Title of Invention

"A HETEROCYCLIC [3,2-F]-QUINOLINONE OF FORMULA (I),HAVING AGONIST,PARTIAL AGONIST OR ANTAGONIST ANDROGEN RECEPTOR MODULATOR ACTIVITY"

Abstract The present invention relates to a heterocyclic [3,2-f]-quinolinone of formula (I), having agonist, partial agonist or antagonist androgen receptor modulator activity: wherein n, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, X, Y and Z are described in the specification. The present invention also relates to a pharmaceutical composition thereof and a method of purifying a sample.
Full Text The present invention relates to a heterocyclic [3,2-f]-quinolinone of formula (I), having agonist, partial agonist or antagonist androgen receptor modulator activity
Related Application
The present application claims the benefit of priority to U.S. Provisional Application No. 60/271,189, filed on February 23, 2001 which is incorporated by reference in its entirety.
Field of the Invention
This invention relates to non-steroidal compounds that are modulators (i.e. agonists, partial agonists and antagonists) of androgen receptors and to methods for making and using such compounds.
Background of the Invention
Intracellular receptors (IRs) form a class of structurally-related genetic regulators scientists have named "ligand dependent transcription factors" (R. M. Evans, Science, 240:889, 1988)'. Sex steroid hormone receptors are a recognized subset of the IRs, including androgen receptor (AR), progesterone receptor (PR) and estrogen receptor (ER). Regulation of a gene by such factors requires both the receptor itself and a corresponding ligand, which has the ability to selectively bind to the receptor in a way that affects gene transcription.
The natural hormones for sex steroid receptors have been known for a long time, such as testosterone for AR and progesterone for PR. A compound that binds to a receptor and mimics the effect of the native hormone is referred to as an "agonist", while a compound that inhibits the effect of the native hormone is called an "antagonist." The term "modulators" refers to compounds that are agonists, partial agonists or antagonists.
Synthetic female sex hormones have been widely used in oral contraception, hormone replacement therapy and the treatment of hormone-dependent disorders. The development of new generations of selective estrogen receptor modulators (SERMs) significantly improved women's health. On the other hand, similar hormone therapy for men has not been fully explored due to lack of availability of selective, orally administered, safe agents.

A group of hydroquinoline derivatives was recently described as AR modulators (e.g., U.S.
Patent No. 5,696,130). The compounds described in U.S. Patent No. 5,696,130 include
.indeno[l ,2-g]quinolines, indeno[l ,2-f]quinolines, benzo[b]furano[3,2-g]quinolines,
denzo[b]furano[2,3-y]quinolines, indolo[3,2-g]quinolines, indolo[2,3-f]quinolines,
coumarino[3,4-/]quinolines, coumarino[3,4-f]quinolines, 8-pyranono[5,6-g]quinolines, 10-isocoumarino[4,3-g]quinolines, 10-isoquinolino[4,3-g]quinolines, 8-pyridono[5,6-g]quinolines, 10H-isochromeno-[4,3-g]quinolines, 8H-pyrano[3,2-g-]quinolines, 10-thioisoquinolino[4,3-g]-quinolines, 9-pyrido[3,2-g]quinolines, 8-thiopyranono[5,6-g]quinolines, 6-pyridono[5,6-g]quinolines, 9-thiopyran-8-ono[5,6-g]qumolmes, 7-pyridono[5,6-f]indolines and 5H-isochromeno[3,4-/|quinolines. This group of modulators was developed by using cell-based high-throughput assays, termed cotransfection assays. U.S. Patent No. 5,696,130 does not describe any heterocyclic angular tricyclic or tetracyclic [3,2-f]-quinolinones, [3,2-f]quinoline thiones, [3,2-f]-quinolinimines or [3,2-f]-quinolinone oximes. This group of AR modulators was developed by using cell-based high-throughput assays, termed cotransfection assays.
The entire disclosures of the publications and references referred to herein are incorporated by reference herein and are not admitted to be prior art.
Summary of the Invention
The present invention is directed to tricyclic androgen receptor modulator compounds. This invention is also directed to pharmaceutical compositions containing such compounds as well as methods of using such compounds and pharmaceutical compositions for modulating processes mediated by androgen receptor (AR). More particularly, the invention relates to nonsteroidal compounds and compositions that may be high affinity, high specificity agonists, partial agonists (i.e., partial activators and/or tissue-specific activators) or antagonists for androgen receptor. Also provided are methods of making such compounds and pharmaceutical compositions, as well as intermediates used in their synthesis.
The present invention provides a novel class of AR modulator compounds of the
(Formula Removed)
or


