documents are cited throughout the text of this specification. Each of
the
documents cited herein (including all patents, patent applications, scientific
publications,
manufacturer's specifications, instructions, etc.), whether supra or infra,
are hereby incorporated
by reference in their entirety. Nothing herein is to be construed as an
admission that the
invention is not entitled to antedate such disclosure by virtue of prior
invention.
In the following definitions of the terms: alkyl, heteroalkyl, cycloalkyl,
heterocycloalkyl,
aryl, aralkyl, heteroaryl, heteroaralkyl, alicyclic system, alkenyl,
cycloalkenyl, and alkynyl are
provided. These terms will in each instance of its use in the remainder of the
specification have
the respectively defined meaning and preferred meanings. Nevertheless in some
instances of
their use throughout the specification preferred meanings of these terms are
indicated.
The term "alkyl" refers to a saturated straight or branched carbon chain.
Preferably, the
chain comprises from 1 to 10 carbon atoms, i.e. 1, 2, 3, 4, 5, 6, 7, 8, 9 or
10 e.g. methyl, ethyl
methyl, ethyl, propyl, iso-propyl, butyl, iso-butyl, tert-butyl, pentyl,
hexyl, heptyl, octyl. Alkyl
groups are optionally substituted.
The term "heteroalkyl" refers to a saturated straight or branched carbon
chain. Preferably,
the chain comprises from 1 to 9 carbon atoms, i.e. 1, 2, 3, 4, 5, 6, 7, 8, 9
e.g. methyl, ethyl,
propyl, iso-propyl, butyl, iso-butyl, sec-butyl, tert-butyl, pentyl, hexyl,
heptyl, octyl, which is
interrupted one or more times, e.g. 1, 2, 3, 4, 5, with the same or different
heteroatoms.
Preferably the heteroatoms are selected from 0, S, and N, e.g. CH2-O-CH3, CH2-
O-C2H5, C2H4-
O-CH3, CZH4-O-C2H5 etc. Heteroalkyl groups are optionally substituted.
The terms "cycloalkyl" and "heterocycloalkyl", by themselves or in combination
with
other terms, represent, unless otherwise stated, cyclic versions of "alkyl"
and "heteroalkyl",
respectively, with preferably 3, 4, 5, 6, 7, 8, 9 or 10 atoms forming a ring,
e.g. cyclopropyl,
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cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl etc. The terms
"cycloalkyl" and
"heterocycloalkyl" are also meant to include bicyclic, tricyclic and
polycyclic versions thereof. If
bicyclic, tricyclic or polycyclic rings are formed it is preferred that the
respective rings are
connected to each other at two adjacent carbon atoms, however, alternatively
the two rings are
connected via the same carbon atom, i.e. they form a spiro ring system or they
form "bridged"
ring systems. The term "heterocycloalkyl" preferably refers to a saturated
ring having five
members of which at least one member is a N, 0 or S atom and which optionally
contains one
additional 0 or one additional N; a saturated ring having six members of which
at least one
member is a N, 0 or S atom and which optionally contains one additional 0 or
one additional N
or two additional N atoms; or a saturated bicyclic ring having nine or ten
members of which at
least one member is a N, 0 or S atom and which optionally contains one, two or
three additional
N atoms. "Cycloalkyl" and "heterocycloalkyl" groups are optionally
substituted. Additionally,
for heterocycloalkyl, a heteroatom can occupy the position at which the
heterocycle is attached
to the remainder of the molecule. Preferred examples of cycloalkyl include
cyclopropyl,
cyclobutyl, cyclopentyl, cyclohexyl, 1-cyclohexenyl, 3-cyclohexenyl,
cycloheptyl,
spiro[3,3]heptyl, spiro[3,4]octyl, spiro[4,3]octyl, spiro[3,5]nonyl,
spiro[5,3]nonyl,
spiro[3,6]decyl, spiro[6,3]decyl, spiro[4,5]decyl, spiro[5,4]decyl,
bicyclo[2.2.1]heptyl,
bicyclo[2.2.2]octyl, adamantyl, and the like. Examples of heterocycloalkyl
include 1-(1,2,5,6-
tetrahydropyridyl), 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-
morpholinyl, 3-morpholinyl, 1,8
diaza-spiro-[4,5] decyl, 1,7 diaza-spiro-[4,5] decyl, 1,6 diaza-spiro-[4,5]
decyl, 2,8 diaza-
spiro[4,5] decyl, 2,7 diaza-spiro[4,5] decyl, 2,6 diaza-spiro[4,5] decyl, 1,8
diaza-spiro-[5,4]
decyl, 1,7 diaza-spiro-[5,4] decyl, 2,8 diaza-spiro-[5,4] decyl, 2,7 diaza-
spiro[5,4] decyl, 3,8
diaza-spiro[5,4] decyl, 3,7 diaza-spiro[5,4] decyl, 1-aza-7,11-dioxo-
spiro[5,5] undecyl, 1,4-
diazabicyclo[2.2.2]oct-2-yl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl,
tetrahydrothien-2-yl,
tetrahydrothien-3-yl, 1-piperazinyl, 2-piperazinyl, and the like.
The term "alicyclic system" refers to mono, bicyclic, tricyclic or polycyclic
version of a
cycloalkyl or heterocycloalkyl comprising at least one double and/or triple
bond. However, an
alicyclic system is not aromatic or heteroaromatic, i.e. does not have a
system of conjugated
double bonds/free electron pairs. Thus, the number of double and/or triple
bonds maximally
allowed in an alicyclic system is determined by the number of ring atoms, e.g.
in a ring system
with up to 5 ring atoms an alicyclic system comprises up to one double bond,
in a ring system
with 6 ring atoms the alicyclic system comprises up to two double bonds. Thus,
the
"cycloalkenyl" as defined below is a preferred embodiment of an alicyclic ring
system. Alicyclic
systems are optionally substituted.
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The term "aryl" preferably refers to an aromatic monocyclic ring containing 6
carbon
atoms, an aromatic bicyclic ring system containing 10 carbon atoms or an
aromatic tricyclic ring
system containing 14 carbon atoms. Examples are phenyl, naphthalenyl or
anthracenyl. The aryl
group is optionally substituted.
The term "aralkyl" refers to an alkyl moiety, which is substituted by aryl,
wherein alkyl
and aryl have the meaning as outlined above. An example is the benzyl radical.
Preferably, in
this context the alkyl chain comprises from 1 to 8 carbon atoms, i.e. 1, 2, 3,
4, 5, 6, 7, or 8, e.g.
methyl, ethyl, propyl, iso-propyl, butyl, iso-butyl, sec-butenyl, tert-butyl,
pentyl, hexyl, heptyl,
octyl. The aralkyl group is optionally substituted at the alkyl and/or aryl
part of the group.
Preferably the aryl attached to the alkyl has the meaning phenyl, naphthalenyl
or anthracenyl.
The term "heteroaryl" preferably refers to a five or six-membered aromatic
monocyclic
ring wherein at least one of the carbon atoms are replaced by 1, 2, or 3 (for
the five membered
ring) or 1, 2, 3, or 4, (for the six membered ring) of the same or different
heteroatoms, preferably
selected from 0, N and S; an aromatic bicyclic ring system wherein 1, 2, 3, 4,
5, or 6 carbon
atoms of the 8, 9, 10, 11 or 12 carbon atoms have been replaced with the same
or different
heteroatoms, preferably selected from 0, N and S; or an aromatic tricyclic
ring system wherein
1, 2, 3, 4, 5, or 6 carbon atoms of the 13, 14, 15, or 16 carbon atoms have
been replaced with the
same or different heteroatoms, preferably selected from 0, N and S. Examples
are furanyl,
thiophenyl, oxazolyl, isoxazolyl, 1,2,5-oxadiazolyl, 1,2,3-oxadiazolyl,
pyrrolyl, imidazolyl,
pyrazolyl, 1,2,3-triazolyl, thiazolyl, isothiazolyl, 1,2,3,-thiadiazolyl,
1,2,5-thiadiazolyl, pyridinyl,
pyrimidinyl, pyrazinyl, 1,2,3-triazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, 1-
benzofuranyl, 2-
benzofuranyl, indolyl, isoindolyl, benzothiophenyl, 2-benzothiophenyl, 1 H-
indazolyl,
benzimidazolyl, benzoxazolyl, indoxazinyl, 2, 1 -benzisoxazolyl,
benzothiazolyl, 1,2-
benzisothiazolyl, 2, 1 -benzisothiazolyl, benzotriazolyl, quinolinyl,
isoquinolinyl, 2,3-
benzodiazinyl, quinoxalinyl, quinazolinyl, 1,2,3-benzotriazinyl, or 1,2,4-
benzotriazinyl.
The term "heteroaralkyl" refers to an alkyl moiety, which is substituted by
heteroaryl,
wherein alkyl and heteroaryl have the meaning as outlined above. An example is
the (2-
pyridinyl) ethyl, (3-pyridinyl) ethyl, or (2-pyridinyl) methyl. Preferably, in
this context the alkyl
chain comprises from 1 to 8 carbon atoms, i.e. 1, 2, 3, 4, 5, 6, 7, or 8, e.g.
methyl, ethyl methyl,
ethyl, propyl, iso-propyl, butyl, iso-butyl, sec-butenyl, tert-butyl, pentyl,
hexyl, heptyl, octyl.
The heteroaralkyl group is optionally substituted at the alkyl and/or
heteroaryl part of the group.
Preferably the heteroaryl attached to the alkyl has the meaning oxazolyl,
isoxazolyl, 1,2,5-
oxadiazolyl, 1,2,3-oxadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, 1,2,3-
triazolyl, thiazolyl,
isothiazolyl, 1,2,3,-thiadiazolyl, 1,2,5-thiadiazolyl, pyridinyl, pyrimidinyl,
pyrazinyl, 1,2,3-
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triazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, 1-benzofuranyl, 2-benzofuranyl,
indolyl, isoindolyl,
benzothiophenyl, 2-benzothiophenyl, 1 H-indazolyl, benzimidazolyl,
benzoxazolyl, indoxazinyl,
2,1-benzisoxazolyl, benzothiazolyl, 1,2-benzisothiazolyl, 2,1-
benzisothiazolyl, benzotriazolyl,
2,3-'nenzodiazinyl, quinolinyl, isoquinolinyl, quinoxalinyl, quinazolinyl,
1,2,3-benzotriazinyl, or
1,2,4-benzotriazinyl.
The terms "alkenyl" and "cycloalkenyl" refer to olefinic unsaturated carbon
atoms
containing chains or rings with one or more double bonds. Examples are
propenyl and
cyclohexenyl. Preferably, the alkenyl chain comprises from 2 to 8 carbon
atoms, i.e. 2, 3, 4, 5, 6,
7, or 8, e.g. ethenyl, 1-propenyl, 2-propenyl, iso-propenyl, 1-butenyl, 2-
butenyl, 3-butenyl, iso-
butenyl, sec-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, hexenyl,
heptenyl, octenyl.
Preferably the cycloalkenyl ring comprises from 3 to 8 carbon atoms, i.e. 3,
4, 5, 6, 7, or 8, e.g.
1-cyclopropenyl, 2-cyclopropenyl, 1-cyclobutenyl, 2-cylcobutenyl, 1-
cyclopentenyl, 2-
cyclopentenyl, 3-cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl.
The term "alkynyl" refers to unsaturated carbon atoms containing chains or
rings with
one or more triple bonds. An example is the propargyl radical. Preferably, the
alkynyl chain
comprises from 2 to 8 carbon atoms, i.e. 2, 3, 4, 5, 6, 7, or 8, e.g. ethynyl,
1-propynyl, 2-
propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl,
4-pentynyl,
hexynyl, pentynyl, octynyl.
In one embodiment, carbon atoms or hydrogen atoms in alkyl, cycloalkyl, aryl,
aralkyl,
alkenyl, cycloalkenyl, alkynyl radicals may be substituted independently from
each other with
one or more elements selected from the group consisting of 0, S, and N or with
groups
containing one ore more elements selected from the group consisting of 0, S,
and N.
Embodiments include alkoxy, cycloalkoxy, aryloxy, aralkoxy, alkenyloxy,
cycloalkenyloxy, alkynyloxy, alkylthio, cycloalkylthio, arylthio, aralkylthio,
alkenylthio,
cycloalkenylthio, alkynylthio, alkylamino, cycloalkylamino, arylamino,
aralkylamino,
alkenylamino, cycloalkenylamino, alkynylamino radicals.
Other embodiments include hydroxyalkyl, hydroxycycloalkyl, hydroxyaryl,
hydroxyaralkyl, hydroxyalkenyl, hydroxycycloalkenyl, hydroxyalinyl,
mercaptoalkyl,
mercaptocycloalkyl, mercaptoaryl, mercaptoaralkyl, mercaptoalkenyl,
mercaptocycloalkenyl,
mercaptoalkynyl, aminoalkyl, aminocycloalkyl, aminoaryl, aminoaralkyl,
aminoalkenyl,
aminocycloalkenyl, aminoalkynyl radicals.
In another embodiment, hydrogen atoms in alkyl, cycloalkyl, aryl, aralkyl,
alkenyl,
cycloalkenyl, alkynyl radicals may be substituted independently from each
other with one ore
more halogen atoms. One radical is the trifluoromethyl radical.
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9
If two or more radicals can be selected independently from each other, then
the term
"independently" means that the radicals may be the same or may be different.
The term "pharmaceutically acceptable salt" refers to a salt of the compound
of the
present invention. Suitable pharmaceutically acceptable salts of the compound
of the present
invention include acid addition salts which may, for example, be formed by
mixing a solution of
the compounds of the present invention with a solution of a pharmaceutically
acceptable acid
such as hydrochloric acid, sulfuric acid, fumaric acid, maleic acid, succinic
acid, acetic acid,
benzoic acid, citric acid, tartaric acid, carbonic acid or phosphoric acid.
Furthermore, where the
compound of the invention carries an acidic moiety, suitable pharmaceutically
acceptable salts
thereof may include alkali metal salts (e.g., sodium or potassium salts);
alkaline earth metal salts
(e.g., calcium or magnesium salts); and salts formed with suitable organic
ligands (e.g.,
ammonium, quaternary ammonium and amine cations formed using counteranions
such as
halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, alkyl sulfonate
and aryl sulfonate).
Illustrative examples of pharmaceutically acceptable salts include but are not
limited to: acetate,
adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate,
bicarbonate, bisulfate,
bitartrate, borate, bromide, butyrate, calcium edetate, camphorate,
camphorsulfonate, camsylate,
carbonate, chloride, citrate, clavulanate, cyclopentanepropionate,
digluconate, dihydrochloride,
dodecylsulfate, edetate, edisylate, estolate, esylate, ethanesulfonate,
formate, fumarate,
gluceptate, glucoheptonate, gluconate, glutamate, glycerophosphate,
glycolylarsanilate,
hemisulfate, heptanoate, hexanoate, hexylresorcinate, hydrabamine,
hydrobromide,
hydrochloride, hydroiodide, 2-hydroxy-ethanesulfonate, hydroxynaphthoate,
iodide, isothionate,
lactate, lactobionate, laurate, lauryl sulfate, malate, maleate, malonate,
mandelate, mesylate,
methanesulfonate, methylsulfate, mucate, 2-naphthalenesulfonate, napsylate,
nicotinate, nitrate,
N-methylglucamine ammonium salt, oleate, oxalate, pamoate (embonate),
palmitate,
pantothenate, pectinate, persulfate, 3-phenylpropionate,
phosphate/diphosphate, picrate, pivalate,
polygalacturonate, propionate, salicylate, stearate, sulfate, subacetate,
succinate, tannate, tartrate,
teoclate, tosylate, triethiodide, undecanoate, valerate, and the like (see,
for example, Berge, S.
M., et al, "Pharmaceutical Salts", Journal of Pharmaceutical Science, 1977,
66, 1-19). Certain
specific compounds of the present invention contain both basic and acidic
functionalities that
allow the compounds to be converted into either base or acid addition salts.
The neutral forms of the compounds may be regenerated by contacting the salt
with a
base or acid and isolating the parent compound in the conventional manner. The
parent form of
the compound differs from the various salt forms in certain physical
properties, such as solubility
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in polar solvents, but otherwise the salts are equivalent to the parent form
of the compound for
the purposes of the present invention.
In addition to salt forms, the present invention provides compounds which are
in a
prodrug forrn. Prodrugs of the compounds described herein are those compounds
that readily
5 undergo chemical changes under physiological conditions to provide a
compound of formula (I).
A prodrug is a pharmacologically active or inactive compound that is modified
chemically
through in vivo physiological action, such as hydrolysis, metabolism and the
like, into a
compound of this invention following administration of the prodrug to a
patient. Additionally,
prodrugs can be converted to the compounds of the present invention by
chemical or
10 biochemical methods in an ex vivo environment. For example, prodrugs can be
slowly converted
to the compounds of the present invention when placed in a transdermal patch
reservoir with a
suitable enzyme. The suitability and techniques involved in making and using
prodrugs are well
known by those skilled in the art. For a general discussion of prodrugs
involving esters see
Svensson and Tunek Drug Metabolism Reviews 16.5 (1988) and Bundgaard Design of
Prodrugs,
Elsevier (1985). Examples of a masked carboxylate anion include a variety of
esters, such as
alkyl (for example, methyl, ethyl), cycloalkyl (for example, cyclohexyl),
aralkyl (for example,
benzyl, p-methoxybenzyl), and alkylcarbonyloxyalkyl (for example,
pivaloyloxymethyl).
Amines have been masked as arylcarbonyloxymethyl substituted derivatives which
are cleaved
by esterases in vivo releasing the free drug and formaldehyde (Bungaard J.
Med. Chem. 2503
(1989)). Also, drugs containing an acidic NH group, such as imidazole, imide,
indole and the
like, have been masked with N-acyloxymethyl groups (Bundgaard Design of
Prodrugs, Elsevier
(1985)). Hydroxy groups have been masked as esters and ethers. EP 0 039 051
(Sloan and Little,
Apr. 11, 1981) discloses Mannich-base hydroxamic acid prodrugs, their
preparation and use.
Compounds and also the starting materials for their preparation according to
the
invention can be synthesized by methods and standard procedures known to those
skilled in the
art, i. e. as described in the literature (for example in the standard works,
such as Houben-Weyl,
Methoden der organischen Chemie [Methods of Organic Chemistry], Georg-Thieme-
Verlag,
Stuttgart), under reaction conditions which are known to those skilled in the
art and suitable for
the said reactions. Use can also be made here of variants which are known per
se, but are not
mentioned here in greater detail.
If desired, the starting materials can also be formed in situ by not isolating
them from the
reaction mixture, but instead immediately converting them further into the
compounds of the
present invention. On the other hand, it is possible to carry out the reaction
stepwise. It should be
noted that the general procedures are shown as it relates to preparation of
compounds having
CA 02646541 2008-09-18
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11
unspecified stereochemistry. However, such procedures are generally applicable
to those
compounds of a specific stereochemistry, e.g., where the stereochemistry at a
sterogenic center is
(S) or (R). In addition, the compounds having one stereochemistry (e.g., (R))
can often be
utilized to produce those having opposite stereochemistry (i.e., (S)) using
well-known methods,
for example, by inversion.
Certain compounds of the present invention can exist in unsolvated forms as
well as in
solvated forms, including hydrated forms. In general, the solvated forms are
equivalent to
unsolvated forms and are intended to be encompassed within the scope of the
present invention.
Certain compounds of the present invention may exist in multiple crystalline
or amorphous
forms. In general, all physical forms are equivalent for the uses contemplated
by the present
invention and are intended to be within the scope of the present invention.
Certain compounds of the present invention possess asymmetric carbon atoms
(optical
centers) or double bonds. The racemates, enantiomers, diastereomers, geometric
isomers and
individual isomers are all intended to be encompassed within the scope of the
present invention.
Accordingly, the compounds of this invention include mixtures of
stereoisomers, especially
mixtures of enantiomers, as well as purified stereoisomers, especially
purified enantiomers, or
stereoisomerically enriched mixtures, especially enantiomerically enriched
mixtures. Also
included within the scope of the invention are the individual isomers of the
compounds
represented by formulas (I) to (LXXIII) below as well as any wholly or
partially equilibrated
mixtures thereof. The present invention also covers the individual isomers of
the compounds
represented by the formulas below as mixtures with isomers thereof in which
one or more chiral
centers are inverted. Also, it is understood that all tautomers and mixtures
of tautomers of the
compounds of formulae formulas (I) to (LXXIII) are included within the scope
of the
compounds of formulae formulas (I) to (LXXIII) and preferably the formulae and
subformulae
corresponding thereto.
Racemates obtained can be resolved into the isomers mechanically or chemically
by
methods known per se. Diastereomers are preferably formed from the racemic
mixture by
reaction with an optically active resolving agent.
Examples of suitable resolving agents are optically active acids, such as the
D and L
forms of tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid,
mandelic acid, malic acid,
lactic acid or the various optically active camphorsulfonic acids, such as -
camphorsulfonic acid.
Also advantageous is enantiomer resolution with the aid of a column filled
with an optically
active resolving agent (for example dinitrobenzoylphenylglycine); an example
of a suitable
eluent is a hexane/isopropanol/acetonitrile mixture.
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The diastereomer resolution can also be carried out by standard purification
processes,
such as, for example, chromatography or fractional crystallization.
It is also possible to obtain optically active compounds of formulas (I) to
(LXXIII) by the
methods described above by using starting materials which are already
optically active.
The compounds of the present invention may also contain unnatural proportions
of
atomic isotopes at one or more of the atoms that constitute such compounds.
For example, the
compounds may be radiolabeled with radioactive isotopes, such as for example
tritium (3H),
iodine-125 ("SI) or carbon-14 (14C). All isotopic variations of the compounds
of the present
invention, whether radioactive or not, are intended to be encompassed within
the scope of the
present invention.
General
The present invention provides compositions, compounds and uses of compounds
for
antagonizing estrogen receptor (ER) function in a cell. The compositions which
are useful as
antagonist will typically be those which contain an effective amount of an ER-
modulating
compound. In general, an effective amount of an ER-modulating compound is a
concentration of
the compound that will produce at least 50 percent decrease in ER activity in
a cell-based
reporter gene assay as described in the examples below.
Embodiments of the Invention
In a first aspect the present invention relates to a compound of formula (I)
X
R1 , NNR3
I I
R2 R4
(I)
wherein
X isOorS;
R' is aryl, heteroaryl, aralkyl, cycloalkyl, or heteroaralkyl, optionally
substituted, preferably
with 1, 2, 3, 4 or more substituents selected from the group consisting of
halogen, e.g. F,
Cl, Br or I; CN; NO2; NR'R"; alkyl, in particular CI-C6 alkyl, e.g. Ci, C2,
C3, C4, C5, or
C6 alkyl, preferably methyl, ethyl, propyl, iso-propyl, butyl, iso-butyl, tert-
butyl, pentyl,
hexyl; alkenyl, in particular C2-C6 alkenyl, e.g. C2, C3, C4, C5, or C6
alkenyl, preferably
ethenyl, 1-propenyl, 2-propenyl, 1-iso-propenyl, 2-iso-propenyl, 1-butenyl, 2-
butenyl, 3-
butenyl; alkynyl, in particular C2-C6 alkynyl, e.g. C2, C3, C4, C5, or C6
alkynyl; alkanoyl,
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13
preferably Ci-C6 alkanoyl, e.g. Cl, C2, C3, C4, C5, or C6 alkanoyl; alkenoyl,
in particular
C3-C6 alkenoyl, e.g. C3, C4, C5, or C6 alkenoyl, preferably propenoyl;
alkynoyl, in
particular C3-C6 alkynoyl, e.g. C3, C4, C5, or C6 alkynoyl, preferably
propynoyl; alkoxy,
in particular Ci-C6 aikoxy, e.g. Cl, C2, C3, C4, C5, or C6 alkoxy, preferably
methoxy,
ethoxy, propoxy, iso-propoxy, butoxy, iso-butoxy, tert-butoxy, pentoxy, or
hexoxy;
alkoxyalkyl, in particular CI-C6 alkoxy-Cl-C6 alkyl, e.g. methoxymethyl,
ethoxymethyl,
propoxymethyl, methoxyethyl, ethoxyethyl, propoxyethyl, methoxypropyl,
ethoxypropyl,
or propoxypropyl; -OOC-R"'; -COO-R""'; aryl, in particular phenyl,
naphthalenyl or
anthracenyl; heteroaryl, in particular furanyl, thiophenyl, oxazolyl,
isoxazolyl, 1,2,5-
oxadiazolyl, 1,2,3-oxadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, 1,2,3-
triazolyl, thiazolyl,
isothiazolyl, 1,2,3,-thiadiazolyl, 1,2,5-thiadiazolyl, pyridinyl, pyrimidinyl,
pyrazinyl,
1,2,3-triazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, 1-benzofuranyl, 2-
benzofuranyl, indolyl,
isoindolyl, benzothiophenyl, 2-benzothiophenyl, 1H-indazolyl, benzimidazolyl,
benzoxazolyl, indoxazinyl, 2,1 -benzisoxazolyl, benzothiazolyl, 1,2-
benzisothiazolyl, 2,1-
benzisothiazolyl, benzotriazolyl, quinolinyl, isoquinolinyl, 2,3-
benzodiazinyl,
quinoxalinyl, quinazolinyl, 1,2,3-benzotriazinyl, or 1,2,4-benzotriazinyl;
aralkyl; or
heteroaralkyl; optionally substituted, wherein
R' and R" are independent of each other hydrogen; alkyl; in particular C1-C6
alkyl, e.g.
Ci, C2, C3, C4, C5, or C6 alkyl, alkenyl, in particular C2-C6 alkenyl, e.g.
C2, C3, C4,
C5, or C6 alkenyl; alkynyl, in particular C2-C6 alkynyl, e.g. C2, C3, C4, C5,
or C6
alkynyl; aryl; or heteroaryl, in particular furanyl, thiophenyl, oxazolyl,
isoxazolyl,
1,2,5-oxadiazolyl, 1,2,3-oxadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, 1,2,3-
triazolyl, thiazolyl, isothiazolyl, 1,2,3,-thiadiazolyl, 1,2,5-thiadiazolyl,
pyridinyl,
pyrimidinyl, pyrazinyl, 1,2,3-triazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, 1-
benzofuranyl, 2-benzofuranyl, indolyl, isoindolyl, benzothiophenyl, 2-
benzothiophenyl, 1 H-indazolyl, benzimidazolyl, benzoxazolyl, indoxazinyl, 2,1-
benzisoxazolyl, benzothiazolyl, 1,2-benzisothiazolyl, 2,1 -benzisothiazolyl,
benzotriazolyl, quinolinyl, isoquinolinyl, 2,3-benzodiazinyl, quinoxalinyl,
quinazolinyl, 1,2,3-benzotriazinyl, or 1,2,4-benzotriazinyl; optionally
substituted;
R"' is alkyl, alkenyl, alkynyl, in particular CI-C6 alkyl, e.g. Cl, C2, C3,
C4, C5, or C6
alkyl; and
R""' is hydrogen, alkyl, alkenyl, alkynyl, in particular CI-C6 alkyl, e.g. Ci,
C2, C3, C4,
C5, or C6 alkyl, optionally substituted;
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14
or two or more of substituents of R' are taken together to form a cycloalkyl,
heterocycloalkyl, alicyclic ring system, aryl or heteroaryl, optionally
substituted;
optionally the alkyl moiety of R~, including the alkyl moiety of the aralkyl
and the
heteroaraikyi moiety, respectively is interrupted 1, 2, 3, 4 or more times by
0, N, and/or
S;
it is further preferred that the substituents of R' are substituents of the
aryl and heteroaryl
moiety, respectively;
R 2 is H, alkyl, cycloalkyl, or aryl, optionally substituted;
R3 is aryl, heteroaryl, aralkyl, heteroaralkyl, or linear or branched alkyl,
optionally
substituted, preferably with 1, 2, 3, 4 or more substituents selected from the
group
consisting of halogen, e.g. F, Cl, Br or I; CN; NO2; NR'R"; alkyl, in
particular C1-C6
alkyl, e.g. C1i C2, C3, C4, C5, or C6 alkyl, preferably methyl, ethyl, propyl,
iso-propyl,
butyl, iso-butyl, tert-butyl, pentyl, hexyl; alkenyl, in particular C2-C6
alkenyl, e.g. C2, C3,
C4, C5, or C6 alkenyl, preferably ethenyl, 1-propenyl, 2-propenyl, 1-iso-
propenyl, 2-iso-
propenyl, 1-butenyl, 2-butenyl, 3-butenyl; alkynyl, in particular C2-C6
alkynyl, e.g. C2,
C3, C4, C5, or C6 alkynyl; alkanoyl, preferably CI-C6 alkanoyl, e.g. Cl, C2,
C3, C4, C5, or
C6 alkanoyl; alkenoyl, in particular C3-C6 alkenoyl, e.g. C3, C4, C5, or C6
alkenoyl,
preferably propenoyl; alkynoyl, in particular C3-C6 alkynoyl, e.g. C3, C4, C5,
or C6
alkynoyl, preferably propynoyl; alkoxy, in particular CI-C6 alkoxy, e.g. Cl,
C2, C3, C4,
C5, or C6 alkoxy, preferably methoxy, ethoxy, propoxy, iso-propoxy, butoxy,
iso-butoxy,
tert-butoxy, pentoxy, or hexoxy; alkoxyalkyl, in particular CI-C6 alkoxy-Cl-C6
alkyl, e.g.
methoxymethyl, ethoxymethyl, propoxymethyl, methoxyethyl, ethoxyethyl,
propoxyethyl, methoxypropyl, ethoxypropyl, or propoxypropyl; -OOC-R"'; -
COOR""';
aryl, in particular phenyl, naphthalenyl or anthracenyl; heteroaryl, in
particular furanyl,
thiophenyl, oxazolyl, isoxazolyl, 1,2,5-oxadiazolyl, 1,2,3-oxadiazolyl,
pyrrolyl,
imidazolyl, pyrazolyl, 1,2,3-triazolyl, thiazolyl, isothiazolyl, 1,2,3,-
thiadiazolyl, 1,2,5-
thiadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, 1,2,3-triazinyl, 1,2,4-
triazinyl, 1,3,5-
triazinyl, 1-benzofuranyl, 2-benzofuranyl, indolyl, isoindolyl,
benzothiophenyl, 2-
benzothiophenyl, 1 H-indazolyl, benzimidazolyl, benzoxazolyl, indoxazinyl, 2,1-
benzisoxazolyl, benzothiazolyl, 1,2-benzisothiazolyl, 2,1 -benzisothiazolyl,
benzotriazolyl, quinolinyl, isoquinolinyl, 2,3-benzodiazinyl, quinoxalinyl,
quinazolinyl,
1,2,3-benzotriazinyl, or 1,2,4-benzotriazinyl; optionally substituted, wherein
R' and R" are independent of each other hydrogen; alkyl, in particular CI-C6
alkyl, e.g.
Ci, C2, C3, C4, C5, or C6 alkyl; alkenyl, in particular C2-C6 alkenyl, e.g.
C2, C3, C4,
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C5, or C6 alkenyl; alkynyl, in particular C2-C6 alkynyl, e.g. C2, C3, C4, C5,
or C6
alkynyl; aryl; or heteroaryl, in particular furanyl, thiophenyl, oxazolyl,
isoxazolyl,
1,2,5-oxadiazolyl, 1,2,3-oxadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, 1,2,3-
triazolyi, thiazolyl, isothiazolyl, 1,2,3,-thiadiazolyl, 1,2,5-thiadiazolyl,
pyridinyl,
5 pyrimidinyl, pyrazinyl, 1,2,3-triazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, 1-
benzofuranyl, 2-benzofuranyl, indolyl, isoindolyl, benzothiophenyl, 2-
benzothiophenyl, 1 H-indazolyl, benzimidazolyl, benzoxazolyl, indoxazinyl, 2,1-
benzisoxazolyl, benzothiazolyl, 1,2-benzisothiazolyl, 2,1 -benzisothiazolyl,
benzotriazolyl, quinolinyl, isoquinolinyl, 2,3-benzodiazinyl, quinoxalinyl,
10 quinazolinyl, 1,2,3-benzotriazinyl, or 1,2,4-benzotriazinyl; optionally
substituted;
R"' is alkyl, alkenyl, alkynyl, in particular Ci-C6 alkyl, e.g. Ci, C2, C3,
C4, C5, or C6
alkyl; and
R""' is hydrogen, alkyl, alkenyl, alkynyl, in particular CI-C6 alkyl, e.g. C1,
C2, C3, C4,
C5, or C6 alkyl, optionally substituted;
15 or two or more of substituents of R3 are taken together to form a
cycloalkyl;
heterocycloalkyl; alicyclic ring system; aryl or heteroaryl; optionally
substituted,
preferably with 1, 2, 3, 4 or more substituents selected from the group
consisting of
halogen, e.g. F, Cl, Br or I; CN; NO2; NR'R"; alkyl, in particular Ci-C6
alkyl, e.g. Ci, C2,
C3, C4, C5, or C6 alkyl, preferably methyl, ethyl, propyl, iso-propyl, butyl,
iso-butyl, tert-
butyl, pentyl, hexyl; alkenyl, in particular C2-C6 alkenyl, e.g. C2, C3, C4,
C5, or C6
alkenyl, preferably ethenyl, 1-propenyl, 2-propenyl, 1-iso-propenyl, 2-iso-
propenyl, 1-
butenyl, 2-butenyl, 3-butenyl; alkynyl, in particular C2-C6 alkynyl, e.g. C2,
C3, C4, C5, or
C6 alkynyl; alkanoyl, preferably C1-C6 alkanoyl, e.g. CI, C2, C3, C4, C5, or
C6 alkanoyl;
alkenoyl, in particular C3-C6 alkenoyl, e.g. C3, C4, C5, or C6 alkenoyl,
preferably
propenoyl; alkynoyl, in particular C3-C6 alkynoyl, e.g. C3, C4, C5, or C6
alkynoyl,
preferably propynoyl; alkoxy, in particular CI-C6 alkoxy, e.g. Cl, C2, C3, C4,
C5, or C6
alkoxy, preferably methoxy, ethoxy, propoxy, iso-propoxy, butoxy, iso-butoxy,
tert-
butoxy, pentoxy, or hexoxy; alkoxyalkyl, in particular CI-C6 alkoxy-CI-C6
alkyl, e.g.
methoxymethyl, ethoxymethyl, propoxymethyl, methoxyethyl, ethoxyethyl,
propoxyethyl, methoxypropyl, ethoxypropyl, or propoxypropyl; -OOC-R"'; -COO-
R""'; aryl, in particular phenyl, naphthalenyl or anthracenyl; heteroaryl, in
particular
furanyl, thiophenyl, oxazolyl, isoxazolyl, 1,2,5-oxadiazolyl, 1,2,3-
oxadiazolyl, pyrrolyl,
imidazolyl, pyrazolyl, 1,2,3-triazolyl, thiazolyl, isothiazolyl, 1,2,3,-
thiadiazolyl, 1,2,5-
thiadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, 1,2,3-triazinyl, 1,2,4-
triazinyl, 1,3,5-
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triazinyl, 1-benzofiuanyl, 2-benzofuranyl, indolyl, isoindolyl,
benzothiophenyl, 2-
benzothiophenyl, 1 H-indazolyl, benzimidazolyl, benzoxazolyl, indoxazinyl, 2,1-
benzisoxazolyl, benzothiazolyl, 1,2-benzisothiazolyl, 2,1 -benzisothiazolyl,
benzotriazoiyl, quinolinyl, isoquinolinyl, 2,3-benzodiazinyl, quinoxalinyl,
quinazolinyl,
1,2,3-benzotriazinyl, or 1,2,4-benzotriazinyl; optionally substituted, wherein
R' and R" are independent of each other hydrogen; alkyl, in particular CI-C6
alkyl, e.g.
