WO 2006/124523 PCT/US2006/018276
PYRROLOBENZODIAZEPINES AND HETEROARYL, ARYL AND
CYCLOALKYLAMINO KETONE DERIVATIVES AS FOLLICLE STIMULATING
HORMONE RECEPTOR (FSH-R) ANTAGONISTS
This application claims benefit of priority to U.S. Provisional Patent
Application No. 60/680,321 filed May 12, 2005, which is hereby incorporated by
reference.
FIELD OF THE INVENTION
The present invention relates to pyrrolobenzodiazepines and derivatives
thereof having antagonist activity on the FSH receptor, to methods of making the
same, and to their use as contraceptives.
BACKGROUND OF THE INVENTION
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, luteinizing 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 granulosa 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,
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WO 2006/124523 PCT/US2006/018276
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,
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 antagonists could be
expected to interfere with follicle development and thus ovulation, while maintaining
sufficient estrogen production and beneficial effects on bone mass.
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WO 2006/124523 PCT/US2006/018276
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)).
SUMMARY OF THE INVENTION
In some embodiments, the invention provides compounds represented by the
formula I
or a pharmaceutically acceptable salt thereof,
wherein
R1 and R2 are independently selected from the group consisting of 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, and -NHCO[(C1-C6) alkyl];
R3 is selected from the group consisting of hydrogen, (C1-C6) alkyl, (C1-C6)
alkoxy, hydroxy, amino, (C1-C6) alkylamino, -C(O)(C1-C6)alkyl, and halogen; •
B is B, or B2,
wherein Bi is selected independently from the group consisting of

wherein R5, R6, R7, R8, R9 and R10 are independently, selected from the group
consisting of hydrogen, (C1-C6)alkyl, (C1-C6) alkoxy, hydroxy(C1-C6) alkyl, (C1-
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C6)alkoxy(C1-C6)alkyl, (C2-C7) acyloxy (C1-CB)a!kyl, (C1-C6a!ky!) carbonyl, (C2-C6)
alkenyl, (C2-C6) alkynyl, (C3-C8) cycloalkyl, formyl, (C3-C8)cycloalkylcarbonyl,
carboxy, (C1-C6)alkoxycarbonyl, (C3-C8)cycloalkyloxycarbonyl, aryl(C1-
C6)alkyloxycarbonyl, carbamoyl,-O-CH2-CH=CH2, (C1-C6)a!kyl substituted with 1-3
halogen atoms, trihalomethyi, trifluoromethyl, halogen, OCF3, thio(C1-C6) alkyl, -C(O)
(C1-C6)alkyl, -C(O)aryl optionally substituted by (C1-C6)alkyl; hydroxy, -CH(OH) (C1-
C6)alkyl, -CH(C1-C6) (alkoxy) (C1-C6)aIkyl, nitro,~SO2(C1-C6)alkyl, (C1-C6)
alkylsulfonyl, aminosulfonyl, (C1-C6) alkylaminosulfonyl, -SO2NHR11, -SO2N(R11)2, -
OC (O) N [(C1-C6)alky!] 2,-CONH [(C1-C6) alkyl],-CON [(C1-C6) alky!] 2,-(CH2)pCN ,
(C1-C6) aikylamino, di-(C1-C6) alkylamino, (C1-C6) alkyl di-(C1-C6) alkylamino,
-(CH2)pNR13R14, -(CH2)PCONR13R14, -(CH2)PCOOR12, -CH=NOH, -CH=NO-(C1-C6)
alkyl, trifluoromethylthio,
R11 and R12 are each independently hydrogen, (C1-C6)a!kyl or
C3-C8 cycloalkyl;
R13 and R14 are each independently hydrogen, (C1-C6)alkyl, or
C3-C8 cycloalkyl;
or R13 and R14 can be taken together with the nitrogen to which
they are attached to form a 4-6 membered saturated ring optionally containing up to
two atoms selected from O, S or N;
p is 0 or 1;
A is A1 or A2, wherein

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provided that when A is A2, then B is B2 wherein B2 is

wherein R15and R16 are selected independently from the group consisting of
hydrogen, (C1-C6)alkyl, and halogen;
wherein
R17a, R17b, and R17c are each independently selected from the group
consisting of hydrogen, (C1-C6)alkyl, halogen, hydroxy, aryloxy, and hydroxy(C1-
C8)alkyl;
u is the integer 0,1,2, 3, or 4;
v is the integer 1, 2, 3, or 4;
r is 0 or 1;
R18 is hydrogen or (C1-C6)alkyl; and
R19 is a cycloalkylamine.
R20a and R20b are each independently selected from the group consisting of
hydrogen, (Ci-C6)alkyl, halogen, or aryl; or R20aand R20b can be taken together with
the aryl to which they are attached to form an aromatic bicycle having up to 10 total
ring atoms.
In some embodiments, the invention provides compounds represented by the
formula II
or a pharmaceutically acceptable salt thereof,
wherein R1 - R3, A1 and B1 are as defined above;
In some embodiments, the invention provides compounds represented by the
following formulae:
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In some embodiments, the invention provides compounds represented by the
following formula III:
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or a pharmaceutically acceptable salt thereof,
wherein R1 - R3, A2 and B2 are as defined above;
In some embodiments, the invention provides compounds represented by the
following formulae:

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In some embodiments, the invention provides methods of preparing a
compound of formula I
or a pharmaceutically acceptable salt thereof,
wherein R1 - R3, A and B are as defined above;
said method comprising:
reacting a tricyclic diazepine of formula (1)
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with an acyl halide of formula (4)

where Y is halogen;
under conditions sufficient to produce the desired compound of formula 1.
In some embodiments, the invention provides methods for making a compound of
formula 27

or a pharmaceutically acceptable salt thereof,
wherein R1 - R3 are as defined above, Pg is a protecting group, and A is selected
from
said method comprising
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reaction of the intermediate of formula (26)
. (■
In some embodiments, the invention provides such methods further
comprising deprotecting the compound of formula (27) to yield the intermediate of
formula (28)
then acylating the intermediate of formula (28) to give the compound of formula (I).
In some embodiments, the invention provides methods wherein the
compound of formula (26) is prepared by reacting a tricyclic diazepine of formula (25)
wherein
R1, R2 and R3 are defined hereinbefore, and
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Pg is a protecting group;
with an acid chloride under conditions sufficient to provide the desired intermediate of
formula (26).
In some embodiments, the invention provides methods for preparing a
compound of general formula II

or a pharmaceutically acceptable salt thereof,
wherein R1 - R3 and B1 are as defined above;

R17a, R17b, and R17c are each independently selected from the group consisting
of hydrogen, alkyl, halogen, hydroxy, aryloxy, and hydroxyalkyl;
uis 0, 1,2,3, or 4;
vis 1,2, 3, or 4;
r is 0 or 1;
R18 is hydrogen or alkyl; and
R19 is a cycloalkylamine.
said method comprising:
reacting a compound of formula (2)
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conditions sufficient to produce the desired compound of formula II.
In some embodiments, the invention provides such methods where the
compound of formula (2) is prepared by:
reacting a tricyclic diazepine of formula (1)

wherein R1, R2, and R3 are defined hereinbefore,
with an acyl halide
XCOY
where X is a halide, and Y is halo-(CH2)v-;
under conditions sufficient to produce compound (2).
In some embodiments, the invention provides methods of preparing a
compound according to formula III
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or a pharmaceutically acceptable salt thereof,
wherein R1 - R3, A2 and B2 are as defined above;
said method comprising:
reacting a tricyclic diazepine of formula (5)

with an acid halide of formula 6
A2COY
(6)
wherein Y is halogen;
under conditions to produce a compound according to formula III.
In some embodiments, the invention provides methods for making a
compound of formula (27)
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or a pharmaceutically acceptable salt thereof,
wherein R1 - R3 are as defined above, Pg is a protecting group, and A is A2;
said method comprising
treating a compound of formula (25)

with an acid chloride of formula (4)
ACOY
4
under the conditions sufficient to yield the amide of formula (27)