wherein:
R1 is selected from the group of hydrogen, F, Cl, Br, I, NO2, OR12, SR12, SOR12,
SO2R12, NR12R13, Ci-Cs alkyl, d-C8 haloalkyl and Q-Cg heteroalkyl, wherein the alkyl,
haloalkyl and heteroalkyl groups may be optionally substituted;
R2 is selected from the group of hydrogen, F, Cl, Br, I, CH3, CF3) CHF2, CH2F,
CF2C1, CN, CF2OR12, CH2OR12, OR12, SR12, SOR12, SO2R12, NR12R13, Ci-C8 alkyl, CrC8
haloalkyl, Ci-C8 heteroalkyl, C2-C8 alkenyl and C2-C8 alkynyl, wherein the alkyl,
haloalkyl, heteroalkyl, alkenyl and alkynyl groups may be optionally substituted;
R3 through R8 each independently is selected from the group of hydrogen, F, Cl,
Br, I, OR12, NR12R13, SR12, SOR12, S02R12, C,-C8 alkyl, C,-C8 haloalkyl, C,-C8
heteroalkyl, C2-C8 alkynyl, C2-Cg alkenyl, aryl, heteroaryl and arylalkyl, wherein the alkyl,
haloalkyl, heteroalkyl, alkynyl, alkenyl, aryl, heteroaryl and arylalkyl groups may be
optionally substituted; or
R3 and R5 taken together form a bond; or
R5 and R7 taken together form a bond; or
-R4 and R6 taken together form a three- to eight-membered saturated or unsaturated
carbocyclic or heterocyclic ring, wherein the carbocyclic or heterocyclic ring may
optionally substituted; or
R6 and R8 taken together form a three- to eight-membered saturated or unsaturated
carbocyclic or heterocyclic ring, wherein the carbocyclic or heterocyclic ring may
optionally substituted;
R9 and R10 each independently is selected from the group of hydrogen, F, Cl, Br, I,
CN, OR12, NR12R13, Cm(RI2)2mOR13, SR12, SOR12, S02R12, NRI2C(O)R13, CrC8 alkyl, Ci-
Cg haloalkyl, Ci-Cg heteroalkyl and arylalkyl, wherein the alkyl, haloalkyl, heteroalkyl and
arylalkyl groups may be optionally substituted;
R11 is selected from the group of hydrogen, F, Br, Cl, I, CN, Ci-C8 alkyl, Ci-Cg
haloalkyl, Ci-Cg heteroalkyl, OR14, NR14R13, SR14, CH2R14, C(O)R14, C02R14,
C(O)NR14R13, SOR14 and SO2R14, wherein the alkyl, haloalkyl and heteroalkyl groups
may be optionally substituted;
R12 and R13 each independently is selected from the group of hydrogen, Ci-Cg
alkyl, Ci-Cg haloalkyl, Ci-Cg heteroalkyl, C2-Cg alkenyl, C2-Cg alkynyl, heteroaryl and
aryl, wherein the alkyl, haloalkyl, heteroalkyl, alkenyl, alkynyl, heteroaryl and aryl groups
may be optionally substituted;
R14 is selected from the group of hydrogen, Ci-Cg alkyl, Ci-Cg haloalkyl, Ci-Cg
heteroalkyl, aryl, heteroaryl, C(O)R15, CO2R15 and C(O)NR15R16, wherein the alkyl,
haloalkyl, heteroalkyl, aryl and heteroaryl groups may be optionally substituted;
R15 and R16 each independently is selected from the group of hydrogen, Ci-Cg
alkyl, Ci-Cg haloalkyl, Ci-Cg heteroalkyl, wherein the alkyl, haloalkyl and heteroalkyl
groups may be optionally substituted;
W is OorS;
X is selected from the group of 0, S and N{R14};
Y is selected from the group of 0, S, N{R12}, N{OR12} and CR12R13;
Z is selected from the group of 0, S and N{R12};
n is 0,1 or 2;
mis 0, 1, or2;
and pharmaceutically acceptable salts thereof.
Detailed Description of the Invention
In accordance with the present invention and as used herein, the following terms
are defined with the following meanings, unless explicitly stated otherwise.
The term "alkyl," alone or in combination, refers to an optionally substituted
straight-chain or branched-chain alkyl radical having from 1 to about 12 carbon atoms.
The term also includes substituted straight-chain or branched-chain alkyl radicals having
from 1 to about 6 carbon atoms as well as those having from 1 to about 4 carbon atoms.
Examples of alkyl radicals include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl,
sec-butyl, tert-butyl, tert-amyl, pentyl, hexyl, heptyl, octyl and the like.
The term "alkenyl," alone or in combination, refers to an optionally substituted
straight-chain or branched-chain hydrocarbon radical having one or more carbon-carbon
double-bonds and having from 2 to about 18 carbon atoms. The term also includes
substituted straight-chain or branched-chain hydrocarbon radicals having one or more
carbon-carbon double bonds and having from 2 to about 6 carbon atoms as well as those
having from 2 to about 4 carbon atoms. Examples of alkenyl radicals include ethenyl,
propenyl, butenyl, 1,4-butadienyl and the like.
The term "alkynyl," alone or in combination, refers to an optionally substituted
straight-chain or branched-chain hydrocarbon radical having one or more carbon-carbon
triple-bonds and having from 2 to about 12 carbon atoms. The term also includes
substituted straight-chain or branched-chain hydrocarbon radicals having one or more
carbon-carbon triple bonds and having from 2 to about 6 carbon atoms as well as those
having from 2 to about 4 carbon atoms. Examples of alkynyl radicals include ethynyl,
propynyl, butynyl and the like.
The term "heteroalkyl" refers to alkyl groups, as described above, in which one or
more skeletal atoms are oxygen, nitrogen, sulfur or combinations thereof. The term
heteroalkyl also includes alkyl groups in which one 1 to about 6 skeletal atoms are
oxygen, nitrogen, sulfur or combinations thereof, as well as those in which 1 to 4 skeletal
atoms are oxygen, nitrogen, sulfur or combinations thereof and those in which 1 to 2
skeletal atoms are oxygen, nitrogen, sulfur or combinations thereof.
The term "alkoxy," alone or in combination, refers to an alkyl ether radical, alkyl-
, wherein the term alkyl is denned as above. Examples of alkoxy radicals include
methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, iso-butoxy, sec-butoxy, tert-butoxy
and the like.
The term "aryloxy," alone or in combination, refers to an aryl ether radical wherein
the term aryl is defined as below. Examples of aryloxy radicals include phenoxy,
benzyloxy and the like.
The term "alkylthio," alone or in combination, refers to an alkyl thio radical, alkyl-
S-, wherein the term alkyl is defined as above.
The term "arylthio," alone or in combination, refers to an aryl thio radical, aryl-S-,
wherein the term aryl is defined as below.
The term "oxo" refers to =0.
The term "aryl," alone or in combination, refers to an optionally substituted
aromatic ring system. The term aryl includes monocyclic aromatic rings, polyaromatic
rings and polycyclic aromatic ring systems containing from six to about twenty carbon
atoms. The term aryl also includes monocyclic aromatic rings, polyaromatic rings and
polycyclic ring systems containing from 6 to about 12 carbon atoms, as well as those
containing from 6 to about 10 carbon atoms. The polyaromatic and polycyclic aromatic
rings systems may contain from two to four rings. Examples of aryl groups include,
without limitation, phenyl, biphenyl, naphthyl and anthryl ring systems.
The term "heteroaryl" refers to optionally substituted aromatic ring systems
containing from about five to about 20 skeletal ring atoms and having one or more
heteroatoms such as, for example, oxygen, nitrogen and sulfur. The term heteroaryl also
includes optionally substituted aromatic ring systems having from 5 to about 12 skeletal
ring atoms, as well as those having from 5 to about 10 skeletal ring atoms. The term
heteroaryl may include five- or six-membered heterocyclic rings, polycyclic
heteroaromatic ring systems and polyheteroaromatic ring systems where the ring system
has two, three or four rings. The terms heterocyclic, polycyclic heteroaromatic and
polyheteroaromatic include ring systems containing optionally substituted heteroaromatic
rings having more than one heteroatom as described above (e.g., a six membered ring with
two nitrogens), including polyheterocyclic ring systems of from two to four rings. The
term heteroaryl includes ring systems such as, for example, furanyl, benzofuranyl,
chromenyl, pyridyl, pyrrolyl, indolyl, quinolinyl, N-alkyl pyrrolyl, pyridyl-N-oxide,
pyrimidoyl, pyrazinyl, imidazolyl, pyrazolyl, oxazolyl, benzothiophenyl, purinyl,
indolizinyl, thienyl and the like.
The term "heteroarylalkyl" refers to a Ci-C4 alkyl group containing a heteroaryl
group, each of which may be optionally substituted.
The term "heteroarylthiq" refers to the group -S-heteroaryl.
The term "acyloxy" refers to the ester group -OC(0)-R, where R is hydrogen,
alkyl, alkenyl, alkynyl, aryl, or arylalkyl, wherein the alkyl, alkenyl, alkynyl and arylalkyl
groups may be optionally substituted.
The term "carboxy esters" refers to -C(O)OR where R is alkyl, aryl or arylalkyl,
wherein the alkyl, aryl and arylalkyl groups may be optionally substituted.
The term "carboxamido" refers to
where R and R' each independently is selected from the group of hydrogen, alkyl,
aryl and arylalkyl, wherein the alkyl, aryl and arylalkyl groups may be optionally
substituted.
The term "cycloalkyl", alone or in combination, refers to a monocyclic, bicyclic or
tricyclic alkyl radical wherein each cyclic moiety has from 3 to about 8 carbon atoms.
Examples of cycloalkyl radicals include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl
and the like.
The term "arylalkyl," alone or in combination, refers to an alkyl radical as defined
above in which one hydrogen atom is replaced by an aryl radical as defined above, such
as, for example, benzyl, 2-phenylethyl and the like.
The terms haloalkyl, haloalkenyl, haloalkynyl and haloalkoxy include alkyl,
alkenyl, alkynyl and alkoxy structures, as described above, that are substituted with one or
more fluorines, chlorines, bromines or iodines, or with combinations thereof.
The terms cycloalkyl, aryl, arylalkyl, heteroaryl, alkyl, alkynyl, alkenyl, haloalkyl
and heteroalkyl include optionally substituted cycloalkyl, aryl, arylalkyl, heteroaryl, alkyl,
alkynyl, alkenyl, haloalkyl and heteroalkyl groups.
The term "carbocycle" includes optionally substituted, saturated or unsaturated,
three- to eight-membered cyclic structures in which all of the skeletal atoms are carbon.
The term "heterocycle" includes optionally substituted, saturated or unsaturated,
three- to eight-membered cyclic structures in which one or more skeletal atoms is oxygen,
nitrogen, sulfur, or combinations thereof.
The term "acyl" includes alkyl, aryl, heteroaryl, arylalkyl or heteroarylalkyl
substituents attached to a compound via a carbonyl functionality (e.g., -CO-alkyl, -COaryl,
-CO-arylalkyl or -CO-heteroarylalkyl, etc.}.
"Optionally substituted" groups may be substituted or unsubstituted. The
substituents of an "optionally substituted" group may include, without limitation, one or
more substituents independently selected from the following groups or designated subsets
thereof: alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, haloalkenyl, haloalkynyl,
cycloalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, alkoxy, aryloxy, haloalkoxy, amino,
alkylamino, dialkylamino, alkylthio, arylthio, heteroarylthio, oxo, carboxyesters,
carboxamido, acyloxy, hydrogen, F, Cl, Br, I, CN, NO2, NH2, N3) NHCH3, N(CH3)2, SH,
SCH3, OH, OCH3, OCF3, CH3, CF3, C(0)CH3, CO2CH3, CO2H, C(O)NH2, OR9, SR9 and
NR10Rn. An optionally substituted group may be unsubstituted (e.g., -CE^CHs), fully
substituted (e.g., -CF2CF3), monosubstituted (e.g., -CH2CH2F) or substituted at a level
anywhere in-between fully substituted and monosubstututed (e.g., -CH2CF3).
The term "halogen" includes F, Cl, Br and I.
The term "mediate" means affect or influence. Thus, for example, conditions
mediated by an androgen receptor are those in which an androgen receptor plays a role.
Androgen receptors are known to play a role in conditions including, for example, acne,
male-pattern baldness, sexual dysfunction, impotence, wasting diseases, hirsutism,
hypogonadism, prostatic hyperplasia, osteoporosis, cancer cachexia, and hormone-
•N
dependent cancers.
The term "selective" refers to compounds that display reactivity towards a
particular receptor (e.g., an androgen receptor) without displaying substantial crossreactivity
towards another receptor (e.g., glucocorticoid receptor). Thus, for example,
selective compounds of the present invention may display reactivity towards androgen
receptors without displaying substantial cross-reactivity towards glucocorticoid receptors.
In one embodiment, selective compounds of the present invention display at least
50-fold greater reactivity towards a particular receptor than towards another receptor. In
another embodiment, selective compounds of the present invention display at least
100-fold greater reactivity towards a particular receptor than towards another receptor. In
yet another embodiment, selective compounds of the present invention display at least
500-fold greater reactivity towards a particular receptor than towards another receptor. In
still another embodiment, selective compounds of the present invention display at least
1,000-fold greater reactivity towards particular receptor than towards another receptor.
Compounds of the present invention may be represented by the formula(Figure Removed):
wherein:
R1 is selected from the group of hydrogen, F, Cl, Br, I, NO2, OR12, SR12, SOR12,
S02R12, NR12R13, C,-Cg alkyl, C,-C8 haloalkyl and C,-C8 heteroalkyl, wherein the alkyl,
haloalkyl and heteroalkyl groups may be optionally substituted;
R2 is selected from the group of hydrogen, F, Cl, Br, I, CH3, CF3, CHF2, CH2F,
CF2C1, CN, CF2OR12, CH2OR12, OR12, SR12, SOR12, SO2R12, NR12R13, CrC8 alkyl, Ci-C8
haloalkyl, Ci-Cg heteroalkyl, C2-Cg alkenyl and C2-Cg alkynyl, wherein the alkyl,
haloalkyl, heteroalkyl, alkenyl and alkynyl groups may be optionally substituted;
R3 through R each independently is selected from the group of hydrogen, F, Cl,
Br, I, OR12, NR12R13, SR12, SOR12, S02R12, Ci-Cg alkyl, CrC8 haloalkyl, C,-C8
heteroalkyl, C2-Cg alkynyl, C2-C8 alkenyl, aryl, heteroaryl and arylalkyl, wherein the alkyl,
haloalkyl, heteroalkyl, alkynyl, alkenyl, aryl, heteroaryl and arylalkyl groups may be
optionally substituted; or
R3 and R5 taken together form a bond; or
R5 and R7 taken together form a bond; or
R4 and R6 taken together form a three- to eight-membered saturated or unsaturated
carbocyclic or heterocyclic ring, wherein the carbocyclic or heterocyclic ring may
optionally substituted; or
f o
R and R taken together form a three- to eight-membered saturated or unsarurated
carbocyclic or heterocyclic ring, wherein the carbocyclic or heterocyclic ring may
optionally substituted;
R9 and R10 each independently is selected from the group of hydrogen, F, Cl, Br, I,
CN, OR12, NRI2R13, Cm(R12)2mOR13, SR12, SOR12, SO2R12, NR12C(0)R13, C,-C8 alkyl, Cr
Cg haloalkyl, Ci-Cg heteroalkyl and arylalkyl, wherein the alkyl, haloalkyl, heteroalkyl and
arylalkyl groups may be optionally substituted;
R11 is selected from the group of hydrogen, F, Br, Cl, I, CN, C,-Cg alkyl, CrC8
haloalkyl, C,-Cg heteroalkyl, OR14, NRI4R13, SR14, CH2R14, C(O)R14, CO2R14,
C(0)NR14R13, SOR14 and S02R14, wherein the alkyl, haloalkyl and heteroalkyl groups
may be optionally substituted;
R12 and R13 each independently is selected from the group of hydrogen, C]-Cg
alkyl, CpCg haloalkyl, Ci-Cg heteroalkyl, C2-Cg alkenyl, C2-Cg alkynyl, heteroaryl and
aryl, wherein the alkyl, haloalkyl, heteroalkyl, alkenyl, alkynyl, heteroaryl and aryl groups
may be optionally substituted;
R14 is selected from the group of hydrogen, Ci~Cg alkyl, Cj-Cg haloalkyl, Q-Cg
heteroalkyl, aryl, heteroaryl, C(0)R15, C02R15 and C(O)NR15R16, wherein the alkyl,
haloalkyl, heteroalkyl, aryl and heteroaryl groups may be optionally substituted;
R15 and R16 each independently is selected from the group of hydrogen, Ci-Cg
alkyl, CpCg haloalkyl, Ci-Cg heteroalkyl, wherein the alkyl, haloalkyl and heteroalkyl
groups may be optionally substituted;
WisOorS;
X is selected from the group of 0, S and N{R14};
Y is selected from the group of 0, S, N{R12}, N{OR12} and CR12R13;
Z is selected from the group of 0, S and N{R12};
n is 0, 1 or 2;
m is 0, 1, or 2;
and pharmaceutically acceptable salts thereof.
In one aspect, the present the invention provides compounds represented by
formula I through VIE. In another aspect, the present invention provides a pharmaceutical
composition comprising an effective amount of an AR modulating compound of formula I
13
through VIZI shown above, wherein R1 through R16, m, n, W, X, Y, and Z are as described
above.
In another aspect, the present invention provides a method of modulating processes
mediated by ARs by administering to a patient a pharmaceutically effective amount of a
compound of formula I through VDI shown above, wherein R1 through R16, m, n, W, X,
Y, and Z are as described above. In one aspect, the modulation is activation, while in
another aspect, the modulation is inhibition. In each case, the method involves
administering to a patient a pharmaceutically effective amount of a compound of formula I
through VIII shown above, wherein R1 through R16, m, n, W, X, Y, and Z are as described
above.
With regard to the foregoing variables, the inventors contemplate any combination
of the Markush groups as set forth above and as described in the following table.
(Figure Removed)The compounds of the present invention may be synthesized as pharmaceutically
acceptable salts for incorporation into various pharmaceutical compositions. As used
herein, pharmaceutically acceptable salts include, but are not limited to, hydrochloric,
hydrobromic, hydroiodic, hydrofluoric, sulfuric, citric, maleic, acetic, lactic, nicotinic,
succinic, oxalic, phosphoric, malonic, salicylic, phenylacetic, stearic, pyridine,
ammonium, piperazine, diethylamine, nicotinamide, formic, urea, sodium, potassium,
calcium, magnesium, zinc, lithium, cinnamic, methylamino, methanesulfonic, picric,
tartaric, triethylamino, dimethylamino and tris(hydroxymethyl)aminornethane and the like
and suitable combination of any two or more thereof. Additional pharmaceutically
acceptable salts are known to those skilled in the art.
AR agonist, partial agonist and antagonist compounds of the present invention may
be useful in the treatment of conditions including, but not limited to, hypogonadism,
frailty, wasting diseases, cachexia, osteoporosis, hirsutism, acne, male-pattern baldness,
prostatic hyperplasia, various hormone-dependent disorders and cancers, including,
without limitation, prostate and breast cancer. The compounds of the present invention
may also prove useful in male hormone replacement therapy, female androgen
replacement therapy, stimulation of hematopoiesis, and as anabolic agents and libido
stimulants.
It is understood by those skilled in the art that although the compounds of the
present invention may be typically employed as selective agonists, partial agonists or
antagonists, there may be instances where a compound with a mixed steroid receptor
profile is desirable.
Furthermore, it is understood by those skilled in the art that the compounds of the
present invention, as well as pharmaceutical compositions and formulations containing
these compounds, can be used in a wide variety of combination therapies to treat the
conditions and diseases described above. Thus, the compounds of the present invention
can be used in combination with other hormones and other therapies, including, without
limitation, ehemotherapeutic agents such as cytostatic and cytotoxic agents,
immunological modifiers such as interferons, interleukins, growth hormones and other
cytokines, hormone therapies, surgery and radiation therapy.
Representative AR modulator compounds (i.e., agonists, partial agonists and
antagonists) according to the present invention include:
5,6,7,8-Tetrahydro-7,7-dimethyl-4-trifluoromethylpyridino[3J2-/lquinolin-2(lH)-
one (Compound 104);
5,6,7,8-Tetrahydro-7,7-diethyl-4-trifluoromethylpyridino[3,2-/]quinolm-2(17:r)-one
(Compound 105);
738-Dihydro-7,7-dimethyl-4-trifluoromethylpyridino[3,2-/]quinolin-2(l/f)-one
(Compound 106);
5,6,7,8 -Tetrahydro-7,7,8-trimethyl-4-trifluoromethylpyri.dino [3 ^^quinolin-
2(l//)-one (Compound 107);
8-Ethyl-5,6,7,8-tetrahydro-7J7-dimethyl-4-trifluoromethylpyridino[3,2:/]quinolin-
2(l/f)-one (Compound 108);
5,6,7,8-Tetrahydro-7,7-dimethyl-4-trifluoromethyl-8-propylpyridino[3J2-
/]quinolin-2(l/:/)-one (Compound 109);
8-(2,2,2-Trifluoroethyl)-5J6,7,8-tetrahydro-7,7-diniethyl-4-trifluoromethylpyridino[
3,2-/]qumolm-2(l-/:f)-one (Compound 110);
6-Hydrazino-4-trifluoromethylquinolin-2(lJ::f)-one (Compound 111);
6-Methyl-4-trifluoromethyl-7H-pyrrolo[3,2-_/]quinolin-2(l//)-one (Compound
112);
5-Isopropyl-6-methyl-4-trifluorornethyl-7H-pyrrolo[3,2-/]quinolin-2(lff)-one
(Compound 113);
5-Allyl-6-methyl-4-trifluoromethyl-7flr-pyrrolo[3,2:/]quinolin-2(l/f)-one
(Compound 114);
5-(4-Methoxyphenyl)-6-methyl-4-trifluoromethyl-7//-pyrrolo[3,2-/|quinolin-
2(l.fiO-one (Compound 115);
5-(3-Trifluoromethylphenyl)-6-methyl-4-trifluoromethyl-7//'-pyrrolo[3J2-
/]quinolin-2(lJ!:0-one (Compound 116);
4-Trifluoromethyl-5,6,7,8-tetrahydrocyclopentano[g]pyrrolo[3,2-/]quinolin-2(l/r)-
one (Compound 117);
4-Trifluoromethyl-5J6J7,8,9,10-hexahydrocycloheptano[g]pyrrolo[3,2-/]quinolm-
2')-one (Compound. 118);
(±)-4c,5,6)7,7a(czj),8-Hexahydro-8-trifluoroethyl-4-trifluoromethylcyclopentano-
[g]pyrrolo[3,2-_/]quinolin-2(l.#)-one (Compound 119);
(±)-6,6a,7,8,9,9a(cw)-Hexahydro-6-trifluoroethyl-4-trifluoromethylcyclopentano-
[i]pyrrolo[2,3-g]quinolin-2(l.#)-one (Compound 120);
(±)-4c,5,6>7J7a(cw),8-Hexahydrq-8-ethyl-4-trifluoromethylcyclopentano-
[g]pynrolo[3,2-/|quinolm-2(l.#)-one (Compound 121);
(±)-6,6a,7)8,9,9a(cw)-Hexahydro-6-ethyl-4-trifluoromethylcyclopentano-
[i]pyTrolo[2,3-g]quinolin-2(lJ:f)-one (Compound 122);
(±)-5,6-Dihydro-5,6-cw-dimethyl-7-trifluoroethyl-4-trifluoromethyl-7/fpyrrolo[
3,2-]quinolin-2(17:f)-one (Compound 123);
(±)-7,8-Dihydro-7)8-cw-dimethyl-6-trifluoroethyl-4-trifluoromethyl-6/fpyrrolo[
2,3-]quinolin-2(l//)-one (Compound 124);
(±)-4c,5J6J7,7a(cw),8-Hexahydro-8-propyl-4-trifluoromethylcyclopentano-
[g]pyrrolo-[3,2-/]quinolin-2(l//)-one (Compound 125);
(±)-4c,5,6,7,7a(cJi1),8-Hexahydro-8-(3-furanylmethyl)-4-trifluoromethylcyclopentano[
g]pyrrolo[3J2-/]quinolin-2(l/f)-one (Compound 126);
(±)-4c,5,6,7,7a(czj),8-Hexahydro-8-(3-thiophenemethyl)-4-trifluoromethylcyclopentano[
g]pyrrolo[3,2-/]quinolin-2(lJ:r)-one (Compound 127);
(±)-4c,5,6,7,7a(czj),8-Hexahydro-8-(2-methylpropyl)-4-trifluoromethylcyclopentano[
g]pyrrolo[3,2-/]quinolin-2(l//)-one (Compound 128);
(±)r4c,5)6,7,7a(cu)J8-Hexahydro-8-(2,2,2-chlorodifluoroethyl)-4-
trifluoromethylcyclopentano[g]pyrrolo[3,2:/]quinolin-2(l/:0-one (Compound 129);
(lc.SJJa/.S-Hexahydro-S-cyclopropylmethyM-trifluoromethylcyclopentano[
g]pyrrolo[3.>2-j]quinolin-2(l/f)-one (Compound 130);
(±)-4c,5,6,7J7a(czj),8-Hexahydro-8-(2>2-dimethoxyethyl)-4-trifluoromethylcyclopentano[
g]pyrrolo[3,2-/]quinolin-2(lJc/)-one (Compound 131);
(±)-4c,5,6>7,8,8a(m)-Hexahydro-9-(2J2,2-tTifluoroethyl)-4-trifluoromethyl-9Hcyclohexano[
g]pyrrolo[3,2^/]quinolin-2(lJ:r)-one (Compound 132);
(±)-4c)5,6,7,8,9,9a(cw),10-Octahydro-10-(2,2J2-trifluoroethyl)-4-trifluoromethylcycloheptano[
g]pyrrolo[3,2-/]quinolin-2(l^r)-one (Compound 133);
24
(±)-5,6-c/5-Dihydro-6-ethyl-5-methyl-7-(2,2>2-trifluoroethyl)-4-trifluoromethyl-
7#-pyrrolo[3,2-^quinolin-2(l.ff)-one (Compound 134);
(±)-5,6-cw-Dihydro-5-butyl-6-methyl-7-(2J2,2-trifluoroethyl)-4-trifluoromethyl-
7#-pyrrolo[3,2-/]quinolin-2(l#)-one (Compound 135);
(±)-5,6-cw-Dihydro-5-(4-nitrophenyl)-6-methyl-7-(2,2,2-trifluoroethyl)-4-
trifluoromethyl-7//-pyrrolo[3,2-/]quinolin-2(l/f)-one (Compound 136);
(±)-5,6- cw-Dihydro-5-(4-dimethylaminophenyl)-6-methyl-7-(2,2,2-trifluoroethyl)-
4-trifluoromethyl-7J:r-pyiTo]o[3)2:/]quinolin-2(l/f)-one (Compound 137);
(±)-5J6-cw-Dihydro-5-(4-methoxyphenyl)-6-methyl-7-(2,2,2-trifluoroethyl)-4-
trifluoromethyl-7/r-pyrrolo[3,2:/]quinolin-2(l^/)-one (Compound 138);
(±)-5,6-cw-Dihydro-5-(3-trifluoromethylphenyl)-6-methyl-7-(2,2,2-
trifluoroethyl)-4-trifluoromethyl-7/f-pyrro]o[3,2-/jquinolin-2(l/f)-one (Compound 139);
(±)-5)6-cw-Dihydro-5-(4-fluorophenyl)-6-methyl-7-(2J2,2-trifluoroethyl)-4-
trifluoromethyl-7jff-pyrrolo[3)2:/]quinolm-2(lJfir)-one (Compound 140);
(±)-5,6-Dihydro-5-phenyl-7-(2,2,2-trifluoroethyl)-4-trifluoromethyl-7//-
pyrrolo[3,2-/]quinolin-2(ljy)-one (Compound.141);
(±)-5,6- cw-Dihydro-5-(4-methoxyphenyl)-6-methyl-4-trifluoromethyl-77:/-
pyrrolo[3i,2-f\qu.mo[m-2(lff)-one. (Compound 142);
(±)-5,6- ci'5-Dihydro-5-(4-methoxyphenyl)-6-methyl-7-(2,2-dimethoxyethyl)-4-
trifluoromethyl-7//-pyrrolo[3,2-/]quinolin-2(l//)-one (Compound 143);
(±)-5)6-cw-Dihydro-5-isopropyl-6-methyl-7-(2,2,2-trifluoroethyl)-4-
trifluoromethyl-7^-pyrrolo[3,2-/|quinolin-2(ljy)-one (Compound 144);
(±)-5,6-Dmydro-5-ethyl-6-methyl-7-(2,2,2-trifluoroethyl)-4-trifluoromethyl-7J:7-
pyrrolo[3,2-/]qumolin-2(l/f)-one (Compound 145);
(±)-5,6-Dihydro-5-ethyl-6-propyl-7-(2,2,2-trifluoroethyl)-4-trifluoromethyl-7//-
pyrrolo[3,2-_/]quinoIin-2(lJ::/)-one (Compound 146);
(±)-556-Dihydro-5-(2-ethoxycarbonylethyl)-6-methyl-7-(2,2,2-trifluoroethyl)-4-
trifluoromethyl-7J!:f-pyrrolo[3,2:/]quinolin-2(lff)-one (Compound 147);
6-Ethyl-5-methyl-7^-pyrrolo[3,2-/]quinolin-2(17f)-one (Compound 148);
(±)-5,6-cw-Dihydro-5-methyl-6-ethyl-7-(2,2,2-trifluoroethyl)-7//-pyrrolo[3,2-
/]quinolin-2(l/f)-one (Compound 149);
5)6-Dimethyl-7-(252,2-trifluoroethyl)-4-trifluoromethyl-7//-pyrrolo[3J2-/|quinolin-
2(l#)-one (Compound 150);
6-Ethyl-5-methyl-7-(2,2,2-trifluoroethyl)-7//-pyrrolo[3)2:/]quinolin-2(l/f)-one
(Compound 151);
6-Methyl-7-(2,2,2-trifluoroethyl)-4-trifluoromethyl-7//-pyrrolo[3,2-/]quinolin-
2(ljy)-one (Compound 152);
6-Ethyl-5-methyl-7-(2:2)2-trifluoroethyl)-4-trifluoromethyl-7//-pyrrolo[3;2-
/)quinolin-2(l/f)-one (Compound 153);
5-Ethyl-6-methyl-7-(2,2J2-trifluoroethyl)-4-trifluoromethyl-7//-pyrrolo[3,2-
/]quinolin-2(lf/)-one (Compound 154);
5-Ethyl-6-propyl-7-(2]2,2-trifluoroethyl)-4-trif]uoromethyl-7^'-pyrrolo[3,2-
/]quinolin-2(l/0-°ne (Compound 155);
5,6,7,8-Tetrahydro-8-trifluoroethyl-4-trifluoromethylcyclopentano[g]pyrrolo[3,2-
/]quinolin-2(l//)-one (Compound 156);
8-Trifluoroethyl-4-trifluoromethyl-6,8-dihydrocyclopentano[g]pyrrolo[3,2-
_/]quinolin-2(lf/)-one (Compound 157);
9-Trifluoroethyl-4-trifluoromethyl-9//-benzo [g]pyrrolo [3,2-f\ quinolin-2( 1 H)-on&
(Compound 158);
6-Trifluoroethy]-4-trifluoromethyl-6,7,8,9-tetrahydrocyclopetano[/]pyrrolo[2,3-
g]quinolin-2(l.#)-one (Compound 159);
5-(3-Trifluoromethylphenyl)-6-methyl-7-(2,2)2-trifluoroethyl)-4-trifluoromethyl-
7//-pyrrolo[3,2-/]quinolin-2(l/:r)-one (Compound 160);
5-(4-Fluorophenyl)-6-methyl-7-(2]2,2-trifluoroethyl)-4-trifluoromethyl-7^-
pyrrolo[3,2-_/]quinolin-2(l^r)-one (Compound 161);
5-(2-Ethoxycarbonylethyl)-6-methyl-7-(2,2,2-trifluoroethyl)-4-trifluoromethyl-7J7-
pyrrolo[3,2-/]quinolin-2(lJ;:f)-one (Compound 162);
7-Ethyl-8-methyl-6-(252,2-trifluoroethyl)-4-trifluoromethyl-6/f-pyrrolo[2,3-
g-]quinolin-2(l/f)-one (Compound 163);
5-Hydroxymethyl-6-ethyl-7-(2J2,2-trifluoroethyl)-4-trifluoromethyl-7//-
pyrrolo[3,2-_/]quinolin-2(lJf/)-one (Compound 164);
5-Methyl-6-(l-hydroxyethyl)-7-(2,2,2-tri£luoroethyl)-4-trifluoromethyl-7//-
pyrrolo[3,2-/]quinolin-2(l.H)-one (Compound 165);
5-Methyl-6-acetyl-7-(2J2,2-trifluoroethyl)-4-trifluoromethyl-7J7-pyrrolo[3J2-
j]quinolin-2(l^f)-one (Compound 166);
5-Formyl-6-methyl-7-(2,2,2-trifluoroethyl)-4-trifluoromethyl-77:/-pyrrolo[3,2-
/]quinolin-2(lf/)-one (Compound 167);
5-Acetyloxymethyl-6-ethyl-7-(2,2,2-trifluoroethyl)-4-trifluoromethyl-7f/'-
pynolo[3,2-J]qmno\in-2(lH)-one, (Compound 168);
2-Acetyloxy-5-hydroxymethyl-6-ethyl-7-(2,2,2-trifluoroethyl)-4-trifluoromethyl-
7//-pyrrolo[3,2:/]quinoline (Compound 169);
6-Ethyl-7-(2,2,2-trifluoroethyl)-4-trifluoromethyl-77/-pyrrolo[3,2-j]quinolin-
2(l#)-one (Compound 170);
5-Ethoxymethyl-6-ethyl-7-(2;2,2-trifluoroethyl)-4-trifluoromethyl-7//-pyrrolo[3,2-
/]quinolin-2(l//)-one (Compound 171);
6-(l-Methoxyethyl)-5-methyl-7-(2!2,2-trifluoroethyl)-4-trifluoromethyl-7/7-
pyrrolo[3,2-/|quinolin-2(lJ:/)-one (Compound 172);
7-Allyl-6-methyl-4-trifluoromethyI-5Jf/-pyrrolo[2,3-y]quinolin-2(l//)-one
(Compound 173);
6-Ethyl-7-methyl-4-trifluoromethyl-5//-pyrrolo[2J3-jr]quinolin-2(1^0-one
(Compound 175);
7-(3-Trifluoromethylphenyl)-6-methyl-4-trifluoromethyl-5^/-pyrrolo[2,3-
/]quinolin-2(l^/)-one (Compound 176);
7r(2-Hydroxyethyl)-6-methyl-4-trifluoromethyl-5//'-pyrrolo[2,3-y]quinolin-2(l/0-
one (Compound 177);
(+)-4c,5)6)7,7a(c/5),8-Hexahydro-8-trifluoroethyl-4-trifluoromethylcyclopentano-
[g]pyrrolo[332-/]quinolin-2(l//)-one (Compound 178);
(-)-4c,5,6,7,7a(cw)58-Hexahydro-8-trifluoroethyl-4-trifluoromethylcyclopentanorR]
pyrrolor3,2-/lquinolin-2(1^0-one,(Compound 179);
4-Trifluoromethyl-657-dihydro-7,7,9-trimethyl-pyrido[2,3-g-]quinolin-2(l^r)-one
(Compound 180);
8-(2,2J2-Trifluoroethyl)-5,6)7,8-tetrahydro-5,7;7-trimethylpyrido[3,2-/]quinolin-
2(l/f)-one (Compound 182);
4,5;7-Tri(trifluoromethyl)pyrido[3,2-/|quinolin-2(l^)-one (Compound 185);
5,7-Bis(trifluoromethyl)pyrido[3,2-/]quinolin-2(l//)-one (Compound 186);
4-Trif]uoromethyl-7-methy]-6,7,8)9-tetrahydropyrido[2)3-^]quinolin-2(lJ:0-one
(Compound 187);
4-Trifluoromethyl-7>8-dihydro-6//-pyrrolo[2,3-g]quinolin-2(l/r)-one (Compound
190);
4-Trifluoromethyl-5,6)7>8-tetrahydropyrido[2,3-g]quinolin-2(ljy)-one (Compound
192);
4-Trifluoromethyl-7-methyl-6-propyl-6,7,8,9-tetrahydropyrido[2,3-g]quinolin-
2(l#)-one (Compound 194);
4-Trifluoromethyl-7-methyl-6-cyclopropylmethyl-6,7,8,9-tetrahydropyrido[2,3-
g-]quinolin-2(l//)-one (Compound 195);
4-Trifluoromethyl-7-methyl-6-ethyl-6)7,8,9-tetrahydropyrido[2,3-g]quinolin-
2(l/f)-one (Compound 196);
4-Trifluoromethyl-7-methyl-6-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydropyrido[2,3-
]quinolin-2(l/:/)-one (Compound 197);
4-Trifluoromethyl-6-(2,2,2-trifluoroethyl)-6,,7,8,9-tetrahydropyrido[2J3-g-]quinolin-
2(l//)-one (Compound 198);
4-Trifluoromethyl-6-propyl-6,7,8,9-tetrahydropyrido[2.,3-gJquinolm-2(lfr)-one
(Compound 199);
4-Trifluoromethyl-6-ethyl-6,7)8,9-tetrahydropyrido[2,3-g]quinolin-2(ljy}-one
(Compound 200);
4-Trifluoromethyl-6-cyclopropylmethyl-6,7,8,9-tetrahydropyrido[2,3-g-]quinolin-
2(lfT)-one (Compound 201);
6,7-Dihydro-8,8-dimethyl-4-(trifluoromethyl)-8^-pyrano[3,2-g]quinolin-2(l/f)-
pne (Compound 202);
6,7-Dihydro-8,8,10-trimethyl-4-(trifluoromethyl)-8H'-pyraiio[3,2-g]quinolm-
2(l//)-one (Compound 206);
(±)-637-Dihydro-6-ethyl-4-methyl-8H-pyrano[3,2-g-]quinolin-2(l//)-one
(Compound 210);
(±)-7,8-Dihydro-8-ethyl-4-methyl-6^-pyrano[2,3-/]quinolin-2(l/f)-one
(Compound 215);
(±)-6,7-Dihydro-6-ethyl-4-trifluoromethyl-8//-pyrano[3,2-^]quinolin-2(lf/)-one
(Compound 216);
(-)-6J7-Dihydro-6-ethyl-4-trifluoromethyl-8^-pyrano[3,2-^]quinolin-2(l/f)-one
(Compound 217);
(+)-6)7-Dihydro-6-ethyl-4-trifluoromethyl-8^-pyrano[3,2-^-]quinolin-2(lf/)-one
(Compound 218);
(±)-6,7-Dihydro-6-ethyl-3-fluoro-4-trifluoromethyl-8H-pyrano[3,2-^]quinolin-
2(l/f)-one (Compound 219);
(±)-6,7-Dihydro-6-ethyl-4-trifluoromethyl-l-methyl-8//'-pyrano[3,2-^]quinolin-
2(lH)-one (Compound 220);
(±)-6,7-Dihydro-6-ethyl-3-fluoro-4-trifluoromethyl-l-methyl-8Jf/-pyrano[3,2-
g]quinolin-2(17:/)-one (Compound 221);
(±)-6J7-Dihydro-6-ethyl-2!4-bis(trifluoromethyl)-8//'-pyrano[3)2-g-]quinoline
(Compound 222);
6,8)8-Trimethyl-4-trifluoromethyl-8f/-pyrano[3,2-5r]coumarin (Compound 223);
6-Ethyl-8,8-dimethyl-4-trifluoromethyl-8//'-pyrano[3,2-g]coumarin (Compound
227);
(±)-5,6-Dihydro-6-hydroxymethyl-4-trifluoromethylpyrrolo[3,2-flquinolin-2(lH)-
one (Compound 228);
(±)-5,6-Dihydro-7-ethyl-6-hydroxymethyl-4-trifluoromethylpyrrolo[3,2-f]quinolin-
2(lH)-one (Compound 229);
7,8-Dihydro-6-(2,2,2-trifluoroethyl)-4-trifluoromethylpyrrolo[2,3-g]quinolin-
2(lH)-one (Compound 230);
6-(2,2^-Tiifluoro£thyl);i4-triflu.oromethylDvrrDlor2.3-elauinolin-2(lH)-Qne
(Compound 231);
8-Chloro-6-(2,2,2-trifluoroethyl)-4-trifluoromethylpyrrolo[2,3-g]quinolin-2(lH)-
one (Compound 232);
5-Methyl-7-(2,2,2-trifluoroethyl)-4-trifluoromethylpyiTolo[3>2-f]quinolin-2(lH)-
one (Compound 233);
f]quinolin-2(lH)-one (Compound 234);
5,6-Dimethyl-7-(2,2-difluorovinyl)-4-trifluoromethyl-7H-pyrrolo[3,2-f]quinolin-
2(lH)-one (Compound 235).
Within such group, representative compounds include:
8-Ethyl-5,6,7,8-tetrahydro-7,7-dimethyl-4-trifluoromethylpyridino[3,2-/]qumolin-
2(l#)-one (Compound 108);
5,6,7,8-Tetrahydro-7,7-dimethyl-4-trifluoromethyl-8-propylpyridino[3,2-
Jquinolin-2(ljy)-one (Compound 109);
8-(2,2,2-Trifluoroethyl)-5)6J7)8-tetrahydro-7J7-dirnethyl-4-trifluoromethylpvridino[
3,2-/]qumolin-2(lJ:/)-one (Compound 110);
(±)-4c,5,6)7,7a(cw),8-Hexahydro-8-trifluoroethyl-4-trifluoromethylcyclopentano-
[g]pyrrolo[3,2-/)quinolin-2(l//)-one (Compound 119);
(±)-6,6a,7,8,9,9a(cfj')-Hexahydro-6-trifluoroethyl-4-trifluoromethylcyclopentano-
[i]pyrrolo[2,3-g]quinolin-2(l//)-one (Compound 120);
(±)-4c,5,6,7,7a(cw),8-Hexahydro-8-ethyl-4-trifluoromethylcyclopentano-
[g]pyrrolo[3,2-y]qumolin-2(l//)-one (Compound 121);
(±)-5,6-Dihydro-5)6-cw-dimethyl-7-trifluoroethyl-4-trifluoromethyl-7//'-
pyrrolo[3,2-/]quinolin-2(l/f)-one (Compound 123);
(±)-7,8-Dihydro-7,8-cyj-dimethyl-6-trifluoroethyl-4-trifluoromethyl-6^rpyrrolo[
2,3-g']quinolin-2(17:f)-one (Compound 124);
(±)-4c,5,6,7,7a(cw).,8-Hexahydro-8-propyl-4-trifluoromethylcyclopentano-
[g]pyrrolo-[3,2-/]quinolin-2(lJ:f)-one (Compound 125);
(±)-4c,5,6,7,7a(cw),8-Hexahydro-8-(2,2,2-chlorodifluoroethyl)-4-
trifluoromethylcyclopentano[g]pyrrolo[3,2-/]quinolin-2(l/f)-one (Compound 129);
(±)^c,5,6^7,7a(c/j),8-Hexahydro-8-cyclqprppylmethyl-4-trifluorornethylcyclopentano[
g]pyrrolo[332-/]quinolin-2(lf/)-one (Compound 130);
(±)-4c,5,6,7,8,8a(c/j)-Hexahydro-9-(2,2,2-trifluoroethyl)-4-trifluoromethyl-9Hcyclohexano[
g]pyrrolo[3,2:/]quinolin-2(l/jr)-one (Compound 132);
(±)-5,6-cw-Dihydro-6-ethyl-5-methyl-7-(2J2>2-trifluoroethyl)-4-trifluoromethyl-
7#-pyrrolo[3,2-/)quinolin-2(l.#)-one (Compound 134);
(±)-536-cw-Dihydro-5-butyl-6-methyl-7-(2,2r2-trifluoroethyl)-4-trifluoromethyl-
7//-pyrrolo[3,2-/]quinolin-2(l.ff)-one (Compound 135);
(±)-5)6-Dihydro-5-ethyl-6-methyl-7-(2,2>2-trifluoroethyl)-4-trifluoromethyl-7/fpyrrolo[
3,2-/]qumolin-2(17:f)-one (Compound 145);
(±)-5)6-Dihydro-5-ethyl-6-propyl-7-(2,2,2-trifluoroethyl)-4-trifluoromethyl-7//-
pyrrolo[3,2-_/]qumolin-2(l/f)-one (Compound 146);
(±)-5)6-cw-Dihydro-5-methyl-6-ethyl-7-(2,2,2-trifluoroethyl)-7J:/'-pyrrolo[3,2-
/]quinolin-2(l//)-one (Compound 149);
5,6-Dimethyl-7-(2)2,2-trifluoroethyl)-4-trifluoromethyl-77:r-pyrrolo[3,2-y]quinolin-
2(l//)-one (Compound 150);
6-Memyl-7-(2,2,2-trifluoroethyl)-4-trifluoromethyl-7/:/-pyrrolo[3,2-/]quinolin-
2(l/f)-one (Compound 152);
6-Ethyl-5-methyl-7-(2,2,2-trifluoroethyl)-4-trifluoromethyl-7//-pyrrolo[3,2-
/]quinolin-2(lff)-one (Compound 153);
5-Ethyl-6-methyl-7-(2,2J2-trifluoroethyl)-4-trifluoromethyl-7f/-pyrrolo[3,2-
/jquinolin-2(l//)-°ne (Compound 154);
S.ej.S-Tetrahydro-S-trifluoroethyl^-trifluoromethylcyclopentanotgjpyrrolofS^-
/]quinolin-2(l//)-one (Compound 156);
6-Trifluoroethyl-4-trifluoromethyl-6,7,8,9-tetrahydrocyclopetano[/]pyrrolo[2,3-
^]quinolin-2(lJ:f)-one (Compound 159);
7-Ethyl-8-methyl-6-(2,2,2-trifluoroethyl)-4-trifluoromethyl-6//-pyrrolo[2,3-
g-]quinolin-2(l/f)-one (Compound 163);
6-Ethyl-7-(2,2>2-trifluoroethyl)-4-trifluoromethyl-7J:/'-pyrrolo[3,2-/jquinolin-
2(l//)-one (Compound 170);
(+)-4c,5,6,7,7a(cw),8-HexahydTO-8-trifluoroethyl-4-trifluoromethylcyclopentano-
[g]pyrrolo[3,2-/]qu!inolin-2(l/f)-one (Compound 178);
(-)-4c,5,6,7,7a(cw),8-Hexahydro-8-trifluoroethyl-4-trifluoromethylcyclopentano-
[g]pyrrolo[3,2-/]qumolin-2(l^)-one (Compound 179);
8-(232,2-Trifluoroethyl)-5)6)7,8-tetrahydro-5,7)7-trimethylpyrido[3)2-/lquinolin-
2(lH)-one (Compound 182);
4-Trifluoromethyl-7-methyl-6-(2,2,2-trifluoroethyl)-6,7)8)9-tetrahydropyrido[2J3-
g]quinolin-2(l//)-one (Compound 197);
6,7-Dihydro-8,8-dimethyl-4-(trifluoromethyI)-8f/-pyrano[3,2-g]quinolin-2(lJy)-
one (Compound 202);
(-)-637-Dihydro-6-ethyl-4-trifluoromethyl-8//-pyrano[3,2-g-]quinolin-2(lf/)-one
(Compound 217); and
(+)-6,7-Dihydro-6-ethyl-4-trifluoromethyl-8/:/'-pyrano[3)2-g]quinolin-2(l//)-one
(Compound 218).
The sequences of steps for several general schemes to synthesize the compounds of
the present invention are shown below. In each of the Schemes the R groups (e.g., Rj, R2,
etc.) correspond to the specific substitution patterns noted in the Examples. However, it
will be understood by those skilled in the art that other functionalities disclosed herein at
the indicated positions of compounds of formulas I through VIII are also potential
substiruents for the analogous positions on the structures within the Schemes.
(Figure Removed)Scheme I describes the synthesis of the tricyclic quinolinones of structure 7.
Treatment of 6-nitro-2rquinolinone (structure 1) with alkyl halide such as 2-iodopropane
in the presence of CsF followed by a palladium catalyzed hydrogenation provide
aminoquinoline of structure 2. Copper catalyzed coupling reaction of structure 2 and
propargyl acetate such as structure 3 followed by a copper catalyzed cyclization
regioselectively afford tricyclic quinoline derivatives of structure 4. Reduction of
dihydroquinolines of structure 4 with NaBH4 gives tetrahydroquinolines of structure 5.
Acid catalyzed hydrolysis of structure 5 provides quinolinones of structure 6. Selective
alkylation at 8-position with an aldehyde or acid in the presence of a reducing agent such
as NaBH4 afford compounds of structure 7.
(Figure Removed)Scheme II describes the synthesis of angular and linear indole/indoline analogues
of structures 13-17. Treatment of 6-amino-2-quinolinones of structure 8 with NaNCh in
strongly acidic conditions such as concentrated HC1 generates hydrozines of structure 9.
Reaction of compound of structure 9 with a ketone such as structure 10 in acidic
conditions affords a mixture of pyrroloquinolinones of structures 11 and 12, which can be
separated by chromatography. Reductive alkylation of the indole nitrogen atom in
structure 11 or 12 with an acid or aldehyde in the presence of a reducing agent such as
NaBBU results in the formation of the reduced and alkylated products of structure 13 or 14.
Oxidation of structure 13 or 14 provides analogues of structure 15,16 or 17.
Scheme III describes side chain manipulation of compounds of structure 18.
Treatment of compounds of structure 18 with an oxidating reagent such as DDQ or MnOj
affords products of structure 19. Acylation of compounds of structure 19 with acetyl
anhydride in the presence of DMAP generates compounds of structures 20 and 23.
Compounds of structure 21 is a by-product of the acylation reaction. Treatment of
compounds of structure 19 with HCI in methanol gives the ether products of structure 22.
Scheme IV describes the preparation of tricyclic compounds of structure 26 by
Fischer indole synthesis. Treatment of the 5-aminoquinolmone of structure 24 with
'NaN0'2 in:'acidic cbnditibris'provides-the hydrozihe intermediates of structure 25.
Condensation of the hydrozine (structure 25) and a ketone of structure 10 followed by acid
catalyzed cyclization afford compounds of structure 26.
Scheme V describes the preparation of tricyclic analogues from 6-
aminoquinolinones of structure 8. Skraup reaction of an aminoquinoline of structure 8 in
acetone at high temperature affords compounds of structures 27 or 28 that depends on the
substituent RI. Treatment of compounds of structure 27 under a reductive alkylation
condition such as NaBELi in TFA provides compounds of structure 29. Condensation of
the aminoquinolines of structure 8 with l,l,l,5,5,5-hexafluoro-2,4-pentadione affords
(Figure Removed)Scheme VI describes the synthesis of the tricyclic compounds of structures 34 and
34a. Nitration of a tetrahydroquinoline of structure 31 provides compounds of structure
32. Palladium catalyzed hydrogenation of compounds of structure 32 followed by the
Knorr reaction afford the mixture compounds of structures 33 and 33a. Selective
alkylation of compounds of structures 33 and 33a gives compounds of structures 34 and
Scheme VII describes the synthesis of the tricyclic pyranoquinolines of structures
39 and 41. Alkylation of 3-nitrophenols of structure 35 gives compounds of structure 36.
Thermal cyclization of the propargyl ethers of structure 36 affords the chromenes of
structure 37. Reduction of the nitro group by hydrogenation provides the aminochromans
'of'structure'38; An alternatWroute starts'with-reduEtion of the nitro group in compounds
of structure 3 6 with zincfpowder follow ed:by acylatiorito give the compound of structure
36a. Cyclization at high temperature, followed by palladium catalyzed hydrogenation,
provides the chroman of structure 38a. Hydrolysis of the acetyl group affords
aminochroman of structure 38. Treatment of compounds of structure 38 with a ketoester
such as ethyl 4,4,4-trifluoro-3-ketobutyrate under Knorr condition gives compounds of
structures 39 and 40. In the case when the diketone of structure 42a is used, a quinoline of
structure 42 is the product. Methvlation of comnounds of structure 39 with iodomethane
and sodium hydride affords compounds of structure 41
(Struture Removed)
Scheme VTII describes the synthesis of the tricyclic coumarins of structure 47.
Annulation to form compounds of structure 44 is accomplished by heating 1,3-resorcinol
and 3,3-dimethylacrylic acid in TFA. Grignard addition to chromenones of structure 44
affords compounds of structure 45, which is dehydrated under acidic condition to give
chromenes of structure 46. Treatment of the hydroxychromenes of structure 46 with a
ketoester such as ethyl 4,4,4-trifluoroacetoacetate in the presence of POCl] affords
compounds of structure 47.
(Structure Removed)
Scheme IX describes the general procedure to convert the 2-quinolinone
derivatives to the typical 2-substituted quinoline derivatives. Treatment of compounds of
structures 48 and 49 with ahaloalkyl in the presence of a catalyst such as CsF produces
the corresponding
2-alkoxy quinoline compounds of structures 50 and 51. Treatment of compounds of
structures 48 and 49 with an acyl halide in the presence of a base, such as triethylamine,
affords the 2-acyloxy quinolines of structures 52 and 53.
The compounds of the present invention also include racemates, stereoisomers,
optically pure enantiomers and mixtures of said compounds, including isotopically-labeled
and radio-labeled compounds. Such isomers can be isolated by standard resolution
techniques, including fractional crystallization and chiral column chromatography.
As noted above, the androgen receptor modulator compounds of the present
invention can be combined in a mixture with a pharmaceutically acceptable carrier to
provide pharmaceutical compositions useful for treating the biological conditions or
disorders noted herein in mammalian and particularly in human patients. The particular
carrier employed in these pharmaceutical compositions may take a wide variety of forms
depending upon the type of administration desired. Suitable administration routes include
enteral (e.g., oral), topical, suppository and parenteral (e.g., intravenous, intramuscular and
subcutaneous).
In preparing the compositions in oral liquid dosage forms (e.g., suspensions, elixirs
and solutions), typical pharmaceutical media, such as water, glycols, oils, alcohols,
flavoring agents, preservatives, coloring agents and the like can be employed. Similarly,
when preparing oral solid dosage forms (e.g., powders, tablets and capsules), carriers such
as starches, sugars, diluents, granulating agents, lubricants, binders, disintegrating agents
and the like may be employed. Due to their ease of administration, tablets and capsules
represent a desirable oral dosage form for the pharmaceutical compositions of the present
invention.
For parenteral administration, the carrier typically will include sterile water,
although other ingredients that aid in solubility or serve as preservatives, may also be
included. Furthermore, injectable suspensions may also be prepared, in which case
appropriate liquid carriers, suspending agents and the like may be employed.
For topical administration, the compounds of the present invention may be
formulated using bland, moisturizing bases, such as ointments or creams. Examples of
suitable ointment bases are petrolatum, petrolatum plus volatile silicones, lanolin and
water in oil emulsions such as Eucerin™, available from Beiersdorf (Cincinnati, Ohio).
Examples of suitable cream bases are Nivea™ Cream, available from Beiersdorf
(Cincinnati, Ohio), cold cream (USP), Purpose Cream™, available from Johnson &
Johnson (New Brunswick, New Jersey), hydrophilic ointment (USP) and Lubriderm™,
available from Warner-Lambert (Morris Plains, New Jersey).
The pharmaceutical compositions and compounds of the present invention
generally will be administered in the form of a dosage unit (e.g., tablet, capsule, etc.). The
compounds of the present invention generally are administered in a daily dosage of from
about 1 p-g/kg of body weight to about 500 mg/kg of body weight. Typically, the
compounds of the present invention are administered in a daily dosage of from about 10
ug/kg to about 250 mg/kg of body weight. Most often, the compounds of the present
invention are administered in a daily dosage of from about 20 (J.g/kg to about 100 mg/kg
body weight. As recognized by those skilled in the art, the particular quantity of
pharmaceutical composition according to the present invention administered to a patient
will depend upon a number of factors, including, without limitation, the biological activity
desired, the condition of the patient and the patient's tolerance for the drug.
The compounds of this invention also have utility when labeled (e.g., radiolabeled,
isotopically-labeled and the like) as ligands for use in assays to determine the
presence of AR in a cell background or extract. They are particularly useful due to their
ability to selectively activate androgen receptors and can therefore be used to determine
the presence of such receptors in the presence of other steroid receptors or related
intracellular receptors.
These invention methods comprise contacting the cell or cell extract with the
compounds of the present invention which have been labeled and testing the contacted cell
or cell extract to determine the presence of AR.' Testing can be accomplished via testing
for activation of androgen receptor(s) (e.g., via elevated presence of the product of
androgen mediated process(es)), via separation of the bound compound/receptor
combination and the like, which techniques are known to those of skill in the art.
Due to the selective specificity of the compounds of this invention for steroid
receptors, these compounds can be used to purify samples of steroid receptors in vitro.
Such purification can be carried out by mixing samples containing steroid receptors with
one or more of the compounds of the present invention so that the compounds bind to the
receptors of choice and then isolating the bound ligand/receptor combination by separation
techniques which are known to those of skill in the art. These techniques include column
separation, filtration, centrifugation, tagging and physical separation and antibody
complexing, among others.
The compounds and pharmaceutical compositions of the present invention can be
used in the treatment of the diseases and conditions described herein. In this regard, the
compounds and compositions of the present invention may prove particularly useful as
modulators of male sex steroid-dependent diseases and conditions such as the treatment of
hypogonadism, sexual dysfunction, acne, male-pattern baldness, wasting diseases,
hirsutism, prostatic hyperplasia, osteoporosis, impotence, cancer cachexia, various
hormone-dependent cancers, including, without limitation, prostate and breast cancer. The
compounds of the present invention may also prove useful in male hormone replacement
therapy, stimulation of hematopoiesis, male contraception and as anabolic agents.
The compounds of the present invention may be extremely potent activators of AR,
displaying 50% maximal activation of AR (e.g., activation of AR, determined by
measurement of luciferase production levels compared to levels achieved by
dihydrotestosterone (DHT)) at a concentration of less than 100 nM (Cotransfection assay
concentration), at a concentration of less than 50 nM, at a concentration of less than 20
nM, or even at a concentration of 10 nM or less. (See, for example, Biological Examples.)
Alternatively, the compounds of the present invention may be extremely potent
inhibitors of AR, displaying 50% maximal inhibition of AR (e.g., inhibition of AR,
determined by measurement of luciferase production levels compared to levels achieved
by dihydrotestosterone (DHT)) at a concentration of less than 100 nM (Cotransfection
assay concentration), at a concentration of less than 50 nM, at a concentration of less than
20 nM, or even at a concentration of 10 nM or less. (See, for example, Biological
Examples.)
In one embodiment, the selective compounds of the present invention generally do
not display undesired cross-reactivity with other steroid receptors, as is seen with the
compound mifepristone (RU486; Roussel Uclaf), a known PR antagonist that displays an
undesirable cross reactivity on GR and AR, thereby limiting its use in long-term, chronic
administration.
The invention will be further illustrated by reference to the following non - limiting
Examples.
EXAMPLE 1
7,8-Dihvdro-7,7-dimethvl-2-isopropoxv-4-trifluoromethyl-8H-pvridinor3,2-/f1quinoline
(Compound 101, Structure 4 of Scheme I. where Rj= R? = methyl)
6-Amino-2-isopropoxy-4-trifluoromethylquinoline (Compound 102, Structure 2 of
Scheme I):
In a 250-mL r.b. flask, a solution of 4-trifluoromethyl-6-nitroquinolinone (structure
1 of Scheme I) (3.78 g, 14.6 mmol) in DMF (75 mL) was treated with CsF (12.41 g, 73
mmol, 5.0 equiv.) and 2-iodopropane (11.09 g, 73 mmol, 5.0 equiv). The reaction mixture
was stirred at room temperature (rt) for 18 h. The reaction mixture was quenched with
H2O (100 mL) and extracted with EtOAc (3 x 200 mL). The combined EtOAc extracts
were washed with saturated aqueous NH4C1 solution (300 mL), H2O (300 mL) and brine
(300 mL). Dried (MgSO^, filtered and concentrated in vacua. The residue was purified by
flash column chromatography (SiC^, 5 x 20 cm, 2% EtOAc in hexane as eluent) to afford
3.94 g (90%) of the 2-isopropoxyquinoline as a white solid. Rf 0.81 (Si02,10% EtOAc-
hexane). 'H NMR (400 MHz, CDC13) 8.93 (s, 1H), 8.47 (dd, 1H, J= 9.2, 2.5) 7.98 (d, 1H,
J= 9.2), 7.32 (s, 1H), 5.62 (septet, 1H, J= 6.2), 1.45 (d, 1H, J= 6.2).
In a 100-mL r.b. flask, a solution of 2-isopropoxy-4-trifluoromethyl-6-
nitroquinolinone (1.0 g, 3.3 mmol) in a 3:1 ratio of CH2Cl2/MeOH (40 mL) was treated
with 10% Pd/C (168 mg, 16 wt. % equiv). The resulting mixture was stirred under H2 (1
arm) at rt for 18 h. The reaction mixture was filtered through a pad of celite and the celite
cake was rinsed with MeOH (100 mL). The filtrate was concentrated in vacua to give 0.85
g (95%) of compound 102 as colorless oil that was used immediately in the next reaction
without further purification. Rf 0.27 (SiO2,10% EtOAc-hexane). 'H NMR (400 MHz,
CDC13) 7.70 (d, 1H, J = 9.6) 7.13 (m, 3H), 5.49 (septet, 1H, J= 6.2), 3.89 (s, 2H), 1.39 (d,
lH,y=6.2).
7,8-Dihydro-7,7-dimethyl-2-isopropoxy-4-trifluoromethyl-8H-pyridino[3,2-
/jquinoline (Compound 101, Structure 4 of Scheme I, where RI = R2 = methyl):
In a 250-mL r.b. flask, a solution of compound 102 (4.55g, 16.8 mmol) in THF
(150 mL) was treated with Cu(I)Cl (0.167g, 0.168 mmol, 10 mol%) and 2-acetoxy-2-
methyl-3-butyne (structure 3 of Scheme I, where RI = R2 - methyl) (3.19 g, 25.3 mmol,
1.5 equiv). The reaction mixture was heated to reflux for 18 h. After cooling to rt, the
reaction mixture was filtered through a pad of celite and the celite cake was rinsed with
EtOAc (300 mL). The filtrate was washed with saturated aqueous NBUCl solution (150
mL), H2O (150 mL) and brine (150 mL). Dried (MgSC^), filtered and concentrated in
vacua. The residue was purified by flash column chromatography (SiO2> 5 x 20 cm, 5%
EtOAc in hexane as eluent) to afford 4.85 g (86%) of compound 101 as a yellow-greenish
solid. Rf 0.53 (SiO2> 10% EtOAc-hexane). 'H NMR (400 MHz, CDC13) 7.57 (d, 1H, J=
8.9), 7.19 (s, 1H), 6.95 (d, 1H,J= 8.9), 6.91 (d, m,J = 10), 5.50-5.43 (m, 2H), 4.06 (s,
1H), 1.38 (d, 6H, J= 6.2), 1.33 (s, 6H).
EXAMPLE 2
5.6.7,8-Tetrahydro-7,7-dimethyl-2-isopropoxv-4-trifluoromethYlpvridinor3.2 -flquinoline
(Compound 103, Structure 5 of Scheme I. where Ri= R? = methyl)
In a 250-mL r.b. flask, a solution of compound 101 (3.64g, 10.8 mmol) in TFA (50
mL) was treated with NaBELi caplets (4.5g, 119 mmol, 11 equiv). The reaction mixture
was stirred at it for 20 h. The reaction mixture was poured onto 200 mL of ice-water,
neutralized with NaHCO3 powder to pH 7 and extracted with EtOAc (3 x 250 mL). The
combined extracts were washed with brine (2 x 200 mL), dried (MgSC^), filtered and
concentrated in vacua. The residue was purified by flash column chromatography (SiO2, 5
x 20 cm, 5% EtOAc in hexane as eluent) to afford 3.38 g (92%) of compound 103 as a
yellow solid. Rf 0.50 (SiO2,10% EtOAc-hexane). 'H NMR (400 MHz, CDC13) 7.56 (d,
IH, J= 8.8), 7.24 (s, IH), 6.89 (d, IH, J= 8.8), 5.46 (septet, IH, /= 6.2), 3.85 (s, IH),
3.07 (t,2H,J= 6.5), 1.68(t, 2H,J=6.5), 1.38 (d, 6E,J= 6.2), 1.26 (s,6H).