Ci, C2, C3, C4, C5, or C6 alkyl; alkenyl, in particular C2-C6 alkenyl, e.g.
C2, C3, C4,
C5, or C6 alkenyl; alkynyl, in particular C2-C6 alkynyl, e.g. C2, C3, C4, C5,
or C6
alkynyl; aryl; or heteroaryl, in particular furanyl, thiophenyl, oxazolyl,
isoxazolyl,
1,2,5-oxadiazolyl, 1,2,3-oxadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, 1,2,3-
triazolyl, thiazolyl, isothiazolyl, 1,2,3,-thiadiazolyl, 1,2,5-thiadiazolyl,
pyridinyl,
pyrimidinyl, pyrazinyl, 1,2,3-triazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, 1-
benzofuranyl, 2-benzofuranyl, indolyl, isoindolyl, benzothiophenyl, 2-
benzothiophenyl, 1H-indazolyl, benzimidazolyl, benzoxazolyl, indoxazinyl, 2,1-
benzisoxazolyl, benzothiazolyl, 1,2-benzisothiazolyl, 2,1 -benzisothiazolyl,
benzotriazolyl, quinolinyl, isoquinolinyl, 2,3-benzodiazinyl, quinoxalinyl,
quinazolinyl, 1,2,3-benzotriazinyl, or 1,2,4-benzotriazinyl; optionally
substituted;
R"' is alkyl, alkenyl, alkynyl, in particular C1-C6 alkyl, e.g. Cl, C2, C3,
C4, C5, or C6
alkyl; optionally the alkyl moiety of R3, including the alkyl moiety of the
aralkyl and the
heteroaralkyl moiety, respectively is interrupted 1, 2, 3, 4 or more times by
0, N, and/or
S;
it is further preferred that the substituents of R3 are substituents of the
aryl and heteroaryl
moiety, respectively;
R4 is H, alkyl, alkenyl, or alkynyl, optionally substituted;
or R3 and R4 together form a heterocycloalkyl ring or an alicyclic system,
optionally substituted,
preferably with 1, 2, 3, 4 or more substituents selected from the group
consisting of
halogen, e.g. F, Cl, Br or I; CN; NO2; NR'R"; alkyl, in particular CI-C6
alkyl, e.g. Cl, C2,
C3, C4, C5, or C6 alkyl, preferably methyl, ethyl, propyl, iso-propyl, butyl,
iso-butyl, tert-
butyl, pentyl, hexyl; alkenyl, in particular C2-C6 alkenyl, e.g. C2, C3, C4,
C5, or C6
alkenyl, preferably ethenyl, 1-propenyl, 2-propenyl, 1-iso-propenyl, 2-iso-
propenyl, 1-
butenyl, 2-butenyl, 3-butenyl; alkynyl, in particular C2-C6 alkynyl, e.g. C2,
C3, C4, C5, or
C6 alkynyl; alkanoyl, preferably CI-C6 alkanoyl, e.g. Cl, C2, C3, C4, C5, or
C6 alkanoyl;
alkenoyl, in particular C3-C6 alkenoyl, e.g. C3, C4, C5, or C6 alkenoyl,
preferably
propenoyl; alkynoyl, in particular C3-C6 alkynoyl, e.g. C3, C4, C5, or C6
alkynoyl,
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preferably propynoyl; alkoxy, in particular CI-C6 alkoxy, e.g. Cl, C2, C3, C4,
C5, or C6
alkoxy, preferably methoxy, ethoxy, propoxy, iso-propoxy, butoxy, iso-butoxy,
tert-
butoxy, pentoxy, or hexoxy; alkoxyalkyl, in particular Ci-C6 alkoxy-Ci-C6
alkyl, e.g.
methoxymethyl, ethoxymethyl, propoxymethyl, methoxyethyl, ethoxyethyl,
propoxyethyl, methoxypropyl, ethoxypropyl, or propoxypropyl; -OOC-R"'; -
COOR`9';
aryl, in particular phenyl, naphthalenyl or anthracenyl; heteroaryl, in
particular furanyl,
thiophenyl, oxazolyl, isoxazolyl, 1,2,5-oxadiazolyl, 1,2,3-oxadiazolyl,
pyrrolyl,
imidazolyl, pyrazolyl, 1,2,3-triazolyl, thiazolyl, isothiazolyl, 1,2,3,-
thiadiazolyl, 1,2,5-
thiadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, 1,2,3-triazinyl, 1,2,4-
triazinyl, 1,3,5-
triazinyl, 1-benzofuranyl, 2-benzofuranyl, indolyl, isoindolyl,
benzothiophenyl, 2-
benzothiophenyl, 1 H-indazolyl, benzimidazolyl, benzoxazolyl, indoxazinyl, 2,1-
benzisoxazolyl, benzothiazolyl, 1,2-benzisothiazolyl, 2, 1 -benzisothiazolyl,
benzotriazolyl, quinolinyl, isoquinolinyl, 2,3-benzodiazinyl, quinoxalinyl,
quinazolinyl,
1,2,3-benzotriazinyl, or 1,2,4-benzotriazinyl; optionally substituted, wherein
R' and R" are independent of each other hydrogen; alkyl, in particular CI-C6
alkyl, e.g.
Ci, C2, C3, C4, C5, or C6 alkyl; alkenyl, in particular C2-C6 alkenyl, e.g.
C2, C3, C4,
C5, or C6 alkenyl; alkynyl, in particular C2-C6 alkynyl, e.g. C2, C3, C4, C5,
or C6
alkynyl; aryl; or heteroaryl, in particular furanyl, thiophenyl, oxazolyl,
isoxazolyl,
1,2,5-oxadiazolyl, 1,2,3-oxadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, 1,2,3-
triazolyl, thiazolyl, isothiazolyl, 1,2,3,-thiadiazolyl, 1,2,5-thiadiazolyl,
pyridinyl,
pyrimidinyl, pyrazinyl, 1,2,3-triazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, 1-
benzofuranyl, 2-benzofuranyl, indolyl, isoindolyl, benzothiophenyl, 2-
benzothiophenyl, 1 H-indazolyl, benzimidazolyl, benzoxazolyl, indoxazinyl, 2,1-
benzisoxazolyl, benzothiazolyl, 1,2-benzisothiazolyl, 2,1 -benzisothiazolyl,
benzotriazolyl, quinolinyl, isoquinolinyl, 2,3-benzodiazinyl, quinoxalinyl,
quinazolinyl, 1,2,3-benzotriazinyl, or 1,2,4-benzotriazinyl; optionally
substituted;
R"' is alkyl, alkenyl, alkynyl, in particular CI-C6 alkyl, e.g. C1, C2, C3,
C4, C5, or C6
alkyl; and
R""' is hydrogen, alkyl, alkenyl, alkynyl, in particular CI-C6 alkyl, e.g. Cl,
C2, C3, C4,
C5, or C6 alkyl, optionally substituted;
and pharmaceutically acceptable salts thereof.
The compounds of the general formula (I) according to the present invention
may be
prepared according to the following scheme I:
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x
x
N
R1 ~H Lie Providing agent R1 N~
I ~ Providing agent
H H
(1) (2)
X
HNR3 (4) R1 ,N R3
I Base I
R4 H R4
(3) (5)
alkylating, arylating agent X
Base R 1 , N R3
1
(6) R2 R4
(7)
wherein R~, R2, R3, R4 and X are as defined above, or have the particularly
preferred
meanings as defined below, Lie is a conventional leaving group such as
halogen, sulfonyl or the
like. If in the final compound R4 has the meaning H it is preferred that R4 in
compounds (3), (5)
or (7) is a protecting group, which is cleaved at the end of the synthesis
process, accordingly, R4
may have the meaning protecting group for intermediates of the compounds
according to
formual (I). The above process comprise reacting a compound of the genera
formula (1) with a
-C(=X)-group providing agent in an organic solvent to obtain a compound of the
general formula
(2) and successively reacting the compound of formula (2) with a compound of
the general
formula (3) to give the compound of the general formula (5). Then the compound
of the general
formual (5) may be reacted with an alkylating or arylating agent in the
presence of a base to give
a compound of the general formula (6), wherein the nitrogen residue is
substituted with R2
wherein R2 does not mean hydrogen.
The -C(=X)-group-providing agent used in the above reaction may include 1,1-
carbonyldiimidazole, 1, 1 -carbonylthiodiimidazole, phosgene, thiophosgene,
carbonyldiphenoxide and phenylchloroformate, and it may be used in an amount
of 1-1.5
equivalent, preferably 1-1.1 equivalent to the starting compound (1).
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19
The reaction may be carried out in a conventional organic solvent such as, for
example,
tetrahydrofuran, dichloromethane, acetonitrile, chloroform and
dimethylformamide.
The reaction is preferably carried out in the presence of a coupling agent
such as a
conventional inorganic or an organic base.
Such conventional inorganic or organic bases used in the reaction may include
sodium
hydride, potassium hydride, sodium hydroxide, potassium hydroxide, sodium
carbonate,
potassium carbonate, cesium carbonate, sodium bicarbonate, potassium
bicarbonate,
triethylamine, pyridine and DBU.
The reaction may be carried out at a temperature between 3 C and boiling point
of the
solvent used, preferably at 50 C-100 C and for 5-48 hours, preferably for 10-
24 hours.
The reaction of the compound (2) with the compound (3) to give the compound
(5) may
be carried out in the presence of a conventional organic solvent at the
temperature of 50-100 C
for 5-48 hours. The compound (3) may be used by 1-1.5 equivalent.
The reaction is preferably carried out in the presence of a conventional
inorganic or
organic base, such as sodium hydride, potassium hydride, sodium hydroxide,
potassium
hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium
bicarbonate,
potassium bicarbonate, triethylamine, pyridine, DBU or the like.
Then, the compound of the formula (5) may be reacted with an alkylating agent
(including agents that are capable of transferring a cycloalkyl) or an
arylating agent in the
presence of a conventional organic or inorganic base to give a compound of the
general formula
(6).
The alkylating agent and arylating agent used in the above step may include
alkylhalide,
preferably (Ci_g)-alkylhalide; alkylsulfonate, preferably (C1_8)-
alkylsulfonate; cycloalkyl halide,
preferably (C3_10)-cycloalkyl halide; cycloalkyl sulfonate, preferably (C3_1o)-
cycloalkyl sulfonate;
or arylhalide which all may or may not be substituted as indicated in more
detail below.
Substituted or unsubstituted (CI_g)-alkylhalide preferably means methyl
chloride, methyl
bromide, methyl iodide, ethyl chloride, ethyl bromide, ethyl iodide, propyl
chloride, propyl
bromide, propyl iodide, butyl chloride, butyl bromide, butyl iodide, pentyl
chloride, pentyl
bromide, pentyl iodide, bromo ehtylacetate or the like.
Substituted or unsubstituted (C1_8)-alkylsulfonate preferably means methyl
sulfonate,
ethyl sulfonate, propyl sulfonate, butyl sulfonate, pentyl sulfonate or the
like.
Substituted or unsubstituted (C3_1o)-cycloalkyl halid preferably means
cyclopropyl
chloride, cyclopropyl bromide, cyclopropyl iodide, cyclobutyl chloride,
cyclobutyl bromide,
cyclobutyl iodide, cyclopentyl chloride, cyclopentyl bromide, cyclopentyl
iodide, cyclohexyl
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chloride, cyclohexyl bromide, cyclohexyl iodide, cyclopropyl methyl chloride,
cyclopropyl
methyl bromide, cyclopropyl methyl iodide, cyclobutyl methyl chloride,
cyclobutyl methyl
bromide, cyclobutyl methyl iodide, cyclopentyl methyl chloride, cyclopentyl
methyl bromide,
cyclopeiityi methyl iodide, cyclohexyl methyl chloride, cyclohexyl methyl
bromide, cyclohexyl
5 methyl iodide, or the like.
Substituted or unsubstituted aryl halide preferably means benzyl chloride,
benzyl
bromide, benzyl iodide, benzoyl chloride, benzoyl bromide, benzoyl iodide,
toluyl chloride,
toluyl bromide and toluyl iodide.
Substituted or unsubstituted (C3_1o)-cycloalkyl sulfonate preferably means
cyclopropyl
10 sulfonate, cyclobutyl sulfonate, cyclopentyl sulfonate, cyclohexyl
sulfonate, cyclopropyl methyl
sulfonate, cyclobutyl methyl sulfonate, cyclopentyl methyl sulfonate and
cyclohexyl methyl
sulfonate.
Aryl sulfonate preferably means benzyl sulfonate, benzoyl sulfonate, toluyl
sulfonate, or
the like.
15 The reaction may be carried out in a conventional organic solvent as such
as, for
example, tetrahydrofuran, dichloromethane, chloroform, dimethyl sulfoxide,
acetonitrile and
dimethylformamide.
The conventional inorganic or organic base used in above step may include
sodium
hydride, potassium hydride, sodium hydroxide, potassium hydroxide, sodium
carbonate,
20 potassium carbonate, cesium carbonate, sodium bicarbonate, potassium
bicarbonate,
triethylamine, pyridine and DBU.
In the above reaction process, if any acid material is formed, a basic
material may be
added as a scavenger in order to eliminate the acid material from the reaction
phase. Such basic
material may be alkali metal hydroxide, alkali earth metal hydroxide, alkali
metal oxide, alkali
earth metal oxide, alkali metal carbonate, alkali earth metal carbonate,
alkali metal hydrogen
carbonate, alkali earth metal hydrogen carbonate such as for example, sodium
hydroxide,
potassium hydroxide, calcium hydroxide, magnesium hydroxide, magnesium oxide,
calcium
oxide, potassium carbonate, sodium carbonate, calcium carbonate, magnesium
carbonate,
magnesium bicarbonate, sodium bicarbonate, calcium bicarbonate or the like,
and organic
amines.
R4 or any substituent of R~, RZ, R3, and/or R4, which would undergo unwanted
reactions when
carrying out a synthesis according to scheme I may be protected by a
conventional protecting
group, which is not cleaved during the reactions according to schema I but is
cleavable under
known conditions. The skilled person is aware of a large variety of protection
groups, which can
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21
be employed in organic synthesis. Protecting groups are reviewed in, for
example, Wuts, P.G.M.
and Greene, T.W., Protective Groups in Organic Chemistry, 3`d Ed., 1999; Wily
& Sons Inc. and
in Kocienski, P.J., Protecting groups. 2d Ed., 2000, Thieme Medical
Publishing. Protecting
groups are organized in these reference books according to the functionalities
that are protected
as well as according to the conditions which remove the respective protecting
groups selectively.
Particularly preferred protective groups, which can be used are:
(i) protective group removed at acidic conditions, preferably at a pH between
4 and 6, which
is selected from the group consisting of Boc or Trityl protecting groups;
(ii) a protecting group removed by a nucleophile, which is selected from the
group consisting
of Fmoc or Dde protecting groups;
(iii) a protecting group removed by hydrogenolysis consisting of the allyl
type, the tert-butyl
type, the benzyl type or Dmab (4,4-dimethyl-2,6-dicyclohexylidene)-3-
methylbutyl]-
amino}benzyl ester ;
(iv) a protecting group removed by radiation, which is selected from the group
consisting of
nitroveratryloxy carbonyl, nitrobenzyloxy carbonyl, dimethyl
dimethoxybenzyloxy
carbonyl, 5-bromo-7-nitroindolinyl, o-hydroxy-a-methyl cinnamoyl, and 2-
oxymethylene
anthraquinone.
In a preferred embodiment of the compounds of the invention
Ri is aryl, heteroaryl, aralkyl, or heteroaralkyl optionally substituted
preferably as outlined
above and/or interrupted 1, 2, 3, 4 or more times by 0, N and/or S;
R2 is H, or Ci to C4 alkyl, optionally substituted;
R3 is aryl, heteroaryl, aralkyl, heteroaralkyl, linear or branched C, to C20
alkyl, optionally
substituted as outlined above and/or interrupted 1, 2, 3, 4 or more times by
0, N and/or S;
and
R4 is H, or C1 to C4 alkyl, optionally substituted;
or R3 and R4 together form a heterocycloalkyl ring, optionally substituted,
preferably as outlined
above.
In a further preferred embodiment RI is C3_10 cycloalkyl, preferably
cyclopropyl,
cyclobutyl, cyclopentyl, cyclohexyl, 1-cyclohexenyl, 3-cyclohexenyl,
cycloheptyl,
spiro[3,3]heptyl, spiro[3,4]octyl, spiro[4,3]octyl, spiro[3,5]nonyl,
spiro[5,3]nonyl,
spiro[3,6]decyl, spiro[6,3]decyl, spiro[4,5]decyl, spiro[5,4]decyl,
bicyclo[2.2.1]heptyl,
bicyclo[2.2.2]octyl, or adamantyl.
In a further preferred embodiment of the compound of the present invention
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22
R' is C1-C4 aralkyl, or CI-C4 heteroaralkyl, optionally substituted preferably
with 1, 2, 3, 4
or more substituents selected from the group consisting of halogen, e.g. F,
Cl, Br or I;
CN; NO2; NR'R"; alkyl, in particular Ci-C6 alkyl, e.g. Ci, C2, C3, C4, C5, or
C6 alkyl,
preferabiy methyl, ethyl, propyl, iso-propyl, butyl, iso-butyl, tert-butyl,
pentyl, hexyl;
alkenyl, in particular C2-C6 alkenyl, e.g. C2, C3, C4, C5, or C6 alkenyl,
preferably ethenyl,
1-propenyl, 2-propenyl, 1-iso-propenyl, 2-iso-propenyl, 1-butenyl, 2-butenyl,
3-butenyl;
alkynyl, in particular C2-C6 alkynyl, e.g. C2, C3, C4, C5, or C6 alkynyl;
alkanoyl,
preferably CI-C6 alkanoyl, e.g. Cl, C2, C3, C4, C5, or C6 alkanoyl; alkenoyl,
in particular
C3-C6 alkenoyl, e.g. C3, C4, C5, or C6 alkenoyl, preferably propenoyl;
alkynoyl, in
particular C3-C6 alkynoyl, e.g. C3, C4, C5, or C6 alkynoyl, preferably
propynoyl; alkoxy,
in particular CI-C6 alkoxy, e.g. Cl, C2, C3, C4, C5, or C6 alkoxy, preferably
methoxy,
ethoxy, propoxy, iso-propoxy, butoxy, iso-butoxy, tert-butoxy, pentoxy, or
hexoxy;
alkoxyalkyl, in particular C1-C6 alkoxy-Cl-C6 alkyl, e.g. methoxymethyl,
ethoxymethyl,
propoxymethyl, methoxyethyl, ethoxyethyl, propoxyethyl, methoxypropyl,
ethoxypropyl,
or propoxypropyl; -OOC-R"'; -COO-R""'; aryl, in particular phenyl,
naphthalenyl or
anthracenyl; heteroaryl, in particular furanyl, thiophenyl, oxazolyl,
isoxazolyl, 1,2,5-
oxadiazolyl, 1,2,3-oxadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, 1,2,3-
triazolyl, thiazolyl,
isothiazolyl, 1,2,3,-thiadiazolyl, 1,2,5-thiadiazolyl, pyridinyl, pyrimidinyl,
pyrazinyl,
1,2,3-triazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, 1-benzofuranyl, 2-
benzofuranyl, indolyl,
isoindolyl, benzothiophenyl, 2-benzothiophenyl, 1 H-indazolyl, benzimidazolyl,
benzoxazolyl, indoxazinyl, 2, 1 -benzisoxazolyl, benzothiazolyl, 1,2-
benzisothiazolyl, 2,1-
benzisothiazolyl, benzotriazolyl, quinolinyl, isoquinolinyl, 2,3-
benzodiazinyl,
quinoxalinyl, quinazolinyl, 1,2,3-benzotriazinyl, or 1,2,4-benzotriazinyl;
optionally
substituted, wherein
R' and R" are independent of each other hydrogen; alkyl, in particular CI-C6
alkyl, e.g.
Ci, C2, C3, C4, C5, or C6 alkyl; alkenyl, in particular C2-C6 alkenyl, e.g.
C2, C3, C4,
C5, or C6 alkenyl; alkynyl, in particular C2-C6 alkynyl, e.g. C2, C3, C4, C5,
or C6
alkynyl; aryl; or heteroaryl, in particular furanyl, thiophenyl, oxazolyl,
isoxazolyl,
1,2,5-oxadiazolyl, 1,2,3-oxadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, 1,2,3-
triazolyl, thiazolyl, isothiazolyl, 1,2,3,-thiadiazolyl, 1,2,5-thiadiazolyl,
pyridinyl,
pyrimidinyl, pyrazinyl, 1,2,3-triazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, 1-
benzofuranyl, 2-benzofuranyl, indolyl, isoindolyl, benzothiophenyl, 2-
benzothiophenyl, 1 H-indazolyl, benzimidazolyl, benzoxazolyl, indoxazinyl, 2,1-
benzisoxazolyl, benzothiazolyl, 1,2-benzisothiazolyl, 2, 1 -benzisothiazolyl,
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23
benzotriazolyl, quinolinyl, isoquinolinyl, 2,3-benzodiazinyl, quinoxalinyl,
quinazolinyl, 1,2,3-benzotriazinyl, or 1,2,4-benzotriazinyl; optionally
substituted;
R"' is alkyl, alkenyl, alkynyl, in particular CI-C6 alkyl, e.g. Cl, C2, C3,
C4, C5, or C6
alkyl, optionally substituted; and
R""' is hydrogen, alkyl, alkenyl, alkynyl, in particular CI-C6 alkyl, e.g. C1,
C2, C3, C4,
C5, or C6 alkyl, optionally substituted;
and
R3 and R4 together form a heterocycloalkyl ring, optionally substituted
preferably with 1, 2, 3, 4
or more substituents selected from the group consisting of halogen, e.g. F,
Cl, Br or I;
CN; NO2; NR'R"; alkyl, in particular C1-C6 alkyl, e.g. C1, C2, C3, C4, C5, or
C6 alkyl,
preferably methyl, ethyl, propyl, iso-propyl, butyl, iso-butyl, tert-butyl,
pentyl, hexyl;
alkenyl, in particular C2-C6 alkenyl, e.g. C2, C3, C4, C5, or C6 alkenyl,
preferably ethenyl,
1-propenyl, 2-propenyl, 1-iso-propenyl, 2-iso-propenyl, 1-butenyl, 2-butenyl,
3-butenyl;
alkynyl, in particular C2-C6 alkynyl, e.g. C2, C3, C4, C5, or C6 alkynyl;
alkanoyl,
preferably Ci-C6 alkanoyl, e.g. Cl, C2, C3, C4, C5, or C6 alkanoyl; alkenoyl,
in particular
C3-C6 alkenoyl, e.g. C3, C4, C5, or C6 alkenoyl, preferably propenoyl;
alkynoyl, in
particular C3-C6 alkynoyl, e.g. C3, C4, C5, or C6 alkynoyl, preferably
propynoyl; alkoxy,
in particular Ci-C6 alkoxy, e.g. C1, C2, C3, C4, C5, or C6 alkoxy, preferably
methoxy,
ethoxy, propoxy, iso-propoxy, butoxy, iso-butoxy, tert-butoxy, pentoxy, or
hexoxy;
alkoxyalkyl, in particular C1-C6 alkoxy-Cl-C6 alkyl, e.g. methoxymethyl,
ethoxymethyl,
propoxymethyl, methoxyethyl, ethoxyethyl, propoxyethyl, methoxypropyl,
ethoxypropyl,
or propoxypropyl; -OOC-R"'; -COO-R""'; aryl, in particular phenyl,
naphthalenyl or
anthracenyl; heteroaryl, in particular furanyl, thiophenyl, oxazolyl,
isoxazolyl, 1,2,5-
oxadiazolyl, 1,2,3-oxadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, 1,2,3-
triazolyl, thiazolyl,
isothiazolyl, 1,2,3,-thiadiazolyl, 1,2,5-thiadiazolyl, pyridinyl, pyrimidinyl,
pyrazinyl,
1,2,3-triazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, 1-benzofuranyl, 2-
benzofuranyl, indolyl,
isoindolyl, benzothiophenyl, 2-benzothiophenyl, 1 H-indazolyl, benzimidazolyl,
benzoxazolyl, indoxazinyl, 2, 1 -benzisoxazolyl, benzothiazolyl, 1,2-
benzisothiazolyl, 2,1-
benzisothiazolyl, benzotriazolyl, quinolinyl, isoquinolinyl, 2,3-
benzodiazinyl,
quinoxalinyl, quinazolinyl, 1,2,3-benzotriazinyl, or 1,2,4-benzotriazinyl;
optionally
substituted, wherein
R' and R" are independent of each other hydrogen; alkyl, in particular C1-C6
alkyl, e.g.
Ci, C2, C3, C4, C5, or C6 alkyl; alkenyl, in particular C2-C6 alkenyl, e.g.
C2, C3, C4,
C5, or C6 alkenyl; alkynyl, in particular C2-C6 alkynyl, e.g. C2, C3, C4, C5,
or C6
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24
alkynyl; aryl; or heteroaryl, in particular furanyl, thiophenyl, oxazolyl,
isoxazolyl,
1,2,5-oxadiazolyl, 1,2,3-oxadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, 1,2,3-
triazolyl, thiazolyl, isothiazolyl, 1,2,3,-thiadiazolyl, 1,2,5-thiadiazolyl,
pyridinyl,
pyrimidinyl, pyrazinyl, 1,2,3-triazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, 1-
benzofuranyl, 2-benzofuranyl, indolyl, isoindolyl, benzothiophenyl, 2-
benzothiophenyl, 1 H-indazolyl, benzimidazolyl, benzoxazolyl, indoxazinyl, 2,1-
benzisoxazolyl, benzothiazolyl, 1,2-benzisothiazolyl, 2,1 -benzisothiazolyl,
benzotriazolyl, quinolinyl, isoquinolinyl, 2,3-benzodiazinyl, quinoxalinyl,
quinazolinyl, 1,2,3-benzotriazinyl, or 1,2,4-benzotriazinyl; optionally
substituted;
R"' is alkyl, alkenyl, alkynyl, in particular Ci-C6 alkyl, e.g. Ci, C2, C3,
C4, C5, or C6
alkyl;
R""' is hydrogen, alkyl, alkenyl, alkynyl, in particular CI-C6 alkyl, e.g. Ci,
C2, C3, C4,
C5, or C6 alkyl, optionally substituted.
In a preferred embodiment of the compound of the present invention
R' is aryl; optionally substituted, preferably with 1, 2, 3, 4 or more
substituents selected
from the group consisting of halogen, e.g. F, Cl, Br or I; CN; NO2; NR'R";
alkyl, in
particular CI-C6 alkyl, e.g. C1, C2, C3, C4, C5, or C6 alkyl, preferably
methyl, ethyl,
propyl, iso-propyl, butyl, iso-butyl, tert-butyl, pentyl, hexyl; alkenyl, in
particular C2-C6
alkenyl, e.g. C2, C3, C4, C5, or C6 alkenyl, preferably ethenyl, 1-propenyl, 2-
propenyl, 1-
iso-propenyl, 2-iso-propenyl, 1-butenyl, 2-butenyl, 3-butenyl; alkynyl, in
particular C2-C6
alkynyl, e.g. C2, C3, C4, C5, or C6 alkynyl; alkanoyl, preferably Cj-C6
alkanoyl, e.g. Cl,
C2, C3, C4, C5, or C6 alkanoyl; alkenoyl, in particular C3-C6 alkenoyl, e.g.
C3, C4, C5, or
C6 alkenoyl, preferably propenoyl; alkynoyl, in particular C3-C6 alkynoyl,
e.g. C3, C4, C5,
or C6 alkynoyl, preferably propynoyl; alkoxy, in particular CI-C6 alkoxy, e.g.
Cl, C2, C3,
C4, C5, or C6 alkoxy, preferably methoxy, ethoxy, propoxy, iso-propoxy,
butoxy, iso-
butoxy, tert-butoxy, pentoxy, or hexoxy; alkoxyalkyl, in particular Ci-C6
alkoxy-Cl-C6
alkyl, e.g. methoxymethyl, ethoxymethyl, propoxymethyl, methoxyethyl,
ethoxyethyl,
propoxyethyl, methoxypropyl, ethoxypropyl, or propoxypropyl; -OOC-R"'; -COO-
R""'; aryl, in particular phenyl, naphthalenyl or anthracenyl; heteroaryl, in
particular
furanyl, thiophenyl, oxazolyl, isoxazolyl, 1,2,5-oxadiazolyl, 1,2,3-
oxadiazolyl, pyrrolyl,
imidazolyl, pyrazolyl, 1,2,3-triazolyl, thiazolyl, isothiazolyl, 1,2,3,-
thiadiazolyl, 1,2,5-
thiadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, 1,2,3-triazinyl, 1,2,4-
triazinyl, 1,3,5-
triazinyl, 1-benzofuranyl, 2-benzofuranyl, indolyl, isoindolyl,
benzothiophenyl, 2-
benzothiophenyl, 1 H-indazolyl, benzimidazolyl, benzoxazolyl, indoxazinyl, 2,1-
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benzisoxazolyl, benzothiazolyl, 1,2-benzisothiazolyl, 2, 1 -benzisothiazolyl,
benzotriazolyl, quinolinyl, isoquinolinyl, 2,3-benzodiazinyl, quinoxalinyl,
quinazolinyl,
1,2,3-benzotriazinyl, or 1,2,4-benzotriazinyl; optionally substituted, wherein
R' and R" are independent of each other hydrogen; alkyl, in particular Ci-C6
alkyl, e.g.
5 Cl, C2, C3, C4, C5, or C6 alkyl; alkenyl, in particular C2-C6 alkenyl, e.g.
C2, C3, C4,
C5, or C6 alkenyl; alkynyl, in particular C2-C6 alkynyl, e.g. C2, C3, C4, C5,
or C6
alkynyl; aryl; or heteroaryl, in particular furanyl, thiophenyl, oxazolyl,
isoxazolyl,
1,2,5-oxadiazolyl, 1,2,3-oxadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, 1,2,3-
triazolyl, thiazolyl, isothiazolyl, 1,2,3,-thiadiazolyl, 1,2,5-thiadiazolyl,
pyridinyl,
10 pyrimidinyl, pyrazinyl, 1,2,3-triazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl,
1-
benzofuranyl, 2-benzofuranyl, indolyl, isoindolyl, benzothiophenyl, 2-
benzothiophenyl, 1 H-indazolyl, benzimidazolyl, benzoxazolyl, indoxazinyl, 2,1-
benzisoxazolyl, benzothiazolyl, 1,2-benzisothiazolyl, 2, 1 -benzisothiazolyl,
benzotriazolyl, quinolinyl, isoquinolinyl, 2,3-benzodiazinyl, quinoxalinyl,
15 quinazolinyl, 1,2,3-benzotriazinyl, or 1,2,4-benzotriazinyl; optionally
substituted;
R"' is alkyl, alkenyl, alkynyl, in particular CI-C6 alkyl, e.g. Ci, C2, C3,
C4, C5, or C6
alkyl; and
R""' is hydrogen, alkyl, alkenyl, alkynyl, in particular Ci-C6 alkyl, e.g. Cl,
C2, C3, C4,
C5, or C6 alkyl, optionally substituted;
20 and
R3 and R4 together form a heterocycloalkyl ring, optionally substituted
preferably with 1, 2, 3, 4
or more substituents selected from the group consisting of halogen, e.g. F,
Cl, Br or I;
CN; NO2; NR'R"; alkyl, in particular C1-C6 alkyl, e.g. Cl, C2, C3, C4, C5, or
C6 alkyl,
preferably methyl, ethyl, propyl, iso-propyl, butyl, iso-butyl, tert-butyl,
pentyl, hexyl;
25 alkenyl, in particular C2-C6 alkenyl, e.g. C2, C3, C4, C5, or C6 alkenyl,
preferably ethenyl,
1-propenyl, 2-propenyl, 1-iso-propenyl, 2-iso-propenyl, 1-butenyl, 2-butenyl,
3-butenyl;
alkynyl, in particular C2-C6 alkynyl, e.g. C2, C3, C4, C5, or C6 alkynyl;
alkanoyl,
preferably C i-C6 alkanoyl, e.g. C i, C2, C3, C4, C5, or C6 alkanoyl;
alkenoyl, in particular
C3-C6 alkenoyl, e.g. C3, C4, C5, or C6 alkenoyl, preferably propenoyl;
alkynoyl, in
particular C3-C6 alkynoyl, e.g. C3, C4, C5, or C6 alkynoyl, preferably
propynoyl; alkoxy,
in particular Ci-C6 alkoxy, e.g. Ci, C2, C3, C4, C5, or C6 alkoxy, preferably
methoxy,
ethoxy, propoxy, iso-propoxy, butoxy, iso-butoxy, tert-butoxy, pentoxy, or
hexoxy;
alkoxyalkyl, in particular CI-C6 alkoxy-Cl-C6 alkyl, e.g. methoxymethyl,
ethoxymethyl,
propoxymethyl, methoxyethyl, ethoxyethyl, propoxyethyl, methoxypropyl,
ethoxypropyl,
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26
or propoxypropyl; -OOC-R"'; -COO-R""'; aryl, in particular phenyl,
naphthalenyl or
anthracenyl; heteroaryl, in particular furanyl, thiophenyl, oxazolyl,
isoxazolyl, 1,2,5-
oxadiazolyl, 1,2,3-oxadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, 1,2,3-
triazolyl, thiazolyl,
isotl-iiazolyl, 1,2,3,-thiadiazolyl, 1,2,5-thiadiazolyl, pyridinyl,
pyrimidinyl, pyrazinyl,
1,2,3-triazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, 1-benzofuranyl, 2-
benzofuranyl, indolyl,
isoindolyl, benzothiophenyl, 2-benzothiophenyl, 1 H-indazolyl, benzimidazolyl,
benzoxazolyl, indoxazinyl, 2,1-benzisoxazolyl, benzothiazolyl, 1,2-
benzisothiazolyl, 2,1-
benzisothiazolyl, benzotriazolyl, quinolinyl, isoquinolinyl, 2,3-
benzodiazinyl,
quinoxalinyl, quinazolinyl, 1,2,3-benzotriazinyl, or 1,2,4-benzotriazinyl;
optionally
substituted, wherein
R' and R" are independent of each other hydrogen; alkyl, in particular CI-C6
alkyl, e.g.
