WO 2006/124581 PCT/US2006/018420
PYRROLOBENZODIAZEPINES AND HETEROCYCLIC CARBOXAM1DE
DERIVATIVES AS FOLLICLE STIMULATING HORMONE RECEPTOR (FSH-R)
ANTAGONISTS
This application claims benefit of priority to U.S. Provisional Patent
Application No. 60/680,235 filed May 12, 2005, which is hereby incorporated in its
entirety.
BACKGROUND OF THE INVENTION
The present invention relates to pyrrolobenzodiazepines and derivatives
thereof having antagonist activity on the FSH receptor, and to their use as
contraceptives.
Reproduction in women depends upon the dynamic interaction of several
compartments of the female reproductive system. The hypothalamic-pituitary-
gonadal axis orchestrates a series of events affecting the ovaries and the uterine-
endometrial compartment that leads to the production of mature ova, ovulation, and
ultimately appropriate conditions necessary for fertilization. Specifically, luteinizing
hormone-releasing hormone (LHRH), released from the hypothalamus, initiates the
release of the gonadotropins, luteneizing hormone (LH) and follicle stimulating
hormone (FSH) from the pituitary. These hormones act directly on the ovary to
promote the development of selected follicles by inducing granuiosa and theca cell
proliferation and differentiation. FSH stimulates aromatization of androgens to
estrogens and increases the expression of LH receptors in the theca cells. The
follicles, in turn, secrete steroids (estradiol, progesterone) and peptides (inhibin,
activin). Estradiol and inhibin levels progressively increase during the follicular phase
of the menstrual cycle until ovulation. Inhibin decreases FSH secretion from the
pituitary gland, while estradiol acts on the hypothalamus and pituitary to induce the
LH surge in mid-cycle, which results in ovulation. Afterwards, the post-ovulation,
ruptured follicle forms the corpus luteum, which produces progesterone. Ovarian
hormones, in turn, regulate the secretion of gonadotropins through a classical long-
loop negative feedback mechanism. The elucidation of these control mechanisms
has provided opportunities for the development of effective strategies to control
fertility, including both enhancement of fertility and contraception. For recent reviews
of FSH action see: "FSH Action and Intraovarian Regulation", B.C.J.M. Fauser Editor,
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WO 2006/124581 PCT/US2006/018420
Parthenon Publishing Group, Vol. 6,1997 and A.J. Hsueh, T. Bicsak, X.-C. Ja, K.D.
Dahl, B.C.J.M. Fauser, A.B. Galway, N. Czwkala, S. Pavlou, H. Pakoff, J. Keene, I.
Boime, Granulosa "Cells as Hormone Targets: The Role of Biologically Active
Follicle-Stimulating Hormone in Reproduction", Rec. Prog. Horm. Res., 45, 209-
227,1989.
Current hormonal contraception methods are steroidal in nature (progestins
and estrogens) and modulate long-loop feedback inhibition of gonadotropin
secretion, as well as affecting peripheral mechanisms such as sperm migration and
fertilization. The development of specific antagonists of the receptor for FSH (FSH-R)
would provide an alternative strategy for hormonal contraception. Such antagonists
would block FSH-mediated follicular development leading to a blockade of ovulation,
thereby producing the desired contraceptive effect. Support for the effectiveness of
this strategy is provided by the mechanism that causes resistant ovary syndrome
which results in infertility in women. The infertility experienced by these women is the
result of non-functional FSH receptors (K. Aittomaki, J.L.D. Lucena, P. Pakarinen, P.
Sistonen, J. Tapainainnen, J. Gromoll, R. Kashikari, E.-M. Sankila, H. Lehvaslaiho,
A.R. Engel, E. Nieschlag, I. Huhtaniemi, A. de la Chapelle "Mutations in the Follicle-
Stimulating Hormone Receptor Gene Causes Hereditary Hypergonadotropic Ovarian
Failure" Cell, 82, 959-968,1995). This approach to contraception may be applicable
to men as well, since idiopathic male infertility seems to be related to a reduction in
FSH binding sites. In addition, men with selective FSH deficiency are oligo- or
azoospermic with normal testosterone levels and present normal virilization (G.
Lindstedt, E. Nystrom, C. Matthews, I. Ernest, P.O. Janson, K. Chattarjee, Clin. Lab.
Med., 36, 664,1998). Therefore, orally active, low molecular weight FSH antagonists
may provide a versatile novel method of contraception. Such an antagonist could be
expected to interfere with follicle development and thus ovulation, while maintaining
sufficient estrogen production and beneficial effects on bone mass.
FSH actions are mediated by binding of the hormone to a specific
transmembrane G protein-coupled receptor exclusively expressed in the ovary,
leading to activation of the adenyl cyclase system and elevation of intracellular levels
of the second messenger cAMP (A, Mukherjee, O.K. Park-Sarge, K. Mayo,
Endocrinology, 137, 3234 (1996)).
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WO 2006/124581 PCT/US2006/018420
SUMMARY OF THE INVENTION
Some embodiments of the invention include a compound of formula I:
or a pharmaceutically acceptable salt thereof,
wherein
R1 and R2 are independently selected from hydrogen, (C1-C6) alkyl, halogen,
cyano, trifluoromethyl, hydroxyl, (C1-C6) alkoxy, -OCF3, carboxy, (C1-C6
alkoxy)carbonyl, -CONH2, -CONH[(C1-C6) alkyl], -CON[(C1-C6) alkyl]2,amino, (C1-C6)
alkylamino or -NHCO[(C1-C6) alkyl];
R3 is a substituent selected from hydrogen, (C1-C6) alkyl, (C1-C6) alkoxy,
hydroxy, amino, (C1-C6) aikylamino, -C(O)(C1-C6)a!kyl, or halogen;

wherein R5, R6, R7, R5, R9 and R10 are independently, selected from
the group consisting of hydrogen, alkyl, (C1-C6)a!kyl, alkoxy, (C1-C6) alkoxy,
hydroxyalkyl, hydroxy(C1-C6) alkyl, alkyloxyalkyl, (C1-C6)alkoxy(C1-C6)aIkyl, (C2-C7)
acyloxy (C1-C6)alkyl, (C1-C6alkyl) carbonyl, (C2-C6) alkenyl, (C2-C6) alkynyl, (C3-C8)
cycloalkyl, formyl, (C3-C8)cycloalkylcarbonyl, carboxy, (C1-C6)alkoxycarbonyl, (C3-
C8cycloalkyl) oxycarbonyl, aryl(C1-C6)alkyloxycarbonyl, carbamoyl,-O-CH2- CH=CH2,
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(C1-C6)alkyl substituted with 1-3 halogen atoms, trihalomethyl, trifluoromethyl,
halogen, OCF3, thioalkyl, thio(C1-C6) alkyl, -C(O) alkyl, -C(O)aryl optionally
substituted by alkyl; hydroxy, -CH(OH)alkyl, -CH(alkoxy)alkyl, nitro, -SO2alkyl, (C1-C6)
alkylsulfonyl, aminosulfonyl, (C1-C6) alkylaminosulfonyl, -SO2NHR11, -SO2N(R11)2, -
OC (O) N [(C1-C6)a!kyl] 2,-CONH [(C1-C6) alkyl],-CON [(C1-C6) alkyl] 2,-(CH2)pCN ,
(C1-C6) alkylamino, di-(C1-C6) alkylamino, (C1-C6) alkyl di-(C1-C6) alkylamino,
-(CH2)pNR13R14, -(CH2)pCONR13R14, -(CH2)PCOOR12, -CH=NOH, -CH=NO-(C1-C6)

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R23 is alkyl, C1-C6 alkyl, or an optionally substituted (C6-C20)
aralkyl.
Other embodiments of the invention provide methods of making such
compounds or pharmaceutically acceptable salts thereof.
Other embodiments of the inventions will be apparent to those of skill in the
art upon reading of the rest of this specification and claims.
DETAILED DESCRIPTION OF THE INVENTION
In some embodiments, the invention provides compounds of formula (I):

or a pharmaceutically acceptable salt thereof,
wherein
R1 and R2 are independently selected from hydrogen, (C1-C6) alkyl, halogen,
cyano, trifluoromethyl, hydroxyl, (C1-C6) alkoxy, -OCF3, carboxy, (C1-C6
alkoxy)carbonyl, -CONH2, -CONH[(C1-C6) alkyl], -CON[(C1-C6) alkyl]2, amino, (C1-C6)
alkylamino or -NHCO[(C1-C6) alkyl];
R3 is a substituent selected from hydrogen, (C1-C6) alkyl, (C1-C6) alkoxy,
hydroxy, amino, (C1-C6) atkylamino, -C(O)(C1-C6)alkyl, or halogen;


WO 2006/124581 PCT/US2006/018420
wherein R5, R6, R7, R8, R9 and R10 are independently, selected from
the group consisting of hydrogen, alkyl, (C1-C6)alkyl, alkoxy, (C1-C6) alkoxy,
hydroxyalkyl, hydroxy(C1-C6) alkyl, alkyloxyalkyl, (C1-C6)alkoxy(C1-C6)alkyl, (C2-C7)
acyloxy (C1-C6)alkyl, (C1-C6alkyl) carbonyl, (C2-C6) alkenyl, (C2-C6) alkynyl, (C3-C8)
cycloalkyl, formyl, (C3-C8)cycloalkylcarbonyl, carboxy, (C1-C6)alkoxycarbonyl, (C3-
C8 cycloalkyl) oxycarbonyl, aryl(C1-C6)alkyloxycarbonyl, carbamoyl,-O-CH2- CH=CH2,
(C1-C6)alkyl substituted with 1-3 halogen atoms, trihalomethyl, trifluoromethyl,
halogen, OCF3, thioalkyl, thio(C1-C6) alkyl, -C(O) alkyl, -C(O)aryl optionally
substituted by alkyl; hydroxy, -CH(OH)alkyl, -CH(alkoxy)alkyl, nitro, -SO2alkyl, (C1-C6)
alkylsulfonyl, aminosulfonyl, (C1-C6) alkylaminosulfonyl, -SO2NHR11, -SO2N(R11)2, -
OC (O) N [(C,-C6)alkyl] 2,-CONH [(C1-C6) alkyl],-CON [(C1-C6) alkyl] 2,-(CH2)pCN ,
(C1-C6) alkylamino, di-(C1-C6) alkylamino, (C1-C6) alkyl di-(C1-C6) alkylamino,
-(CH2)pNR13R14, -(CH2)pCONR13R14, -(CH2)PCOOR12, -CH=NOH, -CH=NO-(C1-C6)

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M is selected from the group consisting of
wherein R17and R18 are optionally substituted aryl;
R19, R20, R21 and R22are each independently (C1-C6)
alkyl;
R23 is alkyl, C1-C6 alkyl, or an optionally substituted (C6-
C20) aralkyl.
Acyl, as used herein, refers to the group R-C(=O)- where R is an alkyl group
of 1 to 6 carbon atoms. For example, a C2 to C7 acyl group refers to the group R-
C(=O)- where R is an alkyl group of 1 to 6 carbon atoms. One suitable acyl is acetyl.
Alkenyl, as used herein, refers to an alkyl group having one or more double
carbon-carbon bonds. Example alkenyl groups include, but are not limited to, ethenyl,
propenyl, butenyl, pentenyl, hexenyl, butadienyl, pentadienyl, and hexadienyl. In
some embodiments, alkenyl groups can be substituted with up to four substituent
groups, as described below. Suitably the alkenyl is a 2 to 6 carbon moiety.
Alkoxy. as used herein, refers to an -O-alkyl group. Example alkoxy groups
include methoxy, ethoxy, propoxy (e.g., n-propoxy and isopropoxy), t-butoxy, and the
like. An alkoxy group can contain from 1 to about 20,1 to about 10,1 to about 8,1 to
about 6,1 to about 4, or 1 to about 3 carbon atoms. In some embodiments, alkoxy
groups can be substituted with up to four substituent groups, as described below.
Alkoxyalkyl, employed alone or in combination with other terms, refers to an
alkoxy, as herein before defined, which is further covalently bonded to an
unsubstituted (C1-C10) straight chain or unsubstituted (C2-C10) branched-chain
hydrocarbon. Examples of alkoxyalkyl moieties include, but are not limited to,
chemical groups such as methoxymethyl, -CH2CH(CH3)OCH2CH3, and homologs,
isomers, and the like. In certain embodiments the alkoxyalkyl moiety is a (C1
C6)alkoxy(C1-C6)alkyl or a (C1-C4)alkoxy(C1-C4)alkyl moiety.
Alkoxycarbonyl, employed alone or in combination with other terms, is defined
herein as, unless otherwise stated, an alkoxy group, as herein before defined, which
is further bonded to a carbonyl group to form an ester moiety. Examples of
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WO 2006/124581 PCT/US2006/018420
alkoxycarbonyl moieties include, but are not limited to, chemical groups such as
methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl, sec-butoxycarbonyl, tert-
butoxycarbonyl, decanoxycarbonyl, and homologs, isomers, and the like.
Alkyl is meant to refer to a saturated hydrocarbon group which is straight-
chained or branched. Example alkyl groups include, but are not limited to, methyl
(Me), ethyl (Et), propyl (e.g., n-propyl and isopropyl), butyl (e.g., n-butyl, isobutyl, s-
butyl, t-butyl), pentyl (e.g., n-pentyl, isopentyl, neopentyl) and the like. Alkyl groups
can contain from 1 to about 20,1 to about 10,1 to about 8,1 to about 6,1 to about 4,
or 1 to about 3 carbon atoms. In some embodiments, alky] groups can be substituted
with up to four substituent groups, as described below. Lower alkyl is intended to
mean alkyl groups having up to six carbon atoms.
Alkylamino, employed alone or in combination with other terms, refers to a
moiety with one alkyl group, wherein the alkyl group is an unsubstitued (C1-C6)
straight chain herein before defined alkyl group or an unsubstitued (C3-C8) herein
before defined cycloalkyl group. Examples of alkylamino moieties include, but are
not limited to, chemical groups such as -NH(CH3), -NH(CH2CH3), -NH-cyclopentyl,
and homologs, and the like.
Alkylaminosulfonyl employed alone, or unless otherwise stated, is an
alkylamino moiety, as herein before defined, which is further bonded to a sulfonyl
group.
Alkylsulfonyl, as used herein, refers to the group R-S(O)2- where R is an alkyl
group, as herein before defined.
Alkynyl, as used herein, refers to an alkyl group having one or more triple
carbon-carbon bonds. Examples of alkynyl groups include, but are not limited to,
ethynyl, propynyl, butynyl, pentynyl, and the like. In some embodiments, alkynyl
groups can be substituted with up to four substituent groups, as described below.
The alkynyl moiety is suitably a 2 to 6 carbon atom alkynyl.
Aroyl, as used herein, refers to the group Ar-C(=O)- where Ar is aryl as
defined below. For example, a C6 to C14 aroyl moiety refers to the group Ar-C(=O)-
where Ar is an aromatic 6 to 14 or 5 to 13 membered carbocylic ring.
Aryl, as used herein, refers to aromatic carbocyclic groups including
monocyclic or polycyclic aromatic hydrocarbons such as, for example, phenyl, 1-
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WO 2006/124581 PCT/US2006/018420
naphthyl, 2-naphthyl, anthracenyl, phenanthrenyl, and the like. In some
embodiments, aryl groups have from 5 to about 20 carbon atoms. In some preferred
embodiments, aryl groups are phenyl or naphthyl groups that optionally contain up to
four, preferably up to 2, substituent groups as described below. The aryl moiety is
suitably a 6 to 14 carbon atom moiety.
Arylalkyl or aralkyl, as used herein, refers to a group of formula -alkyl-aryl,
wherein aryl is as herein before defined. Preferably, the alkyl portion of the arylalkyl
group is a lower alkyl group, i.e., a C1-C6 alkyl group, more preferably a C1-C3 alkyl
group. Examples of aralkyl groups include, but are not limited to, benzyl and
naphthylmethyl groups. In some preferred embodiments, arylalkyl groups can be
optionally substituted with up to four, preferably up to 2, substituent groups.
Aryloxy, as used herein, refers to an -O-aryl group, wherein aryl is as
hereinbefore defined for example and not limitation, phenoxy.
Carbamoyl, as used herein, refers to the group, -C(=O)N<.
Carbonyl, employed alone or in combination with other terms, is defined
herein as, unless otherwise stated, a bivalent one-carbon moiety further bonded to