EXAMPLE 3
5,6J,8-Tetrahvdro-7.7-dimethvl-4-trifluoromethYlpyridino[3,2-/1quinolin-2(lff)-one
(Compound 104. Structure 6 of Scheme I, where R^= Rj = methyl)
In a 250-mL r.b. flask, a solution of compound 103 (3.97g, 11.7 mmol) in AcOH
(50 mL) was treated with cone. HC1 (50 mL). The reaction mixture was heated to 95°C
and stirred for 4 h. After cooling to rt, the reaction mixture was poured onto ice-water,
neutralized with NaHCO3 powder to pH 7 and extracted with EtOAc (3 x 500 mL). The
combined extracts were washed with H20 (500 mL) and brine (500 mL), dried (MgSCXj),
filtered and concentrated in vacua. The residue was purified by recrystallizing from
EtOAc/hexane to afford 3.42 g (98%) of compound 104 as a yellow-orange solid. ]H
NMR (400 MHz, CDC13) 10.35 (br. s, IH), 7.27 (d, IH, 7= 8.6), 7.25 (s, IH), 6.82 (d, IH,
J= 8.6), 3.80 (s, IH), 3.03(t, 2H,J= 6.5), 1.67 (t, 2H,J= 6.5), 1.24 (s,6H).
EXAMPLE 4
5.6.7.8-Tetrahvdro-7.7-diethvl-4-trifluoromethvlpvridmor3.2-/1quinolin-2(lH)-one
(Compound 105. Structure 6 of Scheme I. where Rr= Rg = ethyl)
This compound was prepared in a similar fashion as described in Examples 1, 2
and 3 from compound 102 and 2',2'-diethylpropargyl acetate (structure 3 of Scheme I,
where R, = R2 = ethyl). Spectral data for compound 105: !H NMR (400 MHz, CDC13)
7.22 (s, IH), 7.14 (d, J= 8.7, IH), 6.83 (d, J= 8.7, IH), 3.78 (bs, IH), 2.98 (t, J = 6.5,
2H), 1.67 (t, J= 6.5, 2H), 1.49 (q, J = 7.4, 6H), 0.89 (t, J= 7.4, 4H).
EXAMPLE 5
7,8-Dihvdro-7J-dimethyl-4-trifluoromethvlpvridino[3.2-/]quinolin-2(l^n-one
(Compound 106, Structure 4a of Scheme I. where Rj= R.7 - hydrogen)
This compound was prepared in a similar fashion as that described in Example 3
from compound 101. Spectral data for compound 106: *H NMR (500 MHz, acetone-d)
11.0 (bs, 1H), 7.24 (d, J= 8.8, 1H), 7.05 (d, J = 8.8, 1H), 6.98 (s, 1H), 6.78 (d, J= 10.3,
1H), 5.62 (bs, 1H), 5.558 (dd, J= 9.8, 1.9, 1H), 1.30 (s, 6H).
EXAMPLE 6
5,6,7,8-Terrahydro-7.7.8-trimethvl-4-trifluoromethvlpvridinor3,2:/1quinolin-2(l^n-one
(Compound 107, Structure 7 of Scheme I. where RL = R? = Ri = methyl)
In a 25-mL r.b. flask, a solution of compound 104 (structure 6 of Scheme I, where
RI = R2 = methyl, 41 mg, 0.15 mmol) in MeOH (5 mL) was treated with formaldehyde (5
mL, 37 wt. % solution in water), AcOH (2 mL) and NaCNBHs (excess). The reaction
mixture was stirred at rt for 24 h. The reaction mixture was poured onto ice-water (50
mL), neutralized with NaHCOj powder to pH 7 and extracted with EtOAc (3x50 mL).
The combined extracts were washed with H2O (50 mL) and brine (50 mL), dried
(MgSC>4), filtered and concentrated in vacua. The residue was purified by flash column
chromatography (SiC>2, 1 x 20 cm, 50% EtOAc in hexane as eluent) to afford 32 mg (75%)
of 107 as an orange solid: Rf 0.40 (SiO2,2:l = EtOAc:hexane); !H NMR (400 MHz,
CDCl3)11.45(br. s, 1H), 7.23 (d, 1H,J= 9.1), 7.22 (s, 1H), 7.05 (d, 1H, J= 9.1), 2.97 (t,
2H, J= 6.2), 2.88 (s, 3H), 1.71 (t, 2H, J= 6.2), 1.27 (s, 6H).
EXAMPLE 7
8-Ethvl-5.6.7,8-tetrahydro-7,7-dimethyl-4-trifluoromethylpvridino[3,2-/]quinolin-2(17/)-
one (Compound 108. Structure 7 of Scheme I. where Rjj= R£ = methyl, RI = ethyl)
In a 25-mL r.b. flask, a solution of compound 104 (structure 6 of Scheme I, where
RI = R2 = methyl) (35.3 mg, 0.119 mmol) in MeOH (5 mL) was treated with acetaldehyde
(2 mL), AcOH (2 mL) and NaCNBHs (excess). The reaction mixture was stirred at rt for
24 h. The reaction mixture was poured onto ice-water (50 mL), neutralized with NaHCOs
powder to pH 7 and extracted with EtOAc (3 x 50 mL), The combined extracts were
washed with H2O (50 mL) and brine (50 mL), dried (MgS04), filtered and concentrated in
vacua. The residue was purified by flash column chromatography (SiO2, 1 x 20 cm, 50%
EtOAc in hexane as eluent) to afford 19.1 mg (50%) of compound 108 as an orange solid:
Rf 0.51 (SiO2,2:l = EtOAc:hexane); 'H NMR (400 MHz, CDC13) 11.42 (br. s, 1H), 7.23
(d, 1H, J= 9.2), 7.21 (s, 1H), 7.05 (d, 1H, J= 9.2), 3.38 (q, 2H, J= 7.0), 2.97 (t, 2H, J =
6.2), 1.71 (t, 2H,./= 6.2), 1.27 (s, 6H), 1.17 (t, 3H, J= 7.0).
EXAMPLE 8
5,6.7,8-Tetrahvdro-7.7-dimethYl-4-trifluoromethvl-8-propvlpvridinoF3.2-/1quinolin-2fljy)-
one (Compound 109, Structure 7 of Scheme I. where R^ = Rg = methyl, Ry= propyl)
In a 25-mL r.b. flask, a solution of compound 104 (structure 6 of Scheme I, where
R[ = R2 = methyl) (34 mg, 0.115 mrnol) in MeOH (5 mL) was treated with
propionaldehyde (2 mL), AcOH (2 mL) and NaCNBH3 (excess). The reaction mixture was
stirred at rt for 24 h. The reaction mixture was poured onto ice-water (50 mL), neutralized
with NaHCOj powder to pH 7 and extracted with EtOAc (3 x 50 mL). The combined
extracts were washed with H20 (50 mL) and brine (50 mL), dried (MgSO4), filtered and
concentrated in vacua. The residue was purified by flash column chromatography (SiO2) 1
x 20 cm, 50% EtOAc in hexane as eluent) to afford 13.2 mg (34%) of compound 109 as an
orange solid: Rf 0.51 (SiO2,2:l = EtOAc:hexane); 'H NMR (400 MHz, CDC13) 10.89(br.
s, 1H), 7.28 (d, 1H, J = 9.0), 7.21 (s, 1H), 7.01 (d, 1H, J= 9.0), 3.20 (t, 2H, /== 7.7), 2.96
(t, 2H, /= 6.1), 1.70 (t, 2H, J = 6.1), 1.60-1.50 (m, 2H), 1.25 (s, 6H), 0.92 (t, 3H, J= 7.3).
EXAMPLE 9
8-(2.2.2-Trifluoroethvl)-5.6.7.8-tetrahvdro-7.7-dimethvl-4-trifluoromethvl-pvridino[3,2-
/]quinolin-2f 1-ffl-one (Compound 110, Structure 7 of Scheme I. where Rj_ = R2 = methyl.
Ri = 2.2.2-trifluoroethvl)
In a 100-mL r.b. flask, a solution of compound 104 (structure 6 of Scheme I, where
R, = R2 = methyl) (0.59 g, 2.0 mmol) in TFA (15 mL) was treated with NaBH4 (6.0 g).
The reaction mixture was heated to 95°C and stirred for 6 h. The reaction mixture was
diluted with-EtOAc (50 mL) and poured onto ice-water (50 mL), neutralized with
NaHCO3 powder to pH 7 and extracted with EtOAc (2 x 100 mL). The combined extracts
were washed with H2O (150 mL) and brine (150 mL), dried (MgSO4), filtered and
concentrated in vacua. The residue was purified by flash column chromatography (SiO2, 3
x 20 cm, 50% EtOAc in hexane as eluent) to afford 0.62 g (81%) of compound 110 as a
yellow solid: Rf 0.56 (Si02,2:1 = EtOAc:hexane); 'H NMR (400 MHz, Acetone-d6) 11.0
(s, 1H), 7.43 (d, 1H, /= 9.2), 7.35 (d, 1H, J= 9.2), 7.05 (s, 1H), 4.22 (q, 2H, /= 9.0), 2.98
(t,2H, 7=6.1), 1.77(t,2H,J=6.1), 1.31 (s,6H).
EXAMPLE 10
6-Hvdrazino-4-trifluoromethvlauinolin-2rin-one (Compound 111. Structure 9 of Scheme
II. where R^ = trifluoromethvl)
In a 250 mL r.b. flask a suspension of 6-amino-4-trifluoromethylquinolin-2(l//)-
one (structure 8 of Scheme II, where R) = trifluoromethyl) (2.28 g, 10 mmol) in 10 mL
cone. HC1 was cooled to -1 °C and a solution of NaNC2 (0.40 g, 12 mmol) in water (5
mL) was added dropwise in 20 min. The dark yellow suspension was stirred at -1 °C for 1
h and then a solution of SnCl2'2H20 (5.2 g, 15 mmol) in cone. HC1 (10 mL) was added
dropwise in 10 min. The light yellow suspension of the hydrazine was stirred at -1°C for
2 h and then used directly or kept in a refrigerator at -1°C until it was used (the crude
compound can be stored for at least one month without decomposition).
EXAMPLE 11
6-Methvl-4-trifluoromethvl-7H-pyrrolor3.2-/1quinolin-2(lAr)-one (Compound 112.
Structure 11 of Scheme II, where Ri = H. R; = methyl. R^ = trifluoromethvl)
To the crude suspension of compound 111 (-0.4 M) in aqueous HC1 was added a
solution of acetone (structure 10 of Scheme E, 2-5 eq.) in an equal volume of EtOH and
the mixture was heated in a sealed tube at 130°C for 2 h. Then the mixture was diluted
with an equal volume of water while still hot and allowed to cool to rt. The precipitate was
filtered and washed with water to give compound 112 as a yellow solid: 'H NMR (500
MHz, acetone-*/*) 11.1 (bs, 1 H), 10.6 (bs, 1 H), 7.69 (d, J= 8.8, 1 H), 7.25 (d, J = 8.8, 1
H), 6.94 (s, 1 H), 6.64 (s, 1 H), 2.51 (s, 3 H).
EXAMPLE 12
5-Isopropyl-6-methvl-4-rrifluoromethvl-7H-pvrrolof3.2:?1quinQlin-2(lffl-one (Compound
113. Structure 11 of Scheme II, where RT = isopropyl. R? = methyl Rj^ = trifluoromethvl')
To the crude suspension of compound 111 (structure 9 of Scheme II, where R] =
trifluoromethyl) (~0.4 M) in aqueous HC1 was added a solution of a ketone (structure 10
of Scheme II) (2-5 eq.) in an equal volume of EtOH and the mixture was refluxed for 2 h.
Then the mixture was diluted with an equal volume of water while still hot and allowed to
cool to rt. The precipitate was filtered and washed with water to give the indole as a
mixture of regioisomers. The ratio of angular and linear isomers was determined by 'H
NMR. The mixture of regioisomers could be separated by chromatography (Silica gel,
hex/EtOAc 1:1 to 0:1 gradient). Spectra data for compound 113: 'H NMR (500 MHz,
DMSO-rftf) 12.2 (bs, 1H), 11.3 (bs, 1H), 7.52 (d, J= 8.8, 1H), 7.03 (d, J= 8.8, 1H), 6.87
(s, 1H), 3.30-3.24 (m, 1H), 6.64 (s, 1H), 2.48 (s, 3H), 1.22 (d, J= 6.8, 6H).
EXAMPLE 13
5-Allyl-6-methyl-4-trifluoromethvl-7//-pYrrolo[3.2:/1quinoIin-2(lJ:ir)-one (Compound 114.
Structure 11 of Scheme II, where RT = allyl. R? = methyl. Ri = trifluorornethvl)
This compound was prepared in a similar fashion as that described in Example 12
from compound 111 (structure 9 of Scheme II, where RI = trifluoromethyl) and 5-hexen-
2-one (structure 10 of Scheme II) as a yellow solid: 'H NMR (500 MHz, DMSO-^j) 12.3
(bs, 1H), 11.5 (bs, 1H), 7.59 (d, /= 8.8, 1H), 7.10 (d, J= 8.8, 1H), 6.89 (s, 1H), 5.82-5.76
(m, 1H), 4.85 (dd, J= 10.8, 2.0, 1H), 4.76 (dd, J= 17.1, 2.0, 1H), 3.50 (d, J= 5.9, 2H),
2.33 (s, 3H).
EXAMPLE 14
5-(4-Methoxvphenvl)-6-methvl-4-rrifluoromethvl-7^f-pvrrolor3.2-/]quinolin-2(lff)-one
(Compound 115. Structure 11 of Scheme II. where R^ = 4-methoxyphenyl. Rg = methyl.
Ri = trifluoromethyl)
This compound was prepared in a similar fashion as that described in Example 12
from compound 111 (structure 9 of Scheme II, where RI = trifluoromethyl) and l-(4-
methoxyphenyl)acetone (structure 10 of Scheme II) as a yellow solid: !H NMR (500 MHz,
DMSO-4y) 12.3 (bs, 1 H), 11.7 (bs, 1 H), 7.64 (d, J= 8.8, 1 H), 7,14 (d, J= 8.8, 1 H), 7.06
(d, J= 8.8, 2 H), 6.91 (d, J= 8.8, 2 H), 6.68 (s, 1 H), 3.77 (s, 3 H), 2.22 (s, 3 H).
EXAMPLE 15
5-(3-TrifluQromethvlphenvl)-6-methvI-4-trifluoromethvl-7//'-pvrrolo[3.2:?1quinolin-
2(lff)-o-ne (Compound 116. Structure 11 of Scheme n. where RT = 3-
trifluoromethvlphenyl. R2 = methyl, R^ = trifluoromethYl)
This compound was prepared in a similar fashion as that described in Example 12
from compound 111 (structure 9 of Scheme II, where RI = trifluoromethyl) and l-(3-
trifluoromethylphenyl)acetone (structure 10 of Scheme n) as a yellow solid: 'H NMR
(500 MHz, DMSO-rfd) 12.4 (bs, IH), 11.9 (bs, IH), 7.69 (d, J= 8.8, IH), 7.62-7.59 (m,
2H), 7.53 (bd, /= 4.9, IH), 7.41 (s, IH), 7.21 (d, J= 8.8, 2H), 6.73 (s, 1 H), 2.27 (s, 3H).
EXAMPLE 16
4-Trifluoromethyl-5.6.7.8-tetra]ivdrocvclopentanofg1pvrrolo[3,2:/]quinolin-2fl/jr)-one
(Compound 117. Structure 11 of Scheme n, where R3. R2 = -CH2CH2CH;-. R]_ =
trifluoromethyl
This compound was prepared in a similar fashion as that described in Example 12
from compound 111 (structure 9 of Scheme II, where RI = trifluoromethyl) and
cyclopentanone (structure 10 of Scheme IT) as a yellow solid: 'H NMR (500 MHz,
DMSO-j) H-6 (bs, IH), 10.5 (bs, IH), 7.73 (d, J= 8.8, IH), 7.26 (d, J= 8.8, IH), 6.92
(s, IH), 3.05-3.02 (m, 2H), 2.91-2.88 (m, 2H), 2.47-2.43 (m, 2H).
EXAMPLE 17
4-Trifluoromethvl-5.6.7.8.9.10-hexahvdrocycloheptano[g1pvrrolo[3.2:/]quinolin-2(lJL/)-
one (Compound 118. Structure 11 of Scheme II. where Ri. R2 = -(CH?)r, RL =
trifluoromethyl)
This compound was prepared in a similar fashion as that described in Example 12
from compound 111 (structure 9 of Scheme II, where R] = trifluoromethyl) and
cycloheptanone (structure 10 of Scheme IE) as a yellow solid: 'H NMR (500 MHz,
DMSO-Jtf) 11.4(bs, IH), 10.5 (bs, IH), 7.63 (d, J= 8.3, IH), 7.17 (d,J= 8.3, IH), 6.91
(s, IH), 2.98-2.94 (m, 2 H), 2.91-2.87 (m, 2 H), 1.92-1.86 (m, 2H). 1.81-1.75 (m, 2H),
1.69-1.63(m,2H).
EXAMPLE 18
f±)-4c.5.6.7.7a(cjj').8-Hexahvdro-8-(2,2.2-trifluoroethvl')-4-trifluoromethvlcvclopentano-
[g1pyrrolor3.2-/]quinolin-2(l.fi')-on6 (Compound 119. Structure 13 of Scheme II, where
R3, R2 = -(CH2)r, R! = trifluoromethvl. R4 = 2.2.2-trifluoroethyl)
To a solution of compound 117 (structure 11 of Scheme n, where Rj, R: = -
(CH2)3-, 1.30 g, 4.45 mmol) in TFA (40 mL) in a 250 mL r.b. flask was added a pellet
(0.75 g, 22 mmol) of NaBH4. Two more pellets of NaBEU were added with 30 min
intervals and the mixture was stirred at rt for 16 h until the starting material was
consumed. Water was carefully added (-150 mL) and the yellow precipitate was filtered
and washed with water. The yellow solid was purified by column cnromatography (Silica
gel, hex:EtOAc, 7:3) to give compound 119 (1.27 g, 76%) as a yellow solid: 'H NMR
(500MHz, CDC13) 12.3 (bs, IH), 7.28 (d,J= 8.8, IH), 7.19 (s, IH), 6.87 (d, J = 8.8, IH),
4.30 (d, /=4.9, 2H), 4.06-4.02 (m, 2H), 3.74-3.58 (m, 2H), 2.15-2.13 (m, 2H), 1.77-1.66
(m,3H), 1.58-1.53 (m, IH).
EXAMPLE 19
(±)-6,6a.7.8.9,9afeVHexahvdrQ-6-(2,2.2-trifluoroethvl)-4-trifluoromethylcvclopentanori1pVTrQlor2.3-
g1quinolin-2(l#)-one ("Compound 120. Structure 14 of Scheme II. where
R3j R; - -fCHj^-JR-i= trifluoromethyl, R^ - 2.2,2-trifluoroethyl)
This compound was isolated as a regioisomer of compound 119 (structure 13 of
Scheme II, where R3, R2 = -(CH2)3-, RI = trifluoromethyl, R« = trifluoroethyl) in the same
reaction process as a yellow solid: 1HNMR (500 MHz, CDC13) 12.4 (bs, IH), 7.18 (s,
IH), 7.03 (s, IH), 6.64 (s, IH), 4.35 (dd, J= 6.3, 6.3, IH), 3.89-3.85 (m, IH), 3.76 (q, JH.F
= 9.3, IH), 2.14-2.06 (m, IH), 1.98-1.92 (m, IH), 1.888-1.82 (m, IH), 1.79-1.70 (m, 2H),
1.59-1.53 (m, IH).
EXAMPLE 20
(±V4c.5.6.7.7a('c^l.8-Hexahvdro-8-ethYl-4-trifluoromethvlcvclopentano-[g]pYrrolof3,2-
/|quinolin-2('IJjr)-one (Compound 121, Structure 13 of Scheme II. where Ri, R? = -(CH^h-
. RI = trifluoromethvl Ra = ethyl)
This compound was prepared in a similar fashion as that described in Example 18
from Compound 117 (structure 11 of Scheme II, where R3, R2 =
-(CH2)r) and acetic acid. 'HNMR (500 MHz, CDClj) 12.0 (bs, IH), 7.21 (d,J= 8.3, IH),
7.19 (s, IH), 6.87 (d, J= 8.8, IH), 4.30 (d, J= 4.9, 2H), 4.06-4.02 (m, 2H), 3.74-3.58 (m,
2H), 2.15-2.13 (m, 2H), 1.77-1.66 (m, 3H), 1.58-1.53 (m, IH).
EXAMPLE 21
(±)-6,6a,7.8.9.9a g1quinolin-2(l#)-one ("Compound 122. Structure 14 of Scheme II. where Rj. R? = -(CH;V
. RI = trifluoromethyl. R^i = ethyl)
This compound was isolated as a regioisomer of compound 121 (Structure 13 of
Scheme II, where R3, R2 = -(CH2)3-, Ri = trifluoromethyl, R^ = ethyl) in the same reaction
described in Example 20 as a yellow solid: 1E NMR (500 MHz, CDC13) 11.9 (bs, 1H),
7.08 (s, 1H), 6.99 (s, 1 H), 6.41 (d, 7=2.0, 1 H), 4.30-4.27 (m, 1H), 3.79-3.75 (m, 1H),
3.34 (dq, .7=7.3, 7.3, 1H), 3.21 (dq, 7=7.3, 7.3, 1H), 2.08-2.01 (m, 1H), 1.89-1.86 (m,
1H), 1.82-1.79 (m, 1H), 1.72-1.65 (m, 2 H), 1.58-1.52 (m, 1H), 1.18 (t, .7=7.3, 3H).
EXAMPLE 22
(±)-5.6-Pihydro-5.6-cM-dimethyl-7-C2.2,2-trifluoroethvl)-4-trifluoromethyl-7//-
pyrrolo[3,2-/1quinolin-2dff)-one (Compound 123. Structure 13 of Scheme H where RT =
R2 = methyl, Rx = trifluoromethyl, Rj = 2.2.2-trifluoroethyl)
This compound was prepared in a similar fashion as that described in Examples 12
and 18 from Compound 111 (Structure 9 of Scheme II, where RI = trifluoromethyl) and 2-
butanone. 'H NMR (500 MHz, CDC13) 12.3 (bs, 1H), 7.32 (d, J= 8.8, 1H), 7.21 (s, 1H),
6.95 (d, J= 8.8, 1H), 3.75-3.53 (m, 4H), 1.38 (d, J= 6.8, 3H), 0.98 (d, J= 6.8, 3H).
EXAMPLE 23
±)-7.8-Dihvdro-7.8-m-dimethvl-6-r2.2.2-trifluoroethvl)-4-trifluoromethvl-6/jrpyrrolof2.3-
g1quinolin-2flJ:n-one fCompound 124. Structure 14 of Scheme n. where R^ =
R; = methyl, R_i = trifluoromethyl, R^ = 2,2,2-trifluoroethyl)
This compound was isolated as a regioisomer of compound 123 (Structure 13 of
Scheme II, where R3 = R2 = methyl, RI = trifluoromethyl, R4 = trifluoroethyl) in the same
reaction described in Example 22 as a yellow solid: 'H NMR (500 MHz, CDC13) 12.1 (bs,
1H), 7.13 (d, J= 1.5, 1H), 7.04 (s, 1H), 6.76 (s, 1H), 3.75-3.60 (m, 2H), 3.33 (dq, J= 6.3,
5.9, 1H), 2.95 (dq, J= 7.3, 5.9, 1H), 1.41 (d, J= 7.3, 3H), 1.39 (d, J= 6.3, 3H).
EXAMPLE 24
(+)-4c.5.6.7.7arci5').8-Hexahvdro-8-propvl-4-trifluoromethvlcvclopentano-rg1pvrrolo-[3.2-
/1quinolin-2(l.ff)-one (Compound 125, Structure 13 of Scheme II. where Rj. Rg = -CCH-?)^
...Ri = trifluoromethyl. Ri = propyj)
This compound was prepared in a similar fashion as that described in Example 18
from Compound 117 (structure 11 of Scheme II, where R3, R2 =
-(CHz)3-) and propionic acid. 'H NMR (500 MHz, CDC13) 10.4 (bs, 1H), 7.31 (dd, J= 8.8,
1.8, 1H), 7.20 (s, 1H), 6.78 (d, J= 8.8, 1H), 4.28-4.26 (m, 1H), 3.96-3.95 (m, 1H), 3.14-
. 3.05 (m,2H), 2.06-2.03 (m,2H), 1.72-1.51 (m, 6H), 0.95 (t, J= 7.3, 3H).
EXAMPLE 25
(±)-4c,5,6,7,7a(ct.y).8-Hexahydro-8-(3-furanvlmethvn-4-trifluoromethylcvclopentano[
g]pvrrolo[3,2-/1quinolin-2(ljy)-one (Compound 126. Structure 13 of
Scheme II. where Ra. R2 = -fCH?);-. RI - trifluoromethvl Ra = 3-furanylmethyll
This compound was prepared in a similar fashion as that described in Example 18
from Compound 117 (structure 11 of Scheme II, where R3, R2 = -(CH2)3-) and 3-furoic
acid. 'H NMR (500 MHz, CDC13) 12.2 (bs, 1H), 7.36-7.35 (m, 1H), 7.29 (s, 1H), 7.22 (d,
J= 8.8, 1H), 7.16 (s, 1 H), 6.82 (d, J= 8.3, 1H), 6.26 (d, J=l .0, 1H), 4.27-4.22 (m, 2H),
4.08 (d,/= 16.1, 1H), 3.97-3.91 (m, 1H), 2.12-2.08 (m, 1H), 2.03-2.01 (m, 1H); 1.72-1.70
(m,3H), 1.60-1.58 (m, 1H).
EXAMPLE 26
(±)-4c.5.6,7.7a(c;5),8-Hexahvdro-8-(3-thiophenemethyl)-4-trifluoromethy]-
cyclopentano[g]pyrrolo[3.2-/]quinolin-2(l//)-one (Compound 127. Structure 13 of
Scheme II. where R^.Rg = -fCH?V. RI = trifluoromethyl, R» = 3-thiophenemethyl)
This compound was prepared in a similar fashion as that described in Example 18
from Compound 117 (structure 11 of Scheme II, where R3, R2 = -(CHa)3-) and 3-
thiophenecarboxylic acid. 'H NMR (500 MHz, CDC13) 10.9 (bs, 1H), 7.29 (dd, J= 5.4,
2.9, 1H), 7.13 (s, 1H), 7.07 (d, J= 8.3, 1H), 7.06 (s, 1H), 6.96 (dd, J= 5.4, 1.5, 1H), 7.12-
7.04 (m, 1H), 6.72 (d, J= 8.3, 1H), 4.38.(d, J= 16.1, 1H), 4.26 (d, J= 16.1, 1H), 4.27-
4.25 (m, 1H), 3.98-3.94 (m, 1H), 2.16-2.07 (m, 1H), 2.04-2.22 (m, 1H), 1.78-1.68 (m, 3H),
1.60-1.54 (m,lH).
EXAMPLE 27
(±)-4c.5.6J.7a(cfj).8-Hexahvdro-8-f2-methvlpropvl)-4-trifluoromethvlcvclopentano[
g]pvrrolo[3,2-/1quinolin-2('lf/)-one (Compound 128, Structure 13 of
Scheme II, where R^ R? = -CCH^i-, R^ = trifluoromethvl. Rj = 2-methvlpropyl)
This compound was prepared in a similar fashion as that described in Example 18
from Compound 117 (structure 11 of Scheme II, where R3, R2 = -(CHa)3-) and isobutyric
acid. 'H NMR (500 MHz, CDC13) 12.2 (bs, IH), 7.20 (d, /= 8.8, IH), 7.15 (s, IH), 6.74
(d, J= 8.8, IH), 4.22-4.19 (m, IH), 3.98-3.93 (m, IH), 2.93 (dd, J= 14.3, 7.3, IH), 2.81
(dd, J= 14.3, 7.9, IH), 2.14-2.00 (m, 3H), 1.72-1.63 (m, 3H), 1.56-1.52 (m, 1 H), 0.97 (d,
J= 6.7, 3H), 0.92 (d, J= 6.7, 3H).
EXAMPLE 28
(+)-4c,5.6.7.7a(cfj).8-Hexahvdro-8-(2,2,2-chlorodifluoroethyl)-4-
trifluoromethy]cvclopentano[g1pvrrolo[312-/]quinolin-2(l//)-one (Compound 129,
Structure 13 of Scheme H where R3, R2 = -(CHgV. Rj = trifluoromethvl R chlorodifluoroethyl)
This compound was prepared in a similar fashion as that described in Example 18
from Compound 117 (structure 11 of Scheme II, where R3, R2 = -(CH2)3-) and
chlorodifluoroacetic acid. 'H NMR (500 MHz, CDC13) 12.3 (bs, IH), 7.38 (d,/= 8.8, 1
H), 7.29 (s, IH), 7.00 (d, J= 8.8, IH), 4.46-4.44 (m, IH), 4.09-4.05 (m, IH), 3.94-3.81 (m,
2H), 2.21-2.12 (m, 2H), 1.81-1.74 (m, 2H), 1.69-1.63 (m, IH), 1.56-1.52 (m, 1 H).
EXAMPLE 29
-4c,5.6.7.7a(cfj),8-Hexahvdro-8-cvclopropvlmethvI-4-trifluoromethvlcYcIopmtanorg1pWQlo[
3.2-/]quinolin-2(I#Vone (Compound 130. Structure_13 of
Scheme H. where Ri. Rz = -fCHzk-, & = trifluorqmethvl Rj, = cyclopropvlmethyl)
This compound was prepared in a similar fashion as that described in Example 18
from Compound 117 (structure 11 of Scheme II, where R3, RZ = -(GH^s-) and
cyclopropanecarboxylic acid. 'HNMR (500 MHz, CDC13) 12.4 (bs, IH), 7.25 (d,J= 8.8,
IH), 7.16 (s, IH), 6.84 (d, /= 8.8, IH), 4.41-4.38 (m, IH), 3.97-3.92 (m, 1 H), 3.18 (dd, J
= 14.9,5.5, IH), 2.90 (dd, 7=14.9,7.3, IH), 2.14-2.04 (m, 2H), 1.78-1.66 (m, 3H), 1.55-
1.49 (m, IH), 0.97-0.92 (m, IH), 0.61-0.55 (m, IH), 0.53-0.47 (m, IH), 0.28-0.22 (m, IH),
0.19-0.14 (m, IH).
EXAMPLE 30
(±)-4c.5,6.7Ja(ci5).8-Hexahvdro-8-(2.2-dimethoxyethyl)-4-trifluoromethvlcyclopsntano[
g1pvn:olo[3.2-/lquinQliri-2(l/f)-one (Compound 131. Structure 13 of
Scheme IL where R3, R? = -(C&V, RI = trifluoromethyl. R^ = 2.2-dimethoxyethyl)
This compound was prepared in a similar fashion as that described in Example 18
from Compound 117 (structure 11 of Scheme II, where R3, R2 = -(CE^s-) and
dimethoxyacetaldehyde. 'HNMR(500MHz, CDC13) 11.1 (bs, IH), 7.14 (s, IH), 7.12 (d,
J= 8.8, IH), 6.91 (d, J= 8.8, IH), 4.43 (dd, J= 5.9, 4.4, IH), 4.31-4.30 (m, IH), 3.94-
3.93 (m, IH), 3.41 (s, 6H), 3.30 (dd, J= 15.1, 5.9, IH), 3.21 (dd, J= 15.1, 4.4, IH), 2.12-
2.09 (m, 2H), 1.72-1.55 (m, 4H).
EXAMPLE 31
f±V4c.5.6.7.8.8a(c^)-Hexahydro-9-(2.2.2-trifluoroethvn-4-rrifluoromethvl-9Hcvc]
ohexano[g]pyirolQ[3.2-/1quinolm-2(lff)-one (Compound 132. Structure 13 of Scheme
H. where R3. Ra = -(CHjV. RI_= trifluoromethyl R^ = 2.2.2-trifluorpethyl)
This compound was prepared in a similar fashion as that described in Examples 12
and 18 from Compound 111 (structure 9 of Scheme II, where RI = trifluoromethyl) and
cyclohexanone. 'H NMR (500 MHz, CDC13) 12.1 (bs,.lH), 7.29 (d,7= 8.8, IH), 7.19 (s,
IH), 7.02 (d, J= 8.-83 IH), 3.70-3.60 (m, 2H), 3.56 (m, IH), 3.41-3.38 (m, IH), 2.14 (d, J
= 14.6, IH), 1.75-1.67 (m, 3H), 1.61-1.56 (m, 2H), 1.31-1.25 (m, IH), 1.05-0.98 (m, IH).
EXAMPLE 32
(±)-4c.5.6.7,8.9.9afcfjX10-Octahydro-lO-('2.2.2-tiifluoroethvl)-4-trifluoromethvlcvcloheptanorg]
pvrrolor3,2-/]quinolin-2(l.ff)-one (Compound 133. Structure 13 of
Scheme II. where Ra. R2 = -CCHgV. Rj. = trifluoromethvl. R4 = 2,2.2_-trifluoroethyl}
This compound was prepared in a similar fashion as that described in Example 18
from Compound 118 (structure 11 of Scheme II, where R3, R2 = -(CH2)5-). ]H NMR (500
MHz, CDC13) 12.0 (bs, 1H), 7.32 (d, J= 8.8, 1H), 7.25 (s, 1H), 6.98 (d, J= 8.8, 1H), 3.96-
3.91 (m, 1H), 3.73-3.62 (m, 3H), 2.36-2.26 (m, 2H), 1.93-1.86 (m, 3H), 1.78-1.69 (m, 2H),
1.48-1.36 (m, 3H).
EXAMPLE 33
(±)-5.6-c/j-DihYdro-6-ethvl-5-methyl-7-(2.2,2-trifluoroethyl')-4-trifluoromethvl-7gpvrrolo[
3.2:/1quinolin-2(ljy)-one (Compound 134. Structure 13 of Scheme n. where Rj =
methyl. R; = ethyl Rj = trifluoromethvl Rj = 2.2,2-rrifluoroethyl)
This compound was prepared in a similar fashion as that described in Examples 12
and 18 from Compound 111 (structure 9 of Scheme II, where RI = trifluoromethyl) and 3-
pentanone.'H NMR (500 MHz, CDC13) 11.6 (bs, 1H), 7.26 (d,/= 8.3, 1H), 7.15 (s, 1H),
6.74 (d, J= 8.3, 1H), 4.25 (dd, J= 7.3, 3.4, 1H), 3.96-3.91 (m, 1H), 3.29 (dq, J= 7.3, 7.3,
1H), 3.16 (dq, /= 7.3, 7.3, 1H), 1.965-1.85 (m, 2H), 1.08 (t, J= 7.3, 3H), 0.98 (d, J= 6.3,
3H).
EXAMPLE 34
(±1-5,6- cM-Dihvdro-5-butvl-6-methvl-7-(2,212-trifluoroethv])-4-trifluoromethy]-7J:J'-
pyrrolof3,2-/]quinoliri-2(l.g)-one ("Compound 135. Structure 13 of Scheme II. where Ri =
butyl. R = methyl. RL = trifluoromethvl RI = 2.2.2-trifluoroethvl)
This compound was prepared in a similar fashion as that described in Examples 12
and 18 from Compound 111 (structure 9 of Scheme II, where RI = trifluoromethyl) and 2-
heptanone. 'H NMR (500 MHz, CDC13) 12.1 (bs, 1H), 7.29 (d, J= 8.8, 1H), 7.20 (s, 1H),
6.94 (d, J= 8.8, 1H), 3.76-3.68 (m, 1H), 3.67-3.57 (m, 2H), 3.47-3.43 (m, 1H), 1.74-1.66
(m, 1H), 1.44 (d,/=6.8, 3H), 1.36-1.29 (m, 1H), 1.28-1.20 (m, 1H), 1.20-1.12 (m, 3H),
0.81 (t,J=7.3,3H).
EXAMPLE 35
(±)-5.6-CM-Dihydro-5-(4-nitrophenvn-6-methYl-7-(2.2.2-h-ifluoroethvl')-4-
trifluoromethvl-7//-pvrrolor3,2-/1quinolin-2ri//)-Qne (Compound 136. Structure 13 of
Scheme II. where Ri = 4-nitrophenyl. R; = methyl. R^ = trifluoromethvl. R* = 2.2.2-
trifluoroethyl)
This compound was prepared in a similar fashion as that described in Examples 12
and 18 from Compound 111 (Structure 9 of Scheme II, where RI = trifluoromethyl) and 4-
nitrophenylacetone. 'H NMR (500 MHz, CDC13) 12.1 (bs, 1H), 8.05 (d, J= 8.3, 2H), 7.47
(d, J= 8.8, 1H), 7.13 (d, /= 8.8, 1H), 7.13 (s, 1H), 6.90 (bs, 2H), 4.79 (d, /= 7.3, 1H),
4.11 (dq, J= 7.3, 6.3, 1H), 3.78-3.61 (m, 2H), 0.96 (d, J= 6.3, 3H).
EXAMPLE 36
(±)-5.6-c-Dihvdro-5-(4-dimethvlaminophenYl)-6-methvl-7-(2.2.2-trifluoroethvl)-4-
trifluoromethvl-7#-pvrrolor3.2-/1quinolin-2(l./jr)-one (Compound 137. Structure 13 of
Scheme II. where RT = 4-dimethvlaminophenyl, R? = methyl. Rj^ = trifluoromethyl. R^ =
2.2.2-trifluoroethvl)
This compound was prepared in a similar fashion as that described in Examples 12
and 18 from Compound 111 (Structure 9 of Scheme II, where RI = trifluoromethyl) and 4-
dimethylaminophenylacetone. 'H NMR (500 MHz, CDC13) 12.3 (bs, 1H), 7.40 (d, J= 8.8,
1H), 7.09 (s, 1H), 7.06 (d, J= 8.8, 1H), 6.56-6.52 (m, 4H), 4.59 (d, J= 7.3, 1H), 3.96 (dq,
J= 7.3, 6.3, 1H), 3.77-3.67 (m, 1H), 3.67-3.57 (m, 1H), 2.86 (s, 6H), 0.95 (d, /= 6.3, 3H).
EXAMPLE 37
(±)-5.6-c^-Dihvdro-5-('4-methoxvphenvl)-6-methvl-7-(2.2.2-trifluoroethvll-4-
trifluoromethvl-7ff-pvrrolof3.2-/1quinolin-2(l//)-one (Compound 138. Structure 13 of
Scheme II. where Ri = 4-methoxyphenyl. R2 = methyl. R^ = trifluoromethyl. R£ = 2.2.2-
trifluoroethvl)
This compound was prepared in a similar fashion as that described in Example 18
from Compound 115 (Structure 11 of Scheme II, where R3 = 4-methoxyphenyl, R2 =
methyl, R, = trifluoromethyl). !H NMR (500 MHz, CDC13) 11.6 (bs, 1H), 7.36 (d,/= 8.8,
1H), 7.09 (s, 1H), 7.07 (d, /= 8.8, 1H), 6.71 (d, J= 8.8, 2H), 6.63 (bs, 2H), 4.63 (d, J=
7.3, 1H), 3.99 (dq, J= 7.3, 6.3, 1H), 3.74-3.58 (m, 2H), 3.73 (s, 3H), 0.94 (d, 7= 6.3, 3H).
EXAMPLE 38
(±)-5.6-cM-Dihvdro-5-(3-trifluorornethylphenyl)-6-methvl-7-(2.2.2-trifluoroethyl)-4-
trifluoromethvl-7^-pvrrolo[3.2-/1quinolin-2(l/-/)-one (Compound 139, Structure 13 of
Scheme II, where R3 = S-trifluoromethylphenyl, R? = methyl. R_^ = trifluoromethvl. Ra =
2.2.2-trifluoroethyl)
This compound was prepared in a similar fashion as that described in Example 18
from Compound 116 (Structure 11 of Scheme II, where R3 = 3-trifluoro-methylphenyl, R2
= methyl, R, = trifluoromethyl). ]HNMR (500 MHz, CDC13) 12.8 (bs, 1H), 7.51 (d, J=
8.8, 1H), 7.43 (d, J= 7.8, 1H), 7.30-7.26 (m, 1H), 7.14 (s, 1H), 7.12 (d, J= 8.8, 1H), 7.12-
7.04 (m, 1H), 6.92-6.78 (bs, 1H), 4.74 (d, J= 6.8, 1H), 4.08 (dq, J= 6.8, 6.3, 1H), 3.78-
3.60 (m, 2H), 0.93 (d, J= 6.3, 3H).
EXAMPLE 39
(±)-5,6-c;-Dihvdro-5-('4-fluorophenvn-6-methyl-7-f2.2.2-rrifluoroethyl)-4-
trifluoromethv]-7#-pyrro]of3,2-/1quinolin-2f lH)-one (Compound 140, Structure 13 of
Scheme II, where R^ = 4-fluorophenvl R2 = methyl. Rj. = trifluoromethvl. Rj = 2.2.2-
trifluoroethyl)
This compound was prepared in a similar fashion as that described in Examples 12
and 18 from Compound 111 (Structure 9 of Scheme II, where RI = trifluoromethyl) and 4-
fluorophenylacetone. 'H NMR (500 MHz, CDC13) 10.6 (bs, 1H), 7.28 (d, 7= 8.8, 1H),
7.08 (s, 1H), 7.07 (d, 7 = 8.8, 1H), 6.88-6.85 (m, 2H), 6.68 (bs, 2H), 4.66 (d, 7= 6.8, 1 H),
4.01 (dq, 7=6.8,6.3, 1H), 3.73-3.67 (m, 2H), 3.67-3.60 (m, 1H), 0.94 (d,7= 6.3, 3H).
EXAMPLE 40
(±)-5.6-Dihvdro-5-phenvl-7-f2.2.2-trifluoroethvn-4-trifluoromethvl-7JHr-pvrrolo[3.2-
/1quinolin-2('l//)-one (Compound 141. Structure 13 of Scheme IT. where RI - phenyl. R =
H. R! = trifluoromethvl, Rj = 2.2.2-trifluoroethyn
This compound was prepared in a similar fashion as that described in Examples 12
and 18 from Compound 111 (Structure 9 of Scheme II, where R) = trifluoromethyl) and
phenylacetaldehyde. 'H NMR (500 MHz, CDC13) 12.6 (bs, 1H), 7.48 (d, 7= 8.8, 1H),
7.20-7.14 (m, 3H), 7.14 (s, 1H), 7.05 (d, 7= 8.8, 1H), 6.76-6.74 (m, 2H), 4.89 (d, 7= 8.3,
2H), 3.93 (dd, 7= 8.3, 8.3, 1H), 3.84-3.77 (m, 1H), 3.64-3.56 (m, 1H), 3.55 (d, 7= 8.8,
1H).
EXAMPLE 41
(+V5.6- cM-Dihvdro-5-(4-methoxYphenYl)-6-methvl-4-trifluoromethyl-7J:/'-pviTolof3.2-
/)quinolin-2f lH)-one ("Compound 142. Structure 13 of Scheme II. where R^ = 4-
methoxyphenyl. R? = methyl. R^ = trifluoromethvl. R^ = H)
This compound was isolated as a minor product from the same reaction described
in Examples 37. 'H NMR (500 MHz, CDC13) 12.0 (bs, 1H), 7.32 (d, 7= 8.8, 1H), 7.09 (s,
1H), 7.14 (d, 7= 8.8, 1H), 7.08 (s, 1H), 6.73 (d, 7= 8.8, 2H), 6.65 (bs, 2H), 4.60 (d, 7=
7.3, 1H), 4.21 (dq, J= 7,3, 6.3, 1H), 3,73 (s, 3H), 1.25 (bs, 1H), 0.92 (d, 7= 6.3, 3H).
EXAMPLE 42
f±)-5.6- c-Dihvdro-5-('4-niethoxvphenvn-6-methyl-7-(2.2-dimethoxyethyl')-4-
tTifluoromethyl-7#:pvirolor3,2-/1quinolin-2(lffi-one (Compound 143, Structure 13 of
Scheme II. where Rj = 4-methoxyphenvl. R2 = methyl, R1_= trifluoromethvl. Rd = 2.2-
dimethoxvethvn
This compound was prepared in a similar fashion as that described in Example 30
from Compound 115 (Structure 11 of Scheme II, where R3 = 4-methoxyphenyl, R2 =
methyl, R, = trifluoromethyl). JH NMR (500 MHz, CDC13) 11.7 (bs, IH), 7.33 (d,J= 8.8,
IH), 7.17 (d, J= 8.8, IH), 7.07 (s, IH), 6.69 (bd, J= 8.8, 2H), 6.63 (bs, 2H), 4.58 (d, J=
7.3, IH), 4.31 (dd, J= 5.9, 3.9, IH), 3.93 (dq, .7= 7.3, 6.8, IH), 3.73 (s, 3H), 3.41 (s, 3H),
3.37 (s, 3H), 3.27 (dd, J= 15.1, 3.9, IH), 3.22 (dq, J= 15.1, 5.9, IH), 0.92 (d, /= 6.8,
3H).
EXAMPLE 43
f±)-5.6-cfj-Dihvdro-5-isopropvl-6-methyl-7-(2,2.2-trifluoroethyn-4-trifluoromethvl-7/fpvrrolof3.2-/]
quinolm-2f'ljy)-one (Compound 144, Structure 13 of Scheme n. where R^ =
isopropyl. R? = methyl, Rj^ = trifluoromethvl R^ = 2,2,2-trifluoroethyl')
This compound was prepared in a similar fashion as that described in Example 18
from Compound 113 (Structure 11 of Scheme II, where R3 = isopropyl, R2 = methyl, RI =
trifluoromethyl). ]HNMR (500 MHz, CDC13) 11.6 (bs, IH), 7.25 (d,J= 8.3, IH), 7.17 (s,
IH), 6.93 (d, J= 8.3, IH), 3.80 (dq, J= 6.8, 6.8, IH), 3.69-3.52 (m, 2H), 3.40 (dd, J= 6.8,
5.4, IH), 1.96-1.88(m, IH), 1.53 (d, J= 6.8, 3H), 0.83 (d, J= 6.8, IH), 0.79 (d, J= 7.3,
3H).
EXAMPLE 44
(±V5.6-Dihvdro-5-ethvl-6-methv]-7-2,2,2-rrifluoroethvl)-4-trifluoromethvI-7//-
pyrro1o|'3.2-/1quinolm-2riJ:Jl-one (Compound 145. Structure 13 of Scheme It, where Rj =
ethyl. R? = methyl. RI - trifluoromethyl. R4 = 2.2.2-trifluoroethyll
This compound was prepared in a similar fashion as that described in Examples 12
and 18 from Compound 111 (Structure 9 of Scheme II, where R, = trifluoromethyl) and 2-
pentanone. }H NMR (500 MHz, CDC13) 12.3 (bs, IH), 7.29 (d, /= 8.8, IH), 7.23 (s, IH),
6.98 (d, J= 8.8, IH), 3.84-3.78 (m, IH), 3.71-3.59 (m, 2H), 3.46-3.43 (m, IH), 1.78-1.70
(m, 2H), 1.47 (d, /= 6.8, 3H), 0.86 (t, J= 7.3, 3H).
EXAMPLE 45
f±)-5.6-Dihvdro-5-6thvl-6-propvl-7-f2.2.2-trifJuoroethvlV4-trifluoromethvl-7J:/-
pyrrolo[3,2:/]quinolin-2(:'ljy)^one fCompound 146; Structure 13 of Scheme II. where Ry=
ethyl. R? = propyl. Ri_ = trifluoromethyl R4 = 2.2.2-rrifluoroethyl)
This compound was prepared in a similar fashion as that described in Examples 12
and 18 from Compound 111 (Structure 9 of Scheme II, where RI = trifluoromethyl) and 4-
heptanone. 'H NMR (500 MHz, CDC13) 12.1 (bs, IH), 7.30 (d, J= 8.8, IH), 7.19 (s, IH),
6.95 (d,/=8.8, IH), 3.70-3.51 (m, 4H), 1.88-1.53 (m, 4H), 1.47-1.36 (m, 2H), 1.05 (l,J=
7.3, 3H), 0.70 (t,J= 7.3, 3H).
EXAMPLE 46
f±)-5.6-Dihydro-S-(2-ethoxvcarbonylethvl')-6-methvl-7-r2.2.2-trifluoroethvl)-4-
trifluoromethvl-7Jy-pyrrolo['312-/]quinQlrn-2rif/)-one fCompound 147. Structure 13 of
Scheme II. where R^ = 2-ethoxycarbonylethvl, R2 = methvl. Rj^ = trifluoromethyl. Rj =
2.2.2-trifluoroethvl)
This compound was prepared in a similar fashion as that described, in Examples 12
and 18. 'H NMR (500 MHz, CDC13) 11.6 (bs, IH), 7.27 (d, J= 8.8, IH), 7.20 (s, IH),
6.95 (d, J= 8.8, IH), 4.01 (q, J= 7.3, 2H), 3.82-3.76 (m, IH), 3.70-3.58 (m, 2H), 3.56-
3.52 (m, IH), 2.40-2.32 (m, IH), 2.15-2.08 (m, IH), 2.05-1.98 (m, IH), 1.70-1.62 (m, IH),
1.46 (d, J= 6.4, 3H), 1.18 (t, J= 7.3, 3H).
EXAMPLE 47
6-Ethyl-5-methvl-7#-pwolof3.2:/]quinolin-2(l#)-one (Compound 148. Structure 11 of
Scheme II. where RT = methyl, R? = ethyl RI = H)
This compound was prepared in a similar fashion as that described in Example 12
from structure 9 of Scheme II (where RI = H) and 3-pentanone as a yellow solid: 'H NMR
(500 MHz, DMSO-rftf) 11.23 (s, 1H), 8.58 (d, J= 9.5, 1H), 7.56 (d, J=8.6, 1H), 7.14 (d, J
= 8.6, 1H), 6.69 (d, J= 9.5, 1H), 2.76 (q, J= 7.5, 1H), 2.50 (s, 1H), 2.44 (s, 3H), 1.23 (t, J
= 7.5, 3H).
EXAMPLE 48
(±)-5,6-c/5-Dihvdro-5-methvI-6-ethvl-7-(2.2,2-trifluoroethvl')-7Jjr-pYrrolo[3.2-/1quinolm-
2(l/f)-one (Compound 149, Structure 13 of Scheme II, where R1 = methyl. R? = ethyl. Ri_
= H, R4 = 2,2.2-trifluoroethyl)
This compound was prepared in a similar fashion as that described in Example 18
from Compound 148 (Structure 11 of Scheme n, where R3 = methyl, R2 = ethyl, R, = H).
'H NMR (500 MHz, CDC13) 11.16 (s, 1H), 7.75 (d, /= 9.5, 1H), 6.81 (d, J= 8.5, 1H),
6.71 (d, .7=9.6, 1H), 3.60-3.45 (m, 3H), 3.44-3.31 (m, 1H), 1.89-1.75 (m, 2H), 1.11 (d,J
= 6.8, 3H), 1.06 (t,/= 7.3, 3H).
EXAMPLE 49
5,6-Dimethvl-7-(2.2,2-trifluoToethvl)-4-trifluoromethvl-7Ar-pvrrolo[3.2-/1quinolin-2('lJ:none
(Compound 150. Structure 15 of Scheme II. where R3 = R; = methyl, R^ =
trifluoromethvl R^ = 2.2.2-trifluoroethyn
To a solution of Compound 123 (Structure 13 of Scheme n, where R3 =R2 =
methyl, R, = trifluoromethyl, R4 = 2,2,2-trifluoroethyl) (0.35 g, 0.97 mmol) in 30 mL
CH^Cb was added DDQ (0.35 g, 1.5 mmol, 1.5 eq) in small portions. The resulting green
mixture was stirred at it for about 60 min until almost no more starting material was
visible on TLC. Then 5% aq. NaHCOs (30 mL) was added and the mixture was extracted
with EtOAc (3 x 50 mL) and the combined organic layers were washed with 5% aq.
NaHCO3 (30 mL) and brine, dried over MgS04 and concentrated. Purification by
chromatography (Silica gel, hexane:EtOAc 2:1 to 0:1 gradient) afforded Compound ISO
(195 mg, 56%) as a slightly yellow solid: 'H NMR (500 MHz, CDC13) 11.4 (bs, 1H), 7.55
(d,/= 8.8, IH), 7.17 (d,7= 8.8, IH), 7.16 (s, IH), 4.71 (q, JH-e= 8.3, 2H), 2.43 (s, 3H),
2.33 (s, 3H).
An alternate oxidation method was also used as described as follow:
To a solution of Compound 123 (10 mg, 0.03 mmol) in 10 mL CHaC^ was added
Mn02 (approx. 0.3 g, 3.5 mmol, 100 eq) in portions until no more starting material was
visible on TLC. Then EtOAc (10 mL) was added and the suspension was filtered through
a short pad of celite. The solids were rinsed several times with EtOAc and the combined
filtrates were concentrated. Purification by chromatography (Silica gel, hexanerEtOAc 2:1
to 0:1 gradient) afforded Compound 150 as a slightly yellow solid.
EXAMPLE 50
6-Ethvl-5-methvl-7-f2.2.2-trifluoroethvl)-7jy-pvrrolo[3.2-/]quinolin-2fl//)-Qne
(Compound 151. Structure 15 of Scheme II, where RT = methyl, Rg = ethyl, Rj_ = H. Rg =
2.2.2-trifluoroethvl)
This compound was prepared in a similar fashion as that described in Example 49
from Compound 149 (Structure 13 of Scheme II, where R3 = methyl, R2 = ethyl, RI = H,
R4 = 2,2,2-trifluoroethyl). 'H NMR (500 MHz, CDC13) 11.20 (s, IH), 8.54 (d, J= 9.7,
IH), 7.46 (d, J = 8.6, IH), 7.16 (d, J= 8.7, IH), 6.77 (d, J= 9.7, IH), 4.69 (q, J= 8.4, 2H),
2.83 (q, J= 7.6, 2H), 2.56 (s, 3H), 1.23 (t, J= 7.6, 3H).
EXAMPLE 51
6-Methvl-7-('2,2.2-trifluoroethvl)-4-rrifluorornethvl-7Ar-pvrrolo[3.2-/1quinolin-2fl//)-one
(Compound 152, Structure 15 of Scheme II. where Ra = H. R2 = methyl. Rj =
trifluoromethvl Rd = 2.2.2-trifluoroethyn
This compound was prepared in a similar fashion as that described in Examples 18
and 49 from Compound 112 (Structure 11 of Scheme II, where R3 = H, R2 = methyl, RI =
trifluoromethyl). 'H NMR (500 MHz, CDC13) 11.1 (bs, IH), 7.92 (d, J= 8.8, IH), 7.39 (d,
J= 8.8, IH),, 6.99 (s, IH), 6.80 (s, IH), 5.18 (q, JH.F = 8.8, IH), 2.58 (s, 3H).
EXAMPLE 52
6-Ethvl-5-methvl-7-(2.2.2-Mfluoroethyl)-4-rrifluQrQmethYl-7//-pvrrolor3,2-/]qumoliri-
2(1 ffVone (Compound 153. Structure 15 of Scheme n, where Ra = methyl, R = ethyl, R_
= trifluoromethyl. Ra = 2,2.2-frifuioro.ethvj)
This compound was prepared hi a similar fashion as that described in Example 49
from Compound 134 (Structure 13 of Scheme II, where R3 = methyl, R? = ethyl, RI =
trifluoromethyl, R, = 2,2,2-trifluoroethyl). 1H NMR (500 MHz, CDC13) 12.2 (bs, IH),
7.57 (d, J= 8.8, IH), 7.25 (d, J= 8.8, IH), 7.18 (s, IH), 4.62 (q, JH.F = 8.3, 2H), 2.45 (q, J
= 7.8, 2H), 2.34 (d, J= 1.9, 3H), 1.24 (t, J= 7.8, 3H).
EXAMPLE 53
5-Ethyl-l-me1iiyl-7-(2.2.2-triiluoToethvn-4-trifluorpmethvl-77/-pyrrolo[3.2-?1quino]in-
2(\H)-one (Compound 154. Structure 15 of Scheme n. where RT = ethyl Rg = methyl. R^
= trifluoromethyl. R^ = 2.2.2-tiifluoroethyl)
This compound was prepared in a similar fashion as that described in Example 49
from Compound 145 (Structure 13 of Scheme II, where R3 = ethyl, Rj = methyl, RI =
trifluoromethyl, R, = 2,2,2-trifluoroethyl). 1H NMR (500 MHz, CDC13) 12.6 (bs, IH),
7.56 (d, J= 8.8, IH), 7.28 (d, J= 8.8, IH), 7.17 (s, IH), 4.70 (q, -/„-/•= 8.3, 2H), 2.89 (q, J
= 1.3, 2H), 2.46 (s, 3H), 1.01 (t, J=7.3, 3H).
EXAMPLE 54
5-EthY]-6-propYl-7-(2.2.2-trifluoroethyl)-4-rrifluorQrnethyl-7/jr-pvn-olo[3.2-/]quinolin-
2flJ:n-one (Compound 155. Structure 15 of Scheme II, where RI = ethyl, R; ^propyl. RI
= trifluoromethyl, R^ = 2,2.2-trifluoroethyl)
This compound was prepared in a. similar fashion as that described in Example 49
from Compound 146 (Structure 13 of Scheme II, where Rj = ethyl, RI = propyl, Rj =
trifluoromethyl, R, = 2,2,2-trifluoroethyl). 'H NMR (500 MHz, CDC13) 11.7 (bs, 1 H),
7.55 (d, J= 8.8, IH), 7.19 (d, J= 8.8, IH), 7.15 (s, IH), 4.71 (q, JH-F= 8.3, 2H), 2.88 (q, J
= 7.3, 2H), 2.79 (t, J= 7.8, 2H), 1.64-1.58 (m, 2H), 1.06 (t, /= 7.3, 3H), 0.98 (t, /= 7.3,
3H).
EXAMPLE 55
5.6.7.8-Terrahydro-8-trifluoroethvI-4-trifluorQmethylcvclopentanorg1pvrrolor3.2-
/)quinolm-2(l//)-one (Compound 156. Structure 15 of Scheme II. where Ri. R2 = -(
. Ri = trifluoromethvl. R^ = trifluoroethvP
This compound was prepared in a similar fashion as that described in Example 49
from Compound 119 (Structure 13 of Scheme II, where R3, R2 =
-(CH2)3-, Ri = trifluoromethyl, R 1H), 7.57 (d,J = 8.8, 1H), 7.21 (d,J=8.8, 1H), 7.20 (s, 1H), 4.66 (q,Jir.f= 8.3, 2H),
3.16-3.14 (m, 2H), 2.93-2.90 (m, 2H), 2.53-2.49 (m, 2H).
EXAMPLE 56
8-Trifluoroethvl-4-trifluoromethvl-6.8-dihvdrocyclopentanorg]pvrrolor3,2-/1quinolin-
2(lH)-one (Compound 157. Structure 17 of Scheme II. where R| = trifluoromethvl. Ra =
2.2.2-trifluoroethyl)
This compound was isolated as a minor product in the same reaction as that
described in Example 55 from Compound 119 (Structure 13 of Scheme II, where R3, R2 =
-(CH2)r, Ri = trifluoromethyl, K^ = trifluoroethyl). *H NMR (500 MHz, CDC13) 12.2 (bs,
1H), 7.58 (d,J= 9.3, 1H), 7.48 (d,J= 9.3, 1H), 7.30 (s, lH),5.16(s, 1H), 4.67-4.63 (m,
1H), 4.63 (s, 1H), 4.21-4.16 (m, 1H), 2.77 (d, J= 11.2, 1H), 2.65 (d, J= 10.7, 1H).
EXAMPLE 57
9-Trifluoroethvl-4-trifluoromethvl-9//-ben2org1pyrrolo[3.2:/1quinolin-2nff)-one
(Compound 158. Structure 15 of Scheme n. where R3, Rg = -(CH=CH)?-. Rj_ =
trifluoromethyl. R* = trifluoroethyl)
This compound was prepared in a similar fashion as that described in Example 49
from Compound 132 (Structure 13 of Scheme II, where R3, R2 = -(CHj)*-, RI =
trifluoromethyl, R4 = 2,2,2-trifiuoroethyl). 'H NMR (500 MHz, CDC13) 11.4 (bs, IH),
8.39 (d, J= 8.8, IH), 8.19 (d, J= 8.8, IH), 7.82 (d, J= 8.3, IH), 7.76 (d, J= 9.3, IH), 7.57
(t, J= 7.3, IH), 7.34 (t, J= 8.3, IH), 7.21 (s, IH), 5.46 (q, JH.F = 8.3, 2H).
EXAMPLE 58
6-Trifluoroethyl-4-trifluoromethvl-6,7.8,9-tetrahydrocyclopetanor/]pyrrolo[2.3-
g1quinolin-2rijy)-one (Compound 159. Structure 16 of Scheme II. where Rj. R? = -CCH2V
. RX = trifluoromethyl. Ra = trifluoroethyl)
This compound was isolated as a regioisomer of Compound 156 in Example 49. ]H
NMR (500 MHz, CDC13) 10.8 (bs, IH), 7.84 (s, IH), 7.47 (s, IH), 6.81 (s, IH), 5.13 (q,
JH.F=93, IH), 3.06-3.00 (m, 2H), 2.62-2.56 (m, 2H).
EXAMPLE 59
5-(3-TrifluoromethvlphenYn-6-methvl-7-(2.2.2-trifluoroethvn-4-trifluoromethvl-7//'-
pyrrolo[3.2-/]quinolin-2(l^f)-one (Compound 160. Structure 15 of Scheme II. where Rj =
3-trifluoromethvlphenyl R? = methyl. Rr = trifluoromethyl. Rj = 2.2.2-trifluoroethyl)
This compound was prepared in a similar fashion as that described in Example 49
from Compound 139 (Structure 13 of Scheme II, where R3 = 3-trifluoromethylphenyl, R2
= methyl, RI = trifluoromethyl, R4 = 2,2,2-trifiuoroethyl). 'H NMR (500 MHz, CDCb)
12.8 (bs, IH), 7.65 (d, J= 8.8, IH), 7.60 (d,/= 8.3, IH), 7.53 (dd, J= 8.3, 8.3, IH), 7.46
(s, IH), 7.45 (d, J= 8.3, IH), 7.39 (d, J= 8.8, IH), 7.00 (s, IH), 4.78 (q, JH.F= 8.3, 2H),
2.33 (s, 3H).
EXAMPLE 60
5-(/4-FluorophenvlV6-memvl-7-f2.2.2-trifluoroethvn-4-trifluoromethvl-7//-pvn-olo[3.2-
/1quinolin-2f]J:D-one (Compound 161. Structure IS of Scheme n, where Ri = 4-
fluorophenyl. R? = methyl. Rj = trifluoromethyl. R^ - 2.2.2-trifluoroethvn
This compound was prepared in a similar fashion as:that described in Example 49
from Compound 140 (Structure 13 of Scheme II, where R3 = 4-fluorophenyl, R2 = methyl,
RI = trifluoromethyl, R4 = 2,2,2-trifluoroethyl). 'H NMR (500 MHz, CDC13) 11.1 (bs,
1H), 7.98 (d, J= 8.8, 1H), 7.40 (d, 7= 8.8, 1H), 7.29 (dd, J= 8.8, 5.4, 1H), 7.16 (dd, J=
8.8, 8.3, 1H), 6.76 (s, IE), 5.26 (q, Ja.F = 8.8, 2H), 2.38 (s, 3H).
EXAMPLE 61
5-C2-Ethoxycarbonylethvl')-6-methyl-7-r2,2,2-triiluoroethyl')-4-trifluoromethvl-7ffpvrrolo|
3.2-/]quinolin-2(lff)-one (Compound 162. Structure 15 of Scheme II. where Rj =
2-ethoxycarbonylethvl Rg = methyl, R = trifluoromethvl. Rj = 2.2.2-trifluoroethvn
This compound was prepared in a similar fashion as that described in Example 49
from Compound 147 (Structure 13 of Scheme n, where R3 = 2-ethoxycarbonylethyl, R2 =
methyl, R, = trifluoromethyl, R4 = 2,2,2-trifluoroethyl). 'H NMR (500 MHz, CDC13) 11.7
(bs, 1H), 7.55 (d, J= 8.3, 1H), 7.21 (d, J= 8.8, 1H), 7.17 (s, 1H), 4.71 (q, JH.F= 7.8, 2H),
3.94 (q, /= 7.3, 2H), 3.24 (t, .7=7.3, 2H), 2.49 (s, 3H), 2.38 (t,J= 7.3, 3H), 1.07 (t, J=
13, 3H).
EXAMPLE 62
7-Ethvl-8-methyl-6-(2.2.2-trifluoroethyl')-4-trifluoromethyl-6^-pyrrolor2.3-g1quinolin-
2(lJT)-one (Compound 163. Structure 16 of Scheme II. where Ry= ethyl, R; = methyl, Rj^
= trifluoromethvl. R^ = 2.2.2-trifluoroethyl)
This compound was a regioisomer of Compound 153 and prepared in a similar
fashion as that described in Example 52. 'H NMR (500 MHz, CDC13) 9.4 (bs, 1H), 7.68 (s,
1H), 7.25 (s, 1H), 6.99 (s, 1H), 4.69 (q, JH.F= 8.3, 2H), 2.85 (q, /= 7.8, 2H), 2.30 (s, 3H),
1.25 (t,J= 7.8, 3H).
EXAMPLE 63
5-Hydroxvmethvl-6-ethvl-7-(212,2-trifluoroethvl)-4-trifluoromethyl-7JH'-pvrrolo[3.2-
1quinolin-2(l//)-one (Compound 164, Structure 19 of Scheme HI, where Ri =
hydroxymethvl R = ethyl. Rj = 2,2,2-trifluoroethvl')
This compound was prepared by the general oxidation procedure described in
Example 49 from Compound 153 (Structure 18 of Scheme HI, where R2 = ethyl). 'H NMR
(500 MHz, CDC13) 12.4 (bs, IH), 7.84 (d, J= 8.8, IH), 7.24 (d, J= 8.8, IH), 7.02 (s, IH),
5.10 (q, .7= 8.8, 2H), 4.92 (s, 2H), 4.85 (bs, IH), 3.00 (q,: J= 7.3, 2H), 1.29 (t, J= 7.3,
3H).
EXAMPLE 64
5-Methvl-6-(l-hydroxvethylV7-('2.2.2-trifluoroethyn-4-trifluoromethyl-7//'-pvrrolor3.2-
1quinolin-2(l#)-one (Compound 165. Structure 19 of Scheme III, where R3 = methyl, R4
= 1-hydroxyethyl, Rj = 2.2.2-trifluoroethvl)
This compound was prepared by the general oxidation procedure described in
Example 49 from Compound 153 (Structure 18 of Scheme HI, where R2 = ethyl). 'HNMR
(500 MHz, CDC13) 11-2 (bs, IH), 7.89 (d, J= 8.8, IH), 7.33 (d, J= 8.8, IH), 6.96 (s, IH),
5.63-5.54 (m, IH), 5.49-5.44 (m, IH), 5.37-5.28 (m, IH), 4.81-4.77 (m, IH), 2.37 (d, J=
2.4, 3H), 1.62(d,J=6.8, 3H).
EXAMPLE 65
5-Methvl-6-acetvl-7-(2,2,2-trifluoroethyl)-4-trifluoromethvl-7flr-pYiTolor3.2-/1quinolin-
2(lH)-one (Compound 166. Structure 19 of Scheme HI. where RT = methyl. R^ = acetvl.
Rs = 2.2.2-trifluoroethyl)
This compound was isolated as an over oxidized product in Example 64. *H NMR
(500 MHz, CDC13) 10.5 (bs, IH), 7.64 (d, J= 8.8, IH), 7.31 (s, IH), 7.20 (d, /= 8.8, IH),
5.39 (q, JH.F = 7.8, 2H), 2.72 (s, 3H), 2.64 (s, 3H).
68
XAMPLE 66
5-FQrmYl-6-methvl-7-r2.2.2-trifluoroethvlV4-trifluoromethvI-7jy-pyrrolor3,2-f|quinoiiTi-
2(lH]-one (Compound 167. Structure 19 of Scheme HI. where Rs = fbmiYl^R4 = methyl.
RJ = 2.2.2-trifluoroethvn
This compound was prepared by the general-oxidation procedure described in
Example 49 from Compound 150 (Structure 18 of Scheme HI, where RI = R2 = methyl).
'H NMR (500 MHz, CDCh) 11.9 (bs, 1H), 10.16 (d, .7= 1.5, 1H), 8.04 (d,-7=8.8, 1H),
7.49 (d, /= 8.8, 1H), 7.00 (s, 1H), 5.37 (q, JH.F = 8.8, 2H), 2.85 (s, 3H).
EXAMPLE 67
5-Acetyloxymethvl-6-ethvl-7-f2.2.2-trifiuoroethylV4-trifluoroTnethyl-7tf-pyrrolof3.2-
/]quinolin-2('l/j')-one (Compound 168, Structure 20 of Scheme IIP
In a 50 mL r.b. flask, a solution of 30 mg (0.08 mmol) of Compound 164
(Structure 19 of Scheme III, where R3 = hydroxymethyl, R4 = ethyl, RS = 2,2,2-
trifluoroethyl) in 10 mL THF was treated with triethylamine (0.5 rnL, 3.5 mmol, 40 eq)
followed by acetic anhydride (0.2 mL, 2 mmol, 25 eq) and DMAP (1 mg, 0.008 mmol, 0.1
eq). The mixture was stirred at rt for 2 h and then 30 mL 2N HC1 and 20 mL EtOAc added
and vigorously stirred for 1 h. The layers were separated and the water layer was extracted
with EtOAc (20 mL). The combined organic layers were washed with 20 mL portions of
2N HC1, water, 2N NaOH and brine and dried over MgSO4. Concentration followed by
purification by flash chromatography (hexane: EtOAc 5:1 to 0:1 gradient) afforded
Compound 168. 'H NMR (500 MHz, CDC13) 11.1 (bs, 1H), 7.54 (d, J= 8.8, 1H), 7.25 (d,
.7=8.8, lH),7.13(s, lH),4.73(q,/ff.F=8.3,2H},4.68 (s,2H), 3.26 (s, 3H), 2.92 (q,J =
7.3, 2H), 1.27 (t,J= 7.3, 3H).
EXAMPLE 68
2-Acetyloxy-5-hYdroxvmethvl-6-ethyl-7-(2,2,2-trifluoroethvn-4-trifluoromethvl-7Hpyrrolo[
3.2-/f1quinoline (Compound 169, Structure 23 of Scheme lET)
This compound was prepared by treatment of Compound 164 (Structure 19 of' Scheme III, where-Rj^ hydroxymethyl,,'R4 = ethyl, R5 •= 2,2,2-trifluorpethyl) with acetic
anhydride in.Example 67. !H NMR (500 MHz, CQC13).7.79 (s, 2 H), 7.57 (s, 1H), 4.98 (s,
2H), 4.82 (q, JH.F= 8.3, 2H), 3.03 (q, J= 7.8, 2H), 2.43 (s, 3H), 1.33 (t, J= 7.8, 3H).
EXAMPLE 69
6-Ethyl-7-(r2.2.2-trifluoroethvl')-4-trifluoromethyl-7JJ'-pyrrolo[3.2:/]quinolin-2ri/0-one
(Compound 170. Structure 21 of Scheme III)
This compound was isolated as a by-product in the treatment of Compound 164
(Structure 19 of Scheme III, where R3 = hydroxymethyl, 4 = ethyl, R5 = 2,2,2-
trifluoreethyl) with acetic anhydride in Example 67. HNMR (500 MHz, CDC13) 11.2 (bs,
IH), 7.94 (d, J= 8.8, IH), 7.39 (d, J= 8.8, IH), 7.00 (s, IH), 6.82 (d, J= 2.0, IH), 5.19 (q,
JH.F= 8.8, 2H), 2.94 (q, J= 7.3, 2H), 1.42 (t, J = 7.3, 3H).
EXAMPLE 70
5-Ethoxvmethvl-6-ethyl-7-(2.2.2-trifluoroethvl)-4-trifluoromethvl-7/7-pvrrolo[3.2-
/|quinolin-2(lJ:/)-one (Compound 171, Structure 20 of Scheme nil
This compound was isolated as a by-product in the treatment of Compound 164
(Structure 19 of Scheme III, where R3 = hydroxymethyl, R« = ethyl, R5 = 2,2,2-
trifluoroethyl) with acetic anhydride in Example 67. 'H NMR (500 MHz, CDC13) 11.3 (bs,
IH), 7.92 (d, /= 8.8, IH), 7.34 (d, J= 8.8, IH), 6.95 (s, IH), 5.22 (q, JH.F= 8.8, 2H), 4.72
(s, 2H), 3.37 (q, J= 6.8, 2H), 3.00 (q, J= 7.3, 2H), 1.29 (t, J= 7.3, 3H), 1.07 (t, /= 6.8,
3H).
EXAMPLE 71
6-(l-Methoxvethvl)-5-methvl-7-(2.2.2-trifluoroethvl)-4-trifliioromethy]-7J::/-pvrrolo[3.2-
/1quinolin-2(l//)-one (Compound 172, Structure 22 of Scheme HI)
In a 50 mL r.b. flask, a solution of 5 mg (0.01 mmol) of Compound 165 (Structure
19 of Scheme HI, where R3 = methyl, R4 = 1 -hydroxyethyl, R5 = 2,2,2-trifluoroethyl) in 5
mL MeOH was treated with aqueous 2.5 N HC1 (2 mL, 5 mmol). The mixture was stirred
at it for 20 h and then 30 mL water was added and the water layer was extracted with
EtOAc (2x30 mL). The combined organic layers were washed with brine and dried over
MgSCXt. Concentration followed by purification by flash chromatography (hexane: EtOAc
2:1 to 1:1 gradient) afforded 4.2 mg of Compound 172 as a slightly yellow solid, 'H NMR
(500 MHz, CDC13) 13.2 (bs, IH), 7.64 (d, J= 8.8, IH), 7.39 (d, J= 8.8, IH), 7.20 (s, IH),
5.27-5.20 (m, IH), 4.69-4.85 (m, 2H), 3.25 (s, 3H), 2.37 (d, J= 1.8, 3H), 1,63 (d, J= 7.0,
3H).
EXAMPLE 72
7-Allvl-6-methvl-4-trifluoromethvl-5flr-pvrrolol'2,3-/1quinolin-2('lJ:r)-one (Compound 173.
Structure 26 of Scheme IV. where R; = methyl. R^ = allyl)
In a 250 mL r.b. flask a suspension of 5-amino-4-trifluoromethylquinolin-2-one
(Structure 24 of Scheme IV) (42 mg, 0.18 mmol) in 4 mL cone. HC1 was cooled to -1°C
and a solution of NaNC>2 (20 mg, 0.6 mmol) in water (0.5 mL) was added dropwise in 1
min. The dark brown suspension was stirred at -1°C for 1 h and then a solution of
SnCl2'2H2O (0.20 g, 0.6 mmol) in cone. HC1 (1 mL) was added dropwise in 1 min. The
light yellow suspension of Compound 174 (Structure 25 of Scheme IV) was stirred at-
1°C for 30 min and then kept in a refrigerator at
-1°C for 3 days. To the crude suspension of the hydrazine was added a solution of 5-
hexen-2-one (0.1 mL, 0.9 mmol, 5 eq) in 5 mL of EtOH and the mixture was refluxed for
3 h. Then the mixture was diluted with 30 mL of water and extracted with EtOAc (2 x 30
mL) and the combined organic layers were washed with brine, dried over MgSCM and
concentrated. Purification by chromatography (Silica gel, hex:EtOAc 3:1) afforded
Compound 173 as a yellow solid. 'H NJVCR. (500 MHz, CDC13) 11.1 (bs, IH), 9.3 (bs, IH),
7.80 (d, J= 8.3, IH), 7.26 (d, J= 8.3, IH), 6.95 (s, IH), 6.02-5.95 (m, IH), 5.05 (dd, J=
17.1, 2.0, IH), 4.97 (dd, J= 9.8, 2.0, IH), 3.50 (d, J= 6.3, IH), 2.46 (s, 3H).
EXAMPLE 73
6-Ethyl-7-methvl-4-trifluorometh.yl-5//'-pvrrolo[2.3-/r|quinolin-2(lJ:A-oneCCompound
175. Structure 26 of Scheme IV. where R; = ethyl. R2 = methyl)
This compound was prepared in a similar fashion as that described in Example 72
from Compound 174 (Structure 25 of Scheme IV) and 3-pentanone. 'H NMR (500 MHz,
CDC13) 11.2 (bs, IH), 9.1 (bs, IH), 7.79 (d, J= 8.3, IH), 7.27 (d, J= 8.8, IH), 6.96 (s,
IH), 2.87 (q, J = 7.8, 2H), 2.27 (s, IH), 1.27 (t, J= 7.8, 3H).
EXAMPLE 74
7-(3-Trifluoromethvlphenyl)-6-methvl-4-trifluoromethyl-5J:r-pvrrolo[2.3:/1quinolin-
2(l//)-one (Compound 176, Structure 26 of Scheme IV, where R? = methyl. R2 = 3-
trifluoromethylphenyn
This compound was prepared in a similar fashion as that described in Example 72
from Compound 174 (Structure 25 of Scheme IV) and 3-trifluorophenylacetone. 'HNMR
(500 MHz, CDC13) 12.9 (bs, IH), 8.9 (bs, IH), 7.90 (d, J= 8.8, IH), 7.71 (s, IH), 7.64 (s,
3H), 7.30 (d, J= 8.8, IH), 7.29 (s, IH), 2.59(s, 3H).
EXAMPLE 75
7-(2-Hvdroxvethvl)-6-methvl-4-trifluoromethyl-5J/-pvrrolo[2,3-/]quinolin-2(l/f)-one
(Compound 177. Structure 26 of Scheme IV, where R? = methyl. Rj = 2-hydroxvethyl)
This compound was prepared in a similar fashion as that described in Example 72
from Compound 174 (Structure 25 of Scheme IV) and 5-hydroxy-2-pentanone. !H NMR
(500 MHz, CDC13) 1 1.3 (bs, IH), 9.4 (bs, IH), 7.89 (d, J= 8.5, IH), 7.29 (d, J= 8.5, IH),
6.97 (d, J= OX, IH), 3.78 (t, 7= 7.3, 2H), 3.23 (t, J= 7.3, 2H), 2.51 (s, 3H).
EXAMPLE 76
(+)-4c.5.6.7.7a(c;'j').8-Hexahydro-8-trifluoroethvl-4-trifluoromethylcvclopentanorg]
pvrrolor3,2-/lquinolin-2(ljy)-one (Compound 178, Structure 13 of Scheme n. where
= trifluoromethyl. Rj = trifluoroethyl) and (-V4c,5.6.7,7a(ci'j),8-
Hexahvdro-8-trifluoroethvl-4-trifluoromethylcvclopentano-rg1pyrrolor3.2-/]quinolin-
2(lH)-one (Compound 179, Structure 13 of Scheme II. where Rj. R? = -fCH?)r. Rj =
trifluoromethyl, R^ = trifluoroethvll
Compounds 178 and 179 were enantiomers of Compound 119 and separated by
chiral HPLC.
EXAMPLE 77
4-Trifluoromethvl-6,7-dihydro-7.7.9-trimethyl-pvridor2.3-g1quinolin-2(l//)-one
Compound 180. Structure 28 of Scheme V, where Rj^ = trifluoromethyl)
A mixture of Compound 181 ("Structure 8 of Scheme V. where Ri =
trifluoromethyl), iodine and acetone in a sealed tube was heated at 135°C overnight and
the mixture was concentrated. Chromatography of the crude mixture afforded Compound
180 as a yellow solid. 'H NMR (500 MHz, CDC13) 7.21 (s, 1H), 6.83 (m, 1H), 6.77 (s,
1H), 5.68 (s, 1H), 5.46 (bs, 1H), 2.02 (s, 3H) and 1.31 (s, 6H).
EXAMPLE 78
8-(2.2.2-Trifluoroethvn-5.6.7.8-tetrahvdro-5.7.7-trimethvlr)vridof3.2-/1quinolin-2n^n-one
(Compound 182, Structure 29 of Scheme V. where R_i = H)
A mixture of Compound 183 (Structure 8 of Scheme V, where RI = H), iodine and
acetone in a sealed tube was heated at 135°C overnight and the mixture was concentrated.
Chromatography of the crude mixture afforded Compound 184 (Structure 27 of Scheme
V, where R] = H) as a yellow solid.
Compound 184 was treated with TFA and NaBEU in a similar fashion as that
described in Example 18 to afford Compound 182 as a yellow solid. 'H NMR (400 MHz,
CDC13) 11.29 (s, 1H), 7.96 (d, J= 9.9, 1H), 7.15 (d, J= 9.1, 1H), 7.06 (d, /= 9.1, 1H),
6.69 (d, /= 9.8, 1H), 3.84 (q, J= 8.7, 2H), 3.41- 3.47 (m, 1H), 2.08 (dd, J= 13.6, 7.3,