wherein A is A2 as defined hereinbefore.
In some embodiments, the invention provides such methods further
comprising deprotecting the compound of formula (27) to yield the intermediate of
formula (28)
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" then acylating the intermediate of formula (28) to give the compound of formula (I)
wherein B is as defined above.
In some embodiments, the invention provides the product made by any of the
processes.
These and other embodiments will be recognized by those of skill in the art
upon reading this specification.
DETAILED DESCRIPTION OF THE INVENTION
In some embodiments, the invention provides compounds of formula (I):

or a pharmaceuticaily acceptable salt thereof,
wherein
R1 and R2 are independently selected from the group consisting of hydrogen,
(C1-C6) alkyl, halogen, cyano, trifluoromethyl, hydroxyl, (C1-C6) alkoxy, -OCF3,
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carboxy, (C1-C6 alkoxy)carbonyl, -CONH2, -CONH[(Ci-C6) alkyl], -CON[(C1-C6) alkyl]2,
amino, (C1-C6) alkylamino, and -NHCO[(C1-C6) alkyl];
R3 is selected from the group consisting of hydrogen, (C1-C6) alkyl, (C1-C8)
alkoxy, hydroxy, amino, (C1-C6) alkylamino, -C(O)(C1-C6)alkyl, and halogen;
B is B, or B2,
wherein B1 is selected independently from the group consisting of

wherein R5l R6, R7, R8, R9 and R10 are independently, selected from the group
consisting of hydrogen, (C1-C6)alkyl, (C1-C6) alkoxy, hydroxy(C1-C6) alkyl, (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-C6) cycloalkyl oxycarbonyl, aryl(C1-
C6)aikyioxycarbonyi, carbamoyi,-O-CH2-CH=CH2, (C1-C6)alkyl substituted wiih i-3
halogen atoms, trihalomethyl, trifluoromethyl, halogen, OCF3, thio(C1-C6) alkyl, -C(O)
(C1-C6)alkyl, -C(O)aryl optionally substituted by (C1-C6)alkyl; hydroxy, -CH(OH)(C1-
C6)alkyl, -CH(C1-C6)(alkoxy)(C1-C6)alkyl, nitro, -SO2(C1-C6)alkyl, (C1-C6) alkylsulfonyl,
aminosulfonyl, (C1-C6) alkylaminosulfonyl, -SO2NHR11, -SO2N(R11)2, -OC (O) N [(C1-
C6)alkyl] 2,-CONH [(C1-C6) alkyl],-CON t(C1-C6) alkyl] 2,-(CH2)pCN , (C1-C6)
) alkylamino, di-(C1-C6) alkylamino, (C1-C6) alkyl di-(C1-C6) alkylamino, -(CH2)pNR13RM,
-(CH2)PCONR13R14, -(CH2)PCOOR12, -CH=NOH, -CH=NO-(C1-C6) alkyl,

R11 and R12are each independently hydrogen, (C1-C6)alkyl, or
C3-C8 cycloalkyl;
R13 and R14 are each independently hydrogen, (C1-C6)alkyl, or
C3-C8 cycloalkyl;
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or R13 and R14 can be taken together with the nitrogen to which
they are attached to form a 4-6 membered saturated ring optionally containing up to
two atoms selected from 0, S or N;
p is 0 or 1;

provided that when A is A2, then B is B2 wherein B2 is

wherein R15 and R16 are selected independently from the group consisting of
hydrogen, C1-C6 alky], C1-C6 alkoxy, cyano, -CF3, and halogen;
wherein
R17a, R17b, and R17c are each independently selected from the group
consisting of hydrogen, (C1-C6)alkyl, halogen, hydroxy, aryloxy, and hydroxy(C1-
C6)alkyl;
u is the integer 0,1, 2, 3, or 4;
v is the integer 1,2,3, or 4;
r is 0 or 1;
R18 is hydrogen or C1-C6 alkyl; and
R19 is a cycloalkylamine or a C4-C8 cycloalkylamine;
R20aand R2Ob are each independently selected from the group consisting of
hydrogen, (C1-C6)alkyl, halogen, or aryl; or R20a and R20b can be taken together with
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the aryl to which they are attached to form an aromatic bicycle having up to about 10
total ring atoms.
Other embodiments will be readily ascertainable to those of skill in the art
upon reading this specification and claims.
Alkyl refers 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. Alkyl groups preferably contain 1 to 6 carbon atoms. In some
embodiments, alkyl groups can be substituted with up to four substituent groups, as
described below.
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.
Alkenyl, as used herein, refers to an alkyl group having one or more double
carbon-carbon bonds. Alkenyl groups preferably contain 2 to 6 carbon atoms.
Example alkenyl groups include, but are not limited to; ethenyl. propenyl. butenyl,
pentenyl, hexenyl, butadienyl, pentadienyl, hexadienyl, and the like. In some
embodiments, alkenyl groups can be substituted with up to four substituent groups,
as described below.
Alkoxy, as used herein, refers to an -O-alkyl group. Example alkoxy groups
include, but are not limited to, 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.
Alkoxy groups preferably contain 1 to 6 carbon atoms. In some embodiments, alkoxy
groups can be substituted with up to four substituent groups.
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 (C3-C10) branched-chain
hydrocarbon. Alkoxyalkyl groups are preferably (C1-C6)alkoxy (C1-C6)alkyl.
Examples of alkoxyalkyl moieties include, but are not limited to, chemical groups
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such as, but not limited to, methoxymethyl, -CH2CH(CH3)OCH2CH3, and homologs,
isomers, and the like.
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
alkoxycarbonyl moieties include, but are not limited to, chemical groups such as, but
not limited to, methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl, sec-
butoxycarbonyl, tert-butoxycarbonyl, decanoxycarbonyl, and homologs, isomers, and
the like.
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.
Cycloalkyl groups preferably contain 3 to 8 carbon atoms. Examples of cycloalkyl
groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,
cycloheptyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptatrienyl,
norbornyl, norpinyl, norcarnyl, adamantyl, and the like. Also included in the definition
of cycloalky! are moieties that have one or more aromatic rings fused to (i.e.: having
a bond in common with) the cycloalkyl ring, for example, benzo derivatives of
cyclopentane (indanyl), cyclohexane (tetrahydronaphthyl), and the like.
Alkylamino, employed alone or in combination with other terms, refers to a
moiety with one alkyl group, wherein the alkyl group is an unsubstituted (C1-C6)
straight chain hereunto before defined alkyl group or an unsubstituted (C3-C8)
hereunto before defined cycloalkyl group. Examples of alkylamino moieties include,
but are not limited to, chemical groups such as, but not limited to, -NH(CH3),
-NH(CH2CH3), -NH-cyclopentyl, and homologs, and the like.
Alkylaminosulfony! refers to 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 hereinbefore defined.
Alkynyl, as used herein, refers to an alkyl group having one or more triple
carbon-carbon bonds. Alkynyl groups preferably contain 2 to 6 carbon atoms.
Examples of alkynyl groups include, but are not limited to, ethynyl, propynyl, butynyl,
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pentynyl, and the like. In some embodiments, alkynyl groups can be substituted with
up to four substituent groups, as described below.
Aryl, as used herein, refers to aromatic carbocyclic groups including
monocyclic or polycyclic aromatic hydrocarbons such as, but not limited to, for
example, phenyl, 1-naphthyl, 2-naphthyl anthracenyl, phenanthrenyl, and the like. In
some embodiments, aryl groups have from 5 to about 20 carbon atoms. Aryl groups
preferably contain 6 to 14 carbon atoms. In some preferred embodiments, aryl
groups are pheny! or naphthyl groups that optionally contain up to four, preferably up
to 2, substituent groups as described below.
Aroyl, as used herein, refers to the group Ar-C(=O)- where Ar is aryl as
defined above. For example, a C7 to C15 aroyl moiety refers to the group Ar-C(=O)-
where Ar is an aromatic 6 to 14 membered carbocylic ring.
Arylalkyl or aralkyl, as used herein, refers to a group of formula -alkyl-aryl.
Preferably, the alkyl portion of the arylalkyl group is a lower alkyl group, i.e., a C1-C6
alkyl group, more preferably a C1-C4 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.
Bicyclic system, as used herein, refers to a saturated, partially saturated, or
aromatic bicycle having 6-20 total ring atoms, preferably 8-12 total ring atoms, and
most preferably 10 total ring atoms, and from 0-3 ring heteroatoms selected from O,
S, and N, preferably with 1 ring heteroatom. Exemplary bicyclic systems include, but
are not limited to, naphthyl, quinoline, and isoquinoline.
Carbamoyl, as used herein, refers to the group, -C(=O)N<.
Carbonyl, employed alone or in combination with other terms, refers to a
bivalent one-carbon moiety further bonded to an oxygen atom with a double bond.
An example is
Carboxy as employed herein refers to -COOH.
Cyano, as used herein, refers to -CN.
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Cycloalkylalkyl, as used herein, refers to a group of formula -alkyl-
cycloalkyl, wherein alkyl and cycloalkyl are as hereinbefore defined, for example a
cyclopropylmethyl group.
Cycloalkylcarbonyl, as used herein, refers to a group of formula -carbonyl-
cycloalkyl, wherein cycloalkyl is as hereinbefore defined, for example
cyciohexylcarbonyl.
Dialkylamino, employed alone or in combination with other terms, refers to a
moiety with two independent alkyl groups, wherein the alkyl groups are unsubstitued
(C1-C6) straight chain hereunto before defined alkyl groups or unsubstitued (C3-C8)
hereunto before defined cycloalkyl groups. The two groups may be linked to form an
unsubstituted cycloalkylamino group preferably containing 1-6 carbon atoms.
Examples of dialkylamino moieties include, but are not limited to, chemical groups
such as, but not limited to, -N(CH3)2, -N(CH2CH3)2, -NCH3(CH2CH3), and
homologs, and the like.
Dialkylaminoalkyl, employed alone or in combination with other terms, refers
to 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, but not limited to, -
CH2N(CH3)2, -CH2CH2N(CH2CH3)2, -CH2CH2CH2NCH3(CH2CH3), and homologs, and
the like.
Halo or halogen includes fluoro, chloro, bromo, and iodo.
Hunig'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, refers to a
(C1-C10) straight chain hydrocarbon, preferably a C1-C6 alkyl, terminally substituted
with a hydroxyl group. Examples of hydroxyalkyl moieties include, but are not limited
to, chemical groups such as, but not limited to, -CH2OH, -CH2CH2OH, -
CH2CH2CH2OH, and higher homologs.
Nitro, employed alone or in combination with other terms, is defined herein
as, -NO2.
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Thioalkyl, employed alone or in combination with other terms, is defined
herein as sulfur covalently bonded to an alkyl group, preferably a C1-C6 alkyl group,
as defined above.
Optionally substituted, as used hereinbefore, refers to a moiety having from 1
to about 5 substituents, preferably from 1 to 4 substituents, more preferably from 1 to
3 substituents, most preferably 1 or 2 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.
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-C6 alkyl is specifically intended to
individually disclose methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, isobutyl, etc.
In some embodiments, the invention provides a compound wherein A is A1