Carboxy as employed herein refers to -COOH.
Cyano, as used herein, refers to CN.
Cycloalkyl, as used herein, refers to non-aromatic carbocyclic groups
including cyclized alkyl, alkenyl, and alkynyl groups. Cycloalkyl groups can be
monocyclic (e.g., cyclohexyl) or poly-cyclic (e.g. 2, 3, or 4 fused ring) ring systems.
Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl,
cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl,
cycloheptatrienyl, norbornyl, norpinyl, norcarenyl, adamantyl, and the like. Also
included in the definition of cycloalkyl are moieties that have one or more aromatic
rings fused (i.e., having a bond in common with) to the cycloalkyl ring, for example,
benzo derivatives of cyclopentane (indanyl), cyclohexane (tetrahydronaphthyl), and
the like.
Cycloalkylalkyl, as used herein, refers to a group of formula -alkyl-cycloalkyl,
for example a cyclopropylmethyl group. The alkyl group is suitably a C1 to C6 alkyl as
defined above and the cycloalkyl group is as defined above.
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Cycloalkylcarbonyl, as used herein, refers to a group of formula -carbonyl-
cycloalkyl, for example cyclohexylcarbonyl. The cycloalkyl moiety is as defined
above.
Dialkylamino, employed alone or in combination with other terms, or unless
otherwise stated, is a moiety with two independent alkyl groups, wherein the alkyl
groups are unsubstitued (C1-C6) straight chain herein before defined alkyl groups or
unsubstitued (C3-C8) herein before defined cycloalkyl groups. The two groups may
be linked together to form an unsubstituted (C1-C6) -alkylene- group. Examples of
dialkylamino moieties include, but are not limited to, chemical groups such as
and homologs, and the like.
Dialkylaminoalkyl employed alone or in combination with other terms, or
unless otherwise stated, is a dialkylamino moiety, as herein before defined, which is
further covalently bonded to a straight chain alkyl group of 1-6 carbon atoms.
Examples of dialkylaminoalkyl moieties include, but are not limited to, chemical
groups such as -CH2N(CH3)2, -CH2CH2N(CH2CH3)2l -CH2CH2CH2NCH3(CH2CH3),
and homologs, and the like.
Halo or halogen includes fluoro, chloro, bromo, and iodo.
HOnig's Base is N,N-diisopropylethylamine, also indicated herein as i-Pr2NEt.
Hydroxy or hydroxyl, as used herein, refers to OH.
Hydroxyalkyl, employed alone or in combination with other terms, is defined
herein as, unless otherwise stated, a (C1-C10) straight chain hydrocarbon, e.g. a (C1-
C6) alkylterminally substituted with a hydroxyl group. Examples of hydroxyalkyl
moieties include, but are not limited to, chemical groups such as -CH2OH, -
CH2CH2OH, -CH2CH2CH2OH, and higher homologs.
Nitro, employed alone or in combination with other terms, is defined herein
as, -NO2.
Substituted, as used herein, refers to a moiety, such as an aryl or heteroaryl,
having from 1 to about 5 substituents, and more preferably from 1 to about 3
substituents independently selected from a halogen atom, a cyano group, a nitro
group, a hydroxyl group, a C1-C6 alkyl group, or a C1-C6 alkoxy group. Preferred
substituents are a halogen atom, a hydroxyl group, or a C1-C6 alkyl group.
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Thioalkyl, employed alone or in combination with other terms, is defined
herein as sulfur covalently bonded to an alkyl group e.g. a (C1-C6) alkyl group as
defined above.
At various places in the specification, substituents of compounds of the
invention are disclosed in groups or in ranges. It is specifically intended that the
invention include each and every individual subcombination of the members of such
groups and ranges. For example, the term C1-6 alkyl is specifically intended to
individually disclose methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, isobutyl, etc.
Some embodiments provide such compounds wherein R15 and R16 are each
hydrogen; and t is 1. Still further embodiments provide compounds wherein M is
selected from the group consisting of
In other embodiments, the invention provides such compounds wherein M is selected
from the group consisting of
In some embodiments, Q is (a) and, thus, B has the formula:

In some embodiments, the invention provides compounds wherein R1, R2 and
R3 are each hydrogen.
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In some embodiments, the invention provides compounds of formula I having
the Formula:
or a pharmaceutically acceptable salt thereof. In some such embodiments, R5 is
selected from H, or C1-C3 alkyl. In some further embodiments, R8 and R9 are
independently selected from H, C1-C3 alkyl, or C1-C3 alkoxy.
In other such embodiments, R5 is selected from H, or C1-C3 alkyl; and R8 and
R9 are independently selected from H, C1-C3 alkyl, or C1-C3 alkoxy. In some further
embodiments, M is
wherein R17is an optionally substituted aryl. In some embodiments, R17 is phenyl,
optionally substituted with from 1 to 3 substitutents selected from C1-C3 alkyl, C1-C3
alkoxy, and halogen. In some embodiments, C1-C3 alkoxy is methoxy.
In some embodiments, R5 is selected from H, or C1-C3 alkyl; and R8 and R9
are independently selected from H, C1-C3 alkyl, or C1-C3 alkoxy and M is
wherein R18 is an optionally substituted aryl. In some such embodiments, R18 is
phenyl, optionally substituted with from 1 to 3 substitutents selected from C1-C3 alkyl,
C1-C3 alkoxy, and halogen. In some embodiments, the halogen is chlorine.
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In some embodiments, R5 is selected from H, or C1-C3 alkyl; and R8 and R9
are independently selected from H, C1-C3 alkyl, or C1-C3 alkoxy and M is
wherein R19 is C1-C6 alkyl, preferably methyl.
In some embodiments, R5 is selected from H, or C1-C3 alkyl; and R8 and R9
are independently selected from H, C1-C3alkyl, C1-C3 alkoxy and M is

wherein R20 is C1-C6 alkyl, preferably methyl.
In some embodiments, R5 is selected from H, or C1-C3 alkyl; and R8 and R9
are independently selected from H, C1-C3 alkyl, or C1-C3 alkoxy and M is

wherein R21 and R22 are each independently C1-C6 alkyl. In some embodiments, the
invention provides such compounds where R21 and R22 are the same. In some
embodiments, R21 and R22 are each methyl.
In some embodiments, R5 is selected from H, or C1-C3 alkyl; and R8 and R9
are independently selected from H, C1-C3 alkyl, or C1-C3 alkoxy and M is

In some embodiments, R5 is selected from H, and C1-C3 alkyl; and R8 and R9
are independently selected from H, C1-C3 alkyl, C1-C3 alkoxy and M is

wherein R23 is optionally substituted C5-C20 aralkyl, preferably benzyl.
In some embodiments, the invention provides compounds according to claim
1, wherein M is
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wherein R17 is an optionally substituted aryl. In some embodiments, the invention
further provides such compounds wherein R17 is a phenyl, optionally substituted with
from 1 to 3 substituents selected from C1-C3 alkyl, C1-C3 alkoxy, and halogen. In
some embodiments, the C1-C3 alkoxy of said R17 is methoxy.
In some such embodiments, M is
wherein R18 is an optionally substituted aryl. In some such embodiments, R18 is a
phenyl, optionally substituted with from 1 to 3 substituents selected from C1-C3 alkyl,
C1-C3 alkoxy, and halogen, preferably chlorine.
In other embodiments, the invention provides compounds of formula I, and
pharmaceutically acceptable salts thereof, M is

wherein R19 is C1-C6 alkyl, preferably methyl.
In other embodiments, the invention provides compounds of formula I, and
pharmaceutically acceptable salts thereof, wherein M is
wherein R2o is C1-C6 alkyl, preferably methyl.
In other embodiments, the invention provides compounds of formula I, and
pharmaceutically acceptable salts thereof, M is

wherein R21 and R22 are each independently C1-C6 alkyl. In some embodiments, R21
and R22 are the same. In some such embodiments, R21 and R22 are each methyl.
In other embodiments, the invention provides compounds of formula I, and
pharmaceutically acceptable salts thereof, wherein M is

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It is understood by those practicing the art that some of the compounds of this
invention, depending on the definition of the various substituents, can contain one or
more asymmetric centers, and can give rise to enantiomers and diastereomers. The
present invention includes all stereoisomers including individual diastereomers and
resolved, enantiomerically pure R and S stereoisomers; as well as racemates, and all
other mixtures of R and S stereoisomers and pharmaceutically acceptable salts
thereof, which possess the indicated activity. Optical isomers may be obtained in
pure form by standard procedures known to those skilled in the art. it is also
understood that this invention encompasses all possible regioisomers, E-Z isomers,
endo-exo isomers, and mixtures thereof which posses the indicated activity. Such
isomers can be obtained in pure form by standard procedures known to those skilled
in the art.
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It is understood by those practicing the art that some of the compounds of this
invention, depending on the definition of B, may be chiral due to hindered rotation,
and give rise to atropisomers which can be resolved and obtained in pure form by
standard procedures known to those skilled in the art. Also included in this invention
are all polymorphs and hydrates of the compounds of the present invention.
The invention also includes pharmaceutically acceptable salts of the
compounds of formula I. By "pharmaceutically acceptable salt", it is meant any
compound formed by the addition of a pharmaceutically acceptable base and a
compound of formula I to form the corresponding salt. By the term
"pharmaceutically acceptable" it is meant a substance that is acceptable for use in
pharmaceutical applications from a toxicological perspective and does not adversely
interact with the active ingredient. Pharmaceutically acceptable salts, including
mono- and bi- salts, include, but are not limited to, those derived from such organic
and inorganic acids such as, but not limited to, acetic, lactic, citric, cinnamic, tartaric,
succinic, fumaric, maleic, malonic, mandelic, malic, oxalic, propionic, hydrochloric,
hydrobromic, phosphoric, nitric, sulfuric, glycolic, pyruvic, methanesulfonic,
ethanesulfonic, toluenesulfonic, salicylic, benzoic, and similarly known acceptable
acids.
Other embodiments of the invention provide methods for preparing a
compound of formula I, or pharmaceuticaiiy acceptable salts thereof, described
above wherein the method comprises reacting a trichloroacetyl compound of formula
(2)
where, R1, R2, R3, and B are defined above,
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with an appropriately substituted primary or secondary amine of formula (3)
RH
(3)
where R is defined above,
under conditions sufficient to yield a compound of Formula (I). In some
embodiments, the reaction occurs in the presence of 1,4-dioxane, dimethylsulfoxide,
or both. In some embodiments, the reaction occurs in the presence of an organic
base. In some embodiments, the organic base is a tertiary amine, preferably triethyl
amine or N,N-diisopropylethylamine. In some embodiments, the reaction is
performed in a solvent, such as, but not limited to, acetonitrile. When solvent is
present, the reaction is performed at a temperature of from about ambient to the
refluxing temperature of the solvent.
In some embodiments, the trichloroacetyl compound of formula (2) is
prepared by reacting a tricyclic azepine of formula (1)