1H), 1.88 (dd, J= 13.6, 7.3, 1H), 1.39 (s, 3H), 1.35 (d, J= 6.7, 3H), 1.08 (s, 3H).
EXAMPLE 79
4.5.7-Triftrifluoromethyl)pyridof3,2-/lquinolm-2flffl-one (Compound 185, Structure 30
of Scheme V. where R| = trifluoromethyl)
A mixture of Compound 181 and l,l,l,5,5,5-hexafluoro-2,4-pentadiene was heated
to 170°C for 2 h and was poured into ice-water. The crude mixture was extracted with
EtOAc and the combined organic phase was concentrated. Chromatography provided
Compound 185 as a white solid. 'H NMR (400 MHz, acetone-d6) 11.15 (s, 1H), 8.25 (s,
1H), 8.04 (d, J= 9.0, 1H), 7.58 (d, J= 9.0, 1H), 6.99 (s, 1H).
EXAMPLE 80
5,7-Bis(trifluoromethvnp\Tidor3.2-/]quinolin-2(l#)-one (Compound 186, Structure 30 of
Scheme V. where R1 = H)
This compound was prepared in a similar fashion as that described in Example 79
from Compound 183-(Structure 8 of Scheme V, where R, =H) as a white solid. 'HNMR
(40.0MHz, CDCl3),12.49;(s, 1H), 8.60 (d, J= 9,2,1H), 8.28 (d,J=9.4, 1H), 8.19 (s, 1H),
7.99 (d, J= 9.4, 1H), 6.79 (d, J= 9.9, 1H).
EXAMPLE 81
4-Trifluoromethvl-7-methvl-6.7,8,9-tetrahvdropVTidor2.3-,e1quinolin-2flJ:Jr)-one
(Compound 187, Structure 33 of Scheme VI, where R = methyl, n = 1)
Preparation of l-acetyl-2-methyl-6-nitrotetrahydroquinoline (Compound 188,
Structure 32 of Scheme VI, where R, = methyl, n = 1)
In a 100-raL r.b. flask, a solution of Compound 189 (Structure 31 of Scheme VI,
where R] = methyl, n = 1) (1.56 g, 8.2 mmol) in 1,2-dichloroethane (15 mL) was treated
with Yb(OTf)3 (0.622 g, 1.0 mmol, 12 mol%) and fuming nitric acid (2.0 mL, 47.0 mmol,
5.7 equiv). The reaction mixture was stirred at rt for 16 h. The reaction mixture was
diluted with CH2C12 (50 mL), washed with H20 (50 mL) and brine (50 mL). Dried
(MgSCU), filtered and concentrated in vacua. The residue was purified by flash column
chromatography (SiCh, 4 x 20 cm, 25% EtOAc/hexane as eluent) to afford 1.22 g (63%) of
Compound 188 as white solid. Rf 0.45 (Si02
r 50% EtOAc/hexane). 'H NMR (400 MHz,
CDC13) 8.10-8.00 (m, 2H), 7.44 (d, 1H, /= 8.5), 4.76-(sixtet, 1H, J= 6.6), 2.85-2.79 (m,
1H), 2.74-2.68 (m, 1H), 2.38- 2.30 (m, 1H), 2.24 (s, 3H), 1.58-1.54 (m, 1H), 1.18 (d, 3H, J
= 6.6).
4-Trifluoromethyl-7-methyl-6,7,8,9-tetrahydropyrido[2,3-g-]quinolm-2(l/r)-one
(Compound 187, Structure 33 of Scheme VI, where R] = methyl, n = 1)
In a 100-mL r.b. flask, a solution of Compound 188 (1.22 g, 5.2 mmol) in a 1:1
mixture of CH2Cl2/EtOH (30 mL) was treated with 10% Pd/C (140 mg, 11 wt % equiv).
The reaction mixture was stirred under hydrogen (1 atm) at rt for 18 h. The reaction
mixture was filtered through a pad of celite and rinsed with CH2C12 (100 mL). The filtrate
was concentrated to give 1.02 g (96%) of the corresponding amine which was used
immediately in the next reaction without further purification.
In a 100-mL r.b. flask, a solution of the amine (1.02 g, 5.0 mmol) in a 95:5 mixture
of toluene/water (30 mL) was heated to reflux for 16 h. After cooling to rt, the reaction
mixture was dried (NlgSC^), filtered and concentrated in vacua. The residue was then
dissolved in 20 mL cone. H2S04 and heated to 95°C for 4 h. The reaction mixture was
cooled to rt and poured onto 200 mL of ice-water, neutralized with 6NNaOH to pH 7 and
extracted with EtOAe (3 x 250 mL). The combined extracts were washed with brine (2 x
200 mL), dried (MgSC4), filtered and concentrated in vacua. The residue was purified by
flash column chromatography (SiO2, 3x20 cm, 50-70% EtOAc in hexane gradient eluent)
to afford 0.21 g (15%) of Compound 187 as a yellow solid. Rf 0.30 (SiO2( 2:1 =
EtOAcrhexane). ]H NMR (400 MHz, CDC13) 11.70 (s, 1H), 7.11 (s, 1H), 7.00 (s, 1H),
6.80 (s, 1H), 4.02 (br. s, 1H), 3.48-3.43 (m, 1H), 2.95-2.91 (m, 2H), 2.01-1.96 (m, 1H),
1.25 (d, 3H, J = 6.1), 0.89-0.85 (m, 1H).
EXAMPLE 82
4-Trifluoromethvl-7.8-dihvdro-6//:-pyrrolo[2.3-e]quinolin-2(lJ:/)-onef Compound 190.
Structure 33 of Scheme VI. where R_i = H. n = 0)
This compound was prepared in a similar fashion as that described in Example 81
from Compound 191 (Structure 31 of Scheme VI, where R, = H, n = 0). ]H NMR
(acetone-d6) 7.28 (s, 1H), 6.82 (s, 2H), 5.25 (bs, 1H), 3.60 (t, J= 8.2, 2H), 3.12 (t, J= 8.2,
2H).
EXAMPLE 83
4-Trifluoromethvl-5.6J.8-tetrahvdropyrido[2,3-g]quinolin-2(l.ff)-one (Compound 192.
Structure 33 of Scheme VI. where Rj^ = H. n = 1)
This compound was prepared in a similar fashion as that described in Example 81
from Compound 193 (Structure 31 of Scheme VI, where R, = H, n = 1). 'H NMR (400
MHz, CDC13) 11.18 (s, 1H), 7.09 (s, 1H), 7.00 (s, Hi), 6.80 (s, 1H), 4.08 (s, 1H), 3.35 (t,
2H, J= 5.4), 2.91 (t, 2H, J= 6.4), 1.97 (m, 2H).
EXAMPLE 84
4-Trifluoromethvl-7-methvl-6-propyl-6.7.8,9-terrahydropyrido[2.3-g]quinolin-2(l//)-one
(Compound 194, Structure 34 of Scheme VI. where R^ = methyl. R? = propyl, n - 1)
In a 25-mL r.b. flask, a solution of Compound 187 (Structure 33 of Scheme VI,
where R, = methyl, n = 1) (12.2 mg, 0.043 mmol) in MeOH (5 mL) was treated with
propionaldehyde (2 mL), AcOH (2 mL) and NaCNBHb. The reaction mixture was.stirred
at rt for 18 h. The reaction mixture was poured onto ice-water (50 mL), neutralized with
NaHCOs to pH 7 and extracted with EtOAc (3 x 50 mL). The combined extracts were
washed with H20 (50 mL) and brine (50 mL), dried (MgSCU), filtered and concentrated in
vacua. The residue was purified by flash column chromatography (SiOi, 50%
EtOAc/hexane as eluent) to afford 5.0 mg (34%) of Compound 194 as a yellow solid. Rf
0.51 (Si02> 2:1= EtOAc:hexane). !H NMR (400 MHz, CDC13) 11.45 (br. s, IH), 7.09 (s,
IH), 7.00 (s, IH), 6.75 (s, IH), 3.55 (m, IH), 3.35-3.29 (m, IH), 3.21-3.12 (m, IH), 2.95-
2.80 (m, 2H), 2.00-1.78 (m, 2H), 1.72-1.60 (m, IH), 1.17 (d, 3H, J= 6.5), 0.97 (t, 3H, J =
7.3), 0.89-0.85 (m, IH).
EXAMPLE 85
4-Trifluoromethvl-7-methvl-6-cvcIopropylmethvl-6.7.8.9-tetrahvdropvridor2.3-
g1quinolin-2(lff)-one ("Compound 195. Structure 34 of Scheme VI. where Ri = methyl. R
= cyclopropylmethyl. n = 1)
This compound was prepared in a similar fashion as that described in Example 84
from Compound 187 (Structure 33 of Scheme VI, where R] = methyl, n =1) and
cyclopropanecarboxaldehyde. !H NMR (400 MHz, CDC13) 10.91 (br. s, IH), 7.14 (s, IH),
7.01 (s, IH), 6.94 (s, IH), 3.65 (m, IH), 3.35 (dd, IH, 7= 15.0, 5.5), 3.09 (dd, IH, J=
15.0, 6.2), 2.97-2.82 (m,2H), 2.00-1.94 (m, IH), 1.84-1.79 (m, IH), 1.17 (d, 3H,J= 6.5),
0.88-0.85 (m, IH), 0.58 (m, 2H), 0.28 (dd, 2H, J= 10.3, 5.0).
EXAMPLE 86
4-Trifluoromethvl-7-methvl-6-ethvl-6.7,8.9-tetrahvdropvrido[2.3-g1quinolin-2(l^r)-one
(Compound 196. Structure 34 of Scheme VI, where Rj^ = methyl. R^ = ethyl, n - 1)
This compound was prepared in a similar fashion as that described in Example 84
from Compound 187 (Structure 33 of Scheme VI, where RI = methyl, n =1) and
acetaldehyde. 1H NMR (400 MHz, CDC13) 11.19 (br. s, IH), 7.11 (s, IH), 7.00 (s, IH),
6.80 (s, IH), 3.55 (m, IH), 3.47-3.32 (m, 2H), 2.93-2.80 (m, 2H), 1.93-1.79 (m, 2H), 1.22
(t,3H,J = 7.0), 1.18 (d,3H,J = 6.4).
EXAMPLE 87
4-Trifluoromethvl-7-methvI-6-f2.2.2-trifluoroethvl)-6.7.8.9-tetrahvdropvridoi'2.3-
g]quinolin-2(lJ/)-one (Compound 197. Structure 34 of Scheme VI. where Rj^ = methyl. R;
= 2.2,2-trifluoroethyl. n = 1)
This compound was prepared in a similar fashion as that described in Example 84
from Compound 187 (Structure 33 of Scheme VI, where RI = methyl, n =1) and
trifluoroacetaldehyde ethyl hemiacetal. 'H NMR (400 MHz, CDC13) 11.08 (br. s, IH),
76
7.06 (s, 1H), 7.00 (s, 1H), 6.99 (s, 1H), 3.99 (m, 1H), 3.81 (m, 1H), 3.67 (m, 1H), 3.10-
2.95 (m, 1H), 2.92-2.82 (m, 1H), 2.07-1.97 (m, 1H), 1.93-1.80 (m, 1H), 1.19 (d, 3H, J =
6.5).
EXAMPLE 88
4-Trifluoromethvl-6-r2,2.2-trifluoroethyn-6.7.8.9-tetrahvdropvridof2,3-g1q.uinolin-2ClJ?jr)-
one (Compound 198. Structure 34 of Scheme VI. where R^ = H. R? = 2.2.2-trifluoroethyl.
This compound was prepared in a similar fashion as that described in Example 84
from Compound 192 (Structure 33 of Scheme VI, where RI = H, n =1) and
trifluoroacetaldehyde ethyl hemiacetal. 'H NMR (400 MHz, CDC13) 11.32 (br. s, 1H),
•7.11 (s, 1H), 7.02 (s, 1H), 6.99 (s, 1H), 3.88 (q, 2H, J= 8.9), 3.47 (t, 2H, J= 5.6), 2.93 (t,
2H, J = 6.3), 2.03 (m, 2H).
EXAMPLE 89
4-Trifluoromethvl-6-propvl-6.7.8.9-tetrahvdropyridor2.3-g1quinolin-2flJ:jr)-one
(Compound 199. Structure 34 of Scheme VI, where Rj = H. R2 = propyl n = 1)
This compound was prepared in a similar fashion as that described in Example 84
from Compound 192 (Structure 33 of Scheme VI, where RI = H, n =1) and
propionaldehyde. !H NMR (400 MHz, CDC13) 11.23 (br. s, 1H), 7.07 (s, 1H), 6.99 (s, 1H),
6.78 (s, 1H), 3.34 (t, 2H, J = 5.6), 3.26 (t, 2H, J = 7.4), 2.88 (t, 2H, J = 6.3), 1.97 (m, 2H),
1.65 (m, 2H), 0.97 (t, 3H, J = 7.4).
EXAMPLE 90
4-Trifluorornethyl-6-ethvl-6.7.8.9-tetrahvdropyrido[2,3-gTc[uino1in-2(l/:D-one (Compound
200, Structure 34 of Scheme VI, where R1 = H. R; = ethyl, n = 1)
This compound was prepared in a similar fashion as that described in Example 84
from Compound 192 (Structure 33 of Scheme VI, where RI = H, n =1) and acetaldehyde.
'H NMR (400 MHz, CDC13) 11.23 (br. s, 1H), 7.07 (s, 1H), 7.00 (s, 1H), 6.82 (s, 1H), 3.39
(q, 2H, J = 7.1), 3.31 (t, 2H, J = 5.6), 2.88 (t, 2H, J = 6.4), 1.98 (m, 2H), 1.18 (t, 3H, J =
.7.1).'
77
EXAMPLE 91
4-Trifluoromethvl-6-cyclopropvlinethvl-6.7.8.9-tetrahvdropvridof2,3-glqumolin-2rijy)-
one f Compound 201. Structure 34 of Scheme VI. where R^ = H, R; = cyclopropvlmethvl.
This compound was prepared in a similar fashion as that described in Example 84
from Compound 192 (Structure 33 of Scheme VI, where RI = H, n =1) and
cyclopropanecarboxaldehyde. 'H NMR (400 MHz, CDC13) 11.44 (br. s, 1H), 7.06 (s, 1H),
7.00 (s, 1H), 6.92 (s, 1H), 3.40 (t, 2H, J = 5.6), 3.21 (d, 2H, J = 6.2), 2.90 (t, 2H, J = 6.3),
1.99 (m, 2H), 1.07 (m, 1H), 0.58 (m, 2H), 0.27 (m, 2H).
EXAMPLE 92
6.7-Dihvdro-8.8-dimethvl-4-ftrifluoromethyn-8//'-pvrano[3;2-g]quinolin-2flJtf)-one
(Compound 202. Structure 39 of Scheme VII, where % = % = R3 = H, R2 = methyl. Rd =
triflubromethyl)
General Method A: Substitution of a propargyl alcohol with a phenol. To a
solution of the propargyl alcohol (1.16 equiv) and DBU (l,8-diazabicyclo[5.4.0]undec-7-
ene, 1.3 equiv) in CH3CN (0.5 mL/rnmol) stirred at -5°C was added trifluoroacetic
anhydride (1.16 equiv) and the flask was stirred for 40 min. In a second flask, to a mixture
of the phenol (1.0 equiv) and CuCl (0.01 equiv) in CH3CN (0.8 mL/mmol) was added
DBU (1.5 equiv) at 0°C. This solution was added via cannula to the first flask. The
mixture was stirred at 0°C for 4 h, then allowed to warm to rt. The mixture was
partitioned between EtOAc (10 mL/mmol) and water (5 mlVmmol) and the aqueous layer
was extracted with EtOAc. The combined organic layers were washed sequentially with 1
N N55HS04 (5 mL/mmol), NaHC03 (5 mL/mmol) and brine (5 mL/mmol), dried over
MgSO/t, filtered and concentrated. Flash chromatography affords the desired product as
an oil.
l-Nitro-3-(l,l-dimethylprop-2-ynloxy)benzene (Compound 203, Structure 36 of
Scheme VH, where Rj = R3 = H, R2 = methyl).
This compound was prepared by the above General Method A from 2-methyl-3-
bu'tyn-2-ol (0.976 g, 11.6 mmol) and 3-nitrophenol (1.39 g, 10.0 mmol) in 40% yield (0.76
g) after flash chromatography (hexanes:EtOAc 9:1). 'H NMR (400 MHz, CDC13) 8.11 (t,
78
J=2.2, 1H), 7.86-7.96 (m, 1H), 7.48-7.55 (m, 1H), 7.43 (t, J= 8.1, 1H), 2.66 (s, 1H), 1.70
(s, 6H).
General Method B: Thermal cyclization of a propargyl phenyl ether to a 2Hchromene.
A solution of the propargyl phenyl ether was heated in N,N-diethylaniline (1-2
M) at 195°C or reflux for 12-30 h, whereupon the dark brown solution was partitioned
between EtOAc (10 mL/mmol) and IN NaHSOn (5 mL/mmol). The aqueous layer was
extracted with EtOAc (10 mL/mmol) and the combined organic layers were washed
sequentially with IN NaHSO* (10 mL/mmol) and brine (10 mL/mmol), dried over
MgSCU, filtered and concentrated. Flash chromatography (EtOAc:hexanes) afforded the
desired product.
2,2-Dimethyl-7-nitro-2W-chromene (Compound 204, Structure 37 of Scheme VII,
where R, = R3 = H, R2 = methyl).
This compound was prepared by the above General Method B from Compound
203 (0.703 g, 3.71 mmol) in 1.9 mL ATjV-diethylaniline heated at 195°C for 14 h in 18%
yield (130 mg) after flash chromatography (hexanes:EtOAc 9:1). 'H'NMR (400 MHz,
CDC13) 7.71 (dd, J= 8.3, 2.2, 1H), 7.61 (d, J= 2.1, 1H), 7.07 (d, J= 8.3, 1H), 6.37 (d, J=
9.9, 1H), 5.82 (d, J= 9.9, 1H), 1.47 (s, 6H).
7-Amino-2,2-dimethyl-2//-chroman (Compound 205, Structure 38 of Scheme VII,
where R, = R3 = H, R2 A suspension of Compound 204 (124 mg, 0.655 mmol) and 10% Pd-C (6.2 mg,
.5 wt %) in 1.3 mL EtOAc and 1.3 mL EtOH was stirred under an atmosphere of hydrogen
for 16 h, whereupon the mixture was filtered through Celite and concentrated. Flash
chromatography (hexanes:EtOAc 3:1) afforded 112 mg (97%) of Compound 205. 'H
NMR (400 MHz, CDC13) 8 6.83 (d, J= 8.0, 1H), 6.21 (dd, .7= 8.0, 2.3, 1H), 6.14 (d, J=
2.2, 1H), 3.50 (v. broad s, 2H), 2.66 (t, J= 6.7, 2H), 1.76 (t, J= 6.7, 2H), 1.31 (s, 3H).
79
6,7-Dihydro-8,8-dimethyl-4-(trifluoromethyl)-8f/-pyrano[3,2-g]quinolin-2(lJ:/)-
one (Compound 202, Structure 39 of Scheme VII, where RI = R3 = R5 = H, R2 = methyl,
R4 = trifluoromethyl).
A solution of Compound 205 (9 mg, 0.050 mmol) and 4,4,4-trifluoroacetoacetate
(57 mg, 0.30 mmol) was heated at 190°C in a sealed tube for 20 h, whereupon the mixture
was cooled and precipitated with hexanes. Flash chroriiatbgraphy (CH2Cl2:MeOH 92:8)
afforded 4 mg of a brown solid. Final purification by HPLC (ODS semi-prep column,
MeOH:water 7:3, 3 mL/min) afforded 1.1 mg (7%) of Compound 205, a white film. 'H
NMR (400 MHz, acetone-d^) 10.9 (broad s, IH), 7.50 (s, IH), 6.84 (s, IH), 6.69 (s, IH),
2.93 (t,J= 6.8, 2H), 1.91 (t,/=6.8, 2H), 1.38 (s,6H).
EXAMPLE 93
6.7-Dihvdro-8.8.10-trimethvl-4-ftrif]uoromethvn-8Jtf-pyrano|'3.2-g1quinolin-2(lJcJr)-one
-(Compound 206, Structure 39 of Scheme VII, where R., = R, = methyl. RI = Rj = H.:R4 =
trifluoromethyl)
l-Nitro-2-methyl-3-(l,l-dimethylprop-2-ynloxy)benzene (Compound 207,
Structure 36 of Scheme VII, where R, = R2 = methyl, R3 = H)
This compound was prepared by General Method A (EXAMPLE 92) from 2-
methyl-3-butyn-2-ol (0.976 g, 11.6 mmol) and 2-methyl-3-nitrophenol (1.53 g, 10.0
mmol) in 61% (1.34 g) yield after flash chromatography (hexanes:EtOAc 11:1). ]H NMR
(400 MHz, CDC13) 7.72 (d, J= 7.9, IH), 7.49 (d, J= 7.8, IH), 7.22 (t, J= 8.0, IH), 2.60
(s, IH), 2.36 (s,3H), 1.69 (s,6H).
2,2,8-Trimethy]-7-nitro-2#-chromene (Compound 208, Structure 37 of Scheme
VH, where RI = R2 = methyl, R3 = H).
This compound was prepared by General Method B (EXAMPLE 92) from
Compound 207 (0.415 g, 1.89 mmol) in 2 mL tyAf-diethylaniline heated at 190°C for 16 h
in 59% yield (59%) after flash chromatography (hexanes:EtOAc 9:1). ]H NMR (400
MHz, CDC13) 7.39 (d, J= 8.2, IH), 6.91 (d, J= 8.2, IH), 6.33 (d, J= 9.8, IH), 5.78 (d, J=
9.8, IH), 2.36 (s, 3H), 1.46 (s, 6H).
7-Amino-2,2,8-trimethyl-2#-chroman (Compound 209, Structure 38 of Scheme
VH, where RI. = R2 = methyl, Rj = H).
A suspension of Compound 208 (241 mg, 1.10 mmol) and 10% Pd-C (12 mg, 5 wt
%) in 2.2 mL EtOAc and 2.2 mL EtOH was stirred under an atmosphere of hydrogen for
16 h, whereupon the mixture was filtered through Celite and concentrated. Flash
•chromatography (hexanes:EtOAc 3:1) afforded 210 mg (100%) of Compound 209. 'H
NMR (400 MHz, CDC13) 6.72 (d, J= 8.0, 1H), 6.24 (d, J= 8.0, 1H), 3.48 (broad s, 2H),
2.68 (t, J= 6.8, 2H), 2.01 (s, 3H), 1.74 (t, J= 6.8, 2H), 1.31 (s, 6H).
6,7-Dihydro-8,8,10-trirnethyl-4-(trifluoromethyl)-8J:r-pyrano[3,2-g]quinolin-
2(lJ7)-one (Compound 206, Structure 39 of Scheme VII, where R, = R2 = methyl, R3 = R5
= H, R4 = trifluoromethyl).
A solution of Compound 209 (39 mg, 0.21 mmol) and 4,4,4-trifluoroacetoacetate
(195 mg, 1.03 mmol) in 0.5 mL diphenyl ether was heated at 190°C in a sealed tube for 44
h, whereupon the mixture was cooled and precipitated with hexanes and filtered. Flash
chromatography (GEbCl?:ether) afforded 6.5 mg (10%) of Compound 209 as a white solid.
'H NMR (400 MHz, CDC13) 9.07 (broad s, 1H), 7.40 (s, 1H), 6.82 (s, 1H), 2.89 (t, J= 6.7,
2H), 2.26 (s, 3H), 1.86 (t, .7=6.7, 2H), 1.39 (s, 6H).
81
EXAMPLE 94
(±)-6,7-Dihvdro-6-ethvl-4-methvl-8J:/-pvranor3,2-g1quinolin-2('lH)-onefCompound 210.
Structure 39 of Scheme VII. where R1 = R2 = Rj = H. R3 = ethyl. & = methyl)
l-Nitro-3-(pent-2-ynyloxy)benzene (Compound 211, Structure 36 of Scheme VII,
where R, = R2 = H, R3 = ethyl)
To a solution of S-nitrophenoI (7.5 g, 54 irimol) arid E^COs (10.4 g, 75.6 mmol) in
27 mL DMF was added 2-pentynylmethanesulfonate (10.5 g, 65 mmol) and the mixture
was stirred at rt for 18 h, whereupon the mixture was partitioned in etherwater (200
mL:200 mL). The aqueous layer was extracted with ether (2 x 100 mL) and the combined
organic layers were washed sequentially with water (3 x 100 mL) and brine (50 mL), dried
overMgSCU, filtered and concentrated to afford 11.1 g (ca. 100%) of Compound 211 as a
light brown oil. 'H NMR (400 MHz, CDC13) 7.80-7.90 (m, 2H), 7.40-7.50 (m, 1H), 7.27-
7.35 (m, 1H), 4.76 (t, J= 2.1, 2H), 2.18-2.28 (m, 2H), 1.13 (t, J= 7.4, 3H).
l-Acetamido-3-(pent-2-ynyloxy)benzene (Compound 212, Structure 36a of
Scheme VII, where R3 = ethyl, R, = R2 = H).
A suspension of Compound 211 (15.1 g, 73.5 mmol), Zn dust (325 mesh, 19.2 g,
294 mmol) and calcium chloride dihydrate (21.6 g, 147 mmol) in 300 mL 95%
ethanol/water was heated at reflux for 20 h, whereupon the reaction mixture was filtered
while hot through Celite and rinsed with 300 mL hot ethanol. The filtrate was
concentrated to brown paste, which was partitioned between EtOAc (200 mL), water (200
mL) and 0.1 M HC1 (25 mL). The aqueous layer was extracted with EtOAc (2 x 100 mL)
and the combined organic layers were washed sequentially with water (100 mL) and brine
(100 mL), dried over MgSCM, filtered and concentrated to 12.6 g of a brown oil. This
material was dissolved in 28 mL pyridine, cooled to 0QC, then DMAP (433 mg, 3.54
mmol) and acetic anhydride (8.68 g, 85.1 mmol) was added. After 20 min, the mixture
was allowed to warm to rt and the mixture was stirred for 6 h. The reaction was quenched
by the addition of 1 mL MeOH and the reaction mixture was partitioned between EtOAc
(200 mL) and water (200 mL). The aqueous layer was extracted with EtOAc (2 x 100
mL) and the combined organic layers were washed sequentially with 2N NaHSO4 (3 x 100
mL), water (100 mL), NaHCO3 (100 mL) and brine (100 mL), dried over MgSO4, filtered
82
and concentrated. Flash chromatography (EtOAc:hexanes 3:2) afforded 9.6 g (62%) of
Compound 212. *H NMR (400 MHz, CDC13) 7.42 (broad s, 1H), 7.24 (broad s, 1H), 7.20
(t, J= 8.1, 1H), 7.06 (broad d, J= 8.1, 1H), 6.73 (dd, .7 = 8.1, 1.8, 1H), 4.64 (t, J= 2.0,
2H), 2.18-2.28 (m, 2H), 2.16 (s, 3H), 1.25 (t, J= 7.4, 3H).
7-Acetamido-4-ethyl-2/:/r-chromane (Compound 213, Structure 38a of Scheme YE,
where R3 = ethyl, R, = R2 = H).
A solution of Compound 212 (1.52 g, 7.00 mmol) in 3.5 mL A A-diethylaniline
was heated at reflux for 30 h, whereupon the brown solution was partitioned between
EtOAc (60 mL) and IN NaHSC^ (30 mL). The aqueous layer was extracted with EtOAc
(2 x 30 mL) and the combined organic layers were washed sequentially with NaHSCM (2 x
15 mL) brine (30 mL), dried over MgSCU, filtered and concentrated. Flash
chromatography (EtOAc:hexanes 1:1) afforded 0.44 g (29%) of Compound 213 as alight
amber oil. This was carried on directly by treatment with 10% Pd-C (21 mg, 5 wt%) in
4.7 mL EtOAc and 4.7 mL EtOH and was stirred in 1 atm H2 for 6 h, whereupon the
mixture was filtered through Celite and concentrated to an oil. Flash chromatography
(EtOAc:hexanes 1:1) afforded 0.42 g (100%, or 29% for the two-steps) of Compound 213.
'H NMR (400 MHz, CDC13) 5 6.98-7.10 (m, 3H), 6.92 (s, 1H), 4.08-4.22 (m, 2H), 2.60-
2.70 (m, 1H), 2.14 (s, 3H), 2.00-2.10 (m, 1H), 1.75-1.90 (m, 2H), 1.48-1.58 (m, 1H), 0.98
(t, J= 7.4, 3H).
7-Amino-4-ethylchroman (Compound 214, Structure 38 of Scheme VII, where RI
= R2 = H, R3 = ethyl).
A solution of Compound 213 (0.42 g, 1.9 mmol) in 3.8 mL 2N HC1 was heated at
reflux for 16 h, whereupon the solution was partitioned between EtOAc (40 mL) and
saturated NaHC03 (20 mL). The aqueous layer was extracted with EtOAc (2 x 20 mL)
and the combined organic layers were washed with brine (20 mL), dried over MgSi,
filtered and concentrated. Flash chromatography (EtOAc:hexanes 1:1) afforded 0.30 g
(90%) of Compound 214. 'H NMR (400 MHz, CDC13) 6.91 (d, J= 8.0, 1H), 6.24 (dd, J=
8.0, 2.4, 1H), 6.14 (d,V=2.4, 1H), 4.05-4.19 (m, 2H), 3.52 (broad s, 2H), 2.55-2.65 (m,
1H), 1.95-2.05 (m, 1H), 1.70-1.85 (m, 2H), 1.42-1.52 (m, 1H), 0.97 (t, .7=7.4, 3H).
83
(6,7-Dihydro-6-ethyl-4-methyl-8/f-pyrano[3,2-g-]quinolin-2(l//)-one
(Compound 210; Structure 39 of Scheme VII, where R, = R2 = R5 = H, R3 = ethyl, R4 =
methyl).
To a solution of Compound 214 (53 mg, 0.30 mmol) and triethylamine (60 mg,
0.60 mmol) in 3 mL CH2C12 was added diketene (50 mg, 0.60 mmol) at 0°C. The solution
was allowed to warm to rt and after 2 h was concentrated to an oil. Flash chromatography
(EtOAc:hexanes 3:2) afforded 46 mg (59%) of 7-acetoacetamido-4-ethylchroman, an oil.
A portion of this material was carried on directly. A solution of 7-acetoacetamido-4-
ethylchroman in 0.2 mL PPA (polyphosphoric acid) was heated at 100°C for 4 h. The
mixture was precipitated with water and neutralized with 6N NaOH. The mixture was
extracted with EtOAc (3 x 20 mL) and the combined organic layers were washed with
brine, dried over MgSC-4, filtered and concentrated. Flash chromatography
(EtOAc:CH2Cl2 7:3) afforded 5 mg of a solid. Final purification by HPLC (CDS semiprep
column, MeOH:water 7:3, 3 mL/min) afforded 3.4 mg (36%) of Compound 210 as a
white solid. ]H NMR (400 MHz, CDC13) 10.5 (broad s, 1H), 7.39 (s, 1H), 6.68 (s, 1H),
6.35 (s, 1H), 4.17-4.30 (m, 2H), 2.72-2.82 (m, 1H), 2.43 (s, 3H), 2.02-2.12 (m, 1H), 1.80-
1.92 (m, 2H), 1.55-1.65 (m, 1H), 1.03 (t, J= 7.4, 3H).
EXAMPLE 95
M-7.8-Dihydro-8-ethYl-4-methyl-6//'-pvrano[2.3:/]quinolin-2(l/jr)-one (Compound 215.
Structure 40 of Scheme VII. where R? = Rs = H. R3 = ethyl, RA/= methyl)
This compound was isolated as a by-product from-the preparation of Compound
210 described in Example 94. 'H NMR (400 MHz, CDCli!) 10.9 (s, 1H),7.21 (d, J = 8.4,
1H), 6.81 (d, J = 8.4, 1H), 6.37 (s, 1H), 4.17-4.30 (m, 2H), 2.67-2.77 (m, 1H), 2.65 (d, J =
0.9, 3H), 2.00-2.10(m, 1H), 1.78-1.90
(m, 2H), 1.50-1.60 (m, 1H), 1.00 (t, J = 7.3, 3H).
EXAMPLE 96
M-6.7-Dihvdro-6-ethvl-4-trifluoromethvl-8//'-Dvranor3.2-g-1quinolin-2ajy)-one
f Compound 216. Structure 39 of Scheme VII. where Rx = R = R; = H. R3 = ethyl. Ra =
trifluoromethyl)
: A solution of .Compound 214 (Structure 38 of Scheme YE, where RI = R2 = H, R3
= ethyl) (14 mg, 0.079 mmol) and ethyl 4,4,4-trifluoroacetoacetate (17 mg, 0.095 rnmol)
in 0.8 mL benzene was heated at reflux for 14 h. The solution was concentrated and
purified by flash chromatography (hexanes:EtOAc 3:2) to afford 21 mg of an oil. This
was treated with PPA and heated at 100°C for 6 h. The dark brown sludge was partitioned
between water (20 mL) and ethyl acetate (20 mL). The aqueous layer was extracted with
EtOAc (2 x 20 mL) and the combined organic layers were washed with brine, dried over
MgSO4, filtered and concentrated. Flash chromatography (CH^C^EtOAc 4:1) afforded
5.7 mg (29%) of a white solid. Final purification by HPLC(ODS semi-prep column,;
MeOH:water 7:3, 3 mL/rnin) afforded 3.4 mg (17%) of Compound 216 as a white solid.
'H NMR (400 MHz, CDC13) 11.2 (broad s 1H), 7.54 (s, 1H), 6.86 (s, 1H), 6.77 (s, 1H),
4.22-4.32 (m, 2H), 2.75-2.85 (m, 1H), 2.05-2.15 (m, 1H), 1.80-1.90 (m, 2H), 1.55-1.65
(m,2H), 1.03 (t,J= 7.3, 3H).
EXAMPLE 97
M-6.7-Dihvdro-6-ethvl-4-trifluorQmethYl-8Jj'-pvranor3,2-glquinolin-2('17f)-one
(Compound 217, Structure 39 of Scheme Vn. where Rj^ = R? = Rs = H. Rj = ethyl. Rj =
trifluoromethyl) and C+)-6.7-Dihvdro-6-ethvl-4-trifluoromethvl-8//-pvrano[3.2-g]quinolin-
2(lffi-OT\e (Compound 218. Structure 39 of Scheme VIL where RI = R? = Rs = H. R, =
•*• -*: ~ -i
ethyl. Rj = trifluoromethvl'l
Compound 216 was separated into its constitutive enantiomers via chiral HPLC on
a semi-prep Chiralcel AD column (hexanes:isopropanol 97:3, 5.0 mL/min) to afford
Compound 217 and Compound 218. Data for Compound 217: /R 46.5 min
(hexanesrisopropanol 97:3). Data for Compound 218: /R 58.3 rain (hexanes.isopropanol
97:3).
EXAMPLE 98
(±)-6,7-Dihvdro-6-ethvl-3-fluoro-4-trifluoromethvl-8//-Pvranol'3.2-g1q-uinolin-2('l/n-one
(Compound 219, Structure 39 of Scheme VII. where R_i = R2 = H, R3 = ethyl. R4 =
trifluoromethvl. Rs = F)
A solution of Compound 214 (Structure 38 of Scheme VII, where RI = R2 = H, R3
= ethyl) (100 mg, 0.56 mmol) and ethyl 2,4)4,4-tetrafluoro-3,3-dihydroxybutanoate (185
mg, 0.84 mmol) was heated at 130°C for 20 h. The .mixture was passed through a plug of
silica gel (EtOAc) and concentrated to a brown oil. This oil was treated with 1.5 mL PPA
and heated at 100°C for 6 h, then precipitated with cold water and neutralized with 6N
NaOH. The mixture was extracted with EtOAc (3 x 25 mL) and the combined organic
layers were washed with brine (25 mL), dried over MgSC>4, filtered and concentrated.
Flash chromatography (CH2Cl2:EtOAc 4:1) afforded 70 mg (48%) of Compound 219 as a
white solid. 'H NMR (400 MHz, CDC13) 11.8 (broad s, 1H), 7.58 (s, 1H), 6.84 (s, 1H),
4.22-4,32 (m, 2H), 2.78-2.88 (m, 1H), 2.05-2.15 (m, 1H), 1.80-1.95 (m, 2H), 1.55-1.68
(m, 1H), 1.03 (t, .7=7.4, 3H).
EXAMPLE 99
(±)-6,7-Dihvdro-6-ethvl-4-trifluoromethvl-l-methyl-8^/-pvrano[3,2-g]quinolin-2(17/)-one
(Compound 220. Structure 41 of Scheme VH where Rj_ = R2 = Rs = .H. RI = ethyl. R =
trifluoromethvl)
General Method: N-Methylation of a pyridone with sodium hydride and Mel. To
a suspension of the pyridone (1 equiv) and NaH (60% mineral oil dispersion, 1.2-2.5
equiv) in THF (0.05 M) was added Mel (1.2-2.5 equiv). The mixture was stirred for 24 h
and partitioned between CH2Cl2 and pH 7 phosphate buffer"; The aqueous layer was 7
extracted with CH2C12 and the combined organic layers were washed with brine, dried
over MgSC4, filtered and concentrated and purified as indicated.
This compound was prepared according to the General Method described above
from Compound 216 (Structure 39 of Scheme VII, where R, = R2 = R5 = H, R3 = ethyl, R4
= trifluoromethyl) (7.2 mg, 0.024 mmol), NaH (1.0 mg, 0.029) and Mel (2 uL, 0.029
mmol) in 51% yield (3.8 mg),after flash chromatography (CH2Cl2:MeOH 24:1). 'H NMR
(400 MHz, CDC13) 5 7.58 (broad s, 1H), 6.90 (s, 1H), 6.81 (s, 1H), 4.24-4.36 (m, 2H),
3.65 (s, 3H), 2.75-2.85 (m, 1H), 2.07-2.17 (m, 1H), 1.80-1.95 (m, 2H), 1.58-1.68 (m, 1H),
1.04 (t,J= 7.4, 3H).
EXAMPLE 100
(±V6.7-Dihvdro-6-ethvl-3-fluoro-4-trifluoromethYl-l-methYl-8J:/'-pvrano[3.2-g1quinolin-
2(l#)-6ne (Compound 221. Structure 41 of Scheme VII, where Rj = R2 = H. R^ = ethyl,
RA = trifluoromethyl. Rg = F)
. This compound was prepared according to General Method in Example 99 from
Compound 219 (Structure 3.9 of Scheme VII, where R, = R2 = H, R3 = ethyl, It( =
trifluoromethyl, R5 = F) (11 mg, 0.034 mmol), NaH (3.0 mg, 0.085 mmol) and Mel (5.2
uL, 0.085 mmol) in 30% yield (3.4 mg) after purification by flash chromatography
(CH2Cl2:MeOH24:l). 'H NMR (400 MHz, CDC13) 7.61 (s, 1H), 6.80 (s, 1H), 4.22-4.36
(m, 2H), 3.70 (s, 3H), 2.77-2.87 (m, 1H), 2.05-2.15 (m, 1H), 1.80-1.95 (m, 2H), 1.55-1.65
(m, 1H), 1.03 t, 7=7.4, 3H).
EXAMPLE 101
(±)-6.7-Dihydro-6-ethvl-2.4-bis(trifluoromethyl)-87:/'-pvrano[3.2-g1quinoline (Compound
222, Structure 42 of Scheme VII, where Rj_ = R2 = H. R3 = ethyl)
To a solution of Compound 214 (Structure 38 of Scheme VII, where RI = R2 = H,
RS = ethyl) (30 mg, 0.17 mmol) and 1,1,1,5,5,5-hexafluoropentan-2,4-dione in 0.8 rnL
toluene was heated at 60°C for 18 h, whereupon/-toluensulfonic acid monohydrate (6.4
mg, 0.034 mmol) was added and the solution heated at 60°C for 6 h. The mixture was
concentrated to an oil and purified by flash chromatography (CH2Cl2:hexanes 1:1) to
afford 29 mg (49%) of Compound 222 as a yellow oil. 'H NMR (400 MHz, CDC13) 7,94
(s, 1H), 7.79 (s, 1H), 7.65 (s, 1H), 4.32-4.44 (m, 2H), 2.98-3.08 (m, 1H), 2.14-2.24 (m,
1H), 1.88-2.04 (m, 2H), 1.68-1.86 (m, 1H), 1.08 (t,J= 7.4, 3H).
EXAMPLE 102
6,8.8-Trimethvl-4-trifluoromethvl-87:/'-pvranor3.2-g1coumarin (Compound 223. Structure
47 of Scheme VIII. where R = methyl')
2,2-Dimethyl-7-hydroxy-4-chromanone (Compound 224, Structure 44 of Scheme
VIH).
1,3-Resorcinol (Structure 43 of Scheme VET) (lg, 9.1 mmol) and 3,3-
dimethylacrylic acid (909 mg, 9.1 mmol) were dissolved in trifluoroacetic acid (10 mL)
and stirred at 80°C for 2 h. The reaction was made basic with 20% KOH to pH 7. The
mixture was partitioned between EtOAc (50 mL) and water (50 mL). The aqueous was
extracted with EtOAc (2 x 50 mL). The combined organic layers were washed
sequentially with water (50 mL) and brine (50 mL), dried over Na2SC>4, filtered and
concentrated. Flash chromatography (25% EtOAc/hexanes) afforded 1.5g (87%) of
Compound 224. 'H NMR (400 MHz, acetone-d6) 9.26 (bs, 1H), 7.66 (d, J = 8.7, 1H),
6.51 (dd, 7=8.7, 2.1, 1H), 6.33 (d, J= 2.1, 1H), 2.64 (s, 2H), 1.42 (s,6H).
2,2,4-Trimethyl-4,7-dihydroxychroman (Compound'225, Structure 45 of Scheme
VIII, where R = methyl).
Compound 224 (250 mg, 1.3 mmol) was dissolved in diethyl ether and cooled to
0°C. Methyl magnesium bromide (3.0M, 2.6 mL, 7.8 mmol) was added slowly via
syringe. The reaction was allowed to warm to room temperature. After 2 h the reaction
was quenched with water and partitioned between EtOAc (25 mL) and water (25 mL). The
aqueous was extracted with EtOAc (2 x 25 mL). The combined organic layers were
washed sequentially with water (25 mL,) and brine (25 mL), dried over Na2S04, filtered
and concentrated. Flash chromatography (30% EtOAc/hexanes) afforded 220 mg (81%)
of Compound 225. 'HNMR (400 MHz, acetone-d6) 8.16 (s, 1H), 7.32 (d,J= 8.5, 1H),
6.4 (dd, /= 8.5, 2.5, 1H), 6.2 (d, J= 2.5, 1H), 3.7 (s, 1H), 2.03(s, 2H), 1.5 (s, 3H), 1.36 (s,
3H),1.33(s,3H).
2,2,4-Trimethyl-7-hydroxy-2fl'-chromene (Compound 226, Structure 46 of Scheme
VEI, where R = methyl).
2,2,4-trimethyl-4I7-dihydroxychroman (225) (220 mg, 1.06 mmol), was dissolved
in CH2Cl2 (5 mL) and treated with p-toluene sulfonic acid monohydrate (25 mg, 0.13
mmol). The resulting solution was stirred at rt for 2 h. The reaction was quenched with
NaHCOa (sat.) to pH 7 and the mixture was partitioned between EtOAc (25 mL) and water
(25 mL). The aqueous was extracted with EtOAc (2 x 25 mL). The combined organic
. layers were washed sequentially with water (25 mL) and brine (25 mL), dried over
Na2SO4) filtered and concentrated. Flash chromatography (15% EtOAc/hexanes) afforded
135 mg (67%) of Compound 226. 'H NMR (400 MHz, acetone-d6) 8.37 (s, 1H), 7.0 (dd,
J= 8.4, 2.4, 1H), 6.26 (d, J=2.4, 1H), 5.32 (s, 1H), 1.94 (s, 3H), 1.33 (s, 6H).
6,8,8-Trimethyl-4-trifluoromethyl-8//-pyrano[3,2-g-Jcoumarin (Compound 223,
Structure 47 of Scheme VET, where R = methyl).
Compound 226 (60 mg, 0.31 mmol) and ethyl-4,4,4-trifluoroacetoacetate (116 mg,
0.63 mmol) were dissolved in toluene and treated with POCls (97 mg, 0.63 mmol) and
stirred at 100°C for 8 h. The reaction was allowed to cool down to rt. The reaction was
quenched slowly with dropwise addition of water and partitioned between EtOAc (25 mL)
and water (25 mL). The aqueous was extracted with EtOAc (3 x 25 mL). The combined
organic layers were washed sequentially with water (25 mL) and brine (25 mL), dried over
Na2S04, filtered and concentrated. Flash chromatography (5% EtOAc/hexanes) afforded
40 mg (41%) of Compound 223. 'H NMR (400 MHz, acetone-d6) 7.43 (s, 1H), 6.8 fs,
1H), 6.7 (s, 1H), 5.75 (s, 1H), 2.08 (s, 3H), 1.46 (s, 6H).
EXAMPLE 103
6-Ethyl-8,8-dimethyl-4-trifluorometfavl-8flr-Pvranof3.2-g1coumarin (Compound 227.
Structure 47 of Scheme VIII. where R = ethyl)
4-Ethyl-2,2-dimethyl-7-hydroxy-2/f-chromene (Compound 228, Structure 46 of
Scheme VEI, where R = ethyl).
Compound 224 (200 mg, 1.04 mmol) was dissolved in diethyl ether and cooled to
0°C.. Ethyl magnesium bromide (3.0M, 1.7 mL, 5.2 mmol) was added slowly via syringe.
The reaction was allowed to warm to room temperature. After 2 h the reaction was
quenched with water and partitioned between EtOAc (25 mL) and water (25 mL). The
aqueous was extracted with EtOAc (2 x 25 mL). The combined organic layers were
washed sequentially with water (25 mL) and brine (25 mL), dried over Na2S04, filtered
and concentrated. The crude material was dissolved in CHjCk (5 mL) and treated with ptoluene
sulfonic acid monohydrate (25 mg, 0.13 mmol). The resulting solution was stirred
at rt for 2 h. The reaction was quenched with NaHC03 (sat) to pH 7 and the mixture was
partitioned between EtOAc (25 mL) and water (2 5 mL). The aqueous was extracted with
EtOAc (2 x 25 mL). The combined organic layers were washed sequentially with water
(25 mL) and brine (25 mL), dried over Na2SO4, filtered and concentrated. Flash
chromatography (15% EtO Ac/hex anes) afforded 220 mg (81%) of Compound 228. 'H
NMR (400 MHz, acetone-d6) 8.4 (bs, IH), 7.15 (d, J= 8.5, IH), 6.38 (dd, /= 8.5, 2.5,
IH), 6.28 (d, .7-2.5, IH), 5.3 (s, IH), 2.34 (q, J= 7.4, 2H), 1.11 (t, J= 7.4, 3H).
6-Ethyl-8,8-dimethyl-4-rrifluoromethyl-8/7-pyrano[3,2-g-]coumarin (Compound
227, Structure 47 of Scheme VIII, where R = ethyl).
Compound 228 (60 mg, 0.29 mmol) and ethyl-4,4,4-trifluoroacetoacetate (107 mg,
0.58 mmol) were dissolved in toluene and treated with POCh (90 mg, 0.58 mmol) and
stirred at 100°C for 8 h. The reaction was allowed to cool down to rt. The reaction was
quenched slowly with dropwise addition of water and partitioned between EtO Ac (25 mL)
and water (25 mL). The aqueous was extracted with EtOAc (3 x 25 mL). The combined
organic layers were washed sequentially with water (25 mL) and brine (25 mL), dried over
Na2S04, filtered and concentrated. Flash chromatography (5% EtOAc/hexanes) afforded
29 mg (31%) of Compound 227. 'H NMR (400 MHz, acetone-d6) 7.48 (s, IH), 6.81 (s,
IH), 6.69 (s, IH), 5.74 (s, IH), 2.48 (q, J= 7.4, 2H), 1.47 (s, 6H), 1.18 (t, J= 7.5, 3H).
EXAMPLE 104
(±V5.6-Dihvdro-6-hydroxvmethvl-4-trifluoromethvlpvrrolor3,2-flquinolin-2(lH)-one
(Compound 228. Structure 33a of Scheme VI. where R^ = hydroxymethyl. n - 0)
Compound 228 was prepared according to a similar procedure described in
Example 81: 'H NMR (500 MHz, acetone-d6) 11.02 (bs, IH), 7.39 (d, /= 8.8, IH), 7.10
(d, J= 8.8, IH), 7.01 (s, IH), 3.94 (m, 2H), 3.86 (m, IH), 3.55 (m, IH), 1.42 (d, J= 6.1,
2H).
EXAMPLE 105
(±)-5,6-Dihvdro-7-ethvl-6-hvdroxvmethvl-4-rrifluQromethvlpyrrolor3,2-f1quinolin-2(lHV
one (Compound 229. Structure 34a of Scheme VI. where Rj_ = hvdroxvmethyl. R2 = ethyl.
Compound 229 was prepared by ethylation of Compound 228: ]H NMR (500
MHz, CDC13) 11,71 (bs, IH), 7.21 (d,J= 8.5, IH), 7.15 (s, IH), 6.80 (d, J= 8.5, IH), 3.74
90
(m, 1H), 3.48 (m, 1H), 3.32 (m, 1H), 3.19 (m, 1H), 2.78 (m, 1H), 1.34 (d, J= 5.9, 2H),
1.11 (t,J= 6.5, 3H).
EXAMPLE 106
7.8-Dihvdro-6-f2.2.2-trifluoroethvn-4-trifluor6methylpvrrolo[2.3-g'lc}uinolin-2(lH)-one
(Compound 230, Structure 34 of Scheme VI, where Rj_ = H. R2 = 2.2.2-trifluoroethvl. n =
&
Compound 230 was prepared according to a similar .procedure described in
Example 81: 'HNMR (500'MHz, acetone-d6) 11.10 (bs, 1H), 7.32 (s, 1H), 6.82 (s, 1H),
6.80 (s, 1H), 4.13 (q, /= 10.0, 2H), 3.73 (t, J= 8.5, 1H), 3.22 (t, J= 8.5, 1H).
EXAMPLE 107
6-(2.2,2-Trifluoroethvl)-4-trifluoromethylpyiTolor2.3-g1quinolin-2(lH')-one (Compound
231. Structure 34b of Scheme VI. where R, = & = H. R? = 2.2.2-trifluoroethvn
Compound 231 was prepared by oxidation of Compound 230: 'H NMR (500 MHz,
acetone-d6) 10.93 (bs, 1H), 7.98 (s, 1H), 7.73 (s, 1H), 7.69 (d, J= 3.5, 1H), 6.87 (s, 1H),
6.71 (dd,J= 3.5 and 1.0, 1H), 5.31 (q, J=9.0, 2H).
EXAMPLE 108
8-Chloro-6-('2.2.2-trifluoroethylV4-trifluorornethYlpyrrolo[2,3-g]quinolm-2(lH)-one
(Compound 232, Structure 34b of Scheme VI. where RQ = H. RT = Cl. Rz = 2.2,2-
trifluoroethyl')
Compound 232 was prepared by chloronation of Compound 232: 'H NMR (500
MHz, acetone-d6) 11.04 (bs, 1H), 8.06 (s, 1H), 7.85 (s, 1H), 7.70 (s, 1H), 6.95 (s, 1H),
5.36'(q,y=9.0,-2H).
EXAMPLE 109
5-MethYl-7-(2.2.2-trifluoroethvn-4-rrifluoromethvlpvrrolo[3.2-f1quinolin-2(lH)-one
(Compound 233. Structure 19 of Scheme m. where R4 = H. Ri = methyl, R5 = 2,2.2-
trifluoroethvn
This compound was isolated as an over oxidation product of Compound 150
(Structure 18 of Scheme III, where R^ = R^ = methyll by the general oxidation procedure
described in Example 49: !H NMR (500 MHz, DMSO-rf*) 12.2 (bs, 1H), 7.95 (d, J=> 8.8,
1H), 7.27 (d, J= 8.8, 1H), 6.99 (s, 1H), 6.66 (s, 1H), 5.27 (q, JH.F = 8.8, 2H), 2.53 (s, 3H).
EXAMPLE 110
6-Formvl-5-methvl-7-f2,2,2-trifluoroethyl)-4-trifluoromethvl-7J7-pyrrolo[3.2-
/]quinoUn-2flg)-one (Compound 234. Structure 19 of Scheme HI. where Rj = formyl Ri
= methyl. Rs = 2.2.2-trifluoroethyl)
This compound was prepared by the general oxidation procedure described in
Example 49 from Compound 150 (Structure 18 of Scheme HI, where RI = R2 = methyl).
'H NMR (500 MHz, DMSO-dtf) 11.9 (bs, 1H), 10.18 (s, 1H), 8.06 (d, J= 8.8, 1H), 7.52 (d,
J= 8.8, 1H), 7.07 (s, 1H), 5.65 (q, JH.F= 8.8, 2H), 2.62 (s, 3H).
EXAMPLE 111
5.6-Dimethvl-7-f2.2-difluorovinvl)-4-trifluorQmethyl-7J7-pyrrolor3.2-/]quinolin-
2(l/jr)-one (Compound 235. Structure 19 of Scheme ni. where R^ = R^ = methyl. Rs = 2.2-
difluorovinyl)
This compound was isolated as an over oxidation product of Compound ISO
(Structure 18 of Scheme HI. where Rj^ = Rj = methyl) by the general oxidation procedure
described in Example 49: 'H NMR (500 MHz, DMSO-ck) 12.4 (bs, 1H), 7.76 (d, J= 8.8,
1H), 7.65 (d, J= 8.8, 1H), 7.16 (s, 1H), 5.05-5.00 (m, 1H), 2.45 (d, J= 0.9, 3H), 1.96 (s,
3H).
EXAMPLE 112
Steroid Receptor Activity
Utilizing the "cis-trans" or "co-transfection" assay described by Evans et al.,
Science. 240:889-95 (May 13, 1988), the disclosure of which is incorporated by reference
herein , the compounds of the present invention were tested and found to have strong,
specific activity as agonists, partial agonists and antagonists of AR. This assay is
described in further detail in U.S. Patent Nos. 4,981,784 and 5,071,773, the disclosures of
which are incorporated herein by reference.
The co-transfection assay provides a method for identifying functional agonists
and partial agonists which mimic, or antagonists which inhibit, the effect of native
hormones and quantifying their activity for responsive IR proteins. In this regard, the cotransfection
assay mimics an in vivo system in the laboratory. Importantly, activity in the
co-transfection assay correlates very well with known in vivo activity, such that the cotransfection
assay functions as a qualitative and quantitative predictor of a tested
compoundsjH vz'vo pharmacology. See, e.g., T. Berger et al. 41 J. SteroidBiochem.
Molec. Biol. 773 (1992), the disclosure of which is herein incorporated by reference.
In the co-transfection assay, a cloned cDNA for an IR (e.g., human PR, AR or GR)
under the control of a constitutive promoter (e.g., the SV 40 promoter) is introduced by
transfection (a procedure to induce cells to take up foreign genes) into a background cell
substantially devoid of endogenous IRs. This introduced gene directs the recipient cells to
make the IR protein of interest. A second gene is also introduced (co-transfected) into the
same cells in conjunction with the IR gene. This second gene, comprising the cDNA for a
reporter protein, such as firefly luciferase (LUC), controlled by an appropriate hormone
responsive promoter containing a hormone response element (HRE). This reporter "
plasmid functions as a reporter for the transcription-modulating activity of the target IR.
Thus, the reporter acts as a surrogate for the products (mRNA then protein) normally
expressed by a gene under control of the target receptor and its native hormone.
The co-transfection assay can detect small molecule agonists or antagonists of
target IRs. Exposing the transfected cells to an agonist ligand compound increases
reporter activity in the transfected cells. This activity can be conveniently measured, e.g.,
by increasing luciferase production, which reflects compound-dependent, IR-mediated
increases in reporter transcription. A partial agonist's activity can be detected in a manner
similar to that of the full agonist, except that the maximum measured activity, e.g.,
luciferase production, is less than that of an agonist standard. For example, for AR,'a
partial agonist can be detected by measuring increased luciferase production, but the
maximum effect at high concentration is less than the maximum effect for
dihydrotestosterone. To detect antagonists, the co-transfection assay is carried out in the
presence of a constant concentration of an agonist to the target DR. (e.g., progesterone for
PR) known to induce a denned reporter signal. Increasing concentrations of a suspected
antagonist will decrease the reporter signal (e.g., luciferase production). The cotransfection
assay is therefore useful to detect both agonists and antagonists of specific
IRs. Furthermore, it determines not only whether a compound interacts with a particular
IR, but whether this interaction mimics (agonizes) or blocks (antagonizes) the effects of
the native regulatory molecules on target gene expression, as well as the specificity and
strength of this interaction.
The activity of selected steroid receptor modulator compounds of the present
invention were evaluated utilizing the co-transfection assay and in standard IR binding
assays, according to the following illustrative Examples.
Co-transfection assay
CV-1 cells (African green monkey kidney fibroblasts) were cultured in the
presence of Dulbecco's Modified Eagle Medium (DMEM) supplemented with 10%
charcoal resin-stripped fetal bovine serum then transferred to 96-well microtiter plates one
day prior to transfection.
To determine AR agonist and antagonist activity of the compounds of the present
invention, the CV-1 cells were transiently transfected by calcium phosphate
coprecipitation according to the procedure of Berger et al., 41 J. Steroid Biochem. Mol.
Biol, 733 (1992) with the following plasmids: pShAR (5 ng/well), MTV-LUC reporter
(100 ng/well), pRS-B-Gal (50 ng/well) and filler DNA (pGEM; 45 ng/well). The receptor
plasmid, pRShAR, contains the human AR under constitutive control of the S V-40
promoter, as more fully described in J.A. Simental et al., "Transcriptional activation and
nuclear targeting signals of the human androgen receptor", 266 J. Biol. Chem., 510 (1991).
The reporter plasmid, MTV-LUC, contains the cDNA for firefly luciferase (LUC)
under control of the mouse mammary tumor virus (MTV) long terminal repeat, a
conditional promoter containing an androgen response element. See e.g., Berger et al.
supra. In addition, pRS-B-Gal, coding for constitutive expression of E. coli Bgalactosidase
(B-Gal), was included as an internal control for evaluation of transfection
efficiency and compound toxicity.
Six hours after transfection, media was removed and the cells were washed with
phosphate-buffered saline (PBS). Media containing reference compounds (i.e.
progesterone as a PR agonist, mifepristone ((llp,17p)-ll-[4-(dimethylamino)phenyl]-17-
hydroxy-17-(l-propynyl)estra-4,9-dien-3-one: RU486; Roussel Uclaf) as aPR antagonist;
dihydrotestosterone (DHT; Sigma Chemical) as an AR agonist and 2-OH-flutamide (the
active metabolite of 2-methyl-N-[4-nitro-3-(trifluoromethyl)phenyl]pronanamide;
Schering-Plough) as an AR antagonist; estradiol (Sigma) as an ER agonist and ICI
164,384 (N-butyl-3;17-dihydroxy-N-methyl-(7-a,17-p)-estra-l)3,5(10)-triene-7-
undecanamide; ICI Americas) as an ER antagonist; dexamethasone (Sigma) as a GR
agonist and RU486 as a GR antagonist; and aldosterone (Sigma) as a MR agonist and
spironolactone ((7-a-[acetylthio]-17-a-hydroxy-3-oxopregn-4-ene-21-carboxylic acid ylactone;
Sigma) as an MR antagonist) and/or the modulator compounds of the present
invention in concentrations ranging from 10" to 10" M were added to the cells. Three
to four replicates were used for each sample. Transfections and subsequent procedures
were performed on a Biomek 1000 automated laboratory work station.
After 40 hours, the cells were washed with PBS, lysed with a Triton X-l 00-based
buffer and assayed for LUC and 13-Gal activities using a luminometer or
spectrophotometer, respectively. For each replicate, the normalized response (NR) was
calculated as:
LUC response/ß-Gal rate
where B-Gal rate = ß-GaMxlO-5/ß-Gal incubation time.
The mean and standard error of the mean (SEM) of the NR were calculated. Data
was plotted as the response of the compound compared to the reference compounds over
the range of the dose-response curve. For agonist experiments, the effective concentration
that produced 50% of the maximum response (ECso) was quantified. Agonist efficacy
was a function (%) of LUC expression relative to the maximum LUC production by the
reference agonist for PR, AR, ER, GR or MR. Antagonist activity was determined by
testing the amount of LUC expression in the presence of a fixed amount of DHT as an AR
agonist and progesterone as a PR agonist at the ECso concentration. The concentration of
test compound that inhibited 50% of LUC expression induced by the reference agonist was
quantified (IC5Q)- In addition, the efficacy of antagonists was determined as a function
(%) of maximal inhibition.
IR Binding assay
AR Bjnding: For the whole cell binding assay, COS-1 cells in 96-well microtiter
plates containing DMEM-10% FBS were transfected as described above with the
95
following plasmid DNA: pRShAR (2 ng/well), pRS-B-Gal (50 ng/well) and pGEM (48
ng/well). Six hours after transfection, media was removed, the cells were washed with
PBS and fresh media was added. The next day, the media was changed to DMEM-serum
free to remove any endogenous ligand that might be complexed with the receptor in the
cells.
After 24 hours in serum-free media, either a saturation analysis to determine the
Kd for tritiated dihydrotestosterone (^H-DHT) on human AR or a competitive binding
assay to evaluate the ability of test compounds to compete with ^H-DHT for AR was
performed. For the saturation analysis, media (DMEM-0.2% CA-FBS) containing ^HDHT
(in concentrations ranging from 12 nM to 0.24 nM) in the absence (total binding) or
presence (non-specific binding) of a 100-fold molar excess of unlabeled DHT were added
to the cells. For the competitive binding assay, media containing 1 nM ^H-DHT and test
compounds in concentrations ranging from 10~10 to 10~6 M were added to the cells.
Three replicates were used for each sample. After three hours at 37°C, an aliquot of the
total binding media at each concentration of ^H-DHT was removed to estimate the amount
of free ^H-DHT. The remaining media was removed, the cells were washed three times
with PBS to remove unbound ligand and cells were lysed with a Triton X-100-based
buffer. The lysates were assayed for amount of bound ^H-DHT and B-Gal activity using a
scintillation counter or spectrophotometer, respectively.
For the saturation analyses, the difference between the total binding and the
nonspecific binding, normalized by the fi-Gal rate, was defined as specific binding. The
specific binding was evaluated by Scatchard analysis to determine the K See e.g.. D. Rodbard, "Mathematics and statistics of ligand assays: an illustrated guide"
In: J. Langon and J.J. Clapp, eds., Ligand Assay, Masson Publishing U.S.A., Inc., New
York, pp. 45-99, (1981), the disclosure of which is herein incorporated by reference. For
the competition studies, the data was plotted as the amount of ^H-DHT (% of control in
the absence of test compound) remaining over the range of the dose-response curve for a
given compound. The concentration of test compound that inhibited 50% of the amount of
bound in the absence of competing ligand was quantified (IC5Q) after log-logit
transformation. The Kj values were determined by application of the Cheng-Prusoff
equation to the IC5Q values, where:
for JH-DHT
(Equation Removed)
After correcting for non-specific binding, IC5Q values were determined. The IC5Q
value is defined as the concentration of competing ligand needed to reduce specific
binding by 50%. The ICso value was determined graphically from a log-logit plot of the
data. The K; values were determined by application of the Cheng-Prusoff equation to the
IC5Q values, the labeled ligand concentration and the K The agonist, antagonist and binding activity assay results of selected androgen
receptor modulator compounds of present invention and the standard reference compounds
on AR, as well as the cross-reactivity of selected compounds on the PR, ER, MR and GR
receptors, are shown in Tables 1-2 below. Efficacy is reported as the percent maximal
response observed for each compound relative to the reference agonist and antagonist
compounds indicated above. Also reported in Tables 1-2 for each compound is its
antagonist potency or ICso (which is the concentration (nM), required to reduce the
maximal response by 50%), its agonist potency or ECso (nM).
Table1 Cotransfection and competitive binding data of selected androgen receptor modulator compounds of present invention and the reference agonist compound, digydrotestosterone (DHY) and reference antagonists compound, 2-hydroxyflutamide (Flut) and casodex (Cas) on ar.
(Table Removed)
Pharmacological and Other Applications
As will be discernible to those skilled in the art, the androgen or progesterone
receptor modulator compounds of the present invention can be readily utilized in
pharmacological applications where AR or PR antagonist or agonist activity is desired and
where it is desired to minimize cross reactivities with other steroid receptor related IRs. In
vivo applications of the invention include administration of the disclosed compounds to
mammalian subjects and in particular to humans.
The following Example provides illustrative pharmaceutical composition
formulations:
EXAMPLE 113
Hard gelatin capsules are prepared using the following ingredients:
Quantity
(mH/capsulel
COMPOUND 153 140
Starch, dried 100
Magnesium stearate 10
Total 250 mg
The above ingredients are mixed and filled into hard gelatin capsules in 250 mg quantities.
A tablet is prepared using the ingredients below:
Quantity
(me/tablet)
COMPOUND 153 ' 140
Cellulose, microcrystalline 200
Silicon dioxide, fumed 10
Stearic acid 10
Total 360 mg
The components are blended and compressed to form tablets each weighing 360 mg.
Tablets, each containing 60 mg of active ingredient, are made as follows:
Quantity
(me/tablet)
COMPOUND 153 60
Starch 45
Cellulose, microcrystalline 35
Polyvinylpyrrolidone (PVP)
(as 10% solution in water) 4
Sodium carboxymethyl starch (SCMS) 4.5
Magnesium stearate 0.5
Talc 1.0
Total 150mg
The active ingredient, starch and cellulose are passed through a No. 45 mesh U.S. sieve
and mixed thoroughly. The solution of PVP is mixed with the resultant powders, which
are then passed through a No. 14 mesh U.S. sieve. The granules so produced are dried at
50°C and passed through a No. 18 mesh U.S. sieve. The SCMS, magnesium stearate and
talc, previously passed through a No. 60 mesh U.S. sieve and then added to the granules
which, after mixing, are compressed on a tablet machine to yield tablets each weighing
150 mg.
Suppositories, each containing 225 mg of active ingredient, may be made as
follows:
Quantity
(me/suppository)
COMPOUND 153 225
Saturated fatty acid glycerides 2.000
Total 2,225 mg
The active ingredient is passed through a No. 60 mesh U.S. sieve and suspended in the
saturated fatty acid glycerides previously melted using the minimum heat necessary. The
mixture is then poured into a suppository mold of normal 2 g capacity and allowed to cool.
An intravenous formulation may be prepared as follows:
Quantity
COMPOUND 153 " lOOmg
isotonic saline 1000 mL
glycerol lOOmL
The compound is dissolved in the glycerol and then the solution is slowly diluted with
isotonic saline. The solution of the above ingredients is then administered intravenously at
a rate of 1 mL per minute to a patient.
The present invention includes any combination of the various species and
subgeneric groupings falling within the generic disclosure. This invention therefore
includes the generic description of the invention with a proviso or negative limitation
removing any subject matter from the genus, regardless of whether or not the excised
material is specifically recited herein.
While in accordance with the patent statutes, description of the various
embodiments and processing conditions have been provided, the scope of the invention is
not to be limited thereto or thereby. Modifications and alterations of the present invention
will be apparent to those skilled in the art without departing from the scope and spirit of
the present invention.
Therefore, it will be appreciated that the scope of this invention is to be defined by
the appended claims, rather than by the specific examples which have been presented by
way of example.