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In some embodiments, B is B1, and B1 is

In some embodiments, B is B1, and B1 is ,

In some embodiments, the invention provides compounds of formula I
wherein A is A2 and B is B2.
In some such embodiments A2 is

In other such embodiments, A2 is

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WO 2006/124523 PCT/US2006/018276
In some embodiments, the invention provides compounds represented by the
formula II ,
or a pharmaceutically acceptable salt thereof,
wherein R1 - R3, A1 and B1 are as defined above;
In some embodiments, the invention provides such compounds of formula II, wherein
A1 is
In some embodiments, the invention provides such compounds of formula II, wherein
u is 2.
In some embodiments, the invention provides such compounds of formula II, wherein
r is 0.
In some embodiments, the invention provides such compounds of formula II, wherein
A1 is

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In some embodiments, the invention provides such compounds of formula II,
wherein B-\ is
In some such embodiments, each of R5-R10 is hydrogen. In some embodiments,
one of R8-R10 is alkyl, in some preferred embodiments, one of R8-R10 is methyl.
In other embodiments, B1 is
In some embodiments, one of R8-R10 is alkoxy, preferably, one of said R8-R10 is
methoxy.
In other embodiments, Bi is
In some embodiments the invention provides compounds of formula II where
A1 is
In some such embodiments, v is 1. In others, r is 0. In yet other
embodiments, v is 1 and r is 0. In some such embodiments, the ring nitrogen is in
the 3-position.
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In some such embodiments, each of R5-R10 is hydrogen. In some embodiments,
one of R8-R10 is alkyl, preferably one of said R8-R10 is methyl.
In some embodiments, the invention provides a compound of formula II wherein A1 is

Other embodiments of the invention provide compounds represented by the
formula III
or a pharmaceutically acceptable salt thereof,
wherein R1 - R3, A2 and B2 are as defined above;
In some such embodiments the invention provides compounds of formula III
wherein A2 is
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In some such embodiments, u is 0. In some such embodiments, R20a is halogen,
preferably chlorine.
In some embodiments the invention provides compounds of formula III
wherein R20a and R20b taken together with the aryl to which they are attached to form
a bicyclic structure. In some embodiments, the bicyclic structure is naphthalene.
In some embodiments the invention provides compounds of formula III
wherein R20a is aryl, preferably phenyl.
In some embodiments the invention provides compounds of formula III where
A2 is
In some embodiments the invention provides compounds of formula III
wherein A2 is
In some embodiments the invention provides compounds of formula III
wherein R20a is alkyl, particularly C(CH3)3.
In some embodiments the invention provides compounds of formula III
wherein A2 is
In some such embodiments B2 is
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one of R15 or R16 is halogen, particularly chlorine. In some such
embodiments, the other one of R15 or R16 is alkyl, particularly methyl. In some
preferred embodiments, R15 is 4-chloro and R16 is 2-methyl.
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Some exemplary compounds include, but are not limited to, those in the
following table:
)
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Those practicing the art will readily recognize 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
diastereorners 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.
Those practicing the art will readily recognize that some of the compounds of
this invention, depending on the definition of various subsituents, 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.
Some embodiments of the invention also includes pharmaceutically
acceptable salts of the compounds disclosed herein. By "pharmaceutically
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acceptable salt", it is meant any compound formed by the addition of a
pharmaceutically acceptable base and a compound disclosed herein 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.
METHODS
GENERAL SYNTHETIC SCHEMES FOR PREPARATION OF COMPOUNDS
The compounds of the present invention may be prepared according to one
or more of the general processes outlined below.
The compounds of general formula (II) wherein B is B1 which is

(e) can be conveniently prepared as shown in Scheme I.
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According to the above preferred process, a tricyclic diazepine of formula (1)
wherein R1, R2, and R3 are defined hereinbefore, is reacted with an acyl halide
preferably an acid chloride where X is Cl in an aprotic organic solvent such as, but
not limited to, 1,4-dioxane at temperatures ranging from -10° C to reflux, to provide
the desired intermediate of formula (2) where Y is haloalkyl, preferably chloroalkyl.
Subsequent reaction of the intermediate of formula (2) with an appropriate amine of
formula (3) at temperatures ranging from ambient to the refluxing temperature of the
solvent or in the absence of a solvent to the melting point of the reactants, provides
the desired compounds of formula (II) wherein R1, R2, R3, and A1 are as defined
hereinbefore. When the amine of formula (3) is an appropriately substituted
pyridylamine or a dialkylamine. The compounds of formula (1) can be further
converted to their N-oxides by treatment with an oxidizing agent such as, but not
limited to, a peracid or other pyridine oxidizing agents known in the literature at
temperatures ranging from -40 °C to ambient temperature.
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Thus, a tricyclic diazepine of formula (1) wherein R1 R2, and R3 are defined
hereinbefore, is reacted with an acyl haiide, preferably an acid chloride of formula (4),
wherein Y is Cl, either in the presence of an aprotic organic solvent such as, but not
limited to, N-methyl-2-pyrrolidinone at temperatures ranging from ambient to reflux,
or in the absence of a solvent to the melting point of the reactants, and in the
presence or absence of an organic base such as, but not limited to, 2,6-lutidine, to
provide the desired compounds of formula (II) wherein R1, R2, R3,and A1 are as
defined hereinbefore. The compounds of formula (II) of Scheme II can be further
converted to their N-oxides by treatment with an oxidizing agent such as, but not'
limited to, a peracid or other pyridine oxidizing agents known in the literature at
temperatures ranging from -40 °C to ambient temperature.
The compounds of formula (III) wherein R1 R2, R3, A2 and B2 are defined
hereinbefore, can be prepared as shown in Scheme III by reacting a tricyclic
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diazepine of formula (5) with an acid halide, preferably an acid chloride of formula
(4), where Y is Cl under the conditions of Scheme II.
Scheme III