where, R1, R2, R3, and B are defined above,
with perhaloalkanoyl halide under conditions sufficient to provide the desired
trichloroacetyl compound of formula (2). In some embodiments, the perhaloalkanoyl
halide is trichloroacetyl chloride. In some embodiments, the reaction occurs in the
presence of an organic base, such as, but not limited to, N,N-diisopropyiethyl amine,
in an aprotic organic solvent. The organic solvent may be any suitable aprotic
organic solvent, such as but not limited to dichloromethane or 1,4-dioxane. In some
such embodiments, the reaction is performed at temperatures of from about -10 °C to
about ambient.
Some embodiments of the invention provide methods for making a compound
of Formula I comprising coupling a compound of Formula (4)
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where, R1, R2, R3, and B are defined above,
where W is OH or halogen, with an appropriately substituted primary or secondary
amine of formula (3)
RH
(3)
where R is defined above,
under conditions sufficient to yield a compound of formula (I) of claim 1. In some
embodiments, W is Cl or Br. In some embodiments, the coupling of the acyl halide of
formula (4) with the substituted amine of formula (3) is performed in the presence of
a tertiary amine in an aprotic solvent. Suitable aprotic solvents include, but are not
limited to, dichloromethane, N,N-dimethylformamide, and tetrahydrofuran. An
exemplary tertiary amine is N,N-diisopropylethylamine. In some embodiments, the
coupling of the acyl halide of formula (4) with the substituted amine of formula (3) is
performed at a temperature of from about ambient to the reflux temperature of the
solvent.
In other embodiments, W is OH.
AMIDATION
In some embodiments, the coupling comprises reacting the carboxylic acid (4)
with a primary or secondary amine of formula (3) in the presence of at least one of an
activating reagent or a coupling reagent under conditions sufficient to yield a
compound of formula (I). Suitable activating agents include, but are not limited to,
triphosgene in an aprotic solvent, N,N-dicyclohexylcarbodiimide, 1-ethyl-3-(3-
dimethylamino-propyl)carbodiimide hydrochloride in the presence of 1-hydroxy
benzotriazole; or N.N'-carbonyldiimidazole in an aprotic solvent. In some such
embodiments, the reaction occurs in the presence of an organic base, such as but
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WO 2006/124581 PCT/US2006/018420
not limited to the tertiary amines. The organic base can be, but is not limited to, N,N-
diisopropylethylamine.
In some embodiments, the reaction is performed in the presence of a
catalyst, such as but not limited to, 4-(dimethylamino)pyridine.
In some embodiments, the coupling reagent is selected from
hydroxybenzotriazole tetramethyluronium hexafluorophosphate, diphenylphosphoryl
azide, diethyl cyano phosphonate, or benzotriazoH-yl-oxy-tris-(dimethylamino)
phosphonium hexafluorophosphate.
ACYLATION
Some embodiments of the invention provide methods for making a compound
of Formula I comprising coupling a compound of Formula (4)

where, R1, R2, R3, and B are defined above,
wherein W is Cl or Br, which is prepared by conversion of a compound of Formula 4
wherein W is OH, with an appropriately substituted primary or secondary amine of
formula (3)
RH
(3)
where R is defined above,
under conditions sufficient to yield a compound of formula (I). In some such
embodiments, the conversion process comprises reacting a compound of Formula 4
wherein W is OH with thionyl halide or an oxalyl halide. In some embodiments,
conversion occurs in the presence of at least one of an inorganic base, such as but
not limited to potassium carbonate, and an organic base in an aprotic solvent. In
some embodiments, the organic base includes but is not limited to, pyridine, 4-
(dimethylamino)pyridine, or a tertiary amine, such as but not limited to triethylamine.
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WO 2006/124581 PCT/US2006/018420
Suitable aprotic solvents include, but are not limited to, dichloromethane, N,N-
dimethylformamide, and tetrahydrofuran. In some embodiments, conversion is
performed at a temperature of from about -5°C to about 50°C.
Some embodiments of the invention provide methods of preparing a
compound of Formula I comprising reacting a tricvclic diazepine of formula (1)
where, R1, R2, R3, and B are defined above,
with diphosgene and a primary or secondary amine of formula (3)
RH
(3)
where R is defined above,
in an aprotic solvent under conditions sufficient to yield a compound according to
formula (I). Any suitable aprotic solvent can be used, including but not limited to,
dichloromethane. In some embodiments, the reaction occurs in the presence of an
organic base, such as but not limited to triethylamine.
GENERAL SYNTHETIC SCHEME(S) FOR PREPARATION OF COMPOUNDS
The compounds of the present invention can be prepared according to one or
more of the general processes outlined below.
The compounds of general formula (I) wherein B is

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WO 2006/124581 PCT/US2006/018420

According to the above preferred process, a tricyclic azepine of formula (1)
wherein R1, R2, R3 and B are defined hereinbefore, is reacted with perhaloalkanoyl
halide, preferably trichloroacetyl chloride, in the presence of an organic base such
as, but not limited to, N,N-diisopropylethyl amine (H0nig's base) in an aprotic organic
solvent such as, but not limited to, dichloromethane or 1,4-dioxane, at temperatures
ranging from about -10 °C to about ambient, to provide the desired trichloroacetyl
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WO 2006/124581 PCT/US2006/018420
intermediate of formula (2). Subsequent reaction of the intermediate of formula (2)
with an appropriately substituted primary or secondary amine of formula (3) in
refluxing 1,4-dioxane or with dimethylsulfoxide optionally in the presence of an
organic base such triethylamine, in a solvent such as, but not limited to, acetonitrile,
at temperatures ranging from about ambient to the refluxing temperature of the
solvent, yields the desired compounds of formula (I) wherein R1, R2, R3 and B are
as defined hereinbefore.
Another preferred process is shown in Scheme II below.
Scheme II


WO 2006/124581 PCT/US2006/018420
According to the above preferred process the trichloroacetyl intermediate of
formula (2) is hydrolyzed with aqueous base such as, but not limited to, sodium
hydroxide, in an organic solvent such as, but not limited to, tetrahydrofuran or
acetone at temperatures ranging from about -10 °C to about ambient, to yield the
intermediate acid of formula (4). The required activation of the carboxylic acid (4) for
the subsequent coupling with a primary or secondary amine of formula (3) can be
accomplished in several ways. Thus, the intermediate of formula (4) can be
converted to an acyl halide preferably a chloride or bromide of formula (5), where J is
COCI or COBr, by reaction with thionyl chloride, ihionyl bromide, oxalyl chloride, or
oxalyl bromide or similar reagents known in the art, either neat or in the presence of
an inorganic base such as, but not limited to, potassium carbonate, or in the
presence of an organic base such as, but not limited to, pyridine, 4-
(dimethylamino)pyridine, or a tertiary amine such as, but not limited to, triethylamine
in an aprotic solvent such as, but not limited to, dichloromethane, N,N-
dimethylformamide or tetrahydrofuran at temperatures ranging from about -5 °C to
about 50 °C to yield the intermediate acylated derivative (5). Subsequent coupling of
the acyl chloride or acyl bromide of formula (5), where J is COCI or COBr, with an
appropriately substituted primary or secondary amine of formula (3) in the presence
of a stoichiometric amount of H0nig's base, in an aprotic solvent such as, but not
limited to, dichloromethane, N,N-dimethylformamide or tetrahydrofuran, at
temperatures ranging from about ambient to the reflux temperature of the solvent,
provides the desired compounds of formula (I) wherein R1, R2, R3 and B are as
defined hereinbefore.
Alternatively, the acylating species can be a mixed anhydride of the
corresponding carboxylic acid, such as, but not limited to, that prepared by treating
said acid of formula (4) with 2,4,6-trichlorobenzoyl chloride in an aprotic organic
solvent such as, but not limited to, dichloromettiane according to the procedure of
Inanaga et al., Bull. Chem. Soc. Jpn. 52,1989 (1979). Treatment of said mixed
anhydride of formula (5) with an appropriately substituted primary or secondary
amine of formula (3) in an aprotic solvent such as, but not limited to, dichloromethane
at temperatures ranging from about ambient to trie reflux temperature of the solvent,
provides the desired compounds of formula (I) wherein R1, R2, R3 and B are as
defined hereinbefore.
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Alternatively, amidation of the carboxylic acids of formula (4) can be
effectively carried out by treatment of said acid with triphosgene in an aprotic solvent
such as, but not limited to, dichloromethane, followed by reaction of the activated
intermediate with an appropriately substituted primary or secondary amine of formula
(3) in the presence of an organic base such as, but not limited to, Hiinig's base at
temperatures ranging from about -10°C to about ambient.
Another preferred process for the preparation of the compounds of the
present invention of formula (I) wherein R1, R2, R3 and B are as defined hereinbefore,
consists of treating the acid of formula (4) with an activating reagent such as, but not
limited to, N,N-dicyclohexylcarbodiimide or 1-ethyl-3-(3-dimethylamino-
propyl)carbodiimide hydrochloride in the presence of 1-hydroxybenzotriazole,
followed by reaction of the activated intermediate with an appropriately substituted
primary or secondary amine of formula (3), preferably in the presence of an organic
base such as, but not limited to, Hunig's base and a catalytic amount of 4-
(dimethylamino)pyridine in an aprotic solvent such as, but not limited to,
dichloromethane, N,N-dimethyIformamide or tetrahydrofuran at temperatures ranging
from about -10oC to about ambient.
In another preferred process, said acid of formula (4) can be activated by
treatment with other activating agents such as, but not limited to, N,N'-
carbonyldiimidazole in an aprotic solvent such as, but not iimited to, dichioromethane
or tetrahydrofuran, at temperatures ranging from about -10°C to the reflux
temperature of the solvent. Subsequent reaction of the activated intermediate
imidazolide with an appropriately substituted primary or secondary amine of formula
(3) provides the desired compounds of formula (I) wherein R1, R2, R3 and B are as
defined hereinbefore.
Alternatively, the coupling of the appropriately substituted primary or
secondary amine of formula (3) with said acid of formula (4) can be effectively carried
out by using hydroxybenzotriazole tetramethyluronium hexafluorophosphate as the
coupling reagent in the presence of an organic base such as, but not limited to,
Hunig's base and in a solvent such as, but not limited to, N.N-dimethylformamide at
temperatures ranging from about -10 °C to about ambient, to provide in good isolated
yield and purity the desired compounds of formula (I) wherein R1, R2, R3 and B are as
defined hereinbefore.
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WO 2006/124581 PCT/US2006/018420
Related coupling reagents such as, but not limited to, diphenylphosphoryl
azide, diethyl cyano phosphonate, benzotriazol-1-yl-oxy-tris-(dimethylamino)
phosphonium hexafluorophosphate and all other known in the literature that have
been used in the formation of amide bonds in peptide synthesis can also be used for
the preparation of compounds of formula (I) wherein R1, R2, R3 and B are as defined
hereinbefore.
The method used for the preparation of compounds of formula (I) from the
intermediate carboxylic acid of formula (4) is ultimately chosen on the basis of its
compatibility with the R1, R2, R3 and B groups, and its reactivity with the tricyclic
diazepine of formula (1).
Another preferred process for the preparation of (I) is shown in Scheme III. A
tricyclic diazepine of formula (1) is reacted with diphosgene in an aprotic solvent such
as, but not limited to, dichloromethane, preferably in the presence of an organic base
such as, but not limited to, triethylamine, followed by reaction of the resulting
acylated intermediate with an appropriately substituted primary or secondary amine
of formula (3), to provide the desired compounds of formula (I) wherein R1, R2, R3
and B are as defined hereinbefore.
Scheme III

The tricyclic diazepines of formula (1) of Scheme I wherein B is

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WO 2006/124581 PCT/US2006/018420

Thus, a tricyclic diazepine of formula (6) is treated with an appropriately
substituted acylating agent such as, but not limited to, an aroyl halide, preferably an
appropriately substituted acyl chloride or acylbromide of formula (7), where J is
COCI or COBr, wherein B is ultimately chosen on the basis of its compatibility with
the present reaction scheme, in the presence of an inorganic base such as, but not
limited to, potassium carbonate, or in the presence of an organic base such as, but
not limited to, pyridine, 4-(dimethylamino)pyridine, or a tertiary amine such as, but not
limited to, triethylamine, N,N-diisopropylethyl amine or N,N-dirhethylaniline, in an
aprotic solvent such as, but not limited to, dichloromethane, N,N-dimethylformamide,
tetrahydrofuran or 1,4-dioxane, at temperatures ranging from about -5 °C to about 50
°C to provide intermediates of general formula (1).
Alternatively, the acylating species of formula (7) can be a mixed anhydride of
the corresponding carboxylic acid, such as, but not limited to, that prepared by
treating said acid with 2,4,6-trichlorobenzoyl chloride in an aprotic organic solvent
such as, but not limited to, dichloromethane according to the procedure of Inanaga et
a!., Bull. Chem. Soc. Jpn., 52,1989 (1979). Treatment of said mixed anhydride of
general formula (7) with a tricyclic diazepine of formula (6) in a solvent such as, but
not limited to, dichloromethane, and in the presence of an organic base such as, but
not limited to, 4-(dimethylamino)pyridine, at temperatures ranging from about 0°C to
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WO 2006/124581 PCT/US2006/018420
the reflux temperature of the solvent, yields the intermediate acylated derivative of
formula (1) of Scheme IV.
The acylating intermediate of formula (7) is ultimately chosen on the basis of
its compatibility with the B groups, and its reactivity with the tricyclic diazepine of
formula (6).
The desired intermediates of formula (7) of Scheme IV wherein B is (a) can
be conveniently prepared by a process shown in Scheme V. Thus, an appropriately
substituted aryl iodide, aryl bromide, aryl chloride, or aryl trifluoromethane sulfonate
of formula (8), wherein Pg is a carboxylic acid protecting group, preferably Pg is alkyl
or benzyl, M is I, Br, Cl, OTf, and R5, R6 and R7 are defined hereinbefore, is reacted
with an aryl tri(alkyl)tin(IV) derivative of formula (9), where T is Sn(alkyl)3, preferably
Sn(n-Bu)3) wherein R8, R9 and R10 are defined hereinbefore, in the presence of a
Pd(0) catalyst, and in the presence or absence of inorganic salts (e.g. LiCI or
copper(l) salts) to provide the intermediate ester of formula (10). Subsequent
unmasking of the carboxylic function by hydrolysis, hydrogenolysis or similar
methods known in the art, followed by activation of the intermediate acid of formula
(11) provides the desired compounds of formula (7) wherein R5, R6, R7, R8, R9 and
R10 are hereinbefore defined, suitable for coupling with the tricyclic diazepine of
formula (6).
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WO 2006/124581 PCT/US2006/018420