Cl, C2, C3, C4, C5, or C6 alkyl; alkenyl, in particular C2-C6 alkenyl, e.g.
C2, C3, C4,
C5, or C6 alkenyl; alkynyl, in particular C2-C6 alkynyl, e.g. C2, C3, C4, C5,
or C6
alkynyl; aryl; or heteroaryl, in particular furanyl, thiophenyl, oxazolyl,
isoxazolyl,
1,2,5-oxadiazolyl, 1,2,3-oxadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, 1,2,3-
triazolyl, thiazolyl, isothiazolyl, 1,2,3,-thiadiazolyl, 1,2,5-thiadiazolyl,
pyridinyl,
pyrimidinyl, pyrazinyl, 1,2,3-triazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, 1-
benzofuranyl, 2-benzofuranyl, indolyl, isoindolyl, benzothiophenyl, 2-
benzothiophenyl, 1 H-indazolyl, benzimidazolyl, benzoxazolyl, indoxazinyl, 2,1-
benzisoxazolyl, benzothiazolyl, 1,2-benzisothiazolyl, 2,1 -benzisothiazolyl,
benzotriazolyl, quinolinyl, isoquinolinyl, 2,3-benzodiazinyl, quinoxalinyl,
quinazolinyl, 1,2,3-benzotriazinyl, or 1,2,4-benzotriazinyl; optionally
substituted;
R"' is alkyl, alkenyl, alkynyl, in particular C1-C6 alkyl, e.g. C1, C2, C3,
C4, C5, or C6
alkyl; and
R""' is hydrogen, alkyl, alkenyl, alkynyl, in particular C]-C6 alkyl, e.g. Cl,
C2, C3, C4,
C5, or C6 alkyl, optionally substituted.
In a preferred embodiment of the compound of the present invention
R 2 is H or Ci to C4 alkyl, e.g. Cl, C2, C3, or C4 alkyl, preferably methyl,
ethyl, propyl, iso-
propyl, butyl, iso-butyl, or tert-butyl. R2 has this preferred meaning in
particular in the
context of the preferred meanings of R1, R3, and/or R4 as outlined above.
In a preferred embodiment of the compound of the present invention the terms
aralkyl
and heteroaralkyl, in particular if used to indicate the meaning of R' and/or
R3 or of a substituent
thereof, have the following preferred meanings:
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27
(i) aralkyl preferably is benzyl, (1-napthyl) methyl, (2-napthyl) methyl,
phenyl ethyl, (1-
napthyl) ethyl, (2-napthyl) ethyl, phenyl propyl, (1-napthyl) propyl, (2-
napthyl) propyl
optionally substituted at the alkyl and/or aryl moiety, preferably with 1, 2,
3, 4 or more
substituents selected from the group consisting of halogen, e.g. F, Cl, Br or
I; CN; NOZ;
NR'R"; alkyl, in particular Ci-C6 alkyl, e.g. C1, C2, C3, C4, C5, or C6 alkyl,
preferably
methyl, ethyl, propyl, iso-propyl, butyl, iso-butyl, tert-butyl, pentyl,
hexyl; alkenyl, in
particular C2-C6 alkenyl, e.g. C2, C3, C4, C5, or C6 alkenyl, preferably
ethenyl, 1-propenyl,
2-propenyl, 1-iso-propenyl, 2-iso-propenyl, 1-butenyl, 2-butenyl, 3-butenyl;
alkynyl, in
particular C2-C6 alkynyl, e.g. C2, C3, C4, C5, or C6 alkynyl; alkanoyl,
preferably Ci-C6
alkanoyl, e.g. Ci, C2, C3, C4, C5, or C6 alkanoyl; alkenoyl, in particular C3-
C6 alkenoyl,
e.g. C3, C4, C5, or C6 alkenoyl, preferably propenoyl; alkynoyl, in particular
C3-C6
alkynoyl, e.g. C3, C4, C5, or C6 alkynoyl, preferably propynoyl; alkoxy, in
particular Ci-
C6 alkoxy, e.g. C1, C2, C3, C4, C5, or C6 alkoxy, preferably methoxy, ethoxy,
propoxy,
iso-propoxy, butoxy, iso-butoxy, tert-butoxy, pentoxy, or hexoxy; alkoxyalkyl,
in
particular Ci-C6 alkoxy-Ci-C6 alkyl, e.g. methoxymethyl, ethoxymethyl,
propoxymethyl,
methoxyethyl, ethoxyethyl, propoxyethyl, methoxypropyl, ethoxypropyl, or
propoxypropyl; -OOC-R"'; -COO-R""'; aryl, in particular phenyl, naphthalenyl
or
anthracenyl; heteroaryl, in particular furanyl, thiophenyl, oxazolyl,
isoxazolyl, 1,2,5-
oxadiazolyl, 1,2,3-oxadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, 1,2,3-
triazolyl, thiazolyl,
isothiazolyl, 1,2,3,-thiadiazolyl, 1,2,5-thiadiazolyl, pyridinyl, pyrimidinyl,
pyrazinyl,
1,2,3-triazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, 1-benzofuranyl, 2-
benzofuranyl, indolyl,
isoindolyl, benzothiophenyl, 2-benzothiophenyl, 1 H-indazolyl, benzimidazolyl,
benzoxazolyl, indoxazinyl, 2, 1 -benzisoxazolyl, benzothiazolyl, 1,2-
benzisothiazolyl, 2,1-
benzisothiazolyl, benzotriazolyl, quinolinyl, isoquinolinyl, 2,3-
benzodiazinyl,
quinoxalinyl, quinazolinyl, 1,2,3-benzotriazinyl, or 1,2,4-benzotriazinyl;
optionally
substituted, wherein
R' and R" are independent of each other hydrogen; alkyl, in particular Ci-C6
alkyl, e.g.
Cl, C2, C3, C4, C5, or C6 alkyl; alkenyl, in particular C2-C6 alkenyl, e.g.
C2, C3, C4,
C5, or C6 alkenyl; alkynyl, in particular C2-C6 alkynyl, e.g. C2, C3, C4, C5,
or C6
alkynyl; aryl; or heteroaryl, in particular furanyl, thiophenyl, oxazolyl,
isoxazolyl,
1,2,5-oxadiazolyl, 1,2,3-oxadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, 1,2,3-
triazolyl, thiazolyl, isothiazolyl, 1,2,3,-thiadiazolyl, 1,2,5-thiadiazolyl,
pyridinyl,
pyrimidinyl, pyrazinyl, 1,2,3-triazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, 1-
benzofuranyl, 2-benzofuranyl, indolyl, isoindolyl, benzothiophenyl, 2-
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benzothiophenyl, 1 H-indazolyl, benzimidazolyl, benzoxazolyl, indoxazinyl, 2,1-
benzisoxazolyl, benzothiazolyl, 1,2-benzisothiazolyl, 2,1-benzisothiazolyl,
benzotriazolyl, quinolinyl, isoquinolinyl, 2,3-benzodiazinyl, quinoxalinyl,
quinazolinyl, 1,2,3-benzotriazinyl, or 1,2,4-benzotriazinyl; optionally
substituted;
R"' is alkyl, alkenyl, alkynyl, in particular Ci-C6 alkyl, e.g. Cl, C2, C3,
C4, C5, or C6
alkyl, optionally substituted; and
R""' is hydrogen, alkyl, alkenyl, alkynyl, in particular Ci-C6 alkyl, e.g. Cl,
C2, C3, C4,
C5, or C6 alkyl, optionally substituted;
and the
heteroaralkyl preferably is (2-furanyl) methyl, (3-furanyl) methyl, (2-
furanyl) ethyl, (3-furanyl)
ethyl, (2-oxazolyl) methyl, (4-oxazolyl) methyl, (5-oxazolyl) methyl, (2-
oxazolyl) ethyl,
(4-oxazolyl) ethyl, (5-oxazolyl) ethyl, (2-isoxazolyl) methyl, (3-isoxazolyl)
methyl, (4-
isoxazolyl) methyl, (2-isoxazolyl) ethyl, ethyl (3-isoxazolyl), ethyl (4-
isoxazolyl), (3-
(1,2,5-oxadiazolyl)) methyl, (4-(1,2,5-oxadiazolyl)) methyl, (3-(1,2,5-
oxadiazolyl)) ethyl,
(4-(1,2,5-oxadiazolyl)) ethyl, (4-(1,2,3-oxadiazolyl)) methyl, (5-(1,2,3-
oxadiazolyl))
methyl, (4-(1,2,3-oxadiazolyl)) ethyl, (5-(1,2,3-oxadiazolyl)) ethyl, (2-
pyrrolyl) methyl,
(3-pyrrolyl) methyl, (2-pyrrolyl) ethyl, (3-pyrrolyl) ethyl, (2-imidazolyl)
methyl, (4-
imidazolyl) methyl, (2-imidazolyl) ethyl, (4-imidazolyl) ethyl, (3-pyrazolyl)
methyl, (4-
pyrazolyl) methyl, (3-pyrazolyl) ethyl, (4-pyrazolyl) ethyl, (4-(1,2,3-
triazolyl) methyl, (4-
(1,2,3-triazolyl) ethyl, (3-(1,2,4-triazolyl) methyl, (3-(1,2,4-triazolyl)
ethyl, (2-
thiophenyl) methyl, (3-thiophenyl) methyl, (2-thiophenyl) ethyl, (3-
thiophenyl) ethyl, (2-
thiazolyl) methyl, (4-thiazolyl) methyl, (5-thiazolyl) methyl, (2-thiazolyl)
ethyl, (4-
thiazolyl) ethyl, (5-thiazolyl) ethyl, (3-isothiazolyl) methyl, (4-
isothiazolyl) methyl, (5-
isothiazolyl) methyl, (3-isothiazolyl) ethyl, (4-isothiazolyl) ethyl, (5-
isothiazolyl) ethyl,
(4-(1,2,3,-thiadiazolyl)) methyl, (5-(1,2,3,-thiadiazolyl)) methyl, (4-(1,2,3,-
thiadiazolyl))
ethyl, (5-(1,2,3,-thiadiazolyl)) ethyl, (3-(1,2,5-thiadiazolyl)), (3-(1,2,5-
thiadiazolyl))
ethyl, (2-pyridinyl) methyl, (3-pyridinyl) methyl, (4-pyridinyl) methyl, (2-
pyridinyl)
ethyl, (3-pyridinyl) ethyl, (4-pyridinyl) ethyl, (2-pyrimidinyl) methyl, (4-
pyrimidinyl)
methyl, (5-pyrimidinyl) methyl, (2-pyrimidinyl) ethyl, (4-pyrimidinyl) ethyl,
(5-
pyrimidinyl) ethyl, (2-pyrazinyl) methyl, (3-pyrazinyl) methyl, (2-pyrazinyl)
ethyl, (3-
pyrazinyl) ethyl, (4-(1,2,3-triazinyl) methyl, (5-(1,2,3-triazinyl)) methyl,
(4-(1,2,3-
triazinyl)) ethyl, (5-(1,2,3-triazinyl)) ethyl, (3-(1,2,4-triazinyl)) methyl,
(5-(1,2,4-
triazinyl)) methyl, (6-(1,2,4-triazinyl)) methyl, (3-(1,2,4-triazinyl)) ethyl,
(5-(1,2,4-
triazinyl)) ethyl, (6-(1,2,4-triazinyl)) ethyl, (2-(1,3,5-triazinyl) methyl,
(2-(1,3,5-triazinyl)
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ethyl, (2-(1-benzofuranyl)) methyl, (3-(1-benzofuranyl)) methyl, (4-(1-
benzofuranyl))
methyl, (6-(1-benzofuranyl)) methyl, (7-(1-benzofuranyl)) methyl, (2-(1-
benzofuranyl))
ethyl, (3-(1-benzofuranyl)) ethyl, (4-(1-benzofuranyl)) ethyl, (6-(1-
benzofuranyl)) ethyl,
(7-( i-benzoiuranyl)) methyl, (4-(1-benzofuranyl)) ethyl, (1-(2-benzofuranyl))
methyl, (4-
(2-benzofuranyl)) methyl, (5-(2-benzofuranyl)) methyl, (1-(2-benzoftiranyl))
ethyl, (4-(2-
benzofuranyl)) ethyl, (5-(2-benzofuranyl)) ethyl, (2-indolyl) methyl, (3-
indolyl) methyl,
(4-indolyl) methyl, (5-indolyl) methyl, (6-indolyl) methyl, (7-indolyl)
methyl, (2-indolyl)
ethyl, (3-indolyl) ethyl, ethyl (4-indolyl), ethyl (5-indolyl), ethyl (6-
indolyl), ethyl (7-
indolyl), methyl (1-isoindolyl), (4-isoindolyl) methyl, (5-isoindolyl) methyl,
(1-
isoindolyl) ethyl, (4-isoindolyl) ethyl, (5-isoindolyl) ethyl, (2-(1-
benzothiophenyl))
methyl, (3-(1-benzothiophenyl)) methyl, (4-(1-benzothiophenyl)) methyl, (6-(1-
benzothiophenyl)) methyl, (7-(1-benzothiophenyl)) methyl, (2-(1-
benzothiophenyl))
ethyl, (3 -(1 -benzothiophenyl)) ethyl, (4-(1-benzothiophenyl)) ethyl, (6-(1-
benzothiophenyl)) ethyl, (7-(1-benzothiophenyl)) methyl, (1-(2-
benzothiophenyl))
methyl, (4-(2-benzothiophenyl)) methyl, (5-(2-benzothiophenyl)) methyl, (1-(2-
benzothiophenyl)) ethyl, (4-(2-benzothiophenyl)) ethyl, (5-(2-
benzothiophenyl)) ethyl,
(1-indazolyl) methyl, (4-(1 H-indazolyl)) methyl, (5-(1 H-indazolyl)) methyl,
(6-(1 H-
indazolyl)) methyl, (7-(1 H-indazolyl)) methyl, (1-indazolyl) ethyl, (4-(1 H-
indazolyl))
ethyl, (5-(1H-indazolyl)) ethyl, (6-(1H-indazolyl)) ethyl, (7-(1H-indazolyl))
ethyl, (2-
benzimidazolyl) methyl, (4-benzimidazolyl) methyl, (5-benzimidazolyl) methyl,
(2-
benzimidazolyl) ethyl, (4-benzimidazolyl) ethyl, (5-benzimidazolyl) ethyl, (2-
benzoxazolyl) methyl, (4-benzoxazolyl) methyl, (5-benzoxazolyl) methyl, (6-
benzoxazolyl) methyl, (7-benzoxazolyl) methyl, (2-benzoxazolyl) ethyl, (4-
benzoxazolyl)
ethyl, (5-benzoxazolyl) ethyl, (6-benzoxazolyl) ethyl, (7-benzoxazolyl) ethyl,
(3-
indoxazinyl) methyl, (4-indoxazinyl) methyl, (5-indoxazinyl) methyl, (6-
indoxazinyl)
methyl, (7-indoxazinyl) methyl, (3-indoxazinyl) ethyl, (4-indoxazinyl) ethyl,
(5-
indoxazinyl) ethyl, (6-indoxazinyl) ethyl, (7-indoxazinyl) ethyl, (3-(2,1-
benzoxazolyl))
methyl, (4-(2,1-benzoxazolyl)) methyl, (5-(2,1-benzoxazolyl)) methyl, (6-(2,1-
benzoxazolyl)) methyl, (7-(2,1-benzoxazolyl)) methyl, (3-(2,1-benzoxazolyl))
ethyl, (4-
(2,1-benzoxazolyl)) ethyl, (5-(2,1-benzoxazolyl)) ethyl, (6-(2,1-
benzoxazolyl)) ethyl, (7-
(2,1-benzoxazolyl)) ethyl, (2-benzothiazolyl) methyl, (4-benzothiazolyl)
methyl, (5-
benzothiazolyl) methyl, (6-benzothiazolyl) methyl, (7-benzothiazolyl) methyl,
(2-
benzothiazolyl) ethyl, (4-benzothiazolyl) ethyl, (5-benzothiazolyl) ethyl, (6-
benzothiazolyl) ethyl, (7-benzothiazolyl) ethyl, (3-(1,2-benzisothiazolyl))
methyl, (4-(1,2-
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benzisothiazolyl)) methyl, (5-(1,2-benzisothiazolyl)) methyl, (6-(1,2-
benzisothiazolyl))
methyl, (7-(1,2-benzisothiazolyl)) methyl, (3-(1,2-benzisothiazolyl)) ethyl,
(4-(1,2-
benzisothiazolyl)) ethyl, (5-(1,2-benzisothiazolyl)) ethyl, (6-(1,2-
benzisothiazolyl)) ethyl,
(7-(1,2-benzisoihiazoiyi)) ethyl, (3-(2,1-benzisothiazolyl)) methyl, (4-(2,1-
5 benzisothiazolyl)) methyl, (5-(2,1-benzisothiazolyl)) methyl, (6-(2,1-
benzisothiazolyl))
methyl, (7-(2,1-benzisothiazolyl)) methyl, (3-(2,1-benzisothiazolyl)) ethyl,
(4-(2,1-
benzisothiazolyl)) ethyl, (5-(2,1-benzisothiazolyl)) ethyl, (6-(2,1-
benzisothiazolyl)) ethyl,
(7-(2,1-benzisothiazolyl)) ethyl, (4-benzotriazolyl) methyl, (5-
benzotriazolyl) methyl, (4-
benzotriazolyl) ethyl, (5-benzotriazolyl) ethyl, (2-quinolinyl) methyl, (3-
quinolinyl)
10 methyl, (4-quinolinyl) methyl, (5-quinolinyl) methyl, (7-quinolinyl)
methyl, (8-
quinolinyl) methyl, (2-quinolinyl) ethyl, (3-quinolinyl) ethyl, (4-quinolinyl)
ethyl, (5-
quinolinyl) ethyl, (7-quinolinyl) ethyl, (8-quinolinyl) ethyl, (1-
isoquinolinyl) methyl, (3-
isoquinolinyl) methyl, (4-isoquinolinyl) methyl, (5-isoquinolinyl) methyl, (6-
isoquinolinyl) methyl, (7-isoquinolinyl) methyl, (8-isoquinolinyl) methyl, (1-
15 isoquinolinyl) ethyl, (3-isoquinolinyl) ethyl, (4-isoquinolinyl) ethyl, (5-
isoquinolinyl)
ethyl, (6-isoquinolinyl) ethyl, (7-isoquinolinyl) ethyl, (8-isoquinolinyl)
ethyl, (1-(2,3-
benzodiazinyl)) methyl, (4-(2,3-benzodiazinyl)) methyl, (5-(2,3-
benzodiazinyl)) methyl,
(6-(2,3-benzodiazinyl)) methyl, (7-(2,3-benzodiazinyl)) methyl, (8-(2,3-
benzodiazinyl))
methyl, (1-(2,3-benzodiazinyl)) ethyl, (4-(2,3-benzodiazinyl)) ethyl, (5-(2,3-
20 benzodiazinyl)) ethyl, (6-(2,3-benzodiazinyl)) ethyl, (7-(2,3-
benzodiazinyl)) ethyl, (8-
(2,3-benzodiazinyl)) ethyl, (2-quinoxalinyl) methyl, (3-quinoxalinyl) methyl,
(5-
quinoxalinyl) methyl, (6-quinoxalinyl) methyl, (2-quinoxalinyl) ethyl, (3-
quinoxalinyl)
ethyl, (5-quinoxalinyl) ethyl, (6-quinoxalinyl) ethyl, (2-quinazolinyl)
methyl, (4-
quinazolinyl) methyl, (5-quinazolinyl) methyl, (6-quinazolinyl) methyl, (7-
quinazolinyl)
25 methyl, (8-quinazolinyl) methyl, (2-quinazolinyl) ethyl, (4-quinazolinyl)
ethyl, (5-
quinazolinyl) ethyl, (6-quinazolinyl) ethyl, (7-quinazolinyl) ethyl, (8-
quinazolinyl) ethyl,
(4-(1,2,3-benzotriazinyl)) methyl, (5-(1,2,3-benzotriazinyl)) methyl, (6-
(1,2,3-
benzotriazinyl)) methyl, (7-(1,2,3-benzotriazinyl)) methyl, (8-(1,2,3-
benzotriazinyl))
methyl, (4-(1,2,3-benzotriazinyl)) ethyl, (5-(1,2,3-benzotriazinyl)) ethyl, (6-
(1,2,3-
30 benzotriazinyl)) ethyl, (7-(1,2,3-benzotriazinyl)) ethyl, (8-(1,2,3-
benzotriazinyl)) ethyl,
(3-(1,2,4-benzotriazinyl)) methyl, (5-(1,2,4-benzotriazinyl)) methyl, (6-
(1,2,4-
benzotriazinyl)) methyl, (7-(1,2,4-benzotriazinyl)) methyl, (8-(1,2,4-
benzotriazinyl))
methyl, (3-(1,2,4-benzotriazinyl)) ethyl, (5-(1,2,4-benzotriazinyl)) ethyl, (6-
(1,2,4-
benzotriazinyl)) ethyl, (7-(1,2,4-benzotriazinyl)) ethyl, or (8-(1,2,4-
benzotriazinyl)) ethyl,
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optionally substituted preferably with 1, 2, 3, 4 or more substituents
selected from the
group consisting of halogen, e.g. F, Cl, Br or I; CN; NO2; NR'R"; alkyl, in
particular Cl-
C6 alkyl, e.g. Cl, C2, C3, C4, C5, or C6 alkyl, preferably methyl, ethyl,
propyl, iso-propyl,
butyl, iso-butyi, tert-butyl, pentyl, hexyl; alkenyl, in particular C2-C6
alkenyl, e.g. C2, C3,
C4, C5, or C6 alkenyl, preferably ethenyl, 1-propenyl, 2-propenyl, 1-iso-
propenyl, 2-iso-
propenyl, 1-butenyl, 2-butenyl, 3-butenyl; alkynyl, in particular C2-C6
alkynyl, e.g. C2,
C3, C4, C5, or C6 alkynyl; alkanoyl, preferably CI-C6 alkanoyl, e.g. Cl, C2,
C3, C4, C5, or
C6 alkanoyl; alkenoyl, in particular C3-C6 alkenoyl, e.g. C3, C4, C5, or C6
alkenoyl,
preferably propenoyl; alkynoyl, in particular C3-C6 alkynoyl, e.g. C3, C4, C5,
or C6
alkynoyl, preferably propynoyl; alkoxy, in particular C1-C6 alkoxy, e.g. C1,
C2, C3, C4,
C5, or C6 alkoxy, preferably methoxy, ethoxy, propoxy, iso-propoxy, butoxy,
iso-butoxy,
tert-butoxy, pentoxy, or hexoxy; alkoxyalkyl, in particular C1-C6 alkoxy-Cl-C6
alkyl, e.g.
methoxymethyl, ethoxymethyl, propoxymethyl, methoxyethyl, ethoxyethyl,
propoxyethyl, methoxypropyl, ethoxypropyl, or propoxypropyl; -OOC-R"'; -
COOR""';
aryl, in particular phenyl, naphthalenyl or anthracenyl; heteroaryl, in
particular furanyl,
thiophenyl, oxazolyl, isoxazolyl, 1,2,5-oxadiazolyl, 1,2,3-oxadiazolyl,
pyrrolyl,
imidazolyl, pyrazolyl, 1,2,3-triazolyl, thiazolyl, isothiazolyl, 1,2,3,-
thiadiazolyl, 1,2,5-
thiadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, 1,2,3-triazinyl, 1,2,4-
triazinyl, 1,3,5-
triazinyl, 1-benzofuranyl, 2-benzofuranyl, indolyl, isoindolyl,
benzothiophenyl, 2-
benzothiophenyl, 1 H-indazolyl, benzimidazolyl, benzoxazolyl, indoxazinyl, 2,1-
benzisoxazolyl, benzothiazolyl, 1,2-benzisothiazolyl, 2, 1 -benzisothiazolyl,
benzotriazolyl, quinolinyl, isoquinolinyl, 2,3-benzodiazinyl, quinoxalinyl,
quinazolinyl,
1,2,3-benzotriazinyl, or 1,2,4-benzotriazinyl; optionally substituted, wherein
R' and R" are independent of each other hydrogen; alkyl, in particular C1-C6
alkyl, e.g.
Cl, C2, C3, C4, C5, or C6 alkyl; alkenyl, in particular C2-C6 alkenyl, e.g.
C2, C3, C4,
C5, or C6 alkenyl; alkynyl, in particular C2-C6 alkynyl, e.g. C2, C3, C4, C5,
or C6
alkynyl; aryl; or heteroaryl, in particular furanyl, thiophenyl, oxazolyl,
isoxazolyl,
1,2,5-oxadiazolyl, 1,2,3-oxadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, 1,2,3-
triazolyl, thiazolyl, isothiazolyl, 1,2,3,-thiadiazolyl, 1,2,5-thiadiazolyl,
pyridinyl,
pyrimidinyl, pyrazinyl, 1,2,3-triazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, 1-
benzofuranyl, 2-benzofuranyl, indolyl, isoindolyl, benzothiophenyl, 2-
benzothiophenyl, 1 H-indazolyl, benzimidazolyl, benzoxazolyl, indoxazinyl, 2,1-
benzisoxazolyl, benzothiazolyl, 1,2-benzisothiazolyl, 2,1 -benzisothiazolyl,
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32
benzotriazolyl, quinolinyl, isoquinolinyl, 2,3-benzodiazinyl, quinoxalinyl,
quinazolinyl, 1,2,3-benzotriazinyl, or 1,2,4-benzotriazinyl; optionally
substituted;
R"' is alkyl, alkenyl, alkynyl, in particular CI-C6 alkyl, e.g. Ci, C2, C3,
C4, C5, or C6
aikyl; and
R""' is hydrogen, alkyl, alkenyl, alkynyl, in particular C1-C6 alkyl, e.g. Ci,
C2, C3, C4,
C5, or C6 alkyl, optionally substituted.
In a preferred embodiment of the compound of formula (I) R' has one of the
following
structures:
0 O O, Rb O ORb
ORb O I\ I\ O, Rb
(CH2)s (CHz)s Rb ~ (CH2)s (CH2)s (CH2)s
(Ra)k * (Ra)k * (Ra)k * (Ra)k * (Ra)k *
ORc Rb, O
Rc Rc
Rb~O t~(QH Rb~OO~Rc IO,
z)s (CH2)s (CH2)s Rb1O (CH2)s
(Ra)k * (Ra)k * (Ra)k * (Ra)k *
NRdRe Hal 0-1,
(CH2)s (CHZ)s (CHz)s
(Ra)k (Ra) k or (Ra)k
wherein
Ra is halogen, e.g. F, Cl, Br or I; CN; NOZ; -NR'R"; alkyl, in particular CJ-
C6 alkyl, e.g. Ci,
C2, C3, C4, C5, or C6 alkyl, preferably methyl, ethyl, propyl, iso-propyl,
butyl, iso-butyl,
tert-butyl, pentyl, hexyl; alkenyl, in particular C2-C6 alkenyl, e.g. C2, C3,
C4, C5, or C6
alkenyl, preferably ethenyl, 1-propenyl, 2-propenyl, 1-iso-propenyl, 2-iso-
propenyl, 1-
butenyl, 2-butenyl, 3-butenyl; alkynyl, in particular C2-C6 alkynyl, e.g. C2,
C3, C4, C5, or
C6 alkynyl; alkanoyl, preferably C1-C6 alkanoyl, e.g. Cl, C2, C3, C4, C5, or
C6 alkanoyl;
alkenoyl, in particular C3-C6 alkenoyl, e.g. C3, C4, C5, or C6 alkenoyl,
preferably
propenoyl; alkynoyl, in particular C3-C6 alkynoyl, e.g. C3, C4, C5, or C6
alkynoyl,
preferably propynoyl; alkoxy, in particular C1-C6 alkoxy, e.g. Ci, C2, C3, C4,
C5, or C6
alkoxy, preferably methoxy, ethoxy, propoxy, iso-propoxy, butoxy, iso-butoxy,
tert-
butoxy, pentoxy, or hexoxy; alkoxyalkyl, in particular C1-C6 alkoxy-Cl-C6
alkyl, e.g.
methoxymethyl, ethoxymethyl, propoxymethyl, methoxyethyl, ethoxyethyl,
propoxyethyl, methoxypropyl, ethoxypropyl, or propoxypropyl; -OOC-R"'; -COO-
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R""'; aryl, in particular phenyl, naphthalenyl or anthracenyl; heteroaryl, in
particular
furanyl, thiophenyl, oxazolyl, isoxazolyl, 1,2,5-oxadiazolyl, 1,2,3-
oxadiazolyl, pyrrolyl,
imidazolyl, pyrazolyl, 1,2,3-triazolyl, thiazolyl, isothiazolyl, 1,2,3,-
thiadiazolyl, 1,2,5-
thiadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, 1,2,3-triazinyl, 1,2,4-
triazinyl, 1,3,5-
triazinyl, 1-benzofuranyl, 2-benzofuranyl, indolyl, isoindolyl,
benzothiophenyl, 2-
benzothiophenyl, 1 H-indazolyl, benzimidazolyl, benzoxazolyl, indoxazinyl, 2,1-
benzisoxazolyl, benzothiazolyl, 1,2-benzisothiazolyl, 2, 1 -benzisothiazolyl,
benzotriazolyl, quinolinyl, isoquinolinyl, 2,3-benzodiazinyl, quinoxalinyl,
quinazolinyl,
1,2,3-benzotriazinyl, or 1,2,4-benzotriazinyl; optionally substituted;
or two adjacent Ra together form an aryl or heteroaryl residue, preferably
resulting in a
two or three membered aryl or heteroaryl;
wherein
R' and R" are independent of each other hydrogen; alkyl, in particular CI-C6
alkyl, e.g.
Cl, C2, C3, C4, C5, or C6 alkyl; alkenyl, in particular C2-C6 alkenyl, e.g.
C2, C3, C4,
C5, or C6 alkenyl; alkynyl, in particular C2-C6 alkynyl, e.g. C2, C3, C4, C5,
or C6
alkynyl; aryl; or heteroaryl, in particular furanyl, thiophenyl, oxazolyl,
isoxazolyl,
1,2,5-oxadiazolyl, 1,2,3-oxadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, 1,2,3-
triazolyl, thiazolyl, isothiazolyl, 1,2,3,-thiadiazolyl, 1,2,5-thiadiazolyl,
pyridinyl,
pyrimidinyl, pyrazinyl, 1,2,3-triazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, 1-
benzofuranyl, 2-benzofuranyl, indolyl, isoindolyl, benzothiophenyl, 2-
benzothiophenyl, 1 H-indazolyl, benzimidazolyl, benzoxazolyl, indoxazinyl, 2,1-
benzisoxazolyl, benzothiazolyl, 1,2-benzisothiazolyl, 2,1 -benzisothiazolyl,
benzotriazolyl, quinolinyl, isoquinolinyl, 2,3-benzodiazinyl, quinoxalinyl,
quinazolinyl, 1,2,3-benzotriazinyl, or 1,2,4-benzotriazinyl; optionally
substituted;
R"' is alkyl, alkenyl, alkynyl, in particular CI-C6 alkyl, e.g. Cl, C2, C3,
C4, C5, or C6
alkyl, optionally substituted; and
R""' is hydrogen, alkyl, alkenyl, alkynyl, in particular CI-C6 alkyl, e.g. Cl,
C2, C3, C4,
C5, or C6 alkyl, optionally substituted;
Rb and R are independent of each other hydrogen, alkyl, in particular CI-C6
alkyl, e.g. Cl, C2,
C3, C4, C5, or C6 alkyl, preferably methyl, ethyl, propyl, iso-propyl, butyl,
iso-butyl, tert-
butyl, pentyl, hexyl; alkenyl, in particular C2-C6 alkenyl, e.g. C2, C3, C4,
C5, or C6
alkenyl, preferably ethenyl, 1-propenyl, 2-propenyl, 1-iso-propenyl, 2-iso-
propenyl, 1-
butenyl, 2-butenyl, 3-butenyl; alkynyl, in particular C2-C6 alkynyl, e.g. C2,
C3, C4, C5, or
C6 alkynyl; optionally substituted;
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Rd and Re are independent of each other hydrogen, alkyl, in particular C1-C6
alkyl, e.g. Ci, C2,
C3, C4, C5, or C6 alkyl, preferably methyl, ethyl, propyl, iso-propyl, butyl,
iso-butyl, tert-
butyl, pentyl, hexyl; alkenyl, in particular C2-C6 alkenyl, e.g. C2, C3, C4,
C5, or C6
aikenyi, preferably ethenyl, 1-propenyl, 2-propenyl, 1-iso-propenyl, 2-iso-
propenyl, 1-
butenyl, 2-butenyl, 3-butenyl; alkynyl, in particular C2-C6 alkynyl, e.g. C2,
C3, C4, C5, or
C6 alkynyl; optionally substituted;
Hal is F, Cl, Br or I, preferably F, Cl or Br;
s is an integer of 0 to 4, i.e. 0, 1, 2, 3, or 4, preferably 0, 1, or 2;
k is an integer of 0 to 4, i.e. 0, 1, 2, 3, or 4, preferably 0, 1, or 2, i.e.
up to the maximum
number of substituents on the phenyl; and
* marks the bond of R' to the compound of formula (I).