We claim:
1. A heterocyclic [3,2-f]-quinolinone of formula (I), having agonist, partial agonist or antagonist androgen receptor modulator activity:


(Formula Removed)
wherein;
R1 is selected from among hydrogen, halogen, NO2, OR12, SR12, SOR12, SO2R12, NR12R13, C1-C8 alkyl, C1-C8 haloalkyl and C1-C8 heteroalkyl, wherein the alkyl, haloalkyl and heteroalkyl groups may be optionally substituted; R2 is selected from among hydrogen, halogen, CH3, CF3, CHF2, CH2F, CF2CI, CN, CF2OR12, CH2OR, OR12, SR12, SOR12, SO2R12, NR12R13, C1-C8alkyl, C1-C8 haloalkyl, C1-C8 heteroalkyl, C2-C8 alkenyl and C2-C8 alkynyl, wherein
the alkyl, haloalkyl, heteroalkyl, alkenyl and alkynyl groups may be
optionally substituted;
R3 through R8 each independently is selected from among hydrogen,
halogen, OR12, NR12R13, SR12, SOR12, SO2R12, C1-C8 alkylC1-C8 haloalkyl,
C1-C8 heteroalkyl, C2-C8 alkynyl, C2-C8 alkenyl, aryl, heteroaryl and
arylalkyl, wherein the alkyl, haloalkyl, heteroalkyl, alkynyl, alkenyl, aryl,
heteroaryl and arylalkyl groups may be optionally substituted; or
R3 and R5 taken together form a bond; or
R5 and R7 taken together form a bond; or
R4 and R6 taken together form a three- to eight-membered saturated or
unsaturated carbocyclic or heterocyclic ring, wherein the carbocyclic or
heterocyclic ring may be optionally substituted; or
R6 and R8 taken together form a three- to eight-membered saturated or
unsaturated carbocyclic or heterocyclic ring, wherein the carbocyclic or
heterocyclic ring may be optionally substituted;