The desired intermediates of formula (7) of Scheme IV wherein Q is (b) can
be prepared by a process analogous to that exemplified in Scheme V by replacing
intermediates of formula (9) with appropriately substituted naphthyl intermediates.
Alternatively, the desired intermediates of formula (10) of Scheme V wherein
Q is (a) can be prepared by coupling of the iodide, bromide, chloride, or
trifluoromethane sulfonate of formula (8), where M is I, Br, Cl or OTf, with an
appropriately substituted aryl boron derivative of formula (9), where preferably T is
B(OH)2, in the presence of a palladium catalyst such as, but not limited to,
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WO 2006/124581 PCT/US2006/018420
palladium(ll) acetate or tetrakis(triphenylphosphine)palladium(0) and an organic base
such as, but not limited to, triethylamine or an inorganic base such as, but not limited
to, sodium, potassium, or cesium carbonate with or without added
tetrabutylammonium bromide or tetrabutylammonium iodide, in a mixture of solvents
such as, but not limited to, toluene-ethanol-water, acetone-water, water or water-
acetonitrile, at temperatures ranging from about ambient to the reflux temperature of
the solvent (Suzuki, Pure & Appl. Chem. 66, 213-222 (1994), Badone et al., J. Org.
Chem. 62, 7170-7173 (1997), Wolfe et al. J. Am. Chem. Soc. 121, 9559 (1999),
Shen, Tetr. Letters 38, 5575 (1997)). The exact conditions for the Suzuki coupling of
the halide and the boronic acid intermediates are chosen on the basis of the nature
of the substrate and the substituents. The desired intermediates of formula (10) of
Scheme V can be similarly prepared from the bromide of formula (8), where M is Br,
and the boronic acid of formula (9) in a solvent such as, but not limited to, dioxane in
the presence of potassium phosphate and a Pd(0) catalyst.
Alternatively, a palladium-catalyzed cross-coupling reaction of an aryl halide,
or trifluoromethane sulfonate of formula (9), where T is Br, I or OTf, with a pinacolato
derivative of formula (8), where M is B(OH)2, or SnBu3) yields the desired
intermediate of formula (10) which is converted to a compound of formula (1) in the
manner of Scheme V.
The desired intermediates of formula (10) of Scheme V wherein Q is (b) can
be prepared in analogous fashion by replacing intermediates of formula (9) with
appropriately substituted naphthyl intermediates.
The required appropriately substituted aryl halides of formula (8), where M is
Br or I, of Scheme V are either available commercially, or are known in the art, or can
be readily accessed in quantitative yields and high purity by diazotization of the
corresponding substituted anilines of formula (8), where Pg is H, alkyl or benzyl, and
M is N.H2, followed by reaction of the intermediate diazonium salt with iodine and
potassium iodide in aqueous acidic medium essentially according to the procedures
of Street et al,. J. Med. Chem. 36,1529 (1993) and Coffen et al., J. Org. Chem. 49,
296 (1984) or with copper(l) bromide, respectively (March, Advanced Organic
Chemistry, 3rd Edn., p.647-648, John Wiley & Sons, New York (1985)).
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WO 2006/124581 PCT/US2006/018420
Alternatively, the desired intermediates of formula (11) of Scheme V wherein
Q is (a) can be conveniently prepared as shown in Scheme VI by cross-coupling
reaction of an appropriately substituted pinacolato boronate of formula (13) wherein
R8, R9 and R10 are hereinbefore defined, with an aryl triflate of formula (14), where W
is OTf, or an aryl halide where the halide Br, or I, wherein R5, R6 and R7 are defined
hereinbefore, according to the general procedures of Ishiyama et al., Tetr. Lett. 38,
3447-3450 (1997) and Giroux et al. Tetr. Lett. 38, 3841-3844 (1997), followed by
basic or acidic hydrolysis of the intermediate nitrile of formula (15) (cf. March,
Advanced Organic Chemistry, 3rd Edn., John Wiley & Sons, New York, p. 788
(1985)).
Scheme VI

Alternatively, reaction of an iodide, bromide, chloride, or trifluoromethane
sulfonate of formula (12), where L is Br, Cl, I, or OTf, with a boronic acid ortrialkyl
tin(IV) derivative of formula (14), where W is B(OH)2, or SnBu3, yields the desired
intermediate of formula (15) which is converted to a compound of formula (11) in the
manner of Scheme VI.
The desired intermediates of formula (15) of Scheme VI where Q is (b) can be
prepared in analogous fashion by replacing intermediates of formulas (13) with
appropriately substituted naphthyl intermediates.
The desired phenyl boronic esters of formula (13) of Scheme VI can be
conveniently prepared by the palladium-catalyzed cross-coupling reaction of
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WO 2006/124581 PCT/US2006/018420
bis(pinacolato) diboron of formula (16) with an appropriately substituted aryl halide of
formula (12), preferably a bromide or iodide, where L is Br, I, or an aryl triflate, where
L is OTf, according to the published procedures of Ishiyama et al., J. Org. Chem.
60,7508-7510 (1995) and Giroux et al., Tetr. Lett. 38, 3841-3844 (1997).
The desired compounds of formula (1) of Scheme IV wherein Q is (a) can be
alternatively prepared by a process shown in Scheme VII.
Scheme VII

Thus, a tricyclic diazepine of formula (6) is treated with an appropriately
substituted acylating agent such as, but not limited to, a halo aroyl halide, preferably
an iodo aroyl chloride or bromo aroyl bromide of formula (17), where J is COCI or
COBr; and K is I, Br, wherein R5, R6 and R7 are hereinbefore defined, using any of
the procedures hereinbefore described, to provide the acylated intermediate of
general formula (18) of Scheme VII.
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WO 2006/124581 PCT/US2006/018420
Alternatively, the acylating species of formula (17) can be a mixed anhydride
of the corresponding carboxylic acid. Treatment of said mixed anhydride of general
formula (17) with a tricyclic diazepine of formula (6) according to the procedure
described hereinbefore yields the intermediate acylated derivative of formula (18).
The acylating intermediate of formula (17) is ultimately chosen on the basis of
its compatibility with the R5, R6 and R7 groups, and its reactivity with the tricyclic
diazepine of formula (6).
A Stille coupling reaction of a compound of formula (18), where K is I, with an
appropriately substituted organotin reagent such as, but not limited to, a trialkyltin(IV)
derivative, preferably a tri-n-butyltin(IV) derivative of formula (9), where T is SnBu3,
where R8, R9 and R10 are hereinbefore defined, in the presence of a catalyst such as,
but not limited to, tetrakis (triphenylphosphine) palladium (0), in an aprotic organic
solvent such as, but not limited to, toluene and N,N-dimethylformamide, at
temperatures ranging from about ambient to about 150°C (cf. Farina et al., J. Org.
Chem, 59, 5905 (1994) and references cited therein), affords the desired compounds
of formula (1) wherein R1, R2, R3, R5, R6, R7, R8, R9 and R10 are as defined
hereinbefore.
Alternatively, reaction of a compound of formula (18), where K is Cl, Br or I,
with an appropriately substituted aryl boronic acid of formula (9), where" T is B(OH)2,.
wherein R5, R6, R7, R8, R9 and R10 are hereinbefore defined, in a mixture of solvents
such as, but not limited to, toluene-ethanol-water, in the presence of a Pd(0)'catalyst
and a base such as, but not limited to, sodium carbonate, at temperatures ranging
from about ambient to the reflux temperature of the solvent, yields the desired
compounds of formula (1) wherein R1, R2, R3, R5, R6, R7, R8, R9 and R10 are as
defined hereinbefore.
The preferred substituted aroyl chlorides(bromides) of formula (17) of
Scheme VI!, where K is I, Br; and J is COCl or COBr, wherein R5, R6 and R7 are as
defined hereinbefore, are either available commercially, or are known in the art, or
can be readily prepared by procedures analogous to those in the literature for the
known compounds.
The intermediates of formula (9), where T is Sn(alkyl)3, and alkyl is preferably
n-butyl, of Scheme VII are either commercially available, or can be conveniently
prepared as shown in Scheme VIII from the corresponding bromo starting materials
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of formula (19) wherein R8, R9, and R10 are hereinbefore defined, by first reacting
them with n-butyl lithium followed by reaction of the intermediate lithiated species
with a trialkyl (preferably trimethyl or tri-n-butyl)tin(IV) chloride, preferably trimethyl
tin(IV) chloride or tri-n-butyl tin(IV) chloride.
Scheme VIII

The preferred substituted aryl boronic acids of formula (9), where T is B(OH)2,
are either available commercially, or are known in the art, or can be readily prepared
by procedures analogous to those in the literature for the known compounds.
The desired compounds of formula (1) of Scheme VII wherein B is (b) can be
prepared in analogous fashion by replacing intermediates of formula (9) with
appropriately substituted naphthyl intermediates.
Alternatively, as shown in Scheme IX, the appropriately substituted aroyl
halides, preferably aroyl chlorides of formula (20) where J= COCI, where R5, R6 and
R7 are hereinbefore defined, are reacted with a tricyciic diazepine of formula (6) to
provide the intermediate bromides of formula (21). Subsequent reaction of (21) with
an hexa alkyl-di-tin (preferably hexa-n-butyl-di-tin(IV)) in the presence of a Pd(0)
catalyst such as tetrakis(tri-phenylphosphine)palladium(0) and lithium chloride or
copper(l) salts, provides the stannane intermediate of formula (22). Further reaction
of the tri-n-butyl tin(IV) derivative (22) with the appropriately substituted aryl halide of
formula where 23, M = bromo or iodo, wherein R8, R9, and R10 are hereinbefore
defined, in the presence of a Pd(0) catalyst such as tetrakis(triphenylphosphine)
palladium(O), yields the desired compounds of formula (1) wherein Q is (a), and R1,
R2, R3, R5, R6, R7, R8, R9 and R10 are defined hereinbefore.
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WO 2006/124581 PCT/US2006/018420

The desired compounds of formula (1) of Scheme IX wherein Q is (b) can be
prepared in analogous fashion by replacing intermediates of formula (23) with
appropriately substituted naphthyl intermediates.
Alternatively, the desired compounds of formula (1) of Scheme IX wherein Q
is (a) can be prepared as shown in Scheme X.

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WO 2006/124581 PCT/US2006/018420
Thus, an appropriately substituted biphenyl of formula (24) wherein
R5, R6, R7, R8, R9 and R10 are defined hereinbefore, is treated with carbon monoxide
in the presence of a tricyclic diazepine of formula (6), a palladium(O) catalyst
preferably PdBr2(Ph3P)2 and a tertiary amine preferably n-tributylamine, in a solvent
such as, but not limited to, anisole or dioxane, at temperatures ranging from about
ambient to the reflux temperature of the solvent (cf. Schoenberg et al. J. Org. Chem.
39,3327 (1974)) to provide the desired compounds of formula (1) wherein R1, R2, R3,
R5, R6, R7, R8, R9 and R10 are defined hereinbefore.
In analogous fashion one can prepare compounds of formula (1) of Scheme X
wherein Q is (b) provided that the intermediates of formula (24) are replaced by the
appropriately substituted naphthyl intermediates.
A preferred process for the preparation of the desired compounds of general
formula (I) of Scheme I wherein B is selected from the group (a) or (b) defined
hereinbefore is shown in Scheme XI
-38-


Thus, a tricyclic diazepine of formula (25) wherein R1, R2 and R3 are defined
hereinbefore, carrying a protecting group (Pg) such as, but not limited to,
fluorenylalkoxycarbonyl group, preferably a fluorenyimethyloxycarbonyl (Pg is Fmoc)
group, or an alkoxycarbonyl protecting group preferably a tert-butyloxycarbonyl (Pg is
Boc) group is reacted with a perhaloalkanoyl halide preferably trichloroacetyl
chloride, in the presence of an organic base such as, but not limited to, N,N-
diisopropylethyl amine (Hünig's base) or a tertiary amine such as, but not limited to,
triethylamine, optionally in the presence of catalytic amounts of 4-(dimethylamino)
pyridine, in an aprotic organic solvent such as, but not limited to, dichloromethane, at
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WO 2006/124581 PCT/US2006/018420
temperatures ranging from about -10 °C to about ambient to provide the desired
trichloroacetyl intermediate of formula (26). Subsequent reaction with a primary or
secondary amine of formula (3) under the conditions of Scheme I yields the
intermediate amide of formula (27) where Pg is Boc, which is then deprotected
(intermediate 28) and acylated to the desired product of formula (I). Alternatively, the
conversion of (26) to the intermediate of formula (28) can be carried out in a single
step by treatment of the intermediate of formula (26) where Pg is Fmoc, with a
primary amine of formula (3) in the presence of dimethylsulfoxide in an aprotic
solvent such as, but not limited to, acetonitrile, at reflux temperature of the solvent.
Alternatively, hydrolysis of the trichloroacetate intermediate (26) with aqueous
base such as, but not limited to, sodium hydroxide in an organic solvent such as, but
not limited to, acetone, at temperatures ranging from about -10°C to about ambient,
is accompanied by simultaneous removal of the protecting group (Pg is Fmoc) and
yields the intermediate acid of formula (29) as shown in Scheme XII. The required
amidation of the carboxylic acid of formula (29) can be effectively accomplished by
treating the carboxylic acid of formula (29) with an activating reagent such as, but not
limited to, N,N-dicyclohexylcarbodiimide or 1-ethyl-3-(3-dimethylamino-propyl)
carbodiimide hydrochloride in the presence of 1-hydroxybenzotriazole, followed by
reaction of the activated intermediate with an appropriately substituted primary or
secondary amine of formula (3) preferably in the presence of Hunig's base or a
catalytic amount of 4-(dimethylamino)pyridine, in an aprotic solvent such as, but not
limited to, dichloromethane, N,N-dimethylformamide or tetrahydrofuran, at
temperatures ranging from about -10°C to about ambient. Subsequent acylation of
the amide of formula (28) under the conditions of Scheme IV provides the desired
compounds of formula (I).
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WO 2006/124581 PCT/US2006/018420

Other coupling reagents known in the literature that have been used in the
formation of amide bonds in peptide synthesis can also be used for the preparation of
compounds of formula (28). The method of choice for the preparation of compounds
of formula (28) from the intermediate carboxylic acid of formula (29) is ultimately
chosen on the basis of its compatibility with the R1, R2, and R3 groups.
Alternatively, the intermediate acids of formuia (29) of Scheme XII wherein
R1 ,R2, and R3 are defined hereinbefore, can be obtained by reacting a tricyclic
diazepine of formula (6) with an excess of acylating agent preferably trifluoroacetic
anhydride or trichloroacetyl chloride in the presence of an inorganic base such as,
but not limited to, potassium carbonate or an organic base such as, but not limited to,
N,N-diisopropylethylamine, in an aprotic solvent such as, but not limited to, N,N-
dimethylformamide, followed by basic hydrolysis of the intermediate bis-trifluoroacetyl
(trichloroacetyl) intermediate of formula (30) preferably with aqueous sodium
hydroxide in a protic organic solvent such as, but not limited to, ethanol, at
temperatures ranging from about ambient to the reflux temperature of the solvent as
exemplified in Scheme XIII.
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WO 2006/124581 PCT/US2006/018420