In a preferred aspect the heterocycloalkyl formed by R3 and R4 is selected
from the group
consisting of (1,2,5,6-tetrahydropyridyl), 1,4, diaza heptyl, 1,4 diaza octyl,
1,5 diaza octyl,
piperidinyl, morpholinyl, morpholinyl, 1,8 diaza-spiro-[4,5] decyl, 1,7 diaza-
spiro-[4,5] decyl,
1,6 diaza-spiro-[4,5] decyl, 2,8 diaza-spiro[4,5] decyl, 2,7 diaza-spiro[4,5]
decyl, 2,6 diaza-
spiro[4,5] decyl, 1,8 diaza-spiro-[5,4] decyl, 1,7 diaza-spiro-[5,4] decyl,
2,8 diaza-spiro-[5,4]
decyl, 2,7 diaza-spiro[5,4] decyl, 3,8 diaza-spiro[5,4] decyl, 3,7 diaza-
spiro[5,4] decyl, 1,4-
diazabicyclo[2.2.2]oct-2-yl, 1 aza 7,11 dioxo-spiro[5,5] undecyl and
piperazinyl optionally
substituted, preferably with 1, 2, 3, 4 or more substituents selected from the
group consisting of
halogen, e.g. F, Cl, Br or I; CN; NO2; NR'R"; alkyl, in particular C1-C6
alkyl, e.g. Ci, C2, C3,
C4, C5, or C6 alkyl, preferably methyl, ethyl, propyl, iso-propyl, butyl, iso-
butyl, tert-butyl,
pentyl, hexyl; alkenyl, in particular C2-C6 alkenyl, e.g. C2, C3, C4, C5, or
C6 alkenyl, preferably
ethenyl, 1-propenyl, 2-propenyl, 1-iso-propenyl, 2-iso-propenyl, 1-butenyl, 2-
butenyl, 3-butenyl;
alkynyl, in particular C2-C6 alkynyl, e.g. C2, C3, C4, C5, or C6 alkynyl;
alkanoyl, preferably Ci-C6
alkanoyl, e.g. Ci, C2, C3, C4, C5, or C6 alkanoyl; alkenoyl, in particular C3-
C6 alkenoyl, e.g. C3,
C4, C5, or C6 alkenoyl, preferably propenoyl; alkynoyl, in particular C3-C6
alkynoyl, e.g. C3, C4,
C5, or C6 alkynoyl, preferably propynoyl; alkoxy, in particular Ci-C6 alkoxy,
e.g. C1, C2, C3, C4,
C5, or C6 alkoxy, preferably methoxy, ethoxy, propoxy, iso-propoxy, butoxy,
iso-butoxy, tert-
butoxy, pentoxy, or hexoxy; alkoxyalkyl, in particular C1-C6 alkoxy-Cl-C6
alkyl, e.g.
methoxymethyl, ethoxymethyl, propoxymethyl, methoxyethyl, ethoxyethyl,
propoxyethyl,
methoxypropyl, ethoxypropyl, or propoxypropyl; -OOC-R"'; -COO-R""'; aryl, in
particular
phenyl, naphthalenyl or anthracenyl; heteroaryl, in particular furanyl,
thiophenyl, oxazolyl,
isoxazolyl, 1,2,5-oxadiazolyl, 1,2,3-oxadiazolyl, pyrrolyl, imidazolyl,
pyrazolyl, 1,2,3-triazolyl,
thiazolyl, isothiazolyl, 1,2,3,-thiadiazolyl, 1,2,5-thiadiazolyl, pyridinyl,
pyrimidinyl, pyrazinyl,
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1,2,3-triazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, 1-benzofuranyl, 2-
benzofuranyl, indolyl,
isoindolyl, benzothiophenyl, 2-benzothiophenyl, 1 H-indazolyl, benzimidazolyl,
benzoxazolyl,
indoxazinyl, 2,1-benzisoxazolyl, benzothiazolyl, 1,2-benzisothiazolyl, 2,1-
benzisothiazolyl,
bcnzotriazolyl, quinoiinyl, isoquinolinyl, 2,3-benzodiazinyl, quinoxalinyl,
quinazolinyl, 1,2,3-
5 benzotriazinyl, or 1,2,4-benzotriazinyl; optionally substituted, wherein
R' and R" are independent of each other hydrogen; alkyl, in particular C1-C6
alkyl, e.g. Cl, C2,
C3, C4, C5, or C6 alkyl; alkenyl, in particular C2-C6 alkenyl, e.g. C2, C3,
C4, C5, or C6
alkenyl; alkynyl, in particular C2-C6 alkynyl, e.g. C2, C3, C4, C5, or C6
alkynyl; aryl; or
heteroaryl, in particular furanyl, thiophenyl, oxazolyl, isoxazolyl, 1,2,5-
oxadiazolyl,
10 1,2,3-oxadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, 1,2,3-triazolyl,
thiazolyl, isothiazolyl,
1,2,3,-thiadiazolyl, 1,2,5-thiadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl,
1,2,3-triazinyl,
1,2,4-triazinyl, 1,3,5-triazinyl, 1-benzofuranyl, 2-benzofuranyl, indolyl,
isoindolyl,
benzothiophenyl, 2-benzothiophenyl, 1 H-indazolyl, benzimidazolyl,
benzoxazolyl,
indoxazinyl, 2,1 -benzisoxazolyl, benzothiazolyl, 1,2-benzisothiazolyl, 2,1-
15 benzisothiazolyl, benzotriazolyl, quinolinyl, isoquinolinyl, 2,3-
benzodiazinyl,
quinoxalinyl, quinazolinyl, 1,2,3-benzotriazinyl, or 1,2,4-benzotriazinyl;
optionally
substituted;
R"' is alkyl, alkenyl, alkynyl, in particular C1-C6 alkyl, e.g. Ci, C2, C3,
C4, C5, or C6 alkyl,
optionally substituted; and
20 R""' is hydrogen, alkyl, alkenyl, alkynyl, in particular C1-C6 alkyl, e.g.
C1, C2, C3, C4, C5, or
C6 alkyl, optionally substituted;
In a further preferred embodiment the compound of the present invention has a
structure
according to formula (II)
R6
R7 R5
1 1 R8 (Ct'2)m X J ~ R11
R12 --1Y Rg N N
R2
R13 /NRlo
(CHR14)x
25 (II)
wherein R 2 has the meaning as outlined above, in particular the preferred
meanings, and wherein
R5, R6, R', R8 and R9 are independent of each other H, halogen, e.g. F, Cl, Br
or I; CN; NO2;
NR'R"; alkyl, in particular CI-C6 alkyl, e.g. Ci, C2, C3, C4, C5, or C6 alkyl,
preferably
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methyl, ethyl, propyl, iso-propyl, butyl, iso-butyl, tert-butyl, pentyl,
hexyl; alkenyl, in
particular C2-C6 alkenyl, e.g. C2, C3, C4, C5, or C6 alkenyl, preferably
ethenyl, 1-propenyl,
2-propenyl, 1-iso-propenyl, 2-iso-propenyl, 1-butenyl, 2-butenyl, 3-butenyl;
alkynyl, in
particular C2-C6 aikynyl, e.g. C2, C3, C4, C5, or C6 alkynyl; alkanoyl,
preferably Ci-C6
alkanoyl, e.g. Cl, C2, C3, C4, C5, or C6 alkanoyl; alkenoyl, in particular C3-
C6 alkenoyl,
e.g. C3, C4, C5, or C6 alkenoyl, preferably propenoyl; alkynoyl, in particular
C3-C6
alkynoyl, e.g. C3, C4, C5, or C6 alkynoyl, preferably propynoyl; alkoxy, in
particular Ci-
C6 alkoxy, e.g. C1, C2, C3, C4, C5, or C6 alkoxy, preferably methoxy, ethoxy,
propoxy,
iso-propoxy, butoxy, iso-butoxy, tert-butoxy, pentoxy, or hexoxy; alkoxyalkyl,
in
particular Cl-C6 alkoxy-Cl-C6 alkyl, e.g. methoxymethyl, ethoxymethyl,
propoxymethyl,
methoxyethyl, ethoxyethyl, propoxyethyl, methoxypropyl, ethoxypropyl, or
propoxypropyl; -OOC-R"'; -COO-R""'; aryl, in particular phenyl, naphthalenyl
or
anthracenyl; heteroaryl, in particular furanyl, thiophenyl, oxazolyl,
isoxazolyl, 1,2,5-
oxadiazolyl, 1,2,3-oxadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, 1,2,3-
triazolyl, thiazolyl,
isothiazolyl, 1,2,3,-thiadiazolyl, 1,2,5-thiadiazolyl, pyridinyl, pyrimidinyl,
pyrazinyl,
1,2,3-triazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, 1-benzofuranyl, 2-
benzofuranyl, indolyl,
isoindolyl, benzothiophenyl, 2-benzothiophenyl, 1 H-indazolyl, benzimidazolyl,
benzoxazolyl, indoxazinyl, 2,1-benzisoxazolyl, benzothiazolyl, 1,2-
benzisothiazolyl, 2,1-
benzisothiazolyl, benzotriazolyl, quinolinyl, isoquinolinyl, 2,3-
benzodiazinyl,
quinoxalinyl, quinazolinyl, 1,2,3-benzotriazinyl, or 1,2,4-benzotriazinyl;
optionally
substituted, wherein
R' and R" are independent of each other hydrogen; alkyl, in particular C1-C6
alkyl, e.g.
Cl, C2, C3, C4, C5, or C6 alkyl; alkenyl, in particular C2-C6 alkenyl, e.g.
C2, C3, C4,
C5, or C6 alkenyl; alkynyl, in particular C2-C6 alkynyl, e.g. C2, C3, C4, C5,
or C6
alkynyl; aryl; or heteroaryl, in particular furanyl, thiophenyl, oxazolyl,
isoxazolyl,
1,2,5-oxadiazolyl, 1,2,3-oxadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, 1,2,3-
triazolyl, thiazolyl, isothiazolyl, 1,2,3,-thiadiazolyl, 1,2,5-thiadiazolyl,
pyridinyl,
pyrimidinyl, pyrazinyl, 1,2,3-triazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, 1-
benzofuranyl, 2-benzofuranyl, indolyl, isoindolyl, benzothiophenyl, 2-
benzothiophenyl, 1 H-indazolyl, benzimidazolyl, benzoxazolyl, indoxazinyl, 2,1-
benzisoxazolyl, benzothiazolyl, 1,2-benzisothiazolyl, 2,1 -benzisothiazolyl,
benzotriazolyl, quinolinyl, isoquinolinyl, 2,3-benzodiazinyl, quinoxalinyl,
quinazolinyl, 1,2,3-benzotriazinyl, or 1,2,4-benzotriazinyl; optionally
substituted;
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R"' is alkyl, alkenyl, alkynyl, in particular CI-C6 alkyl, e.g. Cl, C2, C3,
C4, C5, or C6
alkyl; and
R""' is hydrogen, alkyl, alkenyl, alkynyl, in particular CI-C6 alkyl, e.g. Ci,
C2, C3, C4,
C5, or C6 alkyl, optionally substituted;
or two or more of R5, R6, R7, Rg and R9 are taken together to form a
cycloalkyl,
heterocycloalkyl, alicyclic ring system, aryl or heteroaryl, optionally
substituted
preferably with 1, 2, 3, 4 or more substituents selected from the group
consisting of
halogen, e.g. F, Cl, Br or I; CN; NO2; NR'R"; alkyl, in particular Ci-C6
alkyl, e.g. Cl, C2,
C3, C4, C5, or C6 alkyl, preferably methyl, ethyl, propyl, iso-propyl, butyl,
iso-butyl, tert-
butyl, pentyl, hexyl; alkenyl, in particular C2-C6 alkenyl, e.g. C2, C3, C4,
C5, or C6
alkenyl, preferably ethenyl, 1-propenyl, 2-propenyl, 1-iso-propenyl, 2-iso-
propenyl, 1-
butenyl, 2-butenyl, 3-butenyl; alkynyl, in particular C2-C6 alkynyl, e.g. C2,
C3, C4, C5, or
C6 alkynyl; alkanoyl, preferably Cl-C6 alkanoyl, e.g. C1, C2, C3, C4, C5, or
C6 alkanoyl;
alkenoyl, in particular C3-C6 alkenoyl, e.g. C3, C4, C5, or C6 alkenoyl,
preferably
propenoyl; alkynoyl, in particular C3-C6 alkynoyl, e.g. C3, C4, C5, or C6
alkynoyl,
preferably propynoyl; alkoxy, in particular CI-C6 alkoxy, e.g. C1, C2, C3, C4,
C5, or C6
alkoxy, preferably methoxy, ethoxy, propoxy, iso-propoxy, butoxy, iso-butoxy,
tert-
butoxy, pentoxy, or hexoxy; alkoxyalkyl, in particular C1-C6 alkoxy-Cl-C6
alkyl, e.g.
methoxymethyl, ethoxymethyl, propoxymethyl, methoxyethyl, ethoxyethyl,
propoxyethyl, methoxypropyl, ethoxypropyl, or propoxypropyl; -OOC-R"'; -COO-
R""'; aryl, in particular phenyl, naphthalenyl or anthracenyl; heteroaryl, in
particular
furanyl, thiophenyl, oxazolyl, isoxazolyl, 1,2,5-oxadiazolyl, 1,2,3-
oxadiazolyl, pyrrolyl,
imidazolyl, pyrazolyl, 1,2,3-triazolyl, thiazolyl, isothiazolyl, 1,2,3,-
thiadiazolyl, 1,2,5-
thiadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, 1,2,3-triazinyl, 1,2,4-
triazinyl, 1,3,5-
triazinyl, 1-benzofuranyl, 2-benzofuranyl, indolyl, isoindolyl,
benzothiophenyl, 2-
benzothiophenyl, 1 H-indazolyl, benzimidazolyl, benzoxazolyl, indoxazinyl, 2,1-
benzisoxazolyl, benzothiazolyl, 1,2-benzisothiazolyl, 2,1 -benzisothiazolyl,
benzotriazolyl, quinolinyl, isoquinolinyl, 2,3-benzodiazinyl, quinoxalinyl,
quinazolinyl,
1,2,3-benzotriazinyl, or 1,2,4-benzotriazinyl; optionally substituted, wherein
R' and R" are independent of each other hydrogen; alkyl, in particular Ci-C6
alkyl, e.g.
Cl, C2, C3, C4, C5, or C6 alkyl; alkenyl, in particular C2-C6 alkenyl, e.g.
C2, C3, C4,
C5, or C6 alkenyl; alkynyl, in particular C2-C6 alkynyl, e.g. C2, C3, C4, C5,
or C6
alkynyl; aryl; or heteroaryl, in particular furanyl, thiophenyl, oxazolyl,
isoxazolyl,
1,2,5-oxadiazolyl, 1,2,3-oxadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, 1,2,3-
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38
triazolyl, thiazolyl, isothiazolyl, 1,2,3,-thiadiazolyl, 1,2,5-thiadiazolyl,
pyridinyl,
pyrimidinyl, pyrazinyl, 1,2,3-triazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, 1-
benzofuranyl, 2-benzofuranyl, indolyl, isoindolyl, benzothiophenyl, 2-
benzothiophenyl, 1 H-indazolyl, benzimidazolyl, benzoxazolyl, indoxazinyl, 2,1-
benzisoxazolyl, benzothiazolyl, 1,2-benzisothiazolyl, 2, 1 -benzisothiazolyl,
benzotriazolyl, quinolinyl, isoquinolinyl, 2,3-benzodiazinyl, quinoxalinyl,
quinazolinyl, 1,2,3-benzotriazinyl, or 1,2,4-benzotriazinyl; optionally
substituted;
R"' is alkyl, alkenyl, alkynyl, in particular CI-C6 alkyl, e.g. Cl, C2, C3,
C4, C5, or C6
alkyl, optionally substituted; and
R""' is hydrogen, alkyl, alkenyl, alkynyl, in particular C1-C6 alkyl, e.g. Cl,
C2, C3, C4,
C5, or C6 alkyl, optionally substituted.
R10 is H, alkyl, alkenyl, alkynyl, alkoxy, alkanoyl, alkenoyl, alkynoyl, aryl,
heteroaryl,
aralkyl, or heteroaralkyl, optionally substituted preferably with 1, 2, 3, 4
or more
substituents selected from the group consisting of halogen, e.g. F, Cl, Br or
I; CN; NOZ;
NR'R"; alkyl, in particular Ci-C6 alkyl, e.g. Cl, C2, C3, C4, C5, or C6 alkyl,
preferably
methyl, ethyl, propyl, iso-propyl, butyl, iso-butyl, tert-butyl, pentyl,
hexyl; alkenyl, in
particular C2-C6 alkenyl, e.g. C2, C3, C4, C5, or C6 alkenyl, preferably
ethenyl, 1-propenyl,
2-propenyl, 1-iso-propenyl, 2-iso-propenyl, 1-butenyl, 2-butenyl, 3-butenyl;
alkynyl, in
particular C2-C6 alkynyl, e.g. C2, C3, C4, C5, or C6 alkynyl; alkanoyl,
preferably CI-C6
alkanoyl, e.g. C1, C2, C3, C4, C5, or C6 alkanoyl; alkenoyl, in particular C3-
C6 alkenoyl,
e.g. C3, C4, C5, or C6 alkenoyl, preferably propenoyl; alkynoyl, in particular
C3-C6
alkynoyl, e.g. C3, C4, C5, or C6 alkynoyl, preferably propynoyl; alkoxy, in
particular Cl-
C6 alkoxy, e.g. Cl, C2, C3, C4, C5, or C6 alkoxy, preferably methoxy, ethoxy,
propoxy,
iso-propoxy, butoxy, iso-butoxy, tert-butoxy, pentoxy, or hexoxy; alkoxyalkyl,
in
particular CI-C6 alkoxy-Cl-C6 alkyl, e.g. methoxymethyl, ethoxymethyl,
propoxymethyl,
methoxyethyl, ethoxyethyl, propoxyethyl, methoxypropyl, ethoxypropyl, or
propoxypropyl; -OOC-R"'; -COO-R""'; aryl, in particular phenyl, naphthalenyl
or
anthracenyl; heteroaryl, in particular furanyl, thiophenyl, oxazolyl,
isoxazolyl, 1,2,5-
oxadiazolyl, 1,2,3-oxadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, 1,2,3-
triazolyl, thiazolyl,
isothiazolyl, 1,2,3,-thiadiazolyl, 1,2,5-thiadiazolyl, pyridinyl, pyrimidinyl,
pyrazinyl,
1,2,3-triazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, 1-benzofuranyl, 2-
benzofuranyl, indolyl,
isoindolyl, benzothiophenyl, 2-benzothiophenyl, 1H-indazolyl, benzimidazolyl,
benzoxazolyl, indoxazinyl, 2, 1 -benzisoxazolyl, benzothiazolyl, 1,2-
benzisothiazolyl, 2,1-
benzisothiazolyl, benzotriazolyl, quinolinyl, isoquinolinyl, 2,3-
benzodiazinyl,
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39
quinoxalinyl, quinazolinyl, 1,2,3-benzotriazinyl, or 1,2,4-benzotriazinyl;
optionally
substituted, wherein
R' and R" are independent of each other hydrogen; alkyl, in particular CI-C6
alkyl, e.g.
Cl, C25 C3, C43 C5, or C6 alkyl; alkenyl, in particular C2-C6 alkenyl, e.g.
C2, C3, C4,
C5, or C6 alkenyl, alkynyl, in particular C2-C6 alkynyl, e.g. C2, C3, C4, C5,
or C6
alkynyl; aryl; or heteroaryl, in particular furanyl, thiophenyl, oxazolyl,
isoxazolyl,
1,2,5-oxadiazolyl, 1,2,3-oxadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, 1,2,3-
triazolyl, thiazolyl, isothiazolyl, 1,2,3,-thiadiazolyl, 1,2,5-thiadiazolyl,
pyridinyl,
pyrimidinyl, pyrazinyl, 1,2,3-triazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, 1-
benzofuranyl, 2-benzofuranyl, indolyl, isoindolyl, benzothiophenyl, 2-
benzothiophenyl, 1 H-indazolyl, benzimidazolyl, benzoxazolyl, indoxazinyl, 2,1-
benzisoxazolyl, benzothiazolyl, 1,2-benzisothiazolyl, 2, 1 -benzisothiazolyl,
benzotriazolyl, quinolinyl, isoquinolinyl, 2,3-benzodiazinyl, quinoxalinyl,
quinazolinyl, 1,2,3-benzotriazinyl, or 1,2,4-benzotriazinyl; optionally
substituted;
R"' is alkyl, alkenyl, alkynyl, in particular Ci-C6 alkyl, e.g. Cl, C2, C3,
C4, C5, or C6
alkyl, optionally substituted; and
R""' is hydrogen, alkyl, alkenyl, alkynyl, in particular CI-C6 alkyl, e.g. C1,
C2, C3, C4,
C5, or C6 alkyl, optionally substituted;
R", R12, R13 and R'4 are independent of each other are H, halogen, e.g. F. Cl,
Br or I; CN; NO2;
NR'R"; alkyl, in particular C1-C6 alkyl, e.g. Ci, C2, C3, C4, C5, or C6 alkyl,
preferably
methyl, ethyl, propyl, iso-propyl, butyl, iso-butyl, tert-butyl, pentyl,
hexyl; alkenyl, in
particular C2-C6 alkenyl, e.g. C2, C3, C4, C5, or C6 alkenyl, preferably
ethenyl, 1-propenyl,
2-propenyl, 1-iso-propenyl, 2-iso-propenyl, 1-butenyl, 2-butenyl, 3-butenyl;
alkynyl, in
particular C2-C6 alkynyl, e.g. C2, C3, C4, C5, or C6 alkynyl; alkoxy, in
particular Cj-C6
alkoxy, e.g. Ci, C2, C3, C4, C5, or C6 alkoxy, preferably methoxy, ethoxy,
propoxy, iso-
propoxy, butoxy, iso-butoxy, tert-butoxy, pentoxy, or hexoxy; optionally
substituted;
m is an integer of 0 to 4, i.e. 0, 1, 2, 3, or 4, preferably 0, 1, or 2; and
x is I or 2, preferably 1.
In a preferred embodiment of the compound of formula (II) the left
(Co4)alkylphenyl
residue, i.e. R', has one of the following structures:
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O O O, Rb O
W(CH ORbO O, Rb
)m (CH
1-1 z}rn Rb (CHZ)m ~(CHZ)m
(Ra)k (Ra)k (Ra)k (Ra)k
ORb ORc Rb, O
Rb-' O t~(QHOM Rb" O X O~Rc O, Rc
(CH2)m (CH2)m (CH2)m
(Ra)k (Ra)k (Ra)k (Ra)k
(( Rc NRdRe HaI I\
Rb, O (CH2)m (CH2)m (CHZ)m / (CH2)m
(Ra)k (Ra)k (Ra)k or (Ra)k
wherein
5 Ra is halogen, e.g. F, Cl, Br or I; CN; NO2; -NR'R"; alkyl, in particular C1-
C6 alkyl, e.g. Cl,
C2, C3, C4, C5, or C6 alkyl, preferably methyl, ethyl, propyl, iso-propyl,
butyl, iso-butyl,
tert-butyl, pentyl, hexyl; alkenyl, in particular C2-C6 alkenyl, e.g. C2, C3,
C4, C5, or C6
alkenyl, preferably ethenyl, 1-propenyl, 2-propenyl, 1-iso-propenyl, 2-iso-
propenyl, 1-
butenyl, 2-butenyl, 3-butenyl; alkynyl, in particular C2-C6 alkynyl, e.g. C2,
C3, C4, C5, or
10 C6 alkynyl; alkanoyl, preferably CI-C6 alkanoyl, e.g. Cl, C2, C3, C4, C5,
or C6 alkanoyl;
alkenoyl, in particular C3-C6 alkenoyl, e.g. C3, C4, C5, or C6 alkenoyl,
preferably
propenoyl; alkynoyl, in particular C3-C6 alkynoyl, e.g. C3, C4, C5, or C6
alkynoyl,
preferably propynoyl; alkoxy, in particular CI-C6 alkoxy, e.g. Ci, C2, C3, C4,
C5, or C6
alkoxy, preferably methoxy, ethoxy, propoxy, iso-propoxy, butoxy, iso-butoxy,
tert-
15 butoxy, pentoxy, or hexoxy; alkoxyalkyl, in particular Ci-C6 alkoxy-Cl-C6
alkyl, e.g.
methoxymethyl, ethoxymethyl, propoxymethyl, methoxyethyl, ethoxyethyl,
propoxyethyl, methoxypropyl, ethoxypropyl, or propoxypropyl; -OOC-R"'; -COO-
R""'; aryl, in particular phenyl, naphthalenyl or anthracenyl; heteroaryl, in
particular
furanyl, thiophenyl, oxazolyl, isoxazolyl, 1,2,5-oxadiazolyl, 1,2,3-
oxadiazolyl, pyrrolyl,
20 imidazolyl, pyrazolyl, 1,2,3-triazolyl, thiazolyl, isothiazolyl, 1,2,3,-
thiadiazolyl, 1,2,5-
thiadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, 1,2,3-triazinyl, 1,2,4-
triazinyl, 1,3,5-
triazinyl, 1-benzofuranyl, 2-benzofuranyl, indolyl, isoindolyl,
benzothiophenyl, 2-
benzothiophenyl, 1 H-indazolyl, benzimidazolyl, benzoxazolyl, indoxazinyl, 2,1-
benzisoxazolyl, benzothiazolyl, 1,2-benzisothiazolyl, 2, 1 -benzisothiazolyl,
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benzotriazolyl, quinolinyl, isoquinolinyl, 2,3-benzodiazinyl, quinoxalinyl,
quinazolinyl,
1,2,3-benzotriazinyl, or 1,2,4-benzotriazinyl; optionally substituted;
or two adjacent Ra together form an aryl or heteroaryl residue, preferably
resulting in a
two or three membered aryl or heteroaryl;
wherein
R' and R" are independent of each other hydrogen; alkyl, in particular CI-C6
alkyl, e.g.
Ci, C2, C3, C4, C5, or C6 alkyl; alkenyl, in particular C2-C6 alkenyl, e.g.
C2, C3, C4,
C5, or C6 alkenyl; alkynyl, in particular C2-C6 alkynyl, e.g. C2, C3, C4, C5,
or C6
alkynyl; aryl; or heteroaryl, in particular furanyl, thiophenyl, oxazolyl,
isoxazolyl,
1,2,5-oxadiazolyl, 1,2,3-oxadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, 1,2,3-
triazolyl, thiazolyl, isothiazolyl, 1,2,3,-thiadiazolyl, 1,2,5-thiadiazolyl,
pyridinyl,
pyrimidinyl, pyrazinyl, 1,2,3-triazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, 1-
benzofuranyl, 2-benzofuranyl, indolyl, isoindolyl, benzothiophenyl, 2-
benzothiophenyl, 1 H-indazolyl, benzimidazolyl, benzoxazolyl, indoxazinyl, 2,1-
benzisoxazolyl, benzothiazolyl, 1,2-benzisothiazolyl, 2,1 -benzisothiazolyl,
benzotriazolyl, quinolinyl, isoquinolinyl, 2,3-benzodiazinyl, quinoxalinyl,
quinazolinyl, 1,2,3-benzotriazinyl, or 1,2,4-benzotriazinyl; optionally
substituted;
R"' is alkyl, alkenyl, alkynyl, in particular CI-C6 alkyl, e.g. Cl, C2, C3,
C4, C5, or C6
alkyl, optionally substituted; and
R""' is hydrogen, alkyl, alkenyl, alkynyl, in particular CI-C6 alkyl, e.g. C1,
C2, C3, C4,
C5, or C6 alkyl, optionally substituted;
Rb and R are independent of each other hydrogen, alkyl, in particular CI-C6
alkyl, e.g. Cl, C2,
C3, C4, C5, or C6 alkyl, preferably methyl, ethyl, propyl, iso-propyl, butyl,
iso-butyl, tert-
butyl, pentyl, hexyl; alkenyl, in particular C2-C6 alkenyl, e.g. C2, C3, C4,
C5, or C6
alkenyl, preferably ethenyl, 1-propenyl, 2-propenyl, 1-iso-propenyl, 2-iso-
propenyl, 1-
butenyl, 2-butenyl, 3-butenyl; alkynyl, in particular C2-C6 alkynyl, e.g. C2,
C3, C4, C5, or
C6 alkynyl; optionally substituted;
Rd and Re are independent of each other hydrogen, alkyl, in particular C1-C6
alkyl, e.g. Cl, C2,
C3, C4, C5, or C6 alkyl, preferably methyl, ethyl, propyl, iso-propyl, butyl,
iso-butyl, tert-
butyl, pentyl, hexyl; alkenyl, in particular C2-C6 alkenyl, e.g. C2, C3, C4,
C5, or C6
alkenyl, preferably ethenyl, 1-propenyl, 2-propenyl, 1-iso-propenyl, 2-iso-
propenyl, 1-
butenyl, 2-butenyl, 3-butenyl; alkynyl, in particular C2-C6 alkynyl, e.g. C2,
C3, C4, C5, or
C6 alkynyl; optionally substituted;
Hal is F, Cl, Br or I, preferably F, Cl or Br;
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42
m is an integer of 0 to 4, i.e. 0, 1, 2, 3, or 4, preferably 0, 1, or 2;
k is an integer of 0 to 4, i.e. 0, 1, 2, 3, or 4, preferably 0, 1, or 2, i.e.
up to the maximum
number of substituents on the phenyl; and
* marks the bond of R' to the compound of formula (II). In this context it is
particularly
preferred that R10 has the preferred meanings indicated below.
In a further preferred embodiment of the compound according to formula (II)
R10 has a
structure according to formula (III)
R'
(CH2)n R
s~
R9' R7'
R$'
(III),
wherein R5', R6', RT, R8' and R9' are independent of each other H, halogen,
e.g. F, Cl, Br or I;
CN; NO2; -NR'R"; alkyl, in particular C1-C6 alkyl, e.g. C1, C2, C3, C4, C5, or
C6 alkyl,
preferably methyl, ethyl, propyl, iso-propyl, butyl, iso-butyl, tert-butyl,
pentyl, hexyl;
alkenyl, in particular C2-C6 alkenyl, e.g. C2, C3, C4, C5, or C6 alkenyl,
preferably ethenyl,
1-propenyl, 2-propenyl, 1-iso-propenyl, 2-iso-propenyl, 1-butenyl, 2-butenyl,
3-butenyl;
alkynyl, in particular C2-C6 alkynyl, e.g. C2, C3, C4, C5, or C6 alkynyl;
alkoxy, in
particular CI -C6 alkoxy, e.g. CI, C2, C3, C4, C5, or C6 alkoxy, preferably
methoxy, ethoxy,
propoxy, iso-propoxy, butoxy, iso-butoxy, tert-butoxy, pentoxy, or hexoxy;
alkoxyalkyl,
in particular CI-C6 alkoxy-Cl-C6 alkyl, e.g. methoxymethyl, ethoxymethyl,
propoxymethyl, methoxyethyl, ethoxyethyl, propoxyethyl, methoxypropyl,
ethoxypropyl,
or propoxypropyl; -OOC-R"'; -COO-R""'; aryl, in particular phenyl,
naphthalenyl or
anthracenyl; heteroaryl, in particular furanyl, thiophenyl, oxazolyl,
isoxazolyl, 1,2,5-
oxadiazolyl, 1,2,3-oxadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, 1,2,3-
triazolyl, thiazolyl,
isothiazolyl, 1,2,3,-thiadiazolyl, 1,2,5-thiadiazolyl, pyridinyl, pyrimidinyl,
pyrazinyl,
1,2,3-triazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, 1-benzofuranyl, 2-
benzofuranyl, indolyl,
isoindolyl, benzothiophenyl, 2-benzothiophenyl, 1H-indazolyl, benzimidazolyl,
benzoxazolyl, indoxazinyl, 2,1-benzisoxazolyl, benzothiazolyl, 1,2-
benzisothiazolyl, 2,1-
benzisothiazolyl, benzotriazolyl, quinolinyl, isoquinolinyl, 2,3-
benzodiazinyl,
quinoxalinyl, quinazolinyl, 1,2,3-benzotriazinyl, or 1,2,4-benzotriazinyl;
optionally
substituted;
wherein R' and R" are independent of each other hydrogen; alkyl, in particular
Cj-C6
alkyl, e.g. Cl, C2, C3, C4, C5, or C6 alkyl; alkenyl, in particular C2-C6
alkenyl, e.g.
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43
C2, C3, C4, C5, or C6 alkenyl; alkynyl, in particular C2-C6 alkynyl, e.g. C2,
C3, C4,
C5, or C6 alkynyl; aryl; or heteroaryl, in particular furanyl, thiophenyl,
oxazolyl,
isoxazolyl, 1,2,5-oxadiazolyl, 1,2,3-oxadiazolyl, pyrrolyl, imidazolyl,
pyrazolyl,
1,2,3-triazolyi, thiazolyl, isothiazolyl, 1,2,3,-thiadiazolyl, 1,2,5-
thiadiazolyl,
pyridinyl, pyrimidinyl, pyrazinyl, 1,2,3-triazinyl, 1,2,4-triazinyl, 1,3,5-
triazinyl, 1-
benzofuranyl, 2-benzofuranyl, indolyl, isoindolyl, benzothiophenyl, 2-
benzothiophenyl, 1 H-indazolyl, benzimidazolyl, benzoxazolyl, indoxazinyl, 2,1-
benzisoxazolyl, benzothiazolyl, 1,2-benzisothiazolyl, 2,1 -benzisothiazolyl,
benzotriazolyl, quinolinyl, isoquinolinyl, 2,3-benzodiazinyl, quinoxalinyl,
quinazolinyl, 1,2,3-benzotriazinyl, or 1,2,4-benzotriazinyl; optionally
substituted;
R"' is alkyl, alkenyl, alkynyl, in particular CI-C6 alkyl, e.g. C1, C2, C3,
C4, C5, or C6
alkyl, optionally substituted; and
R""' is hydrogen, alkyl, alkenyl, alkynyl, in particular Ci-C6 alkyl, e.g. Cl,
C2, C3, C4,
C5, or C6 alkyl, optionally substituted;
or two or more of R5, R6, R', Rg and R9 are taken together to form a
cycloalkyl,
heterocycloalkyl, alicyclic ring system, aryl, or heteroaryl, optionally
substituted; and
n is an integer of 0 to 4, i.e. 0, 1, 2, 3, or 4, preferably 0, 1, or 2. In
this context it is
particularly preferred that x is 1.