The compounds of formula (111) of Scheme II) wherein A2 contains a pyridine
moiety can be further converted to their N-oxides by treatment with an oxidizing
agent such as, but not limited to, a peracid or other pyridine oxidizing agents known
in the literature at temperatures ranging from -40 °C to ambient temperature.
The tricyciic diazepines of formula (1) of Scheme! wherein B is B1 which is

Scheme IV

Thus, a tricyciic diazepine of formula (6) is treated with an appropriately
substituted acylating agent, preferably an appropriately substituted acyl chloride or
acy) bromide of formula (7), where J is COCi or COBr, respectively, in the presence
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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-dimethylaniline, in an aprotic solvent such as, but
not limited to, dichloromethane, N,N-dimethylformamide, tetrahydrofuran or 1,4-
dioxane, at temperatures ranging from -5 °C to 50 °C to provide intermediates of
general formula (1) wherein B1 is defined hereinbefore.
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 al., 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-(dimethylaminopyridine), at temperatures ranging from 0 °C to the
reflux temperature of the solvent, yields the intermediate acylated derivative (1) of
Scheme IV.
The acyiating intermediate of formula (7) is ultimately chosen on the basis of
its compatibility with B groups, and its reactivity with the tricyclic diazepine of formula
(6).
The desired intermediates of formula (7) of Scheme IV wherein B is B^ and 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
trifiuoromethane sulfonate of formula (8), wherein Pg is a carboxylic acid protecting
group, preferably Pg is alkyl or benzyl, M is I, Br, Cl, or 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, and wherein R8, R9 and R10 are defined
hereinbefore, in the presence of a Pd(0) catalyst, 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,
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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).
Scheme V

The desired intermediates of formula (7) of Scheme IV wherein B is B1 and B1
i can be prepared by a process analogous to that exemplified in
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Scheme V by replacing intermediates of formula (9) with appropriately substituted
naphthyl intermediates.
Alternatively, the desired intermediates of formula (10) of Scheme V wherein

B is B1 and B1 is can be prepared by the coupling of the intermediate of
formula (8) where M is I, Br, Cl or OTf, and an appropriately substituted aryl boron
derivative of formula (9), preferably where T is B(OH)2, in the presence of a palladium
catalyst such as, but not limited to, palladium(ll) acetate or
tetrakis(triphenylphosphine) palladium(O) and an organic base such as, but not
limited to, triethylamine or an inorganic base such as, but not limited to, sodium
carbonate, potassium carbonate, 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 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
boronate, or boronic acid or trialkyltin(IV) 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.
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The desired intermediates of formula (10) of Scheme V wherein B is B1 and
B1 is 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 NH2, 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)).
Alternatively, the desired intermediates of formula (11) of Scheme V wherein

B is B1 and B1, is 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 or
an aryl halide of formula (14), where W is OTf, Br, 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)).
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Alternatively, reaction of an intermediate of formula (12), where L is Br, Cl, I, or
OTf with a derivative of formula (13), where W is B(OH)2, or SnBu3, yields the desired
intermediate of formula (15) which is converted to intermediate (11) in the manner of
Scheme VI.
The desired intermediates of formula (15) of Scheme VI where B is B-i and Bi
can be prepared in analogous fashion by replacing intermediates of
formula (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
bis(pinacolato)diboron of formula (16) with an appropriately substituted aryl halide or
aryl triflate of formula (12), where L is OTf. In preferred aryl halides of formula (12) L
is Br, or 1. The reaction is carried out according to the described procedures of
Ishiyama et al., J. Org. Chem. 60, 7508-7510 (1995) and Giroux et al., Tetr, Lett. 38,
3841-3844(1997).
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The desired compounds of formula (1) of Scheme IV wherein B is B1 and B1
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 of formula (17),
preferably where J is COCI or COBr, and K is I, or 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.
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 (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).
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A Stille coupling reaction of the compound of formula (18), where K is I with
an appropriately substituted organotin reagent such as, but not limited to, a
trialkyltin(IV) derivative of formula (9), 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
CC (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. Preferably the trialkyltin(IV) derivative of
formula (9) is a tri-n-butyltin(IV) derivative T is SnBu3).
Alternatively, reaction of a compound of formula (18), where K is CI, 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, and in the presence of a Pd(0)
catalyst and a base such as, but not limited to, sodium carbonate, at temperatures
ranging from 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 or bromides of formula (17) of
Scheme VII, where K is I, or Br and J is COCI 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 particularly
where alkyl is n-butyl, of Scheme VII are either commercially available, or can be
conveniently prepared as shown in Scheme VIII from the corresponding bro.mo
starting materials 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
iithiated species with a trialkyl tin(IV) chloride, such as, but not limited to, trimethyl
tin(IV) chloride or tri-n-butyl tin(IV) chloride.
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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 B1 and B1
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, J= COCI) where R5, R6 and R7 are
hereinbefore defined, are reacted with a tricyclic 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 (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 B is B1 which is w , and R1, R2, R3, R5,
R6, R7, R8, R9 and R10 are defined hereinbefore.
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The desired compounds of formula (1) of Scheme IX wherein B is B1 and B1 is
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 B

is B1 and B1 is (a) can be prepared as shown in Scheme X.
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Thus, an appropriately substituted biphenyl of formula (24) wherein
R5, R6, and R7 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 B is B1 and B1 is 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), and corresponding formulas (II) and (111) of Schemes I -III wherein B is B1

or B2 wherein B1 is selected from the group (a) and
B2 is defined hereinbefore, is shown in Scheme XI
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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,
fluorenylaikoxycarbonyl group, preferably a fluorenylmethyloxycarbonyl group (Pg is
Fmoc), or an alkoxycarbonyl protecting group preferably a tert-butyloxycarbonyl
group (Pg is Boc) is reacted with an acid chloride under the conditions of Scheme I to
provide the desired intermediate of formula (26). Subsequent reaction with an
appropriate amine of formula (3) under the conditions of Scheme I provides the
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intermediate of formula (27) wherein A is A, as defined hereinbefore. Where the
amine of formula (3) is an appropriately substituted pyridylamine or dialkylamine.
Alternatively, treatment of (25) with an acid chloride of formula (4) under the
conditions of Schemes ll-lll also yields the intermediate of formula (27) wherein A is
A2 as defined hereinbefore. The compound of formula (27) is then deprotected to
yield the intermediate of formula (28) and, then acylated to the desired product of
formula (I). Alternatively, the conversion of intermediate of formula (26) to the
intermediate of formula (28) can be carried out in a single step by choosing
appropriate reaction conditions.
Preferred processes for the preparation of compounds of formula (II) of

Scheme I wherein B is B1 and B1 is , and R1, R2, R3, R5, R6, R7, R8, R9.
and R10 are defined hereinbefore, also utilize acylation of the intermediate of formula
(28) of Scheme XI with an acylating agent of formula (17) of Scheme VII, as shown in
Scheme XII. Subsequent coupling of the intermediate of formula (29), 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(dipheny!phosphino)ferrocene]dichloro pa)ladium(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 of formula (II).
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is B1 and B1 is (a) and R1, R2, R3, R5, R6, R7, R8, R9, and R10 are defined
hereinbefore, can be prepared as shown in Scheme XII) by acylation of the
intermediate of formula (28) of Scheme XI with an acylating agent of formula (20) of
Scheme IX.
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is B1 and B1 is (a) and R1, R2, R3, R5, R6, R7, R8, R9, and R10 are defined
hereinbefore, can be prepared by acylation of the intermediate of formula (28) of
Scheme XI with an acylating agent of formula (7) of Scheme V, wherein J is
hereinbefore defined, as shown in Scheme XIV