Preferred processes for the preparation of compounds of formula (I) of
Scheme I wherein Q is (a), and R1, R2, R3, R5, R6, R7, R8, R9, and R10 are defined
hereinbefore, also utilize acylation of the intermediate (28) of Scheme XII with an
acylating agent of formula (17) of Scheme VII, as shown in Scheme XIV. Subsequent
coupling of the intermediate of formula (31), where K is Br or I, with an appropriately
substituted aryl boronic acid of formula (9), where T is B(OH)2, in a mixture of
solvents such as, but not limited to, dimethoxyethane and water or acetonitrile and
water, in the presence of a Pd(0) catalyst such as, but not limited to,
tetrakis(triphenylphosphine)palladium(0) or a Pd(ll) catalyst such as, but not limited
to, [1,1'-bis(diphenylphosphino)ferrocene]dichloro palladium(ll), and a base such as,
but not limited to, potassium or sodium carbonate, at temperatures ranging from
about ambient to reflux, yields the desired compound (I).
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WO 2006/124581 PCT/US2006/018420

Alternatively, the preferred compounds of formula (I) of Scheme I wherein Q
is (a) and R1, R2, R3, R5, R6, R7, R8, R9, and R10 are defined hereinbefore, can be
prepared as shown in Scheme XV by acylation of the intermediate (28) of Scheme
XII with an acylating agent of formula (20) of Scheme IX.
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WO 2006/124581 PCT/US2006/018420

Alternatively, the preferred compounds of formula (I) of Scheme (I) wherein Q
is (a) and R1, R2, R3, R5, R6, R7, R8, R9, and R10 are defined hereinbefore, can be
prepared by acylation of the amide intermediate of formula (28) of Scheme XII with
5 an acylating agent of formula (7) of Scheme V, wherein J is hereinbefore defined, as
shown in Scheme XVI.
Scheme XVI

A preferred process for the preparation of the amide intermediate of formula
(31) of Scheme XIV is shown in Scheme XVII. A tricyclic benzodiazepine of formula
(6) is acylated with an acylating agent of formula (17), where K is Br or 1, to provide
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WO 2006/124581 PCT/US2006/018420
the intermediate of formula (34). This is in turn, is reacted with a perhaloalkanoyl
halide preferably trichloroacetyl chloride, under the conditions of Scheme I to provide
the trichloroacetyl intermediate of formula (35). Subsequent reaction of the
intermediate of formula (35) with an appropriate primary or secondary amine also
under the conditions of Scheme I provides the desired product of formula (31).
Scheme XVII

BRIEF DESCRIPTION OF BIOLOGICAL TEST PROCEDURE(S) AND TEXT
SUMMARY OF RESULTS.
PHARMACOLOGY
The FSH antagonist activities of the compounds of this invention were
demonstrated by evaluating representative compounds of this invention in the
following test procedures.
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WO 2006/124581 PCT/US2006/018420
FOLLICLE-STIMULATING HORMONE RECEPTOR-DEPENDENT CRE-
LUCIFERASE REPORTER GENE ASSAY FOR THE IDENTIFICATION OF
FOLLICLE-STIMULATING HORMONE (FSH) ANTAGONISTS
This procedure was used to identify and determine the relative potencies of
human FSH receptor antagonists using a Chinese hamster ovarian cell line that
stably produces the human FSH receptor and a luciferase reporter gene regulated by
cAMP response elements.
MATERIALS AND METHODS: REAGENTS
COMPOUND VEHICLE: Stock compounds were solubilized in an appropriate
vehicle, preferably phosphate buffered saline (PBS) or dimethyl sulfoxide (DMSO), at
30 mM. The compounds were subsequently diluted in DMSO to working dilutions of
1 and 20 or 30 mM for 2-dose testing format and 1 µM -10 mM for dose-response
format. The DMSO dilutions were diluted 500-fold in sterile growth medium [D-
MEM/F-12 (GIBCO/BRL; Grand Island NY) containing 15 mM HEPES, 2 mM I-
glutamine, pyridoxine hydrochloride, phenol red and 5% FetalClone II (HyClone
Laboratories, Inc; Logan, UT), 0.2% DMSO, 100 units penicillin G/ml, and 100 µg
streptomycin sulfate/ml (GIBCO/BRL)]. The concentration of the vehicle in each of
the compound dilutions was the same.
POSITIVE CONTROLS: Purified human FSH (>98%) was purchased from Cortex
Biochem, Inc. (San Leandro, CA) and a known FSH-R thiazolidinone antagonist was
obtained from the Wyeth Research compound repository.
PREPARATION OF CELLS
The CHO FSH-R 6CRE-Luc cells (1D7 cells) were obtained from Affymax
(Palo Alto, CA). These Chinese hamster ovary cells (CHO-K1) were genetically
engineered to stably express the recombinant human FSH receptor gene and a
luciferase reporter gene under the regulation of 6 copies of a cAMP response
element. The cells were plated one day prior to treatment into 96-well white opaque
plates at a density of 50,000 cells/100 µl/well in growth medium. On the day of
treatment, the growth medium was removed from the wells by aspiration and 50 of
fresh growth medium was added to each well. The cells were incubated at 37 °C in a
humidified incubator with 5% CO2/95% air.
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WO 2006/124581 PCT/US2006/018420
ASSAY
Test compounds diluted to 2X final concentration in growth medium
containing 2X EC50 purified human FSH (0.8 ng/ml) were added to the wells to
achieve a final volume of 100 µl of medium containing 0.25% (v/v) vehicle. The
treated cells were incubated for 4 hours at 37 °C in a humidified incubator with 5%
CO2/95% air. At the end of the incubation period, luciferase activity was measured
by chemiluminescence using a commercially available kit (LucScreen, Tropix, Inc.,
Bedford, MA) according to the manufacturer's specifications, except that Buffer 1 and
Buffer 2 were mixed together in equal proportion prior to the addition of 100 µI of the
combined reagents to each well. Chemiluminescence was detected using a
luminometer (EG & G Berthold Microlumat LB 96 P, Wallac, Gaithersburg, MD) with
chemiluminescence measured for 1 sec/well.
Background luminescence was measured for each well prior to the addition of the
LucScreen reagent.
EXPERIMENTAL GROUPS
In the 96-well 2-dose format, each compound was tested in duplicate at each
dose. The controls were also tested in duplicate on each plate and consisted of
vehicle control and 3 positive controls (EC50 of phFSH (0.4 ng/ml), EC100 of phFSH
(1000 ng/ml), and IC50 of 3-[(2S*,5R*)-5-{[2-(1H-lndol-3-yl)-ethylcarbamoyl]-methyl}-
4-oxo-2-(5-phenylethynyi-thiophen-2-yi)-thia2oiidin-3-yl3-benzamide (2 µM) in the
presence of EC50 of purified human FSH). One plate was used to test a maximum of
22 compounds.
In the 96-well dose-response format, each compound was tested in triplicate
at each of 6 doses in the presence of the EC50 of purified human FSH. The EC50 of
purified human FSH alone was tested in triplicate with each test compound. The
doses chosen to test each compound were extrapolated from the initial 2-dose
screening process. Along with the test compounds, purified human FSH was also
tested in a dose response (0.03, 0.1, 0.3,1,3,10, and 30 ng/ml) for a positive control
and quality control. One plate was used for 3 test compounds and the FSH positive
control.
ANALYSIS OF THE RESULTS
Luciferase activity is expressed as relative light units/sec/well. Luciferase
activity in antagonist was compared to the appropriate negative and positive controls.
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WO 2006/124581 PCT/US2006/018420
For 2-dose testing, results are reported as luciferase activity and are expressed as %
inhibition of the response obtained from the EC50 of FSH. For dose-response testing,
results are reported as IC50 values. Data were analyzed statistically by one-way
analysis of variance with appropriate weighting and transformation and relevant
paired test as determined by Biometrics (Wyeth Research, Princeton, NJ). IC50
values were calculated using the Stat/Excel program developed by Biometrics with
appropriate weighting and transformation.
REFERENCE COMPOUNDS
Test compounds were compared to the effect of purified human FSH and 3-
[(2S*,5R*)-5-{[2-(1H-lndol-3-yl)-ethylcarbamoyl]-methyl}-4-oxo-2-(5-phenylethynyl-
thiophen-2-yl)-thiazolidin-3-yl]-benzamide in 2-dose format and EC50 concentration of
purified human FSH in dose-response format.
REFERENCES
1. Kelton, CA, Cheng, S.V.Y., Nugent, N.P., Schweickhardt, R.L., Rosenthal, J.L.,
Overton, S.A., Wands, G.D., Kuzeja, J.B., Luchette, C.A., and Chappel, S.C. (1992).
The cloning of the human follicle stimulating hormone receptor and its expression in
COS-7, CHO, and Y-1 cells. Mol. Cell. Endocrinol. 89:141-151.
2. Tilly, J.L., Aihara, T., Nishimori, K., Jia, X.-C, Billig, H., Kowalski, K.I., Perlas,
E.A., and Hsueh, A.J.W. (1992). Expression of recombinant human follicle-
stimulating hormone receptor: Species-specific ligand binding, signal transduction,
and identification of multiple ovarian messenger ribonucleic acid transcripts.
Endocrinology 131:799-806.
3. George, S.E., Bungay, P.J., and Naylor, LH. (1997). Evaluation of a CRE-
directed luciferase reporter gene assay as an alternative to measuring cAMP
accumulation. J. Biomol. Screening 2:235-240.
IN VITRO BIO-ASSAY OF AGONISTS AND ANTAGONISTS TO THE FSH
RECEPTOR. SELECTIVITY AND DEPENDENCY OF AGONISTS AND
ANTAGONISTS TO THE FSH RECEPTOR
This assay was used to verify in vitro potency, efficacy, selectivity and
receptor dependency of hits found to inhibit an FSH-R-CRE-luciferase driven
reporter.
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WO 2006/124581 PCT/US2006/018420
METHODS: REAGENTS
COMPOUND VEHICLE: Stock compounds were solubilized in 100% DMSO (Sigma
Chemical Co.) at a concentration of 30 mM. The compounds were subsequently
diluted in sterile assay medium consisting of Opti-MEM® I (Life Technologies) with
0.1% (w/v) BSA (Sigma), prior to use in the bio-assay. The final concentration of
DMSO in the assay is 0.1%.
PREPARATION OF CHO-3D2 CELLS
The day prior to the experiment, CHO-3D2 cells (hFSH-R)(1) were plated into
96-well tissue culture plates (Falcon) at a density of 30,000 cells/well in DMEM/F12
medium (Life Technologies) supplemented with 5% Fetal Clone II (Hyclone), 2 mM L-
glutamine (Life Technologies) and penicillin/streptomycin (100 U/ml, Life
Technologies). Plated cells are then incubated at 37° C in a humidified 5% CO2 /95%
air, atmosphere.
ASSAY:
On the day of the assay, cells were washed three times with 100 µl/well of
assay medium consisting of Opti-MEM® I (Life Technologies) with 0.1% (w/v) BSA
(Sigma). Medium was removed and 100 µl of assay medium was added to each well.
Plates were incubated for an additional 30 minutes at 37 °C. Medium was then
removed and cells were challenged for 30 minutes at 37 °C in 50 µl of assay media
containing vehicle, purified hFSH (>95% pure; Cortex Biochem, inc., San Leandro,
CA) in the presence or absence of test compounds. Reactions were terminated by
the addition of 50 µl of 0.2N hydrochloric acid to each well and cAMP-accumulation
was measured by radioimmunoassay (RIA) using a commercially available kit
(Amersham).
EXPERIMENTAL GROUPS
All test compounds were evaluated in a dose-response paradigm ranging
from about 0.01 to about 3Q µM. Controls and test compounds were evaluated in
quadruplicate in a 96-well format. Cells were treated with vehicle, hFSH at EC20 (1.85
ng/mL = 53 pM), or the compounds in the presence or absence of hFSH at its EC2o
dose. The ability of the compounds to inhibit the cAMP-accumulation induced by
hFSH was evaluated by RIA.
In every assay the EC2o concentration was calculated and only those
experiments in which the EC20 concentrations were equal to 1.85 ± 0.4 ng/mL were
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WO 2006/124581 PCT/US2006/018420
accepted as valid. In the 96-well format, the first column contained the negative
control (assay media + 0.1% DMSO), the second column contained the positive
control, hFSH at its EC20 + 0.1% DMSO (1.85 ng/ml or 53 pM), followed by six
concentrations of the compound ranging from about 0.03 - 30/µM in the presence of
the hFSH at its EC20 concentration (1.85 ng/ml or 53 pM).
Along with the test compounds, FSH was also run as a positive control in the
agonist mode using concentrations ranging from about 0.1-1000 ng/ml.
SELECTIVITY STUDIES
cAMP accumulation assays using CHO-25 (hTSH-R) ceils were performed as
described above for the CHO-3D2 cells with the following exceptions: CHO-25 cells
were plated at a density of 50,000 cells/well (2). All test compounds were evaluated
in a dose-response paradigm ranging from about 0.01 to 30 µM. Controls and test
compounds were evaluated in quadruplicate. Cells were treated with vehicle, hTSH
at EC2o (5nM; hTSH >98% pure, Cortex Biochem, Inc.), or the compounds in the
presence or absence of the hTSH at its EC20 concentration. The ability of the
compounds to inhibit cAMP-accumulation induced by hTSH was evaluated by RIA.
Along with the test compounds, hTSH was also run as a positive control in the
agonist mode using concentrations ranging from about 0.01 µM-1000 µM.
NON-RECEPTOR MEDIATED RESPONSES:
cAMP-accumulation assays using CHO-K1 (parental cell line) cells were
performed as described above for the CHO-3D2 cells. All test compounds were
evaluated in a dose-response paradigm ranging from about 0.01 to 30 µM. Controls
and test compounds were evaluated in quadruplicate. Cells were treated with vehicle,
5 µM forskolin that induces the equivalent fmol/ml concentration of cAMP-
accumulation induced by the hFSH at its EC20 (5 µM forskolin, Sigma Chemical Co;
previously calculated during characterization of the bio-assays), or the compounds in
the presence or absence of the 5 µM forskolin. The ability of the compounds to
inhibit the cAMP-accumulation induced by forskoiin was evaluated by RiA.
Along with the test compounds, forskolin was also run as a positive control in
agonist mode using concentrations ranging from about 0.01 µM to 1000 µM.
ANALYSIS OF RESULTS
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WO 2006/124581 PCT/US2006/018420
cAMP accumulation is expressed as fmol/ml. cAMP accumulation in the
agonist mode, or the ability of the compound to inhibit hFSH-, hTSH-, or forskolin-
induced cAMP-accumuiation in the antagonist mode, was compared to the
appropriate negative and positive controls. Data were analyzed by one-way analysis
of variance and significant differences between treatments and control determined by
Least Significant Difference test.
REFERENCE COMPOUNDS
Test compounds were compared to the effect of purified human FSH. In the
paradigm, hFSH induced a concentration-dependent increase in cAMP accumulation,
with apparent EC80=22.55 ng/ml, EC50=6.03 ng/ml and EC20=1.85 ng/ml, calculated
using a four-parameter logistic equation. The same comparison was performed with
hTSH and forskolin.
BIOLOGICAL ACTIVITY
Based on the results obtained in the standard pharmacological test
procedures, the compounds of this invention were shown to block cellular function of
FSH, in vitro, including the production of second messenger cAMP and estradiol in
rat ovarian granulosa cells. Representative compounds of this invention were found
to selectively interact with the FSH receptor, but do not antagonize binding of FSH to
its receptor (Table 1).
As such, the compounds of this invention may be useful as female
contraceptive agents.
Table 1