In a further preferred embodiment the compound has a structure according to
formula
and/or R9' are substituted by
(II), R10 has a structure according to formula (III), and at least R 5 '
halogen, e.g. F, Cl, Br or I; CN; NO2; -NR'R"; alkyl, in particular CI-C6
alkyl, e.g. C1, C2, C3,
C4, C5, or C6 alkyl, preferably methyl, ethyl, propyl, iso-propyl, butyl, iso-
butyl, tert-butyl,
pentyl, hexyl; alkenyl, in particular C2-C6 alkenyl, e.g. C2, C3, C4, C5, or
C6 alkenyl, preferably
ethenyl, 1-propenyl, 2-propenyl, 1-iso-propenyl, 2-iso-propenyl, 1-butenyl, 2-
butenyl, 3-butenyl;
alkynyl, in particular C2-C6 alkynyl, e.g. C2, C3, C4, C5, or C6 alkynyl;
alkoxy, in particular CI-C6
alkoxy, e.g. Cl, C2, C3, C4, C5, or C6 alkoxy, preferably methoxy, ethoxy,
propoxy, iso-propoxy,
butoxy, iso-butoxy, tert-butoxy, pentoxy, or hexoxy; alkoxyalkyl, in
particular CI-C6 alkoxy-Ci-
C6 alkyl, e.g. methoxymethyl, ethoxymethyl, propoxymethyl, methoxyethyl,
ethoxyethyl,
propoxyethyl, methoxypropyl, ethoxypropyl, or propoxypropyl; -OOC-R"'; -COO-
R""'; aryl,
in particular phenyl, naphthalenyl or anthracenyl; heteroaryl, in particular
furanyl, thiophenyl,
oxazolyl, isoxazolyl, 1,2,5-oxadiazolyl, 1,2,3-oxadiazolyl, pyrrolyl,
imidazolyl, pyrazolyl, 1,2,3-
triazolyl, thiazolyl, isothiazolyl, 1,2,3,-thiadiazolyl, 1,2,5-thiadiazolyl,
pyridinyl, pyrimidinyl,
pyrazinyl, 1,2,3-triazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, 1-benzofuranyl,
2-benzofuranyl,
indolyl, isoindolyl, benzothiophenyl, 2-benzothiophenyl, 1H-indazolyl,
benzimidazolyl,
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44
benzoxazolyl, indoxazinyl, 2,1-benzisoxazolyl, benzothiazolyl, 1,2-
benzisothiazolyl, 2,1-
benzisothiazolyl, benzotriazolyl, quinolinyl, isoquinolinyl, 2,3-
benzodiazinyl, quinoxalinyl,
quinazolinyl, 1,2,3-benzotriazinyl, or 1,2,4-benzotriazinyl; optionally
substituted;
wherein
R' and R" are independent of each other hydrogen; alkyl, in particular CI-C6
alkyl, e.g. C1, C2,
C3, C4, C5, or C6 alkyl; alkenyl, in particular C2-C6 alkenyl, e.g. C2, C3,
C4, C5, or C6
alkenyl; alkynyl, in particular C2-C6 alkynyl, e.g. C2, C3, C4, C5, or C6
alkynyl; aryl; or
heteroaryl, in particular furanyl, thiophenyl, oxazolyl, isoxazolyl, 1,2,5-
oxadiazolyl,
1,2,3-oxadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, 1,2,3-triazolyl,
thiazolyl, isothiazolyl,
1,2,3,-thiadiazolyl, 1,2,5-thiadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl,
1,2,3-triazinyl,
1,2,4-triazinyl, 1,3,5-triazinyl, 1-benzofuranyl, 2-benzofuranyl, indolyl,
isoindolyl,
benzothiophenyl, 2-benzothiophenyl, 1 H-indazolyl, benzimidazolyl,
benzoxazolyl,
indoxazinyl, 2,1 -benzisoxazolyl, benzothiazolyl, 1,2-benzisothiazolyl, 2,1-
benzisothiazolyl, benzotriazolyl, quinolinyl, isoquinolinyl, 2,3-
benzodiazinyl,
quinoxalinyl, quinazolinyl, 1,2,3-benzotriazinyl, or 1,2,4-benzotriazinyl;
optionally
substituted;
R"' is alkyl, alkenyl, alkynyl, in particular C1-C6 alkyl, e.g. Cl, C2, C3,
C4, C5, or C6 alkyl,
optionally substituted; and
R""' is hydrogen, alkyl, alkenyl, alkynyl, in particular CI-C6 alkyl, e.g. C1,
C2, C3, C4, C5, or
C6 alkyl, optionally substituted.
In a further preferred embodiment of the compound according to formula (II)
R10 has a
structure according to formula
~
0 / 0
* (CH2)n * (CH2) j 0 * (CH2) j (CHz) j
/ l ~ ~
O O
(Ra)k (Ra)k (Ra)k (Ra)k
~ J
0
* (CH2)n 0
O (CH2)n O * (CH2)n
(Ra)k * (CH2) j
(Ra)k O \
0~ 0 (Ra)k (Ra)k
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(CH )n * (CH )n *(CHz)n (CHz)n
ici iIi0iIiiID
(Ra)k (Ra)k (Ra)k (Ra)k
* (CHz)n (CHz)n * (CHz)n * (CHz)n
(Ra)k (Ra)k (Ra)k (Ra)k
0
OH
0
* (CHz)n ~ ~ * (CHz)n
(CHZ)n = (CHz)n A
~~
(Ra)k Ra)k E--D (Ra)k (Ra)k
O
*
(CHz)n OH '-(CHz)n *~ (CHz)n
OH
(Ra)k (Ra)k (Ra)k
Hal
*~(CHn (CHz)n (CH)n
jHaI l1HaI
5 (Ra)k (Ra)k or (Ra)k
wherein
Ra is halogen, e.g. F, Cl, Br or I; CN; NOZ; -NR'R"; alkyl, in particular Ci-
C6 alkyl, e.g. Cl,
C2, C3, C4, C5, or C6 alkyl, preferably methyl, ethyl, propyl, iso-propyl,
butyl, iso-butyl,
tert-butyl, pentyl, hexyl; alkenyl, in particular C2-C6 alkenyl, e.g. C2, C3,
C4, C5, or C6
10 alkenyl, preferably ethenyl, 1-propenyl, 2-propenyl, 1-iso-propenyl, 2-iso-
propenyl, 1-
butenyl, 2-butenyl, 3-butenyl; alkynyl, in particular C2-C6 alkynyl, e.g. C2,
C3, C4, C5, or
C6 alkynyl; alkoxy, in particular Ci-C6 alkoxy, e.g. Cl, C2, C3, C4, C5, or C6
alkoxy,
preferably methoxy, ethoxy, propoxy, iso-propoxy, butoxy, iso-butoxy, tert-
butoxy,
pentoxy, or hexoxy; alkoxyalkyl, in particular CI-C6 alkoxy-Cl-C6 alkyl, e.g.
15 methoxymethyl, ethoxymethyl, propoxymethyl, methoxyethyl, ethoxyethyl,
propoxyethyl, methoxypropyl, ethoxypropyl, or propoxypropyl; -OOC-R"'; -COO-
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46
R""'; aryl, in particular phenyl, naphthalenyl or anthracenyl; heteroaryl, in
particular
furanyl, thiophenyl, oxazolyl, isoxazolyl, 1,2,5-oxadiazolyl, 1,2,3-
oxadiazolyl, pyrrolyl,
imidazolyl, pyrazolyl, 1,2,3-triazolyl, thiazolyl, isothiazolyl, 1,2,3,-
thiadiazolyl, 1,2,5-
ihiadiazoiyi, pyridinyl, pyrimidinyl, pyrazinyl, 1,2,3-triazinyl, 1,2,4-
triazinyl, 1,3,5-
triazinyl, 1-benzofuranyl, 2-benzofuranyl, indolyl, isoindolyl,
benzothiophenyl, 2-
benzothiophenyl, 1H-indazolyl, benzimidazolyl, benzoxazolyl, indoxazinyl, 2,1-
benzisoxazolyl, benzothiazolyl, 1,2-benzisothiazolyl, 2,1 -benzisothiazolyl,
benzotriazolyl, quinolinyl, isoquinolinyl, 2,3-benzodiazinyl, quinoxalinyl,
quinazolinyl,
1,2,3-benzotriazinyl, or 1,2,4-benzotriazinyl; optionally substituted;
or two adjacent Ra together form an aryl or heteroaryl residue, preferably
resulting in a
two or three membered aryl or heteroaryl; optionally substituted;
wherein
R' and R" are independent of each other hydrogen; alkyl, in particular C1-C6
alkyl, e.g.
Ci, C2, C3, C4, C5, or C6 alkyl; alkenyl, in particular C2-C6 alkenyl, e.g.
C2, C3, C4,
C5, or C6 alkenyl; alkynyl, in particular C2-C6 alkynyl, e.g. C2, C3, C4, C5,
or C6
alkynyl; aryl; or heteroaryl, in particular furanyl, thiophenyl, oxazolyl,
isoxazolyl,
1,2,5-oxadiazolyl, 1,2,3-oxadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, 1,2,3-
triazolyl, thiazolyl, isothiazolyl, 1,2,3,-thiadiazolyl, 1,2,5-thiadiazolyl,
pyridinyl,
pyrimidinyl, pyrazinyl, 1,2,3-triazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, 1-
benzofuranyl, 2-benzofuranyl, indolyl, isoindolyl, benzothiophenyl, 2-
benzothiophenyl, 1 H-indazolyl, benzimidazolyl, benzoxazolyl, indoxazinyl, 2,1-
benzisoxazolyl, benzothiazolyl, 1,2-benzisothiazolyl, 2, 1 -benzisothiazolyl,
benzotriazolyl, quinolinyl, isoquinolinyl, 2,3-benzodiazinyl, quinoxalinyl,
quinazolinyl, 1,2,3-benzotriazinyl, or 1,2,4-benzotriazinyl; optionally
substituted;
R"' is alkyl, alkenyl, alkynyl, in particular Ci-C6 alkyl, e.g. Cl, C2, C3,
C4, C5, or C6
alkyl, optionally substituted; and
R""' is hydrogen, alkyl, alkenyl, alkynyl, in particular CI-C6 alkyl, e.g. Ci,
C2, C3, C4,
C5, or C6 alkyl, optionally substituted;
Hal is F, Cl, Br or I, preferably F, Cl or Br;
n is an integer of 0 to 4, i.e. 0, 1, 2, 3, or 4, preferably 0, 1, or 2;
k is an integer of 0 to 4, i.e. 0, 1, 2, 3, or 4, preferably 0, 1, or 2, i.e.
up to the maximum
number of substituents on the respective aryl or heteroaryl;
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A, B, D and E are each independently of each other selected from carbon,
oxygen and nitrogen
atoms, with the proviso that at least two of A, B, D and E are carbon atoms,
more preferably A is
an oxygen or nitrogen atom and B, D, and E are carbon atoms; and
' marks the bond between R' and the compound according to formual (II).
In a further preferred embodiment the compound has a structure according to
formula
(IV)
X R11 R12
R1 , N~N
I N-R15
R2
R13 R14
(IV)
wherein R' and R 2 have the meaning as outlined above, in particular the
preferred meanings
outlined above and wherein
R", R'Z, R13 and R14 are independent of each other are H, halogen, e.g. F, Cl,
Br or I; CN; NO2;
NR'R"; alkyl, in particular Ci-C6 alkyl, e.g. Ci, C2, C3, C4, C5, or C6 alkyl,
preferably
methyl, ethyl, propyl, iso-propyl, butyl, iso-butyl, tert-butyl, pentyl,
hexyl; alkenyl, in
particular C2-C6 alkenyl, e.g. C2, C3, C4, C5, or C6 alkenyl, preferably
ethenyl, 1-propenyl,
2-propenyl, 1-iso-propenyl, 2-iso-propenyl, 1-butenyl, 2-butenyl, 3-butenyl;
alkynyl, in
particular C2-C6 alkynyl, e.g. C2, C3, C4, C5, or C6 alkynyl; alkoxy, in
particular C1-C6
alkoxy, e.g. Cl, C2, C3, C4, C5, or C6 alkoxy, preferably methoxy, ethoxy,
propoxy, iso-
propoxy, butoxy, iso-butoxy, tert-butoxy, pentoxy, or hexoxy; and
R15 is H; CN; -NR'R"; -SOz-R"", alkyl, in particular CI-C6 alkyl, e.g. Cl, C2,
C3, C4, C5, or
C6 alkyl, preferably methyl, ethyl, propyl, iso-propyl, butyl, iso-butyl, tert-
butyl, pentyl,
hexyl; alkenyl, in particular C2-C6 alkenyl, e.g. C2, C3, C4, C5, or C6
alkenyl, preferably
ethenyl, 1-propenyl, 2-propenyl, 1-iso-propenyl, 2-iso-propenyl, 1-butenyl, 2-
butenyl, 3-
butenyl; alkynyl, in particular C2-C6 alkynyl, e.g. C2, C3, C4, C5, or C6
alkynyl; alkanoyl,
preferably CI-C6 alkanoyl, e.g. Cl, C2, C3, C4, C5, or C6 alkanoyl; alkenoyl,
in particular
C3-C6 alkenoyl, e.g. C3, C4, C5, or C6 alkenoyl, preferably propenoyl;
alkynoyl, in
particular C3-C6 alkynoyl, e.g. C3, C4, C5, or C6 alkynoyl, preferably
propynoyl; alkoxy,
in particular CI-C6 alkoxy, e.g. Ci, C2, C3, C4, C5, or C6 alkoxy, preferably
methoxy,
ethoxy, propoxy, iso-propoxy, butoxy, iso-butoxy, tert-butoxy, pentoxy, or
hexoxy;
alkoxyalkyl, in particular CI-C6 alkoxy-Cl-C6 alkyl, e.g. methoxymethyl,
ethoxymethyl,
propoxymethyl, methoxyethyl, ethoxyethyl, propoxyethyl, methoxypropyl,
ethoxypropyl,
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or propoxypropyl; -OOC-R"'; -COO-R""'; aryl, in particular phenyl,
naphthalenyl or
anthracenyl; heteroaryl, in particular furanyl, thiophenyl, oxazolyl,
isoxazolyl, 1,2,5-
oxadiazolyl, 1,2,3-oxadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, 1,2,3-
triazolyl, thiazolyl,
isothiazolyl, 1,2,3,-thiadiazolyl, 1,2,5-thiadiazolyl, pyridinyl, pyrimidinyl,
pyrazinyl,
1,2,3-triazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, 1-benzofuranyl, 2-
benzofuranyl, indolyl,
isoindolyl, benzothiophenyl, 2-benzothiophenyl, 1 H-indazolyl, benzimidazolyl,
benzoxazolyl, indoxazinyl, 2,1 -benzisoxazolyl, benzothiazolyl, 1,2-
benzisothiazolyl, 2,1-
benzisothiazolyl, benzotriazolyl, quinolinyl, isoquinolinyl, 2,3-
benzodiazinyl,
quinoxalinyl, quinazolinyl, 1,2,3-benzotriazinyl, or 1,2,4-benzotriazinyl;
aralkyl, in
particular aryl-Cl-C6-alkyl, e.g. phenyl methyl, or phenyl ethyl; or
heteroaralkyl, in
particular hetero-CI -C6-alkyl; optionally substituted;
wherein R' and R" are independent of each other hydrogen; alkyl, in particular
CI-C6
alkyl, e.g. C1, C2, C3, C4, C5, or C6 alkyl; alkenyl, in particular C2-C6
alkenyl, e.g.
C2, C3, C4, C5, or C6 alkenyl; alkynyl, in particular C2-C6 alkynyl, e.g. C2,
C3, C4,
C5, or C6 alkynyl; aryl; or heteroaryl, in particular furanyl, thiophenyl,
oxazolyl,
isoxazolyl, 1,2,5-oxadiazolyl, 1,2,3-oxadiazolyl, pyrrolyl, imidazolyl,
pyrazolyl,
1,2,3-triazolyl, thiazolyl, isothiazolyl, 1,2,3,-thiadiazolyl, 1,2,5-
thiadiazolyl,
pyridinyl, pyrimidinyl, pyrazinyl, 1,2,3-triazinyl, 1,2,4-triazinyl, 1,3,5-
triazinyl, 1-
benzofuranyl, 2-benzofuranyl, indolyl, isoindolyl, benzothiophenyl, 2-
benzothiophenyl, 1 H-indazolyl, benzimidazolyl, benzoxazolyl, indoxazinyl, 2,1-
benzisoxazolyl, benzothiazolyl, 1,2-benzisothiazolyl, 2, 1 -benzisothiazolyl,
benzotriazolyl, quinolinyl, isoquinolinyl, 2,3-benzodiazinyl, quinoxalinyl,
quinazolinyl, 1,2,3-benzotriazinyl, or 1,2,4-benzotriazinyl; optionally
substituted;
R"' is alkyl, alkenyl, alkynyl, in particular C1-C6 alkyl, e.g. Cl, C2, C3,
C4, C5, or C6
alkyl, optionally substituted,
R"" is hydrogen, in particular Ci-C6 alkyl, e.g. Ci, C2, C3, C4, C5, or C6
alkyl,
preferably methyl, ethyl, propyl, iso-propyl, butyl, iso-butyl, tert-butyl,
pentyl,
hexyl; alkenyl, in particular C2-C6 alkenyl, e.g. C2, C3, C4, C5, or C6
alkenyl,
preferably ethenyl, 1-propenyl, 2-propenyl, 1-iso-propenyl, 2-iso-propenyl, 1-
butenyl, 2-butenyl, 3-butenyl; alkynyl, in particular C2-C6 alkynyl, e.g. C2,
C3, C4,
C5, or C6 alkynyl; aryl, in particular phenyl, naphthalenyl or anthracenyl;
heteroaryl, in particular furanyl, thiophenyl, oxazolyl, isoxazolyl, 1,2,5-
oxadiazolyl, 1,2,3-oxadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, 1,2,3-
triazolyl,
thiazolyl, isothiazolyl, 1,2,3,-thiadiazolyl, 1,2,5-thiadiazolyl, pyridinyl,
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pyrimidinyl, pyrazinyl, 1,2,3-triazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl,
1-benzofuranyl, 2-benzofuranyl, indolyl, isoindolyl, benzothiophenyl, 2-
benzothiophenyl, 1 H-indazolyl, benzimidazolyl, benzoxazolyl, indoxazinyl, 2,1-
benzisoxazoiyi, benzothiazolyl, 1,2-benzisothiazolyl, 2,1 -benzisothiazolyl,
benzotriazolyl, quinolinyl, isoquinolinyl, 2,3-benzodiazinyl, quinoxalinyl,
quinazolinyl, 1,2,3-benzotriazinyl, or 1,2,4-benzotriazinyl; aralkyl,
heteroaralkyl,
optionally substituted, and
R""' is hydrogen, alkyl, alkenyl, alkynyl, in particular CI-C6 alkyl, e.g. Ci,
C2, C3, C4,
C5, or C6 alkyl, optionally substituted;
In a further preferred embodiment R' in the structure according to formula (I)
or formula
(IV) has a structure according to formula (V)
R6
R7 R5
I
R8 (C\n
R9
(V)
R5, R6, R', R$ and R9 are independent of each other H, halogen, e.g. F, Cl, Br
or I; CN; NO2;
-NR'R"; alkyl, in particular Ci-C6 alkyl, e.g. C1, C2, C3, C4, C5, or C6
alkyl, preferably
methyl, ethyl, propyl, iso-propyl, butyl, iso-butyl, tert-butyl, pentyl,
hexyl; alkenyl, in
particular C2-C6 alkenyl, e.g. C2, C3, C4, C5, or C6 alkenyl, preferably
ethenyl, 1-propenyl,
2-propenyl, 1-iso-propenyl, 2-iso-propenyl, 1-butenyl, 2-butenyl, 3-butenyl;
alkynyl, in
particular C2-C6 alkynyl, e.g. C2, C3, C4, C5, or C6 alkynyl; alkoxy, in
particular CI-C6
alkoxy, e.g. Cl, C2, C3, C4, C5, or C6 alkoxy, preferably methoxy, ethoxy,
propoxy, iso-
propoxy, butoxy, iso-butoxy, tert-butoxy, pentoxy, or hexoxy; alkoxyalkyl, in
particular
Ci-C6 alkoxy-C1-C6 alkyl, e.g. methoxymethyl, ethoxymethyl, propoxymethyl,
methoxyethyl, ethoxyethyl, propoxyethyl, methoxypropyl, ethoxypropyl, or
propoxypropyl; -OOC-R"'; -COO-R""'; aryl, in particular phenyl, naphthalenyl
or
anthracenyl; heteroaryl, in particular furanyl, thiophenyl, oxazolyl,
isoxazolyl, 1,2,5-
oxadiazolyl, 1,2,3-oxadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, 1,2,3-
triazolyl, thiazolyl,
isothiazolyl, 1,2,3,-thiadiazolyl, 1,2,5-thiadiazolyl, pyridinyl, pyrimidinyl,
pyrazinyl,
1,2,3-triazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, 1-benzofuranyl, 2-
benzofuranyl, indolyl,
isoindolyl, benzothiophenyl, 2-benzothiophenyl, 1 H-indazolyl, benzimidazolyl,
benzoxazolyl, indoxazinyl, 2, 1 -benzisoxazolyl, benzothiazolyl, 1,2-
benzisothiazolyl, 2,1-
benzisothiazolyl, benzotriazolyl, quinolinyl, isoquinolinyl, 2,3-
benzodiazinyl,
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quinoxalinyl, quinazolinyl, 1,2,3-benzotriazinyl, or 1,2,4-benzotriazinyl;
optionally
substituted;
wherein R' and R" are independent of each other hydrogen; alkyl, in particular
C1-C6
alkyl, e.g. Ci, C2, C3, C4, C5, or C6 alkyl; alkenyl, in particular C2-C6
alkenyl, e.g.
5 C2, C3, C4, C5, or C6 alkenyl; alkynyl, in particular C2-C6 alkynyl, e.g.
C2, C3, C4,
C5, or C6 alkynyl; aryl; or heteroaryl, in particular furanyl, thiophenyl,
oxazolyl,
isoxazolyl, 1,2,5-oxadiazolyl, 1,2,3-oxadiazolyl, pyrrolyl, imidazolyl,
pyrazolyl,
1,2,3-triazolyl, thiazolyl, isothiazolyl, 1,2,3,-thiadiazolyl, 1,2,5-
thiadiazolyl,
pyridinyl, pyrimidinyl, pyrazinyl, 1,2,3-triazinyl, 1,2,4-triazinyl, 1,3,5-
triazinyl, 1-
10 benzofuranyl, 2-benzofuranyl, indolyl, isoindolyl, benzothiophenyl, 2-
benzothiophenyl, 1 H-indazolyl, benzimidazolyl, benzoxazolyl, indoxazinyl, 2,1-
benzisoxazolyl, benzothiazolyl, 1,2-benzisothiazolyl, 2, 1 -benzisothiazolyl,
benzotriazolyl, quinolinyl, isoquinolinyl, 2,3-benzodiazinyl, quinoxalinyl,
quinazolinyl, 1,2,3-benzotriazinyl, or 1,2,4-benzotriazinyl; optionally
substituted;
15 R"' is alkyl, alkenyl, alkynyl, in particular CI-C6 alkyl, e.g. Cl, C2, C3,
C4, C5, or C6
alkyl, optionally substituted; and
R""' is hydrogen, alkyl, alkenyl, alkynyl, in particular C1-C6 alkyl, e.g. C1,
C2, C3, C4,
C5, or C6 alkyl, optionally substituted;
or two or more of R5, R6, R', Rg and R9 are taken together to form a
cycloalkyl,
20 heterocycloalkyl, alicyclic ring system, aryl, or heteroaryl, optionally
substituted; and
n is an integer of 0 to 4, i.e. 0, 1, 2, 3, or 4, preferably 0, 1, or 2.
In a further preferred embodiment of the compound of the present invention
R' is CI-C4 aralkyl, e.g. C1, C2, C3, or C4 aralkyl or C1-C4 heteroaralkyl,
e.g. Cl, C2, C3, or
C4 heteroaralkyl; and
25 R3 is aryl, heteroaryl, C1-C4 aralkyl, or Ci-C4 heteroaralkyl, optionally
substituted,
preferably with 1, 2, 3, 4 or more substituents selected from the group
consisting of
halogen, e.g. F, Cl, Br or I; CN; NO2; NR'R"; alkyl, in particular C1-C6
alkyl, e.g. C1, C2,
C3, C4, C5, or C6 alkyl, preferably methyl, ethyl, propyl, iso-propyl, butyl,
iso-butyl,
tert-butyl, pentyl, hexyl; alkenyl, in particular C2-C6 alkenyl, e.g. C2, C3,
C4, C5, or C6
30 alkenyl, preferably ethenyl, 1-propenyl, 2-propenyl, 1-iso-propenyl, 2-iso-
propenyl, 1-
butenyl, 2-butenyl, 3-butenyl; alkynyl, in particular C2-C6 alkynyl, e.g. C2,
C3, C4, C5, or
C6 alkynyl; alkanoyl, preferably C1-C6 alkanoyl, e.g. Cl, C2, C3, C4, C5, or
C6 alkanoyl;
alkenoyl, in particular C3-C6 alkenoyl, e.g. C3, C4, C5, or C6 alkenoyl,
preferably
propenoyl; alkynoyl, in particular C3-C6 alkynoyl, e.g. C3, C4, C5, or C6
alkynoyl,
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preferably propynoyl; alkoxy, in particular Ci-C6 alkoxy, e.g. Ci, C2, C3, C4,
C5, or C6
alkoxy, preferably methoxy, ethoxy, propoxy, iso-propoxy, butoxy, iso-butoxy,
tert-
butoxy, pentoxy, or hexoxy; alkoxyalkyl, in particular CI-C6 alkoxy-Cl-C6
alkyl, e.g.
methoxymethyl, ethoxymethyl, propoxymethyl, methoxyethyl, ethoxyethyl,
propoxyethyl, methoxypropyl, ethoxypropyl, or propoxypropyl; -OOC-R"'; -COO-
R""'; aryl, in particular phenyl, naphthalenyl or anthracenyl; heteroaryl, in
particular
furanyl, thiophenyl, oxazolyl, isoxazolyl, 1,2,5-oxadiazolyl, 1,2,3-
oxadiazolyl, pyrrolyl,
imidazolyl, pyrazolyl, 1,2,3-triazolyl, thiazolyl, isothiazolyl, 1,2,3,-
thiadiazolyl, 1,2,5-
thiadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, 1,2,3-triazinyl, 1,2,4-
triazinyl, 1,3,5-
triazinyl, 1-benzofuranyl, 2-benzofuranyl, indolyl, isoindolyl,
benzothiophenyl, 2-
benzothiophenyl, 1 H-indazolyl, benzimidazolyl, benzoxazolyl, indoxazinyl, 2,1-
benzisoxazolyl, benzothiazolyl, 1,2-benzisothiazolyl, 2, 1 -benzisothiazolyl,
benzotriazolyl, quinolinyl, isoquinolinyl, 2,3-benzodiazinyl, quinoxalinyl,
quinazolinyl,
1,2,3-benzotriazinyl, or 1,2,4-benzotriazinyl; optionally substituted, wherein
R' and R" are independent of each other hydrogen; alkyl, in particular C1-C6
alkyl, e.g.
Cl, C2, C3, C4, C5, or C6 alkyl; alkenyl, in particular C2-C6 alkenyl, e.g.
C2, C3, C4,
C5, or C6 alkenyl; alkynyl, in particular C2-C6 alkynyl, e.g. C2, C3, C4, C5,
or C6
alkynyl; aryl; or heteroaryl, in particular furanyl, thiophenyl, oxazolyl,
isoxazolyl,
1,2,5-oxadiazolyl, 1,2,3-oxadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, 1,2,3-
triazolyl, thiazolyl, isothiazolyl, 1,2,3,-thiadiazolyl, 1,2,5-thiadiazolyl,
pyridinyl,
pyrimidinyl, pyrazinyl, 1,2,3-triazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, 1-
benzofuranyl, 2-benzofuranyl, indolyl, isoindolyl, benzothiophenyl, 2-
benzothiophenyl, 1 H-indazolyl, benzimidazolyl, benzoxazolyl, indoxazinyl, 2,1-
benzisoxazolyl, benzothiazolyl, 1,2-benzisothiazolyl, 2,1 -benzisothiazolyl,
benzotriazolyl, quinolinyl, isoquinolinyl, 2,3-benzodiazinyl, quinoxalinyl,
quinazolinyl, 1,2,3-benzotriazinyl, or 1,2,4-benzotriazinyl; optionally
substituted;
R"' is alkyl, alkenyl, alkynyl, in particular CI-C6 alkyl, e.g. CI, C2, C3,
C4, C5, or C6
alkyl, optionally substituted; and
R""' is hydrogen, alkyl, alkenyl, alkynyl, in particular CI-C6 alkyl, e.g. Ci,
C2, C3, C4,
C5, or C6 alkyl, optionally substituted;
or two or more substituents are taken together to form a cycloalkyl,
heterocycloalkyl,
alicyclic ring system, aryl or heteroaryl, wherein R' and R" are independent
of each
other hydrogen, alkyl, alkenyl, or alkynyl.
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In a preferred embodiment of the compound of formula (V) the substituents R5,
R6, R7,
R8, and R9 of the left (Co4)alkylphenyl residue, i.e R1, have a structure:
O OyO\Rb O
W((CH2)n ORb ~ ( O O, Rb O, Rb
I/ CH 2 )n (CH2)n (CH z )n (CH 2)n
)
(Ra)k * (Ra)k * (Ra)k * (Ra)k * (Ra)k *
ORc Rb, O
Rb' O Rb" O O" Rc O, Rc (( Rn
(CH2)n (CH2)n /(CH2)n , O ((CH2)n
(Ra)k (Ra)k (Ra)k (Ra)k
NRdRe
( Hal ( 0--"(CH2)n
CH2)n CH2)n 5 (Ra)k (Ra)k or (Ra)k *\ ~
wherein
Ra is halogen, e.g. F, Cl, Br or I; CN; NO2; -NR'R"; alkyl, in particular Ci-
C6 alkyl, e.g. C1,
C2, C3, C4, C5, or C6 alkyl, preferably methyl, ethyl, propyl, iso-propyl,
butyl, iso-butyl,
tert-butyl, pentyl, hexyl; alkenyl, in particular C2-C6 alkenyl, e.g. C2, C3,
C4, C5, or C6
alkenyl, preferably ethenyl, 1-propenyl, 2-propenyl, 1-iso-propenyl, 2-iso-
propenyl, 1-
butenyl, 2-butenyl, 3-butenyl; alkynyl, in particular C2-C6 alkynyl, e.g. C2,
C3, C4, C5, or
C6 alkynyl; alkanoyl, preferably C1-C6 alkanoyl, e.g. Cl, C2, C3, C4, C5, or
C6 alkanoyl;
alkenoyl, in particular C3-C6 alkenoyl, e.g. C3, C4, C5, or C6 alkenoyl,
preferably
propenoyl; alkynoyl, in particular C3-C6 alkynoyl, e.g. C3, C4, C5, or C6
alkynoyl,
preferably propynoyl; alkoxy, in particular C1-C6 alkoxy, e.g. Cl, C2, C3, C4,
C5, or C6
alkoxy, preferably methoxy, ethoxy, propoxy, iso-propoxy, butoxy, iso-butoxy,
tert-
butoxy, pentoxy, or hexoxy; alkoxyalkyl, in particular Ci-C6 alkoxy-Ci-C6
alkyl, e.g.
methoxymethyl, ethoxymethyl, propoxymethyl, methoxyethyl, ethoxyethyl,
propoxyethyl, methoxypropyl, ethoxypropyl, or propoxypropyl; -OOC-R"'; -COO-
R""'; aryl, in particular phenyl, naphthalenyl or anthracenyl; heteroaryl, in
particular
furanyl, thiophenyl, oxazolyl, isoxazolyl, 1,2,5-oxadiazolyl, 1,2,3-
oxadiazolyl, pyrrolyl,
imidazolyl, pyrazolyl, 1,2,3-triazolyl, thiazolyl, isothiazolyl, 1,2,3,-
thiadiazolyl, 1,2,5-
thiadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, 1,2,3-triazinyl, 1,2,4-
triazinyl, 1,3,5-
triazinyl, 1-benzofuranyl, 2-benzofuranyl, indolyl, isoindolyl,
benzothiophenyl, 2-
benzothiophenyl, 1 H-indazolyl, benzimidazolyl, benzoxazolyl, indoxazinyl, 2,1-
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benzisoxazolyl, benzothiazolyl, 1,2-benzisothiazolyl, 2, 1 -benzisothiazolyl,
benzotriazolyl, quinolinyl, isoquinolinyl, 2,3-benzodiazinyl, quinoxalinyl,
quinazolinyl,
1,2,3-benzotriazinyl, or 1,2,4-benzotriazinyl; optionally substituted;
or iwo aajacent Ra together form an aryl or heteroaryl residue, preferably
resulting in a
two or three membered aryl or heteroaryl;
wherein
R' and R" are independent of each other hydrogen; alkyl, in particular C1-C6
alkyl, e.g.
Cl, C2, C3, C4, C5, or C6 alkyl; alkenyl, in particular C2-C6 alkenyl, e.g.