R9 and R10 each independently is selected from among hydrogen, halogen,
CN, OR12, NR12R13, Cm(R12)2mOR13, SR12, SOR12, SO2R12, NR12C(0)R13, C1-C8
alkyl, C1-C8 haloalkyl, C1-C8 heteroalkyl and arylalkyl, wherein the alkyl,
haloalkyl, heteroalkyl and arylalkyl groups may be optionally substituted;
R12 and R13 each independently is selected from among hydrogen, C1-C8
alkyl,C1-C8 haloaikyl, C1-C8 heteroalkyl, C2-C8 alkenyl, C2-C8 alkynyl,
heteroaryl and aryl, wherein the alkyl, haloaikyl, heteroalkyl, alkenyl,
alkynyl, heteroaryl and aryl groups may be optionally substituted;
R14 is selected from among hydrogen, C1-C8alkyl, C1-C8 haloaikyl, C1-C8
heteroalkyl, aryl, heteroaryl, C(0)R15, CO2R15 and C(0)NR15R16, wherein the
alkyl, haloaikyl, heteroalkyl, aryl and heteroaryl groups may be optionally
substituted;
R15 and R16 each independently is selected from among hydrogen, C1-C8
alkyl, C1-C8 haloalkyl, and C1-C8 heteroalkyl, wherein the alkyl, haloaikyl
and heteroalkyl groups may be optionally substituted;
X is N{R14};
Y is O;
Z is N{R12};
n is 0, 1 or 2; and
m is 0, 1 or 2;
and pharmaceutically acceptable salts thereof.
2. A compound as claimed in claim 1, wherein R2 is selected from among
hydrogen, F, CI, Br, CF3, CF2CI, CF2H, CFH2, C1-C6alkyl, C1-C6 haloalkyl and C1-C6 heteroalkyl, wherein the alkyl, haloaikyl and heteroalkyl groups may be optionally substituted.
3. A compound as claimed in claim 1, wherein R2 is selected from among
CF2OR12, CH2OR12, OR12, SR12, SOR12, SO2R12 and NR12R13. 4.A compound as claimed in claim 1, wherein R2 is selected from among hydrogen, F, CI, Br, CF3, CF2CI, CF2H, CFH2, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 heteroalkyl, C2-C4 alkenyl and C2-C4 alkynyl, wherein the alkyl, haloaikyl, heteroalkyl, alkenyl and alkynyl groups are optionally substituted.