CRE cAMP
% inhibition IC50 IC50 %
Example (µM) (µM) (µM) Efficacy
2 42.61 1.2 79
4 >30
5 10.18 0.6 96
6 3.3 0.3 81
7 26(30)
8 >30
10 30
11 30
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EXAMPLES
EXAMPLE 1
2, 2, 2,-Trichloro-1-{10-[(2'-methoxy-1,1'-biphenyl-4-yl)carbonyl)-10, 11-dihydro-5H-
pyrrolo[2,1-c][1,4]ben2odiazepin-3-yl}ethanone
Trichloroacetyl chloride (2.63 mL, 23.6 mmol) was added dropwise over five
minutes to a solution of (2'-methoxy-biphenyl-4-yl)-(5H,11H-pyrrolo[2,1-
c][1,4]benzodiazepin-10-yl)-methanone (3.0 g, 7.60 mmol) and N,N-diisopropylethyl
amine (2.65 mL, 15.2 mmol) in dichloromethane (60 mL). The reaction was stirred
under nitrogen at room temperature overnight and then quenched with water. The
organic layer was washed with 0.1 N hydrochloric acid and water, dried over
anhydrous magnesium sulfate, filtered and concentrated to an oil. The oil was
purified by flash chromatography over silica gel Merck-60 using a 0-5% gradient of
ethyl acetate in dichloromethane to give the title compound (2.34 g) as a yellow
foam.
MS[(+)ESI, m/z]: 539 [M+H]+
Anal. Calcd for C28H21CI3N2O3 + 0.2 C4H8O2: C 62.05, H 4.09, N 5.03. Found: C
62.28, H 4.47, N 4.86
EXAMPLE 2
10-[(2'-Methoxy-1,1 '-biphenyl-4-yl)carbonyl]-N-[(1 -methyl-1 H-pyrrol-2-yl)methyl]-
10,11 -dihydro-5H-pyrrolo[2,1 -c][1,4]benzodiazepine-3-carboxamide
To a suspension of 2,2,2-trichloro-1-{10-[(2'-methoxy-1,1'-biphenyl-4-
yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}ethanone of
Example 1 (1.175 g, 2.17 mmole) in acetonitrile (15 mL) was added (1-methyl-1H-
pyrrol-2-yl)methylamine (0.263 g, 2.38 mmole) followed by dimethylsulfoxide (0.710
g, 9.06 mmole) and triethylamine (0.400 g, 4 mmole). The mixture was heated under
nitrogen at 80 °C for 4 hours. The solvent was removed in vacuo, and the residue
was flash chromatographed on silica Merck-60 using a gradient of 0-25% of ethyl
acetate in dichloromethane, to provide a yellow foam that yields a solid (0.464 g)
upon treatment with ethyl acetate and hexane, mp 148-150 °C.
MS [(+)ESI) m/z]: 531.16 [M+H]+
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WO 2006/124581 PCT/US2006/018420
Anal. Calcd for C33H30N4O3: C 74.70, H 5.70, N 10.56. Found: C 74.56, H 6.15, N
10.20.
EXAMPLE 3
2,2,2,-Trichloro-1-10-[(2,2',6'-trimethyl-1,1'-biphenyl-4yl)carbonyl]-10, 11-dihydro-5H-
pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}ethanone
STEP A. 2,2',6'-Trimethyl-biphenyl-4-carboxylic acid methyl ester
2,6-Dimethyl boronic acid (13.7 g, 91 mmol) and 3-methyl benzoic acid
methyl ester (20.9 g, 91 mmol) were dissolved in toluene (425 mL). Then ethanol
(250 mL) and water (250 mL) were added followed by sodium carbonate (38.7 g, 365
mmole). The system was purged with nitrogen and then tetrakis triphenylphospine
palladium (0) catalyst (10.5 g, 9 mmol) was added. The mixture was heated under
nitrogen for 21 hours and filtered through celite. The cake was washed with a large
amount of ethyl acetate, the combined filtrate was washed with water and brine, dried
over anhydrous magnesium sulfate, and concentrated to give a solid. Flash
chromatography of the residue over silica gel Merck-60 using a gradient of 0-20%
ethyl acetate in hexane as the eluant, gave the title compound as a white solid (19.2
g, 83%).
Anal. Calcd. for C17H18O2: C 80.28; H 7.13. Found: C 80.37; H 7.21
STEP B. 2,2',6'-Trimethyi-biphenyi-4-carboxy!ic acid
A solution of 2,2',6'-trimethyl-biphenyl-4-carboxylic acid methyl ester of Step
A (18.5 g, 75.4 mmole) in tetrahydrofuran was treated with 1 N sodium hydroxide
(250 mL) and heated at 90 °C for 20 hours. The mixture was acidified to pH ~1 with
concentrated hydrochloric acid, extracted with dichloromethane, dried over
anhydrous magnesium sulfate, and concentrated to give the title compound as a
white powder (15.63 g). Recrystallization from aqueous ethanol provided white
plates, m.p. 172-173 °C.
MS [(-)ES, m/z]: 239.1 [M-H]
Anal. Calcd. For. C16H16O2: C 79.97, H 6.71. Found: C 79.71, H 6.70
STEP C. (5H, 10)-[(2,2',6'-Trimethyl-1,1'-biphenyl-4-yl)carbonyl]-10,11-dihydro-5H-
pyrrolo[2,1-c][1,4]benzodiazepine
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The 2,2',6'-trimethyl-biphenyl-4carboxylic acid of Step B (11.4 g, 47.4 mmol)
was stirred with 35 rnL (479 mmol) of thionyl chloride, and heated to 70 °C for 3
hours. The excess thionyl chloride was removed under vacuum with the aid of
toluene. The crude acid chloride was dissolved in dichloromethane (100 mL) and a
solution of 10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine (12.23 g, 47.4 mmol)
in dichloromethane (50 mL) was added dropwise. After stirring overnight at room
temperature, the mixture was washed with water, 1N hydrochloric acid, saturated
aqueous sodium bicarbonate, and brine, dried over anhydrous magnesium sulfate,
filtered and concentrated. Flash chromatography of the residue on silica gel Marck-
60 using a gradient from 1:1 to 4:1 of dichloromethane in hexane gave the pure title
compound which was recrystallized from aqueous ethanol as fine translucent plates,
m.p. 170-171 °C.
MS [(+)ES, m/J: 407.2 [M+H]+
Anal. Calcd for C28H26N2O 0.15 H2O: C 82.18, H 6.48, N 6.85. Found: C 82.28, H
6.32, N 6.76.
STEP D. 2,2,2-Trichloro-1-{10-[(2,2',6'-trimethyl-1,1'-biphenyl-4-yl)carbonyl]-10,11-
dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}ethanone 0.15 water
To a solution of (5H, 10M(2,2',6'-trimethyl-1,1'-biphenyl-4-yl)carbonyi]-10,11-
dihydro-5H-pyrroio[2,1-c][1,4]benzodiazepine of Step C (7.934 g, 19.5 mrnol) in
dichloromethane (160 mL) was added trichloroacetyl chloride (11 g, 60.5 mmol, 3.1
eq.), N,N-diisopropylethyl amine (5.54g, 43 mmol, 2.2 eq.) and 4-(dimethylamino)
pyridine (10 mole %). The mixture was stirred for 16.5 hours at room temperature,
then quenched with water (100mL) and stirred for 1 hour. The organic layer was
washed with 0.1 N hydrochloric acid and brine, dried over anhydrous magnesium
sulfate, and concentrated to a yellow foam.
MS [(+)ES, m/z]: 551.1 [M+H]+
Anal. Calcd. For. C30H25Cl3N2O2 H2O: C 64.97, N 4.60, H, 5.05. Found: C 64.79, H
4.97, H 4.58
EXAMPLE 4
N-[(5-Methylisoxazol-3-yl)methyl]-10-[(2,2' ,6'-trimethyl-1,1 '-biphenyl-4-y!)carbonyl]-
10, 11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide
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WO 2006/124581 PCT/US2006/018420
The title compound was prepared according to the procedure of Example 2
starting from 2,2,2-trichloro-1-{10-[(2,2', 6'-trimethyl-1,1'-biphenyl-4-yl)carbonyl]-10,11-
dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}ethanone of Example 3 (1.8 g, 3.26
mmole), (5-methyl-3-isoxazolyl)methylamine (0.305 g, 2.7 mmole), dimethylsulfoxide
(1.06 g, 13.6 mmole), and triethylamine (0.605 g, 6 mmole) in 20 mL of acetonitrile.
The residue was flash chromatographed on silica Merck-60 using a gradient from 0
to 35% of ethyl acetate in dichloromethane, to provide an orange-yellow foam.
Recrystallization from ethyl acetate/ dichloromethane/ hexane gave a white powder
(0.334 g), m.p. 233-234 °C.
MS[(+)ESI,m/z]: 545.2 [M+H]+
Anal. Calcd. for C34H32N4O3 0.15 C5H10O2: C 74.49, H 6.00, N 10.04. Found: C
74.46, H 6.11, N 10.06. :
EXAMPLE 5
10-[(2l-Methoxy-1,1'-biphenyl-4-yl)carbonyl]-N-[(5-methylisoxazol-3-yl)methyl]-10,11-
dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide
The title compound was prepared according to the procedure of Example 2
starting from 2,2,2-trichloro-1-{10-[(2'-methoxy-1,1'-biphenyl-4-yl)carbonyl]-10,11-
dihydro-5H-pyrrolo[2,1-c][,4]benzodiazepin-3-y!}ethanone of Example 1 (1.483 g,
2.75 mmole), (5-methyl-3-isoxazoyl)methylamine (0.256 g 1.0 eq), dimethylsulfoxide
( 5.0 eq.0.896 g, 11.45 mmole), and triethylamine (2.2 eq , 0.510 g, 5 rnrnole) in 20
ml. of acetonitrile. The residue was absorbed on silica gel Merck-60 and flash
chromatographed using a gradient from 0 to 20% of ethyl acetate in
dichloromethane, to provide a foam (0.460 g) which yielded an off-white solid upon
treatment with ethyl acetate/ hexane, m.p. 111-113 °C.
MS[+)ESI, m/z]: 533.12 [M+H]+
Anal. Calcd for C32H28N4O4: C 72.17, H 5.30, N 10.52. Found: C 71.85, H 5.27, N
10.25
EXAMPLE 6
N-[(2,5-Dimethyl-3-furyl)methyl]-10-[(2'-methoxy-1,1'-biphenyl-4-yl)carbonyl]-10,11-
dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide
The title compound was prepared according to the procedure of Example 2
starting from 2,5-dimethyl-3-fury!)methy!amine (0.264 g, 2.1 mmole), 2,2,2-trichloro-
1-{10-[(2'-methoxy-1,1'-biphenyl-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-
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WO 2006/124581 PCT/US2006/018420
c][1,4]benzodiazepin-3-yl}ethanone of Example 1 (1.138 g, 2.1 mmole), triethylamine
(0.470 g, 2.2 eq., 4.6 mmole) and dimethylsulfoxide (1.1g, 5.0 eq.,10.5 mmole) in 20
mL of acetonitrile. Flash chromatography of the residue on silica Merck-60 using a
gradient elution of 30 to 45% ethyl acetate in hexane gave a white powder (0.453 g).
Further purification was achieved by prep HPLC, Primesphere C18, 2 X 25 cm
column, 68% acetonitrile in water containing trifluoroacetic acid, 100 ml/min, 254 nm
detection. The pure fractions were neutralized with ammonium hydroxide and
evaporated to an amorphous solid (0.153 g).
MS [(+)ESI, m/z]: 546.2 [M+H]+
MS [(-)ESI, m/z]: 544.2 [M-Hf
EXAMPLE 7
N-[(4-Benzylmorpholin-2-yl)methyl]-10-[(2'-methoxy-1,r-biphenyl-4-yl)carbonyl]-
10,11 -dihydro-5H-pyrrolo[2,1 -c][1,4]benzodiazepine-3-carboxamide
The title compound was prepared according to the procedure of Example 2
starting from 2,2,2-trich!oro-1-{10-[(2'-methoxy-1,1 '-biphenyl-4-yl)carbonyf]-10,11-
dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}ethanone of Example 1 (0.619 g,
1.15 mmole), (4-benzyl-1,4-oxazinan-2-yl)-methylamine (01.97 g, 0.955 mmole),
dimethylsulfoxide (0.374 g, 4.8 mmole), and triethylamine ( 0.213 g, 2.1 mmole) in 15
mL of acetonitrile. The residue was adsorbed on silica Merck-60 and purified by flash
chromatography (0-75% ethyl acetate in dichioromethane) to provide an off white
solid (0.241 g), m.p. 180-182 °C
MS [(+)ESI, m/z]: 627.19 [M+H]+
Anal. Calcd for C39H38N4O4: 0.35 C5H10O2: C 73.79, H 6.25, N 8.52. Found: C 73.62,
H 6.07, N 8.55.
EXAMPLE 8
N-[(1 -Methyl-1 H-pyrrol-2-yl)methyl]-10-[(2,2',6'-trimethyl-1,1 '-biphenyl-4-yl)carbonyl]-
10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide
The title compound was prepared according to procedure of Example 2
starting from 2,2,2-trichloro-1-{10-[(2,2l,6l-trimethyl-1l1l-biphenyl-4-yl)carbonyl]-10,11-
dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}ethanone of Example 3 (1.4 g, 2.5'
mmole), (1-methyl-1H-pyrrol-2-yl)methylamine (0.234 g, 2.1 mmole),
dimethylsulfoxide (0.822 g, 10.5 mmole) and triethyl amine (0.470 g, 4.6 mmole) in
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WO 2006/124581 PCT/US2006/018420
15 mL of acetonitrile, Flash chromatography of the residue on silica gel Merck-60 (0-
25% ethyl acetate in dichloromethane) gave a foam (0.924 g) which solidified upon
treatment with ethyl acetate/hexane/dichloromethane, mp. 222-224 °C.
MS [(+)ESI, m/z]: 543.3 [M+H]+; [(-)ESI, mz]: 541.3 [M-HT
EXAMPLE 9
2,2,2-Trichloro-1-{10-[(2,2'-dimethyl-1,1'-bipheny!-4-yl)carbonyl]-10,11-dihydro-5H-
pyrrolo[2,1-c]t1,4]benzodiazepin-3-yl}ethanone
STEP A. Methyl 2,2'-dimethyl-1,1'-biphenyl-4-carboxylate
A mixture of methyl 4-bromo-3-methylbenzoate (25.0 g, 110 mmol), o-
tolylboronic acid (16.5 g, 120 mmol) and potassium carbonate (50 g, 360 mmol) in
dioxane : water (300 mL : 200 mL) was purged with nitrogen for 1hour. [1,1'-
bis(Diphenylphosphino)ferrocene] dichloropalladium [II] (4.5 g, 5.5 mmol) was added
and the reaction mixture heated to 100 °C with vigorous stirring for 3.5 hours. The