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The tricyclic diazepines of formula (5) of Scheme ill wherein B2 is defined
hereinbefore, can be conveniently prepared as shown in Scheme XV by reacting the
diazepine of formula (6) with an appropriately substituted acylating agent such as,
but not limited to, an aryloxy acetyl chloride or an aryloxy acetyl bromide of formula
(32), where J is COCI or COBr, under the conditions of Scheme IV.
Scheme XV

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.
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 uM - 10 mM for dose-response format. The
DMSO dilutions were diluted 500-fold in sterile growth medium [D-MEM/F-12
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(GIBCO/BRL; Grand Island NY) containing 15 mM HEPES, 2 mM l-glutamine,
pyridoxine hydrochloride, phenol red and 5% FetalClone II (HyClone Laboratories,
Inc; Logan, UT), 0.2% DMSO, 100 units penicillin G/ml, and 100 (jg 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 WAY-162002 (an 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 µl 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.
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 ul 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 µl of the
combined reagents to each well. Chemiluminescence was detected using a
luminometer (EG & G Berthold Microlumat LB 96 P, Waliac, 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
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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 IC50of 3-[(2S*,5R*)-5-{[2-(1H-lndol-3-yl)-ethylcarbamoyl]-methyl}-
4-oxo-2-(5-phenylethynyl-thiophen-2-yl)-thiazolidin-3-yl]-benzamide (2 uM) 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 closes 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.
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, C.A., 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,
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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.
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:
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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 ul 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 ul 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 0.01 to 30 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 is 53
pM), or the compounds in the presence or absence of hFSH at its EC20 dose. The
ability of the compounds to inhibit the cAMP-accumulation induced by hFSH was
evaluated by RIA.
In every assay the EC20 concentration was calculated and only those
experiments in which the EC20 concentrations were equal to 1.85 + 0.4 ng/mL were
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 0.03 - 30µM 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 0.1-1000 ng/ml.
SELECTIVITY STUDIES
cAMP accumulation assays using CHO-25 (hTSH-R) cells 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 0.01 to 30 uM. Controls and test
compounds were evaluated in quadruplicate. Cells were treated with vehicle, hTSH
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WO 2006/124523 PCT/US2006/018276
at EC20 (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 0.01 pM-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 0.01 to 30 µM. Controls and
test compounds were evaluated in quadruplicate. Cells were treated with vehicle, 5
uM forskolin that induces the equivalent fmol/ml concentration of cAMP-accumulation
induced by the hFSH at its EC20 (5 uM forskolin, Sigma Chemical Co; previously
calculated during characterization of the bio-assays), or the compounds in the
presence or absence of the 5 uM forskolin. The ability of the compounds to inhibit
the cAMP-accumulation induced by forskolin was evaluated by RIA.
Along with the test compounds, forskolin was also run as a positive control in
agonist mode using concentrations ranging from 0.01 µM to 1000 µM.
ANALYSIS OF RESULTS
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-accumulation 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 ECB0=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
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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.