C2, C3, C4,
C5, or C6 alkenyl; alkynyl, in particular C2-C6 alkynyl, e.g. C2, C3, C4, C5,
or C6
alkynyl; aryl; or heteroaryl, in particular furanyl, thiophenyl, oxazolyl,
isoxazolyl,
1,2,5-oxadiazolyl, 1,2,3-oxadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, 1,2,3-
triazolyl, thiazolyl, isothiazolyl, 1,2,3,-thiadiazolyl, 1,2,5-thiadiazolyl,
pyridinyl,
pyrimidinyl, pyrazinyl, 1,2,3-triazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, 1-
benzofuranyl, 2-benzofuranyl, indolyl, isoindolyl, benzothiophenyl, 2-
benzothiophenyl, 1 H-indazolyl, benzimidazolyl, benzoxazolyl, indoxazinyl, 2,1-
benzisoxazolyl, benzothiazolyl, 1,2-benzisothiazolyl, 2, 1 -benzisothiazolyl,
benzotriazolyl, quinolinyl, isoquinolinyl, 2,3-benzodiazinyl, quinoxalinyl,
quinazolinyl, 1,2,3-benzotriazinyl, or 1,2,4-benzotriazinyl; optionally
substituted;
R"' is alkyl, alkenyl, alkynyl, in particular C1-C6 alkyl, e.g. Ci, C2, C3,
C4, C5, or C6
alkyl, optionally substituted; and
R""' is hydrogen, alkyl, alkenyl, alkynyl, in particular CI-C6 alkyl, e.g. Cl,
C2, C3, C4,
C5, or C6 alkyl, optionally substituted;
Rb and R are independent of each other hydrogen, alkyl, in particular C1-C6
alkyl, e.g. C1, C2,
C3, C4, C5, or C6 alkyl, preferably methyl, ethyl, propyl, iso-propyl, butyl,
iso-butyl, tert-
butyl, pentyl, hexyl; alkenyl, in particular C2-C6 alkenyl, e.g. C2, C3, C4,
C5, or C6
alkenyl, preferably ethenyl, 1-propenyl, 2-propenyl, 1-iso-propenyl, 2-iso-
propenyl, 1-
butenyl, 2-butenyl, 3-butenyl; alkynyl, in particular C2-C6 alkynyl, e.g. C2,
C3, C4, C5, or
C6 alkynyl; optionally substituted;
Rd and Re are independent of each other hydrogen, alkyl, in particular CI-C6
alkyl, e.g. Cl, C2,
C3, C4, C5, or C6 alkyl, preferably methyl, ethyl, propyl, iso-propyl, butyl,
iso-butyl, tert-
butyl, pentyl, hexyl; alkenyl, in particular C2-C6 alkenyl, e.g. C2, C3, C4,
C5, or C6
alkenyl, preferably ethenyl, 1-propenyl, 2-propenyl, 1-iso-propenyl, 2-iso-
propenyl, 1-
butenyl, 2-butenyl, 3-butenyl; alkynyl, in particular C2-C6 alkynyl, e.g. C2,
C3, C4, C5, or
C6 alkynyl; optionally substituted;
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Hal is F, Cl, Br or I, preferably F, Cl or Br;
n is an integer of 0 to 4, i.e. 0, 1, 2, 3, or 4, preferably 0, 1, or 2;
k is an integer of 0 to 4, i.e. 0, 1, 2, 3, or 4, preferably 0, 1, or 2, i.e.
up to the maximum
number of substituents on the phenyl; and
* marks the bond between the substituent according to formula (V) and the
remaining
compound according to formula (I) or (IV). In this context it is particularly
preferred that R' 5 has
the preferred meanings indicated below.
In a further preferred embodiment of the compound according to formula (IV)
R15 has a
structure according to formula
O
(CHZ)n 0 (CHZ)n ~ '(CH2) j (CHZ) j
~ 1 1 ~
O O
(Ra)k (Ra)k (Ra)k I (Ra)k
/ J
O
(CH2)n 0
O (CH2) j O ~(CHz)n
(Ra)k (CH2)n (Ra)k O
O~ O (Ra)k I (Ra)k
/Rb
(CH2)n 0 (CHz)n O Rb
OI (CH2)n CHZ) O
J r
(Ra)k (Ra)k (Ra)k (Ra)k
Rc
Rb 0
O (CH2)n Rb
(CH2)n (CH2)n O.
~ I (Ra)k '(CHZ)n 0 (Ra)k Rb (Ra)k RC O, Rb RC, (Ra)k
O
Rc
0
(CH2)n ~ (CH2)n (CH2)/
xo O (CH2) j
~ I 0
(Ra)k Rb (Ra)k (Ra)k (Ra)k
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(CH2)n (CHZ)n (CH2)n (CH2)n (CH2)n
(Ra)k (Ra)k (Ra)k (Ra)k (Ra)k
O 0
(CH2)n 0
I . (CH2)n
(CHz) (CH\jp` B (CHZ)
G,E~ID 1III
(Ra)k (Ra)k \ (Ra)k 0
O O
O A
(CH2)n A A N \
~ \ / \ / \ (CHz)n EI~ B
~ ~ C (Ra)k
EI ~B (Ra)k B
E~
D (Ra)k D (Ra)k O
0
OH (CHz)n v '(CHz)n
~'(CH2)n OH (CHz)n
OH
(Ra)k (Ra)k (Ra)k (Ra)k
Hal
(CH2) j (CHz)/ Hal
(CHz)n
iI1IIIi Hal
5 (Ra)k (Ra)k (Ra)k (Ra)k
O 0
(CHz)n (CHz)n
(Ra)k or (Ra)k O
wherein
Ra is halogen, e.g. F, Cl, Br or I; CN; NO2; -NR'R"; alkyl, in particular Ci-
C6 alkyl, e.g. Cl,
C2, C3, C4, C5, or C6 alkyl, preferably methyl, ethyl, propyl, iso-propyl,
butyl, iso-butyl,
10 tert-butyl, pentyl, hexyl; alkenyl, in particular C2-C6 alkenyl, e.g. C2,
C3, C4, C5, or C6
alkenyl, preferably ethenyl, 1-propenyl, 2-propenyl, 1-iso-propenyl, 2-iso-
propenyl, 1-
butenyl, 2-butenyl, 3-butenyl; alkynyl, in particular C2-C6 alkynyl, e.g. C2,
C3, C4, C5, or
C6 alkynyl; alkanoyl, preferably CI-C6 alkanoyl, e.g. Cl, C2, C3, C4, C5, or
C6 alkanoyl;
alkenoyl, in particular C3-C6 alkenoyl, e.g. C3, C4, C5, or C6 alkenoyl,
preferably
15 propenoyl; alkynoyl, in particular C3-C6 alkynoyl, e.g. C3, C4, C5, or C6
alkynoyl,
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preferably propynoyl; alkoxy, in particular CI-C6 alkoxy, e.g. Cl, C2, C3, C4,
C5, or C6
alkoxy, preferably methoxy, ethoxy, propoxy, iso-propoxy, butoxy, iso-butoxy,
tert-
butoxy, pentoxy, or hexoxy; alkoxyalkyl, in particular CI-C6 alkoxy-C1-C6
alkyl, e.g.
rnerhoxymethyl, ethoxymethyl, propoxymethyl, methoxyethyl, ethoxyethyl,
propoxyethyl, methoxypropyl, ethoxypropyl, or propoxypropyl; -OOC-R"'; -COO-
R""'; aryl, in particular phenyl, naphthalenyl or anthracenyl; heteroaryl, in
particular
furanyl, thiophenyl, oxazolyl, isoxazolyl, 1,2,5-oxadiazolyl, 1,2,3-
oxadiazolyl, pyrrolyl,
imidazolyl, pyrazolyl, 1,2,3-triazolyl, thiazolyl, isothiazolyl, 1,2,3,-
thiadiazolyl, 1,2,5-
thiadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, 1,2,3-triazinyl, 1,2,4-
triazinyl, 1,3,5-
triazinyl, 1-benzofuranyl, 2-benzofuranyl, indolyl, isoindolyl,
benzothiophenyl, 2-
benzothiophenyl, 1 H-indazolyl, benzimidazolyl, benzoxazolyl, indoxazinyl, 2,1-
benzisoxazolyl, benzothiazolyl, 1,2-benzisothiazolyl, 2, 1 -benzisothiazolyl,
benzotriazolyl, quinolinyl, isoquinolinyl, 2,3-benzodiazinyl, quinoxalinyl,
quinazolinyl,
1,2,3-benzotriazinyl, or 1,2,4-benzotriazinyl; optionally substituted;
or two adjacent Ra together form an aryl or heteroaryl residue, preferably
resulting in a
two or three membered aryl or heteroaryl;
wherein
R' and R" are independent of each other hydrogen; alkyl, in particular CI-C6
alkyl, e.g.
Cl, C2, C3, C4, C5, or C6 alkyl; alkenyl, in particular C2-C6 alkenyl, e.g.
C2, C3, C4,
C5, or C6 alkenyl; alkynyl, in particular C2-C6 alkynyl, e.g. C2, C3, C4, C5,
or C6
alkynyl; aryl; or heteroaryl, in particular furanyl, thiophenyl, oxazolyl,
isoxazolyl,
1,2,5-oxadiazolyl, 1,2,3-oxadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, 1,2,3-
triazolyl, thiazolyl, isothiazolyl, 1,2,3,-thiadiazolyl, 1,2,5-thiadiazolyl,
pyridinyl,
pyrimidinyl, pyrazinyl, 1,2,3-triazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, 1-
benzofuranyl, 2-benzofuranyl, indolyl, isoindolyl, benzothiophenyl, 2-
benzothiophenyl, 1 H-indazolyl, benzimidazolyl, benzoxazolyl, indoxazinyl, 2,1-
benzisoxazolyl, benzothiazolyl, 1,2-benzisothiazolyl, 2,1 -benzisothiazolyl,
benzotriazolyl, quinolinyl, isoquinolinyl, 2,3-benzodiazinyl, quinoxalinyl,
quinazolinyl, 1,2,3-benzotriazinyl, or 1,2,4-benzotriazinyl; optionally
substituted;
R"' is alkyl, alkenyl, alkynyl, in particular CI-C6 alkyl, e.g. C1, C2, C3,
C4, C5, or C6
alkyl, optionally substituted; and
R""' is hydrogen, alkyl, alkenyl, alkynyl, in particular C1-C6 alkyl, e.g. C1,
C2, C3, C4,
C5, or C6 alkyl, optionally substituted;
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Rb and R' are independent of each other hydrogen, alkyl, in particular Ci-C6
alkyl, e.g. Cl, C2,
C3, C4, C5, or C6 alkyl, preferably methyl, ethyl, propyl, iso-propyl, butyl,
iso-butyl, tert-
butyl, pentyl, hexyl; alkenyl, in particular C2-C6 alkenyl, e.g. C2, C3, C4,
C5, or C6
alkenyl, preferably ethenyl, 1-propenyl, 2-propenyl, 1-iso-propenyl, 2-iso-
propenyl, 1-
butenyl, 2-butenyl, 3-butenyl; alkynyl, in particular C2-C6 alkynyl, e.g. C2,
C3, C4, C5, or
C6 alkynyl; cycloalkyl, in particular (C3_10)-cycloalkyl, preferably
cyclopropyl,
cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, heteroalkyl in particular
(Cl-
C6)heteroalkyl, e.g. Cl, C2, C3, C4, C5, or C6 heteroalkyl, cycloheteroalkyl,
in particular
(C3_10)-cycloheteroalkyl; optionally substituted;
Hal is F, Cl, Br or I, preferably F, Cl or Br;
n is an integer of 0 to 4, i.e. 0, 1, 2, 3, or 4, preferably 0, 1, or 2;
k is an integer of 0 to 4, i.e. 0, 1, 2, 3, or 4, preferably 0, 1, or 2, i.e.
up to the maximum
number of substituents on the respective aryl or heteroaryl;
For six-membered rings A, B, D, E and G are each independently of each other
selected from
carbon and nitrogen atoms, with the proviso that at least two, preferably
three, four or five of A,
B, D, E and G are carbon atoms, more preferably A is a nitrogen atom and B, D,
E, and G are
carbon atoms or D is nitrogen and A, B, E, and G are carbon atoms. For five-
membered rings A,
B, D, and E are each independently of each other selected from carbon, oxygen,
sulphur and
nitrogen atoms, with the proviso that at least two of A, B, D, and E are
carbon atoms, more
preferably A is an oxygen or sulphur atom and B, D, and E are carbon atoms or
D is oxygen or
nitrogen and A, B, and E are carbon atoms. If R15 has the preferred meanings
indicated above, it
is particularly preferred that R' has a structure according to formula (V),
wherein the substituents
R5, R6, R', R8 and R9 have the indicated preferred meanings.
In a further preferred embodiment the compound of the present invention has a
structure
according to formula (VI)
R6 R17
R7 , R5 R16 R18
~ x
R19
R8 \ (CH2) ~ ~(CH2)P R20
R9 N N
R2 R4
(VI)
wherein
R5, R6, R', R8 and R9 are independent of each other H, halogen, e.g. F, Cl, Br
or I; CN; NO2;
-NR'R"; alkyl, in particular CI-C6 alkyl, e.g. Cl, C2, C3, C4, C5, or C6
alkyl, preferably
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58
methyl, ethyl, propyl, iso-propyl, butyl, iso-butyl, tert-butyl, pentyl,
hexyl; alkenyl, in
particular C2-C6 alkenyl, e.g. C2, C3, C4, C5, or C6 alkenyl, preferably
ethenyl, 1-propenyl,
2-propenyl, 1-iso-propenyl, 2-iso-propenyl, 1-butenyl, 2-butenyl, 3-butenyl;
alkynyl, in
particular C2-C6 alkynyl, e.g. C2, C3, C4, C5, or C6 alkynyl; alkoxy, in
particular Ci-C6
alkoxy, e.g. Cl, C2, C3, C4, C5, or C6 alkoxy, preferably methoxy, ethoxy,
propoxy, iso-
propoxy, butoxy, iso-butoxy, tert-butoxy, pentoxy, or hexoxy; alkoxyalkyl, in
particular
CI-C6 alkoxy-Ci-C6 alkyl, e.g. methoxymethyl, ethoxymethyl, propoxymethyl,
methoxyethyl, ethoxyethyl, propoxyethyl, methoxypropyl, ethoxypropyl, or
propoxypropyl; -OOC-R"'; -COO-R""'; aryl, in particular phenyl, naphthalenyl
or
anthracenyl; heteroaryl, in particular furanyl, thiophenyl, oxazolyl,
isoxazolyl, 1,2,5-
oxadiazolyl, 1,2,3-oxadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, 1,2,3-
triazolyl, thiazolyl,
isothiazolyl, 1,2,3,-thiadiazolyl, 1,2,5-thiadiazolyl, pyridinyl, pyrimidinyl,
pyrazinyl,
1,2,3-triazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, 1-benzofuranyl, 2-
benzofuranyl, indolyl,
isoindolyl, benzothiophenyl, 2-benzothiophenyl, 1H-indazolyl, benzimidazolyl,
benzoxazolyl, indoxazinyl, 2,1-benzisoxazolyl, benzothiazolyl, 1,2-
benzisothiazolyl, 2,1-
benzisothiazolyl, benzotriazolyl, quinolinyl, isoquinolinyl, 2,3-
benzodiazinyl,
quinoxalinyl, quinazolinyl, 1,2,3-benzotriazinyl, or 1,2,4-benzotriazinyl;
optionally
substituted;
wherein R' and R" are independent of each other hydrogen; alkyl, in particular
CI-C6
alkyl, e.g. C1, C2, C3, C4, C5, or C6 alkyl; alkenyl, in particular C2-C6
alkenyl, e.g.
C2, C3, C4, C5, or C6 alkenyl; alkynyl, in particular C2-C6 alkynyl, e.g. C2,
C3, C4,
C5, or C6 alkynyl; aryl; or heteroaryl, in particular furanyl, thiophenyl,
oxazolyl,
isoxazolyl, 1,2,5-oxadiazolyl, 1,2,3-oxadiazolyl, pyrrolyl, imidazolyl,
pyrazolyl,
1,2,3-triazolyl, thiazolyl, isothiazolyl, 1,2,3,-thiadiazolyl, 1,2,5-
thiadiazolyl,
pyridinyl, pyrimidinyl, pyrazinyl, 1,2,3-triazinyl, 1,2,4-triazinyl, 1,3,5-
triazinyl, 1-
benzofuranyl, 2-benzofuranyl, indolyl, isoindolyl, benzothiophenyl, 2-
benzothiophenyl, 1 H-indazolyl, benzimidazolyl, benzoxazolyl, indoxazinyl, 2,1-
benzisoxazolyl, benzothiazolyl, 1,2-benzisothiazolyl, 2,1 -benzisothiazolyl,
benzotriazolyl, quinolinyl, isoquinolinyl, 2,3-benzodiazinyl, quinoxalinyl,
quinazolinyl, 1,2,3-benzotriazinyl, or 1,2,4-benzotriazinyl; optionally
substituted;
R"' is alkyl, alkenyl, alkynyl, in particular CI-C6 alkyl, e.g. C1, C2, C3,
C4, C5, or C6
alkyl, optionally substituted; and
R""' is hydrogen, alkyl, alkenyl, alkynyl, in particular CI-C6 alkyl, e.g. Cl,
C2, C3, C4,
C5, or C6 alkyl, optionally substituted;
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or two or more of R5, R6, R', Rg and R9 are taken together to form a
cycloalkyl,
heterocycloalkyl, alicyclic ring system, aryl, or heteroaryl, optionally
substituted;
and
or two or more of R5, R6, R7, R and R9 are taken together to form a
cycloalkyl,
heterocycloalkyl, alicyclic ring system, aryl, or heteroaryl, optionally
substituted; and
R16, R17 , R18, R19 and R20 are independent of each other H, halogen, CN, NO2,
NR'R", alkyl,
alkenyl, alkynyl, alkoxy, are independent of each other H, halogen, e.g. F,
Cl, Br or I;
CN; NO2; -NR'R"; alkyl, in particular CI-C6 alkyl, e.g. Cl, C2, C3, C4, C5, or
C6 alkyl,
preferably methyl, ethyl, propyl, iso-propyl, butyl, iso-butyl, tert-butyl,
pentyl, hexyl;
alkenyl, in particular C2-C6 alkenyl, e.g. C2, C3, C4, C5, or C6 alkenyl,
preferably ethenyl,
1-propenyl, 2-propenyl, 1-iso-propenyl, 2-iso-propenyl, 1-butenyl, 2-butenyl,
3-butenyl;
alkynyl, in particular C2-C6 alkynyl, e.g. C2, C3, C4, C5, or C6 alkynyl;
alkoxy, in
particular Ci-C6 alkoxy, e.g. CI, C2, C3, C4, C5, or C6 alkoxy, preferably
methoxy, ethoxy,
propoxy, iso-propoxy, butoxy, iso-butoxy, tert-butoxy, pentoxy, or hexoxy;
alkoxyalkyl,
in particular CI-C6 alkoxy-Cl-C6 alkyl, e.g. methoxymethyl, ethoxymethyl,
propoxymethyl, methoxyethyl, ethoxyethyl, propoxyethyl, methoxypropyl,
ethoxypropyl,
or propoxypropyl; -OOC-R"'; -COO-R""'; aryl, in particular phenyl,
naphthalenyl or
anthracenyl; heteroaryl, in particular furanyl, thiophenyl, oxazolyl,
isoxazolyl, 1,2,5-
oxadiazolyl, 1,2,3-oxadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, 1,2,3-
triazolyl, thiazolyl,
isothiazolyl, 1,2,3,-thiadiazolyl, 1,2,5-thiadiazolyl, pyridinyl, pyrimidinyl,
pyrazinyl,
1,2,3-triazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, 1-benzofuranyl, 2-
benzofuranyl, indolyl,
isoindolyl, benzothiophenyl, 2-benzothiophenyl, 1 H-indazolyl, benzimidazolyl,
benzoxazolyl, indoxazinyl, 2, 1 -benzisoxazolyl, benzothiazolyl, 1,2-
benzisothiazolyl, 2,1-
benzisothiazolyl, benzotriazolyl, quinolinyl, isoquinolinyl, 2,3-
benzodiazinyl,
quinoxalinyl, quinazolinyl, 1,2,3-benzotriazinyl, or 1,2,4-benzotriazinyl;
optionally
substituted;
wherein R' and R" are independent of each other hydrogen; alkyl, in particular
CI-C6
alkyl, e.g. Cl, C2, C3, C4, C5, or C6 alkyl; alkenyl, in particular C2-C6
alkenyl, e.g.
C2, C3, C4, C5, or C6 alkenyl; alkynyl, in particular C2-C6 alkynyl, e.g. C2,
C3, C4,
C5, or C6 alkynyl; aryl; or heteroaryl, in particular furanyl, thiophenyl,
oxazolyl,
isoxazolyl, 1,2,5-oxadiazolyl, 1,2,3-oxadiazolyl, pyrrolyl, imidazolyl,
pyrazolyl,
1,2,3-triazolyl, thiazolyl, isothiazolyl, 1,2,3,-thiadiazolyl, 1,2,5-
thiadiazolyl,
pyridinyl, pyrimidinyl, pyrazinyl, 1,2,3-triazinyl, 1,2,4-triazinyl, 1,3,5-
triazinyl, 1-
benzofuranyl, 2-benzofuranyl, indolyl, isoindolyl, benzothiophenyl, 2-
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benzothiophenyl, I H-indazolyl, benzimidazolyl, benzoxazolyl, indoxazinyl, 2,1
-
benzisoxazolyl, benzothiazolyl, 1,2-benzisothiazolyl, 2,1 -benzisothiazolyl,
benzotriazolyl, quinolinyl, isoquinolinyl, 2,3-benzodiazinyl, quinoxalinyl,
quinazolinyl, 1,2,3-benzotriazinyl, or 1,2,4-benzotriazinyl; optionally
substituted;
5 R"' is alkyl, alkenyl, alkynyl, in particular CI-C6 alkyl, e.g. Cl, C2, C3,
C4, C5, or C6
alkyl, optionally substituted; and
R""' is hydrogen, alkyl, alkenyl, alkynyl, in particular CI-C6 alkyl, e.g. Cl,
C2, C3, C4,
C5, or C6 alkyl, optionally substituted;
or two or more of R16, R17 , R18, R19 and R20 are taken together to form a
cycloalkyl,
10 heterocycloalkyl, alicyclic ring system, aryl, or heteroaryl, optionally
substituted;
o is 1 to 4, e.g. 1, 2, 3, or 4, preferably 1 or 2; and
p is 0 to 4, e.g. 0, 1, 2, 3, or 4, preferably 0, 1, or 2.
In above preferred embodiment, wherein the compound has a structure according
to
formula (VI) it is particularly preferred that
15 R 2 is H, alkyl, in particular C1-C6 alkyl, e.g. Ci, C2, C3, C4, C5, or C6
alkyl, optionally
substituted; and
R4 is H, alkyl, in particular CI-C6 alkyl, e.g. Cl, C2, C3, C4, C5, or C6
alkyl, optionally
substituted.
In a further preferred embodiment of the compound of the present invention
20 R' is Ci to C4 aralkyl or Ci or C4 heteroaralkyl, optionally substituted;
and
R3 is branched or linear Ci to C10 alkyl, e.g. Ci, C2, C3, C4, C5, C6, C7, C8,
C9, and C10 alkyl,
optionally substituted, preferably with 1, 2, 3, 4 or more substituents
selected from the
group consisting of halogen, e.g. F, Cl, Br or I; CN; NO2; NR'R"; alkyl, in
particular Cl-
C6 alkyl, e.g. Cl, C2, C3, C4, C5, or C6 alkyl, preferably methyl, ethyl,
propyl, iso-propyl,
25 butyl, iso-butyl, tert-butyl, pentyl, hexyl; alkenyl, in particular C2-C6
alkenyl, e.g. C2, C3,
C4, C5, or C6 alkenyl, preferably ethenyl, 1-propenyl, 2-propenyl, 1-iso-
propenyl, 2-iso-
propenyl, 1-butenyl, 2-butenyl, 3-butenyl; alkynyl, in particular C2-C6
alkynyl, e.g. C2,
C3, C4, C5, or C6 alkynyl; alkanoyl, preferably C1-C6 alkanoyl, e.g. C1, C2,
C3, C4, C5, or
C6 alkanoyl; alkenoyl, in particular C3-C6 alkenoyl, e.g. C3, C4, C5, or C6
alkenoyl,
30 preferably propenoyl; alkynoyl, in particular C3-C6 alkynoyl, e.g. C3, C4,
C5, or C6
alkynoyl, preferably propynoyl; alkoxy, in particular C1-C6 alkoxy, e.g. Cl,
C2, C3, C4,
C5, or C6 alkoxy, preferably methoxy, ethoxy, propoxy, iso-propoxy, butoxy,
iso-butoxy,
tert-butoxy, pentoxy, or hexoxy; alkoxyalkyl, in particular C1-C6 alkoxy-Cl-C6
alkyl, e.g.
methoxymethyl, ethoxymethyl, propoxymethyl, methoxyethyl, ethoxyethyl,
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61
propoxyethyl, methoxypropyl, ethoxypropyl, or propoxypropyl; -OOC-R"'; -COO-
R""'; aryl, in particular phenyl, naphthalenyl or anthracenyl; heteroaryl, in
particular
furanyl, thiophenyl, oxazolyl, isoxazolyl, 1,2,5-oxadiazolyl, 1,2,3-
oxadiazolyl, pyrrolyl,
imidazolyl, pyrazoiyi, 1,2,3-triazolyl, thiazolyl, isothiazolyl, 1,2,3,-
thiadiazolyl, 1,2,5-
thiadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, 1,2,3-triazinyl, 1,2,4-
triazinyl, 1,3,5-
triazinyl, 1-benzofuranyl, 2-benzofuranyl, indolyl, isoindolyl,
benzothiophenyl, 2-
benzothiophenyl, 1 H-indazolyl, benzimidazolyl, benzoxazolyl, indoxazinyl, 2,1-
benzisoxazolyl, benzothiazolyl, 1,2-benzisothiazolyl, 2,1 -benzisothiazolyl,
benzotriazolyl, quinolinyl, isoquinolinyl, 2,3-benzodiazinyl, quinoxalinyl,
quinazolinyl,
1,2,3-benzotriazinyl, or 1,2,4-benzotriazinyl; optionally substituted, wherein
R' and R" are independent of each other hydrogen; alkyl, in particular CI-C6
alkyl, e.g.
Ci, C2, C3, C4, C5, or C6 alkyl; alkenyl, in particular C2-C6 alkenyl, e.g.
C2, C3, C4,
C5, or C6 alkenyl; alkynyl, in particular C2-C6 alkynyl, e.g. C2, C3, C4, C5,
or C6
alkynyl; aryl; or heteroaryl, in particular furanyl, thiophenyl, oxazolyl,
isoxazolyl,
1,2,5-oxadiazolyl, 1,2,3-oxadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, 1,2,3-
triazolyl, thiazolyl, isothiazolyl, 1,2,3,-thiadiazolyl, 1,2,5-thiadiazolyl,
pyridinyl,
pyrimidinyl, pyrazinyl, 1,2,3-triazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, 1-
benzofuranyl, 2-benzofuranyl, indolyl, isoindolyl, benzothiophenyl, 2-
benzothiophenyl, 1 H-indazolyl, benzimidazolyl, benzoxazolyl, indoxazinyl, 2,1-
benzisoxazolyl, benzothiazolyl, 1,2-benzisothiazolyl, 2, 1 -benzisothiazolyl,
benzotriazolyl, quinolinyl, isoquinolinyl, 2,3-benzodiazinyl, quinoxalinyl,
quinazolinyl, 1,2,3-benzotriazinyl, or 1,2,4-benzotriazinyl; optionally
substituted;
R"' is alkyl, alkenyl, alkynyl, in particular C1-C6 alkyl, e.g. C1, C2, C3,
C4, C5, or C6
alkyl, optionally substituted; and
R""' is hydrogen, alkyl, alkenyl, alkynyl, in particular CI-C6 alkyl, e.g. C1,
C2, C3, C4,
C5, or C6 alkyl, optionally substituted;
optionally the alkyl moiety is interrupted 1, 2, 3, 4, or more times by N, S,
and/or 0
moiety(ies).
It is preferred that in the context of foregoing embodiment that R2 and R4
have the
preferred and particularly preferred meanings as outlined above, preferably R2
is H, alkyl, in
particular Ci-C6 alkyl, e.g. Ci, C2, C3, C4, C5, or C6 alkyl, optionally
substituted; and R4 is H,
alkyl, in particular Ci-C6 alkyl, e.g. Cl, C2, C3, C4, C5, or C6 alkyl,
optionally substituted.
In a further preferred embodiment of the compound according to formula (VI)
the right
(C1_4)alkylphenyl residue, i.e. R3, has one of the following meanings:
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/ ~
0 0
(CHZ) j ~(CHZ) j ~ '(CHz) j (CH2/
~ v~ O O
(Ra)k (Ra)k (Ra )k I (Ra)k ~
~ J
O
CH i 0
( 2)P ~ ~ 1-1 (CH2) j O (CH2)P
(Ra)k (CH2)/
(Ra)k O \
O~ O (Ra)k I (Ra)k
(CH )p (CH )p (CHZ)p (CH2)P
2 I O 2/ IO / I I
(Ra)k (Ra)k (Ra)k (Ra)k
(CHz)p (CH2)P (CH2)p (CH2)p
(Ra)k (Ra)k (Ra)k (Ra)k
Hal
CHZ) H (CH2) j OH (CH2) j (CH2) j
III1OH
(Ra)k (Ra)k (Ra)k (Ra)k
(CH2)p Hal (CH2)p
iHal
(Ra)k or (Ra)k
wherein
Ra is halogen, e.g. F, Cl, Br or I; CN; NOZ, -NR'R"; alkyl, in particular C1-
C6 alkyl, e.g. Ci,
C2, C3, C4, C5, or C6 alkyl, preferably methyl, ethyl, propyl, iso-propyl,
butyl, iso-butyl,
tert-butyl, pentyl, hexyl; alkenyl, in particular C2-C6 alkenyl, e.g. C2, C3,
C4, C5, or C6
alkenyl, preferably ethenyl, 1-propenyl, 2-propenyl, 1-iso-propenyl, 2-iso-
propenyl, 1-
butenyl, 2-butenyl, 3-butenyl; alkynyl, in particular C2-C6 alkynyl, e.g. C2,
C3, C4, C5, or
C6 alkynyl; alkoxy, in particular CI-C6 alkoxy, e.g. Cl, C2, C3, C4, C5, or C6
alkoxy,
preferably methoxy, ethoxy, propoxy, iso-propoxy, butoxy, iso-butoxy, tert-
butoxy,
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pentoxy, or hexoxy; alkoxyalkyl, in particular CI-C6 alkoxy-Cl-C6 alkyl, e.g.
methoxymethyl, ethoxymethyl, propoxymethyl, methoxyethyl, ethoxyethyl,
propoxyethyl, methoxypropyl, ethoxypropyl, or propoxypropyl; -OOC-R"'; -COO-
R""'; aryl, in particular phenyl, naphthalenyl or anthracenyl; heteroaryl, in
particular
furanyl, thiophenyl, oxazolyl, isoxazolyl, 1,2,5-oxadiazolyl, 1,2,3-
oxadiazolyl, pyrrolyl,
imidazolyl, pyrazolyl, 1,2,3-triazolyl, thiazolyl, isothiazolyl, 1,2,3,-
thiadiazolyl, 1,2,5-
thiadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, 1,2,3-triazinyl, 1,2,4-
triazinyl, 1,3,5-
triazinyl, 1-benzofuranyl, 2-benzofuranyl, indolyl, isoindolyl,
benzothiophenyl, 2-
benzothiophenyl, 1 H-indazolyl, benzimidazolyl, benzoxazolyl, indoxazinyl, 2,1-
benzisoxazolyl, benzothiazolyl, 1,2-benzisothiazolyl, 2, 1 -benzisothiazolyl,
benzotriazolyl, quinolinyl, isoquinolinyl, 2,3-benzodiazinyl, quinoxalinyl,
quinazolinyl,
1,2,3-benzotriazinyl, or 1,2,4-benzotriazinyl; optionally substituted;
or two adjacent Ra together form an aryl or heteroaryl residue, preferably
resulting in a
two or three membered aryl or heteroaryl;
wherein
R' and R" are independent of each other hydrogen; alkyl, in particular CI-C6
alkyl, e.g.
C1, C2, C3, C4, C5, or C6 alkyl; alkenyl, in particular C2-C6 alkenyl, e.g.
C2, C3, C4,
C5, or C6 alkenyl; alkynyl, in particular C2-C6 alkynyl, e.g. C2, C3, C4, C5,
or C6
alkynyl; aryl; or heteroaryl, in particular furanyl, thiophenyl, oxazolyl,
isoxazolyl,
1,2,5-oxadiazolyl, 1,2,3-oxadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, 1,2,3-
triazolyl, thiazolyl, isothiazolyl, 1,2,3,-thiadiazolyl, 1,2,5-thiadiazolyl,
pyridinyl,
pyrimidinyl, pyrazinyl, 1,2,3-triazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, 1-
benzofuranyl, 2-benzofuranyl, indolyl, isoindolyl, benzothiophenyl, 2-
benzothiophenyl, 1 H-indazolyl, benzimidazolyl, benzoxazolyl, indoxazinyl, 2,1-
benzisoxazolyl, benzothiazolyl, 1,2-benzisothiazolyl, 2,1 -benzisothiazolyl,
benzotriazolyl, quinolinyl, isoquinolinyl, 2,3-benzodiazinyl, quinoxalinyl,
quinazolinyl, 1,2,3-benzotriazinyl, or 1,2,4-benzotriazinyl; optionally
substituted;
R"' is alkyl, alkenyl, alkynyl, in particular CI-C6 alkyl, e.g. Cl, C2, C3,
C4, C5, or C6
alkyl, optionally substituted; and
R""' is hydrogen, alkyl, alkenyl, alkynyl, in particular CI-C6 alkyl, e.g. Cl,
C2, C3, C4,
C5, or C6 alkyl, optionally substituted;
Hal is F, Cl, Br or I, preferably F, Cl or Br;
n is an integer of 0 to 4, i.e. 0, 1, 2, 3, or 4, preferably 0, 1, or 2;
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k is an integer of 0 to 4, i.e. 0, 1, 2, 3, or 4, preferably 0, 1, or 2, i.e.
up to the maximum
number of substituents on the phenyl.
In a particular preferred embodiment the compound of the present invention is
selected
from the group of compounds indicated in Table 1 below or a pharmaceutically
acceptable salt of
such a compound.
Table 1
i
I
F
F.