cooled reaction mixture was filtered through Celite and the cake washed with ethyl
acetate (500 mL). The combined organic phases were washed with 1 M aqueous
sodium hydroxide (500 mL) and brine (500 mL), dried over anhydrous potassium
carbonate, filtered and concentrated in vacuo to afford a dark oil (28.6 g).
Purification by flash chromatography using 2 % ethyl acetate in hexanes as solvent
provided the title compound (24.7 g) as a pale yellow oil.
HRMS. Calcd for C16H17O2: 241.12231. Found [(+)ESI, m/z]: 241.12205.
Anal. Calcd for C16H16O2: C 79.97, H 6.71. Found: C 79.67, H, 6.61.
STEP B. 2,2'-Dimethyl-biphenyl-4-carboxylic acid
To a solution of methyl 2,2'-dimethyl-1,1'-biphenyl-4-carboxylate of Step A
(24.7 g, 103 mmol) in 5 :1 tetrahydrofuran : methanol (200 mL) was added 1 M
aqueous sodium hydroxide (108 mL, 108 mmol). The reaction mixture heated at
reflux for 1 hour, cooled and then concentrated in vacuo to remove organic solvents.
The resulting aqueous solution was cooled to 0 °C and 2 M aqueous hydrochloric
acid (60 mL, 120 mmol) added slowly followed by water (60 mL) to facilitate stirring of
the precipitated product. The suspension was stirred for 1 h at 0 °C then filtered to
afford the title compound (22.6 g) as a white solid, m. p. 140-143 °C.
MS [(+)ESI, m/z]: 225 [M-H]-.
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WO 2006/124581 PCT/US2006/018420
STEPC. (10,11-Dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-10-yl)-(2,2'-dimethyl-
biphenyl-4-yl)-methanone
To a suspension of 2,2'-dimethyl-biphenyl-4-carboxylic acid of Step B (22.4 g,
99.0 mmol) in dry dichloromethane (500 mL) at room temperature under nitrogen
was added dry N, N-dimethylformamide (5 mL) followed by the. dropwise addition of
2.0 M solution of oxalyl chloride in dichloromethane (60 mL, 120 mmol). The reaction
mixture was stirred at room temperature for 2 hours then concentrated in vacuo and
the residue redissolved in dry dichloromethane (200 mL). The solution was .
concentrated in vacuo to afford the crude acid chloride as a brown oil. The acid
chloride was dissolved in dichloromethane (500 mL), 10,11-dihydro-5H-pyrrolo[2,1-
c][1,4]benzodiazepine (21.9 g, 119 mmol) was added followed by N, N-
diisopropylethylamine (87 mL, 500 mmol) and the reaction mixture stirred at room
temperature under nitrogen for 16 hours. The reaction mixture was then washed with
1 M aqueous hydrochloric acid (5x1 L), 10% aqueous sodium hydroxide (1 L) and
brine (500 mL), dried over anhydrous magnesium sulfate, filtered and concentrated in
vacuo to give a dark foam. Purification by flash chromatography using a solvent
gradient of 2.5 to 40% ethyl acetate in hexane gave a tan solid that was recrystallized
from ethyl acetate/hexane to afford the title compound (12.4 g) as a pale orange
solid. Purification of the mother liquors by flash chromatography yielded additional
title compound (11.5 g) as a white solid, m.p. 145-148 °C.
MS [(+)ESI, m/z]: 393 [M+H]+.
Anal. Calcd for C27H24N2O: C 82.62, H 6.16, N 7.14. Found: C 82.26, H 5.83, N
6.50.
STEP D. 2,2,2-TrichIoro-1-{10-[(2,2'-dimethyl-1,1'-biphenyl-4-yl)carbonyl]-10,11-
dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}ethanone
To a solution of (10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-10-yl)-
(2,2'-dimethyl-biphenyl-4-yl)-methanone of Step C (8.38 mmol) and triethylamine
(16.76 mmol) in dichloromethane (30 mL) at ~5°C was added, rapidly dropwise,
trichloroacetyl chloride (25 mmol). The mixture was allowed to stir and warm to room
temperature overnight. The mixture was washed with 0.1 N hydrochloric acid and
dilute brine, then dried over anhydrous sodium sulfate, and evaporated to leave a
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WO 2006/124581 PCT/US2006/018420
light green oil. The compound was purified by filtration over a plug of Merck silica
gel-60 eluting with dichloromethane and then treated with hot ethyl acetate/ hexane
(3/1) to yield a light yellow crystalline solid, m.p. 212-214 °C.
MS K+XESI, m/z]: 537 [M+H]+
Anal. Calcd for C29H23CI3N2O2: C 64.76, H 4.31, N 5.21. Found: C 64.70, H 4.35, N
4.96.
EXAMPLE 10
10-[(2,2'-Dimethyl-1,1'-biphenyl-4-yl)carbonyl]-N-{[5-(4-methoxyphenyl)-1,2,4-
oxadiazol-3-yl]methyl}-10,11 -dihydro-5H-pyrrolo[2,1 -c][1,4]benzodiazepine-3-
carboxamide
STEP A. [5-(4-Methoxyphenyl)-1,2,4-oxadiazol-3-yl]methylamine
To a solution of 3-chloromethyl-5-(4-methoxy-phenyl)-[1,2,4]oxadiazole (8.90
mmol) in N,N-dimethylformamide (10 mL) was added sodium azide (17.8 mmol).
This mixture was stirred at room temperature for 20 hours. The reaction mixture was
poured into water (30 mL) and extracted with dichloromethane (3x). The combined
organic extracts were combined and washed with water (2x), dried over anhydrous
sodium sulfate, and evaporated. Then clear oily residue was placed under high
vacuum and gently warmed for 18 hours. Upon cooling the material solidified. This
solid was dissolved in teterahydrofuran (15 mL) and treated with triphenylphosphine
(9.0 mmoi). Bubbling was immediately evident. This mixture was stirred for 16 hours
and then treated with water (3.0 mL). This was heated in a 45 °C oil bath for 3 hours.
The product was purified by flash chromatography (silica gel; 2:1
ether/dichloromethane), m.p. 66-68 °C.
MS [(+)(ESI, m/z]: 206 [M+H]+
Anal. Calcd for C10H11N3O2: C 58.53, H 5.40, N 20.48. Found: C 58.5, H 5.38, N
20.59.
STEP B. 10-[(2,2'-Dimethyl-1,1'-biphenyl-4-yl)carbonyl]-N-{[5-(4-methoxyphenyl)-
1,2,4-oxadiazol-3-yl]methyl}-10,11-dihydro-5H-pyrro!o[2,1-c][1,4]benzodiazepine-3-
carboxamide
A mixture of 2,2,2-trichloro-1-{10-[(2,2'-dimethyl-1,1'-biphenyl-4-yl)carbonyl]-
10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}ethanone of Example 9 (0.26
mmol), dimethylsulfoxide (100 uL) and [5-(4-methoxyphenyl)-1,2,4-oxadiazol-3-
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WO 2006/124581 PCT/US2006/018420
yl]methylamine of Step A (0.546 mmol) in acetonitrile (2.5 mL) was heated to 85° C
for 16 hours. After cooling the solvent was evaporated and the residue was taken up
in dichloromethane (10 mL). This was washed with water (2x), dried over anhydrous
sodium sulfate, and evaporated. The residue was purified by HPLC (Normal phase,
Luna CN bonded packing) and crystallized from ethyl acetate/hexane, m.p. 133-135
°C.
MS [(+) ESI, m/z]: 622 [M+H]+
Anal. Calcd for C38H33N5O4: C 73.18, H 5.33, N 11.23. Found: C 71.95, H 5.64, N
11.52.
EXAMPLE 11
N-{[2-(4-Chlorophenyl)-1,3-thiazol-4-y!]methyl}-104(2,2'-dimethyl-1,1 '-biphenyl-4-
yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide
STEP A. 2-(4-Chlorophenyl)-1,3-thiazol-4-yl]methylamine
The title compound was prepared from 4-chloromethyl-2-(4-chloro-phenyi)-
thiazole according to the procedure of Example 10, Step A, m.p. 61-64 °C.
MS [(+)ESI, m/z]: 225 [M+H]+
Anal. Calcd for C10H9CIN2S: C 53.45, H 4.04, N 12.47. Found: C 53.57, H 4.05, N
12.45.
STEP B. N-{[2-(4-Chlorophenyl)-1,3-thiazol-4-yl]methyl}-10-[(2,2'-dimethyl-1,1'-
biphenyl-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-
carboxamide
The title compound was synthesized from 2,2,2-trichloro-1-{10-[(2,2'-dirnethyl-1,1'-
biphenyl-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-
yljethanone of Example 9 and 2-(4-chloro-phenyl)-thiazol-4-yl]-methylamine of Step
A according to the procedure of Example 10, Step B, m.p. 198-201 °C.
MS [(+)ESI, m/z]: 641 [M+H]+
EXAMPLE 12
10-[(2,2'-Dimethyi-1,1'-biphenyi-4-yi)carbonyl]-N-(piperidin-3-ylmethyl)-10,11-dihydro-
5H-pyrrolo[2,1 -c][1,4]benzodiazepine-3-carboxamide
STEP A. tert-Butyl 3-{[({10-[(2,2'-dimethyl-1,1'-biphenyl-4-yl)carbonyl]-10,1dihydro-
5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}carbonyl)amino]methyl}piperidine-1-
carboxylate
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WO 2006/124581 PCT/US2006/018420
To a suspension of 2,2,2-trichloro-1-{10-[(2,2'-dimethyl-1,1'-biphenyI-4-
yl)carbonyl]-10,11-dihydro-5H-pynrolo[2,1-c][1,4]benzodiazepin-3-yl}ethanone of
Example 9 (0.54 g, 1.0 mmol) and 3-aminomethyl-piperidine-1-carboxylic acid tert-
butyl ester (0.43 g, 2.0 mmol) in dry acetonitrile (5 mL) was added dimethylsulfoxide
(0.35 mL, 4.9 mmol) and the reaction mixture heated to 80 "C under nitrogen for 3
days. The cooled reaction mixture was diluted with dichloromethane (25 mL),
washed with water (2 x 25 mL) and brine (25 mL), dried over anhydrous potassium
carbonate, filtered and concentrated in vacuo to afford a brown oil (0.81 g).
Purification by flash chromatography using a solvent gradient of 3 to 20% ethyl
acetate in dichloromethane gave the title compound (0.45 g) as a white foam.
HRMS. Calcd for C39H45N4O4 633.34354. Found [(+)ESI, m/z]: 633.34262.
STEP B. 10-[(2,2'-Dimethyl-1,1 '-biphenyl-4-yl)carbonyl]-N-(piperidin-3-ylmethyl)-
10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide
To a solution of tert-butyl 3-{[({10-[(2,2'-dimethyl-1,1'-biphenyl-4-yl)carbonyl]-
10,11 -dihydro-5H-pyrrolo[2,1 -c][1,4]benzodiazepin-3-
yl}carbonyl)amino]rnethyl}piperidine-1-carboxylate of Step A (0.42 g, 0.66 mmol) in
dry dichloromethane (3 mL) was added trifluoroacetic acid (0.51 mL, 6.6 mmol) and
the reaction, mixture stirred at room temperature under nitrogen for 20 hours. The
reaction mixture was then diluted with dichioromethane (50 mL), washed wiih 1 fvi
sodium hydroxide solution (50 mL) and brine (50 mL), dried over anhydrous
magnesium sulfate, filtered and concentrated in vacuo to afford a pink glass.
Purification by flash chromatography using a solvent gradient of 2.5 to 10% ammonia
saturated methanol in dichloromethane gave a pale yellow oil (0.31 g).
Crystallization from diethyl ether (2 mL) afforded the title compound (0.19 g) as a
pale yellow solid.
HRMS. Calcd for C34H37N4O2: 533.29111. Found [(+)ESI, m/z]: 533.29102.
Ail references, including but not limited to articles, texts, patents, patent
applications, and books, cited herein are hereby incorporated by reference in their
entirety.
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WO 2006/124581 PCT/US2006/018420
WHAT IS CLAIMED IS:
1. A compound represented by the Formula I:
or a pharmaceutically acceptable salt thereof,
wherein
R1 and R2 are independently selected from hydrogen, (C1-C6) alkyl, halogen,
cyano, trifluoromethyl, hydroxyl, (C1-C6) alkoxy, -OCF3, carboxy, (C1-C6
alkoxy)carbonyi, -CONH2, -CONH[(C1-C6) alkyl], -CON[(C1-C6) alkyl]2,amino,(C1-C6)
alkylamino or -NHCO[(C1-C6) alkyl];
R3 is a substituent selected from hydrogen, (C1-C6) alkyl, (C1-C6) alkoxy,
hydroxy, amino, (C1-C6) alkylamino, -C(O)(C1-C6)alkyl, or halogen;
/"
wherein R5, R6, R7, R8, R9 and R10 are independently, selected from
the group consisting of hydrogen, alkyl, (C1-C6)alkyl, alkoxy, (C1-C6) alkoxy,
hydroxyalkyl, hydroxy(C1-C6) alkyl, alkyloxyalkyl, (C1-C6)alkoxy(C1-C6)alkyl, (C2-C7)
acyloxy (C1-C6)alkyl, (C1-C6alkyl) carbonyl, (C2-C6) alkenyl, (C2-C6) alkynyl, (C3-C8)
cycloalkyl, formyl, (C3-C8)cycloalkylcarbonyl, carboxy, (C1-C6)alkoxycarbonyl, (C3-
C8cycloalkyl) oxycarbonyl, aryl(C1-C6)alkyloxycarbonyl, carbamoyl,-O-CH2-CH=CH2,
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WO 2006/124581 PCT/US2006/018420
(C1-C6)alkyl substituted with 1-3 halogen atoms, trihalomethyl, trifluoromethyl,
halogen, OCF3, thioalkyl, thio(C1-C6) alkyl, -C(O) alkyl, -C(O)aryl optionally
substituted by alkyl; hydroxy, -CH(OH)alkyl, -CH(alkoxy)alkyl, nitro, -SO2alkyl, (C1-C6)
alkylsulfonyl, aminosulfonyl, (C1-C6) alkylaminosulfonyl, -SO2NHRn, -SO2N(Rn)2, -
OC (0) N [(C1-C6)alkyl] 2,-CONH [(C1-C6) alky!],-CON [(C1-C6) alkyl] 2,-(CH2)pCN ,
(C1-C6) alkylamino, di-(C1-C6) alkylamino, (C1-C6) alkyl di-(C1-C6) alkylamino,
-(CH2)PNR13R14, -(CH2)pCONR13R14, -(CH2)PCOOR12, -CH=NOH, -CH=NO-(C1-C6)