EXAMPLES
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EXAMPLE 1
1-{10-[(2,2'-Dimethyl-1,1'-biphenyl-4-yl)cartbonyrl-10,11-dihydro-5H-pyrrolo[2,1-
c][1,4]benzodia2epin-3-yl}-2-(pyridin-3-y!amino)ethanone formic acid salt
STEP A. (10,11-Dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-10-yl)-(2,2'-dimethyl-
bipheny!-4-yl)-methanone
A solution of 0.45 g (0.002 mole) of 2,2'-dimethyl-1,1'-biphenyl-4-carboxylic
acid in 50 mL of thionyl chloride was heated under reflux overnight. The excess
thionyl chloride was stripped off in vacuo. To the residue was added 0.37 g (0.002
mole) of 10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine and 50 mL of 1,4-
dioxane followed by 0.24 g (0.002 mole) of N,N-dimethylaniline. After standing for
three hours, the reaction solution was poured into 300 mL of water to provide 0.6 g of
title compound which was used directly in the next step after drying .
MS [(+)ESI, m/z]: 393 [M+H]+.
STEP B. 2-Chloro-1-[10-(2,2'-dimethyl-biphenyl-4-carbonyl)-10,11-dihydro-5H-
pyrro!o[2,1-c][1,4]benzodiazepine-3-yl]-ethanone
A solution containing 0.992 g (0.001 mole) of (10,11-dihydro-5H-pyrrolo[2,1-
c][1,4]benzodiazepin-10-yl)-(2,2'-dimethy!-1,1'-biphenyl-4-yl)-methanone of Step A
and 0.16 g (0.001 mole) of chloroacetyl chloride in 20 mL of 1,4-dioxane was heated
under reflux with stirring for two hours. The solvent was removed in vacuo and the
residue was used directly in the next step.
MS [(+)ESI, m/z]: 469 [M+H)+
Step C. 1-{10-[(2,2-Dimethyl-1,1'-biphenyM-yl)carbonyl]-10,11-dihydro-5H-
pyrroIo[2,1-c][1,4]benzodiazepin-3-yl}-2-(pyridin-3-ylamino)ethanone formic
acid salt
To the crude 2-chloro-1-[10-(2,2'-dimethyl-1,1'-biphenyl-4-carbonyl)-10,11-
dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-yl]-ethanone of Step B was added
0.94 g (0.010 mole) of 3-aminopyridine. The reaction mixture was heated neat to the
melting temperature and kept at this temperature for twenty minutes. It was then
allowed to cool to room temperature and the residue was washed several times with
water to remove the excess 3-aminopyridine. The remaining crude product was
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purified by hplc (formic acid/acelonitrile/water) to provide the title compound as the
formic acid salt.
MS [(+)ESI, m/z]: 527 [M+H]+.
EXAMPLE 2
1-110-(1,1'-Biphenyl-ylcarbonyl)-10,11-dihydro-5H-pyrrolo(2,1-c][1,4]
benzodiazepin-3-yl]-3-pyridin-3-ylpropan-1-one formic acid salt
A mixture of 1.13 g (0.00 3 mole) of (5H,10)-[(1.r-biphenyl-4-yl)carbonyl]-
10,11-dihydro-5H-pyrroio[2,1-c][1,4]benzodiazepine and 0.003 mole of 3-pyridin-3-yI-
propionyl chloride hydrochloride (generated via the reaction of 3-pyridinyl-3-yl-
propionic acid with thionyl chloride) was heated to the melting point, keeping the
temperature at this level for twenty minutes. The reaction mixture was allowed to cool
to room temperature and the residue was neutralized with 10% aqueous sodium
bicarbonate and then washed with water. The crude product thus obtained was
purified by HPLC (formic acid/acetonitrile/water) to provide the title compound as the
formic acid salt.
MS [(+)ESI, m/z]: 498 [M+H]+
EXAMPLE 3
1-{10-[(2'-Methoxy-1,1'-biphenyl-4-yl)carbonyl]-10,1-dihydro-5H-pyrrolo[2,1-
c][1,4]benzodiazepin-3-yl}-3-pyridin-3-ylpropan-1-one
A mixture of (2'-methoxy--1,1'-biphenyl-4-yl)-(5H,11H-pyrrolo[2,1-
c][1,4]benzodiazepin-10-yl)-methanone (0.503 g, 1.27mmole), 3-pyridin-3-yl-
propionyl chloride hydrochloride salt (0.473 g, 2.3 mmole), 2,6-lutidine (0.478 g, 4.46
mmole) and N-methyi-2-pyrrolidinone (1.5 mL) was heated under nitrogen at 120 °C
for 30 minutes. The mixture was diluted with 30 mL of dichloromethane. The organic
phase was washed with 1 N sodium hydroxide and brine, and dried over anhydrous
magnesium sulfate. The solvent was removed in vacuo and the residue was purified
by preparative HPLC, Primesphere 10 C18 5 X 25 cm column, 48% acetonitrile in
water containing 0.1% trifiuoroacetic acid, 100 mL/min, 254 nm detection. The eluate
was neutralized with aqueous sodium hydroxide and the volatiles removed in vacuo.
The residue was extracted with dichloromethane, the extracts were dried over
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anhydrous magnesium sulfate and evaporated to provide the title compound as an
off-white amorphous solid.
MS [(+)ESI, m/z]: 528.18 [M+H]+
EXAMPLE 4
{10-[(4-Chloro-2-methylphenoxy)acetyl]-10,11-dihydro-5H-pyrrolo[2,1-
c][1,4]benzodiazepin-3-yl}(4-chlorophenyl)methanone
STEP A. 4-Chloro-o-tolyloxyacetic acid chloride
To a cold suspension of 4-chloro-o-tolyloxyacetic acid (17.4 mmol) in 40 mL
of dry dichloromethane was added oxalyl chloride (39.15 mmoi) followed by one drop
of N,N-dimethylformamide. Bubbling began immediately. After 30 minutes the
reaction mixture was warmed in a 45° oil bath for 1.5 h. The solution was cooled to
room temperature and all volatiles were removed by evaporation. Move dry
dichloromethane was added and this was again evaporated in vacuo. Finally, dry
toluene was added to the residue and this was evaporated at reduced pressure. The
crude acid chloride was used without further purification in the following step.
STEP B. 10-t(4-Chloro-2-methylphenoxy)acetyl]-10,11-dihydro-5H-pyrrolo[2,1c] [1,4]
benzodiazepine
To a solution of the crude acid chloride of Step A (17.4 mmol) in
dichloromethane (25 mL) was added a solution of 10,11-dihydro-5H-pyrrolo[2,1-
c][1,4]benzodiazepine (17.4 mmol) and triethylamine (19.14 mmol) in
dichloromethane (25 mL) in a rapid dropwise fashion. After stirring for one hour at
room temperature, the reaction mixture was washed with 0.1 N aqueous hydrochloric
acid (2x) and water (1x), dried over anhydrous sodium sulfate, and evaporated. The
product was isolated by crystallization from hot ethyl acetate/tert-butyl methyl ether
(2/1), mp 166-167 °C.
MS t(+)ESI, m/z]: 367 [M+H]+
Anal. Calcd for C21H19CIN2O2:C 68.76, H 5.22, N 7.64. Found: C 68.53, H 5.18, N
7.53.
STEPC.{10-[(4-Chloro-2-methylphenoxy)acetyl}-10,11-dihydro-5H-pyrrolo[2,1-
c][1,4]benzodiazepin-3-yl}(4-chlorophenyl)methanone
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A solution of 10-[(4-chloro-2-methylphenoxy)acetyl]-10,11-dihydro-5H-
pyrrolo[2,1-c][1,4]benzodiazepine of Step B (0.68 mmol), 4-ch!orobenzoyl chloride
(1.02 mmol) and 2,6-lutidine (1.02 mmol) in N-methyl-2-pyrrolidinone (0.33 mL) was
heated to 115 °C under a nitrogen atmosphere for 16 hours. To the cooled reaction
mixture was added dichloromethane (5 mL). The organic solution was washed with
water (2x), 1N aqueous hydrochloric acid (1x), 0.5 N aqueous sodium hydroxide (1x),
and water (1x). The organic phase was dried over anhydrous sodium sulfate, and
evaporated. HPLC was used for the purification of the title compound which was
then crystallized from hot ethyl acetate/hexane, mp 175-176 °C.
MS [(+)ESI, m/z]: 505 [M+H1+
Anal. Calcd for C28H22Cl2N2O3: C 66.54, H 4.39, N 5.54. Found: C 66.58, H 4.60, N
5.36.
EXAMPLE 5
1-{10-[(4-Chloro-2-methylphenoxy)acetyl]-10,11-dihydro-5H-pyrro!o[2,1-c3
[1,4]benzodiazepin-3-yl}-3-pheny)propan-1-one
The title compound (m.p. 130-134 °C) was prepared from the 10-[(4-chloro-2-
methylphenoxy)acetyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine of
Example 4, Step B and phenyl propionyl chloride in the manner of Example 4, step
C.
MS [(+)ESI, m/z]: 499 [M+H]+
Anal. Calcd for C30H27CIN2O3 0.15 C5H10O2: C 71.75, H 5.55, N 5.47. Found: C
71.77, H 5.54, N 5.46.
EXAMPLE 6
{10-[(4-Chloro-2-methylphenoxy)acetyl]-10,11-dihydro-5H-pyrrolo[2,1-
c][1,4]benzodiazepin-3-yl}(1-naphthyl)methanone
The title compound (m.p. 130-134 °C) was prepared from the 10-[(4-chloro-2-
methylphenoxy)acetyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine of
Example 4, Step B and 1-naphthoyl chloride in the manner of Example 4, step C..
MS K+)ESI, m/z]: 521 [M+H]+
Anal. Calcd forC32H25CIN2C3 1.2 C5H10O2: C 70.52, H 5.56, N 4.47. Found: C
70.39, H 5.30, N 4.60.
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EXAMPLE 7
1,1'-Biphenyl-4-yl{10-[(4-chloro-2-methylphenoxy)acetyll-10,11-dihydro-5H-
pyrroIo[2,1-c][1,4]benzodiazepin-3-yl}methanone
The tile compound (m.p. 102-105 °C) was prepared from the 10-[(4-ch!oro-2-
methy[phenoxy)acetyl]-10,11-dihydro-5H-pyrro!o[2,1-c][1,4]benzodiazepineof
Example 4, Step B and 4-(1,1 '-biphenyl) carbonyl chloride in the manner of Example
4, step C.
MS [(+)ESI, m/z]: 547 [M+H]+
Anal. Calcd for C34H27CIN2O3-C5H10O2: C 73.43, H 5.23, N 4.81. Found: C 73.34, H
4.93, N 4.90.
EXAMPLE 8
(4-Tert-butylphenyl){10-[(4-chloro-2-methylphenoxy)acetyl]-10,11-dihydro-5H-
pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}methanone
The title compound (m.p. 168 °C) was prepared from 10-[(4-chloro-2-
methylphenoxy)acetyl]-10,11-dihydro-5H-pyrrolo[2,1-c]t1,4]benzodiazepine of
Example 4, Step B and 4-tert-butyl benzoyl chloride in the manner of Example 4, step
C.
MS [(+)ESI, m/z]: 527 [M+Hf
Anal. Calcd for C32H31CIN2O3: C, 72.92; H, 5.93; N, 5.31. Found: C, 72.53; H, 5.92;
N, 5.20.
EXAMPLE 9
1,1l-Biphenyl-2-yl{10-[(4-chloro-2-methylphenoxy)acetyl]-10,11-dihydro-5H-
pyrro!o[2,1-c][1,4]benzodiazepin-3-yl}methanone
The title compound was prepared from 10-[(4-ch!oro-2-
methylphenoxy)acetyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine of
Example 4, Step B and 2-(1,1'-biphenyl) carbonyl chloride in the manner of Example
4, step C.
MS [(+)ESI, m/z]: 547.1 [M+H]+
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EXAMPLE 10
{10-[(4-Chlorophenoxy)acetyl]-10,11-dihyciro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-
yl}(4-chlorophenyl)methanone
STEP A. 10-[(4-Chlorophenoxy)acetyl]-10,11-dihydro-5H-pyrrolo[2,1c][1,4]
benzodiazepine
The title compound (mp 120-122 °C) was prepared from 10,11-dihydro-5H-
pyrrolo[2,1-c][1,4]benzodiazepine and 4-chlorophenoxyacetyl chloride in the manner
of Example 4, step B.
MS [(+)ESI, m/z]: 353 [M+H]+
Anal. Calcd for C20H17ClN2O2: C 68.09, H 4.86, N 7.94. Found: C 67.82, H 4.87, N
7.87.
STEP B. {10-[(4-Chlorophenoxy)acetyl]-10,11-dihydro-5H-
pyrrolo[2,1c][1,4]benzodiazepin-3-yl}(4-chIorophenyI)methanone
The title compound (m.p. 195 °C) was prepared from 10-[(4-
chlorophenoxy)acetyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine of
Example 14 and 4-chlorobenzoyl chloride in the manner of Example 4, step C.
MS [(+)ESI, m/z]: 491 [M+H]+
Anal. Calcd for C27H20Cl2N2O3: C 66.00, H 4.10, N 5.70. Found: C 65.67, H 4.07,
N 5.45.
EXAMPLE 11
1_{10-[(4-Chlorophenoxy)acetyl]-10,11-dihydro-5H-pyrro!o[2,1-c][1,4] benzodiazepin-
3-yl}-3-phenylpropan~1 -one
The title compound (m.p. 126-128 °C) was prepared from 10-[(4-
chlorophenoxy)acetyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine of
Example 10, Step A and phenyl propionyl chloride in the manner of Example 4, step
C.
MS [(+)ESI, m/z]: 485 [M+H]+
Anal. Calcd for C29H25CIN2O3:C 71.82, H 5.20, N 5.78. Found: C 71.52, H 5.31, N
5.66.
EXAMPLE 12
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(4-tert-Butylphenyl){10-[(4-ch!orophenoxy)acetyl]-10,11-dihydro-5H-pyrro!o[2,1-
c][1,4]benzodiazepin-3-yl}methanone
The title compound (m.p. 171 °C) was prepared from 10-[(4-
chlorophenoxy)acety!]-10,11-dihydro-5H-pyrro!o[2,1-c][1,4]benzodiazepine of
Example 10, Step A and 4-tert-butyl benzoyl chloride in the manner of Example 4,
step C.
MS [(+)ESI, m/z]: 513[M+H]+
Anal. Calcd for C31H29ClN2O3-0.15 C5H10O2:C 72.12, H 5.78, N 5.32. Found: C
72.04, H 5.51, N 5.30.
EXAMPLE 13
1,1'-Biphenyl-4-yl{10-[(4-chlorophenoxy)acetyl]-10,11-dihydro-5H-pyrrolo[2,1-
c][1,4]benzodiazepin-3-yl}methanone
The title compound (m.p. 155-157 °C) was prepared from 10-[(4-
chlorophenoxy)acetyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepineof
Example 10, Step A and 4-(1,1'-biphenyi) carbonyl chloride in the manner of
Example 4, step C. MS [(+)ESI, m/z]: 533.1 [M+H]+
EXAMPLE 14
1,1'-Biphenyl-2-yl{10-[(4-chlorophenoxy)acetyl]-10,11-dihydro-5H-pyrroto[2,1-
c][1,4Jbenzodiazepin-3-y!}methanone
The title compound was prepared from 10-[(4-chlorophenoxy)acetyl]-10,11-
dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine of Example 10, step A and 2-(1,1'-
biphenyl) carbonyl chloride in the manner of Example 4, step C.
MS [(+)ESI, m/z]: 533.1 [M+H]+
EXAMPLE 15
1-{10-[(2'-Methyl-1,1'-biphenyi-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-
c][1,4]benzodiazepin-3-yl}-3-pyridin-3-ylpropan-1-one
The title compound (m.p. 135-136 °C) was prepared from (2'-methyl-1,1'-
biphenyl-4-yl)-(5H,11H-pyrrolo[2,1-c][1,4]benzodiazepin-10-yl)-methanone and 3-
pyridin-3-yl-propionyl chloride in the manner of Example 4, step C.
MS [(+)ESI, m/z]: 512.18 [M+H]+
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Anal. Calcd for C34H29N3O2 0.10 C5H10O2: C 79.39, H 5.77, N 8.07. Found: C
79.29, H 5.88, N 8.16.
All 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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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 the group consisting of hydrogen,
(C1-C6) alkyl, halogen, cyano, trifluoromethyl, hydroxyl, (C1-C6) alkoxy, -OCF3,
carboxy, (C,-C6 alkoxy)carbonyl, -CONH2, -CONH[(C1-C6) alkyi], -CON[(C1-C6) alkyl]2,
amino, (C1-C6) alkylamino, and -NHCO[(C1-C6) alkyl];
R3 is selected from the group consisting of hydrogen, (C1-C6) alkyl, (C1-C6)
alkoxy, hydroxy, amino, (C1-C6) alkylamino, -C(O)(C1-C6)alkyl, and halogen;
B is B1 or B2,
wherein B, is selected independently from the group consisting of