I \ I \ F ~ \
N O
0 ar
(VII) (VIII) (IX)
__,,Nys
V SyN ( / q
O ~ / N O
(X) (XI) (XII)
'Y O
Ny~
(XIII) (XIV) (XV)
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o--
\ s
S N
xo
N
~\N \ S o a
(XVI) (XVII) (XVIII)
\
- ~ -~ ~ - P
5
(XIX) (XX) (XXI)
N-,T~,
N
0 I \ N
N
O
\ \ I / / \
C
(XXII) (XXIII) (XXIV)
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\i /
\ I o
I
N
V
N ~ \ I
N / \ \ I
~O
/P
(XXV) (XXVI) (XXVII)
N-y
- ~ ,
(XXVIII) (XXIX) (XXX)
I \ \
~ \I
N` ~S
~NI/
F ~ \
p
(XXXI) (XXXII) (XXXIII)
~I o\
o
S
Os
(XXXIV) (XXXV) (XXXVI)
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er
(XXXVII) (XXXVIII) (XXXIX)
S OH F F \ / 1\
0 N
_
/P
\ / - ~ s
(XL) (XLI) (XLII)
N
S
0)XO
(XLIII) (XLIV) (XLV)
N jp S N S N J OH
~ O N
O
OH O
(XLVI) (XLVII) (XLVIII)
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N ~/\/ I
I s\~, ~/ ~
~ \ \ I \
ci
(XLIX) (L) (LI)
/ \ I \ \
S
0
\ / - - I \
(LII) (LIII) (LIV)
I N~s
O
s
(LV) (LVI) (LVII)
F
I / I
I / / \
N~\S
CI ~
(LVIII) (LIX) (LX)
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XIF
-N
rv ~
~-N
/~ \ I
O~ N N F F
F
\ S \ F
( ~ I O-}-F
I
F
(LXI) (LXII) (LXIII)
I S
N
01~
$
\ / I
(LXIV) (LXV) (LXVI)
In a further aspect the present invention relates to compounds according to
formula (LXVII)
Xzz~S
N 4
R21 R22
(LXVII)
wherein
R21 is aralkyl, preferably C, to C4 aralkyl; or heteroaralkyl, preferably C,
to C4 heteroaralkyl;
wherein the alkyl and/or the aryl or heteroaryl moiety are optionally
substituted
preferably with 1, 2, 3, 4 or more substituents selected from the group
consisting of
halogen, e.g. F, Cl, Br or I; CN; NO2; NR'R"; alkyl, in particular CI-C6
alkyl, e.g. Ci, C2,
C3, C4, C5, or C6 alkyl, preferably methyl, ethyl, propyl, iso-propyl, butyl,
iso-butyl,
tert-butyl, pentyl, hexyl; alkenyl, in particular C2-C6 alkenyl, e.g. C2, C3,
C4, C5, or C6
alkenyl, preferably ethenyl, 1-propenyl, 2-propenyl, 1-iso-propenyl, 2-iso-
propenyl, 1-
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butenyl, 2-butenyl, 3-butenyl; alkynyl, in particular C2-C6 alkynyl, e.g. C2,
C3, C4, C5, or
C6 alkynyl; alkanoyl, preferably CI-C6 alkanoyl, e.g. Cl, C2, C3, C4, C5, or
C6 alkanoyl;
alkenoyl, in particular C3-C6 alkenoyl, e.g. C3, C4, C5, or C6 alkenoyl,
preferably
propenoyl; alkynoyl, in particular C3-C6 alkynoyl, e.g. C3, C4, C5, or C6
alkynoyl,
5 preferably propynoyl; alkoxy, in particular C1-C6 alkoxy, e.g. C1, C2, C3,
C4, C5, or C6
alkoxy, preferably methoxy, ethoxy, propoxy, iso-propoxy, butoxy, iso-butoxy,
tert-
butoxy, pentoxy, or hexoxy; alkoxyalkyl, in particular C1-C6 alkoxy-C1-C6
alkyl, e.g.
methoxymethyl, ethoxymethyl, propoxymethyl, methoxyethyl, ethoxyethyl,
propoxyethyl, methoxypropyl, ethoxypropyl, or propoxypropyl; -OOC-R"'; -COO-
10 R""'; aryl, in particular phenyl, naphthalenyl or anthracenyl; heteroaryl,
in particular
furanyl, thiophenyl, oxazolyl, isoxazolyl, 1,2,5-oxadiazolyl, 1,2,3-
oxadiazolyl, pyrrolyl,
imidazolyl, pyrazolyl, 1,2,3-triazolyl, thiazolyl, isothiazolyl, 1,2,3,-
thiadiazolyl, 1,2,5-
thiadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, 1,2,3-triazinyl, 1,2,4-
triazinyl, 1,3,5-
triazinyl, 1-benzofuranyl, 2-benzofuranyl, indolyl, isoindolyl,
benzothiophenyl, 2-
15 benzothiophenyl, 1 H-indazolyl, benzimidazolyl, benzoxazolyl, indoxazinyl,
2,1-
benzisoxazolyl, benzothiazolyl, 1,2-benzisothiazolyl, 2, 1 -benzisothiazolyl,
benzotriazolyl, quinolinyl, isoquinolinyl, 2,3-benzodiazinyl, quinoxalinyl,
quinazolinyl,
1,2,3-benzotriazinyl, or 1,2,4-benzotriazinyl; optionally substituted, wherein
R' and R" are independent of each other hydrogen; alkyl, in particular C1-C6
alkyl, e.g.
20 Ci, C2, C3, C4, C5, or C6 alkyl; alkenyl, in particular C2-C6 alkenyl, e.g.
C2, C3, C4,
C5, or C6 alkenyl; alkynyl, in particular C2-C6 alkynyl, e.g. C2, C3, C4, C5,
or C6
alkynyl; aryl; or heteroaryl, in particular furanyl, thiophenyl, oxazolyl,
isoxazolyl,
1,2,5-oxadiazolyl, 1,2,3-oxadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, 1,2,3-
triazolyl, thiazolyl, isothiazolyl, 1,2,3,-thiadiazolyl, 1,2,5-thiadiazolyl,
pyridinyl,
25 pyrimidinyl, pyrazinyl, 1,2,3-triazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl,
1-
benzofuranyl, 2-benzofuranyl, indolyl, isoindolyl, benzothiophenyl, 2-
benzothiophenyl, 1 H-indazolyl, benzimidazolyl, benzoxazolyl, indoxazinyl, 2,1-
benzisoxazolyl, benzothiazolyl, 1,2-benzisothiazolyl, 2,1 -benzisothiazolyl,
benzotriazolyl, quinolinyl, isoquinolinyl, 2,3-benzodiazinyl, quinoxalinyl,
30 quinazolinyl, 1,2,3-benzotriazinyl, or 1,2,4-benzotriazinyl; optionally
substituted;
R"' is alkyl, alkenyl, alkynyl, in particular CI-C6 alkyl, e.g. Cl, C2, C3,
C4, C5, or C6
alkyl, optionally substituted; and
R""' is hydrogen, alkyl, alkenyl, alkynyl, in particular Ci-C6 alkyl, e.g. Ci,
C2, C3, C4,
C5, or C6 alkyl, optionally substituted;
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R22 is aryl, in particular phenyl, naphthalenyl or anthracenyl; or heteroaryl,
in particular
furanyl, thiophenyl, oxazolyl, isoxazolyl, 1,2,5-oxadiazolyl, 1,2,3-
oxadiazolyl, pyrrolyl,
imidazolyl, pyrazolyl, 1,2,3-triazolyl, thiazolyl, isothiazolyl, 1,2,3,-
thiadiazolyl, 1,2,5-
thiadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, 1,2,3-triazinyl, 1,2,4-
triazinyl, 1,3,5-
triazinyl, 1-benzofuranyl, 2-benzofuranyl, indolyl, isoindolyl,
benzothiophenyl, 2-
benzothiophenyl, 1 H-indazolyl, benzimidazolyl, benzoxazolyl, indoxazinyl, 2,1-
benzisoxazolyl, benzothiazolyl, 1,2-benzisothiazolyl, 2, 1 -benzisothiazolyl,
benzotriazolyl, quinolinyl, isoquinolinyl, 2,3-benzodiazinyl, quinoxalinyl,
quinazolinyl,
1,2,3-benzotriazinyl, or 1,2,4-benzotriazinyl; wherein the aryl or heteroaryl
are optionally
substituted, preferably with 1, 2, 3, 4 or more substituents selected from the
group
consisting of halogen, e.g. F, Cl, Br or I; CN; NOZ; NR'R"; alkyl, in
particular CI-C6
alkyl, e.g. Cl, C2, C3, C4, C5, or C6 alkyl, preferably methyl, ethyl, propyl,
iso-propyl,
butyl, iso-butyl, tert-butyl, pentyl, hexyl; alkenyl, in particular C2-C6
alkenyl, e.g. C2, C3,
C4, C5, or C6 alkenyl, preferably ethenyl, 1-propenyl, 2-propenyl, 1-iso-
propenyl, 2-iso-
propenyl, 1-butenyl, 2-butenyl, 3-butenyl; alkynyl, in particular C2-C6
alkynyl, e.g. C2,
C3, C4, C5, or C6 alkynyl; alkanoyl, preferably Cl-C6 alkanoyl, e.g. C1, C2,
C3, C4, C5, or
C6 alkanoyl; alkenoyl, in particular C3-C6 alkenoyl, e.g. C3, C4, C5, or C6
alkenoyl,
preferably propenoyl; alkynoyl, in particular C3-C6 alkynoyl, e.g. C3, C4, C5,
or C6
alkynoyl, preferably propynoyl; alkoxy, in particular C1-C6 alkoxy, e.g. CI,
C2, C3, C4,
C5, or C6 alkoxy, preferably methoxy, ethoxy, propoxy, iso-propoxy, butoxy,
iso-butoxy,
tert-butoxy, pentoxy, or hexoxy; alkoxyalkyl, in particular CI-C6 alkoxy-Cl-C6
alkyl, e.g.
methoxymethyl, ethoxymethyl, propoxymethyl, methoxyethyl, ethoxyethyl,
propoxyethyl, methoxypropyl, ethoxypropyl, or propoxypropyl; -OOC-R"'; -
COOR""';
aryl, in particular phenyl, naphthalenyl or anthracenyl; heteroaryl, in
particular furanyl,
thiophenyl, oxazolyl, isoxazolyl, 1,2,5-oxadiazolyl, 1,2,3-oxadiazolyl,
pyrrolyl,
imidazolyl, pyrazolyl, 1,2,3-triazolyl, thiazolyl, isothiazolyl, 1,2,3,-
thiadiazolyl, 1,2,5-
thiadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, 1,2,3-triazinyl, 1,2,4-
triazinyl, 1,3,5-
triazinyl, 1-benzofuranyl, 2-benzofuranyl, indolyl, isoindolyl,
benzothiophenyl, 2-
benzothiophenyl, 1 H-indazolyl, benzimidazolyl, benzoxazolyl, indoxazinyl, 2,1-
benzisoxazolyl, benzothiazolyl, 1,2-benzisothiazolyl, 2,1-benzisothiazolyl,
benzotriazolyl, quinolinyl, isoquinolinyl, 2,3-benzodiazinyl, quinoxalinyl,
quinazolinyl,
1,2,3-benzotriazinyl, or 1,2,4-benzotriazinyl; optionally substituted, wherein
R' and R" are independent of each other hydrogen; alkyl, in particular Ci-C6
alkyl, e.g.
Ci, C2, C3, C4, C5, or C6 alkyl; alkenyl, in particular C2-C6 alkenyl, e.g.
C2, C3, C4,
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C5, or C6 alkenyl; alkynyl, in particular C2-C6 alkynyl, e.g. C2, C3, C4, C5,
or C6
alkynyl; aryl; or heteroaryl, in particular furanyl, thiophenyl, oxazolyl,
isoxazolyl,
1,2,5-oxadiazolyl, 1,2,3-oxadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, 1,2,3-
triazolyl, thiazolyl, isothiazolyl, 1,2,3,-thiadiazolyl, 1,2,5-thiadiazolyl,
pyridinyl,
pyrimidinyl, pyrazinyl, 1,2,3-triazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, 1-
benzofuranyl, 2-benzofuranyl, indolyl, isoindolyl, benzothiophenyl, 2-
benzothiophenyl, 1H-indazolyl, benzimidazolyl, benzoxazolyl, indoxazinyl, 2,1-
benzisoxazolyl, benzothiazolyl, 1,2-benzisothiazolyl, 2, 1 -benzisothiazolyl,
benzotriazolyl, quinolinyl, isoquinolinyl, 2,3-benzodiazinyl, quinoxalinyl,
quinazolinyl, 1,2,3-benzotriazinyl, or 1,2,4-benzotriazinyl; optionally
substituted;
R"' is alkyl, alkenyl, alkynyl, in particular CI-C6 alkyl, e.g. Cl, C2, C3,
C4, C5, or C6
alkyl, optionally substituted; and
R""' is hydrogen, alkyl, alkenyl, alkynyl, in particular CI-C6 alkyl, e.g. Cl,
C2, C3, C4,
C5, or C6 alkyl, optionally substituted;
and
X is 0 or S, preferably O.
In a preferred embodiment of the compound according to formula (LXVII) R21 has
a
structure according to formula (LXVIII)
R24
R25 , R23
~
R26 \ (CHA
R27
(LXVIII)
R23, R24, R25, R26 and R27 are independent of each other H, halogen, e.g. F,
Cl, Br or I; CN; NO2;
NR'R"; alkyl, in particular CI-C6 alkyl, e.g. Cl, C2, C3, C4, C5, or C6 alkyl,
preferably
methyl, ethyl, propyl, iso-propyl, butyl, iso-butyl, tert-butyl, pentyl,
hexyl; alkenyl, in
particular C2-C6 alkenyl, e.g. C2, C3, C4, C5, or C6 alkenyl, preferably
ethenyl, 1-propenyl,
2-propenyl, 1-iso-propenyl, 2-iso-propenyl, 1-butenyl, 2-butenyl, 3-butenyl;
alkynyl, in
particular C2-C6 alkynyl, e.g. C2, C3, C4, C5, or C6 alkynyl; alkanoyl,
preferably Cj-C6
alkanoyl, e.g. Ci, C2, C3, C4, C5, or C6 alkanoyl; alkenoyl, in particular C3-
C6 alkenoyl,
e.g. C3, C4, C5, or C6 alkenoyl, preferably propenoyl; alkynoyl, in particular
C3-C6
alkynoyl, e.g. C3, C4, C5, or C6 alkynoyl, preferably propynoyl; alkoxy, in
particular Ci-
C6 alkoxy, e.g. C1, C2, C3, C4, C5, or C6 alkoxy, preferably methoxy, ethoxy,
propoxy,
iso-propoxy, butoxy, iso-butoxy, tert-butoxy, pentoxy, or hexoxy; alkoxyalkyl,
in
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particular C1-C6 alkoxy-C1-C6 alkyl, e.g. methoxymethyl, ethoxymethyl,
propoxymethyl,
methoxyethyl, ethoxyethyl, propoxyethyl, methoxypropyl, ethoxypropyl, or
propoxypropyl; -OOC-R"'; -COO-R""'; aryl, in particular phenyl, naphthalenyl
or
anthracenyl; heteroaryl, in particular furanyl, thiophenyl, oxazolyl,
isoxazolyl, 1,2,5-
oxadiazolyl, 1,2,3-oxadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, 1,2,3-
triazolyl, thiazolyl,
isothiazolyl, 1,2,3,-thiadiazolyl, 1,2,5-thiadiazolyl, pyridinyl, pyrimidinyl,
pyrazinyl,
1,2,3-triazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, 1-benzofuranyl, 2-
benzofuranyl, indolyl,
isoindolyl, benzothiophenyl, 2-benzothiophenyl, 1 H-indazolyl, benzimidazolyl,
benzoxazolyl, indoxazinyl, 2,1-benzisoxazolyl, benzothiazolyl, 1,2-
benzisothiazolyl, 2,1-
benzisothiazolyl, benzotriazolyl, quinolinyl, isoquinolinyl, 2,3-
benzodiazinyl,
quinoxalinyl, quinazolinyl, 1,2,3-benzotriazinyl, or 1,2,4-benzotriazinyl;
optionally
substituted, wherein
R' and R" are independent of each other hydrogen; alkyl, in particular C1-C6
alkyl, e.g.
Cl, C2, C3, C4, C5, or C6 alkyl; alkenyl, in particular C2-C6 alkenyl, e.g.
C2, C3, C4,
C5, or C6 alkenyl; alkynyl, in particular C2-C6 alkynyl, e.g. C2, C3, C4, C5,
or C6
alkynyl; aryl; or heteroaryl, in particular furanyl, thiophenyl, oxazolyl,
isoxazolyl,
1,2,5-oxadiazolyl, 1,2,3-oxadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, 1,2,3-
triazolyl, thiazolyl, isothiazolyl, 1,2,3,-thiadiazolyl, 1,2,5-thiadiazolyl,
pyridinyl,
pyrimidinyl, pyrazinyl, 1,2,3-triazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, 1-
benzofuranyl, 2-benzofuranyl, indolyl, isoindolyl, benzothiophenyl, 2-
benzothiophenyl, 1 H-indazolyl, benzimidazolyl, benzoxazolyl, indoxazinyl, 2,1-
benzisoxazolyl, benzothiazolyl, 1,2-benzisothiazolyl, 2,1 -benzisothiazolyl,
benzotriazolyl, quinolinyl, isoquinolinyl, 2,3-benzodiazinyl, quinoxalinyl,
quinazolinyl, 1,2,3-benzotriazinyl, or 1,2,4-benzotriazinyl; optionally
substituted;
R"' is alkyl, alkenyl, alkynyl, in particular CI-C6 alkyl, e.g. C1, C2, C3,
C4, C5, or C6
alkyl, optionally substituted; and
R""' is hydrogen, alkyl, alkenyl, alkynyl, in particular C1-C6 alkyl, e.g. C1,
C2, C3, C4,
C5, or C6 alkyl, optionally substituted;
or two or more of R23, R24, RZS, R26 and R27 are taken together to form a
cycloalkyl,
heterocycloalkyl, alicyclic ring system, aryl, or heteroaryl, optionally
substituted; and
q is an integer of 1 to 4, i.e. 1, 2, 3, or 4, preferably 1 or 2.
In a preferred embodiment R21 has a structure according to
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74
/
~(CH )q0 ~(CH2)4 0 (CH2)q (CH2)40 (CHZ) j
Z'. (Ra)k
O O
(Ra)k (Ra)k (Ra)k I (Ra)k
I
~
\ O/ ~(CH2) j O~(C 0
HZ)q (CH2) j O
(C"z)~
(Ra)k O
0 (Ra)k (Ra)k (Ra)k
(CHz) (CHZ) j (CH2) j (CH2) j
O
(Ra)k (Ra)k (Ra)k (Ra)k
~-(CHz)/ (CH2) j (CHz) j (CHz)qOH
(Ra)k (Ra)k (Ra)k (Ra) k
Hal
(CH2) j OH (CH2) j (CHz) (CHz) j Hal
~ - ~ I
OH
(Ra)k (Ra)k (Ra)k (Ra)k
Rb ORb
/
0R \(CHz) j (CHz)
~-(CH2) j (CH2)q0 (CH2) j I
O O
(Ra)k Hal (Ra)k (Ra)k (Ra)k Rb (Ra)k RC
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Rc
0
CHZ)q Rb Rc NRdRe
p(CHZ)q ~
(Ra)k (CH2)q (C~)q
~
(Ra)k O
p, Rb RC, O \ (Ra)k Rb (Ra)k
(CHZ)q NRdRe \(CH2) j ~(CH2)
4
(Ra)k (Ra)k NRdRe (Ra)k N
or
wherein
Ra is H, halogen, e.g. F, Cl, Br or I; CN; NO2; NR'R"; alkyl, in particular CI-
C6 alkyl, e.g.
5 Cl, C2, C3, C4, C5, or C6 alkyl, preferably methyl, ethyl, propyl, iso-
propyl, butyl, iso-
butyl, tert-butyl, pentyl, hexyl; alkenyl, in particular C2-C6 alkenyl, e.g.
C2, C3, C4, C5, or
C6 alkenyl, preferably ethenyl, 1-propenyl, 2-propenyl, 1-iso-propenyl, 2-iso-
propenyl, 1-
butenyl, 2-butenyl, 3-butenyl; alkynyl, in particular C2-C6 alkynyl, e.g. C2,
C3, C4, C5, or
C6 alkynyl; alkanoyl, preferably CI-C6 alkanoyl, e.g. Cl, C2, C3, C4, C5, or
C6 alkanoyl;
10 alkenoyl, in particular C3-C6 alkenoyl, e.g. C3, C4, C5, or C6 alkenoyl,
preferably
propenoyl; alkynoyl, in particular C3-C6 alkynoyl, e.g. C3, C4, C5, or C6
alkynoyl,
preferably propynoyl; alkoxy, in particular CI-C6 alkoxy, e.g. C1, C2, C3, C4,
C5, or C6
alkoxy, preferably methoxy, ethoxy, propoxy, iso-propoxy, butoxy, iso-butoxy,
tert-
butoxy, pentoxy, or hexoxy; alkoxyalkyl, in particular CI-C6 alkoxy-CI-C6
alkyl, e.g.
15 methoxymethyl, ethoxymethyl, propoxymethyl, methoxyethyl, ethoxyethyl,
propoxyethyl, methoxypropyl, ethoxypropyl, or propoxypropyl; -OOC-R"'; -COO-
R""'; aryl, in particular phenyl, naphthalenyl or anthracenyl; heteroaryl, in
particular
furanyl, thiophenyl, oxazolyl, isoxazolyl, 1,2,5-oxadiazolyl, 1,2,3-
oxadiazolyl, pyrrolyl,
imidazolyl, pyrazolyl, 1,2,3-triazolyl, thiazolyl, isothiazolyl, 1,2,3,-
thiadiazolyl, 1,2,5-
20 thiadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, 1,2,3-triazinyl, 1,2,4-
triazinyl, 1,3,5-
triazinyl, 1-benzofuranyl, 2-benzofuranyl, indolyl, isoindolyl,
benzothiophenyl, 2-
benzothiophenyl, 1 H-indazolyl, benzimidazolyl, benzoxazolyl, indoxazinyl, 2,1-
benzisoxazolyl, benzothiazolyl, 1,2-benzisothiazolyl, 2, 1 -benzisothiazolyl,
benzotriazolyl, quinolinyl, isoquinolinyl, 2,3-benzodiazinyl, quinoxalinyl,
quinazolinyl,
25 1,2,3-benzotriazinyl, or 1,2,4-benzotriazinyl; optionally substituted,
wherein
R' and R" are independent of each other hydrogen; alkyl, in particular C1-C6
alkyl, e.g.
Cl, C2, C3, C4, C5, or C6 alkyl; alkenyl, in particular C2-C6 alkenyl, e.g.
C2, C3, C4,
C5, or C6 alkenyl; alkynyl, in particular C2-C6 alkynyl, e.g. C2, C3, C4, C5,
or C6
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alkynyl; aryl; or heteroaryl, in particular furanyl, thiophenyl, oxazolyl,
isoxazolyl,
1,2,5-oxadiazolyl, 1,2,3-oxadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, 1,2,3-
triazolyl, thiazolyl, isothiazolyl, 1,2,3,-thiadiazolyl, 1,2,5-thiadiazolyl,
pyridinyl,
pyrimidinyl, pyrazinyl, 1,2,3-triazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, 1-
benzofuranyl, 2-benzofuranyl, indolyl, isoindolyl, benzothiophenyl, 2-
benzothiophenyl, 1 H-indazolyl, benzimidazolyl, benzoxazolyl, indoxazinyl, 2,1-
benzisoxazolyl, benzothiazolyl, 1,2-benzisothiazolyl, 2,1 -benzisothiazolyl,
benzotriazolyl, quinolinyl, isoquinolinyl, 2,3-benzodiazinyl, quinoxalinyl,
quinazolinyl, 1,2,3-benzotriazinyl, or 1,2,4-benzotriazinyl; optionally
substituted;
R"' is alkyl, alkenyl, alkynyl, in particular C1-C6 alkyl, e.g. C1, C2, C3,
C4, C5, or C6
alkyl, optionally substituted; and
R""' is hydrogen, alkyl, alkenyl, alkynyl, in particular Ci-C6 alkyl, e.g. C1,
C2, C3, C4,
C5, or C6 alkyl, optionally substituted;
Rb and R are independent of each other hydrogen, alkyl, in particular C1-C6
alkyl, e.g. Cl, C2,
C3, C4, C5, or C6 alkyl, preferably methyl, ethyl, propyl, iso-propyl, butyl,
iso-butyl, tert-
butyl, pentyl, hexyl; alkenyl, in particular C2-C6 alkenyl, e.g. C2, C3, C4,
C5, or C6
alkenyl, preferably ethenyl, 1-propenyl, 2-propenyl, 1-iso-propenyl, 2-iso-
propenyl, 1-
butenyl, 2-butenyl, 3-butenyl; alkynyl, in particular C2-C6 alkynyl, e.g. C2,
C3, C4, C5, or
C6 alkynyl; cycloalkyl, in particular (C3_1o)-cycloalkyl, preferably
cyclopropyl,
cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, heteroalkyl in particular
(Ci-
C6)heteroalkyl, e.g. C1, C2, C3, C4, C5, or C6 heteroalkyl, cycloheteroalkyl,
in particular
(C3_io)-cycloheteroalkyl; optionally substituted;
Rd and Re are independent of each other hydrogen, alkyl, in particular Ci-C6
alkyl, e.g. Cl, C2,
C3, C4, C5, or C6 alkyl, preferably methyl, ethyl, propyl, iso-propyl, butyl,
iso-butyl, tert-
butyl, pentyl, hexyl; alkenyl, in particular C2-C6 alkenyl, e.g. C2, C3, C4,
C5, or C6
alkenyl, preferably ethenyl, 1-propenyl, 2-propenyl, 1-iso-propenyl, 2-iso-
propenyl, 1-
butenyl, 2-butenyl, 3-butenyl; alkynyl, in particular C2-C6 alkynyl, e.g. C2,
C3, C4, C5, or
C6 alkynyl; optionally substituted;
Hal is F, Cl, Br or I, preferably F, Cl or Br;
q is an integer of 0 to 4, i.e. 0, 1, 2, 3, or 4, preferably 0, 1, or 2, most
preferably 1;
k is an integer of 0 to 4, i.e. 0, 1, 2, 3, or 4, preferably 0, 1, or 2, i.e.
up to the maximum
number of substituents on the phenyl residue.
In a further preferred embodiment of the compound according to formula (LXVII)
RZ1
has a structure according to formula (LXIX)
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R30--~ (CH2)r
R29 R28
(LXIX)
R28, R29, and R30 are independent of each other H, halogen, e.g. F, Cl, Br or
I; CN; NOZ; NR'R";
alkyl, in particular CI-C6 alkyl, e.g. Cl, C2, C3, C4, C5, or C6 alkyl,
preferably methyl,
ethyl, propyl, iso-propyl, butyl, iso-butyl, tert-butyl, pentyl, hexyl;
alkenyl, in particular
C2-C6 alkenyl, e.g. C2, C3, C4, C5, or C6 alkenyl, preferably ethenyl, 1-
propenyl, 2-
propenyl, 1-iso-propenyl, 2-iso-propenyl, 1-butenyl, 2-butenyl, 3-butenyl;
alkynyl, in
particular C2-C6 alkynyl, e.g. C2, C3, C4, C5, or C6 alkynyl; alkanoyl,
preferably CI-C6
alkanoyl, e.g. Ci, C2, C3, C4, C5, or C6 alkanoyl; alkenoyl, in particular C3-
C6 alkenoyl,
e.g. C3, C4, C5, or C6 alkenoyl, preferably propenoyl; alkynoyl, in particular
C3-C6
alkynoyl, e.g. C3, C4, C5, or C6 alkynoyl, preferably propynoyl; alkoxy, in
particular Cl-
C6 alkoxy, e.g. Ci, C2, C3, C4, C5, or C6 alkoxy, preferably methoxy, ethoxy,
propoxy,
iso-propoxy, butoxy, iso-butoxy, tert-butoxy, pentoxy, or hexoxy; alkoxyalkyl,
in
particular CI-C6 alkoxy-Cl-C6 alkyl, e.g. methoxymethyl, ethoxymethyl,
propoxymethyl,
methoxyethyl, ethoxyethyl, propoxyethyl, methoxypropyl, ethoxypropyl, or
propoxypropyl; -OOC-R"'; -COO-R""'; aryl, in particular phenyl, naphthalenyl
or
anthracenyl; heteroaryl, in particular furanyl, thiophenyl, oxazolyl,
isoxazolyl, 1,2,5-
oxadiazolyl, 1,2,3-oxadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, 1,2,3-
triazolyl, thiazolyl,
isothiazolyl, 1,2,3,-thiadiazolyl, 1,2,5-thiadiazolyl, pyridinyl, pyrimidinyl,
pyrazinyl,
1,2,3-triazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, 1-benzofuranyl, 2-
benzofuranyl, indolyl,
isoindolyl, benzothiophenyl, 2-benzothiophenyl, 1 H-indazolyl, benzimidazolyl,
benzoxazolyl, indoxazinyl, 2,1-benzisoxazolyl, benzothiazolyl, 1,2-
benzisothiazolyl, 2,1-
benzisothiazolyl, benzotriazolyl, quinolinyl, isoquinolinyl, 2,3-
benzodiazinyl,
quinoxalinyl, quinazolinyl, 1,2,3-benzotriazinyl, or 1,2,4-benzotriazinyl;
optionally
substituted, wherein
R' and R" are independent of each other hydrogen; alkyl, in particular CI-C6
alkyl, e.g.
Ci, C2, C3, C4, C5, or C6 alkyl; alkenyl, in particular C2-C6 alkenyl, e.g.
C2, C3, C4,
C5, or C6 alkenyl; alkynyl, in particular C2-C6 alkynyl, e.g. C2, C3, C4, C5,
or C6
alkynyl; aryl; or heteroaryl, in particular furanyl, thiophenyl, oxazolyl,
isoxazolyl,
1,2,5-oxadiazolyl, 1,2,3-oxadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, 1,2,3-
triazolyl, thiazolyl, isothiazolyl, 1,2,3,-thiadiazolyl, 1,2,5-thiadiazolyl,
pyridinyl,
pyrimidinyl, pyrazinyl, 1,2,3-triazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, 1-
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benzofuranyl, 2-benzofuranyl, indolyl, isoindolyl, benzothiophenyl, 2-
benzothiophenyl, 1 H-indazolyl, benzimidazolyl, benzoxazolyl, indoxazinyl, 2,1-
benzisoxazolyl, benzothiazolyl, 1,2-benzisothiazolyl, 2,1 -benzisothiazolyl,
benzotriazolyi, quinolinyl, isoquinolinyl, 2,3-benzodiazinyl, quinoxalinyl,
quinazolinyl, 1,2,3-benzotriazinyl, or 1,2,4-benzotriazinyl; optionally
substituted;
R"' is alkyl, alkenyl, alkynyl, in particular CI-C6 alkyl, e.g. Cl, C2, C3,
C4, C5, or C6
alkyl, optionally substituted; and
R""' is hydrogen, alkyl, alkenyl, alkynyl, in particular Ct-C6 alkyl, e.g. Cl,
C2, C3, C4,
C5, or C6 alkyl, optionally substituted;
or two or more of R28, R29, and R30 are taken together to form a cycloalkyl,
heterocycloalkyl, alicyclic ring system, aryl, or heteroaryl, optionally
substituted; and
r is an integer of 1 to 4, i.e. 1, 2, 3, or 4, preferably 1 or 2.
In a preferred embodiment of the compound according to formula (LXVII) R22 has
a
structure according to formula (LXX)
R35
R34
R31 R33
R32
(LXX)
R31, R32, R33, R34 and R35 are independent of each other H, H, halogen, e.g.
F, Cl, Br or I; CN;
NO2; NR'R"; alkyl, in particular CI-C6 alkyl, e.g. Cl, C2, C3, C4, C5, or C6
alkyl,
preferably methyl, ethyl, propyl, iso-propyl, butyl, iso-butyl, tert-butyl,
pentyl, hexyl;
alkenyl, in particular C2-C6 alkenyl, e.g. C2, C3, C4, C5, or C6 alkenyl,
preferably ethenyl,
1-propenyl, 2-propenyl, 1-iso-propenyl, 2-iso-propenyl, 1-butenyl, 2-butenyl,
3-butenyl;
alkynyl, in particular C2-C6 alkynyl, e.g. C2, C3, C4, C5, or C6 alkynyl;
alkanoyl,
preferably CI-C6 alkanoyl, e.g. Cl, C2, C3, C4, C5, or C6 alkanoyl; alkenoyl,
in particular
C3-C6 alkenoyl, e.g. C3, C4, C5, or C6 alkenoyl, preferably propenoyl;
alkynoyl, in
particular C3-C6 alkynoyl, e.g. C3, C4, C5, or C6 alkynoyl, preferably
propynoyl; alkoxy,
in particular CI-C6 alkoxy, e.g. Cl, C2, C3, C4, C5, or C6 alkoxy, preferably
methoxy,
ethoxy, propoxy, iso-propoxy, butoxy, iso-butoxy, tert-butoxy, cyclobutoxy,
pentoxy,
cyclopentoxy, cyclohexoxy or hexoxy; alkoxyalkyl, in particular CI-C6 alkoxy-
Ci-C6
alkyl, e.g. methoxymethyl, ethoxymethyl, propoxymethyl, methoxyethyl,
ethoxyethyl,
propoxyethyl, methoxypropyl, ethoxypropyl, or propoxypropyl; -OOC-R"'; -COO-
R""'; aryl, in particular phenyl, naphthalenyl or anthracenyl; heteroaryl, in
particular
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furanyl, thiophenyl, oxazolyl, isoxazolyl, 1,2,5-oxadiazolyl, 1,2,3-
oxadiazolyl, pyrrolyl,
imidazolyl, pyrazolyl, 1,2,3-triazolyl, thiazolyl, isothiazolyl, 1,2,3,-
thiadiazolyl, 1,2,5-
thiadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, 1,2,3-triazinyl, 1,2,4-
triazinyl, 1,3,5-
triazinyl, i-benzofuranyl, 2-benzofuranyl, indolyl, isoindolyl,
benzothiophenyl, 2-
benzothiophenyl, 1 H-indazolyl, benzimidazolyl, benzoxazolyl, indoxazinyl, 2,1-
benzisoxazolyl, benzothiazolyl, 1,2-benzisothiazolyl, 2,1 -benzisothiazolyl,
benzotriazolyl, quinolinyl, isoquinolinyl, 2,3-benzodiazinyl, quinoxalinyl,
quinazolinyl,
1,2,3-benzotriazinyl, or 1,2,4-benzotriazinyl; optionally substituted, wherein
R' and R" are independent of each other hydrogen; alkyl, in particular Cl-C6
alkyl, e.g.
Cl, C2, C3, C4, C5, or C6 alkyl; alkenyl, in particular C2-C6 alkenyl, e.g.