5. A compound as claimed in claim 4, wherein R2 is selected from among hydrogen, F, CI, CF3, CF2C1, CF2H, CFH2 and optionally substituted C1-C4 alkyl.
6. A compound as claimed in claim 1, wherein R9 and R10 each independently is selected from among hydrogen, F, CI, Br, C1-C6 alkyl, C1-C6 haloalkyl and C1-C6 heteroalkyl, wherein the alkyl, haloalkyl and heteroalkyl groups may be optionally substituted
7. A compound as claimed in claim 6, wherein R9 and R10 each independently is selected from among hydrogen, F, CI, C1-C4 alkyl, C1-C4 haloalkyl and C1-C4 heteroalkyl, wherein the alkyl, haloalkyl and heteroalkyl groups may be optionally substituted.
8. A compound as claimed in claim 7, wherein R9 and R10 each independently is
selected from among hydrogen, F and CH3.
9. A compound as claimed in claim 1, wherein R1 is selected from among
hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl and C1-C6 heteroalkyl,
wherein the alkyl, haloalkyl and heteroalkyl groups may be optionally
substituted.
10. A compound as claimed in claim 9, wherein R11 is selected from among
hydrogen, F, CI, C1-C4 alkyl, C1-C4 haloalkyl and C1-C4 heteroalkyl, wherein
the alkyl, haloalkyl and heteroalkyl groups may be optionally substituted.
11. A compound as claimed in claim 9, wherein R1 is hydrogen or F.
12. A compound as claimed in claim 1, wherein R11 is selected from among hydrogen, F, Br, CI, CN, C1-C6alkyl, C1-C6 haloalkyl and C1-C6 heteroalkyl, OR14, NR14R13, SR14, CH2R14, C(0)R14, CO2R14, C(0)NR14R13, SOR14 and SO2R14, wherein the alkyl, haloalkyl and heteroalkyl groups may be optionally substituted.
13. A compound as claimed in claim 12, wherein R11 is selected from among hydrogen, F, CI, OR14, SR14 and NR14R13, CH2R14, C(0)R14, CO2R14, C(0)NR14R13, SOR14, SO2R14 and optionally substituted C1-C4 alkyl.
14. A compound as claimed in claim 13, wherein R11 is selected from among F, CI, OR14 and SR14.
15. A compound as claimed in claim 14, wherein R11 is OR14.