wherein R5, R6, R7, R8, Rg and R10 are independently, selected from the group
consisting of hydrogen, (C1-C6)alkyl, (C1-C6) alkoxy, hydroxy(C1-C6) alkyl, (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)cycloalkyloxycarbonyl, aryl(C1-
C6)alkyloxycarbonyl, carbamoyl,-O-CH2- CH=CH2, (C1-C6)alkyl substituted with 1-3
halogen atoms, trihalomethyl, trifluoromethyl, halogen, OCF3, thio(Ci-C6) alkyl, -C(O)
(C1-C6)alkyl, -C(O)aryl optionally substituted by (C1-C6)alkyl; hydroxy, -CH(OH) (C1-
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C6)alkyl,-CH(C1-C6) (alkoxy) (C1-C6)alkyl, nitro, -SO2(C1-C6)aIkyl, (C1-C6)
alkylsulfonyl, aminosulfonyl, (C1-C6) alkylaminosulfonyl, -SO2NHR11, -SO2N(R11)2, -
OC (O) N [(C1-C6)alkyl] 2,-CONH [(C1-C6) alkyl],-CON [(C1-C6) alkyl] 2l-(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)

R11 and R12are each independently hydrogen, (C1-C6) alkyl, or
C3-C8 cycloalkyl;
R13 and R14 are each independently hydrogen, (C1-C6) alkyl or
C3-C8 cycloalkyl;
or R13 and R14 can be taken together with the nitrogen to which
they are attached to form a 4-6 membered saturated ring optionally containing up to
two atoms selected from O, S or N;
p is 0 or 1;
A is A1 or A2, wherein

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wherein R15 and R16 are selected independently from the group consisting of
hydrogen, (C1-C6) alkyl, and halogen;
wherein
R17a, R17b, and R17c are each independently selected from the group
consisting of hydrogen, (C1-C6) alkyl, halogen, hydroxy, aryloxy, and hydroxy (C1-C6)
alkyl;
u is the integer 0,1, 2,3, or 4;
v is the integer 1, 2, 3, or 4;
r is 0 or 1;
R18 is hydrogen or (C1-C6) alkyl; and
R19 is a cycloalkylamine.
R20a and R20b are each independently selected from the group consisting of
hydrogen, (C1-C6) alkyl, halogen, oraryl; or R20aand R2ob can be taken together with
the aryl to which they are attached to form an aromatic bicycle having up to 10 total
ring atoms.
2. A compound according to claim 1, wherein A is A1.
3. A compound according to claim 2, wherein A1 is

4. A compound according to claim 2, wherein A1 is

5. A compound according to claim 2, wherein A1 is
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6. A compound according to any one of claims 2 to 5, wherein B is B1, and B1 is
7. A compound according to any one of claims 2 to 5, wherein B is B17 and B1 is

8. A compound according to claim 1, wherein A is A2 and B is B2.
9. A compound according to claim 8, wherein A2 is

10. A compound according to claim 8, wherein A2 is
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11. A compound represented by the formula II

or a pharmaceutically acceptable salt thereof,
wherein R1 - R3, A1 and B1 are as defined for claim 1.
12. A compound according to claim 11, wherein A1 is

13. A compound according to claim 12, wherein u is 2.
14. A compound according to claim 12 or 13, wherein r is 0.
15. A compound according to claim 12, wherein A1 is

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16. A compound according to any one of claims 12 to 15, wherein B1 is

(a)
17. A compound according to claim 16, wherein each of R5-R10 is hydrogen.
18. A compound according to claim 16, wherein one of R8-R10 is alkyl.
19. A compound according to claim 18, wherein said one of R8-R10 is methyl.
20. A compound according to claim 16, wherein B1 is