-63-

R23 is alkyl, C1-C6 alkyl, or an optionally substituted (C6-
C20) aralkyl.
2. A compound according to claim 1, wherein R15 and R16 are each hydrogen;
and t is 1.
3. A compound according to claim 1 or claim 2, wherein M is selected from the
group consisting of

4. A compound according to claim 1 or claim 2, wherein M is selected from the
group consisting of
5. A compound according to any one of claims 1 to 4, wherein B has the
formula:
6. A compound according to any one of claims 1 to 5, wherein R1, R2 and R3 are
each hydrogen.
7. A compound according to claim 1, having the Formula:
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WO 2006/124581 PCT/US2006/018420

or a pharmaceutically acceptable salt thereof.
8. A compound according to claim 7, wherein R5 is selected from H, and C1-C3
alkyl.
9. A compound according to claim 7 or claim 8, wherein R8 and R9 are
independently selected from H, C1-C3 alkyl, and C1-C3 alkoxy.
10. A compound according to claim 1, claim 2 or any one of claims 5 to 9,
wherein M is
wherein R17 is an optionally substituted aryl.
11. A compound according to claim 10, wherein R17 is a phenyl, optionally
substituted with from 1 to 3 substituents selected from C1-C3 alkyl, C1-C3 alkoxy, and
halogen.
12. A compound according to claim 11, wherein said C1-C3 alkoxy of said R17 is
methoxy.
13. A compound according to claim 1, having the following Formula:


14. A compound of Formula I as claimed in claim 1, claim 2 or any one of claims
5 to 9, wherein M is
wherein R18 is an optionally substituted aryl;
or a pharmaceutically acceptable salt thereof.
15. A compound according to claim 14, wherein R18 is a phenyl, optionally
substituted with from 1 to 3 substituents selected from C1-C3 alkyl, C1-C3 alkoxy, and
halogen.
16. A compound according to claim 15, wherein said halogen is chlorine.
17. A compound according to claim 1, having the following formula:


18. A compound of claim 1 or claim 2 or any one of claims 5 to 9 wherein M is

or a pharmaceutically acceptable salt thereof.
19. A compound according to claim 18, wherein R19 is methyl.
20. A compound according to claim 1, having the following formula:

21. A compound according to claim 1 having the following formula:
-67-


22. A compound of claim 1 or claim 2 or any one of claims 5 to 9 wherein M is

wherein R20 is C1-C6 alkyl;
or a pharmaceutically acceptable salt thereof.
23. A compound according to claim 22, wherein R20 is methyl.
24. A compound according to claim 1, having the following formula:

25. A compound according to claim 1, having the following formula:
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WO 2006/124581 PCT/US2006/018420


WO 2006/124581 PCT/US2006/018420

wherein R23 is optionally substituted C7-C2o aralkyl.
33. A compound according to claim 32 wherein R23 is benzyl.
34. A compound according to claim 1 having the following formula:
-70-


35. A method for preparing a compound of claim 1, comprising:
reacting a trichloroacetyl compound of formula (2)

with an appropriately substituted primary or secondary amine of formula (3)
RH
(3)
under conditions sufficient to yield a compound of Formula (I).
36. The method of claim 35, wherein said reaction occurs in the presence of 1,4-
dioxane, dimethylsulfoxide, or both.
37. The method of claim 36 wherein said reaction occurs in the presence of an
organic base.
38. The method of claim 37 wherein said organic base is a tertiary amine.
39. The method of claim 38 wherein said tertiary amine is triethyl amine or N,N-
diisopropylethylamine.
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WO 2006/124581 PCT/US2006/018420
40. The method of any one of claims 27 to 39 wherein said reaction is performed
in a solvent.
41. The method of claim 40 wherein said solvent is acetonitrile.
42. The method of claim 41, wherein reaction is performed at a temperature of
from about ambient to the refluxing temperature of the solvent.
43. The method of claim 35, wherein said trichloroacetyl compound of formula (2)
is prepared by:
reacting a tricyclic azepine of formula (1)

with perhaloalkanoyl halide under conditions sufficient to provide the desired
trichloroacetyl compound of formula (2).
44. The method of claim 43, wherein said perhaloalkanoyl halide is trichloroacetyl
chloride.
45. The method of claim 43 or ciaim 44, wherein said reaction occurs in the
presence of an organic base in an aprotic organic solvent.
46. The method of claim 45 wherein said organic base is N,N-diisopropylethyl
amine.
47. The method of claim 45, wherein said aprotic organic solvent is
dichloromethane or 1,4-dioxane.
48. The method of any one of claims 45 to 47, wherein said reaction is performed
at a temperatures of from about -10 °C to about ambient.
49. A method for making a compound of Formula I according to claim 1,
comprising:
coupling a compound of Formula (4)
-72-


where W is OH or halogen;
with an appropriately substituted primary or secondary amine of formula (3)
RH
(3)
under conditions sufficient to yield a compound of formula (I) of claim 1.
50. The method of claim 49 wherein W is Cl or Br.
51. The method of claim 50 wherein the coupling of the acyl halide of formula (4)
with the substituted amine of formula (3) is performed in the presence of a tertiary
amine in an aprotic solvent.
52. The method according to claim 51, wherein said aprotic solvent is
dichloromethane, N,N-dimehtyl formamide, or tetrahydrofuran; and the tertiary amine
is N.N-diisopropylethylamine.
53. The method of claim 51, wherein the coupling of the acyl halide of formula (4)
with the substituted amine of formula (3) is performed at a temperature of from about
ambient to the reflux temperature of the solvent.
54. The method of claim 49 wherein W is OH.
55. The method of claim 54 wherein said coupling comprises:
reacting said carboxylic acid (4) with a primary or secondary amine of formula
(3) in the presence of at least one of an activating reagent or a coupling reagent
under conditions sufficient to yield a compound of formula (I).
56. The method of claim 55, wherein said activating agent is selected from:
triphosgene in an aprotic solvent
N,N-dicyclohexylcarbodiimide or 1-ethyl-3-(3-dimehtylamino-
propyl)carbodiimide hydrochloride in the presence of 1-hydroxy benzotriazole; or
N,N'-carbonyldiimidazole in an aprotic solvent.
-73-

57. The method of claim 56, wherein said reaction occurs in the presence of an
organic base.
58. The method of claim 57, wherein said organic base is a tertiary amine.
59. The method of claim 57, wherein said organic base is N,N-
diisopropylethylamine.
60. The method of any one of claims 57 to 59, wherein said reaction is performed
in the presence of a catalyst.
61. The method of claim 60, wherein said catalyst is 4-(dimethylamino)pyridine.
62. The method of any one of claims 55 to 61, wherein said coupling reagent is
selected from hydroxybenzotriazole tetramethyluronium hexafluorophosphate,
diphenylphosphoryl azide, diethyl cyano phosphonate, or benzotriazol-1-yl-oxy-tris-
(dimethylamino) phosphonium hexafluorophosphate.
63. The method of claim 51 wherein said compound of Formula 4 wherein W is Cl
or Br is prepared by conversion of a compound of Formula 4 wherein W is OH.
64. The method of claim 54, wherein said conversion comprises:
reacting said compound of Formula 4 wherein W is OH with thionyl halide or
an oxalyl halide.
65. The method of claim 64, wherein said conversion occurs in the presence of at
least one of an inorganic base and an organic base in an aprotic solvent.
66. The method of claim 65 wherein said inorganic base is potassium carbonate.
67. The method of claim 65, wherein said organic base is pyridine, 4-
(dimethylamino)pyridine, or a tertiary amine.
68. The method of claim 67, wherein said tertiary amine is triethylamine.
69. The method of claim 65, wherein said aprotic solvent is dichloromethane,
N,N-dimethylformamide, or tetrahydrofuran.
70. The method of claim 65, wherein said conversion is performed at a .
temperature of from about -5"C to about 50°C.
71. A method of preparing a compound of Formula I according to claim 1,
comprising:
reacting a tricyclic diazepine of formula (1)
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with diphosgene and a primary or secondary amine of formula (3)
RH
(3)
in an aprotic solvent under conditions sufficient to yield a compound according to
formula (I).
72. The method of claim 71, wherein said solvent is dichloromethane.
73. The method of claim 71, wherein said reaction occurs in the presence of an
organic base.
74. The method of claim 73, wherein said organic base is triethylamine.
75. A method for preparing a compound of claim 1, comprising:
reacting a trichloroacetyl compound of formula (26)

where Pg is a protecting group, with an appropriately substituted primary or
secondary amine of formula (3)
RH
(3)
under conditions sufficient to yield an intermediate amide of formula (27)
-75-


76. The method of claim 75, wherein Pg is selected from the group consisting of
a fluorenyl alkoxy carbonyl and an alkoxy carbonyl.
77. The method of claim 76, wherein Pg is fluorenyl methyloxy carbonyl.
78. The method of claim 75, wherein Pg is tert-butyloxy carbonyl.
79. The method of any one of claims 75 to 78, wherein said reaction occurs in the
presence of 1,4-dioxane, dimethylsulfoxide, or both.
80. The method of claim 79 wherein said reaction occurs in the presence of an
organic base.
81. The method of claim 80 wherein said organic base is a tertiary amine.
82. The method of claim 81 wherein said tertiary amine is triethyl amine or N,N-
diisopropylethylamine.
83. The method of claim 80 wherein said reaction is performed in a solvent.
84. The method of claim 83 wherein said solvent is acetonitrile.
85. The method of claim 84, wherein reaction is performed at a temperature of
from about ambient to the refluxing temperature of the solvent.
86. The method of claim 75, further comprising deprotecting the intermediate
amide of formula (27) under conditions sufficient to yield an intermediate of formula
(28)
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87. The method of claim 88, further comprising acylating the intermediate of
formula (28) under conditions sufficient to produce a compound of formula I.
88. The method of claim 75, wherein said trichloroacetyl compound of formula
(26) is prepared by:
reacting a tricyclic azepine of formula (1)

where Pg is a protecting group, with perhaloalkanoyl halide under conditions
sufficient to provide the desired trichloroacetyl compound of formula (26).
89. The method of claim 88, wherein said perhaloalkanoyl halide is trichloroacetyl
chloride.
90. The method of claim 88 or claim 89, wherein said reaction occurs in the
presence of an organic base in an aprotic organic solvent.
91. The method of claim 90 wherein said organic base is N,N-diisopropylethyl
amine.
92. The method of claim 90, wherein said aprotic organic solvent is
dichloromethane or 1,4-dioxane.
93. The method of any one of claims 88 to 92, wherein said reaction is performed
at temperatures of from about -10 °C to about ambient.
94. A method for preparing a compound according to claim 1, comprising:
reacting a compound of formula (26)
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where Pg is a protecting group, with an aqueous base, and
removing Pg to yield an intermediate of formula (29)

95. The method of claim 94, further comprising treating the intermediate of
formula (29) with an activating agent and an appropriately substituted primary or
secondary amine of formula (3)
RH
(3)
under conditions sufficient to yield an intermediate of formula (28)

96. The method of claim 95 further comprising acylating the intermediate of
formula (28) under conditions sufficient to yield a compound of formula I.
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The invention provides compounds of formula (1) or a pharmaceutically
acceptable salt thereof, wherein R, R1, R2, R3, and B are as defined in the accompanying
specification. Methods of making such compounds are also provided.