16. A compound as claimed in claim 1, wherein n is 1.
17. A compound as claimed in claim 1, wherein n is 0.
18. A compound as claimed in claim 1, wherein R12 is selected from among
hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-
C6 alkynyl, heteroaryl and aryl, wherein the alkyl, haloalkyl, heteroalkyl,
alkenyl, alkynyl, heteroaryl and aryl groups may be optionally substituted.
19. A compound as claimed in claim 18, wherein R12 is selected from among hydrogen, C1-C4 alkyl, C1-C4 haloalkyl and C1-C4 heteroalkyl, wherein the alkyl, haloalkyl and heteroalkyl groups may be optionally substituted.
20. A compound as claimed in claim 1, wherein R13 is selected from among hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, heteroaryl and aryl, wherein the alkyl, haloalkyl, heteroalkyl, alkenyl, alkynyl, heteroaryl and aryl groups are optionally substituted.

21. A compound as claimed in claim 20, wherein R13 is selected from among hydrogen, C1-C4 alkyl, C1-C4 haloalkyl and C1-C4 heteroalkyl, wherein the alkyl, haloalkyl and heteroalkyl groups may be optionally substituted.
22. A compound as claimed in claim 1, wherein X is NH.
23. A compound as claimed in claim 1, wherein R3 and R4 each independently
is selected from among hydrogen, C1-C6 alkyl, C1-C6 haloalkyl and C1-C6
heteroalkyl, wherein the alkyl, haloalkyl and heteroalkyl groups may be
optionally substituted; or
R3 and R5 taken together form a bond; or
R4 and R6 taken together form a four to six membered saturated or unsaturated carbocyclic or heterocyclic ring, wherein the carbocyclic or heterocyclic ring may be optionally substituted.
24. A compound as claimed in claim 23, wherein R3 and R4 each independently
is selected from among hydrogen, C1-C4 alkyl, C1-C4 haloalkyl and C1-C4
heteroalkyl, wherein the alkyl, haloalkyl and heteroalkyl groups may be
optionally substituted.
25. A compound as claimed in claim 1, wherein R5 and R7 each independently
is selected from among hydrogen, C1-C6 alkyl, C1-C6 haloalkyl and C1-C6

heteroalkyl, wherein the alkyl, haloalkyl and heteroalkyl groups are optionally substituted; or R5 and R7 taken together form a bond.
26. A compound as claimed in claim 25, wherein R5 and R7 each independently is selected from among hydrogen, C1-C4 alkyl, C1-C4 haloalkyl and C1-C4 heteroalkyl, wherein the alkyl, haloalkyl and heteroalkyl groups may be optionally substituted.
27. A compound as claimed in claim 1, wherein R6 and R8 each independently is selected from among hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 heteroalkyl, heteroaryl and aryl, wherein the alkyl, haloalkyl, heteroalkyl, heteroaryl and aryl groups may be optionally substituted; or
R6 and R8 taken together form a three to eight membered saturated or unsaturated carbocyclic or heterocyclic ring, wherein the carbocyclic or heterocyclic ring may be optionally substituted.
28. A compound as claimed in claim 27, wherein R6 and R8 each independently
is selected from among hydrogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4
heteroalkyl, heteroaryl and aryl, wherein alkyl, haloalkyl, heteroaryl and aryl
may be optionally substituted; or
R6 and R8 taken together form a four to six membered saturated or unsaturated carbocyclic or heterocyclic ring, wherein the carbocyclic or heterocyclic ring may be optionally substituted.
29. A compound as claimed in claim 1, wherein:
R1 is selected from among hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl
and C1-C6 heteroalkyl, wherein the alkyl, haloalkyl and heteroalkyl groups
may be optionally substituted;
R2 is selected from among hydrogen, F, CI, Br, CF3, CF2CI, CF2H, CFH2, Ci-
C6 alkyl, C1-C6 haloalkyl and C1-C6 heteroalkyl, wherein the alkyl, haloalkyl
and heteroalkyl groups may be optionally substituted; and
R3 and R4 each independently is selected from among hydrogen, C1-C6 alkyl,
C1-C6 haloalkyl and C1-C6 heteroalkyl, wherein the alkyl, haloalkyl and
heteroalkyl groups may be optionally substituted.
30. A compound as claimed in claim 29, wherein:

R5 through R8 each independently is selected from among hydrogen, C1-C6 alkyl, C1-C6 haloalkyl and C1-C6 heteroalkyl, wherein the alkyl, haloalkyl and heteroalkyl groups may be optionally substituted; or R6 and R8 taken together form a four to six membered saturated or unsaturated carbocyclic or heterocyclic ring, wherein the carbocyclic or heterocyclic ring may be optionally substituted.
31. A compound as claimed in claim 30, wherein:
R9 and R10 each independently is selected from among hydrogen, F, CI, Br,
C1-C6 alkyl, C1-C6 haloalkyl and C1-C6 heteroalkyl, wherein the alkyl,
haloalkyl and heteroalkyl groups may be optionally substituted;
R12 is selected from among hydrogen, C1-C6 alkyl C1-C6 haloalkyl and C1-C6
heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, heteroaryl and aryl, wherein the
alkyl, haloalkyl, heteroalkyl, alkenyl, alkynyl, heteroaryl and aryl groups may
be optionally substituted; and
R14 is selected from among hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6
heteroalkyl, C(0)R15, CO2R15 and C(0)NR15R16, wherein the alkyl, haloalkyl
and heteroalkyl groups may be optionally substituted.
32. The compound of claim 1, wherein:
R5 and R7 taken together form a bond;
R9 and R10 each independently is selected from among hydrogen, halogen, CN, OR12, NR12R13, SR12, SOR12, SO2R12, NR12C(0)R13, Ci-C8 alkyl, Ci-Cs haloalkyl, Ci-Cs heteroalkyl and arylalkyl; and n is 0.
33. A compound as claimed in claim 1, wherein the compound is selected
among:
5,6,7,8-Tetrahydro-7,7-dimethyl-4-trifluoromethyl-pyridino[3,2-f]quinolin-2(1H)-one; 5,6,7,8-Tetrahydro-7,7-diethyl-4-trifluoromethyl-pyridino[3,2-f]quinolin-2(l.H)-one ;
5,6,7,8-Tetrahydro-7,7,8-trimethyl-4-trifluoromethylpyridino[3,2-f]quinolin-2{lH)-one;

8-Ethyl-5,6,7,8-tetrahydro-7,7-dimethyl-4-trifluoromethylpyridino[3,2-f]quinolin-2 [1H)- one;
5,6,7,8-Tetrahydro-7,7-dimethyl-4-trifluoromethyl-8-propylpyridino[3,2-f]quinolin-2(lH)-one ;
8-(2,2,2-Trifluoroethyl)-5,6,7,8-tetrahydro-7,7-dimethyl-4-trifluoromethylpyridino- [3,2-f] -quinolin-2 (1H) -one;
6-Methyl-4-trifluoromethyl-7H-pyrrolo[3,2-f]quinolin-2(lH)-one;
5-Isopropyl-6-methyl-4-trifluoromethyl-7H-pyrrolo[3,2-f]quinolin-2(lH)-one ;
5-Allyl-6-methyl-4-trifluoromethyl-7H-pyrrolo[3,2-f]quinolin-2(lH)-one ;
5-(4-Methoxyphenyl)-6-methyl-4-trifluoromethyl-7H-pyrrolo[3,2-f]quinolin-2(lH)-one;
5-(3-Trifluoromethylphenyl)-6-methyl-4-trifluoromethyl-7H-pyrrolo[3,2-f]quinolin-2(lH)-one ;
4-Trifluoromethyl-5,6,7,8-tetrahydrocyclopentano[g]pyrrolo[3,2-f]quinolin-2{lH)-one;
4-Trifluoromethyl-5,6,7,8,9,10-hexahydrocycloheptano[g]pyrrolo[3,2-f]quinolin-2(1H)-one ;
(±)-4c,5,6,7,7a(cis),8-Hexahydro-8-trifluoroethyl-4-trifluloromethylcyclopentano-[g]pyrrolo[3,2-f]quinolin-2(lH)-one;
(±)-4c,5,6,7,7a(cis),8-Hexahydro-8-ethyl-4-
trifluoromethylcyclopentano[g]pyrrolo-[3,2-f]quinolin-2(lH)-one; (±)-5,6-Dihydro-5,6-cis-dimethyl-7-trifluoroethyl-4-trifluoromethyl-7H-pyrrolo[3,2-f]-quinolin-2(lH)-one;
(±)-4c,5,6,7,7a(cis),8-Hexahydro-8-propyl-4-trifluoromethylcyclopentano-[g]pyrrolo-[3,2-f]quinolin-2(lH)-one;
(±)-4c,5,6,7,7a(cis),8-Hexahydro-8-(3-furanylmethyl)-4 trifluoromethylcyclopentano-[g]pyrrolo[3,2-f]quinolin-2(lH)-one;
(±)-4c,5,6,7,7a(cis),8-Hexahydro-8-(3-thiophenemethyl)-4-trifluoromethylcyclopentano-[g]pyrrolo[3,2-f]quinolin-2(lH)-one;

(±)-4c,5,6,7,7a(cis),8-Hexahydro-8-(2-methylpropyl)-4-trifluoromethylcyclopentano- [g] pyrrolo[3,2-f]quinolin-2 (1H) -one;
(±)-4c,5,6,7,7a(cis),8-Hexahydro-8-(2,2,2-chlorodifluoroethyl)-4-trifluoromethylcyclo-pentano[g]pyrrolo[3,2-f]quinolin-2(lH)-one;
(±)-4c,5,6,7,7a(cis),8-Hexahydro-8-cyclopropylmethyl-4-trifluoromethylcyclopentano- [g] -pyrrolo [3,2-f]quinolin-2 (1H) -one;
(±)-4c,5,6,7,7a(cis),8-Hexahydro-8-(2,2-dimethoxyethyl)-4-trifluoromethylcyclo-pentano [g]pyrrolo [3,2-f] quinolin-2 (1H) -one;
(±)-4c,5,6,7,8,8a(cis)-Hexahydro-9-(2,2,2-trifluoroethyl)-4-trifluoromethyl-9H-cyclo-hexano[g]pyrrolo[3,2-f]quinolin-2(lH)-one ;
(±)-4c,5,6,7,8,9,9a(CIs),10-Octahydro-10-(2,2,2-trifluoroethyl)-4-trifluoromethylcyclo-heptano [g] pyrrolo [3,2-f] quinolin-2 (1H) -one;
(±)-5,6-cis-Dihydro-6-ethyl-5-methyl-7-(2,2,2-trifluoroethyl)-4-trifluoromethyl-7H-pyrrolo[3,2-f]quinolin-2(l.H)-one;
(±)-5,6-cis-Dihydro-5-butyl-6-methyl-7-(2,2,2-trifluoroethyl)-4-trifluoromethyl-7H-pyrrolo[3,2-f] quinolin- 2 (1H) -one;
(±)-5,6-cis-Dihydro-5-(4-nitrophenyl)-6-methyl-7-(2,2,2-trifluoroethyl)-4-trifluoro-methyl-7H-pyrrolo[3,2-f] quinolin-2 (1H) -one;
(±)-5,6-cis-Dihydro-5-(4-dimethylaminophenyl)-6-methyl-7-(2,2,2-trifluoroethyl)-4-trifluoromethyl-7H-pyrrolo[3,2-f]quinolin-2(lH)-one;
(±)-5,6-CIs-Dihydro-5-(4-methoxyphenyl)-6-methyl-7-(2,2,2-trifluoroethyl)-4-trifluoro-methyl-7H-pyrrolo[3,2-f]quinolin-2(lH)-one;
(±)-5,6-cis-Dihydro-5-(3-trifluoromethylphenyl)-6-methyl-7-(2,2,2-tiifluoroethyl)-4-trifluoromethyl-7H-pyrrolo[3,2-f]quinolin-2(lH)-one;
(±)-5,6-cis-Dihydro-5-(4-fluorophenyl)-6-methyl-7-(2,2,2-trifluoroethyl)-4-trifluoro-methyl-7H-pyrrolo[3,2-f]quinolin-2(lH)-one;
(±)-5,6-Dihydro-5-phenyl-7-(2,2,2-trifluoroethyl)-4-trifluoromethyl-7H-pyrrolo[3,2-f]-quinolin-2(lH)-one;
(±)-5,6-cis-Dihydro-5-(4-methoxyphenyl)-6-methyl-4-trifluoromethyl-7H-pyrrolo[3,2-f]-quinolin-2(l.H)-one;

(±)-5,6-cis-Dihydro-5-(4-methoxphenyl)-6-methyl-7-(2,2-dimethoxyethyl)-4-trifluoro-methyl-7H-pyrrolo[3,2-f]quinolin-2(lH)-one;
(±)-5,6-cis-Dihydro-5-isopropyl-6-methyl-7-(2,2,2-trifluoroethyl)-4-trifluoromethyl-7H-pyrrolo [3,2-f]quinolin- 2 (1H) -one;
(±)-5,6-Dihydro-5-ethyl-6-methyl-7-(2,2,2-trifluoroethyl)-4-trifluoromethyl-7H-pyrrolo-[3,2-f]quinolin-2(lH)-one;
(±)-5,6-Dihydro-5-ethyl-6-propyl-7-(2,2,2-trifluoroethyl)-4-trifluoromethyl-7H-pyrrolo-[3,2-f]quinolin-2(lH)-one;
(±)-5,6-Dihydro-5-(2-ethoxycarbonylethyl)-6-methyl-7-(2,2,2-trifluoroethyl)-4-trifluoro-methyl-7H-pyrrolo[3,2-f]quinolin-2(lii)-one;
6-Ethyl-5-methyl-7H-pyrrolo[3,2-f]quinolin-2(lH)-one;
(±)-5,6-cis-Dihydro-5-methyl-6-ethyl-7-(2,2,2-trifluoroethyl)-7H-pyrrolo[3,2-f]quinolin-2( lH)-one;
5,6-Dimethyl-7-(2,2,2-trifluoroethyl)-4-trifluoromethyl-7H-pyrrolo[3,2-f]quinolin-2(lH)-one;
6-Ethyl-5-methyl-7-(2,2,2-trifluoroethyl)-7H-pyrrolo[3,2-f]quinolin-2(lH)-one ;
6-Methyl-7-(2,2,2-trifluoroethyl)-4-trifluoromethyl-7H-pyrrolo[3,2-f]quinolin-2(lH)-one;
6-Ethyl-5-methyl-7-(2,2,2-trifluoroethyl)-4-trifluoromethyl-7H-pyrrolo[3,2-f]-quinolin-2(lH)-one;
5-Ethyl-6-methyl-7-(2,2,2-trifluoroethyl)-4-trifluoromethyl-7H-pyrrolo[3,2-f]-quinolin-2 (1H)-one;
5-Ethyl-6-propyl-7-(2,2,2-trifluoroethyl)-4-trifluoromethyl-7H-pyrrolo[3,2-f]quinolin-2(lH)one;
5,6,7,8-Tetrahydro-8-trifluoroethyl-4-trifluoromethylcyclopentano [g] pyrrolo[3,2-f] -quinolin-2 (1H) - one;
8-Trifluoroethyl-4-trifluoromethyl-6,8-dihydrocyclopentano[g]pyrrolo[3,2-f]quinolin-2 (1H) -one;
9-Trifluoroethyl-4-trifluoromethyl-9H-benzo[g]pyrrolo[3,2-f]quinolin-2(lH)-one;

5-(3-Trifluoromethylphenyl)-6-methyl-7-(2,2,2-trifluoroethyl)-4-trifluoromethyl-7H-pyrrolo[3,2-f]quinolin-2(l.H)-one (Compound no. 160);
5-(4-Fluorophenyl)-6-methyl-7-(2,2,2-trifluoroethyl)-4-trifluoromethyl-7H:-pyrrolo-[3,2-f]-quinolin-2(l.H)-one;
5-(2-Ethoxycarbonylethyl)-6-methyl-7-(2,2,2-trifluoroethyl)-4-trifluoromethyl-7H-pyrrolo[3,2-f]quinolin-2(lH)-one;
5-Hydroxymethyl-6-ethyl-7-(2,2,2-trifluoroethyl)-4-trifluoromethyl-7H-pyirolo[3,2-f]-quinolin-2(l.H)-one ;
5-Methyl-6-(l-hydroxyethyl)-7-(2,2,2-trifluoroethyl)-4-trifluoromethyl-7H-pyrrolo-[3,2-/]-quinolm-2(lJFi)-one;
5-Methyl-6-acetyl-7-(2,2,2-1rifluoroethyl)-4-trifluoromethyl-7H-pyn-olo[3,2-/]-quinolin-2(lH)-one;
5-Formyl-6-methyl-7-(2,2,2-trifluoroethyl)-4-trifluoromethyl-7H-pyrrolo[3,2-f]-quinolin-2(lH)-one;
6-Ethyl-7-(2,2,2-trifluoroethyl)-4-trifluoromethyl-7H-pyrrolo[3,2-f]quinolin-2(lH)-one;
5-Ethoxymethyl-6-ethyl-7-(2,2,2-trifluoroethyl)-4-trifluoromethyl-7H-pyrrolo[3,2-f]-quinolin-2(lH)-one;
6-(l-Methoxyethyl)-5-methyl-7-(2,2,2-trifluoroethyl)-4-trifluoromethyl-7H-pyrrolo [3,2-f]quinolin-2 (1H) -one;
(+)-4c,5,6,7,7a(cis),8-Hexahydro-8-trifluoroethyl-4-trifluoromethylcyclopentano- [g] -pyrrolo [3,2-f]]quinolin-2 (1H) -one;
(-)-4c,5,6,7,7a(cis),8-Hexahydro-8-trifluoroethyl-4-trifluoromethylcyclopentano- [g] -pyrrolo [3,2-f] quinolin-2 (1H) -one;
8-(2,2,2-Trifluoroethyl)-5,6,7,8-tetrahydro-5,7,7-trimethylpyrido[3,2-f]quinolin-2(1H)-one;
(±)-5,6-Dihydro-6-hydroxymethyl-4-trifluoromethylpyrrolo[3,2-/|quinolin-2{lH)-one;
(±)-5,6-Dihydro-7-ethyl-6-hydroxymethyl-4-trifluoromethylpyrrolo[3,2-f]quinolin-2(lfJ)-one;

5-Methyl-7-(2,2,2-trifluoroethyl)-4-trifluoromethylpyrrolo[3,2-f]quinolin-2(lH)-one;
6-Formyl-5-methyl-7-(2,2,2-trifluoroethyl)-4-trifluoromethyl-7H-pyrrolo[3,2-f]-quinolin-2(l.H)-one; and
5,6-Dimethyl-7-(2,2-difluorovinyl)-4-trifluoromethyl-7H-pyrrolo[3,2-f]quinolin-2{lH)-one.
34. A compound as claimed in claim 1, wherein the compound is selected from among:
8-Ethyl-5,6,7,8-tetrahydro-7,7-dimethyl-4-trifluoromethylpyridino[3,2-f]quinolin-2(lJi)-one;
5,6,7,8-Tetrahydro-7,7-dimethyl-4-trifluoromethyl-8-propylpyridino[3, 2-f]quinolin-2(lii)-one ;
8-(2,2,2-Trifluoroethyl)-5,6,7,8-tetrahydro-7,7-dimethyl-4-trifluoromethylpyridino-[3,2-f]-quinolin-2 {lH)-one; (±)-4c,5,6,7,7a(cis),8-Hexahydro-8-trifluoroethyl-4-trifluoromethylcyclopentano-[g]pyrrolo[3,2-f]quinolin-2(lH)-one;
(±)-4c,5,6,7,7a(cis),8-Hexahydro-8-ethyl-4-trifluoromethylcyclopentano[g]-pyrrolo[3,2-f]-quinolin-2(lH)-one;
(±)-5,6-Dihydro-5,6-cis-dimethyl-7-trifluoroethyl-4-trifluoromethyl-7H-
pyrrolo[3,2-f]-quinolin-2 (1H) -one;
(±)-4c,5,6,7,7a(cis),8-Hexahydro-8-propyl-4-
trifluoromethylcyclopentano[g]pyrrolo-[3,2-f]quinolin-2(1H)-one;
(±)-4c,5,6,7,7a(cis),8-Hexahydro-8-(2,2,2-chlorodifluoroethyl)-4-
trifluoromethylcyclo-pentano-[g]-pyrrolo[3,2-f]quinolin-2(lH)-one;
(±)-4c,5,6,7,7a(cis),8-Hexahydro-8-cyclopropylmethyl-4-trifluoromethylcyclopentano- [g]pyrrolo[3,2-f]quinolin-2 (1H) -one;
(±)-4c,5,6,7,8,8a(cis)-Hexahydro-9-(2,2,2-trifluoroethyl)-4-trifluoromethyl-9H-cyclo-hexano[g]pyrrolo[3,2-f]quinolin-2(lH)-one; (±)-5,6-cz's-Dihydro-6-ethyl-5-methyl-7-(2,2,2-trifluoroethyl)-4-trifluoromethyl-7H-pyrrolo[3,2-f]quinolin-2(lH)-one;

(±)-5,6-cis-Dihydro-5-butyl-6-methyl-7-(2,2,2-trifluoroethyl)-4-
trifluoromethyl-7H-pyrrolo[3,2-f]quinolin-2(lH)-one;
(±)-5,6-Dihydro-5-ethyl-6-methyl-7-(2,2,2-trifluoroethyl)-4-trifluoromethyl-
7H-pyrrolo[3,2-f]quinolin-2(lH)-one;
(±)-5,6-Dihydro-5-ethyl-6-propyl-7-(2,2,2-trifluoroethyl)-4-trifluoromethyl-
7H-pyrrolo[3,2-f]quinolin-2(lH)-one;
(±)-5,6-cis-Dihydro-5-methyl-6-ethyl-7-(2,2,2-trifluoroethyl)-7H-pyrrolo[3,2-
f]-quinolin-2(lH)-one;
5,6-Dimethyl-7-(2,2,2-trifluoroethyl)-4-trifluoromethyl-7H-pyrrolo[3,2-f]quinolin-
2(lH)-one;
6-Methyl-7-(2,2,2-trifluoroethyl)-4-trifluoromethyl-7H-pyrrolo[3,2-f]quinolin-2(lH)-one;
6-Ethyl-5-methyl-7-(2,2,2-trifluoroethyl)-4-trifluoromethyl-7H-pyrrolo[3,2-f]-quinolin-2(lH)-one;
5-Ethyl-6-methyl-7-(2,2,2-trifluoroethyl)-4-trifluoromethyl-7H-pyrrolo[3,2-y]-quinolin-2( 1H)-one;
5,6,7,8-Tetrahydro-8-trifluoroethyl-4-
trifluoromethylcyclopentano[g]pyrrolo[3,2-f]-quinolin-2(lH)-one; 6-Trifluoroethyl-4-trifluoromethyl-6,7,8,9-tetrahydrocyclopetano[i]pyrrolo[2,3-g]-qumolin-2( 1 H)-one; (+)-4c,5,6,7,7a(cis),8-Hexahydro-8-trifluoroethyl-4-trifluoromethylcyclopentano- [g] -pyrrolo [3,2-f]quinolin-2 (1H) -one; (-)-4c,5,6,7,7a(cis),8-Hexahydro-8-trifluoroethyl-4-trifluoromethylcyclopentano- [g] -pyrrolo [3,2 -f]quinolin-2 (1H) -one; and
8-(2,2,2-Trifluoroethyl)-5,6,7,8-tetrahydro-5,7,7-trimethylpyrido[3,2-f]quinolin-2( l.H)-one.
35. A compound as claimed in claim 1, wherein the compound provides 50% maximal activation of AR at a concentration of less than 100 nM.
36. A compound as claimed in claim 1, wherein the compound provides 50%

maximal activation of AR at a concentration of less than 50 nM.
37. A compound as claimed in claim 1, wherein the compound provides 50% maximal activation of AR at a concentration of less than 20 nM.
38. A compound as claimed in claim 1, wherein the compound provides 50% maximal activation of AR at a concentration of less than 10 nM.
39. The compound of formula (I) as claimed in claim 1, as and when used in a
pharmaceutical composition along with a pharmaceutically acceptable
carrier.



Documents:

01284-delnp-2003-abstract.pdf

01284-delnp-2003-claims.pdf

01284-delnp-2003-correspondence-others.pdf

01284-delnp-2003-description (complete)-01-10-2008.pdf

01284-delnp-2003-description (complete)-18-07-2008.pdf

01284-delnp-2003-description (complete).pdf

01284-delnp-2003-form-1.pdf

01284-delnp-2003-form-18.pdf

01284-delnp-2003-form-2.pdf

01284-delnp-2003-form-3.pdf

01284-delnp-2003-form-5.pdf

01284-delnp-2003-pct-101.pdf

01284-delnp-2003-pct-210.pdf

01284-delnp-2003-pct-220.pdf

01284-delnp-2003-pct-304.pdf

01284-delnp-2003-pct-401.pdf

01284-delnp-2003-pct-409.pdf

01284-delnp-2003-pct-416.pdf

1284-DELNP-2003-Abstract-(01-10-2008).pdf

1284-DELNP-2003-Abstract-(18-07-2008).pdf

1284-DELNP-2003-Claims-(18-07-2008).pdf

1284-DELNP-2003-Claims-(23-09-2008).pdf

1284-DELNP-2003-Claims-(30-09-2008).pdf

1284-delnp-2003-complete specification (granted).pdf

1284-DELNP-2003-Correspondence-Others-(18-07-2008).pdf

1284-DELNP-2003-Correspondence-Others-(23-09-2008).pdf

1284-DELNP-2003-Description (Complete)-(01-10-2008).pdf

1284-DELNP-2003-Form-1-(01-10-2008).pdf

1284-DELNP-2003-Form-1-(18-07-2008).pdf

1284-DELNP-2003-Form-2-(01-10-2008).pdf

1284-DELNP-2003-Form-2-(18-07-2008).pdf

1284-DELNP-2003-Form-3-(18-07-2008).pdf

1284-DELNP-2003-Form-3-(23-09-2008).pdf

1284-DELNP-2003-GPA-(18-07-2008).pdf

1284-DELNP-2003-Others-Document-(18-07-2008).pdf

1284-DELNP-2003-Others-Document-(23-09-2008).pdf

1284-DELNP-2003-Petition-137-(18-07-2008).pdf

1284-DELNP-2003-Petition-138-(18-07-2008).pdf


Patent Number 227582
Indian Patent Application Number 01284/DELNP/2003
PG Journal Number 05/2009
Publication Date 30-Jan-2009
Grant Date 14-Jan-2009
Date of Filing 13-Aug-2003
Name of Patentee LIGAND PHARMACEUTICALS INCORPORATED
Applicant Address 10275 SCIENCE CENTER DRIVE, SAN DIEGO, CALIFORNIA 92121, U.S.A.
Inventors:
# Inventor's Name Inventor's Address
1 LIN ZHI 7794 ROAN ROAD, SAN DIEGO, CALIFORNIA 92129, U.S.A.
2 CORNELIS ARJAN VAN OEVEREN 7675 PALMILLA DRIVE, #6315, SAN DIEGO, CALIFORNIA 92122, U.S.A.
3 JYUN-HUNG CHEN 7614 PALMILLA DRIVE, #58, SAN DIEGO, CALIFORNIA 92122, U.S.A.
4 ROBERT I. HIGUCHI 434 MARVIEW DRIVE, SOLANA BEACH, CALIFORNIA 92075, U.S.A.
PCT International Classification Number C07D 471/00
PCT International Application Number PCT/IB02/00537
PCT International Filing date 2002-02-23
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 60/271,189 2001-02-23 U.S.A.