21. A compound according to claim 16, wherein one of R8-R10 is alkoxy.
22. A compound according to claim 21 wherein said one of R8-R10 is methoxy.
23. A compound according to claim 16 wherein B, is

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24. A compound according to claim 12 represented by the following formula:
25. A compound according to claim 12 represented by the following formula:

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26. A compound according to claim 12 represented by the following formula:

27. A compound according to claim 11, wherein A, is

28. A compound according to claim 27, wherein v is 1.
29. A compound according to claim 27, wherein r is 0.
30. A compound according to claim 27, wherein v is 1 and r is 0.
31. A compound according to claim 30, wherein the ring nitrogen is in the 3-
position.
32. A compound according to clam 27, represented by the following formula:
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33. A compound according to any one of claims 27 to 32, wherein B1 is

34. A compound according to claim 33, wherein each of R5-R10 is hydrogen.
35. A compound according to claim 33, wherein one of R8-R10 is alky!.
36. A compound according to claim 33, wherein said one of R8-R10 is methyl.
37. A compound according to claim 11, wherein A1 is

38. A compound represented by the formula III
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or a pharmaceutically acceptable salt thereof,
wherein R1 - R3, A2 and B2 are as defined for claim 1.
39. A compound according to claim 38, wherein A2 is

40. A compound according to claim 39, wherein u is 0.
41. A compound according to claim 39 or 40, wherein R20a is halogen.
42. A compound according to claim 41, wherein said R20a is chlorine.
43. A compound according to claim 39, represented by the following formula:
r
44. A compound according to claim 39, represented by the following formula:
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45. A compound according to claim 39, represented by the following formula:

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46. A compound according to claim 39, represented by the following formula:
47. A compound according to claim 40, wherein R20a and R20b taken together with
the aryl to which they are attached form a bicyclic structure.
48. A compound according to claim 47, wherein said bicyclic structure is
naphthalene.
49. A compound according to claim 40 represented by the formula:

50. A compound according to claim 39 or 40, wherein R20a is aryl.
51. A compound according to claim 50, wherein said R20a is phenyl.
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52. A compound according to claim 40, wherein A2 is

53. A compound according to claim 40, wherein A2 is

54. A compound according to claim 52 represented by the formula:

55. A compound according to claim 52 represented by the formula:
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56. A compound according to claim 53 represented by the formula:

57. A compound according to claim 53 represented by the formula:
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58. A compound according to claim 39 or 40, wherein R20a is alkyl.
59. A compound according to claim 58 wherein said R20a is C(CH3)3.
60. A compound according to claim 59 represented by the formula:

61. A compound according to claim 59 represented by the formula:
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62. A compound according to claim 38, wherein A2 is

63. A compound according to any one of claims 38 to 42, 47, 48, 50-53, 58, 59,
or 62, wherein B2 is

one of R15 or R16 is halogen.
64. A compound according to claim 63 wherein said R15 or R16 is chlorine.
65. A compound according to claim 63 or 64, wherein the other of said one of R15
or R16 is alkyl.
66. A compound according to claim 65, wherein said alkyl is methyl.
67. A compound according to claim 63, wherein R15 is 4-ch!oro and R16 is 2-
methyl.
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68. A method for preparing a compound of general formula II

or a pharmaceutically acceptable salt thereof,
wherein R1 - R3 and B1 are as defined for any one of claims 11 to 37;
A1 is selected from the group consisting of

R17a, R1b, and R17care each independently selected from the group consisting
of hydrogen, aikyl, halogen, hydroxy, aryloxy, and hydroxyalkyl;
u is 0,1, 2, 3, or 4;
v is 1,2, 3, or4;
r is 0 or 1;
R18 is hydrogen or alkyl; and
R19 is a cycloalkylamine;
said method comprising:
reacting a compound of formula (2)
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conditions sufficient to produce the desired compound of formula II.
69. The method of claim 68, wherein the compound of formula (2) is prepared by:
reacting a tricyclic diazepine of formula (1)

wherein R1, R2, and R3 are defined hereinbefore,
with an acyl halide
XCOY
where X is a halide, and Y is halo-(CH2)v-;
under conditions sufficient to produce compound (2).
70. The method of claim 68 or 69, wherein said reaction occurs in an aprotic
solvent.
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71. The method of claim 70, wherein said aprotic solvent is 1,4-dioxane.
72. the method of claim 71, wherein the reaction temperature is -10°C to the
reflux temperature of the solvent.
73. The method of claim 68 or 69, wherein the reaction is performed at a
temperature from about ambient to the melting point of the reactants.
74. The method of claim 69, wherein X is Cl.
75. The method of claim 69, wherein Y is chloroalkyl.
76. A method of preparing a compound of formula I

or a pharmaceutically acceptable salt thereof,
wherein R1 - R3, A and B are as defined for any one of claims 1 to 10;
said method comprising:
reacting a tricyclic diazepine of formula (1)

with an acyl halide of formula (4)
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where Y is halogen;
under conditions sufficient to produce the desired compound of formula I.
77. A method of preparing a compound according to formula III

or a pharmaceutically acceptable salt thereof,
wherein R1 - R3, A2 and B2 are as defined for any one of claims 38 to 67;
said method comprising:
reacting a tricyclic diazepine of formula (5)
with an acid halide of formula 6
A2COY
(6)
wherein Y is halogen;
under conditions to produce a compound according to formula III.
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78. The method of claim 76 or 77 wherein said reaction occurs in the presence of
an aprotic organic solvent.
79. The method of claim 78 wherein said aprotic organic solvent is N-methyl-2-
pyrrolidinone.
80. The method of claim 78 or 79, wherein the reaction temperature ranges from
ambient to the solvent's reflux temperature.
81. The method of claim 76 or 77, wherein the reaction temperature ranges from
ambient to the melting point of the reactants.
82. The method of any one of claims 76 to 80 wherein said reaction occurs in the
presence of an organic base.
83. The method of claim 82, wherein said organic base is 2,6-lutidine.
84. A method for making a compound of formula 27

or a pharmaceutically acceptable salt thereof,
wherein R1 - R3 are as defined for any one of claims 1 to 10, Pg is a protecting group,
and A is selected from

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said method comprising
reaction of the intermediate of formula (26)

under the conditions sufficient to provide the intermediate of formula (27)
85. The method of claim 84, further comprising deprotecting the compound of
formula (27) to yield the intermediate of formula (28)

then acylating the intermediate of formula (28) to give the compound of formula (I)

wherein B is as defined for any one of claims 1 to 10.
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86. The method of claim 84 or 85 wheren Pg is selected from the group
consisting of a fluorenylalkoxycarbonyl group, or an alkoxycarbonyl group. .
87. The method of claim 84 or 85 wherein Pg is fluorenylmethyloxycarbonyl.
88. The method of claim 84 or 85 wherein Pg is a tert-butyloxycarbonyl group
89. The method of any one of claims 84 to 88 wherein said compound of formula
(26) is prepared by reacting a tricyclic diazepine of formula (25)
wherein
R1, R2 and R3 are defined hereinbefore,
Pg is a protecting group;
with an acid c'nioride under conditions sufficient to provide the desired intermediate of
formula (26).
90. A method for making a compound of formula 27

or a pharmaceutically acceptable salt thereof,
wherein R1 - R3 are as defined for any one of claims 1 to 10, Pg is a protecting group,
and A is A2;
said method comprising
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treating a compound of formula (25)

with an acid chloride of formula (4)
ACOY
4
under the conditions sufficient to yield the amide of formula (27)

wherein A is A2 as defined hereinbefore.
91. The method of claim 90, further comprising:
deprotecting the compound of formula (27) to yield the intermediate of
formula (28)
then acylating the intermediate of formula (28) to give the product of formula (I)
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wherein B is as defined for any one of claims 1 to 10.

The invention provides compounds of formula (I) or a pharmaceutically acceptable salt thereof, wherein R, R1, R2,
R3, A, and B are as defined in the accompanying specification. Methods of making such compounds are also provided.