C2, C3, C4,
C5, or C6 alkenyl; alkynyl, in particular C2-C6 alkynyl, e.g. C2, C3, C4, C5,
or C6
alkynyl; aryl; or heteroaryl, in particular furanyl, thiophenyl, oxazolyl,
isoxazolyl,
1,2,5-oxadiazolyl, 1,2,3-oxadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, 1,2,3-
triazolyl, thiazolyl, isothiazolyl, 1,2,3,-thiadiazolyl, 1,2,5-thiadiazolyl,
pyridinyl,
pyrimidinyl, pyrazinyl, 1,2,3-triazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, 1-
benzofuranyl, 2-benzofuranyl, indolyl, isoindolyl, benzothiophenyl, 2-
benzothiophenyl, 1 H-indazolyl, benzimidazolyl, benzoxazolyl, indoxazinyl, 2,1-
benzisoxazolyl, benzothiazolyl, 1,2-benzisothiazolyl, 2, 1 -benzisothiazolyl,
benzotriazolyl, quinolinyl, isoquinolinyl, 2,3-benzodiazinyl, quinoxalinyl,
quinazolinyl, 1,2,3-benzotriazinyl, or 1,2,4-benzotriazinyl; optionally
substituted;
R"' is alkyl, alkenyl, alkynyl, in particular CI-C6 alkyl, e.g. Cl, C2, C3,
C4, C5, or C6
alkyl, optionally substituted; and
R""' is hydrogen, alkyl, alkenyl, alkynyl, in particular C1-C6 alkyl, e.g. C1,
C2, C3, C4,
C5, or C6 alkyl, optionally substituted;
or two or more of R31, R32, R33, R34 and R35 are taken together to form a
cycloalkyl,
heterocycloalkyl, alicyclic ring system, aryl, or heteroaryl, optionally
substituted. It is
particularly preferred that R22 has this preferred meaning, if R21 either has
a structure
according to formula (LXVIII) or (LXIX). It this context is particular
preferred that q and
r, respectively, have the meaning 1.
In a preferred embodiment of the compound of formula (LXVII) the substituent
R22
according to formula (LXX) has a structure as follows:
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O O O, Rb O
ORb O --- I\ O, Rb Ei:;:111oRb
Rb
(Ra)k (Ra)k (Ra)k (Ra)k (Ra)k
ORc Rb, 0
O, Rn
Rb" O Rb-~O O"Rc O'Rc x
/ Rb, O (Ra)k (Ra)k (Ra)k (Ra)k
O
d e
NR R Hal 011~ 0 1~1 O
/
(Ra)k (Ra)k (Ra)k (Ra)k (Ra)k (Ra)k
~
O O
O O" O" O" ,O
\O
(Ra)k (Ra)k (Ra)k (Ra)k or
0
O
I (Ra)k
5 Hal
wherein
Ra H, H. halogen, e.g. F, Cl, Br or I; CN; NOZ; NR'R"; alkyl, in particular CI-
C6 alkyl, e.g.
Ci, C2, C35 C4, C5, or C6 alkyl, preferably methyl, ethyl, propyl, iso-propyl,
butyl, iso-
butyl, tert-butyl, pentyl, hexyl; alkenyl, in particular C2-C6 alkenyl, e.g.
C2, C3, C4, C5, or
10 C6 alkenyl, preferably ethenyl, 1-propenyl, 2-propenyl, 1-iso-propenyl, 2-
iso-propenyl, 1-
butenyl, 2-butenyl, 3-butenyl; alkynyl, in particular C2-C6 alkynyl, e.g. C2,
C3, C4, C5, or
C6 alkynyl; alkanoyl, preferably CI-C6 alkanoyl, e.g. Cl, C2, C3, C4, C5, or
C6 alkanoyl;
alkenoyl, in particular C3-C6 alkenoyl, e.g. C3, C4, C5, or C6 alkenoyl,
preferably
propenoyl; alkynoyl, in particular C3-C6 alkynoyl, e.g. C3, C4, C5, or C6
alkynoyl,
15 preferably propynoyl; alkoxy, in particular Ci-C6 alkoxy, e.g. C1, C2, C3,
C4, C5, or C6
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alkoxy, preferably methoxy, ethoxy, propoxy, iso-propoxy, butoxy, iso-butoxy,
tert-
butoxy, cyclobutoxy, pentoxy, cyclopentoxy, cyclohexoxy or hexoxy;
alkoxyalkyl, in
particular Ci-C6 alkoxy-C1-C6 alkyl, e.g. methoxymethyl, ethoxymethyl,
propoxymethyl,
inethoxyethyl, ethoxyethyl, propoxyethyl, methoxypropyl, ethoxypropyl, or
propoxypropyl; -OOC-R"'; -COO-R""'; aryl, in particular phenyl, naphthalenyl
or
anthracenyl; heteroaryl, in particular furanyl, thiophenyl, oxazolyl,
isoxazolyl, 1,2,5-
oxadiazolyl, 1,2,3-oxadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, 1,2,3-
triazolyl, thiazolyl,
isothiazolyl, 1,2,3,-thiadiazolyl, 1,2,5-thiadiazolyl, pyridinyl, pyrimidinyl,
pyrazinyl,
1,2,3-triazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, 1-benzofuranyl, 2-
benzofuranyl, indolyl,
isoindolyl, benzothiophenyl, 2-benzothiophenyl, 1 H-indazolyl, benzimidazolyl,
benzoxazolyl, indoxazinyl, 2, 1 -benzisoxazolyl, benzothiazolyl, 1,2-
benzisothiazolyl, 2,1-
benzisothiazolyl, benzotriazolyl, quinolinyl, isoquinolinyl, 2,3-
benzodiazinyl,
quinoxalinyl, quinazolinyl, 1,2,3-benzotriazinyl, or 1,2,4-benzotriazinyl;
optionally
substituted, wherein
R' and R" are independent of each other hydrogen; alkyl, in particular Ci-C6
alkyl, e.g.
Ci, C2, C3, C4, C5, or C6 alkyl; alkenyl, in particular C2-C6 alkenyl, e.g.
C2, C3, C4,
C5, or C6 alkenyl; alkynyl, in particular C2-C6 alkynyl, e.g. C2, C3, C4, C5,
or C6
alkynyl; aryl; or heteroaryl, in particular furanyl, thiophenyl, oxazolyl,
isoxazolyl,
1,2,5-oxadiazolyl, 1,2,3-oxadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, 1,2,3-
triazolyl, thiazolyl, isothiazolyl, 1,2,3,-thiadiazolyl, 1,2,5-thiadiazolyl,
pyridinyl,
pyrimidinyl, pyrazinyl, 1,2,3-triazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, 1-
benzofuranyl, 2-benzofuranyl, indolyl, isoindolyl, benzothiophenyl, 2-
benzothiophenyl, 1 H-indazolyl, benzimidazolyl, benzoxazolyl, indoxazinyl, 2,1-
benzisoxazolyl, benzothiazolyl, 1,2-benzisothiazolyl, 2,1 -benzisothiazolyl,
benzotriazolyl, quinolinyl, isoquinolinyl, 2,3-benzodiazinyl, quinoxalinyl,
quinazolinyl, 1,2,3-benzotriazinyl, or 1,2,4-benzotriazinyl; optionally
substituted;
R"' is alkyl, alkenyl, alkynyl, in particular C1-C6 alkyl, e.g. Ci, C2, C3,
C4, C5, or C6
alkyl, optionally substituted; and
R""' is hydrogen, alkyl, alkenyl, alkynyl, in particular Ci-C6 alkyl, e.g. Cl,
C2, C3, C4,
C5, or C6 alkyl, optionally substituted;
or two adjacent Ra are taken together to form a cycloalkyl, heterocycloalkyl,
alicyclic
ring system, aryl, or heteroaryl; optionally substituted;
Rb and Rc are independent of each other hydrogen, alkyl, in particular Ci-C6
alkyl, e.g. Ci, C2,
C3, C4, C5, or C6 alkyl, preferably methyl, ethyl, propyl, iso-propyl, butyl,
iso-butyl, tert-
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butyl, pentyl, hexyl; alkenyl, in particular C2-C6 alkenyl, e.g. C2, C3, C4,
C5, or C6
alkenyl, preferably ethenyl, 1-propenyl, 2-propenyl, 1-iso-propenyl, 2-iso-
propenyl, 1-
butenyl, 2-butenyl, 3-butenyl; alkynyl, in particular C2-C6 alkynyl, e.g. C2,
C3, C4, C5, or
C6 alkynyl; cycloalkyi, in particular (C3_1o)-cycloalkyl, preferably
cyclopropyl,
cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, heteroalkyl in particular
(Cl-
C6)heteroalkyl, e.g. Cl, C2, C3, C4, C5, or C6 heteroalkyl, cycloheteroalkyl,
in particular
(C3_1o)-cycloheteroalkyl; optionally substituted;
Rd and Re are independent of each other hydrogen, alkyl, in particular CI-C6
alkyl, e.g. Cl, C2,
C3, C4, C5, or C6 alkyl, preferably methyl, ethyl, propyl, iso-propyl, butyl,
iso-butyl, tert-
butyl, pentyl, hexyl; alkenyl, in particular C2-C6 alkenyl, e.g. C2, C3, C4,
C5, or C6
alkenyl, preferably ethenyl, 1-propenyl, 2-propenyl, 1-iso-propenyl, 2-iso-
propenyl, 1-
butenyl, 2-butenyl, 3-butenyl; alkynyl, in particular C2-C6 alkynyl, e.g. C2,
C3, C4, C5, or
C6 alkynyl; optionally substituted;
Hal is F, Cl, Br or I, preferably F, Cl or Br;
n is an integer of 0 to 4, i.e. 0, l, 2, 3, or 4, preferably 0, 1, or 2;
k is an integer of 0 to 4, i.e. 0, 1, 2, 3, or 4, preferably 0, 1, or 2, i.e.
up to the maximum
number of substituents on the phenyl. In this context it is particularly
preferred that R21 has a
structure according to formula (LXVIII) or (LXIX) indicated above.
In a particular preferred embodiment the compound of the present invention has
a
structure according to formula (LXXI), (LXXII) or (LXXIII)
o r
s
-o
(LXXI) (LXXII)
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O
S
0 \
~
O
(LXXIII)
or is a pharmaceutically acceptable salt thereof.
A further aspect of the present invention is a pharmaceutical composition
comprising an
effective amount of at least one compound of the present invention and a
pharmaceutically
acceptable carrier or excipient.
For preparing pharmaceutical compositions from the compounds of the present
invention,
pharmaceutically acceptable carriers can be either solid or liquid. Solid form
preparations
include powders, tablets, pills, capsules, cachets, suppositories, and
dispersible granules. A solid
carrier can be one or more substances, which may also act as diluents,
flavoring agents, binders,
preservatives, tablet disintegrating agents, or an encapsulating material.
In powders, the carrier is a finely divided solid, which is in a mixture with
the finely
divided active component. In tablets, the active component is mixed with the
carrier having the
necessary binding properties in suitable proportions and compacted in the
shape and size desired.
The powders and tablets preferably contain from 5% to 80%, more preferably
from 20%
to 70% of the active compound. Suitable carriers are magnesium carbonate,
magnesium stearate,
talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth,
methylcellulose, sodium
carboxymethylcellulose, a low melting wax, cocoa butter, and the like. The
term "preparation" is
intended to include the formulation of the active compound with encapsulating
material as a
carrier providing a capsule in which the active component with or without
other carriers, is
surrounded by a carrier, which is thus in association with it. Similarly,
cachets and lozenges are
included. Tablets, powders, capsules, pills, cachets, and lozenges can be used
as solid dosage
forms suitable for oral administration.
For preparing suppositories, a low melting wax, such as a mixture of fatty
acid glycerides
or cocoa butter, is first melted and the active component is dispersed
homogeneously therein, as
by stirring. The molten homogeneous mixture is then poured into convenient
sized molds,
allowed to cool, and thereby to solidify.
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Liquid form preparations include solutions, suspensions, and emulsions, for
example,
water or water/propylene glycol solutions. Liquid forms are particularly
preferred for topical
applications to the eye. For parenteral injection, liquid preparations can be
formulated in solution
in aqueous polyethylene glycol solution.
Aqueous solutions suitable for oral use can be prepared by dissolving the
active
component in water and adding suitable colorants, flavors, stabilizers, and
thickening agents as
desired. Aqueous suspensions suitable for oral use can be made by dispersing
the finely divided
active component in water with viscous material, such as natural or synthetic
gums, resins,
methylcellulose, sodium carboxymethylcellulose, and other well-known
suspending agents.
Also included are solid form preparations, which are intended to be converted,
shortly
before use, to liquid form preparations for oral administration. Such liquid
forms include
solutions, suspensions, and emulsions. These preparations may contain, in
addition to the active
component, colorants, flavors, stabilizers, buffers, artificial and natural
sweeteners, dispersants,
thickeners, solubilizing agents, and the like.
The pharmaceutical preparation is preferably in unit dosage form. In such form
the
preparation is subdivided into unit doses containing appropriate quantities of
the active
component. The unit dosage form can be a packaged preparation, the package
containing discrete
quantities of preparation, such as packeted tablets, capsules, and powders in
vials or ampoules.
Also, the unit dosage form can be a capsule, tablet, cachet, or lozenge
itself, or it can be the
appropriate number of any of these in packaged form.
In a further aspect the present invention concerns the use of compounds of the
invention
in the production of a medicament for treating, ameliorating or preventing
diseases, conditions
and/or disorders which benefit from disruption of cellular replication. These
agents have the
potential to be used in the treatment of a large number of different diseases,
in particular acute
lymphoblastic leukemia (in particular childhood), acute myeloid leukemia/other
myeloid
malignancies, B-cell lymphoma, brain tumors (in particular childhood),
ependymoma (in
particular childhood),Ewing's Sarcoma, extracranial germ cell tumors (in
particular childhood),
extragonadal germ cell tumors, gastric cancer (Wils J and Bleiber H (1989)
Eur. J. Cancer Clin.
Oncol. 25:3-8), gastrointestinal carcinoid tumors, gestational trophoblastic
tumors, Hodgkin's
lymphoma, Kaposi's sarcoma, medulloblastoma (childhood), liver cancer (in
particular
childhood), Merkel cell carcinoma, myelodysplastic/myeloproliferative
diseases, neuroblastoma,
non-Hodgkin's lymphoma (childhood), non-small cell lung cancer (Klastersky
(1986) Semin.
Oncol. 13:104-14), osteosarcoma/malignant fibrous histiocytoma of bone,
ovarian germ cell
tumors, ovarian epithelial cancer, retinoblastoma, rhabdomyosarcoma (in
particular childhood),
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small cell lung cancer (Comis RL (1986) Semin Oncol. 13:75-8), supratentorial
primitive
neuroectodermal tumors and pineoblastoma (childhood), testicular cancer
(Einhorn LH (1988)
Semin. Oncol. 3:9-15), thymoma and thymic carcinoma, unusual cancers of
childhood, visual
pathway and hypothalamic glioma, Wilms' tumor (Green DM (1987) Cancer 60:602-
11), other
5 childhood kidney tumors and bone marrow transplantation (Stadtmauer et al.
(1989) 13(8):639-
50).
It is further preferred that the hyperproliferative diseases are selected from
the group
consisting of precancerosis; dysplasia; metaplasia; carcinomas of the
gastrointestinal or
colorectal tract, liver, pancreas, kidney, bladder, prostate, endometrium,
ovary, testes, melanoma,
10 dysplastic oral mucosa, invasive oral cancers, small cell and non-small
cell lung carcinomas,
hormone-dependent breast cancers, independent breast cancers, transitional and
squamous cell
cancers, neurological malignancies including neuroblastoma, gliomas,
astrocytomas,
osteosarcomas, soft tissue sarcomas, hemangioamas, endocrinological tumors,
hematologic
neoplasias including leukemias, lymphomas, and other myeloproliferative and
15 lymphoproliferative diseases, carcinomas in situ, hyperplastic lesions,
adenomas, fibromas,
histiocytosis, chronic inflammatory proliferative diseases, vascular
proliferative diseases and
virus-induced proliferative diseases, skin diseases characterized by
hyperproliferation of
keratinocytes and/or T cells.
In a further aspect the present invention concerns the use of compounds of the
invention
20 in the production of a medicament for treating, ameliorating or preventing
diseases, conditions
and/or disorders which benefit from a reduced cellular replication. There are
a large number of
different diseases that may be treated by the compounds disclosed in this
invention and include,
in particular acute lymphoblastic leukemia (in particular childhood), acute
myeloid
leukemia/other myeloid malignancies, B-cell lymphoma, brain tumors (in
particular childhood),
25 ependymoma (in particular childhood), Ewing's Sarcoma, extracranial germ
cell tumors (in
particular childhood), extragonadal germ cell tumors, gastric cancer,
gastrointestinal carcinoid
tumors, gestational trophoblastic tumors, Hodgkin's lymphoma, Kaposi's
sarcoma,
medulloblastoma (childhood), liver cancer (in particular childhood), merkel
cell carcinoma,
myelodysplastic/myeloproliferative diseases, neuroblastoma, non-Hodgkin's
lymphoma
30 (childhood), non-small cell lung cancer, osteosarcoma/malignant fibrous
histiocytoma of bone,
ovarian germ cell tumors, ovarian epithelial cancer, retinoblastoma,
rhabdomyosarcoma (in
particular childhood), small cell lung cancer, supratentorial primitive
neuroectodermal tumors
and pineoblastoma (childhood), testicular cancer, thymoma and thymic
carcinoma, unusual
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86
cancers of childhood, visual pathway and hypothalamic glioma, Wilms' tumor,
other childhood
kidney tumors and bone marrow transplantation.
The precancerosis treatable with the compounds of the present invention are
preferably
selected from the group consisting of precancerosis of the skin, in particular
actinic keratosis,
cutaneaous horn, actinic cheilitis, tar keratosis, arsenic keratosis, x-ray
keratosis, Bowen's
disease, bowenoid papulosis, lentigo maligna, lichen sclerosus, and lichen
rubber mucosae;
precancerosis of the digestive tract, in particular erythroplakia,
leukoplakia, Barrett's esophagus,
Plummer-Vinson syndrome, crural ulcer, gastropathia hypertrophica gigantea,
borderline
carcinoma, neoplastic intestinal polyp, rectal polyp, porcelain gallbladder;
gynaecological
precancerosis, in particular carcinoma ductale in situ (CDIS), cervical
intraepithelial neoplasia
(CIN), leukoplakia, endometrial hyperplasia (grade III), vulvar dystrophy,
vulvar intraepithelial
neoplasia (VIN), hydatidiform mole; urologic precancerosis, in particular
bladder papillomatosis,
Queyrat's erythroplasia, testicular intraepithelial neoplasia (TIN),
leukoplakia; carcinoma in situ
(CIS); precancerosis caused by chronic inflammation, in particular pyoderma,
osteomyelitis,
acne conglobata, lupus vulgaris, and fistula.
Dysplasia is frequently a forerunner of cancer, and is found mainly in the
epithelia; it is
the most disorderly form of non-neoplastic cell growth, involving a loss in
individual cell
uniformity and in the architectural orientation of cells. Dysplastic cells
often have abnormally
large, deeply stained nuclei, and exhibit pleomorphism. Dysplasia
characteristically occurs
where there exist chronic irritation or inflammation. Dysplastic disorders
which can be treated
with the compounds of the present invention include, but are not limited to,
anhidrotic
ectodermal dysplasia, anterofacial dysplasia, asphyxiating thoracic dysplasia,
atriodigital
dysplasia, bronchopulmonary dysplasia, cerebral dysplasia, cervical dysplasia,
chondroectodermal dysplasia, cleidocranial dysplasia, congenital ectodermal
dysplasia,
craniodiaphysial dysplasia, craniocarpotarsal dysplasia, craniometaphysial
dysplasia, dentin
dysplasia, diaphysial dysplasia, ectodermal dysplasia, enamel dysplasia,
encephalo-ophthalmic
dysplasia, dysplasia epiphysialis heminelia, dysplasia epiphysialis multiplex,
dysplasia
epiphysalis punctata, epithelial dysplasia, faciodigitogenital dysplasia,
familial fibrous dysplasia
of jaws, familial white folded dysplasia, fibromuscular dysplasia, fibrous
dysplasia of bone,
florid osseous dysplasia, hereditary renal-retinal dysplasia hidrotic
ectodermal dysplasia,
hypohidrotic ectodermal dysplasia, lymphopenic thymic dysplasia, mammary
dysplasia,
mandibulofacial dysplasia, metaphysical dysplasia, Mondini dysplasia,
monostotic fibrous
dysplasia, mucoepithelial dysplasia, multiple epiphysial dysplasia,
oculoauriculovertebral
dysplasia, oculodentodigital dysplasia, oculovertebral dysplasia, odontogenic
dysplasia,
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ophthalmomandibulomelic dysplasia, periapical cemental dysplasia, polyostotic
fibrous
dysplasia, pseudoachondroplastic spondyloepiphysial dysplasia, retinal
dysplasia, septo-optic
dysplasia, spondyloepiphysial dysplasia, and ventriculoradial dysplasia.
Metaplasia is a form of controlled cell growth in which one type of adult or
fully
differentiated cell substitutes for another type of adult cell. Metaplastic
disorders, which are
treatable are preferably selected from the group consisting of agnogenic
myeloid metaplasia,
apocrine metaplasia, atypical metaplasia, autoparenchymatous metaplasia,
connective tissue
metaplasia, epithelial metaplasia, intestinal metaplasia, metaplastic anemia,
metaplastic
ossification, metaplastic polyps, myeloid metaplasia, primary myeloid
metaplasia, secondary
myeloid metaplasia, squamous metaplasia, squamous metaplasia of amnion,
symptomatic
myeloid metaplasia and regenerative metaplasia.
Many skin diseases are characterized by hyperproliferation of keratinocytes
and/or T
cells. Examples of such diseases which are treatable with the compounds of the
present invention
comprise without limitations psoriasis in particular psoriasis vulgaris,
psoriasis capitis, psoriasis
guttata, psoriasis inversa; neurodermatitis; ichtyosises; alopecia areata;
alopecia totalis; alopecia
subtotalis; alopecia universalis; alopecia diffusa; atopic dermatitis; lupus
erythematodes of the
skin; dermatomyositis of the skin; atopic eczema; morphea; scleroderma;
alopecia areata
Ophiasis type; androgenic alopecia; allergic contact dermatitis; irritative
contact dermatitis;
contact dermatitis; pemphigus vulgaris; pemphigus foliaceus; pemphigus
vegetans; scarring
mucous membrane pemphigoid; bullous pemphigoid; mucous membrane pemphigoid;
dermatitis; dermatitis herpetiformis Duhring; urticaria; necrobiosis
lipoidica; erythema nodosum;
prurigo simplex; prurigo nodularis; prurigo acuta; linear IgA dermatosis;
polymorphic light
dermatosis; erythema solaris; exanthema of the skin; drug exanthema; purpura
chronica
progressiva; dihydrotic eczema; eczema; fixed drug exanthema; photoallergic
skin reaction; and
periorale dermatitis.
In a further preferred embodiment the hyperproliferative disorders are those
which
benefit from a reduced estrogen receptor signalling, i.e. disorders associated
with an increased
estrogen receptor signalling, if compared to healthy tissue. This particular
suitability of the
compounds of the present invention is based on the fact, that the compounds of
the present
invention potentially through inhibiting cellular replication but possibly
also through an
additional activity of the compounds of the present invention exert a strong
inhibition of estrogen
receptor signalling. Thus preferred diseases, conditions and/or disorders
which can be treated are
selected from the group consisting of mammary tumors, endometrial tumors and
tumors of the
uterus. Whether a disease is associated an increased estrogen receptor
activity can be measured
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by a variety of art known methods including determination of ER expression
level in the
diseased tissue by, e.g. immunological methods, which determine the amount of
expressed
protein, by methods determining the amount of transcribed ER encoding nucleic
acids, e.g. RT-
PCR, Northern-blots, nuclear run-ons etc., and determining the activity of a
nucleic acid
construct comprising an ER-receptor recognition element, which drives
expression of a
detectable reporter, e.g. CAT, luciferase, GFP etc as described in more detail
in the Experimental
Section below. Preferably, the disorders which benefit from a reduced estrogen
receptor
signalling are those, which show in the diseased tisse an increase in estrogen
receptor signalling
by at least 10%, preferably by at least 20%, 30%, 40%, 50%, 60%, 70%, if
compared to healthy
tissue. Preferably this increase is measured on the basis of a nucleic acid
comprising an ER-
receptor recognition element and the increase of the expression of a reporter
driven by this
element.
The quantity of active component in a unit dose preparation administered in
the use of the
present invention may be varied or adjusted from about 1 mg to about 1000 mg
per m2,
preferably about 5 mg to about 150 mg/m2 according to the particular
application and the
potency of the active component. The pharmaceutical composition can, if
desired, also contain
other compatible therapeutic agents (e.g., cytotoxic or cytostatic compounds,
including, but not
limited to, pure or mixed anti-estrogens such as faslodex, tamoxifen or
raloxifen; any inhibitors
of topoisomerase I or II, such as camptothecin (topo I) or etoposide (topo
II); any compound that
acts through inhibiting aromatase activity, such as anastrozole or letrozole;
any preparation that
interferes with HER2 signalling such as herceptin; any compound that
interchelates DNA, such
as doxorubicin. Particularly preferred cytostatic or cytotoxic drugs, which
can be combined with
the compounds of the present invention are alkylating substances, anti-
metabolites, antibiotics,
epothilones, nuclear receptor agonists and antagonists, anti-androgenes, anti-
estrogens, platinum
compounds, hormones and antihormones, interferons and inhibitors of cell cycle-
dependent
protein kinases (CDKs), inhibitors of cyclooxygenases and/or lipoxygenases,
biogeneic fatty
acids and fatty acid derivatives, including prostanoids and leukotrienes,
inhibitors of protein
kinases, inhibitors of protein phosphatases, inhibitors of lipid kinases,
platinum coordination
complexes, ethyleneimenes, methylmelamines, trazines, vinca alkaloids,
pyrimidine analogs,
purine analogs, alkylsulfonates, folic acid analogs, anthracendiones,
substituted urea,
methylhydrazin derivatives, in particular acediasulfone, aclarubicine,
ambazone,
aminoglutethimide, L-asparaginase, azathioprine, bleomycin, busulfan, calcium
folinate,
carboplatin, carpecitabine, carmustine, celecoxib, chlorambucil, cis-platin,
cladribine,
cyclophosphamide, cytarabine, dacarbazine, dactinomycin dapsone, daunorubicin,
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dibrompropamidine, diethylstilbestrole, docetaxel, doxorubicin, enediynes,
epirubicin,
epothilone B, epothilone D, estramucin phosphate, estrogen, ethinylestradiole,
etoposide,
flavopiridol, floxuridine, fludarabine, fluorouracil, fluoxymesterone,
flutamide fosfestrol,
furazoiidone, gemcitabine, gonadotropin releasing hormone analog,
hexamethylmelamine,
hydroxycarbamide, hydroxymethylnitrofurantoin, hydroxyprogesteronecaproat,
hydroxyurea,
idarubicin, idoxuridine, ifosfamide, interferon a, irinotecan, leuprolide,
lomustine, lurtotecan,
mafenide sulfate olamide, mechlorethamine, medroxyprogesterone acetate,
megastrolacetate,
melphalan, mepacrine, mercaptopurine, methotrexate, metronidazole, mitomycin
C,
mitopodozide, mitotane, mitoxantrone, mithramycin, nalidixic acid, nifuratel,
nifuroxazide,
nifuralazine, nifurtimox, nimustine, ninorazole, nitrofurantoin, nitrogen
mustards, oleomucin,
oxolinic acid, pentamidine, pentostatin, phenazopyridine,
phthalylsulfathiazole, pipobroman,
prednimustine, prednisone, preussin, procarbazine, pyrimethamine, raltitrexed,
rapamycin,
rofecoxib, rosiglitazone, salazosulfapyridine, scriflavinium chloride,
semustine streptozocine,
sulfacarbamide, sulfacetamide, sulfachlopyridazine, sulfadiazine,
sulfadicramide,
sulfadimethoxine, sulfaethidole, sulfafurazole, sulfaguanidine, sulfaguanole,
sulfamethizole,
sulfamethoxazole, co-trimoxazole, sulfamethoxydiazine, sulfamethoxypyridazine,
sulfamoxole,
sulfanilamide, sulfaperin, sulfaphenazole, sulfathiazole, sulfisomidine,
staurosporin, tamoxifen,
taxol, teniposide, tertiposide, testolactone, testosteronpropionate,
thioguanine, thiotepa,
tinidazole, topotecan, triaziquone, treosulfan, trimethoprim, trofosfamide,
UCN-01, vinblastine,
vincristine, vindesine, vinblastine, vinorelbine, and zorubicin, or their
respective derivatives or
analogs thereof. Several of the above indicated drugs are now administered
simultaneously for
cancer therapy and, consequently, it is also envisioned that more than one
cytostatic and/or
cytotoxic drug is comprised in compositions of the present invention.
In therapeutic use as an antagonist of estrogen receptor signaling, acting
through
inhibition of cellular replication, the compounds utilized in the use of the
invention are
administered at the initial dosage of about 0.05 mg/kg to about 20 mg/kg
daily. A daily dose
range of about 0.05 mg/kg to about 2 mg/kg is preferred, with a daily dose
range of about 0.05
mg/kg to about 1 mg/kg being most preferred. The dosages, however, may be
varied depending
upon the requirements of the patient, the severity of the condition being
treated, and the
compound being employed. Determination of the proper dosage for a particular
situation is
within the skill of the practitioner. Generally, treatment is initiated with
smaller dosages, which
are less than the optimum dose of the compound. Thereafter, the dosage is
increased by small
increments until the optimum effect under circumstances is reached. For
convenience, the total
daily dosage may be divided and administered in portions during the day, if
desired.
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BRIEF DESCRIPTION OF THE FIGURES
Fig. 1: Depicts the elements of the plasmid ERE-TK-luc used to transfect MCF-7
cells to
provide a cell based quantitative estimate of estrogen signalling.
5 Fig.2: Depicts the complete DNA sequence of reporter plasmid ERE-TK-luc.
Fig. 3: Summarizes the results of various assays performed with the particular
preferred
compounds of the present invention depicted in Table 1 and indicated in
formula
(LXXI), (LXXII) or (LXXIII). Depicted are from left to right for each compound
the
IC50 of MCF-7 cells transfected, with ERE-TK-luc, which uses an ER element to
drive
10 expression of luciferase; the cytotoxicity on MCF-7 cells.
Fig. 4: Depicts cell cycle phase distribution of cells of MCF-7 cells, the
cell cycle analysis and
4'-6-Diamidino-2-phenylindole (DAPI) staining of MCF-7 cells treated with
selected
preferred compounds of the invention.
Fig. 5: Depicts the IC50 of selected compounds on either an ER signalling luc
or a beta actin
15 promoter luc construct, the toxicity on various cell lines, i.e. MCF-7
(human breast
cancer cells), HL-60 (human promyelocytic leukemia cell line), OVCAR-3 (human
ovary adenocarcinoma cell) and HFF (human forskin fibroblast cell line) and
the results
of RT-PCR for ERa, cyclin D1, cyclin Bl, cdc2 and control with or without the
compound.
EXPERIMENTAL SECTION
Cellular assay for the identification of compounds
A cell-based screen designed to detect compounds that activate or inhibit
estrogen
signalling was constructed by transfecting a reporter construct into MCF-7
cells, an ER positive
cell line. The reporter construct consists of an estrogen response element
that controls expression
of a luciferase reporter gene.
In essence, the ERa positive breast adenocarcinoma cell line MCF-7, arrayed in
96 well
format with 5000 cells per well, was transfected with 0.05 g of ERE-TK-luc
(map is shown in
Fig. 1; the full DNA sequence of the plasmid is shown in Fig. 2; SEQ ID No. 1)
using 0.2 g of
polyethylimine (mol.wt. ca 25,000) as a transfection reagent. Cells were co-
incubated with
substances under test at a final concentration of 3 M for 24 hours. Responses
to test substances
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were scored against control replicates containing either no compound (no
inhibition) or
containing faslodex at a final concentration of 5x10'8M (100% inhibition).
This assay was screened against a chemical library provide by a commercial
supplier
under a confidentiality agreement. This library was generated by standard
combinatorial
chemistry using well known procedures. A series of nitrofurans were identified
in this initial
screen. These hits were then confirmed by determination of the IC50 of the
effect these
compounds had in inhibiting estrogen signalling. Then the common structure
within the series
identified in this initial screen was used to perform a sub-structure search
on a larger library to
obtain further candidate molecules. The respective responses of exemplary
compounds identified
in the screen on estrogen receptor signalling are indicated below in Fig. 3.
Determination of distribution in cell cycle
This was performed essentially as described in "Current protocols in
cytometry" John
Willey and Sons, inc. New York, section 7.5.1 - 7.5.24. Sub-confluent,
exponentially growing
MCF-7 cells were treated for 24 hours. The cell cycle distribution of a total
of 10,000 cells was
then determined by flow cytometry following fixation and permeabilization of
cells in alcohol
and treatment with propidium iodide. Cells were gated to exclude cell debris
and aggregates
consisting of 2 or more cells (see Fig. 3 and Fig. 4).
Cytotoxicity assay
The cytotoxicity of compounds was estimated by co-incubating 2000 cells in 96
well
plate format for three days with varying concentrations of the respective
compound. Relative cell
number was then estimated by determining the level of cellular ATP using
ATPlite 1 step reagent
supplied by Perkin Elmer, Germany.
Western blotting
An estimation of the expression level of ERa, cyclin D1, cyclin B1 and cdc2
was
obtained by western blot analysis of cells treated for 16 hours with the
compound under
evaluation at a concentration of 10 M. All results are compared to untreated
control samples.
Western blotting was performed using 2x105 cells per well as described in
"Antibodies, A
laboratory manual." Harlow and Lane, 1988, Cold Spring Harbor, chapter 12,
p471-p504.
Proteins resolved by SDS-PAGE were transferred onto PVDF membranes, blocked
with low fat
milk powder and then stained with the following primary antibodies: anti-ERa:
sc-543; Santa
Cruz Biotechnology; cycling D1: sc-8396; Santa Cruz Biotechnology; cyclin B1:
sc-753; Santa
CA 02646541 2008-09-18
WO 2007/107352 PCT/EP2007/002504
92
Cruz Biotechnology; cdc2: sc-954; Santa Cruz Biotechnology. Primary antibodies
were detected
with horse radish peroxidase conjugated anti-rabbit IgG and visualized on
photographic film
using the Amersham ECL detection system (Amersham biosciences,
Buckinghamshire, UK).
Visualization of DNA in cells
Cells were grown on glass coverslips, treated with compound under test at 10
M for 16
hours, washed twice with phosphate buffered saline (PBS) and then fixed with
methanol at -
20 C. Cells were then rehydrated in PBS, stained for 10 minutes with 10 mM
diamino propidium
iodide (DAPI; Sigma, Germany) then washed twice with PBS. Cells were
visualised and
recorded using an Olympus Fluoview 1000 laser scanning confocal microscope.
